Rhodium Catalyzed Enantio- and Regioselective Hydrofunctionalization of Allene and Pd-PEPPSI Catalyzed Amination of Heteroaryl Derivatives
By Shaista Parveen
Dissertation
Submitted to the Department of Chemistry, Quaid-I-Azam University, Islamabad, in Partial Fulfillment of the Requirements for the Degree Of
Doctor of Philosophy
in
Organic Chemistry
Department of Chemistry Quaid-i-Azam University Islamabad-45320, Pakistan 2018
In the name of Allah, the most gracious, the most merciful
O My Lord! Expand for me my breast and make my work easy for me loosen the knot from my tongue so they may understand my speech.”
(Ta’Ha, 25-28)
Ibn Mus’ud (R.A) reported; Muhammad (Sallallahu ‘Alayhi Wasallam) said: “Envy is permitted only in two cases: A man upon whom Allah bestows wealth, and he disposes of it rightfully, and a man upon whom Allah has bestowed knowledge which he applies and teaches it.”
(Bukhari and Muslim)
To my Mother, Sisters and Brother To My husband & To my hardworking Supervisor
“Do not go where the path may lead, go instead where there is no path and leave a trail.” Ralph Waldo Emerson (1803-1882).
ACKNOWLEDGEMENTS Some feats cannot be accomplished alone
All praises be to ALLAH, the CREATOR of all the creatures of the universe, Who created us in the structure of human beings as the best creature. Many thanks to Him, Who blessed us with knowledge to differentiate between right and wrong. Many many thanks to Him as He blessed us with the Holy Prophet, MUHAMMAD (sallallahoalaihewaalehewasallam) for Whom the whole universe is created and Who enabled us to worship Allah. He (HAZRAT MUHAMMAD (sallallahoalaihewaalehewasallam) brought us out of darkness and enlightened to the way of Heaven. Completing this degree was never going to be easy, but the support that I have received from the people around me has made it an incredible experience that I will cherish for the rest of my life.
Foremost, I feel pleasure to express my deep sense of gratitude to my profoundly learned research supervisor Dr. Abbas Hassan Khan, Department of Chemistry, Quaid-i-Azam University, Islamabad, for his unparalleled way of supervision and encouraging attitude as well as for his outstanding motivation. His dedication, personal interest and provoking guidance enabled me to complete this tedious task.
It is my privilege to thank Prof. Dr. Shahid Hameed, Chairman, Department of Chemistry, Quaid-i-Azam University, Islamabad and Head of Organic Section Prof. Dr Aamer Saeed for providing necessary research facilities. I am thankful to all faculty members of Chemistry Department for their kindness, expertise and support.
I really appereciate the support and guidance of Prof. Dr. Bernhard Breit, University of Freiburg, Germany. His invaluable guidance and financial support made me to achieve the research task during my stay in his reseach group for one year. I am also very thankful to Breit research group for their motivational and supportive behavior.
I want to acknowledge DAAD (German Academic Exchange Service) Germany for granting me research grant for six month, being one of the contributer in completing this research degree.
I would extend my thanks to University of Science & Technology Bannu for granting me study leave as well as financial assistance and would appreciate the cooperative behavior of faculty members of Chemistry deprtment of this university.
Special thanks offered to Abbas research group at Department of Chemistry, Quaid- i-Azam University, Islamabad, i.e. Waqar Ahmed, Ismat Ullah khan, Rifhat Bibi, Amna Murtaza, Haseen Ahmad, Altaf Saeed, Muhammad Ilyas, Muhammad Yaseen, Tayyeba Gul, Ghulam Murtaza, Muhammad Salman, Amna Hussain, Fouzia Rehman, Ambreen, Khuram, Zarghoona, Komal, Safdar, Bisma, Asif and Maryam for their company and respect
I want to pay my deepest sense of gratidute to all my family members especially to my extremely loving and caring mother and sisters, for their faith in me and for always being there for me. My mother, symbol of sustainability for me throughout my life, made this task easy for me by her prayers and provisions. Immense support from my family made me strong enough to overcome all my difficulties. Truly, they are my real strength.
Shaista Parveen
Table of Content
List of Table …………………………………………………………………………ix
List of Figures …………………………………………………………………...…xiii
List of Schemes……………………………………………………………………..xiv
Abbreviations ……………………………………………………………...... xxv
Abstract…………………………………………………………………………...xxvii
General Introduction……………………...... 1 A. Theoretical Background…………………………………………………………..1 A.1. Molecular Chirality and Chiral Transformations………………………..………2 A.1.1. Transition Metal Asymmetric Catalysis…………………...……….…..4 A.1.2. Privileged Ligands and Catalysis………………………………….…...6 A.2. Transition Metal Catalysed Asymmetric Allylation Reactions…………………7 A.2.1. Stereoselective Allylic C-C Bond-Forming Reactions…………………7 A.2.1.1. Aldol Reaction as Representative Methodology for C-C Bond Formations………………………………………………….…7 A.2.1.2. Stereoselective Allylic Substitution for C-C Bond Formation 8 A.2.1.3. Hydrofunctionalization of Allenes and Alkynes with Carbon- Nucleophiles………………………………………….……..12 A.2.2. Stereoselective Allylic C-N Bond-Forming Reactions………………..19 A.2.2.1. State of the Art Syntheses of Allylic Amines……………....19 A.2.2.2. Allylic Amination via allylic C-H oxidation (C-H Activation) ………………….……………………………………………23 A.2.2.3. Allylic Substitution with Nitrogen-Nucleophiles…….…...... 25 A.2.2.4. Hydrofunctionalization of Allenes and Alkynes with Nitrogen-Nucleophiles……………………...... 29 A.2.2.5. The Breit type Hydroamination of Allenes and Alkyne…....38 A.2.3. Breit Type Hydrofunctionalization of Allene and Alkyne with Oxygen
i
and Sulfur Pro-nucleophile...………...... 41 A.2.3.1. Hydrofunctionalization with O-Nucleophiles………...... ….42 A.2.3.2. Hydrofunctionalization with S-Nucleophiles…………….…45 A.3. Pd-PEPPSI Catalyzed Carbon-Nitrogen Bond Forming Cross Coupling Reactions……………………………………………….……………………...47 A.3.1. Pd Catalyzed Carbon-Nitrogen Bond Formation: Buchwald-Hartwig Amination………………………………………………………………47 A.3.2. N-Heterocyclic Carbene: Gateway to Pd-PEPPSI Complexes ……….49 A.3.3. Design and Preparation of Pd–PEPPSI Complexes……….…………..53 A.3.4. Pd-PEPPSI Mediated Buchwald-Hartwig Amination………...... 56 A.3.5. Mechanism for Pd-PEPPSI catalyzed Buchwald-Hartwig Amination……………………………………………………..63 A.4. Introduction to Heterocycles…………………………………………………..66 A.4.1. Pyridazinone (1,2-Diazinones)……………………………………...…67 A.4.2. Azlactone…………………………………………………………....…69 A.4.3. Thiazole………………………………………………………………..73 B. Task…………………………………………………………………………..…..75 B.1. Regio- and Enantioselective Pyridazinones (1,2-Diazinones) Addition to Terminal Allenes and Evaluation of Follow Up Reactions Involving Final Product……………………………………………………………………....…75 B.2. Rhodium-Catalyzed Regioselective Addition of Azlactone to Internal Alkyne and its Utilization for Heterocyclic Synthesis…………………………...76 B.3. Pd-PEPPSI Mediated Cross Coupling Methodology for the Synthesis of Aryl/Alkyl-Heteroaryl Amine Derivatives of Substituted Thiazoles and Oxazoles……………………………………………………………...…..78 C. Results and Discussion……………………………………………………….….80 C.1. Regio- and Enantioselective Pyridazinones Addition to Terminal Allenes toward Regio- and Enantioselective N-allylic Pyridazinones…………..……..80 C.1.1. Regio- and Enantioselective Pyridazinones Addition to Terminal Allenes……………………………………………………………...….80 C.1.1.1. Regioselectivity……………………………………………..81
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C.1.1.2. Optimization of the Reaction Conditions………………...…82 C.1.1.3. Substrate Scope ………………………………………..…....96 C.1.1.3.1. Screening of Allene Substrates……..……….…...96 C.1.1.3.2. Scope Exploration for Pyridazinone Substrates...100 C.1.1.4. Determination of Absolute Stereochemistry……………….105 C.1.1.5. Mechanistic Investigations by Labeling Experiments…..…106 C.1.1.5.1. Isotopic distribution in Final Product by Mass Spectrometry ……………………………………………………………107 C.1.1.5.2. 1H-NMR Analysis Deuterated Product…….…………….107 C.1.1.6. Proposed Mechanism of Rh-Catalyzed Coupling of Pyridazinone Derivatives with Terminal Allenes………….108 C.1.1.7. Follow-Up Chemistry Involving Assorted transformations of N-Allyl Pyridazinone……………………………………109 C.1.1.8. Summary and Conclusions………………………..….……113 C.2. Rhodium-Catalyzed Regioselective Domino Azlactone-Alkyne Coupling/Aza- Cope Rearrangement: A Facile Access to 2-Allyl-3-oxazolin-5-ones and Trisubstituted Pyridines………………………………………………….…..115 C.2.1. Rhodium Catalyzed Regioselective Domino Azlactone-Alkyne Coupling/Aza-Cope Rearrangement………………………………....115 C.2.1.1. Identification of the Tandem Product: Evidence of Aza-Cope Rearrangement………………………………………….…116 C.2.1.2. Evaluation of Ligand for Regioselective Azlactone-Alkyne Coupling…………………………………………………...118 C.2.1.3. Optimization of the Reaction Conditions with DPEphos 101 Ligand………………………………………………….…..121 C.2.1.4. Substrate Scope of the Rhodium-Catalyzed Domino Azlactone- Alkyne Coupling/Aza-Cope Rearrangement………….…..125 C.2.1.4.1. Screening of Internal Alkyne Substrates…….....125 C.2.1.4.2. Scope exploration using substituted azlactone and substituted internal alkyne……………………...128 C.2.1.4.3. Rhodium-Catalyzed Domino Azlactone
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Formation/Azlactone-Alkyne Coupling/Aza-Cope Rearrangement……………………….…………130 C.2.1.5. Investigation upon Regioselectivity and Involvement of Aza -Cope Rearrangement in Azlactone Allylation…………….132 C.2.1.6. Mechanistic Investigations……………………………...…134 C.2.1.7. Synthetic Utility of the Investigated Methodology………..136 C.2.1.7.1. Scalability of the Coupling Reaction………...... 136 C.2.1.7.2. Synthesis of 2,3,6-Trisubstituted Pyridines..…..137 C.2.1.8. Summary and Conclusions………………………………...141 C.3. Pd-PEPPSI Mediated Cross Coupling Methodology for the Synthesis of Aryl/Alkyl-Heteroaryl Amine Derivatives of Substituted Thiazoles and Oxazoles 143 C.3.1. Pd-PEPPSI Catalyzed Synthesis of Thiazol/Oxazol Substituted Biaryl Amine Derivatives………………………………………………...…..143 C.3.1.1. Evaluation of Ligand System for Amination of 4-(4- Bromophenyl) -2-alkyl/aryl Thiazole……………………...145 C.3.1.1.1. Change of Amination Methodology: Utilization of Pd-PEPPSI Precatalysts………………………….147 C.3.1.1.2. Pd-PEPPSI Catalyzed Synthesis of Thiazol/Oxazol Substitutes Aniline: Cross Coupling of Hetero-aryl Derivatives with Aromatic Amine………………149 C.3.1.2. Substrate Scope for Pd-PEPPSI-IPentCl Catalyzed Synthesis of Biaryl or Alkyl-Aryl Amine Derivatives of Thiazole Heterocycle………………………………………………..154 C.3.1.3. Synthesis of Oxazole Anilines via Pd-PEPPSI-IPentCl Catalyzed Amination of Bromophenyl Oxazole Heterocycle ………………………………..…………………………….159 C.3.1.4. Summary and Conclusions………………………………...162 D. Summary……………………………………………….………………….…...163 D.1. Regio- and Enantioselective Pyridazinone Addition to Terminal Allenes Regio- and Enantioselective Pyridazinone Addition to Terminal Allenes……….….163 D.2. Rhodium-Catalyzed Regioselective Addition of Azlactone to Internal Alkyne
iv
and its Utilization for Heterocyclic Synthesis………………………………...164 D.3. Pd-PEPPSI Mediated Cross Coupling Methodology for the Synthesis of Aryl/Alkyl-Heteroaryl Amine Derivatives of Substituted Thiazoles and Oxazoles……………………………………………………………………...166 E. Experimental Part………………………………………………………….……168 E.1 General Remarks…………………………………………………………..…..168 E.1.1. Working Techniques……………………………………………..…..168 E.1.1.1. Chromatography……………………………….………….169 E.1.1.2. Nuclear Magnetic Resonance……………………….…….169 E.1.1.3. Mass Spectrometry………………………………………..170 E.1.1.4. Optical Rotation…………………………………………...170 E.1.1.5. Melting Points……………………………………………..171 E.1.1.6. Drying, Degassing and Purification of Solvents…………..171 E.1.1.7. Starting Materials and Reagents ………………………….172 E.2. Rhodium Catalyzed Pyridazinone Ad.dition to Terminal Allene (Section A).173 E.2.1. Substrate Syntheses (Allene Substrates)……………………………..173 E.2.1.1. Synthesis of Hexa-4,5-dien-1-ylbenzene 472……………..173 E.2.1.2. Synthesis of 2-(Hexa-4,5-dien-1-yl)isoindoline-1,3-dione .509 ..……………………………………………………...…....174 E.2.1.3. Synthesis of 1-(propa-1,2-dien-1-yl)cyclohexanol 501…...175 E.2.1.4. Synthesis of propa-1,2-dien-1-ylcyclohexane 497….….…177 E.2.1.5. Synthesis of hexa-4,5-dien-1-ol 513……………….……...178 E.2.1.6. Synthesis of tert-butyl(hexa-4,5-dien-1-yloxy)dimethylsilane 517………………………………………………… …….179 E.2.1.7. Synthesis of 5-(trityloxy)penta-1,2-diene 515…………….180 E.3. Catalysis…………………………………………………………………..…..181 E.3.1. General Procedures…………………………………………………..181 E.3.1.1. Procedure A: Synthesis of Chiral N-Allyl Pyridazinones (473, 494-520 and 523-537)……………………………………..181 E.3.1.2. General for Procedure Synthesis of Racemic N-Allyl
Pyridazinones using [{Rh(cod)Cl}2]/ rac-BINAP 281 Catalyst
v
System (GP-B)……………………………………...…….181 E.3.1.3. General Procedure for Synthesis of Racemic N-Allyl
Pyridazinones using [{Rh(cod)Cl}2]/ rac-3,5-iPr-4-NMe2- MeOBiphep Catalyst System (GP-C)…...………..….……182 E.3.1.4. Procedure employed for scaling up of reaction for the synthesis N-Allyl Pyridazinone……………………………………....183 E.3.2. Ligand Screening…………………………………….....……………183 E.3.3. Reaction Condition Screening……………………...………………..184 E.3.4. Synthesis of the Branched N-Allylic Pyridazinone Products from Allenes………………………………………………………………..187 E.3.4.1. Synthesis of the Branched N-Allylic Pyridazinone using 6-Chloropyridazin-2(1H)-one with Various Allenes……....188 E.3.4.2. Synthesis of the branched N-allylic pyridazinone using substituted pyridazin-2(1H)-one with 6-phenyl-1,2-hexadiene ……………………………………………………………...203 E.3.5. Mechanistic investigation by Labeling Experiment…………………211 E.3.5.1. Hydrogen- Deuterium Exchange reaction using D-substrate ………………………………………………………….…212 E.3.6. Transformations involving N-Allyl Pyridazinone………………...…212 E.3.7. Crystal Data and Absolute Configuration…………………………....216 E.4. Rhodium Catalyzed Coupling of Azlactone with Terminal Alkynes…………219 E.4.1. Substrate Synthesis (Synthesis of Internal Alkynes)………………...219 E.4.1.1. Procedure A: Preparation of Aromatic Internal Alkynes.....219 E.4.1.1.1. 1-Nitro-4-(prop-1-yn-1-yl)benzene 565………....220 E.4.1.1.2. 1-(Prop-1-yn-1-yl)-4-(trifluoromethyl)benzene 567 ………………………………..……………….220 E.4.1.1.3. 4-(Prop-1-yn-1-yl)-1,1'-biphenyl 573…….…..221 E.4.1.1.4. 1-Methyl-2-(prop-1-yn-1-yl)benzene 577...….221 E.4.2. Catalysis…………………………………………………………..….223 E.4.2.1. General Procedures………………………………………..223 E.4.2.1.1. General Procedure A for Rhodium-Catalyzed
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Tandem Azlactone-Alkyne Coupling/Aza-Cope Rearrangement (GP-E)……………………….223 E.4.2.1.2. General Procedure F for Rhodium-Catalyzed Tandem Azlactone Formation /Azlactone-Alkyne Coupling/Aza-Cope Rearrangement (GP-F)…...223 E.4.2.1.3. General Procedure G for Sequential Synthesis of 2, 3,6-Trisubstituted Pyridines from Azlactones and Internal Alkynes (GP-G)…………………..…..223 E.4.2.1.3. General Procedure H for Sequential Synthesis of 2, 3, 6-Trisubstituted Pyridines from N-Acyl Amino acid and Internal Alkynes (GP H)………...……224 E.4.3. Ligand Screening………………………………….…………………224 E.4.4. Reaction Condition Screening……………………….………………225 E.4.5. Rhodium-Catalyzed Tandem Azlactone-Alkyne Coupling/Aza-Cope Rearrangement…………………………………..……………………227 E.4.6. Rhodium-Catalyzed Tandem Azlactone Formation/Azlactone-Alkyne Coupling/Aza-Cope Rearrangement………………………..………..241 E.4.7. Rhodium Catalyzed Synthesis of 2, 3, 6-Trisubstituted Pyridines from Azlactones and Internal Alkynes……………………………………..245 E.5. Pd-PEPPSI Catalyzed Amination of Heteroaryl Derivatives…………..…….252 E.5.1. Substrate Syntheses…………………………………………………..252 E.5.1.1. Procedure for the Synthesis of Substituted Thiazole (GP-I) ………………………………………………………..…...252 E.5.1.1.1. 4-(4-Bromophenyl)-2-methylthiazole 622…....252 E.5.1.1.2. 4-(4-Bromophenyl)-2-phenylthiazole 660…....253 E.5.1.2. Procedure for the Synthesis of Substituted Oxazole …..(GP-J) ………………………………………………………….....253 E.5.1.2.1. 4-(4-Bromophenyl)-2-methyloxazole 664…....254 E.5.1.2.2. 4-(4-Bromophenyl)-2-phenyloxazole 665…....254 E.5.2. Catalysis……………………………………………………………...256 E.5.2.1. General Procedures for Catalysis………………………….256
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E.5.2.1.1. General Procedure for Synthesis of N-alkyl-aryl Thiazole amines (GP-K)…………………..…..256 E.5.2.1.2. General Procedure for Synthesis of N-aryl Oxazole Anilines (GP-L).……….……………………….268 E.5.2.1.3. General Procedure for Synthesis of Aryl/alkyl- Heteroaryl Anilines (GP-M).…………………..256 E.5.3. Ligand and Reaction Conditions Screening for Aliphatic Amines…..257 E.5.4. Ligand and Reaction Conditions Screening for Aromatic Amines.….258 E.5.5. Syntheses and Characterization of Biaryl and alkyl-arylThiazole/ Oxazole amines………………………………………………………259 F. List of Ligands Structure.…………………………………………………....276 G. List of Publications……………..…………………………………………....278 H. Similarity Index Report……………………………………………………...281 I References…………………………………………………………………….282
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List of Tables
Table C.1 Achiral ligands screening…………………………………...... ………83
Table C.2. Control experiments…………………………………………..………83
Table C.3. Screening of Chiral ligand under standard reaction conditions………84
Table C.4. Rhodium sources screening under standard conditions………………87
Table C.5. Solvent screening under standard reaction conditions………………89
Table C.6. Temperature screening under standard reaction conditions………….90
Table C.7. Concentration screening under standard reaction conditions………...91
Table C.8. Screening of substrates ratio under standard reaction conditions….…92
Table C.9. Screening of catalyst loading and ratio of the catalyst: ligand under standard reaction conditions…………………………………..………92
Table C.10. Additives Screening………………………………………………..…93
Table C.11. Scope exploration of the allene coupling partner under optimized reaction conditions………………...... 96
Table C.12. Scope of the pyridazinone coupling partner under optimized reaction conditions………………………...... 101
Table C.13. Distribution of deuterium in the final allylated product……..……...107
Table C.14. Ligand screening for hydrocarbonation reaction under standard conditions…………………………………………………….……...120
Table C.15. Acidic additives screening under standard reaction conditions….…122
Table C.16. Solvent and molar ratio screening under standard reaction conditions ………………………………………………………………….……123
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Table C.17. Scope exploration of the internal alkyne coupling partner under optimized reaction conditions………………………………………………….………125
Table C.18. Scope exploration using substituted azlactone and substituted internal alkyne under optimized reaction conditions……………………………….………128
Table C.19. Domino azlactone formation/azlactone-alkyne coupling/aza-Cope rearrangement……………………………………………………………....130
Table C. 20. Sequential protocol for the synthesis of 2,3,6-trisubstituted pyridines…….138
Table C. 21. Ligands screening for amination of 4-(4-bromophenyl)-2-methylthiazole…..146
Table C. 22. Screening of Pd-PEPPSI complexes for amination of 4-(4- bromophenyl)-2-methylthiazole……………………………….…….148
Table C.23. Base screening for amination of 4-(4-bromophenyl)-2-methylthiazole with aromatic amine using Pd-PEPPS-IPr complex………….……..150
Table C.24. Solvent screening for amination of 4-(4-bromophenyl)-2- methylthiazole with aromatic amine using Pd-PEPPS-IPr complex …………………………………………………………………..…..151
Table C.25. Screening of Pd-PEPPSI complexes for amination of 4-(4- bromophenyl)-2-methylthiazole with aromatic amine……….…...... 152
Table C.26. Scope exploration for 4-(4-boromophenyl)-2-methyl thiazole amination under optimized reaction conditions………………………………...155
Table C.27. Exploration of 4-(4-boromophenyl)-2-phenyl thiazole amination under optimized reaction conditions……………………………………….158
Table C.28. Scope exploration for 4-boromophenyl substituted oxazole amination under optimized reaction conditions………………………………………….……..160
Table E.1. Ligand Screening…………………………………………….……...184
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Table E.2. Condition screening for the enantioselective coupling of terminal allene with pyridazinone………………………………………………………….……….185
Table E.3. Crystallographic parameters for the crystal of “510”...... 218
Table E.4. Condition screening for the regioselective coupling of Internal alkyne with azlactone……………………………………………………….225
Table E.5. Condition screening for the regioselective coupling of Internal alkyne with azlactone……………………………………………………….226
Table E.6. Ligands and conditions screenings for aliphatic amines……………257
Table E.7. Ligands and conditions screenings for anilines……………………..258
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List of Figures
Figure A.1. Enantiomers of thalidomide………………………………………..…..2
Figure A.2. Various examples bioactive molecules demonstrating differences in biological activity of enantiomers………………………………...... 3
Figure A.3. Examples of privileged bidentate ligands commonly used in asymmetric catalysis…………….………………………..………..…..6
Figure A.4. Small selection of structurally diverse bioactive products, bearing chiral amines in their scaffolds……………………………………………...19
Figure A.5. Buchwald-Hartwig Amination Ligands………...... 48
Figure A.6. A comparison of the Shape and Steric Topographies of the NHC and Phosphine Ligands……………………….…………………………...49
Figure A.7. Herrmann’s Investigations on Synthesis of NHC-Pd Comp………….51
Figure A.8. Some Classes of NHC-Ligands Based on the Carbene Backbone……52
Figure A.9. Grubbs 1st and Second Generation Catalysts…………………………53
Figure A.10. Selected Monoligated Pd-NHC Complexes……………….………….54
Figure A.11. Second Generation Pd-PEPPSI Complexes with more sterically encumbered NHCs Backbone………………………………………...55
Figure A.12. Bioactive molecules with N-allyl pyridazinone core……………..…..67
Figure A.13. Tautomeric Equilibrium in Pyridazinone…………………………..…68
Figure A.14. Representation of structural features and tautomerism in Azlactone ……………………………………………………………………...…70
Figure A.15. Thiazole derivatives found in nature………………………………….73
Figure A.16. Commercially available Thiazole based drugs……………………….74
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Figure C.1. Tautomerism in pyridazinone (1,2-diazinone)…………………….....81
Figure C.2. 13C-NMR shift comparison for N/O selectivity………………………82
Figure C.3. Chiral ligands utilized in present synthetic methodology…………..……86
Figure C.4. ORTEP structure of compound 510 showing its absolute configuration ……………………………………………………………………….105
Figure C.5. 1H-NMR Spectrum of the Deuterated Product showing % D- Exchange………………………………………………………….....108
Figure C.6. Representation of the reactive behavior of azlactone………………116
Figure C.7. Representation of 1H NMR splitting pattern for allyl moiety……….117
Figure C.8. Representation of 1H NMR splitting pattern for rearranged product……………………………………………………………....117
Figure C.9. Achiral ligands, with their bite angles, used to investigate the bite angle effect…………………………………………………………………121
Figure C.10. Pd-PEPPSI catalysts system developed by M. G. Organ……………143
Figure C.11. Phosphine and NHC based ligands systems utilized in this protocol ……………………………………………………………………….147
.Figure D.1. The best ligands for the present regio- and enantioselective rhodium catalyzed pyridazinone addition to terminal allenes ………………..163
Figure E.1. Screw-cap flasks for the Rh-catalyzed coupling reactions (a: 10 ml, b: 1 ml)………………………………………………………………..….168
Figure E.1. Functionalized allenes used in this protocol………………..…….…181
Figure E.3. ORTEP structure of compound “510” showing its absolute configuration…………………………………………………….…..216
Figure E.4. X-ray crystallographic analysis of “510”……………………………217
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List of Schemes
Scheme A.1. Pioneering investigations on asymmetric hydrogenation by Ryoji Noyori…………………………...... ………………...... 5 Scheme A.2. Asymmetric hydrogenation of -ketoamine as an example of enantioselective hydrogenation, by Ryoji Noyori…….…...... 5
Scheme A.3. Generalized Aldol and nucleoühilic allylation reaction: Examples of classical stereoselective C-C bond-forming reactions…………………6
Scheme A.4. Iridium catalysis for asymmetric allylation, alternative to previously reported allylation reactions…………………...... 8
Scheme A.5. Historical allylic substitution via palladium catalysis by Tsuji and Trost……………………………………………………………………9
Scheme A.6. The catalytic cycle and mechanism for Tsuji-Trost allylation reaction………………………………………………………………..11
Scheme A.7. Iridium vs palladium catalysis with inherent branched and linear selectivities……………………………………………………………11
Scheme A.8. Helmchen’s investigations on regio- and enantioselective allylic substitutions………………………………………………………..…11
Scheme A.9. Extended substrate scope in asymmetric allylic substitution by Hartwig and co-workers…………………………………………………….….11
Scheme A.10. Stereoselective allylic substitutions by Carreira and co-workers using racemic branched allylic alcohols……………………………...……..12
Scheme A.11. Metal-catalyzed hydrofunctionalization of different allenes and alkynes to allylic moieties………………………………………………….….13
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Scheme A.12. Initial work on hydrofunctionalization of allenes with carbon- nucleophile by Yamamoto…………………………………...……….13
Scheme A.13. Yamamoto’s investigations on Intramolecular Pd-catalyzed hydrocarbonation of allenes………………………………...…...……14
Scheme A.14. Branched selectivity in palladium-catalyzed hydrofunctionalization of allene with C-nucleophiles…………………………………..…….….15
Scheme A.15. Pd-catalyzed branched-selective hydrocarbonation of allenes by Trost and co-workers……………………………………………...………...15
Scheme A.16. Intramolecular enantioselective hydrocarbonation of allenes with indoles by Widenhoefer et al..………………………………….…….16
Scheme A.17. Trost asymmetric synthesis of pyrrolinoindoline core of Gliocladin C by Intramolecular hydrocarbonation of allene…………………..…....16
Scheme A.18. Rh-catalyzed decarboxylative hydrocarbonation of allene by Breit et al. …………………………………...... 17
Scheme A.19. Intramolecular enantioselective palladium-catalyzed hydrocarbonation of alkynes by Yamamoto et al.……………………………………..…17
Scheme A.20. Enantioselective Ru-catalyzed C-C bond formation via allene- hydrometalation using Alkyne−Alcohol redox pair by Krische et al....18
Scheme A.21. Breit and Dong investigation on intermolecular rhodium-catalyzed decarboxylative hydrocarbonation of alkynes………………………..18
Scheme A.22. Convergent approach to γ,δ-unsaturated dienones by carbon- nucleophiles addition to alkyne reported by Breit et al.………….…..19
Scheme A.23. State of the art synthetic protocols for chiral allylic amines synthesis………………………………………………………...….…20
xv
Scheme A.24. Synthesis of chiral amine via Ru-catalyzed asymmetric transfer hydrogenation…………………………………………………….…...21
Scheme A.25. Ellman’s investigation on diastereoselective synthesis of chiral amine………………………………………………………….....……21
Scheme A.26. Chiral amines from N-tosyl and N-sulfonyl ketimines by Hayashi et al...... 22
Scheme A.27. Enantioselective hydrogenative coupling of alkynes to aromatic and aliphatic N-benzylsulfonyl aldimines………………………….……...22
Scheme A.28. Generalized concept of metal catalyzed C-H amination………….…..23
Scheme A.29. Pd-catalyzed oxidative C-H amination furnishing linear product predominantly…………………………………………………...... ….23
Scheme A.30. Pd-catalyzed oxidative amination of terminal alkenes………………..24
Scheme A.31. Pd-catalyzed intramolecular diastereoselective allylic C-H amination reported by White et al………………………………………..………24
Scheme A.32. The mechanism of allylic amination showing Pd(II) intermediate involved in allylic substitution………………………………..………25
Scheme A.33. Hayashi’s pioneering investigation on Pd-catalyzed allylic amination ‘’’’’’’’’’’’’…………………………………………………………….26
Scheme A.34. Dai’s investigations on enantio- and branchedselective allylic substitution……………………………….…………………………...26
Scheme A.35. Regio- and enantioselective allylic substitution reported by Dai et al. ………………………………………………………………………...27
Scheme A.36. Enantioselective allylic amination reaction by using chiral Rh- Tangphos complex by Samas et al. …………………………………..27
xvi
Scheme A.37. Ir-catalyzed asymmetric allylic aminations with N,N-diacylamines and o-nosylamide as ammonia equivalent…………….…………………..28
Scheme A.38. Ir-catalyzed asymmetric allylic amination reported by Hartwig et al. ………………………………...... 28
Scheme A.39. Ir-catalyzed asymmetric allylic amination via stereospecific substitution of allylic alcohol……………………………………..…..29
Scheme A.40. Hydroaminations of alkene, alkynes and allenes……………………..30
Scheme A.41. Possible hydroamination pathways, followed under transition metal catalyzed conditions………………………………………………..…31
Scheme A.42. Markovnikov selectivity observed in Pt-catalyzed hydroamidation of vinyl arenes………………………………………………………..….32
Scheme A.43. Vinyl substituted triazoles via gold catalyzed Markovnikov hydroamination of alkynes…………………………...…....………….33
Scheme A.44. Rh-catalyzed N-allylation of benzotrizole via anti-Morkovnikof hydroamination of allene……………………………………..………33
Scheme A.45. Ru-catalyzed regioselective synthesis of enamides……………,.……34
Scheme A.46. In situ isomerization of alkyn to allene in catalytic hydroamination…34
Scheme A.47. Organo-lanthanides catalyzed intramolecular hydroamination ofamino- allenes by Mark et al……………………………………………….....35
Scheme A.48. Gold catalyzed intramolecular hydroamination of amino-allenes by Toste et al.…………………………………………………….……....35
Scheme A.49. Pd-catalyzed haydromination of alkynes by Yamamoto et al……...…..36
Scheme A.50. Gold catalyzed intermolecular hydroamination of allenes…….……...37
xvii
Scheme A.51. Widenhoefer’s investigations on gold catalyzed intermolecular hydroamination………………………………………………..….…..37
Scheme A.52. Addition of nitrogen nucleophile to internal alkynes by Yamamoto et al. ………………………………..……………………………………….....37
Scheme A.53. Rh-catalyzed hydroamination of alkynes reported by Dong et al. ………………..……………………………………………….……………38
Scheme A.54. Enantioselective coupling of anilines with allenes reported by Breit et al. ………………………………………………………..………………….38
Scheme A.55. Enantioselective coupling of aryl hydrazines with allenes and their one- pot conversion to N-allylic indoles……………………………….…..39
Scheme A.56. Rh-catalyzed regiodivergent hydroamination of allene with imidazole derivatives……………………………………………………..….…..40
Scheme A.57. Rh-catalyzed insertion of tetrazoles and pyridine to terminal allenes ………………………………………………………………………...40
Scheme A.58. Transition metal catalyzed coupling of ammonia surrogates with allenes………………………………………………………………...40
Scheme A.59. Regioselective metal-catalyzed allylic substitution described by Helmchen et al. ……………………………………………………………..……41
Scheme A.60. Seminal publication of Breit et al. on the hydrooxycarbonylation of terminal alkynes…………………………………………………...….43
Scheme A.61. Convergent approach to chiral allylic esters reported by Breit et al. utilizing allene moiety……………...... 42
Scheme A.62. Convergent approach to chiral allylic esters reported by Breit et al. using alkyne precusors……………...... 43
Scheme A.63. Rhodium-catalyzed enantioselective macrolactonization by Breit and co-workers…………………………………………………………….43 xviii
Scheme A.64. Convergent approach to chiral allylic alcohols reported by Breit et al. . .………………………………………………………………………..44
Scheme A.65. Proposed catalytic cycle for the hydrooxycarbonylation of alkynes and allenes with carboxylic acids…………………………………..…..…45
Scheme A.66. Enantioselective hydrothiolation of terminal and internal allenes reported by Breit et al. …………………………………………….….45
Scheme A.67. Enantioselective hydrothiolation of terminal and internal allenes reported by Breit et al. ……………………………………………….46
Scheme A.68. Enantioselective hydrothiolation of terminal and internal allenes reported by Breit et al. …………………………………………….….46
Scheme A.69. Generalized Protocol for Buchwald-Hartwig Amination……...……..47
Scheme A.70. Buchwald-Hartwig Amination Utlilizing X-Phos ligand……….…….49
Scheme A.71. First stable Carbene isolated Arduengo et al. in 1991…………….….50
Scheme A. 72. One pot synthesis of Pd-PEPPSI Complex…………………………...54
Scheme A. 73. Pd-PEPPSI-IPr catalyzed amination utilizing secondary amines.……56
Scheme A. 74. Pd-PEPPSI-IPr catalyzed aminationat room temperature…………….57
Scheme A. 75. Nolan’s investigations on amination using modified Pd-PEPPSI-SIPr catalyst system………………………………………………….….....58
Scheme A. 76. Pd-PEPPSI-IPentCl catalyzed synthesis of triarylamines by Organ et al. ………………………………………………………………………...59
Scheme A. 77. Amination of deactivated chloroarenes utilizing Pd-PEPPSIIPentCl-o- Picoline by Organ and co-workers…………………………………...59
Scheme A. 78. Organ et al. investigations on selective monoarylation of primary amines utilizing Pd-PEPPSIIPentCl precatalyst…………………….…60
xix
Scheme A. 79. Lavigne’s investigations utilizing modified Pd–PEPPSI-IPr(NMe2)2 precatalyst…………………………………………………………….61
Scheme A. 80. N-Heteroarylation of optically pure amino esters utilizing Pd- PEPPSI-IPentCl-o-picoline precatalyst……………………………..…62
Scheme A. 81. Coupling of 2-aminopyridine derivatives to various aryl chlorides using Pd-PEPPSI-IPentCl precatalyst………………………..……………....63
Scheme A. 82. Mechanism for Pd-PEPPSI catalyzed amination………………...…...64
Scheme A. 83. Synthesis of Pyridazinone derivatives………………………..…..…..68
Scheme A. 84. Derivatization of substituted pyridazinones…………………..….….69
Scheme A. 85. Azlactone formation from N-, O-acylation of α-amino acid with subsequent cyclization……………………….……………………….70
Scheme A. 86. Synthesis of enantiomerically pure amino acid by dynamic kinetic resolution using DEMAP derivatives……………………………………….………….71
Scheme A. 87. Quaternary amino acid from catalytic asymmetric synthesis of azlactones …………………………………………………….....……71
Scheme A. 88. Oxazole synthesis utilizing azlactone via Friedel–Crafts/Robinson– Gabriel reaction…………………………………………………..…...72
Scheme A. 89. Synthesis of Pyrrole and Imidazole utilizing oxazolones…..……....72
Scheme B.1. Possible N- or O-selectivity for the rhodium catalyzed pyridazinone addition to terminal allenes…………………………...………………75
Scheme B.2. Follow up chemistry involving possible regioisomer: synthesis of N- functionalized pyridazinones……………………………………...….76
Scheme B.3. Possible regioselectivity and rearrangement in Rh-catalyzed azlactone alkyne coupling……………………………………………….………77
xx
Scheme B.4. Evaluation of an idea of in situ generation of azlactone……………...77
Scheme B.5. Heterocyclic synthesis-follow up chemistry invovling expected rearranged product……………………………………………………78
Scheme B.6. Pd-PEPPSI catalyzed synthesis of thiazole/oxazole substituted biaryl amine derivatives…………………………………….……………….78
Scheme C.1. Initial experiment for the rhodium-catalyzed diazinone addition to terminal allene……………………………………...…………………81
Scheme C.2. Rhodium catalyzed regioselective N-allylation of pyridazinone…..…82
Scheme C.3. Optimized conditions for the regio- and enantioselective rhodium catalyzed coupling of 6-chloropyridazinone 471 with 3- phenylpropylallene 472.………………………………………………95
Scheme C.4. Labelling experiment using Deuterated substrate under optimized reaction conditions……………………………………....…………..106
Scheme C.5. Proposed mechanism for the rhodium catalyzed N-allylation of pyridazionone………………………………...... 109
Scheme C.6. Assorted transformations of N-allyl pyridazinone………………..…109
Scheme C.7. Pd/C catalyzed Hydrogenation of N-Allyl Pyridazinone……………110
Scheme C.8. Hydroboration Oxidation of N-Allyl Pyridazinone…………………111
Scheme C.9. [{Rh(CO)2acac}]/ 6-DPPon Catalyzed Hydroformylation of N-Allyl Pyridazinone 473…………………………………………………….112
Scheme C.10. Oxidative cleavage of 6-chloro-1-(6-phenylhex-1-en-3-yl)pyridazin- 2(1H)-one 473 by ozonolysis……………………………………..…113
Scheme C.11. Rhodium catalyzed allylic alkylation via azlactone insertion to internal alkyne………………………………………………………….…….115
xxi
Scheme C.12. Initial experiment for the rhodium-catalyzed azlactone addition to internal alkyne……………………………………………….…...….116
Scheme C.13. Rhodium catalyzed tandem azlactone-alkyne coupling/aza-Cope rearrangement…………………………………………...... 118
Scheme C.14. Rhodium catalyzes hydroesterification and hydrocarbonation of alkynes………………………………………………………………119
Scheme C.15. Optimized conditions for the regioselective rhodium catalyzed coupling of azlactone 550 with 1- phenyl-1- propyne 551………………....…124
Scheme C.16. Rhodium-catalyzed coupling of 2,4-diphenyl-3-oxazolinone with 2- octyne……………………………………………………………..…133
Scheme C.17. Proposed catalytic cycle for the Rh-catalyzed hydrocarbonation of internal alkynes C with azlactone G, followed by aza-Cope rearrangement…………………………………………..……………135
Scheme C.18. Coupling of 1-phenyl-1-propyne 551 with 2,4-diphenyl-3-oxazolinon 550 on a 4.2 mmol scale……………………………………………..136
Scheme C.19. Microwave assisted synthesis of tri-substituted pyridine…………...137
Scheme C.20 Microwave assisted carbon dioxide extrusion and rearrangement to pyridine including a mechanistic rationale………………….…..…..138
Scheme C.21 Sequential protocol for the synthesis of 2,3,6-trisubstituted pyridines starting form N-acyl amino Acids………………………….…..……140
Scheme C.22 Pd-PEPPSI catalyzed synthesis of thiazole/oxazole substituted biaryl amine derivatives……………………………………………………144
Scheme C.23 Initial experiment for the Pd-catalyzed cross coupling of 4-(4- bromophenyl)-2-methylthiazole 622 with Aliphatic Amine………...145
xxii
Scheme C.24 Initial experiment for the Pd-PEPPSI catalyzed cross coupling of 4-(4- bromophenyl)-2-methylthiazole with aromatic amine………………149
Scheme C.25 Optimized conditions for the Pd-PEPPSI catalyzed amination of Br- phenyl-thiazole 622 with 4-methyl aniline 629………………..……154
Scheme D.1. Newly developed strategy for regio- and enantioselective rhodium catalyzed pyridazinones addition to terminal allenes...... 163
Scheme D.2. Assorted transformations of N-allyl pyridazinone…………...….…..164
Scheme D.3. Regioselective rhodium catalyzed coupling of azlactone 426 with 1- phenyl-1- propyne 463………………………………………...... 165
Scheme D.4. Microwave assisted synthesis of tri-substituted pyridine………...…166
Scheme D.5. Pd-PEPPSI mediated Cross coupling ravtion for thiazole and oxazole amines synthesis……………………………………………………..167
Scheme E.1. Phenyl propylallene synthesis……………………………………….173
Scheme E.2. 2-(Hexa-4,5-dien-1-yl)isoindoline-1,3-dione 509 synthesis ………..174
Scheme E.3. 1-Ethynylcyclohexanol 501a synthesis………………………..….....175
Scheme E.4. 1-(Propa-1,2-dien-1-yl)cyclohexanol 501 synthesis…………….…..176
Scheme E.5. Propa-1,2-dien-1-ylcyclohexane 497 synthesis…………….……….177
Scheme E.6. Hexa-4,5-dien-1-ol 513 synthesis………………..……………….…178
Scheme E.7. tert-Butyl(hexa-4,5-dien-1-yloxy)dimethylsilane 517 synthesis……179
Scheme E.8. Synthesis of 5-(trityloxy)penta-1,2-diene 515 …………………...... 180
Scheme E.9. General represerntation of N-allylation of pyridazinone………...... 187
Scheme E.10. Labeling experiment using D-substrate………………………….….211
Scheme E.11. General procedure for internal alkyne synthesis………………….....219
xxiii
Scheme E.12. Synthesis of substituted thiazole………………………………….....252
Scheme E.13. Synthesis of substituted Oxazole…………………………….……...253
xxiv
Abbreviations
Abbreviations
rac Racemic D Deuterated °C Degree(s) Celcius dba Dibenzylideneacetone 9‐BBN 9‐Borabicyclo[3.3.1]nonan DFT Density functional theory dm dimethoxy EA Ethyl acetate Acac Acetylacetonate 1,2‐DCE 1,2‐Dichlorethane Ad Adamantyl‐ DCM Dichlormethane DTBM Bis(3,5‐di‐tert‐Butyl‐4‐ DDQ 2,3‐dichloro‐5,6‐dicyano‐p‐ methoxyphenyl) benzoquinone APCI Atmospheric pressure ∆G change in Gibbs free chemical ionization (MS) energy aq. Aqueous dr Diastereomeric ratio
Ar Aryl moiety dist. Distilled Boc tert‐Butyloxycarbonyl‐ DM 3,3’‐dimethylphenyl Bz Benzoyl Bn Benzyl‐ IiPr 1,3‐diisopropylimidazol‐2‐ DMAP 4‐(dimethylamino)pyridine ylidene m.p. Melting point DMF N,N‘‐Dimethylformamide b.p. boiling point DMSO Dimethylsulfoxide
CH Cyclohexane α Specific rotation Cod Cyclooctadiene Nu Nucleophile Cp Cyclopentadiene ee enantiomeric excess ESI Electrospray Ionisation er enantiomeric ratio Et Ethyl‐ V Volume Cp* 1,2,3,4,5‐ HPLC High‐Performance Liquid Pentamethylcyclopentadien Chromatography equiv. Equivalent PE Petroleum ether (40‐60) K Kelvin(s)
xxv Abbreviations
H Hour(s) PMB para‐Methoxybenzyl Quant. Quantitative p‐TSA para‐Toluene sulfonic acid Rf Retention factor i‐Pr iso‐propyl HRMS High Resolution Mass SIPr 1,3‐bis(2,6‐ Spectrometry diisopropylphenyl) tBu tert‐Butyl TBS tert‐Butyldimethylsilyl TFA Trifluoroacetic acid TLC Thin‐Layer m.p. Melting point TMS TrimethylsilaneCh t h n‐ Normal tR retention time CSA Camphor sulfonic acid Tol Tolyl NHC N‐heterocyclic carbene Ts Tosyl
xxvi Abstract
Abstract
Transition metal catalyzed reactions have had a large impact on the human progress for the last century. Development of new environmentally benign approaches for the synthesis of biologically important molecules in atom and step economical way is highly desirable. Investigating new and more effective transition metal catalyzed strategies for C-C and C-X bond formation is one of the most important aspects of this research area. The prospect for such developments is probed in the context of this doctoral thesis. We investigated rhodium catalyzed Carbon-Carbon and Carbon- Nitrogen bond forming protocols involving hydrocarbonation and hydroamination of alkyne and allene as well as Pd-PEPPSI mediated cross coupling methodology for the synthesis of heteroaryl amine derivatives.
Rhodium catalyzed regio- and enantioselective allylation strategies were inspected utilizing heterocyclic backbones i.e pyridazinones and azlactones for the hydroamination of terminal allenes and hydrocarbonation of internal alkynes respectively. Regio- and enantioselective allylation of pyridazinone by hydroamination of terminal allene utilizing [{Rh(cod)Cl}2] and (S)-2,2’-Bis[bis(3,5- diisopropyl-4-dimethylaminophenyl)phosphino]-6,6’-dimethoxy-1,1’-biphenyl catalyst system led to the synthesis of N-allylated diazinone moieties in excellent yield and enantioselectivities. Broad functional group compatibility was observed using a diverse range of functionalized allenes and substituted pyridazinones. Assorted synthetic transformations of the N-allyl pyridazinones led to the preparation of a small library of N-functionalized pyridazinones as valuable intermediates providing proficient access to important pharmaceutical building blocks. Regioselective hydrofunctionalization of easily accessible internal alkynes were utilized for the rhodium catalyzed allylation of azlactone derivatives to synthesize biologically and synthetically important 2-allyl-3-oxazolin-5-ones moieties in highly regioselective manner. Reaction conditions optimizations and ligand screenings for the current reaction led us to explore [{Rh(cod)Cl}2] and DPEphos catalyst system leading to 2- allyl-3-oxazolin-5-one in highly regioselective manner. This newly developed protocol
xxvii Abstract
provides an example of cascade reaction involving aza-Cope rearrangement which extended further to a triple domino reaction sequence by combining it with in situ generation of azlactone formation from the corresponding N-acylamino acid precursors. Exploring the synthetic utility and scope of the investigated hydrocarbonation methodology led to the de novo synthesis of structurally appealing trisubstituted pyridine with the variety of aryl substituents in controllable fashion. Thus making a perfect cascade type sequence involving azlactone formation/ azlactone-allylation, aza-Cope rearrangement and microwave assisted thermolysis to obtained trisubstituted pyridines. The investigated reaction presents a concise and flexible approach for the regioselective synthesis of allylated azlactone moieties as well as trisubstituted pyridines.
Pd-PEPPSI catalyzed cross coupling strategy was investigated for the Buchwald- Hartwig amination of azole-based heterocycles moieties. Pd-PEPPSI precatalysts were utilized to cross couple azole derivatives with the diverse range of functionalized anilines and aliphatic amines to synthesized respective heteroaryl/aryl-alkyl amines. A range of structurally intriguing drug-like aromatic amines was synthesized utilizing both electron-deficient and electron-rich anilines, cross coupled with thiazole and oxazole based heteroaryl bromide moieties in excellent yields. Utilization of Pd- PEPPSI mediated amination protocol permitted an efficient, simple and elegant approach to synthesize a diverse range of thiazole and oxazole amines which could present highly active biological entities as well as may serve as precursors for drug synthesis.
xxviii Introduction | 1
General Introduction
Nature and its hidden truths always present challenging actualities to humanity. Chemistry distinguishes itself from other disciplines in approaching these challenges by its ability to design structure for function, unconstrained by what is available to it. An enabling key to this freedom is the effectiveness of the synthetic strategies to solve problems of selectivity which is an utmost feature of biological system. Complex molecular syntheses require proficient methodologies with atom and step economy as well as ease of purification, for which transition metal catalysis constitutes a core competency.
Transition metal catalysis constitutes a discipline of organometallic chemistry which involves the use of transition metal as catalyst participating in the chemical transformations. The transition metal catalyst system usually consists of organic monodentate or bidentate ligands, in which the transition metal atom such as Pd, Cu, Au, Rh, Sn, Ru, and Ir etc, linked to ligand’s heteroatom(s) mainly phosphorous, nitrogen, oxygen by coordinate covalent bond. The catalyst system has the ability to lower activation energy barrier between the original and transition state of the reacting molecules as well as to turnover and restart new catalytic cycle until complete consumption of limiting reagent. Transition metal catalysis provides state of the art methodologies for the construction of carbon-carbon and carbon-heteroatom bonds in most feasible ways that avoid tedious synthetic procedures. Advent of transition metal catalysis leads to the substantial development of academia and industry, which are consistently working on designing inexpensive ligands and catalyst that leads to rapid fine-tuning for specific chemical transformations especially in the contexts of total synthesis, process development, and medicinal chemistry.
Theoretical Background | 2
A. Theoretical Background
A.1. Molecular Chirality and Chiral Transformations
Biological systems provide an example of inherently disymmetric matter as life denpend on molecular chirality. Chiral receptors and enzymes as interacting tools inside the body of living organisms make the interaction to outside world more precise and accurate. Chiral environment of the biological systems recognize the drug molecule with absolute configuration, leading to the marked differences in the pharmacological activities of enantiomers. The captivating example of this phenomenon, arise in 1960s with unfortunate historical incident of Thalidomide (Figure A.1),1a,b bringing the recognition of molecular chirality into light. This intrinsic universal feature of matter becomes a great key of investigation in field of science and technology.
Figure A.1. Enantiomers of thalidomide
In early 1990s, the stereochemical constitutions of about 90 % of synthetic chiral drugs were racemic which was the clear sign of the difficulty in the synthesis of enantiopure compounds.1c In 1992, the Food & Drug Administration (FDA) in US introduced guide-lines to increase the awareness regarding commercialization of enantiomerically pure clinical drugs.1d These marketing regulations lead to the significant increase in the requirements of single-enantiomer drug which leads the scientific community to design synthetic pathways with high level of enantiocontrol. Other examples of differences in the pharmacological behavior of enantiomers, demonstrating structure activity relation, are depicted in Figure A.2.2
Theoretical Background | 3
Figure A.2. Various examples bioactive molecules demonstrating differences in
biological activity of enantiomers
Discovering efficient protocols to achieve chiral drug as single active isomer, has prove to be a considerable challenge for modern synthetic community. Thus gaining access to enantiomerically pure compounds is a very important endeavor in the development of pharmaceuticals, agrochemicals and flavoring agents etc.
Previously, enantiomerically pure compounds were obtained by the classical resolution of a racemates or chiral pool synthesis. Readily accessible naturally occurring chiral compounds such as amino acids, tartaric and lactic acids, carbohydrates, terpenes, or alkaloids were utilized. Asymmetric synthesis involving stereoselective conversion of a prochiral compound to a chiral product is one of the most attractive approach that provides a flexible synthetic access to wide array of enantiopure organic moieties.3a-c The major requirements for practical asymmetric synthesis include high level of stereoselection, high rate of reaction, productivity, atom economy, cost efficacy, operational ease, environmental friendliness, and low energy consumption. Traditional strategies reported for asymmetric synthesis involved the uses of stoichiometric amounts of chiral directing groups i.e. chiral auxiliaries. The chiral auxiliary mediated synthesis although is convenient for small to medium scale reactions, but on larger scales their use is only practical if these expensive moieties are
Theoretical Background | 4
readily recyclable, otherwise it does not meet to the criteria of an ideal enantioselective synthesis.
A.1.1. Transition Metal Asymmetric Catalysis
Scientists have always been fascinated by the challenge to achieve absolute stereocontrol in the reaction starting from achiral compounds. Asymmetric catalysis is an integrated chemical approach to the synthesis of chiral moieties under mild conditions with maximum enatioselection. Major breakthroughs in chemical catalysis4 in last few decades are the fruits of efforts to control molecular chirality.5 These investigations lead to the synthesis of vast array of enantiopure drugs as well as other bioactive compounds including agrochemicals, pheromones, flavors, and fragrances etc.6a-b
The use of chiral organometallic complex as molecular catalyst is one of the most powerful strategy for asymmetric synthesis to obtained chiral molecules in high stereoselective and productive manner. The chiral ligand along with achiral metal center that possess suitable three-dimensional structure leads to catalytic reaction with perfect enantioselectivity and desired stereoselection.
In asymmetric catalysis, the prochiral substrate interacts with chiral ligands, having precise and fixed configuration around the transition metal catalyst, making organometallic complex. This complex further reacts with corresponding reacting species through a diastereomeric transition state leading to two reaction pathways. The extent of chirality transfer from chiral catalyst to prochiral substrates arise from the competition between these two mechanistic pathways. The extent of enantioselectivity is determined by the free energy difference between the two diastereomeric transition states. Usually only 2 kcal/mol energy differences is enough to obtain more than 90% of a single enantiomer. 7
Theoretical Background | 5
Scheme A.1. Pioneering investigations on asymmetric hydrogenation by Ryoji Noyori
The history of asymmetric catalysis began with pioneering investigations of William S. Knowle (1960s) and Ryoji Noyori (1980s), sharing 2001 Nobel Prize, on asymmetric hydrogenation using chiral complexes. W. S. Knowle used Rh/DiPMAP complex for the synthesis of L-DOPA 30 (Scheme A.6)8 while R. Noyori used Ru/BINAP (Scheme A.2)9a,b complex for the asymmetric hydrogenation as well as reduction of ketone which are among the major breakthroughs in the field of asymmetric catalysis.
Scheme A.2. Asymmetric hydrogenation of -ketoamine as an example of enantioselective hydrogenation, by Ryoji Noyori
Theoretical Background | 6
A.1.2. Privileged Ligands and Catalysis
Over the past decades, asymmetric catalysis has evolved into a very dynamic and rapidly growing area of research attracting an increasing number of chemists from various disciplines.10 With the availability of powerful synthetic catalysts, the level of enantioselectivity observed is very high which was previously considered beyond reach of non-enzymatic processes.11-13
The principles underlying asymmetric catalysis with small molecules and enzymes are fundamentally the same. This concept was founded by William S. Knowle with an idea that these man-made species would have a highly specific match towards the reacting substrates as like enzymes. Therefore they can have large range of applications in the respective field.14a,b The best synthetic catalysts are supposed to demonstrate high levels of enantioselectivity for the reactions of wide range of substrates. The criteria is met surprizingly by “privileged ligands” (Figure A.3) which work exactly in the same way as bioactive molecules do against the number of biological targets.15.
Figure A.3. Examples of privileged bidentate ligands comonly used in asymetric catalysis
The story behind the discovery of these structures is different in each case. For instance, BINAP 20 and BINOL are completely synthetic molecules developed to
Theoretical Background | 7
exploit the axial dissymmetry induced by the restricted rotation about the biaryl bond.15b,c The design of TADDOL 27 was driven by practical considerations because it is derived from tartaric acid the least expensive chiral starting material with two-fold symmetry available from natural sources.15d,e Bis(oxazoline) ligands 26 were inspired by the framework of vitamin B12.15f The general applicability of these structures makes them useful not only for the practical synthesis of enantiomerically pure compounds but also for the discovery of novel enantioselective processes. In practice the development of a new asymmetric reaction often begins with a lead result discovered through a systematic screen of known privileged catalyst structures, followed by optimization of the ligand structure and reaction conditions. This approach accounts for a significant proportion of new asymmetric methodologies reported every year.16
A.2. Transition Metal Catalysed Asymmetric Allylation Reactions
The major goal of synthetic organic chemistry is the evolution of new C-C and C-X bond formation. The development of low-cost and atom economical strategies for the conversion of readily available starting materials is one of the great deal in the field of industrial chemistry especially regarding to the development of a “green” chemistry.17 The following sections include a brief overview about the recent investigations towards the evolution of C-C and C-X bond forming strategies, especially with regards to C-C and C-N bonds constructed in an allylic enviroment.
A.2.1. Stereoselective Allylic C-C Bond-Forming Reactions
A.2.1.1. Aldol Reaction as Representative Methodology for C-C Bond Formations
Stereoselective C-C bond forming reactions present emerging methodologies in the last decades. The established reaction types are asymmetric aldol19 and nucleophilic allylation20 reactions leading to chiral alcohols and amines. Stereoselectivity is induced either by carrying out the chiral auxiliary mediated reaction or by the using chiral catalysts (Scheme A.3).18,20 In the upcoming years, allyl metal reagents such as various allylboron,20d-f allyltitanium,20g allyltin,20h-j or allylsilicon20k,l species were
Theoretical Background | 8
successfully employed for the allylation of imines or aldehyde to afford allylic amine 30 or alcohol 31 respectively.
Scheme A.3. Generalized Aldol and nucleoühilic allylation reaction: Examples of classical stereoselective C-C bond-forming reactions
Problems associated with synthesis and use of allyl metal reagents were circumvented by Krische and co-workers (2007).21,22 They utilized commercially available allylacetate 33 for the allylation of aldehyde in alcohol oxidation level reaction, leading to homoallylic alcohols 35 in good yields and with excellent enantioselectivities (Scheme A.4) 22a
Scheme A.4. Iridium catalysis for asymmetric allylation, alternative to previously reported allylation reactions.
A.2.1.2. Stereoselective Allylic Substitution for C-C Bond-Formation
The most important historical allylic substitution is the Tsuji-Trost allylic substitution reaction, discovered in 1965 by Jiro Tsuji23a and later further established by Barry M. Trost in 1973 (Scheme A.5).23b,24a,b
Theoretical Background | 9
Scheme A.5. Historical allylic substitution via palladium catalysis by Tsuji and Trost
This reaction leads to allylic product involving palladium-catalyzed allylic substitution strategy. The chemo-, regio- and enantioselectivities of the final product are strongly dependent upon the choice of palladium sources and stereochemical environment of ligand.24
The catalytic cycle involves the following general steps: 1) The precoordination of the palladium catalyst to the double bond of the olefin results in the oxidative addition to form the π-allyl species in the next step (Step 2).
Scheme A.6. The catalytic cycle and mechanism for Tsuji-Trost allylation reaction
The last two steps in the catalytic cycle involve the nucleophilic attack (Step 3) leading to substitution product and the elimination process (Step 4) to regenerate the catalyst (Scheme A.6). The chemo-, regio- and enantioselectivities strongly influenced by the nature of substrate, nucleophile, metal and ligands used.25
Theoretical Background | 10
It is evident from the formation of π-allyl species that two regioisomers are possible in this allylation process. Depending upon the choice of metal and reaction conditions, the reaction can lead to single regioisomer selectively.
Scheme A.7. Iridium vs palladium catalysis with inherent branched and linear selectivities
The branched selective strategies like iridium catalysis attract many researchers for further elaboration and investigations (Scheme A.7).26 Helmchen,27 Hartwig,28 Carreira29 and various others30 present a bulk of experimental efforts in elaborating Tsuji-Trost reaction using different carbon nucleophile, utilizing iridium based organometallic reagents along with chiral phosphoramidite ligands.
The branched allylic product formed as a result of this reaction, open up a pathway toward derivatizations and follow-up chemistry. This fact leads to the synthesis of chiral building blocks which are powerful synthetic tools for drug syntheses and medicinal chemistry.
Seminal report in this research area was presented by Helmchen et.al27 by investigating iridium-catalyzed asymmetric allylic substitution of allyl carbonate with different malonic acid derivatives, utilizing chiral phosphino-oxazoline ligands (PHOX-ligands).27d They presented their initial investigations using chiral starting material27i,j extending to achiral allylic moieties by optimizing ligand structure, going from Ox-ligand family to phosphorous amidate ligand 50 family (Scheme A.8).27b,c
Theoretical Background | 11
Scheme A.8. Helmchen’s investigations on regio- and enantioselective allylic substitutions
Hartwig28 in 2005, utilized Helmchen results to extend the reaction scope to various substrate classes, using unstable silylenolates 52 derivatives of carbonyl compounds. The reaction proceed with high yields, excellent enantioselectivities and outstanding regioselectivities (Scheme A.9).28a
Scheme A.9. Extended substrate scope in asymmetric allylic substitution by Hartwig et al.
Carreira29 and co-workers further extended the scope to alkylation of allylic alcohols. They utilized diverse range of carbon nucleophile, derived from synthetically important precursors like vinyl, aldehyde, esters, nitriles, chlorides and acetates (Scheme A.10a).29a,c-e,h The concept of dual catalysis has successfully implemented during the stereodivergent allylation of linear aldehyde 59 by iridium-amine catalysis (Scheme A.10b).29b,f,g
Theoretical Background | 12
Scheme A.10. Stereoselective allylic substitutions by Carreira using racemic branched allylic alcohols
A.2.1.3. Hydrofunctionalization of Allenes and Alkynes with Carbon- Nucleophiles
From the above investigations of various research groups the involvement of π-allyl intermediates in allylic substitution become obvious. Iridium-catalysis provides an elegant strategy to carbon-carbon bond via allylic substitution in highly regio- and enantioselective manner.29 One of the drawbacks associated with these methodologies is the lack of atom economy. Since the formation of π-allyl complex from starting material like allylic carbonate, free and protected alcohols, halides and acetates leads to the generation of stoichiometric amounts byproduct.
Theoretical Background | 13
To cope with this issue many research groups put their efforts to extend the scope of this strategy to allenes 63 and alkyne 64. These classes of compound provide redox- neutral moieties which lead to metal-allyl complex 65/66 by simple hydrometalation. The rest of catalytic cycle and product generation proceeds in the similar fashion to afford the desired allylic product (Scheme A.11).31,37,38
Scheme A.11. Metal-catalyzed hydrofunctionalization of different allenes and alkynes to allylic moieties
Important contributions in this area of research are from the research groups of Yamamoto,31 Trost,32 Toste,33 Widenhoefer,34 and Krische.35 They presented very impressive, elaborated and remarkable protocols via palladium-, gold-, or iridium- catalyzed addition processes of carbon-based pronucleophiles to allenes and alkyne to form valuable allylic building blocks.
The first investigation report on transition metal catalyzed addition reactions to allenes was presented by Yamamoto and co-workers in 1994 (Scheme A.12).
Scheme A.12. Hydrofunctionalization of allenes with carbon-nucleophile by Yamamoto et al.
Theoretical Background | 14
They coupled malonic acid derivatives as active methylene species using
Pd(dba)2/DPPB 72 to obtained linear product exclusively with very good yield and high E:Z selectivity (99:1) (Scheme A.12).31a
An intramolecular variant of Yamamoto’s reaction was developed to address the syntheses of carbocycles 31b and heterocycles31c such as furanes or pyranes. Starting from ω-substituted allenylic methylene active compounds 73 or 74, the palladium- catalyzed cyclization reaction led to the corresponding products in good yields and with good diastereoselectivities (Scheme A.13).
Scheme A.13. Yamamoto’s investigations on Intramolecular Pd-catalyzed hydrocarbonation of allenes
Following the Yamamoto’s initial report on allene hydrocarbonation, Trost and co- worker elaborated the reaction by investigating its regio- and enantioselective version in an atom economical fashion. Branched selectivity was found in the final allylic product using palladium catalyzed hydrocarbonation of oxo-substituted allene 77. Asymmetric hydrocarbonation of allenes with active methylene species was successfully investigated afterward by applying Trost-ligand 80 (Scheme A.14).32b This reaction opens up a pathway to synthesize unique and valuable chiral building blocks in just a single step.
Theoretical Background | 15
Scheme A.14. Branched selectivity in palladium-catalyzed hydrofunctionalization of allene with C-nucleophiles
Other important carbon nucleophiles such as azlactones 81 were proved to be very good coupling counterparts in the addition reaction, leading to the product with high yield, enantio-, and diastereoselectivities. The allylated azlactone moieties 82 gave access to a number of un-natural amino acids, upon simple hydrolysis (Scheme A.15).32b,e
Scheme A.15. Pd-catalyzed branched-selective hydrocarbonation of allenes by Trost et al.
Widenhoefer and co-workers expanded this methodology by emphasizing on the allylation of carbon nucleophile utilizing terminal and internal allenes. They elaborated the scope of reaction by utilizing gold catalysis for intramolecular allylation of indole derivatives 83 to obtained the desired carbocycle 84 in very good yield along with high enantioselectivity (Scheme A.16).34a,b
Theoretical Background | 16
Scheme A.16. Intramolecular enantioselective hydrocarbonation of allenes with indoles by Widenhoefer et al.
Trost developed an intermolecular version of the reaction utilizing bezyloxy-allene 77 and indole derivative 86 in the asymmetric synthesis of pyrrolinoindoline 87 core of gliocladin C 88 (Scheme A.17).34c
Scheme A.17. Trost asymmetric synthesis of pyrrolinoindoline core of Gliocladin C by Intramolecular hydrocarbonation of allene
In 2014, Breit and coworkers increased the nucleophile scope in this type of hydrocarbonation reaction. They successfully allylated β-ketoacids 90 via rhodium catalyzed chemo- and regioselective decarboxylative addition to terminal allenes 89 (Scheme A.18).35
Theoretical Background | 17
Scheme A.18. Rh-catalyzed decarboxylative hydrocarbonation of allene by Breit et al.
Yamamoto implemented this methodology on alkyne to extend the substrate scope. They used the concept of hydrofunctionalization of allene, generated in situ from the isomerization of starting alkyne.36 In their seminal report they presented palladium catalyzed intramolecular hydrocarbonation of cyano substituted alkynyl substrate 92, affording corresponding allylic product 93 in good yield and excellent enantioselectivities (Scheme A.19).36b
Scheme A.19. Intramolecular enantioselective palladium-catalyzed hydrocarbonation of alkynes by Yamamoto et al.
In 2015, Krische group used alkyne-allene isomerization phenomenon in their investigations involving allylic alcohol 97. They investigated ruthenium catalyzed redox-neutral carbonyl allylation of alkyne via transfer hydrogenation, starting from alkyne-alcohol redox pair (95, 96) (Scheme A.20).37
Theoretical Background | 18
H2Ru(CO)(PPh3)3 (5 mol%) L98(5 mol%) OH R1 OH 2,4,6-(2-Pr) PhSO H(5mol%) Cy P 3 3 2 2 P(But) + R Fe 2 2 R Bu4NI (10 mol%) R1 Me 2-PrOH (200 mol%) THF (1M), 95 °C, 24h 97 SL-J009-1, (L) 98 95 96 18 examples R1 = alkyl, (FG)-alkyl, alkylenyl up to 85% yield, 96% ee R2= alkyl, (FG)-alkyl, alkylenyl, >20:1 dr aryl, (FG)-alkyl
Scheme A.20. Enantioselective Ru-catalyzed C-C bond formation via allene- hydrometalation using Alkyne−Alcohol redox pair by Krische et al.
Very recently in 2016, Breit and Dong research groups reported rhodium catalysis for decarboxylative addition of β-ketoacids 90 to internal alkyne 99 to afford racemic γ,δ- enones 100 in high yield and very good chemo- and regioselectivity (Scheme A.21).38,91a
Scheme A.21. Breit and Dong investigation on intermolecular Rh-catalyzed decarboxylative hydrocarbonation of alkynes
Moreover, switching to DPEphos ligand 101 the active methylene compounds such as 1,3-dicarbonyl compounds 103 can also serve as very good carbon-based nucleophiles in the addition reaction of alkyne 102. It provides a valuable pathway for the synthesis of important carbon skeleton 104 (Scheme A.22).39
Theoretical Background | 19
Scheme A.22. Convergent approach to γ,δ-unsaturated dienones by carbon- nucleophiles addition to alkyne reported by Breit et al.
A.2.2. Stereoselective Allylic C-N Bond-Forming Reactions
A.2.2.1. State of the Art Syntheses of Allylic Amines
Nitrogen-based heterocycles presenting key moieties in the bioactive cores of natural products and drug molecules, constituting a class of most important building blocks in the areas of natural product synthesis, medicinal chemistry and organic materials (Figure A.4).40
Figure A.4. Selected examples of structurally diverse bioactive products, bearing chiral amines in their scaffolds
Theoretical Background | 20
Chiral amines constitute the pharmachophoric scaffolds of more than 25 drugs molecules in the top 150 most important drugs. Due to their immense importance and utility, synthetic strategies approaching chiral amines in atom and step economical fashion are invaluable areas of organic synthesis (Scheme A.23).41
Scheme A.23. State of the art synthetic protocols for chiral allylic amines synthesis
Investigations involving allylic amines cover a rich area of organic synthesis due to the fact that the generated allylic amine not only contains an important C-N moiety as well as olefinic double bond which is available for further transformations.42
Commercially important source for chiral allylic amine is the use of kinetic resolution 43a or the enzymatic resolution43b of racemic allylic amine 115, which can be synthesized in bulk quantities on industrial scale. The major drawback in these
Theoretical Background | 21 methodologies is the lack of atom economy, as they produced stoichiometric amounts of waste.
Previous syntheses of chiral amine were carried only by transition metal catalyzed asymmetric reduction of an imine 125 with hydrogen surrogates or under transfer hydrogenation conditions by Ryoji Noyori and co-workers utilizing chiral Ru-
(sulfonyl)-1,2-diphenylethylenediamine (TsDPEN) type catalyst 127 (Scheme A.24).44
Scheme A.24. Synthesis of chiral amine via Ru-catalyzed asymmetric transfer hydrogenation
The hydrogenation of imines was proved to have very limited scope due to the respective hydrogenation of allylic double bond. To conserve the valuable double bond asymmetric addition to imine was investigated by various research groups.45,46
Ellman and co-workers reported asymmetric synthesis of amine by the diastereoselective addition of Grignard reagent 129 to chiral N-tert-butanesulfinyl- imine 128. The reaction resulted α-branched amine 131 in 88-97% yield as single enantiomer after hydrolysis (Scheme A.25). 45a,b
Scheme A.25. Ellman‘s investigation on diastereoselective synthesis of chiral amine
Theoretical Background | 22
The reaction is highly stereoselective, however with limited applications. The chiral auxiliary adds two extra steps into the reaction pathway, making it unfavorable in term of step and atom economy.
A catalytic asymmetric versions of this reaction has been investigated by various research groups by utilizing chiral organometallic species as well as metal-ligand catalyst systems.46a-e Enantioselective allylation of imine with allyl-metal reagent involving transmetalation to catalytic active species, provided another useful transformation for the synthesis of chiral allylic amines. Tamio Hayashi and co- workers investigated rhodium catalyzed asymmetric addition of potassium organotrifluoroborates 133 to N-sulfonyl ketimines 132, using chiral rhodium-diene complex 135 (Scheme A.26).46c,e
Scheme A.26. Chiral amines from N-tosyl and N-sulfonyl ketimines by Hayashi et al.
To circumvent the issues associated with transmetalation strategy for allylic amine, Krische and co-workers47a-c made significant contributions to this field.
Scheme A.27. Enantioselective hydrogenative coupling of alkynes to aromatic and aliphatic N-benzylsulfonyl aldimines
Theoretical Background | 23
They investigated iridium-catalyzed redox neutral hydrogenative protocol for imine via hydrogenative coupling of alkyne 137 with imine 136 (Scheme A.27).47c
It is obvious from the above discussion that the synthesis of chiral allylic amine is one of the most effective and practical area of research in the field of organic synthesis. This area provides multitude of advanced methodologies in recent decade including aza-clasien rearrangement,48,49 various other types of transition metal catalyzed like gold,50 zirconium51 and titanium52 or enzymatic53 rearrangement reactions, all leading to the synthesis of a variety of chiral allylic amines.
A.2.2.2. Allylic Amination via allylic C-H oxidation (C-H Activation)
Another broad category of chiral allylic amine synthesis is allylic amination which is a leading concept of oxidative allylic C-H amination (Scheme A.28).
Scheme A.28. Generalized concept of metal catalyzed C-H amination
Palladium catalyzed allylic alkylation via C-H activation corresponds to Tsuji-Trost reaction for C-C bond formation (Scheme A.2.1.2). The intermolecular amination version of this reaction under oxidative conditions exclusively leads to linear amine product (Scheme A.29).54-56
Scheme A.29. Palladium catalyzed oxidative C-H amination furnishing linear product predominantly
Theoretical Background | 24
The allylic amine synthesis via catalytic oxidative amination has been established both inter and intramoleculary. This process needs stoichiometric amounts of oxidizing reagents which is necessary for catalyst regeneration.
The intermolecular version of the reaction was developed by Liu54 and White,55,56 utilizing aerobic oxidation and quinones respectively (Scheme A.30).
Scheme A.30. Pd- catalyzed oxidative amination of terminal alkenes
Christina White and co-worker elucidated the intramolecular oxidative C-H amination of terminal alkene to amino-alcohols 153, starting from enantiomerically pure homo or bisallylic carbamates 151. The reaction proceeded with branched selectivity and high diastereomeric ratio, as the oxidative insertion of amine nucleophile led to the formation of more stable rings (Scheme A.31).57a-g
Scheme A.31. Pd-catalyzed intramolecular diastereoselective allylic C-H amination reported by White et al.
Theoretical Background | 25
A.2.2.3. Allylic Substitution with Nitrogen-Nucleophiles
Metal-catalyzed allylic substitution is valuable and prevailing methodology to obtain allylic amines.24-29,42 Synthesis of chiral allylic amine utilizing palladium catalyzed asymmetric allylic substitution reactions of alkenes with nitrogen nucleophiles including diverse range of amines, nitrogen heterocycles, ammonia or suitable ammonia surrogates, were investigated very broadly and making rich area of organic research in the recent past.58
Scheme A.32. The mechanism of allylic amination showing Pd (II) intermediate involved in allylic substitution
Mechanism for the allylic amination via substitution of allyl moiety with some leaving groups like carbonates, halides, acetates, phosphate etc, involved the oxidative addition of Pd(0) to C-X bond of the substrate. This leads to the formation of π-allyl complex A 153 which is in equilibrium with the σ-allyl complex B 154 (Scheme A.32). The complex B kinetically converted to the branched allyl amine by the attack of N-nucleophile through the intermediate C (155).59b-d The reaction is reversible, intermediate C reconvert to the π-allyl complex A (153) leading to thermodynamic linear product 157.59a
Theoretical Background | 26
The regioselectivities in these reactions can be controlled by ligand and catalyst design as well as additive59d-h and solvents. The reaction conditions play a key role in controlling the rate of isomerization and thus achieving kinetic regioselectivity.59f
In 1990 Hayashi and co-worker performed pioneering investigation on allylic amination from allylic acetate 168, catalyzed by chiral ferrocenylphosphine-palladium complexes 161, leading to the branched allylic amine 160 with 84% enantiomeric excess (Scheme A.33).59g
Scheme A.33. Hayashi’s pioneering investigation on Pd-catalyzed allylic amination
In 2003, Dai and co-workers modified this reaction. They were able to increase the enantioselectivities up to 98% with excellent yield and regioselectivity, by tuning the ferrocene back bone of the ligand (Scheme A.34).59d-h
Scheme A.34. Dai’s investigations on enantio- and branchedselective allylic substitution
In the overall mechanism of this process the [σ-π]-allyl complex,60 formed by the oxidative insertion of metal to the C-X bond of the allylic substrate, can be scavenged by variety of nitrogen nucleophiles. This fact opens up a way to investigate other metals along with different reaction parameters to improve the overall selectivity of the allylic substitution.
Theoretical Background | 27
Furthermore Dai and co-workers tuned the allylic substitution reaction for branched selectivity.
Scheme A.35. Regio- and enantioselective allylic substitution reported by Dai et al.
Branched allylic amines 168 were obtained when they used rhodium instead of palladium. They utilized reactive lithium amide nucleophile 167 to couple with enantiopure allylic carbonate 166 to afford the desired product in very high yield and excellent enantioselectivity (Scheme A.35).61a,b
Samas et al. made advancement in this field using rhodium/chiral ligand 171 to prepare chiral allylic amine 170 in enanticonversion manner from racemic allylic carbonate 169 (Scheme A.36).61c
Scheme A.36. Enantioselective allylic amination reaction by using chiral Rh- Tangphos complex by Samas et al.
Recently, iridium catalysis, an elemental congener to rhodium in term of its reactivity and selectivity, was utilized for asymmetric allylic substitution with amines and ammonia surrogates.62 It is thoroughly investigated by groups of scientists including Helmchen,63 Hartwig64 and Carreira.65
Theoretical Background | 28
Helmchen et al., in 2006, explore the iridium catalysis for the direct amination of allylic carbonate 172 with ammonia equivalent 173 such as o-nosylamide, phathlimide and carbamates etc. The allylic substitution step yielding allylic o-nosylamide followed by hydrolysis led to the synthesis of primary allylic amine 174 with very good yield and enantioselectivity (Scheme A.37).63a
Scheme A.37. Ir-catalyzed asymmetric allylic aminations with N,N-diacylamines and o-nosylamide as ammonia equivalent
Hartwig et al. investigations64 involve the allylic substitution of achiral, linear allylic carbonates 172 with aromatic amine such as anilines, using Ir(I)-phosphoramidite catalyst system 54. The branched chiral allyl-aryl amine 176 were synthesized in excellent yields with very good regio- and enantioselectivities (Scheme A.38).64b
Scheme A.38. Ir-catalyzed asymmetric allylic amination reported by Hartwig et al.
Carreira and co-workers further documented the stereospecific allylic amination of chiral unactivated allylic alcohol 177, via enantiospecific substitution. They used Ir/phosphoramidite-alkene catalyst system 160, utilizing sulfamic acid as
Theoretical Background | 29 pronucleophile. The substitution process led to benzyl protected allylic primary amines 189 in good yield with excellent enantioselectivities (Scheme A.39).65a
Scheme A.39. Ir-catalyzed asymmetric allylic amination via stereospecific substitution of allylic alcohol
A.2.2.4. Hydrofunctionalization of allenes and alkynes with nitrogen- nucleophiles
Hydroamination is usually referred to the hydrofunctionalization of unsaturated carbon skeletons like alkene 180, alkyne 183 and allenes 186 with nitrogen based pronucleophiles to form C-N along with a C-H bond. This process provides low cost and atom economical access to highly valuable amine building blocks from readily available starting materials (Scheme A.40). 66
Historical investigations on hydroamination include use of acid67 or base,68 as catalyst to activate the unsaturated moieties. Among metal catalysts mercury69 and copper,70 are the most primitive. Other transition metals also established as hydroaminating catalyst with passage of time because of their stability, low toxicity, high selectivity and high level of functional group tolerance. Catalytic hydroamination is one of the most important fields,66 as the synthesis of free amine from the addition reaction of ammonia to C-C multiple bond is considered as one of the fore most reaction in field of metal catalysis.71
Theoretical Background | 30
Scheme A.40. Hydroaminations of alkene, alkynes and allenes
Hydroamination of alkene moiety (a) leads to the formation of simple alkyl amines while that of alkynes generates enamine which undergoes imine-enamine tautomerism in case of primary amine nucleophile. Addition of nitrogen pronucleophile to allenes (c) results in three different possible products such as allyl amine, enamine and imine (Scheme A.40).66a
The hydroamination of C−C multiple bonds follow various mechanisms. The selectivity and efficiency of the process depend on various catalytic pathways. The choice of catalytic route is determined by the nature of catalyst system, substrate combination and reaction conditions. Transition metal catalyzed N-H insertion pathways can be divided broadly into four categories depending upon the nature of initiation step of the catalytic cycle (Scheme A.41). (a) π-Coordination of C−C multiple bond and electron deficient metal complex formation, followed by nucleophilic insertion of N-nucleophile (π-Lewis acid complex formation). (b) Initiated by the formation of M-N bond followed by insertion of alkene/alkyne moiety into this bond. (c) Initiated by metal-hydride formation, followed by migratory insertion. (d) Formation of metal-alkyne coordinating moiety followed by rearrangement to vinylidene complexes.66b
Theoretical Background | 31
Scheme A.41. Possible hydroamination pathways, followed under transition metal catalyzed conditions
The Lewis acid coordination pathway (a) is most common, which is initiated by the activation of C-C multiple bond by electron deficient catalyst system leading to η2- coordination intermediate. The nucleophile attack occurs in an anti-configuration, followed by successive protonolysis and reductive elimination. This step proceedes with retention of configuration leading to the formation of addition product with anti- stereoselectivity (Scheme A.41a). Pathway (a) is common for electron-deficient substrates like alkene/alkyne derivatives such as terminal alkenes/alkynes, diynes, or propiolic acid along with electron-rich N-H moieties. Electron deficient nitrogen nucleophile such as amides, ureas, carbnamates, lactums and sulfonamides etc can enter into this pathway in combination with various classes of alkenes i.e ethylene, aliphatic and internal alkenes, styrenes, and allenes.
Theoretical Background | 32
Widenhoefer’s investigastions on the hydroamidation of terminal alkene utilizing
[PtCl2(C2H4)]2 system provides an example of this type of mechanistic pathway (Scheme C.42).66j
Scheme A.42. Markovnikov selectivity observed in Pt-catalyzed hydroamidation of styrenes
Another observed catalytic pathway is mechanism b. The initial step is the formation of the M-N bond by oxidative addition or ligand exchange process. The migratory insertion of the unsaturated carbon moiety into the M-N bond leads to the formation of desired C-N bond. This pathway follows Markovnikov addition leading to syn- hydroaminating product. This reaction type needs at least two coordinating sites on metal center, for nucleophile as well as for C−C multiple bonds. Steric hindrance play an important role in migratory insertions of the alkene/alkyne or allene,72a,b thus the metal preferentially reside on the less hindered side. This pathway is one of the most describe pathway for the addition of anilines and amides to alkenes, allenes, and alkynes resulting in the preferential formation of Morkovnikov product.
Gold-catalyzed Markovnikov hydroamination of internal alkynes with triazoles, reported by Shi et al. provides an example of the mechanistic pathway b. This process involved the M-N bond formation through metal-enamine intermediate which lead to the desired N-vinyl product with Markovnikov selectivity (Scheme C.43)72c
Theoretical Background | 33
Scheme A.43. Vinyl substituted triazoles via gold catalyzed Markovnikov hydroamination of alkynes
Mechanism c is complementary to pathway b, as it involves M-H bond in the migratory insertion step of C-C multiple bond instead of M-N bond. Acidic additive like carboxylic acid or acidic N-H group such as an amide or aryl amine leads to the formation of M−H bond by oxidative addition to the metal center. This pathway type is usually described for the low-valent transition metals like Rh, Ir, Ru, and Pd complexes. In case of other metals such as example Cu, Fe and Co catalysts, the generation of M−H bond involves hydride transfer from silanes or dehydrogenation of alcohols. In any case, M-H bond formation is then followed by the migratory insertion of the alkene, alkyne, or allene leading to the respective intermediate by inserting the metal to the less hindered C-atom. The reductive elimination process subsequently leads to the formation of anti-Markovnikov addition product (Scheme A.41c). Rhodium catalyzed benzotriazole addition to terminal allene, investigated by Breit et al. presents an elegant example of reaction occur through mechanistic pathway c (Scheme C.44).86d
Scheme A.44. Rh-catalyzed N-allylation of benzotrizole via anti-Morkovnikof hydroamination of allene
Theoretical Background | 34
Catalytic pathway d also starts with the coordination of metal to form M-H species, followed by insertion to alkyne moiety. This process leads to the formation of vinyl−metal species which rearrange to give corresponding vinylidene complex. These complexes are susceptible to nucleophile attack at α-C along with the reductive elimination of metal leading to the formation of Markovnikov addition product with syn-selectivity. This type of mechanistic pathway is usually described for the ruthenium catalyzed hydroamidations of alkynes. The stereochemistry of the product can be controlled by the ligand which can be revert to anti-Markovnikov selectivity by the selection of appropriate ligand.
Ruthenium catalyzed anti-Markovnikov addition of secondary amide derivatives to terminal alkynes to synthesized enamides is an example of the mechainistic pathway d (Scheme C.45).72d
Scheme A.45. Ru-catalyzed regioselective synthesis of enamides
In case of alkyne hydroamination with palladium and rhodium catalysts the involvement of alkyne-allene isomerization is investigated by the use of acid additives.73 This fact increase the substrate scope for the allene hydroamination as alkyne provide an easily accessible allene precursor. Alkyne can be easily converted to allylamine by atom/step economical and redox neutral hydroamination process (Scheme A.46).
Scheme A.46. In situ isomerization of alkyn to allene in catalytic hydroamination
Theoretical Background | 35
Synthesis of N-heterocycles via intramolecular hydroamination is one of the thoroughly investigated fields. Concerning the allene hydroamination, both intramolecular and intermolecular reactions are well established. The intramolecular hydroamination catalyzed by organo-lanthanides complexes 206 (Scheme A.47),74 transition-metal complexes of Ti and Zr,75 and late transition-metal complexes like Pd,76Ag, Au77, are more generally investigated processes.
Scheme A.47. Organo-lanthanides catalyzed intramolecular hydroamination of amino-allenes by Mark et al.
The intramolecular gold-catalysis give an easy access to highly valuable five-seven membered nitrogen-based heterocycles via hydroamination of internal allene.78 The first gold catalyzed intramolecular addition of N-nucleophiles to allenes was 78a investigated by Toste and co-workers using R-xylyl-BINAP(AuCl)2 complex 207 to afford N-heterocycles 208 with excellent yields and enantioselectivities (Scheme A.48).
Scheme A.48. Gold catalyzed intramolecular hydroamination of amino-allenes by Toste et al.
Theoretical Background | 36
Palladium catalysis provides another privileged catalyst system for both intra and intermolecular hydroamination processes. Yamamoto and co-workers investigated an enabling methodology for the asymmetric synthesis of pyrrolidines, isoindolines or piperidines etc with high enantioselection. They utilized ω-alkynyl substituted amines 210 for intramolecular hydroamination catalyzed by chiral norphos-based ligands 212, 213 (Scheme A.49).79, 80b
[{Pd (dba) }] (5 mol%) NHNf 2 3 Nf L 213 or L 214 (25 mol%) N R R n n PhCO2H(10 mol%) 210 C H (0.1 M) 6 6 211 100 °C, 48-72 h n=0,1 n=0,1 R1 = (FG-)aryl, alkyl 8 examples Nf = Nonaflourobutansulfonyl up to 95% yield, up to 95% ee up to 20:1 E:Z
Me PPh PTol2 2 PPh PTol2 2 (R,R)-Tolyl-Renorphos, L 213 (R,R)-Me-Norphos, L 214
Scheme A.49. Pd-catalyzed hydroamination of alkynes by Yamamoto et al.
Intermolecular hydroamination of allene and alkyne with nitrogen nucleophile is one of the most important and thoroughly investigated strategies for the synthesis of allylic amine derivatives. Gold catalysis achieved much importance during last decades in the field of synthetic organic chemistry particularly for the allylamine synthesis.81
Yamamoto and co-workers (2006) have developed synthesis of branched 217 and linear allylamine 215 derivative using gold catalyzed intermolecular hydroamination of asymmetric allenes 216. The reaction proceeds smoothly at room temperature in very good yield and excellent enantioselectivities leading to chiral branched allylic amine 217, with chirality transfer from allene to the product (Scheme A.50). 82
Theoretical Background | 37
Scheme A.50. Gold catalyzed intermolecular hydroamination of allenes
An analogous concept of gold catalysis was demonstrated by Widenhoefer and co- workers (2012) for the asymmetric intermolecular addition of nitrogen nucleophiles to allenes. The reaction results in the formation of chiral allylic amines 219 with good enantioselectivities and yields (Scheme A.51).83
Scheme A.51. Widenhoefer’s investigations on gold catalyzed intermolecular hydroamination
Yamamoto and co-workers used palladium catalysis for the synthesis of allylamine derivatives 223. They investigated intermolecular hydroamination of internal alkyne 221 with substituted aromatic amines 222 to obtained the desired product in very high yield and E:Z selectivity (Scheme A.52).84
Scheme A.52. Addition of nitrogen nucleophile to internal alkynes by Yamamoto et al.
Theoretical Background | 38
Rhodium catalysis for hydroamination is investigated by Breit and Dong research groups in recent years. Breit et al. present pioneering investigations in this side of synthetic chemistry utilizing rhodium catalyzed hydroamination concept.93 Dong and co-workers reported on Breit methodology by presenting hydroamination of internal alkynes with N-heterocycles such as indolines 224. They used internal aryl alkynes 99 as previously used by Yamamoto (Scheme A.52)84 along with acidic additives. They synthesized both linear 225 and branched allylic products 226 with good yields and selectivities (Scheme A.53).85
Scheme A.53. Rh-catalyzed hydroamination of alkynes reported by Dong et al.
A.2.2.5. The Breit type Hydroamination of Allenes and Alkyne
The field of rhodium catalysis for hydroamination of allene and alkyne is broadly investigated by Breit et al. starting with hydrofunctionalization of allene with aromatic amines. They synthesized branched allylic amines in excellent yield with high level of regio- and enantioselection (Scheme A.54).86a Furthermore the methodology is extended to various other amine, nitrogen-heterocycles and ammonia surrogates.
Scheme A.54. Enantioselective coupling of anilines with allenes by Breit et al.
Theoretical Background | 39
A captivating development in this area is the synthesis of chiral N-allylated indole by simple hydroamination of allene with substituted hydrazine 233. Initially branched allylic hydrazides 234 were obtained in good yields with high N1-selectivity as well as enantioselectivities. These hydrazides led to the formation of enantioenriched indoles 235 via Fischer indolization with wide array of functional groups. This reaction represented the first asymmetric route toward branched N-allylic indoles 235 via Rh- catalyzed C−N bond forming reaction (Scheme A.55).86b
Scheme A.55. Enantioselective coupling of aryl hydrazines with allenes and their one-pot conversion to N-allylic indoles
Breit and co-workers also developed a straightforward methodology for the synthesis of N-allylic heterocycles from the direct hydroamination of allenes. They described rhodium catalyzed addition of imidazole derivatives 238 to allene 196 in regio- and enantioselective manner. This protocol gave an access to wide range of branched allylic products 239. Utilizing palladium catalysis instead of rhodium linear products 240 were obtained in excellent yields with very high E:Z selectivities (Scheme A.56).86c
Theoretical Background | 40
Scheme A.56. Rh-catalyzed regiodivergent hydroamination of allene with imidazole derivatives
Rhodium catalyzed hydrofunctionalization strategy is successfully utilized to allylate various N-heterocycles such as pyrazole, tetrazoles,86e benzotriazoles,86d and pyridones.86f Some examples of the series are represented below (Scheme A.57).
Scheme A.57. Rh-catalyzed insertion of tetrazoles and pyridone to terminal allenes
Furthermore, they recently developed the synthesis of free allylic amine as hydrochloride salt 250 in highly regio- and enantioselective manner. They utilized the hydroamination methodology for coupling allenes 196 with ammonia surrogates such as diphenylimines 249. Upon hydrolysis free allylic amine in the form of
Theoretical Background | 41 hydrochloride salt was afforded in high yield and excellent enantioselectivity (Scheme A.58). 86g
Scheme A.58. Transition metal catalyzed coupling of ammonia surrogates with allenes
A.2.3. Breit Type Hydrofunctionalization of Allene and Alkyne with Oxygen and Sulfur Pro-nucleophile
As described earlier in previous sections, transition metal catalyzed allylic substitution is one of the most powerful strategies to obtain branched allylic compounds with high selectivities and yields in a straightforward manner. Allylic substitution using oxygen and sulfur pronucleophiles is recently investigated strategies to synthesize allylic alcohols, thiols and other derivatives.9,28 The number of methodologies for the asymmetric C-O bond-formation is visibly lower in synthetic literature than that for asymmetric C-C or C-N bond-formation. This is because of the fact that the starting materials used in these substitution reactions are usually branched or linear allylic esters or carbonates 251. For instance the iridium catalyzed regioselective allylic substitution of allyl ester with water furnishing allylic alcohols 252 in very good yields and enantioselectivities, investigated by Helmchen and co-workers (Scheme A.59).87
Scheme A.59. Regioselective metal-catalyzed allylic substitution by Helmchen et al.
Theoretical Background | 42
The disadvantage of this methodology is its lack of atom economy since stoichiometric amounts of a leaving group are disposed off at the end of reaction as waste disposal. The preparative significance in this case is much lower as compared to nitrogen and carbon nucleophiles, used in allylic substitution reactions. This is because of the fact that the starting material itself equals to the targeted structure, despite of the immense importance of the newly generated stereocenter.
Hydrofunctionalization as an alternative to allylic substitution is an important and popular methodology. Hydrofunctionalization of allene and alkyne provides an appealing route to branched allylic C-O moieties in redox-neutral fashion. Various groups especially Yamamoto,88 Widenhoefer,89 Toste,90 and Krische91 research groups are involved in investigating oxygen-nucleophiles in order to perform hydrofunctionalization reaction with allenes and alkynes to synthesize valuable allylic substituted building blocks. Similarly Breit research group investigated hydrofunctionalization reactions of allene and alkyne with various pronucleophiles such as carbon92, nitrogen,93 oxygen94 and sulfur.95
A.2.3.1. Hydrofunctionalization with O-Nucleophiles
The first investigation in this area was published in 2011 by coupling of terminal alkyne 102 with carboxylic acid 254 under rhodium catalysis condition. This reaction led to the formation of racemic allylic esters 255 in an atom-economic fashion without any additives used for catalyst activation and regeneration (Scheme A.60).94a
Scheme A.60. Seminal publication of Breit et al. on the hydrooxycarbonylation
Asymmetric version of this reaction was investigated to furnish chiral branched allylic esters 258 with excellent regio-, and enantioselectivities. They utilized rhodium with
Theoretical Background | 43
DIOP ligand in the hydrofunctionalization of terminal allenes 256 to obtained branched allyl ester with excellent regio- and enantioselectivities (Scheme A.61).94b
Scheme A.61. Convergent approach to chiral allylic esters reported by Breit et al. utilizing allene moiety
Further modification of the catalyst backbone from (R,R)-DIOP ligand 259 to cyclopentyl substituted DIOP 262, made a way to branched allylic ester 261 from readily available terminal alkynes 102 (Scheme A.62). 94c
Scheme A.62. Convergent approach to chiral allylic esters reported by Breit et al. using alkyne precusors
Intramolecular version of rhodium catalyzed asymmetric hydroxylation is used for the small ring sized lactone as well as macrolactones 264 syntheses in very good yields and excellent selectivities (Scheme A.63). 94d,e
Scheme A.63. Rh-catalyzed enantioselective macrolactonization by Breit et al.
Theoretical Background | 44
Recently, this methodology is utilized for the synthesis of enantioriched branched allylic ethers 267 in mild and efficient manner. Hydro-alkoxylation of terminal allene 196 and internal alkyne 99 using simple and functionalized alcohols 266 led to the desired product in good yield with excellent ee values (Scheme A.64). 94h
Scheme A.64. Convergent approach to chiral allylic alcohols reported by Breit et al.
Extensive mechanistic investigations based on the above results and deuterium labeling experiments were carried out by Breit et al.94 The involvement of π-allyl species is anticipated which is generated by hydrometallation of allene/allene- intermediate.94a-c The proposed mechanistic cycle involves five general steps, depicted in Scheme A.65. The oxidative insertion step involves the insertion of rhodium [I] catalyst into the O-H bond of the carboxylic acid source (step I) leading to the formation of hydrido-rhodium complex A. This rhodium complex hydrometallates the alkyne substrate in the next step (step II) generating vinyl-rhodium species B. Complex B either release vinyl ester as a byproduct C or undergoes isomerization to corresponding allene (step III). In step IV the allene intermediate undergoes hydrometalation to give π-allyl complex D. The complex D undergoes reductive elimination (step V) leading to the corresponding allylic ester. This mechanism is also proved by kinetic studies using DFT (BP86/def2-SVP) calculations.94e
Theoretical Background | 45
O O 2 R O H 1 R2 OH O R 2 R1 H carboxylic acid R alkyne O [Rh]III H product H V I (A) II
O I O [Rh] O R2 R2 III R2 O 2 O [Rh] III +R CO2H III O [Rh] R2 O [Rh] R1 O [Rh]III H H R1 (B) (D) (A) -allyl H -allyl R1 vinyl Rh-complex
O IV III O R2 H (C)
R1 R1 • allene Scheme A.65. Proposed catalytic cycle for the hydrooxycarbonylation of alkynes and allenes
A.2.3.2. Hydrofunctionalization with S-Nucleophiles
Breit hydrofunctionalization methodology is also successfully employed to the syntheses of allyl thiaolated compounds. In this regard the first investigation by Breit research group was the rhodium catalyzed addition of sulfonyl hydrazides 270 to terminal alkynes 102, leading to racemic branched allylic sulfones 271 in good yield and regioselectivities (Scheme A.66; right side).95a Recently this concept also utilized for the hydrothiolation of terminal allene 196 as well (Scheme A.66; left side).95b
Scheme A.66. Enantioselective hydrothiolation of terminal and internal allenes
Theoretical Background | 46
Further achievements involving asymmetric version of this reaction is the rhodium catalyzed enantioselective allyl thiol synthesis via hydrothiolation of allenes with a variety of substituted aromatic or aliphatic thiols 272. This process furnish allylic thioethers which subsequently oxidized to sulfones 273 in excellent yield and regio- and enantioselectivities (Scheme A.67).95c
Scheme A.67. Enantioselective hydrothiolation of terminal and internal allenes
Further utilization of hydrothiolation strategy is revealed by the syntheses of a remarkable series of different enantioenriched Z-allylic thioethers (sulfones 277). These thioethers are synthesized in the form of sulfones by thiols 276 addition to substituted internal allenes 275 in very good yield and excellent enantioselectivities (Scheme A.68).95d
[{Rh(cod)Cl}2] (4.5 mol%) O R3 L 278 (9.0 mol%) O S R2 P R1 • R2 + R3SH PTSA (30 mol%) 1 2.5 equiv. mCPBA R P 275 276 DCE (0.25 M), 70 °C, 16 h 277
1 2 (S,S)-Me-duphos, L 278 R =R = (FG-)alkyl, cycloalkyl 8examples 3 R = (FG-)aryl up to 83% yield, up to 96% ee up to 99:1 Z:E
Scheme A.68. Enantioselective hydrothiolation of terminal and internal allenes reported by Breit et al.
Theoretical Background | 47
A.3. Pd-PEPPSI Catalyzed Carbon-Nitrogen Bond Forming Cross Coupling Reactions
Cross coupling reactions present an extremely versatile and mainstream synthetic tool in organic synthesis towards the construction of C-C and C-heteroatom bonds.96 These synthetic procedures constitute a class of methodologies which matured with passage of time to widely applicable techniques in natural product synthesis, pharmaceuticals, materials sciences, and catalysts designing and preparation. Carbon-nitrogen bond forming cross coupling reactions, catalyzed by transition metal catalysts is exceptionally broad and classical research area in organic chemistry.97
A.3.1. Pd-Catalyzed Carbon-Nitrogen Bond Formation: Buchwald Hartwig Amination The palladium catalyzed aryl amine synthesis, commonly dubbed as Buchwald– Hartwig amination is a powerful and practical strategy for the cross coupling of amines with aryl halides. This process was developed as a single synthetic laboratory procedure and become most versatile and applicable technique in academia and synthetic chemical industry. Furthermore, researchers in chemical industries utilized this methodology as standard procedure for amine synthesis in there toolbox to synthesize amine derivative on multi gram scale.98
Stephen L. Buchwald and John F. Hartwig are the pioneer investigators in this field and opened a new chapter in the field of transition metal catalyzed cross coupling chemistry with a new approach to synthesize C-N bond containing compounds 280 using phosphine based ligands 76 or 282.99 A generalized practical protocols for the coupling of amines 280 with aryl halides 279 in the presence of a base utilizing second generation Buchwald-Hartwig ligands illustrated in the Scheme A.69.100
Scheme A.69. Generalized Protocol for Buchwald-Hartwig Amination
Theoretical Background | 48
The chelating bisphosphines BINAP 282, DPPF 76 and DtBPF 284 defined the state of the art ligand system for Pd-catalyzed amination reaction (Figure A.5).101 Buchwald in 1998102 reported monodentate phosphine ligands with a biphenyl backbone (290- 295) which is one of the major breakthroughs in this field. These ligands greatly enhanced the scope of aminations to aryl chlorides and unactivated aryl halides even under very mild conditions.103
Ferrocene-based Phosphine Ligands
R NMe PPh 2 PtBu 2 PPh PPh PtBu 2 Fe 2 2 2 Fe Fe Fe Fe Ph Ph PPh t Ph Ph 2 P Bu2 Ph DPPF, 76 R= OMe, NMe JosiPhos type DtBPF Q-Phos 2 283 284 285 Chelating Biarylphosphine ligands 282 O PPh2 PPh2 O O PPh2 PPh2 PPh2 PPh2 PPh PPh2 PPh2 O 2 NMe2 O BINAP 281 BIPHEP Xanthphos Segphos Aminophosphines 286 287 288 289 Buchwald's ligands- Biphenyl based Phosphine ligands
OMe
PCy MeO P(Cy)2 PCy2 2 P(t-Bu)2 PCy2 PCy 2 i-Pr i-Pr i-Pr i-Pr NMe2 PrOi OiPrMeO OMe
i-Pr i-Pr JohnPhos RuPhos SPhos BrettPhos X-Phos Dave-Phos 290 291 292 293 294 295
Figure A.5. Buchwald-Hartwig amination ligands
The design of the new bulky 2,4,6-triisopropyl-substituted ligands BrettPhos 294104c and X-Phos 295104a led to the most active and stable biphenyl based ligands allowing the use of arenesulfonates 284d as well as aqueous amination protocols (Scheme A.70).104
Theoretical Background | 49
Scheme A.70. Buchwald-Hartwig amination utlilizing X-Phos ligand
A.3.2. N-Heterocyclic Carbene: Gateway to Pd-PEPPSI Complexes
Tertiary phosphines occupy a preponderant place as ancillary ligands in palladium chemistry which is one of the most studied transition metal catalyzed pathway for organic reactions. Bulky tri-substituted phosphines enjoying the popularity of being electronically rich and sterically demanding ligands that catalyze challenging transformations with greater selectivity along with mild conditions and feasibility.105 N-Heterocyclic carbenes (NHCs) are the only class of ligands that has been able to replace the widely applicable tertiary phosphines106 as alternative ligand system. Both of these two electron donor ligands show a combination of strong σ-donating properties with shielding steric pattern allowing the stabilization of metal center leading to the great enhancement in their catalytic activity.107
Phosphines and NHCs have similar electronic structure but there is a large difference in their topology when coordinated to the metal center. 108
Figure A.6. A comparison of the shape and steric topographies of the NHC and Phosphine ligands
Theoretical Background | 50
The three substituents of the phosphine situated backwards from the metal thus forming a cone, while the substituents on the NHC (on the nitrogen atoms) project forward making a pocket around the metal center (Figure A.6).
This kind of arrangement present in the NHC allows the topology of the substituents to have much stronger impact on the properties of metal center. Both the ligand classes phosphines and NHCs can be probed by incorporating substituents with predefined stereoelectronic properties. In phosphine moieties these substituents are directly attached to the donor atom. Therefore the steric and electronic effects cannot be separated. In contrast, NHCs principally allow their steric and electronic properties to be tuned independently. The reason behind the fact is that the flanking substituents attached to ring nitrogen determining the steric bulk of the ligand, are not directly connected to the carbene carbon atom. Therefore they have only limited effect on the electronic density of the central atom.109 The electronic properties of NHC are totally related with heterocyclic moiety which is largely responsible for the electronic properties of these ligands.110
The history of N-heterocyclic carbenes (NHCs) begins back in 1968 by its first independent synthesis, carried out by Wanzlick et al.111 The key event in the history of NHCs was the isolation of the stable carbene IAd (1,3-bis(adamantyl)imidazol-2- ylidene 297 (Scheme A.71) by A. J. Arduengo in 1991.112
Scheme A.71. First stable carbene isolated Arduengo et al. in 1991
The stability of these NHCs allowed the scientific community to examine the properties and reactivity of this class of compounds more closely. 113 Further, the poineeering investigations by Herrmann et al. (1995) upon the utilization of this class of compounds as spectator ligands in the synthesis of organo transition-metal
Theoretical Background | 51 complexes 291 and 292 leads to unwrap the remarkable potential of NHCs in transition metal catalysis.113
Figure A.7. Herrmann’s investigations on synthesis of NHC-Pd Complex
These seminal investigationes led to the development of variety of many other NHC backbones114 and their transition metal complexes as well as to the evaluation of their catalytic applications. However only imidazolium 300 or 4,5-dihydroimidazolium NHC 301 salts are proved to have wide spread applications in homogeneous catalysis (Figure A.8).108
Early investigations have shown that N-heterocyclic carbenes constitute a versatile class of ligands mimicking tertiary phosphines. They act as two-electron donors and their stereoelectronic properties can be modulated by varying the substitution pattern on the heterocyclic nitrogen moieties.115 The nucleophilic NHC ligands appear to have several advantages over commonly utilized phosphines:
metal complex stabilizing effect improved stability resistance of metal complex to ligand dissociation
These factors reveal that the process did not requires any stoichiometric amounts of ligand to prevent the aggregation of the catalyst as a bulk metal.116
As a consequence of the above attractive features, the numbers of catalytic reactions increase the use of NHC metal complexes as catalyst. Specific examples are the use of metal carbene complexes in olefin metathesis 117 hydrosilylation,118 and Ru-catalyzed furan synthesis119 etc.
Theoretical Background | 52
O O
N N N N N N R N N R R N N R R R R R R R 300 301 302 304 305
R N R N S N O N N N R R R R N N R R R
306 307 308 309 310
N N N N N N
311 312 313 R N N R N N N N N N
= 314 315 316 R N N R Cl Cl N N N N N N
317 318 319
Figure A.8. Some classes of NHC-ligands based on the carbene backbone
The major breakthrough in this field was the development of Grubbs second generation catalysts 322 (Figure A.9) for olefin metathesis that contain the bulky carbene SIMes ligand instead of two tricyclohexylphosphine moieties. Grubbs was awarded Nobel Prize in Chemistry in 2005 with Chuvan Strock in recognition of their contributions toward the development of olefin metathesis.120
st Figure A.9. Grubbs 1 and Second generation catalysts
Theoretical Background | 53
The increasing level of understanding of the role of NHC ligands in transition metal catalysis open a quest to design even more sophisticated ligand systems.
A.3.3. Design and Preparation of Pd–PEPPSI Complexes
In addition to electronic and steric factors of the NHC ligands, access to the catalytically active metal complex is crucial for high levels of reactivity. Besides the inherent advantages associated with NHC ligands (i.e., stability, steric, electronic, tunability)121 these ligands contribute high stability to their metal complexes, thus allowing the indefinite storage and easy handling of the synthesized metal complexes. These well-defined complexes permit a control over the Pd/ligand ratio that avoids the use of excess of expensive ligand. As a result the number of well-defined NHC containing palladium (II) complexes is growing and their use in coupling reactions is witnessing increase interest.108,122
A number of monoligated Pd-NHC complexes have been prepared by various researchers in last decades such as Caddick and Cloke,123,110b Bellemin-Laponnaz and Gade,124 Nolan,125 Beller,126 Herrmann,127 and Organ128 (Figure A.10) demonstrating the high levels of reactivity of these complexes correlated with the steric environment around Pd.129
Over the course of the last decade Organ and co-workers developed a family of air- stable, user-friendly palladium NHC pre-catalysts, the PEPPSI series,130-134 (PEPPSI: pyridine enhanced precatalyst preparation, stabilization, and initiation) systematically varying the electronic and steric properties around the metal center and probing the architects of these carbene ligands.131
The first-generation pre-catalysts Pd-PEPPSI-IMes 331, Pd-PEPPSI-IEt 332 and Pd- PEPPSI-IPr 333 in this series are prepared by heating their precursor imidazolium salts with PdCl2 and a mild base (K2CO3) in the presences of 3-chloropyridine to obtained the corresponding Pd-PEPPSI complexes in nearly quantitative yields (Scheme A.72).132
Theoretical Background | 54
Figure A.10. Selected monoligated Pd-NHC complexes
Organ’s first generation Pd-PEPPSI complexes are utilized for various coupling process and evaluted the outstanding catalyst performance, particularly in Suzuki– Miyaura,133 Negishi,134 and Kumada–Tamao–Corriu135 cross-coupling reactions as well as Buchwald–Hartwig amination.136a,b
Scheme A.72. One pot synthesis of Pd-PEPPSI complex
Theoretical Background | 55
Results obtained in various reactions showed that the yields are consistently high with catalyst’s steric bulk of the precatalyst used. For example, in the case of Pd-PEPPSI- IPr 333 the yields were much greater than those obtained with less bulky Pd-PEPPSI- IEt 332 or Pd-PEPPSI-IMes 331. Furthermore, recent investigations on further increasing the steric bulk in NHC backbones at ortho positions of the N-phenyl moieties led to increase in the catalyst activity and performance. Therefore Organ137a-i and some other reseaerch groups138a-h investigated second generation Pd-PEPPSI complexes (334-339) (Figure A.11) which made feasible and most tolerant methodology for challanging cross coupling reactions.
Figure A.11. Second generation Pd-PEPPSI complexes with more sterically encummered NHCs backbone
The NHC-Pd chemistry combines the fundamentals of transition metal catalysis and pure organic methodology. It provides the field with excellent opportunities leading to an “ideal catalyst system” exhibiting remarkable stability. It allows the probing and fine-tuning of the ligand backbone in order to control the activation and catalytic activity making a way to exciting discoveries to come.
Theoretical Background | 56
A.3.4. Pd-PEPPSI Mediated Buchwald-Hartwig Amination
Pd-PEPPSI mediated amination methodology is investigated by Micheal G. Organ and his co-workers in much detail. They inspected the mechanism involved by probing the ligand backbones as well as the reaction conditions and screening of additives to propose quantifying protocols for the cross couplings of most challenging substrates like electron rich alkyl-aryl chlorides and electron deficient amine counterparts.139
Recently, they demonstrated the modification of the ligand possessing most efficient reactivity leading to the amination of deactivated coupling partners by using carbonate base at room temperature. This procedure presents most simple and proficient amination methodology for diverse array of sensitive functionality.140
Initial investigations reported by Organ et al. on the Buchwald-Hartwig amination involved the use of Pd-PEPPSI precatalyst which provided the milder procedure to couple cholor/bromo arenes with variety of secondary amine in very high yields (Scheme A.73).141
Scheme A.73. Pd-PEPPSI-IPr catalyzed amination utilizing secondary amines
Theoretical Background | 57
The scope of Pd-PEPPSI-IPr ligand was elaborated by investigating room temperature amination of hindered amine as well a variety of heterocyclic amines (Scheme A.74).
Scheme A.74. Pd-PEPPSI-IPr catalyzed aminationat room temperature
The amination of highly sterically hindered 2-chloro-m-xylene with 2,6- diisopropylaniline affording the desired product 353 in 90% yield is worth mentioning.141
Pd-PEPPSI-IPr 333 precatalyst was modified by Nolan and his co-worker by inserting phenyl substitutions on 1,3-bis(2, diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene moiety 357 to perform the amination at room temperature. Selected examples are depicted below (Scheme A.75).142
In 2013, Organ et al. demonstrated the modification in NHC backbone by synthesizing Pd-PEPPSI-IPent (IPent = 2,6-(3-pentyl)pentylphenyl-2H-imidazol-2-ylidene) precatalyst 335 that have a profound impact on the reactivity and selectivity in a variety of cross coupling reactions. Dramatic improvements were achieved by synthesizing and utilizing the chlorinated analogue Pd-PEPPSI-IPentCl 336, in which the Cl substituents were installed upon the imidazolidine ring. This catalyst system established baseline reactivity for Pd-PEPPSI precatalyst series by performing most
Theoretical Background | 58 challenging cross coupling of electron rich and sterically hindered oxidative addition partners.
Theoretical Background | 59
Scheme A.76. Pd-PEPPSI-IPentCl catalyzed synthesis of triarylamines by Organ et al. deactivated coupling partner just by using mild carbonate base at room temperature in excellent yield (Scheme A.77).140
Scheme A.77. Amination of deactivated chloroarenes utilizing Pd-PEPPSIIPentCl-o- Picoline by Organ et al.
Theoretical Background | 60
Secondary amines are useful synthetic intermediates as well as valuable commodities for investigations in the field of medicine, drug discovery and material sciences.146a-d They are difficult to selectively synthesize from the direct arylation/alkylation of primary amines. Palladium catalyzed amination reaction of aryl halides presented one of the most efficient methodologies for the synthesis of secondary amine serving as a valuable counterpart to reductive amination and substitution reactions.145 Organ et al. evaluated their Pd-PEPPSI precatalyst for this purpose. Using Pd-PEPPSI-IPentCl 335 catalyst system the desired secondary aniline products were obtained in excellent yields as the catalyst enhanced the binding selectivity for the primary amine leading to the synthesis of secondary amine product selectively (Scheme A.78).137e
Scheme A.78. Organ’s Investigations on selective monoarylation of primary amines utilizing Pd-PEPPSIIPentCl precatalyst
Lavigne et al. reported Pd-PEPPSI precatalyst decorated with dimethyl amine moiety inserted upon the imidazolium ring of the NHC backbone. It is revealed that the precatalyst Pd–PEPPSI-IPr(NMe2)2 338 shows high catalyst performance for the cross coupling between various aryl chlorides and a broad range of amines, including
Theoretical Background | 61
secondary amines, primary alkyl and arylamines, in the presence of Cs2CO3 base. They reported superior performance of this ligand in terms of activity and selectivity, low catalyst loading, and substrate scope as compare to the unmodified Pd–PEPPSI- IPr 333 precatalyst (Scheme A.79).147
(NMe ) Scheme A.79. Lavigne’s investigations utilizing modified Pd–PEPPSI-IPr 2 2 precatalyst
Chiral aromatic amine compounds are important building blocks for the synthesis of many important bioactive molecules.148 Enantioselective synthesis of optically pure amines is one of the most investigated areas of scientific research. Organ research group in 2016 investigated the Pd-PEPPSI catalyzed cross coupling methodology for the synthesis of N-heteroaryl α-aminoacids (esters). They utilized Pd-PEPPSI-IPentCl- o-picoline 374 precatalyst for the N-heteroarylation of optically pure aminoacidesters in very high yield and excellent stereoretention. They used tert- butylaminoacidesters which are readily accessible substrates. They developed mild, robust and efficient method to synthesize N-heteroaryl α-aminoacidesters with high level of enantiopurity which can be easily converted to corresponding carboxylic acids (Scheme A.80).149
Theoretical Background | 62
Scheme A.80. N-heteroarylation of optically pure aminoacid sters tilizing Pd- PEPPSI-IPentCl-o-picoline precatalyst
N-Aryl-2-aminopyridine motifs presents a class of medicinally important compounds.150a-c The synthesis of these entities involving transition metal catalyzed cross coupling methodology establishing C-N bond utilizes halo-pyridines or amino- pyridines as one of the reaction counterparts. These types of catalytic reactions always encountered a problem of catalyst poisoning as these nuclei are able to form highly stable complexes with metal center. Organ’s Pd-PEPPSI amination protocol presented an elegent procedure to cross couple the amino pyridine derivatives to variety of aryl and heteroarylchlorides under mild conditions using NaBHT or carbonate base. Recently they effectively utilized Pd-PEPPSI-IPentCl 335 precatalyst to couple (hetero)-aryl chloride with both electon rich and poor amino pyridines to obtained N- aryl-2-aminopyridine moieties in good to excellent yields (Scheme A.81). The main reason of the success of the ligand is the steric bulk which effectively promotes reductive elimination as well as prevents the catalyst poisoning by avoiding the catalyst to go to resting state by the formation of aminopyridine-Pd coordination complex which inhibits precatalyst activation and make the catalyst cycle switched off.150
Theoretical Background | 63
Scheme A.81. Coupling of 2-aminopyridine derivatives to various aryl chlorides using Pd- PEPPSI-IPentCl precatalyst A.3.5. Mechanism for Pd-PEPPSI catalyzed Buchwald-Hartwig Amination
Mechanism for Buchwald-Hartwig amination methodology involving phosphine based ligands is thoroughly investigated.151 Generally the mechanism involved three major steps; oxidative addition, amine insertion/ deprotonation reductive elimination
The mechanistic cycle followed by amination process catalyzed by Pd-PEPPSI precatalyst is illustrated in Scheme A.82. The cycle is initiated with the activation of precatalyst in which the Pd-metal undergoes reduction to give active Pd-species (NHC-Pd (0), A), supported and stabilized by the NHC ligand attached. This Pd (0) species then entered into the catalytic cycle and under oxidative addition with aryl halide substrate, to Pd-(II) complex B. The nature of the primary supporting ligand plays a crucial role in determining which step in the cycle is rate limiting. The nature of ancillary ligand also determined the reactivity and mode of action of the reacting substrates. NHC-ligands provide more electron rich metal center than the phosphine based ligand because of the strong σ-electron donation. This fact leads to the feasible
Theoretical Background | 64
and smooth insertion of NHC-Pd through the Ar-X bond in oxidative addition step, leading to the formation of Pd-(II) intermediate B. The oxidative addition is not a rate limiting step as more electron rich catalyst system makes it more feasible and faster.
Scheme A.82. Mechanism for Pd-PEPPSI catalyzed amination
The most important challenge to metal catalyzed amination process is the intervening steps of amine coordination to the metal center and deprotonation by abstraction of the amine hydrogen. These two processes are usually treated togather. In this step of the catalytic cycle, amine is coordinated to the Pd-II intermediate (B) leading to the generation of tetra-coordinated Pd-(II) adduct (C). The ease of formation of this adduct as well as nature of this step, being slow or fast, depends upon the nature of amine substrate. The deprotonation of Pd-(II) intermediate C with a base (base-M) leads to anionic amido complex C which then loses MX to give tri-coordinate complex D or E depending upon the nature of amine. Finally reductive elimination process leads to targeted aryl-alkyl or diaryl amine with concomitant regeneration of the initial Pd (0) species (A).
Theoretical Background | 65
In case of primary and secondary alkyl amines involving aryl aminations, the amine coordination to the electrophilic Pd-(II) center is favorable owing to their slight more basic nature. But in deprotonation step the lower pKa value (in range of 8-10) of corresponding metal–ammonium complex masy pose a challenge. The deprotonation of the Pd-ammonium complex may become the rate-determining step (RDS), according to the reported kinetic studies (C in Scheme A.83).141,152 This step usually requires strong base such as KOtBu for completion.153 The choice of base is usually related with nature of oxidative addition partner (the electrophile) which become a transient ligand upon the Pd center affecting the lewis acidity of the Pd complex. Electron poor OA coupling partner lower the pKa of the Pd-ammonium adduct and therefore, improve the kinetics of the RDS. In case of aryl amination with anilines, the deprotonation is no longer rate limiting step but reductive elimination of the final product may become rate determining. This is according to the fact that aniline addition and deprotonation follow first order reaction kinetics as pKa of anilines relative to that of aliphatic amines is approximately decreased up to 10 logarithmic units. The deprotonation by carbonate base is rapid and less dependent on the electronic environment of the OA partner. The OA partner however has a role in the reductive elimination step. More electron deficient aryl derivatives increase the overall reaction kinetics as these kinds of arenes liable to reductive eliminate faster as compare to the electron rich systems. In case of amine counterpart, it is observed that more nucleophilic the amine, higher will be the rate of reductive elimination. This is because of the fact that electron rich amines have better reducing power assisting the overall electronics of the system. This fact places less incentive on ligand sterics i.e Pd-PEPPSI-IPr 333 system adequately give amination with electron rich amine i.e alkyl amine as well as electron donating substituted anilines. In turn, electron deficient aniline possessing not enough basicity for the reduction of Pd-(II), the catalyst must play its role accommodating this shortcoming through its steric factors. Hence the Pd-PEPPSI-IPentCl 336 ligand is superior to the IPr/IPent ligand in the coupling of electron-deficient anilines. 144,147,154
Theoretical Background | 66
A.4. Introduction to Heterocycles
Nature abounds in heterocyclic compounds as many of them found in biological system with profound importance. Some of the major ingredients of life like vitamins, porphyrins (hemoglobin), coenzymes, DNA, and RNA are based upon the heterocyclic rings. Complex heterocyclic compounds constituted classes of medically important moieties such as antibiotics,155a anticancers,155b antitumor155c and anti HIV155d etc. As a consequence the development of new versatile and efficient strategies for the construction of heterocycles has always been one of the main focuses of synthetic community in chemical research.155e
The second half of the twentieth century brought about major breakthrough in organic synthesis.155-156 Wide array of novel transformations are investigated with the help of transition metal catalysis along with concomitant improvement in the classical reaction methodologies. The application of transition metal catalysis in heterocyclic synthesis became valuable and widely accepted tool that immensely broadened the scope of transformations.156a Transition metal catalysis provides efficient and modern synthetic procedures for the syntheses of well established classes of heterocycles. Most important impact of this area of research is the development of diversity oriented elementary reactions to generate reactive functionalities leading to the formation of new complex heterocyclic scaffolds in economically sustainable and environmentally benign fashion.157 Recognition of the significance of transition metal catalysis lead to the opening of new pathways enabling the facile synthesis of compounds with great molecular complexity. It also makes possible the improvement in the selectivities of classical reactions and in some cases leads to its complete reversal in step and atom economical fashion, even on the industrial level.158
The applications of transition metal catalyzed reactions in the chemistry of heterocyclic compounds have two different aspects. One of them related to the synthesis of the heterocyclic backbone itself, while in the other aspect of this application, the heterocyclic fragment is utilized as one of the reaction components. Both reaction groups are equally important for the chemistry of heterocyclic compounds.159 The aforementioned transition metal catalyzed strategies for the
Theoretical Background | 67 heterocyclic synthesis and functionalization are the examples of the second group of reactions. This section comprises the introductory discussion upon the heterocycles frequently mentioned in the upcoming sections.
A.4.1. Pyridazinone (1,2-Diazinones)
Pyridazin-3(2H)-one derivatives 412 belong to 1,2-diazinone class of heterocycles, representing an important and active class of compounds possessing a wide spectrum of pharmacological activities.160 They constitute a large class of pharmacophores having a vast array of biological and physiological relevance as drug candidates such as anti-asthmatic agents,161 HCV inhibitors,162a-c anti-diabetics,163a,b gamma secretase modulators,164a,b anti-cancer,165a,b anti-hypertensive,166a,b and with antinoceceptive167 activities.
Figure A.12. Bioactive molecules with N-allyl pyridazinone core
They have attracted considerable attention due to their immense pharmacological importance. Substituted pyridazinones are utilized for the synthesis of several potentially useful drugs in recent years. Several studies upon structure-activity relationship have indicated that the free NH group adjacent to the carbonyl moiety in diazine system may present an essential site of binding for variety of biological receptors.168
Theoretical Background | 68
N-Substituted pyridazinone is usually prepared by condensation of substituted hydrazines with diacids,169a,b or by treating pyridazinones with alkyl or aryl halides.170a,b Asymmetric variants are synthesized by displacement reactions of pyridazinones using chiral moieties.171a,b Example of the synthesis of substituted pyridazinone derivatives is the Friedel–Craft acylation of aromatic hydrocarbon with succinic anhydride. β-Substituted benzoylpropionic acid 419 initially undergoes Lewis acid catalyzed reaction which upon reaction with hydrazine leads to desired pyridazinone derivatives 420 (Scheme A.83).172
Scheme A.83. Synthesis of Pyridazinone derivatives
Pyridazinone 412 exists in two possible tautomeric forms depending upon the relative free energies. DFT calculations showed that the most stable tautomer is the 2H- pyridazin-3-one 412, the keto form which is 6.975-12.689 kcal/mol more stable than the hydroxy tautomer.173 The tautomerization of the simplest pyridazinone 421 into pyridazol 422 has been theoretically studied using DFT methods at the B3LYP/6- 311++G** level.174
Figure A.13. Tautomeric Equilibrium in Pyridazinone
Tautomerization of pyridazinone 421 into pyridazol 422 is an endothermic process. Although from the structural features pyridazol 422 should be more stable than the pyridazinone 412 tautomer due to its expected high aromatic character. In order to
Theoretical Background | 69 explain the relative stability of these two tautomers other factors, besides aromaticity, should be taken into consideration. In pyridazinone 412 skeleton a stabilizing carbonyl functional group is present, responsible for its higher stability. The steric repulsion between the two lone pairs on the adjacent nitrogen atom is also a destabilizing factor in pyridazole 422. Based on these factors it is clear that pyridazole 422 tautomer is less stable than the pyridazinone 421 despite of its higher aromatic character.174
Pyridazinones are utilized in variety of synthetic procedures for the synthesis of bioactive molecules.160 2,4,5-Trisubstituted-3(2H)-pyridazinones are well-known compounds in agrochemical industry and pharmaceutical research.175 These moieties are synthesized by suzuki cross coupling methodology using chloropyridazinones (Scheme A.84).175a
Scheme A.84. Derivatization of substituted pyridazinones
A.4.2. Azlactone
Oxazolones or azlactones 426 are heterocyclic compounds that contain a nitrogen atom in the β-position of ester functionality. They are commonly observed in the well known butenolide structures176a presenting dual nature having both nucleophilic and electrophilic reactive sites. The versatility of oxazolone chemistry is associated with three nucleophilic and one electrophilic site making its chemical behaviour more interesting.176b
The presence of acidic hydrogen (pKa ~ 9) makes azlactone chemistry more versatile. The enol tautomer has aromatic character that can react with various electrophiles (Figure A.14).177 Its resonance structures show that the reaction condition can direct
Theoretical Background | 70
the electrophile either toward α-carbonyl (C-4) or aminal (C-2) positions. In these situations at least one stereogenic center can be generated. The presence of electrophile sites enable azlactone to involve in the reaction with nucleophiles. The aminal (C-2) position proved to be very reactive in reactions with electrophilices.175
Figure A.14. Representation of structural features and tautomerism in Azlactone
Azlactones can be easily prepared from readily available amino acids. The process involved the amidation of amino acid in the presence of acyl chloride followed by intramolecular cyclization. In some cases one-pot procedure can be adopted (Scheme A.85).178
Scheme A.85. Azlactone formation from N-, O-acylation of α-amino acid with subsequent cyclization
The particular reactivity of azlactone is responsible for its popularity among various research groups especially those involved in the development of catalytic synthetic methodologies.179 Azlactone provide a valuable synthetic tool for the preparation of more complex amino acid derivatives in enantiomerically pure form by simple dynamic kinetic resolution (Scheme A.86).180
Theoretical Background | 71
Scheme A.86. Synthesis of enantiomerically pure amino acid by dynamic kinetic resolution using DEMAP derivatives
In addition to this, the oxazolone scaffold 441 has also been investigated for stereocontrolled construction of quaternary stereocenters. These are particularly utilized in the preparation of challenging quaternary amino acid derivatives 442 (Scheme A.87).181
Scheme A.87. Quaternary amino acid from catalytic asymmetric synthesis of azlactones
Highly substituted oxazoles can be synthesized from oxazolones derivatives. The protocol consists of one-pot Friedel–Crafts/Robinson–Gabriel synthesis to produce 2,4,5-trisubstituted oxazoles 445 (Scheme A.88).182
Theoretical Background | 72
Scheme A.88. Oxazole synthesis utilizing azlactone via Friedel–Crafts/Robinson– Gabriel reaction
Pyrrole and imidazole scaffolds can be generated from 1,3-dipolar cycloadditions of oxazolones. These processes occur when oxazolone is in its dipole form called “münchnone” 446, 449 wherein it undergoes reaction with dipolarophiles such as alkynes and nitriles to yield pyrrole 448 and imidazole 450 respectively (Scheme A.89).183
Scheme A.89. Synthesis of Pyrrole and Imidazole utilizing oxazolones
It is demonstrated that oxazolone is an important class of compounds, containing numerous reactive sites which allow diverse range of transformations. Further utilization of rich chemistry of the oxazolones can undoubtedly lead to the synthesis of novel biologically active compounds and can open up a way for new pharmaceutical applications.
Theoretical Background | 73
A.4.3. Thiazoles
Thiazole or 1,3-thiazole is an important heterocycle and among the most intensively investigated class of five-membered aromatic heterocycles. The 1,3-thiazolium ring is present in thiamine 451 (vitamin B1), in various derivatives of penicillins 452 as well as in many other natural products.184 Therefore thiazole plays a prominent role in biological processes.185
Figure A.15. Thiazole derivatives found in nature
Large numbers of thiazole derivatives have been investigated as active pharmaceutical ingredients in several drugs, for their medicinal potentials. They constitute a broad category of antibiotics,186 anti-tumour,187 anti-inflammatory,188 anti-hypertensive,189 anti-hyperlipidemic,190a and several other biologically important motifs.190b-l Besides these, thiazoles are also useful synthetic intermediates and common substructures in numerous bioactive compounds.191a-i Thus, this family of heterocycles has been widely studied and utilized in the field of organic and medicinal chemistry.192a-k
Thiazole is one of the top five aromatic heterocycles which are basic core of 9% of the total number of U.S. FDA approved small drug molecules.193a This class of small drug molecules includes thiazole, indole, imidazole, tetrazole, and benzimidazole.193b In the analysis of the structures of unique FDA approved drugs, thiazole is one of the most frequently found heterocycles among these five-membered aromatic nitrogen heterocycles. It is widely used functional group constituting a large class of β-lactam antibiotics. About 67% of all thiazole containing pharmaceuticals belong to this important class.193 Some examples of marketed drug with thiazole core are depicted in Figure A.16.
Theoretical Background | 74
Figure A. 16. Commercially available Thiazole based drugs
Thiazole ring structure is found in several commercially available drugs due to its pharmacological activities.193 Therefore it occupies a prominent position in the process of drug discovery. It is also used in the optimization process for probing the structure- activity relationship. As a result, thiazoles moieties are frequently included in designing new chemical strategies for methodology development as well synthesis of bioactive molecules. This is also used as a core structure for the synthesis of libraries of diverse rang of novel organic compounds.194 Thus thiazole is one of the most frequently investigated nuclei in the field of organic and medicinal chemistry.195
Task | 75
B. Task
B.1. Regio- and Enantioselective Pyridazinones (1,2-Diazinones) Addition to Terminal Allenes and Evaluation of Follow Up Reactions Involving Final Product
Transition metal catalyzed hydroamination is one of the powerful methodology, as variety of nitrogen nucleophiles are available, that can be used as pronucleophile in regio and enantioselective rhodium catalyzed synthesis of allylic derivatives. Therefore in context of this doctoral dissertation, the potential of hydroamination strategy involving terminal allene 196 was investigated, keeping in mind the chemo, regio, and enantioselective rhodium catalyzed addition of pyridazinones 412 to terminal allenes, leading to the formation of N-allylated heterocycles 458, 460 (Scheme B.1).
Scheme B.1. Possible N- or O-selectivity for the rhodium catalyzed pyridazinone addition to terminal allenes
As pyridazinone having two reaction centers, can serves as N as well as O- nucleophile, the final product will be identified for isomerism and then the investigations upon the rhodium catalyzed addition to terminal allene for regio and enantioselective synthesis of N-allylated pyridazinone will be carried out. For this purpose various ligands will be screen as well as optimizations of reaction conditions will be carried out to obtain the desired product in excellent yield with high regio and enatiocontrol.
Moreover, the utilization of the resultant allylic moiety will be evaluated by follow up transformations, in which the final N-allylated pyridazinones will be treated with
Task | 76
various reagents to selectively convert into functionalized building blocks and to synthesize a small library of N-allyl diazinone heterocycles.
Scheme B.2. Follow up chemistry involving possible regioisomer: Synthesis of N- functionalized pyridazinones
B.2. Rhodium-Catalyzed Regioselective Addition of Azlactone to Internal Alkyne and its Utilization for Heterocyclic Synthesis
Rhodium catalyzed strategy for hydrocarbonation reactions, investigated by Breit et al., involving regio and/or enantioselective addition to allene and alkyne, leading to the allylic carbon-carbon bond formation. We aimed to extend the scope of Breit-type hydrocarbonation by coupling azlactone as carbon nucleophile with internal alkyne utilizing rhodium catalysis conditions.
Rhodium catalyzed regioselective addition of azlactones to internal alkynes will be investigated, in which we expect various fruitful results, as the possibility of two regioisomers formation may lead to domino type reaction. The regioisomeric ratio in the final product will be evaluated as well as the onward rearrangement possible in the C-4 branched product 464, making a favorable system for [3,3] sigmatropic rearrangement (aza-Cope rearrangement) and the final product will be confirm whether it is C-4 allylated product (4-allyl-2-oxazolin-5-one 465) or the C-2 rearranged product (2-allyl-3-oxazolin-5-one 466) (Scheme B.3).
Task | 77
Scheme B.3. Possible regioselectivity and rearrangement in Rh-catalyzed azlactone alkyne coupling
As azlactone are synthesize from amino acid precursors, so the idea of in situ generation of azlactone by utilizing amino acids as starting material will be evaluated (Scheme B.4).
Scheme B.4 Evaluation of an idea of in situ generation of azlactone
For this purpose, a suitable ligand was to evaluate by ligand screening as well as the optimized reaction conditions by optimization process which can lead to install more C-4 branched regioselectivity, so the rearranged product.
The resulting C-2 allylated azlactone, an N, O-acetal, could of great interest, therefore the follow up chemistry involving the final product will also be studied in this dissertation. Furthermore, a sequential methodology for the final synthesized heterocycles will be developed as starting from amino acid precursor leading to set up a cascade type sequence (Scheme B.5).
Task | 78
Scheme B.5. Heterocyclic synthesis: follow up chemistry invovling expected rearranged product B.3. Pd-PEPPSI Mediated Cross Coupling Methodology for the Synthesis of Aryl/Alkyl-Heteroaryl Amine Derivatives of Substituted Thiazoles and Oxazoles
Owing to the widespread presence of arylated amines in pharmaceuticals, natural products, organic materials, process chemistry, and catalysts designing and preparations, carbon-nitrogen bond forming cross coupling reactions, catalyzed by transition metal complexes constitute exceptionally broad and classical research area of organic chemistry. Due to immense importance of aryl amination, we will investigatd upon the synthesis of aryl-heteroaryl amines by utilizing Pd-PEPPSI catalyzed amination protocol, pioneered by M. G. Organ as one of the powerful research methodologies and quantifying protocols for the cross couplings of most challenging substrates. We will utilize this protocol for aryl-alkyl and biaryl amine derivatives of azole family of biologically active precursors like thiazole and oxazole.
Scheme B.6. Pd-PEPPSI catalyzed synthesis of thiazole/oxazole substituted biaryl amine derivatives
Task | 79
For this purpose, Pd-ligand catalyst system will be investigated initially for the alkyl amine coupling with azole substrate, with an idea of in situ generation of active catalyst using Pd-salt as metal source along with mono and bidentate phosphine ligand. The Pd-precatalyst (PEPPSI series) will be evaluated for their potential in the respective amination using alkyl amine as well as aryl amines. Reactions conditions will also be investigated by optimization process to obtain optimized reaction conditions. These optimized conditions will be utilized for both of the azole substrates i.e thiazole and oxazoles to synthesize the desired thiazole/oxazole amines respectively.
Results and Discussion | 80
C. Results and Discussion Section A C.1. Regio- and Enantioselective Pyridazinones Addition to Terminal Allenes toward Regio- and Enantioselective N-allylic Pyridazinones
C.1.1. Regio- and Enantioselective Pyridazinones Addition to Terminal Allenes
The current rhodium catalyzed allylation chemistry deals with the stereoselective N- allylation of nitrogen heterocycle pyridazinone (1,2-diazinone) via hydroamination of terminal allene. N-Allylation of pyridazinone is identical to previously described N/O allylation of pyridone.96f Pyridone allylation involves N vs. O selectivity, normally depends on solvents, bases, substrates, and additives.196 Rhodium catalysis promotes regioselective allylation of pyridone leading to the formation of major N-allyl regioisomer by the selection of appropriate ligand. We designed to study allylation of pyridazinone which is isoelectronic to 2-pyridones. ‐Chiral N-alkylated pyridazinone derivatives usually synthesized by the N-alkylation of diazinone nuclei with chiral electrophiles under basic conditions.197 These methods suffers lack of atom economy requiring multiple steps and leading to generate stoichiometric amount of waste. The requirements of chiral electrophiles further increase the structural limitations of the process. The direct enantioselective functionalization of pyridazinone to synthesize chiral N-substituted moieties from achiral starting material with the aid of chiral catalyst is still very rare.198
Herein we report the enantioselective synthesis of N-substituted pyridazinone utilizing rhodium catalyzed chemo-, regio-, and enantioselective addition of pyridazinone to terminal allenes furnishing chiral N-allylated pyridazinone in step and atom economical way (Scheme C.1).
Initial experimentation involving rhodium catalyzed addition of pyridazinone 471 to 3-phenylpropylallene 472 was conducted. The desired reaction occurred in the
presence of [{Rh(cod)Cl}2] (2.5 mol %) and DPPB (diphenylphosphinobutane 77) (5.0 mmol%) in 1,2-dichloroethane (DCE) at 80 °C for 24 h resulting in 100%
Results and Discussion | 81 conversion. The reaction leads to the expected regioselective product 473 or 474 in 92% yield with 9:1 branched and linear ratio (Scheme C.1). However as in previous investigation the expected product was supposed to be a mixture of both N and O allylation products96f.
Scheme C.1. Initial experiment for the rhodium-catalyzed diazinone addition to terminal allene
C.1.1.1. Regioselectivity
The rhodium catalyzed N-allylation of pyridazinone was expected to occur with the formation of both N and O allylated product. The reason behind the fact is the close resemblance of this skeleton with the previously investigated pyridone nucleus having two nucleophilic sites. The reactivity of this heterocyclic moiety depends upon the tautomerism shown in Figure C.1. It is established that the keto form is more stable as compare to the enol form. The stability of keto form 421 of the pyridazinone makes it more nucleophilic from nitrogen position. This observation shows that the rhodium catalyzed hydroamination of allene with pyridazinone will give the N-allylation product.
Figure C.1. Tautomerism in pyridazinone (1,2-diazinone)
Results and Discussion | 82
Furthermore, the N-selectivity in pyridazinone allylation came from 13C-NMR of the final allylation product. In pyridone allylation, these two products were identified using 13C-NMR shifts at δ 75.8 and 56.2 ppm, respectively for O and N product,96f while in this case a single N product was identified from 13C-NMR shift at δ 60.4 ppm (Figure C.2)
Figure C.2. 13C-NMR shift comparison for N/O selectivity
These observations showed the N-selectivity of pyridazinone, confirming the expected reactivity and behavior of diazine type nuclei in rhodium catalyzed allylation which lead to the formation of N1-allylated heterocyclic moieties (Scheme C.2).
Scheme C.2. Rhodium catalyzed regioselective N-allylation of pyridazinone
C.1.1.2. Optimization of the Reaction Conditions
The initial optimization of reaction conditions of the ligands screening was performed with achiral ligands (Table C.1). This indicated that using rac-BINAP 281 as ligand instead of DPPB 72 led to far better isolated yield of 92% along with branched to linear (b:l) ratio (Table C.1; entry 4).
Results and Discussion | 83
Table C.1. Achiral ligands screening
Entry Ligand B:L Yield (%)a 1 DPPB 72 5:1 76 2 DPPP 227 9:1 35
3 (Cy)2P(CH2)4P(Cy)2 477 2:1 46 4 rac-BINAP 281 9:1 97
Reaction conditions: 6-Chloropyridazin-2(1H)-one 471 (0.20 mmol), 3-phenylpropylallene 472
(0.30 mmol), [{Rh(cod)Cl}2] (2.5 mol%), rac-BINAP 281 (5 mol%), DCE (0.4 M), 80 °C, 18 h; [a] isolated yield.
In order to prove the combined involvement of rhodium precursor and ligand in the catalytic activity of our system, control experiments were performed. It proved both metal catalyst and ligand were necessary for the process to occur. Absences of either metal source or the ligand led to the complete inhibition of the reaction (Table C.2; entries 2 and 3).
Table C.2. Control experiments
Entry Catalyst Ligand Yield (%)a
1 [{Rh(cod)Cl}2] rac-BINAP 281 92 2 - rac-BINAP 281 0
3 [{Rh(cod)Cl}2] - 0
Results and Discussion | 84
Reaction conditions: 6-Chloropyridazin-2(1H)-one 471 (0.20 mmol), 3-phenylpropylallene
472 (0.30 mmol), [{Rh(cod)Cl}2] (2.5 mol%), rac-BINAP (210) (5 mol%), DCE (0.4 M), 80 °C, 18 h; [a]: isolated yield.
Based upon the successful investigation on the racemic version of the catalytic process, the chiral version of the reaction was directly investigated. Therefore, rhodium catalyzed process was carried out using many different chiral ligands, utilizing the same initial conditions i.e. DCE as solvent at 80 °C for 18 h (Table C.3). A variety of ligands were used that differ by their structural properties like electronic and steric nature (Figure C.3).
Table C.3. Screening of Chiral ligand under standard reaction conditions
B:L Yield Entry Ligand ee (%)b (%)a 1 (R,R)-DIOP 259 4:1 91 30 2 (R,R)-MeO-Diop 478 5:1 92 33 3 (S)-Segphos 23 2:1 45 46 4 (S)-DM-Segphos 480 9:1 78 72 5 (S)-DTBM-Segphos 237 17:1 82 75 6 (R)-Difluorphos 274 15:1 87 40 7 (R)-BINAP 20 10:1 92 64 8 (R)-dm-BINAP 481 5:1 98 64 9 (R)-DTBM-BINAP 482 12:1 98 69 10 (S)-MeOBiphep 483 15:1 79 41 11 (R)-3,4,5-OMe-MeOBiphep 484 15:1 79 44 12 (R)-DTBM-MeOBiphep 248 9:1 77 82
Results and Discussion | 85
13 (S)-3,5-iPr-4-NMe2-MeOBiphep 485 19:1 96 89 14 (S,S)-Chiraphos 24 3:1 30 rac 15 (R,R)-Methylferrocelane 487 10:1 82 10 16 (R)-Quinox P 22 - n.r - 17 Josiphos SL-J003-1 232 2:1 44 32 18 Josiphos SL-J007-1 487 2:1 32 18 19 Mandyphos SL-M002-1 488 - n.r - 20 Walphos SL-W003-1 489 - 9 n.d Reaction conditions: 6-Chloropyridazin-2(1H)-one 471 (0.20 mmol), 3-phenylpropylallene 472
(0.30 mmol), [{Rh(cod)Cl}2] (2.5 mol%), ligand (5 mol%), DCE (0.4 M), 80 °C, 18 h; [a]: isolated yield; [b]: determined by chiral HPLC; nd: not determined.
The investigations based on chiral ligand screenings showed that many ligands with versatile backbones were active in this process. Most of the ligands led to selective formation of desired chiral branched N-allylic product 386 in acceptable to high yields with moderate to excellent branched to linear regioselectivities. However, some ligands like (S,S)-chiraphos 24 (entry 14), (R,R)-methylferrocelane 487 (entry 15), (R)-quinox P (22) (entry 16), and especially the Josiphos ligands (232 and 487, entries 17 and 18 ) and other related ligand families showed poor results regarding both the yield and enantiomeric excess (entries 19 to 20).
Better results were obtained with ligands families having biphenyl backbone. The biphenyl derivatized ligands family such as (S)-segphos (23) (entry 3), (S)-DM- segphos 480 (entry 4), (S)-DTBM-segphos 237 (entry 5), and (R)-difluorphos 274 (entry 6) show slight increase in yield, b:l ratio and ee values. The excellent yield with good enantioselectivity of 75% observed with (S)-DTBM-segphos 237 (entry 5) and displayed promising results. This is due to the fact that, by increasing the steric bulk of aryl substituents on phosphine moiety of the segphos skeleton an increasing trend in enantioselectivities was observed in going from (S)-segphos 23 to (S)-DTBM- Segphos 237 ( entries 3 to 5) i.e. Ph < DM < DTBM led to progressive improvement in enantioselectivities (46% ee < 72% ee < 75% ee).
Results and Discussion | 86
Figure C.3. Chiral ligands utilized in present synthetic methodology
The experiment using (R)-difluorphos 274 (entry 6) appeared to be an exceptional, leading to high level conversion but poor enantiomeric excess that may be attributed to the electronic effects of the F-substituted biphenyl backbone. Structure selectivity trend was also observed within the BINAP family of ligands (entries 7 to 9) showing that the increasing trend in the yield and enantioselectivities is linear with the electronic and steric environment of the ligands (64%-69%).
The MeOBiphep family of ligands (entries 10 to 13) has followed a similar reactivity trend. (S)-MeOBiphep 483 and (R)-3,4,5-MeO-MeOBiphep 484 (entries 10 and 11) led to similar yield and selectivities. Going to less electron rich and more bulkier ligand (R)-DTBM-MeOBiphep 248 (entry 12) decrease in yield with sharp increase in enantioselectivity (77% yield, 82% ee) was observed.
Results and Discussion | 87
The catalytic behavior of ligand (S)-3,5-iPr-4-NMe2-MeOBiphep 485 was proved to be more pronounced in the current reaction. A sharp increase in yield along with regio- and enantioselectivities (entry 13) indicated that ligand 485 provides an optimum combination of electronic and steric factors necessary for successful asymmetric N-allylation of pyidazinones. This ligand showed the best combination of yield (96%), enantioselectivity (89%) and b:l ratio (19:1). From the catalyst screening it can be inferred that the bite angle has no direct correlation to the selectivity since no real trend was found in accord with the difference in the ligand’s bite angle.
The ligand screening led us to the conclusion that biphenyl backbone in combination with the bis-di-tert-butyl-methoxy and bis-3,5-iso-propyl-4-dimethylamino-methoxy substituted phosphine moieties were required to obtain good yield and enantioselectivities. The most efficient ligand for rhodium catalyzed pyridazinone addition to terminal allenes was proved to be (S)-3,5-iPr-4-NMe2-MeOBiphep 485 with overall yield of 96% and enantioselectivity of 89%. Therefore this ligand is used for the rest of the optimization of the reactions conditions.
With the best ligands in hands and despite the already high enantioselectivity of 89%, there was still a room for improvement. Therefore, further conditions optimizations were carried out. At first, the rhodium sources were considered (Table C.4).
Table C.4. Rhodium sources screening under standard conditions
Entry Rhodium Catalyst Yield (%)a B:Lc ee (%)b
1 [{Rh(cod)Cl}2] 96 19:1 89
2 [Rh(cod)Br]2 98 19:1 87
3 [Rh(cod)I]2 98 >20:1 86 4 [Rh(cod)acac] 90 12:1 80
Results and Discussion | 88
5 [Rh(cod)AcO]2 98 6:1 75
6 [Rh(cod)(OH)]2 98 5:1 75
7 [Rh(cod)2]BF4 26 6:1 44
8 [Ir(cod)Cl]2 0 - - 3 9 [Pd(η -allyl)Cl]2 0 - -
Reaction conditions: 6-Chloro-(2H)-pyridazin-3-one 471 (0.20 mmol), 3-phenylpropylallene
472 (0.30 mmol), catalyst (2.5 mol%), (S)-3,5-iPr-4-NMe2-MeOBiphep 485 (5 mol%), DCE (0.4 M), 80 °C, 18 h; [a]: isolated yield; [b]: determined by chiral HPLC; [c]: 1H NMR of crude. Variation of the metal going from rhodium (entry 1) to iridium (entry 8) or palladium (entry 9) showed that only rhodium metal led to the desired N-allylic product 473. The influence of the associated counter anion in the rhodium dimer sources was then explored (entries 1 to 4) using various rhodium sources. The nature of counter-anion could affect the rate of monomerization of rhodium dimer. It is also possible that these counter ions can influence the outer sphere of the catalytic active species, altering the reactivity of various rhodium sources. Experimental results showed that variations of the halide ions of the [Rh(cod)(halide)]2 complex has a small effect on the overall reaction. In going from chlorine to iodine (entries 1-3), there is a slight increase in the yield but with gradual decrease in and enantioselectivity (89% > 87% > 86%). Other anionic counter ions such as acetate (OAc) and hydroxide (OH) also led to a significant drop in selectivity and slight increase in the yield (entries 5 and 6).
Variation in the nature of the rhodium catalyst i.e. in going form dimeric
[{Rh(cod)Cl}2] to monomeric catalyst [Rh(cod)acac] (entry 4) led to lowers the yield as well as a slight drop in enantioselectivity. On the other hand cationic rhodium sources such as [Rh(cod)2]BF4 did not lead to any improvement in the catalytic activity (entry 7).
All these optimization involving variation in the rhodium sources did not generate any significant improvement in the previous results, therefore the best catalyst system for this rhodium catalyzed allylation reaction remained the initial [{Rh(cod)Cl}2] catalyst leading to 96% yield with 89% enantiomeric excess.
Results and Discussion | 89
Regarding the improvement in reaction conditions system, in order to improve the enantioselectivity, solvent variations were investigated (Table C.5).
Table C.5. Solvent screening under standard reaction conditions
Entry Solvent Yield (%)a B:Lc ee (%)b
1 DCE 96 19:1 89
2 DCM 89 >20:1 86
5 DCE:EtOH (1:1) 9%c - -
6 DCE:EtOH (1:2) 8%c - -
7 DCE:EtOH (1:1)e 11 - 57
8 DCE:EtOH (1:2) e 10 - 51
9 DCE:EtOH (9:1) e 24 - 50
10 THF 67 19:1 54
11 Toluene 83 15:1 53
Reaction conditions: 6-Chloro-(2H)-pyridazin-3-one 471 (0.20 mmol), 3-phenylpropylallene
472 (0.30 mmol), [{Rh(cod)Cl}2] (2.5 mol%), (S)-3,5-iPr-4-NMe2-MeOBiphep 485 (5 mol%), DCE (0.4 M), 80 °C, 18 h; [a] isolated yield; [b]: determined by chiral HPLC; [c] 1H NMR (crude); [d] 1H NMR conversion; [e] 70 °C. Optimizing the reaction solvent, it is observed that the chlorinated solvents such as 1,2-dichloroethane (DCE) was one of the best solvent for the reaction (entry 1). Moving to dichloromethane (DCM) slight drop in the reaction yield and enantioselectivity was observes. Increasing the polarity of the solvent system usinga mixture of DCE/EtOH, previously used in the rhodium catalyzed anilines addition to allenes,95 led to decrease in both yield and enantioselectivities. Other type of organic solvents such as THF or toluene led to moderate to good yield and acceptable
Results and Discussion | 90 enantioselectivity (entries 10 and 11 respectively). The results of solvent optimization would suggest that the solvent polarity may play an important role by affecting the reactivity of reacting substances and especially affect the stability of the catalytic active species which are formed during the catalytic cycle and responsible for the catalysis.
Temperature is also an important parameter for optimizing the enantioselectivity, therefore it was investigated next (Table C.6). Increase in enantioselectivity could be expected by decreasing temperature, so that it may lead to some improvement in the results.
Table C.6. Temperature screening under standard reaction conditions
Entry T (°C) Yield (%)a B:Lc ee (%)b 1 80 96 19:1 89 2 70 90 >20:1 89 3 60 47 20:1 86 4 50 28 >20:1 85 5 40 18% conv.c - n.d 6 rt (25) 0 - -
Reaction conditions: 6-Chloro-(2H)-pyridazin-3-one 471 (0.20 mmol), 3-phenylpropylallene 472
(0.30 mmol), [{Rh(cod)Cl}2] (2.5 mol%), (S)-3,5-iPr-4-NMe2-MeOBiphep 485 (5 mol%), DCE (0.4 M), T °C, 18 h; [a] isolated yield; [b] determined by chiral HPLC; [c] 1H NMR (crude).
Reaction at 70 °C showed slight decrease in the yield (90%) but the enantioselectivity remain the same (entry 2). Further decrease in temperature led to a significant drop in the yield (entries 3 and 4) until the complete shutdown of the reaction at 40 °C (18% conversion) while at room temperature, there was no reaction observed at all (entries 5
Results and Discussion | 91 and 6). The temperature screening did not lead to the expected improvements in the results and thus we moved on to the next parameter. Concentration of the reaction can also play an important role regarding the conversion as well as the enantioselectivity and was investigated next (Table C. 7).
Table.C.7. Concentration screening under standard reaction conditions
Entry x (M) Yield (%)a B:Lc ee (%)b 1 0.1 89 >20:1 84 2 0.2 96 20:1 89 3 0.4 96 19:1 89 4 0.6 95 14:1 89 5 1.0 87 >20:1 79
Reaction conditions: 6-Chloro-(2H)-pyridazin-3-one 471 (0.20 mmol), 3-phenylpropylallene
472 (0.30 mmol), [{Rh(cod)Cl}2] (2.5 mol%), (S)-3,5-iPr-4-NMe2-MeOBiphep 485 (5 mol%), DCE (x M), 80 °C, 18 h; [a] isolated yield; [b] determined by chiral HPLC; [c] 1H NMR (crude).
The concentration optimization results are very interesting. For concentration range between 0.2 and 0.6 M (entries 2 and 4) the reaction led to the same enantioselectivities. The standard reaction concentration (0.4 M) leading to 96% yield and 89% enantioselectivity. A decrease (entry1) or increase (entry 5) in concentration led to decreased in yield as well as enantioselectivity, but the b:l ratio increased significantly. Thus the optimal concentration for this transformation is 0.4 M (entry 3). Concentration screening did not lead to any improvements in the results. We look into the next parameter, the substrates ratio, to see its effect on the reaction selectivities (Table C.8).
Results and Discussion | 92
Table C.8. Screening of substrates ratio under standard reaction conditions
Entry x (equiv.) Yield (%)a B:Lc ee (%)b 1 1.3 90 16:1 87 2 1.5 96 19:1 89 3 2.0 98 20:1 89
Reaction conditions: 6-Chloro-(2H)-pyridazin-3-one 471 (0.20 mmol, 1 equiv.), 3-phenylpropylallene
472 (x mmol, x equiv.), [{Rh(cod)Cl}2] (2.5 mol%), (S)-3,5-iPr-4-NMe2-MeOBiphep 485 (5 mol%), DCE (0.4 M), 80 °C, 18 h; [a] isolated yield; [b] determined by chiral HPLC; [c] 1H NMR (crude).
In the original experiment 1.5 equivalents of allene was used which led to 96% yield and 89 % enantiomeric excess with 19:1 b:l ratio. Reducing the equivalents of allene led to a decrease in yield as well as in selectivities (entry 1), therefore excess of pyridazinone was not investigated. On contrary, an increase in the equivalents of allene was investigated that lead to slight increase in yield and regioselectivity but no significant improvement in the enantioselectivity was observed (entry 3).
From the above reaction conditions optimizations we reached to the best conditions for the reaction in term of rhodium sources, ligand, solvent, temperature, concentration and substrates ratio. The last parameter investigated was the catalyst loading and the catalyst:ligand ratio (Table C.9).
Table C.9. Screening of catalyst loading and ratio of the catalyst: ligand under standard reaction conditions.
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x y Ratio (x:y) Yield B:Lc Entry ee (%)b (mol%) (mol%) (%)a 1 1.25 10 1:4 99 >20:1 82 2 1.25 7.5 1:3 99 9:1 86 3 2.5 10 1:2 99 10:1 89 4 2.5 5.0 1:1 96 19:1 89 5 5 10 1:1 99 >20:1 88
Reaction conditions: 6-Chloro-(2H)-pyridazin-3-one 471 (0.20 mmol), 3-phenylpropylallene 472 (0.30 mmol), [{Rh(cod)Cl}2] (x mol%), (S)-3,5-iPr-4-NMe2-MeOBiphep 485 (y mol%), DCE (0.4 M), 80 °C, 18 h; [a] isolated yield; [b] determined by chiral HPLC; [c] 1H NMR (crude).
Optimization involving variation of the catalyst: ligand ratio indicated that increasing the ratio (entries 1-3) led to increase in the yield and regioselectivity but lower the enantioselectivity as compared to the ratio of 1:1 initially used which gave an excellent combination of yield and selectivities (entry 4). Increasing the loading of the catalyst system for 1:1 ratio (entry 5) showed an increase in yield and regioselectivity but a slight drop in enantiomeric excess. From the overall catalyst loading/ratio optimization an increasing trend was observed only in the yield and regioselectivity of the reaction with increase in catalyst: ligand ratio (entries 1 to 3) as well as in the loading of the catalyst system (entry 5).
After screening various possibilities of catalyst loading and ratio, there was no improvement in the enantioselectivity. Thus we consider the standard catalyst: ligand ratio (1:1) as an optimized and moved further to the additive screening (Table C.10).
Table C.10. Additives Screening
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Reaction conditions: 6-Chloro-(2H)-pyridazin-3-one 471 (0.20 mmol), 3-phenylpropylallene 472)
(0.30 mmol), [{Rh(cod)Cl}2] (2.5 mol%), (S)-3,5-iPr-4-NMe2-MeOBiphep 485 (5.0 mol%), Additives (10 mol%), DCE (0.4 M), 80 °C, 18 h; [a] isolated yield; [b] determined by chiral HPLC; [c] 1H NMR (crude).
The effects of base additive was investigated first due to the critical involvement of
Cs2CO3 in the previously investigated rhodium chemistry of benzoic acids with
Results and Discussion | 95
89 terminal allenes. Unfortunately both inorganic (Cs2CO3; entry 2) as well as organic bases (Et3N; entry 3) led to a significant decrease in the results. Acid additives were also screened (entries 5-9) but no improvement was observed. Organic salts like pyridinium-p-toluene sulfonate (PPTS) was also used (entry 4) which led to the decrease in overall catalytic process. In addition to this, chiral phosphate and sulfonate salts and amino acid were also tried as additives. Binephthol and camphor sulphate based chiral pyridinium salts such as (S)-(+)-pyridiniumbinephthyl phosphate, (S)-(+) pyridiniumcamphor sulphonate (entries 10 and 11). However none of these additives led to the expected improvement in the yield and especially in the enantioselectivity.
Concluding the above optimization process, we screened all the possible parameter in order to improve the enantioselectivity of the catalytic process. As a result of the entire optimization process the best conditions found for present regio- and enantioselective rhodium catalyzed 6-chloro-(2H)-pyridazin-3-one addition to terminal allene are illustrated in Scheme C.3, giving the desired allylic product 473 in 96% isolated yield and 89% ee.
Scheme C.3. Optimized conditions for the regio- and enantioselective rhodium catalyzed coupling of 6-chloro-(2H)-pyridazin-3-one 471 with 3-phenylpropylallene 472
This newly developed reaction is the only enantioselective addition of 1,2-diazinone to terminal allene leading to N-allylated diazinones.199 However, in order to evaluated the generality of the coupling process and making the reaction more appealing in practical point of view, the reaction was inspected further, regarding functional group tolerance, by using different substrates, as well as its suitability for follow-up chemistry by carrying out various transformations.
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C.1.1.3. Substrate Scope
The optimized reaction conditions for the rhodium catalyzed 6-chloro-(2H)-pyridazin- 3-one 471 addition to 3-phenylpropylallene 472, evaluated after series of condition screening depicted in Scheme C.3, were applied to a variety of functionalized terminal allene as well diverse range of pyridazinones.
C.1.1.3.1. Screening of Allene Substrates
We initiated our scope exploration by coupling standard 6-chloro-2H-pyridazin-3-one 471 with a range of structurally diverse allenes (Table C.11). The reaction was conducted by the addition of 6-chloro-2H-pyridazin-3-one 471 to various allene substrates utilizing the optimized reaction conditions. The results of this allene scope are shown in Table C.11.
Table C.11. Scope exploration of the allene coupling partner under optimized reaction conditions
Results and Discussion | 97
Results and Discussion | 98
Results and Discussion | 99
Reaction conditions: Pyridazinones (0.20 mmol), allene (0.30 mmol), [{Rh(cod)Cl}2] (2.5 mol%), 1 (S)-3,5-iPr-4-NMe2-MeOBiphep 485 (5.0 mol%), DCE (0.4 M), 80 °C, 18 h; [a] isolated yield; [b] H NMR (crude); [c] determined by chiral HPLC; [d] 7.5 mol% ligang is used; [e]: after recrystallization; [f] %conversion from 1H NMR n.d: not determined
Large varieties of substituted allenes were tolerated with current methodology and gave smooth reaction yielding N-allylated product with excellent yield and selectivities. As the optimization process was carried out using 3-phenylpropylallene 493, variation in the length of the side chain led the reaction with same success. Phenylethylallene and dodeca-1,2-enylallene 495 led to their respective allylated product in good yield and enantioselectivity (entries 2 and 3). Cycloalkyl substituted allene with variable ring size such as cyclopentyl 497 and cyclohexylallene 499 were also utilized and were well compatible with allylation process giving the desired product in excellent yield (96%) and enantioselectivity up to 92% (entries 4 and 5).
Substituted cycloalkyl moieties such as hydroxycyclohexylallene 501 representing a very good example, showing that even free hydroxyl group in the hindered environment can be well tolerated in this methodology with 83% yield and 85% enantioselectivity (entry 6). Linear aliphatic allene, substituted with various functional groups were used to elaborate the scope of the procedure. In case of phenylester substitution on allene 503 did not interfere in the reaction and led to the desired allylated product 504 in 90% yield with 88% enantiomeric excess (entry 7). Sulphate ester substituted allene 505 presented another beautiful example of functional group tolerances, led to a desired product 506 in very good yield and enantioselectivity (entry 8). Carbonyl moiety in long chain aliphatic allene 507 was proved to be very good coupling counterpart as it gave N-allylation product 508 with excellent yield and enantioselectivity up to 97% and 84% respectively (entry 9). Protected amine and hydroxyl functional groups, present in aliphatic chain of allene, were also proved to be
Results and Discussion | 100
compatible with the catalysis conditions, presenting excellent examples of functional group tolerance. Phthalimide moiety on allene 509 did not show any interference during the catalytic reaction, leading to the desired product 510 in excellent yield (93%) with very high 92% enantioselectivity (entry 10). Allene 511 having amine moiety in linear side chain, protected with two different types of protecting group (Boc and tosyl groups) giving another beautiful example of N-allyl pyridazinone 512 in 75% yield and 74% enantioselectivity (entry 11). The free alcohol functional group in linear chain allene 513 led to the desired allylated product 514 in low yield (26%) with poor 42% enantiomeric excess (entry 12). However, when the allenes with the protected alcohol were used, they appeared to be suitable counterparts for the reaction. The allene with trityl protected alcohol moiety 515 led to the desired N-allylic product 516 with 80% yield and 68% enantioselectivity (entry 13). Similarly, the allylation of pyridazinone with allene bearing TBS protected alcohol moiety 517 resulted in the expected N-allyl product 518 with excellent yield of 97% along with 81% enantioselectivity (entry 14). This is probably because of the fact that TBS group is slightly distant from the reaction centre in allene 517 (entry 14) as compare to the thrityl protected OH moiety 515 which causes more steric hindrance at the reaction site (entry 13). The cyano substituted aliphatic allene 519 led to only 18% conversion to the desired allylated product 520. The probable fact behind the unproductive behaviour of cyano substituted allene is the possible instability of this allene coupling partner at elevated temperature in presence of the rhodium catalyst system (entry 15).
C.1.1.3.2. Scope Exploration for Pyridazinone Substrates
Further investigations were made exploring different functionalized pyridazinone coupling partner, tested for the addition to the standard allene 3-phenylpropylallene 472. The results of this scope exploration are depicted in Table C.12.
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Table C.12. Scope of the pyridazinone coupling partner under optimized reaction conditions
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Reaction conditions: Substituted pyridazinone 325 (0.20 mmol), 3-phenylpropylallene 472 (0.30
mmol), [{Rh(cod)Cl}2] (2.5 mol%), DCE (0.4 M), 80 °C, 18 h; [a] isolated yield for the reaction carried 1 out using 7.5 mol% of (S)-3,5-iPr-4-NMe2-MeOBiphep 485; [b] H NMR (crude); [c]: determined by chiral HPLC; [d] 5.0 mol% ligand is used.
Elaborating the scope and elucidating the practicability of this allylation methodology, we further investigated the couplings of various substituted pyridazinones with
Results and Discussion | 103 standard allene 3-penylpropylallene 472 (Table C.12). Besides mono substituted 2H- pyridazinones disubstituted analogues can be allylated smoothly, with excellent yields and moderate to good enantioselectivities. In addition to the standard 6-chloro-2H- pyridazin-3-one 471, leading to the desired product 473 in 96% yield and 89% ee (entry 1, Table C.12), various other commercially available substituted pyridazinone also gave respective allylation products. The substrate with bromo substituent 522 instead of chloro led to the desired product 523 in excellent yield (94%) with very good enantioselectivity (entry 2). 4,5-Disubstituted substrates were also well tolerated resulting in the desired products in good yields and selectivities. In case of 4,5- dichloro- 524 and 4,5-dibromo-2H-pyridazinones 526, the N-allylated products (525 and 527) were obtained in respective yields of 97% and 98%, with 76% and 75% enantioselectivity along with very high b:l ratio (entries 3 and 4). Moving to aryl and hetero-aryl derivatives of 5-chloropyridazin-3(2H)-one such as 5-chloro-4- phenylpyridazin-3(2H)-one 528 and 5-chloro-4-(thiophen-2-yl)pyridazin-3(2H)-one 430, led to desired N-allylated products with good yields and moderate enantioselectivies (entries 5 and 6). The more electron rich pyridazinone such as methyl and phenoxy substituted moieties the conversion to the product was slow. Thus the desired products were formed in acceptable yields and enantioselectivities. In case of 5-chloro-4-phenoxypyridazin-3(2H)-one 532, the reaction proceeded with moderate yield of 58% along with 47% ee while moving to the 6-methylpyridazin-3(2H)-one 534, the reaction gave the desired product 535 in very low yield and enantioselectivities (entries 7 to 9) and appeared to be not suitable substrate for this process. The probable reason behind the low conversions is the electronic environment of the substrates. Moving from cholro substituent to bromo, there is a decrease in electronegativity of the system which makes pyridazinone more electron rich. This fact leads to the probable decrease in the acidity of NH-moiety which lowers rate of the pyridazinone addition to allene. It is also obvious from the fact that small acidity of the reaction medium is crucial for the formation of reactive species during the mechanistic cycle. Therefore, a gradual decrease in the product ratio was observed in going from more electron deficient system to electronically rich systems.
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The investigation involving scope exploration utilizing various functionalized allene as well variably substituted pyridazinones proved the practicality of our investigated rhodium catalysis for the regio- and enantioselective generation of N-allylic 1,2- diazinones under very mild conditions and in byproduct free manner. This is also presented that the reaction methodology is tolerant and compatible with various sensitive protected functionalities like phthalimide and Boc/tosyl protected amines, esters and trityl/TBS protected alcohol moieties.
Results and Discussion | 105
C.1.1.4. Determination of Absolute Stereochemistry
X-ray crystallographic analysis gave an absolute stereochemistry as it gave all the gross features of the compound (S)-2-(4-(3-chloro-6-oxopyridazin-1(6H)-yl)hex-5- enyl) isoindoline-1,3-dione 509 such as intensity measurements, symmetry, atomic positions, interatomic distances, and atomic displacement parameters which are in complete agreement with structure, elucidated by various physical techniques such as NMR and Mass etc.
Figure C.4. ORTEP structure of compound 509 showing its absolute configuration
The below given analysis showed that the crystal structure of the compound represented properly by the model crystal (Figure C.4), indicating that the compound is enantiomerically pure and the crystal structure belong to the S enantiomer.
Crystal Data. C18H16ClN3O3, Mr = 357.79, orthorhombic, P212121 (No. 19), a = 4.8769 (5) Å, b = 9.1534 (9) Å, c = 37.533 (4) Å, a = b = g = 90°, V = 1675.5 (3) Å3, T
= 100(2) K, Z = 4, Z' = 1, m(MoKa) = 0.251, 3547 reflections measured, 3547 unique
(Rint = 0.0390) which were used in all calculations. The final wR2 was 0.1089 (all data) and R1 was 0.0376 (I > 2(I)).
A colourless block-shaped crystal with dimensions 0.28×0.14×0.13 mm3 was mounted on Mitegen Loops in polyether oil. X-ray diffraction data were collected using a
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Bruker Smart APEXII QUAZAR diffractometer equipped with an Oxford Cryosystems 800 low-temperature device, operating at T = 100(2) K.
Data were measured using Omega and Phi Scans using MoKa radiation (Incoatec Mo Microsource 1st gen., 50 kV, 0.6 mA). The total number of runs and images was based on the strategy calculation from the program APEX2 (Bruker). The maximum resolution achieved was = 26.388°.
C.1.1.5. Mechanistic Investigations by Labeling Experiments
The deuterium labeling experiment was performed in order to investigate the possible mechanism involved in the rhodium catalyzed hydroamination of terminal allene by pyridazinones. The exchange experiment was conducted according to standard rhodium catalyzed conditions, using deuterated 6-chloropyridazin-3(2H)-one (Scheme C.4).
Scheme C.4. Labelling experiment using deuterated substrate under optimized reaction conditions
According to the reported mechanistic evidences93,94 it is expected that the deuterium incorporation occurs mainly at the central position of the allene substrate (Scheme C.5) due to the formation of π-allyl rhodium complex. In the present case the incorporation of deuterium also occur at the Csp atom (26%), but the majority of the deuterium was incorporated surprisingly at the terminal positions of the resulting allyl moiety with a total of 91% D at the terminal position.
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The overall deuterium distribution was calculated from the mass spectrometric analysis as well as 1H-NMR of the deuterated allylated product.
C.1.1.5.1. Isotopic distribution in Final Product by Mass spectrometry
The overall distribution of deuterium in the final allylated product is depicted in Table
C.13, revealing that the relative distribution of d0 product (without any D-atom) is
55% while the product with deuterated Csp is 37% (d1). The product with incorporation of deuterium at two positions and that with all of the three positions were in relative distribution of 8% and 1% respectively.
Table C.13 Distribution of deuterium in the final allylated product
dn (number of Deuterium relative distribution incorporated) (%)
d0 55
d1 37
d2 8
d3 1
C.1.1.5.2. 1H-NMR Analysis Deuterated Product
1H-NMR analysis of the final deuterated product showed the percent H-replacement by deuterium atom. This data indicated the extent of deuterium incorporation for cis/trans hydrogens as well central carbon (Csp), depicting that the cis-H replacement is slightly more, about 47% while trans-H is 44%, obvious from their J values, and also the central carbon is incorporated by deuterium to 26% (Figure C.5).
Results and Discussion | 108
Figure C.5. 1H-NMR spectrum of the deuterated product showing % D-exchange
C.1.1.6. Proposed Mechanism of Rh-Catalyzed Coupling of Pyridazinone Derivatives with Terminal Allenes.
The deuterium labeling studies and previous investigations help to propose the mechanism for current coupling methodology. The mechanism of rhodium catalysis was proposed to follow the cyclic pathway, illustrated in the Scheme C.5. The mechanistic cycle is start with the monomerization of the rhodium dimer
[{Rh(cod)Cl}2] (step I), followed by the oxidative addition of rhodium (I) species into pyridazinone 471 to generate the rhodium (III) complex 456.200 These rhodium (III) species 539 undergo reversible hydrometalation with the allene 540 led to the formation of σ-vinyl rhodium complex 541 which undergo β-hydride elimination to release partially deuterated allene 542, obvious from the deuterium exchange studies. Hydrometalation of this deuterated allene at more substituted side led to the formation of π-allyl-Rh complex 543 which can equilibrated with σ-allyl-Rh complex 544.201 The allyl-Rh complex undergo reductive elimination generating the desired branched N-allylated pyridazinone 545.202
Results and Discussion | 109
Scheme C.5. Proposed mechanism for the rhodium catalyzed N-allylation of pyridazionone
C.1.1.7. Follow-Up Chemistry Involving Assorted Transformations of N-Allyl Pyridazinone
To elucidate the synthetic utility of the synthesized N-allyl pyridazinones we performed assorted transformations, converting the allylic moiety into various useful functional groups (Scheme C.6).
Cl (c) (a) Cl N N N O N O Ph O Cl Ph Me 3 3 N 548 N O 546 Ph Cl 3 Cl
N (d)473 (b) N N O N O Ph O Ph OH 3 3 549 547
o [a] Pd/C (10 mol%), H2 (1atm.), MeOH, 0 C, 10 h, 96%; [b] 9-BBN (excess), THF, o o -78 C-rt, 16 h; then H2O2,NaOH,-10 C - rt, 5 h, 78%; [c] [{Rh(CO)2acac}] (0.5 mol%), 6-DPPon (10 mol%), CO/H2 (1:1, 20 bar), Toluene, 80 °C, 20 h, 91% (L/B 9:1); [d] O3; o PPh3, DCM, -78 C then rt, 5 h, 82%.
Scheme C.6. Assorted transformations of N-allyl pyridazinone
Results and Discussion | 110
C.1.1.7.1. Hydrogenation
Catalytic hydrogenation of is one of the simplest but most powerful methodologies to produce a wide array of chemically and biologically important compounds.203a,b Hydrogenation of functionalized alkene makes the basis of food, medical and fuel industry. Therefore the synthetic research communities always involved in developing new synthetic routes to selectively synthesize saturated alkyl moieties.203 In the current investigations on exploring the synthetic utility of synthesized N-allyl pyridazinones, we selectively hydrogenated the allyl moiety to afford N-alkyl diazinone moieties.203,d
6-Chloro-1-(6-phenylhex-1-en-3-yl)pyridazin-2(1H)-one 473 was successfully hydrogenated using H2-Pd/C system, isolating the desired hydrogenated product 6- chloro-1-(6-phenylhexanyl)pyridazin-2(1H)-one 546 in excellent yield (Scheme C.7).
Scheme C.7. Pd/C catalyzed hydrogenation of N-allyl pyridazinone
The selectivity in the results of this transformation shows that the N-allylated pyridazinone products are well compactible with the hydrogenation conditions, although there is other functionalities which also prone to hydrogenate.
C.1.1.7.2. Hydroxylation via Hydroboration/Oxidation
Alcohols are versatile building blocks constituting one of the most important class organic compounds.87 They presented most powerful way to produce a wide array of chemically and pharmaceutically important compounds as alcohol function can easily derivatized to more complex organic molecules and polymers.204a
Results and Discussion | 111
Hydroboration/oxidation sequence is one of the most practical methodologies used for the synthesis of alcohol from alkene.204b Here we utilized this procedure for the hydroxylation of N-allyl diazinone 473 resulting in the formation of N-substituted pyridazinone with free hydroxyl functionality. The free hydroxyl function makes N- substituted pyridazinone moieties more attractive pharmacophoric precursor for further utilization in the synthesis of bioactive molecules.
6-Chloro-1-(6-phenylhex-1-en-3-yl)pyridazin-2(1H)-one 473 was proved to be compatible with oxidation process, as shown in the Scheme C.8, in which the N- allylated moiety was treated with 9-BBN/H2O2 affording the desired hydroxylated product 547 in good yield.
Scheme C.8. Hydroboration oxidation of N-allyl pyridazinone
The current hydroxylation process indicated the stability of synthesized N-allyl diazinones even in very harsh condition in which a possibility of more than one reaction is there. This representing the synthetic utility of the current rhodium catalyzed synthetic methodology.
C.1.1.7.3. Hydroformylation using Self-Assembly ([{Rh(CO)2acac}]/6-DPPon) Ligand System
Hydroformylation of functionalized terminal alkenes with concomitant introduction of the aldehyde function is synthetically most benign and powerful methodology for skeleton expansions of organic molecules. This process presents a real example of atom economical process.204 It is thus not surprising that it has developed as one of the industrial most important processes relying on homogeneous catalysis. Regioselective
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hydroformylation leading to regiocontrol for hydroformyl group is one of the most challenging and complicated process.205
Herein we reported the regioselective hydroformylation of N-allyl diazinone 473 to represent the synthetic utility of the process by converting the allyl moiety into formyl
group by treating with self-assembly ([{Rh(CO)2acac}]/6-DPPon) ligand system. This reaction led to the desired 4-(3-chloro-6-oxopyridazin-1(6H)-yl)-5-phenylheptanal 548 product in 91% yield with excellent branched: linear regioselectivity (Scheme C.9).
Scheme C.9. [{Rh(CO)2acac}]/6-DPPon catalyzed hydroformylation of N-allyl pyridazinone 473
C.1.1.7.4. Oxidative Cleavage of the Allyl Double Bond by Ozonolysis
Ozonolysis presents clean and effective chemical transformations for the oxidative cleavage of the double bond to yield carbonyl compounds.206 It is an important reaction from the synthetic perspective. The alkenes, a nucleophilic moiety can be converted into carbonyl function which is electrophilic, so these aldehydes and ketones can be kept protected as alkenes, where needed, during synthesis. At the appropriate time this alkenyl moiety can be converted to the aldehyde or ketone when it is its turn to react electrophilically.207
In the current follow up chemistry the N-allylated product 473 was oxidatively cleaved into an aldehyde functional group by treating it with ozone at -78 ᵒC, followed by the
Results and Discussion | 113
addition of PPh3. This process led to the formation of an aldehyde moiety 2-(3-chloro- 6-oxopyridazin-1(6H)-yl)-3-phenylpentanal 549 in 82% yield (Scheme C.10).
Scheme C.10. Oxidative cleavage of 6-chloro-1-(6-phenylhex-1-en-3-yl)pyridazin-2(1H)- one 473 by ozonolysis
In conclusion, the assorted synthetic transformations of the N-allyl pyridazinones lead to the preparation of a small library of N-functionalized pyridazinones, representing valuable pharmaceutical building blocks which can be lead precursors for the synthesis of biologically active entities.208
C.1.1.8. Summary and Conclusions
In this study we investigated regio- and enantioselective rhodium catalyzed hydroamination of terminal allene utilizing 1,2-diazinone family of di-nitrogen heterocycles. In this process N-allyl diazinone were synthesized in asymmetric fashion in excellent yield. Good to excellent level of chemo-, regio and enantioselectivities were observed across the range of functionalized allene and pyridazinone along with high branched to linear ratio in the final allylated product. The process observed was atom and step economical as 1:1 catalyst: ligand ratio was enough for complete conversion of the starting materials to the final product without the aid of any additives. The developed methodology was successfully implemented to increase the scope of the reaction using diverse range of functionalized allene and pyridazinone moieties. Insight into the reaction mechanism was achieved through the deuterium labeling experiments, suggesting the involvement of π-allyl complex in catalytic pathway. Furthermore, functional group interconversions were carried out by treating the resulting N-allyl pyridazinone with various reaction conditions such as
Results and Discussion | 114 hydrogenation, hydroxylation, ozonolysis and hydroformylation to obtained N- functionalized diazinones in excellent yields.
To conclude, the current investigated rhodium catalyzed asymmetric allylation of pyridazinone skeleton via hydroamination of terminal allenes has proved to be a mild, efficient and functional group tolerant strategy for the syntheses of N-allyl-1,2- diazinones in excellent yields, with high levels of chemo, regio, and enantiocontrol under neutral conditions. A broad range of new chiral N-allylated pyridazinones were prepared in an essentially byproduct free manner with high level of asymmetric inductions. The scope of current methodology is explored by coupling a range of various functionalized allenes with wide variety of substituted pyridazinones to synthesize diverse array of new chiral diazinone heterocycles. Furthermore, the final allylated products were successfully transformed into various functional groups in very good yields. These assorted transformation furnished a variety N2-functionalized pyridazinones representing valuable intermediates providing proficient access to pharmaceutical building blocks. It is anticipated that the syntheses of chiral N-allyl pyridazinones presents mild and easily accessible protocol for the syntheses of pharmacophoric parts of diazinone containing bioactive molecules. This methodology open up a way to synthetically important class of chiral/achiral allylic moieties which are most valued in synthetic organic chemistry for both of its versatility for further functionalization. The potential of this protocol for the construction of new stereogenic center can lead to facile asymmetric synthesis. It renders this new approach as a valuable addition to the toolbox of asymmetric allylation chemistry.
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Section B
C.2. Rhodium-Catalyzed Regioselective Domino Azlactone-Alkyne Coupling/Aza-Cope Rearrangement: A Facile Access to 2-Allyl- 3-oxazolin-5-ones and Trisubstituted Pyridines C.2.1. Rhodium Catalyzed Regioselective Domino Azlactone-Alkyne Coupling/Aza-Cope Rearrangement
Rhodium catalysis presents an efficient synthetic strategy for atom economic transformation of both allenes and alkynes leading to functionalized allylic structures via isomerization/addition process, vastly invesitigated by Breit et al.210
The current investigation deals with the rhodium catalyzed allylic alkylation which presents one of the most elegant and powerful synthetic methodology to construct C-C bond. Although terminal allenes92a,211 displayed higher reactivity but the isomeric terminal and internal alkynes39 are easily accessible substrates and synthetically more appealing starting materials. Previous investigated rhodium catalyzed allylic alkylation were decaboxylative insertion of ketoacid to terminal allene leading to α-allyl ketone92a as well as the regioselective addition of 1,3- dicarbonyl compounds to terminal alkynes leading to the formation of α-allylated 1,3-dicarbonyl compounds.212
Current investigation deals with further expansion of this potential synthetic methodology involving allylic alkylation of azlactone as carbon nucleophile via the regioselective insertion to intenal alkynes (Scheme C.11).
2 2 R C-2 R R2 Me O C-2 3 O [Rh] N Aza-Cope R N O + 3 N R O rearrangement O R1 C-4 1 3 O C-4 R R R1 426 463 464 466
Scheme C.11. Rhodium catalyzed allylic alkylation via azlactone insertion to internal alkyne
Results and Discussion | 116
The hypothesis made in the Section C (Task C.2) was that during rhodium catalyzed azlactone insertion to terminal alkyne (Scheme C.3), the 2-allyl-3-oxazolin-5-one derivatives 550 are more likely to obtained than that of isomeric 4-allyl-2-oxazolin-5- one derivatives 465, since the latter is prone to undergo a subsequent aza-Cope rearrangement as a tandem process under the appropriate reaction conditions.213 In order to test the hypothesis, initial reactivity assays were conducted with 2,4- diphenyloxazol-5(4H)-one (550, 0.2 mmol) and 1-phenyl-1-propyne (551, 2 equiv.) as model substrates. To our delight, in the presence of [{Rh(cod)Cl}2] (1 mol%), and DPEphos (101, 2 mol%) in dichloroethane (DCE) at 50 °C (Table C.14, entry 1) the desired tandem product 552 was obtained in 74% yield, along with 4% of the linear C4 allylation product 553 (Scheme C.12).
Scheme C.12. Initial experiment for the rhodium-catalyzed azlactone addition to internal alkyne C.2.1.1. Identification of the Tandem Product: Evidence of Aza-Cope Rearrangement
Oxazol-5-(4H)ones (azlactones) is a masked amino acids, has both nucleophilic and electrophilic sites as shown in Figure C.6, which makes the azlactone as interesting reacting moiety.214
Figure C.6. Representation of the reactive behavior of azlactone
Results and Discussion | 117
Present investigations deals with allylation of azlactone using rhodium catalyzed hydrocarbonation of internal alkyne, utilizes C-4 nucleophilic site of azlactone. Rhodium catalyzed addition of various pronucleophiles to allene and alkyne210 lead to usual allylation product showed specific 1H NMR signals with characteristic splitting pattern for the allyl moiety (Figure C.7).
Figure C.7. Representation of 1H NMR splitting pattern for allyl moiety
1H NMR-analysis of the products of current allylation reaction indicated the absence of typical signals for allyl moiety in their respective region confirming the formation of compound other than the expected C-4 allylated azlactone product.
Figure C.8. Representation of 1H NMR splitting pattern for rearranged product
Spectral analysis of the resulting compounds allowed us to assign the give structure to our final allylation product. In 1H-NMR of the resulting allylated product 552 (Figure C.8), a doublet (d, Ha) and a triplet of a doublet (dt, Hb) were observed within the similar shift region. These signals were assigned to the two vinylic
Results and Discussion | 118
protons (a and b) of the rearranged product while signal for Hc shifts to aliphatic region (2.95-3.12 ppm).215
The structure assignment confirmed the final product as the rearranged product that formed as a result of aza-Cope rearrangement. The allylic double bond of the C-4 allylation branched product 4-allyl-2-oxazolin-5-one derivatives 552a undergo [3,3]- sigmatropic rearrangement with imine moiety of the azlactone ring leading to the formation of major C-2 allylation product 2-allyl-3-oxazolin-5-one derivatives 552 (Scheme C.13).
Scheme C.13. Rhodium catalyzed tandem azlactone-alkyne coupling/aza-Cope rearrangement
C.2.1.2. Evaluation of Ligand for Regioselective Azlactone-Alkyne Coupling
The present reaction conditions used for the desired allylation of azlacton were adopted from the previous investigations on rhodium catalyzed hydroesterification94c and hydrocarbonation38a of alkyne. In both case the catalyst system containing rhodium precursor/DPEphos 101 led to excellent results in term of yield and regioselectivity (Scheme C.14).
Results and Discussion | 119
Scheme C.14. Rhodium catalyzes hydroesterification and hydrocarbonation of
alkynes
Therefore, we utilized the reported condition for our reaction which involved the treatment of 2,4-diphenyloxazol-5(4H)-one (550, 0.2 mmol) with 1-phenyl-1-propyne
(551, 2 equiv.) in the presence of [{Rh(cod)Cl}2] (1 mol%), and DPEphos 101 (2 mol%) in dichloroethane (DCE) at 50 °C (Table C.14, entry 1). The desired tandem product 552 was obtained in 74% yield, along with 4% of the linear C-4 allylation product 553.
Results and Discussion | 120
Table C.14. Ligand screening for hydrocarbonation reaction under standard conditions
Entry Ligands Bite angles Conversion Yield of Yield of (%) 552 (%)a 553(%)a 1 DPPE 557 85ᵒ 33 n.d. n.d. 2 DPPP 227 91ᵒ 39 n.d. n.d. 3 DPPB 72 98ᵒ 56 37 10 4 DPPF 76 99ᵒ 100 86 5 5 DPEphos 101 102ᵒ 100 96 2 6 Xantphos 558 111ᵒ 41 10 n.d.
Reaction conditions: Azlactone 551(0.2 mmol), 552 (0.3 mmol), [{Rh(cod)Cl}2] (1 mol%), 1 DPEphos 101 (2 mol%), Ph2CHCOOH (0.02 mmol, 10 mol%), DCE (0.6 mL); [a] H NMR yield using 1,3,5-trimethylbenzene as internal standard.
The ligand screenings involve the achiral bidentate ligands (Figure C.9/Table C.14), given in the increasing order of their P-M-P bite angles.216 The influence of the ligand bite angle on the yields of final products as well as branched: linear selectivity was investigated, under standard conditions at 50 °C (Table C.14).
The effect of the bite angle on the reaction rate appears to be significant regarding the chemoselectivity toward the rearranged product 552. It is evident that in going from small bite angles ligand, such as DPPE 557, DPPP 227 and DPPB 72 the reaction rate is increased successively with the increase in conversion (33%-56%) and selectivity of the reaction (0-37%) (entries 1-3). The conversion and isolated yield of the desired product increased up to 100% and 87% respectively when the bite angle increased to 99°, as in case of DPPF 76 (entry 3). The amount of the desired rearranged product
Results and Discussion | 121 steadily increased to maximum (96%) with the use of the ligand DPEphos 101 having bite angle of approximately 102°217 (entry 4). Increasing to even larger bite angles as in the case of Xantphos 558 with bite angle of 111° the conversion and yield as well as selectivity dropped down dramatically (entry 5). A catalysis reaction performed with Rh/Xantphos 558 catalyst system led to only 44% of overall reaction conversion with 10% of isolated yield.
Figure C.9. Achiral ligands with their bite angles
The overall ligand screening revealed that the diphenyl ether ligand DPEphos 101 was considered as a ligand of choice for the rhodium catalyzed hydrocarbonation of internal alkyne using azlactone. This ligand is used for the rest of the reaction conditions optimizations. With the best ligands in hands and despite the already high level of conversion (96%), there was still a room for the improvements as well as to understand the reaction, further conditions optimizations were carried out.
C.2.1.3. Optimization of the Reaction Conditions with DPEphos 101 Ligand
Previous investigations on rhodium catalyzed hydrocarbonation of terminal and internal alkyne have revealed that using catalytic amount of Brønsted acid enhanced
Results and Discussion | 122 reaction rate and increase selectivity.212 The -/-allyl rhodium intermediate formation is promoted by the acid cocatalyst facilitating alkyne-allene isomerization, thus promoting the addition process involving terminal and internal alkyne.212,94c,40,38b We speculated that addition of suitable Brønsted acid cocatalyst can also facilitate the azlactone addition to internal alkyne. Therefore we screen various acid additives utilizing our model reaction conditions (Table C.15).
Table C.15. Acidic additives screening under standard reaction conditions
Entry Additives Conversion Yield of 468 Yield of 469 (%) (%)a (%)a 1 - 85 74 4
2 Ph2CHCOOH 100 96 4 3 PhCOOH 69 60 2
4 p-TSA.H2O 100 36 4 5 PPTS 74 57 7
Reaction conditions: Azlactone 551 (0.2 mmol), 552 (0.3 mmol), [{Rh(cod)Cl}2] (1 mol%), DPEphos 101 (2 mol%), additive (0.02 mmol, 10 mol%), DCE (0.6 mL); [a] 1H NMR yield using 1,3,5-trimethylbenzene as internal standard. (p-TSA= p- toluenesulfonic acid , PPTS = pyridinium 4-toluenesulfonate)
In the absence of acid additive, the conversion and selectivity of the reaction is considerably low (entry 1) demonstrating its importance for current coupling reaction. Screening other acids, for instance benzoic acid, the conversion lowers to 69% while yields became 64% and 4% for 552 and 553, respectively (entry 3). Using p- toluenesulfonic acid (p-TSA) and pyridinium p-toluenesulfonate (PPTS) led to inferior results (Table C.15, entries 4 and 5). It is evident from the afore mentioned
Results and Discussion | 123 observations that the suitable acid additive for the current hydrocarbonation process is diphenylacetic acid, as it led to excellent results, both in term of conversion and yield.
The influences of the solvent, molar ratio of alkyne counterpart and temperature were investigated (Table C.16). In case of solvent screening, non-polar and polar aprotic solvents were used in the optimization process.
Table C.16. Solvent and molar ratio screening under standard reaction conditions
Entr Molar Solvent Conversion (%) Yield of Yield of y Ratio (x) 468 (%)a 469 (%)a 1 2.0 DCE 100 96 2
2 2.0 CH3CN 97 74 2 3 2.0 DCM 92 87 3 4 2.0 THF 59 42 5 5 2.0 toluene 42 27 3 6 1.5 DCE 97 95 2 7b 1.5 DCE 100 98 (94c) 2 8 b 1.2 DCE 88 77 2
Reaction conditions: Azlactone 551(0.2 mmol), 552 (0.3 mmol), [{Rh(cod)Cl}2] (1 mol%), DPEphos 1 101 (2 mol%), Ph2CHCOOH (0.02 mmol, 10 mol%), DCE (0.6 mL); [a] H NMR yield using 1,3,5- trimethylbenzene as internal standard. (p-TSA= p-toluenesulfonic acid; [b] T = 60 °C [c] isolated yield.
Solvent optimization showed that besides DCE, other polar aprotic solvents such as acetonitrile (CH3CN) and dichloromethane (DCM) also work well in the reaction leading to 74% - 87% NMR yield of the product, respectively (entries 2 and 3) while THF led to inferior results gave only 42% yield reported by NMR (entry 4). Less polar
Results and Discussion | 124 solvent toluene the desired product was afforded in 27% yield based on NMR (entry 6). As a result of solvent screening, the DCE was proved be the best solvent for the current reaction.
The next parameter studied was the molar ratio of the alkyne coupling partner. When the amount of alkyne counterpart was decreased to 1.5 equivalents the reaction rate was also decreased (entry 6). Using 1.5 equivalent of alkyne coupling partner 551, increase in temperature led to the increase in extent of reaction. At 60 °C the reaction rate was significantly increased resulting in the complete conversion. The desired product was obtained in 98% yield based on NMR and in 94% isolated yield (entry 7).
Keeping the reaction temperature 60 °C, the reaction was carried out with decreased molar ratio of substrates (entry 8). In these conditions significant decrease was observed both in the conversion and yield of reaction.
Concluding the above optimization process, the best conditions for rhodium catalyzed coupling of azlactone with internal alkyne found with DPEphos 101 are depicted in Scheme C.14.
Scheme C.15. Optimized conditions for the regioselective rhodium catalyzed coupling of azlactone 550 with 1- phenyl-1- propyne 551
This newly developed reaction is the only rhodium catalyzed regioselective domino azlactone-alkyne coupling/aza-Cope rearrangement, leading to allylated azlactone moieties.218 In order to evaluate the generality of the coupling process and making the reaction more appealing in practical point of view, the reaction scope was studied as well as its suitability for follow-up chemistry.
Results and Discussion | 125
C.2.1.4. Substrate Scope of the Rhodium-Catalyzed Domino Azlactone-Alkyne Coupling/Aza-Cope Rearrangement
The optimized reaction conditions found were tested regarding both the azlactone and internal alkyne coupling partner (Table C.17 and Table C.18). One of the major advantages of the process is the ease of availability of both coupling partners. Many functionalized internal alkynes are commercially available while substituted azlactones can be easily synthesized from protected amino acid precursors which are abundantly available.
C.2.1.4.1. Screening of Internal Alkyne Substrates
We initiated our scope exploration by coupling standard 2,4-diphenyloxazol-5(4H)- one 551 with a range of structurally diverse internal alkyne (Table C.17). The reaction was conducted by the addition 2,4-diphenyloxazol-5(4H)-one 551 to various internal alkyne substrates utilizing the given optimized reaction conditions. The results of this scope exploration are depicted in Table C.17.
Table C.17. Scope exploration of the internal alkyne coupling partner under optimized reaction conditions
Results and Discussion | 126
Results and Discussion | 127
Me Me Ph
O e 11 N 83 89:11 Me O Ph 577 578
Reaction conditions: [a] Azlactone 550 (0.2 mmol), 463 (0.3 mmol), [{Rh(cod)Cl}2] (x mol%),
DPEphos 101 (y mol%), Ph2CHCOOH (0.02 mmol), DCE (0.6 mL); [b] Isolated yield; [c] The R/L ratio was determined by 1H NMR spectroscopy of the crude reaction mixture using 1,3,5- trimethylbenzene as internal standard; [d] x= 1 mol%, y= 2 mol%; [e] x= 4 mol%, y= 8 mol%; [f] x= 2 mol%, y= 4. Reaction scope showed that most of the internal alkynes substituted with aromatic moiety gave the desired products in good to excellent yields demonstrating the generality of the investigated hydrocarbonation methodology over a wide range of functional groups. Aryl methyl alkynes bearing either electron-donating or electron-withdrawing substituents on the aromatic ring were compatible providing the desired products in good to excellent yields. 4-Halo substituted alkyne such as F, Cl, Br, led to high reaction rates giving the desired rearranged product in range of 98% to 80%, with very high ratio of rearranged: linear (R: L) isomers (entries 2-4). In case of electron withdrawing substituents at 4-position of aromatic ring of the alkyne coupling partner, the yield is nearly quantitative (98%) as in case of nitro substituted aromatic alkyne
Results and Discussion | 128
565 along with excellent regioselectivity (entry 5), while CF3- group 567showed little decrease in the yield as well as R:L ratio (entry 6). Carbonyl functionalized internal alkynes (569,571) also gave complete conversions under the optimized reaction conditions, with respective yield of 90% and 84% for keto and formyl group in good to fair regioselectivity in the final product (entry 7 and 8). Moving to aryl and alkyl substituted aromatic alkynes (573, 575, 577) the yield of the desired product was very good in case of biaryl alkyne (entry 9) while in case of methyl substituent, there was a slight decrease observed in the overall yield (entry 10 and 11). In case of methoxy substituted alkyne 579 the yield of the desired product 580 was excellent (92%) along with very good regioselectivity (entry 12).
The generality of the process is indicated by testing various alkyne substrates, giving the desired product in good yield, exhibiting relatively wide substrate scope. The rearranged product R was always a major product, with R: L selectivities ranging from 88:12 to excellent >95:5.
C.2.1.4.2. Scope Exploration using Substituted Azlactones and Substituted Internal Alkynes
Functionalized azlactone derivatives of the standard 2,4-diphenyloxazol-5(4H)-one 550 (Table C.18, entry 1) along with aliphatic and hetero-arylalkyne resulted in good reactivity. In some cases there was a decreasing trend observed in yield and regioselectivity. The example of heteroaryl alkyne is thienyl substituted propyne 581, and that of aliphatic alkyne is ester substituted propyne 583 which were well tolerated yielding the desired products 582 and 584 in 87% and 51% yield with 91:9 to > 95:5 R: L ratio, respectively (Table C.18, entries 1 and 2).
Table C.18. Scope exploration using substituted azlactone and substituted internal alkyne under optimized reaction conditions
Results and Discussion | 129
Reaction conditions: 492 (0.2 mmol), 207 (0.3 mmol), [{Rh(cod)Cl}2] (x mol%), DPEphos (y
mol%), Ph2CHCOOH (0.02 mmol), DCE (0.6 mL); [a] Isolated yield; [b] The R/L ratio was determined by 1H NMR spectroscopy of the crude reaction mixture using 1,3,5-trimethylbenzene as internal standard; [c] x= 1 mol%, y= 2 mol%; [d] x= 4 mol%, y= 8 mol%, [e] x= 2 mol%, y= 4 mol%. Moreover, azlactone bearing 4-methyl substituent as well as a bulkier naphthyl group at C-4 position reacted well with standard alkyne 551 furnishing 586 and 588 in almost quantitative yields and excellent regioselectivity (entries 3 and 4).
The above investigation upon scope exploration for current allylation methodology utilizing functionalized internal alkyne as well as various substituted azlactone derivatives, proved the practicality of rhodium catalysis for regioselective allylation of
Results and Discussion | 130
azlactone accompanied with aza-Cope rearrangement leading to domino type reaction under mild conditions. This is also presented that the reaction methodology is compatible with various functionalities leading to the generation of number of allylated azlactone derivatives.
C.2.1.4.3. Rhodium-Catalyzed Domino Azlactone Formation/Azlactone-Alkyne Coupling/Aza-Cope Rearrangement
To expend the utility of the hydrocarbonation reaction we envisioned to explore the domino reaction using N-protected amino acid as a precursor of azlactone, combining in situ generation of azlactone with its rhodium catalyzed allylation via hydrocarbonation of internal alkyne. To our delight, addition of acetic anhydride along with various N-protected amino acids in DCM solvent instead of DCE, the desired C-2 allylation product obtained in good to excellent yield (Table C.19). The reaction proceeded through cascade sequence involving tandem azlactone formation/azlactone- alkyne coupling/aza-Cope rearrangement.
Below table showed that the amino acid protected with substituted acyl moieties could be good starting materials to synthesized allyl azlactones. Most of the acyl amino acids bearing substituents like methyl, methoxy and halo groups reacted well in good to excellent yields with very high regioselectivities (entries 2-5). Electron deficient acyl moiety such as triflouromethyl substituted acyl amino acid were well tolerated and carried through the sequence efficiently (entry 6). Furthermore, the 3-oxazolin-5- one embedded with a methyl group along with linear allylic group at the C-2 position was also afforded, albeit in a low yield (entry 7).
Table C.19. Domino azlactone formation/azlactone-alkyne coupling/aza-Cope rearrangement
Results and Discussion | 131
OMe
O 3 74e 81:9 HOOC NH O N Ph 593 O Ph 594
Results and Discussion | 132
Reaction conditions N-Acyl amino acid 589 (0.2 mmol), 551 (0.3 mmol), [{Rh(cod)Cl}2] (x mol%),
DPEphos 101 (y mol%), Ac2O (0.22 mmol), DCM (0.6 mL); [a] Isolated yield; [b] The R/L ratio was determined by 1H NMR spectroscopy of the crude reaction mixture using 1,3,5- trimethylbenzene as internal standard; [c] x= 1 mol%, y= 2 mol%; [d] x= 4 mol%, y= 8 mol%; [e] x= 2 mol%, y= 4.
This practice made a cascade type sequences which include high step economy and reduced waste generation usually associated with multistep process. Investigation on the cascade sequence combined with the use of common and easily available organic compound increased the efficiency and utility of this methodology which is measured in terms of number of bonds formed during the course of overall sequence as well as its applicability to wide range of substrate classes.
C.2.1.5. Investigation upon Regioselectivity and Involvement of Aza-Cope Rearrangement in Azlactone Allylation
Rhodium catalyzed addition of pronucleophile to allenes and alkynes have very rich chemistry and well investigated reaction mechanism. Pervious investigations showed that rhodium catalysis for allene/alkyne chemistry preceded with its specific branched selectivity,210 as compare to the palladium chemistry which represent linear selectivity.23,24a Here rhodium catalyzed allylation of azlactone represented the same phenomenon leading to the branched selective reaction, ends up with formation of rearranged product. To explore the behavior of reacting moieties in the rhodium catalysis condition as well as to get insight into the reaction mechanism we performed
Results and Discussion | 133 controlled reaction utilizing 2-octyne 603, treated with 2,4-diphenyl-3-oxazolinone 550 under standard reaction conditions, illustrated in the Scheme C.15.
Scheme.C.16. Rhodium catalyzed coupling of 2,4-diphenyl-3-oxazolinone 550 with 2-octyne 603
Azlactone allylation proceeds with the formation of branched and linear C-4 allylation product, in which the branched product undergoes aza-Cope rearrangement leading to the C-2 allylation product 2-allyl-3-oxazolin-5-one 552 (Section C.2.1.1). The above sets of experiment revealed that by changing the conditions the branched product can be trapped and isolated (Scheme C.15). Reaction under condition set 1 representing the usual reaction condition for allylation of azlactone yielding the C-2 rearranged product 605 in 60% isolated yield while C-4 branched product 604 in just 22% yield (dr <20:1). When the reaction carried out under condition set 2 i.e long reaction time with low temperature, the ratio of C-4 branched product 604 was increased and obtained in 80% yield (dr = 3.7:1) along with only 8% of rearranged product 605.
This investigation provide evidence for the fact that the rhodium catalyzed hydrocarbonation of internal alkyne using azlactone as C-nuleophile proceeds in cascade sequence involving allylation-aza-Cope rearrangement. On the basis of this investigation we obtained preliminary insights into the reaction mechanism.218
Results and Discussion | 134
C.2.1.6. Mechanistic Investigations
Mechanism involved in the rhodium catalyzed addition of various nucleophile to alkyne is thoroughly investigated by Breit and his coworkers.86,93,94 The nature of the allylation product of the current addition methodology and the above experiment revealed that the mechanism of this process also involved the formation of π-allyl rhodium complex F (Scheme C.17) which has been investigated previously in the rhodium catalyzed addition of benzoic acid to terminal alkynes.39,94a-c Here in this case the formation of the allylic addition product of azlactone H suggested that π-allyl rhodium complex F is also an intermediate in the present catalytic cycle. Based on previous investigations,12,210,212 a plausible mechanism for the reaction is depicted in Scheme C.17. According to the reported mechanism for rhodium catalyzed addition process, the catalytic cycle involved in azlactone allylation consists of the following six main steps (I-VI). The overall mechanism can be divided into two parts (i) the isomerization of the internal alkyne C to the allene E, with the help of acid additive in a first cycle, followed by (ii) the addition of the nucleophilic species to the internal double bond of E. The carboxylic acid additive A is oxidatively added to the Rh (I) source leading to the formation of rhodium hydride complex B. This step involves the oxidation of rhodium metal changing its oxidation state from +I to +III. Coordination of the internal alkyne C to the complex B followed by hydrometalation of alkynyl moiety leads to the vinyl-Rh species D. This complex D undergoes β- hydride elimination process completing the isomerization of internal alkyne to allene E, reforming a rhodium hydride complex B, at the same time. The allene formed undergoes second hydrometalation with Rh (III) species to form the rhodium π-allyl complex F which is in equilibrium with the linear σ-complex F'. This step is the product developing in which the allylic carbon in complex F is supposedly attacked by the azlactone nucleophile through its enol form G'. The reductive elimination step V leads to the formation of branched selective allylic product H as well as Rh (I) catalyst. This is usually final step which give the final allylic product in an inner sphere process as observed for other pronucleophiles.210
Results and Discussion | 135
In current azlactone chemistry the resulting allylic product H undergo a step further through aza-Cope rearrangement led to the formation of rearranged product H'.
Scheme.C.17. Proposed catalytic cycle for the Rh-catalyzed hydrocarbonation of internal alkynes C with azlactone G, followed by aza-Cope rearrangement
There are several other additional investigations in literature supporting the above proposed mechanism. C. Bianchini et al. had shown the preferable insertion of Rh into an O-H bond over the C-H bond219 while mechanistic investigations by Breit et al. indicated the formation of the intermediate regioisomeric allene F. The formation of isomeric allene is based on the fact that the catalysis involving allene as a starting material also led to the same branched product with comparable results.94a Additionally the mechanism is further supported by the similarities between Rh catalysis and the Ir-catalysis mentioned previously by Krische et al. for addition to 91 1,1-dimethyl allene. The regioselectivity mentioned for Rh is same to that reported 221a-c frequently for Ir. Furthermore, the above illustrated proposed mechanism can explain the formation of rearrangement product which is possible only when the catalytic cycle ended up with branched regioisomer.
Results and Discussion | 136
C.2.1.7. Synthetic Utility of the Investigated Methodology
C.2.1.7.1. Scalability of the Coupling Reaction
In order to evaluate the importance of the developed methodology in term of practical use the scalability of the coupling reaction was investigated. Due to the use of expensive rhodium precursor the typical coupling procedure was scaled relative to the limiting substrate. The scaling up of the developed reaction is necessary in order to evaluate the application of this chemistry in natural product synthesis and industry. Therefore it is essential to investigate the reproducibility of the current reactione on large scale. For this reason the catalysis with the standard substrates 2,4-diphenyl-3- oxazolinon 550 and 1-phenyl-1-propyne 551 was performed on 4.2 mmol scale (Scheme C.15)
Scheme C.18. Coupling of 1-phenyl-1-propyne 551 with 2,4-diphenyl-3-oxazolinon 550 on a 4.2 mmol scale
The above scheme represented the large scale coupling reaction under the optimized reaction conditions (Table C.16, entry 7). It is obvious that the reaction on this scale also gave the desired product in comparable yield, although with slight decrease in the overall yield (86%). 1.3 g of pure C-2 allylated azlactone 552 could be isolated. The slightly lower yield might be owed to the sensitivity of the catalytic system to environmental factors, such as oxygen and moisture which is usually more pronounced due to the necessary adjustments regarding the large reaction vessel used for the up-scaling process.
Results and Discussion | 137
C.2.1.7.2. Synthesis of 2,3,6-Trisubstituted Pyridines
Substituted pyridine is one of the most important, versatile organic substance having broad spectrum of reactivity in pharmaceuticals,222 agrochemicals,223 ligands,224 as well as in organocatalysis225 and materials science.226 The development of new synthetic methodologies for their diverse and flexible construction in atom and step economical manner from inexpensive and readily available starting materials under mild reaction conditions, has always been the main focus of synthetic organic chemists. A synthetic protocol for pyridine with variety of multi substitution patterns has always been a significant and attractive research theme in the area of synthetic organic and medicinal chemistry.227 The current hydrocarbonation methodology can be utilized to the efficient and convenient synthesis of pyridine moiety with diverse range of substitutions in controllable patterns (Scheme C.16).
Scheme C.19. Microwave assisted synthesis of tri-substituted pyridine
The key step in this strategy is the oxidative decarboxylation of 2-allyl-3-oxazolin-5- one 552 derivatives, led to aromatization of this highly substituted adduct. The aromatization occurred through the microwave assisted thermolysis accompanied with carbon dioxide extrusion, leading to nitrogen ylide intermediate which upon oxidative reorganization led to the formation of trisubstituted pyridines228 518 (Scheme C.17).
The advantage in this methodology is the use of microwave irradiation during the self- condensation reaction of sterically encumbering moiety leading to the facile synthesis of azaheterocycles.
Results and Discussion | 138
Scheme C.20. Microwave assisted carbon dioxide extrusion and rearrangement to pyridine including a mechanistic rationale
This newly developed simple sequential protocol for the synthesis of 2,3,6- trisubstituted pyridines was applied to various substituted azlactones as well as internal alkynes. Thus, after the rhodium catalyzed domino azlactone-alkyne coupling/aza-Cope rearrangement, exposure to microwaves in xylene furnished pyridines with three distinct substituents (Table C.20).
Table C.20. Sequential protocol for the synthesis of 2,3,6-trisubstituted pyridines
Results and Discussion | 139
Reaction conditions: 426 (0.25 mmol), 463 (0.375 mmol), [{Rh(cod)Cl}2] (0.01 mol), DPEphos 101
(0.02 mol), Ph2CHCOOH (0.025 mmol), DCE (1.0 mL), xylene (1.0 mL); [b] isolated yield.
The given procedure for pyridine synthesis showcases the importance and efficiency of the current methodology especially in regards to the formation of unsymmetrically substituted pyridines. 2-Allyl-3-oxazolin-5-one derivatives were directly cyclized to heterocyclic backbones by microwave irradiation in very good yield (Table C.20). Conversion of allylated azlactone to synthetically useful moieties in a single step without intermediated isolation and purification made the reaction more atom/step economical. Most of the given pyridines were prepared for the first time indicating the
Results and Discussion | 140 significance of our methodology which extends the scope of existing pyridine syntheses.218 As described earlier that rhodium catalyzed allylation of azlactone, follow a domino type reaction sequence, can be started from the substrate precursor such N-acyl amino acid leading to the final product via aza-Cope rearrangement which were also found to undergo microwave-assisted azaheterocycle formation in very good yield (Table C.19). Thus above protocol of pyridine synthesis was successfully applied to the domino azlactone allylation making a perfect cascade type sequence involving azlactone formation/azlactone-alkyne coupling/aza-Cope rearrangement/microwave assisted thermolysis to obtained trisubstituted pyridine in moderate to good yields (Scheme C.18).
Scheme.C.21. Sequential protocol for the synthesis of 2,3,6-trisubstituted pyridines starting form N-acyl amino acids.
Results and Discussion | 141
C.2.1.8. Summary and Conclusions
In this study we investigated regioselective rhodium catalyzed hydrocarbonation of internal alkynes utilizing azlactone as C-nucleophile which proceeded with concomitant aza-Cope rearrangement providing an efficient regioselective access to synthetically and pharmaceutically useful 2-allyl-3-oxazolin-5-one derivatives over isomeric 4-allyl-2-oxazolin-5-one derivatives. Good to excellent yields and regioselectivities were observed across the range of functionalized aryl and alkyl internal alkynes as well as substituted azlactone derivatives. Electron donating and withdrawing functionalities in both azlactone and alkyne coupling partners were well tolerated. The new tandem process was extended further to a triple domino reaction sequence by combining it with in situ generation of azlactone formation from the corresponding N-acyl amino acid. Various amino acids with functionalized acyl protecting groups were utilized to afford the final rearranged allylated products in good yields with excellent regioselectivities. Mechanism of reaction was studied by isolating the C-4 branched product by adjusting reaction parameters which undergo aza-Cope rearrangement to give final C-2 allylation product.
Synthetic utility and scope of the investigated hydrocarbonation methodology was evaluated by applying it to the synthesis of azaheterocycles. Various structurally appealing trisubstituted pyridine moieties were efficiently synthesized with variety of aryl substituents. The 2-allyl-3-oxazolin-5-one derivatives were aromatized to the targeted pyridines via oxidative decarboxylation through microwave assisted thermolysis. This protocol was also applied to various substituted azlactones as well internal alkynes. The newly developed simple sequential protocol for the synthesis of 2,3,6-trisubstituted pyridines was successfully applied to the triple domino azlactone allylation strategy, starting from acyl amino acids. Thus making a perfect cascade type reaction sequence involving azlactone formation/ azlactone-alkyne coupling/ aza- Cope rearrangement/ microwave assisted thermolysis to obtained trisubstituted pyridines.
Results and Discussion | 142
Concluding this section, we have developed a concise and flexible approach for the regioselective synthesis of allylated azlactone moieties which follows domino reaction sequence via the rhodium catalyzed hydrocarbonation of internal alkyne, involving aza-Cope rearrangement. The reaction proceeded with a broad spectrum of functional group tolerance allowing the coupling of various sensitive and reactive alkynes in excellent yield. Furthermore, the described catalytic pathway was utilized for de novo synthesis of trisubstituted pyridine derivatives providing an access to a variety of regioselectively substituted pyridines. This synthesis involves a microwave assisted oxidative decarboxylation requiring no special starting materials and steps. Therefore, this synthetic procedure presents a part of “new catalytic chemistry” in which the sequential transformations permit an efficient, simple, elegant, and often highly selective entry to a multitude of complex compounds. This methodology combines several reactions which occur in domino or consecutive manner to form a cascade type sequence providing an access to virtually important class of organic compound from renewable resources.
Results and Discussion | 143
Section C
C.3. Pd-PEPPSI Mediated Cross Coupling Methodology for the Synthesis of Aryl/Alkyl-Heteroaryl Amine Derivatives of Substituted Thiazoles and Oxazoles
C.3.1. Pd-PEPPSI Catalyzed Synthesis of Thiazole/Oxazole Substituted Alkyl- Aryl and Biaryl Amine Derivatives
Pd-PEPPSI catalyst system is developed by M .G. Organ for cross coupling reactions. They investigated the amination reactions utilizing their Pd-PEPPSI precatalysts by inspecting the mechanism involved and tuning the NHC backbones (Figure C.10). The Pd-PEPPSI catalysis provides a quantifying protocols for the cross couplings of most challenging substrates like electron rich alkyl-aryl chlorides and electron deficient amine counterparts.105,229a,b
Figure C.10. Pd-PEPPSI catalysts system developed by M. G. Organ
The most important component of this process is the steric and electronic environment of the two coupling partners that determines the extent of feasibility and practicality of the process as well as functional group tolerance. The nature of coupling substrate presents real challenge to the scientists to establish general, operationally simple and user friendly conditions with greater selectivity, yield and functional group tolerance.230
Results and Discussion | 144
Designing and synthesis of heterocycles is one of the most important research areas in pharmaceuticals, agriculture sciences and drug discovery. Heterocyclic building blocks play major roles in medicines, materials, copolymers, process chemistry and ligand synthesis.233 Nitrogen and sulfur heterocycles also acts as spectacular ligands for variety of organic transformations, leading many researchers to develop efficient synthetic routes to these ubiquitous structures.234 An eclectic array of these parent heterocyclic compounds can be easily prepared by classical synthetic routes. However, the transition metal catalyzed synthesis of these heterocycles present a real challenge to the researchers due to competing side reaction that may inhibit the catalytic activity of the catalyst system. One of most important inhibitory phenomenon caused by nitrogen and sulfure containing heterocycles is the catalyst poisoning.235 Therefore, the current investigation is important as it deals with cross coupling of thiazoles and oxazoles with amine, as these compounds can inhibit the catalytic behavior of the metal involved.
Pd-PEPPSI catalysis is utilized for the coupling of azole family of heterocycles to evaluate the scope of this methodology in coupling of moieties which are capable to inhibit the catalyst system. The current investigation involves cross coupling of substituted thiazole and oxazole with variety of alkyl and aryl amine, utilizing Pd- PEPPSI complexes (Scheme C.22).
Scheme C.22. Pd-PEPPSI catalyzed synthesis of thiazolo/oxazolo substituted biaryl amine derivatives
Our investigation commenced with the initial experimentation involving the cross coupling of standard thiazole substrate 4-(4-bromophenyl)-2-methylthiazole 622 with secondary amine N-methylbenzylamine 623. The desired reaction occurred in the
Results and Discussion | 145
presence of Pd2(dba)3 (2.5 mol%), rac-BINAP 281 (10 mol%) and K2CO3 in toluene at 100 °C for 24 h, leading to expected cross coupled product 624 in only 21% yield (Scheme C.23).
Scheme C.23. Initial experiment for the Pd-catalyzed cross coupling of 4-(4-bromophenyl)- 2-methylthiazole 622 with aliphatic amine
We first chose N-methylbenzylamine 623, rather than anilines due to their electron rich nature that can easily undergo amine complexation leading to relatively faster reaction rate.152
C.3.1.1. Evaluation of Ligand System for Amination of 4-(4-Bromophenyl)-2- alkyl-aryl Thiazole
The present reaction conditions used for the desired cross coupling of bromo-phenyl derivatives of thiazole and oxazole were adopted from the previous investigations on the C-N cross coupling strategies utilizing electron rich, bulky tertiary phosphine 231a-e ligands due to their established activity. Initial reaction using Pd2(dba)3/BINAP system gave only 21% yield of the desired coupling product (Table C.21, entry 1). We optimize the catalyst system by screening various combinations of Pd-precursors with mono and bidentate ligands (Table C.21).
Our initial studies involved the Pd2(dba)3 as Pd-source along with bidentate ligand BINAP 281, led to the cross coupled product in only 21% yield (entry 1). Using DPPF 76 and Xanthphos 558, the yield did not improved (entries 2 and 3). Moving to
monodentate ligand such as P(o-Tol)3 625 or P(Cy)3 626, the yields were 21% and 15% respectively (entries 4 and 5). We also investigated N-heterocyclic carbene based ligand i.e NHC-IMes 627, providing more electron rich carbene center, with an idea of
Results and Discussion | 146 in situ generation of Pd-NHC catalyst. However lesser yield was observed using this ligand (entry 6).
Table C.21. Ligands screening for amination of 4-(4-bromophenyl)-2-methylthiazole
Entry Ligand Yield (%)a
1 BINAP 281 21 2 DPPF 76 21
3 Xanthphos 558 22
4 P(o-Tol)3 625 21
5 P(Cy)3 626 15
6 NHC-IMes 627 16
Reaction conditions: 4-(4-Boromophenyl)-2-methyl thiazole 622 (0.31 mmol, 1 equiv.), N-
methylbenzylamine 623 (0.62 mmol, 2 equiv.), K2CO3 (0.628 mmol, 2 equiv.), toluene (0.3 M) at 100 °C for 24h; [a] isolated yields.
The facts behind this type of process, using free NHC-salt 627 for the amination process relied on the generation of free carbene in situ from a precursor azolium salt in the presence of a Pd(II) or Pd(0) source.131a,232 The rate and efficiency of active catalyst formation is, however difficult to control under the usual reaction conditions leading not only to potential wastage of precious Pd-metal as well as ligand precursor but also results in poor reproducibility.132-136
Results and Discussion | 147
C.3.1.1.1. Change of Amination Methodology: Utilization of Pd-PEPPSI Precatalysts
The above optimization of phosphine based and NHC based ligands for the current amination process, it is obvious that our thiazole coupling counterpart did not react in the above utilized reaction conditions.
To circumvent the aforementioned drawback associated with in situ generated catalytic systems (entry 6), we utilized well-defined, air and moisture-stable Pd- PEPPSI precatalyst (Figure C.11) in order to enhance the scope and utility of these complexes. These types of precatalysts allow a strict control of the ligand/palladium ratio (1:1) and enhanced catalytic activity (Table C.22).
Figure C.11. Phosphine and NHC based ligands systems utilized in this protocol
Results and Discussion | 148
Pd-PEPPSI precatalysts (PEPPSI = pyridine enhanced precatalyst preparation stabilization and initiation) mediated amination methodology is vastly investigated by Micheal G. Organ and co-workers.139-141 They demonstrated the modification of the ligand, possessing most efficient reactivity leading to the amination of profoundly deactivated coupling systems. This procedure presents most simple and proficient amination methodology for diverse array of sensitive functionality.137,149,150
Table C.22. Screening of Pd-PEPPSI complexes for amination of 4-(4- bromophenyl)-2-methylthiazole
Entry Pd-Precursor Yield (%)a
1 Pd-PEPPSI-IMes 331 20
2 Pd-PEPPSI-IPr 333 85
3 Pd-PEPPSI-IPent 335 95
4 Pd-PEPPSI-IPentCl 336 99
Reaction conditions: 4-(4-Boromophenyl)-2-methyl thiazole 622 (0.31 mmol, 1 equiv.), N- methylbenzylamine 623 (0.62 mmol, 2 equiv.), KOtBu (0.628 mmol, 2 equiv.), toluene (0.3 M) at 100 °C for 24h; [a] Isolated yields.
From the above catalyst optimization studies (Table C.22), it is obvious that the steric bulk of the NHC ligand play an important role in the generation of C-N coupled product. The steric bulk of NHC ligand helps in reductive elimination as the amine complex formed is more stable due to the steric shielding, decreasing the chance of competing β-hydride elimination leading to increase in the extent of cross coupling reaction. As the yield for the secondary alkyl amine 623 coupling with our standard 4- (4-bromophenyl)-2-methylthiazole 622 was very low with Pd-PEPPSI-IMes 331 (entry 1) which gradually increased to 85% in going to Pd-PEPPSI-IPr 333 (entry 2). The fact behind the increase in the rate of the cross coupling reaction is well
Results and Discussion | 149 established from the literature that the use of sterically demanding and electron rich ligands such as N-heterocyclic carbenes help to facilitate the oxidative insertion of less reactive aryl moieties by providing more electron rich metal center. The steric bulk of NHC ligands enhance the rate of reductive elimination of the final product which determines the yield of the reaction.137,138 The trend in the reactivity can be seen from the above catalyst optimizations Table C.22, as there is a sharp increase in the yield with the increase in the steric bulk of the ligand. Thus precatalyst with more sterically demanding NHC-backbone such as Pd-PEPPSI-IPent 335 and Pd-PEPPSI-IPentCl 336 led to final coupled product in nearly quantitative yields (entries 3 and 4).
C.3.1.1.2. Pd-PEPPSI Catalyzed Synthesis of Thiazole/Oxazole Substituted Aniline: Cross Coupling of Heteroaryl Derivatives with Aromatic Amine
Amine compounds constitute one of the most diverse classes of organic compounds. Aromatic amines behave very differently from the aliphatic one. This fact presents a real challenge when come to investigate the amine reactivity. In the current investigations we reported the synthesis of thiazole/oxazole substituted aniline by coupling of heteroaryl derivatives with various aromatic amines. We started our investigation by studying the cross coupling of 4-methylaniline with model substrate 4-(4-bromophenyl)-2-methylthiazole using Pd-PEPPSI-IPr 333 catalyst system (Scheme C.24).
Scheme C.24. Initial experiment for the Pd-PEPPSI catalyzed cross coupling of 4-(4-bromophenyl)-2-methylthiazole with aromatic amine
The reaction led to the formation of final amination product in 45% yield while under same reaction conditions the representative aliphatic amine N-methylbenzylamine gave 85% of cross coupled product (Table C.22, entry 2). The fact goes back to
Results and Discussion | 150
basicity of aromatic amine as well as their varying behavior during the reaction. By compare the pKa of a typical secondary amine such as N-methylbzylamine and morpholine which are in range of 30-35 with that of aniline (pKa ~25),152b anomalous behavior could expect during addition/coordination process with Pd due to its electron poor nature relative to alkyl amines.
In the amination catalytic cycle (Scheme A.82) the electronic nature of the Pd-metal changes from being nucleophilic (during oxidative addition (OA)) to being electrophilic during amine coordination/deprotonation and reductive elimination steps. Due to the strong σ-donating nature of N-heterocyclic carbenes,236 the amine coordination and/or deprotonation become rate limiting steps rather than the oxidative addition step.128,131,132 Therefore the electron rich Pd-center discourage the amine coordination/deprotonation of aryl-Pd-amide complex (C, Scheme A.82). Thus the relative more electron rich character of Pd-PEPPSI-IPr derivative is the reason behind the low yield of aromatic amine coupling with our 4-(4-bromophenyl)-2- methylthiazole substrate.
Table C.23. Base screening for amination of 4-(4-bromophenyl)-2-methylthiazole with aromatic amine using Pd-PEPPS-IPr complex
Entry Base Yield (%)a
1 KOtBu 45 2 NaOtBu 54
3 K3PO4 n.r 4 KOH n.r 5 NaOH n.r
Reaction conditions: 4-(4-Boromophenyl)-2-methyl thiazole (0.31 mmol, 1 equiv.), 4- methylaniline (0.62 mmol, 2 equiv.), base (0.628 mmol, 2 equiv.), toluene (0.3 M) at 100 °C for 24 h; [a] Isolated yield.
Results and Discussion | 151
The fact that the deprotonation of aryl-Pd-amide complex is a rate limiting step led us to screen the base and solvent for the above process.
The choice of base was critical, as shown by the above Table C.23. The most appropriate base in this process was sodium tert-butoxide (entry 2) which is one of the strongest organic bases leading to the desired product in 54% yield. Other strong inorganic bases were also optimized in the current coupling reaction but neither proved to be good for this conversion. Thus, we considered the sodium tert-butoxide as suitable base for amination of our heterocyclic system using aromatic amines.
Solvent also play an important role in the catalyst activation129,141,154 and can improve the rate of reaction leading to high yield of the desired product. We screened various organic solvent using our standard reaction conditions (Table C.24).
Table C.24. Solvent screening for amination of 4-(4-bromophenyl)-2- methylthiazole with aromatic amine using Pd-PEPPS-IPr complex
Entry Base Yield (%)a
1 Toluene 54 2 THF n.r
3 DMF 10 4 DMSO <5 5 1,4-dioxane 10
Reaction conditions: 4-(4-Boromophenyl)-2-methyl thiazole (0.31 mmol, 1 equiv.), 4- methylaniline (0.62 mmol, 2 equiv.), NaOtBu (0.628 mmol, 2 equiv.), solvent (0.3 M) at 100 °C for 24 h; [a] Isolated yield. From the solvent screening, toluene is proved to be an appropriate solvent for the coupling of our substrate, using Pd-PEPPSI complexes (Table C.24).
Results and Discussion | 152
Reaction conditions optimization for hetero-aryl substrate coupling with aromatic amine, utilizing Pd-PEPPSI-IPr catalyst revealed that this representative complex sluggishly catalyzed the current process as compare to the amination with aliphatic amine, where it worked well (Table C.22). Furthermore, optimizations of other reaction parameter did not show any improvement in the reaction. Thus we moved further to vary the steric and electronic properties of ancillary ligands by utilizing various other Pd-PEPPSI complexes. The main basic advantage of the use of PEPPSI series of catalyst is the easy tunibility of the NHC backbone which greatly alter the reactivity and efficiency of the catalyst system. Organ et al. by modifying the backbone of the NHC core, observed a profound impact on reactivity and selectivity, thereby leading to dramatic improvements in cross-coupling reactions.137a-d Thus the synthesis of Pd–PEPPSI-IPent 335 and Pd–PEPPSI-IPentCl 336 by introducing the 2,6-di(3-pentyl) groups on the phenyl rings of the imidazolium backbone of the ligand. The incorporation of these bulky neo-pentyl groups imparting bulkiness and flexibility to the NHC ligand which was the most impressive and major breakthrough achieved by Organ and coworkers to address the reaction of most challenging combination of substrates.131a,107a,137b,f Thus we utilized these precatalyst in our present investigation in order to increase the extent and yield of amination of our thiazole and oxazole substrate with aromatic amine (Table C.25).
Table C.25. Screening of Pd-PEPPSI complexes for amination of 4-(4- bromophenyl)-2-methylthiazole with aromatic amine
Entry Pd-Precursor Yield (%)a
1 Pd-PEPPSI-IMes 331 <10
Results and Discussion | 153
2 Pd-PEPPSI-IPr 333 54
3 Pd-PEPPSI-IPent 335 68 4 Pd-PEPPSI-IPentCl 336 88
5 Pd-PEPPSI-IHept 339 99
Reaction conditions: 4-(4-Boromophenyl)-2-methylthiazole (0.31 mmol, 1 equiv.), 4- methylaniline (0.62 mmol, 2 equiv.), NaOtBu (0.628 mmol, 2 equiv.), toluene (0.3 M) at 100 °C for 24h; [a] Isolated yield.
The most impressive results were obtained in going from Pd–PEPPSI-IPr 333 to Pd– PEPPSI-IPentCl 336 increasing the yield up to 88% (entry 4). The yield became nearly quantitative when Pd-PEPPSI-IHept 339 was used because of the most sterically encumbered NHC backbone in this type of ligand. The reason behind this reactivity order could explain on the basis of reaction mechanism (Scheme A.82). As it is established by the M. G. Organ that neither the oxidative addition step (aryl halide insertion upon the Pd-center) nor the reductive elimination of the product, are the rate limiting steps in the amination process.114,129,132,136b It is established that the rate limiting step in this process is the amine coordination to form Pd-ammonium complex as well as (in some cases) the deprotonation of this complex to give Pd-amine complex which further undergo reductive elimination to give the cross coupling product.139a.,141,144 The most reactive and general catalyst would be one that combines bulk around the Pd center, to assist reductive elimination as well as relatively electron poor Pd-center that encourage aniline coordination and promote deprotonation. Thus the Pd-PEPPSI-IPentCl 336 presents combination of these structural features, having bulky IPent (3-pentyl) groups and the electron-withdrawing chlorine atoms, leading to promote very difficult and challenging cross coupling reactions.137a
Concluding the above optimization process all the possible parameters were screened in order to improve the yield of the cross coupled product. We succeeded to improve the yield of the desired product by changing the backbone of the ancillary ligand in Pd-PEPPSI complex. Thus the final optimized conditions, for synthesis of ary- heteroaryl amine derivatives via amination of 4-(4-boromophenyl)-2-methylthiazole with aromatic amine, are illustrated in the Scheme C.25.
Results and Discussion | 154
Scheme C.25. Optimized conditions for the Pd-PEPPSI catalyzed amination of 4-(4- boromophenyl)-2-methylthiazole 622 with 4-methyl aniline 629
The Pd-PEPPSI mediated amination protocol utilized for the syntheses of biaryl or alkyl-aryl amine derivatives of thiazole/oxazole heterocycles is reported for the first time with very good results. In order to evaluated the generality of the process as well as making the reaction more appealing in practical point of view this methodology was inspected further. Various substituted heterocyclic substrates and diverse range of amine counterpart, both alkyl and aryl, were utilized in order to synthesize heterocyclic amine moieties which could be lead precursors in the synthesis of biologically active entities.
C.3.1.2. Substrate Scope for Pd-PEPPSI Catalyzed Synthesis of Biaryl or Alkyl- Aryl Amine Derivatives of Thiazole Heterocycle
The optimized reaction conditions, utilizing Pd-PEPPSI-IPentCl catalyst, for the amination of thiazole derivatives with aliphatic and aromatic amine counterparts assessed after series of condition screening, illustrated in Scheme C.25. We further evaluated the generality of this protocol by applying to a variety of functionalized aromatic /aliphatic amine as well as to different thiazole skeletons.
The optimized reaction conditions were applied to increase the substrate scope. The effect of the electronic environment of the aniline on the rate of cross coupling reaction in thiazole amination, are depicted in the above table (Table C.26).
Results and Discussion | 155
Table C.26. Scope exploration for 4-(4-boromophenyl)-2-methyl thiazole amination under optimized reaction conditions
Results and Discussion | 156
Results and Discussion | 157
Reaction conditions: 4-(4-Boromophenyl)-2-methyl thiazole (0.31 mmol, 1 equiv.), aryl/alkyl- amine (0.62 mmol, 2 equiv.), NaOtBu (0.62 mmol, 2 equiv), toluene (0.3 M) at 100 °C for 24 h; [a] Isolated yield; [b] Pd-PEPPSI-IPent (2 mol%); [c] 3 equiv. of base used; [d] Pd-PEPPSI-IPentCl (4 mol%) and 3 equiv. of base used; [e] Pd-PEPPSI-IPr (2 mol%).
The results were comparable and aligned closely according to the observation regarding the Pd-PEPPSI catalyst behavior. As it described in the literature that the electron-donating groups on the aniline increase the rate, as the coordination of amine made feasible by the electron donating group.144,141,152 A similar trend was indicated in the amination of 4-(4-bromophenyl)thiazole derivative, in going from more electron donating to electron withdrawing substituents. The methoxy substituted anilines (entries 4-6) the yields obtained were high (90-96%) with even simple Pd-PEPPSI- IPent 335 system. When methyl substituted anilines as well as simple aniline were used, the yield slightly decrease to 88% however became nearly quantitative when the amount of base was increased to 3 equivalents (entries 1-3). Mono and di halogenated anilines were also proved to be reactive coupling partner in thiazole amination as were coupled in good to excellent yield (entries 7-10). There is slight decrease in the reaction yield when electron deficient anilines were utilized in this methodology, such as 3-triflouromethyl 650 and 4-nitroaniline 652, the yield observed were 88 and 90% (entries 11 and 12). Increasing the catalyst and base loadings, the yield increases to 98% and 96% respectively. N-substituted aniline 654 was also successfully coupled with the standard substrate leading to the formation of trisubstituted amine in 79% yield (entry 13). Aliphatic amines were successfully coupled in very good yield, utilizing Pd-PEPPSI-IPr 333 catalyst. N-Methylbenzylamine 623 and morpholine 658 were proved to be nice coupling counterparts in this system, yielding the desired
Results and Discussion | 158
coupled product in range of 85-88% while with Pd-PEPPSI-IPent 335 (2 mol%) the reaction gave the cross coupled products in nearly quantitative yields (entries 14 and 16). n-Butylamine 656 behaved different in comparison to the other aliphatic amine as utilizing PEPPSI-IPr 333 catalyst it led to desired coupled product in just 15% yield but changing the catalyst system to Pd-PEPPSI-IPentCl 336 (2 mol%), it furnished the cross coupled product 657 in 79% yield.
Under the optimized condition, the generality of this reaction was further explored using phenyl substituted thiazole substrate (4-(4-boromophenyl)-2-phenylthiazole)) 682. This substrate was used to cross coupled with electron rich and electron deficient anilines as well as aliphatic amine counterparts (Table C.27).
Table C.27. Exploration of 4-(4-boromophenyl)-2-phenyl thiazole amination under optimized reaction conditions
Results and Discussion | 159
Reaction conditions: 4-(4-Boromophenyl)-2-phenylthiazole (0.31 mmol, 1 equiv.), aryl/alkyl-amine (0.62 mmol, 2 equiv.), NaOtBu (0.93 mmol, 3 equiv.), toluene (0.3 M) at 100 °C for 24 h; [a] Isolated yield.
Amination of phenyl substituted thiazole skeleton also proved the generality and efficiency Pd-PEPPSI catalysis for C-N bond forming reaction. In this case (4-(4- boromophenyl)-2-phenylthiazole)) 660 was cross coupled with 4-methoxyaniline 636 as a representative example for electron rich aniline, in 88% yield (entry 1). 3- Triflouromethylaniline 650 led to the desired product in 74% yield (entry 2), representing that the electron deficient aniline also gave excellent coupling with phenyl substituted thiazole. Morpholine 658, as an example of aliphatic amine, was also successfully coupled furnishing the desired cross couple products 663 in excellent yield of 80% (entry 3).
The reaction scope exploration for amination of thiazole derivatives with variety of aromatic and aliphatic amine, utilizing Pd-PEPPSI catalyzed amination protocol proved the practicality of this procedure. This synthetic procedure proceeded with step economy leading to the synthesis of alkyl-aryl amine derivatives of substituted thiazole heterocycles, generating a number of heterocyclic amine moieties.
C.3.1.3. Synthesis of Oxazole Anilines via Pd-PEPPSI-IPentCl Catalyzed Amination of Br-phenyl Oxazole Heterocycles
Oxazole are isoelectronic to thiazoles, belonging to the same family of azole, with closely related properties and synthetic behavior. Encouraged by the above mention results for Pd-PEPPSI catalyzed amination obtained with thiazoles, we applied this methodology for the amination of oxazole, in order to synthesize various aromatic oxazole amine derivatives. Applying the standard reaction conditions, optimized earlier for thiazole derivatives, it was found that both methyl and phenyl substituted oxazole could employed as suitable substrate in the current amination procedure,
Results and Discussion | 160 giving the corresponding desired products in good yields. The results are summarized in Table C.28.
Table C.28. Scope exploration for 4-boromophenyl substituted oxazole amination under optimized reaction conditions
Reaction conditions: 4-(4-Boromophenyl)-2-methyl/phenyl oxazole (0.31 mmol, 1 equiv.), aniline (0.62 mmol, 2 equiv.), NaOtBu (0.62 mmol, 2 equiv), toluene (0.3 M) at 100 °C for 24 h; [a] Isolated yield.
Under the optimized condition, the current Pd-PEPPSI catalyzed amination protocol was utilized for the amination of various oxazole derivatives, by coupling methyl as well as phenyl substituted oxazole substrates (4-(4-boromophenyl)-2-methyloxazole)
Results and Discussion | 161
664 and 4-(4-boromophenyl)-2-phenyl oxazole) 665, with substituted anilines. Both of the substrates were cross coupled with electron rich and electron deficient aniline counterparts (Table C.28). The results illustrated in the above table, are in complete accordance with trend observed in the amination of thiazole. Methoxy substituted aniline 636 gave the cross coupling products (666, 668) in excellent yield in both case (entries 1 and 3), while slight decrease in yield was observed with 4-triflouroaniline 650, furnishing the cross coupled products (667, 669) in range of 78%-85% (entries 2 and 4).
Results and Discussion | 162
C.3.1.4. Summary and Conclusion for Section C
The current investigation deals with synthesis of azole based amines. Various derivatives of thiazole and oxazole are utilized as representative members of azole family. Pd-PEPPSI catalyzed amination strategy was utilized to cross couple azole derivatives with diverse range of functionalized anilines and aliphatic amines to synthesized respective aryl-alkyl and heteroaryl amines in excellent yield using mild reaction conditions. Both electron-donating and electron-withdrawing substituted aniline were well tolerated in the reaction with various azole derivatives.
This protocol allowed us to prepare a diverse range of structurally intriguing, drug-like aromatic amines by utilizing both electron-deficient and electron-rich anilines cross coupled with thiazole/oxazole based heteroaryl bromide moieties. It is shown that Pd- PEPPSI complexes are effective catalysts for the coupling of aliphatic amines as well mono- and disubstituted anilines to heteroaryl bromide. Aniline nucleophiles, being intrinsically electron poor presenting a class of reluctant coupling partners in the amination process. Therefore the above investigation is an effective extension to the amination of heterocycles. Broad spectrum of functionalized anilines were coupled, leading to a successful transformation that permit an efficient, simple and elegant process to synthesis a diverse thiazole and oxazole based amine which could present highly active biological entities as well as may serve as precursors for drug synthesis.
Summary| 163
D. Summary
D.1. Regio- and Enantioselective Pyridazinone Addition to Terminal Allenes
The first task of this PhD work was to develop intermolecular rhodium catalysis for the regio- and enantioselective addition of pyridazinones to terminal allenes. Optimization of the reaction conditions were performed, led to the successful completion of current investigations. The bulky (S)-3,5-iPr-4-NMe2-MeOBiphep 485 was found to be the best ligands for the present transformation (Figure D.1).
Figure D.1. The best ligands for the present regio- and enantioselective rhodium catalyzed pyridazinone addition to terminal allenes
Various branched N-allylic pyridazinones were synthesized in good to excellent yields as well as enantioselectivities (Scheme D.1).
Scheme D.1. Newly developed strategy for regio- and enantioselective Rh-catalyzed pyridazinones addition to terminal allenes
Summary| 164
Follow up chemistry with these branched N-allylic pyridazinone moieties were successfully performed allowing the synthesis of various interesting substituted diazinones derivatives (Scheme D.2) with good yields.
Cl (c) (a) Cl N N N O N O Ph O Cl Ph Me 3 3 N 548 N O 546 Ph Cl 3 Cl
N (d)473 (b) N N O N O Ph O Ph OH 3 3 549 547
o [a] Pd/C (10 mol%), H2 (1atm.), MeOH, 0 C, 10 h, 96%; [b] 9-BBN (excess), THF, o o -78 C-rt, 16 h; then H2O2,NaOH,-10 C - rt, 5 h, 78%; [c] [{Rh(CO)2acac}] (0.5 mol%), 6-DPPon (10 mol%), CO/H2 (1:1, 20 bar), toluene, 80 °C, 20 h, 91% (L/B 9:1); [d] O3; o PPh3, DCM, -78 C then rt, 5 h, 82%.
Scheme D.2. Assorted transformations of N-allyl pyridazinone
D.2. Rhodium-Catalyzed Regioselective Addition of Azlactone to Internal Alkyne and its Utilization for Heterocyclic Synthesis
The second task of this PhD work was to investigate the regioselective rhodium catalyzed hydrocarbonation of internal alkynes utilizing azlactone as C-nucleophile. Preliminary reaction condition optimizations showed that the azlactone allylation preceded with concomitant aza-Cope rearrangement wich provid an efficient regioselective access to synthetically and pharmaceutically useful 2-allyl-3-oxazolin- 5-one derivatives over isomeric 4-allyl-2-oxazolin-5-one derivatives (Scheme D.3).
Summary| 165
Scheme D3. Regioselective rhodium catalyzed coupling of azlactone 426 with 1- phenyl-1- propyne 463
Good to Excellent yields and regioselectivities were observed across the range of functionalized aryl and alkyl internal alkynes as well as substituted azlactone derivatives. The new tandem process was extended further to a triple domino reaction sequence by combining it with in situ generation of azlactone formation from the corresponding N-acyl amino acid. Various amino acids with functionalized acyl protecting groups were utilized to afford the final rearranged allylated products in good to excellent yields with excellent regioselectivities.
Synthetic utility and scope of the investigated methodology were evaluated by applying to the synthesis of azaheterocycles. Various structurally appealing trisubstituted pyridine moieties were efficiently synthesized with variety of aryl substituents (Scheme D.4).
Summary| 166
Scheme D.4. Microwave assisted synthesis of trisubstituted pyridine
This protocol was applied to various substituted azlactones as well internal alkynes. The newly developed simple sequential protocol for the synthesis of 2,3,6- trisubstituted pyridines was successfully applied to the triple domino azlactone allylation strategy, starting from acyl amino acids. Thus making a perfect cascade type reaction sequence involving azlactone formation/ azlactone-alkyne coupling/ aza- Cope rearrangement/ microwave assisted thermolysis to obtained trisubstituted pyridines.
D.3. Pd-PEPPSI Mediated Cross Coupling Methodology for the Synthesis of Aryl/Alkyl-Heteroaryl Amine Derivatives of Substituted Thiazoles and Oxazoles
The third task of this PhD work was to investigate the application of Pd-PEPPSI catalysed Buchwald-Hartwig amination strategy for alkyl-aryl and heteroaryl amine synthesis (Scheme D.5). The target of this study was the synthesis of azole based amines.
Summary| 167
Scheme D.5. Pd-PEPPSI mediated cross coupling reaction for thiazole and oxazole amines synthesis
Various derivatives of thiazole and oxazole were utilized as representative members of azole family. Pd-PEPPSI precatalysts were successfully utilized to cross couple these azole derivatives with diverse range of functionalized anilines and aliphatic amines to synthesized respective alkyl-aryl and heteroaryl amines in excellent yield. Both electron-donating and electron-withdrawing substituted aniline were well tolerated in the reaction with various azole derivatives.
Experimental Part | 168
E. Experimental Part
E.1. General Remarks E.1.1. Working Techniques
All the experiments in Section A and B in this dissertation were performed at the Institute for Organic Chemistry of the Albert-Ludwig’s-University Freiburg in the research group of Prof. Dr. Bernhrd Breit while that for section C were performed at the Department of Chemistry, QAU Islamabad in Dr. Abbas research group.
All reactions were carried out in flame-dried glassware under inert atmosphere (argon/nitrogen). All the glasswares were flame-dried under vacuum, cooled to room temperature and backfilled with argon. All the Rh-catalyzed reactions for the newly developed methodologies were carried run in screw-cap flasks/tubes with a YOUNG cap in order to ensure an oxygen-free atmosphere throughout the reaction (Figure E.1).
Figure E.1. Screw-cap flasks for the Rh-catalyzed coupling reactions (a: 10 ml, b: 1 ml).
Experimental Part | 169
All given yields are isolated yields, unless noted differently. The conversions given for catalytic reactions were determined from the crude 1H-NMRs of the reaction mixture.
E.1.1.1. Chromatography
Thin Layer Chromatography (TLC) was performed on aluminum plates pre-coated with silica gel (MACHEREY-NAGEL, SIL G-25, UV254), developed using different mixtures of solvents, given as under: hexanes, dichloromethane, diethylether, ethyl acetate, methanol, pet-ether and pentane. The TLC plates were visualized under UV fluorescence (max = 254 nm), and/or by staining/spraying with one of the mixtures given below followed by drying using heating gun.
KMnO4 stain: KMnO4 in 0.5 M aq. K2CO3 (1% w/v). Ninhydrin stain: ninhydrine (0.6 g ) and 6 ml glacial acetic acid in n- butanol (200 ml). Anisaldehyde stain: anisaldehyde (5 ml), glacial acetic acid (3.75 ml)
and conc. H2SO4 (12.5 ml) in 250 ml ethanol
Chromatographic purification was performed using silica gel (230-400 mesh). For products sensitive to oxidation degassed solvents were used and the purification performed under argon pressure (Argon 5.0, Sauerstoffwerk Friedrichshafen).
Chiral HPLC, performed on MERCK HITACHI HPLC apparatus having the following specifications, pump: L-7100, UV detector: D-7400, oven: L-7360; columns: Chiralpak AD-3, AD-H, IC, Chiralcel OD-3, OD-H, OJ-H, (25cm x 4.6mm), Daicel Lux C-1, C-2, C-3, C-4, (50cm x 4.6mm).
E.1.1.2. Nuclear Magnetic Resonance
NMR (Nuclear Magnetic Resonance) spectroscopic data were recorded on a BRUKER Avance 400 spectrometer with frequencies 400 MHz and 100.61 MHz for 1H and 13C respectively, and/or on VARIAN Mercury (300 MHz and 75.5 MHz for 1H and 13C respectively).
Experimental Part | 170
Unit for all 1H NMR spectra used, is ppm (parts per million), downfield of TMS and were measured relative to the chloroform signals at 7.26 ppm. 13C NMR spectra were
also reported relative to residual CHCl3 signal at 77.16 ppm and were obtained with 1H-decoupling. 1H NMR data for all molecules are described in the following method; chemical shift (in ppm), multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; quin, quintet; m, multiplet; br. s. broad signal), coupling constant (Hz). Data for 13C NMR spectra are described in term of chemical shift values () described in ppm. All 13C-
NMR spectra were reported in ppm values, taking either residual CHCl3 (77.16 ppm)
or residual C6D5H (128.06 ppm) peaks as an internal standard.
E.1.1.3. Mass Spectrometry
HRMS (High resolution mass spectrometry) were obtained on a Thermo Scientific Advantage and a Thermo Scientific Executive instrument at the Analytic Department at the Institute for Organic Chemistry, University of Freiburg Germany, using chemical ionization mass spectrometry (110 eV, source temperature 200 °C), performed on a TSQ 700 mass spectrometer. EI mass spectra were recorded on a Thermo Scientific TSQ 700 (ionization energy: 70 eV, source temperature: 200 °C) while ESI and APCI high resolution mass spectra were obtained on a Thermo Scientific Executive instrument and a Finnigan MAT 95XL, a Thermo Scientific Advantage with given specifications: (2.5 μL/min sample solution carried in a flow of 100 μL/min MeOH/MeCN with spray voltage 4-5 kV, and ion transfer tube temperature 250-300 °C, vaporizer: 300-400 °C).
E.1.1.4. Optical Rotation
The optical rotation of chiral compounds was determined on a A. Krüss Optronic P8000-T apparatus and calculated for a given temperature according to the following formula:
Experimental Part | 171
: measured value for optical rotation d: length of the cuvette in dm T: temperature in °C c: concentration in g/100 ml
E.1.1.5. Melting Points
The melting points for solids were measured on a Büchi Dr. Tottoli melting point apparatus.
E.1.2. Drying, Degassing and Purification of Solvents
Hexanes and ethyl acetate used in extractions and column chromatographic purification were distilled using rotary evaporator. Other solvents were purchased in analytical grade and used without further purification. Flasks for absolute solvents were flame-dried three times under oil pump vacuum and backfilled with argon. Unless mentioned otherwise, absolute solvents were dried prior to being filled into the flasks using a M. Braun Solvent Purification System 800. For this the solvents were dried over two separate columns. All absolute solvents and reagents were dried and purified as follows and stored under argon.
1,2-Dichloroethane: Distilled over CaH2 and Degassed by three freeze-pump-thaw cycles. Ethanol: Degassed by purging for 1 h with a constant flow of argon.
Tetrahydrofuran: Distilled over sodium metal and degassed by three freeze pump- thaw cycles.
Toluene: Distilled over sodium metal and degassed by three freeze-pump-thaw cycles.
Experimental Part | 172
E.1.3. Starting Materials and Reagents
Substrates: Various substituted pyridazinones were purchased from Sigma-Aldrich, ABCR, Alfa Aesar while some are derivatized from dichloro precursors, using literature reported procedures.237 Allene and alkyne substrates were also purchased from Sigma-Aldrich, ABCR, Alfa Aesar while some were synthesized according to known procedures in our group.
Ligand and Rhodium catalyst: Ligands and rhodium precursors were purchased from Sigma-Aldrich, ABCR, Alfa-Aesar and used without further purifications. MeO- Biphep based ligands used in the schemes was either purchased or synthesized in the laboratory using standard procedures.238
Deuterated samples: Deuterated pyridazinone was prepared by dissolving 6-Chloro-
(2H)-pyridazin-3-one in a mixture of D2O and CD3OD followed by evaporation of the solvents under reduced pressure. Three times reiteration of this procedure delivered deuterated pyridazinone with a deuterium-hydrogen exchange resulting in greater than 99% deuterium labeling.
Experimental Part | 173
Section A
E.2. Rhodium Catalyzed Pyridazinone Addition to Terminal Allene
E.2.1. Substrate Syntheses
E.2.1.1. Synthesis of hexa-4,5-dien-1-ylbenzene (472)
Scheme E.1. Synthesis of hexa-4,5-dien-1-ylbenzene
The precursor was prepared according to a modified procedure reported by Jamison et al.239
To magnesium turnings (2.48 g, 102 mmol, 1.2 equiv.) in THF (50 mL) a solution of 1-bromo-3-phenylpropane (13.0 mL, 17.0 g, 85.4 mmol) in THF (150 mL) was added dropwise. After addition the mixture was heated to reflux for 1.5 h. After cooling to −78 °C LiBr (2.00 g, 23.0 mmol, 27 mol%) and CuBr (1.00 g, 6.97 mmol, 8 mol%) in THF (50 mL) were added. A solution of propargyl bromide (80% solution in toluene, 11.0 mL, 12.1 g, 102 mmol, 1.2 equiv.) in THF (30 mL) was added slowly, maintaining the temperature below −50 °C. After stirring for additional 15 min at −78 °C the mixture was allowed to warm to rt. The mixture was quenched with saturated aq. NH4Cl solution (200 mL) and separated the aqueous phase followed by extraction with pentane (3 × 100 mL). The organic phases were combined, dried over Na2SO4 and concentrated using rotary vacuum evaporator. Flash chromatographic purification using pentane could not yield a pure product. A second purification was done by vacuum distillation (0.7 mbar, 65 °C), providing the alkyne as a colorless oil (7 g, 50%). Utilization of synthesized alkyne second step for the synthesis of desired allene
Experimental Part | 174
product was done according to the reported procedure (Beauchemin et al).240 To a stirred solution of 5-phenylpentyne (5 g, 33.0 mmol), taken in 1,4-dioxane solvent (300 mL), were added paraformaldehyde (2.1 g, 66 mmol, 2.0 equiv.), dicyclohexylamine (13 mL, 12 g, 66.1 mmol, 2.0 equiv.) and CuBr (1.42 g, 10 mmol, 0.3 equiv.). The resulting reaction mixture was refluxed for 18 h. After completion, the reaction mixture was cooled to room temperature and was filtered through a pad of silica, washed with DCM and concentrated under vacuum. The resulting mixture was purified by flash chromatography using pentane and the desired allene was obtained after vacuum distillation (120 °C, 10 mbar) as a colorless liquid (4.4 g, 23.7 mmol, 73%).
Analytical Data of 472:
TLC (SiO2): Rf = 0.55 (hexanes: ethyl acetate = 5:1) 1 HNMR (400 MHz, CDCl3): δ = 7.34–7.25 (m, 2 H), 7.22–7.16 (m, 3 H), 5.15-5.12 (m, 1 H), 4.70 (td, J = 3.4, 6.7 Hz, 2 H), 2.71–2.62 (m, 2 H), 2.10–2.02 (m, 2 H), 1.81–1.73 (m, 2 H). 13 CNMR (100 MHz, CDCl3): δ = 208.5, 142.6, 128.7, 128.4, 125.9, 89.9, 75.1, 35.4, 30.9, 27.9. The analytical data for the compound is in accordance with that of the previously reported one.241
E.2.1.2. Synthesis of 2-(hexa-4,5-dien-1-yl)isoindoline-1,3-dione (509)
Scheme E.2. Synthesis of 2-(hexa-4,5-dien-1-yl)isoindoline-1,3-dione 509
86 Prepared in analogy to a literature procedure.
Experimental Part | 175
The solution of 2-(pent- 4-yn-1-yl)isoindoline-1,3-dione (2.13 g, 10.0 mmol) in 1,4- dioxane (100 ml) was added with dicyclohexylamine (4 ml, 20.0 mmol, 2 equiv.), CuBr (430 mg, 3 mmol, 0.3 equiv.), and paraformaldehyde (750 mg, 25.0 mmol, 2.5 equiv) and allowed to stirred at reflux temperature for 18h. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was dissolved in diethyl ether, filtered through silica pad and dried under vacuum. The crude product was purified by flash column chromatography using pet.ether/ethyl acetate as eluting system (9:1), affording the allene product as white solid (1.73 g, 77 %).
Analytical Data of 509:
TLC (SiO2): Rf = 0.25 (pet. ether: ethyl acetate = 9:1).
1 H-NMR (300 MHz, CDCl3): = 7.85-7.83 (m, 2H), 7.72-7.70 (m, 2H), 5.14-5.12 (m, 1H), 4.69-4.67 (m, 2H), 3.72 (t, J = 7.3 Hz, 2H), 2.08-2.06 (m, 2H), 1.84-1.81 (m, 2H) ppm.
13 C-NMR (100 MHz, CDCl3): = 208.6, 168.5, 134.0, 132.3, 123.3, 89.0, 75.5, 37.6, 27.8, 25.6 ppm. The analytical data of the compound was in complete agreement with the literature reported values.242
E.2.1.3. Synthesis of 1-(propa-1,2-dien-1-yl)cyclohexanol (501)
(a) 1-Ethynylcyclohexanol (501a):
Scheme E.3. Synthesis of 1-Ethynylcyclohexanol 501a
The solution of cyclohexanone (4.2 ml, 40 mmol, 1.0 equiv.) in dry THF (10 ml) was added ethynylmagnesium bromide (96 ml (0.5 M in THF), 48 mmol, 1.2 equiv.). The
Experimental Part | 176
temperature was maintained at 0 °C. After 20 min stirring at this temperature, the reaction mixture was allowed to warm at rt and concentrated under vacuum. The
residues were quenched with saturated aq. NH4Cl (10 ml) and the aqueous layer was
extracted with Et2O (3 × 20 ml). The combined organic fractions were dried over
Na2SO4 and concentrated under vacuum. The desired alkyne was purified by vacuum distillation (bp. 82-86 °C) colorless oil (4.5 g, 90%).
Analytical Data of 501a:
1 H-NMR (300 MHz, CDCl3): = 2.48 (s, 1H), 1.83-1.98 (m, 2H), 1.65-1.76 (m, 2H), 1.63-1.49 (m, 5H), 1.16-1.37 (m, 1H) ppm.
13 C-NMR (100 MHz, CDCl3): = 87.1, 71.6, 67.9, 39.1, 24.6, 22.8 ppm. The analytical data of the compound was in complete agreement with the reported literature.243a
(b) Synthesis of 1-(propa-1,2-dien-1-yl)cyclohexanol (501):
Scheme E.4. Synthesis of 1-(propa-1,2-dien-1-yl)cyclohexanol 501
Prepared from 1-ethynylcyclohexanol 501a according to the same procedure as described for 2-(hexa-4,5-dien-1-yl)isoindoline-1,3-dione 501. The desired allene was purified by flash column chromatography using silica gel and hexanes: ethyl acetate (10:1–1:1) eluting system to afford the desired allene as colorless oil (1.0 g, 75%).
Analytical Data of 501:
TLC (SiO2): Rf = 0.17 (hexanes: ethyl acetate = 10:1).
1 H-NMR (300 MHz, CDCl3): = 1.25-1.44 (m, 2H), 1.44-1.57 (m, 4H), 1.57-1.70 (m, 4H), 4.87 (d, J = 6.7 Hz, 2H), 5.30 (t, J = 6.7 Hz, 1H) ppm.
Experimental Part | 177
13 C-NMR (100 MHz, CDCl3): = 206.0, 99.2, 78.0, 70.3, 38.1, 25.3, 22.3 ppm. The analytical data of the compound was in complete agreement with the literature.243a,b
E.2.1.4. Synthesis of propa-1,2-dien-1-ylcyclohexane (497)
Scheme E.5. Synthesis of propa-1,2-dien-1-ylcyclohexane 497
Cyclohexylallene 200 was synthesized according to a modified literature procedure.94c,244
Dried magnesium turnings (15 g, 606 mmol, 1.01 equiv.) placed under vacuum in a three necked round bottom flask (1 L) equipped with a reflux condenser, a mechanical stirrer and a dropping funnel. The apparatus was evacuated under vacuum and back filled with argon. THF (100 ml) was added followed by cyclohexylbromide (4 ml, 32 mmol). After initiation of Grignard reaction, the remaining cyclohexylbromide (70 ml, 568.4 mmol) solution in THF (400 ml) was added dropwise. The reaction mixture was stirred at reflux temperature for 1 h. At -78 °C temperature mixture was added with CuBr (6.0 g, 42 mmol, 0.7 mol%) and LiBr (11.98 g, 138 mmol, 0.23 eq) and stirred further for 20 minutes. Propargyl bromide (68 ml (80% in toluene), 1.2 equiv.) solution in THF (180 ml) was added dropwise at -78 °C. After complete addition, the reaction mixture was allowed to stir for 1 h at -78 °C then for 3 h at rt. The reaction was worked up by pouring the mixture into a saturated aqueous solution of NH4Cl (500 ml) and extracted with n-pentane (3 x 150 ml). The combined organic fractions were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by vacuum fractional distillation (57 °C, 19 mbar) to afford desired cyclohexylallene as a colorless liquid (33.4 g, 46%).
Analytical Data of 497:
Experimental Part | 178
TLC (SiO2): Rf = 0.61 (hexanes: ethyl acetate = 10:1). 1 H-NMR (400 MHz, CDCl3): δ = 5.10-5.18 (m, 1H), 4.69 (dd, J = 6.8, 3.3 Hz, 2 H), 1.93 - 2.03 (m, 1 H), 1.79-1.67 (m, 4 H), 1.68-1.59 (m, 1 H), 1.34- 1.04 (m, 5 H) ppm. 13 C-NMR (100 MHz, CDCl3): δ = 207.5, 96.2, 75.5, 36.8, 33.1, 26.3, 26.1 ppm. The analytical data of the coumpound was in complete agreement with the literature.244
E.2.1.5. Synthesis of hexa-4,5-dien-1-ol (513)
Scheme E.6. Synthesis of hexa-4,5-dien-1-ol 513
The reaction was performed according to literature reported procedure.245
Pent-4-yn-1-ol (10.0 g, 118.9 mmol, 1.0 equiv.) dissolved in dry THF (240.0 mL) was taken in 500 ml round bottom flask. Paraformaldehyde (9.589 g, 319.3 mmol, 2.0 equiv.), copper (I) bromide (6.9 g, 47.8 mmol, 30 mol%) and dicyclohexyl amine (63.6 mL, 319.31 mmol, 2 equiv.) were added in a gradual manner under atmosphere of argone. The reaction mixture was stirred at 110 °C for 24 hours. The reaction was allowed to cool to rt and then neutralized with dilute HCl (2 M). The mixture was
extracted using Et2O (4 x 20 ml) and the combined organic layers were dried over
MgSO4, filtered and concentrated under reduced pressure. The crude product was
purified by flash column chromatography (Et2O/ n-pentane = 1:3) and the product was obtained as a yellow oil (2.5 g, 20%).
Analytical Data of 513:
TLC (SiO2): Rf= 0.29 (n-pentane: Et2O = 3:1)
Experimental Part | 179
1 H-NMR (400 MHz, CDCl3): δ = 5.12 (quin, J = 6.8 Hz, 2 H), 4.69-4.68 (m, 2 H), 3.68 (t, J = 6.0 Hz, 2 H), 2.17 - 2.01 (m, 2 H), 1.76 - 1.61 (m, 2 H) ppm. 13 C-NMR (100 MHz, CDCl3): δ = 206.3, 90.4, 74.6, 62.2, 39.2, 27.6, 26.1ppm. The analytical data of the compounds were identical with that of the reported one.245b
E.2.1.6. Synthesis of tert-butyl(hexa-4,5-dien-1-yloxy)dimethylsilane (517)
TBSCl (1.3 equiv.) Imidazole (1.4 equiv.) HO DMAP (0.1 equiv.) TBSO • • DCM, rt, 16 h 65% yield C6H10O C12H24OSi 98.14 212.41 517
Scheme E.7. Synthesis of tert-butyl(hexa-4,5-dien-1-yloxy)dimethylsilane 517
Hexa-4,5- dien-1-ol (1.0 equiv., 2.380 g, 24.25 mmol) was treated with TBSCl (4.8 g, 31.53 mmol, 1.3 equiv.) in the presences of imidazole (2.3 g, 34.0 mmol, 1.4 equiv.) and DMAP (0.300 g, 2.43 mmol, 0.1 equiv.) in DCM solvent (60 mL) under inert atmosphere. The reaction mixture was stirred at rt 16 hours. After completion of reaction shown by TLC, the reaction was quenched by dropwise addition of saturated solution of NH4Cl, and extracted with DCM (3 x 20 ml). The combined organic fractions were dried (MgSO4), filtrated and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel using n- pentane: DCM (1:1) as eluting phase to afford desired allene product as colorless oil (3.4 g, 65%).
Analytical Data of 517:
TLC (SiO2): Rf= 0.69 (n-pentane: DCM = 1:1) 1 H-NMR (400 MHz, CDCl3): δ = 5.12 (quin, J = 6.8 Hz, 1 H), 4.68-4.66 (m, 2 H), 3.66 (t, J = 6.5 Hz, 2 H), 2.14 - 2.00 (m, 2 H), 1.70 - 1.60 (m, 2 H), 0.92 (s, 9 H), 0.07 (s, 6 H) ppm.
Experimental Part | 180
13 C-NMR (100 MHz, CDCl3): δ = 208.3, 89.8, 74.6, 61.7, 30.9, 28.8, 26.1, 25.9, -2.3 ppm. The analytical data of these compounds were identical with that reported.93a-c, 246
E.2.1.7. Synthesis of 5-(Trityloxy)penta-1,2-diene (515)
Scheme E.8. Synthesis of 5-(trityloxy)penta-1,2-diene 515
Prepared in analogy to a literature procedure.248 Prepared from 5-(trityloxy)buta-1-yne (515a) according to the same procedure as described for 2-(hexa-4,5-dien-1-yl)isoindoline-1,3-dione 509. The crude product was purified by flash chromatography on silica gel using hexanes: ethyl acetate (50:1) as eluent to give the desired allene 515 as colorless liquid (2.1 g, 63%).
Analytical Data of 515:
TLC (SiO2): Rf= 0.40 (hexanes: ethyl acetate = 50:1)
1 H-NMR (300 MHz, CDCl3): = 7.42-7.47 (m, 6H), 7.18-7.36 (m, 9H), 5.16 (m, 1H), 4.62 (m, 2H), 3.13 (t, J = 6.8 Hz, 2H), 2.32 (m, 2H) ppm.
13 C-NMR (100 MHz, CDCl3): = 208.9, 144.3, 128.9, 127.7, 127.0, 87.3, 86.6, 74.8, 63.4, 29.5 ppm. The analytical data of these compounds were identical with that reported.93c
The following terminal allenes have been prepared in our working group according to literature.
Experimental Part | 181
Figure E.2. Functionalized allenes used in this protocol
E.3. Catalysis E.3.1. General Procedures E.3.1.1. General Procedure for Synthesis of Chiral N-Allyl Pyridazinones (473, 494-520 and 523-537) (GP-A)
A 1 ml screw-cap Schlenk tube was flame-dried under vacuum, backfilled with argon and cooled to room temperature using a standard Schlenk line apparatus. The tube was charged with all solid substances like substituted pyridazinone (0.2 mmol, 100 mol %,
1 equiv), [{Rh(cod)Cl}2] (2.4 mg, 0.005 mmol, 2.5 mol %) and (S)-3,5-iPr-4-NMe2- MeOBiphep 485 (10.9 mg, 0.01 mmol, 5 mol %). The reaction tube was placed under vacuum and backfilled with argon three times. Freshly distilled DCE (0.5 ml, 0.4 M) followed by allene (0.30 mmol, 150 mol %, 1.5 equiv.) were added via syringe under argon. The reaction tube was sealed by a screw cap. The resulting mixture was stirred at 80 °C for 24 hrs. After cooling to room temperature, the solvent was removed under vacuum and the residue was purified by flash column chromatography on silica gel with hexanes and ethyl acetate as eluent.
E.3.1.2. General Procedure for Synthesis of Racemic N-Allyl Pyridazinones using [{Rh(cod)Cl}2]/ rac-BINAP 281 Catalyst System (GP-B)
The procedure B was utilized for the synthesis of racemic samples of compounds 473, 494-519.
Experimental Part | 182
1 ml screw-cap Schlenk tube was flame-dried under vacuum, backfilled with argon and cooled to room temperature using a standard Schlenk line apparatus. The tube was charged with all solid substances including substituted pyridazinone (26.1 mg, 0.2
mmol, 100 mol %), [{Rh(cod)Cl}2] (2.4 mg, 0.005 mmol, 2.5 mol %) and rac-BINAP 281 (9.3 mg, 0.015 mmol, 5 mol %). The reaction tube was placed under vacuum and backfilled with argon and repeated for three times. Freshly distilled DCE (0.5 ml, 0.4 M) followed by allene (0.30 mmol, 150 mol %) were added via syringe under argon. The reaction tube was sealed by a screw cap. The resulting mixture was stirred at 80 °C for 18 hours. After cooling to room temperature, the solvent was removed under vacuum and the residue was purified by flash column chromatography using silica gel with hexanes and ethyl acetate as eluting system.
E.3.1.3. General Procedure for Synthesis of Racemic N-Allyl Pyridazinones
using [{Rh(cod)Cl}2]/ rac-3,5-iPr-4-NMe2-MeOBiphep Catalyst System (GP- C)
The procedure C was utilized for the synthesis of racemic samples of compounds 523-537.
1 ml screw-cap Schlenk tube was flame-dried under vacuum, backfilled with argon and cooled to room temperature using a standard Schlenk line apparatus. The tube was charged with all solid substances including substituted pyridazinone 412 (0.2 mmol,
100 mol %), [{Rh(cod)Cl}2] (2.4 mg, 0.005 mmol, 2.5 mol %) and rac-3,5-iPr-4-
NMe2-MeOBipheo (16.3mg, 0.015 mmol, 7.5 mol %). The reaction tube was placed under vacuum and backfilled with argon three times. Freshly distilled DCE (0.5 ml, 0.4 M) followed by allene (0.30 mmol, 150 mol %) were added via syringe under argon. The reaction tube was sealed by a screw cap. The resulting mixture was stirred at 80 °C for 24 hours. After cooling to room temperature, the solvent was removed under vacuum and the residue was purified by flash column chromatography on silica gel with hexanes and ethyl acetate as eluent.
Experimental Part | 183
E.3.1.4. Procedure Employed for Scaling Up of Reaction for the Synthesis N- Allyl Pyridazinone
A 10 ml screw-cap Schlenk tube was flame-dried under vacuum, backfilled with argon and cooled to room temperature using a standard Schlenk line apparatus. The tube was charged with all solid substances like 6-chloropyridazin-2(1H)-one 471 (225.76 mg,
1.73 mmol, 100 mol %), [{Rh(cod)Cl}2] (21.3 mg, 0.0432 mmol, 2.5 mol %) and (S)-
3,5-iPr-4-NMe2-MeOBiphep 485 (94.4 mg, 0.0865 mmol, 5 mol %). The reaction tube was placed under vacuum and backfilled with argon three times. Freshly distilled DCE (5 ml, 0.35 M) followed by 1-phenyl-propylallene 472 (411.3 mg, 2.59 mmol, 150 mol %) were added via syringe under argon. The reaction tube was sealed by a screw cap. The resulting mixture was stirred at 80 °C for 24 hrs. After cooling to room temperature, the solvent was removed under vacuum and the residue was purified by flash column chromatography (SiO2, hexanes: ethyl acetate = 3:1) to afford the desired product as a colorless oil (475 mg, 95%).
E.3.2. Ligand Screening
All reactions shown in Table E.1 below, have been performed according to procedure A at a reaction temperature of 80 °C using the following amounts of substrates, catalyst and solvent: 6-chloropyridazin-2(1H)-one 471 (26.1 mg, 0.2 mmol, 1.0 equiv.), 1-phenyl-propylallene 472 (71 mg, 0.30 mmol, 1.5 equiv.), [{Rh(cod)Cl}2] (2.4 mg, 0.005 mmol, 2.5 mol %), ligand (0.01 mmol, 5 mol %) and 0.5 ml DCE (0.4 M) solution, relative to 6-chloropyridazin-2(1H)-one 471.
Experimental Part | 184
Table E.1. Ligand Screening
As a result of the above ligand screening, (S)-3,5-iPr-4-NMe2-MeOBiphep 485 was used as a chiral ligand for further optimization of the reaction conditions.
E.3.3. Reaction Conditions Screening
All reactions depicted in Table E.3.2 given below have been performed according to procedure A using the given amounts of catalyst, substrates and additive. The amounts of substance for the reaction were taken assuming the pyridazinone as limiting reagent. The pyridazinone substrate was 0.20 mmol while the coupling counterpart allene was taken 1.5 equivalents (i.e. the ratio of substrates (allene:pyridazinone) is
1.5:1). The mol % values for the metal source, (S)-3,5-iPr-4-NMe2-MeOBiphep 485 and additive used are given relative to the limiting substrate.
Experimental Part | 185
Table E.2. Condition screening for the enantioselective coupling of terminal allene with pyridazinone
Experimental Part | 186
Table E.2. Condition screening for the enantioselective coupling of terminal allene with pyridazinone (continue).
additives c entry x/mol% (y mol%) o a b ee (%) solvent metal source (z mol%) T( C) t/h Yield(%) b:l
17 Toluene [{Rh(cod)Cl}2] 2.5 5 - 80 18 8315:1 53
18 DCE:EtOH (1:1) [{Rh(cod)Cl}2] 2.5 5 - 80 18 9%conv.- n.d.
[{Rh(cod)Cl} ] - n.d. 19 DCE:EtOH (1:2) 2 2.5 5 - 80 18 8%conv.
20 *DCE:EtOH (1:1) [{Rh(cod)Cl}2] 2.5 5 - 70 18 11 - n.d.
21 *DCE:EtOH (1:2) [{Rh(cod)Cl}2] 2.5 5 - 70 18 10 - 57
22 DCE:EtOH (9:1) [{Rh(cod)Cl}2] 2.5 5 - 80 18 24 - 51
23 DCE [{Rh(cod)Cl}2] 2.5 5 PPTS (10mol%) 70 18 52 1:1 65
24 DCE [{Rh(cod)Cl}2] 2.5 5 PPTS (20mol%) 70 18 43 2:1 71
25 DCE [{Rh(cod)Cl}2] 2.5 5 PTSA 70 18 50 1:1 64
37 65 26 DCE [{Rh(cod)Cl}2] 2.5 5 CSA 70 18 1:1
70 27 DCE [{Rh(cod)Cl}2] 2.5 5 Cs2CO3(10mol%) 80 18 8:1 76
DCE 68 6:1 72 28 [{Rh(cod)Cl}2] 2.5 5 Cs2CO3(20mol%) 80 18
Toluene [{Rh(cod)Cl} ] 97 2:1 53 29 2 2.5 5 PhCOOH 80 18
Toluene [{Rh(cod)Cl} ] 83 >20:1 82 30 2 2.5 5 CF3COOH 80 18
31 Toluene [{Rh(cod)Cl}2] 2.5 5 PhCOOH 70 18 90 6:1 40
32 DCE[Rh(COD)(OH)]2 2.5 5 - 80 18 99.5 5:1 75
33 DCE [Rh(COD)(OAc)]2 2.5 5 - 80 18 99.5 6:1 75
(a) isolated yields (b) from 1HNMR of crude reaction mixture (c) determined by chiral HPLC analysis
Experimental Part | 187
Table E.2. Condition screening for the enantioselective coupling of terminal allene with pyridazinone (continue).
E.3.4. Synthesis of Branched N-Allylic Pyridazinone Products from Allenes
Scheme E.9. General represerntation of N-allylation of pyridazinone
Experimental Part | 188
All products (racemic and chiral) were synthesized according to procedure A and B, at 80 °C with a reaction time of 24 hours using the conditions depicted in the Table 23 which are optimized reaction conditions obtained at a result of verity of reaction parameter screening. The amounts of reagents used are pyridazinone (0.2 mmol, 1.0
equiv.), allene (0.30 mmol, 1.5 equiv.), [{Rh(cod)Cl}2] (2.4 mg, 0.005 mmol, 2.5 mol
%), (S)-3,5-iPr-4-NMe2-MeOBiphep 485 (10.9 mg, 0.01 mmol, 5 mol %), DCE (0.5 ml, 0.4 M). In cases where one or more reaction parameters differed from those used as standard additional information has been added to the respective reaction product.
E.3.4.1. Synthesis of Branched N-Allylic Pyridazinone using 6-Chloropyridazin- 2(1H)-one with Various Allenes
E.3.4.1.1. (S)-6-Chloro-1-(6-phenylhex-1-en-3-yl)pyridazin-2(1H)-one 473
The reaction was performed according to procedure A with 6-phenyl-1,2-hexadiene (71 mg, 0.30 mmol, 1.5 equiv.) and 6-chloropyridazin-2(1H)-one 471 (26.1 mg, 0.2 mmol, 1.0 equiv.). The crude product was purified by flash column chromatography
using SiO2 and hexanes: ethyl acetate (4:1) as eluting system to afford the desired allylated product as colorless oil (82.6 mg, 96 %).
Analytical Data of 473:
TLC (SiO2): Rf = 0.24 (hexanes: ethyl acetate = 2:1).
1 H NMR (400 MHz, CDCl3): δ 7.22-7.06 (m, 5H), δ 7.11 (d, J = 9.5 Hz, 1H), 6.88 (d, J = 9.7 Hz, 1H), 5.88 (ddd, J = 17.4, 9.8, 7.3 Hz, 1H), 5.52-5.46 (m, 1H), 5.27-5.19 (m, 2H), 2.66-2.61 (m, 2H), 2.00-1.79 (m, 2H), 1.68-1.48 (m, 2H).
Experimental Part | 189
13 C NMR (100 MHz, CDCl3): δ 158.8, 141.9, 137.4, 136.2, 131.8, 128.5, 128.4, 125.9, 118.5, 112.6, 60.4, 35.4, 32.8, 27.6 ppm. + HRMS-ESI (m/z): [M+Na] calcd for C16H17ON2ClNa, 311.09216; found, 311.09213. HPLC (CHIRALCEL LC-2, λ = 230 nm, n-heptane: EtOH = 96:4, 0.5 ml/min): tR = 8.33 min (major-peak), 9.04 min; 89% ee. 25 [α]D = + 1.3 º (c = 1, CHCl3).
E.3.4.1.2. (S)-6-Chloro-2-(5-phenylpent-1-en-3-yl)pyridazin-3(2H)-one (494)
The reaction was performed according to procedure A with 5-phenyl-1,2-pentadien 493 (43.26 mg, 0.30 mmol, 1.5 equiv.) and 6-chloropyridazin-2(1H)-one 471 (26.1 mg, 0.2 mmol, 1.0 equiv.). The crude product was purified by flash column chromatography using SiO2 and hexanes: ethyl acetate (4:1) as eluting system to afford the desired product as colorless oil (52.8 mg, 96%).
Analytical Data of 494:
TLC (SiO2): Rf = 0.26 (hexanes: ethyl acetate = 2:1).
1 H NMR (400 MHz, CDCl3): δ 7.28-7.23 (m 2H), 7.18-7.14(m, 3H), 7.09 (d, J = 9.7 Hz, 1H), 6.86 (d, J = 9.7 Hz, 1H), 5.99 (ddd, J = 17.1, 10.2, 7.5 Hz, 1H), 5.54-5.48 (m, 1H), 5.30-5.23 (m, 2H), 2.69-2.61 (m, 1H), 2.57-2.49 (m, 1H), 2.35-2.25 (m, 1H), 2.16-2.07 (m, 1H).
13 C NMR (100 MHz, CDCl3): δ 158.8, 141.0, 137.5, 136.0, 131.9, 128.5, 128.4, 128.2, 127.0, 126.0, 118.6, 60.4, 34.7, 32.4 ppm. + HRMS-ESI (m/z): [M+Na] calcd for C15H15ON2ClNa, 297.0765; found, 297.0767. HPLC (CHIRALPAK AD-3), λ = 210 nm, n-heptane: EtOH = 50:50, 1 ml/min): tR = 3.36 min (major-peak); 3.69 min, 88% ee.
Experimental Part | 190
25 [α]D = + 45.8 ° (c = 1.53, CHCl3).
E.3.4.1.3. (S)-6-Chloro-2-(heptadec-1-en-3-yl)-pyridazin-3(2H)-one (496)
The reaction was performed according to procedure A with heptadeca-1,2-diene 495 (66.7 mg, 0.30 mmol, 1.5 equiv.) and 6-chloropyridazin-2(1H)-one 471 (26.1 mg, 0.2 mmol, 1.0 equiv.). The crude product was purified by flash column chromatography
using SiO2 and hexanes: ethyl acetate (4:1) as eluting system to afford the desired product as colorless oil (63.7 mg, 90.3%).
Analytical Data of 496:
TLC (SiO2): Rf = 0.33 (hexanes: ethyl acetate = 2:1).
1 H NMR (400 MHz, CDCl3): δ 7.11 (d, J = 9.5 Hz), 6.87 (d, J = 9.5 Hz), 5.95 (ddd, J = 17.5, 9.9, 7.3 Hz, 1H), 5.46-5.40 (m, 1H), 5.26-5.18 (m, 2H), 1.84-1.73 (m, 2H), 1.23 (br. s, 22H), 0.87 (t, J = 6.8, 3H) ppm.
13 C NMR (100 MHz, CDCl3): δ 158.9, 137.3, 136.4, 132.9, 131.8, 129.0, 128.6, 118.2, 60.6, 33.2, 31.9, 29.3, 29.5, 29.4, 29.2, 25.8, 22.7, 14.1 ppm. + HRMS-APCl (m/z): [M+H] calcd for C20H34ON2Cl, 353.23542; found, 353.23553. HPLC (CHIRALCEL OD-3), λ = 210 nm, n-heptane: EtOH = 98:2, 1 ml/min): tR = 4.58 min, 5.58 min (major-peak); 81% ee. 25 [α]D = + 13.1 ° (c = 0.89, CHCl3).
Experimental Part | 191
E.3.4.1.4. (S)-6-Chloro-2-(1-cyclohexylallyl)pyridazin-3(2H)-one (498)
The reaction was performed according to procedure A with propa-1,2- dienylcyclohexane 497 (36.6 mg, 0.30 mmol, 1.5 equiv.) and 6-chloropyridazin- 2(1H)-one 471 (26.1 mg, 0.2 mmol, 1.0 equiv.). The crude product was purified by flash column chromatography using SiO2 and hexanes: ethyl acetate (4:1) as eluting system to afford the desired allylated product as colorless oil (42.3 mg, 84%).
Analytical Data of 498:
TLC (SiO2): Rf = 0.24 (hexanes: ethyl acetate = 2:1).
1 H NMR (400 MHz, CDCl3): δ 7.09 (d, J = 9.7 Hz), 6.86 (d, J = 9.5 Hz), 5.98 (ddd, J = 17.1, 10.2, 8.9 Hz, 1H), 5.29-5.21 (m, 2H), 5.14 (t, J = 9.4, 1H), 1.94-1.60 (m, 5 H), 1.38-0.91 (m, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ 159.1, 137.2, 135.4, 132.7, 131.8, 119.8, 66.1, 40.1, 29.8, 29.2, 26.2, 25.8, 25.7 ppm. + HRMS-ESI (m/z): [M+Na] calcd for C13H17ON2ClNa, 275.09216; found, 275.09213. HPLC (CHIRALPAK AD-3), λ = 210 nm, n-heptane: EtOH = 50:50, 1 ml/min): tR = 2.6 min (major-peak); 2.9 min, 88% ee. 25 [α]D = + 52.3 ° (c = 1.31, CHCl3). Melting point: 42 °C
Experimental Part | 192
E.3.4.1.5. (S)-6-Chloro-2-(1-cyclopentylallyl)pyridazin-3(2H)-one (500)
The reaction was performed according to procedure A with propa-1,2-dien-1- ylcyclopentane 499 (32.4 mg, 0.30 mmol, 1.5 equiv.) and 6-chloropyridazin-2(1H)- one 471 (26.1 mg, 0.2 mmol, 1.0 equiv.). The crude product was purified by flash column chromatography using SiO2 and hexanes: ethyl acetate (4:1) as eluting system to afford the desired allylated product as colorless oil (46.2 mg, 98%).
Analytical Data of 500:
TLC (SiO2): Rf = 0.44 (hexanes: ethyl acetate = 2:1).
1 H NMR (400 MHz, CDCl3): δ 7.11 (d, J = 9.60 Hz, 1 H), 6.88 (d, J = 9.60 Hz, 1 H), 6.06-5.8 (m, 1H), 5.35-5.12 (m, 2H), 2.59-2.43 (m, 1H), 1.85-1.71 (m, 1H), 1.711.44 (m, 5H), 1.41-1.24 (m, 1H), 1.23-1.09 (m, 1H) ppm.
13 C NMR (100 MHz, CDCl3): δ 159.0, 137.3, 136.0, 132.8, 131.9, 118.8, 65.7, 42.8, 30.1, 29.6, 25.4, 25.1 ppm. + HRMS-ESI (m/z): [M+Na] calcd for C12H15ON2ClNa, 261.0765; found, 261.0768. HPLC (DAICEL Lux C-2, λ = 313 nm, n-heptane: EtOH = 97:3, 0.5 ml/min): tR = 12.6 min, 15.1 min (major-peak); 92% ee. 25 [α]D = − 9.3 ° (c = 1.33, CHCl3).
Experimental Part | 193
E.3.4.1.6. (S)-6-Chloro-2-(1-(1-hydroxycyclohexyl)allyl)pyridazin-3(2H)-one (502)
The reaction was performed according to procedure A with 1-(propa-1,2-dienyl)- cyclohexanol 501 (41.6 mg, 0.30 mmol, 1.5 equiv.) and 6-chloropyridazin-2(1H)-one 471 (26.1 mg, 0.2 mmol, 1.0 equiv.). The crude product was purified by flash column chromatography using SiO2 and hexanes: ethyl acetate (4:1) as eluting system to afford the desired allylation product as colorless oil which solidified after 2-3 weeks (44.8 mg, 83%).
Analytical Data of 502:
TLC (SiO2): Rf = 0.29 (hexanes: ethyl acetate = 2:1).
1 H NMR (400 MHz, CDCl3): δ 7.17 (d, J = 9.4 Hz), 6.94 (d, J = 9.5 Hz), 6.27 (ddd, J = 17.1, 10.2, 8.6 Hz, 1H), 5.36-5.28 (m, 2H), 5.26 (d, J = 8.4 Hz, 1H), 3.57 (br. s, 1H), 1.20-1.78 (m, 10 H) ppm.
13 C NMR (100 MHz, CDCl3): δ 159.3, 137.8, 133.3, 132.5, 132.0, 121.2, 73.3, 35.5, 35.0, 25.6, 21.6, 21.5 ppm. + HRMS-ESI (m/z): [M+Na] calcd for C13H17ON2ClNa, 291.08708; found: 291.08725. HPLC (CHIRALPAK AD-3), λ = 210 nm, n-heptane: EtOH = 75:25, 1 ml/min): tR = 3.7 min (major-peak); 4.2 min, 85% ee (improved after recrystallization). 25 [α]D = + 26.4 ° (c = 0.533, CHCl3).
Experimental Part | 194
E.3.4.1.7. (S)-4-(3-Chloro-6-oxopyridazin-1(6H)-yl)-hex-5-enyl benzoate (504)
The reaction was performed according to procedure A with hexa-4,5-dienyl benzoate 503 (61 mg, 0.30 mmol, 1.5 equiv.) and 6-chloropyridazin-2(1H)-one 471 (26.1 mg, 0.2 mmol, 1.0 equiv.). The crude product was purified by flash column
chromatography using SiO2 and hexanes: ethyl acetate (3:1) as eluting system to afford the desired allylated product as colorless oil (86.3 mg, 90.2 %).
Analytical Data of 504:
TLC (SiO2): Rf = 0.37 (hexanes: ethyl acetate = 2:1).
1 H NMR (400 MHz, CDCl3): δ 8.04-8.01 (m, 2H), 7.57-7.52 (m, 1H), 7.45-7.40 (m, 2H), 7.12 (d, J = 9.7 Hz, 1H), 6.89 (d, J = 9.4 Hz, 1H), 5.98 (ddd, J = 17.1, 10.2, 7.6 Hz, 1H), 5.55-5.49 (m, 1H), 5.32-5.23 (m, 2H), 4.32 (t, J = 6.94 Hz, 2H), 2.14-2.05 (m, 1H), 2.01-1.92 (m, 1H), 1.85-1.63 (m, 2 H) ppm.
13 C NMR (100 MHz, CDCl3): δ 166.5, 158.8, 137.6, 133.1, 132.9, 131.9, 130.3, 129.6, 128.4, 118.9, 64.3, 60.2, 29.8, 25.4 ppm. + HRMS-APCl (m/z): [M+H] calcd for C17H18ON2Cl, 333.1000; found, 333.0998. HPLC (CHIRALCEL OD-3), λ = 210 nm, n-heptane: EtOH = 65:35, 1 ml/min): tR = 3.96 min (major-peak), 5.53 min; 88 % ee. 25 [α]D = + 37.1 º (c = 0.80, CHCl3).
Experimental Part | 195
E.3.4.1.8. (S)-6-Chloro-2-(6-(phenylsulfonyl)hex-1-en-3-yl)pyridazin-3(2H)-one (506)
The reaction was performed according to procedure A with 1-(hexa-4,5- dienylsulfonyl)benzene 505 (66.69 mg, 0.30 mmol, 1.5 equiv.) and 6-chloropyridazin- 2(1H)-one 471 (26.1 mg, 0.2 mmol, 1.0 equiv.). The crude product was purified by flash column chromatography using SiO2 and hexanes: ethyl acetate (2:1) as eluting system to afford the desired allylated product as colorless oil (69 mg, 98%).
Analytical Data of 506:
TLC (SiO2): Rf = 0.64 (hexanes: ethyl acetate = 2:1).
1 HNMR (400 MHz, CDCl3): δ 7.89-7.87 (m, 2H), 7.67-7.62 (m, 1H), 7.58-7.53 (m, 2H), 7.10 (d, J = 9.7 Hz), 6.85 (d, J = 9.5 Hz), 5.90 (ddd, J = 17.1, 10.1, 7.7 Hz, 1H), 5.41-5.35 (m, 1H), 5.25-5.20 (m, 2H), 3.19-3.05 (m, 2H), 2.06-1.97 (m, 1H), 1.93- 1.83 (m, 1H), 1.72-1.64 (m, 2 H) ppm.
13 CNMR (100 MHz, CDCl3): δ 158.7, 139.1, 137.8, 135.3, 133.7, 133.2, 131.9, 129.3, 128.1, 119.2, 59.5, 55.5, 31.6, 19.2 ppm. + HRMS-ESI (m/z): [M+Na] calcd for C16H17O3N2ClSNa, 375.0541; found, 375.0539. HPLC (CHIRALPAK AD-3), λ = 210 nm, n-heptane: EtOH = 50:50, 1 ml/min): tR = 2.9 min (major-peak), 3.6 min; 78% ee. 25 [α]D = + 15.7 º (c = 1.13, CHCl3).
Experimental Part | 196
E.3.4.1.9. (S)-6-Chloro-2-(16-oxoheptadec-1-en-3-yl)pyridazin-3(2H)-one (508)
The reaction was performed according to procedure A with hepta-5,6-dien-2-one 507 (75.1 mg, 0.30 mmol, 1.5 equiv.) and 6-chloropyridazin-2(1H)-one 471 (26.1 mg, 0.2 mmol, 1.0 equiv.). The crude product was purified by flash column chromatography using SiO2 and hexanes: ethyl acetate (4:1) as eluting system to afford the desired allylated product as white solid (73.6 mg, 97 %).
Analytical Data of 508:
TLC (SiO2): Rf = 0.40 (hexanes: ethyl acetate = 2:1).
1 H NMR (400 MHz, CDCl3): δ 7.11 (d, J = 9.5 Hz), δ 6.88 (d, J = 9.7 Hz), 5.95 (ddd, J = 17.1, 10.2, 7.5 Hz, 1H), 5.46-5.41 (m, 1H), 5.27-5.18 (m, 2H), 2.40 (t, J = 7.4, 2H), 2.12 (br. s, 3H), 1.94-1.85 (m, 1H), 1.82-1.73 (m, 1H), 1.25 (br. s, 18H) ppm.
13 C NMR (100 MHz, CDCl3): δ209.3, 158.9, 137.4, 136.4, 132.9, 131.8, 118.2, 60.6, 43.9, 33.2, 29.9, 29.6, 29.5, 29.4, 29.2, 25.8, 23.7 ppm. + HRMS-ESI (m/z): [M+Na] calcd for C21H33O2N2ClNa, 403.2123; found, 403.2123. HPLC (CHIRALCEL OD-3), λ = 230 nm, n-heptane: iPrOH = 95:5, 0.5 ml/min): tR = 16.3 min (major-peak), 18.6 min; 84% ee. 25 [α]D = + 14.5 º (c = 0.33, CHCl3). Melting point: 44 °C
Experimental Part | 197
E.3.4.1.10. (S)-2-(4-(3-Chloro-6-oxopyridazin-1(6H)-yl)hex-5-enyl)isoindoline- 1,3-dione (510)
The reaction was performed according to the standard procedure A, with 2-(hexa-4,5- dienyl-)isoindoline-1,3-dione 509 (68.1 mg, 0.30 mmol, 1.5 equiv.) and 6- chloropyridazin-2(1H)-one 471 (26.1 mg, 0.2 mmol, 1.0 equiv.). The crude product was purified by flash column chromatography using SiO2 and hexanes: ethyl acetate (3:1) as eluting system to afford the desired allylated product as a white solid (66.8 mg, 93%).
Analytical Data of 510:
TLC (SiO2): Rf = 0.18 (hexanes: ethyl acetate = 2:1).
1 H NMR (400 MHz, CDCl3): δ 7.85-7.80 (m, 2H), 7.72-7.67 (m, 2H), 7.11 (d, J = 9.5 Hz, 1H), 6.87 (d, J = 9.5 Hz, 1H), 5.94 (ddd, J = 17.1, 10.2, 7.8 Hz, 1H), 5.50-5.45 (m, 1H), 5.29-5.20 (m, 2H), 3.76-3.64 (m, 2H), 2.01-1.81 (m, 2H), 1.74-1.54 (m, 2 H) ppm.
13 C NMR (100 MHz, CDCl3): δ 158.9, 144.0, 137.1, 135.8, 132.8, 131.9, 128.7, 127.7, 126.9, 118.2, 86.7, 60.0, 58.4, 33.2 ppm. + HRMS-ESI (m/z): [M+Na] calcd for C18H16O3N3ClNa, 380.07724; found, 380.07742.
HPLC (CHIRALPAK AD-3R, λ = 210 nm, CH3CN:H2O = 93:7, 0.4 ml/min): tR = 6.7 min, 7.9 min (major-peak); 92 % ee. 25 [α]D = − 8.8 ° (c = 0.3, CHCl3). Melting point: 106 °C.
Experimental Part | 198
E.3.4.1.11. (S)-Tert-butyl-(2-(3-chloro-6-oxopyridazin-1(6H)-yl)but-3-en-1- yl)(tosyl)carbamate (512)
The reaction was performed according to the standard procedure A, with tert-butyl buta-2,3-dien-1-yl(tosyl)carbamate 511 (97.0 mg, 0.30 mmol, 1.5 equiv.) and 6- chloropyridazin-2(1H)-one 471 (26.1 mg, 0.2 mmol, 1.0 equiv.). The crude product
was purified by flash column chromatography using SiO2 and hexanes: ethyl acetate (2:1) as eluting system to afford the desired allylation product as white solid (68 mg, 75%).
Analytical Data of 512:
TLC (SiO2): Rf = 0.16 (hexanes: ethyl acetate = 2:1). 1 H NMR (400 MHz, CDCl3): δ = 7.77-7.74 (m, 2H), 7.28-7.26 (m, 2H), 7.10 (d, J = 8.0 Hz), 6.97 (d, J = 8.0 Hz), 6.12 (ddd, J = 17.1, 10.1, 7.7 Hz, 1H), 5.93-5.87 (m, 1H), 5.42-5.33 (m, 2H), 4.45-4.39 (m, 1H), 4.12-4.07 (m, 1H), 2.42 (s, 3H), 1.35 (s, 9H) ppm.
13 CNMR (100 MHz, CDCl3): δ 159.1, 150.8, 137.7, 133.2, 132.0, 129.31, 128.1, 120.0, 84.9, 60.3, 49.1, 27.9, 21.7 ppm + HRMS-ESI (m/z): [M+Na] calcd for C20H24O5N3ClSNa, 476.1058; found, 476.1060. HPLC (CHIRALPAK AD-3), λ = 210 nm, n-heptane: EtOH = 60:40, 1 ml/min): tR = 2.9 min (major-peak), 3.6 min; 78% ee. 25 [α]D = − 9.8 ° (c = 0.3, CHCl3). Melting point: 110 °C.
Experimental Part | 199
E.3.4.1.12. (S)- 6-Chloro-2-(1-hydroxyhex-3-en-2-yl)pyridazin-3(2H)-one (514)
The reaction was performed according to the standard procedure A, with hexa-4,5- dien-1-ol 513 (29.1 mg, 0.30 mmol, 1.5 equiv.) and 6-chloropyridazin-2(1H)-one 471 (26.1 mg, 0.2 mmol, 1.0 equiv.). The crude product was purified by flash column chromatography using SiO2 and hexanes: ethyl acetate (3:1) as eluting system to afford the desired allylated product as a white solid (12.8 mg, 20%).
Analytical Data of 514:
TLC (SiO2): Rf = 0.21 (hexanes: ethyl acetate = 2:1).
1 H NMR (400 MHz, CDCl3): δ 6.98 (d, J = 9.0 Hz), 6.71 (d, J = 9.0 Hz), 5.83 (ddd, J = 17.0, 10.1, 7.5 Hz, 1H), 5.32-5.28 (m, 1H), 4.98-4.25 (m, 2H), 3.78-3.69 (m, 2H), 1.55-1.48 (m, 2H) ppm.
13 CNMR (100 MHz, CDCl3): δ 159.1, 137.7, 137.0, 133.0, 131.6, 117.2, 62.9, 62.6, 27.4, 27.1 ppm. + HRMS-ESI (m/z): [M+Na] calcd for C10H13O2N2ClNa, 251.0598; found, 251.0600.
HPLC (CHIRALPAK AD-3R), λ = 210 nm, :H2O = 93:7, 0.4 ml/min): tR = 6.7 min, 7.9 min (major-peak); 40 % ee. 25 [α]D = − 10.8 ° (c = 0.3, CHCl3).
Experimental Part | 200
E.3.4.1.13. (S)-6-Chloro-2-(5-(trityloxy)pent-1-en-3-yl)pyridazin-3(2H)-one (516)
The reaction was performed according to the standard procedure A, with 5- (trityloxy)penta-1,2-diene 515 (97.9mg, 0.30 mmol, 1.5 equiv.) and 6-chloropyridazin-
2(1H)-one 471 (26.1 mg, 0.2 mmol, 1.0 equiv.). The crude product was using SiO2 and hexanes: ethyl acetate (3:1) as eluting system to afford the desired allylated product as a white solid (78.1 mg, 86 %).
Analytical Data of 516:
TLC (SiO2): Rf = 0.17 (hexanes: ethyl acetate = 2:1). 1 H NMR (400 MHz, CDCl3): δ = 7.41-7.38 (m, 6 H), 7.28-7.22 (m, 11 H), 6.71 (d, J = 9.0 Hz), 6.49 (d, J = 9.0 Hz), 5.83 (ddd, J = 17.0, 10.5, 5.9 Hz, 1 H), 5.46- 5.40 (m, 1 H), 5.23-5.19 (m, 2H), 3.36 - 3.32 (m, 2 H), 2.13-189 (m, 2H) ppm. 13 C NMR (100 MHz, CDCl3): 159.1, 143.9, 137.1, 135.1, 133.0, 131.6, 129.2, 128.2, 126.2, 117.3, 94.5, 61.8, 59.9, 34.1. + HRMS-ESI (m/z): [M+Na] calcd for C28H25O2N2ClNa, 479.1537; found, 479.1539. HPLC (CHIRALPAK AD-3), λ = 210 nm, n-heptane: iPrOH = 90:10, 1 ml/min): tR = 7.9 min (major-peak), 6.6 min; 78% ee. 25 [α]D = −12.8 ° (c = 0.3, CHCl3).
Experimental Part | 201
E.3.4.1.14. (S)-2-(6-(Tert-butyldimethylsilyloxy)hex-1-en-3-yl)-6-chloropyridazin- 3(2H)-one (518)
The reaction was performed according to procedure A with 6-Tert- butyldimethylsilyloxy-1,2-hexadien 517 (64 mg, 0.30 mmol, 1.5 equiv.) and 6- chloropyridazin-2(1H)-one 471 (26.1 mg, 0.2 mmol, 1.0 equiv.). The crude product was purified b using SiO2 and hexanes: ethyl acetate (4:1) as eluting system to afford the desired allylated (SiO2, hexanes: ethyl acetate = 4:1) to afford the desired product as colorless oil (68 mg, 98.5 %).
Analytical Data of 518:
TLC (SiO2): Rf = 0.52 (hexanes: ethyl acetate = 2:1). 1 H NMR (400 MHz, CDCl3): δ = 7.11 (d, J = 9.5 Hz, 1H), 6.87 (d, J = 9.5 Hz, 1H), 5.95 (ddd, J = 17.1, 10.2, 7.5 Hz, 1H), 5.49-5.43 (m, 1H), 5.27-5.19 (m, 2H), 3.60 (t, J = 6.8 Hz, 6H), 0.87 (br. s, 9H).
13 C NMR (100 MHz, CDCl3): δ 158.2, 137.4, 136.3, 132.9, 131.8, 118.3, 62.5, 60.3, 29.6, 29.1, 26.0, 18.4 ppm. + HRMS-ESI (m/z): [M+Na] calcd for C16H27O2N2ClNaSi, 365.1423; found, 365.1423. HPLC (CHIRALPAK AD-H, λ = 210 nm, n-heptane: EtOH = 98:2, 0.5 ml/min): tR = 8.24 min (major-peak); 9.33 min, 81% ee. 25 [α]D = + 12.4 º (c = 0.55, CHCl3).
Experimental Part | 202
E.3.4.1.15. 3-(3-Chloro-6-oxopyridazin-1(6H)-yl)hept-4-enenitrile (520)
The reaction was performed according to the standard procedure A, with hexa-4,5- dienenitrile 519 (28 mg, 0.30 mmol, 1.5 equiv.) and 6-chloropyridazin-2(1H)-one 471 (26.1 mg, 0.2 mmol, 1.0 equiv.). The crude product was purified by flash column
chromatography using SiO2 and hexanes: ethyl acetate (2:1) as eluting system to afford the desired allylated product as light yellow oil (21.2 mg, 31%).
Analytical Data of 520:
TLC (SiO2): Rf = 0.20 (hexanes: ethyl acetate = 2:1).
1 H NMR (400 MHz, CDCl3): δ 7.10 (d, J = 9.0 Hz), 6.86 (d, J = 9.5 Hz), 5.89 (ddd, J = 17.0, 10.2, 7.6 Hz, 1H), 5.80-5.79 (m, 1H), 5.23-5.19 (m, 2H), 2.38- 2.30 (m, 2H), 1.93-1.89 (m, 2H) ppm.
13 CNMR (100 MHz, CDCl3): δ 159.2, 137.2, 135.0, 133.0, 131.7, 119.2, 117.3, 61.3, 26.6, 12.5 ppm. + HRMS-ESI (m/z): [M+Na] calcd for C10H10ON3ClNa, 246.0471; found, 223.0473. HPLC Analysis: Not determined
Experimental Part | 203
E.3.4.2. Synthesis of Branched N-Allylic Pyridazinone using Substituted Pyridazin-2(1H)-one with 6-Phenyl-1,2-hexadiene
E.3.4.2.1. (S)-6-Bromo-1-(6-phenylhex-1-en-3-yl)pyridazin-2(1H)-one (523)
The reaction was performed according to procedure A with 6-phenyl-1,2-hexadiene 472 (47.4 mg, 0.3 mmol, 1.5 equiv.) and 6-bromoopyridazin-2(1H)-one 522 (35 mg, 0.2 mmol, 1.0 equiv.). The crude product was purified by flash column chromatography using SiO2 and hexanes: ethyl acetate (2:1) as eluting system to afford the desired allylated product as colorless oil (65.2 mg, 98 %).
Analytical Data of 523:
TLC (SiO2): Rf = 0.37 (hexanes: ethyl acetate = 2:1).
1 H NMR (400 MHz, CDCl3): δ 7.29-7.23 (m, 3H), 7.20-7.13 (m, 4H), 6.78 (d, J = 9.7 Hz, 1H), 5.95 (ddd, J = 17.1 Hz, 10.2, 7.7, 1H), 5.50-5.44 (m, 1H), 5.27-5.19 (m, 2H), 2.68-2.58 (m, 2H), 2.00-1.91(m, 1H), 1.88-1.79 (m, 1H), 1.68-1.48 (m, 2H).
13 C NMR (100 MHz, CDCl3): δ 158.9, 141.9, 136.2, 135.7, 131.6, 128.47, 128.44, 126.3, 125.9, 60.5, 35.4, 32.9, 27.6 ppm. + HRMS-ESI (m/z): [M+Na] calcd for C16H17ON2BrNa, 355.0416; found, 355.0418. HPLC (CHIRALPAK LA-2, λ = 210 nm, n-heptane: IPA = 95:5, 0.5 ml/min): tR = 13.7 min (major peak), 18.2 min; 72% ee. 25 [α]D = − 2.1 ° (c = 0.95, CHCl3).
Experimental Part | 204
E.3.4.2.2. (S)-4,5-Dichloro-1-(6-phenylhex-1-en-3-yl)pyridazin-2(1H)-one (525)
The reaction was performed according to procedure A with 6-phenyl-1,2-hexadiene 472 (47.4 mg, 0.3 mmol, 1.5 equiv.) and 4,5-dichloropyridazin-3(2H)-one 524 (33 mg, 35 mg, 0.2 mmol, 1.0 equiv.). The crude product was purified by flash column chromatography using SiO2 and hexanes: ethyl acetate (10:1) as eluting system to afford the desired allylated product as colorless oil (64 mg, 98.2 %).
Analytical Data of 525: TLC (SiO2): Rf = 0.60 (hexanes: ethyl acetate = 5:1).
1 H NMR (400 MHz, CDCl3): δ 7.79 (s, 1H), 7.28-7.24 (m, 2H), 7.19-7.12 (m, 3H), 5.99 (ddd, J = 17.2, 10.2, 7.6 Hz, 1H), 5.55-5.49 (m, 1H), 5.28-5.20 (m, 2H), 2.67- 2.57 (m, 1H), 2.02-1.93 (m, 1H) , 1.90-1.80 (m, 1H) , 1.68-1.46 (m, 2H) ppm.
13 C-NMR (100 MHz, CDCl3): δ 159.6, 141.8, 135.99, 135.90, 136.61, 134.1, 129.47, 128.44, 125.9, 118.8, 61.7, 35.4, 32.7, 27.6 ppm. + HRMS-ESI (m/z): [M+Na] calcd for C16H16ON2Cl2Na, 345.0534; found, 345.0534. HPLC (CHIRALCEL OJ-H, λ = 210 nm, n-heptane: EtOH = 90:10, 0.5 ml/min): tR = 10.2 min, 11.9 min (major-peak); 76% ee. 25 [α]D = − 42.8 ° (c = 0.46, CHCl3).
Experimental Part | 205
E.3.4.2.3. (S)-4,5-Dibromo-1-(6-phenylhex-1-en-3-yl)pyridazin-2(1H)-one (527)
The reaction was performed according to procedure A with 6-phenyl-1,2-hexadiene 471 (47.4 mg) and 4,5-dibromopyridazin-3(2H)-one 526 (19.2 mg, 0.2 mmol, 1.0 equiv.). The crude product was purified by flash column chromatography using SiO2 and hexanes: ethyl acetate (4:1) as eluting system to afford the desired allylated product as colorless oil (46.8 mg, 92 %).
Analytical Data of 527:
TLC (SiO2): Rf = 0.25 (hexanes: ethyl acetate = 2:1).
1 H NMR (400 MHz, CDCl3): δ 7.81 (s, 1H), 7.28-7.24 (m, 2H), 7.19-7.12 (m, 3H), 5.92 (ddd, J = 17.2, 10.2, 7.7 Hz, 1H), 5.53-5.47 (m, 1H), 5.28-5.20 (m, 2H), 2.68- 2.57 (m, 2H), 2.02-1.92 (m, 1H) , 1.89-1.80 (m, 1H) , 1.68-1.46 (m, 2H) ppm.
13 C-NMR (100 MHz, CDCl3): δ 156.8, 141.8, 137.3, 135.9, 130.4, 130.1, 130.0, 128.47, 128.44, 125.9, 118.8, 62.0, 35.4, 32.7, 27.6 ppm. + 81 HRMS-APCL (m/z): [M+H] calcd for C16H17ON2Br Br, 412.9682; found, 412. 9681. HPLC (CHIRALCEL AD-3), λ = 210 nm, n-heptane: EtOH = 97:3, 0.5 ml/min): tR = 10.3 min, 12.6 min (major-peak); 75% ee. 25 [α]D = − 9.4 ° (c = 1.60, CHCl3)
Experimental Part | 206
E.3.4.2.4. (S)-5-Chloro-4-phenyl-(6-phenylhex-1-en-3-yl)pyridazin-2(1H)-one (529)
The reaction was performed according to procedure A with 6-phenyl-1,2-hexadiene 472 (47.4 mg, 0.3 mmol, 1.0 equiv.) and 5-chloro-4-phenylpyridazin-3(2H)-one 528 (41.3 mg, 0.2 mmol, 1.0 equiv.). The crude product was purified by flash column chromatography using SiO2 and hexanes: ethyl acetate (10:1) as eluting system to afford the desired allylated product as colorless oil (56.2 mg, 78 %).
Analytical Data of 529:
TLC (SiO2): Rf = 0.1 (hexanes: ethyl acetate = 2:1).
1 H NMR (400 MHz, CDCl3): δ 7.87 (s, 1H), 7.45-7.39 (m, 5H), 7.29-7.24 (m, 2H), 7.20-7.14 (m, 3H), 5.99 (ddd, J = 17.2, 10.2, 7.6 Hz, 1H), 5.58-5.53 (m, 1H), 5.29- 5.21 (m, 2H), 2.64 (t, J = 7.1 , 1H), 2.06-1.97 (m, 1H) , 1.92-1.83 (m, 1H) , 1.72-1.52 (m, 2H) ppm.
13 C-NMR (100 MHz, CDCl3): δ 159.2, 143.0, 137.7, 137.1, 136.4, 135.2, 131.3, 129.7, 129.3, 128.5, 128.4, 125.9, 118.4, 60.9, 35.4, 32.7, 27.7 ppm. + HRMS-ESI (m/z): [M+Na] calcd for C22H22ON2ClNa, 387.1237; found: 387.1237. HPLC (CHIRALPAK LA-2, λ = 313 nm, n-heptane: IPA = 97:3, 0.5 ml/min): tR = 20.2 min (major peak), 26.6 min; 80% ee. 25 [α]D = − 6.9 º (c = 0.90, CHCl3).
Experimental Part | 207
E.3.4.2.5. (S)-5-chloro-2-(6-phenylhex-1-en-3-yl)-4-(thiophen-2-yl)pyridazin- 3(2H)-one (531)
The reaction was performed according to procedure A with 6-phenyl-1,2-hexadiene 472 (47.4 mg, 0.3 mmol, 1.0 equiv.) and 5-chloro-4-(thiophen-2-yl)pyridazin-3(2H)- one 530 (43 mg, 0.2 mmol, 1.5 equiv.). The crude product was purified by flash column chromatography using SiO2 and hexanes: ethyl acetate (20:1) as eluting system to afford the desired allylated product as colorless oil (55 mg, 79%).
Analytical Data of 531:
TLC (SiO2): Rf = 0.51 (hexanes: ethyl acetate = 10:1).
1 H NMR (400 MHz, CDCl3): δ 8.26 (dd, J = 3.9, 1.0 Hz, 1H), 7.85 (s, 1H), 7.65 (dd, J = 5.1, 1.0 Hz, 1H), 7.20-7.15 (m, 2H), 7.19 (q, J = 5.1, 3.9 Hz, 1H), 7.16-7.13 (m, 3H), 5.99 (ddd, J = 17.1, 10.2, 7.6 Hz, 1H), 5.59-5.52 (m, 1H), 5.22-5.12 (m, 2H), 2. 76-2.62 (m, 1H), 2.00-1.87 (m, 1H), 1.85-1.73 (m, 1H) , 1.68-1.43 (m, 2H) ppm.
13 C-NMR (100 MHz, CDCl3): δ 158.3, 141.9, 137.8, 136.3, 132.4, 131.7, 131.39, 131.30, 129.7, 128.48, 128.41, 126.3, 125.90, 118.4, 61.1, 35.5, 32.8, 27.7 ppm. + HRMS-APCI (m/z): [M+H] calcd for C20H20ON2ClS, 371.0979, found: 371.0983. HPLC (CHIRALCEL OD-H, λ = 313 nm, n-heptane: IPA = 95:5, 0.5 ml/min): tR = 14.7 min (major-peak), 16.3 min; 76% ee. 25 [α]D = − 6.9 º (c = 0.90, CHCl3).
Experimental Part | 208
E.3.4.2.6. (S)-5-Chloro-4-phenoxy-2-(6-phenylhex-1-en-3-yl)pyridazin-3(2H)-one (533)
The reaction was performed according to procedure A with 6-phenyl-1,2-hexadiene 472 (47.4 mg, 0.3 mmol, 1.5 equiv.) and 5-chloro-4-phenoxypyridazin-3(2H)-one 532 (41.3 mg, 0.2 mmol, 1.0 equiv.). The crude product was purified by flash column
chromatography using SiO2 and hexanes: ethyl acetate (10:1) as eluting system to afford the desired allylated product as colorless oil (33.1 mg, 58%).
Analytical Data of 533:
TLC (SiO2): Rf = 0.1 (hexanes: ethyl acetate = 2:1).
1 H NMR (400 MHz, CDCl3): δ 7.89 (s, 1H), 7.30-7.24 (m, 6H), 6.90-7.12 (m, 4H), 5.92 (ddd, J = 17.2, 10.2, 7.6 Hz, 1H), 5.55-5.51 (m, 1H), 5.26-5.19 (m, 2H), 2.61 (t, J = 7.1 , 1H), 2.04-1.95 (m, 1H) , 1.90-1.81 (m, 1H) , 1.71-1.50 (m, 2H) ppm.
13 C-NMR (100 MHz, CDCl3): δ 159.2, 157.1, 137.7, 137.1, 136.4, 135.2, 131.3, 129.7, 129.3, 128.5, 128.4, 125.9, 118.4, 60.9, 35.4, 32.7, 27.7 ppm. ]+ HRMS-ESI (m/z): [M+Na calcd for C22H21O2N2ClNa, 403.8616, found: 403.8618. HPLC (CHIRALPAK LA-2, λ = 313 nm, n-heptane: IPA = 97:3, 0.5 ml/min): tR = 22.2 min (major peak), 28.6 min; 63% ee. 25 [α]D = − 8.9 º (c = 0.55, CHCl3).
Experimental Part | 209
E.3.4.2.7. (S)-4-Methyl-1-(6-phenylhex-1-en-3-yl)pyridazin-2(1H)-one (535)
The reaction was performed according to procedure A with 6-phenyl-1,2-hexadiene 472 (47.4 mg, 0.3 mmol, 1.5 equiv.) and 4-methylpyridazin-2(1H)-one 534 (22.2 mg, 0.2 mmol, 1.0 equiv.). The crude product was purified by flash column chromatography using SiO2 and hexanes: ethyl acetate (2:1) as eluting system to afford the desired allylated product as colorless oil (20 mg, 37 %).
Analytical Data of 535:
TLC (SiO2): Rf = 0.21 (hexanes: ethyl acetate = 2:1).
1 H NMR (400 MHz, CDCl3): δ 7.21-7.16 (m, 2H), 7.11-7.06 (m, 3H), 6.94 (d, J = 12 Hz, 1H), 6.76 (d, J = 12 Hz, 1H), 5.93 (ddd, J = 17.1 Hz, 10.2, 7.7, 1H), 5.51-5.44 (m, 1H), 5.17-5.07 (m, 2H), 2.61-2.48 (m, 2H), 2.23 (s, 3H), 1.97-1.88 (m, 1H), 1.80- 1.70 (m, 1H), 1.60-1.39 (m, 2H).
13 C NMR (100 MHz, CDCl3): δ 159.1, 143.8, 141.8, 136.9, 133.1, 129.1, 128.5, 128.1, 125.9, 117.2, 62.4, 35.7, 30.8, 21.1, 20.3 ppm. + HRMS-ESI (m/z): [M+Na] calcd for C17H20ON2Na, 291.1469; found, 291.1471. HPLC (CHIRALCEL OD-3), λ = 210 nm, n-heptane: IPA = 90:10, 0.5 ml/min): tR = 21.1 min, 23.71 min (major peak); 47% ee. 25 [α]D = − 10.1 ° (c = 0.31, CHCl3).
Experimental Part | 210
E.3.4.2.8. (S)-5-Methyl-1-(6-phenylhex-1-en-3-yl)pyridazin-2(1H)-one (537)
The reaction was performed according to procedure A with 6-phenyl-1,2-hexadiene 472 (47.4 mg, 0.3 mmol, 1.5 equiv.) and 5-methylpyridazin-2(1H)-one 536 (22.2 mg, 0.3 mmol, 1.0 equiv.). The crude product was purified by flash column
chromatography using SiO2 and hexanes: ethyl acetate (2:1) as eluting system to afford the desired allylated product as colorless oil (20.2 mg, 40 %).
Analytical Data of 537:
TLC (SiO2): Rf = 0.21 (hexanes: ethyl acetate = 2:1).
1 H NMR (400MHz, CDCl3): δ 7.21-7.16 (m, 2H), 7.11-7.06 (m, 3H), 6.93 (s, 1H), 6.21 (s, 1H), 5.83 (ddd, J = 17.1 Hz, 10.2, 7.7, 1H), 5.50-5.43 (m, 1H), 5.16-5.04 (m, 2H), 2.60-2.47 (m, 2H), 2.22 (s, 3H), 1.97-1.88 (m, 1H), 1.80-1.70 (m, 1H), 1.60-1.39 (m, 2H).
13 C NMR (100 MHz, CDCl3): δ 158.5, 143.2, 137.6, 136.8, 135.7, 135.5, 128.5, 128.1, 125.9, 117.2, 63.1, 35.8, 30.8, 21.1, 15.3 ppm. + HRMS-ESI (m/z): [M+Na] calcd for C17H20ON2Na, 291.1469; found, 291.1471. HPLC (CHIRALCEL OD-3), λ = 210 nm, n-heptane: IPA = 90:10, 0.5 ml/min): tR = 11.2 min (major peak), 16.6 min; 43% ee. 25 [α]D = − 14.1 ° (c = 0.35, CHCl3).
Experimental Part | 211
E.3.5. Mechanistic investigation by Labeling Experiment E.3.5.1. Hydrogen- Deuterium Exchange reaction using D-substrate
Scheme.E.10. Labeling experiment using D-substrate
The deuterium labeling experiment was performed according to standard rhodium catalyzed conditions,86f using deuterated 6-chloropyridazinone (537). In this method a 1 ml screw-cap Schlenk tube was flame-dried, under vacuum/argone, was charged with with all solid substances like 6-chloropyridazinone-d1 (5a) (26.1 mg, 0.2 mmol,
100 mol %), [{Rh(cod)Cl}2] (2.4 mg, 0.005 mmol, 2.5 mol %) and (S)-3,5-iPr-4-
NMe2-MeOBiphep 485 (10.9 mg, 0.01 mmol, 5 mol %). The reaction tube was evacuated and backfilled with argon three times. Freshly distilled DCE (0.5 ml, 0.4 M) followed by allene 472 (0.30 mmol, 150 mol %) were added via syringe under argon and reaction tube was, after sealing with screw cap, stirred at 80 °C for 24 hrs. After cooling to room temperature, the reaction mixture was concentrated under vacuum and purified by flash column chromatography (hexanes: ethyl acetate = 3:1, Rf = 0.43) and the deuterated allyl product 538 was obtained, as light yellow oil, in 85% yield.
Analytical Data of 538:
TLC (SiO2): Rf = 0.24 (hexanes: ethyl acetate = 2:1).
1 H NMR (400MHz, C6D6): δ 7.14-7.10 (m, 2H), δ 7.05-7.00 (m, 3H), 6.16 (d, J = 8.0 Hz, 1H), 6.00 (d, J = 8.0 Hz, 1H), 5.86 (ddd, J = 17.4, 9.8, 7.3 Hz, 1H), 5.62-5.59 (m, 1H), 5.11-5.06 (m, 1H), 4.96-4.96 (m, 1H), 2.49-2.38 (m, 2H), 1.92-1.85 (m, 1H), 1.70-1.62 (m, 1H), 1.54-1.38 (m, 2H).
13 C NMR (100 MHz, C6D6): δ 158.2, 142.1, 136.7, 131.9, 131.4, 128.5, 128.4, 126.1, 118.1, 118.0, 60.1, 36.4, 33.0, 32.9, 27.9 ppm.
Experimental Part | 212
+ HRMS-ESI (m/z): [M+Na] calcd for C16H17ON2ClNa, 311.09216; found, 311.09213.
E.3.6. Transformations involving N-Allyl Pyridazinone
E.3.6.1. Syntheses and Characterization of Pyridazinone Transformation Products: E.3.6.1.1. 6-Chloro-2-(1-phenylbutan-2-yl)pyridazin-3(2H)-one (546)
6-Chloro-1-(6-phenylhex-1-en-3-yl)pyridazin-2(1H)-one (rac-473) (115 mg, 0.4 mmol, 100 mol % ) and Pd (10 wt% Pd/C, 4.2 mg, 0.04 mmol, 10 mol %) were stirred in MeOH (5 ml) under H2 atmosphere (1 atm) at 0 ºC for 10 h. The reaction mixture was filtrated over a pad of celite, rinsed with ethyl acetate (10 ml) and concentrated under reduced pressure. The residue was purified via flash column chromatography using hexane: ethyl acetate (3:1) as eluting system to give the desired hydrogenated product 546 as white solid (112 mg, 97%).
Analytical Data of 546:
TLC (SiO2): Rf = 0.46 (hexanes: ethyl acetate = 2:1)
1 H NMR (400 MHz, CDCl3): δ 7.18-7.12 (m, 3H), 7.27-7.23 (m, 2H), 7.10 (d, J = 9.59 Hz, 1H), 6.88 (d, J = 9.59 Hz, 1H), 5.03-4.95 (m, 1H), 2.67-2.53 (m, 2H), 1.89- 1.75 (m, 2H), 1.74-1.65 (m, 2H), 1.62-1.52 (m, 1H), 1.51-1.48 (m, 1H), 0.80 (t, J = 7.39 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ 159.9, 142.0, 137.4, 132.6, 131.6, 128.4, 128.3, 125.8, 59.3, 35.5, 33.2, 27.6, 10.5 ppm. + HRMS-ESI (m/z): [M+Na] calcd for C16H19ON2ClNa, 313.1078; found, 313.10788. Melting point: 54 °C.
Experimental Part | 213
E.3.6.1.2. 6-Chloro-2-(1-hydroxy-6-phenylhexan-3-yl)pyridazin-3(2H)-one (547)
The solution of (6-chloro-1-(6-phenylhex-1-en-3-yl)pyridazin-2(1H)-one 473(150 mg, 0.52 mmol, 100 mol%) in THF was cooled to -78 ºC and 9-BBN (0.5 M in THF, 4.8 ml, 1.3 mmol, 250 mol %) was added dropwise over a period of 20 min. The reaction mixture was maintained at this temperature for 1 hour and gradually warmed to room temperature and stirred overnight. The reaction mixture was cooled again to 0 ºC and basified with NaOH (2 M aqueous, 3 mmol, 580 mol %) followed by the slow addition of H2O2 (~ 4 ml, 30 % w/w in H2O) were successively added. The reaction mixture was stirred for 4 h along with gradual warming to room temperature. Water (5 ml) was added and the reaction mixture was partitioned using ethyl acetate. The aqueous layer was successively extracted with ethyl acetate (3×20 ml). The combined organic layers were dried over sodium sulphate, filtered and concentrated under vacuum. The crude reaction mixture was purified via flash chromatography using hexanes: ethyl acetate (2:1) as eluent and the hydroxylated product 547 was isolated as colorless oil (125mg, 78%).
Analytical Data of 547:
TLC (SiO2): Rf = 0.25 (chloroform: methanol = 15:1)
1 H NMR (400 MHz, CDCl3): 7.28-7.23 (m, 2H), 7.19-7.11 (m, 4H), 6.92 (d, J = 9.72 Hz, 1H), 5.19 (dddd, J = 10.69, 9.71, 4.93, 3.60 Hz, 1 H), 3.58 (ddd, J = 12.00, 5.31, 3.66 Hz, 1 H), 3.28 (ddd, J = 12.00, 10.11, 3.66 Hz, 1 H), 2.67-2.56 (m, 2H), 2.05-1.92 (m, 2H), 1.87-1.79 (m, 1H), 1.76-1.67 (m, 1H), 1.62-1.42 (m, 2H) ppm.
13 C NMR (100 MHz, CDCl3): 160.5, 141.8, 138.5, 133.2, 131.3, 128.4, 128.3, 125.9, 58.5, 54.5, 37.3, 35.3, 33.0, 27.7 ppm.
Experimental Part | 214
+ HRMS-ESI (m/z): [M+Na] calcd for C16H19N2ClNa, 329.10273; found, 329.10266.
E.3.6.1.3. 4-(3-Chloro-6-oxopyridazin-1(6H)-yl)-5-phenylpentanal (548)
The reaction was performed under previously reported hydroformylation conditions.249
A solution of [Rh(CO)2acac] (0.3 mg, 1 μmol, 0.5 mol %) and 6-DPPon (5.6 mg, 0.02 mmol, 10 mol %) in toluene (2.0 mL 0.01 M) was added in a high pressure autoclave. The solution was stirred at room temperature for 10 min. 6-chloro-1-(6-phenylhex-1- en-3-yl)pyridazin-2(1H)-one (473, 53.7 mg, 0.4 mmol, 100 mol %) dissolved in toluene (2 ml) was added to autoclave and the reaction mixture was stirred at 80 °C under CO/H2 (20 bar) for 20 hrs. The reaction mixture was filtrated over a short silica column, rinsed with ethyl acetate and concentrated under vacuum. The resulting crude product was purified by flash column chromatography (chloroform: methanol = 50:1) to give 548 as a colorless oil (41.8 mg, 91%, b:l 9:1).
Analytical Data of 548:
TLC (SiO2): Rf = 0.11 (chloroform: methanol = 15:1)
1 H NMR (400 MHz, CDCl3): 9.69 (t, J = 1.13 Hz, 1H), 7.28-7.23 (m, 2H), 7.18- 7.11 (m, 4H), 6.88 (d, J = 9.72 Hz, 1H), 5.10-5.03 (m, 1H), 2.67-2.54 (m, 2H), 2.46- 2.37 (m, 1H), 2.34-2.26 (m, 1H), 2.12-1.98 (m, 2H), 1.94-1.84 (m, 1H), 1.74-1.66 (m, 1H), 1.63-1.52 (m, 1H), 1.51-1.42 (m, 1H) ppm.
13 C NMR (100 MHz, CDCl3): 200.8, 159.7, 141.8, 138.0, 133.0, 131.7, 128.4, 125.9, 57.1, 40.4, 35.3, 33.3, 27.5, 26.2 ppm. + HRMS-ESI (m/z): [M+Na] calcd for C17H19O2N2ClNa, 341.10273; found, 341.10266.
Experimental Part | 215
E.3.6.1.4. 2-(3-Chloro-6-oxopyridazin-1(6H)-yl)-5-phenylpentanal (549)
6-chloro-1-(6-phenylhex-1-en-3-yl)pyridazin-2(1H)-one 473 (3aa, 100 mg, 0.347 mmol, 100 mol %) was dissolved in DCM (3.5 ml, 0.1 M) and temperature was lowered to 78 °C. O3 was bubbled. The formation of ozonide intermediate was indicated by appearance of blue color in 5 minutes. The reaction vessel was degassed with N2 until the solution became colorless. PPh3 (137 mg, 0.52 mmol, 150 mol %) was added at the same temperature. The reaction mixture was then allowed to come to ambient temperature in 4 hrs. The reaction mixture was quenched with saturated ammonium chloride and extracted with DCM (10 ml x 3). The combined organic layer was dried with magnesium sulphate. The aldehyde product 549 was isolated as colorless oil (82 mg, 82%) by flash column chromatography using hexanes: ethyl acetate (1:1) as eluent.
Analytical Data of 549:
TLC (SiO2): Rf = 0.30 (chloroform: methanol = 15:1)
1 H NMR (400 MHz, CDCl3): 9.60 (s, 1H), 7.29-7.24 (m, 2H), 7.20-7.14 (m, 3H), 7.21 (d, J = 9.72 Hz, 1H), 6.96 (d, J = 9.72 Hz, 1H), 5.31 (dd, J = 9.92, 4.74 Hz, 1H), 2.73-2.59 (m, 2H), 2.27-2.16 (m, 1H), 2.10-2.00 (m, 1H), 1.75 -1.58 (m, 2H) ppm.
13 C NMR (100 MHz, CDCl3): δ 195.9, 159.2, 141.3, 138.6, 134.1, 131.9, 128.5, 128.4, 126.1, 35.2, 27.5, 27.3 ppm. + HRMS-ESI (m/z): [M+Na] calcd for C15H15N2ClNa, 313.07143; found, 313.07150.
Experimental Part | 216
E.3.7. Crystal Data and Absolute Configuration:
Single colourless block-shaped crystals of 2-(4-(3-Chloro-6-oxopyridazin-1(6H)- yl)hex-5-enyl)isoindoline-1,3-dione 510 were obtained by recrystallisation. A suitable crystal (0.28×0.14×0.13) mm3 was selected and mounted on a Bruker Smart APEXII QUAZAR diffractometer. The crystal was kept at T = 100(2) K during data collection. The structure was solved with the ShelXT-2014/5 (Acta Cryst., A71, 3-8) structure solution program, using the intrinsic phasing solution method. The model was refined with version 2016/6 of ShelXL-2016/6 (Acta Cryst., C71, 3-8) using full matrix least squares on F2 minimisation.
2-(4-(3-Chloro-6-oxopyridazin-1(6H)-yl)hex-5-enyl)isoindoline-1,3-dione (510)
Figure E.3. ORTEP structure of compound 510 showing its absolute configuration.
Crystal Data: C18H16ClN3O3, Mr = 357.79, orthorhombic, P212121 (No. 19), a = 4.8769(5) Å, b = 9.1534(9) Å, c = 37.533(4) Å, α = β = = 90°, V = 1675.5(3) Å3, T = 100(2) K, Z = 4, Z' = 1, μ(MoKα) = 0.251, 3547 reflections measured, 3547 unique (Rint = 0.0390) which were used in all calculations. The final wR2 was 0.1089 (all data) and R1 was 0.0376 (I > 2(I)).
A colourless block-shaped crystal with dimensions 0.28×0.14×0.13 mm3 was mounted on Mitegen Loops in polyether oil. X-ray diffraction data were collected
Experimental Part | 217 using a Bruker Smart APEXII QUAZAR diffractometer equipped with an Oxford Cryosystems 800 low-temperature device, operating at T = 100(2) K.
Cell parameters were retrieved using the SAINT (Bruker, V8.37) software and refined using SAINT (Bruker, V8.37) on 9943 reflections, 280 % of the observed reflections. Data reduction was performed using the SAINT (Bruker, V8.37) software which corrects for Lorentz polarisation. The final completeness is 99.60 out to 26.388 in . The absorption coefficient of this material is 0.251 at this wavelength ( = 0.71073) and the minimum and maximum transmissions are 0.582623 and 0.745372.
The structure was solved in the space group P212121 (# 19) by intrinsic phasing using the ShelXT-2014/5 (Acta Cryst., A71, 3-8) structure solution program and refined by full matrix least squares on F2 using version 2016/6 of ShelXL-2016/6 (Acta Cryst., C71, 3-8). All non-hydrogen atoms were refined anisotropically. Hydrogen atom positions were calculated geometrically and refined using the riding model.
There is a single molecule in the asymmetric unit, which is represented by the reported sum formula. In other words: Z is 4 and Z' is 1. The Flack parameter was refined to 0.00(2). Determination of absolute structure using Bayesian statistics on Bijvoet differences using SHELXL.
Figure E.4. X-ray crystallographic analysis of “510”
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Compound SH_2_34N_final CCDC number 1511721 Z 4 Formula C18H16ClN3O3 Z' 1 Dcalc./ g cm‐3 1.418 Wavelength/Å 0.71073 /mm‐1 0.251 Radiation type MoK Formula Weight 357.79 min/° 1.085 Colour colourless max/° 26.388 Shape block Measured Refl. 3547 Size/mm3 0.28×0.14×0.13 Independent Refl. 3547 T/K 100(2) Reflections Used 3402 Crystal System orthorhombic Rint 0.0390 Flack Parameter 0.00(2) Parameters 227 Space Group P212121 Restraints 0 a/Å 4.8769(5) Largest Peak 0.494 b/Å 9.1534(9) Deepest Hole ‐0.194 c/Å 37.533(4) GooF 1.081 /° 90 wR2 (all data) 0.1089 /° 90 wR2 0.1078 /° 90 R1 (all data) 0.0394 V/Å3 1675.5(3) R1 0.0376
Table E.3. Crystallographic parameters for the crystal of “510”
Determination of X-ray analysis and the derivation of ORTEP structures were done by Dr. Daniel Kratzert, Inorganic & Analytical Department, Albert Ludwigs University Freiburg. The details of crystallographic investigation are available as cif file on the website of Cambridge Crystallographic Data Centre (www.ccdc.cam.ac.uk/data_request/cif) under CCDC deposition number 1511721.
Experimental Part | 219
Section B
E.4. Rhodium Catalyzed Coupling of Azlactone with Terminal Alkynes
E.4.1. Substrate Synthesis
E.4.1.1. General Procedure D: Preparation of Aromatic Internal Alkynes
Scheme.E.11. General procedure for the synthesis of internal alkyne
Solution of starting reagent 1-bromoprop-1-ene (1.9 ml, 22.4 mmol, 1.5 equiv.) in dry THF (20 ml) was cooled to −78 °C and treated with nBuLi (2.5 M in hexanes, 12.2 ml, 32.8 mmol, 2.2 equiv.) over a period of 30 min. The reaction mixture was stirred for 2 hours. H2O (0.6 ml, 32.8 mmol, 2.2 equiv.) was added to the reaction mixture and the temperature was raised to 0 °C. At this temperature, [Pd(PPh3)2Cl2] (527 mg, 0.75 mmol, 5.0 mol%), CuI (284 mg, 1.50 mmol, 10 mol%), Ar-X (14.9 mmol, 1.0 equiv.) and iPr2NH (21.0 ml, 150.0 mmol, 10.0 equiv.) were successively added and the resulting mixture was then warmed to rt and stirred for 4-24 hours. The reaction was quenched with saturated aqueous NH4Cl (15 ml) and extracted with EtOAc (3 × 20 ml). Combine organic fractions were dried over MgSO4, filtered and concentrated under reduced pressure. The resulting crude product was purified by silica gel flash column chromatography using hexanes to obtain the respective internal alkyne.86h,92b
Experimental Part | 220
E.4.1.1.1. 1-Nitro-4-(prop-1-yn-1-yl)benzene (565)
The reaction was performed according to procedure D with 1-bromo-4-nitrobenzene (3.0 g, 14.9 mmol). The desired product was obtained as a white solid (1.1 g, 6.6 mmol, 44 %).
Analytical Data of 565:
TLC (SiO2): Rf = 0.11 (chloroform: methanol = 15:1)
1 H NMR (400 MHz, CDCl3): = 8.16 (m, 2H), 7.62 (m, 2H), 1.89 (s, 3H) ppm.
13 C-NMR (100 MHz, CDCl3): δ = 147.3, 133.1, 131.5, 127.5, 123.8, 85.5, 79.8, 4.7 ppm. Melting point: 107-109 °C
E.4.1.1.2. 1-(Prop-1-yn-1-yl)-4-(trifluoromethyl)benzene (567)
The desired alkyne was synthesized according to procedure D using 1-iodo-4- (trifluoro- methyl)benzene (4.0 g, 14.9 mmol). The desired product 567 was afforded as acolorless oil (2.3 g) in 83 % yield.
Analytical Data of 567: TLC (SiO2): Rf = 0.45 (hexanes). 1 H-NMR (400 MHz, CDCl3): δ = 7.54-7.46 (m, 4H), 1.96 (s, 3H) ppm. 13 C-NMR (100 MHz, CDCl3): δ = 132.4, 130.2, 128.4, 126.0, 124.4, 88.1, 79.2, 4.8 ppm.
Experimental Part | 221
E.4.1.1.3. 4-(Prop-1-yn-1-yl)-1,1'-biphenyl (573)
Biphenyl propyne was synthesized according to procedure D by using 4-bromo-1,1'- biphenyl (4.6 g, 20.0 mmol). The desired product 573 was isolated as a white solid (3.1 g) with 80 % overall yield, by using column chromatography.
Analytical Data of 573:
TLC (SiO2): Rf = 0.10 (hexanes). 1 H-NMR (400 MHz, CDCl3): δ = 7.69-7.55 (m, 4H), 7.55-7.51 (m, 2H), 7.49-7.42 (m, 3H), 1.89 (s, 3H) ppm. 13C-NMR (100 MHz, CDCl3): δ = 140.8, 140.6, 132.4, 129.2, 127.9, 127.3, 127.2, 123.3, 85.9, 79.9, 4.8 ppm. Melting point: 64 °C.
E.4.1.1.4. 1-Methyl-2-(prop-1-yn-1-yl)benzene (577)
1-Methyl-4-(prop-1-yn-1-yl)benzene 577 was synthesized from 4-methylphenyl- acetylene by simple methylation process. In this case 1-ethynyl-4-methylbenzene (2.4 ml, 2.2 g, 19.2 mmol, 1.0 equiv.) dissolved in THF (20 ml) was treated with nBuLi (2.5 M in hexanes, 10.7 ml, 28.8 mmol, 1.5 equiv.) at −20 °C, with dropwise addition over 30 minutes. The solution was stirred for 1 hour at this temperature. The reaction mixture was further treated with MeI (3.6 ml, 8.2 g, 57.6 mmol, 3.0 equiv.) over a period of 30 minutes and allowed to stir for another 4.5 hour. The reaction was
Experimental Part | 222
quenched by the addition of sat. aq. NH4Cl (5 ml) and extracted with EtOAc (2 × 10 ml). The combined organic fractions were dried over Na2SO4 and concentrated under reduced pressure. The desired product 577 was obtained after vacuum fraction distillation of reaction mixture at 73 °C // 230 mbar as colorless oil with 92 % yield (2.3 g).
Analytical Data of 577:
TLC (SiO2): Rf = 0.10 (hexanes) 1 H-NMR (400 MHz, CDCl3): δ = 7.28 (m, 2H), 7.08 (m, 2H), 2.05 (s, 3H) ppm. 13 C-NMR (100 MHz, CDCl3): δ = 137.8, 131.7, 129.3, 121.3, 85.3, 80.1, 21.7, 4.7 ppm. Boiling Point: 73 °C (230 mbar).
Experimental Part | 223
E.4.2. Catalysis
E.4.2.1. General Procedures
E.4.2.1.1. General Procedure for Rhodium-Catalyzed Tandem Azlactone- Alkyne Coupling/Aza-Cope Rearrangement (GP-E)
To a dried 5 mL schlenk tube were added [{Rh(cod)Cl}2] (x mol%), DPEphos 101 (y mol%), diphenylacetic acid (4.2 mg, 0.02 mmol), azlactone 426 (0.2 mmol), alkyne 463 (0.3 mmol), and dry DCE (0.6 mL) sequentially under the atmosphere of Ar and the tube was then sealed. The reaction mixture was stirred at 60 oC for 18 hours. After cooling to room temperature, the solvent was removed by rotary evaporation and the resulting crude mixture was analyzed by 1H-NMR to determine the ratio of 552/553. The crude product was purified by flash column chromatography on silica gel.
E.4.2.1.2. General Procedure for Rhodium-Catalyzed Tandem Azlactone Formation /Azlactone-Alkyne Coupling/Aza-Cope Rearrangement (GP-F)
To a dried 5 mL schlenk tube were added [{Rh(cod)Cl}2] (x mol%), DPEphos 101 (y mol%), N-acyl amino acid 5 (0.2 mmol), 1-phenyl-1-propyne 551 (37.6 μL , 34.8 mg, 0.3 mmol), acetic anhydride (20.8 μL , 22.5 mg, 0.22 mmol), and dry DCM (0.6 mL) sequentially under the atmosphere of Ar and then the tube was sealed. The reaction mixture was stirred at 60 oC for 18 hours. After cooling to room temperature, the solvent was removed by rotary evaporation and the resulting crude mixture was analyzed by 1H-NMR to determine the ratio of 552/553. The crude product was purified by flash column chromatography on silica gel.
E.4.2.1.3. General Procedure for Sequential Synthesis of 2, 3, 6- Trisubstituted Pyridines from Azlactones and Internal Alkynes (GP-G)
To a dried 5 mL schlenk tube were added [{Rh(cod)Cl}2] (4.9 mg, 0.01 mmol), DPEphos 101 (10.8 mg, 0.02 mmol), diphenylacetic acid (5.3 mg, 0.025 mmol), azlactone 426 (0.25 mmol), alkyne 463 (0.375 mmol), and dry DCE (1.0 mL) sequentially under the atmosphere of Ar and then the tube was sealed. The reaction
Experimental Part | 224
mixture was stirred at 60 °C for 18 hours. After cooling to room temperature, the solvent was removed by rotary evaporation and the resulting crude mixture was then dissolved in 1.0 mL of xylene, transferred to a 5 mL microwave tube, and heated under microwave irradiation at 120 °C for 1.5 h. After cooling to room temperature, the solvent was removed by rotary evaporation and the crude product was purified by flash column chromatography on silica gel.
E.4.2.1.4. General Procedure for Sequential Synthesis of 2, 3, 6- Trisubstituted Pyridines from N-Acyl Amino acid and Internal Alkynes (GP-H)
To a dried 5 mL schlenk tube were added [{Rh(cod)Cl}2] (3.9 mg, 0.008 mmol), DPEphos 101 (8.6 mg, 0.016 mmol), 2-(4-bromobenzamido)-2-phenylacetic acid (66.8 mg, 0.2 mmol), alkyne 463 (0.3 mmol), acetic anhydride (20.8 μL , 22.5 mg, 0.22 mmol), and dry DCM (0.6 mL) sequentially under the atmosphere of Ar and then the tube was sealed. The reaction mixture was stirred at 60 °C for 18 hours. After cooling to room temperature, the solvent was removed by rotary evaporation and the resulting crude mixture was then dissolved in 1.2 mL of xylene and heated under microwave at 120 °C for 1.5 h. After cooling to room temperature, the solvent was removed by rotary evaporation and the crude product was purified by flash column chromatography on silica gel.
E.4.3. Ligand Screening
All reactions shown in Table E.4 have been performed according to procedure (GP- E) at a reaction temperature of 50 °C using the following amounts of substrates, catalyst and solvent: 2,4-diphenyloxazol-5(4H)-one 550 (47.4 mg, 0.2 mmol, 1.0
equiv.), 1-phenyl-propyne 551 (71 mg, 0.30 mmol, 1.5 equiv.), [{Rh(cod)Cl}2] (2.4 mg, 0.005 mmol, 2.5 mol %), ligand (0.01 mmol, 5 mol %) and 0.5 ml DCE (0.4 M solution relative to 2,4-diphenyloxazol-5(4H)-one 550.
Experimental Part | 225
Table E.4. Ligands screening for the regioselective coupling of internal alkyne with azlactone:
E.4.4. Reaction Conditions Screening
All reactions depicted in Table E.5, given below have been performed according to procedure (GP-E) using the given amounts of catalyst, substrates and additive. The amounts of substances for the reaction were taken, assuming the azlactone as limiting reagent. The azlactone substrate was 0.20 mmol while the coupling counterpart 1- phenyl-1-propyne was taken 2.0 equivalents (i.e. the ratio of substrates (alkyne: azlactone) is 2:1). The mol %-values for the metal source, DPEphos 101(15) and additive used are given relative to the limiting substrate.
Experimental Part | 226
Table E.5. Condition screening for the regioselective coupling of internal alkyne with azlactone:
entry x solvent conversion (%) yield of 3a (%)[a] yield of 4a (%)[a]
1[b] 2.0 DCE 85 74 4
2 2.0 DCE 100 96 2
3[c] 2.0 DCE 69 60 2
4[d] 2.0 DCE 74 57 7
5[e] 2.0 DCE 100 36 4
6 2.0 DCM 92 87 3
7 2.0 CH3CN 59 74 2
8 2.0 toluene 42 27 3
9 2.0 THF 97 42 5
10 1.5 DCE 97 95 2
11 [f] 1.5 DCE 100 98 (94[g]) 2
12 [f] 1.2 DCE 88 77 2
[a] 1H NMR yield using 1,3,5-trimethylbenzene as internal standard; [b] No acid was added; [c] 10 mol% of
PhCOOH instead of Ph2CHCOOH was added; [d] 10 mol% of PPTS instead of Ph2CHCOOH was added. PPTS = pyridinium 4-toluenesulfonate; [e] 10 mol% of TsOHxH2O instead of Ph2CHCOOH was added; [f] The reaction was carried out at 60 °C; [g] Isolated yield
Experimental Part | 227
E.4.5. Rhodium-Catalyzed Tandem Azlactone-Alkyne Coupling/Aza-Cope Rearrangement
All products were synthesized according to procedure GP-E at 60 °C with a reaction time of 18 hours using the conditions, depicted in the Table E.4. (entry 11) which are optimized reaction conditions, obtained at a result of verity of reaction parameter screening. The amounts of reagents used are azlactone 426 (0.2 mmol, 1.0 equiv.), substituted alkyne 463 (0.30 mmol, 1.5 equiv.), [{Rh(cod)Cl}2] (1 mol %), DPEPhos 101(2 mol%), DCE (0.5 ml, 0.4 M). In cases where one or more reaction parameters differed from those used as standard, additional information has been added to the respective reaction product.
E.4.5.1. 2-(3-Phenyl-2-propenyl)-2,4-diphenyl-oxazol-5(2H)-one (552)
The reaction was performed following GP-E with [{Rh(cod)Cl}2] (1.0 mg, 0.002 mmol), DPEphos 101(2.2 mg, 0.004 mmol), 2,4-diphenyloxazol-5(4H)-one 550 (47.5 mg, 0.2 mmol), 1-phenyl-1-propyne 552 (37.6 μl, 34.9 mg, 0.3 mmol). The crude product was purified by flash column chromatography on silica gel (CH/toluene = 2/1) to afford the desired product as a white solid (66.5 mg, 94%).
Analytical Data of 552:
TLC (SiO2): Rf = 0.53 (n-hexane: ethyl acetate = 10:1) 1 H-NMR (400 MHz, CDCl3): δ = 8.33-8.29 (m, 2 H), 7.62-7.57 (m, 2 H), 7.49-7.43 (m, 1 H), 7.42-7.25 (m, 5 H), 7.19-7.07 (m, 5 H), 6.35 (dt, J = 16.0, 1.1 Hz, 1 H), 5.87 (dt, J = 16.0, 7.1 Hz, 1 H), 3.08 (ddd, J = 14.4, 7.5, 1.1 Hz, 1 H), 3.02 (ddd, J = 14.0, 7.4, 1.4 Hz, 1 H) ppm.
Experimental Part | 228
13 C-NMR (100 MHz, CDCl3): δ 163.9, 156.3, 138.7, 136.8, 136.4, 132.5, 128.9, 128.7, 128.54, 128.47, 127.6, 126.3, 126.0, 120.7, 106.1, 45.1 ppm. + HRMS-ESI (m/z): [M+Na] calcd for C24H19NO2Na, 376.1313; found: 376.1308. Melting Point: 88-90 oC.
E.4.5.2. 2-(3-(4-Bromophenyl)-2-propenyl)-2,4-diphenyl-oxazol-5(2H)-one (560)
The reaction was performed following GP-E with [{Rh(cod)Cl}2] (4.0 mg, 0.008 mmol), DPEphos 101(8.6 mg, 0.016 mmol), 2,4-diphenyloxazol-5(4H)-one 550 (47.5 mg, 0.2 mmol), 1-(4-bromophenyl)-1-propyne (58.5 mg, 0.3 mmol). The crude product was purified by flash column chromatography on silica gel (CH/toluene = 2/1) to afford the desired product as a white solid (69.2 mg, 80%).
Analytical Data of 560:
TLC (SiO2): Rf = 0.44 (n-hexane: ethyl acetate = 10:1) 1 H-NMR (400 MHz, CDCl3): δ = 8.41-8.37 (m, 2 H), 7.68-7.65 (m, 2 H), 7.59-7.54 (m, 1 H), 7.51-7.46 (m, 2 H), 7.44-7.34 (m, 5 H), 7.11-7.07 (m, 2 H), 6.39 (d, J = 15.6 Hz, 1 H), 5.83 (dt, J = 16.0, 7.3 Hz, 1 H), 3.17 (ddd, J = 14.4, 7.5, 1.3 Hz, 1 H), 3.10 (ddd, J = 14.4, 7.2, 1.2 Hz, 1 H) ppm. 13 C-NMR (100 MHz, CDCl3): δ = 163.9, 156.3, 138.5, 135.7, 135.2, 132.6, 131.6, 128.9, 128.8, 128.7, 128.6, 128.5, 127.8, 126.0, 121.6, 121.5, 106.0, 45.0 ppm. + 79 HRMS-APCI (m/z): [M+H] calcd for C24H19 BrNO2, 432.0599; found: 432.0594; + 81 [M+H] calcd for C24H19 BrNO2, 434.0579; found: 434.0573. Melting Point: 102-103 °C.
Experimental Part | 229
E.4.5.3. 2-(3-(4-Chlorophenyl)-2-propenyl)-2,4-diphenyl-oxazol-5(2H)-one (562)
The reaction was performed following GP-E with [{Rh(cod)Cl}2] (4.0 mg, 0.008 mmol), DPEphos 101(8.6 mg, 0.016 mmol), 2,4-diphenyloxazol-5(4H)-one 550 (47.5 mg, 0.2 mmol), 1-(4-chlorophenyl)-1-propyne 561 (45.2 mg, 0.3 mmol). The crude product was purified by flash column chromatography on silica gel (CH/toluene = 2/1) to afford the desired product as a white solid (76.1 mg, 98%).
Analytical Data of 562:
TLC (SiO2): Rf = 0.44 (n-hexane: ethyl acetate = 10:1) 1 H-NMR (400 MHz, CDCl3): δ = 8.32-8.28 (m, 2 H), 7.60-7.55 (m, 2 H), 7.49-7.43 (m, 1 H), 7.42-7.36 (m, 2 H), 7.35-7.25 (m, 3 H), 7.14-7.09 (m, 2 H), 7.08-7.03 (m, 2 H), 6.29 (d, J = 16.0 Hz, 1 H), 5.84 (dt, J = 16.0, 7.3 Hz, 1 H), 3.07 (ddd, J = 14.4, 7.6, 1.2 Hz, 1 H), 3.00 (ddd, J = 14.2, 7.4, 1.2 Hz, 1 H) ppm. 13 C-NMR (100 MHz, CDCl3): δ = 163.9, 156.3, 138.5, 135.2, 135.1, 133.3, 132.6, 128.9, 128.75, 128.72, 128.65, 128.6, 128.5, 127.5, 126.0, 121.5, 106.0, 45.0 ppm. + HRMS-APCL (m/z): [M+H] calcd for C24H19ClNO2, 388.1104; found: 388.1099, + 37 [M+H] calcd for C24H19 ClNO2, 390.1075; found: 390.1069. Melting Point: 110-111 °C.
Experimental Part | 230
E.4.5.4. 2-(3-(4-Fluorophenyl)-2-propenyl)-2,4-diphenyl-oxazol-5(2H)-one (564)
The reaction was performed following GP-E with [{Rh(cod)Cl}2] (4.0 mg, 0.008 mmol), DPEphos 101(8.6 mg, 0.016 mmol), 2,4-diphenyloxazol-5(4H)-one 550 (47.5 mg, 0.2 mmol), 1-(4-fluorophenyl)-1-propyne 563 (40.3 mg, 0.3 mmol). The crude product was purified by flash column chromatography on silica gel (cyclohexane/toluene = 2/1) to afford the desired rearranged product as a white solid (66.9 mg, 90%).
Analytical Data of 564:
TLC (SiO2): Rf = 0.43 (n-hexane: ethyl acetate = 10:1) 1 H-NMR (400 MHz, CDCl3): δ = 8.43-8.39 (m, 2 H), 7.71-7.67 (m, 2 H), 7.59-7.54 (m, 1 H), 7.53-7.46 (m, 2 H), 7.45-7.35 (m, 3 H), 7.23-7.17 (m, 2 H), 6.97-6.90 (m, 2 H), 6.40 (d, J = 16.0 Hz, 1 H), 5.88 (dt, J = 16.0, 7.4 Hz, 1 H), 3.17 (ddd, J = 14.1, 7.5, 1.3 Hz, 1 H), 3.10 (ddd, J = 14.2, 7.4, 1.2 Hz, 1 H) ppm. 13 C-NMR (100 MHz, CDCl3): δ = 163.9, 162.3 (d, J = 247.0 Hz), 156.3, 138.6, 135.2, 132.9 (d, J = 3.4 Hz), 132.5, 128.9, 128.74, 128.72, 128.6, 128.5, 127.8 (d, J = 8.0 Hz), 126.0, 120.4 (d, J = 2.1 Hz), 115.4 (d, J = 21.8 Hz), 106.0, 45.0 ppm. + HRMS-ESI (m/z): [M+Na] calcd for C24H18FNO2Na, 394.1219; found: 394.1214. Melting Point: 104-106 °C.
Experimental Part | 231
E.4.5.5. 2-(3-(4-Nitrophenyl)-2-propenyl)-2,4-diphenyl-oxazol-5(2H)-one (566)
The reaction was performed following GP-E with [{Rh(cod)Cl}2] (4.0 mg, 0.008 mmol), DPEphos 101(8.6 mg, 0.016 mmol), 2,4-diphenyloxazol-5(4H)-one 550 (47.5 mg, 0.2 mmol), 1-(4-nitrophenyl)-1-propyne 565 (48.4 mg, 0.3 mmol). The crude product was purified by flash column chromatography on silica gel (CH/toluene = 1/1) to afford the desired product as a yellow solid (78.2 mg, 98%).
Analytical Data of 566:
TLC (SiO2): Rf = 0.41 (n-hexane: ethyl acetate = 10:1) 1 H-NMR (400 MHz, CDCl3): δ = 8.43-8.39 (m, 2 H), 8.13-8.07 (m, 2 H), 7.70-7.65 (m, 2 H), 7.60-7.55 (m, 1 H), 7.52-7.46 (m, 2 H), 7.46-7.33 (m, 5 H), 6.50 (d, J = 16.0 Hz, 1 H), 6.17 (dt, J = 16.0, 7.4 Hz, 1 H), 3.23 (ddd, J = 14.2, 7.4, 1.2 Hz, 1 H), 3.15 (ddd, J = 14.3, 7.3, 1.3 Hz, 1 H) ppm. 13 C-NMR (100 MHz, CDCl3): δ = 163.8, 156.3, 147.0, 142.9, 138.3, 134.3, 132.7, 129.1, 128.8, 128.7, 128.6, 128.3, 126.8, 126.0, 125.9, 123.9, 105.8, 45.1 ppm. + HRMS-APCI (m/z): [M+H] calcd for C24H19N2O4, 399.1345; found: 399.1339. Melting Point: 119-120 °C.
Experimental Part | 232
E.4.5.6. 2-(3-(4-Trifluoromethylphenyl)-2-propenyl)-2,4-diphenyl-oxazol-5(2H)- one (568)
The reaction was performed following GP-E with [{Rh(cod)Cl}2] (4.0 mg, 0.008 mmol), DPEphos 101(8.6 mg, 0.016 mmol), 2,4-diphenyloxazol-5(4H)-one 550 (47.5 mg, 0.2 mmol), 1-(4-trifluoromethylphenyl)-1-propyne 567 (55.2 mg, 0.3 mmol). The crude product was purified by flash column chromatography on silica gel (CH/toluene = 2/1) to afford the desired product as a white solid (67.5 mg, 80%).
Analytical Data of 568:
TLC (SiO2): Rf = 0.46 (n-hexane: ethyl acetate = 10:1) 1 H-NMR (400 MHz, CDCl3): δ = 8.43-8.39 (m, 2 H), 7.70-7.66 (m, 2 H), 7.60-7.55 (m, 1 H), 7.53-7.47 (m, 4 H), 7.46-7.35 (m, 3 H), 7.35-7.30 (m, 2 H), 6.65 (d, J = 15.6 Hz, 1 H), 6.08 (dt, J = 16.0, 7.3 Hz, 1 H), 3.20 (ddd, J = 14.0, 7.6, 1.2 Hz, 1 H), 3.13 (ddd, J = 14.0, 7.2, 1.2 Hz, 1 H) ppm. 13 C-NMR (100 MHz, CDCl3): δ = 163.9, 156.3, 140.1, 138.5, 135.0, 132.7, 129.5 (q, J = 32.3 Hz), 129.0, 128.8, 128.7, 128.6, 128.5, 128.2, 126.4, 126.0, 125.5 (q, J = 3.9 Hz), 124.1 (q, J = 271.9 Hz), 105.9, 45.0 ppm. + HRMS-ESI (m/z): [M+H] calcd for C25H19F3NO2, 422.1368; found: 422.1362. Melting Point: 138-140 °C.
E.4.5.7. 2-(3-(4-Acetylphenyl)-2-propenyl)-2,4-diphenyl-oxazol-5(2H)-one (570)
Experimental Part | 233
The reaction was performed following GP-E with [{Rh(cod)Cl}2] (4.0 mg, 0.008 mmol), DPEphos 101(8.6 mg, 0.016 mmol), 2,4-diphenyloxazol-5(4H)-one 550 (47.5 mg, 0.2 mmol), 1-(4-acetylphenyl)-1-propyne 569 (43.3 mg, 0.3 mmol). The crude product was purified by flash column chromatography on silica gel (CH/toluene = 1/1) to afford the desired product as a yellow solid (64.1 mg, 84%).
Analytical Data of 570:
TLC (SiO2): Rf = 0.51 (n-hexane: ethyl acetate = 10:1) 1 H-NMR (400 MHz, CDCl3): δ = 9.95 (s, 1 H), 8.42-8.38 (m, 2 H), 7.78-7.75 (m, 2 H), 7.69-7.66 (m, 2 H), 7.59-7.54 (m, 1 H), 7.51-7.46 (m, 2 H), 7.45-7.35 (m, 5 H), 6.49 (d, J = 15.6 Hz, 1 H), 6.14 (dt, J = 16.0, 7.4 Hz, 1 H), 3.21 (ddd, J = 14.2, 7.4, 1.2 Hz, 1 H), 3.14 (ddd, J = 14.3, 7.3, 1.3 Hz, 1 H) ppm. 13 C-NMR (100 MHz, CDCl3): δ = 191.6, 163.9, 156.3, 142.6, 138.4, 135.5, 135.3, 132.7, 130.1, 129.0, 128.80, 128.75, 128.6, 128.4, 126.8, 126.0, 124.7, 105.9, 45.2 ppm. + HRMS-ESI (m/z): [M+Na] calcd for C25H19NO3Na, 404.1263; found: 404.1257. Melting Point: 117-119 °C.
E.4.5.8. 2-(3-(4-Acetylphenyl)-2-propenyl)-2,4-diphenyl-oxazol-5(2H)-one (572)
O
H3C Ph NO
Ph O C26H21O3N 395.15 572
The reaction was performed following GP-E with [{Rh(cod)Cl}2] (4.0 mg, 0.008 mmol), DPEphos 101(8.6 mg, 0.016 mmol), 2,4-diphenyloxazol-5(4H)-one 550 (47.5 mg, 0.2 mmol), 1-(4-acetylphenyl)-1-propyne 571 (47.5 mg, 0.3 mmol). The crude product was purified by flash column chromatography on silica gel (CH/toluene = 1/1) to afford the desired product as a white solid (71.2 mg, 90%).
Analytical Data of 572:
Experimental Part | 234
TLC (SiO2): Rf = 0.60 (n-hexane: ethyl acetate = 10:1) 1 H-NMR (400 MHz, CDCl3): δ = 8.41-8.38 (m, 2 H), 7.86-7.82 (m, 2 H), 7.69-7.65 (m, 2 H), 7.59-7.54 (m, 1 H), 7.51-7.46 (m, 2 H), 7.45-7.35 (m, 3 H), 7.33-7.29 (m, 2 H), 6.47 (d, J = 16.0 Hz, 1 H), 6.10 (dt, J = 16.0, 7.4 Hz, 1 H), 3.20 (ddd, J = 14.1, 7.5, 1.3 Hz, 1 H), 3.13 (ddd, J = 14.2, 7.4, 1.2 Hz, 1 H) ppm. 13 C-NMR (100 MHz, CDCl3): δ = 197.4, 163.9, 156.3, 141.3, 138.5, 136.2, 135.4, 132.7, 129.0, 128.79, 128.75, 128.7, 128.6, 128.5, 126.4, 126.0, 123.9, 105.9, 45.1, 26.5 ppm. + HRMS-ESI (m/z): [M+Na] calcd for C26H21NO3Na, 418.1419; found: 418.1414. Melting Point: 135-137 °C.
E.4.5.9. 2-(3-([1,1'-Biphenyl]-4-yl)allyl)-2,4-diphenyloxazol-5(2H)-one (574)
The reaction was performed following GP-E with [{Rh(cod)Cl}2] (4.0 mg, 0.008 mmol), DPEphos 101(8.6 mg, 0.016 mmol), 2,4-diphenyloxazol-5(4H)-one 550 (47.5 mg, 0.2 mmol), 4-(prop-1-yn-1-yl)-1,1'-biphenyl 573 (57.7 mg, 0.3 mmol). The crude product was purified by flash column chromatography on silica gel (CH/toluene = 2/1) to afford the desired product as a white solid (77.4 mg, 90%).
Analytical Data of 574:
TLC (SiO2): Rf = 0.59 (n-hexane: ethyl acetate = 10:1) 1 H-NMR (400 MHz, CDCl3): δ = 8.48-8.43 (m, 2 H), 7.75-7.71 (m, 2 H), 7.61-7.55 (m, 3 H), 7.54-7.48 (m, 4 H), 7.48-7.34 (m, 5 H), 7.39-7.32 (m, 3 H), 6.51 (d, J = 16.0 Hz, 1 H), 6.05 (dt, J = 16.0, 7.4 Hz, 1 H), 3.23 (ddd, J = 14.1, 7.5, 1.3 Hz, 1 H), 3.16 (ddd, J = 14.2, 7.4, 1.2 Hz, 1 H) ppm.
Experimental Part | 235
13 C-NMR (100 MHz, CDCl3): δ = 163.9, 156.3, 140.6, 140.4, 138.6, 135.9, 135.8, 132.5, 128.9, 128.7, 128.5, 127.3, 127.2, 126.9, 126.7, 126.0, 120.8, 106.1, 45.1 ppm. + HRMS-APCI (m/z): [M+H] calcd for C30H24NO2, 430.1807; found: 430.1802. Melting Point: 128-130 °C.
E.4.5.10. 2-(3-(3-Methylphenyl)-2-propenyl)-2,4-diphenyl-oxazol-5(2H)-one (576)
The reaction was performed following GP-E with [{Rh(cod)Cl}2] (1.0 mg, 0.002 mmol), DPEphos 101(2.2 mg, 0.004 mmol), 2,4-diphenyloxazol-5(4H)-one 550 (47.5 mg, 0.2 mmol), 1-(3-methylphenyl)-1-propyne 575 (26.1 mg, 0.3 mmol). The crude product was purified by flash column chromatography on silica gel (CH/toluene = 2/1) to afford the desired product as a colourless oil (65.5 mg, 89%).
Analytical Data of 576:
TLC (SiO2): Rf = 0.60 (n-hexane: ethyl acetate = 10:1) 1 H- NMR (400 MHz, CDCl3): δ = 8.41-8.38 (m, 2 H), 7.69-7.66 (m, 2 H), 7.58-7.53 (m, 1 H), 7.51-7.45 (m, 2 H), 7.44-7.34 (m, 3 H), 7.16-7.11 (m, 1 H), 7.06-6.99 (m, 3 H), 6.40 (d, J = 16.0 Hz, 1 H), 5.94 (dt, J = 15.6, 7.4 Hz, 1 H), 3.16 (ddd, J = 14.0, 7.6, 1.2 Hz, 1 H), 3.10 (ddd, J = 14.3, 7.3, 1.3 Hz, 1 H), 2.29 (s, 3 H) ppm. 13 C-NMR (100 MHz, CDCl3): δ = 164.0, 156.3, 138.7, 138.1, 136.8, 136.5, 132.5, 128.9, 128.8, 128.7, 128.60, 128.55, 128.43, 128.38, 127.1, 126.0, 123.4, 120.5, 106.2, 45.1, 21.3 ppm. + HRMS-APCI (m/z): [M+H] calcd for C25H22NO2, 368.1651; found: 368.1645.
Experimental Part | 236
E.4.5.11. 2-(3-(2-Methylphenyl)-2-propenyl)-2,4-diphenyl-oxazol-5(2H)-one (578)
The reaction was performed following GP-E with [{Rh(cod)Cl}2] (4.0 mg, 0.008 mmol), DPEphos 101(8.6 mg, 0.016 mmol), 2,4-diphenyloxazol-5(4H)-one 550 (47.5 mg, 0.2 mmol), 1-(2-methylphenyl)-1-propyne 577 (26.1 mg, 0.3 mmol). The crude product was purified by flash column chromatography on silica gel (CH/toluene = 2/1) to afford the desired product as a colourless oil (61.0 mg, 83%).
Analytical Data of 578:
TLC (SiO2): Rf = 0.60 (n-hexane: ethyl acetate = 10:1) 1 H-NMR (400 MHz, CDCl3): δ = 8.45-8.43 (m, 1 H), 8.42-8.41 (m, 1 H), 7.72-7.70 (m, 1 H), 7.70-7.69 (m, 1 H), 7.59-7.54 (m, 1 H), 7.52-7.46 (m, 2 H), 7.46-7.35 (m, 3 H), 7.25-7.22 (m, 1 H), 7.15-7.06 (m, 3 H), 6.64 (d, J = 15.6 Hz, 1 H), 5.84 (dt, J = 15.6, 7.4 Hz, 1 H), 3.20 (ddd, J = 14.0, 7.6, 1.2 Hz, 1 H), 3.10 (ddd, J = 14.1, 7.3, 1.3 Hz, 1 H), 2.21 (s, 3 H) ppm. 13 C-NMR (100 MHz, CDCl3): δ = 164.0, 156.3, 138.7, 136.1, 135.4, 134.8, 132.5, 130.1, 128.8, 128.74, 128.73, 128.6, 128.5, 127.5, 126.04, 126.00, 125.9, 122.2, 106.1, 45.3, 19.6 ppm. + HRMS-ESI (m/z): [M+Na] calcd for C25H22NO2, 368.1651; found: 368.1645.
E.4.5.12. 2-(3-(4-Methoxyphenyl)-2-propenyl)-2,4-diphenyl-oxazol-5(2H)-one (580)
Experimental Part | 237
The reaction was performed following GP-E with [{Rh(cod)Cl}2] (4.0 mg, 0.008 mmol), DPEphos 101(8.6 mg, 0.016 mmol), 2,4-diphenyloxazol-5-(4H)-one 550 (47.5 mg, 0.2 mmol), 1-(4-methoxyphenyl)-1-propyne 579 (43.9 mg, 0.3 mmol). The crude product was purified by flash column chromatography on silica gel (CH/toluene = 1/1) to afford the desired product as a white solid (70.6 mg, 92%).
Analytical Data of 580:
TLC (SiO2): Rf = 0.54 (n-hexane: ethyl acetate = 10:1) 1 H-NMR (400 MHz, CDCl3): δ = 8.43-8.39 (m, 2 H), 7.72-7.68 (m, 2 H), 7.59-7.54 (m, 1 H), 7.51-7.46 (m, 2 H), 7.45-7.40 (m, 2 H), 7.40-7.35 (m, 1 H), 7.21-7.16 (m, 2 H), 6.82-6.77 (m, 2 H), 6.37 (d, J = 16.0 Hz, 1 H), 5.95 (dt, J = 16.0, 7.4 Hz, 1 H), 3.78 (s, 3 H), 3.16 (ddd, J = 14.0, 7.6, 1.2 Hz, 1 H), 3.09 (ddd, J = 14.0, 7.3, 1.3 Hz, 1 H) ppm. 13 C-NMR (100 MHz, CDCl3): δ = 164.0, 159.3, 156.2, 138.7, 135.8, 132.4, 129.6, 128.8, 128.71, 128.70, 128.6, 128.5, 127.5, 126.0, 118.3, 113.9, 106.2, 55.2, 45.1 ppm. + HRMS-APCI (m/z): [M+H] calcd for C25H22NO3, 384.1600; found: 384.1594. Melting Point: 113-115 oC.
E.4.5.13. 2-(3-(2-Thiophenyl)-2-propenyl)-2,4-diphenyl-oxazol-5(2H)-one (582)
The reaction was performed following GP-E with [{Rh(cod)Cl}2] (4.0 mg, 0.008 mmol), DPEphos 101(8.6 mg, 0.016 mmol), 2,4-diphenyloxazol-5(4H)-one 550 (47.5 mg, 0.2 mmol), 2-(1- olumn chromatography on silica gel (CH/toluene = 2/1) to afford the desired produPropynyl)thiophene 581 (36.7 mg, 0.3 mmol). The crude product was purified by flash cct as a colourless oil (62.6 mg, 87%).
Analytical Data of 582:
Experimental Part | 238
TLC (SiO2): Rf = 0.46 (n-hexane: ethyl acetate = 10:1) 1 H-NMR (400 MHz, CDCl3): δ = 8.43-8.38 (m, 2 H), 7.70-7.66 (m, 2 H), 7.59-7.54 (m, 1 H), 7.51-7.46 (m, 2 H), 7.45-7.35 (m, 3 H), 7.09 (dt, J = 5.2, 0.8 Hz, 1 H), 6.90 (dd, J = 5.2, 3.6 Hz, 1 H), 6.85 (dt, J = 3.6, 0.5 Hz, 1 H), 6.58-6.52 (m, 1 H), 5.82 (dt, J = 15.6, 7.6 Hz, 1 H), 3.13 (ddd, J = 14.4, 7.6, 1.2 Hz, 1 H), 3.07 (ddd, J = 14.1, 7.3, 1.3 Hz, 1 H), 2.29 (s, 3 H) ppm. 13 C-NMR (100 MHz, CDCl3): δ = 163.9, 156.3, 141.7, 138.5, 132.5, 129.3, 128.9, 128.74, 128.72, 128.5, 127.3, 126.0, 125.6, 124.3, 120.3, 106.0, 45.0 ppm. + HRMS-ESI (m/z): [M+Na] calcd for C22H17NO2SNa, 382.0878; found: 382.0872.
E.4.5.14. Methyl-4-(5-oxo-2,4-diphenyl-2,5-dihydrooxazol-2-yl)but-2-enoate (584)
The reaction was performed following GP-E with [{Rh(cod)Cl}2] (4.0 mg, 0.008 mmol), DPEphos 101(8.6 mg, 0.016 mmol), 2,4-diphenyloxazol-5(4H)-one 550 (47.5 mg, 0.2 mmol), methyl but-2-ynoate 583 (29.4 mg, 0.3 mmol). The crude product was purified by flash column chromatography on silica gel (CH/toluene = 1/1) to afford the desired product as a colourless oil (34.2 mg, 51%).
Analytical Data of 584:
TLC (SiO2): Rf = 0.41 (n-hexane: ethyl acetate = 10:1) 1 H-NMR (400 MHz, CDCl3): δ = 8.43-8.41 (m, 1 H), 8.41-8.39 (m, 1 H), 7.64-7.61 (m, 2 H), 7.60-7.55 (m, 1 H), 7.52-7.47 (m, 2 H), 7.44-7.34 (m, 3 H), 6.74 (dt, J = 15.6, 7.6 Hz, 1 H), 5.88 (dt, J = 15.6, 1.4 Hz, 1 H), 3.68 (s, 3 H), 3.14 (ddd, J = 14.4, 7.6, 1.2 Hz, 1 H), 3.08 (ddd, J = 14.4, 7.4, 1.4 Hz, 1 H) ppm. 13 C-NMR (100 MHz, CDCl3): δ = 165.9, 163.6, 156.4, 139.3, , 138.0, 132.8, 129.2, 128.84, 128.79, 128.7, 128.3, 126.5, 125.9, 105.2, 51.6, 44.2 ppm.
Experimental Part | 239
+ HRMS-APCI (m/z): [M+H] calcd for C20H18NO4, 336.1236; found: 336.1230.
E.4.5.15. 2-(3-Phenyl-2-propenyl)-2-(naphthalen-2-yl)-4-phenyl-oxazol-5(2H)-one (586)
The reaction was performed following GP-E with [{Rh(cod)Cl}2] (2.0 mg, 0.004 mmol), DPEphos 101(4.3 mg, 0.008 mmol), 2-(naphthalen-2-yl)-4-phenyloxazol- 5(4H)-one 585 (57.5 mg, 0.2 mmol), 1-phenyl-1-propyne 552 (37.6 μl, 34.9 mg, 0.3 mmol). The crude product was purified by flash column chromatography on silica gel (CH/toluene = 2/1) to afford the desired product as a white solid (79.9 mg, 99%).
Analytical Data of 586:
TLC (SiO2): Rf = 0.56 (n-hexane: ethyl acetate = 10:1) 1 H-NMR (400 MHz, CDCl3): δ = 8.36-8.32 (m, 2 H), 8.05 (d, J = 1.6 Hz, 1 H), 7.83- 7.74 (m, 3 H), 7.72 (dd, J = 8.6, 1.8 Hz, 1 H), 7.49-7.37 (m, 5 H), 7.15-7.07 (m, 5 H), 6.38 (dt, J = 15.6, 1.2 Hz, 1 H), 5.91 (dt, J = 16.0, 7.4 Hz, 1 H), 3.18 (ddd, J = 14.2, 7.4, 1.2 Hz, 1 H), 3.11 (ddd, J = 14.2, 7.4, 1.2 Hz, 1 H) ppm. 13 C-NMR (100 MHz, CDCl3): δ = 164.0, 156.4, 136.8, 136.4, 136.0, 133.2, 132.9, 132.6, 128.79, 128.76, 128.6, 128.5, 128.4, 127.7, 127.6, 126.8, 126.6, 126.3, 125.2, 123.6, 120.7, 106.3, 45.0 ppm. + HRMS-ESI (m/z): [M+Na] calcd for C28H22NO2, 404.1651, found: 404.1645. Melting Point: 114-116 °C
Experimental Part | 240
E.4.5.16. 2-(3-Phenyl-2-propenyl)-2-(4-methylphenyl)-4-phenyl-oxazol-5(2H)-one (588)
The reaction was performed following GP-E with [{Rh(cod)Cl}2] (1.0 mg, 0.002 mmol), DPEphos 101(2.2 mg, 0.004 mmol), 2-(4-methylphenyl)-4-phenyloxazol- 5(4H)-one 587 (50.3 mg, 0.2 mmol), 1-phenyl-1-propyne 551 (37.6 μl, 34.9 mg, 0.3 mmol). The crude product was purified by flash column chromatography on silica gel (CH/toluene = 2/1) to afford the desired product as a yellow solid (72.1 mg, 98%).
Analytical Data of 588:
TLC (SiO2): Rf = 0.52 (n-hexane: ethyl acetate = 10:1) 1 H-NMR (400 MHz, CDCl3): δ = 8.42-8.39 (m, 2 H), 7.59-7.54 (m, 3 H), 7.51-7.46 (m, 2 H), 7.27-7.18 (m, 7 H), 6.45 (dt, J = 15.6, 1.3 Hz, 1 H), 5.98 (dt, J = 16.0, 7.3 Hz, 1 H), 3.17 (ddd, J = 14.0, 7.6, 1.2 Hz, 1 H), 3.11 (ddd, J = 14.4, 7.2, 1.2 Hz, 1 H), 2.37 (s, 3 H) ppm. 13 C-NMR (100 MHz, CDCl3): δ = 164.0, 156.2, 138.8, 136.8, 136.2, 135.7, 132.4, 129.2, 128.72, 128.70, 128.6, 128.5, 127.6, 126.3, 125.9, 120.8, 106.2, 45.0, 21.1 ppm. + HRMS-APCI (m/z): [M+H] calcd for C25H22NO2, 368.1651, found: 368.1645. Melting Point: 112-114 °C
E.4.5.17. 2-(Oct-2-en-1-yl)-2,4-diphenyloxazol-5(2H)-one (605)
Experimental Part | 241
The reaction was performed following GP-E with [{Rh(cod)Cl}2] (3.0 mg, 0.006 mmol), DPEphos 101(9.7 mg, 0.018 mmol), 2,4-diphenyloxazol-5(4H)-one 550 (47.5 mg, 0.2 mmol), 2-octyne 603 (33.1 mg, 0.3 mmol). The crude product was purified by flash column chromatography on silica gel (CH/toluene = 2/1) to afford 604 (45.9 mg, 66%) and 605 (15.3 mg, 22%) as colourless oil.
Analytical Data of 605:
TLC (SiO2): Rf = 0.55 (n-hexane: ethyl acetate = 10:1) 1 H-NMR (400 MHz, CDCl3): δ = 8.43-8.39 (m, 2 H), 7.67-7.63 (m, 2 H), 7.59-7.54 (m, 1 H), 7.52-7.46 (m, 2 H), 7.43-7.32 (m, 3 H), 5.52 (dtt, J = 15.2, 7.0, 1.1 Hz, 1 H), 5.18 (dtt, J = 15.2, 7.2, 1.6 Hz, 1 H), 3.00-2.88 (m, 2 H), 1.91 (q, J = 6.5 Hz, 2 H), 1.28-1.07 (m, 6 H), 0.81 (t, J =7.2 Hz, 3 H) ppm. 13 C-NMR (100 MHz, CDCl3): δ = 164.1, 156.2, 139.0, 138.7, 132.4, 128.70, 128.69, 128.5, 126.0, 120.3, 106.1, 44.5, 32.5, 31.1, 28.8, 22.4, 13.9 ppm. + HRMS-APCI (m/z): [M+H] calcd for C23H26NO2, 348.1964; found: 348.1958.
E.4.6. Rhodium-Catalyzed Tandem Azlactone Formation/Azlactone-Alkyne Coupling/Aza-Cope Rearrangement
To a dried 5 mL schlenk tube were added [{Rh(cod)Cl}2] (x mol%), DPEphos 101(y mol%), N-acyl amino acid 589 (0.2 mmol), 1-phenyl-1-propyne 551 (37.6 μL, 34.8 mg, 0.3 mmol), acetic anhydride (20.8 μL, 22.5 mg, 0.22 mmol), and dry DCM (0.6 mL) sequentially under the atmosphere of Ar and then the tube was sealed. The reaction mixture was then stirred at 60 oC for 18 hours. After cooling to room temperature, the solvent was removed by rotary evaporation and the resulting crude mixture was analyzed by 1H-NMR to determine the ratio of 552/553. The crude product was purified by flash column chromatography on silica gel.
Experimental Part | 242
E.4.6.1. 2-(4-Methoxyphenyl)-4-phenyl-2-(3-phenyl-2-propenyl)-oxazol-5(2H)- one (594)
The reaction was performed following GP-F with [{Rh(cod)Cl}2] (4.0 mg, 0.008 mmol), DPEphos 101 (8.6 mg, 0.016 mmol), and 2-(4-methoxybenzamido)-2-phenyl acetic acid 593 (57.1 mg, 0.2 mmol). The crude product was purified by flash column chromatography on silica gel (CH/toluene = 2/1) to afford the desired product as a white solid (56.7 mg, 74%).
Analytical Data of 594:
TLC (SiO2): Rf = 0.47 (n-hexane: ethyl acetate = 10:1) 1 H-NMR (400 MHz, CDCl3): δ = 8.44-8.40 (m, 2 H), 7.63-7.59 (m, 2 H), 7.59-7.55 (m, 1 H), 7.52-7.47 (m, 2 H), 7.30-7.19 (m, 5 H), 6.96 (t, J = 2.6 Hz, 1 H), 6.94 (t, J = 2.6 Hz, 1 H), 6.46 (dt, J = 15.6, 1.2 Hz, 1 H), 5.99 (dt, J = 16.0, 7.3 Hz, 1 H), 3.83 (s, 3 H), 3.17 (ddd, J = 14.3, 7.5, 1.3 Hz, 1 H), 3.11 (ddd, J = 14.2, 7.2, 1.4 Hz, 1 H) ppm. 13 C-NMR (100 MHz, CDCl3): δ = 164.0, 159.9, 156.1, 136.8, 136.2, 132.4, 130.8, 128.7, 128.6, 128.5, 127.6, 127.3, 126.3, 120.9, 113.9, 106.1, 55.3, 45.1 ppm. + HRMS-ESI (m/z): [M+H] calcd for C25H22NO3, 384.1600; found: 384.1594. Melting Point: 115-117 °C
E.4.6.2. 2-(4-Bromophenyl)-4-phenyl-2-(3-phenyl-2-propenyl)-oxazol-5(2H)-one (596)
Experimental Part | 243
The reaction was performed following GP-F with [{Rh(cod)Cl}2] (4.0 mg, 0.008 mmol), DPEphos 101 (8.6 mg, 0.016 mmol), and 2-(4-bromobenzamido)-2-phenyl acetic acid 595 (66.8 mg, 0.2 mmol). The crude product was purified by flash column chromatography on silica gel (CH/toluene = 2/1) to afford the desired product as a white solid (82.1 mg, 95%).
Analytical Data of 596:
TLC (SiO2): Rf = 0.48 (n-hexane: ethyl acetate = 10:1)
1 H-NMR (400 MHz, CDCl3): δ = 8.42-8.38 (m, 2 H), 7.60-7.53 (m, 5 H), 7.52-7.47 (m, 2 H), 7.29-7.19 (m, 5 H), 6.44 (dt, J = 16.0, 1.1 Hz, 1 H), 5.96 (dt, J = 15.6, 7.3 Hz, 1 H), 3.13 (ddd, J = 14.0, 7.6, 1.2 Hz, 1 H), 3.06 (ddd, J = 14.1, 7.3, 1.3 Hz, 1 H) ppm. 13 C-NMR (100 MHz, CDCl3): δ = 163.7, 156.4, 137.6, 136.7, 136.6, 132.7, 131.7, 128.78, 128.76, 128.5, 128.4, 127.8, 127.7, 126.3, 123.1, 120.3, 105.6, 45.1 ppm. + 79 HRMS-ESI (m/z): [M+Na] calcd for C24H19 BrNO2, 432.0599; found: 432.0594; + 81 [M+H] calcd for C24H19 BrNO2, 434.0579; found: 434.0573. Melting Point: M.P.: 128-130 °C E.4.6.3. 2-(4-Chlorophenyl)-4-phenyl-2-(3-phenyl-2-propenyl)-oxazol-5(2H)-one (598)
The reaction was performed following GP-F with [{Rh(cod)Cl}2] (4.0 mg, 0.008 mmol), DPEphos 101(8.6 mg, 0.016 mmol), and 2-(4-chlorobenzamido)-2- phenylacetic acid 597 (57.9 mg, 0.2 mmol). The crude product was purified by flash column chromatography on silica gel (CH/toluene = 2/1) to afford the desired product as a colourless oil (69.0 mg, 89%).
Analytical Data of 598:
Experimental Part | 244
TLC (SiO2): Rf = 0.48 (n-hexane: ethyl acetate = 10:1) 1 H-NMR (400 MHz, CDCl3): δ = 8.32-8.28 (m, 2 H), 7.54-7.50 (m, 2 H), 7.50-7.45 (m, 1 H), 7.42-7.36 (m, 2 H), 7.31-7.27 (m, 2 H), 7.19-7.08 (m, 5 H), 6.34 (dt, J = 16.0, 1.1 Hz, 1 H), 5.86 (dt, J = 16.0, 7.4 Hz, 1 H), 3.03 (ddd, J = 14.0, 7.6, 1.2 Hz, 1 H), 2.97 (ddd, J = 14.2, 7.4, 1.2 Hz, 1 H) ppm. 13 C-NMR (100 MHz, CDCl3): δ = 163.7, 156.4, 137.1, 136.6, 134.9, 132.7, 128.78, 128.76, 128.7, 128.5, 128.4, 127.7, 127.5, 126.3, 120.3, 105.6, 45.2 ppm. + 35 HRMS-ESI (m/z): [M+H] calcd for C24H19 ClNO, 388.1104; found: 388.1099; + 37 [M+H] calcd for C24H19 ClNO2, 390.1075; found: 390.1069.
E.4.6.4. 2-(4-Trifluoromethylphenyl)-4-phenyl-2-(3-phenyl-2-propenyl)-oxazol- 5(2H)-one (600)
The reaction was performed following GP-F with [{Rh(cod)Cl}2] (4.0 mg, 0.008 mmol), DPEphos 101(8.6 mg, 0.016 mmol), and 2-phenyl-2-(4-(trifluoromethyl)- benzamido)acetic acid 599 (64.7 mg, 0.2 mmol). The crude product was purified by flash column chromatography on silica gel (CH/toluene = 2/1) to afford the desired product as a colourless oil (67.4 mg, 80%).
Analytical Data of 600:
TLC (SiO2): Rf = 0.46 (n-hexane: ethyl acetate = 10:1) 1 H-NMR (400 MHz, CDCl3): δ = 8.33-8.29 (m, 2 H), 7.75-7.70 (m, 2 H), 7.61-7.52 (m, 2 H), 7.50-7.46 (m, 1 H), 7.42-7.37 (m, 2 H), 7.19-7.09 (m, 5 H), 6.35 (dt, J = 16.0, 1.1 Hz, 1 H), 5.86 (dt, J = 16.0, 7.4 Hz, 1 H), 3.06 (ddd, J = 14.3, 7.5, 1.3 Hz, 1 H), 3.00 (ddd, J = 14.2, 7.4, 1.2 Hz, 1 H) ppm. 13 C-NMR (100 MHz, CDCl3): δ = 163.6, 156.6, 142.4, 136.9, 136.6, 132.8, 131.1 (q, J = 32.7 Hz), 128.82, 128.80, 128.5, 128.3, 127.8, 126.6, 126.3, 125.6 (q, J = 3.8 Hz), 123.8 (q, J = 272.3 Hz), 120.0, 105.4, 45.2 ppm.
Experimental Part | 245
+ HRMS-ESI (m/z): [M+Na] calcd for C25H18F3NO2Na, 444.1187; found: 444.1182.
E.4.6.5. 2-Methyl-4-phenyl-2-(3-phenyl-2-propenyl)-oxazol-5(2H)-one (602)
The reaction was performed following GP-F with [{Rh(cod)Cl}2] (2.0 mg, 0.004 mmol), DPEphos 101(4.3 mg, 0.008 mmol), and 2-acetamido-2-phenylacetic acid 601 (38.6 mg, 0.2 mmol). The crude product was purified by flash column chromatography on silica gel (CH/toluene = 2/1) to afford the desired product as a colourless oil (15.7 mg, 27%).
Analytical Data of 602:
TLC (SiO2): Rf = 0.52 (n-hexane: ethyl acetate = 10:1) 1 H-NMR (400 MHz, CDCl3): δ = 8.37-8.35 (m, 2 H), 7.59-7.54 (m, 1 H), 7.51-7.46 (m, 2 H), 7.34-7.26 (m, 4 H), 7.24-7.19 (m, 1 H), 6.52 (d, J = 16.0 Hz, 1 H), 6.09 (dt, J = 15.6, 7.4 Hz, 1 H), 2.88 (ddd, J = 14.2, 7.8, 1.4 Hz, 1 H), 2.82 (ddd, J = 14.4, 7.2, 1.2 Hz, 1 H), 1.71 (s, 3 H) ppm. 13 C-NMR (100 MHz, CDCl3): δ = 164.3, 156.3, 136.8, 135.8, 132.4, 128.75, 128.67, 128.6, 128.5, 127.7, 126.3, 121.5, 105.0, 42.9, 24.5 ppm. + HRMS-ESI (m/z): [M+Na] calcd for C19H18NO2, 292.1338, found: 292.1332.
E.4.7. Rhodium Catalyzed Synthesis of 2, 3, 6-Trisubstituted Pyridines from Azlactones and Internal Alkynes
All products were synthesized according to procedure GP-G/H at 60 °C with a reaction time of 18 hours using azlactone/N-acyl amino acid (0.25 mmol, 1.0 equiv.), substituted alkyne (0.375 mmol, 1.5 equiv.), [{Rh(cod)Cl}2] (4.9 mg, 0.01 mmol, 1 mol%), DPEphos 101(10.8 mg, 0.02 mmol, 2 mol%), diphenylacetic acid (5.3 mg, 0.025 mmol) and dry DCE (1.0 ml), to get crude allylated product which further
Experimental Part | 246 processed for the synthesis of trisubstitutes pyridines using microwave irridiarion at 120 oC for 1.5 hours.
E.4.7.1. 2,3,6-Triphenylpyridine (606)250
The reaction was performed following GP-G with 2,4-diphenyloxazol-5(4H)-one 552 (59.3 mg, 0.25 mmol), and 1-phenyl-1-propyne 551 (46.9 μL, 43.6 mg, 0.375 mmol). The crude product was purified by flash column chromatography on silica gel (CH/toluene = 2/1) to afford the desired product 606 as a white solid (68.2 mg, 89%).
Analytical Data of 606:
TLC (SiO2): Rf = 0.56 (n-hexane: ethyl acetate = 10:1) 1 H-NMR (400 MHz, CDCl3): δ = 8.14-8.10 (m, 2 H), 7.75 (d, J = 8 Hz, 1 H), 7.73 (d, J = 8.0 Hz, 1 H), 7.47-7.41 (m, 4 H), 7.39-7.34 (m, 1 H), 7.27-7.15 (m, 8 H) ppm. 13 C-NMR (100 MHz, CDCl3): δ = 156.6, 155.6, 140.4, 140.0, 139.3, 139.1, 134.4, 130.1, 129.5, 128.9, 128.6, 128.3, 127.7, 127.1, 126.9, 118.5 ppm. + HRMS-APCI (m/z): [M+H] calcd for C23H18N, 308.1439; found: 308.1434. Melting Point: 121-125 °C.
E.4.7.2. 6-(Naphthalen-2-yl)-2,3-diphenylpyridine (612)
The reaction was performed following GP-G with 2-(naphthalen-2-yl)-4- phenyloxazol-5(4H)-one 611 (71.8 mg, 0.25 mmol), and 1-phenyl-1-propyne 551 (46.9 μL, 43.6 mg, 0.375 mmol). The crude product was purified by flash column
Experimental Part | 247 chromatography on silica gel (CH/toluene = 2/1) to afford the desired product 612 as a solid (61.5 mg, 69%).
Analytical Data of 612:
TLC (SiO2): Rf = 0.55 (n-hexane: etrhylacetate = 10:1) 1 H-NMR (400 MHz, CDCl3): δ = 8.60-8.58 (m, 1 H), 8.28 (dd, J = 8.8, 2.0 Hz, 1 H), 7.95-7.89 (m, 2 H), 7.88 (d, J = 8.4 Hz, 1 H), 7.84-7.81 (m, 1 H), 7.77 (d, J = 8.4 Hz, 1 H), 7.50-7.42 (m, 4 H), 7.26-7.15 (m, 8 H) ppm. 13 C-NMR (100 MHz, CDCl3): δ = 156.8, 155.6, 140.5, 140.1, 139.5, 136.5, 134.5, 133.8, 133.6, 130.3, 129.6, 128.8, 128.40, 128.38, 127.9, 127.7, 127.2, 126.5, 126.4, 126.3, 124.8, 118.8 ppm. + HRMS-APCI (m/z): [M+H] calcd for C27H20N, 358.1596; found: 358.1590. Melting Point: 144-146 °C.
E.4.7.3. 3-(4-Fluorophenyl)-6-(naphthalen-2-yl)-2-phenylpyridine (613)
The reaction was performed following GP-G with 2-(naphthalen-2-yl)-4- phenyloxazol-5(4H)-one 611 (71.8 mg, 0.25 mmol), and 1-(4-fluorophenyl)-1-propyne 563 (50.3 mg, 0.375 mmol). The crude product was purified by flash column chromatography on silica gel (CH/toluene = 2/1) to afford the desired product 613 as a white solid (75.0 mg, 80%).
Analytical Data of 613:
TLC (SiO2): Rf = 0.63 (hexanes: ethyl acetate = 10:1) 1 H-NMR (400 MHz, CDCl3): δ = 8.67-8.65 (m, 1 H), 8.35 (dd, J = 8.8, 2.0 Hz, 1 H), 8.03-7.97 (m, 2 H), 7.95 (d, J = 8.4 Hz, 1 H), 7.93-7.88 (m, 1 H), 7.82 (d, J = 8.0 Hz, 1 H), 7.56-7.44 (m, 4 H), 7.34-7.29 (m, 3 H), 7.24-7.18 (m, 2 H), 7.03-6.96 (m, 2 H) ppm.
Experimental Part | 248
13 C-NMR (100 MHz, CDCl3): δ = 162.0 (d, J= 247.7 Hz), 156.7, 155.5, 140.2, 139.2, 136.2, 135.9 (d, J= 3.4 Hz), 133.7, 133.5, 133.4, 131.1 (d, J= 8.1 Hz), 130.1, 128.7, 128.3, 127.9, 127.6, 126.4, 126.3, 126.2, 124.6, 118.7, 115.3 (d, J= 21.9 Hz) ppm. + HRMS-APCI (m/z): [M+H] calcd for C27H19NF, 376.1502; found: 376.1496. Melting Point: 123-125 °C.
E.4.7.4. 6-(Naphthalen-2-yl)-2-phenyl-3-(thiophen-2-yl)pyridine (614)
The reaction was performed following GP-G with 2-(naphthalen-2-yl)-4- phenyloxazol-5(4H)-one 611 (71.8 mg, 0.25 mmol), and 2-(1-propynyl)thiophene 581 (45.8 mg, 0.375 mmol). The crude product was purified by flash column chromatography on silica gel (CH/toluene = 1/1) to afford the desired product 614 as a white solid (70.9 mg, 78%).
Analytical Data of 614:
TLC (SiO2): Rf = 0.64 (n-hexane: ethyl acetate = 10:1) 1 H-NMR (400 MHz, CDCl3): δ = 8.64-8.62 (m, 1 H), 8.31 (dd, J = 8.6, 2.2 Hz, 1 H), 8.01-7.86 (m, 5 H), 7.64-7.58 (m, 2 H), 7.55-7.49 (m, 2 H), 7.40-7.35 (m, 3 H), 7.28 (dd, J = 5.0, 1.0 Hz, 1 H), 6.95 (dd, J = 5.2, 3.6 Hz, 1 H), 6.84 (dd, J = 3.6, 1.2 Hz, 1 H) ppm. 13 C-NMR (100 MHz, CDCl3): δ = 157.1, 155.6, 141.4, 140.5, 139.3, 136.2, 133.8, 133.6, 129.8, 128.8, 128.4, 128.2, 128.0, 127.7, 127.6, 127.4, 127.3, 126.5, 126.4, 126.3, 126.2, 124.7, 118.7 ppm. + HRMS-APCI (m/z): [M+H] calcd for C25H18NS, 364.1160; found: 364.1154. Melting Point: 136-138 °C.
Experimental Part | 249
E.4.7.5. 3-([1,1'-Biphenyl]-4-yl)-6-(4-bromophenyl)-2-phenylpyridine (619)
The reaction was performed following GP-G with 4-(prop-1-yn-1-yl)-1,1'-biphenyl 563 (57.7 mg, 0.3 mmol). The crude product was purified by flash column chromatography on silica gel (CH/toluene = 2/1) to afford the desired product 619 as a white solid (45.3 mg, 49%).
Analytical Data of 619:
TLC (SiO2): Rf = 0.61 (n-hexane: ethyl acetate = 10:1) 1 H-NMR (400 MHz, CDCl3): δ = 7.98-7.94 (m, 2 H), 7.74 (d, J = 8.0 Hz, 1 H), 7.67 (d, J = 8.0 Hz, 1 H), 7.55-7.50 (m, 4 H), 7.47-7.40 (m, 4 H), 7.38-7.32 (m, 2 H), 7.29- 7.23 (m, 1 H), 7.23-7.17 (m, 5 H) ppm. 13 C-NMR (100 MHz, CDCl3): δ = 156.8, 154.4, 140.4, 140.3, 140.0, 139.4, 138.7, 137.0, 134.3, 131.8, 130.3, 129.9, 128.8, 128.5, 128.0, 127.9, 127.5, 127.00, 126.97, 123.5, 118.7 ppm. + 79 HRMS-APCI (m/z): [M+H] calcd for C29H21N Br, 462.0857; found: 462.0852; + 81 [M+H] calcd for C29H21N Br, 464.0837; found: 464.0831. Melting Point: 229-230 °C.
E.4.7.6. 3-(4-Fluorophenyl)-6-(4-bromophenyl)-2-phenylpyridine (620)
Experimental Part | 250
The reaction was performed following GP-H with 1-(4-fluorophenyl)-1-propyne 563 (40.3 mg, 0.3 mmol). The crude product was purified by flash column chromatography on silica gel (CH/toluene = 2/1) to afford the desired product 6f as a white solid (48.5 mg, 60%).
Analytical Data of 620:
TLC (SiO2): Rf = 0.65 (n-hexane: ethyl acetate = 10:1) 1 H-NMR (400 MHz, CDCl3): δ = 7.95 (t, J = 2.2 Hz, 1 H), 7.93 (t, J = 2.2 Hz, 1 H), 7.67 (d, J = 8.0 Hz, 1 H), 7.64 (d, J = 8.0 Hz, 1 H), 7.53 (t, J = 2.2 Hz, 1 H), 7.51 (t, J = 2.2 Hz, 1 H), 7.38-7.32 (m, 2 H), 7.22-7.17 (m, 3 H), 7.11-7.06 (m, 2 H), 6.93-6.86 (m, 2 H) ppm. 13 C-NMR (100 MHz, CDCl3): δ = 162.2 (d, J= 249.3 Hz), 156.8, 154.6, 140.1, 139.3, 137.8, 135.8 (d, J= 3.3 Hz), 133.7, 131.8, 130.6 (d, J= 7.8 Hz), 130.1, 128.5, 128.0, 127.9, 123.5, 118.2, 115.4 (d, J= 21.5 Hz) ppm. + 79 HRMS-APCI (m/z): [M+H] calcd for C23H16NF Br, 404.0450, found: 404.0445; + 81 [M+H] calcd for C23H16NF Br, 406.0430; found: 404.0424. Melting Point: 156-158 °C.
E.4.7.7. 6-(4-Bromophenyl)-2-phenyl-3-(thiophen-2-yl)pyridine (621)
The reaction was performed following GP-H with 2-(1-Propynyl)thiophene 581 (36.7 mg, 0.30 mmol). The crude product was purified by flash column chromatography on silica gel (CH/toluene = 1/1) to afford the desired product 621 as a gray solid (40.8 mg, 52%).
Analytical Data of 621:
TLC (SiO2): Rf = 0.66 (n-hexane: ethyl acetate = 10:1)
Experimental Part | 251
1 H-NMR (400 MHz, CDCl3): δ = 8.02 (t, J = 2.4 Hz, 1 H), 8.00 (t, J = 2.2 Hz, 1 H), 7.89 (d, J = 8.0 Hz, 1 H), 7.71 (d, J = 8.4 Hz, 1 H), 7.61 (t, J = 2.2 Hz, 1 H), 7.59 (t, J = 2.2 Hz, 1 H), 7.56-7.51 (m, 2 H), 7.37-7.33 (m, 3 H), 7.28 (dd, J = 5.2, 1.2 Hz, 1 H), 6.94 (dd, J = 5.0, 3.4 Hz, 1 H), 6.82 (dd, J = 3.4, 1.0 Hz, 1 H) ppm. 13 C-NMR (100 MHz, CDCl3): δ = 157.2, 154.5, 141.2, 140.3, 139.3, 137.7, 131.8, 129.7, 128.5, 128.2, 128.0, 127.9, 127.4, 127.3, 126.3, 123.6, 118.2 ppm. + 79 HRMS-APCI (m/z): [M+H] calcd for C21H15NS Br, 392.0109; found: 392.0104; + 81 [M+H] calcd for C21H15NS Br, 394.0088; found: 394.0084. Melting Point: 164-166 °C.
Experimental Part | 252
Section C
E.5. Pd-PEPPSI Catalyzed Amination of Heteroaryl Derivatives E.5.1. Substrate Synthesis
E.5.1.1. Procedure for the Synthesis of Substituted Thiazole (GP-I)
Scheme E.12. Synthesis of substituted thiazole
Substituted thiazole substrates 468a were synthesized by treating 4-bromophenacyl bromide 468c (21.4 mmol, 100 mol%, 1 equiv.) with thioamide (32.1 mmol%, 1.5 equiv.) in ethanol (35 ml) at 50 ᵒC for 18 hours.251 Reaction the mixture was diluted with water and the desired product was precipitated out which was collected and purified with flash column chromatography using n-hexane: ethyl acetate (20:1) as eluting system.
E.5.1.1.1. 4-(4-Bromophenyl)-2-methylthiazole (622)
4-(4-Bromophenyl)-2-methylthiazole 468 was synthesized according to procedure I by using 4-bromophenacyl bromide 468c (4.23 g, 21.4 mmol, 100 mol%, 1 equiv.) with thioacetamide (2.40 g, 32.1 mmol%, 1.5 equiv.). The desired product was obtained as yellow solid as a result of flash column chromatography using n-hexane: ethyl acetate (20:1) with 66 % yield.
Analytical Data of 622:
TLC (SiO2): Rf = 0.46 (n-hexanes: ethyl acetate = 20:1).
Experimental Part | 253
1 H NMR (300 MHz, CDCl3) δ = 7.86 (s, 1H), 7.79 (d, J = 6.9 Hz, 2H), 7.58 (d, J = 6.9 Hz, 2H), 2.77 (s, 3H) ppm. 13 C NMR (75 MHz, CDCl3): δ = 169.4, 153.1, 132.2, 132.0, 128.3, 123.1, 108.7, 19.3 ppm. Melting Point: 79-82 °C.
E.5.1.1.2. 4-(4-Bromophenyl)-2-phenylthiazole (660)
4-(4-bromophenyl)-2-phenylthiazole 660 was synthesized according to procedure A by using 4-bromophenacyl bromide 468c (4.23 g, 21.4 mmol, 100 mol%, 1 equiv.) with thiobenzamide (4.4 g, 32.1 mmol%, 1.5 equiv.). The desired product was obtained as off white solid as a result of flash column chromatography (n-hexane: ethylacetate (20:1) with 76 % yield.
Analytical Data of 660:
TLC (SiO2): Rf = 0.51 (n-hexanes: ethylacetate = 20:1). 1 H NMR (300 MHz, CDCl3): δ = 8.01 (s, 1H), 7.89-7.81 (m, 4H), 7.55-7.03 (m, 5H) ppm. 13 C NMR (75 MHz, CDCl3): δ = 170.4, 153.2, 143.3, 132.2, 132.0, 130.9, 129.2, 128.7, 128.3, 123.1, 115.7 ppm. Melting Point: 80-86 °C.
E.5.1.2. Procedure for the Synthesis of Substituted Oxazole (GP-J)
Scheme E.13. Synthesis of substituted oxazole
Experimental Part | 254
4-Bromophenacyl bromide 468c (2.5 g, 8.9 mmol, 1 equiv.) and amide (22.485 mmol, 2.5 equiv.) were heated to 130 oC for 3 hours under nitrogen atmosphere. The reaction was monitored by TLC and after completion ice cold water was added to reaction mixture and extracted with ethyl acetate (3x20). The combined organic layers were
washed with 1M NaOH and then dried over Na2SO4 and concentrated under vacuum. The residues were purified via flash column chromatography (n-hexane: ethyl acetate; 20:1).252
E.5.1.1.3. 4-(4-Bromophenyl)-2-methyloxazole (664)
4-(4-Bromophenyl)-2-methyloxazole 664 was synthesized according to procedure J by using 4-bromophenacyl bromide 468c (4.23 g, 21.4 mmol, 100 mol%, 1 equiv.) with acetamide (1.38 g, 22.485 mmol, 2.5 equiv.). The desired product was obtained as yellow solid as a result of flash column chromatography (n-hexane: ethyl acetate (20:1) in 54 % yield.
Analytical Data of 664:
TLC (SiO2): Rf = 0.37 (n-hexanes: ethyl acetate = 20:1). 1 H NMR (300 MHz, CDCl3): δ = 7.78 (d, J = 6.8 Hz, 2H), 7.69 (s, 1H), 6.56 (d, J = 6.8 Hz, 2H), 2.62 (s, 3H) ppm. 13 C NMR (75 MHz, CDCl3): δ = 161.0, 140.1, 132.6, 132.1, 129.7, 128.3, 123.1, 14.2 ppm. Melting Point: 122-124 °C.
E.5.1.2.2. 4-(4-Bromophenyl)-2-phenyloxazole (665)
Experimental Part | 255
4-(4-Bromophenyl)-2-phenyloxazole 683 was synthesized according to procedure I by using 4-bromophenacyl bromide 468c (4.23 g, 21.4 mmol, 100 mol%, 1 equiv.) with benzamide (2.7 g, 22.485 mmol, 2.5 equiv.). The desired product was obtained as light yellow solid as a result of flash column chromatography (n-hexane: ethyl acetate (20:1) with 68 % yield.
Analytical Data of 683:
TLC (SiO2): Rf = 0.44 (n-hexanes: ethyl acetate = 20:1). 1 H NMR (300 MHz, CDCl3): δ = 8.18-8.15 (m, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.68 (s, 1H), 7.67-7.62 (m, 3H), 7.58 (d, J = 8.4 Hz, 2H) ppm. 13 C NMR (75 MHz, CDCl3): δ = 159.4, 140.1, 139.9, 132.2, 130.7, 129.7, 129.2, 128.7, 128.3, 127.6, 123.1 ppm. Melting Point: 133-136 °C.
Experimental Part | 256
E.5.2. Catalysis
E.5.2.1. General Procedures for Catalysis
E.5.2.1.1. General Procedure for Synthesis of N-alkyl-aryl Thiazole amines (GP- K)
10 ml screw-cap seal tube was charged with all solid substances including substituted thiazole 468 (0.3 mmol, 1.0 equiv), Pd-PEPPSI-IPentCl 336 (5.4 mg, 0.00628mmol, 4 mol %) and NaOtBu (60 mg, 0.628 mmol, 2 equiv). Toluene (1 ml, 0.3 M) and substituted amine/aniline 469 (0.628 mmol, 2 equiv) were added by syringe. The tube was purge with nitrogen and sealed with screw cap. The resulting reaction mixture was stirred at 100 °C for 24 hours. The reaction mixture was cooled to room temperature and passed through a pad of celite using ethyl acetate, concentrated under reduced pressure and purified by flash column chromatography on silica gel with hexanes and ethyl acetate as eluting system.
E.5.2.1.2. General Procedure for Synthesis of N-aryl Oxazole Anilines (GP-L)
10 ml screw-cap seal tube was charged with all solid substances including substituted oxazole 468b (0.3 mmol, 1.0 equiv), Pd-PEPPSI-IPentCl 336 (5.4 mg, 0.00628mmol, 4 mol %) and NaOtBu (60 mg, 0.628 mmol, 2 equiv). Toluene (1 ml, 0.3 M) and substituted aniline 469 (0.628 mmol, 2 equiv) were added by syringe. The tube was purge with nitrogen sealed with a screw cap. The resulting reaction mixture was stirred at 100 °C for 24 hours. The reaction mixture was cooled to room temperature and passed through a pad of celite using ethyl acetate, concentrated under reduced pressure and purified by flash column chromatography on silica gel with hexanes and ethyl acetate as eluting system.
E.5.2.1.3. General Procedure for Synthesis of Aryl/alkyl-Heteroaryl Anilines (GP-M)
10 ml screw-cap tube was charged with all solid substances including 4-(4- bromophenyl)-2-methyl-thiazole 622 (0.3 mmol, 1.0 equiv), Pd- source (2.5 mol%), ligand( 10 mol %) and base (0.628 mmol, 2 equiv.). Toluene (1 ml, 0.3 M) and
Experimental Part | 257 substituted amine/aniline (0.628 mmol, 2 equiv) were added by syringe. The tube was purge with nitrogen and sealed with screw cap. The resulting reaction mixture was stirred at 100 °C for 24 hours. The reaction mixture was cooled to room temperature and was passed through a pad of celite using ethyl acetate, concentrated under reduced pressure and purified by flash column chromatography on silica gel with hexanes and ethyl acetate as eluting system.
All the reactions performed during the condition optimizations were carried according to this procedure.
E.5.3. Ligand and Reaction Conditions Screening for Aliphatic Amines
All reactions shown in Table E.6 have been performed according to procedure (GP- M) at a reaction temperature of 100 °C using the following amounts of substrates, catalyst and solvent: 4-(4-bromophenyl)-2-methyl-thiazole 622 (80 mg, 0.31 mmol, 1 equiv.), N-methylbenzylamine 623 (74 mg, 0.62 mmol, 2 equiv.), K2CO3 (85.6 mg,
0.62 mmol, 2 equiv.), Pd2dba3 (0.0075 mmol, 2.5 mol %), ligand (0.03 mmol, 10 mol%) and 1 ml toluene (0.3 M solution relative to 4-(4-bromophenyl)-2-methyl- thiazole 622 (Table E.6).
Table E.6. Ligands and conditions screenings for aliphatic amines
Experimental Part | 258
E.5.4. Ligand and Reaction Conditions Screening for Aromatic Amines
All reactions shown in Table E.7 have been performed according to procedure (GP- M) at a reaction temperature of 100 °C using the following amounts of substrates, catalyst and solvent: 4-(4-bromophenyl)-2-methyl-thiazole 622 (80 mg, 0.31 mmol, 1 equiv.), 4-methylaniline 629 (66 mg, 0.62 mmol, 2 equiv.), base (0.62 mmol, 2 equiv.), Pd-PEPPSI catalyst (0.006 mmol, 2 mol%) and 1 ml toluene (0.3 M solution relative to 4-(4-bromophenyl)-2-methyl-thiazole 622 (Table E.7).
Table E.7. Ligands and conditions screenings for anilines
Experimental Part | 259
E.5.5. Syntheses and Characterization of Biaryl or alkyl-aryl Thiazole/Oxazole amines
All products were synthesized according to procedure GP-M at 100 °C with a reaction time of 24 hours using the conditions, depicted in the Table E.7 (entry 12), which are optimized reaction conditions, obtained at a result of conditions optimization process. The amounts of reagents used are substitute thiazole/oxazole 468a/468b (0.3 mmol, 1.0 equiv.), aliphatic/aromatic amine 469 (0.628 mmol, 2 equiv.), Pd-PEPPSI-IPentCl 336 (5.4 mg, 0.00628mmol, 4 mol %) and NaOtBu (60 mg, 0.628 mmol, 2 equiv.), in dry distill toluene for 24 h. In cases where one or more reaction parameters differed from those used as standard, additional information has been added to the respective reaction product.
Experimental Part | 260
E.5.5.1. 4-Methyl-N-(4-(2-methylthiazol-4-yl)phenyl)aniline (630)
The reaction was performed according to procedure K using 4-(4-bromophenyl)-2- methyl-thiazole 622 (80 mg, 0.31 mmol, 1 equiv.) and 4-methylaniline 629 (66 mg, 0.62 mmol, 2 equiv.). The crude product was purified by flash column
chromatography on SiO2 using hexanes: ethyl acetate (10:1) as eluting system to obtain the desired product as yellow solid (73 mg, 85 %).
Analytical Data of 630:
TLC (SiO2): Rf = 0.33 (hexanes: ethyl acetate = 4:1). 1 H NMR (300MHz, CDCl3): δ = 8.36 (br. s, 1H), 7.76 (d, J = 9.0 Hz, 2H), 7.67 (s, 1H), 7.37 (d, J = 9.0 Hz, 2H), 7.25-7.20 (m, 4H), 2.71 (s, 3H), 2.32 (s, 3H). 13 C NMR (75 MHz, CDCl3): δ = 165.3, 154.7, 144.4, 140.6, 130.1, 129.6, 127.4, 125.7, 118.5, 115.8, 110.7, 20.7, 19.4 ppm. + MS-EI (m/z): [M] calcd for C17H16N2S, 280.1071; found, 296.1069. Melting point: 132-136 °C.
E.5.5.2. 2-Methyl-N-(4-(2-methylthiazol-4-yl)phenyl)aniline (633)
The reaction was performed according to procedure K using 4-(4-bromophenyl)-2- methyl-thiazole 622 (80 mg, 0.31 mmol, 1 equiv.) and 2-methylaniline 632 (66 mg, 0.62 mmol, 2 equiv.). The crude product was purified by flash column
chromatography on SiO2 using hexanes: ethyl acetate (10:1) as eluting system to obtain the desired product as light yellow solid (71 mg, 83 %).
Experimental Part | 261
Analytical Data of 633:
TLC (SiO2): Rf = 0.34 (hexanes: ethyl acetate = 4:1). 1 H NMR (300 MHz, CDCl3): δ = 7.80 (d, J = 9.0 Hz, 2H), 7.33-7.20 (m, 3H), 7.17 (s, 1H), 7.01 (d, J = 9.0 Hz, 2H), 7.03-6.98 (m, 1H), 6.52 (br. s, 1H), 2.81 (s, 3H), 2.30 (s, 3H) ppm. 13 C NMR (75 MHz, CDCl3): δ = 167.6, 153.9, 144.4, 139.1, 131.8, 128.4, 126.6, 125.7, 123.2, 122.5, 121.7, 119.5, 108.7, 19.3 ppm. + MS-EI (m/z): [M] calcd for C17H16N2S, 280.1071; found, 296.1069. Melting point: 135-136 °C.
E.5.5.3. N-(4-(2-Methylthiazol-4-yl)phenyl)aniline (635)
The reaction was performed according to procedure K using 4-(4-bromophenyl)-2- methyl-thiazole 622 (80 mg, 0.31 mmol, 1 equiv.) and aniline 634 (57 mg, 0.62 mmol,
2 equiv.). The crude product was purified by flash column chromatography on SiO2 using hexanes: ethyl acetate (10:1) as eluting system to obtain the desired product as light brown solid (71 mg, 87 %).
Analytical Data of 635:
TLC (SiO2): Rf = 0.33 (hexanes: ethyl acetate = 4:1). 1 H NMR (300 MHz, CDCl3): δ = 7.09 (d, J = 9.0 Hz, 2H), 7.73 (d, J = 9.0 Hz, 2H), 7.67-7.64 (m, 2H), 7.51 (s, 1H), 7.54-7.44 (m, 2H), 6.52 (br. s, 1H 2.77 (s, 3H) ppm. 13 C NMR (75 MHz, CDCl3): δ = 169.6, 153.2, 142.4, 129.5, 128.4, 122.6, 120.7, 119.6, 108.7, 19.3 ppm. + MS-EI (m/z): [M] calcd for C16H14N2S, 266.0915; found, 266.0913. Melting point: 138 °C.
Experimental Part | 262
E.5.5.4. 4-Methoxy-N-(4-(2-methylthiazol-4-yl)phenyl)aniline (637)
The reaction was performed according to procedure A using 4-(4-bromophenyl)-2- methyl-thiazole 622 (80 mg, 0.31 mmol, 1 equiv.) and 4-methoxyaniline 636 (76.3 mg, 0.62 mmol, 2 equiv.). The crude product was purified by flash column chromatography on SiO2 using hexanes: ethyl acetate (10:1) as eluting system to obtain the desired product as light brown solid (87.5 mg, 95 %).
Analytical Data of 637:
TLC (SiO2): Rf = 0.33 (hexanes: ethyl acetate = 4:1). 1 H NMR (300 MHz, CDCl3): δ = 7.78 (d, J = 9.0 Hz, 2H), 7.67 (s, 1H), 7.37 (d, J = 9.0 Hz, 2H), 7.38-736 (m, 2H), 7.20 (d, J = 8.6 Hz, 2H), 5.52 (br. s, 1H), 3.67 (s, 3H), 2.32 (s, 3H) ppm. 13 C NMR (75 MHz, CDCl3): δ = 169.6, 153.3, 152.9, 142.4, 134.6, 128.4, 124.5, 122.5, 119.7, 115.3, 108.6, 55.8, 19.3 ppm. + MS-EI (m/z): [M] calcd for C17H16ON2S, 296.1020; found, 296.1018. Melting point: 142-146 °C.
E.5.5.5. 3-Methoxy-N-(4-(2-methylthiazol-4-yl)phenyl)aniline (639)
The reaction was performed according to procedure K using 4-(4-bromophenyl)-2- methyl-thiazole 622 (80 mg, 0.31 mmol, 1 equiv.) and 3-methoxyaniline 638 (76.3 mg, 0.62 mmol, 2 equiv.). The crude product was purified by flash column
Experimental Part | 263
chromatography on SiO2 using hexanes: ethyl acetate (10:1) as eluting system to obtain the desired product as brown solid (84 mg, 91 %).
Analytical Data of 639:
TLC (SiO2): Rf = 0.30 (hexanes: ethyl acetate = 4:1). 1 H NMR (300 MHz, CDCl3): δ = 7.73 (d, J = 9.0 Hz, 2H), 7.68 (s, 1H), 7.38 (d, J = 9.0 Hz, 2H), 7.37-732 (m, 1H), 7.21-6.66 (m, 3H), 5.50 (br. s, 1H), 3.70 (s, 3H), 2.33 (s, 3H) ppm. 13 C NMR (75 MHz, CDCl3): δ = 169.6, 159.8, 153.3, 142.4, 130.6, 128.4, 122.5, 119.5, 110.3, 102.7, 55.8, 19.3 ppm. + MS-EI (m/z): [M] calcd for C17H16ON2S, 296.1020; found, 296.1018. Melting point: 147-150 °C.
E.5.5.6. 2-Methoxy-N-(4-(2-methylthiazol-4-yl)phenyl)aniline (341)
The reaction was performed according to procedure K using 4-(4-bromophenyl)-2- methyl-thiazole 622 (80 mg, 0.31 mmol, 1 equiv.) and 2-methoxyaniline 640 (76.3 mg, 0.62 mmol, 2 equiv.). The crude product was purified by flash column chromatography on SiO2 using hexanes: ethyl acetate (10:1) as eluting system to obtain the desired product as light brown solid (85 mg, 92 %).
Analytical Data of 641:
TLC (SiO2): Rf = 0.35 (hexanes: ethyl acetate = 4:1). 1H NMR (300 MHz, CDCl3): δ = 7.72 (d, J = 9.0 Hz, 2H), 7.68 (s, 1H), 7.38 (d, J = 9.0 Hz, 2H), 7.17-6.95 (m, 4H), 6.01 (br. s, 1H), 3.79 (s, 3H), 2.33 (s, 3H) ppm. 13 C NMR (75 MHz, CDCl3): δ = 169.6, 153.3, 150.2, 142.4, 129.1, 128.4, 122.1, 121.9, 119.6, 115.2 113.3, 55.8, 19.3 ppm. + MS-EI (m/z): [M] calcd for C17H16ON2S, 296.1020; found, 296.1018. Melting point: 148-152 °C.
Experimental Part | 264
E.5.5.7. 4-Flouro-N-(4-(2-methylthiazol-4-yl)phenyl)aniline (643)
The reaction was performed according to procedure K using 4-(4-bromophenyl)-2- methyl-thiazole 622 (80 mg, 0.31 mmol, 1 equiv.) and 4-flouroaniline 642 (68 mg, 0.62 mmol, 2 equiv.). The crude product was purified by flash column
chromatography on SiO2 using hexanes: ethyl acetate (10:1) as eluting system to obtain the desired product as brown solid (82.6 mg, 94 %).
Analytical Data of 643:
TLC (SiO2): Rf = 0.38 (hexanes: ethyl acetate = 4:1). 1 H NMR (300 MHz, CDCl3): δ = 7.79 (d, J = 9.0 Hz, 2H), 7.18 (s, 1H), 7.12-7.08 (m, 2H), 7.03 (d, J = 9.0 Hz, 2H), 7.04-6.98 (m, 2H), 5.72 (br. s, 1H), 2.81 (s, 3H) ppm. 13 C NMR (75 MHz, CDCl3): δ = 169.4, 156.7, 153.3, 142.4, 138.0, 128.4, 126.4, 122.7, 119.5, 116.8, 108.7, 19.7 ppm. + MS-EI (m/z): [M] calcd for C16H13FN2S, 284.0820; found, 284.0818. Melting point: 185-190 °C.
E.5.5.8. 4-Chloro-N-(4-(2-methylthiazol-4-yl)phenyl)aniline (645)
The reaction was performed according to procedure K using 4-(4-bromophenyl)-2- methyl-thiazole 622 (80 mg, 0.31 mmol, 1 equiv.) and 4-chloroaniline 644 (79 mg, 0.62 mmol, 2 equiv.). The crude product was purified by flash column
chromatography on SiO2 using hexanes: ethyl acetate (10:1) as eluting system to obtain the desired product as light yellow solid (85 mg, 91 %).
Experimental Part | 265
Analytical Data of 645:
TLC (SiO2): Rf = 0.32 (hexanes: ethyl acetate = 4:1). 1 H NMR (300 MHz, CDCl3): δ = 7.79 (d, J = 9.0 Hz, 2H), 7.25-7.19 (m, 1H), 7.20 (d, J = 9.0 Hz, 2H), 7.08 (s, 1H), 7.06-7.01 (m, 3H), 5.92 (br. s, 1H), 2.79 (s, 3H) ppm. 13 C NMR (75 MHz, CDCl3): δ = 166.1, 154.6, 142.6, 142.3, 129.3, 127.5, 127.4, 125.7, 119.2, 117.6, 110.5, 19.2 ppm. + MS-EI (m/z): [M] calcd for C16H13ClN2S, 300.0525; found, 300.0523. Melting point: 151-152 °C.
E.5.5.9. 2-Chloro-N-(4-(2-methylthiazol-4-yl)phenyl)aniline (647)
The reaction was performed according to procedure K using 4-(4-bromophenyl)-2- methyl-thiazole 622 (80 mg, 0.31 mmol, 1 equiv.) and 2-chloroaniline 647 (79 mg, 0.62 mmol, 2 equiv.). The crude product was purified by flash column chromatography on SiO2 using hexanes: ethyl acetate (10:1) as eluting system to obtain the desired product as yellow solid (82 mg, 88 %).
Analytical Data of 647:
TLC (SiO2): Rf = 0.45 (hexanes: ethyl acetate = 4:1). 1 H NMR (300 MHz, CDCl3): δ = 8.18 (br. s, 1H), 7.77 (d, J = 9.0 Hz, 2H), 7.62 (s, 1H), 7.04 (d, J = 9.0 Hz, 2H), 7.10-7.01 (m, 4H), 2.89 (s, 3H) ppm. 13 C NMR (75 MHz, CDCl3): δ = 167.8, 145.8, 139.8, 135.8, 128.97, 128.93, 128.25, 127.3, 127.2, 26.7 ppm. + MS-EI (m/z): [M] calcd for C16H13ClN2S, 300.0525; found, 300.0523. Melting point: 148-152 °C.
Experimental Part | 266
E.5.5.10. 2,4-Dichloro-N-(4-(2-methylthiazol-4-yl)phenyl)aniline (649)
The reaction was performed according to procedure K using 4-(4-bromophenyl)-2- methyl-thiazole 622 (80 mg, 0.31 mmol, 1 equiv.) and 2,4-dichloroaniline 648 (207 mg, 0.62 mmol, 2 equiv.). The crude product was purified by flash column
chromatography on SiO2 using hexanes: ethyl acetate (10:1) as eluting system to obtain the desired product as light brown solid (94 mg, 90 %).
Analytical Data of 649:
TLC (SiO2): Rf = 0.32 (hexanes: ethyl acetate = 4:1). 1 H NMR (300 MHz, CDCl3): δ = 8.19 (br. s, 1H), 7.77 (d, J = 9.0 Hz, 2H), 7.62 (s, 1H), 7.45-7.33 (m, 1H), 7.34 (d, J = 9.0 Hz, 2H), 7.14-7.07 (m, 2H), 2.78 (s, 3H) ppm. 13 C NMR (75 MHz, CDCl3): δ = 169.7, 153.3, 142.5, 131.4, 130.8, 129.3, 128.4, 127.8, 125.2, 122.4, 121.8, 119.6, 108.7, 19.8 ppm. + MS-EI (m/z): [M] calcd for C16H12Cl2N2S, 334.0135; found, 334.9133. Melting point: 190-196 °C.
E.5.5.11. 3-Triflouromethyl-N-(4-(2-methylthiazol-4-yl)phenyl)aniline (651)
The reaction was performed according to procedure K using 4-(4-bromophenyl)-2- methyl-thiazole 622 (80 mg, 0.31 mmol, 1 equiv.) and 3-triflouromethylaniline 650 (100 mg, 0.62 mmol, 2 equiv.). The crude product was purified by flash column
chromatography on SiO2 using hexanes: ethyl acetate (10:1) as eluting system to obtain the desired product as off white solid (98 mg, 95 %).
Experimental Part | 267
Analytical Data of 651:
TLC (SiO2): Rf = 0.54 (hexanes: ethyl acetate = 4:1). 1 H NMR (300 MHz, CDCl3): δ = 7.84 (d, J = 9.0 Hz, 2H), 7.39-7.31 (m, 2H), 7.24- 7.22 (m, 2H), 7.18 (s, 1H), 7.13 (d, J = 9.0 Hz, 2H), 6.09 (br. s, 1H), 2.80 (s, 3H) ppm. 13 C NMR (75 MHz, CDCl3): δ = 166.1, 154.5, 143.5, 141.7, 129.8, 128.2, 127.6, 120.1, 118.5, 117.2, 113.6, 110.8, 19.2 ppm. + MS-EI (m/z): [M] calcd for C17H13 F3N2S, 334.0789; found, 334.0787. Melting point: 178-180 °C.
E.5.5.12. 4-Nitro-N-(4-(2-methylthiazol-4-yl)phenyl)aniline (653)
The reaction was performed according to procedure K using 4-(4-bromophenyl)-2- methyl-thiazole 622 (80 mg, 0.31 mmol, 1 equiv.) and 4-nitroaniline 652 (85 mg, 0.62 mmol, 2 equiv.). The crude product was purified by flash column chromatography on
SiO2 using hexanes: ethyl acetate (10:1) as eluting system to obtain the desired product as orange colored solid (85 mg, 86 %).
Analytical Data of 653:
TLC (SiO2): Rf = 0.28 (hexanes: ethyl acetate = 7:3). 1 H NMR (300 MHz, DMSO-d6): δ = 8.02 (d, J = 9.3 Hz, 2H), 7.82 (d, J = 9.0 Hz, 2H), 7.18 (s, 1H), 7.40 (d, J = 9.3 Hz, 2H), 7.37 (d, J = 9.0 Hz, 2H), 6.05 (br.s, 1H), 2.80 (s, 3H) ppm. 13 C NMR (75 MHz, DMSO-d6): δ = 169.6, 153.3, 148.6, 142.4, 137.4, 128.4, 124.9, 123.1, 122.0, 119.6, 108.6, 19.3 ppm. + MS-EI (m/z): [M] calcd for C16H14O2N3S, 311.0765; found, 311.0763. Melting point: 178-180 °C.
Experimental Part | 268
E.5.5.13. N-Methyl-4-(2-methylthiazol-4-yl)-N-phenylaniline (655)
The reaction was performed according to procedure K using 4-(4-bromophenyl)-2- methyl-thiazole 622 (80 mg, 0.31 mmol, 1 equiv.) and N-methylaniline 654 (74 mg, 0.62 mmol, 2 equiv.). The crude product was purified by flash column
chromatography on SiO2 using hexanes: ethyl acetate (10:1) as eluting system to obtain the desired product as brown solid (70.2 mg, 80 %).
Analytical Data of 655:
TLC (SiO2): Rf = 0.57 (hexanes: ethyl acetate = 4:1). 1 H NMR (300 MHz, CDCl3): δ = 7.79 (d, J = 9.0 Hz, 2H), 7.36-7.31(m, 2H), 7.18 (s, 1H), 7.15-7.12 (m, 2H), 7.07-7.0 (m, 1H), 7.04 7.76 (d, J = 9.0 Hz, 2H), 3.38 (s, 3H), 2.80 (s, 3H) ppm. 13 C NMR (75 MHz, CDCl3): δ = 165.9, 154.9, 148.7, 148.6, 129.3, 127.2, 126.6, 122.2, 121.9, 119.0, 110.2, 40.4, 29.7, 19.3 ppm. + MS-EI (m/z): [M] calcd for C16H14N2S, 280.1071; found, 280.1069. Melting point: 166-168 °C.
E.5.5.14. N-Benzyl-N-methyl-4-(2-methylthiazol-4-yl)aniline (624)
The reaction was performed according to procedure K using 4-(4-bromophenyl)-2- methyl-thiazole 622 (80 mg, 0.31 mmol, 1 equiv.) and N-methylbenzylamine 623 (74 mg, 0.62 mmol, 2 equiv.). The crude product was purified by flash column
chromatography on SiO2 using hexanes: ethyl acetate (10:1) as eluting system to obtain the desired product as light brown solid (80 mg, 88 %).
Experimental Part | 269
Analytical Data of 624:
TLC (SiO2): Rf = 0.29 (hexanes: ethyl acetate = 4:1). 1 H NMR (300 MHz, DMSO-d6): δ = 7.73 (d, J = 9.0 Hz, 2H), 7.53 (s, 1H), 7.34-7.29 (m, 2H), 7.24-7.20 (m, 3H), 7.76 (d, J = 9.0 Hz, 2H), 4.60 (s, 2H), 3.04 (s, 3H), 2.67 (s, 3H) ppm. 13 C NMR (75 MHz, DMSO-d6): δ = 165.9, 154.9, 149.2, 139.3, 128.9, 127.4, 127.1, 123.0, 112.4, 109.8, 55.5, 19.4 ppm. + MS-EI (m/z): [M] calcd for C18H18N2S, 294.1228; found, 294.1226. Melting point: 146-147 °C.
E.5.5.15. N-Butyl-4-(2-methylthiazol-4-yl)aniline (657)
The reaction was performed according to procedure K using 4-(4-bromophenyl)-2- methyl-thiazole 622 (80 mg, 0.31 mmol, 1 equiv.) and n-butylamine 656 (45 mg, 0.62 mmol, 2 equiv.). The crude product was purified by flash column chromatography on
SiO2 using hexanes: ethyl acetate (10:1) as eluting system to obtain the desired product as light brown solid (61.2 mg, 79 %).
Analytical Data of 657:
TLC (SiO2): Rf = 0.38 (hexanes: ethyl acetate = 4:1). 1 H NMR (300 MHz, CDCl3): δ = 7.72 (d, J = 9.0 Hz, 2H), 7.08 (s, 1H), 6.65 (t, J = 9.0 Hz, 4H), 3.77 (br.s, 1H), 3.15 (t, J = 6 Hz, 2H), 2.77 (s, 3H), 1.66-1.58 (m, 2H), 1.49-1.41 (m, 2H), 0.98 (t, J = 6.0 Hz, 3H) ppm. 13 C NMR (75 MHz, CDCl3): δ = 165.9, 155.6, 148.2, 127.4, 124.0, 112.7, 108.8, 43.7, 31.5, 20.3, 19.3, 14.0 ppm. + MS-EI (m/z): [M] calcd for C14H18N2S, 246.1228; found, 246.1226. Melting point: 133-134 °C.
Experimental Part | 270
E.5.5.16. 4-(4-(2-Methylthiazol-4-yl)phenyl)morpholine (659)
The reaction was performed according to procedure K using 4-(4-bromophenyl)-2- methyl-thiazole 622 (80 mg, 0.31 mmol, 1 equiv.) and morpholine 658 (54 mg, 0.62 mmol, 2 equiv.). The crude product was purified by flash column chromatography on
SiO2 using hexanes: ethyl acetate (10:1) as eluting system to obtain the desired product as white solid (62 mg, 83 %).
Analytical Data of 659:
TLC (SiO2): Rf = 0.30 (hexanes: ethyl acetate = 4:1). 1 H NMR (300 MHz, CDCl3): δ = 7.79 (d, J = 9.0 Hz, 2H), 7.67 (s, 1H), 6.98 (d, J = 9.0 Hz, 2H), 3.74 (t, J = 6.0 Hz, 4H), 3.15 (t, J = 6.0 Hz, 4H), 2.69 (s, 3H) ppm. 13 C NMR (75 MHz, CDCl3): δ = 167.9, 156.6, 149.2, 128.4, 122.6, 112.7, 108.7, 66.3, 53.2, 19.3 ppm. + MS-EI (m/z): [M] calcd for C14H16ON2S, 260.1020; found, 260.1018. Melting point: 148-149 °C.
E.5.5.17. 4-Methoxy-N-(4-(2-phenylthiazol-4-yl)phenyl)aniline (661)
The reaction was performed according to procedure A using 4-(4-bromophenyl)-2- phenyl-thiazole 660 (98 mg, 0.31 mmol, 1 equiv.) and 4-methoxyaniline 622 (66 mg, 0.62 mmol, 2 equiv.). The crude product was purified by flash column
chromatography (SiO2, hexanes: ethylacetate = 10:1) to obtained as yellow solid (71 mg, 88 %).
Analytical Data of 661:
TLC (SiO2): Rf = 0.32 (hexanes: ethylacetate = 4:1).
Experimental Part | 271
1 H NMR (300 MHz, DMSO-d6): δ = 8.36 (br. s, 1H), 8.07-8.04 (m, 2H), 7.95 (d, J = 9.0 Hz, 2H), 7.51-7.44 (m, 3H), 7.35 (s, 1H), 7.38-7.35 (m, 2H), 7.37 (d, J = 9.0 Hz, 2H), 7.04 (d, J = 9.0 Hz, 2H), 3.89 (s, 3H) ppm. 13 C NMR (75 MHz, CDCl3): δ = 170.7, 153.2, 152.8, 143.3, 142.4, 134.7, 130.9, 129.2, 128.7, 128.4, 124.5, 122.5, 119.6, 115.2, 111.5, 55.8 ppm. + MS-EI (m/z): [M] calcd for C22H18ON2S, 358.1177; found, 358.1175. Melting point: 168-170 °C.
E.5.5.18. 3-Methoxy-N-(4-(2-methylthiazol-4-yl)phenyl)aniline (662)
The reaction was performed according to procedure A using 4-(4-bromophenyl)-2- phenyl-thiazole 660 (98 mg, 0.31 mmol, 1 equiv.) and 4-methoxyaniline 636 (100 mg, 0.62 mmol, 2 equiv.). The crude product was purified by flash column chromatography (SiO2, hexanes: ethylacetate = 10:1) to obtained as brown solid (110 mg, 90 %).
Analytical Data of 662:
TLC (SiO2): Rf = 0.29 (hexanes: ethylacetate = 4:1). 1 H NMR (300MHz, CDCl3): δ = 8.36 (br. s, 1H), 8.08 (d, J = 9.0 Hz, 2H), 7.73 (d, J = 9.0 Hz, 2H), 7.73-7.69 (m, 1H), 7.69 (s, 1H), 7.63-7.56 (m, 4H), 7.37 (d, J = 9.0 Hz, 2H), 7.23-7.13 (m, 2H) ppm. 13 C NMR (75 MHz, CDCl3): δ = 170.6, 153.2, 143.3, 142.4, 132.2, 130.9, 129.9, 128.8, 128.4, 124.1, 123.8, 122.5, 119.9, 118.8, 114.6, 111.5 ppm. + MS-EI (m/z): [M] calcd for C22H15F3N2S, 396.0945; found, 396.0943. Melting point: 180-186 °C.
Experimental Part | 272
E.5.5.19. 4-(4-(2-Phenylthiazol-4-yl)phenyl)morpholine (663)
The reaction was performed according to procedure A using 4-(4-bromophenyl)-2- phenyl-thiazole 660 (98 mg, 0.31 mmol, 1 equiv.) and morpholine 658 (54 mg, 0.62 mmol, 2 equiv.). The crude product was purified by flash column chromatography
(SiO2, hexanes: ethylacetate = 10:1) to obtained as light yellow solid (80 mg, 80 %).
Analytical Data of 663:
TLC (SiO2): Rf = 0.34 (hexanes: ethylacetate = 4:1). 1 H NMR (300 MHz, CDCl3): δ = 8.08-8.04 (m, 2H), 7.95 (d, J = 9.0 Hz, 2H), 7.51-7. 45 (m, 3H), 7.35 (s, 1H), 7.04 (d, J = 9.0 Hz, 2H), 3.93 (t, J = 6.0 Hz, 4H), 3.26 (t, J = 6.0 Hz, 4H) ppm. 13 C NMR (75 MHz, CDCl3): δ = 167.6, 156.1, 133.8, 129.9, 128.9, 127.2, 126.5, 115.7, 110.7, 98.7, 66.3 ppm. + MS-EI (m/z): [M] calcd for C19H18ON2S, 322.1177; found, 322.1175. Melting point: 135-140 °C.
E.5.5.20. 2-Methoxy-N-(4-(2-methyloxazol-4-yl)phenyl)aniline (666)
The reaction was performed according to procedure L using 4-(4-bromophenyl)-2- methyl-oxazole 664 (73 mg, 0.31 mmol, 1 equiv.) and 2-methoxyaniline 622 (66 mg, 0.62 mmol, 2 equiv). The crude product was purified by flash column chromatography
on SiO2 using hexanes: ethyl acetate (10:1) as eluting system to obtain the desired product as off white (77 mg, 89 %).
Analytical Data of 666:
TLC (SiO2): Rf = 0.26 (hexanes: ethyl acetate = 4:1).
Experimental Part | 273
1 H NMR (300 MHz, CDCl3): δ = 8.03 (br. s, 1H), 7.78 (d, J = 9.0 Hz, 2H), 7.58 (s, 1H), 7.09 (d, J = 9.0 Hz, 2H), 7.95 (d, J = 9.0 Hz, 2H), 6.90 (d, J = 9.0 Hz, 2H), 3.94(s, 3H), 2.52 (s, 3H). 13 C NMR (75 MHz, CDCl3): δ = 161.7, 148.4, 142.5, 140.4, 132.4, 132.0, 126.5, 123.5, 120.8, 120.3, 118.1, 115.1, 110.58, 55.6, 14.0 ppm + MS-EI (m/z): [M] calcd for C17H16O2N2, 280.1249; found, 280.1247. Melting point: 169-172 °C.
E.5.5.21. N-(4-(2-Methyloxazol-4-yl)phenyl)-3-(trifluoromethyl)aniline (667)
The reaction was performed according to procedure L using 4-(4-bromophenyl)-2- methyl-oxazole 664 (73 mg, 0.31 mmol, 1 equiv.) and 3-triflouromethylaniline 650 (100 mg, 0.62 mmol, 2 equiv.). The crude product was purified by flash column chromatography on SiO2 using hexanes: ethyl acetate (10:1) as eluting system to obtain the desired product as light brown solid (90 mg, 86%).
Analytical Data of 667:
TLC (SiO2): Rf = 0.41 (hexanes: ethyl acetate = 4:1). 1 H NMR (300 MHz, CDCl3): δ = 8.23 (br. s, 1H), 7.78 (d, J = 9.0 Hz, 2H), 7.58 (s, 1H), 7.60-7.56 (m, 2H), 7.37 (d, J = 9.0 Hz, 2H), 7.25-7.13 (m, 2H), 2.62 (s, 3H) ppm. 13 C NMR (75 MHz, CDCl3): δ = 161.1, 142.5, 142.2, 140.1, 132.6, 131.9, 129.9, 128.4, 124.1, 120.2, 119.6, 118.8, 114.6, 14.2 ppm. + MS-EI (m/z): [M] calcd for C17H13F3ON2, 318.1017; found, 318.1015. Melting point: 178-180 °C.
E.5.5.22. 4-Methoxy-N-(4-(2-phenyloxazol-4-yl)phenyl)aniline (668)
Experimental Part | 274
The reaction was performed according to procedure L using 4-(4-bromophenyl)-2- phenyloxazole 665 (93 mg, 0.31 mmol, 1 equiv.) and 4-methoxyaniline 622 (66 mg, 0.62 mmol, 2 equiv.). The crude product was purified by flash column
chromatography on SiO2 using hexanes: ethyl acetate (10:1) as eluting system to obtain the desired product as white solid (72.3 mg, 80%).
Analytical Data of 668:
TLC (SiO2): Rf = 0.36 (hexanes: ethyl acetate = 4:1). 1 H NMR (300MHz, DMSO-d6): δ = 8.36 (br. s, 1H), 8.16-8.08 (m, 2H), 7.73 (d, J = 9.0 Hz, 2H), 7.69-7.62 (m, 3H), 7.60 (s, 1H), 7.38-7.35 (m, 2H), 7.35 (d, J = 9.0 Hz, 2H), 7.10 (d, J = 9.0 Hz, 2H), 3.89 (s, 3H) ppm. 13 C NMR (75 MHz, CDCl3): δ = 159.4, 152.8, 142.4, 140.1, 139.9, 134.7, 130.6, 129.2, 128.7, 128.4, 127.5, 124.5, 120.2, 119.6, 115.2, 55.8 ppm. + MS-EI (m/z): [M] calcd for C22H17O2N2, 342.1405; found, 342.1403. Melting point: 149-153 °C.
E.5.5.23. N-(4-(2-Phenyloxazol-4-yl)phenyl)-3-(trifluoromethyl)aniline (669)
The reaction was performed according to procedure L using 4-(4-bromophenyl)-2- phenyloxazole 665 (93 mg, 0.31 mmol, 1 equiv.) and 3-triflouromethylaniline 650 (100 mg, 0.62 mmol, 2 equiv.). The crude product was purified by flash column
chromatography on SiO2 using hexanes: ethyl acetate (10:1) as eluting system to obtain the desired product off white solid (96 mg, 78 %).
Analytical Data of 669:
TLC (SiO2): Rf = 0.49 (hexanes: ethyl acetate = 4:1). 1 H NMR (300 MHz, CDCl3): δ = 8.36 (br. s, 1H), 8.18 (d, J = 9.0 Hz, 2H), 7.74-7.65 (m, 2H), 7.72 (d, J = 9.0 Hz, 2H), 7.60 (s, 1H), 7.63-7.56 (m, 3H), 7.37 (d, J = 9.0 Hz, 2H), 7.23-7.14 (m, 2H) ppm.
Experimental Part | 275
13 C NMR (75 MHz, CDCl3): δ = 159.4, 142.4, 142.2, 131.9, 130.6, 129.9, 128.7, 128.4, 127.5, 124.1, 123.9, 120.2, 119.6, 118.8, 114.6 ppm. + MS-EI (m/z): [M+H] calcd for C22H15F3ON2, 380.1173; found, 380.1171. Melting point: 155-157 °C.
List of Publications| 276
F. List of Ligands Structures
List of Publications| 277
List of Publications| 278
List of Publiations
The results of this dissertation have already been partially published:
[1] “Chemo-, Regio-, and Enantioselective Rhodium-Catalyzed Allylation of Pyridazinones with Terminal Allenes” Shaista Parveen, Changkun Li, Abbas Hassan, Bernhard Breit, Org. Lett. 2017, 19, 2326-2329.
[2] “Rhodium-Catalyzed Regioselective Domino Azlactone-Alkyne Coupling/Aza-Cope Rearrangement: A Facile Access to 2-Allyl-3-oxazolin-5-ones and Trisubstituted Pyridines” Jinqiang Kuang, Shaista Parveen, and Bernhard Breit, Angew. Chem. 2017, 129, 8542- 8545; Angew. Chem. Int. Ed. 2017, 56, 8422-8425.
Publications| 279
Publications| 280
Similarity Index Report| 281
Refernces| 282
References
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