One Step Copper-Catalyzed Functionalization of Pyridines with Alkynes and Organoindium Reagents
A thesis submitted to McGill University in partial fulfillment of the requirements of the degree of M.Sc.
By
Ramsay E. Beveridge
April 2007
Department of Chemistry
McGill University
Montreal, Quebec, Canada
© Ramsay E. Beveridge 2007 This thesis is dedicated to all of the wonderful teachers that I’ve had who provided inspiration for the study of chemistry: Prof. B.A. Arndtsen, Mr. Charles “Chuck” Eisner, Prof. J. Roscoe, Prof. J.T. Banks, Prof. J. Clyburne, Prof. R.A. Gossage, and in particular to my high school chemistry teacher Ms. McDonald. ABSTRACT
The copper-catalyzed synthesis of functionalized pyridines and partially reduced pyridine derivatives has been developed and the results are presented herein. These studies have shown that pyridines (and related aromatic heterocycles) in the presence of chloroformates will undergo effective coupling with terminal alkynes and organoindium reagents using simple copper (I) salt catalysts to give good yields of dihydropyridine products. In addition, performing these reactions in tandem with base or oxidative additives has led to the copper-catalyzed one-pot preparation of substituted aromatic pyridines.
RÉSUMÉ
Une méthode catalytique médiée par le cuivre pour la synthèse des dérivés de pyridines ainsi que celles partiellement réduites est décrite dans le texte qui suit. Cette étude démontre que les pyridines (et autres hétérocycles aromatiques reliés), lorsque quaternisées in-situ par des réactifs tel que les chloroformates, celles-ci peuvent être couplées avec des alcynes terminaux ou des réactifs organo-indium au moyen de simple sels de cuivre (I) pour générer, bon rendement, des dihydropyridines. De plus, lorsque cette réaction est effectuée en tandem, soit avec l’ajout d’une base ou d’un agent oxydant, ce processus nous offre une méthodologie en un pot envers la synthèse de pyridines substituées.
i Acknowledgements
I’d first like to thank all the members, past and present, of the Arndtsen Lab. It’s been a great experience working with such great, hard-working, and motivated people. You’ve all been a constant source of support and help. Especially those involved in the MCRC initiative, I’ll never be the same again. But most of all, I thank you for being friends.
And of course, this thesis could not have come together without the guidance and motivation of Prof. Arndtsen. His attention to detail, strong work ethic, scientific approach, and direction are much appreciated, especially when it came time to put pen to paper!
I’d also like to thank all of the other organic labs here at McGill for being so generous with reagents, materials, equipment, and know-how. It’s been a pleasure to be part of the department community for so long.
I would particularly like to thank Dr. Alain Lesimple from the McGill Proteomics department, and Chantal Marotte, the graduate studies coordinator in the chemistry department. Alain- I am fairly certain that I will never meet a more motivated and helpful mass spectrometrist ever again. All of your hard work is much appreciated! Chantal- I don’t think anyone could ever complete graduate studies in chemistry at McGill without your guidance and help. Thank you.
ii TABLE OF CONTENTS
Chapter 1- Introduction: Synthetic Utility of Nucleophilic Additions to N-activated Pyridines 1.0 Perspective…………………………………………………...... pg. 1 1.1 Formation of Pyridinium Salts……………………………………..pg. 4 1.2 Nucleophilic Additions to Pyridinium Salts………………………..pg. 8 1.3 Organic Nucleophilic Additions………………………………….....pg.10 1.4 Organometallic Nucleophilic Additions……………………………pg. 19 1.5 Organometallic Additions to Pyridinium Salts Towards Library Development……………………………………………………………..pg.26 1.6 Asymmetric Additions to Pyridinium Salts………………………..pg.28 1.7 Conclusion and Overview of Thesis………………………………..pg. 35 1.8 References…………………………………………………………...pg. 36
Chapter 2- Development of a Copper-Catalyzed Coupling of Pyridines, Alkynes, and Chloroformates 2.0 Preface……………………………………………………………….pg. 43 2.1 Introduction………………………………………………………….pg. 43 2.2 Results and Discussion………………………………………………pg. 44 2.3 Conclusion……………………………………………………………pg. 49 2.4 Experimental………………………………………………………...pg. 50 General Procedures……………………………………………...pg. 50 Spectroscopic Data……………………………………………….pg. 51 1H and 13C NMRs………………………………………...... pg. 56 2.5 References……………………………………………………………pg. 75
Chapter 3- A One-pot Copper-Catalyzed Synthesis of Alkynyl Pyridines 3.0 Preface………………………………………………………………..pg. 76 3.1 Introduction…………………………………………………………..pg. 76 3.2 Results and Discussion……………………………………………….pg. 77 3.3 Conclusion…………………………………………………………….pg. 81
iii 3.4 Experimental………………………………………………………….pg. 81 General Procedures……………………………………………….pg. 81 Spectroscopic Data………………………………………………..pg. 83 1H and 13C NMRs………………………………………...... pg. 87 3.5 References…………………………………………………………….pg. 102
Chapter 4- Towards a General Method of Pyridine Functionalization by Copper- Catalyzed Organoindium Addition 4.0 Preface………………………………………………………………..pg. 106 4.1 Introduction…………………………………………………………..pg. 106 4.2 Results and Discussion……………………………………………….pg. 107 4.3 Conclusion…………………………………………………………….pg. 112 4.4 Experimental…………………………………………………………pg. 113 General Procedures………………………………………………pg. 113 Spectroscopic Data………………………………………………..pg. 114 1H and 13C NMRs………………………………………...... pg. 119 4.5 References…………………………………………………………….pg. 138
Chapter 5- Conclusions and Future Work 5.1 Summary of Thesis…………………………………………………...pg. 141 5.2 Future Work………………………………………………………….pg. 142 5.3 References…………………………………………………………….pg. 144
Appendix A- Studies Directed Towards Using a Copper-Catalyzed Organoindium Addition to Prepare Substituted Pyridines A.1 Introduction………………………………………………………….pg. 145 A.2 Results and Discussion………………………………………………pg. 145 A.3 Conclusion……………………………………………………………pg. 148 A.4 Experimental………………………………………………………...pg. 149 General Procedures and Spectroscopic Data…………………...pg. 149 1H and 13C NMRs………………………………………………..pg. 151
iv A.5 References………………………………………………………….pg. 153
v LIST OF FIGURES AND SCHEMES
Figure 1.1 Representative important commercial and natural pyridines………pg. 2
Figure 2.1 Imines and pyridine in catalytic carbon-carbon bond formation...... pg. 44 Scheme 1.1 Typical commercial methods of pyridine synthesis……………...pg. 3
Scheme 1.2 Resonance structures of pyridine showing difference in p-electron densities
…………………………………………………………………….pg. 5
Scheme 1.3 Formation of pyridinium salts by reaction with various electrophilic agents
……………………………………………………………………..pg. 5
Scheme 1.4 Alternative, non-quaternization preparations of pyridinium salts
…………………………………………………..…………………pg. 8
Scheme 1.5 Regioisomers resulting from nucleophilic addition to pyridinium salts
……………………………………………………………………pg. 9
Scheme 1.6 Alkoxy additions to pyridinium salts……………………………..pg. 10
Scheme 1.7 Pyridines in “Reissert”-type Reactions…………………………...pg. 11
Scheme 1.8 A catalytic enantioselective Reissert-Type reaction……………...pg. 11
Scheme 1.9 Catalytic enantioselective cyanide addition to pyridinium salts and
application to the synthesis of dopamine D4 antagonist CP-293,019
…………………………………………………………………….pg. 12
Scheme 1.10 Effective addition of iso-cyanides to nicotinamides as an efficient entry to
substituted nicotinonitrile compounds…..……………………….pg. 13
Scheme 1.11 Synthesis of the indolo-alkaloid geissoschizine using the “Wenkert
procedure”…………………………………………………….....pg. 14
vi Scheme 1.12 Strategies to access highly complex indolo-alkaloid skeletons using
pyridinium salts………………………………………………..pg. 15
Scheme 1.13 Examples of chiral indolo-alkaloid synthesis via pyridinium salt additions
.....………………………………………………………………pg. 16
Scheme 1.14 Synthesis of 4-(2-oxo-alkyl)-pyridines by enolate addition to N-acyl
pyridinium salts….……………………………………………..pg. 16
Scheme 1.15 Application of an asymmetric enolate addition to a pyridinium salt: Total
synthesis of (+)-cannibativine………………………………….pg. 17
Scheme 1.16 Addition of π-basic aromatics to pyridines activated with triflic anhydride
and its application to the synthesis of 4-aryl-substituted pyridines
...... ….pg. 19
Scheme 1.17 Direct addition of phenyl-magnesium bromide or phenyl-lithium to
pyridine…………………………………………………………pg. 20
Scheme 1.18 Aryl grignard addition to N-acyl salts of 3,4-lutidine for the regioselective
synthesis of substituted pyridines……………………………….pg. 20
Scheme 1.19 Regioselective 1,4-addition of a grignard reagent in the synthesis of 4-
substituted pyridines using the quaternization agent to block the ortho
positions………..………………………………………………..pg. 21
Scheme 1.20 Addition of grignards to N-acyl pyridinium salts and the affect of catalytic
copper (I) iodide towards the isolation of piperidines and
pyridines…………………………………………………………pg. 22
Scheme 1.21 Grignard additions to N-alkoxycarboxy pyridinium chlorides as a method
for the synthesis of 2-substituted pyridines...…………………….pg. 23
vii Scheme 1.22 Regioselective α-addition of an alkynyl-grignard to an N-acyl pyridinium
salt and application to the synthesis of the piperidine alkaloid (+/-)-
monomorine…………………………………………………..pg. 24
Scheme 1.23 General Manipulations of the 4-pyridone resulting from organometallic
addition to an N-acyl-4-methoxy-pyridinium salt...………….pg. 25
Scheme 1.24 Application of allyl-tin additions to pyridinium salts towards the synthesis of (+/-)-coniine synthesis……………………………………..pg. 26
Scheme 1.25 Solution-phase parallel synthesis of some N-tBoc-protected piperidines ……………………………………………………………….pg. 27 Scheme 1.26 Solid-phase pyridinium salt REACAP approaches to heterocycle synthesis
………………………………………………………………..pg. 28
Scheme 1.27 Diastereoselective Grignard addition to 3-TIPS-4-methoxy-pyridine using chiral cyclohexyl chloroformates…………………………….pg. 29
Scheme 1.28 Representative natural products synthesized using the “Comins Protocol” ……………………………………………………………….pg. 30
Scheme 1.29 Regioselective organometallic 1,2-addition to unsubstituted N-imidate pyridinium salts……………………………………………….pg. 31
Scheme 1.30 Asymmetric organometallic reagent addition to N-imidate pyridinium salts and application to the chiral synthesis of interesting heterocycles
………………………………………………………………..pg. 32
Scheme 1.31 Examples of other chiral pyridines and quaternized pyridines for asymmetric additions to pyrdinium salts……………………..pg. 33 Scheme 1.32 Examples of catalytic enantioselective additions to salts of quinoline and isoquinoline…………………………………...pg. 34
viii Scheme 1.33 Arndtsen lab copper-catalyzed one-pot multicomponent routes to highly functionalized α-substituted amides…………………………..pg. 35 Scheme 2.1 Proposed mechanism for the copper catalyzed addition of terminal alkynes to pyridine……………………………………………………….pg. 46
Scheme 2.2 Hoffman elimination of Hunigs base with phenyl chloroformate …………………………………………………………………..pg. 48 Scheme 3.1 Copper-catalyzed multicomponent coupling of pyridines, acyl Chlorides and alkynes………………………………………………………pg. 76 Scheme 4.1 Proposed mechanism of copper-catalyzed coupling of pyridines with organoindium reagents…………………………………………..pg. 108 Scheme 5.1 Pyridine derivatives obtained through copper-catalyzed couplings with activated N-acyl pyridinium salts………………………………..pg. 141 Scheme 5.2 Potential solid-phase product synthesis using polystyrene supported Chloroformates…………………………………………………..pg. 142 Scheme 5.3 Catalytic enantioselective cyclic propargylcarbamate synthesis...pg. 143 Scheme 5.4 Potential oxidative addition of N-acyl pyridinium salts towards new chemistry development…………………………………………..pg. 144 Scheme A.1 Copper-catalyzed coupling of substituted pyridines and organoindium Reagents…………………………………………………………pg. 145 Scheme A.2 Two-step Fmoc and TBAF mediated synthesis of 4-phenylpyridine …………………………………………………………………..pg. 148 Scheme A.3 Oxidation of partially reduced substituted benzoxazole and benzothiazole ………………………………………………………………….pg. 148
ix LIST OF TABLES
Table 2.1. Copper-catalyzed coupling of pyridines, chloroformates and alkynes…pg. 45
Table 2.2 Copper-catalyzed multicomponent coupling of pyridines, chloroformates and
alkynes…………………………………………………………………..pg. 47
Table 2.3. Copper-catalyzed multicomponent coupling of N-Heterocycles, acyl
chlorides and alkynes…………………………………………………..pg. 49
Table 3.1 Towards a direct copper-catalyzed synthesis of 2-ethynyl-pyridines….pg. 77
Table 3.2 One pot tandem alkyne coupling and oxidation route to 2-ethynyl pyridines
…………………………………………………………………………..pg. 78
Table 3.3 A base mediated synthesis of 2-phenyl-alkenyl-pyridines……………..pg. 79
Table 4.1 Addition of (Ph)3In reagent to pyridine and ethyl chloroformate………pg. 107
Table 4.2. Copper-catalyzed coupling of pyridines and organoindium reagents….pg. 109
Table 4.3 Copper-catalyzed coupling of organoindium reagents to aromatic
N-heterocycles………………………………………………………….pg. 111
Table A.1 Oxidation attempts to prepare 4-phenylpyridine using a copper-catalyzed
organoindium route……………………………………………………pg. 146
Table A.2 Base mediated one-pot one-step synthesis of 4-phenylpyridine………pg. 147
x LIST OF ABBREVIATIONS
OTf DDQ triflouromethane sulfonate 2,3-dichloro-5,6-dicyano-1,4-quinone THF o-chloranil tetrahydrofuran 3,4,5,6-tetrachloro-1,2-quinone EtOAc mCPBA ethyl acetate meta-Chloro-perbenzoic acid
Et2O MPEP diethyl ether 2-methyl-6-(phenylethynyl)pyridine DABCO TMS 1,4-diazabicyclo[2.2.2]octane Trimethylsilane DBU MeOH 1,8-diazabicyclo(5.4.0)undec-7-ene Methanol TBAF EWG tetrabutylammonium flouride Electron-withdrawing group Fmoc eq. 9-flourenylmethyloxycarbonyl Equivalents Troc [O] 2,2,2-trichloro-ethyl-chloroformate Oxidative conditions DMF [H] Dimethylformamide Reductive (hydrogenation) conditions mGluR5 HMQC Human metabotropic glutamate receptor Heteronuclear Multiple Quantum NADH Coupling Nicotinamide adenine dinucleotide HMBC (reduced form) Heteronuclear Multiple-bond Coupling NADP NOESY Nicotinamide adenine dinucleotide Nuclear Overhauser Effect Spectroscopy phosphate NMR Nulcear Magnetic Resonance
xi HRMS High Resolution Mass Spectrometry MO Molecular Orbital Ar Aryl LA Lewis Acid Nu- Nucleophile E+ Electrophile TFA Triflouro-acetic acid Alloc Allyl Chloroformate TCC Trans-α-cumyl-cyclohexanol de Diastereomeric excess dr Diastereomeric ratio DMSO Dimethyl-sulfoxide REACAP Resin Activation/Capture Approach
xii CHAPTER 1
Synthetic Utility of Nucleophilic Additions to N-activated Pyridines
1.0 Perspective
Heterocycles make-up over half of all known organic compounds1 and pyridine bases represent one of the most prevalent nitrogen heterocycle sub-groups. The first pyridine bases were isolated from bone pyrolysis and coal tar residues in the mid-19th century. The pyridine structure was correctly proposed some 20 years later as a mono- aza-analogue of benzene, where one carbon atom of the benzene ring has been replaced with a nitrogen.2
The first commercialization of a pyridine derivative came in the 1930’s when it was found that niacin was useful in the prevention of dermatitis and dementia.2 Since then countless pyridines have found industrial applications, including constituents of latex and other polymers, herbicides, insecticides, pharmaceuticals, adhesives and as a reaction medium.3 In the pharmaceutical industry alone, it has been estimated that the pyridine core is in over 7000 existing therapeutic agents,2,4 which is no surprise since pyridines also play important roles in nature. For example, the pyridine nucleotide NADP is involved in various oxidation-reduction processes crucial to metabolism, and pyridine is also found in the important vitamins niacin and vitamin B6 as well as in potent alkaloids like nicotine (Figure 1.1).2
1 CONH 2 -O P O O O N O OH -O P O HO O HO OH N OH Me N H O N N NH2 N
Nicotine Pyridoxine (Vitamin B6) HO N N OH NH 2 NADP
CONH 2 NC CN
SO2 N N NN H Cl N Cl Niacin 2-vinyl Pyridine (latex and polymer precursor) Sulphapyridine Pyridinenitrile (antibacterial) (fungicide)
Figure 1.1 Representative important commercial and natural pyridines
This high bio-activity and commercial importance of pyridines has increased demand for these molecules beyond what can be extracted from coal tars, and synthetic methods for the construction of this important core have been developed. Pyridine itself can be produced commercially in ~ 60-70% yield by the vapour phase condensation of crotonaldehyde, formaldehyde, steam, air and ammonia at high temperature over a silica- alumina catalyst.2 Alkyl substituted pyridines are typically produced by the cyclizations of alkynes and nitriles catalyzed by cobalt complexes (Scheme 1.1).5 While many other substituted pyridines can be synthesized using related condensation methods (e.g. Hantzsh pyridine synthesis, Guareschi synthesis, Chichibabin Synthesis)5 or other metal catalyzed cyclizations,6 problems in regioselectivity, harsh reaction conditions, and restricted availability of starting materials can at times limit the diversity and scope of these syntheses. This can restrict the ability to develop specific pyridine structures crucial for natural product synthesis or product development where specific characteristics are necessary.
2 Gas-phase High Temperature Condensation Pyridine Synthesis:
O silica-alumina catalyst H2OO2 NH3 O N
Cobalt-Catalyzed Cyclization: R1 Co(I) Catalyst R NR 2 R1 R2 3 NR3
Hantsch Dihydropyridine and Pyridine Synthesis: Ar Ar
RO2CCO2R RO2CCO2R RO2C Ar [-2H] NH3 ONMe MeMe N Me Me O H
Guareschi Pyridine Synthesis: CN CO Et Me 2 Me
HC(OEt)3 CN O TsOH OEt H2N Me
Me O Et O 2C O Et O 2CMeN
Chichibabin Pyridine Synthesis: OH R R RR -H O/[O] R 2 3 NH3 O N N
R R
Scheme 1.1 Typical commercial methods of pyridine synthesis
If a desired pyridine is not commercially available, it must be synthesized. The direct ring functionalization of commercially available pyridines is perhaps the most straight-forward route to highly substituted pyridines. Electrophilic and nucleophilic aromatic substitution reactions provide routes to simple substituted pyridines, but are limited by the incompatibility of many functional groups to the harsh conditions required.5 Metallation strategies have proven to be powerful methods for the regioselective addition of many functionalities, but too often require the presence of a
3 directing group, which must be installed and removed in separate steps.7 Transition metal catalyzed cross-couplings (e.g. Suzuki, Negishi, Stille, Sonogoshira, or Heck couplings)8 are mild and general methods for incorporation of various organic groups onto the pyridine ring. These methods require the initial generation of the correctly positioned halogenated (or more recently N-oxide)9 pyridine precursor, which can be cumbersome for the synthesis of complex pyridines.
The ability of pyridine bases to form quaternary salts with a number of electrophilic reagents is a well studied area of chemistry.10 These azaaromatic salts are extremely useful for a number of transformations including oxidations, reductions and cycloadditions. In particular, the addition of nucleophilic reagents to N-alkyl or N-acyl pyridinium salts has seen great success in the last 25 years in the synthesis of many useful pyridine derivatives, especially alkaloids.11 This chapter will provide a general overview of pyridinium salt formation, the synthetic utility of nucleophilic additions to these interesting electrophiles, and the impact this area has had in organic synthesis.
1.1 Formation of Pyridinium Salts
Although pyridine is a six-membered aromatic compound like benzene, the fact that it contains a nitrogen atom changes its reactivity drastically from other purely carbon-containing aromatic compounds. For example, pyridines do not undergo electrophilic aromatic substitutions as easily as benzene, but will undergo nucleophilic aromatic substitutions more readily.5 This observed difference is a direct result of the presence of the electronegative nitrogen atom, which influences the p-electron densityon the ring carbon atoms. The increased susceptibility of pyridine towards nucleophilic aromatic substitution becomes clear when resonance structures are drawn, which clearly show the C-2 (or a) and C-4 (or ?) positions as more electron deficient than the other ring atoms (Scheme 1.2). This analysis is also supported by MO ab initio calculations.5b
4 NNN N
Scheme 1.2 Resonance structures of pyridine showing difference in p-electron densities
These resonance structures also illustrate why it is so difficult to perform traditional electrophilic aromatic substitution reactions on pyridines. While the carbon atoms of the pyridine ring are more electrophilic, the nitrogen atom of pyridine is relatively electron rich and therefore nucleophilic. The nucleophilicity/basicity of the pyridine nitrogen is evidenced by the observed formation of pyridinium salts when it is exposed to electrophilic substrates, shown below in Scheme 1.3. R
X N R R R1
X N N X R1X H R =alkyl Ar HX 1 ArX R R R Lewis-acid A,HX
N N N X KO3SONH2 R1COCl LA KI A R CO H R 1 3 R
R N I N X
NH 2 OR N 1 O
Scheme 1.3 Formation of pyridinium salts by reaction with various electrophilic agents5a
5 The above scheme shows that a diverse set of quaternary pyridine salts can be synthesized by the direct addition of pyridines to an electrophile. In contrast with other aromatic N-heterocycles (i.e. pyrrole), the donation of the nitrogen lone pair in these reactions does not destroy the aromaticity of pyridine, and it remains isoelectronic with benzene.12 These salts are, however, much more polarized than benzene or simple pyridine, and further exaggerate the electrophilicity of the ortho- and para-carbon atoms.
The quaternization of pyridines in this manner are equilibrium processes and the amount of salt produced is dependant on both the nature and concentration of the electrophile and the pyridine. Obviously, higher concentrations and electrophilicities of the electrophile will result in more pyridinium salt formation compared to the reaction of the same amount of pyridine with a more dilute or less reactive electrophile. The rate of pyridinium salt formation is also dependant on these factors. For example, quaternization of pyridine with an acyl halide is typically instant at room temperature with complete salt formation within minutes to an hour, whereas quaternization with an alkyl halide requires longer reaction times.
In addition, steric and electronic effects are major contributing factors towards the efficiency and rates of these quaternization reactions. Substitution of pyridine with a simple methyl group at the a-position reduces the rate of N-alkylation by approximately a factor of three, and when there is extreme steric hindrance, as in the case of 2,6-di-t- butylpyridine, no reaction is observed with methyl-iodide.13 If, however, these electron- rich alkyl groups are well removed from the reaction site, they can increase the rate of quaternization by donating electron density into the ring. For example, 3-methyl pyridine will react 1.5 times faster with methyl-iodide than pyridine. Conversely, withdrawing electron density from the pyridine ring will slow reaction rates: substitution of pyridine at C-3 with simple chlorine slows the N-methylation reaction by a factor of 7.13
While simple quaternization of pyridine with electrophiles is the most common route to pyridinium salts, there exist a number of alternative routes for their formation (Scheme
6 1.4). The reaction of primary amines with the extremely electrophilic N-2,4- dinitrophenyl pyridinium salt releases 2,4-dinitro aniline and results in a new N-alkyl activated pyridinium species. This reaction was first reported by Zincke14 in 1903 and is now known as the Zincke reaction. This reaction has a deceptively complex mechanism which was the subject of many studies,15 but today is frequently used as a useful method to prepare chiral pyridinium salts16 via the addition of chiral amines. Another common non-quaternization route to pyridinium salts is by treatment of pyrylium salts or ions with primary (or in rare cases secondary) alkyl amines. This results in nucleophilic addition to the a-position of the pyrylium ion to give a dihydropyran, which ring opens then self condenses producing the N-alkyl pyridinium salt.17 Condensation of a,ß-unsaturated ketones with primary amines and carbonyl-containing compounds with acidic hydrogens will also yield pyridinium salts via a related mechanism.10b Lastly, the oxidation or rearrangement of dihydropyridines17b,18 can also yield pyridinium salts, although this route is seldom used due to lack of scope.
7 Access to an N-alkyl chiral pyridinium salt via the Zincke reaction:16a
NH2
NH2 NO2 N N Cl n Cl NO2 Ph Me -BuOH, reflux H 90% Ph H Me
NO2
NO2
Pyridinium ion synthesis by primary amine addition to a pyrylium ion:17a
Ar Ar Ar Ar
RNH 2 NHR NHR
ArO Ar ArO Ar ArO Ar ArN Ar H R Representative condensation procedure for pyridinium salt synthesis:10b
R2 R2
Cl R3 R3 C2Cl6 NH3 xylenes, reflux 5-6hrs R1 O R OR4 R1 N R4
R Cl Oxidation of N-dodecylacridan to the N-dodecylacridium chloride NAD+ model:18a
Fe C l3
N N Cl C12H25 C12H25
Scheme 1.4 Alternative, non-quaternization preparations of pyridinium salts
1.2 Nucleophilic Additions to Pyridinium Salts
The pronounced susceptibility of pyridinium salts to nucleophilic addition at the a- and ?-positions has been exploited in the synthesis of many useful structures.5,10,11,19,20 These additions have been used to synthesize a range of biologically relevant structures, including NADH mimics and alkaloids,11 as well as providing easy access to synthetically useful dihydropyridines19 and pyridines.20
8 The addition of a nucleophile to a pyridinium salt can result in either 1,2 or 1,4 addition, depending on the nature of the nucleophile, pyridine ring substitution, nature of the pyridinium salt, and conditions or additives used in the reaction (Scheme 1.5). The exact reasons for the difference in the position of attack by nucleophiles is not entirely understood, however, some studies on this issue have postulated that an intermediate charge-transfer complex21 could be involved, or that the hard or soft nature of the nucleophile is the determining factor.22
Nu
R R2 R2 2
Nu
Conditions N N N Nu
R R1 X R1 1 1,4-dihydropyridine 1,2-dihydropyridine Scheme 1.5 Regioisomers resulting from nucleophilic addition to pyridinium salts
The rest of this chapter will provide a concise review of nucleophilic additions to pyridinium salts. Additions to pyridine N-oxides, and salts of benzo-fused pyridines (e.g. quinoline and isoquinoline) and related aza-aromatics will be largely ignored, but a few selected important examples will be included. A variety of nucleophiles will be considered and reviewed, however, particular emphasis will be to show the synthetic utility of nucleophilic additions to pyridinium salts and using this reactivity towards the synthesis of bio-active targets.
In a general sense, nucleophiles in additions to pyridinium salts can be divided into either organic or organometallic compounds. Organic nucleophiles can be considered as simple substituted amines and alcohols (including ammonia and the hydroxide ion), as well as carbanions such as enolates,∗ malonates,* isocyanides and the cyanide ion. Organometallic nucleophiles, however, are typically considered to be anionic carbon sources which can be either covalently or ionicly bonded to a metal.
∗ Although these often also contain a metal, they will be considered organic nucleophiles here since the nucleophilic carbon is not bonded to the metal.
9 These include but are not limited to: organo-magnesium, -lithium, -cuprate, -titanium, - boronic acid or –borate, -zinc, -indium, and -tin reagents. While a number of organic nucleophiles have been added to pyridinium salts, organometallic species are far more common coupling partners, due in large part to the diversity of organometallic agents available.
1.3 Organic Nucleophile Additions
The hydroxide ion is believed to be the earliest reported nucleophile to be added to a pyridinium salt. The products of these reactions were originally proposed to be 1- substituted-2-hydroxy-1,2-dihydropyridines,23 but were later found to transform into 2- pyridones24 (Scheme 1.6). When related alkoxide nucleophiles are added to N-methyl salts of 3-substituted pyridines, more stable products can be isolated.25 In these cases, reversible addition occurs, and longer reaction times leads to the formation of the more stable 1,4-adduct.25a
OR2
R R
OH OR2 R=H R= CN, ketone, amide NO N N X R1 R1 R1 2-Pyridone Product 4-alkoxy-dihydropyridine
Scheme 1.6 Alkoxy additions to pyridinium salts
Simple benzo-fused pyridine derivatives such as quinoline and isoquinoline, easily undergo cyanide ion addition to their N-acyl salts in what is known as the Reissert reaction.26 While these “Reissert compounds”are useful heterocyclic products,27 this reaction does not work well for most simple pyridines, often giving very low yields of the pyridine “Reissert” analogues (N-acyl-2-cyano-1,2-dihydropyridines).28 Efficient addition of cyanide ion to pyridinium salts occurs only when the pyridine ring is substituted with electron-withdrawing groups (e.g. ketones, amides, or cyano- substituents), or activated with more electron deficient chloroformates. These give
10 predominantly 1,4-cyano addition (non-“Reissert” addition) under thermodynamic control (Scheme 1.7).29
CN
R2 R2 "" "" CN CN
R1 =Ph R1 =Ph,OEt NC N R2 =H N R2 =COR2,CN N X
Ph O R1 O R1 O "Reissert" Addition 1,4-cyano Addition 0.5-3% yield 30-75% yield
Scheme 1.7 Pyridines in “Reissert”-type reactions
A recent advance in this chemistry has been the development of a catalytic enantioselective addition of cyanide ions to N-acyl quinoline and isoquinoline salts using chiral lewis acids (Scheme 1.8).30
R R1 R1 R1 TMSCN / RCOCl 1 9mol% Catalyst or or N N -400C, CH Cl /Toluene N 2 2 N CN COR 24-112 hrs COR CN
RI Me 57 - 99%Yield; 54 - 96% ee Catalyst = RI = O Al Cl PO O 2 RI
Scheme 1.8 A catalytic enantioselective Reissert-type reaction30
Most importantly, these conditions were improved in a later report to include the catalytic asymmetric addition of cyanide ions to N-acyl pyridinium salts, in the first ever reported catalytic enantioselective addition to a pyridinium salt.31 This provides regio- and enantio-selective access to very useful Reissert-addition (α-addition of cyanide) pyridine products, which are difficult to access even in a racemic fashion by other
11 methods. This reaction was also applied to the synthesis of the highly selective dopamine
D4 antagonist CP-293,019 (Scheme 1.9).
Z O Ph Z O R Ligand = S Et 2AlCl (5-10%) R 10mol% Ligand O NC N OH TMSCN (2eq.) N I OH I R O O R CO2Cl (1.4eq.) O o 42-98%Yield S CH2Cl2,-60 C, 5-36hrs 57-99% ee Ph
O O O 1) H2 Pd/C (88%) Et AlCl (5-10%) 2 NMe 2) TsCl, Et3N (82%) 10mol% Ligand 2 NMe 2 NMe 2 3) NaOH (68%) TMSCN (2eq.) NC N N N MeCO Cl (1.4eq.) NHTs H 2 Me O O CH Cl ,-60oC, 5hrs 2 2 98% Yield F 91% ee O 1) NaBH CN, AcOH 3 O 2) BrCH2CH2Br, Cs2CO3 NMe 2
N N Ts N N N 55% Yield CP-293,019 N F
Scheme 1.9 Catalytic enantioselective cyanide addition to pyridinium salts and
application to the synthesis of dopamine D4 antagonist CP-293,019
Until recently, the addition of related isocyanides to activated quaternary pyridines was unknown, although successful examples of isocyanide reaction with salts of quinoline and isoquinoline had been reported.32 One possible reason for this difference in reactivity was proposed by the Lavilla group, who postulated that a reversible addition may occur with isocyanides and pyridinium salts. They proposed that stabilization of the nitrilium ion formed after additioncould alloweffective trapping of the isocyanide addition products. It was found that by using pyridines substituted in the 3-position with carboxyamido groups, they could isolate 4-amido substituted 1,4-
12 dihydropyridines in good yield (Scheme 1.10).33 This reaction represents the only known addition of isocyanides to pyridinium salts giving dihydropyridine products,34 and was also applied to the synthesis of other interesting pyridine derivatives, including amido- substituted aromatic pyridines, isoquinolines, and cis-indoloquinolizidines.
R2 HN O
CN R2 e M yl CO 2 ex HN O = loh R 1 yc O = c Q N R 2 DD R1X CN 86% R2NC R NH = 2 Base R 1 t rip 2 = c to MeOH or CH2Cl2 yc ph N loh yl N TF ex A yl N R1 N 60-67% Yield H R1=Bn,FMOC,CO2Me, NC Alloc, triptophyl t R2= -Bu, cyclohexyl, 2,6-di-methyl-phenyl HN O 84% 3:1 trans:cis
Stabilized intermediate: R2N O NH
N
R1
Scheme 1.10 Effective addition of iso-cyanides to nicotinamides as an efficient entry to substituted nicotinonitrile compounds
A variety of other carbanion sources (e.g. enolates, malonates, and nitro-alkanes) have been employed in addition reactions with quaternary pyridinium salts. This chemistry has been reviewed up to 1982.19b,c Interestingly, these reactions were not commonly used for the synthesis of target structures until the late 1980’s. It has since become a general route to many bio-active molecules.19a,35 Some examples of these are shown below.
13 Wenkert and co-workers introduced an efficient protocol for the addition of carbon nucleophiles to pyridinium salts for the synthesis of a variety of indolo-alkaloids in the 1980’s (i.e. the “Wenkert Procedure”).35,36 The procedure typically involves the addition of an indolo-type enolate to an N-alkyl pyridinium salt, followed by an intramolecular cyclization on the resulting dihydropyridine. A representative example is shown in Scheme 1.11 for the synthesis of geissoschizine.37
SPh
SPh Br N N N LDA
N O
O CO2Me CO2Me
TsOH-C6H6 LiI SPh
N H N N H H N H O MeO2C OH H (+/-) - geissoschizine CO2Me
Scheme 1.11 Synthesis of the indolo-alkaloid geissoschizine using the “Wenkert procedure”37
Simple variation of the indole enolate and the pyridinium salt led to the discovery that a number of other indole-type alkaloid skeletons can be constructed (Scheme 1.12),35a where the first step is always the regioselective 1,4-addition of the indole enolate to the N-alkyl pyridinium salt. The convergent nature of these approaches, as well as the relative ease of diversification of the starting materials, make these attractive synthetic strategies to these heterocycle cores. This protocol was used to synthesize a number of
14 complex bio-active molecules, including akagerine,37 camptothecin,38 ervitsine,39 and vinoxine.40
N N
N N N N
C-Mavacurine Alkaloids Strychnos Alkaloids Akuammiline group Alkaloids
Y Y
3 CO2Me 3 1 N X 2 N 2 3 N N X N N 2 X R MeO2C R 1 1 MeO2C Y
Scheme 1.12 Strategies to access highly complex indolo-alkaloid skeletons using pyridinium salts34a
In addition to these examples, use of a chiral enolate resulted in the synthesis of the enantio-enriched indole alkaloid products (-)-isovallesiachotamine and (+)- vallesiachotamine.41 Conversely, enantioselective products can also be obtained when the pyridinium salt employed contains a chiral auxiliary, as in the case of the synthesis of (-)-N-methylervitsine.42 These examples are summarized in Scheme 1.13.
15 Chiral enolate route to (-)-isovallesiachotamine:
O N Br CO2Me OO H O HN N N H H
t CO2 Bu
Chiral pyridinium salt route to (-)-N-methylervitsine:
MeN I Me N H H
N N O N O Me Me O MeO Scheme 1.13 Examples of chiral indolo-alkaloid synthesis via pyridinium salt additions
The addition of simple enolates to pyridinium salts can also lead to interesting products outside of the indole alkaloids set. When titanium enolates are added to a mixture of pyridine and phenyl chloroformate, a mixture of 1,2- and 1,4-isomers is obtained.43 Treatment of these purified product(s) with elemental sulfur and catalytic Pd/C leads to decomposition of the 1,2-isomer, and exclusive isolation of the aromatic 4- (2-oxo-alkyl)-pyridines from the mixture (Scheme 1.14).
O O R 1 R2 R R1 R2 R O R R1 OTi S8 R R2 5% Pd/C H R2 N 0 Napthalene N THF, -78 C R N 1 32-71% N 52-93% PhO O CO2Ph 1,2-minor isomer PhO O 4-(2-oxo-alkyl)-pyridine 1,4-major isomer
Scheme 1.14 Synthesis of 4-(2-oxo-alkyl)-pyridines by enolate addition to N-acyl pyridinium salts
16 In addition, the Comins group has shown that zinc enolates add with excellent regio- and diastereo-selectivity to pyridinium salts quaternized with the chiral chloroformate (+)-TCC44 (TCC= trans-2-(α-cumyl)-cyclohexyl). These additions are analogous to the related reactions of organometallic reagents developed by the Comins group to chiral pyridinium salts, and are often referred to as the “Comins Protocol” (see Schemes 1.23, 1.27 and 1.28). The utility of this selective enolate addition was applied to the first asymmetric synthesis of (+)-cannabisativine,45 a natural product isolated from the common marijuana plant (Scheme 1.15).
O OMe 1) ClZnO O TIPS TIPS Et H O Et O Cl + Et N N 2) H3O CO R* Et 2 CO2R* O O de > 95% (1) R*= (+)-TCC 85%
10 steps
H H 8steps HO O N H H O BnO N C5H11 OH OMe NH C5H11 O O NH (2) 30% from (1) (+)-cannabisativine 19steps, 9% overall yield
Scheme 1.15 Application of an asymmetric enolate addition to a pyridinium salt: Total synthesis of (+)-cannibativine45
17 There are a few examples in the literature where π-basic nucleophiles (i.e. indoles, pyrroles, imidazoles) can be added to pyridinium salts, although the regioselectivity is poor unless the heterocyclic nucleophile is tethered to the pyridine.46 In a related procedure, the intramolecular attack of an enamide on a pyridinium salt was found to provide a diversifiable method to various indolo-alkaloids.47
Very recently there was an interesting report from the Corey group, on the highly regioselective addition of nucleophilic aromatics to N-triflic pyridinium salts.48 This procedure, outlined in Scheme 1.16, is interesting for a number of reasons. The novel use of triflic anhydride as a pyridine activating agent resulted in a highly electron-poor (electrophilic) pyridinium intermediate in a simple and rapid procedure. The increased reactivity of this compound allowed for a variety of π-basic nucleophiles to be used in this reaction including pyrroles and electron rich aromatics. In addition, this reaction is tolerant of ortho-electron withdrawing groups on the pyridine ring (i.e. 2-bromo- and 2- cyano-pyridines). These are typically unreactive as pyridinium salt precursors, presumably due to the increased steric bulk and lower nucleophilicity of the pyridine. To illustrate the potential advantage of this procedure, a base-mediated aromatization protocol was also developed to allow access to 4-substituted aromatic pyridines.
18 N Me N N Tf 38% Tf
Me O R Pyrrole R 0 CH2Cl2,-30C Indole or Tf N NMe2 5mins Anisoyl Tf 2O N R N OTf Tf R=H,2-Me,3-Me,2-CN,2-Br,2-OMe,3-CO2Me 57-86%
TfN NMe
84%
TfN NMe NNMe
t-BuOK MeO DMSO MeO rm. temp., 30mins 100% NMe Tf N 2 N NMe2
R R
Scheme 1.16 Addition of π-basic aromatics to pyridines activated with triflic anhydride and its application to the synthesis of 4-aryl-substituted pyridines48
1.4 Organometallic Nucleophile Addition
Electrophilic pyridinium salts undergo addition with a variety of nucleophiles, however, the most common route to their functionalization probably involves reaction with organometallic reagents. Of the many organometallic reagents that can effectively add to pyridinium salts, the use of Grignard reagents are perhaps the most common. This is likely due to their ease of preparation, commercial availability, and the range of transferable organic groups available.
19 Prior to their reaction with pyridinium salts, it was found that phenyl-Grignard reagents underwent a direct, regioselective nucleophilic aromatic substitution with pyridine at low temperature. This coupling is presumed to go through an intermediate nitrogen bound Mg dihydropyridine adduct, which oxidizes upon isolation (Scheme 1.17). The same results can also be obtained when phenyl-lithium is added directly to pyridine. However, this reaction works poorly for other organo-lithium and –magnesium reagents, and is not functional group tolerant.5
+ M-Phenyl H or air -780C; THF N NPh N Ph M= Mg, Li M
(Not isolated)
Scheme 1.17 Direct addition of phenyl-magnesium bromide or phenyl-lithium to pyridine
In early attempts to increase the efficiency and utility of this reaction, it was found that addition of an acyl halide (i.e. chloroformate or acid chloride) to pyridines, forming an N-acyl pyridinium salt, followed by Grignard addition led to the formation of 1,2-dihydropyridine derivatives (Scheme 1.18).49,50 These early addition reports were regioselective because the 4-position was blocked by using a 4-substituted pyridine. Treating these dihydropyridines with elemental sulfur provided access to 2,4-di- substituted pyridines.49d
Me Me Me
Me Me Me ArMgBr S8, reflux Cl N Ar N Ar N
27-56% Yield RO O RO O
Scheme 1.18 Aryl Grignard addition to N-acyl salts of 3,4-lutidine for the regioselective synthesis of substituted pyridines
20 In contrast to the above studies, the regioselective 1,4-addition of Grignard reagents can be obtained with pyridines quaternized as N-(2,6-dimethyl-4-oxopyridin-1- yl) salts. This bulky N-substituent blocks the ortho positions of the pyridine ring, allowing the exclusive addition of the organo-magnesium to the 4-position.51 The resulting 1,4-dihydropyridines were too unstable to characterize, but the corresponding aromatic 4-substituted pyridines could be obtained and characterized by heating the crude intermediate in air (Scheme 1.19).
R1 1 R R R R
BF4 N N R1MgX N MeN Me MeN Me R= H, 2-Me, 3-Me R1=Et,i-Pr, n-Bu, Bn,Ar 20-90% O O
(Not purified)
Scheme 1.19 Regioselective 1,4-addition of a Grignard reagent in the synthesis of 4- substituted pyridines using the quaternization agent to block the ortho positions
A more detailed investigation on the interaction of Grignard reagents and N-acyl pyridinium salts shortly after the above example showed that these compounds did favour addition to the 2-position, even when the 4-position isn’t blocked, but that a mixture of 1,2- and 1,4-regioisomers was common. 52 Specifically, very poor regio-specificity was observed when alkyl Grignards were used. This study did find, however, that adding a catalytic amount of copper (I) iodide to the reaction mixture resulted in almost exclusive 1,4-addition of alkyl and aryl Grignards (Scheme 1.20). This procedure is a significant improvement over the Sammes protocol50 (Scheme 1.19) in its efficiency and simplicity, and was also amenable to the isolation of 4-substituted pyridines when the addition products were refluxed with sulfur. In addition to the aromatic pyridines, this study also
21 showed that catalytic reduction of the dihydropyridine mixtures could yield the substituted piperidines.
R2 2 R 1 R R 1 1 1 R R R1
2 , Pd/C R MgX H2 N R2 2 N N N R N Cl CO2R CO2R CO2R CO2R CO2R (1) (2) (Not separated) 56-82% Combined Yield R2= Aryl 93:7 (1):(2) R2=Alkyl 1:1 2:1 (1):(2)
R1 R
+ trace 1,2 < 5% 2 1 R x R eflu N R1 R , r 1 S 8 27-77% Isolated Yield R2MgX N 5% CuI Cl N R2 N H R2 2 , P CO2R d/ C R1 CO2R CO2R (Not separated) +trace1,2<5% N
CO2R 30-79% Combined Yield
Scheme 1.20 Addition of Grignards to N-acyl pyridinium salts and the effect of catalytic copper (I) iodide towards the isolation of piperidines and pyridines52
Although 4-substituted pyridines can be effectively prepared using this copper catalyzed Grignard addition to pyridinium salts and tandem oxidation protocol (Scheme 1.20), the preparation of the 2-substituted regioisomer pyridines was restricted to the harsh direct addition of organometallic reagents to pyridine (Scheme 1.17), or by using blocking groups (Scheme 1.18).
An exception to these examples involves the use of pyridine N-oxides in an interesting one-pot procedure.53 Pyridine N-oxides can react with chloroformates to give N-alkoxycarboxy pyridinium salts which rearrange spontaneously after addition of
22 Grignard reagents to yield 2-substituted pyridines (Scheme 1.21). The driving force for these reactions is proposed to be the formation of an alkylcarbonic acid. While some 4- addition most likely occurs in these reactions, the resulting 1,4-dihydropyridine is not arranged properly to allow for this favourable rearrangement. A few other examples of this reaction with other organometallic agents (e.g. organo-zincs and silver-acetylides) have also been reported.54 At a time when palladium catalyzed cross-coupling reactions were not fully developed as mild and versatile methods to construct substituted pyridines, these syntheses represented simple and relatively general routes to these important compounds.20
R1
N
OCO2R R1MgX RCO 2Cl (Not isolated) N N Cl
O OCO2R R1 N H O O
RO O
RO OH
N R1 R1= alkyl, vinyl, aryl, alkynyl 41-85%
Scheme 1.21 Grignard additions to N-alkoxycarboxy pyridinium chlorides as a method for the synthesis of 2-substituted pyridines
The first application of the addition of organometallic reagents to pyridinium salts for natural product synthesis came from Yamaguchi and co-workers, in the total synthesis of piperidine alkaloids (+/-)-solenopsin A and (+/-)-monomorine.55 Both syntheses were
23 extremely short, and were based on the group’s findings that alkynyl Grignards add almost exclusively to the 2-position of an N-acyl pyridinium salt in the absence of catalytic copper salts. Simple metal catalyzed hydrogenation then gave the piperidine core skeleton. In the case of monomorine, just two more short steps resulted in the isolation of the natural product in 32% overall yield (Scheme 1.22).55b
BrMg O
O H2,Pt-C/MeOH Me N Me N Me N TH F Cl OO CO2Me CO2Me CO2Me O O
2steps
Me N
Bu (+/-)-monomorine 5steps 32%overall
Scheme 1.22 Regioselective α-addition of an alkynyl-Grignard to an N-acyl pyridinium salt and application to the synthesis of the piperidine alkaloid (+/-)- monomorine
A useful development for the synthesis of natural products via addition of organometallic reagents to pyridinium salts was developed in the late 1980’s and early 1990’s by Comins and co-workers. They discovered that the addition of Grignard reagents to 4-methoxy-N-acyl pyridinium salts, followed by treatment with acid, provided a straightforward route to substituted 4-pyridones (Scheme 1.23).11a These structures could then be easily manipulated into highly substituted products with good stereo- and regio-control. This method was then applied to the racemic synthesis of some indolizidine, quinolizidine, and piperidine alkaloids.56
24 OMe R
N
1) R1CO2Cl 2) R2-M + 3) H3O
O R O O R R
R2 N R3 R2 N R2 N CO2R1 CO2R1 CO2R1
O R3 R R3 4
R2 N R2 N
OH O CO2R1 CO2R1 R R R3
R2 N R2 N
CO2R1 CO2R1
Scheme 1.23 General manipulations of the 4-pyridone resulting from organometallic addition to an N-acyl-4-methoxy-pyridinium salt11a
These reports by Comins and Yamaguchi represented new synthetic strategies for the construction of biologically active piperidines and related alkaloids using organometallic reagents in additions to activated pyridiniums. A number of examples of using Grignard reagents in additions to pyridinium salts to make bio-active or structurally interesting compounds have since been reported.57,58 Other organometallic species have been similarly used to prepare dihydropyridine intermediates including organo-zincs,59 organo-cuprates,60 and others.61
While very effective, Grignard reagents are often not compatible with acidic or electrophilic functional groups. Thus, protected forms of these units are typically
25 employed in Grignard addition to pyridinium salts.11a In contrast, organotin compounds are more functional group compatible, and have been found to react with N-acyl pyridinium salts. However, these reactions are limited to benzyl, allyl, or alkynyl group transfer.62 Benzyl-tin addition is 4-selective, and in some cases, 4,4-di-substituted dihydropyridines can be prepared when 4-substituted pyridinium salts are used.62b The addition of allyl- or alkynyl-tin reagents are α-selective, while preferential 4-addition occurred in the case of crotyl- or prenyl-tin reagents.62c,d A short synthesis of the piperidine alkaloid (+/-)-coniine was also accomplished via allyl-tin addition to an N-acyl pyridinium salt (Scheme 1.24).62a
1) H /Pd Bu Sn 2 3 2) TMSI N Cl N N H MeO O MeO O (+/-)-coniine
Scheme 1.24 Application of allyl-tin additions to pyridinium salts towards the synthesis of (+/-)-coniine
1.5 Organometallic Additions to Pyridinium Salts Towards Library Development
Combinatorial chemistry and Diversity Oriented Synthesis (DOS) are two examples of methodologies developed in response to pharmaceutical companies growing need for techniques that increase the speed and efficiency of compound synthesis.63 Crucial to the effectiveness of combinatorial chemistry are reactions that couple more than two reagents together in one-pot, better known as “multicomponent coupling reactions,” from which compound libraries can be constructed. Nucleophilic additions to pyridinium salts involve the one-pot formation of a substituted dihydropyridine from three separate materials, and are therefore multicomponent. Due to the importance of the structures that can be obtained from such additions, there has been some research in using pyridinium additions in solid or solution phase parallel synthesis.
26 As one example, a number of 4-substituted piperidines have been prepared by a solution-phase parallel synthesis method involving the copper-catalyzed regioselective addition of organo-zinc reagents to N-acyl pyridinium salts.64 The dihydropyridine intermediates were first transformed into their N-Boc-protected derivatives, then reduced to the piperidines by an in situ palladium catalyzed transfer hydrogenation (Scheme 1.25).
R R R
PhCO2Cl + - RZnX or R Zn NH4 HCOO 2 KOtBu 5% CuCN*LiBr Pd/C, MeOH N N N N Boc Boc PhO O Overall Yield = 88-93% R = alkyl, aryl
Scheme 1.25 Solution-phase parallel synthesis of some N-tBoc-protected piperidines
Similar studies have also been performed on solid-supports. For example, using a solid-supported chloroformate resin, a method termed Resin Activation/Capture Approach (REACAP) Technology was developed to prepare various dihydropyridines, pyridines, and interesting bicyclic products. This involves the addition of Grignard reagents to polystyrene supported pyridinium salts (Scheme 1.26).65
27 O
R R N R 2 H 1 O O Cl O
O Cl N O N
Polystyrene Resin N R1 R R H
NR1 O R N R1 O O O N N R NR O 2 R Cl O O O Cl O
Polystyrene Resin
N R1
R O
Scheme 1.26 Solid-phase pyridinium salt REACAP approaches to heterocycle synthesis
1.6 Asymmetric Additions to Pyridinium Salts
Section 1.4 showed that the addition of organometallic reagents to pyridinium salts can provide access to interesting complex heterocyclic cores, though in a racemic fashion. Asymmetric organometallic additions to N-quaternized pyridines could therefore provide routes to enantio-pure biologically relevant molecules. One approach could involve the use of stoichiometric chiral chloroformate quaternization agents. For example, Comins has shown that excellent diastereo-selective additions occur using simple chiral cyclohexyl chloroformates in Grignard additions to 4-methoxy-pyridines 66 (Scheme 1.27). Optimized conditions showed that a TIPS (Si(iPr)3) blocking group at position C-3, and trans-α-cumyl-cyclohexanols as the chiral auxiliaries are necessary for good selectivities with a variety of Grignard reagents (e.g. alkyl-, aryl-, vinyl-, and
28 alkynyl-magnesiums). While the original reaction used only Grignard reagents as the nucleophile, other organometallic compounds were also found to be selective, efficient coupling partners (i.e. organo-cuprates or organo-zincs).
OH Ph
O OMe 1) R*COCl i Si(Pr)3 2) R -MgX i 2 Si(Pr)3 + 8-phenylmenthol 3) H3O R* = R2 N or N *R O OH Ph d.e. = 60-94% Yield = 66-88%
trans-α-cumyl-cyclohexanol
Scheme 1.27 Diastereoselective Grignard addition to 3-TIPS-4-methoxy-pyridine using chiral cyclohexyl chloroformates
A detailed investigation of this system revealed that the face-selective addition was most likely due to a π-stack complex between the charged pyridinium and the phenyl of the cumyl group on the auxiliary. This effectively blocks one face of the pyridinium salt,66b allowing for selective addition on the opposite face. It was also found that the chloroformate derived from trans-α-cumyl-cyclohexanol (TCC) was the simplest to prepare and resolve, and has since been the auxiliary of choice for this reaction.66c The combined asymmetric control of the addition, and straightforward manipulations of the products (Scheme 1.23), has since allowed for the enantio-pure synthesis of a variety of alkaloids and bio-active products (Scheme 1.28).11a,66b,67,68 This convergent strategy is now commonly referred to as the “Comins Protocol”, and remains an important route to heterocyclic structures.
29 OH O HO OH OH H O N OH H N N H H O N 1-deoxynojirimycin O O (+)-streptazolin
(+)-hyperaspine
N
OH OMe O N H (-)-porantheridine Si(iPr)3 perhydrohistrionicotoxin
N O OH CO2R*
OH
OH N
N (+)-elaeokinine OH O (+)-allopumillotoxin 267A H N
H N Me (+)-luciduline plumerinine
Scheme 1.28 Representative natural products synthesized using the “Comins Protocol”
Recently, the Charette group has reported that amides in the presence of trifluoromethane-sulfonic acid, can activate pyridine towards an α-selective reaction with a variety of organometallic reagents. This reaction proceeds via the stereoselective formation of (E)-imidate pyridinium salts (Scheme 1.29). Grignard additions to this interesting new pyridinium species gave almost exclusive 1,2-addition even when mixed cuprates were used.69 This unprecedented highly α-selective organometallic addition is presumed to arise from a chelation assisted attack of the nucleophile due to the strong interaction of the metal with the imidate nitrogen lone pair. Aromatic 2-substituted
30 pyridines were also prepared via this site-selective method after treating the purified 69 70d products with either DDQ or a mixture of Mn(OAc) and H5IO6.
O OTf Tf2O, Pyridine N Ph NMe Ph N
Me (E)-imidate-pyridinium ion O
1) Tf2O, R1 NR2 R3 2) R -M 60-96% Yield 3 N N R OTf M 3 >90% 1,2-addition N R1 N R1 N R 2 R2 M = MgBr, Cu/Mg, Zn Proposed coodination assisted R3= alkyl, aryl, heteroaryl, alkynyl, vinyl regioselectiveaddition
Scheme 1.29 Regioselective organometallic 1,2-addition to unsubstituted N-imidate pyridinium salts
Considering the large chiral pool of amides available, this site-selective addition can also be performed with asymmetric induction. In particular, the use of a chiral (E)- imidate derived from (S)-Valinol leads to excellent regio- and diastereo-control.69 This method has since been used by Charette to prepare synthetic drug candidates and other interesting heterocyclic cores using organometallic additions (Scheme 1.30).69,70 The straightforward preparation of the chiral activator auxiliary, and the high selectivities observed even when ring-unsubstituted pyridinium salts are used, makes this a very attractive approach.
31 HO
Me N OH H (+)-Julifloridine
N n-Pr R H 1 (R)-(-)-coniine
R1 CF3 O 1) Tf2O, N
2) R2-M 65-89% Yield Ph NH N R 2 >90:5 dr O
OR CF3 Ph N N Ph OR H (-)-L-733,061 R= Me, Bn
N R HN R NH H R N N (-)-B arrenazines N
Ph tetrahydropyrroloimidazoles
Scheme 1.30 Asymmetric organometallic reagent addition to N-imidate pyridinium salts and application to the chiral synthesis of interesting heterocycles
A number of other related chiral auxiliary approaches have been reported for asymmetric additions to pyridinium salts. These include the use ofN-pyridinium ylides,71 a bicyclic chiral acid chloride,72 or chiral primary amines in the Zincke reaction14,73 (Scheme 1.31). Other examples of asymmetric control in these types of reactions employ pyridines containing a chiral auxiliary at C-3 of the ring. Common chiral inducing groups include oxazolines,74 thiocarbonyls,75 nicotinic amides,76 and aminals77 (Scheme 1.31).
32 Other chiral N-quaternization examples:
Cl N O N Y O N N O R1 H N R2 Chiral Zincke salts O Wanner's chiral acid chloride
N-pyridinium ylides
Pyridine ring C-3 chiral auxiliary examples:
R1 R1 O S N O N R2 N R S N 2
N R N N Thiocarb onyls Aminals Oxazolines
O N
N O N
N Bn O Me O Nicotinic amides
Scheme 1.31 Examples of other chiral pyridines and quaternized pyridines for asymmetric additions to pyrdinium salts
These chiral auxiliary approaches are effective, although they do show certain scope limitations, and of course require the use of a stoichiometric amount of the auxiliary, which is subsequently removed. While a catalytic enantioselective approach to pyridinium salt addition would be more efficient, only recently have these been reported. Examples most commonly involve additions to related quinoline and isoquinolinium salts, including the catalytic asymmetric addition of organolithium reagents,78 nitriles30,79 (Scheme 1.8), silyl-ketene acetals,80 and a copper-catalyzed alkynylation81 (Scheme 1.32). Thus far, however, there is only the one known catalytic enantioselective addition
33 to a pyridinium salt involving the lewis-acid and lewis-base bi-functional catalyzed cyanide addition previously mentioned in this chapter (Scheme 1.9).31
Asymmetric Organo-lithium addition to quinolinium salts catalyzed by (-)-sparteine:
1) RLi, L* * N 2) ClCO2Me N R
CO2Me R= Me, n-B u, Ph 62-79% ee Et Et L*= O O N or N N N (-)-sparteine Pri iPr Enantioselective thiourea-catalyzed acyl mannich reaction of isoquinoline:
Catalyst: R R 0 1) TrocCl, Et2O0-23 C tBu S N N 2) 2eq. OTBS Tro c But2N N N i H2C O Pr H H CO2iPr 10% Catalyst, Et O-780C O N 2 67-86% Yield, 60-92% ee Me Ph
Copper-catalyzed enantioselective alkyne addition to an isoquinolinium salt:
OMe OMe Br 10eq. HTMS N 5% CuBr, 5.5% QUINAP N MeO MeO 0 1eq. Et3N, CH2Cl2,-55 C
Br Br Q UINAP: TMS N 67% Yield, 83% ee
PPh2
Scheme 1.32 Examples of catalytic enantioselective additions to salts of quinoline and isoquinoline
34 1.7 Conclusion and Overview of Thesis
This chapter has illustrated that the addition of nucleophiles to pyridinium salts can be a powerful synthetic strategy for heterocycle synthesis. The robust nature of this chemistry in terms of the quaternization agent (or method), pyridines employed, broad nucleophile choice, and subsequent transformations possible, have all made this an important method to prepare complex natural products and bio-active compounds. However, while stoichiometric organometallic reagents are perhaps the most common nucleophiles employed in these types of reactions, they are not always compatible with common functional groups. For example, Grignard reagents are capable of transferring a number of organic units but are not compatible with alcohol or aldehyde containing pyridinium salts.11a
One alternative to the use of strong stoichiometric organometallic reagents would be to use mild, metal catalyzed addition routes. While catalytic addition of copper salts with organometallic reagents, such as Grignards and organo-zincs, in pyridinium salt additions allows for preferential 1,4-regio-control, these still rely on using a stoichiometric amount ofreactive organometallic compound limiting compatibility. The Arndtsen lab has previously developed mild, and general, copper-catalyzed addition routes to highly functionalized α-substituted amides. These reactions involve the coupling of simple organic (e.g. terminal alkynes82), or mild organometallic (e.g. organostannane 83 or organoindium84) nucleophiles with reactive N-acyl iminium salts in the presence of a simple copper(I) salt catalyst (Scheme 1.33).
O O
R1 HR4 R1 R1 N O R N R N or 10% Cu 3 3 or Bu3Sn R4 rm. temp. 450C R Cl or R2 H 3 R2 R2 R4 1/3 In(R4)3 20 mins 72hrs H H R4
Scheme 1.33 Arndtsen lab copper-catalyzed one-pot multicomponent routes to highly functionalized α-substituted amides
35 These reactions possess good functional group compatibility and give high yields of product under mild conditions without the need to use strong stoichiometric organometallic reagents. Considering that aromatic azine heterocycles such as pyridine contain an unsaturated imine C=N unit, this thesis will attempt to develop similar mild, and simple, copper-catalyzed methods of pyridine functionalization via easily prepared N-acyl pyridinium salts.
1.8 References
1 Sainsbury, Malcolm; Heterocyclic Chemistry, Wiley-Interscience, New York, 2002. 2 Henry, Gavin D.; Tetrahedron 2004, 60, 6043. 3 Higashio, Y., Shoji, T.; Appl. Catal. A 2004, 260, 251. 4 a) Roth, H. J., Kleemann, A.; Pharmaceutical Chemistry. Drug Synthesis; Prentice Hall Europe, London, 1988, Vol. 1, p 407. b) MDDR: MDL Drug Data Registry, by MDL Informations Systems, Inc; San Leandro, California, USA. 5 a) Eicher, T., Hauptmann, S.; The Chemistry of Heterocycles, Wiley-VCH Weinheim, Ger., 2003; b) Joule, J.A., Mills, K.; Heterocyclic Chemistry, Blackwell Science, Oxford UK, 2000. 6 a) For a review on Construction of Pyridine Rings by Metal-Mediated [2+2+2] Cycloadditions see: Varela, J., Saa, C.; Chem. Rev. 2003, 103, 3787. b) for an example of another metal catalyzed cyclization strategy to pyridines and related structures via aza- zirconacycles see: Takahashi, T.; J. Am. Chem. Soc. 2002, 124, 5059. 7 For a review of directed metalation as a strategy for the functionalization of pyridines, quinolines, and diazines see: Queguiner, G., Marsais, F., Snieckus, V., Epsztajn, J.; Advances in Heterocyclic Chemistry 1991, 52, 187. 8 Diederich, F., Stang, P.; Metal Catalyzed Cross-Coupling Reactions; Wiley-VCH: New York, 1998. 9 Campeau, L-C., Rousseaux, S., Fagnou, K.; J. Am. Chem. Soc. 2005, 127, 18020-18021. 10 For reviews on the chemistry ofN-substituted pyridinium salts see: a) Sliwa, W.; Curr. Org. Chem. 2003, 7, 995. b) Sliwa, W.; Heterocycles 1989, 29, 557. c) Sliwa, W.; Heterocycles 1986, 24, 181.
36 11 a) For a review on using N-acyl pyridinium salts for the synthesis of alkaloids see: Comins, D.L., Joseph, S.; Advances in Nitrogen Heterocycles 1996, 2, 251. and for more recent accounts: b) Bates, R.W., Kanicha, S.E.; Tetrahedron 2002, 58, 5957. c) Buffat, M.; Tetrahedron 2004, 60, 1701. 12 Krygowski, T.M.; J. Org. Chem. 2005, 70, 8859. 13 Brown, H.C., Cahn, A.; J. Am. Chem. Soc. 1955, 77, 1715. 14 Zincke, Th.; Justus Liebigs Ann. Chem. 1903, 330, 361.
15 (a) Kunugi, S., Okubo, T., Ise, N.; J. Am. Chem. Soc. 1976, 98, 2282. b) Marvell, E. N., Caple, G., Shahidi, I.; J. Am. Chem. Soc. 1970, 92, 5641. c) Marvell, E. N., Shahidi, I.; J. Am. Chem. Soc. 1970, 92, 5646. 16 a) Genisson, Y., Marazano, C., Mehmandoust, M., Gnecco, D., Das, B.C.; Synlett 1992, 431. b) Wong, Y-S., Marazano, C., Gnecco, D., Genisson, Y., Chiaroni, A., Das, B.C.; J. Org. Chem. 1997, 62, 729. c) Guilloteau-Bertin, B., Compere, D., Gil, L., Marazano, C., Das, B.C.; Eur. J. Org. Chem. 2000, 1391-1399. d) dos Santos, D.C., de Freitas-Gil, R.P., Gil, L., Marazano, C.; Tetrahedron Lett. 2001, 42, 6109. e) Viana, G.H.R., Santos, I.C., Alves, R.B., Gil, L., Marazano, C., Gil, R.P.F.; Tetrahedron Lett. 2005, 46, 7773. 17 a) Sliwa, W., Matusiak, G.; Heterocycles 1985, 23, 1513. and references therein. b) Katritzky, A. R.; Tetrahedron 1980, 36, 679. 18 a) Shinkai, S., Tsuno, T., Manabe, O.; J. Chem. Soc., Perkins Trans. II 1984, 661. b) for an interesting recent example see: Zhou, X., Kovalev, E., Klug, J., Khodorkovsky, V.; Org. Lett. 2001, 3, 1725. 19 For reviews on the chemistry of dihydropyridines including their synthesis from nucleophilic additions to pyridinium salts see: a) Lavilla, R.; J. Chem. Soc., Perkin Trans. 1, 2002, 1141–1156. b) Meyers, A.I., Stout, D.; Chem.Rev. 1982, 82, 223-243. c) Eisner, U., Kuthan, J.; Chem. Rev. 1972, 72, 1-42; and for a recent account of their use in tetrahydroquinoline syntheses: d) Lavilla, R., Carranco, I., Luis Diaz, J., Bernabeu, M.C., de la Rosa, G.; Molec. Div. 2003, 6, 171–175. 20 For a review on regioselective substitution in aromatic six-membered nitrogen heterocycles including a section on the regioselective synthesis of pyridines via
37 nucleophilic additions to pyridinium salts see: Comins, D.L., O’Connor, S.; Adv. in Het. Chem. 1988, 44, 199. 21 Kosower, E.M., Klinedienst; J. Amer. Chem. Soc. 1956, 78, 3497. 22 a) Lyle, R.E., Gauthier, G.J.; Tetrahedron Lett. 1965, 4615. b) Yamaguchi, R., Mochizuki, K., Kozima, S., Takaya, H.; J. Chem. Soc. Chem. Comm. 1993, No. 12, 981. 23 Hofmann, A.W.; Ber., 1881, 14, 1497. 24 a) Decker, H.; Ber. 1892, 25, 3326. b) Decker, H.; Ber., 1903, 36, 2568. 25 a) Damji, S., Fyfe, C.A.; J. Org. Chem. 1979, 44, 1757. b) Speelman, J.C., Kellogg, R.M.; J. Org. Chem. 1990, 55, 647. 26 a) “Reissert compounds,” Popp, F.D., Adv. Heterocycl. Chem., 1968, 9, 1. b) “Developments in the chemistry of Reissert compounds (1968-1978),” Adv. Heterocycl. Chem., 1979, 24, 187. and references therein. 27 For a solid-phase example giving access to substituted isoquinolines see: Lorsback, B., Miller, R.B., Kurth, M.; J. Org. Chem. 1996, 61, 8716-8717. 28 Popp, F.D., Takeuchi, I., Kant, J., Hamada, Y.; J. Chem. Soc., Chem. Comm., 1987, 1765. and references therein.
29 a) Eisner, U., Kuthan, J.; Chem. Rev. 1972, 72, 1-42 and references therein. b) Duarte, F.F., Popp, F.D., Holder, A.J.; J. Heterocycl. Chem., 1993, 30(4), 893. c) Reuss., R.H., Smith, N.G., Winters, L.J.; J. Org. Chem., 1974, 39, 2027. 30 Takamura, M., Funabashi, K., Kanai, M., Shibasaki, M.; J. Am. Chem. Soc. 2001, 123, 6801-6808. 31 Ichikawa, E., Suzuki, M., Yabu, K., Albert, M., Kanai, M., Shibasaki, M.; J. Am.
Chem. Soc. 2004, 126, 11808-11809. 32 a) Diaz, J.L., Miguel, M., Lavilla, R.; J. Org. Chem. 2004, 69, 3550-3553. b) Ugi, I., Bottner, E.; Liebigs Ann. Chem. 1963, 670, 74. 33 Williams, N.O., Masdeu, C., Diaz, J.L., Lavilla, R.; Org. Lett. 2006, ASAP, published on web. 34 Isocyanides have been added to N-flouropyridinium fluoride salts as a route to 2- picolinamides: Kiselyov, A.S.; Tetrahedron Lett. 2005, 46, 2279.
38 35 For reviews on the “Wenkert Procedure” applied to pyridinium salts see: a) Bosch, J., Bennasar, M.L.; Synlett 1995, 587. b) Bosch, J., Bennasar, M.L., Amat, M.; Pure Appl. Chem. 1996, 68, 557. 36 a) Wenkert, E.; Pure Appl. Chem. 1981, 53, 1271. b) Wenkert, E., Guo, M., Pestchanker, M.J., Shi, Y-J, Jankar, Y.D.; J. Org. Chem. 1989, 54, 1166 and references therein. 37 Bennasar, M.-L., Jimenez, B., Vidal, B., Sufi, B.A., Bosch, J.; J. Org. Chem. 1999, 64, 9605. 38 Bennasar, M.-L., Juan, C., Bosch, J.; Chem. Comm. 2000, 2459. 39 a) Bennasar, M.-L., Vidal, B., Bosch, J.; J. Org. Chem. 1997, 62, 3597. b) Bennasar, M.-L., Vidal, B., Kumar, R., Lazaro, A., Bosch, J.; Eur. J. Org. Chem. 2000, 3919. 40 a) Bosch, J., Bennasar, M.-L., Zulaica, E., Feliz, M.; Tetrahedron Lett. 1984, 25, 3119. b) Bennasar, M.-L., Alvarez, M., Lavilla, R., Zulaica, E., Bosch, J.; J. Org. Chem. 1990, 55, 1156. 41 Amann, R., Arnold, K., Spitzner, D., Majer, Z., Snatzke, G.; Liebigs Ann. 1996, 349. 42 Bennasar, M.-L., Zulaica, E., Alonso, Y., Mata, I., Molins, E., Bosch, J.; Chem. Comm. 2001, 1166. 43 Comins, D.L., Brown, J.; Tetrahedron Lett. 1984, 25, 3297. 44 a) Comins, D.L., Kuethe, J.T., Hong, H., Lakner, F., Concolino, T.E., Rheingold, A.L.; J. Amer. Chem Soc. 1999, 121, 2651. b) Comins, D.L., Hong, H.J.; J. Org. Chem. 1993, 58, 5035. c) Comins, D.L., Hong, H.J.; J. Amer. Chem. Soc. 1993, 115, 8851. 45 a) Kuethe, J.T., Comins, D.L.; J. Org. Chem. 2004, 69, 5219. b) Kuethe, J.T., Comins, D.L.; Org. Lett. 2000, 2, 855. 46 a) Lavilla, R., Gotsens, T., Guerrero, M., Masdeu, C., Santano, M.C., Minguillon, C., Bosch, J.; Tetrahedron 1997, 53, 13959. b) Lavilla, R., Gotsens, T., Gavalda, J.M., Santano, M.C., Bosch, J.; J. Chem. Res. (S) 1996, 380. c) Winter, J., Retey, J.; Chem. Eur. J. 1997, 3, 410. 47 Lavilla, R., Gullon, F., Bosch, J.; Eur. J. Org. Chem. 1998, 373. 48 Corey, E.J., Tian, Y.; Org. Lett. 2005, 7, 5535.
39 49 a) Eddy, N.B., Murphy, J.G., May, E.L.; J. Org. Chem. 1957, 22, 1370. b) Fraenkel, G., Cooper, J.W., Fink, C.M.; Angew. Chem. Int. Ed. Engl. 1970, 9, 523. c) Lyle, R.E., Marshall, J.L., Comins, D.L.; Tetrahedron Lett. 1977, 18, 1015. d) Lyle, R.E., Comins, D.L.; J. Org. Chem. 1976, 41, 3250. 50 Comins, D.L., Mantlo, N.B.; J. Org. Chem. 1985, 50, 4410. 51 Katritzky, A.R., Beltrami, H., Sammes, M.P.; J. Chem. Soc. Perk. Trans. (1) 1980, 2480. 52 Comins, D.L., Abdullah, A.H.; J. Org. Chem. 1982, 47, 4315. 53 Webb, Thomas; Tetrahedron Lett. 1985, 26, 3191. 54 a) Al-Arnout, A., Courtois, G., Miginiac, L.; J. Organomet. Chem. 1987, 139. b) Nishiwaki, N., Minakata, S., Komatsu, M., Ohshiro, Y.; Chem. Lett. 1989, 773. 55 a) Synthesis of (+/-)-solenopsin see: Nakazono, Y., Yamaguchi, R., Kawinisi, M.; Chem. Lett. 1984, 7, 1129. b) for the synthesis of (+/-)-monomorine see: Yamaguchi, R., Hata, E.-I., Matsuki, T., Kawanisi, M.; J. Org. Chem. 1987, 52, 2094. c) for a review of both syntheses in detail and some of the groups other Grignard addition work see: Yamaguchi, R., Matsuki, Y., Hata, E.-I., Kawanisi, M.; Bull. Chem. Soc. Jpn. 1987, 60, 215. 56 Comins, D.L., Joseph, S.P., Goehring, R.R.; J. Am. Chem. Soc. 1994, 116, 4719 and references therein. 57 a) Guilloteau-Bertin, B., Compere, D., Gil, L., Marazano, C., Das, B.C.; Eur. J. Org. Chem. 2000, 1391. b) Barbier, D., Marazano, C., Riche, C., Das, B.C., Poitier, P.; J. Org. Chem. 1998, 63, 1767. c) Ohno, A., Oda, S., Yamazaki, N.; Tetrahedron Lett. 2001, 42, 399. 58 Pabel, J., Hofman, G., Wanner, K.T.; Bioorg. Med. Chem. Lett. 2000, 10, 1377. 59 a) Krapcho, A.P., Waterhouse, D.J.; Heterocycles 1999, 51, 737. b) mixed zinc-copper: Le Gall, E., Gosmini, C., Nedelec, J-Y., Perichon, J.; Tetrahedron 2001, 57, 1923. 60 a) Bennasar, M.L., Juan, C., Bosch, J.; Tetrahedron Lett. 1998, 39, 9275. b) Bennasar, M.L., Juan, C., Bosch, J.; Tetrahedron Lett. 2001, 42, 585. c) Shih, K-S., Liu, C.W., Hsieh, Y-J., Chen, S-F., Ku, H., Liu, L.T., Lin, Y-C., Huang, H-L., Wang, C-L.; Heterocycles 1999, 51, 2439.
40 61 a) For an organo-titanium example: Gundersen, L-L., Rise, F., Undheim, K.; Tetrahedron 1992, 48, 5647. b) An indium mediated allylation and synthesis of (+/-)- dihydropinidine: Loh, T-P., Lye, P-L., Wang, R-B., Sim, K-Y.; Tetrahedron Lett. 2000, 41, 7779. c) for an organo-cadmium example see ref. 52. 62 a) Yamaguchi, R., Moriyasu, M., Yoshioka, M., Kawanisi, M.; J. Org. Chem. 1985, 50, 287. b) Yamaguchi, R., Moriyasu, M., Kawanisi, M.; Tetrahedron Lett. 1986, 27, 211. c) Yamaguchi, R., Hata, E-I., Utimoto, K.; Tetrahedron Lett. 1988, 29, 1785. d) Yamaguchi, R., Moriyasu, M., Yoshioka, M., Kawinisi, M.; J. Org. Chem. 1988, 53, 3507. 63 Armstrong, R., Combs, A., Tempest, P., Brown, D., Keating, T.; Acc. Chem. Res. 1996, 29, 123-131. 64 Wang, X., Kauppi, A.M., Olsson, R., Almqvist, F.; Eur. J. Org. Chem. 2003, 4586. 65 a) Chen, C., Munoz, B.; Tetrahedron Lett. 1998, 39, 3401. b) Chen, C., McDonald, I.A., Munoz, B.; Tetrahedron Lett. 1998, 39, 217. c) Chen, C., Wang, B., Munoz, B.; Synlett 2003, 2404. d) Chen, C., Munoz, B.; Tetrahedron Lett. 1998, 39, 6781. e) Chen, C., Munoz, B.; Tetrahedron Lett. 1999, 40, 3491. 66 a) Comins, D.L, Guerra-Weltzien, L.; Tetrahedron Lett. 1996, 37, 3807. b) Comins, D.L., Joseph, S.P., Goehring, R.R.; J. Am. Chem. Soc. 1994, 116, 4719 and references therein. c) Comins, D.L., Salvador, J.M.; J. Org. Chem. 1993, 58, 4656. 67 For specific reviews of the synthetic utlity of asymmetric additions to 3-TIPS-4- methoxy-pyridines see: a) Joseph, S., Comins, D.L.; Curr. Opin. Drug Disc. 2002, 5, 870. b) Comins, D.L.; J. Heterocyclic Chem. 1999, 36, 1491. 68 For recent examples from Scheme 1.29 that weren’t reviewed: a) (+)-hyperaspine synthesis; Comins, D.L., Sahn, J.J.; Org. Lett. 2005, 7, 5227. b) plumerinine synthesis; Comins, D.L., Zheng, X., Goehring, R.R.; Org. Lett. 2002, 4, 1611. 69 Charette, A.B., Grenon, M., Lemire, A., Pourashraf, M., Martel, J.; J. Am. Chem Soc. 2001, 123, 11829. 70 a) Focker, T., Charette, A.B.; Org. Lett. 2006, 8, 2985. b) Lemire, A., Charette, A.B.; Org. Lett. 2005, 7, 2747. c) Lemire, A., Beaudoin, D., Grenon, M., Charette, A.B.; J.
41 Org. Chem. 2005, 70, 2368. d) Lemire, A., Grenon, M., Pourashraf, M., Charette, A.B.; Org. Lett. 2004, 6, 3517. 71 Legault, C., Charette, A.B.; J. Am. Chem. Soc. 2003, 125, 6360. 72 Hoesl, C.E., Maurus, M., Pabel, J., Polborn, K., Wanner, K.T.; Tetrahedron 2002, 58, 6757. 73 a) Guilloteau-Bertin, B., Compere, D., Gil, L., Marazano, C., Das, B.C.; Eur. J. Org. Chem. 2000, 1391. and references therein. b) Genisson, Y., Marazano, C., Das, B.C.; J. Org. Chem. 1993, 58, 2052. 74 a) Meyers, A.I., Natale, N.R., Wettlaufer, D.G.; Tetrahedron Lett. 1981, 22, 5123. b) Meyers, A.I., Oppenlaender, T.; J. Chem. Soc. Chem. Comm. 1986, 920. c) Meyers, A.I., Oppenlaender, T.; J. Am. Chem. Soc. 1986, 108, 1989. 75 Yamada, S., Misono, T., Ichikawa, M., Morita, C.; Tetrahedron 2001, 57, 8939. 76 a) Bennasar, M.-L., Zulaica, E., Alonso, Y., Bosch, J.; Tetrahedron: Asymm. 2003, 14, 469. b) Yamada, S., Morita, C.; J. Am. Chem. Soc. 2002, 124, 8184. 77 a) Gosmini, R., Mangeney, P., Alexakis, A., Commercon, M., Normant, J.-F.; Synlett 1991, 111. b) Mangeney, P., Gosmini, R., Raussous, S., Commercon, M., Alexakis, A.; J. Org. Chem. 1994, 59, 1877. 78 a) Amiot, F., Cointeaux, L., Silve, E.J., Alexakis, A.; Tetrahedron 2004, 60, 8221. b) Cointeaux, L., Alexakis, A.; Tetrahedron: Asymm. 2005, 16, 925. 79 a) Takamura, M., Funabashi, K., Kanai, M, Shibasaki, M.; J. Am. Chem. Soc. 2000, 122, 6327. b) Funabashi, K., Ratni, H., Kanai, M., Shibasaki, M.; J. Am. Chem. Soc. 2001, 123, 10784. 80 Taylor, M.S., Tokunaga, N., Jacobsen, E.N.; Angew. Chem. Int. Ed. 2005, 44, 6700. 81 Taylor, A.M., Schreiber, S.L.; Org. Lett. 2006, 8, 143. 82 Black, D.A., Arndtsen, B.A.; Org. Lett. 2004, 6, 1107. 83 Black, D.A., Arndtsen, B.A.; J. Org. Chem. 2005, 70, 5133. 84 Black, D.A., Arndtsen, B.A.; Org. Lett. 2006, 8, 1991.
42 CHAPTER 2
Development of a Copper-Catalyzed Coupling of Pyridines, Alkynes, and Chloroformates
2.0 Preface
A copper-catalyzed method to couple terminal alkynes with pyridines in the presence of an acid chloride (or chloroformate) is described. The reaction is extremely efficient and regioselective, generating the partially reduced N-acyl-2-ethynyl-1,2- dihydropyridine products in ~20 minutes at room temperature. This work is the foundation for the future development for the synthesis of aromatic pyridine derivatives in Chapter 3, as well as successful application to the asymmetric preparation of enantio- enriched dihydropyridine (and dihydroquinoline) products.
2.1 Introduction
Partially reduced dihydropyridine derivatives are useful intermediate structures for a variety of transformations, including the formation of piperidines, pyridines, and complex natural products.1 Perhaps the most common route to prepare these compounds is by nucleophilic addition to N-activated pyridinium salts. While a range of stoichiometric organic and organometallic nucleophiles can be employed in these reactions, problems in functional group compatibility and regioselectivity of the addition can occur.1 Metal-catalyzed addition reactions can provide attractive alternatives to the use of stoichiometric nucleophiles in coupling reactions with electrophiles, especially in terms of reaction scope and the potential for enantio-control. 2 Currently, however, there exist only a few examples of metal catalyzed additions to quaternary pyridinium salts.3 These include the lewis-acid/lewis-base bi-functional catalyzed enantioselective cyanide addition,3a and the iridium or copper-catalyzed addition of alkynes.3b-d
Recently, we have reported that the addition of acid chlorides (or chloroformates) to imines can activate these substrates towards metal catalyzed coupling
43 reactions with a range of substrates (e.g. organostannanes,4 organoindium reagents,5 or terminal alkynes3c) as a versatile route to synthesize functionalized α-substituted amides. In light of the resonance structure similarity between imines and nitrogen-containing heterocycles such as pyridine, we became intrigued with the potential that pyridine itself might participate in similar coupling reactions (Figure 2.1). Described below are our studies towards the design of a copper-catalyzed method to couple pyridine derivatives with chloroformates and alkynes as a mild, and general route to cyclic propargylcarbamates and other functionalized heterocycles.
O O RCl RCl activationR' activation N N RH Catalytic C-C Bond Formation?
Figure 2.1 Imines and pyridine in catalytic carbon-carbon bond formation
2.2 Results and Discussion
Preliminary screening from our initial communication showed that pyridine undergoes a clean copper catalyzed coupling with phenylacetylene and benzoyl chloride to generate 2.1 in good yield (Table 2.1).3c While effective, attempts to couple other terminal alkynes with pyridine in the presence of benzoyl chloride resulted in very poor yields (entry 1b). Low yields were also observed with other metal salts as catalysts (entries 1c, 1d). Considering the electrophilicity of chloroformates, we examined the possibility that they might both interact strongly with pyridine, as well as similarly activate the heterocycle towards reaction. As shown in entries 1g-h, a number of common nitrogen protecting group reagents (Troc-Cl, Fmoc-Cl) can also participate in the coupling, providing access in this case to N-protected cyclic amines. Notably, this reaction is extremely rapid (20 minutes at ambient temperature), forms exclusively the 1,2-addition product, and employs only simple alkynes as the carbon-carbon bond
44 forming partner with pyridine. In addition, these chloroformates are compatible with coupling a number of functionalized alkynes (entries 1i-l).
Table 2.1. Copper-catalyzed coupling of pyridines, chloroformates and alkynesa
O R 1 R N O 10% Cat. 2 + + HRi N 2 Pr NEt R Cl 2 1 CH3CN 20min, RT 2.1
Entry Cat. R1 R2 Yield 2.1 1a CuI Ph Ph 73% b 1b CuI Ph n-C4H9 33% 1c CuOTfc Ph Ph 31%
1d Zn(OTf)2 Ph Ph - 1e CuI OEt Ph 82% b 1f CuI OCH2CCl3 Ph 88% 1g CuI OPh Ph 84%
1h CuI (9-fluorenyl)CH2O Ph 62% 1i CuI OEt n-C4H9 83% 1j CuI OEt TMS 72%
1k CuI OPh CH2Cl 64% 1l CuI OPh CO2Et 78% a) Typical experimental procedure: 0.5 mmole pyridine, 0.6 mmole acid chloride, 0.5 mmole alkyne,
combined with ~2 mL CH3CN in the glove box, added to a mixture of 0.05 mmole catalyst and 0.7 mmole iPr2NEt in ~1 mL CH3CN and the solution stirred at rm. temp. for 20 mins. b) NMR yields. c) Cu(OTf) benzene complex used.
A potential mechanism of this multicomponent reaction involves the reaction between in situ generated copper-acetylide and pyridinium salt (Scheme 2.1). The observed regioselectivity of this reaction is in contrast with copper mediated Grignard additions to pyridinium salts, which instead favor the opposite 1,4 addition product,6 and is selective relative to many related additions to pyridinium salts, which often lead to 1,2- and 1,4-product mixtures.1 Considering the formation of a coordinatively unsaturated and sterically unencumbered copper-acetylide, coordination to the amide (or carbamate) carbonyl of the pyridinium salt may direct the ortho-addition, in a similar manner to what has been observed by the Charrette group in mixed cuprate Grignard additions to N- imidate pyridinium salts.7 It’s interesting to note that the stoichiometric addition of other
45 metal acetylides (e.g. magnesium-,8 silver-,9 and tin-acetylides10) to N-acyl pyridinium salts also result in preferential (or exclusive) 1,2-addition products.
R1 O R2 N LnCuX 2 2.1 R H i Pr2NEt N R1 O Cl N + i + - O - Pr2NEtH X 2 LnCu R R1 Cl
Scheme 2.1 Proposed mechanism for the copper catalyzed addition of terminal alkynes to pyridine
A number of functionalized pyridines were tested in this reaction. As shown in Table 2.2, the coupling is relatively general, and is compatible with halogen, alkyl, aryl,11 and even sensitive aldehyde functionalized pyridines. The latter typically need to be protected in related organometallic additions to prevent carbonyl addition.10,12 The reactions remained highly ortho-selective, although regio-isomeric mixtures of the two possible ortho-addition products were obtained for entries 2a and 2b. In the case of entry 2b, it’s likely that the presence of the aldehyde in the 3-position helps direct the addition to the more sterically encumbered 2-position, resulting in a 1:1 mixture of the 1,2- and 1,6- addition products.13 More curious is the preferential addition to the more sterically hindered 2-position of 3-picoline (entry 2a). The literature does show that this interesting regioselectivity is typical for this substrate in related additions.14
46 Table 2.2 Copper-catalyzed multicomponent coupling of pyridines, chloroformates and alkynesa R R O 1.4eq. iPr2NEt 10% CuI + R Cl + HPh N 1 CH CN R N 3 OR 2 20min RT 1 2.1
Entry Pyridine R1 Product Yield 2.1 (%)
Me Me b 2a N OPh N 78 Ph PhO O (3:1)
O O H H 78b N N (55:45) 2b OPh Ph PhO O
Br Br
2c N OPh N 84 Ph PhO O
2d 62
N OCHClCH3 N Ph H3CClHCO O
2e N OPh N 70 Ph PhO O
OO 2f NCN OPh N 67c
OO 2g NBr OPh N 54c a) Typical experimental procedure: 0.5 mmole pyridine, 0.6 mmole chloroformate, 0.5 mmole alkyne, combined in ~2 mL CH3CN in the glove box then added to a stirring vial of 0.05 mmole CuI and 0.7 mmole iPr2NEt in ~1 mL CH3 CN and the solution stirred at rm. temp. for 20 mins. b) combined yield of both regioisomers (ratio of 2,3 : 2,5 products from 1HNMR of the crude rxn mixture). c) reaction heated for 1 hr at 450C.
47 It can be seen in Table 2.2 that attempts to couple 2-substituted pyridines failed (entries 2f, g). This trend is typical of these substrates, since the increased steric hindrance of these substituents inhibits pyridinium salt formation.1,15 Instead, these reactions led to the formation of a Hoffmann elimination product, resulting from the 16 interaction of Hunigs base (iPr2NEt) with phenyl chloroformate (Scheme 2.2).
B
OO OO OOH + N N Cl N Cl
- B= iPr2NEt, pyridine, Cl
Scheme 2.2 Hoffman elimination of Hunigs base with phenyl chloroformate
Importantly, this catalytic approach to heterocycle alkynylation is not limited to pyridines, and other nitrogen containing heterocycles can be similarly functionalized (Table 2.3). For example, quinoline reacts smoothly under these conditions (entries 3a and 3b), as do the biologically relevant pyrimidine and pyrazine di-nitrogen heterocycles. In these latter cases, two equivalents of chloroformate, alkyne, and base are needed for efficient coupling (entries 3c-d).17 Functionalization of these substrates is typically difficult using related N-acyl quaternization procedures, and represents interesting new products.1
48 Table 2.3. Copper-catalyzed multicomponent coupling of N-Heterocycles, acid chlorides and alkynesa
O 1.4eq. iPr2NEt + 10% CuI R Cl + HR2 1 N N CH3CN 20mins RT R2 R1 O
Entry Heterocycle R1 R2 Product %Yield
N 3a OEt CO2Et N 75 CO Et EtO O 2
3b N Ph Ph N 75 Ph Ph O
OOPh N 3c OPh Ph N 79b
N N Ph PhO O N O O N OPh 3d N OPh Ph N OPh 54b,c N N Ph Ph Ph PhO O PhO O
21
a) Typical experimental procedure: 0.5 mmole heterocycle, 0.6 mmole acyl chloride, 0.5 mmole alkyne,
combined with ~2 mL CH3CN in the glove box, added to a mixture of 0.05 mmole catalyst and 0.7 mmole iPr2NEt in ~1 mL CH3CN and the solution stirred at rm. temp. for 20 min. b) 2eq. chloroformate, alkyne, and 2.8 eq. iPr2NEt used. c) combined yield of addition products.
2.3 Conclusion
In summary, a mild and regioselective copper (I) catalyzed method of coupling alkynes with pyridines in the presence of chloroformates (or acid chlorides) has been developed. This methodology can be extended to the alpha functionalization of other N- containing heterocycles. The products of this coupling, N-acyl-2-ethynyl-1,2- dihydropyridines, can be useful intermediates, and an enantioselective variant of this reaction was subsequently developed in our laboratory.18
49 2.4 Experimental
General Procedures:
All manipulations were performed under an inert atmosphere in a Vacuum Atmospheres 553-2 dry box. All reagents were purchased from Aldrich® and used as
received. Acetonitrile was distilled from CaH2 under nitrogen. Deuterated acetonitrile was dried as its protonated analogue, but was transferred under vacuum from the drying agent, and stored over 4Å molecular sieves. Deuterated DMSO and chloroform were dried over 3 Å molecular sieves.
1H and 13C NMR spectra were recorded on Varian Mercury 300 MHz, Mercury 400 MHz, Unity 500MHz, and JEOL 270 MHz spectrometers. 2D COSY spectra were recorded on a Varian Mercury 300MHz spectrometer, 2D HMQC, HMBC and 1D NOESY experiments were recorded on a Varian Mercury 400 MHz spectrometer. Mass spectra were obtained from the McGill University mass spectral facilities.
Typical Procedure for the Synthesis of Cyclic-Propargylcarbamates:
Pyridine (40 mg, 0.5 mmol), ethyl chloroformate (61 mg, 0.62 mmol) and phenylacetylene (50 mg, 0.5 mmol) were mixed in ~2 mL of acetonitrile and added to a
vial of stirring CuI (9 mg, 0.05 mmol) and iPr2NEt (105 μL, 0.7 mmol) in ~1 mL of acetonitrile in the glove box. The reaction mixture was stirred at ambient temperature for 20 minutes then removed from the box and solvent removed by rotory evaporation. The crude residue was dissolved in CH2Cl2 and the product isolated by column chromatography using ethyl acetate/hexanes as eluent (5, 10, or 20% EtOAc:Hexanes; 1 13 Rf’s ~ 0.5-0.8 in 20% EtOAc:Hex). All compounds were characterized by H and C NMR and HRMS. Compound 1a has been previously reported.3c Regioselectivities for compounds 2a and 2b were determined by 1D NOESY and 2D 1H-13C HMQC.19
50 Spectroscopic Data:
N-phenacyl-2-phenylethynyl-1,2-dihydropyridine (Table 2.1, entry 1a) Isolated 1 Yield: 73 %. H NMR (300 MHz, 60 °C, CDCl3): δ 7.68-7.54 (d, 3H), 7.52-7.37 (m, 7H), 6.42 (br, 1H), 6.13 (m, 2H), 5.82 (br, 1H), 5.40 (br, 1H). 13C NMR (68.0 MHz, 60 °C,
CDCl3): δ 169.4, 133.9, 131.9, 130.9, 128.7, 128.4, 128.3, 128.1, 126.7, 122.6, 122.3,
120.0, 106.7, 86.1, 83.0, 43.0. HRMS (M+H) for C20H15NO, calculated: 285.1154, found: 285.1149. ethyl 2-(phenylethynyl)pyridine-1(2H)-carboxylate (Table 2.1, entry 1e) Isolated 1 Yield: 82 %. H NMR (300 MHz, 60 °C, CDCl3): d 7.32-7.41 (m, 2H), 7.21-7.28 (m, 3H), 6.8 (d, 1H), 6.0 (m, 1H), 5.79 (d, 1H), 5.65 (t, 1H), 5.36 (t, 1H), 4.32 (q, 2H), 1.37 13 (t, 3H). C NMR (67.9 MHz, 60 °C, CDCl3): d 153.4, 131.9, 128.1, 125.2, 122.9, 122.5,
122.3 118.6, 105.1, 86.8, 82.2, 62.5, 44.2, 14.4. HRMS (M+H) for C16H15NO2, calculated: 254.1183, found: 254.1176. phenyl 2-(phenylethynyl)pyridine-1(2H)-carboxylate (Table 2.1, entry 1g) Isolated 1 Yield: 84 %. H NMR (500 MHz, 60 °C, CDCl3):d 7.38-7.44 (m, 4H), 7.21-7.3 (m, 6H), 6.94 (s, 1H), 6.09 (q, 1H), 5.96 (s, 1H), 5.76 (s, 1H), 5.45 (t, 1H). 13C NMR (500 MHz,
60 °C, CDCl3): d 151.3, 132.1, 129.5, 128.4, 125.9, 125.0, 122.9, 122.4, 121.7, 121.0,
119.4, 106.5, 86.5, 83.7, 44.8. HRMS (M+Na) for C20H15NO2, calculated: 324.1003, found: 324.0994.
(9H-fluoren-9-yl)methyl 2-(phenylethynyl)pyridine-1(2H)-carboxylate (Table 2.1, 1 entry 1h) Isolated Yield: 62 %. H NMR (300 MHz, 60 °C, CDCl3): d 7.61-7.79 (m, 4H), 7.22-7.43 (m, 9H), 6.79-6.83 (br, 1H), 6.0-6.08 (q, 1H), 5.78-5.83 (br, 1H), 5.63-5.72 (t, 1H), 5.39-5.45 (t, 1H), 4.43-4.62 (br, 2H), 4.27-4.38 (t, 1H). 13C NMR (68.0 MHz, 60 °C,
CDCl3): d 155.2, 143.8, 141.4, 132.0, 128.1, 127.8, 127.2, 122.7, 120.0, 105.8, 86.6, 83.5,
70.0, 68.7, 47.3, 44.4. HRMS (M+H) for C28H21NO2, calculated: 404.1652, found: 404.1646.
51 ethyl 2-(hex-1-ynyl)pyridine-1(2H)-carboxylate (Table 2.1, entry 1i) Isolated Yield: 1 83 %. H NMR (300 MHz, 60 °C, CDCl3):d 6.72-6.77 (d, 1H), 5.87-5.95 (q, 1H), 5.49- 5.58 (br, m, 2H), 5.25-5.33 (t, 1H), 4.21-4.34 (q, 2H), 2.12-2.19 (t, 2H), 1.27-1.48 (m, 13 5H), 0.82-0.94 (t, 3H). C NMR (75.5 MHz, 60 °C, CDCl3): d 125.3, 121.7, 119.7,
105.1, 83.9, 77.9, 62.5, 44.0, 30.8, 21.9, 18.6, 14.5, 13.5. HRMS (M+Na) for C14H19NO2, calculated: 256.1316, found: 256.1306.
2-Trimethylsilanylethynyl-2H-pyridine-1-carboxylic acid ethyl ester (Table 2.1, 1 entry 1j) Isolated Yield: 72 %. H NMR (400 MHz, 60 °C, CDCl3):d 6.71-6.78 (d, 1H), 5.87-5.96 (q, 1H), 5.52-5.59 (br, 2H), 5.27-5.34 (t, 1H), 4.21-4.36 (m, 2H), 1.31-1.38 (t, 13 3H), 0.18 (s, 9H). C NMR (68.0 MHz, 60 °C, CDCl3): d 153.8, 125.3, 122.3, 118.9,
105.1, 103.0, 87.8, 62.6, 44.5, 14.6, -0.003. HRMS (M+H) for C13H19NO2Si, calculated: 250.1265, found: 250.1258.
2-(3-Chloro-prop-1-ynyl)-2H-pyridine-1-carboxylic acid phenyl ester (Table 2.1, 1 entry 1k) Isolated Yield: 64 %. H NMR (500 MHz, 60°C, CDCl3): d 7.35-7.41 (m, 2H), 7.16-7.25 (m, 3H), 6.83-6.89 (br, 1H), 6.01-6.09 (q, 1H), 5.72-5.78 (br, 1H), 5.61-5.68 13 (br, 1H), 5.41-5.45 (t,1H), 4.15-4.18 (s, 2H). C NMR (68.0 MHz, 60 °C, CDCl3): d 151.2, 129.5, 129.0, 125.0, 122.7, 121.6, 118.6, 106.3, 83.7, 78.5, 44.4, 30.3. HRMS
(M+Na) for C15H12ClNO2, calculated: 296.0450, found: 296.0449.
phenyl 2-(3-ethoxy-3-oxoprop-1-ynyl)pyridine-1(2H)-carboxylate (Table 2.1, entry 1 1l) Isolated Yield: 78 %. H NMR (300 MHz, 60 °C, CDCl3):d 7.33-7.42 (m, 2H), 7.19- 7.29 (m, 3H), 6.86-6.93 (d, 1H), 6.06-6.13 (q,1H), 5.81-5.87 (d, 1H), 5.59-5.67 (m, 1H), 5.41-5.48 (t, 1H), 4.20-4.25 (q, 2H), 1.22-1.35 (t, 3H). 13C NMR (68.0 MHz, 60 °C,
CDCl3): d 153.3, 151.0, 129.6, 126.1, 121.6, 117.0, 106.4, 83.7, 75.5, 62.2, 44.0, 14.1.
HRMS (M+H) for C17H15NO4, calculated: 298.1081, found: 298.1074.
phenyl 3-methyl-2-(phenylethynyl)pyridine-1(2H)-carboxylate (Table 2.2, entry 2a) Isolated Yield: 78 % of a 3:1 mixture of 2,3:2,5 regioisomers. 1H NMR (300 MHz, 60 °C,
CDCl3):d 7.7.34-7.47 (m, 5H), 7.19-7.33 (m, 10H), 6.80-6.84 (d, 1H, major 2,3 isomer),
52 6.69-6.73 (br, 0.3H, minor 2,5 isomer), 5.96-6.01 (br, d, 0.6H, minor 2,5 isomer), 5.77- 5.83 (br, d, 1H, major 2,3 isomer), 5.67-5.73 (s, 1H, major 2,3 isomer), 5.42-5.48 (t, 1H, major 2,3 isomer), 2.00 (s, 3H, major 2,3 isomer), 1.86 (s, 1H, minor 2,5 isomer). 13C
NMR (67.9 MHz, 60 °C, CDCl3): d 151.9 (minor), 151.2 (major), 132.0, 129.3, 128.3, 128.2, 126.2, 125.7, 121.6, 120.8, 117.8, 115.7, 106.9, 85.9, 83.6, 49.3 (major), 49.1
(minor), 20.2 (major), 17.7 (minor). HRMS (M+Na) for C21H17NO2, calculated: 338.1159, found: 338.1154. phenyl 3-formyl-2-(phenylethynyl)pyridine-1(2H)-carboxylate (Table 2.2, entry 2b) 1 Isolated Yield: 40%. HNMR (400MHz, CDCl3): d 9.56 (s, 1H), 7.45-7.18 (m, 10H), 6.95-6.98 (d, 1H), 6.44 (s, 1H), 5.78-5.73 (t, 1H). 13C NMR (67.9 MHz, 60 °C,
CDCl3): d 188.1, 150.8, 139.2, 132.8, 132.0, 130.0, 129.7, 129.5, 128.9, 128.6, 128.2,
126.2, 121.3, 105.1, 85.2, 83.9, 42.6. HRMS (M+Na) for C20H14NO3, calculated: 352.0952, found: 352.0939. phenyl 5-formyl-2-(phenylethynyl)pyridine-1(2H)-carboxylate (Table 2.2, entry 2b) 1 Isolated Yield: 38%. HNMR (300MHz, CDCl3): d 9.39 (s, 1H), 7.45-7.20 (m, 10H), 6.63-6.58 (d, 1H), 6.01-5.97 (d, 1H), 5.87-5.79 (q, 1H). 13C NMR (67.9 MHz, 60 °C,
CDCl3): d 187.0, 150.7, 141.1, 132.0, 131.8, 129.7, 128.9, 128.3, 128.1, 126.5, 122.3,
121.2, 119.8, 117.6, 85.4, 71.9, 47.1 . HRMS (M+Na) for C20H14NO3, calculated: 352.0952, found: 352.0939. phenyl 5-bromo-2-(phenylethynyl)pyridine-1(2H)-carboxylate) (Table 2.2, entry 2c) 1 Isolated Yield: 84%. H NMR (500 MHz, 60 °C, CDCl3): d 7.19-7.49 (m, 10H), 6.98- 7.02 (d, 1H), 6.38-6.41 (d, 1H), 6.03 (s, 1H), 5.39-5.43 (t, 1H). 13C NMR (67.9 MHz, 60
°C, CDCl3): d 150.9, 132.1, 129.4, 128.7, 128.2, 126.2, 126.0, 124.7, 122.3, 121.4, 120.9,
111.7, 106.2, 84.8, 84.1, 52.2. HRMS (M+Na) for C20H14BrNO2, calculated: 402.0108, found :402.0102.
N-1-chloro-ethyl-4-t-butyl-2(phenylethynyl)pyridine-1(2H)-carboxylate (Table 2.2, 1 entry 2d) Isolated Yield: 62%. H NMR (300 MHz, CDCl3):d 7.43-7.25 (m, 5H), 6.80-
53 6.64 (br, 2H), 5.77-5.72 (br, d, 1H), 5.58-5.49 (br, t, 1H), 5.46-5.42 (br, 1H), 1.89-1.84 13 (d, 3H), 1.13 (s, 9H). C NMR (67.9 MHz, 60 °C, CDCl3): d 154.9, 142.7, 131.9, 131.7, 128.6, 127.8, 123.0, 111.1, 107.5, 86.6, 83.3, 83.1, 44.9, 33.9, 28.6, 25.8. HRMS (M+Na) for C20H22NO2Cl, calculated: 366.1239, found: 366.1231. phenyl 3,5-dimethyl-2-(phenylethynyl)pyridine-1(2H)-carboxylate (Table 2.2, entry 1 2e) Isolated Yield: 70%. H NMR (500 MHz, 60 °C, CDCl3):d 7.33-7.44 (m, 4H), 7.17- 7.31 (m, 6H), 6.53-6.62 (br, 1H), 5.59-5.70 (br, 2H), 1.99 (s, 3H), 1.81 (s, 3H). 13C NMR
(68.0 MHz, 60 °C, CDCl3): d 151.3, 132.0, 129.5, 128.3, 126.2, 125.6, 122.9, 121.6,
120.8, 117.1, 115.6, 86.1, 83.2, 48.6, 20.0, 17.8. HRMS (M+H) for C22H19NO2, calculated: 330.1496, found: 330.1490. phenyl ethyl(isopropyl)carbamate (Table 2.2, entry 2f) Isolated Yield: 67%. 1H NMR
(300 MHz, 60 °C, CD3CN): d 7.42-7.39 (t, 2H), 7.25-7.21 (t, 1H), 7.16-7.12 (d, 2H), 4.37-4.25 (br, 1H), 3.39-3.26 (br, 2H), 1.34-1.18 (br, 9H). 13C NMR (68.0 MHz, 60 °C,
CD3CN): d 154.0, 152.1, 129.2, 129.1, 124.9, 121.9, 117.0, 116.8, 48.5, 38.0, 20.1, 14.9.
HRMS (M+H) for C12H17NO2, calculated: 208.1332, found: 208.1328. phenyl(2-(phenylethynyl)quinolin-1(2H)-yl)methanone (Table 2.3, entry 3a) Isolated 1 Yield: 75%. H NMR (300 MHz, 60 °C, CDCl3): d 7.44-7.18 (m, 12H), 7.12-7.05 (t, 1H), 6.96-6.89 (t,1H), 6.70-6.66 (d, 1H), 6.24-6.16 (m, 2H). 13C NMR (68.0 MHz, 60
°C, CDCl3): d 169.7, 135.5, 135.3, 132.1, 130.9, 129.3, 128.6, 128.4, 128.3, 127.4, 127.2,
126.8, 126.5, 126.0, 125.9, 125.4, 122.7, 85.4, 84.0, 44.7. HRMS (M+H) for C24H17NO, calculated: 336.1320, found: 336.1380.
Ethyl 2-(3-ethoxy-3-oxoprop-1-ynyl)quinoline-1(2H)-carboxylate (Table 2.3, entry 1 3b) Isolated Yield: 75%. H NMR (200 MHz, CDCl3):d 7.64 (d, 1H, J = 8.1 Hz), 7.24 (m, 1H), 7.13 (m, 2H), 6.58 (d, 1H, J = 9.0 Hz), 6.02 (d, 1H, J = 6.0 Hz), 5.98 (dd, 1H, J = 6.0 Hz, 3.0 Hz), 4.37-4.17 (m, 2H), 4.13 (dd, 2H, J = 7.2 Hz, 7.2 Hz), 1.32 (t, 3H, J = 13 7.2 Hz), 1.22 (t, 3H, J = 7.2 Hz). C NMR (75.0 MHz, CDCl3): d 153.9, 153.3, 134.2,
54 128.5, 127.6, 127.1, 126.2, 124.9, 124.5, 122.8, 83.7, 75.3, 63.1, 62.3, 44.1, 14.6, 14.1.
HRMS (M+H) for C17H18NO4 calculated: 300.1230; found: 300.1228.
diphenyl 2-(phenylethynyl)pyrazine-1,4-dicarboxylate (Table 2.3, entry 3c) Isolated 1 Yield: 79%. H NMR (300 MHz, 60 °C, CDCl3): d 7.16-7.48 (m, 16H), 6.44-6.75 (br, 13 m, 2H), 5.74 (s, 1H). C NMR (68.0 MHz, 60 °C, CDCl3): d 150.9, 150.0, 132.1, 131.8, 129.5, 129.4, 129.2, 128.4, 126.3, 126.0, 121.4, 121.3, 108.8, 105.9, 106.1, 86.2, 81.8,
66.5, 51.1, 49.9. HRMS (M+H) for C26H18N2O4, calculated: 423.1347, found: 423.1333.
diphenyl 2,4-bis(phenylethynyl)pyrimidine-1,3(2H,4H)-dicarboxylate (Table 2.3, entry 3d) Isolated Yield: 54% of a 2:1 mixture of the bis-addition product 1 (C34H24N2O4): mono-addition product (C26H20N2O4). H NMR (300 MHz, 60 °C,
CDCl3): d 7.60-7.03 (m, 33H), 5.79-5.72 (s, 1H, bis-add), 5.52-5.22 (m, br, 1H, bis-add), 4.72-4.51 (t, 0.5H, mono-add), 4.39-4.19 (br, 0.5H, mono-add). 13C NMR (67.9 MHz, 60
°C, CDCl3): d 153.5 (mono), 152.7 (mono), 150.5 (bis), 150.1 (bis), 132.4, 132.2, 129.9, 129.8, 129.7, 129.6, 129.4, 128.9, 128.7, 128.5, 128.0, 126.4, 126.2, 123.2, 122.9, 122.6, 122.4, 122.1, 108.3 (bis), 105.2 (bis), 106.3 (mono), 85.9 (bis), 85.7 (mono), 84.1 (bis), 82.9 (mono), 54.4 (bis), 44.0 (mono), 43.1 (bis), 39.9 (mono). HRMS (M+Na) for
C34H24N2O4, calculated: 547.1636, found: 547.1622. HRMS (M+Na) for C26H20N2O4, calculated: 447.1323, found: 447.1312.
55 1H and 13C NMR Spectra:
N Ph EtO O
N Ph EtO O
56 N Ph PhO O
N Ph PhO O
57 N Ph O O
N Ph O O
58 N n-C H EtO O 4 9
N n-C H EtO O 4 9
59 N TMS EtO O
N TMS EtO O
60 N CH Cl PhO O 2
N CH Cl PhO O 2
61 N CO Et PhO O 2
N CO Et PhO O 2
62 Me Me
N N Ph Ph PhO O PhO O 3:1
Me Me
N N Ph Ph PhO O PhO O 3:1
63 Me
N Ph PhO O
Me
N Ph PhO O
64 Br
N Ph PhO O
Br
N Ph PhO O
65 O
H
N Ph PhO O
O
H
N Ph PhO O
66 O
H
N Ph PhO O
O
H
N Ph PhO O
67 N Ph H3CClHCO O
N Ph H3CClHCO O
68 N Ph PhO O
N Ph PhO O
69 O N
O
O N
O
70 N Ph Ph O
N Ph Ph O
71 N CO Et EtO O 2
N CO Et EtO O 2
72 OOPh
N
N Ph PhO O
OOPh
N
N Ph PhO O
73 O O
N OPh N OPh
N N Ph Ph Ph PhO O PhO O
21
HRMS supporting mixture of both structures:
O O
N OPh N OPh
N N Ph Ph Ph PhO O PhO O
21
74 2.4 References
1 For reviews on nucleophilic additions to pyridinium salts see: a) Eicher, T., Hauptmann, S., The Chemistry of Heterocycles, Wiley-VCH Weinheim, Ger., 2003. b) Joule, J.A., Mills, K., Heterocyclic Chemistry, Blackwell Science, Oxford UK, 2000. c) Lavilla, R.; J. Chem. Soc., Perkin Trans. 1, 2002, 1141–1156. b) Meyers, A.I., Stout, D.; Chem.Rev. 1982, 82, 223-243. d) Eisner, U., Kuthan, J.; Chem. Rev. 1972, 72, 1-42. e) For a review on using these additions for the synthesis of pyridines: Comins, D.L., O’Connor, S.; Adv. in Het. Chem. 1988, 44, 199. f) For a review on using these additions for the synthesis of alkaloids see: Comins, D.L.; Joseph, S.; Advances in Nitrogen Heterocycles 1996, 2, 251. 2 Diederich, F.; Stang, P.; Metal Catalyzed Cross-Coupling Reactions; Wiley-VCH: New York, 1998. 3 a) For a metal-catalyzed enantioselective cyanide addition to pyridinium salts: Ichikawa, E., Suzuki, M., Yabu, K., Albert, M., Kanai, M., Shibasaki, M.; J. Am. Chem. Soc. 2004, 126, 11808-11809. b) For an iridium catalyzed TMS-acetylene addition to quinolinium and iso-quinolinium salts see: Yamazakai, Y., Fujita, K.-I., Yamaguchi, R.; Chem. Lett. 2004, 33, 1316. c) Our initial communication on a copper (I) catalyzed multicomponent synthesis of a cyclic-propargylamide: Black, D.A., Arndtsen, B.A.; Org. Lett. 2004, 6, 1107. d) After this report a similar alkynylation using a 0.5eq.
CuI/iPr2NEt system in CH2Cl2 was reported: Yadav, J.S., Reddy, B.V.S., Sreenivas, M., Sathaiah, K.; Tetrahedron Lett. 2005, 46, 8905. 4 Black, D.A., Arndtsen, B.A.; J. Org. Chem. 2005, 70, 5133. 5 Black, D.A., Arndtsen, B.A.; Org. Lett. 2006, 8, 1991. 6 a) Bennasar, M.-L., Roca, T., Monerris, M., Juan, C., Bosch, J.; Tetrahedron 2002, 58, 8099. b) Comins, D.L., Stroud, E.D.; Heterocycles 1986, 24, 3199. c) Abdullah, A., Comins, D.L.; J. Org. Chem. 1982, 47, 4315. 7 Charette, A.B., Grenon, M., Lemire, A., Pourashraf, M., Martel, J.; J. Am. Chem Soc. 2001, 123, 11829.
75 8 a) Yamaguchi, R., Nakazono, Y., Kawanisi, M.; Tetrahedron Lett. 1983, 24, 1801. b) Yamaguchi, R., Matsuki, Y., Hata, E.-I., Kawanisi, M.; Bull. Chem. Soc. Jpn. 1987, 60, 215 and references therein. 9 a) Agawa, T., Miller, S.I.; J. Amer. Chem. Soc. 1961, 83, 449. b) Nishiwaka, N., Minakata, S., Komatsu, M., Ohshiro, Y.; Chem. Lett. 1989, pp. 773-776. 10 Yamaguchi, R., Hata, E.-I., Utimoto, K.; Tetrahedron Lett. 1988, 29, 1785. 11 The dihydropyridine resulting from addition of phenylacetylene to 4-phenyl-pyridine in the presence of a number of chloroformates was too unstable to fully characterize but is supported by the clean isolation of the corresponding aromatic 2-phenylethynyl-4- phenyl-pyridine in Chapter 3 of this thesis. 12 Comins, D.L., Smith, R.K., Stroud, E.D.; Heterocycles 1984, 22, 339. 13 Ring carbonyl assisted attacks have been reported in some organometallic additions to pyridinium salts: Yamaguchi, R., Hata, E.-I., Utimoto, K.; Tetrahedron Lett. 1988, 29, 1785. 14 a) Sundberg, R.J., Hamilton, G., Trindle, C.; J. Org. Chem. 1986, 51, 3672. b) Comins, D.L., Abdullah, A.H.; J. Org. Chem. 1982, 47, 4315 and references therein. 15 a) For an interesting recent report on the selective 4-addition of π-basic aromatic compounds to triflic anhydride activated salts of 2-cyano- and 2-bromo-pyridines see: Corey, E.J., Tian, Y.; Org. Lett. 2005, 7, 5535. b) For an example of an organoindium addition to an N-acyl salt of 2-cyano-pyridine see Chapter 4 of this thesis. 16 Attempts to circumvent this problem using other chloroformates or acid chlorides and a variety of other bases including K3PO4,Cs2CO3, DBU and DABCO failed. 17 The bis- addition products are also solely observed when only 1eq. of chloroformate and alkyne are used but in much lower yield. 18 a) Black, D.A.; Ph. D. Thesis, McGill University, 2006, ch. 6. b) Black, D.A., Beveridge, R.E., Arndtsen, B.A.; Manuscript in Preparation. 19 Regioselectivities were also confirmed by the isolation and characterization of the corresponding aromatic alkynyl-pyridines in Chapter 3 of this thesis.
76 CHAPTER 3
A One-Pot Copper-Catalyzed Synthesis of Alkynyl Pyridines
3.0 Preface
A mild, efficient and regioselective copper-catalyzed method to couple terminal alkynes with pyridines in the presence of a chloroformate (or acid chloride) was developed in Chapter 2. By applying our reaction methodology from Chapter 2 in a tandem oxidation protocol, a one-pot copper-catalyzed method to access 2-alkynyl- pyridines has been developed, and is presented here in Chapter 3. This reaction has been used to synthesize a number of aromatic alkynyl pyridines directly from the parent heterocycles. In addition, alkenyl-pyridines were prepared via a related procedure.
3.1 Introduction
The pyridine core is found in a variety of natural products,1 ligands,2 dendrimers,3 polymers,4 and synthetic biologically-active compounds.5 For example, pyridine containing alkaloids have been found to exhibit potent cytotoxic, antimicrobial, and antiviral activities,1 while simple substituted pyridines can behave as antagonists of human metabotropic glutamate receptors (mGluR5), and cytotoxic agents to human cancer cells.5 Due to the broad utility of substituted pyridines, their construction remains a constantly active area of research.6 Currently, the most common approach to functionalize pyridines under mild conditions involves transition-metal catalyzed cross- coupling reactions with halogenated (or metallated) pyridines (e.g. Suzuki,7 Heck,8 Sonogashira,9 or Stille10 couplings), or more recently with pyridine N-oxides.11 The initial generation of the correctly positioned halogenated pyridine precursor (or N-oxide) prior to functionalization is required for this chemistry.
We have recently reported a regio-selective copper catalyzed alkynylation of pyridine in the presence of an acid chloride or chloroformate activator.12 This mild coupling was highly efficient, yielding the partially reduced pyridine derivatives 3.1 in only ~ 20 minutes with a variety of terminal alkynes at ambient temperature (Scheme
76 3.1). Since dihydropyridines can serve as precursors to aromatic substituted pyridines,13 we considered the potential of applying this catalytic coupling to the development of a one-pot route to regioselectively access substituted aromatic pyridines. This would provide a straightforward method to directly derivatize the parent pyridine with simple alkynes. Our progress towards this goal is described below.
1.4eq. iPr2NEt O 10% CuI HR2 N R1 Cl CH3CN N 20 min RT R2 R1=Ph,OEt R2=Ph,CO2Et R1 O OPh, Troc n-C4H9,TMS 3.1 Fmoc CH2Cl2 62-88% Yield Scheme 3.1 Copper-catalyzed multicomponent coupling of pyridines, acyl Chlorides and alkynes
3.2 Results and Discussion
Our initial efforts towards the synthesis of 3.2 (Table 3.1) probed the effect of treating the in situ generated 3.1 with various oxidants. As shown in entries 1a-e, no oxidized products were formed with oxygen or peroxide sources, or even with the known dihydropyridine oxidant, elemental sulfur.13c,14 While these early attempts resulted in almost complete dihydropyridine recovery or decomposition, a moderate yield of 2- phenylalkynyl-pyridine 3.2 was obtained when the crude reaction mixture was treated with a stoichiometric amount of Cu(II)OTf15 (entry 1e).
In contrast to these results, treatment of the in situ generated 3.1 with DDQ (2,3- dichloro-5,6-dicyano-1,4-quinone), or the related quinone o-chloranil (3,4,5,6- tetrachloro-1,2-quinone),16 resulted in the high yield formation of 2-alkynyl pyridine 3.2 (Table 3.1, entries 1f, 1g). Interestingly, this copper mediated coupling/oxidation can also be performed in a single step, provided a stoichiometric amount of CuI is employed and the oxidant is added last to the reaction mixture (entry 1h).17 While this procedure is not as efficient as the copper-catalyzed route, it does provide a direct route to the substituted pyridine 3.2.
77 Table 3.1 Towards a direct copper-catalyzed synthesis of 2-ethynyl-pyridinesa
1) 1.4eq. iPr NEt; 10% CuI O 2 CH CN 20 min RT + 3 + EtO Cl HPh N N 2) [O] conditions Ph 3.2
Entry [O] Time (hrs) Temp. (0C) Yield 3.2 (%) 1a air 48 45 - 1b O2 46 rm. temp. - 1c H2O2 16 65 - - 1d S8 40 45 1e Cu(OTf)2 16 65 33 1f DDQ 1 45 81 1g o-chloranil 1 45 83 1h DDQ 16 45 81b
(a) Typical experimental procedure: 0.5 mmole pyridine, 0.6 mmole chloroformate, 0.5 mmole alkyne in
~2 mL CH3CN in the glove box added to 0.05 mmole CuI and 0.7 mmole iPr2NEt in ~1 mL CH3CN and the solution stirred for 20 mins, followed by oxidant. b) 1eq. CuI used, DDQ added last to the reaction pot after only brief (~30 secs) stirring.
A number of pyridines were found to undergo successful conversion to the 2- alkynyl-pyridines under these tandem copper-catalyzed alkyne coupling and DDQ oxidation conditions (Table 3.2). Aryl, alkyl, halogen, and even sensitive aldehyde functionalities are tolerated, leading to the formation of new alkynyl-pyridines not easily accessible through other routes (e.g. Sonagoshira coupling). A range of acid chlorides or chloroformates can be used in this reaction, though ethyl chloroformate generally gave the highest yields.
While exclusive α-alkyne substitution is observed for all aromatic products, regio-isomeric mixtures of the dihydropyridine intermediates were observed in entries 2f18 and 2g.19 However, in each case only one of the regioisomers was found to be reactive towards oxidation. In the case of entry 2f, the 2-alkynyl-3-picoline product isolated is an interesting regio-isomer of the highly selective human mGlu5 receptor antagonist MPEP.5a,b
78 Table 3.2 One pot tandem alkyne coupling and oxidation route to 2-ethynyl pyridinesa
1) 1.4eq. iPr2NEt; 10% CuI R R O CH3CN 20min RT ++HR R Cl 2 o N N 1 2) 1eq. DDQ; 45 C 1hr R2
EntryHeterocycle R1 R2 Product % Yield
N N 2a Ph Ph Ph 45
N N 2b Troc Ph Ph 55
N N 2c OPh Ph Ph 60
N N 2d OPh CO2Et CO2Et 54
Br Br
N N 2e OEt Ph Ph 73
Me Me
N N 2f OEt Ph Ph 69
O O H H 2g N OEt Ph N 33 Ph
N N 2h OEt Ph Ph 39
Ph Ph
2i N OEt Ph N 43 Ph
2j OEt Ph 40 N N Ph
(a) Typical experimental procedure: 0.5 mmole pyridine, 0.6 mmole acid chloride, 0.5 mmole alkyne in ~2 mL CH3 CN in the glove box added to 0.05 mmole CuI and 0.7 mmole iPr2NEt in ~1 mL CH3CN and the solution stirred for 20 min, exposed to air and 1 eq. DDQ added and the reaction flask placed in a 45o C bath for 1 hr.
79 In addition to alkynylated pyridines, this approach can also provide access to 2- alkenyl pyridine derivatives. While probing the potential use of bases to deprotect the propargylcarbamate intermediates and facilitate oxidation,20 it was found that treatment of crude in situ generated 3.1 with base and overnight heating yielded the alkenyl pyridine products 3.3. Our preliminary results show this rearrangement to be base
dependant (Table 3.3, entries 3a-f). Use of K2CO3 in methanolprovided the highest overall conversion, though in a 1:1 E/Z mixture (entry 3f). Use of KOtBu did give exclusive formation of the trans-isomer in very poor yield (entry 3d), however, when the more hindered base DABCO is used the more hindered cis-isomer is the only product isolated in moderate yield (entry 3e).
Table 3.3 A base mediated synthesis of 2-phenyl-alkenyl-pyridinesa
R 1) 1.4eq. iPr NEt; 10% CuI R R R O 2 1 CH3CN 20min RT ++HR1 R1 N EtO Cl N N 2) BASE E Z 650C 16hrs 3.3
b c Entry R R1 BASE %Yield (E:Z) 3a H Ph Pyridine (5eq.) - 3b H Ph iPr2Net (10eq.) - d 3c H Ph K3PO4 (5eq.) - 3d H Ph KOtBu (2.2eq) 5 (100: 0) 3e H Ph DABCO (5eq.) 49 (0:100) 3f H Ph K2CO3/MeOH 80 (1:1) 3g H CO2Et DABCO (5eq.) 30 (1:2.5) 3h H CO2Et K2CO3/MeOH trace 3i 4-Ph Ph DABCO (5eq.) 29 (0:100) 3j 4-Ph Ph K2CO3/MeOH 36 (1.2:1) 3k 3-Br Ph DABCO (5eq.) 61 (1:3) 3l 3-Br Ph K2CO3/MeOH 18 (1:1) a) Typical experimental procedure: 0.5 mmole pyridine, 0.6 mmole ethyl chloroformate, 0.5 mmole alkyne
in ~2 mL CH3 CN in the glove box added to 0.05 mmole CuI and 0.7 mmole iPr2NEt in ~1 mL CH3CN and the solution stirred for 20 mins, exposed to air and base added and the reaction flask placed in a 65oC bath for 16 hrs. b) Combined yield of both isomers. c) Ratio of isolated amounts of stereoisomers. d) 1eq. of
18-crown -6-ether was added to solubilize the K3PO4.
Cyclic propargylcarbamates, N-acyl-2-ethynyl-1,2-dihydropyridines, have been previously reported to undergo base mediated isomerization to alkenyl-pyridines, though
80 in low yield and stereoselectivity.21 This rearrangement is proposed to proceed via base mediated allene formation, and carbamate de-protection.21a The observed Z-selectivity when an excess of DABCO is used (entries 3e, g, i, k) could be explained by the re- protonation of the central carbon of the allene from the less hindered face by protonated DABCO.22 We have preliminarily probed the use of this reaction to synthesize other alkenyl-pyridines and a similar stereochemical outcome was observed for these substrates (entries 3g-l), though in low overall yield.
3.3 Conclusion
A one-pot tandem copper-catalyzed coupling and oxidation protocol has been developed to regioselectively synthesize alkynyl pyridines directly from the parent heterocycles and terminal alkynes. In addition, a number of 2-alkenyl pyridines can be prepared in a related procedure by coupling the copper-catalyzed reaction with a base mediated rearrangement. Both these reactions provide efficient, one-pot access to 2- functionalized pyridines.
3.4 Experimental
General Procedures:
Unless otherwise noted, all manipulations were performed under an inert atmosphere in a Vacuum Atmospheres 553-2 dry box or by using standard Schlenk or vacuum line techniques. All reagents were purchased from Aldrich® and used as received. Acetonitrile was distilled from CaH2 under nitrogen. Deuterated acetonitrile was dried as its protonated analogue, but were transferred under vacuum from the drying agent, and stored over 4Å molecular sieves. Deuterated DMSO and chloroform were dried over 3 Å molecular sieves.
1H and 13C NMR’s were recorded on Varian Mercury 200 MHz, 300 MHz, Mercury 400 MHz, Unity 500 MHz, and JEOL 270 MHz spectrometers, and 1D NOESY
81 spectra were recorded on a Varian Mercury 400 MHz spectrometer. Regioselectivities for all compounds were determined by 1H NMR and 1D NOESY and by comparison to literature data.23 Stereoselectivities for the alkenyl-pyridines were determined by comparison to literature data24 and by the size of the coupling constant (J in Hz). 25 Mass spectra were obtained from the McGill University mass spectral facilities.
Typical Procedure for the Copper-Catalyzed DDQ Oxidation Synthesis of 2- alkynyl-pyridines:
Pyridine (40 mg, 0.5 mmol), ethyl chloroformate (61 mg, 0.62 mmol) and phenylacetylene (50 mg, 0.5 mmol) were mixed in ~2 mL of acetonitrile and added to a
vial of stirring CuI (9 mg, 0.05 mmol) and iPr2NEt (105 μL, 0.7 mmol) in ~1 mL of acetonitrile in the glove box. The reaction mixture was stirred at ambient temperature for 20 minutes. The vial was removed from the glove box, exposed to air and DDQ (114 mg, 0.5 mmol) was added. The resulting black solution was placed in a 450C bath for 1 hr then columned directly through silica gel using ethyl acetate/hexanes as eluent. All compounds were characterized by 1H and 13C NMR and HRMS.
One-pot Copper-Mediated Synthesis of 2-phenylalkynyl-pyridine (Table 3.1, entry 1h):
Pyridine (16 mg, 0.2 mmol), ethyl chloroformate (24 mg, 0.24 mmol) and phenylacetylene (20 mg, 0.2 mmol) were mixed in ~1 mL of acetonitrile and added to a
vial of stirring CuI (38 mg, 0.2 mmol) and iPr2NEt (40 μL, 0.28 mmol) in ~1 mL of acetonitrile in the glove box. The reaction mixture was stirred briefly (< 30 seconds),
then 4 equal portions of a CH3CN solution (~1 mL) of DDQ (45 mg, 0.2 mmol) was added in only ~10-20 second intervals at ambient temperature. After 20 minutes, the vial was removed from the glove box, exposed to air and the black solution was placed in a 450C bath for 16 hrs then columned directly through silica gel using ethyl acetate/hexanes as eluent.
82 Copper-Catalyzed Synthesis of 2-alkenyl-pyridines using sat’d K2CO3 and MeOH (Table 3.3, entries 3f, h, j, l):
Pyridine (40 mg, 0.5 mmol), ethyl chloroformate (61 mg, 0.62 mmol) and phenylacetylene (50 mg, 0.5 mmol) were mixed in ~2 mL of acetonitrile and added to a vial of stirring CuI (9 mg, 0.05 mmol) and iPr2NEt (105 μL, 0.7 mmol) in ~1 mL of acetonitrile in the glove box. The reaction mixture was stirred at ambient temperature for
20 minutes then brought out of the box and ~2 mL of sat’d K2CO3 and ~2 mL of MeOH were added and the slurried solution was stirred and heated at 650C for 16 hrs. When complete, 5 mL H2O was added and the organics were extracted 3x with 5 mL portions of
CH2Cl2, dried (MgSO4), concentrated, then chromatographed on silica gel with EtOAc/Hexanes as eluent to yield purified product. All compounds were characterized by 1H and 13C NMR and HRMS.
Copper-Catalyzed Z-selective Synthesis of 2-alkenyl-pyridines using DABCO (Table 3.3, entries 3e, g, i, k):
Pyridine (40 mg, 0.5 mmol), ethyl chloroformate (61 mg, 0.62 mmol) and phenylacetylene (50 mg, 0.5 mmol) were mixed in ~2 mL of acetonitrile and added to a vial of stirring CuI (9 mg, 0.05 mmol) and iPr2NEt (105 μL, 0.7 mmol) in ~1 mL of acetonitrile in the glove box. The reaction mixture was stirred at ambient temperature for 20 minutes then DABCO (280 mg, 2.5 mmole) was added and the reaction was stirred and heated at 650C for 16 hrs. The crude reaction mixture was cooled to room temperature then columned directly through silica gel using EtOAc/Heaxanes as eluent.
Spectroscopic Data:
2-(phenylethynyl)pyridine (Table 3.1, entry 1f)23a Isolated yield: 81%. 1H NMR
(300MHz, CDCl3): δ 8.61-8.59 (d, 1H), 7.72-7.61 (t, 1H), 7.60-7.51 (br, 3H), 7.22-7.38 13 (br, 4H). C NMR (68.0MHz, CDCl3): δ 149.9, 143.4, 136.7, 132.2, 129.3, 128.6, 127.5,
83 123.0, 122.3, 90.0, 88.4. HRMS (M+H) for C13H9N, calculated: 180.0815, found: 180.0807.
Pyridin-2-yl-propynoic acid ethyl ester (Table 3.2, entry 2d)23d Isolated yield: 54%. 1 H NMR (300MHz, CDCl3): δ 8.62-8.60 (d, 1H), 7.72-7.69 (t, 1H), 7.59-7.57 (d, 1H), 13 7.35-7.31 (m, 1H), 4.31-4.25 (q, 2H), 1.37-1.31 (t, 3H). C NMR (68.0MHz, CDCl3): δ 153.9, 150.8, 140.6, 136.6, 128.7, 125.0, 84.0, 79.6, 62.7, 14.4. HRMS (M+H) for
C10H9NO2, calculated: 176.0713, found: 176.0704.
5-Bromo-2-phenylethynyl-pyridine (Table 3.2, entry 2e)23c Isolated yield: 73%. 1H
NMR (500MHz, CDCl3): δ 8.58-8.56 (d, 1H), 7.92-7.90 (d, 1H), 7.64-7.61 (d, 2H), 7.39- 13 7.36 (m, 3H), 7.12-7.09 (m, 1H). C NMR (68.0MHz, CDCl3): δ 148.5, 144.0, 140.1,
132.4, 129.6, 128.7, 124.1, 123.8, 122.2, 94.3, 87.7. HRMS (M+H) for C13H8BrN, calculated: 257.9920, found: 257.9911.
3-Methyl-2-phenylethynyl-pyridine (Table 3.2, entry 2f)23b Isolated yield: 69%. 1H
NMR (300MHz, CDCl3): δ 8.46-8.42 (d, 1H), 7.56-7.62 (m, 3H), 7.39-7.36 (m, 3H), 7.19-7.15 (m, 1H), 2.54 (s, 3H), 2.37 (s, 0.15H, minor regioisomer). 13C NMR
(68.0MHz, CDCl3): δ 150.8, 147.6, 143.4, 137.2, 136.2, 132.2, 129.1, 128.6, 126.8,
122.8, 93.3, 87.7, 19.7. HRMS (M+H) for C14H11N, calculated: 194.0871, found: 194.0962.
6-Phenylethynyl-pyridine-3-carbaldehyde (Table 3.2, entry 2g)23e Isolated yield: 1 33%. H NMR (500MHz, CDCl3): δ 10.14 (s, 1H), 9.07 (s, 1H), 8.20-8.14 (d, 1H), 7.68- 13 7.61 (m, 3H), 7.43-7.35 (m, 3H). C NMR (68.0MHz, CDCl3): δ 190.1, 152.6, 148.6, 136.1, 132.6, 130.0, 128.7, 128.8, 127.6, 121.7, 93.8, 88.6. HRMS (M+H+MeOH) for
C14H9N0, calculated: 240.1026, found: 240.1017 .
3,5-Dimethyl-2-phenylethynyl-pyridine (Table 3.2, entry 2h) Isolated Yield: 39%. 1 H NMR (300MHz, CDCl3): δ 8.29 (s, 1H), 7.64-7.56 (m, 2H), 7.38-7.33 (m, 4H), 2.48 13 (s, 3H), 2.34 (s, 3H). C NMR (67.9 MHz, CDCl3): δ 148.0, 140.3, 137.7, 132.7, 131.9,
84 128.8, 128.6, 128.4, 122.8, 92.4, 87.6, 19.4, 18.4. HRMS (M+H) for C15H13N, calculated: 208.1058, found: 208.1118.
4-phenyl-2-(phenylethynyl)pyridine (Table 3.2, entry 2i) Isolated yield: 43%. 1H
NMR (500MHz, CDCl3): δ 8.62-8.66 (d, 1H), 7.79 (s, 1H), 7.60-7.67 (m, 4H), 7.44-7.53 13 (m, 4H), 7.36-7.39 (m, 3H). C NMR (68.0MHz, CDCl3): δ 150.7, 149.0, 144.2, 137.7, 132.3, 129.6, 129.4, 129.2, 128.6, 127.2, 125.4, 122.5, 121.0, 89.5, 89.0. HRMS (M+H) for C19H13N, calculated: 256.1128, found: 256.1118.
4-tert-butyl-2-(phenylethynyl)pyridine (Table 3.2, entry 2j) Isolated yield: 40%. 1H
NMR (500MHz, CDCl3): δ 8.50-8.52 (d, 1H), 7.58-7.62 (m, 1H), 7.55 (s, 1H), 7.36-7.39 13 (m, 3H), 7.21-7.28 (m, 2H). C NMR (68.0MHz, CDCl3): δ 160.6, 150.2, 143.5, 132.3,
129.1, 128.6, 124.6, 122.6, 120.3, 89.3, 88.8, 35.0, 30.7. HRMS (M+H) for C17H17N, calculated: 236.1441, found: 236.1432.
2-[(E)-2-phenylethenyl]-pyridine (Table 3.3, entry 3f)24a Isolated yield: 40%. 1H
NMR (300MHz, CDCl3): δ 8.62-8.61 (d, 1H), 7.68-7.57 (m, 4H), 7.40-7.25 (m, 4H), 13 7.20-7.12 (m, 2H). C NMR (67.9MHz, CDCl3): δ 155.7, 149.7, 136.7, 136.6, 132.8,
128.8, 128.4, 128.0, 127.2, 122.2, 122.1. HRMS (M+H) for C13H11N, calculated: 182.0967, found: 182.0964.
2-[(Z)-2-phenylethenyl]-pyridine (Table 3.3, entry 3f)24a Isolated yield: 40%. 1H
NMR (300MHz, CDCl3): δ 8.59-8.58 (d, 1H), 7.45-7.40 (t, 1H), 7.27-7.22 (m, 5H), 7.17- 7.14 (d, 1H), 7.10-7.06 (t, 1H), 6.85-6.81 (d, 1H, J=12Hz), 6.70-6.66 (d, 1H, J=12Hz). 13 C NMR (67.9MHz, CDCl3): δ 156.4, 149.6, 136.8, 135.7, 133.3, 130.6, 128.9, 128.3,
127.6, 123.9, 121.8. HRMS (M+H) for C13H11N, calculated: 182.0967, found: 182.0964.
Z-Ethyl-3-(pyridin-2-yl)acrylate (Table 3.3, entry 3g)24b Isolated yield: 22%. 1H
NMR (400MHz, CDCl3): δ 8.60-8.59 (d, 1H), 7.67-7.65 (m, 2H), 7.26-7.19 (t, 1H), 6.96-
6.93 (d, 1H, J=12Hz, CH=CHCO2Et), 6.15-6.12 (d, 1H, J=12Hz, CH=CHCO2Et), 4.24-
85 13 4.19 (q, 2H), 1.28-1.24 (t, 3H). C NMR (67.9MHz, CDCl3): δ 166.9, 153.8, 149.4,
139.9, 136.2, 124.6, 123.3, 123.2, 60.8, 14.3. HRMS (M+H) for C10H11NO2, calculated: 178.0880, found: 178.0862.
E-Ethyl-3-(pyridin-2-yl)acrylate (Table 3.3, entry 3g)24b Isolated yield: 9%. 1H NMR
(500MHz, CDCl3): δ 8.65-8.64 (d, 1H), 7.73-7.67 (m, 2H [7.70-7.67 d, J=15Hz,
CH=CHCO2Et), 7.44-7.42 (d, 1H, J=10Hz Ar-H), 7.27-7.25 (t, 1H), 6.96-6.93 (d, 1H, 13 J=15Hz CH=CHCO2Et), 4.30-4.26 (q, 2H), 1.36-1.32 (t, 3H). C NMR (68.0MHz,
CDCl3): δ 167.0, 153.3, 150.4, 143.5, 136.9, 124.4, 124.3, 122.7, 60.9, 14.5. HRMS
(M+H) for C10H11NO2, calculated: 178.0880, found: 178.0862.
4-Ph-2-[(Z)-2-phenylethenyl]pyridine (Table 3.3, entry 3i)24c Isolated yield: 29% 1 H NMR (300MHz, CDCl3): δ 8.64-8.62 (d, 1H), 7.39-7.26 (m, 12H), 6.93-6.89 (d, 1H, 13 J=12Hz), 6.78-6.74 (d, 1H, J=12Hz). C NMR (125.7MHz, CDCl3): δ 157.0, 150.2, 148.0, 138.4, 137.1, 133.8, 130.9, 129.2, 129.1, 129.0, 128.6, 127.9, 127.1, 122.3, 120.0.
HRMS (M+H) for C19H15N, calculated: 258.1275, found: 258.1277.
4-Ph-2-[(E)-2-phenylethenyl]pyridine (Table 3.3, entry 3j)24c Isolated yield: 20% 1 H NMR (500MHz, CDCl3): δ 8.66-8.65 (d, 1H), 7.73 (s, 1H), 7.70-7.67 (m, 2H [7.70- 7.67, d, 1H, J=15Hz]), 7.62-7.60 (m, 3H), 7.52-7.29 (m, 6H), 7.27-7.24 (m, 2H [7.27- 13 7.24, d, 1H, J=15Hz]). C NMR (125.7MHz, CDCl3): δ 156.4, 150.3, 149.3, 138.6, 137.0, 133.2, 129.3, 129.2, 129.0, 128.6, 128.2, 127.4, 127.2, 120.5, 120.4. HRMS
(M+H) for C19H15N, calculated: 258.1275, found: 258.1277.
3-Br-6-[(Z)-6-phenylethenyl]pyridine (Table 3.3, entry 3k) Isolated yield: 46%. 1H
NMR (300MHz, CDCl3): δ 8.46-8.45 (d, 1H), 7.90-7.87 (d, 1H, J=9Hz), 7.19-7.05 (m, 6H), 6.85-6.81 (d, 1H, J=12H), 6.76-6.72 (d, 1H, J=12Hz). 13C NMR (68.0MHz,
CDCl3): δ 155.9, 148.2, 140.5, 136.2, 134.8, 129.4, 128.2, 128.0, 127.9, 123.6, 121.3.
HRMS (M+H) for C13H10BrN, calculated: 260.0069, found: 260.0068.
86 1H and 13C NMR Spectra:
N
N
87 N O OEt
N O OEt
88 Br
N
Br
N
89 Me
N
Me
N (Minorisomerpk)
Me
N
90 O H
N
O H
N
91 Ph
N Ph
Ph
N Ph
92 N
N
93 N
N
94 NPh
NPh
95 Ph
N
Ph
N
96 CO2Et
N
CO2Et
N
97 O N OEt
O N OEt
98 Ph
N Ph
Ph
N Ph
99 Ph
Ph
N
Ph
Ph
N
100 Br Ph
N
Br Ph
N
101 3.5 References
1 For some recent examples see: a) Nunez, M.J., Guadano, A., Jimenez, I.A., Ravelo, A.G., Gonzalez-Coloma, A., Bazzocchi, I.L.; J. Nat. Prod. 2004, 67, 14-18. b) Kitamura, A., Tanaka, J., Ohtani, I.I., Higa, T.; Tetrahedron 1999, 55, 2487-24. c) O’Hagan, David; Nat. Prod. Rep. 2000, 17, 435–446. d) Duan, H., Takaishi, Y., Momota, H., Ohmoto, Y., Taki, T., Jia, Y., Li, D.; J. Nat. Prod. 2001, 64, 582. e) Tsukamoto, S., Takahashi, M., Matsunaga, S., Fusetami, N., van Soet, R.W.M.; J. Nat. Prod. 2000, 63, 682-684. f) Chang, F-R., Hayashi, K-I., Chen, I-H., Liaw, C-C., Bastow, K.F., Nakanishi, Y., Nozaki, H., Cragg, G.M., Wu, Y-C., Lee, K-H.; J. Nat. Prod. 2003, 66, 1416-1420. g) Horiuch, M., Murakami, C., Fukami, N., Yu, D., Chen, T-H., Bastow, K.F., Zhang, D-C., Takaishi, Y., Imakura, Y., Lee, K-H.; J. Nat. Prod. 2006, 69, 1271. 2 Pyridines are used extensively as ligands, for reviews in this area see: a) von Zelewsky, A.; Coord. Chem. Rev. 1999, 190-192; 811-825. b) van Koten, G., Albrecht, M.; Angew. Chem. Int. Ed. 2001, 40, 3750 – 3781. c) Belda, O., Moberg, C.; Coord. Chem. Rev. 2005, 249(5-6), 727-740. d) Desimoni, G., Faita, G., Quadrelli, P.; Chem. Rev. 2003, 103, 3119-3154. e) Chelucci, G., Thummel, R.; Chem. Rev. 2002, 102, 3129-3170. 3 a) Shifrina, Z.B., Rajadurai, M.S., Firsova, N.V., Bronstein, L.M., Huang, X., Rusanov, A.L., Muellen, K.; Macromolecules 2005, 38, 9920-9932. b) Rauckhorst, M.R., Wilson, P.J., Hatcher, S.A., Hada, C.M., Parquette, J.R.; Tetrahedron 2003, 59, 3917–3923. 4 a) Zheng, J.Y., Feng, X.M., Bai, W.B., Qin, J.G., Zhan, C.M.; Eur. Polym. J. 2005, 41, 2770–2775. b) duBois, C.J., Abboud, K.A., Reynolds, J.R.; J. Phys. Chem. B 2004, 108, 8550-8557. c) Yamamoto, T., Yamaguchi, I., Yasuda, T.; Adv. Polym. Sci. 2005, 177, 181–208. 5 a) Alagille, D., Baldwin, R.M., Roth, B.L., Wroblewski, J.T., Grajkowska, E., Tamagnan, G.D.; Bioorg. Med. Chem. 2005, 13, 197–209. b) Yu, M., Tueckmantel, W., Wang, X., Zhu, A., Kozikowski, A.P., Brownell, A-L.; Nucl. Med. Biol. 2005, 32, 631– 640. c) Jakopec, S., Dubravcic, K., Polanc, S., Kosmrlj, J., Osmak, M.; Toxicol. In Vitro 2006, 20, 217–226. d) Jacguemard, U., Routier, S., Dias, N., Lansiaux, A., Goossens, J- F., Bailly, C., Merour, J-Y.; Eur. J. Med. Chem. 2005, 40, 1087–1095. e) Xiao-fei Zhou,
102 Xinning Yang, Qi Wang, Robert A. Coburn, and Marilyn E. Morris; Drug Metabolism and Disposition (2005), 33(8), 1220-1228. 6 a) A recent review on the construction of pyridines: Henry, G.; Tetrahedron 2004, 60, 6043–6061. b) A recent example of a new method: Altuna-Urquijo, M., Stanforth, S.P., Tarbit, B.; Tetrahedron Lett. 2005, 46, 6111–6113. 7 a) A review: Schroter, S., Stock, C., Bac, T.; Tetrahedron 2005, 61, 2245–2267. b) Cailly, T., Fabis, F., Bouillon, A., Lemaitre, S., Sopkova, J., de Santos, O., Rault, S.; Synlett 2006, pp. 53–56. c) Couve-Bonnaire, S., Carpentier, J-F., Mortreux, A., Castanet, Y.; Tetrahedron 2003, 59, 2793–2799. 8 a) Masselot, D., Charmant, J.P.H., Gallagher, T.; J. Am. Chem. Soc. 2006, 128, 694- 695. b) Lachance, N., April, M., Joly, M-A.; Synthesis 2005, pp. 2571–2577. c) Zhao, J., Yang, X., Jia, X., Luo, S., Zhai, H.; Tetrahedron 2003, 59, 9379–9382. 9 a) Krauss, J., Bracher, F.; Arch. Pharm. Pharm. Med. Chem. 2004, 337, 371-375. b) Feuerstein, M., Doucet, H., Santelli, M.; Tetrahedron Lett. 2005, 46, 1717–1720. c) Sonogashira, K. In Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi, E.-I., Ed.; Wiley-Interscience: New York, 2002 p 493. d) Sonogashira, K. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley- VCH: Weinheim, 1998; p 203. 10 a) Hervet, M., Thery, I., Gueiffier, A., Enguehard-Gueffier, C.; Helv. Chem. Acta 2003, 86, 3461-3469. b) Heller, M., Schubert, U.S.; J. Org. Chem. 2002, 67, 8269-8272. 11 a) Recently an interesting reaction was developed employing pyridine N-oxides in palladium catalyzed type cross-couplings: Campeau, L.-C., Rousseaux, S., Fagnou, K.; J. Am. Chem. Soc. 2005, 127, 18020-18021. b) This methodology was also applied to aromatic diazine N-oxides: Leclerc, J.-P., Fagnou, K., Angew. Chem Int. Ed. 2006, 45, 7781-7786. 12 Black, D.A., Beveridge, R.E., Arndtsen, B.A.; Manuscript in Preparation 13 For reviews on the chemistry of dihydropyridines including their oxidation see: a) Lavilla, R.; J. Chem. Soc. Perkin Trans. 1 2002, 1141–1156. b) Meyers, A.I., Stout, D.; Chem.Rev. 1982, 82, 223-243. c) For an account of using nucleophilic additions to
103 pyridinium salts as a method of regioselective functionalization of pyridines see: Comins, D.L., O’Connor, S.; Adv. in Het. Chem. 1988, 44, 199. 14 Specific examples: a) Lyle, R.E., Comins, D.L.; J. Org. Chem. 1976, 41, 3250. b) Comins, D.L., Abdullah, A.H.; J. Org. Chem. 1982, 47, 4315. c) Comins, D.L., Brown, J.; Tetrahedron Lett. 1984, 25, 3297. 15 For some recent reviews on copper and copper complexes and their use in oxidative organic transformations see: a) Schultz, M.J., Sigman, M.S.; Tetrahedron 2006, 62, 8227. b) Mukherjee, R.; Comp. Coord. Chem. (II) 2004, 6, 747. c) Puzari, A., Baruah, J.B.; J. Mol. Cat. A 2002, 2, 149. d) Feringa, B.; Bioinorg. Chem. Copper 1993, 306. 16 DDQ is a more cost effective quinone oxidant: Aldrich Chem. Co. lists 10g of DDQ at $39 whereas 5g of the same purity grade of o-chloranil is listed at $43. 17 These results suggest that the dihydropyridine intermediate must be formed prior to the addition of the oxidant. 18 The initial alkyne addition to the N-acyl salt of 3-picoline yields a 3:1 mixture of regioisomers selective for the 2-phenylethynyl-3-methyl-1,2-dihydropyridine. After oxidation a small amount of the minor 6-phenylethynyl-3-methyl-pyridine is present in a 9:1 ratio in favour of the major isomer shown. 19 The unreacted 2-phenylethynyl-3-carboxaldehyde-1,2-dihydropyridine regioisomer of compound 2f was almost completely recovered after oxidation. 20 Base mediated aromatizations of dihydropyridines to pyridines are known: a) Fraenkel, G., Cooper, J.W., Fink, C.M.; Angew. Chem. Int. Ed. Engl. 1970, 9, 523. see also ref. 13; recent examples include: b) Corey, E.J., Tian, Y.; Org. Lett. 2005, 7, 5535. c) Singh, R.P., Eggers, G.V., Shreeve, J.M.; Synthesis 2002, 1009. 21 a) Earliest specific report: Agawa, T., Miller, S.I.; J. Amer. Chem. Soc. 1961, 83, 449. b) A useful recent example of using this transformation in a solid-phase approach to some 2-alkenyl-pyridines: Chen, C., Wang, B., Munoz, B.; Synlett 2003, No. 15, 2404. 22 This is consistent with a report on selective Z-enedione synthesis via an IBX-mediated rearrangement of 2-alkynyl alcohols: a) Crone, B., Kirsch, S.F.; Chem. Comm. 2006, pp. 764-766. b) and other base catalyzed rearrangements of acetylenic derivatives: Iwai, I.; Mech. of Mol. Migrations 1969, 2, 73-116.
104 23 References for known 2-alkynyl-pyridine compounds are as follows: a) 2- phenylethynyl-pyridine (Table 3.1, entry 1f): (i) Wang, B., Bonin, M., Micouin, L.; Org. Lett. 2004, 6, 3481. (ii) Shirakawa, E., Kitabata, T., Otsuka, H., Tsuchimoto, T.; Tetrahedron 2006, 61, 9878. b) for both regioisomers of 3-Methyl-2-phenylethynyl- pyridine (Table 3.2, entry 2f): Alagille, D., Baldwin, R.M., Roth, B.L., Wroblewski, J.T., Grajkowska, E., Tamagnon, G.D.; Bioorg. Med. Chem. 2005, 13, 197. c) 3-Br-6- phenylethynyl-pyridine (Table 3.2, entry 2e): Tilley, J.W., Zawoiski, S.; J. Org. Chem. 1988, 53, 386. d) Pyridin-2-yl-propynoic acid ethyl ester (Table 3.2, entry 2d): Sakamoto, T., Shiga, F., Yasuhara, A., Uchiyama, D., Kondo, Y., Yamanaka, H.; Synthesis 1992, No. 8, 746. e) 6-Phenylethynyl-pyridine-3-carbaldehyde (Table 3.2, entry 2g) has not been reported, however, the other ortho-phenyl-alkynyl regioisomer has been reported: (i) Yue, D., Larock, R.C.; Org. Lett. 2004, 6, 1581. (ii) Roesch, K.R., Larock, R. C., J. Or. Chem. 2002, 67, 86. 24 References for known 2-alkenyl compounds are as follows: a) 2-phenylethenyl- pyridine (Table 3.3, entry f): Chen, C., Wang, B., Munoz, B.; Synlett 2003, No. 15, 2404. b) Ethyl-3-(pyridin-2-yl)acrylate (Table 3.3, entry 3g): Heimgartner, G., Raatz, D., Reisser, O.; Tetrahedron 2005, 61, 643-655. c) 4-Ph-2-[(Z)-2-phenylethenyl]pyridine (Table 3.3, entry 3i): Ciutolini, M.A., Byrne, N.E.; J. Chem. Soc. Chem. Commun. 1988, 1230-1231. 25 The coupling constant J for trans isomers is always larger (>10 Hz) than cis isomers and is typically ~15Hz for E-alkenyl-pyridines (see ref 24).
105 CHAPTER 4
Towards a General Method of Pyridine Functionalization by Copper-Catalyzed Organoindium Addition
4.0 Preface
The previous chapters of this thesis have described mild and regioselective methods to couple pyridines with terminal alkynes in the presence of chloroformates (or acid chlorides) and a copper (I) catalyst. While these provide access to both 2-alkynyl- pyridines, and the partially reduced 2-ethynyl-1,2-dihydropyridines, these reactions are limited to the functionalization of pyridines with terminal alkynes. This chapter will outline our attempt to develop a more general method of pyridine ring substitution by a copper-catalyzed addition of organoindium reagents to activated N-acyl pyridinium salts. The reaction was found to be tolerant of various pyridine ring functionalities, but regioselectivities were low. However, this reaction is amenable to the mild functionalization of aromatic azine heterocycles (e.g. benzoxazole, benzothiazole, pthalazine).
4.1 Introduction
The addition of stoichiometric organometallic nucleophiles to N-acyl pyridinium salts is an attractive route to access functionalized pyridine derivatives.1,2 A variety of nucleophiles have been used in this chemistry including Grignards,3 organo-zincs,4 organo-tins,5 and others.6,7 The products of these reactions, 1,2-or 1,4-dihydropyridine derivatives, are interesting products which display some biological activity as NADH mimics,8 and are also useful synthetic intermediates in the synthesis of pyridines2 and natural products.9,10,11 There are, however, some limitations for the synthesis of these compounds in terms of regioselectivity, functional group compatibility, and the use of organometallic reagents that can be employed.
With regards to the latter, many of the common organometallic reagents used in these reactions can be incompatible with common functional groups. For example,
106 regio-control in Grignard additions can be achieved using blocking groups on the pyridine ring, 12 chelation-assisted directed addition,13 or catalytic copper salt influences,3a but these reagents are still not compatible with carbonyl or alcohol containing pyridinium salts.9a The use of other milder organometallic reagents such as organostannanes have been reported to demonstrate better functional group tolerance, but these are restricted to the transfer of allyl-, benzyl- or alkynyl-units.5 For these reasons, it would be advantageous to develop a mild, general, and regioselective method to synthesize these important partially reduced pyridine derivatives.
We have recently reported that pyridines can be functionalized with terminal alkynes in the presence of a copper (I) catalyst to give N-acyl-2-ethynyl-1,2- dihydropyridines in only 20 minutes at ambient temperature.14 While this represents a mild, regioselective, and catalytic method to derivatize pyridine, it is limited to the use of alkynes. Organoindium reagents have been found to be very useful reagents in cross- coupling chemistry. 15 These substrates can transfer all of their organic groups to the electrophile coupling partner (providing high atom economy), and generate low toxicity
InCl3 as by-product. In addition, organoindium reagents are not highly nucleophilic and therefore display good functional group compatibility. We have recently reported that imines can be coupled with organoindium reagents in the presence of acid chlorides and copper catalysts, providing a mild and general route to α-substituted amides.16 Considering the resonance similarity of imines and pyridine, we have investigated the potential of developing a mild and general site-selective method of pyridine functionalization using easily prepared tri-organoindium reagents in a similar procedure.17
4.2 Results and Discussion
As shown in Table 4.1, triphenylindium reacts very slowly with pyridine and ethyl chloroformate, resulting in a poor yield of 4.1 (entry 1a). We have previously demonstrated, however, that copper (I) salts can catalyze the reaction of in situ generated N-acyl iminium salts with these reagents, presumably by transmetallation of the organic
107 units from indium to copper to form a more reactive organo-cuprate intermediate.16 Similarly, we have found that copper(I) salts can significantly improve the efficiency of this reaction (Table 4.1, entries b-e). In the case of CuCl, the addition is both regioselective and high yielding, providing 4.1 in 85% yield (entry 1e).
a Table 4.1 Addition of (Ph)3In reagent to pyridine and ethyl chloroformate Ph
O Catalyst ++ 1/3 InPh3 N EtO Cl N 1:1 THF:CH3CN 0 45 C16hrs EtO O 4.1 Entry Catalyst Yield 4.1 (%) 1a None 8 1b CuI 46 1c CuBr 48 1d Cu(II)(OTf)2 57 1e CuCl 85
a) Typical reaction procedure: pyridine (40 mg, 0.5 mmole), and ethyl chloroformate (61 mg, 0.6 mmole) are combined in the glove box in ~2 mL of CH3CN then added to a vial of CuCl (5 mg, 0.05 mmole) in ~1 mL CH3 CN. To this solution is added (Ph)3In (0.18 mmole) in ~3 mL of THF, the vial is then capped and placed in a 45o C bath for 16 hrs.
The mechanism of this reaction is presumed to occur by transmetallation of an organic fragment from an organoindium reagent to copper, generating a more reactive organo-cuprate in situ (Scheme 4.1). The organo-cuprate could then trap any electrophilic pyridinium salt formed generating product, allowing the copper to re-enter the catalytic cycle. The exact structure of the reactive organometallic species is unknown, and could be a “free” un-coordinated organo-cuprate, or a mixed organoindium/organocuprate.
108 R1 O R1 O
N N R2 + CuCl
2 2 R Cl(x)InR (3-x)
R1 O Cl 2 N O N Cl(x+1)InR (2-x) + R1 Cl CuR2
Scheme 4.1 Proposed mechanism of copper-catalyzed coupling of pyridines with organoindium reagents
As shown in Table 4.2, a variety of functionalized pyridines were compatible with organoindium coupling. This includes a number of halogen, alkyl, nitrile, and even sensitive ring-carbonyl substituted pyridines. The latter can be sensitive to the use of more potent nucleophiles in additions, and often require protection.9a In addition, a range of aryl-indiums can be employed, as well as vinyl substrates. While most reactions were found to give preferential 1,4-addition, regioisomeric mixtures were observed in most cases. For example, in the case of 3-acyl pyridine (Table 4.2, entry2a) all three regioisomers were isolated in equal amounts. Interestingly, the corresponding substituted aromatic pyridine is isolated in entry 2f, presumably formed by the rapid oxidation of the in situ generated N-acyl-1,4-dihydropyridine 4.1.18 This chemistry was also shown to be capable of derivatizing 2-cyano-pyridine (entry 2d), a typically unreactive substrate in related additions.19 However, other similarly 2-substituted pyridines did not yield substituted dihydropyridine addition products (Table 2, entries 2h-k). In the case of entry 2l, effective allyl ketone addition was observed.
109 Table 4.2. Copper-catalyzed coupling of pyridines and organoindium reagentsa
R3 R R1 R1 1 O 10% CuCl ++ 1/3 In(R3)3 + N R2 Cl N N R3 1:1 THF:CH3CN 0 45 C16hrs R2 O R2 O 1,4-addition 1,2-addition
c b Entry Heterocycle R2 R3 Product(s) %Yield
O O O O Me Me Me 2a Me OPh 33 Vinyl N N N N PhO O PhO O PhO O
1:1:1
OMe Br OMe Br Br 2b OEt OMe 35d N N N EtO O EtO O 2:1
O O O
2c OPh Ph N N 55 N PhO O PhO O 2:1
2d OPh Ph 37 (71)e NC N NC N NC N Ph O O Ph O O
3: 1
O O 2e Br OPh Br 15 (31)e N N Ph Ph O O F
Me 2f OEt 48 N F Me
N
Me Me 2g OEt Me Me 37 (59)f N N N Et O2C Me Me EtO O 2: 1 2h OPh -- Br N
Me 2i O OPh -- N
F 2j O OPh -- N Me
2k O OPh HO 62 N N Me Allyl Me
110 a) Typical reaction procedure: pyridine (0.5 mmole), and chloroformate (0.6 mmole) are combined in the
glove box in ~2 mL of CH3CN then added to a vial of CuCl (5 mg, 0.05 mmole) in ~1 mL CH3CN. To this o solution is added (R3)3In (0.18 mmole) in ~3 mL of THF, the vial is then capped and placed in a 45 C bath for 16 hrs. b) Combined yield of all regioisomers. c) Isolated amounts of regioisomers. d) 450C for 24 hrs. e) 450C for 72 hrs. f) 550C for 48 hrs.
While low regioselectivities were observed with pyridines, a number of benzo- fused heterocycles have been found to undergo regioselective functionalization using this protocol. As shown in Table 4.3, this copper-catalyzed derivatization methodology was effective in transferring aryl, alkyl, and vinyl groups to a range of heterocycles (pthalazine, benzoxazole, benzothiazole) in good yield. This chemistry is particularly applicable to these heterocycles containing more than one heteroatom in the ring (Table 4.3, entries 3a-e), since functionalization of these substrates under related addition conditions with nucleophiles can lead to ring-opened products.20,21
111 Table 4.3 Copper-catalyzed coupling of organoindium reagents to aromatic N-heterocyclesa
O 10% CuCl + + 1/3 In(R ) 2 3 N R2 N R1O Cl 1:1 THF:CH3CN R O O 450C16hrs 1
Entry Heterocycle R1 R2 Product(s) %Yield
O O 3a N 61 N CHCCl vinyl O 3 Cl 3CHCO
S S 3b N 91 N Et Ph O EtO
S S 3c N 39 N CHClCH3 iPr O H3CClHCO
N O 3d N 38 CHClCH3 Ph N OCHClCH3 N
EtO N N OEt 3e N 65 Et Et N
a) Typical reaction procedure: heterocycle (0.5 mmole), and chloroformate (0.6 mmole) are combined in
the glove box in ~2 mL of CH3CN then added to a vial of CuCl (5 mg, 0.05 mmole) in ~1 mL CH3CN. To o this solution is added (R2)3In (0.18 mmole) in ~3 mL of THF, the vial is then capped and placed in a 45 C bath for 16 hrs.
4.3 Conclusion
This study has shown that the copper-catalyzed coupling of organoindium reagents with nitrogen containing heterocycles, in the presence of a chloroformate activator, can provide a mild approach to generate partially reduced heterocycle derivatives. Investigations on the application of this coupling towards the synthesis of substituted aromatic pyridines, as well as a catalytic enantioselective variant with chiral ligands are underway.
112 4.4 Experimental
General Procedures
Unless otherwise noted, all manipulations were performed under an inert atmosphere in a Vacuum Atmospheres 553-2 dry box or by using standard Schlenk or vacuum line techniques. All reagents were purchased from Aldrich® and used as received. Acetonitrile was distilled from CaH2 under nitrogen. Deuterated acetonitrile was dried as its protonated analogue, but was transferred under vacuum from the drying agent, and stored over 4Å molecular sieves. Deuterated DMSO and chloroform was dried over 3 Å molecular sieves. All organo-indium reagents were prepared from 15a commercially available Grignard reagents and InCl3 by standard literature procedures and used fresh.
All compounds were characterized by 1H and 13C NMR and HRMS. Regioselectivities for all compounds were determined by 1H NMR, 1D NOESY and 2D 1H-13C HMQC and HMBC experiments, and by comparison to literature data. 1H and 13C were recorded on Varian Mercury 200MHz, 300 MHz, 400 MHz, Unity 500MHz, and JEOL 270 MHz spectrometers. 1D NOESY spectra were recorded on a Varian Mercury 400MHz spectrometer, 2D 1H-13C HMQC and HMBC were recorded on a Varian Mercury 400 or Unity 500MHz spectrometer. Mass spectra were obtained from the McGill University mass spectral facilities.
Typical Procedure for the Synthesis of tri-Organoindium Reagents:
The appropriate Grignard reagent in a solution of THF (0.5 mmole Grignard) was added 0 to a schlenk flask under N2 containing InCl3 (0.18 mmole, 39 mg) in THF at -78 C over a period of 30 minutes (total volume ~ 3 mL THF). The solution was then allowed to warm to room temperature and stirred an additional 30-60 minutes until the solution became relatively clear. The schlenk was then purged into the glove box and the solution used fresh as is.
113 Typical Procedure for the Copper-Catalyzed Coupling of Pyridines, Chloroformates and Organoindium Reagents:
Pyridine (0.5 mmole, 40 mg) and ethyl chloroformate (0.6 mmole, 62 mg) and Copper (I) chloride (0.05 mmole, 5 mg) were combined in the glove box in ~3 mL CH3CN in a large screw cap vial. To this solution was added Ph3In reagent solution (0.18 mmole Ph3In) in ~3 mL THF. The vial was capped, brought out of the box and the reaction mixture was stirred and heated at 450C for 16 hrs. After completion, the solution was concentrated in vacuo, and dissolved in ~30 mL Et2O. Et2O layer washed with sat’d NaHCO3 (~15 mL), then back-extracted with ~15 mL Et2O. Organic layers combined, dried (MgSO4), filtered, and concentrated. The crude residue was then taken up in ~2-3 mL CH2Cl2 and purified by flash column chromatography through silica gel using 10% EtOAc:Hexanes as eluent.
Spectroscopic Data:
Ethyl-4-phenylpyridine-1(4H)-carboxylate (Table 4.1, entry 1e) Isolated Yield: 85%. 1 H NMR (200MHz, CDCl3): δ 7.39-7.22 (m, 5H), 7.03-6.80 (dd, 2H), 5.07-4.85 (br, 2H), 4.36-4.22 (q, 2H), 4.21-4.16 (t, 1H), 1.38-1.31 (t, 3H). 13C NMR (67.9 MHz,
CDCl3): δ 151.5, 145.9, 128.7, 127.8, 127.2, 126.7, 109.5, 62.6, 39.2, 14.4. HRMS
(M+Na) for C14H15NO2; calculated: 252.1003, found: 252.0998.
Phenyl 5-acetyl-2-vinylpyridine-1(2H)-carboxylate (Table 4.2, entry 2a) Isolated 1 Yield: 11%. H NMR (300MHz, CDCl3): δ 7.92 (s, 1H), 7.45-7.12 (m, 5H), 6.66-6.60 (d, 1H), 5.99-5.80 (m, 1H), 5.70-5.61 (m, 1H), 5.43-5.37 (t, 1H), 5.31-5.18 (m, 2H), 2.33 13 (s, 3H). C NMR (67.9 MHz, CDCl3): δ 193.6, 150.7, 134.5, 129.6, 129.4, 129.3,
126.3, 121.3, 120.5, 119.4, 119.0, 116.9, 55.6, 24.8. HRMS (M+Na) for C16H15NO3; calculated: 292.0952, found: 292.0940.
Phenyl 3-acetyl-4-vinylpyridine-1(4H)-carboxylate (Table 4.2, entry 2a) Isolated 1 Yield: 11%. H NMR (300MHz, CDCl3): δ 8.00-7.98 (s, 1H), 7.45-7.18 (m, 5H), 7.05-
114 6.99 (br, d, 1H), 6.00-5.87 (m, 1H), 5.31-5.20 (br, 1H), 5.15-5.04 (m, 2H), 4.10-4.03 (t, 13 1H), 2.38 (s, 3H). C NMR (67.9 MHz, CDCl3): δ 195.8, 150.6, 149.7, 139.7, 132.8, 132.7, 129.6, 126.4, 121.5, 121.2, 115.4, 111.9, 35.0, 25.2. HRMS (M+Na) for
C16H15NO3; calculated: 292.0952, found: 292.0940.
Phenyl 3-acetyl-2-vinylpyridine-1(2H)-carboxylate (Table 4.2, entry 2a) Isolated 1 Yield: 11%. H NMR (200MHz, CDCl3): δ 7.43-7.22 (m, 4H), 7.18-7.09 (d, 2H), 7.06- 6.99 (d, 1H), 6.17-6.00 (br, 1H), 5.89-5.69 (m, 1H), 5.60-5.52 (t, 1H), 5.21-5.09 (m, 2H), 13 2.38 (s, 3H). C NMR (67.9 MHz, CDCl3): δ 194.7, 150.9, 133.2, 133.1, 132.6, 132.1,
130.2, 129.4, 126.0, 121.4, 115.4, 105.0, 52.4, 24.9. HRMS (M+Na) for C16H15NO3; calculated: 292.0952, found: 292.0940.
Ethyl 3-bromo-4-(2-methoxyphenyl)pyridine-1(4H)-carboxylate (Table 4.2, entry 1 2b) Isolated Yield: 35%. H NMR (200MHz, CDCl3): δ 7.38-7.17 (m, 3H), 7.01-6.84 (br, m, 3H), 4.98-4.88 (m, 1H), 4.33-4.26 (q, 2H), 3.85 (s, 3H), 3.82-3.77 (d, 1H), 1.37- 13 1.31 (t, 3H). C NMR (67.9 MHz, CDCl3): δ 156.9, 150.9, 131.5, 129.7, 128.6, 124.9, 120.8, 120.6, 111.6, 109.1, 106.9, 63.1, 55.8, 40.5, 14.5. HRMS (M+Na) for
C15H16BrNO3; calculated: 360.0214, found: 360.0205.
Phenyl 3-formyl-4-phenylpyridine-1(4H)-carboxylate (Table 4.2, entry 2c) Isolated 1 Yield: 38%. H NMR (300MHz, CDCl3): δ 9.41 (s, 1H), 7.91 (s, 1H), 7.48-7.20 (m, 10H), 7.12-7.08 (d, 1H), 5.40-5.35 (m, 1H), 4.59-4.57 (t, 1H). 13C NMR (67.9 MHz,
CDCl3): δ 189.8, 150.5, 149.4, 143.5, 139.4, 129.7, 128.6, 128.1, 127.0, 126.6, 123.8,
121.2, 121.0, 113.8, 37.0. HRMS (M+Na) for C19H15NO3; calculated: 328.0952, found: 328.0942.
Phenyl 3-formyl-6-phenylpyridine-1(6H)-carboxylate (Table 4.2, entry 2c) Isolated 1 Yield: 17%. H NMR (200MHz, CDCl3): δ 9.39 (s, 1H), 7.82 (s, 1H), 7.43-7.20 (m, 8H), 7.12-6.89 (br, 2H), 6.62-6.56 (d, 1H), 6.02-5.98 (d, 1H), 5.82-5.75 (m, 1H). 13C
NMR (67.9 MHz, CDCl3): δ 187.1, 150.5, 142.0, 129.7, 129.5, 128.9, 128.6, 128.1,
115 127.0, 126.4, 123.8, 121.1, 119.5, 115.7, 59.6. HRMS (M+Na) for C19H15NO3; calculated: 328.0952, found: 328.0942.
Phenyl 2-cyano-4-phenylpyridine-1(4H)-carboxylate (Table 4.2, entry 2d) Isolated 1 Yield: 53%. H NMR (200MHz, CDCl3): δ 7.48-7.24 (m, 10H), 7.14-7.09 (dd, 1H), 13 6.07-6.03 (m, 1H), 5.20-5.13 (m, 1H), 4.36-4.31 (t, 1H). C NMR (75.5 MHz, CDCl3): δ 150.6, 148.9, 142.6, 129.7, 129.4, 129.3, 127.9, 127.8, 126.5, 123.6, 121.4, 114.0,
111.5, 110.1, 40.4. HRMS (M+Na) for C19H14N2O2; calculated: 325.0955, found: 325.0947.
Phenyl 6-cyano-2-phenylpyridine-1(2H)-carboxylate (Table 4.2, entry 2d) Isolated 1 Yield: 18%. H NMR (300MHz, CDCl3): δ 7.42-7.25 (m, 10H), 6.44-6.42 (d, 1H, 13 J=6Hz), 6.32-6.28 (m, 2H), 6.15-6.13 (d, 1H, J=6Hz). C NMR (75.5 MHz, CDCl3): δ 151.8, 150.9, 137.7, 130.8, 129.6, 129.0, 127.3, 127.1, 126.3, 125.8, 121.5, 121.3, 115.0,
110.6, 55.6. HRMS (M+Na) for C19H14N2O2; calculated: 325.0955, found: 325.0947.
Phenyl 5-bromo-3-formyl-2-phenylpyridine-1(2H)-carboxylate (Table 4.2, entry 2e) 1 Isolated Yield: 31%. H NMR (300MHz, CDCl3): δ 9.40 (s, 1H), 7.91 (s, 1H), 7.50- 13 7.21 (m, 10H), 7.09-6.98 (br, 1H), 4.69 (s, 1H). C NMR (67.9 MHz, CDCl3): δ 188.6, 150.4, 140.9, 137.4, 129.8, 128.6, 128.5, 127.7, 126.8, 123.5, 122.1, 121.0, 119.3,
11.7, 45.6. HRMS (M+Na) for C19H14BrNO3; calculated: 406.0057, found: 406.0048.
4-(4-flourophenyl)-3-methylpyridine (Table 4.2, entry 2f) Isolated Yield: 48%. 1H 13 NMR (500MHz, CDCl3): δ 8.49-8.45 (d, 1H), 7.30-7.11 (m, 5H), 2.25 (s, 1H). C
NMR (125 MHz, CDCl3): δ 163.8, 161.8, 151.5, 148.5, 147.5, 135.2, 130.5, 124.3,
115.8-115.6 (d, JC-F = 20Hz), 17.4. HRMS (M+H) for C12H10FN; calculated: 188.0896, found: 188.0869.
116 Ethyl 4-(2,6-dimethylphenyl)quinoline-1(4H)-carboxylate (Table 4.2, entry 2g) 1 Isolated Yield: 40%. H NMR (500MHz, CDCl3): δ 8.04-8.01 (d, 1H), 7.22-7.19 (t, 1H), 7.10-6.92 (m, 5H), 6.62-6.59 (d, 1H), 5.21-5.18 (m, 2H), 4.38-4.32 (q, 2H), 2.52- 13 1.90 (br, 6H), 1.41-1.38 (t, 3H). C NMR (125 MHz, CDCl3): δ 153.0, 139.4, 136.0, 130.8, 129.5, 127.2, 127.1, 126.6, 125.1, 125.0, 121.6, 121.5, 113.7, 62.5, 38.1, 20.9,
14.6. HRMS (M+H) for C20H21NO2; calculated: 308.1662, found: 308.1643.
Ethyl 2-(2,6-dimethylphenyl)quinoline-1(2H)-carboxylate (Table 4.2, entry 2g) 1 Isolated Yield: 19%. H NMR (500MHz, CDCl3): δ 7.99-7.96 (d, 1H), 7.21-7.18 (t, 1H), 7.02-6.95 (m, 5H), 6.53-6.50 (t, 1H), 6.39-6.36 (d, 1H), 5.66-5.61 (m, 1H), 4.19- 13 4.05 (dq, 2H), 2.23 (s, 6H), 1.17-1.12 (t, 3H). C NMR (125 MHz, CDCl3): δ 155.6, 139.5, 137.2, 136.5, 129.5, 128.6, 127.1, 127.0, 124.8, 123.8, 123.7, 123.3, 122.1, 62.2,
57.1, 20.7, 14.2. HRMS (M+H) for C20H21NO2; calculated: 308.1662, found: 308.1643.
2-pyridin-2-ylpent-4-en-2-ol (Table 4.2, entry 2k) Isolated Yield: 62%. 1H NMR
(300MHz, CDCl3): δ 8.53-8.51 (d, 1H), 7.71-7.65 (t, 1H), 7.38-7.33 (d, 1H), 7.20-7.18 (m, 1H), 5.67-5.60 (m, 1H), 5.02-4.98 (m, 3H), 2.60-2.56 (d, 2H), 1.55 (s, 3H). 13C
NMR (67.9 MHz, CDCl3): δ 164.7, 147.6, 136.8, 133.9, 121.9, 119.4, 118.2, 74.0, 48.0,
28.5. HRMS (M+H) for C10H13NO; calculated: 164.10709, found: 164.10699.
2,2,2-trichloroethyl 2-vinyl-1,3-benzoxazole-3(2H)-carboxylate (Table 4.3, entry3 a) 1 Isolated Yield: 61%. H NMR (200MHz, CDCl3): δ 7.63-7.47 (br, 1H), 7.02-6.81 (m, 3H), 6.55-6.51 (d, 1H), 6.11-5.92 (m, 1H), 5.66-5.59 (d, 1H), 5.46-5.40 (d, 1H), 4.88- 13 4.82 (s, 2H). C NMR (67.9 MHz, CDCl3): δ 150.3, 149.8, 132.0, 128.2, 124.5, 121.6,
120.1, 114.8, 109.2, 94.9, 93.3, 75.4. HRMS (M+H) for C12H10Cl3NO3; calculated: 321.9825, found: 321.9799.
Ethyl 2-phenyl-1,3-benzothiazole-3(2H)-carboxylate (Table 4.3, entry 3b) Isolated 1 Yield: 91%. H NMR (300MHz, CDCl3): δ 7.86-7.81 (d, 1H), 7.35-7.22 (br, m, 5H),
117 7.18-7.10 (d, 2H), 7.04-6.98 (t, 1H), 6.97 (s, 1H), 4.26-4.19 (q, 2H), 1.25-1.21 (t, 3H). 13 C NMR (68.0 MHz, CDCl3): δ 153.0, 142.6, 138.4, 128.8, 128.5, 127.4, 125.6, 125.4,
124.5, 122.4, 117.4, 66.9, 62.6, 14.4. HRMS (M+Na) for C16H15NO2S; calculated: 308.0723, found: 308.0714.
1-chloroethyl 2-isopropyl-1,3-benzothiazole-3(2H)-carboxylate (Table 4.3, entry 3c) 1 Isolated Yield: 39%. H NMR (200MHz, CDCl3): δ 7.84-7.45 (br, 1H), 7.17-6.97 (m, 3H), 6.74-6.63 (q, 1H), 5.67-5.66 (d, 1H), 2.27-2.12 (m, 1H), 1.92-1.84 (m, 3H), 0.98- 13 0.86 (m, 6H). C NMR (125 MHz, CDCl3): δ 150.3, 138.4, 129.9, 125.2, 122.2, 118.0,
83.2, 72.9, 35.2, 25.6, 18.4, 16.2. HRMS (M+H) for C13H16ClNO2S; calculated: 286.0689, found: 286.0660.
1-chloroethyl 1-phenylphthalazine-2(1H)-carboxylate (Table 4.3, entry 3d) Isolated 1 Yield: 38%. H NMR (200MHz, CDCl3): δ 7.79-7.86 (d, 1H), 7.48-7.41 (t, 1H), 7.40- 7.31 (m, 2H), 7.28-7.20 (m, 6H), 6.70-6.64 (q, 1H), 6.60 (s, 1H), 1.92-1.85 (m, 3H). 13C
NMR (67.9 MHz, CDCl3): δ 152.0, 143.6, 143.4, 142.8, 133.1, 132.1, 128.7, 128.6,
128.0, 127.0, 126.6, 126.3, 83.6, 57.1, 25.4. HRMS (M+Na) for C17H15ClN 2O2; calculated: 337.0722, found: 337.0712.
Ethyl 1-ethylphthalazine-2(1H)-carboxylate (Table 4.3, entry 3e) Isolated Yield: 1 65%. H NMR (200MHz, CDCl3): δ 7.67-6.61 (s, 1H), 7.44-7.21 (m, 3H), 7.14-7.07 (d, 1H), 5.43-5.32 (t, 1H), 4.40-4.29 (q, 2H), 1.75-1.60 (m, 2H), 1.40-1.31 (t, 3H), 0.85-0.76 13 (t, 3H). C NMR (67.9 MHz, CDCl3): δ 154.3, 142.9, 133.7, 131.3, 128.1, 126.4,
125.7, 124.0, 62.8, 54.9, 27.9, 14.7, 9.6. HRMS (M+H) for C13H16N2O2; calculated: 233.1311, found: 233.1281.
118 1H and 13C NMR Spectra:
Ph
N
EtO O
Ph
N
EtO O
119 O Ph
N
PhO O
O Ph
N
PhO O
120 O
N Ph
PhO O
O
N Ph
PhO O
121 Ph
N CN
PhO O
Ph
N CN
PhO O
122 NC NPh
PhO O
NC NPh
PhO O
123 O
N
PhO O
O
N
PhO O
124 O
N
PhO O
O
N
PhO O
125 O
N
PhO O
O
N
PhO O
126 F
N
F
N
127 N
EtO O
N
EtO O
128 N
EtO O
N
EtO O
129 O Br
Ph N
PhO O
O Br
Ph N
PhO O
130 O
N OCl N
O
N OCl N
131 S Ph N O EtO
S Ph N O EtO
132 O
N O Cl3CH2CO
O
N O Cl3CH2CO
133 Et O
N OEt N
Et O
N OEt N
134 OMe Br
N
EtO O
OMe Br
N
EtO O
135 S
N O H3CClHCO
S
N O H3CClHCO
136 OH N Me
OH N Me
137 4.5 References
1 For reviews on the chemistry of dihydropyridines including their synthesis from nucleophilic additions to pyridinium salts see: a) Lavilla, R., J. Chem. Soc., Perkin Trans. 1, 2002, 1141–1156. b) Meyers, A.I., Stout, D., Chem.Rev. 1982, 82, 223-243. c) Eisner, U., Kuthan, J., Chem. Rev. 1972, 72, 1-42 2 a) For a review on the regioselective synthesis of pyridines via nucleophilic additions to pyridinium salts see: Comins, D.L., O’Connor, S.; Adv. in Het. Chem. 1988, 44, 199. Some recent examples: b) Williams, N.A.O., Masdeu, C., Diaz, J.L., Lavilla, R.; Org. Lett. 2006, 8, 5789. c) Bennasar, M-L., Zulaica, E., Roca, T., Alonso, Y., Monerris, M.; Tetrahedron Lett. 2003, 44, 4711. d) Krapcho, P.A., Waterhouse, D.J., Hammach, A., Domenico, R.D., Menta, E., Oliva, A., Spinelli, S.; Synthetic Comm. 1997, 27, 781. e) Lemire, A., Grenon, M., Pourashraf, M., Charett, A.B.; Org. Lett. 2004, 6, 3517. f) Chen, C., Wang, B., Munoz, B.; Synlett 2003, 2404.
3 Selected examples: a) Comins, D.L., Abdullah, A.H.; J. Org. Chem. 1982, 47, 4315. b) Yamaguchi, R., Matsuki, Y., Hata, E.-I., Kawanisi, M.; Bull. Chem. Soc. Jpn. 1987, 60, 215. c) Guilloteau-Bertin, B., Compere, D., Gil, L., Marazano, C., Das, B.C.; Eur. J. Org. Chem. 2000, 1391. d) Barbier, D., Marazano, C., Riche, C., Das, B.C., Poitier, P.; J. Org. Chem. 1998, 63, 1767. e) Ohno, A., Oda, S., Yamazaki, N.; Tetrahedron Lett. 2001, 42, 399. f) Pabel, J., Hofman, G., Wanner, K.T.; Bioorg. Med. Chem. Lett. 2000, 10, 1377. 4 a) Krapcho, A.P., Waterhouse, D.J.; Heterocycles 1999, 51, 737. b) mixed zinc-copper: Le Gall, E., Gosmini, C., Nedelec, J-Y., Perichon, J.; Tetrahedron 2001, 57, 1923. 5 a) Yamaguchi, R., Moriyasu, M., Yoshioka, M., Kawanisi, M.; J. Org. Chem. 1985, 50, 287. b) Yamaguchi, R., Moriyasu, M., Kawanisi, M.; Tetrahedron Lett. 1986, 27, 211. c) Yamaguchi, R., Hata, E-I., Utimoto, K.; Tetrahedron Lett. 1988, 29, 1785. d) Yamaguchi, R., Moriyasu, M., Yoshioka, M., Kawinisi, M.; J. Org. Chem. 1988, 53, 3507.
6 Some organo-cuprate examples: a) Bennasar, M.L., Juan, C., Bosch, J.; Tetrahedron Lett. 1998, 39, 9275. b) Bennasar, M.L., Juan, C., Bosch, J.; Tetrahedron Lett. 2001, 42,
138 585. c) Shih, K-S., Liu, C.W., Hsieh, Y-J., Chen, S-F., Ku, H., Liu, L.T., Lin, Y-C., Huang, H-L., Wang, C-L.; Heterocycles 1999, 51, 2439.
7 a) An organo-titanium example: Gundersen, L-L., Rise, F., Undheim, K.; Tetrahedron 1992, 48, 5647. b) for an organo-cadmium example see ref. 3a. 8 a) Meyers, A.I., Oppenlaender, T.; J. Am. Chem. Soc. 1986, 108, 1989. b) Burgess, V.A., Davies, S.G., Skerlj, R.T.; Tetrahedron: Asymm. 1991, 2, 299. c) Obika, S., Nishiyama, T., Tatematsu, S., Miyashita, K., Imanishi, T.; Tetrahedron 1997, 53, 3073. 9 a) For a review on using N-acyl pyridinium salts for the synthesis of alkaloids see: Comins, D.L.; Joseph, S.; Advances in Nitrogen Heterocycles 1996, 2, 251.; and for more recent accounts: (b) Bates, R.W., Kanicha, S.E.; Tetrahedron 2002, 58, 5957. (c) Buffat, M.; Tetrahedron 2004, 60, 1701. 10 For reviews of the synthetic utility of asymmetric additions to 3-TIPS-4-methoxy- pyridines towards natural product synthesis see: a) Joseph, S., Comins, D.L.; Curr. Opin. Drug Disc. 2002, 5, 870. b) Comins, D.L.; J. Heterocyclic Chem. 1999, 36, 1491. 11 Some recent examples of natural product or bio-active compound synthesis from organometallic additions to pyridinium salts: a) Lemire, A., Charette, A.B.; Org. Lett. 2005, 7, 2747. b) Focken, T., Charette, A.B.; Org. Lett. 2006, 8, 2985. c) Kuethe, J.T., Comins, D.L.; J. Org. Chem. 2004, 69, 5219. d) Bennasar, M-L., Zulaica, E., Alsonso, Y., Bosch, J.; Tetrahedron: Asymm. 2003, 14, 469. 12 a) Eddy, N.B., Murphy, J.G., May, E.L.; J. Org. Chem. 1957, 22, 1370. b) Fraenkel, G., Cooper, J.W., Fink, C.M.; Angew. Chem. Int. Ed. Engl. 1970, 9, 523. c) Lyle, R.E., Marshall, J.L., Comins, D.L.; Tetrahedron Lett. 1977, 18, 1015. d) Lyle, R.E., Comins, D.L.; J. Org. Chem. 1976, 41, 3250. e) Comins, D.L., Joseph, S.P., Goehring, R.R.; J. Am. Chem. Soc. 1994, 116, 4719 and references therein. 13 Charette, A.B., Grenon, M., Lemire, A., Pourashraf, M., Martel, J.; J. Am. Chem Soc. 2001, 123, 11829. 14 a) Beveridge, R.E.; M.Sc. Thesis McGill University 2007. b) Black, D.A., Beveridge, R.E., Arndtsen, B.A.; Manuscript in Preparation. 15 Selected examples: a) Pe´rez, I.; Sestelo, J. P.; Sarandeses, L. A.; J. Am. Chem. Soc. 2001, 123, 4155. and references therein b) Rodriguez, D., Sestelo, J. P., Sarandeses, L.
139 A.; J. Org. Chem. 2004, 69, 8136. c) Riveiros, R., Rodri´guez, D., Sestelo, J. P., Sarandeses, L. A.; Org.Lett. 2006, 8, 1403. d) Li, C.-J., Chan, T.-H.; Tetrahedron 1999, 55, 11149. e) Chauhan, K. K., Frost, C. G.; J. Chem. Soc., Perkin Trans. 1 2000, 3015. f) Ranu, B. C.; Eur. J. Org. Chem. 2000, 2347. g) Fausett, B. W., Liebeskind, L. S.; J. Org. Chem. 2005, 70, 4851. h) Takami, K., Yorimitsu, H., Shinokubo, H., Matsubara, S., Oshima, K.; Org. Lett. 2001, 3, 1997. i) Lee, S. W., Lee, K., Seomoon, D., Kim, S., Kim, H., Kim, H., Shim, E., Lee, M., Lee, S., Kim, M., Lee, P. H.; J. Org. Chem. 2004, 69, 4852. j) Lee, P. H., Lee, S. W., Seomoon, D.; Org. Lett. 2003, 5, 4963. 16 Black, D.A., Arndtsen, B.A.; Org. Lett. 2006, 8, 1991. 17 An indium mediated regioselective allylation of N-acyl pyridinium salts has been reported previously: Loh, T-P., Lye, P-L., Wang, R-B., Sim, K-Y.; Tetrahedron Lett. 2000, 41, 7779. 18 1,4-dihydropyridines are more susceptible to oxidation than the 1,2-regioisomer: Comins, D.L., Brown, J.; Tetrahedron Lett. 1984, 25, 3297. see also refs 2a-d. 19 This is presumably due to these substrates inhibition of pyridinium salt formation, see ref. 1. For a recent example of effective 2-cyano- and 2-bromo-pyridinium salt nucleophilic addition see: Corey, E.J., Tian, Y.; Org. Lett. 2005, 7, 5535. 20 a) Babudri, F., Florio, S., Inguscio, G.; Synthesis 1985, 522. b) Babudri, F., Bartolli, G., Florio, S., Ingrosso, G.; Tetrahedron Lett. 1984, 25, 2047. 21 Organotin reagents can functionalize these substrates in the presence of chloroformates: a) Itoh, T., Hasegawa, H., Nagata, K., Ohsawa, A.; J. Org. Chem. 1994, 59, 1319. b) Itoh, T., Hiroshi, H., Kazuhiro, O., Mamiko,O., Ohsawa, A.; Tetrahedon Lett. 1992, 33, 5399. c) Zhou, J-Y., Chen, Z-G., Wu, S-H.; Synlett 1995, 1117.
140 CHAPTER 5
Conclusions and Future Work
5.1 Summary of Thesis
Nucleophilic addition to N-acyl pyridinium salts is an attractive route to construct substituted pyridine derivatives.1 While effective, the high reactivity of many common organometallic reagent nucleophiles can limit the scope of this chemistry. This thesis has demonstrated how copper catalysis can be used to couple pyridines, and related aromatic heterocycles, with simple substrates, such as terminal alkynes and organoindium reagents, via reactive N-acyl aromatic azine salts. Overall, this provides a mild method to directly functionalize pyridines, and has been used to access a range of pyridine derived products (Scheme 5.1), all in one pot reactions.
R1 R1
N N R1 R3 R3 R2 O 10% Cu HR3 R3 N R Ph 1 R1 O In(R3)3 R Cl 2 N R N 3 N
R2 O
Scheme 5.1 Pyridine derivatives obtained through copper-catalyzed couplings with activated N-acyl pyridinium salts
The copper-catalyzed alkynylation of pyridines in the presence of acyl halide activators has been found to allow the regioselective preparation of a variety of N-acyl-2- ethynyl-1,2-dihydropyridines and other partially reduced alkynylated heterocycles (Chapter 2). This mild, efficient, 20 minute coupling protocol was then used in tandem with oxidants or base to prepare 2-alkynyl- and 2-alkenyl-pyridines directly from the parent heterocycles in one-pot (Chapter 3). In addition, mild organoindium reagents were found to be effective coupling partners with N-acyl aromatic azine salts in the presence of
141 a copper (I) salt catalyst (Chapter 4). This has provided both an atom economical, and relatively general route to construct a range of functionalized heterocycles.
5.2 Future Work
The reactions developed in this thesis are all well designed for application to solid-phase library development. Using a method similar to the REACAP technology outlined in Chapter 1,2 polystyrene supported chloroformate resins could be used in conjunction with the chemistries developed in this thesis for the solid-phase synthesis of substituted pyridines (Scheme 5.2). This method could also potentially be used for the synthesis of piperidines, and other reduced heterocycles if these copper-catalyzed reactions were performed in tandem with hydrogenation sources. Solution-phase hydrogenations with these couplings are also possible. Overall, this could provide a mild and straightforward route to pyridine derivative library development for high-throughput screening. R2 R1 R1
N R 2 N R R HR2 or1/3 In(R2)3 R2 10% Cu cat./[H]/Base R1 1/3 In(R2)3 10%CuCl/Base
N R1 R1 O N Cl O N O Cl HR O 2 10% CuI/Base R1
HR2 N R 10% CuI/DDQ 2
R1
N
R2 Scheme 5.2 Potential solid-phase product synthesis using polystyrene supported chloroformates
142 Considering that the reactions in this thesis are all catalytic in copper, and generate chiral products, there is the potential to achieve enantio-control in these transformations using chiral ligands. In the case of the copper-catalyzed alkyne addition chemistry, this has already been extensively investigated in this laboratoryas a route to prepare chiral cyclic-propargylcarbamates, using axially chiral PINAP ligands (Scheme 5.3).3 The use of organoindium reagents in a related protocol with pyridines is inhibited by the need to separate regioisomers. Catalytic enantioselective organoindium addition would most likely be successful with benzo-fused heterocycles (pthalazine, benzoxazole, benzothiazole, isoquinoline), which contain only one addition site.
O 5% CuCl 5.5% L* * HR Et O Cl 2 N iPr NEt N 2 CH Cl /CH CN R1 2 2 3 Et O O -780C, 14 hr R1=Ph 33%Yield,77%ee R1= TMS 43% Yield, 80% ee Me L*= HN Ph
N N
MeO PPh2
Scheme 5.3 Catalytic enantioselective cyclic propargylcarbamate synthesis
Finally, there is an analogy to be made with these N-acyl pyridinium salts and other metal-catalyzed reactions developed in our laboratory involving related N-acyl iminium salts. Research in our lab has shown that imines in the presence of acid chlorides will oxidatively add to palladium or nickel (0) sources to give amido-metallo- cycles, which have interesting carbon monoxide insertion chemistry. 4 These results have led to the mild, general preparation of a number of bio-active compounds from readily- available starting materials.5 By exploring the use of pyridines in these routes interesting new chemistries could be invented (Scheme 5.4).
143 New Chemistry ?? X Pd(0) N N Pd(L) 2 O R1 O R1 ???
Scheme 5.4 Potential oxidative addition of N-acyl pyridinium salts towards new chemistry development
5.3 References
1 a) Lavilla, R., J. Chem. Soc., Perkin Trans. 1, 2002, 1141–1156. b) Meyers, A.I., Stout, D., Chem.Rev. 1982, 82, 223-243. 2 a) Chen, C., Munoz, B.; Tetrahedron Lett. 1998, 39, 3401. b) Chen, C., McDonald, I.A., Munoz, B.; Tetrahedron Lett. 1998, 39, 217. c) Chen, C., Wang, B., Munoz, B.; Synlett 2003, 2404. d) Chen, C., Munoz, B.; Tetrahedron Lett. 1998, 39, 6781. e) Chen, C., Munoz, B.; Tetrahedron Lett. 1999, 40, 3491. 3 a) Black, D.A.; Ph. D. Thesis, McGill University, 2006, ch. 6. b) Black, D.A., Beveridge, R.E., Arndtsen, B.A.; Manuscript in Preparation. 4 Dghaym, R.D., Dhawan, R., Arndtsen, B.A.; Angew. Chem. Int. Ed. 2001, 40, 3228. 5 a) Dhawan, R., Dghaym, R. D., Arndtsen, B. A.; J. Am. Chem. Soc. 2003, 125, 1474- 1475. b) Dhawan, R., Arndtsen, B. A.; J. Am. Chem. Soc 2004, 126, 468-469. c) Siamaki, A. R., Arndtsen, B. A.; J. Am. Chem. Soc. 2006, 128, 6050-6051. d) Davis, J.L., Dhawan, R., Arndtsen, B.A.; Angew. Chem. Int. Ed. 2004, 43, 590. e) Dhawan, R., Dghaym, R.D., St. Cyr, D.J., Arndtsen, B.A.; Org. Lett. 2006, 8, 3927.
144 APPENDIX A
Studies Directed Towards Using a Copper-Catalyzed Organoindium Addition to Prepare Substituted Pyridines
A.1 Introduction
The research described in Chapter 4 of this thesis demonstrated that organoindium reagents could undergo a copper catalyzed coupling with pyridines and chloroformates, as a mild route to prepare partially reduced pyridine derivatives (Scheme A.1). While useful, a direct pyridine ring substitution is a more desirable synthetic goal because of the widespread application of functionalized aromatic pyridine structures.1 Considering that dihydropyridines can be oxidized to substituted pyridines,2 we envisioned incorporating oxidative conditions with the copper-catalyzed organoindium coupling from Chapter 4 as a potential one pot route to generate substituted pyridines. Our preliminary studies towards this goal are described herein.
R R 2 R R1 1 1 O 10% CuCl + + 1/3 In(R2)3 + N PhO Cl N N R2 1:1 THF:CH3CN R = vinyl, Ar 45-650C 14-72 hrs PhO O PhO O R1=2-CN,3-Br 3 3-CHO, 3-Acyl 1,4-addition 1,2-addition 1,4:1,2 selectivity from 1:1 3:1
Scheme A.1 Copper-catalyzed coupling of substituted pyridines and organoindium reagents
A.2 Results and Discussion
Our initial attempts at this reaction examined the copper-catalyzed reaction of pyridine, ethyl chloroformate, and triphenylindium reagent in the presence of air or under an atmosphere of oxygen, neither of which were successful (Table A.1, entries 1a, 1b). As shown, treatment of the crude reaction pot containing impure intermediate product A.1 with DDQ or o-chloranil quinone oxidants, also failed to yield any 4-phenyl-pyridine
145 product (entries 1c, 1d). It was found, however, that addition of base and mild heating produced A.2 in low yield (entries 1e,f).3
Table A.1 Oxidation attempts to prepare 4-phenylpyridine using a copper-catalyzed organoindium routea Ph Ph
O 10% CuCl [O] + + 1/3 InPh3 N N EtO Cl 1:1 THF:CH3CN N EtO O 450C16hrs A.1 A.2 (not isolated)
Entry [O] Temp. (0C) Time (hrs) Yield A.2 (%) 1ab Air 45 16 - b 1b O2 45 16 - 1c DDQ 45 1 - 1d o-chloranil rm. temp. 1 - 1e Sat’d K2CO3 65 6 12 1f 0.5M KOH 65 6 20
a) Typical reaction procedure: pyridine (40 mg, 0.5 mmole), and ethyl chloroformate (61 mg, 0.6 mmole) are combined in the glove box in ~2 mL’s of CH3CN then added to a vial of CuCl (5 mg, 0.05 mmole) in
~1 mL CH3CN. To this solution is added InPh3 (0.18 mmole) in ~3 mL’s of THF, the vial is then capped and placed in a 45oC bath for 16 hrs then exposed to the conditions described above. b) Modification of initial organoindium coupling conditions (i.e. pyridine, ethyl chloroformate, triphenylindium, CuCl in solvent heated in the presence of air or O2 instead of under N2).
A more convergent approach to 4-phenyl-pyridine was then considered by performing the copper-catalyzed reaction in the presence of base. Direct addition of base to the reaction pot was investigated (Table A.2), and the results showed that addition of ~2 equivalents of DABCO to the reaction pot produced the desired transformation in a low but promising 34% yield (Table A.2, entry 2g). Unfortunately, further attempts to optimize the oxidation conditions using DABCO were unsuccessful (entries 2h-k).
146 Table A.2 Base mediated one-pot one-step synthesis of 4-phenylpyridinea
Ph 10% CuCl O BASE ++1/3 InPh EtO Cl 3 N 1:1 THF:CH3CN N 450C16hrs A.2
Entry Base %Yield A.2 2a Pyridine (5eq.) - 2b NaH (2.4eq.) -
2c K2CO3 (5eq.) 2.5
2d Cs 2CO3 (5eq.) 5 2e DBU (2.2eq.) 10
2f K3PO4 (5eq.) 13 2g DABCO (2.2eq.) 34 2h DABCO (2.2eq.) 25b 2i DABCO (2.2eq.) 15c 2j DABCO (1.2eq.) 27d 2k DABCO (5eq.) 6 a) Typical reaction procedure: pyridine (40 mg, 0.5 mmole), and ethyl chloroformate (61 mg, 0.6 mmole) are combined in the glove box in ~2 mL’s of CH3CN then added to a vial of CuCl (5 mg, 0.05 mmole) in
~1 mL CH3CN. To this solution is added InPh3 (0.18 mmole) in ~3 mL’s of THF then base as shown above. The vial is then capped and placed in a 45oC bath for 16 hrs. b) 450C for 82 hrs. c) 800C for 16 hrs. d) 650C for 24 hrs.
It was then considered that using a more labile chloroformate may result in a more efficient reaction. Drawing an analogy of this procedure with popular amine protecting group strategies, use of Fmoc-Cl as the chloroformate pyridine activator did result in a moderate yield of 4-phenyl-pyridine after a TBAF (tetrabutylammonium flouride) carbamate deprotection (Scheme A.2).4
147 Ph 1) 10% CuCl 1:1 THF:CH3CN O 450C16hrs + + 1/3 InPh3 Fmoc Cl 2) 0.1 M TBAF/DMF N 0 N 55 C4hrs A.2 53% Yield
Scheme A.2 Two-step Fmoc and TBAF mediated synthesis of 4-phenylpyridine
Similar aromatization studies were performed with other heterocycles obtained from organoindium coupling. It was found that treatment of purified A.3 with DDQ or o- chloranil provided good to excellent conversion to the corresponding aromatic 2-phenyl- benzothiazole A.4 (Scheme A.4). When the partially reduced benzoxazole product A.5 was exposed to similar conditions, however, no reaction occurred and complete recovery of the starting material was obtained.
S [O] S N 0 N O CH3CN, 45 C4hrs EtO A.3 A.4 [O] = DDQ, 61% o-chloranil, 87% O DDQ N NP O 0 CH3CN, 45 C4hrs Cl3CH2CO
A.5
Scheme A.3 Oxidation of partially reduced substituted benzoxazole and benzothiazole
A.3 Conclusion
In conclusion, a base mediated procedure for the synthesis of 4-phenyl-pyridine via copper-catalyzed organoindium addition has been developed. It is believed that these methods could also be applied in other organoindium couplings to give substituted
148 aromatic pyridine products. In addition, 2-phenyl-benzothiazole was prepared using the known dihydropyridine oxidants DDQ and o-chloranil.
A.4 Experimental
General Procedures
Unless otherwise noted, all manipulations were performed under an inert atmosphere in a Vacuum Atmospheres 553-2 dry box or by using standard Schlenk or vacuum line techniques. All reagents were purchased from Aldrich® and used as
received. Acetonitrile was distilled from CaH2 under nitrogen. Deuterated acetonitrile was dried as its protonated analogue, but was transferred under vacuum from the drying agent, and stored over 4Å molecular sieves. Deuterated DMSO and chloroform were dried over 3 Å molecular sieves. Organo-indium reagents were prepared as in Chapter 4 of this thesis.
1H and 13C spectra were recorded on Varian Mercury 300 MHz and JEOL 270 MHz spectrometers. Mass spectra were obtained from the McGill University mass spectral facilities. Characterization data for compunds A.2 and A.4 agree with previously reported data.
TBAF and Fmoc Mediated Synthesis of 4-phenylpyridine (Compound A.2, Scheme A.2):
Pyridine (0.5 mmole, 40 mg) and Fmoc (9-flourenylmethyloxycarbonyl) -Cl (0.6 mmole, 156 mg) and copper (I) chloride (0.05 mmole, 5 mg) were combined in the glove
box in ~3 mL CH3CN in a large screw cap vial. To this solution was added Ph3In reagent solution (0.18 mmole) in ~3 mL THF. The vial was capped, brought out of the box and the reaction mixture was stirred and heated at 450C for 16 hrs. The solvent was reduced in vacuo then 4.5 mL of DMF and 0.5 mL of a 1.0 M TBAF (tetrabutylammonium
149 fluoride) solution in THF were added and the mixture heated at 550C for 4 hrs. When
complete, 25 mL Et2O added and the organics washed with 10 mL 0.5 M KOH and 6x
with H2O; aqueous extracts were then washed with 25 mL Et2O which was then washed
4x with 10 mL H2O to completely remove the DMF. Organic extracts were combined,
dried (MgSO4), and the Et2O removed to give 125 mg of crude material which was
dissolved in CH2Cl2 and columned through silica gel using 10% EtOAc:Hexanes to give 1 41 mg (53%) of 4-phenylpyridine (Rf ~ 0.15 in 20% EtOAc:Hex). H NMR (300MHz, 13 CDCl3): δ 8.67-8.62 (d, 2H), 7.67-7.61 (m, 2H), 7.53-7.42 (m, 5H). C NMR (67.9
MHz, CDCl3): δ 150.3, 148.4, 138.2, 129.2, 129.1, 127.1, 121.7. HRMS (M+H) for
C11H9N; calculated: 156.0834, found: 156.0808.
DABCO Mediated Synthesis of 4-phenylpyridine (Compound A.2, Table A.2 entry 2g):
Pyridine (0.5 mmole, 40 mg) and ethyl chloroformate (0.6 mmole, 124 mg) and copper (I) chloride (0.05 mmole, 5 mg) were combined in the glove box in ~3 mL
CH3CN in a large screw cap vial. To this solution was added Ph3In reagent solution (0.18
mmole Ph3In) in ~3 mL THF and DABCO (1.1 mmol, 123 mg). The vial was capped, brought out of the box and the reaction mixture was stirred and heated at 450C for 16 hrs.
The solvent was reduced in vacuo, then 5 mL Et2O and 5 mL H2O added and the vial was stirred for 30 minutes at room temperature then the layers separated and the aqueous
layer washed 2x with 5 mL of Et2O. The organics were combined, dried (MgSO4),
filtered and Et2O rotovaped off and the crude product dissolved in CH2Cl2 and columned through silica gel using 10% EtOAc: Hexanes as eluent to give 26 mg (34%) of 4- phenylpyridine.
Synthesis of 2-phenyl-benzothiazole (Compound A.4, Scheme A.3):
Compound A.3 (0.15 mmol, 42 mg) and o-chloranil (0.15 mmol, 37 mg) were 0 mixed in 5 mL CH3CN and heated at 45 C for 4 hrs. The solution was then columned directly through silica gel using 5% EtOAc:Hex as eluent to give 28 mg (87%) of 2-
150 phenyl-benzothiazole (Rf ~ 0.6 in 20% EtOAc:Hex, CAUTION: the Rf of the starting 1 material compound A.3 is very similar). H NMR (300MHz, CDCl3): δ 8.13-8.07 (m, 3H), 7.93-7.90 (d, 1H, J = 9Hz), 7.54-7.45 (m, 4H), 7.40-7.36 (t, 1H). 13C NMR (75.5
MHz, CDCl3): δ 168.3, 154.4, 135.3, 133.9, 131.2, 129.2, 127.8, 126.5, 125.4, 123.5,
121.8. HRMS (M+H) for C13H9NS; calculated: 212.0529, found: 212.0528.
1H and 13C NMR Spectra for Compounds A.2 and A.4:
N
N
151 S
Ph
N
S
Ph
N
152 A.5 References
1 a) Eicher, T., Hauptmann, S., The Chemistry of Heterocycles, Wiley-VCH Weinheim, Ger., 2003; b) Joule, J.A., Mills, K., Heterocyclic Chemistry, Blackwell Science, Oxford UK, 2000. c) Henry, Gavin D., Tetrahedron 2004,60, 6043. and references therein. 2 a) Lavilla, R., J. Chem. Soc., Perkin Trans. 1, 2002, 1141–1156. b) Meyers, A.I., Stout, D., Chem.Rev. 1982, 82, 223-243. c) Eisner, U., Kuthan, J., Chem. Rev. 1972, 72, 1-42. d) Comins, D.L., O’Connor, S.; Adv. in Het. Chem. 1988, 44, 199. 3 Base mediated aromatization of dihydropyridines are known: a) Fraenkel, G., Cooper, J.W., Fink, C.M.; Angew. Chem. Int. Ed. Engl. 1970, 9, 523. recent examples include: b) Corey, E.J., Tian, Y.; Org. Lett. 2005, 7, 5535. c) Singh, R.P., Eggers, G.V., Shreeve, J.M.; Synthesis 2002, 1009. d) Chen, C., Wang., Munoz, B.; Synlett 2003, No. 15, 2404. 4 Ueki, M., Ameniya, M.; Tetrahedron Lett. 1987, 28, 6617.
153