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SYNTHESES USING ISONITRILES a Thesis Presented by DIONYSIOS PAPAIOANNOU in Partial Fulfilment of the Requirements for the Award

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SYNTHESES USING ISONITRILES a Thesis Presented by DIONYSIOS PAPAIOANNOU in Partial Fulfilment of the Requirements for the Award SYNTHESES USING ISONITRILES A Thesis presented by DIONYSIOS PAPAIOANNOU in partial fulfilment of the requirements for the award of the degree of DOCTOR OF PHILOSOPHY OF THE UNIVERSITY OF LONDON Hofmann Laboratory Chemistry Department DECEMER 1977 Imperial College London S17 2AY To my Parents and Grandmother 2rovS Tovets kat ytayta you 3 ACKNOWLEDGEMENTS I wish to thank : Professor Sir Derek Barton, FRS, for all the encouragement and assistance he has given me, and for • his patient and perceptive guidance of this project. Dr. A. G. M. Barrett for cosupervising this project, for reading the manuscript and giving valuable suggestions. Dr D. A. Widdowson for cosupervising part of this work. Dr. S. Singh for helpful discussions and Dr. R. W. Read for useful suggestions and for reading this Thesis. All my friends and colleagues in the Hofmann Laboratory,_ past and present, whose advice, assistance and good-fellowship were of great value. The staff of the Chemistry Department for their essential analytical, spectral and technical services. Dionysios Papaioannou • ABSTRACT The reactions of isonitriles with carbonyl compounds or their derivatives under basic and acidic conditions and the chemistry of toluene-4-sulphonylmethyl isocyanide (TosMIC) are reviewed. Recent developments in phenol oxidative coupling are also summa.rised. Novel oxidants, including vanadium oxyhalides and thallium(III) trifluoro- acetate, and electroorganic coupling are described in full. Isonitriles have been studied and shown to be useful intermediates in the synthesis of 1-benzylisoquinolines. A novel approach to these alkaloids,. based on TosMIC as a C-N-C synthon and the available aromatic aldehyde C6-C1 units, was explored. The reaction of isonitriles with the acetals of electron rich aromatic aldehydes catalysed by trifluoroacetic acid provided in good yield the alkaloid precursor skeleton. The in vitro cyclisation of bisphenolic substrates as models for the biosynthesis of erysodienone.have been examined. TosMIC and derived isonitriles have been employed in the synthesis of novel bisphenolic derivatives. Phenol oxidative coupling of such substrates lacking a nitrogen function gave a carbocyclic analogue of the biosynthetically important dibenzazonine. This gave further support to an initial C-C coupling rather than the alternative C-N coupling in the phenol oxidative coupling step in the biosynthesis of erysodienone. Further oxidation with diphenylseleninic anhydride gave, in a novel reaction, an o-quinone derivative and not the expected biphenonquinone. • 6 CONTENTS Acknowledgements 3 Abstract • CHAPTER 1. ISONITRILES IN ORGANIC SYNTHESIS 8 1.1 Introduction 9 1.2 Acid induced reactions 10 1.2.1 Lewis acid induced reactions 10 1.2.2 Passerini reaction 18 1.2.3 Four component condensation reactions 22 1.2.4 Reactions of isonitriles with acetals 33 1.3 Base induced reactions 35 1.3.1 Introduction 35 1.3.2 Synthesis of heterocycles 37 1.3.3 Extended chain isonitriles 43 1.3.4 Olefin formation 45 1.4 Toluene-4-sulphonylmethyl isocyanide 51 1.4.1 Introduction 51 1.4.2 Construction of heterocycles 55 1.4.3 Miscellaneous transformations '60 CHAPTER 2, RECENT DEVELOPMENTS IN PHENOL OXIDATIVE COUPLING 65 CHAPTER 3, NOVEL SYNTHESES OF 1-BENZYLISOQUINOLINES 86 3.1 Results and Discussion 87 3.2 Experimental 116 • 7 CHAPTER 4, SOME STUDIES RELATED TO THE BIO- SYNTHESIS OF ERYTHRINA ALKALOIDS 135 4,1 Results and Discussion 136 4.2 Experimental 163 REFERENCES 188 CHAPTER 1 ISONITRILES IN ORGANIC SYNTHESIS 9 1.1 INTRODUCTION Isonitriles are readily available compounds, useful for the synthesis of a wide variety of compounds and are commonly prepared, usually in high yields, by dehydration of N-monosubstituted formamides1,2 using phosgene3, phosphoryl chloride4, toluene-4-sulphonyl chloride51 tri- phenylphosphinejtetrachloromethane8, chloromethylenedi- methylammonium chloride7, or dibromotriphenylphosphorane8 in the presence of a base, usually triethylamine. They are also prepared from the corresponding amines by the Hofmann carbylamine reactionl0 , under phase transfer reaction conditions9 The ylide character of isonitriles accounts for their wide variety of reactions where the isonitrile can act either as a nucleophile or an electro- phile. The isocyano group can also stabilise a-carbanions for reasons which are not fully understood. Dipole stabilisation of the anion is suspected11 mesomeric stabilisation playing no part12 The reactions of iso- nitriles have been frequently reviewed1'57158 and thus this chapter is limited to the acid induced (Section 1.2) and base induced (Section 1.3) reactions with aldehydes, ketones, and their derivatives, and the chemistry of the toluene-4-sulphonylmethyl isocyanide (Section 1.4). 10 1.2 ACID INDUCED REACTIONS 1 ,2.1 Lewis acid induced reactions Kabbel3 and Saegusa et al. 14 independently reported • that with Lewis acid catalysis aldehydes and ketones reacted with isonitriles in the ratio of 1:2 to form the 2,3-diiminooxetanes (1) generally in high yield. 6F3 BF I "-.1, (1 3 :O R CO• 1 ((I+ cif rC-----1■1—R- 3 R1--C—CN—R3 1/ \ 2 ! 2 R R 11 Derivatives with a-hydrogens were isomerised to the unsaturated iminoamides (2), which were further hydrolysed with aqueous acid to form the derived keto- amides15 (3). 13F3 1.4 k.c) zNR3 " 3 RCN-7---C—C—CONHR RC1-1—C--- 3 11 3 1 2 NR R2 NR (2) (1) 3 RCH=C—C—CONHR II R2 0 (3) The methylenepyruvamide derivatives (3) were also prepared by Muller and Zeeh16 from ketones and isonitriles, in the presence of an equivalent of boron trifluoride etherate in aprotic solvents. The 213-diiminooxetanes (1) could be cleaved with hydrogen halides or aqueous carboxylic acids15 to afford the (3-substituted amides (4). b 12 H P f\1R3 0 1 ICO NHR3 R—C--CV R—C 3 I 3 1 2 NR - X R- NR (4) The diiminooxetanes derived from aldehydes (1, R1=H) gave unsaturated hydroxyacrylamides15 (5) on reaction with carboxylic acids. With bromoacetic acid a 13-lactam. (6) was the sole product17 ,„H ( NR3 3 CONHR 2 I-\ (J 4 R —C H —C 3 3 /1 NR • I NR 4 R.. RCO-2 z ) 3 2 .-CONHR , 4 NCOR HO' 1 3 (5) 13 2 R CONHR3 0 3 / 2 CONHR /C=C\ 3 HO N, R H NR3 /CH2---c( CH /) 2 Br ° Br 0 (5, R4. CH2Br) 3 0 CONHR 2 NR3 O (6) Reactions of isonitriles with aldehydes and ketones lead to different products when one of the components is an aromatic derivative. Thus aromatic isonitriles afforded indoleninesl8 (7) while aromatic carbonyl compounds afforded indole carboxamides19 (8) 14 0 BF3 C6H5-NC ■••■■••• 2 N CONHC6H5 1/4N-C6H5 (7) 3 \-+ NR 0 -CH3 CH3 3 R CONHR3 R3 (8) Although aldehydes and ketones react with iso- nitriles normally with carbon to carbon bond formation, 4-methoxybenzoylmethyl isocyanide (9), on heating, gave 4-methoxyphenyl oxazole (10), in almost quantitative yield. In this case an oxygen to carbon bond was formed2° CH 0 CHO 3 3 (9) (10) Schiff bases also reacted with isonitriles, with acid catalysis, to afford various products. Thus aluminium trichloride induced condensation of alkyl isonitriles with the azomethines (11 1' Rl. alkyl) afforded imidazolidines21,22 (12). With the azomethines (11, Rl = phenyl) the N,N'-diphenyl-1-phenyl-2-alkyliminoethylene- diamine (13) was formed22. 16 2 AICI3 C6H50-1=--NR1 R —N C (ii) C6H5 (ii AIC13 V C6H5 1 1 1 R—N—CH—C 2 t AtC13 NR cyclisation R1= C6H5 2.H20 H2O C 6H5 ..../R1 6H5 H 2 NHCHC NH NR 211 RN H C6H5 (1 2 ) (13) 1.7 On the other hand imine (11, Rl= aryl) on heating with t-butyl isocyanide afforded21 azetidines (14) or indoles (15), depending on the substituent X. Traces of hydrogen chloride usually present in the solvent carbon tetrachloride catalysed the above reactions. • C6H C6H5CH=N X -F 2 R-2-N H N 2 / 2 R N NR (14) C6H5CH N k CHC6H5 (15) 18 Consistent with the above mechanism only the 1:2 adduct (14) was formed with the nitro-derivative (X.NO2). In the unsubstituted imine (X=H) the 1:1 adduct (15) and the 1:2 adduct (14) were major and minor products respectively. 1.2.2 Passerini reaction Isonitriles often undergo multicomponent reactions in which more than two reactants combine to form a single product, usually in high yield. For example isonitriles reacted with carboxylic acids and carbonyl compounds, with the exception23 of sterically hindered ketones or some al p-unsaturated ketones, to form a-acyloxycarboxamides24'25 (16). The above type of reaction is known as the Passerini reaction. 0 11 3 H R-1 C- R 2 + R R -CO2 0 4 R CO-C-CONHR3 1/ \.2 R R (16) A variety of different mechanisms has been proposed1 for this reaction but none to date has been experimentally proven. Passerini postulated the geminal diol monocarboxylates (17) as intermediates in this reaction. 2 0 R R 111 2 4 4 \ RCR R CO2H R CO2—C —OH (17) R3NC (16) Baker and Stanonis26 and Dewar27 postulated the dipolar species (18) as an intermediate. 2 0 - R + 31 1 II 2 + R3NC 1. RCR R 0- (18) 4 R CO2H R2 1 n+ 3 (16)-1 R —C—C—NR k OH 0 \R4 20 Another mechanism, which is consistent with the well-known tendency of isonitriles to undergo a-additions, postulated28 the intermediacy of the iminoester (19). 0 111 2 4 4 „.0 C) R CR R CO2H R —C- 11 0 R2 --- 3 R 0...H 0 R4—C// \r (16) -7R1 0—C/ 1-< (19) NR3 In the Passerini reaction replacement of the carboxylic acid by hydrazoic acid29 or aluminium azide28 gave the derived tetrazole (20). 0 R0 CR2 + R3NC -F HN3 o. 1 R2 1 2 R\ R 3 / 3 — C —N—R HO—C—C N--R HO—C I I I Nw-N (20) 21 With hydrazoic acid an electrophilic carbonyl compound was required since in a competing reaction the acid was found to react with isonitriles giving the tetrazole (21).
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