SYNTHETIC APPLICATIONS OF THE SHAPIRO REACTION A thesis submitted by ROBERT MICHAEL ADLINGTON in partial fulfilment of the requirements for the award of the degree of DOCTOR OF PHILOSOPHY OF THE UNIVERSITY OF LONDON CHEMISTRY DEPARTMENT IMPERIAL COLLEGE LONDON SW72AY. SEPTEMBER, 1980. ACKNOWLEDGEMENTS I wish to thank Dr. A.G.M. Barrett for his supervision and friendship during this project. I am also grateful to C.R.A. Godfrey for friendship, Mrs. M. Serrano -Widdowson for her patient typing of this thesis and my colleagues of the Chemistry Department. A special thanks to Kathy, Elanor, Lesley and Fred for encouragement and support. CONTENTS page ABSTRACT 1 INTRODUCTION 2 SECTION I: THE MECHANISM OF THE SHAPIRO REACTION 4 SECTION II: THE SYN-DILITHIO EFFECT 11 SECTION III: IMPORTANT FACTORS RELATING TO THE SHAPIRO REACTION 19 (a) THE SIGNIFICANCE OF CORRECT BASE CHOICE 19 (b i) THE DYNAMIC EFFECT OF DIFFERING SOLVENTS 22 (b ii) SPECIFIC SOLVENTS 23 (c) COMPARISONS OF DIFFERENT ARYLSULPHONYL- RESIDUES 25 (d) THE SIGNIFICANCE OF THE STRUCTURE OF THE KETONE PRECURSOR 29 SECTION IV: RECENT ADVANCES IN THE APPLICATION OF THE SHAPIRO REACTION 35 RESULTS AND DISCUSSION SECTION V: FORMATION OF a-METHYLENE- y-LACTONES BY APPLICATION OF THE SHAPIRO REACTION 38 SECTION VI: SULTONE FORMATION FROM 2,4,6-TRI-ISO- PROPYLBENZENESULPHINIC ACID 50 SECTION VII: NOVEL SYNTHESES OF DIMETHYLENE LACTONES 58 (a) Novel Synthesis of 3,5-Dimethylene- tetrahydrofuran-2-one 58 (b) Novel Syntheses of 3,6-Dimethylene- tetrahydropyran-2-ones 65 SECTION VIII: PREPARATION OF STABILISED VINYL CARBAN IONS 70 SECTION IX: SYNTHETIC APPLICATIONS OF STABILISED VINYL CARBANIONS 82 (a) Studies towards the Preparation of. Obtusilactones 82 (b) The Preparation of a-Methylene --,Lactams 87 page SECTION X: SOME OTHER APPLICATIONS OF THE SHAPIRO 90 REACTION (a) The Preparation of Acetylenes 90 (b) Some Unexpected Results Observed During Sulphonylhydrazone Forming Reactions 94 (c) Reactions of Methyl Acetoacetate 2,4,6-Tri-iso-propylbenzenesulphonyl- hydrazone 95 (d) Reactions of the Vinyl Carbanions with Carbon Disulphide 96 EXPERIMENTAL 98 REFERENCES 198 PUBLICATIONS ABSTRACT The Shapiro reaction is reviewed. The mechanism and synthetic applications of the characteristic reaction intermediates are discussed. A new concise preparation of 3-methylenetetrahydrofuran-2-ones derived via the Shapiro reaction is described; two ketones (or ketone plus aldehyde) and carbon dioxide are shown to be the synthetic equiva- lent of the a-methylene-y-lactones. The basic reaction has been extended to the preparation of the novel 3,5-dimethylenetetrahydrofuran-2-one and 3,6-dimethylenetetrahydropyran-2-one systems. Studies towards the preparation of obtusilactone derivatives, via a novel carbonyl stabilised vinyl carbanion,are reported. The preparation of 3-methylene-azetidin- 2-ones is described. Some unusual reaction products, including a novel sultone derived from 2,4,6-tri-iso-propylbenzenesulphinic acid, are described. 2. INTRODUCTION Toluene-4-sulphonylhydrazine has been shown to react with ketones to form toluene-4-sulphonylhydrazone derivatives in high yield. These substrates (1) reacted with mild bases to form a metallated derivative (2) which upon heating produced a diazo compound (3)51 by the a-eli- mination of the metal arylsulphinate (Scheme 1). The fate of the diazo H o/N Ts N TsNHNl-12 R~ 2 (1) IM+X- IV' NNTs Heat 1 R2 R (3) (2.) = toluene-4-sulphonyl SCHEME 1 compound (3) in the presence of excess base was largely dependent upon the nature of the solvent. If no proton source was available or if the available proton source reacted too slowly with the diazo intermediate, molecular nitrogen would be eliminated and a carbene (4) generated. If, however, proton donation was faster than nitrogen elimination, a diazonium ion was formed. The diazonium ion could lose nitrogen, giving a carbonium ion (5) which would expel a proton with or without previous rearrangement51 (Scheme 2). These reactions are known as the aprotic 3. and protic Bamford-Stevens reactions respectively. (3) N2—~ Ri R2 (4) or H Nz H H® (3) R1 <R2 (5) SCHEME 2 With an alkyllithium reagent, ketone toluene-4-sulphonylhydra- zones with an a-hydrogen atom, were found to react to form the least substituted, unrearranged alkene (6) (Scheme 3). This reaction is termed the Shapiro reaction. H NN Ts 1) RU R CH=CHCH R2R3 R ~/ 2)H20 ' CHRR3 (6) SCHEME 3 4. SECTION I : THE MECHANISM OF THE SHAPIRO REACTION In his introductory communication1, Shapiro suggested that the Shapiro reaction proceeded by a carbanion mechanism (Scheme 4) involving the approach of the alkyllithium reagent at the least hindered and most acidic proton. Other base induced toluene-4-sulphonylhydrazone decompositions are comparable 48,50 H L; NNTs RLi NNTs ( R2HC K 1H H R Li H20 3 R2/~ R3 (7) SCHEME 4 Formation of the vinyl carbanion (7) was consistent with capture by deuterium oxide for a limited number of arylsulphonylhydrazone derivatives1,3. For example', the reaction of camphor toluene-4-sulpho- nylhydrazone (8) with greater than two equivalents of n-butyllithium at room temperature in hexane, followed by deuterium oxide quenching, gave 2-deuterio-2-bornene (10). The position of the deuterium atom was con- firmed by nmr spectroscopy. However', the reaction of 5a-androstan-17- one toluene-4-sulphonylhydrazone (13) with methyllithium in diethyl ether at room temperature gave, on deuterium oxide quenching, the p16 5. androstene containing 60% mono^deuterio-alkene (14). More surprisingly1, the reaction of camphor toluene-4-sulphonylhydrazone (8) with methylli- thium in diethyl ether and subsequently with deuterium oxide gave the 2-bornene (10) with only 10% deuterium incorporation. Shapiro con- cluded that the vinyl carbanion (7) was a reaction intermediate, R (10) =D RR2= H (8) R=H (9) R=D (11)F= H, R2 D (12)R=Li, R2 H H (14) plausibly partially protonated by solvent prior to the additōn of the deuterium oxide quench (Scheme 5). Indeed, Shapiro was able to identify 1 1 R Li RH Li EtO Et + CH3CHO E t+ L i O Et 2/\R 2 / \3 + CH2=CH2 SCHEME 5 6. ethanol in the reaction mixture, and quantitative gas determination1 showed that greater than three equivalents of gas (nitrogen and methane) were produced in his ethereal experiments. Shapiro1 was also able to show that a-proton abstraction had occurred. The reaction of 3,3-dideuteriocamphor toluene-4-sulphonyl- hydrazone (9) with alkyllithium reagents gave 3-deuterio-2-bornene (11). In an attempt to clarify the solvent effect, Shapiro11 conducted further experiments using hexane as reaction solvent. He found that 1,3-diphenylacetone toluene-4-sulphonylhydrazone gave 1,3-diphenylpropene and an undefined mono-deuteriopropene derivative under usual reaction conditions, followed by deuterium oxide quenching. The reaction, however, was heterogeneous. More significantly 1,1,3,3-tetradeuterio-1,3- diphenylacetone toluene-4-sulphonylhydrazone (15) gave both a tetra- deuterio-(16) and a trideuterio-alkene product under the same sequence followed by a water quench (Scheme 6). The product (16) could only have D n 1) BuLi, Hexane Ph (16) Ph 2) H2O 7. Ph N N Ts CD2Ph H (15) + d3 -alkene SCHEME 6 7. resulted from the reaction of a vinyl carbanion intermediate (7) with the initial substrate, or its monoanion derivative. This result indica- tes that Shapiro's initial choice1 of camphor toluene-4-sulphonyl- hydrazone (8) as a model compound was not representative; 2-lithio-2- bornene (12) would be particularly hindered and unlikely to abstract an a-proton from a substrate molecule (or its monoanion equivalent). Hence the vinyl carbanion (12) could be quenched by external deuterium oxide. The steric hindrance of electrophilic attack on 2-lithio-2- 19,23. bornene (12) has been shown in subsequent experiments Reaction of carbanion (12) with other electrophiles, N,N-dimethylformamide and chlorotrimethylsilane, gave only 10-15% yields of the trapped products. In further, more rigorous experiments, Shapiro was able to substan- tiate his mechanistic proposals. Treatment of a ketone toluene-4-sulpho- nylhydrazone in diethyl ether at -78° with one equivalent of methyllithi- 15,51 um ,followed by the addition of methyl iodide and warming to 55°, gave monomethylation on nitrogen. If the ketone toluene-4-sulphonyl- hydrazone15 was treated with two equivalents of methyllithium at low temperature, a discrete dianion (17) was formed which was trapped by electrophiles, deuterium oxide, methyl iodide and acetone on carbon. Warming of the dianion species (17)to room temperature gave the vinyl carbanion intermediate (19) and nitrogen. If N,N,N',N'-tetrāmethyl- ethylenediamine (TMEDA), with or without benzene15 as cosolvent,was used as reaction solvent, then addition of electrophiles (E'+) after gas evolution gave products derived from the vinyl carbanion intermediate (19) in addition to the normal Shapiro olefin product (Scheme 7). Shapiro15 also claimed to have trapped the vinyl diimide anion (18) in low yield, however, no evidence was offered. 8. Li NNTs NNTs NNTs MeI 78° 55° R R R R R ,1R"Li1 7e° 2RLi, 78° j TMEDA Li H NNTs NNTs 1)E® E9=D2O,Mel, H2) 2O CH3COC3 R R R R — (17) - 25; SLOW NaLi -R OB) East Li R R — Os) - E E1 f E =Et Br) Mel, nPrBr SCHEME 7 9. In an accompanying publication, Bond14 demonstrated that vinyl carbanion intermediates (7) could also be generated by the reaction of ketone benzenesulphonylhydrazones in TMEDA with four equivalents of n-butyllithium at -50°, followed by warming to room temperature. Subsequent addition of deuterium oxide gave deuterio-olefins in high yields with high deuterium incorporations (Table 1). TABLE 1 Ketone Product Yield Deuterium (%) incorporation (%) 0 D 100 91 )4c6H 13 H13 ar.0 98 93 96 94 Ph/ PhCH2 Furthermore, Bond20 has shown that the vinyl carbanion inter- mediate (7),generated from a ketone toluene-4-sulphorty t.hydrazone with three and a half equivalents of alkyllithium reagent in TMEDA, could be trapped with a variety of electrophiles, ketones, alkyl halides, carbon dioxide and aldehydes, in moderate to high yields.