Shapiro and Bamford-Stevens reactions – revisited

The Shapiro as well as the Bamford-Stevens reactions are very convenient methods for preparing numerous olefinic compounds from ketones and aldehydes via sulfonylhydrazones. These reactions allow preparation not only simple molecules with a double bond but also larger, complex systems that could have biological activity. Therefore, the synthetical aspects of above-mentioned reactions are of broad interest to organic chemists. This mini review describes the application of Shapiro as well as Bamford-Stevens reactions in the preparation of olefinic compounds.


Introduction
The Shapiro and Bamford-Stevens reactions are excellent synthetical tools which allow the instalment of a double bond into a molecule without adding an additional carbon atom.In recent years, different modifications have been made in this synthetic area, and numerous compounds have been prepared by application of this methodology.
The contribution of 2020 by Mukund Ghavre 1 summarizes the recent developments on Shapiro and Bamford-Stevens reaction, however some important references need be added in order to bring the topic up to date.For this reason we have decided to "revisit" this research area.To facilitate our approach we have not repeated, except for a few examples, the papers listed by Ghavre, 1 but have focused our attention on new contributions.
The Bamford-Stevens reaction was first reported in 1952 2 , while in 1967 Shapiro presented the variant of the original procedure 3 .Generally, the reaction leads to the formation of an alkene when the tosyl hydrazone of an aldehyde or ketone is treated with a strong base.Mechanistically it is a simple elimination reaction followed by a 1,2-hydrogen shift or a protonation in the last step of the reaction.
The Bamford-Stevens reaction and the Shapiro reaction have very similar mechanistic pathways.There is a broad spectrum of bases that can be used, that are important to the course of the reaction.The Bamford-Stevens reaction generally yields highly substituted olefins (thermodynamic products), while the Shapiro reaction yields less substituted olefins because kinetic products were being formed preferentially.In the original reaction developed by Bamford and Stevens strong bases such as NaOMe, NaH, LiH, NaNH2, etc. were used, while in the Shapiro reaction the bases used are alkyllithiums and Grignard reagents.

Shapiro and Bamford-Stevens Reactions -Achievements in Recent Years
In 2014 Baldwin et al. reported the preparation of bicyclo [5.4.0]undeca-2,9-diene 2, employing the Shapiro modification of the Bamford-Stevens reaction, from the bicyclo[5.4.0]undec-9-en-2-one 1.The reaction was carried out in the presence of p-toluenesulfonyl hydrazide, CH3Li and TMEDA as a base and gave 2 in 52% yield. 4
In the same year, Letort et al. published a diastereoselective Shapiro reaction between trisyl hydrazone 5 and aldehydes 6a, 6b using t-BuLi as a base.After acidic hydrolysis of the trimethylsilyl ether, the trans diols 7a and 8a were obtained in 43% and 40% yields, respectively, and the products 7b and 8b in 76% combined yield. 5 In 2014 the entry presented by Olbrich et al. 6 involved the generation of hydrazone 10 from the ketone 9 and further reaction with methyllithium in TMEDA solution.The last step allowed the formation of dihydrobarrelene (11) in 71% yield, without further purification.Also in 2014, Lutz et al. described the conversion of starting ketone 12 to hydrazone 13 and its subsequent functionalization to alkene derivative 14 in 85% yield, as a yellowish oil.The last step, which involved the Shapiro reaction, was reported to form the product with the less substituted double bond.Compound 14 was found to display antiproliferative activity against L-929 cells.  i et al. studied the formation of the substituted cyclohexene 22 employing Shapiro reaction methodology.The starting ketone 21 was converted into the tosyl hydrazone and subsequent reaction with methyllithium led to the formation of the desired cyclic alkene 22, in 81% yield. 9Compound 20 (-)-carvone was also converted to 22 in 55% yield, in a three-step synthetic transformation.In 2015 Fu et al. reported the preparation of enol derivatives employing the Shapiro reaction.Acetophenone (23) as well as cyclopentanone (27a) and cyclohexanone (27b) reacted with 2,4,6-triisopropylbenzenesulfonyl hydrazide (TPSH) and formed trisyl hydrazone derivatives 24, 28a and 28b in 63, 68 and 68% yields, respectively.Further treatment with n-BuLi in the presence of bicyclo[4.2.0]octa-1,3,5-trien-7-one (25) produced alcohols 26, 29a and 29b in 70, 47 and 50% yields, respectively.All obtained alcohols were unstable. 10ang and Dou described the synthesis of olefins 32a and 32b.The starting ketone was converted into hydrazone derivative 31, in 95% yield.Treatment of 31 with LiH provided a mixture of olefins 32a and 32b in 75% yield and in a ratio 15:1.This was the first example of employing lithium hydride as a base in a Shapiro reaction.Using sodium hydride, noticeably lower yields of products (37% yield) were observed. 11In 2016 Buchy et al. investigated the Shapiro reaction with the use of the deuterated isopropylidene endgroup.Firstly, the two-step modification yielded (prop-1-en-2-yl-d5)lithium (35) from trisylhydrazone 34 upon treatment with the n-butyllithium and TMEDA.Trisyl hydrazone 34 was synthesized from deuterated acetone (33) and trisyl hydrazine.Condensation of vinyllithium intermediate 35 with squalen-aldehyde 36 formed allylic alcohol 37, in 59% yield.After efficient application of the isopropylidene terminal group, this method was applied to modify a functionalized compound on both ends.Reaction of vinyllithium 35 and dialdehyde 38 a mixture of two derivatives was obtained, diol 39a and allylic alcohol 39b in 20% and 15% yields, respectively. 12ramoto et al. studied the Shapiro reaction by using five different acetophenone derivatives 40a-e and TPSH.The first step led to the formation of hydrazones 41a-e in yields ranging from 67 to 81%.Subsequent treatment with n-butyllithium in the presence of acrolein, proceeded to afford a series of allylic alcohols 42a-e, in 82 to 97% yields. 13e synthesis of dihydrofuran derivative 45 has been achieved by the Yakura group.The tosyl hydrazone 44 was synthesized in 96% yield from the reaction of ketone 43 with tosyl hydrazide.Treatment of 44 with sodium cyanoborohydride and p-toluenesulfonic acid in DMF led to the formation of desired unsaturated compound 45 in 40% yield.The last step was postulated to proceed through the Bamford−Stevens reaction. 14This method was also reported in another publication of the Yakura group.
Lehne, Ernst and Hopf investigated the synthesis of aromatic hydrocarbons carrying a vinyl substituent.The synthesis of vinyl[2.2.2]paracyclophane (48) featured a conversion of the ketone group of compound 46 to a tosyl hydrazone group in compound 47.The latter was obtained in 79% yield as a mixture of diastereoisomers (ratio 2:1) while further treatment with the n-BuLi led to target molecule 48, in 38% yield.Aromatic hydrocarbons are interesting intermediates, mostly as dienes for Diels-Alder reactions or for polymerization reactions. 16 2017, Yang et al. reported the preparation of clovan-2,9-dione employing the Shapiro reaction as a key, middle step.The synthetic route involved the conversion of the carbonyl group of 49 into a tosyl hydrazone in compound 50 by refluxing with TsNHNH2.The Shapiro reaction of compound 50 with n-butyllithium provided cyclic alkene 51, in 52% yield. 17ng et al. synthesized (-)-englerin in 20 steps that included the Shapiro reaction as the one of key steps.Mixing n-BuLi and hydrazone 53 at -78 °C and further addition of the α,β-unsaturated aldehyde 52 at 40 °C allowed the formation of alcohol 54, in 88% yield, as the main diastereoisomer. 18darau et al. reported the preparation of six-membered spiro olefin 56 by applying the Shapiro reaction.The tosyl hydrazide was mixed with ketone 55 and subsequent treatment with n-butyllithium at low temperature furnished the target alkene, but in only 34% yield. 19rden and Gleason reported a synthesis of a hydrocarbon 58 using the Shapiro-Heath reaction.Ketone 57 was converted to the tosyl hydrazone derivative which was subsequently subjected to reaction with two equivalents of n-butyllithium at low temperature.The hydrocarbon 58 that was isolated amounting to an overall yield of 68%. 20 2019 Singh et al. reported an efficient preparation of 1-phenyl-2-(β-d-glycopyranosyl)ethenes 60a-c employing the Bamford-Stevens methodology.Ketones 59a-c were subjected to reaction with p-toluenesulfonyl hydrazide and acetic acid as a catalyst.The hydrazones obtained were used in the second step involving NaOMe in MeOH which produced the basic conditions.The styrene C-glycosides 60a-c were formed selectively as trans products in 89%, 89% and 84% yields, respectively.Formation of the (E)-ethenes was confirmed by NMR spectroscopy (coupling constants of double bond protons 3 JHH=16 Hz). 21multi-step synthesis of myrsinoic acid F, which is an anti-inflammatory agent, was reported by Mikusek et al.The Shapiro reaction was involved as a key step to obtain an alkenyl iodide that is required to complete the synthesis of the target molecule.Therefore, 2,4,6-triisopropylbenzenesulfonyl hydrazone (61) reacted with nbutyllithium at -78 °C, then prenyl bromide was added to the reaction mixture.In continuation, another equivalent of n-BuLi was added and reaction mixture was allowed to warm up.Subsequently, the reaction mixture was cooled to -78 °C again and the solution was treated with 1,2-diiodoethane.This procedure led to a 91% yield of the iodo-olefin 62. 22  Zimdars et al. prepared functionalized acylsilanes using the Shapiro reaction as a middle step.Ketone 63b was converted into tosyl hydrazone 64b in 90% yield.Compound 64a was commercially available.Further treatment of compounds 64a,b with n-BuLi in the presence of TMEDA and TMSCl led to the formation of vinylsilanes 65a-b, in 48 and 66% yield, respectively. 23ier et al. investigated the transfer hydrogenation protocol for imines, olefins as well as N-heteroarenes using cobalt complexes.Thus, a structurally challenging, polycyclic olefin was synthesized according to the Shapiro reaction protocol.The starting ketone 66 was mixed with tosyl hydrazide in dichloromethane leading to the formation of hydrazone 67, in 52% yield.The second step was undertaken without further purification.Compound 67 reacted with n-BuLi in THF and tricyclic olefin 68 was produced, in 49% yield. 24rillo et al. published a synthesis of natural isomeric ent-beyerene diterpenes which showed antileishmanial activity and were considered as potential drugs for skin leishmaniasis chemotherapy.The synthesis started from natural stevioside which was hydrolyzed to isosteviol (69a), esterified to 69b and then transformed into tosyl hydrazone 70b, in 90% yield.Subsequent subjection to the Bamford-Stevens basic reaction conditions under microwave radiation, caused the conversion of hydrazone 70b into ethyl beyerenoate (71b), in 95% yield.Further reduction of the ester group of 71b to a hydroxymethyl group with LiAlH4 led to the formation of the desired beyerenol. 25 SO 2 HN N 1. n-BuLi, THF, -78 °C -> 60 °C 2. A report by Pinkerton et al. described the preparation of the seco-limonoid BDC ring system containing limonoids.The synthetic route involved the Shapiro reaction as a key internal step.Ketone 72 reacted with Li and NH3, then was mixed with tosyl hydrazide to obtain the hydrazone derivative.Finally, reaction of the latter with lithium N,N-diisopropylamide in anhydrous THF afforded the cyclohexene 73, in 76% yield. 26 2020 Fumito et al. reported the multi-step synthesis of perhydroazulenes.The Shapiro reaction was used to convert the unsaturated β-hydroxy ketone 74 into cyclic unsaturated alcohol 75.Compound 74 found to be unstable, therefore, on formation it was subjected to subsequent reactions.Firstly, the olefin group was hydrogenated in the presence of hydrogen and PtO2 as catalyst.Further treatment with tosyl hydrazide led to the corresponding tosyl hydrazone, which was reacted with TMEDA and n-BuLi to give diastereomerically pure product 75, in 44% yield. 27schat et al. presented the synthesis of functionalized hydropentalenes which play an important role as ligands for asymmetric catalysis and as building blocks for natural products.The Shapiro reaction was employed as a middle step in the synthetic path.Thus, the ketone functionality, in the acetal-protected ketone 76 was removed by reaction with tosyl hydrazide to afford an intermediate tosyl hydrazone which was further treated with n-BuLi in the presence of TMEDA, to produce cyclic alkene 77, in 82% yield. 28lkinson et al. presented the synthesis of 4,5-dimethoxyphenanthrene (79) via the Bamford-Stevens reaction.Firstly, dialdehyde 78 was converted into the corresponding bistosyl hydrazone by the reaction with tosyl hydrazide and subsequently, using sodium hydride, transformed into the desired cyclic alkene 79, but in only 18% yield. 29© AUTHOR(S) Bi et al. published a strategy to prepare tetrahydrocarbazol-1-ones and indolo[2,3-a]carbazoles with, among others, arylhydrazines.This work presents an efficient one-pot synthetic route for the functionalization of alkenylboronic acids.The cyclic alkenylboronic acids 82 were obtained from the ketones 80 in the reaction with tosyl hydrazide and subsequently, with TMEDA, n-butyllithium and then 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.The last step involved treating compounds 82 with NaIO4 to afford final products 83, in good yields. 30bayashi's group synthesized (S)-α-phellandrene, an important terpene product, through a three-step sequence, involving the Shapiro reaction under conditions of continuous flow, for the first time.The procedure consists of platinum-catalyzed hydrogenation, subsequent formation of hydrazone and finally the application of the Shapiro reaction.The first step was the selective hydrogenation of alkene 84 in the presence of dimethylpolysilane Pt catalyst (DMPS-Pt) supported on activated carbon and calcium phosphate (AC-CP).Next the α,β-unsaturated ketone group of 85 was reacted with tosyl hydrazide in the presence of sulfonic acid resin and the obtained tosyl hydrazone 86 was subjected to the Shapiro reaction yielding the desired product 87, in 88% yield and 96% purity. 31 the end of 2021, Lombardo et al. reported an enantiopure kilogram synthesis of (S)-1-benzyl-4-bromo-3methyl-1,2,3,6-tetrahydropyridine (92) which is an important precursor to other piperidines, used as intermediates in drug synthesis.Ketone 88 reacted with tosyl hydrazide to yield tosyl hydrazone 89, in 87% yield.Subsequent Shapiro reaction gave bromoalkene 90 and olefin 91 as a byproduct which was removed by chromatographic separation.Final addition of di-p-toluoyl-L-tartaric acid provided salt 92, in 95% yield. 32ng et al. 33 investigated the synthesis of di-, tri-as well as tetra-substituted alkenylboronates due to the catalytic oxidative borylation reaction of tosyl hydrazones 94 from ketones 93.A highly efficient and practical method was presented for the synthesis of 83 alkenyl derivatives 95.

n-BuLi
Furthermore, Wang's group using the same strategy synthesized the cyclic alkenylboronates which cannot be prepared by alkene hydroboration.The final products were obtained from the corresponding cyclic N-tosyl hydrazones 96a-j in moderate (33% for 97j) to good yields (88% for 97g).At the beginning of 2022, Prunet et al. presented two synthetic routes towards Taxol synthesis involving a relay ring-closing metathesis reaction.A Shapiro reaction was used as a middle step to obtain the diol 100 via the reaction of trisyl hydrazone 99 with aldehyde 98, in the presence of t-BuLi. 34 2022, Sukowski and co-workers reported a new catalytic system which was based on Pd/norbornene as well as S,O-ligand for the arylation of aryl esters.Norbornene 103 was prepared by Bamford-Stevens reaction using camphor 101 as a starting material and reacted it with tosyl hydrazide.In the second step, the desired product was obtained in 27% yield after reaction with MeLi. 35 et al. presented the visible-light-inducted annulation of phosphoryl diazomethylarenes and pyridinium 1,4-zwitterionic thiolates leading to the dicarboxylate derivatives.The diazophosphinates and diazophosphonates were synthesized from tosyl hydrazones 105a-p which reacted with sodium carbonate to yield the final products 106a-p in rather moderate yields.

(b-d), or iodine, produced aldehyde 19a, alcohols 19b-d or iodide 19e in
Sharpe and Johnson published in 2015 a report using five different tosyl hydrazone derivatives in a typical Shapiro reaction.The starting ketone 15 was transformed into tosyl hydrazone 16 in 97% yield.Oxidation of 16 with m-CPBA caused ring closure and allowed formation of a pyran, via initial stereoselective epoxidation in the presence of a tosyl hydrazone group.The next step involved protection of the alcohol by a TBS group that gave the silyl ether tosyl hydrazone 17, in 77% yield.Methylation of 17 with MeI in the presence of n-BuLi proceeded to give product 18 in 95% yield.The last step, a Shapiro reaction, followed by treatment with either DMF, different aldehydes X Cl, Br, CF 3 , OCF 3 , OCHF 2 , Me, t-Bu, Ph, OMe, NMe 2 , SMe