Addition of nucleophiles to ( E )-3-phenylsulfonylprop-2-enenitrile: a route to β -substituted α , β -unsaturated nitriles and to acetals of cyanoacetaldehyde

( E )-3-Phenylsulfonylprop-2-enenitrile reacts with sulfur-, oxygen-and carbon-based nucleophiles to yield ( E )-configured β -substituted α , β -unsaturated nitriles via a regiospecific addition-elimination sequence.


Introduction
We have recently reported 1 on the powerful dienophilic reactivity of (E)-3-phenylsulfonylprop-2-enenitrile 1.This strongly electron-deficient alkene undergoes facile cycloaddition reactions with a variety of dienes to yield Diels-Alder adducts.We demonstrated that benzenesulfinic acid could be eliminated from some of these adducts when they were treated with the strong base potassium tert-butoxide: compound 1 is therefore an effective cyanoacetylene 2 equivalent in cycloaddition chemistry.Cyanoacetylene itself is a relatively unstable 2 species, existing 3 in interstellar dust clouds and in the atmosphere of Titan, the largest moon of Saturn.We considered that the nitrile 1 should also be capable of acting as a cyanoacetylene equivalent in nucleophilic addition reactions.Thus (Figure 2), reaction of 1 with a nucleophile at its sulfonyl-substituted olefinic carbon atom should lead to the trisubstituted addition product 3. Subsequent base-catalysed elimination of benzenesulfinic acid from 3 should then yield a βsubstituted α,β-unsaturated nitrile 4. In an alternative reaction pathway, where 1 might act as an equivalent for phenylsulfonylethyne 5, a nucleophile could attack 1 at C-2, leading to a different addition product 6.Elimination of hydrogen cyanide from 6 would then give an α,β-unsaturated sulfone 7. The regioselectivity of a reaction between a nucleophile and the alkene 1 is difficult to predict ab initio.Nesmeyanov et al. 4 have suggested that the regioselectivities of nucleophilic addition reactions to ethenes 8 bearing different electron-withdrawing groups at C-1 and at C-2 may be determined by the relative stabilities of the intermediate carbanionic species 9 and 10.Although this approach fails to take account of factors such as solvation and steric hindrance it provides a useful starting point for considering these reactions.Reactions of the Michael acceptor 1 with the secondary amine pyrrolidine have been described by Benedetti et al. 5 When an excess of pyrrolidine was employed the major products obtained from these reactions were the β-amino-α,β-unsaturated nitrile 11 and the β-amino-α,β-unsaturated sulfone 12, formed in 1 : 1 ratio.Following Nesmayanov, 4 this result was interpreted as reflecting the comparable stabilities of each of the intermediate carbanions 13 and 14 (pK a for H 3 CSO 2 Ph = 29; pK a for H 3 CCN = 31: both values are for DMSO solutions 6 ).
The same group 5 also investigated the reaction of 1 with methanol in the presence of catalytic amounts of sodium methoxide.The acetal 15 was obtained as the sole product, presumably via further addition of methoxide ion to β-methoxyacrylonitrile 16 that was formed by an initial addition-elimination reaction between the sulfonylnitrile 1 and methoxide.Benedetti et al. suggest 5 that the regioselectivity of this overall reaction is only apparent, that both of the intermediate carbanions 17 and 18 are actually formed, and that the outcome reflects the fact that elimination of cyanide ion from 18 cannot compete with the elimination of the better leaving group methoxide.It was clear that a study of the reactions between the reactive alkene 1 and a wider spectrum of nucleophiles was warranted.In this paper we describe the outcome of our investigations into the addition reactions between 1 and a range of sulfur-, oxygen-and carbon-based species.

Results and Discussion
We first examined the reactions of the nitrile 1 with thiophenol.When exposed to one equivalent each of thiophenol and triethylamine in chloroform solution (E)-β-thiophenylacrylonitrile 19 was obtained in 76% yield.This compound has been synthesised previously by several authors, [7][8][9] but each of the routes that have been described are multi-step, and most give mixtures of (E)-and (Z)-products.We did not detect measurable amounts of (Z)-isomers in this or any of the other addition -elimination reaction products described in this paper.
When 1 was reacted with a fourfold excess of each of thiophenol and triethylamine the thioacetal 20 (90%) was formed.This compound represents a masked form of cyanoacetaldehyde, and has been synthesised previously via a less direct route.Reactions of (E)-phenylsulfonylprop-2-enenitrile 1 with dithiols could be controlled to yield either monomeric or dimeric products.Thus, when 1 was reacted with one equivalent of ethanedithiol in the presence of four equivalents of triethylamine the major product was 2cyanomethyl-1,3-dithiolane 21 (77%). 11The minor product of this reaction was the dimeric thioenol ether 22. Similar results were obtained when propane-1,3-dithiol was employed as nucleophile, yielding 2-cyanomethyl-1,3-dithiane 23 (53%), together with lesser amounts of the bis-thioether 24.The dimeric products 22 and 24 could be made to predominate (in yields of, respectively, 89 and 94%) by reacting two equivalents of 1 with one equivalent of dithiol in the presence of triethylamine.The dithiane 23 has been previously obtained in 26% yield via reaction of the chlorozinc derivative of 1,3-dithiane with iodoacetonitrile. 12hen 2-hydroxyethanethiol was used as the nucleophile, addition to 1 took place exclusively through its sulfur atom in the presence of triethylamine, to yield the thioenol ether 25 (47%).No trace of the oxathiolane 26, a potential cyclisation product, could be detected.
Failure of the hydroxyl group of 25 to undergo an intramolecular nucleophilic addition reaction under the conditions that were employed was duplicated when we attempted to carry out the addition of alcohols to 1 under the same regime.However, reaction of 1 with a slight excess of sodium ethoxide in THF afforded β-ethoxyprop-2-enenitrile 27 in 51% yield.This contrasts with the result obtained by Benedetti et al. 5 who obtained the acetal 15, the product of sequential addition-elimination-addition reactions, by reaction of 1 with catalytic sodium methoxide in methanol.We have obtained the corresponding diethyl acetal 28 in 72% yield by reaction of 1 with an excess of sodium ethoxide in THF.An advantage of using our conditions is that reaction can be terminated at the β-alkoxypropenenitrile stage.The  syntheses of some βalkoxypropenenitriles have been described by Scotti, 13 who prepared them from the (E)-or (Z)isomers of 3-chloropropenenitrile, and also by Prange 14 who utilised a more complex route involving high-pressure condensation of the anion of acetonitrile with carbon monoxide, followed by trapping of the derived enolate using chloroethane.
We next examined the addition of carbon nucleophiles to 1.All attempts to effect the addition of stabilised carbanionic species, such as the anions of diethyl malonate, ethyl acetoacetate or pentane-2,4-dione, met with failure.The starting material 1 was recovered, and material derived from it via probable anionic polymerisation 1 was formed.However, the addition of Grignard reagents to (E)-phenylsulfonylprop-2-enenitrile 1 proceeded smoothly at the sulfonyl terminus to give the expected products of an addition-elimination sequence.Thus, ethyl-, cyclohexyl-, phenyl-and hex-1-ynylmagnesium halides all afforded useful yields of the derived (E)-α,β-unsaturated nitriles 32 (57%), 33 (59%), 34 (78%) and 35 (68%).The α,β-unsaturated sulfones 36 that would result from 1 via attack of an organomagnesium compound at C-2 were not detected.Since the addition of an organomagnesium reagent to 1 cannot be a reversible process we conclude that nucleophilic attack by the organometallic takes place regiospecifically at C-3.

Experimental Section
General Procedures. 1 H NMR spectra were obtained for solutions in CDCl 3 using a JEOL PMX-60 spectrometer.Coupling constants J are reported in Hz.IR spectra were recorded as liquid films (L) or Nujol mulls (N) using Perkin-Elmer 298, Perkin-Elmer 883 or Paragon FT-IR instruments.Melting points were obtained using a Stuart Scientific SMP2 apparatus and are uncorrected.TLC was performed using Merck 60F 254 silica-coated plates.Column chromatography was carried out using Merck Kieselgel 60, 70-230 mesh.All solvents were distilled before use.Elemental analyses were performed by the Microanalytical Laboratory, University College Dublin.
(E)-3-Phenylsulfonylprop-2-enenitrile (1).Was prepared as described by us 1 and had m.p. 93-94 o C (ethyl acetate -hexane).(E)-3-Thiophenylprop-2-enenitrile (19).The sulfone 1 (4.0 g, 20 mmol) and freshly distilled thiophenol (2.28 g, 20 mmol) were dissolved in chloroform (50 mL).To this stirred solution was added triethylamine (2.1 g, 20 mmol) at such a rate that the temperature of the mixture did not exceed 25 o C.After 2 hr the solvent was evaporated, the residue was taken up in ether and the ethereal extract was washed with hydrochloric acid solution and then with sodium hydroxide solution.The extract was dried, solvent was removed, and the residue was distilled to give the product 19 as an oil (  20).(a) From (E)-3-phenylsulfonylprop-2-enenitrile (1).To a stirred solution of the sulfone 1 (1.93 g) in chloroform (30 mL) with thiophenol (4.4 g, 4 eq.) was added triethylamine (4.04 g, 4 eq.) at such a rate that the temperature did not rise about 20 o C.After 2 hr solvent was evaporated at reduced pressure and the residue was taken up in ether.The extract was washed sequentially with dilute hydrochloric acid and with sodium hydroxide solution, dried and evaporated to yield the thioacetal 20 as an oil (2.44 g, 90%) (lit. 10