Application of phase-transfer catalysis (PTC) to reactions of C-H acids with chloroethylenes

2-Phenylalkanenitriles 1 react under PTC conditions with 1,1-or cis-dichloroethylene giving ethynylated products 2 . Nitriles 1 , α -substituted desoxybenzoines 6 , 2-substituted phenylacetaldehydes 8 , 1,3-dialkylindene 10 and substituted diethylmalonates 12 afford with trichloroethylene 1,2-dichlorovinylated derivatives, respectively 3 , 7 , enol ethers 9 , 11 and 13 . PTC reaction of trans-dichloroethylene with 1 or 10 lead to formation of 2-chlorovinylated 14 or ethynylated 16 products, respectively. In majority of cases the products were formed in good yield. The course of these reactions is rationalized.


Introduction
1,1-Dichloroethylene (vinylidene chloride, VC), cis-1,2-dichloroethylene (cis-DE) or trichloroethylene (TRI) easily eliminate hydrogen chloride with formation of chloroacetylene (CA) 1 or dichloroacetylene (DCA), 2,3 respectively when treated with alkali metal hydroxide in the presence of a catalyst, a quaternary ammonium salt 1,2 or in aprotic dipolar solvent 3 (phasetransfer catalysis, PTC [4][5][6][7] ).Both CA and DCA exhibit electrophilic properties hence easily add nucleophiles.From practical point of view the nucleophiles are usually present in reaction mixtures, adding to in situ generated CA or DCA.Thus, PTC technique was successfully applied to reactions of TRI with oxygen, 8 selenium 9-11 and nitrogen 2,[12][13][14][15] nucleophiles leading to formation of the corresponding 1,2-dichlorovinyl substituted derivatives and/or other products.However, PTC has not been used to reactions of C-H acids with dichloroethylenes or TRI.The results of experiments carried out by us in this subject are briefly reviewed below.

Scheme 1
The process was carried out at reflux (ca.40°C) of cyclohexane-ethyl ether mixture, for 2.5-5 h, but preparation of sterically crowded i-propyl derivative 1c required longer time, under inert gas.The use of the latter is essential to prevent oxidation of nitriles 1 to the corresponding phenones and violent burning of chloroacetylene in air.For the latter reason the use of ethyl ether is very desirable since it stabilizes chloroacetylenes by formation of the complexes. 21The process did not take place without the catalyst.Essentially the same results gave cis-DE, but its use did not show any advantages, also it is much more expensive than VC.Careful examination of a mixture from the reaction of 1a with VC carried out at 18°C revealed the presence of a small amount of trans-2-chlorovinyland 1-chlorovinyl substituted derivative, the latter was converted into 2a after prolonged reaction.These compounds may result from cis-addition of 1a¯ to CA and its addition to C-1 of CA, respectively.

Scheme 2
Reasonable route of their formation is given on Scheme 3.

Cl Cl Cl
Cl Cl The carbanions 1¯ by trans-addition to DCA produced highly basic dichlorovinyl anions 3¯ which after protonation afforded trans-products 3. The process was carried out at 5-10°C in ethyl ether, benzyltriethylammonium chloride (TEBAC) as a catalyst was less effective than TBAHS.
When the reaction of nitrile 1c with TRI was performed at ca 35°C products 2c and 4 predominated (Scheme 4, yields determined by GC).The product 4 may be formed either via a cis-addition of 1c¯ to DCA and subsequent elimination of hydrogen chloride, via halogenophilic reaction of 1c¯ with DCA or, less probably, via addition of this anion to TRI, followed by elimination of two equivalents of hydrogen chloride.All these mechanisms were identified in reactions of nucleophiles with TRI or DCA. 23,24Ethynyl substituted derivative 2c probably results from a halogenophilic attack of any anion present in the system on 4. Dichlorovinylation of nitriles substituted at C-2 with a heteroatom afforded products 3i-m which after unmasking of the carbonyl group should give dichlorovinyl-substituted ketones.This transformation was exemplified by efficient conversion of nitrile 3i into transdichlorovinylphenyl ketone (5, Scheme 5).3.2.Reactions of α-substituted desoxybenzoines and α-substituted phenylacetaldehydes PTC dichlorovinylation is not restricted to nitriles 1. Desoxybenzoines α-substituted with alkyl 6a-e or heteroatom 6f-h group reacted with TRI in the presence of 50% aq.sodium hydroxide and TBAHS as a catalyst in ethyl ether to give the expected products 7 usually as mixtures of transand cis-isomers 25

Scheme 6
Because of larger steric crowding in enolate anions, in comparision with nitrile ones, the formation of both stereoisomers of products 7 is probably a result of competitive trans (major pathway) and cis (minor pathway) addition of enolate anions 6¯ to DCA.The result of PTC reaction of ketone 6b with independently synthesized DCA 3 confirmed participation of the latter in the process with TRI.While α-(phenyl)alkylmethyl ketones formed rather complex products mixtures with TRI under PTC conditions (probably isomeric methyl enolate anion was involved), α-(cyano)-α-(phenyl)acetone (6i) afforded dichlorovinylated product 7i in moderate yield (Scheme 6).Ambident character of enolate anions generated from phenylacetaldehyde derivatives 8 was evidenced in their reactions with TRI: only O-trans-dichlorovinyl substituted derivatives 9 were isolated in good yield, the best results gave 50% aq.sodium hydroxide/DMSO base/solvent system 25 (Scheme 7).Apart from spectral data, structure of 9 was confirmed by acid catalyzed hydrolysis which led to formation of the starting aldehyde 8 and others products, due to possible cleavage of both carbon-carbon double bonds.

Scheme 8
Reaction with less acidic ethyl diethylmalonate (12a) did occur in the presence of solid potassium carbonate and TBAHS or in DMSO, while the product 13a was obtained in good yield when 50% aq.sodium hydroxide and TBAHS as a catalyst in diluted with ethyl ether organic phase, were used (with lesser amount of ethyl ether ester functionalities in 12a hydrolyzed).On the other hand, in the case of more acidic phenyl diethylmalonate (12b) solid-liquid carbonate system was sufficiently basic for preparation of 13b.

Reactions of C-H acids with trans-dichloroethylene (trans-DE)
4.1.Reactions of 2-substituted phenylacetonitriles trans-DE eliminates hydrogen chloride on treatment with base, but not as easily as the cis-isomer does. 17Therefore we doubted its usefulness in PTC reactions with C-H acids.Much to our surprise, phenylacetonitriles substituted at C-2 with alkyl 1a-c,e,h or a heteroatom group 1j entered reaction with trans-DE under typical PTC conditions giving trans-2-chlorovinyl substituted nitriles 14 20,27

Scheme 10
Some C-H acids like diphenylacetonitrile, phenylacetonitrile substituted at C-2 with oxy or thio group and 1,3-diphenylbutan-1-one proved inert toward trans-DE.Furthermore, we did not observe formation of CA from trans-DE under PTC conditions, and the products 14 were formed under slightly stronger reaction conditions than used for the typical ethynylation process.Therefore addition-elimination route leading to 14 is correct (Scheme 11).

Scheme 12
The reactions described above were carried out in a solid-liquid PTC system, in the presence of powdered potassium hydroxide and TBAHS as a catalyst in ethyl ether-cyclohexane mixture (in liquid-liquid PTC system much indenes 10 remained intact).There are two routes according to which ethynylation of indenes 10 may occur. 26trans-DE is not so prone to eliminate hydrogen chloride like other dichloethylenes but this process may take place by means of basic indene anions [pK a of heptamethylindene and 2-phenylpropionitrile (1a) are 27.4 and 23, respectively 28 ].If so, addition-elimination route with participation of CA is possible.Another approach consists of addition of indene anions to trans-DE followed by elimination of two equivalents of hydrogen chloride.Detailed investigation revealed that indene anion is indeed basic enough to promote elimination of hydrogen chloride from both trans-DCE as well as from chlorovinylated intermediates.So, these routes probably compete during formation of ethynylated indenes 16.

Conclusions
Results of our investigations indicate that simple PTC methodology allows to synthesize variety of ethynylated, 1,2-dichlorovinylated or 2-chlorovinylated C-H acids using cheap chloroethylenes.Utilization of other C-H acids, elucidation of mechanistic aspects of these processes as well as application of the products formed in organic synthesis is actually searched.
© ARKAT USA, Inc (Scheme 9).Steric crowding around a carbanion center in 1c required the use of a solid-liquid system (powdered potassium hydroxide and TBAHS as a catalyst) to prepare nitrile 14c, albeit in low yield.Cleavage of 14j with Cu(II) salt gave trans-2-chlorovinylphenylketone(15)in moderate yield (Scheme 10).