Reactivity of α-Oxophosphonium Ylides: A Contribution to the Mechanistics

Ylides 1f and 1g react with chlorine, with bromine and with N-chlorosuccinimide in the presence of a range of nucleophiles. The 2,3-disubstitutedbutenedioates obtained in this way allow us to gather more information about the mechanism involved. Ylide 1c was also studied showing similar reactivity and leading to the highly selective synthesis of 2,3-disubstituted-3-phenylpropenoates.


Introduction
We have previously studied the reactivity of diethyl 2-oxo-3-triphenylphosphoranylidenebutanedioate 1a with chlorine and bromine in the presence of a range of nucleophiles [1].Triphenylphosphine oxide was eliminated and 2,3-disubstituted diethyl butenedioates were formed (Scheme 1).The reaction of N-bromosuccinimide and N-chlorosuccinimide in methanol also gave 2,3disubstituted diethylbutenedioates. Several of the reactions were highly stereoselective whereas others gave both (E) and (Z) isomers.The method offers a route to some simple tetrasubstituted alkenes of a type that was poorly represented in the literature.The formation of the observed products was explained by postulating isomeric halonium ions as intermediates.These halonium ions could interconvert by way of an acyclic cation (Scheme 2).The opening of the two halonium ions by a nucleophile would lead to the isomeric alkenes after the elimination of triphenylphosphine oxide.

Scheme 3.
Abell et al [3] has also described the reaction of α-oxophosphonium ylides, bearing a terminal carboxylic acid group acting as the nucleophile, with Br2 or SOCl2 and NEt3 which leads to the formation of E-and Z-halo enol lactones.The cyclization proceeds via a halophosphonium salt followed by loss of triphenylphosphine oxide.

Results and Discussion
We decided to investigate this type of reactions with ylides with the general structure 1 where R 1 and R 2 are ester groups, the ylides 1f and 1g.These compounds should show a reactivity similar to 1a in the reaction with halogens and N-chlorosuccinimide in the presence of nucleophiles.However, since ylides 1f and 1g have R 1 ≠ R 2 the study of these reactions with a reagent system XY (electrophile/nucleophile), where X ≠ Y, could allow the gathering of more information concerning the proposed mechanism.
The stabilized ylides 3-oxo-2-triphenylphosphoranylidinebutanedioates 1f and 1g were prepared and their reactions studied.The comparision of the product obtained from 1a [1] with those from 1f and 1g allowed us to establish their stereochemistry.
Table 2 shows the results obtained with ylide 1g.The reaction with hypobromous acid and acetic acid gave this time a mixture of isomers (Z)-8 and (E)-8 being the Z isomer the major component (78:22) in 88% overall yield.The reaction with hypochlorous acid and acetic acid gave a mixture of isomers (Z)-9 and (E)-9 in 50% yield.Ylide 1g also reacted with N-chlorosuccinimide in the presence of methanol giving alkene (E)-10 in 44% yield.On the basis of the 13 C nmr analysis it was possible to determine the regioisomers obtained in the reactions of ylides 1f and 1g.From the 13 C nmr of diethyl (Z)-2,3-dichlorobutenedioate and of ethyl methyl (Z)-2,3-dichlorobutenedioate (Z)-4 we could determine the effect of the substitution of an ethyl ester group by a methyl ester group (Table 3).This substitution leads to a decrease of the chemical shift of the α carbon (∆δ = -0.43)and an increase of the chemical shift of the β carbon (∆δ = + 0.31).Table 3. 13 C chemical shifts (ppm) of diethyl (Z)-2,3-dichloro-butenedioate [1]  The values for the chemical shifts of double bond carbons of alkenes 4-10 were estimated by adding these increments to the chemical shifts of the corresponding diethyl esters.Table 4 shows the results of this analysis for the products (the Z isomers) of the reactions of ylides 1f and 1g with hypobromous and hypochlorous acids in the presence of acetic acid.The comparison of the estimated values with the experimental values allow us to define the regioisomers obtained in each case.The same analysis was carried out with the other alkenes.These results show that the electrophile attacks the carbon of the triphenylphosphoranylidene group of the starting ylide as postulated in Scheme 2. This fact is in agreement with the known halogenation of α-oxophosphonium ylides which gives the salt 11 [4] (Scheme 4).
The reactivity of ylide 1c was also studied.We have previously described the reaction of this ylide with NCS or NBS in the presence of azidotrimethylsilane leading to the corresponding haloazidoalkene with high selectivity [2] (Scheme 3) The reaction of the same ylide with chlorine led to the formation of dichloroalkene 12 with elimination of triphenylphosphine oxide.By analogy with the reactivity of the previously studied ylides we concluded that 12 was the Z isomer and was obtained in 69% yield (Table 5).The reaction with hipobromous acid and acetic acid gave 13 (60% yield) and the reaction with N-chlorosuccinimide in methanol gave alkene 14 in 98% yield.In all cases the reactions showed high stereoselectivity.

Conclusion
The results obtained from the study of the reactivity of ylides 1f, 1g and 1c clearly indicate that the reactions studied follow the mechanism described in Scheme 2, where the halogen binds exclusively to the carbon of the phosphoranylidene group of the starting ylide and the oxygen which is eliminated in the process is from the keto carbonyl group.

General
Unless otherwise indicated all common reagents and solvents were used as obtained from commercial suppliers without further purification.IR spectra were recorded on a Perkin Elmer 1720X FTIR spectrometer. 1 H and 13 C NMR spectra were recorded in deuteriochloroform on a Bruker AMX300 spectrometer.Mass spectra were recorded on a VG Micromass 7070E instrument by chemical ionisation (CI) with isobutane (except where indicated otherwise) or where indicated under electron impact.M.p.'s were recorded on a Leitz Wetzlar 799 hot stage and are uncorrected.Flash column chromatography was performed with Merck 9385 silica as the stationary phase.

1-Ethyl 4-methyl 2-oxo-3-triphenylphosphoranylidenebutanedioate (1f)
Methyl triphenylphosphoranylideneacetate [6] (10.93 g, 32.7 mmol) was dissolved in toluene (80 mL) and the resulting solution was cooled at 5-10 °C.Ethyl oxalyl chloride (3.6 mL, 32.83 mmol) was added dropwise.The reaction mixture was stirred at 5-10 °C for 5 min then at room temperature for 30 min.Diethyl ether (80 mL) was added and an oil separated out.The solution was decanted from the oil and the solvent was removed under reduced pressure.The residue was triturated with ether to give a colourless solid which was isolated by filtration.Water was added to the oil separated by decantation and the resulting solution was extracted with chloroform.After evaporating the solvent and addition of ether, more solid was obtained, giving altogether 8.66 g (70%).

4-Ethyl 1-methyl 2-oxo-3-triphenylphosphoranylidenebutanedioate (1g)
Ethyl triphenylphosphoranylideneacetate [6] (10.39 g, 29.84 mmol) was dissolved in toluene (75 mL) and the resulting solution was cooled at 5-10 °C.Methyl oxalyl chloride (2.1 mL, 29.96 mmol) was added dropwise.The reaction mixture was stirred at 5-10 °C for 5 min then at room temperature for 30 min.Diethyl ether (70 mL) was added and an oil separated out.The solution was decanted from the oil and the solvent was removed under reduced pressure.The residue was triturated with ether to give a colourless solid which was isolated by filtration.Water was added to the oil separated by decantation and the resulting solution was extracted with chloroform.After evaporating the solvent and addition of ether, more solid was obtained, giving altogether 7.46 g (62%).

Ethyl methyl (Z)-2,3-dichlorobutenedioate (Z)-4
The ylide 1f (5.82 g, 13.35 mmol) was dissolved in chloroform (120 mL) and a solutions of chlorine (1 g, 14.1 mmol) in chloroform (120 mL) was added The mixture was stirred at room temperature for 5 min.The organic phase was washed with an aqueous solution of sodium bisulfite and dried over MgSO 4 .The residue obtained upon removal of the solvent was purified by column chromatography [ethyl acetate-hexane (2:1)] leading to the separation of triphenylphosphine oxide and isolation of the diester (Z)-4, an oil, that was purified by distillation at 73 °C/0.1.7Torr (2.18 g, 72%).

1-Ethyl 4-methyl (Z)-2-acetoxy-3-bromobutenedioate (Z)-5
The ylide 1f (3.87 g, 8.9 mmol) was dissolved in a mixture of acetic acid (35 mL) and chloroform (75 mL) and solutions of bromine (1.17 g, 7.3 mmol) and sodium bicarbonate (0.87 g, 10.3 mmol) in water (75 mL) were added.The reaction mixture was stirred at room temperature for 24 h and the organic phase was washed with an aqueous solution of sodium bisulfite and dried over MgSO 4 .The residue obtained upon removal of the solvent was purified by column chromatography [ethyl acetatehexane (2:1)] leading to the separation of triphenylphosphine oxide and isolation of the diester (Z)-5, an oil, that was purified by distillation at 112.5 °C/0.1.7Torr (2.04 g, 78%).

4-Ethyl 1-methyl 2-chloro-3-methoxybutenedioate (E)-7
The ylide 1f (5.82 g, 13.35 mmol) was dissolved in chloroform (60 mL) and a solution of chlorine (2.55 g, 36 mmol) in methanol (45 mL) was added.The reaction was complete after 5 min at room temperature.The organic phase was washed with an aqueous solution of sodium bisulfite and dried over MgSO 4 .The residue obtained upon removal of the solvent was purified by column chromatography [ethyl acetate-hexane (2:1)] leading to the separation of triphenylphosphine oxide and the isolation of the enol ether (E)-7 (1.33 g, 44%) as an oil.

4-Ethyl 1-methyl (Z)-and (E)-2-acetoxy-3-chlorobutenedioate (Z)-9 / (E)-9
The ylide 1g (5.82 g, 13.35 mmol) was dissolved in a mixture of acetic acid (52.5 mL) and chloroform (110 mL) and a solution of chlorine (7.8 g, 10.95 mmol) and sodium bicarbonate (1.32 g, 15.45 mmol) in water (110 mL) was added.The reaction mixture was stirred at room temperature for 24 h and the organic phase was then washed with an aqueous solution of sodium bisulfite and dried over MgSO 4 .The residue obtained upon removal of the solvent was purified by column chromatography [ethyl acetate-hexane (2:1)] leading to the separation of triphenylphosphine oxide and the isolation of a mixture of the alkenes (Z)-9 and (E)-9 (1.67 g, 50%) as an oil, that was purified by distillation at 133 °C/1.7 Torr. 1 H NMR (Z)-9 δ:

4-Ethyl 1-methyl 3-chloro-2-methoxybutenedioate (E)-10
The ylide 1g (3.84 g, 8.8 mmol) was dissolved in chloroform (40 mL) and a solution of Nchlorosuccinimide (1.2 g, 8.8 mmol) in methanol (64 mL) was added.The reaction was complete after 5 min at room temperature.The organic phase was washed with an aqueous solution of sodium bisulfite and dried over MgSO 4 .The residue obtained upon removal of the solvent was purified by column chromatography [ethyl acetate-hexane (2:1)] leading to the separation of triphenylphosphine oxide and the isolation of the enol ether (E)-10 (1.33 g, 44%) as an oil, that was purified by distillation at 119 °C/1.7 Torr.
The residue obtained upon removal of the solvent was purified by column chromatography [ethyl acetate-hexane (1:1)] leading to the separation of triphenylphosphine oxide and isolation of 12, an oil, that was purified by distillation at 23 °C / 2.5 Torr (1.5 g, 69%).
The residue obtained upon removal of the solvent was purified by column chromatography [ethyl acetate-hexane (1:1)] leading to the separation of triphenylphosphine oxide and isolation of 13, an oil, that was purified by distillation at 82.5°C/1.5 Torr (0.84 g, 60%).

Ethyl (E)-2-chloro-3-methoxy-3-phenylpropenoate (14)
The ylide 1c (0.5 g, 1.1 mmol) was dissolved in chloroform (5 mL) and a solution of Nchlorosuccinimide (0.15 g, 1.1 mmol) in methanol (8 mL) was added.The reaction was complete after 10 min at room temperature.The organic phase was washed with an aqueous solution of sodium bisulfite and dried over MgSO 4 .The residue obtained upon removal of the solvent was purified by column chromatography [ethyl acetate-hexane (3:1)] leading to the separation of triphenylphosphine oxide and the isolation of 14 (0.26 g, 98%) as an oil, that was purified by distillation at 91.7 °C/1.5 Torr.

Table 1 .
Products obtained from the ylide 1f.

Table 2 .
Products obtained from the ylide 1g.

Table 5 .
Products obtained from the ylide 1c.