Synthesis of 3,3-diarylpyrrolidines from diaryl ketones

3,3-Diarylsuccinic acids 4 were prepared from diaryl ketones by the Knoevenagel condensation with ethyl cyanoacete followed by KCN addition and hydrolysis. These were cyclised using primary amines to the respective diarylpyrrolidones 7 , which were finally reduced to 3,3-diarylpyrrolidines using BH 3. THF.


Introduction
Nitrogen-containing five membered rings are interesting synthetic targets as they are the basis of many natural and bioactive products. 1Thus molecules such as 3,3-diaryloxindoles exhibit antibacterial, antiprotozoal and antiinflamatory activities. 2 Succinimides and hydantoins show antimuscarinic and anticonvulsant activity; 3 and the 3,3-diphenyl derivatives of these compounds are potent anticonvulsants. 4In all the above-mentioned compounds, it is noteworthy to specify that the 3,3-diaryl derivatives are shown to be more biologically important.Pyrrolidines are another important class of bioactive molecules, which are extensively studied 5 and have been shown to inhibit glycosidases. 6However, there is hardly any report in the literature on the general synthesis of 3,3-diarylpyrrolidines.The methods to 3,3-diarylpyrrolidines known in the literature include the preparation of 3,3-diphenylpyrrolidine from: a) diarylacetonitriles, 7 b) 4phenoxy-or 4-bromo-2,2-diphenylbutylamine hydrochloride, 8 and c) 4-amino-3,3diphenylbutan-1-ol hydrochloride. 9Considering the importance of pyrrolidines and their derivatives 2,10 as bioactive compounds, we have undertaken an investigation on the synthesis of their 3,3-diaryl derivatives from readily available benzophenones.We herein report the results of our studies.

Results and Discussion
The condensation of benzophenone 1a with ethyl cyanoacetate under Knoevenagel conditions gave ethyl (α-cyano-β,β-diphenyl)acrylate 2a 11 following the literature procedure, with a slight modification.We found that the use of a three-fold excess of ammonium acetate as a catalyst leads to the cyanoacrylate 2a with a yield of 90% compared to the previously reported 41% yield.Under this improved condition, other diaryl ketones also reacted with ethyl cyanoacetate to yield the corresponding diaryl acrylates 2b−d and 2h−i in moderate to good yields.NMR spectra of all the diaryl acrylates (except 2a and 2m) indicated the presence of E and Z isomers in solution (CDCl 3 ).Since the double bond is fully substituted, it is difficult to determine the isomer ratio and to assign each signal to the respective isomer.Diarylacrylate 2m derived from pyridyl phenyl ketone exists as a single isomer in CDCl 3 as seen from the 1 H NMR.
The subsequent conversion of 2a into 2,2-diphenylsuccinic acid 4a through the dicyanoester 3a was achieved through hydrolysis and decarboxylation. 11Diphenylsuccinic acid 4a was cyclized to the anhydride 5a by treatment with acetyl chloride.Subsequent reaction of 5a with benzyl amine gave the succinimic acid 6a, which was cyclized to succinimide 7a in refluxing acetic anhydride (Scheme 1). 4 Other succinimides 7b−h were also prepared following the above procedure.These were characterized by 1 H and 13 C NMR and were directly used for the reduction without further analytical characterization.
Scheme 1 2-Cyano-3,3-diarylacrylates, 2i and 2m, prepared from the corresponding benzophenones were treated with KCN and the intermediate dicyano derivatives obtained were subjected to acid hydrolysis.However, in these cases, we could not isolate the expected acids.Apart from our normal hydrolytic condition (H 2 SO 4 /H 2 O/AcOH), attempts were made using HCl, but without any success.Other work up modifications like bringing the pH to neutral also did not help in isolating the succinic acids.Succinimic acid 6j, derived from 4-nitrobenzophenone and aniline, failed to ring close under the conditions tried.Apart from our normal procedure, we have tried heating 6j neat to 150 o C, which eventually led to a complex mixture that could not be characterized.Whereas, anthrone and o-chloro benzophenone failed to undergo the condensation with ethyl cyanoacetate, o,o'dichlorobenzophenone did react, surprisingly, but the isolated yield (<10%) was insufficient to proceed to subsequent steps.
Reduction of succinimides to the final pyrrolidine was carried out by BH 3 .THF, which was generated in situ from NaBH 4 and I 2 following the method by Periasamy. 12Thus, refluxing 7a with an excess of BH 3 -THF, generated from NaBH 4 and I 2 , for 12h afforded 65% of 3,3diphenylpyrrolidine 8a.(Scheme 2) Other pyrrolidone diones 7b−h also reacted similarly giving the corresponding pyrrolidines 8b−h in reasonably good yields.3-Phenyl-3-(2-naphthyl)-1-tert-butylpyrrolidine-2,5-dione 7h was prepared starting from 2naphthyl phenyl ketone in 61% yield.When the reduction of 7h was tried using BH 3 .THF, only the mono reduced product 9 was isolated in 89% yield (Scheme 2).The structure of 9 was confirmed from 1 H and 13 C NMR data.Use of a large excess (10 eq.) of the reagent and prolonged refluxing did not give the expected pyrrolidine.An attempted reduction using LiAlH 4 resulted in complete decomposition of the material.This could probably be due to two factors: 1) the steric hindrance by the bulky t-butyl group and (2) the reduced electrophilicity of the amide carbonyl by the electron releasing t-butyl group.In conclusion, we have elaborated a general synthesis of 3,3-diarylpyrrolidines from readily available benzophenones.Benzophenones with electron withdrawing as well as electron donating substituents could be used effectively for the preparation of respective succinic acids.However, under the specific acidic hydrolytic condition, the use of benzophenones containing basic nitrogens is not recommended.Generally, while any primary amine could be used for the preparation of pyrrolidones 7, the final reduction restricts the use of amines like t-butylamine, which offers significant steric hindrance.Given the above-described caveats, this procedure has proven itself useful for the preparation of 3,3-diarylpyrrolidines.

Experimental Section
General Procedures.Melting points were determined using a Bristoline hot-stage microscope and are uncorrected. 1H (300 MHz) and 13 C (75 MHz) NMR spectra were recorded on a 300 MHz NMR spectrometer in chloroform-d solution.Column chromatography was performed on silica gel (230−400 mesh).Elemental analyses were performed on a Carlo Erba-1106 instrument.General procedure for the preparation of 2-cyano-3,3-diarylacrylates (2).Diarylketone (50 mmol) was taken in benzene (50 mL) along with ethyl cyanoacetate (50 mmol).Ammonium acetate (150 mmol) was added in 2h intervals (50 mmol each time) and the mixture was refluxed for 24h with azeotropic water removal.The reaction mixture was cooled and washed with water (3x100 mL) followed by saturated solution of sodium chloride (100 mL).The organic layer was dried over sodium sulfate, concentrated and the crude mixture was purified by crystallization.