Microwave-assisted reactions of allenic esters: [3+2] anellations and allenoate-Claisen rearrangement

The reactivity of allenic esters towards an activated N -sulfonylimine and electron-deficient alkenes with a phosphine under microwave irradiation is explored. The methodology is shown to be efficient for the one-step synthesis of 3-pyrrolines and cyclopentenes in a regio-and diastereoselective manner. This formal [3+2] cycloaddition is complete within five minutes. It was also demonstrated that microwave irradiation is the best energy source to carry out the Lewis acid catalyzed allenoate-Claisen rearrangement leading to 3-(pyrrolidin-1-yl)hepta-2,6-dienoates.


Introduction
2][3][4] The inherent instability associated to the cumulated double bonds has been widely exploited for synthetic purposes.This structural feature makes addition to allenes very favourable, since it involves a relief in strain.We have developed an asymmetric Wittig reaction that allows the synthesis of allenic esters 1 with axial chirality and an approach to chiral -amino esters 3 involving the stereoselective reduction of -enamino esters 2 bearing a chiral auxiliary in the ester moiety, obtained from the nucleophilic addition of amines to the chiral 2,3-allenoates (Scheme 1). 5,6This drove us to explore other aspects of the reactivity of 2,3-butadienoates.

Scheme 1
It is known that addition of nucleophiles to electron-deficient allenes occurs at the electrophilic ,-carbon-carbon double bond to give Michael type adducts. 7However, reactivity inversion (umpolung) can be achieved.Cristau et al. observed that in the presence of phosphines the addition takes place at the ,-carbon-carbon double bond. 8They found that the reaction of methyl 2,3-butadienoate (4) with triphenylphosphine followed by the addition of NaI afforded a phosphonium iodide 5, which allows nucleophilic attack at the -carbon leading to the synthesis of 4-substituted-but-2-enoate 6 (Scheme 2).

Scheme 2
Lu et al. explored the reactivity of the intermediates 8 generated from butadienoates and phosphines as the three-carbon synthon in [3+2] anellation reactions (Scheme 3).They reported that reaction with electron-deficient alkenes, 9 and N-tosylimines 10 led to the formation of fivemembered formal [3+2] cycloadducts 9.The use of chiral phosphines as catalyst for the formal enantioselective [3+2] cycloaddition of electron-deficient allenes with electron-deficient alkenes and imines has also been reported. 11,12The reaction of N-tosylimines with ethyl 2,3-butadienoate and ethyl penta-2,3-dienoate has been systematically studied in the presence of various nitrogen and phosphine Lewis base promoters. 13Particular interesting also is the allenoate-Claisen rearrangement allowing the stereoselective synthesis of -enamino esters 11 comprising 1,2tertiary-quaternary carbon stereogenic centers from simple butadienoates and allylic amines. 14he versatility of 2,3-butadienoate reactivity makes the gathering of new data on these synthetic building blocks a relevant research goal.In this context, the reactivity of allenes towards activated imines and electron-deficient alkenes with phosphine catalysis under microwave irradiation as well as the microwave-assisted allenoate-Claisen rearrangement was explored.

Issue in
Lewis Acid Scheme 3

Results and Discussion
3-Pyrrolines are particularly interesting heterocycles since they can be used as intermediates in natural product synthesis 15 and show diverse biological activities. 16A significant number of synthetic approaches to pyrrolines has been reported. 17The one-step synthesis of 3-pyrrolines via phosphine-catalysed condensation of allenes and imines is an interesting route to this important class of compounds.We carried out the reaction of benzyl 2,3-butadienoate 12a 18a,14 with Nbenzylidenebenzenesulfonamide 13 18b in the presence of triphenylphosphine at room temperature, which gave the expected 3-pyrroline 14a in a regioselective fashion and in 69% yield.Compound 14a was also obtained using conventional thermolysis reaction conditions.Carrying out the reaction at 50 ºC for 1 hour gave product 14a in 58% yield, at 100 ºC for 1 hour 3-pyrroline 14a was isolated in 38% yield, and after 2.5 hours at 100 ºC compound 14a was obtained in significantly lower yield (15%).We observed that under microwave irradiation at 100 ºC for 5 minutes, 3-pyrroline 14a could be obtained in good yield (64%).Carrying out this microwave-assisted reaction at lower temperature (50 ºC) after 5 minutes the [3+2] cycloadduct was isolated in 35% yield.Irradiation at 150 ºC leads to the degradation of the starting materials without any evidence of the target molecule (Table 1).The results obtained using the optimized conditions for the microwave-assisted [3+2] anellation reaction clearly demonstrate the advantage of using this nonconventional energy source, which allows the reduction of the reaction time to 5 minutes still leading to the desired cycloadduct in good yield.The reactivity of -(t-butyl)allenoate 12b 18a with N-sulfonylimine 13 in the presence of phosphines was also studied (Table 1).A microwave-assisted process using triphenylphosphine as catalyst, did not allow the formation of any product.However, in the presence of tributylphosphine in toluene at room temperature, the cis-3-pyrroline 14b was obtained exclusively in a stereoselective fashion (44% yield).Upon microwave irradiation at 100 ºC for 5 minutes the same diastereoselectivity was observed and the [3+2] cyclized product 14b obtained in 50% yield.A similar behaviour was also previously observed where more nucleophilic phosphines such as tributylphosphine instead of triphenylphosphine were required to carry out the reaction of N-sulfonylimines with sterically demanding -(t-butyl)-allenoates. 19 In contrast with this observation, the reaction of -methylallenoate 12c 18a,14 with Nbenzylidenebenzenesulfonamide 13 can be carried out in the presence of triphenylphosphine affording the cis-3-pyrroline 14c.Under conventional reaction conditions this heterocycle was obtained in 38% yield, whereas the microwave-assisted reaction led to the same product in 43% yield in a short reaction time.The synthesis of cyclopentenes via [3+2] anellation of benzyl 2,3-butadienoate 12a with electron-deficient alkenes was explored (Table 2).Allene 12a reacted with methyl vinyl ketone (15a, 1 equiv) in the presence of triphenylphosphine in toluene at 70 ºC to produce the regioisomeric cyclopentenes 16 and 17a in 70% overall yield.The observed regioselectivity is in agreement with the one reported by Lu et al.. 9 This reaction could be carried out under microwave irradiation at 50 ºC for 5 minutes giving esters 16 (26%) and 17a (37%).Performing the microwave-assisted reaction at 70 ºC for 5 minutes gave the same products with a slight improvement in the overall yield (66%).The triphenylphosphine-catalyzed [3+2] anellation of benzyl 2,3-butadienoate 12a and acrolein 15b in toluene at 70 ºC gave regioselectively benzyl 4-formylcyclopent-1enecarboxylate 17b in 74% yield.

Table 1. [3+2] Anellation reaction of butadienoates with imine 13
Unfortunately, under microwave irradiation the cycloadduct 17b could only be obtained in 24% yield due to the polymerization of the acrolein.Attempts to improve the yield using an excess of acrolein were not successful.

Table 2.
[3+2] anellation of allene 12a with methyl vinyl ketone and acrolein Benzyl 2,3-butadienoate 12a reacted with diethyl fumarate 18 under conventional reaction conditions, using tributylphosphine as catalyst, to give the trans-cyclopent-3-ene-1,2,3tricarboxylate 19 in 80% yield, as a single isomer.Under microwave irradiation at 50 ºC for 5 minutes the same product was isolated in 75% yield (Scheme 4).We decided to look into the Lewis acid catalyzed allenoate-Claisen rearrangement and explore the possibility of carrying out the reactions under microwave irradiation in order to determine whether this process could be applied for stereoselective carbon-carbon bond construction.The reaction of allenes 12a and 12c with tertiary allylamine 1cinnamylpyrrolidine 14 (20) in the presence of AlCl3 or Zn(OTf)2 was studied.
Diastereoselective preparation of -enamino ester 23b was observed from -methylallenoate 12c and allylic amine 20 in the presence of Lewis acids via [3,3]-sigmatropic rearrangement of the corresponding zwitterionic allyl-vinylammonium complexe (Table 3).The reaction catalyzed by AlCl3 using the conventional reaction conditions gave the rearrangement adduct 23b in 59% yield and 67:33 syn:anti selectivity (entry 3).The observed diastereoselectivity in the C-C bond formation can be explained by considering that there is a -facial discrimination in the cumulene addition step leading to selective formation of the E-enamino intermediate and the propensity of [3,3]-sigmatropic rearrangements to occur via chair-like transition states.The reaction carried out at 100 ºC for 1 hour afforded compound 23b in similar yield and selectivity (entry 4).Carrying out the microwave irradiation at 50 ºC for 30 minutes an improvement of the yield and stereoselectivity was observed (entry 5) and irradiation at 100 ºC for 15 minutes the desired adduct was obtained in even higher yield (91%) and 76:24 syn:anti selectivity (entry 6).Using the conventional reaction conditions and Zn(OTf)2 as catalyst, -enamino ester 23b was obtained in 64% yield with moderate stereoselectivity (entries 7 and 8).Microwave irradiation at 100 ºC for 15 minutes allowed the synthesis of adduct 23b in a significant higher yield (entries 9 and 10).

Conclusions
Herein, we have reported that [3+2] anellation reactions of butadienoates with Nbenzylidenebenzenesulfonamide and electron-deficient alkenes can be carried out under microwave irradiation.The results disclosed in this paper indicate the success of this approach for the regio-and diastereoselective preparation of 3-pyrrolines and cyclopentenes.It was also demonstrated that the microwave-assisted reaction of butadienoates with 1cinnamylpyrrolidine in the presence of Lewis acids afforded efficiently and selectively 3-(pyrrolidin-1-yl)hepta-2,6-dienoates via allenoate-Claisen rearrangement.

Experimental Section
General Procedures. 1 H NMR spectra were recorded on an instrument operating at 400 MHz. 13   C spectra were recorded on an instrument operating at 100 MHz.The solvent was deuteriochloroform except where indicated otherwise.IR spectra were recorded on a Perkin Elmer 1720X FTIR spectrometer.Mass spectra were recorded on a Bruker FTMS APEXIII instrument under electrospray ionization (ESI) or HP 6890 Plus instrument under electron impact (EI).Mps were recorded on a Reichert hot stage and are uncorrected.Flash column chromatography was performed with Merck 9385 silica as the stationary phase.

Synthesis of 3-pyrrolines and cyclopentenes. General procedure
Method A. To a mixture of imine or alkene (1.0 mmol) and PPh3 or PBu3 (0.2 mmol) in toluene (1.5 mL) a solution of allene (1.0 mmol) in toluene was added.The mixture was then stirred at room temperature under nitrogen.The reaction was monitored by TLC.After the reaction was completed, the solvent was removed under reduced pressure and the crude product was purified by flash chromatography [ethyl acetate-hexane].Method B. A suspension of imine 13 or alkene 15 or 18 (0.6 mmol), PPh3 or PBu3 (0.12 mmol) and allene 12 (0.6 mmol) in toluene (1 mL) was irradiated in a microwave reactor (CEM Focused Synthesis System, Discover S-Class) for 5 min with the temperature set to 100 ºC for the synthesis of 3-pyrrolines 14, 70 ºC for cyclopentenes 16 and 17 and 50 ºC for cyclopentene 19.The solvent was removed under reduced pressure and the crude product was purified by flash chromatography [ethyl acetate-hexane].Ar-H).C 54.9, 66.5, 68.9, 126.9, 127.9, 128.

Table 3 .
Lewis acid-catalyzed allenoate-Claisen rearrangement ©ARKAT USA, Inc.a Product ratio determined by 1 H NMR analysis.b Using toluene as solvent.