Asymmetric conjugate addition of ketones to nitroalkenes catalyzed by chiral bifunctional sulfamides

C hiral bifunctional sulfamides were found to be efficient catalysts for the conjugate addition of ketones to nitroalkenes. Moderate to good enantioselectivities and yields were achieved for the reaction of acetone with a variety of β -aryl-nitroethylenes. Base additives were found to be more efficient than acid additives for the transformation. The reaction of methoxyacetone and cyclopentanone also provided the adducts with moderate enantioselectivities, however in low chemical yields.


Introduction
In recent years asymmetric organocatalysis has emerged as a powerful tool for the synthesis of optically active compounds. 1A large number of asymmetric reaction have been achieved using chiral amines, thioureas (ureas) and other organic small molecules as the catalysts.3] Chiral bifunctional thiourea-amine catalysts, developed by Jacobsen 4 and the others [5][6] , were found to be highly efficient for the conjugate addition of aldehydes and ketones to nitroalkenes.8] However the preparation of these thiourea-amine catalysts generally requires tedious synthetic procedures, and the catalytic activity remains to be improved.Recently we developed a novel kind of chiral bifunctional sulfamide organocatalysts.The catalysts were readily prepared from amines and chiral cyclohexane-1,2-diamine with catechol sulfate.The stronger acidity of N-H bond of the sulfamide than the corresponding thiourea is expected to improve the catalytic activity.Excellent enantioselectivities and yields were obtained for the conjugate addition of aldehydes to nitroalkenes. 9As an extended study of the chiral sulfamide catalysts, herein we report their application in the asymmetric conjugate addition of ketones to nitroalkenes.

Results and Discussion
Chiral sulfamides 1a-1f were prepared according to previously reported procedures. 9The conjugate addition of acetone to trans-β-nitrostyrene 2a was carried out in the presence of 1a-1f and the results are summarized in Table 1.Although 1a was found to be highly efficient for the asymmetric conjugate addition of aldehydes to nitroalkenes, 9 it provided the adduct product 4a in low yield and with moderate enantioselectivity (Table 1, entry 1).The yield was improved significantly by the addition of 20 mol% benzoic acid (Table 1, entry 2).It is noted that in the 1a-catalyzed addition of aldehydes to nitroalkenes, acid additives were detrimental and only base additives were efficient. 9The result implicated some inherent difference between the reaction of ketones and aldehydes.Sulfamides 1b, 1c and 1d were also efficient for the reaction (Table 1, entries 3-5).Sulfamide 1b, derived from (S)-1-phenylethylamine and (R,R)-cyclohexane-1,2-diamine, provided slightly better enantioselectivity and yield than 1a.In comparison, sulfamide 1c derived from (R)-1-phenylethylamine and (R,R)-cyclohexane-1,2-diamine, provided the adduct 4a in the same absolute configuration and with slightly lower enantioselectivity.The fact suggests that the enantioselective induction is mainly controlled by the chiral cyclohexanediamine unit.The additional chiral center only exerts small effects on the enantioselectivity.Sterically demanding 1d provided 4a with lower yield and enantioselectivity.Sulfamide 1e and 1f were totally inefficient for the reaction (Table 1, entries 6-7).The result confirms the importance of the primary amino group for the catalytic activity.A number of solvents were then screened using 1b as the catalyst and the results are listed in Table 2.The reaction solvent exerted significant effect on the yield and enantioselectivity.Generally the polar solvents resulted in lower yields and enantioselectivities (Table 2, entries 1-4).Water could also be used as the reaction solvent and provided the product with good enantioselectivity (71% ee), however in low yield (Table 2, entry 2).The best yield (87%) was achieved in ether (Table 2, entry 6), however the best enantioselectivity (84% ee) was obtained in toluene (Table 2, entry 9).Thus Et 2 O and toluene were selected for further optimization study.In the organocatalytic conjugate addition of ketones to nitroalkenes, Brønsted acids were generally used as the efficient additives. 10However in our recent study of asymmetric conjugate addition of aldehydes to nitroalkenes catalyzed by chiral sulfamides, bases such as DIPEA and DMAP, were found to be extremely efficient additives. 9To obtain a clear understanding of the additive effect, a range of acid and base additives were examined in the reaction of 2a with acetone.The results are summarized in Table 3. Initially benzoic acid, acetic acid, p-nitro-benzoic acid, trifluoroacetic acid and (d)-camphor-10-sulfonic acid were studied in toluene (Table 3, entries 1-5).p-Nitro-benzoic acid provided the product 4a with good enantioselectivity, but the yield was poor.Trifluoroacetic acid and (d)-camphor-10-sulfonic acid were inefficient and no product could be obtained.Base additives such as imidazole, DIPEA, TEA and DMAP, were also examined (Table 3, entries 6-9).Imidazole provided 4a with good yield and enantioselectivity.DMAP afforded better enantioselectivity, however in lower yield.DIPEA and TEA provided 4a in low yields (Table 3, entries 8 and 9).Furthermore the acid and base additives were examined in ether and similar results were observed (Table 3, entries 10-18).Finally imidazole/ether system was selected for further study (Table 3, entry 15).The scope of the reaction was studied with a variety of β-aryl-nitroethylenes and ketones and the results are summarized in Table 4.The reaction of substituted β-phenyl-nitroethylenes with acetone provided the adducts with moderate yields and enantioselectivities (table 4, entries 2-7).ortho, meta and para-chlorophenyl-nitroethylene afforded the product with similar enantioselectivity and yield (Table 4, entries 2-4).2-Nitrophenyl-nitroethylene 2e gave the product with moderate enantioselectivity and in low yield.4-Methoxylphenyl-nitroethylene 2f and 4-methylphenyl-nitroethylene 2g provided the products in the same yield, but 2f afforded better enantioselectivity.Heteroaryl-nitroethylenes, such as 2h and 2i, were also applicable in the transformation.The corresponding adducts were obtained with good yields and moderate enantioselectivities (Table 4, entry 8-9).While methoxyacetone was used in the reaction with 2a, two diastereoisomeric adducts were obtained with moderate enantioselectivity and yield (Table 4, entry 10).The reaction of cyclopentanone gave the adduct with good enantioselectivity, however in low yield (Table 4, entry 11).Several other ketones, including cyclohexanone, acetophenone, 2-butanone, were examined in the reaction with β-nitrostyrene under the optimized reaction conditions, however the reactions were sluggish and almost no product was obtained.Using benzoic acid as the additive did not provide any improvements.The reactions of β-cyclohexyl nitroethylene and β-butyl nitroethylene with acetone were also studied, but only trace of the products was obtained.
A catalytic mechanism of chiral sulfamides is proposed in Scheme 2. 5c An imine intermediate A is generated from the catalyst 1b and acetone.The tautomerization of A is promoted by the base additive and provides the enamine B. Hydrogen bonding between the nitro group of nitrostyrene with the sulfamide (intermediate C), increases the nucleophilicity of nitrostyrene.The neucleophilic attack of enamine occurs from si face of double bond and provides intermediate D. The consequent proton transfer and hydrolysis give the product and regenerate the catalyst 1b.The base additive is proposed to accelerate also the proton transfer step by removing proton from the imine cation.

Conclusions
In summary, chiral bifunctional sulfamides were found to be efficient catalysts for the conjugate addition of ketones to nitroalkenes.Moderate to good enantioselectivities and yields were achieved for the reaction of acetone with a variety of β-aryl-nitroethylenes.Methoxyacetone and cyclopentanone were also applicable in the transformation with lower chemical yields.Base additives were found to be more efficient than acid additives for the reaction.Further development of more efficient chiral sulfamide catalysts is currently under investigation.

Experimental Section
General Procedures.All solvents were used as commercial anhydrous grade without further purification.All reactions were carried out under open air. 1 H NMR spectra and 13 C NMR spectra were recorded on a Bruker AVANCE 400 MHz spectrometer.High-resolution mass spectra were obtained with the Thermo MAT 95XP mass spectrometer.The low resolution mass spectra were obtained at the Thermo Trace GC Ultra-DSQ.Infrared (IR) spectra were recorded on a Bruker Tensor 37 spectrophotometer.Enantiomeric excesses were determined by HPLC using Daicel Chiralcel AS-H and OD-H column and eluting with n-hexane/ i-PrOH solution.

.
The screening of chiral sulfamides 1a-1f a a The reactions were carried out with 2a (0.15 mmol), 1a-1f (0.03 mmol) in acetone (0.3 mL).b Isolated yields.c Determined by chiral HPLC analysis.d e The reaction was carried out without benzoic acid.f No reaction.

Table 2 .
The effect of reaction solvents a