Solvent-free synthesis of enantioenriched β-silyl nitroalkanes under organocatalytic conditions

An enantioselective 1,4-conjugate addition of nitromethane to β-silyl α,β-unsaturated carbonyl compounds catalyzed by bifunctional squaramide catalysts has been developed. This methodology offers both enantiomers of β-silyl nitroalkanes in good to excellent yields (up to 92%) and enantioselectivities (up to 97.5% ee) under solvent-free conditions at room temperature. Control experiments reveal that the presence of a β-silyl group in the enones is crucial for high reactivity under the optimized reaction conditions.

As a part of our ongoing program for the development of asymmetric catalytic approaches for the synthesis of enantioenriched organosilanes [29,37,38], we present herein an organocatalyzed conjugate addition reaction of nitromethane to β-silyl enones to afford chiral β-silyl nitroalkanes (Scheme 1). Notably, the developed method was not only carried out under solvent-free conditions at room temperature but was found to be tolerant to moisture and air. Therefore, this method offers an attractive and robust option for the preparation of chiral β-silyl nitroalkanes. In sharp contrast to the aforesaid reaction, organocatalytic conjugate addition reactions of nitroalkanes to enones have been well studied [39][40][41][42][43]. To the best of our knowledge, organocatalyzed or metal-catalyzed enantioselective conjugate additions of nitroalkanes to β-silyl enones are not yet known.

Results and Discussion
The optimization study began with the conjugate addition reaction between β-TMS enone 1a and nitromethane (2) as the model reaction. An uncatalyzed background reaction was not observed while performing the model reaction in toluene as a solvent at 30 °C for 24 h. To our delight, when the same reaction was carried out in presence of 5 mol % catalyst I in toluene at 30 °C for 48 h, the desired product 3a was obtained in 84% yield with 60% ee ( Table 1, entry 1). Catalyst II was found to be unproductive as only 25% conversion of β-TMS enone 1a was observed (Table 1, entry 2). Gratifyingly, catalyst III furnished product ent-3a in 85% yield (Table 1, entry 3) with excellent enantioselectivity (94% ee). Whereas catalyst IV gave ent-3a in 85% yield with slightly lower enantioselectivity (91% ee) as compared to catalyst III (Table 1, entry 4). Catalyst V also led to product 3a in 66% yield and 78% ee (Table 1, entry 5). Catalyst VI, a pseudoenantiomer of catalyst V deliv-Scheme 1: Selected methods for the synthesis of enantioenriched β-silyl nitroalkanes, synthesis of chiral organosilanes from β-silyl α,βunsaturated carbonyl compounds, and the present work.
ered ent-3a in 78% yield with 80% ee (Table 1, entry 6). The catalytic performance of the squaramide catalysts was also explored for the model reaction. Catalyst VII afforded the With the acceptable optimized reaction conditions in hand, we next investigated the generality and limitations of this enantioselective conjugate addition reaction. Under the optimized reaction conditions, the conjugate addition reaction of nitromethane (2) to a variety of β-silylenones 1 was carried out and the results are summarized in Scheme 2. β-Silylenones bearing electron- donating, electron-withdrawing groups and halogen substituents in the meta or para position of the phenyl ring reacted smoothly and furnished the desired products 3a-k in good to excellent yields (71.5-92%) and enantioselectivities (76-97.5% ee). The β-silylenone with a strong electron-withdrawing group (cyano) attached to the phenyl ring, was found to be most reactive as the reaction completed within 4 h and afforded the product 3e in good yield (88%) and enantioselectivity (95.5% ee). The β-silylenone with a naphthyl substituent also took part in the conjugate addition reaction and gave the corresponding product 3j in good yield (83%) and enantioselectivity (76% ee). The reaction also tolerated a 2-thienyl-substituted β-silylenone and the desired product 3k was obtained in good yield (88%) and enantioselectivity (97.5% ee). However, β-silylbutenone 1l failed to participate in the conjugate addition reaction with nitromethane under the optimized reaction conditions. Pleasingly, using 9-amino-9-deoxyepihydroquinidine (IX)-benzoic acid as organocatalyst system (see Supporting Information File 1 for details) promoted the addition reaction and product 3l was formed in good yield (79%) and excellent enantioselectivity (99% ee). The conjugate addition reaction between malononitrile and β-silylenone 1a was also investigated using 5 mol % of catalyst VII under the optimized reaction conditions. To our delight, the reaction completed within 4 h and the desired product 3m was isolated in excellent yield (97%) with moderate enantioselectivity (52% ee). β-Silylenone 2n bearing a o-chloro substituent in the aromatic ring remained unreactive under the optimized reaction conditions probably due to steric hindrance.
The facile synthesis of both enantiomers of the targeted compounds is of paramount importance since biological activities are dictated by the absolute configuration of the products. To our delight, catalyst VIII, the pseudoenantiomeric catalyst of VII, allowed to synthesize the enantiomeric products ent-3 (Scheme 3) in high yields and enantioselectivities comparable to the corresponding enantiomers 3 under the optimized reaction conditions. The same set of β-silylenones was explored and an almost similar trend in reactivities, yields as well as enantioselectivities was observed. To probe the role of the β-silyl group, the reaction of tert-butylsubstituted enone 3o and nitromethane (2) was conducted under the standard reaction conditions using catalyst VII or VIII, affording only trace amounts of products 4 or ent-4 even after stirring for 48 h [44]. When the same reaction was performed in the presence of 10 equivalents of nitromethane using catalyst VII, the product 4 was isolated in 26% yield and 89.5% ee after 96 h whereas the catalyst VIII led to ent-4 in 25% yield and 95% ee (Scheme 4). This observation confirmed that the presence of the β-silyl group in the enones played a key role in the high reactivity under the optimized reaction conditions.
The stereochemistry of the silicon-substituted chiral center in compound ent-3k was found to adopt "(S)" configuration which was unambiguously established by single crystal X-ray diffraction analysis (Figure 1) [45].
To prove the scalability of this synthetic method, we examined the synthesis of 3c and ent-3d in a 1 mmol scale (Scheme 5).
The products 3c and ent-3d were isolated even with better yields while the enantiomeric excess was unperturbed.

Conclusion
In summary, we have outlined bifunctional squaramidecatalyzed 1,4-conjugate addition reaction of nitromethane to β-silyl α,β-unsaturated carbonyl compounds to access a series of chiral β-silyl nitroalkanes in high yields and good to excellent enantioselectivities at room temperature. The notable features of this reaction are access to both the (R) and (S) enantiomers of the products, solvent-free synthesis, mild reaction conditions, low catalyst loading, and use of only a small excess of nitromethane (2.5 equivalents with respect to limiting reagent).

Supporting Information
Supporting Information File 1 Experimental data and copies of spectra.