Organocatalytic asymmetric Michael/acyl transfer reaction between α-nitroketones and 4-arylidenepyrrolidine-2,3-diones.

An organocatalytic asymmetric Michael/acyl transfer reaction between α-nitroketones and 4-arylidenepyrrolidine-2,3-diones is reported. A bifunctional thiourea catalyst was found to be effective for this reaction. With 10 mol % of the catalyst, good results were attained for a variety of 1,5-dihydro-2H-pyrrol-2-ones under mild reaction conditions.

Introduction

The Michael reaction is a powerful reaction that has been so far applied for the formation of carbon–carbon and carbon–heteroatom bonds in organic synthesis [1-2]. After the renaissance of organocatalysis in the year 2000, this field has been applied tremendously for the development of catalytic asymmetric conjugate addition reactions [3-5]. In particular, the conjugate addition of nitroalkanes and their derivatives to enones has drawn the attention of organic chemists as the corresponding products can be chemoselectively converted to a variety of useful structures [6]. Thus a variety of methods has been developed with a range of different catalysts [7-9]. One of the challenges is to employ highly substituted enones in the reaction. Indeed, additional substituents, especially at the α-position of enones/activated olefins, decreases the reactivity significantly because of unfavorable steric interactions. To overcome this problem, reactive Michael donors must be used to achieve a good conversion in the reaction. In recent years, α-nitroketones have emerged as active nucleophiles in Michael reactions and a range of substrates have been explored [10]. Also, α-nitroketones have been found to be a popular nucleophilic acyl transfer reagent. In 2011, three research groups namely Wang, Yan and Kwong independently revealed the organocatalytic asymmetric conjugate addition of α-nitroketones to β,γ-unsaturated α-keto esters with the concomitant acyl transfer reaction to the keto group [11-13]. Consequently, our group developed an organocatalytic asymmetric Michael–acyl transfer reaction of α-nitroketones with unsaturated pyrazolones, 2-hydroxycinnamaldehydes, γ/δ-hydroxyenones, o-quinone methides, etc. [14-18]. Other groups also contributed contemporarily [19-21].

In recent years 4-arylidenepyrrolidine-2,3-diones have been explored mainly for the preparation of bicyclic dihydropyran derivatives through the catalytic inverse-electron-demand hetero-Diels–Alder reaction [22-24]. We postulated that 4-arylidenepyrrolidine-2,3-diones could also be suitable reaction partners of α-nitroketones. However, during the progress of our work, Bonne, Bugaut and co-workers have shown one example for the reaction of 2-nitroacetophenone with 4-benzylidenepyrrolidine-2,3-dione and only moderate enantioselectivity (50% ee) was achieved (Scheme 1) [25]. Herein, we report a better enantioselective version of the reaction between α-nitroketones and 4-arylidenepyrrolidine-2,3-diones (Scheme 1).

Scheme 1

Reactions of α-nitroketones with unsaturated pyrazolone and with 4-benzylidenepyrrolidine-2,3-dione.

Results and Discussion

Initially a model reaction was examined between N-benzyl-4-benzylidenepyrrolidine-2,3-dione (1a) and 2-nitro-1-phenylethanone (2a) in the presence of the quinine-derived bifunctional squaramide catalyst I in dichloromethane at room temperature (Table 1). Delightfully, after stirring for 12 hours, a product was isolated in 70% yield that was characterized as compound 3a and was supposed to be formed through conjugate addition followed by benzoyl-transfer reaction. However, only 20% enantiomeric excess was achieved. Then, the tert-leucine-derived squaramide catalyst II was employed and here both yield and ee slightly improved. Next, we turned our attention to bifunctional thiourea catalysts [26-27] that proved to be fruitful. Thus, the quinine and cinchonidine-derived bifunctional thiourea catalysts III and IV were employed in the reaction and moderate enantiomeric excesses were achieved. The yield and enantioselectivity further improved when using the tert-leucine-derived thiourea catalyst V. Also, Takemoto’s catalyst VI [28] was suitable for the reaction though a moderate enantiomeric excess was detected. Finally, the best catalyst turned out to be the pyrrolidine-containing bifunctional thiourea catalyst VII and the desired product was isolated in 80% yield with 80% ee. Then, solvent optimization was carried out to obtain better enantioselectivities. A similar enantioselectivity was attained in α,α,α-trifluorotoluene and tetrahydrofuran as the solvent, whereas in chloroform a slightly improved enantioselectivity of 86% ee was observed. Finally, the best solvent was found to be 1,2-dichloroethane and the product 3a was obtained in 82% yield with 90% ee.

Table 1

Catalyst screening and optimization of the reaction conditions.

entrya	catalyst	solvent	yieldb	eec
1	I	CH2Cl2	70	20
2	II	CH2Cl2	73	34
3	III	CH2Cl2	76	55
4	IV	CH2Cl2	78	52
5	V	CH2Cl2	80	74
6	VI	CH2Cl2	75	50
7	VII	CH2Cl2	80	80
8	VII	PhCF3	78	78
9	VII	THF	80	80
10	VII	CHCl3	80	86
11	VII	(CH2Cl)2	82	90

aReactions were carried out with 0.1 mmol of 1a and 0.1 mmol of 2a in 0.6 mL solvent at 25 °C for 12 hours; bisolated yield after silica gel column chromatography; cdetermined by chiral HPLC.

After having identified the optimized conditions we ventured in the scope and generality of the reaction. Initially a variety of α-nitroketones 1 having different aryl substituents were tested (Table 2). In fact, different ortho-, meta-, and para-substitutions on the phenyl group were compatible with the reaction conditions and satisfactory results were obtained (Table 2, entries 2–11). For example, p-tolyl-containing nitroketone 2b delivered the product 3b in 80% yield with 88% ee (Table 2, entry 2). A similar enantioselectivity was obtained for product 3c with a p-anisyl group (Table 2, entry 3). Interestingly, the enantioselectivity dropped slightly when replacing a p-methoxy substituent with a p-ethoxy group and product 3d was isolated in 78% yield with 80% ee (Table 2, entry 4). Also, a biphenyl group was tolerated and a good result was achieved (Table 2, entry 5). Then, 4-fluoro and 4-bromo-containing nitroketones 2f and 2g were employed in the reaction and gratifyingly the same 90% ee were obtained for both products 3f and 3g (Table 2, entries 6 and 7). meta-Substitutions were also tolerated in the reaction although decreased enantioselectivities were detected for the products 3h and 3i, respectively (Table 2, entries 8 and 9). Then, o-methyl- and o-methoxyphenyl-substituted nitroketones 2j and 2k were employed in the reaction. Here also, the reactions progressed well to provide products 3j and 3k in moderate yields and enantioselectivities (Table 2, entries 10 and 11). The 2-naphthyl-substituted nitroketone 2l also participated in the reaction to deliver 3l in 80% ee (Table 2, entry 12). Moreover, the hydrocinnamyl group containing nitroketone 2m also took part in the reaction and the corresponding product 3m was isolated in 65% yield with 64% ee (Table 2, entry 13). Finally, nitroketone 2n with a cyclohexyl group was engaged in the reaction and a moderate enantioselectivity was detected for product 3n (Table 2, entry 14).

Table 2

Scope of α-nitroketones 2 in the reaction with 1a.

entrya	R	3	yieldb	eec
1	Ph	3a	80	90
2	4-MeC6H4	3b	80	88
3	4-MeOC6H4	3c	82	88
4	4-EtOC6H4	3d	78	80
5	4-PhC6H4	3e	82	82
6	4-FC6H4	3f	79	90
7	4-BrC6H4	3g	78	90
8	3-MeC6H4	3h	70	72
9	3-MeOC6H4	3i	72	66
10	2-MeC6H4	3j	65	68
11	2-MeOC6H4	3k	68	70
12	2-naphthyl	3l	75	80
13	PhCH2CH2	3m	65	64
14	cyclohexyl	3n	70	72

aThe reactions were carried out with 0.1 mmol of 1a and 0.1 mmol of 2 in 0.6 mL 1,2-dichloroethane at 25 °C for 12 hours; bisolated yield after silica gel column chromatography; cdetermined by chiral HPLC.

In the next step, we investigated the scope of the reaction of substrate 2a with a variety of pyrrolidine-2,3-diones 1 having different benzylidene substituents under the optimized conditions (Table 3). It turned out that a range of substitutions was tolerated and good results were attained. Initially, different para-substituted arylidene substrates were screened that smoothly afforded products 3o–s (Table 3, entries 1–5). For example, the pyrrolidine-2,3-dione 1b with a 4-methylbenzylidene-substituent provided the product 3o in 83% yield and 72% ee (Table 3, entry 1). A similar enantioselectivity was obtained with the 4-tert-butylenzylidene-substituted pyrrolidine-2,3-dione 1c (Table 3, entry 2). Then, different 4-halobenzylidene-substituted pyrrolidine-2,3-diones 1d–f were employed in the reaction and mixed results were obtained. Although product 3q having a 4-fluorophenyl-substitution was isolated in 80% yield and 84% ee, slightly decreased enantioselectivities were obtained for the corresponding 4-chloro- (3r, 70% ee) and 4-bromophenyl (3s, 76% ee) derivatives (Table 3, entries 3–5). These products could be particularly useful for further transformations via cross-coupling reactions. The ortho-fluoroarylidene-substituted pyrrolidine-2,3-dione 1g also participated in the reaction to deliver product 3t in 86% ee (Table 3, entry 6). 2,4-Disubstitution at the aromatic ring was also tolerated in the reaction and a moderate enantioselectivity was observed for the 2,4-difluorophenyl-substituted product 3u (Table 3, entry 7). The 3,5-dimethoxybenzylidene-containing pyrrolidine-2,3-dione 1i was prepared and also engaged in the reaction. Here also, a smooth conversion was detected and the product 3v was isolated in 80% yield with 72% ee (Table 3, entry 8). Finally, pyrrolidine-2,3-dione 1j containing a heteroaromatic group was also screened and an acceptable enantioselectivity for the 2-thienyl-substituted product 3w was witnessed (Table 3, entry 9).

Table 3

Scope of pyrrolidine-2,3-diones 1 in the reaction with 2a.

entrya	R1	1	3	yieldb	eec
1	4-MeC6H4	1b	3o	83	72
2	4-t-BuC6H4	1c	3p	80	72
3	4-FC6H4	1d	3q	80	84
4	4-ClC6H4	1e	3r	79	70
5	4-BrC6H4	1f	3s	82	76
6	2-FC6H4	1g	3t	79	86
7	2,4-F2C6H3	1h	3u	78	72
8	3,5-(MeO)2C6H3	1i	3v	80	72
9	2-thienyl	1j	3w	81	82

aReactions were carried out with 0.1 mmol of 1 and 0.1 mmol of 2a in 0.6 mL 1,2-dichloroethane at 25 °C for 12 hours; bisolated yield after silica gel column chromatography; cdetermined by chiral HPLC.

To further expand the scope of the reaction, 4-benzylidenedihydrofuran-2,3-dione (4) was prepared and reacted with nitroketones 2b and 2c, respectively. To our delight, the reactions proceeded smoothly at room temperature providing the desired products 5a and 5b in good yields and enantioselectivities (Scheme 2).

Scheme 2

Reaction of 4-benzylidenedihydrofuran-2,3-dione (4) with α-nitroketones 2b,c. Reaction conditions: furan 4 (0.1 mmol), α-nitroketone 2 (0.1 mmol), 10 mol % VII in 0.6 mL 1,2-dichloroethane were reacted at 25 °C for 12 hours. Yields correspond to isolated yields after silica gel column chromatography and ees were determined by chiral HPLC.

Conclusion

In summary, in this paper we reported an organocatalytic asymmetric Michael/acyl transfer reaction between α-nitroketones and 4-arylidenepyrrolidine-2,3-diones/4-benzylidenedihydrofuran-2,3-dione. The products were obtained in good yields with moderate to high enantioselectivities. An easily available bifunctional thiourea catalyst was employed in the methodology.

Experimental part.