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DOI: 10.1039/C4RA09128K (Communication) RSC Adv., 2014, 4, 49930-49933

Organocatalytic asymmetric vinylogous Michael addition of 3-alkylidene oxindoles to α-substituted β-nitroacrylates: facile construction of a chiral all-carbon quaternary center†

Yuan Zhong‡ ab, Shixiong Ma‡ab, Zhaoqing Xu*b, Min Changa and Rui Wang*ab
aSchool of Life Sciences, Lanzhou University, Lanzhou, 730000, P.R. China. E-mail: wangrui@lzu.edu.cn
bKey Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, P.R. China. E-mail: zqxu@lzu.edu.cn

Received 23rd August 2014 , Accepted 25th September 2014

First published on 25th September 2014

Abstract

A highly enantioselective vinylogous Michael addition reaction of 3-alkylidene oxindoles to α-substituted β-nitroacrylates has been developed by using a cinchona alkaloid-squaramide bifunctional organocatalyst, which provides a series of chiral products bearing all-carbon quaternary stereocenters in excellent yields with high enantioselectives (up to 97%).

In the past decade, several asymmetric catalytic routes have been developed for the synthesis of β,β-disubstituted nitrocompounds derivatives which are the most important synthetic precursors of β,β-disubstituted β-amino acids.1 In this regard, developing efficient methodologies via asymmetric catalysis (either metal- or organocatalysis) for the synthesis of these compounds with chiral all-carbon quaternary stereocenters under organocatalytic conditions is highly desirable.2 It is a powerful strategy that uses stereoselective conjugate addition reactions3 of a nucleophile to α-substituted-β-nitroacrylate4 for the construction of nitro-containing compounds with outstanding yields and enantioselectivities.5 Recently, the vinylogous Michael addition reaction has attracted a great deal of attention as it is an effective way for enantioselective carbon–carbon bond formation in the γ-position.6 Our group have recently developed a novel method7 of generating trifluoromethylated compounds using a series of 3-alkylidene oxindoles as nucleophiles which can react at the α- or γ-position with an electrophilic reagent.8 We envisioned that 3-alkylidene oxindoles could also serve as substrates and react with α-substituted β-nitroacrylates through a vinylogous addition with complete γ-selectivity and close to perfect alkene geometry control by using a proper catalyst.9 Moreover, the reaction would lead to a stereocontrolled formation of optically active compound bearing an all-carbon quaternary stereogenic center in excellent yields and high enantioselectives (Scheme 1).10
image file: c4ra09128k-s1.tif
Scheme 1 Vinylogous Michael addition reactions between α-substituted β-nitroacrylates and nucleophiles.

We initially carried out the investigation by using α-substituted β-nitroacrylate 1a (1.5 equiv.) and 3-alkylidene oxindole 2a (1 equiv.) as the substrates, quinine 3a (10 mol%) as the catalyst, and toluene as the solvent. The reaction proceeded smoothly within 36 hours at room temperature. However, the desired vinylogous adduct 4a was obtained in 7% yield with low enantiomeric excess of 56% (Table 1, entry 1).

Table 1 Optimization of reaction conditionsa

image file: c4ra09128k-u1.tif
Entry Cat. Solvent Yieldb (%) Z[thin space (1/6-em)]:[thin space (1/6-em)]Ec eed (%)
a Reaction conditions: unless specified, a mixture of 1a (0.15 mmol), 2a (0.1 mmol) and a catalyst (10 mol%) in a solvent (0.2 mL) was stirred for 36 h at rt.b Isolated yields.c Determined by 1H NMR.d Determined by chiral HPLC.e 1a (0.1 mmol) and 2a (0.1 mmol) were used.f 1a (0.1 mmol) and 2a (0.15 mmol) used.g 5 mol% of catalyst was used.h 15 mol% of catalyst was used.
1 3a Toluene 7 n.d. −56
2 3b Toluene 98 11[thin space (1/6-em)]:[thin space (1/6-em)]1 −83
3 3c Toluene 39 6[thin space (1/6-em)]:[thin space (1/6-em)]1 −6
4 3d Toluene 10 4[thin space (1/6-em)]:[thin space (1/6-em)]1 −53
5 3e Toluene 17 5[thin space (1/6-em)]:[thin space (1/6-em)]1 −92
6 3f Toluene 40 10[thin space (1/6-em)]:[thin space (1/6-em)]1 −41
7 3g Toluene 99 >20[thin space (1/6-em)]:[thin space (1/6-em)]1 95
8 3g THF 80 8[thin space (1/6-em)]:[thin space (1/6-em)]1 91
9 3g CH2Cl2 74 6[thin space (1/6-em)]:[thin space (1/6-em)]1 82
10 3g CHCl3 68 11[thin space (1/6-em)]:[thin space (1/6-em)]1 71
11 3g CH3CN 47 11[thin space (1/6-em)]:[thin space (1/6-em)]1 80
12 3g MeOH 30 8[thin space (1/6-em)]:[thin space (1/6-em)]1 7
13e 3g Toluene 80 20[thin space (1/6-em)]:[thin space (1/6-em)]1 94
14f 3g Toluene 75 16[thin space (1/6-em)]:[thin space (1/6-em)]1 94
15g 3g Toluene 73 >20[thin space (1/6-em)]:[thin space (1/6-em)]1 94
16h 3g Toluene 65 >20[thin space (1/6-em)]:[thin space (1/6-em)]1 91

After a carefully screening of a variant of bifunctional thiourea catalysts, quinine-derived thiourea 3b was proved to be superior, which gave the desired product 4a in excellent yield (98%) and good ee value (83%), albeit with 11[thin space (1/6-em)]:[thin space (1/6-em)]1 ratio between Z- and E-isomers (entry 2). Other bifunctional thiourea catalysts, such as 3c, 3d and 3e exhibited worse results under the same conditions (entries 3–5). Finally, bifunctional squaramide catalysts11 were tested in the reaction, of which quinine derived squaramide 3g resulted in excellent yield and Z[thin space (1/6-em)]:[thin space (1/6-em)]E selectivity (entries 6 and 7). A subsequent solvent screening turned out that toluene was the ideal solvent, other solvents acted out with diminishing yields, Z[thin space (1/6-em)]:[thin space (1/6-em)]E selectivities and ee values (entries 8–12). Interestingly, changing the ratio of two substrates loading had negative effect on enantioselectivity (entries 13 and 14). Also, decreasing or increasing the catalyst loading led to a great decrease in the yield and stereoselectivity of the reactions (entries 15 and 16).

With the optimized reaction conditions (Table 1, entry 7) in hand, the substrate scopes on the variation of 1 were summarized in Table 2. Non-substituted or electron-withdrawing substituents at the para-position on the aromatic ring in β-nitroacrylates (1a–1d) were all well-tolerated in the transformation, and gave the corresponding products 4a–4d in good yields, high regioselectivities and excellent ees (entries 1–4). The substrates with electron-donating substituents at para-position afford the enantioselectivities at the same levels, although the yields were moderate (entries 5 and 6, 4e and 4f). The substrates with ortho- and di-substituents on aryl ring (1g and 1h) were all compatible in the reaction with good enantioselectivities and acceptable yields (entries 7 and 8). The naphthyl and thienyl substituted β-nitroacrylates (1i and 1j) proceeded smoothly under standard conditions, which gave the desired products in good enantioselectivities, whereas the yield was a little low for 4j (entries 9 and 10).

Table 2 Scope of α-substituted β-nitroacrylates 1a

image file: c4ra09128k-u2.tif
Entry R1 (1) Product Yieldb (%) Z[thin space (1/6-em)]:[thin space (1/6-em)]Ec eed (%)
a Reaction conditions: unless specified, a mixture of 1a (0.15 mmol), 2a (0.1 mmol) and 3g (10 mmol%) in toluene (0.2 mL) was stirred for 36 h at rt.b Isolated yields.c Determined by 1H NMR.d Determined by chiral HPLC.
1 C6H4 (1a) 4a 99 >20[thin space (1/6-em)]:[thin space (1/6-em)]1 95
2 4-FC6H4 (1b) 4b 83 >20[thin space (1/6-em)]:[thin space (1/6-em)]1 96
3 4-ClC6H4 (1c) 4c 81 17[thin space (1/6-em)]:[thin space (1/6-em)]1 95
4 4-BrC6H4 (1d) 4d 82 >20[thin space (1/6-em)]:[thin space (1/6-em)]1 96
5 4-MeC6H4 (1e) 4e 53 11[thin space (1/6-em)]:[thin space (1/6-em)]1 95
6 4-MeOC6H4 (1f) 4f 36 9[thin space (1/6-em)]:[thin space (1/6-em)]1 92
7 3-ClC6H4 (1g) 4g 68 >20[thin space (1/6-em)]:[thin space (1/6-em)]1 86
8 3,5-Me2C6H4 (1h) 4h 56 11[thin space (1/6-em)]:[thin space (1/6-em)]1 96
9 2-Naphthyl (1i) 4i 86 18[thin space (1/6-em)]:[thin space (1/6-em)]1 92
10 2-Thienyl (1j) 4j 29 6[thin space (1/6-em)]:[thin space (1/6-em)]1 86

To further investigate the substrate scopes, 3-alkylidene oxindoles 2 with different substituents were applied in the reaction under optimal conditions (Table 3). By replacing methyl with phenyl or substituted phenyl in 3-alkylidene oxindoles (2a–2c), unexceptionable yields (82–87%), high enantioselectivities (94–97%), and good Z[thin space (1/6-em)]:[thin space (1/6-em)]E selectivities (>20[thin space (1/6-em)]:[thin space (1/6-em)]1) were obtained (entries 1–3). Substrates 2d and 2e with Et- and H- on the alkene, respectively, were relatively unreactive for this reaction with only trace amounts of products detected (entries 4 and 5, 4n and 4o). It is worth noting that the replacement of Boc group with methoxy carbonyl (Moc) group as the protection resulted in a moderate yield and good ee value (entry 6, 4p).12 Furthermore, different substituents on the benzene ring of the oxindoles 2g–2j led to a wide range of yields (51–81%) and high enantioselectivities (94–97%), which revealed that variation of substituents have a large influence on the yields and Z[thin space (1/6-em)]:[thin space (1/6-em)]E selectivities of the products and slight on stereoselectivities (entries 7–10, 4q–4t).

Table 3 Scope of 3-alkylidene oxindole 2a

image file: c4ra09128k-u3.tif
Entry R2, R3 (2) PG Product Yieldb (%) Z[thin space (1/6-em)]:[thin space (1/6-em)]Ec eed (%)
a Reaction conditions: unless specified, a mixture of 1a (0.15 mmol), 2a (0.1 mmol) and 3g (10 mmol%) in toluene (0.2 mL) was stirred for 36 h at rt.b Isolated yields.c Determined by 1H NMR.d Determined by chiral HPLC.
1 H, C6H4 (2a) Boc 4k 87 >20[thin space (1/6-em)]:[thin space (1/6-em)]1 97
2 H, 4-ClC6H4 (2b) Boc 4l 86 >20[thin space (1/6-em)]:[thin space (1/6-em)]1 95
3 H, 4-MeC6H4 (2c) Boc 4m 82 >20[thin space (1/6-em)]:[thin space (1/6-em)]1 94
4 H, ethyl (2d) Boc 4n Trace — —
5 H, — (2e) Boc 4o Trace — —
6 H, CH3 (2f) Moc 4p 53 9[thin space (1/6-em)]:[thin space (1/6-em)]1 85
7 5-F, H (2g) Boc 4q 62 13[thin space (1/6-em)]:[thin space (1/6-em)]1 97
8 5-Br, H (2h) Boc 4r 51 9[thin space (1/6-em)]:[thin space (1/6-em)]1 97
9 5-Me, H (2i) Boc 4s 81 >20[thin space (1/6-em)]:[thin space (1/6-em)]1 94
10 6-Cl, H (2j) Boc 4t 64 14[thin space (1/6-em)]:[thin space (1/6-em)]1 94

We next focused on removing the Boc group on product 4c under acidic condition, which give the N-unprotected oxindole ring 5 in very good yield and unexceptionable stereoselectivity. Moreover, the NH of the unprotected oxindole 5 can be easily further modified. The absolute configuration for enantiopure compound 5 were determined by X-ray crystallographic analysis (Scheme 2).13


image file: c4ra09128k-s2.tif
Scheme 2 Removal of the Boc group in 4c and the X-ray structure of 5.

Based on the previous reports and the electrospray ionization high resolution mass spectrometry (ESI-HRMS) analysis of the reaction mixture,14 we proposed a squaramide promoted bifunctional catalysis mechanism for this transformation: catalyst 3g activated the 3-alkylidene oxindole 2a to form a minimum intermediate A, which undergo an asymmetric Michael addition with the α-substituted β-nitroacrylate 1a, providing the product 4a and regenerating of the squaramide catalyst (Scheme 3).


image file: c4ra09128k-s3.tif
Scheme 3 A proposed reaction mechanism and observation of complex A and complex B.

In the presence of 3g under standard reaction conditions, we observed signals at m/z 904.3517 and m/z 1111.4059 by in situ electrospray ionization high resolution mass spectrometry of the reaction mixture, which correspond to the complex A (3g + 2a) + H+ and the complex B (3g + 2a + 1a) + H+, respectively.

In summary, we have developed an efficient organocatalytic asymmetric Michael addition of 3-alkylidene oxindoles and α-substituted β-nitroacrylates. The stereocenters and alkene geometries of the products were precisely controlled by the bifunctional squaramide catalyst (up to 97% ee, >20[thin space (1/6-em)]:[thin space (1/6-em)]1 Z[thin space (1/6-em)]:[thin space (1/6-em)]E, and 99% yield). Future study will focus on the application of the methodology to synthesize other types of chiral β,β-disubstituted nitrostyrene derivatives nitro-containing compounds and evaluate their bioactivities.

Acknowledgements

We are grateful for the grants from the NSFC (nos 91213303, 21102141, 21272107, and 21202072), the National S&T Major Project of China, and the Fundamental Research Funds for the Central Universities (nos 860976 and 861188).

Notes and references

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  12. The Boc/Moc protecting groups maybe enhance the acidity of the γ-methyl protons in 2, thereby allowing the enolization of the substrates to be more facile.
  13. ESI.†.
  14. For details, see the ESI.†.

Footnotes

† Electronic supplementary information (ESI) available: Experimental details of synthesis and characterization, supportive evidence and results. CCDC 1007906. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ra09128k
‡ These authors contributed equally.
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