Xin
Han
a,
Xiangfei
Wu
a,
Chang
Min
a,
Hai-Bing
Zhou
ab and
Chune
Dong
*ab
aLaboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, Wuhan University School of Pharmaceutical Sciences, Wuhan, 430071, China
bKey Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 200032, China. E-mail: cdong@whu.edu.cn; Tel: 86-2768759586
First published on 13th June 2012
The C3-symmetric cinchonine-squaramide catalyzed asymmetric Michael addition of β-ketosulfones to nitroalkenes is presented. Subsequent transformation leads to chiral cyclic nitrones with excellent results (up to 85% yield and >99% ee). The catalyst can be recovered and reused for six cycles without losing activity and selectivity.
On the other hand, C3-symmetric chiral molecules have recently emerged as powerful organocatalysts in several asymmetric transformations,10–13 as well as its application in the areas of molecular recognition and material sciences.14,15 Due to its unique chiral environment in asymmetric transformations, the C3-symmetric chiral molecule has great potential to explore. In consideration of the excellent performance of squaramide organocatalysts, pioneered by Rawal's group and later exploited by other groups,16,17 we recently developed a novel C3-symmetric cinchonine-squaramide for asymmetric Michael addition of 1,3-dicarbonyl compounds to nitroalkenes, high yields with excellent enantioselectivities and diastereoselectivities were achived.18a During our ongoing study on novel C3-symmetric squaramide catalyzed asymmetric transformations,18 we envisioned the possibility of applying these chiral C3-symmetric squaramide catalysts to develop a highly enantioselective conjugate addition of β-ketosulfones to nitroalkenes. Also, the poor solubility of the C3-squaramide in organic solvents enable its easy recovery by a simple precipitation method, allowing its operational recycling. Moreover, there is no report on the C3-symmetric squaramide catalyzed conjugate addition of ketosulfones so far. In our work, we discovered that the application of readily available C3-symmetric cinchonine-squaramide results in a drastic improvement in enantioselectivity, providing a straightforward protocol for a direct synthesis of optical pure nitrones from enantioselective Michael addition of β-ketosulfones to nitroalkenes.
Herein, we describe the first C3-symmetric cinchonine-squaramides as a highly efficient, recyclable robust catalyst for the enantioselective addition of β-ketosulfones to nitroalkenes, which afforded valuable chiral nitrones in satisfactory yields and excellent enantioselectivities (up to >99% ee).
Entry | Catalyst (mol%) | Solvent | T (°C) | Yield 5a (%)b | ee (%)c |
---|---|---|---|---|---|
a Reaction conditions: 0.2 mmol of 2a, 0.4 mmol of 3a, indicated amount of catalyst in 1.0 mL of appropriate solvent for 24 h. The adduct 4a was reduced by zinc (70 equiv.) in THF/NH4Cl (1![]() ![]() |
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1 | 5 (1a) | CH2Cl2 | rt | 66 | 98 |
2 | 2.5 (1a) | CH2Cl2 | rt | 67 | 96 |
3 | 1 (1a) | CH2Cl2 | rt | 73 | 92 |
4 | 5 (1a) | CH2Cl2 | 0 | 65 | 98 |
5 | 5 (1a) | CH2Cl2 | −20 | 68 | 91 |
6 | 5 (1a) | THF | rt | 76 | >99 |
7 | 5 (1a) | C6H6 | rt | 71 | 97 |
8 | 5 (1a) | Toluene | rt | 61 | 95 |
9 | 5 (1a) | DMF | rt | 65 | 81 |
10 | 5 (1b) | THF | rt | 63 | 88 |
11 | 5 (1c) | THF | rt | 61 | 90 |
12 | 5 (1d) | THF | rt | 60 | 96d |
Encouraged by these results, we next probed the scope of the reaction with a variety of nitro olefins and different β-ketosulfones with 5 mol% of C3 catalyst 1a in THF at room temperature. The results are summarized in Table 2. Generally, the Michael addition reaction catalyzed by 1a underwent cleanly to give adduct 4 in full conversion, followed by reduction, the desired cyclic nitrones 5 were furnished in up to 85% overall yield and >99% ee. As illustrated in Table 2, nitroalkenes bearing electron-withdrawing groups on the aryl rings reacted smoothly with ketosulfone 2a, exclusively affording the corresponding products in excellent ee values (>99%) (Table 2, entries 1–4). In addition, alkylketosulfone 2b was also evaluated, giving chiral nitrones 5e and 5h in 98% ee and 86% ee, respectively (entries 5 and 8). Under the same reduction conditions, nitrone 5l was afforded in 83% ee (entry 14). With respect to alkyl-substituted ketosulfone, somewhat higher enantionselectivity was achieved when xylene was used as a solvent. For example, in the case of 2b, changing the solvent from THF to xylene resulted in an obvious improved enantioselectivity (entry 9, 80% ee vs. entry 8, 86% ee). Furthermore, the reaction of 2a with nitrostyrene in xylene gave the desired product in >99% ee (entry 2). Interestingly, heteroaromatic nitroalkene was also tolerated, leading to the corresponding product 5i in 70% yield and 82% ee (entry 10). Alkyl nitroalkenes generally were less active in this kind of asymmetric transformation. We found that in our case, the alkyl nitroalkene was also tolerated compared to its aryl congeners. For example, when 1-nitropent-1-ene was used in this kind of asymmetric transformation, the desired product was obtained in good enantioselectivities (91% ee) (entry 15).
Entry | R1 | R2 | R3 | Yield of 5 (%)b | ee (%)ce |
---|---|---|---|---|---|
a Unless otherwise noted, the reactions were carried out with 0.2 mmol of ketosulfone 2, 0.4 mmol of nitroalkene 3 in 1.0 mL of THF in the presence of 0.01 mmol of 1a at rt for 24 h. The adduct 4 was reduced by zinc (70 equiv.) in THF/NH4Cl (1![]() ![]() |
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1 | Ph | Ph | o-ClC6H4 | 5a 66 | >99 |
2d | Ph | Ph | Ph | 5b 65 | >99 |
3 | Ph | Ph | p-ClC6H4 | 5c 65 | >99 |
4 | Ph | Ph | p-FC6H4 | 5d 70 | >99 |
5 | Me | p-MeC6H4 | 2,4-(Cl)2C6H3 | 5e f 69 | 98 |
6 | Ph | Ph | 2,4-(Cl)2C6H3 | 5f 70 | 90 |
7 | Me | Ph | 2,4-(Cl)2C6H3 | 5g f 64 | 90 |
8d | Me | p-MeC6H4 | o-ClC6H4 | 5h 65 | 86 |
9 | Me | p-MeC6H4 | o-ClC6H4 | 5h 65 | 80 |
10 | Ph | Ph | 2-Thienyl | 5i 70 | 82 |
11 | Ph | Ph | 3,5-(CF3)2C6H3 | 5j 85 | 80 |
12d | Me | Ph | o-ClC6H4 | 5k 70 | 86 |
13 | Me | Ph | o-ClC6H4 | 5k 62 | 86g |
14 | Me | p-MeC6H4 | Ph | 5l 50 | 83 |
15 | Ph | Ph | nPr | 5m 56 | 91 |
The poor solubility of our C3-symmetric catalyst 1a in organic solvents enabled its easy recovery. Therefore, to determine the recycling ability of catalyst, 1a was recovered after the catalytic process by simple precipitation from the reaction mixture with the addition of ethyl ether and then was reused in the Michael addition of 2a with 3a under the optimized reaction conditions (Table 3). As summarized in Table 3, recycled 1a was carried through at least six runs of Michael addition that simply involved transfer of the recovered catalyst to a new reaction vessel followed by the addition of substrate and solvent. It is noteworthy that in each case the catalyst was recovered in high yield (89–92%) after the reaction was completed and maintained its catalytic activity even after six cycles (95–99% ee).
Cycle no. | Recovery rate (%) | Yield 5a (%)b | ee (%)c |
---|---|---|---|
a All reactions were carried out with 0.75 mmol 2a, 1.5 mmol 3a in 5 mL of THF in the presence of 5 mol% 1a for 24 h. b Isolated yield. c ee values were determined by HPLC analysis on 5a using a chiralpac AD column. | |||
1 | — | 76 | >99 |
2 | 92 | 71 | 98 |
3 | 89 | 73 | 96 |
4 | 90 | 65 | 97 |
5 | 91 | 69 | 95 |
6 | 91 | 70 | 96 |
(3R, 4S)-3-(2-Chlorophenyl)-5-phenyl-4-(phenylsulfonyl)-3,4-di-hydro-2H-pyrroline-1-oxide (5a): [α]20D = + 8.1 (c = 0.3, CHCl3), 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 7.2 Hz, 2H), 7.74 (d, J = 7.3 Hz, 2H), 7.57 (t, 1H), 7.45–7.37 (m, 3H), 7.30–7.25 (m, 3H), 7.19 (m, 2H), 7.10 (d, J = 4 Hz, 1H), 4.96 (s, 1H), 4.78 (m, 2H), 4.02 (dt, 1H). 13C NMR (100 MHz, CDCl3) δ: 137.9, 137.1, 134.5, 133.2, 130.4, 129.5, 129.3, 129.1, 128.2, 128.0, 127.7, 127.4, 126.8, 75.0, 69.7, 35.0. HPLC analysis on a Chiralpack AD column (15% i-PrOH in hexanes; flow rate = 0.9 mL min−1; λ = 220 nm; t minor = 65.5 min, t major = 70.5 min, ee > 99%).
(3R, 4S)-3,5-Diphenyl-4-(phenylsulfonyl)-3,4-dihydro-2H-pyrro-line-1-oxide (5b): [α]20D = + 16.0 (c = 0.2, CHCl3), 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 7.5 Hz, 2H), 7.68 (d, J = 7.4 Hz, 2H), 7.54 (d, J = 7.6 Hz, 1H), 7.38–7.18 (m, 10H), 4.86 (s, 1H), 4.68 (dd, J = 8.0 Hz, 1H), 4.28 (d, J = 8.0 Hz, 1H), 4.14 (bd, J = 12 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 141.1, 136.9, 133.5, 130.2, 129.6, 129.2, 129.0, 128.8, 128.2, 128.1, 127.4, 126.1, 69.6, 37.7, 29.6. HPLC analysis on a Chiralpack IB-H column (10% i-PrOH in hexanes; flow rate = 1.0 mL min−1; λ = 220 nm; t minor = 34.8 min, t major = 40.4 min, ee > 99%).
(3R, 4S)-3-(4-Chlorophenyl)-5-phenyl-4-(phenylsulfonyl)-3,4-di-hydro-2H-pyrroline-1-oxide (5c): [α]20D = −1.5 (c 0.1, CH2Cl2), 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8 Hz, 2H), 7.67 (d, J = 4 Hz, 2H), 7.55 (t, J = 8 Hz, 1H), 7.37–7.20 (m, 7H), 7.14 (d, J = 8.0 Hz, 2H), 4.80 (s, 1H), 4.69 (d, J = 8.0 Hz, 1H), 4.28 (d, J = 8 Hz, 1H), 4.09 (br, J = 16 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 139.4, 136.8, 134.3, 129.8, 129.3, 129.0, 128.2, 127.6, 127.4, 69.9, 37.2, 28.9. HPLC analysis on a Chiralpack IB-H column (10% i-PrOH in hexanes; flow rate = 1 mL min−1; λ = 220 nm; t major = 37.5 min, t minor = 52.2 min, ee > 99%).
(3R, 4S)-3-(4-Fluorophenyl)-5-phenyl-4-(phenylsulfonyl)-3,4-di-hydro-2H-pyrroline-1-oxide (5d): [α]20D = −2.5 (c 0.1, CH2Cl2), 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 4 Hz, 2H), 7.67 (d, J = 8 Hz, 2H), 7.54 (t, J = 8.0 Hz, 1H), 7.38–7.15 (m, 7H), 7.02 (t, J = 8.0 Hz, 2H), 4.81 (s, 1H), 4.69 (dd, J = 8.0 Hz, 1H), 4.29 (d, J = 8.0 Hz, 1H), 4.09 (dd, J = 8, 16 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 163.8, 160.9, 136.8, 134.5, 133.7, 130.3, 129.2, 129.0, 128.2, 128.0, 127.9, 127.5, 127.4, 116.7, 116.4, 76.7, 70.0, 37.1. HPLC analysis on a Chiralpack IB column (10% i-PrOH in hexanes; flow rate = 1.0 mL min−1; λ = 220 nm; t minor = 36.0 min, t major = 46.5 min, ee > 99%).
3-[2,4-Bis(chloro)phenyl]-5-phenyl-4-(4-tolysulfonyl)-3,4-dihyd-ro-2H-pyrroline-1-oxide (5e): [α]20D = −7.69 (c 0.26, EtOAc), 1H NMR (400 MHz, CDCl3) δ 7.80 (br, 2H), 7.45 (d, J = 8.0 Hz, 1H), 7.37–6.99 (m, 3H), 6.97 (dd, J = 8.0 Hz, 1H), 4.24 (br, 1H), 4.13–4.12 (m, 2H), 3.80–3.70 (m, 1H), 2.49 (s, 3H), 2.37 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 136.7, 135.0, 130.2, 129.9, 129.8, 129.7, 129.1, 129.0, 128.9, 128.2, 127.7, 71.6, 66.7, 31.9, 22.6. HPLC analysis on a Chiralpack AD-H column (10% i-PrOH in hexanes; flow rate = 1 mL min−1; λ = 220 nm; t major = 25.6 min, t minor = 31.4 min, ee = 98%). HRMS Calcd for C18H17Cl2NO3S: 398.0373 Found: 398.0379.
3-[2,4-Bis(chloro)phenyl]-5-phenyl-4-(phenylsulfonyl)-3,4-dihy-dro-2H-pyrroline-1-oxide (5f): [α]20D = + 3.86 (c = 0.44, EtOAc), 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.0 Hz, 2H), 7.72 (d, J = 4.0 Hz, 2H), 7.57 (t, J = 8.0 Hz, 1H), 7.45 (d, J = 2.0 Hz, 1H), 7.39 (t, J = 7.8 Hz, 2H), 7.32 (dd, J = 15.8, 8.6 Hz, 3H), 7.19 (dd, J = 8.4, 2.0 Hz, 1H), 7.03 (d, J = 8.0 Hz, 1H), 4.88 (s, 1H), 4.78 (dd, J = 8.0 Hz, 1H), 4.70 (d, J = 8.0 Hz, 1H), 4.00 (d, J = 12.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 134.6, 130.5, 130.2, 129.3, 129.1, 128.4, 128.3, 127.7, 127.3, 74.9, 69.4, 34.7. HPLC analysis on a Chiralpack IB-H column (10% i-PrOH in hexanes; flow rate = 1 mL min−1; λ = 220 nm; t major = 34.6min, t minor = 46.1 min, ee = 90%). HRMS Calcd for C17H15Cl2NO3S: 384.0221 Found: 384.0222.
3-[2,4-Bis(chloro)phenyl]-5-methyl-4-(4-phenylsulfonyl)-3,4-dihydro-2H-pyrroline-1-oxide (5g): [α]20D = −7.27 (c 0.22, EtOAc), 1H NMR (400 MHz, CDCl3) δ 7.96 (br, 1H), 7.79 (m, 1H), 7.75–7.51 (m, 3H), 7.36 (d, 1H), 7.24–7.07 (m, 1H), 6.97 (br, 1H), 4.25 (s, 1H), 4.20–4.11 (m, 2H), 3.80–3.75 (m, 1H), 2.32 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 136.6, 135.0, 130.2, 129.9, 129.8, 129.7, 129.1, 129.0, 128.9, 127.8, 71.6, 66.6, 31.9, 22.6. HPLC analysis on a Chiralpack AD-H column (10% i-PrOH in hexanes; flow rate = 1.0 mL min−1; λ = 220 nm; t minor = 32.8 min, t major = 43.8 min, ee = 90%). HRMS Calcd for C22H17Cl2NO3S: 446.0373 Found: 446.0379.
3-[2-Chlorophenyl]-5-methyl-4-(4-tolysulfonyl)-3,4-dihydro-2H-pyrroline-1-oxide (5h): [α]20D = −1.77 (c 0.30, EtOAc), 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.26–7.23 (m, 3H), 6.97 (d, J = 8.0 Hz, 1H), 4.43 (br, 1H), 4.14 (s, 1H), 4.10 (s, 1H), 3.80 (br, 1H), 2.47 (s, 3H), 2.25 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 133.0, 132.8, 130.4, 129.0, 127.8, 127.5, 126.5, 66.7, 31.9, 29.7, 22.6. HPLC analysis on a Chiralpack IB-H column (10% i-PrOH in hexanes; flow rate = 1 mL min−1; λ = 220 nm; t major = 42.1 min, t minor = 53.1 min, ee = 80%). HRMS Calcd for C18H18ClNO3S: 364.0772 Found: 364.0769.
(3R, 4S)-5-Phenyl-4-(phenylsulfonyl)-3-(thiophen-2-yl)-3,4-dihy-dro-2H-pyrroline-1-oxide (5i): [α]20D = −36.90 (c 0.1, CHCl3), 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.0 Hz, 2H), 7.68 (d, J = 8.0 Hz, 2H), 7.55 (t, J = 8.0 Hz, 2H), 7.36–7.19 (m, 7H), 6.98–6.89 (m, 1H), 4.97 (s, 1H), 4.72 (dd, J = 8.0, 4.0 Hz, 1H), 4.61 (d, J = 4.0 Hz, 1H), 4.12 (d, J = 4.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 143.4, 136.9, 134.6, 133.4, 130.3, 129.3, 129.0, 128.2, 127.6, 127.3, 125.1, 124.7, 70.7, 63.7, 34.0, 29.7. HPLC analysis on a Chiralpack AD-H column (30% i-PrOH in hexanes; flow rate = 0.8 mL min−1; λ = 220 nm; t minor = 41.5 min, t major = 54.6 min, ee = 81%).
(3R, 4S)-3-[3, 5-Bis (trifluouomethyl) phenyl]-5-phenyl-4-(phen-ylsulfonyl)-3, 4-dihydro-2H-pyrroline-1-oxide (5j): [α]20D = + 10 (c = 0.1, CHCl3), 1H NMR (400 MHz, CDCl3) δ 7.88 (t, J = 8.0 Hz, 3H), 7.59 (m, 4H), 7.57 (t, J = 8.0 Hz, 1H), 7.37 (t, J = 8.0 Hz, 3H), 7.21–7.31 (m, 2H), 4.83–4.76 (m, 1H), 4.50 (d, J = 8.0, 1H), 4.16 (brd, J = 16.0 Hz, 1H), 4.11 (dt, J = 8.0, 4.0Hz, 1H). 13C NMR (100 MHz, CDCl3) δ: 143.3, 138.8, 136.4, 134.8, 133.3, 133.0, 130.6, 129.4, 129.1, 128.3, 127.3, 126.7, 122.5, 122.5, 69.1, 37.3, 29.7. HPLC analysis on a Chiralpack AD-H column (20% i-PrOH in hexanes; flow rate = 0.5 mL min−1; λ = 220 nm; t major = 12.9 min, t minor = 16.5 min, ee = 80%).
(3R, 4S)-3-(2-Chlorophenyl)-5-methyl-4-(4-phenylsulfonyl)-3,4-dihydro-2H-pyrroline-1-oxide (5k): [α]20D = −10.8 (c 0.46, EtOAc), 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 7.9 Hz, 2H), 7.73 (s, 1H), 7.62 (t, J = 7.7 Hz, 2H), 7.34 (d, J = 8.0 Hz, 1H), 7.25–7.13 (m, 2H), 6.97 (s, 1H), 4.43 (s, 1H), 4.28 (m, 2H), 3.85 (m, 1H), 2.23 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 138.8, 137.2, 136.7, 136.6, 134.8, 132.9, 130.4, 129.8, 129.5, 129.0, 127.8, 127.4, 66.8, 36.0, 29.6, 13.0. HPLC analysis on a Chiralpack AD-H column (10% i-PrOH in hexanes; flow rate = 1.0 mL min−1; λ = 220 nm; t major = 40.9 min, t minor = 53.8 min, ee = 86%). HRMS Calcd for C17H16ClNO3S: 350.0621 Found: 350.0612.
(3R, 4S)-5-methyl-3-phenyl-4-tosyl-3,4-dihydro-2H-pyrroline-1-oxide (5l): [α]20D = −21.8 (c 0.3, CHCl3), 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.2 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 7.29 (s, 3H), 7.01 (d, J = 5.6 Hz, 2H), 4.34 (s, 1H), 4.08 (s, 2H), 3.86 (d, J = 7.9 Hz, 1H), 2.49 (s, 3H), 2.20 (d, J = 21.8 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ: 170.31, 146.31, 140.56, 133.72, 130.48, 129.51, 128.90, 128.18, 126.05, 81.15, 38.61, 29.69, 21.78, 14.10. HPLC analysis on a Chiralpack IB column (10% i-PrOH in hexanes; flow rate = 1.0 mL min−1; λ = 220 nm; t major = 47.5 min, t minor = 54.0 min, ee = 86%).
(3R, 4S)-3-phenyl-4-(phenylsulfonyl)-5-propyl-3,4-dihydro-2H-pyrroline-1-oxide (5m): [α]20D = −10.8 (c 0.34, EtOAc), 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 7.1 Hz, 2H), 7.65 (d, J = 7.4 Hz, 2H), 7.55 (t, J = 7.5 Hz, 1H), 7.44–7.30 (m, 3H), 7.29 (d, J = 4.5 Hz, 2H), 4.22 (dd, J = 14.0, 7.5 Hz, 1H), 3.69 (d, J = 14.1 Hz, 1H), 3.01 (q, J = 7.3 Hz, 1H), 2.09 (d, J = 32.1 Hz, 1H), 1.67 (dt, J = 14.4, 7.3 Hz, 4H), 1.01 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ: 137.60, 134.45, 130.23, 129.25, 129.01, 128.16, 127.51, 73.97, 68.50, 34.26, 29.71, 27.65, 10.69. HPLC analysis on a Chiralpack OD-H column (8% i-PrOH in hexanes; flow rate = 1.0 mL min−1; λ= 220 nm; t minor = 59.3 min, t major = 76.0 min, ee = 91%).
Footnote |
† Electronic Supplementary Information (ESI) available: NMR and HPLC spectra of compounds 5. See DOI: 10.1039/c2ra21162a/ |
This journal is © The Royal Society of Chemistry 2012 |