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• 2-咪唑啉结构存在于许多重要的活性天然产物中，并且广泛应用于生物活性二氨基酸衍生物的制备^[1-3]，因此，对于2-咪唑啉衍生物的制备具有重要意义。异氰基羧酸酯和亚胺不对称Mannich反应是获得2-咪唑啉化合物的重要方法。1996年，Hayashi等^[4]报道了金催化的异氰基乙酸酯与N-Ts芳香酰亚胺的不对称Mannich反应，以＞99:10dr的非对映选择性得到了cis-构型的主产物。此后，对于此类反应的研究获得到了很大的发展，但是，大多是基于金、铷、钯及铜等金属催化的反应^[5-10]。2010年，Lu等^[11]首次报道了有机催化的异氰基乙酸甲酯与N-Ts芳香醛亚胺的不对称Mannich反应，以最高70%ee(对映体过量值)的对映选择性得到trans-构型的2-咪唑啉。目前，有机催化该类反应获得光学活性2-咪唑啉的报道很少，2012年，Nakamura^[12]报道了手性硫脲衍生物有机催化异氰基乙酸甲磺酰酯与N-2-吡啶磺酰基亚胺的不对称Mannich反应，得到了最高达96%ee对映选择性。本文将多种金鸡纳生物碱衍生物1a~1g(图 1)作为有机催化剂用于异氰基乙酸甲酯和N-Ts芳香醛亚胺的不对称Mannich反应，得到了最高达82%ee的对映选择性，并拓宽了反应底物范围。

  图 1

  

  图 1.  催化剂1a-1g的结构

  Figure 1.  The structure of catalysts 1a-1g

  下载: 全尺寸图片 幻灯片

  1.   实验部分

  1.1   试剂和仪器

  Bruker Avance-500型核磁共振谱仪(NMR，德国Bruker公司)；FT-ICR型高分辨质谱仪(HRMS，德国Bruker公司)；LC-20A型高效液相色谱仪(HPLC, 日本岛津公司)，Chiralcel OD-H型手性色谱柱(日本大赛璐公司)；VERTEX70型傅里叶变换红外光谱仪(FTIR, 德国Bruker公司)。

  奎宁购自Acros试剂；奎尼丁购自Fluka试剂，4A型分子筛(科密欧)购自Aladdin试剂；其它试剂均为市售分析纯产品。芳香醛亚胺根据文献[13]方法合成，催化剂1a-1g根据文献[14]方法合成。

  1.2   不对称Michael加成反应

  于5 mL圆底烧瓶中依次加入异氰基乙酸甲酯(0.22 mmol)、催化剂(0.02 mmol)、亚胺(0.20 mmol)、分子筛(200 mg)和甲苯(0.5 mL), 室温搅拌反应24 h，薄层色谱(TLC)监测。反应结束后，经硅胶柱层析分离，V(正己烷):V(乙酸乙酯)=12:1洗脱，得到油状产品3a-3k。

  (4S, 5R)-4-(甲氧羰基)-5-苯基-N-对甲基苯磺酰基-2-咪唑啉(3a)  ¹H NMR(500 MHz, CDCl₃), δ:7.65(d, J=2.0 Hz, 1H), 7.47(d, J=8.5 Hz, 2H), 7.26~7.16(m, 7H), 5.08(d, J=7.5 Hz, 1H), 4.67(dd, J=2.0, 7.5 Hz, 1H), 3.70(s, 3H), 2.41(s, 3H); HPLC(Daicel Chilralcel OD-H, V(hex):V(iPrOH)=95:5, 0.8 mL/min, 254 nm), t_R:35.7 min(minor), 40.2 min(major); [α]_D²⁰=-32.5(c 1.06, THF)。

  (4S, 5R)-4-(甲氧羰基)-5-(2-氟)苯基-N-对甲基苯磺酰基-2-咪唑啉(3b)  ATR-FTIR(KBr), σ/cm^-1:3430, 1742, 1620, 1444, 1360, 1271, 1173, 1024, 879, 756, 607, 549;¹H NMR(500 MHz, CDCl₃), δ:7.62(d, J=2.0 Hz, 1H), 7.52(d, J=8.5 Hz, 2H), 7.28~7.17(m, 4H), 7.08(t, J=6.5 Hz, 1H), 6.90(t, J=9.0 Hz, 1H), 5.28(d, J=7.5 Hz, 1H), 4.72(dd, J=2.0, 7.5 Hz, 1H), 3.69(s, 3H), 2.41(s, 3H); ¹³C NMR(125 MHz, CDCl₃), δ:169.2, 149.8, 144.9, 134.1, 130.5(d, J=33.0 Hz), 129.8(×2), 129.4(d, J=12.5 Hz), 129.0, 128.2, 127.4(×2), 124.5(d, J=13.5 Hz), 115.8(d, J=83.0 Hz), 78.6, 58.7, 52.9, 21.6;HRMS(ESI+):m/zC₁₈H₁₈FN₂O₄S⁺[M+H]⁺计算值:377.09658, 实测值:377.09671;HPLC(Daicel Chilralcel OD-H, V(hex):V(iPrOH)=80:20, 0.6 mL/min, 254 nm), t_R:23.2(major) min, 25.5 min(minor); [α]_D²⁰=-18.7(c 0.73, THF)。

  (4S, 5R)-4-(甲氧羰基)-5-(2-三氟甲基)苯基-N-对甲基苯磺酰基-2-咪唑啉(3c)  ATR-FTIR(KBr), σ/cm^-1:3425, 1745, 1618, 1450, 1363, 1313, 1299, 1158, 1120, 879, 672, 617, 552;¹H NMR(500 MHz, CDCl₃), δ:7.76(s, 1H), 7.67(d, J=8.5 Hz, 2H), 7.57~7.50(m, 2H), 7.48~7.40(m, 2H), 7.33(d, J=8.5 Hz, 1H), 5.40(d, J=5.5 Hz, 1H), 4.51(d, J=5.0 Hz, 1H), 3.59(s, 3H), 2.45(s, 3H); ¹³C NMR(125 MHz, CDCl₃), δ:168.9, 151.0, 145.3, 133.4, 132.9, 130.0(×2), 129.7, 129.0(m), 128.4, 127.7(×2), 126.9, 126.4, 125.8(d, J=17.5 Hz), 80.6, 58.9, 52.7, 21.6;HRMS(ESI+):m/z C₁₉H₁₈F₃N₂O₄S⁺[M+H]⁺计算值:427.09339, 实测值:427.09385;HPLC(Daicel Chilralcel OD-H, V(hex):V(iPrOH)=80:20, 0.8 mL/min, 254 nm), t_R:13.8 min(major), 16.1 min(minor); [α]_D²⁰=-23.2(c 0.85, THF)。

  (4S, 5R)-4-(甲氧羰基)-5-(3-氯)苯基-N-对甲基苯磺酰基-2-咪唑啉(3d)  ATR-FTIR(KBr), σ/cm^-1:3419, 1745, 1687, 1447, 1360, 1313, 1275, 1160, 880, 660, 566, 547;¹H NMR(500 MHz, CDCl₃), δ:7.65(d, J=2.5 Hz, 1H), 7.47(d, J=8.5 Hz, 2H), 7.25~7.17(m, 3H), 7.14~7.09(m, 2H), 6.99(d, J=7.5 Hz, 1H), 6.84(s, 1H), 5.08(d, J=7.5 Hz, 1H), 4.62(dd, J=2.5, 7.5 Hz, 1H), 3.72(s, 3H), 2.40(s, 3H); ¹³C NMR(125 MHz, CDCl₃), δ:169.5, 150.0, 145.2, 139.9, 134.3, 130.2, 129.9(×2), 128.7, 128.2, 127.3(×2), 126.9, 125.4, 79.8, 63.2, 53.0, 21.6；HRMS(ESI+):m/z C₁₈H₁₈ClN₂O₄S⁺ [M+H]⁺计算值:393.06703, 实测值:393.06703;HPLC(Daicel Chilralcel OD-H, V(hex):V(iPrOH)=90:10, 0.6 mL/min, 254 nm), t_R:49.8 min(minor), 53.8 min(major); [α]_D²⁰=-28.3(c 1.05, THF)。

  (4S, 5R)-4-(甲氧羰基)-5-(3-甲基)苯基-N-对甲基苯磺酰基-2-咪唑啉(3e)  ATR-FTIR(KBr), σ/cm^-1:3423, 1740, 1687, 1441, 1360, 1305, 1157, 880, 804, 663, 547;¹H NMR(500 MHz, CDCl₃), δ:7.65(d, J=2.0 Hz, 1H), 7.46(d, J=7.0 Hz, 2H), 7.19(d, J=8.0 Hz, 2H), 7.14~7.10(m, 1H), 7.04(d, J=7.5 Hz, 1H), 6.97(d, J=7.5 Hz, 1H), 6.84(s, 1H), 5.07(d, J=7.5 Hz, 1H), 4.65(dd, J=2.0, 7.0 Hz, 1H), 3.70(s, 3H), 2.38(s, 3H), 2.20(s, 3H); ¹³C NMR(125 MHz, CDCl₃), δ:169.8, 150.1, 144.6, 138.6, 137.9, 134.7, 129.7(×2), 129.3, 128.7, 127.4, 127.3(×2), 124.3, 79.9, 63.8, 52.9, 21.6, 21.2;HRMS(ESI+):m/z C₁₉H₂₁N₂O₄S⁺[M+H]⁺计算值:373.12165, 实测值:373.12182;HPLC(Daicel Chilralcel OD-H, V(hex):V(iPrOH)=80:20, 1.0 mL/min, 254 nm), t_R:10.3 min(minor), 11.3 min(major); [α]_D²⁰=-31.8(c 0.92, THF)。

  (4S, 5R)-4-(甲氧羰基)-5-(4-氟)苯基-N-对甲基苯磺酰基-2-咪唑啉(3f)  ¹H NMR(500 MHz, CDCl₃), δ:7.68(s, 1H), 7.47(d, J=8.5 Hz, 2H), 7.21(d, J=8.0 Hz, 2H), 7.16~7.10(m, 2H), 6.92(t, J=8.5 Hz, 2H), 5.08(d, J=7.5 Hz, 1H), 4.64(d, J=7.5 Hz, 1H), 3.71(s, 3H), 2.41(s, 3H); HPLC(Daicel Chilralcel OD-H, V(hex):V(iPrOH)=80:20, 1.0 mL/min, 254 nm), t_R:26.0 min(major), 29.1 min(minor); [α]_D²⁰=-29.5(c 0.63, THF)。

  (4S, 5R)-4-(甲氧羰基)-5-(4-氯)苯基-N-对甲基苯磺酰基-2-咪唑啉(3g)  ¹H NMR(500 MHz, CDCl₃), δ:7.64(s, 1H), 7.46(d, J=7.0 Hz, 2H), 7.24~7.16(m, 4H), 7.08(d, J=8.0 Hz, 2H), 5.03(d, J=6.5 Hz, 1H), 4.61(d, J=6.5 Hz, 1H), 3.69(s, 3H), 2.41(s, 3H); HPLC(Daicel Chilralcel OD-H, V(hex):V(iPrOH)=80:20, 1.0 mL/min, 254 nm), t_R:20.2 min(major), 26.5 min(minor); [α]_D²⁰=-35.0(c 0.85, THF)。

  (4S, 5R)-4-(甲氧羰基)-5-(4-甲基)苯基-N-对甲基苯磺酰基-2-咪唑啉(3h)   ¹H NMR(500 MHz, CDCl₃), δ:7.64(s, 1H), 7.46(d, J=7.5 Hz, 2H), 7.19(d, J=7.5 Hz, 2H), 7.04(s, 4H), 5.01(d, J=7.0 Hz, 1H), 4.65(d, J=7.0 Hz, 1H), 3.69(s, 3H), 2.40(s, 3H), 2.31(s, 3H); HPLC(Daicel Chilralcel OD-H, V(hex):V(iPrOH)=80:20, 1.0 mL/min, 254 nm), t_R:14.5 min(minor), 16.2 min(major); [α]_D²⁰=-49.2(c 0.68, THF), 文献值^[11]：[α]_D²⁰=+40(c 1.0, THF)。

  (4S, 5R)-4-(甲氧羰基)-5-(4-异丙基)苯基-N-对甲基苯磺酰基-2-咪唑啉(3i)  ¹H NMR(500 MHz, CDCl₃), δ:7.65(s, 1H), 7.41(d, J=7.5 Hz, 2H), 7.12(d, J=7.5 Hz, 2H), 7.06~7.01(m, 4H), 5.10(d, J=7.0 Hz, 1H), 4.68(d, J=7.0 Hz, 1H), 3.71(s, 3H), 2.88~2.78(m, 1H), 2.37(s, 3H), 1.20(d, J=6.0 Hz, 6H); HPLC(Daicel Chilralcel OD-H, V(hex):V(iPrOH)=80:20, 1.0 mL/min, 254 nm), t_R:11.7 min(minor), 13.4 min(major); [α]_D²⁰=-39.3(c 1.01, THF), 文献值^[11]：[α]_D²⁰=+35(c 1.0, THF)。

  (4S, 5R)-4-(甲氧羰基)-5-(4-叔丁基)苯基-N-对甲基苯磺酰基-2-咪唑啉(3j)  ¹H NMR(500 MHz, CDCl₃), δ:7.66(s, 1H), 7.39(d, J=7.0 Hz, 2H), 7.18(d, J=7.5 Hz, 2H), 7.11(d, J=7.5 Hz, 2H), 7.02(d, J=7.5 Hz, 2H), 5.13(d, J=7.0 Hz, 1H), 4.68(d, J=7.0 Hz, 1H), 3.71(s, 3H), 2.36(s, 3H), 1.27(s, 9H); HPLC(Daicel Chilralcel OD-H, V(hex):V(iPrOH)=80:20, 1.0 mL/min, 254 nm), t_R:11.5 min(minor), 13.4 min(major); [α]_D²⁰=-43.5(c 0.88, THF), 文献值^[11]：[α]_D²⁰=+32(c 1.0, THF)。

  (4S, 5R)-4-(甲氧羰基)-5-(4-甲氧基)苯基-N-对甲基苯磺酰基-2-咪唑啉(3k)  ¹H NMR(500 MHz, CDCl₃), δ:7.66(s, 1H), 7.44(d, J=8.5 Hz, 2H), 7.18(d, J=8.0 Hz, 2H), 7.06(d, J=8.5 Hz, 2H), 6.74(d, J=8.5 Hz, 2H), 5.04(d, J=7.5 Hz, 1H), 4.65(d, J=7.0 Hz, 1H), 3.77(s, 3H), 3.70(s, 3H), 2.39(s, 3H); HPLC(Daicel Chilralcel OD-H, V(hex):V(iPrOH)=80:20, 1.0 mL/min, 254 nm), t_R:33.4 min(major), 40.4 min(minor); [α]_D²⁰=-30.5(c 0.75, THF)。

  2.   结果与讨论

  2.1   催化剂1a-1g催化不对称Michael加成反应

  将催化剂1a-1g用于异氰酸甲酯与苯甲醛亚胺2a的不对称Mannich反应中，考察各种催化剂的催化性能。并考察温度、溶剂及催化剂用量对反应立体选择性的影响，结果见表 1。

  表 1

  

  表 1  异氰基乙酸甲酯与苯甲醛亚胺的不对称Mannich反应条件筛选^a

  Table 1.  Screening of reaction conditions for the asymmetric Mannich reaction^a

  下载: 导出CSV

  Entry	Cat.	Solvent	Temperature/℃	x(catalyst)/%	Yield/%b	dr(trans/cis)c	ee of trans/%d
  1	1a	PhMe	r.t.	10	64	90/10	12
  2	1b	PhMe	r.t.	10	62	＞99/1	57
  3	1c	PhMe	r.t.	10	69	95/5	48
  4	1d	PhMe	r.t.	10	68	＞99/1	50
  5	1e	PhMe	r.t.	10	60	88/12	8
  6	1f	PhMe	r.t.	10	58	90/10	5
  7	1g	PhMe	r.t.	10	60	93/7	10
  8	1b	DCM	r.t.	10	62	＞99/1	30
  9	1b	Et2O	r.t.	10	45	＞99/1	7
  10	1b	MeCN	r.t.	10	43	＞99/1	12
  11e	1b	PhMe	r.t.	10	70	＞99/1	74
  12e	1b	PhMe	0	10	62	＞99/1	69
  13e	1b	PhMe	-20	10	46	＞99/1	54
  14e	1b	PhMe	r.t.	5	62	＞99/1	70
  15e	1b	PhMe	r.t.	20	71	＞99/1	73
  a.All of the reactions were performed with the N-tosyl benzaldimine(0.20 mmol), catalyst(0.02 mmol), and methyl isocyanoacetate(0.22 mmol) in 1 mL of solvent at room temperature for 24 h; b.isolated yield; c.the diastereo ratio(dr) was determined by 1H NMR; d.the enantio excess(ee) was determined by HPLC analysis(Chiralcel OD-H); e.4A molecular sieve(200 mg) was added.

  由表 1结果可以看出:1)7种催化剂均能顺利催化异氰基乙酸甲酯与苯甲醛亚胺的不对称Mannich反应，得到45%~71%的产率。其中奎宁衍生物催化剂1b表现出最好的催化性能(＞99:1 dr(非对映比)，57%ee，Entry 4)。通过测定其比旋光值，并与文献报道的比旋光值进行比较^[11]，确定主要产物的绝对构型为(4S, 5R)。而奎尼丁衍生物1d催化该反应得到了trans-(4R, 5S)构型的主产物(50%ee，Entry 2)；2)溶剂对反应的立体选择性有显著影响，甲苯是最佳溶剂(Entry 2)，乙醚为溶剂时仅得到了7%ee的立体选择性(Entry 9)；3)加入分子筛对反应的对映选择性有明显的影响，产品的ee值提高了17%(Entry 11 vs Entry 2)；4)降低温度对该反应的立体选择性无改善，当温度由室温降至0和-20 ℃，产物的对映选择性和反应产率均有所降低(Entries 12-13 vs Entry 11)；5)催化剂的摩尔分数由10%增加至20%或降至5%，反应的对映选择性未提高(Entries 14-15 vs Entry 11)。综上所述，筛选出的最佳催化剂体系为：摩尔分数为10%的催化剂1b，甲苯为溶剂，4A分子筛，室温反应。

  2.2   底物的扩展

  将筛选出的催化条件应用于不同取代苯甲醛亚胺的不对称Mannich反应中，考察催化剂体系的普适性，结果见表 2。

  表 2

  

  表 2  异氰基乙酸甲酯和不同取代苯甲醛亚胺的不对称Mannich反应^a

  Table 2.  Scope of the enantioselective Mannich reaction of aromatic aldimines^a

  下载: 导出CSV

  Entry	Product	R	Yield/%b	dr(trans/cis)	ee of trans/%c
  1	3a	C6H5	70	＞99/1	74
  2	3b	2-F-C6H4	58	＞99/1	30
  3	3c	2-CF3-C6H4	60	＞99/1	37
  4	3d	3-Cl-C6H4	55	＞99/1	41
  5	3e	3-Me-C6H4	72	＞99/1	55
  6	3f	4-F-C6H4	65	93/7	69
  7	3g	4-Cl-C6H4	66	96/4	58
  8	3h	4-Me-C6H4	80	＞99/1	82
  9	3i	4-iPr-C6H4	68	＞99/1	68
  10	3j	4-tBu-C6H4	70	＞99/1	74
  11	3k	4-OMe-C6H4	62	＞99/1	78
  a.All of the reactions were performed with the aldimine(0.20 mmol), catalyst 1b(0.02 mmol), and methyl isocyanoacetate(0.22 mmol) and catalyst(0.02 mmol) in 0.5 mL toluene; b.isolated yield; c.determined by HPLC analysis(Chiralcel OD-H).

  结果表明，筛选出的催化剂体系能够顺利催化异氰基乙酸甲酯与不同取代苯甲醛亚胺的不对称Mannich反应，得到了55%~80%的产率。其中，对位取代的苯甲醛亚胺在该反应中表现出较好的立体选择性(Entries 6-11)，4-甲基苯甲醛亚胺为底物的反应得到了最高的ee值(82%ee，Entry 8)；而邻位取代苯甲酰亚胺的反应得到较差的对映选择性(Entries 2-3)；由此可知芳环上取代基种类和位置对反应的立体选择性有明显的影响。

  3.   结论

  将金鸡纳生物碱衍生物催化剂用于异氰基乙酸甲酯与芳香醛亚胺的不对称Mannich反应。筛选出最佳催化剂体系，并将其应用于11种不同取代苯甲醛亚胺的反应，得到了最高达82%ee的对映选择性和＞99:1的非对映选择性。反应的普适性还有待于进一步提高。

• 1. [1]

     Viso A, Pradilla R F, García A. α, β-Diamino Acids:Biological Significance and Synthetic Approaches[J]. Chem Rev, 2005, 105(8):  3167-3196. doi: 10.1021/cr0406561

  2. [2]

     Liu H, Du D M. Recent Advances in the Synthesis of 2-Imidazolines and Their Applications in Homogeneous Catalysis[J]. Adv Synth Catal, 2009, 351(4):  489-519. doi: 10.1002/adsc.v351:4

  3. [3]

     Ding H, Friestad G K. Asymmetric Addition of Allylic Nucleophiles to Imino Compounds[J]. Synthesis, 2005, 2005(17):  2815-2829. doi: 10.1055/s-2005-872181

  4. [4]

     Hayashi T, Kishi E, Soloshonok V A. Erythro-Selective Aldol-Type Reaction of N-Sulfonylaldimines with Methyl Isocyanoacetate Catalyzed by Gold(Ⅰ)[J]. Tetrahedron Lett, 1996, 37(28):  4969-4972. doi: 10.1016/0040-4039(96)00981-1

  5. [5]

     Lin Y R, Zhou X T, Dai L X. Ruthenium Complex-Catalyzed Reaction of Isocyanoacetate and N-Sulfonylimines:Stereoselective Synthesis of N-Sulfonyl-2-Imidazolines[J]. J Org Chem, 1997, 62(6):  1799-1803. doi: 10.1021/jo961598p

  6. [6]

     Zhou X T, Lin Y R, Dai L X. A Simple and Practical Access to Enantiopure 2, 3-Diamino Acid Derivatives[J]. Tetrahedron:Asymmetry, 1999, 10(5):  855-862. doi: 10.1016/S0957-4166(99)00052-X

  7. [7]

     Aydin J, Kumar K S, Eriksson L. Palladium Pincer Complex-Catalyzed Condensation of Sulfonimines and Isocyanoacetate to Imidazoline Derivatives[J]. Adv Synth Catal, 2007, 349(17/18):  2585-2594.

  8. [8]

     Zhou X T, Lin Y R, Dai L X. A Catalytic Enantioselective Access to Optically Active 2-Imidazoline from N-Sulfonylimines and Isocyanoacetates[J]. J Org Chem, 1999, 64(4):  1331-1334. doi: 10.1021/jo980949s

  9. [9]

     Benito-Garagorri D, Bocokić V, Kirchner K. Copper(Ⅰ)-Catalyzed Diastereoselective Formation of Oxazolines and N-Sulfonyl-2-Imidazolines[J]. Tetrahedron Lett, 2006, 47(48):  8641-8644.

  10. [10]

      Aydin J, Rydén A, Szabó K J. Chiral Palladium-Pincer Complex Catalyzed Asymmetric Condensation of Sulfonimines and Isocyanoacetate[J]. Tetrahedron:Asymmetry, 2008, 9(15):  1867-1870.

  11. [11]

      Zhang Z W, Lu G, Chen M M. Organocatalytic Asymmetric Mannich-Type Reaction of N-Sulfonylimines with Isocyanoacetate Leading to Optically Active 2-Imidazoline-4-Carboxylates[J]. Tetrahedron:Asymmetry, 2010, 21(13/14):  1715-1721.

  12. [12]

      Nakamura S, Maeno Y, Ohara M. Enantioselective Synthesis of Imidazolines with Quaternary Stereocenters by Organocatalytic Reaction of N-(Heteroarenesulfonyl)imines with Isocyanoacetates[J]. Org Lett, 2012, 14(12):  2960-2963. doi: 10.1021/ol301256q

  13. [13]

      Cheng L, Liu L, Jia H. Enantioselective Organocatalytic Anti-Mannich-Type Reaction of N-Unprotected 3-Substituted 2-Oxindoles with Aromatic N-Ts-Aldimines[J]. J Org Chem, 2009, 74(12):  4650-4653. doi: 10.1021/jo9006688

  14. [14]

      Zhang T Y, He W, Zhao X Y. Asymmetric Oxaziridination Catalyzed by Cinchona Alkaloid Derivatives Containing Sulfide[J]. Tetrahedron, 2013, 69(35):  7416-7422. doi: 10.1016/j.tet.2013.06.061

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  图 1  催化剂1a-1g的结构

  Figure 1  The structure of catalysts 1a-1g

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  表 1  异氰基乙酸甲酯与苯甲醛亚胺的不对称Mannich反应条件筛选^a

  Table 1.  Screening of reaction conditions for the asymmetric Mannich reaction^a

  Entry	Cat.	Solvent	Temperature/℃	x(catalyst)/%	Yield/%b	dr(trans/cis)c	ee of trans/%d
  1	1a	PhMe	r.t.	10	64	90/10	12
  2	1b	PhMe	r.t.	10	62	＞99/1	57
  3	1c	PhMe	r.t.	10	69	95/5	48
  4	1d	PhMe	r.t.	10	68	＞99/1	50
  5	1e	PhMe	r.t.	10	60	88/12	8
  6	1f	PhMe	r.t.	10	58	90/10	5
  7	1g	PhMe	r.t.	10	60	93/7	10
  8	1b	DCM	r.t.	10	62	＞99/1	30
  9	1b	Et2O	r.t.	10	45	＞99/1	7
  10	1b	MeCN	r.t.	10	43	＞99/1	12
  11e	1b	PhMe	r.t.	10	70	＞99/1	74
  12e	1b	PhMe	0	10	62	＞99/1	69
  13e	1b	PhMe	-20	10	46	＞99/1	54
  14e	1b	PhMe	r.t.	5	62	＞99/1	70
  15e	1b	PhMe	r.t.	20	71	＞99/1	73
  a.All of the reactions were performed with the N-tosyl benzaldimine(0.20 mmol), catalyst(0.02 mmol), and methyl isocyanoacetate(0.22 mmol) in 1 mL of solvent at room temperature for 24 h; b.isolated yield; c.the diastereo ratio(dr) was determined by 1H NMR; d.the enantio excess(ee) was determined by HPLC analysis(Chiralcel OD-H); e.4A molecular sieve(200 mg) was added.

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  表 2  异氰基乙酸甲酯和不同取代苯甲醛亚胺的不对称Mannich反应^a

  Table 2.  Scope of the enantioselective Mannich reaction of aromatic aldimines^a

  Entry	Product	R	Yield/%b	dr(trans/cis)	ee of trans/%c
  1	3a	C6H5	70	＞99/1	74
  2	3b	2-F-C6H4	58	＞99/1	30
  3	3c	2-CF3-C6H4	60	＞99/1	37
  4	3d	3-Cl-C6H4	55	＞99/1	41
  5	3e	3-Me-C6H4	72	＞99/1	55
  6	3f	4-F-C6H4	65	93/7	69
  7	3g	4-Cl-C6H4	66	96/4	58
  8	3h	4-Me-C6H4	80	＞99/1	82
  9	3i	4-iPr-C6H4	68	＞99/1	68
  10	3j	4-tBu-C6H4	70	＞99/1	74
  11	3k	4-OMe-C6H4	62	＞99/1	78
  a.All of the reactions were performed with the aldimine(0.20 mmol), catalyst 1b(0.02 mmol), and methyl isocyanoacetate(0.22 mmol) and catalyst(0.02 mmol) in 0.5 mL toluene; b.isolated yield; c.determined by HPLC analysis(Chiralcel OD-H).

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