杂双金属复合物ZABDP催化芳香酮与芳香醛的直接不对称Aldol反应

doi:10.7503/cjcu20160752

摘要/Abstract

摘要：

合成了新型的手性铝/锌杂双金属复合物(R,S,S)-3,3'-二[(N-二苯基脯氨醇)甲基]-2,2'-二羟基-1,1'-联萘酚铝/锌复合物(ZABDP). 在催化芳香酮与芳香醛的羟醛缩合(Aldol)反应中, 该复合物中的铝作为路易斯酸活化醛, 锌的烷氧化物作为Brønsted碱, 使苯乙酮形成活性锌的烯醇化物, 2种金属的应用使得芳香醛与芳香酮的直接不对称Aldol反应顺利进行, 反应的对映选择性最高达90%, 产率最高达99%.

关键词: 不对称合成, 不对称催化, 杂双金属, Aldol反应, 芳香酮

Abstract:

A chiral Al/Zn heterobimetallic complex,(R,S,S)-3,3'-bis[(N-diphenylprolinol) methyl]-2,2'-bis-(methoxymethyl)-1,1'-binaphthol Al/Zn heterobimetallic complex(ZABDP) was designed as catalyst, to catalyze the direct asymmetric Aldol reaction of acetophenones and aromatic aldehydes. The Al center acts as a Lewis acid to activate the aldehydes while ethylzinc alkoxide functions as a Brønsted base to form the reactive zinc enolates in the complex ZABDP. The distinct actors of the two different metals contribute to the efficient direct asymmetric Aldol reaction, the highest e.e. value is 90% and yield is 99%.

Key words: Asymmetric synthesis, Asymmetric catalysis, Heterobimetallic, Aldol reaction, Acetophenone

中图分类号:

O621.3

TrendMD:

李霄, 高立国, 弓莹, 马亚军, 马向荣. 杂双金属复合物ZABDP催化芳香酮与芳香醛的直接不对称Aldol反应. 高等学校化学学报, 2017, 38(5): 778.

LI Xiao, GAO Liguo, GONG Ying, MA Yajun, MA Xiangrong. Direct Asymmetric Aldol Reaction of Acetophenones and Aromatic Aldehydes Catalyzed by Chiral Al/Zn Heterobimetallic Compounds ZABDP^†. Chem. J. Chinese Universities, 2017, 38(5): 778.

图/表 10

Fig.1 Comparison of dinuclear zincate(A) and Al/Zn bimetallic(B) complex

Table 1 Appearance, melting points and optical rotation for compounds 1—21

Compd.	Appearance	m. p./℃	[α $] D 20$ /(°)(CHCl₃)
1	White solid	51—52(50—52.5^[29])	26(c 1.6)
2	White solid	43—45	61(c 1.55)
3	Pale yellow oil		8(c 8.0)
4	Pale yellow oil		26(c 3.45)
5	White solid	115—117(115—116^[29])	65(c 2.0)
6	White solid	85—86(85—87^[29])	123(c 0.7)
7	White solid	107—109	-44(c 0.5)
8	White solid	100—102(101—102^[29])	38(c 7.2)
9	White solid	47—48.5(47—49^[29])	70(c 1.35)
10	White solid	82—84(82—84^[29])	11(c 8.5)
11	White solid	39—41(39—42^[29])	27(c 2.03)
12	White solid	68—69(67—69^[29])	90(c 1.4)
13	White solid	95—96(94—96^[29])	155(c 2.0)
14	White solid	82—83(82—84^[29])	33(c 3.2)
15	White solid	78—79.5(78—79^[29])	54(c 5.6)
16	White solid	61(60—61^[29])	10(c 9.6)
17	White solid	68—71	28(c1.6)
18	Pale yellow oil		4(c 0.8)
19	Pale yellow oil		4(c 1.0)
20	White solid	107(106—107^[29])	35(c 4.25)
21	White solid	116—117(116—117^[29])	42(c 1.4)

Table 1 Appearance, melting points and optical rotation for compounds 1—21

Compd.	Appearance	m. p./℃	[α $] D 20$ /(°)(CHCl₃)
1	White solid	51—52(50—52.5^[29])	26(c 1.6)
2	White solid	43—45	61(c 1.55)
3	Pale yellow oil		8(c 8.0)
4	Pale yellow oil		26(c 3.45)
5	White solid	115—117(115—116^[29])	65(c 2.0)
6	White solid	85—86(85—87^[29])	123(c 0.7)
7	White solid	107—109	-44(c 0.5)
8	White solid	100—102(101—102^[29])	38(c 7.2)
9	White solid	47—48.5(47—49^[29])	70(c 1.35)
10	White solid	82—84(82—84^[29])	11(c 8.5)
11	White solid	39—41(39—42^[29])	27(c 2.03)
12	White solid	68—69(67—69^[29])	90(c 1.4)
13	White solid	95—96(94—96^[29])	155(c 2.0)
14	White solid	82—83(82—84^[29])	33(c 3.2)
15	White solid	78—79.5(78—79^[29])	54(c 5.6)
16	White solid	61(60—61^[29])	10(c 9.6)
17	White solid	68—71	28(c1.6)
18	Pale yellow oil		4(c 0.8)
19	Pale yellow oil		4(c 1.0)
20	White solid	107(106—107^[29])	35(c 4.25)
21	White solid	116—117(116—117^[29])	42(c 1.4)

Table 2 1H NMR, 13C NMR data for new or pale yellow oil compounds

Compd.	¹H NMR(CDCl₃), δ	¹³C NMR(CDCl₃), δ
2	(300 MHz)7.96—7.93(m, 2H), 7.60—7.55(m, 1H), 7.48—7.43(m, 2H), 7.33(d, J=8.1 Hz, 2H), 7.18(d, J=8.1 Hz, 2H), 5.33—5.29(m, 1H), 3.58(s, 1H), 3.37—3.35(m, 2H), 2.35(s,3H)	(300 MHz) 200.3, 140.0, 137.4, 136.6, 133.6, 129.2, 128.7, 128.2, 125.7, 69.9, 47.4, 21.2
3	(400 MHz) 7.96(d,J=7.6 Hz, 2H), 7.59(t, J=7.6 Hz, 1H), 7.47(t, J=8.0 Hz, 2H), 7.29—7.21(m, 3H), 7.12(d, J=7.2 Hz, 1H), 5.32(t, J=6.0 Hz, 1H), 3.37(d, J=5.6 Hz, 2H)^[29]
4	(300 MHz) 7.98—7.95(m, 2H), 7.62—7.57(m, 2H), 7.50—7.45(m, 2H), 7.30—7.16(m, 3H), 5.58(t, J=5.7 Hz, 1H), 3.52(d, J=1.8 Hz, 1H), 3.33—3.31(m 2H), 2.36(s, 3H)^[37]	(300 MHz) 200.31, 140.90, 136.53, 134.06, 133.69, 130.45, 128.74, 128.17, 127.47, 125.50, 66.49, 46.49, 46.09, 19.14
7	(300 MHz) 8.01—7.96(m, 4H), 7.73—7.68(m, 1H), 7.63—7.58(m, 1H), 7.50—7.44(m, 3H), 5.88—5.84(m, 1H), 4.02(s, 1H), 3.78—3.71(dd, J=2.1, 15.6 Hz ,1H), 3.26—3.17(dd, J=9.3, 8.4 Hz,1H)	(300 MHz) 199.96, 138.6, 136.3, 133.9, 128.8, 128.4, 128.3, 128.2, 124.5, 65.9, 46.5
17	(300 MHz) 7.96(d, J=7.2 Hz, 2H), 7.62—7.57(m, 1H), 7.50—7.45(m, 2H), 7.34—7.29(m, 2H), 7.15—7.13(m, 1H), 5.46—5.41(dd, J=5.7, 3.0 Hz, 1H), 3.63(d, J=3.3 Hz 1H), 3.42(d, J=6.0 Hz, 2H)	(200 MHz) 200.1, 144.2, 136.5, 133.7, 128.7, 128.2, 126.3, 125.6, 120.9, 66.6, 46.5
18	(400 MHz) 7.96(d, J=7.2 Hz, 2H), 7.60(t, J=7.2 Hz, 1H), 7.48(t, J=7.6 Hz, 2H), 4.35—4.29(m, 1H), 3.16(dd, J=2.8, 17.4 Hz, 1H), 3.04(dd, J=8.8, 17.8 Hz, 1H), 1.91—1.85(m, 1H), 1.64—1.57(m, 1H), 1.29—1.22(m, 1H), 0.96(dd, J=3.2, 6.8 Hz, 6H)^[29]
19	(400 MHz) 7.97(d, J=7.2 Hz, 2H), 7.60(t, J=7.6 Hz, 1H), 7.48(t, J=7.6 Hz, 2H), 4.24—4.22(m, 1H), 3.18(dd, J=2.8, 17.6 Hz, 1H), 3.05(dd, J=4.4, 17.6 Hz, 1H), 1.65—1.43(m, 4H), 0.97(t, J=7.2 Hz, 3H)^[29]

Table 2 1H NMR, 13C NMR data for new or pale yellow oil compounds

Compd.	¹H NMR(CDCl₃), δ	¹³C NMR(CDCl₃), δ
2	(300 MHz)7.96—7.93(m, 2H), 7.60—7.55(m, 1H), 7.48—7.43(m, 2H), 7.33(d, J=8.1 Hz, 2H), 7.18(d, J=8.1 Hz, 2H), 5.33—5.29(m, 1H), 3.58(s, 1H), 3.37—3.35(m, 2H), 2.35(s,3H)	(300 MHz) 200.3, 140.0, 137.4, 136.6, 133.6, 129.2, 128.7, 128.2, 125.7, 69.9, 47.4, 21.2
3	(400 MHz) 7.96(d,J=7.6 Hz, 2H), 7.59(t, J=7.6 Hz, 1H), 7.47(t, J=8.0 Hz, 2H), 7.29—7.21(m, 3H), 7.12(d, J=7.2 Hz, 1H), 5.32(t, J=6.0 Hz, 1H), 3.37(d, J=5.6 Hz, 2H)^[29]
4	(300 MHz) 7.98—7.95(m, 2H), 7.62—7.57(m, 2H), 7.50—7.45(m, 2H), 7.30—7.16(m, 3H), 5.58(t, J=5.7 Hz, 1H), 3.52(d, J=1.8 Hz, 1H), 3.33—3.31(m 2H), 2.36(s, 3H)^[37]	(300 MHz) 200.31, 140.90, 136.53, 134.06, 133.69, 130.45, 128.74, 128.17, 127.47, 125.50, 66.49, 46.49, 46.09, 19.14
7	(300 MHz) 8.01—7.96(m, 4H), 7.73—7.68(m, 1H), 7.63—7.58(m, 1H), 7.50—7.44(m, 3H), 5.88—5.84(m, 1H), 4.02(s, 1H), 3.78—3.71(dd, J=2.1, 15.6 Hz ,1H), 3.26—3.17(dd, J=9.3, 8.4 Hz,1H)	(300 MHz) 199.96, 138.6, 136.3, 133.9, 128.8, 128.4, 128.3, 128.2, 124.5, 65.9, 46.5
17	(300 MHz) 7.96(d, J=7.2 Hz, 2H), 7.62—7.57(m, 1H), 7.50—7.45(m, 2H), 7.34—7.29(m, 2H), 7.15—7.13(m, 1H), 5.46—5.41(dd, J=5.7, 3.0 Hz, 1H), 3.63(d, J=3.3 Hz 1H), 3.42(d, J=6.0 Hz, 2H)	(200 MHz) 200.1, 144.2, 136.5, 133.7, 128.7, 128.2, 126.3, 125.6, 120.9, 66.6, 46.5
18	(400 MHz) 7.96(d, J=7.2 Hz, 2H), 7.60(t, J=7.2 Hz, 1H), 7.48(t, J=7.6 Hz, 2H), 4.35—4.29(m, 1H), 3.16(dd, J=2.8, 17.4 Hz, 1H), 3.04(dd, J=8.8, 17.8 Hz, 1H), 1.91—1.85(m, 1H), 1.64—1.57(m, 1H), 1.29—1.22(m, 1H), 0.96(dd, J=3.2, 6.8 Hz, 6H)^[29]
19	(400 MHz) 7.97(d, J=7.2 Hz, 2H), 7.60(t, J=7.6 Hz, 1H), 7.48(t, J=7.6 Hz, 2H), 4.24—4.22(m, 1H), 3.18(dd, J=2.8, 17.6 Hz, 1H), 3.05(dd, J=4.4, 17.6 Hz, 1H), 1.65—1.43(m, 4H), 0.97(t, J=7.2 Hz, 3H)^[29]

Table 3 Selection of the optimal liganda

Entry	Ligand(5%, molar ratio to substrate)	Solvent	Yield^b(%)	e.e.^c	Entry	Ligand(5%, molar ratio to substrate)	Solvent	Yield^b(%)	e.e.^c
1	L-a	DMF	13.3	10	6	L-b	DMSO	1.8	12
2	L-b	DMF	19.0	40	7	L-b	ClCH₂CH₂Cl	1.8	15
3	L-b	THF	2.7	12	8	L-b	MeCN	16.0	39
4	L-b	Et₂O	5.3	9	9	L-b	NMP
5	L-b	Toluene	4.9	18

Table 4 Selection of the optimal additivea

Entry	Additive(%, molar ratio to substrate)	Yield^b(%)	e.e.^c(%)	Entry	Additive(%, molar ratio to substrate)	Yield^b(%)	e.e.^c(%)
1		19.0	40	9	Et₂NH(60)	19	60
2	Et₃N(80)	7.5	51	10	Et₂NH(100)	22	61
3	DIPEA(80)	11.0	49	11	Et₂NH(120)	26	43
4	TMEDA(80)	4.4	51	12^d	Et₂NH(80)/0.4 nm MS	21	80
5	Tetrahydropyrrole(80)	9.3	60	13^d^,^e	Et₂NH(80)/Ph₃PS/0.4 nm MS	29	63
6	2,6-Lutidine(80)	12.4	46	14^d^,^e	Et₂NH(80)/Ph₃POP/0.4 nm MS	23	70
7	NMM(80)	3.1	27	15^d^,^e	Et₂NH(80)/Ph₃P/0.4 nm MS	24	65
8	Et₂NH(80)	23.0	66

Table 5 Selection of the optimal ratio of Al and Zna

Entry	n(Me₃Al)/mmol	n(Et₂Zn)/mmol	Yield^b(%)	e.e.^c(%)
1	0.01	0	11	20
2	0.005	0.0025	16	56
3	0.005	0.0038	17	63
4	0.005	0.005	23	56
5	0.005	0.006	21	80
6	0.005	0.075	15	75
7	0.005	0.0088	35	64

Table 6 Further optimization of reaction conditionsa

Entry	Me₃Al(%, molar ratio to substrate)	Et₂Zn(%, molar ratio)	T/℃	L-b(%, molar ratio to substrate)	Yield^b(%)	e.e.^c(%)
1	5	6	r. t.	5	31	24
2	5	6	0	5	26	35
3	5	6	-20	5	21	80
4	5	6	-78	5	18	66
5	20	24	-20	20	50	80
6^d	20	24	-20	20	74	82

Table 7 Results of asymmetric Aldol reaction of acetophenones and aromatic aldehydes catalyzed by chiral ZABDPa

Entry	R	Yield^b(%)	e.e.^c(%)	Entry	R	Yield^b(%)	e.e.^c(%)
1	Ph	74	82	11	3-MeOC₆H₄	99	85
2	4-MeC₆H₄	23	71	12	2-MeOC₆H₄	48	56
3	3-MeC₆H₄	77	80	13	1-Napth	57	80
4	2-MeC₆H₄	60	76	14	2-Napth	80	80
5	4-NO₂C₆H₄	90	80	15	2-Furyl	63	90
6	3-NO₂C₆H₄	35	75	16	2-Thiophene	85	77
7	2-NO₂C₆H₄	94	71	17	3-Thiophene	33	73
8	4-ClC₆H₄	65	73	18	Isovaleric	64	83
9	3-ClC₆H₄	72	82	19	n-Butyl	68	65
10	2-ClC₆H₄	75	46

Scheme 1 Acetonaphthones’ direct asymmetric Aldol reaction

Scheme 2 Proposed reaction mechanism of direct asymmetic Aldol reaction of acetophenones and aromatic aldehydes catalyzed by chiral Al/Zn heterobimetallic compounds ZABP

参考文献 38

[1]	Alcaide B., Almendros P., Eur. J. Org. Chem., 2002, 2002(10), 1595—1601
[2]	Trost B. M., Brindle C. S., Chem. Soc. Rev., 2010, 39(5), 1600—1632
[3]	Palomo C., Oiarbide M., García J. M., Chem. Soc. Rev., 2004, 33(2), 65—75
[4]	Xu D., Xie X. T., Zheng P., Wang Y. C., Yunnan Chemical Technology, 2016, 43(3), 52—61
	(徐丹, 谢笑天, 郑萍, 王永超.云南化工, 2016,43(3), 52—61)
[5]	Li H., Xu D. Z., Wu L. L., Wang Y. M., Chem. Res. Chinese Universities, 2012, 28(6), 1003—1010
[6]	Xiao J., Li G. W., Zhang W. Q., Chem. Res. Chinese Universities, 2013, 29(2), 256—262
[7]	Li X., Han Y., Tan B. X., Wang B., Cheng J. P., Chem. J. Chinese Universities, 2014, 35(9), 1908—1911
	(李鑫, 韩玉, 谈柏轩, 王斌, 程津培.高等学校化学学报, 2014,35(9), 1908—1911)
[8]	Yu X. X., Wang Q., Zhou Y., Gao R. J., Wang Y. W., Chem. J. Chinese Universities, 2015, 36(12), 2454—2460
	(于潇潇, 王琦, 周烨, 高仁钧, 王英武.高等学校化学学报, 2015,36(12), 2454—2460)
[9]	Mahrwald R., Modern Aldol Reactions, Vol.2: Metal Catalysis, Wiley-VCH, Weinheim, 2004, 1—342
[10]	Casiraghi G., Zanardi F., Appendino G., Rassu G., Chem. Rev., 2000, 100(6), 1929—1972
[11]	Singh P., Bhardwaj A., J. Med. Chem., 2010, 53(9), 3707—3717
[12]	Johnson J. S., Evans D. A., Acc. Chem. Res., 2000, 33(6), 325—335
[13]	Li H. J., Tian H. Y., Wu Y. C., Chen Y. J., Liu L., Wang D., Li C. J., Adv. Synth. Catal., 2005, 347(9), 1247—1256
[14]	Mlynarski J., Jankowska J., Adv. Synth. Catal., 2005, 347(4), 521—525
[15]	Denmark S. E., Heemstra J. R. Jr., Org. Lett., 2003, 5(13), 2303—2306
[16]	Kiyooka S., Takeshita Y., Tanaka Y., Higaki T., Wada Y., Tetrahedron Lett., 2006, 47(26), 4453—4456
[17]	Li H.J., Tian H. Y., Chen Y. J., Wang D., Li C. J.,Chem. Commun., 2002, (24), 2994—2995
[18]	Zhao J. F., Tan B. H., Loh T. P., Chem. Sci., 2011, 2(2), 349—352
[19]	Yu J., Zhao X., Miao Z., Chen R., Org. Biomol. Chem., 2011, 9(19), 6721—6726
[20]	Yoshikawa N., Kumagai N., Mutsunaga S., Moll G., Ohshima T., Suzuki T., Shibasaki M., J. Am. Chem. Soc., 2001, 123(10), 2466—2467
[21]	Kumagai N., Matsunaga S., Yoshikawa N., Ohshima T., Shibasaki M., Org. Lett., 2001, 3(10), 1539—1542
[22]	Trost B. M., Ito H., J. Am. Chem. Soc., 2000, 122(48), 12003—12004
[23]	Trost B. M., Ito H., Silcoff E. R., J. Am. Chem. Soc., 2001, 123(14), 3367—3368
[24]	Trost B. M., Yeh V. S. C., Angew. Chem. Int. Ed., 2002, 41(5), 861—863
[25]	Trost B. M., Mino T., J. Am. Chem. Soc., 2003, 125(9), 2410—2411
[26]	Trost B. M., Fettes A., Shireman B. T., J. Am. Chem. Soc., 2004, 126(9), 2660—2661
[27]	Trost B. M., Shin S., Sclafani J. A., J. Am. Chem. Soc., 2005, 127(24), 8602—8603
[28]	Li G. W., Wang X. J., Zhao W. X., Lu L. J., Liu G. J., Wang M. C., Progress in Chemistry, 2012, 24(2/3), 348—360
	(李高伟, 王晓娟, 赵文献, 鲁刘杰, 刘冠军, 王敏灿.化学进展, 2012,24(2/3), 348—360)
[29]	Li H., Da C. S., Xiao Y. H., Li X., Su Y. N., J. Org. Chem., 2008, 73(18), 7398—7401
[30]	Shibasaki M., Yoshikawa N., Chem. Rev., 2002, 102(6), 2187—2210
[31]	Notz W., Tanaka F., Barbas C. F., Acc. Chem. Res., 2004, 37(8), 580—591
[32]	Matsunaga S., Shibasaki M., Bull. Chem. Soc. Jpn., 2008, 81(1), 60—75
[33]	Mihara H., Xu Y., Sheperd N. E., Matsunaga S., Shibasaki M., J. Am. Chem. Soc., 2009, 131(24), 8384—8385
[34]	Handa S., Gnanadesikan V., Matsunaga S., Shibasaki M., J. Am. Chem. Soc., 2010, 132(13), 4925—4934
[35]	Iwata M., Yazaki R., Chen I. H., Sureshkumar D., Kumagai N., Shibasaki M., J. Am. Chem. Soc., 2011, 133(14), 5554—5560
[36]	Li K., Yang G. Q., Liu Y. Y., Zhang W. B., Chinese Journal of Organic Chemistry, 2013, 33(4), 749—759
	(李昆, 杨国强, 刘媛媛, 张万斌.有机化学, 2013,33(4), 749—759)
[37]	Morohashi N., Hattori T., Yokomakura K., Kabuto C., Miyano S., Tetrahedron Letters, 2002, 43(43), 7769—7772
[38]	Downey C. W., Johnson M. W., Tetrahedron Letters, 2007, 48(20), 3559—3562