Direct Asymmetric Aldol Reaction of Acetophenones and Aromatic Aldehydes Catalyzed by Chiral Al/Zn Heterobimetallic Compounds ZABDP†

doi:10.7503/cjcu20160752

Abstract

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

CLC Number:

O621.3

TrendMD:

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^†[J]. Chem. J. Chinese Universities, 2017, 38(5): 778.

Figures/Tables 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 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

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