Malononitrile and Cyanoacetic Acid Esters Involved Cascade Reaction of (-)-Methyl 3-Dehydroshikimate†

doi:10.7503/cjcu20140656

Abstract

Abstract:

With the diminishing of fossil oil reserves, chemical conversion and value-added utilization of renewable biomass have become a worldwide topic for chemists. It was demonstrated that the reaction between (-)-methyl 3-dehydroshikimate(3-MDHS) and several active methylene compounds under facile conditions gave rise to substituted 2-aminobenzofurans in moderate to good yields. The process involved the formation of a new C—C bond through condensation, followed by a sequential aromatization/cyclization reaction. The chemoselective hydrolysis of compound 3a was also realized. The structures of the synthesized compounds were characterized by ¹H NMR, ¹³C NMR, MS and IR. The ready availability of biosourced starting materials, the convenient reaction conditions as well as the easy workup procedures made this protocol a practical method for the chemical conversion of the renewable biomass (-)-shikimic acid.

Key words: (-)-Methyl 3-dehydroshikimate, Active methylene compound, 2-Aminobenzofuran, Renewable biomass

CLC Number:

O626

TrendMD:

WANG Dejian, ZHANG Ensheng, XU Tianlong, LI Jun, HUANG Tongkun, ZOU Yong. Malononitrile and Cyanoacetic Acid Esters Involved Cascade Reaction of (-)-Methyl 3-Dehydroshikimate^†[J]. Chem. J. Chinese Universities, 2015, 36(2): 267.

Figures/Tables 6

Fig.1 Biological active molecules with benzofuran subunit

Scheme 1 Active methylene compound involved chemical conversion of (-)-methyl 3-dehydro-shikimate

Table 1 Appearance, yields, melting points, MS and IR data for compounds 3a—3e and 4a—4b

Compd.	Appearance	Yield(%)	m.p./℃	EI-MS, m/z	IR(KBr), $ν ˙$ /cm^-1
3a	White needle crystal	97.2	260—261	216(M⁺), 185, 157, 129, 102, 75	3409, 3320, 2950, 2212, 1718, 1646, 1583, 1460, 1246, 1186, 1101, 997, 887, 758, 729
3b	Pale yellow solid	70.3^a	116—118	263(M⁺), 232, 217, 186, 174, 158, 130, 102	3429, 3307, 2981, 2954, 1683, 1639, 1545, 1473, 1438, 1367, 1296, 1242, 1190, 1097, 1045, 993, 897, 764, 698
3c	White solid	78.3^a	194—196	249(M⁺), 217, 186, 174, 158, 146, 130, 102, 93	3428, 3320, 3006, 2954, 1695, 1643, 1544, 1475, 1438, 1298, 1245, 1191, 1105, 1041, 993, 893, 819, 765
3d	White solid	68.1^a	238—239	279(M⁺), 248, 233, 205, 177, 162, 151, 118, 101	3527, 3403, 3272, 3218, 2985, 1666, 1541, 1502, 1446, 1384, 1340, 1299, 1255, 1180, 1101, 1002, 871, 775, 734
3e	Pale yellow solid	67.9^a	203—204	265(M⁺), 250, 235, 222, 207, 194, 176, 148, 133, 120, 105	3450, 3338, 2954, 2858, 1684, 1635, 1537, 1446, 1379, 1305, 1240, 1186, 1120, 1087, 1012, 873, 773, 736
4a	White needle crystal	85.5	212—213	234(M⁺), 217, 186, 174, 158, 146, 130, 102, 90, 76, 65, 51	3392, 3303, 3201, 2952, 1702, 1650, 1525, 1483, 1436, 1367, 1301, 1259, 1191, 1105, 993, 960, 885, 767, 665
4b	White solid	79.2	> 280	225.0269^b [M+Na]⁺	3427, 3330, 3205, 2829, 2652, 2210, 1678, 1654, 1581, 1464, 1419, 1361, 1313, 1265, 1196, 1115, 1053, 991, 926, 891, 833, 766, 729

Table 1 Appearance, yields, melting points, MS and IR data for compounds 3a—3e and 4a—4b

Compd.	Appearance	Yield(%)	m.p./℃	EI-MS, m/z	IR(KBr), $ν ˙$ /cm^-1
3a	White needle crystal	97.2	260—261	216(M⁺), 185, 157, 129, 102, 75	3409, 3320, 2950, 2212, 1718, 1646, 1583, 1460, 1246, 1186, 1101, 997, 887, 758, 729
3b	Pale yellow solid	70.3^a	116—118	263(M⁺), 232, 217, 186, 174, 158, 130, 102	3429, 3307, 2981, 2954, 1683, 1639, 1545, 1473, 1438, 1367, 1296, 1242, 1190, 1097, 1045, 993, 897, 764, 698
3c	White solid	78.3^a	194—196	249(M⁺), 217, 186, 174, 158, 146, 130, 102, 93	3428, 3320, 3006, 2954, 1695, 1643, 1544, 1475, 1438, 1298, 1245, 1191, 1105, 1041, 993, 893, 819, 765
3d	White solid	68.1^a	238—239	279(M⁺), 248, 233, 205, 177, 162, 151, 118, 101	3527, 3403, 3272, 3218, 2985, 1666, 1541, 1502, 1446, 1384, 1340, 1299, 1255, 1180, 1101, 1002, 871, 775, 734
3e	Pale yellow solid	67.9^a	203—204	265(M⁺), 250, 235, 222, 207, 194, 176, 148, 133, 120, 105	3450, 3338, 2954, 2858, 1684, 1635, 1537, 1446, 1379, 1305, 1240, 1186, 1120, 1087, 1012, 873, 773, 736
4a	White needle crystal	85.5	212—213	234(M⁺), 217, 186, 174, 158, 146, 130, 102, 90, 76, 65, 51	3392, 3303, 3201, 2952, 1702, 1650, 1525, 1483, 1436, 1367, 1301, 1259, 1191, 1105, 993, 960, 885, 767, 665
4b	White solid	79.2	> 280	225.0269^b [M+Na]⁺	3427, 3330, 3205, 2829, 2652, 2210, 1678, 1654, 1581, 1464, 1419, 1361, 1313, 1265, 1196, 1115, 1053, 991, 926, 891, 833, 766, 729

Table 2 1H NMR and 13C NMR data for compounds 3a—3e and 4a—4b

Compd.	¹H NMR(400 MHz, DMSO-d₆), δ	¹³C NMR(100 MHz, DMSO-d₆), δ
3a	8.50(s, 2H, NH₂), 7.74(d, 1H, J=1.6 Hz, 4-ArH), 7.70(dd, 1H, J₁=8.4 Hz, J₂=1.6 Hz, 6-ArH), 7.48(d, 1H, J=8.4 Hz, 7-ArH), 3.86(s, 3H, OCH₃)	166.6, 166.0, 150.5, 128.7, 125.8, 123.2, 116.6, 114.7, 110.0, 60.1, 52.2
3b	8.12(d, 1H,J=1.6 Hz, 4-ArH), 7.98(s, 2H, NH₂), 7.66(dd, 1H, J₁=8.4 Hz, J₂=2.0 Hz, 6-ArH), 7.41(d, 1H, J=8.4 Hz, 7-ArH), 4.28(q, 2H, J=7.2 Hz, CH₂), 3.85(s, 3H, OCH₃), 1.33(t, 3H, J=7.2 Hz, CH₃)	166.4, 165.7, 164.1, 151.1, 127.8, 125.4, 122.7, 119.2, 109.5, 81.2, 59.1, 52.0, 14.6
3c	8.12(d, 1H,J=0.8 Hz, 4-ArH), 8.04(s, 2H, NH₂), 7.68(dd, 1H, J₁=8.4 Hz, J₂=1.6 Hz, 6-ArH), 7.43(d, 1H, J=8.4 Hz, 7-ArH), 3.86(s, 3H, OCH₃), 3.81(s, 3H, OCH₃)	166.4, 165.7, 164.4, 151.1, 127.8, 125.4, 122.7, 119.1, 109.6, 81.1, 52.0, 50.6
3d	10.28(s, 1H, ArOH), 7.88(s, 2H, NH₂), 7.65(d, 1H, J=1.2 Hz, 6-ArH), 7.20(d, 1H, J=1.6 Hz, 4-ArH), 4.26(q, 2H, J=8.0 Hz, CH₂), 3.82(s, 3H, OCH₃), 1.31(t, 3H, J=8.0 Hz, CH₃)	166.5, 165.5, 164.2, 140.9, 139.0, 129.3, 126.0, 110.9, 109.9, 81.9, 58.9, 52.0, 14.6
3e	10.28(s, 1H, ArOH), 7.91(s, 2H, NH₂), 7.63(d, 1H, J=1.6 Hz, 6-ArH), 7.20(d, 1H, J=1.6 Hz, 4-ArH), 3.82(s, 3H, OCH₃), 3.78(s, 3H, OCH₃)	166.4, 165.4, 164.4, 140.8, 138.9, 129.1, 125.9, 110.7, 109.8, 81.6, 52.0, 50.4
4a	8.23(d, 1H,J=1.6 Hz, 4-ArH), 7.78(s, 2H, NH₂), 7.66(dd, 1H, J₁=8.4 Hz, J₂=2.0 Hz, 6-ArH), 7.42(d, 1H, J=8.4 Hz, 7-ArH), 6.96(s, 2H, CONH₂), 3.87(s, 3H, OCH₃)	166.7, 166.5, 164.9, 150.9, 127.2, 125.2, 122.1, 118.7, 109.4, 84.2
4b	12.90(s, 1H, COOH), 8.44(s, 2H, NH₂), 7.73(s, 1H, 4-ArH ), 7.68(dd, 1H, J₁=8.4 Hz, J₂=1.2 Hz, 6-ArH), 7.44(d, 1H, J=8.4 Hz, 7-ArH)	167.0, 166.4, 150.3, 128.4, 126.9, 123.3, 116.7, 114.7, 109.7, 60.0

Table 3 Reaction of 3-MDHS(2) with active methylene compounds

Entry	Base	Solvent	Time/h	t/℃	Product	Yield(%)
1	Piperidine	EtOH	5	80	3a	85
2		H₂O	4	95	3a	97
3	Piperidine	EtOH	6	80	3b, 3d	65, 17
4	DMAP	EtOH	6	80	3b, 3d	70, 15
5	DMAP	EtOH	6	60	3b, 3d	18, 68
6	DMAP	EtOH	6	80	3c, 3e	78, 19
7	DMAP	EtOH	6	60	3c, 3e	10, 68
8	DMAP	EtOH	10	80	3f	42
9	Pyridine	EtOH	10	80	3f	59
10	Et₃N	EtOH	6	80	3f	60
11	DMAP	EtOH	8	75	3f	39
12	DMAP	EtOH	8	80	3f	50

Scheme 2 Proposed mechanism for the reaction of ethyl cyanoacetate with (-)-methyl 3-dehydroshikimate

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