丙二腈及氰乙酸酯参与的3-脱氢莽草酸甲酯缩合-芳构化-环合串联反应

doi:10.7503/cjcu20140656

高等学校化学学报 ›› 2015, Vol. 36 ›› Issue (2): 267.doi: 10.7503/cjcu20140656

丙二腈及氰乙酸酯参与的3-脱氢莽草酸甲酯缩合-芳构化-环合串联反应

王德建^1,⁴, 张恩生^1,⁴, 徐田龙^1,⁴, 李军³, 黄桐堃¹, 邹永^1,²()

1. 中国科学院广州化学研究所, 广州 510650
2. 中山大学药学院, 广州 510006
3. 浙江大学医学院附属第二医院, 杭州 313000
4. 中国科学院大学, 北京 100049

收稿日期:2014-07-14 出版日期:2015-02-10 发布日期:2015-01-06
作者简介:联系人简介: 邹永, 男, 博士, 教授, 博士生导师, 主要从事药物合成研究. E-mail: zou_jinan@163.com
基金资助:
国家自然科学基金(批准号: 21272280, 81301890)、广东省自然科学基金(批准号: S2013010014278)、广东省新药设计与评价重点实验室基金(批准号: 2011A060901014)、广州市科技计划项目(批准号: 2014J4100224)、浙江省自然科学基金(批准号: LY13H160010)和浙江省中医药优秀青年人才基金(批准号: 2012ZQ017)资助

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

WANG Dejian^1,⁴, ZHANG Ensheng^1,⁴, XU Tianlong^1,⁴, LI Jun³, HUANG Tongkun¹, ZOU Yong^1,^2,^*()

1. Guangzhou Institute of Chemistry, Chinese Academy of Sciences, Guangzhou 510650, China
2. School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
3. The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 313000, China
4. University of Chinese Academy of Sciences, Beijing 100049, China

Received:2014-07-14 Online:2015-02-10 Published:2015-01-06
Contact: ZOU Yong E-mail:zou_jinan@163.com
Supported by:
Supported by the National Natural Science Foundation of China(Nos.21272280, 81301890), the Guangdong Natural Science Foundation, China(NoS2013010014278 ), the Guangdong Provincial Key Laboratory of Construction Foundation, China(No.2011A060901014), the Science & Technology Program of Guangzhou City, China(No.2014J4100224), the Natural Science Foundation of Zhejiang Province, China(NoLY13H160010 ) and the Traditional Chinese Medicine Foundation of Zhejiang Province, China(No.2012ZQ017)

摘要/Abstract

摘要：

3-脱氢莽草酸甲酯与丙二腈、氰乙酸乙酯及氰乙酸甲酯等活性亚甲基化合物在一定条件下发生缩合、芳构化及环合反应, 可方便地构建C—C键并得到多取代的2-氨基苯并呋喃类化合物(3a~3e, 4a和4b), 其中化合物3a中的氰基和甲氧羰基可分别进行选择性水解. 该方法具有原料易得、条件温和、操作简单及收率高等优点, 为可再生生物质资源莽草酸的多样化转化和利用提供了新思路.

关键词: 3-脱氢莽草酸甲酯, 活性亚甲基化合物, 2-氨基苯并呋喃, 可再生生物质

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

中图分类号:

O626

TrendMD:

王德建, 张恩生, 徐田龙, 李军, 黄桐堃, 邹永. 丙二腈及氰乙酸酯参与的3-脱氢莽草酸甲酯缩合-芳构化-环合串联反应. 高等学校化学学报, 2015, 36(2): 267.

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

图/表 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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丙二腈及氰乙酸酯参与的3-脱氢莽草酸甲酯缩合-芳构化-环合串联反应

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

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丙二腈及氰乙酸酯参与的3-脱氢莽草酸甲酯缩合-芳构化-环合串联反应

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

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