吡唑并[2,3-c]吡喃酮衍生物的一锅法熔融合成

doi:10.7503/cjcu20170594

摘要/Abstract

摘要：

在无溶剂条件下, 以双分子的β-酮酸酯和取代肼为原料进行升温熔融反应, 经一锅法合成了15种不同取代的吡唑并[2,3-c]吡喃酮类化合物(4a~4o). 化合物4a~4o的结构经红外光谱(IR)、核磁共振波谱(NMR)和高分辨质谱(HRMS)确证. 该方法克服了传统合成方法中溶剂对环境造成的污染及分步合成的不便, 收率可达40%~85%. 该方法具有无溶剂参与、条件温和、收率高及操作简便等优点, 符合绿色化学和节约型经济理念. 研究了反应速度、产率与取代基的关系; 利用超高液相色谱-高分辨质谱联用(UPLC-HRMS)仪检测跟踪反应, 发现并确定了新的中间体C, 据此提出了一种新的反应机理. 此外, 中间体C含有四元环结构, 并以稳定的形式存在, 此类中间体的发现为制备四取代的环丁烷类化合物提供了新思路.

关键词: 无溶剂法, 熔融法, 一锅法, 吡唑并[2,3-c]吡喃酮, 反应机理

Abstract:

Pyrano[2,3-c]pyrazol-6-ones are widely used in the field of medicine and pesticide as a kind of skeletal molecules with high research value and important biological activity. In this work, 15 different substituted pyrano[2,3-c]pyrazol-6-ones(4a-4o) were synthesized rapidly and efficiently under solvent-free conditions by one-pot reaction with two molecules β-keto ester and substituted hydrazine as the starting materials. The yields ranged from 40% to 85%. The products were confirmed by infrared spectroscopy(IR), nuclear magnetic resonance spectroscopy(NMR) and high resolution mass spectrometry data(HRMS). Compared with the traditional synthetic methods, this work overcomes the environmental pollution caused by the use of solvent and the inconvenience of stepwise reaction and has the advantages of solvent-free, mild condition, high yield and easy operation, which also conforms to the green chemistry and economical economy. In addition, the relationship between the reaction rate and yield with the substituent was discussed. The melting reaction process was tracked by ultra-high performance liquid chromatography/high resolution mass spectrometry(UPLC-HRMS) and a new intermediates C was found and identified. Accordingly, a new reaction mechanism for this kind of reaction was proposed, which gave a new understanding of this kind of reaction. In addition, the intermediate C contains a quaternary ring structure but exists in a stable form, which provides a new method for the synthesis of four substituted cyclic butane compounds and ideas for constructing the unstable carbocyclic ring.

Key words: Solvent-free method, Melting method, One-pot reaction, Pyrano[2,3-c]pyrazol-6-one derivative, Reaction mechanism

中图分类号:

O626.21

TrendMD:

崔思乾, 卢俊瑞, 谢志强, 卢博为, 刘金彪, 刘梅, 马瑶, 胡新龙, 李贾东. 吡唑并[2,3-c]吡喃酮衍生物的一锅法熔融合成. 高等学校化学学报, 2018, 39(4): 688.

CUI Siqian, LU Junrui, XIE Zhiqiang, LU Bowei, LIU Jinbiao, LIU Mei, MA Yao, HU Xinlong, LI Jiadong. One-pot Fasion Synthesis of Pyrano[2,3-c]pyrazol-6-one Derivatives^†. Chem. J. Chinese Universities, 2018, 39(4): 688.

图/表 7

Scheme 1 One-pot solvent-free synthesis of pyrazolo[2,3-c]pyrone compounds

Table 1 Melting points and ESI-TOF-MS data of the target compounds 4a-4j and 4l-4o*

Compd.	m. p.(Ref.)/℃	ESI-TOF-MS(calcd.), m/z[M+H]⁺	Compd.	m. p.(Ref.)/℃	ESI-TOF-MS(calcd.), m/z[M+H]⁺
4a	144-147(145^[27])	241.0982(241.0977)	4h	200-203(199-200^[28])	286.0834(286.0828)
4b	174-175(175-176^[27])	179.0823(179.0820)	4i	181-182(181-182^[28])	255.1141(255.1134)
4c	239-241(245^[28])	165.0668(165.0664)	4j	228-230(229-233^[27])	242.0936(242.0930)
4d	124-126(126^[28])	275.0593(275.0587)	4l	138-139(140^[27])	303.1139(303.1133)
4e	158-160	275.0584(275.0587)	4m	158-160(158^[28])	275.0594(275.0587)
4f	181-183(180^[28])	275.0582(275.0587)	4n	187-189	331.1453(331.1453)
4g	172-174	259.0882(259.0883)	4o	181-182	255.1139(255.1134)

Table 2 Optimization of reaction conditionsa

Entry	n(1a)/n(2a)	Temperature/℃	t/h	Yield^b(%)	Entry	n(1a)/n(2a)	Temperature/℃	t/h	Yield^b(%)
1	1:2	110	4	57.76	8	1:2.5	150	4	86.87
2	1:2	130	4	68.35	9	1:3	150	4	85.05
3	1:2	150	4	85.14	10	1:3.5	150	4	84.77
4	1:2	170	4	73.25	11	1:4	150	4	81.31
5	1:2	160	4	76.67	12	1:2	150	2	66.78
6	1:2	180	4	70.93	13	1:2	150	3	76.12
7	1:2	140	4	74.59	14	1:2	150	5	72.68

Table 3 Solvent-free preparation of products 4a-4o through different hydrazine and β-keto estera

Entry	Product	R	R¹	R²	t/h	Yield^b(%)
1	4a	Ph	CH₃	H	4	85.14
2	4b	CH₃	CH₃	H	2.5	70.89
3	4c	H	CH₃	H	2	72.56
4	4d	o-ClPh	CH₃	H	5	40.42
5	4e	m-ClPh	CH₃	H	4	65.21
6	4f	p-ClPh	CH₃	H	4	79.45
7	4g	p-FPh	CH₃	H	4	70.28
8	4h	p-NO₂Ph	CH₃	H	4	58.32
9	4i	p-CH₃Ph	CH₃	H	4	87.45
10	4j	Pyridine	CH₃	H	3	61.36
11	4k	Pyrazine	CH₃	H	3	65.17
12	4l	Ph	Ph	H	5	78.87
13	4m	Ph	CH₃	Cl	4	78.88
14	4n	Ph	CH₃	CH₂Ph	5	74.32
15	4o	Ph	CH₃	CH₃	3	70.24

Scheme 2 Possible mechanism for the formation of compound 5

Table 4 The intermediate structures of the rection process identified by UPLC-HRMS

Peak No.	t_R/min	HRMS, m/z[M+1]⁺	Molecular ionic formula	Product ion
1	7.637	221.1299	C₁₂H₁₇N₂ $O 2 +$	175.0882 149.0930 133.0779 106.0667
2	4.683	175.0884	C₁₀H₁₁N₂O⁺	147.0918 133.0779 130.0664 98.9857
3	9.016	573.2739	C₃₂H₃₇N₄ $O 6 +$	501.2517 399.1917 309.1222 287.1402 241.0986 215.1194 175.0877
4	7.829	241.1014	C₁₄H₁₃N₂ $O 2 +$	215.1191 183.0928 175.0900 141.1141 118.0655 98.9655

Table 4 The intermediate structures of the rection process identified by UPLC-HRMS

Peak No.	t_R/min	HRMS, m/z[M+1]⁺	Molecular ionic formula	Product ion
1	7.637	221.1299	C₁₂H₁₇N₂ $O 2 +$	175.0882 149.0930 133.0779 106.0667
2	4.683	175.0884	C₁₀H₁₁N₂O⁺	147.0918 133.0779 130.0664 98.9857
3	9.016	573.2739	C₃₂H₃₇N₄ $O 6 +$	501.2517 399.1917 309.1222 287.1402 241.0986 215.1194 175.0877
4	7.829	241.1014	C₁₄H₁₃N₂ $O 2 +$	215.1191 183.0928 175.0900 141.1141 118.0655 98.9655

Scheme 3 Possible mechanism for the formation of compound 4a

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