Mannich Reaction of Aromatic Ketones Based on Acetic Acid as Solvent and Catalyst†

doi:10.7503/cjcu20131050

Abstract

Abstract:

Mannich reaction is one of the most important methods for preparation of β-amino ketones and aldehydes and α,β-unsaturated carbonyl compounds, as well as one of the most important basic reaction types in organic chemistry and it is widely applied as a key step in the synthesis of numerous pharmaceuticals and natural products. However, during the synthesis of 1-aryl acrylic ketone 2 by the Mannich reaction of aromatic ketones, formaldehyde and secondary amine using acetic acid as solvent and catalyst, the Mannich base and expected α,β-unsaturated ketones 2 were not obtained and another kind of compounds 3, 2-aryl formyl allyl acetate were obtained in moderate to good yields(65%—73%). The structure of compounds 3 was confirmed by ¹H NMR, ¹³C NMR, HRMS and IR spectra. The reasons of producing compounds 3 were studied and the results suggested that the special structure of aromatic ketones and excess acetic acid in reaction are responsible for the exceptional Mannich reaction. In addition, the reaction mechanism was postulated.

Key words: Mannich reaction, α, β, -Unsaturated ketone, 2-Aryl formyl allyl acetate, Acetic acid

CLC Number:

O626

TrendMD:

BU Huijuan, ZHANG Jing, MU Boshuai, LI Yuan. Mannich Reaction of Aromatic Ketones Based on Acetic Acid as Solvent and Catalyst^†[J]. Chem. J. Chinese Universities, 2014, 35(9): 1912.

Figures/Tables 7

References 20

[1]	Guo Q. S., Zhao C. G., Arman. H., Tetrahedron Lett., 2012, 53(36), 4866—4869
[2]	Wang H. G., Liu D. H., Zhang Z. Q., Li Y. X., Yang Q. B., Du J. S., Chem. J. Chinese Universities,2012, 33(5), 1074—1077
	(王恒国, 刘大海, 张朝群, 李耀先, 杨清彪, 杜建时. 高等学校化学学报, 2012, 33(5), 1074—1077)
[3]	Song Z. C., Wang S. S., Song Q. L., Shu T., Zhao W. J., Chem. J. Chinese Universities,2012, 33(4), 744—749
	(宋志成, 王世盛, 宋其玲, 舒涛, 赵伟杰. 高等学校化学学报, 2012, 33(4), 744—749)
[4]	Jacobine A. M., Puchlopek A. L. A., Zercher C. K., Briggs J. B., Jasinski J. P., Butcher R. J., Tetrahedron,2012, 68, 7799—7805
[5]	Li N. G., Song S. L., Shen M. Z., Tang Y. P., Shi Z. H., Tang H., Shi Q. P., Fu Y. F., Duan J. A., Bioorg. Med. Chem., 2012, 20, 6919—6923
[6]	Zhong W. H., Wu Y. T., Zhang X. X., Su W. K., Chin. J. Med. Chem., 2008, 18(6), 426—428
	(钟为慧, 吴窈窕, 张兴贤, 苏为科. 中国药物化学杂志, 2008, 18(6), 426—428)
[7]	Shi M., Cui S. H., Liu Y. H., Tetrahedron,2005, 61(21), 4965—4970
[8]	Yue C. B., Yi T. F., Zhu C. B., Liu L., J. Ind. Eng. Chem., 2009, 15(5), 653—656
[9]	He M., Pan Z. X., Bai S., Li P., Zhang Y. P., Jin L. H., Hu D. Y., Yang S., Song B. A., Sci. China Chem., 2013, 56(3), 321—328
[10]	Wang L. M., Han J. W., Sheng J., Fan Z. Y., Tian H., Chin. J. Org. Chem., 2005, 25(5), 591—594
	(王利民, 韩建伟, 盛佳, 樊兆玉, 田禾. 有机化学, 2005, 25(5), 591—594)
[11]	Tang Z. L., Xia Z. W., Ma H. W., Liu H. W., Ou X. M., Chin. J. Appl. Chem., 2013, 30(9), 993—998
	(唐子龙, 夏赞稳, 马红伟, 刘汉文, 欧晓明. 应用化学, 2013, 30(9), 993—998)
[12]	Yuan J., Su X., Zhang X., Cong L., Guo C., Chem. Res. Chinese Universities,2011, 27(6), 955—957
[13]	Chen J. L., Xie Z. F., Xing Y., Chin. J. Org. Chem., 2011, 31(10), 1714—1718
	(陈君丽, 解正峰, 邢烨. 有机化学, 2011, 31(10), 1714—1718)
[14]	Wang L. M., Han J. W., Sheng J., Tian H., Fan Z. Y., Catal. Commun., 2005, 6(3), 201—204
[15]	Zhang P., Huang J. H., Wang L. Z., Liu W., Li Y., Chin. J. Org. Chem., 2010, 30(12), 1939—1943
	(张萍, 黄金华, 王兰芝, 刘薇, 李媛. 有机化学, 2010, 30(12), 1939—1943)
[16]	Bugarin A., Jones K. D., Connell B. T., Chem. Commun., 2010, 46, 1715—1717
[17]	de Mancilha M., de Conti R., Moran P. J. S., Rodrigues J. A. R.,Arkivoc, 2001, (vi), 85—93
[18]	Zhang P., Xuan Y., Li W., Li Y., Chin. J. Org. Chem., 2011, 31(8), 1240—1244
	(张萍, 宣烨, 刘薇, 李媛. 有机化学, 2011, 31(8), 1240—1244)
[19]	Arend M., Westermann B., Risch N., Angew. Chem. Int. Ed., 1998, 37, 1044—1070
[20]	Takahashi H., Kashiwa N., Hashimoto Y., Nagasawa K., Tetrahedron Lett., 2002, 43, 2935—2938

Ketone	n(Ketone 1)∶n(HCHO)	Amine	n(Ketone 1)∶n(Amine)	Time/h	Product	Yield^b(%)
1a	1∶1.2	Et₂NH	1∶1.0	2	3a	30
1a	1∶1.2	Et₂NH	1∶1.0	4	3a	31
1a	1∶1.5	Et₂NH	1∶1.0	5	3a	43
1a	1∶3.0	Et₂NH	1∶2.0	3	3a	69
1a	1∶6.0	Et₂NH	1∶0.5	4	3a	67
1a	1∶3.0	Morpholine	1∶2.0	4	3a	38
1a	1∶3.0	(i-Pr)₂NH	1∶1.0	4	3a	45
1b	1∶1.3	Et₂NH	1∶1.0	5	3b	35
1b	1∶1.5	Et₂NH	1∶1.5	5	3b	40
1b	1∶3.0	Et₂NH	1∶2.0	3	3b	72

Ketone	n(Ketone 1)∶n(HCHO)	Amine	n(Ketone 1)∶n(Amine)	Time/h	Product	Yield^b(%)
1a	1∶1.2	Et₂NH	1∶1.0	2	3a	30
1a	1∶1.2	Et₂NH	1∶1.0	4	3a	31
1a	1∶1.5	Et₂NH	1∶1.0	5	3a	43
1a	1∶3.0	Et₂NH	1∶2.0	3	3a	69
1a	1∶6.0	Et₂NH	1∶0.5	4	3a	67
1a	1∶3.0	Morpholine	1∶2.0	4	3a	38
1a	1∶3.0	(i-Pr)₂NH	1∶1.0	4	3a	45
1b	1∶1.3	Et₂NH	1∶1.0	5	3b	35
1b	1∶1.5	Et₂NH	1∶1.5	5	3b	40
1b	1∶3.0	Et₂NH	1∶2.0	3	3b	72

Ketone	Solvent	Amine	Catalyst	Time/h	Product	Yield^b(%)
1a	HOAc	Et₂NH	HOAc	3	3a	69
1a	EtOH	Et₂NH	HOAc^c	5
1a	TFA	Et₂NH	TFA	15
1a	THF	Et₂NH	HOAc^c	12
1b	HOAc	Et₂NH	HOAc	3	3b	72
1b	EtOH	Et₂NH	HOAc^c	12
1b	TFA	Et₂NH	TFA	15
1b	THF	(i-Pr)₂NH	TFA^d	12
1b	THF	Et₂NH	HOAc^c	10

Ketone	Solvent	Amine	Catalyst	Time/h	Product	Yield^b(%)
1a	HOAc	Et₂NH	HOAc	3	3a	69
1a	EtOH	Et₂NH	HOAc^c	5
1a	TFA	Et₂NH	TFA	15
1a	THF	Et₂NH	HOAc^c	12
1b	HOAc	Et₂NH	HOAc	3	3b	72
1b	EtOH	Et₂NH	HOAc^c	12
1b	TFA	Et₂NH	TFA	15
1b	THF	(i-Pr)₂NH	TFA^d	12
1b	THF	Et₂NH	HOAc^c	10

Entry	Ar	Product	Yield^b(%)	Entry	Ar	Product	Yield^b(%)
1	C₆H₅	3a	69	9	3-F-C₆H₄	3i	71
2	4-F-C₆H₄	3b	72	10	2,4-F₂-C₆H₃	3j	70
3	4-Cl-C₆H₄	3c	70	11	3,4-F₂-C₆H₃	3k	65
4	4-Br-C₆H₄	3d	73	12	3-Cl-C₆H₄	3l	68
5	4-CH₃-C₆H₄	3e	68	13	3-NO₂-C₆H₄	3m	73
6	4-OCH₃-C₆H₄	3f	68	14	2-Naphthyl	3n	69
7	4-NO₂-C₆H₄	3g	72	15	4-C₆H₅C₆H₄	3o	71
8	2-F-C₆H₄	3h	72