Synthetic Method of Caffeic Acid Phenethyl Ester by Heck Reaction†

doi:10.7503/cjcu20141076

Abstract

Abstract:

Many caffeic acid ester compounds are known because of their various pharmacological activities, with great commercial values such as medicine, health-care products and functional foods, especially caffeic acid phenethyl esters. Existing synthetic methods for caffeic acid esters, such as “acyl halide”, the alkylation, catalytic esterification, condensation agent method, Wittig reaction and Knoevenagel condensation, present certain limitation for their wide use. This research aims to explore a synthetic method with versatile conditions for caffeic acid esters by Heck reaction using commercially available materials. A total of three steps were operated to synthesize caffeic acid phenethyl ester(CAPE) protecting reaction, Heck reaction and de-protecting reaction, with 4-bromocatechol and acrylic acid phenethyl alcohol ester as starting materials. CAPE was obtained in a moderate yield of 40% under the optimized conditions of Heck reaction, which were V(Toluene)∶V(DMF)=4∶1, Pd(OAc)₂(0.05 mmol), Ph₃P(0.15 mmol), NEt₃(2 mmol), reaction temperature of 90 ℃ and reaction time of 24 h. Compared with the exising synthestic methods, the new method of constructing caffeic acid ester by Heck reaction developed in this work had advantages of versatile conditions, commercially available materials and simple synthetic steps.

Key words: Caffeic acid phenethyl ester, Synthesis, Heck reaction

CLC Number:

O621.3

TrendMD:

YANG Fengzhi, ZHANG Man, XIE Jin, XIE Dongsheng, FU Lei. Synthetic Method of Caffeic Acid Phenethyl Ester by Heck Reaction^†[J]. Chem. J. Chinese Universities, 2015, 36(5): 914.

Figures/Tables 4

References 25

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Protecting group	Protection yield(%)	Heck reaction yield^*(%)	De-protection yield(%)	Total yield(%)
—COOC(CH₃)₃	84	22	85	16
—COCH₃	96	26	94	23
—CH₃	100	82	≤20	≤16
—CH₂—	70	79	≤20	≤11

Protecting group	Protection yield(%)	Heck reaction yield^*(%)	De-protection yield(%)	Total yield(%)
—COOC(CH₃)₃	84	22	85	16
—COCH₃	96	26	94	23
—CH₃	100	82	≤20	≤16
—CH₂—	70	79	≤20	≤11

Entry	Solvent	Temperature/℃	Time/h	Conversion(%)	Yield(%)
Entry	Solvent	Temperature/℃	Time/h	Conversion(%)	CAPE	4-Br catechol	Others
1	DMF	100	3	100	26	58	16
2	1,4-Dioxane	Reflux	12	94	9	37	48
3	ACN	Reflux	12	87	12	45	30
4	Toluene	Reflux	24	30	18	Race	12
5	Xylene	Reflux	24	36	21	Race	15
6	V(Toluene)∶V(DMF)=4∶1	Reflux	24	92	39	41	12
7	V(Toluene)∶V(DMF)=4∶1	90	24	81	44	28	9
8	V(Toluene)∶V(DMF)=4∶1	70	24	24	6	14	4

Entry	Solvent	Temperature/℃	Time/h	Conversion(%)	Yield(%)
Entry	Solvent	Temperature/℃	Time/h	Conversion(%)	CAPE	4-Br catechol	Others
1	DMF	100	3	100	26	58	16
2	1,4-Dioxane	Reflux	12	94	9	37	48
3	ACN	Reflux	12	87	12	45	30
4	Toluene	Reflux	24	30	18	Race	12
5	Xylene	Reflux	24	36	21	Race	15
6	V(Toluene)∶V(DMF)=4∶1	Reflux	24	92	39	41	12
7	V(Toluene)∶V(DMF)=4∶1	90	24	81	44	28	9
8	V(Toluene)∶V(DMF)=4∶1	70	24	24	6	14	4

Entry	Product	Heck reaction yield(%)	De-protection yield(%)	Total yield(%)	m.p./℃(ref.)
1		44	94	40	128—130(126—128^[19])
	(5)
2		42	93	37	122—124(121—122^[25])
3		23	79	17	151—153(150—152^[19])
4		41	75	29	144—147(147—148^[19])
5		38	95	35	152—154(150—151^[19])
6		26	87	22	133—135(132—133^[19] )