Study on the Cyanide Substitution Reaction of Acetone Cannolhydrin as Cyanogen Source

doi:10.6023/cjoc20210203

Abstract

The cyano substitution reaction is an important method for introducing cyano functional groups in organic synthesis. In this paper, a series of cyano compounds were synthesized by nucleophilic substitution reaction using acetone cyanohydrin as cyanation reagent and aliphatic haloalkanes R—X (X=Cl, Br, I) as substrates. The results show that the cyanation product can be obtained by reacting the acetone cyanohydrin with the corresponding halogenated alkanes at 50 ℃, and the yield can reach 70%~99%. The reaction solvent is the mixture of tetrahydrofuran (THF) and 1,3-dime- thylimidazolinone (DMI) (volume ratio of 3:1), and the base is LiOH?H₂O. This reaction uses cheap and low toxicity acetone cyanohydrin instead of highly toxic sodium cyanide or other expensive cyanide reagents requiring harsh conditions and it also does not require precious metals as catalysts. The reaction conditions is mild so that it has extensive application and great value of practical application.

Key words: haloalkane, acetone cyanohydrin, cyanide substitution, cyanide

Cite this article

Fang Guo, Jun You, Wenju Wu, Yanchao Yu, Bin Jing, Bo Liu. Study on the Cyanide Substitution Reaction of Acetone Cannolhydrin as Cyanogen Source[J]. Chinese Journal of Organic Chemistry, 2021, 41(5): 1968-1973.

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Entry	Base	Amount of base/equiv.	Time/h	Yield/%
1	咪唑	1.5	24	Trace
2	N-丁基咪唑	1.5	24	Trace
3	无水哌嗪	1.5	10	20
4	三乙胺	1.5	10	23
5	吡啶	1.5	10	40
6	叔丁醇钾	1.5	10	25
7	DMAP	1.5	10	53
8	NaOH	1.5	10	62
9	LiOH?H₂O	1.1	6	85
10	LiOH?H₂O	1.2	5	89
11	LiOH?H₂O	1.3	4	92
12	LiOH?H₂O	1.5	3	98
13	LiOH?H₂O	1.8	3	95
14	LiOH	1.5	3	98
15	CH₃COONa	1.5	10	Trace
16	Na₂CO₃	1.5	10	Trace
17	K₂CO₃	1.5	10	Trace
18	NaHCO₃	1.5	10	Trace
19^b	NaOH	1.5	10	60
20^b	CH₃COONa	1.5	10	Trace
21^b	Na₂CO₃	1.5	10	Trace

Entry	Base	Amount of base/equiv.	Time/h	Yield/%
1	咪唑	1.5	24	Trace
2	N-丁基咪唑	1.5	24	Trace
3	无水哌嗪	1.5	10	20
4	三乙胺	1.5	10	23
5	吡啶	1.5	10	40
6	叔丁醇钾	1.5	10	25
7	DMAP	1.5	10	53
8	NaOH	1.5	10	62
9	LiOH?H₂O	1.1	6	85
10	LiOH?H₂O	1.2	5	89
11	LiOH?H₂O	1.3	4	92
12	LiOH?H₂O	1.5	3	98
13	LiOH?H₂O	1.8	3	95
14	LiOH	1.5	3	98
15	CH₃COONa	1.5	10	Trace
16	Na₂CO₃	1.5	10	Trace
17	K₂CO₃	1.5	10	Trace
18	NaHCO₃	1.5	10	Trace
19^b	NaOH	1.5	10	60
20^b	CH₃COONa	1.5	10	Trace
21^b	Na₂CO₃	1.5	10	Trace

Entry	Substrate R—X	Time/h	Product (4)	Yield/%
1	PhCH₂Cl	3.5	PhCH₂CN (4a)	88
2	PhCH₂CH₂Cl	4.0	PhCH₂CH₂CN (4b)	85
3	ClCH₂CH₂CN	4.0	CNCH₂CH₂CN (4c)	78
4	ClCH₂CH₂Cl	4.5	CNCH₂CH₂CN (4c)	77
5	ClCH₂CH₂CH₂CH₂Cl	3.5	CNCH₂CH₂CH₂CH₂CN (4d)	79
6	ClCH₂CH₂COOCH₂CH₃	4.0	CNCH₂CH₂COOCH₂CH₃ (4e)	77
7	ClCH₂CH₂CH₂CH₃	7.0	CNCH₂CH₂CH₂CH₃ (4f)	71
8	Cl(CH₂)₇CH₃	6.5	CN(CH₂)₇CH₃ (4g)	72
9	Cl(CH₂)₁₁CH₃	5.5	CN(CH₂)₁₁CH₃ (4h)	72
10	Cl(CH₂)₁₃CH₃	5.0	CN(CH2)₁₃CH₃ (4i)	74
11	Cl(CH₂)₁₅CH₃	4.5	CN(CH₂)₁₅CH₃ (4j)	76
12	Cl(CH₂)₁₇CH₃	4.0	CN(CH₂)₁₇CH₃ (4k)	77
13	PhCH₂CH₂CH₂Br	3.0	PhCH₂CH₂CH₂CN (4l)	91
14	PhCHBrCH₃	4.0	PhCHCNCH₃(4m)	91
15	PhCHBrPh	5.0	PhCHCNPh (4n)	93
16	BrCH₂CH₂COOCH₃	4.0	CNCH₂CH₂COOCH₃(4o)	85
17	BrCH₂CH₂CH₂COOCH₃	3.5	CNCH₂CH₂CH₂COOCH₃ (4p)	89
18	Br(CH₂)₆COOCH₂CH₃	3.0	CN(CH₂)₆COOCH₂CH₃ (4q)	93
19	BrCH₂CH₂Br	4.0	CNCH₂CH₂CN (4c)	80
20	BrCH₂CH₂CH₂CH₂Br	3.0	CNCH₂CH₂CH₂CH₂CN (4d)	85
21	BrCH₂CH₂CH₂CH₃	6.0	CNCH₂CH₂CH₂CH₃ (4f)	75
22	Br(CH₂)₇CH₃	5.5	CN(CH₂)₇CH₃ (4g)	77
23	Br(CH₂)₁₁CH₃	4.5	CN(CH₂)₁₁CH₃ (4h)	79
24	Br(CH₂)₁₃CH₃	4.0	CN(CH₂)₁₃CH₃ (4i)	81
25	Br(CH₂)₁₅CH₃	3.5	CN(CH₂)₁₅CH₃ (4j)	83
26	Br(CH₂)₁₇CH₃	3.0	CN(CH₂)₁₇CH₃ (4k)	86
27	PhCH₂I	2.5	PhCH₂CN (4a)	99
28	PhCH₂CH₂CH₂I	2.5	PhCH₂CH₂CH₂CN (4l)	92
29	PhCHICH₃	3.0	PhCHCNCH₃ (4m)	93
30	ICH₂CH₂CH₂COOCH₃	3.0	CNCH₂CH₂CH₂COOCH₃ (4p)	90
31	ICH₂CH₂CH₂CH₃	5.0	CNCH₂CH₂CH₂CH₃ (4f)	80
32	I(CH₂)₇CH₃	4.5	CN(CH₂)₇CH₃ (4g)	83
33	I(CH₂)₁₁CH₃	4.0	CN(CH₂)₁₁CH₃(4h)	85
34	I(CH₂)₁₃CH₃	3.5	CN(CH₂)₁₃CH₃ (4i)	87
35	I(CH₂)₁₅CH₃	3.0	CN(CH₂)₁₅CH₃ (4j)	89
36	I(CH₂)₁₇CH₃	2.5	CN(CH₂)₁₇CH₃ (4k)	92

Entry	Substrate R—X	Time/h	Product (4)	Yield/%
1	PhCH₂Cl	3.5	PhCH₂CN (4a)	88
2	PhCH₂CH₂Cl	4.0	PhCH₂CH₂CN (4b)	85
3	ClCH₂CH₂CN	4.0	CNCH₂CH₂CN (4c)	78
4	ClCH₂CH₂Cl	4.5	CNCH₂CH₂CN (4c)	77
5	ClCH₂CH₂CH₂CH₂Cl	3.5	CNCH₂CH₂CH₂CH₂CN (4d)	79
6	ClCH₂CH₂COOCH₂CH₃	4.0	CNCH₂CH₂COOCH₂CH₃ (4e)	77
7	ClCH₂CH₂CH₂CH₃	7.0	CNCH₂CH₂CH₂CH₃ (4f)	71
8	Cl(CH₂)₇CH₃	6.5	CN(CH₂)₇CH₃ (4g)	72
9	Cl(CH₂)₁₁CH₃	5.5	CN(CH₂)₁₁CH₃ (4h)	72
10	Cl(CH₂)₁₃CH₃	5.0	CN(CH2)₁₃CH₃ (4i)	74
11	Cl(CH₂)₁₅CH₃	4.5	CN(CH₂)₁₅CH₃ (4j)	76
12	Cl(CH₂)₁₇CH₃	4.0	CN(CH₂)₁₇CH₃ (4k)	77
13	PhCH₂CH₂CH₂Br	3.0	PhCH₂CH₂CH₂CN (4l)	91
14	PhCHBrCH₃	4.0	PhCHCNCH₃(4m)	91
15	PhCHBrPh	5.0	PhCHCNPh (4n)	93
16	BrCH₂CH₂COOCH₃	4.0	CNCH₂CH₂COOCH₃(4o)	85
17	BrCH₂CH₂CH₂COOCH₃	3.5	CNCH₂CH₂CH₂COOCH₃ (4p)	89
18	Br(CH₂)₆COOCH₂CH₃	3.0	CN(CH₂)₆COOCH₂CH₃ (4q)	93
19	BrCH₂CH₂Br	4.0	CNCH₂CH₂CN (4c)	80
20	BrCH₂CH₂CH₂CH₂Br	3.0	CNCH₂CH₂CH₂CH₂CN (4d)	85
21	BrCH₂CH₂CH₂CH₃	6.0	CNCH₂CH₂CH₂CH₃ (4f)	75
22	Br(CH₂)₇CH₃	5.5	CN(CH₂)₇CH₃ (4g)	77
23	Br(CH₂)₁₁CH₃	4.5	CN(CH₂)₁₁CH₃ (4h)	79
24	Br(CH₂)₁₃CH₃	4.0	CN(CH₂)₁₃CH₃ (4i)	81
25	Br(CH₂)₁₅CH₃	3.5	CN(CH₂)₁₅CH₃ (4j)	83
26	Br(CH₂)₁₇CH₃	3.0	CN(CH₂)₁₇CH₃ (4k)	86
27	PhCH₂I	2.5	PhCH₂CN (4a)	99
28	PhCH₂CH₂CH₂I	2.5	PhCH₂CH₂CH₂CN (4l)	92
29	PhCHICH₃	3.0	PhCHCNCH₃ (4m)	93
30	ICH₂CH₂CH₂COOCH₃	3.0	CNCH₂CH₂CH₂COOCH₃ (4p)	90
31	ICH₂CH₂CH₂CH₃	5.0	CNCH₂CH₂CH₂CH₃ (4f)	80
32	I(CH₂)₇CH₃	4.5	CN(CH₂)₇CH₃ (4g)	83
33	I(CH₂)₁₁CH₃	4.0	CN(CH₂)₁₁CH₃(4h)	85
34	I(CH₂)₁₃CH₃	3.5	CN(CH₂)₁₃CH₃ (4i)	87
35	I(CH₂)₁₅CH₃	3.0	CN(CH₂)₁₅CH₃ (4j)	89
36	I(CH₂)₁₇CH₃	2.5	CN(CH₂)₁₇CH₃ (4k)	92

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