Synthesis and Biological Activities of Novel Cyanoacrylate Derivatives Carrying 5-Arylisoxazole Group†

doi:10.7503/cjcu20160510

Abstract

Abstract:

In order to find novel cyanoacrylate derivatives with potent biological activities, fourteen new cyanoacrylates bearing a 5-arylisoxazole moiety were synthesized by multistep synthetic procedures with two key intermediates 5 and 6. The intermediate 5 was synthesized from methyl 5-arylisoxazolyl-3-carboxylate via reduction, chlorination, condensation, and hydrazine cleavage. The structures of target compounds 7 were confirmed by ¹H NMR,¹³C NMR and elemental analysis. The bioassay data showed that some target compounds exhibited good herbicidal activities at the dosage of 1500 g/ha. In postemergence treatment, compounds 7h, 7i, and 7m had 90%, 40%, and 100% herbicidal activity against Brassica juncea at 1500 g/ha, compounds 7m and 7n showed 100% and 80% herbicidal activity against Stellaria media at 1500 g/ha, compounds 7m and 7n displayed 100% and 85% inhibitory rates against Chenopodium serotinum L. at 1500 g/ha. In addition, some of the title compounds had satisfactory anti-tumor activities. Compounds 7b and 7c showed wonderful inhibitory activities against HepG2 cells with the IC₅₀values of 3.2 and 10.1 μmol/L, respectively.

Key words: Isoxazole, Cyanoacrylate, Biological activity

CLC Number:

O626

TrendMD:

SHI Yujun, FANG Yuan, LI Yang, CHEN Jia, LI Gang, WANG Qingmin, DAI Hong. Synthesis and Biological Activities of Novel Cyanoacrylate Derivatives Carrying 5-Arylisoxazole Group^†[J]. Chem. J. Chinese Universities, 2017, 38(3): 421.

Figures/Tables 8

References 21

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Compd.	m. p./℃	Compd.	m. p./℃	Compd.	m. p./℃
1a	152—153	3c	56—57	6b	154—156
1b	149—150	4a	156—158	6c	67—69
1c	150—151	4b	157—158	6d	33—34
2a	70—71	4c	155—157	6e	109—110
2b	92—93	5a	55—56	6f	66—67
2c	68—69	5b	55—57	6g	71—72
3a	58—59	5c	54—55	6h	33—35
3b	59—60	6a	69—70

Compd.	m. p./℃	Compd.	m. p./℃	Compd.	m. p./℃
1a	152—153	3c	56—57	6b	154—156
1b	149—150	4a	156—158	6c	67—69
1c	150—151	4b	157—158	6d	33—34
2a	70—71	4c	155—157	6e	109—110
2b	92—93	5a	55—56	6f	66—67
2c	68—69	5b	55—57	6g	71—72
3a	58—59	5c	54—55	6h	33—35
3b	59—60	6a	69—70

Compd.	¹H NMR(CDCl₃, 400 MHz), δ
1a	7.80—7.82(m, 2H, ArH), 7.17—7.21(m, 2H, ArH), 6.89(s, 1H, Isoxazole H), 4.01(s, 3H, OCH₃)
1b	7.75(d, J=8.0 Hz, 2H, ArH), 7.47(d, J=8.0 Hz, 2H, ArH), 6.83(s, 1H, Isoxazole H), 4.01(s, 3H, OCH₃)
1c	7.57—7.67(m, 2H, ArH), 7.30—7.34(m, 1H, ArH), 6.92(s, 1H, Isoxazole H), 4.02(s, 3H, OCH₃)
2a	7.71—7.73(m, 2H, ArH), 7.11—7.15(m, 2H, ArH), 6.53(s, 1H, Isoxazole H), 4.79(s, 2H, CH₂)
2b	7.66(d, J=8.4 Hz, 2H, ArH), 7.47(d, J=8.0 Hz, 2H, ArH), 6.57(s, 1H, Isoxazole H), 4.80(s, 2H, CH₂), 3.13(s, 1H, OH)
2c	7.57—7.61(m, 1H, ArH), 7.51(s, 1H, ArH), 7.24—7.30(m, 1H, ArH), 6.57(s, 1H, Isoxazole H), 4.81(s, 2H, CH₂), 2.21(s, 1H, OH)
3a	7.71(d, J=8.0 Hz, 2H, ArH), 7.45(d, J=8.0 Hz, 2H, ArH), 6.63(s, 1H, Isoxazole H), 4.64(s, 2H, CH₂)
3b	7.66(d, J=8.4 Hz, 2H, ArH), 7.40(d, J=8.0 Hz, 2H, ArH), 6.62(s, 1H, Isoxazole H), 4.64(s, 2H, CH₂)
3c	7.53—7.58(m, 2H, ArH), 7.25—7.32(m, 1H, ArH), 6.62(s, 1H, Isoxazole H), 4.64(s, 2H, CH₂)
4a	7.66—7.90(m, 6H, ArH), 7.41(d, J=8.0 Hz, 2H, ArH), 6.54(s, 1H, Isoxazole H), 5.00(s, 2H, CH₂)
4b	7.66—7.90(m, 6H, ArH), 7.41(d, J=6.8 Hz, 2H, ArH), 6.54(s, 1H, Isoxazole H), 5.00(s, 2H, CH₂)
4c	7.47—7.90(m, 6H, ArH), 7.21—7.27(m, 1H, ArH), 6.52(s, 1H, Isoxazole H), 5.00(s, 2H, CH₂)
5a	7.70(d, J=8.0 Hz, 2H, ArH), 7.43(d, J=8.0 Hz, 2H, ArH), 6.52(s, 1H, Isoxazole H), 3.99(s, 2H, CH₂), 2.13(s, 2H, NH₂)
5b	7.70(d, J=7.2 Hz, 2H, ArH), 7.44(d, J=7.2 Hz, 2H, ArH), 6.52(s, 1H, Isoxazole H), 3.99(s, 2H, CH₂), 1.85(s, 2H, NH₂)
5c	7.50—7.61(m, 2H, ArH), 7.23—7.29(m, 1H, ArH), 6.51(s, 1H, Isoxazole H),4.00(s, 2H, CH₂),1.90(s, 2H, NH₂)
6a	6.86—6.99(m, 4H, ArH), 4.54(s, 2H, CH₂), 4.21(s, 2H, CH₂), 2.76(s, 3H, SCH₃), 2.61(s, 3H, SCH₃)
6b	7.38(d,J=8.0 Hz, 2H, ArH), 6.81(d, J=8.0 Hz, 2H, ArH), 4.55(s, 2H, CH₂), 4.22(s, 2H, CH₂), 2.77(s, 3H, SCH₃), 2.61(s, 3H, SCH₃)
6c	7.36(s, 1H, ArH), 7.19(d, J=8.4 Hz, 1H, ArH), 6.94(d, J=8.8 Hz, 1H, ArH), 4.60(s, 2H, CH₂), 4.30(s, 2H, CH₂), 2.77(s, 3H, SCH₃), 2.61(s, 3H, SCH₃)
6d	4.36(s, 2H,CH₂), 3.72(s, 2H, CH₂), 3.58(q, J=7.2 Hz, 2H, CH₂), 2.76(s, 3H, SCH₃), 2.61(s, 3H, SCH₃), 1.21(t, J=7.2 Hz, 3H, CH₃)
6e	6.91—7.31(m, 5H, ArH), 4.56(s, 2H, CH₂), 4.25(s, 2H, CH₂), 2.75(s, 3H, SCH₃), 2.60(s, 3H, SCH₃)
6f	6.79—7.00(m, 3H, ArH), 4.59(s, 2H, CH₂), 4.35(s, 2H, CH₂), 2.77(s, 3H, SCH₃), 2.62(s, 3H, SCH₃)
6g	6.78—7.05(m, 3H, ArH), 4.55(s, 2H, CH₂), 4.30(s, 2H, CH₂), 2.77(s, 3H, SCH₃), 2.61(s, 3H, SCH₃)
6h	4.37(s, 2H, CH₂), 3.68(s, 2H, CH₂), 3.41(s, 3H, OCH₃), 2.76(s, 3H, SCH₃), 2.61(s, 3H, SCH₃)

Compd.	¹H NMR(CDCl₃, 400 MHz), δ
1a	7.80—7.82(m, 2H, ArH), 7.17—7.21(m, 2H, ArH), 6.89(s, 1H, Isoxazole H), 4.01(s, 3H, OCH₃)
1b	7.75(d, J=8.0 Hz, 2H, ArH), 7.47(d, J=8.0 Hz, 2H, ArH), 6.83(s, 1H, Isoxazole H), 4.01(s, 3H, OCH₃)
1c	7.57—7.67(m, 2H, ArH), 7.30—7.34(m, 1H, ArH), 6.92(s, 1H, Isoxazole H), 4.02(s, 3H, OCH₃)
2a	7.71—7.73(m, 2H, ArH), 7.11—7.15(m, 2H, ArH), 6.53(s, 1H, Isoxazole H), 4.79(s, 2H, CH₂)
2b	7.66(d, J=8.4 Hz, 2H, ArH), 7.47(d, J=8.0 Hz, 2H, ArH), 6.57(s, 1H, Isoxazole H), 4.80(s, 2H, CH₂), 3.13(s, 1H, OH)
2c	7.57—7.61(m, 1H, ArH), 7.51(s, 1H, ArH), 7.24—7.30(m, 1H, ArH), 6.57(s, 1H, Isoxazole H), 4.81(s, 2H, CH₂), 2.21(s, 1H, OH)
3a	7.71(d, J=8.0 Hz, 2H, ArH), 7.45(d, J=8.0 Hz, 2H, ArH), 6.63(s, 1H, Isoxazole H), 4.64(s, 2H, CH₂)
3b	7.66(d, J=8.4 Hz, 2H, ArH), 7.40(d, J=8.0 Hz, 2H, ArH), 6.62(s, 1H, Isoxazole H), 4.64(s, 2H, CH₂)
3c	7.53—7.58(m, 2H, ArH), 7.25—7.32(m, 1H, ArH), 6.62(s, 1H, Isoxazole H), 4.64(s, 2H, CH₂)
4a	7.66—7.90(m, 6H, ArH), 7.41(d, J=8.0 Hz, 2H, ArH), 6.54(s, 1H, Isoxazole H), 5.00(s, 2H, CH₂)
4b	7.66—7.90(m, 6H, ArH), 7.41(d, J=6.8 Hz, 2H, ArH), 6.54(s, 1H, Isoxazole H), 5.00(s, 2H, CH₂)
4c	7.47—7.90(m, 6H, ArH), 7.21—7.27(m, 1H, ArH), 6.52(s, 1H, Isoxazole H), 5.00(s, 2H, CH₂)
5a	7.70(d, J=8.0 Hz, 2H, ArH), 7.43(d, J=8.0 Hz, 2H, ArH), 6.52(s, 1H, Isoxazole H), 3.99(s, 2H, CH₂), 2.13(s, 2H, NH₂)
5b	7.70(d, J=7.2 Hz, 2H, ArH), 7.44(d, J=7.2 Hz, 2H, ArH), 6.52(s, 1H, Isoxazole H), 3.99(s, 2H, CH₂), 1.85(s, 2H, NH₂)
5c	7.50—7.61(m, 2H, ArH), 7.23—7.29(m, 1H, ArH), 6.51(s, 1H, Isoxazole H),4.00(s, 2H, CH₂),1.90(s, 2H, NH₂)
6a	6.86—6.99(m, 4H, ArH), 4.54(s, 2H, CH₂), 4.21(s, 2H, CH₂), 2.76(s, 3H, SCH₃), 2.61(s, 3H, SCH₃)
6b	7.38(d,J=8.0 Hz, 2H, ArH), 6.81(d, J=8.0 Hz, 2H, ArH), 4.55(s, 2H, CH₂), 4.22(s, 2H, CH₂), 2.77(s, 3H, SCH₃), 2.61(s, 3H, SCH₃)
6c	7.36(s, 1H, ArH), 7.19(d, J=8.4 Hz, 1H, ArH), 6.94(d, J=8.8 Hz, 1H, ArH), 4.60(s, 2H, CH₂), 4.30(s, 2H, CH₂), 2.77(s, 3H, SCH₃), 2.61(s, 3H, SCH₃)
6d	4.36(s, 2H,CH₂), 3.72(s, 2H, CH₂), 3.58(q, J=7.2 Hz, 2H, CH₂), 2.76(s, 3H, SCH₃), 2.61(s, 3H, SCH₃), 1.21(t, J=7.2 Hz, 3H, CH₃)
6e	6.91—7.31(m, 5H, ArH), 4.56(s, 2H, CH₂), 4.25(s, 2H, CH₂), 2.75(s, 3H, SCH₃), 2.60(s, 3H, SCH₃)
6f	6.79—7.00(m, 3H, ArH), 4.59(s, 2H, CH₂), 4.35(s, 2H, CH₂), 2.77(s, 3H, SCH₃), 2.62(s, 3H, SCH₃)
6g	6.78—7.05(m, 3H, ArH), 4.55(s, 2H, CH₂), 4.30(s, 2H, CH₂), 2.77(s, 3H, SCH₃), 2.61(s, 3H, SCH₃)
6h	4.37(s, 2H, CH₂), 3.68(s, 2H, CH₂), 3.41(s, 3H, OCH₃), 2.76(s, 3H, SCH₃), 2.61(s, 3H, SCH₃)

Compd.	Appearance	m. p. /℃	Yield(%)	Elemental analysis(%, calcd.)
Compd.	Appearance	m. p. /℃	Yield(%)	C	H	N
7a	Yellow solid	122—123	50	56.75(56.62)	3.78(3.92)	8.48(8.61)
7b	Yellow solid	>280	52	51.78(51.89)	3.73(3.60)	7.98(7.89)
7c	Yellow solid	198—199	53	52.73(52.88)	3.60(3.47)	7.95(8.04)
Compd.	Appearance	m. p. /℃	Yield(%)	Elemental analysis(%, calcd.)
Compd.	Appearance	m. p. /℃	Yield(%)	C	H	N
7d	Yellow solid	>280	51	56.40(56.28)	4.86(4.97)	10.25(10.36)
7e	Yellow solid	124—125	47	58.67(58.78)	4.41(4.29)	8.82(8.94)
7f	Yellow solid	130—131	52	54.89(54.77)	3.92(3.80)	8.18(8.33)
7g	Yellow solid	121—122	49	54.47(54.60)	3.72(3.59)	8.45(8.31)
7h	Yellow solid	130—131	51	54.73(54.60)	3.46(3.59)	8.17(8.31)
7i	Yellow solid	215—216	52	52.87(53.01)	4.57(4.45)	10.42(10.30)
7j	Yellow solid	94—96	48	54.21(54.09)	4.66(4.78)	9.83(9.96)
7k	Yellow solid	217—218	46	58.46(58.59)	4.18(4.06)	8.77(8.91)
7l	Yellow solid	222—223	45	54.47(54.60)	3.73(3.59)	8.43(8.31)
7m	Yellow solid	213—214	47	52.93(52.81)	4.08(4.19)	10.15(10.26)
7n	Yellow solid	>280	50	53.74(53.89)	4.66(4.52)	10.04(9.92)