Microwave-assisted One-pot Conversion of Salicylaldehydeoximes to 2-(Difluoromethoxy)benzonitriles†

doi:10.7503/cjcu20150670

Abstract

Abstract:

Eight 2-(difluoromethoxy)benzonitrile derivatives including seven novel compounds were synthesized in moderate yields by one-pot multistep reaction of salicylaldehydeoximes using sodium 2-chloro-2,2-di-fluoroacetate(SCDA) as difluoromethylating reagent and potassium carbonate as base under microwave-assisted condition. The structures of all novel compounds were confirmed by nuclear magnetic resonance spectrum(¹H NMR, ¹³C NMR, ¹⁹F NMR), infrared spectrum(IR) and high resolution mass spectrum(HRMS). The effects of difluorocarbene reagent, alkali, solvent, microwave power, reaction temperature and time on the reaction were considered. The optimized reaction conditions: salicylaldehydeoximes(2 mmol), 2-chloro-2,2-difluoroacetate(3 mmol), K₂CO₃(3 mmol) and N,N-dimethylformamide(2 mL), microwave power 300 W, reaction temperature 85 ℃, reaction time 20 min. A possible mechanism was proposed on the basis of the experiments and contrast tests.

Key words: Salicylaldehydeoxime, 2-(Difluoromethoxy)benzonitrile, Difluoromethylation, Microwave

CLC Number:

O625.6

TrendMD:

WANG Tao, HUA Mingqing, LIU Weihan, HUANG Yan, ZHANG Qi. Microwave-assisted One-pot Conversion of Salicylaldehydeoximes to 2-(Difluoromethoxy)benzonitriles^†[J]. Chem. J. Chinese Universities, 2016, 37(3): 498.

Figures/Tables 6

Scheme 1 Synthetic route of the target compounds

Table 1 Appearance, yields, melting points, IR and HRMS data of compounds 3a—3h

Compd.	Appearance	Yield(%)^a	m. p./℃	IR(KBr), $ν ˙$ /cm^-1	HRMS, m/z^b
3a	Yellow liquid	50		3081, 2235, 1601, 1493, 1452, 1386, 1249, 1129, 761	192.0231
3b	Yellow solid	46	45—47	3112, 2239, 1488, 1387, 1274, 1240, 1138, 1075, 885, 825	225.9842
3c	Yellow solid	58	56—58	3107, 2234, 1489, 1391, 1282, 1246, 1137, 1068, 885, 816	269.9343
3d	Yellow liquid	33		3043, 2931, 2236, 1595, 1502, 1386, 1256, 1221, 1132, 827	206.0388
Compd.	Appearance	Yield(%)^a	m. p./℃	IR(KBr), $v ˙$ /cm^-1	HRMS, m/z^b
3e	Yellow liquid	22		3092, 2244, 1490, 1537, 1354, 1272, 1151, 1091, 842, 793	237.0091
3f	Yellow solid	18	52—55	3079, 2951, 2230, 1613, 1507, 1460, 1390, 1305, 1207, 1126, 816	222.0337
3g	Tawny liquid	22		3109, 2979, 2217, 1613, 1525, 1407, 1356, 1269, 1199, 1125, 802	241.1147
3h	Yellow solid	31	50—52	3083, 2930, 2233, 1602, 1468, 1387, 1261, 1202, 1111, 790	206.0388

Table 1 Appearance, yields, melting points, IR and HRMS data of compounds 3a—3h

Compd.	Appearance	Yield(%)^a	m. p./℃	IR(KBr), $ν ˙$ /cm^-1	HRMS, m/z^b
3a	Yellow liquid	50		3081, 2235, 1601, 1493, 1452, 1386, 1249, 1129, 761	192.0231
3b	Yellow solid	46	45—47	3112, 2239, 1488, 1387, 1274, 1240, 1138, 1075, 885, 825	225.9842
3c	Yellow solid	58	56—58	3107, 2234, 1489, 1391, 1282, 1246, 1137, 1068, 885, 816	269.9343
3d	Yellow liquid	33		3043, 2931, 2236, 1595, 1502, 1386, 1256, 1221, 1132, 827	206.0388
Compd.	Appearance	Yield(%)^a	m. p./℃	IR(KBr), $v ˙$ /cm^-1	HRMS, m/z^b
3e	Yellow liquid	22		3092, 2244, 1490, 1537, 1354, 1272, 1151, 1091, 842, 793	237.0091
3f	Yellow solid	18	52—55	3079, 2951, 2230, 1613, 1507, 1460, 1390, 1305, 1207, 1126, 816	222.0337
3g	Tawny liquid	22		3109, 2979, 2217, 1613, 1525, 1407, 1356, 1269, 1199, 1125, 802	241.1147
3h	Yellow solid	31	50—52	3083, 2930, 2233, 1602, 1468, 1387, 1261, 1202, 1111, 790	206.0388

Table 2 1H NMR, 13C NMR and 19F NMR data for compounds 3a—3h*

Compd.	¹H NMR(400 MHz), δ	¹³C NMR(100 MHz), δ	¹⁹F NMR(376 MHz), δ
3a	7.92—7.95(m, 1H), 7.60—7.64(m, 1H), 7.34(t, J=7.6 Hz, 1H), 7.25(d, J=8.4 Hz, 1H), 6.67(t, J=72.8 Hz, 1H)	151.9, 134.4, 134.0, 125.8, 119.7, 115.2(t,J=263.7 Hz, 1C), 115.0, 105.9	-81.5
3b	7.64(d,J=2.8 Hz, 1H), 7.56—7.59(m, 1H), 7.29(d, J=9.2 Hz, 1H), 6.64(t, J=71.2 Hz, 1H)	150.2, 134.4, 133.3, 131.4, 121.7, 114.9(t,J=266.0 Hz, 1C), 113.7, 107.8	-82.5
3c	7.78(d, J=2.4 Hz, 1H), 7.70—7.73(m, 1H), 7.22(d, J=8.8 Hz, 1H), 6.45(t, J=71.6 Hz, 1H)	150.7, 137.4, 136.2, 121.8, 118.4, 114.8(t,J=265.9 Hz, 1C), 113.6, 108.0	-82.6
3d	7.44(d,J=2.0 Hz, 1H), 7.38—7.40(m, 1H), 7.18(d, J=8.8 Hz, 1H), 6.60(t, J=72.4 Hz, 1H), 2.36(s, 3H)	149.6, 136.1, 135.0, 134.0, 120.1, 115.2(t,J=263.8 Hz, 1C), 115.2, 105.9, 20.4	-82.0
3e	8.59(d,J=2.4 Hz, 1H), 8.50—8.53(m, 1H), 7.56(d, J=9.2 Hz, 1H), 6.83(t, J=70.4 Hz, 1H)	156.0, 144.2, 129.7, 129.6, 119.4, 114.7(t,J=268.5 Hz, 1C), 112.9, 106.6	-83.7
3f	7.54(d, J=9.2 Hz, 1H), 6.69—6.80(m, 1H), 6.76—6.77(m, 1H), 6.62(t, J=72.0 Hz, 1H), 3.84(s, 3H)	164.2, 153.4, 134.9, 115.4, 115.2(t, J=263.4 Hz, 1C), 111.2, 106.3, 97.4, 56.0	-82.3
3g	7.37(d, J=8.8 Hz, 1H), 6.58(t, J=72.8 Hz, 1H), 6.44—6.47(m, 1H), 6.38—6.39(m, 1H), 3.38(q, J=6.8 Hz, 4H), 1.18(t, J=7.2 Hz, 6H)	153.8, 151.7, 134.5, 117.0, 115.5(t, J=261.8 Hz, 1C), 108.4, 102.3, 90.2, 44.8(s, 2C), 12.2(s, 2C)	-81.1
3h	7.50—7.53(m, 2H), 7.28(t, J=7.2 Hz, 1H), 6.63(t, J=73.2 Hz, 1H), 2.37(s, 3H)	149.8, 136.4, 134.2, 131.5, 126.9, 116.2(t, J=264.3 Hz, 1C), 115.6, 108.7, 16.5	-80.3

Table 3 Effects of heating power, temperature and time on the reactiona

Entry	P/W	Temperature/℃	Time/min	Yield(%)^b
Entry	P/W	Temperature/℃	Time/min	3a	4a
1	300	70	20	18	<5
2	300	80	20	35	<5
3	300	85	20	50	<5
4	300	90	20	38	<5
5	300	100	20	17	11
6	300	85	10	45	<5
7	300	85	15	48	<5
8	300	85	25	32	<5
9	300	85	40	19	<5
10		85	60
11	200	85	20
12	400	85	20	46	<5

Table 4 Optimization of reaction conditionsa

Entry	Difluoromethylating reagent, n/mmol	Base, n/mmol	Solvent, V/mL	Yield(%)^b
Entry	Difluoromethylating reagent, n/mmol	Base, n/mmol	Solvent, V/mL	3a	4a
1	ClF₂CCOONa, 3	K₂CO₃, 3	DMF, 2	50	<5
2	ClF₂CCOONa, 3	K₂CO₃, 3	PhMe, 2
3	ClF₂CCOONa, 3	K₂CO₃, 3	MeCN, 2
4	ClF₂CCOONa, 3	K₂CO₃, 3	DMAc, 2	26	<5
5	ClF₂CCOONa, 3	K₂CO₃, 3	NMP, 2	16	<5
6	ClF₂CCOONa, 3	K₂CO₃, 3	EA, 2
7	ClF₂CCOONa, 3	K₂CO₃, 3	DMF, 5	13	<5
8	ClF₂CCOONa, 3	K₂CO₃, 3	DMF, 1	13	<5
9	ClF₂CCOONa, 3		DMF, 2
10	ClF₂CCOONa, 3	Na₂CO₃, 3	DMF, 2	40	<5
11	ClF₂CCOONa, 3	Cs₂CO₃, 3	DMF, 2	36	<5
12	ClF₂CCOONa, 3	K₂CO₃, 2.4	DMF, 2	27	<5
13	ClF₂CCOONa, 3	K₂CO₃, 4	DMF, 2	35	<5
14	BrF₂CCOOK, 3	K₂CO₃, 3	DMF, 2	15	<5
15	BrF₂CCOOC₂H₅, 3	K₂CO₃, 3	DMF, 2	31	<5
16	Ph₃P⁺CF₂COO^-, 3	K₂CO₃, 3	DMF, 2
17	ClF₂CCOONa, 2.4	K₂CO₃, 3	DMF, 2	15	<5
18	ClF₂CCOONa, 4	K₂CO₃, 3	DMF, 2	44	<5

Scheme 2 Proposed reaction mechanism of coversion salicylaldehydeoxime to 2-(difluoromethoxy)benzonitrile

References 41

[1]	Cheng Y., Guo A. L., Guo D. S., Curr. Org. Chem., 2010, 14, 977—999
[2]	Sperry J. B., Sutherland K., Org. Process Res. Dev., 2011, 15(3), 721—725
[3]	Fuchibe K., Koseki Y., Aono T., Sasagawa H., Ichikawa J., J. Fluorine Chem., 2012, 133, 52—60
[4]	Sperry J. B., Farr R. M., Levent M., Ghosh M., Hoagland S. M., Varsolona R. J., Sutherland K., Org. Process Res. Dev., 2012, 16(11), 1854—1860
[5]	Prakash G. K. S., Ganesh S. K., Jones J. P., Kulkarni A., Masood K., Swabeck J., Olah G. A., Angew. Chem. Int. Ed., 2012, 51(48), 12090—12094
[6]	Levin V. V., Zemtsov A. A., Struchkova M. I., Dilman A. D., Org. Lett., 2013, 15(4), 917—919
[7]	Liu G., Wang X., Xu X. H., Lu X., Tokunaga E., Tsuzuki S., Schibata N., Org. Lett., 2013, 15(5), 1044—1047
[8]	Min Q. Q., Yin Z., Feng Z., Guo W. H., Zhang X., J. Am. Chem. Soc., 2014, 136(4), 1230—1233
[9]	Matheis C., Jouvin K., Goossen L. J., Org. Lett., 2014, 16(22), 5984—5987
[10]	Thomoson C. S., Wang L., Dolbier W. R. J., J. Fluorine Chem., 2014, 168, 34—39
[11]	Huang Y., He X., Li H., Weng Z., Eur. J. Org. Chem., 2014, 33, 7324—7328
[12]	Wang W., Hua M., Huang Y., Zhang Q., Zhang X., Wu J., Chem. Res. Chinese Universities, 2015, 31(3), 362—366
[13]	Zhao Y., Huang W., Zheng J., Hu J., Org. Lett., 2011, 13(19) , 5342—5345
[14]	Wang F., Huang W., Hu J., Chin. J. Chem., 2011, 29(12), 2717—2721
[15]	Iida T., Hashimoto R., Aikawa K., Ito S., Mikami K., Angew. Chem. Int. Ed., 2012, 51(38), 9535—9538
[16]	Dolbier W. R. J., Battiste M. A., Chem. Rev., 2003, 103(4), 1071—1098
[17]	Leroux F., Jeschke P., Schlosser M., Chem. Rev., 2005, 105(3), 827—856
[18]	Taylor E. C., Macor J. E., Pont J. L., Tetrahedro., 1987, 43(21), 5145—5158
[19]	Mederski W. W. K. R., Osswald M., Dorsch D., Christadler M., Schmitges C. J., Wilm C., Bioorg. Med. Chem. Lett., 1999, 9(4), 619—622
[20]	Rádl S. , KonviČcka P. , Váchal P. , J. Heterocycl. Chem. J. Heterocycl. Chem.,2000, 37(4), 855—862
[21]	Firouzabadi H., Jamalian A., Tamami M., Iranpoor N., Lett. Org. Chem., 2006, 3(4), 267—270
[22]	Sardarian A. R., Shahsavari-Fard Z., Shahsavari H. R., Ebrahimi Z., Tetrahedron Lett., 2007, 48(14), 2639—2643
[23]	Tamilselvana P., Basavarajub Y. B., Sampathkumarc E., Murugesand R., Catal. Commun., 2009, 10(5), 716—719
[24]	Ramón R. S., Bosson J., Díez-González S., Marion N., Nolan S. P., J. Org. Chem., 2010, 75(4), 1197—1202
[25]	Davoodnia A., Khojastehnezhad A., Bakavoli M., Tavakoli-Hoseini N., Chinese J. Chem., 2011, 29(5), 978—982
[26]	Whiting E., Lanning M. E., Scheenstra J. A., Fletcher S., J. Org. Chem., 2015, 80(2), 1229—1234
[27]	Hegedüs A., Cwik A., Hell Z., Horváth Z., Esekc Á., Uzsokic M., Green Chem., 2002, 4, 618—620
[28]	Ma D. L., Li X. L., Hao L., Zhang P. Z., Chen H., Zhao Y., Chem. J. Chinese Universities, 2014, 35(5), 959—964
	(马东来, 李小六, 郝乐, 张平竹, 陈华, 赵影. 高等学校化学学报, 2014, 35(5), 959—964)
[29]	Kuang D. Z., Feng Y. L., Yu J. X., Zhang F. X., Jiang W. J., Peng Y., Zhu X. M., Tan Y. X., Chem. J. Chinese Universities, 2014, 35(8), 1629—1634
	(邝代治, 冯泳兰, 庾江喜, 张复兴, 蒋伍玖, 彭雁, 朱小明, 谭宇星. 高等学校化学学报, 2014, 35(8), 1629—1634)
[30]	Li L., Wang F., Ni C., Hu J., Angew. Chem. Int. Ed., 2013, 52(47), 12390—12394
[31]	Aldred R., Johnston R., Levin D., Neilan J., J. Chem. Soc. Perkin. Trans. 1,1994, 13, 1823—1831
[32]	Babua M. S. S., Krishnab P. G., Reddya K. H., Philip G. H., Main Group Chem., 2009, 8(2), 101—114
[33]	Aakeröy C. B., Sinha A. S., Epa K. N., Spartz C. L., Desper J., Chem. Commun., 2012, 48(92), 11289—11291
[34]	Kao C., Chen K., Journal of the Chinese Chemical Society,1935, 3, 22—26
[35]	Moghadam M., Tangestaninejad S., Mirkhani V., Mohammadpoor-Baltork I., Moosavifar M., Appl. Catal. A-Gen., 2009, 358(2), 157—163
[36]	Gigant N., Claveau E., Bouyssou P., Gillaizeau I., Org. Lett., 2012, 14(3), 844—847
[37]	Xu J., Wang X., Shao C., Su D., Cheng G., Hu Y., Org. Lett., 2010, 12(9), 1964—1967
[38]	Shelke K. F., Spakal S. B., Shitole N. V., Shingate B. B., Shingare M. S., Org. Commun., 2009, 2(3), 72—78
[39]	Ohsawa A., Kawaguchi T., Igeta H., Chem. Pharm. Bull., 1982, 30(12), 4352—4358
[40]	McIntyre N. R., Lowe E. W. J., Merkler D. J., J. Am. Chem. Soc., 2009, 131, 10308—10319
[41]	Martin B., Christoph B., Christine B., Markus G., Bibia H., Thierry S., Jodi T. W., [Ortho-Bi(hetero)aryl]-[2-(meta-bi(hetero)aryl)-pyrrolidin-1-yl]-methanone Derivatives as Orexin Receptor Antagonists and Their Preparation WO 2014057435, 2014-04-17