[3+2] Cyclization of Difluoroacetohydrazonoyl Bromides with β-(N,N-Dimethylamino)enones/Enoates/Enamides

doi:10.6023/cjoc202311001

Abstract

A [3+2] cyclization of difluoromethyl nitrile imines generated in situ from difluoroacetohydrazonoyl bromides with β-(N,N-dimethylamino)enones/enoates/enamides in the presence of base is described. The cycloaddition reaction pro- duced the pyrazoline intermediates, from which 3,4-disubstituted-3-difluoromethylpyrazoles were obtained in moderate to good yields via spontaneous elimination of the Me₂NH molecule. The reaction is fully regioseclective by the interaction of lowest unoccupied molecular orbital (LUMO) of the 1,3-dipoles and highest occupied molecular orbital (HOMO) of electron-rich alkenes (inverse-electron-demand). This approach expands the types of [3+2] cyclization involved difluoro- methyl nitrile imines, which provides a simple, efficient and novel method for the synthesis of 3-difluoromethylpyrazoles.

Key words: 3-difluoromethylpyrazoles, difluoroacetohydrazonoyl bromides, [3+2] cyclization, regioselectivity

Cite this article

Xiaoyong Li, Danfeng Huang, Yuxiu Zhou, Xiaokang Liu, Kehu Wang, Junjiao Wang, Yulai Hu. [3+2] Cyclization of Difluoroacetohydrazonoyl Bromides with β-(N,N-Dimethylamino)enones/Enoates/Enamides[J]. Chinese Journal of Organic Chemistry, 2024, 44(4): 1226-1239.

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Fig. & Tab. 12

Figure 1. Selected drug and agrochemical molecules containing 3-difluoromethylpyrazole moiety

Scheme 1. Synthesis of 3-difluoromethylpyrazoles by [3+2] cyclization of fluorinated diazoalkanes with alkynes or alkenes

Scheme 2. Synthesis of 3-(difluoromethyl)pyrazoles by [3+2] cyclization of difluoroacetohydrazonoyl halides with alkynes or alkenes

Entry	Mole ratio of 1a/2a/base	Base	Solvent	Time/h	Temp./℃
1	1.0/1.0/1.0	K₂CO₃	THF	12	25	70
2	1.2/1.0/1.2	K₂CO₃	THF	12	25	75
3	1.2/1.0/1.5	K₂CO₃	THF	12	25	72
4	1.5/1.0/1.5	K₂CO₃	THF	14	25	84
5	1.5/1.0/2.0	K₂CO₃	THF	14	25	76
6	1.5/1.0/1.5	K₂CO₃	1,4-Dioxane	72	25	60
7	1.5/1.0/1.5	K₂CO₃	Toluene	72	25	44
8	1.5/1.0/1.5	K₂CO₃	DCM	48	25	73
9	1.5/1.0/1.5	K₂CO₃	DCE	48	25	74
10	1.5/1.0/1.5	K₂CO₃	EtOH	72	25	50
11	1.5/1.0/1.5	K₂CO₃	MeCN	14	25	72
12	1.5/1.0/1.5	Na₂CO₃	THF	24	25	69
13	1.5/1.0/1.5	Cs₂CO₃	THF	14	25	45
14	1.5/1.0/1.5	NaHCO₃	THF	30	25	30
15	1.5/1.0/1.5	Et₃N	THF	30	25	35
16	1.5/1.0/1.5	DBU	THF	30	25	Trace
17	1.5/1.0/1.5	K₂CO₃	THF	20	0	74
18	1.5/1.0/1.5	K₂CO₃	THF	8	40	70

Table 1. Optimization of conditions for the [3+2] cyclization of difluoroacetohydrazonoyl bromides with β-(N,N-dimethylamino)- enones

Figure 2. Crystal structure of compound 3a

Table 2. [3+2] cyclization of difluoroacetohydrazonoyl bromides with β-(N,N-dimethylamino)enones

Table 3. [3+2] cyclization of difluoroacetohydrazonoyl bromides with β-(N,N-dimethylamino)enoates

Table 4. [3+2] cyclization of difluoroacetohydrazonoyl bromides with β-(N,N-dimethylamino)enamides

Scheme 3. Gram-scale reaction

Scheme 4. A possible mechanism of [3+2] cyclization of difluoromethyl nitrile imines and acetyl ketone

Scheme 5. A possible mechanism of [3+2] cyclization of difluoromethyl nitrile imines and β-(N,N-dimethylamino)enone

Scheme 6. Synthesis of compound 1a

References 29

[1]	(a) Mykhailiuk P. K. Chem. Rev. 2021, 121, 1670. doi: 10.1021/acs.chemrev.0c01015 pmid: 33382252
	(b) Ogawa Y.; Tokunaga E.; Kobayashi O.; Hirai K.; Shibata N. iScience 2020, 23, 101467. doi: 10.1016/j.isci.2020.101467 pmid: 33382252
	(c) Du S.; Tian Z.; Yang D.; Li X.; Li H.; Jia C.; Wang M.; Qin Z. Molecules 2015, 20, 8395. doi: 10.3390/molecules20058395 pmid: 33382252
[2]	Yossi Z.; Sod-Moriah G.; Yeffet D.; Berliner A.; Amir D.; Gershonov E. J. Med. Chem. 2019, 62, 5628. doi: 10.1021/acs.jmedchem.9b00604
[3]	Mcloughlin J. I.; Louis St.; Metz S. C. US 2005223526, 1992.
[4]	(a) Qiu S.-S.; Bai Y.-L. Modern Agrochem. 2015, 14, 1. (in Chinese)
	(仇是胜, 柏亚罗, 现代农药, 2015, 14, 1.)
	(b) Qiu S.-S.; Bai Y.-L. Modern Agrochem. 2014, 13, 1. (in Chinese)
	(仇是胜, 柏亚罗, 现代农药, 2014, 13, 1.)
	(c) Jorges W.; Heinrich J. D.; Lantzsch R.WO 2006024388, 2006.
	(d) Gewehr M.; Dietz J.; Blettner C.; Grammenos W.WO 2006087343, 2006.
	(e) Ehrenfreund J.; Tobler H.; Walter H.WO 2004035589, 2004.
	(f) Ehrenfreund J.; Tobler H.; Walter H.WO 03074491, 2003.
[5]	(a) McMillan S. K.; Boria P.; Moore G. E.; Widmer W. R.; Bonney P. L.; Knapp D. W. J. Am. Vet. Med. Assoc. 2011, 239, 1084. doi: 10.2460/javma.239.8.1084 pmid: 9135032
	(b) Penning T. D.; Talley J. J.; Bertenshaw S. R.; Carter J. S.; Collins P. W.; Docter S.; Graneto M. J.; Zhang Y. Y.; Isakson P. C. J. Med. Chem. 1997, 40, 1347. pmid: 9135032
[6]	(a) Zeng J.; Xu Z; Ma J.-A. Chin. J. Org. Chem. 2020, 40, 1105. (in Chinese) doi: 10.6023/cjoc201912024 pmid: 21806021
	(曾俊良, 许志红, 马军安, 有机化学, 2020, 40, 1105.) doi: 10.6023/cjoc201912024 pmid: 21806021
	(b) Fustero S.; Sánchez-Roselló M.; Barrio P.; Simán-Fuentes A. Chem. Rev. 2011, 111, 6984. doi: 10.1021/cr2000459 pmid: 21806021
[7]	Sakamoto R.; Kashiwagi H.; Maruoka K. Org. Lett. 2017, 19, 5126. doi: 10.1021/acs.orglett.7b02416 pmid: 28898083
[8]	Bacauanu V.; Cardinal S.; Yamauchi M.; Kondo M.; Fernandez D. F.; Remy R.; Macmillan D. W. C. Angew. Chem., Int. Ed. 2018, 57, 12543. doi: 10.1002/anie.201807629 pmid: 30067304
[9]	Giornal F.; Pazenok S.; Rodefeld L.; Lui N.; Vors J.-P.; Leroux F. R. J. Fluorine Chem. 2013, 152, 2. doi: 10.1016/j.jfluchem.2012.11.008
[10]	(a) Das A.; Ishitani H.; Kobayashi S. Adv. Synth. Catal. 2019, 361, 5127. doi: 10.1002/adsc.v361.22
	(b) Qiao L.; Zhai Z. W.; Cai P. P.; Tan C. X.; Weng J. Q.; Han L.; Liu X. H.; Zhang Y. G. J. Heterocycl. Chem. 2019, 56, 2536. doi: 10.1002/jhet.v56.9
[11]	(a) Herrera A. G.; Schmitt E.; Panossian A.; Vors J.-P.; Pazenok S.; Leroux F. R. J. Fluorine Chem. 2018, 214, 17. doi: 10.1016/j.jfluchem.2018.07.010
	(b) Iminov R. T.; Mashkov A. V.; Vyzir I. I.; Chalyk B. A.; Tverdokhlebov A. V.; Mykhailiuk P. K.; Babichenko L. N.; Tolmachev A. A.; Volovenko Y. M.; Biitseva A. Eur. J. Org. Chem. 2015, 2015, 886. doi: 10.1002/ejoc.v2015.4
	(c) Wan C.; Pang J. Y.; Jiang W.; Zhang X. W.; Hu X. G. J. Org. Chem. 2021, 86, 4557. doi: 10.1021/acs.joc.0c02980
[12]	(a) Hamper B. C. J. Fluorine Chem. 1990, 48, 123. doi: 10.1016/S0022-1139(00)82607-X
	(b) Linderman R. J.; Kirollos K. S. Tetrahedron Lett. 1989, 30, 2049. doi: 10.1016/S0040-4039(01)93708-6
[13]	Sosnovskikh V. Y.; Irgashev R. A.; Moshkin V. S.; Kodess M. I. Russ. Chem. Bull. 2008, 57, 2146. doi: 10.1007/s11172-008-0291-5
[14]	(a) Nett M.; Grote T.; Lohmann J. K.; Dietz J.; Smidt S. P.; Rack M.; Zierke T.WO 2008152138, 2008.
	(b) Lantzsch R.; Wolfgang J.; Pazenok S.WO 2005042468, 2004.
[15]	Mykhailiuk P. K. Angew. Chem., Int. Ed. 2015, 54, 6558. doi: 10.1002/anie.201501529 pmid: 25801346
[16]	Mertens L.; Hock K. J.; Koenigs R. M. Chem.-Eur. J. 2016, 22, 9542. doi: 10.1002/chem.201601707 pmid: 27168358
[17]	(a) Britton J.; Jamison T. F. Angew. Chem., Int. Ed. 2017, 56, 8823. doi: 10.1002/anie.201704529 pmid: 28544160
	(b) Britton J.; Jamison T. F. Eur. J. Org. Chem. 2017, 2017, 6566. doi: 10.1002/ejoc.v2017.44 pmid: 28544160
[18]	(a) Lebed P. S.; Fenneteau J.; Wu Y.; Cossy J.; Mykhailiuk P. K. Eur. J. Org. Chem. 2017, 2017, 6114. doi: 10.1002/ejoc.v2017.41
	(b) Li J.; Yu X. L.; Cossy J.; Lv S. Y.; Zhang H. L.; Su F.; Mykhailiuk P. K.; Wu Y. Eur. J. Org. Chem. 2017, 2017, 266. doi: 10.1002/ejoc.v2017.2
[19]	Zeng J. L.; Chen Z.; Zhang F. G.; Ma J.-A. Org. Lett. 2018, 20, 4562. doi: 10.1021/acs.orglett.8b01854
[20]	(a) Kowalczyk A.; Utecht-Jarzyńska G.; Mlostoń G.; Jasiński M. Org. Lett. 2022, 24, 2499. doi: 10.1021/acs.orglett.2c00521 pmid: 35343703
	(b) Wang K.-H.; Liu H.; Liu X.; Bian C.; Wang J.; Su Y.; Huang D.; Hu Y. Asian J. Org. Chem. 2022, 11, e202200103. doi: 10.1002/ajoc.v11.6 pmid: 35343703
	(c) Tian Y.; Li J; Zhang F.; Ma J.-A. Adv. Synth. Catal. 2021, 363, 2093. doi: 10.1002/adsc.v363.8 pmid: 35343703
[21]	Zhou Y.; Gao C. F.; Ma H.; Nie J.; Ma J.-A.; Zhang F. G. Chem. Asian J. 2022, 17, e202200436. doi: 10.1002/asia.v17.15
[22]	(a) Han T.; Wang K.-H.; Yang M.; Zhao P.; Wang F.; Wang J.; Huang D.; Hu Y. J. Org. Chem. 2022, 87, 498. doi: 10.1021/acs.joc.1c02521
	(b) Ren Y.; Ma R.; Feng Y.; Wang K.-H.; Wang J.; Huang D.; Lv X.; Hu Y. Asian J. Org. Chem. 2022, e202200438.
[23]	Ren Y.; Ma R.; Li X.; Wang K.-H.; Wang J.; Huang D.; Lv X.; Hu Y. Tetrahedron 2023, 149, 33711.
[24]	(a) Singh M. S.; Chowdhury S.; Koley S. Tetrahedron 2016, 72, 1603. doi: 10.1016/j.tet.2016.02.031
	(b) Shawali A. S. Chem. Rev. 1993, 93, 2731. doi: 10.1021/cr00024a007
[25]	(a) Chandanshive J. Z.; Gonzalez P. B.; Tiznado W.; Bonini B. F.; Caballero J.; Femoni C.; Franchini M. C. Tetrahedron 2012, 68, 3319. doi: 10.1016/j.tet.2012.02.068 pmid: 11463282
	(b) Ponti A.; Molteni G. J. Org. Chem. 2001, 66, 5252. pmid: 11463282
	(c) Tanaka K.; Maeno S.; Mitsuhashi K. Chem. Lett. 1982, 11, 543. doi: 10.1246/cl.1982.543 pmid: 11463282
[26]	(a) Song W.; Liu Y.; Yan N.; Wan J.-P. Org. Lett. 2023, 25, 2139. doi: 10.1021/acs.orglett.3c00636
	(b) Li X.; Chen Z.; Chen W.; Xie X.; Zhou H.; Liao Y.; Yu F.; Huang J. Org. Lett. 2022, 24, 7372. doi: 10.1021/acs.orglett.2c02905
	(c) Nagireddy A.; Dattatri K. R.; Nanubolu J. B.; Reddy M. S. J. Org. Chem. 2022, 87, 1240. doi: 10.1021/acs.joc.1c02575
	(d) Duan L.; Wang X.; Gu Y.; Hou Y.; Gong P. Org. Chem. Front. 2020, 7, 2307. doi: 10.1039/D0QO00555J
	(e) Feng J.; He T.; Xie Y.; Yu Y.; Baell J. B.; Huang F. Org. Biomol. Chem. 2020, 18, 9483. doi: 10.1039/D0OB01958E
	(f) Wakade S. B.; Tiwari D. K.; Phanindrudu M.; Pushpendra.; Tiwari, D. K. Tetrahedron 2019, 75, 4024. doi: 10.1016/j.tet.2019.06.030
[27]	(a) Tu L.; Gao L.; Wang X.; Shi R.; Ma R.; Li J.; Lan X.; Zheng Y.; Liu J. J. Org. Chem. 2021, 86, 559. doi: 10.1021/acs.joc.0c02244
	(b) Yıldırım M.; Dirtirst Y. Tetrahedron Lett. 2011, 67, 3209. doi: 10.1016/j.tet.2011.03.017
[28]	(a) Kowalczyk A.; Utecht-Jarzyńska G.; Mlostoń G.; Jasiński M. J. Fluorine Chem. 2021, 241, 10969. pmid: 29392253
	(b) Utecht G.; Fruziński A.; Jasiński M. Org. Biomol. Chem. 2018, 16, 1252. doi: 10.1039/c7ob03126b pmid: 29392253
	(c) Oh L. M. Tetrahedron Lett. 2006, 47, 7943. doi: 10.1016/j.tetlet.2006.08.138 pmid: 29392253
[29]	Kantlehner W.; Mezgera J.; Ivanov I. C. Z. Naturforsch. 2014, 69, 519. doi: 10.5560/znb.2014-4053

二氟甲基溴代腙与β-(N,N-二甲氨基)烯酮/丙烯酸酯/丙烯酰胺的[3+2]环化反应研究