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

doi:10.6023/cjoc202311001

摘要/Abstract

报道了在碱存在下, 由二氟甲基溴代腙原位生成的二氟甲基腈亚胺与β-(N,N-二甲氨基)烯酮/丙烯酸酯/丙烯酰胺的[3+2]环化反应. 该反应首先产生了一个吡唑啉中间体, 然后从该中间体上自发消除一分子二甲胺, 最后以中等至良好的产率得到了一系列3,4-二取代-3-二氟甲基吡唑类化合物. 该反应具有高度的区域选择性: 即它是由1,3-偶极体的最低空轨道和富电子烯烃的最高占有轨道相互作用的反电子需求的环加成反应. 该方法拓展了二氟甲基腈亚胺参与的[3+2]环化反应的类型, 提供了一种简单、高效地合成3,4-二取代-3-二氟甲基吡唑类化合物的新方法.

关键词: 3-二氟甲基吡唑, 二氟甲基溴代腙, [3+2]环化, 区域选择性

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

引用此文

李晓勇, 黄丹凤, 周玉秀, 刘小康, 王克虎, 王君娇, 胡雨来. 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[J]. 有机化学, 2024, 44(4): 1226-1239.

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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图/表 12

图1. 一些含有3-(二氟甲基)吡唑结构单元的医药和农药分子

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

图式1. 通过重氮化合物和烯烃或炔烃的[3+2]环化反应合成3-(二氟甲基)吡唑

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

图式2. 通过二氟甲基卤代腙和烯烃或炔烃的[3+2]环化反应合成3-(二氟甲基)吡唑

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

表1. 二氟甲基溴代腙和β-(N,N-二甲氨基)烯酮的[3+2]环化反应条件优化a

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

图2. 化合物3a的晶体结构

Figure 2. Crystal structure of compound 3a

表2. 二氟甲基溴代腙和β-(N,N-二甲氨基)烯酮的[3+2]环化反应a

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

表3. 二氟甲基溴代腙和β-(N,N-二甲氨基)丙烯酸酯的[3+2]环化反应a

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

表4. 二氟甲基溴代腙和β-(N,N-二甲氨基)丙烯酰胺的[3+2]环化反应a

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

图式3. 克级规模反应

Scheme 3. Gram-scale reaction

图式4. 二氟甲基腈亚胺和炔酮的[3+2]环化反应可能的反应机理

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

图式5. 二氟甲基腈亚胺和β-(N,N-二甲氨基)烯酮的[3+2]环化反应可能的反应机理

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

图式6. 化合物1a的合成

Scheme 6. Synthesis of compound 1a

参考文献 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