Research Progress in the Synthesis of Azaindoline and Its Derivatives

doi:10.6023/cjoc202308025

Abstract

The azaindoline skeleton exists in a wide range of bioactive molecules and natural products, and has significant biological and pharmaceutical activities. The synthesis of these compounds has attracted great attention from chemists. However, due to the electron-deficient nature of the pyridine ring where the nitrogen atom is located, many traditional methods for the synthesis of indoline cannot effectively construct the azaindoline skeleton. In recent years, chemists have been exploring the synthesis of azaindoline skeleton and have made some progress. According to the different reaction types, the synthesis of azaindolines in recent years and the key reaction mechanisms are reviewed and discussed, and the future development prospect of this research field is prospected.

Key words: azaindoline, synthesis, catalytic reaction

Cite this article

Hao Ye, Haibin Zhang, Ya'nan Wu, Xinxing Wu. Research Progress in the Synthesis of Azaindoline and Its Derivatives[J]. Chinese Journal of Organic Chemistry, 2024, 44(4): 1106-1123.

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Fig. & Tab. 34

Figure 1. Azaindoline-containing bioactive molecules

Scheme 1. Synthesis of azaindoline skeleton based on allylpalladium intermediate

Scheme 2. Synthesis of azaindoline skeleton by palladium-cata- lyzed three-component reaction

Scheme 3. Synthesis of azaindoline skeleton by palladium-cata- lyzed C(sp3)—H activation reaction

Scheme 4. Palladium-catalyzed Heck cyclization/Suzuki coupling to synthesize azaindoline

Scheme 5. Palladium-catalyzed Heck cyclization/Sonogashira coupling for the synthesis of azaindoline

Scheme 6. Palladium-catalyzed Heck cyclization/dearomatization spirocyclization of phenol for the synthesis of azaindoline

Scheme 7. Palladium-catalyzed Heck cyclization/Hiyama coupling for the synthesis of azaindoline

Scheme 8. Palladium-catalyzed Heck cyclization/insertion of CO for the synthesis of azaindoline

Scheme 9. Palladium-catalyzed Heck cyclization/the insertion of CO for the synthesis of furoazaindoline

Scheme 10. Palladium-catalyzed intramolecular dearomative Heck cyclization for the synthesis of azaindolone

Scheme 11. Palladium-catalyzed dearomative methoxyallylation of 3-nitroazaindole

Scheme 12. Iron-catalyzed amination of strong C(sp3)—H bonds to synthesize azaindoline

Scheme 13. Titanocene catalyzed epoxide-opening annulation to synthesize azaindoline

Scheme 14. Yttrium-catalyzed synthesis of azaindolines via C—H cyclization of functionalized pyridines

Scheme 15. Mechanism for yttrium-catalyzed C—H cyclization of functionalized pyridines

Scheme 16. Synthesis of azaindoline by multi-step reaction without metal catalyst

Scheme 17. Synthesis of azaindoline by radical cyclization

Scheme 18. Synthesis of azaindoline by directed ortho-metal- lation/transmetallation approach

Scheme 19. A free radical cyclizations for the synthesis of azaindoline

Scheme 20. Three-component synthesis of 6-azaindolines and its tricyclic derivatives

Scheme 21. Synthesis of iodoazaindoline through the “halogen dance” process

Scheme 22. Preparation of the isomeric azaindolines by intramolecular carbolithiation reaction

Scheme 23. Synthesis of polyfluorinated 5-azaindolines by free radical substitution reaction

Scheme 24. Synthesis of polyfluorinated 7-azaindolines by free radical substitution reaction

Scheme 25. Synthesis of 2,2-disubstituted azaindolines by intramolecular cyclization in acidic media

Scheme 26. Synthesis of azaindolines by the ring-opening of sulfamidates

Scheme 27. Synthesis of four azaindoline families by inter-/intramolecular annulative diamination of vinylpyridines

Scheme 28. Synthesis of azaindoline by redox reaction

Scheme 29. Enantioselective synthesis of 4- and 6-azaindolines by a cation-directed cyclization

Scheme 30. Synthesis of azaindoline by Fischer azaindolization reaction

Scheme 31. Synthesis of 4-azaindolines using phase-transfer catalysis via an intramolecular Mannich reaction

Scheme 32. Syntheses of heterocycle-2,3-fused azaindoline derivatives

Scheme 33. Synthesis of 7-azaindoline through domino reactions of 2-fluoro-3-methylpyridine and aldehydes

References 34

[1]	(a) Cheung M.; Hunter R. N. III; Peel M. R.; Lackey K. E. Heterocycles 2001, 55, 1583. doi: 10.3987/COM-01-9267 pmid: 2145433
	(b) Ting P. C.; Kaminski J. J.; Sherlock M. H.; Tom W. C.; Lee J. F.; Bryant R. W.; Watnick A. S.; McPhail A. T. J. Med. Chem. 1990, 33, 2697. pmid: 2145433
	(c) Kumar V.; Dority J. A.; Bacon E. R.; Singh B.; Lesher G. Y. J. Org. Chem. 1992, 57, 6995. doi: 10.1021/jo00051a062 pmid: 2145433
	(d) Wood E. R.; Kuyper L.; Petrov K. G.; Hunter R. N.; Harris P. A.; Lackey K. Bioorg. Med. Chem. Lett. 2004, 14, 935. doi: 10.1016/j.bmcl.2003.12.004 pmid: 2145433
	(e) Yuan C.; Pan C. Chin. J. Org. Chem. 2023, 43, 156. (in Chinese) doi: 10.6023/cjoc202205034 pmid: 2145433
	(袁成, 潘长多, 有机化学, 2023, 43, 156.) doi: 10.6023/cjoc202205034 pmid: 2145433
[2]	(a) Gonzalez-Lopez De Turiso F.; Shin Y.; Brown M.; Cardozo M.; Chen Y.; Fong D.; Hao X.; He X.; Henne K.; Hu Y. L.; Johnson M. G.; Kohn T.; Lohman J.; McBride H. J.; McGee L. R.; Medina J. C.; Metz D.; Miner K.; Mohn D.; Pattaropong V.; Seganish J.; Simard J. L.; Wannberg S.; Whittington D. A.; Yu G.; Cushing T. D. J. Med. Chem. 2012, 55, 7667. doi: 10.1021/jm300679u pmid: 22876881
	(b) Takai K.; Inoue Y.; Konishi Y.; Suwa A.; Uruno Y.; Matsuda H.; Nakako T.; Sakai M.; Nishikawa H.; Hashimoto G.; Enomoto T.; Kitamura A.; Uematsu Y.; Kiyoshi A.; Sumiyoshi T. Bioorg. Med. Chem. Lett. 2014, 24, 3189. doi: 10.1016/j.bmcl.2014.04.085 pmid: 22876881
	(c) Bai B.; Xu F.; Yang J.; Zhang G.; Mao D.; Wang N. Chin. J. Org. Chem. 2021, 41, 2335. (in Chinese) doi: 10.6023/cjoc202102011 pmid: 22876881
	(白冰, 徐芳琳, 杨静, 张改红, 毛多斌, 王宁, 有机化学, 2021, 41, 2335.) doi: 10.6023/cjoc202102011 pmid: 22876881
[3]	(a) Mérour J.-Y.; Routier S.; Suzenet F.; Joseph B. Tetrahedron 2013, 69, 4767. doi: 10.1016/j.tet.2013.03.081
	(b) Popowycz F.; Mérour J.-Y.; Joseph B. Tetrahedron 2007, 63, 8689. doi: 10.1016/j.tet.2007.05.078
	(c) Popowycz F.; Routier S.; Joseph B.; Mérour J.-Y. Tetrahedron 2007, 63, 1031. doi: 10.1016/j.tet.2006.09.067
	(d) Liang R.-X.; Xu D.-Y.; Yang F.-M.; Jia Y.-X. Chem. Commun. 2019, 55, 7711. doi: 10.1039/C9CC03566D
	(e) Liu K.; Song Y.-F.; Gao Y.; Luo J.-Q.; Jia Y.-X. Chem. Commun. 2022, 58, 5893. doi: 10.1039/D2CC01650H
	(f) Liang R.-X.; Jia Y.-X. Acc. Chem. Res. 2022, 55, 734. doi: 10.1021/acs.accounts.1c00781
	(g) Hu Y.-Y.; Xu X.-Q.; Deng W.-C.; Liang R.-X.; Jia Y.-X. Org. Lett. 2023, 25, 6122. doi: 10.1021/acs.orglett.3c02092
	(h) Lu J.; He Y.; Ren L.; Li D.; Pan X.; Yang L.; Wang J.; Wei S.; Wei J. Synlett 2023, doi: 10.1055/a-2184-5014.
	(i) Huang H.; Li X.; Su J.; Song Q. Chin. J. Org. Chem. 2023, 43, 1146. (in Chinese) doi: 10.6023/cjoc202210031
	(黄华, 李鑫, 苏建科, 宋秋玲, 有机化学, 2023, 43, 1146.)
	(j) Zhang Z.; Yi J.-J.; Aslam M.; Wan J.-P.; Sun M. Synthesis 2023, 55, 3617. doi: 10.1055/a-2002-5931
[4]	Desarbre E.; Mérour J.-Y. Tetrahedron Lett. 1996, 37, 43. doi: 10.1016/0040-4039(95)02079-9
[5]	Schramm O. G.; Dediu N.; Oeser T.; Müller T. J. J. J. Org. Chem. 2006, 71, 3494. pmid: 16626130
[6]	Rousseaux S.; Davi M.; Sofack-Kreutzer J.; Pierre C.; Kefalidis C. E.; Clot E.; Fagnou K.; Baudoin O. J. Am. Chem. Soc. 2010, 132, 10706. doi: 10.1021/ja1048847 pmid: 20681703
[7]	Schempp T. T.; Daniels B. E.; Staben S. T.; Stivala C. E. Org. Lett. 2017, 19, 3616. doi: 10.1021/acs.orglett.7b01606
[8]	Wu X.-X.; Liu A.; Xu S.; He J.; Sun W.; Chen S. Org. Lett. 2018, 20, 1538. doi: 10.1021/acs.orglett.8b00106
[9]	Wu X.-X.; Tian H.; Wang Y.; Liu A.; Chen H.; Fan Z.; Li X.; Chen S. Org. Chem. Front. 2018, 5, 3310. doi: 10.1039/C8QO00964C
[10]	Ye H.; Zhang R.; Xia X.; Ding Y.; Sun M.; Shi L.; Jiang G.; Wu X.-X. Synthesis 2021, 53, 4079. doi: 10.1055/a-1542-4258
[11]	Ye H.; Wu L.; Zhang M.; Jiang G.; Dai H.; Wu X.-X. Chem. Commun. 2022, 58, 6825. doi: 10.1039/D2CC02152H
[12]	Li X.; Zhou B.; Yang R.-Z.; Yang F.-M.; Liang R.-X.; Liu R.-R.; Jia Y.-X. J. Am. Chem. Soc. 2018, 140, 13945. doi: 10.1021/jacs.8b09186
[13]	Xie J.-H.; Zheng C.; You S.-L. Angew. Chem., Int. Ed. 2021, 60, 22184. doi: 10.1002/anie.v60.41
[14]	Das S. K.; Roy S.; Khatua H.; Chattopadhyay B. J. Am. Chem. Soc. 2020, 142, 16211. doi: 10.1021/jacs.0c07810
[15]	Wipf P.; Maciejewski J. P. Org. Lett. 2008, 10, 4383. doi: 10.1021/ol801860s
[16]	Ye P.; Shao Y.; Zhang F.; Zou J.; Ye X.; Chen J. Adv. Synth. Catal. 2020, 362, 851. doi: 10.1002/adsc.v362.4
[17]	Spivey A. C.; Fekner T.; Spey S. E.; Adams H. J. Org. Chem. 1999, 64, 9430. doi: 10.1021/jo991011h
[18]	Viswanathan R.; Prabhakaran E. N.; Plotkin M. A.; Johnston J. N. J. Am. Chem. Soc. 2003, 125, 163. doi: 10.1021/ja0284308 pmid: 12515518
[19]	Davies A. J.; Brands K. M. J.; Cowden C. J.; Dolling U. H.; Lieberman D. R. Tetrahedron Lett. 2004, 45, 1721. doi: 10.1016/j.tetlet.2003.12.096
[20]	Bacqué E.; El Qacemi M.; Zard S. Z. Org. Lett. 2004, 6, 3671. pmid: 15469320
[21]	Fayol A.; Zhu J. Org. Lett. 2005, 7, 239. pmid: 15646967
[22]	Nguyen H. N.; Wang Z. J. Tetrahedron Lett. 2007, 48, 7460. doi: 10.1016/j.tetlet.2007.08.076
[23]	Bailey W. F.; Salgaonkar P. D.; Brubaker J. D.; Sharma V. Org. Lett. 2008, 10, 1071. doi: 10.1021/ol702862d
[24]	Laot Y.; Petit L.; Zard S. Z. Org. Lett. 2010, 12, 3426. doi: 10.1021/ol101240f
[25]	Liu Z.; Qin L.; Zard S. Z. Org. Lett. 2014, 16, 2704. doi: 10.1021/ol500985f
[26]	Métro T.-X.; Fayet C.; Arnaud F.; Rameix N.; Fraisse P.; Janody S.; Sevrin M.; George P.; Vogel R. Synlett 2011, 5, 684.
[27]	Moss T. A.; Hayter B. R.; Hollingsworth I. A.; Nowak T. Synlett 2012, 23, 2408. doi: 10.1055/s-00000083
[28]	Danneman M. W.; Hong K. B.; Johnston J. N. Org. Lett. 2015, 17, 3806. doi: 10.1021/acs.orglett.5b01783 pmid: 26186041
[29]	Nuhant P.; Allais C.; Chen M. Z.; Coe J. W.; Dermenci A.; Fadeyi O. O.; Flick A. C.; Mousseau J. J. Org. Lett. 2015, 17, 4292. doi: 10.1021/acs.orglett.5b02098
[30]	Lamb A. D.; Davey P. D.; Driver R. W.; Thompson A. L.; Smith M. D. Org. Lett. 2016, 18, 5372. doi: 10.1021/acs.orglett.6b02744
[31]	Simmons B. J.; Hoﬀmann M.; Champagne P. A.; Picazo E.; Yamakawa K.; Morrill L. A.; Houk K. N.; Garg N. K. J. Am. Chem. Soc. 2017, 139, 14833. doi: 10.1021/jacs.7b07518 pmid: 29022706
[32]	Wang J.; Liu Y.; Wei Z.; Cao J.; Liang D.; Lin Y.; Duan H.; J. Org. Chem. 2020, 85, 4047. doi: 10.1021/acs.joc.9b03025
[33]	Nishi T.; Mishima N.; Kato H.; Yamada K. Synlett 2021, 32, 1034. doi: 10.1055/s-0037-1610771
[34]	Xu X.; Ou M.; Wang Y.-E.; Lin T.; Xiong D.; Xue F.; Walsh P. J.; Mao J. Org. Chem. Front. 2022, 9, 2541. doi: 10.1039/D2QO00339B

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