C4-Methylation and C4-Methylation/Carbonyl Migration of Indoles via Steric Control

doi:10.6023/cjoc202510028

Abstract

The development of methylation protocol has attracted intense attention owing to “magic methyl effect” in drug discovery. Meanwhile, the indole scaffold is prevalence in the natural products and pharmacophores. Despite the advances in other site selective methylation, there is scarce reports for C4 methylation of indoles and combination of a carbonyl group rearrangement with C—H methylation on indole ring. Herein, the C4 methylation of indoles and the steric controlled C4-methylation/carbonyl group migration are reported. The large steric hindrance at carbonyl group facilitates the carbonyl group migration, which provides a straightforward protocol for the synthesis of C2/C4 disubstituted indoles.

Key words: methylation, carbonyl group dancing, Pd catalysis, magic methyl effect

Cite this article

Henan Xie, Yaohang Cheng, Guanghui An. C4-Methylation and C4-Methylation/Carbonyl Migration of Indoles via Steric Control[J]. Chinese Journal of Organic Chemistry, 2026, 46(2): 475-485.

Export EndNote|Reference Manager|ProCite|BibTeX|RefWorks

share this article

Fig. & Tab. 9

Scheme 1. C—H methylation of indoles

Entry	Catalyst	Acid	Temp/℃	Yield^b/%
Entry	Catalyst	Acid	Temp/℃	3a	4a
1	Pd(OAc)₂	TFA	50	74	—
2	Pd(TFA)₂	TFA	50	72	—
3	—	TFA	50	—	—
4	Pd(OAc)₂	HOAc	50	16	—
5	Pd(OAc)₂	TsOH•H₂O	50	—	—
6	Pd(OAc)₂	—	50	—	—
7	Pd(OAc)₂	TFA	60	53	4
8	Pd(OAc)₂	TFA	70	26	8
9	Pd(OAc)₂	TFA	80	19	12
10^c	Pd(OAc)₂	TFA	50	86	—
11^c^,^d	Pd(OAc)₂	TFA	50	88	—

Table 1. Optimization of the reaction conditionsa

Scheme 2. Substrate scope of C4-methylation Standard conditions: 1 (0.2 mmol, 1.0 equiv.), 2 (3.0 equiv.), Pd(OAc)2 (10 mol%), Cu(OAc)2 (20 mol%), TFA (2.0 equiv.), DCE (2.0 mL), air, 50 ℃, 3 h, isolated yields. a 5 h.

Scheme 3. Effect of substituents at aliphatic carbonyl group

Entry	Acid	Temp./℃	Yield^b/%
Entry	Acid	Temp./℃	3p	6a
1	TFA	50	18	53
2	TFA	40	15	25
3	TFA	60	16	52
4	PivOH	50	0	0
5	TsOH•H₂O	50	0	0
6	—	50	0	0
7^c	TFA	50	9	65
8^c^,^d	TFA	50	0	75

Table 2. Optimization of the reaction conditionsa

Scheme 4. Substrate scope of C4-methylation/carbonyl group dance reaction Standard conditions: 1 (0.2 mmol, 1 equiv.), 2 (3.0 equiv.), Pd(OAc)2 (10 mol%), Cu(OAc)2 (20 mol%), TFA (2.0 equiv.), KOAc (1.0 equiv.), DCE (2.0 mL), air, 50 ℃, 6 h, isolated yields.

Entry	Catalyst	Additive	Acid	Time/h	Yield^b/%
1	—	—	—	6	0
2	Pd(OAc)₂	—	—	6	0
3	—	Cu(OAc)₂	—	6	0
4	—	—	TFA	6	79
5^c	—	—	TFA	6	88
6^c			TFA	12	90

Table 3. Control reactionsa

Scheme 5. Mechanism studies

Scheme 6. Proposed mechanism

References 27

[1]	(a) Pinheiro P. D. S. M.; Franco L. S.; Fraga C. A. M. Pharmaceuticals 2023, 16, 1157. doi: 10.3390/ph16081157 pmid: 24151256
	(b) Leung C. S.; Leung S. S. F.; Tirado-Rives J.; Jorgensen W. L. J. Med. Chem. 2012, 55, 4489. doi: 10.1021/jm3003697 pmid: 24151256
	(c) Aynetdinova D.; Callens M. C.; Hicks H. B.; Poh C. Y. X.; Shennan B. D. A.; Boyd A. M.; Lim Z. H.; Leitch J. A.; Dixon D. J. Chem. Soc. Rev. 2021, 50, 5517. doi: 10.1039/d0cs00973c pmid: 24151256
	(d) Barreiro E. J.; Kümmerle A. E.; Fraga C. A. M. Chem. Rev. 2011, 111, 5215. doi: 10.1021/cr200060g pmid: 24151256
	(e) Schönherr H.; Cernak T. Angew. Chem. Int. Ed. 2013, 52, 12256. doi: 10.1002/anie.201303207 pmid: 24151256
[2]	Angell R.; Aston N. M.; Bamborough P.; Buckton J. B.; Cockerill S.; deBoeck S. J.; Edwards C. D.; Holmes D. S.; Jones K. L.; Laine D. I.; Patel S.; Smee P. A.; Smith K. J.; Somers D. O.; Walker A. L. Bioorg. Med. Chem. Lett. 2008, 18, 4428. doi: 10.1016/j.bmcl.2008.06.048
[3]	(a) Aguilar D.; Fernández I.; Cuesta L.; Yañez-Rodríguez V.; Soler T.; Navarro R.; Urriolabeitia E. P.; López Ortiz F. J. Org. Chem. 2010, 75, 6452. doi: 10.1021/jo101151s pmid: 20815393
	(b) Meyers A. I.; Pansegrau P. D. Tetrahedron Lett. 1983, 24, 4935. doi: 10.1016/S0040-4039(01)99815-6 pmid: 20815393
	(c) Meyer N.; Seebach D. Chem. Ber. 1980, 113, 1304. doi: 10.1002/cber.v113:4 pmid: 20815393
[4]	(a) Snieckus V. Chem. Rev. 1990, 90, 879. doi: 10.1021/cr00104a001
	(b) Townsend C. A.; Bloom L. M. Tetrahedron Lett. 1981, 22, 3923. doi: 10.1016/S0040-4039(01)82027-X
[5]	(a) Shang R.; Ilies L.; Nakamura E. J. Am. Chem. Soc. 2015, 137, 7660. doi: 10.1021/jacs.5b04818 pmid: 24124892
	(b) Agrawal T.; Cook S. P. Org. Lett. 2014, 16, 5080. doi: 10.1021/ol5024344 pmid: 24124892
	(c) Sun C.; Fürstner A. Angew. Chem. Int. Ed. 2013, 52, 13071. doi: 10.1002/anie.v52.49 pmid: 24124892
	(d) Thuy-Boun P. S.; Villa G.; Dang D.; Richardson P.; Su S.; Yu J.-Q. J. Am. Chem. Soc. 2013, 135, 17508. doi: 10.1021/ja409014v pmid: 24124892
	(e) Dai H.-X.; Stepan A. F.; Plummer M. S.; Zhang Y.-H.; Yu J.-Q. J. Am. Chem. Soc. 2011, 133, 7222. doi: 10.1021/ja201708f pmid: 24124892
	(f) Giri R.; Maugel N.; Li J.-J.; Wang D.-H.; Breazzano S. P.; Saunders L. B.; Yu J.-Q. J. Am. Chem. Soc. 2007, 129, 3510. doi: 10.1021/ja0701614 pmid: 24124892
	(g) Chen X.; Goodhue C. E.; Yu J.-Q. J. Am. Chem. Soc. 2006, 128, 12634. doi: 10.1021/ja0646747 pmid: 24124892
[6]	Wu M.-C.; Li M.-Z.; Chen Y.-X.; Liu F.; Xiao J.-A.; Chen K.; Xiang H.-Y.; Yang H. Org. Lett. 2022, 24, 6412. doi: 10.1021/acs.orglett.2c02439
[7]	(a) Chen S.; Feng B.; Zheng X.; Yin J.; Yang S.; You J. Org. Lett. 2017, 19, 2502. doi: 10.1021/acs.orglett.7b00730 pmid: 19946913
	(b) Kalepu J.; Gandeepan P.; Ackermann L.; Pilarski L. T. Chem. Sci. 2018, 9, 4203. doi: 10.1039/C7SC05336C pmid: 19946913
	(c) Petrini M. Chem.-Eur. J. 2017, 23, 16115. doi: 10.1002/chem.201702124 pmid: 19946913
	(d) Bandini M.; Eichholzer A. Angew. Chem. Int. Ed. 2009, 48, 9608. doi: 10.1002/anie.200901843 pmid: 19946913
	(e) Sandtorv A. H. Adv. Synth. Catal. 2015, 357, 2403. doi: 10.1002/adsc.v357.11 pmid: 19946913
	(f) Leitch J. A.; Bhonoah Y.; Frost C. G. ACS Catal. 2017, 7, 5618. doi: 10.1021/acscatal.7b01785 pmid: 19946913
	(g) Wen J.; Shi Z. Acc. Chem. Res. 2021, 54, 1723. doi: 10.1021/acs.accounts.0c00888 pmid: 19946913
	(h) Zheng K.; Chen C.; Xu H.; Mao J.; Shen C. J. Org. Chem. 2025, 90, 15567. doi: 10.1021/acs.joc.5c01558 pmid: 19946913
	(i) Wang Y.; Wang J.; Chen C.; Song L.; Wang Z.-L.; Wei W.; Yi D. Chem. Commun. 2025, 61, 10812. doi: 10.1039/D5CC02744F pmid: 19946913
	(j) Xu J.; Hong Y.; Xu R.; Wang Y.; Guo Y.; Shen J.; Zhao Y.; Li W. Org. Chem. Front. 2024, 11, 6166. doi: 10.1039/D4QO01351D pmid: 19946913
	(k) Zhang M.; Nan G.; Zhao X.; Wei W. Chin. J. Org. Chem. 2022, 42, 4315 (in Chinese). doi: 10.6023/cjoc202209013 pmid: 19946913
	(张孟琪, 南光明, 赵晓辉, 魏伟, 有机化学, 2022, 42, 4315.) doi: 10.6023/cjoc202209013 pmid: 19946913
	(l) Xu J.; Cheng K.; Shen C.; Bai R.; Xie Y.; Zhang P. ChemCatChem 2018, 10, 965. doi: 10.1002/cctc.v10.5 pmid: 19946913
[8]	(a) Tonin M.; Zell D.; Müller V.; Ackermann L. Synthesis 2016, 49, 127. doi: 10.1055/s-0036-1588890
	(b) Sun Y.; Zhang W.; Liu Y.; Zhang Z.; Hu M.; Liu X.; Qin H.; Lu H. Org. Chem. Front. 2025, 12, 6415. doi: 10.1039/D5QO00869G
[9]	(a) Han X.; Yuan Y.; Shi Z. J. Org. Chem. 2019, 84, 12764. doi: 10.1021/acs.joc.9b01114
	(b) Qiu X.; Wang P.; Wang D.; Wang M.; Yuan Y.; Shi Z. Angew. Chem. Int. Ed. 2019, 58, 1504. doi: 10.1002/anie.v58.5
[10]	Wu Z.; Wei F.; Wan B.; Zhang Y. J. Am. Chem. Soc. 2021, 143, 4524. doi: 10.1021/jacs.0c13057
[11]	(a) Voronin I. O.; Nesterova T. N.; Strelchik B. S.; Zhuravskii E. A. Kinet. Catal. 2014, 55, 705. doi: 10.1134/S0023158414060147
	(b) Tsai T. Appl. Catal., A 1999, 181, 355. doi: 10.1016/S0926-860X(98)00396-2
	(c) Bellussi G.; Bohnet M.; Bus J.; Drauz K.; Greim H.; Jackel K.-P.; Karst U.; Kleemann A.; Kreysa G.; Laird T.; Meier W.; Ottow E.; Roper M.; Scholtz J.; Sundmacher K.; Ulber R.; Wietelmann U. Ullmann’s Encyclopedia of Industrial Chemistry, Wiley-VCH, Weinheim, 2010.
[12]	(a) Schnürch M.; Spina M.; Khan A. F.; Mihovilovic M. D.; Stanetty P. Chem. Soc. Rev. 2007, 36, 1046. pmid: 12098253
	(b) Sammakia T.; Stangeland E. L.; Whitcomb M. C. Org. Lett. 2002, 4, 2385. pmid: 12098253
	(c) Bunnett J. F. Acc. Chem. Res. 1972, 5, 139. doi: 10.1021/ar50052a004 pmid: 12098253
[13]	(a) Nakahara H.; Yamaguchi J. Org. Lett. 2022, 24, 8083. doi: 10.1021/acs.orglett.2c03442 pmid: 36286610
	(b) Niu Y.; Yan C.-X.; Yang X.-X.; Bai P.-B.; Zhou P.-P.; Yang S.-D. Org. Chem. Front. 2022, 9, 1023. doi: 10.1039/D1QO01454D pmid: 36286610
[14]	Matsushita K.; Takise R.; Muto K.; Yamaguchi J. Sci. Adv. 2020.
[15]	Ishiga W.; Ohta M.; Kodama T.; Tobisu M. Org. Lett. 2021, 23, 6714. doi: 10.1021/acs.orglett.1c02280
[16]	Alonso M.; Lonardi G.; Arpa E. M.; Roure B.; Ruffoni A.; Leonori D. Nat. Commun. 2025, 16, 7502. doi: 10.1038/s41467-025-62549-5
[17]	Taskesenligil Y.; Aslan M.; Cogurcu T.; Saracoglu N. J. Org. Chem. 2023, 88, 1299. doi: 10.1021/acs.joc.2c00716
[18]	(a) Cheng Y.; Yu S.; He Y.; An G.; Li G.; Yang Z. Chem. Sci. 2021, 12, 3216. doi: 10.1039/D0SC05409G
	(b) Song Q.; Zhang L.; Wang B.; Chen Z.; Jin W.; Xia Y.; Wu S.; Liu C.; Zhang Y. Org. Lett. 2024, 26, 3685. doi: 10.1021/acs.orglett.3c04123
	(c) Wei X.; Zeng M.; Li Y.; Wang D.; Wang J.; Liu H. Org. Lett. 2024, 26, 2473. doi: 10.1021/acs.orglett.4c00654
	(d) Vasu D.; Yorimitsu H.; Osuka A. Angew. Chem. Int. Ed. 2015, 54, 7162. doi: 10.1002/anie.v54.24
[19]	Senior A.; Ruffell K.; Ball L. T. Nat. Chem. 2022, 15, 386. doi: 10.1038/s41557-022-01101-0 pmid: 36509853
[20]	Gu K.; Hall M. T.; Tucker Z. D.; Durling G. M.; Ashfeld B. L. Nat. Commun. 2025, 16, 97. doi: 10.1038/s41467-024-55246-2
[21]	(a) He Y.; Tian C.; An G.; Li G. Chin. Chem. Lett. 2024, 35, 108546. doi: 10.1016/j.cclet.2023.108546
	(b) Wang X.; An G.; Li G. ChemCatChem 2024, 16, e202301523.
	(c) Cheng Y.; Zhang X.; An G.; Li G.; Yang Z. Chin. Chem. Lett. 2023, 34, 107625. doi: 10.1016/j.cclet.2022.06.048
	(d) Lv X.; Cheng Y.; Zong Y.; Wang Q.; An G.; Wang J.; Li G. ACS Catal. 2023, 13, 7310. doi: 10.1021/acscatal.3c00901
[22]	(a) Iqubal A.; Jash A.; Das P. Org. Lett. 2025, 27, 7643. doi: 10.1021/acs.orglett.5c02223
	(b) Simkó D. Cs.; Elekes P.; Pázmándi V.; Novák Z. Org. Lett. 2018, 20, 676. doi: 10.1021/acs.orglett.7b03813
[23]	(a) Yang Y.; Gao P.; Zhao Y.; Shi Z. Angew. Chem. Int. Ed. 2017, 56, 3966. doi: 10.1002/anie.v56.14
	(b) Borah A. J.; Shi Z. Chem. Commun. 2017, 53, 3945. doi: 10.1039/C7CC01274H
	(c) Pitts A. K.; O’Hara F.; Snell R. H.; Gaunt M. J. Angew. Chem. Int. Ed. 2015, 54, 5451. doi: 10.1002/anie.v54.18
[24]	Gao W.-C.; Jiang S.; Wang R.-L.; Zhang C. Chem. Commun. 2013, 49, 4890. doi: 10.1039/c3cc40797g
[25]	Efimenko I. A.; Podobedov R. E.; Shishilov O. N.; Rezinkova Y. N.; Churakov A. V.; Kuzmina L. G.; Garbuzova I. A.; Lokshin B. V. Inorg. Chem. Commun. 2011, 14, 426. doi: 10.1016/j.inoche.2010.12.018
[26]	Wang M.; Zhao Y.; Zhao Y.; Shi Z. Sci. Adv. 2020, 6, eaba0946.
[27]	Yang Q. Q.; Xiao C.; Lu L. Q.; An J.; Tan F.; Li B. J.; Xiao W. J. Angew. Chem. Int. Ed. 2012, 51, 9137. doi: 10.1002/anie.v51.36

位阻调控的吲哚C4位甲基化和C4甲基化/羰基重排反应