Pd-Catalyzed [3＋2] Cycloaddition/Dearomatization of Indole-3-carboxylates with Trimethylenemethane

doi:10.6023/cjoc202602022

Abstract

A formal [3＋2] cycloaddition between indole-3-carboxylate derivatives and trimethylenemethane (TMM) donor is disclosed. The reaction proceeds smoothly in toluene at ambient conditions via a Pd-catalyzed dearomatization process, delivering a series of substituted 2,3-fused cyclopentannulated indolines (up to 99% yield). The reaction exhibits high functional group tolerance for indole derivatives under the standard conditions. Remarkably, the synthetic utility of this method was demonstrated by transformation of the products such as hydrolysis of ester, removal of Ts group, Sonogashira coupling reaction and reduction of ester and halogen.

Key words: cycloaddition, dearomatization, indole, palladium catalysis, trimethylenemethane

Cite this article

Qingxia Zhang, Jiahao Xie, Qing Gu, Shuli You. Pd-Catalyzed [3＋2] Cycloaddition/Dearomatization of Indole-3-carboxylates with Trimethylenemethane[J]. Chinese Journal of Organic Chemistry, 2026, 46(9): 3759-3768.

Export EndNote|Reference Manager|ProCite|BibTeX|RefWorks

share this article

Fig. & Tab. 7

References 10

[1]	For selected reviews, see: (a) Zhang, D.; Song, H.; Qin, Y. Acc. Chem. Res. 2011, 44, 447. doi: 10.1021/ar200004w
	(b) Kaushik, N. K.; Kaushik, N.; Attri,, P.; Kumar, N.; Kim, C. H.; Verma, A. K.; Choi, E. H. Molecules 2013, 18, 6620. doi: 10.3390/molecules18066620
	(c) Blaising, J.; Polyak, S. J.; Pecheur, E.-I. Antiviral Res 2014, 107, 84. doi: 10.1016/j.antiviral.2014.04.006
	(d) Zhang, M.-Z.; Chen, Q.; Yang, G.-F. Eur. J. Med. Chem. 2015, 89, 421. doi: 10.1016/j.ejmech.2014.10.065
	(e) Thakur, A.; Singh, A.; Kaur, N.; Ojha, R.; Nepali, K. Bioorg. Chem. 2020, 94, 103436. doi: 10.1016/j.bioorg.2019.103436
	(f) Nieto, M. J.; Lupton, H. K. Curr. Med. Chem. 2021, 28, 4828. doi: 10.2174/0929867327666201102114923
	(g) Hawash, M. Biomolecules 2022, 12, 1843. doi: 10.3390/biom12121843
[2]	For selected reviews on dearomatization reaction, see: (a) Zhuo, C.-X.; Zheng, C.; You, S.-L. Acc. Chem. Res. 2014, 47, 2558. doi: 10.1021/ar500167f
	(b) Sun, W.; Li, G.; Hong, L.; Wang, R. Org. Biomol. Chem. 2016, 14, 2164. doi: 10.1039/C5OB02526E
	(c) Wu, W.-T.; Zhang, L.; You, S.-L. Chem. Soc. Rev. 2016, 45, 1570. doi: 10.1039/C5CS00356C
	(d) Huang, G.; Yin, B. Adv. Synth. Catal. 2018, 361, 405. doi: 10.1002/adsc.v361.3
	(e) Sheng, F.-T.; Wang, J.-Y.; Tan, W.; Zhang, Y.-C.; Shi, F. Org. Chem. Front. 2020, 7, 3967. doi: 10.1039/D0QO01124J
	(f) Wang, Z. Org. Biomol. Chem. 2020, 18, 4354. doi: 10.1039/D0OB00818D
	(g) Zheng, C.; You, S.-L. ACS Cent. Sci. 2021, 7, 432. doi: 10.1021/acscentsci.0c01651
	(h) Liu, Y.-Z.; Song, H.; Zheng, C.; You, S.-L. Nat. Synth. 2022, 1, 203. doi: 10.1038/s44160-022-00039-y
	(i) Pang, M.; Chang, H.; Feng, Z.; Zhang, J. Chin. J. Org. Chem. 2023, 43, 1271 (in Chinese).
	庞明杨, 常宏宏, 冯璋, 张娟, 有机化学, 2023, 43, 1271). doi: 10.6023/cjoc202210026
	(j) Cheng, Y.-Z.; Li, M.; Wang, R.-X.; Zhu, L.-H.; Shen, W.-J.; Zou, X.-X.; Gu, Q.; You, S.-L. Prog. Chem. 2024, 36, 1785.
[3]	(a) Trost, B. M.; Ehmke, V.; O'Keefe, B. M.; Bringley, D. A. J. Am. Chem. Soc. 2014, 136, 8213. doi: 10.1021/ja5044825
	For a recent example of related dearomatization, see:(b) Zeng, W.-L.; Xia, Q.; Li, C.-Q.; Wang, M.-Y.; Jin, W.-Y.; Ding, H.; Li, W. J. Am. Chem. Soc. 2024, 146, 30764. doi: 10.1021/jacs.4c12303
[4]	For selected examples on metal-catalyzed dearomatization reaction of 3-nitroindoles, see: (a) Awata, A.; Arai, T. Angew. Chem., Int. Ed. 2014, 53, 10462. doi: 10.1002/anie.v53.39 pmid: 28418676
	(b) Zhao, J.-Q.; Zhou, M.-Q.; Wu, Z.-J.; Wang, Z.-H.; Yue, D.-F.; Xu, X.-Y.; Zhang, X.-M.; Yuan, W.-C. Org. Lett. 2015, 17, 2238. doi: 10.1021/acs.orglett.5b00850 pmid: 28418676
	(c) Gerten, A. L.; Stanley, L. M. Org. Chem. Front. 2016, 3, 339. doi: 10.1039/C5QO00346F pmid: 28418676
	(d) Gee, Y. S.; Rivinoja, D. J.; Wales, S. M.; Gardiner, M. G.; Ryan, J. H.; Hyland, C. J. T. J. Org. Chem. 2017, 82, 13517. doi: 10.1021/acs.joc.7b02624 pmid: 28418676
	(e) Laugeois, M.; Ling, J.; Ferard, C.; Michelet, V.; Ratovelomanana- Vidal, V.; Vitale, M. R. Org. Lett. 2017, 19, 2266. doi: 10.1021/acs.orglett.7b00784 pmid: 28418676
	(f) Rivinoja, D. J.; Gee, Y. S.; Gardiner, M. G.; Ryan, J. H.; Hyland, C. J. T. ACS Catal. 2017, 7, 1053. doi: 10.1021/acscatal.6b03248 pmid: 28418676
	(g) Sun, M.; Zhu, Z.-Q.; Gu, L.; Wan, X.; Mei, G.-J.; Shi, F. J. Org. Chem. 2018, 83, 2341. doi: 10.1021/acs.joc.7b03259 pmid: 28418676
	(h) Zhang, J.-Q.; Tong, F.; Sun, B.-B.; Fan, W.-T.; Chen, J.-B.; Hu, D.; Wang, X.-W. J. Org. Chem. 2018, 83, 2882. doi: 10.1021/acs.joc.8b00046 pmid: 28418676
	(i) Suo, J.-J.; Liu, W.; Du, J.; Ding, C.-H.; Hou, X.-L. Chem.-Asian J. 2018, 13, 959. doi: 10.1002/asia.v13.8 pmid: 28418676
	(j) Suo, J.-J.; Du, J.; Jiang, Y.-J.; Chen, D.; Ding, C.-H.; Hou, X.-L. Chin. Chem. Lett. 2019, 30, 1512. doi: 10.1016/j.cclet.2019.04.028 pmid: 28418676
	(k) Ling, J.; Mara, D.; Roure, B.; Laugeois, M.; Vitale, M. R. J. Org. Chem. 2020, 85, 3838. doi: 10.1021/acs.joc.9b03459 pmid: 28418676
	(l) Xie, J.-H.; Zheng, C.; You, S.-L. Angew. Chem., Int. Ed. 2021, 60, 22184. doi: 10.1002/anie.v60.41 pmid: 28418676
	(m) Wan, Q.; Xie, J.-H.; Zheng, C.; Yuan, Y.-F.; You, S.-L. Angew. Chem., Int. Ed. 2021, 60, 19730. doi: 10.1002/anie.v60.36 pmid: 28418676
	(n) Pandit, S.; Pandey, V. K.; Adhikari, A. S.; Kumar, S.; Maurya, A. K.; Kant, R.; Majumdar, N. J. Org. Chem. 2023, 88, 97. doi: 10.1021/acs.joc.2c01869 pmid: 28418676
	(o) Dou, P.-H.; Fu, X.-H.; Chen, Y.; Ge, Z.-Z.; Zhou, M.-Q.; Wang, Z.-H.; You, Y.; Yang, L.; Zhang, Y.-P.; Zhao, J.-Q.; Yuan, W.-C. Org. Lett. 2024, 26, 3310. doi: 10.1021/acs.orglett.4c01003 pmid: 28418676
	(p) Chen, Y.; Zhang, X.-H.; Wang, Z.-H.; Yang, L.; You, Y.; Zhao, J.-Q.; Zhou, M.-Q.; Lu, J.-H.; Yin, J.-Q.; Yuan, W.-C. Org. Lett. 2025, 27, 11776. doi: 10.1021/acs.orglett.5c03560 pmid: 28418676
[5]	For selected examples on organocatalyzed or metal-free catalyzed dearomatization reaction of 3-nitroindoles, see: (a) Andreini, M.; De Paolis, M.; Chataigner, I. Catal. Commun. 2015, 63, 15. doi: 10.1016/j.catcom.2014.07.042
	(b) Li, Y.; Tur, F.; Nielsen, R. P.; Jiang, H.; Jensen, F.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2016, 55, 1020. doi: 10.1002/anie.v55.3
	(c) Yue, D.-F.; Zhao, J.-Q.; Chen, X.-Z.; Zhou, Y.; Zhang, X.-M.; Xu, X.-Y.; Yuan, W.-C. Org. Lett. 2017, 19, 4508. doi: 10.1021/acs.orglett.7b02068
	(d) Liu, X.; Yang, D.; Wang, K.; Zhang, J.; Wang, R. Green Chem. 2017, 19, 82. doi: 10.1039/C6GC02517J
	(e) Li, K.; Goncalves, T. P.; Huang, K.-W.; Lu, Y. Angew. Chem., Int. Ed. 2019, 58, 5427. doi: 10.1002/anie.v58.16
	(f) Wang, H.; Zhang, J.; Tu, Y.; Zhang, J. Angew. Chem., Int. Ed. 2019, 58, 5422. doi: 10.1002/anie.v58.16
	(g) Mei, M.-S.; Wang, Y.-H.; Hu, Q.; Li, Q.-H.; Shi, D.-Y.; Gao, D.; Ge, G.; Lin, G.-Q.; Tian, P. Chem. Commun. 2020, 56, 10718. doi: 10.1039/D0CC04462H
	(h) Huang, H.; Li, Q.-Z.; Liu, Y.-Q.; Leng, H.-J.; Xiang,, P.; Dai, Q.-S.; He, X.-H.; Huang, W.; Li, J.-L. Org. Chem. Front. 2020, 7, 3862. doi: 10.1039/D0QO00868K
	(i) Wang, H.; Hu, Q.; Wang, M.; Guo, C. iScience 2020, 23, 100840. doi: 10.1016/j.isci.2020.100840
	(j) Dai, X.; Zhang, F.; Dai, L.; Lu, Y. CCS Chem. 2023, 5, 2023. doi: 10.31635/ccschem.023.202302806
[6]	For selected reviews on electron-deficient indoles, see: (a) Cerveri, A.; Bandini, M. Chin. J. Chem. 2020, 38, 287. doi: 10.1002/cjoc.v38.3
	(b) Rkein, B.; Bigot, A.; Birbaum, L.; Manneveau, M.; De Paolis, M.; Legros, J.; Chataigner, I. Chem. Commun. 2021, 57, 27. doi: 10.1039/D0CC06658C
	(c) Wang, N.; Ren, J.; Li, K. Eur. J. Org. Chem. 2022, 2022, e202200039.
	(d) Wang, H.; Xie, H.; Guo, S.-M.; Duan, R.; Lin, Y.-W.; Zhang, J. Org. Chem. Front. 2026, 13, 1458. doi: 10.1039/D5QO01566A
[7]	Cheng, Q.; Zhang, F.; Cai, Y.; Guo, Y.-L.; You, S.-L. Angew. Chem., Int. Ed. 2018, 57, 2134. doi: 10.1002/anie.v57.8
[8]	Zhang, Q.-X.; Gu, Q.; You, S.-L. Org. Lett. 2022, 24, 8031. doi: 10.1021/acs.orglett.2c03262
[9]	Zhang, Q.-X.; Li, Y.; Wang, J.; Yang, C.; Liu, C.-J.; Li, X.; Cheng, J.-P. Angew. Chem., Int. Ed. 2020, 59, 4550. doi: 10.1002/anie.v59.11
[10]	Porcu, S.; Luridiana, A.; Martis, A.; Frongia, A.; Sarais, G.; Aitken, D. J.; Boddaert, T.; Guillot, R.; Secci, F. Chem. Commun. 2018, 54, 13547. doi: 10.1039/C8CC07571A

Entry	Ligand	Solvent	[Pd]	t/h	Yield^b/%
1	L1	Toluene	Pd₂dba₃	5	>95
2	L2^d	Toluene	Pd₂dba₃	36	n.d.^c
3	L3^e	Toluene	Pd₂dba₃	36	n.d.^c
4	L4^f	Toluene	Pd₂dba₃	36	n.d.^c
5	L5^g	Toluene	Pd₂dba₃	36	n.d.^c
6	L6^h	Toluene	Pd₂dba₃	36	n.d.^c
7	L1	THF	Pd₂dba₃	16	93
8	L1	1,4-Dioxane	Pd₂dba₃	6	94
9	L1	DCM	Pd₂dba₃	16	52
10	L1	CH₃CN	Pd₂dba₃	16	29
11	L1	Toluene	Pd(dba)₂	5	92
12ⁱ	L1	Toluene	Pd₂dba₃	5	94
13ⁱ^,^j	L1	Toluene	Pd₂dba₃	9	95
14ⁱ^,^j^,^k	L1	Toluene	Pd₂dba₃	10	95^l

Entry	Ligand	Solvent	[Pd]	t/h	Yield^b/%
1	L1	Toluene	Pd₂dba₃	5	>95
2	L2^d	Toluene	Pd₂dba₃	36	n.d.^c
3	L3^e	Toluene	Pd₂dba₃	36	n.d.^c
4	L4^f	Toluene	Pd₂dba₃	36	n.d.^c
5	L5^g	Toluene	Pd₂dba₃	36	n.d.^c
6	L6^h	Toluene	Pd₂dba₃	36	n.d.^c
7	L1	THF	Pd₂dba₃	16	93
8	L1	1,4-Dioxane	Pd₂dba₃	6	94
9	L1	DCM	Pd₂dba₃	16	52
10	L1	CH₃CN	Pd₂dba₃	16	29
11	L1	Toluene	Pd(dba)₂	5	92
12ⁱ	L1	Toluene	Pd₂dba₃	5	94
13ⁱ^,^j	L1	Toluene	Pd₂dba₃	9	95
14ⁱ^,^j^,^k	L1	Toluene	Pd₂dba₃	10	95^l

Entry	Substrate	Temp./℃	t/h	Yield^b/%	ee^c/%
1	1a	25	0.5	92	39
2	1a	0	1.5	90	53
3	1a	-20	4	93	59
4	1a	-40	24	90	63
5	1f	-20	24	97	61
6	1h	-20	24	93	61

Entry	Substrate	Temp./℃	t/h	Yield^b/%	ee^c/%
1	1a	25	0.5	92	39
2	1a	0	1.5	90	53
3	1a	-20	4	93	59
4	1a	-40	24	90	63
5	1f	-20	24	97	61
6	1h	-20	24	93	61

[1]	Ming Lü, Bodi Zhao, Minghao Xu, Xiaotian Qi. Diastereoselectivity Control in Stepwise [2＋2] Cycloadditions of Oxazolones with Alkenes: A Theoretical Study of Non-covalent Interactions [J]. Chinese Journal of Organic Chemistry, 2026, 46(9): 3731-3736.
[2]	Jingrui He, Yunxin Wang, Haibo Mei, Jianlin Han. Electrochemical Direct Acyloxylation of Indoles with Ammonium Carboxylates as Acyloxyl Sources [J]. Chinese Journal of Organic Chemistry, 2026, 46(9): 3578-3586.
[3]	Qianwei Zhang, Ling-Quan Kong, Zili Chen, Zhi-Xiang Yu. Mechanistic Study of the Formal [6＋2−1] Cycloaddition of Benzoquinones and Alkynes to Tropones [J]. Chinese Journal of Organic Chemistry, 2026, 46(9): 3624-3629.
[4]	Xuepeng Fu, Jianshu Wang, Shuqing Chen, Honggang Cheng, Qianghui Zhou. Precise Synthesis of Multisubstituted Indoles Enabled by Palladium/Norbornene Cooperative Catalysis [J]. Chinese Journal of Organic Chemistry, 2026, 46(8): 3053-3067.
[5]	Lei Tang, Gang Zhao. Silver-Catalyzed Asymmetric Cycloaddition Reaction of Difluoro- methyl Containing Vinyl Indoles and Azodicarboxylates [J]. Chinese Journal of Organic Chemistry, 2026, 46(8): 3255-3267.
[6]	Lingyue Li, Jiapei Zhang, Shuo Zhang, Luyuan Cui, Xigong Liu, Lei Liu. Ligand-Free Copper-Catalyzed Oxidative Rearrangement of Tetrahydro-β-carbolines [J]. Chinese Journal of Organic Chemistry, 2026, 46(7): 2789-2795.
[7]	Kai-Kai Zhao, Run-Qi Fan, Guo-Qiang Lin, Chen-Guo Feng. Synthesis of tert-Butyl Sulfoxide-Oxazoline Ligands and Their Application in Palladium-Catalyzed Asymmetric Allylic Alkylation [J]. Chinese Journal of Organic Chemistry, 2026, 46(6): 2458-2463.
[8]	Chao Zhang, Zhou Luo, Shen Zhao, An Shen, Guoqiang Yang, Yuanyuan Liu. Constructing Chiral Indanes by a Ligand Relay-Enabled Pd-Catalyzed Asymmetric [4+1] Annulation via Carbene Insertion/Tsuji-Trost Cascade [J]. Chinese Journal of Organic Chemistry, 2026, 46(6): 2431-2441.
[9]	Tianmeng Jia, Shuai Sun, Wei Sun, Yijin Su. Three-Component Reaction of N-Acylalkylpyridinium Bromides, Conjugated Alkynyl Carbonyl Compounds and Alcohols for the Synthesis of 3-Alkyl Indolizines: Air as Oxidant [J]. Chinese Journal of Organic Chemistry, 2026, 46(6): 2387-2398.
[10]	Pengfei Yang, Yuting Ma, Wanxin Xu, Yumeng Sun, Hailing Yang. Deprotection of N-Acyl Indole-Type Amides Based on Si—O Bond Cleavage [J]. Chinese Journal of Organic Chemistry, 2026, 46(5): 2112-2120.
[11]	Panpan Guo, Yabo Zhang, Wenhe Shi, Liangjun Chen, Ran Guo. Amine-Catalyzed Addition Reaction of Isatins with Allenoates for the Synthesis of Enyne-Containing 3-Hydroxyoxindoles [J]. Chinese Journal of Organic Chemistry, 2026, 46(5): 2051-2058.
[12]	Dan Yang, Tianzhen Li, Jingyi Bai, Honghao Zhang, Feng Shi. Visible-Light Photoredox-Catalyzed Reductive Dearomatization of Indoles [J]. Chinese Journal of Organic Chemistry, 2026, 46(4): 1699-1712.
[13]	Yi-Fan Tan, Lei Jiao. Palladium-Catalyzed Radical Reactions via Pd(I) Pathway: A Brief Summary of Reaction Patterns and Recent Progress [J]. Chinese Journal of Organic Chemistry, 2026, 46(4): 1303-1319.
[14]	Xin Chen, Shutao Wang, Wen-Peng Yang, Chuyang Wang, Xin-Hua Duan, Li-Na Guo. Visible-Light Induced Copper-Catalyzed C—C Bond Cleavage/Coupling of Spiro Dihydroquinazolinones with Isatins: a Synthetic Method to 3-Alkyl-3-hydroxy-2-oxindoles [J]. Chinese Journal of Organic Chemistry, 2026, 46(4): 1685-1698.
[15]	Cui Wei, Jinqiu Liu, Can Deng, Ning Zou, Wenjun Zhou. Recent Advances on the Synthesis of Spirofluorene-Based Compounds [J]. Chinese Journal of Organic Chemistry, 2026, 46(3): 817-839.

钯催化吲哚-3-羧酸酯和三亚甲基甲烷的环加成去芳构化反应