Enantioselective synthesis of N-allylindoles via palladium-catalyzed allylic amination/oxidation of indolines

Abstract

A highly efficient synthesis of N-allylindoles was realized via palladium-catalyzed asymmetric allylic amination/oxidation sequential reaction of indolines. The N-alkylated indole derivatives were obtained with up to 91% yield and 97% ee.

---

Chiral indole moieties are embedded extensively in numerous biologically active natural products and pharmaceuticals, therefore the enantioselective functionalization of indoles is now becoming one of the most important research areas.¹ In this regard, enormous efforts have been made towards the synthesis of various functionalized chiral indole scaffolds in the past two decades.² For the most studied Friedel–Crafts reaction, it is well developed for the C-3 alkylation of indole because C-3 is the innately most reactive site of the indole core.³ Recently, the enantioselective C-2 alkylation of indoles was also realized.⁴ While the methods for the asymmetric synthesis of 3-substituted and 2-substituted indoles are well established, the development of catalytically enantioselective synthesis of N-substituted indoles is relatively slow.⁵

Transition-metal-catalyzed allylic substitution reaction is one of the most powerful method for the construction of C–C and C–X bonds.^6,7 During our efforts towards the asymmetric functionalization of indoles,⁸ recently, we reported the asymmetric synthesis of N-allylindoles via the iridium-catalyzed allylic alkylation/oxidation of indolines (eqn (1), Scheme 1).⁹ The method provided highly enantioenriched N-allylindoles bearing a terminal alkene, which could be utilized in the enantioselective synthesis of one diastereomer of natural product yuremamine. This two-step strategy has not been explored for other transition-metal-catalysis except for iridium. In addition, the substituted N-allylindoles are also popular structural motifs in natural alkaloids and biologically active compounds.^10,11 Therefore, in this paper, we would like to report our results on Pd-catalyzed allylic amination of indolines/oxidation sequence, providing an efficient synthesis of enantioenriched 1,3-diarylallyl indoles (eqn (2), Scheme 1).

Scheme 1 One-pot synthesis of substituted N-allylindoles via Pd-catalyzed allylic alkylation of indolines/oxidation sequence.

At the outset, indoline 1a and (E)-1,3-diphenylallyl acetate 2a were chosen as the model substrates, and the results are summarized in Table 1. In the presence of 5 mol% of [Pd(C₃H₅)Cl]₂, 11 mol% of the Phox ligand L1, and 2.0 equiv. of Na₂CO₃, the reaction of 1a with 2a in THF for 12 h gave the (E)-1,3-diphenylallyl indoline 3aa in 99% yield and 95% ee (entry 1, Table 1). The effects of chiral ligands were examined next. Ligands L2 and L4–L7 were found to be suitable ligands to afford 3aa in moderate to good yields with moderate ee (entries 2 & 4–7, Table 1). However, the reaction with ligand L3 proceeded in low yield with moderate ee (entry 3, Table 1).

Table 1 Optimization of the reaction conditions^a

Entry	Ligand	Solvent	Base	t/h	Conv.^b (%)	Yield^c (%)	ee^d (%)
a Reaction conditions: 0.24 mmol of 1a, 0.2 mmol of 2a, 0.4 mmol of base in solvent (2.0 mL) at room temperature.b Determined by ^1H NMR of the crude reaction mixture.c Isolated yield of 3aa.d Determined by HPLC analysis.
1	L1	THF	Na2CO3	12	100	99	95
2	L2	THF	Na2CO3	12	100	94	47
3	L3	THF	Na2CO3	12	90	28	50
4	L4	THF	Na2CO3	12	96	90	43
5	L5	THF	Na2CO3	12	72	70	14
6	L6	THF	Na2CO3	12	72	71	47
7	L7	THF	Na2CO3	12	100	97	86
8	L1	THF	Li2CO3	33	73	71	69
9	L1	THF	Cs2CO3	33	89	73	86
10	L1	THF	K3PO4	15	100	96	75
11	L1	THF	KOAc	15	100	90	67
12	L1	THF	DBU	15	100	60	95
13	L1	THF	Et3N	21	99	92	77
14	L1	THF	NaOAc	21	60	60	58
15	L1	THF	DABCO	21	20	—	30
16	L1	DCM	Na2CO3	23	100	93	86
17	L1	Dioxane	Na2CO3	23	100	75	91
18	L1	Toluene	Na2CO3	23	100	94	71
19	L1	Et2O	Na2CO3	23	100	93	83
20	L1	CH3CN	Na2CO3	23	83	—	62

---

In addition, various bases such as Li₂CO₃, Cs₂CO₃, K₃PO₄, KOAc, DBU, Et₃N, NaOAc and DABCO were also tested (entries 8–15, Table 1). The examination of bases led to the discovery of Na₂CO₃ as the optimal base. Meanwhile screening of various solvents (entries 16–20, Table 1) led to the identification of THF as the best solvent. After systematic optimization studies, the best reaction conditions are the following: 1a and 2a in THF with 5 mol% of [Pd(C₃H₅)Cl]₂, 11 mol% L1, and 2.0 equiv. of Na₂CO₃ at room temperature. This process produces (E)-1,3-diphenylallyl indoline 3aa in 99% yield and 95% ee (entry 1, Table 1). Next, we investigated the one-pot allylic amination of indolines/oxidation sequence. To our great delight, with DDQ as an efficient oxidant, the oxidation reaction of 3aa to 4aa went smoothly in 10 min at room temperature without loss of the optical purity, affording (E)-1,3-diphenylallyl indole 4aa in 80% yield and 95% ee (Scheme 2).

Scheme 2 One-pot synthesis of substituted N-allylindoles.

Under the above optimized reaction conditions, various substituted indolines and allylic acetates were explored to examine the generality of the process. The results are summarized in Table 2. The stereochemistry of the products was assigned as S based on an X-ray crystallographic analysis of enantiopure 4aa. The reaction of C-2 methyl substituted indoline 1b gave product 4ba in 81% yield and 96% ee (entry 2, Table 2). Notably, when indoline 1c bearing a phenyl group at the C-2 position, the reaction could also react smoothly, providing product 4ca in 53% yield and 96% ee (entry 3, Table 2). The substrates bearing either an electron-donating group (3-Me, 4-Me, 5-OMe, 7-Me) or an electron-withdrawing group (5-Cl, 6-Br) on the indoline core all reacted and gave the corresponding indole products in moderate to good yields with excellent ee (72–82% yields, 93–97% ee, entries 4–9, Table 2). When the electrophile was switched to (E)-1,3-di(para-chlorophenyl)-allylic acetate 2b, the reaction occurred smoothly to afford indole product 4ab in excellent yield and ee (91% yield, 97% ee, entry 10, Table 2). However, when (E)-1,3-dimethylallyl acetate 2c was utilized, the reaction took place with only moderate yield and ee (48% yield, 39% ee, entry 11, Table 2).

Table 2 The reaction substrate scope

Entry	1, R^1	2, R^2	4, Yield^a (%)	ee^b (%)
a Isolated yield of 4.b Determined by HPLC analysis.
1	1a, R^1 = H	2a, R^2 = Ph	4aa, 80	95
2	1b, R^1 = 2-Me	2a, R^2 = Ph	4ba, 81	96
3	1c, R^1 = 2-Ph	2a, R^2 = Ph	4ca, 53	96
4	1d, R^1 = 3-Me	2a, R^2 = Ph	4da, 72	97
5	1e, R^1 = 4-Me	2a, R^2 = Ph	4ea, 77	95
6	1f, R^1 = 5-OMe	2a, R^2 = Ph	4fa, 72	61
7	1g, R^1 = 7-Me	2a, R^2 = Ph	4ga, 82	93
8	1h, R^1 = 5-Cl	2a, R^2 = Ph	4ha, 75	97
9	1i, R^1 = 6-Br	2a, R^2 = Ph	4ia, 73	96
10	1a, R^1 = H	2b, R^2 = 4-ClC6H4	4ab, 91	97
11	1a, R^1 = H	2c, R^2 = Me	4ac, 48	39

---

The kinetic resolution reaction of C-2 methyl substituted indoline 1b has also been carried out. To our disappointment, under the optimized reaction conditions, indoline 1b was recovered in 31% yield with only 4% ee (Scheme 3).

Scheme 3 The kinetic resolution reaction with substrate 1b.

In summary, we have developed a highly efficient synthesis of enantio-enriched N-1,3-diarylallyl indoles via palladium-catalyzed enantioselective allylic amination of indolines/oxidation sequence. The N-alkylated indole derivatives were obtained with up to 91% yield and 97% ee. Further studies on the substrate scope and applications of the enantioenriched N-allylindoles are currently underway in our laboratory.

Acknowledgements

We thank the National Basic Research Program of China (973 Program 2010CB833300) and the National Natural Science Foundation of China (21025209, 21121062, 21332009) for generous financial support.

Notes and references

1. (a) J. Bosch and M.-L. Bennasar, Synlett, 1995, 587; (b) J. A. Joule and K. Mills, Heterocyclic Chemistry, Blackwell Science, Oxford, 4th edn, 2000; (c) D. J. Faulkner, Nat. Prod. Rep., 2002, 19, 1; (d) M. Somei and F. Yamada, Nat. Prod. Rep., 2004, 21, 278; (e) S. Agarwal, S. Cammerer, S. Filali, W. Frohner, J. Knoll, M. P. Krahl, K. R. Reddy and H.-J. Knolker, Curr. Org. Chem., 2005, 9, 1601; (f) S. E. O'Connor and J. J. Maresh, Nat. Prod. Rep., 2006, 23, 532; (g) A. J. Kochanowska-Karamyan and M. T. Hamann, Chem. Rev., 2010, 110, 4489.
2. For reviews, see: (a) M. Bandini, A. Melloni and A. Umani-Ronchi, Angew. Chem., Int. Ed., 2004, 43, 550; (b) T. B. Poulsen and K. A. Jørgensen, Chem. Rev., 2008, 108, 2903; (c) S.-L. You, Q. Cai and M. Zeng, Chem. Soc. Rev., 2009, 38, 2190; (d) M. Bandini and A. Eichholzer, Angew. Chem., Int. Ed., 2009, 48, 9608; (e) M. Zeng and S.-L. You, Synlett, 2010, 1289.
3. For selected examples of asymmetric C-3 alkylation of indoles, see: (a) J. Zhou and Y. Tang, J. Am. Chem. Soc., 2002, 124, 9030; (b) J. F. Austin and D. W. C. MacMillan, J. Am. Chem. Soc., 2002, 124, 1172; (c) D. A. Evans, K. R. Fandrick and H.-J. Song, J. Am. Chem. Soc., 2005, 127, 8942; (d) Y.-Q. Wang, J. Song, R. Hong, H. Li and L. Deng, J. Am. Chem. Soc., 2006, 128, 8156; (e) Y.-X. Jia, J. Zhong, S.-F. Zhu, C.-M. Zhang and Q.-L. Zhou, Angew. Chem., Int. Ed., 2007, 46, 5565; (f) M. Rueping, B. J. Nachtsheim, S. A. Moreth and M. Bolte, Angew. Chem., Int. Ed., 2008, 47, 593; (g) J. Itoh, K. Fuchibe and T. Akiyama, Angew. Chem., Int. Ed., 2008, 47, 4016; (h) P. Bachu and T. Akiyama, Chem. Commun., 2010, 46, 4112; (i) G. Cera, M. Chiarucci, A. Mazzanti, M. Mancinelli and M. Bandini, Org. Lett., 2012, 14, 1350; (j) S. Zhu and D. W. C. MacMillan, J. Am. Chem. Soc., 2012, 134, 10815; (k) Y.-M. Wang, J. Wu, C. Hoong, V. Rauniyar and F. D. Toste, J. Am. Chem. Soc., 2012, 134, 12928; (l) J.-R. Gao, H. Wu, B. Xiang, W.-B. Yu, L. Han and Y.-X. Jia, J. Am. Chem. Soc., 2013, 135, 2983; (m) J. E. Spangler and H. M. L. Davies, J. Am. Chem. Soc., 2013, 135, 6802; (n) H. Xiong, H. Xu, S. Liao, Z. Xie and Y. Tang, J. Am. Chem. Soc., 2013, 135, 7851.
4. Selected recent examples: (a) M. S. Taylor and E. N. Jacobsen, J. Am. Chem. Soc., 2004, 126, 10558; (b) J. Seayad, A. M. Seayad and B. List, J. Am. Chem. Soc., 2006, 128, 1086; (c) M. J. Wanner, R. N. S. van der Haas, K. R. de Cuba, J. H. van Maarseveen and H. Hiemstra, Angew. Chem., Int. Ed., 2007, 46, 7485; (d) D. A. Evans, K. R. Fandrick, H.-J. Song, K. A. Scheidt and R. Xu, J. Am. Chem. Soc., 2007, 129, 10029; (e) I. T. Raheem, P. S. Thiara, E. A. Peterson and E. N. Jacobsen, J. Am. Chem. Soc., 2007, 129, 13404; (f) S. Lee and D. W. C. MacMillan, J. Am. Chem. Soc., 2007, 129, 15438; (g) Q. Kang, X.-J. Zheng and S.-L. You, Chem.–Eur. J., 2008, 14, 3539; (h) M. Zeng, Q. Kang, Q.-L. He and S.-L. You, Adv. Synth. Catal., 2008, 350, 2169; (i) D. J. Mergott, S. J. Zuend and E. N. Jacobsen, Org. Lett., 2008, 10, 745; (j) I. T. Raheem, P. S. Thiara and E. N. Jacobsen, Org. Lett., 2008, 10, 1577; (k) N. V. Sewgobind, M. J. Wanner, S. Ingemann, R. de Gelder, J. H. van Maarseveen and H. Hiemstra, J. Org. Chem., 2008, 73, 6405; (l) Y.-F. Sheng, G.-Q. Li, Q. Kang, A.-J. Zhang and S.-L. You, Chem.–Eur. J., 2009, 15, 3351; (m) L. Hong, C. Liu, W. Sun, L. Wang, K. Wong and R. Wang, Org. Lett., 2009, 11, 2177; (n) L. Hong, W. Sun, C. Liu, L. Wang, K. Wong and R. Wang, Chem.–Eur. J., 2009, 15, 11105; (o) D. Huang, F. Xu, X. Lin and Y. Wang, Chem.–Eur. J., 2012, 18, 3148; (p) M. Zeng, W. Zhang and S. You, Chin. J. Chem., 2012, 30, 2615; (q) H.-G. Cheng, L.-Q. Lu, T. Wang, Q.-Q. Yang, X.-P. Liu, Y. Li, Q.-H. Deng, J.-R. Chen and W.-J. Xiao, Angew. Chem., Int. Ed., 2013, 52, 3250; (r) Y. Zhang, X. Liu, X. Zhao, J. Zhang, L. Zhou, L. Lin and X. Feng, Chem. Commun., 2013, 49, 11311.
5. (a) B. M. Trost, M. J. Krische, V. Berl and E. M. Grenzer, Org. Lett., 2002, 4, 2005; (b) M. Bandini, A. Eichholzer, M. Tragni and A. Umani-Ronchi, Angew. Chem., Int. Ed., 2008, 47, 3238; (c) H.-L. Cui, X. Feng, J. Peng, J. Lei, K. Jiang and Y.-C. Chen, Angew. Chem., Int. Ed., 2009, 48, 5737; (d) L. M. Stanley and J. F. Hartwig, Angew. Chem., Int. Ed., 2009, 48, 7841; (e) D. Enders, C. Wang and G. Raabe, Synthesis, 2009, 4119; (f) L. Hong, W. Sun, C. Liu, L. Wang and R. Wang, Chem.–Eur. J., 2010, 16, 440; (g) B. M. Trost, M. Osipov and G. Dong, J. Am. Chem. Soc., 2010, 132, 15800; (h) Q. Cai, C. Zheng and S.-L. You, Angew. Chem., Int. Ed., 2010, 49, 8666; (i) M. Bandini, A. Bottoni, A. Eichholzer, G. P. Miscione and M. Stenta, Chem.–Eur. J., 2010, 16, 12462; (j) Y. Xie, Y. Zhao, B. Qian, L. Yang, C. Xia and H. Huang, Angew. Chem., Int. Ed., 2011, 50, 5682; (k) Y.-C. Shi, S.-G. Wang, Q. Yin and S.-L. You, Org. Chem. Front., 2014, 1 10.1039/c3qo00008g.
6. For reviews: (a) B. M. Trost and D. L. Van Vranken, Chem. Rev., 1996, 96, 395; (b) B. M. Trost and M. L. Crawley, Chem. Rev., 2003, 103, 2921; (c) Z. Lu and S. Ma, Angew. Chem., Int. Ed., 2008, 47, 258; (d) B. M. Trost, T. Zhang and J. D. Sieber, Chem. Sci., 2010, 1, 427.
7. Selected examples for transition-metal-catalyzed allylic substitution reactions with indoles: (a) M. Bandini, A. Melloni and A. Umani-Ronchi, Org. Lett., 2004, 6, 3199; (b) M. Kimura, M. Futamata, R. Mukai and Y. Tamaru, J. Am. Chem. Soc., 2005, 127, 4592; (c) N. Kagawa, J. P. Malerich and V. H. Rawal, Org. Lett., 2008, 10, 2381; (d) M. Bandini and A. Eichholzer, Angew. Chem., Int. Ed., 2009, 48, 9533; (e) B. Sundararaju, M. Achard, B. Demerseman, L. Toupet, G. V. M. Sharma and C. Bruneau, Angew. Chem., Int. Ed., 2010, 49, 2782; (f) M. Bandini, A. Bottoni, M. Chiarucci, G. Cera and G. P. Miscione, J. Am. Chem. Soc., 2012, 134, 20690; (g) Y. Liu and H. Du, Org. Lett., 2013, 15, 740; (h) T. D. Montgomery, Y. Zhu, N. Kagawa and V. H. Rawal, Org. Lett., 2013, 15, 1140; (i) Q.-L. Xu, C.-X. Zhuo, L.-X. Dai and S.-L. You, Org. Lett., 2013, 15, 5909.
8. Selected examples from our group: (a) Q. Kang, Z.-A. Zhao and S.-L. You, J. Am. Chem. Soc., 2007, 129, 1484; (b) Q. Cai, Z.-A. Zhao and S.-L. You, Angew. Chem., Int. Ed., 2009, 48, 7428; (c) Q.-F. Wu, H. He, W.-B. Liu and S.-L. You, J. Am. Chem. Soc., 2010, 132, 11418; (d) Q. Cai, C. Zheng, J.-W. Zhang and S.-L. You, Angew. Chem., Int. Ed., 2011, 50, 8665; (e) Q. Yin and S.-L. You, Chem. Sci., 2011, 2, 1344; (f) Q. Cai, C. Liu, X.-W. Liang and S.-L. You, Org. Lett., 2012, 14, 4588; (g) Q.-F. Wu, C. Zheng and S.-L. You, Angew. Chem., Int. Ed., 2012, 51, 1680; (h) C.-X. Zhuo, Q.-F. Wu, Q. Zhao, Q.-L. Xu and S.-L. You, J. Am. Chem. Soc., 2013, 135, 8169; (i) Q.-L. Xu, L.-X. Dai and S.-L. You, Chem. Sci., 2013, 4, 97; (j) X. Zhang, L. Han and S.-L. You, Chem. Sci., 2014, 5, 1059.
9. (a) W.-B. Liu, X. Zhang, L.-X. Dai and S.-L. You, Angew. Chem., Int. Ed., 2012, 51, 5183; (b) For pioneering studies on synthesis of N-alkylated indoles via alkylation/oxidation of indolines, see: S. Bayindir, E. Erdogan, H. Kilic and N. Saracoglu, Synlett, 2010, 1455; (c) H. Kilic, S. Bayindir, E. Erdogan and N. Saracoglu, Tetrahedron, 2012, 68, 5619; (d) For a recent asymmetric study: A. K. Ghosh and B. Zhu, Tetrahedron Lett., 2013, 54, 3500.
10. For a review, see: U. Galm, M. H. Hager, S. G. van Lanen, J. Ju, J. S. Thorson and B. Shen, Chem. Rev., 2005, 105, 739.
11. Selected examples: (a) F. Tillequin, M. Koch, M. Bert and T. Sevenet, J. Nat. Prod., 1979, 42, 92; (b) E. O. M. Orlemans, W. Verboom, M. W. Scheltinga, D. N. Reinhoudt, P. Lelieveld, H. H. Fiebig, B. R. Winterhalter, J. A. Double and M. C. Bibby, J. Med. Chem., 1989, 32, 1612; (c) D. Paris, M. Cottin, P. Demonchaux, G. Augert, P. Dupassieux, P. Lenoir, M. J. Peck and D. Jasserand, J. Med. Chem., 1995, 38, 669; (d) P. E. Mahaney, A. T. Vu, C. C. McComas, P. Zhang, L. M. Nogle, W. L. Watts, A. Sarkahian, L. Leventhal, N. R. Sullivan, A. J. Uveges and E. J. Trybulski, Bioorg. Med. Chem., 2006, 14, 8455; (e) L. S. Fernandez, M. S. Buchanan, A. R. Carroll, Y. J. Feng, R. J. Quinn and V. M. Avery, Org. Lett., 2009, 11, 329.

---

Footnote

† Electronic supplementary information (ESI) available. CCDC 979724. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ra00701h

---