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Cite this: Org. Chem. Front., 2014, 1, 39

N-alkylation of indole via ring-closing metathesis/ isomerization/Mannich cascade under ruthenium/ chiral phosphoric acid sequential catalysis†
Yan-Chao Shi, Shou-Guo Wang, Qin Yin and Shu-Li You*
A sequential catalysis by combining the Zhan-1B catalyst with chiral phosphoric acid has been utilized for N-alkylation of indole through a ring-closing metathesis/double bond isomerization/Mannich reaction cascade. Enantioenriched γ-lactams were synthesized in up to 92% yield and 95% ee.

Published on 23 December 2013. Downloaded on 29/03/2014 02:14:45.

Received 8th October 2013, Accepted 25th October 2013 DOI: 10.1039/c3qo00008g rsc.li/frontiers-organic

Introduction
Cascade reactions have broad applications in organic synthesis,1 often reduce time, labor and waste, and enable the construction of complex targets from simple starting materials. It has been proved to be a very efficient strategy to synthesize the indole alkaloids through cascade reactions involving the alkylation of indole.2 Recently, the combination of transition-metal catalyst and chiral phosphoric acid (CPA) has become a subject of intense research for developing new transformations beyond the utilization of the single catalytic system.3,4 Inspired by the pioneering work of Xiao and coworkers on the Ru-catalyzed tandem cross-metathesis/intramolecular Friedel–Crafts alkylation of indoles,5 we recently introduced a sequential catalysis involving a Ru-complex and chiral phosphoric acid.6 Several transformations on the asymmetric alkylation of indole have been realized. However, in general, the asymmetric N-alkylation of indole has been much less explored than the asymmetric Friedel–Crafts alkylation reaction of indole at the C3 position.7,8 To be noted, an elegant chiral phosphoric acid catalyzed isomerization of α,β-unsaturated lactam to N-acyl iminium in an enantioselective N-H functionalization of indoles was reported by Huang and co-workers (Scheme 1, top).9 As part of our research program towards the efficient asymmetric transformation of indoles,10 we envisaged that a sequential catalysis combining a Ru-catalyst and chiral phosphoric acid might be able to realize the N-alkylation of indole in a more efficient fashion by employing readily available starting materials (Scheme 1, bottom).

State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China. E-mail: slyou@sioc.ac.cn; Fax: (+86) 21-54925087 † Electronic supplementary information (ESI) available. See DOI: 10.1039/ c3qo00008g

To test our hypothesis, N-allyl-N-benzylacrylamide 1 was treated with 1.2 equivalents of indole (2a) in the presence of 5 mol% chiral phosphoric acid 4a and 5 mol% Zhan-1B in toluene. After stirring at room temperature for 3 days, the reaction gave the desired product 3a in 23% yield and 78% ee (entry 1, Table 1). Prolonging the reaction time to 7 days, the yield of 3a was improved to 52% without decreasing the enantioselectivity (78% ee) (entry 2, Table 1). When the reaction temperature was increased to 50 °C, starting material 1 disappeared after 24 h and the product was obtained in 67% yield and 78% ee (entry 3, Table 1). Under these reaction conditions, more chiral phosphoric acids were tested. First, a series of (S)-BINOL-derived chiral phosphoric acids was tested (entries 1–10, Table 1). The 4-(tert-butyl)-2,6-diisopropylphenyl substituted phosphoric acid afforded an improved enantioselectivity (81% ee, entry 10, Table 1). The sterically congested phosphoric acid catalysts might be crucial for the enantioselective control. Then the (R)-SPINOL-derived phosphoric acids (entries 11–13, Table 1) were screened. To our great delight, the reaction with catalyst 5c bearing 2,4,6triisopropylphenyl groups led to the best combination of yield and enantioselectivity (76% yield, 92% ee, entry 13, Table 1). Examination of the reaction temperatures revealed that the enantioselectivity was not influenced at lower temperature (entries 1 and 2, Table 2) but decreased at higher temperatures (entries 1, 3 and 4, Table 2). The yields decreased at 30 °C and 110 °C comparing to those at 50 °C and 80 °C. Investigation of the ruthenium catalysts disclosed that both the Grubbs II and Hoveyda–Grubbs II catalysts gave excellent enantioselectivity. The Hoveyda–Grubbs II catalyst could give a comparable yield (entry 6, Table 2) but the reaction with Grubbs II catalyst resulted in a lower yield (entry 5, Table 2). The reactions in benzene and o-xylene (entries 7 and 8, Table 2) afforded comparable enantioselectivity but decreased yields, while the reaction in DCE led to the drop of both yield and enantioselectivity (entry 9, Table 2). The optimized reaction conditions obtained

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Org. Chem. Front., 2014, 1, 39–43 | 39

6-(iPr)3-C6H2 Ph 3. 40 | Org.6-(iPr)3-C6H2 2.2 mmol). Table 1 Screening of chiral phosphoric acids Entrya 1d 2e 3 4 5 6 7 8 9 10 11 12 13 a Catalyst 4a 4a 4a 4b 4c 4d 4e 4f 4g 4h 5a 5b 5c R 2. 2014. Chem.6-(iPr)3-C6H2 Yieldb (%) 23 52 67 7 23 16 8 41 53 51 21 12 76 eec (%) 78 78 78 25 −5 21 36 12 50 81 29 33 92 Reaction conditions: 1 (0. 2a (0.4. Downloaded on 29/03/2014 02:14:45. d Room temperature for 3 d. e Room temperature for 7 d.6-(iPr)3-C6H2 2.4.6-(iPr)2-4-tBu-C6H2 4-Cl-C6H4 3.24 mmol). 4 or 5 (5 mol%) in 1. b Isolated yield.5-(CF3)2-C6H3 2. c Determined by HPLC analysis.. Zhan-1B (5 mol%).5-(CF3)2-C6H3 2-Naphthyl 1-Naphthyl SiPh3 9-Anthryl 2. 39–43 This journal is © the Partner Organisations 2014 . Scheme 1 Ring-closing metathesis/isomerization/Mannich reaction sequence. Front.4.4.View Article Online Research Article Organic Chemistry Frontiers Published on 23 December 2013. 1.5 mL toluene.

Scheme 2 Substrate scope for cascade RCM/isomerization/Mannich reaction.5 mL toluene. [Ru] (5 mol%). 1.. c Determined by HPLC analysis.5 mL toluene. Front. Zhan-1B (5 mol%). 2014. (R)-5c (5 mol%) in 1. This journal is © the Partner Organisations 2014 Org.2 mmol). Downloaded on 29/03/2014 02:14:45. Reaction conditions: 1 (0. (R)-5c (5 mol%) in 1.2 mmol). Chem.24 mmol).24 mmol). 39–43 | 41 . Reaction conditions: 1 (0. solvents and Ru catalysts Research Article Entrya 1 2 3 4 5 6 7 8 9 a [Ru] catalyst Zhan-1B Zhan-1B Zhan-1B Zhan-1B Grubbs II Hoveyda–Grubbs II Zhan-1B Zhan-1B Zhan-1B Solvent Toluene Toluene Toluene Toluene Toluene Toluene Benzene o-Xylene DCE T (%) 50 30 80 110 50 50 50 50 50 Yieldb (%) 76 17 72 29 19 73 34 71 31 eec (%) 92 92 85 34 92 92 90 91 83 Published on 23 December 2013. 2 (0. b Isolated yield. 2a (0.View Article Online Organic Chemistry Frontiers Table 2 Screening of temperature.

J.. Am. Chem. 2010. Front. Ed. S. the enantioselectivity of the current study in general is higher comparing with those reported by Huang because two different chiral phosphoric acids were utilized. Enders.9 Therefore. G. Arai and N. Natl. Engl. Soc. The yields are in general moderate to good (52–86% yields) except for 4-Br substituted indole (33% yield). Chem. L. 17. 128. 113.. (e) A. Nie. W. Am. 1996. Yang. A. 132. J.-G.. 183. Enders. Chem.. Angew. 2 For selected organocatalytic reactions.-A. M. Cheng.-G. (q) Y. C. Barbas III. Zhu and J. 21121062. M. Ed. In conclusion. U. Int. 5-Br. W. Cheng. Am. For example.. M. Z. 2009.2 equivalents of indole in toluene at 50 °C (entry 1. Repka and S. Q. The sequential catalysis allowing three distinctive steps to be performed in a cascade displayed superior efficiency over the stepwise reactions. 1996. Chem. Angew. Xiao and D. F. Proc. 1. Grondal. (m) T. 2010.. Walji and D.. 14. X. Angew. Chem. J. Chen and W. Xiao. M. Table 2). 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