Friedel-Crafts Alkylation of Indoles by tert-Enamides in Acetic Acid

Abstract

In acetic acid, Friedel-Crafts alkylation of indoles by tert-enamides proceeded effectively in the absence of any catalyst to afford the pharmacologically and biologically active 2-oxo-1-pyrrolidine derivatives in moderate to good yields. The mechanistic study based on the NMR and HRMS analysis shows that the reaction was promoted by acid catalysis. The hydrogen-bond interaction between tert-enamides and AcOH may also be responsible for the reaction.

acetic acid - Friedel-Crafts alkylation - tert-enamide - indole

References and Notes

1a Gribble GW. Comprehensive Heterocyclic Chemistry II   Vol. 2:  Katritzky AR. Ress CW. Scriven EFV. Bird CW. Pergamon Press; Oxford: 1996.  p.270 

1b Indoles   Sundberg RJ. Academic Press; London: 1996. 

1c Horton DA. Bourne GT. Smythe ML. Chem. Rev.  2003,  103:  893 

1d Humphrey GR. Kuethe JT. Chem. Rev.  2006,  106:  2875 

2a Joule JA. Indole and its Derivatives, In Science of Synthesis (Houben-Weyl: Methods of Molecular Transformations)   Vol. 10:  Thomas EJ. Thieme; Stuttgart: 2000.  Chap. 10.13.

2b Bandini M. Eichholzer A. Angew. Chem. Int. Ed.  2009,  48:  9608 

2c Gribble GW. Pure Appl. Chem.  2003,  75:  1417 

2d Zeng M. You S.-L. Synlett  2010,  1289 

3a Pascual J. Cabarrocas X. Headache  2002,  42:  28 

3b Paredes SD. Korkmaz A. Manchester LC. Tan D.-X. Reiter RJ. J. Exp. Bot.  2009,  60:  57 

4a Trost BM. Fleming I. Organic Synthesis   Vol. 3:  Pergamon Press; Oxford: 1991.  Chap. 1.8. p.293 

4b Meima GR. Lee GS. Garces JM. In Friedel-Crafts Alkylation   Sheldon RA. Bekkum H. Wiley-VCH; New York: 2001.  p.151 

5a Yang L. Deng G. Wang D.-X. Huang ZT. Zhu J. Wang M.-X. Org. Lett.  2007,  9:  1387 

5b Meth-Cohn O. Westwood KT. J. Chem. Soc., Perkin Trans. 1  1984,  1173 

5c Shono T. Matsumura Y. Tsubata K. Sugihara Y. Yamane S.-i. Kanazawa T. Aoki T. J. Am. Chem. Soc.  1982,  104:  6697 

5d Carbery DR. Org. Biomol. Chem.  2008,  6:  3455 

5e Yang L. Wang D.-X. Zheng Q.-Y. Pan J. Huang ZT. Wang M.-X. Org. Biomol. Chem.  2009,  7:  2628 

5f Nilson MG. Funk RL. Org. Lett.  2006,  8:  3833 

5g Yang L. Tong S. Wang D.-X. Huang Z.-T. Zhu J. Wang M.-X. Synlett  2010,  927 

5h Yang L. Zheng Q.-Y. Wang D.-X. Huang Z.-T. Wang M.-X. Org. Lett.  2008,  10:  2461 

5i Yang L. Wang D.-X. Huang Z.-T. Wang M.-X. J. Am. Chem. Soc.  2009,  131:  10390 

5j Yang L. Lei C.-H. Wang D.-X. Huang Z.-T. Wang M.-X. Org. Lett.  2010,  12:  3918 

6a Terada M. Sorimachi K. J. Am. Chem. Soc.  2007,  129:  292 

6b Jia Y.-X. Zhong J. Zhu S.-F. Zhang C.-M. Zhou Q.-L. Angew. Chem. Int. Ed.  2007,  46:  5565 

7a Akiyama S, Niki T, Utsunomiya T, Watanabe J, Nishioka M, Suzuki H, Hayasaka F, and Yamagishi K. inventors; EP  1020447. 

7b Gobert J, Giurgea C, Geerts J.-P, and Bodson G. inventors; EP  172096. 

7c Kenda B, Michel P, and Quesnel Y. inventors; WO  2005054188. 

7d Gobert J, Geerts J.-P, and Bodson G. inventors; EP  0162036. 

7e Schmiesing RJ, and Murray RJ. inventors; US  5334720. 

8 Robinson RG. Jorge RE. Clarence-Smith K. Starkstein S. Neutropsychiatry J. Clin. Neurosci.  2009,  21:  144 

9 Kenda B, Quesnel Y, Ates A, Michel P, Turet L, and Mercier J. inventors; WO  2006128693. 

10a Andreanti F. Andrisano R. Case CD. Tramontini M. J. Chem. Soc.  1970,  1157 

10b Nunomoto S. Kawakami Y. Yamashita Y. Takeuchi H. Eguchi S. J. Chem. Soc., Perkin Trans. 1  1990,  111 

10c Zhang Z. Wang X. Widenhoefer RA. Chem. Commun.  2006,  3717 

11 Niu TM. Huang LH. Wu TX. Zhang YH. Org. Biomol. Chem.  2011,  9:  273 

12 Chen T. Xu X.-P. Ji S.-J. J. Comb. Chem.  2010,  12:  659 

13

General Procedure for the Reaction of N -Vinyl Compound with Nucleophile (Take the Reaction of 1-Vinylpyrrolidin-2-one with Indole as Example) To a mixture of 1-vinylpyrrolidin-2-one (0.1111g, 1.0 mmol) and indole (0.1171g, 1.0 mmol), AcOH (1.0 mL) was added. The reaction system was stirred vigorously at r.t. until the starting materials were completely consumed as indicated by TLC analysis. Then the mixture was poured into H₂O, neutralized by NaHCO₃, and extracted by CH₂Cl₂ (2 × 15 mL). The combined organic layer was washed with brine, dried with anhyd Na₂SO₄, and evaporated under the reduced pressure. The residue was purified by flash column chromatography with EtOAc and PE as eluents to afford pure product 3aa (0.194 g, yield 85%).
1-[1-(2-Methyl-1 H -indol-3-yl)ethyl]pyrrolidin-2-one (3ab) White solid; mp 176-177 ˚C. IR (KBr): 3317, 2974, 2933, 2876, 1656, 1491, 1435, 1287, 1198, 1051, 749 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 1.72 (d, J = 6.9 Hz, 3 H), 1.82-2.00 (m, 2 H), 2.32-2.41 (m, 2 H), 2.48 (s, 3 H), 3.11-3.19 (m, 1 H), 3.53-3.61 (m, 1 H), 5.75 (q, J = 7.2 Hz, 1 H), 7.05-7.12 (m, 2 H), 7.27 (t, J = 1.8 Hz, 1 H), 7.70 (d, J = 7.5 Hz, 1 H), 8.07 (br s, 1 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 174.3, 135.6, 133.9, 128.3, 121.3, 119.9, 119.6, 111.0, 110.8, 44.0, 44.0, 31.9, 18.1, 18.0, 13.0. HRMS (EI): m/z calcd for C₁₅H₁₈N₂O: 242.1419; found: 242.1420.

14 Lakhdar S. Westermaier M. Terrier F. Goumont R. Boubaker T. Ofial AR. Mayr H. J. Org. Chem.  2006,  71:  9088 

15 Jiang R. Wu X.-J. Zhu X. Xu X.-P. Ji S.-J. Eur. J. Org. Chem.  2010,  5946