Regioselective and Versatile Synthesis of Indoles via Intramolecular Friedel-Crafts Heteroannulation of Enaminones

Abstract

A new approach is described for the synthesis of substituted indoles 5, through an intramolecular and regioselective Friedel-Crafts cyclization of enaminones 6a-h catalyzed by Lewis acids. Compounds 6 were prepared from the 2-anilinocarbonyl compounds 7, by treatment with DMFDMA under thermal or microwave (MW) irradiation conditions. An alternative and shorter one-pot two-step synthesis of indoles 5 was achieved starting from compounds 7 and promoted by MW radiation, including the elusive 2-acetylindoles 5i-m.

indoles - enaminones - Friedel-Crafts annulations - Lewis acid catalysis - microwaves

References and Notes

1a Greenhill JV. Chem. Soc. Rev.  1977,  6:  277 

1b Lue P. Greenhill JV. Adv. Heterocycl. Chem.  1996,  67:  207 

1c Elassar A.-ZA. El-Khair AA. Tetrahedron  2003,  59:  8463 

2a Selic L. Grdadolnik SG. Stanovnik B. Helv. Chim. Acta  1997,  80:  2418 

2b Smodis J. Stanovnik B. Tetrahedron  1998,  54:  9799 

2c Stanovnik B. Svete J. Synlett  2000,  1077 

3 Cruz MC. Tamariz J. Tetrahedron Lett.  2004,  45:  2377 

4 Cruz MC. Tamariz J. Tetrahedron  2005,  61:  10061 

5a Gribble GW. Pyrroles and their Benzo Derivatives: Applications, In Comprehensive Heterocyclic Chemistry   Vol. 2:  Katritzky AR. Rees CW. Scriven EFV. Elsevier; Oxford: 1996.  p.207-257  

5b Sundberg RJ. Indoles   Academic Press; St. Louis: 1996. 

5c Joule JA. Indoles, In Science of Synthesis   Vol. 10:  Thomas EJ. Thieme; Stuttgart: 2000.  Chap. 13.

6a Saxton JE. The Monoterpenoid Indole Alkaloids, In Indoles   Part 4:  Wiley-Interscience; New York: 1983. 

6b Abreu P. Pereira A. Heterocycles  1998,  48:  885 

6c Faulkner DJ. Nat. Prod. Rep.  1999,  16:  155 

6d Lousnasmaa M. Tolvanen A. Nat. Prod. Rep.  2000,  17:  175 

6e Steele JCP. Veitch NC. Kite GC. Simmonds MSJ. Warhurst DC. J. Nat. Prod.  2002,  65:  85 

6f Grougnet R. Magiatis P. Fokialakis N. Mitaku S. Skaltsounis A.-L. Tillequin F. Sévenet T. Litaudon M. J. Nat. Prod.  2005,  68:  1083 

7a Bunker AM. Edmunds JJ. Berryman KA. Walker DM. Flynn MA. Welch KM. Doherty AM. Bioorg. Med. Chem. Lett.  1996,  6:  1061 

7b Sechi M. Derudas M. Dallachio R. Dessi A. Bacchi A. Sannia L. Carta F. Palomba M. Ragab O. Chan C. Shoemaker R. Sei S. Dayam R. Neamati N. J. Med. Chem.  2004,  47:  5298 

7c Heinrich T. Böttcher H. Bioorg. Med. Chem. Lett.  2004,  14:  2681 

7d Riendeau D. Aspiotis R. Ethier D. Gareau Y. Grimm EL. Guay J. Guiral S. Juteau H. Mancini JA. Méthot N. Rubin J. Friesen RW. Bioorg. Med. Chem. Lett.  2005,  15:  3352 

7e Yates AS. Doughty SW. Kendall DA. Kellam B. Bioorg. Med. Chem. Lett.  2005,  15:  3758 

8a Black DStC. Pyrroles and their Benzo Derivatives: Reactivity, In Comprehensive Heterocyclic Chemistry   Vol. 2:  Katritzky AR. Rees CW. Scriven EFV. Elsevier; Oxford: 1996.  p.39-117  

8b Zhang H. Larock RC. J. Org. Chem.  2002,  67:  9318 

8c Zhang H. Larock RC. Org. Lett.  2002,  4:  3035 

8d Wynne JH. Stalick WM. J. Org. Chem.  2003,  68:  4845 

8e Agnusdei M. Bandini M. Melloni A. Umani-Ronchi A. J. Org. Chem.  2003,  68:  7126 

8f Duval E. Cuny GD. Tetrahedron Lett.  2004,  45:  5411 

For recent examples, see:

9a Gribble GW. J. Chem. Soc., Perkin Trans. 1  2000,  1045 

9b Scott TL. Söderberg BCG. Tetrahedron Lett.  2002,  43:  1621 

9c Witulski B. Alayrac C. Tevzadze-Saeftel L. Angew. Chem. Int. Ed.  2003,  42:  4257 

9d Walkington A. Gray M. Hossner F. Kitteringham J. Voyle M. Synth. Commun.  2003,  33:  2229 

9e Yue D. Larock RC. Org. Lett.  2004,  6:  1037 

9f Shen M. Li G. Lu BZ. Hossain A. Roschangar F. Farina V. Senanayake CH. Org. Lett.  2004,  6:  4129 

9g Nazaré M. Schneider C. Lindenschmidt A. Will DW. Angew. Chem. Int. Ed.  2004,  43:  4526 

9h Siu J. Baxendale IR. Ley SV. Org. Biomol. Chem.  2004,  2:  160 

9i Amjad M. Knight DW. Tetrahedron Lett.  2004,  45:  539 

9j Ackermann L. Born R. Tetrahedron Lett.  2004,  45:  9541 

9k Arcadi A. Bianchi G. Marinelli F. Synthesis  2004,  610 

9l Hiroya K. Itoh S. Sakamoto T. J. Org. Chem.  2004,  69:  1126 

9m Cacchi S. Fabrizi G. Chem. Rev.  2005,  105:  2873 

9n Barluenga J. Vázquez-Villa H. Ballesteros A. González JM. Adv. Synth. Catal.  2005,  347:  526 

9o Söderberg BCG. Hubbard JW. Rector SR. O’Neil SN. Tetrahedron  2005,  61:  3637 

9p Ackermann L. Org. Lett.  2005,  7:  439 

9q Arcadi A. Cacchi S. Fabrizi G. Marinelli F. Parisi LM. J. Org. Chem.  2005,  70:  6213 

10

Typical Procedure for Preparation of 7b.
Under an N₂ atmosphere, a mixture of 8b (1.0 g, 9.33 mmol) and anhyd K₂CO₃ (1.93 g, 14.0 mmol) in dry acetone (10 mL) was heated to 60 °C for 1 h. Methyl bromoacetate (9, 1.57 g, 10.26 mmol) was added dropwise and the mixture was stirred at 60 °C for 12 h. The mixture was filtered and the solvent was removed under vacuum. The residue was purified by column chromatography over silica gel (20 g/g of sample, hexane-EtOAc, 95:5), to give 1.44 g (86%) of 7b as a brownish solid.
R _f = 0.45 (hexane-EtOAc, 8:2); mp 44-45 °C (hexane-EtOAc, 8:2) [lit. [16] 40 °C]. IR (KBr): 3393, 1741, 1608, 1513, 1439, 1213, 1180, 772 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 2.33 (s, 3 H, CH₃Ar), 3.81 (s, 3 H, CO₂Me), 3.93 (s, 2 H, CH₂N), 4.24 (br s, 1 H, NH), 6.43-6.49 (m, 2 H, H-2, H-6), 6.63 (br d, J = 7.5 Hz, 1 H, H-4), 7.13 (t, J = 7.5 Hz, 1 H, H-5). ¹³C NMR (75.4 MHz, CDCl₃): δ = 21.4 (CH₃Ar), 45.4 (CH₂N), 51.9 (CO₂ CH₃), 109.8 (C-6), 113.6 (C-2), 118.9 (C-4), 129.0 (C-5), 138.8 (C-3), 146.8 (C-1), 171.5 (CO₂Me). MS (70 eV): m/z (%) = 179 (65) [M⁺], 136 (7), 122 (34), 121 (100), 93 (3), 63 (5).

11

Typical Procedure for Preparation of 6b.
A mixture of 7b (0.20 g, 1.12 mmol) and DMFDMA (0.20 g, 1.68 mmol) was heated to 90 °C for 5 h, under an N₂ atmosphere. The crude mixture was evaporated under vacuum and the residue was purified by column chromatography over silica gel (20 g/g of sample, hexane-EtOAc, 8:2), to give 0.21 g (79%) of 6b as an orange solid.
R _f = 0.25 (hexane-EtOAc, 8:2); mp 65-72 °C (decomp., hexane-EtOAc, 8:2). IR (KBr): 3318, 3025, 1735, 1645, 1607, 1488, 1435, 1227, 777 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 2.26 (s, 3 H, CH₃Ar), 3.02 [s, 6 H, N(CH₃)₂], 3.61 (s, 3 H, CO₂CH₃), 4.62 (br s, 1 H, NH), 6.40-6.47 (m, 2 H, ArH), 6.54 (br d, J = 7.8 Hz, 1 H, H-4), 7.04 (dd, J = 7.8, 7.2 Hz, 1 H, H-5), 7.39 (s, 1 H, HC=). ¹³C NMR (75.4 MHz, CDCl₃): δ = 21.5 (CH₃Ar), 41.6 [N(CH₃)₂], 51.1 (CO₂ CH₃), 98.6 (NC=), 110.4 (C-6), 114.1 (C-2), 118.9 (C-4), 128.8 (C-5), 138.7 (C-3), 146.3 (HC=), 149.1 (C-1), 169.6 (CO₂CH₃). MS (70 eV): m/z (%) = 234 (4) [M⁺], 203 (3), 132 (6), 118 (14), 91 (36), 83 (18), 65 (16), 57 (66), 42 (100). Anal. Calcd for C₁₃H₁₈N₂O₂: C, 66.64; H, 7.74; N, 11.96. Found: C, 66.47; H, 7.64; N, 11.74.
NMR spectral data of representative examples. Compound 6a: ¹H NMR (300 MHz, CDCl₃): δ = 3.01 [s, 6 H, N(CH₃)₂], 3.62 (s, 3 H, CO₂CH₃), 4.66 (br s, 1 H, NH), 6.62 (br d, J = 7.5 Hz, 2 H, H-2), 6.72 (t, J = 7.5 Hz, 1 H, H-4), 7.15 (br t, J = 7.5 Hz, 1 H, H-3), 7.40 (s, 1 H, HC=). ¹³C NMR (75.4 MHz, CDCl₃): δ = 41.6 [N(CH₃)₂], 51.1 (CO₂ CH₃), 98.6 (NC=), 113.4 (C-2), 117.9 (C-4), 129.0 (C-3), 146.3 (HC=), 149.1 (C-1), 169.6 (CO₂CH₃).
Compound 6c: ¹H NMR (300 MHz, CDCl₃): δ = 2.22 (s, 3 H, CH₃Ar), 3.01 [s, 6 H, N(CH₃)₂], 3.60 (s, 3 H, CO₂CH₃), 4.52 (br s, 1 H, NH), 6.51-6.57 (m, 2 H, H-2), 6.93-7.00 (m, 2 H, H-3), 7.36 (s, 1 H, HC=). ¹³C NMR (75.4 MHz, CDCl₃): δ = 20.3 (CH₃Ar), 41.6 [N(CH₃)₂], 51.1 (CO₂ CH₃), 99.1 (NC=), 113.4 (C-2), 127.1 (C-4), 129.5 (C-3), 146.1 (HC=), 146.8 (C-1), 169.6 (CO₂CH₃).
Compound 6h: ¹H NMR (300 MHz, CDCl₃): δ = 1.20 (t, J = 7.2 Hz, 3 H, CH ₃CH₂O), 3.03 [s, 6 H, N(CH₃)₂], 3.73 (s, 6 H, OMe), 4.10 (q, J = 7.2 Hz, 2 H, CH₃CH ₂O), 4.70 (br s, 1 H, NH), 5.84 (d, J = 2.1 Hz, 2 H, H-2, H-6), 5.89 (t, J = 2.1 Hz, 1 H, H-4), 7.36 (s, 1 H, HC=). ¹³C NMR (75.4 MHz, CDCl₃): δ = 14.6 (CH₃CH₂O), 41.8 [N(CH₃)₂], 55.05 (OMe), 55.08 (OMe), 59.7 (CO₂ CH₂CH₃), 90.3 (C-4), 92.4 (C-2, C-6), 98.8 (NC=), 146.0 (HC=), 151.5 (C-1), 161.5 (C-3, C-5), 169.0 (CO₂Et).

12

Typical Procedure for Preparation of 5b.
Anhyd AlCl₃ (0.057 g, 0.43 mmol) was added to a solution of 6b (0.10 g, 0.43 mmol) in dry CH₂Cl₂ (100 mL) at r.t. The mixture was stirred at r.t. for 24 h and filtered. The filtrate was washed with H₂O (3 × 25 mL), the organic layer was dried (Na₂SO₄), and the solvent was removed under vacuum. The residue was purified by column chromatography over silica gel (10 g, hexane-EtOAc, 95:5), to give 0.061 g (76%) of 5b as a white solid.
R _f = 0.33 (hexane-EtOAc, 8:2); mp 97-98 °C (hexane-EtOAc, 7:3) [lit. [17] 128-129 °C]. IR (KBr): 3324, 1697, 1527, 1441, 1333, 1262, 1211, 764 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 2.47 (s, 3 H, CH₃Ar), 3.94 (s, 3 H, CO₂Me), 6.99 (dd, J = 8.1, 0.9 Hz, 1 H, H-5), 7.18 (dd, J = 2.1, 0.9 Hz, 1 H, H-3), 7.20 (br s, 1 H, H-7), 7.56 (d, J = 8.1 Hz, 1 H, H-4), 8.85 (br s, 1 H, NH). ¹³C NMR (75.4 MHz, CDCl₃): δ = 22.0 (CH₃Ar), 51.9 (CO₂ CH₃), 108.8 (C-3), 111.5 (C-7), 122.2 (C-4), 123.0 (C-5), 125.3 (ArC), 126.5 (ArC), 135.7 (ArC), 157.3 (C-7a), 162.5 (CO₂CH₃). MS (70 eV): m/z (%) = 189 (24) [M⁺], 175 (17), 157 (87), 129 (91), 103 (80), 102 (100), 77 (69), 51 (69).
NMR spectral data of representative examples.
Compound 5a: ¹H NMR (300 MHz, CDCl₃): δ = 3.95 (s, 3 H, CO₂CH₃), 7.16 (ddd, J = 8.1, 6.8, 1.0 Hz, 2 H, H-5), 7.23 (dd, J = 2.3, 1.0 Hz, 1 H, H-3), 7.33 (ddd, J = 8.4, 6.8, 1.0 Hz, 1 H, H-6), 7.58 (ddd, J = 8.4, 1.0, 0.9 Hz, 1 H, H-7), 7.70 (dd, J = 8.1, 0.9 Hz, 1 H, H-4), 8.98 (br s, 1 H, NH). ¹³C NMR (75.4 MHz, CDCl₃): δ = 52.0 (CO₂ CH₃), 108.8 (C-3), 111.9 (C-7), 120.8 (C-5), 122.6 (C-4), 125.4 (C-6), 127.1 (C-2), 127.4 (C-3a), 136.8 (C-7a), 162.4 (CO₂CH₃).
Compound 5c: ¹H NMR (300 MHz, CDCl₃): δ = 2.43 (s, 3 H, CH₃Ar), 3.94 (s, 3 H, CO₂CH₃), 7.14 (br s, 1 H, H-3), 7.15 (dd, J = 8.4, 1.5 Hz, 1 H, H-6), 7.31 (br d, J = 8.4 Hz, 1 H, H-7), 7.45 (br s, 1 H, H-4), 9.11 (br s, 1 H, NH). ¹³C NMR (75.4 MHz, CDCl₃): δ = 21.4 (CH₃Ar), 51.9 (CO₂ CH₃), 108.2 (C-3), 111.6 (C-7), 121.8 (C-4), 127.0 (C-2), 127.4 (C-6), 127.7 (C-5), 130.1 (C-3a), 135.3 (C-7a), 162.6 (CO₂CH₃).
Compound 5h: ¹H NMR (300 MHz, CDCl₃): δ = 1.39 (t, J = 7.0 Hz, 3 H, CH ₃CH₂O), 3.83 (s, 3 H, OMe), 3.90 (s, 3 H, OMe), 4.38 (q, J = 7.0 Hz, 2 H, CH₃CH ₂O), 6.18 (d, J = 1.5 Hz, 2 H, H-2, H-5), 6.43 (dd, J = 1.5, 0.9 Hz, 1 H, H-7), 7.27 (dd, J = 2.3, 0.9 Hz, 1 H, H-3), 9.10 (br s, 1 H, NH). ¹³C NMR (75.4 MHz, CDCl₃): δ = 14.4 (CH₃CH₂O), 55.3 (OMe), 55.5 (OMe), 60.7 (CO₂ CH₂CH₃), 86.1 (C-7), 92.6 (C-5), 106.7 (C-3), 113.7 (C-3a), 124.8 (C-2), 138.6 (C-7a), 155.0 (C-4), 160.1 (C-6), 162.1 (CO₂Et).

13

CCDC-292937 contains all crystallographic details of this publication and is available free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html or can be ordered from the following address: Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK, fax: [phone]; or [e-mail].

14a Jiménez-Vázquez HA. Ochoa ME. Zepeda G. Modelli A. Jones D. Mendoza JA. Tamariz J. J. Phys. Chem. A  1997,  101:  10082 

14b Herrera R. Jiménez-Vázquez HA. Modelli A. Jones D. Söderberg BC. Tamariz J. Eur. J. Org. Chem.  2001,  4657 

14c Mendoza JA. Jiménez-Vázquez HA. Herrera R. Liu J. Tamariz J. Rev. Soc. Quím. Méx.  2003,  47:  108 

15 Reddy MS. Cook JM. Tetrahedron Lett.  1994,  35:  5413 

16 Ellis F, Naylor A, Wallis CJ, and Waterhouse I. inventors; EP  388,165.  ; Chem. Abstr. 1991, 114, 81891

17 Knittel D. Synthesis  1985,  186