Synthesis of Substituted Indoles and Carbazoles from 2-Fluorophenyl Imines

Abstract

The synthesis of a series of indole and carbazole derivatives from 2-fluorophenyl imines is reported. 2-Fluoroaniline-d ₄ (13) is prepared and used to investigate the mechanism of this indolization. 2-Fluorophenyl enaminone 17 gives the synthetically useful carbazole 20 via a similar indolization and in situ alkylation.

indoles - imines - enaminone - benzyne - nucleophilic aromatic substitution

References

1 For a review of indolization methods see: Pindur U. Adam R. J. Heterocycl. Chem.  1988,  1 

2 Sunberg RJ. Indoles   Academic Press; London: 1996. 

3 Caubere C. Caubere P. Renard P. Bizot-Espiart J.-G. Jamart-Gregoire B. Tetrahedon Lett.  1993,  6889 

4 Kudzma LV. Severnak SA. Benvenga MJ. Ezell EF. Ossipov MH. Knight VV. Rudo FG. Spencer HK. Spaulding TC. J. Med. Chem.  1989,  2534 

5 Certain ¹H- and ¹³C NMR resonances of imines are finely doubled due to closely overlapping spectra of syn- and anti-isomers: Bunnell CA. Fuchs PL. J. Org. Chem.  1977,  2614 

6

2,4-Diphenyl-3H-1-benzazepine(9), mp 129-30 °C. ¹H NMR (CDCl₃): δ = 7.86 (m 2 H), 7.60-7.31 (complex m, 11 H), 7.21 (m, 1 H), 7.07 (s, 1 H), 3.38 (s, 2 H). ¹³C NMR (CDCl₃): δ = 157.33, 146.89, 139.93, 138.24, 134.94, 130.55, 130.15, 129.56, 128.78, 128.53, 128.04, 127.99, 127.90, 126.97, 126.86, 126.82, 123.98, 33.90. Anal. Calcd for C₂₂H₁₇N (295.38): C, 89.46; H, 5.80; N, 4.74. Found: C, 89.24 H, 5.68 N, 4.68.

7

Fluorobenzene-d ₅, 97 atom%D was obtained from Aldrich Chemical Co., Milwaukee WI USA.

8 Schlosser M. Katsoulos G. Takagishi S. Synlett  1990,  747 

9 Iida H. Yuasa Y. Kibayashi C. J. Org. Chem.  1979,  1074 

10 Coates IH, Bell JA, Humber DC, and Ewan GB. inventors; Eur. Pat. Appl. EP  191562. U.S. Adopted Name for: 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one:

11

1,2,3,9-Tetrahydro-4H-carbazole-4-one(21) can be isolated as a tan solid; mp 219-221 °C; R_f 045 (EtOAc-hexanes, 2:1). ¹H NMR (DMSO-d ₆): δ = 11.85 (br s, 1 H), 7.96 (m, 1 H), 7.40 (m, 1 H), 7.15 (m, 2 H), 2.96 (t, J = 6.2 Hz, 2 H), 2.43 (t, J = 6.2 Hz, 2 H), 2.12 (m, 2 H). ¹³C NMR (DMSO-d ₆): δ = 192.78, 152.17, 135.80, 124.49, 122.35, 121.43, 120.14, 111.72, 111.45, 37.77, 23.38, 22.68.

12

Longer reflux gives increasing amounts of the benzazepine side product discussed in the text.

13

If desired the crude imine 3 can be distilled under reduced pressure to give a colorless oil; bp 170-172 °C (0.25 mmHg).

14 Katritzky AR. Wang Z. J. Heterocycl. Chem.  1988,  671 

15 Junjappa H. Synthesis  1975,  798