Novel α-Carboline Synthesis Using Tandem aza-Wittig-Electrocyclization Reaction of Indol-2-yl Phosphorane with Enone

Abstract

Mild thermal reaction of indol-2-yl triphenyl- and ­methyldiphenyl-phosphorane derived from 2-azido-1-methylindole with enones provides a novel entry to 9-methyl-9H-pyrido[2,3-b]indoles through a tandem aza-Wittig-electrocyclization process.

indolyl phosphoranes - enones - aza-Wittig - electro­cyclization - α-carbolines

References and Notes

1a Molina P. Vilaplana MJ. Synthesis  1994,  1197 

1b Wamhoff H. Richardt G. Stolben S. Adv. Heterocycl. Chem.  1995,  64:  125 

1c Fresneda PM. Molina P. Synlett  2004,  1 

2a Molina P. Pastor A. Vilaplana MJ. J. Org. Chem.  1996,  61:  8094 

2b Kobayashi T. Nitta M. Chem. Lett.  1981,  1459 

2c Iino Y. Nitta M. Bull. Chem. Soc. Jpn.  1988,  61:  2235 

2d Molina P. Pastor A. Vilaplana MJ. Tetrahedron Lett.  1993,  34:  3773 

2e Molina P. Pastor A. Vilaplana MJ. Foces-Foces C. Tetrahedron  1995,  51:  1265 

3a Degl’Innocenti A. Funicello M. Scafato P. Spagnolo P. Zanirato P. J. Chem. Soc., Perkin Trans. 1  1996,  2561 

3b Bonini C. Chiummiento M. Funicello M. Spagnolo P. Tetrahedron  2000,  56:  1517 

3c Bonini C. D’Auria M. Funicello M. Romaniello G. Tetrahedron  2002,  58:  3507 

3d Bonini C. Funicello M. Scialpi R. Spagnolo P. Tetrahedron  2003,  59:  7515 

4a Foresti E. Spagnolo P. Zanirato P. J. Chem Soc., Perkin Trans. 1  1989,  1354 

4b Foresti E. Di Gioia MT. Nanni D. Zanirato P. Gazz. Chim. Ital.  1995,  125:  151 

5 Molina P. Fresneda PM. Sanza MA. Foces-Foces C. De Arellano MCR. Tetrahedron  1998,  54:  9623 

6a Bhatti IA. Busby RE. Binmohamed M. Parrick J. Shaw CJG. J. Chem. Soc., Perkin Trans. 1  1997,  3581 

6b Kazerani S. Novak S. J. Org. Chem.  1998,  63:  895 

7a Barun O. Patra PK. Ila H. Junjappa H. Tetrahedron Lett.  1999,  40:  3797 

7b Stolc S. Life Sci.  1999,  65:  1943 

8a Meyer M. Guyot M. Tetrahedron Lett.  1996,  37:  4931 

8b Molina P. Fresneda PM. Sanz MA. Tetrahedron Lett.  1997,  38:  6909 

9a Achab S. Guyot M. Potier P. Tetrahedron Lett.  1995,  36:  2615 

9b Rocca P. Marsais S. Godard A. Queguiner G. Tetrahedron  1993,  49:  49 

10 Tahri A. Buysens KJ. Van der Eycken EV. Vandenberghe DM. Hoornaen GJ. Tetrahedron  1998,  54:  13211 

11a Molina P. Alajarin M. Vidal A. Sanchez-Andrada P. J. Org. Chem.  1992,  57:  929 

11b Molina P. Fresneda PM. Synthesis  1989,  878 

12 Erba E. Gelmi ML. Pocar D. Tetrahedron  2000,  56:  9991 

13 Beccalli EM. Clerici F. Marchesini A. Tetrahedron  2001,  57:  4787 

14 Tanaka K. Kitamura M. Narasaka K. Bull. Chem. Soc. Jpn.  2005,  78:  1659 

15

Preparation of the 1-Methylindol-2-yl Phosphoranes 2a,b.
2-Azido-1-methylindole (1), freshly obtained after filtration through a Florisil^® pad of the crude product from azido transfer reaction of 1-methylindole (1 mmol) with tosyl azide, [4] was dissolved in dry Et₂O (2 mL) and then slowly added to an anhyd Et₂O solution (2 mL) of PPh₃ (1 mmol) at 0 °C under nitrogen. The reaction mixture was stirred at 0 °C for ca. 1 h after which the separated solid material was filtered off to give the triphenylphosphorane (2a, 0.7 mmol, 70%) as a dark-yellow powder, mp 90-92 °C. ¹H NMR (300 MHz, CDCl₃): δ = 7.90-7.33 (m, 15 H), 7.20-7.15 (m, 1 H), 7.10-6.95 (m, 1 H), 6.90-6.80 (m, 2 H), 5.15 (s, 1 H), 3.87 (s, 3 H). ¹³C NMR (50 MHz, CDCl₃): δ = 149.5, 144.4, 137.0, 134.5, 132.4, 132.0, 131.1, 130.0, 129.3, 127.8, 127.0, 125.5, 125.0, 124.3, 121.5, 118.7, 117.5, 117.0, 114.0, 113.7, 111.0, 109.3, 39.0.
The methyldiphenylphosphorane (2b) was similarly pre-pared in 55% yield by azidation of 1-methylindole (1 mmol) followed by direct treatment with methyldiphenylphosphine (1 mmol). The compound 2b was obtained as a viscous oil which showed a tendency to decompose under work-up conditions and was thus employed without purification.
¹H NMR (300 MHz, CDCl₃): δ = 7.95-7.65 (m, 5 H), 7.58-7.40 (m, 5 H), 7.21-7.18 (m, 1 H), 7.15-7.10 (m, 1 H), 6.90-6.80 (m, 2 H), 5.20 (s, 1 H), 3.87 (s, 3 H), 2.23 (d, 3 H, ² J _PH = 12.8 Hz). ¹³C NMR (50 MHz, CDCl₃): δ = 143.6, 141.0, 134.6, 133.0, 132.3, 131.6, 131.5, 130.7, 129.5, 129.2, 129.2, 128.2, 126.1, 125.9, 118.8, 117.0, 116.5, 107.5, 37.0, 14.88.

16

Synthesis of the Carbolines 3a-e. Typical Procedure.
A mixture of the triphenylphosphorane (2a, 1 mmol) and trans-crotonaldehyde (1 mmol) in dry toluene (5 mL) was stirred at 70 °C for ca. 20 h under a stream of nitrogen. After cooling, the solvent was removed in vacuo and the resultant residue chromatographed on a silica gel column by progressive elution with PE-EtOAc mixtures to give 4,9-dimethyl-9H-pyrido[2,3-b]indole (3b, [18] 80%) as an oil. ¹H NMR (300 MHz, CDCl₃): δ = 8.40-8.36 (m, 1 H), 8.20-8.15 (m, 1 H), 7.60-7.55 (m, 1 H), 7.40-7.35 (m, 1 H), 7.23 (s, 1 H), 7.15-7.00 (m, 1 H), 4.10 (s, 3 H), 2.94 (s, 3 H). ¹³C NMR (50 MHz, CDCl₃): δ = 153.3, 150.6, 145.8,143.0, 129.4, 125.8, 125.0, 123.1, 117.3, 116.6, 108.3, 30.0, 27.8.
The carbolines 3a [17b] [17c] and 3e ¹⁴ had physical and/or spectral data consistent with those previously reported. The hitherto unknown carbolines 3c,d were identified on the basis of NMR and MS data as well as elemental analysis.

17a Zhestkov VP. Druzhinina VV. Rudnitskikh AV. Khim. Geterotsikl. Soedin.  1995,  1507 ; Chem. Abstr. 1996, 125, 33513x

17b Clark VM. Cox A. Herbert EJ. J. Chem. Soc. C  1968,  831 

17c Eiter K. Nagy M. Monatsh. Chem.  1949,  80:  607 

17d Eiter K. Monatsh. Chem.  1948,  79:  17 

18 Abramenko PI. Zhurnal Vses. Khim. Obshch. im. D.I. Mendeleeva  1973,  18:  715 ; Chem. Abstr. 1974, 80, 95788b

19

Replacement of phenyl with methyl group(s) on phosphorus could enhance the reactivity of our previous benzothiophen-2-yl and, especially, benzothiophen-3-yl phosphoranes with enones, see ref. 3b,3c.