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

<A NAME="RG08406ST-1A">1a</A> Molina P. Vilaplana MJ. Synthesis  1994,  1197 

<A NAME="RG08406ST-1B">1b</A> Wamhoff H. Richardt G. Stolben S. Adv. Heterocycl. Chem.  1995,  64:  125 

<A NAME="RG08406ST-1C">1c</A> Fresneda PM. Molina P. Synlett  2004,  1 

<A NAME="RG08406ST-2A">2a</A> Molina P. Pastor A. Vilaplana MJ. J. Org. Chem.  1996,  61:  8094 

<A NAME="RG08406ST-2B">2b</A> Kobayashi T. Nitta M. Chem. Lett.  1981,  1459 

<A NAME="RG08406ST-2C">2c</A> Iino Y. Nitta M. Bull. Chem. Soc. Jpn.  1988,  61:  2235 

<A NAME="RG08406ST-2D">2d</A> Molina P. Pastor A. Vilaplana MJ. Tetrahedron Lett.  1993,  34:  3773 

<A NAME="RG08406ST-2E">2e</A> Molina P. Pastor A. Vilaplana MJ. Foces-Foces C. Tetrahedron  1995,  51:  1265 

<A NAME="RG08406ST-3A">3a</A> Degl’Innocenti A. Funicello M. Scafato P. Spagnolo P. Zanirato P. J. Chem. Soc., Perkin Trans. 1  1996,  2561 

<A NAME="RG08406ST-3B">3b</A> Bonini C. Chiummiento M. Funicello M. Spagnolo P. Tetrahedron  2000,  56:  1517 

<A NAME="RG08406ST-3C">3c</A> Bonini C. D’Auria M. Funicello M. Romaniello G. Tetrahedron  2002,  58:  3507 

<A NAME="RG08406ST-3D">3d</A> Bonini C. Funicello M. Scialpi R. Spagnolo P. Tetrahedron  2003,  59:  7515 

<A NAME="RG08406ST-4A">4a</A> Foresti E. Spagnolo P. Zanirato P. J. Chem Soc., Perkin Trans. 1  1989,  1354 

<A NAME="RG08406ST-4B">4b</A> Foresti E. Di Gioia MT. Nanni D. Zanirato P. Gazz. Chim. Ital.  1995,  125:  151 

<A NAME="RG08406ST-5">5</A> Molina P. Fresneda PM. Sanza MA. Foces-Foces C. De Arellano MCR. Tetrahedron  1998,  54:  9623 

<A NAME="RG08406ST-6A">6a</A> Bhatti IA. Busby RE. Binmohamed M. Parrick J. Shaw CJG. J. Chem. Soc., Perkin Trans. 1  1997,  3581 

<A NAME="RG08406ST-6B">6b</A> Kazerani S. Novak S. J. Org. Chem.  1998,  63:  895 

<A NAME="RG08406ST-7A">7a</A> Barun O. Patra PK. Ila H. Junjappa H. Tetrahedron Lett.  1999,  40:  3797 

<A NAME="RG08406ST-7B">7b</A> Stolc S. Life Sci.  1999,  65:  1943 

<A NAME="RG08406ST-8A">8a</A> Meyer M. Guyot M. Tetrahedron Lett.  1996,  37:  4931 

<A NAME="RG08406ST-8B">8b</A> Molina P. Fresneda PM. Sanz MA. Tetrahedron Lett.  1997,  38:  6909 

<A NAME="RG08406ST-9A">9a</A> Achab S. Guyot M. Potier P. Tetrahedron Lett.  1995,  36:  2615 

<A NAME="RG08406ST-9B">9b</A> Rocca P. Marsais S. Godard A. Queguiner G. Tetrahedron  1993,  49:  49 

<A NAME="RG08406ST-10">10</A> Tahri A. Buysens KJ. Van der Eycken EV. Vandenberghe DM. Hoornaen GJ. Tetrahedron  1998,  54:  13211 

<A NAME="RG08406ST-11A">11a</A> Molina P. Alajarin M. Vidal A. Sanchez-Andrada P. J. Org. Chem.  1992,  57:  929 

<A NAME="RG08406ST-11B">11b</A> Molina P. Fresneda PM. Synthesis  1989,  878 

<A NAME="RG08406ST-12">12</A> Erba E. Gelmi ML. Pocar D. Tetrahedron  2000,  56:  9991 

<A NAME="RG08406ST-13">13</A> Beccalli EM. Clerici F. Marchesini A. Tetrahedron  2001,  57:  4787 

<A NAME="RG08406ST-14">14</A> Tanaka K. Kitamura M. Narasaka K. Bull. Chem. Soc. Jpn.  2005,  78:  1659 

<A NAME="RG08406ST-15">15</A>

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.

<A NAME="RG08406ST-16">16</A>

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.

<A NAME="RG08406ST-17A">17a</A> Zhestkov VP. Druzhinina VV. Rudnitskikh AV. Khim. Geterotsikl. Soedin.  1995,  1507 ; Chem. Abstr. 1996, 125, 33513x

<A NAME="RG08406ST-17B">17b</A> Clark VM. Cox A. Herbert EJ. J. Chem. Soc. C  1968,  831 

<A NAME="RG08406ST-17C">17c</A> Eiter K. Nagy M. Monatsh. Chem.  1949,  80:  607 

<A NAME="RG08406ST-17D">17d</A> Eiter K. Monatsh. Chem.  1948,  79:  17 

<A NAME="RG08406ST-18">18</A> Abramenko PI. Zhurnal Vses. Khim. Obshch. im. D.I. Mendeleeva  1973,  18:  715 ; Chem. Abstr. 1974, 80, 95788b

<A NAME="RG08406ST-19">19</A>

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.