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Synlett 2005(4): 661-663  
DOI: 10.1055/s-2005-862394
LETTER
© Georg Thieme Verlag Stuttgart · New York

(PhO)3P·Cl2-Promoted Bischler-Napieralski-Type Cyclization: a Mild Access to β-Carbolines

Alberto Spaggiaria, Paolo Davolia, Larry C. Blaszczakb, Fabio Prati*a
a Università di Modena e Reggio Emilia, Dipartimento di Chimica, via Campi 183, 41100 Modena, Italy
Fax: +39(059)373543; e-Mail: prati.fabio@unimore.it;
b Discovery Chemistry Research and Technologies, Eli Lilly & Co., Lilly Corporate Center, Indianapolis, Indiana, 46285, USA
Further Information

Publication History

Received 17 December 2004
Publication Date:
22 February 2005 (online)

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Abstract

A novel mild access to the β-carboline skeleton is described. The reaction is a Bischler-Napieralski-type cyclocondensation, promoted by (PhO)3P·Cl2, which is performed in dichloromethane at -30 °C. The products are easily obtained in good yields and do not require further chromatographic purification.

Key words

triphenyl phosphite - chlorine - indoles - alkaloids - ­Bischler-Napieralski cyclizations

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17

Synthesis of Tryptamine Amides (1a-d); General Procedure.
Tryptamine (4500 mg, 28 mmol) was dissolved in dry CH2Cl2 (20 mL) in a two-necked 100 mL flask, and Et3N (4.3 mL, 30.8 mmol) was added. The appropriate acyl chloride (1.1 equiv) dissolved in CH2Cl2 (10 mL) was then cautiously dropped in, under vigorous stirring. The reaction mixture was heated to reflux for 90 min, until TLC showed disappearance of starting tryptamine. Thereafter, the mixture was washed with 10% HCl, sat. NaCl and finally with H2O, each time extracting with CH2Cl2. The organic phases were pooled, dried over MgSO4 and evaporated in vacuo, to provide a thick foam which was triturated with light petroleum, thus affording the desired amide as a reddish-brown fine powder (70-92% yield).

18

The role of the base is to shield (PhO)3P·Cl2 from the action of adventitious HCl, which is reported to enhance its degradation into an inactive form. For more detailed mechanistic insights, see Ref. 1,2a.

19

Synthesis of Harmalane Hydrochloride ( 2a).
In a three-necked 50 mL round bottom flask, anhyd CH2Cl2 (15 mL) was cooled to -30 °C under argon atmosphere. Triphenyl phosphite (1.2 mL, 4.6 mmol) was added and Cl2 was bubbled in, until the solution became bright yellow. The color was discharged by addition of a few drops of triphenyl phosphite, and tryptamine acetamide 1a (850 mg, 4.2 mmol) was then added, quickly followed by Et3N (671 µL, 4.83 mmol). The reaction was stirred over a 2-hour period, then the cold bath was removed and the mixture left to stir at r.t. After 12 h, a conspicuous yellow solid had precipitated and was recovered by centrifugation, thus affording 909 mg (98%) of harmalane (2a) as hydrochloride. 1H NMR (200 MHz, DMSO-d 6): δ = 2.79 (3 H, s, Me), 3.19 (2 H, t, J = 8.1 Hz, CH 2CH2N), 3.88 (2 H, t, J = 8.1 Hz, CH2CH 2N), 7.78-8.14 (4 H, m, arom.), 12.87 (1 H, br, NH), 13.07 (1 H, br, HCl). 13C NMR (50 MHz, DMSO-d 6): δ = 19.0, 19.1, 42.1 113.7, 121.6, 122.2, 123.0, 124.3, 126.8, 128.5, 140.9, 167.2. MS: m/z = 221 (M+), 207, 182, 154, 128, 91, 77, 63, 44. Anal. Calcd for C12H13ClN2: C, 65.31; H, 5.94; N, 12.69. Found: C, 65.42; H, 6.05; N, 12.73.

20

Synthesis of 1-Phenyl-4,9-dihydro-3 H -β-carboline ( 2b).
By close analogy to the procedure described above, triphenyl phosphite (1.16 mL, 4.3 mmol) was dissolved in anhyd CH2Cl2 (14 mL) at -30 °C under argon atmosphere. Then, Cl2 was bubbled in, until the solution turned intensely yellow. The color was discharged by addition of a few further drops of triphenyl phosphite and tryptamine benzamide 1b (1000 mg, 3.9 mmol) was added, quickly followed by Et3N (637 µL, 4.58 mmol), and the system was maintained under vigorous stirring over 2 h at -30 °C before removing the cold bath. After an additional 12 h period at r.t., the dark mixture was treated with 10% HCl and extracted with CH2Cl2 (4 × 10 mL). The aqueous phase was then basified to pH 10 with 20% NaOH and repeatedly extracted with CH2Cl2 (4 × 15 mL). The organic phases were pooled, dried and rotary evaporated, to afford 2b (505 mg, 51%) as a yellow fine powder (mp 196-198 °C). 1H NMR (200 MHz, CDCl3): δ = 2.99 (2 H, t, J = 8.5 Hz, CH 2CH2N), 4.06 (2 H, t, J = 8.5 Hz, CH2CH 2N), 7.10-7.85 (9 H, m, arom.), 8.24 (1 H, br, NH). 13C NMR (50 MHz, CDCl3): δ = 19.2, 48.8, 111.9, 117.9, 119.9, 120.4, 124.6, 127.8, 128.8, 129.9, 136.5, 137.6, 159.4. Anal. Calcd for C17H14N2: C, 82.90; H, 5.73; N, 11.37. Found: C, 82.85; H, 5.64; N, 11.49.

24

Application of Banwell’s method [14] to substrate 1b failed to give the expected β-carboline 2b.