Synlett 2008(10): 1479-1482  
DOI: 10.1055/s-2008-1078426
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of New Cyclopropanated Tryptamine Analogues

Claude Szalataa, Janos Sapia, Jan Szymoniakb, Philippe Bertus*b,c, Stéphane Gérard*a
a Institut de Chimie Moléculaire de Reims, UMR CNRS 6229, Faculté de Pharmacie, Université de Reims-Champagne-Ardenne, 51 rue Cognacq-Jay, 51096 Reims Cedex, France
e-Mail: stephane.gerard@univ-reims.fr;
b Institut de Chimie Moléculaire de Reims, , UMR CNRS 6229, UFR Sciences, Université de Reims-Champagne-Ardenne, BP 1039, 51687 Reims Cedex 2, France
c CNRS and Université du Maine, UMR 6011, UCO2M, 72085 Le Mans Cedex 9, France
Fax: +33(2)43833902; e-Mail: philippe.bertus@univ-lemans.fr;
Further Information

Publication History

Received 17 March 2008
Publication Date:
16 May 2008 (online)

Abstract

A series of tryptamine analogues bearing a cyclopropyl­amine unit was prepared, starting from 3-indolyl acetonitriles, through a MeTi(Oi-Pr)3-mediated cyclopropanation.

    References and Notes

  • 1a Vilsmaier E. In The Chemistry of the Cyclopropyl Group   Rappoport Z. Wiley; New York: 1987.  p.1341 
  • 1b Houben-Weyl   Vol. E17a-c:  de Meijere A. Thieme; Stuttgart: 1997. 
  • 2a Suckling CJ. Angew. Chem., Int. Ed. Engl.  1988,  27:  537 
  • 2b Salaün J. Top. Curr. Chem.  2000,  207:  1 
  • 3a Wise R. Andrews JM. Edwards LJ. Antimicrob. Agents Chemother.  1983,  23:  559 
  • 3b Todo Y. Nitta J. Miyajima M. Fukuoka Y. Yamashiro Y. Nishida N. Saikawa I. Narita H. Chem. Pharm. Bull.  1994,  42:  2063 
  • 3c Brighty KE. Castaldi MJ. Synlett  1996,  1097 
  • 3d Högberg M. Sahlberg C. Engelhardt P. Noréen R. Kangasmetsä J. Johansson NG. Öberg B. Vrang L. Zhang H. Sahlberg B.-L. Unge T. Lövgren S. Fridborg K. Bäckbro K. J. Med. Chem.  1999,  42:  4150 
  • 3e Daluge SM. Martin MT. Sickles BR. Livingston DA. Nucleosides Nucleotides  2000,  19:  297 
  • 3f Tichenor MS. MacMillan KS. Stover JS. Wolkenberg SE. Pavani MG. Zanella L. Zaid AN. Spalluto G. Rayl TJ. Hwang I. Baraldi PG. Boger DL. J. Am. Chem. Soc.  2007,  129:  14092 ; and references therein
  • 4a Fujita T. J. Med. Chem.  1973,  16:  923 
  • 4b N-Cyclopropyltryptamine was also described as a potent monoamine oxidase inhibitor. See: Winn M. Horrom BW. Rasmussen RR. Chappell EB. Plotnikoff NP. J. Med. Chem.  1975,  18:  437 
  • 5 Shimamoto K. Ishida M. Shinozaki H. Ohfune Y. J. Org. Chem.  1991,  56:  4167 
  • 6 Vangveragong S. Kanthasamy A. Lucaites VL. Nelson DL. Nichols DE. J. Med. Chem.  1998,  41:  4995 
  • 7 Tsotinis A. Vlachou M. Papahatjis DP. Calogeropoulou T. Nikas SP. Garratt PJ. Piccio V. Vonhoff S. Davidson K. Teh M.-T. Sugden D. J. Med. Chem.  2006,  49:  3509 
  • 8 Raoul M. Patigny D. Fabis F. Dauphin F. Rault S. Sapi J. Laronze J.-Y. J. Enzym. Inhib. Med. Chem.  2006,  251 
  • 9a Glennon RA. J. Med. Chem.  2003,  46:  2795 
  • 9b Holenz J. Mercè R. Diaz JL. Guitart X. Codony X. Dordal A. Romero G. Torrens A. Mas J. Andaluz B. Hernandez S. Monroy X. Sanchez E. Hernandez E. Pérez R. Cubi R. Sanfeliu O. Bushchmann H. J. Med. Chem.  2005,  48:  1781 
  • 10 Sapi J. Grébille Y. Laronze J.-Y. Lévy J. Synthesis  1992,  383 
  • 11a Bertus P. Szymoniak J. Chem. Commun.  2001,  1792 
  • 11b For a review, see: Bertus P. Szymoniak J. Synlett  2007,  1346 
  • An alternative approach involving the titanium-mediated cyclopropanation of N,N-dialkylamides should be envisioned, but requires the preparation of the amides. For the reaction, see:
  • 12a Chaplinski V. de Meijere A. Angew. Chem., Int. Ed. Engl.  1996,  35:  413 
  • 12b de Meijere A. Kozhushkov SI. Savchenko AI. J. Organomet. Chem.  2004,  689:  2033 
  • For related applications, see:
  • 12c Cao B. Xiao D. Joullié MM. Org. Lett.  1999,  1:  1799 
  • 12d Ouhamou N. Six Y. Org. Biomol. Chem.  2003,  1:  3007 
  • 12e Gensini M. de Meijere A. Chem. Eur. J.  2004,  10:  785 
  • 12f Larquetoux L. Kowalska JA. Six Y. Eur. J. Org. Chem.  2004,  3517 
  • 12g Larquetoux L. Ouhamou N. Chiaroni A. Six Y. Eur. J. Org. Chem.  2005,  4654 
  • 12h Faler CA. Joullié MM. Org. Lett.  2007,  9:  1987 
  • 13a Laroche C. Behr JB. Szymoniak J. Bertus P. Plantier-Royon R. Eur. J. Org. Chem.  2005,  5084 
  • 13b Laroche C. Plantier-Royon R. Szymoniak J. Bertus P. Behr J.-B. Synlett  2006,  223 
  • 13c Pearson M. Plantier-Royon R. Szymoniak J. Bertus P. Behr JB. Synthesis  2007,  3589 
  • 15 Bertus P. Szymoniak J. Org. Lett.  2007,  9:  659 
  • 16 Chaplinski V. Winsel H. Kordes M. de Meijere A. Synlett  1997,  111 
  • 20 Street LJ. Baker R. Castro JL. Chambers MS. Guiblin AR. Hobbs SC. Matassa VG. Reeve AJ. Beer MS. Middlemiss DN. Noble AJ. Stanton JA. Scholey K. Hargreaves RJ. J. Med. Chem.  1993,  36:  1529 
14

The ketone by-product might also be obtained by the hydrolysis of metallacycle B (Scheme [2] ). This assumption was ruled out by deuterolysis of the reaction media (no trace of deuterium was observed on the methyl moiety).

17

General Procedure for the MeTi(O i -Pr) 3 -Mediated Cyclopropanation of Nitriles 10a-c and 11a,b (Table 1): To a solution of the nitrile (1 mmol) and MeTi(Oi-Pr)3 (1.5 mmol) in THF (10 mL) was added dropwise under argon the Grignard reagent (1.5 mmol). The yellow solution darkened gradually within 5 min. After stirring for 1.5 h, BF3·OEt2 was added (2 mmol). After 30 min, the dark mixture was quenched with 1 M HCl (10 mL). EtOAc (20 mL) was added, followed by 3 M NaOH (10 mL). The mixture was stirred until the blue aqueous solution become white. The aqueous phase was extracted with EtOAc (2 × 20 mL). After drying (MgSO4) and evaporation of the solvents, the crude material was purified by flash chromatography (EtOAc).

18

Selected data: 1-[(1-Benzenesulfonyl-1 H -indol-3-yl)methyl]cyclopropylamine (12a): pale yellow solid; mp 97-98 °C. IR (neat): 3385, 1447, 1361, 1175 cm-1. 1H NMR (250 MHz, CDCl3): δ = 0.46-0.63 (m, 4 H), 1.50 (br s, 2 H, NH2), 2.72 (s, 2 H), 7.13-7.47 (m, 7 H), 7.78 (d, J = 7.7 Hz, 2 H), 7.94 (d, J = 8.3 Hz, 1 H). 13C NMR (63 MHz, CDCl3): δ = 14.5, 33.7, 35.7, 113.7, 119.8, 120.8, 123.2, 123.7, 124.7, 126.5, 129.1, 131.3, 133.7, 135.2, 137.9. HRMS (ES): m/z [M + H]+ calcd for C18H19N2O2S 327.1167; found: 327.1169.

19

The cyclopropanation of unprotected 8 gave only a low yield of the primary cyclopropylamine.

21

Selected data: N , N -Dimethyl-1-[(1-benzenesulfonyl-1 H -indol-3-yl)methyl]cyclopropylamine (6a): yellow oil. IR (neat): 3365, 2916, 2845, 1634, 1445, 1264, 1119 cm-1. 1H NMR (300 MHz, CDCl3): d = 0.25-0.57 (m, 4 H), 2.45 (s, 6 H), 3.01 (s, 2 H), 7.25-7.52 (m, 7 H), 7.80-7.83 (m, 2 H), 7.98 (d, J = 8.1 Hz, 1 H). 13C NMR (75 MHz, CDCl3): d = 13.3, 21.1, 40.9, 43.7, 113.9, 119.6, 120.3, 123.3, 124.2, 124.7, 126.5, 129.1, 131.7, 133.7, 135.1, 138.0. HRMS (EI): m/z [M+·] calcd for C20H22N2O2S: 354.1402; found: 354.1398. N , N -Dimethyl-1-[(1-methyl-2-vinyl-1 H -indol-3-yl)methyl]cyclopropylamine (7a): yellow oil. IR (neat): 3054, 2986, 2845, 1628, 1437, 1262 cm-1. 1H NMR (300 MHz, CDCl3): d = 0.30-0.55 (m, 4 H), 2.63 (s, 6 H), 3.30 (s, 2 H), 3.70 (s, 3 H), 5.50 (dd, J = 1.2, 11.9 Hz, 1 H), 5.69 (dd, J = 1.2, 17.9 Hz, 1 H), 7.07 (dd, J = 11.9, 17.9 Hz, 1 H), 7.02-7.38 (m, 3 H), 7.54 (d, J = 7.4 Hz, 1 H). 13C NMR (75 MHz, CDCl3): d = 12.2, 18.6, 30.7, 40.4, 44.7, 109.1, 117.3, 118.9, 119.3, 122.1, 125.9, 128.6, 128.7, 135.2, 137.2. HRMS (ES): m/z [M + H+] calcd for C17H23N2: 255.1861; found: 255.1855.