Download PDF
Synlett 2008(18): 2807-2810  
DOI: 10.1055/s-0028-1083544
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

A Very Mild Access to 3,4-Dihydroisoquinolines Using Triphenyl Phosphite-Bromine-Mediated Bischler-Napieralski-Type Cyclization

Daniele Vaccari, Paolo Davoli, Claudia Ori, Alberto Spaggiari, Fabio Prati*
Università di Modena e Reggio Emilia, Via Campi 183, 41100 Modena, Italy
Fax: +39(059)373543; e-Mail: fabio.prati@unimore.it;
Further Information

Publication History

Received 18 July 2008
Publication Date:
15 October 2008 (online)

    Permissions and Reprints All articles of this category

Abstract

Substituted β-phenylethylamides undergo smooth intramolecular cyclization to 3,4-dihydroisoquinolines in good to excellent yields when treated with bromotriphenoxyphosphonium bromide at -60 ˚C in dichloromethane in the presence of triethyl­amine. The reaction proceeds under the mildest conditions ever reported for Bischler-Napieralski-type cyclizations. When chlorotriphenoxyphosphonium choride is used, low yields are obtained instead.

Key words

Bischler-Napieralski cyclization - phosphonium halides - iminoyl halides - isoquinoline alkaloids - necatorone - triphenyl phosphite

    References and Notes

  • 1a Aniszewski T. Alkaloids - Secrets of Life   Elsevier; Amsterdam: 2007. 
    Google Scholar
  • 1b Shulgin AT. Perry WE. The Simple Plant Isoquinolines   Transform Press; London: 2003. 
    Google Scholar
  • 1c Lundström J. In The Alkaloids   Vol. 21:  Brossi A. Academic Press; New York: 1983.  p.255-327  
    Google Scholar
  • 1d The Alkaloids   Vol. 7:  Manske RHF. Academic Press; New York: 1960. 
    Google Scholar
  • 1e The Alkaloids   Vol. 4:  Manske RHF. Holmes HL. Academic Press; New York: 1954. 
    Google Scholar
  • For recent reviews, see:
  • 2a Bentley KW. Nat. Prod. Rep.  2006,  20:  444 
    Google Scholar
  • 2b Bentley KW. Nat. Prod. Rep.  2005,  22:  249 
    Google Scholar
  • 2c Bentley KW. Nat. Prod. Rep.  2004,  21:  395 
    Google Scholar
  • 2d Bentley KW. Nat. Prod. Rep.  2003,  20:  342 
    Google Scholar
  • 3 Bischler A. Napieralski B. Ber. Dtsch. Chem. Ges.  1893,  26:  1903 
    CrossrefGoogle Scholar
  • For reviews, see:
  • 4a Whaley WM. Govindachari TR. Org. React.  1951,  6:  74 
    Google Scholar
  • 4b Kametani T. Fukumoto K. In The Chemistry of Heterocyclic Compounds   Part 1, Vol. 38:  Grethe G. Weissberger A. Taylor EC. Wiley; New York: 1981.  p.139-274  
    Google Scholar
  • 4c Fowler FW. In Comprehensive Heterocyclic Chemistry   Vol. 2:  Katritzky AR. Rees CW. Pergamon; Oxford: 1984.  p.410-416  
    Google Scholar
  • 4d Jones G. In Comprehensive Heterocyclic Chemistry II   Vol. 5:  Katritzky AR. Rees CW. Scriven DFV. Elsevier; Oxford: 1996.  p.179-181  
    Google Scholar
  • For reviews, see:
  • 5a Larghi EL. Amongero M. Bracca ABJ. Kaufman TS. Arkivoc  2005,  (xii):  98 
    Google Scholar
  • 5b Chrzanowska M. Rozwadowska MD. Chem. Rev.  2004,  104:  3341 
    Google Scholar
  • 5c Cox ED. Cook JM. Chem. Rev.  1995,  95:  1797 
    Google Scholar
  • 6a Nagubandi S. Fodor G. J. Heterocycl. Chem.  1980,  17:  1457 
    Google Scholar
  • 6b Nagubandi S. Fodor G. Tetrahedron  1980,  36:  1279 
    Google Scholar
  • 6c Gal J. Wienkam RJ. Castagnoli N. J. Org. Chem.  1974,  39:  418 
    Google Scholar
  • 6d Fodor G. Gal J. Phillips BA. Angew. Chem., Int. Ed. Engl.  1972,  11:  919 
    Google Scholar
  • For selected examples, see:
  • 7a Martin SF. Garrison PJ. J. Org. Chem.  1982,  47:  1513 
    Google Scholar
  • 7b Bosch J. Domingo A. Linares A. J. Org. Chem.  1983,  48:  1075 
    Google Scholar
  • 7c Sotomayor N. Domínguez E. Lete E. J. Org. Chem.  1996,  61:  4062 
    Google Scholar
  • 7d Ishikawa T. Shimooka K. Narioka T. Noguchi S. Saito T. Ishikawa A. Yamazaki E. Harayama T. Seki H. Yamaguchi K. J. Org. Chem.  2000,  65:  9143 
    Google Scholar
  • 7e Capilla AS. Romero M. Pujol MD. Caignard DH. Renard P. Tetrahedron  2001,  57:  8297 
    Google Scholar
  • 7f Batra S. Sabnis YA. Rosenthal PJ. Avery MA. Bioorg. Med. Chem.  2003,  11:  2293 
    Google Scholar
  • For selected examples, see:
  • 8a Doi S. Shirai N. Sato Y. J. Chem. Soc., Perkin Trans. 1  1997,  2217 
    Google Scholar
  • 8b Wang X.-J. Tan J. Grozinger K. Tetrahedron Lett.  1998,  39:  6609 
    Google Scholar
  • 8c Sánchez-Sancho F. Mann E. Herradón B. Synlett  2000,  509 
    Google Scholar
  • 8d Nicoletti M. O’Hagan D. Slawin AMZ. J. Chem. Soc., Perkin Trans. 1  2002,  116 
    Google Scholar
  • 8e Chern M.-S. Li W.-R. Tetrahedron Lett.  2004,  45:  8323 
    Google Scholar
  • 9 Snyder HR. Werber FX. J. Am. Chem. Soc.  1950,  72:  2962 
    Google Scholar
  • 10a Itoh N. Sugasawa S. Tetrahedron  1957,  1:  45 
    Google Scholar
  • 10b Itoh N. Sugasawa S. Tetrahedron  1959,  6:  16 
    Google Scholar
  • 11 Kanaoka Y. Sato E. Yonemitsu O. Ban Y. Tetrahedron Lett.  1964,  5:  2419 
    CrossrefGoogle Scholar
  • 12 Ramesh D. Srinivasan M. Synth. Commun.  1986,  16:  1523 
    CrossrefGoogle Scholar
  • 13 Judeh ZMA. Ching CB. Bu J. McCluskey A. Tetrahedron Lett.  2002,  43:  5089 
    CrossrefGoogle Scholar
  • 14 Hegedüs A. Hell Z. Potor A. Catal. Commun.  2006,  7:  1022 
    CrossrefGoogle Scholar
  • 15 Saito T. Yoshida M. Ishikawa T. Heterocycles  2001,  54:  437 
    Google Scholar
  • 16 Larsen RD. Reamer RA. Corley EG. Davis P. Grabowski EJJ. Reider PJ. Shinkai I. J. Org. Chem.  1991,  56:  6034 
    CrossrefGoogle Scholar
  • 17 Bhattacharijya A. Chattopadhyay P. Bhaumik M. Pakrashi SC. J. Chem. Res., Synop.  1989,  228 
    Google Scholar
  • 18a Banwell MG. Bissett BD. Busato S. Cowden CJ. Hockless DCR. Holman JW. Read RW. Wu AW. J. Chem. Soc., Chem. Commun.  1995,  2551 
    Google Scholar
  • 18b Wang Y.-C. Georghiou PE. Synthesis  2002,  2187 
    Google Scholar
  • 19 Boruah M. Konwar D. J. Org. Chem.  2002,  67:  7138 
    CrossrefPubMedGoogle Scholar
  • 20 Spaggiari A. Blaszczak LC. Prati F. Org. Lett.  2004,  6:  3885 
    CrossrefGoogle Scholar
  • 21 Spaggiari A. Davoli P. Blaszczak LC. Prati F. Synlett  2005,  661 
    Article in Thieme ConnectGoogle Scholar
  • 22a Vaccari D. Davoli P. Bucciarelli M. Spaggiari A. Prati F. Lett. Org. Chem.  2007,  4:  319 
    Google Scholar
  • 22b Vaccari D. Davoli P. Spaggiari A. Prati F. Synlett  2008,  1317 
    Google Scholar
  • 23a

    Acetamides 1a-e,h were prepared by treatment of the parent β-phenylethylamine with Ac2O, whereas for amides 1f,g the appropriate acyl chloride was employed instead. Except for 1a and 1b, which were obtained from commercially available β-phenyl- and 4-methoxy-β-phenylethylamine, respectively, in all other cases the starting β-phenylethylamine was synthesized by condensation of the corresponding aromatic aldehyde with nitromethane in the presence of AcOH and NH4OAc, and subsequent reduction of the resulting nitrostyrene with LAH in THF.7f,²³b In particular, 3-methoxybenzaldehyde, piperonal, veratryl aldehyde, and 3,4,5-trimethoxybenz-aldehyde were used for 1c,d,e-g,h, respectively. In the latter case, the original procedure for the synthesis of mescaline was used.²³c All synthesized β-phenylethylamines were used without any further purification.

  • 23b Sawant D. Kumar R. Maulik PR. Kundu B. Org. Lett.  2006,  8:  1525 
    Google Scholar
  • 23c Späth E. Monatsh. Chem.  1919,  40:  129 
    Google Scholar
  • 25a Fugmann B. Steffan B. Steglich W. Tetrahedron Lett.  1984,  25:  3575 
    Google Scholar
  • 25b Hilger CS. Fugmann B. Steglich W. Tetrahedron Lett.  1985,  26:  5975 
    Google Scholar
  • 26 Antkowiak R. Antkowiak WZ. In The Alkaloids   Vol. 40:  Brossi A. Academic Press; San Diego: 1991.  p.190-340  
    Google Scholar
  • 27 Spaggiari A. Vaccari D. Davoli P. Torre G. Prati F.
    J. Org. Chem.  2007,  72:  2216 
    CrossrefGoogle Scholar
  • 28 Okuda K. Kotake Y. Ohta S. Bioorg. Med. Chem. Lett.  2003,  13:  2853 
    CrossrefGoogle Scholar
  • 29 Liu D. Venhuis BJ. Wikström HV. Dijkstra D. Tetrahedron  2007,  63:  7264 
    CrossrefGoogle Scholar
  • 30 Moore MB. Wright HB. Vernsten M. Freifelder M. Richards RK. J. Am. Chem. Soc.  1954,  76:  3656 
    CrossrefGoogle Scholar
  • 31a Bills JL. Noller CR. J. Am. Chem. Soc.  1948,  70:  957 
    Google Scholar
  • 31b Späth E. Polgar N. Monatsh. Chem.  1929,  51:  190 
    Google Scholar
  • 32a Brossi A. Dolan LA. Teitel S. Org. Synth.  1977,  56:  3 
    Google Scholar
  • 32b Venkov AP. Ivanov II. Tetrahedron  1996,  52:  12299 
    Google Scholar
  • 33a Cortés EC. Romero EC. Ramírez FG. J. Heterocycl. Chem.  1994,  31:  1425 
    Google Scholar
  • 33b Minor DL. Wyrick SD. Charifson PS. Watts VJ. Nichols DE. Mailman RB. J. Med. Chem.  1994,  37:  4317 
    Google Scholar
  • 34a Kuo C.-Y. Wu M.-J. J. Chin. Chem. Soc. (Taipei)  2005,  52:  965 
    Google Scholar
  • 34b von Nussbaum F. Miller B. Wild S. Hilger CS. Schumann S. Zorbas H. Beck W. Steglich W. J. Med. Chem.  1999,  42:  3478 
    Google Scholar
  • 35a Späth E. Monatsh. Chem.  1921,  42:  97 
    Google Scholar
  • 35b Leete E.
    J. Am. Chem. Soc.  1966,  88:  4219 
    Google Scholar
24

Synthesis of 6,7-Dimethoxy-1-phenyl-3,4-dihydro-isoquinoline (2f)
Triphenyl phosphite (0.89 mL, 3.41 mmol) was dissolved in anhyd CH2Cl2 (20 mL) and cooled to -60 ˚C. Bromine (0.18 mL, 3.41 mmol) and anhyd Et3N (0.51 mL, 3.69 mmol) were introduced sequentially under argon flow. N-[2-(3,4-dimeth-oxyphenyl)ethyl]benzamide (1f, 819 mg, 2.84 mmol) was then added in one portion to the bright yellow solution maintained at the same temperature under vigorous stirring. The resulting mixture was gradually warmed to r.t. over a
2 h period, and left to stir overnight. Subsequently, the dark reaction mixture was extracted with 3 M HCl (3 × 15 mL), the combined aqueous layers were basified with 10% aq NaOH until pH = 11 and extracted with CH2Cl2 (3 × 15 mL). The pooled organic phases were dried over MgSO4, filtered, and evaporated under reduced pressure to afford the desired 3,4-dihydroisoquinoline 2f as a brownish liquid (692 mg, 92% yield). ¹H NMR (200 MHz, CDCl3): δ = 2.68 (2 H, t,
J = 7.4 Hz, CH 2CH2N), 3.67 (3 H, s, OMe), 3.77 (2 H, q, J = 7.4 Hz, CH2CH 2N), 3.86 (3 H, m, OMe), 6.75 (2 H, s, arom.), 7.36-7.59 (5 H, m, Ph). ¹³C NMR (50 MHz, CDCl3): δ = 26.0, 47.6, 56.0, 56.1, 110.4, 111.7, 120.0, 121.5, 128.1, 128.7, 129.2, 129.8, 132.5, 139.1, 147.5. MS: m/z = 235 [M+], 220, 204, 190, 177, 162,159, 146, 133, 110, 103, 91, 77, 65. Anal. Calcd for C12H13ClN2: C, 76.38; H, 6.41; N, 5.24. Found: C, 76.59; H, 6.65; N, 5.08.