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Synlett 2012(5): 760-764  
DOI: 10.1055/s-0031-1290532
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

C-1 Alkynylation of N-Methyltetrahydroisoquinolines through CDC: A Direct Access to Phenethylisoquinoline Alkaloids

Kamal Nain Singh*, Paramjit Singh, Amarjit Kaur, Pushpinder Singh
Department of Chemistry, Panjab University, Chandigarh 160014, India
Fax: +91(172)2545074; e-Mail: kns@pu.ac.in;
Further Information

Publication History

Received 16 December 2011
Publication Date:
24 February 2012 (online)

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Abstract

Direct cross-coupling between N-methyltetrahydroisoquinolines and alkynes using CuI-DEAD is presented. It affords the regioselective C-1-alkynylated products in good yield. This regio­selectivity is in contrast to the results reported earlier in the reaction of N,N-dimethylbenzyl amine where the N-methyl alkynylated product was formed exclusively or predominantly. The C-1-substituted propargylic isoquinolines were easily reduced to phenethylisoquinolines with Pd/C. This reaction sequence provides a short route to synthesize methopholine, homolaudanosine and other phenethylisoquinoline alkaloids.

Key words

cross-coupling - regioselectivity - alkaloids - alkynes - amines

    References and Notes

  • 1a Ozturk T. The Alkaloids   Vol. 53:  Cordell GA. Academic Press; New York: 2000.  p.120 
    Google Scholar
  • 1b Wu W. Beal JL. Fairchild EH. Doskotch RW. J. Org. Chem.  1978,  43:  580 
    Google Scholar
  • 1c Menachery MD. Lavanier GL. Wetherly ML. Guinaudeau H. Shamma M. J. Nat. Prod.  1986,  49:  745 
    Google Scholar
  • 1d Bentley KW. Nat. Prod. Rep.  2005,  22:  249 
    Google Scholar
  • 2a Scott JD. Williams RM. Chem. Rev.  2002,  102:  1669 
    Google Scholar
  • 2b Chrzanowska M. Rozwadowska MD. Chem. Rev.  2004,  104:  3341 
    Google Scholar
  • 2c Pedrosa R. Andre C. J. Org. Chem.  2001,  66:  243 ; and references therein
    Google Scholar
  • 3 Byrator E. Sasse BC. Stark H. Schneider G. ChemBioChem  2005,  6:  997 
    Google Scholar
  • 4a Shamma M. The Isoquinoline Alkaloids   Vol. 25:  Blomquist AT. Wasserman H. Academic Press; New York: 1972.  Chap. 24. p.458 
    Google Scholar
  • 4b Battersby AR. Bradbury RB. Herbert RB. Munro MHG. Ramage R. J. Chem. Soc., Perkin Trans. 1  1974,  1394 
    Google Scholar
  • 4c Kametani T. Koizumi M. The Alkaloids   Vol. 14:  Manske R. Academic Press; London: 1979.  Chap. 7. p.265 
    Google Scholar
  • 5a Cass LJ. Frederik WS. Am. J. Med. Sci.  1963,  246:  550 
    Google Scholar
  • 5b Meyers AI. Dickman DA. Boes M. Tetrahedron  1987,  43:  5095 
    Google Scholar
  • 5c Zbigniew C. MacLean DB. Szarek WA. J. Chem. Soc., Chem. Commun.  1987,  7:  1748 
    Google Scholar
  • 5d Zbigniew C. MacLean DB. Can. J. Chem.  1987,  65:  2356 
    Google Scholar
  • 5e Drenth JP. Meer JW. N. Engl. J. Med.  2001,  345:  1748 
    Google Scholar
  • 5f Terkeltaub RA. N. Engl. J. Med.  2003,  349:  1647 
    Google Scholar
  • 5g Tojo E. Önür MA. Freyer AJ. Shamma M. J. Nat. Prod.  1990,  53:  634 
    Google Scholar
  • For representative papers, see:
  • 6a Miyaura N. Suzuki A. Chem. Rev.  1995,  95:  2457 
    Google Scholar
  • 6b Kotha S. Lahiri K. Kashinath D. Tetrahedron  2002,  58:  9633 
    Google Scholar
  • 6c Nicolaou KC. Bulger PG. Sarlah D. Angew. Chem. Int. Ed.  2005,  44:  4442 
    Google Scholar
  • 6d Dyker G. Handbook of C-H Transformation   Wiley-VCH; Weinheim: 2005. 
    Google Scholar
  • 6e Zapf A. Beller M. Chem. Commun.  2005,  431 
    Google Scholar
  • 6f Herreries C. Yao X. Li Z. Li C.-J. Chem. Rev.  2007,  107:  2546 
    Google Scholar
  • 6g Alberico D. Scott ME. Lautens M. Chem. Rev.  2007,  107:  174 
    Google Scholar
  • 6h Miyaura N. Bull. Chem. Soc. Jpn.  2008,  81:  1535 
    Google Scholar
  • 6i Martin R. Buchwald SL. Acc. Chem. Res.  2008,  41:  1461 
    Google Scholar
  • 6j Chen X. Engle K.-M. Wang D.-H. Yu J.-Q. Angew. Chem. Int. Ed.  2009,  48:  5094 
    Google Scholar
  • 6k Bellina F. Rossi R. Chem. Rev.  2010,  110:  1082 
    Google Scholar
  • 6l Liu C. Zhang H. Shi W. Lei A. Chem. Rev.  2011,  111:  1780 
    Google Scholar
  • 7a Li C.-J. Acc. Chem. Res.  2009,  42:  335 
    Google Scholar
  • 7b Scheuermann C.-J. Chem. Asian J.  2010,  5:  436 
    Google Scholar
  • 7c Yeung CS. Dong VM. Chem. Rev.  2011,  111:  1215 
    Google Scholar
  • 8a Li Z.-P. Li C.-J. J. Am. Chem. Soc.  2004,  126:  11810 
    Google Scholar
  • 8b Li Z.-P. Li C.-J. Org. Lett.  2004,  6:  4997 
    Google Scholar
  • 8c Li Z.-P. Li C.-J. J. Am. Chem. Soc.  2005,  127:  3672 
    Google Scholar
  • 8d Li Z.-P. Li C.-J. J. Am. Chem. Soc.  2005,  127:  6968 
    Google Scholar
  • 8e Zhang Y. Li C.-J. J. Am. Chem. Soc.  2006,  128:  4242 
    Google Scholar
  • 8f Murahashi S.-I. Nakae T. Terai H. Komiya N. J. Am. Chem. Soc.  2008,  130:  11005 
    Google Scholar
  • 8g Li Z. Li C.-J. Angew. Chem. Int. Ed.  2008,  47:  7075 
    Google Scholar
  • 8h Sud D. Sureshkumar D. Klussmann M. Chem. Commun.  2009,  3169 
    Google Scholar
  • 8i Shen Y.-M. Li M. Wang S.-Z. Zhan T.-G. Tan Z. Guo C.-C. Chem. Commun.  2009,  953 
    Google Scholar
  • 8j Condie A.-G. Gonzalez-Gomez J.-C. Stephenson C.-R.-J. J. Am. Chem. Soc.  2010,  132:  1464 
    Google Scholar
  • 8k Liu P. Zhou C.-Y. Xiang S. Che C.-M. Chem. Commun.  2010,  2739 
    Google Scholar
  • 9a Ghobrial M. Harhammer K. Mihovilovic MD. Schnurch M. Chem. Commun.  2010,  46:  8836 
    Google Scholar
  • 9b Tsang S.-K. Todd MH. Tetrahedron Lett.  2009,  50:  1199 
    Google Scholar
  • 10 Weinberg NL. Brown EA. J. Org. Chem.  1966,  31:  4058 
    Google Scholar
  • 11a Xu X. Li X. Org. Lett.  2009,  11:  1027 
    Google Scholar
  • 11b Xu X. Li X. Ma L. Ye N. J. Am. Chem. Soc.  2008,  130:  14048 
    Google Scholar
  • 12a Lewis FD. Ho T.-I. Simpson JT. J. Am. Chem. Soc.  1982,  104:  1924 
    Google Scholar
  • 12b Dumbrowski GW. Dinnocenzo JP. Farid S. Goodman JL. Gould IR. J. Org. Chem.  1999,  64:  427 
    Google Scholar
  • 12c Barry JE. Finkelstein M. Mayeda EA. Ross SD. J. Org. Chem.  1974,  39:  2695 
    Google Scholar
  • DDQ-promoted cyanation and VO(acac)2-MCPBA-promoted coupling of nucleophiles like nitroalkanes, ketones and heteroaromatics such as indole and pyrrole with N-alkyltetrahydroisoquinolines have been reported earlier:
  • 13a Sundberg RJ. Theret M.-H. Wright L. Org. Prep. Proced. Int.  1994,  26:  386 
    Google Scholar
  • 13b Jones KM. Karier P. Klussmann M. ChemCatChem  2012,  4:  51 
    Google Scholar
  • 15a Hershberg EB. Oliveto EP. Gerold C. Johnson L. J. Am. Chem. Soc.  1951,  73:  5073 
    Google Scholar
  • 15b Taylor AM. Schreiber SL. Org. Lett.  2006,  8:  143 
    Google Scholar
  • 17a Brossi A. Besendrof H. Pellmont B. Walter M. Schinder O. Helv. Chim. Acta  1960,  43:  1459 
    Google Scholar
  • 17b Brossi A. Besendrof H. Pirk LA. Rheiner A. Med. Chem.  1965,  5:  281 
    Google Scholar
  • 17c Ito K. Furukawa H. Tanaka H. Kato S. J. Pharm. Soc. Jpn.  1970,  90:  1169 
    Google Scholar
14

General Procedure: To a solution of appropriate N-methyltetrahydroisoquinoline (1 mmol) in THF (2 mL), taken in 10-mL two-necked round bottom flask, was added DEAD (1.1 mmol) dropwise in 1-2 min at 0-5 ˚C and the reaction mixture was allowed to reach r.t. and stirred for 1 h. After re-cooling the reaction mixture to 0-5 ˚C, CuI (0.05 mmol) was added followed by dropwise addition of the alkyne (1.5 mmol). The resulting mixture was stirred for 5-6 h at r.t. and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatog-raphy over silica gel using hexane-EtOAc mixture (9:1-6:4) as the eluent to give the pure products 8a-j.
Spectral data of selected compounds:
1-(4-Chlorophenylethynyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (8f): yellow viscous liquid. ¹H NMR (300 MHz, CDCl3): δ = 7.23-7.27 (m, 2 H), 7.15-7.18 (m, 2 H), 6.97 (s, 1 H), 6.49 (s, 1 H), 4.53 (s, 1 H), 3.78 (s, 3 H), 3.77 (s, 3 H), 2.86-2.96 (m, 2 H), 2.78-2.83 (m, 1 H), 2.70-2.73 (m, 1 H), 2.51 (s, 3 H). ¹³C NMR (75 MHz, CDCl3-CCl4): δ = 148.35, 147.54, 134.15, 132.96, 128.54, 126.73, 125.48, 121.62, 111.35, 110.37, 88.59, 85.21, 56.42, 55.96, 55.80, 48.53, 43.58, 28.33. MS (ESI): m/z = 342.1 [M + H]+.
6,7-Dimethoxy-1-(3,4-dimethoxyphenylethynyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline (8h): yellow viscous liquid. ¹H NMR (300 MHz, CDCl3): δ = 6.90 (dd, J = 8.1, 1.8 Hz, 1 H), 6.80 (d, J = 1.8 Hz, 1 H), 6.72 (s, 1 H), 6.65 (d, J = 8.4 Hz, 1 H), 6.49 (s, 1 H), 4.50 (s, 1 H), 3.78 (s, 6 H), 3.77 (s, 6 H), 2.73-2.94 (m, 3 H), 2.58-2.62 (m, 1 H), 2.52 (s, 3 H). ¹³C NMR (75 MHz, CDCl3): δ = 149.39, 148.59, 148.21, 147.45, 127.18, 125.43, 125.00, 115.38, 114.61, 111.27, 110.93, 110.48, 86.14, 85.90, 56.57, 56.52, 55.92, 55.89, 55.74, 48.66, 43.66, 28.39. MS (ESI): m/z = 368.1 [M + H]+.

16

Spectral data of selected phenethylisoquinolines:
1-(4-Methoxyphenethyl)-2-methyl-1,2,3,4-tetrahydro-isoquinoline (10): light yellow oil. ¹H NMR (300 MHz, CDCl3): δ = 7.07-7.14 (m, 6 H), 6.79-6.82 (m, 2 H), 3.77 (s, 3 H), 3.46 (t, J = 5.4 Hz, 1 H), 3.12-3.18 (m, 1 H), 2.64-2.84 (m, 4 H), 2.42-2.47 (m, 1 H), 2.44 (s, 3 H), 2.00-2.09 (m, 2 H). ¹³C NMR (75 MHz, CDCl3): δ = 157.60, 138.18, 134.94, 129.29, 128.71, 127.06, 125.80, 125.74, 113.70, 63.03, 55.22, 48.31, 42.82, 36.93, 30.59, 26.14. Anal. Calcd for C19H23NO: C, 81.10; H, 8.24; N, 4.98. Found: C, 81.19; H, 8.33; N, 4.89.
6,7-Dimethoxy-2-methyl-1-phenethyl-1,2,3,4-tetra-hydroisoquinoline (12):¹7 yellow pasty mass. ¹H NMR (300 MHz, CDCl3): δ = 7.16-7.21 (m, 2 H), 7.09-7.12 (m, 3 H), 6.50 (s, 1 H), 6.44 (s, 1 H), 3.77 (s, 3 H), 3.74 (s, 3 H), 3.44 (t, J = 4.8 Hz, 1 H), 3.11-3.19 (m, 1 H), 2.66-2.87 (m, 4 H), 2.50-2.59 (m, 1 H), 2.44 (s, 3 H), 1.94-2.10 (m, 2 H). ¹³C NMR (75 MHz, CDCl3): δ = 147.46, 147.33, 142.43, 128.74, 128.39, 128.29, 125.85, 125.65, 111.26, 110.06, 62.59, 55.93, 55.76, 47.41, 42.03, 36.64, 31.76, 24.82. MS (ESI): m/z = 308.1 [M + H]+.