Efficient Synthesis of N-Alkyl Tetrahydroisoquinolines by Reductive Amination

Abstract

An expedient access to diverse N-alkyl 1,2,3,4-tetrahydroisoquinolines is reported by reductive amination of aldehydes and ketones with tetrahydroisoquinoline (THIQ) in the presence of Ti(Oi-Pr)₄ and NaBH₄. The N-alkyl THIQ products were rapidly purified by flow-through catch and release technique using commercially available polymer-supported sulfonic acid, MP-TsOH columns.

Key Words

reductive amination - tetrahydroisoquinoline - Ti(Oi-Pr)₄ - NaBH₄ - polymer-supported sulfonic acid column

References

• 1a Ghose AK. Viswanadhan VN. Wendoloski JJ. J. Comb. Chem.  1999,  1:  55 
• 1b Henkel T. Brunne RM. Mueller H. Reichel F. Angew. Chem. Int. Ed.  1999,  38:  643 
• See for example:
• 2a Nielsen TE. Diness F. Meldal M. Curr. Opin. Drug Discov. Dev.  2003,  6:  801 
• 2b Griffith MC. Dooley CT. Houghten RA. Kiely JS. In Molecular Diversity and Combinatorial Chemistry Libraries and Drug Discovery   Chaiken IM. Janda KD. American Chemical Society; Washington DC: 1996.  p.50 
• 2c Rozwadowska MD. Heterocycles  1994,  39:  903 ; and references therein
• 2d Gray NM. Cheng BK. Mick SJ. Lair CM. Contreras PC. J. Med. Chem.  1989,  32:  1242 
• 2e Herbert RB. In Chemistry and Biology of Isoquinoline Alkaloids   Phillipson JD. Roberts MF. Zenk MH. Springer-Verlag; Berlin: 1985.  p.213 
• 3a Scott JD. Williams RD. Chem. Rev.  2002,  102:  1669 
• 3b Aune GJ. Furuta T. Pommier Y. Anti-Cancer Drugs  2002,  13:  545 
• 4 Mokrosz MJ. Bojarsky AJ. Duszynska B. Tatarczynska E. Klodzinska A. Deren-Wesolek A. Charakchieva-Minol S. Chojnacka-Wojcik E. Bioorg. Med. Chem.  1999,  7:  287 
• 5 Parmee ER. Brockunier LL. Singh SB. Candelore MR. Cascieri MA. Deng L. Liu Y. Tota L. Wyvratt MJ. Fisher MH. Weber AE. Bioorg. Med. Chem. Lett.  2000,  10:  2283 
• 6a Gibson AC. Guillo N. Tozer MJ. Tetrahedron  1999,  55:  585 
• 6b Thomas JB. Atkinson RN. Vinson NA. Catanzaro JL. Perretta CL. Fix SE. Mascarella SW. Rothman RB. Xu H. Dersch CM. Cantrel BE. J. Med. Chem.  2003,  46:  3127 ; and references therein
• 7 Mach UR. Hackling AE. Perachon S. Ferry S. Wermuth CG. Schwartz J.-E. Sokoloff P. Stark H. ChemBioChem  2004,  5:  508 
• 8 Reductive amination reactions are extensively reviewed, see for example: Baxter EW. Reitz AB. Org. React. (N.Y.)  2002,  59:  1 ; and references 1-17 therein
• For example, see:
• 9a Bhattacharyya S. Rana S. Gooding OW. Labadie J. Tetrahedron Lett.  2003,  44:  4957 
• 9b Bhattacharyya S. Gooding OW. Labadie J. Tetrahedron Lett.  2003,  44:  6099 
• 9c Bhattacharyya S. Tamanaha L. Vo L. Labadie J. Comb. Chem. High Throughput Screening  2000,  3:  117 
• For example, see:
• 10a Kumpaty HJ. Bhattacharyya S. Rehr EW. Gonzalez AM. Synthesis  2003,  2206 
• 10b Miriyala B. Bhattacharyya S. Williamson JS. Tetrahedron  2004,  60:  1463 ; and references cited therein
• 11a Imwinkelried R. Seebach D. Helv. Chim. Acta  1984,  67:  1496 
• 11b Takahashi H. Tsubuki T. Higashiyama K. Synthesis  1988,  238 
• 14a Siegel MG. Hahn PJ. Dressman BA. Fritz JE. Grunwell JR. Kaldor SW. Tetrahedron Lett.  1997,  38:  3357 
• 14b Shuker AJ. Siegel MG. Matthews DP. Weigel LO. Tetrahedron Lett.  1997,  38:  6149 
• 14c Lawrence MR. Biller SA. Fryszman OM. Poss MA. Synthesis  1997,  553 
• 15a Thurman EM. Mills MS. In Solid-Phase Extraction: Principles and Practice   Wiley; New York: 1998.  p.55 
• 15b Thurman EM. Mills MS. In Solid-Phase Extraction: Principles and Practice   Wiley; New York: 1998.  p.131 

12

The work was presented in part by: Kumpaty H. J., Bhattacharyya S.; 228^th ACS National Meeting, Philadelphia; American Chemical Society: Washington, DC, August 2004; paper ORGN-701

13

The macroporous polystyrene-supported sulfonic acid, MP-TsOH columns (part number: 800477-0050-C) were obtained from Argonaut Technologies.