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Synlett 2011(20): 2997-3001  
DOI: 10.1055/s-0031-1289889
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Sterically Controlled Stereoregulation in Aldol Reactions of 3-Aryl-1-alkyl Dihydrothiouracils

Varun Kumar, Gopal L. Khatik, Vipin A. Nair*
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, Mohali, Punjab 160 062, India
e-Mail: vn74nr@yahoo.com;
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Publikationsverlauf

Received 19 July 2011
Publikationsdatum:
11. November 2011 (online)

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Abstract

Aldol reactions of 3-aryl-1-alkyl dihydrothiouracils were investigated with respect to the orientation of the exocyclic group at N1, electronic effects of the aryl substituent at N3 and the steric demands of the electrophile. The reactions highlight the preference for formation of the anti aldol diastereomer with increasing steric constraints of the reactants.

Key words

aldol reaction - cyclization - aldehyde - dihydrothio­uracils - stereoselectivity

    References and Notes

  • For a comprehensive discussion on aldol reactions, see:
  • 1a Meckleburger HB. Wilcox CS. Comprehensive Organic Synthesis   Vol. 2:  Trost BM. Fleming I. Pergamon Press; New York: 1991.  p.99-131  
    Google Scholar
  • 1b Heathcock CH. Comprehensive Organic Synthesis   Vol. 2:  Trost BM. Fleming I. Pergamon Press; New York: 1991.  p.133-179  
    Google Scholar
  • 1c Heathcock CH. Comprehensive Organic Synthesis   Vol. 2:  Trost BM. Fleming I. Pergamon Press; New York: 1991.  p.181-238  
    Google Scholar
  • 1d Kim BM. Williams SF. Masamune S. Comprehensive Organic Synthesis   Vol. 2:  Trost BM. Fleming I. Pergamon Press; New York: 1991.  p.239-275  
    Google Scholar
  • 1e Mahrwald R. Modern Aldol Reactions   Wiley-VCH Verlag; Weinheim: 2004.  p.1218-1223  
    Google Scholar
  • 1f Yanagisawa A. Kimura K. Nakatsuka Y. Yamamoto H. Synlett  1998,  958 
    Google Scholar
  • 1g Mahrwald R. Costisella B. Gündogan B. Synthesis  1998,  262 
    Google Scholar
  • 1h Mahrwald R. Costisella B. Synthesis  1996,  1087 
    Google Scholar
  • For selected references, see:
  • 2a Evans DA. Bartroli J. Shih TL. J. Am. Chem. Soc.  1981,  103:  2127 
    Google Scholar
  • 2b Evans DA. Aldrichimica Acta  1982,  15:  23 
    Google Scholar
  • 2c Paterson I. Lister MA. McClure CK. Tetrahedron Lett.  1986,  27:  4787 
    Google Scholar
  • 2d Corey EJ. Imwinkelried R. Pikul S. Xiang YB. J. Am. Chem. Soc.  1989,  111:  5493 
    Google Scholar
  • 2e Oppolzer W. Blagg J. Rodriguez I. Walther E. J. Am. Chem. Soc.  1990,  112:  2767 
    Google Scholar
  • 2f Roder H. Helmchen G. Peters E.-M. Peters K. von Schmering H.-G. Angew. Chem., Int. Ed. Engl.  1984,  23:  898 
    Google Scholar
  • 2g Sankhavasi W. Yamamoto M. Kohmoto S. Yamada K. Bull. Chem. Soc. Jpn.  1991,  64:  1425 
    Google Scholar
  • 2h Drewes SE. Malissar DGS. Roos GHP. Chem. Ber.  1991,  124:  2913 
    Google Scholar
  • 2i Yan T.-H. Hung A.-W. Lee H.-C. Chang C.-S. J. Org. Chem.  1994,  59:  8187 
    Google Scholar
  • 2j Raimundo BC. Heathcock CH. Synlett  1995,  1213 
    Google Scholar
  • 2k Yokoyama Y. Mochida K. Synlett  1996,  445 
    Google Scholar
  • For selected references, see:
  • 3a Schetter B. Mahrwald R. Angew. Chem. Int. Ed.  2006,  45:  7506 
    Google Scholar
  • 3b Jiang Y. Hong J. Burke SD. Org. Lett.  2004,  61:  1445 
    Google Scholar
  • 3c Crimmins MT. Dechert A.-MR. Org. Lett.  2009,  11:  1635 
    Google Scholar
  • 3d Evans DA. Hu E. Burch JD. Jaeschke G. J. Am. Chem. Soc.  2002,  124:  5654 
    Google Scholar
  • 4a Xie L. Isenberger KM. Held G. Dahl LM. J. Org. Chem.  1997,  62:  7516 
    Google Scholar
  • 4b Yamago S. Machii D. Nakamura E. J. Org. Chem.  1991,  56:  2098 
    Google Scholar
  • 4c Heathcock CH. Buse CT. Kleschick WA. Pirrung MC. Sohn JE. Lampe J. J. Org. Chem.  1980,  45:  1066 
    Google Scholar
  • 4d Evans DA. Dart MJ. Duffy JL. Rieger DL. J. Am. Chem. Soc.  1995,  117:  9073 
    Google Scholar
  • 4e Evans DA. Rieger DL. Bilodeau MT. Urpi F. J. Am. Chem. Soc.  1991,  113:  1047 
    Google Scholar
  • 4f Evans DA. Côté B. Coleman PJ. Connell BT. J. Am. Chem. Soc.  2003,  125:  10893 
    Google Scholar
  • 5a Baldwin SW. Chen P. Nikolic N. Weinseimer DC. Org. Lett.  2000,  2:  1193 
    Google Scholar
  • 5b Santos LS. Pilli RA. J. Braz. Chem. Soc.  2003,  14:  982 
    Google Scholar
  • 5c Hoshimoto S. Matsunaga H. Kunieda T. Chem. Pharm. Bull.  2000,  48:  1541 
    Google Scholar
  • 6a Demir-Ordu O. Dogan I. Tetrahedron: Asymmetry  2010,  21:  2455 
    Google Scholar
  • 6b Narasimhulu PC. Das P. Synthesis  2009,  474 
    Google Scholar
  • 6c Padakanti S. Kumar CK. Ashok E. Das P. Synthesis  2009,  2709 
    Google Scholar
  • 7a Ulgheri F. Bacsa J. Nassimbeni L. Spanu P. Tetrahedron Lett.  2003,  44:  671 
    Google Scholar
  • 7b Spanu P. de Candia C. Ulgheri F. Tetrahedron Lett.  2010,  51:  2400 
    Google Scholar
  • 7c Ulgheri F. Orrù G. Crisma M. Spanu P. Tetrahedron Lett.  2004,  45:  1047 
    Google Scholar
  • 7d Ulgheri F. Giunta D. Spanu P. Tetrahedron  2008,  64:  11768 
    Google Scholar
  • 7e Mio S. Ichinose R. Goto K. Sugai S. Tetrahedron  1991,  47:  2111 
    Google Scholar
  • 7f Mio S. Shiraishi M. Sugai S. Haruyama H. Sato S. Tetrahedron  1991,  47:  2121 
    Google Scholar
  • 8a Chai S.-Y, Elokdah HM, and Sulkowaski TS. inventors; US Patent  5807864. 
  • 8b Ojima I, Fuchikami T, and Fujita MT. inventors; US Patent  4581452. 
  • 8c Brouwer GW, and Felauer EE. inventors; US Patent  4927451. 
  • 8d Teranishi M, Murakata C, Matsukama I, Susono M, Shuto K, and Ischikawa S. inventors; US Patent  4588729. 
  • 8e Elokdah H. Sulkowski TS. Abou-Gharbia M. Butera JA. Chai S.-Y. McFarlane GR. McKean M.-L. Babiak JL. Adelman SJ. Quinet EM. J. Med. Chem.  2004,  47:  681 
    Google Scholar
  • 8f Okawara T. Nakayama K. Furukawa M. Chem. Pharm. Bull.  1983,  31:  507 
    Google Scholar
  • 9a Kumar V. Nair VA. Tetrahedron Lett.  2010,  51:  966 
    Google Scholar
  • 9b Kumar V. Raghavaiah P. Mobin SM. Nair VA. Org. Biomol. Chem.  2010,  8:  4960 
    Google Scholar
  • 9c Khatik GL. Pal A. Apsunde TD. Nair VA. J. Heterocycl. Chem.  2010,  47:  734 
    Google Scholar
  • 9d Khatik GL. Pal A. Mobin SM. Nair VA. Tetrahedron Lett.  2010,  51:  3654 
    Google Scholar
  • 9e Khatik GL. Kaur J. Kumar V. Tikoo K. Venugopalan P. Nair VA. Eur. J. Med. Chem.  2011,  46:  3291 
    Google Scholar
  • 9f Chouhan M. Senwar KR. Sharma R. Grover V. Nair VA. Green Chem.  2011,  13:  2553 
    Google Scholar
  • 9g Khatik GL. Khurana R. Kumar V. Nair VA. Synthesis  2011,  3123 
    Google Scholar
  • 9h Sharma R. Chouhan M. Nair VA. Tetrahedron Lett.  2010,  51:  2039 
    Google Scholar
  • 9i Chouhan M. Sharma R. Nair VA. Appl. Organomet. Chem.  2011,  25:  470 
    Google Scholar
  • 9j Sharma R. Chouhan M. Sood D. Nair VA. Appl. Organomet. Chem.  2011,  25:  305 
    Google Scholar
  • 9k Randive NA. Kumar V. Nair VA. Monatsh. Chem.  2010,  141:  1329 
    Google Scholar
  • 10 Azizi N. Saidi MR. Tetrahedron  2004,  60:  383 
    Google Scholar
  • 11a Energy calculations were performed using the Gaussian 03 program. Computational calibrations were done on a model compound {(6S)-methyl-3-(4-cyano-3-chlorophenyl)--1-[(S)-1-phenylethyl]-2-thioxotetrahydropyrimidin-4(1H)-one} by energy minimizations using the semi-empirical method MM2, and ab initio calculations by Gaussian B3LYP with basis set 6-31G* (d,p). The outcomes of these independent calculations were perfectly in agreement with the structure of the molecule, as confirmed by single crystal X-ray diffraction analysis, see reference 9b
  • 11b

    The present studies involve another molecule of the same template, and the structure was optimized by ab initio calculation using Gaussian B3LYP.