Chemistry of 1,2,4-Trioxanes: Base-Mediated Formation of Highly Reactive Electrophiles and Their Entrapment with Amines and Thiols [1]

Abstract

6-(1-Arylvinyl)-substituted 1,2,4-trioxanes undergo a highly facile fragmentation under mild basic conditions to furnish 3-aryl-1-hydroxybut-3-en-2-ones, which react very efficiently with various amines and thiols to give Michael adducts. Both the formation of the reactive 3-aryl-1-hydroxybut-3-en-2-ones and their subsequent reaction with amines and thiols can be achieved in one pot.

Key words

1,2,4-trioxanes - hydroxy enones - Michael additions - thiols - amines

1

CDRI Communication No: 6850.

References

• 2a Klayman DL. Science  1985,  228:  1049 
• 2b Bhattacharya AK. Sharma RP. Heterocycles  1999,  51:  1651 
• 2c Borstnik K. Paik I. Shapiro TA. Posner GH. Int. J. Parasitol.  2002,  32:  1661 
• 2d Ploypradith P. Acta Trop.  2004,  89:  329 
• 2e O’Neill PM. Posner GH. J. Med. Chem.  2004,  47:  2945 
• 3a O’Neill PM. Mukhtar A. Ward SA. Bickley JF. Davies J. Bachi MD. Stocks PA. Org. Lett.  2004,  6:  3035 
• 3b O’Neill PM. Pugh M. Davies J. Ward SA. Park BK. Tetrahedron Lett.  2001,  42:  4569 
• 3c Bloodworth AJ. Johnson KA. Tetrahedron Lett.  1994,  35:  8057 
• 3d Posner GH. Oh CH. Milhous WK. Tetrahedron Lett.  1991,  32:  4235 
• 3e Bunnelle WH. Isbell TA. Barnes CL. Qualls S. J. Am. Chem. Soc.  1991,  113:  8168 
• 3f Avery MA. Chong WKM. Detre G. Tetrahedron Lett.  1990,  31:  1799 
• 3g Kepler JA. Philip A. Lee YW. Morey MC. Caroll FI. J. Med. Chem.  1988,  31:  713 
• 3h Jefford CW. Jaggi D. Boukouvalas J. Kohmoto S. J. Am. Chem. Soc.  1983,  105:  6497 
• 4a Peters W. Robinson BL. Tovey G. Rossier JC. Jefford CW. Ann. Trop. Med. Parasitol.  1993,  87:  1 
• 4b Peters W. Robinson BL. Rossier JC. Jefford CW. Ann. Trop. Med. Parasitol.  1993,  87:  9 
• 4c Peters W. Robinson BL. Tovey G. Rossier JC. Jefford CW. Ann. Trop. Med. Parasitol.  1993,  87:  111 
• 4d Kepler JA. Philip A. Lee YW. Morey MC. Carroll FI. J. Med. Chem.  1988,  31:  713 
• 4e Posner GH. Maxwell JP. O’Dowd H. Krasavin M. Xie S. Shapiro TA. Bioorg. Med. Chem.  2000,  8:  1361 
• 4f Posner GH. Jeon HB. Parker MH. Krasavin M. Paik I.-H. Shapiro TA. J. Med. Chem.  2001,  44:  3054 
• 4g Posner GH. Jeon HB. Polypradith P. Paik I.-H. Borstnik K. Xie S. Shapiro TA. J. Med. Chem.  2002,  45:  3824 
• 4h Griesbeck AG. El-Idreesy TT. Fiege M. Brun R. Org. Lett.  2002,  24:  4193 
• 4i O’Neill PM. Mukhtar A. Ward SA. Bickley JF. Davies J. Bachi MD. Stocks PA. Org. Lett.  2004,  18:  3035 
• 4j Griesbeck AG. El-Idreesy TT. Hoinck LO. Lex J. Brun R. Bioorg. Med. Chem. Lett.  2005,  15:  595 
• 5a Singh C. Tetrahedron Lett.  1990,  31:  6901 
• 5b Singh C. Gupta N. Puri SK. Tetrahedron Lett.  2005,  46:  205 
• 6a Singh C. Misra D. Saxena G. Chandra S. Bioorg. Med. Chem. Lett.  1992,  2:  497 
• 6b Singh C. Misra D. Saxena G. Chandra S. Bioorg. Med. Chem. Lett.  1995,  5:  1913 
• 6c Singh C. Gupta N. Puri SK. Bioorg. Med. Chem. Lett.  2003,  13:  3447 
• 6d Singh C. Malik H. Puri SK. Bioorg. Med. Chem.  2004,  14:  459 
• 6e Singh C. Malik H. Puri SK. Bioorg. Med. Chem. Lett.  2005,  15:  4484 
• 6f Singh C, Tiwari P, and Puri SK. inventors; US Patent 6737438  B2.  ; Chem. Abstr. 2004, 140, 270882j
• 7 Singh C. Malik H. Org. Lett.  2005,  25:  5673 
• For similar base-catalyzed fragmentation of dialkylperoxides and bicyclic endoperoxide, see:
• 10a Kornblum N. Delamare HE. J. Am. Chem. Soc.  1951,  73:  880 
• 10b Mete E. Altundas E. Secen H. Turk. J. Chem.  2003,  27:  145 

1

CDRI Communication No: 6850.

8

The stability of 3-aryl-1-hydroxybut-3-en-2-ones 9-12 is low, and this could be one of the reasons why they are obtained in such poor yields.

9

We suggest that this facile formation of 3-aryl-1-hydroxybut-3-en-2-one systems from the trioxanes on reaction with weak bases such as n-butylamine and the equal facile entrapment of these reactive species with amines and thiols may have relevance to the mechanism of the antimalarial action of these trioxanes. n-Butylamine is similar to the lysine side chain of lysine-containing proteins and an appropriate protein can generate the reactive species which could alkylate thiol residues of the same or a nearby protein, vital for the survival of the malarial parasite.