Suzuki-Miyaura and Negishi Approaches to a Series of Forensically Relevant Pyridines and Pyrimidines

Abstract

A library of 5-aryl-4-methylpyrimidines, phenyl ring-substituted derivatives of 4-benzylpyrimidines, 2,6-benzylpyridines, and 2,6-dibenzyl-4-methylpyridines were prepared. The synthesis of 5-aryl-4-methylpyrimidines was accomplished by Suzuki­-Miyaura cross-coupling reaction between arylboronic acids and 5-bromo-4-methylpyrimidine. The 4-benzylpyrimidines and 2,6-benzylpyridines were synthesized by treatment of 4-bromopyrimidine and 2,6-dibromopyridine derivatives with ring-substituted benzylzinc reagents.

Key words

cross-coupling reaction - amphetamine analogues - Leuckart synthesis - drugs - heterocycles

References

• 1a Joule JA. Mills K. Smith GF. In Heterocyclic Chemistry   Chapman & Hall; London: 1995. 
• 1b Itami K. Yamazaki D. Yoshida J.-i. J. Am. Chem. Soc.  2004,  126:  15396 
• 1c Baldwin BC. Corran AJ. Robson M. J. Pestic. Sci.  1995,  44:  81 
• 1d Wong K.-T. Hung TS. Wu ChCh. Lee G.-H. Peng S.-M. Chou Ch.-S. Su YO. Org. Lett.  2002,  4:  513 
• 2a van der Ark AM. Sinnema A. Theeuwen ABE. van der Torn JM. Verweij AMA. Pharm. Weekbl.  1978,  113:  41 
• 2b van der Ark AM. Sinnema A. van der Torn JM. Verweij AMA. Pharm. Weekbl.  1978,  113:  341 
• 2c van der Ark AM. Verweij AMA. Sinnema A. J. Forensic Sci.  1978,  23:  693 
• 3a Cloonan SM. Keating JJ. Corrigan D. O’Brien JE. Kavanagh PV. Wiliams DC. Meegan MJ. Bioorg. Med. Chem.  2010,  18:  4009 
• 3b Bohn M. Bohn G. Blaschke G. Int. J. Leg. Med.  1993,  106:  19 
• 3c Błachut D. Wojtasiewicz K. Czarnocki Z. Forensic Sci. Int.  2005,  152:  157 
• 4a Sinnema A. Verweij AMA. Bull. Narc.  1981,  33:  37 
• 4b Verweij AMA. Forensic Sci. Rev.  1989,  1:  1 
• 5 Waumans D. Bruneel N. Tytgat J. Forensic Sci. Int.  2003,  133:  159 
• 6 Błachut D. Wojtasiewicz K. Krawczyk K. Maurin J. Szawkało J. Czarnocki Z. Forensic Sci. Int.  2011,  in press
• 7a Błachut D. Wojtasiewicz K. Czarnocki Z. Forensic Sci. Int.  2002,  127:  45 
• 7b Błachut D. Maurin JK. Starosta W. Wojtasiewicz K. Czarnocki Z. Z. Naturforsch., B  2002,  57:  593 
• 7c Błachut D. Danikiewicz W. Wojtasiewicz K. Olejnik M. Kalinowska I. Szawkało J. Czarnocki Z. Forensic Sci. Int.  2011,  206:  197 
• 8a Dodson RM. Sayler JK. J. Org. Chem.  1952,  16:  461 
• 8b Muller TJJ. Braun R. Ansorge M. Org. Lett.  2000,  2:  1967 
• 9a Koyama T. Hirota T. Bashon C. Satoh Y. Shinhara Y. Watanabe Y. Matsumoto S. Shinohara Y. Ohmori S. Yamato M. Chem. Pharm. Bull.  1975,  23:  2158 
• 9b Kirkbridge KP. Ward AD. Jenkins NF. Klass G. Coumbaros JC. Forensic Sci. Int.  2001,  115:  53 
• 10 Błachut D. Czarnocki Z. Wojtasiewicz K. Synthesis  2006,  2855 
• 11 Schröter S. Stock Ch. Bach T. Tetrahedron  2005,  61:  2245 
• 12 Schomaker JM. Delia TJ. J. Org. Chem.  2001,  66:  7125 
• 13 Parry PR. Wang Ch. Batsanov AS. Bryce MR. Tarbit B. J. Org. Chem.  2002,  67:  7541 
• 14 Ceide SC. Montalban AG. Tetrahedron Lett.  2006,  47:  4415 
• 15a Van der Plas HC. Rec. Trav. Chim. Bays-Pas  1965,  84:  1101 
• 15b Yamanaka H. Sakamoto T. Nishimura S. Sagi M. Chem. Pharm. Bull.  1987,  35:  3119 
• 17 Wolfe JP. Buchwald SL. Angew. Chem. Int. Ed.  1999,  38:  2413 
• 18 Wiley Registry 8th/NIST 2005 Mass Spectral Library   Wiley; New Jersey: 2006. 
• 19a King LA. Poortman van der Meer AJ. Sci. Justice  2001,  41:  200 
• 19b Westphal F. Rösner P. Junge Th. Forensic. Sci. Int.  2010,  194:  53 
• 20 Abbotto A. Alanzo V. Bradamante S. Pagani GA.
  J. Chem. Soc., Perkin Trans. 2  1991,  481 
• 21 Luke R. W. A. inventors; US Patent US2006/0069109  A1. 
• 22 Metzger A. Schade MA. Knochel P. Org. Lett.  2008,  10:  1107 
• 24 Minato A. Tamao K. Hayashi T. Suzuki K. Kumada M. Tetrahedron Lett.  1980,  21:  845 
• 25 Berstein J. Stearns B. Shaw E. Lott WA. J. Am. Chem. Soc.  1947,  69:  1151 

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The outcome of the reactions was controlled by GC-MS. The advantage of the GC-MS method is that it can be applied to complicated mixtures of compounds, providing useful information of their composition and the products ratio. Obviously, the differences in the mass spectra of closely related isomers cannot be spectacular but due to a similar fragmentation routes, the total ion current should be similar for substrate, final products and by-products formed. Consequently, the intensities (peak area) of the peaks in chromatograms are a good measure for the proportion of substances in the mixture. In our case, the conversion was calculated by comparison of the peak area of remaining substrate with a sum of peak areas of the final product and by-products. The yield of a particular component was calculated by comparing of a peak area of the product with a sum of peak areas recorded for remaining products and substrate (if present).

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Unpublished results.