Preparation of Polyfunctionalized 2,6-Dimethoxypyrimidine Derivatives via Chemo- and Regioselective Direct Zinc Insertion

Abstract

The functionalization at the C4 and/or C5 positions of 2,6-dimethoxypyrimidine derivatives via direct chemo- and regioselective zinc insertions is described. The insertion of commercially available zinc dust into C-I and C-Br bonds, in the presence of LiCl, proceeded under mild reaction conditions. The reactions of the resulting organozinc reagents with electrophiles gave the expected products in good yields. This procedure represents a new method for the polyfunctionalization of uracil derivatives.

insertion - organozinc compounds - zinc - pyrimidine - uracil

References

<A NAME="RT06707SS-1A">1a</A> Knochel P. Leuser H. Gong L.-Z. Perrone S. Kneisel FF. Polyfunctional Zinc Organometallics for Organic Synthesis, In Handbook of Functionalized Organometallics   Knochel P. Wiley-VCH; Weinheim: 2005.  p.251 

<A NAME="RT06707SS-1B">1b</A> Organozinc Reagents   Knochel P. Jones P. Oxford University Press; Oxford: 1999. 

<A NAME="RT06707SS-2A">2a</A> Tagaki K. Hayama N. Inokawa S. Bull. Chem. Soc. Jpn.  1980,  53:  3691 

<A NAME="RT06707SS-2B">2b</A> Tagaki K. Chem. Lett.  1993,  469 

<A NAME="RT06707SS-2C">2c</A> Tagaki K. Shimoishi Y. Sasaki K. Chem. Lett.  1994,  2055 

<A NAME="RT06707SS-2D">2d</A> Majid TN. Knochel P. Tetrahedron Lett.  1990,  31:  4413 

<A NAME="RT06707SS-3A">3a</A> Rieke RD. Li PT. Burns TP. Uhm ST. J. Org. Chem.  1981,  46:  4323 

<A NAME="RT06707SS-3B">3b</A> Arnold RT. Kulenovic ST. Synth. Commun.  1977,  7:  223 

<A NAME="RT06707SS-4A">4a</A> Krasovskiy A. Knochel P. Angew. Chem. Int. Ed.  2004,  43:  3333 

<A NAME="RT06707SS-4B">4b</A> Krasovskiy A. Straub BF. Knochel P. Angew. Chem. Int. Ed.  2006,  45:  159 

<A NAME="RT06707SS-5">5</A> Krasovskiy A. Malakhov V. Gavryushin A. Knochel P. Angew. Chem. Int. Ed.  2006,  45:  6040 

<A NAME="RT06707SS-6A">6a</A> Sakamoto T. Kondo Y. Sato S. Yamanaka H. J. Chem. Soc., Perkin Trans. 1  1996,  459 

<A NAME="RT06707SS-6B">6b</A> Lagoja IM. Chem. Biodiversity  2005,  2:  1 

<A NAME="RT06707SS-7A">7a</A> Schinazi RF. Prusoff WH. J. Org. Chem.  1985,  50:  841 

<A NAME="RT06707SS-7B">7b</A> Chan SA, Chen G, Guo R, and Wu J. inventors; PCT Int. Appl.  2005108377. 

<A NAME="RT06707SS-8A">8a</A> De Corte BL. Kinney WA. Liu L. Ghosh S. Brunner L. Hoekstra WJ. Santulli RJ. Tuman RW. Baker J. Burns C. Proost JC. Tounge BA. Damiano BP. Maryanoff BE. Johnson DL. Galemmo RA. Bioorg. Med. Chem. Lett.  2004,  14:  5227 

<A NAME="RT06707SS-8B">8b</A> Reese CB. Wu Q. Org. Biomol. Chem.  2003,  1:  3160 

<A NAME="RT06707SS-9">9</A> Boudet N. Knochel P. Org. Lett.  2006,  8:  3737 

<A NAME="RT06707SS-10">10</A> Das B. Kundu NG. Synth. Commun.  1988,  18:  855 

<A NAME="RT06707SS-11A">11a</A>

Zn powder was activated by treating first with 1,2-dibromoethane (5 mol%) and then with chlorotrimethyl­-silane (1 mol%).

<A NAME="RT06707SS-11B">11b</A> See: Knochel P. Rozema MJ. Tucker CE. Preparation of Highly Functionalized Reagents, In Organocopper Reagents   Taylor RJK. Oxford University Press; Oxford: 1994.  p.85 

<A NAME="RT06707SS-12">12</A>

Conversion >98%; the reaction conversion was monitored by GC-analysis of hydrolyzed reaction aliquots quenched with aq NH₄Cl.

<A NAME="RT06707SS-13">13</A> Krasovskiy A. Knochel P. Synthesis  2006,  890 

<A NAME="RT06707SS-14">14</A>

Boudet, N. The preparation of this starting material will be published soon elsewhere.

<A NAME="RT06707SS-15A">15a</A> Negishi E. Valente LF. Kobayashi M. J. Am. Chem. Soc.  1980,  102:  3298 

<A NAME="RT06707SS-15B">15b</A> Kobayashi M. Negishi E. J. Org. Chem.  1980,  45:  5223 

<A NAME="RT06707SS-15C">15c</A> Negishi E. Acc. Chem. Res.  1982,  15:  340 

<A NAME="RT06707SS-16">16</A> Piers E. Nagakura I. Synth. Commun.  1975,  5:  193