Furo pyrimidines, formation

Pyrimidines with an oxygen function at C-5 represent the most efficient precursors to furo[3,2-rf]pyrimidines. The formation of 5-propynyloxypyrimidines (240) allows cyclization to furo-pyrimidines (Equation (81)) (241). Treatment of compound (240 R = H) with sodium methoxide in warm DMSO gives the derivative (241 R = Me, R1 = H), whilst the methyl analogue (240 R = Me) undergoes thermal cyclization in DMSO to yield compound (241 R = R1 = Me). A parallel chemistry is described for the sulfur analogues <89JHC1851>. 

Another example of the simultaneous formation of both the pyrrolo and furo compounds has been observed. Nearly identical yields of 102c and 103b were isolated <2005JME5329>. Nonetheless, other 6-substituted derivatives of pyrrolo[2,3- pyrimidines have been prepared without complication, for example, 102d <2001JHC349> and a variety of arylmethyl compounds, illustrated by 102e <2003BMC5155>. 

Lithium diisopropyl amide (LDA) assisted Thorpe-Ziegler cyclization of cyanoenolethers (11) was used to synthesize the ribose-C-glycoside 12, which was further transformed into a furo[3,2-d] pyrimidine (86TL815 90MI1). Other bases such as NaOEt, l,5-diazabicyclo[4,3,0] non-5-ene (DBN), r-BuOK or n-BuLi that were successfully used in pyrrole syntheses (see Section III. A) were not suitable for this furan formation (Scheme 3). 

As with other nitrogen-containing heterocycles, TV-alkylation is a reaction of some interest. This is particularly true when the products are nucleosides. One interesting example of nucleoside formation arises from reaction of a suitable furo[3,4-J]pyrimidine (41) and l-O-acetyl-2,3,5-tribe nzoyl-/ -D-ribose the product formed seems to be solvent dependent. The N-l substituted nucleoside (42 R = tribenzoylribose) is formed in 81 % yield when the heterocycle and the protected sugar are treated with tin(IV) chloride in acetonitrile. However, use of 1,2-dichloroethane as solvent affords only 17% of this product together with 81% of the N-l,N-3 disubstituted product (Equation (10)) <83CPB3074>. 

Furo[2,3-r/]pyrimidines can also be obtained from other 6-substituted-pyrimidines. For example, the 6-chloropyrimidine (219) is converted to the 6-propargyloxy compound (220) which cyclizes to the derivative (221) upon heating <84H(22)2217>. The formation of a 6-methyl isomer is accounted for by a Claisen rearrangement of the 6-allyloxy group (Scheme 16). 

The S5mthesis of furopyrimidines has received a little attention in spite of their wide range of associated bioactivities including antimicrobial, antiviral, antimicotic, and antiplatelet [84-86]. Shaabani et al. reported a three-component condensation reaction of N,N -dimethylbarbituric acid with aldehydes and alkyl or aryl isocyanides at room temperature (RT) in the presence of [BMIM][Br] in a molar ratio of 1 1 (reactant/IL) to afford furo[2,3-d]pyrimidine-2,4(lH,3H)-diones 32 (Scheme 6). The authors cited that the presence of an electron-withdrawing group was necessary and addition of [BMIM][Br] was crucial for the formation of the desired product in high yield [87]. 

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