Pyrroles pyrrolo pyrimidine

This section details syntheses of the pyrrolo[i,2-a]pyrimidine ring system in which only acyclic starting materials are used. In most cases, however, a substituted pyrrole or pyrimidine monocyclic structure is probably an intermediate in this process. These react further under the conditions employed to give the observed bicyclic product. Wollweber et al.31 have provided experimental evidence for just such an intermediate (see below). 

Lauria A, Diana P, Barraja P, Montalbano A, Dattolo G, Cirrincione G (2004) Docking of indolo- and pyrrolo-pyrimidines to DNA. New DNA-interactive polycycles from amino-indoles/pyrroles and BMMA. ARKIVOC 5(2) 263-271... 

The pyrrolo[2,3-c/]pyrimidine anticancer agent is prepared utilizing, as a key sequence, Michael condensation of 2,6-diamino-4(.37/)-pyrimidinone with nitroalkenes, followed by the Nef reaction that leads to the annulated pyrrole ring (Eq. 10.67).98... 

Rl R2 R3 Pyrrole 3-Tosyl Yield, %) Pyrrolo, Z-c pyrimidine Yield, %)... 

In an effort to explore the chemistry of pyrrolodiazines and their quatemized salts (see Section 6.2.2.2), Alvarez-Builla and co-workers prepared a series of pyrrolo[l,2-c]pyrimidines via methodology developed in their laboratory <99JOC7788>. Cyclocondensation of tosylmethyl isocyanide with substituted pyrrole-2-carboxaldehydes 17 produced pyrimidine derivatives 18 sifter removal of the tosyl group. The key to this procedure was the use of tosylmethyl isocyanide, which provided a relatively easily removed tosyl group in comparison to the more problematic decarboxylation of a carboxylic acid functionality. 

As with other series involving the annulation of a pyrimidine ring onto a five-membered ring, the usual requirement is to have two adjacent functional groups, one of which is an amine. The use of a cyano group as the other functional group occupies the majority of examples in such syntheses. Therefore, it is not surprising that this situation holds in the syntheses of pyrrolo[2,3-,y pyrimidines from pyrroles. 

The most common approach to the synthesis of a fused pyrimidine ring involves condensation reactions between adjacent carboalkoxy and amino groups. Therefore, it is not surprising that the majority of pyrrolo[3,2-4]pyrimidines that involve a pyrrole precursor follow this pathway. 

Although strictly speaking this example does not begin with a preformed ring, the explanation for the conversion of 236 into pyrrolo[3,2-tf pyrimidines 237 by heating with an amine appears to proceed via an unisolated pyrrole (Equation 84) <2000H(53)805>. This process can be explained by cyclization of 236 into 3-dimethylamino-4-(2-pyridinyl)pyrrole-2-carboxylate followed by reaction with another molecule of 236 in which the dimethylamino group is substituted by the aminopyrrole derivative. 

Likewise 3-amino-2-cyano-4-(3-methoxyphenyl)-A -carboethoxypyrrole is converted into 7-(3-methoxyphenyl)-pyrrolo[3,2- pyrimidin-4-one by, first decarboxylation, and then cyclization in refluxing formic acid <2006BMCL2091>. Replacing the 3-methoxyphenyl group on the pyrrole with a reduced pyrrole (a mimic of a ribofuranose ring) leads to a 4-aminopyrrolo[3,2- pyrimidine when treated with formamidine acetate <2006BMCL2662>. 

Finally, ortho aminoesters have been used to produce 7-deazaxanthines. For example ethyl 2-amino-5-phenyl-l//-pyrrole-3-carboxylate is first treated with 2-chloroethyl isocyanate in refluxing toluene. The resulting urea derivative is then allowed to react with l-(2-methoxyphenyl)piperazine and cyclized to the expected pyrrolo[2,3-,7 pyrimidin-2,4(177,377)-dione <2006BMCL150>. 

Heterocyclization of oxime 45 with acetylene under similar conditions (87KGS937) formed only 3//-pyrrole 46 in small yield (Scheme 25). However, it became clear later (87TH1) that the products 43 and 46 were pyrrolo[ 1,2-c]pyrimidines 44 and 47 (Scheme 24 and 25). 

This interesting mechanism of heterocyclization of piperidine oximes with acetylene leading to pyrrolo[l, 2-c]pyrimidines was further discussed by Prostakov and co-workers (87KGS1286). l,3,5-Trimethylpiperidin-4-one oxime (48) formed 2,4,5-trimethyl-l,2,3,4-tetrahydropyrrolo[l,2-c]-pyrimidine (50) in 16% yield, evidently, due to aromatization of the intermediate 3//-pyrrole (49) (Scheme 26). 

In 1990 we initially became interested in the possibility of utilizing the acylative version of the Knorr pyrrole synthesis for the construction of pyrrolo[2,3-cf pyrimidines. Over the past 7 years this notion has been... 

At the conclusion, the total synthesis of rigidin (6) proceeded in nine steps and nearly 26% overall yield starting from 6-chlorouracil and ethyl 2,4-dimethoxybenzylglycinate. The utility of the acylative pyrrole annu-lation approach to a highly substituted pyrrolo[2,3-d]pyrimidine system was thus revealed. Next we chose to focus our attention on representative... 

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