Pyrrolo pyrimidine ring

The investigations that describe the syntheses of pyrrolo[2,3-,7 pyrimidines from pyrimidines, with very few exceptions, have nitrogen functionality at the 4/6-position of the pyrimidine ring. Primarily this nitrogen-containing group is an amine moiety. Even within these limits, the major type of pyrimidine precursor has no substituent at position 5. 

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. 

The classic approach to the formation of a fused pyrimidine ring involves cyclization of adjacent amino and cyano (or carbalkoxy) groups. The formation of pyrrolo[3,2-d] pyrimidines, commencing with a suitably substituted pyrrole, follows this route exclusively. Virtually all of the activity using this approach involves the formation of C-nucleosides. 

N-Heterocyclic jS-enamino esters which are unsubstituted in the 1-position are well suited for a double condensation reaction when treated with 1,3-dicarbonyl compounds to give annelation of a [1,2-a] pyrimidine ring. Thus, the condensation of 2-aminopyrroline affords pyrrolo[l,2-a]-pyrimidines.82,114 Shvedov et al. treated 2-amino-3-pyrrolecarbonitrile 187 with / -diketones or ethyl acetoacetate74115 to give 188. No ring closure... 

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). 

Lead tetraacetate Oxidative and reductive pyrrolo[l,2-c]pyrimidine ring opening... 

Pyrimidine ring from guanidine with preceding replacement of hydroxyl by amino groups 5H-Pyrrolo[3,4-d]pyrimidine-7(6H)-ones... 

Molina, P., Eresneda, P.M., and Delgado, S. (2003) Carbodiimide-mediated preparation of the tricyclic pyrido[3, 2 4,5]pyrrolo[l,2-c] pyrimidine ring system and its application to the synthesis of the potent antitumoral marine alkaloid variolin B and analog. J. Org. Chem., 68, 489-499. 

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... 

Some interesting fused 1,2,3-triazole ring systems have been reported. A series of 5-piperidyl-substituted 7-hydroxy-3f/-l,2,3-triazolo[4,5-d]pyrimidines 143 has been synthesized from pipecolinate esters, benzylazides, and cyanoacetamide <06CHE246>. 4-Alkylidene-5,6-dihydro-4//-pyrrolo-[l,2-c][l,2,3]triazoles 144 were prepared from alkylidenecyclopropanes via diiodogenation/Cu(I)-catalyzed 1,3-dipolar cycloaddition/intra-molecular Heck reaction sequence <06SL1446>. 6,6-Dimethyl-2-phenyl-4,5,6,7-tetrahydro-27/-benzotriazol-4-one 145 were prepared from A-(5,5-dimethyl-3-oxocyclohexenyl)-S,S-diphenylsulfilimine and... 

In addition, some Stille adducts have been further manipulated to form condensed heteroaromatic ring systems. The coupling of 4-acetylamino-5-bromopyrimidine 69 and ( )-1-ethoxy-2-(tributylstannyl)ethene resulted in ( )-4-acetylamino-5-(2-ethoxyethenyl)pyrimidine 70, which then cyclized under acidic conditions to furnish pyrrolo[2,3-d]pyrimidine 71. Pyrrolo[3,2-d]pyrimidines were also synthesized in a similar fashion by using 5-acetylamino-4-bromopyrimidine [40]. 

An interesting pyrrolo[l,2-tf]pyrimidine was described as the product of the reaction of the heterocyclic ketene-aminals 236 that was synthesized by cyclocondensation of ketene dithioacetals 237 and 1,3-diamino propane. These compounds reacted with diethyl oxomalonate that behaves as an hetero-enophile, yielding the corresponding products 238 in acceptable to good yield (Scheme 31). A mechanism that involves an aza-ene reaction, via adduct 239 which isomerizes to ketene aminal 240 to produce the lactam ring of 238, has been proposed <1999J(P1)321>. 

Variation of the ring portion of acyclovir has been achieved. Compounds include monocyclic (isocytosine, triazole, imidazole), bicyclic (adenine, 8-azapurine, pyrrolo[2,3-c/]-pyrimidine, pyrazolo[3,4-[Pg.131]

The pyrrolo[2,3-d]pyrimidine 67 ring system can be obtained from 4-amino-substituted pyrimidine oxime 66 and Dowex-50 in water (equation 28) . Similar cyclization was realized in the presence of benzaldehyde and concentrated HCl . ... 

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