Fused Pyrimidines

The cleavage of fused pyrazines represents an important method of synthesis of substituted pyrazines, particularly pyrazinecarboxylic acids. Pyrazine-2,3-dicarboxylic acid is usually prepared by the permanganate oxidation of either quinoxalines or phenazines. The pyrazine ring resembles the pyridine ring in its stability rather than the other diazines, pyridazine and pyrimidine. Fused systems such as pteridines may easily be converted under either acidic or basic conditions into pyrazine derivatives (Scheme 75). 

Pyrimidine-fused pyrrolizines have been prepared from the functionalized tetrahydropyrroles 156 according to Scheme 45 <1989CHE691>. 

Benzo-fused pyrrolizines can be prepared from the palladium-catalyzed reaction of alkynes with imines of 2-halogenoanilines. Pyrimidine-substituted alkynes react in the same way, to produce the pyrimidine-fused pyrrolizines 161 <2001JOC412> (Scheme 48). 

Aminopyrimidines are also known to undergo Michael additions to a,P-unsaturated carbonyl compounds. This methodology was utilized by Insuasty and co-workers using triaminopyrimidines 70 with conjugated ketones 71 to produce a variety of pyrimidine-fused diazepines 72 <00JHC193,00JHC401>. 

A number of pyrimidines fused to five- or six-membered rings have been degraded to substituted pyrimidines and many of these reactions have been summarized elsewhere <1994HC(52)1>. A recent example used Raney nickel to remove a sulfur atom from the imidazo[4, 5 4,5]thieno[3,2-r/]pyrimidinone 966 <20010L3209, 2002JOC3365>. 

In recent years, there has been a greater interest in joining certain heterocyclic systems to [60]-fullerene with pyrimidine-fused 3-sulfolenes as one such case. Three derivatives have been examined in membrane model environments and the aggregation of these derivatives has been studied <2000J(P2)301>. Similar studies have been carried out on furo[2,3- ]pyrimidines <1996JST(385)55>. 

Aryl-substituted amides 39, when treated with triethyl orthoformate, give the corresponding N-arylated pyrimidine-fused rings 40 (Scheme 4) <2000PS(164)299> as well as one example of the triazine 41 <2000PS(164)299>. 

Many drugs based on pyridine derivatives treat symptoms of Parkinson disease. The various pyridine derivatives are bromocriptine 111, an indole-fused quinoline derivative, dexetimide 112, a 4-substituted 1-benzylpiperidine derivative, lisuride 113, an indole-fused quinoline derivative, pergolide 114, another indole-fused quinoline derivative, quinelorane 115, a pyrimidine-fused saturated quinoline derivative, terguride 116, a saturated quinoline derivative, and trihexyphenidyl 117, a 1-substituted piperidine derivative . 

Dimroth-type rearrangements are well documented in fused pyrimidines such as in [l,2,4]triazolo[4,3-a]pyrimidines and [l,2,4]triazolo[4,3-c]pyrimidines under acid or alkaline conditions. The same type of reaction will occur in pyrimidines fused to azoles containing other heteroatoms. Thus, the pyrimidines (695) undergo the Dimroth reaction under both acid and alkaline conditions to furnish the rearranged compounds (696) (74JOC3783). 

C. Heidelberger, Prog. Nucleic Acid Res. Mol. Biol. 4, 1-50 (1965). Pyrimidines, fused ... 

The anti-HIV nucleoside d4T 146 was obtained via a one-pot three-step procedure from the pyrimidine-fused oxazocine 145, which reacted with TfzO followed by treatment with l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and final reduction with Zn/AcOH (Equation 12) <1995TL2711>. 

The pyrimidine-fused 1,4-diazepinol 62 has been converted to the pteridinedione derivative 63 by tosylation and a thermally induced ring contraction <03H(60)2511>. 

Pyridopyrimidines and pyrimidines fused with five- or six-membered heterocycles can be prepared via the ring closure of intermediate ethynylpyrimidines, which are themselves obtained by the Pd-catalyzed cross-coupling of halopyrimidines with alkynic compounds (Scheme 34). ° ""° o-Alkynylanilines such as (51), which are made by Pd-catalyzed coupling reactions of alkynes with o-haloaniline precursors, are easily cyclized to the indoles in the presence of base (Scheme 35). " " Similar meth( s can be employed in the synthesis of isocoumarins," thienopyridines," furopy-ridines" and the marine alkaloid asptamine." ... 

Other synthons for 1,3-dicarbonyl compounds that have been successfully applied include p-chloro-a,P-unsaturated ketones and aldehydes, P-dimethylamino-a,P-unsaturated ketones (easily obtained from ketones by reaction with DMFDMA), P-alkoxy-enones"" and vinyl-amidinium salts."" Alkynyl-ketones react with 5-alkyl-isothioureas, giving 2-alkylthio-pyrimidines" and propiolic acid reacts with urea to give uracil directly in about 50% yield. "" 1,3-Keto-esters with formamidine produce 4-pyrimidinones"" and C-substituted formamidines with ethyl cyanoacetate give 2-substituted-6-amino -pyrimidinones. In analogy, pyrimidines fused to other rings, for example as in quinazolines, can be made from ortho-aminonitriles " and in general, from P-enamino esters. ... 

Pyrimidines fused to other six-membered rings, most frequently in the form of bicyclic structures, can be degraded to corresponding substituted monocyclic pyrimidines. Fused pyrimidine structures described are benzo- (quinazolines), pyrano[2,3-tf]-, pyrazino[2,3-i/j- (pteridines), pyrimido[l,2-u]-, pyrimido[4,5-i/]pyrimidines, and pyrimido[5,4-e]-a -triazines, pyrimido[5,4- f]-v-triazine, pyrim-ido[4,5-i/][l,3]oxazines, pyrimido[5,4-i/][l,3]oxazine, pyrimido[4,5- ][l,4]thiazines, pyrimido[5,4- ][l,4]thiazines, and pyrimido[4,5-e][l,2,4]thiadiazines. References to these reactions can be found in . 

A few examples have appeared of the formation of 3-amino-substituted pyrazine- and quin-oxalinecarboxylic derivatives by nucleophilic decomposition of their pyrimidine-fused ring systems (pteridines and analogues) (see also Section 6.03.4.1) <86JHC843,87JHC1013,91JHC1485>. 

Pyrimidine-fused Systems. - Owing to their pharmaceutical interest, many new thienopyrimidine derivatives are still being synthesized. The reaction of 2-amino-3-cyanothiophens with carbonyl sulphide has been used for the preparation of thieno[2,3-c/j-2-thio-oxopyrimidine. The reaction of 2,5-diamino-3,4-diethoxycarbonylthiophen with phenyl isocyanate in the presence... 

Pyrimidine-fused Systems. - Starting from 5-allyl-6-mercapto-... 

Pyrimidine-fused Systems.—Starting from the corresponding 2-amino-3-cyanothiophen, (194) has been prepared. Compounds such as (195) have been transformed into (196) and further derivatives of this system. 

Given the extensive presence of the pyrimidine ring in numerous compounds of medicinal value, this chapter will primarily focus on the contemporary methods to construct pyrimidine rings and pyrimidine-fused systems. In addition, the syntheses of a few commercial drugs are discussed to showcase the preparations of pyrimidines in industrial settings. 

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