Pyrimidine imines, synthesis

The nucleophilicity of amine nitrogens is also differentiated by their environments. In 2,4,5,6-tetraaminopyrimidine the most basic 3-amino group can be selectively converted to a Schiff base. It is meta to both pyrimidine nitrogens and does not form a tautomeric imine as do the ortho- and /xira-amino groups. This factor is the basis of the commercial synthesis of triamterene. 

Reaction of pyridines with dialkyl acetylenedicarboxylates in the presence of isocyanates in dry CH2C12 at room temperature produced 1-substituted 2-oxo-l,9a-dihydro-2/7-pyrido[l,2-tf]pyrimidine-3,4-dicarboxylates <2004TL1803>. One-pot, three-component synthesis of 1-substituted 2-oxo-l,llb-dihydro-2//-pyrimido[2,l- ]iso-quinoline-3,4-dicarboxylates and 4-(3-chloro-4-methylphenyl)-3-oxo-4,4a-dihydro-3/7-pyrimido[l,2-tf]quinoline-l,2-dicarboxylate was realized by the reaction of isoquinoline and quinoline with isocyanates and dialkyl acetylenedicarboxylates <2004S861>. Diastereomeric mixtures of l-tosyl-2-aryl-l,llb-dihydro-2/7-pyrimido[2,Ttf]isoquinoline-3,4-dicarboxylates were obtained from isoquinoline, iV-tosyl-benzaldehyde imines, and DMAD <2002OL3575>. 

Perhaps the most useful part of the reported synthesis is the facile preparation of (—)-pyrimidoblamic acid (12 Scheme 3). A key to this synthesis is the preparation of the fully substituted pyrimidine 8. This was done by a one-pot inverse electron demand Diels-Alder reaction between the symmetrical triazine 7 and prop-1-ene-1,1-diamine hydrochloride, followed by loss of ammonia, tautomerization, and loss of ethyl cyanoformate through a retro-Diels-Alder reaction. Selective low-temperature reduction of the more electrophilic C2 ester using sodium borohydride afforded 9, the aldehyde derivative of which was condensed with 7V -Boc-protected (3-aminoalaninamide to give the imine 10. Addition of the optically active A-acyloxazolidinone as its stannous Z-enolate provided almost exclusively the desired anti-addition product 11, which was converted into (—)-pyrimidoblamic acid (12). Importantly, this synthesis confirmed Umezawa s assignment of absolute configuration at the benzylic center. 

The dimethoxy isoxazolo[4,5-pyrimidine derivative (96) showed solvent-dependent photochemistry (Scheme 2). Thus, irradiation in ether followed by alkaline hydrolysis gives compound (98) which is believed to be formed via the intermediate (97). The structure of the product (98) was established by synthesis via reductive cleavage of compound (96) to give the imine (99) and subsequent hydrolysis. Photolysis of compound (96) in carbon tetrachloride afforded a mixture of the products (100)-(102) <85JHC156l>. 

A new procedure has been developed by Prajapati and co-workers [97] for the synthesis of pyrimido[4,5-rf]pyrimidines 51. The condensation was carried out in the solid state under microwave irradiations by reacting electron-rich 6-[(dimethy-lamino)methylene]amino uracil that undergoes a [4-1-2] cycloaddition reaction with in situ generated glyoxylate imine to provide novel pyrimido[4,5-if]pyrimidines 51 in excellent yields (Scheme 37). 

The well-known synthesis from thiocyanatovinylaldehydes and nucleophiles <1996CHEC-II(3)319> has been used extensively in the last decade. In particular, new applications for the synthesis of isothiazolo[5,4-r/]pyrimidines 512 <2004CHE1352> and 2-(benzenesulfonylamino)isothiazolium-2-imines 348 have been found <1996RJ01693>. 

Intramolecular [ 2 + 2] photoadditions often proceed very efficiently with good stereochemical and regiochemical control. The vinylogous amide (96) is converted in this way into the adduct (97) with a high level of asymmetric induction retro-Mannich fragmentation of this adduct affords the imine (98), a useful intermediate in a synthesis of vindorosine. Intramolecular [ 2 + 2] photoadditions have also been observed in the N -( -alkenyl)-pyrimidines (99) and afford the diazatricyclodiones (100) as the sole photoproducts. 

Thongh different bonds are made, it is useful to include here the enaminothioimidate shown below for the synthesis of pyrimidin-2-ones and -thiones, by reaction with isocyanates and isothiocyanates, respectively, proceeding via a cycloaddition between the azadiene and the imine unit of the -N=C=S, then loss of dimethylamine to aromatise. ... 

In their synthesis of the pyrimidine segment of the potent antitumor antibiotic bleomycin, Umezawa, Ohno and coworkers have described the reaction of highly functionalized imine (96) with malonic acid monoethyl ester to afford 3-amino ester (97 equation 16)." The low yield of (97) is largely due to elimination of the amino side chain, giving the corresponding acrylate derivative. A subsequent modification of this reaction using a boron enolate overcomes this problem and will be discussed in Section 4.1.3.2.2.ii. 

There are methods for the preparation of pyridine derivatives, but they usually produce highly functionalized pyridines. One method is related to methods shown for the preparation of other heterocycles. When 2,4-pentanedione (117) is treated with ammonium acetate (NH4OAC), the product is an enamine-ke-tone, 128. This enamine subsequently reacts with a second equivalent of 117 to give the acyl addition product (the enamine attacks the carbonyl), which is imine 129. The amine (NH2) group attacks the second carbonyl and elimination gives the aromatic pyridine product (130). There are several variations of this fundamental approach, as well as other completely different approaches. The synthesis of pyrimidines will be delayed until the discussion of DNA and RNA in Chapter 28. 

Polysubstituted pyrimidines 39 can be obtained from a,P-unsaturated imines 38 and amidines or guanidines in a one-pot procedure [270]. The imines 38 are generated in situ in a sequential three-component process from methyl phosphonate, nitriles, and aldehydes (both preferentially aromatic for the utihty of 38 in pyridine synthesis, cf p. 373) ... 

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