Pyrimidine formation amidine

Substituents in a 1,4-quinone may be displaced by nucleophiles in the presence of strong bases an amidine supplies the necessary atoms for pyrimidine formation. When the amino and carbonyl functions are in peri positions, a doubly fused ring is formed by reaction with formamide. 

Substituted pyrimidine N-oxides such as 891 are converted analogously into their corresponding 4-substituted 2-cyano pyrimidines 892 and 4-substituted 6-cya-no pyrimidines 893 [18]. Likewise 2,4-substituted pyrimidine N-oxides 894 afford the 2,4-substituted 6-cyano pyrimidines 895 whereas the 2,6-dimethylpyrimidine-N-oxide 896 gives the 2,6-dimethyl-4-cyanopyrimidine 897 [18, 19] (Scheme 7.6). The 4,5-disubstituted pyridine N-oxides 898 are converted into 2-cyano-4,5-disubsti-tuted pyrimidines 899 and 4,5-disubstituted-6-cyano pyrimidines 900 [19] (Scheme 7.6). Whereas with most of the 4,5-substituents in 898 the 6-cyano pyrimidines 900 are formed nearly exclusively, combination of a 4-methoxy substituent with a 5-methoxy, 5-phenyl, 5-methyl, or 5-halo substituent gives rise to the exclusive formation of the 2-cyanopyrimidines 899 [19] (Scheme 7.6). The chemistry of pyrimidine N-oxides has been reviewed [20]. In the pyrazine series, 3-aminopyrazine N-ox-ide 901 affords, with TCS 14, NaCN, and triethylamine in DMF, 3-amino-2-cyano-pyrazine 902 in 80% yield and 5% amidine 903 [21, 22] which is apparently formed by reaction of the amino group in 902 with DMF in the presence of TCS 14 [23] (Scheme 7.7) (cf. also Section 4.2.2). Other 3-substituted pyrazine N-oxides react with 18 under a variety of conditions, e.g. in the presence of ZnBr2 [22]. 

Almost accidentally, Bienayme and Bouzid discovered that heterocyclic amidines 9-76 as 2-amino-pyridines and 2-amino-pyrimidines can participate in an acid-catalyzed three-component reachon with aldehydes and isocyanides, providing 3-amino-imidazo[l,2-a]pyridines as well as the corresponding pyrimidines and related compounds 9-78 (Scheme 9.15) [55]. In this reachon, electron-rich or -poor (hetero)aromatic and even sterically hindered aliphatic aldehydes can be used with good results. A reasonable rahonale for the formation of 9-78 involves a non-con-certed [4+1] cycloaddition between the isocyanide and the intermediate iminium ion 9-77, followed by a [1,3] hydride shift. 

Two closely related reports of pyrazole generation by condensation of substituted hydrazines with enamino carbonyl compounds have appeared. In situ formation of an enaminoketone, by treatment of a diketone with dimethylformamide dimethyl acetal, was followed by tandem Michael addition-elimination/cyclodehydration under aqueous conditions in sealed microwave vessels (Scheme 3.12)17. Isoxazoles and pyrimidines were also prepared by replacing the substituted hydrazine with hydroxylamine or amidines, respectively (see Chapter 5, Section 5.3.2). The overall process may be regarded as another example of a multi-component coupling. In a similar fashion, enamino propenoates were condensed with substituted hydrazines to afford substituted pyrazoles (see Chapter 5, Section 5.3.2) (Scheme 3.12)18. 

Azole approach. The substituted isothiazole (142) can be reacted with an ortho ester to form a methyleneamine which reacts with hydroxylamine to yield the 5-oxide (143). With amidines, (142) yields 4-amino derivatives (75JHC883). The reaction of 5-amino-4-ethoxycar-bonylisothiazole with iminoethers results in pyrimidine annulation, as in the formation of... 

The reactions of amidines or guanidines with a-functionalized carbonyl compounds continue to be utilized for the synthesis of imidazoles. Thus, the mixed anhydride of acetic and chloroacetic acids reacts with symmetrical diarylguanidines to give l-aryl-2-arylaminoimidazolin-4-ones, and there is competitive formation of imidazoles and pyrimidines in the reaction of benzamidine with 3-bromobenzo-4-pyrones (18). Imidazoles are minor products, but are favored in nonpolar solvents. The use of a-dicarbonyl compounds with guanidine gives 2-amino-4-hydroxy-4-methyl-4//-imid-azoles, which give excellent yields of 2-aminoimidazoles on catalytic hydrogenation. " ... 

Shibata developed an interesting one-pot cascade sequence for the formation of tri-fluoromethyl-substituted pyrimidines. The combination of amidine 592 with enone 593... 

Tautomeric 1,4- and 1,6-dihydropyrimidines easily undergo nucleophilic addition. For example, upon prolonged contact with moisture, the addition of water across the C=C bond, with quantitative formation of 6-hydroxy-1,4,5,6-tetrahydropyrimidines, was observed [Eq. (55)]. The products are identical to those obtained by interaction of a,/ -unsaturated carbonyl compounds with amidines and indicate the reversibility of the dehydration step in the course of dihydropyrimidine formation for 6-hydroxytetrahydro-pyrimidines (Section V,B,1). 

Displacement of an alkoxy by a basic nitrogen group results in the formation of a C—N bond when the nitrogen is part of an amidine, the other nitrogen may attack a suitably positioned carbonyl to form a fused pyrimidine ring. 

The formation of pyrimido[4,5-d]pyrimidines 39 is also observed when 5-acyl-4-chloropy-rimidines 38 are reacted with amidines.108... 

As will be discussed in the next section, 1,5-pentanediones are obtained by Michael addition of acetophenones to chalcones. The addition and cyclization may be merged in one step (see Section II,C,2,g). When acetophenone was condensed with chalcone (74) in the presence of BFg-EtaO or of HC104, jS-phenylpropio-phenone (76) was obtained as by-product its formation is due to hydride transfer to the conjugate acid of chalcone (75), which is the acceptor (experimental data and theoretical calculations show that chalcones are protonated at the oxygen atom). Balaban obtained a 72% yield in the conversion 70 -> 37 using as acceptor chalcone and as catalysts perchloric or sulfuric acids (i.e., 75). The formation of j8-phenylpropiophenone (76) in the Chichibabin synthesis of pyridines from chalcones and ketones in the presence of ammonium acetate, and in the pyrimidine synthesis from chalcones and amidines is undoubtedly due to a similar hydride transfer. 

One of the two undesired reactions is the formation of an JV-formyl derivative of the base accompanied by loss of the nitrogen atom that is required for position 3 in the nascent pyrimidine ring. 7r-Deficiency in the starting material, which disfavors this formylation, encourages dimerization.122 Thus, 2-aminopyridine-3-carbonitrile (101) dimerizes to 2,3 -(2 -amino-pyridyl)-4-aminopyrido[2,3-d]pyrimidine (102). 2-Aminobenzonitrile does not undergo this reaction, whereas its 5-nitro derivative does so readily. The reaction is the addition of the amino group of one molecule across the cyano group of another to form an intermediate amidine.122,4... 

In a novel principle of 1,3-diazine formation phosphazenes like 20 containing an amidine moiety undergo an aza-WiTTiG reaction with a,p-unsaturated aldehydes followed by oxidative electrocyclic ringclosure to pyrimidines 21 [141] ... 

Amidines of perfluorocarboxylic acids are excellent synthons for the preparation of fluoroalkyl pyrimidines. The reaction of 35 with diethyl ethoxy ethylene malonate or malononitrile results in the formation of the corresponding 2-trifluoromethylpyrimidines 36 and 37 in high yield (Fig. 7.11). ... 

Polysubstituted pyrimidines were synthesized from in situ generated a,p-unsaturated imines and the corresponding amidine or guanidine derivatives in a convenient one-pot procedure. It was proposed that the described transformations proceed via the initial formation of o,P-imsaturated imine that undergo nucleophilic attack by a bidentate nucleophile (amidine or guanidine). This step is then followed by elimination of ammonia and aromatization to yield the observed polysubstituted pyrimidine. 

The formation of a pyrimidine ring via an inverse-electron-demand Diels-Alder reaction turned out to be the key step in the total synthesis of (—)-pyrimidoblamic acid (40) reported by Duerfeldt and Boger in 2014 (Scheme 27) (14JA2119). Pyrimidine 41 was prepared via reaction of 1,2,3-triazine 42 (2.0 equivalents) with amidine 43 (1.0 equivalent) in anhydrous acetonitrile.The reaction mixture was first stirred for 14 h at 5 °C then another 6 h at 25 °C, furnishing the desired pyrimidine, 41, as a single diastereomer.With this intermediate, the authors were able to introduce the required stereochemistry for the desired product in one step. 

The [4 + 2] cycloaddilion reaction of 1,2,3-triazines 5 with functionalized amidine 6 leading to the corresponding pyrimidines was successfully used for a total synthesis of (—)-pyrimidoblamic acid 7 and P-3A 8. The powerful reaction of the pyridine core formation was central in the complex synthesis and introduced all necessary stereochemistry in a single step (14JA2119). 

Forsberg et al. (41) discovered that trivalent lanthanide salts (i.e. La (CIO.) are powerful catalysts for the formation of pyrimidines ( >50% yield) fA>m acetonitrile and cyclic secondary amines. The lanthanide ion seems to be catalyze the amidine formation from acetonitrile and amine and may be also be involved in further steps of the reactions (eq. 28j). 

Reaction of amidine 585 with perfluorinated alkene 587 led to the formation of amidine 588, which upon heating with alkali gave a mixture of pyrimidines 590 (7 %) and 589 (34 %) (Scheme 126) [354], Pyrimidine 589 was obtained in 78 % yield when the second step of this sequence was performed using DABCO. 

Vinamidinium salt 840 is a promising reagent for the synthesis of 5-trifluoromethylpyrimidines 841, unsubstituted at positions C-4 and C-6. Compound 840 was prepared from 2,2,2-trifluoropropanoic acid (839). Acid 839 was obtained via radical addition of nifluoromethyl iodide to TBS-enolate 838 of ferf-butyl acetate 837, followed by acidic hydrolysis (Scheme 168) [512], Reaction of 840 with amidines and their analogues led to formation of the corresponding pyrimidines 841 in 54-85 % yields. Additional examples of such transformations were described [347, 513], including also reaction with aminopyrazole 843 (Scheme 169) [514]... 

One more three-component condensation leading to formation of chain-fluorinated pyrimidines 956 was microwave-assisted reaction of malononitrile, 2,2,2-trifluoro-1-phenylethanone and amidine in water (Scheme 203) [594], Attempts to perform this reaction under thermal conditions were unsnccessful. 

ABT-925 (229) was obtained starting from amidine 250 and ethyl triflnoroaceto-acetate to give pyrimidine 251 (Scheme 59) [221], Reaction of 251 with SOCI2 and then - piperazine led to the formation of amine 252. Selective alkylation of 252 with l-bromo-3-chloropropane gave chloride 253, which reacted with thionracil anion to form ABT-925 (229). 

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