Substituted pyrimidine synthesis

Despite considerable localization of tt-electrons at the nitrogen atoms of pyrimidine, the ring system is still sufficiently aromatic to possess substantial stability. This is a great advantage in the primary synthesis of pyrimidines, in the synthesis of pyrimidines from the breakdown or modification of other heterocyclic systems and in the myriad of metatheses required to synthesize specifically substituted pyrimidines. 

The synthesis of 2-substituted pyrimidines from 1,3-dicarbonyl compounds and urea derivatives was first described by Evans2 and was later improved by Hunt, McOmie, and Sayer3 for the preparation of 2-mercapto-4,6-dimethylpyrimidine. Burness4 employed 3-ketobutyraldehyde acetal in this procedure to give 2-mercapto-4-methylpyrimidine. 2-Mercaptopyrimidine has been prepared from 1,1,3,3-tetraethoxypropane and thiourea by variations of this basic method 3 6 6 as well as by the reaction of 2-chloropyrimidine with thiourea 1 or sodium hydrosulfide.8... 

This preparation describes a convenient and general method of synthesis of substituted pyrimidines from compounds containing a /3-dicarbonyl group, either intact or as the corresponding ketal. The usefulness of the 2-mercaptopyrimidines is enhanced by the ease of removal of the mercapto group by desulfurization 9 or oxidation 10 and its replacement by other functional groups.1 ... 

Examples involving the use of organomercury reagents as nucleophiles in aqueous media are also known. Bergstrom studied the synthesis of C-5-substituted pyrimidine nucleosides in aqueous media via a mercurated intermediate using Li2PdCl4 as a catalyst (Eq. 6.42).136... 

The reaction of enolisable ketones with nitriles under the influence of triflic anhydride is a useful general method for the synthesis of 2,4- symmetrically substituted pyrimidines. 

Poullain and co-workers ° synthesized Af-substituted-3,5-diamino-4-nitropyrazoles by treating substituted pyrimidines with Af-alkylhydrazines. 3,5-Diamino-4-nitropyrazole (14) has been synthesized by treating the pyrimidine (13) with hydrazine hydrate. This methodology is limited in scope but the products are useful intermediates for the synthesis of insensitive high explosives. 

A new route to 4-substituted pyrimidines involves the condensation of nitriles with iV-vinyl amides which are activated by trifluoromethanesulfonic anhydride and 2-chloropyridine <2006JA14254>. The method is illustrated by the synthesis of 4-cyclohexyl-2,5-diphenylpyrimidine 627 from A-styrylbenzamide 625 and cyclohexanecarboni-trile 626 in 89% yield <2006JA14254>. 

Enolates can also function as masked aldehydes or ketones and a new synthesis of 2-substituted pyrimidine-5-carboxylic esters 652 used a doubly masked dialdehyde 651, where one aldehyde was protected as an acetal and the other was used in the form of its sodium enolate <2002S720>. 

The pyrimidine synthesis was therefore changed to the alkynyl ketone route as the appropriate precursors could be formed under much milder conditions. Thus, treatment of the chloro aldehyde 1002 with ethynyl Grignards or lithium species at low temperature, followed by mild oxidation with manganese dioxide, gave the desired chloro alkynyl ketones 1003, which could be successfully converted to the pyrimidine products 1004, by condensation with substituted guanidines, without displacement of the chlorine atom <2003X9001, 2005BMC5346>. 

While the alkynyl ketone route occurs under mild conditions, and can provide 4-substituted pyrimidines both substituted and unsubstituted at the 6-position, it cannot provide products substituted at the 5-position. However, this can be achieved by use of an oxidative enone cyclization, as demonstrated by the synthesis of the 3-(5-methylpyrimidinyl)pyrazolo[l,5- ]pyridine 1006 from 1002, where air oxidation of the initial adduct was catalyzed by the addition of palladium on carbon <2003T9001>. 

A synthesis of the monoterpene alkaloid ( )-actinidine has been accomplished through the intramolecular cycloaddition of a substituted pyrimidine (81JCS(P1)1909). Condensation of the diester (756) with formamidine provided the pyrimidine precursor (757) which when heated at its melting point (203 °C) underwent cycloaddition with elimination of isocyanic acid to produce the pyridone (758). Conversion of the pyridone into the chloropyridine was effected with phosphoryl chloride. The chlorine atom was then removed by hydrogenoly-sis over palladium on charcoal to afford the racemic alkaloid (759 Scheme 175). 

Pyrimido[l,6-tf]pyrimidines are conveniently prepared from functionally 4-substituted pyrimidine precursors. Specifically, 4-chloro-, 4-amino- and 4-methylthio-pyrimidines serve as useful intermediates for the synthesis of derivatives of this ring system. 

Thiazolo[5,4-d]pyrimidine, 2,5,7-trichloro-nucleophilic substitution, 6, 686 Thiazolo[3,2-a]pyrimidine-5,7-diones IR spectra, 6, 672 Thiazolopyrimidines synthesis, 5, 572, 574, 578 Thiazolopyrimidines, amino-purine synthesis from, 5, 591 Thiazolo[3,2-a]pyrimidines synthesis... 

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. 

Finally, p-tolyl-substituted pyrimidines and 1,2,4- and 1,3,5-triazines have been found also to undergo the Anil Synthesis,11 whereby several products have been patented as fluorescent whitening agents.84 Thus, for example, 2,4,6-tri(/>-tolyl)-l, 3,5-triazine (197) reacts with 3 moles of benzalaniline to yield the tristilbenyl derivative 198. 

A strong oxidant, mixtures with both organic and inorganic compounds are potentially explosive. It is recommended that the synthesis be not scaled up and be performed with due safety precautions [1], Addition to olefins can prove explosive, especially those bearing hydrogen. It was actually enones reported, 5-substituted pyrimidine-2,4-diones, on which a 6 alkoxy substituent was to be placed by the oxide and corresponding alkanol under base catalysis [2]. 

Scheme 17 Multi-step synthesis of substituted pyrimidines 19-21...

With this versatile alkynone synthesis in hand, the application to the pyrimidine synthesis was tested as well. As previously shown, 4-(indol-3-yl)- and4-(7-aza-indol-3-yl)-2-amino pyrimidines 36, which are structurally related to the marine natural products class of meridianins, have displayed a considerable potential as kinase inhibitors [143]. Therefore, upon reacting indolyl (37, X = CH) and 7-aza-indolyl (45, X = N) substituted alkynones or the pyirolyl ynones 46 with an excess of guanidinium hydrochloride and potassium carbonate in 2-methoxy ethanol at 120°C for 12-24 h the heteroaryl substituted 2-amino pyrimidines 47, 48, and 49 were obtained in good to excellent yields (Scheme 29). 

Ahluwalia VK, Kaila N, Bala S (1987) Synthesis and antifungal and antibacterial activities of some 2-amino-4, 6-substituted-pyrimidines and 4-styryl-6, 7-pyranocoumarins. Indian J Chem Sect B 26B 700-702... 

A fluorous catch and release method was used by Zhang in the synthesis of di-substituted pyrimidines.A fluorous route to hydantoins and thiohydantoins was also reported by the same group. 

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