Synthesis of pyrimidines

Pyrimidines are an interesting class of nitrogen-containing heterocycles which display a broad range of useful properties.Based on a novel cyclocondensation reaction between acetylenic ketones of type 339 and polymer-bound isothiourea 338, Obrecht et developed a versatile and efficient solid-phase synthesis of polymer-bound 2-(alkylthio)-4,6-disubstituted pyrimidines 340, and combined this protocol with the nucleophilic displacement reaction of the 2-sulfonyl group of pyrimidines 47 j gy dgavage reaction. In addition, simple 

Reagents and conditions i) DIEA, DMF. r.t. ii) 50% TFA, CHjCij, r.t. iii) EDCi, DMF, CeFsOH iv) EDCI, HOSu, GHjCIji v) m-CPBA, CHaClai vi) pyrrolidine, dioxane, r.t. vii) R R NH, CHaClj viii) YH, dioxane, 50°C 

Reagents and conditions i) NEtj, DMF, NovaSynf TG Thiol resin (351) ii) m-CPBA, CHjCIji iii) R R NH, CH2CI2 iv) NaOH, H2O, THF, then HCI, THF v) oxalylchlotide. CHsCt vi) R -NHj, GHjCU vii) Ff-NHj. CHjCt viii) NMM, CiCOOiBu, THF ix) NaBH, HjO. THF x) PhOH, PPh, DEAD. NMM 

Reagents and conditions i) DIEA, DMF, A ii) m-CPBA, CHsClj Si) R R NH, CHjClj or dioxane 

A one pot synthesis of pyrano [2,3-d] pyrimidines from thiobarbituric acids under microwave irradiation using basic alumina has been reported. A significant 

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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. 

A synthesis of pyrimidine thiols in a yield of up to 60% from methoxybu-tenyne and thiourea has been described for the first time in (59JCS525). Later, a series of 2-amino-4-alkylpyrimidines (161) has been obtained in 25-27% yield from l-methoxyalk-l-en-3-ynes and guanidine (80°C, H, HoO, 2 h) (70ZOR2369). 

The bromide (5) failed to couple with dialkoxypyrimidines, even at elevated temperatures the failure is probably because of steric conditions imposed by the axially oriented C-4 p-nitrobenzoyloxyl group (see structure 5) this same group in the other halides (la, lb, 2a, 2b, 4a, and 4b) discussed in the foregoing is an equatorial substituent. Accordingly, the preparation of a differently constituted halide of 2-deoxy-D-Zt/xo-hexose is being investigated for the synthesis of pyrimidine nucleosides. 

In a similar way, 1,3-dinitrogen systems such as diamines, amidines, guanidines, aminothiazoles, aminopyridines, ureas and thioureas react with alkynyl-carbene complexes generating the corresponding heterocycles. Of particular interest is the reaction with ureas, as the process can be applied to the easy synthesis of pyrimidine derivatives [88] (Scheme 41). 

Alkynyl ketones 157 were also used for the synthesis of pyrimidines 159 by reacting amidines in acetonitrile at 120 °C in a dedicated microwave synthesizer without the requirement of additional purification (Scheme 56) [104]. 

Laland SG, Serck-Hanssen G (1964) Synthesis of pyrimidin-2-one deoxyribosides and their ability to support die growth of the deoxyriboside-requiring organism lactobacillus acidophilus r26. Biochem J 90 76-81... 

Fig. 4.8 Suggested mechanisms for the synthesis of pyrimidines from cyanoacetaldehyde (CAA) and cyanate, urea or guanidine (Cleaves et al., 2007)...

The synthesis of pyrimidines under specific prebiotic conditions, at low temperature, has apparently been carried out successfully (Fig. 4.8). The formation of the DNA building blocks was carried out by freezing out a dilute solution of cyanoacetaldehyde (CAA) and urea or guanidine. The concentration of CAA was only 1(T3 M, that of guanidine 1M. The reaction took 2 months at 273 K and a pH of 8.1. Yields were as follows ... 

A further unusual feature of the matrix-dependent polycondensation lies in the character of the nucleobases themselves. Purine mononucleotides undergo polycondensation, in good yields, at complementary matrices consisting of pyrimidine polymers. However, the synthesis of pyrimidine oligonucleotides from their mononucleotides at purine matrices is not effective. This important fact means that a pyrimidine-rich matrix leads to a purine-rich nucleic acid, which is itself not suitable to act as a matrix. This phenomenon also occurs when matrices are used which contain both basic species, i.e., purines and pyrimidines. An increase in the amount of purine in a matrix leads to a clear decrease in its effectiveness (Inoue and Orgel, 1983). However, the authors note self-critically that the condensation agent used cannot be considered to be prebiotic in nature. 

The yields of AEG were between 11 and 79%, at starting concentrations of 10 —10 4 M. AEG cyclizes to the lactam, monoketopiperazine, at neutral pH and around 373 K. The synthesis of the monomeric PNA units was carried out three years later (Nelson et al., 2000a, b). The synthesis of pyrimidine-A -acetic acid can be achieved if the reaction of cyanoacetaldehyde with high concentrations of urea mentioned above is modified slightly, with hydantoic acid replacing urea (Robertson and Miller, 1995). 

The condensation of anilides or enamides with nitriles was developed as a general method for the synthesis of pyrimidines or quinazolines such as 35 and 36 <06JACS 14254>. 

Scheme 7.28 Support modification for SPOT synthesis of pyrimidines.

The successfully generated chalcones could be cleaved by treatment with trifluoro-acetic acid or used for the subsequent synthesis of pyrimidines [45], Condensation of the polymer-bound chalcones with benzamidine hydrochloride under microwave irradiation for 30 min furnished the corresponding pyrimidines in good yields after TFA-induced cleavage. This new robust support/linker system for SPOT synthesis has been demonstrated to be compatible with a range of organic reactions and highly applicable for microwave conditions. 

In a related approach from the same laboratory, the perfluorooctylsulfonyl tag was employed in a traceless strategy for the deoxygenation of phenols (Scheme 7.82) [94], These reactions were carried out in a toluene/acetone/water (4 4 1) solvent mixture, utilizing 5 equivalents of formic acid and potassium carbonate/[l,T-bis(diphe-nylphosphino)ferrocene]dichloropalladium(II) [Pd(dppf)Cl2] as the catalytic system. After 20 min of irradiation, the reaction mixture was subjected to fluorous solid-phase extraction (F-S PE) to afford the desired products in high yields. This new traceless fluorous tag has also been employed in the synthesis of pyrimidines and hydantoins. 

Iodopyrimidines 60 could be converted to their Grignard derivatives by the action of i-PrMgCl, which then react with various electrophiles <00T265>. Queguiner and co-workers reported the synthesis of pyrimidines 61 bearing alcohols, aldehydes, and esters through this methodology. 

The first example describes the synthesis of a pyrimidine derivative. Starting from a, 3-unsaturated ketones (see Schemes 1, 8), a library of different heterocycles was prepared in research (Felder and Marzinzik 1998). In preparation for any large-scale synthesis, the availability of starting materials is always considered (Lee and Robinson 1995). For this work, we had to replace Rink amide resin B (Rink 1987), which was used by our colleagues in research for the synthesis of pyrimidine 1 due to its unavailability in large quantities (see Fig. 1). It was replaced with the Rink amide acetamido resin 4, which is well established in peptide amide synthesis (Bernatowicz et al. 1989) and easily accessible. 

Table 1 Solid phase synthesis of pyrimidine 1-TFA salt starting with resins of different loading...

Reduction is used for carbonyl functionalities [71, 230] such as thioesters [231], amides [232], and carbamates [233], as well as for sulfur [234] and selenium [122] compounds. Recently, the synthesis of a potential carbohydrate vaccine is described via an reduction-oxidation sequence [235]. An efficient solid-phase synthesis of pyrimidine derivatives that involved reduction of the corresponding nitro derivatives was developed by Makara et al. in 2001 (Scheme 3.9) [236]. 

Figure 8.29 The initial reactions of glutamine metabolism in kidney, intestine and cells of the immune system. The initial reaction in all these tissues is the same, glutamine conversion to glutamate catalysed by glutaminase the next reactions are different depending on the function of the tissue or organ. In the kidney, glutamate dehydrogenase produces ammonia to buffer protons. In the intestine, the transamination produces alanine for release and then uptake and formation of glucose in the liver. In the immune cells, transamination produces aspartate which is essential for synthesis of pyrimidine nucleotides required for DNA synthesis otherwise it is released into the blood to be removed by the enterocytes in the small intestine or by cells in the liver.

A different, simpler , pathway is involved in the synthesis of pyrimidine nucleotides. A pyrimidine base (orotate), is synthesised first. Then the ribose is added from 5-phosphoribosyl 1-pyrophosphate. The two precursors for the formation of orotate are carbamoylphosphate and aspartate, which form carbamoyl aspartate, catalysed by aspartate carbamoyltransferase. 

The fact that many agents which interrupt the synthesis of pyrimidine nucleotides from orotic acid in animals can also inhibit the growth of experimental neoplasms suggests a search for additional antimetabolites whose locus of action is in this metabolic sequence. Two in vitro biological screening systems were developed for this purpose [202—207]. From a study of systems with oxidative energy sources, 5-bromo-[208—209] (Villa), 5-chloro-[210] (Vlllb) and 5-diazo-orotic acid [211] (IX) were found to inhibit the conversion of orotic acid to the uridine nucleotides by 40—100 per cent [202]. 

Reductive removal of halogen substituents has been of value in the synthesis of pyrimidines and purines since the time of Fisher (1899). Natural purines were de-oxygenated in a sequence of reactions involving the replacement of hydroxyl by chlorine through the reaction with phosphorus pentachloride and the reduction using zinc dust and water [152], 2-Chloropurines 45 are not reduced under these conditions. The 2-iodopurines are however reduced by zinc and water [152]. The elec-... 

Fluorouracil acts by inhibiting synthesis of pyrimidine, and thus the formation of DNA. 

Cytarabine, like the drags described above, also acts by inhibiting synthesis of pyrimidines and thus DNA in cells. 

A general method for the synthesis of pyrimidine A-oxides from amidoximes is described. The conversion involves treatment of various carboxamide oximes 325 with 1,1,3,3-tetramethoxypropane, 2,4-pentanedione or 3-ethoxy-2-methylpropenal in the presence of CF3COOH to afford pyrimidine 1-oxides 326 (equation 141) . 

The synthesis of pyrimidine carboxylic esters can be achieved by palladium-catalyzed carbonylation of halopyrimi-dines with carbon monoxide and an alcohol < 1999T405, 2001S1098>, as shown by the formation of a variety of esters 271 from 2-chloro-4,6-dimethoxypyrimidine 270 <1999T405>. 

An alternative synthesis of pyrimidine boronic acids, which avoids lithiation chemistry altogether, has been developed <2001SL266>. Thus, reaction of 2,4-dimethoxy-5-iodopyrimidine 352 with cedrane-8,9-diolborane 351 using catalytic amounts of Pd(PPh3)4 and Cul gave the intermediate boronate 353 which could be converted to the free boronic acid 354 in 83% yield by transesterification with diethanolamine, followed by treatment with acid (Scheme 3) <2001SL266>. 

The synthesis of pyrimidines by transformation of a five-membered ring is not a general route and only limited examples are known <1994HC(52)1, 1996CHEG-II(6)93>. 

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