Pyrimidines with nucleophiles

Reactions of iV -alkylated or arylated azinium compounds with nucleophiles proceed more readily than those of the parent, uncation-ized azines, and the ring tends to open. The iV -substituent may bring into play an accelerative effect from the London forces of attraction. Increased displaceability of the substituent in iV -alkyl-azinium compounds has been noted for 2-halopyridinium (87) 1-haloisoquinolinium, 4-halopyrimidinium, 4-methoxypyrid-inium (88), 4-phenoxy- and 4-acetamido-quinazolinium (89), 3-methylthiopyridazinium, and 2-car boxymethylthiopyrimidi-nium salts (90). The latter was prepared in situ from the iV -alkyl-pyrimidine-2-thione. The activation can be effectively transmitted to... 

Besides nucleophile-induced transformations the Hetero Diels-Alder (HDA) cycloaddition reactions are also very suitable ways to perform the pyrimidine-to-pyridine ring transformations. They can occur either by a reaction of an electron-poor pyrimidine system with an electron-rich dienophile (inverse HDA reactions) or by reacting an electron-enriched pyrimidine with an electron-poor dienophile (normal HDA reactions) (see Section II.B). 

As in the case of pyrimidine bases discussed previously, adenine and guanine are subject to nucleophilic displacement reactions at particular sites on their ring structures (Figure 1.50). Both compounds are reactive with nucleophiles at C-2, C-6, and C-8, with C-8 being the most common target for modification. However, the purines are much less reactive to nucleophiles than the pyrimidines. Hydrazine, hydroxylamine, and bisulfite—all important reactive species with cytosine, thymine, and uracil—are almost unreactive with guanine and adenine. 

Besides quaternary pyrimidinium salts, pyrimidines with a strong electron-withdrawing substituent on one of the carbons of the pyrimidine ring show enhanced reactivity of the heterocyclic ring toward nucleophiles. In light of the results mentioned previously with pyrimidinium salts, it is not too surprising that reflux of an ethanolic solution of 5-nitropyrimidine with benzamidine hydrochloride or pivalamidine hydrochloride in the presence of triethylamine afforded 5-nitro-2-phenylpyrimidine (108, 84%... 

Nucleophilic displacement of Z-, 4-, and 6-halo substituents by alkoxy or aryloxy ions occurs readily except in the presence of strongly electron-releasing substituents in the ring <1994HC(52)1>. Stepwise reaction can be achieved with di- and trihalo-pyrimidines, with the more reactive 4-position being the first site of reaction. For example, even with the presence of a bulky ortho substituent such as a 5-bromine atom, selective methanolysis at the 4-position was still observed with 5-bromo-2,4-dichloropyrimidine 179 <2006TL4415>. 

Pyrazines undergo nearly all of the same reactions as pyrimidines, from nucleophilic substitution (SnAt) to palladium-catalyzed cross coupling reactions. Displacement of the chlorides via SnAt reactions with nitrogen (157 158) and sulfur-based nucleophiles (158... 

The above reactions are relatively straightforward in terms of mechanism. There are, however, a number of important transformations based on 1,3,5-triazine as starting material, and which result in formation of either pyridine or pyrimidine derivatives. 1,3,5-Triazine reacts very readily with nucleophiles, probably as outlined in equation (197) if X in (31) is a suitable electrophile, cyclization can take place. Thus, when X = CN, 4-amino-5-cyanopyrimidine is obtained, and other illustrative examples are shown in equation (198). This procedure is particularly useful for the preparation of 2-unsubstituted pyrimidines, a class of compound which is not readily accessible by other types of ring formation. The reverse type of transformation, i.e. of pyrimidines to 1,3,5-triazines, is also an important synthetic method, and one which has been studied in detail. Two types of substituted... 

A major recent growth point in substitution reactions has been the synthesis of pteridine glycosides, especially ribosides for study as probes in DNA chemistry taking advantage of the fluorescent properties of pteridines (see Section 10.18.12.4). Typically these reactions are developments of standard methods of glycosylation used with purines and pyrimidines as nucleophiles. In these and in other cases, the ambident nucleophiles within the pterin... 

Similar to haloazoles and haloazines, 7-halo-substituted pyrazolo[l,5-a]-pyrimidine underwent nucleophilic substitution with a variety of nucleophilic reagents to yield substituted pyrazolo[l,5-a]pyrimidines (74GEP2343702 76JAP761789 83AP697). Thus, 7-chloropyrazolo[l,5-a]pyrimidines 228, generally prepared from the 7-oxo derivatives 227 and phosphorus oxychloride, are converted into the 7-thioxo derivative 229 by the action of thio-... 

Chloropyrazolo[3,4-d]pyrimidines underwent ready substitution with nucleophilic reagents. For example, 265 was converted into 266 by amines (74GEP2430454). 

Friedel-Crafts reactions are almost unknown in pyridine and azine chemistry. Direct electrophilic alkylation in the pyrimidine 5-position can be carried out on pyrimidines with at least two strongly donating groups, and more readily with three such groups. Thus, a-haloketones and a-bromocarboxylic esters can be used for direct alkylation of 6-aminouracils (118), for example in the formation of (119). The 5-position can also act as the nucleophile for Michael additions (e.g. 118 — 120, where a subsequent elimination occurs) (92AHC(55)129). For similar reactions in barbituric acids see (85AHC(38)229). 

Reactions of this type are easy if the amino group is quatemized as in, for example, l-(4 -pyridyl)pyridinium chloride (740), which gives pyridine and 4-substituted pyridines [741 Nu = Cl, Br (with PX5), Nu = SH, SR (with SH , SR-), Nu = NH2, NHR (withNH3, NH2R)]. Similarly, NMe3+ groups in pyrimidines undergo nucleophilic displacement. 

As has already been mentioned, nucleophilic displacement of halogen atoms in position 2 and 4 occurs without difficulty. Reduction of 2-chloro- and 2,4-dichloro-thieno[2,3-d]pyrimidines with sodium borohydride gives the corresponding 2-chloro-3,4-dihydro derivatives (Scheme 100) (80CPB3172, 81JMC376,81JHC67). 

Positions 2,4, and 6 of pyrimidine bases are deficient in electrons and are therefore able to react with nucleophilic reagents. The 6 position is especially reactive toward additions, while the 2 position is the least reactive. The corresponding electron-deficient positions in the purine bases are 2, 6, and 8. These positions, which are marked by asterisks on the following structures, have electrophilic character in all of the commonly occurring pyrimidines and purines. 

The majority of pyrimido[4,5-c]pyridazines have been prepared from pyrimidine precursors. The chloropyrimidines (176) give the desired heterocyclic ring (177) on reaction with hydrazine (72BSF1483). Hydrazine also reacts with ethyl a-diazo-/3-oxo-5-(4-chloro-2-methylthiopyrimidine)propionate (178) to give the pyrimido[4,5-c]pyridazine-3-carboxamide (78). A mechanism for this interesting reaction has been proposed as shown, on the basis of the detection of hydrogen azide in the reaction mixture. There is no precedent for the reaction of the a-carbon of a-diazo-/3-oxopropionates with nucleophiles under basic conditions (76CPB2637). 

Oxazinium and -thiazinium cations are 67r-aromatic systems which readily react with nucleophiles at C-6. Ring opening is normally followed by recyclization so that a variety of heterocyclic systems are then formed. The behaviour of the oxygen and sulfur compounds are almost identical and so, as the latter are usually prepared from the former, it is not surprising that most attention has focussed on the reactions of 1,3-oxazinium species (72S333). These versatile synthons react with ammonia, for example, to give pyrimidines, while hydrazines afford pyrazoles and hydroxylamine produces isoxazoles (Scheme 20). 

DMAD reacts almost invariably with nucleophiles at the triple bond and not at a carbonyl group. Ogura and Sakaguchi343 reacted 6-amino-and 6-(substituted amino)-1,3-dimethyluracils (220 R = H, Me, Ph, PhCH2) with DMAD in methanol and obtained a mixture of 5-oxo-(224) and 7-oxopyrido[2,3-d]pyrimidines (223), together with the open-chain intermediate (221), which was cyclized to 223 by heating in DMF. 

N. V Alekseeva, L. N. Yakhontov, Reactions of Pyridines, Pyrimidines, and 1,3,5-Triazines with Nucleophilic Reagents, Russ. Chem. Rev. 1990, 59, 514-530. 

In the 2,3-dihydro-5-oxo-5Ff-oxazolo[3,2-c]pyrimidinium salt (207) there are three sites for reactions with nucleophilic reagents, viz. C-2, C-8a and C-7. Products resulting from attack at C-2 are observed with DMSO, water, alcohols, benzoate, chloride, diethylamine and pyridine. Products resulting from attack at C-8a are observed with water, hydroxide, alcohols, alkoxide and isopropylamine. Diethylamine also causes attack at C-7 of the cation, which results in cleavage of the pyrimidine ring (75JOC1713). 

Under the section dealing with nucleophilic substitution it has been pointed out that the extremely labile 7-methoxy group in the pyrimidine (671) is rapidly substituted by amines. In aqueous acid, however, hydrolytic cleavage of the pyrimidine ring occurs (64JOC2121). 

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