Pyrimidines ANRORC reactions

Further examples of ANRORC reactions are the conversions of quinoline (896) into quinazoline (897) and of pyrimidine (898) into triazine (899). 

Briel et al. (90GEP282011) describe the transformation of thieno[3,2-d]-l,3-oxazin-4-ones 361 into thieno[3,4-d]pyrimidines 362 by heating with ammonia saturated DMF or with primary amines. This transformation is an example of an ANRORC reaction. 

Comparison of this reactivity order with that found in the amination of 2-X-4-phenyl pyrimidines (SCH3 Br = Cl > F > SO2CH3 I > (013)3 > CN see Table 11.5 in Section ll,C,l,d) shows that these reactivity orders differ considerably. The fluoro substituent, especially, which has in the pyrimidine series about the same reactivity order as the chloro or bromo atom, shows in the 1,2,4-triazine series a low ANRORC activity. Comparison of both series of reactivities is, however, a delicate matter, mainly because the yields obtained for the amino compounds in the 1,2,4-triazine series are much lower than those obtained in the pyrimidine series, because of the occurrence of many side reactions, such as ring contraction, dehalogenation, ring transformations, and degenerate ring transformations... 

Investigation of the deethylation with N-labeled ammonia showed that in 18 the label is incorporated for about 100% in the pyrimidine ring. Evidently the Sn(ANRORC) mechanism is operative in the replacement of the quaternary ring nitrogen by the amino nitrogen. The initial step in this deethylation reaction will probably be adduct formation on C-6, i.e., 17. Addition at C-2 is less likely because of the presence of the phenyl group at that position (Scheme III.12). 

One final reaction of the ANRORC type which is of some limited synthetic utility is the conversion of certain 6-substituted 2-bromopyridines into pyrimidines by treatment with sodamide in liquid ammonia (e.g. equation 192). Here, the postulated mechanism involves addition of amide ion at the 4-position, ring opening by cleavage of the C(3)—C(4) bond and loss of the 2-bromo substituent, and ring closure of the acyclic intermediate thus obtained. 

There are two important general types of reaction by which six-membered heterocycles containing two or more heteroatoms can be transformed into other six-membered heterocyclic systems, namely reactions which involve an ANRORC mechanism, and reactions which proceed by a Diels-Alder/retro-Diels-Alder type of mechanism. Transformation of 1,3-oxazinones and -thiazinones into pyrimidones (equations 193 and 194) has been extensively used, especially in the conversion of isatoic anhydride into quinazolinones (e.g. equation 195). 2,4-Diaryl-l,2,3,5-oxathiadiazines, which are readily accessible by reaction of sulfur trioxide with aryl isocyanates, are useful precursors to pyrimidines and 1,3,5-triazines (equation 196). 

The ANRORC mechanism is also supported by the isolation of a small amount of the open-chain 3-amino-l-phenylallylidene cyanamide (36) (Scheme 2) from the products of the reaction of 2-bromo-4-phenyl-pyrimidine as formed from an adduct structurally related to 35a.100... 

The stronger stabilizing effect of a y-aza relative to an a-aza atom is confirmed by the behavior of pyridazine and pyrimidine, which preferably form adducts 29 and 30, respectively. Phenyl substituents discourage ipso attack by NH2", as shown by the observation that in the reactions with 4,6-diphenyIpyrimidine, 2-phenyl-l,3,5-triazine, or 2,4-diphenyl-l,3,5-triazine only CH adducts are detected. However, indirect evidence for adducts resulting from attack at CPh positions is provided by a study of the reaction products from diphenyltriazine and related substrates, unequivocally showing that such adducts are transiently formed along an SN (ANRORC) pathway. 

One of the most important reactions of TAs is their transformation into pyrimidin-4-ones, which proceeds under the action of ammonia and amines according to the ANRORC mechanism. For thiazinones 39 it was suggested (81H851) that the first step is a nucleophilic addition of ammonia to the 2 position of the heterocyclic ring (Scheme 91). 

The reaction of strongly basic amide anions, R -N-R, with chloro- or bromopyridines, -pyrimidines, and other heterocycles can lead to ring opening and subsequent ring closure to result in substituted amino-N-heterocycles (addition of nucleophile, ring opening, ring closure = ANRORC). 

Uracil derivatives can be nitrated at C-5 under conditions that allow retention of a sugar residue at N-1 Nitration at N-3 can also be achieved N-3-nitro-compounds react with amines via an ANRORC mechanism, with displacement of nitramide and incorporation of the amine as a substituted N-3, as shown below. This seqnence has been ntilised to prepare N-3-labelled pyrimidines (31.2.2). An analogous ANRORC process takes l-(2,4-dinitrophenyl)-uracils to 1-arylamino-uracils by reaction with arylamines at room temperatnre. ... 

In a ring-transformation reaction of the Sn-ANRORC type,275 l,3-dimethyl-2,4-dioxo-l,2,3,4-dihydropyrimidine-5-carbonitrile together with substituted acetonitriles affords 6-sub-stituted 7-aminopyrido[2,3-c/]pyrimidine-2,4(l//.3//)-diones.277 -27 3 This method is described in Section 7.2.2.1.1.2.4. 

It has recently been found that the ANRORC mechanism is realized in the reaction of 6-bromo-[l, 2, 4]triazolo[4,3-a]pyrimidine 94 with aliphatic amines under microwave irradiation, thus affording Ai-alkyl-[l,2,4]triazolo[l,5-a] pyrimidin-7-amines 95 (Scheme 61) [129]. 

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