1.2.4- Triazolo pyrimidines rearrangement

Apparently triazolo[4,3-c]pyrimidine rearranges readily into the more stable isomer triazolo[l,5-c]pyrimidine. A detailed study on related systems showed that electronic and steric factors are mainly responsible for this rearrangement (78AJC2505 90T3897 92KGS225) (Scheme 102). 

Hiickel molecular orbital calculations have shown that the 5-position in this ring system has associated with it a greater tt-electron density than is present in the corresponding positions in s-triazolo[4,3-a]pyridine, s-triazolo[4,3-a]pyrimidine, and s-triazolo[4,3-c]pyrimidine. This fact has been used to rationalize the difficulty in rearranging this heterocycle to its s-triazolo[l,5-a] analogue, in contrast to the ease with which the other s-triazolo systems rearrange. 

The reaction of S-alkylated compound 81 with diazotized anilines proceeded via a one pot tandem Japp-Klingemann, Smiles rearrangement and cyclization reactions to afford triazolo-pyrimidines 82. ° The reaction of 83 and 84 were also studied using this tandem protocol,... 

Amino-l,2,4-triazole undergoes a cyclocondensation with 3-etlioxyacrolein (7) to form 1,2,4-triazolo[l,5-a]pyrimidine (3) or its [4,3-u] isomer (5), according to whether it reacts as IH or 4H tautomer 2 or 4. Moreover, the pyrimidines 3 and 5 can interconvert by a Dimroth rearrangement. Since the H NMR spectrum 30a does not enable a clear distinction to be made AMX systems for... 

Assignment of the l,2,4-triazolo[l,5-c]pyrimidine structures to the products obtained from the previously described cyclizations and not the alternative [4,3-c] structures has been rationalized and corroborated on the basis of (a) preference of cyclization at the more nucleophilic triazole ring N2 rather than at its less nucleophilic N4 (65JOC3601 88JMC1014), (b) inability of the obtained products to undergo acid- or base-catalyzed Dimroth rearrangement, a property characteristic of the thermodynamically less stable [4,3-c] isomers (91JMC281), (c) comparison with unequivocally prepared... 

Tlie thermodynamically more stable l,2,4-triazolo[l,5-c]pyrimidines 23 were frequently prepared by Dimroth rearrangement of their thermody-... 

It is important to note that besides these synthetic pathways a very important access to [ 1,2,4]triazolo[ 1,5 z] pyrimidine derivatives is the Dimroth rearrangement of [l,2,4]triazolo[4,3-c]pyrimidine compounds. This type of ring transformation is specifically discussed in Section 11.16.5.2 these possibilities are also reviewed in Section 11.16.7. As these isomerizations always take place into the direction of the [l,2,4]triazolo[l,5-c]pyrimidine ring, in several studies only these products are described without special (or any) note of the primarily formed [l,2,4]triazolo[4,3-c]pyrim-idine ring. Table 17 contains the stmctures of some [l,2,4]triazolopyrimidines and benzologues with a fusion site of the triazole ring that have been formed via transformation of the isomeric [ 1,2,4] triazolo[4,3-f]-pyrimidine compounds with or without isolation of these intermediates. 

Another interesting rearrangement, involving a pyrimidine-pyridine ring transformation combined with a Dimroth rearrangement, is observed when 6-nitro[l,2,4-triazolo][l,5- ]pyrimidine (74) reacts with ethyl cyanoacetate. 

The second important reaction path similar to AT synthesis starts with aminoguanidine derivatives (in this case part of a HP) and proceeds via condensation with a synthon Z (see principle in Scheme 8). In a first step l,2,4-triazolo-[4,3-a]pyrimidines (15) are formed these are often isolable and nearly always transformable into the more stable TPs by Dimroth rearrangement. 

The Dimroth rearrangement (69ZC241) including l,2,4-triazolo[4,3-a] pyrimidines generally proceeds rather easily therefore these compounds, when prepared, are often not isolable (or only by very carefully handling). The extremely fast rearrangement, compared, for example, with that of 1,2,4-triazolo[4,3-a]pyridines, is attributed to the increase in electron de-... 

Muehlstaedt et al. reported an unusual ring transformation in which the thermodynamically more stable 7-amino-6-cyano-l,2,4-triazolo[l,5-a]-pyrimidine (67) underwent an acid-catalyzed retro-Dimroth rearrangement to the thermodynamically less stable 7-amino-6-carboxamido-l,2,4-tria-zolo[4,3-a]pyrimidine (115) (70JPR254). The structure of this product was confirmed by comparison with authentic material obtained (70JPR254) from the acid hydrolysis of the known 7-amino-6-cyano-l,2,4-triazolo[4,3-a]pyrimidine (66) (Scheme 48). 

All steps of a Dimroth rearrangement may be reversible yet the difference in thermodynamic stability in favor of l,2,4-triazolo[l,5-a]pyrimidines (121) drives the isomerization in one direciton (94MI2). 

Synthesis of this ring may be achieved by the construction of one of the heterocycles followed by using it as a basis to build the other ring onto it or by the Dimroth rearrangement of l,2,4-triazolo[4,3-a]pyrimidines. 1,2-Diaminopyrimidines are general precursors, and they can be generated from 1-amino or 2-aminopyrimidines. The 3- and 5-amino-l,2,4-triazoles are alternative precursors that can act as a source of three carbons to complete the pyrimidine ring. 

Displacement of the chlorine atom in 203 with sodium allyloxide in allyl alcohol gave 7-allyloxy-l,2,4-triazolo[l,5-a]pyrimidine (204). This was followed by a thermal Claisen rearrangement to 205-209 in addition to 152. Allylation of 152 with allyl bromide gave the two allylated products 206 and 207 (63CPB851) (Scheme 38). 

A characteristic feature observed during the cyclization of some hy-drazino derivatives of pyrimidines is the rearrangement of the triazolo[4,3-c]pyrimidine intermediate to the triazolo[l,5-c]pyrimidine product. 

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