Pyrimidine Dimroth rearrangement

With readily hydrolyzed (generally fully alkylated) pyrimidines Dimroth rearrangements are possible. Thus 9-methyl-8-thioxo-7,8-dihydropurine results, as expected, from the pyrimidine (272) but also from (273 Scheme 92) (63JCS1276). 

Pyrimidin-5-amine, 4-methylamino-synthesis, 3, 121 Pyrimidin-5-amine, 4-oxo-purfne synthesis from, 5, 582 Pyrimidinamines acylation, 3, 85 alkylation, 3, 86 basic pXa, 3, 60-61 diazotization, 3, 85 Dimroth rearrangement, 3, 86 electrophilic reactions, 3, 68 Frankland-Kolbe synthesis, 3, 116 hydrolysis, 3, 84 IR spectra, 3, 64 N NMR, 3, 64 nitration, 3, 69 Principal Synthesis, 3, 129 reactivity, 3, 84-88 structure, 3, 67 synthesis, 3, 129 Pyrimidin-2-amines alkylation, 3, 61, 86 basic pK , 3, 60 diazotization, 3, 85 hydrogenation, 3, 75 hydrolysis, 3, 84 mass spectra, 3, 66 Pyrimidin-4-amines acidity, S, 310 alkylation, 3, 61, 86 basic pXa, 3, 61 Schifi base, 3, 85 synthesis, 3, 110, 114 1,3,5-triazines from, 3, 518 Pyrimidin-5-amines basic pXj, 3, 61 hydrogenation, 3, 75 reactions... 

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. 

It has been established that in the Dimroth rearrangement of 2-imino-pyrimidines, water plays an essential role (65JCS7071). In water the imine is, in fact, in equilibrium with its hydrate, the carbinolamine 39. That participation of the hydrate is important is shown by the experimental fact that in dry tetrahydrofuran, acetone, dioxane, or ether, the imine is quite stable and is not inclined to undergo rearrangement. However, on addition of a little water, rearrangement occurs its rate is proportional to the concentration of the water (65JCS7071). 

Similar base-induced Dimroth rearrangements have also been reported with the related iminopyrazolo[3,4-d]pyrimidines (60JA3147) and 6-imino-8-azapurines [73JCS(PI)2659]. 

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. 

Scheme 2.4. Process for preparing a pyrimidine by Dimroth "rearrangement."...

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-... 

Type B syntheses starting from HPs require a Dimroth rearrangement. By contrast, in the following reaction paths, the 1,3 orientation of two nitrogen atoms needed to form the triazole ring of the TP is preformed in the pyrimidine precursor. 

Reaction of 104 with ethyl orthoformate affords 105, which gives a mixture of 57% 106 and 36% 107 upon treatment with ammonia in methanol. When alkylamines are used, 6-alkylaminopyrazolo[3,4-d] pyrimidines are produced they are formed via a Dimroth rearrangement of 5-aIkyl-4-iminopyrazolo[3,4-d]pyrimidine (80JA3897). Reaction of 104 with ethyl orthoformate, followed by HjS, gives 3-cyano-4-mercaptopyrazolo[3,4-d]-pyrimidine (84KGS253). 

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. 

Cyclization of 5-methoxy(nitro)-4-hydrazinopyrimidines (485) with tri-ethyl orthoformate gave the l,2,4-triazolo[4,3-c]pyrimidine intermediate 486, which cannot be isolated due to its conversion to its [1,5-c] isomer 487 by a Dimroth rearrangement. However, the 5-benzyloxypyrimidine derivative, under the same conditions, afforded a mixture of the 8-benzyloxy derivatives of both [4,3-c] and [l,5-c]isomers 486 and 487, respectively (86TL3127 89JHC687 90H277) (Scheme 95). 

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