3- - triazolo derivative isomerization

The 1,4-diazocinedione 31 (admixed with a much larger amount of isomeric 1,5-diazocinedione) was hydrolyzed in aqueous acid to give glycine and y-aminobutyric acid, whereas hydrolysis of the triazolo derivative 32, mixed with its 1,5-diazocine isomer, afforded only y-aminobutyric acid (65BSF691). Dibenzodiazocine 112 (R -R = H) (see Section II,C,3,b) was hydrolyzed to... 

In [l,2,4]triazolo[4,3-a]pyrazine (174) bromination took place at the 5-position rather than in the triazole ring (77JOC4197). It was not possible to convert the 3-hydroxy derivative into the 3-chloro analogue (68JHC485). The isomeric [1,5-a] compound (175) was also brominated at C-5 (74TL4539), whereas its 7-oxide gave the 8-chloro derivative under Meisenheimer conditions [80JCS(P1)506]. 

Upon treatment with a base the zwitterionic triazine derivatives 112 undergo a valence bond isomerization yielding l,2,3-triazolo[4,5-d]pyridazine derivatives 113 <00CC1785>. 

The ring closure of 2-[iV-(2-hydroxyethyl)-Ar-mcthyl ]amino[ l, 2,41 triazolo[ 1,5-zz] pyrimidin-5-ones 333, promoted by PPA, gives the major compounds 36 and minor amounts of the isomeric derivatives 334 (Equation 59) <2002JHC319>. 

Many more results were reported in the area of the isomeric [l,2,4]triazolo[4,3-tf]quinoxaline derivatives. With one exception, however, all these studies applied known recognized ring-closure techniques for the synthesis of novel derivatives, in many cases of biological importance (cf. Section 11.16.8.) In Table 15, these derivatives are summarized together with the literature references. 

More novel results were published in the area of the isomeric [l,2,4]triazolo[l,5-c]pyrimidine ring system. In Table 16, a few applications of earlier known methodologies are shown. All these compounds were synthesized by transformation of 4-imino-3-aminopyrimidine or analogous derivatives by reagents providing a one-carbon-atom structural unit (e.g., carboxylic acids or derivatives). 

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. 

Spickett and Wright investigated the reactions of 4-substituted 3-amino-1,2,4-triazoles and EMME in acetic acid for 24-48 hr [67JCS(C)503]. Generally, they obtained [l,2,4]triazolo[l,5-a]pyrimidine-7-ones (1124) in 38-56% yields. In the case of the benzyl derivative (R = CH2Ph), the isomeric triazolo[l, 5-a]pyrimidin-5-one (1125) was also isolated from the mother liquor, in 5% yield. From the 4-ethyl and 4-phenethyl derivatives (R = Et, CH2CH2Ph), l-(l,2,4-triazol-3-yl)pyridin-2-ones (1126) were also obtained in 1-2% yields. 

The ring proton chemical shifts (8 values) of l,2,4-triazolo[l,5-a]pyrimi-dine derivatives are in the order H-7 > H-5 > H-2 > H-6 (64CPB204).The charge densities determined from proton chemical shifts showed a remarkably good correspondence with the charge distributions calculated by the simple Htlckel Molecular orbital (HMO) method (64CPB204). HMO calculations for all possible tautomeric forms of the isomeric triazolopyrimidin-5(7)-ones were also performed (88M341). 

Condensation of 4-amino-5-ethoxycarbonyl-2-hydrazinopyrimidine (351) with triethyl orthoformate gave 5-amino-6-ethoxycarbonyl-l,2,4-triazolo[4,3-a]pyrimidine (354) and not the isomeric 6,7-disubstituted derivative 353. Similarly, 352 and triethyl orthoacetate gave 5-amino-6-(2-ethoxy)ethylidenecarbazoyl-3-methyl-l, 2,4-triazolo [4,3-a]pyrimidine (355) (86H1899) (Scheme 68). 

In comparison, however, isomeric Schiff s base from 2-phenyl-7-formykr-triazolo [ 1,5-a]pyridine (178) is far less reactive and gives, with 176, the styryl derivative 179 in a yield of only 9%.19... 

Related to the mechanism of the above structure is the ring-chain-ring isomerization of 3-(2-pyridyl)-[l, 2,3 triazolo 1,5-zz pyrid-7-yl derivatives (139) into 6- 11, 2,3]triazolo 1,5-a ]pyrid-3-yl ] -2-pyridyl derivatives (141) via a diazo compound 140 [139],... 

In this series of compounds (5) and its derivatives have been the most extensively studied. The parent compound is stable towards mineral acid but in the presence of 4.5N potassium hydroxide solution [l,2,4]triazolo[5,l-a]isoquinoline (7) was obtained. The mechanism for this conversion is similar to that for isomerization of [l,2,4]triazolo[4,3-n]pyridines described earlier and is given in Scheme 3 (71RTC1225). Oxidation of both (5) and (7) with potassium permanganate give 3-(2-carboxyphenyl)-[l,2,4]triazole (121) (71CB3925). 

A variety of 3-substituted 8-nitro-[l,2,4]triazolo[4,3-a]pyridines (70JHC1019) have been prepared via a number of the aforementioned ring closure methods with 2-hydrazino-3-nitropyridine. These products readily undergo rearrangement to the isomeric [1,5-fl] series as described elsewhere in this chapter. Reduction of the 8-nitro substituent of several of these derivatives resulted in the corresponding 8-amino products that offer the potential starting point for other 3,8-disubstituted systems of this type. 

This ring system, often viewed as 2,8-diaza-3-deazapurine, and some of its derivatives have been prepared by diazotization of the appropriate 4,5-diaminopyridazine (69JHC93,70CPB1685) as Scheme 44 represents for the formation of (15) itself. There are no other practical syntheses for this series of compounds. A similar approach has been used for preparing the isomeric [l,2,3]triazolo[4,5-c]pyridazines with the 7-chloro derivative being a useful compound (67JHC555). 

Nagamatsu, T., Fujita, T. The first reiiabie, general synthesis of the 5-oxo derivatives of 5,6-dihydro-1,2,4-triazolo[4,3-c]pyrimidine and the rates of isomerization of the [4,3-c] compounds into their [1,5-c] isomers. Heterocycles 2002, 57, 631-636. 

Tricyclic derivatives are dealt with when the additional ring is a carbocyclic one. Isomeric 1.2,4-triazolo[4,3-a]pyrimidmes (Section II,C) and partially reduced TPs (Sections II,A,6 and IV,D) are mentioned only when they are precursors, potential intermediates, or reaction products of TPs. 

To add a synthesis chosen from the triazoloquinazoline series, the reaction of the activated aryl chloride 2,3-dichloro-6-nitrobenzonitrile and 3-methylthio AT leads to a mixture of isomeric triazolo[5,l-b]- and triazolo[l,5-a]quinazoline derivatives, though both in poor yields (95JHC1359). 

A second common TP synthesis consists in the condensation of a C -synthon with a 2-hydrazinopyrimidine (HP) derivative (e.g., 52, Scheme 14). A triazolo[4,3-a]-pyrimidine (e.g., 53) initially forms that often can be isolated (98ZN(B)1203). Harsher conditions allow it to isomerize to the target TP 54 by Dimroth rearrangement. By contrast, TPs (e.g., 55) can be obtained from HPs in a one-pot reaction (99JFC(96)51). 

Flash vacuum pyrolysis of some substituted [l,2,4]triazolo[3,4-c][l,2,4]benzotriazine derivatives 111 between 450 and 600 C has been studied. The only transformation observed was the unexpected valence bond isomerization of the angularly fused starting compounds to the isomeric linearly fused [l,2,4]triazolo[4,3- ][l,2,4]benzotriazine derivatives 112 <05T7489>... 

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