Triazole, Pyrazole Synthesis

The significance of their work using microwave heating is that the classical approach to cyclocondensation of hydrazones requires 30-35 h with constant heating 

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The triazole ring system has one of the highest Bird 1a values (100). As for pyrazole synthesis, a starting material with a pre-formed N-N bond... 

H. Behbehani, H.M. Ibrahim, S. Makhseed, H. Mahmoud, Applications of 2-aryIhydrazononitriles in synthesis preparation of new indole containing 1,2,3-triazole, pyrazole and pyrazolo[l,5-a]pyrimidine derivatives and evaluation of their antimicrobial activities, Eur. J. Med. Chem. 46 (2011) 1813-1820. 

However, there are differences between o-phenylenediamine and 4,5-diaminopyrazoles in the synthesis of [5.5] systems. For example, the formation of pyrazolo[3,4-d]-[l,2,3]triazole (550) is similar to that of benzotriazole, but all attempts to extend the synthesis of benzimidazoles to the preparation of the imidazo[4,5-c]pyrazole system (551) have failed (78TH40400). 

The classical age of preparative organic chemistry saw the exploration of the extensive field of five-membered heterocyclic aromatic systems. The stability of these systems, in contrast to saturated systems, is not necessarily affected by the accumulation of neighboring heteroatoms. In the series pyrrole, pyrazole, triazole, and tetrazole an increasing stability is observed in the presence of electrophiles and oxidants, and a natural next step was to attempt the synthesis of pentazole (1). However, pentazole has eluded the manifold and continual efforts to synthesize and isolate it. 

Propiolaldehyde diethyl acetal has found numerous synthetic applications in the literature which may be briefly summarized. The compound has been utilized in the synthesis of unsaturated and polyunsaturated acetals and aldehydes by alkylation of metal-lated derivatives, " by Cadiot-Chodkiewicz coupling with halo acetylenes, " and by reaction with organocuprates. Syntheses of heterocyclic compounds including pyrazoles, isoxazoles, triazoles, and pyrimidines have employed this three-carbon building block. Propiolaldehyde diethyl acetal has also been put to use in the synthesis of such natural products as polyacetylenes " and steroids. ... 

Synthesis of cross-conjugated mesomeric betaines containing l-oxo-l//-pyrazolo[l,2-tf]pyrazol-4-ium-3-olate, 1-oxo-1 //-pyrazolof 11.2,4]triazol-4-ium-3-olate, 7-oxo-7//-pyrazolo[l,2-tf][l,2,4]triazol-4-ium-5-olate, 7-oxo-7.//-pyrazolo[ 1.2-//][ 1.2.3 ]mazol-4-ium-5-olate, 3-oxo-3//-pyrazolo[l,2- ][l,2,3,5]thiatriazol-8-ium-l-olate, and 2-hydroxy-pyrazolof 1.2-//][ 1.2.5]m.izin-5-iumH-olate structures was duly covered in CHEC-II(1996) <1996CHEC-II(8)747> and... 

The synthesis and chemistry of pyrazoles, imidazoles, and 1,2,3-triazoles were actively pursued in 2006. A review on the cross-coupling reactions on azoles with two and more heteroatoms for pyrazoles and imidazoles has been published <06EJO3283>. Publications relating to 1,2,4-triazole and tetrazole chemistry were not particularly well represented this year. The solid-phase and combinatorial chemistry of these ring systems have not been investigated compared to past years. No attempt has been made to incorporate all the exciting chemistry or biological applications that have been published this year. 

In some cases a choice of multicomponent or linear protocol for the treatment of pyruvic acids, aminoazole, and aldehydes allows obtaining different heterocycles. For instance, MCR involving 5-aminopyrazoles or sequence pathway via preliminary synthesis of arylidenpyruvic acids led to positional isomers 36 and 37, respectively (Scheme 15) [4, 61, 68]. It is interesting to note that the same strategy applied to 3-amino-l,2,4-triazole or to amino-W-aryl-lH-pyrazole-4-carboxamide reactions gave no effect and the final compound for both the protocols were the same [52, 61, 62]. 

Major advancements in the chemistry of pyrazoles, imidazoles, triazoles, tetrazoles, and related fused heterocyclic derivatives appeared in 1999. Solid-phase combinatorial chemistry of benzimidazoles and tiiazoles has been particularly active. Synthetic routes to all areas continue to be pursued vigorously with improvements and applications. In medicinal chemistry, synthesis and structure-activity relationship (SAR) studies utilizing these core structures have been exploited heavily. The physical organic chemistry of pyrazoles and imidazoles continue. 

Studies on the potential of the electrochemical approach to pyrazolotriazoles 117 showed that under the conditions of bicycle synthesis from 3-amino-4-hydrazonopyrazoles the N-l-unsubstituted triazole ring of 117 was further oxidized in a one-electron peak, followed by proton removal to yield the bis-(l,l )-2-phenylpyrazolo[3,4-i/][l,2,3]triazoles 118. This observation is significant, since in spite of pronounced pharmaceutical applications of pyrazoles, the redox characteristics of substituted pyrazoles have received limited attention (Scheme 13) <2001MI1022>. 

The reaction can be also applied to azoles (e.g., imidazoles, pyrazoles, triazoles, tetrazole) as the N -nucleophile for the hydroaminations of cyclic olefins. In this case, the presence of methyl benzoate sensitizes the photoisomerization of the double bond to form a highly strained ( )-cycloalkene. Protonation of this intermediate by triflic acid (TfOH, 20mol%) and addition of the azole nucleophile completes the reaction sequence [41]. As an example, the expeditious synthesis of l-(l-methylcy-clohexyl)- H-imidazole (27) in 72% yield is shown in Scheme 3.17 [41]. 

Abstract Synthesis methods of various C- and /V-nitroderivativcs of five-membered azoles - pyrazoles, imidazoles, 1,2,3-triazoles, 1,2,4-triazoles, oxazoles, oxadiazoles, isoxazoles, thiazoles, thiadiazoles, isothiazoles, selenazoles and tetrazoles - are summarized and critically discussed. The special attention focuses on the nitration reaction of azoles with nitric acid or sulfuric-nitric acid mixture, one of the main synthetic routes to nitroazoles. The nitration reactions with such nitrating agents as acetylnitrate, nitric acid/trifluoroacetic anhydride, nitrogen dioxide, nitrogen tetrox-ide, nitronium tetrafluoroborate, V-nitropicolinium tetrafluoroborate are reported. General information on the theory of electrophilic nitration of aromatic compounds is included in the chapter covering synthetic methods. The kinetics and mechanisms of nitration of five-membered azoles are considered. The nitroazole preparation from different cyclic systems or from aminoazoles or based on heterocyclization is the subject of wide speculation. The particular section is devoted to the chemistry of extraordinary class of nitroazoles - polynitroazoles. Vicarious nucleophilic substitution (VNS) reaction in nitroazoles is reviewed in detail. 

The construction of a heterocyclic ring from two reagents, one of which contains a nitro group, is widely used in the synthesis of the nitro derivatives of pyrazole, isoxazole, and 1,2,3-triazole. Thus, for example, the reaction of sodionitromalonal-dehyde with substituted hydrazines leads to the corresponding derivatives of 4-nitropyrazole [33, 61, 471 173] (Scheme 63). 

A large body of information on the methods of synthesis, application, structure, and properties of all known five-membered nitroazoles - pyrazoles, imidazoles, triazoles, tetrazoles, oxazoles, isoxazoles, oxadiazoles, thiazoles, isothiazoles, thiadiazoles, selenazoles, selenadiazoles, and their benzo analogs - indazoles, benzimidazoles, benzoxazoles, benzisoxazoles, benzoxadiazoles, benzothiazoles, benzoisothiazoles, benzothiadiazoles, benzotriazoles, benzoselenazoles, and ben-zoselenadiazoles has been systematized, summarized, and critically discussed in this monograph. 

This reaction sequence is representative for the synthesis of 1,2,4-diazaphospholes, which are the phosphorus analogues of the 1,2,4-triazoles. The reaction behaviour resembles that of pyrazoles with an additional reaction centre provided by the P=C double bond. 

In, this mini book we have focused our attention to the application of micro-wave irradiation in synthesis of various important heterocyclic organic compounds viz. pyrazoles, imidazoles, oxazoles, thiazoles, oxadiazoles, oxazolines, triazoles, triazines, benzimidazoles, benzoxazoles and benzthiazoles. The selected heterocyclic moieties are synthetically important due to their interesting pharmacological properties (anti-HIV, anti-parasitic, anti-histaminic, anti-cancer, anti-malarial etc.). 

The reaction between heteroaromatic iV-oxides and 2-chloro, 5-dihydroimidazole 955 results in a formal ureida-tion of the heteroaryls. This reaction was extended to 2- and 4-picoline iV-oxides for the synthesis of 956 and 957, respectively (Scheme 232) <2002JHC911>. The 2-bromine of nitronyl nitroxide 958 is easily displaced with sodium azolides to give spin-labeled azoles (imidazole, pyrazole, triazole) 959 which are prone to hydrolysis to hydroxamide acid anion 960 <2004T99>. 

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