Azole A-oxides

The chemistry of azole-iV-oxides is relatively underdeveloped compared, for example, with that of pyridine iV-oxides, largely because of difficulty in their preparation from the azoles themselves. Some ring synthetic methods can be used, for example the reaction of 1,2-dicarbonyl-mono-oximes with imines as shown.  

1-Benzyloxyimidazole undergoes useful 2-Uthiations hydrogenolysis produces 2-substituted 1-hydroxy-imidazoles and these, in turn, can be converted into the 2-substituted imidazoles by reduction with titanium(III) chloride.  

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It has been demonstrated that the reaction of azole A -oxides with cycloalkane thiones offers a simple and efficient route to azole-thiones. The described reaction sequence has subsequently been found to constitute a useful synthesis of imidazole-2(3//)-thiones (see Scheme 16). 

Azole A-oxides, A-imides and A-ylides are formally betaines derived from A-hydroxy-, A-amino-and A-alkyl-azolium compounds. Whereas A-oxides (Section 3.4.3.12.7) are usually stable as such, in most cases the A-imides (Section 3.4.3.12.5) and A-ylides (Section 3.4.3.12.3) are found as salts, which deprotonate readily only if the exocyclic nitrogen or carbon atom carries strongly electron-withdrawing groups. 

Azolinones and azole A-oxides possess systems which can act either as an electron source or as an electron sink, depending on the requirements of the reaction. 

Azole A/ -oxide groups are readily removed by reduction with Zn/HOAc, HI or PCI3, e.g. in the pyrazole series. 1,2,3-Thiadiazole 3-oxides isomerize on irradiation to the corresponding 2-oxides. 

Begtrup <92ACS1096,92H(33)l 129,92JCS(Pl)2555,93JCS(P1)625> has shown that azole-A-oxides after O-silylation can be used to activate the 3 and 5 ring positions. 

Diazine and Azole A-Oxides in Palladium-Catalyzed Direct Arylation. 35 Keith Fagnou... 

The oxygen of azole A-oxides produces a nucleophihc attack to C=S C-atom of a cycloalkanethione forming a zwitterion, which cyclizes and spontaneously decomposes, yielding the product of this sulfur transfer reaction (Scheme 16). 

Campeau L-C, Stuart DR, Leclerc JP, Bertrand-Laperle M, Villemure E, Sun H-Y, Lasserre S, Guimond N, Lecavallier M, Fagnou K (2009) Palladium-catalyzed direct arylation of azine and azole A-oxides reaction development, scope and applications in synthesis. J Am Chem Soc 131 3291-3306... 

The reactivity of these compounds is somewhat similar to that of the azolonium ions, particularly when the cationic species is involved. However, although the typical reaction is with nucleophiles, the intermediate (20) can lose the A-oxide group to give the simple a-substituted azole (21). Benzimidazole 3-oxides are readily converted into 2-chlorobenzimidazoles in this way. 

Nevertheless, in some azoles the energies of n- and upper ir-orbitals are probably comparable and in such cases A-oxide formation is observed. Thus, 1-methylpyrazole is oxidized by peracetic acid to the 2-oxide in 10% yield. 1-Substituted 1,2,3-triazoles are oxidized by MCPBA at the more basic N(3) to give the corresponding triazole IV-oxides. The yield is lower if an electron-withdrawing substituent is present at the C(4) or C(5) position (87ACS(B)724). Reaction of 3-methylbenzisoxazole (119) with sodium hypochlorite or lead tetraacetate gave the 2-oxide (120) in 70 and 90% yields, respectively <87H(26)2921>. 

The 1,7-electrocyclization of azomethine imines 106 and 109, with an a,13-aromatic bond and the N—O bond of a nitro group as the y,8-bond, has been proposed as a key step in the conversion of azomethine imines 106 (Scheme 33) [62AG(E)158] or diaziridines 108 (Scheme 34) to benzotri-azole- 1-oxides 107 and 110, respectively (72JOC2980). 

In azole N-oxides the bond between the nitrogen and the oxygen atom is formed by an overlap of a lone pair orbital at the N-atom with an empty p-orbital at the oxygen atom. In the literature the N-O bond has been depicted as a dipolar single bond, a double bond, or as an arrow as shown in Scheme 2. The dipolar representation is used here. The double bond representation is usually applied in literature search engines. 

Structurally, the azole N-oxides can be divided into two distinct types. In the 1,2-type (Scheme 1, upper row) the oxygen-substituted nitrogen atom and the heteroatom contributing two electrons to the aromatic Jt-electron sextet of the azole are situated in a 1,2-position. In the 1,3-type these atoms are situated in a 1,3-position (Scheme 1, lower row). 

Due to the polar nature of the N-O bond and due to enhanced charge delocalization the N-oxides are more reactive than the parent azoles toward electrophiles, nucleophiles, and bases. The activated positions in a given azole N-oxide can usually be pointed out by comparison of the stability of the putative intermediates. There are distinct differences between the 1,2- and 1,3-type N-oxides. 

For 1,3-type azole N-oxides, only abstraction of a lateral proton at the 2-position gives an anion in which charge counterbalancing is possible as apparent from resonance structure 48. This explains why protons at this position are more acidic than lateral protons at the 4- and 5-positions of the N-oxide and more acidic than the lateral protons in the parent 3-substituted azole where charge counterbalancing is impossible (Scheme 10). 

Both type 1 and type 2 azole N-oxides like 1 and 9 upon alkylation, acylation, sulfonylation, phosphorylation, or silylation at the oxygen atom give rise to highly reactive N-alkyloxyazolium or N-acyloxyazolium salts, etc., (abbreviated common term oxyazolium salts) which can undergo a series of exquisite and useful reactions with nucleophiles, bases, and electrophiles. In most cases the whole sequence can be run in one pot. Reactions of this kind are discussed in the sections dealing with the individual azole N-oxides. A brief overview, listing the reactions of this kind that have been observed in the azole N-oxide series, is presented below. Some of these reaction types have been observed in a few cases only and... 

The order of reactivity of the individual positions in 1,2-type and 1,3-type azole N-oxides can be predicted by comparison of the relative stability of the intermediate adducts similar to the analyses presented in Schemes 6 and 7. The total sequence including alkylation and final dealkylation constitutes a nucleophilic displacement of a leaving group in an azole /V-oxide, which can be run in a telescoped protocol. 

The acidity of lateral protons of alkoxyazolium salts is enhanced as compared to the corresponding protons in azole N-oxides. Strongest acidity is predicted for protons located laterally at C3 and C5 in 1,2-type and at C2 of 1,3-type N-oxyazolium salts since the corresponding anions through mesomeric delocalization give rise to neutral species. The lateral anion may react with an electrophile as shown in Scheme 18. The overall outcome of the sequence, which can be run in one pot, is replacement of a lateral H with an electrophile. 

The crystal molecular structure of /V1-hydroxylophine A -oxide (= I -hydroxy-2,4,5-triphenyl-17/-imidazole 3-oxide) (59) has been determined [72], This compound presents a case of degenerate or autotrope tautomerism (59a and 59b are identical), which is very common in annular tautomerism of NH-azoles but very rare in functional tautomerism [40], In the solid state, the tautomeric proton is in the middle between two consecutive monomers of the catemer [59]n [72],... 

Azole approach. An important route for the synthesis of 3-hydroxypyridines is the reaction between a substituted furan and ammonia, or a primary amine. If the amino acid cysteine is used, the corresponding fused dihydrothiazole (479) can be obtained. Starting from optically active cysteine the corresponding cyclic enantiomer is obtained provided the fused product carries a 5-substituent, which for steric reasons prevents the otherwise ready racemization. A number of steps are involved in the overall reaction which may perhaps be rationalized by thiazolidine intermediates. The desired oxidation level in the substituted furan can either be reached by a-oxidation in an alkyl side-chain (499) or more generally by raising the furan ring itself to a higher oxidation level as in (500) (81H(15)1349). 

As for azines such as pyridine (Section 2.2.1.2.3), some azoles and their derivatives form A-oxides in which the exocyclic oxide is in conjugation with the ring. 1,2,5-Oxadiazoles, e.g., 46, commonly known as furazans, are oxidized to the A-oxides known as furoxans, e.g., 47. Derivatives of benzofuroxan 48 are well known. Since sulfur can also be oxidized, derivatives such as the 1,2,3-thiadiazole trioxide 49 are not uncommon (Figure 9). 

Nevertheless, in some azoles the energies of n- and upper -orbitals are probably comparable and in such cases A-oxide formation is observed. Thus, 1-methylpyrazole is oxidized by peracetic acid to the 2-oxide in 10% yield. 

A-Oxides of sulfur-containing azoles comprise another class of nonaromatic azoles. 

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