Synthesis of Azoles

Considerable parallelism emerges from an examination of the major methods for the construction of oxazole, thiazole and imidazole ring systems. 

1 From an a-Halo-Carbonyl-Component (or an Equivalent) and a Three-Atom Unit Supplying C-2 and Both of the Heteroatoms 

This route is particularly important for thiazoles and imidazoles. 

Simple examples of this strategy, which for the synthesis of thiazoles is known as the Hantzsch synthesis, are shown below (note there is an important pyridine ring synthesis, also named a Hantzsch synthesis 

The interaction of ammonia with carbon disulfide produces ammonium dithiocarbamate in solution, which reacts with 2-halo-ketones to produce thiazole-2-thiones similarly, methyl dithiocarbamate serves as a component for the construction of 2-methylthiothiazole, reducable to thiazole itself by hydrogenolysis, thus providing a good route to the unsubstituted heterocycle. ° 

1 From an a-halocarbonyl component (or an equivalent) and a three-atom unit supplying C-2 and the heteroatoms 

Simple examples of this strategy, which for the synthesis of thiazoles is known as the Hantzsch synthesis, are shown below the syntheses of 2,4-dimethylthiazole where the heteroatoms are provided by thioacetamide, and 2-aminothiazole, in which 1,2-dichloroethyl ethyl ether is utilised as a synthon for chloroethanal and the heteroatoms derive from thiourea. The use of thioureas as the sulfur component with 2-chloroacetamides as the second unit gives rise to 2,4-diaminothiazoles. Conversion of 1,3-diketones into their 2-phenyliodonium derivatives and reaction of these with thioureas produces 2-amino-5-acylthiazoles. The first step in such ring syntheses is 5-alkylation. A useful variant is the use of an a-diazo ketone in place of the a-halocarbonyl component.  

Microwave accelerated solid state synthesis of spiroindole derivatives has also been described. The products were obtained in few seconds in good yield.  

There are parallels, but also methods unique to particular 1,2-azoles, in the principal methods available for the construction of pyrazoles, isothiazoles and isoxazoles neither the reaction of propene with sulfur dioxide and ammonia at 350°C, which gives isothiazole itself in 65% yield, nor a convenient laboratory synthesis from propargyl aldehyde and thiosulfate have direct counterparts for the other 1,2-azoles. 

Pyrazoles and isoxazoles can be made from a 1,3-dicarbonyl component and a hydrazine or hydroxylamine respectively. 

the most widely used route to pyrazoles and isoxazoles rests on the doubly nucleophilic character of hydrazines and hydroxylamines, allowing them to react in turn with each carbonyl group of a 1,3-diketone, keto-aldehyde (usually with the aldehyde masked as enol ether, acetal or enamine ), p-keto-ester, or an equivalent of one of these. 

When P-keto-esters are used, the products are pyrazolones or isoxa-zolones similarly, P-ketonitriles with hydrazines give aminopyrazoles. 3(5)-Aminopyrazole itself is prepared via a dihydro-precursor formed by addition of hydrazine to acrylonitrile then cyclisation hydrolysis of the first cyclic intermediate in this sequence and dehydrogenation via elimination of p-toluene-sulfinate allows preparation of 3-pyrazolone7  

Generally speaking, unsymmetrical 1,3-dicarbonyl components produce mixtures of 1,2-azole products. Sometimes this difficulty can be circumvented by the use of acetylenic-aldehydes or -ketones, for here a hydrazone or oxime can be formed first by reaction at the carbonyl group and this can then be cyclised in a separate, second step. Pyrazole itself can be formed by the reaction of hydrazine with propargyl aldehyde. Using P-chloro- or -alkoxy-enones as 1,3-dicarbonyl synthons also allows control over the regiochemistry of attack. 

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A one-step synthesis o( mtnles from carbonyls by a reductive cyanation with tosylmethyl isocyanide (TosMIC), also synthesis of 1,3-azole or of ketones... 

Biron E, Chatterjee J et al (2006) Solid-phase synthesis of 1,3-azole-based peptides and peptidomimetics. Org Lett 8 2417-2420... 

TABLE 8.3. SYNTHESIS OF 1,3-OX AZOLES FROM a-DIAZOCARBONYL COMPOUNDS AND NITRILES... 

Azole approach. The cyclization of the 4-ethyloxycarbonyl-5-bis(ethyloxycar-bonyl)methylisoxazole (47) using ammonia has its analogy in the synthesis of 1,3-dihydroxy-isoquinolines (75JCS(P1)2190). 

The 2-acetylamino-l,3-benzenetellurols required as the precursors of 1,3-benzotellur-azoles, can be prepared from tellurium tetrachloride and 2-aminophenyl mercury chlorides. This method allows the synthesis of 1,3-benzotellurazoles with substituents in the para-position to the nitrogen atom2. 

Application of 1,3-Azole C-H Arylation to Target-Oriented Synthesis... 

In 2008, Fagnou [124] achieved multiple C-H arylations of 1,3-azoles such as thiazoles and imidazoles by converting them into the corresponding azole N-oxides. Subsequently, they accomplished the synthesis of Tie2 tyrosine kinase inhibitor 87... 

In 2010, Mural and Shibahara successfully synthesized the same target via sequential C-H arylation of imidazole using their own catalytic system (Scheme 16.25b) [49a]. They discovered that cationic palladium species [Pd(phen)2](PFg)2 (phen = 1,10-phenanthroline) is more effective than neutral palladium catalysts for the C-H arylation of 1,3-azoles and, in order to demonstrate the utility of their catalyst, the synthesis of tyrosine kinase inhibitor was carried out. Their synthesis... 

In 2008, Piguel and coworkers reported the synthesis of annuloline, the first isolated oxazole-containing natural product (Scheme 16.29a) [61]. 5-Aryloxazole 141 was coupled with bromoalkene 142 in the presence of Cul, diamine 143, and LiOt-Bu to dehver annuloline in 75% yield. Although a number of similar C-H alkenylations of 1,3-azoles with alkenyl halides have been reported using transition metal catalysts [62], Piguel s synthesis is the only report of a natural product (albeit structurally simple) synthesized by intermolecular aromatic C-H alkenylation. 

Meanwhile, in 2013, Yamaguchi, Itami, and coworkers reported a C-H alkenylation of 1,3-azoles with enol derivatives (C-H/C-O type alkenylation) or alkenyl esters (decarbonylative C—H alkenylation) as electrophiles and applied this strategy to the formal synthesis of siphonazole B (Scheme 16.29b) [63]. Oxazole 137 was coupled with enol derivative 144 under their nickel catalytic system using the dcype ligand to form alkenyl oxazole 145 in 72% yield by C-H alkenylation at the C2 position of oxazoles. Since oxazole 145 was a known intermediate from the previous synthesis of siphonazole B [64], a convergent formal synthesis of siphonazole B has therefore been achieved. 

Attempts to directly iodinate quinoxaline failed, and the synthesis of 2,3-diphenyl-5,8-dibromoquinoxaline is somewhat more involved (Scheme 9) [61]. Starting from ort/zo-phenylenediamine, reaction with SOCI2 gives benzothia-diazole in high yield. Bromination in HBr furnishes 4,7-dibromobenzothiadi-azole, which can be alkynylated or directly reduced [62]. Reduction of the dibromide with sodium borohydride leaves the halide substituents unmolested but opens the ring to furnish l,4-dibromo-2,3-diaminobenzene. Reaction of this intermediate with a 1,2-dione furnishes a 2,3-disubstituted 5,8-dibromo-quinoxaline. Pd-catalyzed alkynylation finishes the sequence off and removal of the TMS groups yields the desired 5,8-diethynylquinoxaline monomers (Table 9, entries 13,14). 

Reactions of trichloromethyl-substituted 1,3-dielectrophiles 551 with hydrazine afforded hydroxy pyrazoles 552 (Equation 111) <2002TL5005>. Cyclocondensation of alkenones 553 with phenylhydrazine under microwave irradiation furnished 5-trichloromethyl-substituted pyrazoles 554 in excellent yields (Equation 112) <2003TL6669>. 4-Alkoxy-l,l,l-trichloro-3-alken-2-ones were useful precursors for the regiospecific synthesis of 5-trichloromethylpyr-azoles using hydrazines <2002SC419, 2002SC1585>. l,l,l-Trifluoro-4-ethoxy-3-buten-2-one, 3-trifluoroacetyl-3-buten-... 

Tosylmethylisocyanide (TosMIC), can be used for the synthesis of all three 1,3-azole types. 

The problems hindering the total synthesis of epothilones involve (1) stereoselective construction of C3, C6, C7, and C8 chiral centers, (2) synthesis of the thi-azole unit having a 15S-hydroxyl group, (3) construction of (12Z)-olefin, (4) macrocyclization, and (5) stereoselective epoxidation of (12Z)-olefin. The total syntheses of epothilones have been achieved via three strategies for the macrocyclization (Fig. 9) (1) macroaldolization, (2) ring-closing olefin metathesis, and... 

Preparation. - A range of 1,3-dithianylphosphonium salts (218) has been prepared in the course of further studies of sulfur lone pair anomeric effects in these systems.Conventional quatemization reactions have been used in the synthesis of the salt (219) and a range of polymer-supported phosphonium salts (220). A new efficient route to salts of the type (221) has been developed. The of>-azolylalkylphosphonium salts (222) are readily accessible from the reactions of the corresponding a>-bromoalkylphosphonium salts and azoles. Routes to vinylphosphonium salts, e.g., (223), continue to be explored, and their reactivity utilised in the synthesis of phosphonium salts bearing heterocyclic substituents, e.g., (224). The betaine (225) has been... 

The ring synthesis of the tetrahydro-1,3-azoles is simply the formation of N,N-, N,0-or A, S-analogues of aldehyde cyclic acetals the ring synthesis of the 4,5-dihydro-heterocycles requires an acid oxidation level in place of aldehyde. A good route to the aromatic systems is therefore the dehydrogenation of these reduced and partially reduced systems. Nickel peroxide, " manganese(IV) oxide, copper(II) bromide/ base, and bromotrichloromethane/diazabicycloundecane have been used. The example shown uses cysteine methyl ester with a chiral aldehyde to form the tetrahydrothiazole. 

There do not appear to be any examples of 1,2-azoles acting as 1-azadienes in cycloadditions. 4-Nitroisoxazoles react with dienes across the 4,5-bond and in processes useful for the synthesis of purine analogues, 3(5)-aminopyrazoles add to... 

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