1.2.3- Triazoles, 2-substituted, lithiation

Substituted 1,2,3-triazoles undergo lithiation with n-butyllithium at —20 to — 60 °C and reaction... 

Acyl hydrazides are useful precursors for the synthesis of 1,2,4-triazoles. Reaction of acyl hydrazides 149 with imidoylbenzotriazoles 148 in the presence of catalytic amounts of acetic acid under microwave irradiation afforded 3,4,5-trisubstituted triazoles 150 <06JOC9051>. Treatment of A-substituted acetamides with oxalyl chloride generated imidoyl chlorides, which reacted readily with aryl hydrazides to give 3-aryl-5-methyl-4-substituted[ 1,2,4]triazoles <06SC2217>. 5-Methyl triazoles could be further functionalized through a-lithiation and subsequent reaction with electrophiles. ( )-A -(Ethoxymethylene)hydrazinecarboxylic acid methyl ester 152 was applied to the one-pot synthesis of 4-substituted-2,4-dihydro-3//-1,2,4-triazolin-3-ones 153 from readily available primary alkyl and aryl amines 151 <06TL6743>. An efficient synthesis of substituted 1,2,4-triazoles involved condensation of benzoylhydrazides with thioamides under microwave irradiation <06JCR293>. 

A study of the regioselective lithiation of 1-substituted 1,2,4-triazoles has established that for 1-n-alkyl and 1-allyl derivatives monolithiation occurs at ring C(5) whereas 1-propargyl-l//-1,2,4-triazole initially undergoes lithiation at the y-position. ... 

Synthesis of 3(5)-Substituted 1,2,4-Triazoles via a-LiTHiATioN of N -Protected Derivatives... 

This isomerization was confirmed by means of a detailed kinetic NMR study (90T633), but is not detrimental to the synthesis of substituted 1,2,4-triazoles, because in all cases removal of the protecting group leads to a tautomeric mixture of 3- and 5-substituted products. The methods available for removal of the animal function actually depend upon the nature of the added C-5 substituent, with acid hydrolysis occurring only in some cases. More commonly, treatment with NaBH in refluxing ethanol is the method of choice (90T633). Lithiation and derivatization of the SEM protected compound (entry 6) can be achieved without the isomerization shown by the animal derivative, and deprotection can be achieved with either aqueous acid or anhydrous fluoride ion [92H(34)303], However, overall reaction yields are not as high as those for the aminal system. 

Substituted 1,2,4-triazoles have received less attention than their isomeric counterparts, but those results that are available indicate that their lithio derivatives are less stable than their 1-substituted isomers. Thus, in addition to undergoing the expected a-lithiation and reaction at the 5-position, 3-phenyl-4-benzyl-1.2.4-triazole also gave products resulting from ring-opening, even at -78°C (Scheme 65) (86JHC1257). 

The direct lithiation of a 2-substituted 1,2,3-triazole has not been reported. Halogen-metal exchange of 4,5-dibromotriazole with n-butyllithium at — 80 °C occurs smoothly and the subsequent reaction of the lithium intermediate (244) with various electrophiles except aldehydes gives the 4-bromo-5-substituted triazoles (245) (Scheme 46). The corresponding 1-substituted 4,5-dibromo-1,2,3-triazole undergoes a similar reaction at the 5-position . 

Substituted 1,2,3-triazoles, 1,2,4-triazoles and tetrazoles are metallated by n-butyllithium at low temperature at the 5-position. At room temperature 5-lithium derivatives tend to undergo ring opening. No direct lithiation of a 2-substituted 1,2,3-triazole has been reported. 

A review on the metaiation and metal-h ogen exchange reactions of imidazole appeared in 1985. Generally, A -protected imidazoles metalate at the 2-position 1,2-disubstituted imidazoles usually met-alate at the 5-position, unless sterically hindered. Even 2,5-dilithiation of imidazoles has been achieved. 1-Substituted 1,3,4-triazoles can be metalated at the S-position and added to carbonyls in good yield. Oxazoles are easily lithiated at the 2-position, but the resultant anion readily fragments. l-(Phenylthiomethyl)benzimidazole can be lithiated at the 2-position at low temperature (Scheme 21), but higher temperatures afford rearrangement products. ... 

The susceptibility of 1,3,5-triazine to nucleophilic attack with ring opening makes it a synthetically useful equivalent of formate, or formamide, particularly for the synthesis of other heterocycles, such as imidazoles and triazoles (see above). Despite the high susceptibility of 1,2,4-triazines to nucleophilic addition, 3-substituted-6-methoxy-l,2,4-triazines can be successfully lithiated. ... 

A -Substituted 1,2,3-triazoles can be lithiated directly at carbon, but low temperatures must be maintained to avoid ring cleavage by cycloreversion. 

One representative synthesis of prothioconazole starts [95] with the addition of the Grignard derivative of 2-chlorobenzyl chloride on the carbonyl double bond of chloromethyl 1-chloro-cyclopropyl ketone (Scheme 17.19). The untouched chlorine atom of the chloromethyl group is then classically substituted with 1,2,4-triazole. From this intermediate, one way to obtain the 2,4-dihydro-3H-l,2,4-triazole-3-thione of prothioconazole is by direct lithiation of the 1,2,4-triazole at position 5 with n-butyl lithium and reaction with sulfur. The commercially available compound is a mixture of two enantiomers (chirality of the quaternary carbon bearing the hydroxy group). 

The C-5 position of 1,2,3 N-substituted triazoles is the most acidic one and can regioselectively be deprotonated with lithiated bases (Scheme 33) [83]. 

This strategy has been reported for the synthesis of several 1,4,5-trisubstituted triazoles [144] Interestingly, the electrophile is introduced at the beginning of the reaction. Regioselectivity of the reaction, opposite to the one observed using lithiated, magnesiated, or zincated alkynes, suggests that the mechanism is indeed a [3+2] copper-assisted cycloaddition that proceeds via a 5-cuprotriazole, and not a cyclometalation that would have deliver 4-substituted triazoles (Scheme 58)... 

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