Alkylation of 1,2,3-triazoles

Alkylation of 1,2,3-triazole with Ar-(2-bromocthyl)phthalimidc in the presence of Cs2C03 followed by cleavage of the phthalyl moiety with hydrazine provides l-(2-aminoethyl)-l,2,3-triazole 94 in 51% yield <2003JME1116>. A reaction of 4-nitro-l,2,3-triazole with propargyl bromide in the presence of KOH gives a mixture of isomeric 1-propargyl-l,2,3-triazoles 95 and 96 in the equimolar ratio <2003RJ01792>. However, in acidic media, when N-l... 

N-Alkylation of 1,2,3-triazoles and benzotriazoles is readily achieved using (1) alkyl halides, dialkyl sulfates, diazoalkanes, and jS-tosylates or (2) the Mannich reaction. When alkyl halides are used, sodium alkoxide, sodium hydride, or sodium hydroxide is usually employed as the base. The N-alkylation of benzotriazole with alkyl halides proceeds efficiently using powdered NaOH as the base in DMF. The highest yields (80100%) of the alkylated benzotriazoles are obtained when a fourfold excess of NaOFl is employed. A-Alkylbenzotriazoles have been prepared from benzotriazole and alkyl halides using phase-transfer catalysts, e.g., KOFI, benzene, tetrabutyl-ammonium salts or KOH, benzene, polyethylene glycol. 

N-alkylation of 1,2,3-triazoles is readily achieved with various electrophiles under basic conditions [1]. In most of the cases, the reaction is unselective, with the N2 regioisomer being the main compound obtained [77-82]. The strong preference for N2 substitution has generally been explained by steric reasons and/or hard base character of the central nitrogen atom [83]. 

Reactions of salts of 1,2,3-triazole with electrophiles provide an easy access to 1,2,3-triazol-jV-yl derivatives although, usually mixtures of N-l and N-2 substituted triazoles are obtained that have to be separated (see Section 5.01.5). Another simple method for synthesis of such derivatives is addition of 1,2,3-triazole to carbon-carbon multiple bonds (Section 5.01.5). N-l Substituted 1,2,3-triazoles can be selectively prepared by 1,3-dipolar cycloaddition of acetylene or (trimethylsilyl)acetylene to alkyl or aryl azides (Section 5.01.9). 

Triazoline-3,5-dione 184 underwent an ene reaction with olefins 183 to yield trialkylated allylic urazoles 185, which were further elaborated into allylic amines 186 . DBU has been found to be a mild and convenient base for the alkylation of 1,2,4-triazole with various alkyl halides in the high yielding syntheses of 1-substituted-1,2,4-triazoles <00TL1297>. 

Predictably, 1,2,4-triazole is alkylated preferentially at the 1-position [36, 38,39]. Specific alkylation at the 4-position can be achieved by the initial reaction with dibromomethane to form the bis-triazol-l-ylmethane (see below), followed by quat-emization of the triazole system at the 4-position and subsequent C-N cleavage of the 1,1 -methylenebistriazolium salts [40]. 1,2,3-Benztriazole yields a mixture of the isomeric 1- and 2-alkylated derivatives [41]. The 1-isomer predominates, but the ratio depends on whether the reactions are conducted in the presence, or absence, of a nonpolar organic solvent (Table 5.33). Higher ratios of the 1-isomer are obtained under solidrliquid two-phase conditions. Thus, alkylation of 1,2,3-benztriazole with benzyl chloride produces an overall yield of 95% with the l- 2-isomer ratio of ca. 5.7 1 similar reactions with diphenylmethyl and triphenylmethyl chlorides gives overall yields of 95% (9 1 ratio) and 70% (100% 1-isomer), respectively [38], 6-Substituted purines are alkylated at the N9-atom and reaction with 1-bromo-3-chloropropane yields exclusively the 9-chloropropyl derivative (cf. reaction wi phenols) [42]. 

Sol-gel and dip-coating procednres were apphed to prepare copper nanomaterials. Alnmina-snpported copper nanoparticles from Cn(acac)2 and Al(OPr-i)3 were synthesized by Kantam and coworkers by the aerogel procednre. The Cn-Al203 nanoparticles were characterized by several analytical methods and were snccessfuUy nsed as catalysts for the preparation of 1,2,3-triazoles by the reaction of terminal alkynes, NaN3 and alkyl/allyl halides. 

The first UV spectra of 1,2,3-triazoles were reported in 1954 (54JA667), with the parent compound showing a maximum at 210 nm (log e 3.6), being very similar to the spectrum of pyrrole. Substitution of an alkyl group in the 4-position causes a slight bathochromic shift to 215-216 nm. 

The difficulty in trying to forecast which way round a 1,3-dipolar cycloaddition will go is well illustrated when a substituted azide adds to an aUcyne in the synthesis of 1,2,3-triazoles. Reaction of an alkyl azide with an unsymmetrical alkyne, having an electron-withdrawing group at one end and an alkyl group at the other, gives mostly a single triazole. 

Triazoles can also be prepared from in situ formation of azides from halo compormds. For example, 1,4-disubstituted-1,2,3-triazoles 138 were obtained in excellent yields by a convenient one-pot procedure from a variety of aryl and alkyl iodides 136 and terminal alkynes 137 without isolation of potentially unstable organic azide intermediates 05SL2941>. Efficient one-pot synthesis of 1,2,3-triazoles from in situ formation of azides from benzyl and alkyl halides with alkynes has also been reported <05SL943>. 

A-Alkylations and -acylations generally occur at N-1, reflecting the higher nucleophilicity of N-N systems (cf. 14.1.1.2), however 4-alkyl derivatives can be prepared via quatemisation of l-acetyl-l,2,4-triazole or the acrylonitrile or crotononitrile adducts (note that N-1 and N-2 are equivalent until substitution occurs). In alkylations of 1,2,4-triazole, generally a ratio of 9 1, N-l N-3 isomers is present in the crude product, but the minor product is very easily removed even simple distillation completely separates the isomers, illustrating the very large difference in physical properties between isomers. Direct hydroxymethylation of 3,4-disubstituted 1,2,4-triazoles occurs at C-5 by heating with formalin or paraformaldehyde. ... 

The hazardous nature (see Tetrazoles below) of some alkyl azides limits the method in these cases, however A-alkyl- (benzyl) -1,2,3-triazoles can be obtained by preparing the azide in situ, for example using a mixture of sodium azide, the alkyne and a benzyl hahde in situ preparation of aryl azides is also feasible. An alternative method in which the alkyl azide is also generated in situ, is to use a diazo transfer to a primary amine the diazo transfer requires Cu(II) and the cycloaddition needs Cu(I) so a reducing agent is added together with the alkyne following the first phase. ... 

Synthesis of 1,2,3-triazoles from alkyl or aryl azides and active methylene compounds. 

A-Sulfonylamidines can be prepared by three-component coupling [31] of alkynes (R = alkyl, aryl or silyl), sulfonyl azide and amine, which is known as click chemistry. [32] The use of alkyl azides in place of sulfonyl azide without a copper catalyst results in the formation of 1,2,3-triazoles (Scheme 3.18). This reaction shows substrate tolerance to each component. Reaction with an optically active amino ester is performed without racemiza-tion. A-Boc-ynamide (R = NPhBoc) can act as the alkyne component in the synthesis of N-Boc-aminoamidines [33]. 

Several new methods for the preparation of 1,2,3-triazoles were reported in 1997. Thus, various N-alkyl benzotriazoles have been prepared via a Mitsunobu-like transformation involving treatment of primary alcohols with PhaP and NBS followed by benzotriazole <97SC1613>. 2-Aryl-2H-benzotriazoles 73, used as ultraviolet absorbers, were prepared in excellent yield by the reductive cyclization of o-nitrophenylazobenzenes 72 by Sml2 in THF under mild conditions <97TL8303>. 

The alkylation of 1,2,4-triazole prefers to give the N-1 substitued product rather than the N-4 substituted product. However, the alkylation product of either N-1 or N-2 is difficult to predict when triazole has 3- or 5-substituents. Generally, the ratio of both products depends on the properties of the alkylating agent. ... 

Mukheijee N, Ahammed S, Bhadraa S, Ranu BC. Solvent-free one-pot synthesis of 1,2,3-triazole derivatives by the Click reaction of alkyl halides or aryl boronic acids, sodium azide and terminal aUcynes over a C11/AI2O3 surface under ball-milling. Green Chem 2013 15 389-97. 

Sharghi, H., Khalifeh, R., and Doroodmand, M. M. 2009b. Copper nanoparticles on charcoal for multicomponent catalytic synthesis of 1,2,3-triazole derivatives from benzyl halides or alkyl halides, terminal alkynes and sodium azide in water as a green solvent. Adv. Synth. Catal. 351(l-2) 207-218. 

Kantam et al. [59] reported the synthesis of alumina-supported copper NPs from copper(ll) acetylacetonate and aluminum isopropoxide precursors using aerogel protocol. The NPs were characterized by XRD, TEM, Al MAS NMR, X-ray photoelectron spectroscopy (XPS), and ICP-AES. Cu-AiPj NPs are used for the preparation of 1,2,3-triazoles by the reaction of terminal alines, sodium azide, and alkyl/allyl halides (Scheme 5.17). 

A simple one-pot, two-step procedure for the regioselective preparation of 1,2,3-triazoles 99 (Scheme 5.30) was recently reported by Kacprzak. Water, alkyne, sodium ascorbate, and aqueous CUSO4 were added to the DMSO solution of alkyl or aryl azides generated under anhydrous conditions. The product, obtained in good to excellent yields, usually precipitated and it was collected by simple filtration. Only 1,4-regioisomers were detected when monosubstituted alkynes were used. 

---