1.2.3- Triazoles, from -cycloaddition

Diazo compounds generally do not undergo [3 + 2] cycloaddition with unactivated nitriles under purely thermal, noncatalyzed conditions. The formation of 4-R-5-trimethylsilyl-l//-l,2,3-triazoles from the reaction of diazo(trimethylsilyl)-methyl lithium and a broad range of nitriles [RCN R = alkyl, aryl, SEt, OPh, PO(OEt)2] appears to be an exception, but this reaction most likely occurs in a stepwise manner with initial nucleophilic attack at the nitrile (275). 

Intramolecular cycloaddition of (263) in the presence of potassium and AI2O3 leads to 4-phenyl-l,2,3-triazole (70CB1908). For the synthesis of 1-aryl-l,2,3-triazoles from aryl azides and sodium ethoxide see (68JCS(C)i329). 

The simplicity and efficiency of the click chemistry is attractive to fluorine-18 chemistry, where time plays an important role in synthesis due to the relative short half-life of fluorine-18. This one-pot reaction provides a versatile tool for coupling drug-like fragments in high yield and under mild conditions. The product 1,2,3-triazole formed from cycloaddition is biologically stable with polarity and size similar to an amide group that is a common functional group in many radiopharmaceuticals [77],... 

A convenient synthesis, which leads toA-hydrogen-l,2,3-triazoles, utilises the stable (and relatively safe) trimethylsilyl azide. Alternatively, by conducting a cycloaddition in the presence of formaldehyde, A-hydroxymethyl-triazoles are formed (mainly the 2-isomer from isomerisation of initially formed 1-hydroxymethyl-triazole) from which AT-unsubstituted heterocycles can be easily obtained using base azidomethanol is formed in situ and is the entity that adds to the alkyne. ... 

NMeTos, reacts with ammonia to give 1-methyl-1,2,4-triazole (577). Cycloaddition of thionitrosodimethylamine, Me2N—N=S, to the tetrazine ester (578) yields the triazole (579) with extrusion of nitrogen and sulphur.The formation of the triazolinones (580) from AT-phenylbenzonitrile imine (PhC=N—NPh) and aroyl azides involves a Curtius rearrangement of the latter to aryl isocyanates. 

Cycloaddition reactions of l,3,4-oxadiazin-6-ones 97 (R = Ph, R = Ar), via their 2,3-diaza-l,3-diene functionality, are observed by treatment with dipolarophiles. Thus, 2,5-diaryl-l,3,4-oxadiazines 97 react with diaryl nitrilimines 115, which are liberated in situ from the corresponding hydrazonoyl chlorides 114 and triethylamine, to give 1//-1,2,4-triazole A -imines 118 and open-chain products 119 <1996JHG591>. It is reasonable to conclude that intermediates 116 are formed initially from cycloaddition across the adjacent carbonyl-carbon nitrogen double bond and that subsequent CO abstraction gives 177-1,2,4-triazole A -imine derivatives 118. The open-chain adducts 119 are formed from intermediates 117, which result from the reaction of 115 at the carbonyl double bond of the oxadiazinones 97 (Scheme 15). 

S.2.2.4. Triazoles from Azides. Cycloadditions of this type constitute a valuable synthetic route to the triazole ring system. This is shown in Scheme 5.30. This combination dates back to the early work of Huis-gen, but in more recent times it was discovered to be subject to catalysis by Cu(I) compounds. The reactions are fast under mild conditions, have high regiospecificity, and occur in a variety of solvents including water. In addition, reaction products are easily isolated. Reactions with these characteristics have become known as comprising click chemistry this term was coined by K. B. Sharpless. The first and most commonly used reaction referred to by this name is indeed the azide-alkyne cycloaddition, and new interest has developed in triazole hemistry since the discoveiy of the copper catalysis. In addition to its use in organic... 

Azide-alkyne reaction has been known since 1893 when A. Michael reported the first synthesis of 1,2,3-triazoles from diethyl acetylenedicarboxylate and phenyl azide [32]. In the middle of the 20th century, Huisgen systematically studied the family of 1,3-dipolar cycloaddition reactions [33], and henceforth the reaction is known as Huisgen reaction. However, the non-catalyzed Huisgen reaction of azide-... 

FIGURES.21 Reactants 44 and 45 and product 46 in the CB[6]-cataIyzed formation of oligo-triazoles from a 1,3-dipoIar azide-alkyne cycloaddition, as described in Ref. [146]. 

Scheme 3.32 One-pot synthesis of i, 4-disubstituted i, 2,3-triazoles via cycloaddition of aryl and heteroaryl azides prepared in situ from the corresponding aryl halides ...

A one-pot protocol to obtain triazoles from aromatic amines has been reported. The aryl azides, generated in situ from the corresponding amine with r-butyl nitrite and TMSNs, participate in Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition giving l,4-disubstituted-l,2,3-triazoles 244 (Scheme 3.35). 

While this copper-catalyzed 1,3-dipolar azide-alkyne cycloaddition selectively produces 1,4-disubstituted 1,2,3-triazoles, Forkin and Jia et al. have disclosed a complementary ruthenium-catalyzed process for preparing 1,5- and 1,4,5-substituted 1,2,3-triazoles from terminal and internal alkynes, respectively (Scheme 16.6) [10]. 

Abstract Although the synthesis of 1,4- or 1,5-disubstituted 1,2,3-triazoles has been popularized by the recent developments of metal-catalyzed 3-1-2 cycloaddition of organic azides and terminal alkynes, the preparation of 1,4,5-trisubstituted triazoles is less popular. The focus of this chapter is the synthesis of these heterocycles, using condensation reactions and rearrangements, selective preparation of trisubstituted triazoles from disubstituted precursors, and formal [3-1-2] cycloaddition reactions involving internal alkynes. 

In the present review, preparation of 1,2,3-triazoles with substituents at positions 1, 4, and 5 has been divided into three parts condensation reactions and rearrangements, selective preparation of trisubstimted triazoles from disubstituted precursors, and formal [3+2] cycloaddition reactions involving alkynes (Fig. 2). Fused polycyclic 1,2,3-triazoles are out of the scope of this review. For simplicity, all the triazoles described in this review will be 1,2,3-triazoles and will be called triazoles. ... 

An experimental and theoretical investigation of electronic effects in ruthenium catalyzed cycloadditions with internal diarylalkynes has shown that 5-electron-donating group substituted triazoles should be favored [155]. This effect was further observed in the synthesis of 5-amino-triazoles from ynamides (Scheme 65) [156]. 

The copper-catalyzed alkyne-azide cycloaddition is a very useful methodology for the preparation of triazole libraries. Thus, a library of triazole amphiphiles with a variety of functional polar heads and hydrophobic or superhydrophobic tails [97], a 96-product-sized library of 1,2,3-triazoles from organic azides and terminal alkynes [98], and a small hbrary of triazole-conjugated coumarins have been synthesized [99]. 

The possible general mechanism for the enolate-mediated synthesis of 1,2,3-triazoles from active methylene compounds, enolizable aldehydes 69, enolizable ketones 71, and substituted acetonitriles 73 is illustrated in Scheme 4.26. First, the reaction of the catalyst (base) with the CH acid 76 generated the enolate A, which on in situ treatment with Ar-Ng 2 selectively furnished the adduct 1,2,3-triazolines B through a concerted [3-1-2]-cycloaddition or stepwise amination-cyclization reaction. Adduct B further transformed into the 1,2,3-triazole 77 through the rapid elimination of water under ambient conditions induced by the basic nature of the catalyst. 

Free carbenes based on 1,2,4-triazole are not as numerous as those based on imidazole (70ZN(B)1421, 95AGE1021, 97JA6668, 98JA9100). The carbene complex 169 (Ar = Ph, p-Tol) is prepared by the [3 + 2] cycloaddition route from [W(CO)j(C+=NC-HCOOEt)]- and aryldiazonium (930M3241). Oxidative decomplexation causes tautomerization of the 1,2,4-triazole ligand, the products being 170 (Ar= Ph, i-Tol). 

Triazoles have been obtained via microwave-assisted [3-i-2] cycloaddition, under solvent-free conditions [54], starting from organic azides and acetylenic amides at 55 °C for 30 min (Scheme 23). The complete conversion of the reagents into AT-substituted-1,2,3-triazoles 69 was achieved without decomposition and side products. A control reaction carried out at the same temperature in an oil bath did not give the cycHc products, not even after 24 h of reaction time. 

The Cu(I)-catalyzed Huisgen [3 + 2] dipolar cycloaddition was also utilized by Van der Eycken and co-workers to obtain a new class of glycopep-tidomimetics based on the 1,2,3-triazole ring system 78 starting from glu-copyranosyl azide 75 and the pyrazinone compound 76 (Scheme 26) [58]. 

The lH-l,2,4-triazole compounds possess important pharmacological activities such as antifimgal and antiviral activities [18-20]. In the present study, the reactive intermediates 45a-c, prepared in situ from the dichlorides 44a-c, were reacted via the cycloaddition reaction with ethyl cyanoacetate 40 to give, after spontaneous rearrangement, the triazole hydrazides 41a-c. These compoimds were used as starting materials for the synthesis of the... 

---