Triazolines => alkenes

When unacylated azides are used as nitrene precursors, the first reaction with an alkene is a cydoaddition, generating the corresponding 1,2,3-triazoline, which often eliminates N2 under the fierce reaction conditions to give an aziridine product (Scheme 4.9 ). 

In many instances, however, the intermediate triazoline can be isolated and separately converted into the aziridine, often with poor stereoselectivity. The first practical modification to the original reaction conditions generated the (presumed) nitrenes by in situ oxidation of hydrazine derivatives. Thus, Atkinson and Rees prepared a range of N-amino aziridine derivatives by treatment of N-aminophthali-mides (and other N-aminoheterocydes) with alkenes in the presence of lead tetraacetate (Scheme 4.10) [7]. 

Another conceptually unique approach in alkene aziridination has come from Johnston s labs. These workers shrewdly identified organic azides as nitrene equivalents when these compounds are in the amide anion/diazonium resonance form. Thus, when a range of azides were treated with triflic acid and methyl vinyl ketone at 0 °C, the corresponding aziridines were obtained, in synthetically useful yields. In the absence of the Bronsted acid catalyst, cycloaddition is observed, producing triazolines. The method may also be adapted, through the use of unsaturated imi-des as substrates, to give anti-aminooxazolidinones (Scheme 4.25) [32]. 

The regioselectivity observed in these reactions can be correlated with the resonance structure shown in Fig. 2. The reaction with electron-rich or electron-poor alkynes leads to intermediates which are the expected on the basis of polarity matching. In Fig. 2 is represented the reaction with an ynone leading to a metalacycle intermediate (formal [4C+2S] cycloadduct) which produces the final products after a reductive elimination and subsequent isomerisation. Also, these reactions can proceed under photochemical conditions. Thus, Campos, Rodriguez et al. reported the cycloaddition reactions of iminocarbene complexes and alkynes [57,58], alkenes [57] and heteroatom-containing double bonds to give 2Ff-pyrrole, 1-pyrroline and triazoline derivatives, respectively [59]. 

Triazoline imino sugar derivatives 297 that are prospective glycosidase inhibitors have been prepared as single diastereomers in high yield via an lAOC reaction of in situ generated azido alkene 296 (Eq. 32) [78]. m-CPBA oxidation of the dithioacetal groups in the 0-acetylated 5-azido-5-deoxydibenzyl dithio-acetal of o-xylose or D-ribose 294 to the bis-sulfone 295, followed by loss of HOAc between C-1 and C-2 provided the lAOC precursor 296. 

A variety of double bonds give reactions corresponding to the pattern of the ene reaction. Those that have been studied from a mechanistic and synthetic perspective include alkenes, aldehydes and ketones, imines and iminium ions, triazoline-2,5-diones, nitroso compounds, and singlet oxygen, 10=0. After a mechanistic overview of the reaction, we concentrate on the carbon-carbon bond-forming reactions. The important and well-studied reaction with 10=0 is discussed in Section 12.3.2. 

Azines have been prepared by initial condensation of diethoxyphosphinyIhydrazine anions with aldehydes or ketones (Scheme 9). Phosphoryl azides undergo 1,3-dipolar cycloaddition to 2-tetralone enamines to give triazolines, possibly en route to amidines. A full paper on the addition of diethyl dibromophosphoramidate to alkenes(leading to the synthesis of 2-bromoalkylamines) has appeared. ... 

Figure 17.9 A general Huisgen reaction involves the cycloaddition of an azide with an alkene or an azide with an alkyne. The products of these reactions are a triazoline ring or a triazole ring, respectively.

The versatility of permanganate as an oxidant has been greatly enhanced in the past decade by the observation that it can be solubilized in nonaqueous solvents with the aid of phase transfer agents (1). The literature contains descriptions for the use of this procedure for the oxidation of alkenes (2-13), alkynes (13-18), aldehydes (19), alcohols (20), phenols (21,22), ethers (23), sulfides (24,25), and amines (20,26). The dehydrogenation of triazolines has also been achieved by the use of permanganate and a phase transfer agent (27). ... 

The Z-alkene ( ) was subjected to the same sequence (Scheme 4). The triflate ( ) was easily obtained, but in this case reaction with azide ion gave directly the diazoester (22). Molecular models show that the triazoline corresponding to (19) has severe steric interactions and is more accessible to deprotonation (cf. ref. 23). 

Alkenic bonds undergo 1,3-dipolar cycloadditions with azides to give A -l,2,3-triazolines. Azides can add to a wide range of angle-strained, unstrained, and inactivated double bonds to electron-... 

Further disadvantage of the alkyne-azide cycloaddition is the lack of regiospecificity. On the other hand, cycloadditions of azides to alkenes are, in most cases, regioselective and afford 1,5-disubstituted triazolines . Therefore, the regioselective cycloaddition of an azide to an alkene, followed by aromatization (see Section 4.01.5.3.1) is an alternative method for the synthesis of 1,2,3-triazoles. 

In 1984, a facile synthesis of pyrrolo[3,4-/7]indole (5) as a stable indole-2,3-quinodimethane analogue using an intramolecular azide-alkene cycloaddition-cycloreversion strategy was reported (Scheme 9.2) (3). Treatment of bromo compound 3 with NaNs in aqueous tetrahydrofuran (THF) produced the triazoline 4 via an intramolecular 1,3-dipolar cycloaddition of an intermediate azide. Treatment of the triazoline 4 with p-toluenesulfonic acid (p-TSA) effected 1,3-dipolar cycloreversion of 4 to give pyrroloindole 5 in 82% yield along with diethyl diazomalonate. 

Weinreb and co-workers (16) reported a high-pressure-induced 1,3-dipolar cycloaddition of alkyl and phenyl azides with electron-deficient alkenes at ambient temperature. As a representative example, phenyl azide underwent cycloaddition with methyl crotonate (69) at 12 kbar to give the triazoline 70 (43%) and the p-amino diazoester 71 (53%). The high-pressure conditions resulted in high yield and a shorter reaction time (Scheme 9.16). 

Conformational constraints induced by various ortho-substitutents in 1-aUyloxy-2-azidomethylbenzenes (97) were used to accelerate intramolecular cycloadditions of the azide group to alkenes (21) (Scheme 9.21). For the unsubstituted azide 96, high temperature was required for the cycloaddition and the yield of the cycloadduct 100 was low. The monosubstituted azide 97 underwent cycloaddition in refluxing benzene in 10 h to give the cycloadduct 101 in good yield. Disubstituted azides 98 and 99 underwent 1,3-dipolar cycloaddition in 5-7 h to give the triazolines 102 and 103. 

Buchanan et al. (48) reported a new route to the synthesis of the chiral hydroxy-pyrrolidines 234 and 238 from D-erythrose (230) via an intramolecular cycloaddition of an azide with an alkene (Scheme 9.48). Wittig reaction of the acetonide 230 with (carbethoxyethylene)triphenylphosphorane gave the ( ) and (Z) alkenes 231 and 232. On conversion into the triflate followed by its reaction with KN3, the ( ) isomer 231 allowed the isolation of the triazoline 234 in 68% overall yield, which on treatment with sodium ethoxide afforded the diazo ester 235 in 86% yield. 

Ciufolini et al. (61) reported a facile assembly of the benzazocenone 307 as a part of the total synthesis of the antitumor alkaloids mitomycin C (309) and FR 900482 (310) based on intramolecular 1,3-dipolar cycloadditions of aryl azides with electron-rich alkenes (Scheme 9.61). Azide 305 was heated in refluxing toluene with a catalytic amount of K2CO3 to give the triazoline 306 in 55% yield. Irradiation of a solution of the triazoline 306 in wet THF with a sun lamp gave an 84% yield of the required benzazocene 308, which was converted to the target molecules 309 and 310. 

An efficient stereoselective synthesis of the (pyrrolidin-2-ylidene)glycinate intermediate 325 was reported in a total synthesis of carzinophilin (326), employing an intramolecular cycloaddition of an azide with an alkene (63) (Scheme 9.63). The arabinose derivative 319 was converted into the required azide 321 via the triflate 320. Thermolysis of the azide 321 at 50 °C in THF produced the unstable triazoline 322, which on rearrangement gave the (pyrrolidin-2-ylidene)glycinate 325 in 60-72% overall yield from the triflate 320. 

Alkynes react with alkyl and aryl azides to give 1,2,3-triazoles (389 — 390). Suitable phosphoranes behave similarly thus (391) with cyanazide N3CN provides the 1,2,3-triazole-1-carbonitrile (392). Alkenes which are activated by electron-withdrawing groups, or are strained, give 1,2,3-triazolines (393) with azides. 

---