1.3- Dipoles nitrile imines

Less frequently applied are [3 + 2] and [2 + 2] cycloadditions of oxygen-substituted allenes [102-104], Battioni et al. described only a limited number of [3 + 2] cycloadditions of phenyloxy- and methoxyallene with diphenyldiazomethane (157) and the nitrile imine derived from diphenylhydrazonoyl chloride (159) (Scheme 8.40) [102], Both 1,3-dipoles exclusively attack the terminal C=C bond, furnishing cycloadducts 158 and 160. Padwa et al. reported [3 + 2] cycloadditions of methoxyallene 145 with two nitrones which afforded isoxazolidines in low yield [103]. 

Extensive studies on diastereoselectivity in the reactions of 1,3-dipoles such as nitrile oxides and nitrones have been carried out over the last 10 years. In contrast, very little work was done on the reactions of nitrile imines with chiral alkenes until the end of the 1990s and very few enantiomerically pure nitrile imines were generated. The greatest degree of selectivity so far has been achieved in cycloadditions to the Fischer chromium carbene complexes (201) to give, initially, the pyrazohne complexes 202 and 203 (111,112). These products proved to be rather unstable and were oxidized in situ with pyridine N-oxide to give predominantly the (4R,5S) product 204 in moderate yield (35-73%). 

Over the last 25 years both nitrile ylides and nitrile imines have continued to provide fascinating and synthetically useful chemistry. In both cases, the exploitation of [3 + 2]-cycloaddition chemistry with an increasing range of dipolarophiles has continued as a key route to five-membered heterocycles. The major development of new chemistry, however, has been in the extensive exploration of intramolecular reactions both in cycloaddition chemistry and in the electrocycliza-tion of 1,3-dipoles with extended conjugation. Such chemistry harnesses the unique reactivity of 1,3-dipoles in the synthesis of relatively elaborate structures but does require the design and preparation of quite complex reactants containing both the 1,3-dipole precursor and the dipolarophilic component. However, access to this chemistry is becoming much easier via the application of new synthetic procedures... 

The characteristics of the 1,3-dipolar cycloaddition mechanism of azides and other 1,3-dipoles (such as diazoalkanes, azo-methine imines, nitrones, nitrile imines, nitrile oxides) have been described in detail by Huisgen.191 19 According to the author, the addition of a 1,3-dipole (a b c) to a dipolarophile (d e) occurs by a concerted mechanism in which the two new a bonds are formed simultaneously although not necessarily at equal rates (32). As a consequence, a stereoselective cis addition is observed. Thus, the addition of p-methoxyphenyl azide to dimethyl fiynarate (33) yields l-(p-methoxyphenyl)-4,5-froiw-dicarbomethoxy-AMriazoline (34),194 and 4-nitrophenyl azide gives exclusively the respective cis-addition products 35 and 36 on addition to irons- and cis-propenyl propyl ether.196... 

Nitrile imines can have the alkenyl group attached at either end of the 1,3-dipole, through carbon or nitrogen. Predominantly 1,3-cyclizations have been observed although a few 1,1 -cyclizations have been reported. 

Nitrile imines can cyclize to 1,1-cycloadducts if the dipole-dipolarophile parallel plane approach is unfavorable. Thus, cyclopropanes (175a-b) were independently obtained on short-term reaction of the chlorohydrazone precursors with silver carbonate (Scheme 55).93 Longer reaction times afforded a 3 1 b a ratio from either precursor the products were shown to equilibrate. Heating of cyclopropanes (175a-b) afforded a benzodiazepine. 

We have already mentioned the synthetic versatility of silyl thioketones249 which is confirmed because they react with 1,3-dipoles (nitrile oxides, nitrile imines and nitrile ylides) to give regiospecifically silyl thiaheterocycles462. Equation 135 illustrates the reaction between phenyl trimethylsilyl thioketone and diphenyl nitrihmine. 

The silver acetate-promoted 1,3-dipolar cycloaddition of nitrilimines with 3(/f )-pheny]-4(A )-cinnamoyl-2-azetidinone produced the major adduct, 4-(4,5-dihydro- (g) pyrazol-5-yl)carbonyl-2-azetidinones, with high stereoselectivity.70 The 1,3-dipolar cycloadditions of substituted 2,7-dime(liyl-3-thioxo-3,4,5,6-ici.rahydro-2//- 1,2,41 triazepin-5-one with iV-aryl-C-ethoxycarbonylnitrilimines are highly chemoselective, where the sulfur atom of the dipolarophile interacts with the carbon atom of the dipole.71 The enantioselective 1,3-dipolar cycloaddition of nitrile imines with electron deficient acceptors produces dihydropyrazoles in the presence of 10 mol% of chiral Lewis acid catalyst.72... 

A mild procedure was developed for polysubstituted pyrazolines synthesis from 2,5-diaryltetrazoles (addition to Section 6.07.5.2.2) <20070L4155>. This procedure involved the in situ photoactivated generation of the reactive nitrile imine dipoles, followed by spontaneous cycloaddition with 1,3-dipolarophiles. 

The intermolecular 1,3-dipolar cycloaddition route to bicyclic heterocycles has received considerable attention since 1983. Diazoalkanes, N-oxides, nitrile imines, and nitrile oxides have all been used as the 1,3-dipole component in the synthesis of these heterocycles. 

Bougrin et al. (1995) reported the first practical utilization of microwave irradiation with nitrile imine as 1,3-dipole using solvent-free conditions. In this work, a comparative study of the reactivity of diphenylnitrilimine (DPNI) (1) with some dipola-rophiles was made in dry media using microwave irradiation. The good yields were obtained on mineral support in a monomode reactor. 

Some examples are known of 1,3-dipolar cycloaddition reactions of trifluoromethyl-substituted alkenes and alkynes with other dipoles (see Table 12), such as diazomethane.nitrile imines, " " nitronates," and munchones." Depending on reaction conditions, cycloadditions may occur via a two-step process. 

Table 12. [3 + 2] Cycloadditions ofTrifluoromethyl-Substituted Alkenes and Alkynes with Diazomethane and Nitrile Imine Dipoles...

Nitrile imines are 1,3-dipoles, and, if combined with a double-bonded dipolar-ophile, allow access to pyrazolines. In their turn, pyrazohnes [274], if properly substituted, could give rise to pyrazoles after elimination. 

Benzo[b]thiophene 1,1-dioxide 38 and its many derivatives undergo 1,3-dipolar cycloadditions with a variety of 1,3-dipoles such as nitrile oxides (Scheme 27) [123, 127, 128], nitrones (Scheme 28) [127], and nitrile imines (Scheme 29) [129,130]. 

Finally, to conclude this chapter two investigations should be mentioned nitrile imine (139) and fulminic acid (140). Both species are of interest as being 1,3-dipoles. The compounds 102-140 whose PE spectra have been discussed in the preceding chapter are listed in Table 2 together with the corresponding references of the reported PE data. 

An alternative route to the pyrazolino[60]fullerenes involves use of nitrile imines as dipoles - these are prepared in a one-pot procedure starting from hydrazones. 

The following 1,3-dipoles will be considered (a) aryl azides (b) diazoalkanes (c) aryl nitrile oxides (d) nitrile imines (e) azomethine imines (/) azomethine oxides (g) azomethine ylides. (a) to (d) represent 1,3-dipoles with a double bond in their sextet structure, while the last three, from (e) to (g), are without a double bond . All of them have nitrogen as the central atom of the 1,3-dipole. They will be formulated as allyl-like systems, having their negative charge distributed (according to an unspecified balance) at the two sides of the positive nitrogen, e.g. 

Cycloadditions were found to be first-order reactions with respect to both 1,3-dipole and dipolarophile, in all cases so far investigated. There are some limits to kinetic studies of these reactions, as many 1,3-dipoles are very reactive substances. While aryl azides, diazoalkanes, some classes of azomethine imines (for instance sydnones), and some classes of azomethine oxides (nitrones) are stable and isolable, azomethine ylides are usually unstable, an exception being represented by a mesoionic oxazolone that has been used for kinetic investigations benzonitrile oxide has a very limited stability, although some substituted derivatives are stable for long periods nitrile imines are not commonly isolable because of their strong tendency to dimerise. 1,3-Dipoles of... 

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