1.3- Dipoles phenyl azide

Phenyl azide is formed from phenyldiazonium chloride and sodium azide by way of two competing reactions (Figure 12.46). The reaction path to the right begins with a 1,3-dipolar cycloaddition. At low temperature, this cycloaddition affords phenylpentazole, which decays above 0°C via a 1,3-dipolar cycloreversion. This cycloreversion produces the 1,3-dipole phenyl azide as the desired product, and molecular nitrogen as a side product. 

Full details of the reaction of hexahuoro-Dewar-benzene with the 1,3-dipoles, phenyl azide and diazomethane (see Vol. 1, p. 268) are available, and further examples of reactions with 2,2,2-trifluorodiazoethane, 2,4,6-trimethylbenzonitrile oxide, and benzonitrile JV-phenylimide have been described. 2-Methoxypenta-fluorobicyclo[2,2,0]hexa-2,5-diene yields an adduct with phenyl azide by addition to the CF=<1F bond, and cji o-5,6-dibromohexafluorobicyclo[2,2,0]hex-2-ene, but not the corresponding tra/u-dibromo-compound, yields adduct (125). 

Alkynes have been well explored as dipolarophiles in the [3 -t- 21-cycloaddition with almost all possible 1,3-dipoles (78), whereas the reaction of iminoboranes as dipolarophiles has focused on covalent azides as 1,3-dipoles. Most well-characterized iminoboranes were reacted with phenyl azide, according to Eq. (52) (11-14,17, 20). 

Since the discovery of triazole formation from phenyl azide and dimethyl acetylenedicarboxylate in 1893, synthetic applications of azides as 1,3-dipoles for the construction of heterocychc frameworks and core structures of natural products have progressed steadily. As the 1,3-dipolar cycloaddition of azides was comprehensively reviewed in the 1984 edition of this book (2), in this chapter we recount developments of 1,3-dipolar cycloaddition reactions of azides from 1984 to 2000, with an emphasis on the synthesis of not only heterocycles but also complex natural products, intermediates, and analogues. 

In its reaction toward aryl azides, /V-phenylmaleimide is found more active than maleic anhydride with rate constants for phenyl azide addition at 25°C being 72 and 2.8 x 10 6, respectively,28 although on the basis of orbital donor-acceptor interactions between dipoles and dipolarophiles, the reverse should be the case.315 Such anomalies can be explained by taking into consideration not only orbital donor-acceptor interactions but also localization energies thus maleic anhydride with a higher localization energy than V-phenylmaleimide is the less reactive of the two.315... 

Eliminations are mentioned in the preparation of 1,3-dipoles such as diazoalkanes or a-diazoketones (Section 12.5.3) and nitrile oxides (Section 12.5.4), in connection with the decomposition of primary ozonides to carbonyl oxides (Section 12.5.5) and the decomposition of phenylpentazole to phenyl azide (Section 12.5.6). 

In [3 + 2]-cycloaddition reactions a-ketoenamines serve as synthons, reacting with phenyl azide as the 1,3-dipole component. The resulting tetrahydrophenylcyclopenta-triazol-4-ones are interesting and easily accessible heterocycles329 (equation 247). 

With Z-substituted dipolarophiles and phenyl azide, the situation is again delicately balanced and only just dipole-HO-controlled (9.5 eV against 10.7 eV). For the dipole-HO-controlled reaction, we should expect to get adducts oriented as in Fig. 6.36a. However, a phenyl group reduces the coefficient at the neighbouring atom both for the HOMO and for the LUMO, and this will reduce the polarisation of the HOMO. Conversely, it will increase the polarisation for the LUMO and hence increase the effectiveness of the interaction of the LUMO of the dipole with the HOMO of the dipolarophile, as in Fig. 6.36b. The difference in... 

Whereas in the gas phase and in nonpolar solvents sueh as tetraehloromethane and benzene, the 2-azidothiazole (38a) is the more stable isomer, in polar solvents such as dimethyl sulfoxide and hexamethylphosphorie triamide the bieyelie valenee isomer (38b) is the dominant speeies [100]. This result is in line with the faet that the dipole moment of phenyl azide g = 5.2 10 Cm) is smaller than that of cyclie 1,2,3-benzotriazole (// = 13.7 10 Cm). Similar results have been obtained for the valenee isomers of 3-azidopyrazine-l-oxide [204]. 

The dipole moments of substituted phenyl azides were calculated by vector addition of the group moments, assuming that the substituted groups are colinear and lie in the plane of the ring . Significant discrepancies from experimental values are displayed by ortho derivatives, where mutual induction between the close polar groups should occur ortho effect). In nitro derivatives a more extended type of interaction was postulated to account for the discrepancy shown by the para compound . ... 

Cycloadditions are stereospecific cis additions, as has been shown in several cases using geometric isomers as dipolarophiles . In addition to the rigid structure of norbornene, as well-defined approach is preferred, namely the one that gives an exo adduct, as is shown in (a) above for azides, but also occurs with C-phenyl-N-methyl-nitrone and for diphenylnitrilimine -. The alternative approach of the reactants is sterically hindered in the case of norbornene the steric course of reactions of norbornadiene can be different, as was found using phenyl azide as the 1,3-dipole . 

The case of azides is the one where the difference of orientation according to the polar character of Y is best defined These 1,3-dipoles behave as if they had a stable polarisation in the sense Ar-N-N=l, the nitrogen atom on the left receiving electrophilic attack by acrylic esters and acrylonitrile, the terminal atom nucleophilic attack by enamines and vinyl ethers. While it has been argued that the main factor controlling orientation in 1,3-cycloadditions to olehns and acetylenes is a steric one", phenyl azide can add in the usual orientation even to a bulky enamine viz-... 

Phenyl azide appears as a rather unreactive 1,3-dipole. Of the azomethine imines that follow, sydnone is more stable than the open cyano-derivative. Diazomethane is a very reactive compound, but double phenyl substitution reduces its reactivity. The highest rate coefficients are those of reactions of the mesoionic oxazolone. Reactivity varies by five or six orders of magnitude from azide to mesoionic oxazolone. 

Dipoles (i) phenyl azide (carbon tetrachloride. 25 C) - (ii) C-methyl-(V-phenyl-sydnone (p-cymene, I40°C) (iii) picryl azide (chloroform, 25°C) (iv) anhydro-5-hydroxy-2.4-diphenyl-3-methyloxazolium hydroxide, viz. C.C-diphenyl-N-methyl-miinchnone, (benzonitrile. 50°C) (v) benzonitrile oxide (carbon tetrachloride. 25°C) - " . 

The first report of the reaction of 2//-l-benzopyran (139) with various 1,3-dipoles has appeared/ Good yields of single cycloaddition products (140) were obtained upon reaction with nitrile-imines, whereas nitrile oxides gave 1 1 mixtures of the regioisomers (141) and (142), The reactions with diazomethane gave rather inconclusive results, and phenyl azide and diphenyl nitrone failed to react. Similar types of reactions have been carried out using a variety of enones in which the overall conclusion appears to be that simple aliphatic or alicyclic enones produce mixtures of regioisomers upon reaction with nitrile oxides and nitrile imines whereas enones of the chalcone type show only one product. Experts in FMO theory will probably declare these results... 

Rate constants ( 2) for cycloadditions of phenyl azide to substituted ethylenes and acetylenes stretch over seven magnirndes high values were observed for enamines, moderate k2 for the acrylic ester type, and the rate minimum was found for common alkenes and alkynes (Huisgen, Szeimies, Mobius, 1967). hi the PMO treatment of concerted cycloadditions, Reiner Sustmann found the key to the understanding of substituent effects e.g., a plot of k2 for the cycloadditions of Ph-Ns versus the ionization potential of substituted ethylenes and acetylenes furnished a degenerate U shape (1971). Such a plot is a distinguishing feature for each 1,3-dipole and reflects the specific mix of nucleophilic and electrophilic activity, modified by steric effects. 

Further evidence that the polarization effect of the azido group affords a net electron-withdrawal is provided by the magnitude and direction of the dipole moments of organic azides In phenyl... 

Cycloaddition of benzonitrile oxide (28) to myrcene (27) occurs with reaction at both the conjugated double bonds, yielding the two adducts (29) and (30). The less reactive 1,3-dipoles, diazomethane, diphenylnitrilimine, and phenyl- and p-toluenesulphonyl-azide, were unreactive. ... 

Arynes are novel reaction intermediates that react with dienes or 1,3-dipoles to give the corresponding cycloadducts. Recently, many researchers have reported the reaction of benzyne prepared from 2-(trimethylsilyl)phenyl triflate or benzenedia-zonium carboxylate with imines, aminobenzoate, 2-aminobenzophenones, azides, and diazo compounds, which provides various N-containing cycloadducts, such as acridines, acridones, triazoles, and indazoles. Formally, the reaction proceeds in a [2-1-2], [3-1-2], or [4-1-2] manner. Benzyne is an extremely reactive species because of the presence of a strained triple bond and undergoes polar and pericycHc reactions. The lifetime of benzyne in the gas phase has been estimated to around 20 ns (2 X 10" s) by mass spectroscopic techniques. Some spectroscopic properties of benzyne have been determined by Orville Chapman using matrix isolation techniques (Scheme 7.20). 

Recently Yi et al. also utilized 2-perfluoroaIkylethyl azides as 1,3-dipoles in the 1,3-dipolar cycloaddition to phenyl- or butylacetylenes [48]. As a result in the presence of copper(I) salt the corresponding l-fluoroalkyl-4-substituted 1,2,3-triazoles were obtained in about 60 % yield. Note that in this case only anti- isomers were obtained l-fluoroalkyl-4-aryl- or l-fluoroalkyl-4-butyl-l,2,3-triazoles. The authors do not explain the high selectivity of the process, although it may be attributed to the steric effect of the bulky substituents (aryl, butyl). Yi et al. note the relatively high efficiency of the fluoroalkyl 1,4-disubstituted-1,2,3-triazoles as catalysts of aldol condensation which may be easily recovered and reused [48]. Read et al. [49] virtually simultaneously with [48] published the results of their proper exploration of the copper salts catalyzed 1,3-dipolar cycloaddition of fiuo-rinated alkyl azides to acetylenes. This research extended the methodology... 

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