1.3- Dipoles azides

As mentioned already in Section 2.6, it is somewhat arbitrary to discuss diazo transfer reactions to alkenes in isolation from those to activated methylene compounds. The most important activation in methylene compounds is that of a neighboring carbonyl group and, as a consequence, the active methylene compound is in equilibrium with the corresponding enol, i.e., with an alkene as established by the systematic work of Huisgen (review Huisgen, 1984), typical diazo transfers involve 1,3-dipolar cycloaddition of a 1,3-dipole (azides) to a multiple-bond system, the dienophile (see Chapt. 6). In diazo transfer, this dienophile is an alkene or an alkyne, and the primary product is a A -l,2,3-triazoline or a A -l,2,3-triazole,... 

A wide variety of stable 1,3-dipoles (azides, nitrones, diazo compounds and many others) undergo cycloadditions with arynes In this section, a few recent examples that are synthetically useful are described. 

The procedure described is essentially that of Shioiri and Yamada. Diphenyl phosphorazidate is a useful and versatile reagent in organic synthesis. It has been used for racemlzatlon-free peptide syntheses, thiol ester synthesis, a modified Curtius reaction, an esterification of a-substituted carboxylic acld, formation of diketoplperazines, alkyl azide synthesis, phosphorylation of alcohols and amines,and polymerization of amino acids and peptides. - Furthermore, diphenyl phosphorazidate acts as a nitrene source and as a 1,3-dipole.An example in the ring contraction of cyclic ketones to form cycloalkanecarboxylic acids is presented in the next procedure, this volume. 

The interaction of l-methoxybut-l-en-3-yne with aromatic azides proceeds at the unsubstituted acetylenic bond to furnish two structural isomeric triazoles, 166 and 167 (4 1 ratio), due to the different 1,3-dipole orientations (83DIS). 

An in depth account of intramolecular 1,3-dipoIar cycloadditions involving dipoles such as nitrUe oxides, sUyl nitronates, H-nitrones, azides, and nitrUimines is presented with particular emphasis on the stereochemistry during the cycloaddition. Various methods employed for the generation of the dipoles and their applications to stereoselective synthesis are also discussed. 

Other 1,3-dipoles, such are azides and azomethine imines, have also been employed in microwave-induced cycloadditions. The main results reported are reviewed in this section. 

Structure I is the most important of the three. A covalent azide such as HN3 (dipole moment = 1.70 D) can be represented by the resonance structures... 

The cydoaddition of different 1,3-dipoles such as azides [331, 341] and diazoalkanes [342-344] to acceptor-substituted allenes was thoroughly investigated early and has been summarized in a comprehensive review by Broggini and Zecchi [345], The primary products of the 1,3-dipolar cycloadditions often undergo subsequent fast rearrangements, for example tautomerism to yield aromatic compounds. For instance, the five-membered heterocycles 359, generated regioselectively from allenes 357 and diazoalkanes 358, isomerize to the pyrazoles 360 (Scheme 7.50) [331]. 

PM3 calculations of the 2 + 3-cycloaddition of t-butylphosphaacetylene with 2,4,6-triazidopyridine are consistent with the dipole-LUMO-controlled reaction type. An FTIR spectroscopic study of the 1,3-dipolar cycloaddition of aryl azides with acetylenes shows that the rate of reaction increases logarithmically with pressure (below 1 GPa). The 3 -I- 2-cycloaddition between an azide (69) and a maleimide (70) has been greatly accelerated by utilizing molecular recognition between an amidopyridine and a carboxylic acid [see (71)] (Scheme 24). ... 

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). 

The same type of product was isolated from the reaction of the iminoborane alkyl azides R N3 (R = Me, Et, Pr, Bu, iBu, sBu, ra-CsHu, cyclo-CsHg, cyclo-CgHn, Ph(3H2) (19). The azidosilane Me3SiN3 may also behave as a 1,3-dipole [Eq. (40b)], but addition of the SiN bond to iminoboranes [Eq. (40a)] is usually the preferred reaction (Section V,C,8). This is not so when Me3SiN3 is present during the formation of diaryliminoboranes, ArB NAr, as intermediates Both reaction pathways [Eqs. (40a) and (40b)]... 

The use of neutral nucleophiles, such as ammonia and hydrazine, causes a reversal of polarity of one of the transitory dipoles, and these displacement reactions are therefore more favorable than with azide. On the other hand, the greater basicity of these reagents are more likely to cause elimination. 

Organic azides can also act as 1,3-dipoles and undergo [3+2] cycloadditions to the [6,6] double bonds of Cjq, yielding a [6,6] triazoline intermediate 164 (Scheme 4.28), which in some cases can be detected or even isolated [166-170]. 

Closely related to the already mentioned electrocyclizations of N-acyl thione S-imide (see Section 4.14.9.2) are some intermolecular cycloadditions involving this unusual class of 1,3-dipoles. Thus, the thione-S-imide intermediate (233) is probably involved in the formation of spirodithiazoline derivative (234) from the thione (235) and aryl azides <93HCA2147>. Also fluorenone-S-/ -tosylimide affords with carbonyl or thiocarbonyl compounds (R H) the corresponding oxathia- or dithia-zolidine derivatives (236) (Y = O or S) <80BCJ1023> (Scheme 44) (see also Section 4.14.6.1). 

The thiatriazolines (237), which are obtained from isothiocyanates and alkyl azides are potentially masked 1,3-dipoles (see also Section 4.14.6.7) and react with sulfenes to give the sultams (238), probably through the thiapentalene-like transition state/intermediate (239) (Scheme 45) <78JOC4951>. 

The 1,3-dipolar cycloaddition of organic azides with nitriles could give rise to two regioisomers. Since organic azides are Type II 1,3-dipoles on the Sustmann classification (approximately equal HOMO-LUMO gaps between the interacting frontier orbital pairs) the reactions could be dipole HOMO or LUMO controled and the regioselectivity should be determined by the orbital coefficients for the dominant HOMO-LUMO interaction. Such systems show U-shaped kinetic curves in their... 

Treatment of meso-ionic l,2,3,4-oxatriazole-5-thiones (286) (Section VII, I, 3) with boiling ethanoUc ammonia yields the isomers 297. These belong to a new class of meso-ionic heterocycle, which by O-alkylation with triethyloxonium tetrafluoroborate 3rield the salts 298, These are useful intermediates for the sjmthesis of a number of novel types of meso-ionic 1,2,3,4-thiatriazoles (299, 300, and 301). The l,2,3,4-thiatriazol-5-ones (297) have dipole moments in accord with their meso-ionic formulation. They are remarkably stable to acidic hydrolysis, and 1,3-dipolar cycloaddition reactions have not been observed alkaline hydrolysis yields aryl azides. 

The history of cycloaddition chemistry using aliphatic diazo compounds began in the 1890s when Buchner (1) and von Pechmann (2) reported that ethyl diazoacetate and diazomethane underwent cycloaddition across carbon-carbon multiple bonds. Ever since that time, diazo compounds have occupied a major place in [3 +2]-cycloaddition chemistry (3,4). For a long time, diazo compounds, as well as organic azides, have been one of the more synthetically useful classes of 1,3-dipoles. No doubt this was because many different mono- and disubstituted diazo compounds could be prepared (Scheme 8.1) and isolated in pure form, in contrast to other 1,3-dipoles that are typically generated as transient species. 

Organic azides belong to the propargyl-allenyl category of dipoles, and are popular for synthetic transformations because of their ready availability (Scheme 9.1) (1). 

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. 

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