Azide dipoles, cycloaddition

Scheme 1.9. Regioisomeric adducts resulting from [3 + 2] cycloaddition of diazomethane or azide dipoles to C70 (central row), and subsequent extrusion of N2 under formation of the respective 6-6 closed (top row) or 6-5 open (bottom row) structures.

Ciufolini and co-workers demonstrated the use of 1,3-dipolar azide-olefin cycloaddition reactions in the total synthesis of ( )-FR66979 (52) [25], an antitiunor agent which is structurally related to the mitomycins [26]. Thus, the triazoline 50 was obtained as a single diastereomer by smooth cycloaddition of the activated double bond and the dipole in 49 by heating in toluene. Brief photolysis of 50 provided aziridine 51, which fragmented to 52 (Scheme 8B). Other intramolecular azide-alkene cycloaddition in natural product synthesis is illustrated by a munber of examples [27-32]. 

Fig. 1 Cycloaddition reactions employed in nucleic acid labeling with reporter groups (green star). A Cu -mediated azide-alkyne cycloaddition (CuAAC) of a terminal alkyne with an azide. B Strain-promoted azide-alkyne cycloaddition (SPAAC) of an azide with a cyclooctyne derivative. C Staudinger ligation of an azide with a phosphine derivative (not a cycloaddition reaction, see below). D Norbornene cycloaddition of a nitrile oxide as 1,3-dipole and a norbornene as dipolarophile. E Inverse electron-demand Diels- Alder cycloaddition reaction between a strained double bond (norbornene) and a tetrazine derivative. F Photo-cUck reaction of a push-pull-substituted diaiyltetrazole with an activated double bond (maleimide)...

A novel and efficient approach to 4-sulfonamidoquinolines catalyzed by Cul via a cascade reaction of sulfonyl azides with alkynyl imines has been developed by Cheng and Cui (Scheme 8.87). The reaction process includes 1,3-dipole cycloaddition/ketenimine formation/6 r-electrocyclization/[l,3]-H shift. Various 4-sulfonamidoquinolines were afforded in moderate to good yields under this mild copper catalytic system [157]. 

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. 

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). 

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 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. 

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. 

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... 

Concerted cycloaddition reactions of azides are characterized by a large negative entropy of activation, a moderate enthalpy of activation (Table VII), and an almost independence of the rate with respect to solvent polarity.196-199 The high degree of order in the transition state results from the fact that the 1,3-dipole must necessarily orient itself in such a... 

The cycloaddition of azides to multiple -ir-bonds is an old and widely used reaction. Organic azides are well known to behave as 1,3-dipoles in thermal cycloaddition reactions.178 The first example of this reaction was observed by Michael in 1893.179 Since then the addition of azide to carbon-carbon double and triple bonds has become the most important synthetic route to 1,2,3-triazoles, -triazolines and their derivatives.180-184 The cycloadditions of simple organic azides with electron-rich dipolarophiles are LUMO controlled.3 Since the larger terminal coefficients are on the unsubstituted nitrogen in the azide and unsubstituted terminus in the dipolarophiles, the 5-substituted A2-triazolines are favored, in agreement with experiment.185-187 Reactions with electron-deficient dipolarophiles are HOMO controlled, and... 

Azide cycloaddition to electron-deficient dipolarophiles is normally HOMO-dipole LUMO-dipolaro-phile controlled, whereas the reverse is true for electron-rich dipolarophiles. Products with an electron-deficient group at the 5-position or an election-rich group at the 4-position are favored electronically in intramolecular cycloadditions, steric constraints can be expected to outweigh these considerations. 

The l,2,3,4-thiatriazol-5-ones (297) have dipole moments in accord with their meso-ionic formulation.108 They are remarkably stable to acidic hydrolysis, and 1,3-dipolar cycloaddition reactions have not been observed alkaline hydrolysis yields aryl azides. 

Fig. 2.3 shows the core structures of the most important 1,3-dipoles, and what they are all called. As with dienes, they can have electron-donating or withdrawing substituents attached at any of the atoms with a hydrogen atom in the core structure, and these modify the reactivity and selectivity that the dipoles show for different dipolarophiles. Some of the dipoles are stable compounds like ozone and diazomethane, or, suitably substituted, like azides, nitrones, and nitrile oxides. Others, like the ylids, imines, and carbonyl oxides, are reactive intermediates that have to be made in situ. Fig. 2.4 shows some examples of some common 1,3-dipolar cycloadditions, and Fig. 2.5 illustrates two of the many ways in which unstable dipoles can be prepared. 

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