Azides as 1,3-dipoles

An effect of sonication on the cycloaddition of sodium azide to aryl cyanides was observed, essentially a shorter time and an increased yield in the expected 5-aryltetrazples.i9 With the dipole 4-bromobenzenesulfonyl azide and vinyl-ethers as the dipolarophiles, excellent synthetic results were obtained (Fig. 6).  

19 Rusinov, G.L. Ishmetova, R.I. Kitaeva, V.G. Beresnev, D.G. Khim. Geterotsikl Soedin. 1994, 1375-1377 Chem. Abstr. 1995,122, 290795q. 

21 The effect of pressure on this reaction is described in Dauben, W.G. Bunce, R.A. /. Org. Chem. 1982,47,5042-5044. 

The cycloaddition step can be influenced by the cavitational transient high pressures, but mechanistic elements are missing to go further in this analysis. 

The [4+2] cycloaddition certainly represents one of the most important reactions in organic chemistry, and many books and reviews are dedicated to this field.23 Theoretical studies were undertaken, since such an enormous amount of experimental data has been collected that a clear and general view is not obtained readily. Some clarification came with the classification of the reactions in three types according to the electronic demand.24 Besides the theoretical complexity, the experimental conditions are not always easily optimized some reactions occur spontaneously, others need catalysis, pressure and/or heating, encouraging investigators to find improvements by using new activation methods.25 

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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. 

Furthermore, E) and (Z)-substituted alkenes will, depending on the actual mechanism of cycloaddition, yield stereochemically different triazolines or products in equilibrium. These stereochemical considerations are important for the elucidation of the mechanism of 1,3-dipolar cycloadditions involving azides as 1,3-dipoles (see Sect. 6.3 and the reviews by Huisgen, 1984, and Lwowski, 1984). 

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... 

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]. 

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... 

As previously mentioned, short-life cycloalkynes add to reactive dienes such as l,3-diphenylbenzo[c]furan (16) and tetracyclone to give Diels-Alder-type adducts, and the reaction has frequently been used to establish the intermediacy of short-life cyclic acetylenes. The addition reactions have found synthetic applications - > > . The addition of 1-diethylaminobutadienc to cycloalkynes provides an interesting synthetic route for benzo annelation . Intervention of dehydrobullvalene was also confirmed by the formation of DicIs-Alder-type adducts - . At present only azides are used as 1,3 dipoles in the addition reaction with short-life cycloalkynes - - . ... 

It is well known that alkyl azides also behave as 1,3-dipoles in intramolecular thermal cycloaddition reactions. The formation of two carbon-nitrogen bonds leads to triazolines, which are usually not stable. They decompose after the loss of nitrogen to aziridines, diazo compounds, and heterocyclic imines. There are a limited number of examples reported in which the triazoline was isolated [15]. The dipolar cycloaddition methodology has been extremely useful for the synthesis of many natural products with interesting biological activities [16], In recent years, the cycloaddition approach has allowed many successful syntheses of complex molecules which would be difficult to obtain by different routes. For instance, Cha and co-workers developed a general approach to functionalized indolizidine and pyrrolizidine alkaloids such as (-i-)-crotanecine [17] and (-)-slaframine [18]. The key step of the enantioselective synthesis of (-)-swainsonine (41), starting from 36, involves the construction of the bicyclic imine 38 by an intramolecular 1,3-dipolar cycloaddition of an azide derived from tosylate 36, as shown in Scheme 6 [ 19). 

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)...

The 1,3-dipolar systems involved in the cycloaddition reaction with cumulenes include azides, nitrile oxides, nitrile imines, nitrones, azomethine imines and diazo compounds. However, some 1,3-dipolar systems are also generated in the reaction of precursors with catalysts. Examples include the reaction of alkylene oxides, alkylene sulfldes and alkylene carbonates with heterocumulenes. Carbon cumulenes also participate as 1,3-dipols in [3+2] cycloaddifion reactions. Examples include thiocarbonyl sulfides, R2C=S=S, and l-aza-2-azoniaallenes. 

The azide ligands in the complexes [M(N3)aL2] (M = Pd or Pt L = tertiary phosphine) can act as 1,3-dipoles and form a number of [2 + 3] cycloaddition products with organic nitriles, isocyanides, thiocyanates, isothiocyanates, carbon disulphide, and dimethyl acetylenedicarboxylate. Some of the reactions are summarized in Scheme 2. The rate of reaction of cis-[Pt(N3)2L2] with pam-substituted benzonitriles RCeHiCN increases in the... 

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 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]. 

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 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. 

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... 

Perfluoroalkyl-substituted nitriles react readily with various 1,3 dipoles, such as azomethine ylides [755,156,157],azometlune imines [158],diazoalkanes [759],azides [160 161,162], and nitrile ylides [163] to give stable five-membered ring systems (equation 37)... 

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. 

To use 1,3 dipolar cycloadditions in a retrosynthetic sense, it is necessary to know what 1,3 dipoles are available. The list on pages 319-320 is representative of die more common and useful examples, although many others have been reported. Azides, diazo compounds, and nitrones are normally isolable compounds which can be added to a solution of an olefin. Other 1,3 dipolar species such as nitrile oxides and azomethine ylides are not stable molecules they must be generated in the reaction mixture in the presence of the olefin. As might be expected, many different ways to generate 1,3 dipoles have been developed. 

In a recent work <2005EJI2619>, an unstable phosphoniotriazaphospholide 98 was generated by [3+2] cycloaddition of diphosphaallene 97 with trimethylsilyl azide and identified by low-temperature NMR. Above — 20°C, phosphoniotriazaphospholide 98 undergoes a clean fragmentation into iminophosphane 99 and diazomethylenephos-phorane 100, which can also act as a 1,3-dipole for the diphosphacumulene 97 to afford heterocycle 101 as the final product (Scheme 7) <2005EJI2619>. 

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). 

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. 

Alkyl azides readily undergo 1,3-dipolar cycloaddition to arylsulfonyl isothiocyanates (375) to yield thiatriazolines (376). Thermolysis of (376) in the presence of isocyanates or carbodiimides produces 1,2,4-thiadiazole derivatives (378) and (379), respectively. The intermediate formation of a thiaziridinimine (377) has been postulated as indicated in Scheme 137 (75JOC1728, 75S52). The use of isothiocyanates as dipolarophiles produces dithiazolidines (380) instead of the thiadiazole derivatives. In these reactions the intermediate thiazirine (377) functions as a 1,3-dipole with the positive charge primarily localized on sulfur. It was recently proposed that the reaction of oxaziridines (381) with isothiocyanates produces a similar thiazirine intermediate (382) which reacts in a different regiospecific manner with isothiocyanates to produce 1,2,4-thiadiazole derivatives (383) and (384 Scheme 138) (74JOC957). 

It looks as if the more nucleophilic end of the azide has attacked the wrong end of the alkyne but we must remember that (1) it is very difficult to predict which is the more nucleophilic end of a 1,3-dipole and (2) it may be either HOMO (dipole) and LUMO (alkyne) or LUMO (dipole) and HOMO (alkyne) that dominate the reaction. The reason for doing the reaction was to make analogues of natural nucleosides (the natural compounds are discussed in Chapter 49). In this case the OH group was replaced by a cyanide so that a second aromatic ring, a pyridine, can be fused on to the triazole. 

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). 

Ge, Sn) double-bond compounds, while benzaldehyde or benzophenone react with M=N double bonds to give the corresponding [2 -f 2] adducts regioselectively with the formation of M-O bonds. In addition, the [4 + 2] cycloaddition reaction of azametaUenes and phosphametallenes with a,/3-unsaturated aldehydes and ketones have been reported to give the six-membered ring compounds. Other cycloaddition using 1,3-dipoles such as nitrileoxide and azide derivatives were reported. The reactivities of M=E double bond are summarized in Scheme... 

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