1.3- dipolar cycloaddition reactions regiochemistry

An interpretation based on frontier molecular orbital theory of the regiochemistry of Diels Alder and 1,3-dipolar cycloaddition reactions of the triazepine 3 is available.343 2,4,6-Trimethyl-benzonitrile oxide, for example, yields initially the adduct 6.344... 

The [3 + 2]-cycloaddition reactions of allenes with 1,3-dipoles are useful for the construction of a variety of five-membered heterocycles with a high degree of regio- and stereochemical control [67]. Generally, the dipolar cycloaddition reactions are concerted and synchronous processes with a relatively early transition state. The stereoselectivities and regiochemistries are accounted for by the FMO theory The reaction pathway is favored when maximal HOMO-LUMO overlap is achieved. 

From the foregoing survey of heterocyclic hydrazonoyl halides, it appears that the main emphasis has been restricted to both their preparation and use as intermediates for further synthesis. Large areas of their chemistry, particularly regarding their physical and biological properties, remain to be developed. A deeper understanding of some aspects of their 1,3-dipolar cycloaddition reactions, such as regiochemistry and site selectivity in terms of the frontier molecular orbital method, is also needed. 

Upon heating, aziridine 191 opened in the conrotatory manner to give azomethine yhdes 192 and/or 193, which underwent 1,3-dipolar cycloaddition reactions with alkenes and acetylenes. With styrene, for example, pyrrolidine 194 was formed exclusively in 81 % yield, and the regiochemistry of the cycloaddition was ascribed to control by the LUMO of the electron-deficient azomethine ylide. The cis relationship of the phenyl and benzoyl groups was attributed to secondary orbital interactions between them in the transition state. 

Dalla Croce and La Rosa examined the 1,3-dipolar cycloaddition reactions of unsymmetrical munchnones with terminal alkynes to give pyrroles 156 and 157 (Table 4.8). The reaction is generally regioselective the major pyrrole isomer from the monosubstituted munchnones have adjacent hydrogens, irrespective of the munchnone substituent. With the disubstituted munchnones, the major regioisomer is derived from attachment of C-4 of the munchnone and the p-carbon of the alkyne, except for phenylacetylene, which shows the opposite regiochemistry. The authors interpreted this behavior as a consequence of the electron-rich nature of phenylacetylene as a dipolarophile with a larger LUMO coefficient on the a carbon. 

Gowravaram and Gallop adapted the rhodium-catalyzed generation of isomunchnones from diazo imides to the solid-phase synthesis of furans, following a 1,3-dipolar cycloaddition reaction with alkynes. A variety of furans 492 were prepared in this fashion (Fig. 4.150). With unsymmetrical electron-deficient alkynes (e.g., methyl propiolate), the anticipated regiochemistry is observed, e.g., HOMO-dipole LUMO-dipolarophile, as seen previously. 

Shea et al. investigated whether strain involved in alkenes affects reactivity and regiochemistry of the intermolecular 1,3-dipolar cycloaddition reaction [14]. Therefore, the addition of picryl azide (18) with a series of mono-and bicyclic olefins including frans-cycloalkenes and bridgehead alkenes was studied (Scheme 5). In the cases of czs-cyclooctene (16) and ci5-cyclononene (17), decomposition of the initially formed cycloadducts 19 and 20 followed... 

When both the 1,3-dipoIe and the dipolarophile are unsymmetrical, there are two possible orientations for addition. Both steric and electronic factors play a role in determining the regioselectivity of the addition. The most generally satisfactory interpretation of the regiochemistry of dipolar cycloadditions is based on frontier orbital concepts. As with the Diels-Alder reaction, the most favorable orientation is that which involves complementary interaction between the frontier orbitals of the 1,3-dipole and the dipolarophile. Although most dipolar cycloadditions are of the type in which the LUMO of the dipolarophile interacts with the HOMO of the 1,3-dipole, there are a significant number of systems in which the relationship is reversed. There are also some in which the two possible HOMO-LUMO interactions are of comparable magnitude. 

Dipolar cycloaddition of C60 with nitrile oxides was modeled at the B3LYP/6-31G(d,p)//AMl level, and its mechanism and regiochemistry were investigated. Theoretically, the reaction can proceed by four types of additions, viz., closed [6,6], open [5,6], closed [5,6], and open [6,6] additions. Analysis of... 

Diazomethane reacts with 4-nitrobenzenediazonium chloride to give the 1-aryltetrazole 218 (Scheme 8.52) in addition to other products (277). This long-known reaction was revisited when the dipolarophUic character of the arenediazo-nium salt was realized (278). The tetrazole probably arises by a concerted 1,3-dipolar cycloaddition rather than by a two-step process. However, the observed regiochemistry is difficult to reconcile with either mechanism. 

In the full account of this work, Padwa et al. (41) demonstrated that the 1,3-dipolar cycloaddition is an endo cycloaddition and the regiochemistry is consistent with that of a HOMO-dipole controlled process as judged from the products 91 and 92 that arise from the reaction between isomiinchnone 90 and methyl propiolate and phenyl vinyl sulfone, respectively (Scheme 10.15). Iso-miinchnone 90 is also trapped with DMAD to give the expected furan in 41% yield. 

The reaction of nitrile oxides with 4-arylmethylene-5(4//)-oxazolones 675 to give the corresponding spiroisoxazoline oxazolones 676 is also well known.The regiochemistry of this cycloaddition reaction was initially incorrectly assigned but a careful study of the reaction showed that the regiochemistry of the 1,3-dipolar cycloaddition of nitrile oxides is the same as that observed with nitrile imines (Scheme 7.213). Examples of spiroisoxazoline oxazolones are shown in Table 7.49 (Fig. 7.60). 

Dihydropyridines participate in reactions of 1,3-dipolar cycloaddition with some nitrile oxides [363, 364]. The monoester derivative 330 reacts with several nitrile oxides 331 to produce the corresponding isoxazolo[5,4-Z ]pyridine 332 (Scheme 3.111) in moderate to good yields. The regiochemistry of the cycloaddition was predicted in [363] on the basis of the complementary dipoles of the 331 and enamine double bond and was proven by conversion of 332 (R is Me, Ri is COOH) to the 5-cyano-l,4-dihydropyridine-3-carboxylic acid ester 333. 

RSaS stereoisomers.29 The 1,3-dipolar cycloaddition of [60]fullerene with diazomethane, nitrile oxide, and nitrone afforded fullereno-pyrazolines and -isoxazolines. These reactions were modelled at the B3LYP/6-31G(d,p)//AMl level and the reaction mechanisms, regiochemistry, and nature of addition were investigated.30... 

The first example of a bimolecular 1,3-dipolar cycloaddition between an isomtinchnone and an electron-rich dipolarophile was reported by our group several years ago [27]. The reaction of diethyl ketene acetal and isomtinchnone 9 gave cycloadduct 29 in high yield. Again, only one regioisomer was obtained and the regiochemistry encountered is consistent with cycloaddition involving the HOMO of diethyl ketene acetal and the LUMO of isomunchnone 12 (n = 1). 

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