11+2 Cycloaddition, with nitriles concerted

A study of the regioselectivity of the 1,3-dipolar cycloaddition of aliphatic nitrile oxides with cinnamic acid esters has been published. AMI MO studies on the gas-phase 1,3-dipolar cycloaddition of 1,2,4-triazepine and formonitrile oxide show that the mechanism leading to the most stable adduct is concerted. An ab initio study of the regiochemistry of 1,3-dipolar cycloadditions of diazomethane and formonitrile oxide with ethene, propene, and methyl vinyl ether has been presented. The 1,3-dipolar cycloaddition of mesitonitrile oxide with 4,7-phenanthroline yields both mono-and bis-adducts. Alkynyl(phenyl)iodonium triflates undergo 2 - - 3-cycloaddition with ethyl diazoacetate, Ai-f-butyl-a-phenyl nitrone and f-butyl nitrile oxide to produce substituted pyrroles, dihydroisoxazoles, and isoxazoles respectively." 2/3-Vinyl-franwoctahydro-l,3-benzoxazine (43) undergoes 1,3-dipolar cycloaddition with nitrile oxides with high diastereoselectivity (90% de) (Scheme IS)." " ... 

Dipolar addition is closely related to the Diels-Alder reaction, but allows the formation of five-membered adducts, including cyclopentane derivatives. Like Diels-Alder reactions, 1,3-dipolar cycloaddition involves [4+2] concerted reaction of a 1,3-dipolar species (the An component and a dipolar In component). Very often, condensation of chiral acrylates with nitrile oxides or nitrones gives only modest diastereoselectivity.82 1,3-Dipolar cycloaddition between nitrones and alkenes is most useful and convenient for the preparation of iso-xazolidine derivatives, which can then be readily converted to 1,3-amino alcohol equivalents under mild conditions.83 The low selectivity of the 1,3-dipolar reaction can be overcome to some extent by introducing a chiral auxiliary to the substrate. As shown in Scheme 5-51, the reaction of 169 with acryloyl chloride connects the chiral sultam to the acrylic acid substrate, and subsequent cycloaddition yields product 170 with a diastereoselectivity of 90 10.84... 

As suggested in previous similar investigations, as intermediate have been proposed the non-stable, high-energy species 164, formed in low concentration in a reversible cycloaddition-elimination process of 161 with nitriles. This process either occurs in a concerted manner (pathway A) or involves a four-step sequence with the intermediacy of a bipolar species (pathway B). It has been argued that the reaction does not proceed through a thiatetra-azapentalene intermediate, but instead involves a transition state that resembles structure 164. 

The mechanism of 1,3-cycloaddition of nitrile oxides has been a subject of sometimes bitter controversy. While these reactions displayed the regioselec-tivity and stereoselectivity appropriate to concerted pericyclic mechanisms,62 it was suggested that the results were equally in accord with a diradical mechanism.86 However, no direct evidence for a diradical intermediate has been produced, and the balance of the theoretical argument now favors the... 

For intramolecular reactions, the authors have verified that the E and Z stereoisomers of 2-butenyl nitroacetate maintain their stereochemistry in the bicyclic condensation products, in agreement with a concerted cycloaddition step. However, it might be argued that cycloaddition of nitronic acid followed by elimination would give the same result, without intermediate nitrile oxide. 

Kinetic studies using the water-soluble nitrile li revealed first-order dependence in both nitrile and azide and one-half order dependence for zinc bromide. The mechanism of the addition of hydrazoic acid/azide ion to a nitrile to give a tetrazole has been debated, with evidence supporting both a two-step mechanism (Scheme 1, eq 2) and a concerted [2 + 3] cycloaddition (Scheme 1, eq 3). Our mechanistic studies to date imply that the role of zinc is not simply that of a Lewis acid a number of other Lewis acids were tested and caused little to no acceleration of the reaction. In contrast, Zn exhibited a 10-fold rate acceleration at 0.03 M, which corresponds to a rate acceleration of approximately 300 at the concentrations typically used. The exact role of zinc is not yet clear. 

While arylnitrile oxides dimerize in protic solvents and in pure pyridine (cf. 4.04.8.1.3.), they form bis(adducts) (191) and (192) via zwitterions (189) with pyridine in apolar solvents (Scheme 83) <89JHC757,90Gi>. Significantly, the cycloaddition of the nitrile oxide to pyridine to give (190) is not a concerted process. Heterocycles (191) undergo base catalyzed ring cleavage (Scheme 84). 

Azolines of type (13) undergo thermal decomposition in an analogous way to that already discussed for azolones (see Section 4.14.5.2) (Scheme 19). Path (i) is followed by those azolines having Z = S and path (ii) by those with Z = O. Path (i) is a typical retro-1,3-dipolar cycloaddition process, via an intermediate nitrile sulfide, while path (ii) might involve an acyl (Y = Z = O) or thioacyl (Y = S, Z = O) nitrene intermediate (136), which in turn rearranges to iso(thio)cyanate. However, no systematic attempts to trap this possible nitrene intermediate seem to have been made, and so a concerted pathway for the fragmantation cannot be ruled out. 

The controversy between Huisgen and Firestone concerning the mechanism for 1,3-dipolar cycloaddition is longstanding.9,11 For nitrile oxide cycloadditions, experimental data have been interpreted either as supportive of a concerted mechanism9 or in favor of a stepwise mechanism with diradical intermediates.11 Theory has compounded, rather than resolved, this problem. Ab initio calculations on the reaction of fulmonitrile oxide with acetylene predict a concerted mechanism at the molecular otbital level,12,13 but a stepwise mechanism after inclusion of extensive electron correlation.14 MNDO predicts a stepwise mechanism with a diradical intermediate.13 The existence of an extended diradical intermediate such as (4 Scheme 2) has been postulated by Firestone in order to account for the occasional formation of 1,4-addition products such as the oxime (5).11 Of course, the intermediates (4) and (5) for the Firestone mechanism do not correspond to the initial transition states in Firestone s theory. These are attained prior to the formation of, and at higher energy than, the intermediates. 

The mechanism of the decomposition reaction of 5-methoxy- 1,2,3,4-thiatriazole to dinitrogen sulfide and methoxy-nitrile was studied by the DFT method at the CCSD(T)//MP2/6-31+G level of theory <2003JOC6049>. The calculations indicated that this is a concerted retro-[2+3]-dipolar cycloaddition process with an activation energy of 28.9 kcal mol 1 and a reaction energy of 1.9 kcal mol. This unimolecular decomposition is favored due to the entropy gain (25.8 eu) involved in the overall reaction (Scheme 1 and Table 2). 

The other important isoxazole synthesis involves the concerted [3+2] cycloaddition reaction of nitrile oxides 4.18 with either alkynes 4.19 or alkyne equivalents 4.20. 

Tetrazoles of general structure 8.24 can be prepared in a very similar manner to triazoles, except that nitriles are used rather than acetylenes. Once again the reaction with azides is a concerted cycloaddition process. 

Of the 18 systems, some of which are unstable and must be generated in the reaction has been accomplished for at least 15, but not in all cases with a carbon-carbon double bond (the reaction also can be carried out with other double bonds ). Not all aUcenes undergo 1,3-dipolar addition equally well. The reaction is most successful for those that are good dienophUes in the Diels-Alder reaction (15-60). The addition is stereospecific and syn, and the mechanism is probably a one-step concerted process, as illustrated above, " largely controlled by Frontier Molecular Orbital considerations. " In-plane aromaticity has been invoked for these dipolar cycloadditions. " As expected for this type of mechanism, the rates do not vary much with changes in solvent, " although rate acceleration has been observed in ionic liquids. " Nitrile oxide cycloadditions have also been done in supercritical carbon dioxide. There are no simple rules... 

Site selectivity in a number of other concerted cycloadditions which are not [4 + 2] cycloadditions is also explained by frontier orbital control. Thus diphenylketene (332) reacts with isoprene (333) mostly at the more substituted double bond, and with cis-butadiene-l-nitrile (334) at the terminal double bond.263 Dichlorocarbene reacts at the terminal double bond of cycloheptatriene (335),264 and the Simmons-Smith reaction (336 + 337)265 also takes place at the site with the higher coefficients in the HOMO. 

One of the resonance structures of the nitrile oxides is represented by a 1,3-dipole. With alkynes as dipolarophiles, a concerted [3+2] cycloaddition occurs to give isoxazoles 8 ... 

Rickborn and co-workers ° ° isolated the cycloadduct 164 from 4-phenylox-azole through careful manipulation of the experimental conditions (Fig. 3.50). They generated benzyne at 0°C from 1-aminobenzotriazole and lead tetraacetate. Compound 164 was stable at room temperature but, on heating, eliminated benzo-nitrile to give isobenzofuran 162, which could be trapped with A -methylmaleimide to afford a quantitative yield of the tetracyclic derivative 166 as an 88 12 mixture of endo and exo isomers. The cyclic aminal 164 was also sensitive to acid and rearranged to 4-hydroxy-3-phenyl-isoquinoline 165 on exposure to silica gel or a catalytic amount of trifluoroacetic acid. The benzyne cycloadditions were also carried out on 4-(4-nitrophenyl)oxazole and 4-(4-methoxyphenyl)oxazole. A fourfold rate increase was seen for the cycloaddition of the nitrophenyl-substituted oxazole relative to the methoxyphenyl analog, indicating a concerted process with little contribution from a polar intermediate. 

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