Three 1,3-dipolar cycloaddition

C,C,A(rTriaryl-/V(rcyanoazornethine imines (136) are trimerized on heating to (137) via a succession of three 1,3-dipolar cycloadditions, the last being intramolecular (80AG(E)906). 

The Criegee mechanism for the ozonolysis of alkenes (Figure 11.73) can be analyzed in terms of a series of three 1,3-dipolar cycloadditions. The addition of ozone to an alkene leads first to a 1,2,3-trioxacyclopentane structure known variously as an initial ozonide, primary ozonide, or molozonide,... 

Ozonation ofAlkenes. The most common ozone reaction involves the cleavage of olefinic carbon—carbon double bonds. Electrophilic attack by ozone on carbon—carbon double bonds is concerted and stereospecific (54). The modified three-step Criegee mechanism involves a 1,3-dipolar cycloaddition of ozone to an olefinic double bond via a transitory TT-complex (3) to form an initial unstable ozonide, a 1,2,3-trioxolane or molozonide (4), where R is hydrogen or alkyl. The molozonide rearranges via a 1,3-cycloreversion to a carbonyl fragment (5) and a peroxidic dipolar ion or zwitterion (6). 

The distinction between these two classes of reactions is semantic for the five-membered rings Diels-Alder reaction at the F/B positions in (269) (four atom fragment) is equivalent to 1,3-dipolar cycloaddition in (270) across the three-atom fragment, both providing the 47t-electron component of the cycloaddition. Oxazoles and isoxazoles and their polyaza analogues show reduced aromatic character and will undergo many cycloadditions, whereas fully nitrogenous azoles such as pyrazoles and imidazoles do not, except in certain isolated cases. 

The reaction is illustrated by the intramolecular cycloaddition of the nitrilimine (374) with the alkenic double bond separated from the dipole by three methylene units. The nitrilimine (374) was generated photochemically from the corresponding tetrazole (373) and the pyrrolidino[l,2-6]pyrazoline (375) was obtained in high yield 82JOC4256). Applications of a variety of these reactions will be found in Chapter 4.36. Other aspects of intramolecular 1,3-dipolar cycloadditions leading to complex, fused systems, especially when the 1,3-dipole and the dipolarophile are substituted into a benzene ring in the ortho positions, have been described (76AG(E)123). 

When the chain between the azirine ring and the alkene end is extended to three carbon atoms, the normal mode of 1,3-intramolecular dipolar cycloaddition occurs. For example, irradiation of azirine (73) gives A -pyrroline (74) in quantitative yield 77JA1871). In this case the methylene chain is sufficiently long to allow the dipole and alkenic portions to approach each other in parallel planes. 

The 1,3-dipolar cycloaddition reaction of nitrones with alkenes gives isoxazolidines is a fundamental reaction in organic chemistry and the available literature on this topic of organic chemistry is vast. In this reaction until three contiguous asymmetric centers can be formed in the isoxazolidine 17 as outlined for the reaction between a nitrone and an 1,2-disubstituted alkene. The relative stereochemistry at C-4 and C-5 is always controlled by the geometric relationship of the substituents on the alkene (Scheme 8.6). 

A microwave-assisted three-component reaction has been used to prepare a series of 1,4-disubstituted-1,2,3-triazoles with complete control of regiose-lectivity by click chemistry , a fast and efficient approach to novel functionalized compounds using near perfect reactions [76]. In this user-friendly procedure for the copper(l) catalyzed 1,3-dipolar cycloaddition of azides and alkynes, irradiation of an alkyl halide, sodium azide, an alkyne and the Cu(l) catalyst, produced by the comproportionation of Cu(0) and Cu(ll), at 125 °C for 10-15 min, or at 75 °C for certain substrates, generated the organic azide in situ and gave the 1,4-disubstituted regioisomer 43 in 81-93% yield, with no contamination by the 1,5-regioisomer (Scheme 18). 

There are almost no studies of substituent effects on additions to carbon-carbon triple bonds extant in the literature. Bowden and Price (208) have reported a correlation of rates of addition of hydrogen bromide to 3-substituted propiolic acids with the Hammett equation using the Op constants. Unfortunately, there are only three substituents in the set. Sufficient data are available for a single set of 1,3-dipolar cycloaddition. The set studied is shown in Table XXXIII, and the results of the correlation are in Table XXXIV. The correlation was significant the delocalized effect is predominant in this set. 

Oxazole formation can be envisaged as proceeding by three possible pathways 1,3-dipolar cycloaddition of a free ketocarbene to the nitiile (Path A), the formation and subsequent 1,5-cyclisation of a nitrile ylide (Path B) or the formation and subsequent rearrangement of a 2-acyl-2//-azirine (Path C) (Scheme 9). 

Another interesting variation of the 1,3-dipolar cycloaddition involves generation of 1,3-dipoles from three-membered rings. As an example, aziridines 7 and 8 give adducts derived from apparent formation of 1,3-dipoles 9 and 10, respectively.148... 

Pagenkopf s group developed a novel domino process for the synthesis of pyrroles 4-183, which allows for the control over the installation of substituents at three positions and seems to be very suitable for combinatorial chemistry [62]. The process consists of a 1,3-dipolar cycloaddition of an intermediate 1,3-dipole formed from the cyclopropane derivative 4-181 with a nitrile to give 4-182 followed by dehydration and isomerization (Scheme 4.39). The yield ranges from 25 to 93 %, and the procedure also works well with condensed cyclopropanes. 

The mechanism of 1,3-dipolar cycloaddition can be found in Ref. 63 and the references within. The reaction of nitrone with 1,2-disubstituted alkenes creates three contiguous asymmetric centers, in which the geometric relationship of the substituents of alkenes is retained. The synthetic utility of nitrone adducts is mainly due to their conversion into various important compounds. For instance, P-amino alcohols can be obtained from isoxazolidines by reduction with H2-Pd or Raney Ni with retention of configuration at the chiral center (Eq. 8.44). 

To control the stereochemistry of 1,3-dipolar cycloaddition reactions, chiral auxiliaries are introduced into either the dipole-part or dipolarophile. A recent monograph covers this topic extensively 70 therefore, only typical examples are presented here. Alkenes employed in asymmetric 1,3-cycloaddition can be divided into three main groups (1) chiral allylic alcohols, (2) chiral amines, and (3) chiral vinyl sulfoxides or vinylphosphine oxides.63c... 

A spiro[pyrrolidine-2,3 -oxindole] library <1998TL2235> has been synthesized via a three-component 1,3-dipolar cycloaddition in the solution phase. Isatins 432 were treated with L-proline or L-thiaproline and chalcone 433 in a MeOH-H20, CH3CN-H20, or dioxane-H20 solution. Spiropyrrolidines 49 (Scheme 96) were obtained as the sole products in good yield and high purity (Table 15). 

The three-component reaction between isatin 432a, a-aminoacids 433 (proline and thioproline) and dipolarophiles in methanol/water medium was carried out by heating at 90 °C to afford the pyrrolidine-2-spiro-3 -(2-oxindoles) 51. The first step of the reaction is the formation of oxazlidinones 448. Loss of carbon dioxide from oxazolidinone proceeds via a stereospecific 1,3-cycloreversion to produce the formation of oxazolidinones almost exclusively with /razw-stereoselectivity. This /f-azomethine ylide undergo 1,3-dipolar cycloaddition with dipolarophiles to yield the pyrrohdinc-2-r/ V -3-(2-oxindolcs) 51. (Scheme 101) <2004EJ0413>. 

There is an enormous literature on thiocarbonyl compounds, due in part to the technical and industrial importance of many of them, including thioamides, thioureas, xanthates, dithiocarbamates and so forth. An excellent, and recent, general review is available.107 There are also specialized reviews germane to the present chapter Griffin, Woods, and Klayman2 discussed the use of thioureas in the synthesis of heterocycles the preparation of thiazoles from thioamides is included in a three-part volume on Thiazoles 108 the use of carbon disulfide in the synthesis of trithiones and related heterocycles has been reviewed by Mayer109 and Huisgen110 has reported numerous examples of 1,3-dipolar cycloadditions in which carbon disulfide was used. 

Reactions of 2,3-dihydro-17/-1,4-diazepines with mesitonitrile oxide proceed with site- and regiospecific 1,3-dipolar cycloaddition leading to bis[ 1,2,4] oxadiazolo[l,4]diazepine derivatives 160 (326). Of the three compounds 160 only the one with R = R = Ph is formed with trails arranged substituents. The two other products (R = R = Me and R = Me, R = Ph) are mixtures of diastereoiso-mers. The heterotricyclic 6,1 Oa, 11,11 a-tetrahydro-5//-bis[ 1,2,4]oxadiazolo[4,5-d 5 -g][, A diiazeipm.e structure 160 of the obtained bis-adducts indicates that the hetero double bonds are much more reactive than the olefinic ones. No evidence for the formation of monoadducts was obtained. 

Dipolar cycloaddition reactions between three A-benzyl-C-glycosyl nitrones and methyl acrylate afforded key intermediates for the synthesis of glyco-syl pyrrolidines. It was found that furanosyl nitrones (574) and (575) reacted with methyl acrylate to give mixtures of all possible 3,5-disubstituted isoxazolidines (577) and (578). On the other hand, the reaction with pyranosyl nitrone (576) was much more selective and cycloaddition at ambient temperatures afforded only one of the possible Re-endo adducts (579a). The obtained isoxazolidines were transformed into the corresponding (V-benzyl-3-hydroxy-2-pyrrolidinones (580—582) on treatment with Zn in acetic acid (Scheme 2.264) (773). 

First, all these classes of compounds are 1,3-dipoles, that is, they serve as the starting reagents in 1,3-dipolar cycloaddition reactions, which can be considered as a modem powerful method for the synthesis of various heterocyclic and polyfunctional compounds (5). All three dipoles have the common reactive fragment ... 

The first demonstration of fluorous synthesis was in the preparation of small (8-12 members) isoxazo-line and isoxazole libraries by the three-step procedure outlined in Figure 8.1461 All reactions were purified by three-phase liquid-liquid extraction. The starting substrates were simple allylic alcohols which were tagged with the fluorous silyl halide 5 to make substrates 6 for an ensuing dipolar cycloaddition. This was conducted by the Mukaiyama method with a large excess of nitro compound and... 

The 1,3-dipolar cycloaddition of imidazolinone 123 with ethyl m-4,4,4-trifluorocrotonate 124 provided, after 36 h at reflux, the regio- and stereoisomer 125 (90%), accompanied with traces of three other unidentified cycloadducts (10%) <2001JFC275>. Compound 125 was isolated in 70% yield (Scheme 15). The structures of the final product were elucidated by nuclear Overhauser effect (NOE) experiments. This high selectivity is the result of a preferred ///////-orientation of both ester and CF3 groups in the transition state and of an impeded ////////-approach of the CFj-substituted terminus of the alkene to the sterically hindered ct-site of 123. 

A 1,3-dipolar cycloaddition of the nonstabilized azomethine ylide 6 is the key step in a three-component reaction. The azomethine ylides were generated from (2-azaallyl)stannanes or (2-azaallyl)silanes 5 through an intramolecular iV-alkylation/demetallation cascade. The ylides underwent cycloaddition reactions with dipolarophiles yielding indolizidine derivatives 7-9 <2004JOC1919> (Scheme 1). 

In many of the above examples the number of electrons happens to be the same as the number of atoms in each component. But this is not always the case. For example in 1, 3 dipolar cycloaddition, the 1, 3 dipole has four electrons distributed on three atoms. The addition of a 1, 3 dipole to an olefine will give 3+2 carbon atoms in the ring but it will have 4k +2k electrons according to the adopted system... 

The combination of modem valence bond theory, in its spin-coupled (SC) form, and intrinsic reaction coordinate calculations utilizing a complete-active-space self-consistent field (CASSCF) wavefunction, is demonstrated to provide quantitative and yet very easy-to-visualize models for the electronic mechanisms of three gas-phase six-electron pericyclic reactions, namely the Diels-Alder reaction between butadiene and ethene, the 1,3-dipolar cycloaddition of fulminic acid to ethyne, and the disrotatory electrocyclic ringopening of cyclohexadiene. 

In the case of the 1,3-dipolar cycloaddition offulminic acid to ethyne, none of the three common spin bases leads to any particular interpretational advantages. For this reaction, we report the composition of the optimal spin-coupling pattern (2) in the Kotani spin basis, which is orthonormal as a result, the weights of the individual spin functions making up oo are given simply by the squares of the corresponding spincoupling coefficients,... 

The SC descriptions of the electronic mechanisms of the three six-electron pericyclic gas-phase reactions discussed in this paper (namely, the Diels-Alder reaction between butadiene and ethene [11], the 1,3-dipolar cycloaddition offulminic acid to ethyne [12], and the disrotatory electrocyclic ring-opening of cyclohexadiene) take the theory much beyond the HMO and RHF levels employed in the formulation of the most popular MO-based treatments of pericyclic reactions, including the Woodward-Hoffmarm mles [1,2], Fukui s frontier orbital theory [3] and the Dewar-Zimmerman model [4—6]. The SC wavefunction maintains near-CASSCF quality throughout the range of reaction coordinate studied for each reaction but, in contrast to its CASSCF counterpart, it is very much easier to interpret and to visualize directly. 

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