11+2 Cycloaddition, with nitriles 2+2 Cycloadditions

Dihydrofuran (376) and 2,5-dihydrofuran (377) react with nitrile oxides to give furo[2,3-6 ]isoxazoles (378) and furo[3,4-rf]isoxazoles (379), respectively, as cycloadducts. The double bonds of furan, pyrrole and thiophene also react when the nitrile oxide is generated in situ. Thus furan and benzonitrile oxide gave (380), and with 2-methyl-2-oxazoline the cycloadduct (381) was obtained (71AG(E)810). These and related cycloadditions are discussed in Chapter 4.36. 

The two major methods of preparation are the cycloaddition of nitrile oxides to alkenes and the reaction of a,/3-unsaturated ketones with hydroxylamines. Additional methods include reaction of /3-haloketones and hydroxylamine, the reaction of ylides with nitrile oxides by activation of alkyl nitro compounds from isoxazoline AT-oxides (methoxides, etc.) and miscellaneous syntheses (62HC(i7)i). 

The A-benzenesulfonyl imines of hexafluoroacetone readily react with nitrile oxides to give [3-1-2] adducts, apparently in a multistep reaction [151] (equation 36) Although only a few examples of [3-1-2] cycloaddition reactions of this type have been descnbed so far, most 1,3-dipoles should react in this way with predictable regiochemistry [5 146, ISO 151]... 

Cycloaddition of 2-nitrosopyridine 48 with nitrile oxides can give either di-A -oxides such as 49 or 3-mono-A -oxides such as 50 (93JHC287). In general, greater electron withdrawing character in the aromatic substituent appears to favor formation of the di-A -oxides. Sulfur ylides such as compound 51 are obtained from aryl isothiocyanates and l-amino-2-methylthiopyridinium iodides (84JCS(P1)1891) nitrogen ylides can be obtained from a similar reaction (86H(24)3363). 

Thioazadienes 90, formed in situ by the reaction of trimethylsilylimines and isothiocyanates, underwent cycloaddition reactions with nitriles bearing electron-withdrawing groups, to afford 1,3,5-thiadiazines [94] in excellent yield (Equation 2.26). 

Some cycloaddition reactions of 4 are summarized in Scheme 1. This shows that silylene 4 undergoes reactions with nitriles [14], phosphaalkynes [15], silyl azides [16], diazabutadienes [17], 2,2 -bipyridyl and its derivatives [18, 19], a-ketoimines [19], and pyridine-2-aldimines [19]. 

The application of microwaves to the cycloaddition reactions of allyl alcohols 180 with nitrile oxides not only achieved a substantial reduction of the reaction time and an improvement of the adduct yields, but also altered the regioselectivity of the cycloaddition in favor of the nonhydrogen bond-directed cycloadduct 182 (Scheme 9.55) [105]. 

Ethyl 3-azido-l-methyl-177-indole-2-carboxylate 361 is prepared in 70% yield by diazotization of amine 360 followed by substitution of the created diazonium group with sodium azide. In cycloadditions with nitrile anions, azide 361 forms triazole intermediates 362. However, under the reaction conditions, cyclocondensation of the amino and ethoxycarbonyl groups in 362 results in formation of an additional ring. This domino process provides efficiently 4/7-indolo[2,3-i ]l,2,3-triazolo[l,5- ]pyrimidines 363 in 70-80% yield (Scheme 57) <2006TL2187>. 

A mild and greener approach to the synthesis of 1,2,4-triazoles by the dipolar cycloaddition of nitrilimines with nitriles has been reported. The nitrilium intermediates were generated in situ from hydrazonyl chlorides 120 and reacted with the nitriles in a one-pot process. Yields of the 1,3,5-trisubstituted products 121a-o were good in the majority of cases (Equation 37 and Table 20) <2005H(65)1183>. 

Table 20 Cycloaddition reaction of in s/ fu-generated nitrilimines with nitriles to give 1,3,5-trisubstituted 1,2,4-triazole derivatives (Equation 37)...

The conversion of the polystyrene-supported selenyl bromide 289 into the corresponding acid 290 allowed dicyclohexylcarbodiimide (DCC)-mediated coupling with an amidoxime to give the 1,2,4-oxadiazolyl-substituted selenium resin 291 (Scheme 48). Reaction with lithium diisopropylamide (LDA) and allylation gave the a-sub-stituted selenium resin 292, which was then used as an alkene substrate for 1,3-dipolar cycloaddition with nitrile oxides. Cleavage of heterocycles 293 from the resin was executed in an elegant manner via selenoxide syn-elimination from the resin <2005JC0726>. 

Type G syntheses are typified by the 1,3-dipolar cycloaddition reactions of nitrile sulfides with nitriles. Nitrile sulfides are reactive 1,3-dipoles and they are prepared as intermediates by the thermolysis of 5-substituted-l,3,4-oxathiazol-2-ones 102. The use of nitriles as dipolarophiles has resulted in a general method for the synthesis of 3,5-disubstituted-l,2,4-thiadiazoles 103 (Scheme 11). The thermolysis is performed at 190°C with an excess of the nitrile. The yields are moderate, but are satisfactory when aromatic nitrile sulfides interact with electrophilic nitriles. A common side reaction results from the decomposition of the nitrile sulfide to give a nitrile and sulfur. This nitrile then reacts with the nitrile sulfide to yield symmetrical 1,2,4-thiadiazoles <2004HOU277>. Excellent yields have been obtained when tosyl cyanide has been used as the acceptor molecule <1993JHC357>. 

An alternative route to C-linked derivatives involves the 1,3-dipolar cycloaddition reaction of nitrile sulfides with nitriles which yields 3,5-disubstituted-l,2,4-thiadiazoles of unequivocal structure (see Section 5.08.9.8). 

It was found that 2-propenyloxymagnesium bromide reacts much more readily with nitrile oxides than other known dipolarophiles of electron-deficient, electron-rich, and strained types, including 3-buten-2-one, ethyl vinyl ether, and norbomene, respectively (147). Therefore, this BrMg-alkoxide is highly effective in various nitrile oxide cycloaddition reactions, including those of nitrile oxide/Lewis acid complexes. 

Individual aspects of nitrile oxide cycloaddition reactions were the subjects of some reviews (161 — 164). These aspects are as follows preparation of 5-hetero-substituted 4-methylene-4,5-dihydroisoxazoles by nitrile oxide cycloadditions to properly chosen dipolarophiles and reactivity of these isoxazolines (161), 1,3-dipolar cycloaddition reactions of isothiazol-3(2//)-one 1,1-dioxides, 3-alkoxy- and 3-(dialkylamino)isothiazole 1,1-dioxides with nitrile oxides (162), preparation of 4,5-dihydroisoxazoles via cycloaddition reactions of nitrile oxides with alkenes and subsequent conversion to a, 3-unsaturated ketones (163), and [2 + 3] cycloaddition reactions of nitroalkenes with aromatic nitrile oxides (164). 

Cycloaddition with nitrile oxides occur with compounds of practically any type with a C=C bond alkenes and cycloalkenes, their functional derivatives, dienes and trienes with isolated, conjugated or cumulated double bonds, some aromatic compounds, unsaturated and aromatic heterocycles, and fullerenes. The content of this subsection is classified according to the mentioned types of dipolarophiles. Problems of relative reactivities of dienophiles and dipoles, regio- and stereoselectivity of nitrile oxide cycloadditions were considered in detail by Jaeger and... 

Cycloalkene Derivatives Cyclopropenes readily interact with nitrile oxides. Reactions of a broad series of 3,3-disubstituted cyclopropenes with 4-substituted benzonitrile, methoxycarbonyl- and cyanoformonitrile oxides (229) as well as with di(isopropoxy)phosphorylformonitrile oxide (230) give 2-oxa-3-azabicyclo[3.1.0]hexene derivatives 62. Stereoselectivity of the cycloaddition is governed by both steric and polar factors. In particular, steric factors are supposed to prevail for 3-methyl-3-phenylcyclopropene affording 62 [R1 =... 

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... 

Heterocycles Both non-aromatic unsaturated heterocycles and heteroaromatic compounds are able to play the role of ethene dipolarophiles in reactions with nitrile oxides. 1,3-Dipolar cycloadditions of various unsaturated oxygen heterocycles are well documented. Thus, 2-furonitrile oxide and its 5-substituted derivatives give isoxazoline adducts, for example, 90, with 2,3- and 2,5-dihydro-furan, 2,3-dihydropyran, l,3-dioxep-5-ene, its 2-methyl- and 2-phenyl-substituted derivatives, 5,6-bis(methoxycarbonyl)-7-oxabicyclo[2.2.1]hept-2-ene, and 1,4-epoxy-l,4-dihydronaphthalene. Regio- and endo-exo stereoselectivities have also been determined (259). 

Dipolar cycloaddition of 2,4-(trimethylsilyl)- and 2,4-(trimethylgermyl)-substituted thiophene-1,1-dioxides as well as silylated 2,2 -bithiophene-1,1-dioxides was investigated. It was shown that only the C(4)=C(5) double bond of 2,4-disubstituted thiophene-1,1-dioxides interacts with acetonitrile oxide to give thienoisoxazoline dioxides. Bithiophene derivatives were inactive or their reaction with nitrile oxide was accompanied by desilylation. Cycloaddition of benzonitrile oxide with all mentioned sulfones did not occur. The molecular structure of 3a-methyl-5.6a-bis(trimethylgermyl)-3a,6a-dihydrothieno 2.3-c/ isoxazole 4,4-dioxide was established by X-ray diffraction (263). ... 

Dimethyl-3-methylenepyrrolidine-2-thione, which reacts with nitrones regio- and stereoselectively at its exocyclic C=C bond to give only spirocy-cloadducts 116, behaves more complicatedly with nitrile oxides. The latter undergo 1,3-dipolar cycloaddition both to the exocyclic C=C and C=S double bonds with subsequent cycloreversion and formation of spiro-lactams 117 (281). 

Among heteroaromatic compounds able to react with nitrile oxides as dipo-larophiles, furan, probably, is the best known. Recently, a novel nitrile oxide was generated from a sulfoximine and converted in situ to a cycloadduct with furan (Scheme 1.25) (287). The starting racemic N-methyl-S-nitromethyl-S-phenylsul-foximine 124 was prepared in 87% yield via nitration of N,S-dimethyl-S-phenyl-sulfoximine. Reaction of 124 with p-chlorophenyl isocyanate and a catalytic quantity of triethylamine, in the presence of furan, afforded dihydrofuroisoxazole 125, the product of nitrile oxide cycloaddition, in 42% yield (65 35 diastereomer ratio). The reaction of 125 with phenyllithium and methyllithium afforded compounds 126, which are products formed by replacement of the sulfoximine group by Ph and Me, respectively. 

I.3.4.2. Intermolecular Cycloaddition at C=X or X=Y Bonds Cycloaddition reactions of nitrile oxides to double bonds containing heteroatoms are well documented. In particular, there are several reviews concerning problems both of general (289) and individual aspects. They cover reactions of nitrile oxides with cumulene structures (290), stereo- and regiocontrol of 1,3-dipolar cycloadditions of imines and nitrile oxides by metal ions (291), cycloaddition reactions of o-benzoquinones (292, 293) and aromatic seleno aldehydes as dipolarophiles in reactions with nitrile oxides (294). 

Aldimines, Ketimines, and Related Compounds as Dipolarophiles Reactions of aldimines with nitrile oxides proceed readily to give 1,2,4-oxadiazolines independently of the nature of substituents both in dipole and dipolarophile molecules. 1,2,4-Oxadiazolines were prepared by the regiospe-cihc 1,3-dipolar cycloaddition of nitrile oxides with fluoro-substituted aldimines (295). Phosphorylnitrile oxides gave with azomethines, PhCH NR, phosphory-lated 1,2,4-oxadiazolines 129 (296). Expected 1,2,4-oxadiazolines were also obtained from azomethines, derived from 4-formylcoumarine (179) and 1,3-diphenylpyrazole-4-carbaldehyde (297). 

Poly(ethylene glycol) supported liquid-phase syntheses by both the reaction of (polyethylene glycol (PEG))-supported imines with nitrile oxides, generated in situ from aldoximes, (300) and 1,3-dipolar cycloadditions of nitrile oxide, generated in situ on soluble polymers with a variety of imines (301, 302) have been described. The solid-phase synthesis of 1,2,4-oxadiazolines via cycloaddition of nitrile oxide generated in situ on solid support with imines has also been elaborated (303). These syntheses of 1,2,4-oxadiazolines provide a library of 1,2,4-oxadiazolines in good yields and purity. 

Dipolar cycloadditions of 2-ethoxy- and 2-ethylthio-l-azetines 146 (Z = O, S) with nitrile oxides give 4,5,6,6a-tetrahydroazeto[l,2-d]oxadiazoles, for example 147 (315, 316). 

Cyclic imidate esters, 2-ethoxypyrrolin-5-one and 2-ethoxy-1II -indol-3-one, undergo 1,3-dipolar cycloaddition reactions with nitrile oxides, the reaction site being at the pyrroline C=N bond (317). Rigid and sterically congested pyrroline spiro compounds 148 demonstrate complete diastereofacial selection in site and regiospecific cycloaddition reactions with nitrile oxides to give products 149 (318). 

I.3.4.2.6. Compounds with Unusual Double Bonds 1,3-Dipolar cycloaddition of l-chloro-2-phenyl-2-trimetkylsilyl-l-phosphaethene with nitrile oxides, followed by elimination of Me SiCl, results in 3,5-diphenyl-l,4,2-oxaphosphazole 190 (356). Chromium, molybdenum, and tungsten pentacarbonyls of 3,5-diphenyl-).3-phosphinins react with nitrile oxides to give the corresponding 1,3-dipolar cycloadducts, at the P = C bond, see 191 (Ar = Ph, Mes) (357). 

Iodoacetylene (prepared in situ from ethynylmagnesium bromide or tributyl (ethynyl)tin with iodine) was used as a dipolarophile in the 1,3-dipolar cycloaddition reactions with nitrile oxides to produce 2-(5-iodoisoxazol-3-yl)pyridine and 3-(4-fluorophenyl)-5-iodoisoxazole in good yield (70%-90%). Subsequently,... 

---