Nitrilimines, 1,3-dipolar cycloaddition

Upon base treatment with silver carbonate, isoxazolyl-substituted hydrazonoyl chlorides underwent a sequential intra-intermolecular nitrilimine 1,3-dipolar cycloaddition, leading to tetracyclic pyrazolidines (Equation 6) <2000H(53)831>. 

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). 

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>. 

A 1,3-dipolar cycloaddition approach to this group of compounds involving reaction of a nitrilimine and C=N bond have already been mentioned in CHEC-II(1996) <1996CHEC-II(8)421>. Such a transformation has recently been elaborated by an English team <1994J(P1)3563> for the ring closure of the partially saturated oxazine 287 with nitrile oxide to yield the bicyclic product 288 in medium yield (42%). 

In 1981 we published the first paper [22] on the synthesis of s-triazolo[4,3-a]pyridinium salts, 4, by the anodic oxidation of hydrazones 3 in the presence of pyridine (Scheme 5). In our working mechanistic scheme we proposed nitrilimine as the possible intermediate and pointed out that this reaction opens the door to a wide range of heterocyclic systems via anodic oxidation of aldehyde hydrazones through 1,3-dipolar cycloaddition reactions of the nitrilimine involved. 

The 3 + 2-cycloaddition of 1,2-dithiophthalides with nitrilimines yields benzo[c]thio-phenespirothiadiazoles regioselectively. The azomethineimines isoquinolinium-iV-aryllimide and A-(2-pyridyl)imide readily undergo 1,3-dipolar cycloaddition with electron-deficient dipolarophiles, dimethyl fumarate and dimethyl maleate, to yield tetrahydropyrazolo[5,l-a]isoquinolines in high yield. ° The 1,3-dipolar cycloadditions of electron-poor 1,3-dipoles, bicyclic azomethine ylides (27), with ( )-l-A,A-dimethylaminopropene to yield cycloadducts (28) and (29) are examples of non-stereospecific cycloadductions (Scheme 9). The synthesis of protected... 

Little is known about using a P=S bond as a dipolarophilic unit. Indirect evidence of a 1,3-dipolar cycloaddition in the case of 2,2-dimethyl-1-diazopropane with the short-lived amino(thioxo)phosphane R2N—P=S (R = SrMc3) exists (190). More remarkable is the formation of 1,3,4,2-thiadiazaphosphohne 182 from diazo compound 180 and 0.5 equiv of Lawesson s reagent (179) (Scheme 8.41) (241). This and similar results with nitrones and nitrilimines suggest that the monomeric dithiometaphosphate form of 179 can be trapped in a dipolar cycloaddition across the P=S bond. A spontaneous 1,3-R shift in cycloadduct 181 would then lead to the final product. 

Dipolar cycloadditions to azepines are confined to diazomethane and diphenyl-nitrilimine. The former reagent, depending on the nature of the substituents on the H-azepine, either adds at the 4,5-bond to yield pyrazolines (160) or traps the benzeneimine tautomer of the azepine as the bis-pyrazoline (Section 5.16.2.4) (76CB3505). A pyrazoline is also the product from the addition of diphenylnitrilimine to 5//-dibenz[i,/]azepine (B-67MI51600). 

Presumeably, the intermediate nitrilimine may either react with acetonitrile in a 1,3-dipolar cycloaddition reaction or cyclize as a 1,5-dipolar species, according to Eq. (32). 

Photochemical cycloaddition reactions214-218 between sydnones (1) and 1,3-dipolarophiles take place to give products which are different from, but isomeric with, the thermal 1,3-dipolar cycloaddition products.3 These results are directly interpreted in terms of reactions between the 1,3-dipolarophiles and die nitrilimine (316). The photochemical reactions between sydnones and the following 1,3-dipolarophiles have been reported dicyclopentadiene,214 dimethyl acetylene dicarboxylate,213-218 dimethyl maleate,213 dimethyl fumarate,213 indene,21 carbon dioxide,213 and carbon disulfide.217... 

A 1,3-dipolar cycloaddition of indanoneenamines and nitrilimines produces the indeno[2,1 -cjpyrazole (52).135 The yields of such cyclization reactions are high (60-80%). Reactions of A-alkylpyridine-3-ylides with picryl chloride involving cyclization give a mixture of pseudoazulenes 35 and 36.103 An additional preparation of pyrindine 26 is from 1,2- and 1,4-oxides of azonine.55... 

Stable /V-phosphino- and /V-phosphonio-nitrilimines undergo 3 + 2-cycloaddition with electron-poor and electron-rich dipolarophiles, respectively, to produce substituted pyrazolines.101 The first diastereoselective 3 + 2-cycloaddition between bis(trityl)ni-trilimine and an acrylate, (R)-a-(acryloxy)-/f, jS-dimethyl-y-butyrolactone, has been reported.102 The 1,3-dipolar cycloaddition of A, A -diarylbisnitrile imides with cinnamonitriles produces exclusively 5, 5 -dicyano-4,4, 5, 5 -tetrahydro[3, 3 -di-l//-pyrazoles] which yield the corresponding 3,3 -di-l//-pyrazoles on thermal aromatization.103... 

The intramolecular 1,3-dipolar cycloadditions of homochiral nitrilimines derived from methyl esters of glycine, L-alanine, L-phenylalanine, and (S)-2-phenylglycine produced enantiopure 2,3,3a,4,5,6-hexahydropyrrolo[3,4-c]pyrazoles in fair to good overall product yields.50 The thermal reaction of diphenylnitrilimine with N-substituted benzimidazoles (47) produced lV,AP-disubstituted o-phenylenediamines (51). The reaction involved two 1,3-dipolar cycloadditions with two nitrilimine moieties yielding adducts (48-50), followed by a ring opening of the azolic ring of (50) (Scheme 13).51... 

The silver acetate-promoted 1,3-dipolar cycloaddition of nitrilimines with 3(/f )-pheny]-4(A )-cinnamoyl-2-azetidinone produced the major adduct, 4-(4,5-dihydro- (g) pyrazol-5-yl)carbonyl-2-azetidinones, with high stereoselectivity.70 The 1,3-dipolar cycloadditions of substituted 2,7-dime(liyl-3-thioxo-3,4,5,6-ici.rahydro-2//- 1,2,41 triazepin-5-one with iV-aryl-C-ethoxycarbonylnitrilimines are highly chemoselective, where the sulfur atom of the dipolarophile interacts with the carbon atom of the dipole.71 The enantioselective 1,3-dipolar cycloaddition of nitrile imines with electron deficient acceptors produces dihydropyrazoles in the presence of 10 mol% of chiral Lewis acid catalyst.72... 

Partially and perfluorinated thioketones and thioaldehyde were stabilized as anthracene adducts (70). The adducts (70) were prepared in moderate yield from the corresponding carbonyl compounds with P4S10 or Lawesson s reagent in the presence of anthracene under toluene reflux. The generated thiocarbonyl compounds are not accessible in bulk due to their tendency towards polymerization. By thermolysis of the anthracene adducts (70) in the presence of C,N-bis(triisopropylsilyl)nitrilimine (NI), 1,3,4-thiadiazole derivatives (71) were obtained. Also, 1,3-dipolar cycloaddition with bis(trimethylstannyl)diazomethane (BTSD) to give consecutive products (72) from a 1,2-metallotropic migration of primary adducts was discussed. [95LA95]... 

A study of the 1,3-dipolar cycloaddition of pyrazines, pyrimidines and l//-pyrimidinthiones with nitrilimines (80), generated in situ by dehydrohalogenation of the corresponding hydrazonoyl chlorides (79), was carried out. Reaction of pyrimidine-2( l//)-thiones (81) and -4(l//)-thiones with nitrilimines in benzene at reflux gave spiro[pyrimidine-2(l//), 2 (3 f/)-[ 1,3,4]thiadiazoles... 

Intramolecular 1,3-dipolar cycloaddition (see Section 2.04.9.7) has been used to obtain racemic and enantiopure azeto[2, l l,2]pyrrolo[3,4-c]pyrazoles from nitrilimine intermediates (Scheme 20). The relative configuration of the products was established from the NOE enhancements in the H NMR spectra (see Section 2.04.3.2) <2006TA1319>. 

Dipolar cycloadditions between nitrilimines 37, obtained in situ from 36, and alkenyl dipolarophiles 38 afford a mixture of pyrazoles 39 and 41 and tetrazines 40. Tetrazine byproducts 40 were obtained in good yields using 1-hexene as dipolarophile, Cs2C03 as base and with aryl as p-tolyl (50%) or as p-Br-phenyl (67%) <02NJC1340>. 

Khaddar, H., Hamelin, J., and Benhaoua, H. 1999. Microwave-assisted 1,3-dipolar cycloaddition reactions of nitrilimines and nitrile oxides. Journal of Chemical Research, 718-19. Also available at http //www.rsc.org/delivery/ ArticleLinking/DisplayArticlePorPree. cfm doi=a907010i JoumalCode=JC... 

A representative 1,3-dipolar cycloaddition process occurs with yV-aryl-C-(trifiuoromethyl)-nitrilimines, generated from the corresponding hydrazonoyl bromides, c.g. 4. under basic conditions. which can react with dimethyl fumarate and maleate,bicyclic olefins. and dipolarophiles containing cumulative double bonds. With sodium isocyanates as the dipolarophilc the cycloaddition reaction occurs across the C = N bond, while with potassium isothiocyanate it occurs through the C = S bond. ... 

Abdel-Aziz et al. [16] reported the regioselective 1,3-dipolar cycloaddition of nitrilimines with 2-(4-arylidene)-thiazolo-[3,2-a]-benzimidazole-3-(2H)-ones to afford the corresponding pyrazoylbenzimidazole (v). The pyrazolylbenzimidazoles were also examined for their anti-tumor activities against two tumor cell lines, Hep-2 and colon CaCo-2 and encouraging results were obtained. 

Huisgen s studies of 1,3-dipolar cycloadditions leading to a great variety of heterocyclic systems (61MI41203, 8ORCR88O) are applicable to the synthesis of triazoles and derivatives. Nitrilimines (171) formed by dehydrohalogenation of C-halobenzylidenephenylhydrazones (172) react with C=N, C=N (as in CNO) to afford triazoles and triazolines in yields of... 

The one-pot three-component reaction of polyethylene glycol-supported acrylate 623 with aldehydes 621 and hydrazines 622 in the presence of chloramine-T followed by methanolysis afforded pyrazolines 624 in good yields and high purities (Scheme 77) <2003SL1467>. 1,3-Dipolar cycloaddition of resin-supported acrylic acid 625 with the nitrilimines generated in situ by oxidation of the aldehyde phenylhydrazones with (diacetoxy)iodobenzene under microwave irradiation gave 626, which was converted into l-phenyl-3-substituted-2-pyrazolinyl-5-carboxylates 627 (Scheme 78) <2004SC3521>. 

A series of isoindazole-C6o dyads based on pyrazolino[60]fullerene were prepared by 1,3-dipolar cycloadditions of the nitrilimines, generated in situ from hydrazones, to C6o <2002T5821, 2004JOC2661>. 

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