1,3-dipolar cycloaddition reactions with nitrile imines

Dipolar cycloaddition reactions with azides, imines, and nitrile oxides afford synthetic routes to nitrogen-containing heterocycles (25—30). 

Dihydro-l,4-diazepines will perform 1,3-dipolar cycloaddition reactions with nitrile oxides and nitrile imines but it is only the imine bonds in the diazepine that react. Thus, 2,3-dihydro-5,7-diphenyl-1-methyl-17/-1,4-diazepine (64 R = Me) only gave mono adducts (65) with arylnitrile... 

The regioselectivity and reactivity of the 1,3-dipolar cycloaddition reactions of nitril-imines with acrylonitrile and methyl acrylate have been investigated. The 1,3-dipolar cycloaddition reactions of nitrilimines with isatin imines yielded spiro[indolin-3,3 -1,2,4-triazol] derivatives under classical and microwave conditions/ An extensive study of the 1,3-dipolar cycloaddition reactions of nitrilimines with a,/ -unsaturated lactones, thiolactones, and lactams has been presented. In all cases, regioisomeric mixtures were obtained with the 5-substituted pyrazole as the major cycloadduct. me5 o-Tetrakis(pentafluorophenyl)porphyrin (51) reacts with iminonitriles (52) yielding pyrazolin-fused chlorines (53) via a 1,3-dipolar cycloaddition reaction (Scheme 17). ... 

Cyclobut[f]thiophene is a poor dipolarophile and requires prolonged reaction times to produce the 1,3-dipolar cycloaddition product 84 on reaction with diazomethane (Equation 44) <1999J(P1)605>. Reactions with nitrile imines or azomethine imines fail to provide cycloadducts. 

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). 

N-benzyladamantyl-2-imines, and 2-methyleneadamantanes were studied (352, 353). In particular, X-ray single-crystal analysis confirmed the configuration of the oxathiazoline 185, resulting from the favored attack of nitrile oxide on the 5-fluoroadamantane-2-thione. 2-Silyl-substituted oxathiazole 186 was synthesized by the 1,3-dipolar cycloaddition reaction of phenyl triphenylsilyl thioketone with 4-chlorobenzonitrile oxide (354). 

TABLE 7.48. OXAZOLONE SPIROPYRAZOLINES FROM 1,3-DIPOLAR CYCLOADDITION REACTION OF UNSATURATED 5(4//)-OXAZOLONES WITH NITRILE IMINES ... 

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). 

Heteroaromatic A-imines undergo 1,3-dipolar cycloaddition reactions across the A-imine nitrogen atom and the a-position of the ring. With nitriles, triazolopyridines are formed by dehydrogenation of... 

Some examples are known of 1,3-dipolar cycloaddition reactions of trifluoromethyl-substituted alkenes and alkynes with other dipoles (see Table 12), such as diazomethane.nitrile imines, " " nitronates," and munchones." Depending on reaction conditions, cycloadditions may occur via a two-step process. 

It also participates in dipolar cycloaddition reactions, for example with diazo-compounds [221], nitrile oxides [222], nitril-imines [223] and sulphenes [224]. A mixture of products may be isolated including rearrangement products from the original adducts. 

Traceless cleavage of products from the resin can be achieved through an elimination reaction. Aromatization of the product can be the driving force for the elimination. Piperazine resin-bound enamine reacted regioselectively in a 1,3-dipolar cycloaddition with nitrile imines generated in situ (Scheme 11.16). Elimination of the piperazine linker with highly diluted trifluoroacetic acid gave diverse 1,4-diarylpyrazoles in a traceless manner. 

The 1,3-dipolar systems involved in the cycloaddition reaction with cumulenes include azides, nitrile oxides, nitrile imines, nitrones, azomethine imines and diazo compounds. However, some 1,3-dipolar systems are also generated in the reaction of precursors with catalysts. Examples include the reaction of alkylene oxides, alkylene sulfldes and alkylene carbonates with heterocumulenes. Carbon cumulenes also participate as 1,3-dipols in [3+2] cycloaddifion reactions. Examples include thiocarbonyl sulfides, R2C=S=S, and l-aza-2-azoniaallenes. 

A second category of silene reactions involves interactions with tt-bonded reagents which may include homonuclear species such as 1,3-dienes, alkynes, alkenes, and azo compounds as well as heteronuclear reagents such as carbonyl compounds, imines, and nitriles. Four modes of reaction have been observed nominal [2 + 2] cycloaddition (thermally forbidden on the basis of orbital symmetry considerations), [2 + 4] cycloadditions accompanied in some cases by the products of apparent ene reactions (both thermally allowed), and some cases of (allowed) 1,3-dipolar cycloadditions. 

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. 

Some features are characteristic of reactions of nitrile oxides with 2,4,6-cyclo-hep tatrien-l-imines (8-azaheptafulvenes). 1,3-Dipolar cycloaddition to the C=N double bond of N-aryl-2,4,6-cycloheptatrien-l-imines 142 (R = Ar), affording... 

Karlsson and Hogberg (291,292) applied the thiocarbonyl ylide 175 in a diastereoselective 1,3-dipolar cycloaddition with 165. The thiocarbonyl yhde was generated in situ by an elimination reaction. The reaction with 165 gave 176 (R = Bu, BnO, Ph) with selectivities of up to 64—80% de. Furthermore, the cycloaddition of a chiral galactose-derived nitrile imine with 165 has been reported (104). 

Reaction kinetics for the interaction of 5-alkyliminothiatriazoles 52 or 58 with heterocumulenes, nitriles, ketones, imines, or other dipolarophiles a=b show that the decomposition of the thiatriazole is bimolecular, and new heterocyclic five-membered rings 71 are formed (Scheme 15). The term masked 1,3-dipolar cycloaddition was used by L abbe and co-workers for this type of reaction <1978JOC4951>, the thioimidate function being the masked 1,3-dipole. The reaction is thought to involve a thiapentalenic intermediate 70 with hypervalent sulfur. The product 71 is itself a masked dipole and often further reactions take place. 

Electron-poor nitriles react with compound 87 and its derivatives to form the 5-amino-l,2,4-thiadiazole derivatives 104 <1985JOC1295>. Therefore, the formation of product 94 (see Scheme 21) may be explained alternatively by the addition of amidonitrile 93 to compound 90. The mechanism of the formation of product 104 was discussed in detail in CHEC-II(1996) <1996CHEC-II(4)691> but most probably the steps involved are (1) reaction of the electrophilic nitrile with the exocyclic nitrogen of compound 87 or its derivatives (2) loss of nitrogen similarly to the previous reactions and formation of an imine 103 (3) masked 1,3-dipolar cycloaddition/elimination reaction of the nitrile to the imine 103. Since the same nitrile is expelled in the elimination step, only 1 equiv of reagent is needed (Scheme 24). 

The reaction of the acid chloride phenylhydrazone (11) with base gives the nitrile-imine 1,3-dipolar compound (12) which reacts with potassium thiocyanate to give the A2-thiadiazo-line (13 Scheme 1). Thus the cycloaddition occurs at the C=S and not the C=N bond. This regioselectivity can be explained in terms of the frontier orbital treatment. Due to the electron rich nature of the thiocyanate anion, its reaction with (12) is expected to be controlled by the LUMO and HOMO of (12) and the thiocyanate respectively. As the HOMO of the thiocyanate anion has the larger orbital coefficient on the sulfur atom, it can be concluded that the larger orbital coefficient in the LUMO of (12) is on the carbon atom. This is also in agreement with other dipolar cycloadditions (82H( 19)57). 

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