Diazoalkanes, dipolar cycloaddition with

If the C=N function is attached to an electron-withdrawing group, 1,3-dipolar cycloaddition with diazoalkanes occurs leading to 1,2,3-triazoles (5, 276). When diazomethane is used, the initially formed NH-triazole is not isolated due to a rapid subsequent NH deprotonation followed by N-methylation. Consequently, a mixture of the three Wmethyltriazoles is formed when methyl cyanoformate (71) (216) or trichloroacetonitrile (276) (217) is treated with excess diazomethane (Scheme 8.51). Huisgen and co-workers found that methyl diazoacetate reacts with TCNE by a 1,3-dipolar cycloaddition at the C=C bond and not, as published earlier by other authors, at one of the nitrile functions (72). 

According to the nature of the HOMO of diazoalkanes one expects the formation of complexes like X or XI by the formal way of a 1.3-dipolar cycloaddition with... 

Regio- and Diastereoselectivity of Dipolar Cycloadditions with Diazoalkanes... 

Some years ago, Huisgen et al. (1987 b) mentioned that diazoalkane cycloadditions to electron-deficient CC multiple bond compounds and other dipolarophiles represent the class of [3 + 2] cycloadditions that has been most intensively studied for synthetic purposes. This is also evident from the reviews that concentrate on preparative aspects of diazoalkane cycloadditions (Regitz and Heydt, 1984 Stanovnik, 1991). Yet, in contrast to these statements, not a single 1,3-dipolar cycloaddition with a diazoalkane is reported in Organic Syntheses... 

Diazoalkanes (761) regiospecifically underwent 1,3-dipolar cycloaddition with dimethyl l-(formylamino)ethylenephosphonate (760) to alford 5-sub-stituted dimethyl 3-(formylamino)-4,5-dihydro-3//-pyrazole-3-phospho-nates (762) in high yields. Thermal decomposition of the latter followed by hydrolysis, provided a straightforward access to 2-substituted 1-amino-cyclopropanephosphonic acids (763). Aromatisation of (763) under acidic conditions led to 3-phosphorylated pyrazoles (764) (Scheme 193). ... 

The normal electron-demand principle of activation of 1,3-dipolar cycloaddition reactions of nitrones has also been tested for the 1,3-dipolar cycloaddition reaction of alkenes with diazoalkanes [71]. The reaction of ethyl diazoacetate 33 with 19b in the presence of a TiCl2-TADDOLate catalyst 23a afforded the 1,3-dipolar cycloaddition product 34 in good yield and with 30-40% ee (Scheme 6.26). 

The cycloaddition of thiirene dioxide with phenyldiazomethane gave 3,4,5-triphenylpyrazole (165a) and the acyclic a-diazobenzyl 1,2-diphenylvinyl sulfone (164a), both suggested to originate in the common 1,3-dipolar cycloaddition intermediate 1626 (equation 66). Diphenylthiirene dioxide reacts similarly with other diazoalkanes (161b-e). 

Whereas the Rh2(OAc)4-catalyzed addition of diazoalkanes to propargyl alcohols readily gives the insertion of the carbene into the 0-H bond, with only a small amoimt of cyclopropenation of the resulting propargylic ether [54] the 2-diazopropane 59 reacts at 0 °C with l,l-diphenyl-2-propyn-l-ol 62a in dichloromethane and exclusively gives, after 10 h of reaction, only the adduct 63a isolated in 75% yield and corresponding to the regioselective 1,3-dipolar cycloaddition of the 2-diazopropane to the alkyne C - C bond (Scheme 15). 

The 1,3-dipolar cycloaddition reactions to unsaturated carbon-carbon bonds have been known for quite some time and have become an important part of strategies for organic synthesis of many compounds (Smith and March, 2007). The 1,3-dipolar compounds that participate in this reaction include many of those that can be drawn having charged resonance hybrid structures, such as azides, diazoalkanes, nitriles, azomethine ylides, and aziridines, among others. The heterocyclic ring structures formed as the result of this reaction typically are triazoline, triazole, or pyrrolidine derivatives. In all cases, the product is a 5-membered heterocycle that contains components of both reactants and occurs with a reduction in the total bond unsaturation. In addition, this type of cycloaddition reaction can be done using carbon-carbon double bonds or triple bonds (alkynes). 

The transition metal-catalyzed reaction of diazoalkanes with acceptor-substituted alkenes is far more intricate than reaction with simple alkenes. With acceptor-substituted alkenes the diazoalkane can undergo (transition metal-catalyzed) 1,3-dipolar cycloaddition to the olefin [651-654]. The resulting 3//-pyrazolines can either be stable or can isomerize to l//-pyrazolines. 3//-Pyrazolines can also eliminate nitrogen and collapse to cyclopropanes, even at low temperatures. Despite these potential side-reactions, several examples of catalyzed cyclopropanations of acceptor-substituted alkenes with diazoalkanes have been reported [648,655]. Substituted 2-cyclohexenones or cinnamates [642,656] have been cyclopropanated in excellent yields by treatment with diazomethane/palladium(II) acetate. Maleates, fumarates, or acrylates [642,657], on the other hand, cannot, however, be cyclopropanated under these conditions. 

D-Triazoles have been isolated from the reaction of several activated nitriles, such as cyanogen, cyanogen halides, methyl cyanoformate, and cyanic acid esters, with diazoalkanes. The reaction can formally be regarded as a 1,3-dipolar cycloaddition. The v-triazoles may be... 

The energetic 1,3,4-oxadiazole (22) is synthesized from the reaction of the tetrazole (20) with oxalyl chloride. In this reaction the tetrazole (20) undergoes a reverse cycloaddition with the expulsion of nitrogen and the formation of the 1,3-dipolar diazoalkane (21) which reacts with the carbonyl groups of oxalyl chloride to form the 1,3,4-oxadiazole rings. 

In the context of stereoselective organic synthesis, diastereofacial-selective cycloadditions of diazoalkanes and diazoacetates with functionalized alkenes has attracted some attention. 3,4-Disubstituted cyclobutenes were studied as dipolar-ophiles by the groups of Gandolfi and co-workers (113) and Martin and co-workers (114). The transition state structures of the cycloaddition of diazomethane with cis-3,4-dimethylcyclobutene was investigated theoretically by DPT methods (113a). 

The first effective enantioselective 1,3-dipolar cycloaddition of diazoalkanes catalyzed by chiral Lewis acids was reported in the year 20(X) (139). Under catalysis using zinc or magnesium complexes and the chiral ligand (R,/ )-DBFOX/Ph, the reaction of diazo(trimethylsilyl)methane with 3-alkenoyl-2-oxazolidin-2-one 75 (R = H) gave the desilylated A -pyrazolines (4S,5R)-76 (R =Me 87% yield, 99% ee at 40 °C) (Scheme 8.18). Simple replacement of the oxazohdinone with the 4,4-dimethyloxazolidinone ring resulted in the formation of (4R,5S)-77 (R = Me 75% yield, 97% ee at -78 °C). 

The 1,3-dipolar cycloaddition reaction of diazoalkanes with alkenes has also been reported (395). Kanemasa and Kanai (395) used the chiral DBFOX-Ph ligand with various metals such as Ni, Zn, and Mg for the preparation of 255a-c. The reaction of TMS-diazomethane 171 with alkene 241 was catalyzed by 10 mol% of 255b to afford the 1,3-dipolar cycloaddition product 296 in good yields and enantioselectivities of up to 99% ee (Scheme 12.96). Also, the Ni-catalyst 255a and the Mg-catalyst 255c were excellent catalysts for the reaction, resulting in >90% ee in both cases. 

Benzo[6]thiophene 1,1-dioxides undergo [2+4] cycloaddition with 1,3-dienes such as cyclopentadiene, anthracene, etc. (70AHC(11)177>. Cycloaddition with dipolar species such as diazoalkanes (74M550), nitrilimines (74M869) and nitrile oxides (79TL4845) have also been described (Scheme 192). 

A practicable strategy to provide access to chiral pyrazolidine-3-carboxylic acid (16) makes use of asymmetric dipolar cycloaddition of diazoalkanes to u,p-unsaturated carboxylic acid derivatives. For this purpose a chiral auxiliary of the alkene component is used, e.g. Op-polzer s1166 1671 (lf )-2,10-camphorsultam.t164l As shown in Scheme 7, by reaction of (tri-methylsilyl)diazomethane (41) with /V-( aery I oy I )cam p h ors u 11 am (42), the AL(4,5-dihy-dropyrazoline-5-carbonyl)camphorsultam (43) is obtained. Reduction of 44 with sodium cyanoborohydride leads to A-(pyrazolidine-3-carbonyl)camphorsultam (45) as the 35-dia-stereoisomer (ee 9 1) in 65 to 80% yields.[164] The camphorsultam 45 is then converted into the methyl ester 46 by reaction with magnesium methylate without racemizationj1641... 

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