1.3- dipolar cycloaddition reactions with diazoalkanes

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. 

Dipolar cycloaddition reactions constitute a powerful and convergent tool for the preparation of various heterocyclic compounds, which have been widely applied in the synthesis of numerous natural products, pharmaceuticals, and functional materials. The chemistry of 1,3-dipolar cycloaddtion reactions has been well documented in a number of reviews [3]. In this section the focus is on transition-metal-mediated 1,3-dipolar cycloaddition reactions with some important 1,3-dipoles, including azides, diazoalkanes, carbonyl ylides, and azomethine ylides, rather than a full review of the reactions of all types of 1,3-dipoles. 

Dipolar cycloaddition reactions of diazoalkanes with dipolarophiles leading to various heterocycles have been well studied in recent decades [13]. In this section we highlight mainly some recent advances in transition-metal-mediated 1,3-dipolar cycloaddition reactions of diazoalkanes for the construction of pyrazoles, where transition metals are usually utilized as promoters to narrow the energy gap between the two reacting components HOMOdipoiarophiie-LUMOdipoie and/or LUMOdipoiarophiie-HOMOdipoie interactions. 

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 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). 

Although it has been established that the HOMO (diazoalkane)-LUMO (alkene) controlled concerted cycloaddition occurs without intervention of any intermediate for the reactions of simple diazoalkanes with alkenes, Huisgen once proposed a mechanistic alternative 4 namely an initial hypothetical nitrene-type 1,1-cycloaddition reaction of phenyldiazomethane to styrene followed by a vinylcyclopropane-cy-clopentene-type 1,3-sigmatropic rearrangement Control experiments, however, excluded this hypothesis for the bimolecular 1,3-dipolar cycloaddition reaction of diazomethane (Scheme 60).204... 

RC=CKWG) yields 2,4-di-EWG-substituted pyrroles in the presence of copper catalyst but 2,3-di-EWG-substituted pyrroles in the presence of a phosphine catalyst.74 The 3 + 2-cycloaddition of diazoalkanes to (6 )-3-p-tolylsulfinylfuran-2(5//)-one produces diastereoisomeric pyrazolines in almost quantitative yield and with des >98%. (g) The sulfinyl group is responsible for the complete control of the n-facial selectivity in all these reactions.75 The Rh(II)-catalysed intramolecular 1,3-dipolar cycloaddition reaction of diazoamides (57) with alkenyl and heteroaromatic n -bonds yields pen-tacyclic compounds (59), via the ylide (58), in good to excellent yields and in a (g) stereocontrolled manner (Scheme 15).76... 

Dipolar cycloaddition reactions of azolopyridazines with diazoalkanes 91T2925. 

Dipolar cycloaddition reactions of pyridines and azolo- and azino-pyridazines with diazoalkanes 91T2925. 

Examples of 1,3-dipoles include diazoalkanes, nitrones, carbonyl ylides and fulminic acid. Organic chemists typically describe 1,3-dipolar cycloaddition reactions [15] in terms of four out-of-plane 71 electrons from the dipole and two from the dipolarophile. Consequently, most of the interest in the electronic structure of 1,3-dipoles has been concentrated on the distribution of the four Jt electrons over the three heavy atom centres. Of course, a characteristic feature of this class of molecules is that it presents awkward problems for classical valence theories a conventional fashion of representing such systems invokes resonance between a number of zwitterionic and diradical structures [16-19]. Much has been written on the amount of diradical character, with widely differing estimates of the relative weights of the different bonding schemes. 

Dipolar cycloaddition of the diazoalkane ((CH3)2CN2) to (72) in acetone gave the tetracyclic compound (73). The unsubstituted compound did not react. The nitro group at the 6-position activates the C(5)—C(6) and C(7)—C(8) double bonds for cycloaddition <89H(28)259>. It was originally reported that [l,2,4]triazolo[4,3-a]pyridine (29) reacted with DMAD in the presence of 5% Pd/C to give (74) <81IJC(B)10>. It was subsequently shown that this reaction produces three products independent of the use of the palladium catalyst. Initial Michael addition of DMAD to (29) via its... 

The reaction system (6-37) includes the thermal azo-extrusion of a cyclic azo compound to a cyclopropane derivative and the direct formation of cyclopropanes, catalyzed by metal complexes. Synthetic routes to cyclopropane derivatives became an important subject in the last two decades, and one frequently used method is the 1,3-dipolar cycloaddition of a diazoalkane to an alkene followed by thermal or photolytic azo-extrusion of the 4,5-dihydro-3//-pyrazole formed to the cyclopropane derivative (6-37 A). This route can be followed in many cases without isolation, or even without direct observation, of the 4,5-dihydro-3//-pyrazole. Therefore, it is formally very similar to cyclopropane formation from alkenes with diazoalkanes, in which a carbene is first formed by azo-extrusion of the diazoalkane (see Sect. 8.3). As shown in pathway (6-37 B), this step can be catalyzed by copper, palladium, or rhodium complexes (see Sects. 8.2, 8.7, and 8.8). There are cases where it is not clearly known whether route A or B is followed. Scheme 6-37 also includes... 

A (1/7-imidazol-l-yl) silver species (55) has been postulated as the key intermediate in the 3-l-2-cycloaddition reaction of diazoalkanes (54) with benzynes yielding 2-aryl-2H-indazoles (56) (Scheme 18). The 3-I-2-cycloaddition reaction of 3-trifluoromethyl-4-diazopyrazolinones with dialkyl acetylene dicarboxylates, in refluxing toluene, produced spiro 3/f-pyrazole adducts that rearranged to the trifluoromethyl-substituted pyrazolo[l,5-fi(][l,2,4]triazin-7-ones. ° The 1,3-dipolar cycloaddition reaction of aromatic thioketones (58) with 2-aza-1,3-dicarbonyl compounds (57), at 20-50 C, yielded thiadiazoline adducts (59) that readily eliminate nitrogen to produce oxathioles (60) in moderate yields (up to 70%) (Scheme 19). ... 

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 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 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). 

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... 

Reaction of 4-chloro-2-pyrazolin-5-ones with potassium carbonate proceeds along two pathways, leading to diketo derivatives of pyrazoIo[l,2-a]pyrazoIe (syn- and anti- dioxabimanes )- A mechanism involving the intermediate formation of diazacyclopen-tadienone (185) which reacts with its potential extended diazoalkane functionality in dipolar cycloaddition fashion to give syn-dioxabimanes (major product) and anri-dioxabimanes (minor product) has been proposed (Scheme 6) (80JA4983). 

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