Alkenes diazoalkane cycloaddition reactions

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). 

Catalytic cyclopropanation of alkenes has been reported by the use of diazoalkanes and electron-rich olefins in the presence of catalytic amounts of pentacarbonyl(rj2-ris-cyclooctene)chromium [23a,b] (Scheme 6) and by treatment of conjugated ene-yne ketone derivatives with different alkyl- and donor-substituted alkenes in the presence of a catalytic amount of pentacarbon-ylchromium tetrahydrofuran complex [23c]. These [2S+1C] cycloaddition reactions catalysed by a Cr(0) complex proceed at room temperature and involve the formation of a non-heteroatom-stabilised carbene complex as intermediate. 

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. 

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... 

The other major limitation to the route is the problem of obtaining the desired precursor. Since this determines the scope of the reaction we will follow the pattern set in Houben-Weyl, Vol.4/3 and consider the syntheses according to the route by which the five-membered-ring diazene was derived, namely from (1) the addition of diazoalkanes to acyclic alkenes and allenes (2) the addition of diazoalkanes to cyclic alkenes and heterocyclic compounds (3) intramolecular addition of diazoalkanes to double bonds (4) cycloaddition reactions of dialkyl... 

The involvement of trimethylenemethane diradicals in deazetization of diazoalkane-allene adducts or trimethylene diradicals in the deazetization of the adducts of acyclic alkenes often leads to mixture of regioisomers and stereoisomers and from the standpoint of cyclopropane syntheses, this is undesirable. Far fewer problems of this type attend deazetization of the adducts of cyclic or polycyclic alkenes and, furthermore, even a modest amount of strain in the system activates the alkene to diazoalkane addition so that there is no need for activating substituents on the double bond. Cyclopropene is highly reactive towards diazoalkanes (see also Section 1.1.5.1.5.3.1.) and cycloaddition reactions of this type provide a ready entry into the bi-cyclo[1.1.0]butane series. The addition of diphenyldiazomethane to cyclopropene gave 4,4-diphenyl-2,3-diazabicyclo[3.1.0]hex-2-ene (1), which on photolysis gave a mixture of 2,2-diphenylbicyclo[1.1.0]butane (2) and 1,1-diphenylbuta-l,3-diene (3). ... 

Some 1,3-dipoles, such as azides and diazoalkanes, are relatively stable, isolable compounds however, most are prepared in situ in the presence of the dipolarophile. Cycloaddition is thought to occur by a concerted process, because the stereochemistry E or Z) of the alkene dipolarophile is maintained trans or cis) in the cycloadduct (a stereospecihc aspect). Unlike many other pericycUc reactions, the regio- and stereoselectivities of 1,3-dipolar cycloaddition reactions, although often very good, can vary considerably both steric and electronic factors influence the selectivity and it is difficult to make predictions using frontier orbital theory. 

Nowadays a broad range of different 1,3-dipoles, ozone, azides ° and diazoalkanes on the one hand as well as dipoles like nitrones, nitro compounds, carbonyl ylides, nitrile oxides, nitrile imines and ylides on the other hand, are well-established. The addition of these 1,3-dipoles to an alkene is one of the most frequently used cycloaddition reactions in organic synthesis. ... 

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. 

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... 

The reaction of diazoalkanes with acetylenes can give rise to cyclopropenes by two main routes. Some reactions involve an initial loss of nitrogen to generate a carbene which then adds to the acetylene (see Section 1.2.1.), but this section is concerned only with those reactions where the first step is a cycloaddition leading to formation of a 3//-pyrazole. Unlike the parallel series of reactions in the cyclopropane series, where the C-C double bond of the alkene requires activation by a suitable substituent or by strain. Under pressure even acetylene itself will react with diazoalkanes. For example, diphenyldiazomethane underwent addition in good yield and deazetization gave 3,3-diphenylcyclopropene (1). ... 

The reactions of diazoalkanes 9.21 with alkenes lead to pyrazolines 9.22, which are thermally transformed into cyclopropanes. Similar transformations occur during thermal reactions of diazoesters. The use of diazoesters of chiral alcohols did not give useful results, so chiral residues have been introduced on the olefin dipolarophile. Meyers and coworkers [327] carried out the reaction of diazomethane 9.21 (R = R = H) and diazopropane 9.21 (R = R = Me) with chiral lactams 1.92 (R = i-Pr or ferf-Bu, R = Me). These 1,3-dipolar cycloadditions are regioselective, but only CH2N2 leads to an interesting stereoselectivity (Figure 9.9). Morever, when the RM substituent of lactam 1.92 is H, the reaction is no longer stereoselective. 

The principal alternative process in the reaction of sulfenes and diazoalkanes is the formation of the 1,3,4-thiadiazine compound (79) other products may be produced by the further reaction of 78 or 79 (e.g. the alkene or azine by their respective desulfonylations). It has been suggested109 that the initial reaction is to form the zwitterionic intermediate (80), which may then proceed to 78. In a relatively recent study170, which also provides a useful summary of earlier work, it is proposed that a direct [3 -I- 2] cycloaddition of the diazoalkane to the sulfene gives 79 while the alternative reaction to form 80 leads to 78 (equation 55), and that the different reactions derive from the existence of two low-lying sulfene MOs of different symmetries29. 

This mechanism is, however, difficult to apply to the fast cycloaddition of diazoacetates (Alder et al., 1931) and 3-diazobutane-2-one (Diels and Konig, 1938) with alkenes of the bicyclo[2.2.1]heptene type, because alkene C-atoms without electron-withdrawing substituents show no electrophilic character. The reverse sequence of steps in (6-4), i. e., first an additon of N at the central C-atom of the acrylate, would also be unusual, as the N ()ff)-atom of diazoalkanes is only a weak electrophilic center. Fleischmann (in Huisgen s group, 1958) showed that, in such cyclization reactions, the rate of reaction of diazomethane with bicyclic alkenes relative to that of )ff-diazo ketones and 2-diazo-l,3-diketones is higer by a factor of 10" -10. ... 

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... 

The rates of 1,3-dipolar cycloadditions of diazoalkanes to alkenes and alkynes have been determined electron-attracting substituents in the latter increase the rate, in accordance with frontier molecular orbital theory, which predicts that these reactions are controlled by the interaction of the highest occupied molecular orbital of the diazo-compound with the lowest unoccupied molecular orbital of the dipolarophile " the kinetics of the reactions of methyl diazoacetate or phenyl diazomethanesulphonate, on the other hand, give rise to U-shaped activity functions, which is also explained by the theory. Diazomethane or... 

Although from the conceptual point of view such a simple qualitative picture is completely clear, the practical discrimination between the individual alternative reaction paths can be, in a given case, quite complicated. The best that can be done in these cases is to calculate the energies of the molecular oibitals by some quantum chemical method. The typical example where such subtle effects of the quantitative nature play the role is the regioselectivity of 1,3 dipolar cycloadditions [44,45], which is the cycloaddition of substituted alkenes, called in this coimection dipolarophiles, with the so-called 1,3 dipoles as, e.g., azides, diazoalkanes, nitriloxides, nitrones and some other, usually rather unstable species. 

Diazoalkanes were readily decomposed and underwent [2+l]-type cycloaddition to alkenes in the presence of catalytic amounts of rhodium complexes. Rh2(OAc)4 is the simplest complex for the reaction. For example, fluoro-cyclopropane 134 was prepared by the carbene addition to fluoroalkene 133 (Scheme 1.64) [108]. A copper catalyst also catalyzed the addition reaction. 

The treatment of 1,6-enynes with 5mol% amounts of cp RuCl(cod) 382 in the presence of diazoalkanes resulted in the formation of bicyclic cyclopropanes 383 in good yields (Scheme 1.180) [252]. The reaction progressed through the formation of mthenacyclobutene 384, which cleaved to give a mthenium carbene complex 385. A [2-1-2] cycloaddition of the complex 385 with the internal alkene... 

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