Dipolarophiles diazoalkane cycloaddition reactions

Diazoazoles, because of charge polarization and potential bifunctional reactivity of the derived betaine, react with dipolarophiles to give cycloaddition products. Generally all the diazoazoles react with electron-rich, unsaturated derivatives. The cycloaddition reaction with isocyanates is readily observed in the case of the reactive 3-diazopyrazoles, but it is much slower with other diazoazoles. By contrast, reaction with ylides and diazoalkanes is only observed for 3-diazopyrazoles and 3-diazoindazoles. 

An interesting preparation of aliphatic diazoalkanes (R R2C = N2 R1, R2 = alkyl) involves the photolysis of 2-alkoxy-2,5-dihydro-l,3,4-oxadiazoles (see Scheme 8.49). When the photolysis is carried out in the presence of an appropriate dipolarophile, the diazo compounds can be intercepted (prior to their further photolysis) by a [3 + 2] cycloaddition reaction (54). As an example, 2-diazopropane was intercepted with A-phenylmaleimide (54) and norbornenes (55) to give the corresponding A -pyrazolines. 

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. 

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. 

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 mechanism of the reaction has generally been discussed in terms of a thermally allowed concerted 1,3-dipoIar cycloaddition process, in which control is realized by interaction between the highest occupied molecular orbital (HOMO) of the dipole (diazoalkane) and the lowest unoccupied molecular orbital (LUMO) of the dipolarophile (alkyne).76 In some cases unequal bond formation has been indicated in the transition state, giving a degree of charge separation. Compelling evidence has also been presented for a two-step diradical mechanism for the cycloaddition77 but this issue has yet to be resolved. 

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. 

Reports on the advances of asymmetric 1,3-dipolar cycloadditions include the reaction of diazoalkanes to 7V-(2-alkenoyl)oxazolidin-2-ones catalyzed by Mg or Zn complexes of 73, showing cooperative chiral control by the achiral oxazolidinone auxiliary and the chiral ligand.An intramolecular cycloaddition of the same kind from substrates containing a chiral cyclic AiA -dimethylaminal unit adjacent to the dipolarophilic double bond (i.e., 74) proves very successful in the asymmetric sense, although the reaction of an analogous nitrone lacks stereoselectivity. 

Cycloaddition of 1,3-dipolarophiles to alkynes for the synthesis of diazo compounds can also be applied to reaction of diazoalkanes with alkynes (2-91). 2-Diazopropane and 1,2-diarylethynes readily form 3//-pyrazoles (2.229). These pyrazoles isomerize photochemically to the 4-diazo-2-methyl-3,4-diarylbutenes (2.230), i.e., to a vinyldiazo compound (Pincock et al., 1973 Arnold et al., 1976 Leigh and Arnold, 1979). Some cyclopropene (2.231) is formed in a consecutive dediazoniation, i. e., by cyclization of the carbene formed. The method is not useful for unsymmetrically substituted alkynes because these cycloadditions are not regiospecific. It is, however, applicable to the synthesis of diazoalkenes with alicyclic... 

Occasionally, the term 1,3-dipolar cycloaddition is also used for the reaction of diazoalkanes with transition metal complexes, e. g., (6-9), investigated by McCrindle and McAlees (1993). This is not, however, a 1,3-dipolar cycloaddition as coined by Huisgen. This term should not, therefore, be used for reactions that involve a dipolar reagent, but only in a cycloaddition with a dipolarophile, as shown in Huisgen s mechanism (Schemes 6-5 and 6-6). They may be called [3 + 1] dipolar cycloadditions, however, in order to underline the difference to the [3 + 2] reactions. 

An interesting reaction that is not easy to understand is the cycloaddition of diazoalkanes to c/5 -3,4-dichlorocyclobutene (6.60). Franck-Neumann (1969) found that the diazomethane was unexpectedly added on the 5jA2-diastereotopic side of this dipolarophile (6.61). Martin s group (Landen et al., 1988a, b Hake et al., 1988) confirmed this result for diazomethane and 12 monosubstituted diazomethane derivatives. 7A2 /-Addition (6.62) was found only for disubstituted diazomethanes RR C = N2 (R and R = CH3, CgHs) and for diazofluorene. 

The oldest known type of diastereoselectivity is the addition to dipolarophiles that form chiral centers at the reacting atoms. In the context of Buchner s pioneering work on cycloaddition of diazoalkanes (see Sects. 1.1 and 6.2), Buchner investigated the reactions of methyl diazoacetate with ethyl (E)-3-phenylprop-2-enoate (ethyl cinnamate) and of ethyl diazoacetate with methyl ( )-3-phenylprop-2-enoate (Scheme 6-31) with his coworkers Dessauer (1893) and von der Heide (1902). They found two isomeric 4,5-dihydro-3//-pyrazoles 6.69 and 6.70 which, on dehydrogenation, gave the same prototropic mixture of ethyl methyl 4-phenylpyrazole-3,5-dicarboxylates (6-32). The ratio found was 80 20. Ihis surprising result was rationalized 78 years after Buchner s discovery ... 

Cycloadditions were found to be first-order reactions with respect to both 1,3-dipole and dipolarophile, in all cases so far investigated. There are some limits to kinetic studies of these reactions, as many 1,3-dipoles are very reactive substances. While aryl azides, diazoalkanes, some classes of azomethine imines (for instance sydnones), and some classes of azomethine oxides (nitrones) are stable and isolable, azomethine ylides are usually unstable, an exception being represented by a mesoionic oxazolone that has been used for kinetic investigations benzonitrile oxide has a very limited stability, although some substituted derivatives are stable for long periods nitrile imines are not commonly isolable because of their strong tendency to dimerise. 1,3-Dipoles of... 

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. 

The principal synthetic value of these reactions is for the formation of cyclopropanes. The required pyrazoline intermediate can often be made by cycloaddition of diazoalkanes to an appropriate dipolarophile. Scheme 7.13 provides some specific examples. Entries 4-7 illustrate the use of photochemical methods to generate highly strained molecules, which would be difficult to obtain under thermal conditions. 

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