Diazo compounds carbene/carbenoid addition

The acid-induced reaction of aryldiazomethanes with olefins gives arylcyclo-propanes in addition to olefins and esters. The cyclopropanes are formed stereo-specifically and their yields are largest in reactions with olefins which on cation addition give secondary carbonium ion centres. The use of deuteriated acids leads to partial incorporation of deuterium in the cyclopropane adducts, whereas the use of [a- H]-phenyldiazomethane leads to partial loss of deuterium, suggesting a slow proton transfer from the acid to the diazo-compound a carbenoid rather than a free carbene appears to be involved. 

As with any modern review of the chemical Hterature, the subject discussed in this chapter touches upon topics that are the focus of related books and articles. For example, there is a well recognized tome on the 1,3-dipolar cycloaddition reaction that is an excellent introduction to the many varieties of this transformation [1]. More specific reviews involving the use of rhodium(II) in carbonyl ylide cycloadditions [2] and intramolecular 1,3-dipolar cycloaddition reactions have also appeared [3, 4]. The use of rhodium for the creation and reaction of carbenes as electrophilic species [5, 6], their use in intramolecular carbenoid reactions [7], and the formation of ylides via the reaction with heteroatoms have also been described [8]. Reviews of rhodium(II) ligand-based chemoselectivity [9], rhodium(11)-mediated macrocyclizations [10], and asymmetric rho-dium(II)-carbene transformations [11, 12] detail the multiple aspects of control and applications that make this such a powerful chemical transformation. In addition to these reviews, several books have appeared since around 1998 describing the catalytic reactions of diazo compounds [13], cycloaddition reactions in organic synthesis [14], and synthetic applications of the 1,3-dipolar cycloaddition [15]. 

Intramolecular carbene addition reactions have a special importance in the synthesis of strained ring compounds. Because of the high reactivity of carbene or carbenoid species, the formation of highly strained bonds is possible. The strategy for synthesis is to construct a potential carbene precursor, such as diazo compounds or di- or trihalo compounds, which can undergo intramolecular addition to the desired structure. Section E of Scheme 10.5 gives some representative examples. 

The most generally employed approach for the formation of cyclopropanes is the addition of a carbene or carbenoid to an alkene. In many cases, a free carbene is not involved as an actual intermediate, but instead the net, overall transformation of an alkene to a cyclopropane corresponds, in at least a formal sense, to carbene addition. In turn, the most traditional method for effecting these reactions is to employ diazo compounds, R R2 —N2, as precursors. Thermal, photochemical and metal-catalyzed reactions of these diazo compounds have been studied thoroughly and are treated separately in the discussion below. These reactions have been subjects of several comprehensive reviews,8 to which the reader is referred for further details and literature citations. Emphasis in the present chapter is placed on recent examples. 

Cyclopropanation reactions are one set in an array of C-C bond-forming transformations attributable to metal carbenes (Scheme 5.1) and are often mistakenly referred to by the nonspecific term carbenoid. Both cyclopropanation and cyclopropenation reactions, as well as the related aromatic cycloaddition process, occur by addition. Ylide formation is an association transformation, and insertion requires no further definition. All of these reactions occur with diazo compounds, preferably those with at least one attached carbonyl group. Several general reviews of diazo compounds and their reactions have been published recently and serve as valuable references to this rapidly expanding field [7-10]. The book by Doyle, McKervey, and Ye [7] provides an intensive and thorough overview of the field through 19% and part of 1997. 

A select number of transition metal compounds are effective as catalysts for carbenoid reactions of diazo compounds (1-3). Their catalytic activity depends on coordination unsaturation at their metal center which allows them to react as electrophiles with diazo compounds. Electrophilic addition to diazo compounds, which is the rate limiting step, causes the loss of dinitrogen and production of a metal stabilized carbene. Transfer of the electrophilic carbene to an electron rich substrate (S ) in a subsequent fast step completes the catalytic cycle (Scheme I). Lewis bases (B ) such as nitriles compete with the diazo compound for the coordinatively unsaturated metal center and are effective inhibitors of catalytic activity. Although carbene complexes with catalytically active transition metal compounds have not been observed as yet, sufficient indirect evidence from reactivity and selectivity correlations with stable metal carbenes (4,5) exist to justify their involvement in catalytic transformations. 

Aryldiazoacetates constitute an effective class of donor/acceptor diazo compounds in the realm of intermolecular carbenoid transformations [79], Because of their electronic profile, they were expected to display increased chemoselectivity for the desired C-H insertion event, while suppressing unwanted side reactions such as carbene dimerization. Additionally, the regioselectivity was expected to be enhanced in more complex systems due to the attenuated reactivity of the carbenoid. 

Reaction with benzene follows a similar pathway, yielding a bicyclo[3.2.2]nonatriene structure. Vinylcarbenoids also react with pyrroles to give tropanes via a cyclopropanation-Cope rearrangement route. The direct addition of carbenes to acetylenes does not give satisfactory yields of cyclopropanes, but the rhodium carboxylate catalysed reaction of diazo compounds with acetylenes is a useful source of cyclopro-panes. Carbenoids can also attack a carbonyl oxygen atom, giving rise to a zwitterion (249). An excellent review of intramolecular carbenoid reactions has appeared. ... 

Addition of certain copper salts to solutions of diazo compounds also leads to evolution of nitrogen and formation of products of the same general types as those formed in thermal and photochemical decompositions of diazoalkanes. The weight of the evidence, however, indicates that free carbene intermediates are not involved in such reactions. Instead, complexes of the carbene unit with the metal ion catalyst seem to be the actual reactants. Such a complex would be an example of a carbenoid species. Although the product suggests the involvement of a carbene-like reactivity, other evidence rules out a completely free carbene of the type generated by photochemical expulsion of a molecule of nitrogen. 

Tryptophan offers an indole side chain that can be used for ligation chemistry. A water-compatible rhodium carbene can be added to the indole ring (19) [105,139]. The reactive species is generated in situ by a conjugated diazo compound by a rhodium catalyst like rhodium(II) acetate [63,139,149]. The reaction takes place in the two- and three-position of indole. Thus, a mixture of N-alkylated and C-alkylated product is obtained. It is necessary to add hydroxylamine hydrochloride as an additive to bind to the distal rhodium carbenoid complex. The usage of this salt lowers the pH value below 3.5 and therefore limits the scope of this methodology. As a side reaction, the carbene inserts into the O-H bond of water (Table 6). 

Addition of diazo compounds to metallic complexes allows the formation of metal carbenoid species which can react with unsaturated molecules to form new carbon-carbon bonds. The Cp RuCl(cod)-catalyzed addition of diazo compoimds to alkynes led to the selective synthesis of functional 1,3-dienes by the combination of two molecules of diazoaUcane and one molecule of alkyne [115,116] [Eqs. (53) and (54)]. The ruthenium carbene, generated from diazo compound, reacts with the C=C bond to produce vinylcarbene intermediate able to add a second molecule of diazo compotmd to generate dienes. The stereoselective formation of these conjugated dienes results from the selective creation of two C=C bonds, probably due to the possibility for (C5Me5)RuCl moiety to accomodate two cis carbene ligands. This reaction occurred with terminal or internal alkynes as well as 1,3-diynes [115] and was applied successfully to alkynylboronates [116]. 

Heimgartner and co-workers treated a-diazoketones and a-diazoamides 64 with thiones, with and without a catalyst such as Rh(OAc)2 present (1998HCA285). The products were substituted thiiranes 65 and/or substituted 1,3-oxathioles. In all cases, a thiocarbonyl ylide intermediate, which could undergo either a 1,3- or a 1,5-electro-cyclization, was held responsible. The ylide could arise either from addition of a carbene or a carbenoid to S of the thiocarbonyl compound or by loss of N2 from a primary cycloadduct between the diazo and the thiocarbonyl compounds. In one case, such a primary adduct was isolated. The thiirane carboxamides could be desulfurized with (Me2N)3P in tetrahydrofuran (THF) at 60 °C to afford acrylamides 66 (Scheme 11). 

Arbuzov, B.A., Polozov, A.M., and Polezhaeva, N.A., Catalytic and thermal decomposition of 2-diazo-l,3-diphenyl-l,3-propanedione in dimethyl hydrogen phosphite and O,O-diethyl hydi ogen phospho-rothioite, Zh. Obshch. Khim., 54, 1517, 1984 J. Gen. Chem. USSR (Engl. Transl.), 54, 1351. 1984. Arbuzov, B.A., Polozov, A.M., and Polezhaeva, N.A., P-H addition of carbenoids and carbenes as a method for the synthesis of 2-phospho-substituted 1,3-dicarbonyl compounds, Dokl. Akad. Nauk SSSR, Ser. Khim., 287, 849, 1986 Dokl. Chem. (Engl. Transl.), 287, 69, 1986. 

Addition of carbenoids derived from a-diazo carbonyl compounds to prostereogenic olefins can furnish two diastereomeric cyclopropane derivatives (dsjtrans- or euefo/exo-isomers). The metal-catalyzed transfer of alkoxycarbonyl carbenes has been closely investigated it usually furnishes the mwv-substituted cyclopropanes with moderate to good preference. The rhodium(II/-catalyzed reaction of ethyl diazoacetate with various olefins typically demonstrates that the d.r. (trans/cis) increases when the substituent on the olefin becomes sterically more demanding5. 

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