Diazo compounds, electrophilic carbene

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. 

The mechanism through which catalytic metal carbene reactions occur is outlined in Scheme 2. With dirhodium(II) catalysts the open axial coordination site on each rhodium serves as the Lewis acid center that undergoes electrophilic addition to the diazo compound. Lewis bases that can occupy the axial coor-... 

As it is known from experience that the metal carbenes operating in most catalyzed reactions of diazo compounds are electrophilic species, it comes as no surprise that only a few examples of efficient catalyzed cyclopropanation of electron-poor alkeiies exist. One of those examples is the copper-catalyzed cyclopropanation of methyl vinyl ketone with ethyl diazoacetate 140), contrasting with the 2-pyrazoline formation in the purely thermal reaction (for failures to obtain cyclopropanes by copper-catalyzed decomposition of diazoesters, see Table VIII in Ref. 6). 

Interaction of an electrophilic carbene or carbenoid with R—S—R compounds often results in the formation of sulfonium ylides. If the carbene substituents are suited to effectively stabilize a negative charge, these ylides are likely to be isolable otherwiese, their intermediary occurence may become evident from products of further transformation. Ando 152 b) has given an informative review on sulfonium ylide chemistry, including their formation by photochemical or copper-catalyzed decomposition of diazocarbonyl compounds. More recent examples, including the generation and reactions of ylides obtained by metal-catalyzed decomposition of diazo compounds in the presence of thiophenes (Sect. 4.2), allyl sulfides and allyl dithioketals (Sect. 2.3.4) have already been presented. 

The interaction between catalyst and diazo compound may be initialized by electrophilic attack of the catalyst metal at the diazo carbon, with simultaneous or subsequent loss of N2, whereupon a metal-carbene complex (415) or the product of carbene insertion into a metal/ligand bond (416) or its ionic equivalent (417) are formed. This is outlined in a simplified manner in Scheme 43, which does not speculate on the kinetics of such a sequence, nor on the possible interconversion of 415 and 416/417 or the primarily formed Lewis acid — Lewis base adducts. 

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]. 

Dinuclear Rh(II) compounds are another class of effective catalysts (227). Electrophilic carbenes formed from diazo ketones and dimeric Rh(II) carboxylates undergo olefin cyclopropanation. Chiral Rh(II) carboxamides also serve as catalysts for enantioselective cyclopropanation (Scheme 95) (228). The catalysts have four bridging amide ligands, and... 

Like electrophilic addition to diazo compounds [7] from which diazonium ions and, subsequently, carbocations are generated, transition-metal compounds that can act as Lewis acids are potentially effective catalysts for metal carbene transformations. These compounds possess an open coordination site that allows the formation of a diazo carbon-metal bond with a diazo compound and, after loss of dinitrogen, affords a metal carbene (Scheme 5.2). 

Diazocarbonyl compounds, especially diazo ketones and diazo esters [19], are the most suitable substrates for metal carbene transformations catalyzed by Cu or Rh compounds. Diazoalkanes are less useful owing to more pronounced carbene dimer formation that competes with, for example, cyclopropanation [7]. This competing reaction occurs by electrophilic addition of the metal-stabilized carbocation to the diazo compound followed by dinitrogen loss and formation of the alkene product that occurs with regeneration of the catalytically active metal complex (Eq. 5.5) [201. 

Cyclopropane formation occurs from reactions between diazo compounds and alkenes, catalyzed by a wide variety of transition-metal compounds [7-9], that involve the addition of a carbene entity to a C-C double bond. This transformation is stereospecific and generally occurs with electron-rich alkenes, including substituted olefins, dienes, and vinyl ethers, but not a,(J-unsaturated carbonyl compounds or nitriles [23,24], Relative reactivities portray a highly electrophilic intermediate and an early transition state for cyclopropanation reactions [15,25], accounting in part for the relative difficulty in controlling selectivity. For intermolecular reactions, the formation of geometrical isomers, regioisomers from reactions with dienes, and enantiomers must all be taken into account. 

The extensive data accumulated by Nakamura and Otsuka, although interpreted by them as being due to the intervention of metal carbene and metallocyclobutane intermediates, can also be rationalized by an alternative mechanism in which coordination of the chiral Co(II) catalyst with the alkene activates the alkene for electrophilic addition to the diazo compound (Scheme 5.4). Subsequent ring closure can be envisioned to occur via a diazonium ion intermediate, without involving at any stage a metal carbene intermediate. 

Enamine formation occurs by the thermolysis of diazo compounds (Scheme 150)67 109,278 284 288,304 332 453 454 via a carbene-like intermediate.284 332 When R1 = Ph, it enters into competition with hydrogen migration,284,332 and the electrophilic character of the carbene enhances the migration of the dimethylaminophenyl more than the phenyl.332 When triazoline synthesis is carried out at temperatures higher than that at which thermolysis of diazo compounds occurs, enamines are obtained exclusively, as in the addition of phenyl azide to cinnamic nitriles and ketones, with phenyl migration dominating in the nitrile.284 Enamine is also formed quantitatively in the reaction of ethyl diazoacetate with benzylideneaniline at 110°C.455... 

Non-stereospecific cyclopropanation reactions of the diazafluorenylidene (10), generated by photolysis of the diazo compound, indicated a triplet carbene.18 Competition experiments suggested a singlet-triplet equilibrium at room temperature and a Hammett study of additions to substituted styrenes indicated that the carbene reacts as an electrophile (p = —0.65). 

Transition-metal catalysis, especially by copper, rhodium, palladium and ruthenium compounds, is another approved method for the decomposition of diazo compounds. It is now generally accepted that short-lived metal-carbene intermediates are or may be involved in many of the associated transformations28. Nevertheless, these catalytic carbene transfer reactions will be fully covered in this chapter because of the close similarity in reaction modes of electrophilic carbenes and the presumed electrophilic metal-carbene complexes. 

Doyle et al.344 and Wee and Liu345 have reported the ring-closing transformation of a-diazoacetamides 108 and 109 to yield 2(3//)-indolinones over Nafion-H [Eq. (5.136)]. In the transformation of compounds 109 the electrophilic intramolecular substitution is followed by decarboxylation.345 Small amounts of 2-azetidinone derivatives (4—10%) formed through a carbene intermediate were also detected. The yield of products from compounds 108 are even higher than observed in the presence of Rh(OAc)2 often applied in the decomposition of diazo compounds.344... 

The reaction of Ru(TMP) with ethyl diazoacetate yielded a carbene complex, e.g. Ru(CHC02Et)(TMP) [316], An excess of the diazo compound led to catalytic formation of cis- and trans diethyl maleate in an unexpected ratio of 15 1. The nucleophilic ethyl diazoacetate is proposed to attack the electrophilic carbene complex and produce an intermediate betaine-line species which eliminates both Ru(TMP) and N2 to form the maleates. Similar reactions were observed with Os(TTP) complexes [313a], These reactions are reminiscent of the above-mentioned lability of a putative methyleneruthenium porphyrin. 

Rh and Pd-catalysed Reactions of Diazo Compounds via Electrophilic Carbene Complexes... 

Like diazo compounds and aryl azides, diazirines give rise in most instances to unwanted photolysis products besides the desired carbenes, including long-lived electrophilic intermediates. The most serious problem is the generation of diazo compounds (e.g. Fig. 3.13). For example, 3-H-3-aryl-diazirines form diazo isomers to the extent of 30 to 70% when irradiated. These isomers are themselves photolysed to form carbenes, but relatively slowly at wavelengths at which the diazirines absorb (Smith and Knowles, 1973, 1975). 

An interesting reaction between isothiazolone 103 and diazomalonoester was described. It is assumed that the electrophilic carbene formed from a diazo compound attacks the sulfur atom to give ylide 104. Its rearrangement affords product 105 [83JCS(CC)643] (Scheme 34). 

Caibene reagents also functionalize alkanes. Triplet CH2 adds unselecdvely to alkane C—bonds. The product mixture obtained from n-pentane was found to be 48% n-hexane, 3S% 2-methylpentane and 17% 3-methylpentane, so that addition to a primary C—bond appears to be favored. Monochloro-methylcarbene, CHCl, is less reactive and more electrophilic and so the normal tertiary > secondary > primary selectivity pattern was observed. Ethoxycarbonylcarbene, formed on fdiotolysis of the corresponding diazo compound, inserts rather unselectively in to alkane C—H bonds to give the ethoxycarbo-nylmethyl derivatives in ca. 50% yield. Transition metals, such as copper(II) or rhodium(I). also usefully catalyze the insertion of carbenes into alkane C—bonds. 

Due to the electrophilic character of carbenes. they are not expected to easily react with electron-poor alkenes, and the only reported examples concern reactions with diazo compounds (i.e., diazomethane, diazofluorcnc. ethyl diazoacetate. and phenyldiazoniethane ). However, depending on the reaction conditions, carbenes arc not always the reactive species. Cyclopropanes are often obtained by decomposition of pyrazolines which arise from 1,3-dipolar cycloaddilion reactions (see Section 2.1.1.6.2.3.1.). Even when reactions are performed under irradiation, pyrazolines can be obtained as the result of a diradical addition. ... 

Carbenoids are soft electrophiles which present the same trend of reactivities as carbenes, although they generally react more efficiently and more selectively than the free carbenes obtained by the thermal or photochemical decomposition of diazo compounds. 

For example, in attempts to realize benzannelation reactions, alkyloxy aryl carbene complexes of manganese failed to react with alkynes even in refluxing toluene, and the starting compounds could be recovered [4]. The documented low reactivity of the Mn as opposed to Cr and Mo carbene complexes may in part explain why the electrophilic carbene C-atom and the nucleophilic diazo C-atom tolerate each other in the same molecule. Besides, the bulky substituents at the silicon atom protect it fi"om being attacked by nucleophiles leading to desilylation as reported for trimethylsilyl substituted Cr carbene complexes [5]. 

There are several reasons why it is unlikely that loss of nitrogen from the diazo compound, followed by direct addition of the carbene to the double bond, is the mechanism for the reaction. (1) Even though the carbene has two alkyl substituents, it is still quite electrophilic and would not be expected to react with one of the double bonds to the exclusion of the other. (2) There is no catalyst or ultraviolet light to aid in the generation of the carbene. 

The problems are due to the electrophilicity of the metal-carbene intermediates in these transformations, and to competitive, fast dihydropyrazole formation resulting from uncatalyzed thermal [3 + 2] cycloaddition of the diazo compound to the alkene furthermore, o , -unsaturated nitriles often yield 2-vinyloxazoles under the reaction conditions. 

---