Diazoketone insertion

Yanez et al. reported the synthesis of miconazole and analogs through a carbenoid intermediate. The process involves the intermolecular insertion of carbe-noid species to imidazole from a-diazoketones with copper acetylacetonate as the key reaction of the synthetic route [11]. 

Alkyl diazoacetates undergo little or no allylic C/H insertion when decomposed catalytically in the presence of appropriate olefins 6,13,I4). In contrast, such insertions occur with diazomalonates or ot-diazoketones. From the available facts, the conclusion can be drawn that different pathways may lead to what finally looks like the direct or rearranged allylic insertion product, but convincing evidence for one or the other mechanism is available only in a few cases. As Scheme 22 shows, the C/H insertion products 98-100 may arise from one of three major sources ... 

Intramolecular C/H insertion by copper-catalyzed decomposition of a-diazoketones provides a convenient cyclization procedure which is limited, however, to diazo compounds which allow energetically favorable realization of the transition state leading to the cyclized product. 

C—H bond 174-280,28i por comparison, only trace amounts of cyclopentane resulted from the CuS04-catalyzed decomposition of 1 -diazo-2-octanone or l-diazo-4,4-dimethyl-2-pentanone 277). It is obvious that the use of Rh2(OAc)4 considerably extends the scope of transition-metal catalyzed intramolecular C/H insertion, as it allows for the first time, efficient cyelization of ketocarbenoids derived from freely rotating, acyclic diazoketones. This cyelization reaction can also be highly diastereo-selective, as the exclusive formation of a m is-2,3-disubstituted cyclopentane carboxylate from 307 shows281 a). The stereoselection has been rationalized by... 

An interesting application of carbenoid O/H insertion is the synthesis of macrocyclic oxacrown ethers 337 from a,a>-diazoketones 336 and oligoethylene glycols 323). 

The known examples of carbenoid insertion into an S—H bond have been supplemented by the Rh2(OAc)4-catalyzed synthesis of a-phenylthioketones from a-diazoketones and thiophenol 327). By this method, a number of primary and secondary acyclic a-diazoketones, ethyl diazoacetate and cyclic diazoketones such as 2-diazocyclopentanone, 2-diazo-6-methylcyclohexanone and 2-diazocyclohepta-none were converted at room temperature in good to high yield. 

Efforts to realize an intramolecular version of the above reactions met with limited success when monocyclic 4-thio-substituted (3-lactams were used. Cu(acac)2-catalyzed decomposition of diazoketone 358 produced the epimeric carbapenams 359 a, b together with the oxapenam derivative 360 341 these compounds correspond to the C4/S insertion products obtained in intermolecular reactions. Oxapenams were obtained exclusively when the acrylate residue in 359 was replaced by an aryl or heteroaryl substituent 275 342). The different reaction mode of diazoketones 290a, b, which furnish mainly or exclusively carbonyl ylide rather than sulfur ylide derived products, has already been mentioned (Sect. 5.2). 

The CJS insertion reaction was suppressed completely upon catalytic decomposition of diazoketones 361, where the sulfur substituent was alkyl, acyl or thioacyl. It is presumed that sulfonium ylides occur as intermediates which give cepham (or cephem) derivatives in all cases270,343) rather than products of a Stevens rearrangement. 

The Cu(acac)2-promoted transformation 368 - 369 represents an intramolecular carbenoid insertion into the penicillin C5—S bond 347). The original report did not mention the low-yield formation of a second product to which the tricyclic structure 370 was assigned 348,349 >. In both 369 and 370, the original stereochemistry at C-5 of 368 has been inverted this is seen as a consequence of intramolecular nucleophilic a-face attack in a presumed azetidinium enolate intermediate. Attempts to realize a more flexible intermediate which then would have a chance to undergo p-face attack centered on the chain-extended diazoketone 371. Its catalytic decomposition led to the tricycle 372 exclusively, however, C7/N rather than C5/S insertion having taken place 349). 

Wolff rearrangement of a-diazoketones to give ketenes or subsequent products is an often used synthetic procedure the scope and limitations of which are well established 13 390), so that only a few new features of this reaction need to be considered here. Concerning its catalytic version, one knows that copper, rhodium and palladium catalysts tend to suppress the rearrangement390). A recent case to the contrary is provided by the Rh2(OAc)4-catalyzed decomposition of ethyl -2-diazo-3-oxopent-4-enoates 404 from which the p,y-unsaturated esters 405 are ultimately obtained via a Wolff rearrangement 236). The Z-5-aryl-2-diazo-3-oxopent-4-enoates undergo intramolecular insertion into an aromatic C—H bond instead (see Sect. 4.1). 

Two type la syntheses of (3-hydroxypyrroles have appeared. An aza-Nazarov cyclization of l-azapenta-l,4-dien-3-ones produced (3-hydroxypyrroles including 2,2 -bipyrroles <06EJO5339>. A second approach to a (3-hydroxypyrrole involved an intramolecular N-H insertion into a rhodium carbene derived from the decomposition of a diazoketone <06JOC5560>. On the other hand, the photochemical decomposition of the diazoketone led to pyrrolidin-2-ones. 

Ketocarbenes generated from diazoketones give two main type of reactions. The first one is the conventional carbene reaction, i.e. intramolecular insertion into a C—H or C—C bond, as applied in the synthesis of a... 

The signature application for the G-H insertion in synthesis is probably the total synthesis of (—)-tetrodotoxin 126 by Du Bois and Hinman.233 Two stereospecific G-H activation steps, rhodium-catalyzed carbene G-H insertion and carbamate-based nitrene C-H insertion, have been used to install the two tetrasubstituted centers C6 and C8a (Scheme 12). Diazoketone 122 was treated with 1.5mol% Rh2(HNCOCPh3)4, and cyclic ketone 123 was selectively formed in high yield without purification. The reaction of carbamate 124 with 10mol% Rh2(HNCOCF3)4, PhI(OAc)4, and MgO in C6H6 solvent furnished the insertion product 125 in 77% yield. 

Transition metal-catalyzed reactions of ct-diazocarbonyl compounds proceed via electrophilic Fischer-type carbene complexes. Consequently, when cr-diazoketone 341 was treated, at room temperature, with catalytic amounts of [ RhiOAcbh, it gave the formation of a single NH insertion product, which was assigned to the enol stmcture 342. At room temperature, in both solid state and in solution, 342 tautomerizes to give the expected 1-oxoperhydropyr-rolo[l,2-c]oxazole derivative 343 (Scheme 50) <1997TA2001>. 

A density functional study has been made of the competition between Wolff rearrangement and [1,2]-H shift in /S-oxy-a-diazocarbonyl compounds. Silver-catalysed decomposition of a-diazoketones (88 n = 0), derived from A-tosyl a-amino acids in methanol, gave rise to mixtures of products of Wolff rearrangement (89) and direct insertion of the carbene into the NH bond (90). The -amino acid derived species (88 n = 1) gave rise to products of Wolff rearrangement. 

Rhodium(II) carboxylate dimers and their carboxamide counterparts have been demonstrated to be exceptionally useful catalysts for carbene transfer processes involving diazocarbonyl substrates [1]. Doyle s seminal work identified Rh2(OAc)4 as the catalyst of choice for a variety of cyclopropanation, C-H insertion, and ylide rearrangement transformations using diazoketones or diazoesters [2]. Important contributions by Taber [3], Padwa [4], and Davies [5] further established the superior catalytic activity of dirho-dium catalysts and the excellent selectivity of rhodium-[Pg.417]

Padwa et al. (48) examined the behavior of diazoketone 127 under rhodium catalysis and found that the ligands associated with rhodium had a dramatic effect on the distribution of products 128 (from the carbonyl ylide) and 129 (from intramolecular C—H insertion). When rhodium acetate was employed there was a... 

There are several reports in the literature dealing with the bimolecular [3 + 2] cycloaddition reactions of alkynyl-substituted diazo compounds. Propargyl diazoacetate 212, when stored for 2 weeks at 0 °C, was transformed into an oligomer to which the constitution 213 was assigned (273) (Scheme 8.50). The alkynyl-diazoketone 214 requires a much higher temperature and is transformed into pyrazole 215, which probably arises from intermolecular cycloaddition, pyrazole tautomerization, and carbenic N/H insertion (274). The inter-intramolecular... 

The diverse chemistry of carbenes is beyond the scope of this account, but a few typical reactions are shown here to illustrate the usefulness of the photochemical generation of these reactive species. A carbene can insert into a C—H bond, and this finds application in the reaction of an a-diazoamide to produce a P-lactam (5.29). Carbenes derived from o-diazoketones can rearrange to ketenes, and thus a route is opened up to ring-contraction for making more highly strained systems <5.301. Carbenes also react with alkenes, often by cycloaddition to yield cyclopropanes in a process that can be very efficient (5.31) and highly stereoselective (5.321. 

Rhodium(II) acetate catalyzes C—H insertion, olefin addition, heteroatom-H insertion, and ylide formation of a-diazocarbonyls via a rhodium carbenoid species (144—147). Intramolecular cyclopentane formation via C—H insertion occurs with retention of stereochemistry (143). Chiral rhodium (TT) carboxamides catalyze enantioselective cyclopropanation and intramolecular C—N insertions of CC-diazoketones (148). Other reactions catalyzed by rhodium complexes include double-bond migration (140), hydrogenation of aromatic aldehydes and ketones to hydrocarbons (150), homologation of esters (151), carbonylation of formaldehyde (152) and amines (140), reductive carbonylation of dimethyl ether or methyl acetate to 1,1-diacetoxy ethane (153), decarbonylation of aldehydes (140), water gas shift reaction (69,154), C—C skeletal rearrangements (132,140), oxidation of olefins to ketones (155) and aldehydes (156), and oxidation of substituted anthracenes to anthraquinones (157). Rhodium-catalyzed hydrosilation of olefins, alkynes, carbonyls, alcohols, and imines is facile and may also be accomplished enantioselectively (140). Rhodium complexes are moderately active alkene and alkyne polymerization catalysts (140). In some cases polymer-supported versions of homogeneous rhodium catalysts have improved activity, compared to their homogenous counterparts. This is the case for the conversion of alkenes direcdy to alcohols under oxo conditions by rhodium—amine polymer catalysts... 

Examples are known where intermolecular carbenoid transformations between diazomalonates or certain diazoketones and appropriate olefins result in competition between formation of cyclopropane and products derived from allylic C—H insertion2-4. For example, catalytic decomposition of ethyl diazopyruvate in the presence of cyclohexene gave the 7-ejco-substituted norcarane 93 together with a small amount of the allylic C—H insertion product 94 (equation 95)142 143. In some cases, e.g. rhodium(II) decomposition of a-diazo-j8-ketoester 95, the major pathway afforded C—H insertion products 96 and 97 with only a small amount of the cyclopropane derivative 98. In contrast, however, when a copper catalyst was employed for this carbenoid transformation, cyclopropane 98 was the dominant product (equation 96)144. The choice of the rhodium(II) catalyst s ligand can also markedly influence the chemoselectivity between cyclopropanation and C—H... 

For an eventual 1,3-C,H insertion in the copper-catalyzed decomposition of diazoketone 190, see Section ni.E.5.a. 

In addition to the preparations of ethanoadamantane via Lewis acid catalyzed rearrangement of various polycyclic hydrocarbons described above (Section II. A.1), a ring closure reaction of a substituted adamantane has also been developed. Treatment of 2-adamantyl diazoketone with copper results in the intramolecular carbene insertion illustrated in Eq. (48) 14°1. 

Disubstituted 3(2H)-furanones.3 a-Alkoxy diazoketones undergo insertion into an adjacent ether C-H bond in the presence of Rh2(OAc)4 to form 3(2//)-furanones. This reaction was used for a synthesis of optically active ( + )-musearine (2) from D-alanine via (R)-2-bromopropionic acid (1). 

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