Diazoketone formation

An analogous diazoketone formation is observed (409) with cyclopropenone and diphenyl ketene28. ... 

Diazoketone Formation. Reaction of carbamate derivatives of pyroglutamic acid esters with TMSC(Li)N2 below — 100°C gives the corresponding substituted 6-diazo-5-oxo-norleucine esters (eq 35). ... 

In contrast to molecular fluorine, trifluoromethyl hypofluonte has limited synthetic value for geminal fluorination of diazoketones owing to formation of complex mixtures [97]... 

Diazocarbonyl compounds are especially useful in these reactions because of their ease of formation, relative stability, and controlled reactivity in catalytic reactions [ 1,11 ]. As outlined in Scheme 1, a wide diversity of methodologies are available for this synthesis, with access dependent on the nature of Z. Vinyl- and aryldiazoacetates are accessible by other pathways [2]. The order of reactivity toward diazo decomposition has diazoketones and diazoacetates much more reactive than diazoacetoacetates or diazomalonates. However, the influence of electronic effects on reactivities is more pronounced with phenyl- and vinyl-diazoacetates than with diazoacetoacetates and, especially, diazoacetates [12]. 

The role of Lewis acids in the formation of oxazoles from diazocarbonyl compounds and nitriles has primarily been studied independently by two groups. Doyle et al. first reported the use of aluminium(III) chloride as a catalyst for the decomposition of diazoketones.<78TL2247> In a more detailed study, a range of Lewis acids was screened for catalytic activity, using diazoacetophenone la and acetonitrile as the test reaction.<80JOC3657> Of the catalysts employed, boron trifluoride etherate was found to be the catalyst of choice, due to the low yield of the 1-halogenated side-product 17 (X = Cl or F) compared to 2-methyI-5-phenyloxazole 18. Unfortunately, it was found that in the case of boron trifluoride etherate, the nitrile had to be used in a ten-fold excess, however the use of antimony(V) fluoride allowed the use of the nitrile in only a three fold excess (Table 1). 

Palladium(II) acetate was found to be a good catalyst for such cyclopropanations with ethyl diazoacetate (Scheme 19) by analogy with the same transformation using diazomethane (see Sect. 2.1). The best yields were obtained with monosubstituted alkenes such as acrylic esters and methyl vinyl ketone (64-85 %), whereas they dropped to 10-30% for a,p-unsaturated carbonyl compounds bearing alkyl groups in a- or p-position such as ethyl crotonate, isophorone and methyl methacrylate 141). In none of these reactions was formation of carbene dimers observed. 7>ms-benzalaceto-phenone was cyclopropanated stereospecifically in about 50% yield PdCl2 and palladium(II) acetylacetonate were less efficient catalysts 34 >. Diazoketones may be used instead of diazoesters, as the cyclopropanation of acrylonitrile by diazoacenaph-thenone/Pd(OAc)2 (75 % yield) shows142). 

Products of a so-called vinylogous Wolff rearrangement (see Sect. 9) rather than products of intramolecular cyclopropanation are generally obtained from P,y-unsaturated diazoketones I93), the formation of tricyclo[2,1.0.02 5]pentan-3-ones from 2-diazo-l-(cyclopropene-3-yl)-l-ethanones being a notable exception (see Table 10 and reference 12)). The use of Cu(OTf), does not change this situation for diazoketone 185 in the presence of an alcoholl93). With Cu(OTf)2 in nitromethane, on the other hand, A3-hydrinden-2-one 186 is formed 160). As 186 also results from the BF3 Et20-catalyzed reaction in similar yield, proton catalysis in the Cu(OTf)2-catalyzed reaction cannot be excluded, but electrophilic attack of the metal carbene on the double bond (Scheme 26) is also possible. That Rh2(OAc)4 is less efficient for the production of 186, would support the latter explanation, as the rhodium carbenes rank as less electrophilic than copper carbenes. 

The distinction between Pd and Rh catalysts was also verified for diazoketone 190. In this case, the carbonyl ylide was trapped by intramolecular [3+2] cycloaddition to the C=C bond195. Decomposition of bis-diazoketone 191 in the presence of CuCl P(OEt)3 or Rh2(OAc)4 led to the pentacyclic ketone 192 most remarkably, one diazoketone unit reacted by cyclopropanation, the second one by carbonyl ylide formation 194). With [(r 3-C3H5)PdCl]2, a non-separable mixture containing mostly polymers was obtained, although bis-diazoketones with one or two allyl side chains instead of the butenyl groups underwent successful twofold cyclopropanation 196). 

Rhodium(II) acetate was found to be much more superior to copper catalysts in catalyzing reactions between thiophenes and diazoesters or diazoketones 246 K The outcome of the reaction depends on the particular diazo compound 246> With /-butyl diazoacetate, high-yield cydopropanation takes place, yielding 6-eco-substituted thiabicyclohexene 262. Dimethyl or diethyl diazomalonate, upon Rh2(OAc)4-catalysis at room temperature, furnish stable thiophenium bis(alkoxycarbonyl)methanides 263, but exclusively the corresponding carbene dimer upon heating. In contrast, only 2-thienylmalonate (36 %) and carbene dimer were obtained upon heating the reactants for 8 days in the presence of Cul P(OEt)3. The Rh(II)-promoted ylide formation... 

Intramolecular carbonyl ylide formation was also invoked to explain the formation of the AH-1,3-oxazin-5(6//)-ones 291a, b upon copper-catalyzed decomposition of diazoketones 290a, b 270 >. Oxapenam 292, obtained from 290b as a minor product, originates from an intermediary attack of the carbenic carbon at the sulfur atom. In fact, this pathway is followed exclusively if the C(Me, COOMe) group in 290b is replaced by a CH2 function (see Sect. 7.2). 

The reaction, formally speaking a [3 + 2] cycloaddition between the aldehyde and a ketocarbene, resembles the dihydrofuran formation from 57 a or similar a-diazoketones and alkenes (see Sect. 2.3.1). For that reaction type, 2-diazo-l,3-dicarbonyl compounds and ethyl diazopyruvate 56 were found to be suited equally well. This similarity pertains also to the reactivity towards carbonyl functions 1,3-dioxole-4-carboxylates are also obtained by copper chelate catalyzed decomposition of 56 in the presence of aliphatic and aromatic aldehydes as well as enolizable ketones 276). No such products were reported for the catalyzed decomposition of ethyl diazoacetate in the presence of the same ketones 271,272). The reasons for the different reactivity of ethoxycarbonylcarbene and a-ketocarbenes (or the respective metal carbenes) have only been speculated upon so far 276). 

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... 

Intramolecular oxonium ylide formation is assumed to initialize the copper-catalyzed transformation of a, (3-epoxy diazomethyl ketones 341 to olefins 342 in the presence of an alcohol 333 . The reaction may be described as an intramolecular oxygen transfer from the epoxide ring to the carbenoid carbon atom, yielding a p,y-unsaturated a-ketoaldehyde which is then acetalized. A detailed reaction mechanism has been proposed. In some cases, the oxonium-ylide pathway gives rise to additional products when the reaction is catalyzed by copper powder. If, on the other hand, diazoketones of type 341 are heated in the presence of olefins (e.g. styrene, cyclohexene, cyclopen-tene, but not isopropenyl acetate or 2,3-dimethyl-2-butene) and palladium(II) acetate, intermolecular cyclopropanation rather than oxonium ylide derived chemistry takes place 334 ). 

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). 

The reaction of ADC compounds with carbenes and their precursors has already been discussed in Section IV,A- In general, the heterocyclic products are not the result of 1,2-addition but of 1,4-addition of the carbene to the —N=N—C=0 system.1 Thus the ADC compound reacts as a 4n unit in a cheletropic reaction leading to the formation of 1,3,4-oxadiazolines. Recent applications include the preparation of spiro-1,3,4-oxadiazolines from cyclic diazoketones and DEAZD as shown in Eq. (14),133 and the synthesis of the acyl derivatives 85 from the pyridinium salts 86.134 The acyl derivatives 85 are readily converted into a-hydroxyketones by a sequence of hydrolysis and reduction reactions. 

The synthesis of /Mactams from diazoketones and imines can be realized not only by using photochemical reaction conditions but also under the action of microwave irradiation. When the reaction was performed in o-dichlorobenzene at 180 °C, however, the rates of thermal and microwave-assisted formations of -lactams were shown to be identical within the limits of experimental error (80-85% conversion after 5 min) [30]. 

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>. 

With acyl and alkoxycarbonyl azides, 2 -triazoles are isolated, although the l.ff-isomers are detected as intermediates. The reaction is not very general it fails with the corresponding sulfonium ylids, and fairly minor changes in substituents on the phosphorus ylid result in the formation of diazoketones rather than triazoles. ... 

Antibodies Affinity labeling of antibody combining sites as illustrated by anti-dinitrophenyl antibodies, 46, 479 p-azoben-zenearsonate antibody, 46, 492 affinity cross-linking of heavy and light chains, 46, 501 bivalent affinity labeling haptens in the formation of model immune complexes, 46, 505 DNP-based diazoketones and azides, 46, 508 labeling of antilactose antibody, 46, 516. 

The reactions of A -BOC-protected a-amino acids 424 and diazomethane in the presence of iV-methylmorpholine-polystyrene and isobutyl chloroformate resulted in formation of diazoketones 425, which, on treatment with indium(lll) triflate, were cyclized to 4-substituted-tetrahydro-l,3-oxazine-2,5-diones 426 in high overall yields (Scheme 82) <2006TL7969>. 

Decomposition of diazoketone 113 with rhodium acetate led to the formation of a tethered cyclic carbonyl ylide 114 that was poised to undergo an intramolecular cycloaddition, preparing 115 in 60% yield. Interestingly, if DMAD was added to the reaction mixture, the only product arose from intermolecular cycloaddition. 

Chiu s retrosynthetic analysis of the pseudolaric acids proposed a simple intermediate incorporating a bridging ether, similar to that used by Dauben and McMills. Cleavage of the ether bridge further reduced the problem to a tandem ylide formation-cycloaddition through a simple acyclic ot-diazoketone with a tethered olefin (Scheme 4.45). 

Thus far, in the alkaloid series discussed, the nitrogen atom has always been part of the core of the alkaloid strucmre, rather than acting in a dipolarophilic manner in the cycloaddition of the carbonyl ylide. Recently, Padwa et al. (117) addressed this deficiency by conducting model studies to synthesize the core of ribasine, an alkaloid containing the indanobenzazepine skeleton with a bridging ether moiety (Scheme 4.57). Padwa found that indeed it was possible to use a C = N 7i-bond as the dipolarophile. In the first generation, a substimted benzylidene imine (219) was added after formation of the putative carbonyl ylide from diazoketone 218. The result was formation of both the endo and exo adduct with the endo adduct favored in an 8 1 ratio. This indicates that the endo transition state was shghtly favored as dictated by symmetry controlled HOMO—LUMO interactions. 

Silyl-substituted diazoketones 29 cycloadd with aryl isocyanates to form 1,2,3-triazoles 194 (252) (Scheme 8.44). This reaction, which resembles the formation of 5-hydroxy-l,2,3-triazoles 190 in Scheme 8.43, has no analogy with other diazocarbonyl compounds. The beneficial effect of the silyl group in 29 can be seen from the fact that related diazomethyl-ketones do not react with phenyl isocyanate at 70 °C (252). Although the exact mechanistic details are unknown, one can speculate that the 2-siloxy-1-diazo-1-alkene isomer 30 [rather than 29 (see Section 8.1)] is involved in the cycloaddition step. With acyl isocyanates, diazoketones 29 cycloadd to give 5-acylamino-l,2,3-thiadiazoles 195 by addition across the C=S bond (252), in analogy with the behavior of diazomethyl-ketones and diazoacetates (5). 

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