Cyclization of diazoketones

The Cu semicorrin complex (68a) has been successfully used as the catalyst for cyclization of alkenyl diazoketones, though the reactions of some substrates showed modest enantioselectivity (Scheme 74).276 Shibasaki et al. have successfully used the cyclization of diazoketone with Cu bis(oxazoline) (101) for the construction of the CD ring skeleton of phorbol.277... 

Monahan15 used the intramolecular cyclization of diazoketones to prepare the highly hindered l,5,6-triphenyltricyclo[3.1.0.02 ]hexanc-3-one (13) from 1-(1,2,3-triphenylcycloprop-2-enyl)-3-diazopropane-2-one (12). The starting material was... 

More highly substituted aromatics have also been studied in the course of natural product synthesis. For example, rhodium(II) mandelate-catalyzed cyclization of diazoketone 41 produces the ring expanded product 42, which on hydrogenations furnishes the tricyclic lactone 43. ... 

Another example of the acid-catalysed intramolecular cyclization of diazoketones cf. refs. 58, 92, 93) is a high-yielding preparation of polycyclic enones (101) from diazoketones (100). Further reports have appeared on the preparation of fused cyclopentanones by condensations between acetonedicar-boxylate and a-diketones yields are higher if the substituents on the latter substrates are small. An alternative approach to polycyclopentanoids, consisting of successive additions of propargyl alcohol anions to cyclopentanones followed by double dehydrative cyclization and hydrogenation, has been used to prepare the potential dodecahedrane precursor (102) cf ref. 63). The cage compound (103), obtained from 1,4-naphthoquinones and cyclopentadiene, produces the polycyclopentanoid (104) under acyloin condensation conditions. ... 

Tandem cyclization-cycloaddition of diazoketones in the synthesis of some alkaloids 97F303. 

Preparation of the sulfur analogue involves as the first step cyclization of the terephthalic acid derivative 92. The acid is then converted to the acid chloride and this is allowed to react with diazomethane. Rearrangement of the resulting diazoketone (95) under the conditions of the Arndt-Eistert reaction leads to the homologated acid. 

The cyclization of phenolic diazoketones 246 to spirodienones 247 was reinvestigated with Rh2(Me3CCOO)4> Rh2(OAc)4 and Pd(OAc)2 as catalysts235 the yields were found to be better than with CuCl used in earlier studies. 

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. 

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>. 

When thiocarbonyl and ot-diazocarbonyl compounds are combined, acyl-substituted thiocarbonyl ylides 158 are generated from a nonisolable 3-acyl-1,2,4-thiadiazoline 157 (Scheme 8.36). In addition to giving acylthiiranes 159 and 1,3-dithiolanes 160, dipoles 158 can also 1,5-cyclize to produce 1,3-oxathioles 161. Acyl-thiocarbonyl ylides derived from diazoketones [e.g., HC(0)C(N2)R, R = Ph, f-Bu (219,220) 2-diazocyclohexanone (221)] produce 1,3-oxathioles [e.g., 162 (220), Scheme 8.36], while those derived from diazoesters (218,222,223) lead to thiiranes by 1,3-cyclization. Ylides derived from a-diazocarboxamides form 1,3-oxathioles (e.g., 163) and thiiranes (e.g., 159, R = f-Bu, R = NMePh, R = R" = Ph), depending on the nature of the substituents (220). A related 1,5-cyclization of an aminomethyl-thiocarbonyl ylide formed from dimethyl 3-anilino-2-diazobutanedioate was also reported (224). 

The equivalence of sulfur and oxygen in this ring system carries over to NSAIDs as well. Preparation of the sulfur analogue of isoxepac (6-4) starts with the alkylation of thiophenol (27-1) with benzyl chloride (26-1). Cyclization of the intermediate thioether (27-2) then affords the homothioxanthone (27-3). The carboxyl side chain is then extended by means of the Amdt-Eistert homologation reaction. The acid is thus hrst converted to its acid chloride by means of thionyl chloride. Reaction with excess diazomethane leads to the diazoketone (27-4). Treatment of that intermediate with silver benzoate and triethylamine leads the ketone to rearrange to an acetic acid. There is thus obtained tiopinac (27-5) [28]. 

Furanones have been prepared by treatment of y-ketoacids with acetic anhydride. Furanones have also been formed by hydrolysis and dehydrobromination of j8,y-dibromoacids (B-50MI31200). The furan-3(2//)-one system (164) has been prepared by intramolecular cyclization of the diazoketones (163) (74TL3073). Some natural 3(2//)-furanones are known furaneol (166), occurring in strawberries and pineapples, is obtained by acid or base treatment of the dihydroxydiketone (165) (73JOC123). 

The acid-catalyzed decomposition of diazoketones (226) gives rise to cations which then cyclize to 2-iminotetrahydro-l,3-thiazin-5-ones (227). On hydrolysis these lead to the corresponding 2,5-diones (228) (80KGS1327). 

The diazoketone (69) affords thioindoxyl (17) on treatment with hydrochloric acid286 unlike its oxygen analog, which can be obtained by cyclization of 70 (X = 0) with acid, thioindoxyl cannot be obtained by cyclization of the related compound (70) (X = S).286... 

In this context, it is worth mentioning that there is only one other, clear-cut example for the simultaneous occurrence of the acyl(silyl)carbene-to-acylsilene and the acylcarbene-to-silylketene rearrangement of an acylcarbene bearing a Si—Si substituent. Carbene 57, generated by photolysis of diazoketone 56 in benzene, isomerized to both 58 and 59 in about equal amounts44. While the acylsilene cyclized to 1,2-silaoxetene 60, the ketene was isolated and structurally characterized by X-ray diffraction analysis of the derived... 

In the event, iodolactonization of the carboxylate salt derived from the ester 458 afforded 459, and subsequent warming of the iodo lactone 459 with aqueous alkali generated an intermediate epoxy acid salt, which suffered sequential nucleophilic opening of the epoxide moiety followed by relactonization on treatment with methanol and boron trifluoride to deliver the methoxy lactone 460. Saponification of the lactone function in 460 followed by esterification of the resulting carboxylate salt with p-bromophenacylbromide in DMF and subsequent mesylation with methanesulfonyl chloride in pyridine provided 461. The diazoketone 462 was prepared from 461 by careful saponification of the ester moiety using powdered potassium hydroxide in THF followed by reaction with thionyl chloride and then excess diazomethane. Completion of the D ring by cyclization of 462 to the keto lactam 463 occurred spontaneously on treatment of 462 with dry hydrogen chloride. 

Another successful cyclization of this type was carried out by McMills <94TL8311> to produce a simple phorbol analog devoid of most of the oxygenation (Scheme 6). Reaction of a-diazoketone 17 with Rh2(OAc)4 produced the transient oxonium ylide 18 which was... 

A number of miscellaneous methods which involve multibond formation are included here for completeness in spite of the fact that their synthetic utilities do not appear to be great. A reaction which closely resembles the a-halogenokeione-amide method is the cyclization of an a-chloro-a-phenylthioketone (prepared from the diazoketone) with ammonia and a carboxylic acid. It has been used to prepare 2-ethyl-4-methyl-5-phenylthioimidazole in 32% yield [68]. 

Cyclization of /3-mercaptoaldehydes has been reported to give 2-hydroxy-thietanes (which are thioacetals) in 16-84% yield.They are said to be useful as flavoring substances. However, cyclization of 4-mercaptopropene gave only 0.1% of 2-methylthietane. The major product was thiolane. Photolysis of the a-diazoketone of 2,2,5,5-tetramethylthiolane-3,4-dione in methanol gave a 28% yield of 2,2,4,4-tetramethyl-3-carbomethoxythietane. " Several dispirothietanes have been obtained from the bis-hydrazone of 3-thietanone. ... 

An unprecedented cyclopropanation reaction was observed during the reaction of ketene alkylsilyl acetals (191) with bromoform-diethylzinc. When monosubstituted acetals were used, cyclopropanecarboxylic esters (195) were formed by a novel C-H insertion. When disubstituted ketene acetals were used, byproducts such as a,)5-ethylenic esters (197) were also formed presumably via 196 (equation 49). This reaction provides a convenient method for the preparation of the bicyclo[3.1.0] hexane system and can be advantageously compared to the copper-catalysed intramolecular cyclization of unsaturated a-diazoketones . 

A total synthesis of a mixture of diastereoisomers having the constitution of magnolamine was reported recently by Kametani and Yagi 26). Arndt-Eistert reaction of 3-methoxy-4-benzyloxyphenethylamine with the diazoketone prepared from the acid chloride XLVII furnished the diamide LI. Bischler-Napieralski cyclization of the latter afforded the dihydroisoquinoline derivative XLIX, whose methiodide was reduced with sodium borohydride to the stereoisomers of constitution XLV. Debenzylation of the latter mixture gave a noncrystalline product which behaved similarly on paper chromatography to magnolamine and had IR- and UV-spectra which were superimposable on those of the alkaloid. 

The literature on catalytic cyclization of a-diazoketones has a rather recent history, with the majority of papers originating from the 1980s. The copper catalysts originally used (e. g., CUSO4) suffer from an unspecific product spectrum [5] and have largely been replaced by rhodium catalysts, mainly through the work of Doyle and colleagues [3]. 

C—H bond 280,281) comparison, only trace amounts of cyclopentane resulted from the CuSO -catalyzed decomposition of l-diazo-2-octanone or l-diazo-4,4-dimethyl-2-pentanone It is obvious that the use of Rh fOAc) considerably extends the scope of transition-metal catalyzed intramolecular C/H insertion, as it allows for the first time, efficient cyclization of ketocarbenoids derived from freely rotating, acyclic diazoketones. This cyclization reaction can also be highly diastereo-selective, as the exclusive formation of a /r< i5-2,3-disubstituted cyclopentane carboxylate from 307 shows The stereoselection has been rationalized by... 

Two short syntheses of racemic ipalbidine ( )-(842) are shown in Scheme 109. The synthesis by Jefford et al. commenced with conjugate addition between pyrrole and Ae atropate ester 849 followed by homologation of the acid 850 with diazomethane and rhodium-induced intramolecular carbene cyclization of the resulting diazoketone 851 (574). The bicyclic product 852 was converted into ( )-842 in a further four steps. The approach taken by Danishefsky and Vogel centered on acid-catalyzed cyclocondensation between the silyl ketene acetal 853 and A -pyrroline (854) to give indolizidinone 855 (575). Reduction of the lactam and cleavage of the aryl ether completed the synthesis of ( )-842. 

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