Diazoketones cyclization reactions

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... 

A tandem cyclization-cycloaddition reaction was developed as a method for synthesizing polycyclic ring systems which involved a rhodium(II) acetate-induced diazoketone cyclization onto a neighboring carbonyl group to generate an ylide followed by 1,3-dipolar cycloaddition. Thus (208) has been transformed into the 8-substituted pyrrolizidone (209) <89JA645l). 

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 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... 

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>. 

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]. 

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. 

In contrast, in the photolysis of3,6-diphenylpyridazine-N-oxide 28 (R1 = R2 = Ph), a mixture of 3-benzoyl-5-phenylpyrazole 31 and 2,5-diphenylfuran 32 is formed. Diazoketone 29 (R1 = R2 = Ph) undergoes two competing reactions (i) thermal internal cyclization into the pyrazole 31 or (ii) photoinduced formation of a carbene leading to the final furan 32 (Scheme 12.9) therefore, the product distribution depends heavily on the reaction conditions. Thus, the formation of pyrazole 31 (75%) is favored over that of furan 32 (3%) by irradiation in acetone in a Rayonet reactor equipped with lamps irradiating at 350 nm. On the other hand, by irradiation with a Hanovia immersion lamp the yield of 31 decreases to 27%, whereas the yield of 32 increases to 67%. Moreover, the exclusive formation of the furan derivative 32 (43%) was observed by irradiation in the Rayonet reactor at low temperatures (—65 °C) [27]. 

The ambident nucleophilic character of enaminones is again demonstrated by the reaction with keto carbenes, produced in situ from diazoketones. Acyclic enaminones react via the -position to directly yield pyrroles (equation 11). Cyclic enaminones are shown to react at the nitrogen to give adducts which can be cyclized with KOH to... 

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... 

Interestingly, /3,7-unsaturated a-diazoketones are also sources of cyclo-butanones when they are exposed to protic acid. For example, compound XI furnished XII in high yield upon contact with concentrated sulfuric acid (see Scheme 42.3). In a conceptually analogous reaction, /S.y-unsaturated a-diazoketones proved to be useful in the constmction of cyclopentanones XIV" in a polyolefinic cationic cyclization process reminiscent of the mechanism by which plants in nature build their polycyclic triterpenoid metabolites from squalene, that is, XV - XVI. 

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]. 

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. 

---