Diazoketones

In both the photolysis and pyrolysis of diazoketones carbene intermediates have been postulated by analogy with other diazo decompositions, but in the majority of cases the carbene cannot be trapped by olefins. Instead, ready migration of alkyl or aryl groups (bonded to the carbonyl group) to the divalent carbon atom takes place, known as the Wolff rearrangement 

Numerous applications of this reaction can be found in the field of synthetic organic chemistry. 

The quantum yield of nitrogen formation obtained from the photolysis of various diazoketones in methanol has been measured as a function of the nature of the substituent (Table 13) . In general, decreases with increasing polarization of the diazo group p- and w-substituents decrease (j) when R = phenyl. For bis-diazoketones 0 (per N2) is unaffected unless there is strong conjugation. The quantum yields are also lowered in polar media and correlations with the Hammett equation indicates that the excited state is triplet . 

Recent studies have confirmed the singlet state Wolff rearrangement mechanism. 

The gas phase Wolff rearrangement of ketocarbenes has been shown to involve an oxiirene intermediate , viz. 

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A variation of Hantzsch s synthesis, using thioureas in conjunction with a-diazoketones in place of a-halogenoketones, has proved to be generally applicable. In this manner, King and MUler (310) obtained 2-amino-4-phenylthiazole in 67% yield. A wide range of 4-substituted 2-aIkyl (or aryl) aminothiazoles and 2-arylimino-3,4-diarylthiazolines have been prepared by Hampel and Muller (627, 665, 666). 

Thiazole acid chlorides react with diazomethane to give the diazoketone. The later reacts with alcoholic hydrogen chloride to give chloroacetylthiazole (Scheme 16). However, the Wolff rearrangement of the diazoketone is not consistently satisfactory (82). Heated with alcohol in the presence of copper oxide the 5-diazomethylketone (24) gives ethyl 5-thiazoleacetate (25) instead of the expected ethoxymethyl 5-thiazolyl ketone (Scheme 17) (83). 

A solution of 0.46 g of the diazoketone in 100 ml of chloroform is shaken with 22 ml of 48 % hydriodic acid for 1.5 min. After the addition of 400 ml of chloroform, the organic layer is washed successively with a saturated solution of potassium iodide, with a solution of sodium thiosulfate and with water. After drying, evaporation of the solvent yields 0.44 g of a product which is chromatographed over 10 g of alumina (diam. of column 1.0 cm). Elution with benzene (400 ml) and benzene-ether (9 1) (200 ml) gives 0.32 g of 3jS,5) ,19-trihydroxypregnan-20-one 3,19-diacetate (yield 76%) mp 96-99°. 

The diazoketohe synthesis for the preparation of 21-methyl-20-keto steroids has been discussed earlier. 21-Oxygenated derivatives can also be prepared by this route simply by reacting the diazoketone with an appropriate acid-nucleophile combination. For example, reaction of a diazoketone with acetic acid leads to the 21-acetate and boron trifluoride in the presence of methanol affords the 21-methyl ether. 

A solution of 0.38 g of the diazoketone in 2 ml of acetic acid is heated 0.5 hr at 100-105°. Removal of the solvent under reduced pressure and crystallization of the residue from acetone-ether gives 0.27 g of 1 la,21-dihydroxy-pregn-4-ene-3,20-dione 11,21-diacetate mp, 144-146° [a]o 156° (CHCI3). An additional 60 mg of this product is obtained by chromatography of the mother liquor (total yield 72%). 

D. Cyclic a-Diazoketones Ring-Contraction in Photolytic Wolff Rearrangements... 

The photolytic decomposition of a-diazoketones, accompanied by rearrangement to ketene (photolytic Wolff rearrangement), has been used successfully in the preparation of A-nor- and C-norsteroids. The method is reviewed in chapter 15 by R. M. Scribner. ... 

During 1961-2 four independent groups almost simultaneously reported the first syntheses of D-norsteroids, based on the photolysis of 16-diazo-17-ketones. In a typical procedure. Cava and Moroz ° convert the 16-oximino-17-one (93) derived from estrone methyl ether (92) to the diazoketone (94)... 

Cava and Muller " independently showed that epimerization at C-13, which can occur during irradiation of 17-keto steroids, is not observed with diazoketones (94) or (96). 

Photolysis of a-diazoketones has also been used to prepare A-norsteroids. Results in the A-nor series support the ketene intermediate invoked for the assignment of the 16) -configuration to the D-nor acids. Thus, irradiation of 2-diazo-5a-cholestan-3-one (99) gives 2/ -carboxy-A-nor-cholestane (100, R = H) in 45 % yield. ... 

A mixture of 4 g of diazoketone (94) and 2.2 g of sodium bicarbonate in 200 ml of tetrahydrofuran and 180 ml of water is irradiated with a Hanovia 200 W mercury vapor lamp (using a Corex filter) until the starting material has been consumed. After addition of 500 ml of water, followed by extraction of nonacidic products, the solution is acidified, cooled to 0° and filtered to yield 2.95 g (76%) of white crystals of crude acid (95) mp 170-176°. An analytical sample has mp 188°. ° ... 

Retropinacol rearrangement, 416 Ring contraction in photolytic cyclic a-diazoketones rearrangements, 316 12- p/-rockogenin mesylate, 400... 

Diazoketones react with trifluoromcthyl hypofluorite to give a mixture of a,a-difluoro ketones and o-fluoro-a-trifluoromethoxy ketones [70, 71] With elemental fluorine, two fluorine atoms replace the nitrogen in both diazoketones and unactivated diazo eompounds [70, 72, 73] (equation 9)... 

Diazoketones [57] and esters [5S] react with hydrogen fluoride in organic solvents to give a-fluoroketones or esters, pyndinium poly(hydrogen fluoride) offers a convenient medium for the reaction (equation 13) [9]... 

Tnfluoromethyl hypofluonte will fluorinate Schiff bases, giving N,a,a-tn-fluoroatmnes and a-fluoroimines [144] and reacts with diazoketones to give adducts in modest yields [145] (equation 6) At-Substituted aziridines give nng opened products by 1,3 addition of fluonne on nitrogen and trifluoromethoxy on carbon [146] (equation 7)... 

Depending on the fluonnating agent, diazoalkanes, diazoketones, and diazoesters can undergo hydrofluorination, halofluonnation, and geminal difluonnation reactions... 

Diazoketones that are readily prepared from acyl chlorides and diazomethane [92] also undergo a variety of fluorination reactions... 

High yields (65-94%) of geminal difluoro compounds can be obtained tram diazoketones and dilute molecular fluorine [90] (equation 25)... 

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

Chloroximes and enamines have provided aminoisoxazolines which could readily be converted to isoxazoles with acid (610-612). Pyrrazoles were usually obtained from addition of chlorohydrazones to enamines (610,613). The intermediate aminopyrazolines could only be isolated from the reaction of the cyclopentenyl enamine system. Pyrazoles were also obtained from the reactions of enamines with a-diazoketones and a-diazoesters (614). 

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