Diazo group transfers ketones

Fig. 14.29. Preparation of an a-diazoketone (compound E) from a ketone (A) and subsequent Wolff rearrangement of the a-diazoketone. Initially, A is transformed to give the enolate B of its a-formyl derivative. In a Regitz diazo group transfer reaction, this will then be converted into the a-diazoketone E. Ring contraction via Wolff rearrangement occurs and the 10-membered cyclic diazoketone C rearranges in aqueous media to give the nine-membered ring carboxylic acid E via the ketene D.

The importance of a-diazo ketones as synthetic intermediates has led to the development of a number of general methods for their preparation.5 Particularly popular approaches include the acylation of diazo alkanes and the base-catalyzed "diazo group transfer" reaction of sulfonyl azides with 8-dicarbonyl compounds.6-7 While direct diazo transfer to ketone enolates is usually not a feasible process,8-9 diazo transfer to simple ketones can be achieved in two steps by employing an indirect deformylative diazo transfer strategy in which the ketone is first formylated under Claisen condensation conditions, and then treated with a sulfonyl azide reagent such as p-toluenesulfonyl azide.6a,6c,9,i0,11... 

Many of the methods discussed in this section can also be treated as combinations of more than two fragments. For instance, in the cyclization of C,A-diaryl hydrazones (425) with ammonia described in Section 6.11.9.2.2 the a-acylamino-hydrazones are treated as a five-atom fragment, but since these compounds were prepared from methylene ketones (424) via diazo group transfer and acylation of the a-hydrazono-ketones, the entire reaction sequence may be described as a [2 -I- 2 -I-1 -I-1] combination. 

The diazo group transfer reaction fails in nonactivated ketones because of insufficient proton labiality in the compound. This can be circumvented by introducing a formyl group via Claisen reaction to provide additional activation and this formyl group is eliminated in the course of the diazo transfer reaction.4,5 The formylation followed by subsequent diazo transfer reaction is demonstrated with cyclopentanone (52 — 53 — 54)4M, 4c a,p-unsaturated ketone (55 —> 56 — 57)4d and 4-/-Bu-cyclohexanone (58 — 59 - 60).5,21... 

The jV-fluorenyl diazoamide 93 could not be prepared using the tosyl azide however, the diazo group transfer to diketone 92 is effected successfully using 2-azido-l-ethylpyridinium tetrafluoroborate to furnish diazo ketone 93.33... 

Diazo group transfer to 1,2-diketones via ketoxime Mid sulfonyl hydrazone is generally carried out in the presence of organic bases, and affords high yields of diazo compounds. Dichlorotricyclo[2.2.1.0w]heptan-2,3-dione (94) is converted into its monotosylhydrazone 95 which is passed over basic alumina to afford yellow crystalline diazo ketone 96.34 The monohydrazone of 4,5-diketo-[9]paracyclophane (97) is prepared from the diketone Mid further oxidized with MnC>2 to give diazoketone 98. 

Dehydrogenation of a-pyridinealdehyde hydrazone (251) yields not a-pyridyldiazomethane (252) but the cyclic isomer l,2,3-triazolo[3,4-a]pyridine (253).1 A similar ring closure is observed in diazo group transfers onto alkyl or aryl(2-pyridyl)methyl ketone (254) in MeOH/KOEt.1 The diazo intermediate could not be isolated but 3-acyl[l,2,3]triazolo[3,4-a]pyridine (255) is obtained.1... 

In summary, the known preparative methods for the synthesis of [l,2,3]triazolo[l,5-a]pyridines prior to 1983 have been extensively reviewed in a number of different reviews <61CHE749,83AHC(34)80, 84CHEC-I(5)847>. These reviews reveal that the most straightforward methods involves an oxidation of the hydrazone of a pyridine-2-carbaldehyde or ketone, treatment of a tosylhydrazone with a base, cyclization of Af-aminopyridinium oxime mesylates, pyrolysis of pyridyldiazoalkanes, and diazo group (tosyl azide as source of the diazo group) transfer to an active methylene group (e.g., 2-methylpyridines) under basic conditions. 

Diazo Transfer to Ketones. Triisopropylbenzenesulfonyl azide has been used for the direct transfer of the diazo group to ketone enolates under phase transfer conditions to furnish a-diazo ketones (eqs l-4). ... 

One popular method in the synthesis of a-diazo ketones is in the base-catalyzed diazo group transfer reaction of sulfonyl azides with activated dicarbonyl compounds The Regitz Diazo Reaction) While direct diazo transfer to ketone enolates is usually not feasible, a two step deformylative diazo transfer strategy has been employed, whereby a ketone is first... 

Scheme 148). The tosyl group induces ring opening, in preference to hydroxide elimination, to give a triazole. Numerous diazo esters and ketones have been prepared by diazo transfer reactions441 447 4S1 and improved yields obtained using phase-transfer catalysis.452 Diazoalkane formation via retro-1,3-cycloadditions may also be considered as diazo transfer reactions.12... 

The reaction sequence is called the Regitz diazo transfer and requires active methylene compounds as substrates/ Hence it is common to use formic esters to create P-carbonyl compounds from ketones or aldehydes in an aldol reaction. These are used as substrates for deformy-lative diazo transfer reactions in which the diazo group is transferred and the formyl group is removed in one concerted step. The mechanism of the deformylative diazo transfer is shown below. In this case the bulky base NaHMDS ensures deprotonation at the less-hindered a-position of 3, forming the so-called kinetic enolate 13. This enolate is formylated by ethyl formate yielding the P-formyl ketone 14, which is used as substrate in the deformylative diazo transfer. 

Mesyl azide17 is used to transfer the diazo group to acyclic and cyclic ketones (42, 44, and 46) to provide access to corresponding diazo ketones. a-Disubstituted ketone 44 is converted to the diazo ketone 45 via debenzoylation diazo transfer reaction using p-nitrobenzenesufonyl azide in the presence of DBU.18... 

C-Formylation or a-oximation of the highly hindered a-methylene group in the parent ketone is not possible. Direct transfer of the diazo group from tosyl azide under phase transfer conditions has been found unproductive.19 A variety of highly hindered ketones are converted to corresponding diazo ketones with 2,4,6-triisopropylphenylsulfonyl azide under phase-transfer conditions.19 Tetrabutylammonium bromide and 18-crown-6-ether are used as catalysts in these diazo transfer reactions. This method is superior to C-nitrosation followed by diazotization with chloramine. The diazo compounds 66 (55%) and 68 (72%) are obtained using this method. 

It is appropriate to start the discussion on electron-transfer processes to and from diazo compounds with polarographic results on electron additions to a-diazo ketones. For such a reaction one expects the formation of a diazo anion radical, in which the negative charge is localized mainly on the O-atom and to give diazenyl radical character to the diazo group (9.51). 

Although the direct transfer of a diazo-group to certain activated methylene compounds from tosyl azide under phase-transfer conditions has been reported, the method has not found general applicability with simple ketones. However, the replacement of tosyl azide with 2,4,6-tri-isopropylphenylsulphonyl azide now allows this reaction to proceed under phase-transfer conditions in the presence of 18-crown-6. Although the method may not offer significant advantages over established procedures for simple ketones, it is especially useful for cyclic and for hindered ketones. 

Azulene breaks the sulphur-sulphur bond in di(benzothiazol-2-yl) disulphide to give the azulenyl thioether (600). The azidobenzothiazolium salt (601) transfers a diazo-group to phenols with 2-naphthol, for instance, the diazo-ketone (602) is obtained. " ... 

Benzoyl groups are also selectively cleaved during diazo transfer. This method has been used to prepare diazo ketones and diazo esters.142... 

Our retrosynthesis of (—)-kinamycin F (6) is shown in Scheme 3.20 [45]. It was envisioned that (—)-kinamycin F (6) could be prepared from the protected diazofluorene 114 by conversion of the ketone function of 114 to a trans-], 2-diol, followed by deprotection of the acetonide and methoxymethyl ether protecting groups. The diazofluorene 114 was envisioned to arise from diazo transfer to the hydroxyfulvene 115. The cyclopentadiene substructure of 115 was deconstructed by a two-step annulation sequence, to provide the bromoquinone 116 and the p-trimethylsilylmethyl unsaturated ketone 117. The latter two intermediates were prepared from juglone (118) and the silyl ether 119, respectively. 

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