Deformylative diazo-transfer

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... 

Unfortunately, several important classes of a-diazo ketones cannot be prepared in good yield via these standard methods. a -Diazo derivatives of a.p-unsaturated ketones, for example, have previously proved to be particularly difficult to prepare.1113 12 The acylation of diazomethane with a.p-unsaturated acid chlorides and anhydrides is generally not a successful reaction because of the facility of dipolar cycloaddition to conjugated double bonds, which leads in this case to the formation of mixtures of isomeric pyrazolines. Also problematic are diazo transfer reactions involving base-sensitive substrates such as certain a,p-enones and heteroaryl ketones. Finally, the relatively harsh conditions and lack of regioselectivity associated with the thermodynamically controlled Claisen formylation step in the "deformylative" diazo transfer procedure limit the utility of this method when applied to the synthesis of diazo derivatives of many enones and unsymmetrical saturated ketones. 

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. 

In the second step a deformylative diazo transfer occurs. 

This reaction sequence establishes the fifth cyclobutane ring of the ladderane core and is analogous to the reaction from 3 to 5. First P-formyl ketone 26 is formed, which undergoes deformylative diazo transfer in the second step yielding a-diazo ketone 27. The desired pentacyclic carboxylic acid ester 11 is built up via a light-induced IFb rearrangement. 

In the laboratory of K. Fukumoto, the stereoselective total synthesis of (+)-A -capnellene was carried out using an intramolecular Diels-Alder reaction to obtain a tricyclic 5-5-6 system. Since the target molecule was a triquinane, the six-membered ring had to be converted to a five-membered one, a transformation achieved by a Wolff rearrangement. The required a-diazo ketone was prepared via a deformylative diazo transfer reaction and was photolyzed in methanol. The ring-contracted methyl ester was isolated as a 3 1 mixture of separable isomers favoring the a-isomer. 

Formylation followed by the deformylation diazo transfer reaction of 4-chromanone (65) produces 2-diazochromanone(66) in overall yield of 55-60%.24 Diazo transfer from methanesulfonyl azide to dimethylbenzosuberone (67) is achieved via deformylation.25... 

Tricyclodecanone (85) is formylated to 86, then converted to the diazoketone (87) via deformylation diazo transfer reaction using p-toluene sulfonyl azide in the presence of... 

The 3-acetyl group on an indole can be transformed into an a-diazoketone by a deformylative diazo transfer process, involving treatment with base and trifluoroacetylation followed by base-catalyzed reaction with mesylazide (Scheme 136) <90JOC1959>. This methodology has been used in a synthesis of the oxazolyl indole alkaloid pimprinine <9481021 >. 

The direct diazo transfer from sulfonyl azides to methyl ketones is usually not a practicable process, with the exception of the a-diazotization of ketones with 2,4,6-triisopropylbenzenesulfonyl azide under phase-transfer conditions. However, diazomethyl ketones amenable to the Arndt-Eistert reaction can be easily prepared in two steps by a formylation-deformylation diazo-transfer sequence (Regitz procedure ). A related practical method advantageously applies the detrifluoroacetylation of a-trifluoroacetyl ketones tScheme 3 a). The preparation of 2-diazo-1,3-dicarbonyl compounds is commonly best performed with p-toluenesulfonyl azide (TsNg) as the diazo-transfer reagent tScheme 3.9h). > An issue... 

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... 

Diazocycloalkanones with five- to twelve-membered rings can be synthesized by the present procedure in good yields (Table I).4 Diazo transfer with deformylation can also be used for the preparation of bicyclic a-diazo ketones.10,11 A related procedure involving reaction of the sodium salt of an a-(hydroxy methylene)-ketone with p-toluenesulfonyl azide in ethanol has been applied to the synthesis of diazoalkyl ketones, a-diazo aldehydes, and a-diazo carboxylic esters.12... 

Regitz, M., Rueter, J. Reactions of CH-active compounds with azides. XVIII. Synthesis of 2-oxo-1-diazo cycloalkanes by deformylative diazo-group transfer. Chem. Ber. 1968, 101, 1263-1270. 

Regitz, M., Menz, F., Lledhegener, A. Reactions of CH-actIve compounds with azides. XXVIII. Synthesis of a, 3-unsaturated dIazoketones by deformylating diazo group transfer. Liebigs Ann. Chem. 1970, 739, 174-184. 

Diazojasmonate (64) is prepared from the 5-formyl derivative of 63 via a deformylation diazo group transfer reaction with the 4-carboxybenzenesulphonyl derivative.23... 

Diazo transfer to cyclopropenyl ketone (73) is accomplished with diphenylphosphoro ester azide (DPPA). The conversion of tricyclic ketone 75 to the a-formyl derivative followed by the reaction with tosyl azide yields the diazoketone 76 via deformylation.28... 

In addition to previously described syntheses4-5 by diazo group transfer with deformylation,6 2-diazocyclohexanone has been prepared by two variants of this method. In one, the reaction of 2-(hydroxymethylene)cyclohexanone with -toluene-sulfonyl azide is carried out in ether/diethylamine, and an enamine is assumed to be formed as an intermediate 7 in the other, the sodium salt of the hydroxymethylene compound was treated with the lithium salt of p-carboxybenzenesulfonyl azide... 

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