Hydroxymethylene derivatives

By converting the A" -3-ketone into its 2-hydroxymethylene derivative, selective ozonolysis to the 2,3-seco-2,3-dicarboxylic acid can be carried out in the presence of the A -double bond. Weisenborn has thus prepared A-nortesto-sterone and A-norprogesterone. In the latter case, selective formyla-tion at C-2 was achieved by first reducing the 20-ketone to the 20-ol (4). 

Interposition of a methylene group between the phenyl ring and the heterocycle leads to the benzyldiami nopyrimidines, a class of compounds notable for their antibacterial activity. Condensation of hydrocinnamate 54 with ethyl formate leads to the hydroxymethylene derivative 55. In this case, too, the heterocyclic ring is formed by reaction with guanidine. This sequence probably involves initial addition-elimination to the forniyl carbon to form 56 cyclization in this case involves simple amide formation. Tautomerization then affords the hydroxy derivative 57. This is converted to tetroxoprim (58) by first... 

The enolates of ketones can be acylated by esters and other acylating agents. The products of these reactions are [Tdicarbonyl compounds, which are rather acidic and can be alkylated by the procedures described in Section 1.2. Reaction of ketone enolates with formate esters gives a P-ketoaldehyde. As these compounds exist in the enol form, they are referred to as hydroxymethylene derivatives. Entries 1 and 2 in Scheme 2.16 are examples. Product formation is under thermodynamic control so the structure of the product can be predicted on the basis of the stability of the various possible product anions. 

In the next step of the sequence, the authors sought to introduce a hydroxy-methylene substituent at the unsubstituted 7-position of the enone. This bond construction can be carried out by conducting a Baylis-Hillman reaction with formaldehyde. In this instance, the authors used a modification of the Baylis-Hillman reaction which involves the use of a Lewis acid to activate the enone [26]. Under these conditions, the enone 42 is treated with excess paraformaldehyde in the presence of triethylphosphine (1 equiv), lanthanum triflate (5 mol%), and triethanolamine (50 mol%). It is proposed that the lanthanum triflate forms a complex with the triethanolamine. This complex is able to activate the enone toward 1,4-addition of the nucleophilic catalysts (here, triethylphosphine). In the absence of triethanolamine, the Lewis acid catalyst undergoes nonproductive complexation with the nucleophilic catalyst, leading to diminution of catalysis. Under these conditions, the hydroxymethylene derivative 37 was formed in 70 % yield. In the next step of the sequence, the authors sought to conduct a stereoselective epoxidation of the allylic... 

The preparation of dithianes from enamines by reaction with trimethylene dithiotosylate (propane-1,3-dithiol di-p-toluenesulfonate) has been applied with enamines derived from oholostan 3 one, aceto-acetic ester, and phenylacetone.6 7 Reactions of trimethylene dithiotosylate with hydroxymethylene derivatives of ketones also give rise to dithianes thus the hydroxymethylene derivative of cholest-4-en-3-one can be converted to 2,2-(trimethylenedithio)cholest-4-en-3-one. 1,3-Dithiolanes are obtained in a similar manner by reaction of ethylene dithiotosylate1 with the appropriately activated substrate.5,7... 

The HC1 generated in this reaction destroys one equivalent of diazomethane. This can be avoided by including a base, such as triethylamine, to neutralize the acid.74 Cyclic z-diazoketones, which are not available from acyl chlorides, can be prepared by reaction of an enolate equivalent with a sulfonyl azide. This reaction is called diazo transfer 5 Various arenesulfonyl azides76 and methanesulfonyl azide77 are used most frequently. Several types of compounds can act as the carbon nucleophile. These include the anion of the hydroxymethylene derivative of the ketone78 or the dialkylaminomethylene derivative of... 

The reaction of a-bromoacetals with trimethylsilylenolates catalyzed by titanium tetrachloride provides /3-alkoxy-y-bromoketones, which are useful furan precursors (Scheme 33) (75CL527). A new synthesis of acylfurans is exemplified by the formation of the 3-acetyl derivative (146) by heating the brdmoalkene (145) (78JOC4596). 2,2-Dimethyl-3(2//)-furanone (148) has been synthesized from 3-hydroxy-3-methylbutan-2-one treatment with sodium hydride and ethyl formate gave the hydroxymethylene derivative (147), which was cyclized and dehydrated to the furanone (148) with hydrochloric acid (Scheme 34) (71TL4891). O... 

The carbanion formed when chromanone is treated with a base such as sodium methoxide reacts with ethyl formate to give the 3-hydroxymethylene derivative (S95) and such compounds have been used as intermediates (72JHC1341,70IJC203). When treated with isopentyl nitrite, chromanones usually give the 3-isonitroso derivative but this reaction occasionally behaves anomalously without obvious reason. For example, 7-methoxychromanone is readily converted into its 3-isonitroso derivative (596), but with 7-hydroxychromanone the reaction fails <77HC(31)207). 

The chiral heterocycle (81) is deprotonated by trityl sodium and the resulting anion trapped with methyl formate giving the hydroxymethylene derivative (82) <92JCS(P1)517>. 

A 1,2-carbonyl transposition sequence based on the Woodward dithioacetalisa-tion reaction was used to relocate a carbonyl group in 95.1 [Scheme 2.95] to the adjacent position in 95 6.190 A total of 6 steps were required in which the key step was the dithioacetalisation of the a-hydroxymethylene derivative 95 2. After reduction of the carbonyl group, the dithiane was hydrolysed to the a-acetoxy ketone whence dissolving metal reduction removed the acetate function. 

Piers et have completed the synthesis of eremophilenolide (347), using the hydroxymethylene derivative of (336). Thus, dehydrogenation of this compound gave the cross-conjugated keto-aldehyde (348) which was converted in four... 

Carbonyl compounds that do not react with the reagent can be activated by conversion into an enamine or an hydroxymethylene derivative prior to the reaction. Thus cyclohexanone is converted into 2,2-trimethylenedithiocyclohexanone by way of the... 

The second synthesis of septicine used as starting material ethyl homovera-trate, which was formylated to the a-hydroxymethylene derivative (24). Controlled reduction of (24) with sodium borohydride gave mainly the desired )5-hydroxyester, which was converted into the chloride and condensed with ethyl 2-pyrrolidinyl acetate to yield the diester (25). Dieckmann cyclisation of... 

One of the reactions used most extensively to acylate ketones employs formate esters to produce a-formyl or hydroxymethylene ketones. Earlier work has been reviewed this section summarizes the important reactions of these products, particularly in alicyclic chemistry. As an illustration, the conversion of 2-methylcyclohexanone (157) into its 6-hydroxymethylene derivative and the subsequent chemistry of that compound are shown in Scheme 63. Such ketones normally undergo formylation at the less... 

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