A-bromo ketones with aldehydes

The methods previously used to obtain single aldol products (or their dehydrated derivatives) from reactants where several aldol products are possible8 include the reaction of bromozinc enolates, from a-bromo-ketones, with aldehydes 9 the reaction of bromomagnesium enolates, from either a-bromoketones or from ketones and bromomagnesium... 

The aldol-type reaction of a-bromo ketones with aldehydes, mediated by CrCh, has been studied by Dubois and coworkers. The reaction is carried out by addition of (241 equation 80) to a solution of (242) and CrCh in THF. The reaction proceeds with high levels of syn selectivity with bulky bromo ketones (241), independent of the substrate aldehyde used (Table 11, entries 1-6). However, the reaction is stereorandom with bromoacetophenone (entry 7) and selectively anti with 2-bromocyclohexanone (entry 8). No explanation of the stereoselectivity has been advanced, but the reaction is believed not to proceed via a simple chromium enolate since no condensation reaction is obtained by addition of (242) to a solution of (241) and CrCh. Moreover, Nozaki and coworkershave demonstrated that chro-mium(II) chloride treatment of 1-bromocyclododecanone followed by treatment with either methyl iodide or TMS-Cl produces only cyclododecanone. 

An intramolecular analogue of the aforementioned reaction has been encountered during the Darzens condensation of a-bromo ketones with two equivalents of an aryl aldehyde (94TL9367). The intermediate a-keto oxiranes engage in aldol additions to the second aldehyde equivalent before cyclizing to the five-membered heterocyclic ring (Scheme 27). 

Likewise a-keto and a-aldehydo esters have been prepared by the reaction of potassium phenylacetate with a-bromo ketones or aldehydes by an 18-crown-6 catalyzed displacement reaction in acetonitrile or benzene solution. These compounds could be isolated after short reaction times, or they could be converted on continued heating to 2(5H)furanones, the product of intramolecular aldol condensation and... 

The use of -methylmorpholine causes considerable self-condensation of the ketone, and may be used to induce this reaction. However, JV-ethylpiperidine gives very high conversion into the stannous enolate, which may then take part with aldehydes in an eryt ro-selective aldol reaction. The stannous enolate may also be prepared in high yield by the reduction of the a-bromo-ketone with metallic tin, and if it is generated in this way it still gives high eryr ro-selectivity in reactions with aldehydes. ... 

The conversion of the intermediate bromo aldehyde to the dioxane proceeds readily owing to a favorable equilibrium position. However, the equilibrium for the reaction of the bromo ketone with the diol is unfavorable and requires removal of the by-product, water. This is done under mild conditions using... 

Asymmetric induction using catalytic amounts of quininium or A-methyl-ephedrinium salts for the Darzen s reaction of aldehydes and ketones with phenacyl halides and chloromethylsulphones produces oxiranes of low optical purity [3, 24, 25]. The chiral catalyst appears to have little more effect than non-chiral catalysts (Section 12.1). Similarly, the catalysed reaction of sodium cyanide with a-bromo-ketones produces epoxynitriles of only low optical purity [3]. The claimed 67% ee for the phenyloxirane derived from the reaction of benzaldehyde with trimethylsul-phonium iodide under basic conditions [26] in the presence of A,A-dimethyle-phedrinium chloride was later retracted [27] the product was contaminated with the 2-methyl-3-phenyloxirane from the degradation of the catalyst. 

P-Hydroxy ketones. a-Bromo ketones undergo a Reformatsky-type reaction with aldehydes which is promoted by R3Sb but which is only possible with iodine as catalyst. The function of I2 is probably for a Br/I exchange, since I2 is not required in reactions with a-iodo ketones. 

Table 11 Reaction of a-Bromo Ketones (241) with Aldehydes (242) using CiCh (equation 80) ...

Tin(n) triflate mediated cross aldol reactions between a-bromo ketone (124 Scheme 56) and aldehydes afford iyn-a-bromo-P-hydroxy ketones (125) with high stereoselectivity. The resulting halohydrins are converted to the corresponding (Z)-2,3-epoxy ketones (126). Chiral aldehyde (127) reacts with lithium alkynide (128) followed by mesylation and base treatment to give chirally pure ( )-epoxide (129). The initially formed alkoxide anion should be trapped in situ by mesylation, otherwise partial racemization takes place owing to benzoate scrambling (Scheme 56). ... 

Treatment of the epoxy suifones obtained thus with MgBr2 produces a-bromo ketones or a-bromo aldehyde.This conversion can be applied to stereoselective preparations of a-bromo methyl ketones from cyclohexanone derivatives. Thus, treatment of 17-P-hydroxy-5-a-androstan-3-one (134) with 1-chloroethyl phenyl sulfone provides an epoxy sulfone (135), which is cleaved by MgBr2 to give a 99 1 mixture of 3-ace l-3-bromoandrostanes (136 and 137 equation 33), whereas similar treatment of 17-3-hydroxy-5-3-androstan-3-one (138) gives a 4 96 mixture of 3-acetyl-3-bromoandrostanes (139 and 140 equation 34). These facts may reflect the steric course of the initial attack of the a-sulfonyl carbanion on the carbonyl face. 

M. Harmata and co-workers successfully synthesized racemic sterpurene using an intermolecular [4+3] cycloaddition to prepare the key quasi-Favorskii rearrangement precursor. The tricyclic bridgehead a-bromo ketone was first treated with LAH at 0 °C to get the corresponding secondary alcohol. Treatment of this alcohol with KH triggered the expected ring-contraction to afford the 5-6-4 fused tricyclic aldehyde, which was then reduced to the primary alcohol with LAH. 

Another approach, originally discovered by Nozaki and coworkers, is available for the generation of aluminum enolates from a-halo ketones (Scheme 6.26) [46]. This method involves reduction of a bromo group with Bu3SnAlEt2 subsequent reaction with aldehydes or ketones under mild conditions gave aldol adducts in acceptable yields. The aldol step is accelerated by participation of catalytic amounts of PdlPPhj),.. 

Selenolates such as Na2Se, NaSeH, PhSeNa, etc., and tellurolates such as NapTe, NaTeH, PhTeNa, etc., are excellent nucleophiles and can reduce a variety of functional groups by nucleophilic attack or single electron-transfer. On treatment with alkali metal selenolates (or amine salts of HpSe and PhSeH), reduction or reductive selenation of ketones and aldehydes, C=C reduction of a,/l-unsaturated compounds, and reduction of nitrogen compounds such as nitro compounds occur successfully [118, 176]. Compared with these selenolate anions, the corresponding tellurium compounds are highly reactive not only toward the same substrates but also toward halo compounds such as a-bromo ketones and vic-dibromoalkanes [46, 52, 177]. 

The reaction of 2-aminothiazole and 2-aminobenzothiazole with 2-benzoyl-2-bromoacetate has been employed in the preparation of several fused imidazole systems <89JHC1875>. a-Bromo ketones attack the ring nitrogen of 2-aminothiazoles to give the salts (160). The same type of reaction takes place with ethylbromoacetate (Scheme 39). Basihcation of (160) affords the imines (I6I) which are intermediates in the synthesis of imidazo[2,l-h]thiazoles <89JCS(P1)643>. On the other hand, when an a-bromo aldehyde is made to react with 2-aminothiazoles, the salt (162) is formed directly leading to (163) after basification. 

Oxidations using dimethyl sulfoxide activated by various reagents began with discoveries by Komblum and co-workers that primary tosylates and certain a-bromo ketones could be converted into aldehydes and glycoxals, respectively, by treatment with dimethyl sulfoxide as the oxidising agent. This was followed by the discovery several years later by Pfitzner and Moffatt that alcohols could be oxidised to carbonyl compounds with dimethyl sulfoxide, dicyclohexylcarbodiimide (DCC) and phosphoric acid at room temperature.2 Eventually the method developed by Swern and co-workers, involving activation of dimethyl sulfoxide with oxalyl chloride, came to be the most synthetically useful and widely applied of these mild oxidation procedures.3-6... 

Treatment of a-iodo ketone and aldehyde with an equimolar amount of Et3B yielded the Reformatsky type adduct in the absence of PhaSnH (Scheme 21), unlike ot-bromo ketone as shown in Scheme 15 [22], Ethyl radical abstracts iodine to pro-duee carbonylmethyl radical, which would be trapped by EtsB to give the corresponding boron enolate and regenerate an ethyl radical. The boron enolate reacts with aldehyde to afford the adduct. The three-component coupling reaction of tert-butyl iodide, methyl vinyl ketone and benzaldehyde proceeded to give the corresponding adduct 38, with contamination by the ethyl radical addition product 39. The order of stability of carbon-centered radical is carbonylmethyl radical > Bu > Pr > Ef > Me . 

Finally, a-bromo ketones, like x-bromo aldehydes, can also be obtained by way of the isolated enol acetates 703 exactly the calculated amount of bromine is added, with ice-cooling, to the acetate in CC14 and the mixture is then mixed with dry methanol and set aside for two days. This method is valuable when the enol acetate required is readily accessible. A ketone R RCHCOCH3 can afford two isomeric enol acetates A or B which of them is formed may depend on the natures of R and R but also on the reaction conditions. 

Rieke and Uhm have published more details concerning the preparation of a highly reactive zinc by reduction of anhydrous zinc chloride with potassium metal in refluxing THF (5, 753). The Reformatsky reaction of ethyl a-bromo-acetate with various aldehydes and ketones can be conducted in ether at 20° when this reactive form of zinc is used. Yields of hydroxy esters are usually greater than 95%. 

Oxidation Reactions. a-Bromo ketones are dehydrobromi-nated to produce enones in low to good yields, especially when the products are phenolic, by treatment with stoichiometric Pd(Phs P)4 in hot benzene. Primary and secondary alcohols are oxidized in the presence of PhBr, base (NaH or K2CO3) and Pd(PhsP)4 as catalyst to the corresponding aldehydes or ketones. The practical advantages of these methods to alternative strategies have yet to be demonstrated. 

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