A-bromo carbonyl compounds

The reaction of an a-halo carbonyl compound with zinc, tin, or indium together with an aldehyde in water gave a direct cross-aldol reaction product (Eq. 8.90).226,227 A direct Reformatsky-type reaction occurred when an aromatic aldehyde reacted with an a-bromo ester in water mediated by zinc in low yields. Recently, it was found that such a reaction mediated by indium was successful and was promoted by son-ication (Eq. 8.91).228 The combination of BiCl3-Al,229 CdCl2-Sm,230 and Zn-Et3B-Eb0231 is also an effective mediator. Bismuth metal, upon activation by zinc fluoride, effected the crossed aldol reaction between a-bromo carbonyl compounds and aldehydes in aqueous media. The reaction was found to be regiospecific and syn-diastereoselective (Eq. 8.92).232... 

The Gabriel-Cromwell reaction of amines with chiral c/., 3-unsaturated a-bromo carbonyl compounds was exploited for the synthesis of aziridine-2-carboxylic acid derivatives. 79 This procedure was optimized for a solid support synthesis in which the peptide resin was acylated with 2,3-dibromopropanoic acid active ester in the presence of 3 equivalents of NMM to produce directly on resin the a-bromoacrylamide for the addition of amines to produce the aziridine ring. 80 ... 

Dimethyl acetylenedicarboxylate (DMAD) reacts with a-chloro carbonyl compounds to form 2//-pyrans as the major products and furans 19 as minor components (Equation 11) <2005JOC8204>. Under the same reaction conditions the equivalent a-bromo carbonyl compounds and DMAD react to form only the furans 19 <2005JOC8204>. 

One-pot Method The catalyst A, B (0.2 equiv) or C, D (0.1 equiv) was added to a solution of the a-bromo carbonyl compound (1.0 equiv), the alkene (1.2 equiv), and Cs2C03 (1.2 equiv) in MeCN (0.25 M) and stirred at 80 °C for 24 h. The reaction was quenched with aqueous HCl (1 M) and extracted three times with Et20 or EtOAc. The combined organic phases were washed with a saturated aqueous solution of NaHC03, dried (MgS04), and concentrated under reduced pressure. The residue was purified by flash column chromatography. 

With a-bromo carbonyl compounds, substitution leads to two electrophilic groups on neighbouring carbon atoms. Each has a low-energy empty orbital, Jt from C=0 and a from C-Br (this is what makes them electrophilic), and these can combine to form a molecular LUMO (Jt + a ) lower in energy than either. Nucleophilic attack will occur easily where this new orbital has its largest coefficients, shown in orange on the diagram. 

We can use an enolatc for one reagent but the other will have to have umpolung. This is not a very serious kind of umpolung as an a-bromo carbonyl compound will do the job nicely if we select our enol(ate) equivalent carefully. In Chapter 26 we suggested enamines for this job. The synthesis becomes ... 

Lithio-2-(phenylsulfonyl)oxiranes 362 (prepared by deprotonation of compounds 361) reacted with different electrophiles to give the expected products 363 which, by treatment with MgBr2 OEt2, afforded a-bromo carbonyl compounds 364 (Scheme 95)534-537. 

In the absence of carbonyl compounds, allylic bromides treated with Cp2TiCl underwent the expected dimerization process, which has been exploited for the synthesis of symmetrical terpenoids such as squalene and [1-onocerin [82]. In contrast, non-allylic olefinic iodoethers and a-bromo carbonyl compounds underwent 5-exo cyclization to the corresponding tetrahy-drofuran derivatives [83,84]. 

Aldol reactions Enolates are formed from a-bromo carbonyl compounds on reaction with germanium (prepared in situ from Gel and K). The aldol reaction is jyn-selective. 

Zinc(O) is capable of reducing alkyl halides. The interplay of the reductive action of zinc and the ability of aluminum Lewis acids to activate the carbonyl group enabled effective generation of aluminum enolates from a-bromo carbonyl compounds (Scheme 6.25) [45]. This method is convenient for aldol cyclization reaction, producing macrolactones in moderate to high yields. Note that the possibility of a zinc enolate, rather than the aluminum enolate, promoting the actual reactions could not be excluded. 

Later the same group reported that a-bromo carbonyl compounds could be added to terminal alkenes [108] or coupled with allylgallium [109] through intermolec-ular radical reactions still initiated with triethylborane. Another remarkable example was reported by Miyabe et al. They described the indium [110] or triethylborane [111]-mediated radical addition of alkyl iodide to electron deficient C=N bond and C=C bond in water (Eq. 10). 

As stated in the previous section, an extensive effort has been devoted to the development of intermolecular catalytic enantioselective a-alkylation reactions of aldehydes. In 2008, Nicewicz and MacMillan [147] accomplished the direct asymmetric a-alkylation of aldehydes with a-bromo carbonyl compounds (Scheme 8.36) via merging two types of catalysis, photoredox [148] and organo-catalysis. A variety of aliphatic aldehydes and electron-deficient a-bromo carbonyl compounds can be used, affording a-alkylated aldehydes in excellent yields (up to 93%) with outstanding enantioselectivities (up to 99% ee) in a relatively short reaction time. Furthermore, this alkylation protocol represents a technically simple... 

Ru(bpy)3] + as a photoredox catalyst providing an electron-deficient alkyl radical from the starting a-bromo carbonyl compound was used, along with an... 

Keshavarz and Albadi used an azide-supported reagent in a macroporous polymer for developing click chemistry [91]. The reaction involves the nucleophihc addition of the supported azide to a-bromo carbonyl compounds (ketones, amides, or esters) followed by the 1,3-dipolar cycloaddition of the preformed azide to an alkyne catalyzed by a polymer-supported... 

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