Bromination of aldehydes

Bromination of aldehydes (qv) is more compHcated because bromination can take place on the aldehyde carbon as weU as the a-carbon. Acetals are brominated satisfactorily in cold chloroform solution in the presence of calcium carbonate, which reacts with the hydrogen bromide formed (24). 

Bromination of aldehyde N-heteroarylhydrazones in acetic acid in the presence of sodium acetate sometimes leads to intramolecular cyclization of the initial hydrazonoyl bromides to yield the corresponding cyclized products. For example, bromination of N-(5-pyrazolyl)hydrazones 60 under such conditions afforded pyrazolo[5,l-c][l,2,4]triazoles 61, presumably via the hydrazonoyl bromides 5 (70FRP2075583, 70GEP1810463). Similar treatment of the AMieteroarylhydrazones 62 (63T1587), 63 (67JOC1139), and 64 (86S78) afforded the cyclized products 65-67, respectively. 

Bertelsen S, Halland N, Bachmann S, Marigo M, Braunton A, Jprgensen KA (2005) Organocatalytic asymmetric alpha-bromination of aldehydes and ketones. Chem Commun (Camb) 14 4821 1823 Betancort JM, Barbas CF 3rd (2001) Catalytic direct asymmetric Michael reactions taming naked aldehyde donors. Qrg Lett 3 3737-3740... 

Direct chlorination or bromination of aldehydes can occur at the C of the CHO group or at the C atom next to the CHO group. The latter reaction is much the more important. Reaction of the lower aldehydes with chlorine is highly exothermic and must therefore be carried out with good cooling or in a diluent such as methylene dichloride, chloroform, carbon tetrachloride, water, hydrochloric acid, or preformed chloro aldehyde. 

Organocatalysts also successfully mediate the enantioselective a-bromination of aldehydes. For example, aldehyde (5.102) is brominated with high ee using catalyst (5.103) and bromoquinone (5.115). 

In 2005 Jorgensen and coworkers successfully exploited 33 for the first asymmetric a-bromination of aldehydes in the presence of benzoic acid as the cocatalyst and using 4,4-dibromo-2,6-di-f-butylcyclohexa-2,5-dienone as the brominating agent (Scheme 11.30). The analogous a-iodination reaction... 

SCHEME 13.31. Enantioselective a-bromination of aldehydes via enamine catalysis. 

Three secondary amine catalysts have been utilized in the a-bromination of aldehydes (Scheme 13.31). J0rgensen reported the use of two different chiral pyrrolidine catalysts that generated the S enantiomer of the product, while Mamoka reported the use of a binaphthyl-based catalyst that generated the R enantiomer of the product [67-69]. Both employed the same bromine source, 4,4-dibromo-2,6-di-tcrt-butyl-cyclohexa-2,5-dienone (inset in Scheme 13.31), and both reduced the aldehyde products in situ to facilitate product isolation and analysis. 

J0rgensen and co-workers [67] have also reported the a-bromination of three cyclic ketone substrates (Scheme 13.33). This reaction employed the same C2-symmetric imidazolidine catalyst developed by J0rgensen for the a-chlorination of ketones (Scheme 13.23), and the same bromine source used in the a-bromination of aldehydes (Scheme 13.31). 

On the other hand, however, trimethylsilyl-protected catalyst 18 was suitable for the asymmetric bromination of aldehydes, and the resulting a-bromoaldehydes can be diastereoselectively transformed into the corresponding bromohydrin in one-pot (Scheme 7.31) (54). An additional utility of catalyst 18 was highlighted by application to the development of the direct aminoxylation of aldehydes with an oxoammonium salt generated from 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) by in situ oxidation with benzoyl peroxide, allowing for the highly enantioselective synthesis of stable a-aminoxy aldehydes, which could subsequently be reduced to the corresponding alcohol (55). 

Another method of aldehyde bromination, apart from Riehl s established method (432) from bromine at 20°C, is to use trimethylphenyl-ammonium bromide in tetrahydrofuran solution, prepared by Vorlander and Siebert s method (50). However, the yield of 5-phenylthiazole using this method with thioformamide dissolved in dioxane is only 8% (513). 

Syntheses of a,)3-dihalogenoethers can be achieved in various ways the classical method (37), wherein a current of dry gaseous hydrochloric acid, is made to react in an equimolar mixture of ethanol and aldehyde at 20°C first to form the monochloroether (50% yield) and then by the action of bromine, the dibromoether (80 to 90% yield) can be used. The second and simpler method is the direct bromination of ethylvinylether in a chloroformic or dioxane solution if the product is used directly without purification,... 

As in the acid-catalyzed halogenation of aldehydes and ketones, the reaction rate is independent of the concentration of the halogen chlorination, bromination, and iodination all occur at the same rate. Fomnation of the enolate is rate-detemnining, and, once fomned, the enolate ion reacts rapidly with the halogen. 

From resonance structure (12) it is obvious that a —I—M-substit-uent strongly deactivates the 2-position toward electrophilic substitution, and one would thus expect that monosubstitution occurs exclusively in the 5-position. This has also been found to be the case in the chlorination, bromination, and nitration of 3-thiophenecarboxylic acid. Upon chlorination and bromination a second halogen could be introduced in the 2-position, although further nitration of 5-nitro-3-thiopheneearboxylic acid could not be achieved. Similarly, 3-thiophene aldehyde has been nitrated to 5-nitro-3-thiophene aldehyde, and it is further claimed that 5-bromo-3-thiopheneboronic acid is obtained upon bromination of 3-thiopheneboronic acid. ... 

A particularly common cr-substitution reaction in the laboratory is the halogenation of aldehydes and ketones at their a- positions by reaction with Cl2, Br2, or I2 in acidic solution. Bromine in acetic acid solvent is often used. 

The rx bromination of carbonyl compounds by Br2 in acetic acid is limited tc aldehydes and ketones because acids, esters, and amides don t enolize to a suffi cient extent. Carboxylic acids, however, can be a brominaled by a mixture of Br and PBr3 in the HeJI-Volhard-Zelinskii (HVZ) reaction. 

Carbonyl compounds are in a rapid equilibrium with called keto-enol tautomerism. Although enol tautomers to only a small extent at equilibrium and can t usually be they nevertheless contain a highly nucleophilic double electrophiles. For example, aldehydes and ketones are at the a position by reaction with Cl2, Br2, or I2 in Alpha bromination of carboxylic acids can be similarly... 

N-Bromoamino acids form within seconds after mixing aqueous bromine and the amino acid in dilute aqueous solution (ref. 6), but are not stable end products of the reaction. Thus, Friedman and Morgulis (ref. 7) found that the oxidation of amino acids by hypobromite gives aldehydes and nitriles with one carbon atom less than the original amino acid, ammonia and CO2 (Scheme 1). The proportions of aldehyde and nitrile depend on the basicity of the medium, aldehyde formation being favoured by more basic conditions. 

To investigate the feasibility of employing 3-oxidopyridinium betaines as stabilized 1,3-dipoles in an intramolecular dipolar cycloaddition to construct the hetisine alkaloid core (Scheme 1.8, 77 78), a series of model cycloaddition substrates were prepared. In the first (Scheme 1.9a), an ene-nitrile substrate (i.e., 83) was selected as an activated dipolarophile functionality. Nitrile 66 was subjected to reduction with DIBAL-H, affording aldehyde 79 in 79 % yield. This was followed by reductive amination of aldehyde x with furfurylamine (80) to afford the furan amine 81 in 80 % yield. The ene-nitrile was then readily accessed via palladium-catalyzed cyanation of the enol triflate with KCN, 18-crown-6, and Pd(PPh3)4 in refluxing benzene to provide ene-nitrile 82 in 75 % yield. Finally, bromine-mediated aza-Achmatowicz reaction [44] of 82 then delivered oxidopyridinium betaine 83 in 65 % yield. 

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