Synthesis of α-chloroketones and α-chloroaldehydes

Recent Literature

The use of the commercially available trichloromethanesulfonyl chloride enables an efficient α-chlorination of aldehydes, including a catalytic asymmetric version, under very mild reaction conditions. This chlorinating reagent facilitates workup and purification of the product, and minimizes the formation of toxic, chlorinated organic waste.
C. Jimeno, L. Cao, P. Renaud, J. Org. Chem., 2016, 81, 1251-1255.

A fluorous (S)-pyrrolidine-thiourea bifunctional organocatalyst shows good activity and enantioselectivity for direct α-chlorination of aldehydes using N-chlorosuccinimide (NCS) as the chlorine source. The catalyst can be recovered from the reaction mixture by fluorous solid-phase extraction with excellent purity for direct reuse.
L. Wang, C. Cai, D. P. Curran, W. Zhang, Synlett, 2010, 433-436.

A direct organocatalytic enantioselective α-chlorination of aldehydes proceeds for a series of different aldehydes with NCS as the chlorine source using easily available catalysts such as L-proline amide and (2R,5R)-diphenylpyrrolidine. The α-chloro aldehydes are obtained in very good yield and high enantioselectivity.
N. Halland, A. Braunton, S. Bachmann, M. Marigo, K. A. Jorgensen, J. Am. Chem. Soc., 2004, 126, 4790-4791.

A general, rapid, and scalable method for the preparation of α-halogenated ketones using N-alkenoxypyridinium salts as substrates and quaternary ammonium salts as halogen sources offers mild reaction conditions, excellent functional group tolerance, and a wide substrate scope.
N. Wu, M. Jiang, A. Cao, L. Huang, X. Bo, Z. Xu, J. Org. Chem., 2023, 88, 17368-17380.

Aliphatic and aromatic ketones can be directly converted into their corresponding α-chloroketone acetals in very good yields using iodobenzene dichloride in ethylene glycol in the presence of 4 Å molecular sieves at room temperature.
J. Yu, C. Zhang, Synthesis, 2009, 2324-2328.

Methyl ketones can undergo dichlorination to afford α,α-dichloroketones in good yields with precise control of the chemoselectivity. Enabled by the I₂-dimethyl sulfoxide catalytic system, in which hydrochloric acid only acts as a nucleophilic Cl- donor, this straightforward dichlorination reaction is safe and operator-friendly and has high atomic economy and good functional-group tolerance.
J.-C. Xiang, J.-W. Wang, P. Yuan, J.-T. Ma, A.-X. Wu, Z.-X. Liao, J. Org. Chem., 2022, 87, 15101-15113.

HTIB mediates an oxidative transposition of vinyl halides to provide α-halo ketones as useful and polyvalent synthetic precursors. Insights into the mechanism and an enantioselective transformation are reported too.
A. Jobin-Des Lauriers, C. Y. Legault, Org. Lett., 2016, 18, 108-111.

Selective oxyhalogenations of alkynes were achieved in water under very mild conditions in the presence of inexpensive halogenating reagents, such as N-bromosuccinimide and N-chlorosuccinimde, and FI-750-M as amphiphile. No halogenation at the aromatic rings was detected. Reaction medium and catalyst can be recycled.
L. Finck, J. Brals, B. Pavuluri, F. Gallou, S. Handa, J. Org. Chem., 2018, 83, 7366-7372.

An electrochemical oxydihalogenation of alkynes enables the preparation of α,α-dihaloketones using CHCl₃, CH₂Cl₂, ClCH₂CH₂Cl, and CH₂Br₂ as the halogen source at room temperature.
X. Meng, Y. Zhang, J. Luo, F. Wang, X. Cao, S. Huang, Org. Lett., 2020, 22, 1169-1174.

The combination of dimethyl sulfoxide, HCl, and HBr enables a mild, efficient, and practical geminal heterodihalogenation of methyl ketones. This convenient method might be useful for the assembly of bromochloromethyl groups in drug discovery.
J.-f. Zhou, D.-m. Tang, M. Bian, Synlett, 2020, 31, 1430-1434.

In a direct conversion of primary and secondary alcohols into the corresponding α-chloro aldehydes and α-chloro ketones, trichloroisocyanuric acid serves both as stoichiometric oxidant and α-halogenating reagent. For primary alcohols, TEMPO has to be added as an oxidation catalyst, and for the transformation of secondary alcohols MeOH as an additive is essential to promote chlorination of the intermediary ketones.
Y. Jing, C. G. Daniliuc, A. Studer, Org. Lett., 2014, 16, 4932.

The use of enamine catalysis has provided a new organocatalytic strategy for the enantioselective chlorination of aldehydes to generate α-chloro aldehydes, an important chiral synthon for chemical and medicinal agent synthesis.
M. P. Brochu, S. P. Brown, D. W. C. MacMillan, J. Am. Chem. Soc., 2004, 126, 4108-4109.

Catalytic enantioselective fluorination and chlorination reactions of carbonyl compounds were achieved with high enantioselectivity by the use of a dbfox-Ni^II complex.
N. Shibata, J. Kohno, K. Takai, T. Ishimaru, S. Nakamura, T. Toru, S. Kanemasa, Angew. Chem. Int. Ed., 2005, 44, 4204-4207.

The regio- and stereoselective aminochlorination of α,β-unsaturated ketones with N,N-dichloro-p-toluenesulfonamide (4-TsNCl₂) and CuOTf as catalyst provides an easy access to vicinal haloamino ketones, with excellent regioselectivity and good yields. Aromatic and aliphatic enones give opposite regioselectivity.
D. Chen, C. Timmons, S. Chao, G. Li, Eur. J. Org. Chem., 2004, 3097-3101.

Poly{[4-(hydroxy)(tosyloxy)iodo]styrene} was efficient in the halotosyloxylation reaction of alkynes with iodine or NBS or NCS. The polymer reagent could be regenerated and reused.
J.-M. Chen, X. Huang, Synthesis, 2004, 1557-1558.

A mild and rapid formal electrophilic α-azidation of 1,3-dicarbonyl compounds using commercially available Bu₄NN₃ as the azide source is mediated by (diacetoxyiodo)benzene. The reaction conditions are Bäcklund to the ones employed in analogous halogenations with Et₄NX (X = Cl, Br, I).
M. J. Galligan, R. Akula, H. Ibrahim, Org. Lett., 2014, 16, 600-603.

Trimethylchlorosilane was used as chlorine source for the α-chlorination of 1,3-dicarbonyl compounds with phenyliodonium diacetate as oxidant at room temperature to provide α-monochlorinated products in good yield. TMSBr could be used to form monobromide products.
S. Chong, Y. Su, L. Wu, W. Zhang, J. Ma, X. Chen, D. Huang, K.-H. Wang, Y. Hu, Synthesis, 2016, 48, 1359-1370.

Efficient oxidative α-halogenation of 1,3-dicarbonyl compounds has been achieved by employing a system comprising of sub-stoichiometric amounts of TiX₄ (X = Cl, Br) in the presence of environmentally benign hydrogen peroxide (H₂O₂) or peracetic acid (MeCO₃H) as the oxidants. The end point of the reaction is accompanied by a sharp colour change.
R. Akula, M. J. Galligan, H. Ibrahim, Synthesis, 2011, 347-351.

The use of Oxone/aluminum trichloride mixture enables an α,α-dichlorination of β-keto esters and 1,3-diketones in aqueous medium. The dichlorinated compounds have been produced in one step, high yields, and short reaction times.
V. Giannopoulos, N. Katsoulakis, I. Smonou, Synthesis, 2022, 54, 2457-2463.

α-Diazo-β-dicarbonyl compounds were chlorinated using (dichloro)iodobenzene and an activating catalyst. Acyclic diazocarbonyls reacted faster than cyclics, and β-diketones were much faster to react than β-keto esters or β-diesters.
K. E. Coffrey, G. K. Murphy, Synlett, 2015, 26, 1003-1007.

Related

Au-catalyzed hydration of haloalkynes enables an atom-economical synthesis of a wide range of α-halomethyl ketones as an alternative to conventional α-halogenation of ketones. Other outstanding features include excellent yields from both alkyl- and aryl-substituted haloalkynes and wide functional group tolerance.
L. Xie, Y. Wu, W. Yi, L. Zhu, J. Xiang, W. He, J. Org. Chem., 2013, 78, 9190-9191.

A practical one-step method for the preparation of α-chloroketones from readily available, inexpensive phenylacetic acid derivatives utilizes the unique reactivity of an intermediate Mg-enolate dianion, which displays selectivity for the carbonyl carbon of chloromethyl carbonyl electrophiles. Decarboxylation of the intermediate occurs spontaneously during the reaction quench.
M. J. Zacuto, R. F. Dunn, M. Figus, J. Org. Chem., 2014, 79, 8917-8925.

A chemoselective addition of halomethyllithium carbenoids to Weinreb amides at -78°C enables a straightforward synthesis of variously functionalized α,β-unsaturated α'-haloketones. The exceptional stability of the intermediate furnished by the N-methoxy group does not allow a 2nd addition of LiCH₂X and thus prevents from formation of carbinols.
V. Pace, L. Castoldi, W. Holzer, J. Org. Chem., 2013, 78, 7764-7770.