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Synthesis of α-chlorocarboxylic acids and derivatives

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A hypervalent iodine reagent-based α-carbonyl dihalogenation of diazoacetate derivatives with either iodobenzene dichloride or iodotoluene difluoride results in gem-dichlorination or gem-difluorination products, respectively. The reaction is catalyzed by either Lewis acid or Lewis base and proceeds rapidly and chemoselectively to the desired gem-difunctionalized products in very good yield.
J. Tao, R. Tran, G. K. Murphy, J. Am. Chem. Soc., 2013, 135, 16312-16315.

A photochemical Wolff rearrangement, trapping of the generated ketene with a chiral Lewis base catalyst, subsequent enantioselective α-chlorination, and a final nucleophilic displacement of the bound catalyst provides chiral α-chlorinated carboxylic acid esters. The obtained products were successfully utilized for stereospecific nucleophilic displacement reactions with N- and S-nucleophiles.
D. Weinzierl, M. Piringer, P. Zebrowski, L. Stockhammer, M. Waser, Org. Lett., 2023, 25, 3126-3130.

By rendering the α-position of amides electrophilic through a mild and chemoselective umpolung transformation, a broad range of widely available oxygen, nitrogen, sulfur, and halogen nucleophiles can be used to generate α-functionalized amides.
C. R. GonÁalves, M. Lemmerer, C. J. Teskey, P. Adler, D. Kaiser, B. Maryasin, L. GonzŠlez, N. Maulide, J. Am. Chem. Soc., 2019, 141, 18437-18443.

Stable zwitterionic compounds catalyze a synthesis of α,α-dihalo-N-arylacetamides from β-oxo amides and N-halosuccinimides as the halogen sources. The corresponding α,α-dihalo-N-arylacetamides were obtained in very good yields under mild conditions without strong base or acid.
Z. Ke, Y.-P. Lam, K.-S. Chan, Y.-Y. Yeung, Org. Lett., 2020, 22, 7353-73572.

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 Bšcklund 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.

A Rh(III)-catalyzed cascade arylation and chlorination of α-diazocarbonyl compounds with arylboronic acids and N-chlorosuccinimide exhibits excellent functional group tolerance on the organoboron and the diazo reagents. Functionalized α-aryl-α-chlorocarbonyl compounds were obtained in good yields.
F.-N. Ng, Y.-F. Lau, Z. Zhou, W.-Y. Yu, Org. Lett., 2015, 17, 1676-1679.

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.


Treatment of widely available isocyanates with monohalolithium and dihalolithium carbenoids provides α-halo- and α,α-dihaloacetamide derivatives. While monohalolithium carbenoids can be prepared by a smooth lithium-halogen exchange, the preparation of the corresponding dihalo compounds proved to be highly dependent on the base used to realize the deprotonation, with lithium 2,2,6,6-tetramethylpiperidine emerging as optimal.
V. Pace, L. Castoldi, A. D. Mamuye, W. Holzer, Synthesis, 2014, 46, 2897-2909.

Asymmetric hydration of α,α-dichloro aldehydes and α-halo enals via a NHC-catalyzed redox process gives enantioenriched α-chloro and α-fluoro carboxylic acids. The reaction allows the installation of an α-deuterium to give α-deutero α-halo acids using D2O as the deuteron source.
H. U. Vora, T. Rovis, J. Am. Chem. Soc., 2010, 132, 2860-2861.

Synthesis of β-Hydroxy-α-haloesters through Super Silyl Ester Directed Syn-Selective Aldol Reaction
S. Oda, H. Yamamoto, Org. Lett., 2013, 15, 6030-6033.