Synthesis of alkyl chlorides

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A practical nucleophilic substitution of alcohols furnishes alkyl chlorides, bromides, and iodides under stereochemical inversion in the presence of diethylcyclopropenone as a simple Lewis base organocatalyst and benzoyl chloride as a reagent. Moreover, acetyl chloride has been used as a stoichiometric promotor in an invertive S_N-type transformation for the first time.
T. Stach, J. Dräger, P. H. Huy, Org. Lett., 2018, 20, 2980-2983.

Substoichiometric amounts of thiourea additives mediate the halogenation of alcohols under mild conditions. In the the absence of thiourea, oxidation of the alcohol is observed, whereas the substrate can be recovered when excess thiourea is used. Both bromination and chlorination were highly efficient for primary, secondary, tertiary, and benzyl alcohols and tolerate a broad range of functional groups.
A. R. Mohite, R. S. Phatake, P. Dubey, M. Agbaria, A. I. Shames, N. G. Lemcoff, O. Reany, J. Org. Chem., 2020, 85, 12901-12911.

A catalytic Appel reaction using a P(III)/P(V) redox cycling at very low catalyst loadings, hexachloroacetone as the halogen source and phenylsilane as the terminal reductant converted alcohols and epoxides containing a wide variety of functional groups to the respective chlorides and dichlorides in very good yields and with high enantiospecificities for inversion.
J. Tönjes, L. Kell, T. Werner, Org. Lett., 2023, 25, 9114-9118.

The use of chloro tropylium chloride enables a rapid generation of alkyl halides and acyl chlorides from alcohols and carboxylic acids under very mild reaction conditions via aromatic tropylium cation activation. This reactions demonstrate the synthetic potential of tropylium cations in promoting chemical transformations.
T. V. Nguyen, A. Bekensir, Org. Lett., 2014, 16, 1720-1723.

The use of a tetraethylammonium halide in the presences of [Et₂NSF₂]BF₄ (XtalFluor-E) enables efficient chlorination and bromination reactions of a wide range of alcohols. Iodination reactions are also possible albeit in lower yields. As opposed to Appel reactions, water-soluble side products are generated, that facilitate work-up.
M.-F. Pouliot, O. Mahé, J.-D. Hamel, J. Desroches, J.-F. Paquin, Org. Lett., 2012, 14, 5428-5431.

In a catalytic system for the chlorination of alcohols under Appel conditions, benzotrichloride is used as a cheap and readily available chlorinating agent in combination with trioctylphosphane as the catalyst and phenylsilane as the terminal reductant under solvent-free conditions. In total, 27 different primary, secondary, and tertiary alkyl chlorides were synthesized in good yields.
L. Longwitz, S. Jopp, T. Werner, J. Org. Chem., 2019, 84, 7863-7870.

The combination of Ph₃P and easily available 1,2-dihaloethanes (XCH₂CH₂X; X = Cl, Br, or I), was very effective for a mild deoxygenative halogenation of alcohols and aldehydes. The use of (EtO)₃P instead of Ph₃P enables a convenient purification process, as the byproduct (EtO)₃P═O could be removed by aqueous washing. A dehydroxy-fluorination proceeds well in the presence of ICH₂CH₂I and CsF as fluoride source in DMF.
J. Chen, J.-H. Lin, J.-C. Xiao, Org. Lett., 2018, 20, 3061-3064.

The use of α,α-dichlorodiphenylmethane as chlorinating agent and FeCl₃ as the catalyst enables a chlorination of alcohols and carboxylic acids to their corresponding alkyl and acyl chlorides in high yields under mild conditions. In the presence of LiBr or LiI, the respective alkyl bromides and iodides can be generated.
C.-H. Lee, S.-M. Lee, B.-H. Min, D.-S. Kim, C.-H. Jun, Org. Lett., 2018, 20, 2468-2471.

Activation of primary aliphatic alcohols with triphosgene and triethylamine mixtures afforded either alkyl chloride or diethylcarbamate products driven by sterics. The reaction conditions were unexceptionally mild and readily tolerated by a wide range of sensitive functionalities.
C. E. Ayala, A. Villalpando, A. L. Nguyen, G. T. McCandless, R. Kartika, Org. Lett., 2012, 14, 3676-3679.

Unactivated secondary and α-branched primary aliphatic alcohols have been transformed into their corresponding alkyl chlorides in high yields in the presence of triphosgene and pyridine in dichloromethane at reflux. These mild chlorination conditions are stereospecific and well tolerated by numerous sensitive functionalities. Furthermore, no nuisance waste products are generated in the course of the reactions.
A. Villalpando, C. E. Ayala, C. B. Watson, R. Kartika, J. Org. Chem., 2013, 78, 3989-3996.

Ionic liquids [bmim][X] (X = Cl, Br, I, OAc, SCN) are highly efficient reagents for nucleophilic substitution reactions of sulfonate esters derived from primary and secondary alcohols. The newly developed protocol is very environmentally attractive because the reactions use stoichiometric amounts of ionic liquids as sole reagents without additional solvents and activating reagents. Moreover, these ionic liquids can be readily recycled.
Y. Liu, Y. Xu, S. H. Jung, J. Chae, Synlett, 2012, 23, 2663-2666.

Nucleophilic fluorination using CsF or alkali metal fluorides was completed in short reaction time in the presence of [bmim][BF₄] affording the desired products without any byproducts. Facile nucleophilic substitutions such as halogenations, acetoxylation, nitrilation, and alkoxylations in the presence of ionic liquids provided the desired products in good yields.
D. W. Kim, C. E. Song, D. Y. Chi, J. Org. Chem., 2003, 68, 4281-4285.

A user-friendly exchange reaction enables an efficient preparation of alkyl chlorides in excellent yields from secondary alkyl sulfonates by using benzyltributylammonium chloride in acetone. The reaction tolerates functionalized, base-sensitive and hindered secondary alkyl sulfonates.
G. Cahiez, N. Lefèvre, M. Poizat, A. Moyeux, Synthesis, 2013, 45, 231-236.

The preparation of alkenyl halides of any length from inexpensive starting reagents is reported. Standard organic transformations were used to prepare straight-chain α-olefin halides in excellent overall yields with no detectable olefin isomerization and full recovery of any unreacted starting material.
T. W. Baughman, J. C. Sworen, K. B. Wagener, Tetrahedron, 2004, 60, 10943-10948.

The reaction of alcohols and β-amino alcohols with 2,4,6-trichloro[1,3,5]triazine and N,N-dimethylformamide in methylene chloride at room temperature gave the corresponding chlorides, and with NaBr gave the corresponding bromides in high yields.
L. de Luca, G. Giacomelli, A. Porcheddu, Org. Lett., 2002, 4, 553-555.

The counteranions of CuCl₂ functioned as a chloride source in a reductive chlorination of carboxylic acids in the presence of a gallium(III) catalyst and a hydrosiloxane.
N. Sakai, T. Nakajima, S. Yoneda, T. Konakahara, Y. Ogiwara, J. Org. Chem., 2014, 79, 10619-10623.

An efficient, catalytic Hunsdiecker reaction of aliphatic carboxylic acids affords the corresponding chlorodecarboxylation products in high yields under mild conditions in the presence of t-butyl hypochlorite and Ag(Phen)₂OTf as catalyst. The reaction exhibits remarkable functional group compatibility.
Z. Wang, L. Zhu, F. Yin, Z. Su, Z. Li, C. Li, J. Am. Chem. Soc., 2012, 134, 4258-4263.

A mild and metal-free method for the chlorodeboronation of organotrifluoroborates using trichloroisocyanuric acid (TCICA) converts aryl-, heteroaryl-, alkenyl-, alkynyl-, and alkyltrifluoroborates into the corresponding chlorinated products in good yields. This method tolerates a broad range of functional groups.
G. A. Molander, L. N. Cavalcanti, J. Org. Chem., 2011, 76, 7195-7203.

An efficient InCl₃-catalyzed reaction of secondary, tertiary and benzylic alcohols with chlorodimethylsilane in the presence of benzil gave the corresponding organic chlorides under mild conditions. In the absence of benzil, the reducing products through dehydroxyhydration were obtained.
M. Yasuda, S. Yamasaki, Y. Onishi, A. Baba, J. Am. Chem. Soc., 2004, 126, 7186-7187.

An indium(III) hydroxide-catalyzed reaction of carbonyls and chlorodimethylsilane afforded the corresponding deoxygenative chlorination products. Ester, nitro, cyano, or halogen groups were not affected during the reaction course. Typical Lewis acids such as TiCl₄, AlCl₃, and BF₃·OEt₂ showed no catalytic activity. The reaction mechanism is discussed.
Y. Onishi, D. Ogawa, M. Yasuda, A. Baba, J. Am. Chem. Soc., 2002, 124, 13690-13691.

Group 5 and 6 metal chlorides were found as very efficient catalysts for acylative cleavage of ethers. Compared with conventional Lewis acid catalysts, group 5 and 6 metal chlorides showed better results in the catalytic C-O bond cleavage.
Q. Guo, T. Miyaji, R. Hara, B. Shen, T. Takahashi, Tetrahedron, 2002, 58, 7327-7334.

The combination of methanesulfonic acid and inorganic halide salts (CaCl₂, LiBr, LiI) mediates hydrochlorinations, hydrobrominations, and hydroiodinations of unactivated alkenes in acetic acid. This approach uses readily available and inexpensive reagents to provide alkyl halides in very good yields. An example of deuteriochlorination using deuterated acetic acid as solvent is also demonstrated.
X. Bertrand, P. Paquin, L. Chabaud, J.-F. Paquin, Synthesis, 2022, 54, 1413-1421.

A silver-catalyzed chlorination of benzylic, tertiary, and secondary C(sp³)-H bonds proceeded with as low as 0.2 mol % catalyst loading at room temperature under air atmosphere with synthetically useful functional group compatibility.
J. Ozawa, M. Kanai, Org. Lett., 2017, 19, 1430-1433.

Dual photoredox/cobalt catalysis enables a hydrohalogenation of aliphatic alkenes with collidine·HX salts to provide highly functionalized alkyl halides. The catalysts convert a proton and a halide anion to a nucleophilic hydrogen radical equivalent and an electrophilic halogen radical equivalent and deliver them to an alkene moiety. This protocol enables the introduction of F, Cl, Br, or I.
S. Shitutani, K. Nagao, H. Ohmiya, J. Am. Chem. Soc., 2024, 146, 4375-4379.

SnCl₄ and TiCl₄ as Lewis acids and chloride nucleophiles enable selective and regiodivergent openings of unsymmetrical phenonium ions at either the substituted internal position (SnCl₄) or unsubstituted terminal position (TiCl₄). These reactions are highly selective, stereospecific, operationally simple, and proceed in good to excellent yields.
S. Xu, H. M. Holst, S. B. McGuire, N. J. Race, J. Am. Chem. Soc., 2020, 142, 8090-8096.

A silver-catalyzed ring-opening chlorination of cycloalkanols enables a regioselective, efficient, and pratical approach to carbonyl-containing alkyl chlorides with good yields under mild conditions. The chlorinated products are readily transformed into other useful synthetic intermediates and drugs.
F.-Q. Huang, J. Xie, J.-Guo Sun, Y.-W. Wang, X. Dong, L-W. Qi, B. Zhang, Org. Lett., 2016, 18, 684-687.

Halofluorination of alkenes in the presence of trihaloisocyanuric acids and HF•pyridine results in the formation of vicinal halofluoroalkanes in good yields. The reaction is regioselective leading to Markovnikov-oriented products and the halofluorinated adducts follow anti-addition in the case of cyclohexene and 1-methylcyclohexene.
L. T. C. Crespo, R. da S. Ribeiro, M. S. S. de Mattos, P. M. Esteves, Synthesis, 2010, 2379-2382.

In a photoredox vicinal chlorotrifluoromethylation in the presence of Ru(Phen)₃Cl₂ as catalyst, various terminal and internal alkenes can be transformed to their vicinal chlorotrifluoromethylated derivatives using CF₃SO₂Cl as a source for CF₃ radicals and chloride ions.
S. H. Oh, Y. R. Malpani, N. Ha, Y.-S. Jung, S. B. Han, Org. Lett., 2014, 16, 1310-1313.

A highly regioselective chlorothiolation of alkenes with sulfonyl chlorides is compatible with a variety of functional groups and can be scaled up to the gram scale. The employment of readily available reactants and mild reaction conditions makes this process very practical.
J. Wei, S. Liang, L. Jiang, Y. Mumtaz, Y.-b. Yi, J. Org. Chem., 2020, 85, 977-984.

A highly efficient deoxygenative haloboration of aldehydes provides secondary α-haloboronates. Even tertiary α-haloboronates can be readily prepared via the same strategy with ketones. Furthermore, enantioselective chloroboration of carbonyls was successfully achieved to give chiral secondary or tertiary α-chloroboronates.
D. Wang, J. Zhou, Z. Hu, T. Xu, J. Am. Chem. Soc., 2022, 144, 22870-22876.

The use of nBuLi as nucleophilic reagent to attack a boron atom in gem-diborylalkanes to form a tetracoordinate boron species, followed by reaction with readily accessible electrophilic halogen reagents (NCS and NBS) provides α-chloroboronates and α-bromoboronates. The reaction is transition-metal-free and features a broad substrate scope.
S. Liao, J. Liang, C. Li, N. Chen, K. Yang, J. Chen, Q. Song, Org. Lett., 2023, 25, 2938-2933.

Related

A sequential installation of a carbenoid and a hydride into a carbonyl provides halomethyl alkyl derivatives with uniformly high yields and chemocontrol. The tactic is flexible and is not limited to carbenoids. Also, diverse carbanion-like species can act as nucleophiles.
M. Miele, A. Citarella, T. Langer, E. Urban, M. Zehl, W. Holzer, L. Ielo, V. Pace, Org. Lett., 2020, 22, 7629-7634.