N-Chlorosuccinimide (NCS)

N-Chlorosuccinimide (NCS) is a chlorinating and oxidizing agent that is used as source for chlorine in radical reactions and various electrophilic additions.

Recent Literature

N-Halosuccinimides are efficiently activated in trifluoromethanesulfonic acid and BF₃-H₂O, allowing the halogenations of deactivated aromatics. BF₃-H₂O is more economic, easy to prepare, nonoxidizing, and offers sufficiently high acidity.
G. K. S. Prakash, T. Mathew, D. Hoole, P. M. Esteves, Q. Wang, G. Rasul, G. A. Olah, J. Am. Chem. Soc., 2004, 126, 15770-15776.

A mild, efficient, Cu(I)-catalyzed method for the synthesis of aryl chlorides from arylboronic acids is particularly useful for the conversion of electron-deficient arylboronic acids to aryl chlorides, a transformation that is inefficient in the absence of Cu catalysis.
H. Wu, J. Hynes, Jr., Org. Lett., 2010, 12, 1192-1195.

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.

The Lewis base Trip-SMe (Trip = triptycenyl) catalyzes an electrophilic halogenation of unactivated aromatic compounds using N-halosuccinimides (NXS) at ambient temperature in the presence of AgSBF₆ as source of a non-coordinating anion. The π system of the triptycenyl functionality exerts a crucial role for the enhancement of electrophilicity.
Y. Nishii, M. Ikeda, Y. Hayashi, S. Kawauchi, M. Miura, J. Am. Chem. Soc., 2020, 142, 1621-1629.

A highly para-selective halogenation of arenes bearing electron-donating coordinating groups in the presence of a dimidazolium salt rpovides p-haloarenes in good yields. A plausible mechanism for the catalytic reaction is proposed.
J. Chen, X. Xiong, Z. Chen, J. Huang, Synlett, 2015, 26, 2831-2834.

Using cyano as the directing group, a palladium-catalyzed ortho-halogenation (I, Br, Cl) reaction gave good to excellent yields. The method is compatible to arylnitriles with either electron-withdrawing or electron-donating groups. The present method was successfully applied to the synthesis of the precursors of paucifloral F and isopaucifloral F.
B. Du, X. Jiang, P. Sun, J. Org. Chem., 2013, 78, 2786-2791.

Silver carbonate or nickel(II) chloride catalyzes an ortho-C-H bond halogenation of anilides and N-aryl carbamates with N-halosuccinimides to provide 2-haloanilides and carbamates, which may serve as starting materials for the synthesis of pharmaceutically and biologically active compounds.
E. Kianmehr, H. Afaridoun, Synthesis, 2021, 53, 1513-1523.

A mild palladium-catalyzed, regioselective chlorination, bromination, and iodination of arene C-H bonds using N-halosuccinimides as oxidants is described. These transformations can provide products that are complementary to those obtained via conventional electrophilic aromatic substitution reactions.
D. Kalyani, A. R. Dick, W. Q. Anani, M. S. Sanford, Org. Lett., 2006, 8, 2523-2526.

The combination of N-chlorosuccinimide as safe chlorine source with Acr⁺-Mes as the photocatalyst achieves a benzylic C-H bond chlorination under visible light irradiation. This mild and scalable chlorination method worked effectively for electron-deficient substrates. Furthermore, benzylic chlorides could be converted to benzylic ethers smoothly in one-pot by adding sodium methoxide.
M. Xiang, C. Zhou, X.-L. Yang, B. Chen, C.-H. Tung, L.-Z. Wu, J. Org. Chem., 2020, 85, 9080-9087.

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.

Using triethylamine as catalyst in Hunsdiecker reactions with N-halosuccinimides as Br⁺ or I⁺ source, cinnamic acids, and propiolic acids are converted to the corresponding α-halostyrenes and 1-halo-1-alkynes in good isolated yields within 1-5 min.
J. Prakash, S. Roy, J. Org. Chem., 2002, 67, 7861-7864.

Using an efficient visible-light photocatalysis-based method, a mixture of an aldehyde, tert-butyl hydrogen peroxide, and N-chlorosuccinimide afforded an acid chloride in the presence of Ru(bpy)₃Cl₂ as photocatalyst. A subsequent reaction with an amine provided the corresponding amide.
N. Iqbal, E. J. Cho, J. Org. Chem., 2016, 81, 1905-1911.

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 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.

A facile and efficient method for preparing N-tosylhydrazonyl chlorides in good yields is general for a variety of substrates and displays high functional group compatibility.
Q. Zhang, S. Zhang, M. Tang, J. Org. Chem., 2022, 87, 6393-6396.

An operationally simple oxidation-cyanation enables the synthesis of cyanamides using inexpensive and commercially available N-chlorosuccinimide and Zn(CN)₂ as reagents. The method avoids the direct handling of toxic cyanogen halides and is amenable for the cyanation of various primary and secondary amines and aniline derivatives.
N. Kuhl, S. Raval, R. D. Cohen, Org. Lett., 2019, 21, 1268-1272.

Treatment of anilines with N-chlorosuccinimide and 1,8-diazabicyclo[5.4.0]undec-7-ene enables a convenient one-step procedure for the synthesis of symmetrical azobenzenes in good yields in minutes.
A. A. John, Q. Lin, J. Org. Chem., 2017, 82, 9873-9876.

A facile synthesis of hydrazides from N-tosylhydrazones under metal-free conditions was suitable for different substrates and tolerated various substituents. In a subsequent step, a series of indazolones could be prepared from corresponding o-bromobenzohydrazides under mild conditions.
S. Zhang, Q. Zhang, M. Tang, J. Org. Chem., 2022, 87, 3845-3850.

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.

An intramolecular chloroamination of allenes with N-chlorosuccinimide proceeds under mild conditions in the presence of a 1,10-phenanthroline-ligated cationic silver complex and 2,6-lutidine as a base. The reaction tolerates various functional groups. The chloroamination products are useful synthetic intermediates and can be easily transformed into functionalized 3-pyrroline and pyrrole derivatives.
M. Sai, S. Matsubara, Org. Lett., 2011, 13, 4676-4679.

The use of secondary amines and NXS (X = Cl, Br, I) enables an unprecedented copper-catalyzed oxidative aminohalogenation of electron-deficient maleimides. This simple and green multicomponent reaction offers late-stage modification of drug molecules and in situ formation of N-iodoamines for efficient alkene aminoiodination.
X. Zhou, Y. Yao, C. Wang, Y. Xu, W. Zhang, Y. Ma, G. Wu, Org. Lett., 2021, 23, 3669-3673.

A Pd-catalyzed enantioselective aminochlorination of alkenes via a 6-endo cyclization provides convenient access to a wide array of structurally diverse 3-chloropiperidines in good yields with excellent enantioselectivities. Notably, both the sterically bulky chiral pyridinyl-oxazoline (Pyox) ligand and an electrophilic chlorination reagent (NCS) are crucial to the successful reaction.
Y. Zhang, Y. He, T. Liu, W. Guo, Org. Lett., 2023, 25, 2680-2684.

Various 2-aryl-3-arylamino-2-alkenenitriles give N-arylindole-3-carbonitriles in a one-pot manner through NBS- or NCS-mediated halogenation followed by Zn(OAc)₂-catalyzed intramolecular cyclization. The process involves the formation of arylnitrenium ion intermediates, which undergo an electrophilic aromatic substitution to give the cyclized N-arylindoles.
Q. Yan, J. Luo, D. Zhang-Negrerie, H. Li, X. Qi, K. Zhao, J. Org. Chem., 2011, 76, 8690-8697.

A one-pot, cascade reaction sequence of α-azido acrylates and aromatic oximes provides an efficient, straightforward and metal-free synthesis of 3,4,5-trisubstituted isoxazoles under mild reaction conditions via a 1,3-dipolar cycloaddition.
M. Hu, X. He, Z. Niu, Z. Yan, F. Zhou, Y. Shang, Synthesis, 2014, 46, 510-514.

Various primary alcohols were smoothly transformed into 3-substitued isoxazoles in good yields in one pot by successive treatment with PhI(OAc)₂ in the presence of TEMPO, NH₂OH, and then NCS, followed by reaction with alkynes in the presence of Et₃N. The use of PhNHNH₂ instead of NH₂OH and decyl methyl sulfide as additive in a later step enabled the synthesis of pyrazoles.
E. Kobayashi, H. Togo, Synthesis, 2019, 51, 3723-3735.

A divergent and regioselective synthesis of either 3-substituted benzisoxazoles or 2-substituted benzoxazoles from readily accessible ortho-hydroxyaryl N-H ketimines proceeds in two distinct pathways through a common N-Cl imine intermediate: (a) N-O bond formation to form benzisoxazole under anhydrous conditions and (b) NaOCl mediated Beckmann-type rearrangement to form benzoxazole, respectively.
C.-y Chen, T. Andreani, H. Li, Org. Lett., 2011, 13, 6300-6303.

A chlorinative cyclization of aryl alkynoates in the presence of N-chlorosuccinimide (NCS) and Mes-Acr-MeClO₄ as photocatalyst provides 3-chlorocoumarins under visible-light irradiation. The radical initiated reaction proceeds via Cl^- addition, 5-exo-trig spirocyclization and subsequent 1,2-ester migration.
M. Pramanik, A. Mathuri, S. Sau, M. Das, P. Mal, Org. Lett., 2021, 23, 8088-8092.

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 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.

The use of diphenyl selenide as a Lewis base catalyst enables a mild chloroamidation of a wide rand of olefinic substrates including starting materials with acid labile functional groups.
D. W. Tay, I. T. Tsoi, J. C. Er, G. Y. C. Leung, Y.-Y. Yeung, Org. Lett., 2013, 15, 1310-1313.

Structurally diverse sulfonyl chlorides were synthesized via N-chlorosuccinimide chlorosulfonation in good yields from S-alkylisothiourea salts, which can be easily prepared from readily accessible alkyl halides or mesylates and inexpensive thiourea. In large-scale syntheses, the water-soluble byproduct succinimide can be conveniently converted into the starting reagent N-chlorosuccinimide with sodium hypochlorite.
Z. Yang, J. Xu, Synthesis, 2013, 45, 1675-1682.

A smooth oxidation of several thiol derivatives by a combination of N-chlorosuccinimide and dilute hydrochloric acid afforded the corresponding sulfonyl chlorides in good yield.
A. Nishiguchi, K. Maeda, S. Miki, Synthesis, 2006, 4131-4134.

In situ preparation of sulfonyl chlorides from thiols by oxidation with N-chlorosuccinimide (NCS), tetrabutylammonium chloride, and water followed by reaction with amine or sodium azide in the same reaction vessel enables a convenient synthesis of sulfonamides and sulfonyl azides.
H. Veisi, R. Ghorbani-Vaghei, S. Hemmati, J. Mahmoodi, Synlett, 2011, 2315-2320.

A method for the synthesis of N-aroylated sulfoximines involves a manganese oxide promoted C-H activation of methyl arenes to form an aroyl intermediate which then reacts readily with N-chlorosulfoximines to form a series of valuable aroyl sulfoximine derivatives in high yields.
D. L. Priebbenow, C. Bolm, Org. Lett., 2014, 16, 1650-1652.

A one-pot, two-step mechanochemical synthesis of sulfonimidamides requires neither a solvent nor inert conditions. In a mixer mill, sulfinamides are rapidly converted to sulfonimidoyl chlorides by oxidative chlorination with N-chlorosuccinimide (NCS). Subsequent substitutions with amines provides a wide range of diversely substituted sulfonimidamides.
S. Terhorst, T. Jansen, T. Langletz, C. Bolm, Org. Lett., 2022, 24, 4109-4113.