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Clemmensen Reduction

Recent Literature

A reductive coupling of vinyl-substituted aromatic or heteroaromatic and an alkyl bromide or iodide occurs in an aqueous micellar medium in the presence of Zn and a catalytic amount of an Fe(II) salt at rt. The new C-C bond is regiospecifically formed at rt at the β-site of the alkene via a radical process.
H. Pang, Y. Wang, F. Gallou, B. H. Lipshutz, J. Am. Chem. Soc., 2019, 141, 17117-17124.

A nonionic amphiphile (PTS) enables a simple approach to Pd-catalyzed stereoselective sp3-sp2 cross-couplings between alkyl and alkenyl bromides in the presence of zinc powder in water to give coupled products in good yields without prior formation of the organozinc reagents. The reaction is conducted at room temperature and tolerates various functional groups.
A. Krasovskiy, C. Duplais, B. H. Lipshutz, Org. Lett., 2010, 12, 4742-4744.

Zn-Mediated, Pd-Catalyzed Cross-Couplings in Water at Room Temperature Without Prior Formation of Organozinc Reagents
A. Krasovskiy, C. Duplais, B. H. Lipshutz, J. Am. Chem. Soc., 2009, 131, 15592-15593.

In the presence of a Ni catalyst and Zn, various aryl and vinyl bromides are reductively coupled with alkyl bromides in high yields. Under similar conditions, activated aryl chlorides can also be coupled with bromoalkanes. The protocols are highly functional-group tolerant, and the reactions are assembled on the benchtop with no special precautions to exclude air or moisture.
D. A. Everson, B. A. Jones, D. J. Weix, J. Am. Chem. Soc., 2012, 134, 6146-6159.

A room-temperature Ni-catalyzed reductive coupling of aryl bromides with secondary alkyl bromides provides products in good to excellent yields. Slight modification of this protocol allows efficient coupling of activated aryl chlorides with cyclohexyl bromide and aryl bromides with allylic acetate.
S. Wang, Q. Qian, H. Gong, Org. Lett., 2012, 14, 3352-3355.

In a decarboxylative coupling of alkyl N-hydroxyphthalimide esters with aryl iodides in the presence of a nickel catalyst and Zn as reducing agent, no photocatalyst, light, or arylmetal reagent is needed to form alkyl radicals from the carboxylic acid derivative. Methyl, primary, and secondary alkyl groups can all be coupled in good yield.
K. M. M. Huihui, J. A. Caputo, Z. Melchor, A. M. Olivares, A. M. Spiewak, K. A. Johnson, T. A. DiBenedetto, S. Kim, L. K. G. Ackerman, D. J. Weix, J. Am. Chem. Soc., 2016, 138, 5016-5019.

The selectivity challenge associated with cross-coupling of aryl chlorides as inert electrophiles with aryl triflates as reactive ones is overcome using a multimetallic strategy with the appropriate choice of additive. LiCl is essential for effective cross-coupling by accelerating the reduction of Ni(II) to Ni(0) and counteracting autoinhibition of reduction at Zn(0) by Zn(II) salts.
L. Huang, L. K. G. Ackerman, K. Kang, A. M. Parsons, D. J. Weix, J. Am. Chem. Soc., 2019, 141, 10978-10983.

Nickel catalysis accomplishes a decarboxylative cross-coupling of aliphatic acid anhydrides with vinyl triflates or halides. This methodology works well with a broad array of substrates and features abundant functional group tolerance.
H. Chen, S. Sun, X. Liao, Org. Lett., 2019, 21, 3625-3630.

A mild and efficient zinc-mediated decarboxylative alkylation of gem-difluoroalkenes with N-hydroxyphthalimide (NHP) esters provides Z-monofluoroalkenes in good yields. The reaction tolerates a broad range of functional groups and can be easily scaled up.
L. Yu, M.-L. Tang, C.-M. Si, Z. Meng, Y. Liang, J. Han, X. Sun, Org. Lett., 2018, 20, 4579-4583.

S. Wang, Q. Qian, H. Gong, Org. Lett., 2012, 14, 3352-3355.

The efficient olefination from organozinc reagents with aldehydes is exploited in a new synthesis of aryl and alkyl olefins.
J.-X. Wang, Y. Fu, Y. Hu, K. Wang, Synthesis, 2003, 1506-1510.

In the presence of Co(PPh3)2I2, PPh3, water, and zinc powder, the reductive coupling of alkynes with alkenes having an electron-withdrawing substituent proceeded smoothly in acetonitrile to give the corresponding reductive coupling products in fair to excellent yields. Possible mechanisms for this highly regio- and stereoselective ene-yne reaction are proposed.
C.-C. Wang, P.-S. Lin, C.-H. Cheng, J. Am. Chem. Soc., 2002, 124, 9696-9697.

(Ph3P)3RuCl2 is an inexpensive catalyst, that enables a chemoselective reduction of alkyne, ketones, or nitro groups in the presence of Zn/water as a stoichiometric reductant. Depending on the nature of the additive and the temperature, chemoselective reduction of a nitro group in the presence of a ketone or an alkyne was possible.
T. Schabel, C. Belger, B. Plietker, Org. Lett., 2013, 15, 2858-2861.

Ni catalysis enables a transfer hydrogenative alkyne semireduction protocol that can be applied to both internal and terminal alkynes in the presence of formic acid and Zn as the terminal reductants. Both (E)- and (Z)-isomers can be accessed selectively under similar reaction conditions.
E. Richmond, J. Moran, J. Org. Chem., 2015, 80, 6922-6929.

Ni catalysis enables a transfer hydrogenative alkyne semireduction protocol that can be applied to both internal and terminal alkynes in the presence of formic acid and Zn as the terminal reductants. Both (E)- and (Z)-isomers can be accessed selectively under similar reaction conditions.
E. Richmond, J. Moran, J. Org. Chem., 2015, 80, 6922-6929.

A method to produce 1,2-disubstituted olefins in high Z selectivity via reductive cross-coupling of alkyl halides with terminal arylalkynes employs inexpensive and nontoxic catalyst (iron(II) bromide) and reductant (zinc). The substrate scope encompasses primary, secondary, and tertiary alkyl halides, and the reaction tolerates a large number of functional groups.
C. W. Cheung, F. E. Zhurkin, X. Hu, J. Am. Chem. Soc., 2015, 137, 4932-4935.

TiIII catalysis enables a radical addition of unactivated 2° and 3° alkyl chlorides to electron-deficient alkenes, while primary alkyl chlorides or aryl bromides remain untouched. This method offers a new route to C-C bond formation that is complementary to existing protocols.
X. Wu, W. Hao, K.-Y. Ye, B. Jiang, G. Pombar, Z. Song, Song Lin, J. Am. Chem. Soc., 2018, 140, 14836-14843.

The Zn-AcOH reductive system enables a regioselective and rapid ring-opening of donor-acceptor cyclopropanes. 2-(Het)Arylcyclopropane-1,1-diesters as well as donor-acceptor cyclopropanes with other types of electron-withdrawing activating groups provides γ-substituted propyl-1,1-diesters, ketoesters, cyanoesters, cyanoamides, dinitriles, etc., which are not readily accessible with alternative methods.
K. L. Ivanov, E. V. Villemson, G. V. Latyshev, S. I. Bezzubov, A. G. Majouga, M. Ya. Melnikov, E. M. Budynina, J. Org. Chem., 2017, 82, 9537-9549.

Simple and mild indium- and zinc-mediated dehalogenation reactions of vicinal dihalides in an aqueous solvent enable the synthesis of various allenylmethyl aryl ethers and monosubstituted allenes in very good yields.
M.-H. Lin, W.-S. Tsai, L.-Z. Lin, S.-F. Hung, T.-H. Chuang, Y.-J. Su, J. Org. Chem., 2011, 76, 8518-8523.

A Ni-catalyzed carboxylation of benzyl halides with CO2 proceeds under mild conditions at room temperature under atmospheric pressure. The method does not require well-defined and sensitive organometallic reagents and thus is user-friendly and operationally simple.
T. León, A. Correa, R. Martin, J. Am. Chem. Soc., 2013, 135, 1221-1224.

A mild Ni-catalyzed reductive coupling enables the synthesis of alkyl esters from readily available alkyl halides and chloroformates. Unactivated primary and secondary alkyl iodides as well as glycosyl, benzyl, and aminomethyl halides provide products in good yields with high functional group tolerance.
M. Zheng, W. Xue, T. Xue, H. Gong, Org. Lett., 2016, 18, 6152-6155.

A Ni-catalyzed regiodivergent reductive carboxylation of allyl esters with CO2 is mild, user-friendly, and operationally simple. The reaction is characterized by an exquisite selectivity profile that is dictated by the ligand backbone.
T. Moragas, J. Cornella, R. Martin, J. Am. Chem. Soc., 2014, 136, 17702-17705.

A NiCl2(DME)/dppp/Zn system catalyzed an intermolecular insertion of aryl iodides to nitriles to provide variously substituted arylketone derivatives in good yields with tolerance of a wide variety of functional groups.
J.-C. Hsieh, Y.-C. Chen, A.-Y. Cheng, H.-C. Tseng, Org. Lett., 2012, 14, 1282-1285.

Simple nickel complexes of bipyridine and PyBox catalyze the addition of aryl halides to both aromatic and aliphatic aldehydes using zinc metal as the reducing agent. This convenient approach tolerates acidic functional groups that are not compatible with Grignard reactions, yet sterically hindered substrates still couple in high yield.
K. J. Garcia, M. M. Gilbert, D. J. Weix, J. Am. Chem. Soc., 2019, 141, 1823-1827.

A bipyridine-ligated nickel mediates the addition of functionalized aryl halides, a vinyl halide, and a vinyl triflate to epoxides under reducing conditions. For terminal epoxides, the regioselectivity of the reaction depends upon the cocatalyst employed. Iodide cocatalysis results in opening at the less hindered position via an iodohydrin intermediate. Titanocene cocatalysis results in opening at the more hindered position.
Y. Zhao, D. J. Weix, J. Am. Chem. Soc., 2014, 136, 48-51.

Mixing an enone, zinc powder, TMEDA, and an alkyl halide in an aqueous micellar environement containing catalytic amounts of Cu(I) and Au(III) enables conjugate additions in water at room temperature via in situ generated organocopper reagents in good yields. In the presence of Ag(I), the amounts of alkyl halide, Zn, and AuCl3 can be reduced dramatically.
B. H. Lipshutz, S. Huang, W. W. Y. Leong, G. Zhong, N. A. Isley, J. Am. Chem. Soc., 2012, 134, 19985-19988.

The Reformatsky reaction enables the synthesis of medium-chain-length β-hydroxy esters in good yield.
M. Sailer, K. I. Dumichi, J. L. Sorensen, Synthesis, 2015, 47, 79-82.

A Mannich-like zinc-mediated three-component reaction of aromatic halides, amines, and paraformaldehyde allows the straightforward synthesis of a range of functionalized tertiary benzylamines. This procedure involves the in situ formation of arylzinc reagents.
E. Le Gall, A. Decompte, T. Martens, M. Troupel, Synthesis, 2010, 249-254.

A Zn/Cu(OTf)2-mediated addition of alkyl bromides to dehydroalanine (Dha) derivatives including dipeptides and tripeptides provides selective and biocompatible access to various amino acid units in good to high yields in an aqueous medium.
J.-A.  Shin, J. Kim, H. Lee, S. Ha, H.-Y. Lee, J. Org. Chem., 2019, 84, 4558-4565.

A straightforward three-component reaction of preformed aromatic or in situ generated benzylic organozinc reagents with amines and ethyl glyoxylate allows the synthesis of a range of α-amino esters in very good yields. The procedure, which is characterized by its simplicity, allows the concise synthesis of esters bearing a phenylglycine or a phenylalanine scaffold.
C. Haurena, E. Le Gall, S. Sengmany, T. Martens, M. Troupel, J. Org. Chem., 2010, 75, 2645-2650.

A three-component, Ni-catalyzed reductive coupling enables a convergent synthesis of tertiary benzhydryl amines, which are challenging to access by traditional reductive amination methodologies. The condensation of secondary N-trimethylsilyl amines with benzaldehydes provides iminium ions in situ, which react with several distinct classes of organic electrophiles.
C. Heinz, J. P. Lutz, E. M. Simmons, M. M. Miller, W. R. Ewing, A. G. Doyle, J. Am. Chem. Soc., 2018, 140, 2292-2300.

Indium-Catalyzed Henry-Type Reaction of Aldehydes with Bromonitroalkanes
R. G. Soengas, A. M. S. Silva, Synlett, 2012, 23, 873-876.

In acetonitrile as solvent and in the presence of a simple cobalt halide as catalyst, the reduction by zinc dust of a mixture of aldehydes or ketones and allylic acetates affords the corresponding homoallylic alcohols in good yields.
P. Gomes, C. Gosmini, J. Périchon, Synthesis, 2003, 1909-1915.

A rapid and efficient procedure for the solvent-free synthesis of homoallylic and homopropargyl alcohols has been achieved by zinc-mediated Barbier-type reaction of carbonyl compounds at room temperature.
J.-X. Wang, X. Jia, T. Meng, L. Xin, Synthesis, 2005, 2669-2672.

J.-X. Wang, X. Jia, T. Meng, L. Xin, Synthesis, 2005, 2669-2672.

A highly α-regioselective prenylation of imines enables the conversion a wide range of substrates including N- and C-aryl aldimines, N-alkyl aldimines, C-alkyl aldimines, and N- and C-aryl ketimines. The approach uses prenyl bromide as prenyl source and inexpensive zinc as mediator as well as environmentally benign 1,3-dimethyl-2-imidazolidinone (DMI) as solvent.
L.-M. Zhao, S.-Q. Zhang, H.-S. Jin, L.-J. Wan, F. Dou, Org. Lett., 2012, 14, 886-889.

Titanocene dichloride catalyzes the formation of an organozinc species via catalytic activation of allyl halides. Nucleophilic addition to carbonyl derivatives provides the desired homoallylic alcohols in very good yields in short reaction times. This discovery will have wide ranging applicability in the generation of highly reactive organometallic reagents.
L. M. Fleury, B. L. Ashfeld, Org. Lett., 2009, 11, 5670-5673.

Zinc-promoted reduction of 2-(bromomethyl)alkenoates derived from Baylis–Hillman adducts gave (E)-2-methylacrylates in good yield and high stereoselectivity. Synthesis of the male ant pheromone (E)-2,4-dimethyl-2-hexenoic acid was performed using this simple methodology.
L. Fernandes, A. J. Bortoluzzi, M. M. Sa, Tetrahedron, 2004, 60, 9983-9989.

An efficient cobalt-catalyzed reductive coupling reaction of alkyl halides with alkenes bearing electron-withdrawing groups in the presence of water and zinc powder in acetonitrile gave the corresponding Michael-type addition products in high yields. The mechanism is discussed.
P. Shukla, Y.-C. Hsu, C.-H. Cheng, J. Org. Chem., 2006, 71, 655-658.

Cobalt complex/Zn systems effectively catalyze the reductive coupling of activated alkenes with alkynes in the presence of water to give substituted alkenes with very high regio- and stereoselectivity in excellent yields.
H.-T. Chang, T. T. Jayanth, C.-C. Wang, C.-H. Cheng, J. Am. Chem. Soc., 2007, 129, 12032-12041.

A Fe-catalyzed addition of alkyl radicals, formed from the corresponding alkyl halides, to ethynyl ethynylboronic acid pinacol ester provides Z-vinyl boronates in high stereoselectivity. The method works best for tertiary and secondary alkyl iodides.
G. Barzanò, A. Cheseaux, X. Hu, Org. Lett., 2019, 21, 490-493.

A range of polysubstituted allylic zinc chlorides were obtained in good yield using a LiCl-mediated zinc dust insertion in polysubstituted allylic chlorides. A highly diastereoselective synthesis of homoallylic alcohols bearing up to two adjacent quaternary centers by the addition of polysubstituted allylic zinc reagents to carbonyl compounds.
H. Ren, G. Dunet, P. Mayer, P. Knochel, J. Am. Chem. Soc., 2007, 129, 5376-5377.

A dizinc reagent, which acts as an effective bidentate Lewis acid, is easily prepared from diiodomethane and zinc powder.
K. Nomura, K. Oshima, S. Matsubara, Angew. Chem. Int. Ed., 2005, 44, 5860-5863.

Electrochemistry enables smooth Zn-mediated allylic alkylations in aqueous media under air in the presence of a Pd catalyst between a full range of alkyl halides (primary, secondary, and tertiary) and substituted allylic halides.
Y.-L. Lai, J.-M. Huang, Org. Lett., 2017, 19, 2022-2025.

Efficient, simple, cheap, and environmentally benign preparations of cyclopropanes were achieved. One method is based on a 3-exo-trig cyclisation of various electron-deficient 2-iodoethyl-substituted olefins with zinc powder in a mixture of t-butyl alcohol and water, and the other on a 3-exo-tet cyclisation of various 1,3-dihalopropanes with zinc powder in ethanol.
D. Sakuma, H. Togo, Tetrahedron, 2005, 61, 10138-10145.

D. Sakuma, H. Togo, Tetrahedron, 2005, 61, 10138-10145.

A catalytic reductive cocyclooligomerization of enones and three carbene equivalents provides cyclopentanes via a formal [2 + 1 + 1 + 1]-cycloaddition. The reaction is promoted by a (quinox)Ni catalyst and uses CH2Cl2/Zn as the C1 component.
C. M. Farley, Y.-Y. Zhou, N. Banka, C. Uyeda, J. Am. Chem. Soc., 2018, 140, 12710-12714.

The CoI2(dppe)-catalyzed diastereoselective reductive [3 + 2] cycloaddition of allenes and enones gives cyclopentanols in very good yields in the presence of zinc, zinc iodide, and water.
H.-T. Chang, T. T. Jayanth, C.-H. Cheng, J. Am. Chem. Soc., 2007, 129, 4166-4167.

A zinc/indium chloride-mediated pinacol cross-coupling reaction between aldehyde and α,β-unsaturated ketone in aqueous media gives 1,2-diols in good yields with up to 93:7 diastereoselectivity.
Y.-S. Yang, Z.-L. Shen, T.-P. Loh, Org. Lett., 2009, 11, 2213-2215.

A mild and convenient free-radical cyclization of organohalides in the presence of a NiCl2 • DME/Pybox complex as the catalyst and zinc powder in methanol efficiently gives carbo-, oxa-, and azacycles as products in high yields from unsaturated alkyl halides.
H. Kim, C. Lee, Org. Lett., 2011, 13, 2050-2053.

CuI-nanoparticles catalyze a selective synthesis of phenols, anilines, and thiophenols from aryl halides in the absence of both ligands and organic solvents. Anilines were formed selectively with ammonia competing with hydroxylation and thiophenols were generated selectively with sulfur powder after subsequent reduction competing with hydroxylation and amination.
H.-J. Xu, Y.-F. Liang, Z.-Y. Cai, H.-X. Qi, C.-Y. Yang, Y.-S. Feng, J. Org. Chem., 2011, 76, 2296-2300.

(Ph3P)3RuCl2 is an inexpensive catalyst, that enables a chemoselective reduction of alkyne, ketones, or nitro groups in the presence of Zn/water as a stoichiometric reductant. Depending on the nature of the additive and the temperature, chemoselective reduction of a nitro group in the presence of a ketone or an alkyne was possible.
T. Schabel, C. Belger, B. Plietker, Org. Lett., 2013, 15, 2858-2861.

A robust and green protocol for the reduction of functionalized nitroarenes to the corresponding primary amines relies on inexpensive zinc dust in water containing nanomicelles derived from the commercially available designer surfactant TPGS-750-M. This mild process takes place at room temperature and tolerates a wide range of functionalities including common protecting groups.
S. M. Kelly, B. H. Lipshutz, Org. Lett., 2014, 16, 98-101.

An efficient one-pot procedure for the zinc-mediated reduction of nitroarenes in the presence of chloroformates leads to the corresponding N,O-bisprotected hydroxylamines in good yield under ambient conditions in THF-water mixtures. Solvolysis of the bisprotected hydroxylamines with sodium methoxide at room temperature provides access to synthetically versatile N-aryl-N-hydroxy carbamates in excellent yields.
A. Porzelle, M. D. Woodrow, N. C. O. Tomkinson, Synlett, 2009, 798-802.

The combination of zinc powder as reductant and sodium chlorate as oxidant was used to provide an environmentally friendly, effective, and convenient method for the synthesis of aromatic amides in good yields from nitroarenes and aldehydes in a green solvent under atmospheric conditions. Reductants and oxidants with opposing properties can be used together without any adverse effects. In addition, a cooperation seems to improve the yield.
G. Sheng, X. Wu, X. Cai, W. Zhang, Synthesis, 2015, 47, 949-954.

A Ni-catalyzed reductive coupling enables the synthesis of benzonitriles in good yields from aryl (pseudo)halides and 2-methyl-2-phenyl malononitrile (MPMN). MPMN is a bench-stable, carbon-bound electrophilic CN reagent that does not release cyanide under the reaction conditions.
L. R. Mills, J. M. Graham, P. Patel, S. A. L. Rousseaux, J. Am. Chem. Soc., 2019, 141, 19257-19262.

An asymmetric Ni-catalyzed intramolecular reductive Heck reaction of unactivated alkenes tethered to aryl bromides provides various benzene-fused cyclic compounds bearing a quaternary stereogenic center in good to excellent yields and high enantioselectivities. A mechanism involves an enantiodetermining migratory insertion and a subsequent protonation with water or alcoholic solvents.
F. Yang, Y. Jin, C. Wang, Org. Lett., 2019, 21, 6909-6913.

Upon treatment with aqueous sodium hydroxide in DMF, a range of chalcones underwent Michael addition reactions with nitroalkanes. The resulting adducts were reduced in situ with Zn/HCl (aq) to afford substituted Δ1-pyrrolines in high yields after a cyclization.
Y. Liang, D. Dong, Y. Lu, Y. Wang, W. Pan, Y. Chai, Q. Liu, Synthesis, 2006, 3301-3304.

A convenient and highly regioselective method allows the synthesis of 5-methylenepyrrolidinone derivatives from various nitriles and acrylamides via a cobalt-catalyzed reductive coupling reaction. A possible mechanism involves the formation of a cobaltaazacyclopentene intermediate from nitrile and acrylamide, protonation, keto-amide cyclization, and dehydration.
Y.-C. Wong, K. Parthsarathy, C.-H. Cheng, J. Am. Chem. Soc., 2009, 131, 18252-18253.

An efficient and convenient nickel-catalyzed cyclization of 2-iodoanilines with alkynyl aryl ketones gives 2,4-disubstituted quinolines. Naturally occurring quinoline derivatives have been prepared in good yields. The mechanism is discussed.
R. P. Korivi, C.-H. Cheng, J. Org. Chem., 2006, 71, 7079-7082.

Azobenzenes were readily acylated at the 2-position with aldehydes in good yields through a Pd-catalyzed C-H functionalization in the presence of TBHP. The obtained acylated azobenzenes could be efficiently converted into the corresponding indazole derivatives in nearly quantitative yields.
H. Li, P. Li, L. Wang, Org. Lett., 2013, 15, 620-623.

The highly active mixed-ligand catalytic system NiCl2(dppp)/dppf combined with the reducing effect of zerovalent Zn enables a dramatic acceleration of the rate of the neopentylglycolborylation of aryl halides. A diversity of electron-rich and electron-deficient aryl iodides, bromides, and chlorides were efficiently neopentylglycolborylated in very good yields, typically in 1 h or less.
P. Leowanawat, A.-M. Resmerita, C. Moldoveanu, C. Liu, N. Zhang, D. A. Wilson, L. M. Hoang, B. M. Rosen, V. Persec, J. Org. Chem., 2010, 75, 7822-7828.

The mixed-ligand system NiCl2(dppp)/dppf is an effective catalyst for the neopentylglycolborylation of ortho-, meta-, and para-substituted electron-rich and electron-deficient aryl mesylates and tosylates. The addition of Zn powder as a reductant dramatically increases the reaction yield and reduces the reaction time, providing complete conversion in 1-3 h.
D. A. Wilson, C. J. Wilson, C. Moldoveanu, A.-M. Resmerita, P. Corcoran, L. M. Hoang, B. M. Rosen, V. Percec, J. Am. Chem. Soc., 2010, 132, 1800-1801.