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Synthesis of substituted alkanes


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A slow and regular addition of primary alkyl and aryl Grignard reagent enables a high-yielding copper-catalyzed alkylation with alkyl bromides in the absence of ligands. With secondary and tertiary alkyl Grignard reagents, the presence of benzonitrile as a very simple ligand is sufficent. A copper-catalyzed alkylation of organolithium compounds was also studied.
G. Cahiez, O. Gager, J. Buendia, Synlett, 2010, 299-303.

A Pd-NHC catalytic system has been developed, that is capable of cross-coupling various unactivated, primary bromides and alkyl organozinc reagents in high yield at room temperature.
N. Hadei, E. A. B. Kantchev, C. J. O'Brien, M. G. Organ, Org. Lett., 2005, 7, 3805-3807.

The use of 2% Pd2(dba)3/8% PCyp3/NMI in THF/NMP at 80°C achieves the cross-coupling of a range of β-hydrogen-containing primary alkyl iodides, bromides, chlorides, and tosylates with an array of alkyl-, alkenyl-, and arylzinc halides. This method tolerates various functional groups.
J. Zhou, G. C. Fu, J. Am. Chem. Soc., 2003, 125, 12527-12530.

A cobalt-catalyzed cross-coupling of alkyl (pseudo)halides with alkyl Grignard reagents proceeds via an ionic mechanism in the presence of 1,3-butadiene as a ligand precursor and LiI in high yields and high selectivities. Sterically congested quaternary carbon centers could be constructed by using tertiary alkyl Grignard reagents. This reaction is compatible with various functional groups.
T. Iwasaki, H. Takagawa, S. P. Singh, H. Kuniyasu, N. Kambe, J. Am. Chem. Soc., 2013, 135, 9604-9607.

A combination of 20% CoCl2 and chelating nitrogen ligands catalyzes a mild cobalt-catalyzed Negishi-type cross-coupling of various functionalized dialkylzinc reagents with primary and secondary alkyl iodides in acetonitrile. The method allows the construction of molecules with sensitive functional groups at room temperature.
F. H. Lutter, L. Grokenberger, M. Benz, P. Knochel, Org. Lett., 2020, 22, 2941-2945.

Suzuki cross-couplings of alkyl bromides that contain β hydrogens run under surprisingly mild conditions (room temperature). This work represents a significant expansion in the scope of the Suzuki reaction.
M. R. Netherton, C. Dai, K. Neuschütz, G. C. Fu, J. Am. Chem. Soc., 2001, 123, 10099-10100.

Pd(acac)2 catalyzes a cross-coupling reaction of alkyl tosylates and bromides with Grignard reagents in the presence of 1,3-butadiene in good yields. This reaction proceeds efficiently at room temperature using primary and secondary alkyl and aryl Grignard reagents.
J. Terao, Y. Naitoh, H. Kuniyasu, N. Kambe, Chem. Lett., 2003, 890-891.

A dual photo/nickel catalytic manifold performs cross-coupling via a complementary sequence involving free radical generation, radical sorting via selective binding to a Ni(II) center, and bimolecular homolytic substitution (SH2) at a high-valent nickel-alkyl complex. This catalytic manifold enables the cross-coupling of diverse aliphatic carboxylic acids to generate valuable C(sp3)-C(sp3)-products.
A. V. Tsymbal, L. D. Bizzini, D. W. C. MacMillan, J. Am. Chem. Soc., 2022, 144, 21278-21286.

Primary amines can be converted to 1,2-dialkyldiazenes by treatment with O-nosylhydroxylamines in the presence of atmospheric oxygen. Denitrogenation of the diazenes with an iridium photocatalyst then produces a new C-C bond. The reaction tolerates a broad range of functionalities, including heteroaromatics and unprotected alcohols and acids.
K. A. Steiniger, M. C. Lamb, T. H. Lambert, J. Am. Chem. Soc., 2023, 145, 11524-11529.

An alkyl-alkyl cross-coupling of organoboranes, formed in situ via hydroboration of alkenes, and Katritzky alkylpyridinium salts has been developed. Under the mild reaction conditions, a broad range of functional groups, including protic groups, is tolerated. The strategy is also effective with alkynes, enabling a C(sp3)-C(sp2) cross-coupling.
K. M. Baker, D. L. Baca, S. Plunkett, M. E. Daneker, M. P. Watson, Org. Lett., 2019, 21, 9738-9741.

A CoCl2/LiI/1,3-pentadiene catalytic system smoothly cleaved aliphatic C-F bonds under mild conditions and achieved alkyl-alkyl cross-coupling even when sterically hindered tertiary alkyl Grignard reagents were employed. Since alkyl fluorides are inert toward many conditions, the use of the present reaction enables a new multistep synthetic route to construct carbon frameworks.
T. Iwasaki, K. Yamashita, H. Kuniyasu, N. Kambe, Org. Lett., 2017, 19, 3691-3694.

In a practical catalytic cross-coupling of secondary alkyl electrophiles with secondary and primary alkyl nucleophiles under Cu catalysis, the use of TMEDA and LiOMe is critical for the success of the reaction. This cross-coupling reaction occurs via an SN2 mechanism with inversion of configuration.
C.-T. Yang, Z.-Q. Zhang, J. Liang, J.-H. Liu, X.-Y. Lu, H.-H. Chen, L. Liu, J. Am. Chem. Soc., 2012, 134, 11124-11127.

A cobalt-catalyzed decarboxylative methylation of primary and secondary aliphatic redox-active esters with trimethylaluminum provides methylated products without redox fluctuation under mild conditions. The use of triethylaluminum enables a decarboxylative ethylation.
Z.-Z. Wang, G.-Z. Wang, B. Zhao, R. Shang, Y. Fu, Synlett, 2020, 31, 1221-1225.

A reductive coupling of a 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.

The combination of a Ni catalyst with TDAE as sacrificial reductant enables a dicarbofunctionalization of a broad range of olefins with two electrophilic carbon sources under reductive conditions via simultaneous formation of one C(sp3)-C(sp3) and one C(sp3)-C(sp2) bond with exquisite selectivity.
W. Shu, A. García-Domínguez, M. T. Quirós, R. Mondal, D. J. Cárdenas, C. Nevado, J. Am. Chem. Soc., 2019, 141, 13812-13821.

A Ni-catalyzed regioselective alkylarylation of vinylarenes with alkyl halides and arylzinc reagents provides 1,1-diarylalkanes. The reaction proceeds well with primary, secondary and tertiary alkyl halides, and electronically diverse arylzinc reagents.
S. KC, R. K. Dhungana, B. Shrestha, S. Thapa, N. Khanal, P. Basnet, R. W. Lebrun, R. Giri, J. Am. Chem. Soc., 2018, 140, 9801-9805.

A nickel-catalyzed Negishi cross-coupling of alkyl halides, including unactivated tertiary halides, with the boron-stabilized organozinc reagent BpinCH2ZnI provides versatile organoboron products with high functional-group tolerance.
P. Guo, H. Jin, J. Han, L. Xu, P. Li, M. Zhan, Org. Lett., 2023, 25, 1246-1251.

In stereoconvergent, arylamine-directed alkyl-alkyl Suzuki cross-coupling reactions, structure-enantioselectivity studies are consistent with the nitrogen, not the aromatic ring, serving as the primary site of coordination of the arylamine to the catalyst.
Z. Lu, A. Wilsily, G. C. Fu, J. Am. Chem. Soc., 2011, 133, 8154-8157.

Carbamates and sulfonamides serve as directing groups in Ni-catalyzed asymmetric Suzuki reactions for cross-coupling of unactivated alkyl electrophiles. Racemic secondary bromides and chlorides undergo C-C bond formation in a stereoconvergent process in good ee at room temperature in the presence of a commercially available Ni complex and chiral ligand.
A. Wilsily, F. Tramutola, N. A. Owston, G. C. Fu, J. Am. Chem. Soc., 2012, 134, 5794-5797.

A general alkylamination of vinylarenes and an unprecedented diastereoselective anti-carboamination of unsaturated esters provide amines and unnatural β-amino acids. This alkylamination is enabled by an iron catalyst and alkyl diacyl peroxides, that serve as both alkylating reagents and internal oxidizing agents.
B. Qian, S. Chen, T. Wang, X. Zhang, H. Bao, J. Am. Chem. Soc., 2017, 139, 13076-13082.

Screening of a 15-member library of phosphaadamantane ligands has allowed for the rapid determination of the most suitable ligand for facilitating Suzuki-type couplings of alkyl halides or tosylates containing β-hydrogens with either boronic acids or alkylboranes.
T. Brenstrum, D. A. Gerristma, G. M. Adjabeng, C. S. Frampton, J. Britten, A. J. Robertson, J. McNulty, A. Capretta, J. Org. Chem., 2004, 69, 7635-7639.

A rhodium-catalyzed methylenation-hydrogenation cascade process allows the homologation of carbonyl compounds to alkanes in high yields.
H. Lebel, C. Ladjel, J. Org. Chem., 2005, 70, 10159-10161.

An electrochemical reductive functionalization of alkenes with strategic choice of reagents and reaction conditions enables an addition of two distinct electrophiles in a highly chemo- and regioselective fashion. Intermolecular carboformylation, anti-Markovnikov hydroalkylation, and carbocarboxylation of alkenes can be achieved via electroreductive generation of alkyl radical and carbanion intermediates.
W. Zhang, S. Lin, J. Am. Chem. Soc., 2020, 142, 19844-19849.

A nickel-catalyzed reductive cross-coupling reaction of aryl cyclopropyl ketones with easily accessible unactivated alkyl bromides provides γ-alkyl-substituted ketones. Initial mechanistic studies revealed that the reaction proceeds via radical cleavage of the alkyl bromide.
N. Cui, T. Lin, Y.-E. Wang, J. Wu, Y. Han, X. Xu, F. Xue, D. Xiong, P. J. Walsh, J. Mao, Org. Lett., 2022, 24, 3987-3992.

By using synergetic photoredox/copper catalysis, a visible-light-induced, enantioselective carbocyanation of 1,3-dienes with carboxylic acid derivatives and trimethylsilyl cyanide is achieved under mild and neutral conditions. A diverse range of chiral allyl cyanides is produced in generally good efficiency and with high enantioselectivity from bench-stable and user-safe chemicals.
F.-D. Lu, L. Q. Lu, G.-F. He, J.-C. Bai, W.-J. Xiao, J. Am. Chem. Soc., 2021, 143, 4168-4173.

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.

An asymmetric nickel-catalyzed borylative coupling of terminal alkenes with nonactivated alkyl halides provides a broad range of chiral boronic esters with high regio- and enantioselectivity under mild reaction conditions. The success of this three-component strategy is ascribed to the application of a chiral anionic bisoxazoline ligand.
Z. Li, H. Shi, X. Chen, L. Peng, Y. Li, G. Yin, J. Am. Chem. Soc., 2023, 145, 13603-13614.

A transition-metal-free reaction of alkyl sulfonylhydrazones with alkyl boronic acids provides C(sp3)-rich and sterically hindered alkyl boron reagents in a practical and modular manner. The reaction offers broad generality and functional group tolerance.
Y. Yang, J. Tsien, A. B. David, J. M. E. Hughes, R. R. Merchant, T. Qin, J. Am. Chem. Soc., 2021, 143, 471-480.

The reaction of 1,1-bis(pinacolboronate) esters with alkyl halides promoted by metal alkoxides provides organoboronate compounds via alkoxide-induced deborylation and generation of a boron-stabilized carbanion.
K. Hong, X. Liu, J. P. Morken, J. Am. Chem. Soc., 2014, 136, 10581-10584.

A titanocene complex catalyzes a regioselective carbosilylation of terminal alkenes and 2,3-disubstituted 1,3-butadienes with alkyl halides and chlorotrialkylsilanes efficiently at 0°C in THF in the presence of Grignard reagents. Terminal alkenes afford addition products in good yields, whereas in reaction with dienes, alkyl and silyl units are introduced at the 1- and 4-positions to provide allylsilanes.
S. Nii, J. Terao, N. Kambe, J. Org. Chem., 2000, 65, 5291-5297.

A light-induced, Ru-catalyzed three-component alkyl-fluorination of olefins under mild reaction conditions provides a wide range of fluorinated products with good functional group tolerance. A key advantage of this photoredox reaction is the use of generic alkyl groups and nucleophilic fluoride.
W. Deng, W. Feng, Y. Li, H. Bao, Org. Lett., 2018, 20, 4245-4249.