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Categories: C-C Bond Formation > Oxygen-containing molecules > Carbonyl compounds

Synthesis of Carbonyl Compounds by Alkylation or Condensation


Name Reactions

Acetoacetic Ester Synthesis

Mannich Reaction

Recent Literature

A highly efficient α alkylation of ketones with primary alcohols by the use of a recyclable palladium catalyst has been demonstrated.
M. S. Kwon, N. Kim, S. H. Seo, I. S. Park, R. K. Cheedrala, J. Park, Angew. Chem., 2005, 117, 7073-7075.

An efficient dehydrogenative-dehydrative cross-coupling of primary and secondary alcohols catalyzed by a recently developed proton responsive ruthenium phosphine-pyridone complex enables a green route to functionalized ketones. Moreover, selective tandem double alkylation of isopropanol is achieved by sequential addition of different alcohols.
A. R. Sahoo, G. Lalitha, V. Murugesh, C. Bruneau, G. V. M. Sharma, S. Suresh, M. Achard, J. Org. Chem., 2017, 82, 10727-10731.

A phosphine-free pincer ruthenium(III) catalyzed β-alkylation of secondary alcohols with primary and secondary alcohols provides α-alkylated ketones. This transformation is environmentally benign and atom efficient with H2O and H2 as the only byproducts.
D. Bhattacharyya, B. K. Sarmah, S. Nandi, H. K. Srivastava, A. Das, Org. Lett., 2021, 23, 869-875.

Iron catalysis enables a mild, environmentally benign α-methylation of ketones utilizing methanol as the C1 source under visible light irradition. The reaction conditions were favorable for a wide range of ketones with both aromatic and aliphatic backbones.
B. Emayavaramban, P. Chakraborty, P. Dahiya, B. Sundaraaju, Org. Lett., 2022, 24, 6219-6223.

A phenalenyl-based molecule catalyzes a transition-metal-free C-alkylation via a borrowing hydrogen pathway for α-alkylations of ketones, synthesis of substituted quinolines, and 9-monoalkylations of fluorene. A preliminary investigation of the reaction mechanism has been carried out, suggesting a radical-mediated borrowing hydrogen pathway.
A. Banik, P. Datta, S. K. Mandal, Org. Lett., 2023, 25, 1305-1309.

A hexanuclear Cu(I) cluster of 4,6-dimethylpyrimidine-2-thiolate efficiently catalyzes a dehydrogenative cross-coupling of primary and secondary alcohols to α-alkylated ketones. This transformation proceeds through a one-pot sequence of dehydrogenation of the alcohols, aldol condensation, hydrogenation, and dehydrogenation. This catalytic system also enables annulation reactions to yield pyridines and quinolines.
D.-W. Tan, H.-X. Li, D.-L. Zhu, H.-Y. Li, D. J. Young, J.-L. Yao, J.-P. Lang, Org. Lett., 2018, 20, 608-611.

[IrCl(COD)(NHC)] complexes catalyze reactions of primary alcohols with secondary alcohols or ketones to provide various α-alkylated ketones in high yields. The borrowing hydrogen reactions work in the presence of 0.05-0.5% iridium(I) and a catalytic amount of KOH (5-10 mol %) as the base under air atmosphere and within very short reaction times.
S. Genç, S. Günnaz, B. Çetinkaya, S. Gülcemal, D. Gülcemal, J. Org. Chem., 2018, 83, 2875-2881.

An easily accessible N-heterocyclic carbene manganese (NHC-Mn) system catalyzes highly active α-alkylation of ketones with alcohols. This system was efficient for a wide range of ketones and alcohols under mild reaction conditions, and also for the green synthesis of quinoline derivatives.
X.-B. Lan, Z. Ye, M. Huang, J. Liu, Y. Liu, Z. Ke, Org. Lett., 2019, 21, 8065-8070.

An environmentally benign and atom economical cobalt-catalyzed β-alkylation of secondary alcohols with primary alcohols provides ketones via acceptorless dehydrogenative coupling. The reaction produces water and hydrogen gas as the only byproducts.
B. Pandey, S. Xu, K. Ding, Org. Lett., 2019, 21, 7400-7404.

[IrCl(COD)(NHC)] complexes catalyze reactions of primary alcohols with secondary alcohols or ketones to provide various α-alkylated ketones in high yields. The borrowing hydrogen reactions work in the presence of 0.05-0.5% iridium(I) and a catalytic amount of KOH (5-10 mol %) as the base under air atmosphere and within very short reaction times.
S. Genç, S. Günnaz, B. Çetinkaya, S. Gülcemal, D. Gülcemal, J. Org. Chem., 2018, 83, 2875-2881.

Terminal epoxides and primary alcohols can be converted into α-alkylated ketones under borrowing hydrogen conditions in the presence of an N-heterocyclic carbene iridium(I) catalyst, under aerobic conditions, with water as the side product.
S. Genç, S. Gülcemal, S. Günnaz, B. Çetinkaya, D. Gülcemalv, Org. Lett., 2021, 23, 5229-5234.

A photoredox-catalyzed decarboxylative alkylation of silyl enol ethers provides diverse functionalized aryl alkyl ketones in good yields using N-(acyloxy)phthalimides as an easy access alkyl radical source under mild and operationally simple conditions.
W. Kong, C. Yu, H. An, Q. Song, Org. Lett., 2018, 20, 349-352.

A highly efficient Co-based catalytic system, composed of a commercially available Co salt, a tetradentate phosphine ligand, and K2CO3 enables the methylation of C(sp3)-H/C(sp2)-H bonds using methanol as a methylating reagent. The catalytic system showed high catalytic activity for the methylation of C-H bonds in aryl alkyl ketones, aryl acetonitriles, and indoles, with wide substrate scope and good functional group tolerance.
Z. Liu, Z. Yang, X. Yu, H. Zhang, B. Yu, Y. Zhao, Z. Liu, Org. Lett., 2017, 19, 5228-5231.

In the presence of metal-ligand bifunctional iridium complex [Cp*Ir(2,2′-bpyO)(H2O)], a tandem acceptorless dehydrogenation/α-alkylation of secondary and primary alcohols provides α-alkylated ketones in high yields. This protocol offers complete selectivity for α-alkylated ketones and environmentally benign conditions.
R. Wang, J. Ma, F. Li, J. Org. Chem., 2015, 80, 10769-10776.

A Cp*Ir complex bearing a functional bipyridonate ligand is a highly effective and versatile catalyst for the α-alkylation of ketones with primary alcohols under environmentally benign and mild conditions. Furthermore, this complex also exhibited a high level of catalytic activity for the α-methylation of ketones with methanol.
F. Li, J. Ma, N. Wang, J. Org. Chem., 2014, 79, 10447-10455.

An ionic cobalt-PNP complex enables an efficient α-alkylation of ketones with primary alcohols. A broad range of ketone and alcohol substrates provides alkylated ketones in good yields. The method was also successfully applied to a greener synthesis of quinoline derivatives using 2-aminobenzyl alcohol as the alkylating reagent.
G. Zhang, J. Wu, H. Zeng, S. Zhang, Z. Yin, S. Zheng, Org. Lett., 2017, 19, 1080-1083.

An unprecedented Rh-catalyzed direct methylation of ketones with N,N-dimethylformamide shows a broad substrate scope. Mechanistic studies suggest that DMF delivers a methylene fragment followed by a hydride during the methylation process.
Y. Li, D. Xue, W. Lu, C. Wang, Z.-T. Liu, J. Xiao, Org. Lett., 2014, 16, 66-69.

The use of phenyl trimethylammonium iodide (PhMe3NI) as an alternative methylating agent enables a regioselective introduction of a CH3 group in α-position to a carbonyl group in good yields. Quaternary ammonium salts have the advantages of being nonvolatile, noncancerogenic, and easy-to-handle solids.
J. Templ, M. Schnürch, J. Org. Chem., 2022, 87, 4305-4315.

The Cu(acac)2-catalyzed cross-coupling of alkylzinc halides with α-chloroketones introduces primary and secondary alkyl groups adjacent to a ketone carbonyl under mild reaction conditions and in good yield. The reaction proceeds stereospecifically with inversion of stereochemistry.
C. F. Malosh, J. M. Ready, J. Am. Chem. Soc., 2004, 126, 10240-20241.

Indium(III) halide catalyzed the coupling of alkyl chlorides with silyl enolates derived from esters, ketones, and aldehydes to give various α-alkylated carbonyl compounds. A one-pot, three-component reactions of aldehyde enolates, alkyl chlorides, and allylsilanes or alkynylsilanes is described.
Y. Nishimoto, M. Yasuda, A. Baba, Org. Lett., 2007, 9, 4931-4934.

A transition-metal-free coupling of esters with geminal bis(boron) compounds provides an α,α-bis(enolate) equivalent which can be trapped with electrophiles including alkyl halides and fluorinating agents. This presents an efficient, convergent synthetic strategy for the synthesis of α,α-difunctionalized ketones.
C. E. Iacono, T. C. Stephens, T. S. Rajan, G. Pattison, J. Am. Chem. Soc., 2018, 140, 2036-2040.

The use of 4-benzyl Hantzsch esters enables the construction of molecules with all-carbon quaternary centers by visible light-induced photoredox catalysis via transfer alkylation. Reactions of 4-alkyl Hantzsch nitriles as tertiary radical donors joined two contiguous all-carbon quaternary centers intermolecularly.
W. Chen, Z. Liu, J. Tian, J. Li, J. Ma, X. Cheng, G. Li, J. Am. Chem. Soc., 2016, 138, 12312-12315.

Photoirradiation of a mixture of acetone and water containing olefins affords the corresponding methyl ketones efficiently via a water-assisted C-C coupling between the acetonyl radical and olefins.
Y. Shiraishi, D. Tsukamoto, T. Hirai, Org. Lett., 2008, 10, 3117-3120.

An efficient and highly enantioselective conjugate addition of alkylzinc reagents to various cyclic nitroalkenes is promoted in the presence of 0.5-5 mol % (CuOTf)2·C6H6 and 1-10 mol % of chiral amino acid-based phosphine ligands at 0°C in toluene. Depending on the reaction conditions used, either the nitro or the corresponding α-substituted ketone product can be accessed.
C. A. Luchaco-Cullis, A. H. Hoveyda, J. Am. Chem. Soc., 2002, 124, 8192-8193.

Multifunctional palladium catalysis allows a one-pot stereocontrolled synthesis of tetrasubstituted methyl ketones and enynes. The homogeneous palladium dihalide catalyst is used for the bromo-/chloroallylation of alkynes and in situ for subsequent Wacker-Tsuji oxidation or Sonogashira cross-coupling.
A. N. Thadani, V. H. Rawal, Org. Lett., 2002, 4, 4321-4323.

A photo-organocatalytic enantioselective α- and γ-alkylation of aldehydes and enals with bromomalonates occurs under illumination by a fluorescent light bulb in the presence of a commercially available aminocatalyst without any external photoredox catalyst. Mechanistic investigations reveal the ability of transiently generated enamines to directly reach an electronically excited state while reactive radical species from the organic halides are formed.
M. Silvi, E. Arceo, I. D. Jurberg, C. Cassani, P. Melchiorre, J. Am. Chem. Soc., 2015, 137, 6120-6123.

A cobalt-catalyzed α-methoxymethylation of ketones with methanol as a sustainable C1 source, cheap CoCl2·6H2O as catalyst and TBHP as oxidant provides the methoxymethylated products within a short reaction time in very good yield. α-Aminomethylated ketones can be produced by a one-pot methylenation/aza-Michael addition sequence or by a base-mediated conversion of the α-methoxymethyl ketones.
J. Yang, S. Chen, H. Zhou, C. Wu, B. Ma, J. Xiao, Org. Lett., 2018, 20, 6774-6779.

A general site-selective difluoroalkylation of alkyl carboxylic redox esters with difluoroenoxysilanes through photoredox-catalyzed decarboxylation offers high efficiency, mild reaction conditions, and broad substrate scope. The reaction tolerates primary, secondary, and sterically hindered tertiaryl alkyl substrates and can also be extended to aliphatic amine derived pyridinium salts.
H. Song, R. Cheng, Q.-Q. Min, X. Zhang, Org. Lett., 2020, 22, 7747-7751.

Intramolecular halooxygenation and halothionation of N-allylcarboxamides/N-allylcarbothioamides proceeded readily in the presence of (diacetoxyiodo)benzene (PIDA) as the reaction promoter and halotrimethylsilane as the halogen source, providing the corresponding 5-halomethyloxazolines/5-halomethylthiazolines in very good yields. The 5-halomethyl products could be converted to different derivatives via nucleophilic substitution.
G.-Q. Liu, C.-H. Yang, Y.-M. Li, J. Org. Chem., 2015, 80, 11339-113550.