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Synthesis of β-keto carboxylic acids, esters and amides

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An (E)- and (Z)-stereocomplementary preparative method for α,β-disubstituted α,β-unsaturated esters is performed via three general and robust reaction sequences: Ti-Claisen condensation (formylation) of esters to give α-formyl esters, (E)- and (Z)-stereocomplementary enol tosylation using TsCl-N-methylimidazole-Et₃N and LiOH, and stereoretentive Suzuki-Miyaura cross-coupling.
H. Nakatsuji, H. Nishikado, K. Ueno, Y. Tanabe, Org. Lett., 2009, 11, 4258-4261.

Pentafluorophenylammonium triflate (PFPAT) successfully catalyzed the C-acylation of enol silyl ethers with acid chloride to produce various β-diketones in good yield. Similarly, C-acylation of ketene silyl acetals or ketene silyl thioacetals proceeded smoothly to provide also thermodynamically unfavorable α,α-dialkylated β-keto (thio)esters in good yield.
A. Iida, J. Osada, R. Nagase, T. Misaki, Y. Tanabe, Org. Lett., 2007, 9, 1859-1862.

The reaction of magnesium enolates of substituted malonic acid half oxyesters (SMAHOs) as pronucleophiles with various acyl donors allows the synthesis of functionalized α-substituted β-keto esters in good yields. In addition to acyl chlorides and acid anhydrides, the conditions for this decarboxylative Claisen condensation proved also efficient for the use of carboxylic acids as acylating agents.
T. Xavier, P. Tran, A. Gautreau, E. Le Gall, M. Presset, Synthesis, 2023, 55, 598-608.

Activated primary, secondary, and tertiary amides were coupled with enolizable esters in the presence of LiHMDS to obtain β-ketoesters at room temperature in good yields. This efficient and mild protocol also provides β-alkylketoesters via cross-coupling of aliphatic amides with esters.
J. Chen, D. Joseph, Y. Xia, S. Lee, J. Org. Chem., 2021, 86, 5943-5953.

A Ti-crossed Claisen condensation between ketene silyl (thio)acetals and acid chlorides gave α-monoalkylated (thio)esters and thermodynamically unfavorable α,α-dialkylated β-keto (thio)esters in good yield. The protocol was extended to the direct condensation of ketene silyl acetals with carboxylic acids.
A. Iida, S. Nakazawa, T. Okabayashi, A. Horii, T. Misako, Y. Tanabe, Org. Lett., 2006, 8, 5215-5218.

A. Iida, S. Nakazawa, T. Okabayashi, A. Horii, T. Misako, Y. Tanabe, Org. Lett., 2006, 8, 5215-5218.

An efficient and convenient NHC (N-heterocyclic carbene)-catalyzed radical coupling reaction between aldehydes and azobis(isobutyronitrile) (AIBN) provides β-ketonitriles containing a quaternary carbon center in very good yields. This protocol offers broad substrate scope and good functional group tolerance under metal-free and mild reaction conditions.
J.-M. Wang, T. Chen, C.-S. Yao, K. Zhang, Org. Lett., 2023, 25, 3325-3329.

A nickel-catalyzed three-component reductive alkylacylation of electron-deficient activated alkenes with acid anhydrides and tertiary alkyl bromides enables the efficient preparation of a variety of ketones with broad substrate scope and high functionality tolerance starting from simple precursors.
L. Wang, C. Wang, Org. Lett., 2020, 22, 8829-8835.

A photoredox/nickel dual catalytic protocol enables a regioselective three-component carboacylation of alkenes with tertiary and secondary alkyltrifluoroborates as well as acyl chlorides. This redox-neutral protocol can be applied to the rapid synthesis of ketones with high diversity and complexity via a radical relay process. Many functional groups are tolerated under the mild conditions.
Z.-K. Wang, Y.-P. Wang, Z.-W. Rao, C.-Y. Liu, X.-H. Pan, L. Guo, Org. Lett., 2023, 25, 1673-1677.

A chiral scandium(III) N,N'-dioxide complex catalyzes an enantioselective catalytic homologation of acetophenone and related derivatives with α-alkyl α-diazo esters to provide optically active β-keto esters with an all-carbon quaternary center through highly selective alkyl-group migration of the ketones.
F. Tan, M. Pu, J. He, J. Li, J. Yang, S. Dong, X. Liu, Y.-D. Wu, X. Feng, J. Am. Chem. Soc., 2021, 143, 2394-2402.

Enamination of acetoacetamides with Boc-monoprotected ethylenediamine provides β-enamino amides, which can be acylated at the α-carbon with excellent selectivity. These C-acylated derivatives undergo domino fragmentation in acidic media to give the corresponding β-keto amides accompanied by 2-methyl-4,5-dihydro-1H-imidazole.
P. Angelov, Synlett, 2010, 1273-1275.

P. Angelov, Synlett, 2010, 1273-1275.

An one-pot reaction of carboxylic acids and ynol ethers provides β-keto esters under promotion of Ag₂O and a subsequent DMAP-catalyzed rearrangement. This protocol offers mild reaction conditions and a broad substrate scope.
L. Zeng, Z. Lai, S. Cui, J. Org. Chem., 2018, 83, 14834-14841.

An efficient decarbonylative coupling of α-keto acids and ynamides with extrusion of CO enables the synthesis of a broad range of β-keto imides under mild reaction conditions.
R. Chen, L. Zeng, B. Hoang, Y. Shen, S. Cui, Org. Lett., 2018, 20, 3377-3380.

Thioesters undergo chemoselective soft enolization and acylation by N-acylbenzotriazoles on treatment with MgBr₂·OEt₂ and i-Pr₂NEt to give β-keto thioesters without prior enolate formation. The reaction is conducted using untreated CH₂Cl₂ open to the air. The coupled products can be converted directly into β-keto esters, β-keto amides, and β-diketones under mild conditions.
G. Zhou, D. Lim, D. M. Coltart, Org. Lett., 2008, 10, 3809-3812.

Aromatic, aliphatic, and heterocyclic aldehydes are successfully condensed with ethyl diazoacetate in the presence of molybdenum(VI) dichloride dioxide as catalyst to obtain the corresponding β-keto esters in high yields at room temperature.
K. Jeyakumar, D. K. Chand, Synthesis, 2008, 1685-1687.

Aldehydes react readily with ethyl diazoacetate in the presence of 5 mol% of NbCl₅ in dichloromethane to produce the corresponding β-keto esters in good yields with high selectivity. This method allows the preparation of β-keto esters from various aldehydes under mild reaction conditions.
J. S. Yadav, B. V. S. Reddy, B. Eeshwaraiah, P. N. Reddy, Tetrahedron, 2005, 61, 875-878.

The TiCl₄-mediated reaction of esters with benzoyl chloride gave α-benzoylated esters in high yields.
D. F. Taber, R. B. Sheth, P. V. Joshi, J. Org. Chem., 2005, 70, 2851-2854.

A chemoselective α-trifluoroacetylation of tertiary amides with trifluoroacetic anhydride proceeds under mild conditions using 2,4,6-collidine as a weak base. β-Ketoamides containing trifluoroacetyl or perfluoroacyl groups were selectively obtained even in the presence of other functional groups such as ketone, ester, etc.
T. Morita, K. Makino, M. Tsuda, H. Nakamura, Org. Lett., 2023, 25, 8901-8905.

Variations on the Blaise Reaction: Synthesis of 3,5-Dioxopentanoates and 3-Amino-5-oxopent-3-enoates
H. S. P. Rao, N. Muthanna, Synlett, 2016, 27, 2014-2018.

Chelated enolates are good nucleophiles for reactions with acyl halides and imidazolides affording α-amino-β-keto esters. In most cases, the reactions are over after a few minutes and preparatively useful yields are obtained, independent of the protecting groups and electrophile used. With chloroformates as acylating agents, various protected amino malonates become accessible.
K. Schultz, L. Stief, U. Kazmaier, Synthesis, 2012, 44, 600-604.

A convenient two-step preparation of alkylidenepyrrolidines is reported.
M. C. Elliot, S. V. Wordingham, Synthesis, 2006, 1162-1170.

TiCl₄/Et₃N promotes a condensation of acetate and formate esters to provide (E)-β-alkoxy- and (E)-β-aryloxyacrylate moieties. A plausible mechanism involving a bimetallic titanium intermediate for this type of transformation.
J. M. Álvarez-Calero, Z. D. Jorge, G. M. Massanet, Org. Lett., 2016, 18, 6344-6347.