Synthesis of β-keto carboxylic acids, esters and amides
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 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 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.
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 MgBr2ˇOEt2 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.
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.
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.