Categories: C-C Bond Formation > Oxygen-containing molecules > Carbonyl compounds >
Synthesis of aldehydes and ketones
Synergistic, Ir-photoredox/nickel catalytic cross-coupling of in situ activated carboxylic acids and alkyltrifluoroborates enables an efficient and mild method for acyl-Csp3 bond formation. The cross-coupling protocol of structurally diverse carboxylic acids with various potassium alkyltrifluoroborates affords the corresponding aliphatic ketones with high yields in an operationally simple manner.
J. Amani, G. A. Molander, Org. Lett., 2017, 19, 3612-3615.
Carboxylic acids were converted directly in good yields into ketones using excess alkyl cyanocuprates (R2CuLi•LiCN). A substrate with a stereocenter α to the carboxylic acid was converted with very little loss of enantiomeric purity. A variety of functional groups were tolerated including aryl bromides. This direct transformation involves a relatively stable copper ketal tetrahedral intermediate.
D. T Genna, G. H. Posner, Org. Lett., 2011, 13, 5358-5361.
In situ generated activated esters of carboxylic acids and amino acids react with Grignard reagents and CuI to give the corresponding ketones in nearly quantitative yields. The compounds were recovered substantially pure from the reaction mixtures.
L. De Luca, G. Giacomelli, A. Porcheddu, Org. Lett., 2001, 3, 1435-1437.
A cobalt bromide salt catalyzes a Negishi-type cross-coupling of of various glutarimide amides with organozinc compounds. The cross-coupling reactions can also be performed in an eco-compatible solvent such as ethyl acetate on a large scale.
C. Dorval, O. Stetsiuk, S. Gaillard, E. Dubois, C. Gosmini, G. Danoun, Org. Lett., 2022, 24, 2778-2782.
A benzotriazole reagent derived from 2-ethoxydioxolane and benzotriazole can be used as a remarkably stable and versatile electrophilic formylating reagent in reactions with Grignard reagents and organozinc reagents. The procedure is mild, efficient, and tolerable to multifunctional organic molecules, which makes it suitable for multistep syntheses.
A. R. Katritzky, H. H. Odens, M. V. Voronkov, J. Org. Chem., 2000, 65, 1886-1888.
A dual Ni/photoredox system was successfully employed to generate acyl radicals from aldehydes via selective formyl C-H activation. A subsequently cross-coupling with benzylic and allylic pyridinium salts provides ketones. The reaction tolerates a broad range of functional groups.
V. Murugesan, A. Ganguly, A. Karthika, R. Rasappan, Org. Lett., 2021, 23, 5389-5393.
Whereas rhodium complexes modified by PtBu2Me catalyze formate-mediated aldehyde-vinyl bromide reductive coupling-redox isomerization to form branched ketones, PPh3 as less strongly coordinating ligand promotes vinyl- to allylrhodium isomerization en route to linear ketones.
R. A. Swyka, W. G. Shuler, B. J. Spinello, W. Zhang, C. Lan, M. J. Krische, J. Am. Chem. Soc., 2019, 141, 6864-6868.
Unsymmetrical dialkyl ketones can be prepared by the nickel-catalyzed reductive coupling of carboxylic acid chlorides or (2-pyridyl)thioesters with alkyl iodides or benzylic chlorides. Various functional groups are tolerated, including common nitrogen protecting groups and C-B bonds. Even hindered ketones flanked by tertiary and secondary centers can be formed.
A. C. Wotal, D. J. Weix, Org. Lett., 2012, 14, 1363-1365.
N-acylazetidines are bench-stable, readily available amide acylating reagents, in which the reactivity is controlled by amide pyramidalization and strain of the four-membered ring. A general and highly chemoselective synthesis of ketones by the addition of organometallics to N-acylazetidines via stable tetrahedral intermediates offers wide substrate scope and exquisite selectivity for the ketone products.
C. Liu, M. Achtenhagen, M. Szostak, Org. Lett., 2016, 18, 2375-2378.
A convenient electrophile-electrophile cross-coupling of carboxylic acid derivatives and alkylpyridinium salts via C-N bond cleavage provides various functionalized ketones in very good yields. Besides acid chlorides, carboxylic acids were also employed as acylating agents.
F. T. Pulikottil, R. Pilli, R. V. Suku, R. Rasappan, Org. Lett., 2020, 22, 2833-2837.
A visible-light-promoted photoredox/Ni-catalyzed cross-coupling reaction of imides with trifluoroborates provides aliphatic ketones. This operationally simple and mild cross-coupling reaction is performed at ambient temperature and exhibits tolerance for various functional groups.
J. Amani, R. Alam, S. Badir, G. A. Molander, Org. Lett., 2017, 19, 2426-2429.
A range of unsymmetrical ketones has been prepared in good yields from aldehydes in one simple synthetic operation by addition of organolithium compounds followed by an oxidation using N-tert-butylphenylsulfinimidoyl chloride.
J. J. Crawford, K. W. Hederson, W. J. Kerr, Org. Lett., 2006, 8, 5073-5076.
Visible light photoredox/nickel dual catalysis enables a cross-coupling of acyl chlorides with potassium alkyltrifluoroborates via a single-electron-mediated alkyl transfer. This protocol circumvents the restriction of using reactive alkylmetallic nucleophiles in transition-metal-catalyzed acylation and achieves a mild and efficient synthesis of unsymmetrical alkyl ketones.
J. Amani, G. A. Molander, J. Org. Chem., 2017, 82, 1856-1863.
The use of Zn powder in the presence of LiCl in THF allows a simple, high-yielding preparation of a broad range of functionalized aryl- and heteroarylzinc reagents. The synthesis of alkylzinc reagents was performed from inexpensive alkyl bromides.
A. Krasovski, V. Malakhov, A. Gavryushin, P. Knochel, Angew. Chem. Int. Ed., 2006, 45, 6040-6044.
A magnesium amide additive activates and controls the addition of mild Grignard reagents to carboxylate anions and therefore avoids the use of organolithium reagents or activated acyl sources that need to be independently prepared. This strategy enables the modular synthesis of ketones from CO2 and the preparation of isotopically labeled pharmaceutical building blocks in a single operation.
K. Colas, A. C. V. D. dos Santos, A. Mendoza, Org. Lett., 2019, 21, 7851-7856.
A mild and transition-metal-free decarboxylative coupling of aryl aldehydes and tertiary or secondary alkyl carboxylic acid-derived redox-active esters is catalyed by a N-heterocyclic carbene to provide aryl alkyl ketones.
T. Ishii, Y. Kakeno, K. Nagao, H. Ohmiya, J. Am. Chem. Soc., 2019, 141, 3854-3858.
A rhodium-catalyzed tandem butadiene-mediated carbonyl addition-redox isomerization converts primary alcohols to isobutyl ketones. Related reductive coupling-redox isomerizations of aldehyde reactants mediated by sodium formate also are reported.
B. J. Spinello, J. Wu, Y. Cho, M. J. Krische, J. Am. Chem. Soc., 2021, 143, 13507-13512.
Aryldiazomethanes can be generated in situ by simply heating the tosylhydrazones of aromatic aldehydes in the presence of a stoichiometric amount of base in polar protic solvents. In the presence of aldehydes, benzylic ketones are formed in good yields. In addition, tosylhydrazones can be prepared in ethanol and carried through the sequence without isolation.
S. R. Angle, M. L. Neitzel, J. Org. Chem., 2000, 65, 6458-6461.
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.
Using a Pd-NHC catalyst for cross-coupling of phenyl esters and alkyl boranes, alkyl ketones can be prepared in good yields via a Suzuki-Miyaura reaction proceeding by activation of the C(acyl)-O bond, whereas a Pd-dcype catalyst provides alkylated arenes by a modified pathway with extrusion of CO.
J. Masson-Makdissi, J. K. Vandavasi, S. G. Newman, Org. Lett., 2018, 20, 4094-4098.
FeCl2 catalyzes a smooth and convenient acylation of functionalized arylzinc halides and benzylic zinc chlorides with various acid chlorides to provide polyfunctionalized diaryl and aryl benzyl ketones.
A. D. Benischke, M. Leroux, I. Knoll, P. Knochel, Org. Lett., 2016, 18, 3626-3629.
A new Ni catalyst is capable of effecting the rapid cross-coupling of acid fluorides, acid chlorides, acyl cyanides, anhydrides, thioesters, and pyridyl esters with both groups of diorganozinc reagents. Reactions with acid fluorides as electrophilic partners tolerate epimerizable functionality as well as leaving groups.
Y. Zhang, T. Rovis, J. Am. Chem. Soc., 2004, 126, 15964-15965.
A mild procedure enables a convergent ketone assembly from nonstabilized diazoalkanes and aldehydes, including examples of chiral ketone synthesis with disubstituted (internal) nucleophiles. The method’s remarkable tolerance to steric crowding is showcased in a simple approach to achyrofuran, a complex dibenzofuran.
A. J. Wommack, D. C. Moebius, A. L. Travis, J. S. Kingsbury, Org. Lett., 2009, 11, 3202-3205.
A convenient procedure for the synthesis of unsymmetrical ketones from bench-stable tosylhydrazones and aryl aldehydes can be performed in one pot from the parent carbonyl compound and needs only a base without additional promoters.
D. M. Allwood, D. C. Blakemore, S. V. Ley, Org. Lett., 2014, 16, 3064-3067.
A transition-metal-free coupling of aldehydes and ketones with geminal bis(boron) building blocks provides homologated carbonyl compounds upon oxidation. Aldehydes with an enolizable stereogenic center undergo this reaction with complete retention of stereochemistry.
T. C. Stephens, G. Pattison, Org. Lett., 2017, 19, 3498-3501.
Tetraorganoindates, which are easily prepared from 1 eq. of InCl3 and 4 eq. of organometallics, could be employed as effective nucleophilic cross-coupling partners in Pd-catalyzed carbonylative cross-coupling reactions with a variety of halides. The present method gave unsymmetrical ketones in good yields.
S. W. Lee, K. Lee, D. Seomoon, S. Kim, H. Kim, H. Kim, E. Shim, M. Lee, J. Org. Chem., 2004, 69, 4852-4855.
A Ni-catalyzed reductive deaminative cross-electrophile coupling reaction between Katritzky salts and aromatic amides provides ketones. Due to mild reaction conditions and high functional group tolerance, this cross-coupling strategy is expected to be useful for late-stage functionalization of complex compounds.
C.-G. Yu, Y. Matsuo, Org. Lett., 2020, 22, 950-955.
The use of gem-bis(boronates) as precursors enables a construction of quaternary α-aryl aldehydes, in which both groups are installed simultaneously. This methodology provides a general strategy to produce quaternary α-aryl aldehydes with broad scopes and synthetic convenience. In addition, gem-bis(boronates) are readily available from ketones.
P. Zheng, Y. Zhai, X. Zhao, T. Xu, Org. Lett., 2019, 21, 393-396.
An enantioselective Ni-catalyzed reductive cross-coupling of acid chlorides with racemic secondary benzyl chlorides in the presence of Mn0 as a stoichiometric reductant generates acyclic α,α-disubstituted ketones in good yields and high enantioselectivity. The mild, base-free reaction conditions tolerate various functional groups on both coupling partners.
A. H. Cherney, N. T. Kadunce, S. E. Reisman, J. Am. Chem. Soc., 2013, 135, 7442-7445.
Boron Lewis acid promoted formal insertion of aryldiazoalkane into the C-H bond of both aromatic and aliphatic aldehydes enables a novel, catalytic enantioselective route to α-tertiary aryl ketones. In the presence of a chiral (S)-oxazaborolidinium ion catalyst, the reaction proceeded in good yields with excellent enantioselectivities.
B. C. Kang, D. G. Nam, G.-S. Hwang, D.-H. Ryu, Org. Lett., 2015, 17, 4810-4813.
A nickel-catalyzed, multicomponent regio- and enantioselective hydroformylation and carbonylation using chloroformate as a safe CO source provides a wide variety of unsymmetrical dialkyl ketones bearing a functionalized α-stereocenter, including enantioenriched chiral α-aryl ketones and α-amino ketones.
J. Chen, S. Zhu, J. Am. Chem. Soc., 2021, 143, 14089-14096.
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.
Benzylic Aroylation of Toluenes Mediated by a LiN(SiMe3)2/Cs+ System
Y. Gu, Z. Zhang, Y.-E. Wang, Z. Dai, Y. Yuan, D. Xiong, J. Li, P. J. Walsh, J. Mao, J. Org. Chem., 2022, 87, 406-418.
A N-heterocyclic carbene-catalyzed radical relay enables the vicinal alkylacylation of styrenes, acrylates and acrylonitrile with complete regioselectivity using aldehydes and tertiary alkyl carboxylic acid-derived redox-active esters to produce functionalized ketone derivatives.
T. Ishii, K. Ota, K. Nagao, H. Ohmiya, J. Am. Chem. Soc., 2019, 141, 14073-14077.
An operationally simple and mild visible-light, single-electron-transfer (SET), photoredox cross-coupling enables the synthesis of α-alkoxyketones in high yields from various aliphatic and aromatic acyl chlorides and structurally diverse potassium alkoxymethyltrifluoroborates. The bond connection is unique to both alkylboron chemistry and photoredox/Ni catalysis.
J. Amani, E. Sodagar, G. A. Molander, Org. Lett., 2016, 18, 732-735.
The use of readily available and stable Weinreb amides enables a mild and efficient sequential synthesis of β-aminoketones or their derivatives ( e.g., pyrazolines). The reaction proceeds in good to excellent yields for a variety of amides, vinyl Grignard reagents and N-nucleophiles.
A. Gomtsyan, R. J. Koenig, C.-H. Lee, J. Org. Chem., 2001, 66, 3613-3616.
A short, mild, and highly chemoselective addition of organolithium reagents to BF2 complexes of 3-oxopropanoates allows a straightforward preparation 1,3-diketones.
B. Štefane, Org. Lett., 2010, 12, 2900-2903.
The use of an electrophilic cyanation source enables electrocatalytic three-component acylcyanations and aminocyanations of a broad range of simple alkenes. The reaction offers high functional group tolerance and can easily be scaled up.
X. Kong, X. Chen, Y. Chen, Z.-Y. Cao, J. Org. Chem., 2022, 87, 7013-7021.
The addition of (pentafluoroethyl)- and (heptafluoropropyl)lithium to Weinreb and morpholine amides led to polyfluoro ketones in high to quantitative yields in short reaction times. The methodology can provide inhibitors for various lipolytic enzymes, including phospholipase A2.
C. G. Kokotos, C. Baskakis, G. Kokotos, J. Org. Chem., 2008, 73, 8623-2626.
Weinreb amides are efficiently converted into ketones by reaction with alkylidenetriphenylphosphoranes and in situ hydrolysis of the intermediate.
J. A. Murphy, A. G. J. Commeureuc, T. N. Snaddon, T. M. McGuire, T. A. Khan, K. Hisler, M. L. Dewis, R. Carling, Org. Lett., 2005, 7, 945-947.
While 3,4;5,6-di-O-isopropylidene-N-phthaloyl-D-glucosamine propane-1,3-diyl dithioacetal underwent fast β-elimination, the corresponding N-acetyl derivative was easily deprotonated with butyllithium to form the dilithiated intermediate. Stoichiometry and temperature were crucial factors for selective C-C coupling with various electrophiles.
Y.-L. Chen, R. Leguijt, H. Redlich, R. Fröhlich, Synthesis, 2006, 4212-4218.
1-Siloxy-1-alkenylcopper species were generated by 1,2-Csp2-to-O silyl migration of the copper enolates of acyltriphenylsilanes. The alkenylcopper species reacted with methyl, benzyl, allylic, tributylstannyl halides and in the presence of Pd(0) catalyst with aryl and alkenyl iodides to give geometrically pure (Z)-enol silyl ethers.
A. Tsubouchi, K. Onishi, T. Takeda, J. Am. Chem. Soc., 2006, 128, 14268-14269.
α-Halonitriles react with alkyllithium, organomagnesium, and lithium dimethylcuprate reagents generating reactive, metalated nitriles. The rapid halogen-metal exchange with alkyllithium and Grignard reagents allows Barbier-type reactions with various electrophiles.
F. F. Fleming, Z. Zhang, W. Liu, P. Knochel, J. Org. Chem., 2005, 70, 2200-2005.
Photoinduced decatungstate-catalyzed Giese reactions of readily available aldehydes as radical precursors with dehydroalanine provide γ-carbonyl α-amino acids. This mild, robust method is compatible with a wide array of functional groups and has a broad substrate scope.
X. Wang, Y. Chen, H. Song, Y. Liu, Q. Wang, Org. Lett., 2021, 23, 2199-2204.
A visible-light-enabled, photocatalyst-free conjugate addition of 4-acyl-1,4-dihydropyridines to dehydroamino acids provides β-acyl α-amino acids and their deuterated analogues in good yields. 4-Acyl-1,4-dihydropyridines serve both as a radical reservoir and reductant. The reaction can be used for late-stage peptide modification and stereoselective synthesis of chiral oxazolidinones.
L. Liu, Z. Deng, K. Xu, P. Jiang, H. Du, J. Tan, Org. Lett., 2021, 23, 5288-5293.
A green, practical, convenient, and cheap copper-catalyzed oxidative coupling of aromatic alcohols and acetonitrile to β-ketonitriles involves a C-C coupling with loss of two hydrogen atoms from the corresponding two carbons, using oxygen as the terminal oxidant.
J. Shen, D. Yang, Y. Liu, S. Qin, J. Zhang, J. Sun, C. Liu, C. Liu, X. Zhao, C. Chu, R. Liu, Org. Lett., 2014, 16, 350-353.
The conversion of primary nitroalkanes into the corresponding α-nitro ketones readily proceeds using N-acylbenzotriazoles as acylation agents.
A. R. Katritzky, A. A. A. Abdel-Fattah, A. V. Gromova, R. Witek, P. J. Steel, J. Org. Chem., 2005, 70, 9211-9214.
A TiCl4-Mg promoted coupling of various amides with CH2Cl2 and methyl acrylate allows an extremely simple and practical synthesis of 1,5-keto esters. The efficiency of this chemistry is illustrated by the very simple preparation of unusual 4,4-dideuterio-1,5-keto esters using CD2Cl2.
K.-W. Lin, C. Y. Chen, W.-F. Chen, T.-H. Yan, J. Org. Chem., 2008, 73, 4759-4761.
A carbene-catalyzed radical trifluoromethylation of olefins with aldehydes in the presence of Togni reagent provides β-trifluoromethyl-α-substituted ketones with a broad scope and good yields.
B. Zhang, Q. Peng, D. Guo, J. Wang, Org. Lett., 2020, 22, 443-447.
Visible-light-driven hydroacylations and epoxyacylations in water using methylene blue as photoredox catalyst and persulfate as oxidant deliver ketones and epoxyketones from a range of aromatic and aliphatic aldehydes as well as conjugated and nonconjugated olefins as abundant and inexpensive chemical feedstocks.
G. F. P. de Souza, J. A. Bonacin, A. G. Salles, Jr., J. Org. Chem., 2018, 83, 8331-8340.
Under the synergistic actions of photocatalyst Ru(bpy)3Cl2, tert-butyl hydroperoxide, cesium carbonate, and visible light irradiation, a range of styrenes and benzaldehydes smoothly form α,β-epoxy ketones via visible-light-enabled photocatalytic generation of acyl radicals as key intermediates.
J. Li, D. Z. Wang, Org. Lett., 2015, 17, 5260-5263.
An enantioselective copper-catalyzed borylacylation of aryl olefins with acyl chlorides and bis-(pinacolato)diboron proceeds with a 2 mol % catalyst loading and is generally completed within 30 min at room temperature. The resulting chiral β-borylated ketones are versatile intermediates in organic synthesis.
Z. Yang, P. Li, H. Lu, G. Li, J. Org. Chem., 2021, 86, 4616-4624.
Catalytic amounts of weak bases such as sodium carbonate can carry out the ketonic decarboxylation of adipic acid into cyclopentanone selectively. This is in accordance with a mechanism involving decarboxylation and nucleophilic attack at a second carboxyl group. Stereogenic centres in the β-positions retain their stereochemistry.
M. Renz, A. Corma, Eur. J. Org. Chem., 2004, 2036-2039.
tert-Dodecanthiol-catalyzed generation of acyl radicals and their intramolecular addition to double bonds gave 2-substituted five- and six-membered cyclic ketones in good yields.
K. Yoshikai, T. Hayama, K. Nishimura, K.-I. Yamada, K. Tomioka, J. Org. Chem., 2005, 70, 681-683.
A mild, high-yielding and general procedure for the preparation of β-ketophosphonates by condensation of esters and phosphonates provides products in high yields within minutes at 0°C. The reaction procedure is operationally simple and amenable to large-scale preparations.
K. M. Maloney, J. Y. L. Chung, J. Org. Chem., 2009, 74, 7574-7576.
In a one-step synthesis of aliphatic potassium acyltrifluoroborates (KATs) from organocuprates, organolithium and organomagnesium reagents were readily transmetalated onto Cu(I) and coupled with a KAT-forming reagent. The protocol is suitable for primary, secondary and tertiary alkyl substrates.
S. M. Liu, D. Wu, J. W. Bode, Org. Lett., 2018, 20, 2378-2381.