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Synthesis of aldehydes and ketones


Name Reactions

Fukuyama Coupling

Grignard Reaction

Grignard Reaction

Seebach Umpolung

Stetter Synthesis

Weinreb Ketone Synthesis

Recent Literature

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.

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.

A Cu-catalyzed hydrocarbonylative C-C coupling of unactivated alkyl iodides with terminal alkynes enables a highly chemo- and regioselective synthesis of unsymmetrical dialkyl ketones. A variety of functional groups are tolerated, and both primary and secondary alkyl iodides react well.
L.-J. Cheng, N. P. Mankad, J. Am. Chem. Soc., 2017, 139, 10200-10203.

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 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 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.

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 nickel-catalyzed intermolecular hydroacylation reaction of alkenes with simple aldehydes offers an approach to the selective preparation of branched ketones in high yields and selectivities. The origin of the reactivity and regioselectivity of this reaction was investigated computationally.
L.-J. Xiao, X.-N. Fu, M.-J. Zhou, J.-H. Xie, L.-X. Wang, X.-F. Xu, Q.-L. Zhou, J. Am. Chem. Soc., 2016, 138, 2957-2960.

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.

Hybrid phosphorus ligands enable a Rh-catalyzed enantioselective anti-Markovnikov hydroformylation of unfunctionalized 1,1-disubstituted alkenes to provide linear aldehydes with β-chirality in high yields and enantioselectivities under mild conditions. In a large-scale synthesis, a very low catalyst loading (0.05 mol %) furnished the desired product in good yield and undiminished selectivity.
C. You, S. Li, X. Li, J. Lan, Y. Yang, L. W. Chung, H. Lv, X. Zhang, J. Am. Chem. Soc., 2018, 140, 4977-4981.

An effective and operationally simple palladium-catalyzed regioselective hydroformylation of olefins with formic acid provides linear aldehydes in good yield with excellent regioselectivity. 1,3-Bis(diphenylphosphino)propane (dppp) as the ligand plays a crucial role in directing the reaction pathway. The process requires no syngas.
W. Ren, W. Chang, J. Dai, Y. Shi, J. Li, Y. Shi, J. Am. Chem. Soc., 2016, 138, 14864-14867.

Hydroformylation of alkenes can be carried out in a few minutes under microwave activation at a relatively low pressure (2.7 atm) using commercially available catalysts and ligands. After 4 min of microwave irradiation, the corresponding aldehyde is formed in high yield.
E. Petricci, A. Mann, A. Schoenfelder, A. Rota, M. Taddei, Org. Lett., 2006, 8, 3725-3727.

The 6-DPPon/rhodium catalyst allows for the first time a room temperature/ambient pressure hydroformylation of various, structurally diverse terminal alkenes with low catalyst loadings. This protocol omits the need for special pressure equipment and should find wide application in organic synthesis.
W. Seiche, A. Schuschkowski, B. Breit, Adv. Syn. Catal., 2005, 1488-1494.

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 direct asymmetric copper hydride (CuH)-catalyzed coupling of α,β-unsaturated carboxylic acids with aryl alkenes provides chiral α-aryl dialkyl ketones. The reaction tolerates various substrate substitution patterns, sensitive functional groups, and heterocycles.
Y. Zhou, J. S. Bandar, S. L. Buchwald, J. Am. Chem. Soc., 2017, 139, 8126-8129.

Rhodium-catalyzed regioselective arylzincation of terminal allenes affords synthetically useful functionalized allylzinc reagents, which can be protonated or react with various electrophiles such as carbonyl compounds and acetonitrile.
Y. Yoshida, K. Murakami, H. Yorimitsu, K. Oshima, J. Am. Chem. Soc., 2010, 132, 8878-8879.

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.

A regioselective intermolecular hydroacylation of vinalarenes, in which symmetric and mixed carboxylic anhydrides are used as acyl donors, is promoted by a cationic rhodium catalyst ligated by triphenylarsine.
Y.-T. Hong, A. Barchuk, M. J. Krische, Angew. Chem. Int. Ed., 2006, 45, 6885-6888.

A regioselective intermolecular hydroacylation of vinalarenes, in which symmetric and mixed carboxylic anhydrides are used as acyl donors, is promoted by a cationic rhodium catalyst ligated by triphenylarsine.
Y.-T. Hong, A. Barchuk, M. J. Krische, Angew. Chem. Int. Ed., 2006, 45, 6885-6888.

Rhodium (I) bis-olefin complexes catalyzes the addition of electron-rich aromatic aldehydes to olefins to form ketones. Use of a more electron-deficient Rhodium catalyst results in faster reaction rates, better selectivity for linear ketone products and broader reaction scope.
A. H. Roy, C. P. Lenges, M. Brookhart, J. Am. Chem. Soc., 2007, 129, 2082-2093.

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.

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 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.

A cationic rhodium(I)/dppb complex catalyzed direct intermolecular hydroacylation of N,N-dialkylacrylamides with both aliphatic and aromatic aldehydes represents a versatile route to γ-ketoamides in view of high atom economy and commercial availability of substrates.
K. Tanaka, Y. Shibata, T. Suda, Y. Hagiwara, M. Hirano, Org. Lett., 2007, 9, 1215-1218.

A cationic rhodium(I)/(R,R)-QuinoxP* complex catalyzes a highly enantioselective direct intermolecular hydroacylation of α-substituted acrylamides with unfunctionalized aliphatic aldehydes to yield the corresponding γ-ketoamides in high yields with excellent ee values.
Y. Shibata, K. Tanaka, J. Am. Chem. Soc., 2009, 131, 12552-12553.

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.

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.

Various oxo acid derivatives were obtained directly from the reaction of aliphatic and aromatic aldehydes with ω-alkenoic acid derivatives in the presence of rhodium(I) complexes and 2-amino-3-picoline.
E.-A. Jo, C.-H. Jun, Eur. J. Org. Chem., 2006, 2504-2507.

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.

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 highly enantio- and diastereoselective intramolecular Stetter reaction has been developed. Aliphatic and aromatic aldehydes and a broad range of trisubstituted Michael acceptors have been found to afford the desired products in good overall yield with high enantio- and diastereoselectivity.
J. Read de Alaniz, T. Rovis, J. Am. Chem. Soc., 2005, 127, 6284-6289.

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.