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Synthesis of substituted carbonyl compounds by 1,4-additions

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Mixing an enone, zinc powder, TMEDA, and an alkyl halide in an aqueous micellar environement containing catalytic amounts of Cu(I) and Au(III) enables conjugate additions in water at room temperature via in situ generated organocopper reagents in good yields. In the presence of Ag(I), the amounts of alkyl halide, Zn, and AuCl₃ can be reduced dramatically.
B. H. Lipshutz, S. Huang, W. W. Y. Leong, G. Zhong, N. A. Isley, J. Am. Chem. Soc., 2012, 134, 19985-19988.

Tin-free Giese reaction of alkyl iodides with electron-deficient alkenes and the related radical carbonylation process proceeded efficiently in the presence of sodium cyanoborohydride and tetrabutylammonium cyanoborohydride. Transfer of iodine followed by hydride reduction of the resulting carbon-iodine bond is proposed as a possible mechanism.
I. Ryu, S. Uehara, H. Hirao, T. Fukuyama, Org. Lett., 2008, 10, 1005-1008.

Conjugated aldehydes undergo smooth 1,4-addition of dialkylzinc reagents under Pd or Cu catalysis.
J. A. Marshall, M. Herold, H. S. Eidam, P. Eidam, Org. Lett., 2006, 8, 5505-5508.

The use of [2.2]paracyclophane-derived monodentate phosphoramidite ligands enabled a copper-catalyzed asymmetric conjugate addition of diethylzinc to chalcones in excellent yield and enantioselectivity with low catalyst loading.
L. Han, Y. Lei, P. Xing, X.-L. Zhao, B. Jiang, J. Org. Chem., 2015, 80, 3752-3757.

A new tridentate alanine-derived aminohydroxyphosphine ligand induces consistently high enantioselectivity in copper-catalyzed asymmetric conjugate additions of organozinc reagents to various acyclic enones. A highly ordered transition state is proposed.
A. Hajra, N. Yoshikai, E. Nakamura, Org. Lett., 2006, 8, 4153-4155.

A highly enantioselective addition of Grignard reagents to acyclic aliphatic enones provides β-substituted linear ketones with high yields, regio-, and enantioselectivities in the presence of 5 mol % of CuBr·SMe₂ and 6 mol % of JosiPhos diphosphine.
F. López, S. R. Harutyunyan, A. J. Minnaard, B. L. Feringa, J. Am. Chem. Soc., 2004, 126, 12784-12785.

A new P-chiral phosphine bis(sulfonamide) ligand allows the Cu-catalyzed enantioselective conjugate addition of Et₂Zn to various acyclic aliphatic enones with excellent levels of enantioselectivity at ambient temperature.
A. P. Duncan, J. L. Leighton, Org. Lett., 2004, 6, 4117-4119.

A nickel-catalyzed ring-opening allylation of cyclopropanols with allylic carbonates provides δ,ε-unsaturated ketones in moderate to good yields under mild and neutral conditions. The reaction displays linear selectivity for both linear and branched acyclic allylic carbonates and is also applicable to cyclic allylic carbonates.
Y. Sekiguchi, Y. Y. Lee, N. Yoshikai, Org. Lett., 2021, 23, 5993-5997.

A (thio)urea cocatalyst accelerates O-monoacyltartaric acid (MAT)-catalyzed enantioselective conjugate additions of boronic acid to unsaturated ketone.
T. Yoshimitsu, Y. Kuboyama, S. Nishiguchi, M. Nakajima, M. Sugiura, Org. Lett., 2020, 22, 3780-3784.

A domino dehydrochlorination/Mn-enabled radical-based alkyl-alkyl cross-coupling reaction allows a highly efficient alkylation of β-chloro ketones via in situ-generated α,β-unsaturated ketones as reaction intermediates.
J. Wang, Y.-B. Pang, N. Tao, R.-S. Zeng, Y. Zhao, J. Org. Chem., 2019, 84, 15315-15322.

An alkyl-alkyl cross-coupling of organoboranes, formed in situ via hydroboration of alkenes, and Katritzky alkylpyridinium salts has been developed. Under the mild reaction conditions, a broad range of functional groups, including protic groups, is tolerated. The strategy is also effective with alkynes, enabling a C(sp³)-C(sp²) cross-coupling.
K. M. Baker, D. L. Baca, S. Plunkett, M. E. Daneker, M. P. Watson, Org. Lett., 2019, 21, 9738-9741.

A new, readily to prepare, air-stable, crystalline ligand for Cu-catalyzed enantioselective additions of dialkylzincs to cyclic enones provides optimal performance (good to excellent enantioselectivities) at ambient temperature with a range of substrates.
I. J. Krauss, J. L. Leighton, Org. Lett., 2003, 5, 3201-3203.

The 1,4-addition of dialkylzincs to cyclic enones proceeded with ee values up to 99% by using chiral aryl diphosphite ligands derived from H₈-binaphthol.
L. Liang, T. T.-L. Au-Yeung, A. S. C. Chan, Org. Lett., 2002, 4, 3799-3801.

An efficient and practical Cu-catalyzed asymmetric conjugate addition of dialkylzinc reagents to tetrasubstituted cyclic enones afforded quaternary all-carbon stereogenic centers in up to 95% ee. The products can be readily functionalized to afford various synthetically versatile compounds in high optical purity.
A. W. Hird, A. H. Hoveyda, J. Am. Chem. Soc., 2005, 127, 14988-14989.

Cu-catalyzed enantioselective conjugate additions of alkyl- and arylzinc reagents to unactivated cyclic β-substituted enones are promoted in the presence of 2.5-15 mol% of a readily available chiral NHC-based Cu complex, affording the desired products bearing all-carbon quaternary stereogenic centers in good yield and enantioselectivity.
K.-S. Lee, M. K. Brown, A. W. Hird, A. H. Hoveyda, J. Am. Chem. Soc., 2006, 128, 7182-7184.

An additive-free, clean conjugate addition reaction of organosiloxanes to α,β-unsaturated compounds is catalyzed by a cationic rhodium complex in dioxane/water. The mechanism involves a transmetalation step between the rhodium complex and the silicon reagent.
S. Oi, Y. Honma, Y. Inoue, Org. Lett., 2002, 4, 667-669.

A conjugate addition of organosiloxanes to α,β-unsaturated carbonyl compounds catalyzed by a cationic rhodium complex generated from [Rh(cod)(MeCN)₂]BF₄ and (S)-BINAP in dioxane/water gave products in good yields and excellent enantioselectivities.
S. Oi, A. Taira, Y. Honma, Y. Inoue, Org. Lett., 2003, 5, 97-99.

C₂-symmetric chiral diene ligands based on a 3,7-disubstituted bicyclo[3.3.1]nona-2,6-diene readily bind to rhodium(I). These rhodium complexes act as effective catalysts for 1,4-addition of alkenyl- and arylboronic acids to various α,β-unsaturated ketones, including several combinations that were previously difficult to provide high enantioselectivity.
R. Shintani, Y. Ichikawa, K. Takatsu, F.-X. Chen, T. Hayashi, J. Org. Chem., 2009, 74, 869-873.

A chiral diene possessing the bicyclo[2.2.2]octadiene framework substituted with a tertiary alcohol on one of the two double bonds is readily prepared in two steps and is highly effective as a chiral ligand for rhodium-catalyzed asymmetric conjugate addition reactions, giving the corresponding addition products with high enantioselectivity.
K. Okamoto, T. Hayashi, V. H. Rawal, Org. Lett., 2008, 10, 4387-4389.

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.

In a synergistical combination of photoredox catalysis and organocatalysis for the direct β-alkylation of saturated aldehydes, photon-induced enamine oxidation provides an activated β-enaminyl radical intermediate, which readily combines with a wide range of Michael acceptors to produce β-alkyl aldehydes in a highly efficient manner. This redox-neutral, atom-economical C–H functionalization can be achieved both inter- and intramolecularly.
J. A. Terrett, M. D. Clift, D. W. C. MacMillan, J. Am. Chem. Soc., 2014, 136, 6858-6861.

The AgOAc/ThioClickFerrophos complex effectively catalyzed a conjugate addition of glycine imino esters to arylidene and alkylidene malonates, furnishing the corresponding adducts in good yields with high enantioselectivities. The complex also catalyzed a highly enantioselective, conjugate addition to α-enones in the presence of 1,4-diazabicyclo[2.2.2]octane.
T. Konno, S. Watanabe, T. Takahashi, Y. Tokoro, S.-i. Fukuzawa, Org. Lett., 2013, 15, 4418-4421.

Alkyl Grignard reagents, with the exception of tBuMgCl, undergo exclusive or exceptionally highly regioselective 1,4-addition reactions to α,β-γ,δ-unsaturated ketones, while aryl Grignard reagents give mixed results. All Grignard reagents examined gave exclusive 1,4-addition reactions with α,β–γ,δ-unsaturated thiol esters.
E. Amoah, R. K. Dieter, J. Org. Chem., 2017, 82, 2870-2888.

The use of unsaturated methylidene ketones in catalytic conjugate allylations allows a significant expansion in substrate scope and occurs in a highly enantioselective fashion in the presence of a Taddol-derived phosphinite ligand.
L. A. Brozek, J. D. Sieber, J. P. Morken, Org. Lett., 2011, 13, 995-997.

Conjugate addition of dimethyl alkenylboronates to α,β-unsaturated ketones in the presence of catalytic amounts of 3,3'-disubstituted binaphthols provides alkenylation products in good yields and high enantioselectivities.
T. R. Wu, J. M. Chong, J. Am. Chem. Soc., 2007, 129, 4908-4909.

In a catalytic method for the regioselective allylation of α,β-unsaturated aldehydes, the use of an air-stable diethanolamine-complexed boronic acid (DABO boronate) as the allyl transfer reagent promotes conjugate addition over 1,2-addition. Various aryl- and alkyl-substituted enals provide δ,ε-unsaturated aldehyde products in good yields under mild conditions.
P. C. Roest, N. W. M. Michel, R. A. Batey, J. Org. Chem., 2016, 81, 6774-6778.

A direct conjugate addition of simple alkenes to enones has been achieved in the presence of a Ni(0)/PCy₃ catalyst. This reaction is a straightforward method for the introduction of an alkenyl group at the β-position of enones.
S. Ogoshi, T. Haba, M. Ohashi, J. Am. Chem. Soc., 2009, 131, 10350-10351.

Cobalt complex/Zn systems effectively catalyze the reductive coupling of activated alkenes with alkynes in the presence of water to give substituted alkenes with very high regio- and stereoselectivity in excellent yields.
H.-T. Chang, T. T. Jayanth, C.-C. Wang, C.-H. Cheng, J. Am. Chem. Soc., 2007, 129, 12032-12041.

Reductive coupling of enones or enals with alkynes using reducing agents such as organozincs, organoboranes, organosilanes, and methanol is cost-effective, and tolerant of many functional groups. Isotopic labeling strategies have provided supporting evidence for the mechanistic proposals.
W. Li, A. Herath, J. Montgomery, J. Am. Chem. Soc., 2009, 131, 17024-17029.

A nickel-catalyzed intermolecular reductive coupling of enones and alkynes gives γ,δ-unsaturated ketones. The process does not require formation of a vinyl organometallic, and a variety of functional groups including free hydroxyls and esters are tolerated.
A. Herath, B. B. Thompson, J. Montgomery, J. Am. Chem. Soc., 2007, 129, 8712-8713.

A three-component nickel-catalyzed coupling of enals, alkynes, and silanes forms an enol silane and a trisubstituted alkene with >98:2 stereoselectivity. The reaction tolerates a broad range of functionality including aldehydes, ketones, esters, free hydroxyls, and basic secondary amines.
A. Herath, J. Montgomery, J. Am. Chem. Soc., 2008, 130, 8132-8133.

An alkynylation of cyclopropanols with 1-bromo-1-alkynes provides synthetically useful alk-4-yn-1-ones. In this C-C bond formation, functionalized cyclopropanols act as a new class of homoenolate equivalent.
R. V. N. S. Murali, N. N. Rao, J. K. Cha, Org. Lett., 2015, 17, 3854-3856.

A visible-light-induced oxidation of alcohols generates alkoxyl radicals mediated by iodine(III) reagents under mild reaction conditions. The β-fragmentation of alkoxyl radicals enables selective C(sp³)-C(sp³) bond cleavage and alkynylation/alkenylation reactions with various strained cycloalkanols and linear alcohols.
K. Jia, F. Zhang, H. Huang, Y. Chen, J. Am. Chem. Soc., 2016, 138, 1514-1517.

A silver-promoted oxidative ring opening/alkynylation of cyclopropanols with ethynylbenziodoxolones (EBX) enables the formation of alkylated alkynes. Control experiments support a radical mechanism.
C.-Y. Wang, R.-J. Song, Y.-X. Xie, J.-H. Li, Synthesis, 2016, 48, 223-230.

An efficient Na₂S₂O₈-promoted radical coupling of tertiary cycloalkanols with alkynyl hypervalent iodide reagents provides β-, γ- and δ-alkynylated ketones via C-C bond cleavage. This tandem ring-opening/alkynylation procedure offers mild conditions and wide substrate scope.
S. Wang, L.-N. Guo, H. Wang, X.-H. Duan, Org. Lett., 2015, 17, 4798-4801.

A practical Pd-catalyzed protocol for the hydroalkynylation of enones proceeds efficiently with various alkynes as well as with several cyclic and acyclic enones, providing synthetically relevant β-alkynyl ketones in good to excellent yields.
L. Villarino, R. García, F. López, J. L. Mascareñas, Org. Lett., 2012, 14, 2996-2999.

A rapid and simple conjugate alkynylation of acyclic enones using sp-hybridised potassium organotrifluoroborates in the presence of BF₃•OEt₂ is suitable for the preparation of small compound libraries.
F. Bertolini, S. Woodward, Synlett, 2009, 51-54.

An asymmetric 1,3-rearrangement of an alkynyl group of alkynyl alkenyl carbinols took place in the presence of a hydroxyrhodium/(R)-binap catalyst to yield β-alkynylketones in high yields with high enantioselectivity. The present method includes a key β-alkynyl elimination step in the catalytic cycle.
T. Nishimura, T. Katoh, K. Takatshu, R. Shintani, T. Hayashi, J. Am. Chem. Soc., 2007, 129, 14158-14159.

Efficient Addition of Allylsilanes to α,β-Enones Using Catalytic Indium and Trimethylsilyl Chloride
P. H. Lee, D. Seomoon, S. Kim, K. Nagaiah, S. V. Damle, K. Lee, Synthesis, 2003, 2023-2026.

The C₂-symmetric norbornadiene derivative (1R,4R)-2,5-dibenzylbicyclo[2.2.1]hepta-2,5-diene was used as ligand for the rhodium-catalyzed asymmetric 1,4-addition of organoboron and -tin reagents to α,β-unsaturated ketones, which gave high yields of the addition products with up to 99% enantioselectivity.
T. Hayashi, K. Ueyama, N. Tokunaga, K. Yoshida, J. Am. Chem. Soc., 2003, 125, 11508-11509.

A modified binaphthol catalyzes an asymmetric conjugate alkynylation of β-enaminones with potassium alkynyltrifluoroborates via in situ generated organodifluoroboranes. Mechanistic studies revealed the impact of molecular sieves on efficiency and stereocontrol. Additional functionalization provides a diverse set of valuable β-alkynyl-β-amino carbonyl scaffolds.
J.-F. Wang, X. Meng, C.-H. Zhang, C.-M. Yu, B. Mao, Org. Lett., 2020, 22, 7424-7426.

A manganese-catalyzed ring-opening coupling reaction of cyclopropanols with enones enables the facile and efficient preparation of a wide array of synthetically important 1,6-diketones bearing manifold functional groups in good yield. These reaction features broad substrate scope, environmentally benign conditions, inexpensive catalyst, and operational simplicity.
Y.-H. Zhang W.-W. Zhang, Z.-Y. Zhang, K. Zhao, T.-P. Loh, Org. Lett., 2019, 21, 5101-5105.

Gd(OTf)₃ as co-catalyst dramatically accelerated a Ni-catalyzed conjugate addition of cyanide to enones. The substrate scope of the reaction is broad, including cyclic, linear, branched, and aromatic enones. Gadolinium triflate is supposed to facilitate the oxidative addition of Ni(0) to enones, which constitutes a key step in the catalytic cycle.
Y. Tanaka, M. Kanai, M. Shibasaki, Synlett, 2008, 2295-2298.

A catalytic enantioselective direct conjugate addition of nitroalkanes to α,β-unsaturated aldehydes using diphenylprolinol silyl ether as an organocatalyst enables short syntheses of therapeutically useful compounds.
H. Gotoh, H. Ishikawa, Y. Hayashi, Org. Lett., 2007, 9, 5307-5309.

The use of a sulfonamide-thiourea organocatalyst enabels an asymmetric conjugate addition of nitroalkanes to α,β-unsaturated ketones to provide the corresponding γ-nitro carbonyl products in high yields with excellent enantioselectivities.
M. Kawada, K. Nakashima, S.-i. Hirashima, A. Yoshida, Y. Koseki, T. Miura, J. Org. Chem., 2017, 82, 6986-6991.

An N-spiro C₂-symmetric chiral quaternary ammonium bromide efficiently catalyzed the conjugate addition of various prochiral nitroalkanes to cyclic α,β-unsaturated ketones under solid-liquid phase-transfer conditions to afford the corresponding γ-nitro ketones in excellent yields with high levels of diastereo- and enantiocontrol.
T. Ooi, S. Takada, S. Fujioka, K. Maruoka, Org. Lett., 2005, 7, 5143-5146.