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Synthesis of alcohols

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Nozaki-Hiyama Coupling

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The prepartion of Grignard reagents normally requires dry organic solvents, long reaction times, strict control of the reaction temperature, and inert-gas-line techniques. A general mechanochemical synthesis of magnesium-based carbon nucleophiles followed by nucleophilic addition with various electrophiles or Ni-catalyzed cross-coupling can be performed in air using ball milling.
R. Takahashi, A. Hu, P. Gao, Y. Gao, Y. Pang, T. Seo, J. Jiang, S. Maeda, H. Takaya, K. Kubota, H. Ito, Nat. Commun., 2021, 12, 6691-6701.

A combinational effect of quaternary ammonium salts and organic bases enables an added-metal-free catalytic system for nucleophilic addition reactions of a variety of Grignard reagents to diverse ketones in THF as solvent to produce tertiary alcohols in good yields. By using tetrabutylammonium chloride as a catalyst and diglyme as an additive, this system strongly enhances the efficiency of addition at the expense of enolization and reduction.
H. Zong, H. Huang, J. Liu, G. Bian, L. Song, J. Org. Chem., 2012, 77, 4645-4652.

The use of ZnCl₂, Me₃SiCH₂MgCl, and LiCl effectively minimizes problematic side reactions in the 1,2-addition of strongly basic alkyl and aryl Grignard reagents to ketones. Aldimines give secondary amines in high yield. The simplicity of this reliable ZnCl₂•Me₃SiCH₂MgCl•LiCl system might be attractive for industrial as well as academic applications.
M. Hatano, O. Ito, S. Suzuki, K. Ishihara, J. Org. Chem., 2010, 75, 5008-5016.

The nucleophilicity of magnesium ate complexes derived from Grignard reagents and alkyllithiums is remarkably increased compared to that of the original RLi or RMgX, while the basicity of R₃MgLi is decreased, which allows a highly efficient alkyl-selective addition to ketones.
M. Hatano, T. Matsumura, K. Ishihara, Org. Lett., 2005, 7, 573-576.

The electrochemical activation of iron enables an efficient cathodic carbonyl alkylation of aryl ketones or aldehydes with unactivated alkyl halides to provide various tertiary or secondary alcohols under mild conditions. The protocol includes a radical-radical coupling or nucleophilic addition process, and the formation of ketyl radicals and alkyl radicals has been demonstrated.
H. Wu, X. Li, L. Yang, W. Chen, C. Zou, W. Deng, Z. Wang, J. Hu, Y. Li, Y. Huang, Org. Lett., 2022, 24, 9342-9347.

A highly efficient Zn-catalyzed alkylation of ketones and aldimines with Grignard reagents via trialkylzinc(II) ate complexes minimizes problems with the use of only Grignard reagents, which leads to reduction and aldol side products, and the yield of desired alkylation products could be improved.
M. Hatano, S. Suzuki, K. Ishihara, J. Am. Chem. Soc., 2006, 128, 9998-9999.

A variety of functionalized organozinc reagents undergo smooth addition reactions at ambient temperature to carbonyl compounds and carbon dioxide in the presence of stoichiometric amounts of MgCl₂. Several reactions were performed on a large scale.
S. Bernhardt, A. Metzger, P. Knochel, Synthesis, 2010, 3802-3810.

LnCl₃•2 LiCl (Ln = La, Ce, Nd) are superior promoter for the addition of various organometallic reagents to ketones. They also catalyze efficiently the addition of organomagnesium compounds to imines.
A. Krasovskiy, F. Kopp, P. Knochel, Angew. Chem. Int. Ed., 2006, 45, 497-500.

The combination of Me₃SiO^- and Bu₄N⁺ serves as a general activator of organotrimethylsilanes for addition reactions. A broad scope of bench-stable trimethylsilanes (including acetate, allyl, propargyl, benzyl, dithiane, heteroaryl, and aryl derivatives) can be used as carbanion equivalents for synthesis. Reactions are achieved at rt without the requirement of specialized precautions that are commonplace for other organometallics.
M. Das, D. F. O'Shea, J. Org. Chem., 2014, 79, 5595-5607.

NdI₂ is viable one-electron reducing agent in coupling reactions between alkyl chlorides and carbonyl compounds.
W. J. Evans, P. S. Workman, N. T. Allen, Org. Lett., 2003, 5, 2041-2042.

N-phenylfluorenyl β-amino alcohols have been evaluated as catalysts for the enantioselective addition of diethylzinc to benzaldehyde. A ligand with a bulky group at the carbinol stereocenter and a small group α to the nitrogen atom displayed the best catalytic activity and enantioselectivity and was used for the addition of diethylzinc to a variety of aromatic and aliphatic aldehydes.
M. R. Paleo, I. Cabeza, F. J. Sardina, J. Org. Chem., 2000, 65, 2108-2113.

A polystyrene-supported analog of 3-exo-morpholinoisoborneol (MIB) offers increased chemical stability as a ligand in the asymmetric alkylation of aldehydes with Et₂Zn. The supported ligand turned out to be highly active and enantioselective for a broad scope of substrates, allowing repeated recycling. A single-pass, continuous flow process shows only a marginal decrease in conversion after 30 h of operation.
L. Osorio-Planes, C. Rodríguez-Escrich, M. A. Pericàs, Org. Lett., 2012, 14, 1816-1819.

A refined version of Charette's procedure for the preparation of zinc reagents from Grignard reagents minimizes the side reactions in the subsequent catalytic, enantioselective n-alkyl addition of commercially unavailable di(n-alkyl)zinc reagents to aldehydes and ketones.
M. Hatano, T. Mizuno, K. Ishihara, Synlett, 2010, 2024-2028.

CrCl₂ mediates a nucleophilic addition of a primary amine derivative to an aldehyde to provide an alcohol. This radical-polar crossover process is selective for aldehydes and compatible with numerous functional groups, which are not tolerated under classical Grignard-type conditions.
Y. Huang, Z. Liu, W. H. Liu, Org. Lett., 2023, 25, 4934-4939.

Enantioselective decarboxylative Negishi-type alkylations of redox-active esters (RAEs) derivatives of α-oxy carboxylic acids provide enantiopure dialkyl carbinols. An extensive series of applications vividly demonstrate how this method can simplify synthesis.
Y. Gao, B. Zhang, L. Levy, H.-J. Zhang, C. H. P. S. Baran, J. Am. Chem. Soc., 2022, 144, 10992-11002.

Using an electrochemical approach, a ketone acts as a nucleophile when adding to simple unactivated olefins to accomplish an overall transformation similiar to a Grignard addition to unactivated ketones to access tertiary alcohols. This coupling offers a broad reaction scope, is scalable, chemoselective, and requires no precaution to exclude air or water.
P. Hu, B. K. Peters, C. A. Malapit, J. C. Vantourout, P. Wang, J. Li, L. Mele, P.-G. Echeverria, S. D. Minteer, P. S. Baran, J. Am. Chem. Soc., 2020, 142, 20979-20986.

Chromium catalyzes a photochemical, and linear-selective alkylation of aldehydes with alkylzirconium species generated in situ from a wide range of alkenes and Schwartz's reagent. The reaction proceeded with high functional group tolerance at ambient temperature under visible-light irradiation.
Y. Hirao, Y. Katayama, H. Mitsunuma, M. Kanai, Org. Lett., 2020, 22, 8584-8588.

An enantioselective Ni-catalyzed reaction of an alkyl halide (derived from an aldehyde and an acyl bromide), an olefin, and a hydrosilane provides esters of chiral dialkyl carbinols. The method is versatile and tolerates substituents that vary in size and that bear a range of functional groups. A four-component variant of this process, wherein the alkyl halide is generated in situ, is also reported.
Z.-P. Yang, G. C. Fu, J. Am. Chem. Soc., 2020, 142, 5870-5875.

Cathodic reduction enables a regioselective coupling of aliphatic ketones with alkenes via the formation of ketyl radicals and the activation of challenging alkenes under mild electrolysis conditions. This efficient protocol provides diverse tertiary alcohols with substrate-dependent regioselectivity.
H. Wu, W. Chen, W. Deng, L. Yang, X. Li, Y. Hu, Y. Li, L. Chen, Y. Huang, Org. Lett., 2022, 24, 1412-1417.

A nickel-catalyzed reductive coupling of redox-active esters with aliphatic aldehydes using zinc metal as the reducing agent provides silyl-protected secondary alcohols. This protocol is operationally simple, proceeds under mild conditions, and tolerates a variety of functional groups.
J. Xiao, Z. Li, J. Montgomery, J. Am. Chem. Soc., 2021, 143, 21234-21240.

Tandem Ni-catalyzed cross-coupling reactions of aromatic 2-pyridyl esters with alkyl zinc reagents provide secondary benzylic alcohols via carbonyl group reduction by Ni-H species. The Ni-H species is generated in situ via β-hydride elimination of the Negishi reagents. The reaction is catalyzed by bench-stable nickel salts under mild conditions with wide functional group tolerance.
X. Wu, X. Li, W. Huang, W. Wang, H. Xu, L. Cai, J. Qu, Y. Chen, Org. Lett., 2019, 21, 2453-2458.

Barbier-type alkylation of esters with alkyl iodides proceeded smoothly at room temperature in the presence of metallic strontium under argon to afford the corresponding dialkylated alcohols in good yields.
N. Miyoshi, T. Matsuo, M. Wada, Eur. J. Org. Chem., 2005, 4253-4255.

A highly regio- and enantioselective copper-catalyzed reductive hydroxymethylation of styrenes and 1,3-dienes with 1 atm of CO₂ readily provides important chiral homobenzylic alcohols. Moreover, various 1,3-dienes were converted to chiral homoallylic alcohols with high yields and excellent regio-, enantio-, and Z/E-selectivities.
Y.-Y. Gui, N. Hu, X.-W. Chen, L-L. Liao, J.-H. Ye, Z. Zhang, J. Li, D.-G. Yu, J. Am. Chem. Soc., 2017, 139, 17011-17014.

A highly enantioselective addition of dialkylzincs to aromatic, aliphatic, and heteroaromatic aldehydes is based on conjugate Lewis acid-Lewis base catalysis using bifunctional BINOL ligands.
M. Hatano, T. Miyamoto, K. Ishihara, J. Org. Chem., 2006, 71, 6474-6484.

Iron complexes are cheap and effective catalysts for a series of "umpolung" nucleophilic additions of hydrazones at room temperature. The catalytic system offers chemoselectivity and a broad substrate scope.
C.-C. Li, X.-J. Dai, H. Wang, D. Zhu, J. Gao, C.-J. Li, Org. Lett., 2018, 20, 3801-3805.

The catalytic asymmetric addition of alkyl groups to ketones under highly concentrated and solvent-free conditions permits reduction in catalyst loading by a factor of 2- to 40-fold compared with standard reaction conditions employing toluene and hexanes. Using cyclic conjugated enones, solvent-free asymmetric addition followed by a diastereoselective epoxidation using 5.5 M decane solution of tert-butyl hydroperoxide generated epoxy alcohols.
S.-J. Jeon, H. Li, P. J. Walsh, J. Am. Chem. Soc., 2005, 127, 16416-16425.

S.-J. Jeon, P. J. Walsh, J. Am. Chem. Soc., 2003, 125, 9544-9545.

In a highly efficient enantioselective organozinc addition to ketones, chiral phosphoramide-Zn(II) complexes serve as conjugate Lewis acid-Lewis base catalysts. From a variety of nonactivated aromatic and aliphatic ketones, the corresponding optically active tertiary alcohols were obtained in high yields with high enantioselectivities under mild reaction conditions.
M. Hatano, T. Miyamoto, K. Ishihara, Org. Lett., 2007, 9, 4535-4538.

Addition of diethylzinc to aromatic, aliphatic, and α,β-unsaturated aldehydes afforded secondary alcohols in high yield and enantiomeric excess in the presence of β-pinene derived amino alcohols 2-MAP and 3-MAP as chiral auxiliaries. These two amino alcohols provide antipodal enantiofacial selectivity in the dialkylzinc addition reaction.
C. M. Binder, A. Bautista, M. Zaidlewicz, M. P. Krzemiski, A. Oliver, B. Singaram, J. Org. Chem., 2009, 74, 2337-2343.

Highly reactive RMgBr reagents were effectively deactivated by bis[2-(N,N-dimethylamino)ethyl] ether. These chelated Grignard reagents were employed in a highly enantioselective addition to aldehydes catalyzed by a complex of commercially available (S)-BINOL and Ti(Oi-Pr)₄ under mild conditions.
C.-S. Da, J.-R. Wang, X.-G. Yin, X.-Y. Fan, Y. Liu, S.-L. Yu, Org. Lett., 2009, 11, 5578-5581.

Simple procedure, room temperature, and low catalyst loading are the characteristics of a new ClCr(Salen)-catalyzed enantioselective 1,2-addition of the rather unreactive Me₂Zn to a broad range of aldehydes.
P. G. Cozzi, P. Kotrusz, J. Am. Chem. Soc., 2006, 128, 4940-4941.

Chiral α-(carbamoyloxy)alkylcopper reagents, prepared using Hoppe's sBuLi/(-)-sparteine methodology and subsequent transmetalations with ZnCl₂ and CuCN, reacted with various electrophiles to give enantiomerically pure alcohols after deprotection.
J. P. N. Papillon, R. J. K. Taylor, Org. Lett., 2002, 4, 119-122.

The combination of sBuLi and TMEDA in CPME at -60 °C enables deprotonation of unactivated, chiral secondary dialkyl TIB esters. These carbanions were reacted with a range of neopentyl boronic esters which, after 1,2-metalate rearrangement and oxidation, gave a range of tertiary alcohols in high yield and high ee. Further functional group transformations of the tertiary boronic esters were demonstrated.
A. P. Pulis, D. J. Blair, E. Torres, V. K. Aggarwal, J. Am. Chem. Soc., 2013, 135, 16054-16057.

Three highly enantio- and diastereoselective one-pot procedures for the synthesis of cyclopropyl and iodocyclopropyl alcohols with up to four contiguous stereocenters are reported. Route 1 and 2 involve asymmetric addition of an alkylzinc reagent to an enal followed by diastereoselective cyclopropanation using either diiodomethane or iodoform to generate the zinc carbenoid, leading to cyclopropyl or iodocyclopropyl alcohols, respectively. Route 3 entails asymmetric vinylation of an aldehyde with divinylzinc reagents and subsequent diastereoselective cyclopropanation.
H. Y. Kim, A. E. Lurain, P. Garcia-Carcia, P. J. Carroll, P. J. Walsh, J. Am. Chem. Soc., 2005, 127, 13138-13139.

A new fluorous ligand showed excellent asymmetric induction on the addition of dimethylzinc to aldehydes. This ligand can be conveniently recycled and will be useful for synthesis of bioactive compounds with a methyl carbinol moiety.
Y. S. Sokeirik, H. Mori, M. Omote, K. Sato, A. Tarui, I. Kumadaki, A. Ando, Org. Lett., 2007, 9, 1927-1929.

(1S,2R)-2-(N-Morpholino)-1,2-dicyclohexylethanol promotes the enantioselective addition of diethylzinc to aldehydes in high enantiomeric excess.
W. A. Nugent, Org. Lett., 2002, 4, 2133-2136.

Fluorous chiral BINOLs were prepared and used as the ligands for the titanium catalyzed asymmetric addition of Et₂Zn to aromatic aldehydes. Products were isolated by simple fluorous-organic biphase and fluorous solid phase extraction techniques with similar enantioselectivities to that attained in the non-fluorous system. The recovered FBINOLs can be recycled.
Y. Nakamura, S. Takeuchi, K. Okumura, Y. Ohgo, D. P. Curran, Tetrahedron, 2002, 58, 3963-3969.

Nickel catalyzes a multicomponent coupling reaction of terminal alkenes, carbon dioxide, and organoaluminum reagents to provide homoallylic alcohols in good yields with excellent regio- and stereoselectivities.
Y. Mori, C. Shigeno, Y. Luo, B. Chan, G. Onodera, M. Kimura, Synlett, 2018, 29, 742-746.

A wide range of α-prenylated alcohol derivatives could be obtained in good yields by highly α-regioselective zinc-mediated prenylation of various aldehydes and ketones with prenyl bromide at 120°C in HMPA. By simply altering the reaciton solvent and temperature, the method allows the achievement of a highly notable opposite regiocontrol, providing the expected regiochemical product.
L.-M. Zhao, H.-S. Jin, L.-J. Wan, L.-M. Zhang, J. Org. Chem., 2011, 76, 1831-1837.

Boron tris(trifluoroacetate) is an effective catalyst for the homoallyl- and homocrotylboration of aldehydes by cyclopropylcarbinylboronates. This work shows that carboxylates are viable catalytic ligands for homoallyl- and homocrotylations of carbonyl compounds and opens the door to the development of catalytic asymmetric versions of this transformation.
G. J. Dugas, Y.-h. Lam, K. N. Houk, I. J. Krauss, J. Org. Chem., 2014, 79, 4277-4278.

Insertion of 2-substituted dienes into the methanol C-H bond occurs in a regioselective manner to form all-carbon quaternary centers with excellent levels of enantioselectivity using an iridium-PhanePhos catalyst via methanol dehydrogenation, reversible diene hydrometalation, and regioisomeric formation of allyliridium-formaldehyde pairs.
K. D. Nguyen, D. Herkommer, M. J. Krische, J. Am. Chem. Soc., 2016, 138, 14210-14213.

The reaction of (chloromethyl)magnesium chloride-lithium chloride (ClCH₂MgCl·LiCl), a mixed lithium-magnesium carbenoid, with aromatic aldehydes bearing various functional groups enables a highly chemoselective synthesis of a range of aromatic chlorohydrins in high yields.
R. H. V. Nishimura, V. E. Murie, R. A. Soldi, G. C. Clososki, Synthesis, 2015, 47, 1455-1460.

The generation of highly unstable chloromethylmagnesium chloride in a continuous flow reactor and a subsequent reaction with aldehydes and ketones provides chlorohydrins and epoxides in good yields within a total residence time of only 2.6 s. The outcome of the reaction can be tuned by simply using either a basic or an acidic quench.
T. von Keutz, D. Cantillo, C. O. Kappe, Org. Lett., 2020, 22, 7537-7541.

A low loading of a proazaphosphatrane compound efficiently catalyzes the reaction of trimethylsilylacetonitrile (TMSAN) with aldehydes for the synthesis of β-hydroxynitriles under mild reaction conditions. Various functional groups were tolerated, and good to excellent yields were obtained.
K. Wadhwa, J. G. Verkade, J. Org. Chem., 2009, 74, 5683-5686.

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.

Alkoxide-induced nucleophilic pentafluoroethylation and trifluoromethylation of aldehydes, ketones, and imines using pentafluoroethyl phenyl sulfone and trifluoromethyl phenyl sulfone, respectively, have been successfully achieved.
G. K. S. Prakash, Y. Wang, R. Mogi, J. Hu, T. Mathew, G. A. Olah, Org. Lett., 2010, 12, 2932-2935.

A visible-light induced direct C(sp³)-H functionalization of alkylarenes with trifluoromethyl ketones provides valuable benzyl-substituted trifluoromethyl alcohols in a stoichiometric manner. With a bromine radical as the hydrogen atom transfer reagent, primary, secondary, and tertiary benzyl C-H bonds are suitable coupling partners.
Q.-L. Wang, H. Huang, M. Zhu, T. Xu, G. Mao, G.-J. Deng, Org. Lett., 2023, 25, 3800-3805.