Categories: C-C Bond Formation > Oxygen-containing molecules > Alcohols >
Synthesis of alcohols
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Recent Literature
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.
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.
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.
