Catalytic Cross-Coupling of Secondary Alcohols

Article abstract of DOI:10.1021/jacs.9b00025

Herein, an unprecedented ruthenium(II) catalyzed direct cross-coupling of two different secondary alcohols to β-disubstituted ketones is reported. Cyclic, acylic, symmetrical, and unsymmetrical secondary alcohols are selectively coupled with aromatic benzylic secondary alcohols to provide ketone products. A single catalyst oxidizes both secondary alcohols to provide selectively β-disubstituted ketones to broaden the scope of this catalytic protocol. Number of bond activation and bond formation reactions occur in selective sequence via amine-amide metal-ligand cooperation operative in Ru-MACHO catalyst. The product-induced diastereoselectivity was also observed. Kinetic and deuterium labeling experiments suggested that the aliphatic secondary alcohols undergo oxidation reaction faster than benzylic secondary alcohols, selectively assimilating to provide the cross-coupled products. Reactions are sensitive to steric hindrance. This new C-C bond forming methodology requires low catalyst load and catalytic amount of base. Notably, the reaction produces H₂ and H₂O as the only byproducts making the protocol greener, atom economical and environmentally benign.

Full text of DOI:10.1021/jacs.9b00025

Communication
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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Catalytic Cross-Coupling of Secondary Alcohols
Subramanian Thiyagarajan and Chidambaram Gunanathan*
School of Chemical Sciences, National Institute of Science Education and Research, HBNI, Bhubaneswar-752050, India
S
* Supporting Information
Scheme 1. Traditional and Selectivity Challenges in
Synthesis of β-Disubstituted Ketones and Cross-Coupling of
Secondary Alcohols
ABSTRACT: Herein, an unprecedented ruthenium(II)
catalyzed direct cross-coupling of two different secondary
alcohols to β-disubstituted ketones is reported. Cyclic,
acylic, symmetrical, and unsymmetrical secondary alcohols
are selectively coupled with aromatic benzylic secondary
alcohols to provide ketone products. A single catalyst
oxidizes both secondary alcohols to provide selectively β-
disubstituted ketones to broaden the scope of this
catalytic protocol. Number of bond activation and bond
formation reactions occur in selective sequence via
amine−amide metal−ligand cooperation operative in
Ru-MACHO catalyst. The product-induced diastereose-
lectivity was also observed. Kinetic and deuterium labeling
experiments suggested that the aliphatic secondary
alcohols undergo oxidation reaction faster than benzylic
secondary alcohols, selectively assimilating to provide the
cross-coupled products. Reactions are sensitive to steric
hindrance. This new C−C bond forming methodology
requires low catalyst load and catalytic amount of base.
Notably, the reaction produces H2 and H2O as the only
byproducts making the protocol greener, atom econom-
ical and environmentally benign.
lcohols and ketones are prevalent in nature and are highly
Apromising industrial feedstock chemicals. Ketones are
versatile building blocks for the construction of natural
products, polymers, biological and pharmaceutical compounds
and extensively used as industrial solvents.1 Traditional
synthesis of α- and β-substituted ketones involves reaction of
carbonyl compounds under cryogenic conditions with strong
bases (nBuLi, LDA, etc.) followed by addition of toxic alkyl
halides (Scheme 1a). This enolate alkylation approach suffers
from serious drawbacks, which include (i) generation of
stoichiometric metal halides as chemical waste (ii) over
alkylation to di- or trisubstituted ketones, and (iii) homolytic
coupling of carbonyl compounds curtailing the atom economy
of the reactions.2 In addition, organic halides and carbonyl
compounds are expensive and they are not readily available
substrates, which can be replaced by most abundant, cheap and
environmentally benign alcohols for alkylation reactions.
Moreover, alcohols can be obtained from renewable resources
such as lignocellulosic biomass.3 The recent development in
transition metal catalysis aims to develop sustainable, one-step,
and atom economical efficient methodologies for the
preparation of valuable synthetic building blocks by using
easily available starting materials. In this regard, “borrowing
hydrogen” methodology has become one of the most attractive
transformation for C−C and C−N bond formation in organic
synthesis.4,5
Synthesis of α-substituted ketones from ketones and
alcohols is well established.5 Direct cross-coupling of alcohols
Received: January 2, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.9b00025
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Journal of the American Chemical Society
Communication
with hydrogen evolution via acceptorless dehydrogenation is
one of the most atom economical and environmentally benign
methods for constructing new C−C bonds (Scheme 1b).6
Catalytic self-coupling7,8 and cross-coupling9 of primary
alcohols to esters and higher alcohols are reported. Cross-
coupling of secondary alcohols with primary alcohols has been
widely explored.10,11 There are two reports on self-coupling of
secondary alcohols.12 However, the catalytic cross-coupling of
two different secondary alcohols remains unknown.
The major challenge in cross-coupling of secondary alcohols
is to overcome the unwanted self-coupling from aldol
reactions, which generates undesired byproducts and hence,
diminishes the atom economy of the overall transformation
(Scheme 1c). More importantly, synthesis of β-disubstituted
ketones directly from two different secondary alcohols can
usually be accomplished via four-step transformations
(oxidation, aldol condensation, hydrogenation, and oxidation).
Recently, Donohoe and co-workers reported the synthesis of β-
disubstituted ketones via borrowing hydrogen methodology.13
However, the reaction requires stoichiometrically excess
amount of base and the substrate scope is limited to bulky
ketones (e.g., Ph*COCH3, Ph* = pentamethyl phenyl). Thus,
it is desirable to develop a new strategy for the synthesis of β-
disubstituted ketones directly from two different secondary
alcohols (Scheme 1d).
Table 1. Optimization for Cross-Coupling of Secondary
Alcohols Catalyzed by 1
a
b
c
entry cat. (mol %) base (mol %) temp. (°C) conv. (%) yield (%)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
0.5
1
−
2
5
5
10
5
5
5
5
5
−
135
135
125
125
125
115
125
125
125
125
>99
>99
>99
>99
>99
94
>99
>99
5
69 (74)
85 (90)
86 (91)
70 (76)
87 (94)
63 (69)
70 (72)
79 (83)
−
d
e
f
f
10
−
−
−
a
Reaction conditions: 1-phenylethanol (0.5 mmol), cyclohexanol (0.5
mmol), toluene (1.5 mL), catalyst 1 (1 mol %), and KOtBu (5 mol %)
were heated under argon flow. Conversion of 1-phenylethanol was
b
determined by GC analysis using benzene as an internal standard.
c
Yields were calculated for isolated products after column
chromatography; yields calculated from GC analysis of the reaction
d
mixtures are given within parentheses. 2 equiv of cyclohexanol was
e
f
used. 5 mol % of NaOtBu was used. Reaction was performed up to
24 h.
Recently, selective α-alkylation and α-olefination of nitrile
compounds by alcohols were reported from our laboratory
using a commercially available Ru-MACHO catalyst (1).14 On
the basis of these reports, we further envisaged the cross-
coupling of secondary alcohols. Herein, we describe the
synthesis of β-disubstituted ketones directly from two different
secondary alcohols. This catalytic method does not require
stoichiometric oxidants; it only requires a catalyst and catalytic
amount of base. Water and liberated H2 are the only
byproducts of this reaction.
(Scheme 2). In general, methyl, methoxy and benzyloxy
substituted 1-phenylethanols reacted well with cyclohexanol
and provided the corresponding cross-coupled products 2b−2i
in good to high yields. The electron withdrawing group present
in aromatic ring of secondary alcohol slightly diminished the
reactivity as observed in 1-(4-chlorophenyl)ethan-1-ol to 2j.
Notably, heteroaryl and bicyclic aromatic secondary alcohols
were tolerated well and the cross-coupling products 2k−2o
were obtained in good yields (Scheme 2).
Reaction of 1-phenylethanol (0.5 mmol) with cyclohexanol
(0.5 mmol), catalyst 1 (1 mol %), and base (2 mol %) in
toluene solution was heated to 135 °C for an initial
investigation. Further, the reaction mixture was analyzed by
1H NMR spectroscopy and gas chromatography (GC), which
confirmed the complete conversion of 1-phenylethanol and
high reactivity for cross-coupling reaction along with unreacted
acetophenone (in situ generated intermediate) and trace
amount of self-coupled aldol product were detected (entry 1,
Table 1). Notably, overalkylation products and β-alkylated
secondary alcohols were not observed (Scheme 1c). However,
upon increasing base load to 5 mol % and lowering
temperature to 125 °C, resulted in a better outcome and the
cross-coupled product was isolated in 85% and 86% yields
(entries 2, 3, Table 1). Use of 10 mol % of base, diminished
the product formation presumably due to aldol side reactions
(entry 4, Table 1). Further, upon increasing the amount of
cyclohexanol no significant improvement in yield was observed
(entry 5, Table 1). On decreasing catalyst load, use of lower
temperature and replacing KOtBu with NaOtBu provided
considerably lower yields (entries 6−8, Table 1). Other bases
were not effective on the reaction (see SI). In control
experiments performed by employing only base, and without
catalyst and base, no cross-coupling product was observed,
indicating that catalyst and base are essential for the success of
the reaction (entries 9,10, Table 1).
Encouraged by these results, a range of secondary alcohols
was further explored for catalytic cross-coupling reaction. Both
cyclic and acyclic secondary alcohols were directly coupled
with benzylic secondary alcohols, which afforded cross-coupled
ketone products in good to excellent yields (Scheme 3).
Substitution on cyclohexyl ring provided products as a mixture
of diastereoisomers and the diastereomeric ratios were
obtained from 1H NMR of crude reaction mixture. 4-
Methylcyclohexanol was selectively coupled with various 1-
arylethanol derivatives to provide the products 3a−3c (d.r,
80:20, 81:19, 78:22, respectively) in very good yields as a
mixture of diastereoisomers. Representatively, the single-crystal
X-ray structure for major isomer of product 3b is solved, which
revealed the 1,4-cis conformation on cyclohexyl ring.
Accordingly, similar 1,4-cis conformation is assigned for all
major isomers of products 3a−3g. Good yields with similar
diastereoselectivities were also obtained for 4-propyl, 4-tert-
butyl, and 4-phenyl-substituted cyclohexanol derivatives (3d−
3g). Gratifyingly, 1-cycloheptanol and 2-norborneol were
reacted with 1-phenylethanol derivatives and the correspond-
ing products 3h−3k were isolated in very good yields (Scheme
3). 4-Hydroxycyclohexanone ethyleneacetal with 1-(4-
methylphenyl)ethanol provided product 3l in moderate yield.
A sterically hindered substrate, 1,1-diphenylmethanol delivered
cross-coupled product 3m in 68% yield. Finally, the highly
challenging unactivated acyclic aliphatic secondary alcohols
were subjected to catalysis with increased catalyst load of 1 (4
Having optimal reaction conditions in hand, the scope of the
various secondary alcohols on cross-coupling was investigated
B
DOI: 10.1021/jacs.9b00025
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Journal of the American Chemical Society
Communication
Scheme 2. Ruthenium-Catalyzed Selective Cross-Coupling
of Secondary Alcohols Using Cyclohexanol
Scheme 3. Ruthenium-Catalyzed Selective Cross-Coupling
of Secondary Alcohols
a
a
a
Reaction conditions: 1-arylethanol (0.5 mmol), cyclohexanol (0.5
mmol), toluene (1.5 mL), catalyst 1 (1 mol %), and KOtBu (5 mol %)
were heated at 125 °C under argon flow for 4 h. Conversion of 1-
arylethanols determined by GC analysis using benzene as an internal
standard is given within parentheses. Reported yields correspond to
isolated pure compounds. Reaction was performed using 2 mol %
catalyst 1 and 10 mol % base. 4 mol % of catalyst 1 and 20 mol % of
b
c
base were used.
mol %) and base (20 mol %). A variety of secondary alcohols
such as 2-propanol, 2-butanol, 2-pentanol, 3-pentanol, and 4-
heptanol were well tolerated and selectively converted into β-
disubstituted ketones (3n−3t).
Further, experiments aimed at deciphering the mechanistic
insights were performed. When 1-mesitylethanol was reacted
with sterically hindered 2-adamantanol, selective formation of
olefin product 5a was observed (Scheme 4a). GC analysis of
this reaction mixture clearly indicated the absence of alkylated
product. However, the reaction of 1-mesitylethanol with 4-
heptanol under optimized conditions provided alkylated
product 3t and olefin product 5b in 90:10 ratio (Scheme
4b). These results indicate the borrowing hydrogen pathway is
interrupted due to sterically encumbered ruthenium on catalyst
1 and the reaction proceeds via α,β-unsaturated ketone
intermediates. In addition to that deuterium-labeling experi-
ments were conducted and the results imply that the liberated
a
Reaction conditions: A mixture of two secondary alcohols (each 0.5
mmol scale at 1:1 ratio), toluene (1.5 mL), catalyst 1 (1 mol %), and
KOtBu (5 mol %) were heated at 125 °C in open conditions under
1
the argon flow. Diastereomeric ratios (d.r) were determined by H
NMR analysis of crude reaction mixture; major isomer shown. was
determined by GC analysis using benzene as an internal standard and
given within parentheses. Reported yields correspond to isolated pure
compounds. 2 mol % catalyst 1 and 10 mol % base were used. 3 mol
% catalyst 1 and 15 mol % base and 3 equiv of cycloheptanol were
used. 5 mol % of catalyst and 10 mol % base were used. 4 mol %
catalyst 1 and 20 mol % base and 10 equiv of isopropyl alcohol were
used. Reaction was performed using 5 equiv of aliphatic secondary
alcohol, 4 mol % catalyst 1, and 20 mol % base.
b
c
d
e
f
C
DOI: 10.1021/jacs.9b00025
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Journal of the American Chemical Society
Communication
Scheme 4. Mechanistic Studies for the Cross-Coupling of
Secondary Alcohols
Scheme 5. Proposed Mechanism for Cross-Coupling of
Secondary Alcohols
dideutrium/dihydrogen from cyclohexanol are predominantly
reinstalled to unsaturated intermediate rather than dideu-
trium/dihydrogen liberated from 1-phenylethanol (Scheme
4c,d). These observations clearly indicate that the catalytic
cross-coupling of secondary alcohols reactions are sensitive to
steric hindrance. Thus, in addition to the faster dehydrogen-
ation of aliphatic secondary alcohols by catalyst 1, the higher
reactivity of aliphatic cyclic ketones intermediates presumably
due to the conformation strain and the steric compatibility also
facilitates the formation of cross-coupling products by
precluding the self-coupling reactions.
On the basis of these experimental evidence, the catalytic
cycle for cross-coupling of secondary alcohols catalyzed by 1 is
proposed in Scheme 5. Facile O−H, O−D, N−H, and spC−H
bond activation reactions by catalyst 1 have been established in
our previous reports.14,15 Catalyst 1 reacts with base to
generate an unsaturated reactive intermediate I, which has
been previously observed in mass spectrometry analysis.15b,16
The resulted reactive intermediate I further reacts with both
secondary alcohols to provide an alkoxo coordinated
ruthenium intermediates II and II′ as already established.15d
β-Hydride elimination reaction from alkoxoide ligands may
result in formation of ketone intermediates A and B and both
dehydrogenation reactions converge to provide the same
ruthenium dihydride complex III. However, involvement of
other mechanistic pathways cannot be ruled out.17 A base
mediated cross-aldol condensation reaction between in situ
formed ketones A and B produces α,β-unsaturated carbonyl
compound C, which undergoes selective hydrogenation by
complex III to provide desired β-disubstituted ketones. The
amine−amide metal−ligand cooperation operative in these
catalytic intermediates allow the regeneration of active
intermediate I upon hydrogenation as well as liberation of a
H2 molecule by ruthenium dihydride III.
unsymmetrical secondary alcohols were well tolerated. The
reaction proceeded by O−H bond activation of secondary
alcohols by catalyst via amine−amide metal−ligand coopera-
tion to provide corresponding carbonyl intermediates, which
condensed and underwent catalytic hydrogenation to even-
tually deliver the products. Overall, two equivalent of
molecular H2 is obtained from oxidation of two different
secondary alcohols. While one equivalent is used for the
hydrogenation of the α,β-unsaturated carbonyl compound to
provide the desired β-branched ketones, the other equivalent is
liberated as H2. Remarkably, H2O and H2 are the only
byproducts. Use of readily available and challenging starting
materials, broad scope, high selectivity and absence of any
deleterious side reactions in this C−C bond formation will be
beneficial and contribute to the development of new “green”
and “sustainable” catalytic processes in future.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.9b00025.
■
S
Experimental procedures, spectral data, and copies of 1H
and 13C NMR spectra of the products (PDF)
Crystal data of compound 3b (CIF)
AUTHOR INFORMATION
Corresponding Author
*gunanathan@niser.ac.in
■
ORCID
Subramanian Thiyagarajan: 0000-0002-0735-5686
Chidambaram Gunanathan: 0000-0002-9458-5198
Notes
In summary, we have developed an efficient catalytic cross-
coupling of secondary alcohols to provide β-branched ketones.
This methodology provides broad substrate scope. Various
aromatic, heteroaromatic, cyclic, linear, symmetrical, and
The authors declare no competing financial interest.
D
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Communication
(6) Reviews for acceptorless dehydrogenation of alcohols:
(a) Crabtree, R. H. Homogeneous Transition Metal Catalysis of
Acceptorless Dehydrogenative Alcohol Oxidation: Applications in
Hydrogen Storage and to Heterocycle Synthesis. Chem. Rev. 2017,
117, 9228−9246. (b) Khusnutdinova, J. R.; Milstein, D. Metal−
Ligand Cooperation. Angew. Chem., Int. Ed. 2015, 54, 12236−12273.
(c) Gunanathan, C.; Milstein, D. Bond Activation and Catalysis by
Ruthenium Pincer Complexes. Chem. Rev. 2014, 114, 12024−12087.
(d) Gunanathan, C.; Milstein, D. Applications of Acceptorless
Dehydrogenation and Related Transformations in Chemical Syn-
thesis. Science 2013, 341, 1229712.
(7) Selected examples: (a) Das, U. K.; Ben-David, Y.; Leitus, G.;
Diskin-Posner, Y.; Milstein, D. Dehydrogenative Cross-Coupling of
Primary Alcohols To Form Cross-Esters Catalyzed by a Manganese
Pincer Complex. ACS Catal. 2019, 9, 479−484. (b) Paudel, K.;
Pandey, B.; Xu, S.; Taylor, D. K.; Tyer, D. L.; Torres, C. L.; Gallagher,
S.; Kong, L.; Ding, K. Cobalt-Catalyzed Acceptorless Dehydrogen-
ative Coupling of Primary Alcohols to Esters. Org. Lett. 2018, 20,
4478−4481. (c) Nielsen, M.; Junge, H.; Kammer, A.; Beller, M.
Towards a Green Process for Bulk-Scale Synthesis of Ethyl Acetate:
Efficient Acceptorless Dehydrogenation of Ethanol. Angew. Chem., Int.
Ed. 2012, 51, 5711−5713. (d) Sølvhøj, A.; Madsen, R. Dehydrogen-
ative Coupling of Primary Alcohols To Form Esters Catalyzed by a
Ruthenium N-Heterocyclic Carbene Complex. Organometallics 2011,
30, 6044−6048. (e) Gnanaprakasam, B.; Ben-David, Y.; Milstein, D.
Ruthenium Pincer-Catalyzed Acylation of Alcohols Using Esters with
Liberation of Hydrogen under Neutral Conditions. Adv. Synth. Catal.
2010, 352, 3169−3173. (f) Gunanathan, C.; Shimon, L. J. W.;
Milstein, D. Direct Conversion of Alcohols to Acetals and H2
Catalyzed by an Acridine-Based Ruthenium Pincer Complex. J. Am.
Chem. Soc. 2009, 131, 3146−3147. (g) Zhang, J.; Leitus, G.; Ben-
David, Y.; Milstein, D. Facile Conversion of Alcohols into Esters and
Dihydrogen Catalyzed by New Ruthenium Complexes. J. Am. Chem.
Soc. 2005, 127, 10840−10841.
ACKNOWLEDGMENTS
■
We thank SERB New Delhi (EMR/2016/002517), DAE and
NISER for financial support. S.T. thanks UGC for a research
fellowship. We thank Prof. E. Balaraman and Prof. J. V. Yeldho
for their kind help.
REFERENCES
■
(1) (a) Smets, J.; Denutte, H. R. G.; Pintens, A.; Stanton, D. T.; Van
Aken, K.; Laureyn, I. H. H.; Denolf, B.; Vrielynck, F. A. C. U. S. Pat.
Appl. Publ. US 20100137178 A1, 2010. (b) Junzo, O. Modern
Carbonyl Chemistry; Otera, J., Ed.; Wiley-VCH: Weinheim, 2000.
(2) (a) Reetz, M. T. Lewis Acid Induced α-Alkylation of Carbonyl
Compounds. Angew. Chem., Int. Ed. Engl. 1982, 21, 96−108.
(b) Caine, D. Comprehensive Organic Synthesis, Vol. 3; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; pp 1−63.
(3) (a) Barta, K.; Ford, P. C. Catalytic Conversion of Nonfood
Woody Biomass Solids to Organic Liquids. Acc. Chem. Res. 2014, 47,
1503−1512. (b) Vispute, T. P.; Zhang, H.; Sanna, A.; Xiao, R.;
Huber, G. W. Renewable Chemical Commodity Feedstock’s from
Integrated Catalytic Processing of Pyrolysis Oils. Science 2010, 330,
1222−1227.
(4) Reviews for “borrowing hydrogen” methodology: (a) Corma, A.;
Navas, J.; Sabater, M. J. Advances in One-Pot Synthesis Through
Borrowing Hydrogen Catalysis. Chem. Rev. 2018, 118, 1410−1459.
(b) Faisca Phillips, A. M.; Pombeiro, A. J. L.; Kopylovich, M. N.
Recent Advances in Cascade Reactions Initiated by Alcohol
Oxidation. ChemCatChem 2017, 9, 217−246. (c) Chelucci, G.
Ruthenium and Osmium Complexes in C−C Bond-Forming
Reactions by Borrowing Hydrogen Catalysis. Coord. Chem. Rev.
2017, 331, 1−36. (d) Yang, Q.; Wang, Q.; Yu, Z. Substitution of
Alcohols by N-Nucleophiles via Transition Metal-Catalyzed Dehy-
drogenation. Chem. Soc. Rev. 2015, 44, 2305−2329. (e) Nandakumar,
A.; Midya, S. P.; Landge, V. G.; Balaraman, E. Transition-Metal-
Catalyzed Hydrogen-Transfer Annulations: Access to Heterocyclic
Scaffolds. Angew. Chem., Int. Ed. 2015, 54, 11022−11034.
(f) Ketcham, J. M.; Shin, I.; Montgomery, T. P.; Krische, M. J.
Catalytic Enantioselective C-H Functionalization of Alcohols via
Redox-Triggered Carbonyl Addition: Borrowing Hydrogen, Return-
ing Carbon. Angew. Chem., Int. Ed. 2014, 53, 9142−9150. (g) Pan, S.;
Shibata, T. Recent Advances in Iridium-Catalyzed Alkylation of C−H
and N−H Bonds. ACS Catal. 2013, 3, 704−712. (h) Obora, T. D.;
Ishii, Y. Iridium-Catalyzed Reactions Involving Transfer Hydro-
genation, Addition, N-Heterocyclization, and Alkylation Using
Alcohols and Diols as Key Substrates. Synlett 2011, 2011, 30−51.
(8) (a) Aitchison, H.; Wingad, R. L.; Wass, D. F. Homogeneous
Ethanol to Butanol Catalysis-Guerbet Renewed. ACS Catal. 2016, 6,
7125−7132. (b) Xie, Y.; Ben-David, Y.; Shimon, L. J. W.; Milstein, D.
Highly Efficient Process for Production of Biofuel from Ethanol
Catalyzed by Ruthenium Pincer Complexes. J. Am. Chem. Soc. 2016,
138, 9077−9080. (c) Kozlowski, J. T.; Davis, R. J. Heterogeneous
Catalysts for the Guerbet Coupling of Alcohols. ACS Catal. 2013, 3,
1588−1600.
(9) Das, U. K.; Ben-David, Y.; Leitus, G.; Diskin-Posner, Y.;
Milstein, D. Dehydrogenative Cross-Coupling of Primary Alcohols To
Form Cross-Esters Catalyzed by a Manganese Pincer Complex. ACS
Catal. 2019, 9, 479−484.
̈
(i) Bahn, S.; Imm, S.; Neubert, L.; Zhang, M.; Neumann, H.; Beller,
(10) (a) Chakraborty, S.; Daw, P.; Ben David, Y.; Milstein, D.
Manganese-Catalyzed α-Alkylation of Ketones, Esters, and Amides
Using Alcohols. ACS Catal. 2018, 8, 10300−10305. (b) Tan, D. - W.;
Li, H.-X.; Zhu, D.-L.; Li, H.-Y.; Young, D. J.; Yao, J.-L.; Lang, J.-P.
Ligand-Controlled Copper(I)-Catalyzed Cross-Coupling of Secon-
dary and Primary Alcohols to α-Alkylated Ketones, Pyridines, and
Quinolines. Org. Lett. 2018, 20, 608−611. (c) Sahoo, A. R.; Lalitha,
G.; Murugesh, V.; Bruneau, C.; Sharma, G. V. M.; Suresh, S.; Achard,
M. Ruthenium Phosphine-Pyridone Catalyzed Cross-Coupling of
Alcohols To form α-Alkylated Ketones. J. Org. Chem. 2017, 82,
M. The Catalytic Amination of Alcohols. ChemCatChem 2011, 3,
1853−1864. (j) Dobereiner, G. E.; Crabtree, R. H. Dehydrogenation
as a Substrate-Activating Strategy in Homogeneous Transition-Metal
́
Catalysis. Chem. Rev. 2010, 110, 681−703. (k) Guillena, G.; Ramon,
D. J.; Yus, M. Hydrogen Autotransfer in the N-Alkylation of Amines
and Related Compounds using Alcohols and Amines as Electrophiles.
Chem. Rev. 2010, 110, 1611−1641. (l) Watson, A. J. A.; Williams, J.
M. J. The Give and Take of Alcohol Activation. Science 2010, 329,
635−636. (m) Nixon, T. D.; Whittlesey, M. K.; Williams, J. M. J.
Transition Metal Catalysed Reactions of Alcohols Using Borrowing
Hydrogen Methodology. Dalton Trans 2009, 753−762. (n) Hamid,
M. H. S. A.; Slatford, P. A.; Williams, J. M. J. Borrowing Hydrogen in
the Activation of Alcohols. Adv. Synth. Catal. 2007, 349, 1555−1575.
́
́
10727−10731. (d) Jimenez, M. V.; Fernandez-Tornos, J.; Modrego,
́
F. J.; Perez-Torrente, J. J.; Oro, L. A. Oxidation and β-Alkylation of
Alcohols Catalysed by Iridium(I) Complexes with Functionalised N-
Heterocyclic Carbene Ligands. Chem. - Eur. J. 2015, 21, 17877−
17889.
́
(o) Guillena, G.; Ramon, D. J.; Yus, M. Alcohols as Electrophiles in
C-C Bond-Forming Reactions: the Hydrogen Autotransfer Process.
(11) (a) Liu, T.; Wang, L.; Wu, K.; Yu, Z. Manganese-Catalyzed β-
Alkylation of Secondary Alcohols with Primary Alcohols under
Phosphine-Free Conditions. ACS Catal. 2018, 8, 7201−7207.
(b) Roy, B. C.; Debnath, S.; Chakrabarti, K.; Paul, B.; Maji, M.;
Kundu, S. ortho-Amino Group Functionalized 2,2′-Bipyridine based
Ru(II) Complex Catalysed Alkylation of Secondary Alcohols, Nitriles
and Amines using Alcohols. Org. Chem. Front. 2018, 5, 1008−1018.
(c) Shee, S.; Paul, B.; Panja, D.; Roy, B. C.; Chakrabarti, K.; Ganguli,
Angew. Chem., Int. Ed. 2007, 46, 2358−2364.
(5) (a) Huang, F.; Liu, Z.; Yu, Z. C-Alkylation of Ketones and
Related Compounds by Alcohols: Transition-Metal-Catalyzed De-
hydrogenation. Angew. Chem., Int. Ed. 2016, 55, 862−875. (b) Obora,
Y. C-Alkylation by Hydrogen Autotransfer Reactions. Top. Curr.
Chem. 2016, 374, 1−29. (c) Obora, Y. Recent Advances in α-
Alkylation Reactions using Alcohols with Hydrogen Borrowing
Methodologies. ACS Catal. 2014, 4, 3972−3981.
E
DOI: 10.1021/jacs.9b00025
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
K.; Das, A.; Das, G. K.; Kundu, S. Tandem Cross Coupling Reaction
of Alcohols for Sustainable Synthesis of β-Alkylated Secondary
Alcohols and Flavan Derivatives. Adv. Synth. Catal. 2017, 359, 3888−
3893. (d) Wang, Q. F.; Wu, K. K.; Yu, Z. K. Ruthenium(III)-
Catalyzed β-Alkylation of Secondary Alcohols with Primary Alcohols.
Organometallics 2016, 35, 1251−1256.
(12) (a) Chaudhari, C.; Siddiki, S. M. A. H.; Shimizu, K. Self-
Coupling of Secondary Alcohols and α-Alkylation of Methyl Ketones
with Secondary Alcohols by Pt/CeO2 Catalyst. Top. Catal. 2014, 57,
1042−1048. (b) Makarov, I. S.; Madsen, R. Ruthenium-Catalyzed
Self-Coupling of Primary and Secondary Alcohols with the Liberation
of Dihydrogen. J. Org. Chem. 2013, 78, 6593−6598.
(13) Akhtar, W. M.; Cheong, C. B.; Frost, J. R.; Christensen, K. E.;
Stevenson, N. G.; Donohoe, T. J. Hydrogen Borrowing Catalysis with
Secondary Alcohols: A New Route for the Generation of β-Branched
Carbonyl Compounds. J. Am. Chem. Soc. 2017, 139, 2577−2580.
(14) (a) Thiyagarajan, S.; Gunanathan, C. Ruthenium-Catalyzed α-
Olefination of Nitriles Using Secondary Alcohols. ACS Catal. 2018, 8,
2473−2478. (b) Thiyagarajan, S.; Gunanathan, C. Facile Ruthenium-
(II)-Catalyzed α-Alkylation of Arylmethyl Nitriles Using Alcohols
Enabled by Metal−Ligand Cooperation. ACS Catal. 2017, 7, 5483−
5490.
(15) (a) Krishnakumar, V.; Gunanathan, C. Ruthenium-Catalyzed
Selective α-Deuteration of Aliphatic Nitriles Using D2O. Chem.
Commun. 2018, 54, 8705−8708. (b) Krishnakumar, V.; Chatterjee,
B.; Gunanathan, C. Ruthenium-Catalyzed Urea Synthesis by N−H
Activation of Amines. Inorg. Chem. 2017, 56, 7278−7284.
(c) Chatterjee, B.; Gunanathan, C. The Ruthenium-Catalysed
Selective Synthesis of mono-Deuterated Terminal Alkynes. Chem.
Commun. 2016, 52, 4509−4512. (d) Chatterjee, B.; Gunanathan, C.
Ruthenium Catalyzed Selective α-and α,β-Deuteration of Alcohols
Using D2O. Org. Lett. 2015, 17, 4794−4797.
(16) Anaby, A.; Schelwies, M.; Schwaben, J.; Rominger, F.; Hashmi,
A. S. K.; Schaub, T. Study of Precatalyst Degradation Leading to the
Discovery of a New Ru0 Precatalyst for Hydrogenation and
Dehydrogenation. Organometallics 2018, 37, 2193−2201.
̈
(17) Chakraborty, S.; Lagaditis, P. O.; Forster, M.; Bielinski, E. A.;
Hazari, N.; Holthausen, M. C.; Jones, W. D.; Schneider, S. Well-
Defined Iron Catalysts for the Acceptorless Reversible Dehydrogen-
ation-Hydrogenation of Alcohols and Ketones. ACS Catal. 2014, 4,
3994−4003.
F
DOI: 10.1021/jacs.9b00025
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX