Ruthenium-Catalyzed α-Alkylation of Ketones Using Secondary Alcohols to β-Disubstituted Ketones

Article abstract of DOI:10.1021/acs.orglett.0c02787

An assortment of aromatic ketones was successfully functionalized with a variety of unactivated secondary alcohols that serve as alkylating agents, providing β-disubstituted ketone products in good to excellent yields. Remarkably, challenging substrates such as simple acetophenone derivatives are effectively alkylated under this ruthenium catalysis. The substituted cyclohexanol compounds displayed product-induced diastereoselectivity. Mechanistic studies indicate the involvement of the hydrogen-borrowing pathway in these alkylation reactions. Notably, this selective and catalytic C-C bond-forming reaction requires only a minimal load of catalyst and base and produces H2O as the only byproduct, making this protocol attractive and environmentally benign.

Full text of DOI:10.1021/acs.orglett.0c02787

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Letter
Ruthenium-Catalyzed α‑Alkylation of Ketones Using Secondary
Alcohols to β‑Disubstituted Ketones
Subramanian Thiyagarajan,† Raman Vijaya Sankar,† and Chidambaram Gunanathan*
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ABSTRACT: An assortment of aromatic ketones was successfully function-
alized with a variety of unactivated secondary alcohols that serve as alkylating
agents, providing β-disubstituted ketone products in good to excellent yields.
Remarkably, challenging substrates such as simple acetophenone derivatives
are effectively alkylated under this ruthenium catalysis. The substituted
cyclohexanol compounds displayed product-induced diastereoselectivity.
Mechanistic studies indicate the involvement of the hydrogen-borrowing
pathway in these alkylation reactions. Notably, this selective and catalytic C−
C bond-forming reaction requires only a minimal load of catalyst and base and produces H2O as the only byproduct, making this
protocol attractive and environmentally benign.
he hydrogen-borrowing strategy is an attractive method for
C−C and C−N bond formations, and these trans-
relatively underdeveloped. In 2017, the Donohoe group
reported the synthesis of β-branched ketones via α-alkylation
of ketones using secondary alcohols.7 Very recently Co,8 Fe,9
and Mn10-catalyzed α-alkylation of ketones using secondary
alcohols was developed (Scheme 1b). All of these enticing
developments can be summarized as follows: (i) Stoichiometric
excess base is required, which results in aldol side reactions. (ii)
To avoid base-promoted self-condensation, highly hindered aryl
ketones are employed. In general, these methods work only for
pentamethylphenyl (Ph*) ketone or trisubstituted aryl ketones.
(iii) Unsubstituted or other aryl ketones are less successful and,
thus, suffer from a limited substrate scope. Importantly, the Ph*
group averts ketone self-condensation reactions, which can also
be detached to prepare a range of carbonyl derivatives such as
esters and amides through a retro-Friedel−Crafts acylation
reaction.7−10 To circumvent these drawbacks, an efficient
catalytic system is essential for the success of this process and
its broad application, which also should preclude the self-
condensation of the nonsubstituted ketone substrates. Recently,
selective cross-coupling of secondary alcohols to β-disubstituted
ketones was reported by our group.11 However, as far as we
know, there is no general method for α-alkylation of ketones
(especially for acetophenone with no or less substitution) using
secondary alcohols. Thus, a simple catalytic method with a
broad substrate scope is urgently required.
T
formations are fundamentally important in chemical synthesis.1
This strategy becomes acceptable and well-recognized as it
enhances the importance of low waste transformations. In these
processes, the catalyst borrows the hydrogen from alcohols via
oxidation reactions to provide corresponding carbonyl com-
pounds and further concomitant condensation, with nucleo-
philic enolates forming CC bonds. Finally, the “borrowed
hydrogen” by the catalyst is added to the unsaturated
intermediate (CC bonds) to deliver the hydrogenated/
alkylated product. Conventionally, α-alkylated ketones are
prepared from the reaction of ketone enolate species with
alkyl halides.2 The involvement of alkyl halides and a
stoichiometric excess of base produces copious hazardous salt
waste and undesired aldol side products (Scheme 1c) and, thus,
decreases the atom economy. Therefore, the development of a
simple, selective, and atom-economical alkylation reaction for
the construction of C−C bonds is strongly desired. Notably,
alcohols are cheap, readily available, and can be produced from
lignocellulosic biomass.3 Thus, alcohols are considered as
potential alkylating agents that produce water as the only
byproduct.1,4
Ketones are of great importance in biology and industries,
where they are produced on a large scale as solvents, polymer
precursors, and pharmaceuticals.5 The use of primary alcohols
for α-alkylation of ketones and β-alkylation of secondary
alcohols has been well-established, which generates linear
chain α-alkylated ketones.1,4,6 A ruthenium-catalyzed hydro-
gen-borrowing strategy using primary alcohols with ketone
enolates is well-known (Scheme 1a).1,4 However, the use of
secondary alcohols for alkylation reactions is poorly docu-
mented. In contrast to α-branched ketones, formation of β-
disubstituted branched products is more challenging and
Received: August 20, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02787
© XXXX American Chemical Society
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Scheme 1. Selective Catalytic α-Alkylation of Ketones Using
Primary and Secondary Alcohols
Table 1. Optimization for the α-Alkylation of Ketones Using
Secondary Alcohols Catalyzed by 1
a
catalyst
base
alcohol temperature conversion yield
b c
entry (mol %) (mol %) (equiv)
(°C)
(%)
(%)
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1
1
1
0.5
1
200
200
100
20
5
2
5
5
5
2
2
135
125
125
125
125
125
125
120
100
125
125
125
125
125
125
125
>99
>99
>99
>99
>99
40
>99
97
5
95
85
5
>99
55
59
68
70
73
80
35
79
74
1.2
1.2
1.2
1.2
1.5
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
9
10
11
12
13
14
15
16
2.5
75
65
d
e
5
5
5
5
1
1
f
79
75
g
g
h
1
5
>99
a
Reaction conditions: acetophenone (0.5 mmol), cyclohexanol (0.6
mmol), catalyst 1, KOtBu, and toluene (1.5 mL) were heated at 125
°C under open conditions with an argon flow. Conversion of
acetophenone was determined by GC using mesitylene as an internal
b
c
d
standard. Isolated yields after column chromatography. 1,4-Dioxane
e
f
used as a solvent. 5 mol % of Cs2CO3 used as a base. 5 mol % of
g
h
NaOtBu used as a base. Reaction performed twice. Reaction
performed on a 1 mmol scale.
Modern transition metal catalysis is keen on development of
sustainable, one-step, and atom-economical strategies for the
preparation of valuable building blocks from readily available
starting materials. In this regard, we have developed ruthenium
pincer catalyzed selective hydrogenation of epoxides,12 ketazine
synthesis,13 α-alkylation, and α-olefination of nitriles and N,N-
dialkylation of acylhydrazides using alcohols.14 Remarkably,
liberated H2 and H2O are the only byproducts from these green
catalytic methods.
effect on the reaction was noticeable. When 1,4-dioxane was
used as a solvent, product yield was diminished (entry 11).
Whereas use of Cs2CO3 as a base provided no product
formation, NaOtBu produced results comparable to those of
KOtBu (entries 12 and 13). Control experiments confirmed that
no product was formed in the absence of catalyst 1 and base,
implying their requirement in the α-alkylation of ketones
(entries 14 and 15).
Initially, the reaction of acetophenone (0.5 mmol) and
cyclohexanol (1 mmol) was investigated as a model system in
the presence of a ruthenium pincer catalyst 1 (1 mol %, Ru-
MACHO) and 2 equiv of a base (KOtBu) in toluene at 135 °C.
Surprisingly, catalyst 1 was found to exhibit distinctively high
activity in forming the alkylated product 2a along with a trace
amount of aldol side products. The undesired aldol side
products (Scheme 1c) were inseparable from column
chromatography, and thus, we were unable to isolate and
identify them. The complete conversion of acetophenone was
observed in 24 h, and the desired α-alkylated product 2a was
isolated in 59% yield (entry 1, Table 1). When temperature and
the amount of base (KOtBu) and secondary alcohol were
decreased, the product formation was slightly increased (entries
2 and 3). Use of a stoichiometric amount of base resulted in a
considerable amount of aldol side reactions (Scheme 1c and
Table 1,entries 1−3). Thus, decreasing the amount of KOtBu to
20 and 5 mol % resulted in improved product yields of 73 and
80%, respectively (entries 4 and 5). However, use of 2 mol % of
base provided only 40% conversion (entry 6). The product yield
was not improved upon using a slight excess of cyclohexanol
(entry 7). Further, decreasing the temperature and catalyst load
provided considerably lower yields (entries 8−10). The solvent
The reactivity of acetophenone with different secondary
alcohols was explored (Scheme 2). Substituted cyclohexanol
derivatives afforded the corresponding alkylated products 2b−
2e in good to moderate yields. The substitution on the
cyclohexyl ring resulted in products as a mixture of
diastereoisomers. Reaction of cycloheptanol and exo-norborenol
with acetophenone afforded the α-alkylated products 2f and 2g
in 60 and 75% yields, respectively. Highly hindered 2-
adamantanol provided product 2h in 40% yield. Decahydro-
naphthalen-2-ol is well-tolerated in this catalytic protocol and
converted into α-alkylated product 2i in 74% yield (Scheme 2).
Diphenylmethanol provided product 2j in 68% yield. Finally, 5
equiv of 3-pentanol and 4-heptanol reacted with acetophenone
with increased catalyst load (5 mol %) and KOtBu (10 mol %),
and the corresponding alkylated products 2k and 2l were
isolated in moderate yields (Scheme 2).
Next, application of the α-alkylation reaction was extended to
diverse ketones with different secondary alcohols, which
delivered the β-branched ketone products in good to excellent
yields (Scheme 3). Both electron-donating and electron-
withdrawing groups on aryl ketones were well-tolerated in this
catalytic protocol. Reaction of cyclohexanol with a variety of
B
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Scheme 2. Ruthenium-Catalyzed α-Alkylation of
Acetophenone Using Secondary Alcohols
Scheme 3. Ruthenium-Catalyzed α-Alkylation of Ketones
Using Secondary Alcohols
a
a
a
Reaction conditions: acetophenone (0.5 mmol), secondary alcohol
(0.6 mmol), toluene (1.5 mL), catalyst 1 (1 mol %), and KOtBu (5
mol %) were heated at 125 °C under open conditions with a nitrogen
flow. Conversion of acetophenone was determined by GC analysis
using mesitylene as an internal standard and given within parentheses.
Diastereomeric ratios (dr) were determined from 1H NMR analysis of
the crude reaction mixture; only the major isomer is shown. Yields
refer to isolated pure products after column chromatography. 3 mol
% of catalyst 1 and 10 mol % of base were used. Diastereomeric
mixture and dr ratio not determined. Reaction performed using 5
mol % of catalyst 1 and 10 mol % of base. 5 equiv of alcohol was
b
c
d
e
used.
a
Reaction conditions: same as those in the footnote of Scheme 1
b
except that instead of acetophenone, ketone (0.5 mmol) was used. 3
c
mol % of catalyst 1 and 15 mol % of KOtBu were used. 3 equiv of
ketones provided α-alkylated ketone products 3a−3h. 4-Methyl,
4-propyl, 4-tert-butyl, and 4-phenyl-substituted cyclohexanol
derivatives provided products 3i−3l as a mixture of diaster-
eoisomers. Cycloheptanol reacted with 4-methoxyacetophe-
none and resulted in product 3m (68% yield). Diphenylmetha-
nol reacted with 4-cyclohexylacetophenone, and the desired
ketone product 3n was isolated in 64% yield. Interestingly,
unactivated acyclic secondary alcohols are well-tolerated,
enabling the synthesis of β-disubstituted ketones 3o−3r in
very good yields. Remarkably, heteroarene-embedded ketones
successfully participated in α-alkylation with secondary alcohols
and provided products 3e, 3h, 3k, and 3p in moderate to good
yields (Scheme 3). However, reaction of heteroaromatic ketones
such as 2-acetylpyridine, 2-acetylfuran, and 2-acetylthiophene
with cyclohexanol failed to provide the desired α-alkylation
products. Catalytic alkylation of aliphatic ketones such as
cyclopropyl methyl ketone and 2-heptanone with cyclohexanol
were performed, which resulted in an incomplete reaction and
provided complex mixtures, indicating the importance of the
aryl group in ketones.
d
cycloheptanol was used. Reaction performed using 5 equiv of
alcohol, 5 mol % of catalyst 1, and 20 mol % of base. 10 equiv of
e
isopropyl alcohol was used.
Experiments to decipher the reaction pathways and kinetic
analysis were further carried out. Under standard conditions, the
reaction of acetophenone and cyclohexanol catalyzed by 1 was
monitored using GC, which revealed that the consumption of
acetophenone follows first-order kinetics (Figure 1).
Reaction of 1-mesitylethan-1-one with 2-adamantanol reacted
under standard reaction conditions to provide selective
formation of α,β-unsaturated ketone product 4a, which was
isolated in 90% yield (Scheme 4a). Due to the high steric
hindrance on enone 4a, further hydrogenation by the catalyst
was prevented, and this observation confirms the involvement of
enone intermediacy in the reaction. Cyclohexanone reacted with
1-phenylethanol and afforded the α-alkylated ketone product 2a
in 83% yield (Scheme 4b). Use of a catalytic amount of base
minimizes the self-dimerization of in situ formed acetophenone
C
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Scheme 5. Proposed Reaction Mechanism for the
Ruthenium-Catalyzed α-Alkylation of Ketones Using
Secondary Alcohols
Figure 1. Monitoring of the reaction progress by GC. Concentration of
acetophenone (black line) and product 2a (red line) in the catalytic α-
alkylation using cyclohexanol.
Scheme 4. Mechanistic Studies for the α-Alkylation of
Ketones Using Secondary Alcohols
dehydrogenation, which releases the ketone and generates a
ruthenium dihydride intermediate III. An in situ formed ketone
undergoes condensation with aromatic ketone under basic
conditions, leading to the formation of an α,β-unsaturated
carbonyl compound. Finally, an α,β-unsaturated carbonyl
compound intermediate is hydrogenated by ruthenium
dihydride complex III, resulting in the alkylated product,
which regenerates the catalytically active intermediate I. The
amine−amide metal−ligand cooperation in the catalytic system
allows the same oxidation state (+2) in all intermediates
involved in the catalytic cycle.
In conclusion, a ruthenium pincer catalyzed efficient and
convenient method was developed for the α-alkylation of
ketones using secondary alcohols to β-branched ketones.
Contrary to previously reported procedures, this strategy
explored the utility of unsubstituted and nonhindered
acetophenone compounds with a variety of secondary alcohols,
which are used as alkylating agents. Interestingly, this catalytic
method has widespread substrate scope and produces water as
the only byproduct, making it highly atom-economical and
environmentally friendly.
and other aldol side products (see Scheme 1c and Table 1,
entries 1−5), which are observed only in minor amounts.
Notably, cyclohexanone failed to undergo α-alkylation with 1-
phenylethanol. This observation clearly indicates that the aryl
group in ketones is important for the α-alkylation reaction. A
deuterium-labeling experiment was performed with 4-methox-
yacetophenone and deuterated 4-tert-butylcyclohexanol, and the
outcome revealed that the reactions proceeded through the
hydrogen-borrowing pathway. Product 4b was isolated in 74%
yield, which exhibited 99 and 50% deuterium incorporation at
the α- and β-positions, respectively (Scheme 4c). The H/D
scrambling at the β-position may be the result of H/D exchange
between the in situ formed Ru−D intermediate and H2O, and
the preferential deuteration at the α-position is perhaps due to
the selective reaction of catalyst with an α,β-unsaturated
intermediate through the hydrogen-borrowing methodology.
The plausible mechanism for α-alkylation of ketones using
secondary alcohols catalyzed by 1 is delineated in Scheme 5.
Facile O−H, N−H, and sp-C−H bond activation reactions were
established with catalyst 1 in our previous reports.11−15 An
unsaturated reactive intermediate I is formed in situ upon
reaction of 1 with base,15b,16 which further reacts with the
secondary alcohol to result in an alkoxy-ligated intermediate
II.15d Further, the β-hydride elimination reaction leads to
ASSOCIATED CONTENT
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02787.
Experimental procedures, graphical and tabular character-
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AUTHOR INFORMATION
Corresponding Author
■
Chidambaram Gunanathan − School of Chemical Sciences,
National Institute of Science Education and Research (NISER),
Bhubaneswar 752050, India; orcid.org/0000-0002-9458-
5198; Email: gunanathan@niser.ac.in
Authors
Subramanian Thiyagarajan − School of Chemical Sciences,
National Institute of Science Education and Research (NISER),
D
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Biomass Solids to Organic Liquids. Acc. Chem. Res. 2014, 47, 1503−
1512.
(4) (a) Nixon, T. D.; Whittlesey, M. K.; Williams, J. M. J. Transition
Metal Catalyzed Reactions of Alcohols Using Borrowing Hydrogen
Methodology. Dalton Trans. 2009, 753−762. (b) Obora, Y. C-
Alkylation by Hydrogen Autotransfer Reactions. Top. Curr. Chem.
Bhubaneswar 752050, India; orcid.org/0000-0002-0735-
5686
Raman Vijaya Sankar − School of Chemical Sciences, National
Institute of Science Education and Research (NISER),
Bhubaneswar 752050, India
Complete contact information is available at:
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̈
2016, 374, 11. (c) Bahn, S.; Imm, S.; Neubert, L.; Zhang, M.;
Neumann, H.; Beller, M. The Catalytic Amination of Alcohols.
ChemCatChem 2011, 3, 1853−1864. (d) Pan, S.; Shibata, T. Recent
Advances in Iridium-Catalyzed Alkylation of C−H and N−H Bonds.
ACS Catal. 2013, 3, 704−712. (e) Obora, T. D.; Ishii, Y. Iridium-
Catalyzed Reactions Involving Transfer Hydrogenation, Addition, N-
Heterocyclization, and Alkylation Using Alcohols and Diols as Key
Substrates. Synlett 2011, 2011, 30−51. (f) Dobereiner, G. E.; Crabtree,
R. H. Dehydrogenation as a Substrate-Activating Strategy in
Homogeneous Transition-Metal Catalysis. Chem. Rev. 2010, 110,
681−703.
Author Contributions
†S.T. and R.V.S. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(5) (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. Patent
Appl. US 20100137178 A1, 2010. (b) Junzo, O. In Modern Carbonyl
Chemistry; Otera, J., Ed.; Wiley-VCH: Weinheim, 2000.
(6) Gawali, S. S.; Pandia, B. K.; Pal, S.; Gunanathan, C. Manganese(I)-
Catalyzed Cross Coupling of Ketones and Secondary Alcohols with
Primary Alcohols. ACS Omega 2019, 4, 10741−10754.
(7) 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.
(8) Chakraborty, P.; Gangwar, M. K.; Emayavaramban, B.; Manoury,
E.; Poli, R.; Sundararaju, B. α-Alkylation of Ketones with Secondary
Alcohols Catalyzed by Well Defined Cp*Co III-Complexes. Chem-
SusChem 2019, 12, 3463−3467.
(9) Bettoni, L.; Gaillard, S.; Renaud, J.-L. Iron-Catalyzed α-Alkylation
of Ketones with Secondary Alcohols: Access to β-Disubstituted
Carbonyl Compounds. Org. Lett. 2020, 22, 2064−2069.
(10) Waiba, S.; Jana, S. K.; Jati, A.; Jana, A.; Maji, B. Manganese
Complex-Catalyzed α-Alkylation of Ketones with Secondary Alcohols
Enables the Synthesis of β-Branched Carbonyl Compounds. Chem.
Commun. 2020, 56, 8376−8379.
(11) (a) Thiyagarajan, S.; Gunanathan, C. Catalytic Cross-Coupling
of Secondary Alcohols. J. Am. Chem. Soc. 2019, 141, 3822−3827.
(b) Thiyagarajan, S.; Gunanathan, C. Ruthenium-Catalyzed Direct
Cross-Coupling of Secondary Alcohols to β-Disubstituted Ketones.
Synlett 2019, 30, 2027−2034.
(12) Thiyagarajan, S.; Gunanathan, C. Ruthenium-Catalyzed
Selective Hydrogenation of Epoxides to Secondary Alcohols. Org.
Lett. 2019, 21, 9774−9778.
(13) Kishore, J.; Thiyagarajan, S.; Gunanathan, C. Ruthenium(II)-
Catalyzed Direct Synthesis of Ketazines Using Secondary Alcohols.
Chem. Commun. 2019, 55, 4542−4545.
(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. (c) Thiyagarajan, S.; Gunanathan, C. Direct Catalytic Sym-
metrical, Unsymmetrical N,N-Dialkylation and Cyclization of Acylhy-
drazides Using Alcohols. Org. Lett. 2020, 22, 6617−6622.
We thank SERB New Delhi (EMR/2016/002517), DAE, and
NISER for financial support. We thank Prof. J. V. Yeldho, Prof.
Basker Sundararaju, and Prof. B. Gnanaprakasam for their kind
help. S.T. thanks UGC for a research fellowship. R.V.S. thanks
NISER for a research fellowship.
REFERENCES
■
(1) Reviews for hydrogen-borrowing strategy: (a) Watson, A. J. A.;
Williams, J. M. J. The Give and Take of Alcohol Activation. Science
2010, 329, 635−636. (b) 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. (c) Corma, A.; Navas, J.; Sabater, M. J.
Advances in One-Pot Synthesis Through Borrowing Hydrogen
Catalysis. Chem. Rev. 2018, 118, 1410−1459. (d) Guillena, G.;
́
Ramon, D. J.; Yus, M. Alcohols as Electrophiles in C-C Bond-Forming
Reactions: the Hydrogen Autotransfer Process. Angew. Chem., Int. Ed.
2007, 46, 2358−2364. (e) Obora, Y. Recent Advances in α-Alkylation
Reactions using Alcohols with Hydrogen Borrowing Methodologies.
́
ACS Catal. 2014, 4, 3972−3981. (f) 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. (g) 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. (h) Chelucci, G.
Ruthenium and Osmium Complexes in C−C Bond-Forming Reactions
by Borrowing Hydrogen Catalysis. Coord. Chem. Rev. 2017, 331, 1−36.
(i) 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, Returning
Carbon. Angew. Chem., Int. Ed. 2014, 53, 9142−9150. (j) Huang, F.;
Liu, Z.; Yu, Z. C−Alkylation of Ketones and Related Compounds by
Alcohols: Transition-Metal-Catalyzed Dehydrogenation. Angew.
Chem., Int. Ed. 2016, 55, 862−875. (k) Gunanathan, C.; Milstein, D.
Applications of Acceptorless Dehydrogenation and Related Trans-
formations in Chemical Synthesis. Science 2013, 341, 1229712.
(l) 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. (m) Yang, Q.; Wang, Q.; Yu, Z. Substitution of Alcohols by N-
Nucleophiles via Transition Metal-Catalyzed Dehydrogenation. Chem.
Soc. Rev. 2015, 44, 2305−2329.
(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) Chatter-
jee, B.; Gunanathan, C. The Ruthenium-Catalyzed 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.
(2) (a) Arseniyadis, S.; Kyler, K. S.; Watt, D. S. Addition and
Substitution Reactions of Nitrile-Stabilized Carbanions. Org. React.
1984, 31, 1−364. (b) Reetz, M. T. Lewis Acid Induced α-Alkylation of
Carbonyl Compounds. Angew. Chem., Int. Ed. Engl. 1982, 21, 96−108.
(c) Caine, D. In Comprehensive Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon: Oxford, 1991; Vol. 3, pp 1−63.
(3) (a) 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.
(b) Barta, K.; Ford, P. C. Catalytic Conversion of Nonfood Woody
E
https://dx.doi.org/10.1021/acs.orglett.0c02787
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
(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.
F
https://dx.doi.org/10.1021/acs.orglett.0c02787
Org. Lett. XXXX, XXX, XXX−XXX