Ketone Synthesis by a Nickel-Catalyzed Dehydrogenative Cross-Coupling of Primary Alcohols

Article abstract of DOI:10.1021/jacs.9b03280

An intermolecular coupling of primary alcohols and organotriflates has been developed to provide ketones by the action of a Ni(0) catalyst. This oxidative transformation is proposed to occur by the union of three distinct catalytic cycles. Two competitive oxidation processes generate aldehyde in situ via hydrogen transfer oxidation or (pseudo)dehalogenation pathways. As aldehyde forms, a Ni-catalyzed carbonyl-Heck process enables formation of the key carbon-carbon bond. The utility of this rare alcohol to ketone transformation is demonstrated through the synthesis of diverse complex and bioactive molecules.

Full text of DOI:10.1021/jacs.9b03280

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Communication
Ketone Synthesis by a Nickel-Catalyzed
Dehydrogenative Cross-Coupling of Primary Alcohols
Thomas Verheyen, Lars van Turnhout, Jaya Kishore Vandavasi,
Eric S Isbrandt, Wim M. De Borggraeve, and Stephen G. Newman
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b03280 • Publication Date (Web): 15 Apr 2019
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Journal of the American Chemical Society
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Ketone Synthesis by a Nickel-Catalyzed Dehydrogenative Cross-
Coupling of Primary Alcohols
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Thomas Verheyen,†,‡ Lars van Turnhout,†,# Jaya Kishore Vandavasi,†,# Eric S. Isbrandt,† Wim M. De
Borggraeve,‡ Stephen G. Newman*,†
†Centre for Catalysis Research and Innovation, Department of Chemistry and Biomolecular Sciences, University of
Ottawa, Ottawa, Ontario, Canada, K1N 6N5
‡Molecular Design and Synthesis, Department of Chemistry, KU Leuven, 3001 Leuven, Belgium
Supporting Information Placeholder
Net oxidation and reduction reactions are also possible if a
sacrificial hydrogen acceptor or donor is incorporated into
the reaction. For instance, pioneering work by Krische and
ABSTRACT: An intermolecular coupling of primary alcohols
and organotriflates has been developed to provide ketones by
the action of a Ni(0) catalyst. This oxidative transformation is
proposed to occur by the union of three distinct catalytic cycles.
Two competitive oxidation processes generate aldehyde in situ
via hydrogen transfer oxidation or (pseudo)dehalogenation
pathways. As aldehyde forms, a Ni-catalyzed carbonyl-Heck
process enables formation of the key carbon–carbon bond. The
utility of this rare alcohol to ketone transformation is
demonstrated through the synthesis of diverse complex and
bioactive molecules.
Scheme 1. Classical C-C bond formation strategy and recent
redox neutral reports
a) Classical redox manipulation to enable C-C bond formation
OH
X
O
[O]
R
R
activation by
oxidation
OH
Ar
O
[O]
R
R
Ar
M (e.g. Mg)
MX
Ar
Ar
activation by
reduction
In organic synthesis, it is undesirable to carry out redox
reactions that do not actively contribute to the formation of
the desired molecular scaffold.1 Nonetheless, the
adjustment of oxidation state is often necessary to prepare
the desired functionality that enables the key complexity-
building steps to take place. For instance, the addition of
Grignard reagents to aldehydes is among the most
important C–C bond forming reactions available. However,
the aldehyde component often needs to be synthesized by
oxidation of a more abundant alcohol precursor (Scheme
1a). Furthermore, the Grignard reagent must be prepared
by reduction of an organohalide with stoichiometric Mg.
Subsequent manipulation of the product may also be
required. For instance, another oxidation is required if a
ketone product is desired, culminating in 3 redox steps
required for one desirable C—C bond formation.2 This
classical route relies on well-established and reliable
transformations, but exhibits poor efficiency due to the step
count and stoichiometric waste products generated.3
b) Krische and co-workers: Redox-triggered carbonyl allylation
OH
Ru
OH
+
Ar
Ar
via
catalytically
generated
electrophile
O
catalytically
generated
nucleophile
[Ru]
+
R
c) This work: Redox-triggered cross-coupling
Ni
O
OH
OTf
+
Ar
acetone (5 equiv)
(mild oxidant)
R
Ar
R
via
catalytically
generated
electrophile
catalytically
generated
nucleophile
O
[Ni]
+
Ar
R
co-workers showed that redox-triggered carbonyl
allylation can be achieved via reaction between
catalytically-generated nucleophile/electrophile pair
(Scheme 1b), and the oxidation state of the starting material
and product could be manipulated by the inclusion or
exclusion of a mild reducing agent such as isopropanol.5
Recently, these reactions were expanded to engage
organohalides as pro-nucleophiles in catalytic Grignard-
like reactions by the Krische and Weix groups in net
a
The incorporation of oxidation state-manipulating and
complexity-building steps into a single catalytic cycle is a
powerful strategy for overcoming the poor step economy of
some classical synthetic sequences. For instance, borrowing
hydrogen and related hydrogen transfer strategies are
becoming increasingly common to enable redox-neutral
transformations to take place between two reaction
partners that are unreactive in their native oxidation state.4
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reductive transformations,6 highlighting the diversity of
Page 2 of 8
partners (Scheme 2). Different alcohols were used to make
benzophenone derivatives that were electron-neutral (4-
5), electron-rich (6-8), and electron poor (9, 10), along with
double coupling to provide bis-ketone 11. Similar tolerance
was observe for variation of the organotriflate, with
electron-neutral (12, 13), electron-rich (14, 15), electron-
poor (16, 17), and sterically hindered (18) substrates
readily participating. High yields were also observed in the
presence of an aryl chloride (19), unprotected amide (20)
and estrone backbone (21). Heterocycle-bearing alcohols
could also be used to make heterocyclic compounds with
pyridine (22), unprotected indole (23), furan (24), and
thiophene (25) substituents in good yield.
1
2
3
4
5
6
7
8
this strategy.
In contrast to achievements in Ru, Ir, and Rh catalysis, the
incorporation of hydrogen transfer and other oxidation
state-manipulating strategies into Pd(0)- and Ni(0)-
catalyzed cross-coupling reactions is rare.6b, 7 This is in large
part due to the nature of the coupling partners used, which
cannot be readily generated by mild oxidants or reductants.
In a unique demonstration of aldehydes as cross-coupling
partners, our lab recently demonstrated an efficient Ni-
catalyzed coupling to form ketones.8 This transformation is
proposed to occur by a Heck-type mechanism with the
aldehyde acting as an olefin surrogate in the catalytic cycle.
While useful, there are a number of deficiencies with the use
of aldehydes. In addition to being relatively expensive and
unstable, aldehydes are prone to aldol and Tishchenko-type
side reactions.9 In contrast, simple primary alcohols are
abundant, inexpensive, stable precursors; however, their
direct use in C-C bond forming cross-coupling reactions is
rare.10 Inspired by recent efforts in borrowing hydrogen
and related chemistry, we sought to utilize primary alcohols
as cross-coupling partners in catalytic ketone synthesis.
Herein, we present how this can be accomplished in a Ni-
catalyzed process. The transformation is proposed to occur
by multiple oxidation state-manipulating steps, ultimately
using acetone and a slight excess of the triflate coupling
partner as terminal hydrogen acceptors for the oxidative
transformation.
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Table 1: Optimization of the Ni-Catalyzed Coupling of
alcohols with Organotriflatesa
standard conditions
OH
O
Ni(cod)2 (10 mol%)
Triphos (12 mol%)
TfO
+
TMP (2 equiv)
Acetone (5 equiv)
PhMe, 20 h, 130 °C
2
1
3
(1.5 equiv)
Entry Deviation from standard reaction conditions
% Yield
1
2
3
4
5
None
93 (91)b
trace
30
PhCl, PhBr or PhI instead of PhOTf
ArOMs instead of ArOTf
ArONf instead of ArOTf
Cyclohexanone instead of acetone
2-Decanone instead of acetone
Temperature = 110 °C
1.1 equiv ArOTf
67
44
6
7
8
9
10
11
12
13
14c
86
90
62
23
trace
90
64
76
75 (67)b
We began by investigating the reaction of benzyl alcohol 1
with phenyltriflate 2. The combination of Ni(cod)2 (10
mol%) and 1,1,1-tris(diphenylphosphinomethyl)ethane
(Triphos, 12 mol%) as the catalyst, tetramethylpiperidine
(TMP, 2 equiv) as the base, and acetone (5 equiv) as a
hydrogen acceptor enabled formation of ketone 3 in 93%
yield at 130 °C (Table 1, entry 1). As observed in several
other Ni-catalyzed Heck-type reactions, the use of
organo(pseudo)halides with a non-coordinating triflate
group was critical.11 Traditional organohalides provided
only traces of product (entry 2) and alternative
pseudohalides provided only moderate yields (entries 3, 4).
Acetone was conveniently the most effective hydrogen
acceptor of those studied; for instance, use of
cyclohexanone (entry 5) and 2-decanone (entry 6) resulted
in significantly reduced yields. The reaction temperature
can be reduced to 110 °C (entry 7) with almost no decrease
in yield, though 130 °C was later found to be more generally
effective for challenging substrates (Scheme S2). Equimolar
amounts of organotriflate can be used (entry 8) albeit with
a decrease in yield. The use of the multidentate ligand
Triphos12 was particularly important. Structurally similar
dppp provided low yields (entry 9), while Xantphos, dcypp,
BINAP, S-Phos and PPh3 gave only traces of product (entry
10). Similarly, TMP and its more expensive pentamethyl
analog (PMP, entry 11) were particularly effective, though
alternative inorganic and organic bases still gave
appreciable amounts of product (entry 12, 13). Most Ni(II)
salts were found to be ineffective with the exception of
Ni(OTf)2, which gave reasonable amounts of product and
allowed reaction set-up without the need of a glovebox
(entry 14).
Ligand = dppp
Ligand = Xantphos, dcypp, BINAP, S-Phos, PPh3
Base = PMP
Base = K2CO3
Base = NEt3
Ni(OTf)2 instead of Ni(cod)2
aReactions run at 0.2 M concentration on 0.1 mmol scale. Yield
determined by GC-FID of the crude mixture with 1,3,5-
trimethoxybenzene as internal standard. Reaction run on 0.3
mmol scale; isolated yield. Reaction run on 0.3 mmol scale
outside of a glovebox.
b
c
Heterocycle-bearing organotriflates were also well
tolerated, enabling preparation of quinoline (26), pyridine
(27), quinoxaline (28) and benzothiazole (29) containing
products. A robustness screen confirmed this generality
(Scheme S3). Notably, many of these corresponding alcohol
precursors to organotriflates are more readily available
than the analagous organohalides. Next, in contrast to the
previously demonstrated carbonyl-Heck reaction,8a
aliphatic alcohols were found to be excellent coupling
partners. For instance, -primary ketones with aliphatic
chains (30, 31) could be prepared in good yields. Products
bearing -secondary alkyl substituent were similarly
effective, including cyclohexyl (32), cyclopropyl (33),
acyclic (34) and cyclobutyl (35) ketones. -Tertiary ketone
36 could be synthesized from 1-adamantanemethanol,
though the steric hinderance necessitated the use of
elevated temperatures and catalyst loading. Finally an -
chiral ketone could be prepared from the corresponding
With optimized reaction conditions in hand, the reaction of
phenyltriflate was explored with a variety of coupling
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Scheme 2. Reaction scope
1
Ni(cod)2 (10 mol%)
Triphos (12 mol%)
TMP (2 equiv)
OH
O
2
3
4
5
Ar
OTf
+
Ar
PhMe, 20 h, 130 o
Acetone (5 equiv)
C
alcohol
organotriflate
ketone
6
7
8
9
Diarylketone products
O
O
O
O
O
O
O
O
O
O
Ph
Ph
O
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
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50
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F3C
Ph
O
MeO
Ph
OMe
F
a
b
c
4:
5:
6:
7:
8:
9:
10:
11:
12:
80%
83%
90%, 68%
O
96%
70%
88%
91%
81%
76%
O
O
O
O
O
O
O
O
Ph
Ph
H
H
Ph
OMe
Ph
Cl
O
Ph
Ph
Ph
Ph
O
H
CF3
N
OMe
H
13:
14:
15:
16:
17:
18:
30:
19:
20:
21:
90%
75%
86%
90%
70%
88%
83%
71%
91%
O
Heterocyclic products
Aliphatic products
O
O
O
O
O
O
O
Ph
O
S
Ph
Ph
Ph
Ph
Ph
Cl
Ph
N
HN
O
Ph
d
d
22:
23:
25:
93%
73%
74%
88%
24:
31:
32:
33:
81%
72%
75%
78%
69%
Ph
O
O
O
O
MeO
O
O
N
O
O
S
N
Ph
Ph
Ph
Ph
Ph
Ph
Ph
N
N
N
e
26:
27:
28:
29:
34:
35:
36:
37:
32%, 91:9 e.r.
81%
43%
64%
69%
84%
56%
Bioactive molecule synthesis & derivatization
Cl
O
Cl
O
O
Ph
O
O
Cl
O
O
O
HO
N
N
7
Boc
O
N
F
)
H
OMe
O
F
O
Clofoctol derivative
40:
Photoactive Tyr derivative
Idebenone derivative
41
42
43
:
Melperone
Haloperidol
44:
(4-F) 69% (
f
d,f
:
62%
(3-F) 66%
37%
38:
39:
62%
60% , 97:3 e.r.
:
(2-F) 76%
General reaction conditions: alcohol (0.30 mmol), organotriflate (0.45 mmol), TMP (0.6 mmol), Acetone (1.5 mmol), Triphos (12
mol%), Ni(cod)2 (10 mol%) in toluene (1.5 mL), 130 °C for 22h. aNi(OTf)2 (10 mol%), set-up outside of glovebox. bOrganotriflate
(0.90 mmol), TMP (1.2 mmol), Acetone (3.0 mmol). cReaction on 3.0 mmol scale. d140 °C. eNi(cod)2 (20 mol%), Triphos (24 mol%)
and 140 °C. fReaction on 0.2 mmol scale.
enantiopure alcohol starting material with minimal erosion
We next sought to uncover the nature of the oxidation step
in the reaction.17 An experiment was carried out between 4-
Methylbenzyl alcohol 45, 1.5 equivalents of organotriflate
46, and 5 equivalents of 2-dodecanone, allowing the fate of
these reaction components to be tracked (Scheme 3a). A
72% NMR yield of ketone 47 was observed, along with two
reduction side-products, biaryl 48a (50%) and dodecanol
48b (20%), providing a nearly closed redox balance
suggestive of two distinct oxidative pathways. Coupling
with the deuterated alcohol analogue provided substantial
deuterium incorporation in both reduction side-products
(Scheme S8). Catalytic oxidation of alcohols is known both
with sacrificial ketones (Oppenauer oxidation)18 and
sacrificial organo(pseudo)halides,19 both of which could
produce an aldehyde in situ along with the observed
reduction products. Indeed, aldehyde intermediates can be
observed, particularly when quenching reactions before
completion. For instance, when monitoring the reaction of
49 by NMR, aldehyde 50 could be observed throughout,
of enantiopurity (37).
Due to the functional group tolerance of this oxidative
process and the availability of primary alcohols and
phenols, this method is highly applicable to the
derivatization of bioactive molecules. For instance,
photoactive protected tyrosine derivative 38 was prepared,
maintaining the epimerizable sterocenter.13 The
Alzheimer’s therapeutic idebenone and antibacterial agent
clofoctyl could also be readily converted to novel ketone
analogues 39 and 40. Lastly, melperone 41 and haloperidol
44 are two important ketone-containing antipsychotic
therapeutics which are traditionally formed from para-
selective Friedel-Crafts reactions of fluorobenzene and the
corresponding acid chloride.14 These molecules can be
efficiently prepared by Ni-catalyzed oxidative coupling
without limitations on the substitution patterns
available.15,16
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Page 4 of 8
albeit in low concentration (Scheme 3b). Aldehyde 50 was
hydride can reduce the acetone additive via complex VII
and undergo substitution with alcohol starting material to
form VIII (Oxidation Cycle 2).23 -Hydride elimination
provides aldehyde and regenerates metal hydride VI.
1
2
3
4
5
6
7
8
also a viable starting material in the reaction, though yields
were generally low with significant quantities of the
Tishchenko (52) and aldol (53) products being formed
(Scheme 3c and Scheme S10). Gradual formation and
consumption of aldehyde in situ may thus explain the high
efficiency and scope of this oxidative coupling reaction in
comparison to redox neutral carbonyl-Heck, particularly
with aliphatic alcohols.8a, 20 With this information in mind, a
plausible mechanistic pathway is proposed (Scheme 4). The
Ni(0) catalyst I first reacts with organotriflate to form
oxidative addition intermediate II. This species can react
In conclusion, a Ni-catalyzed oxidative coupling of alcohols
and organotriflates has been demonstrated. This reaction
relies on catalytic formation of two reactive species: an aryl-
Ni nucleophile and an aldehyde electrophile. These
intermediates react via a carbonyl Heck-type pathway,
forming ketone products. This oxidative reaction, enabled
by the use of acetone and a small excess of organotriflate
coupling partner, demonstrates a new interface between
cross-coupling reactions with dehydrogenative activation.
In contrast to redox-neutral reactions with stoichiometric
aldehydes, no decomposition and dimerization side
reactions were observed, likely due to the slow in situ
formation of the reactive aldehyde intermediate. We
anticipate the incorporation of mild oxidation state
manipulating steps into diverse transition metal-catalyzed
coupling reactions has much unrealized potential for
efficient chemical synthesis.
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with the alcohol starting material to form alkoxide III via
21
Oxidation Cycle 1.19a,
-Hydride elimination produces
aldehyde and nickel hydride IV, which can undergo
reductive elimination to form I and reduced organotriflate.
Alternatively, arylnickel II can react with aldehyde if
present via insertion to form alkoxide V. -Hydride
elimination produces the ketone product and Ni-hydride VI.
Such species are known
Scheme 3. Mechanistic information
A) Identifying redox balance
Scheme 4. Plausible catalytic cycle
O
(5 equiv)
C8H17
reduction
OH
oxidation
O
Ni(cod)2 (10 mol%)
Triphos (12 mol%)
46
OH
O
O
aldehyde
H
ArOTf
(1.5 equiv)
+
intermediate
Ar
R
R

Ar
C8H17
48b
20%
TMP (2 equiv)
PhMe, 20 h, 130 °C
Ar
O
48a
50%
ArH
[Ni]
47:
72%
OH
45
side-
products
Ar
H
Ar = 4-PhC6H4
[Ni]
IV
III
R
B) Observation of aldehyde as a reaction intermediate
oxidation
cycle 1
O
ketone
base•HOTf
Ni(cod)2 (10 mol%)
product
O
Ar
R
Triphos (12 mol%)
46
H
ArOTf
(1.5 equiv)
triflate counterion
omitted for clarity
Ph
51
Ar
Ar
Ph
OH
Acetone (5 equiv)
TMP (2 equiv)
: 85% after 20 h
ArOTf
49
R
OH
Ar
base•HOTf
base
PhMe (0.2 M), 20 h, 130 °C
[Ni]
I
[Ni]
II
Ph
O
O
50
up to 18% observed
O
productive
cycle
R
base
[Ni]
[Ni]
O
V
H
VI
Ar
R
[Ni]
oxidation
cycle 2
O
O
VII
Ar
R
OH
O
R
R
[Ni]
O
C) Challenges with aldehyde as a reactant
VIII
OH
aldehyde side-reactions
O
R
Ni
O
Ph
O
52
Ph
31
+
+ PhOTf
various
conditions
Ph
H
AUTHOR INFORMATION
Corresponding Author
O
29-44%
50
Ph
H
+
H
Ph
53
stephen.newman@uottawa.ca
Author Contributions
#These authors contributed equally to this work.
to undergo slow reductive elimination to regenerate Ni(0),
which is proposed to be rate determining in other Ni-
22
catalyzed Heck-type reactions.11a,
Alternatively, the
4
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Advances in alpha-Alkylation Reactions using Alcohols with
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Experimental
procedures,
optimization
tables,
troubleshooting, robustness screen, characterization of
organic molecules, mechanistic studies. This material is
available free of charge via the Internet at http://pubs.acs.org.
ACKNOWLEDGEMENT
Financial support for this work was provided by the University
of Ottawa, the National Science and Engineering Research
Council of Canada (NSERC), the Canada Research Chair
program. The Canadian Foundation for Innovation (CFI) and
the Ontario Ministry of Research, Innovation, & Science are
thanked for essential infrastructure. T.V. thanks FWO-
vlaanderen for the FWO-SB PhD fellowship received. E.S.I.
thanks NSERC for a graduate fellowship.
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(5) (a) Nguyen, K. D.; Park, B. Y.; Luong, T.; Sato, H.; Garza, V.
J.; Krische, M. J. Metal-Catalyzed Reductive Coupling of Olefin-
Derived Nucleophiles: Reinventing Carbonyl Addition. Science
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G. A High-Throughput Approach to Discovery: Heck-Type
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Productive
Chloroarene
C-Cl
Bond
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(20) For additional experiments on dimerization of aldehyde see
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(21) Similar oxidation mechanism are well established in the
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Catalyzed Hydrogen Transfer Process. Adv. Synth. Catal. 2011,
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(16) For recent methods to make aryl ketones without the
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Hoang, T. G.; Underwood, S. J.; Gemmel, P. M.; Hardy, M. A.;
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Direct
Transformation of Aldehydes into Esters and Amides. Angew.
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(22) Lin, B. L.; Liu, L.; Fu, Y.; Luo, S. W.; Chen, Q.; Guo, Q. X.
Comparing Nickel- and Palladium-Catalyzed Heck Reactions.
Organometallics 2004, 23, 2114-2123.
(23) (a) Kozuch, S.; Lee, S. E.; Shaik, S. Theoretical Analysis of
the Catalytic Cycle of
Application of the Energetic Span Model. Organometallics 2009,
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A. Pd-Catalyzed Aldehyde to Ester Conversion: A Hydrogen
Functionalization
To
Achieve
Sterically
Controlled
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10025-10033. (b) Ruan, J. W.; Saidi, O.; Iggo, J. A.; Xiao, J. L.
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Transfer Approach. Org. Lett. 2013, 15, 500-503. (c) Krug, C.;
Redox-Economical Coupling of Alcohols and Alkynes to Form
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Eberhardt, N. A.; Wellala, N. P. N.; Li, Y.; Krause, J. A.; Guan, H.
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Hartwig, J. F. Direct Observation of Aldehyde Insertion into
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oxidation
then
then oxidation
multistep synthesis by
stoichiometric oxidation
state manipulation
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BrMg R'
common route
5
6
OH
O
>40 examples
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up to 96% yield
Ni catalyst
TfO R'
H2 acceptor
R
R
R'
integration of cross-
coupling reactivity with
catalytic oxidation
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direct route
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