Catalytic Acceptorless Dehydrogenation of Aliphatic Alcohols

Article abstract of DOI:10.1021/jacs.0c00123

We developed the first acceptorless dehydrogenation of aliphatic secondary alcohols to ketones under visible light irradiation at room temperature by devising a ternary hybrid catalyst system comprising a photoredox catalyst, a thiophosphate organocatalyst, and a nickel catalyst. The reaction proceeded through three main steps: hydrogen atom transfer from the α-C-H bond of an alcohol substrate to the thiyl radical of the photo-oxidized organocatalyst, interception of the generated carbon-centered radical with a nickel catalyst, and β-hydride elimination. The reaction proceeded in high yield under mild conditions without producing side products (except H2 gas) from various alcohols, including sterically hindered alcohols, a steroid, and a pharmaceutical derivative. This catalyst system also promoted acceptorless cross-dehydrogenative esterification from aldehydes and alcohols through hemiacetal intermediates.

Full text of DOI:10.1021/jacs.0c00123

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Article
Catalytic Acceptorless Dehydrogenation of Aliphatic Alcohols
Hiromu Fuse, Harunobu Mitsunuma, and Motomu Kanai
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c00123 • Publication Date (Web): 14 Feb 2020
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Catalytic Acceptorless Dehydrogenation of Aliphatic Alcohols
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Hiromu Fuse,† Harunobu Mitsunuma,*,† and Motomu Kanai*,†
†Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan
ABSTRACT: We developed the first acceptorless dehydrogenation of aliphatic secondary alcohols to ketones under visible
light irradiation at room temperature by devising a ternary hybrid catalyst system comprising a photoredox catalyst, a
thiophosphate organocatalyst, and a nickel catalyst. The reaction proceeded through three main steps: hydrogen atom
transfer from the α-C–H bond of an alcohol substrate to the thiyl radical of the photo-oxidized organocatalyst, interception of
the generated carbon-centered radical with a nickel catalyst, and β-hydride elimination. The reaction proceeded in high yield
under mild conditions without producing side products (except H2 gas) from various alcohols, including sterically hindered
alcohols, a steroid, and a pharmaceutical derivative. This catalyst system also promoted acceptorless cross-dehydrogenative
esterification from aldehydes and alcohols through hemiacetal intermediates.
thiyl radical (RS) acting as a HAT catalyst is generated
through single-electron oxidation of a thiophosphoric acid
(TPA) organocatalyst by a photo-excited acridinium
photoredox catalyst (*Mes-Acr+).10 This HAT catalyst
abstracts a hydrogen atom from an α-C‒H bond of the
alcohol substrate, generating α-oxy carbon-centered radical
3. Then, a nickel(II) catalyst oxidatively intercepts 3, giving
presumed organonickel(III) species 4. Single-electron
reduction of Ni(III) by the reduced form of the photoredox
catalyst (Mes-Acr), followed by β-hydride elimination
affords enol 6, which tautomerizes to product ketone 2.
Hydrogen gas evolves through protonolysis of the nickel(II)
hydride species. This strategy would enable activation of
the unreactive α-oxy C‒H bond of aliphatic alcohols and
suppress undesired side reactions by carbon-centered
radical 3.
Introduction
Oxidation of alcohols to carbonyl compounds is a crucial
process in organic chemistry, and generally requires
stoichiometric oxidants, such as metal oxo reagents,
peroxides and perchlorates, hypervalent iodines, and
molecular oxygen. Catalytic acceptorless dehydrogenation
(CAD) is therefore a more favorable oxidation method,
releasing molecular hydrogen as the sole side product.1
Furthermore, CAD of alcohols is a fundamental chemical
reaction for the potential future hydrogen economy using
alcohols as an energy carrier.1 Transition metal complexes
are common catalysts for CAD of alcohols.2,3 Most of the
reaction conditions reported to date, however, are harsh
(high temperature, typically at >100 C2 or UV irradiation3)
because CAD of alcohols is thermodynamically unfavorable.
Nevertheless, recent studies realized CAD of alcohols under
visible light irradiation at room temperature through the
binary combination of a homogeneous or heterogeneous
photoredox catalyst and a transition metal catalyst (Figure
1a).4 Although the overall process is thermodynamically
uphill at room temperature, photoirradiation can overcome
the kinetic barriers. Despite such progress, the substrate
scope of CAD is predominantly limited to benzylic alcohols,
with aliphatic alcohols generally exhibiting only low
reactivity. Here we report a ternary hybrid catalyst system
that allows for efficient CAD of both aromatic and aliphatic
alcohols under visible light irradiation at room temperature
(Figure 1b).
CAD of aliphatic alcohols has two main difficulties: 1)
activation of aliphatic alcohols via hydrogen atom transfer
(HAT) or an electron transfer process,5 and 2) excessive
reactivity of the α-oxy carbon-centered radical species,
which is prone to side reactions (e.g., pinacol coupling),
following HAT. We hypothesized that a ternary hybrid
catalyst system, which was previously developed for CAD of
tetrahydronaphthalenes and 3-methyl cyclohexene,6 could
contribute to overcome those difficulties.7,8,9 Our reaction
design for CAD of aliphatic alcohols is shown in Figure 1b. A
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Figure 1. Overview of acceptorless dehydrogenation of
mixture using 1,1,2,2-tetrachloroethane as an internal
standard. b10 equiv C–H bond donor was used.
alcohols at room temperature. (a) Previous works: binary
combination of photoredox catalyst and a transition metal
catalyst. (b) Present work: Ternary hybrid catalysis
comprising a photoredox catalyst, an organocatalyst, and a
nickel catalyst, enabling CAD from aliphatic alcohols.
Optimization of the Reaction Conditions. We then
combined the binary HAT catalyst system with the third
component, a transition metal catalyst, for CAD of 2-
dodecanol (1a) as a model substrate (Table 2). The ternary
hybrid catalyst system comprising Ni(NTf2)2xH2O
promoted the reaction in excellent yield (entry 1). When
NiCl2 was used instead of the cationic nickel salt, however,
Results and Discussion
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Assessment of HAT Ability of the Binary Catalyst
System. On the basis of this hypothesis, we first assessed
the ability of the binary catalyst system (mesityl acridinium
[Mes-Acr+] and TPA) for HAT from stable C–H bonds with
varied bond dissociation energies (BDEs) in the radical
conjugate addition to benzalmalononitrile5,12 (Table 1).
Benzaldehyde, toluene, tetrahydrofuran, and methanol
afforded the corresponding products in high yield (entries
1–4), while cyclohexane bearing a greater BDE was not
sufficiently reactive (entry 5). Therefore, the binary catalyst
combination showed promise for the intended HAT process
from aliphatic alcohol 1 to radical 3 (Figure 1b), which
constitutes the entrance to the designed hybrid catalysis.
the
yield
dramatically
decreased
(entry
2).
Pd(BF4)24MeCN afforded the target molecules, but the
reactivity was lower than in the optimized conditions using
the nickel catalyst (entry 3 vs. entry 1). In addition,
Ni(BF4)2xH2O had superior reactivity to Pd(BF4)24MeCN
(entry 3 vs. entries 4 and 5). These results clearly indicate
that the nickel salts are more suitable for CAD of alcohols
than the palladium salt. This tendency was contrasting to
our previous observations in CAD of hydrocarbons, where
both palladium and nickel salts had almost the same
reactivity.6 Control experiments confirmed that the three
catalyst components and visible light irradiation were all
critical for the reaction (entries 6–9).
Table 1. Assessment of HAT Ability of the Binary
Catalyst System.
When
a representative dual catalysis comprising
Ir[dF(CF3)ppy]2(dtbbpy)PF6 and quinuclidine, which was
previously reported for hydrogen atom abstraction from α-
C–H bonds of aliphatic alcohols,10a,b,e was used instead of
Mes-Acr+ and TPA, product 2a was obtained in only 2%
yield (entry 10). MacMillan’s group reported that
tetrabutylammonium phosphate facilitated HAT from the α-
C‒H bonds of alcohols.10b When the phosphate additive was
present,
however,
the
combination
of
Ir[dF(CF3)ppy]2(dtbbpy)PF6 and quinuclidine afforded 2a
in only 9% yield (entry 11). In addition, the phosphate
completely abolished the reactivity of our hybrid catalysis
(entry 12). We speculate that the phosphate would
coordinate to the nickel catalyst, thus diminishing its
cationic character, which is important for the catalyst
activity (Table 2, entry 1 vs. entry 2). Moreover, other HAT-
active thiols10a,11 were not effective for this catalyst system
(entry 13, 14). Therefore, the optimized ternary hybrid
catalyst system in entry 1 was uniquely active for CAD of
aliphatic alcohols. A radical trapping experiment was
conducted (entry 15): in the presence of 1 equiv TEMPO, the
reaction did not proceed and 1a was recovered in 95%. This
result supports an intermediary of a carbon-centered
radical 3 in the catalytic cycle. Hydrogen gas evolution was
confirmed by a two-pot transfer hydrogenation reaction:
rhodium-catalyzed hydrogenation of cyclododecene
proceeded in 84% yield using the hydrogen gas generated
through CAD from cyclododecanol (1g) in a connected
vessel.13
Table 2. Optimization of the Reaction Conditions
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aYield was determined by H NMR analysis of the crude
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Figure 2. Substrate Scope of CAD of Alcoholsa
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aYield was determined by H NMR analysis of the crude
mixture using 1,1,2,2-tetrachloroethane as an internal
standard. bIsolated yield in parentheses. cMeCN (10 mol %)
was added. dWithout Mes-Acr+. Without TPA. Without
e
f
photoirradiation.
gIr[dF(CF3)ppy]2(dtbbpy)PF6
and
quinuclidine were used instead of Mes-Acr+ and TPA,
respectively. hTetrabutylammonium phosphate (25 mol %)
i
was added. Methyl thioglycolate was used instead of TPA.
jTriisopropylsilanethiol was used instead of TPA. 1 equiv
k
TEMPO was added.
Substrate Scope of CAD of Alcohols. Under the
optimized conditions, we investigated the substrate scope
(Figure 2). Simple linear aliphatic secondary alcohols
afforded the product ketones in high yield (2a and 2b).
Cycloalkanols were generally more reactive than linear
alcohols, and various ring-size substrates afforded the
corresponding cyclic ketones in excellent yields (2c–2h).
Specifically, CAD of 1g was performed in a practical scale (5
mmol) by reducing the amount of Ni(NTf2)2xH2O to 0.5
mol % and increasing the substrate concentration to 0.2 M,
and product 2g was obtained in 91% yield, identical to the
yield of the standard scale reaction (0.2 mmol). A benzylic
alcohol bearing a more labile α-C–H bond than aliphatic
alcohols was a competent substrate, giving product 2i in
quantitative yield. Various functional groups were tolerated
under the reaction conditions (2j–2s), including ether (2k),
halogens (2l and 2m), and pinacol boronate (2n), which is
especially sensitive to oxidative conditions. Alcohols
containing heteroaromatics, such as furan and thiophene,
proceeded in good yield (2q and 2r). Also, an alcohol
containing a benzyl ester moiety gave the target compound
without degradation (2s). Steric congestion of the
substrates did not deteriorate the reactivity (2t and 2u).
aYield is isolated yield unless otherwise noted. Yield was
determined by GC analysis of the crude mixture using
b
c
dodecane as an internal standard. 5 mmol scale using 0.5
d
mol % Ni(NTf2)2xH2O at 0.2 M. Yield was determined by
1H NMR analysis of the crude mixture using 1,1,2,2-
e
tetrachloroethane as an internal standard. CH2Cl2 (0.2 M)
was used.
ACDC between Aldehydes and Alcohols. Despite the
broad substrate scope of CAD of secondary alcohols, the
corresponding reaction from primary alcohols did not
produce high yields, likely due to the lability of the product
aldehydes containing a formyl C–H bond under the reaction
conditions, which is weaker than the α-C–H bond of the
starting alcohols (see Table 1). In crude reaction mixtures
of CAD of primary alcohols, we identified esters presumably
generated through dehydrogenation of hemiacetals derived
from the starting alcohols and dehydrogenated
aldehydes.2a,15 This observation led us to apply the ternary
hybrid catalysis to acceptorless cross-dehydrogenative
coupling (ACDC)16 between aldehydes and alcohols (Figure
3). ACDC between aldehydes and alcohols is a challenging
reaction due to the presence of many potential competing
side reaction pathways, such as reduction and
The reaction was applicable to
a natural product
(epiandrosterone) and a drug (oxaprozin) derivative, giving
product ketones 2v and 2w, respectively, both in high yield.
Oxazole rings are susceptible to oxidation,14 but we
observed no significant oxidation of the oxazole ring in 1w.
These results clearly demonstrate the broad substrate
scope and synthetic utility of CAD of secondary alcohols.
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decarbonylation of aldehydes.2a,15c Despite these difficulties,
in the case of the synthesis of 10d. The acetals were not
converted to the esters under the present conditions. The
present conditions were not applicable to the synthesis of
amides or imides using amines or amides as substrates,
instead of alcohols (10m and 10n). Nevertheless, our result
is the first example of ACDC between aldehydes and
alcohols that proceeds at room temperature without using
stoichiometric amounts of external reagents. 18
Xiao’s group15c and Milstein’s group15d achieved ACDC
between aldehydes and primary alcohols or two different
alcohols as starting materials. These seminal works,
however, still required high temperature and/or a
stoichiometric amount of base.
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Figure 3. Concept of ACDC between Aldehydes and
Alcohols
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Figure 5. ACDC between Aldehydes and Alcoholsa
We assumed that cleavage of the weak formyl C‒H bond
of aldehyde 7 by our HAT catalyst system (Mes-Acr+-TPA)
was an undesired side reaction pathway in ACDC, and thus
the rapid formation of hemiacetal intermediate 9 would be
critical. Therefore, we studied the (hemi)acetal formation
step between 7d and 8d under various conditions. Since
hemiacetal 9 is unstable, we observed acetal 11d as the
actual product in those studies (Figure 4). Interestingly,
although either Ni(NTf2)2xH2O or TPA did not promote the
acetal formation by itself (entries 1 and 2), the combination
of Ni(NTf2)2xH2O and TPA afforded acetal 11d in 57% yield
(entry 3).17
Figure 4. Acetal Formation Promoted by Ni(NTf2)2 and
TPAa
aYield is isolated yield unless otherwise noted. bYield in
parenthesis was determined by 1H NMR analysis of the
crude mixture using 1,1,2,2-tetrachloroethane as an
internal standard.
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aYield was determined by H NMR analysis of the crude
mixture using 1,1,2,2-tetrachloroethane as an internal
standard.
Mechanistic Studies. Finally, we conducted mechanistic
studies for the CAD of secondary alcohols, especially for the
desaturation step (Figure 6). We assumed that the
desaturation step proceeds through β-hydride elimination
of organonickel 5, followed by tautomerization (Figure 1b).
This hypothesis is consistent with the following
experimental results. First, benzhydrol, which does not
contain a β-C‒H bond, produced benzophenone in only poor
yield (11%: Figure 6a). This result was in sharp contrast to
the result of dicyclohexylmethanol (1u), which has a
structure similar to that of benzhydrol but has β-C‒H bonds
and greater steric hindrance and afforded product ketone
2u in 72% yield (Figure 2). Benzhydrols were a reactive
class of substrates in previously-developed conditions by
After optimization, the ACDC reaction between nonanal
(7a) and 2,2,2-trichloroethanol (8a) proceeded under
conditions that were identical to those of CAD of secondary
alcohols (Figure 5). Trichloroethyl ester 10a was obtained
in 72% yield. Sterically more congested aldehydes 7b and
7c also afforded corresponding esters 10b and 10c,
respectively, in good yield. In addition, 2,2,2-
trifluoroethanol produced trifluoroethyl ester 10d in 43%
yield. The ACDC also showed a range of functional group
tolerance (10e–i), including ester (10e‒h and 10l), halogen
(10f, 10g, and 10i), ether (10h), phthaloyl-protected amine
(10j), and ketone (10k) functional groups. Yield was
moderate in some entries, because acetals were formed as
a main byproduct: e.g. acetal 11d was obtained in 33% yield
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other groups.4 The low reactivity of benzhydrol in our
alcohols. The catalyst system was also applicable to ACDC
between aldehydes and alcohols, producing esters through
CAD of hemiacetal intermediates. The potent reactivity of
the Ni(NTf2)2xH2O‒TPA combination to promote the
formation of the hemiacetal intermediate was critical for
the ACDC, avoiding undesired C‒H abstraction of aldehydes
by the TPA‒Mes-Acr+ HAT catalyst combination. Extension
of the ternary hybrid catalysis to other dehydrogenation
reactions is ongoing in our laboratory.
system suggests that the reaction mechanism of the present
CAD by the hybrid catalysis is distinct from that of the
previous reactions. Similarly, the yield of CAD of 2-
adamantanol was moderate (27%: Figure 6b), probably
because β-hydride elimination to generate an enol
intermediate is not favorable due to Bredt’s rule. Moreover,
21%-H (corresponding to 84%-H vs. single D) was
incorporated at the α-position of the keto group in 2g,
which was produced from β-D4-1g (Figure 6c). The
observed higher reactivity of a cationic nickel catalyst
(Ni(NTf2)2xH2O) compared with a NiCl2 catalyst may also
be attributable to the accelerated β-hydride elimination by
a cationic nickel complex.6b,19 On the basis of our previous
observation that a thiyl radical (RS) is generated through
photooxidation of TPA by Mes-Acr+6a and the present
finding that a carbon-centered radical was generated from
methanol using the binary catalyst combination (Table 1),
the mechanism depicted in Figure 1b is plausible.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental details and characterization data (PDF)
AUTHOR INFORMATION
Corresponding Author
Figure 6. Mechanistic Information
h-mitsunuma@mol.f.u-tokyo.ac.jp
kanai@mol.f.u-tokyo.ac.jp
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENTS
This work was supported in part by JSPS KAKENHI Grant
Numbers JP17H06442 (M.K.) (Hybrid Catalysis), 18H05969
(H.M.), 19J23073 (H.F.). We wish to thank Prof. Tetsuro
Murahashi and Dr. Koji Yamamoto (Tokyo Institute of
Technology) for helpful discussion and advice.
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aYield was determined by H NMR analysis of the crude
mixture using 1,1,2,2-tetrachloroethane as an internal
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Conclusion
In conclusion, we developed CAD of aliphatic and
aromatic alcohols under visible light irradiation at room
temperature, mediated by the ternary hybrid catalyst
system. The sequence of HAT from aliphatic alcohols
containing high BDEs, oxidative interception of the
resulting carbon-centered radical to organonickel species,
and β-hydride elimination organized by the ternary hybrid
catalysis, was key to achieving this synthetically-useful
transformation. Moreover, expansion of the substrate scope
of the ternary hybrid catalyst system from hydrocarbons6b
to secondary aliphatic alcohols allowed us to obtain
mechanistic information of the β-hydride elimination step
of the complex catalyst system. The fact that nickel salts
were superior to palladium salts is unique to the CAD of
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