Base-free oxidation of alcohols enabled by nickel(ii)-catalyzed transfer dehydrogenation

Article abstract of DOI:10.1039/d0cc03966g

An efficient nickel(ii)-catalyzed transfer dehydrogenation oxidation of alcohols is reported that relies on cyclohexanone as the formal oxidant and does not require the use of an external base. The synthetic utility of this protocol is demonstratedviathe facile oxidation of structurally complicated natural products.

Full text of DOI:10.1039/d0cc03966g

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Base-free oxidation of alcohols enabled by nickel(II)-catalyzed
‡
transfer dehydrogenation
Danfeng Ye,a,b Zhiyuan Liu,b Jonathan L. Sessler,*b and Chuanhu Lei*b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
An efficient nickel(II)-catalyzed transfer dehydrogenation oxidation exploited in the context of alcohol oxidation. Most commonly, the
of alcohols is reported that relies on cyclohexanone as the formal systems in question have relied on a common Ni0 source and used in
oxidant and does not require the use of an external base. The conjunction with
a
stoichiometric amount of base and
synthetic utility of this protocol is demonstrated via the facile organo(pseudo)halides as the formal oxidant (Fig. 1b).14 In addition,
oxidation of structurally complicated natural products.
nickel(II) complexes have been exploited to achieve the
electrocatalytic-15 or O2-mediated oxidations of alcohols (Fig. 1c).16
In spite of the elegance of these achievements, there remain
challenges to address, including the development of catalysts that
are easy-to-handle and which do not require the use of strong base.
As part of a continuing effort to develop new nickel-catalyzed
functional group transformations,17 we have discovered a procedure
that allows for the nickel(II)-catalyzed oxidation of alcohols via
transfer dehydrogenation in the absence of strong base (Fig. 1d). This
system exploits a commercially available ligand and is essentially free
of side reactions, such as the aldol condensation. As detailed below,
this procedure is characterized by a wide substrate scope and is
applicable to the oxidation of secondary alcohols in representative
natural products.
The oxidation of alcohols to the corresponding aldehydes and
ketones is a fundamental transformation in both academe and
industry, reflecting the key role of the carbonyl group in synthesis
and its near-ubiquitous presence in pharmaceuticals, fine chemicals
and fragrances.1 In fact, such oxidations rank among the top 20
reactions in medicinal chemistry.2 Traditionally, stoichiometric
amount of a chromium salt3 (i.e. CrO3, PCC, PDC) were employed.
However, these reagents are hazardous and can result in tedious
isolations and result in an undue environmental burden. Hence,
increasing attention is being focused on transition metal-based
catalytic oxidations.4 In this context, the oxidation of alcohols by
means of transfer-dehydrogenation is well documented in the case
of both homogeneous and heterogeneous catalysts of Ru5 and Ir,6 as
well as heterobimetallic complex of Ru and Rh.7 Notably, Hartwig et
al. disclosed a Ru/PEt3 complex system that may be applied to the
selective oxidation of secondary alcohols and polyol natural
products.8 In contrast, examples of the non-noble metal catalyzed
transfer dehydrogenation of alcohols are scarce.9
Early on Guan,10 and more recently Beller et al.,11 reported
convenient oxidations of secondary alcohols using specific iron
complexes bsased on cyclopentadienyl and PNP-pincer ligands,
respectively. Beller and coworkers also reported a novel catalytic
system for the transfer dehydrogenation of secondary alcohols
comprised of pentacarbonylmanganese bromide and elaborately
designed tridentate NNN-pincer ligands (Fig. 1a).12 Nickel catalysis,
which are attractive from an economic perspective,13 have also been
Fig. 1 Oxidation of alcohols to ketones by non-noble metals.
Initially, we performed a number of test reactions using 1-
phenylethanol (1a) as a model substrate. Through experimentation,
we identified that the reaction could be carried out by using a
catalytic cocktail of Ni(OTf)2 and a strongly donating bisphosphine
1,2-bis(dicyclohexylphosphino)ethane (dcype). Specifically, with this
system acetophenone 2a was obtained in nearly quantitative yield
a. School of Materials Science and Engineering, Shanghai University, Shanghai
200444, China
b. Center for Supramolecular Chemistry & Catalysis and Department of Chemistry,
College of Sciences, Shanghai University, Shanghai 200444, China
Electronic Supplementary Information (ESI) available: Synthetic details and
characterization data. see DOI: 10.1039/x0xx00000x.
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from the corresponding alcohol in toluene under reflux using or electron-donating para-substituents on the arylVierwinAgrticrleeaOcntleinde
DOI: 10.1039/D0CC03966G
cyclohexanone as the hydride acceptor (Table 1, entry 1). Among the smoothly to give
the
corresponding
ketones.
2,6-
many nickel(II) salts tested in these preliminary screening studies, Dichlorophenylethanol displayed reactivity comparable to that of the
Ni(OTf)2 proved superior. This finding is ascribed to the labile counter para-substituted substrates (product 2f). This stands in sharp
anion, which is presumed to allow the formation of alkoxide-nickel contrast to what is seen for various Fe and Mn catalysts where the
species from the alcohol substrate (vide infra). This behaviour is reactions proved particularly sensitive to steric effects on the aryl
reminiscent of many Ni-catalyzed cross-coupling reactions where the moiety.11,12 Heteroaryl rings, such as furan and thiophene, proved
use of a noncoordinating triflate counter anion is critical.18 In well tolerated (2h-2i). In the case of pyridylmethanol, the desired
contrast, we found that Ni(II) salts containing the Cl–, Br–, I– and product was successfully obtained in 83% yield when DMA was used
acetylacetonate (acac) anions showed no activity under the same as the solvent (2j). The present oxidation procedure could also be
reaction conditions (see the Supporting Information). Other common applied to a-substituted derivatives. With butyl and cyclopropyl
diphosphines (DPPF, DPPE, DPPP) and monophosphines (PCy3, Pt- groups, both the reactions furnished the desired ketones in nearly
Bu3, P(2-furyl)3) gave little or no 2a (entries 4, 5). As expected, no quantitative yields (2k-2l). Various benzhydrol derivatives were
product was seen in the absence of a ligand (entry 6). When applying readily oxidised using the same reaction conditions giving access to
acetone as the hydride acceptor, the reaction resulted in a decreased the desired products in excellent yields (2m-2t). However, in the case
yield of 85%. Noticeably, the use of ≥ 20 equiv. of acetone gave yields of a CN-substituted substrate bis(4-cyanophenyl)methanol, only 59%
comprable to those obtained with 5 equiv. of cyclohexanone (see the yield of the ketone was isolated albeit free of any detectable side
Supporting Information). The use of chalcone led to lower yields, product. Additionally, the present method proved compatible with
likely due to its being a weak hydride acceptor. Additionally, in the cyclic 9-fluorenol, xanthydrol and dibenzosuberol substrates (giving
absence of a ketone, negligible product was found in the reaction products 2u to 2w).
mixture, reflecting a need for an effective hydride acceptor. In
addition to toluene, the oxidation reaction proved compatible with a
variety of commonly used solvents, including DMF, DMSO, CH3CN,
1,4-dioxane, and diglyme (see the Supporting Information). On the
other hand, neither CHCl3 nor THF proved suitable, likely owing to
their relatively low boiling points (entry 10 and 11). Consistent with
this result was the finding that there was a sharp decrease in the yield
when the reaction was performed in toluene at 80°C, rather than at
reflux (entry 12).
Table 1. Optimization of the oxidation procedure for 1aa
variation from the standard
conditions
none
Conv. of
1a (%)b
100
13
entry
2a (%)b
1
2
3
99 (94)c
Ni(acac)2 instead of Ni(OTf)2
7
1
.
NiCl2 DME instead of Ni(OTf)2
5
4
5
6
PCy3 instead of dcype
DPPF instead of dcype
without dcype
85
88
15
trace
45
0
Scheme 1 Substrate scope of the aromatic substituted alcohols
tested in this study. Yields refers to isolated yields. (a) DMA was used
as the solvent. (b) DMF was used as the solvent instead of toluene.
7
8
9
10
11
12
acetone instead of cyclohexanone
chalcone instead of cyclohexanone
without cyclohexanone
CHCl3 instead of toluene
THF instead of toluene
80 °C
86
6
15
12
29
15
85
4
3
5
22
13
In addition to aromatic alcohols, the oxidation procedure
was successfully applied to more demanding aliphatic alcohols
(Scheme 2). Substituted cyclohexanols could be readily
oxidised, albeit a slightly longer reaction time was required.
Cyclooctanol and cyclododecanol were also successfully
converted to the target ketones 2ab and 2ac. A variety of acyclic
secondary alcohol proved compatible with this method (2ad to
2aj). In case of the dicyclohexylcarbinol, a sterically hindered
model substrate often used to test putative catalytic systesms,8
the reaction furnished the corresponding ketone 2ai in 48%
yield under the same reaction conditions. However, the more
sterically demanding diisopropylcarbinol, gave a low 14% GC
yield (2aj). The present catalytic system also proved effective in
aConditions: 1a (0.1 mmol), Ni(OTf)2 (2 mol %), ligand (4 mol %),
cyclohexanone (0.5 mmol), solvent (0.5 mL), reflux, 12 h;
bConversion and yield were determined by GC using tetralin as an
internal standard; cYield in parenthesis refers to the isolated yield.
Using the optimal reaction conditions, a diverse array of benzylic
alcohols were tested. As summarized in Scheme 1, para-substituted
acetophenone derivatives irrespective of the electron-withdrawing
2 | J. Name., 2012, 00, 1-3
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the case of allylic alcohol. With isophorol as substrate, the
corresponding unsaturated ketone 2ak was isolated in three types of alcohols were selected as representative
moderate yield on a gram scale (66%), which underscores the substrates, and the kinetics of their oxidation monitored by GC
potential applicability of the present system. Oxidation of (Scheme 4). It was found that aromatic alcohols react much
benzylic primary alcohols allowed access to aryl aldehydes in faster than aliphatic ones. For example, a ca. 60% yield of the
low to moderate yields (2al to 2an). In the case of aliphatic aromatic ketone 2r was obtained within 1 h, while the aliphatic
primary alcohols, e.g. hydrocinnamic alcohol and 1-octanol, ketone 2ac required nearly 5 hours to reach similar levels of
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DOI: 10.1039/D0CC03966G
almost full recovery of the starting alcohols was seen.
conversion under the same reaction conditions. The increased
rate seen in the case of the alcohol bearing an aromatic
substituent is ascribed to the relatively greater acidity of the
parent alcohol. The greater the acidity of the alcohol is thought
to facilitate a key ligand exchange rates in the catalytic cycle
(vide infra).
100
80
60
2r
2k
2ac
40
20
0
0
2
4
6
8
10
12
time (h)
Scheme 4 Reaction kinetic studies: Plot of yield vs time recorded
under the standard reaction conditons.
Scheme 2 Oxidation products derived from aliphatic alcohols. Yields
refer to isolated yields. (a) Calibrated GC yield.
Kinetic isotope effect (KIE) studies were performed in an
effort to gain more insights into the reaction mechanism. When
1ac and deuterated 1ac-[D] were tested separately in two
vessels but under otherwise identical conditions, a kH/kD ratio of
7.2 was found. Similarly, two parallel studies involving 1k and
As a test of the synthetic utility of the present Ni(II)-
catalysed oxidation protocol, a series of natural steroids
carrying secondary alcohols were tested. As is shown in Scheme
3, oxidation of sterols proceed smoothly under the optimized
conditions, although isomerization of the double bond from the
original 5 position to give the more stable enone product was
observed (2ao to 2aq). This isomerization mirrors early reports
in the literatures involving other transition metal-based
catalysts.5b,8,12 The saturated sterol, estradiol was smoothly
converted into the corresponding estrone (2ar). Furthermore,
the oxidation of natural product podophyllotoxin furnished the
desired podophyllotone in reasonable yield (2as). In general, the
nickel-catalyzed process described here using cyclohexanone as
the hydride acceptor proved compatible with olefins, ketones,
phenols, acetals, and lactones as evidenced by these examples.
1k-[D], 1r and 1r-[D] resulted in an apparent primary KIE values
of 2.4 and 2.5, respectively (Scheme 5). Deuterated
cyclohexanol was also detected by GC-MS analysis of the
reaction mixtures. These results are consistent with what is
expected to be a slow b-hydride elimination from the nickel
center,18b,19 and leads us to suggest that loss of the hydride from
alcohol is rate-limiting step in the catalytic process.
Scheme 5 Kinetic isotope effect (KIE) determined from two parallel
reactions.
On basis of these observations, we suggest that the nickel-
catalyzed transfer dehydrogenation begins by displacement of
one of the labile ligands (OTf−) on the Ni(OTf)2 with an alcohol
moiety and concurrent generation of the alkoxide-nickel
Scheme 3 Oxidized forms of natural products obtained from the
corresponding alcohols using the present protocol. Yield refers to
isolated yield. (a) DMSO was used as the solvent instead of toluene;
(b) DMA was used as the solvent instead of toluene.
intermediate
A (Scheme 6). Proton capture from the alcohol
and loss of HOTf then ensues. This step is expected to be
facilitated by the use of electron-rich ligands (e.g., dcype) that
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J. Name., 2013, 00, 1-3 | 3
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serve to increase of electron density around the OTf− anion.18
Elimination from then generates the ketone product while
producing a nickel-hydride complex . The resulting hydride
complex can insert into cyclohexanone and form alkoxide-nickel
. Exchange with a molecule of the alcohol then gives
cyclohexanol and
, which initiates a second cycle.20
b
-
2018, 6, 2362-2369.
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Scheme 6 Proposed catalytic cycle for the nickel-catalyzed transfer
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In conclusion, we have developed an efficient method for
the oxidation of secondary alcohols to ketones that exploits a
simple Ni(II) catalyst in conjunction with transfer
dehydrogenation. The base-free conditions and the wide
applicability of the optimized protocol leads us to propose that
the present method could provide a useful complement to
other strategies designed to effect similar transformations.
Support for this work was provided by Shanghai University,
the National Natural Science Foundation of China (no.
21901155 to C.L.), the Shanghai Rising-Star Program (no.
20Z00128 to C.L.), and the Eastern Scholars program from the
Shanghai Municipal Education Committee.
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Conflicts of interest
There are no conflicts to declare.
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Notes and references
‡ This paper is dedicated to Prof. Mei-Xiang Wang (Tsinghua
University) on the occassion of his 60th birthday.
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TOC text: The oxidation of alcohols was successfully realized via nickel(II)-catalyzed transfer dehydrogenation
under base-free conditions.
Ni(OTf)2 (2 mol %), dcype (4 mol %)
O
OH
cyclohexanone (5.0 equiv.)
R1 R2
R1 R2
45 examples
toluene, reflux,
In situ system Commercial available ligand Base-free conditions
O
H
O
O
O
O
H
O
H
O
H
H
HO
MeO
OMe
OMe
podophyllotone
steric hindered
dicyclohexanone
estrone
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