Catalytic Aerobic Chemoselective α-Oxidation of Acylpyrazoles en Route to α-Hydroxy Acid Derivatives

Article abstract of DOI:10.1021/acs.orglett.7b01293

Catalytic aerobic chemoselective α-oxidation of acylpyrazoles is described. Acylpyrazoles, carboxylic acid oxidation state substrates, were efficiently oxidized under aerobic conditions using TEMPO as an oxygenating agent. The mild catalytic conditions of the present catalysis were amenable to late-stage α-oxidation of various pharmaceutical agents and natural products, leading to previously unreported α-hydroxy acid derivatives in short steps. Preliminary mechanistic studies revealed that in situ generated copper(II) peroxo species served as a Lewis acid/Br?nsted base cooperative catalyst.

Full text of DOI:10.1021/acs.orglett.7b01293

Letter
pubs.acs.org/OrgLett
Catalytic Aerobic Chemoselective α‑Oxidation of Acylpyrazoles en
Route to α‑Hydroxy Acid Derivatives
Seiya Taninokuchi, Ryo Yazaki,* and Takashi Ohshima*
Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan
S
* Supporting Information
ABSTRACT: Catalytic aerobic chemoselective α-oxidation of
acylpyrazoles is described. Acylpyrazoles, carboxylic acid oxidation
state substrates, were efficiently oxidized under aerobic conditions
using TEMPO as an oxygenating agent. The mild catalytic
conditions of the present catalysis were amenable to late-stage α-
oxidation of various pharmaceutical agents and natural products, leading to previously unreported α-hydroxy acid derivatives in
short steps. Preliminary mechanistic studies revealed that in situ generated copper(II) peroxo species served as a Lewis acid/
Brønsted base cooperative catalyst.
α-Hydroxy acid is frequently found in bioactive natural and
non-natural compounds and utilized in a diverse set of synthetic
intermediates.1 Various approaches toward this important class
of α-hydroxy acids have been developed, such as (1)
substitution reaction of prefunctionalized carboxylic acid
derivatives with hydroxide, (2) nucleophilic addition/reduction
of α-ketoacid derivatives, and (3) alkylation of glycolic acid
derivatives.2 A more advantageous straightforward method is α-
oxidation of carboxylic acid derivatives, such as the Rubottom
oxidation3 and Davis oxidation (Scheme 1a).4 Although these
As an oxygenating agent, a commercially available TEMPO
(2,2,6,6-tetramethylpiperidine 1-oxyl) free radical has received
much attention for the synthesis of α-secondary-α-hydroxy
carbonyls.6 TEMPO was initially used for α-oxidation of strong
base-mediated preactivated esters with stoichiometric amounts
of metal oxidants to capture the single electrons (Scheme 1c).7
Recently, a soft enolization methodology was applied to
TEMPO oxidation using a titanium reagent (Scheme 1c).8
Subsequently, a chiral amine-catalyzed enantioselective α-
oxidation of aldehydes was reported under aerobic conditions
without the need for stoichiometric amounts of metal
oxidants.9,10 Although these reaction conditions were very
mild and only a catalytic amount of transition metals was
required, the scope of the carbonyls was limited to aldehydes.11
Thus, the direct use of α-monosubstituted carboxylic acid
derivatives in catalytic α-oxidation has remained a formidable
challenge. Herein, we report the development of a highly
chemoselective and late-stage catalytic aerobic α-oxidation of
acylpyrazoles (Scheme 1d).12
Scheme 1. α-Oxidation of Carboxylic Acid Oxidation State
Substrates to Access α-Hydroxy Acid Derivatives
We first evaluated various copper salts under aerobic
conditions using acylpyrazole 1a and TEMPO (2) (Table 1).
Cationic copper(II) triflate afforded the product 3a in only low
yield (entry 1). Copper(II) acetate, which would potentially
serve as a Lewis acid/Brønsted base cooperative catalyst, turned
out to be a better catalyst, affording 3a in 63% yield (entry
3).13,14 These different propensities for our α-amination
reaction15 led us to hypothesize that the Brønsted basicity
rather than Lewis acidity of the catalyst was important for
efficient promotion of the reaction. Thus, to generate active
Lewis acid/Brønsted base copper species under aerobic
conditions, we investigated copper(I) salts (entries 4−8).16
Although cationic copper(I) triflate afforded the product 3a in
low yield (entry 4), other copper(I) catalysts produced 3a in
better yield (entries 5−8). Among them, copper(I) chloride
α-oxidation methods are reliable and have widespread
applications, the necessary preactivation by stoichiometric
amounts of a strong base limits their functional group
compatibility. Catalytic aerobic α-oxidation reactions were
recently reported (Scheme 1b).5 These reactions are highly
atom-economical because they use O2 as an oxygenating agent,
allowing for the direct introduction of a protecting group free
hydroxy group. The substrate scope of these reactions is limited
to readily enolizable ketones and α-aryl substituted esters for
the efficient nucleophilic activation of carbonyls. In addition,
these methods are applicable only to α,α-disubstituted
carbonyls, affording α-tertiary-α-hydroxy carbonyls.
Received: May 2, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01293
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Organic Letters
Letter
a
a
Table 1. Conditions Optimization
Scheme 2. Substrate Scope
entry
catalyst
yield (%)
entry
catalyst
yield (%)
1
2
3
4
5
Cu(OTf)2
Cu(OCOCF3)2
Cu(OAc)2
CuOTf
18
22
63
35
55
6
7
8
9
CuI
50
55
73
33
CuBr
CuCl
CuCl2
CuCl
b
c
CuOOAc
10
80
a
Conditions: 1a (0.4 mmol), 2 (0.2 mmol), THF (0.2 mL), 24 h.
1
Yields were determined by H NMR analysis using 2-methoxynaph-
thalene as an internal standard. 0.3 mmol of 1a and molecular sieves
b
4 Å were used. Reaction was performed under oxygen atmosphere.
c
Isolated yield. TMP = 1-oxy-2,2,6,6-tetramethylpiperidine.
exhibited the highest catalytic performance, and the desired
product 3a was obtained in 73% yield (entry 8), while the
corresponding copper(II) chloride exhibited poor catalytic
performance (entry 9). During the course of catalyst evaluation,
we found that partial hydrolysis of the acylpyrazoles 1a and 3a
proceeded, leading to the formation of the corresponding
carboxylic acids. Thus, we performed the reaction under dried
oxygen with molecular sieves as a desiccant, and product 3a was
isolated in 80% yield with a reduced amount of 1a (1.5 equiv,
entry 10).17
With the optimal conditions in hand, we next examined the
scope of acylpyrazoles (Scheme 2). The present catalysis
proceeded on gram scale without any detrimental effects, and
product 3a was isolated in 87% yield. Lactic acid derivative 3b
was obtained in high yield. An alkyl bromide functional group
survived during the course of the reaction (3c). The reactions
of sterically congested substrates afforded products 3d and 3e
in synthetically useful yields by increasing the catalyst loading
to 10 mol %. Oxygen functionalities, such as ethyl ether and
TBS ether, were compatible (3f and 3g). An α-hydroxy acid
derivative with primary amino group 3h was isolated in high
yield. Indole and boronate ester functionalities were incorpo-
rated (3i and 3j). It is noteworthy that reactive aldehyde, which
potentially serves as an aldol acceptor under basic conditions,
survived (3k), although the chemical yield was moderate.
Chemoselective α-oxidation was investigated next using
substrates bearing an acidic α-proton (3l−r). Highly reactive
nitroalkyl functionalities that could be deprotonated by catalytic
amounts of a mild base such as triethylamine15,18 did not react
under the optimized conditions, and the desired α-oxy-
acylpyrazole 3l was isolated in high yield.19 Substrates with
aliphatic or aromatic ketones afforded a high yield (3m−o).
Other electron-withdrawing groups, such as ester, nitrile, and
sulfone, were also compatible, affording the corresponding α-
hydroxy acid derivatives chemoselectively (3p−r) and demon-
strating the highly chemoselective nature of our α-oxidation
method.
a
Conditions: 1a (0.3 mmol), 2 (0.2 mmol), THF (0.2 mL), 24 h.
b
c
Isolated yields are shown. Reaction time was 48 h. Gram scale (5.0
mmol) synthesis. 48 h. 10 mol % of CuCl was used. TMP = 1-oxy-
2,2,6,6-tetramethylpiperidine. X = 3,5-dimethylpyrazolyl group.
d
domethacin and zomepirac derivatives) were efficiently
oxidized under mild conditions (3v and 3w). An α-lipoic acid
derivative, which serves as an antioxidant, was chemoselectively
oxidized at the α-position over oxidation-labile cyclic disulfide
functionality (3x). Other α-aliphatic pharmaceutical agents and
natural product derivatives were efficiently converted to the
corresponding α-hydroxy acid derivatives (3y−β).
Further transformation of the products was performed
(Scheme 4). Conversion of an acylpyrazole functionality to
the corresponding methyl ester was catalyzed by Sm(OTf)3
under mild conditions.21 Both α-alkyl- (3a and 3β) and α-aryl-
substituted (3s) α-oxy acylpyrazoles were efficiently trans-
formed into methyl esters 4, followed by treatment with zinc
dust in AcOH to give α-hydroxy esters 5 in high yield.7c
To gain insight into in situ-generated copper species, various
control experiments were investigated (Scheme 5). First, the
reaction was performed under N2 using 5 mol % of CuCl, but
the product 3a was not detected. Even when a substoichio-
metric amount of CuCl (50 mol %) was used, 3a was obtained
in only 3% yield. These results were different from the
previously reported chiral amine-catalyzed reaction,9a,c suggest-
ing that an oxygen was critical to promote the present Cu
catalysis. On the other hand, 50 mol % of CuCl2, which
provided inferior results under standard reaction conditions
(Table 1, entry 9), afforded 3a in moderate yield. These results
We then investigated late-stage α-oxidation of a variety of
pharmaceutical agents and natural products (Scheme 3). The
present catalysis could be efficiently applied to an α-aryl
substrate at room temperature.20 A felbinac derivative and
isoxepac derivative afforded the products 3s and 3t in high
yield. Catalytic α-oxidation of felbinac derivative under air
atmosphere was also achieved, although the yield was
decreased. The rather acidic diaryl NH proton in a diclofenac
derivative was tolerated (3u). α-Heteroaryl substrates (in-
B
DOI: 10.1021/acs.orglett.7b01293
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
resulting copper species were subjected to the standard reaction
conditions under N2 atmosphere (Scheme 6). Preparation of a
Scheme 3. Late-Stage α-Oxidation of Acylpyrazoles
Scheme 6. Actual Catalyst Generation under Oxygen
copper catalyst by premixing CuCl under O2 atmosphere
resulted in poor catalytic performance. Premixed CuCl catalyst
with acylpyrazole 1a under O2 atmosphere afforded product 3a
in only 3% yield. Finally, premixing CuCl with TEMPO under
O2 atmosphere delivered product 3a in 31% yield. On the other
hand, premixing them under N2 atmosphere did not promote
the reaction. These results suggested that TEMPO is essential
to generate an actual copper(II) species with the assistance of
O2.23,24 The ESI-mass spectrum of a mixed solution of
[Cu(CH3CN)4]PF6 with TEMPO under O2 atmosphere
showed the peak at 252 m/z ([Cu(TEMPO) (OOH)]+),
verifying the generation of copper(II) peroxo species.25
Although the exact structure of the active copper(II) species22
remains unclear, we propose that the copper(II) peroxo
complex serves as a Lewis acid/Brønsted base cooperative
catalyst, allowing for chemoselective and facilitated nucleophilic
activation of acylpyrazole.26,27
In conclusion, we developed a highly chemoselective α-
oxidation of acylpyrazoles under aerobic conditions using an in
situ generated copper(II) species serving as a Lewis acid/
Brønsted base cooperative catalyst. Further applications of in
situ generated copper(II) peroxo species to the deprotonative
activation reactions and development of enantioselective
variants are underway in our laboratory.28
a
Conditions: 1a (0.3 mmol), 2 (0.2 mmol), THF (0.2 mL), 24 h.
b
Isolated yields are shown. Reaction was performed at room
temperature. Reaction was performed under air atmosphere instead
of oxygen atmosphere. Reaction time was 48 h. 10 mol % of CuCl
was used. TMP = 1-oxy-2,2,6,6-tetramethylpiperidine. X = for 3,5-
dimethylpyrazolyl group.
c
d
e
Scheme 4. Transformation of the Products
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01293.
Experimental details, characterizations, and NMR spectra
of all products (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: yazaki@phar.kyushu-u.ac.jp.
*E-mail: ohshima@phar.kyushu-u.ac.jp.
Scheme 5. Copper-Mediated Reaction under Nitrogen
ORCID
Ryo Yazaki: 0000-0001-9405-1383
Takashi Ohshima: 0000-0001-9817-6984
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
indicated that copper(I) salts are oxidized in situ by molecular
oxygen, and the resulting copper(II) salts are the actual catalytic
species.22
We also prepared several copper(II) catalysts by premixing
CuCl under distinct conditions (O2 atmosphere), and the
■
This work was financially supported by JSPS KAKENHI Grant
No. JP15H05846 in Middle Molecular Strategy, JP16H01032
in Precisely Designed Catalysts with Customized Scaffolding,
Grant-in-Aid for Scientific Research (C) (No. 16K08166) and
C
DOI: 10.1021/acs.orglett.7b01293
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(15) Tokumasu, K.; Yazaki, R.; Ohshima, T. J. Am. Chem. Soc. 2016,
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(16) For detailed optimization studies, see the Supporting
Platform for Drug Discovery, Informatics, and Structural Life
Science from MEXT. R.Y. thanks Ube Industries, Ltd. Award in
Synthetic Organic Chemistry, Japan.
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(18) (a) Matthews, W. S.; Bares, J. E.; Bartmess, J. E.; Bordwell, F.
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(19) TA trace amount of α-oxidation product of nitroalkane was
detected.
(20) When the reaction was performed at 40 °C using α-aryl
substrate, various side products such as keto acid derivative were
detected.
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DOI: 10.1021/acs.orglett.7b01293
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