Pd(II)-catalyzed ortho -C-H oxidation of arylacetic acid derivatives: Synthesis of benzofuranones

Article abstract of DOI:10.1021/ol403699d

Pd(II)-catalyzed ortho-C-H acetoxylation of arylacetic acid derivatives is demonstrated with the aid of a novel S-methyl-S-2-pyridylsulfoximine (MPyS) directing group (DG). The α-mono- and α-unsubstituted arylacetic acid derivatives were readily employed in the ortho-C-H acetoxylations. The oxidation products are hydrolyzed, and the MPyS-DG is easily recovered, providing ready access to o-hydroxyarylacetic acids. 3-Mono- and 3-unsubstituted benzofuranones are synthesized from o-hydroxyarylacetic acids.

Full text of DOI:10.1021/ol403699d

Letter
pubs.acs.org/OrgLett
Pd(II)-Catalyzed ortho-C−H Oxidation of Arylacetic Acid Derivatives:
Synthesis of Benzofuranones
Raja K. Rit, M. Ramu Yadav, and Akhila K. Sahoo*
School of Chemistry, University of Hyderabad, Hyderabad-500046, India
S
* Supporting Information
ABSTRACT: Pd(II)-catalyzed ortho-C−H acetoxylation of arylacetic
acid derivatives is demonstrated with the aid of a novel S-methyl-S-2-
pyridylsulfoximine (MPyS) directing group (DG). The α-mono- and
α-unsubstituted arylacetic acid derivatives were readily employed in
the ortho-C−H acetoxylations. The oxidation products are hydrolyzed,
and the MPyS-DG is easily recovered, providing ready access to o-
hydroxyarylacetic acids. 3-Mono- and 3-unsubstituted benzofuranones
are synthesized from o-hydroxyarylacetic acids.
ransition-metal-catalyzed C−H bond functionalization has
emerged as a useful, step-economical method for the
Scheme 1. Synthesis of Benzofuranones via Metal-Catalyzed
ortho-C−H Activation of Arylacetic Acid Derivatives
T
direct conversion of C−H bonds proximal to the directing
group, to C−C and C−heteroatom bonds with high
regioselectivity.1 Of note, the oxidation of aryl-C(sp2)−H to
aryl-C(sp2)−O bonds allows the synthesis of structurally
diverse and pharmaceutically important phenol derivatives
from readily accessible starting materials.2,3 Due to the broad
utility of phenol derivatives, the development of effective
strategies for the C(sp2)−H oxidations is desirable.4 Aryl
carboxylic acids and their derivatives efficiently assist in creating
aryl-C(sp2)−O bonds; in contrast, the oxidation of o-C(aryl)−
H bond on arylacetic acid through C−H activation is less
explored.3h
Benzofuranone is an important skeleton widely present in
various natural products and biologically active molecules.5 The
following methods, including (I) condensations of 2-(2-
hydroxyphenyl)acetic acid,6a−c (II) tandem Friedel−Crafts/
condensations of phenol with α-hydroxy acid,6d (III) oxidation
of boronic acids and their derivatives,7 and (IV) transition-
metal-catalyzed coupling reactions of phenol derivatives,8 have
successfully been employed, accessing the benzofuranone
skeletons. Recently, the Yu9a and Shi9b groups have
independently developed Pd(II)-catalyzed direct cyclization of
arylacetic acids for the synthesis of 3,3-disubstituted benzo-
furanones (Scheme 1). On the basis of the Thorpe−Ingold
effect, the α,α′-disubstituted arylacetic acids exclusively
participated in the cyclization by activating the ortho-aryl-C−
H bond (Scheme 1). However, the application of these
methodologies to the synthesis of 3-mono- and 3-unsubstituted
benzofuranones has thus far been unsuccessful.9 Furthermore,
the para- and meta-substituted arylacetic acids underwent
cyclizations efficiently, whereas the ortho-substituted arylacetic
acids reacted sluggishly, delivering poor yield of the
benzofuranones (Scheme 1).9
bond formations inspired us to envisage the synthesis of
structurally diverse benzofuranone from arylacetic acid
derivatives following the acetoxylation of the aryl-C(sp2)−H
bond and lactonization sequence (Scheme 1).10 Furthermore,
we intend to achieve the oxidation of the aryl-C(sp2)−H bond
of ortho-substituted and α-unsubstituted arylacetic acids
(Scheme 1). Herein we demonstrated the Pd(II)-catalyzed
MPyS-DG-assisted ortho-C−H acetoxylation of arylacetic acid
derivatives and the synthesis of 3-unsubstituted benzo-
furanones.
A wide array of phenylacetic acid derivatives having mono-
and bidentate DGs were synthesized and subjected to the
known ortho-aryl-C−H oxidation conditions comprising Pd-
(OAc)2 (10 mol %) and K2S2O8 (1.5 equiv) in AcOH at 50 °C
(Scheme 2).11 The monodentate directing groups −NHOMe
and −NHC6H4-4-NO2 on phenylacetic acid (1a) did not
oxidize the ortho-aryl-C−H bond; surprisingly, the −NHC6F5
Our recent accomplishments on the methylphenyl-
sulfoximine (MPS) and methyl-2-pyridylsulfoximine (MPyS)
reusable DG-assisted aryl-C(sp2)−O and primary β−C(sp3)−O
Received: December 20, 2013
Published: January 30, 2014
© 2014 American Chemical Society
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dx.doi.org/10.1021/ol403699d | Org. Lett. 2014, 16, 968−971

Organic Letters
Letter
a b
,
Scheme 2. Screening of Different Directing Groups
Scheme 3. Acetoxylation of Arylacetic Acid Derivatives
and MPS DGs allowed formation of the desired ortho-C−H
acetoxylation products in <10 and 28% yields, respectively
(Scheme 2).11
To our disappointment, the bidentate DGs 8-amino
quinoline, 2-thiomethyl aniline, and 2-picolyl amine attached
phenylacetic acid derivatives failed to yield the corresponding
ortho-aryl-C−H oxidation products. To our delight, the recently
developed MPyS-DG assists introducing an acetoxy group at
the ortho-aryl-C−H bond in phenylacetic acid moiety,
delivering the desired N-[2-(2-acetoxyphenyl)acetyl]-S-meth-
yl-S-2-pyridylsulfoximine (3a) in 58% yield. Further screening
of the catalysts, oxidants, and solvents led to the finer optimized
conditions [2a (1.0 equiv) in the presence of Pd(OAc)2 (10
mol %), K2S2O8 (1.2 equiv) in 1:1 mixture of AcOH and Ac2O
at 50 °C], producing 3a in 76% isolated yield (eq 1).11
a
Reaction conditions: 2 (0.5 mmol), Pd(OAc)2 (10 mol %), K2S2O8
b
ο
(0.6 mmol), AcOH/Ac2O (3.0 mL, 1:1) at 50 C. Isolated yields.
c
d
Reaction was conducted using 0.25 mmol of 2. A trace amount
(<5%) of sterically hindered o-C-2-acetoxylation product was formed.
e
f
Reaction was conducted with 0.3 mmol of 2p. Heated at 80 °C.
g
AcOH was used as solvent.
3n−q and 3a were successfully obtained in good yields from
the para-substituted and electron-neutral phenylacetic acid
derivatives 2n−q and 2a, respectively. The sterically hindered
2-(3,5-difluorophenyl)acetic acid derivative 2r led to 66% of 3r.
The effect of the α-substituent on arylacetic acid derivative
toward the o-C−H acetoxylations was studied next. The
acetoxylation of α-methyl (2s), α-phenyl (2t), and α-iso-propyl
(2u) substituted compounds occurred smoothly to produce 3s,
3t, and 3u in moderate to good yields.12 Ibuprofen is an anti-
inflammatory drug;13 the MPyS bearing ibuprofen 2v is
acetoxylated to afford 3v in good yield. The α,α′-disubstituted
cyclopropyl (2w)12 and cyclopentyl (2x) compounds were
independently reacted under the optimized conditions, giving
76 and 82% of 3w and 3x, respectively.
The synthetic utility of this method is demonstrated with the
hydrolysis of the acetoxylation products; this would lead to the
o-hydroxyarylacetic acids, a precursor to benzofuranones, and
the recovery of the MPyS DG (Table 1).10,14 Hydrolysis of the
acetoxylated products 3 with 2 N HCl occurred smoothly.
Accordingly, the o-hydroxyarylacetic acids 4′a−d were prepared
from the hydrolysis of 3a, 3f, 3m, and 3v, respectively.
Subsequently, lactonizations of 4′a−d in the presence of POCl3
in ClCH2CH2Cl delivered 3,3-unsubstituted benzofuranones
4a−c and ibuprofen derivative 4d in overall good isolated yields
(entries 1−4, Table 1).
The optimized conditions shown in eq 1 were explored by
examining the scope and generality of the o-C−H acetox-
ylations on compounds 2a−x, and the results are summarized
in Scheme 3. The lower yield encountered in the C−H
oxidation of ortho-substituted arylacetic acids9 provoked us to
investigate the ortho-C−H acetoxylation of MPyS-DG contain-
ing arylacetic acid derivatives (2b−f), at first. Gratifyingly, the
acetoxylated product 3b was isolated in 97% yield from
electron-rich 2-o-tolylacetic acid derivative 2b. The synthetically
important chloro- and bromo-group-substituted 2c and 2d
underwent acetoxylation smoothly to produce 3c and 3d in 95
and 70% yields, respectively. Strong electron-withdrawing
groups CO2Me (2e) and NO2 (2f) on the aryl ring surprisingly
did not affect the reaction outcome, and the desired
acetoxylation products were isolated in excellent yields. The
α-naphthyl derivative 2g gave 87% of 3g. The regioselectivity in
the C−H acetoxylation was evaluated by submitting the meta-
substituted arylacetic acid derivatives to the optimized
conditions. A highly regioselective ortho-acetoxylation occurred
on the sterically less hindered side of the aryl ring in m-Me
(2h), m-OMe (2i), m-Cl (2j), and m-F (2k) substituted
arylacetic acids; the corresponding products were isolated in
high yields [3h (89%), 3i (85%), 3j (89%), and 3k (74%)].11
The m-O-benzyl group on the aryl ring did not affect the
reaction; the acetoxy group was inserted at the less hindered
side, producing 3l in moderate yield. Similarly, the 2-(β-
naphthyl)acetic acid derivative 2m gave the desired acetoxy-
lated product 3m in 84% yield. The ortho-acetoxylated products
We next performed the o-acyloxylation of 2b using different
carboxylic acid solvent. The carboxylate group CD3COO− or
EtCOO− was smoothly incorporated by replacing the o-C−H
bond leading to 5a (82%) and 5b (76%) (Scheme 4). The acid
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dx.doi.org/10.1021/ol403699d | Org. Lett. 2014, 16, 968−971

Organic Letters
Letter
a
Pd(II) species in 6 to Pd(IV) in 7 occurs smoothly with K2S2O8
in AcOH.16 Finally, the reductive elimination of 7 produces the
desired acetoxylated product 3a.
Table 1. Removal of MPyS-DG and Lactonization
The competition experiments were performed to study the
electronic effect of the substituents on the aryl ring (Scheme 6).
Scheme 6. Competition Experiments
The reaction of an equimolar mixture of 2b and 2f under the
optimized conditions gave 3b and 3f in overall 39% yield in a
19:1 ratio. Similarly, a 6:1 mixture of 3i and 3j was observed
from 2i and 2j in overall 43% yield. It appears that the electron-
donating substituents on arenes allow faster reaction over the
electron-deficient arenes.
To show the strength of MPyS DG, the acetoxylation of
carbamate 8 and urea 10 derivatives was independently
conducted under the optimized conditions. The corresponding
C−H acetoxylation products 9 and 11 were isolated in
moderate yield (Scheme 7).
a
Reaction conditions: (i) 3 (0.25 mmol), 3.0 mL of 2 N HCl at 70 °C;
b
(ii) POCl3 (5.0 equiv). Isolated yield of benzofuranones (4) over two
steps. Isolated yields of MPyS.
c
solvent presumably serves as the source of oxygen for the C−O
bond formation.
Scheme 7. Acetoxylation of Carbamate and Urea Derivatives
Scheme 4. Acyloxylation of Arylacetic Acid Derivative
Based on the preliminary mechanistic study and previous
reports, a plausible mechanistic cycle is proposed in Scheme 5.
The activation of the ortho-C−H bond of 2a by the Pd(II)
catalyst through concerted metalation deprotonation (CMD)
leads to cyclometalated species 6. A controlled H/D scrambling
study reveals the reversible nature of C−H activation under the
present catalytic cycle (2i-H/D).11,15 The oxidation of the
In conclusion, we have developed a novel MPyS directing
group assisted Pd(II)-catalyzed o-acetoxylation of arylacetic
acid derivatives with broad substrate scope. The oxidation of o-
substituted arylacetic acids gave excellent yields of the desired
o-C−H acetoxylation products. The acetoxylated products are
successfully hydrolyzed to o-hydroxyarylacetic acid, an effective
precursor to benzofuranones, and MPyS directing group in
good yields. Using this protocol, the 3-mono- and 3-
unsubstituted benzofuranones are readily synthesized. Current
effort is directed at exploring the synthetic applications of this
transformation.
Scheme 5. Plausible Mechanistic Cycle
ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed experimental procedures and spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: akhilchemistry12@gmail.com; akssc@uohyd.ernet.in.
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Letter
(8) (a) Satoh, T.; Tsuda, T.; Kushino, Y.; Miura, M.; Nomura, M. J.
Notes
Org. Chem. 1996, 61, 6476. (b) D’Souza, D. M.; Rominger, F.; Muller,
̈
The authors declare no competing financial interest.
T. J. J. Angew. Chem., Int. Ed. 2005, 44, 153. (c) Matsuda, T.; Shigeno,
M.; Murakami, M. Org. Lett. 2008, 10, 5219. (d) Sue, D.; Kawabata,
T.; Sasamori, T.; Tokitoh, N.; Tsubaki, K. Org. Lett. 2010, 12, 256.
(9) (a) Cheng, X.-F.; Li, Y.; Su, Y.-M.; Yin, F.; Wang, J.-Y.; Sheng, J.;
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(b) Yang, M.; Jiang, X.; Shi, W.-J.; Zhu, Q.-L.; Shi, Z.-J. Org. Lett. 2013,
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ACKNOWLEDGMENTS
■
This research was supported by the DST (Grant No. SR/S1/
OC-34/2009). R.K.R. and M.R.Y. thank CSIR, India, for a
fellowship. We thank Mr. K. Ghosh (University of Hyderabad)
for his help.
(10) (a) Yadav, M. R.; Rit, R. K.; Sahoo, A. K. Chem.Eur. J. 2012,
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(11) For more details, see the Supporting Information.
(12) The C(sp3)−H/N−Me acetoxylation or the cyclopropyl cleaved
products are not observed.
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