Pd-catalyzed ortho-arylation of N-aryloxazolidinones with simple arenes using sodium persulfate

Article abstract of DOI:10.1055/s-0030-1259731

We report a Pd-catalyzed ortho-arylation of N-aryloxazolidinones under mild conditions. Our oxidative cross-coupling consumes sodium persulfate (Na ₂S₂O₈), a green and environmentally benign reagent, as the terminal oxidan

Full text of DOI:10.1055/s-0030-1259731

974
LETTER
Pd-Catalyzed ortho-Arylation of N-Aryloxazolidinones with Simple Arenes
Using Sodium Persulfate
O
xidative ortho-A
h
rylationof
a
N
-Aryloxaz
r
olidinon
l
es es S. Yeung, Vy M. Dong*
Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON, M5S 3H6, Canada
E-mail: vdong@chem.utoronto.ca
Received 15 October 2010
Dedicated to Prof. Xiyan Lu for his contributions to Pd catalysis.
ple arenes involving concomitant oxidation of two C–H
Abstract: We report a Pd-catalyzed ortho-arylation of N-arylox-
azolidinones under mild conditions. Our oxidative cross-coupling
consumes sodium persulfate (Na2S2O8), a green and environmental-
ly benign reagent, as the terminal oxidant. Trifluoroacetic acid
(TFA) is critical for reactivity.
bonds is an attractive alternative.3a,4c,6 By installing func-
tionalities in the substrate capable of coordinating to pal-
ladium, regioselective functionalization is possible.4c,6g–l
Our group reported an oxidative cross-coupling using
Na2S2O8 as the stoichiometric oxidant in the presence of
trifluoroacetic acid (TFA).4c,6i We observed efficient
ortho-arylation of N-aryloxazolidinones with electron-de-
ficient arenes under similar conditions (Table 1). While
strong oxidants (i.e., Na2S2O8) were effective, weaker ox-
idants including copper and silver salts (Table 1, entries
5–11) led to decreased efficiencies. Removing either the
palladium catalyst or TFA led to inhibition of the oxida-
tive cross-coupling (Table 1, entries 1 and 2).
Key words: palladium, arylation, biaryl, cross-coupling, metalla-
cycle
N-Aryloxazolidinones have promising medicinal value as
both antidepressant and antibacterial agents.1 Two notable
examples include DuP 721, linezolid, and toloxatone
(Figure 1). As such, efforts toward their preparation have
attracted attention from the synthetic community.2 Devel-
oping methods for late-stage functionalization of N-aryl-
oxazolidinone would aid the drug-discovery process by
providing an efficient approach for pursuing structure–
activity relationships (SAR). Despite recent develop-
ments in ligand-assisted C–H bond activation,3 cyclomet-
alation directed by the cyclic carbamate functionality is
rare.4 Sanford and co-workers demonstrated that hyperva-
lent iodine reagents were suitable cross-coupling partners
for direct arylation.4a Herein, we report an approach to N-
biphenyloxazolidinones by Pd-catalyzed oxidative ortho-
arylation with simple arenes and sodium persulfate
(Na2S2O8, Scheme 1).
Sanford, 2005
O
O
O
O
cat. [Pd]
N
N
+ [Ph2I]+BF4
–
(1)
Ph
H
This work
O
O
O
O
N
N
cat. [Pd]
oxidant
(2)
+
Ar–H
Ar
H
NHAc
Scheme 1 Catalytic arylation of N-aryloxazolidinones4
O
NHAc
OH
O
O
O
N
N
O
With our optimized conditions, a number of N-arylox-
azolindinones were subjected to ortho-arylation
(Table 2). Electron-deficient arenes (e.g., o-dichloroben-
zene, o-difluorobenzene) were optimal arene coupling
partners. In ortho-disubstituted arenes, arylation favors
functionalization of the C4–H bond selectively; however,
using o-difluorobenzene, a minor regioisomer resulting
from coupling of the C3–H bond was also observed
(Table 2, entries 2, 5, 7, 8, 10, 12–13).
N
O
N
F
Me
Ac
O
DuP 721
linezolid
toloxatone
Figure 1 Examples of therapeutic N-aryloxazolidinones1
Characterization of the regioisomers was confirmed by X-
ray crystallography (Figure 2). This observation contrasts
our related work on oxidative ortho-arylation of O-phe-
nylcarbamates where we observed highly regioselective
coupling with a wide array of simple arenes.4c When we
used 1-chloro-2-fluorobenzene as the cross-coupling part-
ner (Table 2, entries 3 and 6), arylation occurred at both
Biaryl C–C bonds are traditionally formed by transition-
metal-catalyzed cross-coupling of an organohalide with a
suitable organometallic reagent.5 Cross-coupling of sim-
SYNLETT 2011, No. 7, pp 0974–0978
x
x.
x
x.
2
0
1
1
Advanced online publication: 15.03.2011
DOI: 10.1055/s-0030-1259731; Art ID: W34210ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Oxidative ortho-Arylation of N-Aryloxazolidinones
975
Table 2 Oxidative ortho-Arylation of N-Aryloxazolidinonesa
Table 1 Reaction Optimizationa
O
O
O
O
Cl
3
x mol%
Cl
O
H
Cl
Cl
O
4
O
O
N
N
Pd(OAc)2 (10 mol%)
N
N
Pd(OAc)2
+
Ar–H
+
Ar
H
oxidant, TFA
70 °C, 24 h
H
Na2S2O8, TFA
70 °C
R
R
1a–g
2a–m
1a
2a
Entry Substrate
Arene
Product
Yield (%)b
Entry x (mol%) Oxidant (equiv)
TFA (equiv) Yield (%)b
O
O
O
O
O
Cl
1
2
0
10
10
10
10
10
10
10
10
10
10
Na2S2O8 (3)
5
0
5
5
5
5
5
5
5
5
5
0
Cl
O
N
O
N
N
N
N
Cl
Cl
Na2S2O8 (3)
0
1
74
3
Na2S2O8 (3)
91 (74c)
4
Oxone (2)
0
0
1
4
2
2
0
8
1a
2a
5
AgOAc (3)
O
F
F
O
O
N
6
Ag2CO3 (3)
F
F
2
73 (93:7)c
7
Cu(OAc)2 (3)
benzoquinone (3)
Ce(SO4)2·4H2O (3)
Mn(OAc)3·2H2O (3)
O2 (1 atm)
8
1a
2b
9
O
F
Cl
10
11
O
N
O
Cl
F
3
72 (54:41:5)c
a Conditions: substrate (0.2 mmol), o-dichlorobenzene (1 mL).
b Conversion determined by GC analysis.
c Isolated yield after 43 h.
1a
2c
O
Cl
C4 and C5, suggesting that steric factors predominantly
dictate the regioselectivity of C–C bond formation. This
reaction tolerates electron-neutral (Table 2, entries 1–12)
and electron-rich (Table 2, entry 13) N-aryloxazolidino-
nes.
Cl
O
N
O
Cl
Cl
4
99
Oxidative ortho-arylation with electron-neutral and elec-
tron-rich arenes, however, was unproductive (Table 3).
This is likely due to competing homodimerization of ei-
ther the substrate or unactivated arene coupling partner if
either of these components is significantly more electron
rich than the other. Moreover, more electron-rich simple
arenes undergo higher levels of homocoupling than their
electron-poor congeners.4c,6i This reactivity complements
that of N-phenylpyrrolidinones6i (Table 3, entries 4–6).
On the other hand, diphenylimidazolidinones were ineffi-
cient in directed oxidative coupling with o-dimethoxy-
benzene, benzene, and o-dichlorobenzene (Table 3,
entries 7–9).
In analogy to our earlier work,4c,6i we propose the mecha-
nism of this oxidative coupling involves initial ligand-as-
sisted cyclopalladation followed by an arene C–H bond-
activation step. The details of this mechanism, however,
warrant further studies. In summary, we have disclosed an
efficient oxidative arene cross-coupling approach for the
direct functionalization of N-aryloxazolidinones. Our
strategy employs unactivated arenes as the coupling part-
ners using Na2S2O8, an environmentally benign and easy
to handle stoichiometric oxidant.
1b
2d
O
O
O
O
F
F
F
F
O
N
O
N
F
F
5
92 (90:10)c
1b
2e
O
Cl
O
O
N
N
Cl
F
6
97 (56:40:4)c
1b
2f
O
F
O
N
O
N
F
F
7
66 (91:9)c
Et
Et
1c
2g
Synlett 2011, No. 7, 974–978 © Thieme Stuttgart · New York

976
C. S. Yeung, V. M. Dong
LETTER
Table 3 Electronic Effects of Oxidative ortho-Arylationa
Table 2 Oxidative ortho-Arylation of N-Aryloxazolidinonesa
(continued)
X
X
O
Y
O
Pd(OAc)2
(10 mol%)
Y
H
Y
Y
O
O
O
O
N
N
N
N
Pd(OAc)2 (10 mol%)
+
+
Ar–H
H
Ar
Na2S2O8
TFA
70 °C, 24 h
H
Na2S2O8, TFA
70 °C
R
R
2n–u
1a–g
2a–m
1a,h–i
Entry Substrate
Arene
Product
Yield (%)b
38 (94:6)c
99 (84:16)c
Entry
X
Y
Product
Yield (%)b
O
O
F
O
O
O
OMe
F
OMe
O
O
N
O
N
N
N
N
N
F
F
1
O
OMe
0
8
2n
Ph
N
Ph
1d
2h
O
O
O
O
Cl
O
Cl
2
3
4
O
O
H
14
O
N
O
Cl
Cl
9
2o
Cl
1e
2i
O
Cl
F
O
91 (74c)
F
Cl
O
N
O
F
F
N
98 (91:9)c
10
2a
OMe
1e
2j
OMe
O
Cl
O
12 (73d)
Cl
O
CH2
OMe
O
N
N
Cl
Cl
11
99d
2p
1f
2k
O
N
O
O
F
5
6
CH2
H
74 (83e)
F
O
O
N
N
F
F
99 (84:16)c
12
2q
Cl
Cl
O
N
1f
2l
CH2
Cl
3
O
O
F
F
O
N
O
N
F
F
2r
90 (90:10)c
13
Ph
N
OMe
OMe
O
N
OMe
OMe
7
NPh
OMe
0
1g
2m
a Conditions: Substrate (0.2 mmol), arene (1 mL), Pd(OAc)2 (10
mol%), Na2S2O8 (3 equiv), TFA (5 equiv), 35.5–47.5 h.
b Isolated yields.
2s
c Isolated as a mixture of isomeric products. See Supporting Informa-
tion for details.
d K2S2O8 (3 equiv) was used.
Synlett 2011, No. 7, 974–978 © Thieme Stuttgart · New York

LETTER
Oxidative ortho-Arylation of N-Aryloxazolidinones
977
Table 3 Electronic Effects of Oxidative ortho-Arylationa
X
X
Y
Pd(OAc)2
(10 mol%)
Y
H
Y
Y
O
O
N
N
+
H
Na2S2O8
TFA
70 °C, 24 h
2n–u
1a,h–i
Entry
X
Y
H
Product
Yield (%)b
Ph
N
O
N
Figure 2 ORTEP plot of the major isomer of arylation product 2h;
anisotropic displacement ellipsoids are shown at the 50% probability
level
8
NPh
NPh
0
2t
Ph
N
Cl
References
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O
N
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9
Cl
0
2u
a Conditions: substrate (0.2 mmol), arene (1 mL), Pd(OAc)2 (10 mol%),
Na2S2O8 (3 equiv), TFA (5 equiv).
b Conversion determined by GC analysis.
c Isolated yield after 43 h.
d Isolated yield in 0.5 mL o-dimethoxybenzene at 90 °C after 54 h.
e Isolated yield after 23 h.
General Procedure for the Pd-Catalyzed Oxidative ortho-Ary-
lation
In a one-dram vial equipped with a Teflon cap was added the sub-
strate (0.2 mmol), Pd(OAc)2 (0.02 mmol, 10 mol%), Na2S2O8 (0.6
mmol), and the unactivated arene (1 mL). TFA (1 mmol) was added
to the resulting suspension. The vial was stirred on a heating block
at 70 °C for the indicated length of time. The reaction mixture was
cooled to r.t., diluted in EtOAc, and washed with sat. NaHCO3. Sub-
sequently, the aqueous phase was extracted with EtOAc. The com-
bined organic extracts were dried over Na2SO4, concentrated in
vacuo, and the resulting residue was purified by silica gel column
chromatography or preparative TLC (eluent: hexanes–EtOAc) to
afford the pure arylation products. See Supporting Information for
more details.
Supporting Information for this article is available online at
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Acknowledgment
Funding is provided by the University of Toronto, Canada Founda-
tion for Innovation, Ontario Research Fund, Boehringer Ingelheim
Ltd. Canada, and the Natural Sciences and Engineering Research
Council (NSERC) of Canada. V.M.D. is grateful for an Alfred P.
Sloan fellowship and C.S.Y. for an NSERC André Hamer Award
and a Canada Graduate Scholarship.
Synlett 2011, No. 7, 974–978 © Thieme Stuttgart · New York

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C. S. Yeung, V. M. Dong
LETTER
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