First example of quinoxaline-directed C-H activation: A novel method for acetoxylation of arenes

Article abstract of DOI:10.1055/s-0030-1259292

2-Aryl- and 2,3-diarylquinoxalines undergo smooth acetoxylation in the presence of 5 mol% Pd(OAc)₂ and a stoichiometric amount of PhI(OAc)₂ via C-H activation to produce the corresponding acetoxy-susbstituted quinoxaline derivatives

Full text of DOI:10.1055/s-0030-1259292

LETTER
169
First Example of Quinoxaline-Directed C–H Activation: A Novel Method for
Acetoxylation of Arenes
Q
uinoxaline-Dire
.
cted
C
–HA
c
tivation . Subba Reddy,* K. Ramesh, J. S. Yadav
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
E-mail: basireddy@iict.res.in
Received 2 August 2010
Abstract: 2-Aryl- and 2,3-diarylquinoxalines undergo smooth ace-
toxylation in the presence of 5 mol% Pd(OAc)2 and a stoichiometric
N
amount of PhI(OAc)2 via C–H activation to produce the corre-
sponding acetoxy-susbstituted quinoxaline derivatives in excellent
yields with high regioselectivity.
N
AcO
N
Key words: hypervalent iodine reagent, aryl quinoxalines, acetox-
ylation, C–H activation
1
Pd(OAc)2 (5 mol%)
DCE, 90 °C
+
PhI(OAc)2
2
N
AcO
3a
Quinoxalines have received considerable interest from the
pharmaceutical industry because of their interesting prop-
erties such as antiviral, antibacterial, anti-inflammatory,
and antiprotozoal activities, and as kinase inhibitors.1
Scheme 1 Bisacetoxylation of 2,3-diphenylquinoxaline
They have also been evaluated as anticancer, anthel- Similarly, various diarylquinoxalines such as 6-methyl,
mintic, antifungal, and insecticidal agents.2 Furthermore, 6,7-dimethyl, 6-nitro, 6-carboxymethyl, 6-bromo, and 6-
the quinoxaline nucleus is a part of several antibiotics fluoro derivatives participated well in this reaction. No ac-
such as echinomycin, levomycin, and actinomycin which etoxylation was observed at the sp3 C–H in case of meth-
are known to inhibit the growth of gram-positive bacteria yl-substituted quinoxalines (entries 2, 3, 11, and 12,
and to be active against various transplantable tumors.3 Table 1), no ester hydrolysis was observed (entries 5 and
Besides this, they have found applications as dyes, elec- 14, Table 1) and no dehalogenation occurred (entries 6, 7,
troluminescent materials, organic semiconductors, cav- and 15, Table 1). Encouraged by the results obtained with
itands, chemically controllable switches, and DNA arylquinoxalines, we turned our attention to 2,3-diphenyl-
cleaving agents.4,5
hexahydroquinoxaline and 5,6-diphenyl-2,3-dihydropy-
razine. Both substrates underwent smooth acetoxylation
along with aromatization under similar conditions to be-
fore (entries 8 and 9, Table 1, Scheme 2).
C–H activation is a versatile approach for the direct func-
tionalization of aromatic C–H bonds using transition-
metal catalysis.6,7 Directing groups play a key role in the
selective functionalization of C–H bonds,8 usually pos-
sessing a lone pair that can coordinate to the transition-
metal catalyst to direct ortho functionalization via a five-
or six-membered metallacycle.9
AcO
N
N
Pd(OAc)2 (5 mol%)
N
In continuation of our interest on C–H activation,10 we
herein report a novel method for the acetoxylation of aro-
matic systems using the Pd(OAc)/PhI(OAc)2 system. In
this reaction, Pd(OAc)2 acts as a catalyst to activate the ar-
omatic C–H bond via quinoxaline-directed oxidative in-
sertion. PhI(OAc)2 works as an acetoxylation agent as
well as to reoxidize Pd(0) to Pd(II). Initially, we attempted
acetoxylation 2,3-diphenylquinoxaline using 2.2 equiva-
lents PhI(OAc)2 in the presence of 5 mol% Pd(OAc)2, and
reaction proceeded smoothly at 90 °C in 1,2-dichloro-
ethane affording the bisacetoxylated product 3a in 84%
yield (Scheme 1).
DCE, 90 °C
N
+
AcO
3i
PhI(OAc)2
Scheme 2 Bisacetoxylation of dihydropyrazine
These results provided the incentive to study reactions
with monoarylated quinoxalines. Thus, treatment of 2-
phenylquinoxaline with PhI(OAc)2 in the presence of 5
mol% Pd(OAc)2 gave the monoacetoxylated product in
90% (Scheme 3, Table 1).
SYNLETT 2011, No. 2, pp 0169–0172
x
x.
x
x.
2
0
1
1
Advanced online publication: 23.12.2010
DOI: 10.1055/s-0030-1259292; Art ID: D20710ST
© Georg Thieme Verlag Stuttgart · New York

170
B. V. S. Reddy et al.
LETTER
Yield (%)b
84c
Table 1 Pd(OAc)2-Catalyzed Acetoxylation of Arenes Using PhI(OAc)2
Entry
1
Arylquinoxaline 1
Product 2a
Time (h)
12
AcO
N
N
N
N
AcO
AcO
N
N
N
N
2
3
4
5
6
7
8
9
11
10
15
15
14
15
11
10
87c
93c
78c
94c
88c
86c
89c
87c
AcO
AcO
N
N
N
N
AcO
AcO
O2N
N
N
O2N
N
N
AcO
AcO
O
O
N
N
N
MeO
MeO
N
AcO
AcO
Br
N
Br
N
N
N
AcO
AcO
F
N
F
N
N
N
AcO
AcO
N
N
N
N
AcO
AcO
N
N
N
N
AcO
Synlett 2011, No. 2, 169–172 © Thieme Stuttgart · New York

LETTER
Quinoxaline-Directed C–H Activation
171
Table 1 Pd(OAc)2-Catalyzed Acetoxylation of Arenes Using PhI(OAc)2 (continued)
Entry
Arylquinoxaline 1
Product 2a
Time (h)
10
Yield (%)b
AcO
10
91d
92d
95d
88d
91d
90d
N
N
N
N
AcO
N
N
N
11
12
13
14
15
10
10
13
N
AcO
N
N
N
N
AcO
O2N
N
N
O2N
N
N
AcO
O
O
N
N
13
12
N
N
MeO
MeO
AcO
N
F
N
N
F
N
a The products were characterized by IR, NMR, and mass spectrometry.
b Yield refers to pure products after chromatography.
c Conditions: 2.2 equiv of PhI(OAc)2 were used.
d Conditions: 1.1 equiv of PhI(OAc)2 were used
N
N
Probably, the reaction proceeds by oxidative insertion of
Pd(II) into C–H bond via a five-membered transition state
as depicted in Scheme 4. Finally, Pd(0) is converted into
Pd(II) by PhI(OAc)2 to complete the catalytic cycle.
N
Pd(OAc)2 (5 mol%)
+
In summary, we have developed a novel protocol for the
acetoxylation of aromatic compounds via C–H activation.
The experimental procedure is simple, convenient, and
the reaction conditions are amenable to scale-up. This
method provides an easy access to acetoxy-substituted
quinoxalines with diverse chemical structures for biolog-
ical evaluation.
DCE, 90 °C
PhI(OAc)2
N
AcO
3j
Scheme 3 Monoacetoxylation of 2-phenylquinoxaline
Similarly, various 2-phenylquinoxaline derivatives partic-
ipated well in this reaction. No acetoxylation was ob-
served in the absence of either Pd(OAc)2 or PhI(OAc)2.
Among various oxidants such as AgOAc, Mn(OAc)3, and
Cu(OAc)2, PhI(OAc)2 was found to be most effective in
terms of conversion. In all cases, the reactions were clean
and the products were obtained in excellent yields and
characterized by MS, NMR, and IR spectroscopy. The
scope and generality of this process is illustrated in
Table 1.11
Acknowledgment
K.R. thanks CSIR, New Delhi for the award of a fellowship.
References and Notes
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Synlett 2011, No. 2, 169–172 © Thieme Stuttgart · New York

172
B. V. S. Reddy et al.
LETTER
PhI(OAc)2
Pd(0)
Pd(II)
C–H
activation
AcO
PhI(OAc)2
N
N
N
N
AcO
Pd
N
N
intermediate
Scheme 4 A plausible reaction pathway
(2) Sakata, G.; Makino, K.; Kuraswa, Y. Heterocycles 1988, 27,
2481; and references cited therein.
(11) Typical Experimental Procedure
A mixture of 2,3-diphenylquinoxaline (100 mg, 0.35 mmol),
PhI(OAc)2 (250 mg, 0.78 mmol), and Pd(OAc)2 (4 mg, 0.05
mmol) in DCE (5 mL) was stirred at r.t. for 10 min, then the
resulting mixture was heated to 90 °C for 12 h. After
completion of reaction as indicated by TLC, the reaction
mixture was filtered, diluted with H2O and extracted with
CH2Cl2 (2 × 15 mL). The combined organic layers were
dried over anhyd Na2SO4, concentrated in vacuo, and
purified by column chromatography on silica gel (Merck,
60–120 mesh, EtOAc–hexane, 0.5:9.5) to afford pure
bisacetoxy derivative.
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max = 3027, 2923, 2854, 1765, 1620, 1458, 1370, 1190,
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1116, 1031, 909, 758 cm–1. 1H NMR (300 MHz, CDCl3):
d = 2.10 (s, 3 H), 2.48 (s, 3 H), 7.01–7.07 (m, 2 H), 7.24–7.30
(m, 2 H), 7.79 (s, 1 H). 13C NMR (75 MHz, CDCl3): d = 20.3,
20.8, 123.0, 125.5, 128.8, 129.8, 131.3, 131.4, 139.8, 140.0,
148.2, 149.7, 168.9. MS (EI): m/z = 449 [M + Na]. HRMS:
m/z calcd for C26H22N2O4Na: 449.1477; found: 449.1475.
Compound 3e: yellow solid, mp 161–162 °C. IR (KBr):
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nmax = 3029, 2922, 2852, 1769, 1715,1442, 1374, 1310,
1278, 1254, 1181, 1112, 1054, 1027, 907, 807 cm–1. 1H
NMR (300 MHz, CDCl3): d = 2.09 (s, 3 H), 2.10 (s, 3 H),
4.03 (s, 3 H), 7.17 (m, 4 H), 7.41 (m, 4 H), 8.18 (s, 1 H), 8.39
(dd, 1 H, J = 1.8, 8.6 Hz), 8.85 (d, 1 H, J = 1.7 Hz). 13C NMR
(75 MHz, CDCl3): d = 20.8, 20.9, 52.6, 123.2, 125.6, 129.4,
129.8, 130.3, 130.6, 130.7, 131.4, 131.6, 131.7, 140.1,
142.7, 148.3, 151.9, 152.7, 166.1, 168.7, 168.8. MS (EI):
m/z = 479 [M + Na]. HRMS: m/z calcd for C26H20N2O6Na:
479.1219; found: 479.1202.
Compound 3j: pale yellow solid, mp 103–104 °C. IR (neat):
nmax = 3020, 2923, 2852, 1764, 1646, 1544, 1488, 1448,
1369, 1312, 1187, 1108, 1034, 1010, 958, 912, 867, 764 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.23 (s, 3 H), 7.21 (s, 1 H),
7.39–7.57 (m, 2 H), 7.74–7.80 (m, 2 H), 7.91 (dd, 2 H,
J = 1.3, 6.2 Hz), 8.21 (m, 2 H), 9.10 (s, 1 H). 13C NMR (75
MHz, CDCl3): d = 20.9, 123.5, 128.1, 129.1, 129.4 129.5,
129.9, 130.2, 130.3, 130.9, 131.1, 141.1, 148.5, 150.8,
169.3. MS (EI): m/z = 287 [M + Na]. HRMS: m/z calcd for
C16H12N2O2Na: 287.0796; found: 287.0784.
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Synlett 2011, No. 2, 169–172 © Thieme Stuttgart · New York

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