Regioselective ortho-acetoxylation/methoxylation of N-(2-benzoylphenyl) benzamides via substrate directed C-H activation

Article abstract of DOI:10.1016/j.tetlet.2011.08.098

A highly regioselective ortho-acetoxylation of N-(2-benzoylphenyl) benzamides has been achieved using a catalytic amount of Pd(OAc)₂ (10 mol %) and a stoichiometric amount of PhI(OAc)₂ in a mixture of acetic anhydride and acetic acid

Full text of DOI:10.1016/j.tetlet.2011.08.098

Tetrahedron Letters 52 (2011) 5926–5929
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Regioselective ortho-acetoxylation/methoxylation of
N-(2-benzoylphenyl)benzamides via substrate directed C–H activation
⇑
B.V. Subba Reddy , G. Revathi, A. Srinivas Reddy, J.S. Yadav
Discovery Laboratory, Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly regioselective ortho-acetoxylation of N-(2-benzoylphenyl)benzamides has been achieved using a
catalytic amount of Pd(OAc)2 (10 mol %) and a stoichiometric amount of PhI(OAc)2 in a mixture of acetic
anhydride and acetic acid via C–H activation to produce the corresponding 2-acetoxybenzamides in good
yields. ortho-Methoxylation has been accomplished using methanol under similar conditions.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 31 July 2011
Revised 14 August 2011
Accepted 17 August 2011
Available online 23 August 2011
Keywords:
Pd(II) catalysis
Hypervalent iodine
Benzamide
ortho-Acetoxylation/methoxylation
Aromatic C–H activation
The transition metal catalyzed C–H activation has become a
powerful tool for the functionalization of unactivated carbon–
hydrogen bonds to construct carbon–carbon or carbon–heteroatom
bonds.1–5 However, direct functionalization of substrates with sim-
ilar C–H bonds tends to require a directing group.6 Generally, the
directing group possesses a lone pair which coordinates to the tran-
sition metal catalyst to direct ortho functionalization via a five- or
six-membered metallacycle.7 In particular, the oxidation of aro-
matic C–H bonds is a challenging task in organic synthesis.8 The
concept of dual activation in the acetoxylation of amides possessing
a pyridine or 8-aminoquinoline directing group has recently been
reported.9 However, there are no reports on the oxidative function-
alization of carboxamide amides via dual activation of both amide
NH and ortho-chelating carbonyl group.
In continuation of our interest on the functionalization of are-
nes via C–H activation,10 herein, we report a direct method for
the acetoxylation/methoxylation of benzamides activated by both
amide NH and ortho-carbonyl group. Initially, we attempted the
acetoxylation of simple benzamide derived from benzoic acid
and aniline with Ac2O using a catalytic amount of Pd(OAc)2 and a
stoichiometric amount of PhI(OAc)2 in acetic acid at 100 °C. The
reaction was very slow and the desired product was obtained in
40% yield after 24 h. Next, we attempted the acetoxylation of
N-(2-benzoylphenyl)benzamide (1) under similar conditions.
Interestingly, mono-acetoxylated product 3a was obtained in 80%
yield after 5 h (Scheme 1).
The acetoxylation was highly ortho-selective to the amide group.
In acetoxylation reaction, Pd(OAc)2 acts as a catalyst to activate
aromatic C–H bond via an oxidative insertion. PhI(OAc)2 acts as a
co-oxidant to reoxidize Pd(0) to Pd(II). Ac2O acts as an acetoxylating
agent. The efficiency of various co-oxidants such as PhI(OAc)2,
AgOAc, Cu(OAc)2, Mn(OAc)3, and benzoquinone was tested for this
reaction. Of these, PhI(OAc)2 was found to be effective in terms of
conversion. The acetoxylation was also performed using various
amounts of Pd(OAc)2. Though the reaction proceeds with 5 mol %
of Pd(OAc)2, the reaction requires long reaction time, about 12 h,
to furnish comparable yield. Under optimized conditions, the acet-
oxylation typically requires 10 mol % Pd(OAc)2 and a stoichiometric
amount of PhI(OAc)2 to achieve good conversions. Next we have
performed the reaction at various temperatures in various solvents.
The reaction was sluggish either in toluene or in 1,4-dioxane. The
reaction proceeds smoothly at 100–110 °C in acetic acid. Notably,
sterically hindered substrates also participated effectively in acet-
oxylation (Table 1, entry f). No acetoxylation was observed on
remote sp3 C–H bond in case of methyl substituted benzamides
(Table 1, entries g, l, and m).
O
O
10 mol% Pd(OAc)2
N
N
H
H
+ PhI(OAc)2
Ph
Ac2O:AcOH (1:1)
110 0C
OAc
O
Ph
O
2
1
3a
⇑
Corresponding author.
E-mail address: basireddy@iict.res.in (B.V.S. Reddy).
Scheme 1. Acetoxylation of N-(2-benzoylphenyl)benzamide.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.098

B.V.S. Reddy et al. / Tetrahedron Letters 52 (2011) 5926–5929
5927
Table 1
Pd(II)-catalyzed acetoxylation/methoxylation of aromatic carboxamides via C–H activation
Entry
Substrate
Nucleophile
Producta
Time (h)
5.0
Yieldb (%)
Ph
Ph
O
O
O
O
a
Ac2O
80
85
NH
3a
Ph
NH
OAc
Ph
O
O
O
O
Cl
F
b
c
Ac2O
Ac2O
3b
4.0
4.0
Cl
F
NH
NH
OAc
Ph
Ph
O
O
O
O
3c
82
90
NH
OAc
NH
Ph
Ph
Ph
O
O
O
O
3d
MeO
MeO
MeO
MeO
d
Ac2O
6.0
NH
OAc
NH
Ph
O
O
O
O
3e
PhO
e
f
Ac2O
Ac2O
Ac2O
MeOH
5.0
85
30
70
85
PhO
NH
NH
Ph
OAc
Ph
NO2
O
O
O
NO2
O
3f
10
NH
NH
OAc
Ph
Ph
O
O
O
O
3g
g
h
6.0
6.0
NH
NH
OAc
Ph
Me
Me
Ph
O
O
O
O
NH
OMe
4h
NH
Ph
Ph
O
O
O
O
4i
i
MeOH
6.0
80
NH
NH
OMe
F
F
Ph
Ph
Ph
O
O
O
O
Cl
4j
j
MeOH
MeOH
MeOH
MeOH
MeOH
6.0
8.0
8.0
8.0
5.0
82
70
73
75
85
Cl
NH
NH
OMe
Ph
O
O
O
O
k
l
O
O
4k
NH
O
O
NH
OMe
Ph
Ph
Ph
O
O
O
O
4l
Me
Me
NH
OMe
NH
Ph
O
O
O
O
4m
4n
m
n
NH
NH
OMe
Me
Me
Ph
Ph
O
O
O
O
PhO
PhO
NH
OMe
NH
a
All products were characterized by 1H NMR, IR, and mass spectrometry.
Yield refers to pure products after chromatography.
b

5928
B.V.S. Reddy et al. / Tetrahedron Letters 52 (2011) 5926–5929
Acknowledgments
O
O
10 mol% Pd(OAc)2
N
H
N
H
PhI(OAc)2
+
G.R. and A.S.R. thank CSIR, New Delhi for the award of fellow-
ships. J.S. Yadav acknowledges the partial support by King Saud
University for Global Research Network for Organic Synthesis
(GRNOS).
COPh
MeOH, 100 0
C
OMe
O
Ph
2
1
4i
Scheme 2. Methoxylation of N-(2-benzoylphenyl)benzamide.
References and notes
Next, we extended this method to study the methoxylation of
benzamides under similar conditions. Accordingly, we attempted
the methoxylation of N-(2-benzoylphenyl)benzamide (1) in meth-
anol using Pd(OAc)2/PhI(OAc)2. By simply changing the solvent
from acetic acid to methanol, the methoxylated product 4i was
obtained in 85% yield over 6 h (Scheme 2).
1. (a) Dyker, G. Handbook of C–H Transformations: Applications in Organic Synthesis;
Wiley-VCH: Weinheim, 2005; (b) Chatani, N. In Directed Metallation; Springer:
Berlin, 2008; Vol. 24,; (c) Beccalli,
E M.; Broggini, G.; Martinelli, M.;
Sottocornola, S. Chem. Rev. 2007, 107, 5318; (d) Lewis, J. C.; Bergman, R. G.;
Ellman, J. A. Acc. Chem. Res. 2008, 41, 1013; (e) Goj, L. A.; Gunnoe, T. B. Curr. Org.
Chem. 2005, 9, 671; (f) Li, B.; Yang, S.; Shi, Z. Synlett 2008, 949; (g) Diaz-
Requejo, M. M.; Perez, P. J. Chem. Rev. 2008, 108, 3379; (h) Giri, R.; Shi, B.-F.;
Engle, K. M.; Maugel, N.; Yu, J.-Q. Chem. Soc. Rev. 2009, 38, 3242; (i) Daugulis,
O.; Do, J.-Q.; Shabashov, D. Acc. Chem. Res. 2009, 42, 1074.
Interestingly, a variety of aromatic carboxamides bearing sub-
stitutions at ortho-, meta-, and para-positions participated well in
this reaction (Table 1). No dehalogenation was obtained in case
of halogenated substrates (Table 1, entries b, c, i, and j). Notably,
various functional groups such as amide, ketone, halides, ethers,
and methyl functionalities are well tolerated under the reaction
conditions. No acetoxylation was observed 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 effective in
terms of conversion. In all cases, the reactions were clean and
the products were obtained in excellent yields. The products were
characterized by NMR, IR, and mass spectroscopy. The scope and
generality of this process are illustrated with respect to various
benzamides bearing electron-rich as well as electron-deficient sub-
stituents on aromatic ring and the results are presented in Table
1.11
2. (a) Shi, Z.; Li, B.; Wan, X.; Cheng, J.; Fang, Z.; Cao, B.; Qin, C.; Wang, Y. Angew.
Chem., Int. Ed. 2007, 46, 5554; (b) Chiong, H. A.; Daugulis, O. Org. Lett. 2007, 9,
1449; (c) Wakui, H.; Kawasaki, S.; Satoh, T.; Miura, M.; Nomura, M. J. Am. Chem.
Soc. 2004, 126, 8658; (d) Ueda, S.; Nagasawa, H. Angew. Chem., Int. Ed. 2008, 47,
6411; (e) Roy, A. H.; Lenges, C. P.; Brookhart, M. J. Am. Chem. Soc. 2007, 129,
2082; (f) Ozdemir, I.; Demir, S.; Cetinkaya, B.; Gourlaouen, C.; Maseras, F.;
Bruneau, C.; Dixneuf, P. H. J. Am. Chem. Soc. 2008, 130, 1156; (g) Lane, B. S.;
Sames, D. Org. Lett. 2004, 6, 2897; (h) Wang, D.; Wasa, M.; Giri, R.; Yu, J.-Q. J.
Am. Chem. Soc. 2008, 130, 7190; (i) Ko, S.; Kang, B.; Chang, S. Angew. Chem., Int.
Ed. 2005, 44, 455.
3. (a) Wan, X.; Ma, Z.; Li, B.; Zhang, K.; Cao, S.; Zhang, S.; Shi, Z. J. Am. Chem. Soc.
2006, 128, 7416; (b) Giri, R.; Chen, X.; Yu, J.-Q. Angew. Chem., Int. Ed. 2005, 44,
2112; (c) Hull, K. L.; Anani, W. Q.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128,
7134.
4. (a) Desai, L. V.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 9542; (b)
Desai, L. V.; Stowers, K. J.; Sanford, M. S. J. Am. Chem. Soc. 2008, 130, 13285.
5. (a) Thu, H. Y.; Yu, W. Y.; Che, C. M. J. Am. Chem. Soc. 2006, 128, 9048; (b)
Inamoto, K.; Saito, T.; Katsuno, M.; Sakamoto, T.; Hiroya, K. Org. Lett. 2007, 9,
2931.
6. (a) Desai, L. V.; Ren, D. T.; Rosner, T. Org. Lett. 2010, 12, 1032; (b) Chernyak, N.;
Dudnik, A. S.; Huang, C.; Gevorgyan, V. J. Am. Chem. Soc. 2010, 132, 8270; (c)
Yoshikai, N.; Matsumoto, A.; Norinder, J.; Nakamura, E. Angew. Chem., Int. Ed.
2009, 48, 2925; (d) Zhao, X.; Yeung, C. S.; Dong, V. M. J. Am. Chem. Soc. 2010,
132, 5837; (e) Gu, S.; Chen, C.; Chen, W. J. Org. Chem. 2009, 74, 7203.
7. (a) Shabashov, D.; Daugulis, O. Org. Lett. 2005, 7, 3657; (b) Dick, A. R.; Sanford,
M. S. Tetrahedron 2006, 62, 2439; (c) Daugulis, O.; Zaitsev, V. G.; Shabashov, D.;
Pham, Q.-N.; Lazareva, A. Synlett 2006, 3382; (d) Chen, X.; Engle, K. M.; Wang,
D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094; (e) Wasa, M.; Worrell, B. T.;
Yu, J.-Q. Angew. Chem., Int. Ed. 2010, 49, 1275.
8. (a) Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 2300; (b)
Wang, G.-W.; Yuan, T.-T.; Wu, X.-L. J. Org. Chem. 2008, 73, 4717; (c) Wang, G.-
W.; Yuan, T.-T. J. Org. Chem. 2010, 75, 476; (d) Stowers, K. J.; Sanford, M. S. Org.
Lett. 2009, 11, 4584; (e) Desai, L. V.; Malik, H. A.; Sanford, M. S. Org. Lett. 2006, 8,
1141; (f) Kalyani, D.; Sanford, M. S. Org. Lett. 2005, 7, 4149.
We assume that the reaction proceeds via the formation of five-
membered transition state by an oxidative insertion of Pd(II) into
aromatic C–H bond as depicted in Scheme 3. Thus formed palladac-
yle might be stabilized with carbonyl group to induce the ortho-
acetoxylation. The resulting Pd(0) could be converted into Pd(II)
by PhI(OAc)2 to complete the catalytic cycle.
In summary, we have developed a novel protocol for the oxida-
tive functionalization of benzamides bearing ortho-chelating car-
bonyl group via C–H activation. The method is very useful not
only for acetoxylation but also for methoxylation of aromatic sys-
tems. It works for both electron-rich as well as electron-deficient
substrates.
9. Gou, F.-R.; Wang, X.-C.; Huo, P. F.; Bi, H.-P.; Guan, Z.-H.; Liang, Y.-M. Org. Lett.
2009, 11, 5726.
10. (a) Reddy, B. V. S.; Reddy, L. R.; Corey, E. J. Org. Lett. 2006, 8, 3391; (b) Reddy, B.
V. S.; Ramesh, K.; Yadav, J. S. Synlett 2011, 169.
PhI(OAc)2
11. General
procedure
for
acetoxylation:
A
mixture
of
N-(2-
benzoylphenyl)benzamide (361 mg, 1 mmol), PhI(OAc)2 (322 mg, 1 mmol),
Pd(OAc)2 (22 mg, 0.1 mmol), in AcOH (0.5 mL) and Ac2O (0.5 mL) was heated
at 110 °C for the appropriate time under N2 atmosphere. Upon completion of the
reaction as indicated by TLC, the mixture was quenched with water followed by
neutralization with saturated NaHCO3 (20 mL) and then extracted with
dichloromethane (3 Â 20 mL). The combined organic layers were washed with
brine (20 mL) and dried over anhydrous Na2SO4. Removal of the solvent followed
by purification on silica gel (ethyl acetate/n-hexane, 3:7) gave the pure acetoxy
arene. Methoxylation: A mixture of N-(2-benzoylphenyl)benzamide (361 mg,
1 mmol), PhI(OAc)2 (322 mg, 1 mmol), Pd(OAc)2 (22 mg, 0.1 mmol), in MeOH
(0.5 mL) was heated at 100 °C for the appropriate time under N2 atmosphere.
Upon completion of the reaction as indicated by TLC, the mixture was diluted
with water and then extracted with dichloromethane. Removal of the solvent
followed by purification on silica gel (ethyl acetate/n-hexane, 3:7) gave the pure
methoxyarene. Spectroscopic data for selected products: Compound 3b: 2-(2-
Benzoylphenylcarbamoyl)-4-chlorophenyl acetate: 1H NMR (CDCl3, 300 MHz): d
11.39 (br s, 1H), 8.75 (d, J = 9.0 Hz, 1H), 7.92 (d, J = 2.6 Hz, 1H), 7.76–7.69 (m, 2H),
7.65–7.53 (m, 3H), 7.52–7.42 (m, 3H), 7.16–7.09 (m, 2H), 2.32 (s, 3H), 13C NMR
(CDCl3, 75 MHz): d 199.2, 168.9, 162.7, 146.7, 139.6, 138.1, 134.1, 133.3, 132.7,
132.2, 131.8, 130.1, 130.0, 129.4, 128.3, 124.9, 124.3, 122.8, 122.2, 21.0; IR (KBr):
Pd(0)
Pd(II)
C-H
O
activation
PhI(OAc)2
Ac2O
N
H
O
OAc O
Ph
N
H
O
Exclusively formed
O
Ph
N
Pd
O
Ph
L
Favorable complex
AcO
OAc
Pd
O
O
N
H
N
H
m
3421, 2923, 2853, 1773, 1640, 1598, 1448, 1166, 805, 701; ESI-MS: m/z = 416
[M+Na]Å HRMS calcd for C22H16NO4NaCl: 416.0665, found: 416.0665.
O
Ph
O
Ph
Compound 3d: 2-2(-Benzoylphenylcarbamoyl)-3,4-dimethoxyphenylacetate:
1H NMR (CDCl3, 300 MHz): d 10.91 (br s, 1H), 8.76 (d, J = 8.3 Hz, 1H), 7.82–7.70
(m, 2H), 7.64–7.51 (m, 3H), 7.50–7.41 (m, 2H), 7.14–7.06 (m, 1H), 6.96–6.80 (m,
2H), 3.89 (s, 3H), 3.88 (s, 3H), 2.16 (s, 3H). 13C NMR (CDCl3, 75 MHz): d 198.5,
Unfavorable
Not observed
Scheme 3. A plausible reaction pathway.

B.V.S. Reddy et al. / Tetrahedron Letters 52 (2011) 5926–5929
5929
167.6, 162.5, 150.8, 148.5, 141.3, 139.6, 133.8, 133.0, 132.6, 130.0, 128.2, 124.9,
122.5, 122.0, 118.4, 113.8, 61.9, 56.2, 20.8; IR (KBr): 3344, 2923, 1765, 1678,
1022, 952, 829, 756, 702, 635; ESI-MS: m/z = 372 [M+Na]. HRMS calcd for
m
C21H16NO3FNa: 372.1011, found: 372.1009.
1644, 1581, 1479, 1441, 1296, 1268, 1200, 1049, 814, 754, 703; ESI-MS: m/
z = 420 [M+H]. HRMS calcd for C24H22NO6: 420.1447, found: 420.1455.
Compound 4j: N-(2-Benzoylphenyl)-5-chloro-2-methoxy benzamide: 1H NMR
(CDCl3, 300 MHz): d 11.89 (br s, 1H), 8.78 (d, J = 8.9 Hz, 1H), 8.20 (d, J = 2.9 Hz,
1H), 7.78 (d, J = 6.7 Hz, 2H), 7.53–7.58 (m, 2H), 7.46 (t, J = 6.7 Hz, 3H), 7.38 (dd,
J = 8.6 and 2.9 Hz, 1H), 7.09 (t, J = 7.7 Hz, 1H), 6.92 (d, J = 9.6 Hz, 1H), 4.03 (s, 3H);
13C NMR (CDCl3, 75 MHz): d 197.8, 162.8, 156.2, 139.0, 138.2, 133.1, 132.8, 132.7,
Compound 4i: N-(2-Benzoylphenyl)-4-fluoro-2-methoxy benzamide: 1H NMR
(CDCl3, 300 MHz): d 11.76 (br s, 1H), 8.79 (d, J = 9.0 Hz, 1H), 8.29–8.23 (m, 1H),
7.77 (d, J = 6.7 Hz, 2H), 7.61–7.40 (m, 5H), 7.12–7.01 (m, 1H), 6.81–6.64 (m, 2H),
4.05 (s, 3H); 13C NMR (CDCl3, 75 MHz): d 197.9, 167.5, 164.1, 163.2, 139.2, 138.3,
134.6, 134.4, 133.1, 132.6, 132.0, 130.1, 128.2, 126.3, 123.1, 122.2, 108.1, 107.8,
132.0, 130.1, 128.3, 126.4, 126.3, 123.2, 123.1, 122.4, 112.7, 56.1; IR (KBr):
m
3449, 2924, 1646, 1577, 1514, 1448, 1259, 1025, 806, 754; ESI-MS: m/z = 388,
99.5, 99.1, 56.1; IR (KBr):
m
3417, 2924, 1653, 1578, 1442, 1255, 1153, 1106,
[M+Na]. HRMS calcd for C21H16NO3NaCl: 388.0716, found: 388.0707.