Palladium(II)-catalyzed auxiliary-directed C-H activation for the regioselective ortho arylation of N -(2-benzoylphenyl)benzamides

Article abstract of DOI:10.1055/s-0030-1260314

A highly regioselective ortho arylation of N-(2-benzoylphenyl)benzamides has been achieved with aryl iodides in the presence of 10 mol% Pd(OAc)and a stoichiometric amount of AgOAc under solvent-free conditions via C-H activation to produce the correspondi

Full text of DOI:10.1055/s-0030-1260314

2374
LETTER
Palladium(II)-Catalyzed Auxiliary-Directed C–H Activation for the Regio-
selective ortho Arylation of N-(2-Benzoylphenyl)benzamides
C–H
A
ctivation f
a
or the Regi
s
oselective
i
orthoArylat
V
N
-(2-Benz
o
.
ylphenyl)ben
S
zamide
s
ubba Reddy,* G. Revathi, A. Srinivas Reddy, Jhillu S. Yadav
Discovery Laboratory, Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500007, India
E-mail: basireddy@iict.res.in
Received 3 May 2011
obtained in 58% yield after 24 hours. Next, we attempted
Abstract: A highly regioselective ortho arylation of N-(2-ben-
the arylation of N-(2-benzoylphenyl)benzamide with 4-
iodoanisole under similar conditions. To our surprise,
monoarylated product 3a was obtained in 80% yield
(Scheme 1).
zoylphenyl)benzamides has been achieved with aryl iodides in the
presence of 10 mol% Pd(OAc)2 and a stoichiometric amount of
AgOAc under solvent-free conditions via C–H activation to pro-
duce the corresponding 2-arylated benzamides in good yields.
Key words: C–C bond formation, ortho arylation, benzamide, aro-
matic C–H activation
O
N
H
O
The C–H bond activation has emerged as a powerful tool
for the selective activation of aromatic C–H bonds using
transition-metal catalysis.1,2 However, direct functional-
ization of substrates with similar C–H bonds tends to re-
quire a directing group which plays a key role in the
formation of the new products.3 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.4 This method often
allows for the site-selective functionalization of a C–H
bond proximal to a coordinating group. As a result, vari-
ous directing groups such as acetanilides, oxime ethers,
oxazolines, 2-arylpyridines, 2-arylquinolines, and ni-
troarenes have been reported for the functionalization of
both sp2 and sp3 carbons.5 These reactions are generally
ortho selective; however, in some cases, meta selectivity
has also been observed.6 In addition, N-isopropylbenz-
amide and N-methoxybenzamide have been employed for
the activation of aromatic C–H bonds.7 Furthermore,
amides derived from carboxylic acids and 8-aminoquino-
line have also been found to be effective for the activation
of aromatic C–H bonds ortho to carboxyl groups.8 How-
ever, there are no reports on the arylation of aromatic
amides via dual activation of both amide NH and an
ortho-chelating carbonyl group.
O
Ph
Pd(OAc)2 (10 mol%)
1
+
I
N
H
COPh
OMe
AgOAc (1 equiv), 110 °C,
10 h
3 80%
OMe
2
Scheme 1 Arylation of N-(2-benzoylphenyl)benzamide with p-
iodoanisole
The arylation was highly ortho selective to the carboxylic
group. In this reaction the Pd(OAc)2 acts as a catalyst to
activate the aromatic C–H bond via a-ketoamide-directed
oxidative insertion, and the AgOAc acts as a co-oxidant to
reoxidize Pd(0) to Pd(II). The efficiency of various co-
oxidants such as AgOAc, Cu(OAc)2, Mn(OAc)3, and ben-
zoquinone was probed. Of these, silver acetate was found
to be cost effective in terms of conversion. We have also
studied the arylation using various amounts of Pd(OAc)2.
Though the reaction proceeds with 5 mol% Pd(OAc)2, it
requires more than 24 hours to furnish comparable yields.
Under optimized conditions, 10 mol% Pd(OAc)2 and a
stoichiometric amount of AgOAc were necessary to
achieve efficient conversions. Next we have performed
the reaction at various temperatures with or without sol-
vent. The reaction was sluggish either in toluene or in 1,4-
dioxane but proceeded smoothly at 110 °C under solvent-
free conditions. Next, we decided to study the scope of the
reaction with respect to various substrates under these op-
timized conditions. Interestingly, a variety of aromatic
carboxamides bearing substitutions at ortho, meta, and
para positions participated well in the arylation (Table 1).
Notably, sterically hindered ortho-substituted amides par-
ticipated effectively in this reaction (entries 4–6, 8, and 9,
Table 1).
In continuation of our interest on the direct functionaliza-
tion of arenes via C–H activation,9 we herein report for the
first time the arylation of aromatic amides with aryl io-
dides activated by both amide NH and ortho carbonyl
groups. Initially, we attempted the arylation of the benza-
mide derived from benzoic acid and aniline with 4-
iodoanisole using 10 mol% of Pd(OAc)2 and a stoichio-
metric amount of AgOAc under solvent-free conditions.
The reaction was very slow, and the desired product was
SYNLETT 2011, No. 16, pp 2374–2378
x
x
.x
x
.2
0
1
1
Advanced online publication: 13.09.2011
DOI: 10.1055/s-0030-1260314; Art ID: D13511ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Activation for the Regioselective ortho Arylation of N-(2-Benzoylphenyl)benzamides
2375
Table 1 Ligand-Directed Arylation of Aromatic Carboxylic Acids via C–H Activation
Entry
Substrate
Iodorane
Product 3a
Time (h) Yield (%)b
Ph
O
O
O
I
NH
NH
O
1
10
80
MeO
Ph
OMe
Ph
3a
O
O
O
I
NH
NH
O
2
12
75
Me
Ph
Me
3b
Ph
O
O
O
I
NH
NH
3
10
80
F
MeO
F
O
Ph
OMe
3c
Ph
O
OMe
OMe
O
O
MeO
MeO
I
NH
NH
O
4
5
6
8
75
90
65
Me
Ph
Me
Ph
3d
O
OMe
O
OMe
O
MeO
MeO
I
NH
NH
6
MeO
O
Ph
OMe
3e
Ph
O
NO2
O
NO2
O
I
NH
NH
O
10
MeO
Ph
OMe
Ph
3f
O
O
O
I
NH
NH
O
7
6
85
Me
Me
O
Ph
O
3g
Synlett 2011, No. 16, 2374–2378 © Thieme Stuttgart · New York

2376
B. V. Subba Reddy et al.
LETTER
Table 1 Ligand-Directed Arylation of Aromatic Carboxylic Acids via C–H Activation (continued)
Entry
Substrate
Iodorane
Product 3a
Time (h) Yield (%)b
Ph
O
OMe
O
OMe
O
MeO
MeO
I
NH
NH
O
8
12
12
12
75
70
80
Ph
3h
Ph
O
NO2
O
NO2
O
I
NH
9
10
11
12
13
14
NH
O
Ph
3i
Ph
O
NH
O
O
I
NH
Me
Me
MeO
O
Ph
OMe
Ph
3j
O
O
O
O
O
O
I
NH
O
NH
12
15
12
12
78
75
75
80
Me
Me
Ph
Ph
Ph
Ph
3k
Ph
O
O
I
NH
NH
O
Me
Me
Me
Me
Me
Ph
3l
O
O
Me
I
NH
O
NH
3m
Ph
O
O
Me
Me
I
NH
NH
O
Me
Me
3n
a All products were characterized by 1H NMR, IR, and mass spectrometry.
b Yield refers to pure products after chromatography.
Synlett 2011, No. 16, 2374–2378 © Thieme Stuttgart · New York

LETTER
Activation for the Regioselective ortho Arylation of N-(2-Benzoylphenyl)benzamides
2377
Both electron-rich as well as electron-deficient substrates
participated well in this arylation (Table 1). No dehaloge-
nation was obtained in the case of a halogenated substrate
(Table 1, entry 3). In all cases, the reactions were clean,
and the products were obtained in good yields. The prod-
ucts were characterized by mass spectrometry, NMR and
IR spectroscopy. The scope and generality of this process
is illustrated in Table 1.10
References and Notes
(1) (a) Beccalli, E. M.; Broggini, G.; Martinelli, M.;
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6790. (d) Inamoto, K.; Saito, T.; Katsuno, M.; Sakamoto, T.;
Hiroya, K. Org. Lett. 2007, 9, 2931. (e) Giri, R.; Chen, X.;
Yu, J.-Q. Angew. Chem. Int. Ed. 2005, 44, 2112.
(3) (a) Desai, L. V.; Ren, D. T.; Rosner, T. Org. Lett. 2010, 12,
1032. (b) Desai, L. V.; Stowers, K. J.; Sanford, M. S. J. Am.
Chem. Soc. 2008, 130, 13285. (c) Chernyak, N.; Dudnik, A.
S.; Huang, C.; Gevorgyan, V. J. Am. Chem. Soc. 2010, 132,
8270. (d) Yoshikai, N.; Matsumoto, A.; Norinder, J.;
Nakamura, E. Angew. Chem. Int. Ed. 2009, 48, 2925.
(e) Zhao, X.; Yeung, C. S.; Dong, V. M. J. Am. Chem. Soc.
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Chem. 2009, 74, 7203.
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3657. (c) Dick, A. R.; Sanford, M. S. Tetrahedron 2006, 62,
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Pham, Q.-N.; Lazareva, A. Synlett 2006, 3382. (e) Chen,
X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem. Int.
Ed. 2009, 48, 5094. (f) Wasa, M.; Worrell, B. T.; Yu, J.-Q.
Angew. Chem. Int. Ed. 2010, 49, 1275.
We assume that the reaction proceeds via the formation of
a five-membered transition state by an oxidative insertion
of Pd(II) into the aromatic C–H bond as depicted in
Scheme 2. The palladacycle thus formed might be stabi-
lized with the carbonyl group to intiate the ortho arylation.
The resulting Pd(0) could be converted into Pd(II) by
AgOAc to complete the catalytic cycle.
AgOAc
Pd(0)
Pd(II)
C–H
activation
O
O
N
Ar-I
O
H
N
H
Ar
O
Ph
O
Ph
exclusively formed
N
(5) (a) Kakiuchi, F.; Kan, S.; Igi, K.; Chatani, N.; Murai, S.
J. Am. Chem. Soc. 2003, 125, 1698. (b) Bedford, R. B.;
Coles, S. J.; Hursthouse, M. B.; Limmert, M. E. Angew.
Chem. Int. Ed. 2003, 42, 112. (c) Caron, L.; Campeau,
L.-C.; Fagnou, K. Org. Lett. 2008, 10, 4533. (d) Cho, S. H.;
Hwang, S. J.; Chang, S. J. Am. Chem. Soc. 2008, 130, 9254.
(e) Chen, X.; Li, J.-J.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q.
J. Am. Chem. Soc. 2006, 128, 78. (f) Chiong, H. A.; Pham,
Q.-N.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 9879.
(g) Desai, L. V.; Stowers, K. J.; Sanford, M. S. J. Am. Chem.
Soc. 2008, 130, 13285. (h) Shi, Z.; Li, B.; Wan, X.; Cheng,
J.; Fang, Z.; Cao, B.; Qin, C.; Wang, Y. Angew. Chem. Int.
Ed. 2007, 46, 5554.
Pd
O
Ph
L
OAc
favorable complex
Pd
Ar
O
O
N
H
N
H
O
Ph
O
not observed
Ph
unfavorable
Scheme 2 A plausible reaction mechanism
(6) (a) Phipps, R. J.; Gaunt, M. J. Science 2009, 323, 1593.
(b) Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. J. Am. Chem. Soc.
2009, 131, 5072.
(7) (a) Lazareva, A.; Daugulis, O. Org. Lett. 2006, 8, 5211.
(b) Shabashov, D.; Daugulis, O. Org. Lett. 2006, 8, 4947.
(c) Wang, D.-H.; Wasa, M.; Giri, R.; Yu, J.-Q. J. Am. Chem.
Soc. 2008, 130, 7190.
(8) (a) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem.
Soc. 2005, 127, 13154. (b) Reddy, B. V. S.; Reddy, L. R.;
Corey, E. J. Org. Lett. 2006, 8, 3391. (c) Do, H.-Q.;
Daugulis, O. J. Am. Chem. Soc. 2008, 130, 1128.
(9) Reddy, B. V. S.; Ramesh, K.; Yadav, J. S. Synlett 2011, 169.
(10) General Procedure for the Arylation
In summary, we have demonstrated a palladium-catalyzed
auxiliary-directed arylation of benzamides derived from
aromatic carboxylic acids and 2-aminobenzophenone via
C–H activation. The method is highly ortho selective af-
fording biaryls in good yields. It is useful for the arylation
of not only electron-rich but also electron-deficient aro-
matic amides. This method provides an easy access for the
synthesis of a variety of ortho-arylated benzamide deriv-
atives.
A mixture of N-(2-benzoylphenyl)benzamide (1 mmol),
AgOAc (1 mmol), Pd(OAc)2 (0.1 mmol), and iodoarene (3
mmol) was heated at 110 °C under solvent-free conditions
for the appropriate time (see Table 1) under N2 atmosphere.
After completion of the reaction, as indicated by TLC
analysis, the reaction mixture was diluted with CH2Cl2 (30
mL) and then filtered under reduced pressure. Removal of
the solvent followed by purification on silica gel gave the
pure arylated product.
Acknowledgment
GR and ASR thank CSIR, New Delhi, for the award of fellowships.
J. S. Yadav acknowledges the partial support by King Saud Univer-
sity for Global Research Network for Organic Synthesis (GRNOS).
Synlett 2011, No. 16, 2374–2378 © Thieme Stuttgart · New York

2378
B. V. Subba Reddy et al.
LETTER
Spectroscopic Data for Selected Products
N-(2-Benzoylphenyl)-3,4-dimethoxybiphenyl-2-
carboxamide (3h)
N-(2-Benzoylphenyl)-4-methylbiphenyl-2-carboxamide
(3m)
IR (neat): 3446, 1677, 1639, 1583, 1514, 1441, 1295, 1260,
1194, 1159, 942, 758, 699, 642 cm–1.1H NMR (300 MHz,
CDCl3): d = 10.33 (br s, 1 H), 8.67 (d, J = 8.3 Hz, 1 H), 7.59–
7.26 (m, 12 H), 7.06 (t, J = 7.7 Hz, 2 H), 6.92 (t, J = 7.3 Hz,
1 H), 6.82 (t, J = 7.3 Hz, 1 H), 2.44 (s, 3 H). 13C NMR (75
MHz, CDCl3): d = 198.0, 168.8, 139.5, 138.0, 137.3, 136.8,
136.0, 133.6, 132.7, 132.3, 131.1, 130.3, 130.0, 129.1,
128.7, 128.1, 128.0, 127.9, 127.1, 124.0, 122.1, 121.4, 20.9.
ESI-MS: m/z = 392 [M + H]. HRMS: m/z calcd for
C27H22NO2: 392.1650; found: 392.1669.
IR (neat): 3448, 2931, 2852, 1686, 1638, 1579, 1478, 1442,
1294, 1265, 1160, 1105, 1055, 945, 877, 813, 757, 699, 641
cm–1. 1H NMR (300 MHz, CDCl3): d = 10.36 (br s, 1 H), 8.57
(d, J = 8.0 Hz, 1 H), 7.68–6.77 (m, 15 H), 3.93 (s, 3 H), 3.92
(s, 3 H). 13C NMR (75 MHz, CDCl3): d = 198.4, 165.9,
151.9, 146.2, 139.3, 139.2, 137.9, 133.5, 132.6, 132.3,
129.9, 128.4, 128.2, 127.9, 127.3, 126.8, 125.5, 124.1,
122.2, 121.9, 113.4, 61.8, 55.9. ESI-MS: m/z = 438 [M + H].
HRMS: m/z calcd for C28H24NO4: 438.1705; found:
438.1686.
N-(2-Benzoylphenyl)-4,4-dimethylbiphenyl-2-
carboxamide (3n)
N-(2-Benzoylphenyl)-3-nitrobiphenyl-2-carboxamide
(3i)
IR (neat): 3520, 2924, 1679, 1639, 1581, 1259, 771, 699 cm–1.
1H NMR (300 MHz, CDCl3): d = 10.36 (br s, 1 H), 8.68 (d,
J = 8.1 Hz, 1 H), 7.61–7.22 (m, 12 H), 7.01 (t, J = 7.7 Hz, 1
H), 6.90 (d, J = 7.5 Hz, 2 H), 2.44 (s, 3 H), 1.97 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 197.9, 169.0, 139.7, 138.0,
137.1, 136.9, 136.8, 136.7, 136.6, 135.9, 133.6, 132.8,
132.3, 131.2, 130.3, 129.9, 129.2, 128.8, 128.6, 128.3,
128.1, 124.0, 122.0, 121.5, 20.9, 20.8. ESI-MS: m/z = 406
[M + H]. HRMS: m/z calcd for C28H24NO2: 406.1807; found:
406.1807.
IR (neat): 3454, 1684, 1638, 1584, 1444, 1263 758, 698 cm–1.
1H NMR (300 MHz, CDCl3): d = 10.42 (br s, 1 H), 8.44 (d,
J = 8.3 Hz, 1 H), 8.12 (dd, J = 9.0, 1.5 Hz, 1 H), 7.68–7.30
(m, 11 H), 7.09–6.98 (m, 3 H), 6.87 (t, J = 7.5 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 198.3, 164.1, 146.9, 141.5,
138.7, 137.7, 137.3, 135.5, 133.6, 132.5, 131.6, 130.0,
129.7, 128.6, 128.2, 128.1, 128.0, 127.9, 124.3, 123.4,
122.8, 122.4. ESI-MS: m/z = 423 [M + H]. HRMS:
m/z calcd for C26H19N2O4: 423.134; found: 423.133.
Synlett 2011, No. 16, 2374–2378 © Thieme Stuttgart · New York

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