Direct ortho-acetoxylation of anilides via palladium-catalyzed sp 2 C-H bond oxidative activation

Article abstract of DOI:10.1021/jo8003088

(Chemical Equation Presented) Various anilides have been directly ortho-acetoxylated through a Pd(OAc)₂-catalyzed C-H bond activation process. The amide group in anilides was found to functionalize as an elegant directing group to convert aromatic sp² C-H bonds into C-O bonds in high regioselectivity with acetic acid as the acetate source and K ₂S₂O₈ as the oxidant.

Full text of DOI:10.1021/jo8003088

traditional Pd0/II catalysis. Oxidants such as hypervalent iodine
reagents,5a,d benzoyl peroxide,5c and Oxone8 were often em-
ployed to convert PdII to PdIV. The formation of PdIV species
has been confirmed by X-ray crystal structures.9 This brand new
catalyst system opens up a great opportunity to form carbon-
heteroatom and carbon-carbon bonds directly from unactivated
C-H bonds to produce novel organic molecules that cannot be
achieved by common catalysts. With the acetamino group as a
Direct Ortho-Acetoxylation of Anilides via
Palladium-Catalyzed sp2 C-H Bond Oxidative
Activation
Guan-Wu Wang,* Ting-Ting Yuan, and Xue-Liang Wu
Hefei National Laboratory for Physical Sciences at
Microscale, Joint Laboratory of Green Synthetic Chemistry,
and Department of Chemistry, UniVersity of Science and
Technology of China, Hefei,
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Anhui 230026, People’s Republic of China
gwang@ustc.edu.cn
ReceiVed February 5, 2008
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Various anilides have been directly ortho-acetoxylated
through a Pd(OAc)2-catalyzed C-H bond activation process.
The amide group in anilides was found to functionalize as
an elegant directing group to convert aromatic sp2 C-H
bonds into C-O bonds in high regioselectivity with acetic
acid as the acetate source and K2S2O8 as the oxidant.
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10.1021/jo8003088 CCC: $40.75
Published on Web 05/17/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 4717–4720 4717

TABLE 1. Screening Reaction Conditions for the
TABLE 2. Pd-Catalyzed Direct Ortho-Acetoxylation of Anilidesa
Pd(OAc)2-Catalyzed Direct Ortho-Acetoxylation of Acetanilide 1aa
entry
oxidant
solvent
yieldb
1
2
3
4
5
6
7
8
PhI(OAc)2
Oxone
MCPBA
tBuOOH
O2
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
trace
11%
trace
44%
trace
77%
43%
55%
72%
trace
39%
42%
42%
44%
61%
K2S2O8
K2S2O8
K2S2O8
K2S2O8
c
d
e
9
DCE
10
11
12
13
14
15
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
CH3CN
PhMe
dioxane
f
DCE
DCE
g
a Unless otherwise specified, all the reactions were carried out in the
presence of 1 mmol of 1a, 0.05 mmol of Pd(OAc)2, 2 mmol of oxidant
in 5 mL of AcOH, and 5 mL of solvent at 100 °C for 48 h. b Isolated
yields. c 1 mmol of K2S2O8 was employed. d 1.5 mmol of K2S2O8 was
employed. e 2.5 mmol of K2S2O8 was employed. f 2 mol % of Pd(OAc)2
was used. g 3 mol % of Pd(OAc)2 was used.
directing group, the o-C-H of acetanilide could be highly
regioselectively functionalized. Selective oxidative couplings of
anilides with alkyl halides,10a olefins,10b–d haloolefins,10e
trialkoxyarylsilanes,10f arylboronic acids,10g arenes,10h and aryl
iodides10i to construct C-C bonds have been reported. The
C-N10j and C-X (X ) Cl, Br)6b bond formations of acetanil-
ides have also been demonstrated. However, the selective C-O
bond formation process of anilides has remained unknown until
now. Herein, we present the direct ortho-acetoxylation of
anilides through Pd(OAc)2-catalyzed sp2 C-H bond oxidative
activation.
In our initial study, we examined the Pd(OAc)2-catalyzed
acetoxylation with various oxidants and solvents to optimize
the reaction conditions. Acetanilide 1a was chosen as a model
compound. The results are summarized in Table 1. PhI(OAc)2
that was used as a privileged oxidant in Sanford’s systems7,8
was first investigated. However, only trace product was observed
(entry 1, Table 1). When Oxone was employed, the acetoxy-
lation reaction did proceed, yet giving product 2a in 11%
isolated yield (entry 2, Table 1). While m-chloroperoxybenzoic
acid was unable to promote the reaction, peroxide alcohol TBHP
facilitated it successfully with moderate yield (entries 3 and 4,
Table 1). The reaction failed when molecular oxygen was used
as the terminal oxidant (entry 5, Table 1). Much to our pleasure,
when potassium persulfate was employed, the ortho-acetoxylated
product 2a was obtained in 77% yield (entry 6). Reducing the
oxidant loading decreased the yield dramatically, while increas-
ing the loading did not improve it (entries 7-9, Table 1). The
above reactions were performed in acetic acid with 1,2-
dichloroethane as cosolvent. Other cosolvents such as acetoni-
trile, toluene, and dioxane were also screened; all of them proved
to be deleterious to the reaction (entries 10-12, Table 1).
Reaction performed in pure acetic acid also gave a decreased
yield (entry 13, Table 1). When the loading of Pd(OAc)2 was
reduced, the yield was compromised visibly (entries 14 and 15).
As a result, when the reaction was carried out in the presence
a Unless otherwise specified, all the reactions were carried out with 1
mmol of 1, 0.05 mmol of Pd(OAc)2, 2 mmol of K2S2O8 in 5 mL of
AcOH, and 5 mL of DCE at 100 °C for 48 h. b Isolated yields. c The
reaction was performed at 80 °C for 24 h. d CH3CH2CO2H was used
instead of AcOH and the reaction time was 72 h.
of 5 mol % of Pd(OAc)2 with 2 equiv of K2S2O8 as the oxidant
and AcOH/DCE 1:1 as the solvent at 100 °C, the best result
was achieved.
With the optimized conditions in hand, the reaction generality
was investigated with various substituted anilides. The results
are summarized in Table 2. We found that the amide group-
directed C-H bond functionalization protocol was broadly
applicable to a variety of anilides, affording the acetoxylated
products in synthetically valuable yields. Acetanilides with either
electron-donating or electron-withdrawing groups furnished the
expected products (entries 2-10, Table 2). It is noteworthy that
the presence of the halogen, ether, and ketone substituents
(entries 3-6, Table 2) did not interfere with the palladium-
4718 J. Org. Chem. Vol. 73, No. 12, 2008

SCHEME 1. Possible Reaction Mechanism
atom of the anilide, which induced the formation of a cyclo-
palladated intermediate I by chelate-directed C-H activation.
This Pd(II) intermediate was oxidized by K2S2O8 in the presence
of acetic acid to afford a hexacoordinated Pd(IV) intermediate
II, which proceeded through a reductive elimination process to
furnish the final ortho-acetoxylated product and regenerated the
Pd(II) catalyst. The formed Pd(IV) intermediate evidently
deactivated the arene ring for further substitution and disfavored
overoxidation,12 and thus explained the failure of obtaining
bisacetoxylated products in our experiments. It should be noted
that a mechanism involving the common Pd(0)-Pd(II) catalytic
cycle could not be completely excluded.
In conclusion, we have successfully developed an amide
group-directed ortho-acetoxylation of anilides catalyzed by
Pd(OAc)2 with cheap K2S2O8 as a terminal oxidant. This
protocol was convenient, efficient, and applicable for various
substituted anilides. Further investigations on other palladium-
catalyzed direct C-H bond functionalizations are now underway.
catalyzed oxidative activation reaction under our conditions.
Acetoxylation of the acetanilide with a methyl group at the meta-
position afforded product 2g in pretty high yield (93%, entry
7, Table 2). It is not surprising that 3,4-dimethylacetanilide was
also acetoxylated in comparably high yield (92%, entry 8, Table
2). Interestingly, when the substrate with strong electron-
donating groups at 3,4-positions was employed, an accelerated
reaction was observed, giving product 2i in 81% yield after 24 h
at 80 °C (entry 9 vs entry 3, Table 2). When the 3,5-positions
of acetanilide were substituted with a methyl group, the reaction
yield was reduced dramatically, probably ascribed to the steric
hindrance (entry 10, Table 2). Nevertheless, the reaction with
ortho-substituted acetanilides such as 2-methylacetanilide and
2-chloroacetanilide gave a complex mixture with very low
conversion. To expand the scope of anilides, we then examined
the reaction with N-methylated acetanilide (1k) and N-benzoy-
lated aniline (1l), and found that lower yields were obtained in
both cases (entries 11 and 12 vs entry 1, Table 2). Much lower
efficiency was also reported for the chlorination,6b olefination,10c
and arylation10f of anilides with acyl groups other than the acetyl
group. The yield for the olefination of 1k was even 0%.10c These
results along with our own data indicate the significant influence
of the directing groups on the reactions. Other acyloxylation
was also explored. The Pd(OAc)2-catalyzed propionoxylation
of acetanilide 1a afforded the desired product 2m in only
moderate yield, quite lower than that of the corresponding
acetoxylation (entry 13 vs entry 1, Table 2). Because of the
unsatisfactory results shown in entries 11-13 of Table 2, no
efforts had been made to investigate the acetoxylation of other
N-alkylated anilides and N-acylated anilines as well as the
propionoxylation of other anilides.
Experimental Section
General Procedure for the Direct Ortho-Acetoxylation of
Anilide 1a (1b-1m) Catalyzed by Pd(OAc)2. To a stirred solution
of anilide 1a (1b-1m, 1 mmol), Pd(OAc)2 (11 mg, 0.05 mmol),
and K2S2O8 (540 mg, 2 mmol) in DCE (5 mL) at 80 °C was added
AcOH (5 mL). The reaction was monitored by TLC. Upon
completion, the solvent was evaporated to dryness in vacuo. The
residual was separated on a silica gel column with petroleum ether/
ethyl acetate 2/1 as the eluent to get the desired product 2a
(2b-2m).
Compounds 2a,13 2d,14 2e,13 2g,15 and 2j16 have been previously
reported and their identities were confirmed by the comparison with
their reported spectral data.
2-Acetamido-5-methylphenyl Acetate (2b). White solid, mp
154-155 °C. IR (KBr) ν 3356, 2926, 1740, 1688, 1594, 1523, 1367,
1
1307, 1210, 1111, 1025, 897, 814, 667, 594, 562 cm-1; H NMR
(300 MHz, CDCl3) δ 7.91 (1H, d, J ) 8.1 Hz), 7.08 (1H, br), 7.03
(1H, d, J ) 8.1 Hz), 6.93 (1H, s), 2.34 (3H, s), 2.32 (3H, s), 2.15
(3H, s); 13C NMR (75 MHz, CDCl3) δ 169.1, 168.5, 141.3, 135.3,
127.1 (2C), 123.7, 122.6, 24.2, 21.0, 20.9; HRMS (EI-TOF) m/z
[M+] calcd for C11H13NO3, 207.0895, found 207.0900.
2-Acetamido-5-methoxyphenyl Acetate (2c). White solid, mp
117-120 °C. IR (KBr) ν 3294, 1763, 1662, 1607, 1560, 1511, 1420,
1
1373, 1203, 1122, 1022, 901, 818, 772, 716, 580, 509 cm-1; H
NMR (300 MHz, CDCl3) δ 7.32 (1H, d, J ) 2.4 Hz), 7.22 (1H,
dd, J ) 8.7, 2.4 Hz), 7.13 (1H, br), 6.89 (1H, d, J ) 8.7 Hz), 3.80
(3H, s), 2.31 (3H, s), 2.12 (3H, s); 13C NMR (75 MHz, CDCl3) δ
169.5, 168.7, 147.8, 139.5, 131.6, 118.6, 115.8, 112.6, 56.2, 24.1,
20.8; HRMS (EI-TOF) m/z [M+] calcd for C11H13NO4 223.0845,
found 223.0847.
2-Acetamido-5-acetylphenyl Acetate (2f). White solid, mp
150-153 °C. IR (KBr) ν 3339, 2919, 2850, 1740, 1680, 1607, 1523,
1487, 1419, 1363, 1281, 1221, 1127, 1021, 931, 821, 687, 594,
485 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.46 (1H, J ) 8.6, Hz),
7.80 (1H, dd, J ) 8.6, 1.5 Hz), 7.76 (1H, d, J ) 1.5 Hz), 7.36 (1H,
br), 2.57 (3H, s), 2.42 (3H, s), 2.23 (3H, s); 13C NMR (75 MHz,
CDCl3) δ 196.30, 168.60, 168.54, 139.64, 134.46, 133.03, 127.10,
122.19, 121.30, 26.43, 24.74, 21.07; HRMS (EI-TOF) m/z [M+]
calcd for C12H13NO4 235.0845, found 235.0851.
The Pd-catalyzed acetoxylation of aromatic compounds has
been previously reported.11,12 The originally proposed formation
of Ar-OAc via the addition of Pd(II)-OAc across an arene CdC
bond11 was later revised as through a reductive elimination from
an ArPd(IV)OAc intermediate.12 Even though we do not have
any evidence for the reaction mechanism of this ortho-
acetoxylation reaction, we propose a possible pathway (Scheme
1) based on the well-documented literature for the acetoxylation
reaction of various types of compounds via a PdII/PdIV
mechanism,5,7a,b,d,g,m,o,p,9a and especially those with Oxone as
a terminal oxidant.8a,b First, Pd(II) coordinated with the oxygen
2-Acetamido-4,5-dimethylphenyl Acetate (2h). White solid, mp
157-160 °C. IR (KBr) ν 3346, 2922, 1740, 1684, 1599, 1525, 1453,
1401, 1367, 1311, 1225, 1194, 1089, 1020, 918, 884, 675, 584
(13) Li, T.-S.; Li, A.-X. J. Chem. Soc., Perkin Trans. 1. 1998, 12, 1913.
(14) Gershon, H.; Clarke, D. D. Monatsh. Chem. 1991, 122, 935.
(15) Galliani, G.; Rindone, B. J. Chem. Res. 1980, 5, 2524.
(16) Barton, D. H. R.; Blair, L. A.; Magnus, P. D.; Norris, R. J. Chem. Soc.,
Perkin Trans. 1. 1973, 1031.
(11) (a) Eberson, L.; Gomez-Gonzalez, L. Acta Chem. Scand. 1973, 27, 1255.
(b) Eberson, L.; Jo¨nsson, L. Liebigs Ann. Chem. 1977, 233.
(12) Yoneyama, T.; Crabtree, R. H. J. Mol. Catal. A: Chem. 1996, 108, 35.
J. Org. Chem. Vol. 73, No. 12, 2008 4719

1
cm-1; H NMR (300 MHz, CDCl3) δ 7.79 (1H, s), 6.98 (1H, br),
br), 7.85 (2H, d, J ) 7.6 Hz), 7.60-7.49 (3H, m), 7.33-7.26 (1H,
m), 7.21-7.15 (2H, m), 2.37 (3H, s); 13C NMR (75 MHz, CDCl3)
δ 168.8, 165.5, 141.4, 134.8, 132.1, 129.9, 129.0 (2C), 127.1 (2C),
126.7, 125.2, 123.4, 122.2, 21.1; HRMS (EI-TOF): m/z [M+] calcd
for C15H13NO3, 255.0895; found, 255.0897.
6.88 (1H, s), 2.33 (3H, s), 2.23 (3H, s), 2.21 (3H, s), 2.16 (3H, d,
J ) 5.4 Hz); 13C NMR (75 MHz, CDCl3) δ 169.3, 168.4, 139.4,
134.9, 134.0, 127.0, 125.0, 122.9, 24.3, 21.0, 19.5 (2C); HRMS
(EI-TOF) m/z [M+] calcd for C12H15NO3 221.1052, found 221.1054.
2-Acetamido-4,5-dimethoxyphenyl Acetate (2i). White solid,
mp 181-184 °C. IR (KBr) ν 3228, 1772, 1648, 1517, 1445, 1409,
1364, 1265, 1206, 1116, 1017, 909, 879, 856, 526 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.62 (1H, s), 6.95 (1H, br), 6.65 (1H, s),
3.88 (3H, s), 3.84 (3H, s), 2.30 (3H, s), 2.16 (3H, s); 13C NMR (75
MHz, CDCl3) δ 169.3, 168.4, 146.9, 146.2, 134.8, 122.5, 107.4,
105.9, 56.3 (2C), 24.3, 21.0; HRMS (EI-TOF) m/z [M+] calcd for
C12H15NO5 253.0950, found 253.0954.
2-Acetamidophenyl Propionate (2m). White solid, mp 66-69
°C. IR (KBr) ν 3240, 2980, 1762, 1661, 1607, 1537, 1488, 1455,
1373, 1310, 1187, 1142, 1105, 1078, 1007, 890, 758, 466 cm-1
;
1H NMR (300 MHz, CDCl3) δ 8.14 (1H, d, J ) 7.2 Hz), 7.26-7.12
(4H, m), 2.66 (2H, q, J ) 7.3 Hz), 2.17 (3H, s), 1.31 (3H, t, J )
7.3 Hz); 13C NMR (75 MHz, CDCl3) δ 172.4, 168.4, 141.0, 129.8,
126.4, 124.9, 123.3, 122.1, 27.8, 24.5, 9.2; HRMS (EI-TOF) m/z
[M+] calcd for C11H13NO3 207.0895, found 207.0893.
2-(N-Methylacetamido)phenyl Acetate (2k). White solid, mp
Acknowledgement. The authors are grateful for the financial
support from the National Natural Science Foundation of China
(Nos. 20621061 and 20772117) and the National Basic Research
Program of China (2006CB922003).
61-63 °C. IR (KBr) ν 2930, 1767, 1662, 1495, 1430, 1378, 1309,
1
1193, 906, 877, 820, 780, 597, 499 cm-1; H NMR (300 MHz,
CDCl3) δ 7.37-7.17 (4H, m), 3.16 (3H, s), 2.29 (3H, s), 1.85 (3H,
s); 13C NMR (75 MHz, CDCl3) δ 171.0, 168.8, 146.9, 136.8, 129.2,
129.1, 127.3, 123.9, 36.0, 21.8, 20.7; HRMS (EI-TOF) m/z [M+]
calcd for C11H13NO3 207.0895, found 207.0893.
2-Benzamidophenyl Acetate (2l). White solid, mp 112-113 °C.
IR (KBr) ν 3232, 3060, 2926, 1758, 1652, 1597, 1524, 1496, 1443,
1370, 1311, 1286, 1214, 1185, 1105, 928, 754, 713, 587 cm-1; 1H
NMR (300 MHz, CDCl3) δ 8.28 (1H, d, J ) 8.1 Hz), 7.94 (1H,
Supporting Information Available: NMR Spectra of 2a-m.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO8003088
4720 J. Org. Chem. Vol. 73, No. 12, 2008