Palladium-catalyzed ortho-alkoxylation of anilides via C-H activation

Article abstract of DOI:10.1021/jo301964m

A palladium-catalyzed ortho-alkoxylation of anilides with both primary and secondary alcohols via ligand-directed C-H activation has been explored. This alkoxylation promoted by catalytic methanesulfonic acid proceeds well at room temperature in most cases and affords aryl alkyl ethers in moderate to good yields.

Full text of DOI:10.1021/jo301964m

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pubs.acs.org/joc
Palladium-Catalyzed Ortho-Alkoxylation of Anilides via C−H
Activation
Tao-Shan Jiang and Guan-Wu Wang*
CAS Key Laboratory of Soft Matter Chemistry, Hefei National Laboratory for Physical Sciences at Microscale, and Department of
Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, P. R. China
S
* Supporting Information
ABSTRACT: A palladium-catalyzed ortho-alkoxylation of
anilides with both primary and secondary alcohols via ligand-
directed C−H activation has been explored. This alkoxylation
promoted by catalytic methanesulfonic acid proceeds well at
room temperature in most cases and affords aryl alkyl ethers in
moderate to good yields.
INTRODUCTION
RESULTS AND DISCUSSION
■
■
Aryl alkyl ethers are important motifs in many natural products
and pharmaceuticals.1 For their preparation, C−O bond-
forming reactions catalyzed by transition metals such as
copper2 and palladium3 as well as other methods4 become
effective strategies. Early studies on the palladium-catalyzed
acetoxylation of arenes under strong oxidants represent seminal
works in C−H oxygenation.5 Over the past decade, numerous
endeavors have been focused on the palladium-catalyzed C−H
functionalizations with the aid of directing groups by many
groups including Sanford,6 Daugulis,7 Yu,8 and others.9 In this
area, the C−H oxygenation reaction developed by the groups of
Sanford10 and Yu11 represents a critical advance in C−O bond
formation reactions. Despite the success of other C−H
oxygenation methods,12,13 C−H alkoxylation reactions remain
relatively scarce and are limited to the ligand-directed ortho-
alkoxylation mainly using MeOH or EtOH.10a,d,12c Alkoxylation
with secondary alcohols and at ambient temperature is still a
challenging task. Some potential difficulties may be encoun-
tered in alkoxylations with alcohols. First, the in situ formed
palladium alkoxide (Pd−OR) species would weaken the
electrophilicity of Pd(II) if alcohols were used. Second, Pd(II)
is known to oxidize primary and secondary alcohols.14 Third,
strong oxidants (PhI(OAc)2, K2S2O8, Oxone) and high
temperature used in these reactions limit the reaction scopes.
Despite these difficulties, we set forth to develop a more mild
and efficient C−H alkoxylation reaction, particularly with
secondary alcohols as well as other primary alcohols.
To overcome the low efficiency of our previous ortho-
methoxylation of acetanilide,12c we searched for better reaction
conditions. The large beneficial effect of p-toluenesulfonic acid
(PTSA) in promoting the Pd-catalyzed C−H activation
reaction of anilides was first revealed by de Vries, van Leeuwen,
and co-workers in 2002.16 Inspired by this discovery, we
initially tested the reaction by using 10 mol % of Pd(OAc)2, 2
equiv of K2S2O8, 0.5 equiv of PTSA, and 50 equiv of MeOH in
2 mL of dioxane for 24 h at room temperature, and the desired
product 2a was obtained in 12% yield (Table 1, entry 1). To
our delight, when methanesulfonic acid, a stronger organic acid,
was employed, the methoxylated product could be obtained in
25% yield (Table 1, entry 2). Other solvents including 1,2-
dichloroethane (DCE), 1,2-dimethoxyethane (DME), and
dichloromethane (DCM) were screened, the best yield was
42% in DME (Table 1, entries 3−5). Compared with
(NH4)2S2O8 and Oxone, K2S2O8 was better (Table 1, entries
6 and 7 vs entry 4). It is noteworthy that the yield could be
increased dramatically to 62% when 15 equiv of CH3OH was
employed (Table 1, entry 8). The yield of 2a could be further
improved to 64% when only 10 equiv of CH3OH was used
(Table 1, entry 9). However, the yield dropped to 59% from
64% if the amount of CH3OH was reduced to 5 equiv (Table 1,
entry 10 vs entry 9). Interestingly, decreasing the amount of
CH3SO3H to 0.2 equiv could give a better result, and a yield of
68% was achieved (Table 1, entries 11−13). Nevertheless, the
usage of CF3SO3H as the additive, which is a stronger organic
acid and has played an important role on palladium-catalyzed
ligand-directed C−H activation,17 did not improve the
efficiency in our catalytic system (Table 1, entry 14). The
desired product was not obtained in the absence of the
Pd(OAc)2 catalyst (Table 1, entry 15). Finally, when 0.3 mmol
of 1a, 10 mol % of Pd(OAc)2, 0.2 equiv of CH3SO3H, and 2
equiv of K2S2O8 were used, the reaction at ambient temperature
We have recently reported the palladium-catalyzed ortho-
alkoxylation of N-methoxybenzamides.12c When acetanilide was
chosen as the substrate, in which the NHCOCH3 moiety was
the directing group, only poor yield (≤31%) was obtained for
the methoxylation reaction. We reasoned that the efficiency and
scope of the reaction would be improved after further condition
optimization. Herein, we disclose the Pd-catalyzed alkoxylation
of acetanilides with both primary and secondary alcohols under
mild conditions.15
Received: September 12, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo301964m | J. Org. Chem. XXXX, XXX, XXX−XXX

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Table 1. Screening Conditions for the Pd(OAc)2-Catalyzed
Direct Ortho-Methoxylation of Acetanilide
Table 2. Pd-Catalyzed Directed Ortho-Alkoxylation of
a
a
Anilides
CH3OH
(equiv)
additive
(equiv)
yield
(%)
entry
oxidant
K2S2O8
solvent
1
2
50
50
PTSA (0.5)
dioxane
dioxane
12
25
CH3SO3H
(0.5)
K2S2O8
K2S2O8
K2S2O8
K2S2O8
(NH4)2S2O8
Oxone
3
4
50
50
50
50
50
15
10
5
CH3SO3H
(0.5)
DCE
DME
DCM
DME
DME
DME
DME
DME
DME
DME
DME
DME
DME
DME
21
42
15
29
37
62
64
59
67
68
65
54
0
CH3SO3H
(0.5)
5
CH3SO3H
(0.5)
6
CH3SO3H
(0.5)
7
CH3SO3H
(0.5)
8
CH3SO3H
(0.5)
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
9
CH3SO3H
(0.5)
10
11
12
13
14
CH3SO3H
(0.5)
10
10
10
10
10
10
CH3SO3H
(0.3)
CH3SO3H
(0.2)
CH3SO3H
(0.1)
CF3SO3H
(0.2)
b
15
CH3SO3H
(0.2)
c
16
CH3SO3H
(0.2)
66
a
Unless otherwise specified, all the reactions were carried out with 0.2
mmol of 1a, 0.02 mmol of Pd(OAc)2, and 0.4 mmol of oxidant in 2
b
mL of solvent at room temperature for 24 h. The reaction was
c
performed in the absence of Pd(OAc)2. 0.3 mmol of 1a, 0.03 mmol of
Pd(OAc)2, and 0.6 mmol of oxidant were used.
for 24 h gave 2a in 66%, comparable to 0.2 mmol scale (Table
1, entry 16 vs entry 12).
With the optimal conditions in hand (Table 1, entry 16), we
next investigated the scope of this reaction. As summarized in
Table 2, a variety of anilides with either electron-donating or
electron-withdrawing groups on the phenyl ring could be
applied to afford the desired alkoxylated products (2a−v). We
first conducted the alkoxylation reaction with primary alcohols.
Methoxylated and ethoxylated products 2a−e could be
obtained in 45−74% yields by employing 10 equiv of MeOH
and EtOH. For the substrate with the electron-withdrawing
chorine group, increasing the reaction temperature from room
temperature to 60 °C was required. We found that the room-
temperature reaction could be extended to other primary
alcohols such as n-PrOH, n-BuOH, and MeOCH2CH2OH, and
the corresponding alkoxylated products 2f−h were obtained in
37−69% yields although a larger amount (1 mL) of alcohols
was demanded. 2-Chloroethanol, a halogenated alcohol, could
also be employed to provide 2i in 38% yield. Generally, primary
alcohols bearing a longer alkyl chain afforded lower yields (2b,
2e, and 2f vs 2g and 2h). Intriguingly, alkoxylation of anilides
using 1 mL of secondary alcohols proceeded well in this
a
Unless otherwise specified, all the reactions were carried out with 0.3
mmol of 1, 0.03 mmol of Pd(OAc)2, 0.6 mmol of oxidant, and 0.06
b
mmol of CH3SO3H in 2 mL of solvent at 25 °C for 24 h. 10 equiv of
alcohol was used. The reaction was performed at 60 °C. 1 mL of
alcohol was used. CF3SO3H was used instead of CH3SO3H.
c
d
e
B
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catalytic system and afforded 2j−r in 36−77% yields. The
electronic property and position of substituents on the phenyl
ring exhibited significant effects on the reactivity. For example,
alkoxylation of acetanilide bearing a methyl group at the meta
position of the phenyl ring with i-PrOH was more efficient and
afforded a higher yield (77% for 2k) than those for the
unsubstituted and substituted substrates (36−55% for 2j and
2l−o). Other commonly used secondary alcohols including 2-
butanol (s-BuOH), cyclohexanol (c-HexOH), and cyclo-
pentanol (c-PenOH) could be employed and afforded the
desired products in 63−71% yields (2p−r). To further expand
the substrate scope, we performed the reactions of anilides
bearing other directing groups, i.e., N-(m-tolyl)pivalamide (1h)
and N-(m-tolyl)benzamide (1i), with MeOH and i-PrOH,
respectively. Although desired products (2s−v) could be
obtained, their yields (49−69%) were lower than those for
the corresponding methoxylation and isopropoxylation of N-m-
tolylacetamide (1b) (2s−v vs 2b and 2k). Unfortunately,
tertiary alcohols such as t-BuOH failed to react with acetanilide
under otherwise identical conditions. It should be pointed out
that the alkoxylation of acetanilides gave exclusively one
regioisomer, and trace or no dialkoxylation was observed.
The reason for the low yields of some products was that the
starting material could not be consumed completely even after
longer reaction time. It is somewhat surprising that the
electron-rich acetanilide bearing a methoxyl group at the meta-
position afforded only a trace amount of the desired cross-
coupling product; instead, the oxidative C−H homocoupling
product 3 was obtained in 58% yield (Scheme 1).18
Scheme 2. Proposed Mechanism for the C−H Alkoxylation
Reaction
CONCLUSION
■
In summary, we have successfully accomplished the inter-
molecular ortho C−H alkoxylation of anilides with primary or
secondary alcohols under mild conditions and found that
methanesulfonic acid was crucial for the success of this
transformation. We believe that methanesulfonic acid not
only promotes the C−H functionalization but also serves as a
good leaving group, which can be easily substituted by an
alcohol. The final products could be further transformed into
various useful derivatives.
Scheme 1. Homocoupling Reaction of N-(3-
Methoxyphenyl)acetamide
EXPERIMENTAL SECTION
■
General Procedure for the Direct Ortho-Alkoxylation of
Acetanilides. A mixture of acetanilide 1 (0.3 mmol, 1 equiv),
Pd(OAc)2 (0.03 mmol, 0.1 equiv), K2S2O8 (0.6 mmol, 2 equiv),
alcohol (3.0 mmol, 10 equiv; or 1 mL), CH3SO3H (0.06 mmol, 0.2
equiv), and 1,2-dimethoxyethane (2 mL) was stirred at 25 °C (or 60
°C in a few cases) (see Table 2) for 24 h. After the reaction was
complete, the mixture was filtered by a silica gel plug with ethyl acetate
as the eluent and evaporated in vacuum. The residue was purified by
flash column chromatography on a silica gel using petroleum ether/
EtOAc (3:1 to 5:1) as the eluent to give product 2.
N-(2-Methoxyphenyl)acetamide (2a).22 By following the
general procedure, the reaction of 1a (40.6 mg, 0.3 mmol) with
CH3OH (122 μL, 3.0 mol) at 25 °C gave 2a (32.7 mg, 66% yield): 1H
NMR (400 MHz, CDCl3) δ 8.35 (dd, J = 8.0 Hz, J = 1.2 Hz, 1H), 7.75
(br, 1H), 7.03 (td, J = 8.0 Hz, J = 1.2 Hz, 1H), 6.96 (td, J = 8.0 Hz, J =
1.2 Hz, 1H), 6.87 (dd, J = 8.0 Hz, J = 1.2 Hz, 1H), 3.88 (s, 3H), 2.20
(s, 3H).
Based on the previous literature,6,10,12c a possible mechanism
for the alkoxylation of acetanilides is outlined in Scheme 2. We
believe that the role of methanesulfonic acid may be 2-fold: (1)
compared to PTSA, CH3SO3H is a stronger acid and it will
generate more electrophilic Pd(II) species toward C−H
activation. The palladacycle A, which resembles that reported
by Yu,19 is formed with two CH3SO3 anions bridging two
−
N-(2-Methoxy-5-methylphenyl)acetamide (2b).23 By follow-
ing the general procedure, the reaction of 1b (44.8 mg, 0.3 mmol) with
CH3OH (122 μL, 3.0 mol) at 25 °C gave 2b (39.8 mg, 74% yield): 1H
NMR (400 MHz, CDCl3) δ 8.18 (d, J = 1.2 Hz, 1H), 7.72 (br, 1H),
6.82 (dd, J = 8.4 Hz, J = 1.2 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 3.84 (s,
3H), 2.29 (s, 3H), 2.19 (s, 3H).
Pd(II). In this system, m-methoxyl-substituted anilide mainly
affords oxidative C−H homocoupling product; this phenom-
enon is similar to that reported by Sanford18a and Greaney18b
for the electron-neutral and electron-rich arenes. (2) Pallada-
cycle A can be easily substituted by an alcohol to afford
N-(4-Chloro-2-methoxyphenyl)acetamide (2c). By following
the general procedure, the reaction of 1c (50.9 mg, 0.3 mmol) with
CH3OH (122 μL, 3.0 mol) at 60 °C afforded 2c (27.0 mg, 45% yield):
1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 8.8 Hz, 1H), 7.66 (br,
1H), 6.93 (dd, J = 8.8 Hz, J = 2.4 Hz, 1H), 6.85 (d, J = 2.4 Hz, 1H),
3.88 (s, 3H), 2.19 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.1,
148.2, 128.4, 126.4, 120.9, 120.4, 110.7, 55.9, 24.8; IR (KBr) ν 3295,
2959, 2921, 1669, 1596, 1528, 1488, 1400, 1250, 1122, 1022, 875, 813
−
intermediate B since the CH3SO3 anion is a good leaving
group. Pd(IV) complex C is formed by the oxidation of
K2S2O8; subsequent reduction elimination affords the alkoxy-
lated product along with the regeneration of the Pd(II) species.
It should be noted that a mechanism involving a recently
formulated bimetallic Pd(II)/Pd(III) pathway by Ritter20 or
Pd(II)/Pd(0) process proposed by Sunoj21 cannot be excluded.
C
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cm−1; HRMS (ESI-Orbitrap) m/z [M + H+] calcd for C9H11O2N35Cl
200.0473, found 200.0472.
1H), 2.20 (s, 3H), 1.37 (d, J = 6.0 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ 168.0, 145.8, 128.6, 123.4, 120.9, 119.8, 112.5, 71.2, 24.9,
22.2 (2C); IR (KBr) ν 3364, 2974, 2931, 1675, 1596, 1536, 1484,
1452, 1369, 1330, 1289, 1254, 1120, 1048, 1007, 950, 751, 649, 591,
540 cm−1; HRMS (ESI-Orbitrap) m/z [M + H+] calcd for C11H16O2N
194.1176, found 194.1173.
N-(2-Isopropoxy-5-methylphenyl)acetamide (2k). By follow-
ing the general procedure, the reaction of 1b (44.8 mg, 0.3 mmol) with
i-PrOH (1 mL) at 25 °C afforded 2k (47.9 mg, 77% yield): 1H NMR
(400 MHz, CDCl3) δ 8.19 (s, 1H), 7.75 (br, 1H), 6.80 (dd, J = 8.8 Hz,
J = 1.2 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 4.53 (heptet, J = 6.0 Hz,
1H), 2.29 (s, 3H), 2.18 (s, 3H), 1.35 (d, J = 6.0 Hz, 6H); 13C NMR
(100 MHz, CDCl3) δ 168.0, 143.7, 130.6, 128.5, 123.8, 120.4, 112.7,
71.5, 24.9, 22.2 (2C), 20.9; IR (KBr) ν 3313, 2980, 2927, 1669, 1590,
1544, 1485, 1374, 1316, 1258, 1224, 1133, 1106, 951, 800, 732, 663,
605, 571, 534 cm−1; HRMS (ESI-Orbitrap) m/z [M + H+] calcd for
C12H18O2N 208.1332, found 208.1330.
N-(2-Ethoxyphenyl)acetamide (2d).24 By following the general
procedure, the reaction of 1a (40.6 mg, 0.3 mmol) with C2H5OH (175
1
μL, 3.0 mol) at 25 °C gave 2d (28.5 mg, 53% yield): H NMR (400
MHz, CDCl3) δ 8.35 (dd, J = 8.0 Hz, J = 1.2 Hz, 1H), 7.78 (br, 1H),
7.01 (td, J = 8.0 Hz, J = 1.2 Hz, 1H), 6.94 (td, J = 8.0 Hz, J = 1.2 Hz,
1H), 6.85 (dd, J = 8.0 Hz, J = 1.2 Hz, 1H), 4.10 (q, J = 6.9 Hz, 2H),
2.20 (s, 3H), 1.45 (t, J = 6.9 Hz, 3H).
N-(2-Ethoxy-5-methylphenyl)acetamide (2e). By following the
general procedure, the reaction of 1b (44.8 mg, 0.3 mmol) with
C2H5OH (175 μL, 3.0 mol) at 25 °C provided 2e (40.6 mg, 70%
1
yield): H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.73 (br, 1H),
6.80 (d, J = 8.0 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 4.07 (q, J = 6.9 Hz,
2H), 2.29 (s, 3H), 2.19 (s, 3H), 1.44 (t, J = 6.9 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 168.0, 144.8, 130.5, 127.6, 123.7, 120.4, 110.8,
64.3, 25.0, 20.9, 14.9; IR (KBr) ν 3327, 2986, 2929, 1669, 1540, 1470,
1392, 1371, 1254, 1227, 1130, 1043, 914, 881, 795, 735, 682, 609, 530
cm−1; HRMS (ESI-Orbitrap) m/z [M + H+] Calcd for C11H16O2N
194.1176, found 194.1174.
N-(2-Isopropoxy-4-methylphenyl)acetamide (2l). By follow-
ing the general procedure, the reaction of 1d (44.8 mg, 0.3 mmol)
1
with i-PrOH (1 mL) at 25 °C afforded 2l (29.8 mg, 48% yield): H
NMR (400 MHz, CDCl3) δ 8.20 (d, J = 8.4 Hz, 1H), 7.69 (br, 1H),
6.73 (d, J = 8.4 Hz, 1H), 6.69 (s, 1H), 4.57 (heptet, J = 6.0 Hz, 1H),
2.29 (s, 3H), 2.17 (s, 3H), 1.36 (d, J = 6.0 Hz, 6H); 13C NMR (100
MHz, CDCl3) δ 167.8, 145.8, 133.3, 126.1, 121.3, 119.7, 113.5, 71.2,
24.9, 22.2 (2C), 21.3; IR (KBr) ν 3425, 3333, 2979, 2926, 1673, 1603,
1527, 1489, 1452, 1417, 1375, 1329, 1281, 1259, 1128, 1008, 980, 812,
581 cm−1; HRMS (ESI-Orbitrap) m/z [M + H+] calcd for C12H18O2N
208.1332, found 208.1333.
N-(5-Methyl-2-propoxyphenyl)acetamide (2f). By following
the general procedure, the reaction of 1b (44.8 mg, 0.3 mmol) with n-
1
PrOH (1 mL) at 25 °C provided 2f (42.9 mg, 69% yield): H NMR
(400 MHz, CDCl3) δ 8.19 (s, 1H), 7.73 (br, 1H), 6.80 (d, J = 8.0 Hz,
1H), 6.75 (d, J = 8.0 Hz, 1H), 3.96 (t, J = 6.6 Hz, 2H), 2.29 (s, 3H),
2.19 (s, 3H), 1.88−1.79 (m, 2H), 1.05 (t, J = 7.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 168.0, 145.0, 130.5, 127.6, 123.8, 120.4, 110.9,
70.3, 24.9, 22.6, 21.0, 10.5; IR (KBr) ν 3342, 2970, 2919, 1669, 1594,
1538, 1489, 1458, 1254, 1226, 1130, 1068, 979, 879, 797, 667, 605
cm−1; HRMS (ESI-Orbitrap) m/z [M + H+] calcd for C12H18O2N
208.1332, found 208.1335.
N-(2-Butoxy-5-methylphenyl)acetamide (2g). By following the
general procedure, the reaction of 1b (44.8 mg, 0.3 mmol) with n-
BuOH (1 mL) at 25 °C gave 2g (33.9 mg, 51% yield): 1H NMR (400
MHz, CDCl3) δ 8.18 (s, 1H), 7.73 (br, 1H), 6.80 (dd, J = 8.4 Hz, J =
1.2 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 4.00 (t, J = 6.6 Hz, 2H), 2.29 (s,
3H), 2.18 (s, 3H), 1.83−1.76 (m, 2H), 1.54−1.45 (m, 2H), 1.00 (t, J =
7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 168.0, 145.0, 130.4,
127.6, 123.7, 120.3, 110.9, 68.5, 31.2, 24.9, 20.9, 19.3, 13.8; IR (KBr) ν
3312, 2957, 2925, 1663, 1593, 1544, 1492, 1462, 1374, 1259, 1226,
1133, 1023, 808 cm−1; HRMS (ESI-Orbitrap) m/z [M + H+] calcd for
C13H20O2N 222.1489, found 222.1488.
N-(2-Isopropoxy-4,5-dimethylphenyl)acetamide (2m). By
following the general procedure, the reaction of 1e (49.0 mg, 0.3
mmol) with i-PrOH (1 mL) at 60 °C provided 2m (33.9 mg, 51%
1
yield): H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.65 (br, 1H),
6.67 (s, 1H), 4.52 (heptet, J = 6.0 Hz, 1H), 2.19 (s, 6H), 2.17 (s, 3H),
1.34 (d, J = 6.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 167.7, 144.0,
131.5, 128.9, 126.4, 121.1, 114.7, 71.6, 24.9, 22.3 (2C), 19.7, 19.2; IR
(KBr) ν 3424, 3332, 2975, 2926, 1673, 1594, 1527, 1453, 1406, 1375,
1326, 1263, 1202, 1114, 1010, 945, 882 cm−1; HRMS (ESI-Orbitrap)
m/z [M + H+] calcd for C13H20O2N 222.1489, found 222.1488.
N-(4-Acetyl-2-isopropoxyphenyl)acetamide (2n). By following
the general procedure, the reaction of 1f (53.2 mg, 0.3 mmol) with i-
PrOH (1 mL) and CF3SO3H (5.3 μL, 0.06 mmol) replacing
CH3SO3H at 60 °C afforded 2n (33.9 mg, 48% yield): 1H NMR
(400 MHz, CDCl3) δ 8.48 (d, J = 8.4 Hz, 1H), 7.97 (br, 1H), 7.54
(dd, J = 8.4 Hz, J = 2.0 Hz, 1H), 7.52 (d, J = 2.0 Hz, 1H), 4.74 (heptet,
J = 6.0 Hz, 1H), 2.57 (s, 3H), 2.24 (s, 3H), 1.40 (d, J = 6.0 Hz, 6H);
13C NMR (100 MHz, CDCl3) δ 197.0, 168.4, 145.6, 133.0, 132.3,
122.8, 118.4, 110.7, 71.4, 26.3, 25.0, 22.0 (2C); IR (KBr) ν 3326, 2981,
2930, 1672, 1589, 1524, 1485, 1410, 1367, 1328, 1269, 1236, 1197,
1117, 969, 872, 832, 727, 638, 600 cm−1; HRMS (ESI-Orbitrap) m/z
[M + H+] calcd for C13H18O3N 236.1281, found 236.1281.
N-(4-Iodo-2-isopropoxyphenyl)acetamide (2o). By following
the general procedure, the reaction of 1g (78.3 mg, 0.3 mmol) with i-
PrOH (1 mL) at 60 °C gave 2o (34.5 mg, 36% yield): 1H NMR (400
MHz, CDCl3) δ 8.13 (d, J = 8.4 Hz, 1H), 7.69 (br, 1H), 7.25 (dd, J =
8.4 Hz, J = 1.6 Hz, 1H), 7.15 (d, J = 1.6 Hz, 1H), 4.56 (heptet, J = 6.0
Hz, 1H), 2.19 (s, 3H), 1.37 (d, J = 6.0 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ 168.0, 146.4, 130.0, 128.5, 121.4, 121.3, 85.9, 71.8, 25.0, 22.0
(2C); IR (KBr) ν 3318, 2983, 2925, 1669, 1587, 1523, 1481, 1395,
1326, 1247, 1209, 1127, 1105, 954, 812 cm−1; HRMS (ESI-Orbitrap)
m/z [M + H+] calcd for C11H15O2NI 320.0142, found 320.0142.
N-(2-sec-Butoxy-5-methylphenyl)acetamide (2p). By follow-
ing the general procedure, the reaction of 1b (44.8 mg, 0.3 mmol) with
2-butyl alcohol (1 mL) at 25 °C provided 2p (46.5 mg, 70% yield): 1H
NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 7.76 (br, 1H), 6.80 (dd, J =
8.4 Hz, J = 1.2 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 4.30 (sextet, J = 6.0
Hz, 1H), 2.29 (s, 3H), 2.18 (s, 3H), 1.81−1.70 (m, 1H), 1.69−1.59
(m, 1H), 1.30 (d, J = 6.0 Hz, 3H), 0.99 (t, J = 7.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 167.9, 143.9, 130.6, 128.6, 123.7, 120.4, 112.8,
76.6, 29.2, 24.9, 21.0, 19.4, 9.7. IR (KBr) ν 3425, 3337, 2971, 2930,
1685, 1593, 1533, 1472, 1427, 1373, 1253, 1128, 1026, 992, 917, 802,
N-(2-(2-Methoxyethoxy)-5-methylphenyl)acetamide (2h). By
following the general procedure, the reaction of 1b (44.8 mg, 0.3
mmol) with MeOCH2CH2OH (1 mL) at 25 °C gave 2h (24.8 mg,
1
37% yield): H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 8.16 (br,
1H), 6.83 (d, J = 8.0 Hz, 1H), 6.79 (dd, J = 8.0 Hz, J = 1.2 Hz, 1H),
4.13−4.11 (m, 2H), 3.70−3.68 (m, 2H), 3.46 (s, 3H), 2.30 (s, 3H),
2.17 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.3, 144.8, 132.4,
129.5, 123.9, 120.6, 114.8, 70.9, 70.3, 59.0, 24.8, 21.1; IR (KBr) ν
3303, 2924, 1666, 1613, 1552, 1488, 1449, 1431, 1371, 1302, 1260,
783, 694 cm−1; HRMS (ESI-Orbitrap) m/z [M + H+] calcd for
C12H18O3N 224.1281, found 224.1280.
N-(2-(2-Chloroethoxy)-5-methylphenyl)acetamide (2i). By
following the general procedure, the reaction of 1b (44.8 mg, 0.3
mmol) with 2-chloroethanol (201 μL, 3.0 mol) at 25 °C provided 2i
1
(26.0 mg, 38% yield): H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H),
7.89 (br, 1H), 6.81 (dd, J = 8.4 Hz, J = 1.2 Hz, 1H), 6.78 (d, J = 8.0
Hz, 1H), 4.27−4.24 (m, 2H), 3.85−3.82 (m, 2H), 2.30 (s, 3H), 2.19
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.2, 154.2, 144.1, 132.3,
123.9, 120.7, 113.0, 69.8, 42.6, 24.9, 21.1; IR (KBr) ν 3407, 2922,
1677, 1598, 1540, 1484, 1327, 1294, 1253, 1220, 1132, 1078, 1034,
886, 805, 664, 599, 540 cm−1; HRMS (ESI-Orbitrap) m/z [M + H+]
calcd for C11H15O2N35Cl 228.0786, found 228.0782.
N-(2-Isopropoxyphenyl)acetamide (2j). By following the
general procedure, the reaction of 1a (40.6 mg, 0.3 mmol) with i-
1
PrOH (1 mL) at 25 °C gave 2j (31.9 mg, 55% yield): H NMR (400
MHz, CDCl3) δ 8.36 (dd, J = 8.0 Hz, J = 1.2 Hz, 1H), 7.79 (br, 1H),
7.00 (td, J = 8.0 Hz, J = 1.2 Hz, 1H), 6.93 (td, J = 8.0 Hz, J = 1.2 Hz,
1H), 6.87 (dd, J = 8.0 Hz, J = 1.2 Hz, 1H), 4.59 (heptet, J = 6.0 Hz,
D
dx.doi.org/10.1021/jo301964m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
599 cm−1; HRMS (ESI-Orbitrap) m/z [M + H+] calcd for C13H20O2N
222.1489, found 222.1490.
mmol), CH3OH (122 μL, 3.0 mmol), CH3SO3H (3.9 μL, 0.06 mmol),
and 1,2-dimethoxyethane (2 mL) was stirred at 25 °C for 24 h. After
the reaction was complete, the mixture was filtered by a silica gel plug
with ethyl acetate as the eluent and evaporated in vacuum. The residue
was purified by flash column chromatography on a silica gel using
EtOAc as the eluent to give product 3 (28.7 mg, 58% yield): 1H NMR
(400 MHz, CDCl3) δ 7.88 (d, J = 2.8 Hz, 2H), 7.08 (d, J = 8.4 Hz,
2H), 6.88 (br, 2H), 6.77 (dd, J = 8.4 Hz, J = 2.8 Hz, 2H), 3.87 (s, 6H),
1.98 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 168.9, 160.2, 137.0,
131.5, 119.6, 111.3, 107.4, 55.5, 24.5; IR (KBr) ν 3378, 3272, 2963,
1674, 1610, 1580, 1531, 1460, 1423, 1370, 1300, 1254, 1194, 1163,
1126, 1052, 871, 805, 734, 628 cm−1; HRMS (ESI-Orbitrap) m/z [M
+ H+] calcd for C18H21O4N2 329.1496, found 329.1494.
N-(2-(Cyclohexyloxy)-5-methylphenyl)acetamide (2q). By
following the general procedure, the reaction of 1b (44.8 mg, 0.3
mmol) with cyclohexanol (1 mL) at 25 °C provided 2q (46.7 mg, 63%
1
yield): H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.78 (br, 1H),
6.81−6.75 (m, 2H), 4.26−4.19 (m, 1H), 2.29 (s, 3H), 2.18 (s, 3H),
2.01−1.97 (m, 2H), 1.82−1.76 (m, 2H), 1.63−1.34 (m, 6H); 13C
NMR (100 MHz, CDCl3) δ 167.9, 143.6, 130.6, 128.7, 123.7, 120.4,
113.0, 76.9, 31.9 (2C), 25.5, 25.0, 23.8 (2C), 21.0; IR (KBr) ν 3422,
3340, 2932, 2857, 1682, 1593, 1532, 1473, 1427, 1368, 1253, 1218,
1127, 1045, 1020, 966, 801, 598 cm−1; HRMS (ESI-Orbitrap) m/z [M
+ H+] calcd for C15H22O2N 248.1645, found 248.1639.
N-(2-(Cyclopentyloxy)-5-methylphenyl)acetamide (2r). By
following the general procedure, the reaction of 1b (44.8 mg, 0.3
mmol) with cyclopentanol (1 mL) at 25 °C afforded 2r (49.7 mg, 71%
ASSOCIATED CONTENT
■
S
* Supporting Information
1
yield): H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 7.69 (br, 1H),
NMR spectra of products 2a−v and 3. This material is available
6.79 (dd, J = 8.4 Hz, J = 1.2 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 4.80−
4.75 (m, 1H), 2.29 (s, 3H), 2.17 (s, 3H), 1.93−1.65 (m, 8H); 13C
NMR (100 MHz, CDCl3) δ 167.9, 143.9, 130.3, 128.2, 123.7, 120.3,
112.3, 80.5, 32.9 (2C), 25.0, 24.0 (2C), 20.9; IR (KBr) ν 3424, 3340,
2959, 2945, 1683, 1593, 1534, 1474, 1428, 1366, 1253, 1221, 1168,
1126, 987, 801, 598 cm−1; HRMS (ESI-Orbitrap) m/z [M + H+] calcd
for C14H20O2N 234.1489, found 234.1485.
N-(2-Methoxy-5-methylphenyl)pivalamide (2s). By following
the general procedure, the reaction of 1h (57.5 mg, 0.3 mmol) with
CH3OH (122 μL, 3.0 mol) at 25 °C afforded 2s (39.8 mg, 60% yield):
1H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 2.4 Hz, 1H), 8.10 (br,
1H), 6.83−6.80 (m, 1H), 6.75 (d, J = 8.0 Hz, 1H), 3.86 (s, 3H), 2.29
(s, 3H), 1.31 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 176.5, 145.9,
130.6, 127.6, 123.5, 120.2, 109.6, 55.9, 40.0, 27.6, 20.9; IR (KBr) ν
3443, 2960, 1682, 1597, 1533, 1485, 1464, 1427, 1253, 1226, 1169,
1123, 1029, 798 cm−1; HRMS (APCI-Orbitrap) m/z [M + H+] calcd
for C13H20O2N 222.1489, found 222.1482.
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: gwang@ustc.edu.cn.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (Nos. 91021004), National Basic
Research Program of China (2011CB921402), and the Key
Project of Science and Technology of the Department of
Education, Anhui Province, China (KJ2010ZD05).
N-(2-Isopropoxy-5-methylphenyl)pivalamide (2t). By follow-
REFERENCES
■
ing the general procedure, the reaction of 1h (57.5 mg, 0.3 mmol)
1
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with i-PrOH (1 mL) at 25 °C provided 2t (51.6 mg, 69% yield): H
NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 8.22 (br, 1H), 6.80−6.76
(m, 2H), 4.52 (heptet, J = 6.0 Hz, 1H), 2.28 (s, 3H), 1.35 (d, J = 6.0
Hz, 6H), 1.31 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 176.3, 144.1,
130.8, 128.9, 123.5, 120.2, 113.0, 71.8, 40.0, 27.6, 22.3, 21.0; IR (KBr)
ν 3438, 2974, 2929, 1683, 1595, 1533, 1480, 1428, 1251, 1218, 1178,
1120, 1106, 960, 921, 803, 624 cm−1; HRMS (APCI-Orbitrap) m/z
[M + H+] calcd for C15H24O2N 250.1802, found 250.1796.
N-(2-Methoxy-5-methylphenyl)benzamide (2u). By following
the general procedure, the reaction of 1i (63.4 mg, 0.3 mmol) with
CH3OH (122 μL, 3.0 mol) at 25 °C afforded 2u (35.5 mg, 49% yield):
1H NMR (400 MHz, CDCl3) δ 8.53 (br, 1H), 8.39 (d, J = 2.0 Hz,
1H), 7.91−7.88 (m, 2H), 7.57−7.53 (m, 1H), 7.52−7.48 (m, 2H),
6.88 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 3.90 (s,
3H), 2.35 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.2, 146.1,
135.4, 131.6, 130.7, 128.7, 127.5, 127.0, 124.0, 120.5, 109.8, 55.9, 21.0;
IR (KBr) ν 3428, 2922, 1675, 1596, 1534, 1478, 1427, 1252, 1224,
1139, 1028, 799, 707 cm−1; HRMS (APCI-Orbitrap) m/z [M + H+]
calcd for C15H16O2N 242.1176, found 242.1169.
N-(2-Isopropoxy-5-methylphenyl)benzamide (2v). By follow-
ing the general procedure, the reaction of 1i (63.4 mg, 0.3 mmol) with
i-PrOH (1 mL) at 25 °C provided 2v (45.3 mg, 56% yield): 1H NMR
(400 MHz, CDCl3) δ 8.66 (br, 1H), 8.42 (d, J = 1.6 Hz, 1H), 7.91−
7.88 (m, 2H), 7.58−7.54 (m, 1H), 7.53−7.49 (m, 2H), 6.86 (dd, J =
8.4 Hz, 2.0 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 4.58 (heptet, J = 6.0 Hz,
1H), 2.35 (s, 3H), 1.39 (d, J = 6.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 164.8, 144.2, 135.4, 131.6, 130.8, 128.8, 128.7, 126.9, 124.0,
120.4, 112.8, 71.7, 22.3, 21.0; IR (KBr) ν 3426, 2976, 2925, 1676,
1594, 1533, 1472, 1428, 1249, 1136, 1111, 959, 798, 706 cm−1; HRMS
(APCI-Orbitrap) m/z [M + H+] calcd for C17H20O2N 270.1489,
found 270.1482.
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(3). A mixture of N-(3-methoxyphenyl)acetamide (49.6 mg, 0.3
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E
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F
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