Palladium-catalyzed alkoxylation of N-methoxybenzamides via direct sp 2 C-H bond activation

Article abstract of DOI:10.1021/jo902139b

(Chemical Equation Presented) The palladium-catalyzed ortho-alkoxylation of N-methoxybenzamides has been demonstrated. With the CON-HOMe group as a directing group, the aromatic C-H bond can be functionalized efficiently to generate orthoalkoxylated derivatives in moderate to good yields.

Full text of DOI:10.1021/jo902139b

pubs.acs.org/joc
demonstrated its versatility and practicality in organic synthe-
sis.3
Recently, the employment of substrates containing a
Palladium-Catalyzed Alkoxylation of
N-Methoxybenzamides via Direct sp2
C-H Bond Activation
directing group holds a promise for the selective functiona-
lization of C-H bonds.4-12 Significant endeavors have been
focused on exploiting directing groups such as acylaminos,4,5
pyridines,5,6 quinolines/isoquinolines,5,6 oxime ethers,5c,7
oxazolines,8 carboxylic acids,9 N-methoxy amides,10 trifla-
mides,11 and pyrimidinyloxy groups.12 The N-methoxy
amides can be readily transformed to esters13a and amides,13b
or reduced to alkanes.13b Therefore, the C-H activation
with this functionality would be synthetically useful. In Yu’s
recent work, the C-H bond in N-methoxy amides has been
activated to construct the C-C bond10a and the C-N
bond10b with high selectivity. Herein, we describe a highly
selective alkoxylation of N-methoxybenzamides, i.e., C-O
bond formation, through Pd-catalyzed sp2 C-H bond oxi-
dative activation.
Guan-Wu Wang* and Ting-Ting Yuan
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, People’s Republic
of China
gwang@ustc.edu.cn
Received October 5, 2009
We have recently reported the palladium-catalyzed direct
ortho-acetoxylation of anilides.14 Therefore, we first attempted
the methoxylation of acetanilide by replacing acetic acid with
methanol. The reaction was performed with acetanilide 1,
5 mol % of Pd(OAc)2, and 2 equiv of K2S2O8 in MeOH for
48 h, and gave the methoxylated product 2 in 13% yield
(entry 1, Table 1). When 1,2-dichloroethane (DCE) or
dioxane was added as a cosolvent, the yields were improved
to 31% and 26%, respectively (entries 2 and 3, Table 1).
While K2S2O8 was replaced with Oxone in MeOH/DCE,
nearly the same product yield was obtained (entry 4 vs. entry
2, Table 1). Other oxidants such as PhI(OAc)2, m-chloro-
perbenzoic acid (MCPBA), tBuOOH, Cu(OAc)2, Cu(OTf)2,
and O2 gave only a trace amount of product 2 (entries 5-10,
Table 1).
The palladium-catalyzed ortho-alkoxylation of N-meth-
oxybenzamides has been demonstrated. With the CON-
HOMe group as a directing group, the aromatic C-H
bond can be functionalized efficiently to generate ortho-
alkoxylated derivatives in moderate to good yields.
The direct functionalization of arene and alkane C-H
bonds is an exceedingly valuable process in contemporary
organic and organometallic chemistry and still remains a
tremendous challenge.1,2 The recent development of the
palladium-catalyzed C-H activation reaction has widely
Previously, it has already been observed that a subtle
change of the directing groups exerts significant effect on
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476 J. Org. Chem. 2010, 75, 476–479
Published on Web 12/09/2009
DOI: 10.1021/jo902139b
r
2009 American Chemical Society

Wang and Yuan
JOCNote
TABLE 1. Screening Conditions for the Pd(OAc)2-Catalyzed Direct
TABLE 2. Screening Conditions for the Pd(OAc)2-Catalyzed Direct
Ortho-Methoxylation of N-Methoxybenzamide 3aa
Ortho-Methoxylation of Acetanilidea
entry
oxidant
cosolvent
yield
entry
oxidant
cosolvent
time
yield
1
2
3
4
5
6
7
8
9
10
K2S2O8
K2S2O8
K2S2O8
oxone
PhI(OAc)2
MCPBA
tBuOOH
Cu(OAc)2
Cu(OTf)2
O2
13%
31%
26%
30%
trace
trace
trace
trace
trace
trace
1
2
3
4
5
6
7
8
9
10
11
12
13
14b
15c
16d
17e
18f
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
PhI(OAc)2
MCPBA
tBuOOH
Oxone
Cu(OAc)2
Cu(OTf)2
O2
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
8 h
42%
66%
31%
50%
trace
73%
trace
trace
trace
57%
trace
trace
trace
55%
67%
53%
35%
40%
DCE
dioxane
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
THF
PhMe
10 h
12 h
9 h
CH3CN
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
24 h
6.5 h
24 h
24 h
24 h
11 h
24 h
24 h
24 h
12 h
6.5 h
11 h
5 h
aUnless otherwise specified, all the reactions were carried out with
0.25 mmol of 1, 0.0125 mmol of Pd(OAc)2, 0.5 mmol of oxidant, 30 mg of
˚
4 A MS in 2 mL of MeOH, and 2 mL of cosolvent at 55 °C.
the C-H bond activations.4c,e,g,14 We then turned our
attention to other directing groups due to the poor yield
for the methoxylation of acetanilide, of which the
NHCOCH3 moiety was the directing group. A number of
substrates including 4-methylbenzamide, N-benzylidene-4-
methylbenzenesulfonamide, N0-phenylbenzohydrazide, N-
methoxy-2-phenylacetamide, and N-ethylbenzamide failed
to give the corresponding methoxylated products in MeOH.
Much to our pleasure, N-methoxybenzamide (3a) was found
to generate the ortho-methoxylated product 4a in 42% yield
in MeOH (entry 1, Table 2). When DCE was used as
cosolvent, the yield was increased to 66% (entry 2, Table 2).
Other cosolvents such as THF, toluene, and acetonitrile were
also screened, and all of them proved to be deleterious to the
reaction (entries 3-5 vs. entry 2, Table 2). However, when
the reaction was performed in MeOH/dioxane, the product
yield of 4a could be further improved to 73% (entry 6,
Table 2). The efficiency of various oxidants was also
examined. PhI(OAc)2, which was used as a privileged oxi-
dant in Sanford’s systems,5b,6a,7a afforded only a trace
amount of product (entry 7, Table 2). Several peroxides have
been employed as the oxidants for Pd-catalyzed C-H
oxidation,5d,7b,8a,14 and the first used peroxide was
9 h
aUnless otherwise specified, all the reactions were carried out with
0.25 mmol of 3a, 0.0125 mmol of Pd(OAc)2, 0.5 mmol of oxidant, 30 mg
b
˚
of 4 A MS in 2 mL of MeOH, and 2 mL of cosolvent at 55 °C. 0.25 mmol
of K2S2O8 was employed. c0.75 mmol of K2S2O8 was employed.
d0.00625 mmol of Pd(OAc)2 was used. 0.025 mmol of Pd(OAc)2 was
e
f
used. 4 A MS was not added.
˚
reaction was carried out without molecular sieve (entry 18 vs.
entry 6, Table 2). As a result, we found that treating 3a with
5 mol % of Pd(OAc)2 and 2 equiv of K2S2O8 in the presence
of 4 A MS in MeOH/dioxane (1:1) at 55 °C afforded the best
result.
˚
With the optimized conditions in hand, the scope of the
Pd-catalyzed methoxylation reaction was investigated with a
diverse array of substituted N-methoxybenzamides. The
results are summarized in Table 3. Substrates with either
electron-donating or electron-withdrawing groups on the
phenyl group of N-methoxybenzamides could be applied to
afford the desired products 4b-n (entries 2-14, Table 3).
Substrates with a methyl group at the meta-position and/or
para-position of the phenyl ring (3b-d) gave comparable
product yields to that of unsubstituted N-methoxybenza-
mide (3a) (entries 2-4 vs. entry 1, Table 3). When both of the
meta-positions of the phenyl ring were occupied by a methyl
group, the product yield was lower than that of 3d (entry 5 vs
entry 4, Table 3) due to the steric hindrance. It is known that
ortho-substitution on phenyl rings hampers4c,d,14 the Pd-
catalyzed ortho C-H insertions. Hence, it was not surprising
that the o-methyl substitution on the phenyl ring of 3f
reduced product yield significantly (entry 6 vs. entries 2-3,
Table 3). The product yield of 4f could not be improved even
if the reaction time was prolonged to 48 h, and a lot of 3f was
recovered. Substrates with the strong electron-donating
methoxy group at the meta-position (3g) or at both meta-
and para-positions (3h) of the phenyl ring gave lower yields
than their counterparts substituted by the methyl group
(entry 7 vs. entry 3 and entry 8 vs. entry 4, Table 3) because
they tended to react faster and generate more byproducts.
MeCOOOtBu.8a Organic peroxidants including BuOOH
t
and MCPBA were investigated, but both of them failed to
facilitate this reaction (entries 8 and 9, Table 2). When Oxone
was employed as the oxidant, the methoxylation product
could be isolated in moderate yield (entry 10, Table 2). Cu(II)
salts were also ineffective in the methoxylation process
(entries 11 and 12, Table 2). Finally, the reaction conducted
in oxygen atmosphere proved to be infeasible (entry 13,
Table 2). The amount of K2S2O8 and Pd(OAc)2 was further
varied to examine their effect on the product yield. Reducing
or increasing the loading of oxidant K2S2O8 resulted in lower
product yield (entries 14 and 15 vs. entry 6, Table 2). Redu-
cing the catalyst loading (2.5 mol %) gave a decreased yield
(entry 16, Table 2). Surprisingly, a larger amount of Pd-
(OAc)2 (10 mol %) was also harmful to the reaction, afford-
ing product 4a in only 35% yield (entry 17, Table 2). This
methoxylation process was very sensitive to water; the yield
was decreased dramatically to 40% from 73% when the
J. Org. Chem. Vol. 75, No. 2, 2010 477

Wang and Yuan
JOCNote
TABLE 3. Pd-Catalyzed Direct Ortho-Alkoxylation of N-Methoxy-
electron-withdrawing chloro group at the para-position of the
phenyl ring, afforded a comparable yield to that of the corre-
sponding p-methyl-substituted 3c (entry 9 vs. entry 3, Table 3).
Introduction of an additional chloro atom at the meta-position
caused a slightly lower yield (entry 10 vs. entry 9, Table 3).
Interestingly, o-Cl-substituted benzamide 3k provided nearly
the same product yield as the p-Cl-substituted 3i (entry 11 vs.
entry 9, Table 3), not displaying the obvious “ortho-sub-
stituent” effect.4c,d,14 The exact reason for this behavior is
unknown now. Benzamide 3l bearing a p-Br on the phenyl
ring delivered a lower yield than that of the counterpart with
a p-Cl (entry 12 vs. entry 9, Table 3). A similar behavior
was also observed previously by us.14 Benzamide 3m with
a moderate electron-withdrawing COOMe group at the
para-position was successfully ortho-methoxylated in a yield
of 46% (entry 13, Table 3). Gratifyingly, benzamide 3n with
the strong electron-withdrawing p-NO2 group could also be
functionalized to give the desired product, albeit in a low
yield even with a prolonged reaction time (entry 14, Table 3).
This result is still significant because the attempted acetox-
ylation of anilides with strong electron-withdrawing groups
such as NO2 failed. The above substituent effects clearly
disclose the electrophilic nature for the C-H activation
process. To our satisfaction, other alkoxylation of N-meth-
oxybenzamides could be realized by simply changing the
alcohol. Ethoxylated N-methoxybenzamides were obtained
in similar product yields to those of the corresponding meth-
oxylated N-methoxybenzamides when methanol was replaced
with ethanol in the reaction mixtures (entries 15-20, Table 3).
To our delight, N-methoxybenzamide could even be ortho-
alkoxylated by isopropanol, a secondary alcohol, albeit in 20%
yield (entry 21, Table 3). However, tertiary alcohol such as
tBuOH failed to react with N-methoxybenzamide under other-
wise identical conditions. It should be noted that the alkoxyla-
tion of N-methoxybenzamides bearing meta-substituents gave
only one regioisomer (entries 2, 4, 8, 10, 16, and 18, Table 3) due
to the steric factor.
benzamidesa
We believe that the alkoxylation of N-methoxybenza-
mides most likely proceeds through a similar pathway to
that for the acetoxylation of anilides.14 A possible mechan-
ism for the alkoxylation is outlined in Scheme 1. The fist step
involves chelate-directed C-H activation of the substrate to
afford the cyclopalladated intermediate A, followed by
oxidation of the Pd(II) intermediate A to the Pd(IV) inter-
mediate B by K2S2O8 in the presence of an alcohol. In the
final step, carbon-heteroatom bond formation via reductive
elimination affords the alkoxylated product and regenerates
the Pd(II) species. It should be noted that a mechanism
involving the common Pd(0)/Pd(II) catalytic cycle or a
recently formulated bimetallic Pd(II)/Pd(III) pathway15
could not be completely excluded.
In conclusion, we have found that the N-methoxy amide
group (CONHOMe) could be employed as an efficient
ortho-directing group in the Pd-catalyzed sp2 C-H bond
oxidative activation process. Directing groups of the sub-
strates were found to play a crucial role in the C-H
functionalizations. While substrates with the NHCOCH3
group gave methoxylated products in low yields, those with
aUnless otherwise specified, all the reactions were carried out with
0.25 mmol of 3, 0.0125 mmol of Pd(OAc)2, 0.5 mmol of K2S2O8, 30 mg
b
˚
of 4 A MS, 2 mL of MeOH, and 2 mL of dioxane at 55 °C. EtOH was
used. ciPrOH was used.
(15) (a) Powers, D. C.; Ritter, T. Nat. Chem. 2009, 1, 302. (b) Powers,
D. C.; Geibel, M. A. L.; Klein, J. E. M. N.; Ritter, T. J. Am. Chem. Soc. 2009, 131,
17050.
The same phenomenon has also been observed in the ortho-
acetoxylation of anilides.14 Benzamide 3i, which had a weak
478 J. Org. Chem. Vol. 75, No. 2, 2010

Wang and Yuan
JOCNote
SCHEME 1. Possible Reaction Mechanism
evaporated to dryness in vacuo. The residual was separated on
a silica gel column with petroleum ether/ethyl acetate 3:2 as the
eluent to obtain the desired product 4a (4b-u).
Compounds 216 and 4a17 have been previously reported, and
their identities were confirmed by comparison of their spectral
data with reported ones.
N,2-Dimethoxy-5-methylbenzamide (4b): white solid, mp
77-79 °C; IR (KBr) ν 3255, 2980, 2937, 1640, 1611, 1502,
1469, 1307, 1258, 1181, 1116, 1054, 1022, 946, 817, 735, 670,
539 cm-1; 1H NMR (300 MHz, CDCl3) δ 10.23 (1H, br s), 8.00
(1H, d, J = 1.8 Hz), 7.25 (1H, dd, J = 8.4, 1.8 Hz), 6.86 (1H, d,
J = 8.4 Hz), 3.94 (3H, s), 3.89 (3H, s), 2.33 (3H, s); 13C NMR
(75 MHz, CDCl3) δ 164.3, 155.0, 133.8, 132.3, 131.0, 119.1,
111.3, 64.4, 56.1, 20.3; HRMS (EITOF) m/z [Mþ] calcd for
C10H13NO3 195.0895, found 195.0902.
2-Ethoxy-N-methoxybenzamide (4o): white solid, mp 68-69 °C;
IR (KBr) ν 3246, 2974, 2932, 1649, 1602, 1492, 1474, 1302,
1246, 1165, 1120, 1035, 945, 883, 756, 604 cm-1;1HNMR(300MHz,
CDCl3) δ 10.30 (1H, br s), 8.20 (1H, dd, J = 7.8, 1.8 Hz), 7.44 (1H,
ddd, J=8.4, 7.8, 1.8 Hz), 7.09(1H, t, J= 7.8 Hz), 6.95 (1H, d, J=
8.4 Hz), 4.22 (2H, q, J = 6.9 Hz), 3.89 (3H, s), 1.54 (3H, t, J =
6.9 Hz); 13C NMR (75 MHz, CDCl3) δ 164.3, 156.4, 133.3, 132.1,
121.5, 119.8, 112.3, 65.0, 64.5, 14.8; HRMS (EI-TOF) m/z [Mþ]
calcd for C10H13NO3 195.0895, found 195.0903.
2-Isopropoxy-N-methoxybenzamide (4u): yellow oil; IR (KBr)
ν 3357, 2978, 2935, 1672, 1600, 1473, 1291, 1231, 1112, 1038,
949, 886, 756, 665 cm-1; 1H NMR (300 MHz, CDCl3) δ 10.36
(1H, br s), 8.18 (1H, dd, J = 7.8, 1.8 Hz), 7.43 (1H, ddd, J = 8.4,
7.5, 1.8 Hz), 7.07 (1H, dd, J = 7.8, 7.5 Hz), 6.96 (1H, d, J= 8.4 Hz),
4.75 (1H, heptet, J = 6.0 Hz), 3.88 (3H, s), 1.44 (6H, d,
J = 6.0 Hz); 13C NMR (75 MHz, CDCl3) δ 164.5, 155.5,
133.2, 132.4, 121.6, 120.8, 114.0, 72.5, 64.6, 22.3 (2C); HRMS
(EI-TOF) m/z [Mþ] calcd for C10H15NO3 209.1052, found
209.1058.
the CONHOMe group afforded the desired methoxylated
products in much higher yields. Various N-methoxybenza-
mides with either electron-donating or electron-withdraw-
ing groups could be alkoxylated directly and efficiently. The
current Pd-catalyzed alkoxylation of N-methoxybenza-
mides could tolerate functional groups such as chloro,
bromo, ether, ester, and nitro. The final products could
be further manipulated into various derivatives, broaden-
ing the potential synthetic application of the current metho-
dology.
Experimental Section
Typical Procedure for the Direct Ortho-Alkoxylation of
N-Methoxybenzamides 3 Catalyzed by Pd(OAc)2. To a stirred
solution of N-methoxybenzamide 3a (3b-n, 0.25 mmol), Pd-
(OAc)2 (3.3 mg, 0.0125 mmol), K2S2O8 (135 mg, 0.5 mmol), and
Acknowledgment. The authors are grateful for the finan-
cial support from National Natural Science Foundation of
China (20772117) and National Basic Research Program of
China (2006CB922003).
˚
4 A MS (30 mg) in fresh distilled dioxane (2 mL) at 55 °C
was added MeOH, EtOH, or PrOH (2 mL). The reaction
was monitored by TLC. Upon completion, the solvent was
i
Supporting Information Available: Spectral data of 2, 4a,
4c-n, and 4p-t, and NMR spectra of 2 and 4a-u. This material
is available free of charge via the Internet at http://pubs.acs.org.
(16) Kraska, J.; Teodorczyk, Z. Pol. J. Chem. 1984, 58, 1025.
(17) Miyata, O.; Koizumi, T.; Asai, H.; Iba, R.; Naito, T. Tetrahedron
2004, 60, 3893.
J. Org. Chem. Vol. 75, No. 2, 2010 479