Palladium-catalyzed oxidative carbonylation of aromatic C-H bonds of N -alkylanilines with CO and alcohols for the synthesis of o -aminobenzoates

Article abstract of DOI:10.1021/jo502581p

A Pd(II)-catalyzed C-H monocarbonylation of N-alkylanilines for the synthesis of o-aminobenzoates has been developed. Various aliphatic alcohols and phenol were tolerated in the reaction to afford the corresponding o-aminobenzoates in good yields under mild balloon pressure of CO.

Full text of DOI:10.1021/jo502581p

Note
pubs.acs.org/joc
Palladium-Catalyzed Oxidative Carbonylation of Aromatic C−H
Bonds of N‑Alkylanilines with CO and Alcohols for the Synthesis of
o‑Aminobenzoates
Ming Chen, Zhi-Hui Ren, Yao-Yu Wang, and Zheng-Hui Guan*
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Department of Chemistry &
Materials Science, Northwest University, Xi’an 710127, P. R. China
S
* Supporting Information
ABSTRACT: A Pd(II)-catalyzed C−H monocarbonylation of N-
alkylanilines for the synthesis of o-aminobenzoates has been
developed. Various aliphatic alcohols and phenol were tolerated in
the reaction to afford the corresponding o-aminobenzoates in good
yields under mild balloon pressure of CO.
Scheme 1. Palladium-Catalyzed Oxidative Carbonylation of
N-Alkylanilines
arbonylation reactions have proven to be a powerful tool
in organic synthesis, and they have received considerable
C
attention over the past decades.1 In particular, the C−H bond
carbonylation has become a useful method for the synthesis of
carbonyl compounds such as acids,2 ester,3 amides,4 ketone,5
and anhydrides.6 In these reactions, the direct carbonylation
of C−H bonds with CO and alcohols for the synthesis of aryl
esters or vinyl esters have received considerable attention.7
Recently, Pd-, Ru-, or Rh-catalyzed oxidative carbonylation of
urea, N,N-dimethylbenzylamines, indoles, and 2-phenylpyr-
idine for the synthesis of esters were developed by several
research groups including ours.3a,8 Directing groups play an
important role in these reactions. However, only a small
number of functional groups can act as the directing groups
to assist the ortho C−H carbonylation. The search for new
and synthetically versatile directing groups is still a challenging
task in C−H bond carbonylation.9
O-Aminobenzoates and their derivatives are valuable
commodity chemicals and highly reactive intermediates.10
However, the conventional methods for the synthesis of o-
aminobenzoates generally require multistep procedures under
harsh reaction conditions.11 Thus, the development of a
simple and economic method for the synthesis of o-
aminobenzoates is highly desirable. In 2012, we developed a
Pd-catalyzed C−H bond carbonylation of N-alkylanilines,
affording synthetically useful isatoic anhydrides under mild
conditions (Scheme 1, eq 1).6a The reaction proceeded
through a Pd-catalyzed one-pot double carbonylation of N-
alkylanilines via an anthranilic acid intermediate.6a,b Based on
our previous study, we hypothesized that o-aminobenzoates
may be obtained by the Pd-catalyzed C−H bond carbon-
ylation of N-alkylanilines in the presence of an alcohol. In this
paper, we report the Pd-catalyzed monocarbonylation of the
C−H bond of N-alkylanilines for the synthesis of o-
aminobenzoates (Scheme 1, eq 2).
the product of o-aminobenzoate 3aa in 42% yield along with
isatoic anhydride 4aa in 20% yield when the reaction was
performed using Pd(OAc)2 as a catalyst in the presence of
Cu(OAc)2 and KI in DMF at 100 °C (Table 1, entry 1).12
For optimizing the reaction conditions, the effect of bases was
investigated, and we found that base plays an important role
in this oxidative carbonylation reaction. KOAc was found to
be superior to K2CO3, K3PO4, and Cs2CO3 (Table 1, entries
2−5). Various oxidants such as BQ, CuCl2, and CuBr2 were
also screened. Cu(OAc)2 was found to be the optimum
choice (Table 1, entries 7−9). Further, the effect of different
solvents was investigated; however, no improvement was
observed (Table 1, entries 10−13). Surprisingly, the yield of
o-aminobenzoate 3aa increased to 74% in the presence of 3.0
equiv of KOAc, and only 9% yield of byproduct, isatoic
anhydride, was observed (Table 1, entry 14).
After optimization of the reaction conditions, the substrate
scope of the carbonylation was investigated, and the results
are listed in Table 2. This oxidative carbonylation was found
to be a good methodology for the synthesis of o-amino-
We began our study by investigating the Pd-catalyzed
oxidative carbonylation of N-methylaniline 1a and ethanol 2a
under a balloon pressure of CO. We were pleased to obtain
Received: November 12, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/jo502581p
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Table 1. Optimization of Reaction Conditions for the
Carbonylation of N-Methylaniline
Scheme 2. Debenzylation of the o-Aminobenzoate
a
entry
oxidant
base
solvent yield 3aa (%) yield 4aa (%)
standard conditions. However, no reaction was observed
(Table 2, entry 16). Tertiary anilines such as N,N-
dimethylaniline 1q only afforded a trace of ethyl 2-
(dimethylamino)benzoate (Table 2, entry 17).6a
1
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
BQ
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
toluene
THF
42
47
68
53
56
67
11
56
56
20
0
20
7
2
K2CO3
KOAc
K3PO4
Cs2CO3
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
3
11
15
11
12
0
4
Furthermore, we investigated different alcohols for this
carbonylation, and the results are listed in Table 3. To our
delight, we found that both primary and secondary alcohols
afforded the corresponding o-aminobenzoates in good yields.
When methanol was used as a substrate, 70% yield of 3ab was
obtained. Simple alkyl alcohols such as propanol and butanol
were also suitable for this transformation (3ac−ad). However,
the sterically hindered 2-propanol exhibited lower efficiency.
Fortunately, when benzyl alcohol was used as the nucleophile,
the desired products 3af was obtained in 77% yield. In
particular, the reaction proceeded smoothly to afford 3ag in
68% yield when phenol was used as the substrate. However,
the reaction failed to synthesize o-aminobenzamides when
amines, such as piperidine and morpholine, were used instead
of alcohols.
5
b
6
7
8
CuCl2
0
9
CuBr2
0
10
11
12
13
14
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
5
0
DMA
DMSO
DMF
67
50
74
14
10
9
c
a
Reaction conditions: N-methylaniline 1a (0.2 mmol), Pd(OAc)2 (5
mol %), oxidant (1.1 equiv), KI (20 mol %), base (1.5 equiv), ethanol
b
(5.0 equiv), CO (1 atm), solvent (2.0 mL), at 100 °C. KI (1.0 equiv).
c
3.0 equiv of base.
On the basis of the previous studies,6a a plausible
mechanism for this carbonylation is proposed in Scheme 3.
benzoates. Notably, the reaction was successfully performed
on a 1.0 mmol scale to afford o-aminobenzoate 3aa in 65%
yield (Table 2, entry 1). N-Methylanilines with electron-
donating or -withdrawing groups such as methyl, methoxyl,
chloro, and bromo groups on phenyl rings were tolerated
under the reaction conditions, and the corresponding o-
aminobenzoates 3ba−ia were obtained in moderate to good
yields (Table 2, entries 2−9). In general, the electron-rich
substrates were more reactive because of their slightly stronger
nucleophilicity. For example, methyl-substituted o-amino-
benzoates 3ba and 3da were obtained in 72% yield (Table
2, entries 2 and 4). However, the strong electron-donating
methoxy group on the phenyl ring decreased the yield of the
reactions because of the formation of an isatoic anhydride
byproduct (Table 2, entries 5−6). m-Chloro- and -bromo-
substituted N-methylanilines 1h and 1i were transformed into
the corresponding o-aminobenzoates 3ha and 3ia in 44% and
37% yield, respectively, indicating that the carbonylation was
sensitive to electronic features of the N-methylanilines.13
Similarly, the carboxylic ester 3ja from the carbonylation of 2-
naphthylamine 1j was obtained in 50% yield (Table 2, entry
10). In addition, different alkyl substituents on the anilines
were also investigated. N-Ethyl- and propyl-substituted
anilines and tetrahydroquinoline 1k−m were used, and the
anticipated o-aminobenzoates were obtained in 48−67% yields
(Table 2, entries 11−13). N-Benzylaniline 1n also afforded o-
aminobenzoate 3na in 43% yield (Table 2, entry 14), and the
benzyl group can be easily removed under reductive condition
with Pd/C as catalyst to afforded o-aminobenzoate 3oa in
78% yield (Scheme 2).14
Scheme 3. Tentative Mechanism for the Reaction
The C−H bond activation of N-methylaniline by Pd(OAc)2
results in dimeric palladium intermediate A in the presence of
CO,6a followed the insertion of CO into A, and subsequent
coordination to alcohols forms intermediate B assisted by
KOAc. Finally, the reductive elimination of B affords
carbonylation product 3 and Pd(0), which is oxidized to
Pd(II) by Cu(OAc)2 to regenerate the catalyst and complete
the catalytic cycle.
In summary, we developed an efficient Pd-catalyzed
oxidative C−H bond carbonylation of N-alkylanilines with
CO and alcohols for the synthesis of o-aminobenzoates. This
novel Pd-catalyzed carbonylation reaction is an alternative
protocol for the synthesis of valuable o-aminobenzoates in
moderate to good yield under balloon pressure of CO.
Under the optimized conditions, the effect of directing
group was next investigated. When aniline 1o was used as the
substrate, the product, ethyl phenylcarbamate (52%), was
formed along with N,N′-diphenylurea (18%).3e A secondary
amine such as diphenylamine 1p was also examined under the
B
DOI: 10.1021/jo502581p
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The Journal of Organic Chemistry
Note
a
Table 2. Substrate Scope for Carbonylation of N-Alkylaniline Derivatives
a
Reaction conditions: N-alkylaniline 1 (0.2 mmol), Pd(OAc)2 (5 mol %), Cu(OAc)2 (1.1 equiv), KI (20 mol %), KOAc (3 equiv), and ethanol (5.0
b
c
d
equiv) under CO (1 atm) in 2.0 mL of DMF at 100 °C. 1a (1 mmol), DMF (8 mL), 24 h. In the absence of KOAc and at 120 °C. 1.5 equiv of
KOAc. The product ethyl phenylcarbamate was formed in 52% yield, along with N,N′-dipehnylurea in 18% yield.
e
4−24 h and monitored by TLC until reaction completion. Crude
product c was further by silica gel chromatography with hexane/ethyl
acetate (20:1). Finally, c was deprotected by mass fraction 20% HCl
(5 mL) at 120 °C. After the completion, the reaction mixture was
cooled to room temperature, and the reaction mixture was washed
with 3 M NaOH (15 mL) and extracted with ethyl acetate. The
crude product was purified by silica gel chromatography to afford
corresponding products d in 90% yield.15
EXPERIMENTAL SECTION
■
General Information. H and 13C NMR spectra were recorded
at 400 and 100 MHz. The following abbreviations (or combinations
thereof) were used to explain multiplicities: s = singlet, d = doublet, t
= triplet, q = quartet, m = multiplet, b = broad. Coupling constants J
were reported in hertz. All products were characterized by HRMS
1
1
(ESI-TOF-Q); copies of their H NMR and 13C NMR spectra are
provided in the Supporting Information. Unless otherwise stated, all
reagents and solvents were purchased from commercial suppliers and
used without further purification.
Typical Procedure for Synthesis of N-Alkylanilines.
Method 2, synthesis N-benzylaniline: A mixture of 2-propanol (10
mL) with Pd/C (10 mol %, 424 mg) and ammonium formate (20
mmol, 1.2612 g) was stirred in a flask, followed by additionof 1 mL
of H2O to the flask, and the mixture was vigorously stirred for 1 min
to activate Pd/C. Then, aniline (2.0 mmol, 186.1 mg) and
benzaldehyde (2.0 mmol, 212.1 mg) were immediately added to
the reaction mixture, and the reaction mixture was stirred at room
temperature. The progress of the reaction was monitored by TLC.
After reaction completion, the Pd/C catalyst was filtered off on
Method 1: Substituted aniline a (10.0 mmol) was protected with
(Boc)2O (12 mmol, 2.1824 g) in CH3OH (30 mL) at 100 °C for 6
h to afford products b in quantitative yields. Then, anhydrous THF
(8 mL) was added to the pure b, followed by addition of NaH (12
mmol, 288 mg) at <5 °C in an ice bath with vigorous stirring for 1
min. Subsequently, CH3I (12 mmol, 0.75 mL) was injected in the
reaction mixture, and the resulting reaction mixture was stirred for
C
DOI: 10.1021/jo502581p
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The Journal of Organic Chemistry
Note
2.87 (s, 3 H), 2.23 (d, J = 6.4 Hz, 3 H), 2.14 (d, J = 6.4 Hz, 3 H),
1.36 (t, J = 6.8 Hz, 3 H); 13C{1H} NMR (CDCl3, 100 MHz) δ
168.6, 150.5, 144.1, 131.6, 122.4, 111.8, 107.8, 59.9, 29.6, 20.6, 18.5,
14.4; HRMS calcd (ESI) m/z for C12H17NNaO2 [M + Na]+
230.1151, found 230.1158.
Table 3. Substrate Scope for Carbonylation of N-
Methylaniline and Alcohols
a
Ethyl 5-methoxy-2-(methylamino)benzoate (3ea): yield 56%
(23.4 mg), colorless liquid; 1H NMR (CDCl3, 400 MHz) δ 7.44
(s, 1 H), 7.29 (br s, 1 H), 7.04 (d, J = 8.8 Hz, 1 H), 6.61 (d, J = 8.8
Hz, 1 H), 4.32−4.28 (m, 2 H), 3.75 (s, 3 H), 2.86 (s, 3 H), 1.36 (t,
J = 6.8 Hz, 3 H); 13C{1H} NMR (CDCl3, 100 MHz) δ 168.2, 149.0,
147.3, 122.9, 114.5, 111.9, 109.8, 60.2, 55.9, 29.9, 14.3. HRMS calcd
(ESI) m/z for C11H15NNaO3 [M + Na]+ 232.0944, found 232.0947.
Ethyl 4,5-dimethoxy-2-(methylamino)benzoate (3fa): yield 54%
(25.8 mg), white solid; mp 103−104 °C; 1H NMR (CDCl3, 400
MHz) δ 7.62 (br s, 1 H), 7.39 (s, 1 H), 6.11 (s, 1 H), 4.31−4.26
(m, 2 H), 3.91 (s, 3 H), 3.82 (s, 3 H), 2.89 (s, 3 H), 1.38−1.35 (m,
3 H); 13C{1H} NMR (CDCl3, 100 MHz) δ 167.8, 155.1, 149.1,
138.6, 113.6, 100.6, 93.3, 59.6, 56.3, 55.3, 29.5, 14.2. HRMS calcd
(ESI) m/z for C12H17NNaO4 [M + Na]+ 262.1050, found 262.1057.
Ethyl 5-chloro-2-(methylamino)benzoate (3ga): yield 65% (27.7
1
mg), white solid; mp 62−63 °C; H NMR (CDCl3, 400 MHz) δ
7.86 (s, 1 H), 7.64 (br s, 1 H), 7.29 (d, J = 7.2 Hz, 1 H), 6.58 (d, J
= 9.2 Hz, 1 H), 4.33−4.27 (m, 2 H), 2.88 (d, J = 4.8 Hz, 3 H), 1.37
(t, J = 7.2 Hz, 3 H), ; 13C{1H} NMR (CDCl3, 100 MHz) δ 167.6,
150.5, 134.3, 130.6, 118.8, 112.1, 110.8, 60.5, 29.6, 14.3; HRMS
calcd (ESI) m/z for C10H12ClNNaO2 [M + Na]+ 236.0449, found
236.0451.
a
Reaction conditions: N-Methylaniline 1a (0.2 mmol), Pd(OAc)2 (5
mol %), Cu(OAc)2 (1.1 equiv), KI (20 mol %), KOAc (3 equiv), and
alcohol (5.0 equiv) under CO (1 atm) in 2.0 mL of DMF at 100 °C.
b
c
KOAc (1.5 equiv). Alcohol (2.0 equiv).
Ethyl 4-chloro-2-(methylamino)benzoate (3ha): yield 44% (18.7
mg), yellow liquid; H NMR (CDCl3, 400 MHz) δ 7.82 (d, J = 8.4
Celite, and the solvent was removed by rotary evaporation. The
residue was purified by silica gel column chromatography with
hexane/ethyl acetate (50:1) as the eluent.16
1
Hz, 1 H), 7.76 (br s, 1 H), 6.62 (s, 1 H), 6.54 (d, J = 8.4 Hz, 1 H),
4.32−4.27 (m, 2 H), 2.88 (d, J = 5.2 Hz, 3 H), 1.37 (t, J = 7.2 Hz, 3
H); 13C{1H} NMR (CDCl3, 100 MHz) δ 168.1, 152.6, 140.7, 132.8,
114.5, 110.4, 108.6, 60.4, 29.5, 14.3; HRMS calcd (ESI) m/z for
C10H12ClNNaO2 [M + Na]+ 236.0449, found 236.0452.
Typical Procedure for Carbonylation of N-Alkylanilines for
Synthesis of o-Aminobenzoates. A mixture of N-alkylaniline 1
(0.2 mmol), ROH (1.0 mmol), Pd(OAc)2 (5 mol %, 2.2 mg),
Cu(OAc)2 (0.22 mmol, 40 mg), KI (0.04 mmol, 6.6 mg), KOAc (0.6
mmol, 58.8 mg), and DMF (2 mL) was charged in a 10 mL round-
bottom flask. Then, the flask was evacuated and backfilled with CO
(three times, balloon) and stirred at 100 °C. When the reaction was
completed (detected by TLC), the mixture was cooled to room
temperature and vented to discharge the excess CO. The reaction
was quenched with H2O (10 mL) and extracted with EtOAc (3 × 10
mL). The combined organic layers were dried over anhydrous
Na2SO4 and then evaporated in vacuo. The residue was purified by
column chromatography on silica gel to afford the corresponding o-
aminobenzoates 3 with hexane/ethyl acetate (40/1) as the eluent.
Ethyl 2-(methylamino)benzoate (3aa): yield 74% (26.5 mg),
Ethyl 5-bromo-2-(methylamino)benzoate (3ia): yield 37% (19.0
1
mg), colorless liquid; H NMR (CDCl3, 400 MHz) δ 7.99 (s, 1 H),
7.67 (br s, 1 H), 7.41 (d, J = 9.2 Hz, 1 H), 6.54 (d, J = 9.2 Hz, 1
H), 4.33−4.28 (m, 2 H), 2.88 (d, J = 4.8 Hz, 3 H), 1.38 (t, J = 6.8
Hz, 3 H); 13C{1H} NMR (CDCl3, 100 MHz) δ 167.6, 150.8, 137.0,
133.6, 112.5, 111.4, 105.5, 60.6, 29.6, 14.3; HRMS calcd (ESI) m/z
for C10H12BrNNaO2 [M + Na]+ 279.9944, found 279.9942.
Ethyl 3-(methylamino)-2-naphthoate (3ja): yield 50% (22.9 mg),
1
brown liquid; H NMR (CDCl3, 400 MHz) δ 8.49 (s, 1 H), 7.69 (d,
J = 8.0 Hz, 1 H), 7.58 (d, J = 8.0 Hz, 1 H), 7.39 (t, J = 7.2 Hz, 2
H), 7.14 (t, J = 7.2 Hz, 1 H), 6.79 (s, 1 H), 4.40−4.35 (m, 2 H),
2.95 (s, 3 H), 1.43 (t, J = 6.8 Hz, 3 H); 13C{1H} NMR (CDCl3, 100
MHz) δ 168.3, 147.8, 137.8, 133.6, 129.2, 128.7, 125.4, 124.7, 121.8,
114.4, 103.8, 60.7, 29.9, 14.3; HRMS calcd (ESI) m/z for
C14H15NNaO2 [M + Na]+ 252.0995, found 252.1000.
Ethyl 2-(ethylamino)benzoate (3ka): yield 67% (25.9 mg),
colorless liquid; 1H NMR (CDCl3, 400 MHz) δ 7.92 (d, J = 8.0
Hz, 1 H), 7.62 (br s, 1 H), 7.34 (t, J = 7.6 Hz, 1 H), 6.66 (d, J = 7.6
Hz, 1 H), 6.57 (t, J = 7.6 Hz, 1 H), 4.33−4.28 (m, 2 H), 3.24−3.21
(m, 2 H), 1.37 (t, J = 6.8 Hz, 3 H), 1.31 (t, J = 6.8 Hz, 3 H);
13C{1H} NMR (CDCl3, 100 MHz) δ 168.7, 151.1, 134.4, 131.6,
114.1, 111.1, 109.8, 60.1, 37.3, 14.5, 14.3; HRMS calcd (ESI) m/z
for C11H15NNaO2 [M + Na]+ 216.0995, found 216.1000.
1
colorless liquid; H NMR (CDCl3, 400 MHz) δ 7.92 (d, J = 8.0 Hz,
1 H), 7.66 (br s, 1 H), 7.37 (t, J = 7.2 Hz, 1 H), 6.66 (d, J = 8.4 Hz,
1 H), 6.58 (t, J = 7.2 Hz, 1 H), 4.33−4.28 (m, 2 H), 2.90 (d, J = 3.2
Hz, 3 H), 1.37 (t, J = 7.2 H, 3 H); 13C{1H} NMR (CDCl3, 100
MHz) δ 168.7, 152.0, 134.5, 131.5, 114.2, 110.6, 110.1, 60.1, 29.5,
14.3; HRMS calcd (ESI) m/z for C10H13NNaO2 [M + Na]+
202.0838, found 202.0844.
Ethyl 5-methyl-2-(methylamino)benzoate (3ba): yield 72% (27.8
1
mg), colorless liquid; H NMR (CDCl3, 400 MHz) δ 7.74 (s, 1 H),
7.48 (br s, 1 H), 7.22 (d, J = 8.4 Hz, 1 H), 6.61 (d, J = 8.4 Hz, 1
H), 4.35−4.31 (m, 2 H), 2.90 (s, 3 H), 2.26 (s, 3 H), 1.41−1.38 (m,
3 H); 13C{1H} NMR (CDCl3, 100 MHz) δ 168.6, 150.1, 135.5,
131.2, 123.1, 110.7, 109.8, 60.1, 29.6, 20.1, 14.3. HRMS calcd (ESI)
m/z for C11H15NNaO2 [M + Na]+ 216.0995, found 216.1000.
Ethyl 4-methyl-2-(methylamino)benzoate (3ca): yield 60% (23.2
Ethyl 2-(propylamino)benzoate (3la): yield 48% (19.9 mg),
1
colorless liquid; H NMR (CDCl3, 400 MHz) δ 7.91 (d, J = 7.6 Hz,
1 H), 7.71 (br s, 1 H), 7.34 (t, J = 7.2 Hz, 1 H), 6.67 (d, J = 8.4 Hz,
1 H), 6.56 (t, J = 7.6 Hz, 1 H), 4.33−4.28 (m, 2 H), 3.18−3.13 (m,
2 H), 1.74−1.68 (m, 2 H), 1.38 (t, J = 6.8 Hz, 3 H), 1.03 (t, J = 7.2
Hz, 3 H); 13C{1H} NMR (CDCl3, 100 MHz) δ 168.7, 151.3, 134.4,
131.6, 114.0, 111.1, 109.8, 60.1, 44.6, 22.3, 14.3, 11.7; HRMS calcd
(ESI) m/z for C12H17NNaO2 [M + Na]+ 230.1151, found 230.1148.
Ethyl 1,2,3,4-tetrahydroquinoline-8-carboxylate (3ma): yield
49% (20.1 mg), colorless liquid; 1H NMR (CDCl3, 400 MHz) δ
7.79 (br s, 1 H), 7.72 (d, J = 8.0 Hz, 1 H), 7.03 (d, J = 6.8 Hz, 1
H), 6.44 (t, J = 7.6 Hz, 1 H), 4.31−4.26 (m, 2 H), 3.41 (s, 2 H),
2.78−2.75 (m, 2 H), 1.90 (t, J = 5.6 Hz, 2 H), 1.36 (t, J = 6.8 Hz, 3
1
mg), white solid; mp 49−50 °C; H NMR (CDCl3, 400 MHz) δ
7.80 (d, J = 8.0 Hz, 1 H), 7.63 (br s, 1 H), 6.45 (s, 1 H), 6.40 (d, J
= 8.0 Hz, 1 H), 4.31−4.26 (m, 2 H), 2.88 (d, J = 4.4 Hz, 3 H), 2.32
(s, 3 H), 1.35 (t, J = 7.2 Hz, 3 H); 13C{1H} NMR (CDCl3, 100
MHz) δ 168.6, 152.0, 145.2, 131.4, 115.6, 110.8, 107.6, 59.9, 29.4,
22.1, 14.3; HRMS calcd (ESI) m/z for C11H15NNaO2 [M + Na]+
216.0995, found 216.0999.
Ethyl 4,5-dimethyl-2-(methylamino)benzoate (3da): yield 72%
1
(29.8 mg), white solid; mp 48−49 °C; H NMR (CDCl3, 400 MHz)
δ 7.65 (s, 1 H), 7.41 (br s, 1 H), 6.46 (s, 1 H), 4.31−4.26 (m, 2 H),
D
DOI: 10.1021/jo502581p
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The Journal of Organic Chemistry
Note
H); 13C{1H} NMR (CDCl3, 100 MHz) δ 168.8, 148.3, 133.6, 129.3,
122.0, 113.4, 108.6, 60.0, 41.1, 27.8, 20.8, 14.3; HRMS calcd (ESI)
m/z for C12H15NNaO2 [M + Na]+ 228.0995, found 228.0998.
Ethyl 2-(benzylamino)benzoate (3na): yield 43% (21.9 mg),
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H and 13C NMR spectra for products. This
material is available free of charge via the Internet at http://
pubs.acs.org.
1
yellow liquid; H NMR (CDCl3, 400 MHz) δ 8.18 (br s, 1 H), 7.94
(d, J = 7.6 Hz, 1 H), 7.35−7.24 (m, 6 H), 6.63−6.57 (m, 2 H), 4.44
(d, J = 4.8 Hz, 2 H), 4.34−4.29 (m, 2 H), 1.38 (t, J = 6.0 Hz, 3 H).
13C{1H} NMR (CDCl3, 100 MHz) δ 168.7, 150.9, 138.8, 134.5,
131.6, 128.6, 127.1, 127.0, 114.8, 111.6, 110.4, 60.3, 46.9, 14.3;
HRMS calcd (ESI) m/z for C16H17NNaO2 [M + Na]+ 278.1151,
found 278.1157.
AUTHOR INFORMATION
Corresponding Author
*E-mail: guanzhh@nwu.edu.cn.
Notes
■
Ethyl 2-aminobenzoate (3oa): yield 78% (8.1 mg), yellow liquid;
1H NMR (CDCl3, 400 MHz) δ 7.88 (dd, J = 8.0 Hz J = 1.2 Hz, 1
H), 7.26 (dd, J = 15.6 Hz, J = 1.6 Hz, 1 H), 6.66−6.62 (m, 2 H),
5.73 (br s, 2 H), 4.35−4.30 (m, 2 H), 1.38 (t, J = 7.2 Hz, 3 H);
13C{1H} NMR (CDCl3, 100 MHz) δ 168.1, 150.4, 133.9, 131.1,
116.6, 116.1, 110.9, 60.2, 14.3; HRMS Calcd (ESI) m/z for
C9H11NNaO2 [M + Na]+ 188.0682, found 188.0685.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by generous grants from the
National Natural Science Foundation of China (NSFC-
21472147, 21272183), Fund of the Rising Stars of Shanxi
Province (2012KJXX-26), and Fund of Graduate School of
NWU (YZZ13039).
Methyl 2-(methylamino)benzoate (3ab): yield 70% (23.1 mg),
1
colorless liquid; H NMR (CDCl3, 400 MHz) δ 7.89 (d, J = 8.0 Hz,
1 H), 7.63 (br s, 1 H), 7.38 (t, J = 7.2 Hz, 1 H), 6.66 (d, J = 8.8 Hz,
1 H), 6.58 (t, J = 7.6 Hz, 1 H), 3.85 (s, 3 H), 2.90 (s, 3 H);
13C{1H} NMR (CDCl3, 100 MHz) δ 169.0, 151.9, 134.6, 131.5,
114.3, 110.7, 109.8, 51.4, 29.5; HRMS Calcd (ESI) m/z for
C9H11NNaO2 [M + Na]+ 188.0682, found 188.0688.
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1
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1
1 H), 7.68 (br s, 1 H), 7.37 (t, J = 7.6 Hz, 1 H), 6.65 (d, J = 8.0 Hz,
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1
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1
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E
DOI: 10.1021/jo502581p
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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J. Org. Chem. XXXX, XXX, XXX−XXX