Aminolysis of aryl ester using tertiary amine as amino donor via c-o and c-n bond activations

Article abstract of DOI:10.1021/jo4023974

An aminolysis reaction between various aryl esters and inert tertiary amines by C-O and C-N bond activations has been developed for the selective synthesis of a broad scope of tertiary amides under neutral and mild conditions. The mechanism may undergo the two key steps of oxidative addition of acyl C-O bond in parent ester and C-N bond cleavage of tertiary amine via an iminium-type intermediate.

Full text of DOI:10.1021/jo4023974

Note
pubs.acs.org/joc
Aminolysis of Aryl Ester Using Tertiary Amine as Amino Donor via
C−O and C−N Bond Activations
Yong-Sheng Bao,* Bao Zhaorigetu, Bao Agula, Menghe Baiyin, and Meilin Jia
College of Chemistry and Environmental Science, Inner Mongolia Key Laboratory of Green Catalysis, Inner Mongolia Normal
University, Hohhot 010022, China.
S
* Supporting Information
ABSTRACT: An aminolysis reaction between various aryl esters
and inert tertiary amines by C−O and C−N bond activations has
been developed for the selective synthesis of a broad scope of
tertiary amides under neutral and mild conditions. The mechanism
may undergo the two key steps of oxidative addition of acyl C−O
bond in parent ester and C−N bond cleavage of tertiary amine via
an iminium-type intermediate.
acyl part of intermediate I could combine via amino group
bonding on the palladium to produce amide.
any esters are produced on an industrial scale and are
Mprimarily used as solvents. The use of these fine
chemicals as substrates of transition-metal catalytic reactions
may offer more environmentally benign and atom-economical
processes. When a transition metal undergoes oxidative
addition into a ester, it can either insert into the acyl C−O
bond or the alkyl C−O bond.1,2 The alkyl C−O bond cleavage
has been studied extensively in the field of cross-coupling
reaction,3 but there are challenges associated with acyl C−O
bond cleavage because of decarbonylation phenomenon.4 So
far, in the rare cases when the acyl C−O bond is activated and
decarbonylation is suppressed, the acyl metal alkoxide
complexes can undergo additional transformations.5
Our previous work confirmed that N-heteroarene-2-carbox-
ylate can oxidative add to palladium via acyl C−O bond
activation, and its alkoxy part could combine with the acyl
group of aldehyde to give a new ester.6 The mechanism
proposed herein indicates that the intermediate I is likely to be
produced in this reaction (see Scheme 1). We consider that
under the right circumstances its acyl part can be taken on to
further chemical transformations. Catalyzed by palladium,
tertiary amine could undergo C−N bond cleavage and generate
a metal complex containing a M−N bond.7 Because an amide is
more stable than ester on the energetic level, we postulated that
Here, we report the first example of aminolysis of aryl ester
using inert tertiary amine as amino donor via C−O and C−N
bond activations. Initially, a set of experiments was carried out
using perfluorophenyl quiline-2-carboxylate 1a with a N-
heteroarene moiety as a coordinating group and N,N-
diethylaniline 2a as model substrates. To our delight, in the
presence of Pd(OAc)2 (5 mol %), the desired product, N-ethyl-
N-phenylquinoline-2-carboxamide 3aa, was isolated after
refluxing 1a and 2a in toluene (Table 1, entry 1). Various
palladium sources and other transition-metal catalysts were also
tested, and the results demonstrated that Pd(OAc)2 was the
best catalyst (entries 2−4). It was noteworthy that no desired
amide 3aa was obtained without any catalyst (entry 5). A series
of ligands were screened in the reaction. The yields of 3aa did
not rise but rather reduced remarkably (entries 6−9). The same
disappointing results were obtained by adding bases LiOAc and
CsF to the reaction solution (entries 10 and 11). Switching to
other solvents, PhCl showed good conversion to the best yield
of 81% (entries 12 and 13). Increasing the temperature to 130
°C does not increase the yield (entry 14).
Using the conditions from Table 1, entry 13, the scope of the
aminolysis reaction was investigated with a variety of tertiary
amines. As shown in Table 2, both trialkyl tertiary amines 2b,
2c and unsaturated triallyl amine 2d were found to react
smoothly with 1a to give the aminolysis products 3ab−ad in
yields up to 91% (Table 2, entries 1−3). Surprisingly, no
product formation was observed with triphenylamine 2e as an
amine source, in which the N atom conjugated with three
benzene rings, thus suggesting that the sp2 C−N bond does not
cleave under these conditions. Because N,N-dimethylaniline
can be oxidized by oxygen in the presence of palladium,8 we
used Michler’s ketone 2f as an aniline analogue and obtained
Scheme 1. Proposed New Strategy for Acyl C−O Bond
Activation of Ester
Received: October 27, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo4023974 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Table 1. Optimization of Aminolysis Reaction between
Table 2. Aminolysis of Perfluorophenyl Quiline-2-
carboxylate 1a with Versatile Tertiary Amines 2
a
Perfluorophenyl Quiline-2-carboxylate 1a and N,N-
a
Diethylaniline 2a
b
T
(°C)
yield
(%)
entry
catalyst
ligand
base
solvent
1
Pd(OAc)2
PdCl2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
xylene
115
115
115
115
115
115
115
115
115
115
115
130
115
130
67
16
2
3
CuCl2
4
FeCl3
5
6
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PPh3
27
26
63
7
Pcy3
8
dppe
9
dipyridyl
10
11
12
13
14
LiOAc
CsF
56
45
75
81
82
PhCl
PhCl
a
General conditions: 1a (0.20 mmol), 2a (1.5 equiv), catalyst (5 mol
b
%), ligand (10 mol %), 24 h. Isolated yield.
the desired amide 3af (Table 2, entry 5). Interestingly, 4-
(diethylamino)benzaldehyde 2g gave the same product 3aa as
2a by means of aminolysis and decarbonylation processes
(Table 2, entry 6). The regioselectivity was observed in the
reaction of 1a with 2h to exclusively cleave the C−N bond of
the sterically less hindered methyl group giving a pair of
stereoisomers 3ah in high yield (Table 2, entry 7). Likewise, N-
alkyl heterocyclic amines 2i−m reacted exclusively at their
exocyclic C−N bond to give cyclic amides 3ai, 3ak, and 3am in
61−84% yield (Table 2, entries 8−12), but when N-
methylpyrrole 2n and N-methylpyrrolidone 2o were used as
substrates, no product formation was observed (Table 2, entries
13 and 14). This further confirmed the hypothesis that the
lone-pair electrons of te N atom participating in the conjugating
system are likely to hinder the C−N bond activation by
palladium.
Next, the scope of this reaction was investigated with respect
to multiple perfluorophenyl carboxylates under the optimized
conditions. As shown in Table 3, every carboxylic ester 1b−l,
including indole-2-carboxylate, furan-2-carboxylate, benzoate,
saturated fatty acid ester, and unsaturated fatty acid ester, reacts
with 2a to give the corresponding amide in 63−82% yield. This
indicates that even without chelation of nitrogen, carboxylates
could undergo acyl−oxygen cleavage as well using the reported
conditions. However, it is clear that the yield of N-heteroarene-
2-carboxylate is significantly higher than the others. In addition,
the aminolysis reaction has good generality and tolerates
various functional groups, such as nitro, cyano, bromo, and
trifluoromethyl groups. Our experiments indicated these
substituent groups on the benzene rings of perfluorophenyl
benzoate showed less of an effect on the yields.
a
General conditions: 1a (0.20 mmol), 2 (1.5 equiv), Pd(OAc)2 (5 mol
b
%), 24 h. Isolated yield.
electron-withdrawing groups on the benzene rings of aryl
picolinate 1ba−d are more beneficial to this reaction. Further
experiments showed that naphthyl-2-yl picolinate 1bf as well as
phenyl picolinate performed the aminolysis reaction expedi-
ently to give the same product in 64% yield. But when ethyl
indole-2-carboxylate 1bg react with 2b, no product was
detected. The result indicated that benzene ring in carboxylates
1 is necessary in the aminolysis reaction and could control the
acyl C−O bond cleavage with the aid of palladium.
We also examined the possibility of the aminolysis reaction
of primary and secondary amines using the reported conditions
(Scheme 2). The reaction of n-butylamine 2p and N-
ethylaniline 2q with perfluorophenyl 4-cyanobenzoate 1j
resulted in higher yields of amides than tertiary amine 2a,
possibly because N−H bond activation is easier than C−N
bond activation. Interestingly, when we surveyed the aminolysis
reaction for the common organic base DBU (1,8-
diazabicyclo[5.4.0]undec-7-ene), which contains two nitrogen
To demonstrate the synthetic utility of the method, other
aryl or alkyl picolinates were used instead of perfluorophenyl
picolinate to react with Et3N 2b. As shown in Table 4, all six
aryl picolinates performed this aminolysis reaction to give the
same product 3bb in satisfactory yields. The results show that
B
dx.doi.org/10.1021/jo4023974 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
atoms in cyclic systems, DBU exclusively cleaved the C−N
bond of bridge of the bicyclic moiety to give diamide 3fr.
Therefore, the aminolysis reaction could be used for the ring-
opening reaction of cyclic tertiary amine and then manipulate
the structure of natural products like as cinchona alkaloids.
To gain some insight into the mechanism of the present
aminolysis process, radical scavenger TEMPO was employed in
the standard reaction, and the desired product 3aa was still
obtained in 80% yield (see the Experimental Section). This
result suggested that a free-radical process is not a requirement
for the present reaction. One could imagine that the carboxylate
is first decomposed to the corresponding carboxylic acid, which
then reacts with the amine to form an amide. However, no sign
of amide formation was observed when the reaction was carried
out with quinoline-2-carboxylic acid under the same conditions.
Therefore, we infer that the aminolysis does not proceed via an
carboxylic acid but via intermediate I. To identify a byproduct,
which is formed by the cleavage of the C−N bond, the reaction
solution of 1d with N-benzyl-N-ethylaniline 2s (the higher
molecular weight amine) was detected with GCMS after the
end of the reaction (see the Supporting Information). Two
kinds of aminated products N-benzyl-N-phenylindole-2-carbox-
amide 3ds and 3ds′ (3da) were detected in an almost 35:1
ratio, which indicated that the sterically less hindered ethyl
group is much more facile for cleavage. The GC area % data
showed that along with with 3ds′ a similar amount of
benzaldehyde was obtained. So this aminolysis reaction proceed
via the formation of an iminium intermediate, which would
cause formation of an aldehyde.9 The GCMS analysis of
reaction solution of 2,3-dichlorophenyl picolinate 1bc with 2m
indicated that alkoxyl group of ester eliminated to 2,3-
dichlorophenol (see the Supporting Information).
Table 3. Screening Perfluorophenyl Carboxylates Scope
Table 4. Screening Aryl Groups of Ester
On the basis of the experiments and previously reported
literature, the possible mechanism and intermediates I−V in
the aminolysis pathway are postulated as follows (Scheme 3).
Initially, Pd0, which is generated from Pd(OAc)2, coordinated
with aryl ester 1 to form intermediate I. Then palladium
underwent an oxidative addition with the acyl C−O bond in
aryl ester 1, generating a PdII intermediate II. Compound II
coordinated to the nitrogen of tertiary amine 2 to give
intermediate III.7 Subsequently, the alkoxide attack on the α
position of the tertiary amine resulted in the phenol, generating
iminium-type intermediate IV via the generally accepted
mechanism.7,10 Intermediate IV was then hydrolyzed to be
converted into the intermediate V by elimination of aldehyde.11
Reductive elimination of V results in the desired tertiary amide
3 and regenerate Pd0 to complete the catalytic cycle.
a
Reaction time is 48 h; no reaction in toluene.
Scheme 2. Aminolysis of Primary, Secondary, And Cyclic
Tertiary Amine
In summary, based on our previous work, we found a special
aminolysis reaction of aryl esters 1 with inert tertiary amine 2
by C−O and C−N bond activations for the synthesis of a broad
scope of tertiary amides 3 under neutral and mild conditions.
By using Pd(OAc)2 as a catalyst, without base and ligand,
various carboxylic esters, including N-heteroarene-2-carbox-
ylate, indole-2-carboxylate, furan-2-carboxylate, benzoate, satu-
rated fatty acid ester, and unsaturated fatty acid ester 1a−l,
could undergo aminolysis with trialkyl, triallyl, N,N-dialkylani-
line, and N-alkyl heterocyclic amines 2a−d,f−m and DBU 2r to
furnish versatile tertiary amides 3 in yields up to 91%. This
study not only increased our understanding of the character of
acyl C−O bond activation but also shed important light on how
to further expand its scope and utility. The interesting
selectivity between the Ar−OAc and ArO−Ac bond activations
C
dx.doi.org/10.1021/jo4023974 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Scheme 3. Possible Mechanism of the Aminolysis Reaction
129.9, 129.7, 127.9, 127.6, 127.3, 120.6, 48.8, 45.9, 31.1, 29.8, 20.4,
19.9, 14.0, 13.7; MS (ESI) m/z 285.10 [M + H]+.
deserves further research into changes in traditional ester
chemistry.
N,N-Diallylquinoline-2-carboxamide 3ad: yield 91% (45.8 mg);
1H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 8.4 Hz, 1H), 8.10 (d, J =
EXPERIMENTAL SECTION
■
8.5 Hz, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.79−7.68 (m, 2H), 7.65−7.54
(m, 1H), 6.04−5.86 (m, 2H), 5.37−5.21 (m, 2H), 5.21−5.03 (m, 2H),
4.22 (d, J = 6.0 Hz, 2H), 4.10 (d, J = 5.9 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ 169.0, 153.9, 146.5, 137.0, 133.9, 132.7, 130.0, 129.8,
128.1, 127.6, 127.5, 120.7, 118.0, 117.9, 50.9, 47.7; MS (ESI) m/z
253.10 [M + H]+. Anal. Calcd for C16H16N2O: C, 76.16; H, 6.39; N,
11.10. Found: C, 75.98; H, 6.33; N, 11.29.
N-(4-(4-(Dimethylamino)benzoyl)phenyl)-N-methylquinoline-2-
carboxamide 3af: yield 55% (45.0 mg); 1H NMR (300 MHz, CDCl3)
δ 8.13 (d, J = 8.5 Hz, 1H), 7.89−7.73 (m, 2H), 7.73−7.59 (m, 4H),
7.59−7.45 (m, 3H), 7.21 (d, J = 7.6 Hz, 2H), 6.60 (d, J = 8.9 Hz, 2H),
3.64 (s, 3H), 3.06 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 194.0,
168.6, 153.5, 153.3, 147.0, 146.7, 137.1, 136.7, 132.6(2C), 130.3(2C),
130.0, 129.7, 127.8, 127.6, 127.5, 126.0(2C), 124.5, 120.7, 110.5(2C),
40.02 (3C); MS (ESI) m/z 410.10 [M + H]+. Anal. Calcd for
C26H23N3O2: C, 76.26; H, 5.66; N, 10.26. Found: C, 76.40; H, 5.48;
N, 10.29.
N-Cyclohexyl-N-methylquinoline-2-carboxamide 3ah (stereo-
isomers): yield 64% (34.3 mg); 1H NMR (400 MHz, CDCl3) δ
8.24 (dd, J = 8.4, 3.3 Hz, 2H), 8.17−8.05 (m, 2H), 7.84 (t, J = 7.2 Hz,
2H), 7.80−7.70 (m, 2H), 7.64 (dd, J = 8.3, 7.3 Hz, 2H), 7.61−7.54
(m, 2H), 4.77−4.50 (m, 1H), 3.80−3.62 (m, 1H), 3.07 (s, 3H), 2.94
(s, 2H), 2.00−1.82 (m, 6H), 1.82−1.67 (m, 4H), 1.66−1.44 (m, 6H),
1.12−0.96 (m, 4H); MS (ESI) m/z 269.10 [M + H]+.
1. Preparation of Aryl Esters (1a−l). A mixture of carboxylic acid
(10 mmol), phenol (10 mmol), DMAP (4-(dimethylamino)pyridine, 1
mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiamide hydro-
chloride (EDC·HCl, 10 mmol) in THF (50 mL) was stirred overnight
at 25 °C. The resulting mixture was filtered, and the filtrate was
evaporated in vacuo. The residue was purified by flash column
chromatography (silica gel, ethyl ether/petroleum ether = 1:3 as
eluent) to afford a corresponding aryl ester 1a−l.
2. General Procedure for the Aminolysis Reaction. General
procedure for the aminolysis reaction: A mixture of ester 1 (0.20
mmol), tertiary amine 2 (0.30 mmol), and Pd(OAc)2 (2.25 mg, 0.01
mmol, 5 mol %) in PhCl (1 mL) was sealed in a 30 mL vial. The
reaction mixture was refluxed at 115 °C for 24 h. After being cooled to
room temperature, the mixture was filtered, and the filtrate was
evaporated in vacuo. The residue was purified by flash column
chromatography (silica gel, ethyl acetate/petroleum ether = 1: 2−1: 5
as an eluent) to afford the desired amide 3.
N-Ethyl-N-phenylquinoline-2-carboxamide 3aa: yield 81% (44.2
mg); 1H NMR (300 MHz, CDCl3) δ 7.98 (d, J = 7.9 Hz, 1H), 7.90 (d,
J = 8.0 Hz, 1H), 7.79−7.57 (m, 2H), 7.55−7.35 (m, 2H), 7.25−6.97
(m, 5H), 4.06 (d, J = 6.6 Hz, 2H), 1.27 (t, J = 6.9 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 168.3, 154.2, 146.7, 142.2, 136.3, 129.9, 129.7,
129.4, 129.0, 128.0, 127.5, 127.0, 120.4, 45.2, 12.8; MS (ESI) m/z
277.10 [M + H]+. Anal. Calcd for C18H16N2O: C, 78.24; H, 5.84; N,
10.14. Found: C, 78.17; H, 5.80; N, 10.31.
Piperidin-1-yl(quinolin-2-yl)methanone 3ai:13 yield 62% (29.7
mg); 1H NMR (300 MHz, CDCl3) δ 8.26 (d, J = 8.3 Hz, 1H), 8.12 (d,
J = 8.5 Hz, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.8−7.71 (m, 1H), 7.71−
7.54 (m, 2H), 3.80 (t, J = 5.0 Hz, 2H), 3.51 (t, J = 5.4 Hz, 2H), 1.85−
1.66 (m, 4H), 1.65−1.55 (m, 2H); MS (ESI) m/z 241.10 [M + H]+.
Morpholino(quinolin-2-yl)methanone 3ak:12 yield 65% (31.4
mg); 1H NMR (300 MHz, CDCl3) δ 8.27 (dd, J = 8.2, 4.9 Hz,
1H), 8.10 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 7.7 Hz, 1H), 7.82−7.70 (m,
2H), 7.70−7.52 (m, 1H), 3.87 (t, J = 4.8 Hz, 4H), 3.75 (t, J = 4.3 Hz,
4H); 13C NMR (100 MHz, CDCl3) δ 167.71, 152.96, 146.44, 137.56,
130.36, 129.52, 128.17, 127.90, 127.72, 120.78, 67.02, 66.82, 47.89,
42.92; MS (ESI) m/z 243.05 [M + H]+.
N,N-Diethylquinoline-2-carboxamide 3ab:12 yield 89% (40.6 mg);
1H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 8.4 Hz, 1H), 8.10 (d, J =
8.5 Hz, 1H), 7.85 (d, J = 8.1 Hz, 1H), 7.79−7.71 (m, 1H), 7.66 (d, J =
8.4 Hz, 1H), 7.63−7.56 (m, 1H), 3.63 (q, J = 7.1 Hz, 2H), 3.45 (q, J =
7.1 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 168.9, 154.5, 146.6, 137.1, 130.0, 129.6,
128.0, 127.7, 127.4, 120.2, 43.5, 40.5, 14.4, 12.9; MS (ESI) m/z 229.05
[M + H]+.
N,N-dibutylquinoline-2-carboxamide 3ac:13 yield 90% (51.1 mg);
1H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 8.4 Hz, 1H), 8.09 (d, J =
8.4 Hz, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.78−7.70 (m, 1H), 7.67 (d, J =
8.4 Hz, 1H), 7.63−7.51 (m, 1H), 3.56 (t, J = 7.9 Hz, 2H), 3.43 (t, J =
7.6 Hz, 2H), 1.82−1.57 (m, 4H), 1.44 (td, J = 14.8, 7.3 Hz, 3H), 1.15
(td, J = 14.7, 7.3 Hz, 2H), 1.00 (t, J = 7.3 Hz, 3H), 0.78 (t, J = 7.3 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 168.9, 154.8, 146.6, 136.8,
Pyrrolidin-1-yl(quinolin-2-yl)methanone 3am:12 yield 84% (37.9
mg); 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 8.5 Hz, 1H), 8.10 (d,
J = 8.5 Hz, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.85 (d, J = 8.1 Hz, 1H),
7.78−7.72 (m, 1H), 7.63−7.56 (m, 1H), 3.88 (t, J = 6.4 Hz, 2H), 3.75
(t, J = 6.6 Hz, 2H), 2.04−1.89 (m, 4H); 13C NMR (100 MHz, CDCl3)
D
dx.doi.org/10.1021/jo4023974 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
δ 166.7, 154.1, 146.5, 136.9, 129.9, 129.7, 128.2, 127.7, 127.6, 120.7,
49.3, 47.0, 26.6, 24.1; MS (ESI) m/z 227.05 [M + H]+.
(t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.7, 142.7,
141.8, 138.1, 130.1, 129.6(2C), 128.4(2C), 127.9, 119.6, 44.6, 18.5,
13.0; MS (ESI) m/z 216.10 [M + H]+. Anal. Calcd for C14H17NO: C,
78.10; H, 7.96; N, 6.51. Found: C, 78.15; H, 8.11; N, 6.37.
N-Ethyl-N-phenylpicolinamide 3ba: yield 79% (35.7 mg); 1H
NMR (300 MHz, CDCl3) δ 8.37 (s, 1H), 7.69−7.53 (m, 1H), 7.37 (d,
J = 5.7 Hz, 1H), 7.23−6.92 (m, 6H), 4.01 (q, J = 6.5 Hz, 2H), 1.25 (t,
J = 8.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 168.3, 154.4, 148.4,
142.5, 136.3, 129.0 (2C), 127.9 (2C), 126.8, 123.8, 123.5, 45.1, 12.8;
MS (ESI) m/z 227.05 [M + H]+. Anal. Calcd for C14H14N2O: C,
74.31; H, 6.24; N, 12.38. Found: C, 74.10; H, 6.33; N, 12.29.
N-Ethyl-N-phenylpyrazine-2-carboxamide 3ca: yield 75% (34.1
N-Ethyl-N-phenylpropionamide 3la:18 yield 63% (22.3 mg); H
1
NMR (400 MHz, CDCl3) δ 7.46−7.40 (m, 2H), 7.39−7.33 (m, 1H),
7.21−7.08 (m, 2H), 3.75 (q, J = 7.2 Hz, 2H), 2.04 (q, J = 7.4 Hz, 2H),
1.11 (t, J = 7.2 Hz, 3H), 1.04 (t, J = 7.5 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 174.0, 142.3, 129.7(2C), 128.3(2C), 128.0, 44.2, 27.9,
13.0, 9.7; MS (ESI) m/z 178.10 [M + H]+.
N,N-Diethylpicolinamide 3bb:19 yield 87% (30.9 mg); H NMR
1
1
mg); H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 8.34 (d, J = 26.4
(300 MHz, CDCl3) δ 8.58 (d, J = 4.7 Hz, 1H), 7.89−7.68 (m, 1H),
7.55 (d, J = 7.8 Hz, 1H), 7.40−7.30 (m, 1H), 3.57 (q, J = 7.1 Hz, 2H),
3.36 (q, J = 7.1 Hz, 2H), 1.27 (t, J = 7.0 Hz, 3H), 1.14 (t, J = 7.1 Hz,
3H). MS (ESI) m/z 379.15 [2 M + Na]+.
Hz, 2H), 7.25−7.12 (m, 3H), 7.06 (d, J = 6.7 Hz, 2H), 4.03 (q, J = 6.8
Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
166.1, 150.2, 144.6, 144.3, 143.2, 129.3(2C), 128.0(2C), 127.4, 124.2,
45.22, 12.72; MS (ESI) m/z 228.10 [M + H]+. Anal. Calcd for
C13H13N3O: C, 68.70; H, 5.77; N, 18.49. Found: C, 68.56; H, 5.90; N,
18.28.
N-Butyl-4-cyanobenzamide 3jp:20 yield 87% (35.1 mg); 1H NMR
(500 MHz, CDCl3) δ 7.86 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz,
2H), 6.40 (s, 1H), 3.45 (dd, J = 13.1, 7.1 Hz, 2H), 1.64−1.51 (m, 2H),
1.49−1.33 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 165.8, 138.8, 132.4, 127.7, 118.1, 114.9, 40.1, 31.6, 20.1,
13.8.
N-Ethyl-N-phenylindole-2-carboxamide 3da: yield 82% (43.3
1
mg); H NMR (300 MHz, CDCl3) δ 9.40 (s, 1H), 7.55−7.46 (m,
3H), 7.40−7.28 (m, 4H), 7.25−7.16 (m, 1H), 7.05−6.94 (m, 1H),
5.18 (d, J = 1.1 Hz, 1H), 3.97 (q, J = 7.1 Hz, 2H), 1.27 (t, J = 7.1 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 161.4, 142.4, 135.2, 130.3, 129.8
(2C), 129.1 (2C), 128.6, 127.7, 124.4, 122.2, 120.2, 111.5, 107.0, 45.8,
12.9; MS (ESI) m/z 265.05 [M + H]+. Anal. Calcd for C17H16N2O: C,
77.25; H, 6.10; N, 10.60. Found: C, 77.14; H, 6.31; N, 10.56.
N-Ethyl-N-phenylfuran-2-carboxamide 3ea:14 yield 72% (30.9
mg); 1H NMR (400 MHz, CDCl3) δ 7.45−7.35 (m, 3H), 7.30 (d, J =
1.0 Hz, 1H), 7.21−7.19 (m, J = 1.9 Hz, 1H), 7.19−7.17 (m, 1H), 6.18
(dd, J = 3.5, 1.7 Hz, 1H), 5.74 (d, J = 3.1 Hz, 1H), 3.91 (q, J = 7.1 Hz,
2H), 1.22 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 159.0,
147.1, 144.3, 142.3, 129.6 (2C), 128.5 (2C), 128.1, 116.3, 110.9, 45.5,
12.8; MS (ESI) m/z 216.05 [M + H]+.
1-Benzoyl-1,5-diazacycloundecan-6-one 3fr:21 yield 90% (49.3
1
mg); H NMR (300 MHz, CDCl3) δ 8.00 (s, 1H), 7.97−7.86 (m,
2H), 7.54−7.35 (m, 3H), 3.59−3.48 (m, 2H), 3.48−3.31 (m, 4H),
2.66−2.52 (m, 2H), 1.80−1.68 (m, 8H); 13C NMR (101 MHz,
CDCl3) δ 177.4, 167.1, 134.5, 131.2, 128.5, 127.1, 49.6, 45.0, 37.1,
35.4, 29.9, 28.4, 27.1, 23.4; MS (ESI) m/z 275.10 [M + H]+.
3. Mechanism Studies. 3.1. Radical-Inhibiting Experiment. A
mixture of perfluorophenyl quiline-2-carboxylate 1a (0.25 mmol),
tertiary amine 2a (0.375 mmol), TEMPO (58.9 mg, 0.375 mmol), and
Pd(OAc)2 (5.6 mg, 0.025 mmol, 10 mol %) in PhCl (1 mL) was
sealed in a 30 mL vial. The reaction mixture was refluxed at 115 °C for
24 h. After being cooled to room temperature, the mixture was filtered
and the filtrate was evaporated in vacuo. The residue was purified by
flash column chromatography (silica gel, ethyl ether/petroleum ether
= 1:5) to afford 3aa in 80% yield.
N-Ethyl-N-phenylbenzamide 3fa:15 yield 73% (32.8 mg); 1H
NMR (300 MHz, CDCl3) δ 7.31−7.11 (m, 8H), 7.07−6.98 (m, 2H),
3.99 (q, J = 7.1 Hz, 2H), 1.23 (t, J = 7.1 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 170.8, 142.9, 136.0, 129.6, 129.2 (2C), 128.6(2C),
127.9(2C), 127.7(2C), 126.9, 45.6, 12.9; MS (ESI) m/z 226.05 [M +
H]+.
3.2. Aminolysis Reaction of Carboxylic Acid. A mixture of
quinoline-2- carboxylic acid (0.25 mmol), tertiary amine 2a (0.375
mmol), and Pd(OAc)2 (5.6 mg, 0.025 mmol, 10 mol %) in PhCl (1
mL) was sealed in a 30 mL vial. The reaction mixture was refluxed at
115 °C for 24 h. After being cooled to room temperature, the mixture
was detected by TLC, and no amide was detected.
N-Ethyl-4-nitro-N-phenylbenzamide 3ga:16 yield 69% (37.2 mg);
1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 8.6 Hz, 2H), 7.43 (d, J =
8.7 Hz, 2H), 7.29−7.22 (m, 2H), 7.22−7.17 (m, 1H), 7.02 (d, J = 7.4
Hz, 2H), 4.00 (q, J = 7.1 Hz, 2H), 1.24 (t, J = 7.1 Hz, 3H); MS (ESI)
m/z 271.05 [M + H]+.
ASSOCIATED CONTENT
■
N-Ethyl-N-phenyl-4-(trifluoromethyl)benzamide 3ha: yield 74%
(43.4 mg); 1H NMR (500 MHz, CDCl3) δ 7.46−7.35 (m, 4H), 7.27−
7.21 (m, 2H), 7.21−7.15 (m, 1H), 7.02 (d, J = 7.5 Hz, 2H), 4.00 (q, J
= 6.8 Hz, 2H), 1.23 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3)
δ 168.7, 142.6, 139.9, 131.2 (q, JC−F = 32.4 Hz), 129.4(2C),
128.9(2C), 128.0(2C), 127.2, 124.8, 124.7, 122.6, 45.4, 12.8; MS
(ESI) m/z 294.33 [M + H]+. Anal. Calcd for C16H14F3NO: C, 65.52;
H, 4.81; N, 4.78. Found: C, 65.58; H, 4.71; N, 4.85.
S
* Supporting Information
1H NMR, 13C NMR, and MS spectra and analysis of GCMS.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: sbbys197812@163.com. Fax: (+86)471-4392442.
■
4-Bromo-N-ethyl-N-phenylbenzamide 3ia:17 yield 65% (39.4 mg);
1H NMR (500 MHz, CDCl3) δ 7.28 (d, J = 8.4 Hz, 2H), 7.24 (d, J =
7.8 Hz, 2H), 7.20−7.13 (m, 3H), 7.01 (d, J = 7.6 Hz, 2H), 3.97 (q, J =
7.1 Hz, 2H), 1.21 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
169.1, 142.9, 135.2, 130.9(2C), 130.4(2C), 129.3(2C), 127.9(2C),
126.9, 123.9, 45.5, 12.8; MS (ESI) m/z 304.33 [M + H]+.
4-Cyano-N-ethyl-N-phenylbenzamide 3ja: yield 75% (37.5 mg);
1H NMR (500 MHz, CDCl3) δ 7.45 (d, J = 8.0 Hz, 2H), 7.37 (d, J =
8.1 Hz, 2H), 7.25 (d, J = 7.7 Hz, 2H), 7.20 (d, J = 7.2 Hz, 1H), 7.00
(d, J = 7.5 Hz, 2H), 3.99 (q, J = 6.9 Hz, 2H), 1.23 (t, J = 7.1 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ 168.3, 142.2, 140.7, 131.6(2C),
129.5(2C), 129.1(2C), 128.0(2C), 127.4, 118.2, 113.0, 45.5, 12.8; MS
(ESI) m/z 251.24 [M + H]+. Anal. Calcd for C16H14N2O: C, 76.78; H,
5.64; N, 11.19. Found: C, 76.96; H, 5.61; N, 11.28.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the Opening Project of Natural Science
Foundation of Inner Mongolia (2010KF02) and the Opening
Project of Major Basic Research of Inner Mongolia (20130902)
are gratefully acknowledged.
REFERENCES
■
(1) Yamamoto, A. Advances in Organometallic Chemistry; Academic
Press: New York, 1992; Vol. 34, p 111.
(2E,4E)-N-Ethyl-N-phenylhexa-2,4-dienamide 3ka: yield 64%
(27.5 mg); 1H NMR (300 MHz, CDCl3) δ 7.47−7.34 (m, 3H),
7.29−7.21 (m, 1H), 7.21−7.10 (m, 2H), 6.12−5.90 (m, 2H), 5.59 (d, J
= 14.9 Hz, 1H), 3.84 (q, J = 7.1 Hz, 2H), 1.76 (d, J = 5.8 Hz, 3H), 1.14
(2) (a) Yamamoto, A.; Kakino, R.; Shimizu, I. Helv. Chim. Acta 2001,
84, 2996. (b) Li, Z.; Zhang, S. L.; Fu, Y.; Guo, Q. X.; Liu, L. J. Am.
Chem. Soc. 2009, 131, 8815.
E
dx.doi.org/10.1021/jo4023974 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(3) (a) Gooßen, L. J.; Gooßen, K.; Stanciu, C. Angew. Chem., Int. Ed.
2009, 48, 3569. (b) Trost, B. M.; Vranken, D. L. V. Chem. Rev. 1996,
96, 395. (c) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921.
(d) Yu, D. G.; Li, B. J.; Shi, Z. J. Acc. Chem. Res. 2010, 43, 1486.
(e) Zapf, A. Angew. Chem., Int. Ed. 2003, 42, 5394.
(4) Yamamoto, T.; Ishizu, J.; Kohara, T.; Komiya, S.; Yamamoto, A. J.
Am. Chem. Soc. 1980, 102, 3758.
(5) Catalysis using acyl C−O activation: (a) Hoang, G. T.; Reddy, V.
J.; Nguyen, H. H. K.; Douglas, C. J. Angew. Chem., Int. Ed. 2011, 50,
1882. (b) Ooguri, A.; Nakai, K.; Kurahashi, T.; Matsubara, S. J. Am.
Chem. Soc. 2009, 131, 13194. (c) Murai, M.; Miki, K.; Ohe, K. Chem.
Commun. 2009, 3466. (d) Tatamidani, H.; Yokota, K.; Kakiuchi, F.;
Chatani, N. J. Org. Chem. 2004, 69, 5615. (e) Tatamidani, H.;
Kakiuchi, F.; Chatani, N. Org. Lett. 2004, 6, 3597. (f) Gooβen, L.;
Paetzold, J. Angew. Chem., Int. Ed. 2002, 41, 1237. (g) Chantani, N.;
Tatamidani, H.; Ie, Y.; Kakiuchi, F.; Murai, S. J. Am. Chem. Soc. 2001,
123, 4849.
(6) Bao, Y. S.; Chen, C. Y.; Huang, Z. Z. J. Org. Chem. 2012, 77,
8344.
(7) (a) Murahashi, S. I.; Hirano, T.; Yano, T. J. Am. Chem. Soc. 1978,
100, 348. (b) Lei, Y.; Wrobleski, A. D.; Golden, J. E.; Powell, D. R.;
́
Aube, J. J. Am. Chem. Soc. 2005, 127, 4552.
(8) (a) Sakakibara, T.; Karasumaru, S.; Kawano, I. J. Am. Chem. Soc.
1985, 107, 22. (b) Murata, S.; Miura, M.; Nomura, M. J. Chem. Soc.,
Chem. Commun. 1989, 116.
(9) Murata, S.; Miura, M.; Nomura, M. J. Org. Chem. 1989, 54, 4700.
(10) (a) North, M. Angew. Chem., Int. Ed. 2004, 43, 4126.
(b) Murahashi, S. I.; Komiya, N.; Terai, H.; Nakae, T. J. Am. Chem.
Soc. 2003, 125, 15312. (c) Murahashi, S. I.; Komiya, N.; Terai, H.
Angew. Chem., Int. Ed. 2005, 44, 6931.
(11) Guo, S. M.; Qian, B.; Xie, Y. J.; Xia, C. G.; Huang, H. M. Org.
Lett. 2011, 13, 522.
(12) Wang, X.; Wang, D. Z. Tetrahedron 2011, 67, 3406.
(13) Coppa, F.; Fontana, F.; Lazzarini, E.; Minisci, F. Heterocycles
1993, 36, 2687.
(14) Maxim, N.; Zugravescu, I.; Fulga, I. Bull. Soc. Chim. Fr. 1939, 6,
1339.
(15) Voronkov, M. G.; Tsyrendorzhieva, I. P.; Rakhlin, V. I. Russ. J.
Org. Chem. 2008, 44, 481.
(16) Schroeder, W. A.; Wilcox, P. E. J. Am. Chem. Soc. 1950, 72, 4309.
(17) CAS no.: 330568-12-2.
(18) Toshiaki, K.; Masato, T. J. Organomet. Chem. 1982, 231, 12.
(19) CAS no.: 6320-61-2.
(20) Goh, K. S.; Tan, C.-H. RSC Adv. 2012, 2, 5536.
(21) Balogh, J.; Kuika, A.; Urge, L.; Darvas, F.; Bakos, J.; Skoda-
Foldes, R. J. Mol. Catal A: Chem. 2009, 302, 76.
F
dx.doi.org/10.1021/jo4023974 | J. Org. Chem. XXXX, XXX, XXX−XXX