Copper-catalyzed dehydrogenative reaction: Synthesis of amide from aldehydes and aminopyridine

Article abstract of DOI:10.1016/j.tet.2013.05.072

We have developed a highly efficient method in the presence of copper catalyst to form amides from aminopyridines and aldehydes. This method is simple, environmental benign and has practical advantages in the amide synthesis.

Full text of DOI:10.1016/j.tet.2013.05.072

Tetrahedron xxx (2013) 1e5
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Copper-catalyzed dehydrogenative reaction: synthesis of amide
from aldehydes and aminopyridine
Sizhuo Yang, Hao Yan, Xiaoyu Ren, Xiaokang Shi, Jian Li, Yuling Wang,
*
Guosheng Huang
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
We have developed a highly efficient method in the presence of copper catalyst to form amides from
aminopyridines and aldehydes. This method is simple, environmental benign and has practical advan-
tages in the amide synthesis.
Received 27 March 2013
Received in revised form 13 May 2013
Accepted 20 May 2013
Available online xxx
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
One-pot
Aldehydes
Amide bond formation
Copper
Dehydrogenative cross-coupling
1. Introduction
transition-metal complexes (such as Cu,12aec Rh,12d Ru,12e Pd,12f Ni,12g
Au,12h Fe12i) and extra oxidant. Besides, metal-free oxidative ami-
The amide bond is a key functional group in organic chemistry. It
plays an important role in the composition of polymers, proteins,
natural products, and pharmaceuticals.1 The most common synthetic
route to these nitrogen-containing compounds relies heavily on the
reactions of activated carboxylic acids and their derivatives with
amines.2 However, this method has the innate drawbacks, for in-
stance, a large amount of byproducts are generated and the activated
carboxylic acid derivatives are not stable. Over the past few years,
alternative procedures of amide synthesis have been developed,
including an azide based modified Staudinger reaction,3 hydrative
reactions between alkynes and azides,4 carbonylation of aryl chlo-
rides to the corresponding amides,5 and oxidative coupling of an
R-bromonitroalkane.6 Recently, direct aldehyde amidation with
amines has drawn attention owing to its economical and the abun-
dant nature of starting materials, for example, the radical-mediated
oxidative amidation with radical initiators7 and light,8 the amida-
tion via Cannizzaro reactions using lithium diisopropylamide (LDA)9
or lanthanide reagents,10 and the NHC catalyst amidation11 were
reported. However, most catalytic amidation processes need
dation from aldehydes13 and the direct oxidative amidation from
alcohols have also been reported.14 Noteworthy all these reactions
require relatively harsh conditions such as light, expensive oxidant,
strong bases or high temperature, so there is still a need for easy and
efficient methods to construct amide bond.
N-(Pyridin-2-yl)benzamide as an important pharmacophore is
widely found in many bioactive compounds, such as the com-
pounds shown in Fig. 1, compound a is a luciferase inhibitor and the
same structure of a has been patented for osteoporosis treatment;15
compound b can be accommodated in the luciferin binding site;16
a series of compound c showed antiulcer activity.17 Recently, we
have developed a simple amidation of this kind of compounds with
copper salts as the catalyst, no other extra oxidant and strong base
are used.
O
O
R
O
N
N
H
N
N
H
N
N
H
NH2
a
b
c
* Corresponding author. Tel.: þ86 931 8912593; fax: þ86 931 8912582; e-mail
address: hgs@lzu.edu.cn (G. Huang).
Fig. 1. Examples illustrating the importance of aminopyridine amide.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.05.072
Please cite this article in press as: Yang, S.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.05.072

2
S. Yang et al. / Tetrahedron xxx (2013) 1e5
Table 2
2. Results and discussions
Copper-catalyzed oxidative amidation of aldehydesa
R2
Initially, benzaldehyde 1a and pyridine-2-amine 2a were chosen
as model substrates for surveying the reaction parameters. Firstly,
the reaction was carried out with CuI at 80 ꢀC in N,N-dime-
thylformamide (DMF). Gratifyingly, the desired N-(pyridin-2-yl)
benzamide 3aa was obtained in 45% after 6 h (Table 1, entry 1).
Then we tried other copper salts and some iron salts to improve the
yield, but no satisfied result was achieved (Table 1, entries 2e5).
When we prolonged the reaction time from 6 h to 12 h, the yield
increased to 73%, and after 24 h, we got a yield of 92% (Table 1,
entries 6 and 7). A reduced amount of CuI gave lower yield (Table 1,
entry 10). As expected, no target product was obtained in the ab-
sence of catalyst (Table 1, entry 11). Furthermore, when O2 was
employed as the oxidant, 85% of desired product was isolated (Table
1, entry 12). Thus, air was chosen as oxidant for its abundance, low
cost, and convenience. Switching the reaction solvent like DMA,
DMSO, CH3CN or NMP didn’t further improve the yield (Table 1,
entries 13e16), and the yield decreased either raised or lowered the
temperature (Table 1, entries 8 and 9). Ultimately, the optimized
conditions were identified (Table 1, entry 7).
O
CuI 80oC
CHO
R2
N
H
N
+
R1
R1
N
NH2
DMF
1a-n
Entry
2a-j
3
R1
R2
Product
Yield (%)
1
2
3
4
5
6
7
8
H
4-Cl
4-Br
4-CH3
4-OCH3
2-Br
2-OCH3
2-F
2-Cl
2,4-Di-Cl
3,4-Di-CH3
3,4-Di-OCH3
Piperonyl
Furyl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
92
82
71
90
85
30
94
58
56
66
82
87
83
45
89
48
74
50
28
Trace
86
53
55
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
3ja
3ka
3la
3ma
3na
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
H
H
4-CH3
4-Cl
Table 1
H
H
5-CH3
5-F
Optimization of the reaction conditionsa
H
H
6-CH3
6-Cl
O
CHO
4-OCH3
4-OCH3
H
4-CH3
4-Cl
4-COOEt
catalyst
olvent
N
H
N
+
N
NH2
3aj
1a
2a
a
3aa
Reaction condition: The reaction was carried out using 1aen (0.47 mmol), 2aej
(0.34 mmol), and catalyst (0.03 mmol) in 2 mL DMF for 24 h at 80 ꢀC.
Entry
Catalyst
Oxidant
Solvent
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
CuI
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
O2
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMA
DMSO
CH3CN
NMP
6
6
6
6
6
12
24
24
24
24
24
24
24
24
24
24
45
20
17
5
32
73
92
63b
80c
35d
0
lower yields (Table 2, entries 6, 8, and 9). To our disappointment,
when other electron-withdrawing groups such as o-NO2, p-NO2 were
tested, only a trace amount of product was detected on the silica gel.
Furthermore, the reaction of the heteroatom-containing aromatic
aldehydes also proceeded efficiently (Table 2, entries 13 and 14).
Subsequently, the substrate scope of aminopyridines was fur-
ther investigated. With the comparison of electron-withdrawing
and electron-donating groups in positions 4, 5, and 6 of amino
(Table 2, entries 15e22), the reaction exhibited the similar activi-
ties, the results indicated that electron-donating 2-aminopyridines
were successfully employed and gave higher yields (Table 2, entries
15 and 17) than those with electron-deficient substituent (Table 2,
entries 16 and 18). However 1a reacted with 2f to produce 3af in
only 28% yield, and nearly trace desired product 3ag could get. This
may be due to the steric hindrance on the pyridine ring, especially
on the electron-deficient functional group. Moreover, different
2-amino heterocycles were also tested (Table 2, entry 23). When
2-aminopyrimidine was subjected to the reaction system, no
reaction was observed, and 2-aminobenzimidazole also didn’t react
as the desired product was not detected.
CuBr
CuCl
Cu(OAc)2
FeCl2
CuI
CuI
CuI
CuI
CuI
d
9
10
11
12
13
14
15
16
CuI
CuI
CuI
CuI
85
87
42
0
Air
Air
Air
Air
CuI
Trace
a
Reaction condition: The reaction was carried out using 1a (0.47 mmol), 2a
(0.34 mmol), and catalyst (0.03 mmol) in 2 mL DMF for 24 h at 80 ꢀC.
b
Reaction condition: The reaction was carried out using 1a (0.47 mmol), 2a
(0.34 mmol), and catalyst (0.03 mmol) in 2 mL DMF for 24 h at 60 ꢀC.
c
Reaction condition: The reaction was carried out using 1a (0.47 mmol), 2a
(0.34 mmol), and catalyst (0.03 mmol) in 2 mL DMF for 24 h at 100 ꢀC.
d
The reaction was carried out using 1a (0.47 mmol), 2a (0.34 mmol), and catalyst
(0.015 mmol) in 2 mL DMF for 24 h at 80 ꢀC.
It is noteworthy that when benzaldehyde was replaced with
corresponding benzoic acid, the expected amide was not achieved
under the optimized reaction conditions. Therefore, the possibility
that amide formation may arise from a transamidation reaction
with a carboxylic acid origin from the direct oxidation of the al-
dehyde should be excluded. Based on the above results, a plausible
mechanism for the direct oxidative amidation of aldehydes for
amide formation is shown in Scheme 1. Intermediate C can be
obtained through complexation under the influence of the Cu(I)
salt. After that the nucleophilic attack of amino to the carbonyl
functional group and the further proton transfer gave a hemiaminal
E, which then may be oxidized by oxygen to produce the target
product F. However, imines couldn’t be employed as the starting
substrates to accomplish the amidation reaction to generate the
target products directly.
Under the optimized reaction conditions, we examined a series of
benzaldehydes and aminopyridines to establish the scope and limi-
tation of the process, and the results are illustrated in Table 2. To our
delight, awiderange of substitutedgroups attached to benzaldehydes
or aminopyridines all give a good yield although the nature of the
substituent in pyridine ring had some influence on the yield. Gener-
ally, benzaldehydes substituted with electron-donating groups
showed better reactivity and a higher yield (Table 2, entries 2e12).
Interestingly, electron-deficient substituent on position-2 of the
benzaldehyde seems have a bad impact, such as chloro and bromo
groups, but the electron-rich ones still give a high yield, such as
methyl and methoxy groups (Table 2, entries 6e10). As a result of the
steric effects from the substituent, the 2-substituted aldehydes show
Please cite this article in press as: Yang, S.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.05.072

S. Yang et al. / Tetrahedron xxx (2013) 1e5
3
(m, 1H), 7.42 (d, J¼8.4 Hz, 2H), 7.04e7.01 (m, 1H); 13C NMR
O
+
(100 MHz, CDCl3):
d 165.0, 151.6, 147.7, 138.5, 138.4, 132.7, 128.9,
Ph
N
NH2
N
NH2
NH2
Ph
N
128.7, 120.0, 114.5; IR (neat, cmꢁ1) 3415, 3197, 3045, 2245, 1673,
1601, 1452, 1308, 1245, 1010, 836, 743, 733; HRMS (ESI) calcd for
Cu(I)
A
Ph
B
Cu
Cu
O
O
D
12H10ClN2O [MþH]þ: 233.0487; found: 233.0482.
C
C
4.2.3. 4-Bromo-N-(pyridin-2-yl)benzamide (3ca). Compound 3ca
was prepared from 1c and 2a according to the typical experimental
procedure shown in Section 4.2.1. Yellow solid (66 mg, 71%). Mp
Cu(I)
O
OH
Ph
132e134 ꢀC; 1H NMR (400 MHz, CDCl3):
d 9.29 (br s, 1H), 8.37 (d,
O
N
NH
F
Ph
J¼8.4 Hz, 1H), 8.13 (s, 1H), 7.80 (d, J¼8.4 Hz, 2H), 7.75 (t, J¼0.8 Hz,
1H), 7.62e7.59 (m, 2H), 7.05 (d, J¼4.8 Hz, 1H); IR (neat, cmꢁ1) 3410,
3185, 3042, 2240, 1678, 1597, 1432, 1354, 1245, 1006, 909, 832, 731;
HRMS (ESI) calcd for C12H10BrN2O [MþH]þ: 276.9979; found:
276.9977.
N
NH
E
Scheme 1. Proposed mechanism of the reaction.
3. Conclusion
4.2.4. 4-Methyl-N-(pyridin-2-yl)benzamide (3da). Compound 3da
was prepared from 1d and 2a according to the typical experimental
procedure shown in Section 4.2.1. Yellow solid (65 mg, 90%). Mp
We have demonstrated a one-pot, efficient copper-catalyst
dehydrogenative cross-coupling to form amides from amino-
pyridines and aldehydes. Using a simple catalyst and air as the
oxidant, the protocol can achieve excellent yields. This current
development makes the environmentally benign and economical
acylation of amines directly with aldehydes come true, which has
wide range of applications in organic synthesis.
100e102 ꢀC; 1H NMR (400 MHz, CDCl3):
d 9.03 (br s, 1H), 8.40 (t,
J¼6.8 Hz, 1H), 8.20 (s, 1H), 7.84e7.80 (m, 2H), 7.74 (d, J¼6.8 Hz, 1H),
7.27 (s, 2H), 7.03 (d, J¼4.8 Hz, 1H), 2.42 (s, 3H); 13C NMR (100 MHz,
CDCl3):
d 165.8, 151.7, 147.8, 142.8, 138.4, 131.4, 129.4, 127.3, 119.7,
114.2, 21.5; IR (neat, cmꢁ1) 3414, 3080, 3028, 2918, 2240, 1673,
1600, 1430, 1323, 1259, 825, 749, 730; HRMS (ESI) calcd for
C
13H13N2O [MþH]þ: 213.1024; found: 213.1028.
4. Experimental
4.1. General
4.2.5. 4-Methoxy-N-(pyridin-2-yl)benzamide (3ea). Compound 3ea
was prepared from 1e and 2a according to the typical experimental
procedure shown in Section 4.2.1. Yellow solid (66 mg, 85%). Mp
Column chromatography was carried out on silica gel. 1H NMR
spectra were recorded on 400 MHz in CDCl3 and 13C NMR spectra
were recorded on 100 MHz in CDCl3 using TMS as internal standard.
IR spectra were recorded on an FT-IR spectrometer and only major
peaks are reported in cmꢁ1. All new compounds were further
characterized by HRMS; copies of their 1H NMR and C NMR spectra
are provided. All melting points were determined without correc-
tion. Commercially available reagents and solvents were used
without further purification.
99e102 ꢀC; 1H NMR (400 MHz, CDCl3):
d 9.32 (br s, 1H), 8.40 (d,
J¼8.4 Hz, 1H), 8.16e8.15 (m, 1H), 7.91 (d, J¼8.8 Hz, 2H), 7.72 (dd,
J¼8, 7.2 Hz, 1H), 7.02e6.99 (m, 1H), 6.94 (d, J¼7.6 Hz, 1H), 6.93 (s,
1H), 3.84 (s, 3H); 13C NMR (100 MHz, CDCl3):
d 165.5, 162.6, 151.9,
147.6, 138.3, 129.2, 126.4, 119.5, 114.3, 113.8, 55.3; IR (neat, cmꢁ1
)
3365, 3084, 3006, 2944, 2231, 1701, 1583, 1436, 1342, 1248, 1165,
838, 780, 734; HRMS (ESI) calcd for C13H13N2O2 [MþH]þ: 229.0978;
found: 229.0977.
4.2.6. 2-Bromo-N-(pyridin-2-yl)benzamide (3fa). Compound 3fa
was prepared from 1f and 2a according to the typical experimental
procedure shown in Section 4.2.1. Yellow solid (28 mg, 30%). Mp
4.2. Reactions of benzaldehyde 1aen with pyridine-2-amine
2aei
82e84 ꢀC; 1H NMR (400 MHz, CDCl3):
d
9.13 (d, J¼12.8 Hz, 1H), 8.39
4.2.1. Typical procedure for the preparation of N-(pyridin-2-yl)ben-
zamide (3aa). A test tube was charged with 1a (0.47 mmol), 2a
(0.34 mmol), and CuI (5.73 mg, 0.03 mmol). Then 2 mL DMF was
added to the reaction system. The reaction mixture was stirred at
80 ꢀC for 24 h. After cooling to room temperature, the solvent was
diluted with 10 mL ethyl acetate and washed with 5 mL brine and
dried over anhydrous Na2SO4. After the solvent was evaporated in
vacuo, the residue was purified by column chromatography, eluting
with petroleum ether/EtOAc (5:1) to afford N-(pyridin-2-yl)ben-
zamide 3aa (62 mg, 92% yield) as yellow solid. Mp 80e82 ꢀC; 1H
(d, J¼8.4 Hz, 1H), 8.32 (dd, J¼4.8, 0.8 Hz, 1H), 8.17e8.13 (m, 1H),
7.78e7.74 (m, 1H), 7.57e7.52 (m, 1H), 7.34e7.30 (m, 1H), 7.22e7.17
(m, 1H), 7.10e7.07 (m, 1H); 13C NMR (100 MHz, CDCl3):
d 161.7,
159.2,151.3,148.0,138.4,134.1,132.0,125.0,121.2,120.1, 116.5,114.6;
IR (neat, cmꢁ1) 3385, 3067, 2248, 1732, 1597, 1503, 1462, 1320, 1248,
788, 731; HRMS (ESI) calcd for C12H10BrN2O [MþH]þ: 276.9981;
found: 276.9977.
4.2.7. 2-Methoxy-N-(pyridin-2-yl)benzamide (3ga). Compound 3ga
was prepared from 1g and 2a according to the typical experimental
procedure shown in Section 4.2.1. Yellow solid (73 mg, 94%). Mp
NMR (400 MHz, CDCl3):
d
8.85 (br s, 1H), 8.40 (d, J¼8.4 Hz, 1H), 8.23
(d, J¼4 Hz, 1H), 7.93 (d, J¼7.2 Hz, 1H), 7.918 (s, 1H), 7.78e7.74 (m,
1H), 7.59e7.55 (m, 1H), 7.51e7.48 (m, 2H), 7.06 (dd, J¼6.8, 5.2 Hz,
70e72 ꢀC; 1H NMR (400 MHz, CDCl3):
d 10.36 (br s, 1H), 8.44 (d,
J¼8.4 Hz, 1H), 8.32e8.31 (m, 1H), 8.27 (dd, J¼7.6, 1.6 Hz, 1H),
1H); 13C NMR (100 MHz, CDCl3):
d 165.8, 151.6, 147.9, 138.5, 134.3,
7.74e7.70 (m, 1H), 7.52e7.47 (m, 1H), 7.12 (t, J¼7.2 Hz, 1H),
132.2, 128.8, 127.2, 119.9, 114.2; IR (neat, cmꢁ1) 3412, 3110, 3030,
2241, 1665, 1595, 1458, 1301, 1260, 773, 753, 700; HRMS (ESI) calcd
for C12H11N2O [MþH]þ: 199.0875; found: 199.0871.
7.05e7.01 (m, 2H), 4.05 (s, 3H); 13C NMR (100 MHz, CDCl3):
d 163.5,
157.4, 151.9, 147.9, 138.1, 133.5, 132.3, 121.3, 121.2, 119.5, 114.6, 111.4,
56.1; IR (neat, cmꢁ1) 3345, 3069, 2975, 2840,1670,1600,1463,1435,
1310, 1240, 1020, 777, 755, 681; HRMS (ESI) calcd for C13H13N2O2
[MþH]þ: 229.0974; found: 229.0977.
4.2.2. 4-Chloro-N-(pyridin-2-yl)benzamide(3ba). Compound 3ba
was prepared from 1b and 2a according to the typical experimental
procedure shown in Section4.2.1. White solid (64 mg, 82%). Mp
4.2.8. 2-Fluoro-N-(pyridin-2-yl)benzamide (3ha). Compound 3ha
was prepared from 1h and 2a according to the typical experimental
procedure shown in Section 4.2.1. Yellow solid (43 mg, 58%). Mp
136e138 ꢀC; 1H NMR (400 MHz, CDCl3):
d
9.47 (br s, 1H), 8.38 (d,
J¼8.4 Hz, 1H), 8.08e8.07 (m, 1H), 7.87 (d, J¼8.4 Hz, 2H), 7.76e7.72
Please cite this article in press as: Yang, S.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.05.072

4
S. Yang et al. / Tetrahedron xxx (2013) 1e5
162e164 ꢀC; 1H NMR (400 MHz, CDCl3):
d
9.90 (br s, 1H), 8.39 (d,
735; HRMS (ESI) calcd for C13H10N2O3 [MþH]þ: 242.0693; found:
J¼8.4 Hz, 1H), 7.75e7.69 (m, 1H), 7.68 (d, J¼4.4 Hz, 1H), 7.61e7.57
242.0691.
(m, 2H), 7.39 (dd, J¼7.6, 1.2 Hz, 1H), 7.36e7.27 (m, 1H), 6.94e6.91
(m, 1H); 13C NMR (100 MHz, CDCl3):
d
166.3, 151.5, 147.4, 138.6,
4.2.14. N-(Pyridin-2-yl)furan-2-carboxamide (3na). Compound 3na
was prepared from 1n and 2a according to the typical experimental
procedure shown in Section 4.2.1. Yellow solid (29 mg, 45%). Mp
137.9, 133.5, 131.6, 129.3, 127.6, 120.0, 119.5, 114.6; IR (neat, cmꢁ1
)
3357, 3080, 1735, 1650, 1576, 1423, 1202, 1034, 898, 778, 752; HRMS
(ESI) calcd for C12H10FN2O [MþH]þ: 217.0775; found: 217.0777.
70e74 ꢀC; 1H NMR (400 MHz, CDCl3):
d 8.81 (br s, 1H), 8.33 (d,
J¼8.4 Hz, 2H), 7.76e7.72 (m, 1H), 7.53 (s, 1H), 7.28 (d, J¼3.6 Hz, 1H),
4.2.9. 2-Chloro-N-(pyridin-2-yl)benzamide (3ia). Compound 3ia
was prepared from 1i and 2a according to the typical experimental
procedure shown in Section 4.2.1. White solid (44 mg, 56%). Mp
7.07 (dd, J¼7.2, 5.2 Hz, 1H), 6.57 (dd, J¼4.8, 1.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3):
d 156.1, 151.0, 148.0, 147.3, 144.7, 138.4, 119.9,
115.8, 114.1, 112.6; IR (neat, cmꢁ1) 3400, 3231, 3118, 3065, 2247,
1678,1595,1578,1522,1434,1310,1269,1228,1166, 776, 758; HRMS
(ESI) calcd for C10H9N2O2 [MþH]þ: 189.0667; found: 189.0664.
134e138 ꢀC; 1H NMR (400 MHz, CDCl3):
d 10.37 (br s, 1H), 8.40 (d,
J¼8.4 Hz, 1H), 7.73e7.69 (m, 1H), 7.62 (d, J¼7.6 Hz, 1H), 7.53 (dd,
J¼4.8, 1.2 Hz, 1H), 7.39e7.38 (m, 2H), 7.35e7.30 (m, 1H), 6.89e6.86
(m, 1H); 13C NMR (100 MHz, CDCl3):
d
165.6, 151.6, 147.2, 138.5,
4.2.15. N-(4-Methylpyridin-2-yl)benzamide (3ab). Compound 3ab
was prepared from 1a and 2b according to the typical experimental
procedure shown in Section 4.2.1. Yellow solid (64 mg, 89%). Mp
135.6, 131.4, 131.0, 130.2, 129.4, 127.0, 119.8, 114.6; IR (neat, cmꢁ1
)
3450, 3233, 3076, 2236, 1674, 1502, 1456, 1438, 1352, 1244, 1124,
1009, 756, 737; HRMS (ESI) calcd for C12H10ClN2O [MþH]þ:
233.0486; found: 233.0482.
110e112 ꢀC; 1H NMR (400 MHz, CDCl3):
d 9.21 (br s,1H), 8.26 (s,1H),
7.97 (d, J¼5.2 Hz, 1H), 7.93 (s, 1H), 7.91 (s, 1H), 7.55 (t, J¼7.2 Hz, 1H),
7.48e7.45 (m, 2H), 6.84 (d, J¼4.8 Hz, 1H), 2.39 (s, 1H); 13C NMR
4.2.10. 2,4-Dichloro-N-(pyridin-2-yl)benzamide (3ja). Compound
3ja was prepared from 1j and 2a according to the typical experi-
mental procedure shown in Section 4.2.1. White solid (60 mg, 66%).
(100 MHz, CDCl3): d 166.0, 151.7, 150.0, 147.3, 134.4, 132.0, 128.7,
127.3, 121.0, 114.8, 21.4; IR (neat, cmꢁ1) 3412, 3180, 3053, 2915,
2243, 1693, 1605, 1512, 1492, 1380, 798, 772, 731, 700; HRMS (ESI)
calcd for C13H13N2O [MþH]þ: 213.1031; found: 213.1028.
Mp 122e124 ꢀC; 1H NMR (400 MHz, CDCl3):
d 10.16 (br s, 1H), 8.37
(d, J¼8.4 Hz, 1H), 7.77e7.72 (m, 1H), 7.69 (d, J¼4.8, 1H), 7.58 (d,
J¼8 Hz, 1H), 7.40 (d, J¼2 Hz, 1H), 7.31 (dd, J¼8.4, 2 Hz, 1H), 6.96 (dd,
4.2.16. N-(4-Chloropyridin-2-yl)benzamide (3ac). Compound 3ac
was prepared from 1a and 2b according to the typical experimental
procedure shown in Section 4.2.1. White solid (38 mg, 48%). Mp
J¼6.8, 5.2 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d 164.4, 151.4, 147.2,
138.7, 137.0, 133.9, 132.0, 130.5, 130.1, 127.4, 120.1, 114.7; IR (neat,
cmꢁ1) 3405, 3081, 3016, 1673, 1599, 1500, 1432, 1357, 1280, 1101,
115e118 ꢀC; 1H NMR (400 MHz, CDCl3):
d 8.87 (br s, 1H), 8.50 (d,
828, 777, 733; HRMS (ESI) calcd for
267.0095; found: 267.0092.
C
12H9Cl2N2O [MþH]þ:
J¼2 Hz, 1H), 8.10 (d, J¼5.2 Hz, 1H), 7.92e7.90 (m, 1H), 7.60e7.57 (m,
1H), 7.52e7.48 (m, 2H), 7.06 (dd, J¼5.6, 2 Hz,1H); 13C NMR (100 MHz,
CDCl3):
d 165.8, 152.5, 148.5, 146.0, 133.9, 132.5, 128.9, 127.2, 120.3,
4.2.11. 3,4-Dimethyl-N-(pyridin-2-yl)benzamide (3ka). Compound
3ka was prepared from 1k and 2a according to the typical experi-
mental procedure shown in Section 4.2.1. Yellow solid (63 mg, 82%).
114.3; IR (neat, cmꢁ1) 3415, 3230, 3104, 3064, 3030, 2873, 2251,
1681, 1566, 1518, 1492, 1403, 1285, 1095, 879, 818, 796, 710; HRMS
(ESI) calcd for C12H10ClN2O [MþH]þ: 233.0487; found: 233.0482.
Mp 101e103 ꢀC; 1H NMR (400 MHz, CDCl3):
d 9.17 (br s, 1H), 8.41 (d,
J¼8.4 Hz,1H), 8.14 (d, J¼4.4 Hz,1H), 7.73 (d, J¼8 Hz, 2H), 7.70 (s,1H),
4.2.17. N-(5-Methylpyridin-2-yl)benzamide (3ad). Compound 3ad
was prepared from 1a and 2d according to the typical experimental
procedure shown in Section 4.2.1. Yellow solid (53 mg, 74%). Mp
7.65 (d, J¼8 Hz, 1H), 7.00 (t, J¼5.6 Hz, 1H), 2.30 (s, 3H), 2.28 (s, 3H);
13C NMR (100 MHz, CDCl3):
d 166.0, 151.8, 147.7, 141.3, 138.3, 137.0,
131.7, 129.8, 128.5, 124.7, 119.5, 114.2, 19.7, 19.6; IR (neat, cmꢁ1
)
100e102 ꢀC; 1H NMR (400 MHz, CDCl3):
d 9.06 (br s, 1H), 8.30 (d,
3240, 3054, 3024, 2973, 2943, 2246, 1676, 1611, 1594, 1500, 1432,
1384, 1263, 1149, 1108, 811, 778, 752, 733; HRMS (ESI) calcd for
C
J¼8.4 Hz, 1H), 7.96 (s, 1H), 7.92 (t, J¼7.6 Hz, 2H), 7.55 (t, J¼2 Hz, 1H),
7.54e7.53 (m, 1H), 7.49e7.45 (m, 2H), 2.27 (s, 3H); 13C NMR
14H15N2O [MþH]þ: 227.1188; found: 227.1184.
(100 MHz, CDCl3): d 165.6, 157.0, 15.8, 138.7, 134.4, 132.2, 128.8,
127.2, 119.4, 110.9, 24.0; IR (neat, cmꢁ1) 3407, 3196, 3051, 2937,
1688, 1526, 1430, 1245, 1072, 835, 773, 736, 700; HRMS (ESI) calcd
for C13H13N2O [MþH]þ: 213.1032; found: 213.1028.
4.2.12. 3,4-Dimethoxy-N-(pyridin-2-yl)benzamide (3la). Compound
3la was prepared from 1l and 2a according to the typical experi-
mental procedure shown in Section 4.2.1. Yellow solid (76 mg, 87%).
Mp 122e125 ꢀC; 1H NMR (400 MHz, CDCl3):
d
9.19 (d, J¼20.4 Hz,
4.2.18. N-(5-Fluoropyridin-2-yl)benzamide (3ae). Compound 3ae
was prepared from 1a and 2e according to the typical experimental
procedure shown in Section 4.2.1. Yellow solid (37 mg, 50%). Mp
1H), 8.39 (d, J¼8.4 Hz, 1H), 8.20 (d, J¼4.4 Hz, 1H), 7.74e7.72 (m, 1H),
7.53e7.50 (m, 2H), 7.05e7.02 (m, 1H), 6.89 (d, J¼7.6 Hz, 1H), 3.93 (s,
3H), 3.92 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
165.4, 152.3, 151.8,
106e108 ꢀC; 1H NMR (400 MHz, CDCl3):
d 8.74 (br s, 1H), 8.43 (dd,
149.0, 147.7, 138.4, 126.7, 120.2, 120.2, 119.6, 114.2, 110.3, 55.9, 55.9;
IR (neat, cmꢁ1) 3255, 3077, 3023, 2903, 1500, 1450, 1230, 915, 838,
754; HRMS (ESI) calcd for C14H15N2O3 [MþH]þ: 259.1086; found:
259.1083.
J¼9.2, 4.4 Hz, 1H), 8.09 (d, J¼2.8 Hz, 1H), 7.91 (d, J¼7.2 Hz, 1H), 7.90
(s, 1H), 7.60e7.56 (m, 1H), 7.52e7.50 (m, 1H), 7.49 (t, J¼1.6 Hz, 1H),
7.47 (d, J¼2.8 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d 165.5, 157.7,
155.2, 147.8, 135.5, 135.3, 134.0, 132.3, 128.9, 127.2, 125.4, 125.2,
114.9; IR (neat, cmꢁ1) 3455, 3284, 3086, 3055, 1651, 1532, 1508,
1368, 1203, 1120, 808, 771, 698; HRMS (ESI) calcd for C12H10FN2O
[MþH]þ: 217.0775; found: 217.0777.
4.2.13. N-(Pyridin-2-yl)benzo[d][1,3]dioxole-5-carboxamide
(3ma). Compound 3ma was prepared from 1m and 2a according to
the typical experimental procedure shown in Section 4.2.1. Yellow
solid (68 mg, 83%). Mp 112e116 ꢀC; 1H NMR (400 MHz, CDCl3):
4.2.19. N-(6-Methylpyridin-2-yl)benzamide (3af). Compound 3af
was prepared from 1a and 2f according to the typical experimental
procedure shown in Section 4.2.1. Yellow solid (20 mg, 28%). Mp
d
9.08 (br s, 1H), 8.36 (d, J¼8.4 Hz, 1H), 8.18 (d, J¼4.4 Hz, 1H),
7.74e7.71 (m, 1H), 7.46 (d, J¼8.4 Hz, 1H), 7.42 (d, J¼0.4 Hz, 1H),
7.04e7.01 (m, 1H), 6.85e6.82 (m, 1H), 6.04 (s, 2H); 13C NMR
76e78 ꢀC; 1H NMR (400 MHz, CDCl3):
d 8.52 (br s, 1H), 8.19 (d,
(100 MHz, CDCl3):
d
165.1, 151.8, 150.9, 148.1, 147.7, 138.3, 128.4,
J¼8.4 Hz, 1H), 7.93 (d, J¼7.2 Hz, 2H), 7.65 (t, J¼8 Hz, 1H), 7.59e7.55
122.1, 119.7, 114.2, 108.0, 107.9, 101.8; IR (neat, cmꢁ1) 3224, 3052,
3020, 2916, 2251, 1668, 1502, 1486, 1433, 1257, 1241, 1038, 910, 777,
(m, 1H), 7.52e7.48 (m, 2H), 2.48 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
165.6, 157.0, 150.8, 138.7, 134.4, 132.2, 128.8, 127.2, 119.4, 110.9,
Please cite this article in press as: Yang, S.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.05.072

S. Yang et al. / Tetrahedron xxx (2013) 1e5
5
24.0; IR (neat, cmꢁ1) 3439, 3346, 3247, 3084, 3042, 1705, 1630,
Supplementary data
1469, 1260, 1103, 811, 775, 700; HRMS (ESI) calcd for C13H13N2O
[MþH]þ: 213.1025; found: 213.1028.
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.05.072.
4.2.20. 4-Methoxy-N-(4-methylpyridin-2-yl)benzamide
(3ah). Compound 3ah was prepared from 1a and 2h according to
the typical experimental procedure shown in Section 4.2.1. Yellow
References and notes
solid (44 mg, 53%). Mp 133e135 ꢀC; 1H NMR (400 MHz, CDCl3):
d 9.18
1. (a) Pattabiraman, V. R.; Bode, J. W. Nature 2011, 480, 471e479; (b) Bode, J. W.
Curr. Opin. Drug Discov. Dev. 2006, 9, 765e775; (c) Cupido, T.; Tulla-Puche, J.;
Spengler, J.; Albericio, F. Curr. Opin. Drug Discov. Dev. 2007, 10, 768e783; (d)
Humphrey, J. M.; Chamberlin, A. R. Chem. Rev. 1997, 97, 2243e2266.
2. (a) Montalbetti, C. A. G. N.; Falque, V. Tetrahedron 2005, 61, 10827e10852; (b)
Valeur, E.; Bradley, M. Chem. Soc. Rev. 2009, 38, 606e631; (c) Londregan, A. T.;
Storer, G.; Wooten, C.; Yang, X.; Warmus, J. Tetrahedron Lett. 2009, 50,
1986e1988.
3. (a) Saxon, E.; Bertozzi, C. R. Science 2000, 287, 2007e2010; (b) Damkaci, F.;
DeShong, P. J. Am. Chem. Soc. 2003, 125, 4408e4409; (c) Kasukhin, L. F. Tetra-
hedron 1992, 48, 1353e1406.
4. (a) Cho, S.; Yoo, E.; Bae, I.; Chang, S. J. Am. Chem. Soc. 2005, 127, 16046e16047;
(b) Chen, Z.-W.; Jiang, H.-F.; Pan, X.-Y.; He, Z.-J. Tetrahedron 2011, 67,
5920e5927.
5. Martinelli, J. R.; Clark, T. P.; Watson, D. A.; Munday, R. H.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2007, 46, 8460e8463.
6. Shen, B.; Makley, D. M.; Johnston, J. N. Nature 2010, 465, 1027e1032.
7. Marko, I. E.; Mekhalfia, A. Tetrahedron Lett. 1990, 31, 7237e7240.
8. Davidson, R. S.; Edwards, J.; Warburton, S. K. J. Chem. Soc., Perkin Trans. 1 1976,
1511e1514.
(br s, 1H), 8.25 (s, 1H), 8.00 (d, J¼4.8 Hz, 1H), 7.91 (d, J¼8.8 Hz, 2H),
6.94 (d, J¼8.8 Hz, 2H), 6.84 (d, J¼4.8 Hz,1H), 3.85 (s, 3H), 2.38 (s, 3H);
13C NMR (100 MHz, CDCl3):
d 165.4, 162.6, 151.9, 149.8, 147.3, 129.2,
126.5,120.7,114.7,113.8, 55.4, 21.3; IR (neat, cmꢁ1) 3386, 3230, 3029,
2972, 2896, 2251, 1669, 1610, 1500, 1433, 1258, 910, 875, 733; HRMS
(ESI) calcd for C14H15N2O2 [MþH]þ: 243.1138; found: 243.1134.
4.2.21. N-(4-Chloropyridin-2-yl)-4-methoxybenzamide
(3ai). Compound 3ai was prepared from 1a and 2i according to the
typical experimental procedure shown in Section 4.2.1. Yellow solid
(77 mg, 86%). Mp 142e144 ꢀC; 1H NMR (400 MHz, CDCl3):
d 8.83 (br
s, 1H), 8.49 (d, J¼1.6 Hz, 1H), 8.13 (d, J¼5.2 Hz, 1H), 7.89 (d, J¼8.4 Hz,
2H), 7.05 (dd, J¼5.6, 1.6 Hz, 1H), 6.98 (d, J¼8.8 Hz, 2H), 3.88 (s, 3H);
13C NMR (100 MHz, CDCl3):
d 165.2, 163.0, 152.7, 148.4, 145.9, 129.2,
125.9, 120.1, 114.3, 114.1, 55.5; IR (neat, cmꢁ1) 3415, 3285, 3226,
3072, 3031, 2948, 2874, 2251, 1675, 1530, 1458, 1322, 1218, 1067,
916, 873, 734; HRMS (ESI) calcd for C13H12ClN2O2 [MþH]þ:
263.0588; found: 263.0587.
9. Ishihara, K.; Yano, T. Org. Lett. 2004, 6, 1983e1986.
10. (a) Zhang, L.; Wang, S.; Zhou, S.; Yang, G.; Sheng, E. J. Org. Chem. 2006, 71,
3149e3153; (b) Seo, S. Y.; Marks, T. J. Org. Lett. 2008, 10, 317e319.
11. (a) Vora, H. U.; Rovis, T. J. Am. Chem. Soc. 2007, 129, 13796e13797; (b) Bode, J.
W.; Sohn, S. S. J. Am. Chem. Soc. 2007, 129, 13798e13799.
12. (a) Yoo, W.; Li, C. J. Am. Chem. Soc. 2006, 128, 13064e13065; (b) Roberta, C.;
Andrea, P.; Giampaolo, G.; Lidia De, L. Org. Lett. 2012, 14, 5014e5017; (c) Wang,
L.; Fu, H.; Jiang, Y. Y.; Zhao, Y. F. Chem.dEur. J. 2008, 14, 10722e10726; (d)
Tillack, A.; Rudloff, I.; Beller, M. Eur. J. Org. Chem. 2001, 523e528; (e) Naota, T.;
Murahashi, S. Synlett 1991, 693e694; (f) Tamaru, Y.; Yamada, Y.; Yoshida, Z.
Synthesis 1983, 474e476; (g) Nakagawa, K.; Onoue, H.; Minami, K. J. Chem. Soc.,
Chem. Commun. 1966, 17e18; (h) Kegnaes, S.; Mielby, J.; Mentzel, U. V.; Jensen,
T.; Fristrup, P.; Riisager, A. Chem. Commun. 2012, 2427e2429; (i) Porcheddu, A.;
De Luca, L. Adv. Synth. Catal. 2012, 354, 2949e2953.
4.2.22. Ethyl 2-benzamidoisonicotinate (3aj). Compound 3aj was
prepared from 1a and 2j according to the typical experimental
procedure shown in Section 4.2.1. Yellow solid (50 mg, 55%). Mp
94e96 ꢀC; 1H NMR (400 MHz, CDCl3):
d 8.93 (s, 1H), 8.86 (br d,
J¼12.8 Hz, 1H), 8.38 (t, J¼4.4 Hz, 1H), 7.96 (s, 1H), 7.94 (d, J¼1.2 Hz,
1H), 7.64 (dd, J¼4.8, 1.2 Hz, 1H), 7.59 (d, J¼7.2 Hz, 1H), 7.52 (t,
J¼7.6 Hz, 2H), 4.44 (q, J¼7.2 Hz, 2H), 1.43 (t, J¼7.2 Hz, 3H); 13C NMR
13. (a) Ekoue-Kovi, K.; Wolf, C. Org. Lett. 2007, 9, 3429e3432; (b) Gao, J.; Wang, G.-
(100 MHz, CDCl3):
d 165.7, 164.9, 152.4, 148.5, 140.3, 133.9, 132.5,
W. J. Org. Chem. 2008, 73, 2955e2958.
128.9,127.2,119.4,113.7, 61.9,14.2; IR (neat, cmꢁ1) 3416, 3058, 2976,
1650, 1443, 1226, 754, 736, 704; HRMS (ESI) calcd for C15H15N2O3
[MþH]þ: 271.1085; found: 271.1083.
14. (a) Nordstom, L. U.; Vogt, H.; Madsen, R. J. Am. Chem. Soc. 2008, 130,
17672e17673; (b) Zweifel, T.; Naubron, J. V.; Grutzmacher, H. Angew. Chem., Int.
Ed. 2009, 48, 559e563; (c) Ghosh, S. C.; Muthaiah, S.; Zhang, Y.; Xu, X.; Homg,
S. H. Adv. Synth. Catal. 2009, 351, 2643e2649; (d) Cheng, C.; Hong, S. H. Org.
Biomol. Chem. 2011, 9, 20e26; (e) Owston, N. A.; Parker, A. J.; Williams, J. M. J.
Org. Lett. 2007, 9, 73e75; (f) Beller, M.; Cornils, B.; Frohning, C. D. J. Mol. Catal. A:
Chem. 1995, 104, 17e85; (h) Ghosh, S. C.; Hong, S. H. Eur. J. Org. Chem. 2010,
4266e4270.
Acknowledgements
15. Heitman, L. H.; Veldhoven, J. D.; Zweemer, A.; Ye, K.; Brussee, J.; IJzerman, A. P. J.
Med. Chem. 2008, 51, 4724e4729.
16. Nakatsu, T.; Ichiyama, S.; Hiratake, J.; Saldanha, A.; Kobashi, N.; Sakata, K.; Kato,
We thank the Fundamental Research Funds for the Central
Universities (lzujbky-2012-74) and National Science Foundation
(NSF-21202067) for financial support.
H. Nature 2006, 440, 372e376.
17. (a) Robert, A; Skaletzky, L. L. U. S. Patent 3,418,325, 1968; (b) Moffett, R. B.;
Robert, A.; Skaletzky, L. L. J. Med. Chem. 1971, 14, 963e968.
Please cite this article in press as: Yang, S.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.05.072