Ligand-Free Copper(I)-Catalyzed Benzylic Acyloxylation of 2-Alkylpyridines under Aerobic Conditions

Article abstract of DOI:10.1021/acs.joc.8b02794

A ligand-free copper(I)-catalyzed benzylic acyloxylation of 2-alkylpyridines with carboxylic acids was realized by using 1.0 atm of O₂ as a green oxidant. The transformation provided a facile access to a wide range of N-heterocyclic esters thro

Full text of DOI:10.1021/acs.joc.8b02794

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Article
Ligand-free Copper(I)-Catalyzed Benzylic Acyloxylation
of 2-Alkylpyridines under Aerobic Conditions
Li Cheng, Yuqian Sun, Wenrong Wang, Changsheng Yao, and Tuanjie Li
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02794 • Publication Date (Web): 22 Feb 2019
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Ligand-free Copper(I)-Catalyzed Benzylic Acyloxylation of 2-Alkylpyridines
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under Aerobic Conditions
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Li Cheng, Yuqian Sun, Wenrong Wang, Changsheng Yao*, Tuan-Jie Li*
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School of Chemistry & Materials Science, Jiangsu Key Laboratory of Green Synthetic
Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou 221116, P.
R. China
R2 R3
R2 R3
O
O
CuBr (20 mol %)
X
+
O
R
R1
X
H
R
OH
PhCl, 130 o
O2 (1.0 atm)
C
R1
N
N
25 examples
up to 82% yield
ligand-free
O2 as the green oxidant
Abstract:
A
ligand-free copper(I)-catalyzed benzylic acyloxylation of
2-alkylpyridines with carboxylic acids was realized by using 1.0 atm of O2 as a green
oxidant. The transformation provided a facile access to a wide range of N-heterocyclic
esters through C-O bond formation, with broad substrate scope and good functional
groups tolerance. Preliminary mechanistic investigations showed that this protocol
included a radical process.
Keywords: CuBr-catalysis; benzylic acyloxylation; 2-alkylpyridines; carboxylic acids
INTRODUCTION
Transition-metal-catalyzed C(sp3)−H functionalization has emerged as a
powerful and appealing tool for the introduction of diverse functional groups into
organic molecules through the direct conversion of C(sp3)−H bonds.1 In particular,
metal-catalyzed acyloxylation of C(sp3)–H has received increasing attention for the
syntheses of functional esters in the past years.2 Currently, notable progress has been
made predominantly with Pd catalyst which allows direct acyloxylation of the C(sp3)–
H bonds into C–O bonds, but these transformations are almost limited to
acetoxylation in the presence of ligands and several kinds of oxidants including
PhI(OAc)2.3 In sharp contrast, the use of low-cost copper catalysts for C(sp3)–H
acyloxylation using aromatic acids as coupling partners is quiet less while
copper-catalyzed C(sp3)–H functionalization has been extensively studied.4 Moreover,
molecular oxygen as a safe and environmentally friendly oxidant is typically usually
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used in many C–O bond formation reactions.5 It has become clear that the
combination of ligand-free copper catalysis with molecular oxygen to achieve the
C(sp3)–H acyloxylation will provide a green and sustainable entry to construct
functional esters.6
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Over the past years, metal-catalyzed C(sp3)–H acyloxylation of N-heteroaryl
compounds has attracted considerable attention as N-heteroaryl esters are frequently
found in a plethora of natural products and play an important role in the field of
medicinal chemistry.7 In 2010, Jiang and co-workers pioneered a Pd-catalyzed
benzylic acetoxylation of 2-alkylheterocycles in AcOH, but this method required 1.0
equivalent of CuI as additive in the presence of 8.0 atm O2 (Scheme 1a).8 Besides,
Bu4NI could also catalyze the benzylic acyloxylation of alkylarenes with aromatic
t
aldehydes presented by BuOOH (Scheme 1b).9 Later, Soulé’s group developed a
copper-promoted benzylic acyloxylation of 2-alkyheterocycle N-oxides for the
synthesis of 2-pyridinemethyl ester derivatives via tandem oxidative coupling and
Boekelheide rearrangement, but this reaction needed 1,10-phenanthroline (Phen) as
the ligand and 3.0 equivalents of di-tert-butyl peroxide (DTBP) as the oxidant
(Scheme 1c).10 Very recently, Yin et al presented a copper-catalyzed C(sp3)−H
acyloxylation of N-heteroaryl methanes via oxidative dehydrogenation (Scheme 1
d).11 In this method, Phen ligand and 3.0 equivalents DTBP were still necessary and
2-metheylpyridine was proven to be ineffective in this transformation. Thus there is
an urgent need to develop a cheap metal-catalyzed, ligand-free and additive-free
strategy to acyloxylate 2-alkylpyridine in the presence of environmentally compatible
and readily available oxidants. Herein, we report a ligand-free copper (I)-catalyzed
benzilic acyloxylation of 2-alkylpyridines by using O2 (1.0 atm) as a green oxidant.
The current protocol represents a unique and sustainable procedure to access a wide
range of 2-pyridinemethyl ester derivatives. Besides, other fused N-heterocycle
derivatives
such
as
6,7-dihydro-5H-cyclopenta[b]pyridine,
5,6,7,8-tetrahydroquinoline, 3-methylisoquinoline and 2-propylpyrazine are tolerated
well in this method (Scheme1 e).
Scheme 1. Direct Benzilic Acyloxylation of 2-Alylpyridines
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R1 R2
R1 R2
O
O
O
Pd(OAc)2, CuI
+
+
X
(a)
(b)
O
O
X
H
OH
N
O2 (8.0 atm)
N
H
O
H
H
nBu4NI
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Ar
Ar
H
R
R
tBuOOH
R2
R2
O
O
O
CuBr(Me2S), Phen
Y
Y
+
+
R3
H
(c)
(d)
Z
H
H
Z
O
O
R3
R1
R1
DTBP
N
O
N
O
CuI, Phen
DTBP
R2
R2 OH
R1 Het
R1 Het
N
N
This work
R2 R3
R2 R3
O
O
(e)
CuBr
+
X
O
R
X
H
R1
R1
R
OH
N
N
O2 (1.0 atm)
RESULTS AND DISCUSSION
Initial optimization was performed using 2-ethylpyridine (1a, 0.1 mmol) and
4-nitrobenzoic acid (2a, 0.12 mmol) in PhCl (0.6 mL) (Table 1). The catalytic activity
of the different copper salts, such as CuCl, CuBr, CuI, Cu(OAc)2, and CuBr2, was
tested under air atmosphere at 120 °C (entries 1-5). Among these salts, CuBr showed
the best catalytic performance, resulting in the desired product 3a in 37 % yield (entry
2). Thus, CuBr was selected as the Cu-catalyst to assess the effect of solvents,
including toluene, PhCF3, DCE, CH3CN and 1,4-dioxane (entries 6-10). All the
attempts did not show any improvement on the reaction yield as compared with PhCl.
Subsequently, the oxidants including O2, BQ (benzoquinone), K2S2O8, TBHP
(tert-butyl peroxide) and DTBP (di-tert-butyl peroxide) were screened for this
transformation (entries 11-15). The experimental results indicated that the presence of
O2 drove the reaction most efficiently, giving 52 % yield of 3a (entry 11). Then, we
explored the other reaction parameters including reaction temperature and the amount
of copper catalyst. The yield was raised to 60 % when the reaction was conducted at
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130 °C (entry 16). It was found that the CuBr loading had an important impact on the
reaction efficiency. An increase of the loading of CuBr was beneficent to the reaction
(entries 17-18), and the use of 20 mol% CuBr led to the best yield of 3a (78 %, entry
9
18).
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Table1. Optimization of Reaction Conditions a
O
O
Cat. (X mol %)
H
HO
O
+
oxidant, solvent
T, 30 h
N
N
NO2
NO2
2a
1a
3a
Entry
1
Cat. (mol %)
CuCl (10)
CuBr (10)
CuI (10)
Oxidant b
air
Solvent
PhCl
T (°C)
120
120
120
120
120
120
120
120
120
Yield (%) f
29
2
air
PhCl
37
3
air
PhCl
10
4
Cu(OAc)2 (10)
CuBr2 (10)
CuBr (10)
CuBr (10)
CuBr (10)
CuBr (10)
CuBr (10)
CuBr (10)
CuBr (10)
CuBr (10)
CuBr (10)
CuBr (10)
CuBr (10)
CuBr (10)
CuBr (20)
CuBr (30)
air
PhCl
15
5
air
PhCl
25
6
air
toluene
PhCF3
DCE
29
7
air
31
8
air
17
9
air
CH3CN
22
10
11
12
13
14
15
16
17
18
19
air
1,4-dioxane 120
11
O2
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
120
120
120
120
120
130
140
130
130
52
BQ c
K2S2O8
TBHP d
DTBP e
O2
48
36
41
43
60
O2
58
O2
78
O2
70
a Reactions were performed with 1a (0.10 mmol, 10.7 mg), 2a (0.12 mmol, 20.0 mg), cat.
(mol %), and oxidant in PhCl (0.6 mL) at T °C, 30 h. bO2 (1.0 atm) and other oxidants (1.2
equivlents), cBQ = benzoquinone, dTBHP = tert-butyl peroxide, eDTBP = di-tert-butyl
peroxide. f Isolated yield.
With the optimized reaction conditions in hand, firstly, the scope of aromatic
acids as coupling reagents for the acyloxylation of 2-ethylpyridine was investigated.
As shown in Table 2, various commercially available aromatic acids and
-unsaturated carboxylic acids were exposed to the standard reaction conditions and
the desired 1-(pyridin-2-yl)ethyl substituted benzoates were successfully afforded
with good yields. Among them, 4-nitrobenzoic acid as the acyloxylation reagent
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showed high reactivity due to the acyloxylated product was furnished in 78 % yield.
Alternatively, thiophene-2-carboxylic acid as a representative heteroaryl acid was
employed to react with substrate 1a under the standard conditions and the
corresponding product 3i was generated with 63 % yield.
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Table 2. Substrate Scope of Aromatic Acidsa,b
O
O
CuBr (20 mol %)
PhCl, 130 oC
O2 (1.0 atm)
+
O
H
R
R
OH
N
N
3
2
1a
O
O
O
O
O
O
N
N
N
N
Cl
NO2
3c,
60 %
O
3a,
3b,
78 %
O
65 %
O
NO2
NO2
O
O
O
N
N
N
O
3f,
73 %
3d,
3e,
68 %
O
71 %
O
O
S
O
O
O
N
N
3i
68 %
3h,
60 %
3g,
78 %
a Reactions were performed with 1 (0.10 mmol), 2 (0.12 mmol), CuBr (20 mol%, 2.86 mg), and
O2 (1.0 atm) in PhCl (0.6 mL) at 130 oC, 30 h. bIsolated yields.
Next, we explored the acyloxylation reaction of a variety of 2-ethylpyridine
derivatives in combination with 4-nitrobenzoic acid as coupling partner under the
standard conditions. The results are summarized in Table 3. Various substituents, such
as methyl (1b), propyl (1c), aryl (1d and 1e) and sulfonamido (1f) functionalities
linked to the ethyl group of 2-ethylpyridines, were proven to be suitable as the
corresponding products 3j-3n were smoothly obtained with 60 %-82 % yields under
the standard conditions. Moreover, both ethyl (1g) and methyl (1h) groups located at
6-postion of pyridine unit also worked well in the transformations, delivering the
desired acyloxylation products 3o and 3p in 62 % and 56 % yields, respectively.
Notably, fused pyridines such as 6,7-dihydro-5H-cyclopenta[b]pyridine and
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5,6,7,8-tetrahydroquinoline were successfully engaged in this copper catalysis,
accessing the corresponding acyloxylation products 3q and 3r efficiently, respectively.
Furthermore, 3-methylisoquinoline could take part in this protocol and afforded
product 3s in 58 % yield. 2-Propylpyrazine was an effective component, leading to
Table 3. Substrate Scope of 2-Alkylpyridinesa,b
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R2 R3
R2 R3
O
O
CuBr (20 mol %)
PhCl, 130 oC
O2 (1.0 atm)
+
X
H
X
O
Ar
O
Ar
OH
R1
R1
N
N
1
2
3
4-(NC)C6H4
O
O
O
3
O
O
N
N
N
NO2
NO2
NO2
3k
, 82 %
3j
, 80 %
3l
, 68 %
H
N
4-(H3CO2C)C6H4
O
O
O
Ts
O
N
O
O
N
N
NO2
NO2
NO2
3o
, 62 %
3n
, 60 %
O
3m
, 64 %
O
O
O
N
O
O
N
N
NO2
NO2
NO2
NO2
3q
, 77 %
3r
3p
, 79 %
, 56 %
O
O
O
O
O
N
O
N
N
N
N
NO2
NO2
3s
3u
3x
, 58 %
, 75 %
3t
, 65 %
O
O
O
O
O
O
N
N
O
O
O
3v
, 72 %
3w
, 71 %
, 64 %
O
O
O2N
O
O
N
N
O
Br
O
3z
, 72 %
3y
, 75 %
a Reactions were performed with 1 (0.10 mmol), 2 (0.12 mmol), CuBr (20 mol%, 2.86 mg), and
O2 (1.0 atm) in PhCl (0.6 mL) at 130 oC for 30 h. bIsolated yields
the formation of product 3t in 65 % yield. The reaction of 8-methylisoquinoline with
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4-nitrobenzolic acid proceeded smoothly to give the corresponding product 3u in 75
% yield under the standard conditions. To expand the scope of this transformation,
4-methoxylbenzoic acid was selected as a representative electron-donating aryl acid to
probe the feasibility of the copper(I)-catalyzed benzylic acyloxylation of
2-alkylpyridines. Delightfully, the reaction worked well to provide the acyloxylated
products 3v-3z 64 %-75 % yields when 2-methylpyridines bearing electronically
neutral (H), rich (methyl and ethyl) and poor (bromo and nitro) groups were reacted
with 4-methoxylbenzoic acid. These results indicated that the electronic property of
the substitutes attached by pyridine ring had little effect on the transformations.
To evaluate the practicality of this protocol, a gram-scale benzilic acyloxylation
reaction of 2-ethylpyridine (1a, 10 mmol) with 4-nitrobenzoic acid (2a, 12 mmol) was
conducted under the standard conditions. Gratifyingly, the reaction proceeded
smoothly, affording product 3a in 64 % yield (Scheme 2).
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Scheme 2. Gram Scale Experiment for the Synthesis of 3a
O
O
CuBr (20 mol %)
H
HO
O
+
O2 (1.0 atm)
130 oC, PhCl
N
N
NO2
NO2
(10.0 mmol)
(12.0 mmol)
3a
2a
1a
To gain mechanistic insight into this reaction, several control experiments were
conducted. When the model reaction was carried out under a nitrogen atmosphere, the
desired product 3a was not obtained, indicating that molecular oxygen was necessary
in this protocol (Scheme 3 a). Then, the reaction was subjected with 3.0 equivalents of
TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) under the standard conditions and
only a trace amount of 3a was detected (Scheme 3 b). These results showed that these
processes included the possibility of a radical mechanism. For H2O2 generated in situ
from O2 via copper catalysis could act as the oxidant for the acyloxylation, the model
reaction was performed with 2.0 equivalents of H2O2 (30 % aqueous H2O2 was used)
under a nitrogen atmosphere and the C(sp3)-H acyloxylation of 2-ethylpyridine took
place efficiently, affording 3a in 35 % yield (Scheme 3 c).
Scheme 3. Control Experiments
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O
O
CuBr (20 mol %)
130 oC, PhCl
(a)
NO2
H
HO
O
+
N
N
N
N2, 30 h
NO2
NO2
NO2
2a
0%
1a
3a
O
O
CuBr (20 mol %)
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(b)
NO2
H
HO
O
+
130 oC, PhCl
N
O2 (1.0 atm), 30 h
TEMPO (3.0 equiv)
2a
trace
1a
1a
3a
O
O
CuBr (20 mol %)
(c)
NO2
H
HO
O
+
30 % aq H2O2
130 oC, PhCl
N2, 30 h
N
N
2a
35%
3a
Based on the abovementioned analysis and literature survey,6b,12 a reasonable
mechanism for this copper(I)-catalyzed benzylic acyloxylation reaction was proposed
to occur via a Cu(I)/Cu(II)/Cu(III) catalytic cycle (Scheme 4). This transformation
pathway was initiated by the coordination of Cu(I) salt with substrate 1a to afford
intermediate A, which underwent oxidation to yield radical species B (Cu(I) to Cu(II))
(detected by HRMS, [M + H]+ = 203.0, see the Surporting Information (SI)) in the
presence of O2. Then, intermediate B was converted into intermediate D (detected by
HRMS, [M + H]+ = 203.0) via intramolecular hydrogen atom transfer (HAT) and
subsequent oxidative addition (Cu(II) to Cu(III)). The following ligand exchange gave
intermediate E (detected by HRMS, [M + H]+ = 336.0). Subsequently, the reductive
elimination of the intermediate E afforded the final product 3a and completed the
catalytic cycle to regenerate the Cu catalyst. The resulting H2O2 served as the oxidant
to participate in this transformation. Moreover, the intermediates F ([M + H]+ = 188.0)
and G or H ([M + H]+ = 187.0) were observed by HRMS.
Scheme 4. Possible Reaction Pathway
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O
N
O
N
Ar
1a
3a
H
H2O
CuI
8
9
O
10
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12
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N
N
CuIII
N
Ar
OH
CuI
A
CuIII
HO
2
H
H
O
H
O2
O
Ar
N
E
CuII
HO
N
CuII
O
G
O
H2O2
N
B
CuIII
N
HO
N
CuII
HO
O
CuII
H
A
D
HO
O OH
C
F
CONCLUSIONS
In summary, starting from easily available aromatic acids, a new ligand-free
copper(I)-catalyzed C(sp3)−H acyloxylation of 2-alkylpyridines has been established
by means of O2 as an environmentally friendly oxidant. This transformation features
broad substrate scope and good functional group tolerance. Further mechanistic
studies are currently underway in our laboratory.
EXPERIMENTAL SECTION
General Information. Unless otherwise mentioned, all reactions sealed by 10
mL LH-20 Schlenk and were monitored by analytical thin-layer chromatography
(TLC), which was visualized by ultraviolet light (254 nm or 365 nm). All reagents
were commercially available and were used without further purification. Purification
of the products was accomplished by flash chromatography using silica gel (200-300
1
mesh). Melting points were determined in open capillaries and were uncorrected. H
NMR spectra were measured on a 400 MHz spectrometer in CDCl3 (100 MHz,
13C{1H} NMR) or DMSO-d6 with a chemical shift (δ) given in ppm relative to TMS
as an internal standard. Data were reported as follows: chemical shift, multiplicity (s =
singlet, d = doublet, t = triplet, q = quartets, m = multiplet), coupling constants (Hz),
integration. High-resolution mass spectra (HRMS) were obtained on a HRMS/MS
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instrument with the technique of atmospheric pressure chemical ionization (APCI)
and TOF analyzer.
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Syntheses of 1d and 1e according to the method reported in the literature.13
A flame-dried 10 mL LH-20 Schlenk equipped with a magnetic stir bar was charged
with 2-ethylpyridine (64.0 mg, 0.6 mmol), Pd(OAc)2 (6.7 mg, 0.03 mmol), AgOAc
(210.0 mg, 1.26 mmol) and atrial iodine (5 mmol) were mixed with acetic acid (1.5
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mL) and heated at 130 C for 47 h. Purification by flash chromatography (silicagel,
mixtures of petroleum ether/ethyl acetate, 10:1, v/v) gave 1d and 1e.
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4-(2-(Pyridin-2-yl)ethyl)benzonitrile (1d): Colorless oil (49.9 mg, 40 % yield); H
NMR (hydrochloride salt; 400 MHz, CDCl3) δ 8.72 (d, J = 5.6 Hz, 1H), 8.29 (t, J =
7.8 Hz, 1H), 7.80 (t, J = 6.6 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 8.0 Hz,
2H), 7.43 (d, J = 8.0 Hz, 2H), 3.56 (t, J = 8.0 Hz, 2H), 3.31 (t, J =8.0 Hz, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ 155.9, 145.4, 144.1, 141.1, 132.5, 129.4, 126.9,
124.7, 118.7, 110.7, 35.5, 34.5; HRMS (APCI-TOF) m/z: [M + H]+ Calcd for
C14H13N2 209.1079; Found 209.1085.
Methyl 4-(2-(pyridin-2-yl)ethyl)benzoate (1e): Colorless oil (65.1 mg, 45 % yield);
1H NMR (hydrochloride salt; 400 MHz, CDCl3) δ 8.71 (d, J =5.6 Hz, 1H), 8.22 (t, J
=7.6 Hz, 1H), 7.89 - 7.86 (m, 2H), 7.75 (t, J =6.4 Hz, 1H), 7.49 (d, J =7.6 Hz, 1H),
7.28 (d, J =8.0 Hz, 2H), 3.86 (s, 3H), 3.54 (t, J =7.4 Hz, 2H), 3.27 (t, J =7.4 Hz, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ 166.7, 156.2, 145.1, 143.8, 141.1, 129.9, 128.6,
127.0, 124.5, 52.0, 35.2, 34.6; HRMS (APCI-TOF) m/z: [M + H]+ Calcd for
C15H16NO2 242.1181; Found 242.1176.
Synthesis of 1f according to the method reported in the literature.14
A flame-dried 50 mL round-bottomed flask equipped with a magnetic stir bar
was charged with 4-toluenesulfonyl chloride (2.3 g, 12 mmol) capped with a rubber
septum and flushed with N2, anhydrous CH2Cl2 (30 mL) was added and then it was
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cooled to 0 C. 2-(pyridin-2-yl) ethanamine (1.2 g, 10 mmol) was added dropwise,
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and the resulting mixture was stirred at 0 C for 3 min. After this time, triethylamine
(TEA, 2.0 g, 20 mmol) was added in one portion. The reaction mixture was stirred for
3 h and slowly allowed to warm to room temperature over that time. The resulting
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mixture was quenched by addition of water and extracted with CH2Cl2 (3 × 30 mL).
The combined organic fractions were washed with brine (30 mL), dried over Na2SO4
and filtrated. After the solvent was removed under reduced pressure, the residue was
recrystallized from CH2Cl2/petroleum ether to afford sulfonyl protected 1f.
4-Methyl-N-(2-(pyridin-2-yl)ethyl)benzenesulfonamide (1f): White solid (2.0 g,
70 % yield); m.p. 114 - 115 °C (reported 120 - 122 °C); 1H NMR (400 MHz, CDCl3)
δ 8.46 (d, J = 4.7 Hz, 1H), 7.73 (d, J = 7.9 Hz, 2H), 7.58 (t, J = 7.7 Hz, 1H), 7.26 (d, J
= 7.7 Hz, 2H), 7.15 - 7.12 (m, 1H), 7.07 (d, J = 7.8 Hz, 1H), 6.14 (t, J = 5.6 Hz, 1H),
3.35 (q, J = 6.0 Hz, 2H), 2.93 (t, J = 6.1 Hz, 2H), 2.40 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 158.8, 148.8, 143.0, 137.1, 136.8, 129.5, 127.0, 123.5, 121.7, 42.3,
36.3, 21.4; HRMS (APCI-TOF) m/z: [M + Na]+ Calcd for C14H16N2O2SNa 299.0830l;
Found 299.0846.
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General Procedure for the Preparation of Products 3. A 10-mL LH-20
Schlenk tube equipped with a magnetic stir bar was charged with CuBr (2.9 mg, 0.02
mmol), 2-alkylpyridines 1 (0.1 mmol), aromatic acids 2 (0.12 mmol), PhCl (0.6 mL).
This tube was evacuated, and refilled with oxygen (1.0 atm). The mixture was stirred
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at 130 C for 30 h, at which time complete consumption of starting material was
observed by TLC. The reaction mixture was diluted with ethyl acetate (30 mL). The
mixture was washed with saturated Na2CO3 solution three times. The organic layer
was separated and dried with MgSO4 filtered. After removal of the solvent under
reduced pressure, the resulting was purified by column chromatography (silicagel,
mixtures of petroleum ether/ethyl acetate, 8:1, v/v) to afford the desired product 3.
Scale-up Experiment. In a dried 50 mL round-bottomed flask equipped with a
magnetic stirrer, add CuBr (286.9 mg, 2.0 mmol), 2-ethylpyridine (1.1 g, 10 mmol),
4-nitrobenzoic acid (2.0 g, 12.0 mmol), PhCl (15 mL). This flask was evacuated, and
refilled with oxygen. The mixture was stirred at 130 oC until complete consumption of
starting material observed by TLC (about 36 h). The reaction mixture was diluted
with ethyl acetate and washed with saturated Na2CO3 solution three times. The
organic layer was separated and dried with MgSO4 filtered. After the removal of the
solvent under reduced pressure, the residue was purified by column chromatography
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(silicagel, mixtures of petroleum ether/ethyl acetate, 8:1, v/v) to afford the desired
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product 3a (1.73 g, 64%).
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1-(Pyridin-2-yl)ethyl 4-nitrobenzoate (3a). Colorless oil (21.2 mg, 78 % yield); H
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NMR (hydrochloride salt; 400 MHz, CDCl3) δ 8.87 (s, 1H), 8.40 - 8.30 (m, 5H), 7.85
- 7.84 (m, 2H), 6.50 (d, J = 6.0 Hz, 1H), 1.98 (d, J = 6.0 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 163.7, 155.9, 150.9, 144.5, 143.6, 134.1, 131.4, 125.6, 123.7, 123.5,
70.9, 21.2; IR (KBr) (v, cm-1) 2922, 2360, 2341, 2341, 1728, 1528, 1343, 1102, 1014;
HRMS (APCI-TOF) m/z: [M + Na]+ Calcd for C14H12N2O4Na 295.0695; Found
295.0701.
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1-(Pyridin-2-yl)ethyl 4-chlorobenzoate (3b). Colorless oil (17.0 mg, 65 % yield); H
NMR (hydrochloride salt; 400 MHz, CDCl3) δ 8.82 (d, J = 5.2 Hz, 1H), 8.27 (t, J =
7.8 Hz, 1H), 8.09 (d, J =11.2 Hz, 2H), 7.81 - 7.74 (m, 2H), 7.45 (d, J = 8.8 Hz, 2H),
6.46 (q, J = 6.8 Hz, 1H), 1.94 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
164.6, 156.7, 144.4, 143.0, 140.4, 131.5, 129.0, 127.2, 125.2, 123.2, 70.1, 21.2; IR
(KBr) (v, cm-1) 1723, 1593, 1270, 1103, 1092, 1070, 1014; HRMS (APCI-TOF) m/z:
[M + Na]+ Calcd for C14H12ClNO2Na 284.0454; Found 284.0457.
1
1-(Pyridin-2-yl)ethyl benzoate (3c). Colorless oil (13.6 mg, 60 % yield); H NMR
(400 MHz, CDCl3) δ 8.60 (d, J = 4.4 Hz, 1H), 8.12 (d, J = 8.0 Hz, 2H), 7.69 (t, J = 7.6
Hz, 1H), 7.57 (t, J = 7.4 Hz, 1H), 7.47 - 7.43 (m, 3H), 7.23 - 7.19 (m, 1H), 6.17 (q, J
= 6.8 Hz, 1H), 1.74 (d, J = 6.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 165.8,
160.5, 149.3, 136.8, 133.0, 130.2, 129.7, 128.4, 122.7, 120.2, 73.6, 20.8; IR (KBr) (v,
cm-1) 1717, 1590, 1573, 1474, 1451, 1435, 1338, 1315, 1270, 1109, 1177, 1070,
1048, 1026, 1001; HRMS (APCI-TOF) m/z: [M + Na]+ Calcd for C14H13NO2Na
250.0844; Found 250.0866.
1-(Pyridin-2-yl)ethyl 4-methoxybenzoate (3d). Colorless oil (17.5 mg, 68 % yield);
1H NMR (hydrochloride salt; 400 MHz, CDCl3) δ 8.59 (d, J = 3.6 Hz, 1H), 8.06 (d, J
= 8.8 Hz, 2H), 7.68 (t, J = 7.6 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.21 - 7.18 (m, 1H),
6.92 (d, J = 8.8 Hz, 2H), 6.14 (q, J = 6.8 Hz, 1H), 3.85 (s, 3H), 1.71 (d, J = 6.8 Hz,
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3H); C{1H} NMR (100 MHz, CDCl3) δ 165.5, 163.4, 160.6, 149.1, 136.9, 131.7,
122.6, 122.5, 120.2, 113.6, 73.2, 55.4, 20.8; IR (KBr) (v, cm-1) 1711, 1606, 1511,
1269, 1256, 1168, 1101; HRMS (APCI-TOF) m/z: [M + Na]+ Calcd for
C15H15NO3Na 280.0950; Found 280.0940.
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1-(Pyridin-2-yl)ethyl 2-nitrobenzoate (3e). Colorless oil (19.3 mg, 71 % yield); H
NMR (hydrochloride salt; 400 MHz, CDCl3) δ 8.78 (d, J = 4.0 Hz, 1H), 8.38 (t, J =
7.4 Hz, 1H), 7.96 - 7.83 (m, 4H), 7.75 - 7.65 (m, 2H), 6.57 (q, J = 6.4 Hz, 1H), 1.88
(d, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 164.1, 155.7, 147.9, 144.8,
142.5, 133.3, 132.3, 130.6, 126.3, 125.5, 123.9, 123.6, 71.2, 20.6; IR (KBr) (v, cm-1)
2924, 1732, 1591, 1574, 1537, 1457, 1445, 1436, 1350, 1286, 1255, 1131, 1072,
1047, 788, 736; HRMS (APCI-TOF) m/z: [M + Na]+ Calcd for C14H12N2O4Na
295.0695; Found 295.0708.
1-(Pyridin-2-yl)ethyl 2-methyl-5-nitrobenzoate (3f). Colorless oil (20.9 mg, 73 %
yield); 1H NMR (hydrochloride salt; 400 MHz, CDCl3) δ 8.85 - 8.82 (m, 2H), 8.41 (s,
1H), 8.25 - 8.22 (m, 1H), 7.92 - 7.88 (m, 2H), 7.44 (d, J = 8.4 Hz, 1H), 6.58 (q, J =6.8
Hz, 1H), 2.76 (s, 3H), 1.94 (d, J =6.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
163.9, 156.2, 148.8, 145.9, 145.3, 142.3, 133.1, 129.0, 126.9, 125.8, 125.7, 123.2,
70.1, 22.1, 21.1; IR (KBr) (v, cm-1) 3419, 1732, 1614, 1522, 1350, 1317, 1272, 1249,
1125, 1070, 781, 737; HRMS (APCI-TOF) m/z: [M + Na]+ Calcd for C15H14N2O4Na
309.0851; Found 309.0846.
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1-(Pyridin-2-yl)ethyl cinnamate (3g). Colorless oil (19.7 mg, 78 % yield); H NMR
(hydrochloride salt; 400 MHz, CDCl3) δ 8.61 (d, J = 2.8 Hz, 1H), 7.75 - 7.67 (m, 2H),
7.54 - 7.51 (m, 2H), 7.40 - 7.37 (m, 4H), 7.21 (dd, J = 6.6 Hz, J = 4.3 Hz, 1H), 6.54
(d, J = 16.0 Hz, 1H), 6.06 (q, J =6.4 Hz, 1H), 1.68 (d, J =6.8 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 166.1, 160.3, 149.2, 145.2, 136.9, 134.3, 130.3, 128.8, 128.1,
122.7, 120.5, 118.0, 73.0, 20.8; IR (KBr) (v, cm-1) 1711, 1636, 1590, 1449, 1331,
1306, 1270, 1256, 1202, 1170, 1071, 979, 767; HRMS (APCI-TOF) m/z: [M + Na]+
Calcd for C16H15NO2Na 276.1001; Found 276.1012.
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1-(Pyridin-2-yl)ethyl 3-(naphthalen-1-yl)acrylate (3h). Colorless oil (18.2 mg, 60 %
yield); 1H NMR (hydrochloride salt; 400 MHz, CDCl3) δ 8.70 (s, 1H), 7.94 - 7.67 (m,
7H), 7.52 - 7.47 (m, 3H), 7.28 - 7.26 (m, 1H), 6.67 (d, J = 15.6 Hz, 1H), 6.13 (s, 1H),
1.73 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.2, 145.4, 137.7, 134.3, 134.2,
133.2, 131.8, 130.1, 128.7, 128.6, 127.8, 127.3, 126.7, 123.5, 123.1, 120.9, 118.1,
72.8, 21.0; IR (KBr) (v, cm-1) 2359, 2341, 1715, 1450, 1307, 1270, 1202, 1171, 1071,
768, 713; HRMS (APCI-TOF) m/z: [M + Na]+ Calcd for C20H17NO2Na 326.1157;
Found 326.1151.
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1-(Pyridin-2-yl)ethyl thiophene-2-carboxylate (3i). Colorless oil (15.8 mg, 68 %
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yield); H NMR (hydrochloride salt; 400 MHz, CDCl3) δ 8.79 (s, 1H), 8.31 (s, 1H),
7.97 (d, J = 3.3 Hz, 1H), 7.85 - 7.78 (m, 2H), 7.62 (d, J = 4.8 Hz, 1H), 7.14 - 7.12 (m,
1H), 6.48 (q, J = 6.3 Hz, 1H), 1.91 (d, J = 6.4 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 160.7, 156.8, 144.7, 142.7, 134.9, 133.6, 132.0, 128.2, 125.3, 123.0, 69.8,
21.4; IR (KBr) (v, cm-1) 3069, 3026, 2986, 2562, 2076, 2003, 1708, 1630, 1618, 1523,
1415, 1368, 1358, 1279, 1265, 1229, 1095, 1075.; HRMS (APCI-TOF) m/z: [M + H]+
Calcd for C12H12NO2S 234.0588; found 234.0589.
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1-(Pyridin-2-yl)propyl 4-nitrobenzoate (3j). Colorless oil (22.9 mg, 80 % yield); H
NMR (hydrochloride salt; 400 MHz, CDCl3) δ 8.85 (s, 1H), 8.40 - 8.26 (m, 5H), 7.77
(s, 2H), 6.27 (s, 1H), 2.38 - 2.32 (m, 2H), 1.08 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 163.9, 155.4, 150.9, 144.2, 143.6, 134.2, 131.4, 125.4, 123.8, 123.7, 75.8,
28.4, 9.8; IR (KBr) (v, cm-1) 3450, 1728, 1640, 1528, 1345, 1299, 1240, 1116, 1102,
1083, 1014, 872, 784; HRMS (APCI-TOF) m/z: [M + Na]+ Calcd for C15H14N2O4Na
309.0851; Found 309.0840.
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1-(Pyridin-2-yl)pentyl 4-nitrobenzoate (3k). Colorless oil (25.8 mg, 82 % yield); H
NMR (hydrochloride salt; 400 MHz, CDCl3) δ 8.67 (s, 1H), 8.30 (s, 4H), 7.85 (s, 1H),
7.49 - 7.38 (m, 2H), 6.11 (t, J = 5.8 Hz, 1H), 2.19 - 2.15 (m, 2H), 1.41 - 1.38 (m, 4H),
13
0.89 (t, J = 6.2 Hz, 3H); C{1H} NMR (100 MHz, CDCl3) δ 164.1, 164.0, 158.0,
150.7, 148.0, 138.8, 135.2, 131.00, 130.97, 123.7, 123.6, 123.5, 121.8, 77.2, 34.6,
27.5, 22.3, 13.9; IR (KBr) (v, cm-1) 3113, 1726, 1528, 1401, 1346, 1270, 1101, 718;
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HRMS (APCI-TOF) m/z: [M + Na]+ Calcd for C17H18N2O4Na 337.1164; Found
337.1142.
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2-(4-Cyanophenyl)-1-(pyridin-2-yl)ethyl 4-nitrobenzoate (3l). Colorless oil (25.4 mg,
68 % yield); 1H NMR (hydrochloride salt; 400 MHz, CDCl3) δ 8.70 (s, 1H), 8.29 (d, J
= 8.8 Hz, 2H), 8.20 (d, J = 8.8 Hz, 2H), 7.81 - 7.77 (m, 1H), 7.53 (d, J = 8.0 Hz, 2H),
7.39 - 7.32 (m, 4H), 6.36 (t, J = 6.2 Hz, 1H), 3.63 - 3.52 (m, 2H); 13C{1H} NMR (100
MHz, CDCl3) δ 163.6, 156.4, 150.8, 148.4, 141.8, 134.6, 132.4, 132.2, 130.9, 130.3,
124.0, 123.7, 122.1, 118.6, 111.0, 76.9, 40.8; IR (KBr) (v, cm-1) 2926, 2225, 1729,
1606, 1590, 1533, 1505, 1469, 1438, 1348, 1273, 1258, 1113, 1099, 1048, 1014,
1006, 991, 874, 855, 837, 817, 779; HRMS (APCI-TOF) m/z: [M + Na]+ Calcd for
C21H15N3O4Na 396.0960; Found 396.0959.
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2-(4-(Methoxycarbonyl)phenyl)-1-(pyridin-2-yl)ethyl
4-nitrobenzoate
(3m).
Colorless oil (26.0 mg, 64 % yield); 1H NMR (hydrochloride salt; 400 MHz, CDCl3) δ
8.88 (s, 1H), 8.31 - 8.13 (m, 5H), 7.93 (d, J = 4.8 Hz, 2H), 7.94 - 7.92 (m, 1H), 7.55
(s, 1H), 7.38 - 7.37 (m, 2H), 6.59 (s, 1H), 3.88 (s, 3H), 3.77 - 3.69 (m, 2H); 13C{1H}
NMR (100 MHz, CDCl3) δ 166.7, 163.6, 154.6, 151.0, 140.2, 140.1, 133.9, 131.3,
130.0, 129.7. 129.4, 125.6, 124.0, 123.8, 75.0, 52.2, 41.0; IR (KBr) (v, cm-1) 2360,
2341, 1723, 1717, 1528, 1344, 1285, 1270, 1103, 1015; HRMS (APCI-TOF) m/z: [M
+ Na]+ Calcd for C22H18N2O6Na 429.1063; Found 429.1046.
2-(4-Methylphenylsulfonamido)-1-(pyridin-2-yl)ethyl
4-nitrobenzoate
(3n).
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Colorless oil (26.5 mg, 60 % yield); H NMR (hydrochloride salt; 400 MHz,
DMSO-d6) δ 8.63 (d, J = 5.2 Hz, 1H), 8.38 (d, J =11.2 Hz, 2H), 8.30 (d, J =10.8 Hz,
2H), 8.18 (t, J = 6.2 Hz, 1H), 8.01 - 7.97 (m, 1H), 7.65 (d, J = 8.4 Hz, 2H), 8.60 (d, J
= 7.6 Hz, 1H), 7.53 - 7.50 (m, 1H), 7.33 (d, J = 8.0 Hz, 2H), 6.04 (t, J = 5.6 Hz, 1H),
3.48 (t, J = 5.8 Hz, 2H), 2.35 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 164.0,
155.6, 151.0, 148.7, 143.2, 138.3, 135.1, 131.6, 130.2, 126.8, 124.5, 124.3, 122.4,
76.0, 46.3, 21.4; IR (KBr) (v, cm-1) 2361, 1733, 1521, 1338, 1154, 1106, 792, 666;
HRMS (APCI-TOF) m/z: [M + Na]+ Calcd for C21H19N3O6SNa 464.0892; Found
464.0899.
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1-(6-Ethylpyridin-2-yl)ethyl 4-nitrobenzoate (3o). Colorless oil (18.6 mg, 62 %
yield); 1H NMR (hydrochloride salt; 400 MHz, CDCl3) δ 8.31 - 8.27 (m, 4H), 8.14 (t,
J = 7.2 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 6.69 (d, J = 6.4
Hz, 1H), 3.35 (d, J = 6.4 Hz, 2H), 1.95 (d, J = 6.4 Hz, 3H), 1.44 (t, J = 7.6 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 163.5, 161.1, 156.7, 150.8, 134.4, 131.1, 124.1,
123.7, 119.7, 70.9, 27.3, 21.4, 13.5; IR (KBr) (v, cm-1) 1727, 1525, 1348, 1293, 1124,
1103, 1082; HRMS (APCI-TOF) m/z: [M + Na]+ Calcd for C16H16N2O4Na 323.1008;
Found 323.0986.
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1-(6-Methylpyridin-2-yl)ethyl 4-nitrobenzoate (3p). Colorless oil (16.0 mg, 56 %
yield); 1H NMR (hydrochloride salt; 400 MHz, DMSO-d6) δ 8.38 (d, J = 9.2 Hz, 2H),
8.30 (d, J = 8.8 Hz, 2H), 8.21 (t, J = 7.8 Hz, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.64 (d, J =
7.6 Hz, 1H), 6.30 (q, J = 6.8 Hz, 1H), 2.71 (s, 3H), 1.75 (d, J = 6.4 Hz, 3H); 13C{1H}
NMR (100 MHz, DMSO-d6) δ 164.0, 155.9, 151.0, 135.1, 131.5, 126.1, 124.4, 120.3,
71.7, 21.0; IR (KBr) (v, cm-1) 1705, 1651, 826, 777, 629; HRMS (APCI-TOF) m/z:
[M + Na]+ Calcd for C15H14N2O4Na 309.0851; Found 309.0835.
6,7-Dihydro-5H-cyclopenta[b]pyridin-7-yl 4-nitrobenzoate (3q). Colorless oil (21.9
1
mg, 77 % yield); H NMR (hydrochloride salt; 400 MHz, CDCl3) δ 8.74 (d, J = 4.0
Hz, 1H), 8.32 (d, J = 8.4 Hz, 2H), 8.25 (d, J = 8.4 Hz, 2H), 8.19 (d, J = 7.6 Hz, 1H),
7.77 (t, J =5.6 Hz, 1H), 6.69 (t, J = 6.4 Hz, 1H), 3.37 - 3.02 (m, 3H), 2.39 - 2.32 (m,
13
1H); C{1H} NMR (100 MHz, CDCl3) δ 164.3, 157.9, 150.6, 146.2, 139.5, 136.3,
135.2, 131.2, 124.7, 123.4, 77.5, 31.0, 28.1; IR (KBr) (v, cm-1) 3734, 3648, 2359,
2342, 1733, 1716, 1697, 1683, 1653, 1646, 1558, 1540, 1521, 1507, 1457; HRMS
(APCI-TOF) m/z: [M + Na]+ Calcd for C15H12N2O4Na 307.0695; Found 307.0699.
5,6,7,8-Tetrahydroquinolin-8-yl 4-nitrobenzoate (3r). Colorless oil (23.5 mg, 79 %
1
yield); H NMR (hydrochloride salt; 400 MHz, CDCl3) δ 8.75 (s, 1H), 8.24 (s, 4H),
8.14 (d, J = 7.2 Hz, 1H), 7.83 - 7.73 (m, 1H), 6.55 (s, 1H), 3.12 - 2.96 (m, 2H), 2.43 -
2.27 (m, 2H), 2.06 - 2.03 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.7, 150.5,
148.4, 144.8, 141.6, 138.2, 135.1, 131.3, 125.6, 123.4, 68.2, 27.9, 27.8, 18.1; IR
(KBr) (v, cm-1) 3860, 3813, 3799, 3794, 3777, 3742, 3730, 3708, 3686, 1732, 1529,
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1347, 1297, 1234, 1159, 1083, 1014, 956, 872, 851; HRMS (APCI-TOF) m/z: [M +
Na]+ Calcd for C16H14N2O4Na 321.0851; Found 321.0850.
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Isoquinolin-3-ylmethyl 4-nitrobenzoate (3s). Light brown oil (17.9 mg, 58 % yield);
1H NMR (hydrochloride salt; 400 MHz, CDCl3) δ 9.31 (s, 1H), 8.32 - 8.28 (m, 4H),
8.03 (d, J = 8.0 Hz, 1H), 7. 89 - 7.86 (m, 2H), 7.76 (t, J = 7.6 Hz, 1H), 7. 67 (t, J =7.4
Hz, 1H), 5.69 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 164.5, 152.6, 150.6, 147.7,
136.2, 135.3, 131.2, 131.0, 128.1, 128.0, 127.8, 126.7, 123.6, 119.6, 68.0; IR (KBr)
(v, cm-1) 2955, 2924, 2868, 2851, 1726, 1519, 1460, 1283; HRMS (APCI-TOF) m/z:
[M + Na]+ Calcd for C17H12N2O4Na 331.0695; Found 331.0693.
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1-(Pyrazin-2-yl)propyl 4-nitrobenzoate (3t). Colorless oil (18.7 mg, 65 % yield); H
NMR (400 MHz, CDCl3) δ 8.70 (s, 1H), 8.59 - 8.54 (m, 2H), 8.32 - 8.25 (m, 4H),
6.06 - 6.02 (m, 1H), 2.23 - 2.15 (m, 2H), 1.03 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 164.0, 154.2, 150.7, 144.24, 144.19, 143.2, 135.1, 130.9, 123.6, 29.7,
27.6, 9.6; IR (KBr) (v, cm-1) 2359, 2342, 1717, 1540, 1526, 1507, 1270, 1102; HRMS
(APCI-TOF) m/z: [M + Na]+ Calcd for C14H13N3O4Na 310.0804; Found 310.0782.
Quinolin-8-ylmethyl 4-nitrobenzoate (3u). White solid (23.1 mg, 75 % yield); m.p.
1
153 - 154 °C; H NMR (400 MHz, CDCl3) δ 8.97 (d, J = 4.0 Hz, 1H), 8.26 (s, 4H),
8.20 (d, J = 8.4 Hz, 1H), 7.86 - 7.84 (m, 2H), 5.57 (t, J = 7.6 Hz, 1H), 7.47 (dd, J =
13
8.3, 4.2 Hz, 1H), 6.14 (s, 2H); C{1H} NMR (100 MHz, CDCl3) δ 165.7, 150.5,
150.0, 146.2, 136.3, 135.8, 133.5, 130.8, 128.9, 128.5, 128.2, 126.2, 123.5, 121.5,
64.2; IR (KBr) (v, cm-1) 2360, 2342, 1719, 1526, 1346, 1128, 1103, 845, 825; HRMS
(APCI-TOF) m/z: [M + Na]+ Calcd for C17H12N2O4Na 331.0695; Found 331.0677.
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Pyridin-2-ylmethyl 4-methoxybenzoate (3v). Colorless oil (17.5 mg, 72 % yield); H
NMR (hydrochloride salt; 400 MHz, CDCl3) δ 8.78 (d, J = 4.0 Hz, 1H), 8.25 (t, J =
7.4 Hz, 1H), 8.08 (d, J = 8.8 Hz, 2H), 7.83 (d, J = 8.0 Hz, 1H), 7.74 (t, J = 5.8 Hz,
1H), 6.94 (d, J = 8.8 Hz, 2H), 5.82 (s, 2H), 3.86 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 165.4, 164.0, 152.9, 143.7, 143.1, 132.2, 125.2, 124.8, 120.8, 113.9, 62.1,
55.5; IR (KBr) (v, cm-1) 2359, 1716, 1605, 1507, 1269, 1264, 1253, 1169, 1102;
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HRMS (APCI-TOF) m/z: [M + Na]+ Calcd for C14H13NO3Na 266.0793; Found
266.0785.
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(5-Methylpyridin-2-yl)methyl 4-methoxybenzoate (3w). Colorless oil (18.3 mg, 71 %
yield); 1H NMR (hydrochloride salt; 400 MHz, CDCl3) δ 8.59 (s, 1H), 8.08 (d, J = 8.8
Hz, 2H), 8.01 (d, J = 7.6 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H),
5.76 (s, 2H), 3.87 (s, 3H), 2.52 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 165.5,
164.0, 149.7, 144.1, 142.9, 136.1, 132.2, 124.6, 121.0, 113.9, 62.1, 55.5, 18.4; IR
(KBr) (v, cm-1) 3730, 2953, 2918, 2849, 2360, 2341, 1731, 1704, 1513, 1462, 1293,
1236, 1168, 1101, 1083, 1013; HRMS (APCI-TOF) m/z: [M + Na]+ Calcd for
C15H15NO3Na 280.0950; Found 280.0930.
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(5-Ethylpyridin-2-yl)methyl 4-methoxybenzoate (3x). Colorless oil (17.4 mg, 64 %
yield); 1H NMR (hydrochloride salt; 400 MHz, CDCl3) δ 8.52 (s, 1H), 8.06 (d, J = 8.8
Hz, 2H), 7.82 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 6.92 (d, J = 9.2 Hz, 2H),
5.61 (s, 2H), 3.85 (s, 3H), 2.74 (q, J = 7.6 Hz, 2H), 1.28 (t, J = 7.6 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 165.7, 163.7, 151.3, 145.1, 140.5, 140.1, 132.0, 123.4,
121.5, 113.7, 64.1, 55.4, 25.8, 14.8; IR (KBr) (v, cm-1) 3445, 1715, 1575, 1510, 1456,
1317, 1278, 1258, 1168, 1101, 1027, 846, 769; HRMS (APCI-TOF) m/z: [M + Na]+
Calcd for C16H17NO3Na 294.1106; Found 294.1120.
(5-Bromopyridin-2-yl)methyl 4-methoxybenzoate (3y). Colorless oil (24.1 mg, 75 %
yield); 1H NMR (hydrochloride salt; 400 MHz, CDCl3) δ 8.67 (s, 1H), 8.05 (d, J = 8.4
Hz, 2H), 7.85 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H),
5.41 (s, 2H), 3.87 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 165.8, 163.6, 154.7,
150.3, 139.6, 131.9, 123.1, 121.9, 119.8, 113.7, 66.2, 55.5; IR (KBr) (v, cm-1) 1728,
1710, 1607, 1576, 1510, 1472, 1452, 1365, 1333, 1317, 1251, 1114, 1103, 1090,
1023, 1006, 841, 830, 769; HRMS (APCI-TOF) m/z: [M + Na]+ Calcd for
C14H12BrNO3Na 343.9898; Found 343.9918.
(4-Nitropyridin-2-yl)methyl 4-methoxybenzoate (3z). White solid (20.7 mg, 72 %
yield); m.p. 87 - 88 °C; 1H NMR (400 MHz, CDCl3) δ 8.91 (d, J = 5.2 Hz, 1H), 8.14
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(d, J =1.6 Hz, 1H), 8.08 (d, J = 9.2 Hz, 2H), 7.98 - 7.96 (m, 1H), 6.97 (d, J = 7.2 Hz,
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2H), 5.58 (s, 2H), 3.88 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 165.7, 163.8,
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160.1, 154.5, 151.7, 131.9, 121.9, 115.3, 113.9, 66.0, 55.5; IR (KBr) (v, cm-1) 1728,
1607, 1576, 1534, 1509, 1464, 1422, 1357, 1286, 1263, 1170, 1101, 1032, 846, 764,
738, 686; HRMS (APCI-TOF) m/z: [M + Na]+ Calcd for C14H12N2O5Na 311.0644;
Found 311.0639.
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ASSOCIATED CONTENT
Supporting Information.
1H and 13C NMR spectra for all pure products. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
E-mail: csyao@jsnu.edu.cn; ltj2008@jsnu.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful for financial support by National Natural Science Foundation of
China (No. 21772070); A Project Funded by the Natural Science Foundation of the
Jiangsu Higher Education Institution (17KJA150003).
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