Zinc (II)-mediated selective O-benzylation of 2-Oxo-1,2-dihydropyridines systems

Article abstract of DOI:10.3390/molecules23071784

The selective O-benzylation of 2-oxo-1,2-dihydropyridines plays a critical role in organic synthesis of natural products and biological active molecules. Herein we report a novel ternary system of ZnO, ZnCl₂ and N,N-diisopropylethylamine (DIEA), that is highly effective for selective O-benzylation of 2-oxo-1,2-dihydropyridines using abundant substituted benzyl halides and related substituted 2-oxo-1,2-dihydropyridines compounds. This process allows access to a variety of O-benzyl products under mild reaction conditions, which are important synthetic intermediates in the protection of functional groups, and represents a new method toward the development for the O-benzylation of 2-oxo-1,2-dihydropyridines.

Full text of DOI:10.3390/molecules23071784

molecules
Article
Zinc (II)-Mediated Selective O-Benzylation of
2-Oxo-1,2-Dihydropyridines Systems
Qifan Zhou, Fangyu Du, Xinjie Liang, Wenqiang Liu, Ting Fang and Guoliang Chen *
Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang
Pharmaceutical University, Shenyang 110016, China; zhouqifan921@126.com (Q.Z.);
dufangyu1993@163.com (F.D.); renashdol@outlook.com (X.L.); liuwenqiang125@163.com (W.L.);
yzftdyx@126.com (T.F.)
* Correspondence: chenguoliang@syphu.edu.cn; Tel.: +86-24-4352-0623
Academic Editors: Artur M. S. Silva and Maria Manuel Marques
Received: 4 July 2018; Accepted: 17 July 2018; Published: 20 July 2018
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: The selective O-benzylation of 2-oxo-1,2-dihydropyridines plays a critical role in organic
synthesis of natural products and biological active molecules. Herein we report a novel ternary
system of ZnO, ZnCl2 and N,N-diisopropylethylamine (DIEA), that is highly effective for selective
O-benzylation of 2-oxo-1,2-dihydropyridines using abundant substituted benzyl halides and related
substituted 2-oxo-1,2-dihydropyridines compounds. This process allows access to a variety of
O-benzyl products under mild reaction conditions, which are important synthetic intermediates in
the protection of functional groups, and represents a new method toward the development for the
O-benzylation of 2-oxo-1,2-dihydropyridines.
Keywords: O-benzylation; N-benzylation; 2-oxo-1,2-dihydropyridines; zinc (II); selectivity
1. Introduction
2-Oxo-1,2-dihydropyridines fragments are ubiquitous reagents in organic synthesis, and some
natural compounds with this structure have emerged as potent antitumor antiviral and attention [
Meanwhile, they are widely used as peptide mimics, which can generate similar physiological activity
with peptides, such as protease [ ], thrombin inhibitor [ ], elastase [ ], and caspase [ ]. There is
1].
2,
3
4
,5
6,
7
8,9
no doubt that the selective O-alkylation of 2-oxo-1,2-dihydropyridines fragments plays a critical
role in organic synthesis of natural product and active molecule. For example, total synthesis
of pyridomacrolidin [10], the pyridone building block was successfully constructed by selective
bis-O-methylation protection and then deprotection (Scheme 1). Youngdale et al. [11] synthesized a
class of oral hypoglycemic agents via sequences reaction, in which selective O-benzylation reaction
was the critical step (Scheme 1).
The 2-oxo-1,2-dihydropyridines system is identified as an ambident anion under alkaline
atmosphere and can form two reaction sites through tautomerism. It is well-known that this reaction
can give both nitrogen and oxygen alkylation. The alkylation reaction is very sensitive to the reaction
conditions, such as the type of counterions and leaving groups, solvents and alkylating agents,
and temperature [12
–15]. As selective O-alkylation and N-alkylation play vital roles in organic
synthesis, more and more methods for selective alkylation have been reported.
Molecules 2018, 23, 1784; doi:10.3390/molecules23071784
www.mdpi.com/journal/molecules

Molecules 2018, 23, 1784
2 of 14
Scheme 1. The synthetic routes of pyridomacrolidin and hypoglycemic agents.
According to reports [16], silver salts promoted O-alkylation of 2-pyridones, and alkaline metal
salts contributed to N-alkylation. Sato et al. [17] utilized cesium fluoride as an efficient catalyst to
obtain N-alkylation in suitable yield, and the selectivity of alkylation mainly depended on the kind
of alkyl halide (Scheme 2). Singh et al. [18] reported a microwave-assisted protocol for the selective
O-alkylation of aromatic imidate using silver carbonate as base (Scheme 2). Meanwhile, they also
used other silver salts such as silver nitrate, silver oxide, silver acetate, and silver sulfate, etc., which
could not afford desired compounds. Vavilina et al. [19] disclosed that ionic liquids accelerated the
O-alkylation reaction of ambident 2-hydroxypyridine anion in comparison with molecular liquids
using silver salt. Kung et al. [20] conducted a process of selective O-benzylation using silver oxide in the
synthesis of 2-pyridone derivatives, which used in the treatment of leukemia (Scheme 2). Apart from
Ag2CO3, and Ag2O, there is another related work by Kumar et al. in the literature using NaI as
heterogeneous promoter [21]. Although the selective O-benzylation product of 2-pyridone can be
obtained in a moderate yield using silver oxide as base, the large consumption of expensive silver salts
limits the large-scale synthesis of products.
(a) Hopkins and coworkers [12]
(b) Sato and coworkers [17]
Br
Br
O
O
O
OBn
N
Bn
CsF
NH
+
N
Ag2CO3
Pentane
NH
+
DMF, 30 oC
87%
100%
(c) Singh and coworkers [18]
(d) Kung and coworkers [20]
(A)
(B)
Cl
O
OBn
N
OBn
Br
O
Ag2CO3,
NC
NC
Ag2O
n-hexane
N
NH
+
NH
+
o
Toluene,
110 oC
150 C, 300 W,
10 min
70%
69%
Scheme 2. Metal-mediated benzylation of ambident anions. (
ambident anions; (B) In this work.
A) Previous work about benzylation of
Herein (Scheme 2), we describe our efforts to prepare O-benzylation of 2-oxo-1,2-dihydropyridines
from the substituted 2-oxo-1,2-dihydropyridines and substituted benzyl halides using ZnO, ZnCl2
and N,N-diisopropylethylamine (DIEA). These reactions occur at 110 ◦C, under argon atmosphere

Molecules 2018, 23, 1784
3 of 14
and afford appropriate yields. This process is general with respect to both the substituted
2-oxo-1,2-dihydropyridines and substituted benzyl halides, which allows preparation of many complex
of O-benzylation of 2-oxo-1,2-dihydropyridines.
2. Results and Discussion
2.1. Optimization of the Reaction Conditions
According to literature [20], 2-(benzyloxy)-4,6-dimethylnicotinonitrile was obtained using silver
oxide as a base in 65% yield. It is considerate that silver oxide is too expensive, so we are committed to
finding a cheaper alternative catalytic system as a replacement.
Initially, we tried to use zinc (II), a subgroup element, which was also expected to catalyze selective
O-benzylation. Unfortunately, O-benzylation product was not detected by TLC when catalyzed by zinc
oxide alone (Table 1, entry 1). Similar results were observed using binary system of zinc oxide and zinc
chloride (Table 1, entry 2). Surprisingly, the desired O-benzylation product was acquired in 71% yield
through adding additional triethylamine to this catalytic system (Table 1, entry 3). We reasoned that
alkaline environment contributed to the O-benzylation reaction. From the perspective of yield, ternary
system of ZnCl2/ZnO/Et3N has better catalytic performance than silver oxide. Afterwards, in order
to identify which component was indispensable in the ternary system, the reaction was carried out
utilizing zinc chloride and triethylamine, but the benzylation reaction did not occur (Table 1, entry 4).
Interestingly, N-benzylation of product
5 was obtained in 15% yield, when using triethylamine as base
without zinc oxide and zinc chloride (Table 1, entry 5). This clearly highlighted the importance of
the application of ternary system of zinc oxide, zinc chloride and triethylamine which collaboratively
promoted selective O-benzylation. Attempts to reduce the amount of catalyst (0.1 equivalent (equiv))
proved unsuccessful, leading to an incomplete reaction with a yield of only 25% (Table 1, entry 6).
Meanwhile, the reaction was carried out in DIEA (1.1 equiv) and zinc salts (0.1 equiv), and experimental
result displayed that the desired compound was obtained in 13% yield. The result proved that zinc
salts also need to be stoichiometric (Table 1, entry 8). However, it was feasible to change the base
with DIEA proving to be optimal in terms of yield and ease of use (Table 1, entries 7, 9). Efforts to
optimize the reaction through modulation of the solvent proved successful, with 1,4-dioxane being the
most effective in the screening reaction (Table 1, entries 9–12). Meanwhile, the benzylation product
was not observed in polar solvents such as ethylene glycol, N,N-dimethylformamide or dimethyl
sulfoxide, on the contrary, nonpolar solvents were favored. When potassium carbonate was used
as a base, the main product was confirmed as N-benzylation of product
along with unreacted starting material and desired compound (Table 1, entry 13). The same result
was obtained using potassium carbonate and DMF (N-benzylation product was characterized by
5 without any selectivity,
5
1H NMR, seeing supporting information page 46). Simultaneously, some conventional Lewis acids,
such as FeCl3, AlCl3, CuCl2 were also examined in the standard conditions, and no satisfactory results
were obtained (Table 1, entries 14–16). Based on optimized experimental data the optimal reaction
conditions was determined (Table 1, entry 8) which used ZnO (1.1 equiv), ZnCl2 (1.1 equiv), DIEA
(1.1 equiv) and dioxane. Under optimized conditions, the desired product 3a was isolated in 90% yield
on a 20 g scale (Table 1, entry 17).
Microwave-assisted organic synthesis, a growing area in synthetic organic chemistry, is based
on the empirical observation that some reactions proceed faster and result in higher yields under
microwave irradiation than under conventional heating. To our knowledge there are only a few
examples dealing with a comparison of the selective alkylation of the 2-pyridone system under
conventional heating and microwave irradiation [22,23]. Therefore, we investigated the use of
microwave irradiation to promote and activate O-benzylation of 1a and 2a (Scheme 3). Experimental
data displayed that the reaction time was shortened from 24 h to 60 min under microwave irradiation.
However, N-benzylation of product
5 and O-benzylation of product 3a were obtained in 21% and

Molecules 2018, 23, 1784
4 of 14
76% yield respectively, and without selectivity. Hence, microwaves were not used in the study of
substrate suitability.
Table 1. Optimization of the reaction conditions for the O-benzylation of 1a and 2a 1.
Yield (%) 2
ZnO
(Equiv)
Lewis Acid
(Equiv)
Base
(Equiv)
Time
(h)
Entry
Solvent
3a
5
3
3
Entry 1
Entry 2
Entry 3
Entry 4
Entry 5
Entry 6
Entry 7
Entry 8
Entry 9
Entry 10
Entry 11
Entry 12
Entry 13
Entry 14
Entry 15
Entry 16
Entry 17 5
1.1
1.1
1.1
–
–
–
–
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Dioxane
Dioxane
Dioxane
Ethylene glycol
DMF
24
24
24
24
24
36
24
24
24
24
24
24
24
24
24
24
24
–
–
–
–
–
–
3
3
3
3
ZnCl2 (1.1)
ZnCl2 (1.1)
ZnCl2 (1.1)
–
TEA (1.1)
TEA (1.1)
TEA (1.1)
TEA (0.1)
TEA (1.1)
DIEA (1.1)
DIEA (1.1)
DIEA (1.1)
DIEA (1.1)
DIEA (1.1)
K2CO3 (1.1)
DIEA (1.1)
DIEA (1.1)
DIEA (1.1))
DIEA (1.1)
71
3
–
–
4
–
15
3
0.1
1.1
0.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
ZnCl2 (0.1)
ZnCl2 (1.1)
ZnCl2 (0.1)
ZnCl2(1.1)
ZnCl2 (1.1)
ZnCl2 (1.1)
ZnCl2 (1.1)
ZnCl2 (1.1)
AlCl3 (1.1)
FeCl3 (1.1)
CuCl2 (1.1)
ZnCl2 (1.1)
25
64
13
90
–
–
–
–
–
–
–
3
3
3
3
3
–
–
–
3
3
3
3
DMSO
DMF
Dioxane
Dioxane
Dioxane
Dioxane
21
73
3
3
–
–
–
–
–
–
–
3
3
3
3
3
86
1
Unless otherwise noted, the reactions were performed with 1a (3.36 mmol), 2a (4.04 mmol), zinc oxide (3.70 mmol),
zinc chloride (3.70 mmol), N,N-diisopropylethylamine (3.70 mmol) in 1,4-dioxane (15 mL) under argon atmosphere
3
at 110 ◦C. 2 Isolated yield after column chromatography. No reaction was detected by thin-layer chromatography
5
(TLC). 4 N-benzylation of product 5 was obtained in 15% yield. The load of 1a was 20 g.
Scheme 3. Microwave-assisted benzylation of 1a and 2a.
2.2. Scope with Respect to Substituted 2-Oxo-1,2-Dihydropyridines
With the optimal conditions in hand, we chose various of substituted 2-oxo-1,2-dihydropyridiness
as substrates to investigate the scope and toleration of functional groups for this method (Table 2).

Molecules 2018, 23, 1784
5 of 14
Table 2. Scope with respect to O-benzylation of substituted 2-oxo-1,2-dihydropyridines with benzyl
chloride 1.
1
Unless noted otherwise, the reactions were performed with 2-oxo-1,2-dihydropyridines (3.36 mmol), benzyl
chloride (4.04 mmol), zinc oxide (3.70 mmol), zinc chloride (3.70 mmol), N,N-diisopropylethylamine (3.70 mmol) in
1,4-dioxane (15 mL) and isolated after column chromatography.
The reaction enjoys wide substrate scope with respect to substituted 2-oxo-1,2-dihydropyridines
(Table 2). A range of functional groups on the 2-oxo-1,2-dihydropyridines proved to be compatible
including methyl, ethyl, isopropyl, disubstituted alkyl. Interestingly, substrates with 4-methyl
substitution afforded better yield than without 4-methy substitution. Although a more sterically
encumbered 2-oxo-1,2-dihydropyridines substrate also reacted without incident, desired compounds
were obtained in lower yield than other substrates. Not surprisingly, this reaction proceeded more
slowly than those no-ring alkyl substitutions. We postulate that the lower yields of 3e and 3f may
be caused the steric hindrance of the double ring was not conducive to the combination of benzyl
groups. The efficiency for the monoalkyl substitution of 2-oxo-1,2-dihydropyridines was not as high
as that for dialkyl substitution, and we predicted that because of the electron-donating nature of
the alkyl, intermediates of transition with higher electron density would rapidly form under the
reaction conditions. Strangely, 3j was obtained in lower yield (62%). We conducted experiments again
which displayed the same results, but N-benzylation of product was not observed by TLC. At the
same time, longer reaction time did not increase yield of 3j. The main reason was that the optimal
condition was not suitable for this substrate. However, the suitability with respect to substrates
will be further enlarged in subsequent experiments. Considering that electron-withdrawing effect of
cyano on 2-oxo-1,2-dihydropyridine, the two substrates without cyano group of pyridin-2(1H)-one
and 5-bromopyridin-2(1H)-one were tested under the standard reaction conditions. The results
displayed that both substrates provided in high yield (3l and 3m) and there was no clear relevance
of cyano group to O-benzylation. This transformation allows direct construction of a substituted
2-oxo-1,2-dihydropyridines bearing O-benzylation substituent, which remains a significant role in
organic synthesis.
2.3. Scope with Respect to Substituted Benzyl Halides
The ability of benzyl chloride to participate in the reaction opens the possibility for sequential
benzylation. The scope of the reaction with respect to substituted benzyl halides is broad (Table 3).

Molecules 2018, 23, 1784
6 of 14
Table 3. Scope with respect to O-benzylation of 1a with substituted benzyl halides 1.
X
ZnO (1.1 equiv)
ZnCl2(1.1 equiv)
DIEA(1.1 equiv)
O
O
R2
NC
NC
Y
NH
N
Y
2
+
R
Dioxane,
argon, 110 oC
1a
2a 2k
-
4a 4k
-
1
Unless noted otherwise, the reactions were performed with 1a (3.36 mmol), zinc oxide (3.70 mmol), zinc chloride
(3.70 mmol), N,N-diisopropylethylamine (3.70 mmol), substituted benzyl halides (4.04 mmol) in 1,4-dioxane (15 mL)
and isolated after column chromatography.
A wide range of functional groups are tolerated, including methyl, chlorides, bromides, nitriles,
nitro, methoxy and tert-butyl groups (Table 3). To our delight, most of the selected benzyl halides
gave satisfactory results under the standard conditions. Both electron-rich and electron-poor benzyl
halide participated differently well in the reaction. Benzyl halides with electron-withdrawing groups,
such as nitro, nitrile, provided the O-benzylation product under the standard reaction conditions
leading to a modest increase in the yield of target compound (92%). On the contrary, benzyl halides
with electron-donating groups, such as methyl and tert-butyl, provided the O-benzylation product in
slightly lower yield. At the same time, it was found that the position of the substituent has not much
effect on the yield of O-benzylation. Heteroaromatic compounds of chloromethyl pyridines, bearing
functional groups, also can be used in the reaction.
However, when iodomethane and iodoethane were used, the temperature had to be reduced
to boiling point. It is regretful that desired compounds were not obtained. Meanwhile, alkylation
reaction was also preceded in autoclave by standard reaction condition, leading to the same result.
In all cases, N-benzylation product were not observed, which was identified by TLC (N-benzylation
and O-benzylation products show large difference about Rf). Certainly, the major byproducts of
N-benzylation product were formed using potassium carbonate as base in N,N-dimethylformamide.
According to the poor reaction performance in polar solvent, we postulate that these
reactions proceed via a SN2 mechanism involving nucleophilic substitution from the electron-rich
2-oxo-1,2-dihydropyridines to the benzyl chloride (Scheme 4). Upon loss of hydrogen, this process
generates an oxygen anion, which undergoes coupling with the transition state of benzylic cation to
afford the desired compound.

Molecules 2018, 23, 1784
7 of 14
Scheme 4. Possible mechanistic pathway.
3. Materials and Methods
3.1. Materials
All of the starting materials, reagents, and solvents are commercially available and used without
further purification. The microwave-assisted reactions were performed using a CEM Discover System
908010 microwave apparatus (Charlotte, NC, USA). Melting points were determined with a X-4
apparatus and were uncorrected. The nuclear magnetic resonance (NMR) spectra were recorded
on a Bruker 600 MHz spectrometer in CDCl3 or DMSO-d6 using tetramethylsilane (TMS) as an
internal standard. Electrospray ionization mass spectrometry (ESI-MS) analyses were recorded in an
Agilent 1100 Series MSD Trap SL (Santa Clara, CA, USA). The reactions were monitored by thin-layer
chromatography (TLC: HG/T2354-92, GF254), and compounds were visualized on TLC with UV light.
3.2. Microwave-Assisted Synthesis of 3a
To a solution of 1a (0.20 g, 1.35 mmol), zinc oxide (0.12 g, 1.48 mmol), zinc chloride (0.20 g,
1.48 mmol), N,N-diisopropylethylamine (0.19 g, 1.48 mmol), 1,4-dioxane (3 mL) was added benzyl
◦
chloride (0.2 g, 1.61 mmol). The mixture was irradiated at 110 C for 60 min in a dedicated CEM
Discover system, operating at a frequency of 2.45 GHz with continuous irradiation power from
0 to 300 W. After completion of the reaction, the insoluble residue was filtered off through celite,
and the cake was washed with ethyl acetate (30 mL). The filtrate was washed with water (10 mL × 2),
once with brine (10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford
crude product. The product was purified by column chromatography on silica gel (ethyl acetate:
petroleum ether = 1:20) to afford O-benzylation in 65% yield and N-benzylation in 21% yield.
1-Benzyl-4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (
5
): Yellow solid, m.p. 104–107 ◦C,
1
Rf = 0.30 (EtOAc:PE = 1:1). H-NMR (CDCl3, 600 MHz):
δ 7.32 (t, J = 7.0 Hz, 2H), 7.28 (d, J = 7.3 Hz,
1H), 7.16 (d, J = 7.3 Hz, 2H), 6.01 (s, 1H), 5.32 (s, 2H), 2.41 (s, 3H), 2.33 (s, 3H).
3.3. General Procedures for the Synthesis of Substituted 2-Oxo-1,2-dihydropyridines of 1a–1k
A substituted alkyl methyl ketone or cyclic ketone (1 equiv) and ethyl formate or ethyl acetic
(1 equiv) was added dropwise to absolute ether solution of sodium metal (1 equiv) for 1 h while
◦
maintained below 20 C. After the addition, the reaction was allowed to stir in an ice bath until
the sodium metal had disappeared. The precipitate was filtered, washed with absolute ether and
dried to give the corresponding compound which was directly used for the next step without
further purification.
To a solution of previous product (1 equiv), and cyanoacetamide (1.05 equiv) in water was stirred
6 min at room temperature. The mixture was added dropwise piperidine acetate solution (0.3 equiv),
which was prepared from piperidine (1 equiv), acetic acid (1 equiv) and water (5 equiv). The solution
was heated to reflux for 2 h. Then, the reactor was cooled to room temperature, and adjusted to pH 4

Molecules 2018, 23, 1784
8 of 14
by 4 N hydrochloric acid. The resulting solid was filtered, respectively washed with water and ether,
and dried to give the corresponding compound which was purified by recrystallizing using menthol
as solvent.
◦
4,6-Dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (1a): 58% yield
,
white solid, m.p. 264–266 C
◦
(lit. [24] 294 C), 1H-NMR (DMSO-d6, 600 MHz):
δ 12.31 (br, 1H), 6.16 (s, 1H), 2.30 (s, 3H), 2.22 (s, 3H).
6-Methyl◦-2-oxo-1,2-dihydropyridine-3-carbonitrile (1b): 58% yield, yellow solid, m.p. 295–297 ◦C (lit. [25
]
293–294 C), 1H-NMR (DMSO-d6, 600 MHz):
δ 12.56 (br, 1H), 8.01 (d, J = 6.1 Hz, 1H), 6.21 (d, J = 5.7 Hz,
1H), 2.27 (s, 3H).
◦
5,6-Dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (1c): 54% yield, yellow solid, m.p. 223–225 C
(lit. [26] 223–225 ◦C), 1H-NMR (DMSO-d6, 600 MHz):
δ 12.46 (br, 1H), 7.94 (s, 1H), 2.23 (s, 3H), 1.98
(s, 3H).
6-Isobutyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (1d): 33% yield, white solid, m.p. 140–142 ◦C (lit. [27
]
◦
149–150 C), 1H-NMR (DMSO-d6, 600 MHz):
δ
12.52 (br, 1H), 8.04 (d, J = 7.3 Hz, 1H), 6.21 (d, J = 7.4 Hz,
1H), 2.41 (d, J = 7.4 Hz, 2H), 1.98–1.91 (m, 1H), 0.87 (d, J = 6.6 Hz, 6H).
2-Oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carbonitrile (1e): 21% yield, yellow solid, m.p. > 300 ◦C,
1H-NMR (DMSO-d6, 600 MHz):
δ
12.75 (br, 1H), 8.01 (s, 1H), 2.80 (t, J = 7.6 Hz, 2H), 2.64 (t, J = 7.3 Hz,
2H), 2.06–2.01 (m, 2H).
◦
2-Oxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonitrile (1f): 25% yield, yellow solid, m.p. 248–249 C (lit. [28
245–248 C), H-NMR (DMSO-d6, 600 MHz):
2.42 (t, J = 6.2 Hz, 2H), 1.70–1.60 (m, 4H).
]
◦
1
δ 11.64 (br, 1H), 7.89 (s, 1H), 2.56 (t, J = 6.1 Hz, 2H),
6-Ethyl-4-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (1g): 24% yield, white solid, m.p. 230–233 ◦C
(lit. [29] 243–244 ◦C), 1H-NMR (DMSO-d6, 600 MHz):
2.32 (s, 3H), 1.15 (t, J = 7.6 Hz, 3H).
δ
12.27 (br, 1H), 6.19 (s, 1H), 2.52–2.48 (q, 4H),
◦
6-Isobutyl-4-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (1h): 42% yield, white solid, m.p. 169–172 C,
1H-NMR (DMSO-d6, 600 MHz):
δ 12.27 (br, 1H), 6.17 (s, 1H), 2.36 (d, J = 7.4 Hz, 2H), 2.32 (s, 3H),
1.97–1.90 (m, 1H), 0.87 (d, J = 6.6 Hz, 6H).
4-Methyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonitrile (1i): 31% yield, white solid, m.p. 247–250 ◦C
◦
(lit. [30] 308–310 C), 1H-NMR (DMSO-d6, 600 MHz):
δ 12.32 (br, 1H), 2.72 (t, J = 5.9 Hz, 2H), 2.38
(t, J = 6.3 Hz, 2H), 2.21 (s, 3H), 1.68–1.66 (m, 4H).
2-Oxo-6-◦propyl-1,2-dihydropyridine-3-carbonitrile (1j): 41% yield, yellow solid, m.p. 141–143 ◦C (lit. [28
]
151–152 C), 1H-NMR (DMSO-d6, 600 MHz):
δ 12.54 (br, 1H), 8.04 (d, J = 7.4 Hz, 1H), 6.23 (d, J = 7.3 Hz,
1H), 2.52–2.49 (t, 2H), 1.63–1.57 (m, 2H), 0.88 (t, J = 7.4 Hz, 3H).
4-Methyl-2-oxo-6-propyl-1,2-dihydropyridine-3-carbonitrile (1k): 25% yield, white solid, m.p. 154–157 ◦C
(lit. [31] 210–211 ◦C), 1H-NMR (DMSO-d6, 600 MHz):
12.29 (br, 1H), 6.19 (s, 1H), 2.46 (t, J = 7.4 Hz,
δ
2H), 2.32 (s, 3H), 1.64–1.56 (m, 2H), 0.88 (t, 7.4 Hz, 3H).
3.4. General Procedures for the Synthesis of 3a–3m
To a solution of substituted 2-oxo-1,2-dihydropyridines (3.36 mmol), zinc oxide (0.30 g, 3.70 mmol),
zinc chloride (0.50 g, 3.70 mmol), N,N-diisopropylethylamine (0.48 g, 3.70 mmol), 1,4-dioxane (15 mL)
was◦added benzyl chloride (0.58 g, 4.04 mmol) under argon atmosphere. The mixture was heated in
110 C oil bath with rapid stirring for the indicated time. The reactor was cooled to room temperature,
and the insoluble residue was filtered off through celite, and the cake was wash with ethyl acetate
(30 mL). The filtrate was washed with water (10 mL
magnesium sulfate, filtered, and concentrated in vacuo to afford crude product. The product was
×
2), once with brine (10 mL), dried over

Molecules 2018, 23, 1784
9 of 14
purified by column chromatography on silica gel (ethyl acetate: petroleum ether = 1:20) to yield the
corresponding compounds.
2-(Benzyloxy)-4,6-dimethylnicotinonitrile (3a): Yield: 0.72 g (90%), white solid, m.p. 86–87 ◦C, Rf = 0.70
1
(EtOAc:PE = 1:10). H-NMR (CDCl3, 600 MHz): δ 7.49 (d, J = 7.5 Hz, 2H), 7.37 (t, J = 7.3 Hz, 2H), 7.31
(t, J = 7.4 Hz, 1H), 6.69 (s, 1H), 5.48 (s, 2H), 2.45 (s, 3H), 2.44 (s, 3H). 13C-NMR (CDCl3, 150 MHz):
δ
163.66, 160.58, 154.48, 136.55, 128.45, 129.91, 127.85, 117.71, 114.97, 94.15, 68.14, 24.55, 20.08. HRMS
(ESI): m/z [M + Na]+ calculated for C15H14N2ONa: 261.1004, found: 261.1010.
◦
2-(Benzyloxy)-6-methylnicotinonitrile (3b): Yield: 0.55 g (73%), white solid, m.p. 80–81 C (lit. [32
]
◦
106 C), Rf = 0.75 (EtOAc:PE = 1:10). 1H-NMR (CDCl3, 600 MHz):
δ
7.74 (d, J = 7.6 Hz, 1H), 7.37
(t, J = 7.3 Hz, 2H), 7.32 (t, J = 7.4 Hz, 1H), 6.82 (d, J = 7.7 Hz, 1H), 5.50 (s, 2H). 13C-NMR (CDCl3,
150 MHz):
δ 163.04, 162.00, 142.91, 136.31, 128.45, 127.99, 127.93, 116.06, 115.63, 93.54, 68.21, 24.76.
HRMS (ESI): m/z [M + Na]+ calculated for C14H12N2ONa: 247.0847, found: 247.0851.
2-(Benzyloxy)-5,6-dimethylnicotinonitrile (3c): Yield: 0.70 g (88%), white solid, m.p. 79–81 ◦C, Rf = 0.72
1
(EtOAc:PE = 1:10). H-NMR (CDCl3, 600 MHz):
δ
7.60 (s, 1H), 7.49 (d, J = 7.3 Hz, 2H), 7.37 (t, J = 7.3 Hz
,
1
2H), 7.30 (t, J = 7.3 Hz, 1H), 5.48 (s, 2H), 2.45 (s, 2H), 2.21 (s, 3H). H-NMR (CDCl3, 150 MHz):
δ
163.06, 162.04, 142.93, 136.35, 128.48, 128.02, 127.95, 116.11, 115.66, 93.55, 68.24, 24.79. HRMS
(ESI): m/z [M + Na]+ calculated for C15H14N2ONa: 261.1004, found: 261.1008.
2-(Benzyloxy)-6-isobutylnicotinonitrile (3d): Yield: 0.74 g (83%), light yellow liquid, Rf = 0.74
1
(
EtOAc:PE = 1:10). H-NMR (CDCl3, 600 MHz):
δ
7.74 (d, J = 7.7 Hz, 1H), 7.48 (d, J = 7.4 Hz, 2H), 7.36
(t, J = 7.3 Hz, 2H), 7.30 (t, J = 7.4 Hz, 1H), 6.77 (d, J = 7.7 Hz, 1H), 5.50 (s, 2H), 2.59 (d, J = 7.2 Hz, 2H),
2.16–2.09 (m, 1H), 0.91 (d, J = 6.7 Hz, 6H). 13C-NMR (CDCl3, 150 MHz):
δ 165.12, 163.02, 142.71, 136.44,
128.42, 127.93, 127.88, 116.31, 115.68, 93.64, 68.17, 47.40, 28.59, 22.39. HRMS (ESI): m/z [M + Na]+
calculated for C17H18N2ONa: 289.1317, found: 289.1323.
2-(Benzyloxy)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carbonitrile (3e): Yield: 0.51 g (61%), light yellow
1
solid, m.p. 68–71 ◦C, Rf = 0.76 (EtOAc:PE = 1:10). H-NMR (CDCl3, 600 MHz):
δ 7.65 (s, 1H), 7.49
(
d, J = 7.4 Hz, 2H), 7.37 (t, J = 7.3 Hz, 2H), 7.31 (t, J = 7.4 Hz, 1H), 5.49 (s, 2H), 2.97 (t, J = 7.7 Hz, 2H),
2.88 (t, J = 7.5 Hz, 2H), 2.18–2.13 (m, 2H). 13C-NMR (CDCl3, 150 MHz):
δ 169.05, 163.67, 138.17, 136.40,
129.59, 128.45, 127.92, 127.72, 116.20, 93.46, 68.29, 34.74, 29.55, 23.06. HRMS (ESI): m/z [M + Na]+
calculated for C16H14N2ONa: 273.1004, found: 273.1014.
2-(Benzyloxy)-5,6,7,8-tetrahydroquinoline-3-carbonitrile (3f): Yield: 0.58 g (66%), white solid, m.p.
67–68 ◦C, Rf = 0.74 (EtOAc:PE = 1:10). 1H-NMR (CDCl3, 600 MHz):
(
δ
7.54 (s, 1H), 7.49
d, J = 7.4 Hz, 2H), 7.37 (t, J = 7.3 Hz, 2H), 7.31 (t, J = 7.3 Hz, 1H), 5.46 (s, 2H), 2.83 (t, J = 6.3 Hz,
2H), 2.67 (t, J = 6.3 Hz, 2H), 1.88–1.84 (m, 2H), 1.81–1.77 (m, 2H). 13C-NMR (CDCl3, 150 MHz):
161.01,
δ
160.43, 143.35, 136.60, 128.41, 127.91, 127.88, 125.20, 115.77, 93.70, 68.02, 32.74, 27.46, 22.44. HRMS (ESI):
m/z [M + Na]+ calculated for C17H16N2ONa: 287.1160, found: 273.1173.
2-(Benzyloxy)-6-ethyl-4-methylnicotinonitrile (3g): Yield: 0.73 g (86%), light yellow liquid, Rf = 0.78
1
(EtOAc:PE = 1:10). H-NMR (CDCl3, 600 MHz):
δ 7.48 (dd, J = 1.3 Hz, 8.2 Hz, 2H), 7.36 (t, J = 7.3 Hz,
2H), 7.30 (t, J = 7.3 Hz, 1H), 6.68 (s, 1H), 5.50 (s, 2H), 2.71 (q, J = 7.6 Hz, 15.1 Hz, 2H), 2.45 (s, 3H),
1.26 (t, J = 7.8 Hz, 3H). 13C-NMR (CDCl3, 150 MHz):
δ 165.49, 163.71, 154.55, 136.66, 129.39, 127.89,
127.86, 116.48, 115.01, 94.22, 68.02, 31.21, 20.13, 13.00. HRMS (ESI): m/z [M + Na]+ calculated for
C17H16N2ONa: 287.1160, found: 273.1173.
2-(Benzyloxy)-6-isobutyl-4-methylnicotinonitrile (3h): Yield: 0.76 g (80%), Colorless liquid, Rf = 0.77
1
(EtOAc:PE = 1:10). H-NMR (CDCl3, 600 MHz):
δ 7.48 (d, J = 7.4 Hz, 2H), 7.36 (t, J = 7.4 Hz, 2H), 7.29
(t, J = 7.3 Hz, 1H), 6.64 (s, 1H), 5.49 (s, 2H), 2.53 (d, J = 7.2 Hz, 2H), 2.45 (s, 3H), 2.15–2.08 (m, 1H),
0.90 (d, J = 6.6 Hz, 6H). 13C-NMR (CDCl3, 150 MHz):
δ 163.69, 163.62, 154.22, 136.67, 128.39, 127.83,
127.81, 117.92, 115.01, 94.23, 68.08, 47.25, 28.50, 22.43, 20.12. HRMS (ESI): m/z [M + Na]+ calculated for
C18H20N2ONa: 303.1473, found: 303.1479.

Molecules 2018, 23, 1784
10 of 14
2-(Benzyloxy)-4-methyl-5,6,7,8-tetrahydroquinoline-3-carbonitrile (3i): Yield: 0.66 g (71%), white solid, m.p.
1
90–92 ◦C, Rf = 0.75 (EtOAc:PE = 1:10). H-NMR (CDCl3, 600 MHz):
δ 7.49 (d, J = 7.4 Hz, 2H), 7.36
(t, J = 7.3 Hz, 2H), 7.29 (t, J = 7.4 Hz, 1H), 5.49 (s, 2H), 2.87 (t, J = 6.2 Hz, 2H), 2.55 (t, J = 5.9Hz, 2H),
2.41 (s, 3H), 1.84–1.76 (m, 4H). 13C-NMR (CDCl3, 150 MHz):
δ 161.32, 159.29, 152.65, 136.90, 128.37,
127.80, 127.76, 124.23, 115.08, 93.42, 67.71, 28.51, 25.35, 22.53, 22.50, 21.49. HRMS (ESI): m/z [M + Na]+
calculated for C18H18N2ONa: 301.1317, found: 301.1360.
2-(Benzyloxy)-6-propylnicotinonitrile (3j): Yield: 0.46 g (62%), light yellow liquid, Rf = 0.73
1
(
EtOAc:PE = 1:10). H-NMR (CDCl3, 600 MHz):
δ
7.75 (d, J = 7.6 Hz, 1H), 7.49 (d, J = 7.2 Hz, 2H), 7.37
(
t, J = 7.3 Hz, 2H), 7.31 (t, J = 7.3 Hz, 1H), 6.79 (d, J = 7.6 Hz, 1H), 5.51 (s, 2H), 2.71 (t, J = 7.4 Hz, 2H),
1.78–1.71 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H). 13C-NMR (CDCl3, 150 MHz):
δ 165.80, 163.13, 142.88, 136.46,
128.45, 127.97, 127.95, 115.92, 115.64, 93.67, 68.18, 40.25, 22.12, 13.76. HRMS (ESI): m/z [M + Na]+
calculated for C16H16N2ONa: 275.1160, found: 275.1159.
2-(Benzyloxy)-4-methyl-6-propylnicotinonitrile (3k): Yield: 0.78 g (82%), Colorless liquid, Rf = 0.72
1
(EtOAc:PE = 1:10). H-NMR (CDCl3, 600 MHz):
δ 7.48 (d, J = 7.3 Hz, 2H), 7.36 (t, J = 7.1 Hz, 2H), 7.30
(t, J = 6.3 Hz, 1H), 6.67 (s, 1H), 5.49 (s, 2H), 2.65 (t, J = 7.4 Hz, 2H), 2.45 (s, 3H), 1.76–1.68 (m, 2H), 0.93
(t, J = 7.3 Hz, 3H). 13C-NMR (CDCl3, 150 MHz):
δ 164.33, 163.70, 154.38, 136.66, 128.39, 127.84, 117.23,
115.01, 94.22, 68.06, 40.05, 22.09, 13.76. HRMS (ESI): m/z [M + Na]+ calculated for C17H18N2ONa:
289.1317, found: 289.1315.
1
2-(Benzyloxy)pyridine (3l): Yield: 0.90 g (93%), Colorless liquid, Rf = 0.75 (EtOAc:PE = 1:10). H-NMR
(CDCl3, 600 MHz): 8.18 (dd, J = 1.4, 5.0 Hz, 1H), 7.60–7.57 (m, 1H), 7.46 (d, J = 7.4 Hz, 2H), 7.37
(
t, J = 5.7 Hz, 2H), 7.31 (t, J = 7.3 Hz, 1H), 6.89–6.87 (m, 1H), 6.81 (d, J = 8.3 Hz, 1H), 5.38 (s, 2H).
13C-NMR (CDCl3, 150 MHz):
δ
163.6, 146.8, 138.6, 137.3, 128.4, 127.9, 127.8, 116.9, 111.3, 67.5. MS (ESI)
m/z [M + H]+ 186.1.
◦
2-(Benzyloxy)-5-bromopyridine (3m): Yield: (92%), White solid, Rf = 0.71 (EtOAc:PE = 1:10), m.p. 54–55 C
(lit.33 56–58 C), 1H-NMR (CDCl3, 600 MHz): 8.20 (d, J = 2.2 Hz, 1H), 7.61 (dd, J = 2.4, 8.8 Hz, 1H), 7.42
◦
(d, J = 7.5 Hz, 2H), 7.35 (t, J = 7.3 Hz, 2H), 7.30 (t, J = 7.3 Hz, 1H), 6.69 (d, J = 8.8 Hz, 1H), 5.33 (s, 2H).
13C-NMR (CDCl3, 150 MHz):
m/z [M + H]+ 264.0, 265.9.
δ 162.4, 147.5, 141.2, 136.9, 128.6, 128.1, 128.0, 113.0, 112.0, 68.1. MS (ESI)
3.5. General Procedures for the Synthesis of 4a–4k
To a solution of 1a (0.5 g, 3.36 mmol), zinc oxide (0.30 g, 3.70 mmol), zinc chloride (0.50 g,
3.70 mmol), N,N-diisopropylethylamine (0.48 g, 3.70 mmol), 1,4-dioxane (15 mL) was added substituted
benzyl halides (4.04 mmol) under argon atmosphere. The mixture was heated in 110 ◦C oil bath with
rapid stirring for the indicated time. The reactor was cooled to room temperature, and the insoluble
residue was filtered off through celite, and the cake was wash with ethyl acetate (30 mL). The filtrate
was washed with water (10 mL
and concentrated in vacuo. The product was purified by column chromatography on silica gel
(ethyl acetate: petroleum ether = 1:20) to yield the corresponding compounds.
×
2), once with brine (10 mL), dried over magnesium sulfate, filtered,
4,6-Dimethyl-2-((4-methylbenzyl)oxy)nicotinonitrile (4a): Yield: 0.68 g (80%), white solid, m.p. 93–95 ◦C,
1
Rf = 0.71 (EtOAc:PE = 1:10). H-NMR (CDCl3, 600 MHz):
δ 7.38 (d, J = 7.9 Hz, 2H), 7.17 (d, J = 7.8 Hz,
2H), 6.68 (s, 1H), 5.44 (s, 2H), 2.45 (s, 3H), 2.43 (s, 3H), 2.35 (s, 3H). 13C-NMR (CDCl3, 150 MHz):
163.72, 160.52, 154.41, 137.68, 133.50, 129.09, 128.06, 117.59, 114.98, 94.13, 68.10, 24.53, 21.21, 20.04.
HRMS (ESI): m/z [M + Na]+ calculated for C16H16N2ONa: 275.1160, found: 275.1169.
δ
◦
2-((4-Chlorobenzyl)oxy)-4,6-dimethylnicotinonitrile (4b): Yield: 0.78 g (85%), white solid, m.p. 119–121 C,
1
Rf = 0.72 (EtOAc:PE = 1:10). H-NMR (CDCl3, 600 MHz):
δ
7.42 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.3 Hz,
163.39, 160.55, 154.56, 135.04,
2H), 6.70 (s, 2H), 5.44 (s, 2H), 2.45 (s, 6H). 13C-NMR (CDCl3, 150 MHz):
δ

Molecules 2018, 23, 1784
11 of 14
133.71, 129.22, 128.61, 117.87, 114.85, 94.14, 67.33, 24.51, 20.06. HRMS (ESI): m/z [M + Na]+ calculated
for C15H13ClN2ONa: 295.0614, found: 295.0616.
◦
2-(Benzyloxy)-4,6-dimethylnicotinonitrile (4c = 3a): Yield: 0.72 g (91%), white solid, m.p. 86–87 C,
Rf = 0.70 (EtOAc:PE = 1:10). H-NMR (CDCl3, 600 MHz):
1
δ 7.48 (d, J = 7.3 Hz, 2H), 7.36 (t, J = 7.3 Hz,
2H), 7.30 (t, J = 7.3 Hz, 1H), 6.68 (s, 1H), 5.48 (s, 2H), 2.45 (s, 3H), 2.43 (s, 3H). 13C-NMR (CDCl3,
150 MHz): 163.66, 160.59, 154.48, 136.55, 128.45, 127.91, 127.87, 127.85, 117.74, 114.97, 94.14, 68.14,
δ
24.56, 20.07. HRMS (ESI): m/z [M + Na]+ calculated for C15H14N2ONa: 261.1004, found: 261.1010.
2-((3,4-D◦ichlorobenzyl)oxy)-4,6-dimethylnicotinonitrile (4d): Yield: 0.90 g (88%), white solid, m.p.
104–106 C, Rf = 0.72 (EtOAc:PE = 1:10). 1H-NMR (CDCl3, 600 MHz):
δ 7.57 (d, J = 1.6 Hz, 1H),
7.43 (d, J = 8.2 Hz, 1H), 7.34 (t, J = 1.7 Hz, 1H), 6.72 (s, 1H), 5.42 (s, 2H), 2.45 (s, 3H), 2.44 (s, 3H).
13C-NMR (CDCl3, 150 MHz):
δ 163.10, 160.57, 154.68, 136.80, 132.47, 131.93, 130.47, 129.84, 127.18,
118.08, 114.72, 94.15, 66.62, 24.49, 20.07. HRMS (ESI): m/z [M + Na]+ calculated for C15H12Cl2N2ONa:
329.0224, found: 329.0222.
2-((2,3-D◦ichlorobenzyl)oxy)-4,6-dimethylnicotinonitrile (4e): Yield: 0.84 g (82%), white solid, m.p.
167–169 C, Rf = 0.73 (EtOAc:PE = 1:10). 1H-NMR (CDCl3, 600 MHz):
δ 7.55 (d, J = 7.7 Hz, 1H),
7.43 (d, J = 6.8 Hz, 1H), 7.24 (t, J = 7.9 Hz, 1H), 5.56 (s, 2H), 2.47 (s, 3H), 2.46 (s, 3H). 13C-NMR (CDCl3,
150 MHz):
δ 163.14, 160.83, 154.62, 136.71, 132.98, 130.73, 129.56, 127.48, 126.65, 118.16, 114.79, 94.08,
65.59, 24.55, 20.10. HRMS (ESI): m/z [M + Na]+ calculated for C15H12Cl2N2ONa: 329.0224, found:
329.0232.
2-((2,4-D◦ichlorobenzyl)oxy)-4,6-dimethylnicotinonitrile (4f): Yield: 0.89 g (86%), white solid, m.p.
146–148 C, Rf = 0.72 (EtOAc:PE = 1:10). 1H-NMR (CDCl3, 600 MHz):
δ 7.56 (d, J = 8.3 Hz, 1H),
7.40 (d, J = 2.0 Hz, 1H), 7.28 (t, J = 2.0 Hz, 1H), 6.73 (s, 1H), 5.51 (s, 2H), 2.47 (s, 3H), 2.46 (s, 3H).
13C-NMR (CDCl3, 150 MHz):
δ 163.11, 160.75, 154.60, 134.08, 133.47, 132.99, 130.91, 129.80, 127.24,
118.11, 114.74, 94.07, 64.88, 24.51, 20.07. HRMS (ESI): m/z [M + Na]+ calculated for C15H12Cl2N2O Na:
329.0224, found: 329.0219.
4,6-Dimethyl-2-((4-nitrobenzyl)oxy)nicotinonitrile (4g): Yield: 0.87 g (92%), white yellow solid, m.p.
1
152–154 ◦C, Rf = 0.50 (EtOAc:PE = 1:10). H-NMR (CDCl3, 600 MHz):
δ 8.24 (d, J = 8.7 Hz, 2H), 7.66
(d, J = 8.7 Hz, 2H), 6.75 (s, 1H), 5.58 (s, 2H), 2.48 (s, 3H), 2.45 (s, 3H). 13C-NMR (CDCl3, 150 MHz):
162.98, 160.68, 154.81, 147.5, 144.01, 127.94, 123.74, 118.31, 114.67, 94.20, 66.74, 24.49, 20.09. HRMS
(ESI): m/z [M + Na]+ calculated for C15H13N3O3Na : 306.0855, found: 306.0852.
δ
◦
2-((4-Bromobenzyl)oxy)-4,6-dimethylnicotinonitrile (4h): Yield: 0.97 g (92%), white solid, m.p. 122–124 C,
1
Rf = 0.68 (EtOAc:PE = 1:10). H-NMR (CDCl3, 600 MHz):
δ
7.49 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.3 Hz
,
2H), 6.70 (s, 1H), 5.42 (s, 2H), 2.45 (s, 3H), 2.44 (s, 3H). 13C-NMR (CDCl3, 150 MHz):
δ
163.37,
160.55, 154.57, 135.56, 131.57, 129.53, 121.86, 117.89, 114.83, 94.16, 67.35, 24.51, 20.07. HRMS (ESI):
m/z [M + Na]+ calculated for C15H12Cl2N2ONa: 329.0224, found: 329.0219.
2-((4-(t◦ert-Butyl)benzyl)oxy)-4,6-dimethylnicotinonitrile (4i): Yield: 0.81 g (82%), white solid, m.p.
80–82 C, Rf = 0.76 (EtOAc:PE = 1:10). 1H-NMR (CDCl3, 600 MHz):
δ 7.42 (d, J = 8.2 Hz, 2H),
7.39 (d, J = 8.2 Hz, 2H), 6.68 (s, 2H), 5.44 (s, 2H), 2.45 (s, 3H), 2.43 (s, 3H), 1.32 (s, 9H). 13C-NMR (CDCl3,
150 MHz):
δ 163.79, 160.58, 154.44, 150.93, 133.51, 127.85, 125.38, 117.63, 115.02, 94.14, 68.09, 34.60, 31.37,
24.58, 20.07. HRMS (ESI): m/z [M + Na]+ calculated for C19H22N2ONa: 317.1630, found: 317.1642.
2-((4-Cyanobenzyl)oxy)-4,6-dimethylnicotinonitrile (4j): Yield: 0.81 g (92%), white solid, m.p. 173–175 ◦C,
1
Rf = 0.53 (EtOAc:PE = 1:10). H-NMR (CDCl3, 600 MHz):
δ
7.66 (d, J = 8.1 Hz, 2H), 7.59 (d, J = 8.2 Hz,
163.05, 160.67,
2H), 6.74 (s, 1H), 5.53 (s, 2H), 2.47 (s, 3H), 2.44 (s, 3H). 13C-NMR (CDCl3, 150 MHz):
δ
154.76, 142.01, 132.32, 127.87, 118.75, 118.25, 114.70, 111.63, 94.17, 66.97, 24.50, 20.09. HRMS (ESI): m/z
[M + Na]+ calculated for C16H13N3ONa: 286.0956, found: 286.0949.

Molecules 2018, 23, 1784
12 of 14
2-((3,4-Dimethoxypyridin-2-yl)methoxy)-4,6-dimethylnicotinonitrile (4k): Yield: 0.81 g (80%), white solid,
◦
1
m.p. 137–139 C, Rf = 0.50 (EtOAc:PE = 1:5). H-NMR (CDCl3, 600 MHz):
δ 8.26 (d, J = 5.5 Hz, 1H), 6.87
(d, J = 5.5 Hz, 1H), 6.70 (s, 1H), 5.56 (s, 2H), 3.95 (s, 3H), 3.94 (s, 3H), 2.46 (s, 3H), 2.44 (s, 3H). 13C-NMR
(CDCl3, 150 MHz):
δ 163.74, 160.69, 159.01, 154.38, 149.69, 145.81, 145.17, 117.68, 115.08, 107.96, 93.88,
66.04, 61.75, 55.76, 24.56, 20.07. HRMS (ESI): m/z [M + Na]+ calculated for C16H17N3O3Na: 322.1168,
found: 322.1183.
Supplementary Materials contain all obtained 1H-NMR and 13C-NMR spectra of compounds
presented in the manuscript.
4. Conclusions
In summary, we have developed a ternary system for the selective O-benzylation of
2-oxo-1,2-dihydropyridines systems that utilizes readily available ZnO, ZnCl2, DIEA, substituted
benzyl halides and related 2-oxo-1,2-dihydropyridines compounds. This protocol proposes a novel
method in C-O bond construction and provides some examples of selective O-benzylation of
2-oxo-1,2-dihydropyridines using readily available starting materials under mild reaction conditions.
This reaction allows the conversion of simple starting materials to complex O-benzyl products,
which are important synthetic intermediates in the protection of functional groups. Efforts to apply
our Zn-based system to other 2-oxo-1,2-dihydropyridines and to expand the scope of the benzylation
reactions to other classes of alkylation are currently underway in our laboratory.
Supplementary Materials: The following are available online.
Author Contributions: Conceptualization, G.C. and Q.Z.; Methodology, Q.Z. and F.D.; Software, T.F. and W.L.;
Formal Analysis, X.L. and F.D.; Writing-Original Draft Preparation, Q.Z. and F.D.; Writing-Review and Editing,
Q.Z. and F.D.; Project Administration, G.C.
Funding: This research was funded by Liaoning Provincial Natural Science Foundation of China (No. 201602707).
Conflicts of Interest: The authors declare no conflicts of interest.
References
1.
Mercedes, T.; Salvador, G.; Margarita, P. New synthetic methods to 2-pyridone rings. Curr. Org. Chem. 2005
9, 1757–1779.
,
2.
Verissimo, E.; Berry, N.; Gibbons, P.; Cristiano, M.L.S.; Rosenthal, P.J.; Gut, J.; Ward, S.A.; O’Neill, P.M. Design
and synthesis of novel 2-pyridone peptidomimetic falcipain 2/3 inhibitors. Bioorg. Med. Chem. Lett. 2008, 18,
4210–4214. [CrossRef] [PubMed]
3.
4.
Sanderson, P.E.J.; Dyer, D.L.; Naylor-Olsen, A.M.; Vacca, J.P.; Gardell, S.J.; Lewis, S.D.; Lucas, B.J., Jr.;
Lyle, E.A.; Lynch, J.J., Jr.; Mulichak, A.M. L-373,890, an achiral, noncovalent, subnanomolar thrombin
inhibitor. Bioorg. Med. Chem. Lett. 1997, 7, 1497–1500. [CrossRef]
Reiner, J.E.; Lim-Wilby, M.S.; Brunck, T.K.; Ha-Uong, T.; Goldman, E.A.; Abelman, M.A.; Nutt, R.F.;
Semple, J.E.; Tamura, S.Y. Investigation of the S3 site of thrombin: Design, synthesis and biological activity
of 4-substituted 3-amino-2-pyridones incorporating P1-argininals. Bioorg. Med. Chem. Lett. 1999, 9, 895–900.
[CrossRef]
5.
6.
Sanderson, P.E.; Cutrona, K.J.; Dorsey, B.D.; Dyer, D.L.; McDonough, C.M.; Naylor-Olsen, A.M.; Chen, I.W.;
Chen, Z.; Cook, J.J.; Gardell, S.J.; et al. L-374,087, an efficacious, orally bioavailable, pyridinone acetamide
thrombin inhibitor. Bioorg. Med. Chem. Lett. 1998, 8, 817–822. [CrossRef]
Veale, C.A.; Bernstein, P.R.; Bryant, C.; Ceccarelli, C.; Damewood, J.R., Jr.; Earley, R.; Feeney, S.W.; Gomes, B.;
Kosmider, B.J.; Steelman, G.B.; et al. Nonpeptidic inhibitors of human leukocyte elastase. 5. design, synthesis,
and X-ray crystallography of a series of orally active 5-aminopyrimidin-6-one-containing trifluoromethyl
ketones. J. Med. Chem. 1995, 38, 98–108. [CrossRef] [PubMed]
7.
Brown, F.J.; Andisik, D.W.; Bernstein, P.R.; Bryant, C.B.; Ceccarelli, C.; Damewood, J.R., Jr.; Edwards, P.D.;
Earley, R.A.; Feeney, S.; Green, R.C.; et al. Design of orally active, non-peptidic inhibitors of human leukocyte
elastase. J. Med. Chem. 1994, 37, 1259–1261. [CrossRef] [PubMed]

Molecules 2018, 23, 1784
13 of 14
8.
9.
Semple, G.; Ashworth, D.M.; Batt, A.R.; Baxter, A.J.; Benzies, D.W.; Elliot, L.H.; Evans, D.M.;
Franklin, R.J.; Hudson, P.; Jenkins, P.D.; et al. Peptidomimetic aminomethylene ketone inhibitors of
interleukin-i[3-converting enzyme (ice). Bioorg. Med. Chem. Lett. 1998, 8, 959–964. [CrossRef]
Semple, G.; Ashworth, D.M.; Batt, A.R.; Baxter, A.J.; Benzies, D.W.; Elliot, L.H.; Evans, D.M.; Franklin, R.J.;
Hudson, P.; Jenkins, P.D.; et al. Pyridone-based peptidomimetic inhibitors of interleukin-lβ-converting
enzyme (ice). Bioorg. Med. Chem. Lett. 1997, 7, 1337–1342. [CrossRef]
10. Baldwin, J.E.; Adlington, R.M.; Conte, A.; Irlapati, N.R.; Marquez, R.; Pritchard, G. Total synthesis of
pyridovericin: Studies toward the biomimetic synthesis of pyridomacrolidin. J. Org. Lett. 2002, 4, 2125–2127.
[CrossRef]
11. Youngdale, G.A.; Oglia, T.F. 1,2-Dihydro-2-oxo-6-(2,2-dimethylpropyl)-3-pyridinecarboxylic acid, analogues,
and derivatives. A new class of oral hypoglycemic agents. J. Med. Chem. 1985, 28, 1790–1796. [CrossRef]
[PubMed]
12. Kornblum, N.; Smiley, R.A.; Blackwood, R.K.; Iffland, D.C. The mechanism of the reaction of silver nitrite
with alkyl halides. The contrasting reactions of silver and alkali metal salts with alkyl halides. The alkylation
of ambident anions. J. Am. Chem. Soc. 1955, 77, 6269–6280. [CrossRef]
13. Kornblum, N.; Paul, J.B.; William, J.L.N. Solvation as a factor in the alkylation of ambident anions:
The importance of the hydrogen bonding capacity of the solvent. J. Am. Chem. Soc. 1963, 85, 1141–1147.
[CrossRef]
14. Kornblum, N.; Seltzer, R.; Haberfield, P. Solvation as a factor in the alkylation of ambident anions:
The importance of the dielectric factor. J. Am. Chem. Soc. 1963, 85, 1148–1154. [CrossRef]
15. Hopkins, G.C.; Jonak, J.P.; Tieckelmann, H.; Minnemeyer, H.J. Alkylations of heterocyclic ambident anions.
I. 2-hydroxypyrimidines. J. Org. Chem. 1966, 31, 3969–3973. [CrossRef]
16. Hopkins, G.; Jonak, J.; Minnemeyer, H.; Tieckelmann, H. Alkylations of heterocyclic ambident anions.
11. alkylation of 2-pyridone salts. J. Org. Chem. 1967, 32, 4040–4044. [CrossRef]
17. Sato, T.; Yoshimatsu, K.; Otera, J. CsF in organic synthesis. tuning of n- or o-alkylation of 2-pyridone. Synlett
1995, 1995, 845–846. [CrossRef]
18. Singh, B.K.; Cavalluzzo, C.; Maeyer, M.D.; Debyser, Z.; Parmarb, V.S.; Eycken, E.V. Microwave-assisted
silver(I)-mediated selective o-alkylation of aromatic imidate systems. Synthesis 2009, 16, 2725–2728.
[CrossRef]
19. Vavilina, G.; Zicmanis, A.; Mekss, P.; Klavins, M. Alkylation of the 2-hydroxypyridine anion in ionic liquid
media. Chem. Heterocyclic. Compd. 2008, 44, 549–558. [CrossRef]
20. Kung, P.P.; Rui, E.; Bergqvist, S.; Bingham, P.; Braganza, J.; Collins, M.; Cui, M.; Diehl, W.; Dinh, D.; Fan, C.;
et al. Design and synthesis of pyridone-containing 3,4-dihydroisoquinoline-1(2H)-ones as a novel class of
enhancer of zeste homolog 2 (EZH2) inhibitors. J. Med. Chem. 2016, 59, 8306–8325. [CrossRef] [PubMed]
21. Kumar, R.N.; Mallarrddy, G.; Nagender, P.; Rao, P.S.; Poorinachandra, Y.; Ranjithreddy, P.; Kumar, C.G.;
Narsaiah, B. Synthesis of novel triazole functionalized pyridine derivatives as potential antimicrobial and
anti-biofilm agents. Indian J. Chem. Sect. B 2016, 55B, 1361–1375.
22. Almena, I.; Diaz-Ortiz, A.; Diez-Barra, E.; de la Hoz, A.; Loupy, A. Solvent-free benzylation of 2-pyridone.
Regiospecific N- or C-alkylation. Chem. Lett. 1996, 27, 333–334. [CrossRef]
23. De la Hoz, A.; Prieto, M.P.; Rajzmann, M.; de Cózar, A.; Díaz-Ortiz, A.; Moreno, A.; Cossíoc, F.P. Selectivity
under microwave irradiation. Benzylation of 2-pyridone: An experimental and theoretical study. Tetrahedron
2008, 64, 8169–8176. [CrossRef]
24. Elassar, A.Z.A. Synthesis and reactions of 3-cyano-4,6-dimethyl-2-pyridone. J. Heterocycl. Chem. 2011, 48,
272–278. [CrossRef]
25. Azuma, Y.; Morone, M.; Nagayama, K.; Kawamata, Y.; Sato, A. Synthesis and reactions of
4-chloro-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile. Heterocycles 2003, 60, 1461–1468. [CrossRef]
26. Raymond, M.P. Condensations of unsymmetrical ketones. I. condensations with ethyl formate. J. Am. Chem.
Soc. 1947, 69, 2670–2672.
27. Hideshi, K.; Hiroshi, M. A convenient synthesis of 2-aminopyridine-3-carbonitriies. J. Heterocycl. Chem. 1977
,
14, 1077–1079.
28. Angel, A.; Celia, A.; Alfonso, G.O.; Rafael, P.; Martina, V. The reaction of
β-aminoenones with substituted
acetonitriles. Regiospecific synthesis of 2(1H)-pyridones. J. Heterocycl. Chem. 1987, 24, 709–713.

Molecules 2018, 23, 1784
14 of 14
29. Akio, S.; Hiroshi, M.B. The cyclization of ethyl cyanoacetate and ketones by ammonium acetate. Bull. Chem.
Soc. Jpn. 1967, 40, 1680–1684.
30. Luisa, M.; Giulia, M.; Pietro, S.; Paola, D.; Maria, G.R.; Franco, B.; Gabriella, B. Synthesis and cardiotonic
activity of esters of 2-substituted 5-cyano1,6-dihydro-6-oxo-3-pyridinecarboxylic acids. Crystal structure of
2-methyl, 2-t-butyl and 2-phenyl esters. Eur. J. Med. Chem. 1989, 24, 517–529.
31. Hassan, M.A.; Soliman, E.A.; Hamed, A.A. Synthesis and reactions of polysubstituted 2(1H)-pyridones and
pyridines. Cheminform 1982, 56, 419–423.
32. Lott, W.A.; Shaw, E. Analogs of aspergillic acid; various antibacterial heterocyclic hydroxamic acids. J. Am.
Chem. Soc. 1949, 71, 70–73. [CrossRef] [PubMed]
Sample Availability: Samples of the compounds are not available from the authors.
©
2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).