Transition metal-free α-methylation of 1,8-naphthyridine derivatives using DMSO as methylation reagent

Article abstract of DOI:10.1039/c9ob01490j

A practical approach to the direct α-methylation of 1,8-naphthyridines under mild reaction conditions has been developed using simple and readily available DMSO as a convenient and environmentally friendly carbon source. This method is transition metal-free and highly chemoselective, shows good functional group tolerance, and uses DMSO as a methyl source, providing efficient and rapid access to an important compound class, 2-methyl-1,8-naphthyridines.

Full text of DOI:10.1039/c9ob01490j

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DOI: 10.1039/C9OB01490J
Journal Name
PAPER
Transition Metal-Free α-Methylation of 1,8-Naphthyridine
Derivatives Using DMSO as Methylation Reagent
Received 00th January 20xx,
Accepted 00th January 20xx
Shaohua Jiang, Zhihai Yang, Ziyin Guo, Yibiao Li, Lu Chen, Zhongzhi Zhu,* and Xiuwen Chen*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A practical approach to the direct α-methylation of 1,8-
naphthyridines under mild reaction conditions has been
developed using simple and readily available DMSO as a
convenient and environmentally friendly carbon source. This
method is transition metal-free and highly chemoselective,
shows good functional group tolerance, and uses DMSO as a
methyl source, providing efficient and rapid access to an
important compound class, 2-methyl-1,8-naphthyridines.
a) Classical approaches
+
"methylation source"
Het
N
Het
N
Me
Me
H
b) MacMillan and Li
hv
Het
N
Me
HO
+
Het
N
DCM, TFA
H
c) Yao (2012)
H
CH3
N
O
PdCl2(MeCN)2
(n-Bu)4NOAc, ZnO/Bu3N
O
+
N
S
R1
R1
H2C
CH3
Ph
Ph
Introduction
This work
R1
R1
R2
O
S
The methyl group is among the most important inert
functional groups in organic chemistry.1 The introduction of a
methyl group into an aromatic molecule (namely methylation)
is an important methodology in organic synthesis. In recent
years, chemists have devoted much attention to the
development of new methylation reagents that have
successfully been applied to the methylation of heteroarenes.2
Usually, the classic tool for aromatic methylation is directed
metal
+
H3C
CH3
R2
N
N
H
N
N
CH3
Scheme 1 Classical and developed synthetic methods for the ortho-methylation
of N-heterocycles
In recent years, dimethyl sulfoxide (DMSO) has been used
as solvent or substrate in organic synthesis owing to its low
cost and low toxicity. 7 DMSO has been widely used in organic
orthometalation,
which
requires
transition
metals,
synthesis as a source of -Me,8 -SMe,9 -SOMe,10 -SO2Me,11
-
stoichiometric amounts of oxidants, or sensitive methylation
reagents (Scheme 1a).3 Recently, MacMillan4 and Li5
developed some simple and mild protocols for the
photoinduced methylation of heteroarenes using MeOH as the
methylation reagent under an ambient atmosphere (Scheme
CH2SMe,12 and -CHO13 groups in recent years. Although using
DMSO as a carbon source has been well studied, to our
knowledge, using DMSO as a methyl source has been less
successful. For example, Yao et al. reported an excellent
palladium-catalyzed alkylation of isoquinoline N-oxides using
DMSO as a methyl surrogate (Scheme 1c), and Russell
presented the methylation of aromatic hydrocarbons by
dimethyl sulfoxide.14 However, using palladium salt reduced
the practicality of this method, and 1,8-naphthyridine
substrates could not be accessed in this transformation. The
1,8-naphthyridine ring system is an attractive structural motif
owing to its wide distribution in bioactive molecules and
pharmaceuticals,2a,15 which include a potent v3 receptor
antagonist A,16 antibacterial agents B,17 and CETP inhibitor C.18
As part of our continuing research interest in the ortho-
functionalization of N-heterocycles,19 we aimed to design a
mild ortho-methylation method for the laboratory methylation
1b). In 2014, Gui et al. presented
a two-step C–H
functionalization method for the methylation of
heteroarenes.6 Despite significant progress in this field, the
development of new synthetic methods for the ortho-
methylation of N-heterocycles in a green, efficient, and metal-
free manner remains highly desirable.
School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020,
China.
E-mail: chenxiuwen2010@126.com; wyuchemzzz@126.com.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
Org. Biomol. Chem.
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8
of 1,8-naphthyridines using a cheap and safe methylation
source.
-
isopropanol
isopropanol
methanol
-
View Article Online
DOI: 10.1039/C9OB01490J
9[c]
10
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
59
28
36
O
CO2H
N
11
ethanol
H
H
NHSO2Ph
H
N
N
12
1-phenylethanol
1-phenylethanol
68
13[d]
A.
av3 antagonist
(64, 73, 71)
CF3
O
O
a Reaction conditions: Unless otherwise stated, all reactions were performed with
1a (0.2 mmol), base (0.4 mmol), alcohol (0.2 mmol), and DMSO (1.5 mL) at 120 oC
F
OH
c
under N2 protection for 8 h. b Isolated yield. Under visible light irradiation (blue
F3C
O
d
Yields from reaction temperatures of 90, 100, and 110 oC,
N
LEDs, 3W).
respectively.
N
N
N
H3CON
N
O
N
O
NH2
B.
C.
CETP inhibitors
antibacterial agents
R1
R1
R2
O
t-BuONa (1 eq.)
1-phenylethanol (1 eq.)
hv
S
+
H3C
CH3
R2
N
N
H
Figure 1 Representative biologically active compounds.
N
N
CH3
1
2
Results and discussion
N
N
N
2b
N
, 75%
N
N
2a
2c
, 73%
, 76 %
Initially, 2-phenyl-1,8-naphthyridine 1a was selected as the
model substrate and DMSO as solvent to investigate different
reaction conditions, and a range of conventional bases and
hydrogen donors (HDs) were evaluated, with the results
summarized in Table 1. First, desired product 2a was detected
in 33% yield when using t-BuOK as base and isopropanol as HD
F
OCH3
N
N
N
N
N
N
2d
2g
2e
2f
, 68%
, 69%
, 76%
Cl
N
N
N
N
N
N
2h
2k
2i
, 71%
, 52%
Ph
, 67%
o
in DMSO at 120 C for 8h (entry 1). Conventional bases, such
CF3
Br
as NaOMe, HCO2Na, NaOH, KOH, and t-BuONa were tested in
the reaction, with t-BuONa found to be the most effective,
affording product 2a in 38% yield (Table 1, entries 2-6). The
control experiment demonstrated that base and HD were
indispensable, because no product was detected in their
absence (Table 1, entries 7 and 8). Performing the reaction
under visible light irradiation (blue LEDs, 3W) led to an
increased yield (entry 9). Several HDs were screened (entries
10-12), with 1-phenylethanol found to be more effective than
other alcohols. Finally, the reaction temperature was
investigated, showing that 100 oC was optimal for this
transformation, affording the desired product in 73% yield
(entry 13).
N
N
O
N
N
N
2l
N
2j
, 63%
, 75%
, 74%
NO2
S
S
N
N
N
N
N
N
2n
2m
2o
, 65%
, 55%
N
, 63%
S
N
N
N
N
N
2p
N
2q
, 65%
, 61%
N
N
N
N
Ph
N
N
Ph
2r
2s
2t
, 72%
, 71%
, 68%
Br
CN
Ph
N
N
Table 1 Optimization of Reaction Conditions a
N
N
N
N
2u
2v
2w
, 32%
, 52%
, 67%
N
O
N
bases, alcohols
N
S
+
N
N
N
2z
H
H3C
CH3
hv
2x
2y
2aa
2ab
, n.d.
Ph
N
N
H
, 12%
, n.d.
, 7%
, n.d.
Ph
N
N
CH3
1a
2a
Scheme 2 Substrate scope of 1,8-naphthyridines.a Standard conditions: 1a (0.2
mmol), t-BuONa (0.4 mmol), 1-phenylethanol (0.2 mmol), and DMSO (1.5 mL) at
100 C under visible light irradiation. Isolated yields.
Entry
Base
Alcohol
Yield (%)[b]
38
t-BuOK
isopropanol
1
2
3
4
5
6
7
With optimized conditions in hand, the 1,8-naphthyridine
substrate scope was explored. Various 1,8-naphthyridines
bearing electron-withdrawing and/or electron-donating groups
were effective for the transformation, with the results
summarized in Scheme 2. Generally, the reactions proceeded
smoothly to afford the desired 2-methylated products in
reasonable to good isolated yields (2a-2w), and the electronic
NaOMe
HCO2Na
NaOH
isopropanol
isopropanol
isopropanol
isopropanol
isopropanol
-
19
17
11
41
12
-
t-BuONa
KOH
t-BuONa
2 | J. Name., 2019, 00, 1-3
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COMMUNICATION
O
S
properties of the aryl ring substituents in the reactants had
little effect on product formation. First, different 2-aryl-1,8-
naphthyridines were employed in the transformation,
affording the desired product in good yields of 52%-76% (2a-
2k). Pleasingly, heteroaryl-substituted 1,8-naphthyridines also
efficiently afforded the corresponding products (2l-2q), which
are potential multidentate ligands for organometallic
chemistry and catalysis applications.20 The structure of 2q was
confirmed by X-ray diffraction analysis. Similarly, 2,3-
disubstituted 1,8-naphthyridines (1r-1v) underwent effective
reaction to generate 2-methylated products (2r-2v).
Interestingly, when 1,8-naphthyridine 1w, bearing two
reactive α-sites, was used as substrate, the coupling reaction
afforded one methyl substituent product (2w). Other
N‑heterocycles such as pyridine, isoquinoline and indole have
been employed for the coupling reaction with DMSO under
standard reaction conditions, however the formation of the
standard conditions
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+
DOI: 10.1039/C9OB01490J
radical inhibitors
(2.0 equiv)
TEMPO BHT
H3C
CH3
(eq 1)
Ph
N
N
Ph
N
N
CH3
1a
2a
, trace
hv
(eq 2)
(eq 3)
(eq 4)
(eq 5)
MeOH
DCM/
TFA, RT
Ph
N
N
Ph
N
N
0%
CH3
1a
1a,
O
t-BuONa, hv
+
S
H3C
D3C
CH3
CD3
Ph
N
N
CH3
Ph
N
N
N
no add 1-phenylethanol
1a
1a
1a,
0%
O
t-BuONa, hv
S
+
Ph
N
N
CD3
82% D
1-phenylethanol
Ph
Ph
N
N
2a
50% D 54% D
O
S
52% D
54% D
t-BuONa, hv
i-propanol-d8
+
D3C
CD3
N
N
CD3
95% D
N
1a
2a-dn
OH
O
t-BuONa, hv
+
+
(eq 6)
(eq 7)
Ph
replace DMSO
with toluene
Ph
N
N
Ph
33 %
Ph
N
N
H
1a
2 equiv
1a', 25%
desired coupling product was not observed, only quinoxaline
and quinoline were able to afford the desired product in 12%
and 7%, respectively.
O
S
standard conditions
+
H3C
CH3
Ph
N
N
Ph
N
N
CH3
H
1a'
2a
, 0%
To gain insight into the reaction pathway, we conducted
several verification experiments (Scheme 3). First, the reaction
was conducted in the presence of radical inhibitors 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO) and 2,6-ditert-butyl-4-
methylphenol (BHT), with only a trace amount of 2a detected
by NMR analysis, showing that radical generation was involved
in this transformation (eq. 1). However, when the reaction was
run under conditions reported by the Li group (CH3OH, hv,
CH2Cl2 and TFA),5 no product was detected, indicating that the
reaction pathway was different to that reported in the
literature. The absence of 1-phenylethanol resulted in no
product generation (eq. 3), indicating that 1-phenylethanol
played a crucial role in product formation, perhaps by acting as
a hydrogen donor. An isotope-labeling experiment confirmed
that the methyl group was obtained from DMSO, while
different deuterium ratios were observed on the newly formed
naphthyridyl unit when isopropanol-d8 was used instead of 1-
phenylethanol. This observation indicates that hydrogen was
transferred from isopropanol-d8 to 1,8-naphthyridine 1a (eq.
4-5).
Scheme 3 Control experiments
On the basis of recent literature reports,13 a plausible
mechanistic pathway is depicted in path I. The reaction starts
from a single electron transfer (SET) give radical intermediate
1a-A and methyl radical, respectively from 1a and DMSO. And
then product 2a is formed via radical coupling of radical
intermediate 1a-A and methyl radical (path I). However, on the
basis of above control experiments and recent literature
reports,21 we believe that the reaction plausible mechanism is
path II. The MPV-O reduction of 1a by 1-phenylethanol under
basic conditions, which gives a sodium alkoxide that interacts
with the imine unit in 1a to form transition state A, was the
key reaction initiation step, and is known in the literature.21b
Through a reversible MPV-O-type hydrogen transfer,22 the
subsequent protonation of A followed by thermodynamically
favorable tautomerization of B liberates acetophenone, allylic
amine B, and tautomer imine C. The reaction is initiated by a
single-electron-transfer caused by t-BuONa and light, which
causes dimethyl sulfoxide to decompose, forming a methyl
radical. Addition of the generated methyl radical to imine C
gives corresponding adduct D, which then interconverts to
imine intermediate E. The dehydroaromatization of E then
affords product 2a.
When the reaction between 2-phenyl-1,8-naphthyridine
and 1-phenylethanol was performed with toluene instead of
DMSO, product 1a’ (25% yield) and acetophenone (33% yield)
were formed. The subsequent reaction of 1a’ with DMSO
under standard conditions failed to give product 2a (eq. 7),
further supporting the effective suppression of over-
hydrogenated tetrahydronaphthyridine formation.
O
S
path I
t-BuONa, hv
CH3
H3
C
CH3
SET
H+
Ph
N
N
CH3
t-BuONa, hv
2a
SET
Ph
N
N
Ph
N
1a-A
N
H
1a
path II
Ph
OH
O
S
+
H3
H
Ph
N
O
N
C
CH3
Ph
N
N
t-BuONa
Ph
Ph
N
N
CH3
A
1a
2a
Na
O
t-BuONa, hv
SET
auto-dehydro
aromatization
Ph
Ph
-H2
hydrogen
transfer
CH3
tautomerization
Ph
SET
Ph
N
N
N
N
N
N
Ph
N
N
H
B
C
D
E
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Journal Name
Scheme 4 Plausible reaction pathways
concentrated by removing the solvent under vacuum, and the
residue was purified by column chromatography to give the
substrates 1.
2-phenyl-1,8-naphthyridine (1a). 19a Known compound, 1H NMR
(400 MHz, CDCl3) δ 9.27 (s, 1H), 8.75 (s, 1H), 8.30 (d, J = 7.9 Hz, 1H),
8.13 (s, 2H), 7.68 – 7.50 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 161.3,
156.9, 155.9, 145.6, 137.0, 136.8, 130.8, 129.5, 128.7, 123.5, 119.9,
View Article Online
DOI: 10.1039/C9OB01490J
Finally, we were interested in demonstrating the
application of obtained compound 2w. The 2-methyl group of
N-heterocycles is a good active site, and acts as a one-carbon
bridge. Under Lewis acid conditions,23 various aldehydes
reacted well to afford a variety of (E)-2-alkenylazaarenes in
moderate to good yields. Using 2-methyl-1,8-naphthyridines
bearing different benzylamine derivatives under different
117.3, 106.7.
19a
2-(p-tolyl)-1,8-naphthyridine (1b).
Known compound, 1H
24
conditions (A and B) gave imidazo-fused N-heterocycles in
NMR (400 MHz, CDCl3) δ 9.17 – 9.07 (m, 1H), 8.27 – 8.14 (m, 4H),
7.99 (d, J = 8.5 Hz, 1H), 7.49 – 7.41 (m, 1H), 7.34 (d, J = 7.9 Hz, 2H),
2.44 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 160.3, 156.2, 153.7, 140.4,
good yields (Scheme 5).
cond. A
R2 = -Ph, , 83%
4a
R1 = 4-Me-Ph, , 85%
N
137.6, 136.7, 135.7, 129.6, 127.8, 121.6, 121.6, 119.5, 21.4.
4b
N
R1 = 4-MeO-Ph, , 78%
R1 = 4-Br-Ph, , 76%
4c
19a
R2
N
2-(3,4-dimethylphenyl)-1,8-naphthyridine (1c).
Known
4d
R1
H2N
R2
CHO
R1
compound, 1H NMR (400 MHz, CDCl3) δ 9.10 (d, J = 1.5 Hz, 1H), 8.16
(dd, J = 14.5, 8.3 Hz, 3H), 7.98 (t, J = 6.7 Hz, 2H), 7.42 (dd, J = 7.7, 4.1
Hz, 1H), 7.27 (d, J = 7.6 Hz, 1H), 2.37 (s, 3H), 2.33 (s, 3H). 13C NMR
(101 MHz, CDCl3) δ 160.4, 156.2, 153.6, 139.1, 137.5, 137.2, 136.7,
N
N
Lewis Acid
cond. B
N
N
CH3
R1 = Ph, , 85%
R3 = 4-Me-Ph, , 78%
3
3a
5a
R1 = 3-Me-Ph, , 81%
3b
A: CuI, Cu(OAc)2, DTBP
B: CuBr2, LiBr, O2
5b
R = 4-MeO-Ph, , 75%
N
N
R1 = 4-Cl-Ph, , 76%
3c
Br
R1 = CHCO2Et, , 72%
N
R3
3d
Scheme 4 Functionalization of methyl substituent in 2w
136.0, 130.1, 129.1, 125.2, 121.5, 119.6, 19.8, 19.7.
19a
2-(3-methoxyphenyl)-1,8-naphthyridine (1d).
Known
1
compound, H NMR (400 MHz, CDCl3) δ 9.07 – 8.95 (m, 1H), 8.06
(dd, J = 16.0, 8.3 Hz, 2H), 7.84 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 7.7 Hz,
1H), 7.39 – 7.25 (m, 2H), 6.93 (d, J = 8.2 Hz, 1H), 3.81 (s, 3H). 13C
NMR (101 MHz, CDCl3) δ 160.2, 160.0, 155.9, 153.7, 139.9, 137.7,
Conclusions
In conclusion, we have described a direct α-methylenation of
1,8-naphthyridines using DMSO as the methyl source that is
achieved under radical reaction conditions. DMSO acts as both
solvent and a one-carbon source in this reaction, providing a
highly atom-economical and environmentally benign approach
to the synthesis of 2-methyl-1,8-naphthyridines. Based on
control experiments, a plausible hydrogen transfer reaction
path was proposed.
136.8, 129.7, 121.8, 120.2, 119.8, 116.7, 112.5, 55.5.
19a
2-(2-fluorophenyl)-1,8-naphthyridine
(1e).
Known
compound, 1H NMR (400 MHz, CDCl3) δ 9.14 (d, J = 2.3 Hz, 1H), 8.27
(d, J = 8.5 Hz, 1H), 8.20 (d, J = 7.4 Hz, 1H), 8.14 – 8.01 (m, 2H), 7.97
(d, J = 8.5 Hz, 1H), 7.58 – 7.39 (m, 2H), 7.18 (t, J = 8.0 Hz, 1H). 13C
NMR (101 MHz, CDCl3) δ 163.3 (d, J = 245.8 Hz), 158.9, 155.9, 154.0,
140.8 (d, J = 7.4 Hz), 138.1, 136.9, 130.3 (d, J = 8.1 Hz), 123.4, 122.1,
121.9, 119.5, 116.9 (d, J = 21.4 Hz), 114.8 (d, J = 23.1 Hz).
25e
2-(4-chlorophenyl)-1,8-naphthyridine
(1f).
Known
Experimental
compound, 1H NMR (400 MHz, CDCl3) δ 9.14 (d, J = 2.4 Hz, 1H), 8.26
(d, J = 7.9 Hz, 3H), 8.20 (d, J = 8.0 Hz, 1H), 7.97 (d, J = 8.5 Hz, 1H),
7.49 (t, J = 7.9 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 159.0, 156.0,
General Information
All experiments were carried out under the standard conditions.
Flash column chromatography was performed over silica gel
154.0, 138.0, 136.9, 136.8, 136.4, 129.2, 129.0, 121.9, 121.8, 119.4.
25e
2-(4-bromophenyl)-1,8-naphthyridine
(1g).
Known
1
(200−300 mesh). H NMR and 13C NMR spectra were recorded on a
compound, 1H NMR (400 MHz, CDCl3) δ 9.13 (d, J = 2.5 Hz, 1H), 8.24
(d, J = 8.5 Hz, 1H), 8.18 (d, J = 8.4 Hz, 3H), 7.96 (d, J = 8.5 Hz, 1H),
7.64 (d, J = 8.4 Hz, 2H), 7.47 (dd, J = 8.0, 4.2 Hz, 1H). 13C NMR (101
MHz, CDCl3) δ 159.1, 156.2, 154.1, 138.0, 137.4, 136.8, 132.0, 129.4,
124.9, 121.9, 121.8, 119.3.
BrukerAV500/400 instrument internally referenced to TMS,
chloroform and DMSO signals. MS analyses were performed on an
Agilent 5975 GC−MS instrument (EI). High resolution mass spectra
(HRMS) were recorded using electrospray ionization (ESI) and time-
of-flight (TOF) mass analysis. Melting points were uncorrected. The
new compounds were characterized by 1H NMR, 13C NMR and
HRMS.
2-(4-(trifluoromethyl)phenyl)-1,8-naphthyridine (1i). 25e Known
compound, 1H NMR (400 MHz, CDCl3) δ 9.15 (dd, J = 4.0, 1.7 Hz, 1H),
8.39 (d, J = 8.2 Hz, 2H), 8.26 (d, J = 8.5 Hz, 1H), 8.19 (dd, J = 8.1, 1.6
Hz, 1H), 7.98 (d, J = 8.5 Hz, 1H), 7.75 (d, J = 8.2 Hz, 2H), 7.48 (dd, J =
8.1, 4.2 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 158.5, 155.9, 154.2,
141.7, 138.2, 136.8, 131.7 (d, J = 32.6 Hz), 128.1, 125.7 (q, J = 3.8
Substrates preparation
1,8-Naphthyridines 1a-1g, 1i-1n, 1q-1s and 1u-1v were known
compounds and prepared via the literature procedures.19a, 25 Other
substrates (1h, 1o, 1t, 1w) were commercially available, and
purchased at J&K Chemic and Energy Chemical. 2-Amino-3-
pyridinecarboxaldehyde (5 mmol), ketones (6 mmol), t-BuOK (20
mol %), and ethanol (10 mL) were introduced in a flask (50 mL).
Hz), 122.7, 122.2, 122.0, 119.6.
25e
2-(4-nitrophenyl)-1,8-naphthyridine (1j).
Known compound,
1H NMR (400 MHz, CDCl3) δ 9.21 (d, J = 3.4 Hz, 1H), 8.50 (d, J = 8.5
Hz, 2H), 8.44 – 8.34 (m, 3H), 8.28 (d, J = 8.0 Hz, 1H), 8.09 (d, J = 8.4
Hz, 1H), 7.57 (dd, J = 7.9, 4.1 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ
157.7, 155.9, 154.6 148.8, 144.3, 138.5, 136.9, 128.8, 124.0, 122.7,
122.3, 119.7.
o
Then, it was stirred at 50 C under atmosphere for 5 hours. After
cooling down to room temperature, the reaction mixture was
4 | J. Name., 2019, 00, 1-3
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19a
2-(naphthalen-2-yl)-1,8-naphthyridine
(1k).
Known conducted in a photochemical reactor equipped with visible light
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1
compound, H NMR (400 MHz, CDCl3) δ 9.13 (s, 1H), 8.79 (s, 1H), irradiation (420 nm<λ<780 nm). After comDpOleIt:i1o0n.10o3f9t/hCe9OreBa0c14ti9o0nJ,
8.47 (d, J = 7.9 Hz, 1H), 8.28 – 8.07 (m, 3H), 7.98 (d, J = 6.4 Hz, 2H), the resulting solution was cooled to room temperature; the
7.89 (s, 1H), 7.48 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 160.1, 156.2, solution was diluted with ethyl acetate (10 mL), washed with water
153.8, 137.7, 136.7, 135.7, 134.3, 133.4, 130.8, 129.0, 128.5, 127.9, (5 mL), extracted with ethyl acetate (3×5 mL), dried over anhydrous
127.7, 127.1, 126.4, 125.0, 121.8, 119.8.
Na2SO4, and concentrated in vacuo. The crude product was purified
Known compound, H by preparative TLC on silica gel to give the desired product (2).
25e
1
2-(furan-2-yl)-1,8-naphthyridine (1l).
NMR (400 MHz, CDCl3) δ 9.03 (s, 1H), 8.12 (d, J = 8.5 Hz, 1H), 8.07 (d,
J = 8.0 Hz, 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.58 (s, 1H), 7.48 (d, J = 3.3
Hz, 1H), 7.36 (dd, J = 8.0, 4.2 Hz, 1H), 6.63 – 6.52 (m, 1H). 13C NMR
(101 MHz, CDCl3) δ 156.0, 153.8, 153.4, 152.1, 144.4, 137.7, 136.7,
Spectral data of compounds
2-methyl-7-phenyl-1,8-naphthyridine (2a). Known compound
2a; Rf = 0.3 (petroleum ether/ethyl acetate = 3/1, v/v); 1H NMR (500
MHz, CDCl3) δ 8.35 – 8.30 (m, 2H), 8.17 (dd, J = 8.4, 3.0 Hz, 1H), 8.05
(dd, J = 8.2, 2.9 Hz, 1H), 7.93 (dd, J = 8.4, 2.9 Hz, 1H), 7.56 – 7.46 (m,
3H), 7.33 (dd, J = 8.2, 2.5 Hz, 1H), 2.83 (s, 3H). 13C NMR (126 MHz,
CDCl3) δ163.3, 160.0, 155.9, 138.7, 137.4, 136.6, 129.9, 128.7, 127.9,
122.6, 119.7, 118.8, 25.7. HRMS (ESI): Calcd. for C15H13N2 [M+H]+:
221.1073; found: 221.1064.
2-methyl-7-(p-tolyl)-1,8-naphthyridine (2b). Yellow solid (52.7
mg, 75% yield), known compound2a ; Rf = 0.3 (petroleum
ether/ethyl acetate = 3/1, v/v); 1H NMR (400 MHz, CDCl3) δ 8.22 (d,
J = 8.0 Hz, 2H), 8.16 – 8.08 (m, 1H), 8.01 (dd, J = 11.8, 5.6 Hz, 1H),
7.89 (dd, J = 11.7, 5.9 Hz, 1H), 7.30 (t, J = 9.0 Hz, 3H), 2.81 (s, 3H),
2.42 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 163.2, 159.9, 155.9, 140.1,
137.2, 136.5, 135.9, 129.5, 127.8, 122.4, 119.5, 118.6, 25.7, 21.4.
HRMS (ESI): Calcd. for C16H15N2 [M+H]+: 235.1230; found: 235.1222.
121.6, 121.5, 118.2, 112.7, 111.8.
25b
2-(1-methyl-1H-pyrrol-2-yl)-1,8-naphthyridine (1m).
Known
1
compound, H NMR (400 MHz, CDCl3) δ 8.94 (s, 1H), 7.96 (m, 2H),
7.70 (d, J = 8.6 Hz, 1H), 7.27 (dd, J = 7.3, 4.2 Hz, 1H), 6.78 (m, 2H),
6.15 (s, 1H), 4.23 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 155.9, 155.3,
153.2, 136.7, 136.5, 131.2, 129.0, 120.9, 120.5, 113.9, 108.1, 38.5.
2-(thiophen-2-yl)-1,8-naphthyridine (1n). 19a Known compound,
1H NMR (400 MHz, CDCl3): δ 9.06 (d, J = 2.5 Hz, 1H), 8.11 (t, J = 8.1
Hz, 2H), 7.83 (t, J = 6.3 Hz, 2H), 7.51 (d, J = 4.8 Hz, 1H), 7.39 (dd, J =
7.9, 4.2 Hz, 1H), 7.15 (t, J = 4.3 Hz, 1H). 13C NMR (101 MHz, CDCl3): δ
156.0, 155.5, 153.8, 144.6, 137.6, 136.7, 130.0, 128.2, 127.1, 121.7,
121.5, 118.7.
25b
2-(pyridin-2-yl)-1,8-naphthyridine (1q).
Known compound,
1H NMR (400 MHz, CDCl3) δ 9.10-9.20 (m, 1H), 8.86 (d, J = 8.0 Hz,
1H), 8.68-8.78 (m, 2H), 8.28 (d, J = 8.4 Hz, 1H), 8.19 (dd, J = 8.0 Hz,
2.0 Hz, 1H), 7.80-7.90 (m, 1H), 7.46 (dd, J = 8.0 Hz, 4.0 Hz, 1H), 7.32-
7.41 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 159.3, 155.8, 155.4, 153.8,
2-(3,4-dimethylphenyl)-7-methyl-1,8-naphthyridine
(2c).
Yellow oil (54.4 mg, 73% yield); Rf = 0.4 (petroleum ether/ethyl
acetate = 3/1, v/v); 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.99 (d,
J = 8.1 Hz, 1H), 7.88 (d, J = 7.8 Hz, 2H), 7.78 (d, J = 8.0 Hz, 1H), 7.20 –
7.14 (m, 2H), 2.71 (s, 3H), 2.24 (d, J = 16.6 Hz, 6H). 13C NMR (101
MHz, CDCl3) δ 163.1, 160.0, 155.9, 138.9, 137.1, 137.0, 136.5, 136.1,
130.0, 129.1, 125.1, 122.3, 119.5, 118.6, 25.7, 19.8, 19.7. HRMS
(ESI): Calcd. for C17H17N2 [M+H]+: 249.1386; found: 249.1377.
2-(3-methoxyphenyl)-7-methyl-1,8-naphthyridine (2d). White
solid (51.0 mg, 68% yield), m.p: 136.2-137.9 oC ; Rf = 0.3 (petroleum
ether/ethyl acetate = 3/1, v/v); 1H NMR (500 MHz, CDCl3) δ8.13 (d, J
= 8.4 Hz, 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.96 – 7.91 (m, 1H), 7.89 (d, J =
8.4 Hz, 1H), 7.79 (d, J = 7.7 Hz, 1H), 7.39 (t, J = 7.9 Hz, 1H), 7.31 (d, J
= 8.2 Hz, 1H), 7.01 (dd, J = 8.2, 2.6 Hz, 1H), 3.91 (s, 3H), 2.81 (s, 3H).
13C NMR (126 MHz, CDCl3) δ163.3, 160.1, 159.8, 155.7, 140.1, 137.4,
136.7, 129.6, 122.7, 120.3, 119.8, 119.1, 116.5, 112.6, 55.6, 25.7.
HRMS (ESI) m/z: [M+H]+ Calcd. for C16H15N2O 251.1179; found:
251.1169.
149.1, 137.8, 137.0, 136.9, 124.6, 122.9, 122.5, 122.1, 120.0.
25b
3-methyl-2-phenyl-1,8-naphthyridine
(1r).
Known
compound, 1H NMR (400 MHz, CDCl3) δ 9.04 (s, 1H), 8.10 (d, J = 8.0
Hz, 1H), 8.00 (s, 1H), 7.68 (d, J = 7.4 Hz, 2H), 7.53 – 7.37 (m, 4H),
2.50 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 163.4, 154.8, 152.9, 140.1,
137.7, 135.9, 130.6, 129.3, 128.6, 128.1, 121.9, 121.8, 20.6.
25b
3-ethyl-2-phenyl-1,8-naphthyridine (1s).
Known compound,
1H NMR (400 MHz, CDCl3) δ 8.98-9.10 (m, 1H), 7.95-8.25 (m, 2H),
7.49-7.68 (m, 2H), 7.32-7.53 (m, 4H), 2.73-2.85 (m, 2H), 1.14 (t, J =
7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 163.5, 154.5, 152.9, 140.2,
136.6, 136.2, 135.9, 129.0, 128.4, 128.0, 121.9, 121.9, 25.9, 14.6.
25c
2-phenyl-1,8-naphthyridine-3-carbonitrile (1u).
Known
compound, 1H NMR (400 MHz, CDCl3): δ 9.27 (s, 1H), 8.75 (s, 1H),
8.30 (d, J = 7.9 Hz, 1H), 8.13 (s, 2H), 7.68 – 7.50 (m, 4H). 13C NMR
(101 MHz, CDCl3) : δ 161.3, 157.0, 155.9, 145.6, 137.0, 136.8, 130.8,
129.5, 128.7, 123.5, 119.9, 117.3, 106.7.
2-(2-fluorophenyl)-7-methyl-1,8-naphthyridine (2e). Yellow
solid (52.5 mg, 69% yield), m.p: 99.9-101.1 C ; Rf = 0.3 (petroleum
19a
5,6-dihydronaphtho[1,2-b][1,8]naphthyridine (1v).
Known
o
compound, 1H NMR (400 MHz, CDCl3) δ 8.95-9.12 (m, 1H), 8.74 (d, J
= 7.6 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.78 (s, 1H), 7.28-7.48 (m, 3H),
7.19 (d, J = 7.2 Hz, 1H), 3.02 (t, J = 6.8 Hz, 2H), 2.92 (t, J = 6.8 Hz, 2H).
13C NMR (101 MHz, CDCl3) δ 156.3, 155.6, 152.6, 139.5, 136.1, 134.5,
133.9, 131.7, 130.4, 127.8, 127.2, 126.9, 122.2, 121.4, 28.4, 28.0.
ether/ethyl acetate = 3/1, v/v); 1H NMR (500 MHz, CDCl3) δ 8.16 (d,
J = 8.4 Hz, 1H), 8.07 (d, J = 10.3 Hz, 1H), 8.05 – 8.01 (m, 2H), 7.86 (d,
J = 8.4 Hz, 1H), 7.44 (td, J = 8.0, 5.9 Hz, 1H), 7.33 (d, J = 8.2 Hz, 1H),
7.20 – 7.09 (m, 1H), 2.82 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 164.3,
163.6, 162.3, 157.1 (d, J = 356.1 Hz), 140.9 (d, J = 7.5 Hz), 137.7,
136.6 (s), 130.2 (d, J = 7.8 Hz), 123.3 (d, J = 2.7 Hz), 122.9, 119.9,
118.7, 116.8 (d, J = 21.2 Hz), 114.8 (d, J = 23.0 Hz), 25.7.19F NMR
Typical procedure for the synthesis of 2.
In a Schlenk tube of 25mL, 1,8-naphthyridines 1 (0.2 mmol), t- (471 MHz, CDCl3) δ -112.9. HRMS (ESI): Calcd. for C15H12FN2 [M+H]+:
BuONa (0.4 mmol, 2.0 equiv), and 1-phenylethanol (0.2 mmol, 1 239.0979; found: 239.0968.
equiv) were dissolved in DMSO (2 mL) under visible light irradiation
2-(4-chlorophenyl)-7-methyl-1,8-naphthyridine (2f). White
(blue LEDs, 3W) and stirred at 100 oC for 8 h, irradiation was solid (57.9 mg, 76% yield), m.p: 189.0-191.1 °C ; Rf = 0.3 (petroleum
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COMMUNICATION
Journal Name
ether/ethyl acetate = 3/1, v/v); 1H NMR (500 MHz, CDCl3) δ 8.31 – 6.1 Hz, 1H), 7.69 – 7.57 (m, 1H), 7.51 (dd, J = 3.1, 2.6 Hz, 1H), 7.27
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8.24 (m, 2H), 8.20 (dd, J = 8.3, 3.1 Hz, 1H), 8.07 (dd, J = 8.1, 2.3 Hz, (dd, J = 7.5, 4.7 Hz, 1H), 6.59 (td, J = 3.3, 1.7DHOz,I:11H0.)1,023.97/8C9(sO,B30H1)4.9103CJ
1H), 7.90 (dd, J = 8.3, 3.5 Hz, 1H), 7.52 – 7.45 (m, 2H), 7.37 (d, J = 8.2 NMR (126 MHz, CDCl3) δ 163.4, 155.7, 153.6, 151.9, 144.2, 137.4,
Hz, 1H), 2.84 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 163.6, 158.7, 136.6, 122.4, 119.6, 117.3, 112.8, 111.5, 25.6. HRMS (ESI): Calcd. for
155.8, 137.7, 137.0, 136.6, 136.2, 129.2, 128.9, 122.9, 119.8, 118.5, C13H11N2O [M+H]+: 211.0866; found: 211.0859.
25.8. HRMS (ESI): Calcd. for C15H12ClN2 [M+H]+: 255.0684; found:
255.0672.
2-methyl-7-(1-methyl-1H-pyrrol-2-yl)-1,8-naphthyridine (2m).
Yellow oil (36.8 mg, 55 % yield); Rf = 0.3 (petroleum ether/ethyl
3-(4-bromophenyl)-7-methyl-1,8-naphthyridine (2g). Grey solid acetate = 2/1, v/v); 1H NMR (500 MHz, CDCl3) δ 8.01 (dd, J = 15.2,
(63.5 mg, 71% yield), known compound 2a; Rf = 0.3 (petroleum 8.3 Hz, 2H), 7.76 (d, J = 8.5 Hz, 1H), 7.29 (d, J = 7.0 Hz, 1H), 6.87 (dd,
ether/ethyl acetate = 3/1, v/v); 1H NMR (500 MHz, CDCl3) δ 8.19 (dd, J = 11.1, 2.1 Hz, 2H), 6.31 – 6.18 (m, 1H), 4.33 (s, 3H), 2.82 (s, 3H).
J = 8.5, 1.1 Hz, 3H), 8.07 (d, J = 8.2 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 13C NMR (126 MHz, CDCl3) δ 162.8, 155.6, 155.2, 136.7, 136.3, 131.5,
7.68 – 7.58 (m, 2H), 7.36 (d, J = 8.2 Hz, 1H), 2.84 (s, 3H). 13C NMR 128.6, 121.8, 120.3, 118.5, 113.6, 108.1, 38.3, 25.7. HRMS (ESI):
(126 MHz, CDCl3) δ 163.6, 158.8, 155.7, 137.7, 137.4, 136.7, 131.9, Calcd. for C14H14N3 [M+H]+: 224.1182; found: 224.1173.
129.4, 124.7, 122.9, 119.8, 118.5, 25.7. HRMS (ESI): Calcd. for
C15H12BrN2 [M+H]+: 299.0178; found: 299.0168.
2-methyl-7-(thiophen-2-yl)-1,8-naphthyridine (2n). White solid
(42.7 mg, 63% yield), known compound2a; Rf = 0.3 (petroleum
3-([1,1'-biphenyl]-4-yl)-7-methyl-1,8-naphthyridine
(2h). ether/ethyl acetate = 3/1, v/v); 1H NMR (500 MHz, CDCl3) δ 8.02 (d,
o
Yellow solid (46.2 mg, 52% yield), m.p: 208.0-210.1 C ; Rf = 0.3 J = 8.4 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.77 (d, 1H), 7.73 (d, J = 8.4
(petroleum ether/ethyl acetate = 3/1, v/v); 1H NMR (500 MHz, CDCl3) Hz, 1H), 7.47 (dd, J = 5.0, 0.5 Hz, 1H), 7.24 (d, J = 8.2 Hz, 1H), 7.15 –
δ 8.44 (d, J = 7.4 Hz, 2H), 8.21 (d, J = 7.7 Hz, 1H), 8.08 (d, J = 7.7 Hz, 7.07 (m, 1H), 2.77 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 163.4, 155.6,
1H), 8.01 (d, J = 8.3 Hz, 1H), 7.78 (d, J = 7.3 Hz, 2H), 7.71 (d, J = 7.4 155.2, 144.7, 137.3, 136.6, 129.7, 128.1, 126.9, 122.4, 119.6, 117.8,
Hz, 2H), 7.49 (t, J = 7.1 Hz, 2H), 7.39 (dd, J = 20.6, 7.6 Hz, 2H), 2.86 (s, 25.6. HRMS (ESI): Calcd. for C13H11N2S [M+H]+: 227.0637; found:
3H). 13C NMR (126 MHz, CDCl3) δ 163.4, 159.5, 155.9, 142.7, 140.4, 227.0630.
137.4, 136.7, 128.9, 128.3, 127.7, 127.4, 127.2, 122.7, 119.7, 118.8,
2-(benzo[b]thiophen-2-yl)-7-methyl-1,8-naphthyridine
(2o).
o
25.7. HRMS (ESI): Calcd. for C21H17N2 [M+H]+: 297.1386; found: Yellow solid (53.8 mg, 65% yield), m.p: 210.6-212.7 C ; Rf = 0.3
297.1374.
(petroleum ether/ethyl acetate = 2/1, v/v); 1H NMR (500 MHz, CDCl3)
2-methyl-7-(4-(trifluoromethyl)phenyl)-1,8-naphthyridine (2i). δ 8.12 (d, J = 8.4 Hz, 1H), 8.06 (s, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.91 (t,
Grey solid (57.9 mg, 67% yield), known compound2a; Rf = 0.3 J = 7.4 Hz, 2H), 7.86 – 7.78 (m, 1H), 7.40 – 7.34 (m, 2H), 7.32 (d, J =
(petroleum ether/ethyl acetate = 3/1, v/v); 1H NMR (500 MHz, CDCl3) 8.2 Hz, 1H), 2.83 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 163.7, 155.7,
δ 8.40 (d, J = 7.9 Hz, 2H), 8.21 (dd, J = 8.2, 3.8 Hz, 1H), 8.08 (dd, J = 155.3, 144.7, 141.6, 140.3, 137.3, 136.6, 125.6, 124.5, 124.5, 123.7,
8.1, 3.5 Hz, 1H), 7.93 (dd, J = 8.2, 3.9 Hz, 1H), 7.74 (d, J = 8.1 Hz, 2H), 122.8, 122.8, 120.1, 118.2, 77.3, 77.1, 76.8, 25.7. HRMS (ESI): Calcd.
7.37 (dd, J = 8.2, 3.0 Hz, 1H), 2.84 (s, 3H). 13C NMR (126 MHz, CDCl3) for C17H13N2S [M+H]+: 277.0794; found: 277.0788.
δ 163.8, 158.3, 155.6, 141.8, 137.9, 136.7, 131.52 (d, J = 32.4 Hz),
2-(7-methyl-1,8-naphthyridin-2-yl) thiazole (2p). Brown solid
128.1, 125.63 (q, J = 3.1 Hz), 125.2, 123.2, 120.1, 118.8, 25.7.19F (44.3 mg, 65% yield), m.p: 123.4-125.1 °C ; Rf = 0.3 (petroleum
NMR (471 MHz, CDCl3) δ -62.6. HRMS (ESI): Calcd. for C16H12F3N2 ether/ethyl acetate = 3/1, v/v); 1H NMR (500 MHz, CDCl3) δ 8.41 –
[M+H]+: 289.0947; found: 289.0935.
8.33 (m, 1H), 8.21 (dd, J = 9.6, 5.5 Hz, 1H), 8.10 – 8.03 (m, 1H), 7.97
2-methyl-7-(4-nitrophenyl)-1,8-naphthyridine (2j). Brown solid (d, J = 1.8 Hz, 1H), 7.53 (dd, J = 3.6, 2.6 Hz, 1H), 7.38 – 7.29 (m, 1H),
(50.1 mg, 63% yield), m.p: 224.0-225.1 °C ; Rf = 0.3 (petroleum 2.81 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 169.0, 163.9, 155.4, 154.0,
ether/ethyl acetate = 2/1, v/v); 1H NMR (500 MHz, CDCl3) δ 8.46 (d, 144.2, 137.9, 136.8, 123.4, 123.2, 121.4, 118.1, 25.7. HRMS (ESI):
J = 7.1 Hz, 2H), 8.38 – 8.26 (m, 3H), 8.12 (d, J = 7.7 Hz, 1H), 7.98 (d, J Calcd. for C12H10N3S [M+H]+: 228.0590; found: 228.0582.
= 7.5 Hz, 1H), 7.42 (d, J = 7.8 Hz, 1H), 2.86 (s, 3H). 13C NMR (126
2-methyl-7-(pyridin-2-yl)-1,8-naphthyridine (2q). Yellow solid
MHz, CDCl3) δ 164.3, 157.3, 155.7, 148.6, 144.5, 138.2, 136.7, 128.7, (30.0 mg, 61% yield), m.p: 115.2-117.5 oC; Rf = 0.3 (petroleum
123.9, 123.7, 120.3, 118.9, 25.8. HRMS (ESI): Calcd. for C15H12N3O2 ether/ethyl acetate = 2/1, v/v); 1H NMR (500 MHz, CDCl3) δ 8.92 (d,
[M+H]+: 266.0924; found: 266.0914.
J = 7.6 Hz, 1H), 8.76 (dd, J = 3.3, 1.4 Hz, 1H), 8.71 (dd, J = 8.4, 1.1 Hz,
2-methyl-7-(naphthalen-2-yl)-1,8-naphthyridine (2k). Yellow 1H), 8.30 (dd, J = 8.4, 1.1 Hz, 1H), 8.14 (dd, J = 8.2, 1.0 Hz, 1H), 7.90
solid (60.8 mg, 75% yield), m.p: 194.4-196.0 °C ; Rf = 0.3 (petroleum (t, J = 7.7 Hz, 1H), 7.50 – 7.39 (m, 2H), 2.88 (s, 3H). 13C NMR (126
ether/ethyl acetate = 3/1, v/v); 1H NMR (500 MHz, CDCl3) δ 8.83 (s, MHz, CDCl3) δ 163.40, 159.04, 155.59, 155.56, 149.04, 137.54,
1H), 8.49 (d, J = 8.6 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 8.08 (dd, J = 11.1, 137.03, 136.81, 124.58, 123.12, 122.61, 120.92, 119.22, 25.75.
8.4 Hz, 2H), 7.99 (t, J = 8.0 Hz, 2H), 7.93 – 7.84 (m, 1H), 7.62 – 7.49 HRMS (ESI): Calcd. for C14H12N3 [M+H]+: 222.1026; found: 222.1018.
(m, 2H), 7.35 (d, J = 8.2 Hz, 1H), 2.87 (s, 3H). 13C NMR (126 MHz,
3,7-dimethyl-2-phenyl-1,8-naphthyridine (2r). Black solid (49.9
CDCl3) δ 163.4, 159.8, 155.8, 137.4, 136.8, 135.8, 134.2, 133.4, mg, 71% yield), m.p: 118.1-119.8 oC ; Rf = 0.3 (petroleum
129.0, 128.4, 127.9, 127.7, 127.0, 126.4, 125.1, 122.7, 119.8, 119.0, ether/ethyl acetate = 3/1, v/v); 1H NMR (400 MHz, CDCl3) δ 8.03 (d,
25.7. HRMS (ESI): Calcd. for C19H15N2 [M+H]+: 271.1230; found: J = 8.2 Hz, 1H), 7.99 (s, 1H), 7.70 (d, J = 7.5 Hz, 2H), 7.50 – 7.41 (m,
271.1219.
3H), 7.34 (d, J = 8.2 Hz, 1H), 2.80 (s, 3H), 2.53 (s, 3H). 13C NMR (101
2-(furan-2-yl)-7-methyl-1,8-naphthyridine (2l). Yellow solid MHz, CDCl3) δ 163.03, 162.31, 154.45, 140.25, 137.49, 135.82,
(46.6 mg, 74% yield), m.p: 123.4-125.1 °C ; Rf = 0.3 (petroleum 129.61, 129.32, 128.43, 127.96, 122.81, 119.74, 25.56, 20.54. HRMS
ether/ethyl acetate = 3/1, v/v); 1H NMR (500 MHz, CDCl3) δ 8.10 (dd, (ESI): Calcd. for C16H15N2 [M+H]+: 235.1230; found: 235.1221.
J = 8.3, 6.1 Hz, 1H), 7.98 (dd, J = 8.1, 6.0 Hz, 1H), 7.88 (dd, J = 8.3,
6 | J. Name., 2019, 00, 1-3
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2-ethyl-7-methyl-2-phenyl-1,8-naphthyridine (2s). Yellow solid 1H). 13C NMR (126 MHz, CDCl3) δ 159.1, 156.0, 153.8, 137.4, 136.8,
View Article Online
(50.6 mg, 68% yield), m.p: 117.4-119.6 oC; Rf = 0.3 (petroleum 136.4, 136.2, 129.1, 128.9, 127.8, 127.6, 121.9, 121.5, 121.2. HRMS
DOI: 10.1039/C9OB01490J
ether/ethyl acetate = 3/1, v/v); 1H NMR (500 MHz, CDCl3) δ 8.06 (dd, (ESI): Calcd. for C16H13N2 [M+H]+: 233.1073; found: 233.1065.
J = 8.2, 3.1 Hz, 1H), 8.02 (d, J = 2.2 Hz, 1H), 7.71 – 7.59 (m, 2H), 7.51
(E)-2-(3-methylstyryl)-1,8-naphthyridine (3b). Yellow oil (39.9
– 7.41 (m, 3H), 7.34 (dd, J = 8.2, 2.9 Hz, 1H), 2.86 (q, J = 7.3 Hz, 2H), mg, 81% yield); Rf = 0.3 (petroleum ether/ethyl acetate = 2/1, v/v);
2.79 (s, 3H), 1.21 (t, J = 7.5 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 1H NMR (500 MHz, CDCl3) δ 9.09 (dd, J = 4.1, 1.9 Hz, 1H), 8.13 – 8.08
163.2, 162.3, 154.0, 140.3, 136.2, 135.7, 135.6, 129.1, 128.3, 127.9, (m, 2H), 7.95 (d, J = 14.2 Hz, 1H), 7.64 (dd, J = 8.4, 5.3 Hz, 1H), 7.45
122.8, 119.9, 25.8, 25.5, 14.8. HRMS (ESI): Calcd. for C17H17N2 (d, J = 6.6 Hz, 2H), 7.42 – 7.36 (m, 2H), 7.30 (dd, J = 11.7, 4.4 Hz, 1H),
[M+H]+: 249.1386; found: 249.1376.
7.16 (d, J = 7.4 Hz, 1H), 2.40 (s, 3H). 13C NMR (126 MHz, CDCl3) δ
2-(4-bromophenyl)-3,7-dimethyl-1,8-naphthyridine (2t). Grey 159.1, 156.1, 153.8, 138.4, 137.3, 136.7, 136.5, 136.2, 129.9, 128.8,
solid (67.4 mg, 72% yield), m.p: 158.0-160.7 °C ; Rf = 0.3 (petroleum 128.2, 127.7, 124.8, 121.9, 121.5, 121.2, 21.5. HRMS (ESI): Calcd. for
ether/ethyl acetate = 3/1, v/v);1H NMR (500 MHz, CDCl3) δ 7.99 (d, J C17H15N2 [M+H]+: 247.1230; found: 247.1224.
= 8.3 Hz, 1H), 7.96 (d, J = 3.4 Hz, 1H), 7.57 (d, J = 2.9 Hz, 4H), 7.31 (d,
(E)-2-(4-chlorostyryl)-1,8-naphthyridine (3c). Yellow oil (40.4
J = 8.2 Hz, 1H), 2.77 (s, 3H), 2.48 (s, 3H). 13C NMR (126 MHz, CDCl3) δ mg, 76% yield); Rf = 0.3 (petroleum ether/ethyl acetate = 1/1, v/v);
162.6, 161.6, 154.3, 139.0, 137.8, 135.9, 131.2, 131.1, 129.4, 123.1, 1H NMR (500 MHz, ) δ 9.10 (dd, J = 4.2, 1.9 Hz, 1H), 8.13 (d, J = 8.5
122.9, 119.9, 25.6, 20.5. HRMS (ESI): Calcd. for C16H14BrN2 [M+H]+: Hz, 2H), 7.94 (d, J = 16.1 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.55 (d, J =
313.0335; found: 313.0335.
8.5 Hz, 2H), 7.43 (dd, J = 8.0, 4.2 Hz, 1H), 7.39 – 7.31 (m, 3H). 13C
7-methyl-2-phenyl-1,8-naphthyridine-3-carbonitrile
(2u). NMR (126 MHz, ) δ 158.6, 156.0, 153.9, 137.5, 136.8, 135.0, 134.7,
White solid (38.2 mg, 52% yield), m.p: 150.4-152.1 °C ; Rf = 0.2 134.7, 129.1, 128.7, 128.2, 122.0, 121.6, 121.4. HRMS (ESI): Calcd.
(petroleum ether/ethyl acetate = 3/1, v/v);1H NMR (500 MHz, CDCl3) for C16H12ClN2 [M+H]+: 267.0684; found: 267.0675.
δ 8.71 – 8.62 (m, 1H), 8.18 – 8.09 (m, 3H), 7.55 (dd, J = 3.4, 2.4 Hz,
Ethyl (E)-3-(1,8-naphthyridin-2-yl)acrylate (3d). White solid
3H), 7.48 (d, J = 8.2 Hz, 1H), 2.90 – 2.85 (m, 3H). 13C NMR (126 MHz, (32.8 mg, 72% yield), m.p: 87.4-90.1°C ; Rf = 0.3 (petroleum
CDCl3) δ 167.4, 161.2, 155.7, 145.1, 136.9, 136.7, 130.6, 129.5, ether/ethyl acetate = 5/1, v/v); 1H NMR (500 MHz, CDCl3) δ 9.19 (s,
128.6, 124.5, 118.0, 117.6, 105.6, 26.1. HRMS (ESI): Calcd. for 1H), 8.26 (dd, J = 14.2, 5.5 Hz, 2H), 7.92 (d, J = 15.8 Hz, 1H), 7.71 (dd,
C16H12N3 [M+H]+: 246.1026; found: 246.1016.
J = 8.3, 1.3 Hz, 1H), 7.55 (dd, J = 7.9, 4.1 Hz, 1H), 7.21 (d, J = 14.2 Hz,
10-methyl-5,6-dihydronaphtho[1,2-b][1,8]naphthyridine (2v). 1H), 4.32 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H). 13C NMR (126
o
Brown solid (49.5 mg, 67% yield), m.p: 140.4-141.7 C ; Rf = 0.3 MHz, CDCl3) δ 166.4, 156.6, 154.3, 142.9, 138.1, 137.2, 125.7, 122.9,
(petroleum ether/ethyl acetate = 3/1, v/v); 1H NMR (500 MHz, CDCl3) 122.6, 122.1, 61.0, 14.3. HRMS (ESI): Calcd. for C13H13N2O2 [M+H]+:
δ 8.77 (d, J = 7.5 Hz, 1H), 7.94 (s, 1H), 7.84 (d, J = 9.2 Hz, 1H), 7.38 229.0972; found: 229.0960.
(dd, J = 14.0, 6.7 Hz, 2H), 7.30 – 7.24 (m, 2H), 3.09 (d, J = 5.3 Hz, 2H),
9-phenylimidazo[1,5-a][1,8]naphthyridine (4a). Brown solid
2.98 (d, J = 5.5 Hz, 2H), 2.80 (d, J = 4.9 Hz, 3H). 13C NMR (126 MHz, (40.7 mg, 83% yield), m.p: 89.0-90.4 °C ; Rf = 0.3 (petroleum
CDCl3) δ 162.1, 156.1, 155.3, 139.4, 136.1, 134.4, 134.2, 130.9, ether/ethyl acetate = 5/1, v/v); 1H NMR (500 MHz, CDCl3) δ 8.32 –
130.3, 127.9, 127.3, 127.1, 122.4, 120.2, 28.4, 28.2), 25.6. HRMS 8.25 (m, 1H), 7.90 (dd, J = 7.7, 1.8 Hz, 1H), 7.83 – 7.79 (m, 2H), 7.61
(ESI): Calcd. for C17H15N2 [M+H]+: 247.1230; found: 247.1219.
(s, 1H), 7.50 – 7.44 (m, 3H), 7.37 (dd, J = 11.1, 5.1 Hz, 1H), 7.31 –
2-methyl-1,8-naphthyridine (2w). White solid (13.8 mg, 32% 7.28 (m, 1H), 6.95 (d, J = 8.2 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ
o
yield), m.p: 95.9-97.7 C; Rf = 0.3 (petroleum ether/ethyl acetate = 146.3, 144.3, 143.9, 136.0, 133.7, 131.4, 130.3, 128.4, 127.3, 123.6,
3/1, v/v); 1H NMR (500 MHz, CDCl3) δ 9.06 – 8.95 (m, 1H), 8.08 (d, J 121.4, 120.2, 119.6, 118.6. HRMS (ESI): Calcd. for C16H12N3 [M+H]+:
= 8.0 Hz, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.40 – 7.34 (m, 1H), 7.32 (d, J = 246.1026; found: 246.1035.
8.2 Hz, 1H), 2.75 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 163.02, 155.79,
9-(p-tolyl)imidazo[1,5-a][1,8]naphthyridine (4b). Brown oil
153.25, 136.94, 136.75, 123.06, 121.39, 120.75, 25.67. HRMS (ESI): (43.5 mg, 85% yield); Rf = 0.3 (petroleum ether/ethyl acetate = 2/1,
Calcd. for C9H9N2 [M+H]+: 145.0760; found: 145.0769. v/v); 1H NMR (500 MHz, CDCl3) δ 8.31 (dd, J = 4.6, 1.7 Hz, 1H), 7.93
2-methylquinoxaline (2x). Grey oid (12% yield), known (dd, J = 7.7, 1.7 Hz, 1H), 7.72 (d, J = 7.9 Hz, 2H), 7.61 (s, 1H), 7.39 (d,
compound 26; Rf = 0.3 (petroleum ether/ethyl acetate = 6/1, v/v); 1H J = 9.3 Hz, 1H), 7.32 (dd, J = 7.7, 4.6 Hz, 1H), 7.28 (d, J = 9.3 Hz, 2H),
NMR (500 MHz, CDCl3) δ 8.72 (s, 1H), 8.04 (dd, J = 8.2, 1.4 Hz, 1H), 6.96 (d, J = 9.3 Hz, 1H), 2.47 (s, 3H). 13C NMR (126 MHz, CDCl3) δ
8.01 (dd, J = 8.2, 1.4 Hz, 1H), 7.76-7.68 (m, 2H), 2.75 (s, 3H). 13C 146.28, 144.42, 144.09, 138.28, 135.95, 131.30, 130.69, 130.15,
NMR (126 MHz, CDCl3) δ 156.0, 148.3, 144.3, 143.3, 132.4, 131.5, 128.02, 123.49, 121.36, 120.27, 119.39, 118.65, 21.56. HRMS (ESI):
131.3, 131.0, 25.0.
Calcd. for C17H14N3 [M+H]+: 260.1182; found: 260.1176.
2-methylquinoline (2z). Yellow oil (7% yield); known compound
9-(4-methoxyphenyl)imidazo[1,5-a][1,8]naphthyridine
(4c).
26; Rf = 0.4 (petroleum ether/ethyl acetate = 6/1, v/v); 1H NMR (500 Yellow oil (42.9 mg, 78% yield); Rf = 0.3 (petroleum ether/ethyl
MHz, CDCl3) δ 8.06 (t, J = 8.3 Hz, 2H), 7.79 (dd, J = 8.2, 1.0 Hz, 1H), acetate = 2/1, v/v); 1H NMR (500 MHz, CDCl3) δ 8.31 (d, J = 4.4 Hz,
7.73 – 7.69 (m, 1H), 7.54 – 7.48 (m, 1H), 7.31 (d, J = 8.3 Hz, 1H), 2.78 1H), 7.92 (d, J = 7.7 Hz, 1H), 7.77 (d, J = 8.5 Hz, 2H), 7.59 (s, 1H), 7.37
(s, 3H). 13C NMR (126 MHz, CDCl3) δ 159.0, 147.7, 136.3, 129.5, (d, J = 9.2 Hz, 1H), 7.32 (dd, J = 7.7, 4.6 Hz, 1H), 6.99 (d, J = 8.5 Hz,
128.5, 127.5, 126.5, 125.8, 122.1, 25.3.
2H), 6.94 (d, J = 9.3 Hz, 1H), 3.91 (s, 3H). 13C NMR (126 MHz, CDCl3)
(E)-2-styryl-1,8-naphthyridine (3a). Yellow oil (39.5 mg, 85% δ 159.77, 146.24, 144.47, 143.88, 135.96, 131.70, 131.22, 126.06,
yield); Rf = 0.3 (petroleum ether/ethyl acetate = 3/1, v/v); 1H NMR 123.37, 121.36, 120.32, 119.31, 118.68, 112.68, 55.32. HRMS (ESI):
(500 MHz, CDCl3) δ 9.10 (s, 1H), 8.18 – 8.05 (m, 2H), 7.96 (d, J = 16.2 Calcd. for C17H14N3O [M+H]+: 276.1131; found: 276.1124.
Hz, 1H), 7.63 (d, J = 8.3 Hz, 3H), 7.45 – 7.37 (m, 4H), 7.36 – 7.30 (m,
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COMMUNICATION
Journal Name
Liukkonen, E. C. Engroff and R. M. Carlson, Synthetic
Commun., 2006, 13, 21; (d) R. A. GarzDaO-SI:a1n0c.1h0e3Vz9i,e/wCT9.AOrPtiBacl0ter1Oa4n,9li0AnJe.
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2018, 24, 10064.
J. Jin and D. W. MacMillan, Nature, 2015, 525, 87.
W. Liu, X. Yang, Z.-Z. Zhou and C.-J. Li, Chem, 2017, 2, 688.
J. Gui, Q. Zhou, C. M. Pan, Y. Yabe, A. C. Burns, M. R. Collins,
M. A. Ornelas, Y. Ishihara and P. S. Baran, J. Am. Chem. Soc.,
2014, 136, 4853.
Y. F. Liu, P. Y. Ji, J. W. Xu, Y. Q. Hu, Q. Liu, W. P. Luo and C. C.
Guo, J. Org. Chem., 2017, 82, 7159.
(a) J. Jia, Q. Jiang, A. Zhao, B. Xu, Q. Liu, W.-P. Luo and C.-C.
Guo, Synthesis, 2016, 48, 421; (b) K.-S. Du and J.-M. Huang,
Green Chem., 2018, 20, 1405; (c) X. Ren, J. Chen, F. Chen and
J. Cheng, Chem. commun., 2011, 47, 6725.
9-(4-bromophenyl)imidazo[1,5-a][1,8]naphthyridine
(4d).
Yellow solid (49.1 mg, 76% yield), m.p: 117.0-119.1 °C; Rf = 0.3
(petroleum ether/ethyl acetate = 2/1, v/v); 1H NMR (500 MHz, CDCl3)
δ 8.32 (dd, J = 4.6, 1.8 Hz, 1H), 7.97 (dd, J = 7.8, 1.7 Hz, 1H), 7.70 (d,
J = 8.4 Hz, 2H), 7.64 – 7.57 (m, 3H), 7.41 (d, J = 9.3 Hz, 1H), 7.36 (dd,
J = 7.7, 4.6 Hz, 1H), 7.00 (d, J = 9.3 Hz, 1H). 13C NMR (126 MHz,
CDCl3) δ 146.3, 144.2, 142.7, 136.2, 132.5, 132.0, 131.5, 130.4,
123.8, 122.7, 121.6, 120.2, 119.7, 118.6. HRMS (ESI): Calcd. for
C16H11BrN3 [M+H]+: 324.0131; found: 324.0125.
4
5
6
7
8
7-bromo-9-(p-tolyl)imidazo[1,5-a][1,8]naphthyridine
(5a).
Yellow oil (52.6 mg, 78% yield); Rf = 0.3 (petroleum ether/ethyl
acetate = 2/1, v/v); 1H NMR (500 MHz, CDCl3) δ 8.32 (dd, J = 4.6, 1.7
Hz, 1H), 7.96 (dd, J = 7.8, 1.7 Hz, 1H), 7.70 (d, J = 8.1 Hz, 2H), 7.40 –
7.33 (m, 2H), 7.27 (d, J = 7.9 Hz, 2H), 7.02 (d, J = 9.3 Hz, 1H), 2.46 (s,
3H). 13C NMR (126 MHz, CDCl3) δ 146.6, 144.1, 143.4, 138.8, 136.3,
130.2, 129.5, 128.6, 128.1, 121.9, 120.3, 120.2, 117.5, 110.6, 21.6.
HRMS (ESI): Calcd. for C17H13BrN3 [M+H]+: 338.0287; found:
338.0276.
9
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7-bromo-9-(4-methoxyphenyl)imidazo[1,5-a][1,8]-
naphthyridine (5b). Yellow oil (52.9 mg, 75% yield); Rf = 0.3
(petroleum ether/ethyl acetate = 1/1, v/v); 1H NMR (500 MHz, CDCl3)
δ 8.32 (dd, J = 4.6, 1.7 Hz, 1H), 7.96 (dd, J = 7.8, 1.7 Hz, 1H), 7.76 (d,
J = 8.8 Hz, 2H), 7.38 – 7.32 (m, 2H), 7.01 (d, J = 9.4 Hz, 1H), 6.99 (d, J
= 8.8 Hz, 2H), 3.91 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 160.1, 146.5,
144.2, 143.2, 136.3, 131.8, 128.5, 124.9, 121.9, 120.3, 120.1, 117.6,
112.7, 110.5, 55.4. HRMS (ESI): Calcd. for C17H13BrN3O [M+H]+:
354.0237; found: 354.0228.
Conflicts of interest
There are no conflicts to declare.
16 M. E. Duggan, L. T. Duong, J. E. Fisher, T. G. Hamill, W. F.
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Acknowledgements
We thank the Foundation of the Department of Education of
Guangdong Province (2018KZDXM070, 2017KZDXM085,
2017KQNCX204), the Foundation for Young Talents
(2018KQNCX272,
2018KQNCX273),
College
Students
Innovation and Entrepreneurship Training Program of Wuyi
University and the “Climbing Program” (pdjh2019b0497)
Special Funds for financial support.
Notes and references
Notes and references
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COMMUNICATION
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DOI: 10.1039/C9OB01490J
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