Iodine mediated: In situ generation of R-Se-I: Application towards the construction of pyrano[4,3- b] quinoline heterocycles and fluorescence properties

Article abstract of DOI:10.1039/c9ob01648a

In this paper, we report the iodine mediated in situ generation of R-Se-I and further its application towards the construction of pyrano[4,3-b]quinolin-1-one derivatives. The structural elaboration of 1-chloro-8-methyl-3-phenylbenzo[b][1,6]naphthyridine 6 was successfully achieved by Sonogashira, Suzuki coupling and dehalogenation reactions. Finally, the synthesized compounds 4a, 5a, 5b, 6, and 7a-7c were studied for photophysical properties including UV-absorption, fluorescence, and quantum yield studies. The synthesized pyranoquinoline derivatives showed λ_max, F_max and Φ_f values in the range of 391-447 nm, 436-486 nm and 0.004-0.301, respectively in chloroform solvent.

Full text of DOI:10.1039/c9ob01648a

Organic &
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PAPER
Iodine mediated in situ generation of R-Se–I:
application towards the construction of pyrano
[4,3-b]quinoline heterocycles and fluorescence
properties†
Cite this: Org. Biomol. Chem., 2019,
17, 9039
Khin Myat Noe Win, Amol D. Sonawane
and Mamoru Koketsu
*
In this paper, we report the iodine mediated in situ generation of R-Se–I and further its application
towards the construction of pyrano[4,3-b]quinolin-1-one derivatives. The structural elaboration of
1-chloro-8-methyl-3-phenylbenzo[b][1,6]naphthyridine 6 was successfully achieved by Sonogashira,
Suzuki coupling and dehalogenation reactions. Finally, the synthesized compounds 4a, 5a, 5b, 6, and
7a–7c were studied for photophysical properties including UV-absorption, fluorescence, and quantum
yield studies. The synthesized pyranoquinoline derivatives showed λmax, Fmax and Φf values in the range of
391–447 nm, 436–486 nm and 0.004–0.301, respectively in chloroform solvent.
Received 26th July 2019,
Accepted 17th September 2019
DOI: 10.1039/c9ob01648a
rsc.li/obc
the synthesis of chalcogen-containing quinolines, including sel-
enium derivatives.15 Besides the pharmacological properties,
Introduction
In modern organic synthesis, functionalized heterocyclic build- the presence of selenium-containing quinolines in a potentially
ing blocks are of great importance because of their wide appli- bioactive molecule can dramatically increase the biological
cation in pharmaceutical and industrial applications.1 Nitrogen- activity of the substrate.16 In our ongoing projects, we have suc-
containing heterocycles are gaining more importance due to cessfully synthesized thieno[2,3-b]quinoline and selenopheno
their interesting numerous applications in synthetic chemistry,2 [2,3-b]quinoline,17 thieno[2,3-c]acridine and furo[2,3-c]acri-
and natural products and because of their potent biological dine,18 2-imino-1,3-thiaselenolanes,19 and selenium-containing
activities.3 Among various N-heterocycles, pyranoquinoline bicyclic β-lactams.20a The main feature of the current strategy
derivatives have gained significant importance in natural pro- includes the use of both iodine and diorganyl diselenide
ducts that are present in many alkaloids4 such as flindersine, reagents in the cyclization reaction for their ability to transform
oricine, geibalasine and verprisine5 and they exhibit a variety of acyclic substrates into different heterocycles and incorporate
biological activities such as anti-inflammatory,6 antibacterial,7 new functionality into the final product, thus making more
and anti-allergic activities.8 Pyranoquinoline is also known for useful heterocycles that are suitable for further transforma-
pharmacological activities such as anti-coagulant,9 coronary tions.20b Herein, we have successfully attempted the synthesis of
constricting10 and cancer cell growth inhibitory activity.11 They 4-(arylselanyl)-3-aryl-1H-pyrano[4,3-b]quinolin-1-one derivatives
are often used as synthetic precursors for the preparation of from alkynylesters. Furthermore, we carried out photophysical
other natural products such as dimeric quinoline alkaloids and studies including UV-absorption spectroscopy, fluorescence,
other polycyclic heterocycles.12 Recently, Larock et al. have and quantum yield studies.
reported a two step synthesis of pyrano[4,3-b]quinolinones from
the corresponding alkynylesters followed by intramolecular
cyclization.13 As per a literature survey, the generation of Ar–Se–
X and its application is highly important, and the syntheses of
Results and discussion
pyranoquinolines and pyranoquinolinones are multistep and
suffer from poor availability of starting materials.14 In addition,
there are a large number of methodologies in the literature for
Our investigations began with the starting material 6-methyl-2-
(phenylethynyl)quinoline-3-carbaldehyde21 2a prepared from
the corresponding 6-methyl-2-chloroquinoline-3-carbalde-
hyde22 1a and phenyl acetylene under Sonogashira coupling
reaction conditions. Furthermore, 2-phenylalkynylquinoline-3-
carboxylate 3a was obtained selectively in excellent yields
without affecting the triple bond13 by using I2 and K2CO3 in
methanol at room temperature (Scheme 1).
Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu
University, Gifu 501-1193, Japan. E-mail: koketsu@gifu-u.ac.jp
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c9ob01648a
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Table 2 Substrate scopes of 4-(arylselanyl)-3-aryl-1H-pyrano[4,3-b]
quinolin-1-one 4a–4t
Diorganyl
diselenides
Entry
1
Alkynl ester (3)
Product (4) % yielda
Scheme 1 Synthesis of methyl 6-methyl-2-(phenylethynyl)quinoline-
3-carboxylate 3a. Reaction conditions: (i) 2-Chloro-6-methylquinoline-
3-carbaldehyde 1a (2.43 mmol), Pd(PPh3)2Cl2 (5 mol%), Et3N
(7.29 mmol), phenyl acetylene (3.65 mmol), CuI (5 mol%), THF (10 mL),
rt, 15 h; (ii) I2 (1.47 mmol), K2CO3 (2.21 mmol), methanol (5 mL), rt, 1 h.
(BuSe)2
2
3
4
5
6
(BuSe)2
(BuSe)2
(BuSe)2
(PrSe)2
(PrSe)2
We first examined the seleno-cyclization reaction of 3a
(0.05 g, 1.0 equiv.) with I2 (0.126 g, 1.0 equiv.) and dibutyl dise-
lenide (0.045 g, 1.0 equiv.) in CH2Cl2 (5 mL) under a nitrogen
atmosphere, the cyclized product 4a was obtained in 16% yield
(Table 1, entry 1). Furthermore we increased the equivalents of
iodine (1.5 and 3.0 equiv.); interestingly the yield was
increased up to 66% (Table 1, entries 2–5). On the other hand,
a higher loading of I2 (4.0 equiv.) led to a slightly lower yield
(Table 1, entries 4–6). Then, we carried out the reactions under
reflux conditions. The experimental conditions described in
Table 1 (entries 9–11) showed that the reaction proceeds under
reflux conditions with the highest yields (83–89%). The chloro-
form solvent used for the reaction was found to be less
effective (Table 1, entries 13 and 14). Also, the reaction did not
proceed in acetonitrile solvent (Table 1, entry 15). The reaction
temperature and iodine equivalents were found to have dra-
matic effects on the present intramolecular cyclization, and a
higher yield of products was obtained when the reaction was
performed under reflux conditions. Also, the reaction was
carried out using (Me-S)2 and (Ph-S)2 but the reaction does not
proceed for dialkyl disulfide as well as for diaryl disulfide.
7
(PrSe)2
(PrSe)2
(MeSe)2
(MeSe)2
(MeSe)2
Table 1 Optimization of reaction conditions on 4-(butylselanyl)-8-
methyl-3-phenyl-1H-pyrano[4,3-b]quinolin-1-one 4a
8
Entry
Solvent
I2 (equiv.)
Temp. (°C)
Yielda 4a (%)
9
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
1.0
1.5
2.0
2.5
3.0
4.0
3.0
1.5
2.5
3.0
3.5
3.0
3.0
3.0
3.0
rt
rt
rt
rt
rt
rt
rt
Reflux
Reflux
Reflux
Reflux
rt
rt
Reflux
Reflux
16
20
61
64
66
59
10
11
42b
47c
85c
89c
83c
22
9
10
11
12
13
14
15
CHCl3
CHCl3
CH3CN
14b
51c
NRc
a Reactions were performed under nitrogen, for 1 h. b Open flask, room
temperature. c Reflux conditions. NR: no reaction.
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Table 2 (Contd.)
ditions. Our results showed that the cyclized products, 4-(alkyl-
selanyl)-3-phenyl-1H-pyrano[4,3-b]quinolin-1-one
derivatives
Diorganyl
diselenides
Entry
12
Alkynl ester (3)
Product (4) % yielda
4a–4t were obtained in excellent yields 70–94% (Table 2).
The structures of all the synthesized compounds 3a–3f, 4a–4t
were characterized by IR, HRMS, 1H- and 13C-NMR spectral
analysis.
(MeSe)2
The plausible mechanism for the formation of pyrano[4,3-
b]quinoline 4 is shown in Fig. 1.23 First, the reaction of mole-
cular iodine (I2) and (R-Se)2 was carried out, which resulted in
the in situ generation of R-Se–I I. Furthermore, compound 3
13
14
15
16
17
(PhSe)2
(PhSe)2
(PhSe)2
(PhSe)2
(PhSe)2
reacts with R-Se–I
I to generate a seleniranium ion II.
Subsequently, the nucleophilic attack of the ester functional
group takes place on the seleniranium ion which resulted in the
intermediate III. Finally the intermediate III results in the target
compound 4 by the elimination of Me–I. A control experiment
was carried out to support the proposed reaction mechanism;
for that purpose we carried out the reaction of 3a (0.02 g, 1
equiv.), diphenyl diselenide (0.02 g, 1 equiv.) and iodine (0.05 g,
3.0 equiv.) in deuterated solvent CDCl3 (1.5 mL) and we have
investigated the formation of the R-Se–I intermediate, and also
the formation of the by-product Me–I by NMR. For the by-
product Me–I, the NMR spectra clearly showed the proton peak
at 2.167 ppm and carbon peak at −23.149 ppm.
Next, the synthesized 4-(butylselanyl)-8-methyl-3-phenyl-1H-
pyrano[4,3-b]quinolin-1-one 4a was functionalized, providing
chemical evidence of the cyclized product 4a. The reaction of
4a with an excess of 28% NH4OH in DMF at 80 °C afforded
compound 5a and 5b (Scheme 2)24 which were characterized
as 8-methyl-3-phenylbenzo[b][1,6]naphthyridin-1(2H)-one (5a)
and 4-(butylselanyl)-8-methyl-3-phenylbenzo[b][1,6]naphthyri-
din-1(2H)-one (5b) from their spectral and analytical data.
Furthermore, the compound 5a was transformed into 1-chloro-
18
19
20
(MeSe)2
(PhSe)2
(MeSe)2
8-methyl-3-phenylbenzo[b][1,6]naphthyridine
6 on reaction
with POCl3 under reflux conditions.24 In addition, the pres-
ence of chlorine in the 8-methyl-3-phenylbenzo[b][1,6]
naphthyridine product 6 is an interesting feature of the cycliza-
a Reactions were performed by using 0.15 mmol of 3, I2 (3.0 equiv.)
and diorganyl diselenides (1.0 equiv.) in CH2Cl2 under reflux con-
ditions for 1 h.
With the optimal reaction conditions in hand (Table 1,
entry 10) we have successfully synthesized pyrano[4,3-b]quino-
lin-1-one derivatives 4a–4t (Table 2). The alkyl substitution at
the quinoline part well tolerated the effect of different diorga-
nyl diselenides and iodine under the reflux reaction con- Fig. 1 Plausible mechanism.
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The UV-Vis absorption spectra of 4a, 5a–5b, 6, 7a–7c in
chloroform are shown in Fig. 2. In the pyranoquinoline deriva-
tives 4a and 5b bearing the R-Se group, the absorption
maximum (λmax) and molar extinction coefficient (ε) values
were found to be (4a: λmax = 391 nm, ε = 4, 960) and (5b: λmax
=
405 nm, ε = 4, 861) (Fig. 2), while the compounds 5a, 6 and
7a–7c show the absorption maximum (λmax) and molar extinc-
tion coefficient (ε) values (5a: λmax = 399 nm, ε = 7, 279; 6:
λmax = 425 nm, ε = 5, 220; 7a: λmax = 447 nm, ε = 5, 524; 7b:
λmax = 434 nm, ε = 4, 051; 7c: λmax = 425 nm, ε = 2, 305). The
fluorescence spectra of 4a, 5a–5b, 6 and 7a–7c in chloroform
are shown in Fig. 3.
The fluorescence maximum (Fmax) and Stokes shift values
were in the range of 436 to 486 nm and 2 to 146 nm, respect-
ively. The fluorescence quantum yield (Φf) values were rela-
tively low (Φf: 0.004–0.301) probably because of the heavy atom
effect.26 The effect of the heavy atom (R-Se) reflects on the fluo-
rescence,27 and compounds 4a and 5b bearing a heavy atom
do not show fluorescence; on the other hand compounds 5a,
6, 7a–7c showed higher fluorescence (Fig. 3). Furthermore, the
fluorescence quantum yield (Φf) value for 5a, 6, 7a–7c was
found to be (Φf = 0.025–0.301) which was higher than the fluo-
rescence quantum yield (Φf) values of 4a (Φf = 0.004) and 5b
(Φf = 0.008) probably due to the absence of the heavy atom
(R-Se) group in 5a.
Scheme 2 Functionalization of 4a, 5a and 6. Reaction conditions: (a)
POCl3, 80 °C, (b) phenyl acetylene, Pd(PPh3)2Cl2, Et3N, THF, room temp-
erature. (c) Phenylboronic acid, Pd(OAc)2, Cs2CO3, DMF, 110 °C. (d)
Methylacrylate, PPh3, Pd(OAc)2, K2CO3, DMF, 110 °C.
tion which allowed further structural elaboration, most
notably by the Sonogashira coupling, Suzuki coupling and
dehalogenation reactions to afford the corresponding diversi-
fied pyrano[4,3-b]quinoline moieties 7a–7c. (Scheme 2).25
Fig. 2 UV-Vis absorption spectra in chloroform of compounds 4a, 5a–5b, 6 and 7a–7c.
Fig. 3 Normalized fluorescence spectra in chloroform of compounds 4a, 5a–5b, 6 and 7a–7c.
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7.5 Hz, 4H), 0.93 (t, J = 7.3 Hz, 6H); 13C-NMR (100 MHz, CDCl3)
δ 33.2, 30.0, 22.7, 13.7; 77Se-NMR (75 MHz, CDCl3) δ 307.8.
Preparation of 1,2-dipropyldiselenide. Yield: 68%; orange
Conclusions
We have developed a synthetic route for the preparation of
pyrano[4,3-b]quinolin-1-one derivatives
4
via the intra- coloured liquid; 1H-NMR (400 MHz, CDCl3) δ 2.86–2.94 (m,
molecular cyclization of alkynylesters promoted by diorganyl 4H), 1.72–1.81 (m, 4H), 1.00 (t, J = 7.3 Hz, 6H); 13C-NMR
diselenide. Next, the structural elaboration of pyrano[4,3-b]qui- (100 MHz, CDCl3) δ 32.4, 24.3, 14.2; 77Se-NMR (75 MHz,
nolin-1-one 4 was done by Sonogashira coupling, Suzuki coup- CDCl3) δ 303.4.
ling and dehalogenation reactions. Finally, the synthesized
compounds were studied for photophysical properties includ-
General procedure for the synthesis of 6-methyl-2-
(phenylethynyl)quinoline-3-carbaldehyde 2a–2f
ing UV-absorption spectroscopy, fluorescence, and quantum
yield studies. The synthesized pyranoquinoline derivatives To a solution of 2-chloro-6-methylquinoline-3-carbaldehyde22
showed λmax
,
Fmax and Φf values in the range from 1a (500 mg, 2.43 mmol, 1.0 equiv.) in dry THF (10 mL) was
mol%), triethylamine
391–447 nm, 436–486 nm and 0.004–0.301, respectively in added Pd(PPh3)2Cl2 (85.33 mg,
5
chloroform solvent. The structures of the products were con- (738.13 mg, 7.29 mmol, 3.0 equiv.), phenyl acetylene
firmed by IR, NMR, and HRMS as well as fluorescence pro- (372.50 mg, 3.65 mmol, 1.5 equiv.), and copper(I) iodide
perties. Further expansion of current strategies and evaluation (23.15 mg, 5 mol%) under nitrogen. The mixture was stirred at
of biological activity are in progress.
room temperature for 15 h.21 After completion of the reaction,
the solvent was evaporated under reduced pressure. The
residue was extracted with ethyl acetate and the organic phase
was washed successively with water and brine. The organic
layer was dried over Na2SO4. The resulting crude product was
purified by column chromatography using n-hexane : ethyl
acetate (92 : 8) as the eluent to afford 2a, yellow solid. Yield:
91%; melting point: 136–138 °C; IR (neat): 2361, 2016, 1965,
Experimental: general
All solvents and reagents were purchased from the suppliers
and used without further purification. IR spectra were
recorded on a JASCO FT/IR-460 Plus spectrophotometer.
Reactions were monitored by thin-layer chromatography (TLC)
carried on silica plates using UV-light or Iodine chamber for
visualization.
Column chromatography was performed on silica gel
(60–120 mesh) using n-hexane and ethyl acetate as eluents.
Evaporation and condensation were carried out in vacuo. NMR
spectra were recorded with JEOL JNM-ECS 400 spectrometers
with tetramethylsilane as an internal standard. Chemical
shifts δ and coupling constants J are given in ppm (parts per
million) and Hz (hertz), respectively. The following abbrevi-
ations were used as follows: s: singlet, d: doublet, t: triplet, m:
multiplet. Additionally unknown compounds are characterized
by HRMS analysis. All known compound data are consistent
with the given literature reports. Melting points were measured
by using a Yanaco micromelting point apparatus.
1700, 1572, 1191, 1099, 946, 830, 803, 769, 582, 564, 528 cm−1
;
1H-NMR (400 MHz, CDCl3) δ 10.75 (s, 1H), 8.59 (s, 1H), 8.02 (d,
J = 9.2 Hz, 1H), 7.64–7.68 (m, 4H), 7.40 (dd, J = 6.9, 4.6 Hz,
3H), 2.53 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ 190.7, 148.7,
142.9, 138.5, 136.2, 135.4, 132.3, 129.8, 128.9, 128.8, 128.6,
128.3, 126.4, 121.5, 95.1, 85.8, 21.7; HRMS (ESI): CDCl3 m/z =
272.1075 calcd. For C19H14NO, found 272.1050 [M + H]+.
7-Methyl-2-(phenylethynyl)quinoline-3-carbaldehyde
(2b).
Yield: 85%; melting point: 196–198 °C; IR (neat): 2986, 2409,
2212, 1689, 1579, 1546, 1487, 1440, 1379, 1145, 1092, 1066,
918, 880, 706, 685, 674, 523 cm−1; 1H-NMR (400 MHz, CDCl3) δ
10.71 (s, 1H), 8.60 (s, 1H), 7.88 (s, 1H), 7.77 (d, J = 8.2 Hz, 1H),
7.67–7.69 (m, 2H), 7.41 (dd, J = 7.3, 4.6 Hz, 4H), 2.55 (s, 3H);
13C-NMR (100 MHz, CDCl3) δ 190.7, 150.3, 144.2, 143.9, 136.6,
132.3, 130.6, 129.8, 129.3, 128.6, 128.3, 124.5, 121.5, 95.2, 85.8,
22.4; HRMS (ESI): m/z = 272.1075 calcd. For C19H14NO, found
272.1046 [M + H]+.
Diselenide preparation
Preparation of 1,2-dibutyldiselenide. Selenium (200 mg,
8-Methyl-2-(phenylethynyl)quinoline-3-carbaldehyde
(2c).
2.53 mmol) was added to a stirred solution of sodium boro- Yield: 81%; melting point: 150–152 °C; IR (neat): 2211, 1781,
hydride (191 mg, 5.07 mmol) in ethanol (20 mL) at 0 °C. 1691, 1583, 1564, 1492, 1482, 1441, 1409, 1387, 1369, 1169,
Stirring was continued for 30 min, at this temperature. 1119, 1073, 1042, 945, 912, 883, 844, 776, 757, 693, 536,
1
Additionally, selenium (200 mg, 2.53 mmol) was added to the 472 cm−1; H-NMR (400 MHz, CDCl3) δ 10.80 (s, 1H), 8.68 (s,
reaction mixture and stirred for 30 min at 0 °C. Finally, iodo- 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.69–7.71 (m, 3H), 7.51 (d, J = 6.9
butane (1.01 mL, 8.87 mmol) was added over a period of Hz, 1H), 7.43 (dd, J = 4.4, 3.0 Hz, 3H), 2.86 (s, 3H); 13C-NMR
5 min. After stirring for an hour at room temperature, the reac- (100 MHz, CDCl3) δ 191.3, 149.4, 142.8, 137.7, 137.3, 133.1,
tion mixture was extracted with n-hexane and washed with 132.4, 129.8, 128.7, 128.1, 127.7, 126.6, 121.7, 94.9, 86.2, 18.2;
water, dried over Na2SO4 and concentrated in vacuo. The crude HRMS (ESI): m/z = 272.1075 calcd. For C19H14NO, found
product was purified over silica gel column chromatography 272.1062 [M + H]+.
(SiO2: n-hexane/toluene = 20/1) to afford dibutyl diselenide as
2-(Phenylethynyl)quinoline-3-carbaldehyde (2d). Yield: 89%;
melting point: 111–113 °C; IR (neat): 2209, 1774, 1692, 1612,
an orange coloured liquid.
Yield: 72%; orange coloured liquid; 1H-NMR (400 MHz, 1580, 1556, 1493, 1444, 1372, 1166, 1146, 1087, 879, 783, 686,
CDCl3) δ 2.92 (t, J = 7.6 Hz, 4H), 1.68–1.75 (m, 4H), 1.42 (q, J = 522, 486, 475 cm−1; 1H-NMR (400 MHz, CDCl3) δ 10.80 (s, 1H),
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8.74 (s, 1H), 8.17 (d, J = 7.8 Hz, 1H), 7.97 (s, 1H), 7.85–7.89 (m, (100 MHz, CDCl3) δ 165.8, 149.4, 143.3, 141.7, 139.6, 132.5,
1H), 7.70–7.72 (m, 2H), 7.64 (d, J = 6.9 Hz, 1H), 7.42–7.45 (m, 130.4, 129.3, 128.5, 128.3, 128.2, 124.8, 124.0, 122.6, 93.3, 88.7,
3H); 13C-NMR (100 MHz, CDCl3) δ 190.8, 150.2, 144.0, 137.2, 52.6, 22.3; HRMS (ESI): m/z = 302.1181 calcd. For C20H16NO2,
133.1, 132.4, 130.0, 129.8, 129.4, 128.9, 128.7, 128.3, 126.5, found 302.1163 [M + H]+.
121.4, 95.7, 85.6; HRMS (ESI): m/z = 258.0919 calcd. For
Methyl 8-methyl-2-(phenylethynyl)quinoline-3-carboxylate
(3c). Yield: 83%; melting point: 67–69 °C; IR (neat): 2216,
C18H12NO, found 258.0891 [M + H]+.
6-Chloro-2-(phenylethynyl)quinoline-3-carbaldehyde
(2e). 1727, 1711, 1612, 1587, 1565, 1491, 1439, 1404, 1261, 1240,
Yield: 78%; melting point: 134–136 °C; IR (neat): 3046, 2207, 1198, 1154, 1092, 1035, 789, 753, 688, 667, 514 cm−1; H-NMR
1690, 1575, 1474, 1364, 1168, 1074, 944, 937, 829, 750, 688, (400 MHz, CDCl3) δ 8.65 (s, 1H), 7.71 (q, J = 3.2 Hz, 2H), 7.60
570, 524 cm−1; 1H-NMR (400 MHz, CDCl3) δ 10.79 (s, 1H), 8.65 (dd, J = 17.6, 7.6 Hz, 2H), 7.36–7.41 (m, 4H), 3.99 (s, 3H), 2.81
(s, 1H), 8.11 (d, J = 9.2 Hz, 1H), 7.94 (d, J = 2.3 Hz, 1H), (s, 3H); 13C-NMR (100 MHz, CDCl3) δ 165.9, 148.2, 140.4,
7.78–7.80 (m, 1H), 7.70 (dd, J = 6.0, 1.8 Hz, 2H), 7.42–7.46 (m, 139.9, 137.4, 132.4, 132.3, 129.3, 128.5, 127.8, 126.5, 125.8,
3H); 13C-NMR (100 MHz, CDCl3) δ 190.5, 148.6, 144.1, 136.5, 125.3, 122.8, 92.8, 89.3, 52.6, 18.1; HRMS (ESI): m/z = 302.1181
134.2, 134.0, 132.4, 130.9, 130.1, 129.4, 128.7, 128.1, 127.1, calcd. For C20H16NO2, found 302.1159 [M + H]+.
1
121.2, 96.2, 85.4; HRMS (ESI): m/z = 292.0529 calcd. For
Methyl 2-(phenylethynyl)quinoline-3-carboxylate (3d). Yield:
92%; melting point: 97–99 °C; IR (neat): 2217, 1728, 1615,
C18H12NO, found 292.0518 [M + H]+.
8-Methoxy-2-(phenylethynyl)quinoline-3-carbaldehyde (2f). 1595, 1584, 1489, 1434, 1414, 1227, 1201, 1127, 1063, 1026,
Yield: 83%; melting point: 142–144 °C; IR (neat): 3010, 2205, 954, 945, 795, 755, 687, 525, 469 cm−1 1H-NMR (400 MHz,
;
1689, 1583, 1459, 1373, 1270, 1126, 1073, 939, 765, 751, 717, CDCl3) δ 8.81 (s, 1H), 8.17 (d, J = 8.7 Hz, 1H), 7.89 (d, J =
686, 524 cm−1; 1H-NMR (400 MHz, CDCl3) δ 10.83 (s, 1H), 8.71 7.8 Hz, 1H), 7.83 (dd, J = 8.7, 6.9 Hz, 1H), 7.73 (q, J = 3.2 Hz,
(s, 1H), 7.69 (dd, J = 7.6, 2.1 Hz, 2H), 7.54–7.59 (m, 2H), 2H), 7.62 (d, J = 8.2 Hz, 1H), 7.39–7.41 (m, 3H), 4.05 (s, 3H);
7.41–7.43 (m, 3H), 7.20–7.22 (m, 1H), 4.13 (s, 3H); 13C-NMR 13C-NMR (100 MHz, CDCl3) δ 165.7, 149.1, 141.7, 139.9, 132.5,
(100 MHz, CDCl3) δ 191.1, 155.0, 142.8, 142.1, 136.9, 132.4, 132.3, 129.4, 129.3, 128.6, 128.5, 128.0, 125.9, 125.6, 122.5,
129.8, 129.3, 128.6, 127.6, 121.7, 121.2, 110.9, 95.6, 86.1, 56.4; 93.5, 88.6, 52.7; HRMS (ESI): m/z = 288.1025 calcd. For
HRMS (ESI): m/z = 288.1025 calcd. For C18H12NO, found C19H14NO2, found 288.0996 [M + H]+.
288.1006 [M + H]+.
Methyl 6-chloro-2-(phenylethynyl)quinoline-3-carboxylate (3e).
Yield: 83%; melting point: 151–153 °C; IR (neat): 3067, 2209,
1707, 1579, 1489, 1437, 1248, 1234, 1064, 833, 752, 688, 655,
General procedure for the synthesis of methyl 6-methyl-2-
(phenylethynyl)quinoline-3-carboxylate 3a–3f
1
528, 513 cm−1; H-NMR (400 MHz, CDCl3) δ 8.70 (s, 1H), 8.10
To a solution of 6-methyl-2-(phenylethynyl)quinoline-3-carbal- (d, J = 9.2 Hz, 1H), 7.87 (d, J = 2.3 Hz, 1H), 7.70–7.77 (m, 3H),
dehyde21 2a (200 mg, 0.737 mmol, 1.0 equiv.) in methanol 7.40 (q, J = 2.3 Hz, 3H), 4.05 (s, 3H); 13C-NMR (100 MHz,
(5 mL) was added I2 (374 mg, 1.47 mmol, 2.0 equiv.) and CDCl3) δ 165.4, 147.5, 141.9, 138.8, 133.9, 133.2, 132.5, 130.8,
K2CO3 (306 mg, 2.21 mmol, 3.0 equiv.). The resulting reaction 129.6, 128.6, 127.1, 126.5, 126.5, 122.3, 94.2, 88.2, 52.9; HRMS
mixture was stirred at room temperature until the total dis- (ESI): m/z = 322.0635 calcd. For C19H14NO2, found 322.0611
appearance of the starting material monitored by TLC. After [M + H]+.
completion, the reaction mixture was quenched with saturated
Methyl 8-methoxy-2-(phenylethynyl)quinoline-3-carboxylate
aqueous Na2S2O3 and water. The resulting reaction mixture (3f). Yield: 97%; yellow liquid; IR (neat): 2952, 2218, 1735,
was extracted using ethyl acetate. The organic layer was dried 1614, 1560, 1492, 1463, 1274, 1186, 1157, 1058, 985, 792, 749,
1
over Na2SO4. The resulting product was purified by column 728, 665, 527 cm−1; H-NMR (400 MHz, CDCl3) δ 8.74 (s, 1H),
chromatography using n-hexane : ethyl acetate (80 : 20) as the 7.71 (q, J = 3.2 Hz, 2H), 7.50 (t, J = 8.0 Hz, 1H), 7.43 (d, J =
eluent to afford 3a, yellow solid. Yield: 84%; melting point: 7.3 Hz, 1H), 7.38 (t, J = 3.2 Hz, 3H), 7.13 (d, J = 7.8 Hz, 1H),
91–93 °C; IR (neat): 2216, 1726, 1582, 1559, 1486, 1440, 1266, 4.09 (s, 3H), 4.03 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ 165.8,
1194, 1174, 1134, 1065, 912, 827, 777, 765, 685, 563, 527 cm−1
;
154.8, 141.0, 140.5, 139.6, 132.4, 129.2, 128.4, 128.4, 127.0,
1H-NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 8.03 (d, J = 8.7 Hz, 126.2, 122.7, 120.1, 110.1, 93.5, 89.0, 56.3, 52.7; HRMS
1H), 7.72 (s, 2H), 7.60–7.63 (m, 2H), 7.38 (t, J = 3.2 Hz, 3H), (ESI): m/z = 318.1130 calcd. For C19H14NO2, found 318.1102
4.02 (s, 3H), 2.53 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ 165.8, [M + H]+.
147.7, 140.7, 139.1, 138.3, 134.7, 132.4, 129.3, 128.8,
128.5, 127.4, 125.9, 125.5, 122.6, 93.1, 88.7, 52.7, 21.7; HRMS
General procedure for the synthesis of 4-(butylselanyl)-8-
methyl-3-phenyl-1H-pyrano[4,3-b]quinolin-1-one 4a–4t
(ESI): m/z = 302.1181 calcd. For C20H16NO2, found 302.1162
[M + H]+.
To a solution of I2 (126 mg, 0.497 mmol, 3.0 equiv.), dibutyl
Methyl 7-methyl-2-(phenylethynyl)quinoline-3-carboxylate diselenide (45 mg, 0.166 mmol, 1.0 equiv.) in CH2Cl2 (5 mL)
(3b). Yield: 86%; melting point: 97–99 °C; IR (neat): 2215, were added, and the resulting mixture was stirred for 20 min.
1726, 1620, 1596, 1545, 1495, 1436, 1421, 1276, 1261, 1230, After this time period, methyl 6-methyl-2-(phenylethynyl)qui-
1193, 1065, 931, 812, 792, 752, 686, 530, 470 cm−1 1H-NMR noline-3-carboxylate14 3a (50 mg, 0.166 mmol, 1.0 equiv.) was
;
(400 MHz, CDCl3) δ 8.75 (s, 1H), 7.93 (s, 1H), 7.72–7.78 (m, added at the same temperature. The reaction was monitored
3H), 7.38–7.44 (m, 4H), 4.03 (s, 3H), 2.58 (s, 3H); 13C-NMR by TLC, and after completion, the reaction mixture was
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quenched with saturated aqueous Na2S2O3 and water. The 2966, 1732, 1610, 1595, 1556, 1484, 1443, 1343, 1202, 1188,
resulting solution was extracted using dichloromethane. The 1067, 1048, 1028, 953, 937, 828, 750, 703, 697, 620, 649 cm−1
;
organic layer was dried over Na2SO4. The crude product was 1H-NMR (400 MHz, CDCl3) δ 9.09 (s, 1H), 8.18 (d, J = 8.7 Hz,
purified by column chromatography using n-hexane : ethyl 1H), 7.74–7.78 (m, 4H), 7.49 (q, J = 3.4 Hz, 3H), 2.93 (t, J =
acetate (82 : 18) as the eluent to afford 4a, yellow solid. Yield: 7.3 Hz, 2H), 2.59 (s, 3H), 1.56 (q, J = 7.3 Hz, 2H), 0.83 (t, J =
89%; melting point: 109–111 °C; IR (neat): 2944, 1737, 1608, 7.3 Hz, 3H; 13C-NMR (100 MHz, CDCl3) δ 162.3, 158.7, 151.7,
1594, 1485, 1456, 1445, 1200, 1187, 1070, 1045, 932, 826, 749, 150.4, 139.9, 137.8, 136.0, 134.2, 130.2, 130.1, 129.6, 127.9,
1
608, 621, 647, 480 cm−1; H-NMR (400 MHz, CDCl3) δ 9.11 (s, 127.8, 127.0, 115.4, 107.8, 30.9, 23.3, 21.8, 14.4; 77Se-NMR
1H), 8.18 (d, J = 8.7 Hz, 1H), 7.74–7.78 (m, 4H), 7.49 (t, J = (75 MHz, CDCl3) δ 195.4; HRMS (ESI): m/z = 410.0659 calcd.
3.4 Hz, 3H), 2.96 (t, J = 7.3 Hz, 2H), 2.60 (s, 3H), 1.52 (t, J = For C22H20NO2Se, found 410.0668 [M + H]+.
7.6 Hz, 2H), 1.25 (q, J = 7.5 Hz, 2H), 0.78 (t, J = 7.3 Hz, 3H);
7-Methyl-3-phenyl-4-(propylselanyl)-1H-pyrano[4,3-b]quinolin-
13C-NMR (100 MHz, CDCl3) δ 162.3, 158.6, 151.7, 150.4, 139.8, 1-one (4f). Yield: 89%; melting point: 163–165 °C; IR (neat):
137.8, 136.0, 134.2, 130.2, 130.1, 129.6, 127.9, 127.8, 127.0, 2964, 1726, 1612, 1593, 1497, 1441, 1372, 1212, 1167, 1066,
115.4, 107.9, 31.9, 28.5, 22.8, 21.8, 13.6; 77Se-NMR (75 MHz, 1044, 1028, 934, 810, 795, 763, 699, 631, 475 cm−1 1H-NMR
;
CDCl3) δ 198.13; HRMS (ESI): m/z = 424.0816 calcd. For (400 MHz, CDCl3) δ 9.13 (s, 1H), 8.07 (s, 1H), 7.92 (d, J = 8.7
C23H22NO2Se, found 424.0817 [M + H]+.
Hz, 1H), 7.76–7.78 (m, 2H), 7.47–7.49 (m, 4H), 2.94 (t, J = 7.3
4-(Butylselanyl)-7-methyl-3-phenyl-1H pyrano[4,3-b]quinolin- Hz, 2H), 2.63 (s, 3H), 1.56 (q, J = 7.3 Hz, 2H), 0.83 (t, J = 7.1 Hz,
1-one (4b). Yield: 82%; melting point: 146–148 °C; IR (neat): 3H); 13C-NMR (100 MHz, CDCl3) δ 162.3, 159.0, 152.5, 151.9,
2950, 1723, 1613, 1598, 1499, 1444, 1425, 1377, 1215, 1172, 145.0, 140.3, 134.2, 130.2, 130.1, 130.0, 129.0, 129.0, 128.0,
1145, 1066, 1049, 1038, 953, 809, 797, 695, 632, 479 cm−1
;
125.1, 114.7, 107.8, 31.0, 23.3, 22.4, 14.4; 77Se-NMR (75 MHz,
1H-NMR (400 MHz, CDCl3) δ 9.13 (s, 1H), 8.07 (s, 1H), 7.91 (d, CDCl3) δ 195.67; HRMS (ESI): m/z = 410.0659 calcd. For
J = 8.2 Hz, 1H), 7.76–7.78 (m, 2H), 7.49 (t, J = 3.2 Hz, 4H), 2.96 C22H20NO2Se, found 410.0658 [M + H]+.
(t, J = 7.3 Hz, 2H), 2.63 (s, 3H), 1.53 (q, J = 7.3 Hz, 2H), 1.26 (t,
6-Methyl-3-phenyl-4-(propylselanyl)-1H-pyrano[4,3-b]quinolin-
J = 7.3 Hz, 2H), 0.78 (t, J = 7.3 Hz, 3H); 13C-NMR (100 MHz, 1-one (4g). Yield: 94%; melting point: 127–129 °C; IR (neat):
CDCl3) δ 162.3, 158.9, 152.5, 151.9, 144.6, 140.3, 134.2, 130.2, 2962, 1725, 1595, 1566, 1488, 1443, 1421, 1371, 1179, 1092,
130.1, 130.0, 128.9, 128.8, 127.9, 125.1, 114.7, 107.9, 32.0, 28.5, 1076, 1064, 787, 771, 764, 689, 624, 649, 611, 599 cm−1
;
22.8, 22.4, 13.6; 77Se-NMR (75 MHz, CDCl3) δ 198.59; HRMS 1H-NMR (400 MHz, CDCl3) δ 9.13 (s, 1H), 7.85 (d, J = 7.8 Hz,
(ESI): m/z = 424.0816 calcd. For C23H22NO2Se, found 424.0824 1H), 7.75–7.78 (m, 3H), 7.48–7.54 (m, 4H), 3.03 (t, J = 7.3 Hz,
[M + H]+.
2H), 2.92 (s, 3H), 1.55 (q, J = 7.5 Hz, 2H), 0.84 (d, J = 7.3 Hz,
4-(Butylselanyl)-6-methyl-3-phenyl-1H-pyrano[4,3-b]quinolin- 3H); 13C-NMR (100 MHz, CDCl3) δ 162.3, 159.0, 151.1, 151.0,
1-one (4c). Yield: 78%; melting point: 92–94 °C; IR (neat): 141.0, 138.0, 134.2, 133.3, 130.2, 130.1, 128.0, 127.4, 127.2,
2923, 1743, 1594, 1567, 1459, 1370, 1229, 1170, 1066, 1027, 127.0, 115.1, 108.1, 30.2, 23.3, 18.2, 14.4; 77Se-NMR (75 MHz,
784, 692, 648, 619, 530 cm−1; 1H-NMR (400 MHz, CDCl3) δ 9.14 CDCl3) δ 200.75; HRMS (ESI): m/z = 432.0479 calcd. For
(s, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.77 (q, J = 3.2 Hz, 3H), C22H19NO2NaSe, found 432.0460 [M + Na]+.
7.49–7.54 (m, 4H), 3.05 (t, J = 7.6 Hz, 2H), 2.92 (s, 3H), 1.51 (t,
3-Phenyl-4-(propylselanyl)-1H-pyrano[4,3-b]quinolin-1-one (4h).
J = 7.6 Hz, 2H), 1.24 (q, J = 7.5 Hz, 2H), 0.78 (t, J = 7.3 Hz, 3H); Yield: 70%; melting point: 146–148 °C; IR (neat): 2963, 1738,
13C-NMR (100 MHz, CDCl3) δ 162.3, 158.9, 151.2, 150.7, 140.9, 1614, 1591, 1559, 1441, 1377, 1243, 1210, 1175, 1066, 1041,
138.0, 134.3, 133.3, 130.2, 130.1, 127.9, 127.4, 127.2, 127.0, 953, 798, 773, 759, 697, 625, 478 cm−1 1H-NMR (400 MHz,
;
115.1, 108.2, 32.0, 27.9, 22.9, 18.2, 13.6; 77Se-NMR (75 MHz, CDCl3) δ 9.21 (s, 1H), 8.29 (d, J = 8.7 Hz, 1H), 8.04 (d, J =
CDCl3) δ 204.0; HRMS (ESI): m/z = 446.0635 calcd. For 8.2 Hz, 1H), 7.92 (t, J = 7.6 Hz, 1H), 7.77 (q, J = 3.2 Hz, 2H),
C23H21NO2NaSe, found 446.0621 [M + Na]+.
7.65 (t, J = 7.6 Hz, 1H), 7.49 (t, J = 3.4 Hz, 3H), 2.94 (t, J = 7.3
4-(Butylselanyl)-3-phenyl-1H-pyrano[4,3-b]quinolin-1-one (4d). Hz, 2H), 1.56 (q, J = 7.3 Hz, 2H), 0.84 (t, J = 7.3 Hz, 3H);
Yield: 78%; melting point: 114–116 °C; IR (neat): 2951, 1738, 13C-NMR (100 MHz, CDCl3) δ 162.1, 159.1, 152.5, 151.6, 140.8,
1615, 1595, 1558, 1425, 1412, 1213, 1178, 1146, 1071, 1043, 134.1, 133.4, 130.3, 130.1, 129.9, 129.3, 127.9, 127.6, 126.9,
970, 797, 754, 700, 626, 478 cm−1; 1H-NMR (400 MHz, CDCl3) δ 115.5, 107.7, 30.9, 23.3, 14.4; 77Se-NMR (75 MHz, CDCl3)
9.20 (s, 1H), 8.28 (d, J = 8.7 Hz, 1H), 8.03 (d, J = 7.8 Hz, 1H), δ 196.13; HRMS (ESI): m/z = 396.0503 calcd. For C21H18NO2Se,
7.90–7.94 (m, 1H), 7.78 (dt, J = 5.3, 2.1 Hz, 2H), 7.65 (t, J = 7.6 found 396.0507 [M + H]+.
Hz, 1H), 7.48–7.51 (m, 3H), 2.97 (t, J = 7.6 Hz, 2H), 1.54 (q, J =
8-Methyl-4-(methylselanyl)-3-phenyl-1H-Pyrano[4,3-b]quinolin-
7.3 Hz, 2H), 1.23–1.30 (m, 2H), 0.79 (d, J = 7.3 Hz, 3H); 1-one (4i). Yield: 85%; melting point: 163–165 °C; IR (neat):
13C-NMR (100 MHz, CDCl3) δ 162.1, 159.0, 152.5, 151.6, 140.8, 2930, 1737, 1626, 1161, 1486, 1442, 1373, 1345, 1203, 1188,
134.2, 133.4, 130.3, 130.1, 129.9, 129.3, 127.9, 127.5, 126.9, 1024, 946, 904, 832, 755, 701, 693, 622, 479 cm−1 1H-NMR
;
115.5, 107.8, 31.9, 28.5, 22.8, 13.6; 77Se-NMR (75 MHz, CDCl3) (400 MHz, CDCl3) δ 9.08 (s, 1H), 8.18 (d, J = 8.7 Hz, 1H),
δ 199.21; HRMS (ESI): m/z = 410.0659 calcd. For C22H20NO2Se, 7.76–7.80 (m, 4H), 7.50 (t, J = 3.2 Hz, 3H), 2.59 (s, 3H), 2.29 (d,
found 410.0658 [M + H]+.
J = 6.4 Hz, 3H); 13C-NMR (100 MHz, CDCl3) δ 162.2, 157.8,
8-Methyl-3-phenyl-4-(propylselanyl)-1H-pyrano[4,3-b]quinolin- 151.5, 150.3, 139.9, 137.8, 136.0, 134.0, 130.4, 130.0, 129.5,
1-one (4e). Yield: 83%; melting point: 143–145 °C; IR (neat): 128.0, 127.8, 127.0, 115.5, 108.8, 21.8, 9.7; 77Se-NMR (75 MHz,
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CDCl3) δ 124.39; HRMS (ESI): m/z = 382.0346 calcd. For CDCl3) δ 311.89; HRMS (ESI): m/z = 444.0503 calcd. For
C20H16NO2Se, found 382.0342 [M + H]+.
C25H18NO2Se, found 444.0492 [M + H]+.
7-Methyl-4-(methylselanyl)-3-phenyl-1H-pyrano[4,3-b]quinolin-
6-Methyl-3-phenyl-4-(phenylselanyl)-1H-pyrano[4,3-b]quinolin-
1-one (4j). Yield: 88%; melting point: 154–156 °C; IR (neat): 1-one (4o). Yield: 82%; melting point: 161–163 °C; IR (neat):
2995, 1665, 1623, 1595, 1570, 1499, 1380, 1218, 1170, 1066, 3051, 1743, 1593, 1574, 1488, 1477, 1444, 1248, 1171, 1084,
1049, 1025, 882, 811, 795, 702, 631, 471 cm−1 1H-NMR 1072, 1021, 949, 784, 773, 731, 699, 687, 651, 620 cm−1
; ;
(400 MHz, CDCl3) δ 9.12 (s, 1H), 8.08 (s, 1H), 7.91 (d, J = 8.2 1H-NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 7.77–7.81 (m, 3H),
Hz, 1H), 7.78–7.81 (m, 2H), 7.50 (t, J = 3.2 Hz, 4H), 2.63 (s, 3H), 7.65 (d, J = 6.9 Hz, 1H), 7.47 (dd, J = 13.1, 5.7 Hz, 4H), 7.34 (dd,
2.29 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ 162.2, 158.2, 152.3, J = 7.3, 2.3 Hz, 2H), 7.08–7.11 (m, 3H), 2.55 (s, 3H); 13C-NMR
151.8, 144.7, 140.3, 134.1, 130.4, 130.0, 128.9, 128.8, 128.0, (100 MHz, CDCl3) δ 162.1, 160.7, 150.6, 150.3, 140.7, 138.4,
125.1, 114.7, 108.8, 22.4, 9.7; 77Se-NMR (75 MHz, CDCl3) 133.9, 133.2, 132.5, 130.5, 130.4, 130.0, 128.9, 128.0, 127.4,
δ 124.70; HRMS (ESI): m/z = 382.0346 calcd. For C20H16NO2Se, 127.0, 126.4, 115.1, 109.6, 17.8; 77Se-NMR (75 MHz, CDCl3) δ
found 382.0348 [M + H]+.
6-Methyl-4-(methylselanyl)-3-phenyl-1H-pyrano[4,3-b]quinolin- C25H17NO2NaSe, found 466.0319 [M + Na]+.
319.28; HRMS (ESI): m/z
=
466.0322 calcd. For
1-one (4k). Yield: 82%; melting point: 147–149 °C; IR (neat):
3-Phenyl-4-(phenylselanyl)-1H-pyrano[4,3-b]quinolin-1-one (4p).
2929, 1733, 1595, 1569, 1487, 1442, 1373, 1229, 1172, 1090, Yield: 71%; melting point: 169–171 °C; IR (neat): 3061, 1735,
1066, 1026, 903, 785, 759, 699, 695, 621 cm−1 1H-NMR 1592, 1573, 1557, 1490, 1334, 1214, 1182, 1056, 1020, 952, 798,
;
(400 MHz, CDCl3) δ 9.13 (s, 1H), 7.85 (d, J = 8.2 Hz, 1H), 759, 734, 688, 700, 628, 475 cm−1; 1H-NMR (400 MHz, CDCl3) δ
7.75–7.81 (m, 3H), 7.49–7.54 (m, 4H), 2.93 (s, 3H), 2.34 (s, 3H); 9.18 (s, 1H), 8.14 (d, J = 7.8 Hz, 1H), 7.99 (d, J = 8.2 Hz, 1H),
13C-NMR (100 MHz, CDCl3) δ 162.2, 158.0, 151.0, 150.6, 140.8, 7.84–7.88 (m, 1H), 7.72–7.74 (m, 2H), 7.59–7.63 (m, 1H),
137.9, 134.1, 133.4, 130.4, 130.0, 128.0, 127.4, 127.2, 126.9, 7.38–7.46 (m, 5H), 7.08–7.11 (m, 3H); 13C-NMR (100 MHz,
115.1, 109.2, 18.1, 9.2; 77Se-NMR (75 MHz, CDCl3) δ 129.01; CDCl3) δ 162.0, 161.0, 151.8, 151.7, 140.8, 133.9, 133.4, 132.0,
HRMS (ESI): m/z = 404.0166 calcd. For C20H15NO2NaSe, found 131.6, 130.5, 130.0, 129.2, 129.0, 128.0, 127.6, 127.0,
404.0151 [M + Na]+.
126.9, 115.5, 109.6; 77Se-NMR (75 MHz, CDCl3) δ 312.97;
4-(Methylselanyl)-3-phenyl-1H-pyrano[4,3-b]quinolin-1-one (4l). HRMS (ESI): m/z = 430.0346 calcd. For C24H16NO2Se, found
Yield: 80%; melting point: 155–157 °C; IR (neat): 3046, 1730, 430.0356 [M + H]+.
1609, 1590, 1574, 1442, 1336, 1212, 1175, 1028, 916, 796, 756,
8-Chloro-3-phenyl-4-(phenylselanyl)-1H-pyrano[4,3-b]quinolin-
1
699, 691, 627, 471 cm−1; H-NMR (400 MHz, CDCl3) δ 9.18 (s, 1-one (4q). Yield: 84%; melting point: 157–159 °C; IR (neat):
1H), 8.28 (d, J = 9.2 Hz, 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.90–7.94 3065, 1732, 1611, 1594, 1574, 1474, 1436, 1196, 1172, 1070,
(m, 1H), 7.79–7.81 (m, 2H), 7.64 (t, J = 7.6 Hz, 1H), 7.50 (t, J = 1047, 833, 734, 690, 681, 635, 617, 486 cm−1
;
1H-NMR
3.2 Hz, 3H), 2.29 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ 162.0, (400 MHz, CDCl3) δ 9.04 (s, 1H), 8.05 (d, J = 9.2 Hz, 1H), 7.92
158.3, 152.3, 151.6, 140.8, 134.0, 133.5, 130.5, 130.0, 130.0, (d, J = 2.3 Hz, 1H), 7.71–7.77 (m, 3H), 7.37–7.48 (m, 5H), 7.10
129.3, 128.1, 127.6, 126.9, 115.5, 108.7, 9.7; 77Se-NMR (t, J = 3.2 Hz, 3H); 13C-NMR (100 MHz, CDCl3) δ 161.6, 161.2,
(75 MHz, CDCl3) δ 125.77; HRMS (ESI): m/z = 368.0190 calcd. 152.1, 150.0, 139.7, 134.3, 133.7, 133.5, 131.9, 131.6, 131.4,
For C19H14NO2Se, found 368.0183 [M + H]+.
130.6, 129.9, 129.3, 129.0, 128.0, 127.8, 127.5, 127.4, 126.9,
8-Methyl-3-phenyl-4-(phenylselanyl)-1H-pyrano[4,3-b]quinolin- 116.2, 109.3; 77Se-NMR (75 MHz, CDCl3) δ 314.51; HRMS
1-one (4m). Yield: 81%; melting point: 137–139 °C; IR (neat): (ESI): m/z = 463.9957 calcd. For C24H16NO2Se, found 463.9968
3043, 1626, 1591, 1484, 1476, 1438, 1437, 1372, 1202, 1188, [M + H]+.
1067, 1045, 935, 830, 738, 703, 692, 649, 621, 613, 478 cm−1
;
8-Chloro-4-(methylselanyl)-3-phenyl-1H-pyrano[4,3-b]quinolin-
1H-NMR (400 MHz, CDCl3) δ 9.06 (s, 1H), 8.03 (d, J = 8.7 Hz, 1-one (4r). Yield: 75%; melting point: 184–186 °C; IR (neat):
1H), 7.67–7.73 (m, 4H), 7.37–7.44 (m, 5H), 7.09 (t, J = 3.2 Hz, 2970, 1738, 1592, 1474, 1442, 1366, 1229, 1217, 1204, 1066,
3H), 2.55 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ 162.1, 160.5, 840, 775, 696, 637, 527 cm−1 1H-NMR (400 MHz, CDCl3)
;
151.1, 150.4, 139.8, 137.9, 136.0, 133.9, 132.1, 131.6, 130.4, δ 9.10 (s, 1H), 8.23 (d, J = 9.2 Hz, 1H), 8.00 (d, J = 2.3 Hz, 1H),
130.0, 129.6, 129.0, 128.0, 127.7, 127.1, 126.8, 115.4, 109.6, 7.78–7.86 (m, 3H), 7.50–7.52 (m, 3H), 2.28 (s, 3H); 13C-NMR
21.7; 77Se-NMR (75 MHz, CDCl3) δ 312.05; HRMS (ESI): m/z = (100 MHz, CDCl3) δ 161.6, 158.6, 152.5, 149.9, 139.8, 134.4,
444.0503 calcd. For C25H18NO2Se, found 444.0499 [M + H]+.
133.8, 133.5, 131.4, 130.6, 130.0, 128.1, 127.6, 127.4, 116.2,
7-Methyl-3-phenyl-4-(phenylselanyl)-1H-pyrano[4,3-b]quinolin- 108.5, 9.7; 77Se-NMR (75 MHz, CDCl3) δ 127.01; HRMS
1-one (4n). Yield: 90%; melting point: 149–151 °C; IR (neat): (ESI): m/z = 401.9800 calcd. For C24H16NO2Se, found 401.9780
3056, 1743, 1733, 1622, 1596, 1567, 1498, 1475, 1443, 1212, [M + H]+.
1172, 1143, 1070, 1041, 1018, 794, 730, 691, 632, 589,
473 cm−1 1H-NMR (400 MHz, CDCl3) δ 9.10 (s, 1H), 7.93 (s, 1-one (4s). Yield: 69%; melting point: 173–175 °C; IR (neat):
1H), 7.87 (d, J = 8.2 Hz, 1H), 7.72 (dd, J = 8.0, 1.6 Hz, 2H), 3051, 1742, 1594, 1572, 1557, 1464, 1267, 1161, 1113, 1070,
6-Methoxy-3-phenyl-4-(phenylselanyl)-1H-pyrano[4,3-b]quinolin-
;
7.37–7.44 (m, 6H), 7.10 (t, J = 3.2 Hz, 3H), 2.57 (s, 3H); 1035, 941, 782, 732, 694, 682, 652, 560 cm−1
;
1H-NMR
13C-NMR (100 MHz, CDCl3) δ 162.1, 161.0, 151.9, 151.9, 144.7, (400 MHz, CDCl3) δ 9.07 (s, 1H), 7.74 (dd, J = 7.3, 2.3 Hz, 2H),
140.3, 134.0, 132.2, 131.4, 130.4, 130.1, 129.9, 129.0, 128.8, 7.56 (dd, J = 7.3, 2.3 Hz, 2H), 7.50–7.51 (m, 2H), 7.42–7.44 (m,
127.9, 126.7, 125.2, 114.7, 109.5, 22.4; 77Se-NMR (75 MHz, 3H), 7.17 (t, J = 4.6 Hz, 1H), 7.06–7.09 (m, 3H), 4.07 (s, 3H);
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13C-NMR (100 MHz, CDCl3) δ 162.0, 160.0, 155.8, 150.7, 143.8, monitored by TLC, the resulting reaction mixture was poured
140.4, 133.9, 133.5, 131.3, 130.4, 130.1, 128.7, 128.1, 127.9, into ice-cold water. The solid product was filtered and washed
127.9, 127.3, 120.7, 115.8, 111.6, 110.8, 56.6; 77Se-NMR with water. The resulting product was purified by column
(75 MHz, CDCl3) δ 314.05; HRMS (ESI): m/z = 460.0452 calcd. chromatography using n-hexane : ethyl acetate (70 : 30) as the
For C24H16NO2Se, found 460.0424 [M + H]+.
eluent to afford 6 as an orange solid. Yield: 96%; melting
6-Methoxy-4-(methylselanyl)-3-phenyl-1H-pyrano[4,3-b]quinolin- point: 150–152 °C; IR (neat): 3023, 2916, 1921, 1624, 1603,
1-one (4t). Yield: 70%; melting point: 191–193 °C; IR (neat): 1553, 1507, 1447, 1395, 1287, 1280, 1136, 1027, 966, 822, 688,
1
2332, 1731, 1595, 1490, 1464, 1263, 1224, 1166, 1114, 1064, 665, 643, 469 cm−1; H-NMR (400 MHz, CDCl3) δ 9.02 (s, 1H),
1042, 974, 783, 746, 709, 690, 563 cm−1 1H-NMR (400 MHz, 8.28 (s, 1H), 8.17–8.19 (m, 2H), 8.08 (d, J = 9.2 Hz, 1H),
;
CDCl3) δ 9.14 (s, 1H), 7.80–7.82 (m, 2H), 7.55–7.58 (m, 2H), 7.69–7.74 (m, 2H), 7.53 (d, J = 7.3 Hz, 2H), 7.45 (t, J = 7.1 Hz,
7.50 (q, J = 2.1 Hz, 3H), 7.21 (dd, J = 7.1, 1.6 Hz, 1H), 4.12 1H), 2.53 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ 152.3, 152.2,
(s, 3H), 2.35 (s, 3H); 13C-NMR (100 MHz, CDCl3) δ 162.1, 157.3, 150.6, 137.4, 137.3, 136.5, 135.7, 129.7, 129.0, 128.4, 127.4,
155.7, 151.1, 143.7, 140.4, 133.9, 130.4, 130.0, 128.1, 128.0, 127.1, 120.1, 116.1, 21.9; HRMS (ESI): m/z = 305.0846 calcd.
127.9, 120.7, 115.7, 111.2, 109.4, 56.5, 9.7; 77Se-NMR (75 MHz, For C19H14N2Cl, found 305.0849 [M + H]+.
CDCl3) δ 130.24; HRMS (ESI): m/z = 398.0295 calcd. For
General procedure for the synthesis of 8-methyl-3-phenyl-1
(phenylethynyl)benzo[b][1,6]naphthyridine (7a)
C24H16NO2Se, found 398.0270 [M + H]+.
General procedure for the synthesis of 8-methyl-3-phenylbenzo
[b][1,6]naphthyridin-1(2H)-one (5a) and 4-(butylselanyl)-8-
methyl-3-phenylbenzo[b][1,6]naphthyridin-1(2H)-one (5b)
To
a
solution of 1-chloro-8-methyl-3-phenylbenzo[b][1,6]
naphthyridine 6 (0.062 mmol, 1.0 equiv.) in 10 mL THF was
added phenyl acetylene (0.080 mmol, 1.5 equiv.), NEt3 (3.0
To a solution of 4a (1 mmol) in 5 mL DMF was added an equiv.), PdCl2(PPh3)2Cl2 (4.4 mg, 5 mol%) and copper(I) iodide
excess of 28% NH4OH and stirred at 80 °C. After completion of (1.19 mg, 5 mol%). The resulting mixture was stirred under a
the reaction, monitored by TLC, the reaction mixture was nitrogen atmosphere at room temperature for 15 h. After com-
poured into ice-cold water. The solid product was filtered and pletion of the reaction, the solvent was removed under
washed with water and dried over Na2SO4. The resulting reduced pressure, the residue was extracted with ethyl acetate
product was purified by column chromatography using and purified by silica gel column chromatography using
n-hexane : ethyl acetate (70 : 30) as the eluent to afford 5a and n-hexane : ethyl acetate (70 : 30) as the eluent to afford 7a as a
5b as yellow solids.
yellow solid. Yield: 60%; melting point: 147–149 °C; IR (neat):
8-Methyl-3-phenylbenzo[b][1,6]naphthyridin-1(2H)-one (5a). 2918, 2850, 2206, 1633, 1595, 1553, 1504, 1492, 1467, 1415,
Yield: 69%; melting point: 235–237 °C; IR (neat): 3007, 2918, 1344, 1174, 1136, 1026, 922, 866, 820, 752, 738, 685, 668, 658,
1
1675, 1654, 1621, 1591, 1499, 1490, 1444, 1220, 934, 862, 823, 650, 549, 527 cm−1; H-NMR (400 MHz, CDCl3) δ 9.23 (s, 1H),
771, 752, 688, 556, 498 cm−1; 1H-NMR (400 MHz, CDCl3) δ 9.26 8.37 (d, J = 0.9 Hz, 1H), 8.25–8.27 (m, 2H), 8.11 (d, J = 8.7 Hz,
(s, 1H), 9.17 (s, 1H), 8.05 (d, J = 8.7 Hz, 1H), 7.76 (dd, J = 8.0, 1H), 7.80–7.83 (m, 3H), 7.70–7.73 (m, 1H), 7.54 (t, J = 7.6 Hz,
1.6 Hz, 4H), 7.54–7.58 (m, 3H), 7.14 (s, 1H), 2.59 (s, 3H); 2H), 7.47 (dd, J = 6.6, 2.5 Hz, 4H), 2.58 (s, 3H); 13C-NMR
13C-NMR (100 MHz, CDCl3) δ 150.3, 142.6, 137.3, 136.6, 135.5, (100 MHz, CDCl3) δ 153.6, 151.1, 149.7, 146.4, 138.7, 136.8,
134.1, 130.3, 129.6, 128.6, 127.9, 126.6, 126.1, 119.7, 106.1, 135.9, 135.6, 132.5, 129.8, 129.3, 129.0, 128.94, 128.7, 127.4,
21.8; HRMS (ESI): m/z = 287.1184 calcd. For C19H15N2O, found 122.3, 122.0, 117.1, 94.9, 86.7, 21.9; HRMS (ESI): m/z =
287.1183 [M + H]+.
371.1548 calcd. For C27H19N2, found 371.1532 [M + H]+.
4-(Butylselanyl)-8-methyl-3-phenylbenzo[b][1,6]naphthyridin-1
(2H)-one (5b). Yield: 22%; melting point: 214–216 °C; IR (neat):
2918, 2867, 1655, 1588, 1569, 1484, 1465, 1440, 1372, 1326,
General procedure for the synthesis of 8-methyl-1,3-
diphenylbenzo[b][1,6]naphthyridine (7b)
1293, 1188, 1125, 1029, 938, 823, 702, 633, 496, 480 cm−1
;
To
a
solution of 1-chloro-8-methyl-3-phenylbenzo[b][1,6]
1H-NMR (400 MHz, CDCl3) δ 9.31 (s, 1H), 9.15 (s, 1H), 8.19 (d, naphthyridine 6 (20 mg, 0.050 mmol, 1.0 equiv.) in 4 mL DMF
J = 9.2 Hz, 1H), 7.79 (s, 1H), 7.71 (dd, J = 8.7, 2.3 Hz, 1H), 7.54 was added phenylboronic acid (9.1 mg, 0.075 mmol, 1.3
(qd, J = 6.8, 3.1 Hz, 5H), 2.95 (t, J = 7.3 Hz, 2H), 2.60 (s, 3H), equiv.), Pd(OAc)2 (1.1 mg, 1 mol%), and Cs2CO3 (48.7 mg,
1.45 (q, J = 7.5 Hz, 2H), 1.21–1.26 (m, 2H), 0.76 (t, J = 7.3 Hz, 0.150 mmol, 3.0 equiv.). The resulting mixture was heated at
3H); 13C-NMR (100 MHz, CDCl3) δ 163.3, 152.3, 150.1, 146.4, 110 °C for 12 h. The solvent was removed under reduced
137.6, 136.9, 136.8, 135.1, 129.8, 129.5, 129.3, 128.4, 127.5, pressure; the residue was extracted with ethyl acetate and
126.4, 119.7, 106.7, 32.0, 28.4, 22.8, 21.8, 13.6; 77Se-NMR brine. The crude was purified by silica gel chromatography
(75 MHz, CDCl3) δ 190.74; HRMS (ESI): m/z = 423.0976 calcd. using n-hexane : ethyl acetate (70 : 30) as the eluent to afford 7b
For C23H23N2OSe, found 423.0982 [M + H]+.
as a yellow solid. Yield: 52%; melting point: 212–214 °C; IR
(neat): 3056, 1634, 1598, 1557, 1514, 1492, 1446, 1338, 1192,
General procedure for the synthesis of 1-chloro-8-methyl-3-
phenylbenzo[b][1,6]naphthyridine (6)
1
1176, 1127, 1028, 925, 820, 792, 705, 693, 656 cm−1; H-NMR
(400 MHz, CDCl3) δ 8.94 (s, 1H), 8.42 (d, J = 0.9 Hz, 1H),
To a solution of 5a (1.0 mmol) was added POCl3 (1.0 mmol 8.32–8.34 (m, 2H), 8.13 (d, J = 9.6 Hz, 1H), 7.88 (dd, J = 8.0, 1.6
mL−1) and refluxed for 12 h. After completion of the reaction, Hz, 2H), 7.70–7.72 (m, 2H), 7.60–7.64 (m, 3H), 7.53 (t, J = 7.6
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Hz, 2H), 7.44 (t, J = 7.3 Hz, 1H), 2.55 (s, 3H); 13C-NMR
(100 MHz, CDCl3) δ 162.6, 152.7, 151.0, 150.6, 139.2, 139.1,
136.5, 136.2, 135.7, 130.4, 129.3, 129.1, 128.9, 128.8, 128.7,
127.5, 127.4, 127.1, 119.9, 115.7, 21.8. HRMS (ESI): m/z =
347.1548 calcd. For C19H14N2Cl, found 347.1535 [M + H]+.
264–287; (c) T. Aggarwal, R. R. Jha, R. K. Tiwari, S. Kumar,
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[b][1,6]naphthyridine (7c)
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benzo[b][1,6]naphthyridine
6
in
4
mL DMF (20 mg,
0.037 mmol, 1.0 equiv.) was added methyl acrylate (6.5 mg,
0.074 mmol, 2.0 equiv.), Pd(OAc)2 (0.4 mg, 0.5 mol%), PPh3
(9.8 mg, 0.037 mmol, 1.0 equiv.) and K2CO3 (10.3 mg,
0.074 mmol, 2.0 equiv.). The resulting mixture was heated
under a nitrogen atmosphere for 12 h.24 The solvent was
removed under reduced pressure, and the residue was
extracted with ethyl acetate and purified by silica gel column
chromatography using n-hexane : ethyl acetate (70 : 30) as the
eluent to afford 7c, yellow solid. Yield: 20%; melting point:
184–186 °C; IR (neat): 2919, 1720, 1634, 1611, 1573, 1557,
1446, 1435, 1399, 1258, 1127, 951, 924, 911, 886, 824, 752, 700,
1
655, 601, 561 cm−1; H-NMR (400 MHz, CDCl3) δ 9.56 (s, 1H),
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8.82 (s, 1H), 8.42 (s, 1H), 8.23–8.25 (m, 2H), 8.14 (d, J = 9.2 Hz,
1H), 7.80 (s, 1H), 7.73 (dd, J = 8.7, 1.8 Hz, 1H), 7.56 (dd, J = 7.1,
1.6 Hz, 2H), 7.44–7.48 (m, 1H), 2.60 (s, 3H); 13C-NMR
(100 MHz, CDCl3) δ 154.7, 153.5, 151.1, 150.0, 139.1, 136.5,
136.1, 135.7, 129.2, 129.1, 129.0, 127.3, 127.1, 121.4, 116.8,
21.9. HRMS (ESI): m/z = 217.1235 calcd. For C19H14N2Cl, found
217.1223 [M + H]+.
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Acknowledgements
This study was supported by the JSPS KAKENHI Grant Number
17550099 (to MK). Authors KMNW and ADS are thankful to
the MEXT: Monbukagakusho for scholarship. The authors are
thankful to Yashihiro Kubota for the help in fluorescence ana-
lysis, and also are thankful to Masayuki Ninomiya and Kaneko
Daiki for help in elemental analysis characterization.
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