Synthesis, Molecular Engineering, and Photophysical Properties of Fluorescent Thieno[3,2-b]pyridine-5(4 H)-ones

Article abstract of DOI:10.1021/acs.joc.8b01924

We describe a synthetic approach for a set of fluorescent thieno[3,2-b]pyridine-5(4H)-one derivatives and their photophysical properties. These fluorophores are prepared by a series of reactions employing the Suzuki-Miyaura cross-coupling reaction and a regioselective aza-[3 + 3] cycloaddition of 3-aminothiophenes with α,β-unsaturated carboxylic acids. Our findings revealed that the photophysical properties are chemically tunable by an appropriate choice of functional group on the thieno[3,2-b]pyridine-5(4H)-one scaffold.

Full text of DOI:10.1021/acs.joc.8b01924

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Note
Synthesis, Molecular Engineering, and Photophysical
Properties of Fluorescent Thieno[3,2-b]pyridine-5(4H)-ones
Dan-Bi Sung, Bohyun Mun, Sol Park, Hyi-Seung Lee, Jihoon
Lee, Yeon-Ju Lee, Hee Jae Shin, and Jong Seok Lee
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01924 • Publication Date (Web): 14 Nov 2018
Downloaded from http://pubs.acs.org on November 15, 2018
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Synthesis, Molecular Engineering, and Photophysical Properties of
Fluorescent Thieno[3,2-b]pyridine-5(4H)-ones
Dan-Bi Sung†, Bohyun Mun†, Sol Park†, ‡, Hyi-Seung Lee†, ‡, Jihoon Lee†, Yeon-Ju Lee†, ‡, Hee Jae
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Shin†, ‡, and Jong Seok Lee*,†, ‡
†Marine Natural Products Chemistry Laboratory, Korea Institute of Ocean Science and Technology (KIOST), Busan,
Republic of Korea
‡Department of Marine Biotechnology, Korea University of Science and Technology, Republic of Korea
Supporting Information
well-defined design strategy for the development of state-of-
the-art fluorescent molecular sensor.
In this communication, we present the design and synthesis
of a series of fluorescent 2-arylthieno[3,2-b]pyridine-5(4H)-one
derivatives [hereafter, collectively referred to as KIOST-Fluor
(KF)] and investigation of the structure-fluorescence
ABSTRACT: We describe a synthetic approach for a set of
fluorescent thieno[3,2-b]pyridine-5(4H)-one derivatives and
their photophysical properties. These fluorophores are
prepared by a series of reactions employing the Suzuki-
Miyaura cross-coupling reaction and a regioselective aza-
[3+3] cycloaddition of 3-aminothiophenes with ,-
unsaturated carboxylic acids. Our findings revealed that the
photophysical properties are chemically tunable by an
appropriate choice of functional group on the thieno[3,2-
b]pyridine-5(4H)-one scaffold.
relationship. We sought to devise
a
concise and
straightforward synthetic approach to a set of KF derivatives.7
R1
NH
R1
HO
O
NH2
O
N
O
4
aza-[3+3] cycloaddition
+
OMe
R2
BOP
R2
Br
2
S
S
5
S
7
R3
R3
KF
1
Fluorescence is undoubtedly an exceptional tool to monitor
a system of interest at a molecular or supramolecular level in a
non-destructive way.1 Fluorescence technology has found
extensive applications in various research areas such as biology,
medicine, pharmaceutics, environment, and food science.2
Over the last several decades, molecular fluorescence has
witnessed a remarkable surge of a substantial number of
small-molecule fluorophores with enhanced photophysical
properties, which again facilitated the current culmination of
fluorescence technology.3 Small-molecule fluorophores offer
several advantages over other fluorescent materials owing to
their outstanding brightness despite the small size, excellent
synthetic accessibility complemented by the inherent
structural versatility, substantial flexibility to assemble
components with a specific function, and high chemical
stability. Currently, a variety of fluorescent core structures are
available, which normally serve as the bases for the design of
new fluorophores.1,4 In general, organic fluorophores are
considerably implemented in the molecular sensor design as a
fluorescent reporter molecule.5 This clearly indicates that they
substantiate the ability of chemistry to solve various problems
in nature. Thus, a wide pool of tailor-made molecular sensors
has been developed based on a modest set of fluorescent core
scaffolds. 1,4
Figure 1. Synthetic strategy for KIOST-Fluor.
The key features in the synthesis of this class of fluorophore
involve the Suzuki-Miyaura cross-coupling reaction, a silica
gel-assisted decarboxylation, and most importantly,
(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium
a
hexafluorophosphate (BOP)8-promoted regioselective aza-[3+3]
cycloaddition9 of 3-amino-5-arylthiophenes with various α,β-
unsaturated carboxylic acids (Figure 1).
Scheme 1. Synthesis of Intermediate 5a
H
R1
OMe
NH2
O
N
a
b
OMe
Br
Br
S
S
O
: R1 = Me, 74%b
: R1 = Bn, 62%b
1
2a
2b
H
H
H
N
R1
R1
OH
R1
N
N
c
d
OMe
R2
R2
R2
S
S
S
O
O
b
b
3
, 33 - 96%
4
5
, 43 - 99%
aReagents and conditions: a. 1.4 eq. NaH, 1.3 eq. MeI (or 1.4
eq. BnBr), DMF, 0 ℃ to room temperature, 18 h; b. 5 mol%
Pd(PPh3)4, 1.2 eq. boronic acid, 1.2 eq. Na2CO3, toluene/H2O =
5 : 2, reflux; c. 1N KOH, EtOH, 70 ℃, 2 h; d. 500 wt% silica
gel, EtOAc/MeOH, 60 ℃, 2 h. bIsolated yield.
On the other hand, discovery of novel fluorophore scaffolds
remains an unfulfilled task, which provides motivation to
apply the innovations of contemporary organic chemistry to
the synthesis of new fluorophore families with enhanced
properties.6 These efforts, together with our understanding of
the properties of specific fluorophore scaffolds, will provide a
As shown in Scheme 1, our synthesis commenced with the
N-monosubstitution of the commercially available methyl 3-
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amino-5-bromothiophene-2-carboxylate
(1).
Thus,
the
acids (Scheme 2). Interestingly, KF derivatives were prepared
1
2
3
4
5
6
7
8
corresponding secondary amine
2
with the designated
via three different synthetic routes outlined in Scheme 1. For
example, when R3 was an electron-withdrawing group
especially acetyl and benzoyl group, KF derivatives were
obtained directly by concurrent dehydrogenation of the
resulting 6,7-dihydrothieno[3,2-b]pyridin-5(4H)-one (Route A,
Scheme 2). However, when R3 was an ester group, preparation
of the desired KIOST-Fluor required further treatment of the
intermediate 6 under mild heating in DMF in the presence of
K2CO3 at 70 ℃ (Route B, Scheme 2, Figure 2).
substituent (R1 = methyl or benzyl group) was prepared
efficiently by treating the starting material 1 with either methyl
iodide or benzyl bromide in the presence of NaH in DMF at
0 ℃ (Scheme 1).
In order to induce fluorescence over a wide spectrum of
emission wavelengths, the coupling between the electron-rich
phenyl groups and the intermediate 2 was attempted, which
was envisioned to finely tune the emission spectra of KF
derivatives. Therefore, diverse phenyl groups with distinct
electron-donating groups (R2 group) were readily introduced
to the intermediate 2 by the Suzuki-Miyaura cross-coupling
reaction to furnish the corresponding 5-arylthiophene
derivative 3 (Table S1 in SI). It is of interest that the key
intermediate 5 was prepared in moderate to excellent yield by
a sequential two-step process including hydrolysis in a mixture
of 1 N KOH and EtOH at 70 ℃, directly followed by a silica
gel-assisted mild decarboxylation of the resulting carboxylic
acid 4 (Scheme 1, see Table S1 in SI for more details).
9
In contrast, no desired product was obtained when R3 was an
unactivated group such as H or Me. To overcome this
limitation, a mild two-step process of halogenation and
elimination was attempted. To our delight, monobromination
using NBS followed by a subsequent elimination reaction
successfully provided the desired products in good yields
(Route C, Scheme 2).
With a set of various KF derivatives, we next measured their
photophysical properties including absorptions, excitations,
emissions, lifetimes, and quantum yields in dichloromethane
and acetonitrile, respectively (Figure 4, see Figure S1 in SI for
more details). The photophysical data of each compound are
summarized in Table S2 in SI. Figure 3 shows images of
representative KF’s in dichloromethane when excited at 365
nm under a UV lamp.
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Scheme 2. Synthetic scheme of KIOST-Fluor
R1
HO
NH
O
Route A
+
R3 = acetyl,
benzoyl,
phenyl
R2
S
5
R3
R1
N
R1
N
O
O
Route B
R3 = methyl ester
R2
S
R2
S
R1
O
R3
R3
6
KF
N
Route C
R3 = H, Me
Br
R2
S
R3
7
Figure 3. Images of representative KIOST-Fluors (KFs) in
dichloromethane (excited at 365 nm under a UV lamp).
Me
Me
Me
Me
MeO
O
OMe
N
O
N
N
O
N
O
MeO
S
S
S
S
The thiophene-based fluorophores typically exhibit weak
fluorescence emission due to significant spin-orbit coupling
which is originated from the heavy atom effect of the sulfur
mediated by charge transfer mixing.11 This results in an
efficient intersystem crossing to the triplet state and a highly
efficient nonradiative transition between the triplet state and
the ground state that induces relaxation without emission. It is
especially noteworthy that the majority of KIOST-Fluors show
strong fluorescence despite the fact that they are the fused-
thiophenes. Therefore, the emission maxima of KIOST-Fluor
showed a wide region of fluorescent emissions (λem: 426–678
nm in dichloromethane; λem: 424–610 nm in acetonitrile) along
with large Stokes shifts (up to 232 nm in dichloromethane; up
to 179 nm in acetonitrile) and high quantum yields (up to 99%
in dichloromethane; up to 98% in acetonitrile). The
fluorescence lifetime (τ) is the average time that a molecule
remains in its excited state before returning to the ground
state via emission of a photon. This intrinsic molecular
property indicates the time available to collect information
from the emission profile. The measured fluorescence lifetimes
of the KF molecules range from 0.63 ns to 6.59 ns (see Table S2
in SI for more details).
6a, 45%
6b
, 48%
6c
, 58%
6d, 65%
O
OMe
O
OMe
O
OMe
Me
O
OMe
Bn
Me
N
O
N
O
N
O
MeO
MeO
PhO
S
S
S
S
6f, 77%
6e, 77%
6g
, 54%
H
O
OMe
O
OMe
Me
Me
N
Me
O
MeO
MeO
MeO
O
O
N
O
N
O
O
O
S
S
6h, 55%
6j
N
6i, 62%
6l, 61%
, 54%
O
O
OMe
Me
Me
O
OMe
Me
O
OMe
Me
Me
N
O
N
O
N
O
Me
N
Me
S
S
S
6m, 76%
Me
N
N
Me
6k, 61%
OMe
O
OMe
Bn
O
OMe
Me
Me
N
O
N
O
N
O
Me
N
Me
Et
Et
Me
N
N
S
S
S
6n, 81%
6o, 73%
6p, 38%
O
OMe
Me
O
OMe
O
OMe
N
O
N
S
6q, 65%
O
OMe
Figure 2. Structures and yields of intermediate 6.
Subsequently, with intermediate 5 in hand, a BOP-promoted
regioselective aza-[3+3] cycloaddition of the intermediate 5
was endeavoured with various α,β-unsaturated carboxylic
Compared to KF-1, which contains a simple phenyl group at
the C2 position, its electron-rich counter parts exhibited
obvious bathochromic shifts (red shifts) in emission.
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Me
Me
Me
Me
Me
Me
Bn
1
2
3
4
5
6
7
N
O
N
O
N
O
N
O
N
O
N
O
N
O
MeO
MeO
MeO
KF-7, 22%[c]
MeO
S
S
S
S
S
S
S
MeO
OMe
H
Me
KF-1, 48%[b]
KF-3, 65%[b]
OMe
OMe KF-4, 49%[b]
O
OMe
KF-5, 42%[b]
KF-6, 45%[c]
O
OMe
KF-2, 50%[b]
O
O
O
OMe
395 nm, 462 nm, 0.63[d]
397 nm, 464 nm, 0.48[d]
396 nm, 463 nm, 0.32[e]
400 nm, 469 nm, 0.51[d]
399 nm, 468 nm, 0.31[e]
370 nm, 427 nm, 0.40[d]
369 nm, 425 nm, 0.98[e]
412 nm, 472 nm, 0.90[d]
371 nm, 426 nm, 0.83[d]
370 nm, 424 nm, 0.42[e]
413 nm, 547 nm, 0.99[d]
400 nm, 558 nm, 0.90[e]
395 nm, 462 nm, 0.46[e]
400 nm, 474 nm, 0.77[e]
Me
Bn
Bn
Me
Me
Me
Me
O
O
N
O
N
O
N
O
N
O
N
O
N
O
N
O
O
O
MeO
MeO
MeO
KF-10, 26%[a]
MeO
PhO
KF-12, 63%[b]
S
S
S
S
S
S
S
Ph
KF-11, 38%[a]
KF-14, 50%[b]
KF-13, 40%[b]
KF-8, 15%[a]
KF-9, 46%[a]
O
OMe
O
Me
O
Me
O
Ph
O
OMe
O
OMe
376 nm, 437 nm, 0.46[d]
375 nm, 435 nm, 0.42[e]
417 nm, 510 nm, 0.98[d]
417 nm, 512 nm, 0.99[d]
413 nm, 547 nm, 0.67[d]
411 nm, 474 nm, 0.62[d]
413 nm, 473 nm, 0.83[d]
400 nm, 469 nm, 0.83[d]
8
9
415 nm, 512 nm, 0.84[e]
415 nm, 515 nm, 0.61[e]
400 nm, 558 nm, 0.48[e]
402 nm, 482 nm, 0.44[e]
401 nm, 478 nm, 0.68[e]
398 nm, 469 nm, 0.63[e]
Me
Me
Me
Me
Me
Bn
Me
Bn
MeO
N Me
N
O
N
O
N
O
N
O
N
O
N
O
N
O
Me
Me
Me
Me
Me
Me
Me
Me
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MeO
N
N
N
N
S
S
S
S
S
S
S
MeO
KF-15, 26%[b]
KF-17, 27%[b]
Me
N
Me
KF-16, 33%[b]
KF-19, 37%[b]
KF-20, 35%[a]
KF-18, 32%[b]
KF-21, 41%[a]
O
OMe
O
OMe
O
OMe
O
OMe
O
OMe
O
Me
O
Ph
418 nm, 485 nm, 0.53[d]
399 nm, 495 nm, 0.38[e]
453 nm, 554 nm, 0.82[d]
419 nm, 599 nm, 0.08[e]
400 nm, 560 nm, 0.01[d]
464 nm, 610 nm, 0.18[d]
414 nm, 537 nm, 0.17[d]
399 nm, 484 nm, n.d.[e]
461 nm, 563 nm, 0.98[d]
421 nm, 610 nm, 0.05[e]
461 nm, 678 nm, 0.01[d]
336 nm, 460 nm, 0.03[e]
397 nm, 504 nm, n.d.[e]
396 nm, 521 nm, n.d.[e]
Me
Me
Me
Me
Me
Me
N
O
N
O
N
O
N
O
N
O
N
O
Et
Et
Ph
Ph
N
Me
N
N
N
N
F3CO
KF-26, 35%[a]
F3C
KF-27, 29%[a]
S
S
S
S
S
S
KF-22, 53%[b]
KF-23, 41%[b]
467 nm, 550 nm, 0.99[d]
417 nm, 587 nm, 0.03[e]
KF-25,47%[a]
O
KF-24, 36%[b]
465 nm, 605 nm, 0.25[d]
401 nm, 511 nm, 0.02[e]
O
OMe
Ph
O
Ph
O
Ph
O
OMe
O
OMe
463 nm, 635 nm, 0.05[d]
398 nm, 504 nm, n.d.[e]
413 nm, 518 nm, 0.85[d]
412 nm, 526 nm, 0.65[e]
413 nm, 511 nm, 0.82[d]
411 nm, 517 nm, 0.80[e]
463 nm, 562 nm, 0.91[d]
460 nm, 605 nm, 0.08[e]
Figure 4. Structures and photophysical data of KIOST-Fluors. aRoute A was applied. bRoute B was applied. cRoute C was
applied. dExcitation maximum, emission maximum, and absolute quantum yield at 10 μM in CH2Cl2. eExcitation maximum,
emission maximum, and absolute quantum yield at 10 μM in CH3CN; n.d., not detected. The reliability of the integrating sphere
system was confirmed by measuring absolute quantum yields of known fluorescent dyes [fluorescein: F = 0.92 (reported: 0.89);
rhodamine 6G: F = 0.92 (reported: 0.92)]10
For example, the emission maxima of KIOST-Fluor
derivatives bearing an oxygen atom on the phenyl ring at the
C2 position, as in the case of KF-12, KF-2, KF-14, KF-13, and
KF-15, tended to gradually red-shift with increase in electron-
donating ability of the R2 group, thus emitting at different
wavelengths (469, 472, 473, 474, and 485 nm, respectively),
while the absorption maxima remained relatively constant
(398–404 nm).
In addition, a similar trend was observed in a series of
nitrogen atom-containing derivatives such as KF-16, KF-22,
KF-23, and KF-24 as they fluoresced at 554, 562, 550, and 605
nm, respectively, with the absorption maxima ranging from
420 to 454 nm. As other examples, two different sets of KIOST-
Fluors (one includes KF-27, KF-26, and KF-25 and the other
includes KF-11 and KF-21 separately) demonstrated the same
trend in emission wavelengths.
KF-2; for dimethylamino group, see: KF-18, KF-17, KF-16) were
prepared and compared with respect to the quantum yield and
the absorption/emission maxima. As a result, it can be
concluded that the para substitution provides improved
photophysical properties including high quantum yield and
significant bathochromic shift in the emission wavelengths
(KF-2 and KF-16).
The brightness of a fluorophore is given by the multiplication
of its molar extinction coefficient (ε) with its quantum yield
(Φ). When a benzyl group was introduced at the R1 position as
a replacement of a methyl group (compounds KF-2/ KF-5 and
KF-9/ KF-10), a normally higher molar extinction coefficient
(ε), and thus, a much greater brightness was obtained with the
exception of KF-16/ KF-19, which had a similar brightness.
With regard to the impact of R3 substituent, an increase in
electron-withdrawing ability from H (KF-6) to methyl (KF-7),
phenyl (KF-8), methyl ester (KF-2), and acetyl (KF-9) with
larger conjugations resulted in bathochromic shifts in the
emission wavelengths from 426, 427, 437, 472, and 510 nm,
respectively.
Considering the regioisomeric effects of specific auxochromes
such as methoxy and dimethylamino groups on the
fluorescence property, a series of ortho-, meta-, and para-
substituted KF derivatives (for methoxy group, see: KF-4, KF-3,
Figure 5. Normalized fluorescence spectra of compounds KF-22 and KF-24. Spectra are normalized with respect to peak
intensities.
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The same bathochromic shifts were observed in both KF-16/
column chromatography was performed on silica gel (70-230
mesh) using distilled organic solvents.
1
KF-20 and KF-19/ KF-21. Therefore, it is reasonable to assume
that the photophysical properties of the KIOST-Fluor can be
fine-tuned by a proper combination of an electron-donating R2
and an electron-withdrawing R3 substituent. Next, we
measured the solvatochromic properties of selected KIOST-
Fluors such as KF-2, KF-22, and KF-24 (Fig. 5, see Figure S2
and Table S3 in SI for compound KF-2). Interestingly, KF-22
showed a broad range of emission wavelengths in the visible
region with increase in solvent polarity (positive
solvatochromism) from 504 to 615 nm, while KF-2 had a
spectrally narrow emission window from 472 to 484 nm (see
Figure S2 and Table S3 in SI). This result indicates that
compared to KF-22, KF-2 is relatively insensitive to solvent
polarity. Notably, a julolidine derivative, KF-24, exhibited red
shifts only in toluene, chloroform, and dichloromethane.
However, its emission wavelengths were remarkably blue-
shifted (hypsochromic shift) in polar solvents, which suggests
a negative solvatochromic character of the KF-24 (Figure 5).12
Finally, carboxylic acid derivatives KF-28 and KF-29 were
prepared by simple hydrolysis of KF-2 and KF-22, respectively,
and their photophysical properties were evaluated under
various pH conditions (from pH 1.0 to 7.0: see Table S4 and
Figure S3 in SI for more details).13 KF-28 bearing a p-methoxy
group on the C2-phenyl ring exhibited a gradual increase in
fluorescence intensity with increasing pH, indicating
photoinduced proton transfer where the emitting form is
carboxylate form of KF-28 because excitation of KF-28 is
followed by excited-state deprotonation. Therefore, the
fluorescence spectrum is unchanged. In contrast to KF-28, KF-
2
3
4
5
6
7
8
9
1H and 13C Spectra were recorded on Varian Unity-Inova 500
MHz and Bruker 600 MHz spectrometer. Chemical shifts are
reported as δ (ppm) values relative to chloroform (CDCl3, δ
7.26) and dimethylsulfoxide (DMSO-d6, δ 2.50) and coupling
constant was noted by Hz units. High resolution mass
spectroscopy (HRMS) data were obtained by a magnetic
sector-electric sector double focusing mass analyzer in Korea
Basic Science Institute (KBSI) in electron ionization (EI)
mode or fast atom bombardment (FAB) mode. Photophysical
properties (UV-vis spectra, emission, excitation, quantum
yield and molecular coefficient) were obtained using UV-Vis
Shimadzu UV1650PC and Fluorescence spectrophotometer
Scinco FS-2 (1 cm quartz cell). Fluorescence lifetimes were
recorded on Edinburgh instruments using a 375 nm laser
source in Korea Advanced Institute of Science and
Technology (KAIST)-Analysis Center for Research
Advancement (KARA).
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60
General Procedure for the Synthesis of 2a-2b
To
a solution of methyl 3-amino-5-bromothiophene-2-
carboxylate 1 (1.00 g, 4.24 mmol, 1.0 equiv.) in DMF (40 mL),
NaH (60% in mineral oil dispersion, 237 mg, 11.9 mmol, 1.4
equiv.) was added at 0 °C. After stirring for 10 min, methyl
iodide (343 μL, 5.51 mmol, 1.3 equiv.) was added and warmed
up to room temperature. The reaction was stirred for 18 h at
room temperature. For quenching the reaction, water (50 mL)
was added and extracted with EtOAc (50 mL) at three times.
The organic layer was dried over Na2SO4, filtered and
evaporated in vacuo. The crude was purified by flash column
chromatography (Hexane/EtOAc = 30/1, v/v) on silica to
afford the product 2a.
29 demonstrated
a significant increase in fluorescence
intensity in response to decrease in pH. This outstanding
enhancement in fluorescence intensity supposedly originated
from the inhibition of fluorescent quenching via photoinduced
electron transfer (PET) due to the protonation of the p-
diethylamino group on the C2-phenyl ring (Table S4 and
Figure S3 in SI).
In conclusion, we have demonstrated the design and
synthesis of a set of fluorescent thieno[3,2-b]pyridine-5(4H)-
ones [KIOST-Fluor (KF)] via the Suzuki-Miyaura cross-
coupling reaction and a regioselective aza-[3+3] cycloaddition
of 3-aminothiophenes with α,β-unsaturated carboxylic acids
promoted by BOP. The photophysical properties of these
fluorophores can be readily fine-tuned by varying the electron-
donating R2 and electron-withdrawing R3 substituents.
It is anticipated that these compounds will readily find
application as a tool for physical, chemical, material, and
biomedical investigations. Studies are ongoing to understand
the fundamental principles of the fluorophores and derive
novel fluorophores with more improved photophysical
properties for their subsequent application to many long-
standing problems.
Methyl 5-bromo-3-(methylamino)thiophene-2-carboxylate (2a)
Compound 2a was obtained as a white solid (783 mg, 3.13
1
mmol, 74%). H NMR (600 MHz, CDCl3) δ 6.67 (br s, 1H),
6.63 (s, 1H), 3.78 (s, 3H), 2.93 (d, J = 5.5 Hz, 3H); 13C{1H}
NMR (150 MHz, CDCl3) δ 164.4, 156.5, 121.8, 119.5, 99.2,
51.3, 31.7; Data are consistent with those reported in the
literature.14
Methyl 3-(benzylamino)-5-bromothiophene-2-carboxylate (2b).
Compound 2b was obtained as a white solid (1.71 g, 5.24
mmol, 62%) starting from benzyl bromide (1.59 g, 9.32 mmol,
1
1.1 equiv.). m.p: 76-77 °C; H NMR (600 MHz, CDCl3) δ
7.31-7.29 (m, 2H), 7.25-7.20 (m, 3H), 6.54 (d, J = 1.2 Hz, 1H),
4.38 (d, J = 4.2 Hz, 2H), 3.75 (s, 3H); 13C{1H} NMR (150
MHz, CDCl3) δ 164.3, 155.4, 138.5, 128.9, 127.6, 127.0,
121.8, 119.9, 100.1, 51.3, 49.0; HRMS (EI): m/z calcd for
C13H12BrNO2S [M]+ 324.9772, found 324.9774.
General Procedure for the Synthesis of 3a-3s
To a solution of 2a (250 mg, 1.00 mmol, 1.0 equiv.) in toluene
(2.5 mL, 0.25 M), phenyl boronic acid (146 mg, 1.20 mmol,
1.2 equiv.), Pd(PPh3)4 (50.9 mg, 0.050 mmol, 0.05 equiv.) and
sodium carbonate (127 mg, 1.20 mmol, 1.2 equiv.) in distilled
water (1 mL) were added. And then, the reaction was heated to
110 °C and stirred for 5 h. After completion of the reaction,
water (5 mL) was added. The crude was extracted with EtOAc
(4 mL) at three times. The organic layer was dried over
Na2SO4, filtered and evaporated in vacuo. The residue was
EXPERIMENTAL SECTION
General Information. All melting points were recorded on a
micro melting point apparatus and are uncorrected. All
anhydrous solvents, boronic acids and other chemical reagents
were of reagent grade quality and used without further
purification unless otherwise noted. The organic reactions
were monitored by thin layer chromatography (TLC) with
0.25-mm pre-coated silica gel plates (Kieselgel 60F254). Flash
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The Journal of Organic Chemistry
purified by flash column chromatography (Hexane/EtOAc =
4/1, v/v) on silica to afford the product 3a.
6.79 (s, 1H), 3.83 (s, 3H), 3.03 (s, 3H); 13C{1H} NMR (150
1
2
3
4
5
6
7
8
MHz, CDCl3) δ 165.4, 158.4, 157.6, 156.6, 149.4, 130.0,
128.7, 127.6, 124.0, 119.5, 118.9, 111.3, 97.1, 51.2, 31.8;
HRMS (EI): m/z calcd for C19H17NO3S [M]+ 339.0929, found
339.0932.
Methyl
3-(methylamino)-5-phenylthiophene-2-carboxylate
(3a). Compound 3a was obtained as a pale yellow solid (128
mg, 0.517 mmol, 52%) starting from 2a (250 mg, 1.00 mmol,
1
1.0 equiv.). H NMR (600 MHz, CDCl3) δ 7.64-7.62 (m, 2H),
Methyl
5-(benzo[d][1,3]dioxol-5-yl)-3-
7.41-7.39 (m, 2H), 7.34-7.34 (m, 1H), 6.85 (s, 1H), 6.68 (br s,
1H), 3.83 (s, 3H), 3.02 (s, 3H); 13C{1H} NMR (150 MHz,
CDCl3) δ 165.3, 157.5, 149.8, 133.7, 129.00, 128.99, 126.1,
111.7, 97.5, 51.1, 31.7; Data are consistent with those reported
in the literature.15
(methylamino)thiophene-2-carboxylate (3f). Compound 3f
was obtained as a pale yellow solid (319 mg, 1.09 mmol, 68%)
starting from 2a (400 mg, 1.60 mmol, 1.0 equiv.),
benzo[d][1,3]dioxol-5-ylboronic acid (318 mg, 1.92 mmol, 1.2
equiv.), Pd(PPh3)4 (92.4 mg, 0.0800 mmol, 0.05 equiv.), 0.4 M
sodium carbonate (4.8 mL) and toluene (6.4 mL). m.p: 124-
9
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12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
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40
41
42
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45
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49
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60
Methyl
5-(4-methoxyphenyl)-3-(methylamino)thiophene-2-
1
125 °C; H NMR (600 MHz, CDCl3) δ 7.14 (dd, J = 8.4 Hz
carboxylate (3b). Compound 3b was obtained as a pale yellow
solid (404 mg, 1.46 mmol, 61%) starting from 2a (600 mg,
2.40 mmol, 1.0 equiv.), 4-methoxyphenylboronic acid (437
mg, 1.84 mmol, 1.2 equiv.), Pd(PPh3)4 (139 mg, 0.12 mmol,
0.05 equiv.), 0.4 M sodium carbonate (7.2 mL) and toluene
and J = 1.8 Hz, 1H), 7.09 (d, J = 1.8 Hz, 1H), 6.82 (d, J = 7.8
Hz, 1H), 6.73 (s, 1H), 6.00 (s, 2H), 3.82 (s, 3H), 3.02 (s, 3H);
13C{1H} NMR (150 MHz, CDCl3) δ 165.4, 157.6, 149.9, 148.6,
148.3, 128.1, 120.3, 111.2, 108.8, 106.6, 101.6, 96.9, 51.2,
31.8; HRMS (EI): m/z calcd for C14H13NO4S [M]+ 291.0565,
found 291.0567.
1
(9.6 mL). m.p: 138-139 °C; H NMR (600 MHz, CDCl3) δ
7.56 (dd, J = 6.9 Hz and J = 2.1 Hz, 2H), 6.92 (dd, J = 6.9 Hz
and J = 2.1 Hz, 2H), 6.75 (s, 1H), 3.84 (s, 3H), 3.82 (s, 3H),
3.02 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 165.4, 160.5,
157.7, 150.0, 127.5, 126.5, 114.4, 110.7, 96.7, 55.5, 51.1, 31.8;
HRMS (EI): m/z calcd for C14H15NO3S [M]+ 277.0773, found
277.0772.
Methyl
5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-
(methylamino)thiophene-2-carboxylate (3g). Compound 3g
was obtained as a pale yellow sticky solid (274 mg, 0.897
mmol, 90%) starting from 2a (250 mg, 1.00 mmol, 1.0 equiv.),
(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)boronic acid (216 mg,
1.20 mmol, 1.2 equiv.), Pd(PPh3)4 (57.0 mg, 0.0500 mmol,
0.05 equiv.), 0.4 M sodium carbonate (2 mL) and toluene (2.5
mL). m.p: 50-51 °C; 1H NMR (600 MHz, CDCl3) δ 7.11 (d, J
= 2.4 Hz, 1H), 7.08 (dd, J = 8.4 Hz and J = 2.4 Hz, 1H), 6.83
(d, J = 8.4 Hz, 1H), 6.70 (s, 1H), 6.64 (br s, 1H), 4.22 (s, 4H),
3.79 (s, 3H), 2.97 (d, J = 4.8 Hz, 3H); 13C{1H} NMR (150
MHz, CDCl3) δ 165.2, 157.5, 149.5, 144.5, 143.6, 127.2,
119.3, 117.6, 114.8, 110.8, 96.6, 64.4, 64.3, 50.9, 31.5; HRMS
(EI): m/z calcd for C15H15NO4S [M]+ 305.0722, found
305.0720.
Methyl
5-(3-methoxyphenyl)-3-(methylamino)thiophene-2-
carboxylate (3c). Compound 3c was obtained as a yellow solid
(218 mg, 0.786 mmol, 66%) starting from 2a (300 mg, 1.20
mmol, 1.0 equiv.), 3-methoxyphenylboronic acid (219 mg,
1.44 mmol, 1.2 equiv.), Pd(PPh3)4 (69.3 mg, 0.06 mmol, 0.05
equiv.), 0.4 M sodium carbonate (3 mL) and toluene (4.8 mL).
1
m.p: 49-50 °C; H NMR (500 MHz, CDCl3) δ 7.30 (t, J = 8.0
Hz, 1H), 7.22 (dt, J = 7.5 Hz and J = 1.1 Hz, 1H), 7.14 (t, J =
2.0 Hz, 1H), 6.90 (dd, J = 2.5 Hz and J = 8.0 Hz, 1H), 6.84 (s,
1H), 6.66 (br s, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.02 (d, J = 5.5
Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 165.4, 157.6,
151.2, 150.9, 134.5, 129.7, 114.6, 113.3, 111.7, 110.0, 97.2,
51.2, 40.7, 31.8; HRMS (EI): m/z calcd for C14H15NO3S [M]+
277.0773, found 277.0775.
Methyl 3-(methylamino)-5-(3,4,5-trimethoxyphenyl)thiophene-
2-carboxylate (3h). Compound 3h was obtained as a yellow
solid (438 mg, 1.30 mmol, 67%) starting from 2a (485 mg,
1.94 mmol, 1.0 equiv.), (3,4,5-trimethoxyphenyl)boronic acid
(493 mg, 2.33 mmol, 1.2 equiv.), Pd(PPh3)4 (112 mg, 0.100
mmol, 0.05 equiv.), 0.4 M sodium carbonate (5.8 mL) and
Methyl
5-(2-methoxyphenyl)-3-(methylamino)thiophene-2-
carboxylate (3d). Compound 3d was obtained as a pale yellow
liquid (217 mg, 0.782 mmol, 65%) starting from 2a (300 mg,
1.20 mmol, 1.0 equiv.), 2-methoxyphenylboronic acid (219
mg, 1.44 mmol, 1.2 equiv.), Pd(PPh3)4 (69.3 mg, 0.06 mmol,
0.05 equiv.), 0.4 M sodium carbonate (3 mL) and toluene (4.8
mL). 1H NMR (500 MHz, CDCl3) δ 7.67 (dd, J = 7.5 Hz and J
= 1.5 Hz, 1H), 7.32 (t, J = 7.8 Hz, 1H), 7.05 (s, 1H), 7.02-6.98
(m, 2H), 6.70 (br s, 1H), 3.95 (s, 3H), 3.83 (s, 3H), 3.03 (s,
3H); 13C{1H} NMR (125 MHz, CDCl3) δ 165.6, 156.7, 156.6,
145.5, 130.0, 128.7, 122.5, 121.1, 113.9, 111.9, 98.7, 55.8,
51.2, 31.8; HRMS (EI): m/z calcd for C14H15NO3S [M]+
277.0773, found 277.0775.
1
toluene (7.8 mL). m.p: 135-136 °C; H NMR (600 MHz,
CDCl3) δ 6.82 (s, 2H), 6.77 (s, 1H), 3.91 (s, 6H), 3.91 (s, 3H),
3.83 (s, 3H), 3.05 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ
165.3, 157.3, 153.7, 150.1, 139.2, 129.5, 111.7, 103.7, 93.0,
61.1, 56.4, 51.3, 31.9; HRMS (EI): m/z calcd for C14H13NO4S
[M]+ 337.0984, found 337.0987.
Methyl
5-(4-(dimethylamino)phenyl)-3-
(methylamino)thiophene-2-carboxylate (3i). Compound 3i was
obtained as a pale red solid (194 mg, 0.668 mmol, 56%)
starting from 2a (300 mg, 1.20 mmol, 1.0 equiv.), (4-
(dimethylamino)phenyl)boronic acid (237 mg, 1.43 mmol, 1.2
equiv.), Pd(PPh3)4 (69.3 mg, 0.0600 mmol, 0.05 equiv.), 0.4 M
sodium carbonate (2 mL) and DMF (4.8 mL). m.p: 130-
Methyl
3-(methylamino)-5-(4-phenoxyphenyl)thiophene-2-
carboxylate (3e). Compound 3e was obtained as a pale yellow
solid (220 mg, 0.648 mmol, 81%) starting from 2a (200 mg,
0.800 mmol, 1.0 equiv.), (4-phenoxyphenyl)boronic acid (205
mg, 0.960 mmol, 1.2 equiv.), Pd(PPh3)4 (46.2 mg, 0.0400
mmol, 0.05 equiv.), 0.4 M sodium carbonate (2 mL) and
toluene (3.2 mL). m.p: 75-76 °C; 1H NMR (600 MHz, CDCl3)
δ 7.60-7.58 (m, 2H), 7.38-7.36 (m, 2H), 7.15 (tt, J = 7.5 Hz
and J = 1.2 Hz, 1H), 7.07-7.05 (m, 2H), 7.03-7.00 (m, 2H),
1
132 °C; H NMR (600 MHz, CDCl3) δ 7.52 (d, J = 9.0 Hz,
2H), 6.71 (s, 1H), 6.70 (d, J = 9.0 Hz, 2H), 3.81 (s, 3H), 3.02
(d, J = 5.4 Hz, 3H), 3.01 (s, 6H); 13C{1H} NMR (150 MHz,
CDCl3) δ 165.5, 158.1, 151.3, 151.0, 127.2, 121.7, 112.2,
109.2, 95.5, 51.1, 40.4, 31.8; HRMS (EI): m/z calcd for
C15H18N2O2S [M]+ 290.1089, found 290.1092.
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The Journal of Organic Chemistry
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Methyl
5-(3-(dimethylamino)phenyl)-3- pyrido[3,2,1-ij]quinolin-9-yl)boronic acid (96.0 mg, 0.440
1
2
3
4
5
6
7
8
(methylamino)thiophene-2-carboxylate (3j). Compound 3j was
obtained as a yellow solid (250 mg, 0.861 mmol, 72%)
starting from 2a (300 mg, 1.20 mmol, 1.0 equiv.), (3-
(dimethylamino)phenyl)boronic acid (237 mg, 1.43 mmol, 1.2
equiv.), Pd(PPh3)4 (69.3 mg, 0.0600 mmol, 0.05 equiv.), 0.4 M
sodium carbonate (2 mL) and toluene (4.8 mL). m.p: 102-
103 °C; 1H NMR (600 MHz, CDCl3) δ 7.26 (t, J = 8.1 Hz, 1H),
7.00 (dd, J = 7.2 Hz and J = 1.2 Hz, 1H), 6.93 (t, J = 2.4 Hz,
1H), 6.84 (s, 1H), 6.74 (dd, J = 8.4 Hz and J = 2.4 Hz, 1H),
6.67 (br s, 1H), 3.83 (s, 3H), 3.04 (d, J = 5.4 Hz, 3H), 3.00 (s,
6H); 13C{1H} NMR (150 MHz, CDCl3) δ 165.4, 157.6, 151.2,
150.9, 134.5, 129.7, 114.6, 113.3, 111.7, 110.0, 97.2, 51.2,
40.7, 31.8; HRMS (EI): m/z calcd for C15H18N2O2S [M]+
290.1089, found 290.1087.
mmol, 1.2 equiv.), Pd(OAc)2 (9.00 mg, 0.0400 mmol, 0.1
equiv.), 1,1`-bis(diphenylphospino)ferrocene (dppf, 22.2 mg,
0.0400 mmol, 0.1 equiv.) and Cs2CO3 (260 mg, 0.800 mmol,
2.0 equiv.) were added. And then, the reaction was heated to
reflux for 18 h. For quenching the reaction, water (2 mL) was
added. The crude was extracted with DCM (3 mL) at three
times. The organic layer was dried over Na2SO4, filtered and
evaporated in vacuo. The mixture was purified by flash
column chromatography (Hexane/EtOAc = 3/1, v/v) on silica
to obtain 3n as a red-orange sticky liquid (45.0 mg, 0.131
mmol, 33%). m.p: 157-159 °C; 1H NMR (600 MHz, CDCl3) δ
7.08 (s, 2H), 6.65 (s, 1H), 3.80 (s, 3H), 3.19 (t, J = 5.7 Hz, 4H),
3.01 (d, J = 4.8 Hz, 3H), 2.76 (t, J = 6.6 Hz, 4H), 2.00-1.95 (m,
4H); 13C{1H} NMR (150 MHz, CDCl3) δ 165.4, 158.1, 151.8,
143.8, 124.8, 121.3, 120.6, 108.6, 94.6, 50.9, 50.0, 31.7, 27.8,
21.9; HRMS (EI): m/z calcd for C19H22N2O2S [M]+ 342.1402,
found 342.1404.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Methyl
5-(2-(dimethylamino)phenyl)-3-
(methylamino)thiophene-2-carboxylate (3k). Compound 3k
was obtained as a yellow liquid (174 mg, 0.599 mmol, 75%)
starting from 2a (200 mg, 0.800 mmol, 1.0 equiv.), (2-
(dimethylamino)phenyl)boronic acid (158 mg, 0.960 mmol,
1.2 equiv.), Pd(PPh3)4 (46.0 mg, 0.0400 mmol, 0.05 equiv.),
0.4 M sodium carbonate (1 mL) and DMF (3.2 mL). 1H NMR
(600 MHz, CDCl3) δ 7.56 (dd, J = 7.8 Hz and J = 1.2 Hz, 1H),
7.28 (td, J = 7.8 Hz and J = 1.4 Hz, 1H), 7.14 (dd, J = 7.8 Hz
and J = 1.2 Hz, 1H), 7.05 (td, J = 7.2 Hz and J = 1.2 Hz, 1H),
6.99 (s, 1H), 6.64-6.63 (m, 1H), 3.83 (s, 3H), 3.02 (d, J = 5.4
Hz, 3H), 2.68 (s, 6H); 13C{1H} NMR (150 MHz, CDCl3) δ
165.8, 156.7, 151.9, 147.9, 129.6, 129.4, 128.0, 123.0, 119.9,
113.5, 98.8, 51.0, 44.3, 31.7; HRMS (EI): m/z calcd for
C15H18N2O2S [M]+ 290.1089, found 290.1093.
Methyl
5-(4-(diphenylamino)phenyl)-3-
(methylamino)thiophene-2-carboxylate (3o). Compound 3o
was obtained as a yellow solid (728 mg, 1.76 mmol, 88%)
starting from 2a (500 mg, 2.00 mmol, 1.0 equiv.), (4-
(diphenylamino)phenyl)boronic acid (693 mg, 2.40 mmol, 1.2
equiv.), Pd(PPh3)4 (116 mg, 0.100 mmol, 0.05 equiv.), 0.4 M
sodium carbonate (3 mL) and toluene (8 mL). m.p: 69-71 °C;
1H NMR (600 MHz, CDCl3) δ 7.94-7.47 (m, 2H), 7.30-7.27
(m, 4H), 7.14-7.12 (m, 4H), 7.08-7.04 (m, 4H), 6.77 (s, 1H),
3.82 (s, 3H), 3.02 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ
165.4, 157.7, 150.0, 148.8, 147.3, 129.5, 127.2, 126.9, 125.1,
123.7, 122.8, 110.6, 96.7, 51.2, 31.8; HRMS (EI): m/z calcd
for C25H22N2O2S [M]+ 414.1402, found 414.1404.
Methyl 5-(4-(diethylamino)phenyl)-3-(methylamino)thiophene-
2-carboxylate (3l). Compound 3l was obtained as an orange
liquid (490 mg, 1.54 mmol, 96%) starting from 2a (400 mg,
1.60 mmol, 1.0 equiv.), N,N-diethyl-4-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)aniline (528 mg, 1.92 mmol, 1.2
equiv.), Pd(PPh3)4 (92.3 mg, 0.0800 mmol, 0.05 equiv.), 0.4 M
sodium carbonate (2 mL) and toluene (6.4 mL). 1H NMR (500
MHz, CDCl3) δ 7.49 (d, J = 9.0 Hz, 2H), 6.70 (s, 1H), 6.65 (d,
J = 9.0 Hz, 2H), 3.82 (s, 3H), 3.37 (q, J = 7.3 Hz, 4H), 3.03 (d,
J = 5.0 Hz, 3H), 1.19 (t, J = 7.0 Hz, 6H); 13C{1H} NMR (125
MHz, CDCl3) δ 165.4, 158.0, 151.4, 148.4, 127.3, 120.6,
111,4, 108.7, 95.1, 50.9, 44.5, 31.7, 12.7; HRMS (EI): m/z
calcd for C17H22N2O2S [M]+ 318.1402, found 318.1405.
Methyl
3-(methylamino)-5-(4-
(3p).
(trifluoromethoxy)phenyl)thiophene-2-carboxylate
Compound 3p was obtained as a yellow solid (365 mg, 1.10
mmol, 69%) starting from 2a (400 mg, 1.60 mmol, 1.0 equiv.),
(4-(trifluoromethoxy)phenyl)boronic acid (395 mg, 1.92 mmol,
1.2 equiv.), Pd(PPh3)4 (92.0 mg, 0.0800 mmol, 0.05 equiv.),
0.4 M sodium carbonate (4.8 mL) and toluene (6.4 mL). m.p:
1
68-70 °C; H NMR (600 MHz, CDCl3) δ 7.64 (d, J = 8.4 Hz,
2H), 7.24 (d, J = 8.4 Hz, 2H), 6.83 (s, 1H), 3.83 (s, 3H), 3.03
(s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 165.3, 157.4,
149.7 (q, JC-F = 1.9 Hz), 148.1, 132.6, 127.6, 121.5, 120.6 (q,
JC-F = 256.1 Hz), 112.3, 98.2, 51.3, 31.8; 19F{1H} NMR (600
MHz, CDCl3)
δ -57.8; HRMS (EI): m/z calcd for
Methyl
3-(methylamino)-5-(4-(4-methylpiperazin-1-
C14H12F3NO3S [M]+ 331.0490, found 331.0490.
yl)phenyl)thiophene-2-carboxylate (3m). Compound 3m was
obtained as a brown solid (113 mg, 0.327 mmol, 82%) starting
from 2a (100 mg, 0.400 mmol, 1.0 equiv.), 4-(4-methyl)-
piperazinylboronic acid (145 mg, 0.480 mmol, 1.2 equiv.),
Pd(PPh3)4 (23.0 mg, 0.0200 mmol, 0.05 equiv.), 0.4 M sodium
Methyl
3-(methylamino)-5-(4-
(trifluoromethyl)phenyl)thiophene-2-carboxylate
(3q).
Compound 3q was obtained as a pale yellow solid (345 mg,
1.09 mmol, 68%) starting from 2a (400 mg, 1.60 mmol, 1.0
equiv.), (4-(trifluoromethyl)phenyl)boronic acid (365 mg, 1.92
mmol, 1.2 equiv.), Pd(PPh3)4 (92.0 mg, 0.0800 mmol, 0.05
equiv.), 0.4 M sodium carbonate (4.8 mL) and toluene (6.4
mL). m.p: 93-95 °C; 1H NMR (600 MHz, CDCl3) δ 7.72 (d, J
= 8.4 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H), 6.91 (s, 1H), 3.84 (s,
3H), 3.04 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 165.3,
157.3, 147.6, 137.2, 130.7, (q, JC-F = 32.5 Hz), 126.3, 126.1 (q,
JC-F = 3.7 Hz), 124.1 (q, JC-F = 270.6 Hz), 112.9, 98.8, 51.4,
31.8; 19F{1H} NMR (600 MHz, CDCl3) δ -62.7; HRMS (EI):
m/z calcd for C14H12F3NO2S [M]+ 315.0541, found 315.0543.
1
carbonate (0.5 mL) and DMF (1.6 mL). m.p: 153-154 °C; H
NMR (600 MHz, CDCl3) δ 7.53 (d, J = 8.4 Hz, 2H), 6.91 (d, J
= 8.4 Hz, 2H), 6.74 (s, 1H), 6.67 (br s, 1H), 3.81 (s, 3H), 3.28
(t, J = 5.1 Hz, 4H), 3.02 (d, J = 5.4 Hz, 3H), 2.57 (t, J = 5.1 Hz,
4H), 2.36 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 165.5,
157.9, 151.7, 150.5, 127.1, 124.6, 115.5, 110.0, 96.2, 55.0,
51.1, 48.4, 46.3, 31.8; HRMS (EI): m/z calcd for C18H23N3O2S
[M]+ 345.1511, found 345.1508.
Methyl
3-(methylamino)-5-(2,3,6,7-tetrahydro-1H,5H-
(3n).
pyrido[3,2,1-ij]quinolin-9-yl)thiophene-2-carboxylate
To a solution of 2a (100 mg, 0.400 mmol, 1.0 equiv.) in
dioxane:H2O (3:1, 1.6 mL), (2,3,6,7-tetrahydro-1H,5H-
Methyl
3-(benzylamino)-5-(4-methoxyphenyl)thiophene-2-
carboxylate (3r). Compound 3r was obtained as a yellow solid
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The Journal of Organic Chemistry
(392 mg, 1.11 mmol, 73%) starting from 2b (500 mg, 1.53
equiv.). 1H NMR (500 MHz, CDCl3) δ 7.36 (t, J = 7.8 Hz, 1H),
1
2
3
4
5
6
7
8
mmol, 1.0 equiv.), 4-methoxyphenylboronic acid (280 mg,
1.84 mmol, 1.2 equiv.), Pd(PPh3)4 (88.6 mg, 0.0800 mmol,
0.05 equiv.), 0.4 M sodium carbonate (4 mL) and toluene (6.1
mL). m.p: 100-102 °C; 1H NMR (600 MHz, CDCl3) δ 7.50 (dd,
J = 6.6 Hz and J = 1.8 Hz, 2H), 7.37-7.33 (m, 4H), 7.29-7.26
(m, 1H), 7.22 (br s, 1H), 6.89 (dd, J = 6.6 Hz and J = 2.4 Hz,
2H), 6.70 (s, 1H), 4.53 (d, J = 6.0 Hz, 2H), 3.84 (s, 3H), 3.82
(s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 165.5, 160.5,
156.7, 150.0, 139.0, 128.9, 127.49, 127.45, 127.1, 126.4,
114.4, 111.2, 97.5, 55.5, 51.2, 49.1; HRMS (EI): m/z calcd for
C20H19NO3S [M]+ 353.1086, found 353.1088.
7.27 (d, J = 7.5 Hz, 1H), 7.23 (s, 1H), 6.93 (dd, J = 2.5 Hz and
J = 8.0 Hz, 1H), 6.89 (d, J = 1.8 Hz, 1H), 5.99 (d, J = 2.0 Hz,
1H), 3.90 (s, 3H), 3.71 (br s, 1H), 2.87 (s, 3H); 13C{1H} NMR
(125 MHz, CDCl3) δ 159.8, 150.2, 142.9, 135.8, 129.7, 117.9,
116.1, 112.7, 111.0, 94.5, 55.1, 32.4; HRMS (EI): m/z calcd
for C12H13NOS [M]+ 219.0718, found 219.0717.
5-(2-Methoxyphenyl)-N-methylthiophen-3-amine
(5d).
Compound 5d was obtained as a dark green oil (139 mg, 0.634
mmol, 86%) starting from 3d (204 mg, 0.736 mmol, 1.0
9
1
equiv.). H NMR (500 MHz, CDCl3) δ 7.62 (dd, J = 7.5 Hz
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
and J = 1.5 Hz, 1H), 7.26 (td, J = 7.9 Hz and J = 1.8 Hz, 1H),
7.09 (d, J = 1.5 Hz, 1H), 7.01-6.96 (m, 2H), 6.00 (d, J = 1.5
Hz, 1H), 3.90 (s, 3H), 3.63 (br s, 1H), 2.84 (s, 3H); 13C{1H}
NMR (150 MHz, CDCl3) δ 155.8, 149.6, 138.7, 128.28,
128.25, 123.4, 120.8, 118.5, 111.6, 95.6, 55.5, 32.7; HRMS
(EI): m/z calcd for C12H13NOS [M]+ 219.0718, found 219.0716.
Methyl
3-(benzylamino)-5-(4-
(3s).
(dimethylamino)phenyl)thiophene-2-carboxylate
Compound 3s was obtained as a pale red solid (371 mg, 1.01
mmol, 66%) starting from 2b (500 mg, 1.53 mmol, 1.0 equiv.),
(4-(dimethylamino)phenyl)boronic acid (304 mg, 1.84 mmol,
1.2 equiv.), Pd(PPh3)4 (88.6 mg, 0.0800 mmol, 0.05 equiv.),
0.4 M sodium carbonate (2 mL) and toluene (6.1 mL). m.p:
135-136 °C; 1H NMR (600 MHz, CDCl3) δ 7.46-7.44 (m, 2H),
7.37-7.33 (m, 4H), 7.28-7.25 (m, 2H), 6.67-6.66 (m, 3H), 4.53
(d, J = 6.0 Hz, 2H), 3.83 (s, 3H), 2.99 (s, 6H); 13C{1H} NMR
(150 MHz, CDCl3) δ 165.5, 157.0, 151.3, 151.0, 139.2, 128.8,
127.4, 127.2, 121.6, 112.2, 109.8, 96.3, 51.1, 49.1, 40.4;
HRMS (EI): m/z calcd for C21H22N2O2S [M]+ 366.1402, found
366.1405.
N-Methyl-5-(4-phenoxyphenyl)thiophen-3-amine
(5e).
Compound 5e was obtained as a pale yellow solid (33.2 mg,
0.118 mmol, 72%) starting from 3e (56.0 mg, 0.165 mmol, 1.0
1
equiv.). m.p: 84-85 °C; H NMR (600 MHz, CDCl3) δ 7.53
(dd, J = 6.6 Hz and J = 1.8 Hz, 2H), 7.38-7.36 (m, 2H), 7.14
(tt, J = 7.2 Hz and J = 1.1 Hz, 1H), 7.07-7.05 (m, 2H), 7.01
(dd, J = 6.6 Hz and J = 1.8 Hz, 2H), 6.79 (d, J = 1.8 Hz, 1H),
5.91 (d, J = 1.2 Hz. 1 H), 2.85 (s, 3H); 13C{1H} NMR (150
MHz, CDCl3) δ 157.1, 156.9, 150.3, 143.0, 129.95, 129.90,
127.0, 123.5, 119.14, 119.06, 115.6, 94.5, 32.7; HRMS (EI):
m/z calcd for C17H15NOS [M]+ 281.0874, found 281.0871.
General Procedure for the Synthesis of 5a-5s
To a solution of 3a (150 mg, 0.600 mmol, 1.0 equiv.) in
ethanol (4 mL, 0.25 M), 1 N KOH (2 mL) was added. The
reaction was heated to 70 °C and stirred for 1 h. After
completion of the reaction, the solvent was evaporated. The
crude was used without further purification. And then,
silicagel (750 mg, 500 wt % of substrate) was added in EtOAc
(2 mL) and MeOH (2 mL) solution (1:1). The reaction was
heated 60 °C and stirred for 2 h. After completion of the
reaction, the silicagel was filtered and the organic layer was
evaporated in vacuo. The residue was purified by flash column
chromatography (Hexane/EtOAc = 3/1, v/v) on silica to afford
the product 5a.
5-(Benzo[d][1,3]dioxol-5-yl)-N-methylthiophen-3-amine (5f).
Compound 5f was obtained as a pale green solid (16.3 mg,
0.0699 mmol, 73%) starting from 3f (28.0 mg, 0.0961 mmol,
1
1.0 equiv.). m.p: 65-66 °C; H NMR (600 MHz, CDCl3) δ
7.05-7.03 (m, 2H), 6.80 (d, J = 2.4 Hz, 1H), 6.72 (s, 1H), 5.97
(s, 2H), 5.86 (s, 1H), 3.63 (br s, 1H), 2.83 (s, 3H); 13C{1H}
NMR (125 MHz, CDCl3) δ 150.2, 148.1, 147.3, 143.5, 129.1,
119.4, 115.5, 108.7, 106.4, 101.3, 94.2, 32.7; HRMS (EI): m/z
calcd for C12H11NO2S [M]+ 233.0511, found 233.0508.
5-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-N-methylthiophen-3-
amine (5g). Compound 5g was obtained as a brown oil (160
mg, 0.647 mmol, 77%) starting from 3g (256 mg, 0.838 mmol,
N-methyl-5-phenylthiophen-3-amine (5a). Compound 5a was
1
obtained as a white solid (105 mg, 0.555 mmol, 92%) starting
1.0 equiv.). H NMR (500 MHz, CDCl3) δ 7.09-7.04 (m, 2H),
1
from 3a (150 mg, 0.600 mmol, 1.0 equiv.). H NMR (600
6.85 (d, J = 8.5 Hz, 1H), 6.72 (d, J = 2.0 Hz, 1H), 5.86 (d, J =
1.5 Hz, 1H), 4.27 (s, 4H), 3.61 (br s, 1H), 2.83 (s, 3H); 13C{1H}
NMR (125 MHz, CDCl3) δ 150.2, 143.7, 143.3, 143.2, 128.5
119.0, 117.6, 115.3, 114.5, 94.1, 64.53, 64.50, 32.7; HRMS
(EI): m/z calcd for C13H13NO2S [M]+ 247.0667, found
247.0668.
MHz, CDCl3) δ 7.59-7.57 (m, 2H), 7.37 (td, J = 7.2 Hz and J
= 1.8 Hz, 2H), 7.28 (tt, J = 7.2 Hz and J = 1.5 Hz, 1H), 6.86 (d,
J = 1.8 Hz, 1H), 5.95 (d, J = 1.8 Hz, 1H), 3.48 (br s, 1H), 2.85
(s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 150.3, 143.6,
134.7, 128.9, 127.6, 125.6, 116.0, 95.0, 32.7; Data are
consistent with those reported in the literature.7a
N-Methyl-5-(3,4,5-trimethoxyphenyl)thiophen-3-amine (5h).
Compound 5h was obtained as a brown oil (298 mg, 1.07
mmol, 90%) starting from 3h (400 mg, 1.19 mmol, 1.0 equiv.).
1H NMR (600 MHz, CDCl3) δ 6.77 (d, J = 1.8 Hz, 1H), 6.75 (s,
2H), 5.89 (d, J = 1.8 Hz, 1H), 3.89 (s, 6H), 3.86 (s, 3H), 2.83
(s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 153.4, 150.2,
143.5, 137.8, 130.5, 115.9, 103.1, 94.7, 61.0, 56.2, 32.7;
HRMS (EI): m/z calcd for C14H17NO3S [M]+ 279.0929, found
279.0930.
5-(4-Methoxyphenyl)-N-methylthiophen-3-amine
(5b).
Compound 5b was obtained as a pale yellow solid (130 mg,
0.593 mmol, 89%) starting from 3b (185 mg, 0.667 mmol, 1.0
1
equiv.). H NMR (600 MHz, CDCl3) δ 7.48 (dd, J = 6.6 Hz
and J = 1.8 Hz, 2H), 6.91 (dd, J = 6.6 Hz and J = 2.4 Hz, 2H),
6.74 (d, J = 1.8 Hz, 1H), 5.87 (d, J = 1.8 Hz, 1H), 3.83 (s, 3H),
2.84 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 159.3, 150.3,
143.6, 127.6, 126.9, 115.1, 114.3, 94.0, 55.5, 32.8; Data are
consistent with those reported in the literature.7a
5-(4-(Dimethylamino)phenyl)-N-methylthiophen-3-amine (5i).
Compound 5i was obtained as a red-brown solid (600 mg, 2.58
mmol, 62%) starting from 3i (1.20 g, 4.13 mmol, 1.0 equiv.).
5-(3-Methoxyphenyl)-N-methylthiophen-3-amine
(5c).
Compound 5c was obtained as a brown oil (122 mg, 0.556
mmol, 85%) starting from 3c (182 mg, 0.656 mmol, 1.0
1
m.p: 125-127 °C; H NMR (600 MHz, CDCl3) δ 7.44 (d, J =
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The Journal of Organic Chemistry
Page 8 of 15
9.0 Hz, 2H), 6.71-6.70 (m, 3H), 5.81 (s, 1H), 2.98 (s, 6H),
13C{1H} NMR (150 MHz, CDCl3) 150.3, 147.7, 147.3, 143.5,
129.4, 128.9, 126.4, 124.6, 123.8, 123.1, 115.2, 94.3, 32.8;
HRMS (EI): m/z calcd for C23H20N2S [M]+ 356.1347, found
356.1349.
2.84 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 150.2, 150.1,
144.5, 126.6, 123.3, 114.0, 112.6, 93.0, 40.6, 32.8; HRMS (EI):
m/z calcd for C13H16N2S [M]+ 232.1034, found 232.1033.
1
2
3
4
5
6
7
8
9
5-(3-(Dimethylamino)phenyl)-N-methylthiophen-3-amine (5j).
Compound 5j was obtained as a brown liquid (109 mg, 0.469
mmol, 86%) using 3j (159 mg, 0.547 mmol, 1.0 equiv.). H
NMR (500 MHz, CDCl3) δ 7.26 (t, J = 8.0 Hz, 1H), 6.96 (d, J
= 7.5 Hz, 1H), 6.94-6.93 (m, 1H), 6.86 (d, J = 1.5 Hz, 1H),
6.70 (dd, J = 8.0 Hz and J = 2.5 Hz, 1H), 5.93 (d, J = 2.0 Hz,
1H), 3.38 (br s, 1H), 3.01 (s, 6H), 2.85 (s, 3H); 13C{1H} NMR
(125 MHz, CDCl3) δ 150.9, 150.1, 144.6, 135.4, 129.5, 115.9,
114.4, 112.0, 109.9, 94.6, 40.7, 32.7; HRMS (EI): m/z calcd
for C13H16N2S [M]+ 232.1034, found 232.1032.
N-Methyl-5-(4-(trifluoromethoxy)phenyl)thiophen-3-amine
(5p). Compound 5p was obtained as a green solid (224 mg,
0.820 mmol, 80%) starting from 3p (339 mg, 1.02 mmol, 1.0
1
1
equiv.). m.p: 121-123 °C; H NMR (600 MHz, CDCl3) δ 7.56
(dd, J = 6.6 Hz and J = 1.8 Hz, 2H), 7.21 (d, J = 9.0 Hz and J
= 0.6 Hz, 2H), 6.82 (d, J = 1.8 Hz, 1H), 5.95 (d, J = 1.2 Hz,
1H), 2.85 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 150.4,
148.6, 141.9, 133.5, 126.9, 121.4, 119.8 (q, JC-F = 255.6 Hz),
116.5, 95.5, 32.7; 19F{1H} NMR (600 MHz, CDCl3) δ -57.9;
HRMS (EI): m/z calcd for C12H10F3NOS [M]+ 273.0435, found
273.0437.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5-(2-(Dimethylamino)phenyl)-N-methylthiophen-3-amine (5k).
Compound 5k was obtained as a yellow liquid (110 mg, 0.473
mmol, 81%) starting from 3k (170 mg, 0.585 mmol, 1.0
N-Methyl-5-(4-(trifluoromethyl)phenyl)thiophen-3-amine (5q).
Compound 5q was obtained as a yellow-green solid (112 mg,
0.435 mmol, 80%) starting from 3q (172 mg, 0.545 mmol, 1.0
1
equiv.). H NMR (600 MHz, CDCl3) δ 7.48 (d, J = 7.8 Hz,
1
1H), 7.23 (t, J = 7.2 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 7.03 (t,
J = 7.5 Hz, 1H), 7.00 (s, 1H), 5.99 (s, 1H), 3.56 (br s, 1H),
2.86 (s, 3H), 2.67 (s, 6H); 13C{1H} NMR (150 MHz, CDCl3) δ
151.3, 149.1, 141.4, 129.5, 128.9, 128.1, 122.8, 119.5, 117.9,
96.4, 44.2, 32.8; HRMS (EI): m/z calcd for C13H16N2S [M]+
232.1034, found 232.1035.
equiv.). m.p: 116-118 °C; H NMR (600 MHz, CDCl3) δ 7.64
(d, J = 8.4 Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H), 6.92 (d, J = 1.8
Hz, 1H), 6.00 (d, J = 1.8 Hz,1H), 2.86 (s, 3H); 13C{1H} NMR
(150 MHz, CDCl3) δ 150.6, 141.7, 138.1, 129.3 (q, JC-F = 32.4
Hz), 125.9 (q, JC-F = 3.8 Hz), 125.6, 124.3 (q, JC-F = 270.1 Hz),
117.0, 96.3, 32.7; 19F{1H} NMR (600 MHz, CDCl3) δ -62.5;
HRMS (EI): m/z calcd for C12H10F3NS [M]+ 257.0486, found
257.0483.
5-(4-(Diethylamino)phenyl)-N-methylthiophen-3-amine (5l).
Compound 5l was obtained as a red-brown solid (41.5 mg,
0.159 mmol, 63%) starting from 3l (80.8 mg, 0.254 mmol, 1.0
N-Benzyl-5-(4-methoxyphenyl)thiophen-3-amine
(5r).
1
equiv.). m.p: 88-90 °C; H NMR (500 MHz, CDCl3) δ 7.44
Compound 5r was obtained as a yellow solid (278 mg, 0.941
mmol, 99%) starting from 3r (336 mg, 0.951 mmol, 1.0
equiv.). m.p: 92-93 °C; 1H NMR (600 MHz, CDCl3) δ 7.48 (d,
J = 9.0 Hz, 2H), 7.42-7.41 (m, 2H), 7.38-7.35 (m, 2H), 7.30 (tt,
J = 7.2 Hz and J = 1.7 Hz, 1H), 6.91 (d, J = 9.0 Hz, 2H), 6.78
(d, J = 1.2 Hz, 1H), 5.89 (d, J = 1.2 Hz, 1H), 4.29 (s, 2H), 3.83
(s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 159.3, 148.8,
143.5, 139.4, 128.7, 127.8, 127.5, 127.4, 126.9, 115.2, 114.3,
94.9, 55.5, 50.5; HRMS (EI): m/z calcd for C18H17NOS [M]+
295.1031, found 295.1033.
(dd, J = 6.5 Hz and J = 2.3 Hz, 2H), 6.70-6.67 (m, 3H), 5.81
(d, J = 1.5 Hz, 1H), 3.62 (br s, 1H), 3.39 (q, J = 7.0 Hz, 4H),
2.84 (s, 3H), 1.20 (t, J = 7.3 Hz, 6H); 13C{1H} NMR (125
MHz, CDCl3) δ 150.2, 147.3, 144.6, 126.8, 122.1, 113.7,
111.7, 92.6, 44.5, 32.7, 12.8; HRMS (EI): m/z calcd for
C15H20N2S [M]+ 260.1347, found 260.1346.
N-Methyl-5-(4-(4-methylpiperazin-1-yl)phenyl)thiophen-3-
amine (5m). Compound 5m was obtained as a brown solid
(123 mg, 0.428 mmol, 82%) starting from 3m (180 mg, 0.521
1
mmol, 1.0 equiv.). m.p: 149-150 °C; H NMR (600 MHz,
N-Benzyl-5-(4-(dimethylamino)phenyl)thiophen-3-amine (5s).
Compound 5s was obtained as a red-brown solid (230 mg,
0.746 mmol, 78%) starting from 3s (350 mg, 0.955 mmol, 1.0
equiv.). m.p: 125-126 °C; 1H NMR (600 MHz, CDCl3) δ 7.45-
7.41 (m, 4H), 7.37 (t, J = 7.5 Hz, 2H), 7.30 (t, J = 7.2 Hz, 1H),
6.74-6.740 (m, 1H), 6.71 (d, J = 8.4 Hz, 2H), 5.84 (d, J = 1.8
Hz, 1H), 4.29 (s, 2H), 3.95 (br s, 1H), 2.98 (s, 6H); 13C{1H}
NMR (150 MHz, CDCl3) δ 150.1, 148.7, 144.4, 139.5, 128.7,
127.8, 127.4, 126.6, 123.2, 114.1, 112.6, 93.9, 50.5, 40.6;
HRMS (EI): m/z calcd for C19H20N2S [M]+ 308.1347, found
308.1351.
CDCl3) δ 7.45 (d, J = 9.0 Hz, 2H), 6.89 (d, J = 9.0 Hz, 2H),
6.73 (s, 1H), 5.84 (s, 1H), 3.60 (br s, 1H), 3.24 (t, J = 4.8 Hz,
4H), 2.83 (s, 3H), 2.57 (t, J = 5.1 Hz, 4H), 2.35 (s, 3H);
13C{1H} NMR (150 MHz, CDCl3) δ 150.7, 150.3, 143.9, 126.5,
126.1, 115.9, 114.6, 93.6, 55.2, 48.9, 46.3, 32.7; HRMS (EI):
m/z calcd for C16H21N3S [M]+ 287.1456, found 287.1459.
N-Methyl-5-(2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-
ij]quinolin-9-yl)thiophen-3-amine (5n). Compound 5n was
obtained as a dark-brown solid (74.3 mg, 0.261 mmol, 89%)
starting from 3n (100 mg, 0.292 mmol, 1.0 equiv.). m.p: 66-
1
68 °C; H NMR (600 MHz, CDCl3) δ 7.00 (s, 2H), 6.65 (s,
General Procedure for the Synthesis of 6a-6q
1H), 5.78 (s, 1H), 3.63 (br s, 1H), 3.16 (t, J = 6.0 Hz, 4H),
2.83 (s, 3H), 2.77 (t, J = 6.6 Hz, 4H), 2.00-1.96 (m, 4H);
13C{1H} NMR (150 MHz, CDCl3) δ 150.1, 145.0, 142.7, 124.5,
122.3, 121.6, 113.6, 92.8, 50.1, 32.8, 27.8, 22.1; HRMS (EI):
m/z calcd for C17H20N2S [M]+ 284.1347, found 284.1346.
To a solution of 5a (29.4 mg, 0.155 mmol, 1.0 equiv.) in DMF
(1.5 mL, 0.1 M), mono-methyl fumarate (25.0 mg, 0.186
mmol, 1.2 equiv.), BOP (83.0 mg, 0.186 mmol, 1.2 equiv.)
and N,N-diisopropylethylamine (67.0 µL, 0.388 mmol, 1.2
equiv.) were added. The reaction was stirred for 5 min at room
temperature. After completion of the reaction, water (2 mL)
was added. The crude was extracted with EtOAc (3 mL) at
three times. The organic layer was dried over Na2SO4, filtered
and evaporated in vacuo. The residue was purified by flash
column chromatography (Hexane/EtOAc = 1/1, v/v) on silica
to afford the product 6a.
5-(4-(Diphenylamino)phenyl)-N-methylthiophen-3-amine (5o).
Compound 5o was obtained as a red-brown solid (150 mg,
0.421 mmol, 43%) starting from 3o (406 mg, 0.979 mmol, 1.0
1
equiv.). m.p: 125-126 °C; H NMR (600 MHz, CDCl3) δ 7.41
(d, J = 8.4 Hz, 2H), 7.29-7.25 (m, 4H), 7.11 (d, J = 7.8 Hz,
4H), 7.05-7.02 (m, 4H), 6.77 (s, 1H), 5.88 (s, 1H), 2.84 (s, 3H);
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The Journal of Organic Chemistry
Methyl
4-methyl-5-oxo-2-phenyl-4,5,6,7-tetrahydrothieno
2-(4-Methoxyphenyl)-4-methyl-6,7-dihydrothieno[3,2-b] py
ridin-5(4H)-one (6f). Compound 6f was obtained as a white
solid (38.2 mg, 0.140 mmol, 77%) starting from 5b (40.0 mg,
0.182 mmol, 1.0 equiv.) and acrylic acid (15.0 μL, 0.218
1
2
3
4
5
6
7
8
[3,2-b]pyridine-7-carboxylate (6a). Compound 6a was
obtained as a pale yellow liquid (21.2 mg, 0.0703 mmol, 45%)
starting from 5a (29.4 mg, 0.155 mmol, 1.0 equiv.). H NMR
(600 MHz, CDCl3) δ 7.56 (d, J = 7.8 Hz, 2H), 7.39 (t, J = 12.5
Hz, 2H), 7.31 (t, J = 6.9 Hz, 1H), 6.99 (s, 1H), 4.03 (t, J = 7.2
Hz, 1H), 3.79 (s, 3H), 3.36 (s, 3H), 3.03 (ddd, J = 7.7 Hz, J =
16.2 Hz and J = 31.5 Hz, 2H); 13C{1H} NMR (150 MHz,
CDCl3) δ 171.3, 167.2, 143.9, 140.4, 133.8, 129.2, 128.2,
125.6, 113.3, 112.5, 52.9, 38.4, 34.4, 30.6; HRMS (EI): m/z
calcd for C16H15NO3S [M]+ 301.0773, found 301.0770.
1
1
mmol, 1.2 equiv.). m.p: 152-153 °C; H NMR (600 MHz,
CDCl3) δ 7.46 (dd, J = 9.5 Hz and J = 2.4 Hz, 2H), 6.91 (dd, J
= 9.5 Hz and J = 2.4 Hz, 2H), 6.87 (s, 1H), 3.83 (s, 3H), 3.34
(s, 3H), 2.94 (t, J = 7.8 Hz, 2H), 2.78 (t, J = 7.8 Hz, 2H);
13C{1H} NMR (150 MHz, CDCl3) δ 168.7, 159.5, 141.6, 139.8,
127.0, 126.8, 115.3, 114.5, 112.5, 55.5, 32.3, 30.5, 20.8;
HRMS (EI): m/z calcd for C15H15NO2S [M]+ 273.0824, found
273.0825.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Methyl 2-(4-methoxyphenyl)-4-methyl-5-oxo-4,5,6,7-tetrahy-
drothieno[3,2-b]pyridine-7-carboxylate (6b). Compound 6b
was obtained as a pale yellow solid (36.3 mg, 0.109 mmol,
48%) starting from 5b (50.0 mg, 0.228 mmol, 1.0 equiv.). m.p:
Methyl 4-methyl-5-oxo-2-(4-phenoxyphenyl)-4,5,6,7-tetrahy-
drothieno[3,2-b]pyridine-7-carboxylate (6g). Compound 6g
was obtained as a yellow solid (25.0 mg, 0.0635 mmol, 54%)
starting from 5e (33.0 mg, 0.117 mmol, 1.0 equiv.). m.p: 56-
58 °C; 1H NMR (600 MHz, CDCl3) δ 7.51 (dd, J = 6.6 Hz and
J = 2.4 Hz, 2H), 7.38-7.35 (m, 2H), 7.14 (tt, J = 7.8 Hz and J
= 2.4 Hz, 1H), 7.05-7.04 (m, 2H), 7.02 (dd, J = 2.4 Hz and J =
6.6 Hz, 2H), 6.91 (s, 1H), 4.02 (t, J = 7.2 Hz, 1H), 3.79 (s, 3H),
3.35 (s, 3H), 3.03 (ddd, J = 47.1 Hz, J = 16.5 Hz and J = 7.2
Hz, 2H); 13C{1H} NMR (150 MHz, CDCl3) δ 171.3, 167.1,
157.6, 156.8, 143.3, 140.4, 130.0, 128.9, 127.1, 123.8, 119.3,
119.2, 112.9, 111.9, 52.9, 38.4, 34.4, 30.6; HRMS (EI): m/z
calcd for C22H19NO4S [M]+ 393.1035, found 393.1039.
1
164-165 °C; H NMR (600 MHz, CDCl3) δ 7.48 (dd, J = 6.9
Hz and J = 1.8 Hz, 2H), 6.92 (dd, J = 6.6 Hz and J = 1.8 Hz,
2H), 6.88 (s, 1H), 4.01 (t, J = 7.5 Hz, 1H), 3.84 (s, 3H), 3.79 (s,
3H), 3.35 (s, 3H), 3.02 (ddd, J = 48.9 Hz, J = 16.2 Hz and J =
7.5 Hz, 2H); 13C{1H} NMR (150 MHz, CDCl3) δ 171.4, 167.2,
159.8, 143.9, 140.3, 126.9, 126.7, 114.5, 112.4, 111.3, 55.5,
52.9, 38.4, 34.5, 30.6; HRMS (EI): m/z calcd for C17H17NO4S
[M]+ 331.0878, found 331.0876.
Methyl 2-(3-methoxyphenyl)-4-methyl-5-oxo-4,5,6,7-tetrahy-
drothieno[3,2-b]pyridine-7-carboxylate (6c). Compound 6c
was obtained as a brown liquid (106 mg, 0.320 mmol, 58%)
Methyl 2-(benzo[d][1,3]dioxol-5-yl)-4-methyl-5-oxo-4,5,6,7-
1
starting from 5c (121 mg, 0.552 mmol, 1.0 equiv.). H NMR
tetrahydrothieno[3,2-b]pyridine-7-carboxylate
(6h).
(500 MHz, CDCl3) δ 7.28 (t, J = 8.0 Hz, 1H), 7.13 (d, J = 8.5
Hz, 1H), 7.05-7.06 (m, 1H), 6.96 (s, 1H), 6.84 (dd, J = 2.3 Hz
and J = 8.3 Hz, 1H), 4.01 (t, J = 7.5 Hz, 1H), 3.83 (s, 3H),
3.77 (s, 3H), 3.33 (s, 3H), 3.00 (ddd, J = 46.8 Hz, J = 19.2 Hz
and J = 8.9 Hz, 2H); 13C{1H} NMR (125 MHz, CDCl3) δ
171.2, 167.0, 160.1, 143.5, 140.3, 135.0, 130.1, 118.0, 113.5,
113.4, 112.5, 111.2, 55.4, 52.8, 38.3, 34.3, 30.5; HRMS (EI):
m/z calcd for C17H17NO4S [M]+ 331.0878, found 331.0876.
Compound 6h was obtained as a yellow solid (32.8 mg,
0.0950 mmol, 55%) starting from 5f (40.5 mg, 0.174 mmol,
1
1.0 equiv.). m.p: 150-151 °C; H NMR (500 MHz, CDCl3) δ
7.03 (dd, J = 8.0 Hz and J = 2.0 Hz, 1H), 7.00 (d, J = 2.0 Hz,
1H), 6.83 (s, 1H), 6.79 (d, J = 8.0 Hz, 1H), 5.97 (s, 2H), 3.99
(t, J = 7.3 Hz, 1H), 3.77 (s, 3H), 3.32 (s, 3H), 3.00 (ddd, J =
49.4 Hz, J = 19.7 Hz and J = 8.9 Hz, 2H); 13C{1H} NMR (150
MHz, CDCl3) δ 171.3, 167.1, 148.3, 147.8, 143.7, 140.2,
128.1, 119.4, 112.7, 111.5, 108.8, 106.2, 101.5, 52.8, 38.3,
34.4, 30.5; HRMS (EI): m/z calcd for C17H15NO5S [M]+
345.0671, found 345.0668.
Methyl 2-(2-methoxyphenyl)-4-methyl-5-oxo-4,5,6,7-tetrahy-
drothieno[3,2-b]pyridine-7-carboxylate (6d). Compound 6d
was obtained as a pale brown solid (134 mg, 0.404 mmol, 65%)
starting from 5d (136 mg, 0.620 mmol, 1.0 equiv.). m.p: 160-
Methyl 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-methyl-5-
oxo-4,5,6,7-tetrahydrothieno[3,2-b]pyridine-7-carboxlate (6i).
Compound 6i was obtained as a yellow solid (130 mg, 0.362
mmol, 62%) starting from 5g (145 mg, 0.586 mmol, 1.0
1
161 °C; H NMR (500 MHz, CDCl3) δ 7.59 (d, J = 7.5 Hz,
1H), 7.28 (t, J = 7.8 Hz, 1H), 7.17 (s, 1H), 7.01-6.98 (m, 2H),
4.02 (t, J = 7.3 Hz, 1H), 3.94 (s, 3H), 3.77 (s, 3H), 3.36 (s, 3H),
3.02 (ddd, J = 57.8 Hz, J = 19.4 Hz and J = 8.6 Hz, 2H);
13C{1H} NMR (125 MHz, CDCl3) δ 171.5, 167.2, 155.8, 139.6,
139.0, 129.0, 128.0, 122.6, 121.1, 115.3, 113.1, 111.7, 55.7,
52.8, 38.4, 34.5, 30.5; HRMS (EI): m/z calcd for C17H17NO4S
[M]+ 331.0878, found 331.0881.
1
equiv.). m.p: 126-128 °C; H NMR (500 MHz, CDCl3) δ 7.02
(d, J = 2.0 Hz, 1H), 6.99 (dd, J = 2.3 Hz and J = 9.0 Hz, 1H),
6.82-6.80 (m, 2H), 4.23 (s, 4H), 3.95 (t, J = 7.3 Hz, 1H), 3.74
(s, 3H), 3.28 (s, 3H), 2.96 (ddd, J = 51.9 Hz, J = 19.8 Hz and J
= 8.7 Hz, 2H); 13C{1H} NMR (125 MHz, CDCl3) δ 171.2,
167.0, 143.8, 143.7, 143.3, 140.1, 127.3, 118.7, 117.7, 114.3,
112.5, 111.4, 64.44, 64.39, 52.7, 38.2, 34.3, 30.4; HRMS (EI):
m/z calcd for C18H17NO5S [M]+ 359.0827, found 359.0825.
Methyl 4-benzyl-2-(4-methoxyphenyl)-5-oxo-4,5,6,7-tetrahy-
drothieno[3,2-b]pyridine-7-carboxylate (6e). Compound 6e
was obtained as a yellow solid (73.3 mg, 0.180 mmol, 77%)
starting from 5r (69.4 mg, 0.235 mmol, 1.0 equiv.). m.p: 99-
Methyl 4-methyl-5-oxo-2-(3,4,5-trimethoxyphenyl)-4,5,6,7-
1
100 °C; H NMR (600 MHz, CDCl3) δ 7.36 (dd, J = 4.2 Hz
tetrahydrothieno[3,2-b]pyridine-7-carboxylate
(6j).
and J = 2.4 Hz, 2H), 7.31 (t, J = 7.5 Hz, 2H), 7.28-7.24 (m,
3H), 6.86 (dd, J = 6.6 Hz and J = 1.8 Hz, 2H), 6.73 (s, 1H),
5.19 (d, J = 16.2 Hz, 1H), 4.99 (d, J = 16.2 Hz, 1H), 4.04 (t, J
= 6.9 Hz, 1H), 3.81 (s, 3H), 3.77 (s, 3H), 3.13 (ddd, J = 47.7
Hz, J = 16.2 Hz and J = 6.9 Hz, 2H); 13C{1H} NMR (150 MHz,
CDCl3) δ 171.4, 167.4, 159.7, 143.7, 139.6, 137.0, 128.9,
127.5, 126.94, 126.92, 126.6, 114.5, 112.9, 111.8, 55.5, 52.9,
47.0, 38.5, 34.7; HRMS (EI): m/z calcd for C23H21NO4S [M]+
407.1191, found 407.1188.
Compound 6j was obtained as a yellow solid (60.4 mg, 0.154
mmol, 54%) starting from 5h (80.0 mg, 0.286 mmol, 1.0
1
equiv.). m.p: 133-134 °C; H NMR (600 MHz, CDCl3) δ 6.89
(s, 1H), 6.73 (s, 2H), 4.02 (t, J = 7.5 Hz, 1H), 3.91 (s, 6H),
3.86 (s, 3H), 3.79 (s, 3H), 3.36 (s, 3H), 3.02 (ddd, J = 38.4 Hz,
J = 16.2 Hz and J = 7.2 Hz, 2H); 13C{1H} NMR (150 MHz,
CDCl3) δ 171.3, 167.2, 153.7, 144.0, 140.2, 138.4, 129.6,
113.2, 112.2, 103.2, 61.1, 56.4, 52.9, 38.3, 34.4, 30.7; HRMS
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Page 10 of 15
(EI): m/z calcd for C19H21NO6S [M]+ 391.1090, found
391.1088.
109.5, 52.7, 44.4, 38.3, 34.5, 30.5, 12.7; HRMS (EI): m/z
calcd for C20H24N2O3S [M]+ 372.1508, found 372.1505.
1
2
3
4
5
6
7
8
9
Methyl 2-(4-(dimethylamino)phenyl)-4-methyl-5-oxo-4,5,6,
Methyl 4-methyl-2-(4-(4-methylpiperazin-1-yl)phenyl)-5-oxo-
4,5,6,7-tetrahydrothieno[3,2-b]pyridine-7-carboxylate (6p).
Compound 6p was obtained as a pale orange solid (26.1 mg,
0.0653 mmol, 38%) starting from 5m (50.0 mg, 0.174 mmol,
1.0 equiv.) The mixture was purified by flash column
chromatography (DCM/MeOH = 15/1, v/v) on silica. m.p:
112-114 °C; 1H NMR (600 MHz, CDCl3) δ 7.45 (d, J = 8.4 Hz,
2H), 6.91 (d, J = 9.0 Hz, 2H), 6.86 (s, 1H), 4.00 (t, J = 7.2 Hz,
1H), 3.78 (s, 3H), 3.34 (s, 3H), 3.30-3.28 (m, 4H), 3.02 (ddd, J
= 49.8 Hz, J = 16.2 Hz and J = 7.2 Hz, 2H), 2.34-2.62 (m, 4H),
2.39 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 171.5, 167.2,
151.0, 144.2, 140.3, 126.6, 125.2, 116.0, 111.9, 110.8, 55.0,
52.9, 48.5, 46.1, 38.4, 34.5, 30.6; HRMS (EI): m/z calcd for
C21H25N3O3S [M]+ 399.1617, found 399.1615.
7-tetrahydrothieno[3,2-b]pyridine-7-carboxylate
(6k).
Compound 6k was obtained as an orange-brown solid (83.1
mg, 0.241 mmol, 61%) starting from 5i (91.6 mg, 0.394 mmol,
1
1.0 equiv.). m.p: 121-123 °C; H NMR (600 MHz, CDCl3) δ
7.43 (d, J = 9.0 Hz, 2H), 6.82 (s, 1H), 6.72 (d, J = 7.8 Hz, 2H),
3.99 (t, J = 7.2 Hz, 1H), 3.78 (s, 3H), 3.34 (s, 3H), 3.02 (m,
8H); 13C{1H} NMR (150 MHz, CDCl3) δ 171.6, 167.3, 150.4,
144.8, 140.2, 126.6, 122.1, 112.6, 111.1, 110.0, 52.8, 40.6,
38.4, 34.5, 30.6; HRMS (EI): m/z calcd for C18H20N2O3S [M]+
344.1195, found 344.1193.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Methyl 2-(3-(dimethylamino)phenyl)-4-methyl-5-oxo-4,5,6,
7-tetrahydrothieno[3,2-b]pyridine-7-carboxylate
(6l).
Compound 6l was obtained as a brown solid (102 mg, 0.296
mmol, 61%) starting from 5j (114 mg, 0.491 mmol, 1.0
equiv.). m.p: 99-100 °C; 1H NMR (600 MHz, CDCl3) δ 7.24 (t,
J = 8.1 Hz, 1H), 6.96 (s, 1H), 6.92 (d, J = 7.8 Hz, 1H), 6.86 (s,
1H), 6.70 (dd, J = 8.4 Hz and J = 2.4 Hz, 1H), 4.02 (t, J = 7.2
Hz, 1H), 3.78 (s, 3H), 3.35 (s, 3H), 3.08-2.96 (m, 8H); 13C{1H}
NMR (150 MHz, CDCl3) δ 171.4, 167.2, 151.0, 144.9, 140.2,
134.5, 129.8, 114.2, 113.1, 112.5, 112.0, 109.5, 52.9, 40.7,
38.4, 34.4, 30.6; HRMS (EI): m/z calcd for C18H20N2O3S [M]+
344.1195, found 344.1193.
Methyl
4-methyl-5-oxo-2-(2,3,6,7-tetrahydro-1H,5H-pyr-
ido[3,2,1-ij]quinolin-9-yl)-4,5,6,7-tetrahydrothieno[3,2-b]py
ridine-7-carboxylate (6q). Compound 6q was obtained as an
orange solid (63.6 mg, 0.160 mmol, 65%) starting from 5n
(70.0 mg, 0.246 mmol, 1.0 equiv.). m.p: 135-137 °C; 1H NMR
(500 MHz, CDCl3) δ 7.00 (s, 2H), 6.77 (s, 1H), 3.98 (t, J = 7.3
Hz, 1H), 3.78 (s, 3H), 3.34 (s, 3H), 3.19 (m, 4H), 3.01 (ddd, J
= 44.0 Hz, J = 16.3 Hz and J = 7.8 Hz, 2H), 2.78 (t, J = 6.5 Hz,
4H), 2.00 (m, 4H); 13C{1H} NMR (125 MHz, CDCl3) δ 171.6,
167.3, 145.3, 143.1, 140.1, 125.0, 124.4, 121.7, 121.6, 121.1,
110.6, 109.4, 52.8, 50.1, 38.4, 34.6, 30.6, 27.8, 22.0; HRMS
(EI): m/z calcd for C22H24N2O3S [M]+ 396.1508, found
396.1504.
Methyl 2-(2-(dimethylamino)phenyl)-4-methyl-5-oxo-4,5,6,
7-tetrahydrothieno[3,2-b]pyridine-7-carboxylate
(6m).
Compound 6m was obtained as a yellow liquid (118 mg, 0.342
mmol, 76%) starting from 5k (105 mg, 0.452 mmol, 1.0
1
equiv.). H NMR (600 MHz, CDCl3) δ 7.52 (d, J = 7.8 Hz,
General Procedure for the Synthesis of KF-1 ~ KF-5, KF-
12 ~ KF-19, KF-22 ~ KF-24 (Route B)
1H), 7.24 (t, J = 7.5 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 7.12 (s,
1H), 7.06 (t, J = 7.2 Hz, 1H), 4.03 (t, J = 6.9 Hz, 1H), 3.79 (s,
3H), 3.38 (s, 3H), 3.04 (ddd, J = 7.1 Hz, J = 16.4 Hz and J =
60.2 Hz, 2H), 2.65 (s, 6H); 13C{1H} NMR (150 MHz, CDCl3)
δ 171.6, 167.2, 151.0, 140.9, 139.0, 128.6, 128.5, 128.4, 123.6,
120.5, 114.5, 113.9, 52.7, 44.4, 38.4, 34.5, 30.4; HRMS (EI):
m/z calcd for C18H20N2O3S [M]+ 344.1195, found 344.1197.
To a solution of 6a (20.2 mg, 0.0670 mmol, 1.0 equiv.) in
DMF (0.7 mL, 0.25 M), potassium carbonate (14.0 mg, 0.100
mmol, 1.5 equiv.) was added. And then, the reaction was
heated to 70 °C and stirred for 1 h. After completion of the
reaction, water (1 mL) was added. The crude was extracted
with EtOAc (1 mL) at three times. The organic layer was dried
over Na2SO4, filtered and evaporated in vacuo. The residue
was purified by flash column chromatography (Hexane/EtOAc
= 1/1, v/v) on silica to afford the product KF-1.
Methyl 4-benzyl-2-(4-(dimethylamino)phenyl)-5-oxo-4,5,6, 7-
tetrahydrothieno[3,2-b]pyridine-7-carboxylate
(6n).
Compound 6n was obtained as an orange liquid (66.3 mg,
0.158 mmol, 81%) starting from 5s (60.0 mg, 0.194 mmol, 1.0
Methyl
4-methyl-5-oxo-2-phenyl-4,5-dihydrothieno[3,2-b]
1
equiv.). H NMR (600 MHz, CDCl3) δ 7.33-7.27 (m, 6H),
pyridine-7-carboxylate (KF-1). Compound KF-1 was obtained
7.25-7.22 (m, 1H), 6.69 (s, 1H), 6.67 (d, J = 8.4 Hz, 2H), 5.19
(d, J = 15.6 Hz, 1H), 4.99 (d, J = 15.6 Hz, 1H), 4.02 (t, J = 6.6
Hz, 1H), 3.77 (s, 3H), 3.12 (ddd, J = 49.8 Hz, J = 16.2 Hz and
J = 6.6 Hz, 2H), 2.96 (s, 6H); 13C{1H} NMR (150 MHz,
CDCl3) δ 171.4, 167.4, 150.3, 144.6, 139.4, 137.0, 128.7,
127.3, 126.9, 126.5, 121.9, 112.4, 111.6, 110.3, 52.7, 46.8,
40.4, 38.4, 34.6; HRMS (EI): m/z calcd for C24H24N2O3S [M]+
420.1508, found 420.1505.
as a yellow solid (9.60 mg, 0.0320 mmol, 48%) starting from
1
6a (20.2 mg, 0.0670 mmol, 1.0 equiv.). H NMR (600 MHz,
CDCl3) δ 7.72 (d, J = 7.2 Hz, 2H), 7.46 (t, J = 7.5 Hz, 2H),
7.41 (t, J = 7.2 Hz, 1H), 7.27 (s, 1H), 7.23 (s, 1H), 4.02 (s, 3H),
3.79 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 165.1, 162.4,
151.3, 145.8, 134.1, 133.4, 129.5, 129.4, 126.4, 119.0, 115.7,
111.3, 53.3, 32.4; Data are consistent with those reported in
the literature.7a
Methyl 2-(4-(diethylamino)phenyl)-4-methyl-5-oxo-4,5,6,7-
Methyl
2-(4-methoxyphenyl)-4-methyl-5-oxo-4,5-dihydrot
tetrahydrothieno[3,2-b]pyridine-7-carboxylate
(6o).
hieno[3,2-b]pyridine-7-carboxylate (KF-2). Compound KF-2
Compound 6o was obtained as a sticky orange solid (166 mg,
0.446 mmol, 73%) starting from 5l (160 mg, 0.614 mmol, 1.0
equiv.). m.p: 62-64 °C; 1H NMR (500 MHz, CDCl3) δ 7.39 (d,
J = 8.5 Hz, 2H), 6.79 (s, 1H), 6.64 (d, J = 8.5 Hz, 2H), 3.97 (t,
J = 7.0 Hz, 1H), 3.77 (s, 3H), 3.38 (q, J = 7.2 Hz, 4H), 3.33 (s,
3H), 3.00 (ddd, J = 46.6 Hz, J = 16.3 Hz and J = 7.1 Hz, 2H),
1.18 (t, J = 7.3 Hz, 6H); 13C{1H} NMR (125 MHz, CDCl3) δ
171.5, 167.2, 147.7, 145.0, 140.1, 126.7, 120.9, 111.7, 110.7,
was obtained as a yellow solid (29.5 mg, 0.0896 mmol, 50%)
1
starting from 6b (60.0 mg, 0.181 mmol, 1.0 equiv.). H NMR
(600 MHz, CDCl3) δ 7.65 (d, J = 9.0 Hz, 2H), 7.22 (s, 1H),
7.17 (s, 1H), 6.97 (d, J = 9.0 Hz, 2H), 4.01 (s, 3H), 3.87 (s,
3H), 3.79 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 165.2,
162.5, 160.8, 151.6, 146.0, 134.1, 127.7, 126.0, 118.1, 114.8,
110.1, 55.6, 53.3, 32.4; Data are consistent with those reported
in the literature.7a
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The Journal of Organic Chemistry
equiv.). m.p: 222-224 °C; 1H NMR (600 MHz, CDCl3) δ 7.17-
Methyl 2-(3-methoxyphenyl)-4-methyl-5-oxo-4,5-dihydro
t
hieno[3,2-b]pyridine-7-carboxylate (KF-3). Compound KF-3
was obtained as a yellow solid (54.8 mg, 0.166 mmol, 65%)
starting from 6c (85.1 mg, 0.257 mmol, 1.0 equiv.). m.p: 155-
156 °C; 1H NMR (600 MHz, CDCl3) δ 7.40 (t, J = 8.1 Hz, 1H),
7.34 (d, J = 7.2 Hz, 1H), 7.29 (d, J = 4.2 Hz, 2H), 7.26-7.25
(m, 1H), 6.98 (dd, J = 8.1 Hz and J = 2.7 Hz, 1H), 4.05 (s, 3H),
3.92(s, 3H), 3.82 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ
165.1, 162.3, 160.3, 151.0, 145.7, 134.6, 134.0, 130.4, 119.0,
118.8, 115.6, 115.0, 111.8, 111.4, 55.6, 53.3, 32.3; HRMS (EI):
m/z calcd for C17H15NO4S [M]+ 329.0722, found 329.0719.
1
2
3
4
5
6
7
8
7.13 (m, 2H), 7.22 (s, 1H), 7.07 (s, 1H), 6.68 (d, J = 8.4 Hz,
1H), 4.29 (s, 4H), 3.98 (s, 3H), 3.72 (s, 3H); 13C{1H} NMR
(150 MHz, CDCl3) δ 165.0, 162.3, 151.0, 145.8, 144.9, 144.0,
133.8, 126.8, 119.6, 118.3, 118.1, 115.1, 114.9, 110.3, 64.6,
64.5, 53.2, 32.2; HRMS (EI): m/z calcd for C18H15NO5S [M]+
357.0671, found 357.0669.
Methyl
4-methyl-5-oxo-2-(3,4,5-trimethoxyphenyl)-4,5-
(KF-15).
dihydrothieno[3,2-b]pyridine-7-carboxylate
Compound KF-15 was obtained as a yellow solid (13.3 mg,
0.0342 mmol, 26%) starting from 6j (52.0 mg, 0.133 mmol,
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
Methyl
2-(2-methoxyphenyl)-4-methyl-5-oxo-4,5-dihydrot
1.0 equiv.). m.p: 205-208 °C; H NMR (600 MHz, CDCl3) δ
hieno[3,2-b]pyridine-7-carboxylate (KF-4). Compound KF-4
was obtained as a yellow solid (47.8 mg, 0.145 mmol, 49%)
starting from 6d (98.6 mg, 0.297 mmol, 1.0 equiv.). m.p: 164-
7.21 (s, 1H), 7.18 (s, 1H), 6.89 (s, 2H), 4.01 (s, 3H), 3.95 (s,
6H), 3.90 (s, 3H), 3.80 (s, 3H); 13C{1H} NMR (150 MHz,
CDCl3) δ 165.2, 162.4, 153.9, 151.4, 145.7, 139.5, 133.9,
129.0, 118.8, 115.4, 111.1, 103.8, 61.2, 56.5, 53.3, 32.4;
HRMS (EI): m/z calcd for C19H19NO6S [M]+ 389.0933, found
389.0930.
1
168 °C; H NMR (600 MHz, CDCl3) δ 7.70 (dd, J = 8.0 Hz
and J = 1.8 Hz, 1H), 7.45 (s, 1H), 7.35 (td, J = 8.0 Hz and J =
1.5 Hz, 1H), 7.17 (s, 1H), 7.05-7.01 (m, 2H), 3.98 (s, 3H),
3.97 (s, 3H), 3.75 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ
165.3, 162.5, 156.5, 147.2, 145.2, 134.1, 130.5, 128.9, 122.1,
121.3, 118.6, 116.4, 113.6, 112.0, 55.8, 53.2, 32.3; HRMS (EI):
m/z calcd for C17H15NO4S [M]+ 329.0722, found 329.0722.
Methyl
2-(4-(dimethylamino)phenyl)-4-methyl-5-oxo-4,5-
(KF-16).
dihydrothieno[3,2-b]pyridine-7-carboxylate
Compound KF-16 was obtained as an orange-red solid (19.6
mg, 0.0572 mmol, 33%) starting from 6k (60.0 mg, 0.174
1
Methyl
4-benzyl-2-(4-methoxyphenyl)-5-oxo-4,5-dihydrot
mmol, 1.0 equiv.). m.p: 178-180 °C; H NMR (600 MHz,
hieno[3,2-b]pyridine-7-carboxylate (KF-5). Compound KF-5
was obtained as a yellow solid (17.8 mg, 0.0439 mmol, 42%)
starting from 6e (42.3 mg, 0.104 mmol, 1.0 equiv.). m.p: 143-
CDCl3) δ 7.60 (d, J = 8.4 Hz, 2H), 7.14 (s, 1H), 7.10 (s, 1H),
6.73 (d, J = 8.4 Hz, 2H), 4.00 (s, 3H), 3.77 (s, 3H), 3.04 (s,
6H); 13C{1H} NMR (150 MHz, CDCl3) δ 165.4, 162.5, 152.6,
151.2, 146.4, 133.9, 127.3, 121.1, 117.2, 114.2, 112.3, 108.5,
53.2, 40.4, 32.3; HRMS (EI): m/z calcd for C18H18N2O3S [M]+
342.1038, found 342.1037.
1
145 °C; H NMR (600 MHz, CDCl3) δ 7.54 (dd, J = 6.9 Hz
and J = 2.1 Hz, 2H), 7.32-7.26 (m, 6H), 7.06 (s, 1H), 6.93 (dd,
J = 6.6 Hz and J = 1.8 Hz, 2H), 5.52 (s, 2H), 4.02 (s, 3H), 3.84
(s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 165.2, 162.4,
160.8, 151.4, 145.6, 135.9, 134.4, 129.1, 127.9, 127.7, 127.2,
126.0, 118.4, 115.4, 114.7, 110.7, 55.6, 53.3, 48.7; HRMS (EI):
m/z calcd for C23H19NO4S [M]+ 405.1035, found 405.1032.
Methyl
2-(3-(dimethylamino)phenyl)-4-methyl-5-oxo-4,5-
(KF-17).
dihydrothieno[3,2-b]pyridine-7-carboxylate
Compound KF-17 was obtained as a yellow solid (22.0 mg,
0.0642 mmol, 27%) starting from 6l (81.2 mg, 0.236 mmol,
1
Methyl 4-methyl-5-oxo-2-(4-phenoxyphenyl)-4,5-dihydroth
ieno[3,2-b]pyridine-7-carboxylate (KF-12). Compound KF-
12 was obtained as a yellow solid (15.0 mg, 0.0383 mmol,
63%) starting from 6g (24.2 mg, 0.0615 mmol, 1.0 equiv.).
m.p: 178-180 °C; 1H NMR (600 MHz, CDCl3) δ 7.67 (dd, J =
8.4 Hz and J = 3.0 Hz, 2H), 7.38 (t, J = 8.1 Hz, 2H), 7.20-7.16
(m, 3H), 7.08-7.05 (m, 4H), 4.01 (s, 3H), 3.78 (s, 3H); 13C{1H}
NMR (150 MHz, CDCl3) δ 165.1, 162.4, 158.9, 156.4, 150.9,
145.9, 134.1, 130.1, 128.2, 127.9, 124.2, 119.7, 119.0, 118.6,
115.4, 110.7, 53.3, 32.4; HRMS (EI): m/z calcd for
C22H17NO4S [M]+ 391.0878, found 391.0875.
1.0 equiv.). m.p: 170-172 °C; H NMR (600 MHz, CDCl3) δ
7.29-7.26 (m, 1H), 7.19 (s, 1H), 7.16 (s, 1H), 7.02 (d, J = 7.2
Hz, 1H), 6.94 (s, 1H), 6.74 (d, J = 8.4 Hz, 1H), 3.99 (s, 3H),
3.75 (s, 3H), 3.01 (s, 6H); 13C{1H} NMR (150 MHz, CDCl3) δ
165.1, 162.3, 152.4, 151.0, 145.7, 134.0, 133.9, 129.9, 118.5,
115.3, 114.5, 113.5, 111.0, 109.8, 53.2, 40.6, 32.3; HRMS (EI):
m/z calcd for C18H18N2O3S [M]+ 342.1038 found 342.1039.
Methyl
2-(2-(dimethylamino)phenyl)-4-methyl-5-oxo-4,5-
(KF-18).
dihydrothieno[3,2-b]pyridine-7-carboxylate
Compound KF-18 was obtained as a yellow solid (28.3 mg,
0.0826 mmol, 32%) starting from 6m (88.0 mg, 0.255 mmol,
1
Methyl 2-(benzo[d][1,3]dioxol-5-yl)-4-methyl-5-oxo-4,5-dih
ydrothieno[3,2-b]pyridine-7-carboxylate (KF-13). Compound
KF-13 was obtained as a yellow solid (13.0 mg, 0.0379 mmol,
40%) starting from 6h (32.8 mg, 0.0950 mmol, 1.0 equiv.).
m.p: 183-184 °C; 1H NMR (600 MHz, CDCl3) δ 7.22 (dd, J =
7.8 Hz and J = 1.8 Hz, 1H), 7.20 (s, 1H), 7.16 (d, J = 1.8 Hz,
1H), 7.13 (s, 1H), 6.87 (d, J = 7.8 Hz, 1H), 6.04 (s, 2H), 4.01
(s, 3H), 3.77 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ
165.1, 162.4, 151.3, 148.9, 148.6, 145.8, 134.0, 127.6, 120.6,
118.5, 115.1, 110.6, 109.1, 106.7, 101.8, 53.3, 32.3; HRMS
(EI): m/z calcd for C17H13NO5S [M]+ 343.0514, found
343.0513.
1.0 equiv.). m.p: 120-122 °C; H NMR (600 MHz, CDCl3) δ
7.60 (d, J = 7.8 Hz, 1H), 7.41 (s, 1H), 7.32 (t, J = 7.8 Hz, 1H),
7.21-7.20 (m, 2H), 7.11 (t, J = 7.8 Hz, 1H), 4.00 (s, 3H), 3.78
(s, 3H), 2.69 (s, 6H); 13C{1H} NMR (150 MHz, CDCl3) δ
165.3, 162.4, 151.9, 149.6, 145.0, 134.3, 129.9, 129.6, 127.9,
123.5, 120.4, 118.6, 117.2, 112.8, 53.1, 44.4, 32.2; HRMS (EI):
m/z calcd for C18H18N2O3S [M]+ 342.1038, found 342.1041.
Methyl
4-benzyl-2-(4-(dimethylamino)phenyl)-5-oxo-4,5-
(KF-19).
dihydrothieno[3,2-b]pyridine-7-carboxylate
Compound KF-19 was obtained as a red solid (18.4 mg,
0.0440 mmol, 37%) starting from 6n (50.0 mg, 0.119 mmol,
1
1.0 equiv.). m.p: 187-189 °C; H NMR (600 MHz, CDCl3) δ
Methyl 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-methyl-5-
oxo-4,5-dihydrothieno[3,2-b]pyridine-7-carboxylate (KF-14).
Compound KF-14 was obtained as a yellow solid (58.4 mg,
0.163 mmol, 50%) starting from 6i (116 mg, 0.323 mmol, 1.0
7.48 (d, J = 9.0 Hz, 2H), 7.32-7.28 (m, 4H), 7.26-7.25 (m, 1H),
7.21 (s, 1H), 7.00 (s, 1H), 6.69 (d, J = 8.4 Hz, 2H), 5.50 (s,
2H), 4.01 (s, 3H), 3.01 (s, 6H); 13C{1H} NMR (150 MHz,
CDCl3) δ 165.3, 162.5, 152.5, 151.0, 146.0, 136.0, 134.3,
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The Journal of Organic Chemistry
Page 12 of 15
129.0, 127.8, 127.3, 127.2, 117.3, 114.6, 112.3, 109.1, 53.2,
0.3283 mmol, 1.2 equiv.), BOP (145 mg, 0.3283 mmol, 1.2
48.6, 40.4; HRMS (EI): m/z calcd for C24H22N2O3S [M]+
equiv.) and DIPEA (119 μL, 0.684 mmol, 2.5 equiv.) were
added. The reaction was stirred at room temperature for 1 h.
For quenching the reaction, water was added. The mixture was
extracted with EtOAc at three times (4 mL). The organic layer
was dried over Na2SO4 and concentrated in vacuo. The crude
was used without further purification. To a solution of crude
(56.4 mg, 0.1963 mmol, 1.0 equiv.) in DCM (1.5 mL, 0.13 M),
N-bromosuccinimide (42 mg, 0.2355 mmol, 1.2 equiv.) and p-
toluenesulfonic acid (3.7 mg, 0.0196 mmol, 0.1 equiv.) were
added. The reaction mixture was stirred at room temperature
for 5 h. After completion of the reaction, water was added.
The mixture was extracted with DCM at three times (5 mL).
The organic layer was dried over Na2SO4 and concentrated in
vacuo. The crude was purified by flash column
chromatography to obtain the product KF-7 as a white solid
(15.9 mg, 0.0557 mmol, 22%, two steps). m.p: 180-182 °C; 1H
NMR (600 MHz, CDCl3) δ 7.58 (dd, J = 6.6 Hz and J = 2.4
Hz, 2H), 7.12 (s, 1H), 6.95 (dd, J = 6.6 Hz and J = 1.8 Hz, 2H),
6.37 (d, J = 1.2 Hz, 1H), 3.85 (s, 3H), 3.69 (s, 3H), 2.35 (d, J =
1.2 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 162.8, 160.5,
147.5, 144.0, 127.5, 126.2, 119.3, 115.6, 114.7, 111.2, 55.6,
31.8, 19.8; HRMS (EI): m/z calcd for C16H15NO2S [M]+
285.0824, found 285.0826.
1
2
3
4
5
6
7
8
9
418.1351, found 418.1348.
Methyl
2-(4-(diethylamino)phenyl)-4-methyl-5-oxo-4,5-
(KF-22).
dihydrothieno[3,2-b]pyridine-7-carboxylate
Compound KF-22 was obtained as an orange solid (29.4 mg,
0.0794 mmol, 53%) starting from 6o (55.8 mg, 0.150 mmol,
1.0 equiv.). m.p: 146-148 °C; H NMR (600 MHz, CDCl3) δ
7.53 (d, J = 9.0 Hz, 2H), 7.08 (s, 1H), 7.02 (s, 1H), 6.66 (d, J =
8.4 Hz, 2H), 3.97 (s, 3H), 3.72 (s, 3H), 3.40 (q, J = 7.2 Hz,
4H), 1.20 (t, J = 7.2 Hz, 6H); 13C{1H} NMR (150 MHz,
CDCl3) δ 165.3, 162.5, 151.7, 148.6, 146.4, 133.8, 127.5,
120.0, 116.8, 114.0, 111.6, 108.0, 53.1, 44.5, 32.2, 12.7;
HRMS (EI): m/z calcd for C20H22N2O3S [M]+ 370.1351, found
370.1354.
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Methyl
4-methyl-2-(4-(4-methylpiperazin-1-yl)phenyl)-5-o
xo-4,5-dihydrothieno[3,2-b]pyridine-7-carboxylate (KF-23).
Compound KF-23 was obtained as a dark red solid (10.0 mg,
0.0252 mmol, 41%) starting from 6p (24.6 mg, 0.0616 mmol,
1
1.0 equiv.). m.p: 135-136 °C; H NMR (600 MHz, CDCl3) δ
7.60 (d, J = 10.2 Hz, 2H), 7.15 (s, 1H), 7.12 (s, 1H), 6.93 (d, J
= 10.8 Hz, 2H), 3.99 (s, 3H), 3.76 (s, 3H), 3.32 (t, J = 5.7 Hz,
4H), 2.62 (t, J = 5.7 Hz, 4H), 2.38 (s, 3H); 13C{1H} NMR (150
MHz, CDCl3) δ 165.3, 162.5, 151.9, 151.8, 146.2, 133.9,
127.3, 124.0, 117.8, 115.6, 114.6, 109.4, 54.9, 53.2, 48.1, 46.2,
32.3; HRMS (EI): m/z calcd for C21H23N3O3S [M]+ 397.1460
found 397.1459.
2-(4-Methoxyphenyl)-4-methyl-7-phenylthieno[3,2-b]pyridi
n-5(4H)-one (KF-8). To a solution of 5b (40 mg, 0.1824 mmol,
1.0 equiv.) in DMF (1.8 mL, 0.1 M), trans-cinnamic acid
(32.4 mg, 0.2189 mmol, 1.2 equiv.), BOP (97 mg, 0.2189
mmol, 1.2 equiv.) and DIPEA (79 μL, 0.456 mmol, 2.5 equiv.)
were added. The reaction was stirred at room temperature for 1
h. For quenching the reaction, water was added. The mixture
was extracted with EtOAc at three times (4 mL). The organic
layer was dried over Na2SO4 and concentrated in vacuo. The
crude was used without further purification. To a solution of
crude (68.8 mg, 0.1969 mmol, 1.0 equiv.) in DCM (2 mL, 0.1
M), N-bromosuccinimide (42 mg, 0.2363 mmol, 1.2 equiv.)
and p-toluenesulfonic acid (3.7 mg, 0.0197 mmol, 0.1 equiv.)
were added. The reaction mixture was stirred at room
temperature for 5 h. After completion of the reaction, water
was added. The mixture was extracted with DCM at three
times (5 mL). The organic layer was dried over Na2SO4 and
concentrated in vacuo. The crude was purified by flash column
chromatography to obtain the product KF-8 as a white solid
(16.4 mg, 0.0472 mmol, 15%, two steps). m.p: 165-167 °C; 1H
NMR (600 MHz, CDCl3) δ 7.68-7.67 (m, 2H), 7.58 (d, J = 8.4
Hz, 2H), 7.52-7.49 (m, 3H), 7.19 (s, 1H), 6.93 (d, J = 8.4 Hz,
2H), 6.60 (s, 1H), 3.85 (s, 3H), 3.77 (s, 3H); 13C{1H} NMR
(150 MHz, CDCl3) δ 162.8, 160.6, 148.8, 147.1, 145.0, 137.5,
129.7, 129.1, 127.8, 127.5, 126.0, 117.4, 114.9, 114.7, 111.2,
55.6, 31.9; HRMS (EI): m/z calcd for C21H17NO2S [M]+
347.0980, found 347.0977.
Methyl
4-methyl-5-oxo-2-(2,3,6,7-tetrahydro-1H,5H-pyr-
ido[3,2,1-ij]quinolin-9-yl)-4,5-dihydrothieno[3,2-b]pyridine-
7-carboxylate (KF-24). Compound KF-24 was obtained as an
orange solid (18.0 mg, 0.0456 mmol, 36%) starting from 6q
(50.0 mg, 0.126 mmol, 1.0 equiv.). m.p: 176-177 °C; 1H NMR
(600 MHz, CDCl3) δ 7.16 (s, 2H), 7.10 (s, 1H), 7.03 (s, 1H),
3.99 (s, 3H), 3.76 (s, 3H), 3.24-3.22 (m, 4H), 2.89 (t, J = 6.6
Hz, 4H), 2.10-2.08 (m, 4H);13C{1H} NMR (150 MHz, CDCl3)
δ 165.4, 162.6, 153.2, 146.5, 144.2, 133.9, 125.0, 121.6, 120.0,
116.6, 114.0, 107.8, 53.1, 50.0, 32.3, 27.9, 21.8; HRMS (EI):
m/z calcd for C22H22N2O3S [M]+ 394.1351, found 394.1347.
Procedures for the Synthesis of KF-6 ~ KF-8 (Route C)
2-(4-Methoxyphenyl)-4-methylthieno[3,2-b]pyridin-5(4H)-
one (KF-6). To a solution of KF-6 (37.9 mg, 0.139 mmol, 1.0
equiv.) in DCM (1.5 mL, 0.25 M), N-bromosuccinimide (28.0
mg, 0.193 mmol, 1.1 equiv.) was added at 0 °C. The reaction
was warmed up to room temperature and stirred for 18 h. After
completion of the reaction, water (2 mL) was added. The
crude was extracted with DCM (2 mL) at three times. The
organic layer was dried over Na2SO4, filtered and evaporated
in vacuo. The residue was purified by flash column
chromatography (Hexane/EtOAc = 1/2, v/v) on silica to afford
the product KF-6 as a white solid (16.9 mg, 0.0623 mmol,
45%). m.p: 158-160 °C; 1H NMR (600 MHz, CDCl3) δ 7.63 (d,
J = 9.0 Hz, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.13 (s, 1H), 6.96 (d,
J = 8.4 Hz, 2H), 6.55 (d, J = 9.0 Hz, 1H), 3.86 (s, 3H), 3.74 (s,
3H); 13C{1H} NMR (150 MHz, CDCl3) δ 162.4, 160.6, 148.9,
145.0, 133.1, 127.6, 126.0, 117.3, 116.6, 114.7, 110.9, 55.6,
32.0; HRMS (EI): m/z calcd for C15H13NO2S [M]+ 271.0667,
found 271.0666.
General Procedure for the Synthesis of KF-9 ~ KF-11, KF-
20 ~ KF-21, KF-25 ~ KF-27 (Route A)
To a solution of 5b (30.0 mg, 0.137 mmol, 1.0 equiv.) in DMF
(1.4 ml), 2-oxo-4-pentenoic acid (18.7 mg, 0.164 mmol, 1.2
equiv.), BOP (77 mg, 0.164 mmol, 1.2 equiv.) and DIPEA (61
μL, 0.343 mmol, 2.5 equiv.) were added. The reaction was
stirred at room temperature for 0.5 h. After completion of the
reaction, water (1 mL) was added. The crude was extracted
with EtOAc (1 mL) at three times. The organic layer was dried
over Na2SO4, filtered and evaporated in vacuo. The residue
2-(4-Methoxyphenyl)-4,7-dimethylthieno[3,2-b]pyridin-5(4 H)-
one (KF-7). To a solution of 5b (60 mg, 0.2736 mmol, 1.0
equiv.) in DMF (2.0 mL, 0.14 M), crotonic acid (26.6 mg,
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The Journal of Organic Chemistry
was purified by flash column chromatography (Hexane/EtOAc 165.5, 153.0, 151.1, 146.2, 139.9, 136.1, 136.0, 133.6, 130.1,
1
2
3
4
5
6
7
8
= 1/1, v/v) on silica to afford the product KF-9.
129.0, 128.8, 127.8, 127.3, 127.2, 121.1, 119.1, 114.3, 112.3,
109.0, 48.7, 40.4; HRMS (EI): m/z calcd for C29H24N2O2S
[M]+ 464.1558, found 464.1562.
7-Acetyl-2-(4-methoxyphenyl)-4-methylthieno[3,2-b]pyridi n-
5(4H)-one (KF-9). Compound KF-9 was obtained as a yellow
solid (9.6 mg, 0.0320 mmol, 48%) starting from 5b (30.0 mg,
0.137 mmol, 1.0 equiv.) and 2-oxo-4-pentenoic acid (18.7 mg,
7-Benzoyl-2-(4-(diphenylamino)phenyl)-4-methylthieno[3,2 -
b]pyridin-5(4H)-one (KF-25). Compound KF-25 was
obtained as a red solid (26.9 mg, 0.0525 mmol, 47%) starting
from 5o (40.0 mg, 0.112 mmol, 1.0 equiv.) and 3-
benzoylacrylic acid (23.7 mg, 0.134 mmol, 1.2 equiv.). m.p:
1
0.164 mmol, 1.2 equiv.). m.p: 221-222 °C; H NMR (600
MHz, CDCl3) δ 7.64 (d, J = 8.4 Hz, 2H), 7.13 (s, 1H), 7.09 (s,
1H), 6.96 (d, J = 9.0 Hz, 2H), 3.86 (s, 3H), 3.78 (s, 3H), 2.65
(s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 197.9, 163.0,
160.8, 152.8, 146.1, 139.1, 127.7, 126.1, 118.3, 114.7, 113.1,
109.6, 55.6, 32.4, 26.3; HRMS (EI): m/z calcd for C17H15NO3S
[M]+ 313.0773, found 313.0772.
1
125-128 °C; H NMR (600 MHz, CDCl3) δ 7.86 (dd, J = 8.4
9
Hz and J = 0.6 Hz, 2H), 7.65-7.27 (m, 1H), 7.56 (dd, J = 6.6
Hz and J = 2.4 Hz, 2H), 7.52 (t, J = 7.8 Hz, 2H), 7.31-7.29 (m,
4H), 7.20 (s, 1H), 7.16-7.14 (m, 4H), 7.11-7.07 (m, 4H), 6.85
(s, 1H), 3.81 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ
194.7, 162.4, 152.2, 149.3, 147.1, 146.3, 139.6, 136.0, 133.6,
130.1, 129.6, 129.0, 128.8, 127.2, 126.4, 125.3, 124.0, 122.5,
119.5, 115.1, 109.8, 32.5; HRMS (EI): m/z calcd for
C33H24N2O2S [M]+ 512.1558, found 512.1556.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7-Acetyl-4-benzyl-2-(4-methoxyphenyl)thieno[3,2-b]pyridi n-
5(4H)-one (KF-10). Compound KF-10 was obtained as a
green solid (20.4 mg, 0.0524 mmol, 26%) starting from 5r
(60.0 mg, 0.203 mmol, 1.0 equiv.) and (E)-4-oxopent-2-enoic
1
acid (27.8 mg, 0.244 mmol, 1.2 equiv.). m.p: 202-204 °C; H
NMR (600 MHz, CDCl3) δ 7.54 (dd, J = 6.6 Hz and J = 1.8
Hz, 2H), 7.33-7.24 (m, 5H), 7.17 (s, 1H), 7.05 (s, 1H), 6.92
(dd, J = 6.9 Hz and J = 2.1 Hz, 2H), 5.52 (s, 2H), 3.83 (s, 3H),
2.67 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 197.9, 163.0,
160.7, 152.8, 145.8, 139.4, 135.8, 129.0, 127.9, 127.7, 127.1,
126.1, 118.5, 114.6, 113.5, 110.1, 55.5, 48.7, 26.4; Data are
consistent with those reported in the literature.7a
7-Benzoyl-4-methyl-2-(4-(trifluoromethoxy)phenyl)thieno
[3,2-b]pyridin-5(4H)-one (KF-26). Compound KF-26 was
obtained as a green solid (22.0 mg, 0.0512 mmol, 35%)
starting from 5p (40.0 mg, 0.146 mmol, 1.0 equiv.) and 3-
benzoylacrylic acid (30.9 mg, 0.175 mmol, 1.2 equiv.). m.p:
1
220-221 °C; H NMR (600 MHz, CDCl3) δ 7.83 (dd, J = 7.2
Hz and J = 1.2 Hz, 2H), 7.72 (dd, J = 8.7 Hz and J = 0.9 Hz,
2H), 7.63 (td, J = 7.8 Hz and J = 1.2 Hz, 1H), 7.50 (t, J = 7.5
Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H), 7.23 (s, 1H), 6.89 (s, 1H),
3.80 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 194.6, 162.4,
150.0, 149.9, 145.9, 139.4, 135.9, 133.7, 132.1, 130.0, 128.9,
127.8, 121.7, 121.3, 120.5 (d, JC-F = 256.2 Hz), 115.6, 111.7,
32.4; 19F{1H} NMR (600 MHz, CDCl3) δ -57.8; HRMS (EI):
m/z calcd for C22H14F3NO3S [M]+ 429.0646, found 429.0649.
7-Benzoyl-4-benzyl-2-(4-methoxyphenyl)thieno[3,2-b]pyrid
in-5(4H)-one (KF-11). Compound KF-11 was obtained as an
orange solid (23.2 mg, 0.0514 mmol, 38%) starting from 5r
(40.0 mg, 0.135 mmol, 1.0 equiv.) and 3-benzoylacrylic acid
(28.6 mg, 0.163 mmol, 1.2 equiv.). m.p: 148-150 °C; 1H NMR
(600 MHz, CDCl3) δ 7.89 (dd, J = 8.1 Hz and J = 1.5 Hz, 2H),
7.65 (tt, J = 7.5 Hz and J = 1.2 Hz, 1H), 7.55-7.52 (m, 4H),
7.34 (d, J = 4.8 Hz, 4H), 6.92 (quin, J = 4.2 Hz, 1H), 7.11 (s,
1H), 6.93-6.91 (m, 3H), 5.54 (s, 2H), 3.83 (s, 3H); 13C{1H}
NMR (150 MHz, CDCl3) δ 194.7, 162.4, 160.7, 151.8, 145.8,
139.9, 135.94, 135.9, 133.6, 130.1, 129.0, 128.8, 127.9, 127.7,
127.2, 126.0, 120.1, 115.0, 114.7, 110.6, 55.5, 48.7; HRMS
(EI): m/z calcd for C28H21NO3S [M]+ 451.1242, found
451.1245.
7-Benzoyl-4-methyl-2-(4-(trifluoromethyl)phenyl)thieno[3, 2-
b]pyridin-5(4H)-one (KF-27). Compound KF-27 was
obtained as a green solid (18.8 mg, 0.0455 mmol, 29%)
starting from 5q (40.0 mg, 0.155 mmol, 1.0 emquiv.) and 3-
benzoylacrylic acid (32.8 mg, 0.186 mmol, 1.2 equiv.). m.p:
236-238 °C; 1H NMR (600 MHz, CDCl3) δ 7.85 (dd, J = 20.1
Hz and J = 7.5 Hz, 4H), 7.72 (d, J = 8.4 Hz, 2H), 7.67 (t, J =
7.2 Hz, 1H), 7.54 (t, J = 7.8 Hz, 2H), 7.38 (s, 1H), 6.94 (s, 1H),
3.85 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 194.5, 162.3,
149.4, 145.7, 139.2, 136.7, 135.8, 133.7, 131.1 (q, JC-F = 33.2
7-Acetyl-2-(4-(dimethylamino)phenyl)-4-methylthieno[3,2-
b]pyridin-5(4H)-one (KF-20). Compound KF-20 was
obtained as a red solid (15.0 mg, 0.0460 mmol, 35%) starting
from 5i (31.0 mg, 0.133 mmol, 1.0 equiv.) and (E)-4-oxopent-
2-enoic acid (28.1 mg, 0.160 mmol, 1.2 equiv.). m.p: 196-
Hz), 130.0, 128.9, 126.5, 126.34-126.31 (m), 124.0 (q, JC-F
=
270.5 Hz), 121.7, 116.0, 112.3, 32.3; 19F{1H} NMR (600 MHz,
CDCl3) δ -62.8; HRMS (EI): m/z calcd for C22H14F3NO2S [M]+
413.0697, found 413.0695.
1
198 °C; H NMR (600 MHz, CDCl3) δ 7.60 (d, J = 8.4 Hz,
2H), 7.08 (s, 1H), 7.03 (s, 1H), 6.73 (d, J = 8.4 Hz, 2H), 3.78
(s, 3H), 3.03 (s, 6H), 2.64 (s, 3H); 13C{1H} NMR (150 MHz,
CDCl3) δ 198.0, 163.1, 154.0, 151.1, 146.5, 139.0, 127.3,
121.3, 117.4, 112.4, 108.0, 40.4, 32.4, 26.4; HRMS (EI): m/z
calcd for C18H18N2O2S [M]+ 326.1089, found 326.1088.
4-Benzyl-2-(4-methoxyphenyl)-5-oxo-4,5-dihydrothieno[3,2 -
b]pyridine-7-carboxylic acid (KF-28). To a solution of KF-2
(26.2 mg, 0.0646 mmol, 1.0 equiv.) in EtOH (2 mL), 1 N
KOH (0.32 mL) was added. The reaction was heated to 70 °C
for 1 h. After completion of the reaction, the solvent was
evaporated and acidified by 1 N HCl (2 mL). The crude was
extracted with EtOAc (3 mL) at 5 times, dried over Na2SO4,
filtered and evaporated in vacuo. The product was obtained as
a yellow solid (19.8 mg, 0.0506 mmol, 78%). m.p: 246-248 °C;
1H NMR (600 MHz, DMSO-d6) δ 7.71 (d, J = 9.0 Hz, 2H),
7.68 (s, 1H), 7.33-7.30 (m, 4H), 7.26-7.23 (m, 1H), 7.02 (d, J
= 9.0 Hz, 2H), 6.95 (s, 1H), 5.51 (s, 2H), 3.80 (3H); 13C{1H}
NMR (150 MHz, DMSO-d6) δ 165.5, 161.3, 160.2, 149.7,
145.6, 136.7, 135.5, 128.6, 127.34, 127.30, 127.2, 125.3,
7-Benzoyl-4-benzyl-2-(4-(dimethylamino)phenyl)thieno[3,2-
b]pyridin-5(4H)-one (KF-21). Compound KF-21 was
obtained as a red solid (25.0 mg, 0.0538 mmol, 41%) starting
from 5s (40.0 mg, 0.130 mmol, 1.0 equiv.) and 3-
benzoylacrylic acid (27.4 mg, 0.156 mmol, 1.2 equiv.). m.p:
1
216-218 °C; H NMR (600 MHz, CDCl3) δ 7.91 (dd, J = 8.4
Hz and J = 1.8 Hz, 2H), 7.64 (tt, J = 7.5 Hz and J =1.3 Hz,
1H), 7.54-7.49 (m, 4H), 7.35-7.33 (m, 4H), 7.27-7.26 (m, 1H),
7.05 (s, 1H), 6.85 (s, 1H), 6.69 (d, J = 9.0 Hz, 2H), 5.54 (s,
2H), 3.01 (s, 6H); 13C{1H} NMR (150 MHz, CDCl3) δ 194.9,
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(4) Wang, B.; Anslyn, E. V., Chemosensors: Principles, Strategies,
and Applications, Wiley: 2011.
117.2, 114.7, 113.9, 111.7, 55.4, 47.4; HRMS (FAB): m/z
calcd for C22H18NO4S [M+H]+ 392.0957, found 392.0954.
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Intracellular Fluorescent Sensors. ACS Sens. 2016, 1, 328–333. (b)
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4601.
2-(4-(Diethylamino)phenyl)-4-methyl-5-oxo-4,5-dihydrothi
eno[3,2-b]pyridine-7-carboxylic acid (KF-29). To a solution
of KF-22 (22.4 mg, 0.0605 mmol, 1.0 equiv.) in EtOH (2.0
mL), 1 N KOH (0.3 mL) was added. The reaction was heated
to 70 °C for 1 h. After completion of the reaction, the solvent
was evaporated and acidified by 1 N HCl (2 mL). The crude
was extracted with EtOAc (3 mL) at 5 times, dried over
Na2SO4, filtered and evaporated in vacuo. The product was
obtained as an orange solid (13.8 mg, 0.0387 mmol, 64%).
m.p: 257-258 °C; 1H NMR (500 MHz, DMSO-d6) δ 7.63 (d, J
= 8.5 Hz, 2H), 7.56 (s, 1H), 6.79 (s, 1H), 6.73 (d, J = 9.0 Hz,
2H), 3.67 (s, 3H), 3.42-3.37 (m, 4H), 1.19 (t, J = 7.0 Hz, 6H);
13C{1H} NMR (150 MHz, DMSO-d6) δ 165.7, 161.3, 151.2,
148.2, 146.5, 127.2, 119.4, 115.5, 112.4, 111.4, 109.4, 43.7,
32.0, 12.5; HRMS (FAB): m/z calcd for C19H21N2O3S [M+H]+
357.1273, found 357.1276.
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Jones, D. S.; Walter, M. G. Thiazolothiazole Fluorophores Exhibiting
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State Intramolecular Proton Transfer by an Yttrium Triflate-
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Iwachi, T.; Someya, S.; Tateno, K.; Kawai, H.; Saito, T.; Kanyiva, K. S.;
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Polyaza[7]helicenes with High Fluorescence and CPL Efficiency.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS
Publications
website
at
DOI:xxxxxxxxxx.
1
Rainbow
Fluorophores
Consisting
of
1,4-Bis(2-
Photophysical properties of fluorophores, H, 13C NMR and
phenylethynyl)benzene Core Skeleton: Design, Synthesis, and Light-
Emitting Characteristics. J. Phys. Chem. A 2015, 119, 8630–8642. (g)
Janiga, A.; Krzeszewski, M.; Gryko, D. T. Diindolo[2,3-b:2',3'-
f]pyrrolo[3,2-b]pyrroles as Electron-Rich, Ladder-Type Fluorophores:
Synthesis and Optical Properties. Chem. Asian J. 2015, 10, 212–218. (h)
Zhao, D.; Wang, W.; Yang, F.; Lan, J.; Yang, L.; Gao, G.; You, J.
Copper-Catalyzed Direct C Arylation of Heterocycles with Aryl
Bromides: Discovery of Fluorescent Core Frameworks. Angew.
Chem., Int. Ed. 2009, 121, 3346-3350. (i) Kim, E.; Koh, M.; Lim, B. J.;
Park, S. B. Emission Wavelength Prediction of a Full-Color-Tunable
HRMS spectral data (PDF).
AUTHOR INFORMATION
Corresponding Author
*
jslee@kiost.ac.kr
ORCID
Jong Seok Lee: 0000-0002-3892-3439
Fluorescent
Core
Skeleton,
9-Aryl-1,2-dihydropyrrolo[3,4-
b]indolizin-3-one. J. Am. Chem. Soc. 2011, 133, 6642–6649.
(7) (a) Lee, J. S.; Kim, K. Reactions of 3-methylamino-5-
phenylthiophene with α,β-unsaturated esters and α,β-unsaturated
nitriles. J. Heterocycl. Chem.2000, 37, 363–372. (b) Thomae, D.;
Kirsch, G.; Seck, P.; Kaminski, T. One-pot synthesis of 7-
hydroxythieno[3,2-b]pyridin-5(4H)-ones. Synthesis 2007, 2153–2156.
(c) Acharya, A.; Gautam, V.; Ila, H. Synthesis of thieno-fused five-
and six-membered nitrogen and oxygen heterocycles via
intramolecular heteroannulation of 4,5-substituted 3-amino or 3-
hydroxy 2-functionalized thiophenes. J. Org. Chem. 2017, 82, 7920–
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Notes
The authors declare financial interests. D.S., B.M., S.P., H.L.,
J.L, Y.L, H.J.S., and J.S.L. have filed patent applications whose
value may be affected by this publication.
ACKNOWLEDGMENT
This work was supported by KIOST (PE99612), Republic of
Korea.
(8) Dormoy, J.-R.; Castro, B.; Rabanal, F.; Giralt, E. Benzotriazol-1-
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