Synthesis of 2,3-dihydrothieno(2,3-b)quinolines and thieno(2,3-b)-quinolines via an unexpected domino aza-MBH/alkylation/aldol reaction

Article abstract of DOI:10.1021/acs.joc.5b02369

An efficient, mild, and convenient method for the preparation of 2,3-dihydrothieno(2,3-b)quinolines and thieno(2,3-b)-quinolines via an unexpected domino aza-Morita-Baylis-Hillman/alkylation/aldol reaction has been developed. The plausible mechanisms for the unexpected reaction are also given.

Full text of DOI:10.1021/acs.joc.5b02369

Note
pubs.acs.org/joc
Synthesis of 2,3-Dihydrothieno(2,3‑b)quinolines and Thieno(2,3‑b)-
quinolines via an Unexpected Domino Aza-MBH/Alkylation/Aldol
Reaction
Pei-Shun Wei, Meng-Xue Wang, Dong-Cheng Xu, and Jian-Wu Xie*
Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Department of Chemistry and Life Science, Zhejiang
Normal University, Jinhua 321004, P. R. China
S
* Supporting Information
ABSTRACT: An efficient, mild, and convenient method for
the preparation of 2,3-dihydrothieno(2,3-b)quinolines and
thieno(2,3-b)-quinolines via an unexpected domino aza-
Morita−Baylis−Hillman/alkylation/aldol reaction has been
developed. The plausible mechanisms for the unexpected
reaction are also given.
Scheme 1. Aza-Morita−Baylis−Hillman (AMBH) Reaction
eveloping novel synthetic methods that require a
minimum number of operations for the construction of
D
new analogues of bioactive heterocyclic compounds represents
a major challenge in synthetic organic and medicinal
chemistries. Quinoline derivatives are unique nitrogen-contain-
ing heterocycles that have attracted particular attention due to
their special place as building blocks in natural products,
pharmaceutical agents, and materials.1−3 Quinoline derivatives
have also been used as organocatalysts for asymmetric
synthesis.4 Thus, a variety of methods are known in the
literature for the synthesis of these interesting scaffolds, which
compounds, which are widely used for the synthesis of
biologically active compounds, medicinal reagents, and natural
products.12 The AMBH reaction is often catalyzed by Lewis
bases, such as a tertiary amine or tertiary phosphine (Scheme
1), and only a few examples of the use of chiral secondary
amines for this reaction have been reported.13 In this study, we
report an unexpected domino AMBH/alkylation/aldol reaction
of o-isothiocyanato-(E)-cinnamaldehydes with α-halocarbonyl
compounds, catalyzed by commercially available, low-cost
secondary amine L-proline, and demonstrate the direct
application of this reaction in the syntheses of 2,3-
dihydrothieno(2,3-b)quinolines and thieno(2,3-b)quinolines.
Recently, we demonstrated that α-halocarbonyl and 2-halo-
1,3-dicarbonyl compounds are readily available and attractive
precursors for the construction of heterocycles via domino
reactions.14 We envisioned that multifunctionalized quinoline
derivative Iaa would be obtained by the domino reaction of
diethyl α-bromomalonate 2a with o-isothiocyanato-(E)-
cinnamaldehyde 1a, as outlined in Scheme 2.
To explore the domino reaction, o-isothiocyanato-(E)-
cinnamaldehyde (1a) and diethyl α-bromomalonate (2a)
were first chosen for the initial screening. The model reaction
was carried out in the presence of NaHCO3 in THF at room
temperature for 24 h (Table 1, entry 1). However, the
inorganic base was inert in this reaction. A similar result was
obtained in the presence of other inorganic bases, such as
Na2CO3 (entry 2). Subsequently, a series of organic bases, such
include named reactions such as Friedlander,5 Combes,6 and
̈
Conrad−Limpach−Knorr syntheses.7 Quinoline derivatives are
often obtained via condensation, Michael addition, or
nucleophilic substitution in these named reactions. However,
these methods usually lack tolerated functional groups.
Recently, many new metal-catalyzed protocols for preparing
quinolines have been developed.8 Among of these quinoline
derivatives, dihydrothieno(2,3-b)quinolines, which contain
both quinoline and thiophene rings, are heterocyclic ring
systems of considerable interest due to several biological and
pharmaceutical activities that are associated with this scaffold.
In addition, some analogues have been found to act as effective
pharmaceutical and biological agents.9,10 As such, we reasoned
that the incorporation of a thiophene heterocyclic unit into
quinolines in one pot might provide new compounds that have
important biological and pharmaceutical activities. In view of
the importance of this class of molecules as well as the lack of
generality and efficiency to access these important synthetic
targets, the development of a novel metal-free and efficient
methodology for the synthesis of dihydrothieno(2,3-b)-
quinolines is still in demand. Being atom-efficient and able to
generate functional groups, the aza-Morita−Baylis−Hillman
(AMBH) reaction between an α,β-unsaturated carbonyl
compound and an imine is recognized as one of the most
fruitful carbon−carbon bond-forming processes (Scheme 1).11
In addition, it affords highly functionalized β-amino carbonyl
Received: October 13, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b02369
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The Journal of Organic Chemistry
Note
Scheme 2. Potential Strategies for the Domino Reaction of
o-Isothiocyanato-(E)-cinnamaldehyde 1a with α-
Bromomalonate 2a
Scheme 3. Preparation of 4H-3,1-Benzothiazine Derivatives
reaction was shown to be quite broad with respect to o-
isothiocyanato-(E)-cinnamaldehydes 1. The novel transforma-
tions proceeded smoothly, giving the substituted quinoline
derivative in good yields. It appeared that the electronics of the
substituents of o-isothiocyanato-(E)-cinnamaldehydes 1 had a
little effect on the efficiency of the domino reactions. Good
yields were obtained in the domino reactions of 2a when there
was an electron-donating substituent on the aryl ring of o-
isothiocyanato-(E)-cinnamaldehydes 1 (Table 2, entries 4−7).
On the contrary, an electron-withdrawing substituent on the
aryl ring of o-isothiocyanato-(E)-cinnamaldehydes tended to
decrease the yield (Table 2, entries 2, 3, 8, and 9). A good yield
was also achieved when -OEt (R2) was replaced with a methyl
group, although the diastereoselectivity was poor (entry 10). In
addition, only racemic compounds 3 were observed when the
reactions were catalyzed by L-proline/DBU in methanol (entry
1). A good result was also obtained when the reaction was
scaled up by 30-fold in comparison with the reaction shown in
Table 2, entry 1 (cf. entry 11). The structure of products 3 was
also established by a single-crystal X-ray diffraction study of
compounds 3ca and 3da (Figure S1).
To extend the scope of the domino reaction further, other
acyclic α-halocarbonyl compounds 2c−2g were utilized as
substrates in the reaction with o-isothiocyanato-(E)-cinnamal-
dehydes 1a in the presence of L-proline/DBU (Table 3). Aside
from obtaining the desired product 2,3-dihydrothieno(2,3-
b)quinoline 3ac in good yield, thieno[2,3-b]quinoline 6ac was
also obtained in 16% yield under the optimal reaction
conditions (entry 1). Apparently the expected domino
reactions and a further deacecylation occurred to generate the
observed thieno[2,3-b]quinoline 6ac. When the loading of the
base DBU was increased, only thieno[2,3-b]quinoline 6ac was
obtained (entry 2). On the other hand, although low reactivity
was observed for other α-halocarbonyl compounds 2d−2g, the
domino reactions also proceeded smoothly under the optimal
reaction conditions due to weak steric hindrance effects and the
highly reactive aldehyde group (entries 4−7). For example,
as TEA, DABCO, and DBU, was also screened. To our
surprise, no reaction occurred when the reaction was catalyzed
by these tertiary amines (entries 3−5). To our delight, the
domino reaction proceeded smoothly when the reaction was
carried out in the presence of secondary amine L-proline in
THF at room temperature for 24 h (Table 1, entry 6).
Interestingly, although it was not what we expected, the
unexpected functionalized 2,3-dihydrothieno(2,3-b)quinoline
3aa was obtained. Then, we investigated the effect of solvent
on the reactivity for this unexpected reaction when L-proline
was used as the catalyst. Among the solvents examined, the use
of methanol gave the best result (entry 7). Low yields were
obtained when DCM or toluene was used as the solvent
(entries 8 and 10). Only trace product 3aa was observed when
the reaction was carried out in the presence of L-proline in
water at room temperature for 24 h due to the low solubility of
2a in water (entry 11). Interestingly, clean product 3aa was
obtained in good yield when DBU was added, and the reaction
time was decreased (entry 12). It is worthy of note here that
product 3aa (entries 13 and 14) was not isolated but that 4H-
3,1-benzothiazine derivatives A and B (Scheme 3) were isolated
in high yields within 30 s when L-proline was replaced with
other secondary amines, such as pyrrolidine and diethyl amine.
Obviously, the secondary amines first attacked the isothiocya-
nate to yield the corresponding thiourea intermediates,
followed by 1,4-conjugate addition to give the corresponding
products.15 On the basis of the above screening results, the
optimal reaction conditions were established (entry 12): 0.10
mmol of 1a, 0.12 mmol of 2a, and 50 mol % L-proline in
methanol for 2 h at room temperaturel then, 120 mol % of
DBU was added, and the reactions were stirred for 1 h.
With the optimal reaction conditions in hand, the scope of
the domino reaction of 2-halo-1,3-dicarbonyl compounds 2
with o-isothiocyanato-(E)-cinnamaldehydes 1 was explored; the
results are summarized in Table 2. The scope of the domino
a
Table 1. Reaction of o-Isothiocyanato-(E)-cinnamaldehyde 1a and α-Bromomalonate 2a under Different Conditions
b
b
entry
sol.
THF
base
yield (%)
entry
sol.
base
yield (%)
1
2
3
4
5
6
7
NaHCO3
Na2CO3
Et3N
8
DCM
L-proline
21
THF
9
acetone
toluene
H2O
L-proline
trace
36
THF
10
11
L-proline
THF
DABCO
DBU
L-proline
trace
75
c
THF
12
Methanol
methanol
methanol
L-proline/DBU
pyrrolidine
Et2NH
THF
L-proline
L-proline
39
73
13
14
methanol
a
Unless otherwise noted, reactions were performed with 0.10 mmol of 1a, 0.12 mmol of 2a, and 50 mol % base in solvent (1.0 mL) at room
b
c
temperature for 24 h. Isolated yields. The reactions were performed with 0.10 mmol of 1a, 0.12 mmol of 2a, and 50 mol % L-proline in methanol
for 2 h at room temperature; then, 120 mol % of DBU was added, and the reactions were stirred for 1 h.
B
DOI: 10.1021/acs.joc.5b02369
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Note
a
Table 2. Scope of the Domino Reaction of o-Isothiocyanato-(E)-cinnamaldehydes 1 with 2-Halo-1,3-dicarbonyl Compounds 2
b
b
entry
R1
(1)
2
3/yield (%)
entry
R1
(1)
2
3/yield (%)
c
1
H
(1a)
(1b)
(1c)
(1d)
(1e)
(1f)
2a
2a
2a
2a
2a
2a
3aa/75
3ba/61
3ca/56
3da/71
3ea/66
3fa/70
7
4-OCH3
3-NO2
4-CI
(1g)
(1h)
(1i)
(1a)
2a
2a
2a
2a
3ga/73
3ha/64
3ia/62
2
3
4
5
6
3-Br
8
4-Br
9
4-CH3
5-CH3
4-OH
10
H
3ab/80
(69:31 dr)
3aa/79
d
11
H
(1a)
2a
a
Unless otherwise noted, reactions were performed with 0.10 mmol of 1, 0.12 mmol of 2, and 50 mol % of L-proline in methanol (1.0 mL) at room
b
c
temperature for 2 h; then, 120 mol % of DBU was added, and the reactions were stirred for 1 h. Isolated yields. Enantiomeric excess (ee) = 0
(determined by chiral HPLC analysis; see the Supporting Information). The reaction was scaled up by 30-fold.
d
a
Table 3. Domino Reaction of o-Isothiocyanato-(E)-cinnamaldehyde 1a with α-Halocarbonyl Compounds
a
Unless otherwise noted, reactions were performed with 0.10 mmol of 1, 0.12 mmol of 2, and 50 mol % of L-proline in methanol (1.0 mL) at room
b
c
temperature for 2 h; then, 120 mol % of DBU was added, and the reactions were stirred for 1 h. Isolated yields. 16% yield of 6ac was also isolated.
d
e
200 mol % of DBU was added. 18% yield of 6ad was also isolated.
quinoline derivative 5ad was obtained as a main product when
ethyl bromoacetate reacted with o-isothiocyanato-(E)-cinna-
maldehyde 1a under the optimal reaction conditions (entry 4).
When the loading of DBU was increased, only thieno[2,3-
b]quinoline 6ad was observed (entry 3). Interestingly, under
the same conditions as above, for acyclic β-phenyl α-
halocarbonyl compounds 2e−2g, 2,3-dihydrothieno(2,3-b)-
quinoline derivative 3ae and thieno[2,3-b]quinolines deriva-
tives 6af−6ag were isolated, respectively (entries 5−7).
However, the diastereoselectivity of 3ae was poor (entry 5).
What would happen if cyclic α-halocarbonyl compounds
(e.g., 2-bromocyclohexane-1,3-dione 2h) were used in this
domino reaction? To address this, we next turned our attention
to the domino reaction of o-isothiocyanato-(E)-cinnamalde-
hyde 1a with 2-bromocyclohexane-1,3-dione 2h. To our
surprise, unexpected ring-opening products thieno[2,3-b]-
quinolines 6 were isolated in good yields (Table 4). After the
unexpected reactions of 2-bromocyclohexane-1,3-dione 2h
were investigated, more experiments were conducted to test
the substrate scope of the domino process and to gain further
insight with regard to the possible reaction mechanism. The
Table 4. Scope of the Domino Reaction of o-Isothiocyanato-
(E)-cinnamaldehydes 1 with 2-Bromocyclohexane-1,3-dione
2h
a
6/yield
b
6/yield
b
entry
R
(1)
(%)
entry
R
(1)
(%)
1
2
3
H
(1a)
(1c)
(1d)
6ah/68
6ch/59
6dh/61
4
5
5-CH3
4-CI
(1e)
(1i)
6eh/69
6ih/56
4-Br
4-CH3
a
Unless otherwise noted, reactions were performed with 0.10 mmol of
1 and 50 mol % of L-proline in methanol (1.0 mL) at room
temperature for 2 h; then, 0.12 mmol of 2 and 100 mol % of DBU
b
were added, and the reactions were stirred at 35 °C for 5 h. Isolated
yields.
electronic effect was also very marginal, and good yields were
achieved for substrates 1 (Table 4, entries 2−5).
C
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Note
A control experiment was conducted to gain some insight
into the mechanism of the domino reaction (Scheme 4).
and moderate to good yields were achieved. Notably, when the
domino AMBH/alkylation/aldol reaction of o-isothiocyanato-
(E)-cinnamaldehyde 1 with 2-bromocyclohexane-1,3-dione 2h
was performed, an unexpected ring-opening occurred, forming
thieno(2,3-b)quinolines 6ah−6ih. A plausible mechanism for
this unprecedented domino AMBH/alkylation/aldol/ring-
opening reaction is also given.
Scheme 4. Control Experiments
EXPERIMENTAL SECTION
■
Quinoline derivatives Ia and Id were obtained in high yields
when o-isothiocyanato-(E)-cinnamaldehydes 1 were stirred in
the presence of L-proline in methanol at room temperature for
2 h.
General Methods. NMR spectra were recorded with tetrame-
thylsilane as the internal standard. TLC was performed on glass-
backed silica plates. Column chromatography was performed using
silica gel (150−200 mesh) eluting with ethyl acetate and petroleum
ether. All NMR spectra were recorded on a 600 or 400 MHz
instrument. Chemical shifts (δ) are reported in ppm downfield from
On the basis of the experimental observations, a possible
mechanism was proposed to explain the domino reaction. As
outlined in Scheme 5, an intramolecular AMBH reaction
1
CDCl3 (δ = 7.26 ppm) or DMSO (δ = 2.50 ppm) for H NMR and
relative to the central CDCl3 resonance (δ = 77.0 ppm) or DMSO
resonance (δ = 39.5 ppm) for 13C NMR spectroscopy. Coupling
constants (J) are given in hertz. ESI-HRMS was measured with an ion
trap mass spectrometer. o-Isothiocyanato-(E)-cinnamaldehydes 1 were
prepared according to literature procedures.16
Scheme 5. Proposed Mechanisms
General Procedure for Synthesis of o-Isothiocyanato-(E)-
cinnamaldehydes. A flask was charged with 6.25 mL (6.84 g, 0.053
mol) of quinoline, 25 mL of dichloromethane, 5.5 g (0.055 mol) of
finely powdered calcium carbonate, and 25 mL of water. The mixture
was stirred vigorously, cooled to 10 °C, and maintained at 10−15 °C;
a solution of 3.75 mL (5.65 g, 0.049 mol) of thiophosgene in 12 mL of
dichloromethane was added over 15 min. The cooling bath was
removed, and the reaction mixture was stirred vigorously at ambient
temperature overnight. The reaction was then filtered. The layers were
separated, and the aqueous layer was extracted with 10 mL of
dichloromethane. The combined organic layers were washed twice
with 15 mL of 2 N hydrochloric acid and then with 15 mL of water
and dried over anhydrous magnesium sulfate. Concentration under
reduced pressure gave crude products. The crude products were
dissolved with heating in 40 mL of cyclohexane, decolorizing carbon
was added, and the mixture was filtered. The filtrate was heated under
reflux for 1 h and allowed to cool with stirring. The resulting solid was
isolated by filtration, washed with cyclohexane, and dried in a vacuum
oven at 40 °C to give ∼8.1 g (87% yield) of o-isothiocyanato-(E)-
cinnamaldehyde.
o-Isothiocyanato-(E)-cinnamaldehyde (1a). The spectra are in
accord with the literature.16 1H NMR (600 MHz, CDCl3) δ 9.76 (d, J
= 7.6 Hz, 1H), 7.74 (d, J = 16.0 Hz, 1H), 7.65 (dd, J = 7.9, 1.2 Hz,
1H), 7.44 (td, J = 8.1, 1.4 Hz, 1H), 7.39−7.31 (m, 2H), 6.75 (dd, J =
16.0, 7.6 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 193.4, 146.0, 139.2,
132.1, 131.3, 130.5, 129.6, 128.2, 127.6, 127.5.
3-(2-Bromo-6-isothiocyanatophenyl)acrylaldehyde (1b). The
spectra are in accord with the literature.16 1H NMR (600 MHz,
CDCl3) δ 9.77 (d, J = 7.5 Hz, 1H), 7.65−7.52 (m, 2H), 7.34 (d, J = 8.0
Hz, 1H), 7.25 (t, J = 8.0 Hz, 1H), 6.89 (dd, J = 16.3, 7.5 Hz, 1H). 13C
NMR (150 MHz, CDCl3) δ 193.5, 146.4, 139.9, 135.0, 132.0, 131.3,
131.3, 129.6, 127.9, 125.5.
3-(5-Bromo-2-isothiocyanatophenyl)acrylaldehyde (1c). The
spectra are in accord with the literature.16 1H NMR (600 MHz,
CDCl3) δ 9.77 (d, J = 7.5 Hz, 1H), 7.75 (d, J = 2.2 Hz, 1H), 7.65 (d, J
= 16.0 Hz, 1H), 7.53 (dd, J = 8.5, 2.2 Hz, 1H), 7.24 (d, J = 8.5 Hz,
1H), 6.72 (dd, J = 16.0, 7.5 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ
192.9, 144.3, 140.4, 134.8, 131.3, 131.2, 130.3, 130.2, 129.5, 121.0.
3-(2-Isothiocyanato-5-methylphenyl)acrylaldehyde (1d). The
spectra are in accord with the literature.16 1H NMR (600 MHz,
CDCl3) δ 9.74 (d, J = 7.6 Hz, 1H), 7.68 (d, J = 16.0 Hz, 1H), 7.43 (s,
1H), 7.24 (d, J = 1.1 Hz, 2H), 6.72 (dd, J = 16.0, 7.6 Hz, 1H), 2.39 (s,
3H). 13C NMR (150 MHz, CDCl3) δ 193.4, 146.1, 138.4, 137.8, 133.0,
130.3, 129.3, 128.6, 127.9, 127.7, 21.2.
occurred (a−d). L-Proline is an effective catalyst for the
formation of iminium I with o-isothiocyanato-(E)-cinnamalde-
hyde 1a (a). Following the addition of L-proline to the activated
alkene, the in situ generated nucleophile adds to R−NCS,
and subsequent elimination of L-proline leads to quinoline
derivative Ia (b−d). After that, a domino alkylation/aldol
reaction proceeds to produce 2,3-dihydrothieno(2,3-b)-
quinoline derivatives 3 (e−h). Intermediate I6a was formed
when o-isothiocyanato-(E)-cinnamaldehyde 1a reacted with 2-
bromocyclohexane-1,3-dione 2h (i), followed by formation of
hemiketal I6b (j). Unstable hemiketal I6b was protonated, and
unexpected ring opening, aromatization, and elimination of an
H2O molecule took place to form product 6ah (k). A similar
reaction mechanism provided product 6ac (l−n). However, the
real reaction mechanism still remains to be explored.
In summary, we have developed an unexpected domino
AMBH/alkylation/aldol reaction of o-isothiocyanato-(E)-cin-
namaldehydes with α-halocarbonyl compounds, catalyzed by
commercially available, low-cost secondary amine L-proline, and
demonstrate the direct application of this reaction in the
syntheses of 2,3-dihydrothieno(2,3-b)quinolines and thieno-
(2,3-b)quinolines. The scope of the reaction was quite broad,
3-(2-Isothiocyanato-4-methylphenyl)acrylaldehyde (1e). The
spectra are in accord with the literature.16 1H NMR (600 MHz,
CDCl3) δ 9.63 (dd, J = 7.6, 1.3 Hz, 1H), 7.54 (d, J = 16.0 Hz, 1H),
7.43 (d, J = 8.0 Hz, 1H), 7.05 (d, J = 9.3 Hz, 2H), 6.59 (ddd, J = 15.9,
D
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Note
7.6, 1.1 Hz, 1H), 2.30 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 193.3,
145.9, 143.2, 138.6, 130.9, 129.5, 128.7, 128.5, 127.2, 126.7, 21.2.
3-(2-Isothiocyanato-5-methoxyphenyl)acrylaldehyde (1g). The
spectra are in accord with the literature.16 1H NMR (600 MHz,
CDCl3) δ 9.77 (d, J = 7.6 Hz, 1H), 7.71 (d, J = 16.0 Hz, 1H), 7.30 (d,
J = 8.8 Hz, 1H), 7.09 (d, J = 2.8 Hz, 1H), 6.98 (dd, J = 8.8, 2.8 Hz,
1H), 6.72 (dd, J = 16.0, 7.6 Hz, 1H), 3.85 (s, 3H). 13C NMR (150
MHz, CDCl3) δ 193.4, 158.4, 145.9, 137.9, 130.7, 130.6, 129.3, 124.0,
118.6, 111.3, 55.7.
3-(2-Isothiocyanato-6-nitrophenyl)acrylaldehyde (1h). The spec-
tra are in accord with the literature.16 1H NMR (600 MHz, CDCl3) δ
9.79 (d, J = 7.3 Hz, 1H), 7.96 (d, J = 7.9 Hz, 1H), 7.77−7.64 (m, 2H),
7.60 (t, J = 7.9 Hz, 1H), 6.63 (dd, J = 16.2, 7.3 Hz, 1H). 13C NMR
(150 MHz, CDCl3) δ 192.7, 148.8, 142.7, 141.0, 135.7, 132.5, 131.9,
130.7, 125.8, 122.9.
3-(5-Chloro-2-isothiocyanatophenyl)acrylaldehyde (1i). The
spectra are in accord with the literature.16 1H NMR (600 MHz,
CDCl3) δ 9.77 (d, J = 7.5 Hz, 1H), 7.67 (d, J = 16.0 Hz, 1H), 7.60 (d,
J = 2.3 Hz, 1H), 7.39 (dd, J = 8.6, 2.3 Hz, 1H), 7.32 (d, J = 8.6 Hz,
1H), 6.73 (dd, J = 16.0, 7.5 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ
192.9, 144.4, 140.3, 133.3, 131.9, 131.3, 130.9, 129.9, 129.3, 127.2.
General Procedure for the Preparation of Diethyl 3-
hydroxythieno[2,3-b]quinoline-2,2(3H)-dicarboxylate. A mix-
ture of o-isothiocyanato-(E)-cinnamaldehyde 1a (18.9 mg, 0.1
mmol), L-proline (0.58 mg, 0.05 mol), and diethyl α-bromomalonate
2a (20 μL, 0.1 mmol) was stirred in methanol (1.0 mL) at room
temperature for 2 h; then, DBU (18 μL, 0.05 mol) was added. The
reaction mixture was stirred at room temperature for 1 h. Then, flash
chromatography on silica gel (20% ethyl acetate/petroleum ether)
gave 3aa as a white solid (26 mg, 75% yield).
Hz, 1H), 7.49−7.41 (m, 2H), 5.86 (s, 1H), 4.36−4.21 (m, 4H), 4.09
(s, 1H), 2.47 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.23 (t, J = 7.1 Hz,
3H).13C NMR (150 MHz, CDCl3) δ 167.9, 167.0, 160.7, 147.3, 135.8,
132.4, 132.2, 131.3, 127.4, 127.2, 126.1, 77.8, 69.5, 62.97, 62.95, 21.4,
13.9, 13.89. ESI-HRMS: calcd for C18H19NO5S+H 362.1057, found
362.1084.
Crystal Data for 3da. See the Supporting Information.
C18H19NO5S (361.4), monoclinic, P21/c; a = 16.5377(2) Å, α =
90.00°; b = 7.97520(10) Å, β = 95.102(2) °; c = 13.0814(2) Å, γ =
90.00°; U = 1723.58(4) Å3; Z = 22; T = 296(2) K; absorption
coefficient 0.217 mm−1; reflections collected 14 875, unique 3960
[R(int) = 0.0172]; refinement by Full-matrix least-squares on F2, data/
restraints/parameters 3960/0/227, goodness-of-fit on F2 = 1.058; final
R indices [I > 2σ(I)] R1 = 0.0427, wR2 = 0.1263; R indices (all data)
R1 = 0.0490, wR2 = 0.1331; largest diff. peak and hole 0.522 and
−0.406 Å−3.
Diethyl 3-Hydroxy-7-methylthieno[2,3-b]quinoline-2,2(3H)-dicar-
boxylate (3ea). Twenty-four milligrams, 66% yield, white solid, mp
1
130−131 °C. H NMR (600 MHz, CDCl3) δ 7.93 (s, 1H), 7.69 (s,
1H), 7.63 (d, J = 8.2 Hz, 1H), 7.28 (dd, J = 8.2, 1.1 Hz, 1H), 5.86 (s,
1H), 4.36−4.18 (m, 4H), 3.64 (s, 1H), 2.52 (s, 3H), 1.31 (t, J = 7.1
Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ
167.9, 167.1, 161.6, 149.1, 140.6, 131.5, 1314, 128.1, 127.8, 127.1,
124.1, 77.9, 69.3, 63.0, 63.0, 21.8, 13.9, 13.9. ESI-HRMS: calcd for
C18H19NO5S + H, 362.1057; found, 362.1072.
Diethyl 3,7-Dihydroxythieno[2,3-b]quinoline-2,2(3H)-dicarboxy-
late (3fa). Twenty-five milligrams, 70% yield, white solid, mp 168−
1
170 °C. H NMR (600 MHz, DMSO) δ 9.98 (s, 1H), 8.04 (s, 1H),
7.70 (d, J = 9.0 Hz, 1H), 7.26 (dd, J = 9.0, 2.7 Hz, 1H), 7.18 (d, J = 2.7
Hz, 1H), 6.66 (d, J = 7.0 Hz, 1H), 5.66 (d, J = 6.5 Hz, 1H), 4.40−4.07
(m, 4H), 1.21 (t, J = 7.1 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H). 13C NMR
(150 MHz, DMSO) δ 168.4, 166.0, 158.9, 155.6, 143.7, 134.4, 131.2,
129.0, 127.7, 122.3, 110.0, 76.2, 70.9, 62.7, 62.6, 14.3, 14.1. ESI-
HRMS: calcd for C17H17NO6S + H, 364.0849; found, 364.0849.
Diethyl 3-Hydroxy-6-methoxythieno[2,3-b]quinoline-2,2(3H)-di-
carboxylate (3ga). Twenty-seven milligrams, 73% yield, white solid,
Diethyl 3-Hydroxythieno[2,3-b]quinoline-2,2(3H)-dicarboxylate
(3aa). Twenty-six milligrams, 75% yield, white solid, mp 127−128
1
°C. H NMR (600 MHz, CDCl3) δ 7.97 (s, 1H), 7.90 (d, J = 8.4 Hz,
1H), 7.73 (d, J = 8.0 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.44 (t, J = 7.5
Hz, 1H), 5.89 (s, 1H), 4.39−4.17 (m, 4H), 3.96 (s, 1H), 1.30 (t, J =
7.1 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ
167.9, 167.0, 161.8, 148.8, 132.4, 131.8, 130.1, 128.2, 127.8, 126.1,
126.0, 77.9, 69.4, 63.0, 63.0, 13.91, 13.90. ESI-HRMS: calcd for
C17H17NO5S + H, 348.0900; found, 348.0933.
1
mp 153−155 °C. H NMR (600 MHz, CDCl3) δ 7.87 (s, 1H), 7.79
(d, J = 9.2 Hz, 1H), 7.28 (dd, J = 9.4, 3.0 Hz, 1H), 7.01 (d, J = 2.8 Hz,
1H), 5.85 (s, 1H), 4.35−4.21 (m, 4H), 3.89 (s, 3H), 3.77 (s, 1H), 1.31
(t, J = 7.1 Hz, 3H), 1.24 (t, J = 7.2 Hz, 3H). 13C NMR (150 MHz,
CDCl3) δ 167.9, 167.1, 158.7, 157.3, 144.8, 132.6, 130.8, 129.1, 127.1,
122.0, 106.4, 78.0, 69.4, 62.99, 62.98, 55.5, 13.91, 13.90. ESI-HRMS:
calcd for C18H19NO6S + H, 378.1006; found, 378.1010.
Diethyl 5-Bromo-3-hydroxythieno[2,3-b]quinoline-2,2(3H)-dicar-
boxylate (3ba). Twenty-six milligrams, 61% yield, white solid, mp 89−
1
90 °C. H NMR (600 MHz, CDCl3) δ 8.36 (s, 1H), 7.88 (d, J = 8.4
Hz, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 5.92 (d, J =
6.7 Hz, 1H), 4.39−4.25 (m, 4H), 3.62 (d, J = 7.4 Hz, 1H), 1.33 (t, J =
7.1 Hz, 3H), 1.25 (t, J = 5.4 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ
167.7, 167.0, 162.9, 149.7, 133.8, 131.1, 130.3, 129.8, 127.8, 125.8,
122.4, 78.0, 69.3, 63.2, 63.1, 13.9, 13.9. ESI-HRMS: calcd for
C17H16BrNO5S + H, 426.0005; found, 426.0010.
Diethyl 6-Bromo-3-hydroxythieno[2,3-b]quinoline-2,2(3H)-dicar-
boxylate (3ca). Twenty-four milligrams, 56% yield, white solid, mp
135−137 °C. 1H NMR (600 MHz, CDCl3) δ 7.88 (d, J = 1.5 Hz, 1H),
7.86 (s, 1H), 7.76 (d, J = 8.9 Hz, 1H), 7.70 (dd, J = 8.9, 1.7 Hz, 1H),
5.88 (s, 1H), 4.39−4.21 (m, 4H), 3.88 (s, 1H), 1.32 (t, J = 7.1 Hz,
3H), 1.23 (t, J = 7.1 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 167.7,
166.9, 162.3, 147.4, 133.44, 133.41, 130.5, 130.1, 129.4, 127.3, 119.6,
77.8, 69.2, 63.18, 63.13, 13.9, 13.9. ESI-HRMS: calcd for
C17H16BrNO5S + H, 426.0011; found, 426.0017.
Diethyl 3-Hydroxy-5-nitrothieno[2,3-b]quinoline-2,2(3H)-dicar-
boxylate (3ha). Twenty-five milligrams, 64% yield, white solid, mp
169−171 °C. 1H NMR (600 MHz, CDCl3) δ 8.79 (s, 1H), 8.25 (dd, J
= 7.7, 1.1 Hz, 1H), 8.21 (d, J = 8.4 Hz, 1H), 7.73 (t, J = 8.1 Hz, 1H),
5.95 (d, J = 5.9 Hz, 1H), 4.41−4.25 (m, 4H), 3.67 (d, J = 7.1 Hz, 1H),
1.34 (t, J = 7.1 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H). 13C NMR (150 MHz,
CDCl3) δ 167.5, 166.8, 164.0, 149.0, 146.0, 135.8, 134.6, 128.2, 127.1,
123.6, 119.3, 78.1, 69.3, 63.35, 63.30, 13.92, 13.91. ESI-HRMS: calcd
for C17H16N2O7S + H, 393.0751; found, 393.0755.
Diethyl 6-Chloro-3-hydroxythieno[2,3-b]quinoline-2,2(3H)-dicar-
boxylate (3ia). Twenty-four milligrams, 62% yield, white solid, mp
160−162 °C. 1H NMR (600 MHz, CDCl3) δ 7.87 (s, 1H), 7.84 (d, J =
8.9 Hz, 1H), 7.71 (d, J = 2.2 Hz, 1H), 7.58 (dd, J = 8.9, 2.2 Hz, 1H),
5.88 (s, 1H), 4.39−4.22 (m, 4H), 3.79 (s, 1H), 1.32 (t, J = 7.1 Hz,
3H), 1.23 (t, J = 7.1 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 167.7,
167.0, 162.1, 147.2, 133.4, 131.6, 130.8, 130.6, 129.3, 126.8, 126.8,
77.9, 69.2, 63.2, 63.1, 13.93, 1392. ESI-HRMS: calcd for
C17H16ClNO5S + H, 382.0510; found, 382.0520.
Ethyl 2-Acetyl-3-hydroxy-2,3-dihydrothieno[2,3-b]quinoline-2-
carboxylate (3ab). Twenty-five milligrams, 80% yield, white solid,
mp 142−144 °C, 3:2 dr. 1H NMR (600 MHz, DMSO) δ 8.27 (d, J =
4.1 Hz, 1H), 8.01 (t, J = 7.5 Hz, 1H), 7.89 (dd, J = 8.1, 5.6 Hz, 1H),
7.79−7.72 (m, 1H), 7.56 (dd, J = 11.1, 3.9 Hz, 1H), 6.80 (d, J = 6.8
Hz, 0.61H), 6.67 (d, J = 7.0 Hz, 0.38H), 5.95 (d, J = 6.5 Hz, 0.61H),
5.75 (d, J = 6.7 Hz, 0.38H), 4.31 (dddd, J = 14.3, 10.9, 9.0, 5.5 Hz,
0.80H), 4.27−4.15 (m, 1.29H), 2.37 (s, 1.73H), 2.36 (s, 1.20H), 1.27
(t, J = 7.1 Hz, 1.28H), 1.19 (t, J = 7.1 Hz, 2.01H). 13C NMR (150
Crystal Data for 3ca. See the Supporting Information.
C H BrNO S (426.27), triclinic, P1; a = 9.0005(5) Å, α =
̅
17 16
5
86.350(3)°; b = 9.8533(5) Å, β = 84.591(3)°; c = 10.2837(5) Å, γ
= 85.213(3)°. U = 903.35(8) Å3; Z = 4; T = 296(2) K; absorption
coefficient 2.418 mm−1; reflections collected 15 339, unique 4179
[R(int) = 0.0428]; refinement by Full-matrix least-squares on F2, data/
restraints/parameters 4179/0/226, goodness-of-fit on F2 = 1.043; final
R indices [I > 2σ(I)], R1 = 0.0489, wR2 = 0.1434; R indices (all data),
R1 = 0.0743, wR2 = 0.1626; largest diff. peak and hole 0.850 and
−0.843 Å−3.
Diethyl 3-Hydroxy-6-methylthieno[2,3-b]quinoline-2,2(3H)-dicar-
boxylate (3da). Twenty milligrams, 56% yield, white solid, mp 157−
159 °C. 1H NMR (600 MHz, CDCl3) δ 7.86 (s, 1H), 7.77 (d, J = 8.4
E
DOI: 10.1021/acs.joc.5b02369
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
MHz, DMSO) δ 198.4, 198.1, 168.8, 166.5, 163.2, 162.6, 148.6, 135.1,
134.9, 132.7, 130.6, 129.0, 127.68, 127.66 126.5, 1264, 126.3, 77.4,
77.2, 75.7, 74.9, 63.1, 62.8, 27.6, 26.4, 14.2, 14.1. ESI-HRMS: calcd for
C16H15NO4S + H, 318.0795; found, 318.0800
1,1′-(3-Hydroxy-2,3-dihydrothieno[2,3-b]quinoline-2,2-diyl)-
diethanone (3ac). Thirty-two milligrams, 83% yield, white solid, mp
189−190 °C, 1H NMR (600 MHz, DMSO) δ 8.25 (s, 1H), 7.98 (d, J
= 8.0 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.75−7.66 (m, 1H), 7.57−
7.49 (m, 1H), 6.66 (d, J = 6.7 Hz, 1H), 5.93 (d, J = 6.6 Hz, 1H), 2.36
(s, 3H), 2.26 (s, 3H). 13C NMR (150 MHz, DMSO) δ 201.1, 199.7,
162.8, 148.7, 135.3, 132.8, 130.6, 128.9, 127.7, 126.4, 126.3, 83.8, 74.8,
28.4, 27.0. ESI-HRMS: calcd for C15H13NO3S + H, 288.0689; found,
288.0685.
1-(Thieno[2,3-b]quinolin-2-yl)ethanone (6ac). Ninteen milligrams,
82% yield, white solid, mp 200−201 °C. 1H NMR (600 MHz, DMSO)
δ 9.06 (s, 1H), 8.46 (s, 1H), 8.21 (d, J = 8.1 Hz, 1H), 8.09 (d, J = 8.6
Hz, 1H), 7.89 (ddd, J = 8.3, 6.8, 1.3 Hz, 1H), 7.66 (dd, J = 11.0, 4.0
Hz, 1H), 2.71 (s, 3H). 13C NMR (150 MHz, DMSO) δ 193.4, 163.0,
148.0, 144.0, 135.2, 132.2, 131.6, 129.9, 129.7, 128.3, 126.4, 125.9,
26.7. ESI-HRMS: calcd for C13H9NOS + H, 228.0478; found,
228.0478.
148.2, 144.0, 133.7, 131.6, 130.8, 128.7, 128.4, 126.5, 125.9, 125.7,
51.7, 37.8, 32.9, 19.4. ESI-HRMS: calcd for C17H15NO3S + H,
314.0845; found, 314.0870.
Methyl 5-(6-Bromothieno[2,3-b]quinolin-2-yl)-5-oxopentanoate
(6ch). Twenty-three milligrams, 59% yield, white solid, mp 203−205
°C. 1H NMR (600 MHz, CDCl3) δ 8.61 (s, 1H), 8.16 (s, 1H), 8.04 (t,
J = 4.4 Hz, 2H), 7.93−7.83 (m, 1H), 3.74 (s, 3H), 3.18 (t, J = 7.2 Hz,
2H), 2.53 (t, J = 7.0 Hz, 2H), 2.23−2.06 (m, 2H). 13C NMR (150
MHz, CDCl3) δ 193.9, 173.5, 163.7, 146.7, 145.0, 134.2, 132.4, 132.2,
130.3, 130.2, 126.7, 126.1, 119.7, 51.7, 37.9, 32.8, 19.4. ESI-HRMS:
calcd for C17H14BrNO3S + H, 391.9951; found, 391.9951.
Methyl 5-(6-Methylthieno[2,3-b]quinolin-2-yl)-5-oxopentanoate
(6dh). Twenty milligrams, 61% yield, white solid, mp 173−174 °C.
1H NMR (600 MHz, CDCl3) δ 8.50 (s, 1H), 8.01 (d, J = 7.7 Hz, 1H),
7.93 (s, 1H), 7.73−7.56 (m, 2H), 3.72 (s, 3H), 3.10 (d, J = 6.4 Hz,
2H), 2.56 (s, 3H), 2.50 (d, J = 6.5 Hz, 2H), 2.12 (d, J = 6.6 Hz, 2H).
13C NMR (150 MHz, CDCl3) δ 193.9, 173.6, 162.5, 147.1, 143.8,
135.7, 133.4, 132.8, 131.5, 128.0, 127.1, 126.6, 125.8, 51.7, 37.8, 32.9,
21.6, 19.4. ESI-HRMS: calcd for C18H17NO3S + H, 328.1002; found,
328.1007.
Methyl 5-(7-Methylthieno[2,3-b]quinolin-2-yl)-5-oxopentanoate
(6eh). Twenty-two milligrams, 69% yield, white solid, mp 172−174
°C. 1H NMR (600 MHz, CDCl3) δ 8.60 (s, 1H), 7.98 (s, 1H), 7.90 (s,
1H), 7.85 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 3.72 (s, 3H),
3.13 (t, J = 7.2 Hz, 2H), 2.62 (s, 3H), 2.51 (t, J = 7.0 Hz, 2H), 2.18−
2.11 (m, 2H). 13C NMR (150 MHz, CDCl3) δ 193.9, 173.6, 163.4,
148.6, 143.3, 141.7, 133.4, 130.9, 128.4, 128.2, 127.2, 126.7, 124.0,
51.7, 37.8, 32.9, 22.2, 19.5. ESI-HRMS: calcd for C18H17NO3S + H,
328.1002; found, 328.1003.
Methyl 5-(6-Chlorothieno[2,3-b]quinolin-2-yl)-5-oxopentanoate
(6ih). Ninteen milligrams, 56% yield, white solid, mp 206−207 °C.
1H NMR (600 MHz, CDCl3) δ 8.61 (s, 1H), 8.16 (s, 1H), 8.04 (d, J =
7.1 Hz, 2H), 7.87 (d, J = 9.1 Hz, 1H), 3.73 (s, 3H), 3.18 (t, J = 6.9 Hz,
2H), 2.53 (t, J = 6.6 Hz, 2H), 2.20−2.11 (m, 2H). 13C NMR (150
MHz, CDCl3) δ 193.9, 173.5, 163.7, 146.7, 145.0, 134.2, 132.4, 132.2,
130.3, 130.2, 126.7, 126.1, 119.7, 51.7, 37.9, 32.8, 19.4. ESI-HRMS:
calcd for C17H14ClNO3S + H, 348.0456; found, 348.0465.
2-Mercaptoquinoline-3-carbaldehyde (Ia). Fourteen milligrams,
73% yield, yellow solid, mp 303−305 °C. 1H NMR (600 MHz,
DMSO) δ 13.98 (s, 1H), 10.72 (s, 1H), 8.36 (s, 1H), 8.01 (d, J = 7.9
Hz, 1H), 7.76 (t, J = 7.7 Hz, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.41 (t, J =
7.5 Hz, 1H). 13C NMR (150 MHz, DMSO) δ 192.3, 181.4, 141.4,
137.4, 134.7, 132.3, 131.1, 125.4, 122.1, 116.7. ESI-HRMS: calcd for
C10H7NOS+H 190.0321, found 190.0323.
(2-Bromophenyl)(thieno[2,3-b]quinolin-2-yl)methanone (6af).
1
Thirty-one milligrams, 84% yield, white solid, mp 175−176 °C. H
NMR (600 MHz, CDCl3) δ 8.58 (s, 1H), 8.13 (d, J = 8.6 Hz, 1H),
7.91 (d, J = 8.2 Hz, 1H), 7.80 (t, J = 7.6 Hz, 1H), 7.70 (d, J = 8.0 Hz,
1H), 7.62 (s, 1H), 7.57−7.46 (m, 3H), 7.45−7.40 (m, 1H). 13C NMR
(150 MHz, CDCl3) δ 189.7, 163.7, 148.4, 143.5, 139.3, 134.3, 133.5,
131.8, 131.4, 131.3, 131.2, 129.0, 128.7, 128.4, 127.3, 126.0, 125.7,
119.6. ESI-HRMS: calcd for C18H10BrNOS + H, 367.9739; found,
367.9739.
Thieno[2,3-b]quinolin-2-yl(p-tolyl)methanone (6ag). Twenty-one
1
milligrams, 68% yield, white solid, mp 207−209 °C. H NMR (600
MHz, CDCl3) δ 8.65 (s, 1H), 8.17 (d, J = 8.6 Hz, 1H), 7.97 (d, J = 8.2
Hz, 1H), 7.91−7.78 (m, 4H), 7.58 (t, J = 7.4 Hz, 1H), 7.38 (d, J = 7.8
Hz, 2H), 2.50 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 189.2, 163.4,
148.2, 144.0, 143.8, 134.4, 133.7, 131.5, 130.8, 129.5, 129.5, 129.4,
129.4, 129.2, 128.7, 128.5, 1259, 125.8, 21.7. ESI-HRMS: calcd for
C19H13NOS + H, 304.0791; found, 304.0819.
Methyl Thieno[2,3-b]quinoline-2-carboxylate (6ad). Eighteen
1
milligrams, 82% yield, white solid, mp 160−161 °C. H NMR (600
MHz, CDCl3) δ 8.60 (s, 1H), 8.12 (d, J = 8.2 Hz, 1H), 8.05 (s, 1H),
7.94 (d, J = 7.7 Hz, 1H), 7.78 (t, J = 6.8 Hz, 1H), 7.55 (t, J = 6.8 Hz,
1H), 3.98 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 163.4, 162.8,
148.1, 134.3, 133.1, 131.0, 130.6, 128.7, 128.4, 128.0, 125.8, 125.7,
52.8. ESI-HRMS: calcd for C13H9NO2S + H, 244.0427; found,
224.0432.
2-Mercapto-6-methylquinoline-3-carbaldehyde (Id). Seventeen
1
milligrams, 84% yield, yellow solid, mp 281−282 °C. H NMR (600
Methyl 2-((3-Formylquinolin-2-yl)thio)acetate (5ad). Twenty-one
1
MHz, DMSO) δ 13.94 (s, 1H), 10.72 (s, 1H), 8.25 (s, 1H), 7.77 (s,
1H), 7.58 (dd, J = 30.1, 8.5 Hz, 2H), 2.37 (s, 3H). 13C NMR (150
MHz, DMSO) δ 192.3, 180.6, 139.8, 137.0, 136.3, 135.0, 132.2, 130.1,
122.1, 116.6, 21.0. ESI-HRMS: calcd for C11H9NOS+H 204.0478,
found 204.0480.
milligrams, 82% yield, white solid, mp 113−1114 °C. H NMR (400
MHz, CDCl3) δ 10.24 (s, 1H), 8.49 (s, 1H), 7.90 (dd, J = 11.8, 8.4 Hz,
2H), 7.84−7.77 (m, 1H), 7.56−7.49 (m, 1H), 4.08 (s, 2H), 3.78 (s,
3H). 13C NMR (101 MHz, CDCl3) δ 189.9, 170.3, 157.0, 149.1, 143.7,
133.2, 129.1, 128.0, 126.9, 126.5, 124.6, 52.6, 32.5. ESI-HRMS: calcd
for C13H11NO3S + H 262.0532; found, 262.0531.
2-(2-(Pyrrolidin-1-yl)-4H-benzo[d][1,3]thiazin-4-yl)acetaldehyde
(A). Twenty-five milligrams, 95% yield. 1H NMR (600 MHz, CDCl3) δ
9.69 (s, 1H), 7.23 (td, J = 7.7, 1.4 Hz, 1H), 7.12 (d, J = 7.3 Hz, 1H),
7.07 (dd, J = 7.5, 1.2 Hz, 1H), 6.97 (td, J = 7.4, 1.0 Hz, 1H), 4.50 (dd,
J = 8.4, 5.9 Hz, 1H), 3.69 (s, 2H), 3.55 (s, 2H), 3.01 (ddd, J = 17.7,
8.4, 1.6 Hz, 1H), 2.84 (dd, J = 17.7, 5.8 Hz, 1H), 1.95 (dd, J = 11.8, 5.8
Hz, 4H). 13C NMR (150 MHz, CDCl3) δ 199.5, 151.4, 145.4, 128.6,
126.0, 124.9, 122.8, 121.1, 50.2, 47.9, 37.4, 37.4, 25.0, 25.0. ESI-
HRMS: calcd for C14H16N2OS + H, 261.1056; found, 261.1052.
2-(2-(Diethylamino)-4H-benzo[d][1,3]thiazin-4-yl)acetaldehyde
(3-Hydroxy-2-methyl-2,3-dihydrothieno[2,3-b]quinolin-2-yl)-
(phenyl)methanone (3ae). Eighteen milligrams, 55% yield, mp 162−
1
163 °C, 3:2 dr. H NMR (600 MHz, CDCl3) δ 8.11 (d, J = 7.4 Hz,
1H), 8.05 (s, 1H), 7.95 (t, J = 7.3 Hz, 2H), 7.79 (d, J = 8.1 Hz, 1H),
7.68−7.41 (m, 5H), 5.96 (s, 0.62H), 5.35 (s, 0.41H), 4.32 (d, J = 17.2
Hz, 0.40H), 3.55 (s, 0.65H), 2.11 (s, 1.14H), 1.89 (s, 1.90H). 13C
NMR (150 MHz, CDCl3) δ 199.9, 160.5, 149.0, 134.3, 134.1, 133.3,
132.1, 131.5, 130.3, 129.78, 129.74, 129.6, 129.5, 128.8, 128.4, 128.1,
128.0, 127.88, 127.85, 126.6, 126.5, 126.0, 125.9, 83.7, 78.8, 66.7, 64.6,
23.3, 21.1. ESI-HRMS: calcd for C19H15NO2S + H, 322.0896; found,
322.0906.
1
(B). Twenty-four milligrams, 91% yield. H NMR (600 MHz, CDCl3)
δ 9.65 (s, 1H), 7.26−7.19 (m, 1H), 7.12−7.05 (m, 2H), 6.97 (td, J =
7.4, 1.1 Hz, 1H), 4.50 (dd, J = 8.1, 6.1 Hz, 1H), 3.65 (dq, J = 14.0, 7.0
Hz, 2H), 3.55 (dq, J = 14.1, 7.0 Hz, 2H), 2.91 (ddd, J = 17.6, 8.2, 1.8
Hz, 1H), 2.79 (ddd, J = 17.6, 6.0, 0.8 Hz, 1H), 1.20 (t, J = 7.1 Hz, 6H).
13C NMR (150 MHz, CDCl3) δ 199.5, 152.1, 145.5, 128.5, 125.8,
124.9, 122.8, 121.4, 49.7, 43.5, 37.5, 37.5, 14.1, 14.1. ESI-HRMS: calcd
for C14H18N2OS + H, 263.1213; found, 263.1211.
Methyl 5-Oxo-5-(thieno[2,3-b]quinolin-2-yl)pentanoate (6ah).
1
Twenty-one milligrams, 68% yield, white solid, mp 160−161 °C. H
NMR (600 MHz, CDCl3) δ 8.64 (s, 1H), 8.14 (d, J = 8.3 Hz, 1H),
8.06−7.88 (m, 2H), 7.81 (t, J = 7.1 Hz, 1H), 7.57 (t, J = 7.0 Hz, 1H),
3.72 (s, 3H), 3.13 (t, J = 6.7 Hz, 2H), 2.51 (t, J = 6.5 Hz, 2H), 2.32−
2.07 (m, 2H). 13C NMR (150 MHz, CDCl3) δ 194.0, 173.6, 163.3,
F
DOI: 10.1021/acs.joc.5b02369
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
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(c) Li, Q.-B.; Zhou, F.-T.; Liu, Z.-G.; Li, X.-F.; Zhu, W.-D.; Xie, J.-W. J.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b02369.
■
S
1H and 13C NMR spectra for all new compounds (PDF)
X-ray structural data for 3da (CIF)
X-ray structural data for 3ca (CIF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: xiejw@zjnu.cn.
Notes
■
The authors declare no competing financial interest.
(16) (a) Hull, R.; Swain, M. L. J. Chem. Soc., Perkin Trans. 1 1976,
653. (b) Farrand, R.; Hull, R. Org. Synth. 1983, 61, 71.
ACKNOWLEDGMENTS
We are grateful for the financial support from the National
Natural Science Foundation, P. R. China (no. 21272214).
■
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DOI: 10.1021/acs.joc.5b02369
J. Org. Chem. XXXX, XXX, XXX−XXX