Lawesson's reagent-initiated domino reaction of aminopropenoyl cyclopropanes: Synthesis of thieno[3,2-c]pyridinones

Article abstract of DOI:10.1039/c2ob06709a

A convenient and efficient synthesis of substituted 2,3-dihydrothieno[3,2- c]pyridin-4(5H)-ones has been developed and relies upon a domino reaction of dimethylaminopropenoyl cyclopropanes initiated by Lawesson's reagent. A mechanism involving regioselect

Full text of DOI:10.1039/c2ob06709a

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PAPER
Lawesson’s reagent-initiated domino reaction of aminopropenoyl
cyclopropanes: synthesis of thieno[3,2-c]pyridinones†
Peng Huang, Rui Zhang, Yongjiu Liang and Dewen Dong*
Received 10th October 2011, Accepted 6th December 2011
DOI: 10.1039/c2ob06709a
A convenient and efficient synthesis of substituted 2,3-dihydrothieno[3,2-c]pyridin-4(5H)-ones has been
developed and relies upon a domino reaction of dimethylaminopropenoyl cyclopropanes initiated by
Lawesson’s reagent. A mechanism involving regioselective thionation, ring-enlargement, and an
intramolecular aza-cyclization sequence is proposed. This protocol was utilized as a one-pot route to
thieno[3,2-c]pyridin-4(5H)-ones with DDQ as an oxidant.
range of chemicals, e.g. electrophiles, nucleophiles and radicals.8
Introduction
During the course of our studies on the chemistry of cyclopro-
panes, we achieved efficient synthesis of substituted pyridin-2
(1H)-ones,9a 1H-pyrazoles,9b isoxazoles,9b and spiro-fused pyra-
zolin-5-one N-oxides10 from readily available activated cyclopro-
panes under Vilsmeier conditions or mediated by hypervalent
iodine reagents. In our recent work, we prepared a series of
dimethylaminopropenoyl cyclopropanes and developed synthesis
of pyridin-2(1H)-ones, 2,3-dihydrofurans, and 2,3-dihydrofuro
[3,2-c]pyridin-4(5H)-ones.11 In the present work, we examined
the reaction behavior of such dimethylaminopropenoyl cyclopro-
panes toward Lawesson’s reagent.12 As a result, we developed a
convenient and efficient synthesis of 2,3-dihydrothieno[3,2-c]
pyridin-4(5H)-ones. Herein, we wish to report our preliminary
results and present a plausible mechanism involving the domino
reactions.
Thieno[3,2-c]pyridines and their analogues have attracted signifi-
cant attention since their core structure is present in a number of
synthetic organic compounds, such as cardiovascular drugs
Ticlopidine and Clopidogrel, along with a broad range of
pharmaceutical activities.1 Among them, thieno[3,2-c]pyridin-4
(5H)-ones are widely used as PRL phosphatase inhibitors,2
blood-platelet aggregation inhibitors,3 and 5-HT3 receptor antag-
onists.4 Additionally, they are versatile intermediates for the syn-
thesis of thieno[3,2-c]pyridines that behave as anti-tumor, anti-
inflammatory, and anti-psychotic agents.5 The synthetic and
pharmacological importance of thieno[3,2-c]pyridin-4(5H)-ones
have directed considerable research activity towards the construc-
tion of the skeleton of such heterocycles.6 The notable synthetic
route is based on the thermal isomerization and cyclization of a
2-(2-isocyanatovinyl)thiophene to form the pyridinone ring as
the key step.5,7 However, most of the established synthetic
approaches suffer from harsh reaction conditions, serious safety
and environmental problems due to their use of thionyl chloride
and sodium azide, and limited substrate scope. To match the
increasing scientific and practical demands, it is of continued
interest and great importance to explore simple and efficient syn-
thetic approaches for the construction of thieno[3,2-c]pyridin-4
(5H)-ones, especially those with wide applicability to achieve
more elaborate and flexible substitution patterns.
Results and discussion
The substrates, dimethylaminopropenoyl cyclopropanes 1, were
prepared according to the procedures described in our previous
reports in high yields (up to 91%).11 Thus, the reaction of 1-[3-
(dimethylamino)acryloyl]-N-phenyl cyclopropanecarboxamide
1a with Lawesson’s reagent (LR, 0.5 equiv.) was first attempted
in benzene at room temperature, however, no reaction was
observed as indicated by TLC examination of the reaction
mixture. When the mixture was heated to reflux for 24 h, the
reaction proceeded and furnished a white solid along with small
amount of intact 1a after work-up and purification by column
chromatography. The product was characterized as 5-phenyl-2,3-
dihydrothieno[3,2-c]pyridin-4(5H)-one 2a (54%) on the basis of
its spectral and analytical data (Scheme 1).
On the other hand, the overwhelming importance of cyclopro-
pane derivatives in organic synthesis has been recognized for
their well-known ‘unsaturated’ character, which can lead to a
variety of ring-opening reactions under the influence of a wide
Changchun Institute of Applied Chemistry, Chinese Academy of
Sciences, Changchun, 130022, China. E-mail: dwdong@ciac.jl.cn
†Electronic supplementary information (ESI) available: Experimental
details, full characterization data, and copies of NMR spectra for com-
pounds 1h–k, 2, and 3. See DOI: 10.1039/c2ob06709a
These results encouraged us to optimize the reaction con-
ditions, including solvent, reaction temperature and the ratio of
LR to 1a. A series of experiments revealed that the reaction
could proceed in other solvents, such as toluene and xylene, and
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Scheme 1 Reaction of 1a with Lawesson’s reagent in benzene.
Table 1 Synthesis of 2,3-dihydrothieno[3,2-c]pyridin-4(5H)-ones 2a
Scheme 2 Reaction of 1m with Lawesson’s reagent.
Entry
1
R1
R2
R3
2
Yield (%)b
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
Ph
H
H
H
H
H
H
H
H
H
H
H
Ph
H
H
H
H
H
H
H
H
H
H
Me
H
2a
2b
2c
2d
2e
2f
2g
2h
2i
82
80
83
84
81
87
74
76
71
83
68
85
2-MeC6H4
4-MeC6H4
2,4-Me2C6H3
2-MeOC6H4
4-MeOC6H4
2-ClC6H4
4-ClC6H4
4-CF3C6H4
Bn
9
10
11
12
1j
1k
1l
2j
2k
2l
Ph
4-MeC6H4
Scheme 3 Plausible mechanism for the domino reaction of 1 with
Lawesson’s reagent.
a Reagents and conditions: 1 (1.0 mmol), LR (0.5 mmol), toluene (dry,
10 mL), reflux, 9–11 h. b Isolated yields.
product 2m was not even detected by means of NMR spec-
troscopy (Scheme 2). This result suggested that the dimethyl-
amino group of substrate 1 is essential to the above domino
reaction, in which it played dual roles as activated group for the
thionation and a good leaving group for the intramolecular aza-
cyclization.14 Nevertheless, all the results demonstrated the
efficiency and synthetic interest of the domino reaction with
respect to a wide range of aminopropenoyl cyclopropanes 1. We
provided a facile and efficient one-pot synthesis of substituted
2,3-dihydrothieno[3,2-c]pyridin-4(5H)-one of type 2.
To gain an insight into the mechanism of the domino reaction,
some separate experiments were conducted. No reaction was
observed when 1a was subjected to N,N-dimethyl formamide
(DMF) in the absence of or in the presence of K2CO3 (1.5
equiv.) at 110 °C. Similarly, no reaction occurred when 1a was
treated with 1.5 equivalents of Lewis acid, such as SnCl4·5H2O,
FeCl3, or ZnCl2, in toluene under reflux. These results suggested
that LR played a crucial role and the thionation triggered the
domino reaction of 1.15 On the basis of all the findings, a plaus-
ible mechanism for the synthesis of 2 is presented in Scheme 3.
Initially, the dissociation of LR produces phosphorus sulfide A
in dry toluene under reflux.16 The strong electron-donating
dimethylamino group of 1 activated its conjugated carbonyl
group, and makes it more liable to be thionated by A than the
carbonyl group of amide moiety.17 The generated oxathiapho-
sphetane B sheds off thioxophosphine oxide to afford thioketone
C,18 which then undergoes regioselective ring-enlargement reac-
tion to form intermediate D.13,19 Finally, intramolecular aza-
cyclization of D along with the release of dimethylamine takes
place to give dihydrothieno[3,2-c]pyridin-4(5H)-one 2.14
0.5 equivalents of LR was sufficient for the dihydrothieno[3,2-c]
pyridin-4(5H)-one synthesis. However, much more LR, for
example more than 0.6 equivalents, would result in a complex
mixture. The optimal results were obtained when 1a was sub-
jected to 0.5 equivalents of LR in dry toluene under reflux for
10 h, whereby the reaction exclusively afforded 2a in 82% yield
(Table 1, entry 1).
Having established the optimal conditions for the dihy-
drothieno[3,2-c]pyridin-4(5H)-one synthesis, we intended to
determine its scope with respect to the R1, R2 and R3 groups. A
series of reactions of aminopropenoyl cyclopropanes 1b–j
bearing varied aryl and alkyl amide groups were then performed
with LR under the identical conditions as for 2a. It was observed
that all the reaction proceeded smoothly to afford the corre-
sponding dihydrothieno[3,2-c]pyridin-4(5H)-ones 2 in moderate
to good yields (Table 1, entries 2–10). The versatility of this
dihydrothieno[3,2-c]pyridin-4(5H)-one synthesis was further
evaluated by subjecting aminopropenoyl cyclopropane 1k and
LR to the identical conditions (Table 1, entry 11). The efficiency
of the cyclization proved to be suitable for aminopropenoyl
cyclopropane 1l to afford the corresponding substituted dihy-
drothieno[3,2-c]pyridin-4(5H)-one 2l in good yield (Table 1,
entry 12). In this case, a single regioisomer was exclusively
obtained, which indicated that the ring-opening reaction or ring-
enlargement proceeded in a regioselective manner.11a,13
To extend the scope of this thieno[3,2-c]pyridinone synthesis,
we prepared 1-cinnamoyl-N-phenylcyclopropane carboxamide
1m and subjected it with LR to toluene under reflux. Unfortu-
nately, the reaction formed a complex mixture, and the desired
1640 | Org. Biomol. Chem., 2012, 10, 1639–1644
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Table 2 One-pot synthesis of thieno[3,2-c]pyridin-4(5H)-ones 3a
analyzer. Mass spectra were recorded on LDI-1700 MALDI-TOF
spectrometer. Melting points were determined on a TECH
X-4 micro-melting point apparatus.
Synthesis and analytical data of substrates 1
R1
R2
R3
3
Yield (%)b
1a–g, 1l, and 1m are known compounds, they were readily pre-
Entry
1
pared according to reported procedures.11,13b,21
1
2
3
4
5
1a
1e
1h
1k
1l
Ph
H
H
H
H
Ph
H
H
H
Me
H
3a
3e
3h
3k
3l
75
78
73
67
82
2-MeOC6H4
4-ClC6H4
Ph
N-(4-Chlorophenyl)-1-[3-(dimethylamino)acryloyl]cycloprop-
1
anecarboxamide (1h). White solid, mp 186–187 °C; H NMR
4-MeC6H4
(300 MHz, CDCl3): δ = 1.46 (dd, J1 = 7.8, J2 = 5.2, 2H), 1.85
(dd, J1 = 7.8, J2 = 5.2, 2H), 2.83 (s, 3H), 3.14 (s, 3H), 4.69 (d, J
= 12, 1H), 7.23–7.28 (m, 2H), 7.56–7.60 (m, 2H), 7.75 (d, J =
12, 1H), 12.27 (s, 1H); 13C NMR (100 MHz, CDCl3): δ = 20.0,
31.2, 37.1, 45.0, 88.0, 121.0, 127.9, 128.5, 137.3, 154.6, 169.2,
196.2. Anal. Calcd. for C15H17ClN2O2: C, 61.54; H, 5.85; N,
9.57. Found: C, 61.31; H, 5.80; N, 9.68.
a Reagents and conditions: 1 (1.0 mmol), LR (0.5 mmol), toluene
(anhydrous, 10 mL), reflux, 9–11 h, then DDQ (1.5 mmol), reflux, 1 h.
b Isolated yields.
Inspired by the above results, we envisaged to explore one-pot
synthesis of thieno[3,2-c]pyridin-4(5H)-ones from 1. Thus, the
reaction of 1a and LR was performed in toluene under reflux for
10 h, and then an oxidant, 2,3-dichloro-5,6-dicyano-1,4-benzo-
quinone (DDQ), was added to the resulting mixture which was
left under reflux for another hour.20 The reaction furnished a
product after work-up and purification by column chromato-
graphy. The product was characterized as 5-phenylthieno[3,2-c]
pyridin-4(5H)-one 3a on the basis of its spectral and analytical
data, and the overall yield reached 75% (Table 2, entry 1). In the
same fashion, some selected aminopropenoyl cyclopropanes 1
were subjected to LR and DDQ in toluene under reflux to afford
the corresponding thieno[3,2-c]pyridin-4(5H)-ones 3 in moderate
to good overall yields (Table 2, entries 2–5). Therefore, we have
provided a facile one-pot synthesis of substituted thieno[3,2-c]
pyridin-4(5H)-ones of type 3.
1-[3-(Dimethylamino)acryloyl]-N-(4-(trifluoromethyl)phenyl)-
cyclopropanecarboxamide (1i). White solid, mp 162–163 °C;
1H NMR (300 MHz, CDCl3): δ = 1.47 (dd, J1 = 7.8, J2 = 5.2,
2H), 1.86 (dd, J1 = 7.8, J2 = 5.2, 2H), 2.83 (s, 3H), 3.14 (s, 3H),
4.68 (d, J = 12, 1H), 7.54 (d, J = 8.7, 2H), 7.73 (d, J = 8.7, 2H),
7.75 (d, J = 12, 1H), 12.53 (s, 1H); 13C NMR (100 MHz,
CDCl3): δ = 20.3, 31.4, 37.2, 45.1, 88.0, 119.5, 124.3 (q, 1JCF
=
2
3
270) 124.9 (q, JCF = 32), 125.9 (d, JCF = 3), 141.8, 154.8,
169.8, 196.3. Anal. Calcd. for C16H17F3N2O2: C, 58.89; H,
5.25; N, 8.58. Found: C, 58.68; H, 5.21; N, 8.65.
N-Benzyl-1-[3-(dimethylamino)acryloyl]cyclopropanecarbox-
1
amide (1j). Liquid. H NMR (300 MHz, CDCl3): δ = 1.31 (t, J
= 3.6, 2H), 1.67 (t, J = 3.6, 2H), 2.70 (s, 3H), 3.00 (s, 3H), 4.45
(t, J = 2.7, 2H), 4.65 (d, J = 12, 1H), 7.18–7.27 (m, 5H), 7.58
(dd, J1 = 12, J2 = 3.0, 1H), 9.80 (s, 1H); 13C NMR (100 MHz,
CDCl3): δ = 17.9, 31.3, 36.4, 42.9, 44.3, 88.6, 126.4, 126.9,
127.9, 138.4, 153.6, 170.5, 195.0. Anal. Calcd. for C16H20N2O2:
C, 70.56; H, 7.40; N, 10.29. Found: C, 70.23; H, 7.46; N, 10.37.
Conclusions
In summary, a facile and efficient one-pot synthesis of substi-
tuted 2,3-dihydrothieno[3,2-c]pyridin-4(5H)-ones 2 is developed
from aminopropenoyl cyclopropanes 1 mediated by Lawesson’s
reagent, which involved sequential regioselective thionation,
ring-enlargement, and intramolecular aza-cyclization reactions.
This protocol was further utilized as a one-pot route to thieno
[3,2-c]pyridin-4(5H)-ones 3 with DDQ as oxidant. The one-pot
procedure is associated with readily available substrates, mild
conditions, and a wide range of potential synthetic products.
Further work on the utilization and extension of the scope of the
methodology are currently under investigation in our laboratory.
1-[3-(Dimethylamino)but-2-enoyl]-N-phenylcyclopropanecar-
boxamide (1k). To a well-stirred solution of 1-acetyl-N-phenyl
cyclopropanecarboxamide (10 mmol) in benzene (25 mL) was
added 1,1-dimethoxy-N,N-dimethylethanamine (15 mmol) drop-
wise within 5 min at room temperature. The reaction mixture
was heated to reflux and stirred for 6 h, then it was slowly
poured into saturated aqueous NaCl (200 mL), which was
extracted with dichloromethane (3 × 20 mL). The combined
organic phase was washed with water, dried over anhydrous
MgSO4, filtered and evaporated in vacuo. The crude product was
purified by column chromatography (silica gel, petroleum ether :
ethyl acetate (3 : 1)) to give 1k as a white solid (73%). White
Experimental
1
solid, mp 137–138 °C; H NMR (300 MHz, CDCl3): δ = 1.36
General methods
(dd, J1 = 7.5, J2 = 5.2, 2H), 1.73 (dd, J1 = 7.5, J2 = 5.2, 2H),
2.54 (s, 3H), 3.01 (s, 6H), 4.78 (s, 1H), 7.04 (t, J = 7.5, 1H),
7.30 (d, J = 7.5, 2H), 7.61 (d, J = 7.5, 2H), 11.51 (s, 1H); 13C
NMR (100 MHz, CDCl3): δ = 16.6, 19.0, 33.5, 40.1, 89.5,
120.0, 123.3, 128.6, 138.7, 164.9, 169.6, 194.8. Anal. Calcd. for
C16H20N2O2: C, 70.56; H, 7.40; N, 10.29. Found: C, 70.90; H,
7.48; N, 10.20.
All reagents were purchased from commercial sources and used
1
without treatment, unless otherwise indicated. H NMR and 13C
NMR spectra were recorded at 25 °C at 400 MHz (or 300 MHz)
and 100 MHz, respectively. IR spectra (KBr) were recorded on
FTIR spectrophotometer in the range of 400–4000 cm−1
.
Elemental analyses were carried out on a Perkin-Elmer PE-2400
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Synthesis and analytical data of 2
CDCl3): δ = 3.18 (t, J = 8.0, 2H), 3.43 (t, J = 8.0, 2H), 3.80 (s,
3H), 6.19 (d, J = 7.2, 1H), 7.02 (d, J = 7.8, 2H), 7.03 (d, J =
7.2, 1H), 7.23 (dd, J1 = 7.8, J2 = 1.5, 1H), 7.38 (t, J = 7.8, 1H);
13C NMR (100 MHz, CDCl3): δ = 32.7, 33.3, 55.7, 101.3,
112.0, 120.6, 126.6, 128.6, 129.1, 129.9, 137.6, 154.2, 154.5,
158.2. IR (KBr, cm−1) 3080, 3064, 2937, 2920, 2881, 2831,
1855, 1643, 1575, 1523, 1500, 1458, 1434, 1352, 1284, 1022,
757. Anal. Calcd. for C14H13NO2S: C, 64.84; H, 5.05; N, 5.40.
Found: C, 64.60; H, 5.09; N, 5.43.
Typical procedure for the synthesis of 2,3-dihydrothieno[3,2-c]
pyridin-4(5H)-ones 2 (with 2a as an example). To a solution of
1a (1.0 mmol) in anhydrous toluene (10 mL) was added Lawes-
son’s reagent (0.5 mmol) in one portion. The mixture was heated
to reflux and stirred for 10 h. After 1a was consumed as moni-
tored by TLC, the reaction was cooled down to room tempera-
ture. The resulting mixture was then poured into saturated
aqueous NaCl (50 mL) and extracted with dichloromethane (3 ×
20 mL). The combined organic phase was washed with water (3
× 20 mL), dried over MgSO4, filtered and concentrated in vacuo.
The crude product was purified by flash column chromatography
(silica gel, petroleum ether : EtOAc (2 : 1)) to give 2a as a white
solid in 82% yield.
5-(4-Methoxyphenyl)-2,3-dihydrothieno[3,2-c]pyridin-4(5H)-one
(2f). White solid, mp 148–150 °C; 1H NMR (300 MHz,
CDCl3): δ = 3.28–3.34 (m, 2H), 3.41–3.47 (m, 2H), 3.84 (s,
3H), 6.21 (d, J = 6.9, 1H), 6.94–6.99 (m, 2H), 7.18 (d, J = 6.9,
1H), 7.23–7.28 (m, 2H); 13C NMR (100 MHz, CDCl3): δ =
32.9, 33.4, 55.5, 101.8, 114.3, 126.8, 127.6, 133.5, 137.1, 154.6,
158.6, 159.2. IR (KBr, cm−1) 3047, 2914, 1637, 1575, 1527,
1490, 1076, 761, 700. Anal. Calcd. for C14H13NO2S: C, 64.84;
H, 5.05; N, 5.40. Found: C, 64.63; H, 5.02; N, 5.46.
5-Phenyl-2,3-dihydrothieno[3,2-c]pyridin-4(5H)-one
(2a).
1
White solid, mp 152–153 °C; H NMR (300 MHz, CDCl3): δ =
3.29–3.37 (m, 2H), 3.42–3.49 (m, 2H), 6.24 (d, J = 6.9, 1H),
7.21 (d, J = 6.9, 1H), 7.34–7.37 (m, 2H), 7.39–7.50 (m, 3H);
13C NMR (100 MHz, CDCl3): δ = 32.8, 33.4, 101.9, 126.6,
5-(2-Chlorophenyl)-2,3-dihydrothieno[3,2-c]pyridin-4(5H)-one
(2g). White solid, mp 184–185 °C; 1H NMR (300 MHz,
CDCl3): δ = 3.26–3.37 (m, 2H), 3.40–3.49 (m, 2H), 6.26 (d, J =
7.2, 1H), 7.04 (d, J = 7.2, 1H), 7.35–7.40 (m, 3H), 7.54 (dd, J1
= 6.0, J2 = 3.0, 1H); 13C NMR (100 MHz, CDCl3): δ = 32.8,
33.2, 102.0, 126.8, 127.6, 129.3, 130.0, 130.3, 131.8, 136.5,
138.0, 155.3, 157.8. IR (KBr, cm−1) 1639, 1587, 1571, 1525,
1492, 1438, 1182, 958, 756, 701. Anal. Calcd. for
C13H10ClNOS: C, 59.20; H, 3.82; N, 5.31. Found: C, 59.38; H,
3.79; N, 5.35.
126.8, 128.1, 129.0, 136.7, 140.6, 154.8, 158.3. IR (KBr, cm−1
)
3083, 2918, 1660, 1589, 1573, 1446, 1263, 746, 678. Anal.
Calcd. for C13H11NOS: C, 68.09; H, 4.84; N, 6.11. Found: C,
68.30; H, 4.80; N, 6.06.
5-o-Tolyl-2,3-dihydrothieno[3,2-c]pyridin-4(5H)-one
(2b).
1
White solid, mp 142–143 °C; H NMR (300 MHz, CDCl3): δ =
2.16 (s, 3H), 3.30–3.36 (m, 2H), 3.44–3.49 (m, 2H), 6.24 (d, J =
6.9, 1H), 7.06 (d, J = 7.2, 1H), 7.16 (d, J = 6.9, 1H), 7.28–7.35
(m, 3H); 13C NMR (100 MHz, CDCl3): δ = 17.6, 32.8, 33.3,
101.8, 126.9, 127.3, 128.8, 130.9, 135.2, 136.8, 139.8, 154.8,
158.1. IR (KBr, cm−1) 3076, 3049, 2981, 2947, 2916, 2881,
2840, 1865, 1643, 1573, 1521, 1490, 1429, 1352, 1276, 1039,
943, 777. Anal. Calcd. for C14H13NOS: C, 69.11; H, 5.39; N,
5.76. Found: C, 69.30; H, 5.44; N, 5.70.
5-(4-Chlorophenyl)-2,3-dihydrothieno[3,2-c]pyridin-4(5H)-one
(2h). White solid, mp 216–217 °C; 1H NMR (300 MHz,
CDCl3): δ = 3.32 (t, J = 8.1, 2H), 3.46 (t, J = 8.1, 2H), 6.25 (d,
J = 7.2, 1H), 7.17 (d, J = 7.2, 1H), 7.31 (d, J = 8.7, 2H), 7.44
(d, J = 8.7, 2H); 13C NMR (100 MHz, CDCl3): δ = 32.9, 33.4,
102.3, 126.8, 127.9, 129.3, 134.1, 136.3, 139.0, 155.2, 158.1. IR
(KBr, cm−1) 3083, 3045, 2948, 2887, 2846, 1880, 1643, 1598,
1575, 1525, 1488, 1434, 1355, 1282, 1016, 945, 840. Anal.
Calcd. for C13H10ClNOS: C, 59.20; H, 3.82; N, 5.31. Found: C,
59.39; H, 3.78; N, 5.36.
5-p-Tolyl-2,3-dihydrothieno[3,2-c]pyridin-4(5H)-one
(2c).
1
White solid, mp 190–191 °C; H NMR (300 MHz, CDCl3): δ =
2.40 (s, 3H), 3.28–3.34 (m, 2H), 3.42–3.48 (m, 2H), 6.22 (d, J =
7.2, 1H), 7.19 (d, J = 7.2, 1H), 7.22–7.28 (m, 4H); 13C NMR
(100 MHz, CDCl3): δ = 21.0, 32.7, 33.3, 101.7, 126.2, 126.7,
129.6, 136.8, 138.0, 154.6, 158.3. IR (KBr, cm−1) 3083, 3024,
2981, 2912, 2848, 1880, 1645, 1575, 1527, 1506, 1436, 1355,
1280, 1257, 1072, 939, 825. Anal. Calcd. for C14H13NOS: C,
69.11; H, 5.39; N, 5.76. Found: C, 68.93; H, 5.34; N, 5.81. MS
calcd. m/z 243.1, found 244.1 [(M + 1)+].
5-[4-(Trifluoromethyl)phenyl]-2,3-dihydrothieno[3,2-c] pyridin-
4(5H)-one (2i). White solid, mp 212–213 °C; 1H NMR
(300 MHz, CDCl3): δ = 3.29–3.35 (m, 2H), 3.44–3.50 (m, 2H),
6.28 (d, J = 7.2, 1H), 7.18 (d, J = 7.2, 1H), 7.51 (d, J = 8.1,
2H), 7.74 (d, J = 8.1, 2H); 13C NMR (100 MHz, CDCl3): δ =
1
3
32.9, 33.4, 102.7, 123.6 (q, JCF = 270), 126.3 (d, JCF = 3),
2
5-(2,4-Dimethylphenyl)-2,3-dihydrothieno[3,2-c]pyridin-4(5H)-
one (2d). White solid, mp 160–161 °C; H NMR (300 MHz,
127.0, 127.1, 130.4 (q, JCF = 33), 136.0, 143.5, 155.6, 158.0.
1
IR (KBr, cm−1) 3085, 1654, 1598, 1571, 1490, 1018, 838, 771,
700. Anal. Calcd. for C14H10F3NOS: C, 56.56; H, 3.39; N, 4.71.
Found: C, 56.75; H, 3.37; N, 4.75. MS calcd. m/z 297.1, found
298.1 [(M + 1)+].
CDCl3): δ = 2.11 (s, 3H), 2.35 (s, 3H), 3.28–3.33 (m, 2H),
3.35–3.47 (m, 2H), 6.21 (d, J = 6.9, 1H), 7.01–7.12 (m, 4H);
13C NMR (100 MHz, CDCl3): δ = 17.4, 21.0, 32.8, 33.3, 101.7,
126.8, 126.9, 127.5, 131.6, 134.7, 136.9, 137.3, 138.6, 154.6,
158.3. IR (KBr, cm−1) 3080, 3051, 2945, 2912, 2875, 1892,
1639, 1579, 1527, 1506, 1425, 1353, 1263, 1062, 946, 885,
823. Anal. Calcd. for C15H15NOS: C, 70.01; H, 5.87; N, 5.44.
Found: C, 70.23; H, 5.81; N, 5.40.
5-Benzyl-2,3-dihydrothieno[3,2-c]pyridin-4(5H)-one
(2j).
1
White solid, mp 88–89 °C; H NMR (300 MHz, CDCl3): δ =
3.27–3.31 (m, 2H), 3.38–3.44 (m, 2H), 5.10 (s, 2H), 6.14 (d, J =
7.2, 1H), 7.13 (d, J = 1H), 7.28–7.36 (m, 5H); 13C NMR
(100 MHz, CDCl3): δ = 32.8, 33.4, 51.4, 102.1, 126.6, 127.9,
128.0, 128.8, 136.0, 136.6, 154.3, 158.7. IR (KBr, cm−1) 3055,
2935, 1639, 1589, 1575, 1529, 1421, 1261, 724, 694. Anal.
5-(2-Methoxyphenyl)-2,3-dihydrothieno[3,2-c]pyridin-4(5H)-one
(2e). White solid, mp 173–174 °C; 1H NMR (600 MHz,
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Calcd. for C14H13NOS: C, 69.11; H, 5.39; N, 5.76. Found: C,
68.90; H, 5.44; N, 5.81.
1573, 1498, 1463, 1438, 1286, 1018, 956, 771. Anal. Calcd. for
C14H11NO2S: C, 65.35; H, 4.31; N, 5.44. Found: C, 65.11; H,
4.28; N, 5.49.
6-Methyl-5-phenyl-2,3-dihydrothieno[3,2-c]pyridin-4(5H)-one
(2k). White solid, mp 179–180 °C; 1H NMR (300 MHz,
CDCl3): δ = 1.92 (s, 3H), 3.28 (t, J = 8.1, 2H), 3.41 (t, J = 8.1,
2H), 6.13 (s, 1H), 7.17 (d, J = 6.9, 2H), 7.40–7.52 (m, 3H); 13C
NMR (100 MHz, CDCl3): δ = 21.6, 32.7, 33.3, 101.9, 123.7,
5-(4-Chlorophenyl)thieno[3,2-c]pyridin-4(5H)-one (3h). White
solid, mp 184–185 °C; H NMR (400 MHz, CDCl3): δ = 6.77
1
(d, J = 7.2, 1H), 7.19 (d, J = 7.2, 1H), 7.34 (d, J = 5.2, 1H),
7.36–7.39 (m, 2H), 7.46–7.48 (m, 2H), 7.69 (d, J = 5.2, 1H);
13C NMR (100 MHz, CDCl3): δ = 102.2, 124.9, 125.6, 128.2,
128.0, 128.5, 129.5, 138.7, 145.0, 154.6, 159.7. IR (KBr, cm−1
)
129.4, 131.1, 132.1, 134.1, 139.3, 147.5, 158.5. IR (KBr, cm−1
)
3068, 3039, 2948, 2916, 2879, 1890, 1633, 1581, 1542, 1485,
1450, 1396, 1271, 1064, 1018, 912, 854, 761, 700. Anal. Calcd.
for C14H13NOS: C, 69.11; H, 5.39; N, 5.76. Found: C, 69.42; H,
5.45; N, 5.72.
3056, 2948, 1641, 1577, 1527, 1481, 1259, 946, 730. Anal.
Calcd. for C13H8ClNOS: C, 59.66; H, 3.08; N, 5.35. Found: C,
59.90; H, 3.05; N, 5.30.
6-Methyl-5-phenylthieno[3,2-c]pyridin-4(5H)-one (3k). White
solid, mp 129–130 °C; H NMR (400 MHz, CDCl3): δ = 2.01
2-Phenyl-5-p-tolyl-2,3-dihydrothieno[3,2-c]pyridin-4(5H)-one
(2l). White solid, mp 140–141 °C; 1H NMR (600 MHz,
CDCl3): δ = 2.40 (s, 3H), 3.49 (dd, J1 = 16.8, J2 = 7.7, 1H),
3.73 (dd, J1 = 16.8, J2 = 7.7, 1H), 5.15 (t, J = 9.0, 1H), 6.21 (d,
J = 7.1, 1H), 7.24 (d, J = 7.1, 1H), 7.26–7.28 (m, 5H), 7.34 (t, J
= 7.8, 2H), 7.44 (d, J = 7.4, 2H); 13C NMR (100 MHz, CDCl3):
δ = 20.9, 41.6, 53.6, 101.4, 125.1, 126.1, 126.9, 127.6, 128.5,
1
(s, 3H), 6.64 (s, 1H), 7.20–7.24 (m, 3H), 7.44–7.47 (m, 1H),
7.50–7.54 (m, 2H), 7.61 (d, J = 5.2, 1H); 13C NMR (100 MHz,
CDCl3): δ = 21.7, 101.4, 123.0, 125.3, 128.3, 128.5, 128.9,
129.5, 138.8, 140.3, 147.8, 160.0. IR (KBr, cm−1) 3078, 3008,
2958, 2921, 1639, 1598, 1577, 1564, 1488, 1294, 769, 700.
Anal. Calcd. for C14H11NOS: C, 69.68; H, 4.59; N, 5.80. Found:
C, 69.44; H, 4.63; N, 5.86.
129.5, 137.2, 137.9, 138.0, 141.5, 153.6, 158.0. IR (KBr, cm−1
)
3041, 2839, 1650, 1610, 1581, 1512, 1249, 1020, 831. Anal.
Calcd. for C20H17NOS: C, 75.20; H, 5.36; N, 4.39. Found: C,
75.45; H, 5.32; N, 4.44.
2-Phenyl-5-p-tolylthieno[3,2-c]pyridin-4(5H)-one (3l). White
1
solid, mp 216–217 °C; H NMR (300 MHz, CDCl3): δ = 2.42
(s, 3H), 6.72 (d, J = 7.2, 1H), 7.22 (d, J = 7.2, 1H), 7.31 (s, 4H),
7.35 (d, J = 7.2, 1H), 7.43 (t, J = 7.5, 2H), 7.67 (d, J = 7.5, 2H),
7.90 (s, 1H); 13C NMR (100 MHz, CDCl3): δ = 21.1, 101.7,
120.8, 126.1, 126.6, 128.3, 129.0, 129.9, 132.2, 132.9, 133.5,
138.2, 138.4, 143.2, 146.8, 158.7. IR (KBr, cm−1) 2954, 1647,
1616, 1577, 1523, 1512, 1413, 1325, 1164, 1062, 837, 754.
Anal. Calcd. for C20H15NOS: C, 75.68; H, 4.76; N, 4.41.
Found: C, 75.90; H, 4.80; N, 4.46.
Synthesis and analytical data of 3
Typical procedure for the synthesis of thieno[3,2-c]pyridin-4
(5H)-ones 3 (with 3a as an example). To a solution of 1a
(1.0 mmol) in anhydrous toluene (10 mL) was added Lawesson’s
reagent (0.5 mmol) in one portion. The mixture was heated to
reflux and stirred for 10 h. After 1a was consumed as monitored
by TLC, DDQ (1.5 mmol) was added. The reaction was stirred
under reflux for a further 1 h, then cooled down to room temp-
erature. The resulting mixture was then poured into saturated
aqueous NaCl (50 mL) and extracted with dichloromethane (3 ×
20 mL). The combined organic phase was washed with water (3
× 20 mL), dried over MgSO4, filtered and concentrated in vacuo.
The crude product was purified by flash column chromatography
(silica gel, petroleum ether : EtOAc (5 : 1)) to give 3a as a white
solid in 75% yield.
Acknowledgements
Financial support of this research by the National Natural
Science Foundation of China (20572013 and 20872136) is
greatly acknowledged.
Notes and references
5-Phenylthieno[3,2-c]pyridin-4(5H)-one (3a). White solid, mp
86–87 °C; H NMR (400 MHz, CDCl3): δ = 6.74 (d, J = 7.2,
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1H), 7.22 (d, J = 7.2, 1H), 7.30 (d, J = 5.2, 1H), 7.40–7.50 (m,
5H), 7.69 (d, J = 5.2, 1H); 13C NMR (100 MHz, CDCl3): δ =
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5-(2-Methoxyphenyl)thieno[3,2-c]pyridin-4(5H)-one
(3e).
1
White solid, mp 147–148 °C; H NMR (300 MHz, CDCl3): δ =
3.81 (s, 3H), 6.74 (d, J = 7.2, 1H), 7.04–7.12 (m, 3H),
7.28–7.32 (m, 2H), 7.40–7.45 (m, 1H), 7.70 (d, J = 5.1, 1H);
13C NMR (100 MHz, CDCl3): δ = 55.7, 101.2, 112.2, 120.7,
124.1, 125.5, 128.8, 129.5, 130.0, 131.1, 133.4, 147.5, 154.5,
158.6. IR (KBr, cm−1) 3066, 3010, 2977, 2842, 1645, 1596,
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