2-Acetylthienopyridine Synthesis via Thiolation and Copper-Catalyzed Cyclization of o-Propynol Fluoropyridine Using Xanthate as a Thiol Surrogate

Article abstract of DOI:10.1021/acs.joc.8b01037

2-Acylthienopyridines and related heterocycles are readily prepared in moderate to good yields under mild conditions by a nucleophilic thiolation, copper-catalyzed cyclization, and an oxidation cascade process using potassium xanthate as the thiol source.

Full text of DOI:10.1021/acs.joc.8b01037

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Note
2-Acetylthienopyridines Synthesis via Thiolation and Cu-catalyzed Cyclization
of ortho-Propynol Fluoropyridine Using Xanthate as a Thiol Surrogate
Yibiao Li, Xianglin Luo, Yan Shao, and Lu Chen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01037 • Publication Date (Web): 16 Jul 2018
Downloaded from http://pubs.acs.org on July 16, 2018
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2-Acetylthienopyridines Synthesis via Thiolation and
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Cu-catalyzed Cyclization of ortho-Propynol Fluoropyridine
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Using Xanthate as a Thiol Surrogate
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Yibiao Li,* Xianglin Luo, Yan Shao and Lu Chen
School of Chemical & Environmental Engineering, Wuyi University, Jiangmen, Guangdong Province, 529090, P. R.
China
Eꢀmail: leeyib268@126.com
ABSTRACT: 2ꢀAcylthienopyridines and related heterocycles are readily prepared in
moderateꢀtoꢀgood yields under mild conditions by a nucleophilic thiolation, copperꢀcatalyzed
cyclization and oxidation cascade process using potassium xanthate as the thiol source. Moreover,
excellent chemoꢀselectivity, broad substrate scope and good functional group tolerance are
prominent features of this transformation.
The development of efficient and sustainable methodologies for the synthesis of heteroatomꢀrich
heterocycles is crucial in modern organic synthesis. Such compounds are prevalent in natural
products, pharmaceuticals and even organic lightꢀemitting materials.1 The 2ꢀacylthienopyridine
scaffold is commonly found in various drug candidates and shows a broad range of bioactivities.
This motif appears as the core of many potential smallꢀmolecule drugs, as reported by several
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research groups (Figure 1). For example, a 2ꢀacylthieno[2,3ꢀb]pyridineꢀbased drug has been
identified for the treatment of hepatitis C.2 Krauze and coꢀworkers have also utilized the
2ꢀacylthieno[2,3ꢀb]pyridine scaffold as a new class of multidrug resistance modulator 2.3 Sugano and
coꢀworkers have found that this motif also appears in promising new antiꢀtumor agents 3, which are
selective against a tumorigenic cell line.4 Other examples of bioactivity include antiꢀproliferative
activity against the NCIꢀ60 cell lines,5 binders to dopamine D2 receptor,6 inhibitors of IκB kinaseꢀβ,7
trans activation of HIVꢀ1,8 and selective inhibition of ICAMꢀ1 and Eꢀselectin expression in human
endothelial cells.9
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Figure 1. Selected 2-acylthieno[2,3-b]pyridine derivatives with biological activities
Despite the importance of 2ꢀacylthienopyridines, synthetic methodology to efficiently construct
this motif is very limited, which hampers further studies and applications in medicinal chemistry.
Sekar and coꢀworkers utilized 2ꢀiodochalcones and xanthate as a sulfur source to synthesize
2ꢀacylbenzothiophene compounds through αꢀCꢀH functionalization.10 Recently, Nguyen and
coꢀworkers
reported an
unusual approach to 2ꢀacylbenzothiophenes by using
N,NꢀDiisopropylethylamine as a sulfur activator to promote the cyclization reaction.11 Compared
with 2ꢀacylbenzothiophene derivatives, 2ꢀacylthienopyridine has broader biological activity;
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however, the pyridyl compound is more challenging to synthesize because of the ability of pyridine
to coordinate to transition metal catalysts, and the electronꢀdeficient nature of a pyridine ring
compared with that of a phenyl ring.12 In addition to acylation reactions and other traditional
synthetic methods, one common approach to the synthesis of 2ꢀacylthienopyridines is the
condensation of 2ꢀhalobenzaldehyde with 2ꢀmercaptoacetone under basic aqueous conditions.13
GonzálezꢀRomero and coꢀworkers reported another approach to the synthesis of
2ꢀacylthienopyridines by converting a benzyl azido group to carbonyl group.14 In these reported
methods, the starting materials were either expensive or required several synthetic steps to prepare.
During the course of our studies into the development of new reactions involving sulfurꢀcontaining
heterocycles using Na2S or potassium xanthate as a thiol source,15 we observed unusually efficient
nucleophilic substitution of aryl fluoride groups by thiol nucleophiles. Herein, we report an efficient
and facile approach to 2ꢀacylthienopyridines and 2ꢀacetylbenzothiophenes. We achieved this by
employing the wellꢀdeveloped Pdꢀcatalyzed Sonogashira reaction between two commercially
available starting materials, followed by nucleophilic thiolation, copperꢀcatalyzed cyclization and
oxidation cascade process.
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Initially, we examined the reaction of 1ꢀ(2ꢀfluoropyridinꢀ3ꢀyl)pentꢀ1ꢀynꢀ3ꢀol 1a and potassium
xanthate in DMSO, without a catalyst, and no product was obtained (Table 1, entry 1). Only a trace
of the desired product 2a was obtained when PdCl2 was used as a catalyst (Table 1, entry 2). To our
delight, CuCl significantly improved the yield and gave the desired product in 68% yield (Table 1,
entry 3). Encouraged by these results, we screened various copper salts to further increase the
efficiency of the reaction (Table 1, entries 3ꢀ7). The results showed that the Cu(acac)2 was superior to
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the other catalysts screened and gave the desired product in 93% yield. Moderate yields (73%) of
desired product 2a were obtained using a decreased amount of EtOCS2K (1.5 equiv.) (Table 1, entry
8). Subsequently, we investigated various thiol surrogates, such as thiourea, Na2S·9H2O, S8 and
(NH4)2S (Table 1, entries 10ꢀ13). None of the thiol surrogates promoted the reaction well, only
Na2S·9H2O generated the 1ꢀ(thieno[2,3ꢀb]pyridinꢀ2ꢀyl)propanꢀ1ꢀone 2a in 31% yield. Finally, a
solvent screen revealed that this transformation works in DMF, DMA and dioxane although they are
all less effective than DMSO (Table 1, entries 14ꢀ16). It seems that the presence of O2 (1 atm) does
not facilitate the reaction (Table 1 entry 17). Decreased yields were obtained when either lower or
elevated reaction temperatures were used (Table 1, entries 18ꢀ19).
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Table 1. Optimization of Reaction Conditions a
entry
catalyst
sulphur source
EtOCS2K
EtOCS2K
EtOCS2K
EtOCS2K
EtOCS2K
EtOCS2K
EtOCS2K
EtOCS2K
solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
Yield (%)b
n.d.
<5
1c
2
ꢀ
PdCl2
3
CuCl
68
4
CuBr
78
5
CuI
81
6
Cu(OTf)2
Cu(acac)2
Cu(acac)2
91
7
93
8d
73
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9e
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
EtOCS2K
thiourea
Na2S·9H2O
S8
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
85
n.d.
31
<5
<5
83
76
23
19
85
36
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12
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17f
18g
19h
(NH4)2S
EtOCS2K
EtOCS2K
EtOCS2K
EtOCS2K
EtOCS2K
EtOCS2K
DMAc
dioxane
dioxane
DMSO
DMSO
a Reaction conditions: alkyne 1 (1.0 mmol), catalyst (10 mol%), sulfur source (2.0 mmol) in solvent
b
c
(3.0 mL) at 100 °C for 12 h; Isolated yields; 1ꢀ(thieno[2,3ꢀb]pyridinꢀ2ꢀyl)propanꢀ1ꢀol was
obtained as major product; d EtOCS2K (1.5 mmol) was used; under N2 condition; under O2 (1 atm)
e
f
condition; g Reaction was carried out at 130 °C; h Reaction was carried out at 80 °C.
To verify the practicality of the process, we next explored the scope of the thiolation, cyclization
and oxidation cascade, as shown in Scheme 1. The results showed that this approach to
2ꢀacylthienopyridines is quite robust. Initially, R2 substituents at the propargyglic alcohol moiety of
1ꢀ(2ꢀalkynyl)fluoropyridine 1 were evaluated (Scheme 1, 2aꢀe). The results demonstrated that methyl,
ethyl, isopropyl, nꢀbutyl, nꢀpentyl, secꢀpentyl and 3ꢀheptyl groups can be well tolerated and gave the
corresponding products in good yields. Cl or Brꢀsubstituted 4ꢀ(2ꢀhalopyridinꢀ3ꢀyl)butꢀ3ꢀynꢀ2ꢀol also
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afforded 2ꢀacetylthienopyridine products 2b in 41% and 10% yields, respectively. This result shows
that the reactivity of nucleophilic substitution on halogen atoms follows the descending order of F >
Cl > Br. Importantly, substrates with an aryl group as the R2 substituent were compatible with this
reaction’s conditions, and the corresponding thiolation/cyclization products 2f and 2g were obtained
in good yields. Next, the R1 substituents on the pyridyl rings of 1ꢀ(2ꢀalkynolyl)fluoropyridine 1 were
evaluated. When 1ꢀ(2ꢀfluoroꢀ5ꢀmethylpyridinꢀ3ꢀyl)heptꢀ1ꢀynꢀ3ꢀol was employed as the substrate, the
desired product 2h was obtained in 83% yield. Subsequently, several substituted 2ꢀfluoro
alkynylpyridines were examined and the results demonstrated that both electronꢀdeficient and
electronꢀrich pyridines reacted with potassium xanthate to give the corresponding
2ꢀacylthienopyridine products in moderateꢀtoꢀgood yields. Notably, 2ꢀacylthieno[2,3ꢀb]pyridines
(2aꢀ2i, 2s), 2ꢀacylthieno[3,2ꢀb]pyridines16 (2jꢀ2l) and 2ꢀacylthieno[2,3ꢀc]pyridines17 (2mꢀ2r) were
readily prepared in good yields by employing this process.
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Scheme 1. Synthesis of 2-acylthienopyridines using xanthate as thiol precursor a
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a Reaction conditions: alkyne 1 (1.0 mmol), Cu(acac)2 (10 mol%), EtOCS2K (2.0 mmol) in DMSO
b
c
(2.0 mL) at 100 °C for 12 h; Yields are given for isolated; 4ꢀ(2ꢀchloropyridinꢀ3ꢀyl)butꢀ3ꢀynꢀ2ꢀol
was used as substrate; d 4ꢀ(2ꢀbromopyridinꢀ3ꢀyl)butꢀ3ꢀynꢀ2ꢀol was used as substrate.
To further broaden the scope of the thiolation, cyclization and oxidation process, a nonꢀpyridyl
aryl fluoride was used. Specifically, when 3ꢀ(2ꢀfluorophenyl)ꢀ1ꢀphenylpropꢀ2ꢀynꢀ1ꢀol was used as
the
substrate,
the
copperꢀcatalyzed
thiolation
and
Sꢀcyclization
of
3ꢀ(2ꢀfluorophenyl)ꢀ1ꢀphenylpropꢀ2ꢀynꢀ1ꢀol afforded 2ꢀacylbenzo[b]thiophenes 3a in 92% yield
(Scheme 2).
Scheme 2. Synthesis of 2-acylbenzo[b]thiophenes
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For a clearer understanding of the reaction mechanism, control reactions were performed. When
the reaction was performed in the absence of copper, 4ꢀethylꢀ1ꢀ (2ꢀfluoroꢀ5ꢀmethylpyridinꢀ3ꢀone) 4a
and 2ꢀethylꢀ1ꢀ5ꢀmethylthieno[2,3ꢀb]pyridinꢀ2ꢀyl) hexanꢀ1ꢀol 4b were formed (Scheme 3). When
these two products were used as reaction substrates under the standard reaction, no
2ꢀacylthienopyridine product was formed. These results suggest that the reaction occurs through a
Cuꢀcatalyzed process rather than a stepwise reaction.
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Scheme 3. Control reactions
Deuteration experiments revealed further insights into the reaction mechanism. When d6ꢀDMSO
was used as the reaction solvent, deuterium atomꢀlabeled product 2s-D was not detected. However,
when D2O was used as the solvent, a deuterium at the 3ꢀposition of thienopyridine 2s–D was
detected. While using hydroxyl deuterium labeled propargyl alcohol as the substrate, no exchange of
deuterium atoms occurred and the normal product 2s was obtained (Scheme 4). These results
indicated that water acted as a proton donor in this transformation.
Scheme 4. Deuteration experiments
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The postulated reaction mechanism for the synthesis of 2ꢀacylthienopyridines is proposed in
Scheme 5. Initially, a nucleophilic substitution reaction occurs at the ortho position of propynol
fluoropyridine 1 with EtOCS2K to provide intermediate A.18 Then, the intermediate A may
undergoes a thioester cleavage and 5ꢀendoꢀdigꢀ cyclization to give the thienylcopper intermediate C
with the aid of copper salts.10,15 Next, a copperꢀcatalyzed oxidation of the alcohol through a similar
cyclometallation process occurs. Although it is currently difficult to determine the detailed of
oxidation mechanism, it seems that the EtOCS2K may help to facilitate the oxidation process through
coordination of potassium xanthate with copper complexes.20
Scheme 5. Proposed mechanism
In conclusion, an efficient and practical nucleophilic thiolation and copperꢀcatalyzed cyclization
method for preparing functionalized 2ꢀacylthienopyridines and 2ꢀacylbenzothiophenes in
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moderateꢀtoꢀgood yields was reported. This thiolation and cyclization method exhibits broad
substrate scope and tolerance of various functional groups. This unprecedented cascade thiolation
and cyclization reaction provides straightforward access to biologically important
2ꢀacylthienopyridine molecules for pharmaceutical chemistry and materials science. Current efforts
are aimed at determining the mechanism in more detail and developing the thiolation and cyclization
process for the synthesis of potential smallꢀmolecule drugs and materials.
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EXPERIMENTAL SECTION
General Information: Unless otherwise noted, all commercial materials and solvents were used
without further purification and all the reactions were carried out in a Schlenk tube equipped with
magnetic stir bar. 1H NMR spectra were recorded in CDCl3 at 400 MHz and 13C NMR spectra were
1
recorded in CDCl3 at 100 MHz respectively, H and 13C NMR were referenced to CDCl3 at δ 7.26
and 77.0 respectively. GC–MS was obtained using electron ionization (Agilent Technologies
7890A/5975C). HRESIMS spectra were acquired using an Agilent 6210 ESI/TOF mass
spectrometer. TLC was performed using commercially prepared 100ꢀ400 mesh silica gel plates
(GF254), and visualization was effected at 254 nm. All the other chemicals were purchased from
Aldrich Chemicals. Commercial reagents were used without further purification.
General Procedure for the Preparation of Ethynylpyridines:
A
mixture of
2ꢀfluoroꢀ3ꢀiodopyridine (1 mmol), butꢀ3ꢀynꢀ2ꢀol (1.2 mmol), PdCl2(PPh3)2 (5 mol%), CuI (10
mol%), Et3N (1 mL) and THF (2 mL), was added successively in a 20 mL Schlenk tube. After
o
stirring for 8 h at 30 C, the solution was filtered though a small amount of silica gel. Then the
residue was concentrated in vacuo and the crude was purified by flash chromatography with
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nꢀhexane/ethyl acetate (10/1, v/v) to afford the 4ꢀ(2ꢀfluoropyridinꢀ3ꢀyl)butꢀ3ꢀynꢀ2ꢀol as a
paleꢀyellow oil in 90% yield.
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General Procedure for the Preparation of 2-Acetylthienopyridines: A mixture of
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4ꢀ(2ꢀfluoropyridinꢀ3ꢀyl)butꢀ3ꢀynꢀ2ꢀol (1 mmol), Cu(acac)2 (10 mol%), EtOCS2K (2.0 mmol) and
o
DMSO (2 mL), was added successively in a 20 mL Schlenk tube. After stirring for 12 h at 100 C,
the solution was filtered though a small amount of silica gel. Then the residue was concentrated in
vacuo and the crude was purified by flash chromatography with nꢀhexane/ethyl acetate (10/1, v/v) to
afford the 1ꢀ(thieno[2,3ꢀb]pyridinꢀ2ꢀyl)ethanones as a paleꢀyellow solid.
1-(Thieno[2,3-b]pyridin-2-yl)propan-1-one (2a): yellow solid (178 mg, 93% yield); mp
155ꢀ156 ; Rf = 0.39 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3) δ 8.67 (s,
1H), 8.16 (d, J = 8.1 Hz, 1H), 7.88 (s, 1H), 7.36 (dd, J = 8.0, 4.6 Hz, 1H), 3.04 (q, J = 7.3 Hz, 2H),
1.28 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 195.1, 163.3, 149.5, 143.2, 133.4, 132.7,
125.9, 120.2, 32.5, 8.3. GCꢀMS (EI, 70 eV) m/z: 191, 177; ESIꢀHRMS (m/z): [M+H]+ calcd for
C10H10NOS, 192.0478, found: 192.0482.
1-(Thieno[2,3-b]pyridin-2-yl)ethanone (2b)19: yellow solid (161 mg, 91% yield); mp 123ꢀ125
;
Rf = 0.41 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 8.17 (d,
J = 8.1 Hz, 1H), 7.88 (s, 1H), 7.38 (d, J = 3.1 Hz, 1H), 2.67 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
192.1, 163.4, 149.6, 143.7, 133.4, 132.78, 126.8, 120.4, 26.6; GC-MS (EI, 70 eV) m/z: 177, 162,
134; ESI-HRMS (m/z): [M+H]+ calcd for C9H8NOS, 178.0321, found 178.0322.
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1-(Thieno[2,3-b]pyridin-2-yl)pentan-1-one (2c): yellow solid (201 mg, 92% yield); mp
105ꢀ106 ; Rf = 0.46 (ethyl acetate / petroleum ether = 1:5); 1H NMR (400 MHz, CDCl3) δ 8.66 (d,
J = 3.4 Hz, 1H), 8.15 (dd, J = 8.1, 1.1 Hz, 1H), 7.87 (s, 1H), 7.34 (dd, J = 8.1, 4.6 Hz, 1H), 2.98 (t, J
= 7.4 Hz, 2H), 1.84 – 1.67 (m, 2H), 1.42 (dq, J = 14.7, 7.4 Hz, 2H), 0.95 (t, J = 7.3 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 194.8, 163.2, 149.4, 143.5, 133.4, 132.7, 126.0, 120.2, 38.8, 26.6, 22.4,
13.8. GCꢀMS (EI, 70 eV) m/z: 219, 190, 177; ESIꢀHRMS (m/z): [M+H]+ calcd for C12H14NOS,
220.0791, found 220.0789.
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2-Methyl-1-(thieno[2,3-b]pyridin-2-yl)pentan-1-one (2d): yellow liquid (207 mg, 89% yield);
Rf = 0.37 (ethyl acetate/petroleum ether = 1:5); 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.18 (d,
J = 8.0 Hz, 1H), 7.91 (s, 1H), 7.37 (dd, J = 7.9, 4.5 Hz, 1H), 3.41 (dd, J = 13.6, 6.8 Hz, 1H), 1.91 –
1.76 (m, 1H), 1.56 – 1.45 (m, 1H), 1.42 – 1.32 (m, 2H), 1.27 (d, J = 6.9 Hz, 3H), 0.92 (t, J = 7.3 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 198.8, 163.3, 149.4, 143.5, 133.6, 132.9, 125.8, 120.3, 42.2,
36.2, 20.7, 17.5, 14.1. GCꢀMS (EI, 70 eV) m/z: 233, 191, 134; ESIꢀHRMS (m/z): [M+H]+ calcd for
C13H16NOS, 234.0947, found 234.0946
2-Ethyl-1-(thieno[2,3-b]pyridin-2-yl)hexan-1-one (2e): yellow liquid (224 mg, 86% yield); Rf =
1
0.41 (ethyl acetate/petroleum ether = 1:5); H NMR (400 MHz, CDCl3) δ 8.68 (d, J = 4.2 Hz, 1H),
8.17 (d, J = 8.0 Hz, 1H), 7.90 (s, 1H), 7.35 (dd, J = 8.1, 4.6 Hz, 1H), 3.34 – 3.19 (m, 1H), 1.88 – 1.75
(m, 2H), 1.67 – 1.54 (m, 2H), 1.29 – 1.25 (m, 4H), 0.91 (t, J = 7.4 Hz, 3H), 0.85 (t, J = 6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 199.0, 163.5, 149.5, 144.6, 133.5, 132.8, 125.8, 120.2, 49.6, 32.1,
29.8, 25.9, 22.8, 13.9, 12.0. GCꢀMS (EI, 70 eV) m/z: 261, 205, 190; ESIꢀHRMS (m/z): [M+H]+
calcd for C15H20NOS, 262.1260, found 262.1259.
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Phenyl(thieno[2,3-b]pyridin-2-yl)methanone (2f)21: yellow solid (208 mg, 87% yield); mp
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96ꢀ98 ; Rf = 0.35 (ethyl acetate/petroleum ether = 1:5); H NMR (400 MHz, CDCl3) δ 8.71 (dd, J
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= 4.5, 1.4 Hz, 1H), 8.16 (dd, J = 8.1, 1.5 Hz, 1H), 8.00 – 7.89 (m, 2H), 7.80 (s, 1H), 7.65 (t, J = 7.4
Hz, 1H), 7.55 (t, J = 7.6 Hz, 2H), 7.38 (dd, J = 8.1, 4.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
189.5, 163.5, 149.7, 142.9, 137.3, 133.5, 132.8, 132.5, 129.4, 129.3 (2C), 128.6 (2C), 120.3. GCꢀMS
(EI, 70 eV) m/z: 239, 211, 162; ESIꢀHRMS (m/z): [M+H]+ calcd for C14H10NOS, 240.0478, found
240.0476.
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(thieno[2,3-b]pyridin-2-yl)(m-tolyl)methanone (2g): yellow solid (228 mg, 90% yield); mp
135ꢀ137 ;Rf = 0.44 (ethyl acetate/petroleum ether = 1: 5 ); 1H NMR (600 MHz, CDCl3) δ 8.70 (d,
J = 4.5 Hz, 1H), 8.16 (d, J = 8.1 Hz, 1H), 7.79 (s, 1H), 7.70 (d, J = 8.9 Hz, 2H), 7.43 (dt, J = 14.8,
7.5 Hz, 2H), 7.37 (dd, J = 8.0, 4.6 Hz, 1H), 2.46 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 189.7,
163.5, 149.6, 143.0, 138.6, 137.3, 133.6, 133.5, 132.5, 129.8, 129.4, 128.4, 126.6, 120.3, 21.4.
GCꢀMS (EI, 70 eV) m/z: 253, 239, 226; HRMS ESI (m/z): calcd for C15H12NOS, 254.0634, found:
254.0629.
1-(5-Methylthieno[2,3-b]pyridin-2-yl)pentan-1-one (2h): yellow solid (193 mg, 83% yield); mp
113ꢀ114 ; Rf = 0.41 (ethyl acetate/petroleum ether = 1: 10); 1H NMR (400 MHz, CDCl3) δ 8.53 (d,
J = 1.9 Hz, 1H), 7.94 (d, J = 1.0 Hz, 1H), 7.82 (s, 1H), 3.04 – 2.92 (m, 2H), 2.48 (s, 3H), 1.78 (dt, J
13
= 20.6, 7.5 Hz, 2H), 1.44 (dq, J = 14.7, 7.4 Hz, 2H), 0.97 (t, J = 7.3 Hz, 3H); C NMR (100 MHz,
CDCl3) δ 194.9, 160.7, 151.0, 143.6, 133.1, 132.7, 129.9, 125.7, 38.9, 26.7, 22.4, 18.4, 13.9. GCꢀMS
(EI, 70 eV) m/z: 233, 204, 176; ESIꢀHRMS (m/z): [M+H]+ calcd for C13H16NOS, 234.0947, found
234.0948.
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2-Ethyl-1-(5-methylthieno[2,3-b]pyridin-2-yl)hexan-1-one (2i): yellow liquid (234 mg, 85%
yield); Rf = 0.39 (ethyl acetate/petroleum ether = 1: 10); 1H NMR (400 MHz, CDCl3) δ 8.54 (d, J =
1.8 Hz, 1H), 7.97 (d, J = 0.8 Hz, 1H), 7.84 (s, 1H), 3.25 (ddd, J = 8.1, 5.4, 2.7 Hz, 1H), 2.48 (s, 3H),
1.88 – 1.75 (m, 2H), 1.64 – 1.52 (m, 2H), 1.30 – 1.26 (m, 4H), 0.92 (t, J = 7.4 Hz, 3H), 0.86 (t, J =
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6.9 Hz, 3H); C NMR (100 MHz, CDCl3) δ 199.1, 160.8, 151.0, 144.6, 133.2, 132.8, 129.9, 125.6,
49.7, 32.2, 29.8, 25.9, 22.8, 18.4, 13.9, 12.0. GCꢀMS (EI, 70 eV) m/z: 275, 219, 204; ESIꢀHRMS
(m/z): [M+H]+ calcd for C16H22NOS, 276.1417, found 276.1418.
1-(Thieno[3,2-b]pyridin-2-yl)pentan-1-one (2j): yellow liquid (171 mg, 78% yield); Rf = 0.37
(ethyl acetate/petroleum ether = 1: 5 ); 1H NMR (400 MHz, CDCl3) δ 8.76 (dd, J = 4.5, 1.3 Hz, 1H),
8.21 (d, J = 8.3 Hz, 1H), 8.12 (s, 1H), 7.35 (dd, J = 8.3, 4.5 Hz, 1H), 3.05 (t, J = 7.4 Hz, 2H), 1.79
(dt, J = 15.1, 7.5 Hz, 2H), 1.44 (dt, J = 14.7, 7.4 Hz, 2H), 0.97 (t, J = 7.3 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 195.0, 155.2, 148.6, 147.0, 136.7, 131.1, 129.3, 121.1, 39.0, 26.7, 22.4, 13.9.
GCꢀMS (EI, 70 eV) m/z: 219, 177, 134; ESIꢀHRMS (m/z): [M+H]+ calcd for C12H14NOS, 220.0791,
found 220.0783.
2-Ethyl-1-(thieno[3,2-b]pyridin-2-yl)hexan-1-one (2k): yellow liquid (211 mg, 81% yield); Rf =
1
0.49 (ethyl acetate/petroleum ether = 1:5); H NMR (400 MHz, CDCl3) δ 8.71 (d, J = 2.9 Hz, 1H),
8.16 (d, J = 8.2 Hz, 1H), 8.11 (s, 1H), 7.30 (dd, J = 8.2, 4.5 Hz, 1H), 3.33 – 3.20 (m, 1H), 1.79 (tt, J
= 14.8, 7.5 Hz, 2H), 1.66 – 1.50 (m, 2H), 1.23 (m, 4H), 0.87 (t, J = 7.4 Hz, 3H), 0.79 (t, J = 6.6 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 199.0, 155.1, 148.4, 147.9, 136.8, 130.9, 129.1, 121.0, 49.7,
32.1, 29.7, 25.8, 22.7, 13.8, 11.9. GCꢀMS (EI, 70 eV) m/z: 261, 205, 162; ESIꢀHRMS (m/z):
[M+H]+ calcd for C15H20NOS, 262.1260, found 262.1258.
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2-Ethyl-1-(5-methylthieno[3,2-b]pyridin-2-yl)hexan-1-one (2l): yellow liquid (228 mg, 83%
yield); Rf = 0.38 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H),
8.11 (s, 1H), 7.29 (d, J = 5.5 Hz, 1H), 3.37 – 3.25 (m, 1H), 2.73 (s, 3H), 1.86 (dt, J = 14.7, 7.5 Hz,
2H), 1.72 – 1.57 (m, 2H), 1.31 (m, 4H), 0.94 (t, J = 7.4 Hz, 3H), 0.87 (t, J = 6.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 199.3, 157.5, 154.7, 147.8, 134.4, 131.1, 128.9, 121.8, 49.8, 32.3, 29.9, 26.0,
24.6, 22.8, 13.9, 12.1. GCꢀMS (EI, 70 eV) m/z: 275, 232, 204; ESIꢀHRMS (m/z): [M+H]+ calcd for
C16H22NOS, 276.1417, found 276.1416.
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1-(Thieno[2,3-c]pyridin-2-yl)propan-1-one (2m): yellow liquid (147 mg, 77% yield); Rf = 0.45
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(ethyl acetate/petroleum ether = 1:5); H NMR (400 MHz, CDCl3) δ 9.18 (s, 1H), 8.53 (d, J = 5.5
Hz, 1H), 7.92 (s, 1H), 7.74 (d, J = 5.5 Hz, 1H), 3.06 (q, J = 7.3 Hz, 2H), 1.27 (t, J = 7.3 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 195.0, 148.3, 145.6, 144.2, 143.4, 137.8, 126.6, 119.2, 32.9, 8.1. GCꢀMS
(EI, 70 eV) m/z: 191, 177; ESIꢀHRMS (m/z): [M+H]+ calcd for C10H10NOS, 192.0478, found
192.0477.
1-(thieno[2,3-c]pyridin-2-yl)pentan-1-one (2n): yellow liquid (166 mg, 76% yield); Rf = 0.41
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(ethyl acetate/petroleum ether = 1:5); H NMR (400 MHz, CDCl3) δ 9.21 (s, 1H), 8.57 (d, J = 5.4
Hz, 1H), 7.94 (s, 1H), 7.76 (d, J = 5.3 Hz, 1H), 3.04 (t, J = 7.4 Hz, 2H), 1.78 (dt, J = 15.1, 7.5 Hz,
2H), 1.44 (dq, J = 14.7, 7.4 Hz, 2H), 0.97 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 194.8,
148.7, 145.7, 144.2, 143.6, 137.7, 126.8, 119.2, 39.4, 26.5, 22.4, 13.9. GCꢀMS (EI, 70 eV) m/z: 219,
190, 107; ESIꢀHRMS (m/z): [M+H]+ calcd for C12H14NOS, 220.0791, found 220.0790.
1-(5-Chlorothieno[2,3-c]pyridin-2-yl)pentan-1-one (2o): yellow liquid (185 mg, 73% yield); Rf
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= 0.43 (ethyl acetate/petroleum ether = 1:10); H NMR (400 MHz, CDCl3) δ 8.96 (s, 1H), 7.86 (s,
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1H), 7.79 (s, 1H), 3.02 (t, J = 7.4 Hz, 2H), 1.77 (dt, J = 15.1, 7.5 Hz, 2H), 1.44 (dd, J = 15.0, 7.4 Hz,
2H), 0.97 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 194.5, 150.7, 147.0, 146.3, 145.2,
136.6, 125.6, 119.1, 39.4, 26.3, 22.3, 13.8. GC-MS (EI, 70 eV) m/z: 253, 224, 168; ESI-HRMS
(m/z): [M+H]+ calcd forC12H13ClNOS, 254.0401, found: 254.0404.
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1-(5-Chlorothieno[2,3-c]pyridin-2-yl)-2-methylpentan-1-one (2p): yellow liquid (230 mg, 86%
yield); Rf = 0.41 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3) δ 8.98 (s, 1H),
7.87 (s, 1H), 7.81 (s, 1H), 3.41 (dd, J = 13.5, 6.8 Hz, 1H), 1.90 – 1.79 (m, 1H), 1.56 – 1.47 (m, 1H),
1.39 (dd, J = 14.4, 7.3 Hz, 2H), 1.28 (d, J = 6.8 Hz, 3H), 0.93 (t, J = 7.3 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 198.6, 150.6, 147.0, 146.3, 145.2, 136.7, 125.4, 119.1, 42.8, 36.0, 20.6, 17.2, 14.1.
GC-MS (EI, 70 eV) m/z: 267, 225, 196; ESI-HRMS (m/z): [M+H]+ calcd for C13H15ClNOS,
268.0558, found: 268.0551.
1-(5-Chlorothieno[2,3-c]pyridin-2-yl)-2-ethylhexan-1-one (2q): yellow liquid (248 mg, 84%
yield); Rf = 0.41 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3) δ 8.95 (s, 1H),
7.86 (s, 1H), 7.79 (s, 1H), 3.32 – 3.14 (m, 1H), 1.91 – 1.77 (m, 2H), 1.69 – 1.55 (m, 2H), 1.25 (dd, J
= 8.5, 5.3 Hz, 4H), 0.89 (t, J = 7.4 Hz, 3H), 0.83 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
198.8, 151.6, 147.0, 146.2, 145.1, 136.7, 125.4, 119.2, 50.2, 31.9, 29.7, 25.6, 22.8, 13.8, 11.9.
GC-MS (EI, 70 eV) m/z: 295, 224, 196; ESI-HRMS (m/z): [M+H]+ calcd for C15H19ClNOS,
296.0870, found 296.0869.
2-Ethyl-1-(5-fluorothieno[2,3-c]pyridin-2-yl)hexan-1-one (2r): yellow liquid (232 mg, 83%
yield); Rf = 0.35 (ethyl acetate/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H),
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7.90 (s, 1H), 7.37 (s, 1H), 3.25 (dq, J = 8.0, 5.5 Hz, 1H), 1.89 – 1.75 (m, 2H), 1.70 – 1.54 (m, 2H),
1.31 – 1.24 (m, 4H), 0.91 (t, J = 7.4 Hz, 3H), 0.84 (dd, J = 8.7, 4.9 Hz, 3H); 13C NMR (100 MHz,
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CDCl3) δ 198.8, 161.6 (d, JCꢀF = 231.8 Hz, 1C), 152.3, 148.8 (d, JCꢀF = 8.4 Hz, 1C), 143.1 (d, JCꢀF
=
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18.18 Hz, 1C), 135.3, 125.8 (d, JCꢀF = 5.7 Hz, 1C), 103.4 (d, JCꢀF = 39.0 Hz, 1C), 50.3, 31.9, 29.7,
25.7, 22.8, 13.8, 11.9. GC-MS (EI, 70 eV) m/z: 279, 223, 208; ESI-HRMS (m/z): [M+H]+ calcd for
C15H19FNOS, 280.1166, found 280.1167.
(5-Methylthieno[2,3-b]pyridin-2-yl)(phenyl)methanone (2s): yellow solid (220 mg, 87% yield);
1
mp 168ꢀ169 ; Rf = 0.41 (ethyl acetate/petroleum ether = 1:5); H NMR (400 MHz, CDCl3) δ 8.53
(s, 1H), 7.96 – 7.84 (m, 3H), 7.71 (s, 1H), 7.62 (t, J = 7.4 Hz, 1H), 7.52 (t, J = 7.6 Hz, 2H), 2.46 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 189.5, 160.8, 151.1, 142.9, 137.4, 133.2, 132.6, 132.5, 130.0,
129.2 (2C), 129.2, 128.5(2C), 18.4. GC-MS (EI, 70 eV) m/z: 253, 225, 176; ESIꢀHRMS (m/z):
[M+H]+ calcd for C15H12NOS, 254.0634, found: 254.0636.
(5-methylbenzo[b]thiophen-2-yl-3-d)(phenyl)methanone (2s-D): yellow solid (206 mg, 81%
1
yield); mp 170ꢀ172 ; Rf = 0.44 (ethyl acetate/petroleum ether = 1:5); H NMR (400 MHz, CDCl3)
δ 8.54 (s, 1H), 7.97 – 7.85 (m, 3H), 7.63 (t, J = 7.4 Hz, 1H), 7.53 (t, J = 7.6 Hz, 2H), 2.47 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 189.5, 160.8, 151.1, 142.8, 137.4, 133.2, 132.6, 132.4 (d, JCꢀD = 4.3
Hz, 1C), 130.0, 129.3 (2C), 129.2, 128.6 (2C), 18.4. GCꢀMS (EI, 70 eV) m/z: 254, 237, 226;
ESIꢀHRMS (m/z): [M+H]+ calcd for C15H11DNOS, 255.0697, found: 255.0703.
Benzo[b]thiophen-2-yl(phenyl)methanone (3a)10a: yellow liquid (219 mg, 92% yield); Rf = 0.42
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(ethyl acetate/petroleum ether = 1:5); H NMR (400 MHz, CDCl3) δ 7.92 (dd, J = 7.6, 4.1 Hz, 3H),
7.88 (d, J = 8.0 Hz, 1H), 7.86 (s, 1H), 7.63 (t, J = 7.2 Hz, 1H), 7.54 (t, J = 7.6 Hz, 2H), 7.49 (t, J =
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7.6 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 189.6, 143.1, 142.7, 139.0,
137.9, 132.4, 132.2, 129.2 (2C), 128.5 (2C), 127.4, 126.0, 125.0, 122.9. GCꢀMS (EI, 70 eV) m/z:
238, 221, 210.
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ASSOCIATED CONTENT
Supporting Information
Copies of NMR spectra for all compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
Leeyib268@126.com
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank the National Natural Science Foundation of China (21302146), the Foundation of the
Department of Education of Guangdong Province (2016KTSCX144, 2017KZDXM085) and Science
Foundation for Young Teachers of Wuyi University (2015td01), Chemical Industry Collaborative
Innovation Center of Yueshan Town 2017(368) and Science and Technology Foundation of Jiangmen
City (2017012) for financial support. We thank James Murray, PhD, from Edanz Group
(www.edanzediting.com/ac) for editing a draft of this manuscript.
REFERENCES
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J. C.; Khanal, S.; Peterson, E. D.; Bach, R. G.; Krumholz, H. M.; Cohen, D. J. Prevalence, predictors,
and outcomes of premature discontinuation of thienopyridine therapy after drugꢀeluting stent
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