Access to functionalized thienopyridines via a reagent-capsule-assisted coupling, thiolation and cyclization cascade sequence

Article abstract of DOI:10.1039/C6OB02351G

Thienopyridines and related heterocycles were prepared in a straightforward manner in moderate to good yields and under mild conditions by palladium-catalysed cross-coupling of ortho-fluorinated iodopyridines and terminal alkynes, followed by a reagent-capsule-assisted thiolation cyclization process. By applying paraffin wax capsules to prevent catalyst poisoning and undesired side reactions, the separation and purification processes were reduced.

Full text of DOI:10.1039/C6OB02351G

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Access to Functionalized Thienopyridines via a Reagent-Capsule-
Assisted Coupling, Thiolation and Cyclization Cascade Sequence
Received 00th January 20xx,
Accepted 00th January 20xx
Jialing Cai, Shuo Huang, Ruenfa He, Lu Chen, Donghan Chen, Shaohua Jiang, Bin Li* and
Yibiao Li*
DOI: 10.1039/x0xx00000x
www.rsc.org/
[5]
Thienopyridines and related heterocycles were prepared in a For example, DRAK2
was reported as drug target for
straightforward manner in moderate to good yields and under treatment of autoimmune diseases. Research by Boschelli and
mild conditions by the palladium-catalysed cross-coupling of co-workers identified thieno[3,2-b]pyridine-based drug
ortho-fluorinated iodopyridines and terminal alkynes, followed by candidate as Src kinase inhibitors.[6] The thieno[3,2-
reagent-capsule-assisted thiolation cyclization process. By d]pyrimidine core was also utilized by Folkes and co-workers,
applying paraffin wax capsules to prevent catalyst poisoning and who reported a new class of orally bioavailable inhibitor for
undesired side reactions, the separation and purification the treatment of cancer, such as
[7] Despite the importance
a
a
3
.
processes were reduced.
of thienopyridines, synthetic methodologies for their
production remain limited, and the provision various of these
heterocycle compounds may represent a bottleneck for
further studies and application in medicinal chemistry. The
transition metal-catalysed cyclization of 3-aminothiophene
derivatives is the most general and versatile synthetic
methodology for the preparation of thienopyridine
heterocycles.[8]
The Sonogashira cross-coupling reaction is a well-recognized,
powerful method for the preparation of arylalkynes and
enynes through Csp-Csp2 bond formation[1]with applications in
pharmaceuticals, natural products and molecular organic
materials.[2] Due to the compatibility of palladium and copper
catalysts, when direct used these acetylene synthons in
subsequent translation, the purification of these acetylene
products appears to be unavoidable, thereby increasing the
manual operations and time consumed. Paraffin capsules
present an alternative solution to this problem. Particularly, in
multi-component reactions based on the Sonogashira cross-
coupling reaction, the reagent may affect the palladium and
copper catalysts and the terminal alkyne encapsulated in the
paraffin wax capsules.[3] During the completion of the cross-
coupling reaction, raising the temperature can melt the
paraffin capsule, releasing reagents and leading to subsequent
reactions. Therefore, reagent encapsulation can not only
protect against air- and moisture-sensitive reagents but also
reduce the amount of required separation and purification
processes.
O
Cl
O
NH2
HN
S
HN
Cl
OMe
S
MeO
MeO
N
O
NH
N
S
N
CN
S
O
N
N
N
N
[thieno[3,2-b]pyridine]
Src Kinase inhibitor 2
[thieno[2,3-b]pyridine]
DRAK2 inhibitor 1
[thieno[3,2-d]pyrimidine]
Potent inhibitor of sirtuins 3
Figure 1 Pharmaceutically active compounds containing
the thienopyridine core.
Our success in preparing benzo[b]furans and
benzo[b]thiophenes using Na2S•9H2O as a thiol surrogate
encouraged us to employ related chemistry for the
preparation of thienopyridine derivatives.[9] To the best of our
knowledge, the sole attempt to involve ethynylpyridine in the
formation of thienopyridine was made by Queiroz and co-
workers, who obtained only 2-(hetero)aryl thienopyridines in
good yields.[10] However, the utility of the above reactions is
limited by their harsh conditions, and aliphatic alkynes do not
react in this chemistry. Using ortho-fluoroiodopyridines as
model substrates, we initially considered employing Na2S·9H2O
in DMSO as the solvent at 130 °C, following the procedure
described by Queiroz and co-workers. In the presence of
Na2S·9H2O, this reaction produced 2-phenylthieno[2,3-
b]pyridine 3a in 23% yield in 12 hours at 130 °C, but also gave
the unexpected 2-phenylfuro[2,3-b]pyridine 4a in 69% yield
The development of sustainable and efficient
methodologies for the synthesis of thienopyridines and related
heterocycles is crucial in modern organic synthesis due to their
wide biological activities and pharmaceutical applications.[4]
School of Chemical & Environmental Engineering, Wuyi University, Jiangmen,
Guangdong Province 529090, China, E-mail: leeyib268@126.com;
andonlee@163.com
†Electronic Supplementary Informaꢀon (ESI) available: General Experimental
information, experimental procedure for product synthesis, full characterization
data, 1H and 13C NMR spectra of all products. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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(Figure 2) (see supporting information). [11] Alternatively, we
envisioned that the weakly nucleophilic thiol surrogate is
essential in this thiolation cyclization process. Gratifyingly, the
yield of 2-phenylthieno[2,3-b]pyridine 3a was improved to 88%
when EtOC(S)SK was employed as the thiol surrogate. In view
of our on-going research to develop new methods in
heterocycle synthesis[12], herein, we report an efficient and
flexible synthetic protocol for the synthesis of thienopyridine
and related heterocycles, utilizing a strategy consisting of
palladium-catalysed sequential coupling, in situ thiolation and
S-cyclization.
View Article Online
Scheme 1 Synthesis of 2-(hetero)arylthieDnOo[I:21,30.-1b0]3p9y/rCid6iOnBe0s2a3,b51G
I
PdCl2(PPh3)2 (5 mol%), CuI ( 10 mol%)
NEt3 (4 equiv), DMSO (2 mL)
EtOCS2K (2 equiv) in capsule, 35 oC, 10 h
then 90 oC, 12 h
R2
R1
R1
R2
+
S
N
N
1
F
2
3
Et
S
S
S
N
N
N
Me
3a, 88%
3c, 85%
3b, 83%
nBu
OMe
Me
S
S
S
N
N
N
Me
3e,87%
3f, 78%
Cl
3b, 82%
I
NMe2
Cl
4a
O
Na2S·9H2O
DMSO, 130 o
Yields:3a: 23%
4a: 69%
S
S
Pd and Cu
N
N
N
S
F
+
Ph
N
+
C
N
N
3g, 77%
3h,84%
3i, 78%
3a
F
2a
1a
F
F
Br
S
N
EtOC(S)SK in paraffin wax capsule,
DMSO, 90 o
3a, yield: 88%
C
S
S
S
N
N
N
N
3l, 76%
3j, 79%
3k, 82%
Figure 2: Synthesis of thieno[2,3-b]pyridines.
Br
CF3
S
S
S
S
N
N
N
Furthermore, simple and practical techniques for paraffin
encapsulation technology have been introduced in organic
synthesis, especially for moisture- or air-sensitive
compounds[13] and multicomponent reactions.[14] Encouraged
by these results, we investigated the substrate scope of
palladium-catalysed coupling, thiolation and cyclization
reactions using a reagent-capsule-assisted method. As shown
in Scheme 1, both electron-deficient and electron-rich
arylalkynes reacted with ortho-fluoroiodopyridines to give the
corresponding thieno[2,3-b]pyridine products in moderate to
3o,90%
3n, 72%
3m, 73%
Cl
H3C
S
S
N
N
S
N
3q, 71%
3r, 68%
3p, 70%
a
Reaction conditions: fluoroiodopyridine
terminal alkyne 2 (1.3 mmol), PdCl2(PPh3)2 (5 mol%), CuI (10
mol%), Et3N (4.0 mmol), EtOC(S)SK (2.0 mol) in paraffin wax
capsule, DMSO (2 mL) at 35 °C for 10 h, then 90 °C for 12h.
1
(1.0 mmol),
b
Yields are given for isolated products.
good yields (Scheme 1). Functional groups, including alkyl, substrates, although the use of arylalkynes and aliphatic
OMe, NMe2, F, Cl, Br, CF3 and pyridine, can be well tolerated. alkynes appeared to facilitate the process, given that alkynols
Notably, we found that the ortho substituents of the benzyl afforded 2-(thieno[2,3-b]pyridin-2-yl)propan-2-ol derivatives in
group did not affected the coupling and annulation reaction slightly lower yields than when using the arylalkyne systems.
(Scheme 1, 3i and 3j). When 2-fluoro-3-iodopyridine and 2-
Scheme 2 Synthesis of 2-alkylthieno[2,3-b]pyridines a,b
fluorophenylacetylene were used as reaction substrates, the 2-
I
PdCl2(PPh3)2 (5 mol%), CuI ( 10 mol%)
NEt3 (4 equiv), DMSO (2 mL)
EtOCS2K (2 equiv) in capsule, 35 oC, 10 h
then 90 oC, 12 h
fluoro moiety on pyridine served as the leaving group and gave
2-(2-fluorophenyl)thieno[2,3-b]pyridine 3j as the sole product.
Substrates bearing heterocycles such as 3-thienyl or 2-pyridyl
groups could also form the corresponding thieno[2,3-
b]pyridine products 3o and 3p in moderate to good yields.
Ortho-fluoroiodopyridines with different substitution patterns
were tested as well. Substituents, including Me and Cl, were
well tolerated (Scheme 1, 3q and 3r).
R1
R2
R2
R1
+
N
1
F
S
N
2
3
S
S
Me
S
N
N
N
3u, 82%
3s, 86%
3t, 81%
S
N
S
Me
N
S
N
3w, 76% c
3v, 85%
To extend the substrate scope, we used aliphatic alkynes to
investigate the possibility of this transformation (Scheme 2).
First, when ortho-fluoroiodopyridine was used as the substrate,
a wide variety of aliphatic alkynes were screened and gave
thieno[2,3-b]pyridine products in good yields. The reaction of
non-1-yne provided a slightly higher yield than that of
OH
CH3
OH
OH
CH3
CH3
CH3
3x, 81%
S
N
S
S
N
N
N
CH3
CH3
3z, 80%
3y, 79%
OH
OH
CH3
S
S
N
CF3
N
S
3ac, 68%
3aa, 73%
3ab, 55%
ethynylcyclopentane (Scheme 2, 3s
-3u). We were pleased to
a
Reaction conditions: fluoroiodopyridine 1 (1.0 mmol),
find that the internal C C triple bond was good tolerated
≡
terminal alkyne 2 (1.3 mmol), PdCl2(PPh3)2 (5 mol%), CuI
(10 mol%), Et3N (4.0 mmol), EtOC(S)SK (2.0 mol) in
paraffin wax capsule, DMSO (2 mL) at 35 °C for 10h, then
under the optimization conditions (Scheme 2, 3v). Notably, the
reaction of octa-1,7-diyne with ortho-fluoroiodopyridine
b
c
afforded
2-(3-(thieno[2,3-b]pyridin-2-yl)propyl)thieno[2,3-
90 °C for 12h. Yields are given for isolated products.
b]pyridine 3w in 76% yield. Furthermore, the presented
method was not limited to the use of arylalkyne derivatives as
octa-1,7-diyne (0.65 mmol) was used.
2 | J. Name., 2015, 00, 1-3
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When ortho-fluoroiodopyridine was used, a wide variety of
propargyl alcohols were successfully employed in this process
View Article Online
DOI: 10.1039/C6OB02351G
Scheme 4 Synthesis of 2-arylfuro[2,3-b]pyridinesa,b
(Scheme 2, 3x
-
3ac). Notably, when 1-ethynylcyclohexanol was
PdCl2(PPh3)2, CuI,
NEt3, DMSO
NaOH in capsule, 35 oC, 10 h
then 80 oC, 12 h
I
R1
R2
R2
R1
+
employed as the substrate, the unexpected dehydration
product 3aa was obtained in 73% yield. Additionally, pent-1-
yn-3-ol also reacted with ortho-fluoroiodopyridine to afford 1-
(thieno[2,3-b]pyridin-2-yl)propan-1-ol 3ab in moderate yields.
Importantly, substrates bearing a CF3 group at the tertiary
alcohol were compatible with this reaction, and the
coupling/cyclization product 3ac was generated in 68% yield.
Next, several sulfur- and nitrogen-containing heterocycles
were prepared using this method (Scheme 3). Starting from
commercially available ortho-fluorinated iodopyridines and
terminal alkynes, moderate to good yields were achieved.
O
N
F
N
1
2
4
Me
C4H9
Me
O
O
N
O
N
N
4a, 87%
4b, 88%
4c,87%
Br
Br
OCH3
O
O
O
N
N
N
N
N
4d,72%
4f, 73%
4e, 78%
Me
Cl
Si Me
Me
O
O
[15], thieno[2,3-c]pyridines
4g, 81%
4h, <5%
Thieno[3,2-b]pyridines (3ad and 3ae
)
a
[16]
[17]
Reaction conditions: flouroiodopyridine 1 (1.0 mmol),
(3af and 3ag
)
,
thieno[3,2-c]pyridines
(
3ah
)
and
[7] were readily prepared via the
terminal alkyne 2 (1.3 mmol), PdCl2(PPh3)2 (5 mol%), CuI (10
mol%), Et3N (4.0 mmol), DMSO (2 mL) and paraffin wax
capsule (NaOH (2.0 mmol) at 35 oC for 10 h, then 80 oC for 12
h. b Yields are given for isolated products.
thieno[3,2-d]pyrimidines (3ai
)
sulfur reagent-capsule-assisted cyclization reaction. 4-F- and 2-
Cl-substituted pyridines afforded the Cl-substituted product
3ah as the sole product in standard condition. Interestingly, 5-
fluoro-4-iodopyrimidines were converted into thieno[3,2-
d]pyrimidines 3ai in moderate yields. This practical reagent
encapsulation method might be useful for further exploration
of the total synthesis of thieno[3,2-d]pyrimidine-based
pharmaceuticals and natural products.[18]
Scheme 5 Proposed mechanism for the cyclization reaction
R
R
S
S
+
KS
OEt
DMSO, 90 o
C
N
F
N
S
OEt
CuI
Scheme 3 Synthesis of high substituted thiophenesa,b
B
A
hydrolysis
From Sonogashira coupling reaction
PdCl2(PPh3)2 (5 mol%), CuI ( 10 mol%)
F
NEt3 (4 equiv), DMSO (2 mL)
EtOCS2K (2 equiv) in capsule, 35 oC, 10 h
then 90 oC, 12 h
R
N
N
1
+
R
CuI
CuI
R
S
5-endo-dig
cyclization
I
3
2
R
R
N
Me
N
H+
N
Me
S
S
N
N
N
SK
S
C
D
S
S
Me
3af, 87%
3ae, 81%
3ad, 85%
Cl
N
N
Cl
N
N
S
S
In conclusion, an efficient and practical palladium-catalysed
cross-coupling, thiolation and cyclization method for preparing
functionalized thienopyridines and related heterocycles in a
one-pot synthetic process that makes use of a reagent
capsuleis was reported. This coupling and cyclization method
displays a variety of substrate scope and well tolerance of
functional groups. The use of reagent encapsulation methods
helped reduce operational procedure and purification of
intermediates, especially greatly promoting the development
of environmentally friendly multicomponent reaction.
S
Cl
3ag, 78%
3ah, 75%
3ai, 62%
a
Reaction conditions: fluoroiodopyridine
1 (1.0 mmol),
terminal alkyne 2 (1.3 mmol), PdCl2(PPh3)2 (5 mol%), CuI (10
mol%), Et3N (4.0 mmol), EtOC(S)SK (2.0 mol) in paraffin wax
capsule, DMSO (2 mL) at 35 °C for 10 h, then 90 °C for 12h.
Yields are given for isolated products.
b
Finally, the transformation of ortho-fluoroiodopyridine and
terminal alkynes to the 2-arylfuro[2,3-b]pyridines derivatives is
highly efficicent under a reagent-capsule-assisted annulation
process. As shown in Scheme 4, the reagent-capsule-assisted
substitution and O-cyclization syntheis of furo[2,3-b]pyridine
derivatives in moderate to good yields. Unfortunately, the
reaction with ethynyltrimethylsilane only affords chaotic
system in strong alkali condition.
Acknowledgements
We thank the National Natural Science Foundation of
China (21302146), Science Foundation for Young Teachers of
Wuyi University (2015td01), Natural Science Foundation of
Guangdong Province (2014A030310211) and Foundation of
Department of Education of Guangdong Province
(2014KQNCX156).
The postulated reaction mechanism for the synthesis of
thienopyridines is proposed in Scheme 5. Initially, there will be
a nucleophilic substitution of ortho-fluorinated iodopyridines
with EtOC(S)SK provide intermediate B[9]
The corresponding
pyridyl thiolate is in situ generated through the hydrolysis of
B[19]
which then undergoes intramolecular cyclization
A
.
C
,
Notes and references
generates thienopyridine products with the aid of CuI.
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