A novel one-pot synthesis of 7-methoxy-2-arylthieno[3,2-b]pyridine-3-ols in domino fashion

Article abstract of DOI:10.1016/j.tetlet.2013.07.024

A simple and efficient synthesis of 7-methoxy-2-arylthieno[3,2-b]pyridine- 3-ols was achieved using a novel one-pot LDA-promoted domino reaction. Although this class of compounds are not very well represented in the literature, similar skeletons are of immense biological importance. A few closely related compounds are reported with multi-step syntheses using harsh conditions and longer reaction time.

Full text of DOI:10.1016/j.tetlet.2013.07.024

Tetrahedron Letters 54 (2013) 5043–5047
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel one-pot synthesis of 7-methoxy-2-arylthieno-
[3,2-b]pyridine-3-ols in domino fashion
a
a
b
Srinu Puvvala a,b, Vinod D. Jadhav a, , Sheikh M. Farooq , Balaram Patro , Ch. Venkata Ramana Reddy
⇑
a GVK Biosciences Private Limited, Medicinal Chemistry Division, 28A, IDA Nacharam, Hyderabad 500076, India
b Department of Chemistry, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad 500085, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and efficient synthesis of 7-methoxy-2-arylthieno[3,2-b]pyridine-3-ols was achieved using a
novel one-pot LDA-promoted domino reaction. Although this class of compounds are not very well rep-
resented in the literature, similar skeletons are of immense biological importance. A few closely related
compounds are reported with multi-step syntheses using harsh conditions and longer reaction time.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 25 April 2013
Revised 2 July 2013
Accepted 4 July 2013
Available online 11 July 2013
Keywords:
7-Methoxy-2-arylthieno[3,2-b]pyridine-3-ol
Domino reaction
Methyl 4-methoxy picolinate
Disulfides
Intramolecular cyclization
O
S
Pyridine derivatives have attracted considerable interest among
medicinal and organic chemists due to their various biological
activities. More particularly, thienopyridines, being bioisosters of
indoles or isoquinolines, have attracted much attention for their
potential biological activity. Some representative bioactive
molecules containing thienopyridine core are depicted in Figure 1.
Baker et al. have reported 3-hydroxyazabenzothiophene (1), as 5-
lipoxygenase and/or cyclooxygenase inhibitors useful in the
treatment of prostaglandin and/or leukotriene mediated diseases.1
Sugano and co-workers reported (3-amino-6-thiophen-2-yl-
thieno[2,3-b]pyridin-2-yl)phenyl methanone (2) as a new type of
N
O
S
NH2
S
N
O
O
O
NH2
S
HN
N
(2)
(3)
(1)
F
Cl
Cl
OH
O
N
O
O
NH
(CH2)3
N
(CH2)4
NC
S
N
N
cytotoxic agent selective against
a
tumorigenic cell line.2
N
N
N
Thienopyridine derivative (3) was reported as potent Luteinizing
hormone receptor (LHR) agonist, useful for the treatment of infer-
tility.3 Boschelli et al. reported the thieno[3,2-b]pyridine (4) as Src
kinase inhibitor, responsible for many cell signaling pathways.
Therefore, it functions as a potential agent for the treatment of a
variety of diseases like cancer, osteoporosis, and stroke.4 New
et al. have reported thienopyridine derivatives (5) and (6) showing
significant CNS activity. These target molecules indicate atypical
antipsychotic-like activity, coupled with potent affinity for
serotonin 5-HT1 and 5-HT2 receptors.5 Thienopyridines are also
of general interest for the chemistry of ligands and theoretical
N
(4)
N
N
S
S
(5)
(6)
Figure 1. Bioactive thienopyridine derivatives.
Herein we report a one pot synthesis of 2-aryl-7-methoxy-3-
hydroxythieno[3,2-b]pyridines in a domino fashion. Literature
methods for the synthesis of thieno[3,2-b]pyridines are based on
the use of either readily accessible 3-aminothiophenes7 and their
N-derivatives8 with stepwise construction of the pyridine ring or
by using thio-pyridines and stepwise construction of the thiophene
ring.9 Berkaoui et al. used the former approach, starting with
3-aminothiophene, in multistep synthesis to get thienopyridines.8a
Fort and co-workers have applied a three-step process for the
organic chemistry due to the presence of a
p-electron rich
thiophene ring and a
p
-electron deficient pyridine ring.6
⇑
Corresponding author.
E-mail address: vinod.jadhav@gvkbio.com (V.D. Jadhav).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.024

5044
S. Puvvala et al. / Tetrahedron Letters 54 (2013) 5043–5047
the Sonogashira product.9e Generally, these methods suffer from
severe disadvantage of limited access to starting materials, low
functional compatibility and/or long-multistep reaction sequences
and low yields.
S
Ar
Ar
S
2
O
N
O
N
LDA (4eq)
S
Ar
O
THF, -78oC, 2h
There is only one multi-step synthesis reported for the synthe-
sis of biologically significant 3-hydroxy-2-arylthieno[3,2-b]pyri-
dines.1 This significant class of compounds is not well explored
probably due to the lack of convenient synthetic methods. The
diversity of biological activities and the lack of a mild method of
synthesis gave us an impulse to the development of a convenient
synthetic route for the thieno[3,2-b]pyridine system. In this con-
text, we have developed a novel one pot method for the first syn-
thesis of 2-aryl-7-methoxy-3-hydroxythieno[3,2-b]pyridines in a
domino fashion. The intermediates generated in situ serve as the
precursors for the next step, ultimately leading to the formation
of the substituted thieno[3,2-b]pyridine derivatives (Scheme 1).
Thus methyl 4-methoxypicolinate 1 on treatment with excess
of lithium diisopropylamide (LDA) (4–5 equiv) in THF at À78 °C,
followed by the addition of arylmethyl disulfide 2 solution in
OH
1
O
3
Scheme 1. Synthesis of 7-methoxy-2-arylthieno[3,2-b]pyridin-3-ols.
construction of the thiophene ring. The key step was regioselective
lithiation–bromination of the 3-methylthiopyridine induced by the
BuLi-LiDMAE superbase (DMAE: 2-(dimethylaminoethanol)). The
successive steps include the Sonogashira coupling and halogeno-
cyclization to give the corresponding 2-substituted (Ph or TMS)
3-halothieno[3,2-b]pyridines.9d However, the overall conversion
was low yielding (17–34%). Recently, Queiroz et al. reported a
two-step method for the synthesis of 2-(hetero)arylthieno[3,
2-b]pyridines. The first step is
a Sonogashira coupling of
2-bromo-3-chloropyridine with several (hetero)arylalkynes to ob-
tain the corresponding 3-chloro(hetero)arylethynylpyridines.
These 3-chloro(hetero)arylethynylpyridines were further cyclized
by treatment with Na2S at 130 °C affording the expected
2-(hetero)arylthienopyridines. In addition, these two reaction
sequences were also performed in one-pot, without isolation of
THF afforded 7-methoxy-2-arylthieno[3,2-b]pyridin-3-ols
3 in
good yield. The efficiency and generality of the method were vali-
dated by reacting several arylmethyl disulfides (Table 1) having
electron withdrawing substituent (entries 5–8) and electron
donating substituent (entries 2–4) with 1 to give corresponding
Table 1
LDA-promoted domino reactions: one-pot synthesis of 7-methoxy-2-arylthieno[3,2-b]pyridine-3-olsa
S
Ar
O
N
O
N
Ar
S
LDA (4eq)
S
Ar
o
O
THF, -78 C, 2h
OH
O
Entry
1
Disulfide
Product
Yieldb (%)
O
S
S
S
68
2a
N
O
3a
OH
O
S
S
S
2
3
59
62
O
N
O
2b
O
OH
3b
S
S
S
2c
N
O
3c
OH
S
S
4
55
S
N
O
OH
2d
3d
F
S
S
S
5
6
71
50
F
N
O
2e
F
F
3e
OH
F
F
S
S
S
N
2f
OH 3f

S. Puvvala et al. / Tetrahedron Letters 54 (2013) 5043–5047
5045
Table 1 (continued)
Entry
Disulfide
Product
Yieldb (%)
F
O
F
S
7
8
49
45
F
S
S
S
N
O
3g
OH
2g
CF
3
CF
3
S
S
F C
3
N
O
OH
3h
2h
Cl
S
S
S
9
62
45
47
40
Cl
N
O
Cl
2i
3i
OH
S
S
S
S
S
S
10
11
S
2j
N
O
3j
OH
O
S
O
S
O
2k
N
O
3k
OH
Br
S
S
S
12
Br
N
2l
Br
3l
OH
a
All the compounds were characterized 1H NMR 13C NMR, IR, and HRMS.
Isolated yields after column chromatography.
b
O
N-Li+
N-Li+
O
N
O
N
O
N
S
Ar
S
N
Ar
Ar
S
2
-
O
N
O
N
N
1B
O
O
1A O
1C
1
N-Li+
Ar
O
N
O
O
N
O
N
S
S
S
S
H
Ar
Ar
O
Ar
N
O
N
N
OH
O
3
1D
1F
1E
Scheme 3
Figure 2. Mechanism of synthesis of 2-arylthieno[3,2-b]pyridin-3-ols.
derivatives in good to acceptable yields. Even five-membered het-
erocyclic disulfides (entries 10 and 11) reacted to give correspond-
ing 3-hydroxythieno[3,2-b]pyridine derivatives in good yields.10
The synthesis includes the use of readily accessible starting
materials. The starting materials methyl 4-methoxypicolinate 1
and disulfides 2 required were prepared using literature meth-
ods.11,12 The diverse availability of mercaptans allows introduction
of a variety of aryl or substituted aryl functionalities at 2-position.
It is pertinent to mention here that the current method allows for
further functionalization at 3 and 7 positions which can open an
access to further elaboration.
The plausible mechanism of the transformation proposed is
shown in Figure 2. The picolinate ester 1 reacts with LDA to give
amide intermediate 1A.13 The amide intermediate 1A after anion
generation at 3-position undergoes thioalkylation with disulfide
2
giving 3-thioalkypyridine-2-amide intermediate 1C. The

5046
S. Puvvala et al. / Tetrahedron Letters 54 (2013) 5043–5047
O
S
S
2b
O
O
O
N
O
N
S
N
O
LDA(1.2eq)
55%
LDA(1.2eq)
O
O
N
N
52%
O
1A O
1
1C
O
LDA(2eq)
48%
S
O
N
OH
3b
Scheme 2. Step-wise synthesis of 2-p-methoxyphenyl thieno[3,2-b]pyridin-3-ol.
S
LDA(4eq)
S
O
+
S
N
4
N
THF,-78oC→RT,2h
OH
O
2c
5
15%
Scheme 3. Synthesis of 2-p-tolylthieno[3,2-b]pyridin-3-ol.
intermediate 1C undergoes lithiation at methylene carbon adjacent
to sulfur, followed by intramolecular nucleophilic substitution
with amide carbonyl to give the corresponding thieno[3,2-b]pyri-
dine system 3 (Fig. 2). The mechanism of the reaction was con-
firmed by the step-wise conversion of methyl 4-
methoxypicolinate into 2-p-methoxyphenylthieno[3,2-b]pyridin-
3-ol 3b (Scheme 2). Thus the picolinate ester 1 was treated with
LDA (1.2 equiv) at À78 °C for 30 min and after normal work-up
and purification by column chromatography, intermediate 1A
was isolated in 55% yield.14 The intermediate 1A was treated with
1,2-bis(4-methoxybenzyl)disulfide 2b in the presence of 1.2 equiv
of LDA at À78 °C for 1 h to give intermediate 1C in 52% yield.15 This
intermediate 1C was treated with LDA (2.5 equiv) at À78 °C for 1 h
to afford title compound 3b in 48% yield. Thus the isolation of the
intermediates 1A, 1C and 3b clearly establishes the mechanism of
the reaction as proposed in Figure 2.
In order to probe the role of different substituents we turned
our attention to methyl 4-methoxypicolinate 1. The methoxy
group at 4-position of methyl 4-methoxypicolinate seems to
facilitate the transformation. Removing the methoxy group from
picolinate and carrying out the reaction with methyl picolinate 4
resulted in a considerable loss of yield of the corresponding 2-(p-
tolyl)thieno[3,2-b]pyridin-3-ol 5, clearly stating the role of the
electron donating group at 4-position of the picolinate
(Scheme 3).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
07.024.
References and notes
1. Baker, R. K.; Rupprexht, K. M.; Pessolano. A. A.; Durette. P.L. US4767766.
2. Hayakawa, I.; Shioya, R.; Agatsuma, T.; Furukawa, H.; Sugano, Y. Bioorg. Med.
Chem. Lett. 2004, 14, 3411.
3. van Straten, N. C. R.; Schoonus-Gerritsma, G. G.; van Someren, R. G.; Draaijer, J.;
Adang, A. E. P.; Timmers, C. M.; Hanssen, R. G. J. M.; van Boeckel, C. A. A.
Chembiochem 2002, 1023, 10.
4. Boschelli, D. H.; Wu, B.; Barrios, S.; Durutlic, H.; Chen, J. J.; Wang, J.; Golas, J. M.;
Lucas, J.; Boschelli, F. J. Med. Chem. 2005, 48, 3891.
5. New, J. S.; Christopher, W. L.; Yevich, J. P.; Butler, R.; Schlemmer, F.; van der
Mealen, C. P.; Cipollina, J. A. J. Med. Chem. 1989, 32, 1147.
6. Webber, J. S.; Woolley, R. G. J. Mol. Struct. (Theochem) 1995, 341, 181.
7. (a) Taylor, E. C.; Macor, J. E. Tetrahedron Lett. 1985, 26, 2419; (b) Deg’Innocenti,
A.; Funicello, M.; Scafato, P.; Spagnolo, P.; Zanirato, P. J. Chem. Soc., Perkin Trans.
1 1996, 2561; (c) Bonini, C.; Chiummiento, L.; Funicello, M.; Spagnolo, P.
Tetrahedron 2000, 56, 1517; (d) Taylor, E. C.; Maor, J. E. Tetrahedron Lett. 1985,
26, 2419.
8. (a) Berkaoui, M.; Outurquin, F.; Paulmier, C. Tetrahedron 1998, 54, 9055; (b)
Ragan, J. A.; Raggon, J. W.; Hill, P. D.; Jones, B. P.; McDermott, R. E.; Munchhof,
M. J.; Marx, M. A.; Casavant, J. M.; Cooper, B. A.; Doty, J. L.; Lu, Y. Org. Process Res.
Dev. 2003, 7, 676; (c) Munchhof, M. J.; Beebe, J. S.; Casavant, J. M.; Cooper, B. A.;
Doty, J. L.; Higdon, R. C.; Hillerman, S. M.; Soderstrom, C. I.; Knauth, E. A.; Marx,
M. A.; Rossi, A. M. K.; Sobolov, S. B.; Sun, J. Bioorg. Med. Chem. Lett. 2004, 14, 21;
(d) Nurkkala, L. J.; Steen, R. O.; Dunne, S. J. Synthesis 2006, 1295; (e) Song, Y.-H.;
Jo, B. S. J. Heterocycl. Chem. 2009, 46, 1132; (f) Shestopalov, A. M.; Rodinovskaya,
L. A.; Shestopalov, A. A. J. Comb. Chem. 2010, 12, 9.
In conclusion, we have developed an efficient, general, and use-
ful one-pot strategy for the synthesis of 7-methoxy-2-arylthie-
no[3,2-b]pyridine-3-ols from methyl 4-methoxypicolinate in
good yields. The mechanism of reaction was also confirmed by
the synthesis and characterization of the intermediates. We believe
that this novel one-pot synthesis of substituted aryl 4-aza-benzo-
thiophenes will serve as a useful alternative to classical methods
and open an access to this medicinally significant class of
compounds.
9. (a) Bremner, D. H.; Dunn, A. D.; Wilson, K. A. Synthesis 1992, 528; (b) Bremner,
D. H.; Dunn, A. D.; Wilson, K. A.; Sturrock, K. R.; Wishart, C. Synthesis 1997, 949;
(c) Bremner, D. H.; Dunn, A. D.; Wilson, K. A.; Sturrock, K. R.; Wishart, C.
Synthesis 1998, 1095; (d) Comoy, C.; Banaszak, E.; Fort, Y. Tetrahedron 2006, 62,
6036; (e) Peixoto, D.; Begouin, A.; Maria-João; Queiroz, R. P. Tetrahedron 2012,
68, 7082.
10. Representative experimental procedure for the synthesis of 3a: To
a stirred
solution of diisopropylamine (1.01 mL, 7.18 mmol) in dry THF (4 mL) was
added n-butyllithium in hexane (1.6 M in hexanes, (4.48 mL, 7.18 mmol) at
À78 °C and stirred for 30 min at the same temperature. Methyl 4-
methoxypicolinate (0.3 g, 1.794 mmol) in THF (3 mL) was added to the above
solution and stirred for further 30 min at the same temperature. Disulfide 2a
(0.53 g, 2.15 mmol) in THF (3 mL) was added at À78 °C and the mixture was
stirred at the same temperature with continuous monitoring by TLC for 2 h.
Saturated NH4Cl solution (10 mL) was added to the reaction mixture and
slowly warmed to room temperature and extracted with ethyl acetate
(3 Â 25 mL). The combined organic layer was dried over anhydrous Na2SO4
and the volatiles were removed under reduced pressure. The resulting crude
Acknowledgments
The authors are thankful to GVK Biosciences Private Limited for
financial support and encouragement. Support from the analytical
Department GVK Biosciences Private Limited is also acknowledged.
Authors are thankful to Nagendra Kondekar and Sanjay Saha for
their support in manuscript preparation.

S. Puvvala et al. / Tetrahedron Letters 54 (2013) 5043–5047
5047
material was purified by column chromatography, eluting with 40% ethyl
acetate in hexanes to afford compound 3a as a pale yellow solid; Yield: 68%;
mp: 206–209 °C; IR (KBr): 3433.03, 2978.89, 1769.04, 1576.34, 1550.88,
1421.84, 1368.75, 1296.84, 1267.41, 1140.03, 1052.09, 695.24 cmÀ1 1H NMR
14. Analytical data of 1A: mp: 116–119 °C; IR (KBr):
m
2967.62, 2931.08, 1632.89,
1595.12, 1563.55, 1464.70, 1438.85, 1340.89, 1033.32 cmÀ1
;
1H NMR
m
(400 MHz, DMSO-d6): d 8.35 (d, J = 5.6 Hz, 1H), 6.98 (dd, J = 6.0, 2.4 Hz, 1H),
6.94 (d, J = 2.4 Hz, 1H); 3.70–3.50 (m, 2H), 1.44 (d, J = 7.0 Hz, 6H), 1.10 (d,
J = 7.0 Hz, 6H); 13C NMR (100 MHz, DMSO-d6): d 167.7, 165.8, 157.9, 149.9,
110.1, 107.0, 55.5, 50.1, 44.7, 20.2, 20.1; ES-MS: 237.2 (M+H)+; HRMS (ESI+): m/
z Calcd for C13H21N2O2: 237.1603 (M+H)+. Found: 237.1615.
;
(400 MHz, DMSO-d6): d 10.61 (s, 1 H), 8.57 (d, J = 5.4 Hz, 1H), 7.91 (d, J = 7.6 Hz,
2H), 7.46 (t, J = 7.6 Hz, 2H), 7.30 (t, J = 7.2 Hz, 1H), 7.07 (d, J = 5.4 Hz, 1H), 4.06
(s, 3H); 13C NMR (75 MHz, DMSO- d6): d 160.2, 150.0, 148.8, 145.1, 133.2,
128.7, 127.1, 126.4, 117.5, 117.2, 102.4, 56.1; ES-MS: 258.0 (M+H)+; HRMS
(ESI+): m/z Calcd for C14H12NO2S: 258.0583 (M+H)+. Found: 258.0580.
11. Donohoe, T. J.; Connolly, M. J.; Walton, L. Org. Lett. 2009, 11, 5562.
12. Karimi, B.; Hazarkhani, H.; Zareyee, D. Synthesis 2002, 17, 2513.
13. The pyridine-2-amides are known to undergo lithiation at 3-position using
LDA. Wright, S. W.; Petraitis, J.; Abelman, M.; Douglas, G. B.; Lori, L. B.; Ronald,
L. C.; Decicco, C. P.; Di Meo, S. V.; Freimark, B.; John, V. G.; Green, A. M.; Jetter, J.
W.; Nelson, D. J.; Orwat, M. J.; Donald, J. P.; Michael, A. P.; Sherk, S. R.; Williams,
J. M.; Magolda, R. L.; Arner, E. C. J. Med. Chem. 1994, 37, 3071.
15. Analytical data of 1C: mp: 101–105 °C; IR (KBr):
1565.58, 151.98, 1462.45, 1430.20, 1370.09, 1335.45, 1293.80, 1248.90,
1035.06 cmÀ1 1H NMR (400 MHz, DMSO-d6): d 8.36 (d, J = 5.6 Hz, 1H), 7.15
m 2972.77, 2935.70, 1634.18,
;
(d, J = 8.8 Hz, 2H), 7.05 (d, J = 5.6 Hz, 1H), 6.82 (d, J = 8.8 Hz, 2H); 3.99 (s, 2H),
3.89 (s, 3H), 3.71 (s, 3H), 3.60–3.50 (m, 1H), 3.38–3.28 (m, 1H), 1.46 (br s, 6H),
1.03 (d, J = 7.0 Hz, 6H); 13C NMR (100 MHz, DMSO-d6): d 166.7, 166.2, 160.4,
158.3, 150.6, 130.0, 129.2, 114.7, 113.6, 106.9, 56.1, 55.0, 50.2, 44.6, 37.7, 20.0;
ES-MS: 389.2 (M+H)+; HRMS (ESI+): m/z Calcd for C21H29N2O3S: 389.1899
(M+H)+. Found: 389.1867; mp: 101–105 °C.