New efficient access to thieno[3,2-b]pyridine derivatives via regioselective lithiation of 3-methylthiopyridine

Article abstract of DOI:10.1016/j.tet.2006.04.008

The synthesis of thieno[3,2-b]pyridines was achieved using a three-step process allowing the construction of the thiophenic ring with 17-34% overall yields. The key step was the regioselective lithiation-bromination of the 3-methylthiopyridine induced by

Full text of DOI:10.1016/j.tet.2006.04.008

Tetrahedron 62 (2006) 6036–6041
New efficient access to thieno[3,2-b]pyridine derivatives via
regioselective lithiation of 3-methylthiopyridine
*
Corinne Comoy, Estelle Banaszak and Yves Fort
`
´
´
´
´
Synthese Organometallique et Reactivite, UMR CNRS 7565, Faculte des Sciences et Techniques,
´
´
`
Universite Henri Poincare—Nancy 1, BP 239, F-54506 Vandoeuvre-les-Nancy, France
Received 14 February 2006; revised 31 March 2006; accepted 3 April 2006
Available online 2 May 2006
Abstract—The synthesis of thieno[3,2-b]pyridines was achieved using a three-step process allowing the construction of the thiophenic
ring with 17–34% overall yields. The key step was the regioselective lithiation–bromination of the 3-methylthiopyridine induced by
BuLi–LiDMAE superbase followed by Sonogashira coupling and halogenocyclization producing the fused heterocycles.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
plained by a strong complexation of lithium by heteroatom
(Cl or O), pyridine nitrogen and dimethyl-aminoethoxide
in a specific lithiated aggregate (Scheme 1).
Due to their isosterism with indolopyridines or isoquinolines,
thienopyridines have attracted much attention because of
their potential biological activity as antipsychotics,1 anti-
bacterians,2 LHreceptoragonists,3 antitumoralagents4 orSrc
kinase inhibitors.5 Possessing a p-electron rich thiophene
ring and a p-electron deficient pyridine ring, these annelated
aromatic heterocycles are also of general interest for the
chemistry of ligands and theoretical organic chemistry.6
FG
FG
BuLi-LiDMAE
Li
N
N
hexane
Li
N
O
FG = OMe, Cl
E+
FG
Generally, these fused heterocyclic compounds are prepared
by the construction of the pyridinic ring from appropriate
substituted thiophene derivatives. These methods suffer from
disadvantage of limited access to starting materials, low-
functional compatibility and/or long-multistep sequences.7
In this context, our group is now interested in the develop-
ment of short polycyclic syntheses8 based on the selective
functionalization of aza-p-deficient heterocycles, such as
pyridines, allowing the opportune garlanding for subsequent
cyclization.
E
N
Scheme 1. Selective functionalization of 3-methoxy and 3-chloropyridines
induced by BuLi–LiDMAE superbase.
In this paper, we focused our attention on regioselective
functionalization of 3-methylthiopyridine 1 to evaluate the
potential cooperative effect of sulfur atom during the metal-
lation step (Scheme 2). In a synthetic context, the introduc-
tion of functionalities at C-2 versus C-6 on the pyridine ring
of sulfur containing derivatives could constitute the key step
of an alternative and rapid route to functionalized thieno[3,2-
b]pyridines (Scheme 3).
Some of our previous investigations,9,10 exhibited the use-
fulness of the monometallic BuLi–LiDMAE superbase
(DMAE: 2-(dimethylamino)ethanol) in apolar solvents
to perform regioselective C-2-lithiation of 3-chloro and
3-methoxypyridines. The exclusive C-2-metallation was ex-
SMe
Li
SMe
versus
N
Li
Li
N
Li
N
N
O
O
Keywords: Thieno[3,2-b]pyridine; Regioselective lithiation; BuLi–LiDMAE
superbase; Sonogashira coupling; Halogenocyclization.
* Corresponding author. Tel.: +33 3 83 68 47 81; e-mail: yves.fort@sor.
uhp-nancy.fr
2a
2b
Scheme 2. Potential cooperative effect of sulfur atom during metallation.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.04.008

C. Comoy et al. / Tetrahedron 62 (2006) 6036–6041
6037
a slight decrease in the selectivity. In contrast at ꢀ95 ꢁC,
the selectivity was increased to 90/10 and the conversion
was limited to 65% (Entry 4). At this temperature the use
of an excess (6 equiv) of superbase allowed us to combine
a high regioselectivity and a yield (89/11 and 73%, respec-
tively, Entry 6). In these conditions, we determined an opti-
mal 1 h condensation time (condensation times up to 2 h led
to degradation of lithiated species). Entries 7–10 finally con-
firmed that with the same excess of superbase, extended or
shorter metallation times as well as a higher temperature
conducted to a decrease in both yield and selectivity. In
agreement with this preliminary study, we have set the
best conditions for the regioselective functionalization of
3-methylthiopyridine 1 as follows: 6 equiv of base in non
complexing toluene, a metallation time of 4 h and a conden-
sation time of 1 h, all the protocol having to be conducted
at ꢀ95 ꢁC.
S
S
R
N
N
N
E
R
S
S
N
Br
Scheme 3. Access to functional thieno[3,2-b]pyridines.
2. Results and discussion
The reactivity of 3-methylthiopyridine 1 was first investi-
gated under various metallation and condensation conditions
to evaluate an efficient and regioselective functionalization
(i.e., C-2 vs C-6). As mentioned in previous works,9,10
apolar solvents such as hexane or toluene have to be used
to allow a strong aggregation between BuLi–LiDMAE and
pyridine substrates. Due to the lack of solubility of 1 in
hexane we chose to use toluene as metallation solvent.11
The expected 2- and 6-lithiopyridine intermediates (2a
and 2b) resulting from an a-lithiation process were trapped
by tetrabromomethane (CBr4) as electrophile in THF to
produce the stable bromide derivatives 3a and 3b.11
As the regioselectivity of this reaction is concerned, our
results confirm the hypothesis of the sulfur atom chelating
effect on the basic system, even if, as expected, the complex-
ing influence appears less strong than in 3-chloro or
3-methoxypyridines.9 It must be noted that no trace of
4-bromo-3-methylpyridine was detected so, this emphasizes
the strong aggregation between BuLi–LiDMAE superbase
and pyridine moieties, which dictate the selectivity of lithia-
tion.
In Table 1, we report the more significant results of this
preliminary study. At first, it appeared to us that standard
conditions used with 3-chloropyridine (3 equiv of superbase
at ꢀ45 ꢁC and hydrolysis at ꢀ20 ꢁC, Entry 1) only conducted
to poor yields (31%) due to some degradation. However, it
was also noticed that the selectivity of 3a/3b increased
when hydrolysis was conducted at ꢀ45 ꢁC (Entry 2). We
then decided to focus our attention on temperatures of metal-
lation, condensation and hydrolysis steps. At ꢀ80 ꢁC, an
interesting increase of yield was obtained (51%, Entry 3)
showing that a lower temperature of metallation limited
the degradation. However, in the same time, we observed
The versatility and the synthetic value of our methodology
were next examined by the introduction of various represen-
tative electrophiles at C-2 and/or C-6 positions (Table 2).
The expected compounds 4–8 were obtained in moderate
to good isolated yields (45–68% overall). Chloride, sulfide
and deuterium are selectively introduced in C-2 position
due to the expected chelating effect of the sulfur atom on
the basic system during the deprotonation step. In contrast,
despite a good conversion rate, iodide derivatives were
obtained in low 11% yield (not reported here) due to a great
instability of the formed products. It can be assumed that the
Table 1. Optimization of the functionalization of 3-methylthiopyridine 1a
S
i) n-BuLi - LiDMAE (n eq)
S
S
toluene, T°C, time
+
N
ii) CBr4 (n eq)
THF, T°C, time
iii) H2O, T°C
N
3a
Br
Br
N
3b
1
Entry
Metallation conditions
Halogenation conditions
Hydrolysis
Yieldsb (%)
Resultsb,c ratio
Base (equiv)
T (ꢁC)
t (h)
CBr4 (equiv)
T (ꢁC)
T (ꢁC)
(3a+3b)
(3a/3b)
1
2
3
4
5
6
7
8
9
10
3
3
3
3
4
6
6
6
6
6
ꢀ45
ꢀ45
ꢀ80
ꢀ95
ꢀ95
ꢀ95
ꢀ95
ꢀ95
ꢀ80
ꢀ80
1
1
4
4
4
4
8
2
4
1
3
3
3
3
4
6
6
6
6
6
ꢀ45
ꢀ45
ꢀ80
ꢀ95
ꢀ95
ꢀ95
ꢀ95
ꢀ95
ꢀ80
ꢀ80
ꢀ20a
ꢀ45
ꢀ20a
ꢀ95
ꢀ95
ꢀ95
ꢀ95
ꢀ95
ꢀ80
ꢀ80
31
29
51
23d
65
73
53
44
61
48
77/23
86/14
82/18
90/10
72/28
89/11
87/13
84/16
82/18
83/17
a
Reaction temperature (ꢀ45 or ꢀ80 ꢁC) was risen to ꢀ20 ꢁC in 15 min.
GC yields and selectivity ratio relative to an internal standard.
Total conversion of 1 was observed.
b
c
d
Conversion rate of reaction was limited to 65%.

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C. Comoy et al. / Tetrahedron 62 (2006) 6036–6041
Table 2. Scope and limitation of the electrophilea
i) n-BuLi - LiDMAE (6 eq)
S
S
R
S
toluene, -95°C, 4h
+
N
1
N
R
N
3-10 b
ii) Electrophile (6 eq)
THF, -95°C, 15 min
iii) H2O, -95°C
3-10 a
Entry
Electrophile
R
Total isolated yieldsb
Ratioc
Isolated yieldsb
a+b (%)
a/b
Isomer a (%)
Isomer b (%)
1
2
3
4
5
6
7
8
CBr4
C2Cl6
I2
Me2S2
Ph2S2
TESCl
DCl/D2O
PhCHO
Br
Cl
I
SMe
68
65
11
49
63
52
—
45
9/1
8/2
8/2
7/3c
9/1
1/9
8/2
2/8
3a (59%)
4a (50%)
5a+5bc,d,e
6a+6bc,e
7a (57%)
8a+8bb,c
9ac (80%)
10a (8%)
3b (9%)
4b (15%)
SPh
7b (6%)
Si(Et)3
D
CH(OH)Ph
9bc(20%)
10b (37%)
a
Reactions performed on 1.33 mmol of 1.
Isolated yields after silica gel chromatography.
GC or 1H NMR yields.
Rapid degradation of the products.
Isolated as a mixture of regioisomers a and b.
b
c
d
e
S
S
S
Electrophile
(2.5 eq)
R-C
C-H
R'
(I2, Br2 or NBS, 2 eq)
PdCl2 (PPh3)2 (5 mol %)
CuI (10 mol %)
Et3N, 1h, 60°C
N
N
N
3a
Br
CH2Cl2
r.t., 30 minutes
E
R'
11 R' = TMS, E = I, 79%
12 R' = TMS, E = Br, 42%
13 R' = Ph, E = I, 88%
14 R' = Ph, E = Br, 83%
9
R' = TMS, 70%
10 R' = Ph, 66%
Scheme 4. Synthesis of thieno[3,2-b]pyridine derivatives.
iodopyridines might be in situ formed and quickly attacked
by remaining n-BuLi or lithium alkoxides. On an other hand,
phenylmethanol or triethylsilyl moieties were introduced
with a reverse regioselectivity (7b and 8b formed as major
products). This inverse selectivity showed the competition
between a chelating effect and a steric hindrance of the
electrophile moiety. Indeed, it may be postulated that the ap-
proach of the sterically hindered electrophile to the lithiated
pyridine aggregate in C-2 position was more difficult than in
C-6 one. This led us to conclude that the condensation step is
strongly controlled by the formation of the product and that
the complexation effect of sulfur part is slight.
In a first step, acetylenic reagents were successfully coupled
in Sonogashira reactions using PdCl2(PPh3)2 (5 mol %) and
CuI (10 mol %) in Et3N as solvent and base. Electrophilic
cyclization was next performed using iodine or bromine as
electrophile. 2-Alkynyl-3-methylthiopyridines 9–10 reacted
efficiently to produce 11, 13 and 14 in excellent yields (79–
88%). In most cases, reaction time did not exceed 30 min at
room temperature. It is noteworthy that reactions with Br2
gave different results from those obtained with I2. Indeed,
no trace of silyl bromide derivative 12 was detected using
Br2 as electrophile while 14 was obtained with good yield.
When Br2 was changed by NBS and the reaction mixture
stirred overnight at room temperature, expected cyclization
product 12 were obtained in acceptable 42% yield. This
result could be explained by a rapid bromodesilylation
producing an unstable 2,3-dibromothieno[3,2-b]pyridine.
Thieno[3,2-b]pyridine derivatives 11, 12, 13 and 14 were
then prepared with overall yields of 33, 17, 34 and 32%,
respectively.
In a synthetic context, the silyl product 8b could have been
involved in Hiyama coupling.12 However, they are only
obtained as a crude intractable and unstable mixture, which
is rapidly degraded in the reaction medium not allowing
further additional range of functionalization by this way of
synthesis.
We next turned our efforts towards the functionalization of
formed halogenated derivatives. Starting from the readily
available 2-bromo-3-methylthiopyridine 3a, a two step
approach to functionalized thienopyridines has then been
examined involving Sonogashira coupling with terminal
acetylenes (trimethysilylacetylene or phenylacetylene) fol-
lowed by an electrophilic cyclization.13 This scheme of
synthesis leads to particularly quite reaction times and very
easy setting to access to thieno[3,2-b]pyridine derivatives
(Scheme 4).
3. Conclusion
In summary, a new synthesis of thieno[3,2-b]pyridines have
been prepared from 3-methylthiopyridine in moderate to
good yields. We believe that the three steps approach based
on the construction of thiophenic ring is a useful alternative
to classical methods and should prove quite useful in hetero-
cyclic synthesis. We are currently aiming to expand this
methodology for the use of other functionalized fused poly-
heterocycles.

C. Comoy et al. / Tetrahedron 62 (2006) 6036–6041
6039
4. Experimental
4.1. General methods
4.4.1.1. 2-Bromo-3-methylthiopyridine (3a). Brown
gummy solid; 1H NMR dH 2.50 (s, 3H), 7.40 (m, 2H), 8.24
(d, J¼2 Hz, 1H); 13C NMR dC 15.43, 123.16, 132.82,
140.69, 145.09, 161.80; IR (NaCl) n 2920, 1542, 1447,
1349, 1113, 1078, 1011, 820, 754; MS (EI) m/z 205 (99),
203 (100), 190 (7), 124 (52), 109 (74), 97 (66), 82 (46), 76
(13), 57 (13), 51 (19); HRMS (ESI+) Calculated for
C6H6BrNS¼202.9405, found [M+H]+¼203.9491.
1H and 13C NMR spectra were recorded at 400 or 250 and
100 MHz, respectively, with CDCl3 as solvent and TMS as
internal standard (for H NMR). HRMS were determined
1
at the Service Central d’Analyse of the CNRS at Vernaison
(France).
4.4.1.2. 6-Bromo-3-methylthiopyridine (3b). White
1
solid; mp 54–56 ꢁC; H NMR dH 2.50 (s, 3H), 7.27 (dt,
4.2. Materials and solvents
J¼4.5, 1.0 Hz, 1H), 7.39 (dd, J¼7.9, 1.7 Hz, 1H), 8.13
(dd, J¼4.8, 1.7 Hz, 1H); 13C NMR dC 15.99, 127.97,
135.33, 136.95, 138.48, 147.90; IR (NaCl) n 2920, 1542,
1447, 1349, 1113, 1078, 1011, 820, 754; MS (EI) m/z 205
(99), 203 (100), 190 (7), 124 (52), 109 (74), 97 (66), 82
(46), 76 (13), 57 (13), 51 (19).
All reagents were commercially available and were purified
by distillation when necessary. n-BuLi was used as a com-
mercial 1.6 M solution in hexanes. 2-(Dimethylamino)
ethanol (DMAE) was distilled and stored over molecular
sieves before use. Toluene and THF were distilled and stored
on sodium wire before use.
4.4.2. 2-Chloro-3-methylthiopyridine (4a) and 6-chloro-
3-methylthiopyridine (4b). Compounds 4a and 4b were
prepared according to the general method described herein
with C2Cl6 (1.896 g, 8 mmol) as electrophile. Purification
of crude product was performed by column chromatography
(eluent: hexane/AcOEt 90/10) and led to the separation
of regioisomers 4a (106 mg, 50%) and 4b (32 mg, 15%),
yield in 4a+4b (138 mg, 65%) with a regioselectivity
4a/4b: 8/2.
4.3. Preparation of 3-methylthiopyridine (1)
A solution of anhydrous THF (80 mL) was cooled at ꢀ80 ꢁC
and t-BuLi (31 mL, 54 mmol) was added dropwise under a
nitrogen atmosphere. Then, a solution of 3-bromopyridine
(4.230 g, 27 mmol) in THF (5 mL) was added dropwise.
After stirring for 30 min at ꢀ80 ꢁC, the reaction medium was
cooled at ꢀ95 ꢁC and dimethyldisulfur (6 mL, 67 mmol) in
THF (5 mL) was added. After stirring for 1 h at ꢀ95 ꢁC,
hydrolysis was performed at ꢀ20 ꢁC with H2O (30 mL). The
aqueous phase was extracted with ethyl acetate (20 mL).
After drying (MgSO4), filtration and solvents evaporation,
the crude product was purified by column chromatography
on a silica gel (Geduran Si 60, 0.063–0.200 mm). The spec-
troscopic data are in conformity with literature.
4.4.2.1. 2-Chloro-3-methylthiopyridine (4a).14 Pale
yellow gummy solid; H NMR dH 2.44 (s, 3H), 7.19 (dt,
1
J¼4.7 Hz, 1H), 7.42 (dd, J¼7.8, 1.3 Hz, 1H), 8.11 (dd,
J¼4.7, 1.5 Hz, 1H); 13C NMR dC 14.88, 122.90, 133.28,
136.13, 144.61, 147.96; IR (NaCl) n 2924, 1547, 1449,
1354, 1120, 1014, 823, 726; MS (EI) m/z 162 (8), 161
(31), 159 (100), 146 (6), 144 (15), 123 (26), 122 (13), 117
(11), 97 (7), 96 (22), 83 (13), 82 (18), 78 (17), 76 (8), 69
(11), 64 (6), 60 (6), 51 (12).
4.4. General procedure for functionalization of
3-methylthiopyridine (1)
4.4.2.2. 6-Chloro-3-methylthiopyridine (4b). Pale
yellow gummy solid; H NMR dH 2.51 (s, 3H), 7.25 (dd,
A solution of 2-(dimethylamino)ethanol (0.8 mL, 8 mmol)
in anhydrous toluene (15 mL) was cooled at ca. ꢀ5 ꢁC,
and n-BuLi (10 mL, 16 mmol) was added dropwise under
a nitrogen atmosphere. After 15 min. at 0 ꢁC, the reaction
medium was cooled at ꢀ95 ꢁC. 3-Methylthiopyridine 1
(166 mg, 1.33 mmol) in anhydrous toluene (5 mL) was
added dropwise. After stirring for 4 h at ꢀ95 ꢁC, a solution
of the appropriate electrophile (8 mmol) in anhydrous THF
(10 mL) was added dropwise. After stirring at ꢀ95 ꢁC dur-
ing the appropriate time, hydrolysis was performed at this
temperature with H2O (30 mL). The aqueous phase was
extracted with ethyl acetate (20 mL). After drying (MgSO4),
filtration and solvent evaporation, the crude product was
purified by column chromatography on a silica gel (0.063–
0.200 mm) with hexane/ethyl acetate mixtures as eluent.
1
J¼8.0, 1H), 7.55 (dd, J¼8.3, 2.6 Hz, 1H), 8.27 (d,
J¼2.4 Hz, 1H); 13C NMR dC 16.18, 124.24, 134.64,
137.33, 147.58, 148.37; IR (NaCl) n 2924, 1547, 1449,
1354, 1120, 1014, 823, 726; MS (EI) m/z 162 (8), 161
(31), 159 (100), 146 (6), 144 (15), 123 (26), 122 (13), 117
(11), 97 (7), 96 (22), 83 (13), 82 (18), 78 (17), 76 (8), 69
(11), 64 (6), 60 (6), 51 (12).
4.4.3. 3-Methylthio-2-phenylthiopyridine (5a) and 3-
methylthio-6-phenylthiopyridine (5b). Compounds 5a and
5b were prepared according to the general method described
herein with Ph2S2 (1.744 g, 8 mmol) as electrophile. Purifi-
cation of crude product was performed by column chroma-
tography (eluent: hexane/AcOEt 90/10) and led to the
separation of regioisomers 5a (177 mg, 57%) and 5b
(18 mg, 6%), yield in 5a+5b (195 mg, 63%) with a regio-
selectivity 5a/5b: 9/1.
4.4.1. 2-Bromo-3-methylthiopyridine (3a) and 6-bromo-
3-methylthiopyridine (3b). Compounds 3a and 3b were
prepared according to the general method described herein
with CBr4 (2.653 g, 8 mmol) as electrophile. Purification
of crude product was performed by column chromatography
(eluent: hexane/AcOEt 90/10) and led to the separation of
regioisomers 3a (159 mg, 59%) and 3b (24 mg, 9%), yield
in 3a+3b (183 mg, 68%) with a regioselectivity 3a/3b: 9/1.
4.4.3.1. 3-Methylthio-2-phenylthiopyridine (5a). Pale
yellow gummy solid; H NMR dH 2.53 (s, 3H), 7.04 (dt,
1
J¼4.8 Hz, 1H), 7.41 (m, 3H), 7.49 (dd, J¼7.8, 1.5 Hz,
1H), 7.55 (m, 2H), 8.20 (dd, J¼4.7, 1.5 Hz, 1H); 13C

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C. Comoy et al. / Tetrahedron 62 (2006) 6036–6041
NMR dC 16.16, 121.05, 128.50, 129.19, 134.14, 134.32,
146.33, 151.90, 157.10; IR (NaCl) n 2921, 1561, 1439,
1352, 1131, 747, 690; MS (EI) m/z 234 (14), 233 (M+,
56), 232 (74), 218 (100), 217 (32), 186 (47), 172 (12),
115 (12), 82 (39), 69 (35), 65 (38), 51 (10); HRMS (ESI+)
Calculated for C12H11NS2¼233.0334, found [M+H]+¼
234.0405.
4.5. Procedure for the palladium-catalyzed formation of
2-(1-alkynyl)-3-methylthiopyridines (9–10)
To a solution of Et3N (10 mL), PdCl2(PPh3)2 (0.070 g,
5 mol %), 2-bromo-3-methylthiopyridine 3a (0.408 g,
2 mmol) and the appropriate terminal acetylene (5 mmol)
(stirring for 5 min beforehand) was added CuI (0.038 mg,
10 mol %) and stirring was continued for another 15 min
before flushing with N2. The mixture was heated to Et3N
reflux and stirred for 1 h. The resulting solution was rapidly
washed with a saturated aqueous NH4Cl solution, and
extracted with dichloromethane (2ꢂ10 mL). After drying
(MgSO4), filtration and solvent evaporation, the crude prod-
uct was purified by column chromatography on a silica gel
(0.063–0.200 mm) with hexane/ethyl acetate mixtures as
eluent.
4.4.3.2. 3-Methylthio-6-phenylthiopyridine (5b). Pale
yellow gummy solid; H NMR dH 2.48 (s, 3H), 6.89 (dd,
1
J¼8.4 Hz, 1H), 7.42 (m, 4H), 7.59 (m, 2H), 8.37 (d,
J¼2.1 Hz, 1H); 13C NMR dC 16.19, 121.46, 128.52,
129.17, 134.10, 135.74, 147.93, 151.30, 158.64; IR (NaCl)
n 2921, 1561, 1439, 1352, 1131, 747, 690; MS (EI) m/z
234 (14), 233 (M+, 56), 232 (74), 218 (100), 217 (32), 186
(47), 172 (12), 115 (12), 82 (39), 69 (35), 65 (38), 51 (10).
4.4.4. Procedure for C-2 and C-6 functionalization of
3-methylthiopyridine (1) with deuterium. A solution of
DMAE (0.8 mL, 8 mmol) in toluene (15 mL) was cooled
at ca. ꢀ5 ꢁC, and n-BuLi (10 mL, 16 mmol) was added drop-
wise under a nitrogen atmosphere. After 15 min at 0 ꢁC, the
reaction medium was cooled at ꢀ95 ꢁC. 3-Methylthiopyri-
dine 1 (166 mg, 1.33 mmol) in toluene (5 mL) was added
dropwise. After 4 h of stirring at ꢀ95 ꢁC, a solution
MeOD (2 mL, 49 mmol) in THF (10 mL) was added drop-
wise. After 1 h of stirring at ꢀ95 ꢁC the solution was dried
(MgSO4), filtrated and solvents were evaporated. The
1H NMR data of the crude mixture allowed to determine a
regioselectivity 6a/6b: 8/2.
4.5.1. 2-(2-Trimethylsilylethyn-1-yl)-3-methylthiopyri-
dine (9). Compound 9 was prepared according to the method
described herein with trimethylsilylacetylene (0.246 g,
5 mmol) as terminal acetylene. Column chromatography
(eluent: hexane/AcOEt 70/30) yielded 9 (0.310 g, 70%) as
1
a brown gummy solid. H NMR dH 0.30 (s, 9H), 2.47 (s,
3H), 7.19 (dt, J¼4.7 Hz, 1H), 7.46 (dd, J¼8.1, 1.3 Hz,
1H), 8.3 (dd, J¼4.1 Hz, 1H); 13C NMR dC ꢀ0.18, 14.69,
101.03, 112.13, 123.24, 128.71, 131.49, 145.30; IR (NaCl)
n 2952, 2157, 1558, 1398, 1247, 1079, 1037, 850, 758,
703; MS (EI) m/z 221 (M+, 55), 206 (97), 190 (17), 176
(29), 130 (14), 84 (100), 51 (14).
4.5.2. 2-(2-Phenylethyn-1-yl)-3-methylthiopyridine (10).
Compound 10 was prepared according to the method
described herein with phenylacetylene (0.255 g, 5 mmol)
as terminal acetylene. Column chromatography (eluent:
hexane/AcOEt 70/30) yielded 10 (0.300 g, 66%) as a brown
4.4.5. (3-Methylthiopyridin-2-yl)phenylmethanol (7a)
and (3-methylthiopyridin-6-yl)phenylmethanol (7b).
Compounds 7a and 7b were prepared according to the
general method described herein with PhCHO (1.744 g,
8 mmol) as electrophile. Purification of crude product was
performed by column chromatography (eluent: hexane/
AcOEt 90/10) and led to the separation of regioisomers 7a
(25 mg, 8%) and 7b (114 mg, 37%), yield in 7a+7b
(139 mg, 45%) with a regioselectivity 7a/7b: 2/8.
1
powder; mp 75–77 ꢁC; H NMR dH 2.51 (s, 3H), 7.23 (dt,
J¼4.8 Hz, 1H), 7.38 (m, 3H), 7.48 (dd, J¼8.0 Hz, 1H),
7.65 (m, 2H), 8.36 (dd, J¼4.6 Hz, 1H); 13C NMR dC
14.82, 86.55, 122.35, 123.02, 128.51, 129.26, 131.57,
132.21, 145.51; IR (NaCl) n 3058, 2918, 2214, 1490,
1410, 1218, 1139, 756, 691; MS (EI) m/z 227 (4), 226
(15), 225 (M+, 65), 224 (100), 223 (53), 222 (11), 209 (8),
191 (8), 180 (8), 150 (11), 148 (39), 139 (13), 111 (13), 77
(13), 51 (13); HRMS (ESI+) Calculated for C14H11NS¼
225.0613, found [M+H]+¼226.0690.
4.4.5.1.
(3-Methylthiopyridin-2-yl)phenylmethanol
1
(7a). White solid; mp 60–62 ꢁC; H NMR dH 2.31 (s, 3H),
5.91 (s, 1H), 7.28 (m, 6H), 7.50 (dd, J¼8.1 Hz, 1H), 8.40
(dd, J¼4.6 Hz, 1H); 13C NMR dC 29.82, 74.75, 121.49,
127.10, 128.07, 128.37, 128.76, 128.92, 134.63, 136.07,
145.50, 157.89; IR (NaCl) n 3391, 2921, 1421, 1393,
1038, 699, 607; MS (EI) m/z 233 (5), 232 (15), 231 (M+,
80), 216 (29), 182 (25), 155 (54), 154 (50), 124 (33), 110
(27), 105 (28), 79 (83), 77 (100), 51 (45); HRMS (ESI+)
Calculated for C13H13NOS¼231.0719, found [M+H]+¼
232.0791.
4.6. Procedure for the iodo- and bromocyclizations
To a solution of 0.25 mmol of the 2-(1-alkynyl)-3-methyl-
thiopyridines 9–10 and 3 mL of CH2Cl2 was added gradu-
ally I2 or Br2 (0.5 mmol) in 2 mL of CH2Cl2. The reaction
mixture was flushed with N2 and stirred at room temperature
for 30 min. The excess of I2 or Br2 was removed by washing
with a saturated aqueous solution of Na2S2O3. The aqueous
solution was then extracted by CH2Cl2 (2ꢂ10 mL). After
drying (MgSO4), filtration and solvent evaporation, the
crude product was purified by column chromatography
on a silica gel (0.063–0.200 mm) with hexane/ethyl acetate
mixtures as eluent.
4.4.5.2.
(3-Methylthiopyridin-6-yl)phenylmethanol
1
(7b). White solid; mp 70–72 ꢁC; H NMR dH 2.50 (s, 3H),
5.75 (s, 1H), 7.10 (dd, J¼8.2 Hz, 1H), 7.28 (m, 5H), 7.52
(dd, J¼8.3, 2.2 Hz, 1H), 8.45 (d, J¼1.9 Hz, 1H); 13C
NMR dC 15.80, 72.40, 123.25, 127.09, 127.71, 127.90,
128.12, 128.49, 128.67, 134.44, 142.15, 143.87, 157.58;
IR (NaCl) n 3391, 2921, 1421, 1393, 1038, 699, 607; MS
(EI) m/z 233 (5), 232 (15), 231 (M+, 80), 216 (29), 182
(25), 155 (54), 154 (50), 124 (33), 110 (27), 105 (28), 79
(83), 77 (100), 51 (45).
4.6.1. 3-Iodo-2-trimethylsilylthieno[3,2-b]pyridine (11).
Compound 11 was prepared according to the method
described herein with I2 (127 mg, 0.5 mmol). Column

C. Comoy et al. / Tetrahedron 62 (2006) 6036–6041
6041
chromatography (eluent: hexane/AcOEt 70/30) yielded 11
Acknowledgements
1
(66 mg, 79%) as a yellow pale solid; mp 79–81 ꢁC; H
NMR dH 0.20 (s, 9H), 6.95 (dt, J¼4.5, 1.3 Hz, 1H), 7.81
(dd, J¼8.1, 1.4 Hz, 1H), 8.47 (dd, J¼4.6, 1.4 Hz, 1H); 13C
NMR dC 0.05, 91.81, 119.95, 130.73, 148.69; IR (KBr)
n 2924, 1384, 1246, 981, 889, 842, 759, 632; MS (EI) m/z
334 (12), 333 (M+, 67), 318 (100), 190 (44), 176 (60), 162
(13), 148 (19), 130 (15), 116 (19), 89 (30), 69 (24), 57
(37); HRMS (ESI+) Calculated for C10H12INSSi¼332.9506,
found [M+H]+¼333.9580.
We gratefully acknowledge financial support from CNRS
and UHP. We thank Dr. Philippe Gros for helpful discussions
during this work and Sandrine Adach for performing ele-
mental analyses and recording low-resolution mass spectra.
Supplementary data
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2006.04.008.
4.6.2. 3-Bromo-2-trimethylsilylthieno[3,2-b]pyridine
(12). Compound 12 was prepared according to the method
described herein with NBS (89 mg, 0.5 mmol). The mixture
stirred at room temperature overnight. Column chromato-
graphy (eluent: hexane/AcOEt 70/30) yielded 12 (30 mg,
References and notes
1. New, J. S.; Christopher, W. L.; Yevich, J. P.; Butler, R.; Schlem-
mer, F.; Van der Mealen, C. P.; Cipollina, J. A. J. Med. Chem.
1989, 32, 1147–1156.
1
42%) as yellow gummy solid; H NMR dH 0.050 (s, 9H),
7.30 (dt, J¼4.5 Hz, 1H), 8.17 (dd, J¼8.1 Hz, 1H), 8.80
(dd, J¼4.5 Hz, 1H); 13C NMR dC 1.64, 29.18, 116.65,
118.81, 129.86, 140.19, 147.58, 153.16; IR (NaCl) n
2955, 2923, 1389, 1250, 994, 893, 842, 759; MS (EI) m/z
287 (70), 285 (M+, 70), 272 (98), 270 (100), 190 (67),
176 (28), 148 (40), 130 (20), 89 (20); HRMS (ESI+) Calcu-
lated for C10H12BrNSSi¼284.9644, found [M+H]+¼
285.9716.
2. Malicorne, G.; Bompart, J.; Giral, L.; Despaux, E. Eur. J. Med.
Chem. 1991, 26, 3–11.
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. Chembio-
chem 2002, 1023–1026.
4. Hayakawa, I.; Shioya, R.; Agatsuma, T.; Furukawa, H.;
Sugano, Y. Bioorg. Med. Chem. Lett. 2004, 14, 3411–3414.
5. Boschelli, D. H.; Wu, B.; Barrios Sosa, A. C.; Durutlic, H.;
Chen, J. J.; Wang, J.; Golas, J. M.; Lucas, J.; Boschelli, F.
J. Med. Chem. 2005, 48, 3891–3902.
4.6.3. 3-Iodo-2-phenylthieno[3,2-b]pyridine (13). Com-
pound 13 was prepared according to the method described
herein with I2 (127 mg, 0.5 mmol). Column chromato-
graphy (eluent: hexane/AcOEt 70/30) yielded 13 (74 mg,
88%) as a yellow gummy solid. 1H NMR dH 7.31 (dt,
J¼4.7 Hz, 1H), 7.50 (m, 3H), 7.73 (m, 2H), 8.12 (dd, J¼
8.1, 1.2 Hz, 1H), 8.82 (dd, J¼4.6, 1.2 Hz, 1H); 13C NMR
dC 83.42, 120.06, 128.81, 129.56, 129.94, 130.42, 134.32,
148.50; IR (NaCl) n 3040, 2924, 2852, 1542, 1479, 1389,
1148, 1073, 785, 750, 694; MS (EI) m/z 338 (13), 337
(M+, 100), 210 (51), 166 (12), 139 (20), 127 (11), 105
(27), 91 (15), 83 (12), 69 (9), 57 (12); HRMS (ESI+) Cal-
culated for C13H8INS¼336.9423, found [M+H]+¼
337.9517.
6. Webber, J. S.; Woolley, R. G. J. Mol. Struct. (Theochem) 1995,
341, 181–200.
7. See for example: (a) Taylor, E. C.; Macor, J. E. Tetrahedron
Lett. 1985, 26, 2419–2422; (b) Deg’Innocenti, A.; Funicello,
M.; Scafato, P.; Spagnolo, P.; Zanirato, P. J. Chem. Soc., Perkin
Trans. 1 1996, 21, 2561–2563; (c) Bonini, C.; Chiummiento,
L.; Funicello, M.; Spagnolo, P. Tetrahedron 2000, 56, 1517–
1521; (d) Taylor, E. C.; Maor, J. E. Tetrahedron Lett. 1985,
26, 2419–2422.
8. Mamane, V.; Fort, Y. J. Org. Chem. 2005, 70, 8220–8223.
9. (a) Choppin, S.; Gros, P.; Fort, Y. Org. Lett. 2000, 2, 803–805;
(b) Choppin, S.; Gros, P.; Fort, Y. Eur. J. Org. Chem. 2001, 66,
603–606; (c) Gros, P.; Choppin, S.; Mathieu, J.; Fort, Y. J. Org.
Chem. 2002, 67, 234–237.
4.6.4. 3-Bromo-2-phenylthieno[3,2-b]pyridine (14). Com-
pound 14 was prepared according to the method described
herein with Br2 (0.26 mL, 0.5 mmol). Column chromato-
graphy (eluent: hexane/AcOEt 70/30) yielded 14 (60 mg,
10. Gros, P.; Fort, Y. Eur. J. Org. Chem. 2002, 67, 3375–3383 and
references cited therein.
11. Note that since commercially available solution of n-BuLi in
hexanes was used, the reaction was realized in a 2:1 toluene/
hexanes mixture. In addition, during the condensation step,
THF is necessary to ensure a rapid quenching by complete
destruction of formed aggregates.
12. Hirabayashi, K.; Mori, A.; Kawashima, J.; Suguro, M.; Nishi-
hara, Y.; Hiyama, T. J. Org. Chem. 2000, 65, 5342–5349.
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1
83%) as a white solid; mp 110–112 ꢁC; H NMR dH 7.30
(dt, J¼4.6 Hz, 1H), 7.50 (m, 3H), 7.80 (m, 2H), 8.12 (dd,
J¼8.1, 1.3 Hz, 1H), 8.80 (dd, J¼4.6, 1.3 Hz, 1H); 13C
NMR dC 107.51, 120.01, 128.87, 129.58, 130.47, 132.16,
148.36, 153.27; IR (NaCl) n 3052, 2926, 1393, 1276,
1074, 894, 754; MS (EI) m/z 291 (85), 289 (M+, 100),
210 (39), 166 (16), 139 (24), 105 (16); HRMS (ESI+)
Calculated for C13H8BrNS¼288.9561, found [M+H]+¼
289.9647.