A rapid synthesis of thieno[2,3-c]pyridine and 2-substituted thieno[2,3-c]pyridines

Article abstract of DOI:10.1055/s-2004-829134

A convenient preparation of thieno[2,3-c]pyridine 3a and of several original 2-substituted-thieno[2,3-c]pyridines 3b-f is achieved by cyclization of the Schiff base resulting from the condensation between a 2- thiophenecarboxaldehyde 1a-f and aminoacetaldehyde dimethyl acetal. This procedure provides especially good yields in the case of 2-halogenated analogues.

Full text of DOI:10.1055/s-2004-829134

SHORT PAPER
1935
A Rapid Synthesis of Thieno[2,3-c]pyridine and 2-Substituted
Thieno[2,3-c]pyridines
Synthesis of
Thien
m
o[2,3-
c
]pyridine
a
n
a
d 2-Substitu
u
ted
T
hieno[
r
c
]pyr
y
idines Graulich,* Jean-François Liégeois
University of Liège, Natural and Synthetic Drugs Research Center, Laboratory of Medicinal Chemistry, avenue de l’Hôpital, 1 (B36),
4000 Liège 1, Belgium
Fax +32(4)3664362; E-mail: A.Graulich@student.ulg.ac.be
Received 27 February 2004; revised 23 April 2004
experimental section). The ring closure was performed in
Abstract: A convenient preparation of thieno[2,3-c]pyridine 3a
refluxing CH2Cl2 with an excess titanium chloride to af-
ford thieno[2,3-c]pyridine 3a (Scheme 1). For the first
time, several 2-substituted thieno[2,3-c]pyridines 3b–f
and of several original 2-substituted-thieno[2,3-c]pyridines 3b–f is
achieved by cyclization of the Schiff base resulting from the con-
densation between a 2-thiophenecarboxaldehyde 1a–f and ami-
noacetaldehyde dimethyl acetal. This procedure provides especially were obtained from the corresponding 5-substituted-2-
good yields in the case of 2-halogenated analogues.
thiophenecarboxaldehyde 1b–f following this pathway
without isolation of intermediates (see experimental sec-
tion). The yields for the synthesis of 2-halogenated
thieno[2,3-c]pyridines are relatively good in comparison
to the corresponding isoquinoline synthesis.7 The synthe-
sis of 2-methyl, 2-ethyl and, particularly, the 2-phenyl an-
alogues gave low yields. The synthesis of thieno[3,2-
c]pyridine with 3-thiophenecarboxaldehyde as starting
material was attempted using this method but the yield
was very low.
Keywords: cyclizations, electrophilic aromatic substitutions, het-
erocycles, Schiff bases, thienopyridine
Thienopyridines are of chemical and pharmacological in-
terest due to their isosterism with quinolines and isoquin-
olines, two important heterocycles in many alkaloids.1
Thieno[2,3-c]pyridine was first prepared by Herz and
Tsai2 and later by Klemm et al.,3 but in both cases the
yields were very low. More recently, Maffrand and Eloy4
have obtained thieno[2,3-c] and [3,2-c]pyridines by using
the Jackson modification of the Pomeranz–Fritsch proce-
dure.5 This method afforded thieno[2,3-c]pyridines in
good yields but this four-step procedure required the iso-
lation and purification of each intermediate.
In conclusion, several 2-substituted thieno[2,3-c]py-
ridines 3b–f were prepared and described for the first
time. By using the Hendrickson procedure, the best results
MeO
OMe
H2N
OMe
OMe
In addition, thieno[2,3-c]pyridine undergoes electrophilic
attack only at C-3 as reported for benzo[b]thiophene,
thieno[2,3-b]- and thieno[3,2-b]pyridines.6 So a synthesis
would be of great synthetic interest which allows for ob-
taining of the C-2 isomers.
ArMe reflux
N
O
R
R
S
S
Dean-Stark trap
H
1a-f
ClCOOEt
MeO
We now report a synthesis of thieno[2,3-c]pyridine 3a and
2-substituted thieno[2,3-c]pyridines 3b–f by the Hen-
drickson modification of the Pomeranz–Fritsch synthe-
sis.7 The classical method of Pomeranz–Fritsch was
carried out in two steps. Firstly, the condensation of an
arylaldehyde with aminoacetaldehyde dimethyl acetal
leads to the corresponding Schiff base and subsequently a
ring closure leads to the cyclized product.8
MeO
OMe
OMe
P(OMe)3
O
O
N
N
O
R
R
S
Cl
S
OEt
OEt
P
MeO
MeO
In the present synthesis, parallel to the Hendrickson pro-
cess described for isoquinoline derivatives, the imine re-
acts with ethyl chloroformate followed by trimethyl
phosphite to form a carbamate-phosphonate intermediate
before the cyclization step. This intermediate carbamate-
phosphonate was used immediately except for 2a, which
was purified by flash chromatography (eluent: EtOAc)
before characterization by IR and NMR experiments (see
2a-f
TiCl4
a : R = H
b : R = Cl
c : R = Br
d : R = Me
e : R = Et
f : R = Ph
R
N
S
3a-f
SYNTHESIS 2004, No. 12, pp 1935–1937
Advanced online publication: 01.07.2004
x
x.
x
x
.
2
0
0
4
Scheme 1 Thieno[2,3-c]pyridines synthesis
DOI: 10.1055/s-2004-829134; Art ID: T02404SS
© Georg Thieme Verlag Stuttgart · New York

1936
A. Graulich, J.-F. Liégeois
SHORT PAPER
material. The resulting crude product was purified by sublimation to
afford a white solid; yield: 44%; mp 61–62 °C.
IR: 1578, 832 cm–1.
were obtained with 2-halogenated analogues 3b–c in
comparison to 2-alkyl 3d–e and 2-phenyl 3f derivatives.
1H NMR (CDCl3): d = 7.22 (s, 1 H, 3-H), 7.53 (d, J = 5.5 Hz, 1 H,
4-H), 8.47 (d, J = 5.5 Hz, 1 H, 5-H), 8.95 (s, 1 H, 7-H).
MS: m/z = 170, 172 [MH+].
Melting points were determined on a Büchi-Tottoli capillary melt-
ing point apparatus in open capillary and are uncorrected. NMR
spectra were recorded on a Bruker AM400 spectrometer at 400
MHz. IR spectra were performed on a Perkin-Elmer FTIR-1750
spectrometer. IR spectra were measured using KBr discs. Only sig-
nificant bands from IR are reported. Elemental analyses were deter-
mined using a Carlo-Erba elemental analyser CHNS-O model
EA1108 and the results are within 0.4% of the theoretical values.
Mass spectra were recorded on a QTOF II (Micromass, Manchester
UK) spectrometer with electrospray mode. All starting materials
1a–f and reagents were obtained from Aldrich Chemical Co. and
were used without further purification. Separations by column chro-
matography were carried out using Merck Kieselgel 60 (230–400
mesh). Concentration and evaporation refer to removal of volatile
materials under reduced pressure (10–15 mm Hg at 30–50 °C) on a
Buchi Rotavapor.
Anal. Calcd for C7H4ClNS: C, 49.56; H, 2.38; N, 8.26. Found: C,
49.30; H, 2.03; N, 8.3.4.
2-Bromothieno[2,3-c]pyridine (3c)
Compound 3c was prepared according to the same chemical path-
way as described for compound 3a using compound 1c as starting
material. The resulting crude product was purified by sublimation to
afford a white solid; yield: 38%; mp 81–82 °C.
IR: 1576, 838 cm–1.
1H NMR (CDCl3): d = 7.35 (s, 1 H, 3-H), 7.56 (d, J = 5.3 Hz, 1 H,
4-H), 8.45 (d, J = 5.3 Hz, 1 H, 5-H), 8.98 (s, 1 H, 7-H).
MS: m/z = 214, 216 [MH+].
Thieno[2,3-c]pyridine (3a); Typical Procedure
Anal. Calcd for C7H4BrNS: C, 39.27; H, 1.88; N, 6.54. Found: C,
39.41; H, 1.84; N, 6.73.
A solution of 2-thiophenecarboxaldehyde (1a) (3.75 mL, 40 mmol)
and aminoacetaldehyde dimethyl acetal (4.4 mL, 40 mmol) in tolu-
ene (50 mL) was refluxed for 3 h using a Dean–Stark trap. After re-
moval of the solvent, the oil was dissolved in anhyd THF (30 mL)
and ethyl chloroformate (3.8 mL, 40 mmol) was added dropwise at
–10 °C. After 5 min under stirring, the cooling bath was removed
and trimethyl phosphite (5.3 mL, 45 mmol) was added at r.t. The so-
lution was evaporated under reduced pressure after 20 h. To remove
traces of trimethyl phosphite, toluene was added and evaporated
twice. The resulting oil was dissolved in anhyd CH2Cl2 (50 mL),
and titanium tetrachloride (26.5 mL, 240 mmol) was added. The
mixture was heated under reflux in an anhyd atmosphere for 24 h.
The reaction medium was poured in a mixture of ice (200 g) and
NH4OH (100 mL). The suspension was filtered and the TiO2 precip-
itate was rinsed with CHCl3 (3 × 50 mL). The organic layers were
collected and extracted with a 1 N aq HCl (2 × 50 mL). The acidic
layer was washed with CH2Cl2 (10 mL) and was then basified with
NH4OH. The suspension was extracted with CH2Cl2 (3 × 50 mL).
The organic solution was dried over anhyd MgSO4 and evaporated
under reduced pressure. The crude product was purified by sublima-
tion to afford thieno[2,3-c]pyridine (3a) as a white solid (1.5 g,
28%); mp 54–55 °C.
2-Methylthieno[2,3-c]pyridine (3d)
Compound 3d was prepared according to the same chemical path-
way as described for compound 3a using compound 1d as starting
material. The resulting crude product was purified by sublimation to
afford a white solid; yield: 17%; mp 52–54 °C.
IR: 1577, 848 cm–1.
1H NMR (CDCl3): d = 2.62 (s, 3 H, CH3), 6.98 (s, 1 H, 3-H), 7.50
(d, J = 5.3 Hz, 1 H, 4-H), 8.40 (d, J = 5.3 Hz, 1 H, 5-H), 8.97 (s, 1
H, 7-H).
MS: m/z = 150 [MH+].
Anal. Calcd for C8H7NS: C, 64.39; H, 4.73; N, 9.39. Found: C,
63.24; H, 4.42; N, 9.37.
2-Ethylthieno[2,3-c]pyridine Hydrochloride (3e)
Compound 3e was prepared according to the same chemical path-
way as described for compound 3a using compound 1e as starting
material. The resulting crude oil was treated with an ethereal HCl
solution to isolate the hydrochloride salt which was further recrys-
tallized in EtOH to afford a white solid; yield: 13%; mp 190–191
°C.
IR: 1577, 719 cm–1.
1H NMR (CDCl3): d = 7.43 (d, J = 5.4 Hz, 1 H, 3-H), 7.48 (d, J =
5.4 Hz, 1 H, 2-H), 7.80 (d, J = 5.4 Hz, 1 H, 4-H), 8.44 (d, J = 5.4
Hz, 1 H, 5-H), 9.11 (s, 1 H, 7-H).
IR: 2420, 1538, 848 cm–1.
1H NMR (CDCl3): d = 1.44 (t, J = 7.6 Hz, 3 H, CH2CH3), 3.11 (q,
J = 7.6 Hz, 2 H, CH2CH3), 7.37 (s, 1 H, 3-H), 8.01 (d, J = 6.3 Hz, 1
H, 4-H), 8.48 (d, J = 6.3 Hz, 1 H, 5-H), 9.39 (s, 1 H, 7-H).
MS: m/z = 136 [MH+].
Anal. Calcd for C7H5NS: C, 62.19; H, 3.73; N, 10.36. Found: C,
61.97; H, 3.64; N, 10.42.
MS: m/z = 164 [MH+].
Anal. Calcd for C9H9NS·HCl: C, 54.13; H, 5.05; N, 7.01. Found: C,
54.14; H, 4.98; N, 7.37.
For characterization, compound 2a (Scheme 1) was isolated by
flash chromatography (eluent: EtOAc). The appropriate fractions
were concentrated and the following IR and NMR data were ob-
tained on the resulting oil.
2-Phenylthieno[2,3-c]pyridine (3f)
Compound 3f was prepared according to the same chemical path-
way as described for compound 3a using compound 1f as starting
material. The resulting crude product was purified by sublimation to
afford a white solid; yield: 2%; mp 169–170 °C.
IR (C2Cl4): 1706 (strong C=O), 1256 (strong P=O), 1190 (weak
POMe), 1043 (very strong POMe) cm–1.
1H NMR (CDCl3): d = 1.27 (t, J = 7 Hz, 3 H, CH2CH3), 3.21 (s, 6
H, 2 × OCH3) 3.37–3.65 [m, 3 H, CH2CH(OCH3)2], 3.74 [t, 6 H,
O=P(OCH3)2], 4.21 (q, J = 7 Hz, 2 H, CH2CH3), 5.75 (d, J = 24.4
Hz, 1 H, H adjacent to P), 6.97–7.36 (m, 3 H, 2-thienyl).
IR: 1578, 1447, 1403, 759 cm–1.
1H NMR (CDCl3): d = 7.38–7.47 (m, 3 H, C6H5), 7.52 (s, 1 H, 3-H),
7.62 (d, J = 5.6 Hz, 1 H, 4-H), 7.73 (t, 2 H, C6H5), 8.47 (d, J = 5.6
Hz, 1 H, 5-H), 9.08 (s, 1 H, 7-H).
2-Chlorothieno[2,3-c]pyridine (3b)
Compound 3b was prepared according to the same chemical path-
way as described for compound 3a using compound 1b as starting
MS: m/z = 212 [MH+].
Synthesis 2004, No. 12, 1935–1937 © Thieme Stuttgart · New York

SHORT PAPER
Synthesis of Thieno[2,3-c]pyridine and 2-Substituted Thieno[2,3-c]pyridines
1937
Anal. Calcd for C13H9NS: C, 73.90; H, 4.29; N, 6.63. Found: C,
73.50; H, 4.22; N, 6.97.
References
(1) Jenkins, G. L.; Hartung, W. H. In The Chemistry of Organic
Medicinal Products, 3rd ed.; Wiley: New York, 1949.
(2) Herz, W.; Tsai, L. J. Am. Chem. Soc. 1953, 75, 5122.
(3) Klemm, L. M.; Shabtai, J.; McCoy, D. R.; Kiang, W. K. T.
J. Heterocycl. Chem. 1968, 5, 883.
(4) Maffrand, J. P.; Eloy, F. J. Heterocycl. Chem. 1976, 13,
1347.
(5) Birch, A. J.; Jackson, A. H.; Shannon, P. V. R. J. Chem. Soc.,
Perkin Trans. 1 1974, 2185.
Acknowledgment
The technical assistance of Y. Abrassart, S. Counerotte and J.-C.
Van Heugen is gratefully appreciated. A. G. is a Research Fellow of
the ‘Fonds pour la formation à la Recherche Industrielle et Agricole
(F. R. I. A.)’ and J.-F. L. is a Senior Research Associate of the
‘Fonds National de la Recherche Scientifique de Belgique (F. N. R.
S.)’.
(6) Dressler, M. L.; Joullié, M. M. J. Heterocycl. Chem. 1970, 7,
1257.
(7) Hendrickson, J. B.; Rodriguez, C. J. Org. Chem. 1983, 48,
3344.
(8) Gensler, W. J. Organic Reactions, Vol. 4; Wiley: New York,
1951, 191.
Synthesis 2004, No. 12, 1935–1937 © Thieme Stuttgart · New York