An efficient and convenient synthesis of 4,5,6,7-tetrahydrothieno[3,2-c] pyridines by a modified Pictet-Spengler reaction via a formyliminium ion intermediate

Article abstract of DOI:10.3987/COM-10-11992

A synthesis of N-formyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridines (5) was achieved in a highly efficient manner via trifluoroacetic acid catalyzed cyclization of formyliminium ion (4), which was produced by imination of 2-(2-thienyl)ethylamine (1) and a carbonyl compound (2) using titanium(IV) tetraisopropoxide followed by formylation with acetic-formic anhydride in a one-pot procedure. This modified Pictet-Spengler reaction provides a convenient method for preparing 4,5,6,7-tetahydrothieno[3,2-c]pyridines (6) possessing various substituents at C-4. The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-10-11992

HETEROCYCLES, Vol. 81, No. 8, 2010
1903
HETEROCYCLES, Vol. 81, No. 8, 2010, pp. 1903 - 1921. © The Japan Institute of Heterocyclic Chemistry
Received, 9th June, 2010, Accepted, 23rd June, 2010, Published online, 25th June, 2010
DOI: 10.3987/COM-10-11992
AN EFFICIENT AND CONVENIENT SYNTHESIS OF
4,5,6,7-TETRAHYDROTHIENO[3,2-c]PYRIDINES BY A MODIFIED
PICTET-SPENGLER REACTION VIA A FORMYLIMINIUM ION
INTERMEDIATE
Michikazu Kitabatake, Aki Hashimoto, Toshiaki Saitoh, Takehiro Sano,
Kunihiko Mohri, and Yoshie Horiguchi*
Showa Pharmaceutical University, 3-3165 Higashi-tamagawagakuen, Machida,
Tokyo 194-8543, Japan: E-mail: horiguti@ac.shoyaku.ac.jp
Abstract – A synthesis of N-formyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridines (5)
was achieved in a highly efficient manner via trifluoroacetic acid catalyzed
cyclization of formyliminium ion (4), which was produced by imination of
2-(2-thienyl)ethylamine (1) and a carbonyl compound (2) using titanium(IV)
tetraisopropoxide followed by formylation with acetic-formic anhydride in a
one-pot procedure. This modified Pictet-Spengler reaction provides a convenient
method for preparing 4,5,6,7-tetahydrothieno[3,2-c]pyridines (6) possessing
various substituents at C-4.
INTRODUCTION
The Pictet-Spengler reaction is a well-known method for constructing 1,2,3,4-tetrahydroisoquinoline and
heteroaryl homologs, which constitute important motifs of naturally occurring bioactive compounds.1 The
synthesis of these compounds by the Pictet-Spengler reaction consists of two steps: the formation of an
imine by condensation of an arylethylamine with a carbonyl compound, and the acid-catalyzed
cyclization of the in situ generated imine. We recently modified both the imination and the cyclization
steps. We discovered that imination in titanium(IV) tetraisopropoxide2 proceeded in a highly effective
manner and that cyclization readily occurred in trifluoroacetic acid (TFA) when the imine was converted

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HETEROCYCLES, Vol. 81, No. 8, 2010
into a formyliminium ion.3 This modified method effectively enables the Pictet-Spengler reaction to be
applied to ketones, which is known to be difficult,4 providing 1,1-disubstituted
1,2,3,4-tetrahydroisoquinolines3 and 1,1-disubstituted tetrahydro--carbolines.5 This modified method
also induced the Pictet-Spengler reaction of phenylethylamine with aldehydes, although the benzene ring
lacks electron-donating groups, providing 1-substituted 1,2,3,4-tetrahydroisoquinolines in high yields.6
Yokoyama et al. reported that no cyclization of imines proceeded in TFA.7
In this paper we describe the modified Pictet-Spengler reaction of 2-(2-thienyl)ethylamine (1) with
aldehydes and ketones, which should provide a convenient method for preparing 4,5,6,7-
tetrahydrothieno[3,2-c]pyridines8 with various substituents at the C-4 position. Some 4-substituted
derivatives
have
been
reported
to
have
biological
activities.
For
example,
4-methyl-4-phenyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (6k) is a known N-methyl-D-aspartate
(NMDA) antagonist,9 and 4-aryl-5-aroyl derivatives containing this ring system are
glucose-6-phosphatase catalytic enzyme inhibitors.10
RESULTS AND DISCUSSION
The Pictet-Spengler reaction was carried out in a one-pot procedure as follows (Scheme 1).
2-(2-Thienyl)ethylamine (1) (1.2 mol equiv) and a carbonyl compound (2) (1.0 mol equiv) were
condensed at 80 °C in titanium(IV) tetraisopropoxide (1.8 mol equiv) for 3 h, and the in situ formed imine
(3) was treated with acetic-formic anhydride (100 mol equiv) at 70 °C for 2 h to produce the
formyliminium ion (4). To this solution, a large excess (100 mol equiv) of TFA was added at 0 °C and
then the solution was heated at 70 °C for an appropriate time, thus producing
N-formyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridines (5). This modified Pictet-Spengler reaction was
applied not only to aldehydes (2a-j and 2q) and but also to ketones (2k-o), which produced various
derivatives with different substitution patterns at the C-4 position. The structure of the product (5) was
assigned by observation of the characteristic C4 carbon signals at and 58.8 ppm (in the case of 5a)
in the 13C NMR spectrum. The results are summarized in Table 1.

HETEROCYCLES, Vol. 81, No. 8, 2010
1905
NH2
S
1
S
7
4
S
HCl or
NaOH
S
6
S
Ti(O-iPr)4
TFA
1
HCO2H-Ac2O
+
N
CHO
2
5
N
R2
NH
R2
N
O
CHO
3
R1
R1
R1
R2
R1
R2
R1
R2
5
6
4
3
2
S
2Me(CH2)nCHO
S
H
S
H
HCl
2c-g
N
1
N
NH
CHO
(CH2)n-1Me
(CH2)nMe
Ti(O-iPr)4
(CH2)n-1Me
(CH2)nMe
1) HCO2H-Ac2O
2) TFA
H
(CH2)n-1Me
(CH2)nMe
H
7
for compound 2c-g: n=1-5
8
9
Scheme 1: Synthesis of 4-substituted 4,5,6,7-tetrahydrothieno[3,2-c]pyridines using modified
Pictet-Spengler reaction
Benzaldehyde (2a), cyclopropanecarboxaldehyde (2h), cyclopentanecarboxaldehyde (2i), and
cyclohexanecarboxaldehyde
(2j)
gave
the
corresponding
4-monosubstituted
N-formyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridines (5a, 5h, 5i, 5j) in yields of 93, 72, 83, and 91%,
respectively. The cyclization of imines (3a and 3j), as already reported by Madsen et al., proceeded in
TFA at room temperature, but the yields of the products (5a and 5j) were only 24% and 8%, respectively.9
This indicated that our modified method has an advantage over the conventional one.
On the other hand, paraldehyde, a trimer of acetaldehyde (2b) and propionaldehyde (2c) gave the
expected products (5b, 5c), although in 24, 12% yields, respectively. This unsatisfactory result of the
reaction may be attributed to the high reactivity of these aldehydes for aldol condensation. In fact, the
reaction of 2c yielded the N-formyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (8c) having a pent-2-en-2yl
side chain at the C4 as a major product in 31% yield. The formation of 8c is readily explained by
assuming the formation of the imine (7c) that is formed from 1 mol eqiv of amine (1) and 2 mol eqiv of
propionaldehyde (2c) as shown in Scheme 1. Other alkyl aldehydes, n-butanal (2d), n-pentanal (2e),
n-hexanal (2f), and n-heptanal (2g), gave the similar results, thus yielding the corresponding
4,5,6,7-tetrahydrothieno[3,2-c]pyridine derivative (5d, 5e, 5f, 5g) in yields of 49-56% together with the
minor one (8d, 8e, 8f, 8g) in yields of 12-14%.

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HETEROCYCLES, Vol. 81, No. 8, 2010
Table1 Synthesis of N-formyl-4,5,6,7-tetrahydrothieno[3.2-c]pyridines (5) using the
Modified Pictet-Spengler reaction of 2-(2-thienyl)ethylamine (1)
Products
Yields (%) Yields (%)
Cyclization of N-formyliminium ion (4)
Aldehydes/
Ketones
R1
H
R2
Ph
Acid
Run
Temp (°C)
Time (h)
16
5
8
1
2
5a
2a
2b
70
93
24
TFA
TFA
H
Me
70
5b
1.5
3
4
5
H
H
2c
2d
2e
Et
TFA
TFA
TFA
70
70
70
5c
5d
5e
12
53
56
8c
(n=1)
1.5
1.5
31
14
13
14
12
n-propyl
n-butyl
(n=2)
8d
8e
H
H
H
(n=3)
(n=4)
(n=5)
1.5
1.5
1.5
6
7
n-pentyl
n-hexyl
TFA
TFA
2f
70
70
5f
49
56
8f
2g
5g
8g
8
9
H
H
H
cyclopropyl
cyclopentyl
TFA
TFA
TFA
5h
5i
2h
2i
70
70
72
83
6
3
10
2j
cyclohexyl
Ph
5j
70
70
70
91
84
74
3
3
3
11
12
Me
Me
2k
2l
TFA
TFA
5k
5l
Me
13
14
2m
2n
Me
Et
TFA
TFA
70
70
5m
5n
74
65
16
16
15
16
17
2o
2p
2q
TFA
TFA
TFA
70
70
70
5o
5p
5q
51
16
3
Ph
H
Ph
H
0
69
1.5
Acyclic ketones such as acetophenone (2k), acetone (2l), and 2-butanone (2m) gave the corresponding,
4,4-disubstituted N-formyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridines (5k, 5l, and 5m) in high yields
(74-84%). Cyclic ketones such as cyclopentanone (2n) and cyclohexanone (2o) also yielded the
corresponding 4-spirocycloalkyl N-formyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridines (5n) and (5o) in
yields of 65% and 51%, respectively. The gradually decreased yields observed in the reactions of cyclic
ketones suggested that the cyclization was sensitive to steric congestion. In the case of benzophenone

HETEROCYCLES, Vol. 81, No. 8, 2010
1907
Table 2 Synthesis of 4-Substitued 4,5,6,7-tetrahydrothieno[3,2-c]pyridines (6) and (9)
Hydrolysis
R1
H
R2
Ph
Reagent
NaOHc)
Run Substrate (5)
Time (h) Products Yields (%)
1
2
3
5a
5b
5c
18
4
6a
6b
6c
84
HCla)
HCla)
H
H
Me
Et
100
100
4
HCla)
HCla)
HCla)
HCla)
4
5
6
7
5d
5e
5f
H
H
H
H
n-propyl
n-butyl
4
4
4
4
6d
6e
6f
76
100
100
63
n-pentyl
n-hexyl
5g
6g
NaOHc)
8
5h
H
cyclopropyl
18
6h
94
HClb)
9
5i
5j
H
H
cyclopentyl
cyclohexyl
Ph
4
6i
6j
94
83
NaOHc)
NaOHc)
10
11
18
18
5k
Me
6k
100
NaOHb)
HCla)
12
13
5l
Me
Me
Me
Et
18
4
6l
67
85
5m
6m
HCla)
HCla)
HCla)
14
15
16
5n
5o
5q
18
4
100
47
6n
6o
6q
H
H
4
93
Substrate (8)
n
1
2
3
Reagent
HCla)
Time (h) Products Yields (%)
17
18
19
8c
8d
8e
4
4
4
9c
9d
9e
100
90
HCla)
HCla)
HCla)
HCla)
100
20
21
8f
4
5
4
4
9f
44
79
8g
9g
a) 10% HCl-EtOH-H2O solution. b) 20% HCl-EtOH-H2O solution.
c) 10% NaOH-EtOH-H2O solution.

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HETEROCYCLES, Vol. 81, No. 8, 2010
(2p) possessing two bulky phenyl groups, the expected product (5p) was not obtained at all. We
previously showed that the reaction of tryptamine with benzophenone (2p) under similar conditions
yielded N-formyl-1,1-diphenyl-1,2,3,4-tetrahydro--carboline, albeit in low yield (24%),4 indicating that
the inhibition of the reaction is attributable to the steric hindrance in the cyclization step, not in the
imination one.
Interestingly, paraformaldehyde (2q) afforded N-formyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (5q), the
skeletal compound of the ring system, in yield of 69%.
Alkaline or acidic hydrolysis of N-formyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridines (5 and 8) afforded the
corresponding 4,5,6,7-tetrahydrothieno[3,2-c]pyridines (6 and 9) in excellent to good yields as shown in
Table 2.
The 4-methyl-4-phenyl derivative (6k) of the NMDA antagonist was prepared previously in a multi-step
operation but in low overall yield (27%).9 This method gave 6k in 84% overall yield by these simple
manipulations.
Thus, the modified Pictet-Spengler reaction of 2-(2-thienyl)ethylamine (1) with carbonyl compounds
provides a convenient and effective method for synthesizing 4,5,6,7-tetrahydrothieno[3,2-c]pyridines (6)
with various substituents at the C-4 position. Particularly, this modified method is of great value in
preparing the sterically congested 4,4-disubstituted derivatives by simple one-pot manipulation.
EXPERIMENTAL
Unless otherwise noted, the following procedures were adopted. Melting points were taken on a
Yanagimoto SP-M1 hot-stage melting point apparatus and are uncorrected. IR spectra were measured as
KBr disks with a HORIBA FT-710 spectrophotometer or Nicolet iS10 spectrophotometer and the values
are given in cm-1. NMR spectra were measured on a JEOL JNM-AL 300 (1H-NMR, 300 MHz; 13C-NMR,
75 MHz) NMR spectrometer in CDCl3 or DMSO-d6 with tetramethylsilane as an internal standard and the
chemical shifts are given in  values. LR-MS were taken on JMS-AM20, and high resolution MS
(HR-MS) on a JEOL JMS-D300 spectrometer at 70 eV (EI-MS) using direct inlet systems. HRFAB-MS
spectra were recorded with JEOL-MS700 spectrometer using glycerol as a matrix. Elemental analyses
were recorded on a ThermoFisherScientific model EA1112 IRMS NC-plus CHNS. TLC was performed

HETEROCYCLES, Vol. 81, No. 8, 2010
1909
on Merck precoated Silica gel 60 F254 plates (Merck). Column chromatography was carried out with silica
gel (Wakogel C-200). The organic extract from each reaction mixture was washed with brine, dried over
anhydrous Na2SO4, and concentrated in vacuo to dryness.
The Pictet-Spengler reaction of 2-(2-thienyl)ethylamine (1) with carbonyl compound (2) : General
procedure.
Method A: A mixture of 1 (1.00 g, 7.86 mmol), carbonyl compound (2) (6.4 mmol) and Ti(O-iPr)4 (3.2 g,
11.3 mmol) was heated at 80 °C for 3 h under an argon atmosphere. To the reaction mixture, a solution of
acetic-formic anhydride [prepared from HCO2H (29.46 g, 0.64 mol) and Ac2O (65.34 g, 0.64 mol)] was
added at 0 °C, then the mixture was heated at 70 °C for 2 h. To this reaction mixture CF3CO2H (72.97 g,
0.64 mol) was added and heated at 70 °C for 3-16 h (Table 1). The reaction mixture was diluted with
MeOH (100 mL) and passed through a short SiO2 column (CHCl3-MeOH) to remove TiO2. The eluent
was concentrated in vacuo to ca. 50 mL and the residue was extracted with CHCl3. After removal of the
solvent of extract in vacuo, the residue was purified by chromatography over SiO2 eluted with
AcOEt-hexane (1:1-1:3) to give 5.
Method B: A mixture of 1 (1.00 g, 7.86 mmol), carbonyl compound (2) (7.86 mmol) and Ti(O-iPr)4 (2.68
g, 9.43 mmol) was heated at 80 °C for 2 h under an argon atmosphere. To the reaction mixture, a solution
of acetic-formic anhydride [prepared from HCO2H (9.05 g, 196.5 mmol) and Ac2O (20.1 g, 196.5 mmol)]
was added at 0 °C, then the mixture was heated at 70 °C for 0.5 h. To this reaction mixture CF3CO2H
(22.41 g, 196.5 mmol) was added and heated at 70 °C for 1.5 h. The reaction mixture was diluted with
MeOH (100 mL) and passed through a short SiO2 column (CHCl3-MeOH) to remove TiO2. The eluent
was concentrated in vacuo to ca. 50 mL and the residue was extracted with CHCl3. After removal of the
solvent of extract in vacuo, the residue was purified by chromatography over SiO2 (AcOEt-hexane
(2:1-1:3)) to give 5 and 8.
5-Formyl-4-phenyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (5a) : Method A
1
Pale yellow prisms recrystallized from hexane-Et2O. mp 80-83 °C IR:1662. H-NMR: 2.87-3.00,
3.42-3.52, 3.65-3.71, 4.48-4.52 (total 4H, each m, H-6 and H-7), 5.74, 6.63 (total 1H, each s, H-4), 6.70,
6.71 (total 1H, each d, J=5 Hz, H-3), 7.14-7.19 (2H, m, H-2 and Ph-H), 7.26-7.38 (4H, m, Ph-H), 8.18,
13
8.51 (total 1H, each s, -CHO). C-NMR: 24.5, 26.1 (C7), 34.4, 40.2 (C6), 52.6, 58.8 (C4), 123.6 (C3),

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HETEROCYCLES, Vol. 81, No. 8, 2010
125.9, 126.3 (C2), 127.7, 127.9 (Ph-CH), 128.3, 128.4 (2 x Ph-CH), 128.5, 128.7 (2 x Ph-CH), 132.6,
132.9 (Ph-C), 133.6, 135.2 (C3a), 139.9, 140.5 (C7a), 161.1, 161.2 (-CHO). LR-EIMS: m/z 243 (M+), 243
(base peak). HR-EIMS m/z (M+): Calcd for C14H13NOS: 243.0718. Found: 243.0669.
5-Formyl-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (5b) : Method B (Using paraldehyde 1.04 g,
7.86 mmol) instead of acetaldehyde as a carbonyl compound)
1
Yellow oil. IR: 1664. H-NMR: 1.43, 1.50 (total 3H , each d, J=7 Hz, -CH3), 2.77-3.14, 3.49-3.58,
3.74-3.81, 4.60-4.67 (total 4H, each m, H-6, H-7), 4.77, 5.42 (total 1H, each q, J=7 Hz, H-4), 6.79, 6.80
(total 1H, each d, J=5 Hz, H-3), 7.14 (1H, d, J=5 Hz, H-2), 8.16, 8.29 (total 1H, each s, -CHO).
13C-NMR: 20.1, 22.9 (CH3), 24.7, 26.1 (C7), 34.2, 40.5 (C6), 46.2. 51.6 (C4), 123.6 (C3),124.7, 125.2 (C2),
131.7, 133.4 (C3a), 136.0, 136.5 (C7a), 161.30, 161.33 (-CHO). LR-EIMS: m/z 243 (M+), 243(base peak).
HR-EIMS m/z (M+): Calcd for C9H11NOS:181.0561. Found: 181.0555.
4-Ethyl-5-formyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (5c) : Method B
Yellow oil. IR: 1672. 1H-NMR: 1.00 (3H , t, J=7 Hz, -CH2CH3), 1.65-1.95 (2H, m, -CH2CH3), 2.82-3.04,
3.50-3.60, 3.76-3.83, 4.64-4.74, (total 4H, each m, H-6, H-7), [4.41 (dd, J=4, 10 Hz), 5.42 (dd, J=5, 9
Hz) total 1H, H-4], 6.80, 6.81 (total 1H, each d, J=5 Hz, H-3), 7.13, 7.14 (total 1H, each d, J=5 Hz,
H-2), 8.22, 8.24 (total 1H, each s, -CHO). HR-EIMS m/z (M+): Calcd for C10H13NOS: 195.0718. Found:
195.0710.
5-Formyl-4-(pent-2-en-2-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (8c): Method B
1
Yellow oil. IR: 1672. H-NMR: 0.91, 0.94 (total 3H, each t, J=7 Hz, -C=CHCH2CH3), 1.67, 1.70 (total
3H, each s, -CH3) 2.01, 2.06 (total 2H, each q, J=7 Hz, -CH2CH3), 2.77-2.97 (2H, m, H-7), 3.23-3.32,
3.46-3.56, 3.66-3.72, 4.30-4.37 (total 2H, each m, H-6), 4.94, 5.82 (total 1H, each s, H-4), 5.10-5.14,
5.22-5.26 (total 1H, each m, -C=CHCH2CH3), 6.70 , 6.71 (total 1H, each d, J=3 Hz, H-3), 7.11, 7.13
(total 1H, each d, J=3 Hz, H-2), 8.23, 8.30 (total 1H, each s, -CHO). HR-FABMS m/z (MH+): Calcd for
C12H18NOS: 208.1160. Found: 208.1158.
5-Formyl-4-propyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (5d) : Method B
Yellow oil. IR: 1672. 1H-NMR: 0.91, 1.00 (total 3H , each t, J=7 Hz, - CH2CH2CH3), 1.38-1.50, 1.68-1.79
(total 4H, each m, -CH2CH2CH3), 2.81-3.00 (2H, m, H-7), 3.02-3.10, 3.50-3.58, 3.57-3.76, 4.65-4.69
(total 2H, each m, H-6), 4.50, 5.40 (total 1H, each dd, J=5, 9 Hz, H-4), 6.79, 6.81 (total 1H, each, d, J=5

HETEROCYCLES, Vol. 81, No. 8, 2010
1911
Hz, H-3), 7.13, 7.16 (total 1H, each , d, J=5 Hz, H-2), 8.20, 8.21 (total 1H, each s, -CHO). HR-FABMS
m/z (MH+): Calcd for C11H16NOS: 210.0953. Found: 210.0953.
5-Formyl-4-(hept-3-en-3-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (8d): Method B
Yellow oil. IR: 1675. 1H-NMR: 0.82, 0.85, 1.00, 1.07 (total 6H, each t, J=7Hz, -CH2CH3,
-C=CH(CH2)2CH3), 1.23-1.36 (2H, m, -CH2CH3), 1.96-2.05, 2.10-2.26 (total 4H, each m,
-C=CH(CH2)2CH3), 2.77-2.92 (2H, m, H-7), 3.07-3.15, 3.45-3.56, 3.62-3.67, 4.40-4.46 (total 2H, each m,
H-6), 4.93, 5.03 (total 1H, each t, J=7 Hz, -C=CH(CH2)2CH3), 5.01, 5.96 (total 1H, each s, H-4),
6.65-6.68 (1H, m, H-3), 7.10-7.12 (1H, m, H-2), 8.22, 8.30 (total 1H, each s, -CHO). HR-FABMS m/z
(MH+): Calcd for C15H22NOS: 264.1423. Found: 264.1440.
4-Butyl-5-formyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (5e) : Method B
1
Yellow oil. IR: 1672. H-NMR: 0.95, 0.97 (total 3H , each t, J=7 Hz, -(CH2)3CH3), 1.26-1.54, 1.63-1.83
(total 6H, each m, (CH2)3CH3), 2.87-2.97 (2H, m, H-7), 2.97-3.16, 3.50-3.57, 3.74-3.77, 4.65-4.71 (total
2H, each m, H-6), 4.51, 5.40 (total 1H, each dd, J=5, 9 Hz, H-4), 6.79, 7.14 (total 1H, each, d, J=5 Hz,
H-3), 7.12, 7.17 (total 1H, each , d, J=5 Hz, H-2), 8.20, 8.21 (total 1H, each s, -CHO). HR-FABMS m/z
(MH+): Calcd for C12H18NOS: 224.1110. Found: 224.1103.
5-Formyl-4-(non-4-en-4-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (8e): Method B
1
Yellow oil. IR: 1675. H-NMR: 0.86, 0.89, 0.93, 0.94 (total 6H, each t, J=7 Hz, -(CH2)2CH3,
-C=CH(CH2)3CH3), 1.25-1.27, 1.34-1.48 (total 6H, each m, -(CH2)2CH3, -C=CH(CH2)3CH3), 1.90-2.10,
2.10-2.21 (total 4H, each m, -(CH2)2CH3, -C=CH(CH2)3CH3), 2.77-2.96, 3.04-3.14, 3.45-3.52, 3.54-3.66,
4.42-4.47 (total 4H, each m, H-6, H-7), 4.96, 5.06 (total 1H, each t, J=7 Hz, -C=CH(CH2)3CH3), 5.00,
5.94 (total 1H, each s, H-4), 6.64, 6.67 (total 1H, each d, J=5 Hz, H-3), 7.10, 7.11 (total 1H, each d, J=5
Hz, H-2), 8.21, 8.29 (total 1H, each s, -CHO). HR-FABMS m/z (MH+): Calcd for C17H26NOS: 292.1735
Found: 292.1736.
5-Formyl-4-pentyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (5f) : Method B
1
Yellow oil. IR: 1672. H-NMR: 0.88, 0.39 (total 3H , each t, J=7 Hz, -(CH2)4CH3), 1.23-1.44 (6H, m,
(CH2)4CH3), 1.67-1.77 (2H, m, (CH2)4CH3), 2.75-3.05, 3.48-3.58, 3.73-3.81, 4.45-4.50 (total 4H, each m,
H-6, H-7), 4.64-4.69, 5.36-5.39 (total 1H, each m, H-4), 6.79 (1H, d, J=4 Hz, H-3), 7.10, 7.11 (total 1H,
each d, J=4 Hz, H-2), 8.188, 8.190 (total 1H, each s, -CHO). HR-FABMS m/z (MH+): Calcd for

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C13H20NOS: 238.1266. Found: 238.1274.
5-Formyl-4-(undec-5-en-5-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (8f): Method B
1
Yellow oil. IR: 1675. H-NMR: 0.81-0.95 (6H, m, -(CH2)3CH3, -C=CH(CH2)4CH3), 1.24-1.58 (10H, m,
-(CH2)3CH3, -C=CH(CH2)4CH3), 1.92-2.24 (4H, m, -(CH2)3CH3, -C=CH(CH2)4CH3), 2.76-4.47 (4H, m,
H-6, H-7), 4.93-5.07 (1H, m, -C=CH(CH2)3CH3), 5.95 (1H, s, H-4), 6.64, 6.65 (total 1H, each d, J=5 Hz,
H-3), 7.08, 7.10 (total 1H, each d, J=5 Hz, H-2), 8.21, 8.29 (total 1H, each s, -CHO). HR-FABMS m/z
(MH+): Calcd for C19H30NOS: 320.2048. Found: 320.2062
5-Formyl-4-hexyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (5g) : Method B
Yellow oil. IR: 1672. 1H-NMR: 0.85-0.89 (3H, m, -(CH2)5CH3), 1.23-1.46 (8H, m, (CH2)5CH3), 1.71-1.81
(2H, m, (CH2)5CH3), 2.80-3.07, 3.49-3.59, 3.74-3.81, 4.47-4.51 (total 4H, each m, H-6, H-7), 5.36-5.40,
4.64-4.70 (total 1H, each m, H-4), 6.81, 6.79 (total 1H, each d, J=3 Hz, H-3), 7.11, 7.13（total 1H, each d,
J=3 Hz, H-2), 8.20, 8.21 (total 1H, each s, -CHO). HR-FABMS m/z (MH+): Calcd for C14H22NOS:
252.1422. Found: 252.1432.
5-Formyl-4-(tridec-6-en-6-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (8g): Method B
1
Yellow oil. IR: 1675. H-NMR: 0.80-0.90 (6H, m, -(CH2)4CH3, -C=CH(CH2)5CH3), 1.23-1.33 (14H, m,
-(CH2)4CH3, -C=CH(CH2)5CH3), 1.89-2.02, (4H, m, -(CH2)4CH3, -C=CH(CH2)5CH3), 2.74-4.46 (4H, m,
H-6, H-7), 4.92-5.07 (1H, m, -C=CH(CH2)3CH3), 5.94 (1H, s, H-4), 6.64, 6.66 (total 1H, each d, J=5 Hz,
H-3), 7.09, 7.10 (total 1H, each d, J=5 Hz, H-2), 8.21, 8.29 (total 1H, each s, -CHO). HR-FABMS m/z
(MH+): Calcd for C21H34NOS: 348.236. Found: 348.2357.
4-Cyclopropyl-5-Formyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (5h) : Method A
1
Colorless prisms recrystallized from hexane-Et2O. mp 88-90 °C IR: 1672. H-NMR: 0.36-0.81(4H, m,
cyclopropyl-CH2), 1.75 (1H, m, cyclopropyl-CH), 2.81-2.99 (2H, m, H-7), 3.20-3.30, 4.62-4.69 (total 2H,
each m, H-6), 3.68-3.86 (1H, m, H-4), 6.92, 6.93 (total 1H, each d, J=5 Hz, H-3), 7.14, 7.15 (total 1H,
each , J=5 Hz, H-2), 8.20 (1H, d, J=4 Hz, -CHO). 13C-NMR: 2.85, 3.68, 4.91(2 x cyclopropyl-CH2), 16.6,
17.2 (cyclopropyl-CH), 24.7, 26.2 (C7), 35.3, 41.3 (C6), 54.1, 60.7 (C4), 123.2, 123.3 (C3), 125.1, 125.7
(C2), 132.1, 133.8 (C3a), 134.6, 135.0 (C7a), 161.1, 161.6 (CHO). LR-EIMS: m/z 207 (M+), 166 (base
peak). HR-EIMS m/z (M+): Calcd for C11H13NOS: 207.0718. Found: 207.0735.
4-Cyclopentyl-5-Formyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (5i) : Method A

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1913
1
Yellow oil. IR: 1670. H-NMR: 1.25-1.79 (8H, m, cyclopentyl-CH2), 2.80-3.01 (2H, m, H-7), 3.05-3.15,
3.59-3.69 (total 2H, each m, H-6), 3.75-3.79, 4.66-4.72 (total 1H, each m, cyclopentyl-CH), 4.23, 5.24
(total 1H, each d, J=10 Hz, H-4), 6.85 (1H, d, J=5 Hz, H-3), 7.10, 7.11 (total 1H, each d, J=5 Hz, H-2),
8.17, 8.22 (total 1H, each s, -CHO). 13C-NMR: 24.1, 25.2 (cyclopentyl-CH2), 24.3, 25.4
(cyclopentyl-CH2), 24.6, 26.3 (cyclopentyl-CH2), 30.0, 30.6 (cyclopentyl-CH2), 31.0, 34.7 (C7), 40.8 (C6),
45.5 (cyclopentyl-CH), 53.9, 60.7 (C4), 122.8 (C3), 125.7, 126.2 (C2), 132.1, 133.8 (C3a), 135.2, 135.6
(C7a), 161.3, 161.5 (-CHO). LR-EIMS: m/z 235 (M+), 166 (base peak). HR-EIMS m/z (M+): Calcd for
C13H17NOS: 235.1031. Found: 235.1010.
4-Cyclohexyl-5-Formyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (5j) : Method A
Yellow oil. IR: 1670. 1H-NMR: 0.95-2.05 (10H, m, cyclohexyl-CH2), 2.79-3.11, 3.57-3.67 (total 4H, each
m, H-6 and H-7), 3.75-3.82, 4.69-4.75 (total 1H, each m, cyclohexyl-CH), 4.21, 5.17 (total 1H, each d,
J=7 Hz, H-4), 6.82, 6.83 (total 1H, each d, J=5 Hz, H-3), 7.11, 7.13 (total 1H, each d, J=5 Hz, H-2), 8.16,
8.21 (total 1H, each s, -CHO). LR-EIMS: m/z 249 (M+), 166 (base peak). HR-EIMS m/z (M+): Calcd for
C14H19NOS: 249.1187. Found: 249.1175.
5-Formyl-4-methyl-4-phenyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (5k) : Method A
1
Colorless plate recrystallized from AcOEt. mp 139-141 °C. IR: 1666. H-NMR: 2.02 (3H, s, -CH3),
2.89-3.05 (2H, m, H-7), 3.75-3.83 (1H, m, H-6), 3.96-4.04 (1H, m, H-6), 6.58 (1H, d, J=5 Hz, H-3), 7.08
13
(1H, d, J=5 Hz, H-2), 7.21-7.36 (5H, m, Ph-H), 8.25 (1H, s, -CHO). C-NMR: 24.6 (C7), 27.7 (CH3 ),
35.8 (C6), 62.6 (C4), 123.2 (C3), 125.6 (C2), 126.7 (2 x Ph-CH), 127.7 (Ph-CH), 128.6 (2 x Ph-CH), 133.5
(C3a), 139.7 (C7a), 144.2 (Ph-C), 162.1 (-CHO). LR-EIMS: m/z 257 (M+), 242 (base peak). HR-EIMS m/z
(M+): Calcd for C15H15NOS: 257.0874. Found: 257.0862.
5-Formyl-4,4-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (5l) : Method A
1
Colorless plates recrystallized from hexane-Et2O. mp 88-90 °C. IR: 1641. H-NMR: 1.69 (6H, s, 2 x -
CH3), 2.83 (2H, t, J=5 Hz, H-7), 3.92 (2H, t, J=5 Hz, H-6), 6.85 (1H, d, J=5 Hz, H-3), 7.12 (1H, d, J=5
13
Hz, H-2), 8.57 (1H, s, -CHO). C-NMR: 24.8 (C7), 29.9 (2x- CH3 ), 35.4 (C6), 57.4 (C4), 123.3 (C3),
124.2 (C2), 133.1 (C3a), 140.7 (C7a), 160.6 (-CHO). LR-EIMS: m/z 195 (M+), 180 (base peak). HR-EIMS
m/z (M+): Calcd for C10H13NOS: 195.0718. Found: 195.0708. Anal. Calcd for C10H13NOS: C, 61.50; H,
6.71; N, 7.17 Found: C, 61.59; H, 6.79; N, 7.33.

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4-Ethyl-5-formyl-1-methyl-4,5,6,7-tetrahydtothieno[3,2-c]pyridine (5m) : Method A
Pale yellow prisms recrystallized from AcOEt-hexane. mp 55-57 °C. IR: 1658. 1H-NMR: 0.58, 0.73 (total
3H, each t, J=7 Hz, -CH2CH3), 1.64 (3H, s, -CH3), 2.02 (2H, qd, J=7, 2 Hz, -CH2CH3), 2.76-2.88 (2H, m,
H-7), 3.81-3.95 (2H, m, H-6), 6.79 (1H, d, J=5 Hz, H-3), 7.13 (1H, d, J=5 Hz, H-2), 8.47 (1H, s, -CHO).
13C-NMR: 7.72, 8.13 (-CH2CH3), 24.3, 25.5 (-CH2CH3), 25.8, 28.2 (-CH3), 32.1, 34.0 (C7), 35.5, 44.3
(C6), 60.3, 62.4 (C4), 122.9, 123.0 (C3), 124.0, 124.1 (C2), 132.7, 133.7 (C3a), 139.3, 140.6 (C7a), 161.0,
162.2 (-CHO). LR-EIMS: m/z 209 (M+), 180 (base peak). HR-EIMS m/z (M+): Calcd for C11H15NOS:
209.0874. Found: 209.0871. Anal. Calcd for C11H15NOS: C, 63.12; H, 7.22; N, 6.69. Found: C, 63.11; H,
7.31; N, 6.90.
5-Formyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-4-spirocyclopentane (5n) : Method A
1
Colorless plates recrystallized from AcOEt-hexane. mp 108-110 °C. IR: 1643. H-NMR: 1.75-2.26 (8H,
m, cyclopentyl), 2.84 (2H, t, J=6 Hz, H-7), 3.91 (2H, t, J=6 Hz, H-6), 6.82 (1H, d, J=5 Hz, H-3), 7.12
(1H, d, J=5 Hz, H-2), 8.33 (1H, s, -CHO). 13C-NMR: 23.8 x 2 (2 x cyclopentyl-CH2), 24.9 (C7), 36.3 (C6),
39.6 x 2 (2 x cyclopentyl-CH2), 68.8 (C4), 123.1 (C3), 124.1 (C2), 134.2 (C3a), 139.4 (C7a), 160.4(d,
-CHO). LR-EIMS: m/z 221 (M+), 151 (base peak). HR-EIMS m/z (M+): Calcd for C12H15NOS: 221.0874
Found: 221.0856. Anal. Calcd for C12H15NOS: C, 65.12; H, 6.83; N, 6.33. Found: C, 65.04; H, 6.80; N,
6.46.
5-Formyl-4,5,6,7- tetrahydrothieno[3,2-c]pyridine-1-spirocyclohexane (5o) : Method A
1
Yellow prisms recrystallized from AcOEt-Et2O. mp 156-159 °C. IR: 1643. H-NMR: 1.33-1.97 (8H, m,
cyclohexyl-CH2), 2.22 (2H, d, J=14 Hz, cyclohexyl-CH2), 2.85 (2H, t, J=6 Hz, H-7), 3.93(2H, t, J=6 Hz,
H-6), 6.87 (1H, d, J=5 Hz, H-3), 7.07 (1H, d, J=5 Hz, H-2), 8.58(1H, s, -CHO). 13C-NMR: 21.7
(cyclohexyl-CH2), 22.0 (cyclohexyl-CH2), 24.5 (cyclohexyl-CH2), 25.5 (C7), 34.9 (C6), 35.9 (2 x
cyclohexyl-CH2), 60.0 (C4), 122.7 (C3), 124.1 (C2), 134.1 (C3a), 142.3 (C7a), 162.3, 162.4(CHO).
LR-EIMS: m/z 235 (M+), 193 (base peak). HR-EIMS m/z (M+): Calcd for C13H17NOS: 235.1031. Found:
235.1046. Anal. Calcd for C13H17NOS: C, 66.34; H, 7.28; N, 5.95. Found: C, 66.47; H, 7.58; N, 5.99.
5-Formyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (5q) : Method B (Using paraformaldehyde (0.24 g)
instead of formaldehyde (7.86 mmol) as a carbonyl compound).
Yellow oil. IR: 1668. 1H-NMR: 2.88, 2.92 (total 2H, each t, J=7 Hz and 6 Hz, H-7), 3.69, 3.86 ( total 2H,

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each t, J=6 Hz, H-6), 4.47, 4.60 (total 2H, t and s, J=2 Hz, H-4), 6.79, 6.80 (total 1H, each d, J=5 Hz,
13
H-3), 7.15, 7.16 (total 1H, each d, J=5 Hz, H-2), 8.19, 8.23 (total 1H, each s, -CHO). C-NMR: 24.3,
25.7 (C7), 37.8, 40.5 (C6), 43.6. 45.6 (C4), 123.7 (C3), 124.2, 124.9 (C2), 130.6, 130.7 (C3a), 132.1, 133.7
(C7a), 161.3, 161.6 (-CHO). HR-EIMS m/z (M+): Calcd for C8H9NOS: 167.0405. Found: 167.0416
Hydrolysis of 5-formyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine.
Typical procedure: NaOH aq hydrolysis. (see Table 2)
A solution of 5 (200 mg) in EtOH (60 mL) and 20% NaOH solution (60 mL) was refluxed for 18 h
under an argon atmosphere. The reaction mixture was diluted with water, and extracted with CHCl3.
The residue was purified by column chromatography over SiO2 with MeOH-CHCl3 (9:1) to give 6.
Typical procedure: HCl aq hydrolysis. (see Table 2)
A solution of 5 and 8 (200 mg) in EtOH (14 mL) and c-HCl (6 mL or 12 mL) was refluxed for 4-18 h
under an argon atmosphere. The reaction mixture was diluted with water, alkalized with 10% NaOH
solution and extracted with CHCl3. The residue was purified by column chromatography over SiO2 with
MeOH-CHCl3 (9:1) to give 6 and 9.
4-Phenyl-4,5,6,7- tetrahydrothieno[3,2-c]pyridine (6a)
Colorless prisms recrystallized from Et2O-hexane. mp 80-82 °C (lit.,10 mp 79.8-80.7 °C ). IR: 3255, 1655.
1H-NMR : 2.83-3.04 (2H, m, H-7), 3.07~3.35 (2H, m, H-6), 5.02 (1H, s, H-4), 6.47 (1H, d, J=5 Hz, H-3),
7.00 (1H, d, J=5 Hz, H-2), 7.26-7.36 (5H, m, Ph-H). 13C-NMR: 26.0 (C7), 42.5 (C6), 60.0 (C4), 121.7 (C3),
126.3 (C2), 127.5 (PhCH), 128.2 (2 x PhCH), 128.4 (2 x PhCH), 134.9 (PhC) 136.8 (C3a), 143.7 (C7a).
LR-EIMS: m/z 215 (M+), 138 (base peak). HR-EIMS m/z (M+): Calcd for C13H13NS:215.0769. Found:
215.0786.
4-Metyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (6b)
Pale yellow oil. IR: 2924, 1653. 1H-NMR : 1.39 (3H, d, J=7 Hz，-CH3), 1.66 (1H，brs, -NH)，2.68-2.90
(2H, m, H-7), 3.01 (1H, ddt, J=12, 5, 4 Hz, H-6), 3.32 (1H, ddd, J=13, 5, 4 Hz, H-6), 4.00 (1H, qt, J=7, 2
Hz, H-4), 6.80 (1H, d, J=5 Hz, H-3), 7.05 (1H, d, J=5 Hz, H-2). 13C-NMR: 22.0 (-CH3), 26.1 (C7), 42.7
(C6), 50.6 (C4), 121.7 (C3), 124.8 (C2), 133.8 (C3a), 139.3 (C7a). HR-EIMS m/z (M+): Calcd for
C8H11NS:153.0612. Found: 153.0588.
4-Ethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (6c)

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Pale yellow oil. IR: 2860, 2927, 1652. 1H-NMR: 1.00 (3H , each t, J=7 Hz, -CH2CH3), 1.54-1.70 (2H, m,
-CH2CH3), 1.92 (1H, dddd, J=15, 11, 8, 4 Hz, H-7), 270-2.91 (1H, m, H-7), 3.00 (1H, ddd, J= 12, 8, 5 Hz,
H-6), 3.32 (1H, ddd, J=12, 5, 4, Hz, H-6), 3.83 (1H, ddd, J=8, 4, 2 Hz, H-4). 6.81 (1H, d, J=5 Hz, H-3),
13
7.05 (1H, d, J=5 Hz, H-2). C-NMR: 10.3 (CH3), 26.2 (C7), 28.6 (-CH2CH3), 38.2, 42.5 (C6), 56.2 (C4),
121.6 (C3), 124.9 (C2), 134.3 (C3a), 138.3 (C7a). HR-FABMS m/z (MH+): Calcd for C9H14NS: 168.0847.
Found: 168.0858.
4-Propyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (6d)
1
Yellow oil. IR: 2958, 2925, 1666. H-NMR: 0.97 (3H, t, J=7 Hz, -(CH2) 2CH3), 1.36-1.65, (2H, m,
-(CH2)2CH3), 2.78-1.89 (2H, m, -(CH2)2CH3), 2.72-2.89 (2H, m, H-7), 2.95-3.04 (1H, m, H-6), 3.28-3.35
(1H, m, H-6), 3.88-3.91 (1H, m, H-4), 6.81 (1H, d, J=5 Hz, H-3), 7.05 (1H, d, J=5 Hz, H-2). 13C-NMR:
14.1 (CH3), 19.1 (-(CH2) 2CH3), 26.1 (C7), 38.2 (-(CH2) 2CH3), 42.4 (C6), 54.6 (C4), 121.6 (C3), 124.8 (C2),
134.0 (C3a), 138.4 (C7a). HR-FABMS m/z (MH+): Calcd for C10H16NS: 182.1003. Found: 182.1004.
4-Butyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (6e)
1
Yellow oil. IR: 2960, 2930, 1668. H-NMR: 0.92 (3H, t, J=7 Hz, -(CH2)3CH3), 1.26-1.54, 1.49-1.62,
1.76-1.89 (total 6H, each m, (CH2)3CH3), 2.71-2.87 (2H, m, H-7), 2.96-3.03 (1H, m, H-6), 3.27-3.35 (1H,
m, H-6), 3.89 (1H, dd, J=2, 7 Hz, H-4), 6.81 (1H, d, J=5 Hz, H-3), 7.05 (1H, d, J=5 Hz, H-2). 13C-NMR:
13.9 (CH3), 22.7 (-(CH2) 3CH3), 25.9 (C7), 28.0 (-(CH2) 3CH3), 35.5 (-(CH2) 3CH3), 42.2 (C6), 54.8 (C4),
121.7 (C3), 124.8 (C2), 133.9 (C3a), 138.7 (C7a). HR-FABMS (MH+): Calcd for C11H18NS: 196.1160.
Found: 196.1151.
4-Pentyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (6f)
1
Yellow oil. IR: 2956, 2929, 1662. H-NMR: 0.90 (3H, t, J=7 Hz, -(CH2)4CH3), 1.26-1.63 6H, m,
(CH2)4CH3), 1.79-1.88 (2H, m, (CH2)4CH3), 2.71-2.88 (2H, m, H-7), 2.95-3.03 (1H, m, H-6), 3.28-3.35
(1H, m, H-6), 3.87-3.89 (1H, m, H-4), 6.81 (1H, each, d, J=5 Hz, H-3), 7.04-7.08 (1H, m, H-2).
13C-NMR: 13.4 (CH3), 22.5 (-(CH2) CH3), 25.5 (C7), 26.1 (-(CH2) CH3), 31.9 (-(CH2)4CH3), 35.9
4
4
(-(CH2) 4CH3), 42.3 (C6), 54.8 (C4), 121.5 (C3), 124.7 (C2), 133.9 (C3a), 138.4 (C7a). HR-FABMS (MH+):
Calcd for C12H20NS: 210.1316. Found: 210.1319.
4-Hexyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (6g)
1
Yellow oil. IR: 2954, 2929, 1662. H-NMR: 0.88 (3H, t, J=7 Hz, -(CH2)5CH3), 1.21-1.60 (8H, m,

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(CH2)5CH3), 1.73-1.84 (2H, m, (CH2)5CH3), 2.71-3.35 (4H, m, H-6, H-7), 3.86-3.89 (1H, m, H-4), 6.81
13
(1H, d, J=5 Hz, H-3), 7.05 (1H, d, J=5 Hz, H-2). C-NMR: 14.0 (CH3), 22.6 (-(CH2)5CH3), 25.9 (C7),
26.1 (-(CH2)5CH3), 29.4 (-(CH2)5CH3), 31.7 (-(CH2) 4CH3), 35.9 (-(CH2) 4CH3), 42.3 (C6), 54.9 (C4),
121.7 (C3), 124.9 (C2), 134.0 (C3a), 138.3 (C7a). HR-FABMS (MH+): Calcd for C13H22NS: 224.1473.
Found: 224.1474.
4-Cyclopropyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (6h)
1
Pale yellow oil. IR: 2920, 1647. H-NMR: 0.31-0.76 (4H, m, cyclopropyl-CH2), 0.95-1.07 (1H, m,
cyclopropyl-CH), 2.72-3.03 (4H, m, H-6 and H-7), 3.30-3.39 (1H, m, H-4), 7.06 (1H, d, J=5 Hz, H-3),
7.08 (1H, d, J=5Hz, H-2). 13C-NMR: 2.46 (cyclopropyl-CH2), 3.84 (cyclopropyl-CH2), 17.0
(cyclopropyl-CH), 26.0 (C7), 42.9 (C6), 60.9 (C4), 121.7 (C3), 125.1 (C2), 134.0 (C3a), 138.0
(C7a).LR-EIMS: m/z 179 (M+), 138 (base peak). HR-EIMS m/z (M+): Calcd for C10H13NS:179.0769.
Found: 179.0793.
1-Cyclopentyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (6i)
1
Yellow oil. IR: 2949, 2866, 1670. H-NMR: 1.20-1.40 (1H, m, cyclopentyl-CH2), 1.45-1.80 (7H, m,
cyclopentyl-CH2), 2.27-2.32 (1H, m, cyclopentyl-CH), 2.79-2.81 (2H, m, H-7), 2.94-3.03 (1H, m, H-6),
3.29~3.36 (1H, m, H-6), 3.84 (1H, d, J=6 Hz, H-4), 6.87 (1H, d, J=5 Hz, H-3), 7.04 (1H, d, J=5 Hz, H-2).
13C-NMR: 25.3 (cyclopentyl-CH2), 26.0 (cyclopentyl-CH2), 26.3 (cyclopentyl-CH2), 28.5
(cyclopentyl-CH2), 30.0 (C7), 42.1 (C6), 44.9 (cyclopentyl-CH), 58.6 (C4), 22.3 (C3), 125.7 (C2), 134.5
(C3a), 138.1 (C7a). LR-EIMS: m/z 207 (M+), 166 (base peak). HR-EIMS m/z (M+): Calcd for
C12H17NS:207.1082. Found: 207.1095.
1-Cyclohexyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (6j)
1
Pale yellow oil. IR: 2925, 1670. H-NMR: 0.99-1.45 (5H, m, cyclohexyl-CH2), 1.65-1.88 (6H, m,
cyclohexyl-CH2, cyclohexyl-CH), 2.65-2.85 (2H, m, H-7), 2.96 (1H, ddd, J=12, 9, 5 Hz, H-6), 3.33 (1H,
dd, J=12, 5, 3 Hz, H-6), 3.82-3.83 (1H, m, H-4), 6.81 (1H, d, J=5 Hz, H-3), 7.06 (1H, d, J=5 Hz, H-6).
13C-NMR: 26.3 (cyclohexyl-CH2), 26.60 (cyclohexyl-CH2), 26.64 (cyclohexyl-CH2), 26.8
(cyclohexyl-CH2), 26.9 (cyclohexyl-CH2), 30.5 (C7), 42.7 (cyclohexyl-CH), 43.0 (C6), 59.9 (C4), 121.4
(C3), 125.0 (C2), 134. 8 (C3a), 137.2 (C7a). LR-EIMS: m/z 221(M+), 138 (base peak). HR-EIMS m/z (M+):
Calcd for C13H19NS: 221.1238. Found: 221.1193.

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4-Methyl-4-phenyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (6k)
Pale yellow oil. HCl-salt, colorless prisms recrystallized from MeOH-Et2O, mp 268-270 °C (sublimed).
1H-NMR (DMSO-d6): 2.06 (3H, s, -CH3), 3.04-3.23 (4H, m, H-7 and H-6), 6.95 (1H, d, J=5 Hz, H-3),
1
7.33-7.46 (5H, m Ph-H), 7.54 (1H, d, J=5 Hz, H-2). The H-NMR was identical with the reported one.9
13C-NMR (DMSO-d6): 21.6 (C7), 26.0 (-CH3), 37.4 (C6), 61.3 (C4), 125.0 (C3), 125.7 (C2), 127.7 (2 x
Ph-CH), 128.6 (2 x Ph-CH), 128.9 (Ph-CH), 132.9 (Ph-C), 135.6 (C3a), 139.8 (C7a).
4,4-Dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (6l)
Pale yellow oil. HCl salt mp 277-280 °C (sublimed), recrystallized from MeOH-Et2O. IR: 2971, 2937,
2892, 1641. 1H-NMR: 1.32 (6H, s, 2 x -CH3), 2.68 (2H, t, J=5 Hz, H-7), 3.10 (2H, t, J=5 Hz, H-6), 6.76
13
(1H, d, J=5 Hz, H-3), 6.96 (1H, d, J=5 Hz, H-2). C-NMR: 26.4 (C7), 30.2 (2 x -CH3), 40.0 (C6), 52.6
(C4), 121.6 (C3), 124.9 (C2), 133.0 (C3a), 142.9 (C7a). LR-EIMS: m/z 167 (M+), 152 (base peak).
HR-EIMS m/z (M+): Calcd for C9H13NS:167.0769. Found: 167.0768.
4-Ethyl-4-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (6m)
1
Yellow oil. HCl salt mp 242-243 °C, recrystallized from MeOH-Et2O. IR: 2962. H-NMR: 0.83 (3H, t,
J=7 Hz, -CH2CH3), 1.33 (3H, s, - CH3), 1.62-1.84 (2H, m, -CH2CH3), 2.74 (2H, t, J=6 Hz, H-7), 3.14
13
(2H, m, H-6), 6.77 (1H, d, J=5 Hz, H-3), 7.03 (1H, d, J=5 Hz, H-2). C-NMR: 8.26 (CH2CH3), 26.4 (-
CH2CH3), 27.7 (-CH3), 34.6 (C7), 39.5 (C6), 55.2 (C4), 121.3 (C3), 125.0 (C2), 133.6 (C3a), 142.1 (C7a).
LR-EIMS: m/z 181 (M+), 58 (base peak). HR-EIMS m/z (M+): Calcd for C10H15NS: 181.0925. Found:
181.0925. HCl salt: Anal. Calcd for C10H16ClNOS: C, 55.16; H, 7.41; N, 6.43. Found: C, 55.27; H, 7.48;
N, 6.63.
4,5,6,7-Tetrahydrothieno[3,2-c]pyridine-4-spirocyclopentane (6n)
Yellow oil. HCl salt mp 264-266 °C, recrystallized from MeOH-Et2O. IR: 2949. 1H-NMR: 1.80-1.89 (8H,
m, cyclopentyl-CH2), 2.75 (2H, t, J=5 Hz, H-7), 3.12 (2H, t, J=5 Hz, H-6), 6.81 (1H, d, J=5 Hz, H-3),
7.03 (1H, d, J=5 Hz, H-2). 13C-NMR: 24.7 (2 x cyclopentyl-CH2), 26.3 (C7), 40.5 (C6), 41.6 (2x
cyclopentyl-CH2), 63.9 (C4), 121.5 (C3), 124.7 (C2), 133.5 (C3a), 142.2 (C7a). LR-EIMS: m/z 193 (M+),
164 (base peak). HR-EIMS m/z (M+): Calcd for C11H15NS:193.0925. Found: 193.0899. HCl salt: Anal.
Calcd for C11H16ClNOS: C, 57.50; H, 7.02; N, 6.10 Found: C, 57.47; H, 7.11; N, 6.28.
4,5,6,7-Tetrahydrothieno[3,2-c]pyridine-4-spirocyclohexane (6o)

HETEROCYCLES, Vol. 81, No. 8, 2010
1919
Yellow oil. IR:2852, 2927. 1H-NMR: 1.25-1.29 (1H, m, cyclohexyl-CH2), 1.57-1.76 (9H, m,
cyclohexyl-CH2), 2.75 (2H, t, J=6 Hz, H-7), 3.11 (2H, t, J=6 Hz, H-6), 6.85 (1H, d, J=5 Hz, H-3), 7.03
(1H, d, J=5 Hz, H-2). 13C-NMR: 21.6 (2 x cyclopentyl-CH2), 25.7 (cyclopentyl-CH2), 26.5 (C7), 37.3
21.6 (2 x cyclopentyl-CH2), 39.0 (C6), 54.4 (C4), 121.4 (C3), 124.9 (C2), 133.6 (C3a), 143.7
(C7a)LR-EIMS: m/z 207 (M+), 58 (base peak). HR-EIMS m/z (M+): Calcd for C12H17NS: 207.1082.
Found: 207.1100.
4,5,6,7-Tetrahydrothieno[3,2-c]pyridine (6q)
Yellow oil. IR: 2925. 1H-NMR: 1.74 (1H, brs, NH), 2.80 (2H, t, J=6 Hz, H-7), 3.15 (2H, t, J=6 Hz, H-6),
13
3.92 (2H, t, J=2 Hz, H-4), 6.74 (1H, d, J=5 Hz, H-3), 7.07 (1H, d, J=5 Hz, H-2). C-NMR: 25.9 (C7),
43.8 (C6), 45.7 (C4), 121.9 (C3), 125.0 (C2), 133.7 (C3a), 134.4 (C7a). HR-EIMS m/z (M+): Calcd for
C7H9NS:139.0453. Found: 139.0430.
4-(Pent-2-en-2-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (9c)
1
Pale yellow oil. IR: 2960, 2928. H-NMR: 0.98 (3H, t, J=7 Hz, -C=CHCH2CH3), 1.51 (3H, t, J=1 Hz,
-CH3), 2.07 (2H, quintet J=7 Hz, -C=CHCH2CH3), 2.39-2.77 (1H, m, H-7), 2.85-2.95 (1H, m, H-7), 3.02
(1H, ddd, J=12, 10, 4 Hz, H-6), 3.26 (1H, ddd, J=12, 5, 3 Hz, H-6), 4.35 (1H, t, J=2 Hz, H-4), 5.43 (1H,
td, J=7, 1 Hz, -C=CHCH2CH3), 6.63 (1H, d, J=5 Hz, H-3), 7.00 (1H, d, J=5 Hz, H-2). HR-FABMS m/z
(MH+): Calcd for C12H18NS: 208.1160. Found: 208.1158.
4-(Hept-3-en-3-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (9d)
1
Yellow oil. IR: 2963, 1651. H-NMR: 0.84 (3H, t, J=7 Hz, -CH2CH3), 0.90 (3H, t, J=7 Hz,
-C=CH(CH2)2CH3), 1.31 (2H, sextet, J=7 Hz, -CH2CH3), 1.84-2.14 (4H, m, -C=CH(CH2)2CH3,),
2.63-2.84 (2H, m, H-7), 2.88-2.96 (1H, m, H-6), 3.16-3.24 (1H, m, H-6), 4.32 (1H, s, H-4), 5.16 (1H, t,
J=7 Hz, -C=CH(CH2)2CH3), 6.56 (1H, d, J=5 Hz, H-3), 6.92 (1H, d, J=5 Hz, H-2). 13C-NMR: 13.9
(CH3), 14.5 (CH3), 21.4 (-CH2CH3), 22.9 (-C=CH(CH2)2CH3), 26.0 (C7), 29.7 (-C=CH(CH2)2CH3), 42.2
(C6), 62.4 (C4), 121.0 (C3), 124.8 (C2), 129.3 (-C=CH(CH2)2CH3), 134.6 (C3a), 136.8 (C7a), 142.4
(-C=CH(CH2)2CH3). HR-FABMS m/z (MH+): Calcd for C14H22NS: 264.1422. Found: 264.1421.
4-(Non-4-en-2-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (9e)
1
Yellow oil. IR: 2962, 1666. H-NMR: 0.89 (6H, t, J=7 Hz, -(CH2)2CH3, -C=CH(CH2)3CH3), 1.26-1.49
(6H, m, -(CH2)2CH3, -C=CH(CH2)3CH3), 1.89-1.98 (4H, m, -(CH2)2CH3, -C=CH(CH2)3CH3), 2.71-2.90

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HETEROCYCLES, Vol. 81, No. 8, 2010
(2H, m, H-7), 3.22-3.29 (2H, m, H-6), 4.38 (1H, s, H-4), 5.22 (1H, t, J=7 Hz, -C=CH(CH2)3CH3), 6.62
13
(1H, t, J=5 Hz, H-3), 6.99 (1H, t, J=5 Hz, H-2). C-NMR: 13.9 (CH3), 14.4 (CH3), 22.4 (-(CH2)2CH3),
23.0 (-C=CH(CH2)3CH3), 25.9 (C7), 27.5 (-(CH2)2CH3),
30.9 (-C=CH(CH2)3CH3), 31.9
(-C=CH(CH2)3CH3), 41.8 (C6), 61.8 (C4), 121.0 (C3), 126.4 (C2), 130.1 (-C=CH(CH2)3CH3), 134.6 (C3a),
136.7 (C7a), 140.5 (-C=CH(CH2)3CH3).HR-FABMS (MH+): Calcd for C16H26NS: 264.1786. Found:
264.1774.
4-(Undec-5-en-5-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (9f)
1
Yellow oil. IR: 2957, 2930, 1652. H-NMR: 0.73 (6H, m, -(CH2)3CH3, -C=CH(CH2)4CH3), 1.18-1.40
(10H, m, -(CH2)3CH3, -C=CH(CH2)4CH3), 1.82-2.10 (4H, m, -(CH2)3CH3, -C=CH(CH2)4CH3), 2.61-2.80
(2H, m, H-7), 2.82-2.94 (1H, m, H-6), 3.14-3.21 (1H, m, H-6), 4.30 (1H, s, H-4), 5.13 (1H, t, J= 7 Hz,
13
-C=CH(CH2)3CH3), 6.54 (1H, d, J=5 Hz, H-3), 6.91 (1H, d, J=5 Hz, H-2). C-NMR: 13.9 (CH3), 14.0
(CH3), 22.5 (-(CH2)3CH3), 23.1 (-C=CH(CH2)4CH3), 26.1 (C7), 27.7 (-(CH2)3CH3), 28.5(-(CH2)3CH3),
29.4 (-C=CH(CH2)4CH3), 31.6 (-C=CH(CH2)4CH3), 32.0 (-C=CH(CH2)4CH3), 42.0 (C6), 62.0 (C4), 120.9
(C3), 126.4 (C2), 129.7 (-C=CH(CH2)4CH3), 134.7 (C3a), 136.9 (C7a), 140.9 (-C=CH(CH2)4CH3).
HR-FABMS (MH+): Calcd for C18H30NS: 292.2099. Found: 292.2092.
4-(Tridec-6-en-6-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (9g)
1
Yellow oil. IR: 2956, 2928, 1653. H-NMR: 0.84-0.90 (6H, m, -(CH2)4CH3, -C=CH(CH2)5CH3),
1.18-1.42 (14H, m, -(CH2)4CH3, -C=CH(CH2)5CH3), 1.89-2.10 (4H, m, -(CH2)4CH3, -C=CH(CH2)5CH3),
2.61-2.99 (3H, m, H-6, H-7), 3.14-3.22 (1H, m, H-6), 4.39 (1H, s, H-4), 5.20 (1H, t, J=7 Hz,
-C=CH(CH2)3CH3), 6.61 (1H, d, J=5 Hz, H-3), 6.99 (1H, d, J=5 Hz, H-2). 13C-NMR: 13.97 (CH3), 14.0
0 (CH3), 22.4 (-(CH2)4CH3), 22.5 (-C=CH(CH2)5CH3), 25.4 (C7), 27.8 (-(CH2)4CH3), 28.8 (-(CH2)4CH3),
29.0 (-(CH2)4CH3), 29.3 (-C=CH(CH2)5CH3), 29.6 (-C=CH(CH2)5CH3), 31.7 (-C=CH(CH2)5CH3), 32.1
(-C=CH(CH2)5CH3), 41.4 (C6), 61.3 (C4), 121.4 (C3), 126.3 (C2), 130.9 (-C=CH(CH2)5CH3), 134.4 (C3a),
135.9 (C7a), 139.9 (-C=CH(CH2)5CH3). HR-FABMS (MH+): Calcd for C20H34NS: 320.2412. Found:
320.2412.
REFERENCES AND NOTES
1. G. Bringmann, C. T. Ewers, and R. Walter, Comprehensive Organic Synthesis, ed. by B. M. Trost and

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I. Fleming, Pergamon Press, Oxford, 1991, Vol. 6, pp. 736-740.
2. K. A. Neidigh, M. A. Avery, J. S. Williamson, and S. Bhattacharyya, J. Chem. Soc., Perkin Trans. 1,
1998, 2527.
3. Y. Horiguchi, H. Kodama, M. Nakamura, T. Yoshimura, K. Hanezi, H. Hamada, T. Saitoh, and T.
Sano, Chem. Pharm. Bull., 2002, 50, 253.
4. G. Bringmann, C. T. Ewers, and R. Walter, Comprehensive Organic Synthesis, ed. by B. M. Trost and
I. Fleming, Vol. 21, Pergamon Press, Oxford, 1991, pp. 736-739.
5. Y. Horiguchi, M. Nakamura, A. Kida, H. Kodama, and T. Sano, Heterocycles, 2003, 59, 691.
6. M. Kitabatake, J. Nagai, K. Abe, Y. Tsuchiya, K. Ogawa, T. Yokoyama, K. Mohri, K. Taguchi, and Y.
Horiguchi, Eur. J. Med. Chem., 2009, 44, 4034.
7. A. Yokoyama, T. Ohwada, and K. Shudo, J. Org. Chem., 1999, 64, 611.
8. The other report of the synthesis of 4,5,6,7-tetrahydrothieno[3,2-c]pyridines: G. L. Grunewald, M. R.
Seim, S. R. Bhat, M. E. Wilson and K. L. Criscione, Bioorg. Med. Chem., 2008, 16, 542.
9. M. Ohkubo, A. Kuno, K. Katsua, Y. Ueda, K. Shirakawa, H. Nakanishi, T. Kinoshita, and H.
Takasugi, Chem. Pharm. Bull., 1996, 44, 778.
10. P. Madsen, J. M. Lundbeck, P. Jakobsen, A. R. Varming, and N. Westergaard, Bioorg. Med. Chem.,
2000, 8, 2277.