A synthesis of heteroaromatic analogues of 1-methyl-1,2,3,4-tetrahydroisoquinoline using the Pummerer-type cyclization reaction: observation of tandem cyclization reaction.

Article abstract of DOI:10.1248/cpb.52.214

The sulfoxides 7b and 7d carrying thiophene or benzothiophene as heteroaromatic nucleophiles, when treated with trifluoroacetic anhydride at room temperature (Pummerer reaction), underwent an intramolecular alkylation in an exclusive manner to yield 4,5,6,7-tetrahydro-7-methyl-4-phenylsulfanylthieno[2,3-c]pyridine-6-carbaldehyde (10) and the corresponding benzothiophene derivative (12b) in high yields, respectively. Thus, this route provides biologically interesting nitrogen heterocycles (1b) and (2b). On the other hand, the sulfoxide (7c) carrying benzofuran as a nucleophile on reaction with TFAA yielded not only the Pummerer-type cyclization product (12a), but also the diastereoisomeric tandem cyclization products (13) and (14) having a noble 11-aza-2-oxa-7-thiatricyclo[4.3.3.0(1,5)]dodecane ring system (B). The formation of these products can be readily rationalized by the intervention of the oxonium ion intermediate (21).

Full text of DOI:10.1248/cpb.52.214

214
Chem. Pharm. Bull. 52(2) 214—220 (2004)
Vol. 52, No. 2
A Synthesis of Heteroaromatic Analogues of 1-Methyl-1,2,3,4-
tetrahydroisoquinoline Using the Pummerer-Type Cyclization Reaction:
Observation of Tandem Cyclization Reaction
Yoshie HORIGUCHI,* Keita OGAWA, Toshiaki SAITOH, and Takehiro SANO
Showa Pharmaceutical University; 3–3165 Higashi-tamagawagakuen, Machida, Tokyo 194–8543, Japan.
Received September 9, 2003; accepted November 18, 2003
The sulfoxides 7b and 7d carrying thiophene or benzothiophene as heteroaromatic nucleophiles, when
treated with trifluoroacetic anhydride at room temperature (Pummerer reaction), underwent an intramolecular
alkylation in an exclusive manner to yield 4,5,6,7-tetrahydro-7-methyl-4-phenylsulfanylthieno[2,3-c]pyridine-6-
carbaldehyde (10) and the corresponding benzothiophene derivative (12b) in high yields, respectively. Thus, this
route provides biologically interesting nitrogen heterocycles (1b) and (2b). On the other hand, the sulfoxide (7c)
carrying benzofuran as a nucleophile on reaction with TFAA yielded not only the Pummerer-type cyclization
product (12a), but also the diastereoisomeric tandem cyclization products (13) and (14) having a noble 11-aza-2-
oxa-7-thiatricyclo[4.3.3.01,5]dodecane ring system (B). The formation of these products can be readily rational-
ized by the intervention of the oxonium ion intermediate (21).
Key words pummerer reaction; thieno[2,3-c]pyridine; benzothieno[2,3-c]pyridine; benzofuro[2,3-c]pyridine; 11-aza-2-oxa-7-
thiatricyclo[4.3.3.01,5]dodecane
In a series of papers we reported the synthesis of 1,2,3,4- induced by the selective dopaminergic neurotoxin, 1-methyl-
tetrahydroisoquinolines,1—6) 1,2,3,4-tetrahydroquinolines,7) 4-phenylpyridinium ion (MPPϩ), and by other endogenous
2,3,4,5-tetrahydro-1H-3-benzazepines,8) 2-quinolones9) using neurotoxins, 1,2,3,4-tetrahydroisoquinoline and 1-benzyl-
an aromatic cyclization of the sulfonium ion in situ formed 1,2,3,4-tetrahydroisoquinoline.12—14)
from a sulfinyl purecursor (Pummerer reaction). The aro-
matic cyclization in the reaction using trifluoroacetic anhy- Results and Discussion
dride (TFAA) as a sole reagent (method A) smoothly pro-
N-Formyl sulfoxides (7a—d), substrates of the Pummerer
ceeded at room temperature when the reactive center of the reaction, were prepared from 2-acetylfuran (4a), 2-acetylthi-
cyclizing benzene ring was activated by the electron-donat- ophene (4b), 2-acetylbenzofuran (4c), and 2-acetylbenzothi-
ing substituent. Furthermore, we found that the Pummerer ophene (4d) in three steps (Chart 2). Condensation of 4 with
substrate which lacks an electron-donating substituent on the 2-phenylsulfanylethylamine in titanium(IV) isopropoxide
cyclizing benzene ring, requires boron trifluoride diethyl followed by NaBH4 reduction of the resulting imines af-
etherate (BF3·Et2O) as an additive reagent (method B) to in- forded the amines 5 in good yields. Formylation of 5 and
duce the aromatic cyclization.2,3) Thus, the investigations then oxidation of the resulting N-formates 6 with sodium
demonstrated that the Pummerer-type cyclization reaction is metaperiodate produced the sulfoxides 7 in high yields,
highly effective and widely applicable for the construction of though the sulfones 8, in some cases, were produced as a by-
aromatic condensed nitrogen heterocycles.10)
product.
Pummerer Reaction of the Sulfoxides 7a, b The sul-
In order to expand the utility of this methodology, we de-
signed a synthesis of nitrogen heterocycles possessing furo-
(1a), thieno- (1b), benzofuro- (2a) and benzothieno[2,3-
c]pyridine (2b), which bear a methyl group on the nitrogen-
containing ring. The compounds with the ring system are ex-
pected to have some biological activities related to parkin-
sonism because of their structural resemblance to 1-methyl-
1,2,3,4-tetrahydroisoquinoline (3), endogenous amine pre-
sent in the human brain,11) which is considered to play an im-
portant role in the prevention of the onset of parkinsonism
Chart 1
Chart 2
To whom correspondence should be addressed. e-mail: horiguti@ac.shoyaku.ac.jp
© 2004 Pharmaceutical Society of Japan

February 2004
215
Chart 3
Chart 4
foxide 7a possessing a furan ring as a nucleophilic aromatic yielded three products 12a, 13, and 14 in yields of 36%,
ring, on treatment with trifluoroacetic anhydride (TFAA) in 35%, and 16%, respectively (Chart 4). The use of BF3·Et2O
benzene at room temperature for 70 min, caused an extensive as an additional reagent (method B) facilitated the reaction to
decomposition to yield no characterizable products. Even a give the same products 12a (30%), 13 (39%), and 14 (27%).
reaction under more mild conditions (0 °C, 10 min) merely In contrast the sulfoxide 7d having benzothiophene ring, on
produced deep colored compounds. These facts suggest that the reaction by either the method A or B, gave 12b in 94%,
the furan ring is highly vulnerable to trifluoroacetic acid 99% yields, respectively.
(TFA) generated in the reaction. The treatment of 7a with
The structures of 12a and 12b as the expected 4-phenyl-
acetic anhydride at 80 °C for 14 d slowly induced a Pum- sulfanyl benzofuro and benzothieno[2,3-c]pyridine deriva-
merer rearrangement to give the a-acetoxyl sulfide 9 in 77% tives were confirmed by their spectral data and the following
yield. Although this product is considered to be an interme- chemical transformations. Reductive removal of the
diate of the Pummerer-type cyclization reaction, any attempt phenylthio group of 12a and 12b with NaBH4–NiCl2 in
leading to the expected cyclization under acidic conditions EtOH produced 15a and 15b in 77% and 71% yields, respec-
was failed. For example, the reaction of 9 with BF3·Et2O in tively. Deprotection of the N-formyl group of 15a and 15b
benzene at room temperature gave no characterizable prod- by alkaline hydrolysis yielded 1,2,3,4-tetrahydro-1-methyl-
ucts.
benzo[4,5]furo- (2a) and 1,2,3,4-tetrahydro-1-methylbenzo-
On the other hand the sulfoxide 7b having thiophene ring, [4,5]thieno[2,3-c]pyridine (2b) in 98% and 83% yields, re-
when reacted with TFAA in benzene at room temperature for spectively.
6 h (method A), underwent the expected cyclization to pro-
Structures of Tandem Cyclization Products 13 and 14
duce 4,5,6,7-tetrahydro-7-methyl-4-phenylsulfanylthieno- The compounds 13 and 14 were identified as the products
[2,3-c]pyridine-6-carbaldehyde (10). This cyclization, on se- formed by two successive intramolecular alkylation reactions
quential treatment of 7b using TFAA and BF3·Et2O (method (tandem cyclization products) as follow. Their respective
B), occurred more rapidly (1 h) to give 10 in an excellent mass spectrum gave the same molecular peak at m/z 323 cor-
yield (93%). Reductive removal of the phenylsulfanyl group responding to the formula C19H17O2NS, which is identical
of 10 with NiCl2–NaBH4 in THF produced 4,5,6,7-tetra- with that of 12a. Their UV and NMR spectral data are very
hydro-7-methylthieno[2,3-c]pyridine-6-carbaldehyde (11) in similar each other, but they are significantly different with
61% yield. Hydrolysis of 11 with NaOH solution gave the those of 12a; the facts indicating that the products 13 and 14
desired product, 4,5,6,7-tetrahydro-7-methylthieno[2,3-c]- have a different skeletal ring system with that of 12a. The
pyridine (1b) in 79% yield.
1H- and 13C-NMR spectra of 13 and 14 exhibited very com-
Pummerer Reaction of the Sulfoxides 7c and 7d plicated signals, thus suggesting that they are present in
Treatment of the sulfoxide 7c having benzofuran ring with CDCl3 as a mixture of two rotational isomers of N–CO bond.
TFAA in benzene at room temperature for 1.5 h (method A) Therefore, accurate assignments of the NMR spectra were

216
Vol. 52, No. 2
difficult. Fortunately, we were able to clarify their structures
including the stereochemistry by the spectral analysis of the
N-deformyl derivatives 16 and 17 which were prepared by al-
kaline hydrolysis of 13 and 14 in 96% and 85% yields, re-
spectively (Chart 5).
C-3 (dC 157.6), to C-17 (dC 137.5), and to C-18 (dC 60.1),
H-10 to C-1 (dC 98.4), and to C-8 (dC 133.6), H-6 to C-8, H-
5 to C-3, H-14 to C12 (dC 129.9), and H-16 to C-12
indicated that 16 is not a derivative of furo[2,3-c]pyridine
skeleton but a derivative of 19-aza-2-oxa-11-thiapentacy-
clo[8.7.3.01,9.03,8.012,17]icosa-3,5,7,12,14,16-hexaene skeleton
(A). This ring system can be constructed by C–C bonding
between the 9a-carbon of benzofuro[2,3-c]pyridine and the
ortho-carbon of 4-phenylsulfanyl group. The other product
17 also exhibited HMBC correlations similar to those of 16.
Thus, the compounds 16 and 17 are assigned as stereoiso-
mers possessing the skeleton of a unique tricyclic bridged
ring system including nitrogen, oxygen, and sulfur atoms
(11-aza-2-oxa-7-thiatricyclo[4.3.3.01,5]dodecane B).
The structures of 16 and 17 have four chiral centers in-
cluding two bridgehead carbons. Therefore, four stereo-
structures (I—IV) as racemate are able to be deduced as
shown in Fig. 2. Differentiation between the stereo-structures
was achieved by nuclear Overhauser effect (NOE) observa-
tions. The diastereomer 16 exhibited 20% NOE between C9-
proton and C18-proton, indicating that these protons are
arranged in 1,3-diaxial cis-relationship concerning to the
piperidine ring. Thus, the relative stereochemistry of 16 is
elucidated to be 1R*, 9S*, 10S*, and 18R* as shown in the
stereo-structure I. On the other hand, the diastereomer 17 ex-
hibited 8% NOE between C9-H and C18-methyl proton, in-
dicating that they are orientating in 1,3-diaxial cis-relation-
ship concerning to the piperidine ring. Thus, the relative
stereochemistry of 17 are assigned to be 1S*, 9R*, 10R*,
and 18R* as shown in the stereo-structure II. The other
stereo-structures III and IV with a equatorial hydrogen at C-9
to the piperidine ring can be discarded since they are not ex-
pected to give such NOEs.
The gross structures of 16 and 17 were deduced from de-
tailed analysis of the 1H- and 13C-NMR data aided by two-di-
mensional (2D) NMR experiments, H–H correlation spec-
troscopy (COSY), C–H COSY and heteronuclear multiple
1
bond correlation (HMBC). Their H- and 13C-NMR data of
16 and 17 indicated that they possessed a same skeleton with
twelve aromatic carbons, one quarternary carbon, three me-
thines, one methylene, and one methyl group. All protons
and carbons were unambiguously assigned from the 2D-
NMR spectra analysis as shown in Table 1. HMBC cor-
relations of 16 as shown in Fig. 1, H-9 to C-7 (dC 129.6), to
Chart 5
Table 1. 1H- and 13C-NMR Chemical Shifts (d, ppm) of Products 16 and
17
16
17
Position
1H
13C
1H
13C
In order to clarify the formation mechanism of the Pum-
merer products 13 and 14, we carried out some experiments.
The treatment of 7c with acetic anhydride at 80 °C for 9 d
1
3
4
5
6
7
8
9
—
—
98.4
157.6
—
—
95.1
158.8
124.7
128.9
126.6
129.4
134.2
47.1
7.17 (dd, Jϭ8, 1 Hz)
7.09 (t, Jϭ8 Hz)
7.06 (t, Jϭ8 Hz)
7.45 (d, Jϭ8 Hz)
—
124.7 7.12 (d, Jϭ8 Hz)
128.8 7.09 (t, Jϭ8 Hz)
126.7 7.06 (td, Jϭ8, 1 Hz)
129.6 7.43 (dd, Jϭ8, 1 Hz)
133.6
46.4 4.47 (s)
—
4.58 (s)
10 3.55 (dd, Jϭ11, 8 Hz)
12
13 7.19 (d, Jϭ8 Hz)
14 6.78 (td, Jϭ8, 1 Hz)
15 7.14 (td, Jϭ8, 1 Hz)
16 6.80 (d, Jϭ8 Hz)
46.8 3.53 (dd, Jϭ12, 8 Hz)
129.9
129.5 7.22 (dd, Jϭ8, 1 Hz)
120.7 6.76 (td, Jϭ8, 1 Hz)
126.2 7.16 (td, Jϭ8, 1 Hz)
110.0 6.82 (d, Jϭ8 Hz)
50.3
—
—
129.7
129.9
120.6
126.3
109.2
137.6
62.3
17
18 3.59 (q, Jϭ7 Hz)
20 3.25 (dd, Jϭ10, 11 Hz) 46.5 3.26 (dd, Jϭ10, 11 Hz)
—
137.5
—
60.1 3.25 (q, Jϭ7 Hz)
46.5
3.42 (dd, Jϭ10, 8 Hz)
21 1.18 (d, Jϭ7 Hz)
3.41 (dd, Jϭ10, 8 Hz)
20.3 1.11 (d, Jϭ7 Hz)
13.4
Fig. 1
Fig. 2

February 2004
217
Chart 6
atmosphere. After cooling, the reaction mixture was diluted with MeOH
(100 ml). To this solution, NaBH4 (2.48 g, 66 mmol) was added in small por-
tions under ice-cooling. The reaction mixture was stirred at room tempera-
ture for 1 h and concentrated in vacuo. Water (ca. 40 ml) was added to the
residue, and the mixture was diluted with MeOH (ca. 500 ml). After removal
slowly caused the Pummerer-rearrangement reaction to af-
ford the a-acetoxyl sulfide 18 in 87% yield. The treatment of
18 with BF3·Et2O in benzene at room temperature for 7 d
slowly induced the cyclization to yield 12a (33%), 13 (32%),
and 14 (32%), which were proved to be identical with the of precipitated inorganic materials by filtration, the filtrate was concentrated
in vacuo. The residue was dissolved in water and acidified by 5% HCl solu-
tion and the mixture was extracted with CHCl3. Purification by column chro-
matography (AcOEt : hexaneϭ1 : 2) of the product gave (1-furan-2-yl)ethyl-
(2-phenylsulfanylethyl)amine (5a) (13.04 g, 97%) as a yellow oil. IR: 1583.
products obtained from the TFAA-induced Pummerer reac-
tion of 7c described above. On the other hand, acidic treat-
ment of the Pummerer product 12a with BF3·Et2O-TFAA,
1H-NMR: 1.37 (3H, d, Jϭ7 Hz, CH3), 2.75 (2H, t, Jϭ6 Hz, SCH2CH2N),
3.02 (2H, t, Jϭ6 Hz, SCH2CH2N), 3.97 (1H, q, Jϭ7 Hz, CHCH3), 6.09 (1H,
d, Jϭ3 Hz, Ar), 6.27 (1H, dd, Jϭ2, 3 Hz, Ar), 7.1—7.3 (6H, m, Ar). 13C-
NMR: 20.3 (CHCH3), 34.4 (SCH2CH2N), 45.4 (SCH2CH2N), 50.9
(CHCH3), 105.3 (ArCH), 109.8 (ArCH), 126.2 (ArCH), 128.8 (ArCHϫ2),
129.8 (ArCHϫ2), 135.6 (ArC), 141.4 (ArCH), 157.5 (ArC). LR-EI-MS m/z:
247 (Mϩ). HR-EI-MS: Calcd for C14H17NOS: 247.1031. Found: 247.1069.
(2-Phenylsulfanylethyl)-(1-thiophen-2-ylethyl)amine (5b) (7.70 g, 81%)
was obtained from 2-acetylthiophene (4b) (4.51 g, 36 mmol) after purifica-
tion by column chromatography (AcOEt : hexaneϭ1 : 1) as a colorless oil.
IR: 1583. 1H-NMR: 1.45 (3H, d, Jϭ7 Hz, CH3), 2.8—3.1 (4H, m,
SCH2CH2N), 4.08 (1H, q, Jϭ7 Hz, CHCH3), 6.9—7.3 (8H, m, Ar). LR-EI-
MS m/z: 263 (Mϩ). HR-EI-MS: Calcd for C14H17NS2: 263.0802. Found:
263.0806.
TFA-TFAA or p-TsOH-acetic anhydride did not cause any
reaction and the starting material was recovered quantita-
tively (see experimental).
The formation mechanism of the products 12a, 13, and 14
is rationalized as shown in Chart 6. The formation of these
products can be initiated by the generally accepted mecha-
nism of the Pummerer reaction. The reaction involves two
processes. One is a nucleophilic attack of the benzofuran ring
on the cationic carbon atom of the sulfonium ion 20 followed
by the aromatization reaction of the formed oxonium ion 21
leading to 12a; the other involves the intramolecular alkyla-
tion of the C-9a carbon of 21 to the ortho-carbon of benzene
ring of the phenylsulfanyl group. The two reactions should
proceed in a competitive manner via the oxonium cation 21,
which, however, on treatment with BF3·Et2O is not generated
(1-Benzofuran-2-ylethyl)-(2-phenylsulfanylethyl)amine (5c) (5.37 g, 88%)
was obtained from 2-acetylbenzofuran (4c) (3.01 g, 18.8 mmol) after purifi-
cation by column chromatography (AcOEt : hexaneϭ1 : 1) as a yellow oil.
IR: 1583. 1H-NMR: 1.59 (3H, d, Jϭ6 Hz, CH3), 2.79 (2H, t, Jϭ6 Hz,
from 12a. The compound with 11-aza-2-oxa-7-thiatricy- SCH2CH2N), 3.04 (2H, t, Jϭ6 Hz, SCH2CH2N), 3.97 (1H, q, Jϭ6 Hz,
CHCH3), 6.47 (1H, s, Ar), 7.1—7.5 (9H, m, Ar). 13C-NMR: 20.5 (CHCH3),
34.5 (SCH2CH2N), 45.4 (SCH2CH2N), 51.4 (CHCH3), 102.4 (ArCH), 111.1
(ArCH), 120.7 (ArCH), 122.6 (ArCH), 123.7 (ArCH), 126.3 (ArCH), 128.3
clo[4.3.3.01,5]dodecane skeleton (B) seems to be hitherto un-
known.
(ArC), 128.8 (ArCHϫ2), 130.0 (ArCHϫ2), 135.3 (ArC), 154.7 (ArC),
Experimental
Unless otherwise noted, the following procedures were adopted. Melting 297.1188. Found: 297.1218.
160.2 (ArC). LR-EI-MS m/z: 297 (Mϩ). HR-EI-MS: Calcd for C18H19NOS:
points were taken on a Yanagimoto SP-M1 hot-stage melting point apparatus
Formylation of 5a. Typical Procedure A solution of formic-acetic
and are uncorrected. IR spectra were measured as films for oils and gums, anhydride prepared from formic acid (74.6 ml, 1.96 mol) and acetic anhy-
and KBr disks for solids with a HORIBA FT-710 spectrophotometer, and the dride (46 ml, 0.49 mol), was added to 5a (12.02 g, 49 mmol) at 0 °C in one
values are given in cmϪ1. NMR spectra were measured on a JEOL JNM-a- portion and then the mixture was heated at 70 °C for 1 h. The reaction mix-
500 (1H-NMR: 500 MHz, 13C-NMR: 125 MHz) or a JEOL JNM-AL300 (1H- ture was concentrated in vacuo and extracted with CHCl3. The residue was
NMR: 300 MHz, 13C-NMR: 75 MHz) NMR spectrometer in CDCl3 with chromatographed (AcOEt : hexaneϭ1 : 2) to give N-(1-furan-2-ylethyl)-N-
tetramethylsilane as an internal standard and the chemical shifts are given in (2-phenylsulfanylethyl)formamide (6a) (12.97 g, 97%) as a yellow oil. IR:
1
d values. Low-resolution electron impact ionization mass spectra (LR-EI- 1672. H-NMR: 1.46, 1.54 (total 3H, each d, Jϭ7 Hz, CH3), 2.5—3.7 (4H,
MS) were taken on JEOL JMS-AM20 mass spectrometer at 70 eV using di-
m, SCH2CH2N), 4.74, 5.68 (total 1H, each q, Jϭ7 Hz, CHCH3), 6.2—6.4
rect inlet probe. High-resolution EI-MS (HR-EI-MS) and was taken on a (2H, m, Ar), 7.1—7.5 (total 6H, m, Ar), 8.09, 8.27 (total 1H, each s,
JEOL JMS-D300 mass spectrometer at 70 eV using direct inlet system. NCHO). LR-EI-MS m/z: 275 (Mϩ). HR-EI-MS: Calcd for C15H17NO2S:
FAB-MS spectra were recorded with JEOL-HX100A spectrometer using 275.0980. Found: 275.0974.
glycerol as a matrix. Elemental analyses were recorded on a Yanaco CHN-
N-(2-Phenylsulfanylethyl)-N-(1-thiophen-2-ylethyl)formamide (6b)
corder MT-3. TLC was performed on Merck precoated silica gel 60 F254 (6.96 g, 91%) was obtained from 5b (7.00 g, 22.8 mmol) after purification by
plates. Column chromatography was carried out with Wakogel C-200. Flash column chromatography (AcOEt : hexaneϭ2 : 3) as a pale yellow oil. IR:
chromatography was carried out with silica gel 60 (Merck) or silica gel 60N 1672. 1H-NMR: 1.57, 1.66 (total 3H, d, Jϭ7 Hz, CH3), 2.7—3.5 (4H, m,
(Kanto). The organic extract from each reaction mixture was washed with SCH2CH2N), 4.97, 5.90 (total 1H, q, Jϭ7 Hz, CHCH3), 6.9—7.3 (8H, m,
brine, dried over anhydrous Na2SO4, and concentrated in vacuo to dryness.
Preparation of 5a. Typical Procedure A mixture of 4a (6.00 g, 54.5 Calcd for C15H17NOS2: 291.0752. Found: 291.0786.
Ar), 8.09, 8.32 (total 1H, s, NCHO). LR-EI-MS m/z: 291 (Mϩ). HR-EI-MS:
mmol), 2-phenylsulfanylethylamine (10.03 g, 66 mmol), and titanium(IV)
N-(1-Benzofuran-2-ylethyl)-N-(2-phenylsulfanylethyl)formamide (6c)
isopropoxide (23.10 g, 81 mmol) was heated at 80 °C for 3 h under an argon (5.25 g, 96%) was obtained from 5c (5.00 g, 16.8 mmol) after purification by

218
Vol. 52, No. 2
stirred for 6 h at the same temperature. The reaction mixture was concen-
trated in vacuo, and the residue was purified by column chromatography
(AcOEt : hexaneϭ1 : 2) to give 10 (841 mg, 89%).
ii) Method B: TFAA (2.27 ml, 16.3 mmol) was added to a solution of 7b
(1.00 g, 3.25 mmol) in benzene (60 ml) at room temperature. After the mix-
ture was stirred for 0.5 h, BF3·Et2O (0.41 ml, 3.25 mmol) was added, and the
reaction mixture was further stirred at the same temperature for 1 h. The re-
action mixture was diluted with H2O and extracted with CHCl3. Purification
by column chromatography (AcOEt : hexaneϭ1 : 2) of the product gave 10
(860 mg, 93%).
4,5,6,7-Tetrahydro-7-methyl-4-phenylsulfanylthieno[2,3-c]pyridine-6-
carbaldehyde (10) Colorless oil. IR: 1670. UV: 220 (17700). 1H-NMR:
1.41, 1.47, 1.49, 1.54 (total 3H, each d, Jϭ7 Hz, CH3), 3.0—4.7 (3H, m, 4-H
and 5-H), 4.85, 4.91, 5.53, 5.60 (total 1H, q, Jϭ7 Hz, 7-H), 6.9—7.6 (7H, m,
Ar), 8.03, 8.05, 8.24, 8.39 (total 1H, each s, NCHO). LR-EI-MS m/z: 289
(Mϩ). HR-EI-MS: Calcd for C15H15NOS2: 289.0595. Found: 289.0635.
Pummerer Reaction of 7a The reaction of 7a with TFAA (5 mol eq)
under the method A or B conditions described above merely yielded unchar-
acterable mixtures.
Pummerer Reaction of 7a with Acetic Anhydride A solution of 7a
(700 mg), Ac2O (25 ml) and pyridine (0.5 ml) was heated at 80 °C for 14 d.
The reaction mixture was concentrated in vacuo, the product was purified by
column chromatography (AcOEt : hexaneϭ1 : 2) to give acetic acid 2-
[formyl-(1-furan-2-ylethyl)amino]-1-phenylsulfanylethyl ester (9) (685 mg,
86%) as colorless oil. IR: 1749, 1676. 1H-NMR: 1.45, 1.46, 1.54, 1.59 (total
3H, each d, Jϭ7 Hz, CH3), 2.00, 2.04, 2.06, 2.09 (total 3H, each s, OAc),
3.2—3.7 (2H, m, NCH2CHS), 4.69, 4.70, 5.58, 5.64 (total 1H, each q,
Jϭ7 Hz, CHCH3), 5.05, 5.85, 6.10 (total 1H, each dd, Jϭ3, 9 Hz,
NCH2CHS), 6.2—6.3 (2H, m, Ar), 7.3—7.5 (6H, m, Ar-H), 8.00, 8.01, 8.23,
8.27 (total 1H, each s, NCHO). LR-EI-MS m/z: 334 (Mϩ). HR-FAB-MS:
Calcd for C17H20NO4S: 334.1116. Found: 334.1113.
column chromatography (AcOEt : hexaneϭ1 : 2) as a pale yellow oil. IR:
1672, 1583. H-NMR: 1.56, 1.63 (total 3H, each d, Jϭ7 Hz, CH3), 2.6—3.1
1
(2H, m, SCH2CH2N), 3.3—3.4 (2H, m, SCH2CH2N), 4.86, 5.78 (total 1H,
each q, Jϭ7 Hz, CHCH3), 6.56, 6.62 (total 1H, each s, Ar), 7.1—7.6 (9H, m,
Ar), 8.15, 8.35 (total 1H, each s, NCHO). LR-EI-MS m/z: 357 (Mϩ). HR-EI-
MS: Calcd for C19H19NO2S: 325.1134, Found: 325.1127.
N-[1-(Benzo[b]thiophen-2-yl)ethyl]-N-(2-phenylsulfanylethyl)formamide
(6d) (7.26 g, 75%) was obtained from 2-acetylbenzo[b]thiophene (4d)
(5.00 g, 28.4 mmol) followed by the formylation of crude resulting amine
(5d) after purification by column chromatography (hexane : AcOEtϭ2:1) as
a pale yellow oil. IR: 1672, 1583. 1H-NMR: 1.63, 1.72 (total 3H, each d,
Jϭ7 Hz, CH3), 2.8—3.5 (4H, m, SCH2CH2N–), 5.02, 5.94 (total 1H, each q,
Jϭ7 Hz, CHCH3), 7.1—8.0 (10H, m, Ar), 8.16, 8.37 (1H, each s, NCHO).
LR-EI-MS m/z: 341 (Mϩ). HR-EI-MS: Calcd for C19H19NOS2: 341.0908.
Found: 341.0925.
Oxidation of 6a with NaIO4. Typical Procedure A solution of 6a
(8.00 g, 29.1 mmol) and NaIO4 (9.30 g, 43.65 mmol) in MeOH (200 ml) and
H2O (50 ml) was stirred at room temperature for 1.5 h. After removal of in-
organic precipitates by filtration, the filtrate was concentrated in vacuo. The
residue was extracted with CHCl3. The product was chromatographed with
AcOEt and AcOEt : MeOHϭ9 : 1 to give 7a (6.23 g, 74%) and 8a (1.67 g,
17%).
N-(1-Furan-2-ylethyl)-N-(2-phenylsulfinylethyl)formamide (7a)
A
colorless oil. IR: 1670. 1H-NMR: 1.41, 1.47, 1.56, 1.60 (total 3H, each d,
Jϭ7 Hz, CH3), 2.2—4.8 (4H, m, SCH2CH2N), 4.76, 4.77, 5.62, 5.72 (total
1H, each q, Jϭ7 Hz, CHCH3), 6.2—6.4 (2H, m, Ar), 7.3—7.6 (6H, m, Ar-
H), 8.05, 8.22, 8.23, 8.24 (total 1H, each s, NCHO). LR-EI-MS m/z: 291
(Mϩ). HR-EI-MS: Calcd for C15H17NO3S: 291.0948. Found: 291.0930.
N-(1-Furan-2-ylethyl)-N-(2-phenylsulfonylethyl)formamide (8a)
A
colorless oil. IR: 1670. 1H-NMR: 1.41, 1.56 (total 3H, each d, Jϭ7 Hz,
CH3), 2.5—3.6 (4H, m, SCH2CH2N), 4.77, 5.61 (total 1H, each q, Jϭ7 Hz,
CHCH3), 6.2—6.4 (2H, m, Ar), 7.3—7.9 (total 6H, m, Ar), 8.08, 8.19 (total
1H, each s, NCHO). LR-EI-MS m/z: 307 (Mϩ). HR-EI-MS: Calcd for
C15H17NO4S: 307.0860. Found: 307.0876.
Treatment of 9 with BF3·Et2O A solution of 9 (333 mg) and BF3·Et2O
(0.13 ml) in benzene (16 ml) was allowed to react at rt for 17 h under stir-
ring. The products obtained as dark reddish oil gave many spots on TLC.
Reductive Desulfurization of 10 NaBH4 (610 mg, 18.1 mmol) was
added in small portions to a stirred solution of 10 (509 mg, 1.76 mmol) and
NiCl2·6H2O (1.26 g, 3.5 mmol) in EtOH (100 ml) under ice-cooling. The
mixture was stirred at room temperature for a further 30 min. To the reaction
mixture H2O (10 ml) was added and filtered. The filtrate was diluted with
H2O and acidified by 5% HCl solution, and the mixture was extracted with
CHCl3. The residue was purified by flash chromatography (AcOEt : hexaneϭ
1 : 1) to give 4,5,6,7-tetrahydro-7-methylthieno[2,3-c]pyridine-6-carbalde-
Oxidation of 6b 7b (2.00 g, 94%) and 8b (76 mg, 3%) were obtained
from 6b (2.00 g, 29.1 mmol) after purification by column chromatography
(AcOEt : hexaneϭ2 : 1 and AcOEt).
N-(2-Phenylsulfinylethyl)-N-(1-thiophen-2-ylethyl)formamide (7b)
1
An orange oil. IR: 1672. H-NMR: 1.56, 1.59, 1.70, 1.75 (total 3H, each d,
Jϭ7 Hz, CH3), 2.3—3.8 (4H, m, SCH2CH2N), 5.0—6.0 (total 1H, m,
CHCH3), 6.9—7.6 (8H, m, Ar), 8.10, 8.24, 8.32 (total 1H, s, NCHO). LR-
EI-MS: m/z: 323 (Mϩ). HR-EI-MS: Calcd for C15H17NO3S2: 323.0650.
Found: 323.0643.
1
hyde (11) (194 mg, 61%) as a colorless oil. IR: 1672. H-NMR: 1.50, 1.59
(total 3H, d, Jϭ7 Hz, CH3), 2.7—4.6 (4H, m, 4-H and 5-H), 4.91, 5.57 (total
1H, q, Jϭ7 Hz, 7-H), 6.7—7.2 (2H, m, Ar), 8.31, 8.35 (total 1H, s, NCHO).
LR-EI-MS m/z: 181 (Mϩ). HR-EI-MS: Calcd for C9H11NOS: 181.0561.
Found: 181.0570.
N-(2-Phenylsulfonylethyl)-N-(1-thiophen-2-ylethyl)formamide (8b)
An orange oil. IR: 1670. 1H-NMR: 1.44, 1.61 (total 3H, each d, Jϭ7 Hz,
CH3), 2.7—3.6 (total 4H, m, SCH2CH2N), 4.94, 5.80 (total 1H, m, CHCH3),
6.8—7.9 (total 8H, m, Ar), 8.10, 8.24, 8.32 (total 1H, s, NCHO). Chemical
ionization (CI)-MS m/z: 308 (Mϩ).
Oxidation of 6c 7c (3.06 g, 97%) and 8c (32 mg, 1%) were obtained
from 6c (3.00 g, 9.24 mmol) after purification by column chromatography
(AcOEt : hexaneϭ2 : 1 and AcOEt).
Hydrolysis of 11 A solution of 11 (600 mg, 3.4 mmol) in EtOH
(10 ml)–10% NaOH (10 ml) was refluxed for 16 h. The reaction mixture was
diluted with H2O and the mixture was extracted with CHCl3. The product
was purified by column chromatography (CHCl3 : MeOHϭ9 : 1) to give
4,5,6,7-tetrahydro-7-methylthieno[2,3-c]pyridine (1b)15) (414 mg, 79%) as a
pale yellow oil (lit (HCl salt: Colorless needles recrystallized from
N-(1-Benzofuran-2-ylethyl)-N-(2-phenylsulfinylethyl)formamide (7c)
1
Colorless oil. IR: 1670. H-NMR: 1.55, 1.61, 1.71, 1.74 (total 3H, each d,
1
EtOH–Et2O, mp 230—234 °C). IR: no carbonyl absorption. H-NMR: 1.45
Jϭ7 Hz, CH3), 2.6—3.2 (2H, m, SCH2CH2N), 3.3—3.7 (2H, m,
SCH2CH2N), 4.8—6.7 (total 1H, m, CHCH3), 6.64, 6.67, 6.69 (total 1H, s,
Ar), 7.1—7.6 (total 9H, m, Ar), 8.14, 8.31, 8.35 (total 1H, each s, NCHO).
LR-EI-MS m/z: 341 (Mϩ). HR-EI-MS: Calcd for C19H19NO3S: 341.1121.
Found: 341.1086.
(3H, d, Jϭ7 Hz, CH3), 2.55—2.75, 2.80—3.45 (each 2H, m, 4-H and 5-H),
4.13 (1H, q, Jϭ7 Hz, 7-H), 6.77 (1H, d, Jϭ5 Hz, 2-H), 7.10 (1H, dd, Jϭ1,
5 Hz, 3-H). 13C-NMR: 23.5 (CH3), 26.8 (C4), 42.9 (C5), 50.6 (C7), 121.9
(C2), 127.5 (C3), 133.8 (C7a), 140.4 (C3a). LR-EI-MS m/z: 153 (Mϩ). HR-
EI-MS: Calcd for C8H11NS: 153.0612. Found: 153.0600.
Pummerer Reaction of 7c i) Method A: TFAA (4.11 ml, 22 mmol) was
added to a solution of 7c (1.50 g, 4.39 mmol) in dry benzene (75 ml) at room
temperature, and the mixtrue was stirred for 1.5 h at the same temperature.
The reaction mixture was diluted with H2O and the mixture was extracted
with CHCl3. The residue was purified by column chromatography (AcOEt :
hexaneϭ1 : 2) to give 12a (516 mg, 36%), 13 (496 mg, 35%), and 14
(230 mg, 16%).
ii) Method B: TFAA (1.02 ml, 7.33 mmol) was added to a solution of 7c
(500 mg, 1.47 mmol) in benzene (30 ml) at room temperature. After the mix-
ture was stirred for 0.5 h, BF3·Et2O (0.56 ml, 4.40 mmol) was added, and the
reaction mixture was further stirred at the same temperature for 0.5 h. The
reaction mixture was diluted with H2O and extracted with CHCl3. Purifica-
tion by column chromatography (AcOEt : hexaneϭ2 : 3) of the product gave
12a (143 mg, 30%), 13 (187 mg, 39%) and 14 (127 mg, 27%).
N-(1-Benzofuran-2-ylethyl)-N-(2-phenylsulfonylethyl)formamide (8c)
1
A colorless oil. IR: 1672. H-NMR: 1.52, 1.68 (total 3H, each d, Jϭ7 Hz,
CH3), 2.7—3.7 (4H, m, SCH2CH2N), 4.90, 5.73 (total 1H, each q, Jϭ7 Hz,
CHCH3), 6.59, 6.64 (total 1H, each s, Ar), 7.2—7.7 (9H, m, Ar), 8.16, 8.27
(total 1H, each s, NCHO). LR-EI-MS m/z: 357 (Mϩ). HR-EI-MS: Calcd for
C19H19NO4S: 357.1020. Found: 357.1008.
Oxidation of 6d N-[1-(Benzo[b]thiophen-2-yl)ethyl]-N-(2-phenyl-
sulfinylethyl)formamide (7d) (1.55 g, 99%) was obtained from 6d (1.50 g,
4.4 mmol) after purification by column chromatography (AcOEt : hexaneϭ
2 : 1) as a pale yellow oil. IR: 1655. 1H-NMR: 1.63, 1.67, 1.78 (total 3H,
each d, Jϭ7 Hz, CH3), 2.4—3.9 (4H, m, SCH2CH2N), 5.06, 5.95, 6.04 (total
1H, each q, Jϭ7 Hz, CHCH3), 7.1—7.8 (10H, m, Ar), 8.16, 8.29, 8.36 (total
1H, s, NCHO). CI-MS m/z: 358 (MHϩ).
Pummerer Reaction of Sulfoxide 7b. Typical Procedure i) Method
A: TFAA (2.27 ml, 16.3 mmol) was added to a solution of 7b (1.00 g,
3.25 mmol) in benzene (60 ml) at room temperature, and the mixture was
1,2,3,4-Tetrahydro-1-methyl-4-phenylsulfanylbenzo[4,5]furo[2,3-c]-

February 2004
219
(2H, m, Ar-H). 13C-NMR: 19.2 (CH3), 22.8 (C4), 42.0 (C3), 48.4 (C1),
111.0 (C8), 111.1 (C4a), 118.6 (C5), 122.3 (C6), 123.3 (C7), 128.3 (C4b),
154.1 (C8a), 156.0 (C9a). LR-EI-MS m/z: 187 (Mϩ). HR-EI-MS: Calcd for
C12H13NO: 187.1000. Found: 187.0997.
pyridine-2-carbaldehyde (12a) Colorless needles recrystallized from
AcOEt–hexane, mp: 184—186 °C. UV: 248 (17000), 281 (3800). IR: 1668,
1662. 1H-NMR: 1.50, 1.56 (total 3H, each d, Jϭ7 Hz, CH3), 3.25, 3.77 (total
1H, dd, Jϭ3, 11 Hz, 3-H), 3.68, 4.75 (total 1H, dd, Jϭ1, 14 Hz, 3-H), 4.4—
4.6 (total 1H, m, 4-H), 4.83, 5.54 (total 1H, each d, Jϭ7 Hz, 1-H), 7.2—7.7
(9H, m, Ar), 8.13, 8.42 (total 1H, each s, NCHO). LR-EI-MS m/z: 323
(Mϩ). HR-EI-MS: Calcd for C19H17NO2S: 323.0981, Found: 323.0980.
Anal. Calcd for C19H17NO2S: C, 70.56; H, 5.30; N, 4.33. Found: C, 70.16;
H, 5.26; N, 4.12.
(1R*,9S*,10S*,18R*)-19-Formyl-18-methyl-19-aza-2-oxa-11-thiapen-
tacyclo[8.7.3.01,9.03,8.012,17]icosa-3,5,7,12,14,16-hexaene (13) Colorless
plates recrystallized from CHCl3–MeOH, mp: 258—260 °C. UV: 261
(8000), 281 (4300), 290 (3800). IR: 1662, 1655, 1597. 1H-NMR: 1.35, 1.39
(total 3H, each d, Jϭ7 Hz, CH3), 3.6—3.8 (3H, m, 10-H and 20-H), 4.23,
4.43 (total 1H, each q, Jϭ7 Hz, 18-H), 4.61, 4.65 (total 1H, each s, 9-H),
6.8—7.5 (8H, m, Ar), 8.34, 8.35 (total 1H, each s, NCHO). LR-EI-MS m/z:
323 (Mϩ). HR-EI-MS: Calcd for C19H17NO2S: 323.0972, Found: 323.0978.
Anal. Calcd for C19H17NO2S: C, 70.56; H, 5.30; N, 4.33. Found: C, 70.27;
H, 5.32; N, 4.15.
1,2,3,4-Tetrahydro-1-methylbenzo[4,5]thieno[2,3-c]pyridine (2b) (86 mg,
83%) was obtained from 17b (118 mg, 0.51 mmol) after purification by col-
umn chromatography (AcOEt : MeOHϭ6 : 1 and 4 : 1) as a colorless oil
(lit16): HCl salt mp: 256—258 °C) (lit17): (S)-1,2,3,4-tetrahydro-1-methyl-
benzo[4,5]thieno[2,3-c]pyridine HCl salt mp: 240—242 °C). IR: no carbonyl
1
absorption. UV: 227 (22500), 265 (6400), 298 (1700). H-NMR: 1.50 (3H,
d, Jϭ7 Hz, CH3), 2.7—2.8 (2H, m, 4-H), 3.11 (1H, ddd, Jϭ14, 13, 7 Hz, 3-
H), 3.44 (1H, td, Jϭ13, 5 Hz, 3-H), 4.23 (1H, qt, Jϭ7, 2 Hz, 1-H), 7.28 (1H,
ddd, Jϭ7.6, 7.3, 1 Hz, 6-H or 7-H), 7.35 (1H, ddd, Jϭ7.6, 7.3, 1 Hz, 6-H or
7-H), 7.58 (1H, d, Jϭ7 Hz, 8-H), 7.79 (1H,d, Jϭ7 Hz, 5-H). 13C-NMR: 23.1
(CH3), 25.0 (C4), 42.3 (C3), 50.6 (C1), 120.7 (C8), 122.4 (C5), 124.0 (C6
and C7), 128.2 (C4a), 138.3 (C9a), 139.5 (C8b), 141.6 (C4b). LR-EI-MS
m/z: 204 (Mϩ). HR-EI-MS: Calcd for C12H13NS: 204.0835. Found:
204.0847.
Hydrolysis of 13. Typical Prcedure A solution of 13 (200 mg) in
EtOH (30 ml) and 10% NaOH (10 ml) was heated under reflux for 1.5 h. The
reaction mixture was diluted with H2O and the mixture was extracted with
CHCl3. Recrystallyzation of the product from AcOEt–hexane gave
(1R*,9S *,10S *,18R*)-18-methyl-19-aza-2-oxa-11-thiapentacyclo-
[8.7.3.01,9.03,8.012,17]icosa-3,5,7,12,14,16-hexaene (16) (175 mg, 96%) as col-
orless plates, mp: 139—142 °C. UV: 261 (7900), 281 (4400), 290 (3700).
IR: 1597. LR-EI-MS m/z: 295 (Mϩ). HR-EI-MS: Calcd for C18H17NOS:
295.1071. Found: 295.1031.
(1S*,9R*,10R*,18R*)-19-Formyl-18-methyl-19-aza-2-oxa-11-thiapen-
tacyclo[8.7.3.01,9.03,8.012,17]icosa-3,5,7,12,14,16-hexaene (14) Colorless
needles recrystallized from CHCl3–MeOH, mp: 245—248 °C. UV: 260
1
(3900), 281 (2100), 290 (1900). IR: 1649, 1595. H-NMR: 1.41, 1.43 (total
3H, each d, Jϭ6 Hz, CH3), 3.4—4.2 (3H, m, 10-H and 20-H), 3.89, 3.99
(total 1H, each q, Jϭ6 Hz, 18-H), 4.54, 4.56 (total 1H, each s, 9-H), 6.8—
7.4 (8H, m, Ar), 8.29, 8.36 (total 1H, each s, NCHO). LR-EI-MS m/z: 323
(Mϩ). HR-EI-MS: Calcd for C18H17NO2S: 323.0952, Found: 323.0979.
Anal. Calcd for C19H17NO2S: C, 70.56; H, 5.30; N, 4.33. Found: C, 70.26;
H, 5.29; N, 4.12.
Pummerer Reaction of 7d i) Method A: 12b (893 mg, 94%) was ob-
tained from 7d (1.00 g, 2.81 mmol) after purification by column chromatog-
raphy (AcOEt : hexaneϭ1 : 2).
(1S*,9R*,10R*,18R*)-18-Methyl-19-aza-2-oxa-11-thiapentacyclo-
[8.7.3.01,9.03,8.012,17]icosa-3,5,7,12,14,16-hexaene (17) (28 mg, 85%) was ob-
tained from 14 (36 mg) as colorless needles recrystallized from AcOEt–
hexane, mp: 169—170 °C. IR: 1597, 1479. UV: 260 (6600), 282 (3700), 289
(3200). LR-EI-MS m/z: 295 (Mϩ). HR-EI-MS: Calcd for C18H17NOS:
295.1068. Found: 295.1032.
ii) Method B: 12b (175 mg, 99%) was obtained from 7d (187 mg,
0.523 mmol).
Pummerer Reaction of 7c with Acetic Anhydride A solution of 7c
(702 mg, 2.06 mmol) in Ac2O (10 ml) was allowed to react at 80 °C for 9 d.
Column chromatography of the product (AcOEt/hexane 1 : 2) gave acetic
acid 2-[(1-benzofuran-2-ylethyl)formylamino]-1-phenylsulfanylethyl ester
1,2,3,4-Tetrahydro-1-methylbenzo[4,5]thieno[2,3-c]pyridine-2-car-
baldehyde (12b) Colorless needles recrystallized from AcOEt–hexane,
mp: 173—175 °C. IR: 1672, 1664. UV: 227 (34300), 259 (13200), 297
(3400). 1H-NMR: 1.35, 1.54, 1.62 (total 3H, each d, Jϭ6 Hz, CH3), 3.3—4.8
(3H, m, 3-H and 4-H), 4.86, 5.00, 5.53, 5.60 (total 1H, each q, Jϭ6 Hz, 1-
H), 7.3—7.9 (9H, m, Ar), 8.09, 8.17, 8.37, 8.47 (total 1H, s, NCHO). LR-
EI-MS m/z: 339 (Mϩ). HR-EI-MS: Calcd for C19H17NOS2: 339.0749,
Found: 339.0748. Anal. Calcd for C19H17NOS2: C, 67.22; H, 5.05; N, 4.13.
Found: C, 66.97; H, 5.02; N, 3.94.
1
(18) (691 mg, 87%) as colorless oil. IR: 1749, 1676. H-NMR: 1.56, 1.57,
1.66, 1.69 (total 3H, each d, Jϭ7 Hz, CH3), 1.82, 2.02, 2.03, 2.07 (total 3H,
each s, OCOCH3), 3.3—3.8 (2H, m, NCH2CHS), 5.46, 6.01, 6.26, 6.28
(total 1H, each dd, Jϭ4, 9 Hz, NCH2CHS), 4.79—4.87, 5.67—5.77 (1H, m,
CHCH3), 6.5—6.6 (1H, m, Ar), 7.1—7.6 (9H, m, Ar-H), 8.06, 8.09, 8.32,
8.36 (total 1H, each s, NCHO).
Reductive Desulfurization of 12a. Typical Experiment NaBH4
(610 mg, 18.8 mmol) was added in small portions to a stirred solution of 12a
(607 mg, 1.88 mmol) and NiCl2·6H2O (1.38 g, 6.6 mmol) in EtOH (100 ml)
under ice-cooling. The mixture was stirred at room temperature for a further
0.5 h. To the reaction mixture H2O (10 ml) was added and filtered. The fil-
trate was diluted with H2O and acidified by 5% HCl solution, and the mix-
ture was extracted with CHCl3. The residue was purified by flash chromatog-
raphy (AcOEt : hexaneϭ2 : 3) to give 1,2,3,4-tetrahydro-1-methylbenzo[4,5]-
furo[2,3-c]pyridine-2-carbaldehyde (15a) (311 mg, 77%) as colorless nee-
dles recrystallized from AcOEt–hexane, mp 258—260 °C. IR: 1662, 1627.
UV: 283 (3600), 277 (4200), 250 (16100). 1H-NMR: 1.53, 1.60 (3H, each d,
Jϭ6 Hz, CH3), 2.7—4.7 (4H, m, 3-H and 4-H), 4.48, 5.52 (total 1H, each q,
Jϭ7 Hz, 1-H), 7.2—7.5 (4H, m, Ar), 8.19, 8.34 (total 1H, s, NCHO). LR-EI-
MS m/z: 323 (Mϩ). HR-EI-MS: Calcd for C13H13NO2: 323.0982, Found:
323.0980.
1,2,3,4-Tetrahydro-1-methylbenzo[4,5]thieno[2,3-c]pyridine-2-carbalde-
hyde (15b) (383 mg, 71%) was obtained from 12b (796 mg, 2.35 mmol) after
purification by column chromatography (benzene : acetoneϭ15 : 2) as a col-
orless oil. IR: 1670, 1654. UV: 229 (23900), 258 (6800), 287 (2100), 297
(1600). 1H-NMR: 1.56, 1.65 (total 3H, d, Jϭ7 Hz, CH3), 2.7—4.7 (4H, m, 3-
H and 4-H), 5.9—6.0 (1H, m, 1-H), 7.2—7.8 (4H, m, Ar), 8.20, 8.35 (total
1H, s, NCHO). LR-EI-MS m/z: 231 (Mϩ). HR-EI-MS: Calcd for
C13H13NOS: 231.0718. Found: 231.0700.
Reaction of 20 with BF3·Et2O A solution of 18 (279 mg, 0.72 mmol)
in benzene (15 ml) was treated with BF3·Et2O (0.27 ml, 2.18 mmol) at room
temperature for 7 d. Column chromatography of the product (AcOEt :
hexaneϭ2 : 3) gave 12a (78 mg, 33%), 13 (76 mg, 32%), and 14 (76 mg,
32%).
Treatment of 12a under Acidic Conditions i) A solution of 12a
(302 mg, 0.93 mmol), TFAA (0.71 ml, 5.11 mmol) in benzene (20 ml) was
treated with BF3·Et2O (0.39 ml, 3.06 mmol) at room temperature for 17 h.
Column chromatography of the residue (AcOEt : hexaneϭ1 : 1) recovered
the starting material 12a (295 mg, 98%).
ii) A solution of 12a (300 mg, 0.93 mmol) TFAA (0.64 ml, 4.65 mmol) in
benzene (20 ml) was treated with TFA (106 mg, 0.93 mmol) at room temper-
ature for 18 h. After treatment in the same manner as described above, re-
covered the starting material 12a (300 mg, 100%).
iii) Treatment of 12a (300 mg, 0.93 mmol) in benzene (20 ml) with TFAA
(0.64 ml, 4.65 mmol), BF3·Et2O (0.39 ml, 3.06 mmol) and TFA (106 mg,
0.93 mmol) at room temperature for 18 h recovered 12a (300 mg, 100%).
iv) Treatment of 12a (300 mg, 0.93 mmol) in benzene (20 ml) with acetic
anhydride (0.46 ml, 4.65 mmol) and p-TsOH (160 mg, 0.93 mmol) at 80 °C
for 18 h recovered 12a (300 mg, 100%).
References
1) Saitoh T., Shikiya K., Horiguchi Y., Sano T., Chem. Pharm. Bull., 51,
667—672 (2003).
2) Shinohara T., Toda J., Sano T., Chem. Pharm. Bull., 45, 813—819
(1997).
3) Shinohara T., Takeda A., Toda J., Terasawa N., Sano T., Heterocycles,
46, 555—565 (1997).
4) Shinohara T., Takeda A., Toda J., Ueda Y., Kohno M., Sano T., Chem.
Pharm. Bull., 46, 918—927 (1998).
Hydrolysis of 15a. Typical Experiment A solution of 15a (201 mg,
1.08 mmol) in EtOH (20 ml)–10% NaOH (10 ml) was refluxed for 1.5 h. The
reaction mixture was diluted with H2O and the mixture was extracted with
CHCl3. The product was purified by column chromatography (AcOEt) to
give 1,2,3,4-tetrahydro-1-methylbenzo[4,5]furo[2,3-c]pyridine (2a) (171 mg,
98%) as a colorless oil. IR: no carbonyl absorption. UV: 244 (13000), 273
(2600), 280 (2200). 1H-NMR: 1.46 (3H, d, Jϭ7 Hz, CH3), 2.5—3.3 (4H, m,
3-H and 4-H), 4.0—4.1 (1H, m, 1-H), 7.2—7.25 (2H, m, Ar-H), 7.4—7.42
5) Shinohara T., Takeda A., Toda J., Sano T., Chem. Pharm. Bull., 46,

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