Synthesis of dihydrothieno[2,3-b]pyridines based on titanium(IV) chloride-mediated Michael reactions of 2-amino-4,5-dihydro-3- thiophenecarbonitriles with α,β-unsaturated ketones

Article abstract of DOI:10.1002/jhet.5570410428

2-Amino-4,5-dihydro-3-thiophenecarbonitriles 1a-c reacted with α,β-unsaturated ketones (e.g. methyl vinyl ketone 2 and benzalacetone 3) in the presence of titanium(IV) chloride to give the corresponding Michael adducts 4a-c and 5a-c. Thermal treatment of

Full text of DOI:10.1002/jhet.5570410428

Jul-Aug 2004
641
Synthesis of Dihydrothieno[2,3-b]pyridines Based on Titanium(IV)
Chloride-Mediated Michael Reactions of 2-Amino-4,5-dihydro-3-
thiophenecarbonitriles with α,β-Unsaturated Ketones
Hiroshi Maruoka, Motoyoshi Yamazaki and Yukihiko Tomioka*
Faculty of Pharmaceutical Sciences, Fukuoka University,
8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan
Received January 24, 2004
2-Amino-4,5-dihydro-3-thiophenecarbonitriles 1a-c reacted with α,β-unsaturated ketones (e. g. methyl
vinyl ketone 2 and benzalacetone 3) in the presence of titanium(IV) chloride to give the corresponding
Michael adducts 4a-c and 5a-c. Thermal treatment of compounds 4a-c and 5a-c with titanium(IV) chloride
caused intramolecular cyclocondensation to yield the corresponding tetrahydrothieno[2,3-b]pyridines 6a-c
and 7a-c. Aromatization of 6a-c and 7a-c with potassium tert-butoxide in refluxing tert-butyl alcohol pro-
ceeded smoothly to afford the corresponding dihydrothieno[2,3-b]pyridines 8a-c and 9a-c.
J. Heterocyclic Chem., 41, 641 (2004).
Pyridine derivatives, especially fused pyridines such as
been reported to be efficient under mild conditions [23-
29]. Having optimized the Michael reaction parameters,
we then examined the reaction with several Lewis acids.
Best results were obtained when 1c was treated with
methyl vinyl ketone 2 in the presence of titanium(IV) chlo-
ride. Indeed, the Michael addition proceeded smoothly at
room temperature giving the corresponding Michael
adduct 4c in 60% yield, and the conjugate addition of the
amino group of 1c to methyl vinyl ketone 2 was not
observed (Scheme 1). The use of various other Lewis
acids, e.g. boron trifluoride diethyl etherate (48%), tin(IV)
chloride (28%) and zinc chloride (13%), resulted in lower
yield. Thus, we started an investigation of titanium(IV)
chloride-mediated Michael-type reaction.
quinolines, are important because of their incidence in
nature [1], their biological properties [2-6] and their utili-
ties as intermediates for the design of biologically active
compounds [7]. Thus, a large number of general methods
for the preparation of pyridine derivatives have recently
reported [8-15]. For these reasons, we are interested in the
development of new methods for the synthesis of pyridine
derivatives.
The Michael addition of primary enamines to α,β-unsat-
urated ketones is an important reaction and this approach
has mainly been used for the formation of new carbon-car-
bon bonds. When α,β-unsaturated ketones are used as
electrophiles, conjugate addition of the β-carbon atom of
enamines to α,β-unsaturated ketones takes place to pro-
duce the initial Michael adducts. Several investigators
have reported that primary enaminonitriles react with α,β-
unsaturated ketones in the presence of a base to give pyri-
dine derivatives [16-20]. In this context, we have previ-
ously described the preparation of Michael adducts from
primary enaminonitriles and α,β-unsaturated ketones, and
the synthesis of dihydrofuro[2,3-b]pyridines [21].
Continuing with our interest in the chemistry of new pyri-
dine derivatives, we report here the results of our investi-
gation, which offer titanium(IV) chloride-mediated
Michael reactions of 2-amino-4,5-dihydro-3-thiophenecar-
bonitriles 1a-c [22] with α,β-unsaturated ketones and a
convenient method for preparing dihydrothieno[2,3-
b]pyridines.
Scheme 1
A base-catalyzed Michael-type reaction of 1a with ben-
zalacetone 3 according to our previous investigation [21]
failed to give the expected Michael adduct 5a and the reac-
tion was not clean. In order to obtain Michael adduct, we
then envisaged that a Lewis acid could act as Michael reac-
tion catalyst. Since there are some disadvantages of base
catalysis, e . g. incompatibility with base sensitivities or
acidic functionalities, ester solvolysis, reverse and other
reactions, Lewis acid-catalyzed Michael reactions have

642
H. Maruoka, M. Yamazaki and Y. Tomioka
Vol. 41
When a mixture of 1a-c with methyl vinyl ketone 2
chloride in refluxing chloroform for 1 hour caused
intramolecular cyclocondensation to afford the corre-
sponding tetrahydrothieno[2,3-b]pyridines 6a-c and 7a-c.
Interestingly, we found the milder condition under which
compounds 6a-c and 7a-c could be obtained in the pres-
ence of titanium(IV) chloride and triethylamine (Table 2).
Several investigators have reported an efficient transfor-
mation and cyclization by the action of a titanium(IV)
chloride-amine combination [32-35]. In our reaction, it
seems likely that since the rate of intramolecular cyclocon-
densation of 4 and 5 could be promoted by using triethy-
lamine as the base at low temperature, 6a-c and 7a were
obtained in somewhat better yields of 51, 44, 60 and 75%,
respectively (entries 2, 4, 6 and 8). Elemental analyses and
spectral data of 6a-c and 7a-c are consistent with the
assigned structures.
On the basis of these results, we examined the direct
conversion of 1a to 6a in a one-pot process. However, our
attempts were unacceptable with respect to yield. A mix-
ture of 1a, methyl vinyl ketone 2 and titanium(IV) chloride
in chloroform stirred at room temperature for 5 hours and
then refluxed for 1 hour provided a trace of 6a, and the
reaction was not clean. Although the reason of the low
yield is not clear at present, this is probably because the
reaction of Michael adduct 4a with the excess of methyl
vinyl ketone 2 would occur.
and/or benzalacetone 3 in the presence of titanium(IV)
chloride was stirred at room temperature, the expected
Michael adducts 4a-c and 5a-c were obtained in moderate
yield (Table 1). In this case, the reactions of 1b with
methyl vinyl ketone 2 and of 1c with benzalacetone 3 gave
Michael adducts 4b and 5c together with tetrahydroth-
ieno[2,3-b]pyridines 6b and 7c in 11 and 9% yield, respec-
tively (entries 2 and 6). The ir spectra of 4a-c and 5a-c dis-
play a band near 2230 cm-1 due to a non-conjugated cyano
group, whereas those of 1a-c show a conjugated cyano
band in the 2160-2170 cm-1 region. The 1H nmr spectra of
4a-c and 5a-c in DMSO-d6 exhibit a D2O exchangeable
signal at δ 5.6-6.0 attributable to the imino proton,
whereas those of 1a-c in deuteriochloroform appear as a
D2O exchangeable signal near δ 4.7 assignable to the
amino protons. In addition, the 1H nmr spectra of 4a,c and
5a show two shinglets near δ 1.3 for the acetyl protons and
two shinglets for the imino proton (see experimental sec-
tion). These observations indicate that 4a,c and 5a exist as
two diastereomers, which would probably be formed by an
e ffect of the configuration of the imino group, the sub-
stituent group at the 3-position and the substituent group at
the 4 or 5-position. Elemental analyses and spectral data of
4a-c and 5a-c are consistent with the assigned structures.
Though the detailed mechanism of the above reaction has
not been clarified yet, the formation of Michael adducts 4
and 5 could be explained by the possible mechanism pre-
sented in Scheme 1.
We next investigated the conversion of Michael adducts
4 and 5 into the fused pyridines. The use of sodium
methoxide was not successful because of the competitive
cleavage of Michael adducts 4a. This result suggests that
when enaminonitriles 1a-c are used as the substrate,
Michael addition reaction does not take place in the pres-
ence of a base. It is well known that titanium(IV) chloride
has been shown to facilitate the formation of enamines or
imines in the reaction of carbonyl compounds with amines
[30,31]. Thus, we tested the effectiveness of titanium(IV)
chloride for intramolecular cyclocondensation of Michael
adducts. Treatment of 4a-c and 5a-c with titanium(IV)
Finally, we have examined the aromatization of 6 and 7.
Compounds 6a-c and 7a-c were allowed to react with
potassium tert-butoxide in refluxing tert-butyl alcohol to
give the corresponding dihydrothieno[2,3-b]pyridines 8a-
c and 9a-c in good yields (Table 3). The structural assign-
ments of 8 and 9 were made on the basis of elemental
analyses and spectral data.

Jul-Aug 2004
Synthesis of Dihydrothieno[2,3-b]pyridines
643
-1
bromide): ν 3171 (NH), 2231 (C≡N), 1631 (C=O) cm ; H nmr
1
(DMSO-d ): δ 1.26 (s, 0.75H, COMe), 1.34 (s, 2.25H, COMe),
6
1.63-2.29 (m, 4H, 4 and 1'-H), 2.49-2.76 (m, 2H, 2'-H), 3.19-3.30
(m, 2H, 5-H), 5.60 (s, 0.75H, NH), 5.72 ppm (s, 0.25H, NH); ms:
+
m/z 197 [M+H] .
Anal. Calcd. for C H N OS: C, 55.08; H, 6.16; N, 14.27.
9
Found: C, 55.10; H, 6.15; N, 14.26.
12 2
Tetrahydro-2-imino-5-methyl-3-(3-oxobutyl)-3-thiophenecar -
bonitrile (4b).
This compound was obtained as colorless needles (0.87 g,
41%), mp 113-115˚ (acetone-petroleum ether); ir (potassium bro-
In conclusion, we have demonstrated that titanium(IV)
chloride-mediated Michael reactions of 2-amino-4,5-dihy-
dro-3-thiophenecarbonitriles 1a-c with α,β-unsaturated
ketones provide a novel and efficient method to prepare
Michael adducts 4a-c and 5a-c. This method is useful
because of its efficiency and the ease of operation.
Furthermore, fused pyridines can be prepared from
Michael adducts in a stepwise fashion. Functionalized
pyridines are important synthons in organic synthesis and
for the preparation of biologically active compounds with
interest in medicinal chemistry.
-1
mide): ν 3222 (NH), 2232 (C≡N), 1625 (C=O) cm ; H nmr
1
(DMSO-d ): δ 1.34 (s, 3H, COMe), 1.62 (d, J = 7.3 Hz, 3H, 5-
6
Me), 1.67-2.28 (m, 3H, 4 and 1'-H), 2.49-2.80 (m, 2H, 4 and 2'-
H), 3.24-3.36 (m, 1H, 2'-H), 3.84-3.88 (m, 1H, 5-H), 5.89 ppm (s,
+
1H, NH); ms: m/z 211 [M+H] .
Anal. Calcd. for C
Found: C, 56.94; H, 6.66; N, 13.38.
H N OS: C, 57.12; H, 6.71; N, 13.32.
10 14 2
Tetrahydro-2-imino-3-(3-oxobutyl)-4-phenyl-3-thiophenecar-
bonitrile (4c).
This compound was obtained as colorless columns (1.63 g,
60%), mp 174-175˚ (acetone-petroleum ether); ir (potassium bro-
-1
mide): ν 3192 (NH), 2232 (C≡N), 1634 (C=O) cm ; H nmr
1
(DMSO-d ): δ 1.31 (s, 0.9H, COMe), 1.36 (s, 2.1H, COMe),
6
EXPERIMENTAL
1.54-1.71 (m, 2H, 1'-H), 1.89-2.08 (m, 2H, 2'-H), 3.40 (dd, J =
5.8, 11 Hz, 1H, 5-H), 3.46-3.54 (m, 1H, 5-H), 3.69-3.74 (m, 1H,
4-H), 5.71 (s, 0.7H, NH), 5.77 (s, 0.3H, NH), 7.37-7.50 ppm (m,
All melting points are uncorrected. The ir spectra were
1
recorded on a JASCO FT/IR-230 spectrometer. The H nmr spec-
+
5H, aromatic H); ms: m/z 273 [M+H] .
tra were recorded on a JEOL JNM-A 500 spectrometer (500
MHz). Chemical shifts (δ) are reported in parts per million (ppm)
relative to tetramethylsilane as internal standard. Positive FAB
mass spectra were obtained on a JEOL JMS-HX 110 spectrome-
ter. Elemental analyses were performed on a YANACO MT-6
CHN analyzer.
Anal. Calcd. for C
Found: C, 66.15; H, 5.89; N, 10.25.
H N OS: C, 66.15; H, 5.92; N, 10.29.
15 16 2
Tetrahydro-2-imino-3-(3-oxo-1-phenylbutyl)-3-thiophenecar-
bonitrile (5a).
This compound was obtained as colorless needles (1.66 g, 61%),
mp 179-181˚ (chloroform-petroleum ether); ir (potassium bromide):
General Procedure for the Preparation of Michael adducts 4a-c
and 5a-c.
-1
ν 3240 (NH), 2232 (C≡N), 1631 (C=O) cm ; H nmr (DMSO-d ):
1
6
δ 1.38 (s, 0.45H, COMe), 1.46 (s, 2.55H, COMe), 1.95-2.00 (m, 1H,
4-H), 2.11-2.35 (m, 3H, 4 and 2'-H), 3.08-3.14 (m, 1H, 1'-H), 3.21-
3.33 (m, 2H, 5-H), 5.84 (s, 0.85H, NH), 5.92 (s, 0.15H, NH), 7.33-
7.41 ppm (m, 5H, aromatic H); ms: m/z 273 [M+H] .
Anal. Calcd. for C H N OS: C, 66.15; H, 5.92; N, 10.29.
15 16 2
Found: C, 66.13; H, 5.91; N, 10.27.
To an ice-cooled and stirred solution of 1a-c (10 mmoles) and
methyl vinyl ketone 2 (1.40 g, 20 mmoles) or benzalacetone 3
(2.92 g, 20 mmoles) in chloroform (30 ml) was added
titanium(IV) chloride (1.90 g, 10 mmoles). After the mixture was
stirred at room temperature for 5 hours (in the case of the prepa-
ration of 4a-c and 5a,b) or overnight (in the case of the prepara-
tion of 5c), anhydrous sodium carbonate (10 g) and a saturated
aqueous sodium carbonate solution (5 ml) were successively
added to the reaction mixture with stirring and ice-cooling. The
solid was removed by filtration and washed with hot chloroform.
The combined filtrates were concentrated in vacuo. Further pro-
cessing of the residue is described in the following paragraphs.
(A) The residue was purified by column chromatography on
silica gel with methylene chloride-acetone (4:1) as the eluent to
give 4a,c and 5a,b.
+
Tetrahydro-2-imino-5-methyl-3-(3-oxo-1-phenylbutyl)-3-thio -
phenecarbonitrile (5b).
This compound was obtained as colorless prisms (1.43 g,
50%), mp 179-180˚ (acetone-petroleum ether); ir (potassium bro-
-1
mide): ν 3187 (NH), 2242 (C≡N), 1631 (C=O) cm ; H nmr
1
(DMSO-d ): δ 1.37 (s, 3H, COMe), 1.51 (d, J = 7 Hz, 3H, 5-Me),
6
1.94-2.25 (m, 3H, 4 and 2'-H), 2.49-2.72 (m, 1H, 2'-H), 3.20 (dd,
J = 2.1, 13.6 Hz, 1H, 1'-H), 3.83-3.86 (m, 1H, 5-H), 5.92 (s, 1H,
+
NH), 7.33-7.41 ppm (m, 5H, aromatic H); ms: m/z 287 [M+H] .
(B) The residue was purified by column chromatography on
silica gel with methylene chloride as the eluent to afford 6b (0.21
g, 11%) and 7c (0.31 g, 9%). Further the elution with methylene
chloride-acetone (4:1) gave of 4b and 5c.
Anal. Calcd. for C
H N OS: C, 67.10; H, 6.34; N, 9.78.
16 18 2
Found: C, 67.14; H, 6.32; N, 9.76.
Tetrahydro-2-imino-3-(3-oxo-1-phenylbutyl)-4-phenyl-3-thio -
phenecarbonitrile (5c).
Tetrahydro-2-imino-3-(3-oxobutyl)-3-thiophenecarbonitrile (4a).
This compound was obtained as colorless needless (1.00 g,
51%), mp 126-128˚ (acetone-petroleum ether); ir (potassium
This compound was obtained as colorless needles (0.93 g,
27%), mp 201-203˚ (chloroform-petroleum ether); ir (potassium

644
H. Maruoka, M. Yamazaki and Y. Tomioka
Vol. 41
-1
bromide): ν 3241 (NH), 2232 (C≡N), 1631 (C=O) cm ; H nmr
(DMSO-d ): δ 1.43 (s, 3H, COMe), 1.83 (dd, J = 2.7, 14.3 Hz,
6
1
-1 1
cm ; H nmr (deuteriochloroform): δ 2.00-2.01 (m, 3H, 6-Me),
2.31-2.35 (m, 1H, 4-H), 2.48 (dd, J = 6.7, 17.4 Hz, 1H, 4-H), 3.31
(dd, J = 5.5, 11 Hz, 1H, 2-H), 3.48 (dd, J = 5.5, 12.2 Hz, 1H, 2-H),
3.83 (dd, J = 11, 12.2 Hz, 1H, 3-H), 5.10-5.12 (m, 1H, 5-H), 7.26-
1H, 2'-H), 2.05-2.11 (m, 1H, 2'-H), 3.26-3.39 (m, 3H, 5 and 1'-H),
3.69 (dd, J = 6.4, 11.6 Hz, 1H, 4-H), 5.90 (s, 1H, NH), 6.88-6.98
(m, 6H, aromatic H), 7.04-7.06 (m, 2H, aromatic H), 7.17-7.18
+
7.43 ppm (m, 5H, aromatic H); ms: m/z 255 [M+H] .
Anal. Calcd. for C
+
ppm (m, 2H, aromatic H); ms: m/z 349 [M+H] .
Anal. Calcd. for C
H N S: C, 70.83; H, 5.55; N, 11.01.
15 14 2
Found: C, 70.90; H, 5.54; N, 11.00.
H N OS: C, 72.38; H, 5.79; N, 8.04.
21 20 2
Found: C, 72.39; H, 5.83; N, 7.97.
2,3,3a,4-Tetrahydro-6-methyl-4-phenylthieno[2,3-b]pyridine-3a-
carbonitrile (7a).
General Procedure for the Preparation of 6a-c and 7a-c from 4a-c
and 5a-c.
This compound was obtained as colorless prisms, mp 165-
166˚ (acetone-petroleum ether); ir (potassium bromide): ν 2232
(A) To an ice-cooled and stirred solution of 4a-c and 5a-c (10
mmoles) in chloroform (30 ml) was added titanium(IV) chloride
(1.90 g, 10 mmoles). After the mixture was refluxed for 1 hour,
anhydrous sodium carbonate (10 g) and a saturated aqueous
sodium carbonate solution (5 ml) were successively added to the
reaction mixture with stirring and ice-cooling. The solid was
removed by filtration and washed with hot chloroform. The com-
bined filtrates were concentrated in vacuo. The residue was puri-
fied by column chromatography on silica gel with methylene
chloride as the eluent to yield 6a (0.81 g, 46%), 6b (0.56 g, 29%),
6c (1.33 g, 52%), 7a (1.68 g, 66%), 7b (1.96 g, 73%) and 7c (2.48
g, 75%), respectively.
-1
1
( C≡N) cm ; H nmr (deuteriochloroform): δ 2.09-2.10 (m, 3H,
6-Me), 2.31 (dd, J = 6.7, 12.8 Hz, 1H, 3-H), 2.59 (dd, J = 4.9,
12.8 Hz, 1H, 3-H), 3.21 (dd, J = 6.7, 11.6 Hz, 1H, 2-H), 3.36
(dd, J = 4.9, 11.6 Hz, 1H, 2-H), 3.62-3.63 (m, 1H, 4-H), 5.26-
5.27 (m, 1H, 5-H), 7.34-7.41 ppm (m, 5H, aromatic H); ms: m/z
+
255 [M+H] .
Anal. Calcd. for C
H N S: C, 70.83; H, 5.55; N, 11.01.
15 14 2
Found: C, 70.89; H, 5.61; N, 11.01.
2, 3, 3a, 4-Tetrahydro-2, 6-dimethyl-4-phenylthieno[2, 3-b]pyri-
dine-3a-carbonitrile (7b).
(B) To an ice-cooled and stirred solution of 4a-c and 5a-c (10
mmoles) and triethylamine (1.01 g, 10 mmoles) in chloroform
(30 ml) was added titanium(IV) chloride (1.90 g, 10 mmoles).
After the mixture was stirred at room temperature for 8 hours,
anhydrous sodium carbonate (10 g) and a saturated aqueous
sodium carbonate solution (5 ml) were successively added to the
reaction mixture with stirring and ice-cooling. After work-up as
described above, 6a (0.91 g, 51%), 6b (0.84 g, 44%), 6c (1.52 g,
60%), 7a (1.91 g, 75%), 7b (1.53 g, 57%) and 7c (2.24 g, 68%)
were obtained.
This compound was obtained as colorless prisms, mp 128-130˚
(acetone-petroleum ether); ir (potassium bromide): ν 2232 (C≡N)
-1
1
cm ; H nmr (deuteriochloroform): δ 1.64 (d, J = 7 Hz, 3H, 2-
Me), 2.09-2.10 (m, 3H, 6-Me), 2.31 (dd, J = 0.9, 13.4 Hz, 1H, 3-
H), 2.52 (dd, J = 7.6, 13.4 Hz, 1H, 3-H), 3.58-3.59 (m, 1H, 4-H),
3.88-3.91 (m, 1H, 2-H), 5.27-5.28 (m, 1H, 5-H), 7.26-7.39 ppm
+
(m, 5H, aromatic H); ms: m/z 269 [M+H] .
Anal. Calcd. for C
Found: C, 71.63; H, 5.99; N, 10.44.
H N S: C, 71.61; H, 6.01; N, 10.44.
16 16 2
2, 3, 3a, 4-Tetrahydro-6-methyl-3, 4-diphenylthieno[2, 3-b]pyri-
dine-3a-carbonitrile (7c).
2,3,3a,4-Tetrahydro-6-methylthieno[2,3-b]pyridine-3a-carboni-
trile (6a).
This compound was obtained as colorless prisms, mp 189-191˚
(acetone-petroleum ether); ir (potassium bromide): ν 2224 (C≡N)
This compound was obtained as colorless prisms, mp 105-107˚
(acetone-petroleum ether); ir (potassium bromide): ν 2227 (C≡N)
-1
cm ; H nmr (DMSO-d ): δ 1.97-1.98 (m, 3H, 6-Me), 3.28-3.47
1
6
-1
1
cm ; H nmr (deuteriochloroform): δ 2.01-2.02 (m, 3H, 6-Me),
2.13-2.26 (m, 2H, 3-H), 2.76 (dd, J = 6.7, 17.1 Hz, 1H, 4-H),
2.91-2.95 (m, 1H, 4-H), 3.23 (dd, J = 6.7, 11.6 Hz, 1H, 2-H),
3.44-3.51 (m, 1H, 2-H), 5.14-5.17 ppm (m, 1H, 5-H); ms: m/z
(m, 2H, 2-H), 4.03 (dd, J = 7.9, 10.3 Hz, 1H, 3-H), 4.11-4.13 (m,
1H, 4-H), 5.07-5.08 (m, 1H, 5-H), 6.94-7.03 (m, 5H, aromatic
+
H), 7.12-7.17 ppm (m, 5H, aromatic H); ms: m/z 331 [M+H] .
Anal. Calcd. for C H N S: C, 76.33; H, 5.49; N, 8.48.
21 18 2
Found: C, 76.28; H, 5.59; N, 8.33.
+
179 [M+H] .
Anal. Calcd. for C H N S: C, 60.64; H, 5.65; N, 15.72.
9
Found: C, 60.54; H, 5.70; N, 15.61.
10 2
General Procedure for the Preparation of 8a-c and 9a-c from 6a-
c and 7a-c.
2,3,3a,4-Tetrahydro-2,6-dimethylthieno[2,3-b]pyridine-3a-car-
bonitrile (6b).
A solution of 6a-c and 7a-c (5 mmoles) and potassium tert-
butoxide (0.56 g, 5 mmoles) in anhydrous tert-butyl alcohol (10
ml) was refluxed for 1 hour. After removal of the solvent in
vacuo, cold water was added to the residue. The resulting mixture
was extracted with chloroform. The extract was dried over anhy-
drous sodium sulfate and concentrated in vacuo. The residue was
purified by column chromatography on silica gel with methylene
chloride as the eluent to afford 8a-c and 9a-c.
This compound was obtained as colorless prisms, mp 101-102˚
(acetone-petroleum ether); ir (potassium bromide): ν 2232 (C≡N)
-1
1
cm ; H nmr (deuteriochloroform): δ 1.74 (d, J = 7.3 Hz, 3H, 2-
Me), 2.02-2.03 (m, 3H, 3-H, 6-Me), 2.16-2.21 (m, 1H, 3-H), 2.36
(dd, J = 7.6, 13.4 Hz, 1H, 3-H), 2.67-2.72 (m, 2H, 4-H), 3.87-3.93
+
(m, 1H, 2-H), 5.17-5.19 ppm (m, 1H, 5-H); ms: m/z 193 [M+H] .
H N S: C, 62.47; H, 6.29; N, 14.57.
Anal. Calcd. for C
Found: C, 62.57; H, 6.34; N, 14.56.
10 12 2
2,3-Dihydro-6-methylthieno[2,3-b]pyridine (8a).
This compound was obtained as pale yellow oil (0.68 g, 90%);
H nmr (deuteriochloroform): δ 2.45 (s, 3H, 6-Me), 3.25 (t, J =
7.9 Hz, 2H, 3-H), 3.38 (t, J = 7.9 Hz, 2H, 2-H), 6.74 (d, J = 7.6
Hz, 1H, 5-H), 7.26 ppm (d, J = 7.6 Hz, 1H, 4-H); ms: m/z 152
+
[M+H] .
2,3,3a,4-Tetrahydro-6-methyl-3-phenylthieno[2,3-b]pyridine-3a-
carbonitrile (6c).
1
This compound was obtained as colorless prisms, mp 122-124˚
(acetone-petroleum ether); ir (potassium bromide): ν 2232 (C≡N)

Jul-Aug 2004
Synthesis of Dihydrothieno[2,3-b]pyridines
645
Eithier, J.-P. Falgueyret, R. W. Friesen, M. Girard, Y. Girard, J. Guay, D.
Riendeau, P. Tagari and R. N. Young, Bioorg. Med. Chem. Lett., 8, 1255
(1998).
Anal. Calcd. for C H NS: C, 63.54; H, 6.00; N, 9.26. Found:
8
C, 63.40; H, 6.02; N, 9.38.
9
2,3-Dihydro-2,6-dimethylthieno[2,3-b]pyridine (8b).
This compound was obtained as pale yellow oil (0.76 g, 92%);
[4] M. E. Zwaagstra, H. Timmerman, A. C. van de Stolpe, F. J. J.
de Kanter, M. Tamura, Y. Wada and M.-Q. Zhang, J. Med. Chem., 41,
1428 (1998).
[5] N. Zhang, B. Wu, D. Powell, A. Wissner, M. B. Floyd, E. D.
Kovacs, L. Toral-Barza and C. Kohler, Bioorg. Med. Chem. Lett., 1 0,
2825 (2000).
[6] D. H. Boschelli, F. Ye, Y. D. Wang, M. Dutia, S. L. Johnson,
B. Wu, K. Miller, D. W. Powell, D. Yaczko, M. Young, M. Tischler, K.
Arndt, C. Discafani, C. Etienne, J. Gibbons, J. Grod, J. Lucas, J. M.
Weber and F. Boschelli, J. Med. Chem., 44, 3965 (2001).
[7] G. Jones, Comprehensive Heterocyclic Chemistry, Vol 2, A.
R. Katritzky and C. W. Ress, eds, Pergamon Press, Oxford, 1984, p 395.
[8] G. Jones, Comprehensive Heterocyclic Chemistry II, Vol 5, A.
R. Katritzky, C. W. Ress and E. F. V. Scriven, eds, Pergamon Press,
Oxford, 1996, p 167.
[9] C. S. Cho, B. H. Oh and S. C. Shim, J. Heterocyclic Chem.,
36, 1175 (1999).
[10] A. Arcadi, F. Marinelli and E. Rossi, Tetrahedron, 55, 13233
(1999).
[11] N. J. Tom and E. M. Ruel, Synthesis, 1351 (2001).
[12] F. Palacios, D. Aparicio and J. Vicario, Eur. J. Org. Chem.,
4131 (2002).
1
H nmr (deuteriochloroform): δ 1.48 (d, J = 6.7 Hz, 3H, 2-Me),
2.45 (s, 3H, 6-Me), 2.89 (dd, J = 6.7, 15.5 Hz, 1H, 3-H), 3.35 (dd,
J = 7.6, 15.5 Hz, 1H, 3-H), 3.97-4.01 (m, 1H, 2-H), 6.73 (d, J =
7.6 Hz, 1H, 5-H), 7.23 ppm (d, J = 7.6 Hz, 1H, 4-H); ms: m/z 166
+
[M+H] .
Anal. Calcd. for C H NS: C, 65.41; H, 6.71; N, 8.48. Found:
9
C, 65.17; H, 6.71; N, 8.72.
11
2,3-Dihydro-6-methyl-3-phenylthieno[2,3-b]pyridine (8c).
This compound was obtained as pale yellow oil (1.06 g, 93%);
1
H nmr (deuteriochloroform): δ 2.48 (s, 3H, 6-Me), 3.43 (dd, J =
9.5, 11 Hz, 1H, 2-H), 3.66 (dd, J = 8.5, 11 Hz, 1H, 2-H), 4.63 (dd,
J = 8.5, 9.5 Hz, 1H, 3-H), 6.74 (d, J = 7.6 Hz, 1H, 5-H), 6.95 (d, J
= 7.6 Hz, 1H, 4-H), 7.25-7.37 ppm (m, 5H, aromatic H); ms: m/z
+
228 [M+H] .
Anal. Calcd. for C
C, 73.97; H, 5.60; N, 6.09.
H NS: C, 73.97; H, 5.76; N, 6.16. Found:
14 13
2,3-Dihydro-6-methyl-4-phenylthieno[2,3-b]pyridine (9a).
[13] G. Guanti, S. Perrozzi and R. Riva, Terahedron: Asymmetry,
13, 2703 (2002).
[14] K. Kobayashi, K. Yoneda, M. Mano, O. Morikawa and H.
Konishi, Chem. Lett., 32, 76 (2003).
[15] A. Wissner, E. Overbeek, M. F. Reich, M. B. Floyd, B. D.
Johnson, N. Mamuya, E. C. Rosfjord, C. Discafani, R. Davis, X. Shi, S.
K. Rabindran, B. C. Gruber, F. Ye, W. A. Hallett, R. Nilakantan, R. Shen,
Y.-F. Wang, L. M. Greenberger and H.-R. Tsou, J. Med. Chem., 46, 49
(2003).
This compound was obtained as colorless prisms (0.93 g,
1
82%), mp 114-116˚ (acetone-petroleum ether); H nmr (deuteri-
ochloroform): δ 2.50 (s, 3H, 6-Me), 3.29-3.35 (m, 4H, 2 and 3-
H), 6.77 (s, 1H, 5-H), 7.35-7.45 ppm (m, 5H, aromatic H); ms:
+
m/z 228 [M+H] .
Anal. Calcd. for C H NS: C, 73.97; H, 5.76; N, 6.16. Found:
14 13
C, 73.87; H, 5.83; N, 6.14.
[16] F. Brody and P. R. Ruby, Pyridine and Its Derivatives, Vol 14,
Part 1, E. Klingsberg, ed, Interscience Publishers, Inc., New York, 1960,
p 99.
[17] J. M. Robinson, L. W. Brent, C. Chau, K. A. Floyd, S. L.
Gillham, T. L. McMahan, D. J. Magda, T. J. Motycka, M. J. Pack, A. L.
Roberts, L. A. Seally, S. L. Simpson, R. R. Smith and K. N. Zalesny, J.
Org. Chem., 57, 7352 (1992).
[18] K. Shibata, I. Katsuyama, H. Izoe, M. Matsui and H.
Muramatsu, J. Heterocyclic Chem., 30, 277 (1993).
[19] A. W. Erian, Chem. Rev., 93, 1991 (1993).
[20] I. Katsuyama, S. Ogawa, Y. Yamaguchi, K. Funabiki, M.
Matsui, H. Muramatsu and K. Shibata, Synthesis, 1321 (1997).
[21] H. Maruoka, M. Yamazaki and Y. Tomioka, J. Heterocyclic
Chem., 39, 743 (2002).
[22] K. Yamagata, Y. Tomioka, M. Yamazaki, T. Matsuda and K.
Noda, Chem. Pharm. Bull., 30, 4396 (1982).
[23] T. A. Blumenkopf and C. H. Heathcock, J. Am. Chem. Soc.,
105, 2354 (1983).
[24] M. Miyashita, T. Yanami, T. Kumazawa and A. Yoshikoshi, J.
Am. Chem. Soc., 106, 2149 (1984).
2,3-Dihydro-2,6-dimethyl-4-phenylthieno[2,3-b]pyridine (9b).
This compound was obtained as colorless prisms (1.01 g,
1
84%), mp 84-86˚ (diethyl ether-petroleum ether); H nmr (deu-
teriochloroform): δ 1.45 (d, J = 6.7 Hz, 3H, 2-Me), 2.50 (s, 3H, 6-
Me), 2.97 (dd, J = 7, 15.5 Hz, 1H, 3-H), 3.41 (dd, J = 7.3, 15.5
Hz, 1H, 3-H), 3.92-3.97 (m, 1H, 2-H), 6.78 (s, 1H, 5-H), 7.35-
+
7.46 ppm (m, 5H, aromatic H); ms: m/z 242 [M+H] .
Anal. Calcd. for C H NS: C, 74.65; H, 6.26; N, 5.80. Found:
15 15
C, 74.62; H, 6.33; N, 5.79.
2,3-Dihydro-6-methyl-3,4-diphenylthieno[2,3-b]pyridine (9c).
This compound was obtained as colorless prisms (1.36 g,
1
90%), mp 98-100˚ (acetone-petroleum ether); H nmr (deuteri-
ochloroform): δ 2.54 (s, 3H, 6-Me), 3.19 (dd, J = 3.1, 11.3 Hz,
1H, 2-H), 3.91 (dd, J = 8.5, 11.3 Hz, 1H, 2-H), 4.71 (dd, J = 3.1,
8.5 Hz, 1H, 3-H), 6.73 (s, 1H, 5-H), 6.93-7.00 (m, 4H, aromatic
+
H), 7.11-7.25 ppm (m, 6H, aromatic H); ms: m/z 304 [M+H] .
Anal. Calcd. for C H NS: C, 79.17; H, 5.65; N, 4.62. Found:
20 17
C, 79.22; H, 5.76; N, 4.56.
[25] M. Pfau, G. Revial, A. Guingant and J. d'Angelo, J. Am.
Chem. Soc., 107, 273 (1985).
[26] A. Guingant and H. Hammami, Terahedron: Asymmetry, 2,
411 (1991).
[27] M. Hamzaoui, O. Provot, F. Grégoire, C. Riche, A. Chiaroni,
F. Gay, H. Moskowitz and J. Mayrargue, Terahedron: Asymmetry, 8, 2085
(1997).
REFERENCES AND NOTES
[1] M. Balasubramanian and J. G. Keay, Comprehensive
Heterocyclic Chemistry II, Vol 5, A. R. Katritzky, C. W. Ress and E. F. V.
Scriven, eds, Pergamon Press, Oxford, 1996, p 245.
[28] M. Koketsu, T. Senda, K. Yoshimura and H. Ishihara, J.
Chem. Soc., Perkin Trans. 1, 453 (1999).
[29] R. Mahrwald, J. Prakt. Chem., 341, 595 (1999).
[30] W. A. White and H. Weingarten, J. Org. Chem., 32, 213
(1967).
[2] A. von Sprecher, M. Gerspacher, A. Beck, S. Kimmel, H.
Weinstner, G. P. Anderson, U. Niederhauser, N. Subramanian and M. A.
Bray, Bioorg. Med. Chem. Lett., 8, 965 (1998).
[31] H. Weingarten, J. P. Chupp and W. A. White, J. Org. Chem.,
[3] D. Dubé, M. Blouin, C. Brideau, C.-C. Chan, S. Desmarais, D.

646
H. Maruoka, M. Yamazaki and Y. Tomioka
Vol. 41
32, 3246 (1967).
[34] T. Tsuritani, S. Ito, H. Shinokubo and K. Oshima, J. Org.
Chem., 65, 5066 (2000).
[35] Z. Han, S. Uehira, T. Tsuritani, H. Shinokubo and K. Oshima,
Tetrahedron, 57, 987 (2001).
[32] R. Carlson, U. Larsson and L. Hansson, Acta Chem. Scand.,
46, 1211 (1992).
[33] M. Shi, J.-K. Jiang and Y.-S. Feng, Org. Lett., 2, 2397 (2000).