Synthesis of dihydrofuro[2,3-b]pyridines by the reaction of 2-amino-4,5-dihydro-3-furancarbonitriles with α,β-unsaturated carbonyl compounds

Article abstract of DOI:10.1002/jhet.5570390420

The reactions of 2-amino-4,5-dihydro-3-furancarbonitriles 1a-d with α,β-unsaturated carbonyl compounds in the presence of sodium ethoxide (0.1 equivalent) gave the corresponding Michael adducts 2a-d, 3a-d and 4a-d. Compounds 2a-d and 3a-c reacted with sodium alkoxide (1 equivalent) to yield the corresponding 7a-alkoxyhexahydrofuro [2,3-b]pyridines 5a-d, 6a-d, 7a-c e and 8a-c. Treatment of 5a-d, 6a-d, 7a-c and 8a-c with potassium tert-butoxide produced the corresponding dihydrofuro[2,3-b]pyridines 9a-d and 10a-c. The reaction of 4a-c with sodium ethoxide (1 equivalent) afforded the corresponding dihydrofuro[2,3-b]pyridines 11a-c.

Full text of DOI:10.1002/jhet.5570390420

Jul-Aug 2002
Synthesis of Dihydrofuro[2,3-b]pyridines by the
Reaction of 2-Amino-4,5-dihydro-3-furancarbonitriles
with α,β-Unsaturated Carbonyl Compounds
743
Hiroshi Maruoka, Motoyoshi Yamazaki and Yukihiko Tomioka*
Faculty of Pharmaceutical Sciences, Fukuoka University,
8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan
Received December 10, 2001
The reactions of 2-amino-4,5-dihydro-3-furancarbonitriles 1a-d with α,β-unsaturated carbonyl com-
pounds in the presence of sodium ethoxide (0.1 equivalent) gave the corresponding Michael adducts 2a-d,
3a-d and 4a-d. Compounds 2a-d and 3a-c reacted with sodium alkoxide (1 equivalent) to yield the corre-
sponding 7a-alkoxyhexahydrofuro[2,3-b]pyridines 5a-d, 6a-d, 7a-c and 8a-c. Treatment of 5a-d, 6a-d, 7a-c
and 8a-c with potassium tert-butoxide produced the corresponding dihydrofuro[2,3-b]pyridines 9a-d and
10a-c. The reaction of 4a-c with sodium ethoxide (1 equivalent) afforded the corresponding dihydro-
furo[2,3-b]pyridines 11a-c.
J. Heterocyclic Chem., 39, 743 (2002).
1
The ir and H nmr spectra of 2-amino-4,5-dihydro-3-
furancarbonitriles 1a-d [1] indicate that 1 exist as the pri-
mary enaminonitrile forms [2] rather than the imine forms.
Therefore, depending on the experimental conditions used,
electrophiles are expected to attack at either the enamino
nitrogen atom or the β-carbon atom (the 3-position of 1) in
the enamine. In fact, we showed that benzoyl chloride in
the presence of sodium hydride attacks the 3-position of 1
to give the intermediate 3-benzoyl-2-imino-3-furancar-
bonitriles which undergo a ring opening to provide the
malononitrile derivatives [3], whereas benzoyl chloride in
pyridine attacks the amino group of 1 to yield 2-benza-
mido-4,5-dihydro-3-furancarbonitriles [1]. When α,β-
unsaturated carbonyl compounds are used as electrophiles,
conjugate addition of the β-carbon atom of enamines to
α,β-unsaturated carbonyl compounds takes place to pro-
duce the initial Michael adducts [4,5]. We now report the
results of the reactions of 1 with α,β-unsaturated carbonyl
compounds in the presence of a base.
When a solution of 1a-d with methyl vinyl ketone and
sodium ethoxide (0.1 equivalent) in diethyl ether or
tetrahydrofuran was stirred at room temperature, the
expected Michael adducts 2a-d were obtained. The conju-
gate addition of the amino group of 1 to methyl vinyl
ketone was not observed. The ir spectra of 2a-d display a
-1
band at near 2230 cm due to a non-conjugated cyano
group, whereas those of 1a-d show a conjugated cyano
-1
1
band in the 2170~2190 cm region. The H nmr spectra of
2a-d exhibit a one-proton singlet at near δ 7.30 attributable
to an imino group, whereas those of 1a-d appear as a two-
proton singlet at near δ 5 assignable to an amino group.
Compounds 1a-d reacted with benzalacetone and cin-
namaldehyde under the same conditions to give the corre-
sponding Michael adducts 3a-d and 4a-d. Elemental
analyses and spectral data of 2-4 are consistent with the
assigned structures.
Primary enamines and α,β-unsaturated carbonyl com-
pounds are the components of the Hantzsch pyridine synthe-
sis [6-8]. Several investigators have reported that primary
enaminonitriles react with α,β-unsaturated carbonyl com-
pounds in the presence of a base to give the pyridines [7, 9-
12]. The Hantzsch synthesis is believed to involve the
adduct initially formed by a Michael addition of an enamine
to an α,β-unsaturated carbonyl compound. Generally, the
adduct has not been isolated under the reaction conditions

744
H. Maruoka, M. Yamazaki and Y. Tomioka
Vol. 39
because of its fast intramolecular cyclization to yield the
pyridine derivative. Hence, we investigated the conversion
of the Michael adducts 2-4 into the pyridines.
cyclization occurred and 4a-d were recovered unchanged.
However, under refluxing ethanol, the reaction of 4a-c
with sodium ethoxide led to the formation of the dihydro-
furo[2,3-b]pyridines 11a-c. In this case, ethanol adducts
such as 5 and 6 could not be obtained and intramolecular
cyclization of 4d did not proceed.
The formation of 5-8 and 9-11 can be explained in terms
of Scheme 2. A Michael addition of 1 to α,β-unsaturated
carbonyl compounds gives the adducts 2-4 which undergo
intramolecular cyclization and dehydration to form the
intermediate dihydropyridines A. Elimination of hydrogen
cyanide from A under basic conditions produces 9-11.
Conjugate addition of ethanol or methanol to A results in
the formation of 5 and 7 or 6 and 8. Unfortunately, the key
intermediate A could not be isolated.
Treatment of 2a-d or 3a-c with sodium ethoxide (1
equivalent) in ethanol at room temperature underwent
cyclization to give the corresponding 7a-ethoxyhexa-
hydrofuro[2,3-b]pyridines 5a-d or 7a-c. Similarly, the
reaction of 2a-d or 3a-c with sodium methoxide afforded
the 7a-methoxyhexahydrofuro[2,3-b]pyridines 6a-d or
8a-c. In contrast, when 3d was treated with sodium ethox-
ide or methoxide, a retro-Michael reaction took place to
1
furnish 1d. The H nmr spectra of 5c, 6b, 6c and 8b show
two triplets at near δ 1.2 for a methyl group of an ethoxy
group of 5c, two doublets at near δ 1.4 for a 2-methyl
group of 6b and 8b, two singlets at near δ 2.1 for a
6-methyl group of 5c, 6b, 6c and 8b, and two singlets at
near δ 3.6 for a methyl group of a methoxy group of 6b, 6c
and 8b. These observations indicate that 5c, 6b, 6c and 8b
exist as two diastereomers, which would probably be
formed by an effect of the configuration of methyl or
phenyl group at the 2-position, ethoxy or methoxy group
and cyano group. The reaction of 1c with benzalacetone
and sodium ethoxide (1 equivalent) in ethanol gave 7c in
42% yield. In a similar way, by the reaction of 1c with ben-
zaldehyde and acetone, 7c was also obtained in a some-
what lower yield of 25%. The adducts 5a-d, 6a-d, 7a-c and
8a-c were treated with potassium tert-butoxide in reflux-
ing tert-butyl alcohol to produce the dihydrofuro-
[2,3-b]pyridines 9a-d and 10a-c. On the other hand, when
a solution of 4a-d with sodium ethoxide (1 equivalent) in
ethanol was stirred overnight at room temperature, no
Compound 5d was converted into 6d by treatment with
sodium methoxide in refluxing methanol, and conversely,
6d was transformed into 5d by treatment with sodium
ethoxide in refluxing ethanol, and 9d was not obtained. This
interconversion probably proceeds through the intermediate
B (Scheme 2), which would be resistant to elimination of
hydrogen cyanide to give 9d due to the absence of phenyl
group at the 4-position. Our results show that sodium ethox-
ide/ethanol or sodium methoxide/methanol system (milder
condition) provides a unique possibility to afford Michael
adducts 2-4 and alcohol adducts 5-8. Aromatization of 5-8
with potassium tert-butoxide in refluxing tert-butyl alcohol
proceeds smoothly to give 9 and 10 in good yields. While,
in the case of intramolecular cyclization of 4, sodium ethox-
ide in refluxing ethanol system is better than potassium tert-
butoxide system (stronger condition).

Jul-Aug 2002
Synthesis of Dihydrofuro[2,3-b]pyridines
745
(deuteriochloroform): δ 1.41 (d, J = 6 Hz, 3H, 5-CH ), 1.80 (dd,
J = 10.5, 13 Hz, 2H, 1'-H), 2.10-2.37 (m, 2H, 4-H), 2.21 (s, 3H,
Subsequently, we undertook a one-pot synthesis of 9-11
from 1 and α ,β-unsaturated carbonyl compounds.
Attempts to prepare 9c or 10c from 1c and methyl vinyl
ketone or benzalacetone according to the method of
Robinson et al. [10] or Shibata et al. [12] were unsuccess-
ful; however, a mixture of 1, benzalacetone or cinnamalde-
hyde and sodium ethoxide (2 equivalents) in ethanol
stirred overnight at room temperature, and then refluxed
for 1 hour provided 10a-c and 11a-c. In the case of 9a-d,
we carried out elimination of hydrogen cyanide by use of
potassium tert-butoxide.
3
COCH ), 2.47-2.81 (m, 2H, 2'-H), 4.43-4.85 (m, 1H, 5-H), 7.24
3
+
ppm (br s, 1H, NH); ms: m/z 195 [M+H] .
Anal. Calcd. for C
H N O : C, 61.84; H, 7.27; N, 14.42.
10 14 2 2
Found: C, 61.95; H, 7.11; N, 14.53.
Tetrahydro-2-imino-3-(3-oxobutyl)-5-phenyl-3-furancarbonitrile
(2c).
This compound was obtained as colorless needles (1.72 g,
67%), mp 114-116° (acetone-petroleum ether); ir (potassium bro-
-1
1
mide): ν 3220 (NH), 2230 (C≡N), 1705 (C=O) cm ; H nmr
(deuteriochloroform): δ 2.05-2.62 (m, 4H, 4-H, 1'-H), 2.20 (s,
3H, COCH ), 2.73-3.13 (m, 2H, 2'-H), 5.52 (dd, J = 5.5, 10.5
3
Hz, 1H, 5-H), 7.30-7.36 (m, 5H, aromatic H), 7.46 ppm (br s, 1H,
NH); ms: m/z 257 [M+H] .
EXPERIMENTAL
+
Anal. Calcd. for C
Found: C, 69.98; H, 6.37; N, 10.66.
H N O : C, 70.29; H, 6.29; N, 10.93.
15 16 2 2
All melting points are uncorrected. The ir spectra were
recorded on a JASCO FT/IR-230 spectrometer. The H nmr spec-
1
tra were recorded on a HITACHI R-90 H spectrometer (90 MHz).
Chemical shifts (δ) are reported in parts per million (ppm) rela-
tive to tetramethylsilane as internal standard. Positive FAB mass
spectra were obtained on a JEOL JMS-HX 110 spectrometer.
Elemental analyses were performed on a HERAUS CHNO-
RAPID analyzer or YANACO MT-6 CHN analyzer.
Tetrahydro-2-imino-3-(3-oxobutyl)-4-phenyl-3-furancarbonitrile
(2d).
This compound was obtained as colorless needles (2.19 g,
86%), mp 147-148˚ (chloroform-petroleum ether); ir (potassium
-1
1
bromide): ν 3192 (NH), 2232 (C≡N), 1692 (C=O) cm ; H nmr
(deuteriochloroform): δ 2.09-2.35 (m, 2H, 1'-H), 2.16 (s, 3H,
General Procedure for the Preparation of Michael adducts 2, 3
and 4.
COCH ), 2.41-3.31 (m, 2H, 2'-H), 3.50 (t, J = 7 Hz, 1H, 4-H),
3
4.49-4.70 (m, 2H, 5-H), 7.29-7.46 ppm (m, 6H, NH, aromatic H);
+
ms: m/z 257 [M+H] .
To a solution of sodium (23 mg, 1 mmole) in anhydrous
ethanol (2 ml) were added 1a-d (10 mmoles) and methyl vinyl
ketone (0.84 g, 12 mmoles), benzalacetone (1.75 g, 12 mmoles)
or cinnamaldehyde (1.58 g, 12 mmoles) and tetrahydrofuran (20
ml, in the case of the preparation of 2a, b) or diethyl ether (20 ml,
2c, 2d, 3a-d and 4a-d) with stirring. The mixture was stirred at
room temperature for 5 hours (2a, b) or 2 hours (2c, 2d, 3a-d and
4a-d). The reaction mixture was neutralized with acetic acid (60
mg, 1 mmole) with stirring and ice-cooling, and then cold water
was added to the resulting mixture. Further processing of the
resulting mixture is described in the following paragraphs.
(A) The resulting mixture was extracted with ethyl acetate.
The extract was dried over anhydrous sodium sulfate and concen-
trated in vacuo. The residue was recrystallized from an appropri-
ate solvent to give 2a, 2b, 2d and 3b.
Anal. Calcd. for C
Found: C, 70.25; H, 6.48; N, 10.70.
H N O : C, 70.29; H, 6.29; N, 10.93.
15 16 2 2
Tetrahydro-2-imino-3-(3-oxo-1-phenylbutyl)-3-furancarbonitrile
(3a).
This compound was obtained as colorless needles (1.24 g, 48%),
mp 157-158° (acetone-petroleum ether); ir (potassium bromide): ν
3214 (NH), 2232 (C≡N), 1707 (C=O) cm ; H nmr (deuterio-
chloroform): δ 1.65 (s, 3H, COCH ), 2.06-2.52 (m, 4H, 4-H, 2'-H),
3.16 (t, J = 8 Hz, 1H, 1'-H), 4.17-4.47 (m, 2H, 5-H), 7.37 (s, 5H,
aromatic H), 7.37 ppm (br s, 1H, NH); ms: m/z 257 [M+H] .
Anal. Calcd. for C
Found: C, 70.26; H, 6.47; N, 10.73.
-1
1
3
+
H N O : C, 70.29; H, 6.29; N, 10.93.
15 16 2 2
Tetrahydro-2-imino-5-methyl-3-(3-oxo-1-phenylbutyl)-3-furan-
carbonitrile (3b).
(B) The precipitate was isolated by filtration, washed with
water, dried and recrystallized from an appropriate solvent to
yield 2c, 3a, 3c, 3d and 4a-d.
This compound was obtained as colorless needles (1.31 g,
49%), mp 162-164° (acetone-petroleum ether); ir (potassium bro-
mide): ν 3246 (NH), 2232 (C≡N), 1702 (C=O) cm ; H nmr
Tetrahydro-2-imino-3-(3-oxobutyl)-3-furancarbonitrile (2a).
-1
1
(deuteriochloroform): δ 1.46 (d, J = 6 Hz, 3H, 5-CH ), 1.63 (s,
This compound was obtained as colorless prisms (1.10 g,
61%), mp 75-77° (acetone-petroleum ether); ir (potassium bro-
mide): ν 3210 (NH), 2240 (C≡N), 1705 (C=O) cm ; H nmr
(deuteriochloroform): δ 2.09-3.12 (m, 6H, 4-H, 1'-H, 2'-H), 2.21
3
3H, COCH ), 1.84-2.06 (m, 1H, 4-H), 2.26-2.58 (m, 3H, 4-H,
3
-1
1
2'-H), 3.22 (dd, J = 7.5, 16 Hz, 1H, 1'-H), 4.55-4.82 (m, 1H, 5-H),
7.35 (s, 5H, aromatic H), 7.35 ppm (br s, 1H, NH); ms: m/z 271
+
[M+H] .
(s, 3H, COCH ), 4.32 (t, J = 6.5 Hz, 2H, 5-H), 7.30 ppm (br s,
3
+
Anal. Calcd. for C
H N O : C, 71.09; H, 6.71; N, 10.36.
16 18 2 2
1H, NH); ms: m/z 181 [M+H] .
Found: C, 71.11; H, 6.73; N, 10.32.
Anal. Calcd. for C
H N O : C, 59.99; H, 6.71; N, 15.35.
19 12 2 2
Found: C, 60.05; H, 6.43; N, 15.10.
Tetrahydro-2-imino-3-(3-oxo-1-phenylbutyl)-5-phenyl-3-furan-
carbonitrile (3c).
Tetrahydro-2-imino-5-methyl-3-(3-oxobutyl)-3-furancarbonitrile
(2b).
This compound was obtained as colorless needles (2.75 g,
83%), mp 184-185° (chloroform-petroleum ether); ir (potassium
This compound was obtained as colorless needles (0.91 g,
47%), mp 102-104° (acetone-petroleum ether); ir (potassium bro-
mide): ν 3245 (NH), 2230 (C≡N), 1700 (C=O) cm ; H nmr
-1
1
bromide): ν 3230 (NH), 2240 (C≡N), 1705 (C=O) cm ; H nmr
(DMSO-d ): δ 1.49 (s, 3H, COCH ), 2.09-2.24 (m, 2H, 4-H),
-1
1
6
3

746
H. Maruoka, M. Yamazaki and Y. Tomioka
Vol. 39
2.39-2.89 (m, 2H, 2'-H), 3.51 (dd, J = 4.5, 11 Hz, 1H, 1'-H), 5.49
(dd, J = 5, 10.5 Hz, 1H, 5-H), 5.61 (br s, 1H, NH), 7.31-7.53 ppm
(m, 10H, aromatic H); ms: m/z 333 [M+H] .
3.95-4.64 (m, 3H, 4-H, 5-H), 5.20-5.35 (m, 1H, CHO), 5.96 (d,
J = 3 Hz, 1H, NH), 6.97-7.32 ppm (m, 10H, aromatic H); ms:
m/z 319 [M+H] .
+
+
Anal. Calcd. for C
H
N O : C, 75.88; H, 6.06; N, 8.43.
Anal. Calcd. for C H N O : C, 75.45; H, 5.70; N, 8.80.
21 20
2
2
20 18 2 2
Found: C, 75.70; H, 6.00; N, 8.49.
Found: C, 75.45; H, 5.65; N, 8.86.
Tetrahydro-2-imino-3-(3-oxo-1-phenylbutyl)-4-phenyl-3-furan-
carbonitrile (3d).
General Procedure for the Preparation of 5a-d, 6a-d, 7a-c and
8a-c from 2a-d or 3a-c.
This compound was obtained as colorless needles (2.29 g,
69%), mp 185-187° (chloroform-petroleum ether); ir (potassium
A mixture of 2a-d or 3a-c (10 mmoles) in a solution of sodium
(0.23 g, 10 mmoles) in anhydrous ethanol (20 ml) or anhydrous
methanol (20 ml) was stirred at room temperature overnight, and
then cold water was added to the reaction mixture. The resulting
mixture was extracted with chloroform. The extract was dried
over anhydrous sodium sulfate and concentrated in vacuo. The
residue was purified by column chromatography on silica gel
with methylene chloride as the eluent to give 5a-d, 6a-d, 7a-c
and 8a-c.
-1
1
bromide): ν 3221 (NH), 2240 (C≡N), 1694 (C=O) cm ; H nmr
(DMSO-d ): δ 1.45 (s, 3H, COCH ), 1.81-2.37 (m, 2H, 2'-H),
6
3
3.41 (dd, J = 3.5, 12 Hz, 1H, 1'-H), 3.92-4.63 (m, 3H, 4-H, 5-H),
5.66 (br s, 1H, NH), 6.98-7.31 ppm (m, 10H, aromatic H); ms:
+
m/z 333 [M+H] .
Anal. Calcd. for C
H N O : C, 75.88; H, 6.06; N, 8.43.
21 20 2 2
Found: C, 75.70; H, 6.18; N, 8.57.
7a-Ethoxy-2,3,3a,4,5,7a-hexahydro-6-methylfuro[2,3-b]pyri-
dine-3a-carbonitrile (5a).
Tetrahydro-2-imino-3-(3-phenylpropanal-3-yl)-3-furancarboni-
trile (4a).
This compound was obtained as colorless plates (0.79 g, 38%),
mp 46-48° (diethyl ether-petroleum ether); ir (potassium bro-
This compound was obtained as colorless prisms (1.96 g,
81%), mp 204-205° dec (methanol-petroleum ether); ir (potas-
sium bromide): ν 3220 (NH), 2230 (C≡N), 1695 (C=O) cm ; H
-1
1
-1
1
mide): ν 2240 (C≡N) cm ; H nmr (deuteriochloroform): δ 1.23
(t, J = 7 Hz, 3H, OCH CH ), 1.63-2.95 (m, 6H, 3-H, 4-H, 5-H),
nmr (DMSO-d ): δ 1.80-2.78 (m, 4H, 4-H, 2'-H), 3.29 (dd, J = 3,
2
3
6
2.06 (s, 3H, 6-CH ), 3.78-4.12 ppm (m, 4H, 2-H, OCH CH );
ms: m/z 209 [M+H] .
12 Hz, 1H, 3'-H), 3.99-4.53 (m, 2H, 5-H), 5.26-5.36 (m, 1H,
CHO), 5.87 (d, J = 4 Hz, 1H, NH), 7.40 ppm (s, 5H, aromatic H);
ms: m/z 243 [M+H] .
3
2
3
+
+
Anal. Calcd. for C H N O : C, 63.44; H, 7.74; N, 13.45.
11 16
2 2
Anal. Calcd. for C
H
N O : C, 69.41; H, 5.82; N, 11.56.
Found: C, 63.65; H, 7.59; N, 13.23.
14 14
2 2
Found: C, 69.41; H, 5.89; N, 11.45.
7a-Ethoxy-2,3,3a,4,5,7a-hexahydro-2,6-dimethylfuro[2,3-b]-
pyridine-3a-carbonitrile (5b).
Tetrahydro-2-imino-5-methyl-3-(3-phenylpropanal-3-yl)-3-
furancarbonitrile (4b).
This compound was obtained as colorless needles (0.84 g,
38%), mp 54-55° (diethyl ether-petroleum ether); ir (potassium
This compound was obtained as colorless prisms (1.25 g,
49%), mp 186-187° (acetone-petroleum ether); ir (potassium bro-
-1
1
bromide): ν 2242 (C≡N) cm ; H nmr (deuteriochloroform): δ
1.23 (t, J = 7 Hz, 3H, OCH CH ), 1.30 (d, J = 6.5 Hz, 3H,
-1
1
mide): ν 3180 (NH), 2240 (C≡N), 1695 (C=O) cm ; H nmr
(DMSO-d ): δ 1.37 (d, J = 6 Hz, 3H, 5-CH ), 1.88-2.38 (m, 4H,
2
3
2-CH ), 1.56-2.48 (m, 5H, 3-H, 4-H, 5-H), 2.07 (s, 3H, 6-CH ),
3
3
6
3
2.88 (dd, J = 8.5, 12.5 Hz, 1H, 5-H), 3.76-4.48 ppm (m, 3H, 2-H,
4-H, 2'-H), 3.26 (dd, J = 3.5, 12.5 Hz, 1H, 3'-H), 4.35-4.79 (m,
1H, 5-H), 5.03-5.24 (m, 1H, CHO), 5.99 (d, J = 5 Hz, 1H, NH),
7.37 ppm (s, 5H, aromatic H); ms: m/z 257 [M+H] .
+
OCH CH ); ms: m/z 223 [M+H] .
2
3
+
Anal. Calcd. for C H N O : C, 64.84; H, 8.16; N, 12.60.
12 18 2 2
Anal. Calcd. for C
H
N O : C, 70.29; H, 6.29; N, 10.93.
Found: C, 64.64; H, 8.16; N, 12.38.
15 16
2 2
Found: C, 70.29; H, 6.37; N, 10.88.
7a-Ethoxy-2,3,3a,4,5,7a-hexahydro-6-methyl-2-phenylfuro-
Tetrahydro-2-imino-5-phenyl-3-(3-phenylpropanal-3-yl)-3-
[2,3-b]pyridine-3a-carbonitrile (5c).
furancarbonitrile (4c).
This compound was obtained as colorless needles (1.50 g,
53%), mp 102-104° (acetone-petroleum ether); ir (potassium bro-
This compound was obtained as colorless needles (2.36 g,
74%), mp 196-197° (chloroform-petroleum ether); ir (potassium
bromide): ν 3210 (NH), 2240 (C≡N), 1690 (C=O) cm ; H nmr
-1
1
mide): ν 2241 (C≡N) cm ; H nmr (deuteriochloroform): δ 1.17
and 1.28 (t, J = 7 Hz, 3H, OCH CH ), 1.69-2.18 (m, 3H, 3-H,
-1
1
2
3
(DMSO-d ): δ 1.89-2.73 (m, 4H, 4-H, 2'-H), 3.45 (dd, J = 3.5,
4-H), 2.09 and 2.11 (s, 3H, 6-CH ), 2.30-2.64 (m, 2H, 3-H, 5-H),
6
3
12.5 Hz, 1H, 3'-H), 5.13-5.29 (m, 1H, CHO), 5.42-5.82 (m, 1H,
5-H), 6.08 (br s, 1H, NH), 7.23-7.53 ppm (m, 10H, aromatic H);
ms: m/z 319 [M+H] .
2.97 and 3.19 (dd, J = 10, 12 Hz, dd, J = 8.5, 12.5 Hz, 1H, 5-H),
3.78-4.25 (m, 2H, OCH CH ), 5.09-5.32 (m, 1H, 2-H), 7.31-7.36
2
3
+
+
ppm (m, 5H, aromatic H); ms: m/z 285 [M+H] .
Anal. Calcd. for C
H
N O •0.1H O: C, 75.03; H, 5.73; N,
Anal. Calcd. for C N O : C, 71.81; H, 7.09; N, 9.85.
H
17 20 2 2
20 18
2
2
2
8.75. Found: C, 74.95; H, 5.75; N, 8.73.
Found: C, 72.07; H, 7.08; N, 9.94.
Tetrahydro-2-imino-4-phenyl-3-(3-phenylpropanal-3-yl)-3-furan-
7a-Ethoxy-2,3,3a,4,5,7a-hexahydro-6-methyl-3-phenylfuro-
carbonitrile (4d).
[2,3-b]pyridine-3a-carbonitrile (5d).
This compound was obtained as colorless needles (2.45 g,
77%), mp 200-201° (chloroform-petroleum ether); ir (potas-
This compound was obtained as colorless needles (1.36 g,
48%), mp 138-140° (acetone-petroleum ether); ir (potassium
-1
-1
1
sium bromide): ν 3165 (NH), 2230 (C≡N), 1690 (C=O) cm ;
bromide): ν 2242 (C≡N) cm ; H nmr (deuteriochloroform): δ
1.34 (t, J = 7 Hz, 3H, OCH CH ), 1.70-2.09 (m, 2H, 4-H), 2.09
1
H nmr (DMSO-d ): δ 1.72-1.92 (m, 1H, 2'-H), 2.45 (dd, J =
6
2
3
5, 13 Hz, 1H, 2'-H), 3.44 (dd, J = 3.5, 12.5 Hz, 1H, 3'-H),
(s, 3H, 6-CH ), 2.31-2.50 (m, 2H, 5-H), 3.34 (t, J = 8.5 Hz, 1H,
3

Jul-Aug 2002
Synthesis of Dihydrofuro[2,3-b]pyridines
747
3-H), 3.94-4.44 (m, 4H, 2-H, OCH CH ), 7.31-7.49 ppm (m, 5H,
aromatic H); ms: m/z 285 [M+H] .
Anal. Calcd. for C H N O : C, 71.81; H, 7.09; N, 9.85.
17 20 2 2
Found: C, 71.81; H, 7.09; N, 9.87.
2
3
+
Anal. Calcd. for C N O : C, 71.81; H, 7.09; N, 9.85.
Found: C, 72.07; H, 7.05; N, 9.79.
H
17 20
2 2
7a-Ethoxy-2,3,3a,4,5,7a-hexahydro-2,6-dimethyl-4-phenyl-
furo[2,3-b]pyridine-3a-carbonitrile (7b).
2,3,3a,4,5,7a-Hexahydro-7a-methoxy-6-methylfuro[2,3-b]pyri-
dine-3a-carbonitrile (6a).
This compound was obtained as colorless columns (0.53 g,
18%), mp 122-124° (acetone-petroleum ether); ir (potassium bro-
-1
1
mide): ν 2232 (C≡N) cm ; H nmr (deuteriochloroform): δ 1.25
(t, J = 7 Hz, 3H, OCH CH ), 1.37 (d, J = 6 Hz, 3H, 2-CH ), 2.10
This compound was obtained as colorless columns (0.23 g,
12%), mp 62-63° (diethyl ether-petroleum ether); ir (potassium
2
3
3
-1
1
(s, 3H, 6-CH ), 2.22-2.99 (m, 5H, 3-H, 4-H, 5-H), 3.86-4.24 (m,
bromide): ν 2240 (C≡N) cm ; H nmr (deuteriochloroform): δ
1.67-2.94 (m, 6H, 3-H, 4-H, 5-H), 2.08 (s, 3H, 6-CH ), 3.56 (s,
3
2H, OCH CH ), 4.34-4.59 (m, 1H, 2-H), 7.39 ppm (s, 5H, aro-
2
3
3
+
matic H); ms: m/z 299 [M+H] .
3H, OCH ), 3.99 ppm (dd, J = 6.5, 8.5 Hz, 2H, 2-H); ms: m/z
3
+
Anal. Calcd. for C N O : C, 72.46; H, 7.43; N, 9.39.
H
195 [M+H] .
18 22
2 2
Found: C, 72.47; H, 7.49; N, 9.38.
Anal. Calcd. for C
H N O : C, 61.84; H, 7.27; N, 14.42.
10 14 2 2
Found: C, 62.13; H, 7.18; N, 14.25.
7a-Ethoxy-2,3,3a,4,5,7a-hexahydro-6-methyl-2,4-diphenyl-
furo[2,3-b]pyridine-3a-carbonitrile (7c).
2,3,3a,4,5,7a-Hexahydro-7a-methoxy-2,6-dimethylfuro[2,3-b]-
pyridine-3a-carbonitrile (6b).
This compound was obtained as colorless prisms (1.55 g,
43%), mp 188-190° (acetone-petroleum ether); ir (potassium
This compound was obtained as colorless prisms (0.25 g,
12%), mp 68-69° (diethyl ether-petroleum ether); ir (potassium
-1
1
bromide): ν 2251 (C≡N) cm ; H nmr (deuteriochloroform): δ
1.17 (t, J = 7 Hz, 3H, OCH CH ), 2.15 (s, 3H, 6-CH ), 2.37-2.89
-1
1
2
3
3
bromide): ν 2242 (C≡N) cm ; H nmr (deuteriochloroform): δ
1.31 and 1.37 (t, J = 6.5 Hz, 3H, 2-CH ), 1.58-1.98 (m, 2H, 4-H),
(m, 4H, 3-H, 4-H, 5-H), 3.07-3.31 (m, 1H, 4-H), 3.71-4.35 (m,
2H, OCH CH ), 5.25-5.44 (m, 1H, 2-H), 7.25-7.50 ppm (m,
3
2
3
2.06 and 2.08 (s, 3H, 6-CH ), 2.28-2.49 (m, 3H, 3-H, 5-H), 2.87
3
+
10H, aromatic H); ms: m/z 361 [M+H] .
(dd, J = 8.5, 12.5 Hz, 1H, 5-H), 3.54 and 3.58 (s, 3H, OCH ),
3
Anal. Calcd. for C N O : C, 76.64; H, 6.71; N, 7.77.
H
+
23 24
2 2
4.15-4.46 ppm (m, 1H, 2-H); ms: m/z 209 [M+H] .
Found: C, 76.92; H, 6.63; N, 7.86.
Anal. Calcd. for C H N O : C, 63.44; H, 7.74; N, 13.45.
11 16
2 2
Found: C, 63.70; H, 7.96; N, 13.77.
2,3,3a,4,5,7a-Hexahydro-7a-methoxy-6-methyl-4-phenyl-
furo[2,3-b]pyridine-3a-carbonitrile (8a).
2,3,3a,4,5,7a-Hexahydro-7a-methoxy-6-methyl-2-phenyl-
This compound was obtained as colorless prisms (0.52 g,
19%), mp 153-154° (acetone-petroleum ether); ir (potassium bro-
furo[2,3-b]pyridine-3a-carbonitrile (6c).
This compound was obtained as colorless needles (0.68 g,
25%), mp 98-100° (acetone-petroleum ether); ir (potassium bro-
-1
1
mide): ν 2241 (C≡N) cm ; H nmr (deuteriochloroform): δ 2.13
(s, 3H, 6-CH ), 2.13-2.95 (m, 5H, 3-H, 4-H, 5-H), 3.61 (s, 3H,
3
-1
1
mide): ν 2236 (C≡N) cm ; H nmr (deuteriochloroform): δ 1.90-
OCH ), 3.96-4.14 (m, 2H, 2-H), 7.37 ppm (s, 5H, aromatic H);
3
2.15 (m, 2H, 4-H), 2.10 and 2.13 (s, 3H, 6-CH ), 2.31-2.65 (m,
3H, 3-H, 5-H), 2.85-3.30 (m, 1H, 5-H), 3.60 and 3.63 (s, 3H,
+
3
ms: m/z 271 [M+H] .
Anal. Calcd. for C
H N O : C, 71.09; H, 6.71; N, 10.36.
16 18 2 2
OCH ), 5.09-5.28 (m, 1H, 2-H), 7.26-7.37 ppm (m, 5H, aromatic
3
Found: C, 71.12; H, 6.72; N, 10.33.
+
H); ms: m/z 271 [M+H] .
2,3,3a,4,5,7a-Hexahydro-7a-methoxy-2,6-dimethyl-4-phenyl-
furo[2,3-b]pyridine-3a-carbonitrile (8b).
Anal. Calcd. for C
Found: C, 71.36; H, 6.43; N, 10.54.
H N O : C, 71.09; H, 6.71; N, 10.36.
16 18 2 2
This compound was obtained as colorless prisms (0.42 g,
15%), mp 151-153° (acetone-petroleum ether); ir (potassium bro-
2,3,3a,4,5,7a-Hexahydro-7a-methoxy-6-methyl-3-phenyl-
furo[2,3-b]pyridine-3a-carbonitrile (6d).
-1
1
mide): ν 2242 (C≡N) cm ; H nmr (deuteriochloroform): δ 1.38
and 1.39 (d, J = 6.5 Hz, 3H, 2-CH ), 2.12 and 2.13 (s, 3H, 6-
This compound was obtained as colorless needles (0.90 g,
33%), mp 167-169° (acetone-petroleum ether); ir (potassium bro-
3
CH ), 1.72-3.07 (m, 5H, 3-H, 4-H, 5-H), 3.60 and 3.63 (s, 3H,
3
-1
1
mide): ν 2242 (C≡N) cm ; H nmr (deuteriochloroform): δ 1.84-
OCH ), 4.18-4.60 (m, 1H, 2-H), 7.37 ppm (s, 5H, aromatic H);
3
+
2.17 (m, 2H, 4-H), 2.11 (s, 3H, 6-CH ), 2.32-2.52 (m, 2H, 5-H),
ms: m/z 285 [M+H] .
3
3.36 (t, J = 9 Hz, 1H, 3-H), 3.66 (s, 3H, OCH ), 4.01 (t, J = 9
3
Anal. Calcd. for C H N O : C, 71.81; H, 7.09; N, 9.85.
17 20 2 2
Hz, 1H, 2-H), 4.35 (t, J = 9 Hz, 1H, 2-H), 7.25-7.47 ppm (m, 5H,
Found: C, 71.86; H, 7.08; N, 9.87.
+
aromatic H); ms: m/z 271 [M+H] .
2,3,3a,4,5,7a-Hexahydro-7a-methoxy-6-methyl-2,4-diphenyl-
furo[2,3-b]pyridine-3a-carbonitrile (8c).
Anal. Calcd. for C
H N O : C, 71.09; H, 6.71; N, 10.36.
16 18 2 2
Found: C, 71.10; H, 6.71; N, 10.39.
This compound was obtained as colorless prisms (0.48 g,
14%), mp 188-190° (acetone-petroleum ether); ir (potassium bro-
7a-Ethoxy-2,3,3a,4,5,7a-hexahydro-6-methyl-4-phenylfuro-
[2,3-b]pyridine-3a-carbonitrile (7a).
-1
1
mide): ν 2242 (C≡N) cm ; H nmr (deuteriochloroform): δ 2.19
(s, 3H, 6-CH ), 2.11-3.09 (m, 5H, 3-H, 4-H, 5-H), 3.70 (s, 3H,
This compound was obtained as colorless prisms (0.54 g,
19%), mp 114-116° (acetone-petroleum ether); ir (potassium bro-
3
OCH ), 5.25 (dd, J = 5, 8.5 Hz, 1H, 2-H), 6.97-7.08 (m, 2H, aro-
3
-1
1
matic H), 7.17-7.33 (m, 3H, aromatic H), 7.37 ppm (s, 5H, aro-
mide): ν 2240 (C≡N) cm ; H nmr (deuteriochloroform): δ 1.25
(t, J = 7 Hz, 3H, OCH CH ), 2.12 (s, 3H, 6-CH ), 2.20-2.94 (m,
+
matic H); ms: m/z 347 [M+H] .
2
3
3
5H, 3-H, 4-H, 5-H), 3.93-4.13 (m, 2H, OCH CH ), 7.37 ppm (s,
5H, aromatic H); ms: m/z 285 [M+H] .
Anal. Calcd. for C H N O : C, 76.28; H, 6.40; N, 8.09.
Found: C, 76.29; H, 6.47; N, 8.05.
2
3
22 22 2 2
+

748
H. Maruoka, M. Yamazaki and Y. Tomioka
Vol. 39
The Preparation of 7c from 1c and Benzalacetone.
Anal. Calcd. for C
H
NO: C, 79.59; H, 6.20; N, 6.63. Found:
14 13
C, 79.52; H, 6.17; N, 6.42.
A mixture of 1c (1.86 g, 10 mmoles), benzalacetone (1.75 g,
12 mmoles) in a solution of sodium (0.23 g, 10 mmoles) in anhy-
drous ethanol (20 ml) was stirred at room temperature overnight,
and then acetic acid (0.60 g, 10 mmoles) was added to the reac-
tion mixture. The solvent was removed in vacuo, and then cold
water was added to the residue. The resulting mixture was
extracted with chloroform. The extract was dried over anhydrous
sodium sulfate and concentrated in vacuo. The residue was puri-
fied by column chromatography on silica gel with methylene
chloride as the eluent to give 7c (1.50 g, 42%). The melting point
and ir spectrum of this compound coincided with those of an
authentic sample prepared from 3c and sodium ethoxide.
2,3-Dihydro-6-methyl-3-phenylfuro[2,3-b]pyridine (9d).
This compound was obtained as colorless prisms [from 5d:
1.48 g (70%), from 6d: 1.27 g (60%)], mp 67-68° (diethyl ether-
1
petroleum ether); H nmr (deuteriochloroform): δ 2.46 (s, 3H, 6-
CH ), 4.35-4.73 (m, 2H, 2-H), 4.94 (dd, J = 7, 8.5 Hz, 1H, 3-H),
3
6.66 (d, J = 7 Hz, 1H, 5-H), 7.14-7.36 ppm (m, 6H, 4-H, aromatic
+
H); ms: m/z 212 [M+H] .
Anal. Calcd. for C
H NO: C, 79.59; H, 6.20; N, 6.63. Found:
14 13
C, 79.49; H, 6.30; N, 6.71.
2,3-Dihydro-6-methyl-4-phenylfuro[2,3-b]pyridine (10a).
The Preparation of 7c from 1c, Benzaldehyde and Acetone.
This compound was obtained as colorless needles [from 7a:
1.89 g (90%), from 8a: 1.71 g (80%)], mp 105-106° (acetone-
petroleum ether); H nmr (deuteriochloroform): δ 2.47 (s, 3H, 6-
A mixture of 1c (1.86 g, 10 mmoles), benzaldehyde (1.59 g, 15
mmoles), acetone (1.59 g, 20 mmoles) in a solution of sodium
(0.23 g, 10 mmoles) in anhydrous ethanol (20 ml) was stirred at
room temperature overnight. After work-up as described above,
compound 7c (0.89 g, 25%) was obtained. The melting point and
ir spectrum of this compound coincided with those of an authen-
tic sample prepared from 3c and sodium ethoxide.
1
CH ), 3.30 (t, J = 8.5 Hz, 2H, 3-H), 4.60 (t, J = 8.5 Hz, 2H, 2-H),
3
6.75 (s, 1H, 5-H), 7.45 ppm (s, 5H, aromatic H); ms: m/z 212
+
[M+H] .
Anal. Calcd. for C
H NO: C, 79.59; H, 6.20; N, 6.63. Found:
14 13
C, 79.69; H, 6.18; N, 6.58.
2,3-Dihydro-2,6-dimethyl-4-phenylfuro[2,3-b]pyridine (10b).
General Procedure for the Preparation of 9a-d and 10a-c from
5a-d, 6a-d or 7a-c, 8a-c.
This compound was obtained as colorless needles [from 7b:
2.08 g (92%), from 8b: 1.83 g (81%)], mp 115-117° (acetone-
A solution of 5a-d, 6a-d, 7a-c or 8a-c (10 mmoles) and potas-
sium tert-butoxide (1.12 g, 10 mmoles) in anhydrous tert-butyl
alcohol (30 ml) was refluxed for 1 hour. After removal of the sol-
vent in vacuo, cold water was added to the residue. The resulting
mixture was extracted with chloroform. The extract was dried
over anhydrous sodium sulfate and concentrated in vacuo. The
residue was purified by column chromatography on silica gel
with methylene chloride as the eluent to yield 9a-d and 10a-c.
1
petroleum ether); H nmr (deuteriochloroform): δ 1.48 (d, J = 6
Hz, 3H, 2-CH ), 2.47 (s, 3H, 6-CH ), 2.88 (dd, J = 7, 16 Hz, 1H,
3
3
3-H), 3.44 (dd, J = 9.5, 16 Hz, 1H, 3-H), 4.77-5.17 (m, 1H, 2-H),
6.74 (s, 1H, 5-H), 7.44 ppm (s, 5H, aromatic H); ms: m/z 226
+
[M+H] .
Anal. Calcd. for C
H NO: C, 79.97; H, 6.71; N, 6.22. Found:
15 15
C, 80.07; H, 6.72; N, 6.25.
2,3-Dihydro-6-methyl-2,4-diphenylfuro[2,3-b]pyridine (10c).
2,3-Dihydro-6-methylfuro[2,3-b]pyridine (9a).
This compound was obtained as colorless needles [from 7c:
2.62 g (91%), from 8c: 2.61 g (91%)], mp 119-121° (acetone-
petroleum ether); H nmr (deuteriochloroform): δ 2.51 (s, 3H, 6-
This compound was obtained as colorless plates [from 5a: 0.88
g (65%), from 6a: 0.92 g (68%)], mp 41-42° (diethyl ether-petro-
1
1
leum ether); H nmr (deuteriochloroform): δ 2.41 (s, 3H, 6-CH ),
3
CH ), 3.27 (dd, J = 8, 16 Hz, 1H, 3-H), 3.76 (dd, J = 9.5, 16 Hz,
3.19 (t, J = 8.5 Hz, 2H, 3-H), 4.59 (t, J = 8.5 Hz, 2H, 2-H), 6.62
(d, J = 7 Hz, 1H, 5-H), 7.34 ppm (d, J = 7 Hz, 1H, 4-H); ms: m/z
3
1H, 3-H), 5.82 (dd, J = 8, 9.5 Hz, 1H, 2-H), 6.80 (s, 1H, 5-H),
+
+
7.25-7.51 ppm (m, 10H, aromatic H); ms: m/z 288 [M+H] .
136 [M+H] .
Anal. Calcd. for C
H NO: C, 83.59; H, 5.96; N, 4.87. Found:
Anal. Calcd. for C H NO: C, 71.09; H, 6.71; N, 10.36. Found:
20 17
8
9
C, 83.47; H, 5.96; N, 4.90.
C, 71.02; H, 6.75; N, 10.37.
General Procedure for the Preparation of 11a-c from 4a-c and
Sodium Ethoxide.
2,3-Dihydro-2,6-dimethylfuro[2,3-b]pyridine (9b).
This compound was obtained as pale yellow oil [from 5b: 1.08
1
A mixture of 4a-c (10 mmoles) in a solution of sodium (0.23 g,
10 mmoles) in anhydrous ethanol (30 ml) was refluxed for 2
hours. 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 anhydrous sodium sulfate
and concentrated in vacuo. The residue was purified by column
chromatography on silica gel with methylene chloride as the elu-
ent to give 11a-c.
g (72%), from 6b: 0.93 g (62%)]; H nmr (deuteriochloroform): δ
1.47 (d, J = 6 Hz, 3H, 2-CH ), 2.41 (s, 3H, 6-CH ), 2.66 (dd, J =
3
3
7, 15.5 Hz, 1H, 3-H), 3.31 (dd, J = 8.5, 15.5 Hz, 1H, 3-H), 4.75-
5.13 (m, 1H, 2-H), 6.60 (d, J = 7 Hz, 1H, 5-H), 7.30 ppm (d, J = 7
+
Hz, 1H, 4-H); ms: m/z 150 [M+H] .
Anal. Calcd. for C H NO: C, 72.46; H, 7.43; N, 9.39. Found:
9
11
C, 72.19; H, 7.46; N, 9.24.
2,3-Dihydro-6-methyl-2-phenylfuro[2,3-b]pyridine (9c).
This compound was obtained as colorless prisms [from 5c: 1.62
2,3-Dihydro-4-phenylfuro[2,3-b]pyridine (11a).
This compound was obtained as colorless columns (1.16 g,
59%), mp 77-78° (diethyl ether-petroleum ether); H nmr (deu-
g (77%), from 6c: 1.48 g (70%)], mp 66-67° (diethyl ether-petro-
1
1
leum ether); H nmr (deuteriochloroform): δ 2.46 (s, 3H, 6-CH ),
3
teriochloroform): δ 3.36 (t, J = 8.5 Hz, 2H, 3-H), 4.62 (t, J = 8.5
3.13 (dd, J = 8, 16 Hz, 1H, 3-H), 3.64 (dd, J = 9.5, 16 Hz, 1H, 3-H),
5.80 (dd, J = 8, 9.5 Hz, 1H, 2-H), 6.66 (d, J = 7 Hz, 1H, 5-H), 7.26-
7.43 ppm (m, 6H, 4-H, aromatic H); ms: m/z 212 [M+H] .
Hz, 2H, 2-H), 6.88 (d, J = 5.5 Hz, 1H, 5-H), 7.47 (s, 5H, aromatic
+
+
H), 8.05 ppm (d, J = 5.5 Hz, 1H, 6-H); ms: m/z 198 [M+H] .

Jul-Aug 2002
Synthesis of Dihydrofuro[2,3-b]pyridines
749
Anal. Calcd. for C H NO: C, 79.17; H, 5.62; N, 7.10. Found:
C, 79.16; H, 5.73; N, 7.12.
chromatography on silica gel with methylene chloride as the elu-
ent to afford 10a (0.97 g, 46%), 10b (0.99 g, 44%), 10c (1.29 g,
45%), 11a (0.86 g, 44%), 11b (0.79 g, 37%) and 11c (0.83 g,
30%), respectively.
13 11
2,3-Dihydro-2-methyl-4-phenylfuro[2,3-b]pyridine (11b).
This compound was obtained as colorless needles (0.97 g,
General Procedure for the Preparation of 9a-d from 1a-d and
Methyl Vinyl Ketone.
1
46%), mp 55-56° (diethyl ether-petroleum ether); H nmr (deu-
teriochloroform): δ 1.50 (d, J = 6 Hz, 3H, 2-CH ), 2.94 (dd, J =
3
7.5, 16.5 Hz, 1H, 3-H), 3.48 (dd, J = 8, 16.5 Hz, 1H, 3-H), 4.77-
5.16 (m, 1H, 2-H), 6.87 (d, J = 5.5 Hz, 1H, 5-H), 7.46 (s, 5H, aro-
matic H), 8.04 ppm (d, J = 5.5 Hz, 1H, 6-H); ms: m/z 212
A mixture of 1a-d (10 mmoles) and methyl vinyl ketone (0.84
g, 12 mmoles) in a solution of sodium (0.46 g, 20 mmoles) in
anhydrous ethanol (30 ml) was stirred at room temperature
overnight. 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 anhydrous sodium sulfate
and concentrated in vacuo. After potassium tert-butoxide (2.24 g,
20 mmoles) was added to the residue in anhydrous tert-butyl
alcohol (30 ml), the mixture 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 anhydrous sodium sulfate and concen-
trated in vacuo. The residue was purified by column chromatog-
raphy on silica gel with methylene chloride as the eluent to yield
9a (0.58 g, 43%), 9b (0.82 g, 55%), 9c (1.01 g, 48%) and 9d
(0.96 g, 45%), respectively.
+
[M+H] .
Anal. Calcd. for C
H NO: C, 79.59; H, 6.20; N, 6.63. Found:
14 13
C, 79.59; H, 6.26; N, 6.65.
2,3-Dihydro-2,4-diphenylfuro[2,3-b]pyridine (11c).
This compound was obtained as colorless needles (0.77 g,
1
28%), mp 120-122° (acetone-petroleum ether); H nmr (deuteri-
ochloroform): δ 3.33 (dd, J = 8, 16.5 Hz, 1H, 3-H), 3.82 (dd, J =
9.5, 16.5 Hz, 1H, 3-H), 5.83 (dd, J = 8, 9.5 Hz, 1H, 2-H), 6.94 (d,
J = 5.5 Hz, 1H, 5-H), 7.25-7.53 (m, 10H, aromatic H), 8.12 ppm
+
(d, J = 5.5 Hz, 1H, 6-H); ms: m/z 274 [M+H] .
Anal. Calcd. for C
H NO: C, 83.49; H, 5.53; N, 5.12. Found:
19 15
C, 83.47; H, 5.67; N, 5.11.
The Preparation of 6d from 5d and Sodium Methoxide.
REFERENCES AND NOTES
A mixture of 5d (1.42 g, 5 mmoles) in a solution of sodium
(0.23 g, 10 mmoles) in anhydrous methanol (50 ml) was refluxed
for 3 hours. 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 anhydrous sodium sulfate
and concentrated in vacuo. The residue was purified by column
chromatography on silica gel with methylene chloride as the elu-
ent to afford 6d (0.84 g, 62%). The melting point and ir spectrum
of this compound coincided with those of an authentic sample
prepared from 2d and sodium methoxide.
[1] T. Matsuda, K. Yamagata, Y. Tomioka and M. Yamazaki,
Chem. Pharm. Bull., 33, 937 (1985).
[2] E. C. Taylor and A. Mckillop, Advances in Organic
Chemistry: Methods and Results, Vol 7, E. C. Taylor, ed, Interscience
Publishers, Inc., New York, 1970, p 3.
[3] K. Yamagata, Y. Tomioka and M. Yamazaki, Chem.
Pharm. Bull., 34, 590 (1986).
[4] G. H. Alt and A. G. Cook, Enamines: Synthesis, Structure
and Reactions, 2nd ed., A. G. Cook, ed, Marcel Dekker, Inc., New
York and Basel, 1988, p 189.
The Preparation of 5d from 6d and Sodium Ethoxide.
[5] S. F. Dyke, The Chemistry of Enamines, Cambridge
University Press 1973, p 31.
A mixture of 6d (1.35 g, 5 mmoles) in a solution of sodium
(0.23 g, 10 mmoles) in anhydrous ethanol (50 ml) was refluxed
for 3 hours. After work-up as described above, compound 5d
(0.31 g, 22%) was obtained. The melting point and ir spectrum of
this compound coincided with those of an authentic sample pre-
pared from 2d and sodium ethoxide.
[6] L. A. Paquette, Principles of Modern Heterocyclic
Chemistry, W. A. Benjamin, Inc., New York, 1968, p 225.
[7] 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.
[8] F. Bossert, H. Meyer and E. Wehinger, Angew. Chem., Int.
Ed. Engl., 20, 762 (1981).
General Procedure for the Preparation of 10a-c and 11a-c from
1a-c and Benzalacetone or Cinnamaldehyde.
[9] A. W. Erian, Chem. Rev., 93, 1991 (1993).
[10] 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).
[11] I. Katsuyama, S. Ogawa, Y. Yamaguchi, K. Funabiki, M.
Matsui, H. Muramatsu and K. Shibata, Synthesis, 1321 (1997).
[12] K. Shibata, I. Katsuyama, H. Izoe, M. Matsui and H.
Muramatsu, J. Heterocyclic Chem., 30, 277 (1993), and references
cited therein.
A mixture of 1a-c (10 mmoles) and benzalacetone (1.75 g, 12
mmoles) or cinnamaldehyde (1.58 g, 12 mmoles) in a solution of
sodium (0.46 g, 20 mmoles) in anhydrous ethanol (30 ml) was
stirred at room temperature overnight, and then refluxed for 1
hours. 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 anhydrous sodium sulfate
and concentrated in vacuo. The residue was purified by column