Synthesis of α-alkylidene-γ-butyrolactones via ring-cleavage/recyclization of 2-amino-4,5-dihydro-3-furancarboxamides

Article abstract of DOI:10.1002/jhet.5570410405

The reactions of 2-amino-4,5-dihydro-3-furancarboxamides 1a,b with cyanomethylene compounds (such as alkyl cyanoacetates and malononitrile) gave the corresponding ring-opened products 2a-f. Compounds 2a-d reacted with methanesulfonic acid to give the corresponding α-alkylidene-γ- butyrolactones 3a-d. On the other hand, treatment of 2e,f with methanesulfonic acid yielded 3-pyridinecarbonitrile derivatives 4a,b.

Full text of DOI:10.1002/jhet.5570410405

Jul-Aug 2004
505
Synthesis of α-Alkylidene-γ-butyrolactones via Ring-cleavage /
Recyclization of 2-Amino-4,5-dihydro-3-furancarboxamides
Fumi Okabe, Yoshinobu Tagawa and Kenji Yamagata*
Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jounan-ku, Fukuoka 814-0180,
Japan
Received February 2, 2004
The reactions of 2-amino-4,5-dihydro-3-furancarboxamides 1a,b with cyanomethylene compounds (such
as alkyl cyanoacetates and malononitrile) gave the corresponding ring-opened products 2a-f. Compounds
2a-d reacted with methanesulfonic acid to give the corresponding α-alkylidene-γ-butyrolactones 3a-d. On
the other hand, treatment of 2e,f with methanesulfonic acid yielded 3-pyridinecarbonitrile derivatives 4a,b.
J. Heterocyclic Chem., 41, 505 (2004).
α-Methylene or α-alkylidene-γ-butyrolactones exhibit a
wide range of biological activities [1], particularly cyto-
toxic and antitumor activity [2], fungitoxicity [3] as well as
plant growth inhibition [4]. Many methods have been
developed for the synthesis of such compounds [5-10]. In
the previous paper, we showed that 2-amino-4,5-dihydro-3-
furancarboxamides 1 react with ammonium acetate to yield
3-diaminomethylene-2(3H)-furanones [11] (Scheme 1).
This reaction probably occurs via Michael addition to the
α,β-unsaturated carboxamide moiety of 1 with ammonia to
form the intermediate adduct, which undergoes cyclization
to provide the observed products. This reaction suggests the
possibility that when compounds 1 are treated with active
methylene compounds, the Michael adduct initially formed
may undergo cyclization to furnish the corresponding
α-a l k y l i d e n e -γ-b utyrolactones. Thus, we have investigated
the reaction of 1 with active methylene compounds.
When a mixture of 2-amino-4,5-dihydro-3-furancarbox-
amides 1a,b and methyl or ethyl cyanoacetate in N,N-
dimethylformamide (DMF) was kept at 60° ring-opening
products 2a-d were obtained in moderate yields, and the
expected 3-methylene-2(3H)-furanones could not be iso-
lated. In a similar manner, the reaction of 1a,b with mal-
ononitrile afforded an inseparable mixture showing many
spots on thin-layer chromatography. When dioxane was
used in place of DMF, compounds 1a,b reacted with mal-
ononitrile at 60° provided 2e,f in good yields. However,
the reaction of 1 with active methylene compounds lacking
cyano group such as dialkyl malonate and alkyl acetoac-
etate failed, and 1 was recovered unchanged. The pmr
spectra of 2c,d,f show two broad singlets at δ 9.1 and 8.3
for a carbamoyl group and two multiplets at δ 4.5 for a
methine group of a secondary alcohol moiety. These obser-
vations indicate that 2c,d,f exist as two diastereomers,
which would probably be formed by an effect of the con-
figuration of carbamoyl group and phenyl group.
Separation of the diastereomers 2c,d,f was attempted by
column chromatography, but was not successful.
expected α-alkylidene-γ-butyrolactones 3a-d in moderate
to good yields. Although all compounds 2 and 3 contain
two stereogenic centers, the absence of signal doubling in
both pmr and cmr spectra for 2a,b,e and 3a-d suggests the
presence of only one diastereomer (as an enantiomeric
pair). The ir spectra of 3a-d reveal a band at near 2200 cm-
1 due to a conjugated cyano group. The pmr spectra exhibit
a one-proton doublet (3a,b) or double doublet (3c,d) at δ
4.3 attributable to the α-methine proton (3-H) of the γ-lac-
tone ring. These observations indicate that 3a-d exist in the
furan-3-yl structure B rather than the furanylidene struc-
ture A. Furthermore, in the pmr spectra of 3a,b the large
vicinal coupling constants (3a: J = 11.3 Hz; 3b: 11.1 Hz)
between the 3- and 4- methine protons in the lactone ring
support a trans relationship of these protons. In the
NOESY spectra of 3c,d the presence of a NOE effect
between the 3- and 5- methine protons suggests a cis
Subsequently, in order to obtain the α-alkylidene-γ-
butyrolactones, we examined the cyclization of com-
pounds 2a-f with acid. The reaction of 2a-d with methane-
sulfonic acid in DMF resulted in the formation of the

506
F. Okabe, Y. Tagawa and K. Yamagata
Vol. 41
13 13
for C) in DMSO-d with TMS as internal standard. C signal
stereochemistry of these protons. The compounds 2a-d
and 3a-d possessing a carbon-carbon double bond, are
expected to give E/Z-isomers, but only one of the geomet-
ric isomers of these compounds could be detected in the
pmr and cmr spectra. It can be assumed that steric and
electronic reasons give preference to one of the isomers.
However, we were not able to prove its structure unam-
biguously. Treatment of 2e and 2f with methanesulfonic
acid in dioxane at 70° led to cyclization to give 3-
pyridinecarbonitrile 4b and furo[3,2-c]pyridine 5 in 50 and
78% yield, and the expected α-alkylidene-γ-butyrolac-
tones could not be isolated. When a mixture of 2e and
methanesulfonic acid in dioxane was stirred at room tem-
perature, the corresponding pyridine derivative 4a was
obtained in 73% yield. Compound 4a was converted into 5
by treatment with methanesulfonic acid in dioxane at 70°.
Compound 4b failed to transform into furo[3,2-c]pyridine
even after 20h heating at 70° in dioxane, and 4b was
recovered unchanged.
6
13
1
assignments were confirmed by the DEPT and C- H COSY
techniques. Mass spectra were acquired with a JEOL JMS-
HX100 instrument at 70 eV. Elemental analyses were performed
using a YANACO MT-6 elemental analyzer.
General Procedures for the Preparation of Ring-opening Products 2.
Procedure A.
A mixture of 1a,b (1.02 g, 5 mmoles), alkyl cyanoacetate (8
mmoles) and DMF (5 ml) was stirred at 60° for 24 hours (in the
case of preparation of 2a,c,d) or 50 hours (2b). The solvent was
removed in vacuo and cold water was added to the residue. The
mixture was extracted with dichloromethane. The extract was
washed with water, dried over anhydrous sodium sulfate and
concentrated in vacuo. The residue was purified by column chro-
matography on silica gel with dichloromethane:acetone (4:1, v/v)
as the eluent to yield 2a-d.
Procedure B.
A suspension of 1a,b (1.02 g, 5 mmoles), malononitrile (0.36
g, 5.5 mmoles) and dioxane (5 ml) was stirred at 60° for 30
hours. After removal of the solvent in vacuo, diethyl ether was
added to the residue. The precipitate was collected, washed with
diethyl ether to give 2e,f.
Methyl 3-Amino-4-carbamoyl-2-cyano-6-hydroxy-5-phenyl-2-
hexenoate (2a).
This compound was obtained as colorless prisms (0.95 g,
63%), mp 191° (dec.) (acetone-petroleum ether); ir (potassium
bromide): ν 3470, 3380, 3280, 3200 (NH, OH), 2205 (C≡N ) ,
-1
1690, 1670 cm (C=O); pmr (DMSO-d ): δ, ppm 3.37 (ddd, J =
6
3.4, 7.0, 11.0 Hz, 1H, 5-H), 3.55-3.65 (m, 2H, CH -6), 3.69 (s,
2
3H, OCH ), 3.92 (d, J = 11.0 Hz, 1H, 4-H), 4.60 (t, J = 4.3 Hz,
3
1H, OH), 7.20-7.30 (m, 5H, aryl), 7.05, 7.68, 8.27, 9.16 (each
br.s, each 1H, NH); cmr (DMSO-d ): δ, ppm 50.2 (C-5), 51.2
6
(OCH ), 51.7 (C-4), 62.7 (C-6), 71.1 (C-2), 118.2 (C≡N), 126.6,
3
127.8, 128.5, 140.1 (C aryl), 167.3 (C-3), 169.0 (C=O), 170.0
+
(C=O); ms: m/z 304 [M+H] .
Anal. Calcd. for C H N O (MW 303.3): C, 59.40; H, 5.65;
15 17 3 4
N, 13.85. Found: C, 59.35; H, 5.73; N, 13.70.
Ethyl 3-Amino-4-carbamoyl-2-cyano-6-hydroxy-5-phenyl-2-
hexenoate (2b).
This compound was obtained as colorless prisms (0.90 g,
57%), m.p. 189° (dec.) (acetone-petroleum ether); ir (potassium
bromide): ν 3410, 3340, 3300, 3200 (NH, OH), 2215 (C≡N ) ,
-1
1675, 1665 cm (C=O); pmr (DMSO-d ): δ, ppm 1.23 (t, J = 7.0
6
Hz, CH ), 3.37 (ddd, J = 5.2, 7.7, 11.3 Hz, 1H, 5-H), 3.55-3.63
3
(m, 2H, 6-H), 3.92 (d, J = 11.3 Hz, 1H, 4-H), 4.10-4.21 (m, 2H,
OCH ), 4.60 (br.s, 1H, OH), 7.19-7.31 (m, 5H, aryl), 7.05, 7.67,
2
8.22, 9.17 (each br.s, each 1H, NH); cmr (DMSO-d ): δ, ppm
6
14.2 (CH ), 50.2 (C-5), 51.7 (C-4), 59.8 (OCH ), 62.7 (C-6),
3
71.3 (C-2), 118.2 (C≡N), 126.6, 127.8, 128.5, 140.1 (C aryl),
2
+
167.3 (C-3), 168.9 (C=O), 169.8 (C=O); ms: m/z 318 [M+H] .
Anal. Calcd. for C H N O (MW 317.3): C, 60.55; H, 6.04;
16 19 3 4
N, 13.24. Found: C, 60.40; H, 5.93; N, 13.09.
EXPERIMENTAL
Methyl 3-Amino-4-carbamoyl-2-cyano-6-hydroxy-6-phenyl-2-
hexenoate (2c).
All melting points are uncorrected. The ir spectra were
recorded on a JASCO A-302 spectrometer or JASCO FT/IR-230
spectrometer. The pmr and cmr spectra were measured with a
This compound (1.40 g, 90%, pale yellow oil) was obtained as
an approximately 1:1 mixture of diastereomers; ir (neat): ν 3560,
1
JEOL JNM-A500 instrument (500.00 MHz for H, 125.65 MHz

Jul-Aug 2004
Synthesis of α-Alkylidene-γ-butyrolactones via Ring-cleavage
507
-1
3410, 3360, 3210 (NH, OH), 2206 (C≡N), 1700, 1670 cm (C=O);
pmr (DMSO-d ): δ, ppm 1.85-1.89 (m, 0.5H, 5-H), 2.08 (s, 1.8H,
0.5H, 4-H), 4.48-4.52 (m, 0.5H, 4-H), 5.40 (d, J = 4.6 Hz, 0.5H,
OH), 5.46 (d, J = 4.6 Hz, 0.5H, OH), 7.21-7.34 (m, 5.5H, aryl,
NH), 7.40, 7.54, 7.64, 8.11, 8.37, 8.48, 8.52 (each br.s, each 0.5H,
6
acetone-CH ), 2.13-2.23 (m, 1.5H, 5-H), 3.66 (s, 1.5H, OCH ),
3
3.67 (s, 1.5H, OCH ), 3.88-3.91 (m, 1H, 4-H), 4.42-4.43 (m, 0.5H,
3
NH); cmr (DMSO-d ): δ, ppm 39.5 (C-3), 40.7 (C-3), 46.3 (C-
6
3
2), 46.8 (C-2), 48.6 (C-2'), 49.7 (C-2'), 69.7 (C-4), 70.2 (C-4),
115.3, 115.4, 116.2, 116.4 (C≡N), 125.5, 125.6, 126.8, 126.9,
127.9, 128.0, 145.1, 145.4 (C aryl), 169.9, 170.1 (C-1'), 172.1,
6-H), 4.50-4.52 (m, 0.5H, 6-H), 5.38 (d, J = 4.5Hz, 0.5 H, OH),
5.40 (d, J = 4.6 Hz, 0.5H, OH), 7.21-7.34 (m, 5.5H, aryl, NH),
7.42, 7.53, 7.68, 8.26, 8.50, 9.11, 9.12 (each br.s each 0.5H, NH);
+
172.6 (C=O); ms: m/z 270 [M+H] .
cmr (DMSO-d ): δ, ppm 30.6 (CH COCH ), 40.0 (C-5), 41.4 (C-
6
5), 46.8 (C-4), 47.5 (C-4), 51.0 (OCH ), 51.1 (OCH ), 69.5 (C-2),
3
3
Anal. Calcd. for C
N, 20.73. Found: C, 62.07; H, 5.34; N, 20.61.
H N O (MW 270.3): C, 62.21; H, 5.22;
14 14 4 2
3
3
70.1 (C-6), 70.2 (C-6), 70.7 (C-2), 117.8 (C≡N), 118.1 (C≡N ) ,
125.5, 125.6, 126.8, 126.9, 127.9, 128.0, 145.3, 145.4 (C aryl),
167.6 (C-3), 167.7 (C-3), 170.5 (C=O), 170.6 (C=O), 170.7 (C=O),
General Procedure for the Preparation of γ-Lactone 3.
+
171.0 (C=O), 206.7 (CH COCH ); ms: m/z 304 [M+H] .
A mixture of 2a-d (2 mmoles), methanesulfonic acid (0.23 g,
2.4 mmoles) and DMF (2 ml) was stirred at 70° for 5 hours. The
solvent was removed in vacuo and cold water was added to the
residue. The mixture was extracted with dichloromethane. The
extract was washed with water, dried over anhydrous sodium sul-
fate and concentrated in vacuo. The residue was purified by col-
umn chromatography on silica gel with dichloromethane as elu-
ent to give 3a-d.
3
H
3
N O • 0.3CH COCH (MW 320.7):
Anal. Calcd. for C
15 17
C, 59.54; H, 5.91; N, 13.10. Found: C, 59.60; H, 5.78; N, 13.10.
3
4
3
3
Ethyl 3-Amino-4-carbamoyl-2-cyano-6-hydroxy-6-phenyl-2-
hexenoate (2d) Semi Hydrate.
This compound (1.57 g, 96%, pale yellow oil) was obtained as
an approximately 1:1 mixture of diastereomers; ir (neat): ν 3560,
-1
3430, 3370, 3220, 3170 (NH, OH), 2210 (C≡N), 1700, 1670 cm
(C=O); pmr (DMSO-d ): δ, ppm 1.21 (t, J = 7.1 Hz, 1.5H, CH ),
Methyl trans-3-Amino-2-cyano-3-(tetrahydro-2-oxo-4-phenyl-
furan-3-yl)propenoate (3a).
6
3
1.22 (t, J = 7.0 Hz, 1.5H, CH ), 1.84-1.90 (m, 0.5H, 5-H), 2.09-
3
2.23 (m, 1.5H, 5-H), 3.90 (dd, J = 5.5, 9.3 Hz, 1H, 4-H), 4.10-
This compound was obtained as colorless needles (0.37 g,
65%), mp 188-189° (acetone-petroleum ether); ir (potassium bro-
mide): ν 3380, 3280, 3220 (NH, OH), 2210 (C≡N), 1780, 1690
4.16 (m, 2H, OCH ), 4.40-4.43 (m, 0.5H, 6-H), 4.49-4.53 (m,
2
0.5H, 6-H), 5.38 (d, J = 4.5Hz, 0.5 H, OH), 5.40 (d, J = 4.5 Hz,
0.5H, OH), 7.21-7.33 (m, 5.5H, aryl, NH), 7.42, 7.52, 7.66, 8.23,
8.47, 9.12, 9.22 (each br.s, each 0.5H, NH); cmr (DMSO-d ): δ,
-1
cm (C=O); pmr (DMSO-d ): δ, ppm 3.64 (s, 3H, OCH ), 4.23
6
3
(ddd, J = 8.3, 10.5, 11.3 Hz, 1H, 4'-H), 4.40 (d, J = 11.3 Hz, 1H,
3'-H), 4.41 (dd, J = 8.3, 10.5 Hz, 1H, 5'-H), 4.68 (t, J = 8.3 Hz,
1H, 5'-H), 7.30-7.44 (m, 5H, aryl), 9.03, 9.17 (each br.s, each 1H,
NH); cmr (DMSO-d ): δ, ppm 47.1 (C-4'), 51.2 (CH ), 52.2 (C-
6
ppm 14.2 (CH ), 14.3 (CH ), 40.0 (C-5), 41.4 (C-5), 46.8 (C-4),
3
47.5 (C-4), 59.5 (OCH ), 59.6 (OCH ), 69.8 (C-2), 70.0 (C-6),
3
2
2
70.1 (C-6), 70.9 (C-2), 117.8 (C≡N), 118.1 (C≡N), 125.5, 125.6,
126.8, 126.9, 127.9, 128.0, 145.3, 145.4 (C aryl), 167.3 (C-3),
167.4 (C-3), 170.5 (C=O), 170.6 (C=O), 170.7 (C=O), 170.9
6
3
3'), 71.5 (C-5'), 71.7 (C-2), 117.7 (C≡N), 127.6, 127.9, 128.7,
135.7 (C aryl), 166.9 (C-3), 167.0 (C=O), 172.0 (C=O); ms: m/z
+
287 [M+H] .
+
(C=O); ms: m/z 318 [M+H] .
Anal. Calcd. for C H N O (MW 286.3): C, 62.93; H, 4.93;
15 14 2 4
N, 9.79. Found: C, 62.79; H, 4.95; N, 9.77.\
Anal. Calcd. for C
H, 6.18; N, 12.88. Found: C, 58.85; H6.20; N, 13.04.
H N O •0.5H O (MW 326.3): C, 58.89;
16 19 3 4 2
Ethyl trans-3-Amino-2-cyano-3-(tetrahydro-2-oxo-4-phenylfu-
ran-3-yl)propenoate (3b).
2 - ( 1 - A m i n o - 2 , 2 - d i c y a n o e t h e n y l ) - 4 - h y d r o x y - 3 - p h e n y l b u -
tanamide (2e).
This compound was obtained as colorless needles (0.30 g,
50%), mp 186-187° (acetone-petroleum ether); ir (potassium bro-
This compound was obtained as colorless columns (0.81 g,
60%), mp 184°(dec.) (acetone); ir (potassium bromide): ν 3480,
-1
-1
3320, 3190 (NH, OH), 2210, 2200 (C≡N), 1705 cm (C=O); pmr
mide): ν 3350, 3280, 3210 (NH), 2210 (C≡N), 1780, 1685 cm
(C=O); pmr (DMSO-d ): δ, ppm 1.18 (t, J = 7.0 Hz, 3H, CH ),
(DMSO-d ): δ, ppm 3.38-3.43 (m, 1H, 3-H), 3.54-3.60 (m, 2H,
6
6
4.06-4.16 (m, 2H, OCH ), 4.23 (ddd, J = 8.2, 10.5, 11.1 Hz, 1H,
3
4-H), 3.87 (d, J = 11.3 Hz, 1H, 2-H), 4.71 (t, J = 4.6 Hz, 1H, OH),
7.19-7.30 (m, 5H, aryl), 7.07, 7.64, 8.08, 8.62 (each br.s, each
1H, NH); cmr (DMSO-d ): δ, ppm 49.4 (C-3), 49.9 (C-2'), 51.0
2
4'-H), 4.39 (dd, J = 8.2, 10.5 Hz, 1H, 5'-H), 4.40 (d, J =11.1 Hz,
1H, 3'-H), 4.68 (t, J = 8.2 Hz, 1H, 5'-H), 7.30-7.45 (m, 5H, aryl),
9.01, 9.18 (each br.s, each 1H, NH); cmr (DMSO-d ): δ, ppm
6
(C-2), 62.8 (C-4), 115.2 (C≡N), 116.2 (C≡N), 126.6, 127.8,
128.5, 139.8 (C aryl), 169.1 (C-1'), 170.8 (C=O); ms: m/z 271
+
[M+H] .
Anal. Calcd. for C H N O (MW 270.3): C, 62.21; H, 5.22;
14 14 4 2
N, 20.73. Found: C, 62.18; H, 5.30; N, 20.61.
6
14.1 (CH ), 47.0 (C-4'), 52.1 (C-3'), 59.9 (OCH ), 71.5 (C-5'),
3
72.0 (C-2), 117.7 (C≡N), 127.6, 127.9, 128.7, 135.7 (C aryl),
2
+
166.6 (C-3), 167.0 (C=O), 172.1 (C=O); ms: m/z 301 [M+H] .
Anal. Calcd. for C
N, 9.33. Found: C, 63.73; H, 5.34; N, 9.30.
H N O (MW 300.3): C, 63.99; H, 5.37;
16 16 2 4
2 - ( 1 - A m i n o - 2 , 2 - d i c y a n o e t h e n y l ) - 4 - h y d r o x y - 4 - p h e n y l -
butanamide (2f).
Methyl cis-3-Amino-2-cyano-3-(tetrahydro-2-oxo-5-phenylfu-
ran-3-yl)propenoate (3c).
This compound (1.12 g, 83%, colorless needles) was obtained
as an approximately 1:1 mixture of diastromers; mp 171° (dec.)
(acetone-petroleum ether); ir (potassium bromide): ν 3560, 3360,
This compound was obtained as colorless prisms (0.42 g,
74%), mp 188-190° (acetone-petroleum ether); ir (potassium bro-
mide): ν 3400, 3280, 3240 (NH, OH), 2210 (C≡N), 1760, 1750,
-1
3200 (NH, OH), 2210, 2200 (C≡N), 1690 cm (C=O); pmr
(DMSO-d ): δ, ppm 1.86-1.92 (m, 0.5H, 3-H), 2.07-2.10 (m,
-1
1690 cm (C=O); pmr (DMSO-d ): δ, ppm 2.50-2.55 (m, 1H, 4'-
6
6
H), 2.90-2.96 (m, 1H, 4'-H), 3.69 (s, 3H, OCH ), 4.29 (dd, J =
0.5H, 3-H), 2.22-2.27 (m, 1H, 3-H), 3.76 (dd, J = 5.5, 8.8 Hz,
0.5H, 2-H), 3.85 (dd, J = 4.9, 10.0 Hz, 0.5H, 2-H), 4.38-4.40 (m,
3
8.3, 12.6 Hz, 1H, 3'-H), 5.65 (dd, J = 5.2, 11.0 Hz, 1H, 5'-H),

508
F. Okabe, Y. Tagawa and K. Yamagata
Vol. 41
7.35-7.61 (m, 5H, aryl), 9.07, 9.25 (each br.s, each 1H, NH); cmr
(DMSO-d ): δ, ppm 36.5 (C-4'), 47.5 (C-3'), 51.2 (CH ), 70.7 (C-
50%), m.p. 267° (dec.) (methanol); ir (potassium bromide): ν
-1
3460, 3350, 3240 (NH, OH), 2220 (C≡N), 1655 cm (C=O); pmr
(DMSO-d ): δ, ppm 2.49-2.54 (m, 2H, 1'-H), 4.61-4.64 (m, 2H,
6
2), 79.7 (C-5'), 118.0 (C≡N), 126.7, 128.3, 128.7, 137.7 (C aryl),
3
6
2'-H), 5.52 (br.s, 1H, OH), 5.88 (s, 2H, NH ), 6.10 (s, 2H, NH ),
+
167.2 (C-3), 167.6 (C=O), 172.0 (C=O); ms: m/z 287 [M+H] .
2
7.21-7.44 (m, 5H, aryl), 9.90 (s, 1H, NH); cmr (DMSO-d ): δ,
2
Anal. Calcd. for C
N, 9.79. Found: C, 62.89; H, 4.99; N, 9.61.
H
N O (MW 286.3): C, 62.93; H, 4.93;
6
ppm 33.0 (C-1'), 69.6 (C-3), 71.9 (C-2'), 83.6 (C-5), 118.6 (C≡N),
126.0, 126.7, 127.6, 145.2(C aryl), 151.9 (C-4), 160.2 (C-2),
15 14
2 4
Ethyl cis-3-Amino-2-cyano-3-(tetrahydro-2-oxo-5-phenylfuran-
3-yl)propenoate (3d).
+
160.9 (C-6); ms: m/z 271 [M+H] .
Anal . Calcd. for C H N O (MW 270.3): C, 62.21, H, 5.22;
14 14 4 2
N, 20.73. Found: C, 62.11; H, 5.34; N, 20.64.
This compound was obtained as colorless needles (0.47 g,
78%), mp 182-184° (acetone-petroleum ether); ir (potassium bro-
6-Amino-2, 3, 4, 5-tetrahydro-4-oxo-3-phenyl-furo[3, 2-c]pyri-
dine-7-carbonitrile (5).
-1
mide): ν 3380, 3280, 3220 (NH), 2200 (C≡N), 1755, 1675 cm
(C=O); pmr (DMSO-d ): δ, ppm 1.23 (t, J = 7.0 Hz, 3H, CH ),
6
2.50-2.57 (m, 1H, 4'-H), 2.90-2.97 (m, 1H, 4'-H), 4.16 (q, J = 7.0
3
A mixture of 2e (0.54 g, 2 mmoles) or 4a (0.56 g, 2 mmoles),
methanesulfonic acid (0.23 g, 2.4 mmoles) and dioxane (2 ml)
was stirred at 70° for 2 hours. The solvent was removed in vacuo
and cold water was added to the residue. The resulting precipitate
was collected by filtration, washed with water and dried to give 5
[from 2e: 0.40 g (78%), from 4a: 0.40 g (78%)], mp 255-256°
(methanol); ir (potassium bromide): ν 3480, 3360, 3240 (NH),
Hz, 2H, OCH ), 4.29 (dd, J = 8.1, 12.6 Hz, 1H, 3'-H), 5.65 (dd, J
2
= 5.5, 11.0 Hz, 1H, 5'-H), 7.36-7.61 (m, 5H, aryl), 9.04, 9.26
(each br.s, each 1H, NH); cmr (DMSO-d ): δ, ppm 14.2 (CH ),
6
36.5 (C-4'), 47.5 (C-3'), 59.8 (OCH ), 70.9 (C-2), 79.7 (C-5'),
3
2
118.0 (C≡N), 126.7, 128.4, 128.7, 137.8 (C aryl), 166.9 (C-3),
+
167.6 (C=O), 172.0 (C=O); ms: m/z 301 [M+H] .
Anal. Calcd. for C H N O (MW 300.3): C, 63.99; H, 5.37;
16 16 2 4
N, 9.33. Found: C, 63.94; H, 5.38; N, 9.21.
-1
2235 (C≡N), 1660 cm (C=O); pmr (DMSO-d ): δ, ppm 4.41
6
(dd, J = 3.2, 9.0 Hz, 1H, 3-H), 4.55 (dd, J = 3.2, 9.0 Hz, 1H, 2-H),
4.96 (t, J = 9.0 Hz, 1H, 2-H), 6.56 (s, 2H, NH ), 7.14-7.36 (m,
2
5H, aryl), 11.97 (s, 1H, NH); cmr (DMSO-d ): δ, ppm 42.9 (C-3),
General Procedure for the Preparation of 3-Pyridinecarbonitriles 4.
6
71.5 (C-7), 80.7 (C-2), 89.7 (=C), 117.3 (C≡N), 126.9, 127.0,
128.5, 142.0 (C aryl), 157.2 (O-C=), 162.5 (C-6), 163.3 (C-4);
A mixture of 2e,f (0.54 g, 2 mmoles), methanesulfonic acid
(0.23 g, 2.4 mmoles) and dioxane (2 ml) was stirred at room tem-
perature (in the case of the preparation of 4a) or 70°(4b) for 5
hours (4a) or 2 hours (4b). The solvent was removed in vacuo
and cold water was added to the residue. The resulting precipitate
was collected by filtration, washed with water and dried to yield
4a,b.
+
ms: m/z 254 [M+H] .
Anal . Calcd. for C H N O (MW 253.3): C, 66.39, H, 4.38;
14 11
N, 16.59. Found: C, 66.12; H, 4.57; N, 16.55.
3 2
REFERENCES AND NOTES
2,4-Diamino-1,6-dihydro-5-(2-hydroxy-1-phenylethyl)-6-oxo-3-
pyridinecarbonitrile (4a) Semi Hydrate.
[1] H. M. R. Hoffmann and J. Rabe, Angew. Chem., Int. Ed.
Engl., 24, 94 (1985).
[2] S. M. Kupchan, M. A. Eakin and A. M. Thomas, J. Med.
Chem., 14, 1147 (1971).
[3] C. R. Hutchinson, J. Org. Chem., 39, 1854 (1974).
[4] Y. Iino, A. Tanaka and K. Yamashita, Agric. Biol. Chem.,
36, 2505 (1972).
[5] R. Ballini, G. Bosia and D. Livi, Synthesis, 1519 (2001).
[6] F. T. Luo, M. W. Wang and Y. S. Lin, Heterocycles, 43,
2725 (1996).
[7] J. Ji and X. Lu, Tetrahedron, 50, 9067 (1994).
[8] X. Lu, Z. Wang and J. Ji, Tetrahedron Lett., 613 (1994).
[9] N. Petragnani, M. C. Ferraz and G. V. J. Silva, Synthesis,
157 (1986).
[10] P. A. Grieco, Synthesis, 67 (1975).
[11] K. Yamagata, F. Okabe, M. Yamazaki and Y. Tagawa,
Monatsch. Chem., 133, 643 (2002).
This compound was obtained as colorless prisms (0.38 g,
73%), m.p. 238° (dec.) (methanol); ir (potassium bromide): ν
-1
3360, 3230 (NH, OH), 2220 (C≡N), 1660 cm (C=O); pmr
(DMSO-d ): δ, ppm 3.90-4.20 (m, 3H, 1'-H, 2'-H), 5.38 (s, 1H,
6
OH), 6.05 (s, 2H, NH ), 6.09 (s, 2H, NH ), 7.15-7.33 (m, 5H,
2
aryl), 9.97 (s, 1H, NH); cmr (DMSO-d ): δ, ppm 40.5 (C-1'), 62.0
2
6
(C-2'), 69.8 (C-3), 87.6 (C-5), 118.4 (C≡N), 125.8, 127.3, 128.4,
140.5 (C aryl), 151.6 (C-4), 160.0 (C-2), 160.9 (C-6); ms: m/z
+
271 [M+H] .
Anal. Calcd. for C H N O •0.5H 0 (MW 279.3): C, 60.21,
14 14 4 2 2
H, 5.41; N, 20.06. Found: C, 60.26; H, 5.25; N, 19.87.
2,4-Diamino-1,6-dihydro-5-(2-hydroxy-2-phenylethyl)-6-oxo-3-
pyridinecarbonitrile (4b).
This compound was obtained as colorless prisms (0.27 g,