Syntheses of pyrrolo- and furo-1,4-dihydropyridine derivatives

Article abstract of DOI:10.3987/COM-04-10252

Methyl 4-aryl-1,4,5,7-tetrahydro-2,7,7-trimethyl-5-oxo-6H-pyrrolo-[4,3-b]pyridine-3-carboxylates and methyl 1,4,5,7-tetrahydro-3-methyl-7-oxo-4-phenylfuro[3,4-b]pyridine-3-carboxylate were synthesized. Attempting synthesis of methyl 4-aryl-1,3,5,7a-tetrah

Full text of DOI:10.3987/COM-04-10252

HETEROCYCLES, Vol. 65, No. 2, 2005
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HETEROCYCLES, Vol. 65, No. 2, 2005, pp. 377 - 386
Received, 14th October, 2004, Accepted, 15th December, 2004, Published online, 17th December, 2004
SYNTHESES OF PYRROLO- AND FURO-1,4-DIHYDRO-
PYRIDINE DERIVATIVES
Keizo Matsuo,* Masami Adachi, Tatsuko Takagi, Sachiko Ueno, Takahiko
Arase, and Fumie Kuroi
Faculty of Pharmaceutical sciences, Kinki University, 3-4-1 Kowakae,
Higashiosaka, Osaka 577-8502, Japan. e-mail: k-matsuo@phar.kindai.ac.jp
Abstract- Methyl 4-aryl-1,4,5,7-tetrahydro-2,7,7-trimethyl-5-oxo-6H-pyrrolo-
[4,3-b]pyridine-3-carboxylates and methyl 1,4,5,7-tetrahydro-3-methyl-7-oxo-
4-phenylfuro[3,4-b]pyridine-3-carboxylate were synthesized. Attempting
synthesis of methyl 4-aryl-1,3,5,7a-tetrahydro-1,1,6-trimethyl-3-oxofuro[3,4-c]-
pyridine-7-carboxylates failed.
1,4-Dihydropyridine derivatives, for example, nifedipine (1) and nicardipine (2), are used clinically for
the treatment of angina pectoris, cerebrovascular disorders, hypertension and so on.1 In the course of our
synthetic studies on the biologically active heterocyclic compounds using tetronic acids, tetramic acids,
thiotetronic acid and their analogs,2 we planned to synthesize methyl 4-aryl-1,4,5,7-tetrahydro-2,7,7-
trimethyl-5-oxo-6H-pyrrolo[4,3-b]pyridine-3-carboxylates (3), methyl 1,4,5,7-tetrahydro-3-methyl-7-
oxo-4-phenylfuro[3,4-b]pyridine-3-carboxylate (4), and methyl 4-aryl-1,3,5,7a-tetrahydro-1,1,6-tri-
methyl-3-oxofuro[3,4-c]pyridine-7-carboxylates (5) expecting their biological activities (Figure 1).
O
R2
CO2R1
R
CO2CH3
CH3O2C
O
O
CH3O2C
CO2CH3
N
HN
O
H
N
N
H
N
H
R
H
O
1: Nifedipine
3a: R= H
4
5a: R=H
b: R=Cl
R1= CH3; R2= 2-NO2
2: Nicardipine
b: R= 2-Cl
c: R= 3-NO2
R1=CH2CH2N(CH3)(CH2C6H5)
R2=3-NO2
Figure 1
For the synthesis of methyl 4-aryl-1,4,5,7-tetrahydro-2,7,7-trimethyl-5-oxo-6H-pyrrolo[4,3-b]pyridine-3-
carboxylates (3), 5,5-dimethyltetramic acid (6)3 was used for the synthon. 3-Arylmethylene-5,5-

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HETEROCYCLES, Vol. 65, No. 2, 2005
dimethyltetramic acids (7a～c) were derived from 6 by treatment with the corresponding aryl aldehydes
in the presence of conc. hydrochloric acid without solvents.4 When 5,5-dimethyl-3-phenyl-
methylenetetramic acid (7a) was treated with methyl acetoacetate in the presence of triethylamine in
1
methanol at refluxing temperature, the Micheal adduct (8a) was obtained in 96% yield. Its H-NMR
spectrum showed that 8a was a mixture of diastereoisomers. When 8a was allowed to react with
ammonium acetate in methanol at room temperature, the alcohol (9a) was isolated in 43% yield.
Elemental analysis and MS spectral data supported the molecular formula of C18H22N2O4. In IR spectrum,
1
the α,β-unsaturated ester and the five membered ring lactam appeared at 1670 cm-1. The H-NMR
spectrum showed the benzylic methine proton signal at δ4.98. For the following dehydration reaction,
the alcohol (9a) was first heated with p-toluenesulfonic acid in benzene, but the isolated product in 41%
yield was the undesired pyridine derivative (10). Therefore, the same reaction was repeated using a
catalytic amount of p-toluenesulfonic acid. On this reaction, the desired dihydropyridine derivative (3a)
1
was isolated in 39% yield. The structure of 3a was fully characterized by IR, H-NMR and MS spectral
data. Other dihydropyridine derivatives (3b, R=2-Cl and 3c, R=3-NO2) were also prepared by similar
reaction procedures to that used for 3a in moderate yields (Scheme 1). In the preparation of 9c, the
intermediate (8c) was not isolated and used directly for the next reaction.
R
R
O
O
O
O
CO2CH3
CO2CH3
CHO
R
HN
HN
HN
(C2H5)3N
CH3OH
c. HCl
OH
O
O
OH
6
7a: R= H (82%)
b: R= 2-Cl (79%)
c: R= 3-NO2 (35%)
8a: (96%)
b: (63%)
c: (not isolated)
R
CO2CH3
R
O
O
HN
O
HN
CO2CH3
CO2CH3
p-TsOH
CH3CO2NH4
CH3OH
HN
C6H6
N
H
N
H
N
OH
10
3a: (39%)
b: (66%)
c: (52%)
9a: (43%)
b: (59%)
c: (76% from 7c)
Scheme 1
For the preparation of methyl 1,4,5,7-tetrahydro-3-methyl-7-oxo-4-phenylfuro[3,4-b]pyridine-3-
carboxylate (4), 3-benzylidene-2-oxo-4-butanolide (11)5 was treated first with methyl acetoacetate in
methanol in the presence of triethylamine at reflux temperature to afford the Michael adduct (12) in 90%
yield. The adduct (12) was then reacted with ammonium acetate in methanol at room temperature
overnight to obtain the hydroxy ester (13) in 54% yield. When 13 was dehydrated by treatment with
catalytic amount of p-TsOH in benzene, the desired furodihydropyridine derivative (4) was obtained in

HETEROCYCLES, Vol. 65, No. 2, 2005
379
93% yield accompanied with the furopyridine derivative (14) (4%) as a by-product (Scheme 2).
O
CO2CH3
CO2CH3
CO2CH3
CH3CO2NH4
O
O
O
(C2H5)3N
CH3OH
(90%)
CH3OH
(54%)
O
N
O
OH
H
O
O
O
OH
13
11
12
CO2CH3
CO2CH3
p-TsOH
+
O
O
O
C6H6
N
N
H
O
4: (93%)
14: (4%)
Scheme 2
For the synthesis of methyl 4-aryl-1,3,5,7a-tetrahydro-1,1,6-trimethyl-3-oxofuro[3,4-c]pyridine-7-
carboxylates (5a, R=H or 5b, R=Cl), 2-aroyl-4,4-dimethyl-2-buten-4-olides (15)6 was used as the starting
material. When 2-benzoyl-4,4-dimethyl-2-buten-4-olide (15a) was treated with methyl acetoacetate in
the presence of triethylamine in methanol at room temperature, the Michael adduct (16) and the alcohol
(17) were isolated in 36 and 38% yields, respectively.
O
O
O
O
CH3O2C
O
CO2CH3
CH3O2C
O
O
O
+
(C2H5)3N
CH3OH, rt
O
O
O
OH
17 (38%)
15a
16 (36%)
O
O
O
CH3O2C
CH3O2C
CH3O2C
CH3CO2NH4
O
O
O
CH3OH
reflux
N
H
O
N
O
16
5a
18 (27%)
Scheme 3
The stereochemistry of α and β-positions of the γ-lactone in 16 supposed to be cis, because, in its
1H-NMR spectrum, these two protons appeared at δ 4.85 (d, J=10.0 Hz) and 3.88 (t, J=10.0 Hz),

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HETEROCYCLES, Vol. 65, No. 2, 2005
respectively. Expecting to obtain the dihydropyridine derivative (5a), successive treatment of the
Michael adduct (16) with ammonium acetate in methanol at refluxing temperature resulted in the isolation
of the pyridine derivative (18) in 27% yield. During the reaction, two spots supposed to be 5a and 18
were observed on the TLC, but TLC analysis of the worked up crude products showed disappearance of
the spot supposed to be 5a. Therefore, the milder reaction conditions were employed next in the hope of
isolation of 5a. Thus, the same reaction was performed at room temperature, however no reaction took
place (Scheme 3).
Since the structure of the by-product (17) in the above reaction was not clear at that stage, 17 was
similarly treated with ammonium acetate in methanol at refluxing temperature. The product isolated in
30% yield was the amine (19), whose structure was confirmed by X-Ray crystallographic analysis. When
17 was reacted with p-TsOH in benzene, α,β-unsaturated ketoester (20) was obtained in 47% yield. These
results indicate the structure of the by-product to be 17.
O
O
O
p-TsOH
C6H6,
H
CH3CO2NH4
CH3O2C
O
CH3O2C
H2N
CH3O2C
O
O
O
O
reflux
CH3OH
(30%)
H
(47%)
OH
17
19
20
O
O
O
O
CO2CH3
H
1)
CH3O2C
CH3O2C
O
O
O
p-TsOH
(C2H5)3N, CH3OH
H
O
C6H6
reflux
(57%)
N
N
2)
CH3CO2NH4
CH3OH, reflux
(20%)
OH
H
Cl
Cl
21
Cl
22
15b
Scheme 4
When 2-(2-chlorobenzoyl)-4,4-dimethyl-2-buten-4-olide (15b) was treated with methyl acetoacetate in
the presence of triethylamine and successively with ammonium acetate, the alcohol (21) was obtained in
20% yield. The cis stereochemistry of the ring junction of 21 was attributed to the coupling constant (10
Hz) between those two methine protons. Dehydration reaction of 21 with p-TsOH in benzene at
refluxing temperature in the hope of the isolation of the dihydropyridine derivative gave again the
pyridine derivative (22) in 57% yield and 5b was not isolated (Scheme 4).
In conclusion, methyl 4-aryl-1,4,5,7-tetrahydro-2,7,7-trimethyl-5-oxo-6H-pyrrolo[4,3-b]pyridine-3-
carboxylates (3a-c) and methyl 1,4,5,7-tetrahydro-3-methyl-7-oxo-4-phenylfuro[3,4-b]pyridine-3-
carboxylate (4) were synthesized. Attempting synthesis of methyl 4-aryl-1,3,5,7a-tetrahydro-1,1,6-
trimethyl-3-oxofuro[3,4-c]pyridine-7-carboxylates (5a, b) failed and the product was the furopyridine
derivatives (18, 22).

HETEROCYCLES, Vol. 65, No. 2, 2005
381
EXPERIMENTAL
Melting points were determined using a Yanagimoto micro-melting point apparatus, model MP-S3, and
are uncorrected. IR spectra were measured with a Hitachi 260-30 infrared spectrophotometer. 1H-NMR
spectra were recorded on a JEOL JNM-GSX270 (270 MHz) spectrometer using tetramethylsilane as the
internal standard. High-resolution MS spectra (HRMS) were measured with a JEOL JMS-HX100
instrument at 70 eV.
Methyl 2-[1-(4,4-dimethyl-3-oxo-4-butanelactum-2-yl)-1-phenyl]methyl-3-oxobutanoate (8a)
Triethylamine (0.25 mL, 1.79 mmol) was added to a solution of methyl acetoacetate (0.546 g, 4.70 mmol)
in MeOH (5 mL) and the solution was stirred for 10 min. To this solution was added dropwise a solution
of 7a (1.004 g, 4.66 mmol) in MeOH (12 mL), and the whole was heated under reflux for 5 h. After
cooling the reaction mixture, the precipitates formed were collected by filtration and crystallized from
MeOH to give 8a (1.489 g, 96%). mp 147-152 ℃. IR (Nujol): 3350, 1710, 1660, 1590, 1240, 1010 cm-1.
1H-NMR (DMSO-d6) δ: 1.13, 1.18 (each 3H, s, CH3), 2.17 (3H, s, CH3), 3.64 (3H, s, OCH3), 4.47 (1H, d,
J=12.0 Hz, CH), 4.99 (1H, d, J=12.0 Hz, CH), 7.2 (7H, m, ArH, OH, NH). HRMS (m/z) Calcd for
C18H21NO5: 331.1420. Found: 331.1423.
Methyl 1,4,4a,5,7-pentahydro-7a-hydroxy-2,7,7-trimethyl-5-oxo-4-phenyl-6H-pyrrolo[4,3-b]-
pyridine-3-carboxylate (9a)
A solution of 8a (3.802 g, 11.47 mmol) and ammonium acetate (4.409 g, 57.19 mmol) in MeOH (150
mL) was stirred at rt overnight. The mixture was concentrated under reduced pressure to give the residue,
to which was added H2O. The precipitates formed were collected by filtration and crystallized from
AcOEt to give 9a (1.623 g, 43%). mp 167-169 ℃. IR (Nujol): 3360, 3170, 1750, 1670, 1600, 1290, 1260,
1090 cm-1. 1H-NMR (DMSO-d6) δ: 1.11, 1.17 (3H, s, CH3), 2.34 (3H, s CH3), 2.86 (1H, s CH), 3.39 (3H,
s, OCH3), 3.35 (3H, s, OCH3), 4.28 (1H, s, OH), 4.98 (1H, s ArCH), 6.14 (1H, br s, NH), 7.15-7.25 (5H,
ArH), 7.63 (1H, s, NH). Anal. Calcd for C18H22N2O4: C, 65.44; H, 6.71; N, 8.48. Found: C, 65.31; H,
6.68; N, 8.53. MS (m/z): 330 (M+), 312, 298, 235, 215.
Methyl 1,4,4a,5,7-pentahydro-7a-hydroxy-2,7,7-trimethyl-5-oxo-4-(2-chlorophenyl)-6H-pyrrolo-
[4,3-b]pyridine-3-carboxylate (9b)
Triethylamine (0.55 mL, 3.94 mmol) was added to a solution of methyl acetoacetate (2.117 g, 18.23
mmol) in MeOH (50 mL) and the solution was stirred for 10 min. To this solution was added dropwise a
solution of 7b (4.571 g, 18.31 mmol) in MeOH (70 mL), and the whole was heated under reflux for 5 h.
After concentration of the mixture under reduced pressure to give the residue, which was purified by SiO2
column chromatography (acetone:hexane=1:2) to afford 8b (4.223 g, 63%), after crystallization from
2-propanol-hexane. This Michael adduct (8b) (4.223 g, 11.54 mmol) was dissolved in MeOH (70 mL). To
this solution was added ammonium acetate (2.661 g, 34.51 mmol), and the whole was stirred at rt
overnight. After concentration, H2O was added to the residue to form the precipitates, which were
collected by filtration and then crystallized from DMSO-H2O to give 9b (2.471 g, 59%). mp 182-183 ℃.
1
IR (Nujol): 3425, 3275, 1740, 1670, 1610, 1290, 1270, 1080 cm-1. H-NMR (DMSO-d6) δ: 1.10, 1.17

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HETEROCYCLES, Vol. 65, No. 2, 2005
(each 3H, s, CH3), 2.38 (3H, s, CH3), 2.86 (1H, s, CH), 3.34 (3H, s, OCH3), 4.69 (1H, s, ArCH), 5.14 (1H,
OH), 6.20 (1H, br s, NH), 7.10-7.36 (4H, m, ArH), 7.62 (1H, s, NH). HRMS (m/z) Calcd for
C18H21N2O4Cl: 364.1190. Found: 364.1198.
Methyl 1,4,4a,5,7,7a-hexahydro-7a-hydroxy-2,7,7-trimethyl-5-oxo-4-(3-nitrophenyl)-6H-pyrrolo-
[4,3-b]pyridine-3-carboxylate (9c)
Triethylamine (0.10 mL, 0.72 mmol) was added to a solution of methyl acetoacetate (0.225 g, 1.94 mmol)
in MeOH (5 mL) and the solution was stirred for 10 min. To this solution was added dropwise a solution
of 7c (0.350 g, 1.34 mmol) in MeOH (24 mL), and the whole was heated under reflux for 2 h.
Concentration of the mixture under reduced pressure gave the crude 8c (0.70 g) as an oil, which was
dissolved in MeOH (18 mL). To this solution was added ammonium acetate (0.505 g, 6.55 mmol), and the
whole was stirred at rt for 5 h. After addition of ammonium acetate (0.207 g, 2.68 mmol), the mixture was
stirred at rt overnight. After concentration, H2O was added to the residue to form the precipitates, which
were collected by filtration and then crystallized from MeOH to give 9c (0.380 g, 76%). mp 189-193 ℃.
1
IR (Nujol): 3290, 1720, 1660, 1600, 1270, 1250, 1210, 1190, 1100, 1060 cm-1. H-NMR (DMSO-d6) δ:
1.09, 1.16 (each 3H, s, CH3), 2.38 (3H, s, CH3), 2.94 (1H, s, CH), 3.34 (3H, s, OCH3), 4.35 (1H, s, OH),
5.51 (1H, s, ArCH), 6.56 (1H, s, NH), 7.51 (1H, t, J=8.0 Hz, ArH), 7.68 (1H, br d, J=8.0 Hz, ArH), 7.82
(1H, s, NH), 7.97 (1H, br d, J=8.0 Hz, ArH), 8.03 (1H, br s, ArH). HRMS (m/z) Calcd for C18H21N3O6:
375.1430. Found: 375.1445.
Methyl 5,7-dihydro-2,7,7-trimethyl-5-oxo-4-phenyl-6H-pyrrolo[4,3-b]pyridine-3-carboxylate (10)
p-TsOH・H2O (0.431 g, 2.72 mmol) was added to a solution of 9a (0.30 g, 0.908 mmol) in C6H6 (20 mL)
and the reaction mixture was heated under reflux for 2 h, during the reaction, water formed was removed
continuously. After cooling, the reaction mixture was concentrated under reduced pressure to give the
residue, which was dissolved in CHCl3. The solution was washed with saturated NaHCO3 aqueous
solution, H2O, and brine, respectively and then dried over Na2SO4. Removal of the solvent gave the
residue, which was crystallized from CHCl3-hexane to afford 10 (0.115 g, 41%). mp 217-220 ℃. IR
(Nujol): 3210, 1710, 1690, 1590, 1570, 1370, 1270, 1160, 1100 cm-1. 1H-NMR (CDCl3) δ: 1.58 (6H, s, 2
x CH3), 2.68 (3H, s, CH3), 3.57 (3H, s, OCH3), 6.31 (1H, s, NH), 7.36-7.42 (5H, m, ArH). Anal. Calcd for
C18H18N2O3: C, 69.66; H, 5.85; N, 9.03. Found: C, 69.72; H, 5.87; N, 9.04.
Methyl 1,4,5,7-tetrahydro-2,7,7-trimethyl-5-oxo-4-phenyl-6H-pyrrolo[4,3-b]pyridine-3-carboxylate
(3a)
p-TsOH・H2O(80 mg, 0.42 mmol) was added to a solution of 9a (0.256 g, 0.775 mmol) in C6H6 (90 mL)
and the reaction mixture was heated under reflux for 1 h, during the reaction, water formed was removed
continuously. After cooling the reaction mixture, the precipitates formed were collected by filtration.
o
Recrystallization of the precipitates from 2-propanol-hexane gave 95 mg (39%) of 3a. mp 198-201 C.
IR (Nujol): 3300, 1710, 1660, 1610, 1220, 1090 cm-1. 1H-NMR (DMSO-d6) δ: 1.29 and 1.31 (each 3H,
s, CH3), 2.32 (3H, s, CH3), 3.47 (3H, s, OCH3), 4.66 (1H, s, ArCH), 7.05-7.25 (5H, m, ArH), 7.29 (1H, s,
CONH), 8.99 (1H, br s, NH). HRMS (m/z) Calcd for C18H20N2O3: 312.1474. Found: 312.1492.

HETEROCYCLES, Vol. 65, No. 2, 2005
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Methyl 1,4,5,7-tetrahydro-2,7,7-trimethyl-5-oxo-4-(2-chlorophenyl)-6H-pyrrolo[4,3-b]pyridine-3-
carboxylate (3b)
3b (0.565 g, 66%) was obtained from 9b (0.90 g, 2.47 mmol) and p-TsOH・H2O (94 mg, 0.493 mmol) by
the same procedure used for 3a. mp 285-289 ℃ (MeOH-hexane). IR (Nujol): 3200, 1700, 1660, 1640,
1270, 1210, 1170, 1080, 1040 cm-1. 1H-NMR (DMSO-d6) δ: 1.28 and 1.32 ( each 3H, s, CH3), 2.30 (3H, s,
CH3), 3.41 (3H, s, OCH3), 5.11 (1H, s, ArCH), 7.10 (1H, s, NH), 7.17-7.26 (4H, m, ArH), 9.02 (1H, s,
NH). Anal. Calcd for C18H19N2O3Cl: C, 62.34; H, 5.52; N, 8.08. Found: C, 62.32; H, 5.58; N, 7.99
Methyl 1,4,5,7-tetrahydro-2,7,7-trimethyl-4-(3-nitrophenyl)-5-oxo-6H-pyrrolo[4,3-b]pyridine-3-
carboxylate (3c)
3c (54 mg, 52%) was obtained from 9c (0.110 g, 0.293 mmol) and p-TsOH・H2O (11 mg, 0.058 mmol) by
the same procedure used for 3a. mp 173-176 ℃ (MeOH). IR (Nujol): 3280, 1710, 1680, 1640, 1610,
1340, 1220, 1190, 1090, 1030 cm-1. 1H-NMR (DMSO-d6) δ: 1.30 and 1.32 ( each 3H, s, CH3), 2.33 (3H, s,
CH3), 3.48 (3H, s, OCH3), 4.83(1H, s, ArCH), 7.42 (1H, s, NH), 7.50-8.02 (4H, m, ArH), 9.20 (1H, s,
NH). HRMS (m/z) Calcd for C18H19N3O5: 357.1325. Found: 357.1317.
3-(2-Methoxycarbonyl-3-oxo-1-phenylbutyl)-2-oxo-4-butanolide (12)
To a solution of methyl acetoacetate (1.83 g, 15.76 mmol) and triethylamine (0.8 mL, 5.74 mmol) in
MeOH (40 mL) was added drop wise a solution of 11 (2.0 g, 10.63 mmol) in MeOH (60 mL), and the
whole was heated under reflux for 4.5 h. After cooling the reaction mixture, the precipitates formed were
collected by filtration to give 12 (2.90 g, 90%). mp 137-138.5 ℃ (2-propanol-hexane). IR (Nujol): 3420,
1
1740, 1680, 1250, 1150, 1130, 1090, 1040, 1000 cm-1. H-NMR (DMSO-d6) δ: 1.98 (3H, s, CH3), 3.63
(3H, s, OCH3), 4.40-4.80 (4H, m, ArCH, OCH2, COCHCO), 7.27 (5H, m, ArH), 9.80 (1H, br s, OH).
HRMS (m/z) Calcd for C16H16O6: 304.0947. Found: 304.0921.
Methyl 1,4,4a,5,7,7a-hexahydro-7a-hydroxy-2-methyl-7-oxo-4-phenylfuro[3,4-b]pyridine-3-
carboxylate (13)
A solution of 12 (0.20 g, 0.66 mmol) and ammonium acetate (0.26 g, 3.37 mmol) in MeOH (10 mL) was
stirred at rt overnight. The mixture was concentrated under reduced pressure to give the residue, to which
was added H2O. The precipitates formed were collected by filtration to give 13 (0.107 g, 54%), which
was crystallized from AcOEt. mp 185-188.5 ℃. IR (Nujol): 3350, 1760, 1675, 1590, 1290, 1220, 1120,
1100, 1000 cm-1. 1H-NMR (DMSO-d6) δ: 2.34 (3H, s CH3), 2.95 (1H, m OCH2CH), 3.39 (3H, s, OCH3),
3.75 (1H, dd, J=10.0, 8.0 Hz, OCH2CH), 3.91 (1H, br s, ArCH), 4.44 (1H, t, J=8.0 Hz, OCH2CH), 5.95
(1H, br s, OH), 7.21 (5H, m, ArH), 7.33 (1H, br s, NH). HRMS (m/z) Calcd for C16H17NO5: 303.1107.
Found: 303.1086.
Methyl 1,4,5,7-tetrahydro-3-methyl-7-oxo-4-phenylfuro[3,4-b]pyridine-3-carboxylate (4) and
Methyl 5,7-dihydro-3-methyl-7-oxo-4-phenylfuro[3,4-b]pyridine-3-carboxylate (14)
p-TsOH・H2O (0.010 g, 0.05 mmol) was added to a solution of 13 (0.30 g, 0.99 mmol) in C6H6 (120 mL)
and the reaction mixture was heated under reflux for 5 min, during the reaction, water formed was

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removed continuously. After cooling, the reaction mixture was washed with saturated NaHCO3 aqueous
solution, H2O, and brine, respectively and then dried over Na2SO4. Removal of the solvent gave the
residue, which was crystallized from C6H6 to afford 4 (0.252 g). The filtrate was concentrated under
reduced pressure and the residue was purified by SiO2 PTLC (C6H6:AcOEt=4:1) to give 4 (11 mg, total
0.263 g, 93%) and 14 (10 mg, 4%). 4: mp 198-200 ℃ (C6H6). IR (Nujol): 3300, 1740, 1710, 1640, 1590,
1500, 1260, 1100 cm-1. 1H-NMR (CDCl3) δ: 2.42 (3H, s, CH3), 3.55 (3H, s, OCH3), 4.51, 4.68 (each 1H,
dd, J=16.5, 1.8 Hz, OCH2C), 4.94 (1H, br s, ArCH), 7.15-7.37 (5H, m, ArH). Anal. Calcd for C16H15NO4:
C, 67.36; H, 5.30; N, 4.91. Found: C, 67.33; H, 5.36; N, 4.83. 14: mp 200-203 ℃ (C6H6). IR (CHCl3):
1782, 1734, 1595, 1456, 1355, 1289, 1218, 1212, 1174, 1101, 1030 cm-1. 1H-NMR (CDCl3) δ: 2.76 (3H, s,
CH3), 3.67 (3H, s, OCH3), 5.27 (2H, s, OCH2), 7.18-7.35 (5H, m, ArH). HRMS (m/z) Calcd for
C16H13NO4: 283.0845. Found: 283.0856.
2-Benzoyl-3-(1-methoxycarbonyl-2-oxopropyl)-4-methyl-4-pentanolide (16) and Methyl
1,3,3a,4,5,6,7,7a-octahydro-4-hydroxy-1,1-dimethyl-4-phenylisobenzofuran-7-carboxylate (17)
To a solution of methyl acetoacetate (0.787 g, 6.78 mmol) and triethylamine (0.4 mL, 2.87 mmol) in
MeOH (10 mL) was added dropwise a solution of 15a (1.008 g, 4.66 mmol) in MeOH (18 mL), and the
whole was stirred at rt for 5 h. The precipitates formed were collected by filtration to give 17 (0.589 g,
38%). After concentration of the filtrate, the residue was crystallized from 2-propanol to give 16 (0.554 g,
1
36%). 16: mp 114-120 ℃. IR (Nujol): 1755, 1730, 1715, 1675, 1595, 1580 cm-1. H-NMR (CDCl3) δ:
1.38, 1.58 (each 3H, s, CH3), 2.14 (3H, s, COCH3), 3.54 (1H, d, J=10.0 Hz, CHCO2CH3), 3.77 (3H, s,
CO2CH3), 3.88 (1H, t, J=10.0 Hz, CHC(CH3)2), 4.85 (1H, d, J=10.0 Hz, CHCOPh), 7.46-8.05 (5H, m,
ArH). Anal. Calcd for C18H20O6: C, 65.05; H, 6.07. Found: C, 65.10; H, 6.09. 17: mp 210-212 ℃. IR
(Nujol): 3400, 1765, 1750, 1710 cm-1. 1H-NMR (DMSO-d6) δ: 1.33, 1.38 (each 3H, s, CH3), 3.73, (3H, s,
OCH3), 5.96 (1H, br s, OH), 7.20-7.61 (5H, m, ArH). Anal. Calcd for C18H20O6: C, 65.05; H, 6.07. Found:
C, 64.92; H, 6.06.
Methyl 1,3-dihydro-1,1,6-trimethyl-3-oxo-4-phenylfuro[3,4-c]pyridine-7-carboxylate (18)
A solution of 16 (0.425 g, 1.28 mmol) and ammonium acetate (0.558 g, 7.24 mmol) in MeOH (17 mL)
was stirred at rt for 6 h, and then heated under reflux for 2 h. The mixture was concentrated under reduced
pressure to give the residue, to which was added H2O. The mixture was extracted with CHCl3 and the
extracts were washed with brine and dried over Na2SO4. Removal of the solvent afforded an yellow oil
(0.422 g), 0.141 g of which was purified by SiO2 column chromatography (ether:hexane=3:2) to give 18
(36 mg, 27%) as colorless crystals. mp 127-130 ℃ (ether). IR (CHCl3): 1760, 1725, 1585, 1275, 1235,
1
1205, 1160, 1120, 1070, 1015 cm-1. H-NMR (CDCl3) δ: 1.74 (6H, s, 2 x CH3), 2.76 (3H, s, CH3), 4.02
(3H, s, OCH3), 7.46-7.94 (5H, m, ArH). Anal. Calcd for C18H17NO4: C, 69.44; H, 5.50; N, 4.50. Found: C,
69.36; H, 5.55; N, 4.40.
Methyl 6-amino-1,3,3a,7a-tetrahydro-1,1-dimethyl-3-oxo-4-phenylisobenzofuran-7-carboxylate (19)
A mixture of 17 (0.374 g, 1.13 mmol) and ammonium acetate (0.500 g, 6.49 mmol) in MeOH (20 mL)
was heated under reflux for 3 h. After addition of further ammonium acetate (0.250 g, 3.24 mmol), the

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mixture was heated under reflux for further 2 h. The mixture was concentrated under reduced pressure to
give the residue, to which was added H2O to form the precipitates. Purification of the products by SiO2
column chromatography (CHCl3) gave 19 (0.108 g, 30%) as yellow crystals. mp 183-185 ℃ (C6H6). IR
1
(Nujol): 3450, 3330, 1755, 1665, 1605, 1535, 1280, 1235, 1190, 1095 cm-1. H-NMR (CDCl3) δ: 1.29,
1.505 (each 3H, s, CH3), 3.75 (3H, s, OCH3), 3.82 (1H, d, J=11.5 Hz, (CH3)2CCH), 4.15 (1H, dd, J=11.5,
2.5 Hz, COCH), 5.99 (1H, d, J=2.5 Hz, =CH), 7.33-7.47 (5H, m, ArH). HRMS (m/z) Calcd for
C18H19NO4: 313.1314. Found: 313.1333. Anal. Calcd for C18H19NO4: C, 69.00; H, 6.11; N, 4.47. Found:
C, 68.98; H, 6.09; N, 4.48.
Methyl 1,3,3a,6,7,7a-hexahydro-1,1-dimethyl-3,6-dioxo-4-phenylisobenzofuran-7-carboxylate (20)
p-TsOH・H2O(1.436 g, 7.55 mmol) was added to a solution of 17 (1.932 g, 5.81 mmol) in C6H6 (250 mL)
and the reaction mixture was heated under reflux for 7 h, during the reaction, water formed was removed
continuously. After cooling, the reaction mixture was washed with saturated NaHCO3 aqueous solution,
H2O, and brine, respectively. The organic layer was dried over Na2SO4 and then concentrated under
reduced pressure to give the brawn oil, which was crystallized from AcOEt-hexane to afford 20 (0.861 g,
47%) as colorless crystals. mp 115-120 ℃. IR (Nujol): 1765, 1740, 1660, 1610, 1260, 1155, 1120, 1010
cm-1. 1H-NMR (CDCl3) δ: 1.39, 1.60 (each 3H, s, CH3), 3.54 (1H, dd, J=11.5, 7.0 Hz, CHC(CH3)2),
3.61 (1H, d, J=11.5 Hz, COCHCO), 3.86 (3H, s, OCH3), 4.47 (1H, dd, J=7.0, 1.0 Hz, ArCCH), 6.54 (1H,
d, J=1.0 Hz, C=CH), 7.40-7.66 (5H, m, ArH). Anal. Calcd for C18H18O5: C, 68.78; H, 5.77; N. Found: C,
68.72; H, 5.72.
Methyl 4-(2-chlorophenyl)-1,3,3a,4,5,7a-hexahydro-4-hydroxy-1,1,6-trimethyl-3-oxofuro[3,4-c]-
pyridine-7-carboxylate (21)
To a mixture of methyl acetoacetate (0.412 g, 3.55 mmol) and triethylamine (0.2 mL, 1.44 mmol) in
MeOH (15 mL) was added dropwise a solution of 15b (0.540 g, 2.15 mmol) in MeOH (10 mL), and the
whole was stirred at rt for 4 h. The reaction mixture was concentrated under reduced pressure to give an
yellow oil (1.489 g), which was dissolved in MeOH (27 mL). Ammonium acetate (0.870 g, 11.3 mmol)
was added to the mixture and the whole was heated under reflux for 3.5 h. After concentration under
reduced pressure, the residue was dissolved in CHCl3. The mixture was washed with H2O and brine, and
then dried over Na2SO4. Removal of the solvent gave an yellow oil (0.801 g), which was purified by SiO2
column chromatography (CHCl3) to afford 21 (0.156 g, 20%). mp 127-129.5 ℃ (C6H6). IR (Nujol):
1
3400, 3300, 1745, 1690 cm-1. H-NMR (CDCl3) δ: 1.35, 1.55 (each 3H, s, CH3), 2.35 (3H, s, =CCH3),
3.63 (3H, s, OCH3), 3.43 (1H, d, J=10.0 Hz, (CH3)2CCH), 4.15 (1H, d, J=10.0 Hz, COCH), 5.15, 5.78
(each 1H, br s, NH, OH), 7.22-7.48 (4H, m, ArH). MS (m/z): 365, 310, 278, 261, 250, 132. HRMS (m/z)
Calcd for C18H20NO5Cl: 365.1030. Found: 365.1159.
Methyl 4-(2-chlorophenyl)-1,3-dihydro-1,1,6-trimethyl-3-oxofuro[3,4-c]pyridine-7-carboxylate (22)
p-TsOH・H2O (54 mg, 0.284 mmol) was added to a solution of 21 (28 mg, 0.077 mmol) in C6H6 (10 mL)
and the reaction mixture was heated under reflux for 4.5 h, during the reaction, water formed was
removed continuously. After cooling, the reaction mixture was washed with saturated NaHCO3 aqueous
solution and brine, and then dried over Na2SO4. Removal of the solvent gave an oil which was purified by

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SiO2 TLC (ether:hexane=3:1) to give 22 (15 mg, 57%) as colorless crystals. mp 118-123 ℃ (C6H6). IR
(Nujol): 1770, 1720, 1575, 1265, 1210, 1125, 1070, 1055, 1020 cm-1. 1H-NMR (CDCl3) δ: 1.74 (6H, s, 2
x CH3), 2.77 (3H, s, CH3), 4.04 (3H, s, OCH3), 7.35-7.54 (4H, m, ArH). HRMS (m/z) Calcd for
C18H16NO4 (M+-Cl): 310.1079. Found: 310.1071.
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