Reaction of 3-ethoxycarbonylindolizine-1,2-dicarboxylic anhydride: Synthesis of 2-acylindolizines and quinones

Article abstract of DOI:10.3987/COM-00-8950

Reaction of indolizine-1,2-dicarboxylic anhydride with Grignard reagents gave 2-acylindolizine-1-carboxylic acids, which were converted to 2-acylindolizines. The anhydride reacted with anisole in the presence of titanium chloride(IV) to afford 2-(4-methox

Full text of DOI:10.3987/COM-00-8950

HETEROCYCLES, Vol. 53, No.10, 2000, pp. 2143 - 2149, Received, 19th May, 2000
REACTION
DICARBOXYLIC
2-ACYLINDOLIZINES AND QUINONES
OF
3-ETHOXYCARBONYLINDOLIZINE-1,2-
ANHYDRIDE: SYNTHESIS OF
Yasuyoshi Miki,* Noriko Nakamura, Ryota Yamakawa, Hiroko Hachiken, and
Ko-ichi Matsushita
Faculty of Pharmaceutical Sciences, Kinki University, 3-4-1, Kowakae,
Higashi-Osaka 577-8502, Japan
Abstract – Reaction of indolizine-1,2-dicarboxylic anhydride with Grignard
reagents gave 2-acylindolizine-1-carboxylic acids, which were converted to
2-acylindolizines. The anhydride reacted with anisole in the presence of titanium
chloride(IV) to afford 2-(4-methoxybenzoyl)indolizine-1-carboxylic acid, which was
also led to 2-(4-methoxybenzoyl)indolizine.
Successive treatment of the
2-acylindolizine-1-carboxylic acids with phosphorus pentachloride and
aluminum(III) chloride provided the corresponding quinones.
Recently, we showed that the 2-carbonyl group of 1-benzylindole-2,3-dicarboxylic anhydride (1) was
more reactive than the 3-carbonyl group toward Grignard reagents1 and 1 was a useful synthon in the
synthesis of 2-acylindoles,1 cyclopent[3,4-b]indol-3-ones,2 and natural products, murrayaquinone-A3 and
ellipticine.4 The chemistry of indolizine, which is an analogue of indole, is not well known compared with
that of indole, and the synthesis of 2-acylindolizines is more difficult than that of 1- or 3-acylindolizines.5
Moreover, there is no useful and general synthesis of 2-acylindolizines and no report about the reactivity of
indolizine-1,2-dicarboxylic anhydride (2). In this paper we show the synthesis of 2 and its application to
the synthesis of 2-acylindolizines and quinones.
O
O
O
O
N
N
O
CH Ph
O
COOEt
2
1
2
The anhydride (2) was prepared from N-ethoxycarbonylmethylpyridinium bromide (3) as follows.
Reaction of 3 with di-tert-butyl acetylenedicarboxylate in the presence of potassium carbonate gave
di-tert-butyl 3-ethoxycarbonylindolizine-1,2-dicarboxylate (4)(85%).
The ester (4) reacted with

trifluoroacetic acid to afford the corresponding indolizine-1,2-dicarboxylic acid (5)(91%), which was
treated with trifluoroacetic anhydride in refluxing dichloromethane to provide the anhydride (2)(77%).
Scheme 1
t
t
t
COOBu
CF COOH
3
BuO C-C≡C-CO Bu
2
2
+
-
Br
N
N
CH Cl
K CO / THF
2
t
2
( 91% )
2
3
COOBu
( 85% )
CH COOEt
2
COOEt
3
4
O
COOH
COOH
(CF CO) O
3
2
O
N
N
CH Cl
2
( 77% )
2
O
COOEt
COOEt
5
2
Reaction of the anhydride (2) with phenylmagnesium bromide in tetrahydrofuran at -78°C gave 2-benzoyl-
3-ethoxycarbonylindolizine-1-carboxylic acid (6a) in 92% yield, but 1-benzoyl-3-ethoxycarbonyl-
indolizine-2-carboxylic acid (7a) was not isolated.
In a similar manner, treatment of 2 with
methylmagnesium bromide afforded 2-acetyl-3-ethoxycarbonylindolizine-1-carboxylic acid (6b) in 96%
yield. 2 also reacted with anisole in the presence of titanium(IV) chloride to give 2-(4-methoxybenzoyl)-3-
ethoxycarbonylindolizine-1-carboxylic acid (6c) in 95% yield. Decarboxylation of 2-benzoylindolizine-1-
carboxylic acid (6a) was performed by treatment of hot quinoline in the presence of copper chromite to
provide ethyl 2-benzoylindolizine-3-carboxylate (8a) in 78% yield. 6b,c were also converted to ethyl
2-acetylindolizine-3-carboxylate (8b) and ethyl 2-(4-methoxybenzoyl)indolizine-1-carboxylate (8c) in 59%
Scheme 2
O
COOH
R-MgX
COR
O
or
N
N
N
COR
COOEt
COOH
COOEt
/ TiCl4
OMe
O
COOEt
2
6
7
a; R = Ph
b; R = Me
N
COR
COOEt
c; R = 4-MeO-Ph
8

and 35% yields, respectively, but treatment of 6c with 20% perchloric acid in hot acetic acid gave 8c in
82% yield.
Treatment of the carboxylic acid (6a) with phosphorus pentachloride, followed by aluminum(III) chloride
afforded the corresponding quinone (9a) in 85% yield. In a similar manner, the carboxylic acid (6c) was
also converted to the quinone (9c) in 37% yield.
Scheme 3
O
COOH
R
R
1) PCl (5 eq)
5
N
N
2) AlCl
3
O
O
(CH2Cl)2
COOEt
COOEt
9a,c
6a,c
Condition
50°C 4 h
reflux 6 h
R
a
c
Yield(%)
85
a; R = H
c; R = OMe
37
EXPERIMENTAL
Melting points were determined on a Yanagimoto micromelting point apparatus and are uncorrected. The
1H-NMR spectra were determined on a JEOL JNM-GSX 270 spectrometer using tetramethylsilane as an
internal standard. The IR spectra were recorded with a JASCO FT/IR-7000 spectrophotometer. The high
MS were recorded on a JOEL JMS-HX100 spectrometer. Column chromatography was performed on E.
Merck silica gel 60 (70-230 mesh or 230-400 mesh). Tetrahydrofuran (THF) was distilled from sodium
and benzophenone prior to use. Phenylmagnesium bromide (1.0 M solution in THF) and
methylmagnesium bromide (1.4 M solution in toluene and tetrahydrofuran) were purchased from Aldrich.
Di-tert-butyl 3-Ethoxycarbonylindolizine-1,2-dicarboxylate (4)
To a suspension of N-ethoxycarbonylmethylpyridinium bromide (3) (19.68 g, 80 mmol) in THF (800 mL)
were added K2CO3 (15.56 g, 120 mmol) and di-tert-butyl acetylenedicarboxylate (18.08 g, 80 mmol) and
the mixture was stirred at rt for 4 days. The insoluble material was filtered off and the filtrated was
concentrated to give a residue, which was purified by column chromatography (n-hexane : AcOEt = 10 : 1)
to give di-tert-butyl 3-ethoxycarbonylindolizine-1,2-dicarboxylate (4) (26.57 g, 85%) as a white solid: mp
1
136-137°C (MeOH). IR (CHCl3) ν: 1734, 1693 cm-1; H-NMR (CDCl3) δ: 1.39 (3H, t, J = 7 Hz,
CH2CH3), 1.63 (9H, s, C(CH3)3), 1.66 (9H, s, C(CH3)3), 4.43 (3H, q, J = 7 Hz, CH2CH3), 6.96 (1H,
dt, J = 7, 1 Hz, H-6), 7.29 (1H, ddd, J = 9, 7, 1 Hz, H-7), 8.19 (1H, dt, J = 9, 1 Hz, H-8), 9.54 (1H,

dt, J = 7, 1 Hz, H-5). Anal. Calcd for C21H27NO6: C, 64.77; H, 6.99; N, 3.60. Found: C, 64.43; H,
6.88; N, 3.32.
3-Ethoxycarbonylindolizine-1,2-dicarboxylic Acid (5)
Trifluoroacetic acid (46.2 mL, 600 mmol) was added to a solution of di-tert-butyl 3-ethoxycarbonyl-
indolizine-1,2-dicarboxylate (4) (23.34 g, 60 mmol) in CH2Cl2 (240 mL) and the mixture was stirred at rt
overnight. The precipitates were collected by filtration and the precipitates were washed with n-hexane to
afford 3-ethoxycarbonylindolizine-1,2-dicarboxylic acid (5)(15.14 g, 91%) as a white solid: mp 221-
1
222°C (from MeOH). IR (Nujol) ν: 1712, 1662 cm-1; H-NMR (DMSO-d6) δ: 1.31 (3H, t, J = 7 Hz,
CH2CH3), 4.32 (3H, q, J = 7 Hz, CH2CH3), 7.22 (1H, dt, J = 7, 1 Hz, H-6), 7.50 (1H, ddd, J = 9, 7, 1
Hz, H-7), 8.29 (1H, dt, J = 9, 1 Hz, H-8), 9.42 (1H, dt, J = 7, 1 Hz, H-5). MS m/z : 277. HRMS m/z
(M+) calcd for C13H11NO6: 277.0586. Found: 277.0576.
3-Ethoxycarbonylindolizine-1,2-dicarboxylic Anhydride (2)
A suspension of 3-ethoxycarbonylindolizine-1,2-dicarboxylic acid (5) (11.08 g, 40 mmol) and
trifluoroacetic anhydride (18.0 mL, 120 mmol) in CH2Cl2 (120 mL) was refluxed for 2 h. The reaction
mixture was evaporated off to provide a solid. The solid was suspended in n-hexane : ether (1 : 1) and the
insoluble solid was collected by filtration to give 3-ethoxycarbonylindolizine-1,2-dicarboxylic anhydride
1
(2) (7.94 g, 77%): mp 173°C (from AcOEt). IR (CHCl3) ν: 1836, 1775, 1705 cm-1; H-NMR (CDCl3) δ:
1.50 (3H, t, J = 7 Hz, CH2CH3), 4.50 (3H, q, J = 7 Hz, CH2CH3), 7.26 (1H, dt, J = 7, 1 Hz, H-6), 7.57
(1H, ddd, J = 9, 7, 1 Hz, H-7), 7.98 (1H, dt, J = 9, 1 Hz, H-8), 9.70 (1H, dt, J = 7, 1 Hz, H-5).
HRMS m/z (M+) calcd for C13H9NO5: 259.0481. Found: 259.0464. Anal. Calcd for C13H9NO5: C, 60.24;
H, 3.50; N, 5.40. Found: C, 60.30; H, 3.50; N, 5.41.
2-Benzoyl-3-ethoxycarbonylindolizine-1-carboxylic Acid (6a)
To a suspension of 3-ethoxycarbonylindolizine-1,2-dicarboxylic anhydride (2) (2.10 g, 8 mmol) in THF
(40 mL) was added phenylmagnesium bromide (16 mL of a 1.0 M THF solution, 16 mmol) at 0°C under
argon and the mixture was stirred for 1 h. The solution was acidified with 10% hydrochloric acid and the
mixture was extracted with CH2Cl2.
The combined extracts were washed with water and dried over
Na2SO4. The solvent was evaporated off to afford a residue, which was purified by column
chromatography (CHCl3: MeOH = 50 : 1) to give 2-benzoyl-3-ethoxycarbonylindolizine-1-carboxylic acid
(6a) (2.50 g, 92%): mp 250-252 °C (THF-n-hexane). IR (Nujol) ν: 1688, 1657 cm-1. 1H-NMR (CDCl3)
δ: 0.85 (3H, t, J = 7 Hz, COOCH2CH3), 4.08 (2H, q, J = 7 Hz, COOCH2CH3), 7.38-7.47 (3H, m, H-3'
and H-5'), 7.10 (1H, dt, J = 7, 1 Hz, H-6), 7.56 (1H, tt, J = 7, 2, 1 Hz, H-4'), 7.86 (2H, dt, J = 7, 1
Hz, H-2' and H-6'), 8.41 (1H, dt, J = 9, 1 Hz, H-8), 9.61 (1H, dt, J = 7, 1 Hz, H-5). Anal. Calcd for
C19H15NO5: C, 67.65; H, 4.48; N, 4.15. Found: C, 67.59; H, 4.53; N, 4.11.
2-Acetyl-3-ethoxycarbonylindolizine-1-carboxylic Acid (6b)
To a suspension of 3-ethoxycarbonylindolizine-1,2-dicarboxylic anhydride (2) (259 mg, 1 mmol) in THF
(40 mL) was added methylmagnesium bromide (1.08 mL of a 1.0 M THF solution, 1.08 mmol) at -78°C
under argon and the mixture was stirred for 30 min, then allowed to reach rt. The reaction mixture was
acidified with 10% hydrochloric acid and the mixture was extracted with CH2Cl2. The combined extracts
were washed with water and dried over Na2SO4. The solvent was evaporated off to afford a residue,

which was purified by column chromatography (CHCl3 : MeOH = 5 : 1) to give 2-acetyl-3-
ethoxycarbonylindolizine-1-carboxylic acid (6b) (264 mg, 96%) as a yellow solid: mp 239-241°C
(MeOH). IR (Nujol) ν: 1710, 1658 cm-1. 1H-NMR (CDCl3) δ: 1.39 (3H, t, J = 7 Hz, COOCH2CH3), 2.68
(1H, s, COCH3), 4.38 (2H, q, J = 7 Hz, COOCH2CH3), 7.08 (1H, dt, J = 7, 1 Hz, H-6), 7.43 (1H, ddd,
J = 9, 7, 1 Hz, H-7), 8.40 (1H, dt, J = 7, 1 Hz, H-8), 9.57 (1H, dt, J = 7, 1 Hz, H-5). HRMS m/z (M+)
calcd for C14H13NO5: 275.0754. Found: 275.0775. Anal. Calcd for C14H13NO5: C, 61.09; H, 4.76; N,
5.09. Found: C, 61.02; H, 4.78; N, 5.10.
3-Ethoxycarbonyl-2-(4-methoxybenzoyl)indolizine-1-carboxylic Acid (6c)
To a suspension of 3-ethoxycarbonylindolizine-1,2-dicarboxylic anhydride (2) (1.04 g, 4 mmol) and
anisole (434 µL, 4 mmol) in CH2Cl2 (16 mL) was added titanium(IV) tetrachloride (8 mL of a 1.0 M
CH2Cl2 solution, 8 mmol) at 0°C and the mixture was stirred for 2 h. Water was added to the reaction
mixture and the mixture was extracted with CH2Cl2. The combined extracts were washed with water and
dried over Na2SO4. The solvent was evaporated off to provide a residue, which was purified by column
chromatography (CHCl3 : MeOH = 10 : 1) to give 3-ethoxycarbonyl-2-(4-methoxybenzoyl)indolizine-1-
carboxylic acid (6c) (1.40 g, 95%) as a white solid: mp 207-208 °C (acetone-n-hexane). IR (Nujol) ν:
1
1698, 1659, 1600 cm-1. H-NMR (CDCl3) δ: 0.90 (3H, t, J = 7 Hz, COOCH2CH3), 3.87 (1H, s, OMe),
4.09 (2H, q, J = 7 Hz, COOCH2CH3), 6.90 (2H, d, J = 9 Hz, H-3' and H-5'), 7.09 (1H, dt, J = 7, 1 Hz,
H-6), 7.81 (2H, d, J = 9Hz, H-2' and H-6'), 7.42 (1H, ddd, J = 9, 7, 1 Hz, H-7), 8.41 (1H, dt, J = 7, 1
Hz, H-8), 9.60 (1H, dt, J= 7, 1 Hz, H-5). HRMS m/z (M+) calcd for C20H17NO6: 367.1056. Found:
367.1072. Anal. Calcd for C20H17NO6: C, 65.39; H, 3.81; N, 4.66. Found: C, 65.21; H, 3.80; N,
4.67.
Ethyl 2-Benzoylindolizine-3-carboxylate (8a)
A mixture of 2-benzoyl-3-ethoxycarbonylindolizine-1-carboxylic acid (6a) (866 mg, 2.6 mmol) and copper
chromite (104 mg) in quinoline (9 mL) was heated to reflux for 30 min and the insoluble material was
removed by filtration through Celite. Water was added to the reaction mixture and the mixture was
extracted with ether. The combined extracts were washed with water, then with 5% hydrochloric acid and
water. The solution was dried over Na2SO4 and evaporated off to give a residue, which was purified by
column chromatography (n-hexane : AcOEt = 5 : 1) to yield 2-benzoyl-3-ethoxycarbonylindolizine (8a)
(590 mg, 78%) as a yellow solid: mp 101-103°C (n-hexane). IR (Nujol) ν: 1681, 1665, 1649 cm-1.
1H-NMR (CDCl3) δ: 0.82 (3H, t, J = 7 Hz, COOCH2CH3), 4.01 (2H, q, J = 7 Hz, COOCH2CH3), 7.43
(6H, m, aromatic protons), 6.65 (1H, s, H-1), 6.91 (1H, dt, J = 7, 1 Hz, H-6), 7.11 (1H, ddd, J = 9, 7,
1 Hz, H-7), 9.47 (1H, dt, J = 7, 1 Hz, H-5). HRMS m/z (M+) calcd for C18H15NO3: 293.1052. Found:
293.1027. Anal. Calcd for C18H15NO3: C, 73.71; H, 5.15; N, 4.78. Found: C, 73.76; H, 5.14; N,
4.75.
Ethyl 2-Acetylindolizine-3-carboxylate (8b)
Using a procedure similar to that described for the preparation of 8a, 8b (59%) was obtained from 6b, mp
85-87 °C (n-hexane) as a pale yellow solid. IR (Nujol) ν: 1687 cm-1; 1H-NMR (CDCl3) δ: 1.38 (3H, t, J =
7 Hz, COOCH2CH3), 2.61 (1H, s, COCH3), 4.39 (2H, q, J = 7 Hz, COOCH2CH3), 6.88 (1H, dt, J = 7,
1 Hz, H-6), 7.07 (1H, ddd, J = 9, 7, 1 Hz, H-7), 7.51 (1H, dt, J = 7, 1 Hz, H-8), 9.39 (1H, dt, J= 7, 1

Hz, H-5). HRMS m/z (M+) calcd for C13H13NO3: 231.0845. Found: 231.0889. Anal. Calcd for
C13H13NO3 C, 73.71; H, 5.15; N, 4.78. Found: C, 73.76; H, 5.14; N, 4.75.
Ethyl 2-(4-Methoxybenzoyl)indolizine-3-carboxylate (8c)
1. In the Presence of Copper Chromite
Using a procedure similar to that described for the preparation of 8a, 8c (35%) was obtained from 6c.
2. In Perchloric Acid
A suspension of 6c (220 mg, 0.6 mmol) in 20% perchloric acid (4 mL) and acetic acid (2 mL) was
refluxed for 25 min. The reaction mixture was diluted with water, neutralized with NaHCO3, and extracted
with CHCl3. The extracts were washed with water, dried over Na2SO4, and evaporated off to give a
residue, which was purified by column chromatography (CHCl3) to afford ethyl 2-(4-methoxybenzoyl)-
1
indolizine-3-carboxylate (8c) (156 mg, 82%) as an oil. IR (Nujol) ν: 1681, 1656, 1599 cm-1. H-NMR
(CDCl3) δ: 0.88 (3H, t, J = 7 Hz, COOCH2CH3), 3.87 (1H, s, OMe), 4.05 (2H, q, J = 7 Hz,
COOCH2CH3), 6.90 (2H, d, J = 9 Hz, H-3' and H-5'), 6.89 (1H, dt, J = 7, 1 Hz, H-6), 7.84 (2H, d, J =
9 Hz, H-2' and H-6'), 7.11 (1H, ddd, J = 9, 7, 1 Hz, H-7), 7.54 (1H, dt, J = 7, 1 Hz, H-8), 9.47 (1H,
dd, J= 7, 1 Hz, H-5). HRMS m/z (M+) calcd for C19H17NO4: 323.1158. Found: 323.1194.
6-Ethoxycarbonylnaphtho[2,3-a]indolizine-7,12-quinone (9a)
A suspension of 2-benzoyl-3-ethoxycarbonylindolizine-1-carboxylic acid (6a) (51 mg, 0.15 mmol) and
phosphorus pentachloride (156 mg, 0.75 mmol) in 1,2-dichloroethane (1 mL) was stirred at rt overnight.
Aluminum(III) chloride (100 mg, 0.75 mmol) was added to the solution and the reaction mixture was
stirred at 50°C for 2 h. The mixture was heated with another aluminum(III) chloride (40 mg, 0.3 mmol) at
50°C under stirring for additional 2 h. The mixture was diluted with water and extracted with CH2Cl2. The
combined extracts were washed with water, dried over Na2SO4, and evaporated off to give a residue,
which was purified by column chromatography (n-hexane : AcOEt = 5 : 1) to afford 6-
ethoxycarbonylnaphtho[2,3-a]indolizine-7,12-quinone (9a) (41 mg, 85%) as a yellow solid: mp 168-169
1
°C (AcOEt). IR (Nujol) ν: 1693, 1674, 1644 cm-1. H-NMR (CDCl3) δ: 1.54 (3H, t, J = 7Hz,
COOCH2CH3), 4.58 (2H, q, J = 7 Hz, COOCH2CH3), 7.12 (1H, dt, J = 7, 1 Hz, H-3), 7.47 (1H, ddd, J
= 9, 7, 1 Hz, H-2), 7.70-7.76 (2H, m, H-8 and H-11), 8.23-8.29 (2H, m, H-9 and H-10). 8.67 (1H, dt,
J = 7, 1 Hz, H-1), 9.32 (1H, dt, J = 7, 1 Hz, H-4). HRMS m/z (M+) calcd for C19H13NO4: 319.0845.
Found: 319.0842. Anal. Calcd for C19H13NO4: C, 71.47; H, 4.10; N, 4.39. Found: C, 71.58; H, 4.20;
N, 4.30.
6-Ethoxycarbonyl-10-methoxynaphtho[2,3-a]indolizine-7,12-quinone (9c)
A suspension of 3-ethoxycarbonyl-2-(4-methoxybenzoyl)indolizine-1-carboxylic Acid (6c) (282 mg, 0.77
mmol) and phosphorus pentachloride (320 mg, 1.54 mmol) in 1,2-dichloroethane (5 mL) was stirred at rt
overnight. Aluminum(III) chloride (205 mg, 1.54 mmol) was added to the solution and the reaction
mixture was refluxed for 6 h. The mixture was diluted with water and extracted with CH2Cl2. The
combined extracts were washed with water, dried over Na2SO4, and evaporated off to give a residue,
which was purified by column chromatography (n-hexane : AcOEt = 5 : 1) to afford 6-ethoxy-10-
methoxycarbonylnaphtho[2,3-a]indolizine-7,12-quinone (9c) (99 mg, 37%) as a red solid: mp 165-168°C
(AcOEt). IR (Nujol) ν: 1670, 1647 cm-1. 1H-NMR (CDCl3) δ: 1.52 (3H, t, J = 7 Hz, COOCH2CH3),

4.56 (2H, q, J = 7 Hz, COOCH2CH3), 3.97 (1H, s, OMe), 7.10 (1H, dt, J = 7, 1 Hz, H-3), 7.18 (1H,
dd, J = 9, 1 Hz, H-9), 7.45 (1H, ddd, J = 9, 7, 1 Hz, H-2), 7.70 (1H, d, J = 1 Hz, H-11), 8.20 (1H, d, J
= 9 Hz, H-8), 8.63 (1H, dt, J = 9, 1 Hz, H-1), 9.28 (1H, dt, J = 7, 1 Hz, H-4). HRMS m/z (M+) calcd
for C20H15NO5: 349.0950. Found: 349.0958. Anal. Calcd for C20H15NO5: C, 68.76; H, 4.33; N, 4.01.
Found: C, 68.75; H, 4.32; N, 4.00.
REFERENCES
1. Y. Miki, H. Hachiken, and I. Yoshikawa, Heterocycles, 1997, 45, 1143.
2. Y. Miki, H. Hachiken, Y. Sugimoto, and N. Yanase, Heterocycles, 1997, 45, 1759.
3. Y. Miki and H. Hachiken, Synlett, 1993, 333.
4. Y. Miki, Y. Tada, N. Yanase, H. Hachiken, and K Matsushita, Tetrahedron Lett., 1996, 37, 7753;
Y. Miki, Y. Tada, and K Matsushita, Heterocycles, 1998, 48, 1593.
5. For reviews, see: T. Uchida and K. Matsumoto, Synthesis, 1976, 209; W. Flitsch, ‘Comprehensive
Heterocyclic Chemistry’, ed. by A. R. Katritzky and C. W. Rees, Pergamon Press, Vol. 4, p. 442
(1984).