Investigation of a green oligomer of an indolizine

Article abstract of DOI:10.24820/ark.5550190.p009.930

An indolizine-based oligomer was synthesized by stirring a solution of 1-(α-alkoxybenzyl)-indolizine derivative in chloroform at room temperature. The oligomer was characterized as an octamer; it was the main component in the obtained mixture of oligomers

Full text of DOI:10.24820/ark.5550190.p009.930

General Papers
ARKIVOC 2016 (vi) 259-273
Investigation of a green oligomer of an indolizine
Haruyasu Asahara,a,b Ayaka Awane,a Kengo Muragishi,a Ryuichi Sugimoto,a,b
Kazuhiko Saigo,a,b and Nagatoshi Nishiwaki*a,b
a School of Environmental Science and Engineering, and b Research Center for Material Science
and Engineering, Kochi University of Technology, Kami, Kochi 782-8502, Japan
E-mail: nishiwaki.nagatoshi@kochi-tech.ac.jp
DOI: https://doi.org/10.24820/ark.5550190.p009.930
Abstract
An indolizine-based oligomer was synthesized by stirring a solution of 1-(α-alkoxybenzyl)-
indolizine derivative in chloroform at room temperature. The oligomer was characterized as an
octamer; it was the main component in the obtained mixture of oligomers. The oligomerization
was accelerated by both acid and light. The green color of the oligomer under acidic conditions
turned yellowish brown under basic conditions; this color change could be repeated by changing
the acidic/basic conditions.
Keywords: Indolizine; pH sensitive behavior; ethynylpyridine; color change; oligomer
Introduction
An indolizine framework consists of an electron-deficient pyridine ring and an [a]-fused electron-
rich pyrrole ring, which provides a biased electron density. Because of such an electronic structure,
indolizine derivatives exhibit potential biological activities1,2 and optical properties.3–5 Therefore,
numerous indolizines have been synthesized by several methods.6–8
Previously, we demonstrated a synthetic method for functionalized indolizines from 2-
ethynylpyridines using functionalities; a nucleophilic ring nitrogen and reactive ethynyl group.9
When a solution of indolizine in chloroform-d was stood at room temperature for 1 day, the color
of the solution changed from yellowish brown to bluish green. This experimental result prompted
us to study this phenomenon; we clarified that an indolizine-based oligomer was formed.10
However, detailed information was not obtained because of poor experimental environment.
After our preliminary finding, any report dealing with indolizine-based oligomer has not been
found to our best of knowledge during the last quarter century, which prompted us to focus and
reinvestigate this phenomenon.
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Results and Discussion
Synthesis of indolizines 4 and 5
Indolizine 4a can be efficiently prepared by the three-component cycloaddition of 2-
phenylethynylpyridine 1a and dimethyl acetylenedicarboxylate 2a in the presence of a proton
source such as methanol 3a which accompanies demethoxycarboxylation of 2a (Scheme 1). The
two proton at the 3-position and on the substituent at the 1-position are derived from methanol,
which was confirmed by conducting the same reaction using methanol-d1, which afforded 4a-d2.
The deuterium at the 3-position was exchanged to proton leading to 4a-d1 upon treatment with
column chromatography on silica gel. Indolizines 4b, 4c, and 4d were prepared in a similar manner
using
a
combination
of
2-(4-methylphenyl)ethynylpyridine
(1b)
and
2-(4-
butylphenyl)ethynylpyridine (1c), diethyl acetylenedicarboxylate 2b, and ethanol 3b. Compared
with other established methods using ethynylpyridines,11–23 this method is environmentally benign
because it is not necessary to use any transition metal catalyst or strong base.
OMe
Ph
OMe
Ph
OMe
Ph
D
D
H
H OMe
N
N
3a
N
N
1
1a
Ph
CH2Cl2
30 oC, 1 d
3
COOMe
4a-d1
H
COOMe
4a-d2
D
COOMe
H
MeOOC
COOMe
4a
2a
Scheme 1. Three component synthesis of indolizine 4a.
When tert-butyl alcohol 3c was used as a proton source, demethoxycarboxylation did not
proceed to afford indolizine 5a. The isolated 5a was quantitatively transformed to 5b upon heating
in methanol 3a; however, further change such as demethoxycarboxylation did not occur even
though 5b was treated with sodium methoxide in methanol under reflux (Scheme 2).
OBut
OMe
MeONa
(2 equiv.)
MeOH 3a
4a
N
N
Ph
Ph
MeOH
reflux 5 h
reflux 5 h
quant.
COOMe
COOMe
MeOOC
MeOOC
5b
5a
Scheme 2. Study on the alkoxy exchangeof 2,3-bis(methoxycarbonyl)indolizines 5.
On the basis of the abovementioned results, a plausible mechanism for the formation of 4a is
illustrated in Scheme 3. This reaction is initiated by [3+2] cycloaddition followed by protonation,
affording 1-benzylideneindolizine intermediate 6. Then a counter anion is introduced on the
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ARKIVOC 2016 (vi) 259-273
substituent at the 1-position, and the 3-position of the indolizine is easily protonated to furnish 7.
When the formed methoxide anion attacks the carbonyl group, demethoxycarboxylation;
subsequent rearomatization of the indolizine framework affords the final product proceeds leading
to 4a, which is consistent with the detection of dimethyl carbonate. On the other hand, the bulky
tert-butoxide cannot attack the ester function because of steric hindrance, thus only deprotonation
at the 3-position occurs to give 5a. Although there is another possibility that
bis(methoxycarbonyl)indolizine 5b serves as the intermediate for this reaction, it is excluded by
the experimental fact shown in Scheme 2.
OMe
Ph
H
_
OMe
H OMe
Ph
+
OMe
N
+N
N
Ph
MeO
_
MeO
N
Ph
E
Me2CO3
MeO H
E
E
E
H
E
O
COOMe
6
7
4a
E = COOMe
Scheme 3. A plausible mechanism for the formation of indolizine 4a.
Oligomerization of indolizine 4
When a solution of indolizine 4 in chloroform-d was allowed to stand at room temperature for one
1
day, the color of the solution changed from yellowish brown to bluish green. The H NMR
spectrum of the green solution showed only the signals of methanol. This indicates that a scarcely
soluble green material was formed in chloroform without any special treatment, simultaneously
eliminating methanol. Similar color change was also observed when indolizine 4a was stood in a
silica gel column, or when a solution of 4a in THF was stirred with 10mol% of hydrochloric acid
at room temperature. These results indicate that oligomerization of 4a occurs under weak acidic
conditions. On the other hand, bis(methoxycarbonyl)indolizines, e.g. 5b, were stable under the
same conditions.
The consumption of 4a was monitored by 1H NMR using three types of deuterated solvents;
benzene−d6, chloroform−d, and acetic acid−d4. Different rates were observed depending on both
the solvent and light. Although no change was observed in benzene−d6 and chloroform−d solutions
in the dark, indolizine 4a was consumed in the acetic acid−d4 solution (Figure 1, upper). In contrast,
the reaction proceeded faster in the light in acetic acid-d4 and chloroform−d solutions. In the case
of benzene−d6, indolizine 4a was slightly converted to an unidentified product, but the color of the
solution did not change (Figure 1, lower). The initial consumption rate of 4a was 4.3 × 10−4 s−1 (in
acetic acid−d4 in the light), 1.8 × 10−4 s−1 (in chloroform−d in the light), and 2.6 × 10−5 s−1 (in
acetic acid−d4 in the dark). Chloroform easily decomposes to hydrogen chloride in light. Hence,
indolizine 4a may have been consumed by the acid.24,25 Because different reaction rates were also
observed in acetic acid−d4 between under light and dark conditions, this reaction is accelerated by
both acid and light; however, the role of light is not well understood.
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Figure 1. Consumption of indolizine 4a in the dark (upper) and light (lower), monitored by 1H
NMR.
Generally, electron-rich heterocyclic compounds such as pyrrole undergo acid catalysed self-
condensation to afford polypyrroles.26–31 Indolizine is also an electron-rich heterocyclic compound,
hence, similar self-condensation is considered to proceed, which is catalyzed by a trace amount of
hydrogen chloride generated by decomposition of chloroform,24,25 however, direct linkage of
bulkier indolizines seems difficult. On the other hand, indolizine 4a has an electrophilic carbon at
the 1-position, which serves as a spacer to diminish the steric hindrance between indolizine
frameworks and facilitate the oligomerization.
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Figure 2 Dimeric product of 4a (Compound 8).
1
Since the H NMR showed only the signals of eliminated methanol after the color was changed,
the NMR spectrum of the product could not be measured; hardly soluble tiny green particles were
homogeneously dispersed in the solvent. Considering the solubility of the monomer 4a, dimer or
trimer should be soluble in organic solvents. However, no signal was observed in the monitoring
1
of the reaction by H NMR because of their extremely small amounts in the reaction mixture.
Fortunately, a trace amount of dimer 8 could be isolated by quick treatment with silica gel column
chromatography of the reaction mixture stopped in a short reaction time (1 h). The spectral data of
8 indicated this was bimolecularly condensed compounds accompanied by elimination of one
1
molecule of methanol (Figure 2). In the H NMR, signals of inner protons (H-5, -6, -8′, Phb,
COOMeb) were observed in higher fields than the signals of the outer protons or the corresponding
signals of monomer 4a. This observation could be explained by that the indolizine rings are
torsionally restrained and the protons at the inside positions are located above the other indolizine
ring.
H+
OMe
Ph
H
+
OMe
Ph
N
OMe
+
N
N
Ph
N
COOMe
Ph
4a
COOMe
COOMe
COOMe
4a
9
OMe
Ph
OMe
Ph
+
N
N
H
oligomer
COOMe
N
COOMe
N
Ph
Ph
COOMe
COOMe
10
8
Scheme 4. A plausible mechanism for the oligomerization of indolizine 4a.
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The dimer 8 was found to be a mixture of isomers (73:27) by 1H NMR and coalesced spectrum
was not obtained at 70 °C. The 13C NMR was too complex to be assigned, but six methoxy carbon
signals were observed.
As shown in Scheme 1, proton exchange of 4a occurs easily under weakly acidic conditions
such as in a silica gel column, which indicates the 3-position has high electron density. In addition,
an alkoxy group can be easily eliminated from the α-alkoxybenzyl group at the 1-position only
when 5a is heated in methanol as shown in Scheme 2. Considering these structural features,
indolizine 4a may have undergone self-condensation in the presence of acid catalyst, forming an
oligomeric structure. In particular, a methanol is easily eliminated from the 1-position as a result
of protonation affording a stable benzylic cation 9. The cation is attacked by another molecule of
4a leading to dimer 8 via deprotonation of the adduct intermediate 10. Oligomerization is achieved
by repeating this sequence.
Me
OMe
OMe
N
N
H
H
COOMe
COOMe
n
n
Oligomer of 4a
Oligomer of 4b
295 g/mol
309 g/mol
Mw = 790, Mn = 524
Mw = 1200, Mn = 1094
n = 2~4
n = 4~5
Me
Bu
OEt
OEt
N
N
H
H
COOEt
COOEt
n
n
Oligomer of 4c
337 g/mol
Oligomer of 4d
379 g/mol
Mw = 1239, Mn = 867
n = 3~6
Mw = 968, Mn = 657
n = 2~4
Figure 3. Structures of oligomers and gel permeation chromatography results.
Since indolizine oligomer 4a was not sufficiently soluble to allow measurement of the 1H NMR
spectrum, a longer alkyl chain was introduced into the indolizine framework to improve the
solubility. The chloroform solutions of each indolizine 4b, 4c, and 4d turned green after standing
at room temperature for one day; however, no signal was observed in the 1H NMR spectra. Then,
these four types of indolizines were subjected to gel permeation chromatography (GPC)
measurements because the measurable concentration for GPC is lower than that for NMR; the
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results are shown in Figure 3. Each oligomer had a similar molecular weight (Mw and Mn), and
the degree of oligomerization was between 2 and 6, contrary to our expectation. The insoluble
oligomers with a higher degree of oligomerization are removed by filtration during the
pretreatment for GPC measurements.
Next, the mass spectrum of the oligomer of indolizine 4b was measured using the MALDI
ionization method (Figure 4). The spectrum showed similar peak patterns repeated at an interval
of 277 Da. This indicated that a methanol molecule was removed from the indolizine. Hence, the
green material was confirmed to be a mixture of oligomers of the indolizine 4b. The mountain
range was observed until 6.0 kDa, where the degree of oligomerization was 20; the octamer was
the main component in the mixture.
2218
2495
1987
1738
3078
3355
3631
3915
4193
4466
5027
3000
4000
9000
5000
6000
7000
8000
2000
m/z
2217.215
2772.404
2294.804
3048.848
3325.723
3448.180
3603.601
2600
2800
3000
2400
3200
3400
3600
3800
m/z
2200
Figure 4. Mass spectrum of the oligomer of indolizine 4b. 1.2−10.0 kDa (upper), 2.1−4.0 kDa
(lower).
pH Sensitive behavior of the oligomer
Although the prepared oligomer was green, it turned yellowish brown by treating with a base such
as sodium hydroxide, ammonia and DBU. This color change was reversible; it turned to green
again by treating with an acid. This color change was confirmed from the UV−visible spectra of
the oligomer (Figures 5). In the UV−visible spectrum, the absorption was observed at 670 nm in
the green state. This absorption disappeared, and a new absorption was observed between 500 nm
and 600 nm in the brown state. This change of color was reversible and its pKobs was 11.1. (Figure
5, right).
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347
H+ OH
0.7
0.6
0.5
0.4
0.3
0.2
0.1
_
1.5
0.75
680
H+ OH
―
Basic
_
_
H+ OH
Conditions
pH = 8.84
0
―
Acidic
pH = 12.91
0
Conditions
400
500
600
700
800
300
500
700
900
Wavelength [nm]
Wavelength [nm]
Figure 5. UV−visible. spectra of the oligomer of indolizine 4b (left) and 4a under different pH
conditions (right).
The reversibility of the color change was studied. To a solution of oligomer of 4b (3 mg,
corresponding to 10 μmol monomer) in methanol (100 mL), either small amount of concentrated
acid or base, 10 M hydrochloric acid or 10 M sodium hydroxide aqueous solution (100–300 μL),
was added until the color of the solution changed. The absorbance at 650 nm was plotted in Figure
6, in which the solution was acidified at even runs, and was basified at odd runs.
Figure 6. The change of absorbance at 650 nm. The solution was basified at odd runs, and the
solution was acidified at even runs.
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In the IR spectrum, although the absorption of the carbonyl group was observed at 1738 cm−1 in
the green state, it shifted to 1668 cm−1 in the brown state (Figure 7). Hence, the carbonyl group
probably became an enolate under the basic conditions. Based on these spectral changes, the
plausible structures of the oligomer in both the states are shown in Scheme 5. As mentioned above,
because an indolizine is easily protonated at the 3-position, the oligomer is present in the
protonated form under acidic conditions, and in the deprotonated form under basic conditions. It
is known that the pyridinium ion serves as an acceptor to form charge-transfer complexes.32,33
Although the similar complex might be formed to produce a green color under acidic
conditions, we have not obtained any evidence at present.
Figure 7. IR spectra of the oligomer of indolizine 4b under acidic (upper) and basic (lower)
conditions.
Conclusions
As a result of revisiting the oligomerization of indolizine 4, both acid catalyst and light were found
to be crucial for this reaction although the role of the light has not clarified. During the synthesis
of indolizines 4 and the oligomer, no metallic reagent26–31 was necessary. The obtained oligomer
shows a green color under acidic conditions and turns to yellowish brown under basic conditions,
which is reversible. The application of this oligomer is under investigation, and the results will be
reported in due course.
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Basic Conditions
Me
Acidic Conditions
Me
+
N
N
H
OMe
+
N
OMe
_
O
N
O
H
OMe
_
O
OMe
O
Me
n/2
OH
Me
n/2
_
_
OH
H+
H+
Me
N
OMe
H
N
O
OMe
O
Me
n/2
Scheme 5. Structural changes in the oligomer of indolizine 4b under acidic and basic
conditions.
Experimental Section
General
All reagents were purchased from commercial sources and used directly without further
purification. 1H and 13C NMR spectra were recorded on Bruker DPX-400 spectrometer (400 MHz
and 100 MHz, respectively), JEOL FT-NMR GSX spectrometer at 270 MHz and JEOL FT-NMR
JMN FX90Q at 90 MHz using TMS and 1,1,2,2-tetrachloroethane as an internal standard. 1H NMR
data is reported as follows: chemical shift (δ, ppm), (chemical shift mutiplicities: s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet), integration, coupling constant (Hz). 13C NMR data
is reported in terms of chemical shift (δ, ppm). IR spectra were recorded on Shimadzu IR Affinity-
1 Spectrometer, and were reported in frequency of absorption. Mass spectra were obtained on a
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Bruker Autoflex II and a JEOL JMS-Q1050GC mass spectrometer using acetonitrile as a solvent
and dithranol (1,8-dihydroxyanthracen-9(10H)-one) as a matrix. High resolution mass spectrum
was recorded with a JEOL JMS-DX303 mass spectrometer. GPC using Shodex column KF-804F
and KF-806L was performed by Shimadzu LC-6A equipped with a Tosoh UV-8020 UV detector
and a Jasco RI-2031 refractive index detector. The measurement of GPC was conducted using
chloroform as a solvent and polystyrene standard as a molecular weight reference. UV-vis. spectra
were measured on a Jasco V-550. Elemental microanalyses were performed using a Yanaco CHN
corder. Melting points were recorded with a Yanaco micro-melting-points apparatus and were
uncorrected.
General procedure for preparation of indolizines 4 9
To a solution of 2-phenylethynylpyridine 1a (179 mg, 1.0 mmol) in dichloromethane (10 mL),
dimethyl acetylenedicarboxylate 2a (213 mg, 1.5 mmol) and methanol 3a (0.81 mL, 20 mmol)
were added, and the resultant mixture was stirred at 30 °C for 1 d. After removal of the solvent,
the residue was treated with column chromatography on silica gel wrapped with aluminium foil to
afford indolizine 4a (eluted with dichloromethane, 177 mg, 0.6 mmol, 60%) as a pale yellow oil.
Other indolizines were also prepared in a similar manner.
1-[Methoxy(phenyl)methyl]-2-methoxycarbonylindolizine (4a). Pale yellow oil. 1H NMR (400
MHz, C6D6, TMS) δ 2.93 (s, 3H), 3.11 (s, 3H), 5.46 (s, 1H), 6.22 (ddd, J 6.4, 7.2, 1.2 Hz, 1H),
6.40 (ddd, J 8.8, 6.4, 0.8 Hz, 1H), 6.53 (s, 1H), 7.09 (ddd, J 8.8, 1.2, 1.2 Hz, 1H), 7.20 (tt, J 7.2,
1.2 Hz, 1H), 7.34 (dd, J 8.0, 7.2 Hz, 2H), 7.75 (dd, J 8.0, 1.2 Hz, 2H), 8.82 (ddd, J 7.2, 0.8, 1.2
13
Hz, 1H); C NMR (100 MHz, CDCl3, TMS) δ 51.5 (CH3), 56.2 (CH3), 75.0 (CH), 100.2 (CH),
110.6 (CH), 114.6 (C), 118.4 (CH), 118.9 (CH), 126.0 (CH), 127.1 (CH), 128.7 (CH), 130.0 (CH),
132.4 (C), 133.9 (C), 136.5 (C), 169.5 (C); IR (neat/cm-1) 1745; MS (FAB) 295 (M+, 37), 264 (23),
236 (100), 220 (14), 204 (14). Anal. Calcd. for C18H17NO3: C, 73.20; H, 5.80; N, 4.74. Found: C,
72.87; H, 5.87; N, 4.69 %.
1-[Methoxy(4-methylphenyl)methyl]-2-methoxycarbonylindolizine (4b). Pale yellow oil (182
mg, 59%): 1H NMR (400 MHz, C6D6, TMS) δ= 2.20 (s, 3H), 2.96 (s, 3H), 3.12 (s, 3H), 5.51 (s,
1H), 6.23 (ddd, J 6.4, 7.2, 1.2 Hz, 1H), 6.41 (ddd, J 9.2, 6.4, 0.8 Hz, 1H), 6.55 (s, 1H), 7.10 (ddd,
J 9.2, 1.2, 1.2 Hz, 1H), 7.17 (d, J 8.0 Hz, 2H), 7.68 (d, J 8.0 Hz, 2H), 8.84 (ddd, J 7.2, 1.2, 0.8 Hz,
1H); 13C NMR (100 MHz, CDCl3, TMS) δ= 14.2 (CH3), 51.5 (CH3), 56.2 (CH3), 75.1 (CH), 100.2
(CH), 110.5 (CH), 114.5 (C), 118.3 (CH), 118.8 (CH), 126.0 (CH), 129.5 (CH), 129.9 (CH), 132.5
(C), 133.6 (C), 133.9 (C), 136.6 (C), 169.5 (C); MS (EI) 309 (M+, 13), 250 (100), 234 (24), 218
(16), 204 (16), 59 (12); IR (KBr/cm-1) 1748. Anal. Calcd. for C19H19NO3: C, 73.77; H, 6.19; N,
4.53. Found: C, 73.49; H, 6.34; N, 4.31 %.
1-[Ethoxy(4-methylphenyl)methyl]-2-ethoxycarbonylindolizine (4c). Pale yellow oil (169 mg,
50%): 1H NMR (400 MHz, C6D6, TMS) δ 0.56 (dd, J 6.8, 6.8 Hz, 3H), 0.72 (dd, J 7.2, 7.2 Hz,
3H), 1.99 (s, 3H), 2.86 (dq, J 8.8, 6.8 Hz, 1H), 3.07 (dq, J 8.8, 6.8 Hz, 1H), 3.52 (dq, J 10.8, 7.2
Hz, 1H), 3.67 (dq, J 10.8, 7.2 Hz, 1H), 5.47 (s, 1H), 6.04 (ddd, J 6.4, 7.2, 1.2 Hz, 1H), 6.21 (ddd,
J 9.2, 6.4, 0.8 Hz, 1H), 6.36 (s, 1H), 6.90 (ddd, J 9.2, 1.2, 1.2 Hz, 1H), 6.97 (d, J 8.0 Hz, 2H), 7.52
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13
(d, J 8.0 Hz, 2H), 8.76 (ddd, J 7.2, 0.8, 1.2 Hz, 1H); C NMR (100 MHz, C6D6, TMS) δ 13.8
(CH3), 15.0 (CH3), 21.0 (CH3), 61.0 (CH2), 64.5 (CH2), 73.9 (CH), 100.1 (CH), 110.3 (CH), 115.1
(C), 118.2 (CH), 118.8 (CH), 126.3 (CH), 129.4 (CH), 129.9 (CH), 132.2 (C), 133.7 (C), 133.9
(C), 136.5 (C), 169.3 (C); MS (EI) 337 (M+, 11), 264 (100), 236 (35), 234 (29), 204 (21), 191 (17),
91 (11). Anal. Calcd. for C21H23NO3: C, 74.75; H, 6.87; N, 4.15. Found: C, 74.68; H, 6.58; N,
4.47 %.
1-[Ethoxy(4-butylphenyl)methyl]-2-ethoxycarbonylindolizine (4d). Pale yellow oil (152 mg,
1
40%); H NMR (400 MHz, C6D6, TMS) δ= 0.79 (t, J 7.2 Hz, 3H), 0.87 (dd, J 7.2, 7.2 Hz, 3H),
0.93 (dd, J 7.2, 7.2 Hz, 3H), 1.30 (tq, J 7.2, 7.2 Hz, 2H), 1.57 (tt, J 7.6, 7.2 Hz, 2H), 2.56 (t, J 7.6
Hz, 2H), 3.05 (dq, J 8.8, 7.2 Hz, 1H), 3.27 (dq, J 8.8, 7.2 Hz, 1H), 3.74 (dq, J 10.8, 7.2 Hz, 1H),
3.89 (dq, J 10.8, 7.2 Hz, 1H), 5.69 (s, 1H), 6.25 (ddd, J 6.4, 7.2, 1.2 Hz, 1H), 6.42 (ddd, J 8.8, 6.4,
0.8 Hz, 1H), 6.59 (s, 1H), 7.12 (ddd, J 8.8, 1.2, 1.2 Hz, 1H), 7.25 (d, J 8.0 Hz, 2H), 7.79 (d, J 8.0
Hz, 2H), 8.97 (ddd, J 7.2, 0.8, 1.2 Hz, 1H); 13C NMR (100 MHz, C6D6, TMS) δ= 13.8 (CH3), 14.0
(CH3), 15.0 (CH3), 22.6 (CH2), 33.9 (CH2), 35.6 (CH2), 61.1 (CH2), 64.5 (CH2), 73.9 (CH), 100.1
(CH), 110.3 (CH), 115.1 (C), 118.2 (CH), 118.8 (CH), 126.3 (CH), 128.9 (CH), 130.0 (CH), 132.2
(C), 133.9 (C), 141.6 (C), 151.7 (C), 169.3 (C); MS (EI) 379 (M+, 13), 306 (100), 278 (31), 263
(22), 234 (25), 204 (42), 192 (21), 161 (42), 107 (18), 91 (96), 77 (36), 69 (27), 57 (25).
1-[tert-Butoxy(phenyl)methyl]-2,3-bis(methoxycarbonyl)indolizine (5a). Colorless plates (304
mg, 77%); mp 118–119 °C; 1H NMR (90 MHz, CDCl3, TMS) δ= 1.22 (s, 9H), 3.87 (s, 3H), 3.95
(s, 3H), 5.94 (s, 1H), 6.80 (ddd, J 8.6, 6.7, 1.9 Hz, 1H), 6.98 (ddd, J 8.6, 8.8, 1.9 Hz, 1H), 7.1–7.6
(m, 5H), 7.73 (ddd, J 8.6, 1.9, 1.2 Hz, 1H), 9.35 (ddd, J 6.7, 1.9, 1.2 Hz, 1H); 13C NMR (23 MHz,
CDCl3, TMS) δ= 27.9 (CH3), 51.0 (CH3), 51.9 (CH3), 68.9 (CH), 74.9 (C), 109.7 (C), 113.8 (CH),
117.8 (C), 119.4 (CH), 121.7 (CH), 125.3 (C), 126.1 (CH), 126.4 (CH), 126.8 (CH), 127.8 (CH),
133.8 (C), 144.0 (C), 160.5 (C), 166.9 (C); IR (neat/cm-1) 1738, 1694; MS (EI) 395 (M+, 44), 338
(27), 322 (100), 306 (86), 262 (25), 230 (53). Anal. Calcd. for C23H25NO5: C, 69.86; H, 6.37; N,
3.54. Found: C, 69.77; H, 6.36; N, 3.54 %.
1-[Methoxy(phenyl)methyl]-2,3-bis(methoxycarbonyl)indolizine (5b). A solution of indolizine
5a (198 mg, 0.5 mmol) in methanol (10 mL) was heated under reflux for 5 hours. After evaporation,
5b (173 mg, 0.49 mmol, 98%) was obtained without any detectable by-product. Pale yellow plates;
mp 107–108 °C; 1H NMR (90 MHz, CDCl3, TMS) δ= 3.38 (s, 3H), 3.89 (s, 3H), 3.92 (s, 3H), 5.58
13
(s, 1H), 6.8–7.6 (m, 8H), 9.38 (br d, J 6.9 Hz, 1H); C NMR (23 MHz, CDCl3, TMS) δ= 51.1
(CH3), 52.1 (CH3), 56.6 (CH3), 78.1 (CH), 109.9 (C), 113.6 (C), 114.0 (CH), 118.7 (CH), 122.2
(CH), 126.2 (CH), 126.8 (CH), 127.0 (CH), 127.2 (C), 127.9 (CH), 133.8 (C), 141.2 (C), 160.4
(C), 166.6 (C); IR (neat/cm-1) 1742, 1704; MS (EI) 353 (M+, 35), 338 (27), 322 (100), 306 (38),
276 (26), 204 (17). Anal. Calcd. for C20H19NO5: C, 67.98; H, 5.42; N, 3.96. Found: C, 67.56; H,
5.32; N, 3.91 %.
Monitoring the oligomerization of indolizine 4a by 1H NMR
To a solution of indolizine 4a (3 mg, 10 μmol) in chloroform-d (0.5 mL), 1,1,2,2-tetrachloroethane
1
(8 mg) was added as an internal standard, and subjected to the measurements of H NMR at
several-minute intervals. The experiment was conducted in the air, and aluminium foil was used
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ARKIVOC 2016 (vi) 259-273
to keep in the dark. The experiment in the light was conducted in the ambient atmosphere witout
irradiation of special light. The reaction rate was calculated by comparison of the integral values
of indolizine 4a and tetrachloroethane. Eliminated molecule was confirmed to be methanol by
comparison of 1H and 13C NMR spectra with those of authentic sample.
Isolation of dimer 8. A solution of 4a (50 mg, 0.17 mmol) in chloroform (15 mL) was stirred at
room temperature for 1 h. The solution was concentrated and the residue was treated with column
chromatography on silica gel to give dimer 8 (eluted with hexane/AcOEt = 90/10, 10 mg, 0.018
mmol) with recovery of 70% of 4a.
Dimer 8. Brownish yellow solid, mp 41–44 °C; The dimer was found to be a mixture of isomers
(73/27) by 1H NMR. 1H NMR (270 MHz, C6D6, TMS) the major isomer δ 2.97 (s, 3H), 3.05 (s,
3H, COOMeb), 3.11 (s, 3H, COOMea), 5.10 (s, 1H, Ha), 6.0–6.4 (m, 5H, H-6, -7, -6′, -7′, -8′), 6.33
(s, 1H, Hb), 6.60 (s, 1H, H-3′), 7.0–7.5 (m, 9H, Phb, H-8, -m, -p), 7.74 (dd, J 6.2, 1.1 Hz, 1H, H-
o), 8.24 (dd, J 6.2, 1.1 Hz, 1H, H-5), 8.72 (dd, J 5.9, 1.1 Hz, 1H, H-5′), the minor isomer ; δ 2.877
(s, 3H, OMe), 2.884 (s, 3H, COOMeb), 3.11 (s, 3H, COOMea), 5.21 (s, 1H, Ha), 6.0–6.4 (m, 5H,
H-6, -7, -6′, -7′, -8′), 6.37 (s, 1H, Hb), 6.68 (s, 1H, H-3′), 7.0–7.5 (m, 9H, Phb, H-8, -m, -p), 7.82
(dd, J 7.3, 1.6 Hz, 2H, H-o), 8.35 (dd, J 6.2, 1.1 Hz, 1H, H-5), 8.84 (dd, J 5.9, 1.1 Hz, 1H, H-5′);
MS (EI) 558(M+, 11), 499 (100); IR (neat/cm-1) 1740. HRMS Calcd. for C35H30N2O5: 558.2156.
Found: 558.2158.
UV-vis spectra of oligomer of 4b
To a suspension of oligomer of 4b (0.3 mg, corresponding to 1 μmol monomer) in methanol (10
mL) was subjected to the measurement of UV-vis spectrum. The solution turned to yellowish
brown when 1 M sodium hydroxide aqueous solution (10 μL, 10 μmol) was added. After drying
up, the residue (0.4 mg) was dissolved into methanol (5 mL), and was subjected to the
measurement of UV-vis. spectrum.
UV-vis spectra of oligomer of 4a under different pH conditions
Several buffer solutions having different pH values were prepared by mixing 0.25 M aqueous
solutions of boric acid and sodium hydroxide with different ratio. A solution (suspension) of
oligomer 4a (1.33 g/L) in 1,4-dioxane was also prepared. After mixing the buffer solution and
dioxane solution (10/1 v/v), pH value and Uv-vis. spectrum were measured.
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