Improved synthesis of cationic pyridinium-substituted indolizines

Article abstract of DOI:10.1055/s-2006-942482

This paper describes the optimization of the synthesis of pyridinium-substituted indolizines. Different conditions, solution and solid-phase synthesis were used for the key step of [3+2] cycloaddition. The best yields and shortest reaction time were obtai

Full text of DOI:10.1055/s-2006-942482

2640
SHORT PAPER
Improved Synthesis of Cationic Pyridinium-Substituted Indolizines
I
mprove
d
Synthe
i
sis of
S
a
ubstituted
I
ndolizines ca Furdui,a Rodica Dinica,b Ioan I. Druta,c Martine Demeunynck*a
a
LEDSS UMR5616 & ICMG-FR2607, Université Joseph Fourier, BP53, 38041 Grenoble cédex 9, France
Fax +33(476)514946; E-mail: martine.demeunynck@ujf-grenoble.fr
b
c
University Dunarea de Jos, Domneasca str 47, Galati 800008, Romania
University ‘Al. I. Cuza’, Organic Chemistry Department, Blvd Carol I 11, Iassi 700506, Romania
Received 24 February 2006; revised 18 April 2006
The ‘salt method’16 has been applied to this reaction in or-
der to form in situ, the pyridinium ylides, that react with
the dipolarophile (ethyl propiolate) to directly give the in-
dolizines 4a–d (Scheme 1). As pointed out previously,17
formation of the indolizines 4a–d probably proceeds via
unstable intermediates, which due to the tendency of sta-
bilization spontaneously undergo an aromatization, possi-
bly through an oxidative dehydrogenating reaction under
ambient conditions. The best results in solution were ob-
tained when the asymmetric diquaternaty salts 2a–d were
treated with a slight excess of ethyl propiolate (1.4 equiv)
in the presence of triethylamine in N-methyl-2-pyrroli-
done as solvent (Scheme 1). The mixture was allowed to
react at moderate temperature (50–60 °C) for about 6–9
hours to complete the conversion. After a conventional
workup the indolizine derivatives 4a–d were obtained in
yields ranging from 53% (4b) to 71% (4c). Following our
previous work on the use of microwave irradiation to
achieve [3+2] cycloaddition,17 we performed the reaction
under similar conditions. The reactions were carried out at
atmospheric pressure in a multimode microwave reactor
(700 W). The reagents, 2a–d and ethyl propiolate, were
first adsorbed on KF–Al2O3. The resulting solids were
subsequently irradiated for ten minutes. The temperature
was measured at 95 °C at the end of the microwave irradi-
ation by introducing a glass thermometer into the reaction
mixture. After workup, compounds 4a–d were isolated in
77–85% yields. To assess the influence of the microwave
irradiation on the reaction, we performed control reactions
by heating the reaction mixtures adsorbed on KF–Al2O3 at
95 °C, under vigorous mechanical stirring without micro-
wave irradiation. As shown in Table 1, a significant in-
crease of the yields was observed under microwave
irradiation.
Abstract: This paper describes the optimization of the synthesis of
pyridinium-substituted indolizines. Different conditions, solution
and solid-phase synthesis were used for the key step of [3+2] cy-
cloaddition. The best yields and shortest reaction time were ob-
tained by microwave-assisted solid-phase synthesis.
Key words: cycloadditions, fused-ring systems, heterocycles, sol-
id-phase synthesis, ylide
A literature survey reveals that indolizines have a special
place in the field of heterocycles, a large number of these
compounds being biologically active molecules, potential
antioxidants, inhibitors of 15-lypoxygenase, or ligands for
the estrogen receptors.1–5 Considering also the well
known fluorescence properties of indolizines and the in-
creasing importance of fluorescence spectroscopy in both
biological and environmental analyses, we are interested
in the synthesis of this class of compounds, as systems
suitable for use in fluorometric analysis.6–10 We11 and
others12,13 have previously described the synthesis of in-
dolizines from pyridinium salts using a [3+2] cycloaddi-
tion reaction. The mono- or bisindolizines thus formed are
fluorescent but display a low solubility in water that pre-
cludes their use as fluorescent indicators in biological sys-
tems. The present paper describes the synthesis of water-
soluble pyridinium-substituted indolizines from asym-
metric diquaternary salts of 4,4¢-bipyridine (Scheme 1).
The novelty of this paper resides in the functionalization
as methylpyridinium at an early stage of the synthesis, pri-
or to the ylide formation and subsequent cycloaddition,
combined with the use of solvent-free microwave reac-
tion.
The asymmetric diquaternary salts 2a–d were prepared by
alkylation of N-methyl-4-pyridyl pyridinium iodide (1),
which in turn was prepared by controlled monomethyla-
tion of bipyridine with methyl iodide. The iodo alkylating
agents (iodo acetophenones and iodo methyl acetate) were
prepared from the commercial bromo derivatives follow-
ing the methods described in the literature.14,15 The diqua-
ternary salts 2a–d were thus obtained in good yields (88–
98% yields). To form the indolizine nucleus, the interme-
diate formation of pyridinium ylides 3a–d was required
for reaction with the alkynes by a cycloaddition process.
The structures of the new compounds were assessed by
spectral analysis (NMR, MS) and elemental analysis. In
particular heteronuclear 2D NMR experiments (GHMBC)
were used to confirm the regioselectivity of the reaction.
Two 3JHC couplings between proton H-2 and both the car-
bonyl and carboxylate carbon atoms were identified. This
result confirms that the cycloaddition of the ylides with
the unsymmetrical ethyl propiolate is regioselective as
previously described for the synthesis of bisindolizines.11
In conclusion, we report the efficient synthesis of asym-
metric diquaternary salts of 4,4¢-bipyridine. We success-
fully reacted these salts as starting materials in a
cycloaddition reaction with ethyl propiolate under basic
SYNTHESIS 2006, No. 16, pp 2640–2642
Advanced online publication: 12.07.2006
DOI: 10.1055/s-2006-942482; Art ID: T02806SS
© Georg Thieme Verlag Stuttgart · New York
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SHORT PAPER
Improved Synthesis of Substituted Indolizines
2641
13C NMR (75 MHz, DMSO-d6): d = 166.9, 150.0, 148.3, 147.4,
I
ICH2COR
146.9, 126.6, 126.5, 60.5, 53.5, 48.3.
Me
N
N
Me
N
N
CH2COR
2I
MS (electrospray): m/z = 243 [M2+ – H+].
MeCN
reflux
2
1
Anal. Calcd for C14H16I2N2O2: C, 33.76; H, 3.24; N, 5.63. Found: C,
33.78; H, 3.33; N, 5.56.
Et3N
NMP
Me
N
N
CHCOR
N-Methyl-N¢-phenacyl-4,4¢-bipyridinium Diiodide (2b)
Red-orange crystals; yield: 89%; mp 248–250 °C.
3
1H NMR (300 MHz, DMSO-d6): d = 9.30–9.36 (m, 4 H), 8.93 (d,
J = 6.5 Hz, 2 H), 8.82 (d, J = 6.5 Hz, 2 H), 8.10 (d, J = 7.9 Hz, 2 H),
7.79–7.84 (m, 1 H), 7.66–7.71 (m, 2 H), 6.63 (s, 2 H, CH2), 4.47 (s,
3 H, NCH3).
13C NMR (75 MHz, DMSO-d6): d = 190.9, 149.9, 148.8, 147.7,
147.2, 135.4, 134.0, 129.7, 128.8, 126.9, 126.8, 66.8, 48.6.
I
a R = OMe
b R = Ph
c R = 4-MeOC6H4
d R = 4-O2NC6H4
CO2Et
NMP
Me
N
N
C
COR
H
atm O2
2
4
CO2Et
Scheme 1
MS (electrospray): m/z = 289 [M2+ – H+].
Anal. Calcd for C19H18I2N2O: C, 41.94; H, 3.34; N, 5.15. Found: C,
41.85; H, 3.23; N, 5.13.
conditions. The presence of the cationic methyl pyridini-
um substituent does not prevent the formation and reactiv-
ity of the ylide. The prolonged reaction time of the
reaction performed in solution is due to the low solubility
of the starting bipyridium salts. The solvent-free solid-
phase synthesis is an answer to this problem. The use of
microwave irradiation to perform the cycloaddition step is
very successful and has major advantages, namely yield
improvement, lower reaction time and easier workup.
N-Methyl-N¢-(p-methoxyphenacyl)-4,4¢-bipyridinium Diiodide
(2c)
Red-orange crystals; yield: 98%; mp 260–262 °C.
1H NMR (300 MHz, DMSO-d6): d = 9.25–9.33 (m, 4 H), 8.93 (d,
J = 6.6 Hz, 2 H), 8.84 (d, J = 6.6 Hz, 2 H), 8.08 (d, J = 8.8 Hz, 2 H),
7.21 (d, J = 8.8 Hz, 2 H), 6.59 (s, 2 H, CH2), 4.48 (s, 3 H, NCH3),
3.91 (s, 3 H, OCH3).
13C NMR (75 MHz, DMSO-d6): d = 188.8, 164.6, 149.5, 148.4,
147.4, 146.9, 131.0, 126.6, 126.5, 114.7, 66.2, 56.1, 48.3.
Melting points were obtained on a Reichert Thermovar instrument
MS (electrospray): m/z = 319 [M2+ – H+].
1
and are uncorrected. H and 13C NMR spectra were recorded on a
Anal. Calcd for C20H20I2N2O2: C, 41.84; H, 3.52; N, 4.88. Found: C,
41.87; H, 3.45; N, 4.80.
Bruker Avance 300 spectrometer with DMSO as internal standard.
Mass spectra were recorded on a Polarisq Thermo Finnigan spec-
trometer. Elemental analyses were performed at ‘Service de mi-
croanalyse, Université Joseph Fourier’. All starting materials were
commercially available.
N-Methyl-N¢-(p-nitrophenacyl)-4,4¢-bipyridinium Diiodide (2d)
Red crystals; yield: 88%; mp 235–236 °C.
1H NMR (300 MHz, DMSO-d6): d = 9.34 (d, J = 6.7 Hz, 2 H), 9.29
(d, J = 7.0 Hz, 2 H), 8.92 (d, J = 7.1 Hz, 2 H), 8.81 (d, J = 6.9 Hz, 2
H), 8.51 (d, J = 8.9 Hz, 2 H), 8.33 (d, J = 9.0 Hz, 2 H), 6.65 (s, 2 H,
CH2), 4.47 (s, 3 H, CH3).
13C NMR (75 MHz, DMSO-d6): d = 190.3, 151.2, 150.1, 148.7,
147.7, 147.2, 138.7, 130.4, 127.0, 126.8, 124.8, 67.1, 48.6.
Preparation of Asymmetric Diquaternary Salts of 4,4¢-Bipyri-
dine (2a–d); General Procedure
Compound 1 (1 mmol) and reactive iodo derivatives (iodoacetophe-
nones or iodomethyl acetate, 1.50 mmol) were suspended in MeCN
(10 mL). The mixture was heated at reflux, under vigorous stirring,
for 15–20 h. The reaction product was separated by filtration of the
hot reaction mixture, washed with boiling MeCN (15 mL) and dried
under vacuum at r.t.
MS (electrospray): m/z = 334 [M2+ – H+].
Anal. Calcd for C19H17I2N3O3: C, 38.74; H, 2.91; N, 7.14. Found: C,
38.68; H, 2.95; N, 7.14.
N-Methyl-N¢-carbomethoxymethyl-4,4¢-bipyridinium Diiodide
(2a)
Red crystals; yield: 88%; mp > 350 °C (decomp.).
1H NMR (300 MHz, DMSO-d6): d = 9.34–9.40 (m, 4 H), 8.92 (d,
J = 6.9 Hz, 2 H), 8.82 (d, J = 6.6 Hz, 2 H), 5.84 (s, 2 H, CH2), 4.47
(s, 3 H, NCH3), 3.80 (s, 3 H, OCH3).
Preparation of N-Methyl-4-(1-ethoxycarbonyl-3-substituted-
indolizin-7-yl)pyridinium Iodide (4a–d); General Procedure
Compound 2a–d (1 mmol) and ethyl propiolate (1.40 mmol) were
suspended in N-methylpyrrolidinone (10 mL). Then Et3N (2 mmol
diluted in 3 mL N-methylpyrrolidinone) was added dropwise under
Table 1 Comparative Yields and Reaction Conditions
Compound Solution
Time (min) Temp (°C) Yield (%)
Solid-phase
Time (min) Temp (°C) Yield (%)
Microwave irradiation
Time (min) Temp (°C) Yield (%)
4a
4b
4c
4d
480
480
360
540
50
50
55
60
63
61
71
53
10
10
10
10
95
95
95
95
57
50
52
47
10
10
10
10
95
95
95
95
84
77
85
71
Synthesis 2006, No. 16, 2640–2642 © Thieme Stuttgart · New York

2642
B. Furdui et al.
SHORT PAPER
vigorous stirring. The solution was slowly heated for 6–9 h at 50–
60 °C. The desired product (4b–d) precipitated after adding EtOAc
(50 mL) to the solution. The precipitate was separated by filtration
and washed with EtOAc (30 mL) and Et2O (20 mL). For purifica-
tion of products 4a–d, the crude precipitate was suspended in H2O
(10 mL) and extracted with CHCl3 (500 mL). The organic phase
was dried over anhydrous Na2SO4 and concentrated under vacuum.
Compounds 4a–d were separated as yellow crystals by precipitation
with Et2O and filtration.
13C NMR (75 MHz, DMSO-d6): d = 184.0, 163.1, 162.9, 151.7,
143.3, 137.9, 132.1, 131.5, 131.3, 129.5, 127.5, 124.8, 123.6, 118.9,
114.3, 113.7, 108.0, 60.4, 55.9, 47.7, 14.6.
MS (electrospray): m/z = 415 [M+].
Anal. Calcd for C25H23N2O4I·H2O: C, 53.53; H, 4.56; N, 5.18.
Found: C, 53.51; H, 4.36; N, 4.91.
N-Methyl-4[1-ethoxycarbonyl-3-(para-nitro)benzoylindolizin-
7-yl]pyridinium Iodide (4d)
Yellow crystals; mp 237–238 °C.
Preparation of N-Methyl-4-(1-ethoxycarbonyl-3-substituted-
indolizin-7-yl)pyridinium Iodide (4a–d) Using Microwave Irra-
diation; General Procedure
1H NMR (300 MHz, DMSO-d6): d = 9.97 (d, J = 7.5 Hz, 1 H), 9.14
(d, J = 5.2 Hz, 2 H), 8.92 (s, 1 H), 8.68 (d, J = 5.2 Hz, 2 H), 8.44 (d,
J = 8.8 Hz, 2 H), 8.08 (d, J = 8.8 Hz, 2 H), 7.98 (d, J = 7.1 Hz, 1 H),
7.76 (s, 1 H), 4.33–4.40 (m, 5 H, NCH3, CH2), 1.36 (t, J = 7.1 Hz, 3
H, CH3).
13C NMR (75 MHz, DMSO-d6): d = 183.3, 162.4, 151.0, 148.9,
145.8, 143.9, 138.1, 132.6, 129.8, 129.2, 128.3, 124.4, 123.6, 122.5,
118.3, 113.9, 108.1, 60.0, 47.1, 14.0.
To a solution of diquaternary salts 2a–d (1 mmol) and ethyl propi-
olate (1.40 mmol) in acetone (5 mL) was added KF–Al2O3 (4 g KF–
Al203/1 g 2a–d) under vigorous stirring. After solvent evaporation,
the resulting solid was irradiated for 10 min in a multimode micro-
wave reactor (700 W). The reaction mixture was then cooled to r.t.,
washed with CHCl3 (50 mL) and filtered. The resulting filtrate was
evaporated under vacuum. The crude residue was treated as de-
scribed above for the reaction in solution.
MS (electrospray): m/z = 430 [M+].
Anal. Calcd for C24H20N3O5I: C, 51.73; H, 3.62; N, 7.54. Found: C,
51.69; H, 3.88; N, 7.47.
N-Methyl-4(1-ethoxycarbonyl-3-methoxycarbonylindolizin-7-
yl)pyridinium Iodide (4a)
Yellow crystals; mp 233–235 °C.
1H NMR (300 MHz, DMSO-d6): d = 9.57 (dd, J = 0.9, 7.5 Hz, 1 H),
9.10 (d, J = 6.9 Hz, 2 H), 8.76 (d, J = 1.1 Hz, 1 H), 8.59 (d, J = 7.0
Hz, 2 H), 7.85 (s, 1 H), 7.83 (dd, J = 2.0, 7.5 Hz, 1 H), 4.39 (s, 3 H,
NCH3), 4.34 (q, J = 7.1 Hz, 2 H, CH2), 3.90 (s, 3 H, OCH3), 1.37 (t,
J = 7.1 Hz, 3 H, CH3).
Acknowledgment
We thank partial financial support from Romanian CNCSIS grant
AT81.
13C NMR (75 MHz, DMSO-d6): d = 163.2, 160.9, 151.9, 146.5,
137.5, 131.0, 128.7, 124.9, 124.4, 119.2, 116.1, 113.6, 108.0, 60.6,
52.4, 47.9, 14.8.
References
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MS (electrospray): m/z = 339 [M+].
Anal. Calcd for C19H19N2O4I·0.5H2O: C, 48.02; H, 4.32; N, 6.10.
Found: C, 48.26; H, 4.35; N, 5.81.
N-Methyl-4-(1-ethoxycarbonyl-3-benzoylindolizin-7-yl)pyri-
dinium Iodide (4b)
Yellow crystals; mp 215–219 °C.
1H NMR (300 MHz, DMSO-d6): d = 9.88 (dd, J = 0.7, 7.4 Hz, 1 H),
9.16 (d, J = 6.5 Hz, 2 H), 8.84 (d, J = 1.2 Hz, 1 H), 8.64 (d, J = 6.7
Hz, 2 H), 7.91 (dd, J = 2.0, 7.4 Hz, 1 H), 7.80–7.84 (m, 2 H), 7.67–
7.72 (m, 2 H), 7.58–7.63 (m, 2 H), 4.42 (s, 3 H, NCH3), 4.35 (q, J =
7.1 Hz, 2 H, CH2), 1.34 (t, J = 7.1 Hz, 3 H, CH3).
13C NMR (75 MHz, DMSO-d6): d = 185.5, 163.2, 151.8, 146.6,
139.3, 138.4, 132.8, 132.7, 129.7, 129.3, 129.2, 128.5, 125.0,
123.5, 119.0, 114.3, 108.5, 60.7, 47.9, 14.8.
(8) Troll, T.; Beckel, H.; Lentner-Bohm, C. Tetrahedron 1997,
53, 81.
MS (electrospray): m/z = 385 [M+].
(9) Hodgkiss, R. J.; Middleton, R. W.; Parrick, J.; Rami, H. K.;
Wardman, P.; Wison, G. D. J. Med. Chem. 1992, 35, 1920.
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Anal. Calcd for C24H21N2O3I·1.5H2O: C, 53.39; H, 4.55; N, 5.38.
Found: C, 53.10; H, 4.40; N, 4.95.
N-Methyl-4-[1-ethoxycarbonyl-3-(para-methoxy)benzoylin-
dolizin-7-yl]pyridinium Iodide (4c)
Yellow crystals; mp 238–240 °C.
1H NMR (300 MHz, DMSO-d6): d = 9.82 (d, J = 7.9 Hz, 1 H), 9.13
(d, J = 6.2 Hz, 2 H), 8.86 (s, 1 H), 8.64 (d, J = 6.4 Hz, 2 H), 7.85–
7.89 (m, 3 H), 7.72 (s, 1 H), 7.15 (d, J = 8.7 Hz, 2 H,), 4.34–4.40
(m, 5 H, NCH3, CH2), 3.89 (s, 3 H, OCH3), 1.36 (t, J = 7.1 Hz, 3 H,
CH3).
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Synthesis 2006, No. 16, 2640–2642 © Thieme Stuttgart · New York