One-pot synthesis of tetrahydroindolizines by catalytic intra- and intermolecular alkylation of 1,2-disubstituted pyrroles

Full text of DOI:10.1134/S1070428010070274

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 7, pp. 1101–1102. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © A.M. Magerramov, I.A. Aliev, S.F. Farzaliev, N.D. Sadykhova, I.M. Akhmedov, 2010, published in Zhurnal Organicheskoi Khimii,
2010, Vol. 46, No. 7, pp. 1099–1100.
SHORT
COMMUNICATIONS
One-Pot Synthesis of Tetrahydroindolizines
by Catalytic Intra- and Intermolecular Alkylation
of 1,2-Disubstituted Pyrroles
A. M. Magerramov, I. A. Aliev, S. F. Farzaliev, N. D. Sadykhova, and I. M. Akhmedov
Baku State University, ul. Z. Khalilova 23, Baku, AZ-1073, Azerbaidjan,
e-mail: idrismecid@yahoo.com
Received August 26, 2009
DOI: 10.1134/S1070428010070274
Tetrahydroindolizine fragment is a structural unit of
many natural and unnatural compounds possessing
diverse biological activity [1–3]. Known methods for
the preparation of tetrahydroindolizine derivatives are
tedious, and the yields of the target products are poor
[4, 5]. Therefore, development of new procedures for
their synthesis is an important problem in medicinal
and organic chemistry.
In the present communication we report on a new
convenient one-step procedure for the synthesis of
tetrahydroindolizines via successive intra- and inter-
molecular alkylations of 2-methyl- and 2-phenyl-1-
(4,4-diethoxybutyl)pyrroles I and II in the presence of
a catalytic amount of Yb(OTf)3 (Scheme 1). The yields
of compounds III and IV were 40–45% when the
reactions were carried out in tetrahydrofuran at room
temperature over a period of three days. A probable
mechanism of formation of tetrahydroindolizines III
and IV (Scheme 2) involves intramolecular nucleo-
philic addition of C5 in the pyrrole ring at the acetal
carbon atom in the side chain, which bears a partial
positive charge enhanced by interaction with the cata-
lyst. Intramolecular ring closure in intermediate com-
plex A gives complex B which reacts with the second
substrate molecule, and subsequent elimination of
ethanol yields the final product.
The structure of compounds III and IV was proved
1
by H and 13C NMR spectroscopy, including COSY,
DEPT, and HMBC techniques, as well as by elemental
analyses. The 1H NMR spectra of III and IV contained
triplets at δ 1.10–1.15 ppm from methyl groups in the
acetal fragment, two quartets at δ 3.30 and 3.50 ppm
(3J = 7.10 Hz) due to OCH2 protons, and a triplet
signal at δ 4.34 and 4.35 ppm from the acetal CH
proton; the intensity ratio of the above signals was
6:2:2:1, in keeping with the assumed structure. Pro-
tons in the methyl group attached to the pyrrole ring
resonated at δ 2.05 and 2.10 ppm, and protons in the
tetrahydroindolizine fragment gave rise to signals at
δ 1.50–1.90 (6-H, 7-H) and 3.85 ppm (8-H). Signals
from protons in the pyrrole and benzene rings appeared
at δ 5.40–5.75 and 7.10–7.45 ppm, respectively.
Compound III displayed in the DEPT spectrum
9 positive signals belonging to CH3 and CH protons
(signals from two methyl groups in the pyrrole ring
overlapped each other) and 7 negative signals from
CH2 groups (signals from the OCH2 groups overlapped
Scheme 1.
R
N
R
Yb(OTf)3
N
N
2
+ 2EtOH
OEt
OEt
OEt
OEt
I, II
III, IV
I, III, R = Me; II, IV, R = Ph.
1101

MAGERRAMOV et al.
1102
Scheme 2.
H
OEt
OEt
OEt
Yb(OTf)3
··
R
R
N
R
δ+
I, II
N
N
–Yb(OTf)3OEt
–H+
OEt
·
Yb(OTf)3
A
Et
Yb(OTf)3
O·Yb(OTf)3
δ+
OEt
III, IV
R
N
–Yb(OTf)3OEt
N
R
OEt
B
each other). Unambiguous signal assignment was also
accomplished on the basis of homonuclear (COSY)
and heteronuclear (HMBC) correlation spectra. The
presence in molecule III of a tetrahydroindolizine
fragment followed from the HMBC spectrum which
revealed correlation between 8-H in the bridgehead
position (δ 3.90 ppm) and quaternary carbon atoms in
both pyrrole rings (δC 131.61 and 134.68 ppm).
8-[1-(4,4-Diethoxybutyl)-5-phenyl-1H-pyrrol-2-
yl]-3-phenyl-5,6,7,8-tetrahydroindolizine (IV). Yield
1 g (40%), Rf 0.42, mp 131–132°C (from heptane).
1H NMR spectrum, δ, ppm: 1.15 t (6H, CH3, J =
7.0 Hz), 1.45–1.90 m (8H, CH2), 3.55–3.90 m (5H,
NCH2, CH), 3.35 q (2H, OCH2, J = 7.1 Hz), 3.50 q
(2H, OCH2, J = 7.1 Hz), 4.34 t (1H, CH), 5.35–5.55 m
(2H, =CH), 5.60–5.70 m (2H, =CH), 7.10–7.45 m
(10H, C6H5). 13C NMR spectrum (CDCl3, 100 MHz),
δC, ppm: 15.80, 23.60, 27.41, 29.61, 31.18, 34.28,
43.00, 43.80, 61.25, 96.45, 102.64, 102.80, 103.45,
105.00, 106.20, 109.60, 126.51, 127.21, 127.33,
128.29, 130.210, 131.60, 133.40, 134.60, 149.50.
Found, %: C 79.55; H 7.76; N 5.90. C32H38N2O2. Cal-
culated, %: C 79.66; H 7.88; N 5.81.
Initial pyrroles I and II were synthesized according
to the procedure described in [6, 7].
General procedure for the synthesis of com-
pounds III and IV. A mixture of 0.01 mol of pyrrole I
or II and 0.001 mol of Yb(OTf)3 in 10 ml of THF was
stirred for 3 days at room temperature. The mixture
was then diluted with water and extracted with ethyl
acetate, the extract was dried over MgSO4, the solvent
was distilled off, and the residue was subjected to
column chromatography on KSK silica gel (0–70 μm)
using hexane–ethyl acetate (9:1) as eluent. The prog-
ress of the reactions was monitored by TLC on Silufol
UV-254 plates using hexane–ethyl acetate (9:1) as
eluent.
The H and 13C NMR spectra were recorded on
a Bruker-400 FT instrument (400 MHz) using CDCl3
as solvent and tetramethylsilane as internal reference.
1
REFERENCES
1. Zhang, Q., Tu, G., Zhao, Y., and Cheng, T., Tetrahedron,
2002, vol. 58, p. 6798.
8-[1-(4,4-Diethoxybutyl)-5-methyl-1H-pyrrol-2-
yl]-3-methyl-5,6,7,8-tetrahydroindolizine (III). Yield
2. Szawkalo, J., Zawaddzka, A., Wojtasiewicz, K., Leniew-
ski, A., Drabowicz, J., and Czaronocki, Z., Tetrahedron:
Asymmetry, 2005, vol. 16, p. 3619.
1
0.8 g (45%), Rf 0.48, oily substance. H NMR spec-
trum, δ, ppm: 1.10 t (6H, CH3, J = 7.0 Hz), 1.50–
1.95 m (8H, 4CH2), 2.05 s (3H, CH3), 2.10 s (3H,
CH3), 3.30 q (2H, OCH2, J = 7.1 Hz), 3.50 q (2H,
OCH2, J = 7.1 Hz), 3.60–3.90 m (5H, NCH2, CH),
4.35 t (1H, CH), 5.40 s (1H, =CH), 5.60 s (1H, =CH),
3. Pla, D., Marchal, A., Olsen, C.A., Albericio, F., and
Alvarezi, M., J. Org.Chem., 2005, vol. 70, p. 8231.
4. Sardina, F.J. and Rapoport, H., Chem. Rev., 1996, vol. 96,
p. 1825.
5. Jefford, C.W., Curr. Org. Chem., 2000, vol. 4, p. 205.
13
5.65–5.75 m (2H, =CH). C NMR spectrum (CDCl3,
6. Demir, A.S., Akhmedov, I.M., Sesenoglu, O., Alpturk, O.,
Apaydin, S., Gercek, Z., and Ibrahimzade, N., J. Chem.
Soc., Perkin Trans. 1, 2001, p. 1162.
7. Demir, A.S., Akhmedov, I.M., Tanyeli, C., Gadzhili, R.A.,
and Gercek, Z., Tetrahedron: Asymmetry, 1997, vol. 8,
p. 753.
100 MHz), δC, ppm: 12.36, 12.98, 15.76, 23.54, 27.40,
29.55, 31.17, 34.26, 42.91, 43.76, 61.24, 102.65,
104.89, 105.30, 106.03, 106.39, 126.67, 127.13,
131.61, 134.68. Found, %: C 73.64; H 9.59; N 7.74.
C22H34N2O2. Calculated, %: C 73.74; H 9.50; N 7.85.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 7 2010