Synthesis of pyrrolidine and tetrahydroazonine derivatives from N-[bis(ethoxycarbonyl)methyl]tetrahydropyridinium bromide and methyl acetylenedicarboxylate

Article abstract of DOI:10.1134/S1070428011110157

The reaction of N-methyl-N-(diethoxycarbonyl)methyltetrahydropyridinium bromide with dimethyl acetylenedicarboxylate in the presence of triethylamine at room temperature afforded 1,2-dimethyl 1-ethyl 2-[(3-vinyl-1-methyl-3-phenyl-2- ethoxycarbonyl)pyrrolidin-2-yl]-ethene-1,1,2-tricarboxylate in 25% yield. Its structure was proved by XRD analysis. At cooling to -20°C the pyrrolidine yield signifi cantly decreased and 3,4-dimethyl 2,2-diethyl 1-methyl-7-phenyl-1, 5,8,9-tetrahydro-2H-azonine-2,2,3,4-tetratcarboxylate was obtained in 31% yield.

Full text of DOI:10.1134/S1070428011110157

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2011, Vol. 47, No. 11, pp. 1738−1741. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © A.T. Soldatenkov, S.A. Soldatova, R.R Suleimanov, K. B. Polyanskii, V.E. Kotsyuba, A.F. Smol’yakov, V.N. Khrustalev, M.Yu. Antipin,
2011, published in Zhurnal Organicheskoi Khimii, 2011, Vol. 47, No. 11, pp. 1700−1703.
Synthesis of Pyrrolidine and Tetrahydroazonine Derivatives
from N-[Bis(ethoxycarbonyl)methyl]tetrahydropyridinium
Bromide and Methyl Acetylenedicarboxylate
A. T. Soldatenkova, S. A. Soldatovaa, R. R Suleimanova, K. B. Polyanskiia,
V. E. Kotsyubaa, A. F. Smol’yakovb, V. N. Khrustalevb, and M. Yu. Antipinb
aRussian University of Peoples Friendship, Moscow, 117198 Russia
e-mail: sa.soldatova@googlemail.com
bNesmeyanov Institute of Organoelemental Compounds, Russian Academy of Sciences, Moscow, Russia
Received July 13, 2010
Abstract—The reaction of N-methyl-N-(diethoxycarbonyl)methyltetrahydropyridinium bromide with dimethyl
acetylenedicarboxylate in the presence of triethylamine at room temperature afforded 1,2-dimethyl 1-ethyl
2-[(3-vinyl-1-methyl-3-phenyl-2-ethoxycarbonyl)pyrrolidin-2-yl]-ethene-1,1,2-tricarboxylate in 25% yield. Its
structure was proved by XRD analysis. At cooling to –20°C the pyrrolidine yield significantly decreased and
3,4-dimethyl 2,2-diethyl 1-methyl-7-phenyl-1,5,8,9-tetrahydro-2H-azonine-2,2,3,4-tetratcarboxylate was obtained
in 31% yield.
DOI: 10.1134/S1070428011110157
Quaternary salts of fused tetrahydropyridinium de-
rivatives possessing an activated methylene group at the
nitrogen react with dialkyl acetylenedicarboxylate in the
presence of bases giving azonine derivatives [1]. Thus ob-
tained tetrahydroindenoazonines or hexahydroazoninoin-
doles according to the internet program PASS [2] may
be of interest for checking their antisclerosis (probability
74–78%) and antileishmaniasis action (71–74%). To
extend the range of initial substrates for this new reaction
we investigated in this study the reaction of salt I with
dimethyl acetylenedicarboxylate (DMAD, II) in the pres-
ence of triethylamine (Scheme 1). The reaction was car-
ried out in anhydrous 1,4-dioxane at various temperatures.
At the room temperature (32 h) the reaction mixture, ac-
cording to HPLC-MS, contains mainly three substances:
~ 20% of initial compound I (m/z 332 [M – Br]+) and two
isomeric compounds with the same molecular mass (473),
~30% each. This mixture of isomers was isolated in the
1
25% yield by chromatography. According to H NMR
spectra it proved to be a mixture of two diastereomers
with the structure of 3-vinyl-substituted pyrrolidine
III in the 1 : 1 ratio. Aiming at proving the molecular
structure and stereochemical features of compound III
we have grown their single crystals and subjected them
Fig. 1.General view of the molecule of compound III accord-
ing XRD data shown with the 50% probability ellipsoids of
nonhydrogen atoms (only one of the two crystallographically
independent molecules is presented).
1738

SYNTHESIS OF PYRROLIDINE AND TETRAHYDROAZONINE DERIVATIVES
1739
Scheme 1.
Hc
CCOOMe
CCOOMe
II
Ph
CCOOMe
CCOOMe
II
Ph
COOMe
COOMe
Ph
Ha
COOEt
N+ COOEt
_
COOEt
COOEt
N
Et3N
Et3N
COOMe
COOEt
N
Me
Br
Me
Me
COOEt
_20°С, 20 h
20°C, 32 h
MeOOC
III
IV
I
to XRD analysis (Fig. 1). The single crystal contained
only one diastereomer, and it was proved that actually
the six-membered ring suffered the contraction into the
five-membered tetrahydropyrrole ring. Also one more
uncommon rearrangement was discovered: This consisted
in the transformation of the residue of the ester of the
dicarboxylic acid (entered into the intermediate product
by the addition of compound II) into the residue of the
mixed ester of tricarboxylic acid .
ate substituents is governed both by the intramolecular
steric causes and by the effects of the crystal packing.
The packing of molecules III is stacking along the c axis.
The molecules are placed at the van der Waals distances.
The conversion of the quaternary salt I into the pyr-
rolidine derivative accompanied by the rearrangement
of an ethoxycarbonyl group may be represented by the
reactions in Scheme 2. To the initially generated by the
action of Et3N N-ylide A electrophile II is added. Then
in the formed 1,4-zwitter-ion B instead of the expected
[1,4]-sigmatropic rearrangement [1] leading to the azo-
nine IV derivative apparently a 1 → 3-acyl shift occurs of
one of the ethoxycarbonyl groups to the carbanion center.
This shift results in the new anhydrobase of ylide C type
that may suffer [1,2]- or [3,2]-sigmatropic rearrangement
with the extension or (as in this case) with the contraction
of the piperidine ring [3].
Pyrrolidine derivative III crystallizes in the triclinic
crystal system, space group P21/c, with two independent
molecules in the unit cell that are distinguished only by the
conformation of two ethyl fragments (C10–C11/C35–C36
and C17–C18/C42–C43) of two carboxylate substituents
(Fig. 2). Therefore below the average geometric param-
eters of these molecules are discussed (Tables 1 and 2).
The pyrrolidine ring in compound III has the envelop
conformation with the deviation of the atom C3 by
0.607 Å from the mean-square plane containing the other
atoms of the ring. Interestingly due to the presence of the
contiguous bulky acceptor substituents at the atoms C2
and C3 the ordinary bond C2–C3 is considerably extended.
The phenyl substituent attached to the atom C3 is in the
axial position [torsion angle N1C2C3C21 –81.9(4) deg],
whereas the vinyl substituent is in the equatorial position
[torsion angle N1C2C3C19 156.3(3) deg]. The sterically
less feasible axial position of the phenyl substituent more
bulky as compared to the vinyl group is evidently due to
the stereoselective direction of the formation reaction of
compound III. The atom N1 takes the trigonal-pyramidal
configuration (sum of the bond angles 340.5°) with the
pseudoequatorial position of the methyl group [torsion
angle C6N1C2C3 –157.9(3) deg]. Compound III is a
diastereomer with two asymmetric centers at the atoms
C2 and C3. The crystal of compound III is a racemate
and is composed of enantiomeric pairs with the relative
configuration of the chiral atoms rac-2R*,3S*. Besides
compound III is the Z-isomer with respect to the double
bond C7=C8. The reciprocal position of the four carboxyl-
Fig. 2. Comparison of conformations of two crystallographi-
cally independent molecules of compound III.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 11 2011

SOLDATENKOV et al.
1740
Scheme 2.
At performing the reaction at –20°C (kinetic control)
dinium derivatives in the presence of a base may depend
not only on the structure of the quaternary salts but also
on the kinetic or thermodynamic control resulting in the
predominant formation either of azonine or pyrrolidine
derivatives.
the reaction mixture according to HPLC-MS contained
four compounds: initial salt I (~40%) and three isomers
of the same molecular mass (m/z 473), namely, two dia-
stereomers of compound III (10% each) and unknown
compound IV (~40%), which we succeeded to isolate
by chromatography in 31% yield. According to the data
In keeping with the prediction of the internet-program
PASS, pyrrolidine III is promising as a stimulator of
the ejection of 5-hydroxytryptamine (probability 79%)
indicating its ability to exhibit experimentally psyco-
stimulating, antipsychotic, and antidepressant properties.
With a high probability (79%) it may be also useful in the
treatment of the cocaine addiction. For azonine derivative
VI the property is predicted of the permeability inhibitors
of the cell membranes that may provide it with a good
probability (73%), with the antiphlogistic, antidiabetic,
and antiviral (against AIDS) action.
1
of IR, mass, and H NMR spectra compound IV is the
azonine derivative.
Therefore the direction of the reaction of the dialkyl
acetylenedicarboxylate with halides of tetrahydropyri-
Table 1. Some bond distances (l) in compound III (average
values are given for two crystallographically independent
molecules)
Bond
l, Å
Bond
l, Å
N1–C2
N1–C5
N1–C6
C2–C3
C2–C7
C3–C4
1.467(5)
1.480(5)
1.469(5)
1.619(5)
1.543(5)
1.538(5)
C3–C19
C3–C21
C4–C5
C7–C8
C19–C20
1.514(6)
1.548(6)
1.514(6)
1.332(5)
1.309(5)
EXPERIMENTAL
The initial 1-methyl-4-phenyl-1,2,3,6-tetrahydropyr-
idine was prepared as described in [4]. 1H NMR spectra
were registered on a spectrometer Bruker Avance DRX-
400 (400 MHz) in CDCl3. IR spectra were recorded
from pellets with KBr on a spectrophotometer Infralyum
FT-801. HPLC-MS was performed on a chromatograph
Agilent 1100 equipped with detectors DAD, ELSD Sedex
75 coupled with a mass spectrometer Agilent LC/MSD
VL, electrospray ionization.
Table 2. Some bond angles (ω) in compound III (average
values are given for two crystallographically independent
molecules)
Angle
ω, deg
Angle
ω, deg
The access to instrument Bruker and Agilent was
helpfully granted by Chembridge Co.
C2N1C5
C2N1C6
C5N1C6
N1C2C3
N1C2C7
N1C2C16
C3C2C7
C3C2C16
C7C2C16
110.4(3)
116.3(3)
113.8(3)
102.7(3)
109.2(3)
111.7(3)
115.6(3)
109.9(3)
107.9(3)
C2C3C4
C2C3C19
C2C3C21
C4C3C19
C4C3C21
C19C3C21
C3C4C5
99.8(3)
111.4(3)
112.6(3)
112.4(3)
112.5(3)
108.3(3)
106.2(3)
106.1(3)
123.7(4)
XRD investigation of compound III. Crystallo-
graphic findings: C25H31NO8, M 473.51, triclinic crystal
system, space group P-1, at 120 K a 8.375(2), b 15.539(4),
c 18.603(5) Å; α 86.994(5), β 84.073(5), γ 88.660(5)
deg, V 1940.4(6) Å3, Z 4, dcalc 1.308 g/cm3, F(000) 1008,
θ 0.098 mm–1, 2θmax 54°. Number of measured reflections
22197, number of independent reflections 10371, number
of observed reflections with I > 2σ(I) 3852. Number of
N1C5C4
C2C7CI8
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 11 2011

SYNTHESIS OF PYRROLIDINE AND TETRAHYDROAZONINE DERIVATIVES
1741
1
refined parameters 569. R1 [I > 2σ(I)] 0.0693, wR2 (all
data) 0.1896. GOF 1.001. The parameters of unit cell
and the intensity of reflections were measured on an
automatic three-circle diffractometer Bruker SMART
1K CCD equipped with a low-temperature device Ox-
ford CryoSystem (120 K, λMOKα-radiation, graphite
monochromator, φ and ω-scanning). The structure of
compound was solved by the direct method and refined
by the full-matrix least-squares anisotropic approxima-
tion for nonhydrogen atoms. The positions of hydrogen
atoms were geometrically calculated in were refined in
the isotropic approximation with fixed position (rider
model) and thermal [Uiso(H) = 1.2Ueq(C)] parameters.All
calculations were carried out using SHELXTL software
[5]. The tables of atomic coordinates, bond lengths, bond
angles and anisotropic thermal parameters of compound
III are deposited in Cambridge Cristallographic Data-
center (CCDC 761903).
(C=O), 1631 (ethenyl C=C). H NMR spectrum, δ, ppm
(mixture of two diastereomers in the ratio 1:1): 1.20 t,
1.30 t (3H each, OCH2CH3 J 7.6 Hz), 2.24 s, 2.28 s (1.5H
each, NMe), 2.68 m (2H, H4), 2.86 m, 3.33 m (1H each,
H5), 3.45 s, 3.69 s (1.5H each, OMe), 3.52 s (3H, OMe),
4.06 q, 4.10 q (1H each, OCH2CH3, J 7.6 Hz), 4.22 q (1H,
OCH2CH3, J 7.6 Hz), 4.72 d.d 4.76 d.d (0.5H each, Ha,
2J 0.8, 3J 17.2 Hz), 5.05 d.d (1H, Hb , 2J 0.8, 3J 10.8 Hz),
6.94 q (1H, HC , J 17.2, 10.8 Hz), 7.17 t (1Harom, J 7.2 Hz),
7.24 m, 7.58 m (2Harom each). Mass spectrum: m/z 474
[M + 1]+. Found, %: C 63.12; H 6.71; N 3.02. C25H31NO8.
Calculated, %: C 63.42; H 6.55; N 2.96. M 473.51.
3,4-Dimethyl 2,2-diethyl 1-methyl-7-phenyl-
1,5,8,9-tetrahydro-2H-azonine-2,2,3,4-tetracarbox-
ylate (IV) was obtained similarly at –20°C (20 h) from
2 g (5 mmol) of salt I. Yield 0.73 g (31%), light-brown
crystals, mp 86–87°C. IR spectrum, ν, cm–1: 1738 (C=O),
1
1636 (ethenyl C=C). H NMR spectrum, δ, ppm: 1.21
t (6H, OCH2CH3, J 7.7 Hz), 2.85 s (3H, NMe), 3.54 s
(6H, OMe), 4.01–4.33 m (6H, H5,8,9), 6.81 t (1H, H6,
J 6.0 Hz), 7.31–7.54 m (5Harom). Mass spectrum: m/z 474
[M + 1]+. Found, %: C 63.62; H 6.86; N 2.81. C25H31NO8.
Calculated, %: C 63.42; H 6.55; N 2.96. M 473.51. From
the reaction mixture compound III was also isolated by
chromatography as two diastereomers, yield 0.13 g (5%).
1-Methyl-4-phenyl-1-bis(ethoxycarbonyl)-methyl-
1,2,3,6-tetrahydropyridinium bromide (I). A solution
of 2.1 g (10 mmol) of 1-methyl-4-phenyl-1,2,3,6-tetrahy-
dropyridine and 2.8 g (10 mmol) of bromomalonic ester
in 20 ml of anhydrous THF was heated for 3 h to boiling
in a nitrogen atmosphere. The mixture was cooled and
diluted with hexane (50 ml). The precipitate was sepa-
rated and purified by recrystallization from acetone. Yield
2.9 g (70%), mp 78°C. IR spectrum, ν, cm–1: 1753 and
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1
1741 sh (C=O), 1629 (C=C). H NMR spectrum, δ, ppm:
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1.27 t (6H, OCH2CH3, J 7.2 Hz), 2.92 m (2H, H3), 3.35 s
(3H, NMe), 3.86 m (2H, H2), 4.33 m (4H, OCH2CH3),
4.41 br.d, 4.53 br.d (1H each, H6 , J 16.5 Hz), 6.03 s (1H,
NCHCOO), 6.15 br.s (1H, H5), 7.18–7.61 m (5Harom).
Found, %: Br 19.52; N 3.42. C19H26BrNO4. Calculated,
%: Br 19.42; N 3.39.
1,2-Dimethyl 1-ethyl 2-[(3-vinyl-1-methyl-3-phe-
nyl-2-ethoxycarbonyl)pyrrolidin-2-yl]ethene-1,1,2-
tricarboxylate (III). A mixture of 2.0 g (5 mmol) of
quaternary salt I, 1.5 g (10 mmol) of compound II, and
1.8 ml (14 mmol) of triethylamine in 30 ml of anhydrous
dioxane was stirred for 32 h at room temperature in
a nitrogen atmosphere. The solvent was evaporated, the
residue was subjected to chromatography on silica gel
of grade 60 (0.063–0.100 mm) purchased from Acros,
gradient elution with the mixture hexane–ethyl acetate
from 1:0 to 1:10. Yield 0.67 g (25%), colorless crystals,
mp 112–113°C. IR spectrum, ν, cm–1: 1731 sh and 1727
4. Schmidle, C.J. and Mansfield, R.C. J. Am. Chem. Soc.,
1956, vol. 78, p. 425.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 11 2011