The first dipolar spirocycle based on 10-(benzylamino)colchicine

Article abstract of DOI:10.1007/s10593-015-1803-5

We have synthesized the first dipolar spirocyclic σ-complex of Meisenheimer type from 10-(benzylamino)colchicine and trinitrobenzene. The chirality of colchicine moiety resulted in magnetic non-equivalence of protons in the trinitrophenyl ring, enabling t

Full text of DOI:10.1007/s10593-015-1803-5

DOI 10.1007/s10593-015-1803-5
Chemistry of Heterocyclic Compounds 2015, 51(10), 948–950
The first dipolar spirocycle based on 10-(benzylamino)colchicine
Anna V. Tkachuk1*, Sergey V. Kurbatov1, Pavel G. Morozov1, Gennadiy S. Borodkin1
1 Southern Federal University,
7 Zorge St., Rostov-on-Don 344090, Russia;
e-mail: a_tkachuk@bk.ru
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2015, 51(10), 948–950
Submitted October 16, 2015
Accepted November 11, 2015
We have synthesized the first dipolar spirocyclic σ-complex of Meisenheimer type from 10-(benzylamino)colchicine and trinitrobenzene.
The chirality of colchicine moiety resulted in magnetic non-equivalence of protons in the trinitrophenyl ring, enabling their use as
diastereotopic markers. The kinetic and activation parameters for the reversible degenerate recyclization of spirocycle were determined
by a dynamic NMR method.
Keywords: colchicine, dipolar spirocycle, nucleophilic aromatic substitution, stereodynamics.
Scheme 1
Dipolar spirocyclic σ-complexes of type А(R) are
stable, preparatively isolable intermediates of intramole-
cular nucleophilic aromatic substitution reactions. In
contrast to the widely known anionic Meisenheimer σ-comp-
lexes, dipolar σ-complexes require much higher capability
of negative and positive charge delocalization in electro-
philic and nucleophilic fragments, respectively. In the case
if the dipolar spirocycle is chiral, it is possible to determine
the energy barrier to enantiomerization A(R)
A(S) by
stereodynamics of the first dipolar spirocycle, a colchicine
derivative.
dynamic NMR methods, using temperature-dependent
evolution of the signal from a diastereotopic CH2 group
located near the chiral center (Scheme 1).1–4 A similar
classical approach to the study of enantiomerization
occurring via bond dissociation and recombination at the
stereocenters has been successfully used earlier not only for
carbon atoms,5,6 but also for atoms of other elements.7,8
This method for measuring the kinetic stability of
spirocycle does not require a previous separation of
enantiomers, but is obviously applicable only to asym-
metric nitrohetarenes, such as dinitrobenzofuroxan,2
dinitrobenzofurazan,4 or dinitrobenzo[e][1,2,3,4]tetrazine
1,3-dioxide,9 and is not suitable for symmetric electro-
philes, for example, trinitrobenzene.
The interaction of 10-(benzylamino)colchicine (1)10 with
picryl chloride likely involves the formation of
a
metastable 10-picrylamino derivative 2. This assumption is
supported by the fact that the reaction of N-alkyl-
aminotropones with 2-chloro-3,5-dinitropyridine and 2,4,6-tri-
chloro-1,3,5-triazine forms exclusively N-arylation pro-
ducts that can be isolated preparatively, while no O-aryl
derivatives have been detected.11 Picrylaminocolchicine 2
undergoes an intramolecular nucleophilic attack, resulting
in the formation of stable dipolar spirocyclic σ-complex 3,
isolated from the reaction medium as red crystals with a
high melting point (Scheme 2).
The spirocyclic structure of picryl derivative 3 was
confirmed by 1H and 13C NMR spectroscopy. Compared to
10-(benzylamino)colchicine (1), the signal of the H-12
The use of chiral nucleophilic moiety allows to avoid
these limitations. In the current work, a natural alkaloid
was used and here we report the synthesis and
0009-3122/15/5110-0948©2015 Springer Science+Business Media New York
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Chemistry of Heterocyclic Compounds 2015, 51(10), 948–950
Scheme 2
Cl
O
O
5
4
MeO
MeO
6
O2N
NO2
Me
MeO
MeO
Me
O
*
NH
*
NH
MeO
MeO
7
Me
*
A
B
NH
8
MeO
NO2
13
+
MeO
O
NO2
12
O
MeO
MeCN, , 30 min
51%
C
NO2
10
N
Ph
O2N
Ph
N
O
Hb
NO2
–
O2N
NH
Ph
1
Ha
NO2
3
2
31 °С
102°С
91 °С
87 °С
74 °С
of temperature-dependent experimental spectra was
converted with the gCVT program (included in the gNMR
software suite) to a set of .spg files compatible with
gNMR. For the spectrum acquired at room temperature,
theoretical modeling of proton signal shape from the
indicator groups was performed, by using a least squares
method to match the experimentally observed signal shape
in .spg file with a computer model that included variation
of chemical shift, width at half height, and spin-spin
coupling constant. The calculated spectrum was compared
via the computer model to a set of other temperature-
dependent spectra, while varying the exchange rate
constant. As a result, the rate constant was determined for
each spectrum and for the respective temperature. The
Gibbs free energy value (ΔG≠) was calculated by Arrhenius
70 °С
41 °С
31 °С
NH
Ha
Hb
equation for each rate constant.
A least squares
Figure 1. The temperature-dependent evolution of proton signals
from the picryl moiety in spirocycle 3.
linearization with a correlation coefficient of no less than
0.98 allowed to find the activation entalphy (ΔH≠) and
enthropy (ΔS≠). Based on literature data,14 we estimate that
the error in determining k did not exceed 15%, ΔG≠ –
0.6 kJ/mol, ΔH≠ – 2 kJ/mol, ΔS≠ – 8 J/mol·K. Thus, the
kinetic and activation parameters for rearrangement involv-
ing the exchange of Ha and Hb protons, obtained by full
analysis of indicator proton signal shape, are the following:
k298 = 0.19 s–1, ΔG≠ = 77.0 kJ/mol, ΔH≠ = 126 kJ/mol,
ΔS≠ = 163 J/mol·K. 298
The reason for exchange of Ha and Hb proton positions
apparently is degenerate recyclization, involving the
cleavage of Cspiro–O bond, torsion rotation around the C–N
bond in the metastable open-chain isomer 2, and
subsequent spirocyclization. The observed inversion of
configuration can be formally linked also to the cleavage
and formation of Cspiro–N bond. We should note that none
of the possible "open" forms were experimentally
observed. However, the previously studied set of kinetic
and activation parameters for the tautomerism and
stereodynamics of several nitroaryl and nitrohetaryl
derivatives of aminotropone, thiotropone, and troponimine1
allows to consider a Cspiro–O bond cleavage mechanism as
the most likely scenario.
1
proton in the H NMR spectrum of the spirocycle 3 was
shifted downfield by 1.42 ppm, the signal of the H-13
proton – by 1.05 ppm, while the signal of the H-8 proton –
by 0.45 ppm. Proton deshielding in the electron-donating
part of the molecule indicated a significant degree of
charge transfer.4,12 The spirocyclic carbon atom appeared in
the spectrum at 105.6 ppm, which is also characteristic for
dipolar spirocyclic σ-complexes.4 The principal difference
from all previously investigated open-chain or spirocyclic
derivatives of trinitrobenzene was the magnetic non-
equivalence of Ha and Hb protons, which appeared not as
two-proton singlets, but rather as two one-proton doublets
at 8.43 and 8.53 ppm. The presence of a chiral center at
position 7 means that the plane containing A, B, and C
rings is diastereofacial. Thus, the Ha and Hb protons, which
are located in the spirocycle at different sides of this plane,
become diastereofacially differentiated and can be used as
diastereotopic markers.
Heating a DMSO-d6 solution of spirocycle 3 resulted in
broadening of the Ha and Hb proton signals (~40°С),
followed by coalescence (~70°С) and further
transformation into a two-proton singlet (~100°С). Cooling
of the solution to room temperature fully restored the
spectrum, without any traces of degradation in the
spirocyclic structure (Fig. 1).
The computational modeling of temperature-dependent
NMR spectra and calculation of rate constants was
performed with the gNMR 5.1 software.13 The obtained set
Thus, the interaction of 10-(alkylamino)colchicine with
aromatic electophiles allowed to synthesize new derivatives
of colchicine, an alkaloid known for its broad spectrum of
biological activity,15 while the use of natural chirally pure
synthetic precursors enables new approaches to the study of
stereodynamics in molecules with flexible structure and
variable stereo configuration.
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Chemistry of Heterocyclic Compounds 2015, 51(10), 948–950
Experimental
149.9 (С-1); 151.2 (С-13); 154.2 (С-3); 154.3 (С-11а); 159.4
(С-7а); 161.7 (С-8а); 169.1 (СОСН3). Found, m/z: 708.1911
1Н and 13С NMR spectra (600 and 150 MHz,
respectively) were acquired on a Bruker Avance-600
spectrometer in DMSO-d6, with TMS as internal standard.
[M+Na]+. C34H31N5NaO11. Calculated, m/z: 708.1912.
1
The Supplementary information file containing Н and
13C NMR spectra of 10-(benzylamino)colchicine (1) is
The assignment of Н and 13С NMR signals was based on
1
available online at http://link.springer.com/journal/10593.
the data of COSY, NOESY, HSQC, and HMBC 2D NMR
experiments. High-resolution mass spectra were recorded
on a Bruker micrOTOF II instrument, electrospray
ionization, positive ion mode (capillary voltage 4500 V).
The mass scanning range was 50–3000 Da. Melting points
were determined in glass capillaries on a PTP apparatus.
Merck Silicagel 60 (36–71 µm) was used for column
chromatography. Picryl chloride16 was synthesized accord-
ing to a published procedure. Benzylaminocolchicine was
synthesized from commercially available colchicine (Alfa
Aesar) and benzylamine (Fluka) following a modified
literature procedure.10
10-(Benzylamino)colchicine (1). Benzylamine (0.25 ml,
2.3 mmol) was added to colchicine (200 mg, 0.5 mmol),
the mixture was stirred and maintained at room temperature
for 3 days. The reaction mixture was separated chro-
matographically on silica gel, eluent CHCl3–EtOH (20:1).
Yield 190 mg (80%), bright-yellow powder, mp 165–166°С
(mp 166–168°С (EtOAc–cyclohexane)6).
This work was performed within the framework of
Project part of the State Assignment for scientific activity
No. 4.129.2014/K from Ministry of Education and Science
of the Russian Federation.
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