Reaction of diaziridine-3,3-dicarboxylic acid dihydrazide with acetone

Article abstract of DOI:10.1016/j.mencom.2009.03.009

Using the reaction of diaziridine-3,3-dicarboxylic acid dihydrazide with acetone, new bicyclic diaziridines 7a,b have been obtained instead of expected tricyclic heterocycle 8.

Full text of DOI:10.1016/j.mencom.2009.03.009

Mendeleev
Communications
Mendeleev Commun., 2009, 19, 81–83
Reaction of diaziridine-3,3-dicarboxylic acid
dihydrazide with acetone
Boriss Strumfs,a Edvards Liepin’sh,a Sergey Belyakov,a
Peteris Trapencieris*a and Remir G. Kostyanovsky*b
a Latvian Institute of Organic Synthesis, LV-1006 Riga, Latvia. Fax: +371 6755 0338; e-mail: peteris@osi.lv
b N. N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. Fax: +7 495 651 2191; e-mail: kost@center.chph.ras.ru
DOI: 10.1016/j.mencom.2009.03.009
Using the reaction of diaziridine-3,3-dicarboxylic acid dihydrazide with acetone, new bicyclic diaziridines 7a,b have been
obtained instead of expected tricyclic heterocycle 8.
Diaziridines are known to display anticancer1–5 and psycho-
tropic6 activity. In this aspect, the chiral diaziridines are of
O
O
O
O
N
special interest, in particular, tricyclic ‘butterfly’ 1a,b (liquids)
HN
HN
NH
N
HN
HN
N
of C2 symmetry.7–10
H
N
NH
N
NH
(H2C)n
(CH2)n
7a
major
7b
minor
N
N
1a n = 1
1b n = 2
Figure 1 Important 1H ® 13C connectivities observed in HMBC spectra.
Assuming that an analogous double cyclization could be
feasible, we have studied the reaction of diaziridine-3,3-dicar-
boxylic acid dihydrazide 6 with acetone in an attempt to obtain
the target tricyclic diaziridine similar to 1b. However, instead of
tricycle 8, a mixture of bicyclic diaziridines 7a and 7b was
obtained (Scheme 1).† The initially formed precipitate consists
of two isomers 7a and 7b, but after recrystallization from
acetone, only bicycle 7b was isolated.
This work aimed to obtain crystalline functionalized tricyclic
diaziridines capable of resolving into enantiomers and thus
potentially useful for structural and biological studies. As we
reported earlier, aziridine-2-carboxylic acid hydrazide reacted
with aldehydes and ketones to give bicyclic aziridines,11 and with
acetone it formed a crystalline conglomerate, which underwent
spontaneous resolution.12
Several attempts to convert the mixture of hydrazones 7a,b
into tricyclic 8 were unsuccessful. Thus, heating a solution
of 7a,b in boiling [2H6]acetone at 60 °C for 10 or 48 h in pure
boiling CD3OD (and with 10 mol% DABCO) produced no changes
in 1H NMR spectra.
The structure of the bicyclic hydrazones was investigated
using NMR spectroscopy. When recrystallised isomer 7b was
dissolved in [2H6]DMSO, signals corresponding to two isomeric
monohydrazones 7a and 7b were observed in an equilibrium
ratio of 3:2. Both structures were confirmed by important
1H ® 13C connectivities observed in HMBC spectra (Figure 1)
and observed NOEs (Figure 2). According to this evidence, the
isomers may differ in the E/Z geometry of the N-acylhydrazone
or in stereochemistry at the diaziridine nitrogen. Stereochemistry
at the diaziridine NH nitrogen seems to be well defined due to a
much higher inversion barrier in diaziridines as compared to
O
O
O
O
i
ii
O
O
O
O
O
N
OH
2
3
O
O
O
O
iii
iv
O
O
O
v
HN NH
N
OTs
4
5
O
O
O
O
H2N
NH2
N
N
HN
HN
NH
N
H
H
HN NH
N
NH
6
7
8
O
O
O
O
O
O
N
N
HN
HN
NH
N
HN
HN
N
HN
HN
NH
H
N
NH
N
NH
N
NH
Scheme 1 Synthesis of diaziridine 7. Reagents and conditions: i, AcOH–H2O,
NaNO2, –5 °C to room temperature, 6 h; ii, NEt3, Et2O, TsCl, 5 °C to room
temperature, 4 h; iii, NH3 (2 equiv.) in MeCN, –40 °C, 1.5 h; iv, 1 mol dm–3
hydrazine in THF, room temperature, 12 h; v, Me2CO (excess), reflux, 1.5 h.
7a
major
7b
minor
Figure 2 Observed NOEs.
– 81 –
© 2009 Mendeleev Communications. All rights reserved.

Mendeleev Commun., 2009, 19, 81–83
simple aziridines. According to X-ray structure of 7b (Figure 3),
O(1)
N(6)
diaziridine NH proton is pointed towards uncyclised substituent
due to electronic repulsions of N(1) and N(2) lone electron
pairs. One more possibility to generate isomers is the planar
inversion of hydrazone nitrogen. However, this is very high
energy process and cannot count for observed exchange cross
peaks on NOESY/ROESY spectra between 7a and 7b. Thus, we
conclude that interconversion of 7a to 7b is restricted rotation
around amide bond as it was observed in the case of other acyl-
hydrazones.13,14 At the same time, the geometry of the preferred
solid state isomer is confirmed, as shown for bicyclic diaziridine
7b according to the X-ray diffraction study (Figure 3).‡
N(4)
C(9)
C(14)
C(7)
N(3)
C(11)
C(15)
C(16)
N(2)
N(8)
C(13)
C(17)
C(12)
O(10)
N(5)
Figure 3 X-ray structure for 7b in representation of atoms as thermal
ellipsoids drawn at 50% probability level.
In summary, bicyclic diaziridines 7 (semi butterfly) have
been synthesised for the first time from diaziridine-3,3-dicar-
boxylic acid dihydrazide and acetone. No tricyclic structure 8
(butterfly) was detected in these studies.
References
1
S. Takase, M. Watanabe, O. Shiratori and Y. Hata, Biochem. Biophys.
Res. Commun., 1982, 104, 746.
2
Y. Kobayashi, C. Sridar, U. M. Kent, S. G. Puppali, J. M. Rimoldi,
H. Zhang, L. Waskell and P. F. Hollenberg, Drug. Metab. Dispos., 2006,
34, 2102.
This work was supported by the Russian Academy of
Sciences and the Russian Foundation for Basic Research (grant
no. 06-03-32840).
3
Y. Hata and M. Watanabe, Biochem. Biophys. Res. Commun., 1982,
106, 526.
4
5
G. Sosnovsky and J. Lukszo, Z. Naturforsch., 1983, B38, 884.
G. Sosnovsky and J. Lukszo, J. Cancer Res. Clin. Oncol., 1984, 107,
217.
†
NMR spectra were recorded on a Varian UNITY INOVA 600 MHz
6
R. G. Kostyanovsky, G. V. Shustov, O. G. Nabiev, S. N. Denisenko,
S. A. Sukhanova and E. F. Lavretskaya, Khim.-Farm. Zh., 1986, 20,
671 (in Russian) (Chem. Abstr., 1987, 106, 27665q).
S. N. Denisenko, E. Pasch and G. Kaupp, Angew. Chem., Int. Ed.
Engl., 1989, 28, 1381.
S. N. Denisenko, G. Kaupp, A. J. Bittner and P. Rademacher, J. Mol.
Struct., 1990, 240, 305.
G. Kaupp, S. N. Denisenko, G. V. Shustov and R. G. Kostyanovsky,
Izv. Akad. Nauk SSSR, Ser. Khim., 1991, 2496 (Bull. Acad. Sci. USSR,
Div. Chem. Sci., 1991, 40, 2173).
spectrometer equipped with a cryoprobe, in [2H6]DMSO solution at
25 °C, and on a 200 MHz NMR Spectrometer Varian 200 Mercury.
Chemical shifts are reported in ppm relative to residual solvent signal
[d (1H) 2.50 ppm, d (13C) 39.5 ppm] (for 600 MHz spectrometer) or TMS
as an internal reference (for 200 MHz spectrometer). Two-dimensional
spectra recorded included DQF-COSY, ROESY, TOCSY, sensitivity-
enhanced 13C-HSQC and 13C–1H HMBC. Pulsed-field gradients were
used for all 13C correlation spectra. The ROESY mixing time was 200 ms,
and the TOCSY mixing time was 70 ms. 13C-HMBC spectra were recorded
with coupling evolution delay for the generation of multiple-bond cor-
relations set to 62.5 ms. All 2D spectra were run with 4096×1024 points
7
8
9
10 G. Kaupp and S. N. Denisenko, Magn. Res. Chem., 1992, 30, 637.
11 P. T. Trapentsier, I. Ya. Kalvin’sh, E. E. Liepin’sh, E. Ya. Lukevits, G. A.
Bremanis and A. V. Eremeev, Khim. Geterotsikl. Soedin., 1985, 774
[Chem. Heterocycl. Compd. (Engl. Transl.), 1985, 21, 646].
12 R. G. Kostyanovsky, P. E. Dormov, P. Trapencieris, B. Strumfs, G. K.
Kadorkina, I. I. Chervin and I. Ya. Kalvin’s, Mendeleev Commun.,
1999, 26.
13 O. V. Hordiyenko, A. V. Biitseva, M. Yu. Kornilov, N. Brosse, A. Hocquet,
B. Jamart-Grégoire, O. V. Shishkin and R. I. Zubatyuk, Eur. J. Org.
Chem., 2006, 2833.
1
data matrix, giving t2 max = 250 ms for H in the acquisition dimension
and t1max = 100 ms for 1H or t1max = 50 ms for 13C for the indirect
dimension. Prior to Fourier transform the data matrix was zero-filled twice
and multiplication by shifted sine-bell window function was applied. For
1H–13C HMBC the magnitude spectra were calculated.
LC-MS analysis was performed on a Waters Acquity ultra performance
liquid chromatography (UPLC) system (Waters Corp., Milford, USA)
(column Acquity UPLC BEH C18 1.7 μm, 2.1×50 mm) coupled to a
Micromass Q-Tof micro API Time Of Flight (TOF) mass spectrometer
(Waters Corp., Milford, USA) equipped with an electrospray source
operating in positive ion mode. The source temperature was set at 120 °C
with a cone gas flow of 30 dm3 h–1. A desolvation gas temperature of
300 °C and a gas flow of 400 dm3 h–1 were employed. The capillary
voltage was set at 3.0 kV and the cone voltage was 45 V.
14 P. Marakos, N. Pouli, S. Papakonstantinou-Garoufalias and E. Mikros,
J. Mol. Struct., 2003, 650, 213.
15 A. J. Zambito and E. E. Howe, Org. Synth., Coll. Vol., 1973, 5, 373.
16 R. G. Kostyanovskii, G. V. Shustov and V. I. Markov, Izv. Akad. Nauk
SSSR, Ser. Khim., 1974, 2823 (Bull. Acad. Sci. USSR, Div. Chem. Sci.,
1974, 23, 2725).
Diester 4 was obtained according to the reported method,15 yield
X-Ray quality crystals of 7b (C9H16N6O2, M = 240.267) were obtained
‡
1
5.22 g (73%). H NMR (200 MHz, [2H6]DMSO) d: 2.47 (s, 3H), 3.84
by slow evaporation of acetone solution of equilibrium mixture of 7a
and 7b. Crystals are triclinic, space group P1, colourless prisms, size
0.07×0.12×0.19 mm, at room temperature (20 2 °C): a = 7.4559(4),
b = 7.7749(4) and c = 11.5958(7) Å, V = 592.94(6) Å3, Z = 2, dcalc
–
(s, 3H), 3.94 (s, 3H), 7.33–7.44 (m, 2H), 7.83–7.94 (m, 2H).
Diaziridine 5 was prepared according to the known procedure16 and
purified by sublimation. Dihydrazide 6 is extremely hygroscopic and,
therefore, was used without purification.
=
= 1.346 g cm–3, m = 0.10 mm–1, F(000) = 256, final R-factor 0.0675. The
data were collected on a Nonius KappaCCD diffractometer at room
temperature (20 2 °C) using MoKα radiation (l = 0.71073 Å) by the j
and w scan method. Accurate lattice parameters were determined from
1569 reflections. Crystallographic computations were carried out with
the Denzo-SMN program17 of Bruker-Nonius. The structures were solved
by an application of the direct method using the programs DETMAX.18,19
The crystal structures were refined by full-matrix least-squares method
Bicyclic diaziridine 7: 170 mg (1.06 mmol) of diaziridine 5 was
dissolved in 10 ml of dry THF (from Na/benzophenone), and 2.2 ml of
1 mol dm–3 hydrazine solution in THF was added. The mixture was
stirred for 12 h under argon. A white precipitate was filtered under argon,
dissolved in dry acetone, and the solution was heated under reflux for
1.5 h. The precipitate was filtered, dried in vacuo and recrystallized from
acetone to give 7b, yield 50 mg (20%). LC-MS, m/z: 263 [M + Na]+.
Major isomer 7a (in solution): 1H NMR (600 MHz, [2H6]DMSO) d:
1.12 (s, 3H, Me), 1.32 (s, 3H, Me), 1.80 (s, 3H, Me), 1.83 (s, 3H, Me),
3.76 (s, 1H, HN), 4.85 (s, 1H, HN), 8.90 (s, 1H, HN), 10.62 (s, 1H, HN).
13C NMR (150 MHz, [2H6]DMSO) d: 17.7, 21.8, 24.9, 25.27, 52.5, 71.3,
159.1, 161.0, 167.9. Minor isomer 7b (in solution): 1H NMR (600 MHz,
[2H6]DMSO) d: 1.16 (s, 3H, Me) 1.17 (s, 3H, Me), 1.87 (s, 3H, Me),
1.94 (s, 3H, Me), 4.10 (s, 1H, HN), 5.16 (s, 1H, HN), 9.42 (s, 1H, HN),
11.32 (s, 1H, HN). 13C NMR (150 MHz, [2H6]DMSO) d: 18.0, 21.5,
24.9, 25.33, 57.7, 71.8, 151.1, 165.2, 167.7.
using the SHELXL97.20 Minimized functional was w[|F |2 – (1/k)|F |2].
Σ
o
c
The final round of refinement was performed with anisotropic thermal
parameters for the non-hydrogen atoms. The hydrogen atoms were refined
using a riding model. The molecular graphics were performed with the
help of the program ORTEP.21
CCDC 689085 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
For details, see ‘Notice to Authors’, Mendeleev Commun., Issue 1, 2009.
– 82 –

Mendeleev Commun., 2009, 19, 81–83
17 Z. Otwinowski and W. Minor, in Methods in Enzymology, eds. C. W.
21 C. K. Johnson, ORTEP-II. A Fortran Thermal-Ellipsoid Plot Program.
Report ORNL-5138, Oak Ridge National Laboratory, Oak Ridge,
Tennessee, USA, 1976.
Carter Jr. and R. M. Sweet, Academic Press, New York, 1997, vol. 276,
p. 307.
18 A. F. Mishnev and S. V. Belyakov, Kristallografiya, 1988, 33, 835 (in
Russian).
19 A. Altomare, G. Cascarano, C. Giacovazzo, A. Guagliardi, M. C. Burla,
G. Polidori and M. Camalli, J. Appl. Crystallogr., 1994, 27, 435.
20 G. M. Sheldrick, SHELXL97. Program for the Refinement of Crystal
Structures, University of Göttingen, Germany, 1997.
Received: 29th August 2008; Com. 08/3205
– 83 –