Bis-aziridinomethanes: Synthesis, structure and properties

Article abstract of DOI:10.1070/MC2001v011n04ABEH001471

Bis-aziridinomethanes were prepared by the reaction of Me₂NCH(OMe)₂ with aziridines and characterised by X-ray diffraction analysis and NMR spectroscopy.

Full text of DOI:10.1070/MC2001v011n04ABEH001471

, 2001, 11(4), 141–143
Bis-aziridinomethanes: synthesis, structure and properties
Remir G. Kostyanovsky,*a Vasilii R. Kostyanovsky,a Boris B. Averkiev,b Konstantin A. Lyssenkob and
Pavel E. Dormova
a N. N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, 117977 Moscow, Russian Federation.
Fax: +7 095 938 2156; e-mail: kost@center.chph.ras.ru
b A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 117813 Moscow, Russian Federation.
Fax: +7 095 135 5085; e-mail: kostya@xray.ineos.ac.ru
10.1070/MC2001v011n04ABEH001471
Bis-aziridinomethanes were prepared by the reaction of Me2NCH(OMe)2 with aziridines and characterised by X-ray diffraction
analysis and NMR spectroscopy.
The incorporation of a nitrogen atom into a three-membered ring
excludes (a) the α -aminoalkylation reaction1 and (b) amide con-
jugation.2 These basic rules result from decreasing the p-char-
acter of the nitrogen lone pair (lp) and hence its electron-do-
nating properties.1(e)–(f),2(a),(d),(e),(g)–(i),3 Limitations (a) and (b) are
most pronounced in the chemistry of bis-aziridinomethanes
(BAMs). These compounds cannot be prepared by typical syn-
theses of usual aminales,4 such as reactions of aziridine with alde-
hydes, as well as 1-aziridinocarbinol or 1-alkoxymethylaziridines.1
Bis-aziridinomethoxymethane also does not react with aziridine
even under severe conditions1(e) [limitation (a)].
In accordance with limitation (b), the first BAMs were obtained
by a mild addition of aziridine to activated acetylenes (bis-adducts
A),5 whereas usual amines give only mono-adducts, which are
amide vinylogs with deactivated double bonds. The simplest BAM
B,6(a) as well as aziridinoform C6(b)–(d) and derivatives D,6(e) was
synthesised by the alkylation of aziridine under the action of
CH2Cl2, CHCl3 and a corresponding gem-dichloroalkane either
in the presence of bases6(c)–(e) or through potassium ethylene-
amide.6(a),(b) The first and second steps of alkylation are deter-
mined by the presence of the easier leaving group Cl– (as com-
pared with X– = OH, OR). In addition, the synthesis of diaza-
quadricyclane E containing a BAM fragment was reported.7
Finally, it was found that 5,5-dimethoxytetrachlorocyclopenta-
1,3-diene reacts with aziridine under mild conditions with for-
mation of BAM F.8 This reaction results from the allylic activa-
tion of MeO groups at both steps of the reaction.
with mp 157.5 (from acetone) and 172.5 °C (from MeOH–Et2O),
both having identical NMR spectra, which correspond to one
diastereomer. Thus, BAM 1 is formed diastereoselectively. In
1
the H NMR spectrum in an aprotic solvent (CDCl3, 18 °C), a
considerable broadening of the upfield signal from the A-Me
group and signals from all aziridine ring protons (particularly,
Ha, Hb and Ha') are observed. In contrast, at 60 °C, the broad-
ening disappeared and the signals due to amide protons Ha, Hs
shifted upfield (0.1 and 0.3 ppm). This temperature dependence
of the spectrum points to the presence of hindered rotation,
nitrogen inversion in the 2-cyanoaziridine moiety, as well as an
intramolecular H-bond in the 2-carbamoylaziridine fragment of 1.
The monocrystals suitable for an X-ray study‡ were grown
only from the higher melting modification of 1 (not described
earlier). According to the X-ray analysis, compound 1 is crys-
tallised as a racemate (space group P1), and asymmetric centres
in 1 [C(2) and C(7)] have identical configurations in contrast to
published data9(a) [Figure 1(a).]
In the crystal of 1, shortened contacts are observed. Namely,
H···H contacts (2.16 and 2.22 Å) formed by the methyl group
H3C(5) with H(7) and H(8B) atoms, and H(2)···N(3) (2.38 Å)
†
Characteristics and spectroscopic data. 1H and 13C NMR spectra were
measured at 400.13 and 100.61 MHz, respectively.
1:9(b) mp 172.5 °C (MeOH–Et2O) and 157.5 °C (acetone) [cf. refs.
9(a),(b)]. 1H NMR (CDCl3 at 50 °C) d: 1.11 (br. s, 3H, A-Me), 1.19 (s,
3H, B-Me), 1.80 (dd, 1H, HC, 3Jtrans 2.9 Hz, 2Jgem 1.2 Hz), 2.06 (dd, 1H,
HB, 3Jcis 6.8 Hz, 2Jgem 1.2 Hz), 2.11 (dd, 1H, HC'
,
3Jcis 2.9 Hz, 2Jgem
2
1.3 Hz), 2.15 (dd, 1H, HB'
,
3Jcis 6.3 Hz, Jgem 1.3 Hz), 2.40 (ddd, 1H,
The reaction of 2-cyanoaziridine with ketones9 (Scheme 1) is
inconsistent with rule (a). There are contradictory data9 on the
structure of the products which possess a high biological acti-
vity; they were described as bis-cyanoaziridinoalkanes.9(c) The
structure of 1 was strictly confirmed; however, data on the rela-
tive configuration are ambiguous. It can be suggested that the
key intermediates in the synthesis of 1 are the structures I1 and
I2. The latter is a product of the transformation of I1 by Pinner
reaction. The aziridinomethylating action of I2 is determined by
the presence of the easily leaving iminoyloxy group as in the
case of the above intermediate 1-chloromethylaziridines. The
Chapman rearrangement of I2 into a corresponding lactam,9(b)
as well as the transformation of the adduct of 2-cyanoaziridine
(I2-type) with substituted cyclohexanone into compound G by
intramolecular aziridinomethylation at the OH group, is well
known.11
On the basis of the above analysis, we proposed a new effi-
cient way for the preparation of BAM 2. It consists in the
dimethylaminomethylenation of aziridine with dimethylformamide
dimethylacetal (Scheme 1).† This reaction is a result of strong
electron donation of Me2N, which increases the mobility of MeO
groups (like allyl activation of MeO groups in the synthesis of
BAM F). A special feature of the NMR spectra of 2 is that all
protons and carbons of the aziridine ring are non-equivalent†
[cf. ref. 1(e)].
3
3
4
3
HA, Jcis 6.8 Hz, Jtrans 2.9 Hz, JAs 0.9 Hz), 2.52 (dd, HA', Jcis 6.8 Hz,
3Jtrans 2.9 Hz), 5.32 (br. s, 1H, Hs), 6.08 (br. s, 1H, Ha).
2: A mixture of aziridine and dimethylformamide dimethylacetal in a
molar ratio of 2:1 was kept at 20 °C for 10–12 h, evaporated and distilled
1
over sodium metal in vacuo, bp 36.5–37 °C (1 torr), yield 65–75%. H
NMR (C6D6) d: 1.10, 1.19, 1.47 and 1.64 (m, 8H, ring protons, ABCD
cis
cis
3
3
spectrum, ∆ nAB 43.0 Hz, nCD 35.5 Hz, JAB 5.4 Hz, JCD 7.1 Hz,
gem
gem
2
trans
3JAtrDans
=
3JBC = 3.8 Hz, JAC = JBD = 0.7 Hz), 1.77 (s, 1H, HC),
2
2.55 (s, 6H, Me2N). 13C NMR (C6D6) d: 22.0 (ddm) and 24.6 (ddm)
(ring carbons, 1J 165.0 Hz, 1J 175.0 Hz), 39.9 (qq, MeN, 1J 133.3 Hz, 3J
4.0 Hz), 105.2 (dm, CH, 1J 153.0 Hz).
‡
Crystallographic data for 1: at 293 K, crystals of C9H14N4O are
triclinic, space group P1, a = 6.309(2) Å, b = 6.791(2) Å, c = 13.082(2) Å,
a = 75.27(2)°, b = 89.20(2)°, g = 83.34(2)°, V = 538.3(2) Å3, Z = 2, d =
= 1.198 g cm–3, m = 0.83 cm–1, F(000) = 208. Intensities of 3384 reflec-
tions were measured with an Enraf Nonius CAD-4 diffractometer at
293 K [l(MoKα ) = 0.710712 Å, graphite monochromator, q/2q-scans,
2q < 60°], and 3117 independent reflections (Rint = 0.0290) were used in
a further refinement. The structure was solved by the direct method and
refined by full-matrix least squares against F2 in the anisotropic
approximation for non-hydrogen atoms. All the hydrogen atoms were
located from the electron density difference synthesis and included in
the refinement in an isotropic approximation. The refinement converged
to wR2 = 0.1316 and GOF = 1.008 for all independent reflection [R1 =
= 0.0433 was calculated against F for 2300 observed reflections with
I > 2s(I)]. All calculations were performed using SHELXTL PLUS 5.0
program. Atomic coordinates, bond lengths, bond angles and thermal
parameters have been deposited at the Cambridge Crystallographic Data
Centre (CCDC). For details, see ‘Notice to Authors’, Mendeleev Commun.,
Issue 1, 2001. Any request to the CCDC for data should quote the full
literature citation and the reference number 1135/92.
BAM 1 was extensively studied as a biologically active com-
pound10 for examining the nitrogen inversion and dynamic effects
in BAMs, as well as for determining the relative configuration.
Compound 1 was found to crystallise in two modifications,
– 141 –

, 2001, 11(4), 141–143
stabilization of a conformation with the antiperiplanar orienta-
tion of lp of the N(2) atom in relation to the C(4)–N(3) bond
[pseudotorsion angle lp–N(2)–C(4)–N(3) is 173°], i.e., by the
anomeric effect nN(2) ® σ *C(4)N(3). The pseudotorsion angle lp-
N(3)–C(4)–N(2) is equal to 45°; this excludes its participation
in the anomeric interaction with the C(4)–N(2) bond. The simul-
taneous antiperiplanar orientations of lp-N(2) and lp-N(3) in
relation to the corresponding CN bonds are sterically hindered
and result in more shortened contacts H···H.
In spite of anomeric interaction, the C(4)–N(2) and C(4)–N(3)
bond lengths are practically the same. Such a situation is typical
of aziridines1(g),6(d) and it is in agreement with recent high level
calculations.12 The best indicator of anomeric effects is the NCN
angles, which are quite close to each other in 1 [110.6(1)°] and
CH2(NH2)2 (113°).12
N
2 CCH2Y
X
N
2 CH2
N 3 CH
B
Space group P63
Z = 6
X = H, CO2Me
Y = CN, CO2Me
R'
R'
C
R'
R
A
N
N
Cl
Cl
O
O
N
2 C
N
P N
O
O
N
3
2
CCl3
Me Me
Cl
Cl
Space group P21/n
Z = 4
R = CO2But
R' = But
F
It should be noted that anomeric effects in aziridines were
confirmed by theoretical and experimental investigations in gas,
liquid and solid states. For tris-aziridinomethane, the calculated
and experimental (GED) lp-NCN, NCN angles are 166.3°, 112.6°
and 172.6°, 114°, respectively.6(d) For 1-methoxymethylaziridine,
the lp-NCO, NCO angles are 174.2°, 113.2° and 161°, 113.4°,
respectively.1(g) In the latter case, the anomeric effect reveals
itself in a considerable decrease in the nitrogen inversion barrier
due to stabilization of the planar transition state.1(g) It can be
demonstrated by comparing 1-dimethylaminomethylaziridine and
its 2,2-dimethyl analogue.13 The transformation of the former
compound into methyl iodide leads to a great decrease in the
nitrogen inversion barrier (by 3.5 kcal mol–1) due to the anomeric
effect n(N) ® σ *(C–N+), whereas upon a similar transformation
of the latter compound the inversion barrier remained unchanged
due to steric hindrances for the anomeric effect. Finally, accord-
ing to an X-ray database, the anomeric effect is also observed in
1-alkoxyaziridine (+)-G11 where it is strengthened by steric strain
which is favourable to lengthening the C–O bond [bond lengths:
N(1)–C(3) 1.418 Å, C(3)–O(1) 1.458 Å; bond angles: lp-N(1)–
C(3)–O(1) 178°, N(1)–C(3)–O(1) 112°].
Space group P1
Z = 2
D
E
Me
NC
NC
N
Me
NH + Me2CO
N
C
OH
HN
O
Me
Me
I1
I2
Hc'
NC
Me-B
Me-A
N
NC
Hb'
Ha
Ha
Hb
Hc
'
NH
N
Ha
N
Hs
1
O
HA
Apparently, the properties of (+)-G and its precursor, an inter-
mediate of the I2 type, are responsible for the enantioselectivity
of 2-cyanoaziridine hydration catalysed by a chiral substituted
cyclohexanone (ee > 99%).11
HB
HD
N
NH
NH
Me2NCHN
MeO
HC
N
Me2NCH(OMe)2
Me2N
C
H
H(4B)
2
H(4A)
(a)
H(6C)
N(4)
NH2
Me
N(1)
O
CN
H(2)
C(6)
C(1)
H(6B)
C(7)
H(6A)
N
C(9)
H(7)
N(3)
C(2)
O(1)
N(2)
O
Me
Me
C(4)
C(8)
H(3A)
H(5C)
C(3)
(+)-G
H(3B)
H(5B)
C(5)
Space group P21
H(8B)
H(5A)
Z = 2
Scheme 1
0a
c
(b)
[Figure 1(a)]. Note that these protons exhibited the most broad-
ened signals in the 1H NMR spectrum [A-Me, Ha, Hb, Ha'
(Scheme 1)]. In the crystal of 1, molecules take part in the
formation of intermolecular hydrogen bonds. Being bonded by
the inversion centre in the crystal, the molecules of 1 form
dimers due to the amide H-bonds. These dimers are combined
into chains directed along the axis c by the H-bonds involving
the nitrile group CN···H–N [Figure 1(b)].
The mutual arrangements of aziridine rings in relation to the
fragment Me2C(4) are different. The angles between the ring
planes N(2)C(2)C(3) and N(3)C(7)C(8) relative to the plane
C(5)C(4)C(6) are 4.3 and 67.4°, respectively. Evidently, the
above shortened contacts are responsible for increasing the angle
N(3)C(4)C(5) up to 115.7(1)° [the other CCN angles at C(4) are
in a range of 105.6–106.2°], as well as for flattening the N(3)
atom as compared with N(2) (the sums of bond angles are 301.4
and 297.6°, respectively).
O(1A)
H(4B)
H(4AB)
N(1)
N(4B)
N(4A)
H(4BA)
O(1)
N(1B)
H(4A)
N(4)
b
Figure 1 (a) The general view of 1. Selected bond lengths (Å): C(1)–N(1)
1.140(2), C(1)–C(2) 1.442(2), N(2)–C(3) 1.446(2), N(2)–C(2) 1.459(2),
N(2)–C(4) 1.479(1), C(2)–C(3) 1.483(2), N(3)–C(7) 1.454(1), N(3)–C(8)
1.463(2), N(3)–C(4) 1.473(1), N(4)–C(9) 1.318(2); selected bond angles
(°): N(3)–C(4)–N(2) 110.6(1), N(3)–C(4)–C(5) 115.7(1), N(2)–C(4)–C(5)
105.6(1), N(3)–C(4)–C(6) 106.1(1), N(2)–C(4)–C(6) 106.0(1), C(5)–C(4)–
C(6) 112.5(1). The parameters of intramolecular H-bonds: N(3)···H(2)
2.38 Å, N(3)···C(2) 2.752(1) Å, C(2)–H(2)–N(3) 99°, N(3)–H(4A) 2.40 Å,
N(3)···N(4) 2.800(1) Å, N(4)–H(4A)–N(3) 109°. (b) The formation of H-
bonded chains directed along crystallographic axis c. The parameters of
H-bonds: O(1)···H(4B) 2.04 Å, N(4)···O(1) 2.908(2) Å, O(1)–H(4B)–N(4)
172(2)°; N(1)···H(4A) 2.52 Å, N(1)···N(4) 3.268(2) Å, N(1)–H(4A)–N(4)
146(1)°.
The observed steric hindrance in 1 is probably caused by the
– 142 –

, 2001, 11(4), 141–143
6
(a) R. G. Kostyanovsky and O. A. Pan’shin, Izv. Akad. Nauk SSSR, Ser.
Khim., 1965, 567 (Bull. Acad. Sci. USSR, Div. Chem. Sci., 1965, 14,
553); (b) R. G. Kostyanovsky, Yu. I. El’natanov, and Kh. Khafizov, Izv.
Akad. Nauk SSSR, Ser. Khim., 1970, 1918 (Bull. Acad. Sci. USSR, Div.
Chem. Sci., 1970, 19, 1815); (c) W. Funke, Liebigs Ann. Chem., 1969,
725, 15; (d) V. P. Novikov, M. Dakkouri, A. V. Golubinskii, M. V. Popik,
L. V. Vilkov, P. E. Dormov, K. A. Lyssenko and R. G. Kostyanovsky,
Mendeleev Commun., 2000, 103; (e) L. I. Zhdanova, V. N. Biyushkin,
I. E. Boldeskul, V. Ya. Semenii and T. I. Malinovskii, Dokl. Akad. Nauk
SSSR, 1986, 287, 635 (in Russian).
G. Michels, R. Mynott and M. Regitz, Chem. Ber., 1988, 121, 357.
O. G. Nabiev, M. A. Shachgeldiev, I. I. Chervin and R. G. Kostyanovsky,
Izv. Akad. Nauk SSSR, Ser. Khim., 1985, 715 (Bull. Acad. Sci. USSR,
Div. Chem. Sci., 1985, 34, 656).
(a) K. F. Koehler, H. Zaddach, G. K. Kadorkina, V. N. Voznesenskii,
I. I. Chervin and R. G. Kostyanovsky, Izv. Akad. Nauk SSSR, Ser.
Khim., 1993, 2136 (Russ. Chem. Bull., 1993, 42, 2049); (b) K. Jahnisch,
E. Schmitz and E. Gründemann, J. Prakt. Chem., 1979, 321, 712; (c)
W. Kampe, M. Thiel, E. Fauland, U. Bicker and G. Habold, USSR Pat.
no. 673167, Bull. Izobret., 1979, no. 25, 234 (in Russian).
This work was supported by the Russian Foundation for Basic
Research (grant nos. 98-03-04119 and 00-03-81187 Bel) and the
Russian Academy of Sciences.
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Received: 4th May 2001; Com. 01/1797
– 143 –