Stereoselective synthesis and ROESY 1H NMR study of bidiaziridines

Article abstract of DOI:10.1021/jo202618u

The bisaziridination reaction of symmetric (E-s-trans-E)-α-diimines using ethyl nosyloxycarbamate as aminating agent yields symmetrically functionalized bidiaziridines, under mild conditions. The reactions take place with very high stereoselectivity givin

Full text of DOI:10.1021/jo202618u

Note
pubs.acs.org/joc
Stereoselective Synthesis and ROESY 1H NMR Study of Bidiaziridines
Laura Carroccia, Maurizio Delfini, Stefania Fioravanti,* Lucio Pellacani,* and Fabio Sciubba
̀
Dipartimento di Chimica, Universita degli Studi “La Sapienza”, P.le A. Moro 5, I-00185 Roma, Italy
S
* Supporting Information
ABSTRACT: The bisaziridination reaction of symmetric (E-s-
trans-E)-α-diimines using ethyl nosyloxycarbamate as aminat-
ing agent yields symmetrically functionalized bidiaziridines,
under mild conditions. The reactions take place with very high
stereoselectivity giving only bidiaziridines with total retention
of the starting α-diimine configuration, as determined by NMR
measurements. Moreover, only a single pure diastereomer,
derived from attack of the aza-anion on the opposite faces of
conjugate system was obtained, starting from chiral substrates. ROESY analyses clearly show that all nitrogens have a stable
pyramidal conformation, and the absolute configurations of new chiral centers were assigned.
iaziridines are rarely reported in the literature, although
they can represent an interesting tool in asymmetric
According to reported X-ray crystallographic analyses and
molecular modeling studies,9,10,15 all the α-diimines were
obtained as a single diastereomer (E-s-trans-E)-1, as confirmed
B
synthesis because of their aptitude to behave as ligands with
some cations, thus mediating asymmetric transformations.1
Recently in this field, ( )-dinitrobiaziridines were successfully
obtained by us through a direct aza-Michael initiated ring
closure (MIRC) reaction on (E,E)-1,4-dialkyl-2,3-dinitro-l,3-
butadienes under very mild conditions, using different alkyl
nosyloxycarbamates (NsONHCO2R, Ns = 4-NO2C6H4SO2; R
= Et or Bn) as aminating agents under heterogeneous
conditions (CH2Cl2/CaO). The reactions occur with high
stereoselectivity, giving essentially only a pair of stereoisomers,
as shown by the enantioselective HPLC analyses performed on
the crude mixtures.2
1
by H NMR spectra performed on the crude mixtures.
With the aim of fixing the optimal reaction conditions, the
aziridination reaction was tested on the diimine 1a. The
reaction was performed following our already tested reaction
conditions, using a molar ratio of substrate/NsONHCO2Et =
1:2, CH2Cl2 as solvent and working in the absence of an added
base at room temperature. These conditions did not give any
amination product, probably due to the decrease of the basicity
of nitrogen atoms in the conjugated imines. By increasing the
molar amount of the aminating agent (up to 3-fold), the
bisaziridination product was obtained in very low yields
(<10%). Then, an organic base (DABCO or Et3N) was
added to promote the carbamate deprotonation, and the molar
ratio of reagents (substrate/NsONHCO2Et/base from 1:1:1 to
1:2:3) was also varied, but only a complex crude reaction
mixture was obtained in all attempts. Finally, working under
heterogeneous conditions (CH2Cl2/CaO), the expected
aziridination reaction was observed, leading to the bifunction-
alization product, even if the reaction was performed by using
an equimolar ratio between the reagents.
The best reaction conditions, namely molar ratio of
substrate/NsONHCO2Et/CaO = 1:2:3, were extended to the
α-diimines 1b−f, and the results are reported in Table 2.
As determined by NMR spectra performed on the crude
mixtures that showed only a singlet for the diaziridinic protons,
the reactions take place with a high stereoselectivity, giving only
meso-bidiaziridines 2 with total retention of the starting α-
diimine configuration. The data were confirmed by ROESY
analyses performed on 2f: the presence of dipolar correlations
between the diaziridinic protons and those belonging to alkyl
substituents on the nitrogen indicates that the latter is on the
Even less reported in the literature is the synthesis of
compounds similar to the biaziridines, namely bidiaziridines,3
interesting three-membered heterocyclic compounds contain-
ing two nitrogen atoms.4
As is well known, diaziridines present a wide-range potential
for application in both theoretical and practical fields, but most
of the methods for their production have not yet been
optimized.5 In this field, in the past we reported the synthesis of
chiral spirodiaziridines starting from optically pure imines by
using NsONHCO2Et as aminating agent in the absence of an
added base at room temperature,6 and under the same
aziridination conditions, trifluoromethyl diaziridines were
recently obtained,7 starting from the corresponding fluorinated
aldimines.8
Continuing our studies on the reactivity of conjugated
systems in the direct amination reactions of CN double
bonds, different α-diimines deriving from glyoxal were
considered as interesting conjugate dienes to obtain bidiazir-
idines.
α-Diimines 1a−h were synthesized by a condensation
reaction between glyoxal and different alkyl amines.9 The
results are reported in Table 1.
Received: December 19, 2011
Published: January 17, 2012
© 2012 American Chemical Society
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Note
CH2 or CH3 of the carbamic moieties, dipolar couplings
corresponding to interproton distances ranging from 3.0 to 3.8
Å were detected between the diaziridinic protons and those on
the alkyl substituent of the nitrogen (Figure 1).
Table 1. Synthesis of (E-s-trans-E)-α-Diimines
ROESY results confirm the different stereochemical outcome
for aziridination of α-diimines with respect to that obtained in
analogous reactions of the 2,3-dinitro dienes.2b The formation
of only meso-2 might be due to a ring closure reaction faster
than the rotation around the C−N single bond (Scheme 1).
As is reported in the literature, the nitrogen inversion in
aziridines and diaziridines is remarkably slow or even
hindered.17 Thus, with the aim of studying the nitrogen atom
chirality and in particular the pyramidal structure stability of the
carbamic nitrogen18−21 present in diaziridines, α-diimines 1g,h
obtained from optically pure primary amines were aziridinated
(Table 3) and the corresponding chiral bidiaziridines 2g,h
considered in the ROESY analyses.
As reported in Figure 2 for (−)-2h, ROESY analysis clearly
shows the presence of dipolar correlations between diaziridinic
protons and those of N-alkyl substituents comparable to those
observed in compound 2f. These results show that the
bisdiaziridination reaction takes place with very high stereo-
selectivity, leading always to a single pure enantiomer, derived
from the attack of aza-anion (NsON−CO2Et) on the opposite
faces of conjugate system, as depicted in Scheme 1. The
stereochemical pathway of the reaction seems to be highly
controlled by steric hindrance on the alkyl residue of amine
moiety.
Moreover, no correlations were observed between the
diaziridinic protons and those of ethylene residue of carbamic
groups, even when variable temperature (298−348 K) NMR
experiments were done.
As a consequence, one can assume that the resonance
structures for the carbamic bond presenting charge separation
and an sp2 hybridization for the nitrogen do not seem to give a
relevant contribution since the ring strain energy is especially
high in three-membered rings. Thus, it is possible to consider
the carbamic nitrogen preferentially hybridized sp3 and a chiral
center as the other diaziridine nitrogen.
a
b
After workup. Ref. 14.
Table 2. Synthesis of meso-Bidiaziridine 2a−f
On the basis of collected data, the absolute configurations of
the new chiral centers can be assigned (Figure 3), in agreement
with the hypothesis that N-bonded substituents in a diaziridine
ring always adopt a trans configuration.22
In conclusion, symmetric (E-s-trans-E)-α-diimines were
converted in the corresponding symmetric meso-bidiaziridines
by a CaO-promoted direct amination reaction, using ethyl
nosyloxycarbamate as aminating agent. Compounds 2 were
obtained with total retention of the starting α-diimine
configuration, as demonstrated by ROESY analyses, independ-
ently from the alkyl residue (linear, branched, or cyclic) present
on the iminic nitrogen. Moreover, not only the alkyl substituted
nitrogens, but also the carbamic nitrogens show a stable
pyramidal structure, even by increasing the temperature. In fact,
starting from chiral α-diimines, a highly stereoselective aza-
anion attack on the opposite faces of conjugate system lead, as
determined by NMR measurements, to enantiomerically pure
bidiaziridines.
a
b
EXPERIMENTAL SECTION
After fast filtration of crude on silica gel using CH2Cl2 as eluent. Ref.
■
16.
General Experimental Methods. Specific rotations were
determined at 20 °C. IR spectra were recorded on a FT/IR
spectrophotometer in CHCl3 as the solvent. 1H NMR and 13C
NMR spectra were recorded by a 300 or 400 NMR spectrometer.
same ring side of the former. In greater detail, while no cross-
peaks were observed between the diaziridinic protons and the
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Note
Figure 1. ROESY spectra of meso-2f. Correlations between the diaziridinic protons and the methylene protons (Ha and Hb) of the pentyl chains.
1
−153.45 (c 2, CHCl3); IR (CHCl3) 1615 cm−1; H NMR (CDCl3) δ
0.67 (d, J = 6.7 Hz, 6H), 0.74 (d, J = 6.8 Hz, 6H), 1.01 (d, J = 6.4 Hz,
6H), 1.50−1.66 (m, 2H), 2.77−2.88 (m, 2H), 7.72 (s, 2 H); 13C NMR
(CDCl3) δ 18.8, 18.9, 19.2, 33.6, 72.0, 159.9; HRMS-ESI (m/z) [M +
H]+ calcd for C12H25N2 197.2018, found 197.2011.
Scheme 1. Nucleophilic Attack of NsON−CO2Et: Pathway
for the Aziridination Reaction
(2R,2′R)-N,N′-(1E,2E)-Ethane-1,2-diylidenebis(3,3-dimethylbutan-
2-amine) [(−)-1h]. 89% yield, brown solid: mp = 32−33 °C; [α]D
1
−225.4 (c 2, CHCl3); IR (CHCl3) 1619 cm−1; H NMR (CDCl3) δ
0.88 (s, 18H), 1.10 (d, J = 6.5 Hz, 6H), 2.93 (q, J = 6.5 Hz, 2H), 7.88
(s, 2H); 13C NMR (CDCl3) δ 17.0, 26.3 (6C), 33.8, 75.2, 160.1;
HRMS-ESI (m/z) [M + H]+ calcd for C14H29N2 225.2331, found
225.2340.
Table 3. Synthesis of Optically Pure Bidiaziridines
(2S,2′S)-N,N′-(1E,2E)-Ethane-1,2-diylidenebis(3,3-dimethylbutan-
2-amine) [(+)-1h]. 91% yield, brown solid: mp = 31−33 °C; [α]D
+225.0 (c 2, CHCl3).
General Procedure for the Synthesis of Bidiaziridines (2a−
h). To a stirred CH2Cl2 (3 mL) solution of (E,E)-α-diimines 1a−h (1
mmol), CaO (3 mmol) and NsONHCO2Et (2 mmol) were added at
room temperature. After the reactions were completed (1H NMR),
hexane was added, and calcium nosylate salts were filtered. The crude
mixtures were filtered through plugs filled with silica gel using CH2Cl2
as eluent, and the solvents were removed in vacuo.
Diethyl 2,2′-Di-tert-butyl-3,3′-bidiaziridine-1,1′-dicarboxylate
(2a). 60% yield, yellow oil: IR (CHCl3) 1735 cm−1; 1H NMR
(CDCl3) δ 1.06 (s, 18H), 1.33 (t, J = 7.1 Hz, 6H), 2.79 (s, 2H), 4.16−
4.32 (m, 4H); 13C NMR (CDCl3) δ 13.9, 25.1 (6C), 56.2, 56.8, 63.0,
161.9; HRMS-ESI (m/z) [M + H]+ calcd for C16H31N4O4 343.2345,
found 343.2351.
Diethyl 2,2′-Dicyclopentyl-3,3′-bidiaziridine-1,1′-dicarboxylate
(2b). 57% yield, brown oil: IR (CHCl3) 1737 cm−1; 1H NMR
(CDCl3) δ 1.33 (t, J = 7.1 Hz, 6H), 1.56−2.01 (m, 16H), 2.42−2.48
(m, 2H), 2.65 (s, 2H), 4.16−4.42 (m, 4H); 13C NMR (CDCl3) δ 14.1,
24.4, 24.6, 30.3, 31.9, 62.4, 63.2, 70.6, 161.5; HRMS-ESI (m/z) [M +
H]+ calcd for C18H31N4O4 367.2345, found 367.2342.
Diethyl 2,2′-Dicyclohexyl-3,3′-bidiaziridine-1,1′-dicarboxylate
(2c). 43% yield, brown oil: IR (CHCl3) 1737 cm−1; 1H NMR
(CDCl3) δ 1.37 (t, J = 7.1 Hz, 6H), 1.14−1.67 (m, 12H), 1.70−1.90
(m, 8H), 1.92−2.10 (m, 2H), 2.67 (s, 2H), 4.20−4.34 (m, 4H); 13C
NMR (CDCl3) δ 14.1, 24.0, 24.2, 25.7, 29.6, 31.4, 62.2, 65.2, 67.9,
161.6; HRMS-ESI (m/z) [M + H]+ calcd for C20H35N4O4 395.2658,
found 395.2651.
CDCl3 was used as the solvent and CHCl3 as the internal standard. If
not otherwise specified, all 13C NMR signals are referred to two
carbon atoms. HRMS analyses were performed using a quadrupole-
time-of-flight (TOF) mass spectrometer equipped with an ESI source
and a syringe pump. The experiments were conducted in the positive
ion mode. Where appropriate, 2D techniques were also used to assist
in structure elucidation. Melting points are uncorrected. NsONH-
CO2Et was synthesized according to literature.23
General Procedure for the Synthesis of α-Diimines (1a−h).
To a stirred 20% aqueous solution of glyoxal (12.0 mL, 100 mmol)
cooled to 0 °C, 110 mmol of primary amine were added dropwise. A
precipitate formed almost immediately. Then, the reaction mixtures
were stirred for an additional 15 min, and the products were filtered
under vacuum.
Diethyl 2,2′-Diisopropyl-3,3′-bidiaziridine-1,1′-dicarboxylate
(2d). 47% yield, orange oil: IR (CHCl3) 1737 cm−1; 1H NMR
(CDCl3) δ 1.10 (d, J = 6.5 Hz, 6H), 1.26 (d, J = 6.3 Hz, 6H), 1.33 (t, J
= 7.1 Hz, 6H), 1.95−2.07 (m, 2H), 2.66 (s, 2H), 4.12−4.36 (m, 4H);
13C NMR (CDCl3) δ 14.1, 19.2, 21.1, 60.7, 62.4, 63.4, 161.5; HRMS-
(2R,2′R)-N,N′-(1E,2E)-Ethane-1,2-diylidenebis(3-methylbutan-2-
amine) [(−)-1g]. 75% yield, pale brown solid: mp = 30−32 °C; [α]D
ESI (m/z) [M + H]+ calcd for C14H27N4O4 315.2032, found 315.2030.
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Note
Figure 2. ROESY spectra of (−)-2h. Dipolar correlations between the diaziridinic protons and those of N-alkyl substituents.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of compounds (E)-(−)-1g and (E)-
(−)-1h were reported. 1H and 13C NMR spectra of compounds
2a−h and ROESY analyses for compounds 2f and (−)-2h were
reported. This material is available free of charge via the
Internet at http://pubs.acs.org.
Figure 3. Absolute configuration of chiral bidiaziridines.
AUTHOR INFORMATION
■
Diethyl 2,2′-Diisobutyl-3,3′-bidiaziridine-1,1′-dicarboxylate (2e).
Corresponding Author
1
52% yield, yellow oil: IR (CHCl3) 1735 cm−1; H NMR (CDCl3) δ
*E-mail: stefania.fioravanti@uniroma1.it (S.F.), lucio.
pellacani@uniroma1.it (L.P.). Fax: +39 06 490631. Phone:
+39 06 49913098 (S.F.), +39 06 49913673 (L.P.).
0.93 (d, J = 6.7 Hz, 6H), 1.01 (d, J = 6.6 Hz, 6H), 1.31 (t, J = 7.1 Hz,
6H), 1.86−2.00 (m, 2H), 2.04 (dd, J = 11.8 Hz, J = 5.6 Hz, 2H), 2.51
(dd, J = 11.8 Hz, J = 8.0 Hz, 2H), 2.95 (s, 2H), 4.14−4.30 (m, 4H);
13C NMR (CDCl3) δ 14.1, 19.2 (4C), 21.1, 60.7, 62.4, 63.4, 161.5;
HRMS-ESI (m/z) [M + H]+ calcd for C16H31N4O4 343.2345, found
343.2351.
Notes
The authors declare no competing financial interest.
Diethyl 2,2′-Dipentyl-3,3′-bidiaziridine-1,1′-dicarboxylate (2f).
ACKNOWLEDGMENTS
■
1
70% yield, yellow oil: IR (CHCl3) 1736 cm−1; H NMR (CDCl3) δ
Universita
̀
degli Studi di Roma “La Sapienza” is gratefully
0.89 (t, J = 6.7 Hz, 6H), 1.33 (t, J = 7.1 Hz, 6H), 1.55−1.71 (m, 12H),
2.24−2.33 (m, 2H), 2.63−2.71 (m, 2H), 2.93 (s, 2H), 4.17−4.33 (m,
4H); 13C NMR (CDCl3) δ 13.8, 14.0, 22.4, 27.6, 29.0, 60.0, 61.5, 63.2,
161.6; HRMS-ESI (m/z) [M + H]+ calcd for C18H35N4O4 371.2658,
found 371.2665.
acknowledged for financial support. We thank Dr. Simona
Gasbarri for experimental support.
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