Chiral 1,2-dialkenyl diaziridines: Synthesis, enantioselective separation, and nitrogen inversion barriers

Article abstract of DOI:10.1002/chir.22405

Trans-1,2-Disubstituted diaziridines form stable enantiomers at ambient conditions because of the two stereogenic pyramidal nitrogen atoms. Functionalized trans-1,2-disubstituted diaziridines can be utilized as a chiral switching moiety between two enantiomeric states in more complex molecular structures. However, the synthesis of functionalized diaziridines is quite challenging, because of the limited tolerance of reaction conditions that can be applied. Here we present a strategy to make trans-1,2-disubstituted diaziridines accessible as versatile building blocks in C-C-bond formations, i.e., the Heck reaction, and therefore introducing aryl substituents. The synthesis of trans-1,2-dialkenyl diaziridines with terminal alkenyl substituents and their stereodynamic properties are described.

Full text of DOI:10.1002/chir.22405

CHIRALITY 27:156–162 (2015)
Chiral 1,2-Dialkenyl Diaziridines: Synthesis, Enantioselective
Separation, and Nitrogen Inversion Barriers
*
KERSTIN ZAWATZKY, MATTHIAS KAMUF, AND OLIVER TRAPP
Organisch-Chemisches Institut, Ruprecht-Karls-Universität Heidelberg, Heidelberg, Germany
ABSTRACT
trans-1,2-Disubstituted diaziridines form stable enantiomers at ambient conditions
because of the two stereogenic pyramidal nitrogen atoms. Functionalized trans-1,2-disubstituted
diaziridines can be utilized as a chiral switching moiety between two enantiomeric states in more
complex molecular structures. However, the synthesis of functionalized diaziridines is quite
challenging, because of the limited tolerance of reaction conditions that can be applied. Here we
present a strategy to make trans-1,2-disubstituted diaziridines accessible as versatile building
blocks in C-C-bond formations, i.e., the Heck reaction, and therefore introducing aryl substituents.
The synthesis of trans-1,2-dialkenyl diaziridines with terminal alkenyl substituents and their
stereodynamic properties are described. Chirality 27:156–162, 2015. © 2014 Wiley Periodicals, Inc.
KEY WORDS: diaziridines; stereogenic pyramidal nitrogen atoms; stereodynamic properties
INTRODUCTION
bleach to achieve oxidative ring closing of the aminals. There-
fore, there are only a few functional groups that tolerate these
restrictions. Transformation of 1-unsubstituted diaziridines to
their bis(2-arylcarbamoyl) derivatives9 is only one of the few
examples that were reported for diaziridines.10 As there is
no efficient method to further functionalize alkyl-substituted
diaziridines, the functional group already has to be present
when synthesizing the diaziridine starting from amines.
Therefore, we synthesized diaziridines with terminal dou-
ble bonds, which are not affected under these reaction condi-
tions. Furthermore, such building blocks allow performing
convergent synthesis strategies, because such diaziridines
can be used in a variety of reactions such as metathesis or
Heck reactions.
1,2-Disubstituted diaziridines (Scheme 1) exist as stable
enantiomers at room temperature due to the high stability
of the two stereogenic pyramidal nitrogen atoms. As the
N-substituents are in trans-orientation, first because of the
repulsion of the nitrogen lone pairs,1 second due to minimiza-
tion of steric interactions, only two enantiomers in the case of
achiral substituents and no cis-isomers are formed. In particu-
lar, 3,3-unsubstituted diaziridines are of great interest because
of the unusual high stereointegrity.2,3 The enantiomerization
barrier is higher compared to diaziridines substituted at the
3-position, where repulsive interactions of the vicinal substitu-
ents destabilize the ground state.4 More recently, Fioravanti
and Pellacani and colleagues presented the stereoselective syn-
thesis of 3,3’-bridged bisdiaziridines.5 Aziridines can coordinate
to a metal ion via the nitrogen atom and can therefore be used
as chiral ligands. Transition metal complexes with different
types of mono- and bisdiaziridines have successfully been
synthesized. Shevtsov et al. reported a series of complexes of
different transition metals with N-(2-aminoethyl)diaziridines,6
while Adedapo et al. were able to prepare Pt complexes of
3,4-substituted diaziridines.7 The same group also synthe-
sized and characterized Rh complexes of adamantyl- and
4-tert-butylcyclohexyldiaziridine and studied their catalytic ac-
tivity for hydrogenation and hydroformylation of alkenes.8
It is more attractive to use diaziridines as chiral switches in
functional organic materials due to the enantiomerization
properties, which can be triggered at elevated temperatures.
Because the enantiomers can be easily separated at ambient
temperature, it is possible to reracemize one of the enantio-
mers in a continuous process and therefore enrich the other
enantiomer. This allows realizing degenerated states ꢀ1 and
+1 in contrast to states 0 and +1 in compounds prone to E/Z
isomerization. The synthesis of tailored diaziridines, which
can be utilized as a switching moiety, is a prerequisite.
So far, little is known about the functionalization of
diaziridines and the synthesis of more complex structures
based on diaziridines. This is mainly due to the low stability
of diaziridines against acids and the typically harsh reaction
conditions used to prepare diaziridines starting from amines,
which involves strong bases and oxidative conditions using
© 2014 Wiley Periodicals, Inc.
Herein we report the synthesis of 1,2-diaziridines, substituted
with terminal alkenyl groups (allyl11 to pentenyl) and the investi-
gation of their stereodynamic properties compared to the well-
known alkyl diaziridines.2–4,12 To determine the activation
parameters ΔH ╪ and ΔS ╪, temperature-dependent measure-
ments using enantioselective dynamic gas chromatography
(DGC) were performed, because the activation energy for the
nitrogen inversion in diaziridines is usually well above
90 kJ molꢀ1 4,13–15 In particular, the influence of the alkenyl chain
.
length was investigated, which provides valuable data for design-
ing novel chiral switchable structures. Furthermore, the
functionalization of these building blocks by a Heck reaction to
form phenyl substituted diaziridines is demonstrated.
MATERIALS AND METHODS
General
All starting materials and deuterated solvents were obtained from com-
mercial suppliers and were used without further purification unless other-
wise stated. Anhydrous solvents were purified using a solvent purification
Contract grant sponsor: European Research Council (ERC); Contract grant
number: 258740, AMPCAT.
*Correspondence to: Oliver Trapp, Ruprecht-Karls-Universität Heidelberg,
Organisch-Chemisches Institut, Im Neuenheimer Feld 270, 69120 Heidelberg,
Germany. E-mail: trapp@oci.uni-heidelberg.de
Received for publication 07 August 2014; Accepted 12 October 2014
DOI: 10.1002/chir.22405
Published online 6 November 2014 in Wiley Online Library
(wileyonlinelibrary.com).

STEREOGENIC NITROGEN
157
oil (1.92 g, 31 %). 1H NMR (300.51 MHz, CDCl3) δ (ppm) 2.52 (s, 2 H)
2.94–3.14 (m, 4 H), 5.12–5.29 (m, 4 H), 5.93 (ddt, J = 17.0, 10.6, 6.1 Hz,
2 H); 13C NMR (75.56 MHz, CDCl3) δ (ppm) 55.8, 63.4, 117.4, 133.9;
HR-MS (EI+) m/z [M]+ calcd for C7H12N2 124.1000, found 124.1020.
Scheme 1. Interconversion of diaziridines enantiomers.
But-3-ene-1-amine hydrochloride (6a).20 A suspension of LiAlH4
(8.72 g, 230 mmol, 1.10 eq.) in anhydrous Et2O (280 mL) was cooled to
0°C and AlCl3 (27.8 g, 209 mmol, 1.00 eq.) was added. Allylcyanide 5
(14.0 g, 16.9 mL, 209 mmol, 1.00 eq.) in dry Et2O (80.0 mL) was added
dropwise. The mixture was stirred for 2 h at 0°C and 1 h at room tem-
perature. The mixture was quenched with 30%-NaOH (150 mL) at 0°C
and extracted with Et2O (3 x 100 mL). Combined organic extracts were ex-
tracted with 6 M HCl (3 x 50 mL) and concentrated in vacuo. But-3-ene-1-
amine hydrochloride 6a was obtained as a colorless solid (21.6 g, 201 mmol,
system prior to distillation. Air- and moisture-sensitive reactions were
conducted in oven-dried glassware by using standard Schlenk line or
dry-box techniques under an inert atmosphere of N2 or Ar. Flash column
chromatography was carried out with silica gel 60 (70–230 mesh) using
the indicated solvents. Thin layer chromatography (TLC) was performed
on silica plates with a UV indicator and visualized using permanganate
stain and/or UV light. 1H nuclear magnetic resonance (NMR) spectra
were recorded either on a 300 MHz or a 600 MHz spectrometer.
13C NMR spectra were recorded either on a 75 MHz or 151 MHz spectrom-
eter. Chemical shifts are reported in parts per million (ppm) and were
calibrated to the residual signals of the deuterated solvents; coupling
constants ( J) are indicated in Hz. High-resolution mass spectra (HR-MS)
were acquired using electron impact ionization (EI). Enantioselective
DGC was performed on a quadrupole–ion trap mass spectrometer
equipped with a split injector (250°C) and a flame ionization detector
(250°C). Helium was used as the inert carrier gas. Separation of the
enantiomers of diaziridines 1, 2, 3 and stereodynamic measurements
were performed on fused silica capillaries (25 m × 0.25 mm i.d. or
50 m × 0.25 mm i.d., 0.25 μm film thickness) coated with 50% (w/w)
heptakis(2,3-di-O-ethyl-6-O-tert-butyldimethylsilyl)-β-cyclodextrin23,24 dis-
solved in 50% (w/w) PS086. The dynamic measurements were repeated
at least three times at each temperature.
1
96 %). H NMR (300.19 MHz, D2O) δ (ppm) 2.48 (q, J = 6.7 Hz, 2 H), 3.14
(t, J = 6.7 Hz, 2 H), 5.22-5.35 (m, 2 H), 5.77-5.95 (m, 1 H). 13C NMR
(75.56 MHz, D2O): δ (ppm) 31.0, 38.8, 119.0, 133.2. MS (EI+) m/z 71.08
[M-HCl]+.
1,2-Di(but-3-en-1-yl)diaziridine (2). But-3-enyl-1-amine hydrochlo-
ride 6a (7.54 g, 70.0 mmol) was added to a solution of NaOH (5.60 g,
140 mmol, 2.00 eq.) in water (7.60 mL) at 0°C. First, a concentrated
formaldehyde solution (1.05 g, 2.80 mL, 35.0 mmol, 0.50 eq., 37% w/w)
and then sodium hypochlorite solution (2.61 g, 18.6 mL, 35.0 mmol,
0.50 eq., 14% w/w) were added dropwise over 30 min. The mixture was
stirred at room temperature for 13 h, the organic layer was separated,
and washed with diluted sodium thiosulfate solution and water. Flash
chromatography (SiO2, DCM/MeOH 99:1, Rf = 0.36) afforded 1,2-di(but-3-
en-1-yl)diaziridine 2 as a clear oil (1.76 g, 33 %). 1H NMR (300.51 MHz,
CDCl3) δ (ppm) 2.26–2.41 (m, 6 H), 2.48 (s, 2 H), 2.52-2.62 (m, 2 H),
4.98–5.15 (m, 4 H), 5.77-5.95 (m, 2 H); 13C NMR (75.56 MHz, CDCl3): δ
(ppm) 33.2, 57.0, 60.6, 116.0, 136.1; GC-MS: m/z 55.2 [C4H7]+, 84.1
[M-C5H8]+, 97.1 [M-C4H7]+,. 111.1 [M-C3H5]+, 125.1 [M-C2H3]+, 151.2
[M-H]+; HR-MS (EI+) m/z calcd for C9H16N2 152.1308, found 152.1297.
High-performance liquid chromatography (HPLC) measurements were
performed on an Agilent Technologies 1200 HPLC (Agilent Technolo-
gies, Palo Alto, CA), equipped with
a binary solvent pump, an
autosampler, membrane solvent degasser, DAD detector, and a quadru-
pole mass spectrometer Agilent 6120, equipped with an APCI source.
Preparative HPLC separations were performed on an Agilent Technolo-
gies 1260 preparative HPLC (Agilent Technologies), equipped with a
binary solvent pump. All operations were controlled by the Agilent
ChemStation software (Agilent Technologies). Enantioselective separa-
tions were performed on a Chiralpak IA column (250 mm, i.d. 4.6 mm,
particle size 5 μm), on a Chiralpak IA-3 column (150 mm, i.d. 2.1 mm,
particle size 3 μm) or on Chiralpak IC column (250 mm, i.d. 4.6 mm, par-
ticle size 5 μm), from Chiral Technologies (Illkirch, France). Preparative
separations were performed on a Chiralpak IA column (250 mm, i.d.
20 mm, particle size 5 μm) or on a Chiralpak IC column (250 mm, i.d.
20 mm, particle size 5 μm), from Chiral Technologies. The solvents used
(n-hexane and 2-propanol) were obtained from Sigma-Aldrich (St. Louis,
MO; HPLC-grade quality). Dynamic HPLC measurements were per-
formed with solutions of 1.0 mg substance in 1.0 mL of the solvent mix-
ture which was also used for the separation of the enantiomers.
17
N-(Pent-4-en-1-yl)phthalimide.
Pentene-1-ol (6.00 g, 7.20 mL,
69.7 mmol), phthalimide (11.3 g, 76.7 mmol, 1.10 eq.) and triphenylphos-
phine (20.1 g, 76.7 mmol, 1.10 eq.) were dissolved in dry THF (40.0 mL)
and cooled to 0°C. Diisopropyl azodicarboxylate (15.5 g, 15.1 mL,
76.7 mmol, 1.10 eq.) was added dropwise. The mixture was stirred for 3 h
at 0°C. The solvent was removed under reduced pressure and the mixture
loaded directly onto a silica column and subjected to flash chromatography
(SiO2, petroleum ether/ethyl acetate 6:1, Rf = 0.50) to furnish N-(Pent-4-en-1-
yl)phthalimide as a colorless oil (14.6 g, 97%). 1H NMR (300.51 MHz,
CDCl3): δ (ppm) 1.80 (quin, J = 7.4 Hz, 2 H), 2.08–2.20 (m, 2 H), 3.71
(t, J = 7.4 Hz, 2 H), 4.94–5.12 (m, 2 H), 5.83 (ddt, J = 17.0, 10.3, 6.6 Hz,
1 H), 7.67-7.77 (m, 2 H), 7.80-7.91 (m, 2 H); 13C NMR (75.56 MHz, CDCl3):
δ (ppm) 27.6, 31.0, 37.6, 115.3, 123.2, 132.2, 133.9, 137.3, 168.4; MS (EI+)
m/z (%) 215.12 (20) [M]+, 160.06 (100) [M-C4H7]+.
Determination of Activation Parameters
Pent-4-enyl-1-amine hydrochloride (8a). 18 N-(Pent-4-en-1-yl)phthal-
imide (14.6 g, 67.9 mmol, 1.00 eq.) was dissolved in dry EtOH (300 mL)
and heated to 50°C. Hydrazine-monohydrate (7.49 g, 7.27 mL, 150 mmol,
2.20 eq.) was added and refluxed for 1 h. The mixture was quenched with
concentrated HCl (80.0 mL) and stirred for 10 min. The white solid was
filtered off and washed with EtOH. EtOH was removed under reduced
pressure and the remaining aqueous solution was made basic by
dropwise addition of NaOH (30% w/w). The solution is extracted with
Et2O (3 x 50.0 mL). Combined organic extracts were extracted with 1 M
HCl (3 x 50.0 mL) and aqueous extracts concentrated in vacuo to afford
pent-4-enyl-1-amine hydrochloride 8a as white solid (7.60 g, 62.5 mmol,
92 %). 1H NMR (300.51 MHz, D2O): δ (ppm) 1.70 (d, J = 7.57 Hz, 2 H),
2.08 (q, J = 6.97 Hz, 2 H), 2.93 (t, J = 7.4 Hz, 2 H), 4.95-5.11 (m, 2 H),
5.80 (ddt, J = 17.0, 10.3, 6.6 Hz, 1 H)); 13C NMR (75.56 MHz, D2O) δ
(ppm) 25.8, 29.7, 39.0, 115.7, 137.4; MS (EI+) m/z (%): 86.10 (3) [M-Cl]+.
Gibbs free activation energies ΔG╪ of enantiomerization of the diaziridines
were calculated according to the Eyring Equation (Eq. (1)) with kB as the
Boltzmann constant (kB = 1.380662x10ꢀ23 JꢁKꢀ1), T as the epimerization
temperature [K], h as Planck’s constant (h = 6.62617ꢁ10ꢀ34 Jꢁs), and R as the
gas constant (R = 8.31441 JꢁKꢀ1ꢁmolꢀ1). The statistical factor κ was set to 0.5
for a reversible degenerated interconversion process.16
k1h
κκBT
ΔG╪ðTÞ ¼ ꢀRT In
(1)
11
1,2-Diallyldiaziridine (1).
Allylamine
4
(7.51 ml, 100 mmol,
1.00 eq.) was added to a solution of NaOH (4.00 g, 100 mmol, 1.00 eq.)
in water (10.0 mL) at 0°C. concentrated formaldehyde solution
A
(3.74 mL, 50.0 mmol, 0.50 eq., 37% w/w) and subsequently sodium
hypochlorite solution (21.2 mL 50.0 mmol, 0.50 eq, 14% w/w) were added
dropwise over 30 min. The mixture was stirred at room temperature for
13 h, then the organic layer was separated and washed with diluted
sodium thiosulfate solution and water. Flash chromatography (SiO2,
DCM/MeOH 99:1, Rf = 0.27 ) afforded 1,2-diallyldiaziridine 1 as a colorless
1,2-Di(pent-4-en-1-yl)diaziridine (3). Pent-4-enyl-1-amine hydro-
chloride 8a (7.76 g, 63.8 mmol) was added to a solution of NaOH
(5.10 g, 127 mmol, 2.00 eq.) in water (7.50 mL) at 0°C. First, a concen-
trated formaldehyde solution (2.38 mL, 31.9 mmol, 0.50 eq., 37% w/w)
Chirality DOI 10.1002/chir

158
ZAWATZKY ET AL.
and then sodium hypochlorite solution (14.1 mL, 31.9 mmol, 0.50 eq., 14%
w/w) were added dropwise over 30 min. The mixture was stirred at room
temperature for 13 h, then the organic layer was separated and washed
with diluted sodium thiosulfate solution and water. Flash chromatogra-
phy (SiO2, DCM/MeOH 99:1, Rf = 0.26 ) afforded 1,2-di(pent-4-en-1-yl)
diaziridine 3 as a clear oil (1.44 g,25 %).1H NMR (300.51 MHz,
CDCl3) δ (ppm) 1.70 (quin, J = 7.43 Hz, 4 H), 2.08 - 2.30 (m, 6 H),
2.45 (s, 2 H), 2.51 (dt, J = 11.93, 7.6 Hz, 2 H), 4.93–5.08 (m, 4 H)
5.82 (ddt, J = 17.0, 10.3, 6.6 Hz, 2 H); 13C NMR (75.56 MHz, CDCl3)
δ (ppm) 27.9, 31.4, 56.8, 60.7, 114.7, 138.3; GC-MS (EI+) m/z = 55.2
[C4H7]+, 84.1 [M-C4H7-C3H5]+, 98.1 [M-C4H7-C2H3]+,. 111.1 [M-C3H5]+,
125.1 [M-C4H7]+, 179.1 [M-H]+; HRMS (EI+) m/z calcd for C11H20N2
180.1621, found 180.1607.
Scheme 2. Structures of the synthesized and investigated 1,2-dialkenyl
diaziridines.
1,2-Dicinnamyldiaziridine (9). Under argon K2CO3 (49.0 mg,
0.35 mmol, 5.54 eq.) and NBu4Br (47.0 mg, 0.15 mmol, 2.28 eq.) were
added to dry MeCN (2 mL). 1,2-Diallyldiaziridine 1 (8.00 mg, 0.06 mmol,
1.00 eq.), iodobenzene (39.4 mg, 0.19 mmol, 3.00 eq.) and Pd(OAc)2
(5 mol%, 3.20 μmol, 0.72 mg) were added subsequently. The mixture
was stirred at 83°C for 24 h. After cooling to room temperature the
mixture was loaded directly onto a silica column (pentane/diethylether
4:1, Rf = 0.16 ) to afford the product as a colorless oil (6.00 mg, 34%). 1H
NMR (600 MHz, CDCl3) δ (ppm) 2.65 (s, 2 H) 3.14–3.32 (m, 4 H) 6.34
(dt, J = 15.9, 6.5 Hz, 2 H) 6.60 (d, J = 15.9 Hz, 2 H) 7.21-7.37 (m, 10 H);
13C NMR (151 MHz, CDCl3) δ (ppm) 56.2, 62.9, 125.5, 126.4, 127.5,
128.5, 132.7, 136.9; HRMS (EI+) m/z calcd for C19H20N2 276.1621, found
276.1641. Rf (Chiralpak IC, 25 cm 4.6 mm, Hex/IPA 98/2, 1.0 mL/min,
20°C) 7.6 min and 8.8 min.
5,5’-Dipent-4,4’-enyldiaziridine-2,2’-diacetoxybiphenyl (10). 2,2’-
Acetoxy-5,5’-diiodobiphenyl (145 mg, 277 μmol, 1.00 eq.) was dissolved
in anhydrous MeCN (16 mL) under argon. 1,2-Di(pent-4-en-1-yl)
diaziridine (3) (50.0 mg, 277 μmol, 1.00 eq.), PPh3 (14.5 mg, 60 μmol,
20 mol%), Pd(OAc)2 (6.20 mg, 30.0 μmol, 10 mol%), NEt3 (76.0 μl,
554 μmol, 2.00 eq.) and Ag2CO3 (76.4 mg, 277 μmol, 1.00 eq.) were added
subsequently. The mixture was stirred at 83°C for 24 h. The crude mixture
was concentrated in vacuo and loaded on a silica column eluting with
EtOAc. The crude mixture was purified by preparative HPLC (26 mg,
21%). Rf (Chiralpak IA, 25 cm 4.6 mm, Hex/IPA 98/2, 1.0 mL/min, 20°C)
18.2 min and 22.6 min. 1H NMR (600 MHz, CDCl3) δ (ppm) 1.60 - 1.69
(m, 4 H), 2.12 (s, 3 H) 2.13 (s, 3 H) 2.19–2.40 (m, 6 H) 2.48 (bs, 2 H)
2.63–2.90 (m, 2 H), 6.08–6.32 (m, 2 H), 6.33–6.49 (m, 2 H), 7.04–7.15
(m, 4 H) 7.40–7.56 (m, 2 H); 13C NMR (151 MHz, CDCl3) δ (ppm) 20.89,
20.92, 27.16, 27.41, 31.33, 32.14, 57.10, 61.66, 62.02, 122.48, 122.51, 127.55,
127.82, 127.90, 127.97, 128.68, 128.91, 128.98, 129.20, 130.84, 131.46,
131.84, 132.25, 146.63, 146.70, 169.45, 169.48. HRMS (ESI+) m/z calcd for
C27H31N2O4 447.2278 found 447.2279.
Scheme 3. Synthesis of 1,2-alkenylsubstituted diaziridines 1, 2, and 3.
hydrazine.20,21 Again, isolation of the corresponding ammo-
nium salt 8a proved to be method of choice (cf. Scheme 3).
The ammonium salts were reacted with formaldehyde and
sodium hypochlorite under basic conditions using two
equivalents of NaOH to release the free amines in situ. The
diaziridines were obtained in moderate yields between 25
and 32% (cf. Scheme 3). Attempts to distill the crude reaction
product failed; however, flash chromatography provided the
reaction products in high purity without decomposition.
Investigation of the stereodynamic properties of the three
diaziridines was carried out using enantioselective DGC.15,22–33
Excellent separation of the enantiomers of these three diazi-
ridines was achieved by gas chromatography using the chiral
stationary phase heptakis(6-O-tert.-butyldimethylsilyl-2,3-di-O-
ethyl)-β-cyclodextrin.34,35 To determine the reaction rate con-
stants, the activation parameters ΔG╪, ΔH ╪, and ΔS ╪ of the
enantiomerization of the diaziridines temperature-dependent
DGC experiments were performed between 80 and 170°C. Rep-
resentative gas chromatograms of the temperature-dependent
separation of the enantiomers of 1,2-diallyldiazirine are
depicted in Figure 1. At 100°C separation of the enantiomers
of 1 was achieved without notable interconversion. Higher
temperatures lead to characteristic plateau formations. Peak
coalescence was observed for 1,2-diallyldiaziridine 1 at
170°C. The reaction rate constant of enantiomerization k1
were determined by unified equation of chromatogra-
phy,36–41 which allows a direct, fast and precise evaluation
of the experimental peak profiles.
RESULTS AND DISCUSSION
The synthesis of the 1,2-dialkenyl diaziridines 1–3 (Scheme 2)
is based on a modified protocol developed by Ohme et al.19 and
Makhova et al.11 where amines are treated with formaldehyde to
form the aminal followed by in situ mono N-chlorination and
nucleophilic ring closing.
1,2-Diallyldiaziridine 1 was obtained from allylamine 4
(cf. Scheme 3).11
To prepare 1,2-dibutenyl- and 1,2-dipentenyldiaziridine 2
and 3 (Scheme 3), respectively, the corresponding amines
3-butenylamine and 4-pentenylamine were synthesized accord-
ing to procedures described in the literature. 3-Butenylamine
20
6b was obtained by reduction of allylcyanide 5 with LiAlH4.
Since isolation from the organic layer proved to be inconvenient
due to the volatility of the free amine 6b, it was isolated as its
corresponding ammonium salt 6a in 91% yield (cf. Scheme 1).
4-Pentenylamine 8b was obtained by Mitsunobu reaction
of 4-pentenol 7 with phthalimide followed by reduction with
Chirality DOI 10.1002/chir

STEREOGENIC NITROGEN
159
Fig. 1. Chromatograms of 1,2-diallyldiaziridine between 100 and 170°C. Separation conditions: 50 m × 250 μm i.d. fused-silica capillary coated with 250 nm
heptakis(6-O-tert.-butyldimethylsilyl-2,3-di-O-ethyl)-β-cyclodextrin dissolved in polydimethylsiloxane PS086 (50% w/w), He as inert carrier gas.
For the evaluation of the activation parameters of enan-
tiomerization of 1,2-diallyldiaziridine 1 experiments between
105 and 145°C (5°C steps) were considered.
characteristic plateau formations were obtained for 1,2-di(but-
3-enyl)diaziridine 2 and 1,2-di(pent-4-enyl)diaziridine 3.
These two diaziridines show very similar stereodynamic
behavior compared to 1,2-diallyldiaziridine 1. At 100°C,
baseline separation of the two enantiomers is achieved and
at 160°C peak coalescence due to rapid interconversion
occurs. The elevated temperature leads to increased peak
plateau formation. Peak coalescence is observed at 160°C
compared to 170°C for the 1,2-diallyl analog. This is attrib-
uted to slightly lower separation factors, so that peak coales-
cence already at lower temperatures occurs. The separation
of 1,2-di(pent-4-enyl) analog 3 was improved by using a
shorter separation column (25 m), improving the quality of
the separation profiles. For evaluation of the kinetic data
experiments between 110 and 140°C in 5°C steps were con-
sidered for 1,2-di(but-3-enyl)diaziridines 2.
Gibbs free activation energies ΔG╪ of enantiomerization of
the diaziridines was calculated according to the Eyring
Equation. The activation enthalpies ΔH ╪ and activation en-
tropies ΔS ╪ were obtained by temperature-dependent mea-
surements and plotting ln(k/T) as a function of T. The
activation enthalpy ΔH╪ of the enantiomerization process
was obtained from the slope and the activation entropy ΔS╪
from the intercept of the Eyring plot. Figure 2 shows the
Eyring plot for interconversion of 1,2-diallyldiaziridine 1. De-
viations of the activation parameters ΔH╪ and ΔS╪ were cal-
culated by error band analysis of the linear regression.
The enantiomerization of 1,2-di(but-3-enyl) diaziridine 2
and 1,2-di(pent-4-enyl)diaziridine 3 were also investigated
by enantioselective DGC. Also, dynamic elution profiles with
For 1,2-di(pent-4-enyl)diaziridine 3 at elevated tempera-
tures peak coalescence was observed, so only measurements
within the temperature range between 100 and 110°C were
considered to obtain kinetic data.
In Table 1 the results are summarized and compared to sat-
urated analogs. Overall, a very good agreement between the
saturated analogs 1,2-di-n-propyl- and 1,2-di-n-butyldiaziridine
can be observed. The interconversion barrier of the
diaziridines slightly decreases with increasing chain length.
These data allow predicting barriers in more complex sys-
tems where the diaziridine moiety is used as dominating a
chiral switching unit.
To further investigate the applicability of the synthesized
alkenyl substituted diaziridines in building more complex
ligand systems, 1,2-diallyldiaziridine 1 was used as the sub-
strate for a Heck reaction (Scheme 4).42 Because of the
sensitivity of diaziridines, mild phosphine-free conditions,
namely, an aromatic iodide, NBu4Br and Pd(OAc)2 and
K2CO3 as additional base were chosen.43 Heck reactions
often require high temperatures, between 110 and 140°C for
Fig. 2. Eyring plot of 1,2-diallyldiaziridine 1 obtained by enantioselective
DGC to determine the activation parameters of enantiomerization. The upper
and lower curves represent the error bands of the linear regression with a
level of confidence of 95%. For the linear regression, three measurements
for each temperature were considered.
TABLE 1. Activation parameter for the enantiomerization of 1,2-diallyldiaziridine 1, 1,2-di(but-3-enyl)diaziridine 2, 1,2-di(pent-4-enyl)diaziridine 3,
1,2-dicinnamyldiaziridine 9, and diaziridine 10 obtained by enantioselective dynamic gas chromatography or racemization studies after preparative
HPLC separation of compounds 9 and 10
Compound
R
ΔG╪ 298K [kJ molꢀ1
]
ΔH ╪ [kJ molꢀ1
]
ΔS ╪ [J molꢀ1 Kꢀ1
]
1
2
3
CH2CH = CH2
119.7
119.5
114.9
118.7
119.8
124.4
122.9
105.2 0.9
102.3 1.9
106.7 8.9
100.7 2.1
103.4 2.6
111.3 3.7
111.8 12.4
ꢀ49
ꢀ58
ꢀ29
ꢀ60
ꢀ55
ꢀ44
ꢀ36
1
2
2
3
3
3
8
(CH2)2CH = CH2
(CH2)3CH = CH2
3
(CH2)2CH3
(CH2)3CH3
4
9
10
CH2CH = CH-Ph
-[(CH2)3CH = CH-Ph(OAc)]2
Chirality DOI 10.1002/chir

160
ZAWATZKY ET AL.
Scheme 4. Double Heck reaction of 1,2-diallyldiaziridine 1 with iodobenzene.
satisfactory conversions. Due to potential decomposition of
diaziridines at high temperatures, refluxing acetonitrile was
used, limiting the temperature to 83°C. A Heck reaction
was performed with 1,2-diallyldiaziridine 1 and iodobenzene
refluxing 24 h in acetonitrile. After flash chromatography,
1,2-dicinnamyldiaziridine 9 was isolated in 34% yield.
Since the starting material could be reisolated, it is most
likely that complete conversion to the desired product did not
occur due to decomposition of the Pd catalyst (formation of
palladium black), but not due to decomposition of the dia-
ziridine. Therefore, a complete conversion can be achieved by
successive reaction of the nonconverted reactants. This demon-
strates that diaziridines are stable under Pd catalysis and can be
applied to more complex systems. Next, we investigated the
stereodynamics of 1,2-dicinnamyldiaziridine 9 to obtain further
insight into the influence on the interconversion barrier of the
remote phenyl groups. Due to the decreased volatility of this
product, enantioselective HPLC was the method of choice to
achieve enantiomer separation. Because of the high intercon-
version barrier of diaziridine 9 and the limited temperature
range of HPLC, dynamic interconversion experiments could
not be performed. Therefore, compound 9 was separated into
its enantiomers by preparative enantioselective HPLC using
the Okamoto type chiral stationary phase (CSP) Chiralpak IC.
One of the enantiomerically pure samples was then heated to
different temperatures for 2 h and the composition of enantio-
mers analyzed (cf. Fig. 3).
Fig. 4. Eyring plot of 1,2-dicinnamyldiaziridine 9 to determine the activation
parameters of enantiomerization. The upper and lower curves represent the
error bands of the linear regression with a level of confidence of 95%. For the
linear regression, three measurements for each temperature were considered.
(ΔG ╪(298.15 K) = 124.4 kJ·molꢀ1, ΔH ╪ = 111.3 3.7 kJ·molꢀ1
ΔS ╪ = ꢀ44 3 J·(K·mol)ꢀ1).
,
In a very similar approach, we used 1,2-di(pent-4-en-1-yl)
diaziridine 3 to bridge 2,2’-diacetoxybiphenyl with a dia-
ziridine in the backbone (Scheme 5). Quantum chemical cal-
culations indicated that at least a chain of five carbon atoms is
needed on both sides of the diaziridine moiety to achieve an
efficient cyclization. Furthermore, quantum chemical calcula-
tions at the DFT B3LYP 6-31G* level of theory predicted that
the interconversion barrier should be around 120 kJ·molꢀ1
,
From the de novo peak areas the enantiomerization rate
constants kenant were calculated according to Eq. (2), where
A represents the area, t the reaction time:
which means that the stereodynamics is solely dominated
by the diaziridine ring and therefore the tropos biphenyl unit
will align according to the stereochemistry of the diaziridine
ring.
major þAminor
In A
Amajor
The interconversion barrier was determined by temperature-
dependent racemization measurements after separation of
the enantiomers by preparative HPLC in the presence of the
CSP Chiralpak IA with a good separation factor α of 1.24. The
activation parameters were obtained by Eyring plot analyꢀsi1s
kenant
¼
(2)
2t
ΔG╪ of enantiomerization was calculated according to the
Eyring equation, ΔH ╪ and ΔS ╪ were obtained from the cor-
responding Eyring plot (cf. Fig. 4), which are in very good
agreement with the experimental data of the 1,2-dialkenyl
diaziridines (cf. Table 1). The enantiomerization barrier of 9
compared to the barrier of 1 is slightly increased, which can
be explained by the increased rigidity of the cinnamyl system
and determined to be ΔG ╪(298.15K)=122.9kJ·mol
ΔH ╪ = 111.8 12.4kJ·molꢀ1, and ΔS ╪ = ꢀ36 8 J·(K·mol)ꢀ1
,
,
which are in very good agreement with the quantum chemical
calculations and the barriers of the other compounds deter-
mined in this study.
Fig. 3. Chromatograms of 1,2-dicinnamyldiaziridine 9 after heating an enantiomerically pure sample to 90–120°C for 2 h.
Chirality DOI 10.1002/chir

STEREOGENIC NITROGEN
161
Scheme 5. Synthesis of 5,5’-dipent-4,4’-enyldiaziridine-2,2’-diacetoxybiphenyl 10 by a double Heck reaction.
11. Makhova NN, Mikhailyuk AN, Kuznetsov VV, Kutepov SA, Belyakov PA.
Effective synthesis of 1,2-di-, 1,2,3-tri-, 1,2,3,3-tetraalkyldiaziridines and
1,5-diazabicyclo[3.1.0]hexanes. Mendeleev Commun 2000;10:182–184.
CONCLUSION
We successfully synthesized alkenyl substituted diaziridines
and investigated their dynamic behavior by enantioselective
DGC and classical racemization analysis. The unified equation
gives access to kinetic parameters (rate constants) and in
combination with the Eyring equation activation parameters
ΔG╪, ΔH╪, and ΔS╪ for the enantiomerization of the here in-
vestigated compounds were obtained. Increasing chain length
of the alkenyl substituents results in no remarkable difference
12. Kamuf M, Trapp O. Stereodynamics of tetramezine. Chirality 2011;23:113–117.
13. Mannschreck A, Seitz W. Trennung inversionsisomerer diaziridine.
langsame inversion am dreibindigen stickstoffatom. Angew Chem
1969;81:224. Angew Chem Int Ed 1969;8:212.
14. Häkli H, Mannschreck A. Column chromatography on triacetylcellulose.
Preparative separation of enantiomeric diaziridines. Angew Chem Int Ed
Engl 1977;16:405–406.
15. Jung M, Schurig V. Determination of enantiomerization barriers by com-
puter simulation of interconversion profiles: enantiomerization of
diaziridines during chiral inclusion gas chromatography. J Am Chem
Soc 1992;114:529–534.
16. Lehn JM. Nitrogen inversion — experiment and theory. Top Curr Chem
1970;15:311–377.
17. Michael FE, Cochran BM. Room temperature palladium-catalyzed intra-
molecular hydroamination of unactivated alkenes. J Am Chem Soc
2006;128:4246–4247.
18. Dawson GW, Doughty KJ, Hick AJ, Pickett JA, Pye BJ, Smart LE,
Wadhams LJ. Chemical precursors for studying the effects of glucosino-
late catabolites on diseases and pests of oilseed rape (Brassica napus) or
related plants. Pest Sci 1993;39:271–278.
╪
of the activation barrier ΔG for the interconversion process
between enantiomeric diaziridines. We also demonstrated that
alkenyl substituted diaziridines can be used as versatile
building blocks in Pd-mediated catalytic reactions, e.g., the
Heck reaction, which was shown for the functionalization of
1,2-diallyldiaziridine and 1,2-di(pent-4-en-1-yl)diaziridine. Fur-
thermore, we have shown that this method is expandable to
more complex substrates and thus be able to build ligands
containing a chiral switch for various metal catalyzed reactions.
ACKNOWLEDGMENTS
19. Ohme R, Schmitz E, Dolge P. Diaziridine aus Aminalen des Formaldehyds.
Chem Ber 1966;99:2104–2109.
Generous financial support by the European Research Coun-
cil (ERC) for a Starting Grant to OT (No. 258740, AMPCAT)
is gratefully acknowledged.
20. Borst ML, van der Riet N, Lemmens RH, de Kanter FJ, Schakel M, Ehlers
AW, Mills AM, Lutz M, Spek AL, Lammertsma K. Strained, stable 2-aza-1-
phosphabicyclo[n.1.0]alkane and -alkene Fe(CO)4 complexes with
dynamic phosphinidene behavior.Chemistry 2005;11:3631–3642.
21. McNaughton BR, Bucholtz KM, Camaaño-Moure A, Miller BL. Self-selec-
tion in olefin cross-metathesis: the effect of remote functionality. Org Lett
2005;7:733–736.
22. Bürkle W, Karfunkel H, Schurig V. Dynamic phenomena during enantiomer
resolution by complexation gas chromatography. J Chromatogr 1984;288:1–14.
23. Trapp O, Schurig V. Stereointegrity of Tröger’s base: gas-chromatographic
LITERATURE CITED
1. Kostyanovsky RG, Shustov GV, Starovoitov VV, Chervin II. Sterically con-
trolled population of the 1,2-cis-form of 1,2-dimethyl-3-tert-butyldiaziridine.
Mendeleev Commun 1998;8:113–116.
2. Mannschreck A, Radeglia R, Gründemann E, Ohme R. Der Diaziridin-
Ring als Asymmetriezentrum. Chem Ber 1967;100:1778–1785.
determination of the enantiomerization barrier.
J Am Chem Soc
3. Trapp O, Sahraoui L, Hofstadt W, Könen W. The stereodynamics of 1,2-
dipropyldiaziridines. Chirality 2010;22:284–291.
2000;122:1424–1430.
24. Trapp O, Schoetz G, Schurig V. Determination of enantiomerization
barriers by dynamic and stopped flow chromatographic methods. Chiral-
ity 2001;13:403–414.
4. Trapp O, Schurig V, Kostyanovsky RG. The control of the nitrogen inver-
sion in alkylsubstituted diaziridines. Chem Eur J 2004;10:951–957.
5. Carroccia L, Delfini M, Fioravanti S, Pellacani L, Sciubba F. Stereo-
selective synthesis and ROESY1H NMR study of bidiaziridines. J Org
Chem 2012;77:2069–2073.
25. Wolf C. Dynamic stereochemistry of chiral compounds — principles and
applications. Cambridge, UK: RSC Publishing; 2008.
26. Gasparrini F, Misiti D, Pierini M, Villani C. Enantiomerization barriers by
dynamic HPLC. Stationary phase effects. Tetrahedron: Asymmetry
1997;8:2069–2073.
27. Oxelbark J, Allenmark S. Inversion barriers in sulfoxide functions studied
by enantioselective liquid chromatography and chiroptical methods.
Chirality 1997;9:638–642.
28. Gasparrini F, Lunazzi L, Mazzanti A, Pierini M, Pietrusiwicz KM, Villani
C. Comparison of dynamic HPLC and dynamic NMR in the study of
conformational stereodynamics: case of the enantiomers of a hindered
secondary phosphine oxide. J Am Chem Soc 2000;122:4776–4780.
6. Shevtsov AV, Petukhova VY, Kutepov SA, Kuznetsov VV, Makhova NN,
Kugzmina NE, Aleksandrov GG. Synthesis, structures of complexes of
N-(ꢀaminoethyl)diaziridines, with transition metal salts. Russ Chem Bull
2000;49:1882–1886.
7. Adedapo A, Avent AG, Carmichael D, Chaloner PA, Hitchcock PB,
Wagenaar A. Novel mono-and bis-metallated complexes of dialkyldia-
ziridines; X-ray diffraction structures of three platinum complexes. J
Chem Soc Chem Commun 1993;186–187.
8. Adedapo A, Benyunes SA, Chaloner PA, Claver C, Hitchcock PB, Ruiz A,
Ruiz N. Rhodium(I) complexes of 4-t-butylcyclohexyldiaziridine and
29. Gasparrini F, D’Acquarica I, Pierini M, Villani C. Chromatographic resolu-
tion and enantiomerization barriers of axially chiral 1-naphthamides. J Sep
Sci 2001;24:941–946.
adamantyldiaziridine: Synthesis, structure and catalytic activity.
Organomet Chem 1993;443:241–247.
J
9. Kamuf M, Rominger F, Trapp O. Investigation of the rearrangement in
alkyl-bridged bis(carbamoyldiaziridine) derivatives. Eur J Org Chem
2012;4733–4739.
10. Skrupskaya T, Kislukhin A, Shevtsov A, Petukhova V, Lyssenko K,
Makhova N. Complexes of α,ω-bis(3,3-dialkyldiaziridin-1-yl)alkanes and
their bis(2-arylcarbamoyl) derivatives with cadmium and nickel salts.
Russ Chem Bull 2008;57:56–62.
30. Cannazza G, Battisti U, Carrozzo MM, Brasili L, Braghiroli D, Parenti C.
Evaluation of stereo and chemical stability of chiral compounds. Chirality
2011;23:851–859.
31. D’Acquarica I, Gasparrini F, Pierini M, Villani C, Zappia G. Dynamic
HPLC on chiral stationary phases: a powerful tool for the investigation
of stereomutation processes. J Sep Sci 2006;29:1508–1516.
Chirality DOI 10.1002/chir

162
ZAWATZKY ET AL.
32. Wolf C. Stereolabile chiral compounds: analysis by dynamic chromatogra-
phy and stopped-flow methods. Chem Soc Rev 2005;34:595–608.
33. Trapp O. Investigation of the stereodynamics of molecules and catalyzed
38. Trapp O. The unified equation for the evaluation of degenerated first
order reactions in dynamic electrophoresis. Electrophoresis 2006;27:
2999–3006.
reactions by CE. Electrophoresis 2010;31:786–813.
39. Trapp O. A novel software tool for high throughput measurements of
interconversion barriers: DCXplorer. J Chromatogr B 2008;875:42–47.
34. Maas B, Dietrich A, Karl V, Kaunzinger A, Lehmann D, Köpke T,
Mosandl A. Tert-butyldimethylsilyl-substituted cyclodextrin derivatives
as versatile chiral stationary phases in capillary GC. J Microcolumn Sep
1993;5:421–427.
40. The software DCXplorer is available from the corresponding author upon
request as an executable program running under the operating system
Microsoft Windows XP, Vista, or 7.
35. Bicchi C, D’Amato A, Rubiolo P. Cyclodextrin derivatives as chiral selectors
for direct gas chromatographic separation of enantiomers in the essential
oil, aroma and flavour fields. J Chromatogr A 1999;843:99–121.
41. Cannazza G, Carrozzo MM, Battisti U, Braghiroli D, Parenti C, Troisi A,
Troisi L. Determination of kinetic parameters of enantiomerization of
benzothiadiazines by DCXplorer. Chirality 2010;22:789–797.
36. Trapp O. Fast and precise access to enantiomerization rate constants in
42. Heck RF. Palladium-catalyzed reactions with olefins of organic halides.
Acc Chem Res 1979;12:146–151.
dynamic chromatography. Chirality 2006;18:489–497.
37. Trapp O. Unified equation for access to rate constants of first-order
reactions in dynamic and on-column reaction chromatography. Anal
Chem 2006;78:189–198.
43. Majumdar KC, Chattopadhyay B. Novel synthesis of medium-sized
heterocycles by palladium-catalyzed intramolecular Heck reaction via
9-endo-trig mode of cyclization. Synthesis 2009;2385–2392.
Chirality DOI 10.1002/chir