Catalytic asymmetric diaziridination

Article abstract of DOI:10.1021/ja401150m

The first catalytic enantio- and diastereoselective synthesis of diaziridines is presented. Aziridination of N-tosyl aldimines applying modified hydroxylamine under asymmetric phase-transfer catalysis furnished optically active diaziridines. The diaziridines are formed as a single diastereomer in up to 96% ee, containing two orthogonal N-protecting groups, which can be deprotected selectively.

Full text of DOI:10.1021/ja401150m

Communication
pubs.acs.org/JACS
Catalytic Asymmetric Diaziridination
Lennart Lykke, Kim Søholm Halskov, Bjørn Dreiø Carlsen, Victor X. Chen, and Karl Anker Jørgensen*
Center for Catalysis, Department of Chemistry, Aarhus University, DK-8000 Aarhus C, Denmark
S
* Supporting Information
collapses via an intramolecular, nucleophilic substitution reaction
furnishing the diaziridine ring.
ABSTRACT: The first catalytic enantio- and diastereose-
lective synthesis of diaziridines is presented. Aziridination
of N-tosyl aldimines applying modified hydroxylamine
under asymmetric phase-transfer catalysis furnished
optically active diaziridines. The diaziridines are formed
as a single diastereomer in up to 96% ee, containing two
orthogonal N-protecting groups, which can be deprotected
selectively.
The use of chiral auxiliary based imines is the only existing
procedure for the synthesis of optically active diaziridines.12
More recently, a catalytic enantioselective amidation of
acylimines to give the open aminals was reported.13
Recently, the aziridination of electron-deficient CC double
bonds, applying acylated hydroxycarbamates or N-protected O-
tosyl hydroxylamines as N-transfer agents, has been achieved for
the formation of optically active aziridines.14 We envisioned that
this type of N-transfer agents might react with CN double
bonds for the asymmetric synthesis of diaziridines. We now
report the first catalytic asymmetric formation of diaziridines
applying a chiral phase-transfer catalyst (Scheme 1).
he development of new efficient and highly selective
T
methodologies for the construction of heterocyclic
structures is a cornerstone in organic synthesis.1 Small
heterocyclic molecules have found applications as reagents or
reactants, as well as have become an essential part of the scaffold
of natural compounds or pharmaceuticals.2 Diaziridines are an
interesting class of strained heterocycles, but surprisingly their
asymmetric synthesis has only been scarcely studied.
Scheme 1. Strategy for the Synthesis of Optically Active
Diaziridines
Diaziridines3 are heterocyclic compounds containing two N-
atoms and one C-atom in a three-membered ring; as such the
diaziridine ring is both a hydrazine and an aminal. This duality is
reflected in the reactivity of this class of compounds.4 These
structures were first reported in the late 1950s by three groups
concurrently.5 Owing to the strained nature of this family of
compounds, the weak N−N bond, and the hydrazine−aminal
duality, these compounds exhibit unusual and interesting
reactivity.6 A remarkable property of diaziridines is that the N-
atoms due to ring stain and lone-pair repulsion are configura-
tionally stable;7 consequently the diaziridine ring possesses three
stereogenic centers. Nevertheless, to the best of our knowledge
no catalytic asymmetric protocol leading to optically active
diaziridines has been reported.
N-Monosubstituted diaziridines have found application as a N-
transfer agent to α,β-unsaturated amides, forming diastereo- and
enantioenriched aziridines.8 Interestingly, depending on the
structure of the diaziridine, the cis- and trans-selectivity could be
controlled. Additionally, diaziridines have found use as 1,3-
dipolar precursors by ring opening in the reaction with various π-
systems.9 Depending on the nature of the diaziridine system it
opens in either a C−N or N−N fashion. Furthermore,
diaziridines have found applications as a protected analog of a
diazine which is used as a carbene precursor.10
Our studies were initiated by examining the diaziridination of
N-tosyl benzaldimine 1a applying the N-transfer agents 2a and
2b (Table 1), which have been successfully applied for the
aziridination of electron-deficient olefins. The reaction was
subjected with various organic and inorganic bases, but
disappointingly no reactivity was observed. Addition of a
catalytic amount of tetrabutylammonium bromide (TBAB) as
a phase-transfer reagent did not promote reactivity (Tabel 1,
entries 1 and 2). We considered that the nucleophilicity of the
carbamate or sulfonamide N-atom might not be sufficient to
undergo addition to 1a. In order to test this hypothesis, we
synthesized N-benzyl O-benzoyl hydroxylamine (2c) which is a
more electron-rich and hence a more nucleophilic N-transfer
agent.15 To our delight, applying N-transfer agent 2c under
phase-transfer conditions using potassium carbonate as a base
afforded 1-benzyl-3-phenyl-2-tosyldiaziridine (4a) in full con-
version (entry 3). Throughout the present work, the synthesized
diaziridines were formed as a single diastereomer. The reaction is
performed as a solid base/organic solvent two-phase system;
hence an aqueous base hydrolyzes the imine. It should be noted
that the reaction also takes place using an organic base (DBU);
however, as stoichiometric amounts of a chiral base would be
required, we decided to follow the phase-transfer catalysis (PTC)
strategy.16
The formation of diaziridines in general proceeds by N−N
bond formation, thus coupling two heteroatoms. Imines can be
oxidized by hydroxylamine O-sulfonic acids or O-esters in an
organic or inorganic base-mediated reaction affording racemic
trans-1,3-substituted diaziridines in excellent yields.11 The
reaction is a two-step sequence initiated by 1,2-addition of the
derivatized hydroxylamine to the imine; the resulting aminal
Received: February 1, 2013
© XXXX American Chemical Society
A
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Journal of the American Chemical Society
Communication
base. It was recognized that potassium bicarbonate was too weak
to mediate the reaction (entry 13). When employing cesium
carbonate the reaction proceeded in full conversion to the
product diaziridine 4a but with inferior enantioselectivity
compared to potassium carbonate (entry 14 vs 7). When
potassium phosphate was used the product diaziridine was
afforded with similar selectivity as with potassium carbonate;
however, the reaction rate was significantly enhanced (entry 15
vs 7). Employing the novel O-diphenylmethylene-modified
catalyst 3e using potassium phosphate afforded the diaziridine
4a with the enantioselectivity increased to 57% ee (entry 16).
Surprisingly, increasing the bulky nature of the O-substituent
further by O-tritylation 3f depleted the enantioselectivity
completely (entry 17). Applying catalyst 3e at a lowered
temperature (−12 °C) furnished the diaziridine product 4a with
an excellent enantiomeric excess of 94% ee (entry 18); however,
further cooling prolonged the reaction time significantly giving
no additional improvement in enantioselectivity. It should be
noted that the reaction time was increased to 72 h for the reaction
to reach acceptable conversion (84%), while the remaining
material was the uncyclized aminal intermediate.
Table 1. Selected Screening Results for Reaction Conditions
for the Enantioselective Diaziridination of N-Tosyl
Benzaldimine 1a
Encouraged by this result, a representative selection of N-tosyl
aldimines was prepared in order to investigate the generality of
the reaction (Scheme 2). We were pleased to find that the high
efficiency demonstrated by catalyst 3e for the model reaction
could be sustained for the diaziridination of a broad range of
imines. Generally, aromatic imines having substituents in the
meta- and para-positions furnished the optically active diaziridine
b
N-
temp
conv
(%)
ee
a
entry
cat.
donor
solvent
base
(°C)
(%)
1
2
3
4
5
6
7
TBAB
TBAB
TBAB
3a
2a
2b
2c
2c
2c
2c
2c
toluene
toluene
toluene
toluene
toluene
toluene
toluene
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
4
4
4
4
4
4
4
−
−
>95
>95
>95
>95
>95
nd
nd
nd
6
3b
17
15
35
Scheme 2. Scope for the Enantioselective Diaziridination of
a
3c
N-Tosyl Aldimines
3d
8
3d
3d
3d
3d
3d
2c
2c
2c
2c
2c
CH2Cl2
K2CO3
4
4
4
4
4
30
nd
19
26
32
32
9
m-xylene K2CO3
72
10
11
12
o-xylene
K2CO3
K2CO3
K2CO3
77
Ph−Cl
Ph−CF3
77
>95
13
14
3d
3d
3d
2c
2c
2c
toluene
toluene
toluene
KHCO3
Cs2CO3
K3PO4
4
4
4
−
>95
nd
27
34
c
15
>95
16
17
3e
3f
2c
2c
2c
toluene
toluene
toluene
K3PO4
K3PO4
K3PO4
4
>95
>95
84
57
0
4
d
18
3e
−12
94
a
All reactions performed on a 0.05 mmol scale using 1a (0.05 mmol),
2 (0.075 mmol), 3 (0.005 mmol), and base (0.1 mmol) in 0.5 mL of
b
anhydrous solvent for 24 h at 4 °C. Determined by chiral stationary
c
d
phase HPLC. Reaction time 4 h. Reaction time 72 h.
We initiated a screening protocol by surveying asymmetric
phase-transfer catalysts and were pleased that cinchonine
quaternized with a 9-methyleneanthracene at the quinuclidine
N-atom, indicating a promising skeleton for catalyst develop-
ment (entries 4−7). It was discovered that the O-benzylated
catalyst 3d catalyzed the reaction in full conversion and up to
35% ee (entry 7). With a promising catalyst in hand we
performed a solvent screening (entries 8−12) and observed that
the reaction only furnished the desired diaziridine to a significant
degree in aromatic solvents; disappointingly, no enhancement
was achieved with regards to conversion or enantioselectivity
when compared to toluene. We then turned our attention to the
a
All reactions performed using 1 (0.05 mmol), 2c (0.075 mmol), 3e
(0.005 mmol), and K3PO4 (0.1 mmol) in 0.5 mL of anhydrous toluene
for 72 h at −12 °C. Isolated yields by FC. Ee determined by chiral
stationary phase HPLC.
B
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Journal of the American Chemical Society
Communication
products in acceptable to high yields with high to excellent
enantioselectivities (products 4b−e,g−j). Imines with aromatic
substituents having an electronic nature ranging from electron-
donating to -withdrawing participated successfully in the
enantioselective diaziridination; however, when aromatic imines
having electron-rich substituents, which are able to conjugate a
lone pair of electrons to the imine, were employed (e.g., p-MeO-
C6H4 or 2-furanyl), no product formation was observed.
Interestingly, a disubstituted aromatic imine was employed in
the reaction affording diaziridine 4j in high yield and
enantioselectivity. Additionally, a 2-naphthyl-based imine also
gave rise to the corresponding diaziridine 4f in high yield and
enantioselectivity. In general ortho-substituted aromatic imines
performed sluggishly in the reaction, probably owing to steric
reasons, although an o-fluoro substituted imine afforded the
product 4k, albeit in a moderate yield and enantioselectivity.
Having surveyed the diaziridination of aromatic aldimines, we
considered the possibility of expanding the developed method-
ology to aliphatic N-tosyl aldimines. Indeed catalyst 3e furnished
cyclohexyl-substituted optically active diaziridine 4l; disappoint-
ingly a moderate yield and enantioselectivity were obtained.
Determination of the relative and absolute configuration of the
optically active diaziridines was carried out by X-ray analysis of
4c, which proved to be the (1R,2R,3S)-1-benzyl-3-aryl-2-
tosyldiaziridine as shown in Figure 1.17 Hence, the remaining
diaziridines 4 were assigned by analogy assuming a common
reaction pathway.
noted that all diastereoisomers of A are higher in energy than A.
These data suggest that the diaziridine should exclusively exist as
diastereoisomer A, which is consistent with the experimental
findings.
Based on experimental observations, we propose a mechanistic
pathway for the catalytic enantio- and diastereoselective
diaziridination of N-tosyl aldimines as outlined in Figure 3.
Figure 3. Mechanistic proposal of the asymmetric diaziridination of N-
tosyl aldimines.
Upon filtration of the reaction mixture (removal of catalyst and
base), prior to reaction completion, the uncyclized aminal adduct
6 was observed in a significant amount by 1H NMR spectroscopy,
and this adduct did not cyclize furnishing the diaziridine 4 in the
absence of the catalyst, even at elevated temperatures. We
propose that the first step is the formation of a contact ion-pair 5,
by reaction of the deprotonated hydroxylamine with the phase-
transfer catalyst, which undergoes an enantioselective addition to
the N-tosyl aldimine. Based on the experimental observations, we
suggest a stepwise reaction mechanism, in which the rate-
determining step consists of an ammonium-ion catalyzed
diastereoselective N−N bond forming cyclization of 6 affording
the diaziridine 4.
To demonstrate the utility of the optically active diaziridines,
we set out to investigate whether the two N-protection groups
could be removed in an orthogonal fashion. To remove the tosyl
moiety, we decided to follow the Ragnarsson procedure,22 which
is a mild and effective Mg-mediated reductive cleavage. The
detosylated diaziridine 7 was isolated in an unoptimized 84%
yield as the cis-isomer without racemization (Scheme 3).
Deprotection of the benzyl-moiety proved much more
challenging, as both benzylamine and the N−N bond of the
diaziridine underwent hydrogenation even when very mild
hydrogenation methodologies were applied. Chloroformate
dealkylation reactions failed to afford any desired product. We
circumvented this challenge by employing the mild dissolved
Figure 1. Single crystal X-ray structure of 4c.
A computational study (M06-2X/6-31+G(d,p))18,19 was
employed to examine the inversion barriers for diaziridine 4a.
Our studies predicted structure A (Figure 2) to be the lowest
Figure 2. Calculated inversion barriers and relative energies of the
diaziridine 4a. Energies are reported in kcal/mol and are relative to the
energy of A.
energy diastereomer and conformer, in agreement with the X-ray
structure of 4c. Consistent with the experimental and theoretical
findings,20 the favored isomer places the two N-substituents trans
to one another. Structure A also takes advantage of a favorable π-
stacking interaction between the two N-substituents (see Figure
1). Conversion of A to C, in which the Ts- and Bn-groups on the
N-atoms have a cis-relationship, proceeds with a barrier of 24.2
kcal/mol. Inversion of the Ts-group in A occurs with a barrier of
22.2 kcal/mol and leads to the all cis-isomer of 4a, which is 16.5
kcal/mol higher in energy than A.21 Inversion of the Ts-group in
C proceeds with a barrier of 21.0 kcal/mol. It should also be
Scheme 3. Orthogonal Deprotection of the Two N-Protection
Groups
C
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Journal of the American Chemical Society
Communication
metal-reduction conditions developed by Angle.23 Treatment of
4a with lithium using a solvent mixture of ethylenediamine,
triethylamine, and THF afforded the debenzylated diaziridine 8
in 53% yield (unoptimized).
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Org. Lett. 2011, 13, 5842.
In conclusion, this work constitutes the first example of a
catalytic asymmetric diaziridination. The developed method-
ology takes advantage of a phase-transfer catalyzed nitrogen
insertion into the π-system of N-tosyl aldimines facilitated by N-
benzyl-O-benzoyl hydroxylamine as the N-transfer agent
affording N-tosyl-N′-benzyl-diaziridines as a single diastereomer
in up to high yields (up to 75%) with high to excellent
enantioselectivity (up to 96% ee) and with absolute diaster-
eocontrol. Experimental observations indicate a stepwise
mechanism in which the rate-determining step is an
ammonium-ion catalyzed N−N bond forming cyclization of an
aminal intermediate. Furthermore, orthogonal N-deprotections
have been demonstrated.
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ASSOCIATED CONTENT
* Supporting Information
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dova, A. Chem.Eur. J.
■
2011, 17, 7904. (c) Pesciaioli, F.; Vincentiis, F. D.; Galzerano, P.;
Bencivenni, G.; Bartoli, G.; Mazzanti, A.; Melchiorre, P. Angew. Chem.,
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S
Experimental procedures, analytical data, and NMR spectra. This
material is available free of charge via the Internet at http://pubs.
acs.org.
AUTHOR INFORMATION
Corresponding Author
kaj@chem.au.dk
■
(15) The synthesis of N-benzyl-O-tosyl hydroxylamine was also
attempted; however, this compound was unstable under basic
conditions.
Notes
The authors declare no competing financial interest.
(16) For reviews on phase-transfer catalysis, see: (a) Ooi, T.; Maruoka,
K. Angew. Chem., Int. Ed. 2007, 46, 4222. (b) Hashimoto, T.; Maruoka,
K. Chem. Rev. 2007, 107, 5656. (c) Brak, K.; Jacobsen, E. N. Angew.
Chem., Int. Ed. 2013, 52, 534. (d) Asymmetric Phase Transfer Catalysis;
Maruoka, M., Ed.; Wiley-VCH: Wienheim, 2008. For recent examples,
see: (e) He, R.; Shirakawa, S.; Maruoka, K. J. Am. Chem. Soc. 2009, 131,
16620. (f) Ma, T.; Fu, X.; Kee, C. W.; Zong, L.; Pan, Y.; Huang, K.-W.;
Tan, C.-H. J. Am. Chem. Soc. 2011, 133, 2828. (g) Shirakawa, S.; Liu, K.;
Maruoka, K. J. Am. Chem. Soc. 2012, 134, 916. (h) Hong, S.; Lee, J.; Kim,
M.; Park, Y.; Park, C.; Kim, M.-H.; Jew, S.-S.; Park, H.-G. J. Am. Chem.
Soc. 2011, 133, 4924. (i) Qi, J.; Beeler, A. B.; Zhang, Q.; Porco, J. A. J.
Am. Chem. Soc. 2010, 132, 13642.
(17) For X-ray analysis details, see Supporting Information. Ortep-3
was used for the X-ray plot: Farrugia, L. J. J. Appl. Crystallogr. 1997, 30,
565.
(18) Calculations were performed with GAUSSIAN09. Geometries
were optimized without symmetry constraints at the M06-2X/6-
31+G(d,p) level of theory ( Zhao, Y.; Truhlar, D. Theor. Chem. Acc.
2008, 120, 215 ) in the gas phase. See Supporting Information for the
details and references for theoretical methods.
(19) The inversion barriers and relative free energies of the
intermediates were also calculated at MP2/cc-pVDZ//M06-2X/6-
31+G(d,p). With this method, the same energetic trends are observed as
with M06-2X/6-31+G(d,p). Barriers for inversion ranged from 26 to 28
kcal/mol, and A is favored over all other isomers by 3−8 kcal/mol. For
details, see Supporting Information.
(20) (a) Nielsen, I. M. B. J. Phys. Chem. A 1998, 102, 3193. (b) Alkorta,
I.; Elguero, J.; Zborowski, K. J. Phys. Chem. A 2007, 111, 1096.
(21) It should be noted that TS-D does not directly connect A to D.
Due to steric crowding, no transition state connecting A to D could be
located. The conformer of A leading to TS-D is 2.5 kcal/mol higher in
energy.
ACKNOWLEDGMENTS
■
This work was financially supported by the Aarhus University,
Carlsberg Foundation, and FNU. Drs. Jacob Overgaard and
Rebecca Davis are acknowledged for performing X-ray analysis
and computational studies, respectively.
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