Synthesis of asymmetric N-arylaziridine derivatives using a new chiral phase-transfer catalyst

Article abstract of DOI:10.1055/s-2005-869976

Substituted N-arylaziridine derivatives were synthesized in an enantioselective manner from N-acyl-N-arylhydroxylamine and electron deficient olefins using chiral phase-transfer catalysts (CPTCs) derived from cinchona alkaloids. The structures of the CPTC

Full text of DOI:10.1055/s-2005-869976

2
022
PAPER
Synthesis of Asymmetric N-Arylaziridine Derivatives Using a New Chiral
Phase-Transfer Catalyst
a
b
Synthesis of
E
As
a
ymmetric
N
g
-Arylaziridi
an es mbaram Murugan,* Ayyanar Siva
a
Department of Physical Chemistry, School of Chemical Sciences, University of Madras, Guindy campus, Chennai-600 025, TN, India
Fax +91(44)22352494; E-mail: murugan_e68@yahoo.com
b
Department of Chemistry, Gandhigram Rural Institute-Deemed University, Gandhigram-624 302, TN, India
Received 7 January 2005; revised 18 March 2005
added requirement that any available method should also
allow enantioselective aziridine formation. The signifi-
cance of the aziridines and their derivatives depend on
Abstract: Substituted N-arylaziridine derivatives were synthesized
in an enantioselective manner from N-acyl-N-arylhydroxylamine
and electron deficient olefins using chiral phase-transfer catalysts
(
CPTCs) derived from cinchona alkaloids. The structures of the their high reactivity giving a variety of ring-opened or
CPTCs were ascertained through various spectral techniques such ring-expanded nitrogen containing compounds. Particu-
1
13
as FT-IR, H NMR, C NMR, and mass spectroscopy, as well as el-
emental analyses. The efficiency and chiral behavior of a range of
CPTCs were studied with respect to both yield and ee. The chemical
yields were in the range of 24–92% and ee was 29–95%. It was ob-
served that the S-enantiomers were more predominant than the R-
enantiomers with cinchonidine as catalyst; whereas the R-enantio-
larly, the presence of electron-withdrawing group on the
aziridine nitrogen plays a key role in the ring-opening re-8
actions, affecting both the regio- and stereoselectivity.
Though, numerous methods are available to prepare azir-
idines or substituted aziridines, the utilization of chiral
mers were more predominant in the case of cinchonine based phase-transfer catalyst (CPTC) is still in its infancy. It is
CPTC. We propose here a suitable mechanism for the formation of also known that the enantioselective synthesis of aziri-
chiral aziridines as well as optimized procedures for a range of N-
arylaziridine derivatives.
dines is of much significance due to its significant appli-
cations in medicinal chemistry.
Key words: enantioselection, cinchona alkaloid, aziridine, hydrox-
In the last 30 years the field of asymmetric catalysis has
amic acids, electron deficient olefins
become the subject of extensive research activity, result-
ing in the development of naturally occurring cinchona al-
kaloids as chiral auxiliaries. Cinchona alkaloids have a
The ability of aziridines to undergo highly regio- and ste-
veritable history in the field of asymmetric synthesis ow-
reoselective ring-opening reactions makes them valuable
ing to their firmly established ability to induce chirality.
1
in organic synthesis. This ability is also known in nature,
Hence, they have been widely used in asymmetric synthe-
where a number of molecules possessing an aziridine ring
have been shown to exhibit potent biological activity,
ses both in homogeneous and heterogeneous reactions.9
These catalysts have shown broad application in mediat-
which is intimately associated with the reactivity of the
ing a variety of synthetically useful transformations with
strained heterocycle. For example, various forms of mito-
9c
high selectivities. Particularly, CPTC has been dominat-
2
mycin, together with porfiromycin and mitiromycin, rep-
10
ed by cinchona and its derivatives although the other
resent an important class of naturally occurring mitosanes,
isolated from soil extracts of Streptomyces verticillatus.3
These mitosanes exhibit both anti-tumor and antibiotic ac-
tivity, their anti-tumor properties result from their ability
10
11
quaternary ammonium salts and metal catalysts have
been reported recently for the asymmetric synthesis. Re-
12,13
actions such as carbon-carbon bond formation,
alkyla-
14a–d
14e–h
14i,j
tion,
Darzen reaction,
Michael addition, aldol
2
to cross-link DNA. Structure-activity relationships have
14k
14l
condensation, and a-hydroxylation of ketones were
performed in the recent past using different CPTCs.
CPTC has also been used to control diastereoslectivity, as
demonstrated by the highly effective and practical synthe-
sis of HIV protease inhibitors by nitro-aldol reactions of
identified the aziridine ring as being essential for antitu-
mor activity and many research studies have concentrated
on synthesizing derivatives of these natural products with
increased potency.4
A number of synthetic aziridines have also been shown to aldehydes with nitromethane.
5
,6
exhibit useful biological properties. Novel antitumor
agents related to mitosanes and mytomycins have recently
been synthesized and demonstrated to possess activity
The synthesis of chiral aziridines was reported by
15
16
Jacobsen and Evans using copper catalysts with chiral
17
dinitrogen ligands. Recently Jacobsen et al. studied the
7
against a variety of cancers. Thus aziridine derivatives
synthesis of chiral aziridines using bisoxazolines cop-
per(I) complex and reported an ee up to 67% with a mod-
are worthy targets for a synthetic organic chemist and it is
essential that efficient methods exist for the facile synthe-
sis of a range of structurally diverse aziridines, with the
18
est chemical yield. Joao Aires-de-sousa et al. have
reported a new enantioselective method for the synthesis
of N-aryl aziridines using N-benzyl cinchona alkaloid de-
rivative as a soluble CPTC. Their study concluded that the
O-pivaloyl-N-phenylhydroxylamines and N-pivaloyl-N-
SYNTHESIS 2005, No. 12, pp 2022–2028
x
x.
x
x
.
2
0
0
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Advanced online publication: 24.06.2005
DOI: 10.1055/s-2005-869976; Art ID: Z00905SS
Georg Thieme Verlag Stuttgart · New York
©

PAPER
Synthesis of Asymmetric N-Arylaziridines
2023
phenylhydroxylamines are efficient aziridinating agents higher than in the case of KOH due to the stronger ionic
+
of electron deficient olefins. They reported different chiral interaction between Na and the N-acyloxy anions 13
+
aziridines using cinchona alkaloid-derived CPTC; but compared to the K ion. Similarly, a higher yield and ee
here the chemical yield is 79% with ee up to 61%.
was observed in the presence of low concentrations of
aqueous NaOH (Table 1, entries 1–3). This is probably
due to the decomposition of CPTC in the presence of high
concentrations of NaOH. Similar results have been report-
ed for C- and O-alkylations of C-benzyl and benzyl ethers,
respectively, using tetrabutylammonium hydrogen sulfate
R2
O
OH
X
R1
N
N
CPTC (10 mol %)
10 % aq NaOH/toluene
r.t., 1–3 h
CH2
R2
+
x
19
as a soluble phase transfer catalyst.
1
2
3
1
2
R = t-Bu, Ph,
R = CO2t-Bu, Ph, SOPh
Table 1 Effect of Base and its Concentration on the Aziridination
CO2Me
X = H, OMe, Cl,
Br, Me, NO2
COOt-Bu
OH
base/toluene
+
N
Scheme 1 Synthesis of aziridine derivatives
N
CO2t-Bu
CPTC 10
Ph
COt-Bu
In this paper, our main focus of attention has been devoted
to the synthesis of efficient and new CPTCs. This in turn
could improve the reaction yield and enantiomeric effi-
ciency. Furthermore, it is also our aim to explore the pos-
sibilities of N-acyl-N-arylhydroxylamines 1 (Scheme 1)
as efficient aziridinating agents due to the presence of
electron deficient atoms. As a first step, CPTC 7 was syn-
thesized from 2-hydroxy-3-chloromethyl-5-methyl benz-
aldehyde (4) and cinchonidine 5 in acetonitrile at 20 °C.
The resulting mixture was stirred with p-toluene sulfonyl-
chloride to give CPTC 9-O-[p-toluenesulfonyl-N-(3-
formyl-5-methyl-2-hydroxybenzyl)]cinchonidinium chlor-
ide (7; 91%). Similarly cinchonine derived CPTC 10, 9-
O-[p-toluenesulfonyl-N-(3-formyl-5-methyl-2-hydroxy-
benzyl]cinchonium chloride was also prepared in 85%
yield following the same experimental methodology as in
Entry Aqueous
Base
Concentration Yield ee
Configuration
(%, w/v)
(%)
84
75
46
38
32
24
(%)
95
85
73
26
15
–
1
2
3
4
5
6
NaOH
NaOH
NaOH
KOH
10
20
30
10
20
30
R
R
R
R
R
–
KOH
KOH
The change of solvent is an important factor in the azirid-
ination reaction (Table 2). The yield and ee have been
found to increase in the order of methanol < diethylether
7
(Scheme 2). In order to examine the catalytic efficiency
of these two chiral quaternary ammonium CPTCs 7 and
0; they were used individually to effect the aziridination
<
toluene. The decreased product yield/ee in highly polar
solvents such as methanol or diethylether may due to the
higher degree of solvation of CPTCs; as a result the effi-
ciency of the catalyst is decreased. In the case of toluene,
which is a low polar solvent, the degree of solvation of
CPTCs is considerably less. So the degree of decay due to
solvation of CPTCs is minimized/ignored.
1
reaction of different hydroxamic acids 1 with different
olefins 2 in a biphasic system with various solvents in the
presence of 10–30% aqueous NaOH/KOH solutions. The
relative and absolute configurations of the aziridine prod-
1
uct 3 were assigned by analyses of their H NMR spectra.
The ee of the N-aryl aziridine products were measured us-
ing chiral HPLC analysis. All the asymmetric aziridina-
tion reactions were carried out using commercially
available hydroxamic acids/substituted hydroxamic acid
as substrate with a view to improving the yields (92%) and
also ee (up to 95%) in the presence of our CPTCs
Table 2 The Effect of Solvent on Yield and Enantiomeric Excess
COOt-Bu
OH
N
20% aq NaOH/
solvent
CPTC 7
+
N
2
CO t-Bu
Ph
COt-Bu
(
Table 1).
Entry Solvent
e
Yield (%) ee (%) Configuration
The influence of base (NaOH or KOH) at different con-
centrations (10–30% w/v) and solvents with different po-
1
2
3
Toluene
2.4
92
56
47
94
58
42
S
S
S
larities (MeOH, Et O, and toluene) for the aziridination
2
Et O
4.2
reaction was also studied to determine their effect on the
chemical yield and ee. The amount of aziridine deriva-
tives and their corresponding ee under different reaction
conditions are presented in Tables 1 and 2. The result re-
veals that changing the base from NaOH to KOH as well
as varying their concentration has a remarkably influence
on the reactions (Table 1). For example, the aziridine
yield and ee obtained in the presence of NaOH is much
2
MeOH
32.63
The product yields and ee for a range of aziridinations are
presented in Table 3. These results reveal that the stereo-
chemical course of the aziridination reaction depends on
the stereochemistry/molecular assembly of the different
Synthesis 2005, No. 12, 2022–2028 © Thieme Stuttgart · New York

2
024
E. Murugan, A. Siva
PAPER
O
O
H
H
N
H
N
H
SO Cl
S
N
N
2
O
CH3
H
HO
Cl–
Cl–
HO
MeCN
HO
O
DMF/CH2Cl2/
K2CO3
HO
N
N
CH3
O
ClH2C
HO
CH3
5
6
7
H3C
Cl–
H
O
H
O
4
H
N
N
OH
O
O
N
S
SO2Cl
MeCN
N
OH
O
CH3
Cl–
N
OH
N
DMF/CH2Cl2/
K2CO3
H
HO
O
H
H
8
9
10
Scheme 2 Formation of various intermediates/molecular assembly to enantioselective aziridinating reaction under CPTCs condition
reactants and CPTCs. Furthermore, the results proved that bility of hydrogen bonding between the free OH present in
the stereochemical course of the aziridination reaction the phenol moiety of the catalyst and N-acyloxy anion or
mainly depends on the stereochemistry of the N-phenyl- carbonyl oxygen (olefin) may also be ignored due to in-
N-hydroxamic acid derivatives 1 as can be seen when a tramolecular hydrogen bonding with the adjacent formyl
number of electron deficient olefins 2 underwent reaction group (Figure 1, 18). Therefore, the a- and b-carbons of
in the presence of CPTCs 6, 7, 9, and 10. The increased the olefinic double bond and N-acyloxy anion are brought
+
yield and ee of each reaction can be mainly attributed to closer towards (in bonding distance) the R N site of cat-
4
an effective contact ion-pair formed between the positive alysts 7 and 10 through electrostatic attraction of the p-
+
quaternary ammonium ions (R N ) and the CPTC (6, 7, 9, bond and ion-pair formation, respectively. This is possible
4
and 10) with N-acyloxy anion 13 due to electrostatic at- due to the absence of hydrogen bonding between the cat-
+
traction and also the same attraction between R N of all alyst and substrates. The formation of the R- and S-isomer
4
the CPTCs with the p-bond present on the a- and b-car- is then solely dependent on chiral transfer between sub-
2
0
bons of the acrylate olefin 2 (15, Scheme 2). Similarly, strate and catalysts.
a decrease in the aziridination product yield and ee may be
due to the formation of a hydrogen bond between the re-
actants (13 and 2) and the free hydroxyl group present at
In cinchonium CPTC 10 the molecular assembly during
chiral exchange would be attributed to the formation of an
+
ion-pair between R N and N-acyloxy anion 13, with the
4
the C (O)-position of the CPTCs 6 and 9 (Scheme 2, 16,
9
quinoline part of catalyst 10 serving as the platform for the
aromatic ring of substrate 1 (Scheme 2).
1
7). In these studies it was established that the O-tosyl de-
rivative of the catalysts (7 and 10) is far superior in form-
Similarly, for the other substrates, the olefin is again ori-
ing the aziridine in high yield (92%) and ee (95%)
+
+
compared to the O-acryloyl derivative already reported.21
ented towards the R N site of the catalyst (R N p-elec-
4
4
trostatic attraction). The molecular assembly when
Here also the mechanistic considerations are the same
arranged in such a manner leads to the formation of R-iso-
namely the prevention of hydrogen bonding at the C -po-
9
21
mers, as observed earlier. In the case of a reaction cata-
lyzed by cinchonidinium CPTC, 7 must also undergo
similar molecular assembly/orientation in such a manner
on the other side, which would lead to the S-isomer of
aziridine derivatives. The increased/decreased chemical
yields/ees of the reaction is mainly due to the presence of
electron-donating/withdrawing group on the N-aromatic
moiety of the hydroxamic acid 1. It is clear from Table 3
that the yield and ee of aziridines increases when electron-
donating groups are present on the aromatic moiety
sition of the catalysts 7 and 10 due to O-derivatization
thus resulting in high yield and ee.
In order to improve the yield and ee further, we synthe-
sized C (O)-protected cinchona derived CPTCs by tosyla-
9
tion. To the best of our knowledge there is no report
available for C (O)-tosylated and N-substitution of 3-
9
formyl-5-methyl-2-hydroxybenzyl cinchona derived
compound as CPTCs. The reaction yield and ee for the re-
action catalyzed by 7 and 10 for all the aziridination reac-
tions were observed to be higher (Table 3, entries 3a–o,)
than for catalysts 6 and 9. This is because, the free OH
present at the C(9)-position of catalyst 7 and 10 has been
derivatized as a tosylate as a result, it facilitates the forma-
tion of N-arylated aziridine. Furthermore, the other possi-
(
Table 3, 3b, 3f, 3o–q). In contrast, the presence of an
electron withdrawing group (Table 3, 3e, 3j, 3m), resulted
in lower yield due to the N-acyloxy anion 13 being gener-
ated in smaller quanities.
Synthesis 2005, No. 12, 2022–2028 © Thieme Stuttgart · New York

PAPER
Synthesis of Asymmetric N-Arylaziridines
2025
O
Cl-
O
RO
N
H
O
N
Spacer
Cl-
Spacer
O
O
Q
N
N
N
O
Ph
Ph
O
C
O
C
O
15
16
Ion-pair formed between R4N+ of CPTC's with
the N-acyloxy anion as a result of electrostatic attraction;
there is also electrostatic attraction between R4N and the
Hydrogen bonding between N-acyloxy anion and
free -OH present at the C9 (O) position of catalysts
6 and 9
+
π-bond of the olefins
O
O
Cl-
H
RO
N
Cl-
N
CH3
O
O
Spacer
O
Q
N
N
O
N
O
H
O
C
Ph
O
H
Ph
O
1
7
C
O
1
8
Hydrogen bonding between the electrophilic α-carbon
of the olefin with the free -OH present at the C9 (O)
position of catalysts 6 and 9
Intramolecular hydrogen bonding between the phenolic
-OH of the benzyl moiety and adjacent aldehyde group
CH3
where, Q = Quinoline
R = H or tosyl
Spacer =
HO
CHO
Figure 1
Table 3 Asymmetric Aziridination of N-Aryl Hydroxamic Acids with Electron-Deficient Olefins
Product Hydroxamic acids
R1
Olefins
R2
CPTC
Aziridines
a
X
(10 mol%)
Yield (%)
ee (%)
94
Configuration
3
3
3
3
3
3
3
3
3
3
3
3
3
a
b
c
d
e
f
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Ph
H
CO -t-Bu
7
10
10
7
79
92
86
87
53
77
56
79
85
41
49
69
92
S
2
4-OMe
4-Cl
CO -t-Bu
95
R
R
S
2
CO -t-Bu
85
2
3-Br
4-COOH
4-OH
H
CO -t-Bu
76
2
Ph
10
10
10
7
75
R
R
R
S
SOPh
82
g
h
i
CO -t-Bu
88
2
4-Br
4-Me
4-NO2
4-Br
4-Me
4-NO2
CO -t-Bu
87
2
CO Me
7
79
S
2
j
Ph
CO -t-Bu
7
43
S
2
k
l
t-Bu
Ph
CO Me
10
10
10
76
R
R
R
2
CO -t-Bu
85
2
m
t-Bu
CO -t-Bu
89
2
Synthesis 2005, No. 12, 2022–2028 © Thieme Stuttgart · New York

2
026
E. Murugan, A. Siva
PAPER
Table 3 Asymmetric Aziridination of N-Aryl Hydroxamic Acids with Electron-Deficient Olefins (continued)
Product Hydroxamic acids
R1
Olefins
R2
CPTC
Aziridines
a
X
(10 mol%)
Yield (%)
ee (%)
–
Configuration
3
3
3
n
o
p
q
t-Bu
t-Bu
t-Bu
t-Bu
4-Br
4-Me
4-Me
4-Me
CO -t-Bu
7
10
6
70
65
24
31
–
2
CO -t-Bu
90
R
S
2
CO -t-Bu
29
2
3
CO -t-Bu
9
32
R
2
a
Isolated yield after chromatography.
The present study has shown that N-arylaziridines can be 1H NMR (CDCl
, 200 MHz): d = 2.1 (s, 3 H), 3.2 (s, 2 H), 5.2 (s, 1
H), 7.1 (m, 1 H), 7.34 (m, 1 H), 9.6 (s, 1 H).
3
successfully synthesized. We also reported two different
stable new CPTCs, 7 and 10. The structure of both these
CPTCs was confirmed using various spectral techniques
like FT-IR, H NMR, C NMR, and mass spectroscopy.
The potential and asymmetric property of the catalysts
was examined by employing them in the synthesis of var-
ious asymmetric N-arylaziridines. The chiral induction ef-
1
3
C NMR (50 MHz): d = 11.45, 20.27, 40.61, 122.10, 124.64,
1
31.81, 136.77, 156.32, 193.30.
1
13
N-(3-Formyl-5-methyl-2-hydroxybenzyl)cinchonidinium Chlo-
ride (6)
A mixture of cinchonidine (5; 3.0 g, 10.19 mmol) and 3-chloro-
methyl-5-methyl-2-hydroxybenzaldehyde (4; 1.88 g, 10.18 mmol)
ficiency of the different reactions was determined by in MeCN (50 mL) was stirred at r.t. for 36 h. The solution was
chiral HPLC analysis. The optimum conditions for the re- washed with a small amount of sat. NaHCO solution (10 mL) and
3
the organic layer was dried, the crude residue was purified by col-
action were a low concentration (10% w/v) of aqueous
umn chromatography (EtOH–cyclohexane, 3:7); yield: 4.35 g
NaOH, a solvent with a low dielectric constant like tolu-
ene, and an electron-donating group present on the N-aryl
group on the hydroxamic acid. It was proven that catalyst
(
89%).
–
1
FT-IR: 3442, 2837, 1730, 1620, 1075 cm .
1
7
favors the formation of the S-enantiomer and catalyst 10
H NMR (300 MHz, CDCl ): d = 1.72–1.76 (m, 4 H), 2.23 (br s, 1
3
favors the R-enantiomer based on their racemization anal- H), 2.32 (s, 3 H), 2.77–2.85 (m, 1 H), 3.13–3.17 (m, 1 H), 3.20–3.25
(
(
m, 4 H), 4.05–4.12 (q, 1 H, J = 6 Hz), 4.5–4.54 (m, 2 H), 4.96–5.03
t, 2 H, J = 10.5 Hz), 5.10–5.13 (d, 1 H, J = 9.0 Hz), 5.73–5.76 (m,
ysis of the products using HPLC. The convenient synthet-
ic procedures described here should facilitate the
syntheses and application of more of these derivatives.
1
H), 7.30–7.98 (m, 8 H), 9.45 (s, 1 H).
1
3
C NMR (75 MHz, CDCl ): d = 21.7, 22.6, 27.4, 31.6, 36.3, 36.5,
3
5
5.2, 60.8, 66.4, 68.1, 79.7, 114.3, 119.5, 121.7, 123.3, 125.4,
Materials were obtained as follows, cinchonine (Fluka), cinchoni-
dine (Fluka), N-acyl-N-arylhydroxylamine (Lancaster, K), p-TsCl
125.8, 126.3, 128.4, 129.8, 127.1, 131.2, 137.1, 140.7, 144.6, 148.2,
159.5, 157.3, 187.2.
MS: m/z (%) = 444.20 (M+).
(
(
Merck), 5-methyl salicylaldehyde (Merck), paraformaldehyde
Merck), all olefins were commercial samples. All solvents were
distilled prior to use. IR spectra were recorded on JASCO-FT-IR
Anal. Calcd for C28H31ClN O : C, 70.21; H, 6.52; N, 5.84. Found C,
2 3
1
model 5300 spectrometer using a KBr pellet. H NMR (300 and 200
70.18; H, 6.48; N, 5.77.
MHz) and 13C NMR (75 and 50 MHz) spectra were recorded in
CDCl on a Bruker AC-200 spectrometer using TMS as an internal
9-O-[p-Toluenesulfonyl-N-(3-formyl-5-methyl-2-hydroxyben-
zyl)]cinchonidinium Chloride (7)
N-(3-Formyl-5-methyl-2-hydroxybenzyl)cinchonidinium chloride
3
standard. Elemental analyses were recorded on Perkin-Elmer 240-
CHN analyzer. Optical rotations were measured with an Autopol II-
automatic polarimeter at r.t. For TLC analysis, plates coated with
silica gel were run in hexane–EtOAc and were developed in an io-
dine chamber. Column chromatography was performed under grav-
ity with silica gel (100–200 mesh). The racemization products of
various N-arylaziridines were analyzed by HPLC using a chiral pir-
cle column with hexane–dioxane (100:0.5) at a flow rate of 0.5mL/
min.
(6; 2.5g, 5.22 mmol), p-TsCl (1.8g, 9.44 mmol), DMF–CH
mL, 1:1), and K CO (0.9g, 6.52 mmol) were refluxed for 36 h.
Then the solution was washed with a solution of MgSO (2 × 15
mL) and then with H O (50 mL). The organic layer was separated
Cl (40
2
2
2
3
4
2
and concentrated; the white solid was recrystallized from EtOH;
yield: 4.22 g (98%).
FT-IR: 3443, 1725, 1670 cm–1.
1
H NMR (300 MHz, CDCl ): d = 1.23 (s, 6 H), 1.60–1.64 (m, 1 H),
3
-Chloromethyl-5-methyl-2-hydroxybenzaldehyde (4)
3
3
(
.82–3.87 (m, 2 H), 3.55–1.63 (m, 11 H), 4.95 (s, 1 H), 5.23–5.30
To a mixture of 5-methyl salicylaldehyde (5 g, 16.5 mmol),
paraformaldehyde (1.43 g, 48.64 mmol) and concd HCl (25 mL)
were added, followed by concd H SO (5–6 drops). The solution
m, 2 H), 5.90–6.05 (m, 1 H), 6.70–8.98 (m, 12 H), 9.87 (s, 1 H).
1
3
2
4
C NMR (75 MHz, CDCl ): d = 20.2, 20.5, 28.7, 31.73, 34.22,
3
was refluxed for 2 h and then HCl gas was passed through the reac-
tion mixture, which was then refluxed for another 2 h. The temper-
ature of the reaction mixture was allowed to cool to r.t. The orange
product obtained, was filtered and washed with HCl (2 × 10 mL),
38.95, 61.45, 61.65, 62.78, 64.33, 76.32, 114.66, 119.75, 123.56,
125.67, 126.42, 128.54, 128.72, 128.74, 129.85, 130.76, 130.73,
131.93, 137.10, 142.49, 143.33, 143.65, 148.12, 148.16, 150.03,
156.20, 190.16.
dried, and recrystallized from CHCl –THF; yield: 4.7g (73%).
3
MS: m/z = 599.17 (M+).
–
1
FT-IR: 3420, 2200, 1730, 1220, 720 cm .
Synthesis 2005, No. 12, 2022–2028 © Thieme Stuttgart · New York

PAPER
Synthesis of Asymmetric N-Arylaziridines
2027
1
Anal. Calcd for C H ClN O S: C, 66.31; H, 5.83; N, 4.42. Found:
H NMR: d = 1.40 (s, 9 H), 1.96 (d, 2 H, J = 7.2 Hz), 2.42 (t, 1 H),
6.58–7.08 (m, 5 H).
3
5
37
2
5
C, 66.28; H, 5.83; N, 4.39.
1
3
C NMR: d = 29.1, 29.8, 43.2, 73.4, 113.3, 118.6, 129.4, 144.2,
N-(3-Formyl-5-methyl-2-hydroxybenzyl)cinchonium Chloride
9)
A mixture of cinchonine (8; 2.6 g, 8.84 mmol) and 3-chloromethyl-
-methyl-2-hydroxybenzaldehyde (4; 0.93 g, 5.4 mmol) in MeCN
50 mL) was stirred at r.t. for 24 h. Then the solution was washed
with sat. NaHCO solution (10 mL), dried over MgSO , the organic
1
72.4.
(
MS: m/z = 220.10.
5
(
Anal. Calcd for C H NO : C, 71.14; H, 7.76; N, 6.38. Found: C,
1
3
17
2
7
1.13; H, 7.76; N, 6.36.
3
4
layer was concentrated, and the residue was recrystallized from
tert-Butyl-1-(4-methoxyphenyl)aziridine-2-carboxylate (3b)
CCl –cyclohexane (1:1); yield: 3.21 g (91.9%).
20
4
Yield: 1.3 g (89%); yellowish oil; [a]D +20 (c, 0.84, CH Cl ).
2
2
–
1
FT-IR: 3440, 2210, 1725, 1218 cm .
FT-IR: 1170, 1465, 1715, 3080 cm–1.
1
H NMR (300 MHz, CDCl ): d = 1.69–1.75 (m, 4 H), 2.02 (s, 1 H),
1
3
H NMR: d = 1.38 (s, 9 H), 1.93–1.95 (m, 2 H), 2.44 (t, 1 H), 3.74
s, 3 H), 6.47–6.50 (m, 2 H), 6.57–6.60 (m, 2 H).
2
.35 (s, 3 H), 2.78–2.88 (m, 1 H), 3.13–3.16 (m, 1 H), 3.22–3.26 (m,
(
4
H), 4.03 (q, 1 H, J = 8.6 Hz), 4.50–4.55 (m, 2 H), 4.95–5.04 (m, 3
1
3
C NMR: d = 28.7, 29.9, 43.6, 56.0, 73.8, 114.3, 115.1, 136.8,
H), 5.72–5.74 (m, 1 H), 7.25–7.32 (m, 1 H), 7.42–7.51 (m, 6 H),
1
51.6, 172.6.
8
.02–8.07 (m, 1 H), 8.63–8.70 (m, 1 H), 9.40 (s, 1 H).
1
3
MS: m/z = 251.15.
C NMR (75 MHz, CDCl ): d = 21.2, 21.2, 28.5, 30.6, 38.2, 38.7,
3
5
1
1
5.2, 61.2, 65.4, 69.3, 79.7, 114.4, 119.7, 121.6, 123.6, 125.4,
25.8, 126.3, 128.4, 128.8, 129.1, 130.2, 137.1, 140.7, 143.6, 148.2,
49.5, 156.3, 190.2.
Anal. Calcd for C14H19NO3: C, 67.46; H, 7.64; N, 5.62. Found: C,
67.45; H, 7.63; N, 5.61.
tert-Butyl-1-(4-chlorophenyl)aziridine-2-carboxylate (3c)
MS: m/z = 445.20.
2
0
Yield: 79%; yellow oil; [a]D +20 (c 0.87, CH Cl ).
2
2
Anal. Calcd for C H ClN O : C, 70.21; H, 6.52; N, 5.84. Found:
2
8
31
2
3
FT-IR (KBr): 1174, 1470, 1710, 3090 cm–1.
C, 70.20; H, 6.51; N, 5.83.
1
H NMR: d = 1.40 (s, 9 H), 1.92–1.95 (m, 2 H), 2.42–2.44 (m, 1 H),
9
-O-[p-Toluenesulfonyl-N-(3-formyl-5-methyl-2-hydroxyben-
6.53–6.56 (m, 2 H), 7.05–7.13 (m, 2 H).
zyl)]cinchonium Chloride (10)
N-(3-Formyl-5-methyl-2-hydroxybenzyl)cinchonium chloride (9;
13
C NMR: d = 28.4, 29.6, 43.7, 73.6, 112.4, 114.5, 129.9, 142.6,
1
75.3.
2
.24 g, 4.8 mmol), p-TsCl (1.5 g, 8.02 mmol), DMF–CH Cl (45
2 2
MS: m/z = 253.09.
mL, 8:1), and K CO (0.7 g, 5.07 mmol) were refluxed for 36 h.
2
3
Then the solution was first washed with a solution of MgSO (25
Anal. Calcd for C H ClNO C, 61.49; H, 6. 31; N, 5.52. Found:
C, 61.47; H, 6.31; N, 5.50.
4
13 16
2:
mL) and then with H O (50 mL). The organic layer was separated,
2
concentrated, and the residual white solid was recrystallized from
EtOH; yield: 2.8 g (90%).
tert-Butyl-1-(3-bromophenyl)aziridine-2-carboxylate (3d)
2
0
–
1
Yield: 90%; yellow oil; [a]D +20 (c 0.80, CH Cl ).
FT-IR: 3400, 2210, 1710, 1220 cm .
2 2
1
1
H NMR: d = 1.41 (s, 9 H), 2.40 (t, 1 H, J = 5.2 Hz), 1.96 (d, 2 H,
J = 7.3 Hz), 6.53–6.56 (m, 1 H), 6.76–6.79 (m, 2 H), 6.96–6.99 (m,
H NMR (CDCl , 300 MHz): d = 1.30 (s, 6 H), 1.62–1.64 (m, 1 H),
3
3
.20–3.40 (m, 2 H), 3.50–3.90 (m, 11 H), 4.90 (s, 1 H), 5.20–5.60
1
H).
(m, 2 H), 5.90–6.10 (m, 1 H), 6.70 (m, 1 H), 6.97–6.99 (m, 1 H),
1
3
7
7
.24–7.26 (m, 1 H), 7.40–7.44 (m, 2 H), 7.50–7.70 (m, 2 H), 7.81–
.84 (m, 2 H), 8.90 (s, 1 H), 10.23 (s, 1 H).
C NMR: d = 29.1, 29.8, 43.2, 73.3, 112.2, 116.4, 121.3, 124.1,
131.7, 146.7, 172.0.
1
3
C NMR (75 MHz, CDCl ): d = 20.7, 21.4, 28.5, 30.72, 38.12,
MS: m/z = 297.04.
3
3
1
1
1
8.93, 61.45, 61.55, 63.78, 65.33, 76.3, 114.67, 119.92, 123.56,
25.67, 126.42, 127.84, 128.7, 128.74, 129.75, 130.7, 130.73,
31.9, 137.10, 140.49, 143.33, 143.6, 148.1, 148.16, 149.0, 156.20,
90.02.
Anal. Calcd for C H BrNO : C, 52.36; H, 5.41; N, 4.70. Found: C,
1
3
16
2
5
2.35; H, 5.39; N, 4.70.
4
-(2-Phenylaziridin-1-yl)benzoic Acid (3e)
2
0
MS: m/z = 599.19.
Yield 86%; [a]D +20 (c 0.86, CH Cl ).
2 2
1
Anal. Calcd for C H ClN O S: C, 66.32; H, 5.84; N, 4.42. Found:
C, 66.32; H, 5.82; N, 4.40.
H NMR: d = 1.91–1.94 (m, 2 H), 2.42 (m, 1 H), 6.81–6.86 (m, 2
H), 7.08–7.16 (m, 5 H), 7.93–7.96 (m, 2 H), 11.13 (s, 1 H).
3
5
37
2
5
1
3
C NMR: d = 36.5, 43.7, 73.4, 113.0, 120.7, 128.2, 128.8, 131.0,
Aziridines 3; General Procedure
1
37.4, 149.7, 172.1.
A solution of N-arylhydroxylamines (1 mmol) and electron-defi-
cient olefin (1 mmol) in toluene (10 mL) containing a suspension of
MS: m/z = 241.10.
1
0% aq NaOH (6 mmol) was stirred at r.t. for 2 h. The progress of
the reaction was monitored by TLC. When no arylhydroxylamine 1
was detected, the reaction mixture was then filtered and the filtrate
was concentrared to dryness. The residue was purified by column
chromatography (hexane–EtOAc, 90:10). Analytical samples were
obtained by crystallization of the residue.
4-(2-Benzenesulfinylaziridine-1-yl)phenol (3f)
Yield: 2.6 g (97%); yellow oil; ee: 82% (77% yield, Chiral HPLC);
2
0
[a]
+20 (c 0.67, CH Cl ).
D
2 2
FT-IR: 1175, 1465, 3100, 3600 cm–1.
1
H NMR: d = 1.91–1.95 (m, 2 H), 2.70–2.74 (m, 1 H), 5.10 (s, 1 H),
6
7
.42–6.49 (m, 4 H), 7.48–7.51 (m, 2 H), 7.30–7.34 (m, 1 H), 7.64–
.66 (m, 2 H).
tert-Butyl-1-phenylaziridine-2-carboxylate (3a)
Yield: 84%; mp 125.5–126.5 °C.
1
3
–
1
C NMR: d = 31.9, 63.4, 114.5, 116.6, 123.5, 129.7, 130.8, 137.1,
46.8, 147.4.
FT-IR: 1178, 1460, 1720, 3100 cm .
1
Synthesis 2005, No. 12, 2022–2028 © Thieme Stuttgart · New York

2
028
E. Murugan, A. Siva
PAPER
MS: m/z = 260.59.
(9) (a) Mccoull, W.; Davis, F. A. Synthesis 2000, 1347.
b) Comprehensive Asymmetric Catalysis; Jacobsen, E. N.;
Pfaltz, A.; Yamamoto, H., Eds.; Springer: Heidelberg,
999. (c) Asymmetric Organic Synthesis; Ojima, I., Ed.;
(
Anal. Calcd for C H NO S: C, 64.78; H, 5.02; N, 5.40. Found: C,
14
13
2
6
4.77; H, 5.02; N, 5.38.
1
VCH: New York, 1993.
10) (a) Ooi, T.; Takeuchi, M.; Kameda, M.; Maruoka, K. J. Am.
Methyl-1-(p-tolyl)aziridine-2-carboxylate (3i)
Yield: 74%; yellow oil.
(
Chem. Soc. 2000, 122, 5228. (b) Ouoka, K. Org. Lett. 2001,
1
H NMR: d = 1.93–1.97 (m, 2 H), 2.35 (s, 3 H), 2.44 (m, 1 H), 3.63
s, 3 H), 6.48–6.50 (m, 2 H), 6.86–8.89 (m, 2 H).
3, 1273. (c) Eddine, E. J.; Cherqaoui, M. Tetrahedron:
(
Asymmetry 1995, 1225.
1
3
(11) (a) Belokon, Y. N.; Kochetkov, K. A.; Churkina, T. D.;
Ikonnikov, N. S.; Chesnokov, A. A.; Larionov, O. V.; Singh,
I.; Parmar, V. S.; Vyskocil, S.; Kagan, H. B. J. Org. Chem.
C NMR: d = 20.9, 29.9, 43.5, 50.2, 113.1, 127.2, 130.3, 141.6,
1
72.4.
MS: m/z = 192.05.
2
000, 65, 7041. (b) Belokon, Y. N.; North, N. Tetrahedron
Anal. Calcd for C H NO : C, 69.09; H, 6.85; N, 7.32. Found: C,
Lett. 2000, 41, 7245. (c) Belokon, Y. N.; Kochetkov, K. A.;
Churkina, T. D.; Ikonnikov, N. S.; Vyskocil, S.; Kagan, H.
B. Tetrahedron: Asymmetry 1999, 1723. (d) Belokon, Y.
N.; North, N.; Churkina, T. D.; Ikonnikov, N. S.; Maleev, V.
I. Tetrahedron 2001, 57, 2491. (e) Tzalis, D.; Knochel, P.
Tetrahedron Lett. 1999, 40, 3685.
11
13
2
6
9.05; H, 6.85; N, 7.30.
tert-Butyl-1-(4-nitrophenyl)aziridine-2-carboxylate (3m)
20
Yield: 90%; [a]D +20 (c 0.86, CH Cl ).
2
2
1
H NMR: d = 1.38 (s, 9 H), 1.89–1.93 (m, 2 H), 2.42–2.50 (m, 1 H),
(
12) Perrad, T.; Plaquevent, J. C.; Desmurs, J. R.; Hebrault, D.
Org. Lett. 2000, 2, 2959.
13) Perisa, M.; Santos, P. P.; Reis Lobo, A. M.; Prabhakar, S. J.
Chem. Soc., Chem. Commun. 1993, 38.
6
.85 (dd, 2 H, J = 4.8 Hz), 8.00–8.11 (dd, J = 4.8 Hz).
1
3
C NMR: d = 28.7, 29.6, 44.1, 73.7, 114.0, 124.5, 137.2, 151.5,
(
1
75.7.
MS: m/z = 265.07.
(14) Selected articles: (a) Jew, S.-S.; Jeong, B.-S.; Yoo, M.-S.;
Huh, H.; Park, H.-g. Chem. Commun. 2001, 1244. (b) Park,
H.-G.; Jeong, B.-S.; Yoo, M.-S.; Huh, H.; Jew, S.-S.
Anal. Calcd for C H N O : C, 59.08; H, 6.10; N, 10.60. Found: C,
1
3
16
2
4
5
9.10; H, 6.08; N, 10.58.
Tetrahedron Lett. 2001, 42, 8775. (c) Park, H.-G.; Jeong,
B.-S.; Yoo, M.-S.; Lee, J.-H.; Lee, Y.; Kim, M.-J.; Jew, S.-
S. Angew. Chem. Int. Ed. 2002, 41, 3036. (d) Park, H.-G.;
Jeong, B.-S.; Yoo, M.-S.; Lee, J.-H.; Kim, M.-G.; Jew, S.-S.
Tetrahedron Lett. 2003, 44, 3497. (e) Arai, S.; Shioiri, T.
Tetrahedron Lett. 1998, 39, 2145. (f) Arai, S.; Ishida, T.;
Shioiri, T. Tetrahedron Lett. 1998, 39, 8299. (g) Arai, S.;
Shirai, T.; Ishida, T.; Shioiri, T. Chem. Commun. 1999, 49.
Acknowledgment
One of the authors (A.S.) thanks Prof. Dr. T. Balakrishnan, Vice-
Chancellor, Periyar University, TN and Prof. P.C. Srinivasan, De-
partment of Organic Chemistry, University of Madras, for their con-
stant support and useful suggestions extended to this work.
(
h) Arai, S.; Ishida, T.; Shioiri, T. Tetrahedron 1999, 55,
6
375. (i) Kanake, S.; Yoshino, T.; Katoh, T.; Terashima, S.
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Synthesis 2005, No. 12, 2022–2028 © Thieme Stuttgart · New York