Copper bis(oxazolines) as catalysts for stereoselective aziridination of styrenes with N-tosyloxycarbamates

Article abstract of DOI:10.1016/j.tet.2012.02.044

A Cu(I)-catalyzed asymmetric aziridination of styrenes with a chiral N-tosyloxycarbamate has been developed. Double stereodifferentiation was observed and both the N-tosyloxycarbamate substituent and the bis(oxazoline) ligand have a significant effect on the yields and diastereoselectivities. The best results for the aziridination were obtained with electron-deficient styrenes. Subsequent ring-opening reactions of styrene-derived aziridines at the benzylic position were observed with various oxygen and nitrogen nucleophiles under Lewis acid catalysis affording the corresponding products with complete inversion of stereochemistry. The strategy was used to synthesize the β-blocker, (R)-nifenalol.

Full text of DOI:10.1016/j.tet.2012.02.044

Tetrahedron 68 (2012) 3396e3409
Contents lists available at SciVerse ScienceDirect
Tetrahedron
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Copper bis(oxazolines) as catalysts for stereoselective aziridination of styrenes
with N-tosyloxycarbamates
*
ꢀ ꢁ
€
ꢀ
Helene Lebel , Michael Parmentier, Olivier Leogane, Karen Ross, Cedric Spitz
ꢀ
ꢀ
ꢀ
Department of Chemistry, Universite de Montreal, PO Box 6128, Station Downtown, Montreal, QC, Canada H3C 3J7
a r t i c l e i n f o
a b s t r a c t
Article history:
A Cu(I)-catalyzed asymmetric aziridination of styrenes with a chiral N-tosyloxycarbamate has been
developed. Double stereodifferentiation was observed and both the N-tosyloxycarbamate substituent
and the bis(oxazoline) ligand have a significant effect on the yields and diastereoselectivities. The best
results for the aziridination were obtained with electron-deficient styrenes. Subsequent ring-opening
reactions of styrene-derived aziridines at the benzylic position were observed with various oxygen
and nitrogen nucleophiles under Lewis acid catalysis affording the corresponding products with com-
Received 9 February 2012
Accepted 16 February 2012
Available online 22 February 2012
Keywords:
Asymmetric catalysis
Bis(oxazolines)
Copper
plete inversion of stereochemistry. The strategy was used to synthesize the b-blocker, (R)-nifenalol.
Ó 2012 Elsevier Ltd. All rights reserved.
Aziridines
Nifenalol
1. Introduction
Many synthetic and semi-synthetic aziridine alkaloids have
anticancer, antibacterial, and/or antimicrobial activity against se-
lected cancer cell lines, pathogenic bacteria, and/or micro-organ-
isms.6 The powerful mutagenic and toxic activities of aziridines are
generally associated with their electrophilic properties to act as
alkylating agents. As a result, aziridines are highly valuable het-
erocyclic compounds in medicinal chemistry and have been in-
Aziridines are one of the smallest nitrogen-containing hetero-
cycles and display important biological activities.1 While other
three-membered rings, such as cyclopropanes and epoxides, are
readily found in natural products, the aziridine moiety is present in
only a few.2 These include the antitumor and antibiotic mitomycin
C,3 as well as the antibacterials madurastatin A14 and azicemicin A5
(Fig. 1).
troduced in
a variety of structures to create novel cancer
chemotherapeutic agents.7 Furthermore, aziridines have been used
as the key structural element to create novel selective inhibitors of
bacterial enzymes, potentially leading to a new class of antibiotics.8
Aziridines are valuable building blocks in organic chemistry due
to their ability to undergo ring-opening reactions with a variety of
nucleophiles.9 Consequently, strategies involving ring-opening re-
actions have been used in process chemistry for the commercial
preparation of pharmaceutical intermediates.10 Aziridines have also
been identified as key intermediates in diversity-oriented synthe-
ses of alkaloids,11 and in the asymmetric total syntheses of
(ꢀ)-renieramycins M and G and (ꢀ)-jorumycin.12 Recently, azir-
idines were reported as masked 1,3-dipoles that react with alkenes,
alkynes, nitriles, and carbonyl compounds to produce various [3þ2]
cycloadducts.13
O
NH2
O
O
O
O
N
NHMe
H2N
H
N
OMe
HO
N
N
NH
O
N
O
HO
H
O
Mitomycin C
N
N
H
NH
OH
O
O
MeO
Madurastatin A1
O
HO
OH
OH
H
In comparison with the number of methods that have been
reported to perform epoxidation reactions, synthetic approaches to
prepare aziridines remain limited particularly in the enantiose-
lective manifold.1,2,14 The methods can be divided into three clas-
ses: 1. intramolecular substitutions; 2. addition to imines; and 3.
aziridination of alkenes (Scheme 1). Intramolecular substitutions
via the cyclization of 1,2-aminoalcohols were historically the first
MeO
Azicemicin A
OH OH
O
Fig. 1. Aziridine natural products.
* Corresponding author. E-mail address: helene.lebel@umontreal.ca (H. Lebel).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.02.044

H. Lebel et al. / Tetrahedron 68 (2012) 3396e3409
3397
method reported for the synthesis of aziridines.15 Since then, novel
precursors have been exploited and many are available as single
stereoisomers.16 The approach remains attractive despite the
lengthy synthetic sequence.
A few years ago, our group introduced N-tosyloxycarbamates as
alternative metal nitrene precursors to perform CeH amination and
aziridination reactions.40 The ease of preparation and the stability
of N-tosyloxycarbamates, as well as the mild reaction conditions
are among the advantages of the method.41 Both copper and rho-
dium complexes catalyzed the aziridination of styrene derivatives
with N-tosyloxycarbamates. We observed that good stereocontrol
could be obtained for the reaction using more sterically hindered or
chiral N-tosyloxycarbamates in the presence of chiral metal com-
plexes.42 Herein, we report the complete details of our studies and
the use of a chiral bis(oxazoline) copper complex with a chiral N-
tosyloxycarbamate to produce enantioenriched aziridines with
high selectivities. Furthermore, one of the aziridines was used as
R3
R1
R3
N
R3
NH
R2
N
LG
R1
R1
R2
R1
R2
a chiral building block to synthesize the b
-blocker, (R)-nifenalol.43
Scheme 1. Synthetic methods to aziridines.
2. Results and discussion
Another approach to synthesize aziridines involves an initial
addition to an imine, followed by a cyclization reaction. For ex-
2.1. Copper-catalyzed enantioselective aziridination
ample, the addition of stabilized anions bearing
a
-leaving groups to
We began our studies by examining the aziridination of 4-
nitrostyrene with TrocNHOTs using catalytic amounts of
Cu(MeCN)4PF6 and a variety of chiral ligands 2, in the presence of
potassium carbonate and molecular sieves in acetonitrile (Table 1).
The carbamate TrocNHOTs was initially selected, as it was pre-
viously shown to display good reactivity in aziridination reactions
with achiral catalysts.40b Indenyl-substituted ligand 2a44 initially
provided the best result in terms of yield (85%) although the en-
antiomeric ratio (73:27) was modest (entry 1). When the reaction
was performed at 0 ꢁC, the enantiomeric ratio was slightly in-
creased, but the yield dropped quite significantly (entry 2). The less
rigid phenyl-substituted ligand 2b45 resulted in similar yield and
enantioselectivity, whereas a more sterically hindered aryl sub-
stituent (2c)46 afforded essentially no product (entries 3 and 4).
Bis(oxazolines) with bulky alkyl groups (2d and 2e)47 resulted in
enantiomeric ratios similar to those obtained with 2b (entries 5 and
6 vs entry 3). The bridging substituents of the ligand were then
modified to examine the effect of the metaleligand chelation angle
(entries 7 and 8). Small substituents or a cyclopropane ring increase
the N]CeCeC]N angle and the bite angle of the ligand. The effect
seems deleterious in the aziridination reaction as shown with li-
gands 2f and 2g,48 which both afforded lower enantioselectivities.
Conversely, substitutions at other positions of the ligand improved
the reaction. When a gem-dimethyl substituent was added at the
alpha position relative to oxygen (ligand 2h),49 higher yield and
enantioselectivity were observed (entry 9).
As ligand 2h was identified as the most promising ligand, it was
tested with other N-tosyloxycarbamates (Table 2). N-Tosylox-
ycarbamates were designed to bear a side chain that could not
undergo intramolecular reaction with the in situ generated metal
nitrene. Furthermore, electron-deficient side chains were chosen,
as they favored metal nitrenes reactive toward both aziridination
and CeH insertion versus decomposition reactions.50 The aromatic
N-tosyloxycarbamates, in particular the most electron poor reagent
1c, was the most reactive of the series, although overall poor yields
and selectivities were obtained (entries 1e3). Chloro-substituted
alkyl N-tosyloxycarbamates were then examined and the best re-
sults were obtained with trichloroethyl-substituted reagents (en-
tries 4e8). Whereas the best yields were obtained with TrocNHOTs
(1e), the best enantioselectivities were observed with the gem-di-
methyl analog 1f, illustrating that a more sterically hindered re-
agent provided better stereochemical discrimination (entries 5 and
6). The enantioselectivities did not change during the course of the
reaction, as the same enantiomeric ratio was measured at partial
conversion (34%) (entry 7). The yield with 1f was only slightly in-
creased when using 10 mol % of catalyst (entry 8). Other variables
were examined, including additives and solvents, but none of them
imines is known as the aza-Darzens reaction.17 Stoichiometric
chiral substrates or reagents have been successfully used to per-
form such a reaction with high levels of stereoselectivity.18 A cat-
alytic version of the methodology using chiral sulfoniums was
described by Aggarwal.19,20 Wulff has recently reported the addi-
tion of diazocarbonyl compounds to imines catalyzed by the chiral
boron Lewis acids VANOL and VAPOL, that proceeded in excellent
yields and enantioselectivities.21,22
The previously described approaches to aziridines involve the
use of nitrogen-containing substrates and the formation of a single
CeN bond to construct the three-membered ring. The aziridination
of alkenes is a more efficient chemical transformation in that it
leads to the formation of two new CeN bonds. Electron-deficient
alkenes have been used in aza-Michael-initiated-ring-closing re-
actions with N-alkoxycarbamates.23 Among them, successful
organocatalytic enantioselective aziridinations of conjugated al-
dehydes and enones have been reported.22d,24 Nitrene transfer by
means of transition metal complexes is possible with unactivated
alkenes using iminoiodinane reagents.25 The seminal work of
Jacobsen26 and Evans27 reported that chiral salen- and
bis(oxazoline)ecopper complexes, respectively, could be used to
induce stereocontrol in the presence of PhI¼NTs or PhI¼NNs as
nitrene precursors. Other chiral diimine ligands were studied and
produced aziridines in high yields and enantioselectivities, notably
as shown by Ding28 for cinnamate derivatives and Xu29 for chalcone
derivatives.30 Other transition metal complexes were reported for
nitrene transfer to alkenes using iminoiodinanes, although with
less efficiency.31 To extend the scope of the reaction and to avoid
the tedious isolation of the iminoiodinane reagent, novel in situ
procedures in which the amine is oxidized with a hypervalent io-
dine reagent have emerged.32 Less than a handful of asymmetric
catalysts derived from copper28,33 and rhodium34 have been de-
vised to perform aziridination reactions under these reaction con-
ditions, with limited substrate scope and selectivities. Conversely
highly efficient enantioselective aziridinations using azides as
nitrene precursors have recently been reported.35,36 Notably the
chiral ruthenium catalyst developed by Katsuki35 and the chiral
porphyrin cobalt complex developed by Zhang36 provided excellent
results. However, the lengthy synthesis of the chiral ligands asso-
ciated with these catalytic systems remains a significant drawback
to the method. Another limitation associated with the method is
the production of notoriously stable N-sulfonyl aziridines.37 Al-
though alternative sulfonyl groups have been introduced, cleavage
of the N-sulfonyl aziridines has not always been reported38 or
proceeded in moderate yields and with the use of excess of ex-
pensive reagents.39

3398
H. Lebel et al. / Tetrahedron 68 (2012) 3396e3409
Table 1
Table 2
Screening of bis(oxazoline) ligands 2 in the copper-catalyzed aziridination of 4-
Copper-catalyzed enantioselective aziridination of 4-nitrostyrene with various N-
nitrostyrene with TrocNHOTs (1e)a
tosyloxycarbamatesa
NTroc
3e
2 (6 mol %)
Cu(CH3CN)4PF6 (5 mol %)
O
O
O
N
N
TrocNHOTs (1e), K2CO3
CH3CN, MS 4Å, 23 °C
O2N
O2N
2h
Ph
R
N
O
(6 mol %)
Ph
O
Cu(CH3CN)4PF6 (5 mol %)
R
OTs
O
N
H
4-Nitrostyrene, K2CO3
CH3CN, MS 4Å, 23 °C
Entry
Ligand
Yieldb (%)
Enantiomeric ratioc
3
O2N
1
Entry
1
N-tosyloxycarbamate
Yieldb (%)
Enantiomeric ratioc
57:43
1
2
3
85
73:27
76:24d
75:25
O
O
O
O
N
N
O
2a
56d
65
O
NHOTs
NHOTs
17
31
1a
F
O
N
N
N
N
F
F
2b
O
Ph
Ph
O
2
3
4
58:42
60:40
80:20
F
F
1b
O
F
F
4
<10
nd
MeO
OMe
O
2c
F
F
O
NHOTs
46
16
1c
F
O
O
5
6
7
62
72:28
73:27d
58:42
Cl
N
N
O
2d
t-Bu
t-Bu
Cl
O
NHOTs
1d
O
O
w10d
O
N
N
N
N
Cl
Cl
5
82
86:14
2e
O
O
NHOTs
NHOTs
i-Pr
i-Pr
1e
Cl
O
O
54
6
52
93:7
2f
O
Cl
Cl
7
8
1f
34d
60e
93:7d
93:7e
Cl
O
O
ndc
69:31c
N
N
N
N
8
2g
9
81
86:14
91:9f
O
F
F
O
NHOTs
NHOTs
O
O
44f
9
82e
15:85e
1g
F
10
2h
Ph
Ph
a
b
c
4-Nitrostyrene (3 equiv), K2CO3 (1.5 equiv).
Isolated yield.
Ratio S/R determined by HPLC on chiral stationary phase.
O
Et Et
11
Decomp.g
d
F
F
O
d
e
1h
The reaction was performed at 0 ꢁC.
F
The antipode of the product shown (3e) was obtained.
a
4-Nitrostyrene (3 equiv), K2CO3 (1.5 equiv).
Isolated yield.
Ratio R/S, determined by HPLC on chiral stationary phase.
Reaction was stopped at partial conversion after 3 h.
Using 10 mol % of Cu(CH3CN)4PF6 and 11 mol % of 2a.
Reaction was run at 0 ꢁC.
b
c
d
e
f
proved advantageous. Trifluoro-substituted reagent 1g was then
prepared, with the hope that such a reagent would provide better
yields, while keeping the same level of enantioselectivity (entries 9
and 10). Although the yield was better, the enantiomeric ratio was
decreased compared to 1f (entry 9). The ratio could be increased by
performing the reaction at 0 ꢁC, but to the detriment of the yield
(entry 10). When a more sterically hindered carbamate reagent was
used (1h), only decomposition of the N-tosyloxycarbamate reagent
was observed.
Furthermore, a series of cyclic N-tosyloxycarbamates were
prepared (Fig. 2), but were found to be unstable under the azir-
idination reaction conditions.
Having identified N-tosyloxycarbamate reagent 1f as the opti-
mal reagent, it was tested in the aziridination reaction with another
substrate, 2-chlorostyrene (Table 3). As observed for the aziridi-
nation of 4-nitrostyrene, bis(oxazoline) 2h49 possessing a gem-di-
methyl substituent at the alpha position relative to oxygen proved
to be superior to the unsubstituted ligand 2b (entries 1 and 2).
g
Decomposition of the N-tosyloxycarbamate reagent was observed.
However, the enantiomeric ratio dropped quite significantly for the
aziridination of 2-chlorostyrene compared to 4-nitrostyrene (Table
2, entry 6 vs Table 3, entry 2). Other ligands 2 possessing different
bridging substituents were then synthesized and tested in the
aziridination of 2-chlorostyrene with reagent 1f. Unfortunately, the
use of ligands with both a more hindered substituent (ligand 2i)
and a cyclic substituent (ligand 2j), which, respectively, decreases
n
O
X
O
NHOTs
X
X
n = 1 or 2
X = F or Cl
Fig. 2. Cyclic N-tosyloxycarbamates.

H. Lebel et al. / Tetrahedron 68 (2012) 3396e3409
3399
Table 3
The stereoselective aziridination of 4-nitrostyrene was per-
formed under the best reaction conditions found previously (see
Table 3) with both enantiomers of chiral N-tosyloxycarbamate re-
agent 1i (Scheme 3). In contrast to what was observed in rhodium-
catalyzed aziridination reactions, the chiral catalyst (as opposed to
the chiral N-tosyloxycarbamate reagent) dictated the facial selec-
tivity. Furthermore, both enantiomers of chiral N-tosylox-
ycarbamate reagent 1i reacted at roughly the same rate to produce
aziridine 3i in similar yields. However, a match and mismatch pair
effect was still observed as enantiomer (S)-1i led to higher enan-
tioselectivities and produced aziridine (R,S)-3i with 97:3
diastereoselectivity.
Screening of bis(oxazoline) ligands 2 in the copper-catalyzed aziridination of 2-
chlorostyrene with dimethyl-TrocNHOTs (1f)a
O
O
Cl
Cl
O
NHOTs
Cl
Cl
N
O
1f
Cl
Cl
4f
2 (6 mol %)
Cu(CH3CN)4PF6 (5 mol %)
K2CO3 / CH3CN, MS 4Å, 23 °C
Cl
Cl
Entry
1
Ligand
Yieldb (%)
Enantiomeric ratioc
67:33
O
N
O
37
71
48
N
N
2b
Ph
Ph
Ph
O
O
Ph
CCl3
O
N
O
2
3
22:78d
78:22
Cl3C
O
NHOTs
N
O
(R)-1i (98% ee)
2h
Ph
Ph
(R,R)-3i
84%, 87.5:12.5 (anti:syn)
Et Et
O
O
O2N
O
O
N
N
N
N
N
2i
2h
Ph
Ph
Ph
Ph
(6 mol %)
O2N
(3 equiv)
Cu(CH3CN)4PF6, (5 mol %)
K2CO3 (1.5 equiv), MS 4Å
CH3CN, 23 °C
O
Ph
CCl3
O
O
4
53
79:21
N
N
O
2j
Ph
Ph
(R,S)-3i
85%, 97:3 (syn:anti)
a
2-Chlorostyrene (3 equiv), K2CO3 (1.5 equiv).
Isolated yield.
Ratio S/R determined by HPLC on chiral stationary phase.
The antipode of the product shown (4f) was obtained.
Ph
O
O2N
b
c
Cl3C
O
NHOTs
d
(S)-1i (98% ee)
Scheme 3. Double stereodifferentiation with N-tosyloxycarbamate 1i.
or increases the bite angle, did not affect the enantioselectivity of
the reaction. Although good results were obtained for the enan-
tioselective aziridination of 4-nitrostyrene, the problematic enan-
tioselective aziridination of 2-chlorostyrene suggested that the
scope of the reaction would be limited. We then decided to in-
vestigate chiral N-tosyloxycarbamate reagents to perform diaster-
eoselective aziridination reactions.
We then tested the same reaction conditions with 2-
chlorostyrene and chiral N-tosyloxycarbamate reagent 1i
(Table 4, entry 3). The desired aziridine was produced in good
yield and stereoselectivity, although the diastereomeric ratio
was somewhat lower to what was obtained with 4-nitrostyrene.
To insure we had the optimal catalyst system, we then in-
vestigated other bis(oxazoline) ligands 2. As previously ob-
served, the phenyl substituted ligand 2h proved to be better
than the more rigid bis(oxazoline) ligand 2a derived from an
aminoindanol (entry 1 vs 3). Furthermore having a gem-di-
methyl substituent at the alpha position relative to oxygen was
also beneficial, as ligand 2b provided a lower diastereomeric
ratio than ligand 2h. The bridging substituents of the ligand
were then examined, but did not lead to any significant im-
provement (entries 4e8). Whereas larger substituents (ligand
2i) produced the same ratio (entry 4 vs 3), smaller substituents
(ligands 2j, 2k, and 2m) or no substituent (ligand 2l51), which
increases the ligand bite angle, proved to be deleterious for the
stereoselectivity (entries 5e8).
2.2. Copper-catalyzed diastereoselective aziridination
We have recently reported a stereoselective rhodium-catalyzed
amination of alkenes using readily available chiral N-tosylox-
ycarbamate reagent 1i.42b Excellent yields and diaster-
eoselectivities were obtained for a large variety of diversely
substituted styrene derivatives with the exception of mono 3-
substituted styrenes. For example, >90:10 diastereoselectivity
was obtained with 2- and 4-bromostyrene, whereas 3-
bromostyrene led to a 73:26 dr (Scheme 2). In addition, it is nec-
essary to use 5 mol % of expensive rhodium dimer catalyst (thus
a total of 10 mol % of rhodium). These limitations prompted us to
examine the reaction using a cheaper option such as copper cata-
lysts and bis(oxazoline) ligands 2.
The copper-catalyzed diastereoselective aziridination with
chiral N-tosyloxycarbamate 1i and ligand 2h was then conducted
with a variety of styrene derivatives (Table 5). Aziridines were
produced from nitro-substituted styrenes in moderate to good
yields and excellent diastereomeric ratios (entries 1 and 2).
Slightly lower diastereomeric ratios were observed with 3- and 4-
halo substituted styrenes (entries 3e6), whereas aziridine 11i
derived from 2-bromostyrene was obtained in excellent diaster-
eoselectivity (entry 7). In contrast to what was observed in
rhodium-catalyzed aziridination reactions, meta-substituted sty-
O
Ph
CCl3
Ph
O
N
O
Cl3C
O
(R)-1i
NHOTs
Rh2[(S)-Br-nttl]4 (5 mol %)
K2CO3 aq (1.5 equiv)
PhCF3 (0.25 M), 23 °C
Br
Br
4-Br (9i) = 77% y., 92:8
3-Br (10i) = 66% y., 74:26
2-Br (11i) = 78% y., 97:3
Scheme 2. Rhodium-catalyzed aziridination of styrenes using N-tosyloxycarbamate
1i.42b
renes
were
not
problematic
substrates
with
the

3400
H. Lebel et al. / Tetrahedron 68 (2012) 3396e3409
Table 4
Table 5
Screening of bis(oxazoline) ligands 2 in the copper-catalyzed aziridination of 2-
Scope of the copper-catalyzed diastereoselective aziridination with chiral N-tosy-
chlorostyrene with PheTrocNHOTs (R)-1ia
loxycarbamate 1ia
O
Ph
CCl3
Ph
O
(R)-1i
Ph
O
O
Ph
CCl3
N
O
Cl3C
O
O
NHOTs
Cl3C
O
(R)-1i
NHOTs
N
O
5i - 13i
R
O
4i
2 (6 mol %)
Cu(CH3CN)4PF6 (5 mol %)
Cl
Cl
R
N
N
K2CO3 / CH3CN, MS 4Å, 23 °C
Ph
Ph
2h (6 mol %)
Cu(CH3CN)4PF6 (5 mol %)
K2CO3 / CH3CN, MS 4Å, 23 °C
Entry
1
Ligand
Yieldb (%)
81
Diastereomeric ratioc
75:25
O
O
O
Entry Styrene
Aziridine
Yieldb (%) Diastereomeric ratioc
N
N
2a
O
Ph
CCl
O N
N
O
O
5i
1
84
50
89:11
93:7
O N
O
2
3
4
85
76
76
80:20
92:8
N
N
N
N
Ph
2b
Ph
Ph
N
O
CCl
2
NO
6i
O
O
NO
O
Ph
CCl
2h
Ph
Ph
N
O
3
70
81:19
Et Et
Cl
O
O
7i
Cl
Cl
92:8
N
N
N
2i
Ph
Ph
O
O
Ph
Cl
N
N
O
CCl
4
47
80
84:16
81:19
O
O
5
74
88:11
8i
N
2k
Ph
Ph
Ph
O
CCl
5
Br
9i
O
O
Br
Br
6
7
66
69
76
81:9
80:20
81:9
N
N
N
N
2j
O
Ph
CCl
Ph
Ph
Br
N
O
O
6
71
73
81:19
89:11
O
O
10i
2l
Ph
Ph
Ph
N
O
CCl
7
Br
11i
O
O
Br
8
N
N
2m
O
Ph
CCl
Ph
Ph
NC
N
O
8
44
82:18
NC
a
2-Chlorostyrene (3 equiv), K2CO3 (1.5 equiv).
Isolated yield.
b
c
12i
Ratio SR/RR (syn/anti) determined by 1H NMR on the crude mixture.
a
Styrene (3 equiv); K2CO3 (1.5 equiv).
Isolated yield.
b
c
Ratio SR:RR (syn:anti), determined by 1H NMR on the crude mixture.
copperebis(oxazoline) system. Overall the diastereomeric ratios
for the copper-catalyzed aziridination of 3- and 4-halo substituted
styrenes were similar (entries 3,4 and 5,6). Whereas the rhodium-
catalyzed aziridination of 3-nitro- and 3-bromostyrene proceeded
in 80:20 and 74:26 diastereomeric ratio (Scheme 2),52 aziridines 5i
and 10i were produced in 89:11 and 82:18 diastereomeric ratio,
respectively, using the copperebis(oxazoline) 2h catalytic system
(entries 1 and 6). Furthermore, the copper catalyst was compatible
with a nitrile functional group (which inhibits rhodium dimer
catalysts) and aziridine 12i was isolated in moderate yield, but
good diastereoselectivity (entry 8).
An advantage of the N-tosyloxycarbamate reagents is the
facile cleavage in the resulting aziridines under mild basic re-
action conditions.42b As such, both the chiral aziridine and al-
cohol were recovered in excellent yields and enantioselectivities
(Scheme 4).
LiOH•H2O
(5 equiv)
O
Ph
Ph
NH
N
O
CCl3 H2O (10 equiv)
+
HO
CCl3
97% y.
>99:1
CH3CN
MeOH, 23 °C
92% y.
99:1
O2N
O2N
99:1 (syn:anti)
Scheme 4. Cleavage of the protecting group and recovery of the chiral alcohol.
It is also possible to perform ring-opening reactions of aziridine
3i with a variety of nucleophiles using a catalytic amount of a Lewis
acid, BF3$OEt2 (Table 6).9 In all cases, the nucleophilic attack oc-
curred at the activated benzylic position and the reaction typically
proceeded with complete inversion of stereochemistry. When an
alcohol or water was used as nucleophile, the corresponding amino
ether or alcohol was recovered in excellent yields and

H. Lebel et al. / Tetrahedron 68 (2012) 3396e3409
3401
Table 6
produce 16 in excellent yield and diastereomeric ratio (entry 1).
Conversely, partial isomerization was observed with halo-
substituted aziridines, indicating that the formation of the ben-
zylic carbocation was competitive (entries 2 and 3). Aminoalcohols
17 and 18 were recovered in excellent yields, but with moderate
diastereomeric ratios. Neither changing the Lewis acid nor the re-
action conditions improved the stereochemical outcome of the
reaction with these substrates.
Ring-opening reactions of aziridines 3i with various nucleophiles
O
Ph
CCl3
Nuc
H
N
Nucleophile
O
CCl3
Ph
N
O
BF3•(OEt)2
(10 mol %)
O
O2N
14a-e
(S,R)-3i (>95:5)
O2N
Entry Conditions
Product
Yielda (%);
diastereomeric
ratiob
3. Conclusions
OMe
H
N
In summary, the aziridination of styrenes with a chiral N-tosy-
loxycarbamate and a chiral copper complex afforded carbamate-
protected aziridines in good yields with good to excellent diaster-
eoselectivities. The selectivity of the system is complementary to
the previously reported system using a chiral rhodium catalyst, as
good results were obtained with meta-substituted styrene sub-
strates. Excellent results were produced for the aziridination of
nitro-substituted styrenes. Ring-opening reactions were performed
with these aziridines to produce a variety of chiral derivatives
typically with complete stereochemical inversion. One of these
intermediates was converted in a few steps into (R)-(ꢀ)-nifenalol.
O
O
CCl
1
2
MeOH (0.1 M), rt, 1 h
93; >95:5
93; >95:5c
14a
O
O
Ph
O N
O N
OH
H
N
H2O/MeCN 1:1 (0.1 M),
rt, 1 h
CCl
14b
Ph
Ph
OAc
H
N
AcOH (3 equiv), DCM
(0.1 M), rt, 1 h
O
O
CCl
3
4
78; 89:11
14c
O
O
O N
4. Experimental section
4.1. General details
PhHN
H
N
PhNH2 (6 equiv),d MeCN
(0.1 M), rt, 24 h
CCl
87; >95:5c
14d
Ph
O N
a
b
c
Isolated yield.
All non-aqueous reactions were run under an inert atmosphere
(argon) with rigid exclusion of moisture from reagents and glass-
ware using standard techniques for manipulating air-sensitive
compounds. All glassware was stored in the oven and/or was
flame dried prior to use under an inert atmosphere of gas. Anhy-
drous solvents were obtained either by filtration through drying
columns (CH2Cl2, CH3CN, methanol) on a GlassContour system
(Irvine, CA) or by distillation over calcium hydride (ethanol). Ana-
lytical thin-layer chromatography (TLC) was performed on pre-
coated, glass-backed silica gel (Merck 60 F254). Visualization of the
developed chromatogram was performed by UV absorbance,
aqueous cerium molybdate, ethanolic phosphomolybdic acid, io-
dine or aqueous potassium permanganate. Flash column chroma-
tography was performed using 230e400 mesh silica (Silicycle) of
the indicated solvent system according to standard technique.
Melting points were obtained on a Buchi melting point apparatus
and are uncorrected. Infrared spectra were recorded on a Perkin
Elmer Spectrum One FTIR spectrometer equipped with a Golden
Gate Diamond ATR and are reported in reciprocal centimeters
(cmꢀ1). Nuclear magnetic resonance spectra were recorded either
on a Bruker AV-700, Bruker AV-400, a Bruker ARX-400, a Bruker
AMX-300 or a Bruker AV-300 spectrometer (700, 400, 400, 300 or
300 MHz, respectively). Chemical shifts for 1H NMR spectra are
recorded in parts per million from tetramethylsilane with the sol-
Ratio RR/SR, determined by HPLC on chiral stationary phase.
One diastereomer by 1H NMR.
d
BF3$(OEt)2 of 20 mol % was used.
diastereomeric ratios (entries 1 and 2). When acetic acid was used,
the desired product was produced in good yields, although with
some erosion of the diastereoselectivity (entry 3). In the latter case,
it is believed that a carbocation pathway (i.e., SN1) is probably
competitive with the predominant SN2 reaction, due to the in-
creased acidity of the reaction mixture. Conversely, using aniline as
a nucleophile led to the ring-opened product in an excellent yield
and conservation of the diastereomeric ratio (entry 4). Ring
opened-product 14b, resulting from the attack of water to aziridine
3i is an advanced chiral building block to access (R)-(ꢀ)-nifenalol,
an important b
-adrenergic receptor blocking drug.43,53 Cleavage of
the chiral alcohol using lithium hydroxide produced the corre-
sponding oxazolidinone, which was then hydrolyzed using stron-
ger basic reaction conditions to lead to aminoalcohol 15 (Scheme
5). Reductive amination using sodium cyanoborohydride in ace-
tone smoothly produced the desired (R)-(ꢀ)-nifenalol in 61% yield.
1. LiOH•H2O (5 equiv)
OH
H2O (10 equiv)
OH
H
N
NH2
CH3CN, MeOH
O
CCl3
vent resonance as the internal standard (chloroform,
d
¼7.27 ppm).
2. NaOH / CH3CN
52%
Chemical shifts for 13C NMR spectra are recorded in parts per mil-
lion from tetramethylsilane using the central peak of deutero-
15
O2N
NaBH3CN
14b
O
Ph
O2N
chloroform (d 77.00 ppm) as the internal standard. All spectra were
obtained with complete proton decoupling. Chemical shifts for 19F
NMR spectra are recorded in parts per million from trichloro-
Acetone
61%
OH
H
N
fluoromethane using the resonance of
a,a,a-trifluorotoluene (d
O2N
ꢀ63.7 ppm) as standard. Optical rotations were determined with
(R)-(-)-Nifenalol
a PerkineElmer 341 polarimeter at 589 or 546 nm. Data are
Scheme 5. Total synthesis of (R)-(ꢀ)-nifenalol.
reported as follows: [
a]temp, concentration (c in g/100 mL), and
solvent. High resolution mass spectra were performed by the
ꢀ
ꢀ
Other aziridines were tested in the ring-opening reactions with
water under the same reaction conditions described previously
(Table 7). Nucleophilic addition to nitro-substituted aziridine 5i
proceeded well with complete inversion of configuration to
Centre regional de spectroscopie de masse de l’Universite de
ꢀ
Montreal. High performance liquid chromatography (HPLC) anal-
yses were performed on a Hewlett Packard 1100 Series quaternary
gradient pump with diode-array detector interfaced with HP

3402
H. Lebel et al. / Tetrahedron 68 (2012) 3396e3409
Table 7
Ring-opening reactions of aziridines with water
O
Ph
CCl3
BF3•(OEt)2
(3 mol %)
OH
H
N
O
CCl3
Ph
N
O
H2O:MeCN, 1:1
(0.1M), rt, 1h
O
R
R
Entry
1
Aziridine
Product
Yielda (%); diastereomeric ratiob
87; 88:12
O
Ph
OH
H
N
N
O
CCl
O N
O
CCl
O N
5i
(88:12)
16
O
Ph
O
Ph
OH
H
N
O
CCl
N
O
CCl
Ph
2
84; 72:28
88; 87:13
7i
17
O
O
Cl
(80:20)
Cl
O
Ph
OH
18
H
N
N
O
CCl
CCl
3
11i
O
Ph
Br
(91:9)
Br
a
Isolated yield.
b
Ratio RR/SR, determined by HPLC on chiral stationary phase.
Chemstation software. Values for enantiomeric excess were de-
termined using a chiral column. Data are reported as follows: col-
umn type, flow, solvent used, and retention time (tR). Analytical
supercritical fluid chromatography (SFC) were performed at Labo-
solvent was removed under reduced. The desired N-tosylox-
ycarbamate 1b (2.78 g, 72% yield) was obtained as a white solid
after flash chromatography (20% EtOAc/hexanes). Rf 0.22 (20%
EtOAc/hexanes); mp 61e62 ꢁC; 1H NMR (400 MHz, CDCl3)
d
8.13 (s,
1H), 7.83 (d, J¼8.4 Hz, 2H), 7.33 (d, J¼8.1 Hz, 2H), 6.91e6.80 (m, 1H),
5.07 (s, 3H), 2.45 (s, 3H); 19F NMR (282 MHz, CDCl3)
ꢀ
ꢀ
ratoire d’Analyse et de Separation Chirale par SFC de l’Universite de
ꢀ
Montreal. Data are reported as follows: column type, eluent, flow
d
ꢀ139.64 to
rate, and retention time (tR).
ꢀ139.84 (m, 1F), ꢀ143.71 to ꢀ143.90 (m, 1F), ꢀ155.37 to ꢀ155.58
(m,1F), ꢀ156.11 to ꢀ156.30 (m,1F); IR (neat) 3200, 2948,1774,1743,
1525, 1490, 1384, 1363, 1228, 1194, 1181, 1120, 1084, 983, 936, 859,
817, 691 cmꢀ1; HMRS (ESIþ) calcd for C15H11NO5F4SNa [MþNa]þ:
416.01863; found: 416.01817.
Unless otherwise stated, commercial reagents were used with-
out purification. K2CO3 was purchased from Aldrich Chemical
Company and finely powdered before use. Cu(MeCN)4PF6 was
purchased from Aldrich Chemical Company and stored in a glove
box under an argon atmosphere at room temperature. BF3$(OEt2)
was purchased from Aldrich Chemical Company and used without
purification. Molecular sieves were dried under reduced pressure at
120 ꢁC for 16 h and stored in dessicator. 1,1,1-Trichloro-2-
methylpropan-2-ol54 and N-tosyloxycarbamates 1a50, 1e,50 and
1i42b were prepared according to known published procedures.
4.2.2. Pentafluorobenzyl N-tosyloxycarbamate (1c). To a solution of
1,10-carbonyldiimidazole (1.78 g, 11.0 mmol) in MeCN (50 mL) was
added pentafluorobenzyl alcohol (1.99 g, 10.0 mmol). The resulting
mixture was stirred at room temperature for 1 h. Hydroxylamine
hydrochloride (2.78 g, 40.0 mmol) was then added followed by
imidazole (2.04 g, 30.0 mmol) and the resulting mixture was stirred
for 4 h. The suspension was concentrated under reduced pressure.
The white residue was dissolved in a 1:1 mixture of ethyl acetate
and HClaq 10% (50 mL). The layers were separated and the aqueous
layer was extracted with ethyl acetate (2ꢂ50 mL). The combined
organic layers were washed with brine (50 mL) and dried over
MgSO4. The solvent was removed under reduced pressure and the
resulting N-hydroxycarbamate used without further purification.
4.2. Preparation of N-tosyloxycarbamates 1b, 1c, 1d, 1f, and 1g
4.2.1. 1,2,3,4-Tetrafluorobenzyl N-tosyloxycarbamate (1b). To a solu-
tion of 1,10-carbonyldiimidazole (1.72 g, 10.6 mmol) in MeCN
(50 mL) was added 1,2,3,4-tetrafluorobenzyl alcohol (1.74 g,
9.68 mmol). The resulting mixture was stirred at room temperature
for 3 h. Hydroxylamine hydrochloride (2.70 g, 39.7 mmol) was then
added followed by imidazole (1.98 g, 29.0 mmol) and the resulting
mixture was stirred for 16 h. The suspension was concentrated
under reduced pressure. The white residue was dissolved in a 1:1
mixture of ethyl acetate and HClaq 10% (50 mL). The layers were
separated and the aqueous layer was extracted with ethyl acetate
(2ꢂ50 mL). The combined organic layers were washed with brine
(50 mL) and dried over MgSO4. The solvent was removed under
reduced pressure and the resulting N-hydroxycarbamate used
without further purification. To a solution of N-hydroxycarbamate
(2.28 g, 9.55 mmol) in ether (90 mL) at 0 ꢁC was added tosyl chlo-
ride (1.91 g, 10.0 mmol). Triethylamine (1.39 mL, 10.0 mmol) was
then slowly added to the solution. The resulting white suspension
was stirred at room temperature for 2 h. Water (25 mL) was added
to the solution and the two layers were separated. The aqueous
layer was washed with ether (2ꢂ20 mL). The combined organic
layers were washed with brine (20 mL), dried over MgSO4, and the
To
a solution of N-hydroxycarbamate (w10 mmol) in ether
(100 mL) at 0 ꢁC was added tosyl chloride (2.09 g, 11.0 mmol).
Triethylamine (1.53 mL, 11.0 mmol) was then slowly added to the
solution. The resulting white suspension was stirred at room
temperature for 2 h. Water (25 mL) was added to the solution and
the two layers were separated. The aqueous layer was washed with
ether (2ꢂ20 mL). The combined organic layers were washed with
brine (20 mL), dried over MgSO4, and the solvent was removed
under reduced pressure. The desired N-tosyloxycarbamate 1c
(1.88 g, 46% yield) was obtained as a white solid after re-
crystallization from a 1:1 mixture of hexanes and chloroform. Rf
0.38 (30% EtOAc/hexanes); mp 96e97 ꢁC; 1H NMR (400 MHz,
CDCl3)
d
7.89 (s, 1H), 7.83 (d, J¼8.4 Hz, 2H), 7.33 (d, J¼8.0 Hz, 2H),
5.13 (t, J¼1.4 Hz, 2H), 2.46 (s, 3H, CH3); 13C NMR (175 MHz, CDCl3)
d
154.5, 146.49e144.74 (m, 1C), 143.01e141.23 (m, 1C),
138.33e136.59 (m, 1C), 129.9, 129.7, 129.5, 108.39e108.11 (m, 1C),

H. Lebel et al. / Tetrahedron 68 (2012) 3396e3409
3403
55.2, 21.7; 19F NMR (282 MHz, CDCl3)
d
ꢀ142.68 (dd, J¼23.1, 7.9 Hz,
ethyloxycarbonyl)-imidazolium tosylate (2.21 g, 5.00 mmol) was
then added to the mixture and the resulting mixture was stirred at
60 ꢁC for 2 h. After cooling to room temperature, Et2O (50 mL) was
added to precipitate the salts, which were filtered off. The solvent of
the filtrate was then removed under reduced pressure to afford the
corresponding N-benzyloxycarbamate. N-Benzyloxycarbamate
(w5 mmol) was dissolved in MeOH (20 mL) and DCM (10 mL). Pd/C
10 wt % (160 mg) was added to the solution. The resulting mixture
was stirred under a hydrogen atmosphere (balloon) for 16 h. The
mixture was filtered through a Celite pad and the solvent was re-
moved under reduced pressure to afford the corresponding N-
hydroxycarbamate, which was used without further purification. To
a solution of N-hydroxycarbamate (w5.00 mmol) in ether (50 mL)
at 0 ꢁC was added tosyl chloride (1.04 g, 5.50 mmol). Triethylamine
(0.77 mL, 5.50 mmol) was then slowly added to the solution. The
resulting white suspension was stirred at room temperature for 2 h.
Water (25 mL) was added to the solution and the two layers were
separated. The aqueous layer was washed with ether (2ꢂ20 mL).
The combined organic layers were washed with brine (20 mL),
dried over MgSO4, and the solvent was removed under reduced
pressure. The desired N-tosyloxycarbamate 1f was obtained as
a white solid (1.28 g, 66% yield) after flash chromatography (15%
EtOAc/hexanes). Rf 0.37 (20% EtOAc/hexanes); mp 101e103 ꢁC; 1H
2F), ꢀ152.60 (tt, J¼20.8, 2.5 Hz, 1F), ꢀ162.6 to ꢀ162.4 (m, 2F); IR
(neat) 3200,1781,1748,1517,1488,1366,1233,1196,1130,1060, 934,
817, 725, 693 cmꢀ1
;
HMRS (ESIþ) calcd for C15H10NO5F5SNa
[MþNa]þ: 434.00921; found: 434.00861.
4.2.3. 1,3-Dichloropropan-2-yl N-tosyloxycarbamate (1d). To a solu-
tion of 1,10-carbonyldiimidazole (3.57 g, 22.0 mmol) in MeCN
(100 mL) was added 1,3-dichloropropan-2-ol (1.91 mL, 20.0 mmol).
The resulting mixture was stirred at room temperature for 3 h.
Hydroxylamine hydrochloride (5.56 g, 80.0 mmol) was then added
followed by imidazole (4.08 g, 60.0 mmol) and the resulting mix-
ture was stirred for 16 h. The suspension was concentrated under
reduced pressure. The white residue was dissolved in a 1:1 mixture
of ethyl acetate and HClaq 10% (100 mL). The layers were separated
and the aqueous layer was extracted with ethyl acetate (2ꢂ100 mL).
The combined organic layers were washed with brine (100 mL) and
dried over MgSO4. The solvent was removed under reduced pres-
sure and the resulting N-hydroxycarbamate used without further
purification. To a solution of N-hydroxycarbamate (w20 mmol) in
ether (200 mL) at 0 ꢁC was added tosyl chloride (4.20 g,
22.0 mmol). Triethylamine (3.07 mL, 12.0 mmol) was then slowly
added to the solution. The resulting white suspension was stirred at
room temperature for 2 h. Water (50 mL) was added to the solution
and the two layers were separated. The aqueous layer was washed
with ether (2ꢂ40 mL). The combined organic layers were washed
with brine (40 mL), dried over MgSO4, and the solvent was re-
moved under reduced pressure. The desired N-tosyloxycarbamate
1d (3.99 g, 59% yield) was obtained as a colorless oil after flash
chromatography (20% EtOAc/hexanes). Rf 0.42 (30% EtOAc/hex-
NMR (400 MHz, CDCl3)
d
7.90 (d, J¼8 Hz, 2H), 7.87 (br s, 1H), 7.38 (d,
J¼8 Hz, 2H), 2.47 (s, 3H), 1.80 (s, 6H); 13C NMR (100 MHz, CDCl3)
d
152.2, 146.0, 129.8, 129.4, 129.3, 104.7, 90.5, 21.5, 21.0; IR (neat)
3240, 2925,1745,1600,1470,1390,1375,1265,1195,1175,1085, 785,
730, 660 cmꢀ1; HMRS (ESIþ) calcd for C12H14Cl3NO5SNa [MþNa]þ:
411.95505; found: 411.95571.
anes); 1H NMR (400 MHz, CDCl3)
d
8.20 (s, 1H), 7.88 (d, J¼8.2 Hz,
4.2.6. 2,2,2-Trifluoro-1,1-dimethylethyl
N-tosyloxycarbamate
2H), 7.38 (d, J¼8.1 Hz, 2H), 5.03e4.93 (quint, J¼5.2 Hz, 1H), 3.60 (d,
(1g). The title compound was prepared from 1,1,1-trifluoro-2-
methylpropan-2-ol (1.64 mL, 15.0 mmol) following the typical
procedure to prepare 1f. The desired N-tosyloxycarbamate 1g was
obtained as a white solid (2.59 g, 51% yield) after flash chroma-
tography (20% EtOAc/hexanes). Rf 0.33 (20% EtOAc/hexanes); mp
J¼5.2 Hz, 4H), 2.47 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 154.0,146.4,
129.8, 129.6, 129.1, 74.3, 41.8, 21.7; IR (neat) 3204, 2964, 1761, 1734,
1597, 1493, 1383, 1245, 1191, 1185, 1086, 813, 730, 702, 657 cmꢀ1
;
HMRS (ESIþ) calcd for C11H13NO5Cl2SNa [MþNa]þ: 363.97837;
found: 363.97837.
102e104 ꢁC; 1H NMR (400 MHz, CDCl3)
d 7.91 (s, 1H), 7.88 (d,
J¼8 Hz, 2H), 7.37 (d, J¼8 Hz, 2H), 2.46 (s, 3H), 1.54 (s, 6H); 13C NMR
4.2.4. N-(2,2,2-Trichloro-1,1-dimethyl-1-ethyloxycarbonyl)-imidazo-
lium tosylate. To a solution of 1,10-carbonyldiimidazole (3.56 g,
22.0 mmol) and potassium hydroxide (0.078 g, 1.4 mmol) in MeCN
(100 mL) at 0 ꢁC was added dropwise 1,1,1-trichloro-2-
methylpropan-2-ol (3.52 g, 20.0 mmol). The mixture was stirred
at room temperature for 5 h. The solvent was then removed under
reduced pressure. The residue was dissolved in Et2O, washed with
saturated NH4Claq, brine, and then dried over MgSO4. The solvent
was removed under reduced pressure. The desired 1,1,1-trichloro-
2-methylpropyl imidazole carboxylate was isolated as a white solid
(4.22 g, 78% yield) and used without further purification. The res-
idue (3.30 g, 12.1 mmol) was dissolved in acetone (12 mL) and p-
toluenesulfonic acid (2.42 g, 12.7 mmol) was added. The resulting
mixture was stirred at room temperature for 30 min. Et2O was
added to the solution and the precipitated salt was filtered and
dried under vacuum for 30 min. The desired product was isolated
as a white solid (4.98 g, 93% yield). Rf 0.22 (20% EtOAc/hexanes); mp
(100 MHz, CDCl3) d 152.5, 146.3, 129.9, 129.7, 129.6, 124.2 (q,
J¼283 Hz, 1C), 82.1 (q, J¼30 Hz, 1C), 21.7, 19.1; 19F NMR (282 MHz,
CDCl3)
d
ꢀ84.9; IR (neat) 3215, 2950, 1740, 1485, 1395, 1270, 1175,
1160, 1135, 730, 650 cmꢀ1; HMRS (ESIþ) calcd for C12H14NF3O5SNa
[MþNa]þ: 364.0437; found: 364.0438.
4.3. Preparation of bis(oxazoline) derivatives 2i, 2j, 2k, and
2m55
4.3.1. (4S,40S)-2,20-(Pentane-3,3-diyl)bis(5,5-dimethyl-4-phenyl-4,5-
dihydrooxazole) (2i). To a solution of bis(oxazoline) 2l51 (0.200 g,
0.560 mmol) in THF (10 mL) were added TMEDA (0.150 mL,
1.12 mmol) and i-Pr2NH (78 mL, 0.56 mmol). The resulting mixture
was then cooled at ꢀ78 ꢁC. n-BuLi (0.450 mL of a 2.5 M solution in
hexanes, 1.12 mmol) was added via syringe to the cold mixture. The
reaction mixture was warmed to ꢀ20 ꢁC and stirred for 20 min. The
solution was cooled to ꢀ70 ꢁC and ethyliodide (90.0
mL, 1.12 mmol)
128e130 ꢁC; 1H NMR (400 MHz, CDCl3)
J¼8 Hz, 2H), 7.61 (d, J¼6 Hz, 2H), 7.16 (d, J¼8 Hz, 2H), 2.34 (s, 3H),
2.09 (s, 6H); 13C NMR (100 MHz, CDCl3)
143.0, 141.7, 140.3, 136.8,
128.8, 125.9, 122.6, 118.7, 103.7, 95.2, 21; IR (neat) 3105, 1810, 1570,
1320, 1235, 1210, 1125, 1110, 1005, 980, 800, 790, 675 cmꢀ1; HMRS
(ESIþ) calcd for C8H10N2Cl3O2 [MþH]þ: 270.9797; found: 270.9802.
d
9.24 (s, 1H), 7.76 (d,
was added. After the addition, the cooling bath was removed and
the mixture was allowed to stir at room temperature for 16 h. The
mixture was quenched with saturated aqueous NH4Cl solution
(2 mL) and diluted with water (3 mL). The resulting mixture was
extracted with Et2O (2ꢂ10 mL). The combined organic layers were
washed with brine (10 mL), dried over Na2SO4, and concentrated
under reduced pressure to afford a dark orange oil. The desired
bis(oxazoline) 2i was obtained as a white solid (180 mg, 76% yield)
d
4.2.5. 2,2,2-Trichloro-1,1-dimethylethyl
N-tosyloxycarbamate
(1f). O-Benzylhydroxylamine (878 mg, 5.50 mmol) and imidazole
(374 mg, 5.50 mmol) were stirred in MeCN (50 mL) at room tem-
after flash chromatography (50% EtOAc/hexanes). Rf 0.62 (50%
25
EtOAc/hexanes); [
a
]
ꢀ137.0 (c 1.00, CHCl3); mp 109e111 ꢁC; 1H
D
perature
for
1 h.
N-(2,2,2-Trichloro-1,1-dimethyl-1-
NMR (400 MHz, CDCl3)
d
7.72 (d, J¼8.7 Hz, 2H), 7.40 (dd, J¼7.2,

3404
H. Lebel et al. / Tetrahedron 68 (2012) 3396e3409
2.1 Hz, 2H), 7.08e7.01 (m, 3H), 6.67 (d, J¼8.7 Hz, 2H), 6.50 (s, 1H),
2.99 (dd, J¼6.4, 3.6 Hz), 2.17 (d, J¼6.3 Hz, 1H), 1.64 (d, J¼3.5 Hz, 1H);
resulting mixture was then cooled at ꢀ78 ꢁC. n-BuLi (0.450 mL of
a 2.5 M solution in hexanes, 1.12 mmol) was added via syringe to
the cold mixture. The reaction mixture was warmed to ꢀ20 ꢁC and
stirred for 20 min. The solution was cooled to ꢀ70 ꢁC and 1,2-
13C NMR (100 MHz, CDCl3)
d 160.3, 147.7, 143.6, 132.3, 129.9, 129.5,
128.0, 127.1, 123.9, 99.0, 84.4, 38.7, 35.7; IR (neat) 2955, 2924, 2856,
1741, 1603, 1515, 1346, 1323, 1305, 1288, 1222, 1181, 1136, 1019, 948,
787, 748, 698 cmꢀ1; HMRS (ESI) calcd for C17H14N2O4Cl3 [MþH]þ:
415.00137; found: 415.00161.
dibromoethane (48 mL, 0.56 mmol) was added. After the addition,
the cooling bath was removed and the mixture was allowed to stir
at room temperature for 16 h. The mixture was quenched with
saturated aqueous NH4Cl solution (2 mL) and diluted with water
(3 mL). The resulting mixture was extracted with Et2O (2ꢂ10 mL).
The combined organic layers were washed with brine (10 mL),
dried over Na2SO4, and concentrated under reduced pressure to
afford a dark orange oil. The desired bis(oxazoline) 2m was
4.3.2. (4S,40S)-2,20-(Cyclopentane-1,1-diyl)bis(5,5-dimethyl-4-
phenyl-4,5-dihydrooxazole) (2j). To a solution of bis(oxazoline) 2l51
(0.100 g, 0.280 mmol) in THF (5 mL) were added TMEDA (73
mL,
0.56 mmol) and i-Pr2NH (39 L, 0.28 mmol). The resulting mixture
m
was then cooled at ꢀ78 ꢁC. n-BuLi (0.370 mL of a 2.5 M solution in
hexanes, 0.56 mmol) was added via syringe to the cold mixture. The
reaction mixture was warmed to ꢀ20 ꢁC and stirred for 20 min. The
solution was cooled to ꢀ78 ꢁC and freshly distilled 1,4-
obtained as a white solid (172 mg, 72% yield) after flash chroma-
25
tography (50% EtOAc/hexanes). Rf 0.68 (50% EtOAc/hexanes); [a]
D
ꢀ116.0 (c 0.50, C6H6); mp 128e130 ꢁC; 1H NMR (400 MHz, CDCl3)
d
7.72 (d, J¼8.7 Hz, 2H), 7.40 (dd, J¼7.2, 2.1 Hz, 2H), 7.08e7.01 (m,
diiodobutane (50
mL, 0.38 mmol) was added. After the addition,
3H), 6.67 (d, J¼8.7 Hz, 2H), 6.50 (s, 1H), 2.99 (dd, J¼6.4, 3.6 Hz, 1H),
2.17 (d, J¼6.3 Hz, 1H), 1.64 (d, J¼3.5 Hz, 1H); HMRS (ESI) calcd for
C25H29N2O2 [MþH]þ: 389.22277; found: 389.22235.
the cooling bath was removed and the mixture was allowed to stir
at room temperature for 16 h. The mixture was quenched with
saturated aqueous NH4Cl solution (1 mL) and diluted with water
(1 mL). The resulting mixture was extracted with Et2O (2ꢂ5 mL).
The combined organic layers were washed with brine (5 mL), dried
over Na2SO4, and concentrated under reduced pressure to afford
a dark orange oil. The desired bis(oxazoline) 2j was obtained as
a white solid (87 mg, 75% yield) after flash chromatography (50%
4.4. Enantioselective aziridination with N-
tosyloxycarbamates 1f and 1g
4.4.1. (R)-1,1,1-Trichloro-2-methylpropan-2-yl 2-(4-nitrophenyl)azir-
idine-1-carboxylate (3f). A suspension of Cu(CH3CN)4PF6 (9.0 mg,
25 ꢀ108.8 (c 0.50,
0.025 mmol), bis(oxazoline) (S,S)-2h (12 mg, 0.030 mmol), and 4 A
ꢂ
EtOAc/hexanes). Rf 0.58 (50% EtOAc/hexanes); [
a
d
]
D
CHCl3); mp 79e81 ꢁC; 1H NMR (400 MHz, CDCl3)
7.72 (d, J¼8.7 Hz,
molecular sieves (200 mg) in MeCN (3 mL) was stirred at room
temperature for 30 min. Potassium carbonate (104 mg,
0.750 mmol), then 4-nitrostyrene (223 mg, 1.50 mmol) were suc-
cessively added. The heterogeneous solution was stirred for 15 min.
2H), 7.40 (dd, J¼7.2, 2.1 Hz, 2H), 7.08e7.01 (m, 3H), 6.67 (d,
J¼8.7 Hz, 2H), 6.50 (s, 1H), 2.99 (dd, J¼6.4, 3.6 Hz, 1H), 2.17 (d,
J¼6.3 Hz, 1H), 1.64 (d, J¼3.5 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
160.3,147.7,143.6, 132.3,129.9,129.5,128.0,127.1,123.9, 99.0, 84.4,
A
solution of 2,2,2-trichloro-1,1-dimethylethyl N-tosylox-
38.7, 35.7; IR (neat) 2955, 2924, 2856, 1741, 1603, 1515, 1346, 1323,
1305, 1288, 1222, 1181, 1136, 1019, 948, 787, 748, 698 cmꢀ1; HMRS
(ESI) calcd for C27H33N2O2 [MþH]þ: 417.25365; found: 417.25428.
ycarbamate (1f) (195 mg, 0.500 mmol) in MeCN (2 mL) was slowly
added over 2 h with a syringe pump. The resulting mixture was
then stirred at room temperature for 12 h. The solution was filtered
and rinsed with Et2O (5 mL), and then the solvent was removed
under reduced pressure. The desired aziridine 3f was obtained as
a yellow oil (95 mg, 52% yield) after flash chromatography (15%
EtOAc/hexanes) on silica gel (pre-treated with 1% Et3N/hexanes).
The enantiomeric ratio was determined by HPLC analysis using
Chiracel-OD column (2% i-PrOH/hexanes at 1.0 mL/min), retention
4.3.3. (4S,40S)-2,20-(Cyclohexane-1,1-diyl)bis(5,5-dimethyl-4-phenyl-
4,5-dihydrooxazole) (2k). To
(0.190 g, 0.520 mmol) in THF (10 mL) were added TMEDA (135
1.04 mmol) and i-Pr2NH (72 L, 0.52 mmol). The resulting mixture
a
solution of bis(oxazoline) 2l51
mL,
m
was then cooled at ꢀ78 ꢁC. n-BuLi (0.415 mL of a 2.5 M solution in
hexanes, 1.04 mmol) was added via syringe to the cold mixture. The
reaction mixture was warmed to ꢀ20 ꢁC and stirred for 20 min. The
solution was cooled to ꢀ70 ꢁC and freshly distilled 1,5-
time: tR (major)¼17.2 min and tR (minor)¼16.7 min (97:3 er). Rf
25
0.55 (30% EtOAc/hexanes); [
a
]
ꢀ80.4 (c 1.00, CHCl3); 1H NMR
D
(400 MHz, C6D6)
d
7.74 (d, J¼8.8 Hz, 2H), 6.76 (d, J¼8.7 Hz, 2H), 2.96
diiodopentane (78
mL, 0.52 mmol) was added. After the addition,
(dd, J¼6.3, 3.5 Hz, 1H), 2.20 (d, J¼6.3 Hz, 1H), 1.78 (s, 3H), 1.76 (s,
the cooling bath was removed and the mixture was allowed to stir
at room temperature for 16 h. The mixture was quenched with
saturated aqueous NH4Cl solution (2 mL) and diluted with water
(3 mL). The resulting mixture was extracted with Et2O (2ꢂ10 mL).
The combined organic layers were washed with brine (10 mL),
dried over Na2SO4, and concentrated under reduced pressure to
afford a dark orange oil. The desired bis(oxazoline) 2k was obtained
3H), 1.65 (d, J¼3.5 Hz,1H); 13C NMR (100 MHz, CDCl3)
d 159.2, 147.4,
143.1, 126.4, 123.1, 105.9, 88.9, 38.0, 34.7, 20.6; IR (neat) 3084, 3010,
2905, 1718, 1599, 1518, 1365, 1307, 1291, 1186, 1147, 1106, 856, 790,
750, 699 cmꢀ1; HMRS (ESI) calcd for. C13H13N2O4Cl3Na [MþNa]þ:
388.9822; found: 388.9833.
4.4.2. (R)-1,1,1-Trifluoro-2-methylpropan-2-yl 2-(4-nitrophenyl)azir-
idine-1-carboxylate (3g). A suspension of Cu(CH3CN)4PF6 (9.0 mg,
as a white solid (183 mg, 81% yield) after flash chromatography
25
ꢂ
(50% EtOAc/hexanes). Rf 0.64 (50% EtOAc/hexanes); [
a
]
D
ꢀ90.6 (c
0.025 mmol), bis(oxazoline) (S,S)-2h (12 mg, 0.030 mmol), and 4 A
0.50, C6H6); mp 93e95 ꢁC; 1H NMR (400 MHz, CDCl3)
d
7.72 (d,
molecular sieves (200 mg) in MeCN (3 mL) was stirred at room
temperature for 30 min. Potassium carbonate (104 mg,
0.750 mmol), then 4-nitrostyrene (223 mg, 1.50 mmol) were suc-
cessively added. The heterogeneous solution was stirred for 15 min.
J¼8.7 Hz, 2H), 7.40 (dd, J¼7.2, 2.1 Hz, 2H), 7.08e7.01 (m, 3H), 6.67
(d, J¼8.7 Hz, 2H), 6.50 (s, 1H), 2.99 (dd, J¼6.4, 3.6 Hz, 1H), 2.17 (d,
J¼6.3 Hz, 1H), 1.64 (d, J¼3.5 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
160.3,147.7,143.6, 132.3,129.9,129.5,128.0,127.1,123.9, 99.0, 84.4,
A
solution of 2,2,2-trifluoro-1,1-dimethylethyl N-tosylox-
38.7, 35.7; IR (neat) 2955, 2924, 2856, 1741, 1603, 1515, 1346, 1323,
1305, 1288, 1222, 1181, 1136, 1019, 948, 787, 748, 698 cmꢀ1; HMRS
(ESI) calcd for C28H35N2O2 [MþH]þ: 431.26984; found: 431.2693.
ycarbamate (1g) (170 mg, 0.500 mmol) in MeCN (2 mL) was slowly
added over 2 h with a syringe pump. The resulting mixture was
then stirred at room temperature for 12 h. The solution was filtered
and rinsed with Et2O (5 mL), and then the solvent was removed
under reduced pressure. The desired aziridine 3g was obtained as
a yellow oil (129 mg, 81% yield) after flash chromatography (15%
EtOAc/hexanes) on silica gel (pre-treated with 1% Et3N/hexanes).
The enantiomeric ratio was determined by HPLC analysis using
4.3.4. (4S,40S)-2,20-(Cyclopropane-1,1-diyl)bis(5,5-dimethyl-4-
phenyl-4,5-dihydrooxazole) (2m). To a solution of bis(oxazoline)
2l51 (0.200 g, 0.560 mmol) in THF (10 mL) were added TMEDA
(0.150 mL, 1.12 mmol) and i-Pr2NH (78 mL, 0.56 mmol). The

H. Lebel et al. / Tetrahedron 68 (2012) 3396e3409
3405
Chiracel-OD column (2% i-PrOH/hexanes at 1.0 mL/min), retention
38.7, 35.7; IR (neat) 2955, 2924, 2856, 1741, 1603, 1515, 1346, 1323,
1305, 1288, 1222, 1181, 1136, 1019, 948, 787, 748, 698 cmꢀ1; HMRS
(ESI) calcd for C17H14N2O4Cl3 [MþH]þ: 415.00137; found:
415.00161.
time: tR (major)¼15.0 min and tR (minor)¼16.7 min (86:14 er). Rf
25
0.38 (20% EtOAc/hexanes); [
a
]
ꢀ71.8 (c 1.10, CHCl3); 1H NMR
D
(400 MHz, CDCl3)
d
7.70 (d, J¼8.8 Hz, 2H), 6.65 (d, J¼8.8 Hz, 2H),
2.84 (dd, J¼6.3, 3.4 Hz, 1H), 2.07 (d, J¼6.3 Hz, 1H), 1.54 (d, J¼3.5 Hz,
1H), 1.49 (s, 3H), 1.46 (s, 3H); 13C NMR (100 MHz, CDCl3)
159.7,
147.6, 144.0, 127.1, 124.6 (q, J¼283 Hz, 1C), 123.7, 81.1 (q, J¼29.8 Hz,
1C), 77.2, 38.5, 35.6, 19.1; 19F NMR (282 MHz, CDCl3)
ꢀ84.8; IR
d
4.5.2. (2S)-(R)-1,1,1-Trichloropropan-2-yl
2-(2-chlorophenyl)azir-
idine-1-carboxylate (4i). The title compound was prepared from 2-
chlorostyrene (208 mg, 1.50 mmol) according to the typical pro-
cedure described to synthesize aziridine 3i. The desired aziridine 4i
was obtained as a colorless oil (155 mg, 76% yield) after flash
chromatography (10% EtOAc/hexanes) on silica gel (pre-treated
with 1% Et3N/hexanes). The diastereomeric ratio was determined
d
(neat) 3002, 1733, 1604, 1522, 1346, 1309, 1162, 1133, 855 cmꢀ1
;
HMRS (ESI) calcd for. C13H14N2O4F3 [MþH]þ: 319.09002; found:
319.09012.
4.4.3. (R)-1,1,1-Trichloro-2-methylpropan-2-yl
2-(2-chlorophenyl)
by 1H NMR on the crude mixture (92:8 dr). Rf 0.74 (30% EtOAc/
25
aziridine-1-carboxylate (4f). A suspension of Cu(CH3CN)4PF6
(9.0 mg, 0.025 mmol), bis(oxazoline) (S,S)-2h (12 mg, 0.030 mmol),
hexanes); [
d
a
]
ꢀ87.3 (c 0.50, CHCl3); 1H NMR (400 MHz, C6D6)
D
7.63 (dd, J¼7.6, 1.7 Hz, 2H), 7.46e7.37 (m, 5H), 7.29e7.26 (m, 2H),
ꢂ
and 4 A molecular sieves (200 mg) in MeCN (3 mL) was stirred at
6.34 (s, 1H), 3.93 (dd, J¼6.4, 3.7 Hz, 1H), 2.86 (d, J¼6.5 Hz, 1H), 2.32
room temperature for 30 min. Potassium carbonate (104 mg,
0.750 mmol), then 2-chlorostyrene (208 mg, 1.50 mmol) were
successively added. The heterogeneous solution was stirred for
15 min. A solution of 2,2,2-trichloro-1,1-dimethylethyl N-tosylox-
ycarbamate (1f) (195 mg, 0.500 mmol) in MeCN (2 mL) was slowly
added over 2 h with a syringe pump. The resulting mixture was
then stirred at room temperature for 12 h. The solution was filtered
and rinsed with Et2O (5 mL), and then the solvent was removed
under reduced pressure. The desired aziridine 4f was obtained as
a colorless oil (137 mg, 77% yield) after flash chromatography (15%
EtOAc/hexanes) on silica gel (pre-treated with 1% Et3N/hexanes).
The enantiomeric ratio was determined by HPLC analysis using
Chiracel-AD column (1% i-PrOH/hexanes at 1.0 mL/min), retention
(d, J¼3.7 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 160.9, 134.4, 133.8,
132.6, 129.9, 129.6, 129.2, 129.1, 128.0, 127.4, 127.1, 99.2, 84.3, 37.8,
35.0; IR (neat) 2953, 1735, 1321, 1172, 1139, 1017, 754 cmꢀ1; HMRS
(ESI) calcd for C17H14NO2Cl4 [MþH]þ: 403.97732; found:
403.97806.
4.5.3. (2S)-(R)-2,2,2-Trichloro-1-phenylethyl 2-(3-nitrophenyl)azir-
idine-1-carboxylate (5i). The title compound was prepared from 3-
nitrostyrene (90 mg, 0.60 mmol) according to the typical procedure
described to synthesize aziridine 3i. The desired aziridine 5i was
obtained as a yellow oil (70 mg, 84% yield) after flash chromatog-
raphy (15% EtOAc/hexanes) on silica gel (pre-treated with 1% Et3N/
hexanes). The diastereomeric ratio was determined by 1H NMR on
25
time: tR (major)¼5.0 min and tR (minor)¼6.9 min (78:22 er). Rf 0.66
the crude mixture (89:11 dr). Rf 0.67 (20% EtOAc/hexanes); [a]
D
25
(20% EtOAc/hexanes);
[
a
]
D
ꢀ96.7 (c 1.00, CHCl3); 1H NMR
ꢀ101.2 (c 0.51, C6H6); 1H NMR (400 MHz, C6D6)
d
7.82 (t, J¼1.8 Hz,
(400 MHz, CDCl3)
d
7.44e7.41 (m, 1H), 7.40e7.35 (m, 1H), 7.30e7.23
1H), 7.70e7.66 (m, 1H), 7.52e7.47 (m, 2H), 7.08e7.04 (m, 3H), 6.96
(d, J¼7.7 Hz, 1H), 6.62 (t, J¼7.9 Hz, 1H), 6.52 (s, 1H), 2.94 (dd, J¼6.4,
3.5 Hz, 1H), 2.30 (d, J¼6.4 Hz, 1H), 1.64 (d, J¼3.5 Hz, 1H); 13C NMR
(m, 2H), 3.82 (dd, J¼6.4, 3.6 Hz, 1H), 2.83 (d, J¼6.7 Hz, 1H), 2.24 (d,
J¼3.6 Hz, 1H), 1.97 (s, 6H); 13C NMR (100 MHz, CDCl3)
d 160.4, 134.6,
133.6, 129.0, 128.9, 127.6, 126.9, 105.9, 89.3, 37.7, 34.7, 21.3, 21.2; IR
(neat) 3005, 2953, 2306, 1730, 1462, 1386, 1303, 1153, 194,
152 cmꢀ1; HMRS (ESI) calcd for. C13H14NO2Cl4 [MþH]þ: 355.97732;
found: 355.97626.
(100 MHz, CDCl3) d 160.3, 148.4, 138.7, 132.3, 130.0, 129.6, 129.5,
128.0, 123.1, 123.0, 121.3, 99.0, 84.4, 38.5, 35.7; IR (neat) 3001, 2970,
1740, 1605, 1515, 1351, 1274, 1228, 1181, 1138, 948, 787, 751,
699 cmꢀ1; HMRS (ESI) calcd for C17H14N2O4Cl3 [MþH]þ: 415.00137;
found: 415.00159.
4.5. Diastereoselective aziridination with N-
tosyloxycarbamate 1i
4.5.4. (2S)-(R)-2,2,2-Trichloro-1-phenylethyl 2-(2-nitrophenyl)azir-
idine-1-carboxylate (6i). The title compound was prepared from 2-
nitrostyrene (90 mg, 0.60 mmol) according to the typical procedure
described to synthesize aziridine 3i. The desired aziridine 6i was
obtained as a colorless oil (42 mg, 50% yield) after flash chroma-
tography (15% EtOAc/hexanes) on silica gel (pre-treated with 1%
Et3N/hexanes). The diastereomeric ratio was determined by 1H
4.5.1. (2S)-(R)-2,2,2-Trichloro-1-phenylethyl 2-(4-nitrophenyl)azir-
idine-1-carboxylate (3i). A suspension of Cu(CH3CN)4PF6 (9.0 mg,
0.025 mmol), bis(oxazoline) (S,S)-2h (12 mg, 0.030 mmol), and 4 A
molecular sieves (200 mg) in MeCN (3 mL) was stirred at room
temperature for 30 min. Potassium carbonate (104 mg,
0.750 mmol), then 4-nitrostyrene (223 mg, 1.50 mmol) were suc-
cessively added. The heterogeneous solution was stirred for 15 min.
ꢂ
NMR on the crude mixture (93:7 dr). Rf 0.70 (20% EtOAc/hexanes);
25
[a
]
ꢀ121.0 (c 0.5, C6H6); 1H NMR (400 MHz, C6D6)
d 7.62 (dd,
D
A
solution of (1R)-2,2,2-trichloro-1-phenylethyl N-tosylox-
J¼8.2, 1.3 Hz, 1H), 7.53e7.44 (m, 3H), 7.08e7.03 (m, 3H), 6.85 (dt,
J¼7.6, 1.3 Hz, 1H), 6.62 (dt, J¼7.7, 1.4 Hz, 1H), 6.52 (s, 1H), 3.97 (dd,
J¼6.7, 3.7 Hz, 1H), 2.50 (d, J¼6.8 Hz, 1H), 1.65 (d, J¼3.6 Hz, 1H); 13C
ycarbamate (1i) (195 mg, 0.500 mmol) in MeCN (2 mL) was slowly
added over 2 h with a syringe pump. The resulting mixture was
then stirred at room temperature for 12 h. The solution was filtered
and rinsed with Et2O (5 mL), and then the solvent was removed
under reduced pressure. The desired aziridine 3i was obtained as
a white solid (174 mg, 85% yield) after flash chromatography (15%
EtOAc/hexanes) on silica gel (pre-treated with 1% Et3N/hexanes).
The diastereomeric ratio was determined by SFC analysis using
Chiracel-AD-H Chiralpak column (25 cm, 35 ꢁC, 7% MeOH at
NMR (100 MHz, CDCl3)
d 160.3, 147.7, 133.9, 132.4, 132.1, 129.6,
129.2, 129.0, 128.6, 127.7, 124.5, 99.1, 84.1, 38.2, 34.7; IR (neat) 3040,
1738, 1525, 1394, 1345, 1173, 805, 743, 701 cmꢀ1; HMRS (ESI) calcd
for C17H14N2O4Cl3 [MþH]þ: 415.00137; found: 415.00168.
4.5.5. (2S)-(R)-2,2,2-Trichloro-1-phenylethyl 2-(4-chlorophenyl)azir-
idine-1-carboxylate (7i). The title compound was prepared from 4-
chlorostyrene (208 mg, 1.50 mmol) according to the typical pro-
cedure described to synthesize aziridine 3i. The desired aziridine 7i
was obtained as a white solid (142 mg, 70% yield) after flash
chromatography (15% EtOAc/hexanes) on silica gel (pre-treated
with 1% Et3N/hexanes). The diastereomeric ratio was determined
150 bar), retention time: tR (minor)¼13.4 min and tR (major)¼
25
17.0 min (97:3 dr). Rf 0.36 (20% EtOAc/hexanes); [
a
]
ꢀ116.0 (c
D
0.50, C6H6); mp 128e130 ꢁC; 1H NMR (400 MHz, CDCl3)
d 7.72 (d,
J¼8.7 Hz, 2H), 7.40 (dd, J¼7.2, 2.1 Hz, 2H), 7.08e7.01 (m, 3H), 6.67
(d, J¼8.7 Hz, 2H), 6.50 (s, 1H), 2.99 (dd, J¼6.4, 3.6 Hz, 1H), 2.17 (d,
J¼6.3 Hz, 1H), 1.64 (d, J¼3.5 Hz, 1H); 13C NMR (100 MHz, CDCl3)
by 1H NMR on the crude mixture (81:19 dr). Rf 0.71 (30% EtOAc/
25
d
160.3,147.7,143.6, 132.3, 129.9,129.5,128.0,127.1,123.9, 99.0, 84.4,
hexanes); [
a]
ꢀ85.2 (c 0.55, CHCl3); 1H NMR (400 MHz, C6D6)
D

3406
H. Lebel et al. / Tetrahedron 68 (2012) 3396e3409
d
7.52e7.46 (m, 2H), 7.08e7.03 (m, 2H), 7.03e6.99 (m, 2H), 6.79 (d,
determined by 1H NMR on the crude mixture (89:11 dr). Rf 0.81
25
J¼8.6 Hz, 2H), 6.53 (s, 1H), 3.04 (dd, J¼6.3, 3.6 Hz, 1H), 2.32 (d,
(30% EtOAc/hexanes);
(400 MHz, C6D6)
[
a
]
ꢀ100.4 (c 0.5, CHCl3); 1H NMR
D
J¼6.4 Hz, 1H), 1.75 (d, J¼3.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
7.67 (d, J¼6.7 Hz, 2H), 7.57 (d, J¼7.8 Hz, 1H),
d
160.6, 134.9, 133.9, 132.5, 129.8, 129.5, 128.7, 128.0, 127.6, 99.1,
7.48e7.39 (m, 4H), 7.33 (t, J¼7.4 Hz, 1H), 7.20 (t, J¼7.2 Hz, 1H), 6.36
84.3, 39.1, 35.3; IR (neat) 3036, 1736, 1321, 1168, 825, 735 cmꢀ1
;
(s, 1H), 3.81 (dd, J¼6.2, 3.7 Hz, 1H), 2.92 (d, J¼6.5 Hz, 1H), 2.30 (d,
HMRS (ESI) calcd for C17H14NO2Cl4 [MþH]þ: 403.97732; found:
J¼3.5 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 160.8, 135.9, 132.5,
403.97749.
132.2, 129.8, 129.6, 129.4, 128.0, 127.9, 127.6, 123.1, 99.1, 84.3, 40.1,
35.1; IR (neat) 3065, 2955, 1736, 1395, 1319, 1294, 1268, 1171, 749,
4.5.6. (2S)-(R)-2,2,2-Trichloro-1-phenylethyl 2-(3-chlorophenyl)azir-
idine-1-carboxylate (8i). The title compound was prepared from 3-
chlorostyrene (83 mg, 1.50 mmol) according to the typical pro-
cedure described to synthesize aziridine 3i. The desired aziridine 8i
was obtained as a white solid (38 mg, 47% yield) after flash chro-
matography (15% EtOAc/hexanes) on silica gel (pre-treated with 1%
Et3N/hexanes). The diastereomeric ratio was determined by 1H
NMR on the crude mixture (84:16 dr). Rf 0.78 (30% EtOAc/hexanes);
698 cmꢀ1
447.92680; found: 447.92676.
;
HMRS (ESI) calcd for C17H14NO2Cl3Br [MþH]þ:
4.5.10. (2S)-(R)-2,2,2-Trichloro-1-phenylethyl
2-(3-cyanophenyl)
aziridine-1-carboxylate (12i). The title compound was prepared
from 3-cyanostyrene (78 mg, 0.6 mmol) according to the typical
procedure described to synthesize aziridine 3i. The desired azir-
idine 12i was obtained as a pale yellow oil (35 mg, 44% yield) after
flash chromatography (10% EtOAc/hexanes) on silica gel (pre-
treated with 1% Et3N/hexanes). The diastereomeric ratio was de-
termined by 1H NMR on the crude mixture (82:18 dr). Rf 0.40 (20%
[
a
]
25 ꢀ97.1 (c 0.61, CHCl3); 1H NMR (400 MHz, C6D6)
d 7.48 (m, 2H),
D
7.13 (t, J¼1.7 Hz, 1H), 7.08e7.01 (m, 3H), 6.99 (d, J¼7.9 Hz, 1H), 6.84
(d, J¼7.7 Hz, 1H), 6.73 (t, J¼7.83 Hz, 1H), 6.52 (s, 1H), 3.02 (dd, J¼6.3,
3.6 Hz, 1H), 2.29 (d, J¼6.4 Hz, 1H), 1.71 (d, J¼3.6 Hz, 1H); 13C NMR
EtOAc/hexanes); [
d 7.53e7.47 (m, 1H), 7.09e7.05 (m, 1H), 6.97 (s, 1H), 6.88 (dd,
a
]
25 ꢀ43.5 (c 0.5, C6H6); 1H NMR (400 MHz, C6D6)
D
(100 MHz, C6D6)
d
160.8, 138.7, 134.8, 132.7, 130.1, 130.0, 129.8,
128.4, 128.2, 126.6, 124.7, 99.3, 84.6, 39.2, 35.6; IR (neat) 2955, 1735,
1290, 1166, 787 cmꢀ1; HMRS (ESI) calcd for C17H14NO2Cl4 [MþH]þ:
403.97732; found: 403.97743.
J¼15.54, 7.77 Hz, 1H), 6.57 (t, J¼7.78, 7.78 Hz, 1H), 6.51 (s, 1H), 2.91
(dd, J¼6.39, 3.55 Hz, 1H), 2.27 (d, J¼6.46 Hz, 1H), 1.59 (d, J¼3.52 Hz,
1H); 13C NMR (100 MHz, CDCl3)
d 160.1, 137.8, 132.0, 131.4, 130.4,
129.7, 129.6, 129.2, 129.1, 127.07, 118.1, 112.5, 98.7 84.1, 38.2, 35.3; IR
4.5.7. (2S)-(R)-2,2,2-Trichloro-1-phenylethyl
2-(4-bromophenyl)
(neat) 2957, 1736, 1485, 1383, 1320, 1277, 1185, 1139, 794 cmꢀ1
;
aziridine-1-carboxylate (9i). The title compound was prepared
from 4-bromostyrene (208 mg, 1.50 mmol) according to the typical
procedure described to synthesize aziridine 3i. The desired azir-
idine 9i was obtained as a pale yellow oil (180 mg, 80% yield) after
flash chromatography (5% EtOAc/hexanes) on silica gel (pre-treated
with 1% Et3N/hexanes). The diastereomeric ratio was determined
HMRS (ESI) calcd for C18H14N2O2Cl3 [MþH]þ: 395.01154; found:
395.01192.
4.6. Ring-opening reactions of aziridines
4.6.1. (R)-2,2,2-Trichloro-1-phenylethyl (R)-2-methoxy-2-(4-
nitrophenyl)ethylcarbamate (14a). Methanol (5 mL, 0.1 M) was
added to aziridine 3i (208 mg, 0.500 mmol) and the mixture was
by 1H NMR on the crude mixture (81:19 dr). Rf 0.70 (30% EtOAc/
25
hexanes); [
d
a
]
ꢀ95.7 (c 0.56, C6H6); 1H NMR (400 MHz, C6D6)
D
7.48e7.42 (m, 2H), 7.15e7.09 (m, 2H), 7.04e6.99 (m, 3H), 6.68 (d,
stirred. BF3$OEt2 (7 mL, 0.05 mmol) was added and the mixture was
J¼8.3 Hz, 2H), 6.48 (s, 1H), 2.98 (dd, J¼6.4, 3.6 Hz, 1H), 2.27 (dd,
stirred at room temperature for 1 h. Upon completion of the re-
action, the solvent was evaporated and the crude product was
purified by flash chromatography (100% CH2Cl2). The desired
product 14a was obtained as a gummy yellow solid (209 mg, 93%
yield). The diastereomeric ratio was determined by HPLC analysis
Chiralpak-AD column (7% i-PrOH/hexanes at 1 mL/min), retention
time: tR (major)¼24.1 min and tR (minor)¼16.0 min (dr >95:5). Rf
J¼6.4, 0.6 Hz, 1H), 1.70 (dd, J¼3.6, 0.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3)
d 160.3, 135.2, 132.2, 131.4, 129.6, 129.3, 127.7, 127.6, 121.7,
98.8, 84.0, 38.8, 35.0; IR (neat) 2955, 1734, 1491, 1320, 1288, 1167,
1071, 822, 747, 699 cmꢀ1; HMRS (ESI) calcd for C17H14NO2BrCl3
[MþH]þ: 447.92680; found: 447.92695.
4.5.8. (2S)-(R)-2,2,2-Trichloro-1-phenylethyl
2-(3-bromophenyl)
0.30 (20% EtOAc/hexanes); 1H NMR (300 MHz, CDCl3)
d 8.13 (d,
aziridine-1-carboxylate (10i). The title compound was prepared
from 3-bromostyrene (275 mg, 1.50 mmol) according to the typical
procedure described to synthesize aziridine 3i. The desired azir-
idine 10i was obtained as a colorless oil (160 mg, 71% yield) after
flash chromatography (10% EtOAc/hexanes) on silica gel (pre-
treated with 1% Et3N/hexanes). The diastereomeric ratio was de-
J¼9 Hz, 2H), 7.58 (d, J¼9 Hz, 2H), 7.46e7.40 (m, 5H), 6.24 (s, 1H),
5.46 (s, 1H), 4.45e4.41 (m, 1H), 3.49e3.52 (m, 1H), 3.27e3.22 (m,
1H), 3.32 (s, 3H); 13C NMR (75 MHz, CDCl3)
d
154.0, 147.7, 146.1,
133.1, 129.6, 129.4, 127.8, 127.3, 123.7, 99.4, 83.3, 81.3, 57.3, 46.9; IR
(neat) 3341, 1736, 1522, 1346, 737 cmꢀ1
; HMRS calcd for
C18H18Cl3N2O5 [MþH]þ 447.0289; found: 447.0276.
termined by 1H NMR on the crude mixture (81:19 dr). Rf 0.57 (20%
25
EtOAc/hexanes); [
C6D6)
a
]
D
ꢀ82.3 (c 0.51, CHCl3); 1H NMR (400 MHz,
4.6.2. (R)-2,2,2-Trichloro-1-phenylethyl (R)-2-hydroxy-2-(4-
nitrophenyl)ethylcarbamate (14b). A mixture of water (2.5 mL)
and acetonitrile (2.5 mL) was added to aziridine 3i (208 mg,
d
7.48 (dd, J¼6.7, 2.7 Hz, 2H), 7.30 (t, J¼1.8 Hz, 1H), 7.08e7.02
(m, 3H), 6.90e6.84 (m, 1H), 6.65 (t, J¼7.8 Hz, 1H), 6.52 (s, 1H), 3.00
(dd, J¼6.3, 3.6 Hz, 1H), 2.28 (d, J¼6.4 Hz, 1H), 1.69 (d, J¼3.6 Hz, 1H);
0.500 mmol) and the mixture was stirred. BF3$OEt2 (7 mL,
13C NMR (100 MHz, CDCl3)
d
160.5, 138.7, 132.5, 131.1, 130.1, 129.9,
0.05 mmol) was added and the mixture was stirred at room tem-
perature for 1 h. EtOAc (3 mL) was added and the layers were
separated. The aqueous layer was washed with EtOAc (2ꢂ3 mL).
The combined organic layers were washed with brine (1ꢂ3 mL),
then dried over MgSO4 and concentrated under reduced pressure.
The crude product was purified by flash chromatography (100%
CH2Cl2). The desired product 14b was obtained as a yellow solid
(201 mg, 93% yield) and as one diastereomer by 1H NMR. Rf 0.06
(20% EtOAc/hexanes); mp 57e64 ꢁC; 1H NMR (300 MHz, CDCl3)
129.5,129.2,128.0,125.0,122.6, 99.1, 84.3, 38.9, 35.4; IR (neat) 3066,
2957, 1735, 1395, 1292, 1167, 786, 698 cmꢀ1; HMRS (ESI) calcd for
C17H14NO2Cl3Br [MþH]þ: 447.92680; found: 447.92721.
4.5.9. (2S)-(R)-2,2,2-Trichloro-1-phenylethyl
2-(2-bromophenyl)
aziridine-1-carboxylate (11i). The title compound was prepared
from 2-bromostyrene (275 mg, 1.50 mmol) according to the typical
procedure described to synthesize aziridine 3i. The desired azir-
idine 11i was obtained as a colorless oil (165 mg, 73% yield) after
flash chromatography (10% EtOAc/hexanes) on silica gel (pre-
treated with 1% Et3N/hexanes). The diastereomeric ratio was
d
8.15 (d, J¼9 Hz, 2H), 7.63 (d, J¼9 Hz, 2H), 7.46e7.37 (m, 5H), 6.25
(s,1H), 5.52 (s,1H), 5.01e4.99 (m,1H), 3.63e3.57 (m,1H), 3.38e3.31
(m, 1H), 3.01 (s, 1H); 13C NMR (75 MHz, CDCl3)
154.0, 147.7, 146.1,
d

H. Lebel et al. / Tetrahedron 68 (2012) 3396e3409
3407
132.9, 129.7, 129.4, 127.8, 126.6, 123.6, 83.5, 72.5, 48.2; IR (neat)
CDCl3) d 154.9, 148.1, 143.3, 132.9, 132.0, 129.7, 129.4, 127.8, 122.8,
3423, 2945, 1723, 1522, 1348, 909 cmꢀ1
;
HMRS calcd for
120.8, 99.4, 83.5, 72.2, 48.2; IR (neat) 3351, 1716, 1528, 1350,
739 cmꢀ1, HMRS calcd for C17H14Cl3N2O5 [MþH]þ 430.9985; found:
430.9974.
C17H19Cl3N3O5 [MþNH4]þ 450.0392; found: 450.0385.
4.6.3. (R)-1-(4-Nitrophenyl)-2-(((R)-2,2,2-trichloro-1-phenylethoxy)
carbonylamino)ethyl acetate (14c). Dichloromethane (5 mL) was
added to aziridine 3i (208 mg, 0.500 mmol) and the mixture was
4.6.6. (R)-2,2,2-Trichloro-1-phenylethyl (R)-2-(4-chlorophenyl)-2-
hydroxyethylcarbamate (17). A mixture of water (1.25 mL) and
acetonitrile (1.25 mL) was added to aziridine 7i (97 mg, 0.24 mmol)
stirred. Acetic acid (90 mL, 1.50 mmol), then BF3$OEt2 (7 mL,
0.05 mmol) were added and the mixture was stirred at room
temperature for 1 h. Water (3 mL) was added and the layers were
separated. The aqueous layer was washed with dichloromethane
(2ꢂ3 mL). The combined organic layers were washed with brine
(1ꢂ3 mL), then dried over MgSO4, and concentrated under reduced
pressure. The crude product was purified by flash chromatography
(20% EtOAc/hexanes). The desired product 14c was obtained as
a yellow solid (185 mg, 78% yield). The diastereomeric ratio was
determined by SFC analysis Chiralpak-AD-H column (25 cm, 40 ꢁC,
10% MeOH at 150 bar), retention time: tR (major)¼11.0 min and tR
(minor)¼9.9 min (dr 89:11). Rf 0.31 (20% EtOAc/hexanes); 1H NMR
and the mixture was stirred. BF3$OEt2 (9 mL of a 10% solution in
ether, 0.007 mmol) was added and the mixture was stirred at room
temperature for 15 min. EtOAc (3 mL) was added and the layers
were separated. The aqueous layer was washed with EtOAc
(2ꢂ3 mL), brine (1ꢂ3 mL), dried over MgSO4, and concentrated
under reduced pressure. The crude product was purified by flash
chromatography (100% CHCl3). The desired product 17 was
obtained as a white solid (86 mg, 84% yield). The diastereomeric
ratio was determined by SFC analysis Chiralcel-OJ-H column
(25 cm, 40 ꢁC, 20% MeOH at 150 bar), retention time: tR (major)¼
4.4 min and tR (minor)¼6.3 min (dr 72:28). Rf 0.35 (20% EtOAc/
(300 MHz, CDCl3)
7.47e7.39 (m, 5H), 6.21 (s, 1H), 5.93e5.91 (m, 1H), 5.25 (s, 1H),
3.63e3.58 (m, 2H), 3.12 (s, 3H); 13C NMR (75 MHz, CDCl3)
169.7,
154.0, 147.6, 144.2, 132.9, 129.7, 129.3, 127.8, 127.1, 123.7, 99.3, 83.4,
d
8.13 (d, J¼9 Hz, 2H), 7.56 (d, J¼9 Hz, 2H),
hexanes); mp 54e60 ꢁC; 1H NMR (300 MHz, CDCl3)
d 7.59 (d,
J¼9 Hz, 2H), 7.44e7.25 (m, 7H), 6.29 (s, 1H), 5.49 (s, 1H), 4.88e4.85
d
(m,1H), 3.49e3.61 (m,1H), 3.24e3.36 (m,1H), 2.53 (s,1H); 13C NMR
(75 MHz, CDCl3)
d 154.7, 139.5, 133.7, 133.0, 129.6, 129.4, 128.6,
73.3, 45.5, 20.8; IR (neat) 3377, 2923, 1721, 1519, 1346, 1236 cmꢀ1
,
127.8, 127.1, 99.5, 83.3, 72.6, 48.3; IR (neat) 3438, 1733, 1515, 1265,
739 cmꢀ1, HMRS calcd for C17H15Cl4NNaO3 [MþNa]þ 443.9708;
found: 443.9698.
HMRS calcd for C19H17Cl3N2NaO6 [MþNa]þ 497.0062; found:
497.0044.
4.6.4. (R)-2,2,2-Trichloro-1-phenylethyl-(R)-2-(4-nitrophenyl)-2-
(phenylamino)ethylcarbamate (14d). Acetonitrile (5 mL) was added
to aziridine 3i (208 mg, 0.500 mmol) and the mixture was stirred.
4.6.7. (R)-2,2,2-Trichloro-1-phenylethyl (R)-2-(2-bromophenyl)-2-
hydroxyethylcarbamate (18). A mixture of water (1.5 mL) and ace-
tonitrile (1.5 mL) was added to aziridine 11i (145 mg, 0.32 mmol)
Aniline (280
mL, 3.00 mmol), then BF3$OEt2 (14
mL, 0.10 mmol) were
and the mixture was stirred. BF3$OEt2 (12 mL of a 10% solution in
added and the mixture was stirred at room temperature for 16 h.
EtOAc (3 mL) was added and the layers were separated. The
aqueous layer was washed with EtOAc (2ꢂ3 mL). The combined
organic layers were washed with brine (1ꢂ3 mL), dried over
MgSO4, and concentrated under reduced pressure. The crude
product was purified by flash chromatography (100% CH2Cl2). The
desired product 14d was obtained as a yellow solid (220 mg, 87%
yield) and as one diastereomer by 1H NMR. Rf 0.29 (20% EtOAc/
ether, 0.01 mmol) was added and the mixture was stirred at room
temperature for 1 h. EtOAc (3 mL) was added and the layers were
separated. The aqueous layer was washed with EtOAc (2ꢂ3 mL),
brine (1ꢂ3 mL), dried over MgSO4, and concentrated under reduced
pressure. The crude product was purified by flash chromatography
(100% CHCl3). The desired product 18 was obtained as a white solid
(132 mg, 88% yield). The diastereomeric ratio was determined by
SFC analysis Chiralcel-OJ-H column (25 cm, 40 ꢁC, 20% MeOH at
150 bar), retention time: tR (major)¼6.0 min and tR (minor)¼
7.6 min (dr 87:13). Rf 0.33 (20% EtOAc/hexanes); mp 56e59 ꢁC; 1H
hexanes); mp 81e86 ꢁC; 1H NMR (300 MHz, CDCl3)
d 8.19 (d,
J¼9 Hz, 2H), 7.59 (d, J¼9 Hz, 2H), 7.54 (d, J¼9 Hz, 2H), 7.47e7.38 (m,
3H), 7.09e7.04 (m, 2H), 6.71e6.67 (m, 1H), 6.36 (d, J¼8 Hz, 3H), 6.31
(s, 1H), 5.30 (s, 1H), 4.74 (s, 1H), 4.63e4.61 (m, 1H), 3.70e3.64 (m,
NMR (300 MHz, CDCl3)
d 7.61e7.50 (m, 4H), 7.45e7.33 (m, 4H),
7.19e7.11 (m, 1H), 6.28 (s, 1H), 5.45 (s, 1H), 5.22e5.19 (m, 1H),
1H), 3.57e3.52 (m, 1H); 13C NMR (75 MHz, CDCl3)
d 155.3, 148.2,
3.72e3.64 (m, 1H), 3.43e3.34 (m, 1H), 3.05 (s, 1H); 13C NMR
147.5, 146.0, 132.8, 129.7, 129.4, 129.1, 127.9, 127.4, 124.1, 118.2, 113.3,
99.3, 83.9, 58.9, 47.1; IR (neat) 3383, 3053, 1728, 1521, 1346,
737 cmꢀ1, HMRS calcd for C23H20Cl3N3NaO4 [MþNa]þ 530.0405;
found: 530.0412.
(75 MHz, CDCl3) d 155.1, 139.8, 133.0, 132.6, 129.6, 129.3, 127.8, 127.7,
127.5, 121.6, 99.5, 83.3, 72.5, 46.6; IR (neat) 3423, 1715, 1515, 1243,
747 cmꢀ1, HMRS calcd for C17H16BrCl3NO3 [MþH]þ 465.9377;
found: 465.9374.
4.6.5. (R)-2,2,2-Trichloro-1-phenylethyl (R)-2-hydroxy-2-(3-
nitrophenyl)ethylcarbamate (16). A mixture of water (1.5 mL) and
acetonitrile (1.5 mL) was added to aziridine 5i (140 mg,
4.7. Total synthesis of (R)-(L)-nifenalol
4.7.1. (R)-2-Amino-1-(4-nitrophenyl)ethanol (15). To a solution of
14b (335 mg, 0.770 mmol) in a mixture of acetonitrile (7.5 mL) and
methanol (3 mL) were added LiOH$H2O (162 mg, 3.86 mmol) and
0.340 mmol) and the mixture was stirred. BF3$OEt2 (13 mL of a 10%
solution in ether, 0.01 mmol) was added and the mixture was
stirred at room temperature for 5 h. EtOAc (3 mL) was added and
the layers were separated. The aqueous layer was washed with
EtOAc (2ꢂ3 mL), brine (1ꢂ3 mL), dried over MgSO4, and concen-
trated under reduced pressure. The crude product was purified by
flash chromatography (100% CHCl3). The desired product 16 was
obtained as a yellow solid (128 mg, 87% yield). The diastereomeric
ratio was determined by HPLC analysis Chiralpak-AD column (7% i-
PrOH/hexanes at 1 mL/min), retention time: tR (major)¼23.8 min
and tR (minor)¼34.2 min (dr 88:12). Rf 0.02 (20% EtOAc/hexanes);
water (139 m
L, 7.72 mmol). After 2 h of stirring at 23 ꢁC, water
(10 mL) and EtOAc (20 mL) were added and the two layers were
separated. The aqueous layer was extracted with EtOAc (3ꢂ20 mL).
The combined organic layers were washed with brine (30 mL),
dried over Na2SO4, and concentrated under reduced pressure to
afford the crude compound as a yellow oil. Purification by flash
chromatography (from 50% EtOAc/Hexanes to 100% EtOAc) yields
the corresponding oxazolidinone as a pale-yellow solid (118 mg,
74% yield). To a solution of this oxazolidinone (78 mg, 0.37 mmol)
in acetonitrile (2 mL) was added a 1 M solution of NaOH (1.87 mL,
1.87 mmol) and the solution was stirred at 23 ꢁC for 20 h. Then,
another portion of a 1 M solution of NaOH (1.87 mL, 1.87 mmol,
mp 43e49 ꢁC; 1H NMR (300 MHz, CDCl3)
d 8.25e8.12 (m, 2H),
7.69e7.26 (m, 7H), 6.26 (s, 1H), 5.54 (s, 1H), 5.01e4.99 (m, 1H),
3.6e3.58 (m, 1H), 3.39e3.30 (m, 1H), 3.10 (s, 1H); 13C NMR (75 MHz,

3408
H. Lebel et al. / Tetrahedron 68 (2012) 3396e3409
5.0 equiv) was added and the solution was stirred at 50 ꢁC for 16 h.
After evaporation under reduced pressure, purification by flash
chromatography (20% MeOH/EtOAc) yields the aminoalcohol 15 as
a pale-yellow solid (48 mg, 71% yield). Rf 0.08 (20% MeOH/EtOAc),
15. (a) Gabriel, S. Chem. Ber. 1888, 21, 1049; (b) Gabriel, S. Chem. Ber. 1888, 21, 2664;
(c) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599.
16. See as a recent example: Kim, S. K.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2004,
43, 3952.
17. Sweeney, J. Eur. J. Org. Chem. 2009, 4911.
1H NMR (400 MHz, CD3OD)
d
8.26 (d, J¼8.5, Hz, 2H), 7.69 (d,
18. Selected examples: (a) Davis, F. A.; Liu, H.; Zhou, P.; Fang, T. N.; Reddy, G. V.;
Zhang, Y. L. J. Org. Chem. 1999, 64, 7559; (b) Hanessian, S.; Cantin, L. D. Tetra-
hedron Lett. 2000, 41, 787; (c) Davis, F. A.; Wu, Y. Z.; Yan, H. X.; McCoull, W.;
Prasad, K. R. J. Org. Chem. 2003, 68, 2410; (d) Stockman, R. A.; Sola, T. M.;
Churcher, I.; Lewis, W. Org. Biomol. Chem. 2011, 9, 5034.
19. (a) Aggarwal, V. K.; Alonso, E.; Fang, G. Y.; Ferrar, M.; Hynd, G.; Porcelloni, M.
Angew. Chem., Int. Ed. 2001, 40, 1433; (b) Aggarwal, V. K.; Illa, O.; Arshad, M.;
Ros, A.; McGarrigle, E. M. J. Am. Chem. Soc. 2010, 132, 1828.
J¼8.5 Hz, 2H), 5.02 (dd, J¼9.4, 3.2 Hz, 1H), 3.21 (dd, J¼9.4, 3.2 Hz,
1H), 2.99 (dd, J¼9.4, 9.4 Hz, 1H); 13C NMR (100 MHz, CD3OD)
d
150.3, 149.2, 128.2, 124.7, 70.9, 47.3; HMRS (ESIþ) calcd for
C8H11N2O3 [MþH]þ: 183.07642; found: 183.07674.
20. See also: (a) Yang, X. F.; Mang, M. J.; Hou, X. L.; Dai, L. X. J. Org. Chem. 2002, 67,
8097; (b) Sunoj, R. B.; Janardanan, D. J. Org. Chem. 2008, 73, 8163.
21. (a) Wulff, W. D.; Antilla, J. C. Angew. Chem., Int. Ed. 2000, 39, 4518; (b) Wulff, W.
D.; Patwardhan, A. P.; Pulgam, V. R.; Zhang, Y. Angew. Chem., Int. Ed. 2005, 44,
6169; (c) Wulff, W. D.; Lu, Z. J.; Zhang, Y. J. Am. Chem. Soc. 2007, 129, 7185; (d)
Wulff, W. D.; Zhang, Y.; Desai, A.; Lu, Z. J.; Hu, G.; Ding, Z. S. Chem.dEur. J. 2008,
14, 3785; (e) Wulff, W. D.; Hu, G.; Huang, L.; Huang, R. H. J. Am. Chem. Soc. 2009,
131, 15615; (f) Vetticatt, M. J.; Desai, A. A.; Wulff, W. D. J. Am. Chem. Soc. 2010,
132, 13104; (g) Wulff, W. D.; Desai, A. A. J. Am. Chem. Soc. 2010, 132, 13100.
22. See also: (a) Maruoka, K.; Hashimoto, T.; Uchiyama, N. J. Am. Chem. Soc. 2008,
130, 14380; (b) Akiyama, T.; Suzuki, T.; Mori, K. Org. Lett. 2009, 11, 2445; (c)
Zhong, G. F.; Zeng, X. F.; Zeng, X.; Xu, Z. J.; Lu, M. Org. Lett. 2009, 11, 3036; (d)
Maruoka, K.; Hashimoto, T.; Nakatsu, H.; Yamamoto, K. J. Am. Chem. Soc. 2011,
133, 9730.
23. Pellacani, L.; Fioravanti, S.; Tardella, P. A. Curr. Org. Chem. 2011, 15, 1465.
24. (a) Cordova, A.; Vesely, J.; Ibrahem, I.; Zhao, G. L.; Rios, R. Angew. Chem., Int. Ed.
2007, 46, 778; (b) Melchiorre, P.; Pesciaioli, F.; De Vincentiis, F.; Galzerano, P.;
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2011, 13, 5744.
4.7.2. (R)-(ꢀ)-Nifenalol. To a solution of the aminoalcohol 15
(40 mg, 0.22 mmol) in acetone (2 mL) was added NaBH3CN (28 mg,
0.44 mmol) at 0 ꢁC and the mixture was stirred at 23 ꢁC for 1 h.
Water (5 mL) and DCM (10 mL) were added and the two layers
were separated. The aqueous layer was extracted with DCM
(3ꢂ10 mL). The combined organic layers were dried over Na2SO4
and concentrated under reduced pressure to afford the crude
compound as a pale-yellow solid. Purification by flash chroma-
tography (15% MeOH/CH2Cl2) yielded the title compound as a pale-
yellow solid (30 mg, 61% yield). Rf 0.16 (15% MeOH/CH2Cl2); mp
111e113 ꢁC (lit.53e 113.2 ꢁC); [
a
]
25 ꢀ37.7 (c 0.7, CHCl3); [
a
]
25 ꢀ12.1 (c
D
D
25
0.7, EtOH) {lit.53e
[
a
]
ꢀ11.3 (c 1.0, EtOH)}; 1H NMR (400 MHz,
D
CDCl3)
d
8.20 (d, J¼8.3 Hz, 2H), 7.55 (d, J¼8.3 Hz, 2H), 4.80 (dd,
J¼9.0, 3.6 Hz, 1H), 3.27 (s large, 1H), 3.02 (dd, J¼12.2, 3.6 Hz, 1H),
2.93e2.87 (m, 1H), 2.63 (dd, J¼12.2, 9.0 Hz, 1H), 1.13 (d, J¼3.7 Hz,
3H), 1.10 (d, J¼3.7 Hz, 3H); 13C NMR (100 MHz, CDCl3 150.1, 147.5,
126.7, 123.8, 70.8, 54.0, 49.2, 22.9, 22.6; HMRS (ESIþ) calcd for
C11H17N2O3 [MþH]þ: 225.12337; found: 225.12369.
25. Karila, D.; Dodd, R. H. Curr. Org. Chem. 2011, 15, 1507.
Acknowledgements
26. Chiral salen copper complexes: (a) Li, Z.; Conser, K. R.; Jacobsen, E. N. J. Am.
Chem. Soc. 1993, 115, 5326; (b) Jacobsen, E. N.; Li, Z.; Quan, R. W. J. Am. Chem.
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T.; Anderson, B. A.; Barnes, D. M. J. Am. Chem. Soc. 1993, 115, 5328.
28. Cinnamate derivatives: Wang, X. S.; Ding, K. L. Chem.dEur. J. 2006, 12, 4568.
29. Chalcone derivatives: (a) Ma, L. G.; Jiao, P.; Zhang, Q. H.; Xu, J. X. Tetrahedron:
Asymmetry 2005, 16, 3718; (b) Ma, L.; Jiao, P.; Zhang, Q.; Du, D.-M.; Xu, J. Tet-
rahedron: Asymmetry 2007, 18, 878.
30. Other examples: (a) Sanders, C. J.; Gillespie, K. M.; Bell, D.; Scott, P. J. Am. Chem.
Soc. 2000, 122, 7132; (b) Gillespie, K. M.; Sanders, C. J.; O’Shaughnessy, P.;
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31. Transition metals other than Cu: (a) Noda, K.; Hosoya, N.; Irie, R.; Ito, Y.; Katsuki,
T. Synlett 1993, 469; (b) Nishikori, H.; Katsuki, T. Tetrahedron Lett. 1996, 37,
9245; (c) Lai, T.-S.; Che, C.-M.; Kwong, H.-L.; Peng, S.-M. Chem. Commun. 1997,
2373; (d) Simonato, J.-P.; Pecaut, J.; Marchon, J.-C.; Robert Scheidt, W. Chem.
Commun. 1999, 989; (e) Liang, J. L.; Huang, J. S.; Yu, X. Q.; Zhu, N. Y.; Che, C. M.
Chem.dEur. J. 2002, 8, 1563; (f) Yamawaki, M.; Tanaka, M.; Abe, T.; Anada, M.;
Hashimoto, S. Heterocycles 2007, 72, 709; (g) Nakanishi, M.; Salit, A. F.; Bolm, C.
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This research was supported by the Natural Science and Engi-
neering Research Council of Canada (NSERC), Johnson & Johnson,
the Canada Foundation for Innovation, the Canada Research Chair
Program, the Universite de Montreal and the Centre in Green
Chemistry and Catalysis (CGCC). We are grateful to Prof. Andre B.
Charette and his group for sharing several bis(oxazoline) ligands as
well as for fruitful discussions. We thank Dr. Phan viet Minh Tan
and Sylvie Bilodeau from the Universite de Montreal NMR Center.
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
References and notes
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