A facile, one-pot synthesis of Ephedra-based aziridines

Article abstract of DOI:10.1016/j.tetasy.2009.07.016

A series of enantiomerically and diastereomerically enriched N-sulfonylaziridines have been prepared by a single-pot process from (1R,2S)- and (1S,2R)-norephedrine and (1S,2S)-pseudonorephedrine. The cyclization process involved N-sulfonylation of the Ephedra alkaloid followed by O-sulfonylation with methanesulfonyl chloride. The bis(sulfonyl)Ephedra derivatives were treated with either hydrazine or sodium hydroxide to afford the N-sulfonylaziridines.

Full text of DOI:10.1016/j.tetasy.2009.07.016

Tetrahedron: Asymmetry 20 (2009) 1969–1974
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A facile, one-pot synthesis of Ephedra-based aziridines
*
Jonathan A. Groeper , Joel B. Eagles, Shawn R. Hitchcock
Department of Chemistry, Illinois State University, Normal, IL 61790-4160, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of enantiomerically and diastereomerically enriched N-sulfonylaziridines have been prepared by
a single-pot process from (1R,2S)- and (1S,2R)-norephedrine and (1S,2S)-pseudonorephedrine. The cycli-
zation process involved N-sulfonylation of the Ephedra alkaloid followed by O-sulfonylation with meth-
anesulfonyl chloride. The bis(sulfonyl)Ephedra derivatives were treated with either hydrazine or sodium
hydroxide to afford the N-sulfonylaziridines.
Received 4 June 2009
Accepted 7 July 2009
Available online 10 September 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
terms of the sulfonyl group that is introduced into the system.
Two equivalents of the sulfonyl chloride must be employed in or-
The application of enantiomerically enriched aziridines as chiral
building blocks1 and as chemical reagents2 continues to enjoy
widespread exposure in asymmetric organic synthesis. There are
a wide variety of methods that can be employed in the synthesis
of these valuable intermediates.3 In 1992, Craig and Berry4 demon-
strated that N-tosylaziridines could be prepared by a three-step se-
der to obtain the product. If the desired sulfonyl group is valuable,
for example, -(+)-10-camphorsulfonyl, then the route of 2 equiv
D
would not be the optimal synthetic pathway as 1 equiv would be
lost as a sulfonate leaving group, resulting in poor atom economy.
Based on this analysis, it would be favorable to develop a one-pot
process where the N-sulfonyl group would be distinct from the O-
sulfonyl leaving group. We envisioned a process that would first
substitute the nitrogen with the desired alkyl- or arylsulfonyl chlo-
ride, followed by the activation of the alcohol with methanesulfo-
nyl chloride, generating an inexpensive and sacrificial sulfonate for
the cyclization stage of the aziridine formation. We report on the
development of a process that addresses the facile preparation of
a variety of Ephedra-based N-sulfonylaziridines in a single-pot
system.
quence from commercially available chiral a-amino acids (Scheme
1). The process involved N-tosylation of the amino acid 1 and sub-
sequent reduction to generate the N-tosylamino alcohol 2, which
in turn was sulfonylated and cyclized under basic conditions (tri-
ethylamine) to afford the N-tosylaziridine 3. In 2003, Leighton
and Krauss5 employed a more effective, single-step process that al-
lowed the formation of chiral N-sulfonylaziridines from either
L-
valinol or
L
-tert-leucinol. More recently, in 2007, Badía et al.6 fur-
ther refined this process so that such aziridines could be obtained
on a large scale in high yield.
2. Results and discussion
We were interested in preparing a series of aziridines derived
from (1R,2S)-norephedrine and (1S,2S)-pseudonorephedrine. Pre-
viously, in 2004, Zhang et al. prepared N-sulfonylaziridines pos-
sessing the Ephedra constitution by iron-catalyzed aziridination
of trans-b-methylstyrene (Scheme 2).7 Later, in 2007, Vinod et al.
reported a two-step synthetic process involving sulfonylation of
(1R,2S)-norephedrine followed by a Mitsunobu cyclization to yield
a series of N-sulfonylaziridines (Scheme 2).8
The methods described in Schemes 1 and 2 serve as the inspira-
tion for the development of a flexible, one-pot method for the
preparation of enantiomerically and diastereomerically pure Epeh-
dra-based aziridines. The most efficient of these processes is the
one developed by Badía et al. However, this process is limited in
This research was initiated by conducting a simple experiment
to determine the viability of preparing Ephedra-based aziridines by
a multistep, one-pot method similar to the one refined by Bádia
et al.6 (1R,2S)-Norephedrine 7 was treated with 2 equiv of meth-
anesulfonyl chloride and excess triethylamine and allowed to stir
to form the putative N,O-bis(methanesulfonyl) derivative 10 with-
in 1 h (Scheme 3). As had been observed in the study by Berry and
Craig,4 it was expected that the presence of triethylamine would
stimulate the formation of the aziridine 9a. The cyclization process
did indeed occur, but not in a timely fashion. There have been
numerous literature examples where triethylamine, sodium
hydride, or an alkali carbonate had been employed in the forma-
tion of sulfonamide aziridines.9 Among the bases that were
explored for this process, it was determined that when hydrazine
was added to the mixture, there was an immediate acceleration
of the cyclization as observed by thin layer chromatography. We
* Corresponding author. Fax: +1 309 438 5538.
E-mail address: hitchcock@ilstu.edu (S.R. Hitchcock).
Present address: Merck Research Laboratories, Rahway, NJ, United States.
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.07.016

1970
J. A. Groeper et al. / Tetrahedron: Asymmetry 20 (2009) 1969–1974
Ts
NH3
CO2
NHTs
CH2OH
N
TsCl, Et3N
1. TsCl, NaOH
2. LiAlH4, Et2O
Craig and Berry4
R1
R1
R1
1
2
3
2 equiv. TsCl
Et3N, DMAP
NH2
CH2OH
Leighton and Krauss,5 Badia et al.6
3
R1
CH2Cl2
4
Scheme 1. Aziridine literature syntheses.
Ts
N
RT, CH3CN, TsN(Na)Br
Fe(porphyrin)Cl
CH3
Ph
Ph
CH3
6
5
Zhang et al.7
SO2R
N
OH
OH
Ph3P, DIAD
THF
RSO2Cl, Et3N
CH2Cl2
NHSO2R
NH2
Ph
Ph
CH3
Ph
CH3
CH3
(1R,2S)-7
8
9
Vinod et al.8a
Scheme 2. Ephedra aziridine synthesis.
were gratified to learn that the hydrazine-mediated cyclization of
10 to the corresponding aziridine 9a was nearly quantitative and
occurred more quickly than the triethylamine-mediated reaction,
presumably due to steric differences as the pKa of the conjugate
acid of triethylamine (10.75)10a,b is reported to be higher than that
of hydrazine (8.07).10c
hydrazine was added to the reaction mixture to induce the forma-
tion of the N-toluenesulfonylaziridine 9b within 1 h in 93% yield
after flash chromatography.
With the test case established for the multistep, one-pot reac-
tion process, other examples were considered. Thus, (1R,2S)-nor-
ephedrine 7 and (1S,2S)-pseudonorephedrine 13 were reacted
first with either p-toluenesulfonyl chloride or o-nitrobenzenesulfo-
nyl chloride and 1 equiv of triethylamine and were allowed to stir
for 1 h (Scheme 5). An additional equivalent of triethylamine and
1 equiv of methanesulfonyl chloride were then added and the reac-
tion mixture was stirred for 1 h. An excess of hydrazine hydrate
Encouraged by this result, we opted to design a multistep, sin-
gle-pot process that would allow for the formation of other N-sulf-
onylaziridines but would not require the use of 2 equiv of a
potentially valuable sulfonyl group. The use of methanesulfonyl
chloride to form the O-sulfonate leaving group was considered to
be ideal as it is commercially inexpensive and very atom econom-
ical. This synthetic route was explored in a stepwise fashion using
(1R,2S)-7 as a test case (Scheme 4). Treatment of (1R,2S)-7 with
p-toluenesulfonyl chloride and triethylamine formed the N-p-tolu-
enesulfonyl derivative 11 in 98% yield within 1 hr as evidenced by
thin layer chromatography. With this time parameter set, (1R,2S)-7
was treated again with p-toluenesulfonyl chloride and triethyl-
amine and then, after 1 h, was treated with methanesulfonyl chlo-
ride and triethylamine and allowed to stir for an hour to form the
O-methanesulfonyl-N-toluenesulfonylnorephedrine derivative 12
in 96% yield. Finally, (1R,2S)-7 was treated under the same
conditions and after the expected formation of 12 in situ,
OH
TsCl, Et3N, THF
NHTs
1 hour
98%
Ph
Ph
CH3
11
OMs
1a. TsCl, Et3N, THF
1b. MsCl, Et3N, THF
96%
NHTs
(1R,2S)-7
CH3
12
SO2CH3
SO2Tol
N
OMs
1a. TsCl, Et3N, THF
1b. MsCl, Et3N, THF
2 equiv. MsCl
Et3N, THF
NH2NH2
N
NHMs
(1R,2S)-7
Ph
1c. NH2NH2-H2O
CH3
10
Ph
CH3
CH3
9a (92%)
Ph
93%
9b
Scheme 3. Multistep, single-pot synthesis of aziridine 9a.
Scheme 4. Development of the single-pot process.

J. A. Groeper et al. / Tetrahedron: Asymmetry 20 (2009) 1969–1974
1971
OH
R2
OMs
1c. NH2NH2-H2O
1a. RSO2Cl, Et3N, CH2Cl2
NH2
CH3
NHSO2R
R1
R1
1b. MsCl, Et3N
R2
CH3
7: R1 = -Ph, R2 = -H
13: R1 = -H, R2 = -Ph
14: R1 = -Ph, R2 = -H
15: R1 = -H, R2 = -Ph
SO2R
N
R2
CH3
R1
9c: R = -o-Ns, R1 = -Ph, R2 = -H (73%)
16a: R = -p-Ts, R1 = -H, R2 = -Ph (87%)
16b: R = -o-Ns, R1 = -H, R2 = -Ph (60%)
Scheme 5. Multistep, one-pot synthesis of norephedrine and pseudonorephedrine aziridines.
was then added and the reactions were stirred until complete
product formation was determined by thin layer chromatography.
The isolated chemical yield for the formation of the aziridines 9c,
16a, and 16b was 73%, 87% and 60%, respectively. The yields for
the N-o-nitrobenzenesulfonyl aziridines 9c and 16b were lower
due to nucleophilicity of the hydrazine–hydrate being used. This
was perhaps due to the enhanced electrophilicity of the benzylic
carbon of the aziridine by way of the sulfonyl group.
In all cases of aziridine formation by inversion of the benzylic
position through nucleophilic substitution, there was no detectable
stereochemical scrambling as determined by 1H NMR spectro-
scopic analysis. Ultimately, the isolation of diastereomerically pure
aziridines (cis-aziridines, J = 7.4–7.7 Hz; trans-aziridines, J = 4.3–
4.7 Hz) suggested that the process of the displacement of the
methanesulfonate group proceeded through an ‘SN2’ type transi-
tion state rather than an ‘SN1’ type ionized intermediate.
and triethylamine to afford the sulfonylated derivatives 17 and
18 in 94% and 83% yields, respectively, after only 1 hr as judged
by thin layer chromatography. This established a time window to
ensure that complete sulfonylation had occurred. At this stage,
the two-step process of forming bis(sulfonylated) intermediates
19 and 20 was investigated. It was determined that the complete
formation of the N-camphorsulfonyl-O-methanesulfonyl Ephedra
derivatives 19 and 20 occurred in a 4-h. time frame. Attempts to
chromatographically purify these intermediates were not success-
ful due to their reactive nature, that is, aziridine formation. The
one-pot bis(sulfonylation) was carried out to yield the putative
intermediates 19 and 20 and these compounds were treated with
hydrazine–hydrate to effect the cyclization. Unfortunately, the
cyclization stage of the reaction proved to be sluggish under these
conditions and the reactions were not complete even after 12 h.
We were gratified to learn that the use of sodium hydroxide/meth-
anol mixture was considerably more effective for the cyclization
process and ultimately led to the formation of the target aziridines
21 and 22 in 82% and 56% overall yield, respectively, for the three
There was also an interest in the synthesis of camphorsulfonyl-
based derivatives 21 and 22 (Scheme 6). In this context, (1R,2S)-7
and (1S,2R)-7 were each reacted with
D
-camphorsulfonyl chloride
O
HO
R1
NH2
R4
O
SO2
SO2Cl
TEA, THF
NH
HO
R1
R2 R3
R4
R2 R3
(1R,2S)-7: R1 = -Ph; R2 = -H; R3 = -H; R4 = -CH3
(1S,2R)-7: R1 = -H; R2 = -Ph; R3 = -CH3; R4 = -H
17: R1 = -Ph; R2 = -H; R3 = -H; R4 = -CH3 (94%)
18: R1 = -H; R2 = -Ph; R3 = -CH3; R4 = -H (83%)
1a.
O
SO2Cl
1c. NaOH, CH3OH
TEA, THF
O
O
SO2
NH
SO2
(1R,2S)-7/(1S,2R)-7
1b. MsCl, TEA, THF
N
MsO
R1
R2
R4
R4
R1 R3
R2 R3
19: R1 = -Ph; R2 = -H; R3 = -H; R4 = -CH3 21: R1 = -Ph; R2 = -H; R3 = -H; R4 = -CH3 (82% overall)
20: R1 = -H; R2 = -Ph; R3 = -CH3; R4 = -H 22: R1 = -H; R2 = -Ph; R3 = -CH3; R4 = -H (56% overall)
Scheme 6. D-Camphorsulfonylaziridine synthesis.

1972
J. A. Groeper et al. / Tetrahedron: Asymmetry 20 (2009) 1969–1974
step, one-pot process. The use of the methanolic base solution re-
quired an overnight process to reach completion as determined by
the TLC analysis. The lower yield of 22 is attributed to potential
conformational differences between intermediates 19 and 20 that
may interfere with the ring-closing process.
was extracted with ethyl acetate and the solvents were removed.
The resulting white solid was triturated with diethyl ether to afford
the title compound in 98% yield. ½a D24
ꢂ
¼ ꢀ2:3 (c 1.0, CH2Cl2). 1H
NMR (400 MHz, CDCl3) d 0.81 (3H, d, J = 7.0 Hz), 2.38 (3H, s), 3.27
(1H, br s), 3.49 (1H, dq, J = 5.5, 7.0 Hz), 4.80 (1H, d, J = 5.5 Hz). 13C
NMR (100 MHz, CDCl3) d 14.6, 21.5, 54.9, 75.7, 126.0, 126.9,
127.6, 128.3, 129.7, 137.7, 140.2, 143.5. IR (Nujol): 3509, 3208,
3. Conclusion
1598, 1324, 1160, 1092, 702 cmꢀ1
. HRMS (ESI) calcd for
C16H20NO3S (M+H+): 306.1164. Found: 306.1168.
A three-step, one-pot process for the formation of N-sulfonylaz-
iridines derived from either norephedrine or pseudonorephedrine
was developed. The combined reactions of the introduction of
the selected arylsulfonyl or camphorsulfonyl group at nitrogen, fol-
lowed by formation of the nucleofuge mesylate, and the base-med-
iated cyclization (hydrazine–hydrate or NaOH/MeOH) proved to be
successful in creating synthetically valuable aziridines.
4.4. (1R,2S)-2-(p-Toluenesulfonamido)-1-phenylpropyl meth-
anesulfonate 12
To a flame-dried, nitrogen purged reaction vessel containing
(1R,2S)-norephedrine, in a 0.3 M THF solution, was added 1.1 equiv
of TEA and the solution was cooled in an ice bath. To this mixture,
1.05 equiv of p-toluenesulfonyl chloride was added and the ice
bath was removed after several minutes. After a 1-h reaction time,
1.1 equiv of TEA was added to the reaction mixture with ice bath
cooling. This was followed by the addition of 1.05 equiv of meth-
anesulfonyl chloride and the bath was removed after several min-
utes. After 1 h, saturated sodium bicarbonate was added and the
THF was removed. The sulfonamide was extracted with ethyl ace-
tate and the solvents were removed to afford a white solid which
was triturated with diethyl ether to provide 12 in 96% yield. Mp:
4. Experimental
4.1. General information
Enantiomerically enriched (1R,2S)- and (1S,2R)-norephedrine
was purchased from Sigma–Aldrich. All reaction vessels were
flame dried and purged under a nitrogen atmosphere. Triethyl-
amine (TEA) was distilled over calcium hydride. All extractions
were dried over anhydrous magnesium sulfate, gravity filtered,
and the solvents were removed under vacuum. Infrared data were
acquired using a Perkin–Elmer Spectrum BX FT-IR spectrophotom-
er on NaCl plates and were reported in reciprocal centimeters
(cmꢀ1). All NMR spectra were recorded in CDCl3 and reported in
parts per million (d scale) with tetramethylsilane as an internal
standard (d = 0 ppm, 1H) or deuterated chloroform as a standard
(d = 77.0 ppm, 13C). On some 1H NMR spectra, the OH and NH peaks
on the spectrum were not observed due to broadening. Optical
rotation data were collected on a JASCO P-1010 digital polarimeter
operating at 589 nm in an 8 ꢁ 100 mm cell. Melting points were
determined using a Laboratory Devices Mel-Temp apparatus and
are uncorrected. Mass Spectral data were collected by the Univer-
sity of Illinois at Urbana-Champaign.
decomposes >90 °C.
½
a 2D5
ꢂ
¼ ꢀ68:7 (c 1.0, CH2Cl2). 1H NMR
(400 MHz, CDCl3): d 1.03 (3H, d, J = 7.0 Hz), 2.43 (3H, s), 2.91 (3H,
s), 3.68 (1H, ddq, J = 3.5, 7.0, 8.6 Hz), 4.95 (1H, d, J = 8.6 Hz), 5.56
(1H, d, J = 3.5 Hz), 7.23–7.36 (7H, m), 7.76 (2H, d, J = 8.2 Hz). 13C
NMR (100 MHz, CDCl3, due to coincidental overlap, some peaks
in the aromatic region are missing) d 15.2, 21.5, 38.6, 53.9, 84.9,
126.3, 127.1, 128.9, 129.8, 135.2, 137.4, 143.7. IR (Nujol): 3305,
3030, 1595, 1454, 1377, 1172, 938, 749, 701 cmꢀ1. HRMS calcd
for C17H25N2O5S2 (M+NH4+): 401.1205. Found: 401.1196.
4.5. (2S,3S)-2-Methyl-3-phenyl-1-toluenesulfonylaziridine 9b
In a flame-dried, nitrogen purged reaction vessel containing
(1R,2S)-norephedrine, in a 0.3 M THF solution, 1.1 equiv of TEA
was added and the solution was cooled in an ice bath. To this,
1.05 equiv of p-toluenesulfonyl chloride was added and the water
bath was removed after several minutes. After a 1-h reaction time,
1.1 equiv of TEA was added to the reaction mixture with ice bath
cooling. This was followed by the addition of 1.05 equiv of meth-
anesulfonyl chloride and the reaction was allowed to proceed for
an additional hour after which 5 equiv of hydrazine was added to
afford aziridine 9b as a colorless oil in 93% yield after flash chroma-
4.2. (2S,3S)-2-Methyl-1-(methanesulfonyl)-3-phenylaziridine 9a
In a flame-dried, nitrogen purged reaction vessel containing
(1R,2S)-norephedrine, in a 0.3 M THF solution, 2.2 equiv of triethyl-
amine was added and the solution was cooled in an ice bath. To
this solution, 2.1 equiv of methanesulfonyl chloride was added
and the reaction was allowed to proceed for an hour after which
5 equiv of hydrazine was added to afford aziridine 9a as a colorless
oil in 92% yield after chromatography. The reaction was monitored
tography. The reaction was monitored by TLC. ½a D25
¼ þ66:2 (c 1.06,
ꢂ
CHCl3). 1H NMR (400 MHz, CDCl3) d 1.82 (3H, d, J = 6.3 Hz), 2.36
(3H, s), 2.90 (1H, dq, J = 4.3, 6.3 Hz), 3.80 (1H, d, J = 4.3 Hz), 7.12–
7.15 (5H, m), 7.23 (2H, d, J = 7.4 Hz), 7.82 (2H, d, J = 8.6 Hz). 13C
NMR (100 MHz, CDCl3) d 14.0, 21.4, 49.0, 49.1, 126.2, 127.1,
127.9, 128.4, 129.4, 135.5, 137.8, 143.8. IR (neat) 3063, 3030,
1602, 748, 699 cmꢀ1. HRMS (ESI) calcd for C16H18NO2S (M+H+):
288.1058. Found: 288.1052.
by TLC (Rf = 0.36, 9:1, hex/EtOAc). ½a D25
ꢂ
¼ ꢀ95:2 (c 0.99, CH2Cl2). 1H
NMR (400 MHz, CDCl3): d 1.78 (3H, d, J = 5.9 Hz), 2.90 (1H, dq,
J = 4.3, 5.9 Hz), 3.07 (3H, s), 3.70 (1H, d, J = 4.3 Hz), 7.26–7.38
(5H, m). 13C NMR (100 MHz, CDCl3) d 13.9, 42.5, 48.8, 48.9,
126.1, 128.2, 128.6, 135.4. IR (neat): 3063, 3031, 1602, 1150, 805,
776, 749, 700 cmꢀ1. HRMS (ESI) calcd for C10H14NO2S (M+H+):
212.0745. Found: 212.0743.
4.6. (2S,3S)-2-Methyl-1-(o-nitrobenzenesulfonyl)-3-phenylaziri-
4.3. N-((1R,2S)-1-Hydroxy-1-phenyl-2-propyl)-p-toluenesulfon-
dine 9c
amide 11
In a flame-dried, nitrogen purged reaction vessel containing
(1R,2S)-norephedrine, in a 0.3 M THF solution, 1.1 equiv of triethyl-
amine (TEA) was added and the solution was cooled in an ice bath.
To this, 1.05 equiv of o-nitrobenzenesulfonyl chloride was added
and the water bath was removed after several minutes. After a 1-
h reaction time, 1.1 equiv of TEA was added to the reaction mixture
with ice bath cooling. This was followed by the addition of
(1R,2S)-Norephedrine was dissolved in THF to afford a 0.3 M
solution with 1.1 equiv of TEA and the solution was placed in an
ice bath. To this solution, 1.05 equiv of p-toluenesulfonyl chloride
was added and the water bath was removed after several minutes.
After 1 h, the reaction was quenched with saturated bicarbonate
and the THF removed under vacuum after which the sulfonamide

J. A. Groeper et al. / Tetrahedron: Asymmetry 20 (2009) 1969–1974
1973
1.05 equiv of methanesulfonyl chloride and the reaction was al-
lowed to proceed for an additional hour after which 5 equiv of
hydrazine were added and the reaction was stirred for 6 h. This
process afforded aziridine 9c as a colorless oil in 72% yield after
chloride (1.74 g, 6.94 mmol) was added slowly. After several min-
utes, the ice bath was removed from the flask, and the reaction was
allowed to proceed with stirring for 1 h. After 1 h, the reaction was
quenched with 25 mL NaHCO3, and the organic solvents were re-
moved by rotary evaporation. The product sulfonamide was ex-
tracted with 3 portions, 50 mL each, of ethyl acetate and the
combined solution were washed with 3 M HCl (50 mL) followed
by brine solution (50 mL). The solution was then dried over mag-
nesium sulfate, gravity filtered, and the solvents were removed un-
der vacuum, which after flash chromatography (80% hexanes, 20%
EtOAc) yielded a thick colorless oil (2.27 g, 6.21 mmol, 94% yield).
chromatography. The reaction was monitored by TLC. ½a D24
¼
ꢂ
ꢀ93:5 (c 0.77, CH2Cl2). 1H NMR (400 MHz, CDCl3) d 1.86 (3H, d,
J = 6.3 Hz), 3.09 (1H, dq, J = 4.7 Hz, J = 6.3 Hz), 3.94 (1H, d,
J = 4.7 Hz), 7.22–7.30 (5H, m), 7.65–7.69 (2H, m), 8.19–8.21 (2H,
m); 13C NMR (100 MHz, CDCl3, due to coincidental overlap, some
peaks in the aromatic region are missing) d 15.0, 50.9, 51.4,
124.1, 126.3, 128.1, 128.3, 130.3, 132.1, 133.9, 135.1, 147.9. IR
(neat): 3094, 3028, 2936, 1592, 1543, 1367, 1165, 747, 699 cmꢀ1
.
½
a 2D4
ꢂ
¼ þ4:3 (c 1.15 CHCl3). 1H NMR (400 MHz, CDCl3) d 0.88
HRMS calcd for C15H15N2O4S (M+H+): 319.0753. Found: 319.0753.
(3H,s), 1.06 (3H, s), 1.09 (3H, d, J = 6.8 Hz), 1.45 (1H, ddd, J = 3.9,
9.3, 12.9 Hz), 1.85 (1H, m), 1.95 (1H, d, J = 18.6 Hz), 2.00–2.09
(1H, m), 2.13 (1H, t, J = 4.4 Hz), 2.34–2.44 (2H, m), 2.82 (1H, d,
J = 4.4 Hz), 2.97 (1H, d, J = 15.0 Hz), 3.49 (1H, d, J = 15.0 Hz), 3.88–
3.96 (1H, m), 4.94 (1H, t, J = 4.0 Hz), 5.03 (1H, d, J = 8.5 Hz), 7.27–
7.40 (5H, m). 13C NMR (125 MHz, CDCl3) d 15.9, 19.6, 19.9, 25.7,
27.0, 42.7, 42.8, 48.5, 51.3, 55.3, 59.0, 75.8, 126.2, 127.7, 128.4,
216.6. IR (neat): 3500, 3296, 1741, 1325, 1137 cmꢀ1. HRMS (ESI)
calcd for C19H28NO4S (M+H+) 366.1739. Found: 366.1728.
4.7. (2S,3R)-2-Methyl-3-phenyl-1-toluenesulonylaziridine 16a
In a flame-dried, nitrogen purged reaction vessel containing
(1S,2S)-pseudonorephedrine in a 0.3 M THF solution, 1.1 equiv of
TEA was added and the solution was cooled in an ice bath. To this,
1.05 equiv of p-toluenesulfonyl chloride was added and the water
bath was removed after several minutes. After a 1-h reaction time,
1.1 equiv of TEA was added to the reaction mixture with ice bath
cooling. This was followed by the addition of 1.05 equiv of meth-
anesulfonyl chloride and the reaction was allowed to proceed for
an additional hour after which 5 equiv of hydrazine was added to
afford the title compound as a colorless oil in 87% yield after flash
4.10. 1-(7,7-Dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)-N-((1S,2R)-
1-hydroxy-1-phenyl-2-propyl)methanesulfonamide 18
To a flame-dried, nitrogen purged 100 mL flask containing
(1S,2R)-norephedrine (1.00 g, 6.61 mmol) dissolved in a 0.30 M
solution of THF (22.0 mL), 1.10 equiv of triethylamine (1.02 mL,
7.28 mmol) was added and the solution was cooled in an ice bath.
chromatography. 1H NMR (300 MHz, CDCl3)
d 1.01 (3H, d,
J = 6.1 Hz), 2.42 (3H, s), 3.18 (1H, dq, J = 6.1, 7.7 Hz), 3.92 (1H,
J = 7.7 Hz), 7.19–7.28 (5H, m), 7.32 (2H, d, J = 8.2 Hz), 7.88 (2H, d,
J = 8.0 Hz). 13C NMR (75 MHz, CDCl3, due to coincidental overlap,
some peaks in the aromatic region were not observed) d 11.9,
21.6, 41.5, 46.0, 127.5, 127.7, 128.2, 129.7, 132.7, 135.2, 144.4. IR
(neat): 1603, 1593, 1319, 1161, 889, 759, 700 cmꢀ1. HRMS calcd
for C16H17NO2S (M+H+): 288.1058. Found: 288.1057.
To the cooled solution, 1.05 equiv of
D-(+)-10-camphorsulfonyl
chloride (1.74 g, 6.94 mmol) was added slowly. After several min-
utes, the ice bath was removed from the flask, and the reaction was
allowed to proceed with stirring for 1 h. After 1 h, the reaction was
quenched with 25 mL NaHCO3, and the organic solvents were re-
moved by rotary evaporation. The product sulfonamide was ex-
4.8. (2S,3R)-2-Methyl-1-(o-nitrobenzenesulfonyl)-3-phenylazir-
tracted with 3 portions, 50 mL each, ethyl acetate and the
idine 16b
solution were washed with 50 mL of 3 M HCl followed by 50 mL
brine solution. The solution was then dried over magnesium sul-
fate, gravity filtered, and the solvents were removed under vac-
uum, which after flash chromatography (80% hexanes, 20%
EtOAc) yielded a thick colorless oil (2.01 g, 5.50 mmol, 83% yield).
To a flame-dried, nitrogen purged reaction vessel containing
(1S,2S)-pseudonorephedrine in a 0.3 M THF solution, 1.1 equiv of
TEA was added and the solution was cooled in an ice bath. To this
mixture, 1.05 equiv of o-nitrobenzenesulfonyl chloride was added
and the water bath was removed after several minutes. After a
1-h reaction time, 1.1 equiv of TEA was added to the reaction mix-
ture with ice bath cooling. This was followed by the addition of
1.05 equiv of methanesulfonyl chloride and the reaction was
allowed to proceed for an additional hour after which 5 equiv of
hydrazine was added to afford the title compound as a colorless
½
a 2D4
ꢂ
¼ þ27:1 (c 1.10, CHCl3) 1H NMR (400 MHz, CDCl3) d 0.89
(3H, s), 1.03 (3H, s), 1.06 (3H, d, J = 6.9 Hz), 1.41–1.48 (1H, m),
1.93 (1H, d, J = 18.7 Hz), 1.94–2.08 (2H, m), 2.13 (1H, t,
J = 4.4 Hz), 2.19–2.18 (1H, m), 2.39 (1H, ddd, J = 3.0, 4.6, 18.6 Hz),
2.74 (1H, d, J = 4.3 Hz), 2.99 (1H, d, J = 15.1 Hz), 3.40 (1H, d,
J = 15.1 Hz), 3.77 -3.85 (1H, m), 4.97 (1H, t, J = 3.7 Hz), 5.47 (1H,
d, J = 7.6 Hz), 7.27–7.39 (5H, m). 13C NMR (100 MHz, CDCl3) d
14.8, 19.6, 19.9, 26.5, 27.0, 42.8, 42.9, 48.6, 51.3, 55.6, 59.3, 76.2,
126.3, 127.6, 128.2, 140.4, 216.6. IR (neat): 3500, 3297, 1738,
oil in 60% yield after chromatography. ½a D24
¼ ꢀ129:1 (c 1.0,
ꢂ
CH2Cl2). 1H NMR (300 MHz, CDCl3) d 1.12 (3H, d, J = 5.9 Hz), 3.42
(1H, dq, J = 5.9, 7.4 Hz), 4.22 (1H, d, J = 7.4 Hz), 7.27–7.35 (5H, m),
7.75–7.78 (2H, m), 8.27–8.29 (2H, m); 13C NMR (75 MHz, CDCl3
due to coincidental overlap, some peaks in the aromatic region
are missing) d 11.6, 44.6, 47.1, 124.2, 127.9, 131.8, 132.2, 132.2,
134.5, 148.3. IR (neat): 3094, 3029, 2933, 1732, 1591, 1537,
1335, 1163, 765, 699 cmꢀ1. HRMS calcd for C15H15N2O4S (M+H+):
319.0753. Found: 319.0740.
3127, 1137 cmꢀ1 HRMS (ESI) calcd for C19H28NO4S (M+H+):
.
366.1739. Found: 366.1749.
4.11. 7,7-Dimethyl-1-(((2S,3S)-2-methyl-3-phenylaziridin-1-yls-
ulfonyl)methyl)bicyclo [2.2.1]heptan-2-one 21
To a flame-dried, nitrogen purged 100 mL flask containing
(1R,2S)-norephedrine (0.700 g, 4.62 mmol) dissolved in a 0.30 M
solution of THF (15.4 mL), 1.10 equiv of triethylamine (0.71 mL,
5.1 mmol) was added and the solution was cooled in an ice bath.
4.9. 1-(7,7-Dimethyl-2-oxobicyclo[2.2.1]-1-heptyl)-N-((1R,2S)-
1-hydroxy-1-phenyl-2-propyl) methanesulfonamide 17
To the cooled solution, 1.05 equiv of
D-(+)-10-camphorsulfonyl
To a flame-dried, nitrogen purged 100 mL flask containing
(1R,2S)-norephedrine (1.00 g, 6.61 mmol) dissolved in a 0.30 M
solution of THF (22.0 mL), 1.10 equiv of triethylamine (1.02 mL,
7.28 mmol) was added and the solution was cooled in an ice bath.
chloride (1.22 g, 4.86 mmol) was added slowly. After several min-
utes, the ice bath was removed from the flask, and the reaction was
allowed to proceed with stirring for 1 h. After 1 h, an additional
1.10 equiv of triethylamine (0.515 g, 5.09 mmol) was added to
the solution, and the solution was returned to an ice bath. To the
To the cooled solution, 1.05 equiv of
D-(+)-10-camphorsulfonyl

1974
J. A. Groeper et al. / Tetrahedron: Asymmetry 20 (2009) 1969–1974
cool solution, methane sulfonyl chloride (0.583 g, 5.09 mmol) was
added dropwise. After several minutes the ice bath was removed,
and the reaction was left to proceed with stirring for 4 h. After
4 h, methanol (10 mL) was added to the reaction, and 2.00 equiv
of 3 M sodium hydroxide (3.10 mL, 9.24 mmol) was added to the
flask. The reaction was left to proceed for 6 h, after which the reac-
tion was quenched with 25 mL NaHCO3, and the organic solvents
were removed by rotary evaporation. The product aziridine was
extracted with 3 portions, 50 mL each, ethyl acetate and the solu-
tion were washed with 50 mL of 3 M HCl followed by 50 mL brine
solution. The solution was then dried over magnesium sulfate,
gravity filtered, and the solvents were removed under vacuum,
which after flash chromatography (90% hexanes, 10% EtOAc)
50 mL brine solution. The solution was then dried over magnesium
sulfate, gravity filtered, and the solvents were removed under vac-
uum, which after flash chromatography (90% hexanes, 10% EtOAc)
yielded
a thick colorless oil (1.29 g, 3.71 mmol, 56% yield).
½
a 2D4
ꢂ
¼ ꢀ79:0 (c 0.91, CHCl3). 1H NMR (400 MHz, CDCl3) d 0.86
(3H, s), 1.11 (3H, s), 1.41 (1H, ddd, J = 3.9, 9.4, 12.6 Hz), 1.70 (1H,
ddd, J = 4.8, 9.4, 14.5 Hz), 1.78 (2H, d, J = 6.0 Hz), 1.92 (1H, d,
J = 18.4 Hz), 1.97–2.06 (1H, m), 2.08 (1H, t, J = 4.3 Hz), 2.37 (1H,
ddd, J = 4.3, 4.3, 18.4 Hz), 2.56 (1H, ddd, J = 3.9, 11.7, 14.5 Hz),
2.87–2.92 (1H, m), 3.05 (1H, d, J = 15.1 Hz), 3.71 (1H, d,
J = 4.3 Hz), 3.81 (1H, d, J = 15.1 Hz), 7.27–7.38 (5H, m). 13C NMR
(75 MHz, CDCl3) d 14.3, 19.8, 20.0, 25.1, 26.9, 42.6, 42.8, 47.8,
49.06, 49.09, 51.6, 58.5, 126.4, 128.3, 128.7, 135.8, 214.3. IR (neat):
1747, 1324, 1149, 752, 700 cmꢀ1. HRMS (ESI) calcd for C19H26NO3S
(M+H+): 348.1633. Found: 348.1627.
yielded
a thick colorless oil (1.32 g, 3.81 mmol, 82% yield).
½
a 2D4
ꢂ
¼ þ118:5 (c 1.03, CHCl3) 1H NMR (400 MHz, CDCl3) d 0.84
(3H, s), 1.10 (3H, s), 1.41 (1H, ddd, J = 3.64, 9.2, 12.0 Hz), 1.71
(1H, ddd, J = 4.8, 9.4, 14.0 Hz), 1.78 (2H, d, J = 6.0 Hz), 1.92 (1H, d,
J = 18.4), 1.99–2.06 (1H, m), 2.08 (1H, app. t, J = 4.4 Hz), 2.36 (1H,
ddd, J = 3.6, 4.4, 18.4 Hz), 2.57–2.64 (1H, M), 2.93 (1H, dq, J = 4.4,
6.0 Hz), 3.18 (1H, d, J = 15.0 Hz), 3.58 (1H, d, J = 15.0 Hz), 3.75
(1H, d, J = 4.3 Hz), 7.27–7.38 (5H, m). 13C NMR (75 MHz, CDCl3) d
14.1, 19.7, 19.9, 24.5, 26.9, 42.5, 42.7, 47.9, 49.0 (48.99), 49.0
(49.01), 51.5, 58.4, 126.4, 128.3, 128.7, 135.7, 214.5. IR (neat):
1747, 1324, 1149, 752, 700 cmꢀ1. HRMS (ESI) calcd for C19H26NO3S
(M+H+): 348.1633. Found: 348.1622.
Acknowledgments
The authors acknowledge support for this work by the National
Science Foundation (NSF CHE-644950). The NMR data collected in
this work are based, in part, upon work supported by the National
Science Foundation under major research instrumentation Grant
CHE-0722385.
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