Scalable synthesis of N -acylaziridines from N -tosylaziridines

Article abstract of DOI:10.1021/jo401267j

N-Acylaziridines are important starting materials for the synthesis of chiral amine derivatives. The traditional methods for producing these activated aziridines have significant drawbacks. The gram scale synthesis of N-acylaziridines by deprotection of N

Full text of DOI:10.1021/jo401267j

Note
pubs.acs.org/joc
Scalable Synthesis of N‑Acylaziridines from N‑Tosylaziridines
Heather Rubin, Jennifer Cockrell, and Jeremy B. Morgan*
Department of Chemistry and Biochemistry, University of North Carolina Wilmington, Dobo Hall, Wilmington, North Carolina
28403, United States
S
* Supporting Information
ABSTRACT: N-Acylaziridines are important starting materials for the
synthesis of chiral amine derivatives. The traditional methods for
producing these activated aziridines have significant drawbacks. The
gram scale synthesis of N-acylaziridines by deprotection of N-
tosylaziridines and reprotection with N-hydroxysuccinimide derivatives
is described. Mono- and disubstituted aziridines perform well, with
complete retention of stereochemical purity. The consistently moderate
yields are linked to the N-tosylaziridine deprotection step, while acylation with N-hydroxysuccinimide derivatives is highly
efficient.
(e.g., R and R′).26 Alkene27,28 and epoxide29,30 starting
N-Acylaziridines are strategic organic intermediates for the
synthesis of nitrogen-containing small molecules.1,2 Early
materials require installation of nitrogen, often from azide
sources, followed by a reductive cyclization. 1,2-Amino alcohols
undergo direct cyclization in the presence of hypervalent
phosphorus reagents31,32 or by Wenker conditions33,34 to
generate 1. Alternatively, the desulfonation of N-tosylaziridines
has been reported35,36 for the synthesis of 1, where the N-
tosylaziridines are readily available from alkenes37−41 or 1,2-
amino alcohols.42 Challenges related to the purification of 1
should not be overlooked as the stability of 1H-aziridines can
be variable.
Our recent efforts to synthesize and exploit the reactivity of
electron-deficient N-acylaziridines required us to generate gram
quantities of these intermediates.11,22 Specifically, the 3,5-
dinitrobenzoyl (DNB) nitrogen protecting group was neces-
sary. Employing the reaction conditions described above,
various issues were encountered leading to low yields of N-
DNB-aziridines (3 where Ar = 3,5-dinitrophenyl, Scheme 1).
Challenges and concerns with the current methods include (1)
byproducts related to aziridine ring-opening were produced
when synthesizing N-acylaziridines thereby complicating
purification, (2) cyclization reactions to generate 1 gave various
yields depending on the nature of R and R′, and (3) potentially
hazardous organic azides are produced as intermediates.
Therefore, we have developed an alternative procedure for
the large scale synthesis of 3 from N-tosylaziridines (4) utilizing
N-hydroxysuccinimide benzoates (5) as the source of acyl
group (Scheme 1).
synthetic efforts describing the formation of these activated
aziridines were met with challenges associated with thermal
aziridine rearrangement.3 As appreciation grew for the sensitive
nature of N-acylaziridines, rearrangement reactions were
developed utilizing both Lewis acidic4−8 and Lewis basic9−11
reaction conditions. Current research has taken advantage of
the chiral or prochiral nature of N-acylaziridines to generate
enantioenriched building blocks by catalytic asymmetric
desymmetrization2,12−20 and kinetic resolution.21,22 A direct
catalytic, asymmetric synthesis of N-acylaziridines remains
elusive.
Methods for the synthesis of N-acylaziridines (3) by
cyclization of amide precursors are rare;23−25 subsequently, 3
is most often prepared by acylation of 1H-aziridines (1 → 3,
Scheme 1). Various methods for the production of 1 have been
developed depending on the necessary aziridine substituents
Scheme 1. Proposed Synthesis of N-Acylaziridines
A survey of common methods for amide formation was
conducted to identify optimum aziridine acylation conditions.
Commercially available rac-2-methylaziridine (6) was subjected
to various reaction conditions in THF in an effort to synthesize
N-DNB-aziridine 10 (Table 1). Reaction outcome was
1
determined by H NMR of the unpurified mixture following
Received: June 13, 2013
Published: August 14, 2013
© 2013 American Chemical Society
8865
dx.doi.org/10.1021/jo401267j | J. Org. Chem. 2013, 78, 8865−8871

The Journal of Organic Chemistry
Note
removed though filtration, and 35 g of 9 was isolated as a white
solid in 75% yield following suspension in DCM and filtration.
Other electron-deficient NHS benzoates were synthesized in a
similar manner on a 50 mmol scale in good yield. Benzoates 12
and 13 could be purified by the standard procedure; however,
compound 14 has higher solubility in DCM and was purified by
column chromatography.
Table 1. Conditions for 1H-Aziridine Acylation
A series of structurally diverse N-DNB-aziridines were
synthesized on gram scale from the necessary DNB-OSu (9)
by performing a deprotection/reprotection sequence beginning
with N-tosylaziridines (Table 2). Literature detosylation
conditions with sodium naphthalenide were employed as
a
b
entry
acyl group
conditions
yield (%)
1
2
3
4
5
6
7
7
7
7
7
8
8
9
TEA, −78 to −30 °C to rt, 1 h
pyridine, −78 to −30 °C to rt, 1 h
1 M NaOH (aq), 0 °C to rt, 16 h
1 M Na2OH3 (aq), 0 °C to rt, 16 h
DCC, 0 °C to rt, 16 h
53
22
0
4
Table 2. Substrate Scope for N-Acylaziridine Synthesis by
90
a
c
Deprotection/Reprotection on a 10 mmol Scale
EDCI, 0 °C to rt, 16 h
0
0 °C to rt, 16 h
99
a
Reactions perform on a 1 mmol scale. For detailed procedures, see
b
1
Experimental Section. Yields determined by H NMR following the
addition of 1,3,5-trimethoxybenzene as an internal standard.
c
A
product consistent with hydrochlorination of 10 was observed in 22%
yield.
aqueous workup. Acid chloride 7, which has often been
employed for N-DNB-aziridine synthesis,11,13,16 gave low to
moderate yields in the presence of standard bases (entries 1−
4). The high reactivity of 7 requires careful temperature control
in the presence of amine bases (entries 1 and 2) and may also
explain the lack of product formation in biphasic conditions
(entries 3 and 4). DCC coupling of carboxylic acid 8 was highly
efficient;43 however, EDCI coupling produced only products
related to chloride opening of 10 (entries 5 and 6). N-
Hydroxysuccinimide (NHS) derivative 9 was the most efficient
with nearly a quantitative yield. The excellent yield observed
with 9 together with ability to remove the NHS byproduct by
aqueous workup directed us to select NHS derivatives for the
scale-up synthesis of N-acylaziridines.
NHS derivatives are readily synthesized from low-cost
carboxylic acids by standard DCC coupling. Amide synthesis
from NHS derivatives is common; however, to our knowledge
1H-aziridines have not been employed as substrates in this type
of amide formation. The requisite DNB reagent (9) was
synthesized by slight modification of a published procedure
(Scheme 2).44 DCC coupling of carboxylic acid 8 and N-
hydroxysuccinimide (11) proceeded smoothly at room temper-
ature over 3 hours in dioxane. The urea byproduct was
Scheme 2. Synthesis of N-Hydroxysuccinimide Benzoates
a
Conditions: (1) N-tosylaziridine (10 mmol), sodium naphthalenide
(25 mmol), DME, −78 °C, 0.25 h; then H2O quench, ether extraction;
b
(2) 9 (12 mmol), 0 → 25 °C, 12 h. Isolated yield from a single run.
c
Ts = p-toluenesulfonyl; DNB = 3,5-dinitrobenzoyl.
8866
dx.doi.org/10.1021/jo401267j | J. Org. Chem. 2013, 78, 8865−8871

The Journal of Organic Chemistry
Note
described, followed by aqueous workup.36 Moderate functional
group compatibility has been demonstrated for this method,
though pendent esters and 2-aryl-N-tosylaziridines are prob-
lematic. In our hands, other N-tosylaziridine deprotection
conditions proved no more efficient than sodium naphthale-
nide.35 Reprotection with 9 could be performed at room
temperature in consistently moderate yields over the
deprotection/reprotection sequence. Disubstituted (entries 1,
2, 4−6) and terminal (entries 3, 7−9) aziridines gave
comparable yields, with the noticeable outlier being the 2-
methyl substrate (entry 9). The low boiling point of 2-
methylaziridine is likely to blame, since removal of solvent is
required prior to reprotection. Silyl ethers are unaffected during
deprotection (entry 6). As expected, stereodefined (entries 4−
6) and enantioenriched (entries 7−9) aziridines maintain
stereochemical purity during the nitrogen protecting group
exchange.
Other electron-deficient NHS benzoates performed equally
well. Aziridine 15a was prepared by direct aziridination of
cyclohexene on large scale. Deprotection of 15a under standard
conditions followed by reprotection with electron-deficient acyl
groups proceeded smoothly in moderate yields on a 10 mmol
scale (Scheme 3). N-Acylaziridines 17−19, which have
previously been prepared in 3 steps from cyclohexene oxide,
are common substrates for nucleophilic desymmetrization
reactions.2
Scheme 4. Alternative Synthesis of 10
stereospecific and enantioselective aziridine ring-opening
reactions.
EXPERIMENTAL SECTION
■
General. 1H NMR spectra were recorded on a 400 MHz
spectrometer. Chemical shifts are reported in ppm from tetrame-
thylsilane with the solvent resonance as the internal standard (CDCl3,
7.27 ppm). Data are reported as follows: chemical shift, integration,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br =
broad, m = multiplet), coupling constants, and assignment. 13C NMR
spectra were recorded on the same spectrometer (100 MHz) with
complete proton decoupling. Chemical shifts are reported in ppm
from tetramethylsilane with the solvent as the internal standard
(CDCl3, 77.0 ppm). High resolution mass spectrometry was acquired
with a TOF-Q instrument via electron spray ionization (ESI, positive
mode). Infrared (IR) spectra were obtained using an FT-IR
spectrometer.
Scheme 3. Synthesis of Electron-Deficient N-Acylaziridines
on a 10 mmol Scale
Liquid chromatography was performed using forced flow (flash
chromatography) on silica gel (SiO2, 32−63 μm). Thin layer
chromatography (TLC) was performed on 0.25 mm silica gel 60
plates. Visualization was achieved UV light (254 nm) or basic
potassium permanganate in water followed by heating. High pressure
liquid chromatography (HPLC) was performed on an instrument
equipped with an autosampler and a UV detector. A Daicel Chiralpak
IA or IB (0.46 cm × 25 cm) column with a mixed solvent (hexane/
isopropanol) at a flow rate of 1 mL/minute was used for data
pertaining to enantiomeric excess calculations, unless otherwise noted.
All reactions were conducted in oven- or flame-dried glassware
under an inert atmosphere of argon. All solvents were purchased as
anhydrous solvents under an inert atmosphere, except 1,4-dioxane,
which was purchased as ACS grade in 500 mL portions. 2-
Methylaziridine (90%, technical grade) was purchased from Aldrich
Chemical Co. All purchased chemicals were used as received.
Survey of 1H-Aziridine Acylation Conditions. 3,5-Dinitroben-
zoyl chloride (7, 0.282 g, 1.2 mmol) was added to a flame-dried round-
bottom flask with a Teflon coated stir bar. THF (4 mL, 0.25 M) was
added, and the reaction flask was cooled to −78 °C. Triethylamine or
pyridine was added (1.2 mmol), followed by rac-2-methylaziridine (6,
78.5 μL, 1 mmol) dropwise. The reaction mixture was warmed to −30
°C and stirred for 1 h under argon. After this time, the reaction was
slowly brought to room temperature and quenched with 20 mL of
water. The mixture was diluted with 20 mL of ethyl acetate, and the
layers were separated. The organic layer was washed with 10 mL of
water and 10 mL of brine, dried over magnesium sulfate, and filtered.
The contents were dried by rotary evaporation and were left under
high vacuum for 3 h. 1,3,5-Trimethoxybenzene (approximately 20 mg)
was added, and the entire mixture was dissolved in chloroform-D for
1H NMR analysis. NOTE: For aqueous bases, THF was reduced to 2
mL, and 2 mL of 1 M Na2CO3 or 1 M NaOH were added at 0 °C
followed by warming to room temperature for 16 h. For carbodiimide
couplings, 3,5-dinitrobenzoic acid (8, 0.26 g, 1.2 mmol) was dissolved
in 4 mL of THF and cooled to 0 °C prior to the addition of aziridine
The described deprotection/reprotection of N-tosylaziridines
is sufficient for the scale-up synthesis of N-acylaziridines;
however, we were generally unsuccessful in efforts to push
yields above 70%. To better understand material loss,
commercially available rac-2-methylaziridine (6) was subjected
to acylation at room temperature to produce rac-10 (Scheme
4). A jump to 86% yield suggests significant material loss was
occurring during N-tosylaziridine deprotection and workup.
Utilizing milder deprotection conditions for 1H-aziridine
formation can be further explored for improving the overall
synthetic procedure. To this end, enantiopure N-Cbz-aziridine
(20) can be deprotected under hydrogenation conditions
utilizing Lindlar’s catalyst, followed by reprotection with 9 in
moderate yield. Since N-Cbz-aziridines are available from
various starting materials,45−47 they represent a viable
alternative to N-tosylaziridines.
In conclusion, a scalable method for the synthesis of
electron-deficient N-acylaziridines is disclosed. Terminal and
disubstituted N-tosylaziridines perform equally well in the
deprotection/reprotection method, consistently producing
moderate yields of N-acylaziridines on gram scale. Improved
access to N-acylaziridines will facilitate future studies of
8867
dx.doi.org/10.1021/jo401267j | J. Org. Chem. 2013, 78, 8865−8871

The Journal of Organic Chemistry
Note
(1 mmol) and N,N′-dicyclohexylcarbodiimide (DCC) or N-(3-
dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI)
(1.2 mmol). The reactions were warmed to room temperature for
16 h. For the N-hydroxysuccinimide reagent, 9 was dissolved in 4 mL
of THF and cooled to 0 °C prior to the addition of aziridine (1
mmol). The reaction was warmed to room temperature for 16 h.
Representative Procedure for the Synthesis of N-Hydrox-
ysuccinimide Benzoates. The following procedure is a slight
modification to a published procedure.44 To a flame-dried 1-L round-
bottom flask equipped with a Teflon-coated magnetic stir bar was
added N-hydroxysuccinimide (1 equiv), followed by 3,5-dinitrobenzoic
acid (1 equiv) and dry 1,4-dioxane (0.3 M). To this solution was
added N,N′-dicyclohexylcarbodiimide (1.05 equiv). A precipitate
began to form, and the mixture warmed slightly. The reaction was
stirred for approximately 3 h at which time the thick suspension was
filtered. The solid was resuspended in fresh 1,4-dioxane (same volume
used during the reaction) and stirred for an additional 15 min. The
suspension was filtered once more, and the combined supernatants
were concentrated via rotary evaporation. The yellow solid was
suspended in hot dichloromethane (∼1 M). After cooling to room
temperature, the product was collected by suction filtration. The solid
was rinsed with dichloromethane.
N-(p-Toluenesulfonyl)-7-azabicyclo[4.1.0]heptane (15a).
Synthesized from cyclohexene (8.10 mL, 80 mmol). Purification by
silica gel chromatography (5:1 hexanes/ethyl acetate) afforded a pale
yellow solid (16.38 g, 82% yield). All spectroscopic data were
consistent with literature values.37,49
N-(p-Toluenesulfonyl)-2-n-hexylaziridine (15c). Synthesized
from 1-octene (15.75 mL, 100 mmol). Purification by silica gel
chromatography (5:1 hexanes/ethyl acetate) afforded a pale yellow oil
(20.06 g, 71% yield). All spectroscopic data were consistent with
literature values.49
Bromine-Catalyzed Aziridination of Olefins. N-Tosylaziridine
was prepared from the corresponding alkene, Chloramine-T trihydrate
(1.1 equiv), and phenyltrimethylammonium tribromide (PTAB) (0.1
equiv) according to the published procedure.38
N-(p-Toluenesulfonyl)-6-azabicyclo[3.1.0]hexane (15b). Syn-
thesized from cyclopentene (3.66 mL, 40 mmol). All spectroscopic
data were consistent with literature values.38
trans-N-(p-Toluenesulfonyl)-2,3-di-n-propylaziridine (15d).
Synthesized from trans-4-octene (2.58 mL, 15 mmol). Purification
by silica gel chromatography (9:1 hexanes/ethyl acetate) afforded a
pale yellow oil (3.91 g, 93% yield). All spectroscopic data were
consistent with literature values.37
2,5-Dioxopyrrolidin-1-yl 3,5-Dinitrobenzoate (9). Synthesized
from 3,5-dinitrobenzoic acid (31.82 g, 150 mmol) to afford an off-
cis-N-(p-Toluenesulfonyl)-2-n-butyl-3-methylaziridine (15e).
Synthesized from cis-2-heptene (2.08 mL, 15 mmol). Purification by
silica gel chromatography (6:1 hexanes/ethyl acetate) afforded a pale
yellow oil (3.49 g, 87% yield). HRMS calcd for C14H21NNaO2S+:
+
white solid (34.93 g, 75% yield). HRMS calcd for C11H7N3NaO8 :
1
332.0131 (M + Na+), found 332.0154 (M + Na+); H NMR (d6-
1
DMSO, 400 MHz) δ 9.17 (t, J = 2.0 Hz, 1H), 9.02 (d, J = 2.0 Hz, 2H),
2.93 (s, 4H); 13C NMR (d6-DMSO, 100 MHz) δ 170.3, 159.6, 149.19,
130.18, 127.55, 124.87, 26.07; IR (NaCl plate) 3076, 1776, 1740, 1542
cm−1.
2,5-Dioxopyrrolidin-1-yl 4-Nitrobenzoate (12). Synthesized
from 4-nitrobenzoic acid (8.36 g, 50 mmol) to afford a white solid
(9.99 g, 76% yield). All spectroscopic data were consistent with
literature values.48
290.1191 (M + Na+), found 290.1185 (M + Na+). H NMR (CDCl3,
400 MHz) δ 7.52 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 8.0 Hz, 2H), 2.62−
2.56 (m, 1H), 2.44−2.39 (m, 1H), 2.12 (s, 3H), 1.22−1.20 (m, 1H),
1.19−1.15 (m, 1H), 1.00−0.85 (m, 7H), 0.52 (t, J = 7.0 Hz, 3H); 13C
NMR (CDCl3, 100 MHz) δ 143.9, 135.5, 129.4, 127.6, 44.6, 39.8, 29.0,
25.8, 22.0, 21.2, 13.6, 11.7; IR (NaCl plate) 2957, 2930, 2872, 1323,
1160 cm−1.
cis-N-(p-Toluenesulfonyl)-2-(2-((tert-butyldiphenylsilyl)oxy)-
ethyl)-3-ethylaziridine (15f). cis-3-Hexen-1-ol (1.77 mL, 15.0
mmol) was converted to the corresponding N-tosylaziridine by the
standard bromine-catalyzed aziridination procedure. Following a silica
gel plug, the hydroxyl group was silylated in dichloromethane (50 mL)
by the addition of tert-butyldiphenylsilyl chloride (4.29 mL, 16.5
mmol), imidazole (2.04 g, 30.0 mmol), and DMAP (0.18 g, 1.5
mmol). The mixture was stirred under argon atmosphere for 24 h at
room temperature. After this time, 30 mL of water was added, and the
mixture was extracted three times with 50 mL of dichloromethane.
The organic layers were combined, washed with brine, and dried over
magnesium sulfate. Purification by silica gel chromatography (4:1
hexanes/ethyl acetate) afforded a yellow oil (6.93 g, 91% yield).
HRMS calcd for C29H38NO3SSi+: 508.2336 (M + H+) found (M +
2,5-Dioxopyrrolidin-1-yl 4-(Trifluoromethyl)benzoate (13).
Synthesized from 4-trifluoromethylbenzoic acid (9.51 g, 50 mmol) to
afford a white solid (9.69 g, 67% yield). HRMS calcd for
+
C12H8F3NNaO4 : 310.0303 (M + Na+), found 310.0296 (M +
Na+); 1H NMR (CDCl3, 400 MHz) δ 8.27 (d, J = 8.0, 2H), 7.80 (d, J
= 8.4, 2H), 2.93 (s, 4H); 13C NMR (CDCl3, 100 MHz) δ 168.93,
160.89, 136.22 (q, J = 32.4 Hz), 131.0, 128.51, 125.99 (m, J = 3.2 Hz),
123.25 (q, J = 271.3 Hz); IR (NaCl plate) 3070, 1772, 1731 cm−1.
2,5-Dioxopyrrolidin-1-yl 3,5-Bis(trifluoromethyl)benzoate
(14). Low isolated yields by crystallization from dichloromethane
required purification of the total crude solid via silica gel column
chromatography (2:1 hexanes/ethyl acetate). Synthesized from 3,5-
bis-trifluoromethylbenzoic acid (13.83 g, 50 mmol) to afford a white
1
H+). 508.2336; H NMR (CDCl3, 400 MHz) δ 7.81 (d, J = 8.4 Hz,
+
solid (13.66 g, 77% yield). HRMS calcd for C13H7F6NNaO4 :
378.0177 (M + Na+), found 378.0172 (M + Na+); 1H NMR
(CDCl3, 400 MHz) δ 8.59 (s, 2H), 8.20 (s, 1H), 2.96 (s, 4H); 13C
NMR (CDCl3, 100 MHz) δ 168.60, 159.69, 132.89 (q, J = 34.3 Hz),
130.57 (d, J = 3.2 Hz), 128.23 (t, J = 3.2 Hz), 127.536, 122.49 (q, J =
271.4 Hz) ; IR (NaCl plate) 3096, 2952, 1783, 1745 cm−1.
2H), 7.80−7.61 (m, 4H), 7.46−7.24 (m, 6H), 7.22 (d, J = 8.4 Hz,
2H), 3.57 (d, J = 7.0 Hz, 1H), 3.55 (d, J = 7.0 Hz, 1H), 1.79−1.72 (m,
1H), 1.65−1.57 (m, 1H), 2.39 (s, 3H), 1.79−1.72 (m, 1H), 1.65−1.57
(m, 1H) 1.55−1.45(m, 1H), 1.46−1.35 (m, 1H), 1.06 (s, 9H), 1.90 (t,
J = 7.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 144.2, 135.5, 135.5,
135.2, 133.6, 129.7, 129.5, 128.0, 127.7, 61.7, 46.0, 42.6, 30.0, 26.9,
21.6, 20.3, 19.2, 11.6; IR (NaCl plate) 3048, 2961, 2930, 1360, 1325,
1184 cm−1.
Cyclization of 1,2-Amino Alcohols. N-Tosylaziridine was
prepared from the corresponding enantiopure amino alcohol by
ditosylation and base-promoted cyclization according to a literature
procedure.42
(S)-N-(p-Toluenesulfonyl)-2-isobutylaziridine (15g). Synthe-
sized from L-leucinol (2.6 mL, 20 mmol). Purification by silica gel
chromatography (5:1 hexanes/ethyl acetate) afforded a yellow oil
(2.96 g, 58% yield). HRMS calcd for C13H19NNaO2S+: 276.1023 (M +
Na+) found 276.1029 (M + Na+); 1H NMR (CDCl3, 400 MHz) δ 7.78
(d, J = 8.4 Hz, 2H), 7.30 (d, J = 8 Hz, 2H), 2.78−2.70 (m, 1H), 2.58
(d, J = 6.8 Hz, 1H), 2.40 (s, 3H), 1.99 (d, J = 4.4 Hz, 1H), 1.64−1.52
(m, 1H), 1.33−1.26 (m, 2H), 0.85 (d, J = 2.6 Hz, 3H), 0.83 (d, J = 2.6
Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 144.5, 135.1, 129.6, 127.9,
General Procedures for Aziridine Synthesis. Iodine-Cata-
lyzed Aziridination of Olefins. The following procedure is a slight
modification to a published procedure.39 A flame-dried round-bottom
flask equipped with a Teflon-coated magnetic stir bar was charged with
the respective olefin (1 equiv) dissolved in a 0.5 M solution of 3:1
deionized water/dichloromethane and then purged with argon.
Chloramine-T trihydrate (1.2 equiv) was added, followed by
tetrabutylammonium bromide (TBAB) (0.1 equiv) and iodine (0.1
equiv). The biphasic solution was allowed to stir at room temperature,
under argon, for 24 h. After this time, the organic phase was collected,
and the aqueous phase was extracted three times with dichloro-
methane (equal volume to reaction volume). The combined organics
were washed with sodium thiosulfate and brine and then dried over
MgSO4. The solvent was removed by rotary evaporation. The crude
material was purified by silica gel chromatography with hexanes/ethyl
acetate mixtures to yield N-tosylaziridine.
8868
dx.doi.org/10.1021/jo401267j | J. Org. Chem. 2013, 78, 8865−8871

The Journal of Organic Chemistry
Note
40.4, 39.0, 34.0, 26.7, 22.8, 21.9, 21.6. IR (NaCl plate) 3102, 2959,
1544, 1386 cm−1.
cis-N-(3,5-Dinitrobenzoyl)-2-n-butyl-3-methylaziridine
(16e). Purification by silica gel chromatography (7:1 hexanes/ethyl
acetate) afforded a white solid (2.16 g, 67% yield). HRMS calcd for
(S)-N-(p-Toluenesulfonyl)-2-isopropylaziridine (15h). Synthe-
sized from L-valinol (3.3 mL, 30 mmol). Purification by silica gel
chromatography (6:1 hexanes/ethyl acetate) afforded a white solid
(5.33 g, 75% yield). HRMS calcd for C12H18NO2S+: 240.1065 (M +
+
C14H17N3NaO5 : 330.1060 (M + Na+), found 330.1057 (M + Na+);
1H NMR (CDCl3, 400 MHz) δ 9.21 (t, J = 2.1 Hz, 1H), 9.12 (d, J =
2.1 Hz, 2H), 2.77−2.70 (m, 2H), 1.85−1.75 (m, 1H), 1.71−1.62 (m,
1H), 1.55−1.39 (m, 7H), 0.95 (t, J = 7.1 Hz, 3H); 13C NMR (CDCl3,
100 MHz) δ175.1, 148.6, 137.0, 128.7, 121.8, 43.0, 39.2, 29.3, 27.1,
22.4, 13.9, 12.9; IR (KBr plate) 3088, 2937, 1677, 1336 cm−1.
cis-N-(3,5-Dinitrobenzoyl)-2-(2-((tert-butyldiphenylsilyl)-
oxy)ethyl)-3-ethylaziridine (16f). Purification by silica gel
chromatography (9:1 hexanes/ethyl acetate) afforded a white solid
(2.62 g, 55% yield). HRMS calcd for C29H33N3NaO6Si+: 570.2031 (M
1
H+) found 240.1062 (M + H+); H NMR (CDCl3, 400 MHz) δ 7.84
(d, J = 8.4 Hz, 2H), 7.34 (d, J = 8 Hz, 2H), 2.63 (d, J = 7.2 Hz, 1H),
2.55−2.50 (m, 1H), 2.46 (s, 3H), 2.11 (d, J = 4.8 Hz, 1H), 1.45−1.38
(m, 1H), 0.91 (d, J = 6.8 Hz, 3H), 0.80 (d, J = 6.8 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) δ 144.4, 135.1, 129.6, 128.1, 46.27, 32.7, 30.1,
21.6, 19.6, 19.1; IR (NaCl plate) 3052, 2965, 1669, 1318 cm−1.
(S)-N-(p-Toluenesulfonyl)-2-methylaziridine (15i). Synthesized
from (S)-2-amino-1-propanol (2.3 mL, 30 mmol). Purification by silica
gel chromatography (3:1 hexanes/ethyl acetate) afforded a white solid
(4.39 g, 70% yield). All spectroscopic data were consistent with
literature values.50
Synthesis of N-Acylaziridines by Deprotection and Repro-
tection of N-Tosylaziridines. In a flame-dried round-bottom flask
equipped with a Teflon-coated magnetic stir bar, the sodium
naphthalenide reagent was freshly prepared by vigorously stirring
finely chopped sodium metal (1.0 equiv) and naphthalene (1.1 equiv)
in dry 1,2-dimethoxyethane (1 M) under argon for 2−3 h at room
temperature.36
A flame-dried round-bottom flask equipped with a Teflon-coated
magnetic stir bar was charged with N-tosylaziridine (10 mmol) and 40
mL of 1,2-dimethoxyethane. The solution was cooled to −78 °C in a
dry ice and acetone bath taking care that the solution did not freeze.
The sodium naphthalenide reagent was added dropwise until the dark
green end point was observed (∼25 mL of stock 1 M solution). The
reaction was quenched with 0.36 mL of water and slowly warmed to
room temperature. An additional 100 mL of water was added, and the
resulting mixture was extracted three times with 80 mL of ether. The
organic layers were combined and dried over magnesium sulfate. The
organics were filtered and concentrated by rotary evaporation to
approximately 30 mL of solution. The flask was purged with argon and
then cooled to 0 °C. The required N-hydroxysuccinimide benzoate
(12 mmol) was added all at once to the stirred solution. The
suspension was allowed to slowly warm to room temperature and
stirred for a total of 15 h. After this time, the mixture was concentrated
via rotary evaporation, affording the crude product, which was purified
by silica gel chromatography to yield the desired N-acylaziridine.
N-(3,5-Dinitrobenzoyl)-7-azabicyclo[4.1.0]heptane (16a). Pu-
rification by silica gel chromatography (4:1 hexanes/ethyl acetate)
afforded a white solid (1.83 g, 63% yield). All spectroscopic data were
consistent with literature values.13
1
+ Na+), found 570.2027 (M + Na+); H NMR (CDCl3, 400 MHz) δ
9.19 (t, J = 2.2 Hz, 1H), 9.12 (d, J = 2.0 Hz, 2H), 7.67−7.63 (m, 4H),
7.47−7.35 (m, 6H), 3.91−3.82 (m, 2H), 2.92 (q, J = 6.4 Hz, 1H), 2.65
(q, J = 6.4 Hz, 1H), 2.11−2.03 (m, 1H), 2.00−1.91 (m, 1H), 1.85−
1.74 (m, 1H), 1.69−1.58 (m, 1H), 1.07 (t, J = 7.5 Hz, 3H), 1.04 (s,
9H); 13C NMR (CDCl3, 100 MHz) δ 175.4, 148.5, 137.1, 135.5,
133.4, 129.7, 128.8, 127.7, 121.8, 61.5, 44.7, 41.2, 30.7, 26.8, 21.2, 19.1,
11.4; IR (KBr plate) 3102, 2931, 1684, 1344 cm−1.
(S)-N-(3,5-Dinitrobenzoyl)-2-isobutylaziridine (16g). Purifica-
tion by silica gel chromatography (6:1 hexanes/ethyl acetate) afforded
+
a white solid (1.55 g, 53% yield). HRMS calcd for C13H15N3NaO5 :
316.0904 (M + Na+), found 316.0903 (M + Na+); 1H NMR (CDCl3,
400 MHz) δ 9.23 (t, J = 2.2 Hz, 1H), 9.17 (d, J = 2.0 Hz, 2H), 2.78−
2.75 (m, 1H), 2.64 (d, J = 6.0 Hz,1H), 2.39 (d, J = 4.0 Hz, 1H), 1.90−
1.78 (m, 2H), 1.38−1.02 (m, 1H), 1.01 (d, J = 2.4 Hz, 3H), 1.00 (d, J
= 2.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 174.5, 148.6, 136.9,
128.7, 121.9, 40.9, 38.5, 33.0, 26.9, 22.6, 22.4; IR (KBr plate) 3102,
1683, 1545, 1345 cm−1.
(S)-N-(3,5-Dinitrobenzoyl)-2-isopropylaziridine (16h). Purifi-
cation by silica gel chromatography (6:1 hexanes/ethyl acetate)
afforded a white solid (1.70 g, 61% yield). HRMS calcd for
+
1
C12H14N3O5 : 280.0928 (M + H+), found 280.0930 (M + H+); H
NMR (CDCl3, 400 MHz) δ 9.21 (t, J = 2.2 Hz, 1H), 9.15 (d, J = 2.0
Hz, 2H), 2.63−2.58 (m, 1H), 2.54 (d, J = 6.4 Hz, 1H), 2.46 (d, J = 4.0
Hz, 1H), 1.91−1.83 (m, 1H), 1.12 (d, J = 6.8 Hz, 3H), 1.05 (d, J = 6.8
Hz, 3H);13C NMR (CDCl3, 100 MHz) δ 174.7, 148.6, 136.9, 128.8,
121.9, 45.0, 31.1, 30.0, 19.9, 18.4; IR (KBr plate) 3094, 1671, 1545,
1342 cm−1.
(S)-N-(3,5-Dinitrobenzoyl)-2-methylaziridine (16i). Purifica-
tion by silica gel chromatography (5:1 hexanes/ethyl acetate) afforded
+
a white solid (0.38 g, 15% yield). HRMS calcd for C10H10N3O5 :
1
252.0615 (M + H+), found 252.0615 (M + H+); H NMR (CDCl3,
400 MHz) δ 9.23 (t, J = 2.0 Hz, 1H), 9.17 (d, J = 2.4 Hz, 2H), 2.79−
2.73 (m, 1H), 2.69 (d, J = 6.0 Hz, 1H), 2.35 (d, J = 3.6 Hz, 1H), 1.51
(d, J = 5.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 174.3, 148.7,
136.9, 128.7, 121.9, 35.8, 32.9, 17.6; IR (KBr plate) 3099, 1681, 1542,
1340 cm−1.
N-(4-Nitrobenzoyl)-7-azabicyclo[4.1.0]heptane (17). Purifica-
tion by silica gel chromatography (8:1 hexanes/ethyl acetate) to afford
a white solid (1.50 g, 61% yield). All spectroscopic data were
consistent with literature values.13
N-(4-Trifluoromethylbenzoyl)-7-azabicyclo[4.1.0]heptane
(18). Purification by silica gel chromatography (3:1 hexanes/ethyl
acetate) to afford a white solid (1.66 g, 57% yield). All spectroscopic
data were consistent with literature values.7
N-(3,5-Bis-trifluoromethylbenzoyl)-7-azabicyclo[4.1.0]-
heptane (19). Purification by silica gel chromatography (8:1
hexanes/ethyl acetate) to afford a white solid (1.99 g, 59% yield).
All spectroscopic data were consistent with literature values.14
Synthesis of 16i from 2-Methylaziridine. To a flame-dried
round-bottom flask equipped with a Teflon-coated magnetic stir bar
were added THF (30 mL, 0.3 M) and 2-methylaziridine (0.8 mL, 10
mmol). The solution was cooled to 0 °C and 2,5-dioxopyrrolidin-1-yl
3,5-dinitrobenzoate (9) (3.71 g, 12 mmol) was added all at once. The
ice bath was removed, and the mixture was stirred for 4 h. After this
time, the suspension was diluted with 50 mL of ethyl acetate and
washed two times with 30 mL of deionized water. The organics were
N-(3,5-Dinitrobenzoyl)-6-azabicyclo[3.1.0]hexane (16b). Pu-
rification by silica gel chromatography (4:1 hexanes/ethyl acetate)
afforded a white solid (1.79 g, 65% yield). All spectroscopic data were
consistent with literature values.13
N-(3,5-Dinitrobenzoyl)-2-n-hexylaziridine (16c). Purification
by silica gel chromatography (6:1 hexanes/ethyl acetate) afforded a
+
white solid (2.09 g, 65% yield). HRMS calcd for C15H19N3NaO5 :
1
344.1217 (M + Na+), found 344.1218 (M + Na+); H NMR (CDCl3,
400 MHz) δ 9.23 (t, J = 2.2 Hz, 1H), 9.17 (d, J = 2.0 Hz, 2H), 2.69−
2.75 (m, 1H), 2.63 (d, J = 6.0 Hz, 1H), 2.38 (d, J = 4.0 Hz, 1H), 1.94−
1.87 (m, 1H), 1.60−1.26 (m, 9H), 0.90 (t, J = 6.8 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) δ 174.4, 148.6, 136.9, 128.8, 121.9, 39.9, 32.3,
31.9, 31.6, 28.9, 26.4, 22.5, 14.0; IR (KBr plate) 3099, 1686, 1545,
1345 cm−1.
trans-N-(3,5-Dinitrobenzoyl)-2,3-di-n-propylaziridine (16d).
Purification by silica gel chromatography (6:1 hexanes/ethyl acetate)
afforded a white solid (1.67 g, 52% yield). HRMS calcd for
+
C15H19N3NaO5 : 344.1217 (M + Na+), found 344.1214 (M + Na+);
1H NMR (CDCl3, 400 MHz) δ 9.22 (t, J = 2.2 Hz, 1H), 9.13 (d, J =
2.0 Hz, 2H), 2.70−2.67 (m, 2H), 1.72−1.64 (m, 2H), 1.53−1.46 (m,
4H), 1.25−1.17 (m, 2H), 0.96 (t, J = 7.4 Hz, 6H); 13C NMR (CDCl3,
100 MHz) δ 174.1, 148.6, 137.9, 128.5, 121.7, 45.3, 33.5, 20.4, 13.7; IR
(KBr plate) 3103, 2875, 1675, 1345 cm−1.
8869
dx.doi.org/10.1021/jo401267j | J. Org. Chem. 2013, 78, 8865−8871

The Journal of Organic Chemistry
Note
then washed with brine and dried over magnesium sulfate. The
mixture was filtered, and volatiles were removed by rotary evaporation.
The product was purified by silica gel chromatography (loaded in
toluene, 3:1 hexanes/ethyl acetate) affording a white solid (2.15 g,
86% yield).
(8) Cardillo, G.; Gentilucci, L.; Gianotti, M.; Tolomelli, A.
Tetrahedron 2001, 57, 2807−2812.
(9) Heine, H. W.; Fetter, M. E.; Nicholson, E. M. J. Am. Chem. Soc.
1959, 81, 2202−2204.
(10) Thyrum, P.; Day, A. R. J. Med. Chem. 1965, 8, 107−111.
(11) Martin, A.; Casto, K.; Morris, W.; Morgan, J. B. Org. Lett. 2011,
13, 5444−5447.
(12) Da Zhang, Z.; Scheffold, R. Helv. Chim. Acta 1993, 76, 2602−
2615.
Benzyl 2-Methylaziridine-1-carboxylate (20). Cbz-L-Alaninol
(4.7 g, 22 mmol) and triphenylphosphine (6.9 g, 26.4 mmol) were
added to a flame-dried round-bottom flask equipped with a Teflon-
coated magnetic stir bar. The solids were dissolved in 74 mL of
toluene (0.3 M). DIAD (5.2 mL, 26.4 mmol) was added dropwise with
stirring. After 1 h, the mixture was concentrated via rotary evaporation.
The product was purified by silica gel chromatography (loaded in
toluene, 2:1 hexanes/ethyl acetate) affording a pale yellow oil (2.99 g,
(13) Fukuta, Y.; Mita, T.; Fukuda, N.; Kanai, M.; Shibasaki, M. J. Am.
Chem. Soc. 2006, 128, 6312−6313.
(14) Rowland, E. B.; Rowland, G. B.; Rivera-Otero, E.; Antilla, J. C. J.
Am. Chem. Soc. 2007, 129, 12084−12085.
+
71% yield). HRMS calcd for C11H13NNaO2 : 214.0844 (M + Na+),
(15) Della Sala, G.; Lattanzi, A. Org. Lett. 2009, 11, 3330−3333.
(16) Larson, S. E.; Baso, J. C.; Li, G. L.; Antilla, J. C. Org. Lett. 2009,
11, 5186−5189.
1
found 214.0845 (M + Na+). H NMR (CDCl3, 400 MHz) δ 7.38−
7.31 (m, 5H), 5.20−5.10 (m, 2H), 2.26−2.50 (m, 1H), 3.52 (d, J = 3.2
Hz, 1H), 1.97 (d, J = 4.0 Hz, 1H), 1.29 (d, J = 2.8 Hz, 3H). 13C NMR
(CDCl3, 100 MHz) δ 163.4, 135.9, 128.6, 128.3, 128.2, 68.1, 33.9,
32.7, 17.5; IR (NaCl plate) 3033, 2969, 1718, 1298 cm−1.
(17) Mita, T.; Jacobsen, E. N. Synlett 2009, 1680−1684.
(18) Senatore, M.; Lattanzi, A.; Santoro, S.; Santi, C.; Della Sala, G.
Org. Biomol. Chem. 2011, 9, 6205−6207.
Synthesis of 16i; Deprotection and Reprotection of 20.
Benzyl 2-methylaziridine-1-carboxylate (20) (2.8 g, 14.6 mmol) and
45 mL of tetrahydrofuran (0.33 M) were added to a flame-dried argon-
purged round-bottom flask equipped with a Teflon-coated magnetic
stir bar. Lindlar’s catalyst (774 mg, 0.365 mmol) was added. The
suspension was purged with hydrogen gas for 2 min and then stirred at
room temperature for 18 h under a hydrogen atmosphere. The flask
was purged with argon, and 2,5-dioxopyrrolidin-1-yl 3,5-dinitroben-
zoate (9) (5.4 g, 17.5 mmol) was added all at once. After stirring for 3
h, the reaction mixture was filtered through Celite and rinsed with 80
mL of ethyl acetate. The solution was washed with 100 mL of
deionized water, washed with brine, and dried over magnesium sulfate.
The mixture was filtered, and volatiles were removed by rotary
evaporation. The product was further purified by silica gel
chromatography (4:1 hexanes/ethyl acetate) affording a white solid
(2.37 g, 65% yield).
(19) Xu, Y. J.; Lin, L. Q.; Kanai, M.; Matsunaga, S.; Shibasaki, M. J.
Am. Chem. Soc. 2011, 133, 5791−5793.
(20) Zhang, Y.; Kee, C. W.; Lee, R.; Fu, X. A.; Soh, J. Y. T.; Loh, E.
M. F.; Huang, K. W.; Tan, C. H. Chem. Commun. 2011, 47, 3897−
3899.
(21) Wu, B.; Parquette, J. R.; RajanBabu, T. V. Science 2009, 326,
1662.
(22) Cockrell, J.; Wilhelmsen, C.; Rubin, H.; Martin, A.; Morgan, J.
B. Angew. Chem., Int. Ed. 2012, 51, 9842−9845.
(23) Boschelli, D. H. Synth. Commun. 1988, 18, 1391−1395.
(24) Wipf, P.; Miller, C. P. Tetrahedron Lett. 1992, 33, 6267−6270.
(25) Yeung, Y. Y.; Gao, X. R.; Corey, E. J. J. Am. Chem. Soc. 2006,
128, 9644−9645.
(26) Sweeney, J. B. In Aziridines and Epoxides in Organic Synthesis;
Yudin, A. K., Ed.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim,
2006; pp 117−144.
(27) Hassner, A.; Matthews, G. J.; Fowler, F. W. J. Am. Chem. Soc.
1969, 91, 5046−5054.
(28) Van Ende, D.; Krief, A. Angew. Chem., Int. Ed. Engl. 1974, 13,
279.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for all purified compounds and
HPLC data for compounds 16g−i. This material is available
free of charge via the Internet at http://pubs.acs.org.
(29) Vanderwerf, C. A.; Heisler, R. Y.; Mcewen, W. E. J. Am. Chem.
Soc. 1954, 76, 1231−1235.
(30) Ittah, Y.; Sasson, Y.; Shahak, I.; Tsaroom, S.; Blum, J. J. Org.
Chem. 1978, 43, 4271−4273.
AUTHOR INFORMATION
Corresponding Author
*E-mail: morganj@uncw.edu.
■
(31) Kelly, J. W.; Eskew, N. L.; Evans, S. A. J. Org. Chem. 1986, 51,
95−97.
(32) Xu, J. X. Tetrahedron: Asymmetry 2002, 13, 1129−1134.
(33) Wenker, H. J. Am. Chem. Soc. 1935, 57, 2328.
(34) Li, X. Y.; Chen, N.; Xu, J. X. Synthesis 2010, 3423−3428.
(35) Alonso, D. A.; Andersson, P. G. J. Org. Chem. 1998, 63, 9455−
9461.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(36) Bergmeier, S. C.; Seth, P. P. Tetrahedron Lett. 1999, 40, 6181−
6184.
The authors are grateful to the Donors of the American
Chemical Society Petroleum Research Fund for financial
support. The HRMS data were collected using a HRMS
instrument purchased with funds from the NSF (CHE-
1039784) and UNCW.
(37) Evans, D. A.; Faul, M. M.; Bilodeau, M. T. J. Am. Chem. Soc.
1994, 116, 2742−2753.
(38) Jeong, J. U.; Tao, B.; Sagasser, I.; Henniges, H.; Sharpless, K. B.
J. Am. Chem. Soc. 1998, 120, 6844−6845.
(39) Kano, D.; Minakata, S.; Komatsu, M. J. Chem. Soc., Perkin Trans.
1 2001, 3186−3188.
REFERENCES
■
(40) Muller, P.; Fruit, C. Chem. Rev. 2003, 103, 2905−2919.
̈
(1) Hu, X. E. Tetrahedron 2004, 60, 2701−2743.
(2) Schneider, C. Angew. Chem., Int. Ed. 2009, 48, 2082−2084.
(3) Heine, H. Mech. Mol. Migr. 1971, 3, 145−176.
(4) Heine, H. W.; Proctor, Z. J. Org. Chem. 1958, 23, 1554−1556.
(5) Nishiguchi, T.; Tochio, H.; Nabeya, A.; Iwakura, Y. J. Am. Chem.
Soc. 1969, 91, 5841−5846.
(6) McManus, S. P.; Hearn, R. A.; Pittman, C. U. J. Org. Chem. 1976,
41, 1895−1898.
(7) Ferraris, D.; Drury, W. J.; Cox, C.; Lectka, T. J. Org. Chem. 1998,
63, 4568−4569.
(41) Omura, K.; Uchida, T.; Irie, R.; Katsuki, T. Chem. Commun.
2004, 2060−2061.
(42) Bieber, L. W.; de Araujo, M. C. F. Molecules 2002, 7, 902−906.
(43) Kalow, J. A.; Schmitt, D. E.; Doyle, A. G. J. Org. Chem. 2012, 77,
4177−4183.
(44) Cline, G. W.; Hanna, S. B. J. Am. Chem. Soc. 1987, 109, 3087−
3091.
(45) Bartoli, G.; Bosco, M.; Carlone, A.; Locatelli, M.; Melchiorre, P.;
Sambri, L. Org. Lett. 2004, 6, 3973−3975.
8870
dx.doi.org/10.1021/jo401267j | J. Org. Chem. 2013, 78, 8865−8871

The Journal of Organic Chemistry
Note
(46) Pesciaioli, F.; De Vincentiis, F.; Galzerano, P.; Bencivenni, G.;
Bartoli, G.; Mazzanti, A.; Melchiorre, P. Angew. Chem., Int. Ed. 2008,
47, 8703−8706.
(47) Deiana, L.; Dziedzic, P.; Zhao, G. L.; Vesely, J.; Ibrahem, I.;
Rios, R.; Sun, J. L.; Cor
́
dova, A. Chem.Eur. J. 2011, 17, 7904−7917.
(48) Schulze, A.; Giannis, A. Adv. Synth. Catal. 2004, 346, 252−256.
(49) Minakata, S.; Hotta, T.; Oderaotoshi, Y.; Komatsu, M. J. Org.
Chem. 2006, 71, 7471−7472.
(50) Cernerud, M.; Adolfsson, H.; Moberg, C. Tetrahedron:
Asymmetry 1997, 8, 2655−2662.
8871
dx.doi.org/10.1021/jo401267j | J. Org. Chem. 2013, 78, 8865−8871