Organocatalytic Olefin Aziridination via Iminium-Catalyzed Nitrene Transfer: Scope, Limitations, and Mechanistic Insight

Article abstract of DOI:10.1021/acs.joc.9b01023

Olefin aziridination via organocatalytic nitrene transfer offers potential complementarity to metal-catalyzed methods; however there is a lack of reports of such reactions in the literature. Herein is reported a method that employs an iminium salt to cata

Full text of DOI:10.1021/acs.joc.9b01023

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Article
Organocatalytic Olefin Aziridination via Iminium-Catalyzed
Nitrene Transfer: Scope, Limitations, and Mechanistic Insight
Shea Johnson, and Michael K. Hilinski
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01023 • Publication Date (Web): 07 Jun 2019
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Organocatalytic Olefin Aziridination via Iminium-Catalyzed Nitrene
Transfer: Scope, Limitations, and Mechanistic Insight
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Shea L. Johnson and Michael K. Hilinski*
Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904-4319
ABSTRACT: Olefin aziridination via organocatalytic nitrene transfer offers potential complementarity to metal-catalyzed meth-
ods, however there is a lack of reports of such reactions in the literature. Herein is reported a method that employs an iminium salt
to catalyze the aziridination of styrenes by [N-(p-toluenesulfonyl)imino]phenyliodinane (PhINTs). These reactions are hypothesized
to proceed via a diaziridinium salt as the active oxidant. In addition to outlining the scope and limitations of the method, evidence
for a polar, stepwise mechanism is presented, which provides new insight into the nature of iminium catalysis of nitrene transfer.
gen source to an electron-deficient olefin followed by ring
closure to provide the aziridine.9 The use of organocatalytic
INTRODUCTION
Organocatalytic atom-transfer oxidation is well established as
nitrene transfer, which involves the formation of an intermedi-
a useful approach for enantioselective epoxidation,1 and more
recent investigations have extended its capability to site-
selective C–H hydroxylation.2 In addition to enabling reactivi-
ty and selectivity complementary to organometallic or enzy-
matic catalysis, the use of organocatalysis can also provide
advantages in cost, toxicity, environmental impact, and ease of
experimental procedure.4 Consequently, we have explored
expanding the scope of this mode of organocatalysis beyond
oxygen transfer3 and in 2018 reported a method for organocat-
alytic nitrene-transfer C(sp3)–H amination (Scheme 1).5 This
method employs a trifluoromethyl iminium salt as the catalyst
in combination with iminoiodinane nitrene precursors. Prelim-
inary mechanistic evidence suggests that the reaction involves
a diaziridinium salt, or related organic nitrenoid, as the active
oxidant.
ate bearing an electrophilic nitrogen atom (e.g. an organic
nitrenoid), should by virtue of its distinct mechanism provide a
complementary organocatalytic aziridination method capable
of functionalizing electron-rich substrates (Scheme 1). Given
this complementarity to existing organocatalytic methods and
further potential complementarity to metal-catalyzed methods,
we have therefore endeavored to expand the scope of imini-
um-catalyzed nitrene transfer to include aziridination. We
report herein the development of a first-generation method and
exploration of its scope. In addition to establishing the initial
capabilities and boundaries of iminium-catalyzed nitrene
transfer in the context of substrate-limited aziridination, these
studies provide new and important mechanistic insights into
the nature of this recently-developed mode of catalysis.
RESULTS AND DISCUSSION
Scheme 1. Applications of organocatalytic nitrene transfer.
Our preliminary investigations established the ability of the
catalytic method developed for C–H amination to be modified
to allow for the successful aziridination of trans-stilbene, us-
ing iminium salt 110 as the catalyst and PhINTs11 as the nitrene
precursor (Scheme 2a).5 Importantly, this un-optimized result
served as significant confirmatory evidence for the formation
of an organic nitrenoid as the active oxidant. Upon further
exploration the reaction conditions, which employed lower
temperature as well a reduced amount of PhINTs relative to
conditions required to achieve C–H amination, we observed
no more than trace amounts of aziridines derived from other
olefins, such as styrene (Scheme 2b). Further complicating the
extension of this initial observation, attempts to achieve
aziridination of styrene at higher temperatures (e.g. 22 °C), led
to the complete and nonselective conversion of the olefin to a
complex mixture of products. To overcome this challenge
required an improved understanding of the factors governing
undesired reaction pathways at this comparatively elevated
temperature.
A separate class of reactions enabled by catalytic nitrene trans-
fer is olefin aziridination,6 which provides value for the prepa-
ration of bioactive molecules both in isolation and as a means
for stepwise olefin functionalization.7 Organocatalysis of
aziridination has previously been developed,8 but is limited to
α,β-unsaturated carbonyl compounds because of its reliance
on a mechanism of conjugate addition of a nucleophilic nitro-
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PhINTces, PhINNs, and others) gave no more than trace
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amounts of aziridine products, in contrast to iminium-
catalyzed C–H amination, which is more tolerant of other imi-
noiodinanes.5,12
Scheme 2. Initial exploration of organocatalytic aziridina-
tion.
Table 1. Optimization of styrene aziridinationa
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entry
PhINTs
(equiv)
solvent
time
(h)
yield
(%)b
1
1
1
1
1
1
1
1
1
2
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2
CH2Cl2
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0
2
CH2Cl2
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CH2Cl2
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CH2Cl2
6.5
6
In a key experiment, we observed that the anticipated aziridi-
nation product 5 was unstable to the reaction conditions at
ambient temperature (Scheme 3) and would decompose to a
complex mixture of products. A series of control experiments
revealed that stability was restored when any one of the rea-
gents (styrene, PhINTs, or catalyst) was omitted. Further op-
timization experiments revealed a dependence of yield of
5c
6d
6d
7d
8
CH2Cl2
25
NR
12
61
72
63
5
3:2 CH2Cl2:hexanes
4:1 CH2Cl2:hexanes
9:1 CH2Cl2:hexanes
9:1 CH2Cl2:hexanes
CH3CN
16
11
11
22
22
22
Scheme 3. Instability of aziridine 5 to reaction conditions
9
10
benzene
aAll reactions were conducted on a 0.2 mmol scale of styrene,
using 20 mol % of catalyst 1, except where noted. bIsolated yield.
NR = no reaction (no consumption of styrene observed). cPhINTs
added in four portions at t = 0, 1.5, 3, 4.5 h. d10 mol % loading of
catalyst 1 was used.
aziridine 5 on reaction time (Table 1). Specifically, at 19 h full
consumption of styrene was observed, but no aziridine was
produced. At a shorter reaction time of 5 h, up to 59% yield of
5 could be obtained (entry 3). However, we discovered that
there was an unusually short window of time in which optimal
yield could be achieved – by 6.5 h, all of the aziridine pro-
duced had been consumed to a complex mixture of products.
Given that this rapid decomposition could complicate repro-
ducibility, we sought to identify alternative conditions that
would lead to enhanced product stability. Our earlier observa-
tion that the stability of the aziridine to the reaction conditions
was dependent on the presence of all components of the reac-
tion mixture led us to explore options to limit the concentra-
tion of PhINTs in solution at any given time. Unfortunately,
PhINTs has limited solubility in CH2Cl2 to begin with, so por-
tionwise addition of the reagent failed to achieve the desired
result. The ultimately successful approach involved the eval-
uation of solvent mixtures of CH2Cl2 with hexanes, in an at-
tempt to keep the effective concentration of PhINTs at a min-
imum throughout the reaction by further limiting its solubility.
In the event, the use of a 9:1 CH2Cl2:hexanes solvent mixture
allowed for better reproducibility, providing a 72% yield when
using 2 equivalents of PhINTs and a reaction time of 22 h
(entry 8). Both catalyst loading and amount of PhINTs could
be reduced by half with only a modest effect on yield (entry
7). Alternatively, acetonitrile could be used as a solvent, alt-
hough the yield in this case was also modestly lower. Control
reactions (not shown) indicate that no styrene is consumed in
the absence of catalyst 1, nor when NaBF4 is used in place of 1
to probe for reactivity caused by the counterion rather than the
iminium. Finally, evaluation of other iminoiodinanes (e.g.
With optimized conditions in hand, we explored the substrate
scope of the method (Table 2). In general, aziridination of
monosubstituted styrenes bearing a range of electron-donating
and withdrawing groups could be achieved, using the olefin as
the limiting reagent. Overall, a positive correlation of reaction
yield with increasing substituent resonance contribution was
observed, as in the halogen series (products 17-20). The pres-
ence of strongly deactivating groups (e.g. –CN, –CF3, –B(pin)
as in substrates 10, 11, and 15 respectively) was found to be
detrimental to reaction performance, resulting in the lowest
isolated yields obtained in the para-substituted series, along
with incomplete consumption of the starting material (30%,
48%, and 45% yields based on recovered starting material,
respectively). At the other end of the spectrum, ortho- and
para-methoxystyrene (not shown) is rapidly and completely
consumed under the reaction conditions to a complex mixture
of products. In addition to establishing the dependence of reac-
tion outcome on electronic and resonance effects, our initial
investigations of substrate scope revealed modest tolerance of
acid-sensitive functionality (product 23) and an aryl boronic
ester (product 26), the latter of which could in principle be
further engaged in cross-coupling reactions to access more
complex aziridine products. Confirming the complementarity
of nitrene-transfer to the previously reported conjugate addi-
tion approaches to organocatalytic aziridination, no aziridina-
tion of chalcone (16) was observed.
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tions. No consumption of the aziridine was observed, estab-
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lishing that selectivity for the trans product is under kinetic
control. Additional mechanistic information was gained by
reevaluating the performance of trans-stilbene as an alternative
1,2-disubstituted substrate under the modified reaction condi-
tions (Scheme 4b). At the elevated temperature (22 versus 4
°C), rather than the aziridine the observed major product of the
reaction was N-tosyl enamine 33, in which an apparent 1,2-
phenyl shift has occurred. This provides additional evidence of
a long-lived benzylic radical or carbocation intermediate. The
change in reaction outcome can be rationalized by the greater
migratory aptitude of phenyl (as in 2) as compared to methyl
(as in 28 or 30).
Table 2. Scope and limitations of iminium-catalyzed
aziridinationa
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alkene
product
yield (%)
Scheme 4. Evidence for a stepwise mechanism
Other key mechanistic insights were gained through the identi-
fication of additional products of these reactions. In particular,
for all successful reactions disclosed in table 2, a small amount
of an imine byproduct (e.g. 34) could be observed and quanti-
1
fied by H NMR of the crude reaction mixture (Scheme 5a).
This intriguing result led us to consider whether these byprod-
ucts were arising from an unusual oxidative cleavage of the
olefin directly to an N-tosyl imine.13 If this were the case, one
would expect to also observe the formimine as a second prod-
uct, which we did not. However, if this product were formed
in trace amounts, subsequent consumption under the reaction
conditions or workup (due to increased electrophilicity com-
pared to 34) might prevent detection. To address this question,
we exposed β-cyclohexylstyrene (4.9:1 mixture of trans:cis) to
the reaction conditions (Scheme 5b). In addition to the aziri-
dine product (exclusively trans), we observed the two ex-
pected imine products of oxidative cleavage (34 and 36) in
equal amounts, confirming our suspicions.
aAll reactions were conducted on a 0.5 mmol scale of alkene.
Isolated yields are reported.
Discoveries made in this initial study of aziridination proved
to be particularly illuminating and have enabled an improved
mechanistic understanding of our relatively recent discovery
of iminium-catalyzed nitrene transfer. For example, in order to
probe whether iminium-catalyzed aziridination is stereospecif-
ic, we evaluated aziridination of both trans- and cis-β-
methylstyrene (Scheme 4a). In each case, only the trans-
aziridine product 29 was observed. The apparent complete
stereoinversion in the case of the cis olefin is unusual and
might suggest either a long-lived benzylic radical or carbo-
cation intermediate, or a thermodynamically controlled reac-
tion. To rule out the latter, we prepared cis-aziridine 31, using
an alternative method, and exposed it to the reaction condi-
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phenyl shift followed by disengagement from the catalyst. In
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this case only the enamine tautomer of the expected product of
this shift is observed. Finally, the unusual oxidative cleavage
can be rationalized by invoking the nucleophilic attack of a
second equivalent of PhINTs on intermediate 41 (path C),
leading to intermediate 42. Driven by the leaving group ability
of iodobenzene, C–C bond cleavage can then occur as shown
to provide the observed imine side products. In addition to
providing a single explanation to account for the variety of
products observed, this mechanism is consistent with the cur-
rent limitation of this method to styrenyl substrates and the
observed substituent effects on reaction yield, which correlate
with ability to stabilize an intermediate carbocation. The in-
clusion of radical inhibitors (BHT, TEMPO) had no effect on
reaction yield or product distribution, suggesting that a radical
pathway is less likely.15 In a larger context, this evidence of a
quite electrophilic nature of the diaziridinium (or related or-
ganic nitrenoid), which has been shown to effect C–H amina-
tion reactions4 as well as the aziridinations demonstrated here,
can potentially be exploited in the future for the design of new
reactions that are complementary to those that can be achieved
using mechanistically distinct metal-catalyzed nitrene transfer
methods.
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Scheme 5. Oxidative cleavage as a minor reaction pathway
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Scheme 7. Proposed aziridination mechanism
In addition, we chose 6-vinyltetralin (37) as a probe to evalu-
ate the relative rate of aziridination versus benzylic C–H ami-
nation (Scheme 6). Despite the fact that in this case, yield of
the aziridination product was low, we did not observe any
amount of the expected C–H amination product, nor could we
identify any other trace products that might arise from subse-
quent consumption of a benzylic amination product. A small
amount of the imine was also formed as was typical for all
substrates. The complete chemoselectivity for aziridination
over σ-bond insertion observed in this case is consistent with
the intermediacy of an organic nitrenoid such as a diaziridini-
um, as we have previously proposed in the case of C–H ami-
nation.
Scheme 6. Evaluation of C–H amination/aziridination se-
lectivity
A mechanistic proposal consistent with all of these observa-
tions is outlined in Scheme 7. We hypothesize that upon nu-
cleophilic attack of catalyst 1 by PhINTs, diaziridinium 40 is
formed via intermediate 39.14 To account for the likelihood of
a stepwise mechanism, we envision that the diaziridinium,
bearing a highly electrophilic nitrogen atom by virtue of its
sulfonamide protecting group, its bond to a cationic nitrogen
atom, and the adjacent trifluoromethyl group, is likely to react
with the olefin in a polar fashion to produce cationic interme-
diate 41. At least three pathways are available to this interme-
diate, which lead to the major product and side products ob-
served for different substrates. Via path A, ring closure to the
aziridine will occur with selectivity for the trans isomer if 41
is sufficiently long-lived to allow for bond rotation. The cati-
onic intermediate can also account for the product of attempt-
ed stilbene aziridination (33) via path B, involving a 1,2-
CONCLUSIONS
In summary, we demonstrated a method for organocatalytic
nitrene-transfer aziridination of styrenes using PhINTs as a
nitrenoid precursor and an iminium salt as the catalyst. Mech-
anistic studies shed new light on the nature of iminium-
catalyzed nitrene transfer, suggesting a stepwise, polar process
driven by the electrophilic nature of the organic nitrenoid.
Overall, this offers a complementary approach to metal cata-
lyzed aziridination, which we currently aim to exploit in order
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pad of silica gel. The filtrate was carefully concentrated in vacuo, and
was purified by silica gel chromatography (10-15% acetone in hex-
anes) to afford the corresponding aziridine.
to develop new synthetic methods aided by our improved
mechanistic understanding.
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4
5
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7
8
9
2-phenyl-N-tosylaziridine (5). Prepared from styrene using the general
procedure for aziridination. Purified on silica using 10-20% acetone
in hexanes. White solid (97.6 mg, 0.357 mmol, 72%). H NMR (600
MHz, CDCl3) δ 7.87 (d, J = 8.3 Hz, 2H), 7.35 – 7.31 (m, 2H), 7.29 (d,
J = 7.5 Hz, 3H), 7.22 (d, J = 2.1 Hz, 2H), 3.78 (dd, J = 7.2, 4.4 Hz,
1H), 2.99 (d, J = 7.2 Hz, 1H), 2.43 (s, 3H), 2.39 (d, J = 4.4 Hz, 1H)
ppm. Matches literature values.25
EXPERIMENTAL DETAILS
1
General Methods. All reagents and solvents were obtained com-
mercially in reagent grade or better quality and used without further
purification. Anhydrous dichloromethane, tetrahydrofuran and hex-
anes were obtained by degassing followed by passing through an
alumina drying column before use. Unless otherwise noted, reactions
were performed under an atmosphere of dry N2. Flash column chro-
matography was performed using silica gel (230-400 mesh) purchased
from Silicycle. 1H and 13C spectra were acquired at 300 K unless
otherwise noted on a Bruker Avance III (600 MHz) or Varian NMRS
(600 MHz) spectrometer. Chemical shifts are reported in parts per
million (ppm δ) referenced to the residual 1H resonance of the solvent.
The following abbreviations are used singularly or in combination to
indicate the multiplicity of signals: s - singlet, d - doublet, t - triplet, q
- quartet, m - multiplet and br – broad. NMR yields were determined
using Methyl-3-nitrobenzoate as an internal standard. High resolution
mass spectrometry was obtained using an Agilent Q-TOF ESI spec-
trometer. Styrenes 2, 4, 6, 28 and 30 were purchased from Sigma
Aldrich Chemicals. Styrenes 7,16 8,17 9,18 10,17 11,16 12,19 14,16 15,20
35,21 37,22 and aziridine 3123 were prepared using previously reported
methods.
2-(4-fluorophenyl)-N-tosylaziridine (17). Prepared from 4-
fluorostyrene using the general procedure for aziridination. Purified
on silica using 10-20% acetone in hexanes. Off-white solid (59.8 mg,,
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12
13
14
15
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17
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21
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23
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1
0.205 mmol, 41%). H- NMR (598 MHz, CDCl3) δ 7.86 (d, J = 8.4
Hz, 2H), 7.35 – 7.32 (m, 2H), 7.19 (dd, J = 8.8, 5.3 Hz, 2H), 6.98 (t, J
= 8.6 Hz, 2H), 3.75 (dd, J = 7.2, 4.4 Hz, 1H), 2.97 (d, J = 7.2 Hz, 1H),
2.44 (s, 3H), 2.35 (d, J = 4.4 Hz, 1H). Matches literature values.24
2-(4-chlorophenyl)-N-tosylaziridine (18). Prepared from 4-
chlorostyrene using the general procedure for aziridination. Purified
on silica using 10-20% acetone in hexanes. Yellow solid (72.5 mg
0.236 mmol, 47%). 1H NMR (598 MHz, CDCl3) δ 7.86 (d, J = 8.3 Hz,
2H), 7.35 – 7.32 (m, 2H), 7.28 – 7.25 (m, 3H), 7.15 (d, J = 8.5 Hz,
2H), 3.73 (dd, J = 7.1, 4.4 Hz, 1H), 2.98 (d, J = 7.1 Hz, 1H), 2.44 (s,
3H), 2.34 (d, J = 4.4 Hz, 1H). Matches literature values.25
2-(4-bromophenyl)-N-tosylaziridine (19) Prepared from 4-
bromostyrene using the general procedure for aziridination. Purified
on silica using 10-20% acetone in hexanes. Yellow solid (57.9 mg,
0.165 mmol, 33%). 1H NMR (598 MHz, CDCl3) δ 7.85 (d, J = 7.9 Hz,
2H), 7.41 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 7.9 Hz, 2H), 7.09 (d, J =
8.2 Hz, 2H), 3.72 (dd, J = 7.0, 4.5 Hz, 1H), 2.98 (d, J = 8.1 Hz, 1H),
2.44 (s, 3H), 2.34 (d, J = 4.4 Hz, 1H). Matches literature values.26
2-(4-iodophenyl)-N-tosylaziridine (20). Prepared from 4-iodostyrene
using the general procedure for aziridination. Purified on silica using
10-20% acetone in hexanes. Yellow solid (64.4 mg, 0.161 mmol,
Synthesis of N-Tosylphenyimidoliodinane (PhINTs) p-
Toluenesulfonamide (65.4 mmol, 11.2 g) and KOH (165.4 mmol,
9.28g) were dissolved in 240 mL of methanol and cooled to 0 C. To
o
the stirred solution was slowly added diacetoxyiodobenzene (65.8
mmol, 21.2 g). The now yellow solution was stirred for 30 minutes at
o
0 C, then was warmed to room temperature and stirred for 3 hours.
The reaction was then cooled to 0 oC and 150 mL ice water was added
o
and the mixture was stirred for an additional 1.5 hours at 0 C. Fol-
lowing this, the mixture was filtered to collect the precipitate, which
was washed with cold methanol followed by ethyl acetate to provide
1
32%). H NMR (600 MHz, CDCl3) δ 7.85 (d, J = 8.3 Hz, 2H), 7.61
1
the product (14.5 g, 83%) as an off-white solid. H NMR (598 MHz,
(d, J = 8.5 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 6.96 (d, J = 8.2 Hz, 2H),
3.70 (dd, J = 7.2, 4.4 Hz, 1H), 2.98 (d, J = 7.2 Hz, 1H), 2.43 (s, 3H),
2.33 (d, J = 4.4 Hz, 1H). Matches literature values.26
DMSO-d6) δ 7.69 (dd, J = 8.3, 1.2 Hz, 2H), 7.45 (dd, J = 8.4, 6.7 Hz,
3H), 7.29 (t, J = 7.8 Hz, 2H), 7.06 (d, J = 7.9 Hz, 2H), 2.27 (s, 3H).
Matches literature values.24
2-(4-cyanophenyl)-N-tosylaziridine (21). Prepared from 4-
cyanostyrene using the general procedure for aziridination. Purified
on silica using 20% acetone in hexanes. Pale yellow semi-solid (36.2
Synthesis of styrene 13. Methyl triphenylphosphonium iodide (11
mmol) was suspended in anhydrous THF (50 mL) under inert atmos-
phere. After cooling to 0˚C, n-butyl lithium (11 mmol) was added
dropwise and the resulting solution was stirred for 5 minutes. The 2-
bromo-6-methoxybenzaldehyde (10 mmol) was added in a single
portion and the reaction mixture was allowed to warm to ambient
temperature. The reaction was monitored by TLC until the benzalde-
hyde was consumed, at which time the reaction was diluted with 50
mL Et2O and filtered through a pad of silica. The filtrate was concen-
trated and purified by silica gel chromatography (2% acetone in hex-
anes) to afford the product 13 as a colorless oil (1.83g, 86%).
1
mg, 0.121 mmol, 24%). H NMR (600 MHz, CDCl3) δ 7.86 (d, J =
8.3 Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H), 7.35 (dd, J = 8.3, 4.2 Hz, 4H),
3.80 (dd, J = 6.6, 3.7 Hz, 1H), 3.02 (d, J = 7.2 Hz, 1H), 2.45 (s, 3H),
2.35 (d, J = 4.3 Hz, 1H). Matches literature values.23
2-(4-trifluoromethylphenyl)-N-Tosylaziridine (22). Prepared from 4-
trifluomethylstyrene using the general procedure for aziridination.
Purified on silica using 10-15% acetone in hexanes. Off white solid.
(50.8 mg, 0.149 mmol, 30%). 1H NMR (598 MHz, CDCl3) δ 7.87 (d,
J = 8.3 Hz, 2H), 7.55 (d, J = 8.1 Hz, 2H), 7.36 – 7.323 (m, 4H), 3.81
(dd, J = 7.2, 4.3 Hz, 1H), 3.02 (dd, J = 7.2, 0.7 Hz, 1H), 2.45 (s, 3H),
2.37 (d, J = 4.4 Hz, 1H). Matches literature values.25
1
2-bromo-6-methoxystyrene (13) H NMR (600 MHz, CDCl3) δ 7.55
(d, J = 2.5 Hz, 1H), 7.32 (dd, J = 8.7, 2.5 Hz, 1H), 6.96 (dd, J = 17.7,
11.1 Hz, 1H), 6.74 (d, J = 8.7 Hz, 1H), 5.72 (d, J = 17.7 Hz, 1H), 5.30
(d, J = 11.1 Hz, 1H), 3.83 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3)
δ 155.9, 131.4, 130.6, 129.2, 128.9, 115.8, 113.2, 112.7, 55.8. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C9H10BrO 212.9915; Found
212.9922.
General procedure for optimization of aziridination. Under in-
ert atmosphere, iminium catalyst 1 and nitrene-precursor were sus-
pended in anhydrous solvent. Styrene (0.1 mmol, 11.5 µL) was added
and the reaction was stirred at room temperature. Upon completion,
the reaction was diluted with 2 mL of ethyl acetate and filtered
through a short silica plug. The crude reaction mixture was concen-
trated on a rotary evaporator and analyzed by NMR using methyl-3-
nitrobenzoate as an internal standard.
General procedure for aziridine synthesis. Under inert atmos-
phere, PhINTs (1 mmol, 373 mg) and iminium catalyst 1 (0.1 mmol,
33 mg) were suspended in a 9:1 DCM:Hexanes mixture (2.5mL total).
The corresponding styrene (0.5 mmol) was added, and the reaction
was stirred at room temperature for 22 hours; upon which time the
mixture was diluted with 5 mL EtOAc and filtered through a short
2-(3-tertbutyldimethylsiloxyphenyl)-N-tosylaziridine (23). Prepared 3-
tertbutyldimethylsiloxystyrene using the general procedure for
aziridination. Purified on silica using 10-20% acetone in hexanes.
1
Light brown solid (92.8 mg, 0.230 mmol, 46%) H NMR (600 MHz,
CDCl3) δ 7.86 (d, J = 8.2 Hz, 2H), 7.35 – 7.31 (m, 2H), 7.13 (t, J =
7.9 Hz, 1H), 6.84 – 6.78 (m, 1H), 6.73 (ddd, J = 8.1, 2.5, 1.0 Hz, 1H),
6.66 – 6.62 (m, 1H), 3.69 (dd, J = 7.2, 4.4 Hz, 1H), 2.98 (d, J = 7.2
Hz, 1H), 2.43 (s, 4H), 2.37 (d, J = 4.5 Hz, 1H), 0.95 (s, 9H), 0.14 (d, J
= 1.4 Hz, 6H). 13C{1H} NMR (150 MHz, CDCl3) δ 155.9, 144.7,
136.6, 135.12, 129.9, 129.7, 128.0, 120.1, 119.6, 118.3, 41.1, 35.8,
25.7, 21.74 18.3, -4.36. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C21H30NO3SSi 404.1710; Found 404.1706.
2-(2-bromo-6-methoxyphenyl)-N-tosylaziridine (24). Prepared 2-
bromo-6-methoxystyrene using the general procedure for
aziridination. Purified on silica using 15-20% acetone in hexanes.
White solid (97.4 mg, 0.255 mmol, 51%). 1H NMR (598 MHz, CDCl-
3) δ 7.88 (s, 2H), 7.35 (d, J = 7.9 Hz, 2H), 7.32 (dd, J = 8.7, 2.5 Hz,
1H), 7.17 (d, J = 2.5 Hz, 1H), 6.70 (d, J = 8.7 Hz, 1H), 4.04 (dd, J =
7.2, 4.4 Hz, 1H), 3.79 (s, 3H), 2.96 (d, J = 7.3 Hz, 1H), 2.45 (s, 3H),
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2.27 (d, J = 4.5 Hz, 1H). 13C{1H} NMR (150 MHz, CDCl3) δ 157.3,
144.8, 135.0, 132.0, 130.0, 129.5, 128.2, 126.0, 113.0, 112.1, 55.8,
36.4, 35.8, 21.8. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C16H17BrNO3S 382.0107; Found 382.0125.
2-(3,5-dimethylphenyl)-N-tosylaziridine (25). Prepared from 3,5-
dimethylstyrene using the general procedure for aziridination. Puri-
fied on silica using 10-15% acetone in hexanes. White semi-solid
(58.8 mg,0.195 mmol, 39%). 1H NMR (600 MHz, CDCl3) δ 7.87 (d, J
= 8.3 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 6.91 (s, 1H), 6.83 (s, 2H),
3.71 (dd, J = 7.2, 4.5 Hz, 1H), 2.94 (d, J = 7.2 Hz, 1H), 2.44 (s, 3H),
2.37 (d, J = 4.5 Hz, 1H), 2.26 (s, 6H). 13C{1H} NMR (150 MHz,
CDCl3) δ 144.7, 138.3, 135.2, 135.0, 130.1, 129.9, 128.1, 124.5, 41.2,
36.0, 21.8, 21.3. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C17H20NO2S: 302.1209; Found 302.1211.
AUTHOR INFORMATION
1
2
3
4
5
6
7
8
Corresponding Author
*E-mail: hilinski@virginia.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to the National Institutes of Health (R01
GM124092) for funding.
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18
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21
22
23
24
25
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27
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29
30
31
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2-(4-phenylboronic acid pinacol ester)-N-tosylaziridine (26). Pre-
pared from 4-(boronic acid pinacol ester)-styrene using the general
procedure for aziridination. Purified on silica using 10-20% acetone
in hexanes. Yellow solid (60.9 mg, 0.152 mmol, 31%). 1H NMR (598
MHz, CDCl3) δ 7.86 (d, J = 7.1 Hz, 2H), 7.72 (d, J = 6.8 Hz, 2H),
7.32 (d, J = 7.6 Hz, 2H), 7.20 (d, J = 7.0 Hz, 2H), 3.75 (dd, J = 7.0,
4.5 Hz, 1H), 3.01 (d, J = 8.6 Hz, 1H), 2.42 (s, 3H), 2.39 (d, J = 4.4
Hz, 1H), 1.32 (s, 12H). 13C{1H} NMR (150 MHz, CDCl3) δ 144.8,
138.2, 135.1, 129.9, 128.1, 126.0 , 84.0, 41.3, 36.1, 25.0, 25.0, 21.8.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H27BNO4S 400.1748;
Found 400.1750.
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1
Off-white solid (34.6 mg, 0.121 mmol, 24%). H NMR (598 MHz,
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3H), 1.86 (d, J = 6.0 Hz, 3H). Matches literature values.23
2-(1,2,3,4-tetrahydronaphthalen-2-yl)-1-tosylaziridine (38). Prepared
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procedure for aziridination. Purified on silica using 10-20% acetone
in hexanes (21% 1H-NMR yield). Imine isolated as yellow oil
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(22.7mg, 0.073 mmol, 15%). H NMR (600 MHz, CDCl3) δ 8.95 (s,
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7.33 (d, J = 7.8 Hz, 2H), 7.16 (d, J = 7.9 Hz, 1H), 2.80 (d, J = 21.6
Hz, 4H), 2.43 (s, 3H), 1.80 (p, J = 3.3 Hz, 4H). 13C{1H} NMR (150
MHz, CDCl3) δ 170.5, 146.0, 144.5, 138.5, 135.7, 132.3, 130.1,
129.9, 129.9, 128.9, 128.1, 77.2, 30.1, 29.3, 22.9, 22.8, 21.8. HRMS
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314.1201.N-(2,2-diphenylvinyl)-4-methylbenzenesulfonamide
(33).
Prepared from trans-stilbene using the general procedure for aziridi-
nation. Purified on silica using 10-20% acetone in hexanes. Off-white
solid (26.1 mg, 0.075 mmol, 15%). 1H NMR (598 MHz, CDCl3) δ
7.72 (d, J = 8.3 Hz, 2H), 7.36 – 7.33 (m, 4H), 7.25 – 7.21 (m, 2H),
7.12 – 7.08 (m, 2H), 6.92 (dd, J = 7.6, 1.8 Hz, 2H), 6.79, (d, J = 11.6
Hz, 1H), 6.25 (d, J = 11.6 Hz, 1H), 2.45 (s, 3H). Matches literature
values.27
Aziridination procedure (1 mmol scale). Under inert atmosphere,
PhINTs (2 mmol, 746 mg) and iminium catalyst 1 (0.2 mmol, 66 mg)
were suspended in a 9:1 DCM:Hexanes mixture (5 mL total). 4-
chlorostyrene (1 mmol, 139 mg) was added, and the reaction was
stirred at room temperature for 22 hours; upon which time the mixture
was diluted with 10 mL EtOAc and filtered through a short pad of
silica gel. The filtrate was concentrated and purified by silica gel
chromatography (10-15% acetone in hexanes) to afford aziridine 18
(154.5 mg, 0.503 mmol, 50%) as a yellow solid.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
NMR spectra for all isolated products (PDF)
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