Direct and Stereospecific Synthesis of N-H and N-Alkyl Aziridines from Unactivated Olefins Using Hydroxylamine-O-Sulfonic Acids

Article abstract of DOI:10.1002/anie.201705530

A Rh^II-catalyzed direct and stereospecific N-H- and N-alkyl aziridination of olefins is reported that uses hydroxylamine-O-sulfonic acids as inexpensive, readily available, and nitro group-free aminating reagents. Unactivated olefins, featuring a wide range of functional groups, are converted into the corresponding N-H or N-alkyl aziridines in good to excellent yields. This operationally simple, scalable transformation proceeds efficiently at ambient temperature and is tolerant towards oxygen and trace moisture.

Full text of DOI:10.1002/anie.201705530

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
International Edition Chemie
www.angewandte.org
Accepted Article
Title: Direct and Stereospecific Synthesis of N-H and N-Alkyl Aziridines
from Unactivated Olefins Using Hydroxylamine-O-Sulfonic Acids
Authors: Zhiwei Ma, Zhe Zhou, and László Kürti
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201705530
Angew. Chem. 10.1002/ange.201705530
Link to VoR: http://dx.doi.org/10.1002/anie.201705530
http://dx.doi.org/10.1002/ange.201705530

Angewandte Chemie International Edition
10.1002/anie.201705530
DOI: 10.1002/anie.201((will be filled in by the editorial staff))
Olefin Aziridination
Direct and Stereospecific Synthesis of N−H and N−Alkyl Aziridines
from Unactivated Olefins Using Hydroxylamine-O-Sulfonic Acids **
Zhiwei Ma, Zhe Zhou and László Kürti*
Aziridines are important synthetic building blocks as well as
substructures in a number of biologically active natural and
unnatural products.[ As one of the smallest member in the family
of nitrogen-containing rings, they provide unique synthetic access to
many important structural motifs and functionalities via ring-
expansion and/or ring-opening reactions, some of which are difficult
to obtain without the intermediacy of aziridines.[ Based on the
electronic properties of the nitrogen atom, aziridines can be
classified as activated (e.g., N−Ts, N−Ns) and non-activated (N−H,
N−alkyl).[ For more than two decades, considerable effort has been
devoted by the synthetic organic chemistry community to the
development of practical methods for the efficient preparation of
aziridines.[ Although significant progress has been made, the
majority of these methods are still limited to the synthesis of
activated aziridines that almost invariably require the removal of the
activating groups in order to obtain the final target compounds.[
readily synthesized from the corresponding N−H aziridines.[6]
Despite alkene aziridination being a key research area for decades,
the direct N−H/alkyl aziridination of unactivated olefins is still
relatively underdeveloped.
1]
Several years ago our group reported, jointly with the Ess and
Falck groups, a rhodium-catalyzed direct aziridination of olefins that
2]
uses
O-(2,4-dinitrophenyl)hydroxylamine
(DPH)
as
the
stoichiometric aminating agent and 2,2,2-trifluoroethanol (TFE) as
1]
[7]
the solvent (Figure 1). To the best of our knowledge, it is still the
only reported method with a general scope that can achieve N−H
and N−Me aziridination on unactivated olefins. This transformation
provides good to excellent yields of the aziridines for a large variety
of olefin substrates, while tolerating a wide range of functional
groups. However, using DPH as the stoichiometric aminating agent
has led to some drawbacks: (a) while DPH can be conveniently
synthesized, its commercial sources are still limited and its price is
relatively high, most likely due to its relatively short shelf life and
its requirement for refrigeration during storage; (b) both DPH and
3]
4]
2
the byproduct 2,4-dinitrophenol have high NO /C ratios and are
toxic – these facts raised safety concerns for industrial applications
and led to the reluctance towards its adoption in large scale
reactions; (c) the by-product 2,4-dinitrophenol sometimes co-elutes
with the aziridine product(s), thus complicating chromatographic
purification and (d) the by-product 2,4-dinitrophenol causes ring-
opening of some of the aziridine products − this necessitates the
lowering of reaction temperature especially for sensitive styrene
substrates.
Therefore, it has been our desire to find an alternative aminating
agent to overcome the aforementioned shortcomings of this
aziridination process, while retaining (and possibly improving) its
operational simplicity, oxygen- and moisture-tolerance, and the
overall high-efficiency. Initially, several commonly used aminating
agents, such as oxaziridines and O-benzoyl hydroxylamine
derivatives were tested under the original aziridination conditions
Figure 1. Current methods for the Rh(II)-catalyzed N-H aziridination of
unactivated olefins.
The need to remove activating groups from the aziridine nitrogen
atom (e.g., −SO R or –CO R) often causes additional synthetic
2 2
[8]
used with DPH. However, no aziridination products were detected.
After a thorough literature survey of inexpensive yet powerful
challenges and loss of valuable materials due to the harsh conditions
necessary to cleave the strong N-sulfonyl and N-acyl bonds.[ In
comparison, the direct N−H aziridination of unactivated olefins is a
more desirable process because: (a) removal of the activating group
is circumvented and (b) virtually any N-substituted aziridine can be
aminating agents, we noted that hydroxylamine-O-sulfonic acid
5]
[9]
(
HOSA) has the potential to be the optimal reagent for our
purposes: (a) HOSA has been widely used for the synthesis of
amines, as well as for the preparation of nitriles, oximes, amides and
[10]
various nitrogen-containing heterocycles;
contain
decomposition temperature: 208−211 °C) and is a widely available
(b) HOSA does not
a
nitro group and it has robust thermal stability
(
and cost-effective commercial source of electrophilic nitrogen; (c)
the byproduct derived from HOSA is an inorganic sulfate after
workup, which can be conveniently removed by simple aqueous
extraction. Among publications focused on HOSA, several reports
on olefin hydroamination drew our attention. In 1964, Brown et.
al. reported a one-pot transformation consisting of an olefin
[
[
∗]
Dr. Z. Ma, Dr. Z. Zhou and Prof. Dr. László Kürti
Department of Chemistry
Rice University, BioScience Research Collaborative
6
500 Main Street, Rm 380, Houston, TX, 77030 (USA)
Fax: (+1) 713-348-5155; E-mail: kurti.laszlo@rice.edu
[11]
∗∗]
Financial support from Rice University, National Institutes of Health
(R01
GM-114609-01),
National
Science
Foundation
hydroboration/HOSA amination sequence to provide the
(CAREER:SusChEM CHE-1455335), the Robert A. Welch
corresponding primary alkylamine products.[
11a]
In 2013, Hartwig et.
Foundation (Grant C-1764), ACS-PRF (Grant 51707-DNI1), Amgen
2014 Young Investigators’ Award for LK) and Biotage (2015 Young
(
al. reported a one-pot anti-Markovnikov olefin hydroamination
Principal Investigator Award) that are greatly appreciated. We thank
Professor Daniel H. Ess (BYU) for helpful discussions.
method via a hydrozirconation/amination sequence using various
[11b]
N−alkyl HOSA derivatives as electrophilic aminating agents.
1
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201705530
versus entry 9), albeit both reactions took 16 h to go to completion.
We propose that the heterogeneous system formed in HFIP with
inorganic bases is likely detrimental to the reaction rate. To explore
the effect of homogeneity, common organic bases soluble in HFIP
were examined (Table 1, entries 10−14) which led to the
identification of pyridine as the optimal base (Table 1, entry 13).
Compared to inorganic bases, the better solubility of pyridine in
HFIP facilitates a rapid aziridination process (within 4 h versus 16
h). A thorough investigation of reaction conditions found that the
use of 1.2 equivalents of both HOSA and pyridine at 0.4 M
concentration is optimal for the aziridination of geranyl acetate
(Table 1, entry 15), and 2.5 hours of reaction time at ambient
temperature is sufficient for the complete conversion. We found that
other common Rh(II) catalysts can also facilitate the aziridination
More recently, the McCubbin group disclosed a transition-metal free
aryl amination method to deliver primary arylamines from aryl
boronic acids using HOSA as the aminating agent.[
11c]
The inherent
advantages of HOSA encouraged us to investigate its potential
utilization in the direct olefin N−H aziridination reaction.
Table 1. Optimization of conditions for the N−H aziridination of
geranyl acetate (4).
Me
Me
Me
Me
Me
Catalyst (mol%)
OAc
Me
OAc
HOSA (1.2 equiv.)
N
H
base
(
1.2 equiv.)
4
5
Solvent, 25 ºC, Time
Entrya Catalyst (mol%)
process (Table 1, entries 16−19). Specifically, Rh
only slight erosion of the aziridination efficiency (74% isolated
yield, 1.5 mol% catalyst loading) compared to Rh (esp) (85%
isolated yield, 1 mol% catalyst loading), while having a wider
commercial availability. The effect of excess pyridine was also
examined and we found that the reaction could tolerate up to at least
10 equivalents of it without losing efficiency (Table 1, entries 20 &
21).
2 4
(OAc) exhibited
Base
Solvent Time Yield (%)
1
2
3
4
5
6
7
8
9
Rh (esp)2 (1 mol%)
Rh2(esp)2 (1 mol%)
None
LiOH
LiOH
LiOH
LiOH
None
KOt-Bu
K2CO3
CsOH
NEt3
TFE
TFE
16 h
16 h
16 h
16 h
16 h
16 h
16 h
16 h
16 h
4 h
4 h
4 h
4 h
4 h
2.5 h
2.5 h
2.5 h
NA
44%
NA
80%
NA
NA
30%
56%
78%
37%
39%
48%
83%
66%
85%
61%
74%
2
2
2
Rh2(esp)2 (1 mol%)
Rh2(esp)2 (1 mol%)
None
Rh2(esp)2 (1 mol%)
Rh2(esp)2 (1 mol%)
MeOH
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
Rh (esp)2 (1 mol%)
2
Rh (esp)2 (1 mol%)
2
1
0
1
2
3
4
5
6
7
8
9
Rh (esp)2 (1 mol%)
2
Table 2. Direct intermolecular N−H aziridination of structurally
diverse olefins using hydroxylamine-O-sulfonic acid (HOSA) as the
stoichiometric aminating agent.
1
1
1
1
1
1
1
1
1
Rh (esp)2 (1 mol%)
DBU
2
Rh (esp)2 (1 mol%)
DMAP
Pyridine
2,6-Lutidine
Pyridine
Pyridine
2
Rh (esp)2 (1 mol%)
2
Rh (esp)2 (1 mol%)
HOSA (3) (1.2 equiv)
2
b,c
c
Rh (esp)2 (1 mol%)
2
pyridine (1.2 equiv)
H
N
Rh (OAc)4 (1 mol%)
R1
R2
R3
R4
2
Rh2(esp)2 (2) (x mol%), 25 ºC
R1
R2
R3
R4
Rh (OAc)4 (1.5 mol%) Pyridine
2
HFIP (0.4 M), 2.5 h
Rh (TFA)4 (1 mol%)
Pyridine
Pyridine
HFIP
HFIP
16 h
16 h
2.5 h
16 h
53%
65%
60%
25%
2
1
mmol scale
Rh (Oct)4 (1 mol%)
2
Structure of Azirdines Derived from Structurally Diverse Olefins
2
2
0
1
Rh (OAc)4 (1.5 mol%) Pyridine, 10 eq HFIP
2
[a]
[b]
(
Entry) Compound #, Catalyst Loading (mol%), Isolated Yield (%)
Rh (OAc)4 (1.5 mol%) Pyridine, 15 eq HFIP
2
Me
a
The reactions were performed at 0.2 mmol scale at 0.2 M concentration unless
Me
NH
NH
Me
OAc
indicated otherwise. b Reaction was performed at 0.4 M concentration. c Reaction was
TBSO
Me
N
H
(
1) 5
(2) 6
(1 mol%); 67%c
(3) 7
2 (1 mol%); 81%
performed at 1 mmol scale.
2
(1 mol%); 85%
2
Monoterpenoid geranyl acetate (4) was selected as the model
compound to examine the possibility of achieving direct olefin N−H
aziridination. When HOSA was initially tested using the original
conditions,[ no aziridine product (5) was detected after 16 h (Table
2 (0.5 mol%); 75% (10 mmol)
Rh2(OAc)4 (1.5 mol%); 74%
single stereoisomer
NH
TBSO
Me
OH
NH
NH
7]
(4) 8
(5) 9
(6) 10
1, entry 1). Hypothesizing that the protonated nitrogen of the HOSA
2
(2 mol%); 80%c
2 (1 mol%); 76%c
2 (1 mol%); 68%
zwitterion prevented the formation of the presumed rhodium-NH-
nitrenoid intermediate,[ an equimolar amount of LiOH was added
to the reaction mixture as a base. Gratifyingly, the reaction took
place and the desired NH-aziridine (5) was obtained after 16 h with
an isolated yield of 44%, along with unreacted starting material (4)
single stereoisomer
single stereoisomer
7]
NH
NH
O
NHAc
HO
NH
(
Table 1, entry 2). Since TFE is slightly acidic (pK
a
~ 12.5), the
(7) 11
(8) 12
(9) 13
(10) 14
2 (1 mol%), 0.5 h; 73%c,d
2
(1 mol%); 66%
2 (1 mol%)
7%c
2 (1 mol%)
acidity of the solvent was considered as a possible influential factor
for the reaction. To test this hypothesis, both the more acidic
1
6
44%
single stereoisomer
Me
Me
a
,1,1,3,3,3-hexafluoro-2-propanol (HFIP, pK ~ 9.3) and the less
acidic MeOH (pK ~15.5) were tested separately as solvents. No
a
NH
Me
NH
Me H
reaction took place when the reaction was carried out in MeOH,
while complete consumption of 4 was observed after 16 h and 5 was
isolated with 80% yield when HFIP was used as the solvent (Table
H
H
HO
(11) 15
(2 mol%), 1 h; 70%c
(12) 16
2 (1 mol%); 88%c
HN
(13) 17
(1 mol%); 86%c,d
single enantiomer
2
1
, entries 3 & 4). A control experiment validated that no conversion
2
single stereoisomer
was observed in the absence of the catalyst (Table 1, entry 5),
demonstrating that the dirhodium complex was essential for the
aziridination process. It is also worth noting that the HOSA
procedure seems to have superior regioselectivity with no detection
of the 2,3-regioisomer of aziridine 5, while the DPH procedure
produces about 6% of this minor regioisomer.
aReaction Conditions: Olefin (1 mmol) was dissolved in 2.5 mL HFIP, followed by the
addition of pyridine (1.2 mmol), HOSA (1.2 mmol) and Rh2esp2 (loading is indicated for
each entry). The reaction was carried out at room temperature for 2.5 h unless indicated
otherwise. bIsolated yield after silica chromatography. The reactions were quenched with
saturated aqueous Na CO . c2 mmol of HOSA and pyridine were used. dA 1:1 mixture of
2
3
HFIP:CHCl3 was used to ensure good solubility of the substrate.
To promote a faster and more efficient aziridination of the starting
material, an array of common bases with varying basicity was
screened in HFIP (Table 1, entries 7−14). When the base was
absent, decomposition of alkene (4) was observed, likely caused by
the acidic nature of HOSA (Table 1, entry 6). Among the inorganic
bases, only CsOH gave comparable yield to LiOH (Table 1, entry 4
With the optimized conditions in hand, we explored the scope of this
new aziridination method using a wide range of structurally diverse
olefins (Table 2). Both cyclic- and acyclic-aliphatic alkenes undergo
smooth aziridination, and this new method tolerates various
functional groups, including esters (Table 2, entry 1), silyl ethers
(
Table 2, entries 2 & 5) and alcohols (Table 2, entries 4, 8 & 13). In
2
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201705530
the case of the aziridination of an allylic acetate (Table 2, entry 9),
intramolecular acyl-transfer to the aziridine N, followed by an aza-
Payne-rearrangement took place to furnish the corresponding
epoxide 13. While this method is compatible with both allylic and
homoallylic alcohols (Table 2, entries 4 and 8), extra loading (2
equivalents) of the aminating agent and pyridine was required to
achieve full conversion.
Isolated olefins underwent aziridination selectively in the
presence of allylic ethers, presumably due to the unfavorable
inductive effect caused by the oxygen atom (Table 2, entry 1). To
enable a direct comparison on the reactivity and efficiency, this new
aziridination method was tested on several substrates that required
prolonged reaction time with the DPH protocol.[ Gratifyingly, the
reaction times were reduced under HOSA conditions in all cases,
while similar or higher isolated yields were obtained (Table 2,
entries 1 & 10−13). As a representative example, the reaction time
required for the aziridination of the natural product cholesterol was
7]
Table 3. Direct intermolecular N−H aziridination of structurally
diverse olefins using hydroxylamine-O-sulfonic acid (HOSA) as the
stoichiometric aminating agent.
reduced from 48 h to 2.5 h, and only half of the original Rh
catalyst loading (1 mol% vs 2 mol%) was required (Table 2, entry
3).
Naturally, we decided to test a number of new, more complicated
substrates in order to gauge the full capability of this new method.
For a terminal alkene, higher Rh (esp) loading (4 mol%) was
2 2
(esp)
HOSA (3) (1.2 equiv)
pyridine (1.2 equiv)
H
N
1
R1
R2
R3
R4
Rh2(esp)2 (2) (x mol%), 25 ºC
R1
R2
R3
R4
HFIP (0.4 M), 2.5 h
1
mmol scale
Structure of Azirdines Derived from Structurally Diverse Olefins
2
2
a]
[b]
(
Entry)[ Compound #, Catalyst Loading (mol%), Isolated Yield (%)
required to enable full conversion (Table 3, entry 1). This
observation is consistent with those reported for terminal olefins in
O
CN
NH
O
HN
2
[7]
our earlier work.
Using this differentiating property,
(
)8 NMe2
NH
O
N
H
chemoselective aziridination of the more substituted alkene was
achieved when both a terminal alkene and an internal alkene were
present in the same molecule (Table 3, entry 2). It is interesting to
note that the presence of an aziridine moiety in the molecule seems
to inhibit further aziridination, as evidenced by the failure to convert
(
1) 18
(2) 19
(3) 20
(1 mol%); 76% 2 (1 mol%); 59%c
(4) 21
(4 mol%); 81%
2 (1 mol%); 84%
2
dr = 1:1
NH
NH
Me
O
O
NH
O
20 to the corresponding bis-aziridine even with excess amount of the
N
H
aminating agent (Table 3, entry 3). With the recent report of a
Rh(II)-catalyzed C-H amination of arenes,[ we were curious to see
whether the arene amination would be a competing side reaction for
the aziridination chemistry on substrates containing both arene and
alkene moieties. When olefin substrates containing arenes with
different electronic properties underwent aziridination, no arene C-H
amination was observed, demonstrating the good chemoselectivity
of this method favoring alkenes over arenes (Table 3, entries 5−10).
Heterocycles containing electron-rich S, O and N atoms were also
tolerated (Table 3, entries 11−16) as well as substrates featuring
cyano groups (entries 4 & 5) and alkynes (entry 9). Acid-sensitive
functionalities such as Boc and acetals were also unaffected by the
reaction conditions (Table 3, entries 16, 17 & 19).
12]
NC
O2N
(8) 25
MeO
(
5) 22
(1 mol%); 91%c
2
(6) 23
(7) 24
2 (1 mol%); 85%
NH
single stereoisomer
2 (1 mol%); 82%
2 (1 mol%); 54%
N
O
O
H
N
O
O
NH
O2N
Cl
Me
( )7
O
Me
( )7
O
(
10) 27
(9) 26
(11) 28
2
(1 mol%); 76%
2
(1 mol%); 62%
2 (1 mol%); 77%
Rh2(OAc)4 (1.5 mol%); 66%
single stereoisomer
single stereoisomer
NH
N
O
NH
O
N
H
O2N
O
N
O
O
S
Complex molecules can undergo aziridination with this method
and give the corresponding aziridines in good to excellent yields
with superb chemoselectivity, demonstrating the potential utility of
this method in natural product synthesis and medicinal chemistry
O
O
(
12) 29
(13) 30
2 (1 mol%); 52%
dr = 1:1
(14) 31
2 (1 mol%); 70%
2
(1 mol%); 51%
single stereoisomer
single stereoisomer
(
Table 2, entry 13; Table 3, entries 17−20).
O
S
O
With these exciting results for the synthesis of N−H aziridines in
NH
N
BocN
+
N
H
hand, we further examined this method for the preparation of
N−alkyl aziridines. The required N−Me and N−i-Pr hydroxylamine-
O-sulfonic acids were prepared from the corresponding
S
O
HO
(16) 33
32a
32b
2
(2 mol%); 63%c
(
15) 32a and 32b (1:1.15)
hydroxylamine hydrochloride salts according to the procedure
2
(1 mol%); 71%
O
O
developed by Hartwig et al.[
11b]
The direct N−alkyl aziridination
O
Me
O
BocHN
O
N
H
proceeded smoothly with olefins (Table 4) and the yields were good
to excellent, albeit decreased slightly compared to the N−H
aziridination process. This reduced efficiency is possibly due to the
steric hindrance originating from the larger N−alkyl groups.
NH
NH
O
NH
O
O
2
O
(
17) 34
(18) 35
(
19) 36
(1 mol%); 51%d
2
(1 mol%); 83%
dr = 1:1
2 (1 mol%); 58%
single enantiomer
Me Me
dr = 1:1
This new N−H and N−alkyl aziridination protocol is
stereospecific − isomerization of double bonds was not detected.
The stereoselectivity was excellent in the case of single enantiomer
cyclic olefins that are conformationally restricted (e.g., cyclohexene
derivative: Table 2, entry 5; cholesterol: Table 2, entry 13; carene:
Table 3, entry 18), while N−H aziridination of acyclic olefins with
remote stereocenters and conformational flexibility proceeded in a
non-stereoselective fashion (Table 3, entries 2, 13, 17 & 19).
H
N
O
O
O
NMe2
O
Me
20) 37
(1 mol%); 73%c
single stereoisomer
OH
(
2
aReaction Conditions: Olefin (1 mmol) was dissolved in 2.5 mL HFIP, followed by the
addition of pyridine (1.2 mmol), HOSA (1.2 mmol) and Rh2(esp)2 (loading is indicated for
each entry). The reaction was carried out at room temperature for 2.5 h unless indicated
otherwise. bIsolated yield after silica chromatography. The reactions were quenched with
saturated aqueous Na2CO3. c2 mmol of HOSA and pyridine were used. d1.2 mmol of
HOSA and 2 mmol of pyridine were used.
The mechanism of this new olefin aziridination process is
[7]
presumably similar to the one postulated for the DPH protocol.
Accordingly, a Rh-nitrenoid is formed via the coordination of the
amino group in HOSA to Rh, and the sequential loss of sulfate
anion. The higher reaction rate in this case likely originates from the
3
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201705530
In summary, we have developed
a novel one-pot and
faster dissociation (i.e., N−O bond cleavage) of sulfate anion from
stereospecific aziridination of unactivated olefins by employing
N−H as well as N−alkyl hydroxylamine-O-sulfonic acids as
powerful aminating agents. This transformation overcomes the
drawbacks associated with the previously reported method that
utilizes DPH as the stoichiometric aminating agent and finally
enables a more environmentally friendly and cost-effective direct
N−H and N−alkyl aziridination of olefins. We anticipate that this
general and operationally simple approach will find wide utility in
the preparation of functional group-rich intermediates as well as the
synthesis and modification of structurally complex molecules.
HOSA compared to the phenoxide anion from DPH.
Table 4. Direct intermolecular N−alkyl aziridination of structurally
diverse olefins using N−alkyl hydroxylamine-O-sulfonic acids
(
N−R−HOSA) as aminating agents.
N-R-HOSA (3b-c) (1.2 equiv)
pyridine (1.2 equiv)
R
N
R1
R2
R3
R4
Rh2(esp)2 (2) (x mol%), 25 ºC
R1
R2
R3
R4
HFIP (0.4 M), 2.5 h
1
mmol scale (3b: R = Me; 3c: R = i-Pr)
Structure of Azirdines Derived from Structurally Diverse Olefins
Entry)[ Compound #, Catalyst Loading (mol%), Isolated Yield (%)
a]
[b]
(
Received: ((will be filled in by the editorial staff))
N
Me
N
Published online on ((will be filled in by the editorial staff))
O
HO
MeN
Me
O
(
)8 NMe2
N
Me
(
)7
(3) 40
2 (1 mol%); 61%
single stereoisomer
NMe
( )7
O
Me
(2) 39c
Keywords: aziridination • dirhodium catalysis •unprotected
aziridines • stereospecific • nitrenoids• hydroxylamine–O-
sulfonic acid
(
1) 38
(4 mol%)
3%
2
2 (2 mol%); 78%
7
single stereoisomer
N
N
Me
Me
O
N
Me
OAc
O
N
Me
O N
2
O
O
Me
Cl
(
5) 42
(6) 43
2 (1 mol%); 75%
(
4) 41
(1 mol%); 61%
single stereoisomer
2
(1 mol%); 84%
2
Rh2(OAc)4 (1.5 mol%); 59% Rh2(OAc)4 (1.5 mol%); 60%
O
N
O
NMe
(
7) 44
(1 mol%); 86%
dr = 1:1
(8) 45c
2
2 (1 mol%); 71%
aReaction Conditions: The olefin (1 mmol) was dissolved in 2.5 mL HFIP, followed by the
addition of pyridine (1.2 mmol), N-Me HOSA (1.2 mmol) and Rh2(esp)2 (as indicated for
each entry). The reaction was carried out at room temperature for 2.5 h unless indicated
otherwise. bIsolated yield after silica gel chromatography. The reactions were quenched
with saturated aqueous Na2CO3. c2 mmol of N-R-HOSA (3b or 3c) and 2 mmol of
pyridine were used.
2
007, 46, 778-781; l) F. Pesciaioli, F. De Vincentiis, P. Galzerano,
G. Bencivenni, G. Bartoli, A. Mazzanti, P. Melchiorre, Angew.
Chem. Int. Ed. 2008, 47, 8703-8706.
[
[
1] For general reviews on aziridine chemistry, see: a) A. Yudin,
Editor., Aziridines and Epoxides in Organic Synthesis, Wiley-VCH
Verlag GmbH & Co. KGaA, 2006; b) J. B. Sweeney, Chem. Soc.
Rev. 2002, 31, 247-258.
2] For reviews on the synthetic utility of aziridines, see: a) W.
McCoull, F. A. Davis, Synthesis 2000, 2000, 1347-1365; b) X. E.
Hu, Tetrahedron 2004, 60, 2701-2743; c) P. Lu, Tetrahedron 2010,
[5] a) D. R. Bobeck, D. L. Warner, E. Vedejs, J. Org. Chem. 2007, 72,
8506-8518; b) L. Li, J. Zhang, Org. Lett. 2011, 13, 5940-5943.
[6] a) M. Sasaki, S. Dalili, A. K. Yudin, J. Org. Chem. 2003, 68, 2045-
2047; b) I. D. G. Watson, S. A. Styler, A. K. Yudin, J. Am. Chem.
Soc. 2004, 126, 5086-5087; c) S. Dalili, A. K. Yudin, Org. Lett.
2005, 7, 1161-1164.
6
6, 2549-2560; d) S. Stankovic, M. D'hooghe, S. Catak, H. Eum, M.
[7] J. L. Jat, M. P. Paudyal, H. Gao, Q.-L. Xu, M. Yousufuddin, D.
Devarajan, D. H. Ess, L. Kürti, J. R. Falck, Science 2014, 343, 61-
65.
Waroquier, V. Van Speybroeck, N. De Kimpe, H.-J. Ha, Chem. Soc.
Rev. 2012, 41, 643-665.
[
[
3] For recent reviews on the synthesis of aziridines, see: a) I. D. G.
Watson, L. Yu, A. K. Yudin, Acc. Chem. Res. 2006, 39, 194-206; b)
H. Pellissier, Tetrahedron 2010, 66, 1509-1555; c) L. Degennaro, P.
Trinchera, R. Luisi, Chem. Rev. 2014, 114, 7881-7929.
4] For representative studies on aziridine synthesis, see: a) D. A.
Evans, M. M. Faul, M. T. Bilodeau, B. A. Anderson, D. M. Barnes,
J. Am. Chem. Soc. 1993, 115, 5328-5329; b) K. B. Hansen, N. S.
Finney, E. N. Jacobsen, Angew. Chem. Int. Ed. Engl. 1995, 34, 676-
[8] a) H. Gao, Z. Zhou, D.-H. Kwon, J. Coombs, S. Jones, N. E.
Behnke, D. H. Ess, L. Kürti, Nature Chemistry 2016, advance
online publication; b) Z. Zhou, Z. Ma, N. E. Behnke, H. Gao, L.
Kürti, J. Am. Chem. Soc. 2017, 139, 115-118.
[9] E. Erdik, J. Saczewski, Hydroxylamine-O-sulfonic acid in e-EROS
Encyclopedia of Reagents for Organic Synthesis, John Wiley &
Sons, Ltd., 2013, pp. 1-10.
[10] a) R. G. Wallace, Aldrichimica Acta 1980, 13, 3-11; b) R. G.
Wallace, Org. Prep. Proced. Int. 1982, 14, 265-267, 269-307; c) E.
Erdik, Hydroxylamine-O-sulfonic Acid in e-EROS Encyclopedia of
Reagents for Organic Synthesis, John Wiley & Sons, Ltd., 2001.
[11] a) H. C. Brown, W. R. Heydkamp, E. Breuer, W. S. Murphy, J. Am.
Chem. Soc. 1964, 86, 3565-3566; b) A. E. Strom, J. F. Hartwig, J.
Org. Chem. 2013, 78, 8909-8914; c) S. Voth, J. W. Hollett, J. A.
McCubbin, J. Org. Chem. 2015, 80, 2545-2553.
6
3
78; c) F. A. Davis, P. Zhou, G. V. Reddy, J. Org. Chem 1994, 59,
243-3245; d) F. A. Davis, H. Liu, P. Zhou, T. Fang, G. V. Reddy,
Y. Zhang, J. Org. Chem. 1999, 64, 7559-7567; e) J. C. Antilla, W.
D. Wulff, J. Am. Chem. Soc. 1999, 121, 5099-5100; f) P. Dauban, L.
Saniere, A. Tarrade, R. H. Dodd, J. Am. Chem. Soc. 2001, 123,
7
1
707-7708; g) K. Guthikonda, J. Du Bois, J. Am. Chem. Soc. 2002,
24, 13672-13673; h) R. Waterman, G. L. Hillhouse, J. Am. Chem.
Soc. 2003, 125, 13350-13351; i) F. A. Davis, Y. Wu, H. Yan, W.
McCoull, K. R. Prasad, J. Org. Chem. 2003, 68, 2410-2419; j) Z. Li,
X. Ding, C. He, J. Org. Chem. 2006, 71, 5876-5880; k) J. Vesely, I.
Ibrahem, G.-L. Zhao, R. Rios, A. Cordova, Angew. Chem., Int. Ed.
[12] M. P. Paudyal, A. M. Adebesin, S. R. Burt, D. H. Ess, Z. Ma, L.
Kürti, J. R. Falck, Science 2016, 353, 1144-1147.
4
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201705530
Olefin Aziridination
Z. Ma, Z. Zhou and L. Kürti*
______Page – Page
Direct and Stereospecific Synthesis of
N−H and N−Alkyl Aziridines from
Unactivated Olefins Using
Hydroxylamine-O-Sulfonic Acids
Herein we report a Rh(II)-catalyzed direct and stereospecific N−H- and N−alkyl
aziridination of olefins that uses hydroxylamine-O-sulfonic acids as inexpensive,
readily available and nitro group-free aminating reagents. Unactivated olefins,
featuring a wide range of functional groups, are converted to the corresponding
N−H or N−alkyl aziridines in good to excellent yields. This operationally simple,
scalable transformation proceeds efficiently at ambient temperature and is tolerant
towards oxygen and trace moisture.
5
This article is protected by copyright. All rights reserved.