Generation and Ring Opening of Aziridines in Telescoped Continuous Flow Processes

Article abstract of DOI:10.1021/acs.orglett.5b01777

A simple method for the preparation of a variety of N-sulfonyl aziridines (10 examples) from 1,2-amino alcohols under continuous flow conditions is described. Using flow based methods, the aziridines can be further ring opened with oxygen, carbon, and hal

Full text of DOI:10.1021/acs.orglett.5b01777

Letter
pubs.acs.org/OrgLett
Generation and Ring Opening of Aziridines in Telescoped
Continuous Flow Processes
Nathanael Hsueh, Guy J. Clarkson, and Michael Shipman*
Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, U.K.
S
* Supporting Information
ABSTRACT: A simple method for the preparation of a
variety of N-sulfonyl aziridines (10 examples) from 1,2-amino
alcohols under continuous flow conditions is described. Using
flow based methods, the aziridines can be further ring opened
with oxygen, carbon, and halide nucleophiles or ring expanded
to imidazolines by Lewis acid promoted reaction with nitriles.
Telescoping the aziridine generation and ring opening steps
together in a microfluidic reactor allows the chemistry to be
undertaken with limited exposure to the potentially hazardous
aziridine intermediates.
ziridines are important building blocks in organic
synthesis, widely used in academic and industrial
Finally, aziridines have been used as precursors to azomethine
ylids in flow as a way to functionalize carbon nanotubes.14
Here, we report a simple, general method for the synthesis of
N-sulfonyl aziridines 2 from 1,2-amino alcohols 1 and explore
their further ring opening to amines 3 (Scheme 1), and ring
A
laboratories to produce a variety of nitrogen containing
molecules.1,2 In particular, they serve as ‘spring-loaded’
electrophiles for C−C and C−heteroatom bond formation by
way of nucleophilic ring opening. The excellent scope,
efficiency, selectivity, and atom economy displayed by these
processes has led them to be included in the small group of
highly valued “click” reactions.3 However, the high reactivity of
aziridines does make them potentially rather hazardous
reagents to handle. For example, aziridine (ethylenimine) is a
powerful alkylating agent that has been classified as being
possibly carcinogenic to humans with strong mutagenic and
genotoxic activity.4 While data on other aziridines are more
limited, it is known that a number of aziridine containing
natural products5 such as the mitomycins6 and azinomycins7
act as cytotoxic agents due to their propensity to alkylate and
cross-linking DNA. Consequently, it is important to limit
exposure to aziridines as a compound class during their
preparation and handling.
Recently, continuous flow methodology has emerged as a
powerful new technique in chemical synthesis.8,9 One of its
many advantages over batch processes is that it can be used to
generate and handle hazardous and reactive reagents in a safe
way.10 For this reason, we felt that flow methodology might
provide a simple and attractive way to produce and handle
aziridines more safely. Surprisingly, the preparation and
utilization of these electrophilic species in laboratory-scale
flow chemistry has received only scant attention.11−14 As far as
we are aware, the only report describing the generation of
aziridines in flow is that by Booker-Milburn, who used
intramolecular photorearrangements of substituted pyrroles to
produce complex tricyclic scaffolds containing the aziridine
ring.11 In other work, Yoshida has lithiated and C-alkylated N-
Bus aziridines in flow12 and, with Luisi, reported their lateral
lithiation and ring opening to 1,2,3,4-tetrahydroisoquinolines.13
Scheme 1. Proposed Approach for the Generation and in
Situ Ring Opening of Aziridines under Continuous Flow
Conditions
expansion to imidazolines, under continuous flow conditions.
Importantly, by telescoping the processes together, we show
that efficient sequences can be realized without exposure to the
potentially hazardous aziridine intermediates.
One of the most common and efficient routes to aziridines
involving activation/ring closure of 1,2-amino alcohol was used
for our studies.2 Importantly, the precursors are widely
available, the reaction tolerates good variability in aziridine
structure and it can be used to access these heterocycles as
single enantiomers. The flow system we used was constructed
from simple, readily available components. Computer-con-
trolled syringe pumps were used to independently deliver the
reagents to a commercial microreactor made from borosilicate
glass via a premixing unit (total reactor volume ca. 2 mL).
Residence times (Rt) were conveniently controlled through
Received: June 19, 2015
Published: July 9, 2015
© 2015 American Chemical Society
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DOI: 10.1021/acs.orglett.5b01777
Org. Lett. 2015, 17, 3632−3635

Organic Letters
Letter
addition rates and substrate concentrations. Most of the
chemistry was conducted using a simple two-input micro-
reactor, although the telescoped processes employed a three-
channel system. Full details of the experimental setup are
provided in the Supporting Information.
Scheme 2. Synthesis of Mono- And Disubstituted Aziridines
5a−j under Continuous Flow
Our studies began with an investigation into the cyclization
of 2-phenyl-2-aminoethanol (4) to N-tosyl aziridine 5a. The
established batch process is performed using TsCl (2.5 equiv),
triethylamine (3 equiv), and cat. DMAP in CH2Cl2 at rt.15
However, this transformation is very slow, taking up to 24 h,
and leads to the formation of Et3N·HCl as a solid precipitate.
To ensure the corresponding flow reaction is homogeneous,
thus preventing potential reactor blockages, we switched to the
use of chloroform as solvent. To reduce the reaction time, the
use of elevated temperatures and larger quantities of reagents
was examined. Details of the optimization process are provided
in Table 1. Variation in the nature of the base was also
Table 1. Optimization of Conditions for Ring Closure of 2-
Phenyl-2-aminoethanol (4) to Aziridine 5a in a Continuous
Flow Reactor
a
b
c
DMAP
TsCl
(equiv)
Rt
yield
(%)
a
entry t (°C)
(equiv)
base (equiv)
(min)
Reaction conditions: RSO2Cl (2.5 equiv), DMAP (0.5 equiv), Et3N
b
c
(4.5 equiv), CHCl3. Isolated yield after chromatography. Ms2O (2.5
equiv), DBU (4.5 equiv), DMAP (0.5 equiv), CHCl3/CH2Cl2 (1:1), Rt
= 16 min, 30 °C. DMAP (2.1 equiv), TsCl, CHCl3, Rt = 15 min then
DBU (4.5 equiv), CHCl3, Rt = 15 min.
1
21
21
21
21
30
35
30
30
30
30
30
30
30
0.5
0.5
0.5
0.5
0.5
0.5
0
Et3N (4.5)
Et3N (4.5)
Et3N (4.5)
Et3N (4.5)
Et3N (4.5)
Et3N (4.5)
Et3N (4.5)
Et3N (3.8)
Et3N (5.3)
DBU (4.5)
Et3N (4.5)
Et3N (4.5)
2.0
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.3
2.5
3.0
8
30
51
53
67
73
70
2
8
d
3
13
40
40
40
40
40
40
40
40
40
40
4
5
benzenesulfonyl (Ns) groups can be introduced at nitrogen
through variation in the sulfonyl chloride used. For N-Ms
derivatives 5c and 5h, better yields were achieved using
methanesufonyl anhydride in combination with DBU. In these
examples, a mixed solvent system (CHCl3/CH2Cl2) was
required to keep the anhydride in solution. Using S-2-phenyl-
2-aminoethanol (4), the preparation of 5a could be achieved
without detectable racemization. For the synthesis of 2,2-
dimethylaziridine 5f, improved yields were obtained using a
three-input microreactor. After initial reaction of 2-amino-2-
methylpropan-1-ol with TsCl/Et3N to give the intermediate
ditosylate, DBU was then added to induce ring closure.
6
7
trace
53
8
0.5
0.5
0.5
0.3
1.0
1.0
9
74
10
11
12
13
trace
61
70
Et3N (4.5)
77
a
b
All reactions performed in CHCl3. Residence time in microreactor.
c
Isolated yield after chromatography.
investigated but hampered by the fact that precipitates occurred
using many bases in the aziridine formation such as pyridine,
2,4,6-collidine, 2,6-lutidine, or piperidine. Hence they proved
unsuitable for use in this flow method and are not detailed in
Table 1. Through these optimization studies, a practical
continuous flow procedure was identified (Table 1, entry 5).
This involved premixing the amino alcohol in CHCl3 with
DMAP (0.5 equiv) and Et3N (4.5 equiv) and combining it in
the microreactor at 30 °C with TsCl (2.5 equiv). In this way,
high yields of 5a could be obtained using a 40 min residence
time. These new conditions are also useful for accelerating
batch processes; for example, they can be used to produce 5a in
72% yield.
Next, we explored the nucleophilic ring opening of
representive aziridines under continuous flow conditions. The
use of a variety of oxygen, carbon, and halide nucleophiles was
examined (Scheme 3). Good to excellent yields were obtained
in most cases by simply combining the aziridine with a
premixed solution of the nucleophile and acid catalyst at
elevated temperatures. Many of these ring openings were
undertaken using Brønsted acids bearing non-nucleophilic
counterions (H2SO4 or MeSO3H) as activators. The reactions
were efficient with 40 min residence times. For the addition of
chloride and fluoride respectively, HCl and BF3·Et2O/iPrOH16
were used as the source of both the nucleophile and activator.
Using unsymmetrical 2-phenyl aziridines 5a and 5c, only a
single regioisomer was observed with attack at the more
substituted carbon. For 6f, produced by Friedel−Crafts
alkylation of 1,3,5-trimethoxybenzene,17 this regiochemical
outcome was unambiguously confirmed by X-ray crystallog-
raphy. With 1,2-disubstituted aziridines, trans-6g−j were
Next, the synthesis of a variety of mono- and disubstituted
aziridines from 1,2-amino alcohols under the optimized
continuous flow conditions were explored (Scheme 2).
Moderate to good yields are seen across a range of substitution
patterns. Tosyl (Ts), methanesulfonyl (Ms), and 4-nitro-
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Organic Letters
Letter
Scheme 3. Nucleophilic Ring Opening of Aziridines under
Continuous Flow Conditions
Scheme 4. Imidazoline Synthesis by Formal (3 + 2)
Cycloaddition of Aziridines 5 with Nitriles under
Continuous Flow Conditions
a
Reaction conditions: R1CN (5 equiv), BF3·Et2O (5 equiv), CH2Cl2,
b
Rt = 5 min. Isolated yield after chromatography.
a
b
Isolated yield after chromatography. H2SO4, H2O/acetone, 70 °C.
Scheme 5. Telescoped Sequences for Generation and
Opening of Aziridines under Continuous Flow Conditions
c
d
e
H2SO4, MeOH/CHCl3, 70 °C. PhOH, MsOH, CHCl3, rt. HCl,
f
Et2O/CHCl3, 70 °C. 1,3,5-Trimethoxybenzene, MsOH, CHCl3, rt.
g
BF3·Et2O, iPrOH, CHCl3, rt.
formed as the only stereoisomer by way of SN2-type opening.
In the case of 6g, produced by fluoride opening of aziridine 5g,
this stereochemical assignment was confirmed by X-ray
crystallography.
Additionally, the synthesis of imidazolines by the Lewis acid
mediated ring expansion of 2-aryl aziridines with nitriles under
continuous flow conditions has been examined.18,19 Using
boron(III) fluoride as a Lewis acid in combination with various
nitriles, imidazolines 7a−g were produced in moderate to good
yields from 2-aryl aziridines (Scheme 4). The yields are broadly
comparable with those obtained in conventional batch
processes.18 A single regioisomer was seen in all cases by way
of initial nucleophilic ring opening at the more substituted
carbon by the nitrile, prior to ring closure. This regiochemical
outcome was confirmed for 7b and 7c by single crystal X-ray
diffraction.
With practical conditions for the synthesis, ring opening, and
ring expansion of aziridines under continuous flow conditions,
we set about ascertaining if telescoped reactions could be
undertaken in which the aziridine is generated and further
reacted without recourse to handling or isolation. Our
preliminary findings are very encouraging as illustrated in
Scheme 5. For this chemistry, a three-input microreactor was
used (see Supporting Information). The use of anhydrides for
aziridine formation gave the best results in these telescoped
sequences.20 The total residence time for these reactions was 28
min (aziridine generation = 16 min; ring opening = 12 min).
In conclusion, we have devised a simple, general route to
aziridines through ring closure of the corresponding 1,2-amino
alcohols under continuous flow conditions. A variety of
substitution patterns are accessible using this method. Further
reactions of the aziridines in flow provides access to a variety of
useful nitrogen containing products by way of regio- and
stereocontrolled opening with nucleophiles, or by ring
a
b
c
NuH/H+ = MeOH/MsOH. NuH/H+ = HCl. MeCN/BF3·Et2O.
expansion. The flow-based processes described generally give
similar yields/selectivities to conventional batch reactions.
However, by telescoping the flow processes together, it is
possible to limit exposure to this potentially hazardous class of
electrophilic reagents and exploit other benefits of this new
technology.9 Work to explore other routes to aziridines in
microreactors is ongoing in our laboratory and will be disclosed
in due course.
ASSOCIATED CONTENT
■
S
* Supporting Information
Details of continuous flow apparatus, experimental procedures,
characterization data for all compounds, chiral HPLC analysis
for 5a, and X-ray data for 6f, 6g, 7b, and 7c. The Supporting
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Org. Lett. 2015, 17, 3632−3635

Organic Letters
Letter
(14) Salice, P.; Rossi, E.; Pace, A.; Maity, P.; Carofiglio, T.; Menna,
E.; Maggini, M. J. Flow Chem. 2014, 4, 79−85.
Information is available free of charge on the ACS Publications
website at DOI: 10.1021/acs.orglett.5b01777.
(15) Vicario, J. L.; Badía, D.; Carrillo, L. ARKIVOC 2007, iv, 304−
311.
AUTHOR INFORMATION
■
(16) Ding, C.-H.; Dai, L.-X.; Hou, X.-L. Synlett 2004, 2218−2220.
(17) Wang, Z.; Sun, X.; Wu, J. Tetrahedron 2008, 64, 5013−5018.
(18) Prasad, B. A. B.; Pandey, G.; Singh, V. K. Tetrahedron Lett. 2004,
45, 1137−1141.
(19) For an alternative route to imidazolines using continuous flow
methodology, see: Martha, C. T.; Heemskerk, A.; Hoogendoorn, J.-C.;
Elders, N.; Niessen, W. M. A.; Orru, R. V. A.; Irth, H. Chem. - Eur. J.
2009, 15, 7368−7375.
(20) Using arylsulfonyl chlorides, lower yields were seen in these
telescoped processes as a result of competitive opening of the aziridine
ring by chloride ion.
Corresponding Author
*E-mail: m.shipman@warwick.ac.uk.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the University of Warwick for financial support. The
Oxford Diffraction Gemini XRD system was obtained, through
the Science City Advanced Materials project: Creating and
Characterizing Next Generation Advanced Materials. We thank
Dr. Andrew J. Clark (University of Warwick) for the generous
loan of equipment.
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