Enantioselective synthesis of diaryl aziridines using tetrahydrothiophene- based chiral sulfides as organocatalysts

Article abstract of DOI:10.1039/c3cc47550f

This work describes catalytic and asymmetric aziridinations (15 examples, 95-98% ee) of benzyl bromide and imines via the imino Corey-Chaykovsky reaction using (thiolan-2-yl)diarylmethanol benzyl ether as an organocatalyst. The catalyst and analogues thereof were prepared through an expeditious and efficient synthetic route featuring a double nucleophilic substitution and Shi epoxidation as key steps.

Full text of DOI:10.1039/c3cc47550f

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Enantioselective synthesis of diaryl aziridines
using tetrahydrothiophene-based chiral
Cite this:DOI: 10.1039/c3cc47550f
sulfides as organocatalysts†
Meng-Ting Huang,a Hsin-Yi Wub and Rong-Jie Chein*b
Received 2nd October 2013,
Accepted 30th October 2013
DOI: 10.1039/c3cc47550f
www.rsc.org/chemcomm
This work describes catalytic and asymmetric aziridinations (15 examples,
95–98% ee) of benzyl bromide and imines via the imino Corey–
Chaykovsky reaction using (thiolan-2-yl)diarylmethanol benzyl ether as
an organocatalyst. The catalyst and analogues thereof were prepared
through an expeditious and efficient synthetic route featuring a double
nucleophilic substitution and Shi epoxidation as key steps.
Chiral aziridines possessing uncommon reactivity have recently
excited much interest among synthetic chemists. They are
important components in natural products1 (e.g. aziridine
carboxylic acid, miomycin, porfiromycin, mistosanes, and
mitiromycin) and biologically active molecules,2 and have been
showcased as important intermediates of nitrogen-containing
compounds in synthetic processes, which may otherwise be
less accessible. Optically active aziridines can be prepared in
numerous ways including SN2 displacement of enantioenriched
b-amino alcohol derivatives,3 asymmetric addition of nitrenes
to olefins, asymmetric addition of carbenes to imines,4 asymmetric
aza-Michael addition,5 aza-Darzens reaction,6 and the imino
Corey–Chaykovsky reaction. Among these burgeoning research
fields, the sulfonium ylide-mediated aziridination developed by
Dai and co-workers7 has captured the imagination of many organic
chemists. For example, Aggarwal’s lab has further exploited this
methodology by incorporating asymmetric and catalytic compo-
nents into the reaction.8 However, a transition metal is required to
generate the carbene in situ from the diazomethane precursor
which is difficult to be prepared in a broad substrate scope.9
Saito’s10 and Huang’s11 groups reported one-pot methods for the
enantioselective synthesis of aziridines from benzyl bromide and
imines mediated by a camphor-derived sulfide and a C2-symmetric
sulfide respectively (Fig. 1, upper panel). Most recently, Aggarwal’s
group disclosed an isothiocineole which gave higher levels of er
Fig. 1 Asymmetric synthesis of diaryl aziridine via sulfide alkylation/
deprotonation.
and dr over a broader range of imines and benzyl substituents.8b
The downside of the later methodologies is that stoichiometric
amounts of chiral sulfides are required to achieve high stereo-
selectivity. We have previously reported an enantioselective synthesis
of (S)-thiolanyl diphenylmethanol (1a) and the application of its
benzyl ether derivative (2a) in an asymmetric, catalytic Corey–
Chaykovsky reaction of benzyl bromide and aldehydes to give
trans-epoxides in high yield with good to high enantiomeric excess.12
Further extension of the application of this chiral sulfide to develop a
metal-free, catalytic, and highly enantioselective aziridination can be
potentially achieved by expanding the repertoire by reacting partners
from aldehydes to imines. In this account, we report our research
results in this regard (Fig. 1, lower panel).
a Department of Chemistry, National Taiwan Normal University, 162,
Heping East Road Section 1, Taipei 10610, Taiwan
b Institute of Chemistry, Academia Sinica, 128 Academia Road Sec. 2, Nankang,
Taipei 11529, Taiwan. E-mail: rjchein@chem.sinica.edu.tw;
Fax: +886-2-2783-1237; Tel: +886-2-2789-8526
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c3cc47550f
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Table 2 Optimization of aziridination
Entry Solvent Additive (equiv.) t (day) Yielda (%) trans/cisb eec (%)
1
2
3
4
5
6
CH3CN
CH2Cl2
THF
Toluene
CH3CN LiOTf (0.2)
CH3CN NaI (0.5)
3
3
3
3
4
2
89
78
68
7
75
85
83/17
84/16
77/23
79/21
80/20
80/20
97
97
97
97
97
98
Scheme 1 Syntheses of (thiolan-2-yl)diarylmethyl ethers (2). Reagents
and conditions: (a) ArMgBr, THF. (b) PTSA (cat.) toluene, 70 1C. (c) Shi
epoxidation. (d) Na2SÁ9H2O, EtOH, sonication. (e) NaH, BnBr, DMF.
a
b
c
Isolated yield. Ratio was determined by 1H NMR. ee of trans
aziridine was determined by HPLC analysis with chiralcel-OD column.
Our initial effort was to prepare a series of tetrahydro-
thiophene-derived chiral sulfides (2a–c), which were readily
available through the procedure reported previously12 with
slight modification (Scheme 1). Commercially available ethyl
5-bromovalerate (3) was reacted with 3 equiv. of phenylmagnesium
bromide, (3,5-dimethylphenyl)magnesium bromide, and (3,5-bis(tri-
fluoromethyl)phenyl)magnesium bromide, respectively, to afford
diarylalcohols 4a–c which were dehydrated in hot toluene in
the presence of PTSA. The resulting diphenylethylenes 5a–c were
subjected to Shi epoxidation conditions13 to make optically active
epoxides 6a–c. After the treatment of a suspension of Na2S in
ethanol solution, (S)-(thiolan-2-yl)diarylmethanols 1a–c were
obtained in total yields of 69–52%. O-Protection of 1a–c with benzyl
bromide under basic conditions in DMF yielded catalysts 2a–c for
the following aziridination process.
With the various chiral sulfide catalysts in hand, the azir-
idination was first performed in a one-pot reaction by stirring
the acetonitrile solution of benzyl bromide and different imines
derived from benzaldehyde respectively in the presence of
K2CO3 and 20 mol% sulfides 2a–2c (Table 1). To our delight,
sulfide 2a successfully catalyzed the imino Corey–Chaykovsky
reaction of benzyl bromide and various N-substituted phenyl-
methanimines (N-Ts 7a, N-Boc 7b, and N-P(O)Ph2 7c, Table 1,
entries 1–3), leading to the corresponding aziridines 8a–8c in
moderate to good yields (63–89%) with excellent enantioselec-
tivities (88–97%) (entries 1–3). Among them, the reaction with
the most sterically hindered imine 7c (entry 3) showed the best
results in both enantio- and diastereoselectivity, and therefore
diphenylphosphine oxide was used as the imine activation group
for the following tests. We next compared the stereo-chemical
outcome of the aziridination catalyzed by the different sulfides
2a, 2b and 2c. Both the sulfides bearing bulkier (2b, entry 4) and
electron poor (2c, entry 5) aromatic groups mediated the reaction
with lower diastereoselectivities than sulfide 2a (entry 3), while
the enantioselectivities remained high. The absolute configu-
ration of aziridine 8c was confirmed by converting it to the
known (+)-(2R,3R)-2,3-diphenylaziridine (9), the optical rotation
([a]2D7 = +333 (c 0.75, CHCl3)) and spectra of which are in good
agreement with those reported in the literature.14
Further optimization of 2a-mediated aziridination of benzyl
bromide and (E)-N-benzylidene-P,P-diphenylphosphinic amide
(7c) showed that acetonitrile is still the best solvent in compar-
ison with dichloromethane, THF, and toluene (Table 2, entries
1–4). Moreover, LiOTf retarded the reaction rate in the imino
case, considering that fact it efficiently accelerated the Corey–
Chaykovsky reaction in our previous report12 (Table 2, entry 5).
0.5 equiv. of NaI addition effectively shortened the reaction
time from 3 days to 2 days without significantly affecting the
stereoselectivity (Table 2, entry 6).
Table 1 Screening of imine protecting groups and THT catalysts
To explore the breadth of the present paradigm for aziridination,
a variety of N-diphenylphosphinic imines 7d–7q were subjected
to this protocol and the outcomes were highlighted in Table 3. It
was found that, in the presence of K2CO3 and NaI in acetonitrile,
chiral sulfide 2a universally catalyzed the reaction of benzyl
bromide with various imines of electron poor (7d–f, 7j, 7p),
neutral (7c, 7n, 7o), or electron rich (7g–i, 7k–m, 7q) aldehydes
via the sulfonium ylide, giving chiral aziridines in moderate to
high yields (73–93%) with dominant trans isomers 8d–8q in
excellent enantiomeric excess (95–97%). In addition, there was
no significant steric limit in respect of reactivity and enantio-
selectivity during the asymmetric aziridination. The reactions
of the imines derived from ortho- (7m, 7p), meta- (7h, 7l), and
para-substituted (7d–7g, 7j, 7k, 7n) benzaldehydes all showed
good results. The only exception occurred in the reaction of
Entry Imine Sulfide t (day) Yielda (%) trans/cisb eec (%)
1
2
3
4
5
7a
7b
7c
7c
7c
2a
2a
2a
2b
2c
1
1.5
3
4.5
4.5
78
63
89
82
25
77/23
85/15
83/17
78/22
72/28
97
88
97
95
97
a
b
c
Isolated yield. Ratio was determined by 1H NMR. ee of trans
aziridine was determined by HPLC analysis with chiralcel-OD column.
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Table 3 The substrate scope of aziridination
In summary, we have synthesized tetrahydrothiophene-derived
chiral sulfides from commercially available ethyl 5-bromovalerate
and extended their applications for the imino Corey–Chaykovsky
reaction in a catalytic, enantioselective, and user-friendly fashion.
The synthetic utility of the asymmetric aziridination was further
exemplified in a two-step synthesis of asymmetric b-amino alcohol.
Further investigations regarding the development of second gen-
eration organocatalysts based on these chiral sulfides and selenium
analogues are currently under way.
We gratefully acknowledge Academia Sinica and the
National Science Council, Taiwan, Republic of China for finan-
cial support and the Mass Lab of the Institute of Chemistry,
Academia Sinica for mass analysis.
Notes and references
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