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Enantioselective synthesis of diaryl aziridines

Cite this: Chem. Commun., 2014,
50, 1101
Received 2nd October 2013,
Accepted 30th October 2013
using tetrahydrothiophene-based chiral
sulfides as organocatalysts†
Meng-Ting Huang,a Hsin-Yi Wub and Rong-Jie Chein*b

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 Fig. 1 Asymmetric synthesis of diaryl aziridine via sulfide alkylation/
chemists. For example, Aggarwal’s lab has further exploited this deprotonation.
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 and dr over a broader range of imines and benzyl substituents.8b
which is difficult to be prepared in a broad substrate scope.9 The downside of the later methodologies is that stoichiometric
Saito’s10 and Huang’s11 groups reported one-pot methods for the amounts of chiral sulfides are required to achieve high stereo-
enantioselective synthesis of aziridines from benzyl bromide and selectivity. We have previously reported an enantioselective synthesis
imines mediated by a camphor-derived sulfide and a C2-symmetric of (S)-thiolanyl diphenylmethanol (1a) and the application of its
sulfide respectively (Fig. 1, upper panel). Most recently, Aggarwal’s benzyl ether derivative (2a) in an asymmetric, catalytic Corey–
group disclosed an isothiocineole which gave higher levels of er Chaykovsky reaction of benzyl bromide and aldehydes to give
trans-epoxides in high yield with good to high enantiomeric excess.12
a
Department of Chemistry, National Taiwan Normal University, 162, Further extension of the application of this chiral sulfide to develop a
Heping East Road Section 1, Taipei 10610, Taiwan
b
metal-free, catalytic, and highly enantioselective aziridination can be
Institute of Chemistry, Academia Sinica, 128 Academia Road Sec. 2, Nankang,
Taipei 11529, Taiwan. E-mail: rjchein@chem.sinica.edu.tw;
potentially achieved by expanding the repertoire by reacting partners
Fax: +886-2-2783-1237; Tel: +886-2-2789-8526 from aldehydes to imines. In this account, we report our research
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c3cc47550f results in this regard (Fig. 1, lower panel).

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Table 2 Optimization of aziridination

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Entry Solvent Additive (equiv.) t (day) Yielda (%) trans/cisb eec (%)
1 CH3CN 3 89 83/17 97
2 CH2Cl2 3 78 84/16 97
3 THF 3 68 77/23 97
4 Toluene 3 7 79/21 97
Scheme 1 Syntheses of (thiolan-2-yl)diarylmethyl ethers (2). Reagents 5 CH3CN LiOTf (0.2) 4 75 80/20 97
and conditions: (a) ArMgBr, THF. (b) PTSA (cat.) toluene, 70 1C. (c) Shi 6 CH3CN NaI (0.5) 2 85 80/20 98
epoxidation. (d) Na2S
9H2O, EtOH, sonication. (e) NaH, BnBr, DMF.
a
Isolated yield. b Ratio was determined by 1H NMR. c 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 moderate to good yields (63–89%) with excellent enantioselec-
available through the procedure reported previously12 with tivities (88–97%) (entries 1–3). Among them, the reaction with
slight modification (Scheme 1). Commercially available ethyl the most sterically hindered imine 7c (entry 3) showed the best
5-bromovalerate (3) was reacted with 3 equiv. of phenylmagnesium results in both enantio- and diastereoselectivity, and therefore
bromide, (3,5-dimethylphenyl)magnesium bromide, and (3,5-bis(tri- diphenylphosphine oxide was used as the imine activation group
fluoromethyl)phenyl)magnesium bromide, respectively, to afford for the following tests. We next compared the stereo-chemical
diarylalcohols 4a–c which were dehydrated in hot toluene in outcome of the aziridination catalyzed by the different sulfides
the presence of PTSA. The resulting diphenylethylenes 5a–c were 2a, 2b and 2c. Both the sulfides bearing bulkier (2b, entry 4) and
subjected to Shi epoxidation conditions13 to make optically active electron poor (2c, entry 5) aromatic groups mediated the reaction
epoxides 6a–c. After the treatment of a suspension of Na2S in with lower diastereoselectivities than sulfide 2a (entry 3), while
ethanol solution, (S)-(thiolan-2-yl)diarylmethanols 1a–c were the enantioselectivities remained high. The absolute configu-
obtained in total yields of 69–52%. O-Protection of 1a–c with benzyl ration of aziridine 8c was confirmed by converting it to the
bromide under basic conditions in DMF yielded catalysts 2a–c for known (+)-(2R,3R)-2,3-diphenylaziridine (9), the optical rotation
the following aziridination process. ([a]27
D = +333 (c 0.75, CHCl3)) and spectra of which are in good
With the various chiral sulfide catalysts in hand, the azir- agreement with those reported in the literature.14
idination was first performed in a one-pot reaction by stirring Further optimization of 2a-mediated aziridination of benzyl
the acetonitrile solution of benzyl bromide and different imines bromide and (E)-N-benzylidene-P,P-diphenylphosphinic amide
derived from benzaldehyde respectively in the presence of (7c) showed that acetonitrile is still the best solvent in compar-
K2CO3 and 20 mol% sulfides 2a–2c (Table 1). To our delight, ison with dichloromethane, THF, and toluene (Table 2, entries
sulfide 2a successfully catalyzed the imino Corey–Chaykovsky 1–4). Moreover, LiOTf retarded the reaction rate in the imino
reaction of benzyl bromide and various N-substituted phenyl- case, considering that fact it efficiently accelerated the Corey–
methanimines (N-Ts 7a, N-Boc 7b, and N-P(O)Ph2 7c, Table 1, Chaykovsky reaction in our previous report12 (Table 2, entry 5).
entries 1–3), leading to the corresponding aziridines 8a–8c in 0.5 equiv. of NaI addition effectively shortened the reaction
time from 3 days to 2 days without significantly affecting the
Table 1 Screening of imine protecting groups and THT catalysts stereoselectivity (Table 2, entry 6).
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
Entry Imine Sulfide t (day) Yielda (%) trans/cisb eec (%) high yields (73–93%) with dominant trans isomers 8d–8q in
1 7a 2a 1 78 77/23 97 excellent enantiomeric excess (95–97%). In addition, there was
2 7b 2a 1.5 63 85/15 88 no significant steric limit in respect of reactivity and enantio-
3 7c 2a 3 89 83/17 97
4 7c 2b 4.5 82 78/22 95 selectivity during the asymmetric aziridination. The reactions
5 7c 2c 4.5 25 72/28 97 of the imines derived from ortho- (7m, 7p), meta- (7h, 7l), and
a
Isolated yield. b Ratio was determined by 1H NMR. c ee of trans para-substituted (7d–7g, 7j, 7k, 7n) benzaldehydes all showed
aziridine was determined by HPLC analysis with chiralcel-OD column. good results. The only exception occurred in the reaction of

1102 | Chem. Commun., 2014, 50, 1101--1103 This journal is © The Royal Society of Chemistry 2014

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Table 3 The substrate scope of aziridination
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a 7 A. H. Li, L. X. Dai and V. K. Aggarwal, Chem. Rev., 1997, 97, 2341.
Isolated yield. b trans/cis ratio was determined by 1H NMR. c ee of
trans aziridines was determined by HPLC analysis.
Scheme 2 Transformation of 8c to 9. Reagents and conditions: (a) LiAlH4,
THF. (b) TFA, acetone–H2O (2 : 1). *ee of 10 was determined by 1H NMR of
its Mosher amide derivative.
2-methoxyphenyl imine 7i and benzyl bromide, resulting in an
almost 1 : 1 ratio of trans and cis isomers.
The resulting diphenyl aziridine could be further functionalized
to 2-amino-1,2-diphenylethanol via a two-step procedure. As shown
in Scheme 2, compound 8c was first treated with 3 equiv. of LiAlH4
in THF to remove the diphenyl phosphine oxide group. The
resulting aziridine 9 was then hydrolyzed under acidic conditions
to afford (1S,2R)-2-amino-1,2-diphenylethanol (10) in 56% total
yield without racemization. This provides the most efficient route
to this important class of chiral b-amino alcohols.15
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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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