Diastereoselective synthesis of functionalized pyrrolidines through N-bromosuccinimide-induced aziridine ring expansion cascade of cinnamylaziridine

Article abstract of DOI:10.1039/c4ob01384k

An efficient aziridine ring expansion cascade of cinnamylaziridine has been developed. N-Bromosuccinimide was used as the promoter. The resulting functionalized pyrrolidines are the fundamental units of many useful molecules.

Full text of DOI:10.1039/c4ob01384k

Organic &
Biomolecular Chemistry
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Diastereoselective synthesis of functionalized
pyrrolidines through N-bromosuccinimide-
induced aziridine ring expansion cascade
of cinnamylaziridine†
Cite this: Org. Biomol. Chem., 2014,
12, 7482
Received 2nd July 2014,
Accepted 6th August 2014
DOI: 10.1039/c4ob01384k
Jing Zhou and Ying-Yeung Yeung*
www.rsc.org/obc
An efficient aziridine ring expansion cascade of cinnamylaziridine
has been developed. N-Bromosuccinimide was used as the promoter.
The resulting functionalized pyrrolidines are the fundamental units
of many useful molecules.
Inefficient chemical synthesis does cause problems in pharma-
ceutical industry and obstructs the development of life-saving
drugs.1 The negative impact of inefficient synthetic processes
on the environment has also become an important concern in
recent years.2 Electrophilic halogen-induced cascade reactions,
which are considered as efficient and environmentally benign
processes since multiple bonds can be formed (sometimes
multiple stereocentres can also be obtained) in a single chemi-
cal operation,3,4 have been developed in recent years.5 For
instance, transformations such as polyene cyclization
(Scheme 1, eqn (1))6 and domino cyclization/cyclic ether ring
expansion (Scheme 1, eqn (2)) have been documented.7 These
reactions have proven to be highly valuable as a number of
applications have been demonstrated. In contrast, the utili-
zation of aziridine in such kind of cascade is less studied.8
Recently, we have reported a novel bromonium ion-initiated
asymmetric aminocyclization–aziridine ring expansion
cascade to afford substituted azepanes 2, which could be
further transformed to other functional molecules (Scheme 1,
eqn (3)).9 We reasoned that the same reaction protocol can be
applied to the homolog cinnamylaziridine 3. Herein, we are
pleased to report the diastereoselective synthesis of pyrrolidine
4,10 which contains three stereocenters through the electrophi-
lic aminocyclization–ring expansion cascade using N-bromo-
succinimide (NBS) as the halogen source (Scheme 1, eqn (4)).
It is noteworthy that functionalized pyrrolidines have been
widely applied in various areas such as medicinal chemistry,11
Scheme 1 NBS-induced aminocyclization–aziridine ring expansion
cascade.
organocatalysts,12 and chiral metal complexations.13 Some
examples are shown in Fig. 1.
3 was readily achievable by metathesis of L-aspartic acid-
derived ethenylaziridine 6 and substituted styrene using
Grubbs 2nd generation catalyst (Scheme 2).14
Initially, 3a was subjected to the investigation using p-nosyl
amide as the nucleophilic partner. In this kind of cyclization
cascade, two possible products, pyrrolidine and piperidine,
can be obtained through path a and path b, respectively (vide
infra, Scheme 3). Ethyl acetate, which was found to be a
superior solvent medium for the cascade reaction of 1 in our
previous study,9a gave poor selectivity of 4a : 5a (1.1 : 1.0)
despite the high overall reaction yield (Table 1, entry 1). The
selectivity was slightly improved when reducing the reaction
temperature to −20 °C (entry 3). After screening some
common organic solvents, it was found that relatively
Department of Chemistry, National University of Singapore, 3 Science Drive 3,
Singapore 117543, Singapore. E-mail: chmyyy@nus.edu.sg; Fax: (+)65 6779 1691;
Tel: (+)65 6516 7760
†Electronic supplementary information (ESI) available. CCDC 970435. For
ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c4ob01384k
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Fig. 1 Examples of pyrrolidine-containing functional molecules.
Scheme 3 Proposed mechanism.
Table 1 Reaction optimization
Scheme 2 The synthesis of 3.
non-polar solvents such as diethyl ether and toluene gave a
sluggish reaction while polar solvents generally gave much
better conversion (entries 4–12). Finally, the optimal solvent
and temperature were found to be acetonitrile and −20 °C,
respectively, which gave the selectivity of 4a : 5a up to 3.2 : 1.0
(entry 7). Other halogenation sources, including N-chlorosucci-
nimide (NCS) and N-iodosuccinimide (NIS), were also exam-
ined under the optimal conditions and the reactions were
found to be sluggish (entries 13 and 14). The structure of pyr-
rolidine 4a was determined by 2D-NMR analysis while piperi-
dine 5a was confirmed by an X-ray crystallographic study on
its tosylated derivative (CCDC 970435).15
Entrya
Solvent
Temp (°C)
Time (h)
Yieldb (%)
4a : 5ac
1
2
3
4
5
6
7
8
EtOAc
EtOAc
EtOAc
THF
Acetone
MeNO3
MeCN
MeCN
CH2Cl2
CHCl3
Et2O
25
0
1
2
8
8
8
82
81
82
79
80
73
82
81
76
70
Trace
Trace
Trace
Trace
1.1 : 1.0
1.3 : 1.0
1.7 : 1.0
1.3 : 1.0
2.0 : 1.0
3.1 : 1.0
3.2 : 1.0
3.2 : 1.0
2.0 : 1.0
1.5 : 1.0
—
Having identified the optimal conditions, we then explored
the scope of the reaction and the results are listed in Table 2.
In all cases, good yields of aziridine ring expansion products
were obtained. No aromatic bromination was observed even
for the electron-rich substituted systems (Table 2, entries 1–4).
Compared with other substrates, ortho-CH3 phenyl system gave
slightly lower reaction yield (72%), presumably due to the
steric repulsion. Similar to our previous discovery,9a it appears
that the electronic effect has no significant effect on the yield
of the reaction. Generally, substrates with electron-rich substi-
tuents gave better regioselectivity, while substrates with rela-
tively electron-poor substituents returned lower selectivity. The
−20
−20
−20
−20
−20
−40
−20
−20
25
8
8
16
16
16
24
24
24
24
9
10
11
12
13d
14e
Toluene
MeCN
MeCN
25
−20
−20
—
—
—
a Reactions were conducted using aziridine 3a (0.1 mmol), NBS
(0.15 mmol), and NsNH2 (0.15 mmol) in solvent (1 mL). b Isolated
yield of the mixture 4a and 5a. c The ratios were determined by 1H
best selectivity (4e : 5e = 4 : 1) was obtained with the tert-butyl NMR analysis of the product mixture. d NCS was used. e NIS was used.
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(grant no. 143-000-547-490) and the GSK-EDB (grant no. 143-
000-564-592). We acknowledge the receipt of a NUS Research
Scholarship (to J.Z.).
Table 2 NBS-induced aminocyclization–aziridine ring expansion
cascade of 3
Notes and references
1 In a US Food and Drug Administration (FDA) report in
2004, it clearly stated that the problem of inefficient chemi-
cal synthesis has on the production of life-saving pharma-
ceuticals. For reference, see: U.S. Food and Drug
Administration, Innovation and Stagnation: Challenge and
Opportunity on the Critical Path to New Medical Products,
2004.
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T. Y. Zhang, Green Chem., 2007, 9, 411; (b) D. J. C. Constable,
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Entrya
Substrate
R
Yieldb (%)
4 : 5c
1
2
3
4
5
6
7
8
3b
3c
3d
3e
3f
3g
3h
3i
4-OCH3
4-CH3
2-CH3
4-t-Bu
4-F
3-F
3-Cl
4-Br
4-COOCH3
3-NO2
80
82
72
80
85
82
84
83
74
67
2.1 : 1.0
3.0 : 1.0
3.8 : 1.0
4.0 : 1.0
3.5 : 1.0
2.7 : 1.0
2.6 : 1.0
3.0 : 1.0
2.3 : 1.0
1.1 : 1.0
9
3j
3k
10d
a Reactions were conducted using aziridine
(0.15 mmol), and NsNH2 (0.15 mmol) in MeCN (1 mL) at −20 °C for
8 h. b Isolated yield of the mixture 4 and 5. c Ratios were determined by
1H NMR analysis of the product mixture. d The reaction time was 16 h.
3
(0.1 mmol), NBS
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In conclusion, we have developed an efficient bromonium ion-
induced aziridine ring expansion cascade to afford function-
alized pyrrolidines containing three stereocenters. These
compounds are potential building blocks in various areas,
and their possible synthetic applications are currently being
studied.
Acknowledgements
We acknowledge the financial supports from the ASTAR-Public
Sector Funding (grant no. 143-000-536-305), the NEA-ETRP
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