N -bromosuccinimide-induced aminocyclization-aziridine ring-expansion cascade: An asymmetric and highly stereoselective approach toward the synthesis of azepane

Article abstract of DOI:10.1021/ol5005609

A novel N-bromosuccinimide induced aminocyclization-aziridine ring expansion cascade is reported. Substituted azepanes were isolated exclusively in good yields. The azepane products could be transformed into a number of functional molecules including piperidines, a bicyclic amine, and a bridgehead amide.

Full text of DOI:10.1021/ol5005609

Letter
pubs.acs.org/OrgLett
N‑Bromosuccinimide-Induced Aminocyclization−Aziridine Ring-
Expansion Cascade: An Asymmetric and Highly Stereoselective
Approach toward the Synthesis of Azepane
Jing Zhou and Ying-Yeung Yeung*
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543
S
* Supporting Information
ABSTRACT: A novel N-bromosuccinimide induced amino-
cyclization−aziridine ring expansion cascade is reported.
Substituted azepanes were isolated exclusively in good yields.
The azepane products could be transformed into a number of
functional molecules including piperidines, a bicyclic amine, and
a bridgehead amide.
cascade is seldom,6 herein we are pleased to report a novel and
lbeit a fundamental organic reaction, electrophilic
highly stereoselective bromoaminocyclization of olefinic
Aactivation of a carbon−carbon double bond by a halonium
ion1 has been revived in recent years mainly in two areas: (1)
aziridine cascade which resulted in the formation of
catalytic and asymmetric halogenation2 and (2) halogen-
enantiopure substituted azepanes, and no piperidine was
detected; ring-opening of activated aziridines by nucleophiles
at the less substituted carbons are commonly observed which
will result in the formation of piperidines in this case.5,6
Functionalized azepanes are useful in various areas such as
biomedical chemistry.7 It is important to note that direct
cyclization (e.g., halocyclization) of olefinic amine/amide to
give azepane is not trivial as such kind of reaction suffers from
high entropy and enthalpy barrier.8 In addition, enantioselective
approach toward substituted azepane remains under-exploited.9
This methodology can be considered as a detour of the direct
seven-membered ring halocyclization in the asymmetric
synthesis of azepanes.10
To verify our hypothesis, enantiopure olefinic aziridine 1a (R
= Boc), which could be readily synthesized from L-glutamic
acid, was subjected to the investigation.11 NBS and NsNH2
were used as the halogenating agent and the nucleophilic
partner, respectively. To our delight, upon halogen source
initiation, the cyclized product azepane 2a was obtained in 54%
yield when using dichloromethane as the solvent. A quick
survey on some common organic solvents revealed that the
reaction worked best in ethyl acetate, and 2a (R = Boc, X = Br)
was obtained in 82% yield (Table 1, entry 1).11
induced cascade and multicomponent reactions, and their
synthetic applications.3,4 In particular, bromonium ion induced
cyclic ether ring-expansion cascade reactions received much
attention due to their facile construction of the scaffolds of
many natural products.3 Recently, our group reported the N-
bromosuccinimide (NBS)-induced multicomponent reactions
which involve cyclic ether ring-opening cascades. By using
epoxide as the nucleophilic partner, the multicomponent
reactions proceeded smoothly, and the methodology has been
successfully applied in the synthesis of bioactive morpholines.4
As a chemical analogue of epoxide, aziridine displays similar
reactivities.5 Because of the highly strained ring system of
aziridine, the lone pair of aziridine’s nitrogen can hardly
resonate with the neighboring conjugated group, which results
in a certain degree of nucleophilicity of aziridine’s nitrogen
(e.g., aziridine A; R ≠ H).5 We reasoned that the olefinic
aziridine A should be able to react with a brominating source to
give the aziridinium ion intermediate B. Subsequently, B could
be attacked by a nucleophile at the tertiary carbon to give the
product C (Scheme 1). Although using aziridine in electrophilic
After subsequent optimization of the reaction temperature, it
was found that the reaction worked better at −30 °C which
resulted in 88% yield of the desired product (Table 1, entries
1−3). The yield was slightly improved to 90% when freshly
recrystallized NBS was applied (entry 4). The reaction
concentration could be increased to 0.1 M (entry 5) with
slightly improved yield, while lowering the concentration
(0.025 M, entry 6) had a significant detrimental effect. The
optimized conditions were then applied to a large-scale reaction
Scheme 1. NBS-Induced Cascade Reaction
Received: February 20, 2014
Published: April 1, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
a
a
Table 1. Reaction Optimization
Table 2. Scope of the Reaction
entry
substrate
Ar
product
yield (%)
b
entry
R
X source
temp (°C)
time (h)
yield (%)
1
2
3
4
5
6
1b
1c
1d
1e
1f
2-Me-C6H4
3-Me-C6H4
4-Br-C6H4
4-Cl-C6H4
3-F-C6H4
2b
2c
2d
2e
2f
70
80
82
83
71
82
81
92
87
73
1
2
3
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Ts
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NCS
NIS
−20
−30
−40
−30
−30
−30
−30
−30
−30
−30
−30
−30
−30
10
48
72
48
48
48
48
48
48
48
48
48
48
82
88
86
90
91
79
88
<5
11
89
86
31
82
c
4
c
c
c
,
,
,
d
e
f
5
6
7
8
9
1g
1h
1i
3-tBuOC(O)-C6H4
4-CHO-C6H4
4-Ph-C6H4
2g
2h
2i
b
7
8
9
1j
2-naphthyl
2j
10
1k
3-thienyl
2k
10
11
12
13
NBP
DBDMH
NBS
NBS
a
Reactions were carried out with olefinic aziridine 1 (0.1 mmol),
recrystallized NBS (0.15 mmol), and NsNH2 (0.15 mmol) in
anhydrous EtOAc (1 mL). The yields were isolated yields. The
corresponding dimethyl acetal protected aldehyde was used as the
starting material.
b
Cbz
a
Reactions were carried out with compound 1a (0.2 mmol), halogen
source (0.3 mmol), and NsNH2 (0.3 mmol) in anhydrous EtOAc (4
mL). Isolated yield. Recrystallized NBS was used. 2 mL of EtOAc
(0.1 M) was used. 8 mL of EtOAc (0.025 M) was used. 1.0 g scale,
0.1 M.
b
c
d
e
f
single diastereoisomer. No bromination on the aromatic ring or
at the benzylic position was observed even for electron-rich
substituted systems (Table 2, entries 1, 2, 8, and 9). Compared
with other substrates, o-CH3-substituted substrate 1b gave 70%
yield, presumably due to the steric repulsion between the bulky
Boc group and the ortho substitution. The electronic effect
appears to be less dominating in this type of reaction. Halogen-
substituted substrates 1d−f (entries 3−5) and ester substrate
1g (entry 6) also performed well. Additionally, the hetero-
aromatic substrate 1k was well tolerated to give 73% yield of
the desired product (entry 10).
Substituted azepane is the pharmacophore of many
interesting bioactive molecules.7 In addition, 2 is a versatile
synthetic precursor of many functional molecules. For instance,
the Boc group in azepane 2a could be removed under an acidic
environment to yield the corresponding deprotected amine,
which could be then transformed into azabicyclo[3.1.0]hexane
derivative 3 simultaneously (Scheme 2).14 Subsequent reaction
with acetic acid gave rise to the piperidine derivative 4. The
stereochemistry was determined by an X-ray crystallographic
study on the tosylate derivative 5.11
Other than acetic acid, 3 could react with p-fluorothiophenol
and trimethylsilyl azide to furnish the thioether 6 and the azide
derivative 9, respectively (Scheme 3). For thioether 6,
subsequent cyclization reaction by connecting the two nitrogen
atoms gave rise to bicyclic systems 7 and 8; these skeletons
consist of a rigid tertiary amine moiety which resembles the
cinchona alkaloid scaffold. The antipodes of 7 and 8 can readily
be prepared from ent-1, which can result in an enantiomeric
pair of privileged catalyst skeletons’ mimics.15 In addition, 8
contains a bridgehead amide which potentially possesses
unusual physical and chemical properties.16
(entry 7); azepane 2a was obtained in 88% yield starting from
1.0 g of 1a. Other halogen sources were also investigated. N-
Chlorosuccinimide (NCS) (entry 8) and N-iodosuccinimide
(NIS) (entry 9) were not as effective as NBS in mediating the
reaction, while some other commonly used brominating agents
such as N-bromophthalimide (NBP) (entry 10) and 1,3-
dibromo-5,5-dimethylhydantoin (DBDMH) (entry 11) gave
comparable yields. Finally, the effect of the N-protecting group
was examined. Cbz-activated aziridine (entry 13) gave
considerably higher yield than that of the Ts group (entry
12). It is noteworthy that the reaction is highly chemo-,
enantio-, and stereoselective in which out of eight possible
stereoisomers (with three stereogeneric centers), 2a was furnished
exclusively and no piperidine product was detected.12 The absolute
configuration of 2a was established unambiguously by an X-ray
crystallographic study of its analogue 2a-Bn (Figure 1).11,13
Having identified the optimal system, we then explored the
scope of the reaction as listed in Table 2. In all cases, good
yields of azepanes were obtained with each product isolated as a
On the other hand, azide 9 could be converted into 1,2-
diamine 10 by the Staudinger reduction. Treatment of 10 with
triphosgene under basic conditions furnished urea 11. These
amine systems consist of modifiable handles which can
potentially be utilized as metal ligands17 and organocatalyst
building blocks.18
Toward a better understanding of the mechanism, we
examined the stability of aziridine in the presence of the
Figure 1. X-ray structure of 2a-Bn (R = Boc; X = Br).
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Organic Letters
Letter
Scheme 2. Synthesis of Piperidine 4
Scheme 4. Proposed Mechanism of the Cyclization
Scheme 3. Synthetic Application of 3
On the other hand, bromination of the olefin at the opposite
side as D to give 2′ through intermediates F and G might be
disfavored due to the steric stress in the pseudo-six-membered
boat transition state F. However, the sole origins of chemo- and
stereoselectiviy remain unclear and are subject to further
investigation.
In conclusion, a novel NBS-induced aminocyclization−
aziridine ring expansion reaction was developed. This method-
ology could be applied in the preparation of functionalized
piperidines and rigid amine systems. Further application to
other substrates is underway.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, characterization data for all new
compounds, and X-ray data (CIF). This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
halogenating agent (Scheme 4). No reaction was observed
when aziridine 12 was mixed with NBS and NsNH2 in ethyl
acetate at 25 °C for 24 h. This suggests that the aziridine ring
was not preopened before the aminocyclization step.
Corresponding Author
*E-mail: chmyyy@nus.edu.sg.
Notes
Based on this result and our previous experience on
electrophilic halogenation reactions, we believe that NBS
might be activated by NsNH2.4,19 Electrophilic addition of
activated NBS to the olefin in substrate 1 would give
bromonium ion intermediate D. Acting as a nucleophile, the
aziridine could then react with bromonium ion to gave
aziridinium ion intermediate E. Finally, NsNH2 would open
the ring to afford the desired azepane compound 2. The
excellent stereoselectivity in the formation of 2 also suggests
that the nucleophilic attacks in D and E were in SN2 manner.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge financial support from ASTAR-Public Sector
Funding (Grant No. 143-000-536-305) and GSK-EDB (Grant
No. 143-000-564-592). We are also thankful for the scholarship
to J.Z. (NUS Research Scholarship). We give special thanks to
Dr. Wu Ji’En (NMRL, NUS) for helpful discussions on NMR
analysis.
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Letter
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