Oxidative Cycloamination of Olefins with Aziridines as a Versatile Route to Saturated Nitrogen-Containing Heterocycles

Article abstract of DOI:10.1021/ja037726q

Highly reactive [5,3] and [6,3] bicyclic aziridines can be readily prepared from the corresponding NH aziridines and N-bromosuccinimide by intramolecular oxidative cycloamination of olefins. These compounds, including surprisingly stable exo-methylene bicyclic aziridines, provide versatile synthetic entries into a wide range of pyrrolidine- and piperidine-containing heterocycles. Copyright

Full text of DOI:10.1021/ja037726q

Published on Web 11/04/2003
Oxidative Cycloamination of Olefins with Aziridines as a Versatile Route to
Saturated Nitrogen-Containing Heterocycles
Mikio Sasaki and Andrei K. Yudin*
DaVenport Research Laboratories, Department of Chemistry, UniVersity of Toronto,
80 St. George Street, Toronto, Ontario, M5S 3H6, Canada
Received August 3, 2003; E-mail: ayudin@chem.utoronto.ca
Selective transfer of nitrogen-containing fragments to readily
available olefins is one of the fundamental ways of incorporating
nitrogen atoms into the frameworks of organic molecules.1 Our
interest in synthetic applications of functionalized aziridines2 has
led to the investigation of their utility in the synthesis of larger
nitrogen-containing heterocycles. Known for the difficulties in
controlling their reactivity, aziridines are rarely used in complex
molecule synthesis.3 If functionalization of an aziridine-containing
building block is required during synthesis, nitrogen protection and
deprotection sequences are unlikely to be successful due to aziri-
dines’ susceptibility to acidic reagents and harsh reaction conditions.
We reasoned that despite its basic character, aziridine nitrogen
should be quite resistant to oxidative degradation so that transfor-
mations of aziridine-containing building blocks can be realized. At
the outset of our investigations, we had observed a significant (0.8
V) difference in the oxidation potential of cyclohexene imine
compared to the value recorded for a typical secondary amine such
as piperidine, known for its low stability toward oxidation.4 This
finding can be explained on the basis of thermodynamically uphill
formation of the iminium species in the case of aziridine oxidation,
which opens a range of opportunities to explore the NH-containing
aziridines in oxidative nitrogen transfer under nonacidic conditions.5
Of particular value are intramolecular versions of such amination
protocols (eq 1) because they should allow for straightforward
syntheses of a wide range of larger ring heterocycles. The resulting
enamine-containing compounds have not received attention in
synthesis.
Figure 1. Aziridine-Containing Building Blocks.
Table 1. Intramolecular Cycloamination of Olefins
entry
R
1
R
2
producta
yieldb
1
2
3
4
5
H
Me
CH2OH
Ph
H
PhCO
PhCO
PhCO
PhCO
2a
2b
2c
3c
76
51
54
67
55
PhCH(OH)
2e
a
Structures were determined by NMR analysis (NOE, HMBC, and
b
COSY). The diastereomeric ratios were as follows: for 2a, 41:59; for
2b, 33:67; for 2c, 33:67; for 3, 19:81. 23% of 2d was also isolated.
c
Toward this goal, aziridine-containing building blocks (1a-e,
Figure 1) were synthesized from commercially available starting
materials.6 The NH portion of 1a-e is separated from the olefin
by the (CH2)2 linker, positioned toward cyclization to give
pyrrolidine- and piperidine-containing heterocycles. The pyrrolidine
and piperidine rings are incorporated into the structures of a wide
range of natural products and pharmaceuticals, which makes them
an important class of targets for stereoselective synthesis.9 If relative
stereochemistry of the products can be controlled during cyclization
and subsequent ring-opening steps, the oxidative aziridine cy-
cloamination methodology should be a valuable addition to the
established methods.10
Figure 2. X-ray Structure of Bicyclic Aziridine 4a.
cinimide (NBS) in DME and water.11 The TLC analysis indicated
complete conversion of the NH aziridine to the corresponding N-Br
species within the first 2 min of the reaction.12 The bromoamine
1f (Figure 1) thus formed attacked the double bond of the mole-
cule to give the cycloamination product. Table 1 shows the scope
of the reaction. The products are [5,3] bicyclic rings in the case
of the terminal double bond-containing substrates, whereas aryl-
substituted double bonds preferentially give six-membered-ring
products.
The resulting bicycles 2a-b were converted into exo-methylene
bicyclic aziridines 4a-b in quantitative yields by dehydrobromi-
nation (eq 2). We attribute surprisingly high stability of the resulting
enamines to the orthogonal orientation of the nitrogen electron pair
in relation to the double bond, evident from the single crystal X-ray
analysis (Figure 2). The X-ray data shows that the bond length
between C(6A) and C(7A) is 1.32 Å, which is typical of an olefin
The double bond functionalization of 1a can be achieved by the
Heck reaction6,7 or by the cross-metathesis.6,8 In the case of meta-
thesis, protection of the NH aziridine was found to be mandatory,
whereas the Heck reaction took place on the parent NH system
using Pd(OAc)2/P(o-tolyl)3 catalyst. Our further studies revealed
that aziridines 1a-e are converted into 1-azabicyclo[3.1.0]hexane
derivatives 2a-e in good yields upon treatment with N-bromosuc-
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J. AM. CHEM. SOC. 2003, 125, 14242-14243
10.1021/ja037726q CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
of heterocyclic products with high levels of stereocontrol. Notably,
the starting materials can be prepared in enantiomerically pure form
using the Julia-Colonna epoxidation reaction followed by epoxide
conversion into aziridine.15 The cycloanimation strategy should be
a valuable addition to existing methods for the construction of
substituted pyrrolidines and piperidines, especially since stereo-
control still poses significant challenges with known methods.
Transition metal-catalyzed versions of these reactions are under
investigation.
system. Worthy of note, this interesting and uncommon structural
motif is present in the azinomycin family of antibiotics.13
Table 2. Ring Opening Reactions of Bicyclic Aziridines 4
entry
R
condition
R
yield
1
2
Acknowledgment. We thank NSERC, Canada Foundation for
Innovation, ORDCF, and University of Toronto for financial
support. Sumitomo Chemical Co, Ltd. is gratefully acknowledged
for a fellowship (M.S.). Andrei Yudin is a Cottrell Scholar of
Research Corporation. We are grateful to Dr. Alan Lough for the
X-ray analysis and to Ms. Julie Lau for proofreading the manuscript.
1
2
3
4
5
H
Me
H
H
H
TMSN3 2 equiv, H2O 10 equiv, DCM, r.t.
TMSN3 2 equiv, H2O 10 equiv, DCM, r.t.
HBF4 1.5 equiv, MeOH, r.t.
AcOH 5 equiv, DCM, r.t.
10% Pd/C (0.1 wt %), H2
N3
N3
OMe
OAc
H
99
95
65
73
99
The bicyclic aziridines 4a-b possess considerable synthetic
potential because of the enamine-like aziridine ring that can be
transformed into an imine/enamine system upon ring opening. The
ring-opening reactions were found to proceed with high yields and
excellent diastereoselectivities. The reactions are regioselective and
afford the corresponding pyrrolidine derivatives. The resulting
enamines are in situ tautomerized into cyclic imines. The reductive
ring opening of aziridine 4a by hydrogen on Pd/C gives five-
membered cyclic imine in excellent yield (Table 2, entry 5).
Aziridine ring opening was also triggered under the reductive
conditions. Upon treatment with hydrazine, valuable 2-allylamine
derivatives can be obtained in good yields (Scheme 1). The resulting
cyclic imines can be readily reduced to pyrrolidines using DIBAL-
H. For example, 5f was reduced to cis-2,5-disubstituted pyrrolidine
5g in excellent yield and diastereoselectivity (Scheme 1). The 2,5-
disubstituted fragments similar to 5g are often seen in natural
products, for example, in pinidine.14
The reactions of [6,3] bicyclic aziridine 3 were also investigated
under hydrazinolysis conditions. The presence of endocyclic bro-
mine substituent in compound 3 suggested further relay of the
aziridine functionality within the bicyclic ring system. Under the
hydrazinolysis conditions, compound 3d was converted into bi-
cyclic aziridine 5h, another valuable precursor to functionalized
pyrrolidines, via ring-opening reaction followed by a ring closing
step (eq 3).
Supporting Information Available: Experimental procedures and
characterization data for all unknown compounds (PDF, CIF). This
material is available free of charge via the Internet at http://pubs.acs.org.
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Scheme 1. Hydrazine Reduction of Bicyclic Aziridine 4a
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a
b
NH2NH2 10 equiv, KOH 3 equiv, ethylene glycol, 100 °C. DIBAL
3 equiv, toluene, -78 °C.
In summary, we have shown that versatile chemistry of func-
tionalized bicyclic aziridines enables rapid construction of a variety
JA037726Q
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