Intramolecular cyclization reactions of aziridines with π-nucleophiles

Article abstract of DOI:10.1016/j.tetlet.2004.05.009

We have found that aziridines will react with a variety of π-nucleophiles in intramolecular cyclization reactions to produce nitrogen containing core structures found in a variety of bioactive molecules. These cyclizations are more general and facile than corresponding intermolecular reactions. We have examined the effects of ring size, π-nucleophile identity and substitution on this reaction.

Full text of DOI:10.1016/j.tetlet.2004.05.009

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5011–5014
Intramolecular cyclization reactions of aziridines
with p-nucleophiles
Stephen C. Bergmeier,* Steven J. Katz, Junfeng Huang, Howard McPherson,
Patrick J. Donoghue and Damon D. Reed
Department of Chemistry and Biochemistry, Ohio University, Clippinger Hall, Athens, OH 45701, USA
Received 10 February 2004; revised 30 April 2004; accepted 4 May 2004
Abstract—We have found that aziridines will react with a variety of p-nucleophiles in intramolecular cyclization reactions to
produce nitrogen containing core structures found in a variety of bioactive molecules. These cyclizations are more general and facile
than corresponding intermolecular reactions. We have examined the effects of ring size, p-nucleophile identity and substitution on
this reaction.
Ó 2004 Elsevier Ltd. All rights reserved.
The reactions of aziridines with nucleophilic reagents
has and continues to be an excellent method for the
introduction of an aminoethyl group. This type of
reaction has been exploited with a variety of nucleo-
philes including heteroatom nucleophiles (e.g., azide,
halide, alcohols, etc.) and carbon nucleophiles (e.g.,
organocuprate reagents, enolates, etc.).1
phile cyclizations with aziridines using simple
p-nucleophiles such as olefins and aromatic rings. These
cyclizations are more general and facile than the corre-
sponding intermolecular reactions and yield a variety of
monocyclic and bicyclic nitrogen containing molecules.
We have examined the scope of this reaction through
examination of the substitution and connectivity of the
p-nucleophile.
Among carbon nucleophiles, the use of p-nucleophiles
to open aziridine rings has received little attention rel-
ative to other types of carbon nucleophiles. Milstein
reported the first reaction between a p-nucleophile
(benzene) and an aziridine ring.2 This reaction was
carried out at 170 °C in the presence of AlCl3. More
recent examples of such reactions have shown that only
limited classes of either aziridines or p-nucleophiles
readily undergo this reaction.3–12 In general, either a
highly reactive p-nucleophile (e.g., indole) or a 2-aryl
aziridine is required for the reaction to proceed. Our
own studies in this area have been directed at the use of
allylsilanes to open aziridine rings in an intramolecular
fashion.13–16
As with the intramolecular aziridine–allylsilane cycliza-
tion reactions, intramolecular p-nucleophile cyclizations
should allow one to prepare several different types of
products depending upon substitution patterns of the
p-nucleophile and reaction conditions. As shown in
Scheme 1, an initial nucleophilic attack of a p-system
onto the aziridine, will generate a cationic intermediate
(3 via attack by an exocyclic p-bond or 2 via attack by
an endocyclic p-bond). These intermediates can lead to
regeneration of the p-system through elimination to
form 4 or 7. A bicyclic product (5 or 6) can also be
obtained through trapping of the cationic intermediate
by the sulfonamide.
We report here our studies on a broader group of
p-nucleophiles in intramolecular reactions with azir-
idines. This is the first report of intramolecular p-nucleo-
These cyclization reactions should have great utility in
the preparation of compounds that comprise the core
structures of a variety of bioactive nitrogen containing
molecules. Compounds such as 4 and 5 should be useful
for the preparation of highly substituted pyrrolidine ring
containing molecules. The pyrrolidine ring is commonly
found in a number of biologically active molecules.17;18
An attractive feature of the preparation of molecules
Keywords: Aziridines; Amines; Bicyclic heterocyclic compounds.
* Corresponding author. Tel.: +1-740-5178462; fax: +1-740-5930148;
e-mail: bergmies@ohio.edu
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.009

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S. C. Bergmeier et al. / Tetrahedron Letters 45 (2004) 5011–5014
Scheme 1.
such as 5 is the ability to generate a quaternary carbon
adjacent to the ring nitrogen. Azabicyclo [x.2.1]-systems
such as 6 are found in a both natural products such as
securinine19;20 and aphanorphine21 as well as unnatural
biologically active molecules.22–25 The cyclic methyl-
amino substituted products such as 7 can be viewed as
conformationally locked analogues of the arylethyl-
amino pharmacophore found in central nervous system
neurotransmitters such as dopamine, serotonin and
norepinephrine.26
Table 1. Arene–aziridine cyclizations
Starting material
(% yield)
Product
(% yield)
NHTs
NTs
10a (75)
7a (97)
NHTs
NTs
F3C
F3C
We have examined both aromatic rings and olefins as
p-nucleophiles. The requisite aziridines were prepared as
shown in Scheme 2. The primary method used for this
study was a Suzuki-coupling route.27 Hydroboration of
olefinic aziridine 8 or 916 followed by coupling to the
appropriate aryl- or olefinic halide produces the azir-
idine 10 or 11. The yields for the coupled products are
shown in Tables 1–3.
10b (74)
7b (83)
NHTs
NTs
H3CO
H3CO
10c (52)
7c (98)
NHTs
NHTs
CH3O
CH3O
NTs
NTs
Some of the required aziridines could not be prepared
using this method due to limitations in the aziridine
substrate for the Suzuki-coupling reaction. These azir-
idines (13a–c and 15) were prepared by a three step
method13 from either aziridine 1213 or 14.28 The aziridine
ring was opened with a copper catalyzed Grignard
reagent followed by desilylation and Mitsunobu ring
closure to provide the requisite aziridines (13 or 15).
H3CO
NHTs
10d (69)
7d, 3:1 (97)
10e (40)
11a (64)
7e (88)
The aryl substituted aziridines were treated with
300 mol % of BF3ÆOEt2 in CH2Cl2 at 0 °C.29 As shown in
Table 1, the yields for this cyclization are generally quite
high. With the exception of substrates 11a and 13a, all of
these reactions were complete in less than 1 h. Although
less Lewis acid could be used, the reaction takes much
longer to go to completion. Both unsubstituted aromatic
rings (10a,e) and those substituted with electron donat-
ing (10c,d) or electron withdrawing (10b) substituents
provide the expected product in excellent yield. The
cyclization of 10d provides a 97% yield of both possible
regioisomers in a 3:1 mixture.
NHTs
NTs
7f (6)
NTs
NHTs
13a (53)a
16 (45)
a Overall yield for three-step sequence from 12.
The formation of the fused seven-membered ring 7f
occurred in 6% yield. Prolonged reaction times (5 days)
and heating provided no improvements in yield.
previous examples of intramolecular cyclizations of az-
iridines with p-nucleophiles yield products in which
nucleophilic attack takes place at the most substituted
carbon of the aziridine ring (a 5-exo or 6-exo-cycliza-
tion).13–15 However when the p-nucleophile is in the ring
The reaction of 13a provided tetrahydronaphthalene 16
in 45% yield. This product is not unexpected. Our

S. C. Bergmeier et al. / Tetrahedron Letters 45 (2004) 5011–5014
5013
Table 2. Endocyclic olefin–aziridine cyclizations
NTs
NTs
1) 9-BBN
2) 3M aq. K3PO4
PdCl2(dppf)•CH2Cl2
R
( )n
Starting olefin (% yield)
Product (% yield)
( )n
8, n = 1
9, n = 2
10, n = 1
11, n = 2
R
X
R = aryl or olefin
NTs
CH3
NTs
CH3
1) R-MgX, CuCN
2) nBu4NF
3) Ph3P, DIAD
NTs
NTs
NTs
TBSO
R
10f (30)
6a (71)
13
12
14
NTs
Ph
MgCl
1)
NTs
Ph
TBSO
CH3
CuCN
10g (55)
6b (63)
2) nBu4NF
H N H
Ts
3) Ph3P, DIAD
CH3
15
H3C
NTs
Scheme 2.
CH3
NTs
CH3
10h (30)
6c (75)
a bicyclic product.29 As shown in Scheme 1, two path-
ways are open to the cationic intermediate formed from
the endocyclic p-nucleophile attack. When the p-nucleo-
phile is an olefin, the sulfonamide nitrogen cyclizes onto
the cationic intermediate (e.g., 2) to provide the bicycle
6. Both alkyl and aryl substitution on the endocyclic
olefin provided sufficient stabilization of the cationic
intermediates to provide bicyclic product (6a and 6b) in
moderate yield. In an effort to see if olefin geometry
would be retained in this cyclization, substituted olefin
10h was subjected to the usual reaction conditions.
While the reaction proceeded in good yield, an
approximately 1:1 mixture of the two diastereomers was
obtained. Attempts to form larger ring systems were not
successful.
CH3
NHTs
NTs
13b (51)
17 (41)
NTs
CH3
NTs
CH3
13c (62)a
6d (72)
a Overall yield for three-step sequence from 12.
Table 3. Exocyclic olefin–aziridine cyclizations
Starting aziridine (% yield)
Product (% yield)
CH3
H3C
The reaction of 13b provided only cyclohexene 17 via a
6-endo-cyclization. As expected, none of the azabicyclo-
[2.1.1]-octane ring system derived from the disfavoured
5-exo-cyclization was observed.
CH3
NTs
CH3
( )n
( )n
N
Ts
10i, n ¼ 1 (41)
5a (41)
5b (75)
11b, n ¼ 2 (70)
We also prepared and cyclized a one carbon shorter
olefinic aziridine 13c. We were quite pleased to see the
formation of the bicyclo-[2.1.1]-system (6d) in 72% yield.
This is a unique ring system that is difficult to prepare
using other methods.
CH3
CH3
H
CH3
CH3
CH3
NTs
H N H
Ts
H
5c (75)
H
We next prepared and examined a series of tri and
disubstituted exocyclic olefins.29 The cyclization of
compounds bearing two alkyl substituents on the ter-
minus of the olefin (10i, 11b) provided the expected
cyclization products, 5a and 5b in good yield. This is
especially exciting as it provides a route to ring systems
containing a quaternary carbon adjacent to the ring
nitrogen. These are in general difficult systems to pre-
pare. The substituted aziridine 15 was also subjected to
the usual reaction conditions to provide bicycle 5c in
good yield. The cyclizations of disubstituted olefins are
not yet particularly successful as 11c gave a 9% yield of
the cyclized product 5d. None of the olefinic products
(e.g., 4) were isolated from these reactions.
15 (33)a
Ph
Ph
NTs
N
H
Ts
11c (74)
5d (9)
a Overall yield for three-step sequence from 14.
being formed the 6-endo-cyclization products (e.g., 16)
are formed in preference to the 5-exo-cyclization
product.16;30–33
Reactions of the aziridine ring with an endocyclic olefin
(olefin in the ring being formed) are shown in Table 2.
Treatment of these olefinic aziridines generally provided
In summary, the intramolecular cyclization reactions
of aziridines with a variety of p-nucleophiles appears
to be a fairly general reaction. The formation of

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S. C. Bergmeier et al. / Tetrahedron Letters 45 (2004) 5011–5014
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fins or trisubstituted exocyclic olefins is a generally high
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Acknowledgements
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This work was supported in part by a grant from the
NSF (CHE-9816208). We would also like to thank the
Department of Chemistry and Biochemistry and the
Office of the Vice-President for Research at Ohio Uni-
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