Ring expansion of substituted norbornadienes for the synthesis of mono- and disubstituted 2-azabicyclo[3.2.1]octadienes

Article abstract of DOI:10.1016/j.tetlet.2008.06.123

We have studied the conversion of substituted norbornadienes into a substituted 2-azabicyclo[3.2.1]octadiene system via reaction with toluenesulfonyl azide. We have found that both and mono- and disubstituted norbornadienes will undergo the cycloaddition/

Full text of DOI:10.1016/j.tetlet.2008.06.123

Tetrahedron Letters 49 (2008) 5363–5365
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Ring expansion of substituted norbornadienes for the synthesis
of mono- and disubstituted 2-azabicyclo[3.2.1]octadienes
*
Nova Emelda, Stephen C. Bergmeier
Department of Chemistry and Biochemistry, Clippinger Laboratories, Ohio University, Athens, OH 45701, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We have studied the conversion of substituted norbornadienes into a substituted 2-azabicyclo[3.2.1]-
octadiene system via reaction with toluenesulfonyl azide. We have found that both and mono- and
disubstituted norbornadienes will undergo the cycloaddition/rearrangement sequence to provide the
bicyclooctadiene ring system as a single regioisomer. The 2-azabicyclo[3.2.1]octane ring system can be
prepared from the unsaturated 2-azabicyclo[3.2.1]octadiene ring system.
Received 22 May 2008
Revised 24 June 2008
Accepted 30 June 2008
Available online 4 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
The 2-azabicyclo[3.2.1]octane ring system 1 is found in a num-
ber of natural products including nordipertenoid alkaloids such as
methyllycaconitine1–3 as well as himandrine.4 In addition a number
of nonnatural biologically active ring systems contain the 2-azabi-
cyclo[3.2.1]octane ring system.5,6 The development of new meth-
ods for the synthesis of this ring system is important both for
natural product synthesis and the preparation of simpler
analogues of these natural products. An attractive option for
PhSO2N3
rt, 3 d, 65%
N
SO2Ph
2a
3a
a) reductions
R
R
b) dihydroxylation
c) cycloaddition
N
R
the synthesis of substituted derivatives of
1 would be the
1
functionalization of the readily available N-phenylsulfonyl 2-azabi-
cyclo[3.2.1]octadiene 2a. N-phenylsulfonyl 2-azabicyclo[3.2.1]oct-
adiene was first reported in 1965.7 This unique compound was
prepared by the reaction of phenylsulfonyl azide with norbornadi-
ene (3a) (Fig. 1). While the yields are only moderate, the reaction
is readily scalable and easy to carry out. It has been reported that
the reaction proceeds through an initial dipolar cycloaddition of
the azide followed by loss of nitrogen to form the fused-ring aziri-
dine. This then undergoes a ring opening reaction to a bicyclo-
[3.1.0]hexene imine. This highly strained bicyclic ring system
then undegoes a Cope rearrangement to form the observed 2-azabi-
cyclo[3.2.1]octadiene 2a.8
Two options exist for the conversion of 2 into the saturated and
substituted ring system 1. The first is the chemical modification of
the parent bicyclo[3.2.1]octadiene ring system. Few examples of
such modifications have been reported. These modifications are
largely limited to the reduction of one or both double bonds,9–11
dihyroxylation of the 6,7-olefin12 and cycloaddition reactions with
the 6,7-olefin.13,14
ArSO2N3
R
N
R
SO2Ar
2b
3b
Figure 1. 2-Azabicyclo[3.2.1]octane ring system.
rangement reaction. The product of this reaction, a substituted
2-azabicyclo[3.2.3]octadiene 2b could then be further modified
via reduction, dihydroxylation, or cycloadditions to provide highly
substituted derivatives of 1 (Fig. 1). This strategy has several
advantages, including the relative ease with which some substi-
tuted norbornadienes can be prepared and the ability to further
substitute the products of such an addition/rearrangement process.
This would then produce derivatives of 1 with a much wider range
of substitution and functionality. A key unknown is the regioselec-
tivity of the cycloaddition/rearrangement process with a substi-
tuted norbornadiene.
Given a unique substituted norbornadiene 4 (Fig. 2), the reac-
tion with a sulfonyl azide could produce four possible products
when R1 ¼ R2 (or two when R1 = R2). Reaction on the opposite side
of the substitution would provide regioisomeric products 5 and 6,
while reaction on the same side would provide regioisomers 7 and
Given the limited methods for the functionalization of 2a, an
alternate option for the synthesis of substituted systems such as
1 is the use of substituted norbornadienes 3b in the addition/rear-
* Corresponding author. Tel.: +1 740 517 8462; fax: +1 740 593 01148.
E-mail address: bergmeis@ohio.edu (S. C. Bergmeier).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.06.123

5364
N. Emelda, S. C. Bergmeier / Tetrahedron Letters 49 (2008) 5363–5365
Table 1
Reaction of monosubstituted norbornadienesa,b
R2
R1
R1
R2
N
SO2Ar
H5
N
SO2Ar
H6
R1
R1
5
6
TsN3
toluene
R2
R1
ArSO2N3
N
R1
N
Ts
Ts
R2
R1
4
5
6
R1
R2
4
R1
Yield (%)
Ratio 5:6
N
N
SO2Ar
SO2Ar
7
4a, CO2Et
6
85:15 5a:6a
94:6, 5c:6c
Only 5d
8
4c, CH2OAc
4d, CH2OTBS
4e, CH2OPiv
50
30
50
Figure 2. Possible products derived from the reaction of a substituted norborna-
diene with a sulfonyl azide.
Only 5e
a
When R2 = H, R2 is not shown for clarity.
The regiochemistry of products 5a–e was determined by the observation of
b
8. One report has briefly examined this reaction.15 Treatment of a
compound where R1 = R2 = CN or R1 = R2 = CO2Me provides largely
a single product 5, where the addition of the phenylsulfonyl azide
occurred distal to the substitution. We wished to determine if
other functional groups, where R1 = R2, would provide the same
level of regiocontrol. More interestingly would be an examination
of the reaction of 4, where R1 ¼ R2. Such compounds would likely
provide only 4 and 5 but a priori it is not obvious which of these
two regioisomers will be formed.
In order to begin to address these questions several monosub-
stituted norbornadienes were prepared as outlined in Scheme 1.
The Diels–Alder cycloaddition of ethyl propiolate with cyclopenta-
diene provided monosubstituted norbornadiene 4a in 83% yield.16
While the Diels–Alder method provides an excellent route for the
synthesis of norbornadienes with electron withdrawing substitu-
ents, an alternate approach was needed for the synthesis of non-
electron withdrawing substituted norbornadienes. Alcohol 4b can
be readily prepared via metallation and reaction of norbornadiene
with formaldehyde.17 The resulting alcohol was acylated or silyl-
ated to provide monosubstituted norbornadienes 4c,18 4d, and 4e.
With a group of monosubstituted norbornadienes in hand, their
reaction with tosyl azide was investigated (Table 1). Based on pre-
vious studies,15 it was expected that addition would occur distal to
the substitution. In concert with the original reaction conditions
and in contrast to the report by Umano et al.,15 all reactions were
carried out at room temperature.19
The reaction of 4a with tosyl azide resulted in only a 6% yield of
an 85:15 mixture of 5a and 6a. This reaction provided multiple
products. The reaction of the acetate provided a significantly better
yield of the product in a 94:6 mixture of 5c/6c. Changing the ester
to a silyl ether (4d) lowered the yield somewhat, but dramatically
improved the product ratio yielding only the 7-substituted product
5d. Suspecting that this moderate change in regioisomer ratio
might be due to the size of the group on the oxygen, the pivalate
ester 4e was prepared. The yield returned to the moderate yield
observed with the acetate and retained the improved ratio of
regioisomers. Clearly the substitution of these monosubstituted
coupling between H5 (d 2.62–3.01) and H6 (d 5.93–6.09) as determined via COSY
experiments.
norbornadienes is of paramount importance. Electron withdrawing
substitution provides little to no product while the substituted
hydroxymethyl derivatives provided a moderate yield of a single
regioisomer.
In order to investigate regioselectivity in the reaction of disub-
stituted norbornadienes, a series of disubstituted norbornadienes
were prepared via the Diels–Alder reaction of cyclopentadiene
with substituted alkynes (Scheme 2). The reaction of diethyl acet-
ylene dicarboxylate with cyclopentadiene provided norbornadiene
4f in 97% yield. Reaction of the diacetate of butyne diol with cyclo-
pentadiene required microwave heating of the reaction to 220 °C in
DMF and provided 4g20 in 50% yield.
In order to prepare norbornadienes where R1 ¼ R2, cyclopenta-
diene was heated with several substituted propiolate esters in a
sealed tube at 160 °C. Norbornadiene 4h21 was obtained in an
almost quantitative yield. Compounds 4i and 4j were prepared in
moderate yield; however, they could not be completely purified
due to contamination with ꢀ40% of an unidentified non-polar
impurity that could not be readily removed.
The ring expansion of symmetrically disubstituted norbornadi-
ene 4f was examined first (Scheme 3). Following the reaction con-
ditions that worked well for norbornadiene itself as well as the
monosubstituted norbornadienes provided only a 4:1 mixture of
aziridine 10 and rearrangement product 5f. Heating the reaction
to 80 °C for 18 h provides the same mixture of aziridine and rear-
rangement product. Increasing the temperature to 110 °C (reflux-
R1
R1
+
R2
R2
4f, R1 = R2 = CO2Et
9
4g, R1 = R2 = CH2OAc
4h, R1 = CO2Me, R2 = Ph
4i, R1 = CO2Et, R2 = nC5H11
4j, R1 = CO2Me, R2 = CH2OPh
CO2Et
a
Scheme 2. Reagents and conditions: 4f, R1 = COOEt, R2 = COOEt, toluene, reflux,
18 h, 97%. 4g, R1 = CH2OAc, R2 = CH2OAc, DMF, microwave, 220 °C, 2 h, 50%. 4 h,
+
EtO2C
R1 = Ph, R2 = COOMe, toluene, sealed tube, 160 °C, 42 h, 99%. 4i, R1 = nC5H11
,
4a
R2 = COOEt, toluene, sealed tube, 160 °C, 60 h, 56%*. 4j, R1 = CH2OPh, R2 = COOMe,
toluene, sealed tube, 160 °C, 60 h, 56%.
b, c, or d
HO
R1
4b
4c, R = CH2OAc
4d, R = CH2OTBS
4e, R = CH2OPiv
TsN3
EtO2C
EtO2C
EtO2C
EtO2C
EtO2C
EtO2C
NTs
N
Ts
4f
5f
10
Scheme 1. Reagents and conditions: (a) CH2Cl2, reflux, 18 h, 83%. (b) CH2Cl2, AcCl,
pyridine, DMAP, 98%. (c) CH2Cl2, Me2tBuSiCl, Et3N, DMAP, 98%. (d) CH2Cl2, pivaloyl
chloride, Et3N, DMAP, 98%.
Scheme 3. Time and temperatures studies on 4f.

N. Emelda, S. C. Bergmeier / Tetrahedron Letters 49 (2008) 5363–5365
5365
Table 2
Reactions of disubstituted norbornadienes22
TsN3
toluene
NTs
N
Ts
R1
R2
R2
R1
R1
R2
TsN3
11
12
13
N
Ts
N
Ts
Scheme 4. Attempted reaction of benzonorbornadiene with tosyl azide.
5
6
4
Starting material
R1
R2
% Yield,a product
relative stereochemistry of the aziridine. We observed no cross-
peaks between the aziridine protons and the bridgehead protons,
indicating a likely exo-aziridine. Consequently, it may be that the
rigidity of the system coupled with the loss of aromaticity in the
rearrangement reaction preclude the rearrangement of this
system.
4f
4g
4h
4i
CO2Et
CO2Et
CH2OAc
Ph
nC5H11
CH2OPh
94, 5f
50, 5g
98, 5h
40, 5i
33, 5j
CH2OAc
CO2Me
CO2Et
4j
CO2Me
a
Yields are relative to tosyl azide.
In conclusion, we have found that mono- and disubstituted
norbornadienes undergo an addition/rearrangement reaction with
tosyl azide. The reaction proceeds with excellent levels of
regiocontrol in modest to excellent yield. This reaction provides
an excellent route for the synthesis of substituted 2-azabi-
cyclo[3.2.1]octadienes. These substituted 2-azabicyclo[3.2.1]octa-
dienes can be readily converted to the reduced bicyclooctane
ring system found in a number of natural products and pharmaco-
logically active molecules.
ing toluene) shows a steadily increasing amount of the rearrange-
ment product. After 3 days in refluxing toluene only the rearrange-
ment product was observed.
With a viable procedure in hand, a range of disubstituted nor-
bornadienes were examined (Table 2). The diester 4f provided 5f
in 94% isolated yield. The yield obtained in refluxing toluene is sim-
ilar to that obtained by Umano et al. in refluxing 1,2-dichloroben-
zene.15 However the use of toluene provides a somewhat more
convenient procedure than using 1,2-dichlorobenzene as the sol-
vent. The diacetate 4g provided 5g in 50% yield.
Acknowledgments
Several nonsymmetrical derivatives were next examined. Our
prediction was that the larger of the two groups R1 or R2 would
end up on the same side of the bicyclic ring as the N–Ts group. A
single product, 5h, was obtained upon treatment of 4h with tosyl
azide. The regiochemistry was determined through NOESY experi-
ments that showed a crosspeak between H1 and H10 on the phenyl
ring. This is consistent with the reactions of the monosubstituted
norbornadienes 4a–e in which the larger group was on the same
side of the ring as the N–Ts group. The reaction of unsymmetrically
disubstituted norbornadienes 4i and 4j provided identical regio-
chemical results. While the yields of 5i and 5j were not as good
as 5h, these were clean reactions providing only a single regio-
isomer. The regiochemistry of 5i and 5j was also assigned by the
presence of a similar crosspeak in a NOESY spectrum, between
the bridgehead H1 and a methylene proton of the alkyl group at
C7 (Fig. 3).
We also wished to examine the reaction of the benzofused nor-
bornadiene 1123 with toluenesulfonyl azide (Scheme 4). Reaction
of 11 with tosyl azide provided only the aziridine 1224 in 77% yield.
All attempts to convert 12 to the desired 13 gave either no reaction
or complete decomposition. These reaction conditions include
heating 12 to over 250 °C, or the addition of a number of Lewis
acids with or without heating. In trying to determine the reason
for the lack of reaction of 12, Umano and coworkers determined
that endo-aziridines (e.g. endo-10) do not undergo the rearrange-
ment reaction to provide the [3.2.1]bicyclic ring system.15 We car-
ried out a NOESY experiment with 12 in order to determine the
We would like to thank The National Agency of Drug & Food
Control, Republic of Indonesia for a graduate fellowship (N.E.).
We would like to thank the National Institutes on Drug Abuse at
the NIH (DA13939) for partial support of this work and Ohio Uni-
versity for support of the BioMolecular Innovation and Technology
(BMIT) Project.
References and notes
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19. Tosyl azide (100 mol %) and a monosubstituted norbornadiene 4 (100 mol %)
were dissolved in toluene (0.5 M). After stirring for 3 days the reaction was
concentrated and chromatographed (10% EtOAc in hexanes) to provide the
product.
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MeO2C
N
H1
Ts
22. Tosyl azide (100 mol %) and a disubstituted norbornadiene 4 (200 mol %) were
dissolved in toluene (0.5 M). The reaction was stirred at rt for 24 h then heated
to reflux for 72 h. The reaction was concentrated and chromatographed to
provide the product and recovered starting norbornadiene.
23. Brooks, P. R.; Caron, S.; Coe, J. W.; Ng, K. K.; Singer, R. A.; Vazquez, E.; Vetelino,
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H1'
5h
Figure 3. Observed NOESY crosspeak for product 5 h.