Position-addressable nano-scaffolds. I. The preparation of N,O-, N,C- and N,N-bridged sesquinorbornadiene succinimides as compact, highly functionalized addressable building blocks

Article abstract of DOI:10.1071/CH02218

Succinimide-functionalized N,O-, N,C-, and N,N-bridged benzo[2]polynorbornanes (benzosesquinorbornadienes) are reported for the first time and are prepared by the cycloaddition of either five-membered cyclic 1,3-dienes onto N-substituted benzo-7-azanorbor

Full text of DOI:10.1071/CH02218

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Aust. J. Chem. 2003, 56, 263–267
Position-Addressable Nano-Scaffolds. I. The Preparation of
N,O-, N,C- and N,N-Bridged Sesquinorbornadiene Succinimides
as Compact, Highly Functionalized Addressable Building Blocks
Ronald N. Warrener,A,C Davor Margetic,A Guangxing SunA and Richard A. RussellB
A
Centre for Molecular Architecture, Central Queensland University, Rockhampton 4702, Australia.
B Centre for Chiral and Molecular Technologies, Deakin University, Geelong 3217, Australia.
C Author to whom correspondence should be addressed (e-mail: r.warrener@cqu.edu.au).
Succinimide-functionalized N,O-, N,C-, and N,N-bridged benzo[2]polynorbornanes (benzosesquinorbornadienes)
are reported for the first time and are prepared by the cycloaddition of either five-membered cyclic 1,3-dienes onto
N-substituted benzo-7-azanorbornadienomaleimides or N-substituted isoindoles onto the appropriate norborna-
dienomaleimides. These products contain an end-fused norbornene (or a 7-substituted relative) and have been
designed to act as alkene BLOCKs for the production of nano-scaffolds with up to six addressable sites supplied by
each norbornene unit. The N-bridges in these BLOCKs (and their coupled products) allow N-substituent mobility
by invertomerization of the sp3 nitrogen whereas the N-substituents on the succinimides are attached to an sp2
nitrogen atom and remain static. Preferred invertomer geometry can be determined using molecular modelling.
Manuscript received: 21 October 2002.
Final version: 9 December 2002.
Introduction
during the course of its synthesis, and such functionality is
position-specifically transported to the molecular scaffold in
the course of the BLOCK assembly process. The resultant
nano-scaffold, e.g. (1), has not only the individual effectors
provided by the BLOCKs but also X groups (O, NR, C N,
N N) and R groups (CO2H, CO2R, CF3, pyridyl etc.) intro-
duced during the various assembly protocols. By working in
the field of N-bridged bicyclo[2.2.1]heptene chemistry, the
method offers an unprecedented opportunity for introducing
dynamic linkages by the attachment of effectors as N-bridged
substituents. The present study reports the first syntheses
of compact, addressable, N-bridged building BLOCKs (2)
(Scheme 1) suitable for the construction of nano-scaffolds of
type (1).
In recent years, our group has developed ‘LEGO’-like build-
ing block techniques for the construction of carbocyclic
scaffolds which allow the attachment of functional units
(‘effector groups’, for definition see ref. [1]) to specific posi-
tions of a carbocyclic frame.[2,3] This protocol is based on
cycloaddition strategies involving the fusion of norbornenes
together (stepwise or in concert) or their linking to a central
spacer component and has been used by us[4–6] and others[7,8]
to produce rigid molecular scaffolds containing a variety of
chromophore combinations and frame geometries. Function-
alized scaffolds of this type have been applied to supramolec-
ular assemblies and as dyads for the elucidation of energy
and electron transfer mechanisms.[6,8] When scaffold con-
struction involves a separate central spacer unit, fusion with
norbornene reagents (BLOCKs) produce molecular scaf-
folds which attain nanometre dimensions (nano-scafffolds).
Size alone is unimportant unless the nano-scaffold can bear
functionality at specific locations. Such addressable nano-
scaffolds encompass the smaller systems reported by Mutter
and coworkers[9,10] for use in peptide chemistry (RAFTs)
in which carbocyclic templates were used to hold peptide
functionality.
Results and Discussion
The benzo-N,X-[2]polynorbornadienes (2) where X = C, N,
and O have been identified as the centrepiece of the syn-
thetic strategy. The N,C-bridged systems have a norbornene
subunit at the terminus of the BLOCK for which stereo-
selective coupling usually affords coupled products with the
extended-frame geometry as depicted in (1). Modification of
the 7-position of the norbornene (X = O, NRꢀ) can be used
to access isomers of (1) at the BLOCK coupling step.[3,11]
Furthermore, there are good opportunities for the synthesis
of stereochemical variants of the BLOCKs (2) using paths A
and B outlined in Scheme 1.[12]
The [n]polynorbornane nano-scaffolds (1) are elegantly
suited for locating different types of effector functionality
ontothemolecularframeworkandarereadilyassembledfrom
norbornene BLOCKs (2) (Scheme 1).[1] Each BLOCK can
carry its own effector functionality, introduced sequentially
© CSIRO 2003
10.1071/CH02218
0004-9425/03/04263

264
R. N. Warrener et al.
Scheme 2. Series A: X = H, R = CO2Bn. Series B: X = F, R = Bn.
as the N-substituent of the succinimide ring in BLOCKs
(23)–(32) (Table 1), following cycloaddition of the various
cyclic 1,3-dienes to the key benzonorbornadienomaleimide
intermediates (16) and (17) (Scheme 3).
Scheme 1. In (1), theY-bridge and R groups are introduced during the
coupling process. Eff1–Eff6 are various effector groups.
The method used for the formation of the dibromo-
maleimide adducts (14a)/(15a) and (14b)/(15b) depended
on the stability of the N-substituted isoindole. For the
more reactive N-CO2Bn isoindole (12a), adduct forma-
tion [(14a) : (15a) = 3 : 1] could be achieved by generation
of (12a) in situ in the presence of N-methyl 3,4-
dibromomaleimide (13) (the N-methyl group is used as the
prototype substituent for Eff6) at room temperature using our
s-tetrazine route from N-CO2Bn 7-azabenzonorbornadiene
(Scheme 1).[12] In the case of the less reactive, but isolable,
N-benzyl 4,5,6,7-tetrafluoroisoindole (12b), forcing condi-
tions at high pressure (14 kbar, RT, 1 week) were required to
effect adduct formation [(14b) : (15b) = 10 : 1] between the
N-methyl 3,4-dibromomaleimide (13) and isoindole (12b).
The proton chemical shifts of the N-Me resonances were used
to assign stereochemistry to the adducts since, in the minor
endo-imide adducts (15a) and (15b), the methyl groups were
shielded by the aromatic ring and resonated at higher field
than those in the exo-imide isomers (14a) and (14b), respec-
tively (see Table 2). Significantly, the major isomers (14a)
and (14b) possessed endo-bromine substituents, a helpful
stereochemical feature for effective debromination.∗
In the path A approach, all the addressable sites
are associated with the highly dienophilic benzo-7-
azanorbornadienomaleimide (3), the synthesis of which
has not previously been reported. By contrast, the path
B approach distributes the effector linkage-points between
the known reagents, 7-oxanorbornadienomaleimide (5,
X = O),[13] and the N-substituted isoindoles (6).[14–16]
We have used a convergent approach for the construc-
tion of the desired benzo-7-azanorbornadienomaleimides
(16) and (17) in which up to six effector sites (Eff1–Eff6)
have been identified and introduced site-selectively by prior
attachment to the different precursor reagents. This method
started from the addition of benzynes (7) (carrying up to four
effectors X) to N-substituted pyrroles (carrying R = Eff5 as
the N-substituent) to form 7-azabenzonorbornadienes (9) in
which five of the effector groups were selectively positioned
(Scheme 2). The remaining effector group (Eff6) was intro-
duced by way of the N-substituent of 3,4-dibromomaleimide
(13) (in this case a methyl group, derived by alkylation of 3,4-
dibromomaleimide with methyl iodide). Eff6 finally appears
∗ The adduct of DBM (1) with cyclopentadiene has the bromine substituents in the exo-position and formed a product derived from trapping of an intermediate
radical by the furan co-reagent.

Position-Addressable Nano-Scaffolds: Sesquinorbornadiene Succinimides
265
Table 1. Product formation from the addition of a selection of cyclic 1,3-dienes (18)–(22) to azanorbornadieno-
maleimides (16) or (17)
Entry Reaction
X, Y
Adduct Relative
N-Me
Adduct Relative
N-Me Yield(%)A
(syn)
percentage
(anti)
percentage
1
2
3
4
5
(16) + (18) H, C
(16) + (19) H, O
(16) + (20) H, C
(16) + (21) H, NZ
(23)
(24)
(25)
(26)
(27)
33
–
33
100
100
δ 2.12
–
δ 2.16
δ 2.10
δ 2.39B
(28)
(29)
(30)
(31)
(32)
67
100
67
–
δ 2.26
δ 2.32
δ 2.20
–
23
49
20
28
C
(17) + (22) F, NAc
–
–
not detected
A Yields are for isolated and recrystallized products. Reactions conducted on < 0.5 mmol scale: yields not optimized.
B
Shifted downfield 0.25 ppm by fluorine groups, see (15a) versus (15b).
compounds were too unstable for isolation and were gen-
erated in situ in the presence of the trapping cycloaddition
agent. Complete stereoselectivity occurred in the reactions
of dienophile (16) with furan (19) (Table 1, Entry 2) to form
the anti-bridged adduct (29) and with N-CO2Bn-pyrrole (21)
(Entry 4) to afford the syn-bridged product (26), thereby
opening up ways to access adducts of either frame geometry.
For cases in which both adduct geometries were required,
these could be achieved by reaction with cyclopentadiene
(18) (favoring anti-isomer (28) 2 : 1) (Table 1, Entry 1) or 6,6-
dimethylfulvene (favouring anti-isomer (30) 2 : 1) (Table 1,
Entry 3). The reaction of N-acetylpyrrole (22) with the
tetrafluorinated dienophile (17) (prototype for effectors 1–4)
gave exclusively the syn-adduct (27) (Table 1, Entry 5).
Again, the upfield shift of the succinimide N-Me proton res-
onances in adducts with endo-succinimide geometry were
used to assign adduct stereochemistry (see Table 1)
Scheme3. (16)and(17)areformedinsituandtrappedwith1,3-dienes.
Z = CO2Bn.
Table 2. Proton chemical shifts δ of the N-methyl groups in
adducts (14) and (15)
Isoindole Adducts N-Me Adducts N-Me Ratio
The path B cycloaddition of N-benzyl 5,6,7,8-tetrafluoro-
isoindole (12b) (the benzyl group served as the model
substituent for Eff5) with N-methyl-7-oxanorbornadieno-
maleimide (33) formed a single stereoisomer (21%) which
was shown to have the syn-N,O-bridged structure (34)
(Scheme 5).† This result highlighted the ability of the path A
and B combinations to achieve new and different structural
outcomes as the anti-N,O-bridged system (29) was formed
exclusively in the reaction of (16) with (19).
(12a)
(12b)
(14a)
(14b)
3.20
3.09
(15a)
(15b)
2.63
2.39
3 : 1A
10 : 1B
A
Conditions: relux, toluene, 90◦C, 2 h; isolated yield.
B
Conditions 14 kbar, room temp., dichloromethane, 1 week;
spectroscopic yield.
A special feature of all these building BLOCKs is the pres-
ence of at least one N-bridge. Substituents (Eff5) attached
to such N-bridges (sp3 hybridized N) have been shown to
undergo invertomerization in related systems. Accordingly,
such effectors have novel dynamic properties and stand in
contrast with N-substituents (Eff6) attached to the succin-
imide rings in which the nitrogen is sp2 hybridized and fixed
in geometry. Reference to BLOCK (34) (Scheme 5) shows
that the benzyl substituent is oriented over the aromatic ring
and this is the preferred invertomer. This assignment is based
on molecular modelling predictions, but is in keeping with
other studies in which similar invertomer preferences have
been supported by nuclear Overhauser effect experiments in
solution and solid-state X-ray studies.[17]
Scheme 4. Z = CO2Bn
Formation of the previously unknown benzo-7-azanor-
bornadienomaleimides (16) and (17) was achieved by
oxidative debromination (Zn/Ag couple) of the respective
dibromo-adducts (14a, 15a) and (14b, 15b) (Scheme 4). Such
In the accompanying communication,[18] we demonstrate
that functionalized alkene BLOCKs, similar to the type
† The N-methyl resonanance of extended-frame adduct (34) occurred at δ 2.39 almost the same as for the bent-frame tetrafluoro adduct (29) (δ 2.32). However,
the expected upfield shift owing to shielding by both the aromatic ring and the alkene, represents another case where the fluorinated aromatic ring has a
modifying effect (see Table).

266
R. N. Warrener et al.
Scheme 5.
a complementary approach to these same products but under
different stereocontrolling factors. Such adducts, contain-
ing up to six addressable effector sites (the imide ring, the
N-bridge, and the aromatic ring) retain a norbornene or 7-
substituted norbornene π-bond at the terminus which makes
them suitable for use as BLOCK reagents in the preparation
of functionalized molecular nano-scaffolds.
Experimental
All compounds were characterized by one-dimensional and two-
dimensional nuclear magnetic resonance spectroscopy and high-
resolution mass spectrometry (HRMS). Representative compounds
follow.
Compound (23). mp 191–192◦C; δH (CDCl3) 1.72 (1 H, d, J 9.3),
2.12 (3 H, s), 3.15 (2 H, d, J 9.3), 3.36 (2 H, s), 5.02 (2 H, s), 5.40
(2 H, s), 6.28 (2 H, s), 7.08–7.30 (9 H, m); δC (CDCl3) 24.07, 47.18,
49.78, 65.97, 68.16, 122.50, 123.16, 128.17, 128.80, 129.16, 136.59,
140.84, 156.03, 176.95; HRMS found 426.1572, C26H22N2O4 requires
m/z 426.1579.
Compound (25). Not isolated; δH (CDCl3) 1.44 (3 H, s), 1.61
(3 H, s), 2.16 (3 H, s), 3.81 (1 H, s), 3.84 (1 H, s), 4.94 (1 H, d, J 12.2),
5.03 (1 H, d, J12.2), 5.37 (1 H, s), 5.46 (1 H, s), 6.36 (2 H, s), 7.08–7.36
(9 H, m).
Scheme 6.
described herein, can form dual 1,3-dipolar coupled products
of the nano-scaffold type. As the norbornene blocks can be
coupled stepwise in some procedures, so this opens the way
to produce different nano-scaffold geometries. For example,
nano-scaffold (1) can be accessed through the coupling of
two BLOCKs of type (2) whereas the coupling of (2) with its
isomer (35) would produce the nano-scaffold (36) in which
the two imides (and their effectors) are on opposite sides of
the scaffold frame (Scheme 6).
The additional feature to note in this type of coupling is
the opportunity to introduce additional effector groups at the
R-positions of (1) and (36) thereby allowing edge substitution
of the nano-scaffold.[19]
Compound (28). mp 141–142◦C; δH (CDCl3) 1.46 (1 H, d, J 9.8),
1.68 (1 H, d, J 9.8), 2.26 (3 H, s), 3.31 (1 H, s), 3.35 (1 H, s), 4.91 (1 H,
d, J 12.2), 5.16 (1 H, d, J 12.2), 5.22 (1 H, s), 5.25 (1 H, s), 5.96 (1 H, s),
6.26 (1 H, s), 7.08–7.34 (9 H, m); δC (CDCl3) 24.70, 47.15, 52.11, 62.61,
62.90, 67.65, 122.43, 122.03, 127.98, 128.15, 128.76, 128.91, 129.19,
134.14, 134.91, 137.01, 144.00, 144.47, 152.17, 177.67; HRMS found
426.1576, C26H22N2O4 requires m/z 426.1579.
Compound (29). mp 147–148◦C; δH (CDCl3) 2.32 (3 H, s), 4.91
(1 H, d, J 12), 5.18–5.21 (5 H, m), 6.20 (1 H, d, J 5), 6.54 (1 H, d, J 5),
7.11–7.37(9 H, m);δC (CDCl3)24.80, 60.53, 60.83, 67.66, 68.70, 81.94,
122.00, 122.39, 128.06, 128.63, 128.87, 129.03, 134.56, 134.86, 136.42,
143.43, 143.90, 152.43, 175.96; HRMS found 428.1385, C25H20N2O5
requires m/z 428.1372.
Compound (30). mp 116–119◦C; δH (CDCl3) 1.39 (3 H, s), 1.40
(3 H, s), 2.20 (3 H, s), 3.80 (1 H, s), 3.85 (1 H, s), 4.96 (1 H, d, J 12.2),
5.17 (1 H, d, J 12.2), 5.26 (1 H, s), 5.30 (1 H, s), 6.02 (1 H, s), 6.35
(1 H, s), 7.08–7.36 (9 H, m).
Conclusion
Compound (34). mp 208–209◦C; δH (CDCl3) 2.39 (3 H, s), 3.40
(2 H, s), 4.93 (2 H, s), 5.32 (2 H, s), 6.57 (2 H, s), 7.26–7.32 (5 H, m);
δC (CDCl3) 24.96, 52.96, 67.47, 68.40, 82.11, 126.37, 128.33, 128.89,
129.43, 138.06, 139.43, 146.10, 174.29; HRMS found 456.1099,
C24H16F4N2O3 requires m/z 456.1097.
This paper has demonstrated how norbornene BLOCKs
with multiple addressable sites can be prepared from
N-substituted benzo-7-azanorbornadienenomaleimides in
differing geometrical shapes (path A), e.g. exclusively
extended-frame topology using addition of furan, exclu-
sively bent-frame topology by addition of N-(CO2Bn)-
pyrrole, and mixtures of both with cyclopentadiene or 6,
6-dimethylfulvene. An alternative combination of reagents,
e.g. 7-oxanorbornadienomaleimide with N-substituted isoin-
doles (path B), where the diene carries the benzo ring allows
Acknowledgments
We thank the Australian Research Council for funding this
research and G. S. thanks Central Queensland University for
the award of a Ph.D. scholarship.

Position-Addressable Nano-Scaffolds: Sesquinorbornadiene Succinimides
267
References
[10] G. V. Nikiforovich, M. Mutter, C. Lehmann, Biopolymers
(Peptide Science) 1999, 50, 361.
[1] R. N. Warrener, D. N. Butler, R. A. Russell, Synlett 1998, 387.
[2] R. N. Warrener, A. C. Schultz, D. N. Butler, S. Wang,
I. B. Mahadevan, R. A. Russell, Chem. Commun. 1997, 1023.
[3] R. N. Warrener, D. Margetic, P. J. Foley, D. N. Butler, A. Winling,
K. A. Beales, R. A. Russell, Tetrahedron 2001, 57, 571.
[4] M. R. Johnston, M. J. Gunter, R. N. Warrener, J. Chem. Soc.,
Chem. Commun. 1998, 2739.
[5] A. C. Schultz, L. S. Kelso, M. R. Johnston, R. N. Warrener,
F. R. Keene, Inorg. Chem. 1999, 38, 4906.
[6] L. S. Kelso, T.A. Smith,A. C. Schultz, P. C. Junk, R. N. Warrener,
K. P. Ghiggino, F. R. Keene, J. Chem. Soc., Dalton Trans. 2000,
2599.
[11] R. N. Warrener, D. N. Butler, D. Margetic, R. A. Russell,
ECHET98 Electronic Conference on Heterocyclic Chemistry
1998, June 29–July 24, 73.
[12] D. N. Butler, D. Margetic, P. J. C. O’Neill, R. N. Warrener,
Synlett 2000, 98.
[13] R. N. Warrener, G. M. Elsey, L. Maksimovic, M. R. Johnston,
C. H. L. Kennard, Tetrahedron Lett. 1995, 36, 7753.
[14] G. M. Priestley, R. N. Warrener,Tetrahedron Lett. 1972, 42, 4295.
[15] J. R. Malpass, G. Sun, J. Fawcett, R. N. Warrener, Tetrahedron
Lett. 1998, 39, 3083.
[16] R. N. Warrener, Eur. J. Org. Chem. 2000, 3363.
[17] R. N. Warrener, D. N. Butler, unpublished results.
[18] R. N. Warrener, H. Sun, M.R. Johnston, Aust. J. Chem. 2003,
56, 269.
[7] A. Lutzen, S. D. Starnes, D. M. Rudkevich, J. Rebek, Jr,
Tetrahedron Lett. 2000, 41, 3777.
[8] K. A. Jolliffe, S. J. Langford, A. M. Oliver, M. J. Shephard,
M. N. Paddon-Row, Chem. Eur. J. 1999, 5, 2518.
[19] R. N. Warrener, D. N. Butler, D. Margetic, F. M. Pfeffer,
R. A. Russell, Tetrahedron Lett. 2000, 41, 4671.
[9] I. M. Eggleston, M. Mutter, Chem. Britain 1996, 39.