Alicyclophanes: A new range of cyclophanes containing rigid alicyclic subunits in place of the aromatic rings

Article abstract of DOI:10.1016/S0040-4039(00)00956-4

Norbornenosuccinimides have been coupled stereoselectively with 2,5- bis(trifluoromethyl-1,3,4-oxadiazole to prepare alicyclic scaffolds 5 and 20. Alkylations of the terminal succinimido-nitrogens of 5 with bis-alkylating agents have produced macrocyclic compounds in a short, high-yielding procedure. Alicyclophanes containing one scaffold subunit were obtained from 1,6-dibromohexane, 1,5-dichloro-3-oxapentane, 1,11-dibromo-3,6,9- trioxaundecane and 9,10-bis(chloromethyl)anthracene. Larger alicyclophanes incorporating two spacer subunits were formed by intermolecular cyclisation of 5 with 1,2-dibromoethane or 19 with m- or p-xylylene dibromide. Reaction of 5 with propargyl bromide, followed by oxidative coupling (CuCl) of the pendant acetylenes provided bis-acetylenic alicyclophane 13. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00956-4

Tetrahedron Letters 41 (2000) 5985±5989
Alicyclophanes: a new range of cyclophanes containing rigid
alicyclic subunits in place of the aromatic rings
Douglas N. Butler* Muhong Shang and Ronald N. Warrener
Centre for Molecular Architecture, Central Queensland University, Rockhampton, Queensland 4702, Australia
Received 19 May 2000; accepted 7 June 2000
Abstract
Norbornenosuccinimides have been coupled stereoselectively with 2,5-bis(tri¯uoromethyl-1,3,4-oxadiazole
to prepare alicyclic sca€olds 5 and 20. Alkylations of the terminal succinimido-nitrogens of 5 with bis-
alkylating agents have produced macrocyclic compounds in a short, high-yielding procedure. Alicyclophanes
containing one sca€old subunit were obtained from 1,6-dibromohexane, 1,5-dichloro-3-oxapentane, 1,11-
dibromo-3,6,9-trioxaundecane and 9,10-bis(chloromethyl)anthracene. Larger alicyclophanes incorporating
two spacer subunits were formed by intermolecular cyclisation of 5 with 1,2-dibromoethane or 19 with
m- or p-xylylene dibromide. Reaction of 5 with propargyl bromide, followed by oxidative coupling (CuCl)
of the pendant acetylenes provided bis-acetylenic alicyclophane 13. # 2000 Elsevier Science Ltd. All rights
reserved.
Keywords: alkylation; cyclophanes; macrocycles; 1,3,4-oxadiazoles; norbornenes; cycloaddition; succinimides.
1
The cyclophanes are a well established sub-class of macrocycles which contain one or more
2
aromatic component(s) embodied in the cyclic frame. In this paper, we report the facile synthesis
of a novel type of modi®ed cyclophane, the alicyclophanes (Fig. 1), in which some or all of the
aromatic rings have been replaced by a rigid, alicyclic subunit comprised of fused bicyclic rings.
An advantage of such compounds is that the alicyclic sca€old components can bear speci®c
3
substituents (e€ectors) and be designed to have a variety of individual framework topologies
5
4
(
curved, rod-like) or properties (polarofacial, lipophilic, etc.). While isolated examples of
macrocycles incorporating multiply-bridged components have been reported in the chemical
literature,6 no systematic synthetic methodology for alicyclophane construction has been
described heretofore.
Reaction of the endo-adduct 3, formed by cycloaddition of cyclopentadiene 1 with maleimide
7
2
, with 2,5-bis(tri¯uoromethyl)-1,3,4-oxadiazole 4 e€ected ecient, stereoselective coupling at
8
the norbornene p-bond to furnish the syn-orientated bis-succinimide 5. This compound acts as a
*
Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00956-4

5
986
Figure 1.
key prototype spacer unit in this study, but a range of related systems is potentially available
3
using our BLOCK coupling techniques.
In a typical procedure, the sca€old bis-succinimide 5 was warmed (60 C) with 1,6-dibromohexane
ꢀ
6
alicyclophane 7 in excellent yield (93%). The cyclic structure of 7 was fully supported by the
in DMF containing solid potassium carbonate for 5 days to a€ord the macrocyclic
8
9
single crystal X-ray structure analysis presented in Fig. 2a. In particular, this structure shows
that the methylene chain is conformationally highly ordered with the four central methylene
subunits adopting the low energy, non-eclipsed conformation (Scheme 1).
Figure 2. X-ray structures of a) alicyclophane 7 and b) open-chain diacetylene 12
Scheme 1.

5
987
Functionality can be incorporated into the macrocyclic ring by the prior positioning of it into
the bis-alkylating agent. Thus, treatment of bis-succinimide 5 with 1,5-dichloro-3-oxapentane 8
8
(
n=1) a€orded the cyclic ether product 9 in 93% yield. The structure of 9 was supported by
NMR spectroscopy and mass spectometry (m/z=574). That larger ring macrocycles can be
produced was established by reaction of 5 with 1,11-dibromo-3,6,9-trioxaundecane 8 (n=3) to
8
furnish the crown ether 10, although the yield dropped o€ (42%) with the longer bis-alkylating
agent.
Molecular modelling (AM1) of these alicyclophanes indicated that the N±N separation of the
Ê
Ê
succinimide nitrogens in 5 is 6.30 A and that this distance expands to 6.63 A upon conversion to
the alicyclophane 7. This calculated distance agrees well with that obtained from the X-ray
Ê
structure of 7 (6.68 A). Again, the calculated N±N separation remains essentially the same (6.56
Ê
A, MM2) in crown ether 10.
In a second route to alicyclophanes, short pendent arms were attached to the succinimide
nitrogen centres and linked by intramolecular cyclisation. Thus, reaction of bis-succinimide
spacer 5 with excess propargyl bromide 11 using the standard basic conditions (K CO , DMF)
2
3
8
9
provided the open-chain bis(N-propargyl) derivative 12 (X-ray structure, Fig. 2b), which was
8
cyclised to the diacetylenic alicyclophane 13 by treatment with Cu[1] (Scheme 2). The requisite
8
13
high symmetry of the cyclic product 13 was evident in the C NMR spectrum (10 resonances)
and the size of the macrocyclic ring was established by hydrogenation (Pd/H ) to alicyclophane 7.
2
Attempts to form 13 directly, by treatment of bis-succinimide 5 with 1,6-dibromohexa-2,4-diyne
were not successful, thereby con®rming the complementarity of the cyclisation methods, a
conclusion reinforced when attempts to form the cyclic ether 9 from cyclisation of the N,N-bis(2-
hydroxyethyl) derivative of 5 by reaction with mesyl chloride/pyridine or DCC were without reward.
Scheme 2.
Introduction of an aromatic ring into the alicyclophanes was also readily achieved by treating the
bis-succinimide spacer 5 with an appropriate aromatic bis-alkylating agent, e.g. 9,10-bis-(chloro-
8
methyl) anthracene 14 produced the alicyclophane 15 (Scheme 3). The structure was based on the
1
mass spectrum (m/z=706) and the H NMR spectrum which displayed the typical through space,
transannular shielding by the anthracene ring. In particular, the endo-protons (Ha) of the
alicyclic spacer unit in 15 were up®eld-shifted by 1.72 ppm relative to those in the starting sca€old 5.
Scheme 3.

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988
Macrocycles containing two alicyclic spacer units were accessed using short-chain bis-alkylating
agents, whence dual intramolecular alkylation was obtained. Reaction of 5 with an equimolar
8
+
equivalent of 1,2-dibromoethane 16 gave the cyclic product 18 (m/z=1083, M+Na ) in 93%
yield, while the same reaction reagents produced the bis(2-bromoethyl) derivative 17 when a
8
large excess (20 fold) of 16 was employed. Separate reaction of the dibromide 17 with spacer 5
1
produced the macrocycle 18 in excellent yield (86%). The H NMR spectrum of 18 in CDCl is
3
broad and ill-de®ned at room temperature and does not symmetrise until the temperature exceeds
ꢀ
9
0 C. We interpret this phenomenon, tentatively, in terms of conformational rotation (18a=18b)
occurring in the ethano linkers (arrows, Scheme 4) and such `crankshaft' mobility may have
potential in the design of molecular devices. The incorporation of two aromatic rings into a
`dimeric' type of macrocycle (cf. Fig. 1) can be achieved using o-xylylene dibromide as the
bis-alkylating agent and this will be discussed elsewhere.
10
Scheme 4.
In addition to the `southern hemisphere'11 macrocycles discussed above, in which the linking
chain is positioned on the bottom face of the alicyclic spacer unit, we have now found that their
`
northern hemisphere' counterparts are also accessible. Thus, bis-alkylation of exo-fused bis-
13
succinimido spacer 20 (Scheme 5), formed by coupling of exo-succinimide 19 with the 1,3,4-
oxadiazole 4, with m-xylylene dibromide 21a produced `dimeric' alicyclophanes 22a (m/z=1235,
+
M+Na ), in which the methano-bridged faces of the alicyclic sca€olds are inward-facing, i.e.
`
northern hemisphere'11 as assessed by molecular modelling. Similarly, 22b was produced by
treatment of 20 with p-xylylene dibromide 21b.
Scheme 5.
In conclusion, given the simplicity of the preparation of the bis-succinimide spacers and the
eciency of their N-alkylation leading to macrocycles, we expect alicyclophanes to o€er

5
989
molecular architects a new arena in which to demonstrate their creativity, and where we will be
contributing further in due course.
Acknowledgements
This research was funded by a grant from the Central Queensland University Merit Grant
Scheme and the Centre for Molecular Architecture. The X-ray crystallographic studies were
conducted by Dr. Alan Lough, University of Toronto, Canada.
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7
8
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. All new compounds gave high resolution mass spectra, H and 13C NMR spectra corresponding to their assigned
1
ꢀ
structures. Compound, mp ( C): 5, >350; 7, >350; 9, >350; 10, >350; 12, 216±217; 13, >350; 15, >350; 17,
274±275; 18, >350; 20, >350; 22a, >350; 22b, >350.
. Archival crystallographic data have been deposited with the Cambridge Crystallographic Data Centre, 12 Union
9
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0. Warrener, R. N.; Shang, M.; Butler, D. N. unpublished results.
1. This concept of `southern' and `northern' descriptors is used in the same sense as that found in subclassifying
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equivalent, in the customary northern direction.
1
1
1
1
2. (a) Warrener, R. N.; Margetic, D.; Amarasekara, A. S.; Russell, R. A. Org. Lett. 1999, 1, 203±206. (b) Warrener,
R. N.; Margetic, D.; Amarasekara, A. S.; Butler, D. N.; Mahadevan, I. B.; Russell, R. A. Org. Lett. 1999, 1, 199±
2
02.
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