Synthesis of bicyclic cyclophanes with chiral cages by sixfold coupling

Article abstract of DOI:10.1016/S0040-4039(02)00137-5

Coupling of (S)-binol with various tribromides afforded bicyclic cyclophanes by sixfold coupling. Coupling of tricarbonyl tribromide with binol gave a novel chiral cyclophane with six co-ordination sites for complexation.

Full text of DOI:10.1016/S0040-4039(02)00137-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1909–1913
Synthesis of bicyclic cyclophanes with chiral cages by
sixfold coupling
Perumal Rajakumar* and Muthialu Srisailas
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600 025, India
Received 3 December 2001; revised 7 January 2002; accepted 18 January 2002
Abstract—Coupling of (S)-binol with various tribromides afforded bicyclic cyclophanes by sixfold coupling. Coupling of
tricarbonyl tribromide with binol gave a novel chiral cyclophane with six co-ordination sites for complexation. © 2002 Elsevier
Science Ltd. All rights reserved.
One of the most fascinating aspects of modern organic
chemistry lies in the synthesis of optically active com-
pounds.1 Chiral compounds play an important role in
the development of medicine such as modification of
enzyme structures2 and advanced materials such as
liquid crystals.3 Chiral macrocycles based on 1,1%-
binaphthol were thoroughly studied by Cram4 and
enantiomeric recognition was optimized using a ratio-
nal approach to host design. Although m-terphenyl
based chiral cyclophanes incorporating binaphthol as a
spacer have been recently reported from our labora-
tory,5 bicyclic cyclophanes with a chiral cavity based on
binol are not known. Furthermore, the synthesis of
cyclophanes involving sixfold coupling is rare6 though,
Anslyn et al.7 have recently reported such coupling.
Herein, we wish to report the synthesis of novel bicyclic
cyclophanes with chiral cages by sixfold coupling of
tribromides and binol.
29.26 and at 70.07 along with aromatic carbons. Com-
pound 3 has a specific rotation of −52.5 (c 0.5, CHCl3).
1
The H NMR of cyclophane 4 showed a singlet at l
4.46 and two doublets at l 5.67 and at 5.98 (J=19.2
Hz) along with aromatic protons. The 13C NMR of
cyclophane 4 showed two singlets at l 29.67 and at
70.01 for CH2Br and OCH2 carbons in addition to the
aromatic carbons. Cyclophane 4 has a specific rotation
of −370.0 (c 0.3, CHCl3). The optical rotation, in
general, increases enormously, if the binol group
becomes more planar or conjugated.9 The increased
value of the specific rotation for the cyclophane 4
indicates that the binol group should be more planar
and strained. Energy minimization calculations using
the MOPAC method (PM3) also indicated the high
degree of strain associated with cyclophane 1 and hence
the formation of 1 is prohibited (Scheme 1).
In our attempts to synthesize cyclophanes of type 1, the
crowding around the central benzene ring has to be
avoided. Hence, we decided to change to a larger spacer
unit. Such a structural modification would increase the
cavity size. The tribromide 2 was alkylated using p-
hydroxybenzaldehyde in DMF in the presence of
K2CO3 to give the trialdehyde 5, which was then con-
verted into a triol by treating with NaBH4 in MeOH.
Treatment of the triol with PBr3 in CH2Cl2 at room
temperature for 12 h gave the tribromide 6 in 62%
yield. Coupling of two equivalents of the tribromide 6
with three equivalents of (S)-binol in the presence of
K2CO3 afforded the bicyclic cyclophane 7 by sixfold
coupling in 22% yield (Scheme 1).
In order to check the feasibility of sixfold coupling of
binol with tribromides to synthesize bicyclic cyclophane
1, two equivalents of (S)-binol were treated with three
equivalents of the tribromide 28 in the presence of
K2CO3 in acetone under high dilution conditions and at
room temperature. The reaction mixture after usual
work-up followed by purification over silica gel using
CHCl3/hexane (1:1) gave compound 3 (34%) in the
forerun of elution followed by compound 4 (18%) on
1
further elution. The H NMR spectrum of compound 3
showed two singlets at l 4.67 and 5.12 along with
aromatic protons. The 13C NMR spectrum of com-
pound 3 showed two types of benzylic carbons at l
The 1H NMR of the cyclophane 7 showed two doublets
at l 4.81 and at 5.01 (J=16.1 Hz) due to the CH2
* Corresponding author. Tel.: +91-044-2351269-213; fax: +91-44-
2352494; e-mail: perumalrajakumar@hotmail.com
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00137-5

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P. Rajakumar, M. Srisailas / Tetrahedron Letters 43 (2002) 1909–1913
The synthetic strategy was then directed towards the
synthesis of functionalized bicyclic cyclophanes. Intro-
duction of carbonyl groups in a cyclophane is impor-
tant since they can be converted into a variety of
functional groups, which will enable in understanding
the complexing ability of such cyclophanes. A novel
tricarbonyl tribromide 12 was obtained by the NBS
bromination of triketone 11, which was prepared by the
reaction of trimesic acid chloride 10 with toluene in the
presence of AlCl3. Treatment of two equivalents of the
tricarbonyl tribromide 12 with (S)-binol under high
dilution conditions afforded the functionalized bicyclic
cyclophane 13 in 12% yield with a specific rotation of
−270.0 (c 0.5, CHCl3) and which was characterized by
spectroscopic and analytical data (Scheme 3).
attached to binol and two doublets at l 4.88 and 4.93
(J=8.3 Hz) due to the CH2 of the mesitylene moiety.
The 13C NMR spectra of the cyclophane 7 showed two
singlets at l 69.35 and 70.65 for the CH2 groups along
with aromatic carbons. The specific rotation of the
cyclophane 7 was found to be −139.16 (c 1.4, CHCl3).
The aromatic units in a cyclophane ensure necessary
rigidity to the host molecule.10 Hence, coupling of the
tribromide 811 with (S)-binol would result in the forma-
tion of a chiral bicyclic cyclophane with a rigid and
non-collapsible cavity. The tribromide 8 was treated
with (S)-binol under high dilution conditions in acetone
to furnish the cyclophane 9 in 15% yield. The
cyclophane 9 shows an optical rotation of −287.50 (c
0.4, CHCl3) and was characterized by spectroscopic and
analytical data (Scheme 2).
It is worthy to note that the cyclophane 7 developed a
deep purple color with tetracyanoethylene (TCNE)

P. Rajakumar, M. Srisailas / Tetrahedron Letters 43 (2002) 1909–1913
1911
Scheme 1.
Scheme 2.

1912
P. Rajakumar, M. Srisailas / Tetrahedron Letters 43 (2002) 1909–1913
Scheme 3.
showing the formation of a charge-transfer complex.
The UV–visible spectrum of the charge-transfer com-
plex shows two absorption maxima at 416 and 398 nm.
The association constant (Ka) was found to be 69.5
M−1.
22%); mp 186°C; [h]2D5 −139.16 (c 1.4, CHCl3); 1H
NMR (CDCl3, 400 MHz) l 4.81 (d, 6H, J=16.1 Hz);
4.88 (d, 6H, J=8.3 Hz); 4.93 (d, 6H, J=8.3 Hz); 5.01
(d, 6H, J=16.1 Hz); 6.33 (d, 12H, J=8.8 Hz); 6.68 (d,
12H, J=8.8 Hz); 7.11 (d, 6H, J=7.81 Hz); 7.13–7.37
(m, 12H); 7.75–7.80 (m, 12H); 7.84 (d, 6H, J=8.8 Hz);
7.88 (d, 6H, J=8.8 Hz); 13C NMR (CDCl3, 100.4
MHz) l 69.35, 70.65, 113.35, 114.61, 115.42, 116.41,
117.49, 120.76, 123.66, 124.74, 125.28, 126.35, 127.86,
128.61, 130.76, 134.10, 138.29, 153.89; m/z (MALDI-
MS) 1722 (M+); anal. calcd for C120H90O12: C, 83.60; H,
5.26; Found: C, 83.44; H, 5.17%.
Reduction of cyclophane 13 with NaBH4 to the corre-
sponding alcohol and charge-transfer complexation
studies of all the cyclophanes prepared with other
receptors are under investigation.
Experimental
In a typical reaction, tribromide 6 (0.72 g, 1 mmol) in
acetone (1.2 L) was treated with (S)-1,1%-binaphthol
(0.429 g, 1.5 mmol) in the presence of anhyd. K2CO3
(14.0 g, 10.1 mmol) at room temperature for 150 h,
after which the reaction mixture was filtered and the
filtrate evaporated to dryness. The residue obtained was
extracted with CH2Cl2 (2×150 mL); washed with water
(3×200 mL), aq. NaOH (25%, 2×100 mL), again with
water (3×150 mL) and with brine (200 mL) and dried
over anhyd. Na2SO4. Evaporation of the organic layer
gave a pale yellow solid, which was chromatographed
over SiO2 using CHCl3 to give cyclophane 7 (0.189 g,
Acknowledgements
M.S. thanks CSIR, New Delhi for financial assistance.
The authors thank RSIC, IIT Madras for spectral data.
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