Synthesis of an annularly linked bicyclic chiral cyclophane by pre-organization of a dibromide

Article abstract of DOI:10.1016/S0040-4039(03)00442-8

An annularly linked bicyclic chiral cyclophane was synthesized from a suitable pre-organized chiral dibromide.

Full text of DOI:10.1016/S0040-4039(03)00442-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2885–2887
Synthesis of an annularly linked bicyclic chiral cyclophane by
pre-organization of a dibromide
Perumal Rajakumar* and Muthialu Srisailas†
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600 025, India
Received 9 December 2002; revised 6 February 2003; accepted 14 February 2003
Abstract—An annularly linked bicyclic chiral cyclophane was synthesized from a suitable pre-organized chiral dibromide. © 2003
Published by Elsevier Science Ltd.
Pre-organization1 of macrocycles plays a vital role in
coupling of bromide 5 with (S)-BINOL was low (8%)
many biochemical mechanisms such as enzyme/sub-
strate activity,2 protein folding,3 antisense applications,4
molecular recognition,5 etc. Stoddart6 has reported the
synthesis of an annularly linked macro bicyclic
cyclophane with a bipyridyl building unit. Such bicyclic
cyclophanes show self-assembly and other novel prop-
erties. Chiral cyclophanes based on BINOL have
recently been reported from our laboratory.7 Herein,
we wish to report the synthesis of a new class of
annularly linked chiral cyclophanes 1 through coupling
a pre-organized chiral dibromide.
and hence further chemical transformations could not
be achieved.
Hence, the scheme was modified by oxidizing the
dichloride 2 with CAN and the resulting 2,6-bis-
(chloromethyl)benzoquinone was then used for coupling
with a suitable dithiol. Cyclophane 14 can function as a
suitable precursor for the synthesis of annularly linked
bicyclic chiral cyclophanes.
Treatment of m-xylenyl dibromide 8 with p-hydroxy-
benzaldehyde in the presence of K2CO3 in DMF gave
dialdehyde 9, which was reduced to diol 10 by NaBH4
in methanol. Diol 10 was then converted into dibro-
mide 11 by treating with PBr3 in CH2Cl2. Dibromide 11
was treated with thiourea in THF to give the thiouro-
nium salt, which was hydrolyzed using KOH in THF to
give dithiol 12. Coupling dithiol 12 with 2,6-bis-
(chloromethyl) benzoquinone in EtOH–benzene under
high dilution conditions10 gave thiacyclophane 13 in
good yield.11 Reduction of the cyclophane 13 into
cyclophane 1412 was carried out smoothly with sodium
dithionate in ethyl acetate at 0°C without affecting the
CꢀS bonds.
Initially, we proposed to synthesize annularly linked
chiral bicyclic cyclophanes of type 1 by coupling the
chiral cyclophane 7 with various dibromides. The
cyclophane 7 was obtained from cyclophane 6 by CAN
oxidation8 followed by reduction using sodium dithio-
nate. Cyclophane 6 was synthesized from the dichloride
2.9 However, the cyclophane 6 gave only uncharacter-
izeable polymeric material after reduction (Scheme 1).
Moreover, the yield of the cyclophane 6 from the
Treatment of the cyclophane 14 with the chiral dibro-
mide 15 in the presence of K2CO3 in acetone at rt for
120 h afforded the annularly linked bicyclic chiral
cyclophane 113 in 10% yield (Scheme 2). Though two
isomers might be expected for the final coupling reac-
tion, only one isomer of 1 was formed. This may be
attributed to the pre-organization of the dibromide 15,
which exclusively reacts with one rotameric form of the
diol 14.
* Corresponding author.
† Present address: Division of Organic Chemistry (Synthesis),
National Chemical Laboratory, Pune 411 008, India.
0040-4039/03/$ - see front matter © 2003 Published by Elsevier Science Ltd.
doi:10.1016/S0040-4039(03)00442-8

2886
P. Rajakumar, M. Srisailas / Tetrahedron Letters 44 (2003) 2885–2887
Scheme 1. Reagents and conditions: (i) p-Hydroxybenzaldehyde, K2CO3, DMF, 60°C, 48 h, 82%; (ii) NaBH4, MeOH, 0°C, 4 h,
94%; (iii) PBr3, CH2Cl2, 0°C, 6 h, 73%; (iv) BINOL, K2CO3, acetone, rt, 120 h, 8%; (v) CAN, CH3CN, 0°C, 2 h, 43%; (vi)
Na2S2O4, EtOAc, 0°C, 22%.
Scheme 2. Reagents and conditions: (i) p-Hydroxybenzaldehyde, K2CO3, DMF, 60°C, 48 h, 86%; (ii) NaBH4, MeOH, 0°C, 4 h,
95%; (iii) PBr3, CH2Cl2, 0°C, 6 h, 87%; (iv) thiourea, THF, 60°C, 6 h, 97%; (v) KOH, THF, 60°C, 6 h, 62%; (vi) KOH,
EtOH/benzene, rt, 24 h, 55%; (vii) Na2S2O4, EtOAc, 0°C, 3 h, 37%; (viii) K2CO3, acetone, rt, 120 h, 10%.
1
The H NMR of the bicyclic cyclophane 1 showed the
-S-CH2- methylene protons as singlets, whereas the
methylene protons attached to the m-xylyl moiety
appeared as two doublets; one doublet appearing at l
4.84 (J=9.3 Hz) while the other doublet merged with
the multiplet of the p-xylyl moiety. Due to the
anisotropic effect of the BINOL group, the methylene
protons of the p-xylyl moiety appeared as multiplets.
The protons of the central benzene ring appeared in the
upfield region at l 6.70 as a singlet along with other
aromatic protons in the region l 6.76 to 7.88 as
multiplets.
The 13C NMR of the chiral cyclophane 1 showed five
distinct signals for methylene carbons in the aliphatic
region in addition to 26 carbons in the aromatic region.
The FAB-MS of the chiral cyclophane 1 showed a
molecular ion peak at 1006, which further supported
the structure of 1.
Semi empirical calculations based on MOPAC (AM1)
have also been carried out for the bicyclic chiral
cyclophane 1 (Fig. 1), which show that both the rings
are perpendicular to each other. It also reveals that the
central benzene ring through which both the rings are

P. Rajakumar, M. Srisailas / Tetrahedron Letters 44 (2003) 2885–2887
2887
Figure 1. Energy minimized structure of bicyclic chiral cyclophane 1.
connected lies perpendicular to both the cyclophane
units. Synthetic studies on other similar annularly
linked bicyclic chiral cyclophanes are under further
investigation.
7. (a) Rajakumar, P.; Srisailas, M. Tetrahedron 2001, 57,
9749–9754; (b) Rajakumar, P.; Srisailas, M. Tetrahedron
Lett. 2002, 43, 1909–1913; (c) Rajakumar, P.; Srisailas,
M. Tetrahedron 2003, 7, 1355–1359.
8. (a) Morey, J.; Saa´, J. M. Tetrahedron 1993, 49, 105–112;
(b) Moolander, G. A. Chem. Rev. 1992, 92, 29–68.
9. Sudhir, U.; Rath, N. P.; Nair, M. S. Tetrahedron 2001,
57, 7749–7753.
10. Kannan, A.; Rajakumar, P.; Kabaleswaran, V.; Rajan, S.
S. J. Org. Chem. 1996, 61, 5090–5102.
Acknowledgements
M.S. thanks CSIR, New Delhi for financial assistance.
The authors thank RSIC, IIT Madras and CDRI,
Lucknow for spectral data. The authors also thank
UGC, New Delhi for financial assistance (SAP III) to
the department.
11. Yield 55%; mp 142°C; IR (KBr, cm−1) 1740 (CꢁO); 1H
NMR (400 MHz, CDCl3) l 3.67 (s, 4H); 3.80 (s, 4H);
5.10 (s, 4H); 6.92 (s, 2H); 7.23–7.78 (m, 12H). Anal. calcd
for C30H26O4S2: C, 70.01; H, 5.09. Found: C, 69.93; H,
4.81.
References
12. Yield 37%; mp 110°C; IR (KBr, cm−1) 3340 (OH); 1H
NMR (400 MHz, CDCl3) l 3.60 (s, 4H); 3.69 (s, 4H);
5.06 (s, 4H); 6.81 (bs, 2H, exchangeable with D2O);
7.13–7.89 (m, 14H). Anal. calcd for C30H28O4S2: C,
69.74; H, 5.46; Found: C, 69.68; H, 5.42.
1. (a) Miller, M. T.; Bachmann, B. O.; Townsend, C. A.;
Rosenzweig, A. C. Nat. Struct. Biol. 2001, 8, 684–689; (b)
Golden, B. L.; Gooding, A. R.; Podell, E. R.; Cech, T. R.
Science 1998, 282, 259–264.
13. Yield 10%; mp 142°C; [h]2D5=−90.0 (c 0.2, CHCl3); 1H
NMR (400 MHz, CDCl3) l 3.19 (s, 4H); 3.29 (s, 4H);
4.84 (d, 2H, J=9.3 Hz); 4.98–5.06 (m, 6H); 5.56–5.59 (m,
4H); 6.70–6.76 (m, 12H); 7.12–7.38 (m, 14H); 7.75–7.88
(m, 8H); 13C NMR (100.4 MHz, CDCl3) l 31.6, 34.2,
70.3, 70.5, 70.6, 115.6, 115.7, 115.8, 115.9, 120.7, 123.6,
125.2, 125.8, 126.2, 126.3, 126.5, 126.6, 126.7, 126.8,
126.9, 127.0, 127.1, 127.8, 127.9, 129.1, 129.2, 129.3,
134.2, 136.3, 142.4, 153.9; m/z (FAB-MS) 1006 (M+).
Anal. calcd for C66H54O6S2: C, 78.70; H, 5.40. Found: C,
78.69; H, 5.09.
2. Severin, K.; Lee, D. H.; Kennan, A. J.; Ghadiri, M. R.
Nature 1997, 389, 706–709.
3. Myers, J. K.; Oas, T. G. Nat. Struct. Biol. 2001, 8,
552–558.
4. Teplova, M.; Minasov, G.; Tereshko, V.; Inamati, G. B.;
Cook, P. D.; Manoharan, M.; Egli, M. Nat. Struct. Biol.
1999, 6, 535–539.
5. Burke, S. D.; Zhao, Q.; Schuster, M. C.; Kiessling, L. L.
J. Am. Chem. Soc. 2000, 122, 4518–4519.
6. Ashton, P. R.; Reder, A. S.; Spencer, N.; Stoddart, J. F.
J. Am. Chem. Soc. 1993, 115, 5286–5287.