Synthesis and conformational behaviour of new intra-annularly linked cyclophane possessing a 1,6-dioxahexa-2,4-diyne spacer

Article abstract of DOI:10.1016/S0040-4039(02)01854-3

The new intra-annularly linked cyclophane 1 was synthesized in five steps from p-cresol by intramolecular Eglington coupling of precyclophane 5. From the ¹H NMR data, it was evident that the cyclophane 1 exists predominantly as conformer 1a rather than 1b at room temperature.

Full text of DOI:10.1016/S0040-4039(02)01854-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7695–7698
Synthesis and conformational behaviour of new intra-annularly
linked cyclophane possessing a 1,6-dioxahexa-2,4-diyne spacer
Perumal Rajakumar* and Venghatraghavan Murali
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600 025, Tamil Nadu, India
Received 27 June 2002; revised 5 August 2002; accepted 30 August 2002
Abstract—The new intra-annularly linked cyclophane 1 was synthesized in five steps from p-cresol by intramolecular Eglington
1
coupling of precyclophane 5. From the H NMR data, it was evident that the cyclophane 1 exists predominantly as conformer
1a rather than 1b at room temperature. © 2002 Elsevier Science Ltd. All rights reserved.
Cyclophanes are attractive synthetic targets due to their
intriguing chemical, physicochemical, and biological
properties.1 The design and synthesis of cyclophanes
possessing rigidly defined cavities and shape-persistent
structures of molecular dimensions are of interest as
molecular hosts in the area of host–guest chemistry.2
Acetylenic units as bridges impart rigidity to the
cyclophanes, and the number of acetylenic units in the
bridge and their connectivity to the arene units control
the size and shape of the cavity present in the
cyclophane.3 The synthesis of multiply bridged
acetylenic thiacyclophanes,4 [2.2.2]metacyclophane-
1,9,17-triyne,5 carbozolylacetylene-derived macrocy-
cles,6 twistophane ion sensors7 and pyxophanes8 have
also been reported. Intermolecular acetylenic coupling
leading to the synthesis of cyclophanes are reported
mostly in poor yield.9 Herein we wish to report the
synthesis of intra-annularly linked cyclophane 1 by
intramolecular Eglington coupling.
p-Cresol on treatment with formalin solution in the
presence of aqueous NaOH (15%) for 5 days afforded
2,6-bis(hydroxymethyl)-4-methyl phenol 2 (80%).10 The
triol 2 was treated with p-xylenyl dibromide in K2CO3/
acetone under reflux for 120 h to give the tetrol 311 in
70% yield. Reaction of the tetrol 3 with 3 equiv. of PBr3
in CH2Cl2 afforded the tetrabromide 4 in 80% yield.
Precyclophane 512 was obtained by the reaction of the
tetrabromide 4 with sodium propargylate. The 1H
NMR spectrum of precyclophane 5 displayed a singlet
at l 2.34 corresponding to the methyl protons and
another singlet at l 2.44 corresponding to the acetylenic
protons (Fig. 1). The methylene protons attached to the
acetylenic carbon appeared as a singlet l 4.20. The
methylene protons attached to the arene unit appeared
as a singlet at l 4.63. The methylene protons present in
the intra-annular tethering unit appeared as a singlet at
l 4.97. The aromatic protons present in the p-xylyl unit
appeared as a singlet at l 7.22. The aromatic protons
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01854-3

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P. Rajakumar, V. Murali / Tetrahedron Letters 43 (2002) 7695–7698
present in the p-cresol unit appeared as a singlet at l
7.52. Application of the Eglington coupling to the
precyclophane 5 in the presence of Cu(OAc)2 in
CH3CN/pyridine (3:1) gave the intra-annularly linked
diyne cyclophane 113 in 40% yield. These reactions are
shown in Scheme 1.
that the aromatic protons present in the p-xylyl unit
appeared as two singlets l 7.05 at l 7.19 (Fig. 1).
Although energy minimized calculations show the pos-
1
sibility of two conformers, the H NMR data clearly
indicate that the conformer 1a is more favoured in
CDCl3 solution at room temperature (Scheme 2). If
conformer 1b was favoured then the aromatic protons
in the p-xylyl unit should appear as two doublets.
1
The H NMR of cyclophane 1 showed a singlet at l
1
2.23 corresponding to the methyl protons. The methyl-
ene protons attached to the acetylenic carbon appeared
as a singlet at l 4.27. The methylene protons attached
to the arene unit also appeared as a singlet at l 4.49.
The aromatic protons present in the p-cresol unit
appeared as a singlet at l 7.56. It is interesting to note
Since the H NMR spectrum of cyclophane 1 shows
two singlets for the p-xylenyl protons, the equilibrium
is shifted towards conformer 1a rather than 1b.
Furthermore, based on energy minimized calcula-
tions, (Fig. 2) conformer 1a is preferred rather than
(Fig. 3) 1b.
Scheme 1. Reagents and conditions: (i) formalin solution, 15% NaOH, 5 days, rt; (ii) p-xylenyl dibromide, K2CO3, acetone, reflux,
5 days; (iii) PBr3 (3 equiv.), CH2Cl2, rt, 12 h; (iv) NaH, propargyl alcohol, THF, reflux, 12 h; (v) Cu(OAc)2, CH3CN/pyridine
(3:1), 80°C, 2 h.

P. Rajakumar, V. Murali / Tetrahedron Letters 43 (2002) 7695–7698
7697
In summary, we have synthesized a new intra-annularly
linked cyclophane possessing a 1,6-dioxahexa-2,4-diyne
spacer by intramolecular Eglington coupling. From the
1H NMR data, it is evident that the cyclophane 1 exists
mainly in conformation 1a rather than 1b (Scheme 2).
The synthesis and conformational behaviour of other
diyne cyclophanes with various tethering units instead
of the p-xylenyl unit is under investigation.
Acknowledgements
V.M. thanks CSIR, New Delhi for a fellowship and the
authors thank DST, New Delhi for financial assistance
and RSIC, I.I.T.Madras for spectral data.
References
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Figure 1. Comparison of the 1H NMR of precyclophane 5
and cyclophane 1.
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38, 6681–6684.
Scheme 2.

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P. Rajakumar, V. Murali / Tetrahedron Letters 43 (2002) 7695–7698
Figure 2. Conformer 1a (MM2) energy 25.53 kcal/mol (total energy).
Figure 3. Conformer 1b (MM2) energy 28.54 kcal/mol (total energy).
6. Maruyama, S.; Hokari, H.; Wada, T.; Sasabhe, H. Syn-
thesis 2001, 1794–1799.
12. Compound 5: Yield 65%, melting point 85°C; IR (cm−1
)
3296, 2922, 2860, 2359, 1618, 1469, 1352, 1259, 1207,
1078, 864, 661, 630; 1H NMR (CDCl3/DMSO-d6) 400
MHz l 2.34 (s, 6H), 2.44 (s, 4H), 4.20 (s, 8H), 4.62 (s,
8H), 4.96 (s, 4H), 7.22 (s, 4H), 7.52 (s, 4H); 13C NMR
(CDCl3/DMSO-d6) 100.4 MHz: 20.8, 57.5, 66.8, 76.7,
74.8, 79.7, 127.9, 130.5, 131.2, 133.9, 137,3, 153.7; m/z:
590 (M+). Anal. calcd for C38H38O6: C, 77.26; H, 6.48.
Found: C, 77.22; H, 6.44%.
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8. Behm, R.; Gloeckner, C.; Grayson, M. A.; Gross, M. L.;
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13. Compound 1: Yield 40%, melting point >300°C; IR
(cm−1) 2963, 2359, 1629, 1519, 1400, 1209, 1145, 1074,
993, 927, 866, 798, 661, 630; 1H NMR (CDCl3/DMSO-
d6) 400 MHz l 2.23 (s, 6H), 4.27 (s, 8H), 4.49 (s, 8H),
5.02 (s, 4H), 7.06 (s, 2H), 7.19 (s, 2H), 7.56 (s, 4H); 13C
NMR (CDCl3/DMSO-d6) 100.4 MHz: 22.9, 58.4, 68.2,
71.3, 75.9, 129.7, 130.7, 131.8, 132.1, 132.8, 133.9, 136.9,
153.4; m/z: 586 (M+). Anal. calcd for C38H34O6: C, 77.80;
H, 5.84. Found: C, 77.77; H, 5.81%.
11. Compound 3: Yield 70%, melting point 185°C; IR (cm−1
)
3328, 2912, 1593, 1452, 1356, 1200, 1142, 1062, 1020, 979,
1
864, 796; H NMR (CDCl3/DMSO-d6) 400 MHz l 2.23
(s, 6H), 4.62 (s, 8H), 4.95 (s, 4H), 7.23 (s, 4H), 7.64 (s,
4H); 13C NMR (CDCl3/DMSO-d6) 100.4 MHz: 20.9,
58.7, 75.8, 127.9, 128.3, 132.9, 134.5, 137.3, 151.5; m/z:
438 (M+). Anal. calcd for C26H30O6: C, 71.21; H, 6.90.
Found: C, 71.14, H 6.84%.