Synthesis and structural characterization of chiral dicationic imidazolophanes

Article abstract of DOI:10.1016/j.tetlet.2005.06.159

Various chiral dicationic benzimidazolophanes were obtained from optically pure (S)-BINOL, benzimidazole and a suitable aryl alkyl dibromide.

Full text of DOI:10.1016/j.tetlet.2005.06.159

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6127–6130
Synthesis and structural characterization of chiral
dicationic imidazolophanes
Perumal Rajakumar,* Subramaniyan Selvam and Manickam Dhanasekaran
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600 025, Tamil Nadu, India
Received 17 March 2005; revised 19 June 2005; accepted 29 June 2005
Available online 19 July 2005
Abstract—Various chiral dicationic benzimidazolophanes were obtained from optically pure (S)-BINOL, benzimidazole and a suit-
able aryl alkyl dibromide.
Ó 2005 Elsevier Ltd. All rights reserved.
Molecular recognition of anionic guests1,2 by synthetic
cationic receptors3 is an area of interest at present.
Developing cationic receptor systems, which are capable
of recognizing, sensing and transporting anionic species
O
O
is an interesting and challenging problem. Due to their
structural versatility and opportunities for synthetic
modifications, cyclophanes have received much attention
in the areas of host-guest complexation, molecular self-
assembly and specific receptor activity. Imidazole-based
dicationic cyclophanes have been used for the synthesis
of carbenoid complexes,4,5 a silver complex,6 and also
exhibit interesting conformational behaviour.7 Chiralo-
phane8,9 and dicationic cyclophanes such as imidazolo-
phanes,10,11 imidazoliophanes,12 triazolophanes,13–15
tetracationic receptors16 and viologen based cyclo-
phanes17,18 have been reported in the literature. How-
ever, to the best of our knowledge the synthesis of
chiral cationic imidazolophanes remains to be explored.
Hence, we report the synthesis and structural characteri-
zation of the (S)-BINOL-based chiral imidazolophanes
1a,b, 2 and 3a–d. Furthermore, the synthesis of cyclo-
phanes 1a and 1b with large cavities is of interest as they
may form complexes with large chiral anions.
O
O
N
N
N
N
N
N
N
N
MeO
2Br-
2Br-
Br
OMe
2
1a para
1b meta
O
O
O
O
The synthesis of dicationic chiral receptors 1a and 1b
can be achieved either from (S)-BINOL and capping
with m-terphenyl dibromide or from m-terphenyl dibro-
mide and capping with (S)-BINOL. Syntheses of all the
cationic chiralophanes depicted above have been carried
out by both routes. Reaction of (S)-BINOL with
N
N
N
N
N
N
N
N
N
2Br-
2Br-
N
Keywords:
Chiral
dicationic
benzimidazolophanes;
Chiral
pyridinoimidazolophanes.
3a para
3b meta
*
3c para
3d meta
Corresponding author. Tel.: +91 4422351269; fax: +91 44
22352494; e-mail: perumalrajakumar@hotmail.com
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.159

6128
P. Rajakumar et al. / Tetrahedron Letters 46 (2005) 6127–6130
2.1 equiv of 4-carbethoxybenzyl bromide gave the dies-
ter 5a, which on reduction with LiAlH4 followed by
reaction with PBr3 gave the dibromide 7a in a 72% yield.
Reaction of the dibromide 7a with 2.1 equiv of benz-
imidazole in CH3CN in the presence of 25% aq NaOH
for 2 days afforded the precyclophane 8a in 78% yield,
which was characterized by spectral and analytical
data.19 Coupling of the precyclophane 8a with 20-bromo-
4,400bis(bromomethyl)-1,10:30100-terphenyl (9) gave the
cyclophane 1a along with other inseparable products
and hence the synthesis of cyclophane 1a in pure form
could not be achieved by this method. In another ap-
proach, the m-terphenyl dibromide 9 was reacted with
2.1 equiv of benzimidazole in the presence of 25% aq
NaOH in CH3CN to give the bridged benzimidazole
derivative 10.
OMe
Br
8a
2
Br
i
OMe
11
OMe
ii
N
iii
7a
N
N
N
OMe
12
Scheme 2. Reagents and conditions: (i) CH3CN, reflux, 5 days, 60%;
(ii) 2.1 eq benzimidazole, aq. NaOH (25%), CH3CN, rt, 2 days, 70%;
(iii) CH3CN, reflux, 5 days, 58%.
The reaction of 10 with 1 equiv of the dibromide 7a in
phane 2 in 60% yield. In another approach, the
dibromide 11 was reacted with 2.1 equiv of benzimid-
azole in the presence of aq. NaOH (25%) to give the bis-
benzimidazole derivative 12, which on further reaction
with the dibromide 7a in CH3CN, gave the dicationic
cyclophane 2 in 58% yield. Hence, benzimidazolophane
2 was synthesized by both routes with comparable yields
(Scheme 2).
CH3CN under reflux for 5 days afforded the cyclophane
1
1a in a 72% yield. The H NMR spectrum of 1a20 dis-
played N-methylene protons as singlets at d 5.72 and d
5.87 and O-methylene protons as doublets at d 5.02
and d 5.11, in addition to 39 aromatic protons. The
methine proton of the imidazole ring system in receptor
1a appeared at d 10.21. A similar sequence using 3-carb-
ethoxybenzyl bromide gave the cyclophane 1b with a
69% yield for the last step (Scheme 1).
1
The H NMR spectrum of benzimidazolophane 222 dis-
played the methoxy protons as a six proton singlet at d
3.80 and doublets for the O-methylene protons at d 4.90
and at d 5.02. The N-methylene protons appeared as
doublets at d 5.78 and d 5.86 integrating for four pro-
tons and a four proton singlet at d 5.73 in addition to
30 aromatic protons. It is noteworthy to mention that
the methine proton of the benzimidazole ring system
appeared as a singlet at d 10.78.
Synthesis of the benzimidazolophane 2 is of interest due
to the presence of the 1,4-dimethoxy-2,5-xylenyl cap-
ping unit. Atropisomerism might be observed for such
a capping unit. The synthesis of cyclophane 2 was car-
ried out by two methods. Reaction of the precyclophane
8a with 1 equiv of 1,4-bis(bromomethyl)-2,5-dimethoxy-
benzene (11)21 in CH3CN afforded the dicationic cyclo-
Br
1a/1b
9
i
iv
O
O
O
O
+
v
mixture of
CO2Et
(a, b)
products
E
E
N
N
N
N
5 (a, b)
5 (a, b) E = CO2Et
6 (a, b) E = CH2OH
7 (a, b) E = CH2Br
8 (a, b)
ii
a = para
b = meta
iii
iv
7a/7b
vi
1a/1b
Br
Br
N
N
N
Br
Br
N
9
10
Scheme 1. Reagents and conditions: (i) (S)-BINOL, K2CO3, DMF, 60 °C, 2 days, 5a (71%), 5b (65%); (ii) LiAlH4, THF, 6 h, 6a (85%), 6b (75%); (iii)
PBr3, CH2Cl2, 0 °C, 4 h, 7a (72%), 7b (82%); (iv) 2.1 equiv benzimidazole, aq. NaOH (25%), CH3CN, rt, 2 days, 8a (78%), 8b (72%) and 10 (70%); (v)
CH3CN, reflux, 5 days; (vi) CH3CN, reflux, 5 days, 1a (72%), 1b (69%).

P. Rajakumar et al. / Tetrahedron Letters 46 (2005) 6127–6130
6129
8a/8b
i
3a/3b
N
Br
Br
ii
iii 7a/7b
N
N
N
N
N
13
O
O
mixture of
products
iv
v
7a/7b
a = para
b = meta
Figure 1. 1H NMR spectrum (methylene protons) of precyclophane 8a
and cyclophane 3a.
N
N
N
N
14 (a, b)
Cyclophanes, which have both electron rich and electron
deficient centres, are called self-complementary cyclo-
phanes. Dicationic cyclophanes of the type 3a–d have
a chiral segment as well as a base segment, that is, a pyr-
idine unit in addition to the dicationic centre. Such
cyclophanes may be used as chiral receptors for chiral
anionic guests as well as chiral carboxylic acids, hence
the synthesis of dicationic chiralophanes 3a–d is of inter-
est. Cyclophanes 3a and 3b were synthesized by two
approaches.
iv
7a/7b
vi
N
3c/3d
N
N
N
Br
Br
N
N
15
Scheme 3. Reagents and conditions: (i) CH3CN, reflux, 5 days, 3a
(65%), 3b (55%); (ii) 2.1 equiv benzimidazole, aq. NaOH (25%),
CH3CN, rt, 2 d, (62%); (iii) CH3CN, reflux, 5 days, 3a (60%), 3b (54%);
(iv) 2.1 equiv imidazole, aq. NaOH (25%), CH3CN, rt, 2 days, 14a
(18%), 14b (20%) and 15 (37%); (v) 2,6-bis(bromomethyl)pyridine,
CH3CN, reflux, 5 days, (vi) CH3CN, reflux, 5 days, 3c (52%) 3d (48%).
In the first synthetic approach, precyclophane 8a, syn-
thesized as reported earlier (Scheme 1) was coupled
with 1 equiv of 2,6-bis(bromomethyl)pyridine to give
the benzimidazolophane 3a23 in 65% yield. It is note-
1
worthy that in the H NMR the methylene protons in
other related cationic chiralophanes and their complex-
ation with chiral anions are underway.
precyclophane 8a appeared as two singlets at d 4.85
and d 5.03, whereas after coupling with 2,6-bis(bromo-
methyl)pyridine, the methylene protons in cyclophane
3a appeared as three pairs of doublets at d 5.26, 5.35,
5.86, 5.95, 6.12 and 6.26 (Fig. 1). Application of a
similar sequence using 3-carbethoxybenzyl bromide
gave the cyclophane 3b24 in a 55% overall yield. Alter-
natively, 2,6-bis(bromomethyl) pyridine was reacted
with 2.1 equiv of benzimidazole and the resulting bis-
benzimidazole 13 was reacted with dibromides 7a/b to
give the cyclophanes 3a/b in 60% and 54% yields,
respectively. Hence, cyclophanes 3a and 3b could be
synthesized by both approaches with comparable yields
(Scheme 3).
Acknowledgements
The authors thank DST, India, for financial assistance
and RSIC, CDRI Lucknow, for FAB-MS spectra.
M.D. thanks CSIR for providing a SRF.
References and notes
1. Ramos, S.; Alcade, E.; Doddi, G.; Mencarelli, P.; Perez-
Garcia, L. J. Org. Chem. 2002, 67, 8463–8468.
2. Ihm, H.; Yun, S.; Kim, H. G.; Kim, J. K.; Kim, K. S. Org.
Lett. 2002, 17, 2897–2900.
Similarly, precyclophanes 14a and 14b were synthesized
from the dibromides 7a/b and imidazole. However,
the sequence with the precyclophane 14a and 2,6-bis-
(bromomethyl)pyridine did not afford the cyclophane
3c. The coupling reaction of the precyclophane 14a/b
with 2,6-bis(bromomethyl)pyridine gave a mixture of
products. Hence, 3c25 and 3d were synthesized by the
coupling reaction of precyclophane 15 with 1 equiv of
dibromide 7a/b. Precyclophane 15 was easily obtained
by the alkylation of 2.1 equiv of imidazole with 2,6-
bis(bromomethyl)pyridine (Scheme 3). Synthesis of
3. Yuan, Y.; Gao, G.; Jiang, Z. L.; You, J. S.; Zhou, Z. Y.;
Yuan, D. Q.; Xie, R. G. Tetrahedron 2002, 58, 8993–8999.
4. Simons, S. R.; Garrison, J. C.; Kofron, W. G.; Tessier, C.
A.; Youngs, W. J. Tetrahedron Lett. 2002, 43, 3423–3425.
5. Baker, M. V.; Skelton, B. W.; White, A. H.; Williams,
W. C. Organometallics 2002, 21, 2674–2678.
6. Garrison, J. C.; Simons, R. S.; Kofron, W. G.; Tessier, C.
A.; Youngs, W. J. Chem. Commun. 2001, 1780–1781.
7. Baker, M. V.; Bosnich, M. J.; Brown, D. H.; Byrne, L. T.;
Hesler, V. J.; Skelton, B. W.; White, A. H.; Williams, W.
C. J. Org. Chem. 2004, 69, 7640–7652.

6130
P. Rajakumar et al. / Tetrahedron Letters 46 (2005) 6127–6130
8. Castro, P.; Diederich, F. Tetrahedron Lett. 1991, 32, 6277–
7.26–7.34 (m, 6H); 7.54–7.56 (m, 2H); 7.64–7.66 (m, 2H);
7.83 (d, 2H, J = 7.9 Hz); 7.87 (d, 4H, J = 9.0 Hz); 8.09 (d,
2H, J = 8.3 Hz); 10.78 (s, 2H); 13C NMR (100 MHz,
DMSO-d6); d 46.8, 50.4, 56.9, 71.1, 113.2, 114.3, 116.2,
116.3, 120.7, 121.9, 124.0, 125.5, 126.6, 127.4, 127.5, 128.2,
128.3, 129.7, 131.3, 131.9, 132.5, 134.2, 139.0, 142.0, 152.0,
154.3; m/z (FAB-MS) 970; (M+ꢁBr); 890 (M+ꢁ2Br).
Elemental Anal. Calcd for C60H50N4O4Br2: C, 68.58; H,
4.80; N, 5.33. Found: C, 68.48; H, 4.65; N, 5.28.
6280.
9. Rajakumar, P.; Srisailas, M. Tetrahedron Lett. 2002, 43,
1909–1913.
10. Rajakumar, P.; Srisailas, M. Tetrahedron Lett. 1997, 38,
5323–5326.
11. Rajakumar, P.; Dhanasekaran, M. Tetrahedron 2002, 58,
1355–1359.
12. Alcade, E.; Alvarez-Rua, C.; Garcia-Granda, S.; Garcia-
Rodriguez, E.; Jesquida, N.; Perez-Garcia, L. Chem.
Commun. 1999, 295–296.
13. Rajakumar, P.; Murali, V. Tetrahedron 2000, 56, 7995–
7999.
14. Rajakumar, P.; Murali, V.; Ganesan, K. Synth. Commun.
2003, 33, 4191–4198.
15. Rajakumar, P.; Murali, V. Chem. Commun. 2001, 2710–
2711.
16. Rajakumar, P.; Srinivasan, K. Eur. J. Org. Chem. 2003,
1277–1284.
30
23. Cyclophane 3a: yield 65%; ½aꢀD ꢁ96.17, (c 0.01, DMSO);
1
mp >300 °C; H NMR (400 MHz, DMSO-d6): d 5.26 (d,
2H, J = 13.6 Hz); 5.35 (d, 2H, J = 13.6 Hz); 5.86 (d, 2H,
J = 15.6 Hz); 5.95 (d, 2H, J = 15.6 Hz); 6.12 (d, 2H,
J = 15.6 Hz); 6.26 (d, 2H, J = 15.6 Hz); 7.32 (s, 2H); 7.36
(d, 4H, J = 7.8 Hz); 7.59 (d, 4H, J = 8.2 Hz); 7.63 (s, 2H);
7.67 (d, 2H, J = 8.8 Hz); 7.71 (d, 2H, J = 8.3 Hz); 7.93–
7.99 (m, 6H); 8.12 (d, 2H, J = 7.8 Hz); 8.31 (t, 4H,
J = 8.8 Hz); 8.37–8.41 (m, 3H); 10.18 (s, 2H); 13C NMR
(100 MHz, DMSO-d6); d 49.4, 50.8, 68.8, 113.5, 115.3,
119.2, 123.2, 123.5, 124.5, 126.4, 126.5, 126.7, 127.3, 127.8,
128.7, 129.2, 130.5, 131.1, 132.8, 133.5, 138.1, 142.8, 151.7,
153.1; m/z (FAB-MS) 911 (M+ꢁBr); 831 (M+ꢁ2Br).
Elemental Anal. Calcd for C57H45N5O2Br2: C, 69.03, H,
4.57; N, 7.06. Found: C, 69.28; H, 4.69; N, 7.20.
17. Deng, N.; Marwaha, V. R.; Garcia, M. E.; Benesi, A.;
Mallouk, T. E. Tetrahedron Lett. 1995, 36, 7599–7602.
18. Garcia, M. E.; Gavin, J. A.; Deng, N.; Andrievsky, A. A.;
Mallouk, T. E. Tetrahedron Lett. 1996, 37, 8313–
8316.
30
30
19. Precyclophane 8a: yield 78%; ½aꢀD ꢁ42.77, (c 0.01,
24. Cyclophane 3b: yield 55%; ½aꢀD ꢁ89.36, (c 0.01, DMSO);
1
CHCl3); mp 122–124 °C; H NMR (400 MHz, CDCl3): d
mp >300 °C; 1H NMR (400 MHz, DMSO-d6): d 5.00
(d, 2H, J = 13.2 Hz); 5.10 (d, 2H, J = 15.4 Hz); 5.18
(d, 2H, J = 13.2 Hz); 5.33 (d, 2H, J = 15.4 Hz); 5.83 (d,
2H, J = 16.0 Hz); 5.86 (d, 2H, J = 16.0 Hz); 6.83 (d,
2H, J = 7.4 Hz); 6.92 (t, 2H, J = 8.0 Hz); 6.98 (d, 2H,
J = 8.6 Hz); 7.03 (d, 2H, J = 7.4 Hz); 7.18 (s, 2H); 7.22–
7.25 (m, 2H); 7.29 (t, 2H, J = 8.0 Hz); 7.32–7.36 (m, 2H);
7.45 (t, 2H, J = 8.0 Hz); 7.51 (d, 2H, J = 9.1 Hz); 7.53 (d,
2H, J = 8.6 Hz); 7.57 (d, 2H, J = 8.0 Hz); 7.71 (d, 2H,
J = 7.4 Hz); 7.94 (t, 4H, J = 9.1 Hz); 8.01 (t, 1H,
J = 7.4 Hz); 9.88 (s, 2H); 13C NMR (100 MHz, DMSO-
d6); d 49.5, 50.6, 69.6, 113.6, 115.7, 119.4, 122.8, 123.7,
124.5, 126.4, 126.6, 126.8, 126.9, 128.0, 128.9, 128.9, 129.2,
130.2, 131.1, 140.0, 133.4, 138.3, 142.7, 152.6, 153.4; m/z
(FAB-MS) 911 (M+ꢁBr), 831 (M+ꢁ2Br). Elemental Anal.
Calcd for C57H45N5O2Br2: C, 69.03; H, 4.57; N, 7.06.
Found: C, 69.28; H, 4.69; N, 7.20.
4.85 (s, 4H); 5.03 (s, 4H); 6.73 (s, 8H); 7.07–7.20 (m, 12H);
7.25 (d, 2H, J = 9.0 Hz); 7.71–7.76 (m, 6H); 7.80 (d, 2H,
J = 9.0 Hz); 13C NMR: (100 MHz, CDCl3); d 48.5, 70.7,
110.1, 115.9, 120.3, 120.7, 122.4, 123.1, 123.9, 125.5, 126.4,
127.0, 127.3, 127.9, 129.4, 129.5, 133.8, 134.1, 134.4, 137.7,
143.1, 143.7, 153.9; m/z (FAB-MS) 726 (M+). Elemental
Anal. Calcd for C50H38N4O2: C, 82.62; H, 5.27; N, 7.71.
Found: C, 82.42; H, 5.18, N, 7.90.
30
20. Cyclophane 1a: yield 72%; ½aꢀD ꢁ4.27, (c 0.01, DMSO);
mp 250 °C; 1H NMR (400 MHz, DMSO-d6): d 5.02 (d,
2H, J = 13.1 Hz); 5.11 (d, 2H, J = 13.1 Hz); 5.72 (s, 4H);
5.87 (s, 4H); 6.87 (d, 4H, J = 8.1 Hz); 6.96 (d, 2H,
J = 8.4 Hz); 7.12–7.16 (m, 2H); 7.20–7.23 (m, 5H); 7.38–
7.43 (m, 6H); 7.47–7.51 (m, 6H); 7.56 (t, 2H, J = 7.4 Hz);
7.64–7.71 (m, 4H); 7.79 (d, 2H, J = 8.0 Hz); 7.93 (d, 2H,
J = 9.1 Hz); 8.03–8.05 (m, 2H); 8.18–8.20 (m, 2H); 10.21
(s, 2H); 13C NMR (100 MHz, DMSO-d6); d 50.2, 50.3,
80.2, 114.9, 116.3, 120.0, 124.4, 125.4, 127.2, 128.0, 128.1,
128.5, 128.7, 128.8, 129.6, 129.9, 130.8, 131.5, 131.7, 131.9,
134.1, 134.2, 134.8, 138.9, 142.5, 143.3, 143.5, 154.2; m/z
(FAB-MS) 1141 (M+ꢁBr); 1061 (M+ꢁ2Br). Elemental
Anal. Calcd for C70H53N4O2Br3: C, 68.81; H, 4.37; N,
4.59. Found: C, 68.66; H, 4.28; N, 4.61.
30
25. Cyclophane 3c: yield: 68%; ½aꢀD ꢁ146.30, (c 0.01, DMSO);
1
mp 198–200 °C; H NMR (400 MHz, DMSO-d6): d 5.05
(d, 2H, J = 13.7 Hz); 5.27 (d, 2H, J = 13.7 Hz); 5.31 (s,
4H); 5.48 (d, 2H, J = 15.6 Hz); 5.60 (d, 2H, J = 15.6 Hz);
7.00 (d, 2H, J = 17.7 Hz); 7.08 (d, 4H, J = 8.0 Hz); 7.16
(d, 4H, J = 8.0 Hz); 7.26 (t, 2H, J = 7.3 Hz); 7.35 (t, 2H,
J = 8.0 Hz); 7.53 (s, 2H); 7.59–7.64 (m, 6H); 8.00–8.02 (m,
3H); 8.05 (d, 2H, J = 9.1 Hz); 9.20 (s, 2H); 13C NMR
(100 MHz, DMSO-d6); d 51.5, 52.6, 68.8, 115.2, 119.2,
121.8, 122.6, 123.6, 124.6, 126.5, 127.2, 128.0, 128.3, 128.8,
129.4, 133.4, 133.6, 136.6, 138.2, 138.8, 153.1, 153.2; m/z
(FAB-MS) 811 (M+ꢁBr); 731 (M+ꢁ2Br). Elemental Anal.
Calcd for C49H41N5O2Br2: C, 66.00; H, 4.63; N, 7.85.
Found: C, 65.90; H, 4.54; N, 7.93.
21. Nair, M. S.; Sudhir, U.; Joly, S.; Rath, N. P. Tetrahedron
1999, 55, 7653.
30
22. Cyclophane 2: yield 60%; ½aꢀD ꢁ55.82, (c 0.01, DMSO);
mp 160 °C; 1H NMR: (400 MHz, DMSO-d6): d 3.80 (s,
6H); 4.90 (d, 2H, J = 13.0 Hz); 5.02 (d, 2H, J = 13.0 Hz);
5.73 (s, 4H); 5.78 (d, 2H, J = 15.0 Hz); 5.86 (d, 2H,
J = 15.0 Hz); 7.01 (d, 4H, J = 8.0 Hz); 7.14–7.21 (m, 8H);