Synthesis of intra-annularly functionalized cationic pyridinophanes

Article abstract of DOI:10.1016/S0040-4020(01)01226-1

The precyclophane 1 derived from 2,6-bis(bromomethyl)pyridine and 2.1 equiv. of benzimidazole afforded pyridinobenzimidazolophanes 6-8 on further reaction with 1 equiv. of 2,6-bis(bromomethyl)pyridine, 3,5-bis(bromomethyl)anisole and 1,3-bis(bromomethyl)-4-nitrophenol, respectively. A similar synthetic strategy was used for the synthesis of pyridinobenzotriazolophanes 9-11. Potential receptors 16 and 17 were also synthesized.

Full text of DOI:10.1016/S0040-4020(01)01226-1

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 1355±1359
Synthesis of intra-annularly functionalized
cationic pyridinophanes
Perumal Rajakumarp and Manickam Dhanasekaran
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai, Tamil Nadu 600 025, India
Received 27 February 2001; revised 13 November 2001; accepted 6 December 2001
AbstractÐThe precyclophane 1 derived from 2,6-bis(bromomethyl)pyridine and 2.1 equiv. of benzimidazole afforded pyridinobenz-
imidazolophanes 6±8 on further reaction with 1 equiv. of 2,6-bis(bromomethyl)pyridine, 3,5-bis(bromomethyl)anisole and 1,3-bis(bromo-
methyl)-4-nitrophenol, respectively. A similar synthetic strategy was used for the synthesis of pyridinobenzotriazolophanes 9±11. Potential
receptors 16 and 17 were also synthesized. q 2002 Elsevier Science Ltd. All rights reserved.
Cyclophanes with heterocyclic ring systems possess binding
sites for metal ions1 and hence can have promising features2
as molecular hosts. Pyridinophanes have been synthesized
by a variety of methods3 and used as model systems to study
the diastereo- and enantioselectivity of certain bio-
chemically important reactions.4 Use of benzimidazole,5
benzotrioazole6 for the synthesis of cyclophanes has also
been recently reported. The use of pyridyl units in host
compounds and their host±guest complexation properties
have also been studied.7 We report herein the synthesis of
a new class of positively charged receptors containing
pyridyl units with either imidazole or triazole building
blocks.
reaction mixture after usual workup afforded the pyridino-
phane 7 in 68% yield. Similarly, reaction of 1 with 1,3-
bis(bromomethyl)-4-nitrophenol9 gave the pyridinophane
8 in 58% yield. In order to test the other route, precyclo-
phane 2 was prepared by stirring benzimidazole with 3,5-
bis(bromomethyl) anisole in CH3CN in the presence of
NaOH. In 1H NMR, the precyclophane 2 displayed a singlet
for three protons at d 3.63 for OCH3 and the ±NCH2±
appeared as another singlet at d 5.22 in addition to the
aromatic protons. Off resonance decoupled 13C NMR
showed the ±NCH2± at d 48.5 and the OCH3 at d 55.3
along with other aromatic carbons. Macrocyclization of 2
with 2,6-bis(bromomethyl)pyridine in CH3CN for ®ve days
afforded the pyridinophane 7 in 65% yield (Scheme 1).
Reaction of 2.1 equiv. of benzimidazole with 1 equiv. of
2,6-bis(bromomethyl)pyridine8 in the presence of aq.
NaOH gave the precyclophane 1 in 62% yield. H NMR
In order to test the synthetic utility of the above sequence for
the synthesis of pyridinobenzotriazolophanes, the precyclo-
phane 3 was prepared from 2,6-bis(bromomethyl)pyridine
and benzotriazole in 39% yield. Coupling of the precyclo-
phane 3 with one more equivalent of 2,6-bis(bromomethyl)-
pyridine, 3,5-bis(bromomethyl)anisole and 1,3-bis-
(bromomethyl)-4-nitrophenol gave the pyridinophanes
9±11 in 42, 59 and 52% yields, respectively (Scheme 2).
1
of 1 showed a singletat d 5.44 for ±NCH2± protons, the
pyridine protons appeared as a doublet at d 6.87 integrating
for two protons and a one proton triplet was observed at d
7.51 in addition to the aromatic protons. Proton decoupled
13C NMR of 1 showed the ±NCH2± carbon at d 50.3 in
addition to seven aromatic carbons. Treatment of the pre-
cyclophane 1 with 1 equiv. of 2,6-bis(bromomethyl)-
pyridine in CH3CN under re¯ux for ®ve days afforded the
pyridinophane 6 in 90% yield. 1H NMR of pyridinophane 6
displayed a singletat d 5.85 for ±NCH2± protons and the
imidazole proton (±N±CHvN±) appeared as a singletat d
9.68 in addition to the aromatic protons. The NCH2±
appeared at d 49.1 in 13C NMR in addition to seven aromatic
carbons. Precyclophane 1 was then re¯uxed with 3,5-
bis(bromomethyl)anisole in CH3CN for ®ve days. The
Similarly, pyridinophanes 12±14 were also prepared
from precyclophane 4 and 2,6-bis(bromomethyl)pyridine,
3,5-bis(bromomethyl)anisole and 1,3-bis(bromomethyl)-4-
nitrophenol in 54, 57 and 45% yields, respectively. Pre-
cyclophane 4 was obtained in 37% yield by the reaction
of 2,6-bis(bromomethyl)pyridine with 2.1 equiv. of
imidazole.
The protonated version of cyclophane 12 was obtained by
reaction with CF3COOH in D2O. The diprotonated cyclo-
Keywords: imidazole; benzotriazole.
Corresponding author. Tel.: 191-44-2351265-213; fax: 191-44-
2352494; e-mail: perumalrajakumar@hotmail.com
1
phane salt 15 was identi®ed by H NMR. The imidazole
proton appeared as usual at d 7.68 and 9.46, however, the
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)01226-1

1356
P. Rajakumar, M. Dhanasekaran / Tetrahedron 58 (2002) 1355±1359
Scheme 1.
pyridine protons appeared at d 8.21 as a doubletfor 4H and
d 8.64 for 2H as a triplet, illustrating the deshielding effect
caused by protonation10 (Scheme 3).
on KRATOS PCKompactSEQ V1.2.2 using a-cyano-
cinnamic acid (CCA). Acetonitrile was freshly dried prior
to use. The precyclophanes were puri®ed using neutral
alumina column chromatography.
Finally, receptors 16 and 17 with large cavities were synthe-
sized from 2,6-bis(bromomethyl)pyridine in 33 and 69%
yields, respectively, by the following sequence (Scheme 4).
1.1. General procedure for the synthesis of
precyclophanes
It is worthy of note that pyridinoimidazolophanes 16 and
17 could be receptors for aliphatic amino acids and
dicarboxylic acids. Synthesis of other macrocyclic pyridino-
phanes and investigation of their receptor activities are
under investigation.
To the solution of imidazole/benzimidazole/benztriazole
(20 mmol) in acetonitrile (50 mL), NaOH solution
(10 mL, 25%) was added and stirred for 10 min. The
dibromide (10 mmol) in acetonitrile (10 mL) was added at
once and stirred for two days at room temperature. After the
completion of the reaction, the reaction mixture was evapo-
rated in vacuo, extracted with CHCl3 (4£50 mL), washed
with brine (2£50 mL) and dried (MgSO4), the solvent was
evaporated in vacuo. The crude product was puri®ed by
column chromatography on neutral alumina using
CH3OH/CHCl3 (1:99) for precyclophanes 1, 2, 4, 5 and
EtOAc/hexane (1:4) for precylophane 3 as eluting solvent.
1. Experimental
1
All the melting points are uncorrected. H and 13C NMR
were obtained on Jeol GSX 400 MHz or Bruker DPX
300 MHz instrument with CDCl3 or DMSO-d6 as solvents.
Chemical shifts are expressed in ppm using TMS as internal
standard. Coupling constant (J) values are given in Hz. IR
spectra were recorded on Shimadzu FT-IR-8300 instrument.
The mass spectra were recorded using Jeol (EI, 70 eV), FAB
mass spectra on JEOL SX 102/DA-6000 using m-nitro-
benzyl alcohol (NBA) as matrix and MALDI mass spectra
1.1.1. Precyclophane 1. 62%, Colourless solid, mp 106±
1088C; 1H NMR dH (300 MHz, CDCl3) 5.44 (s, 4H, NCH2),
6.87 (d, 2H, Jˆ7.7 Hz), 7.51 (t, 1H, Jˆ7.7 Hz), 7.80 (s, 2H),
8.00 (s, 2H); 13C NMR dC (75.47 MHz, CDCl3) 50.3, 109.9,
120.4, 120.5, 122.4, 123.3, 138.5, 155.7; m/z (EI, 70 eV)

P. Rajakumar, M. Dhanasekaran / Tetrahedron 58 (2002) 1355±1359
1357
Scheme 2.
339 (M1); Anal. Calcd for C21H17N5: C, 74.32; H, 5.05; N,
20.63; Found: C, 74.20, H, 4.97, N, 20.33.
(EI, 70 eV) 368 (M1); Anal. Calcd for C19H15N7: C, 66.85;
H, 4.43; N, 28.72; Found: C, 66.61; H, 4.28, N, 28.58.
1.1.2. Precyclophane 2. 66%, Colourless solid, mp 179±
1818C; 1H NMR dH (300 MHz, CDCl3) 3.63 (s, 3H,
±OCH3), 5.22 (s, 4H, NCH2), 6.58 (d, 3H, Jˆ6.8 Hz),
7.24 (m, 6H), 7.82 (d, 2H, Jˆ7.5 Hz), 7.89 (s, 2H); 13C
NMR dC (75.47 MHz, CDCl3) 48.5, 55.3, 109.9, 112.4,
117.8, 120.5, 122.4, 123.2, 138.0, 143.1, 143.9, 160.7; m/z
1.1.3. Precyclophane 3. 39%, Colourless solid, mp
119±1218C; H NMR dH (300 MHz, CDCl3) 5.92 (s, 4H,
NCH2), 7.05 (d, 2H, Jˆ7.7 Hz), 7.36 (s, 6H), 7.57 (t, 1H,
Jˆ7.7 Hz), 8.05 (m, 2H); 13C NMR dC (75.47 MHz, CDCl3)
53.4, 109.7, 120.0, 121.4, 123.9, 127.4, 133.0, 138.4, 146.1,
154.8; m/z (EI, 70 eV) 341 (M1); Anal. Calcd for
1
Scheme 3.

1358
P. Rajakumar, M. Dhanasekaran / Tetrahedron 58 (2002) 1355±1359
Scheme 4.
C23H20N4O: C, 74.98; H, 5.47; N, 15.21; Found: C, 75.10,
H, 5.31, N, 14.98.
1.2.1. Cyclophane 6. 90%, Colourless solid, .3008C
1
decomp.; H NMR dH (300 MHz, DMSO-d6) 5.84 (s, 8H),
7.33 (bs, 8H), 7.91 (bs, 4H), 8.11 (bs, 2H), 9.68 (s, 2H); 13C
NMR dC (75.47 MHz, DMSO-d6) 49.1, 112.1, 121.7, 125.3,
129.4, 137.6, 142.0, 151.7; m/z (MALDI-MS, CCA) 444.9
(M122Br); Anal. Calcd for C28H24N6Br2: C, 55.63; H, 3.97;
N, 13.91. Found: C, 55.55; H, 3.77; N, 14.01.
1.1.4. Precyclophane 4. 37%, Colourless solid, mp 59±
618C; 1H NMR dH (300 MHz, CDCl3) 5.21 (s, 4H,
±NCH2), 6.87 (d, 2H, Jˆ7.7 Hz), 6.95 (s, 2H), 7.08 (s,
2H), 7.59 (m, 3H); 13C NMR dC (75.47 MHz, CDCl3)
52.1, 119.3, 120.2, 129.9, 137.5, 138.5, 156.3; m/z (EI,
70 eV) 239 (M1); Anal. Calcd for C13H13N5: C, 65.25; H,
5.48; N, 29.27; Found: C, 65.19; H, 5.32; N, 28.96.
1.2.2. Cyclophane 7. 68%, Colourless solid, 296±2988C
1
decomp.; H NMR dH (300 MHz, DMSO-d6) 3.89 (s, 3H),
5.73 (s, 4H), 5.84 (s, 4H), 7.33±8.13 (m, 14H); 13C NMR dC
(75.47 MHz, DMSO-d6) 49.5, 50.9, 56.0, 111.93, 113.9,
114.2, 115.19, 123.9, 127.1, 127.2, 130.8, 131.2, 137.1,
139.2, 143.1, 153.5, 160.2; m/z (FAB-MS, NBA) 553
1.1.5. Precyclophane 5. 73%, Colourless solid, mp 142±
1458C; 1H NMR dH (400 MHz, CDCl3) 5.17 (s, 4H
±OCH2), 5.27 (s, 4H, ±NCH2), 6.94 (d, 4H, Jˆ8.8 Hz),
7.13 (d, 4H, Jˆ8.8 Hz), 7.23±7.31 (m, 6H), 7.42 (d, 2H,
Jˆ7.8 Hz), 7.72 (t, 1H, Jˆ7.8 Hz), 7.81 (d, 2H, Jˆ6.7 Hz),
8.10 (d, 2H,); 13C NMR dC (100.40 MHz, CDCl3) 48.3,
70.5, 110.0, 115.2, 120.2, 120.3 122.2, 123.0 127.9, 128.6,
133.8, 137.7, 143.0, 143.8, 156.4, 158.2; m/z (EI, 70 eV)
551 (M1); Anal. Calcd for C35H21N5O2: C, 76.20; H, 5.30;
N, 12.70. Found: 76.20; H, 5.19, N, 12.55.
(M12Br),
473
(M122Br);
Anal.
Calcd
for
C30H27N5OBr2: C, 56.87; H, 4.27; N, 11.06. Found: C,
56.65; H, 4.09; N, 10.92.
1.2.3. Cyclophane 8. 58%, pale yellow solid, 260±2628C
decomp.; IR nmax(KBr); 3414; 1H NMR dH (400 MHz,
DMSO-d6) 5.72 (s, 8H), 7.29± 7.64 (m, 4H), 7.80 (d, 2H,
Jˆ8.3 Hz), 7.85 (d, 2H, Jˆ7.8 Hz), 8.04 (t, 1H, Jˆ7.8 Hz),
8.19 (d, 2H, Jˆ8.3 Hz), 8.73 (s, 2H), 9.46 (s, 2H); 13C NMR
dC (100.40 MHz. DMSO-d6) 47.0, 50.4, 113.7, 114.2,
122.9, 123.8, 126.8, 129.5, 130.8, 131.2, 139.0, 143.0,
153.3; m/z (FAB-MS, NBA) 584 (M12Br), 504
(M122Br); Anal. Calcd for C29H24N6O3Br2: C, 52.41; H,
3.62; N, 12.65. Found: C, 52.25; H, 3.55; N, 3.66.
1.2. General procedure for the synthesis of cyclophanes
To the solution of precyclophanes (6 mmol) in dry aceto-
nitrile (400 mL), dibromide (6 mmol) was added in one
portion and re¯uxed for ®ve days. After completion of the
reaction, the cyclophane was obtained by ®ltration of the
reaction mixture. The cyclophane was thoroughly washed
with acetonitrile and dried in vacuo.
1.2.4. Cyclophane 9. 42%, Colourless solid, 257±2598C
decomp.; 1H NMR dH (300 MHz, DMSO-d6) 6.38 (s,

P. Rajakumar, M. Dhanasekaran / Tetrahedron 58 (2002) 1355±1359
1359
8H),7.62 (s, 4H), 7.65 (s, 4H), 7.76 (d, 4H, Jˆ11.9 Hz),
8.07±8.13 (m, 2H).; 13C NMR dC (75.47 MHz, DMSO-d6)
54.7, 113.9, 122.9, 131.5, 134.9, 139.2, 152.6; m/z (FAB-
MS, NBA) 526 (M12Br), 446 (M122Br); Anal. Calcd for
C26H22N8Br2: C, 51.49; H, 3.63; N, 18.48. Found: C, 51.11;
H, 3.55; N, 18.51.
1.2.10. Cyclophane 15. 1H NMR dH (200 MHz, D2O) 6.07
(s, 8H), 7.68 (s, 4H), 8.21 (d, 4H, Jˆ7.8 Hz), 8.64 (t, 2H,
Jˆ7.8 Hz), 9.46 (s, 2H); 13C NMR dC 52.4, 122.4, 123.4,
138.6, 151.9, 159.6; Anal. Calcd for C24H22Br2F6N6O4: C,
39.36; H, 3.03; N, 11.48; Found: C, 38.99, H, 2.97, N, 11.23.
1.2.11. Cyclophane 16. 33%, Colourless solid, 223±2258C
decomp.; IR nmax(KBr); 1712, 3415; 1H NMR dH
(400 MHz, DMSO-d6) 5.1 (s, 4H), 5.77 (s, 4H), 5.88 (s,
4H), 7.02±8.33 (m, 30H), 10.30 (s, 2H); 13C NMR dC
(100.40 MHz. DMSO-d6) 49.3, 49.5, 70.3, 114.0, 114.2,
115.2, 121.2, 126.4, 127.0, 127.6, 129.0, 129.2, 130.1,
130.9, 131.1, 133.7, 138.0, 140.3, 142.5, 156.0, 158.4,
169.8; m/z (MALDI-MS, CCA) 852.7 (M122Br); Anal.
Calcd for C56H45N5O4Br2: C, 66.47; H, 4.45; N, 6.92;
Found: C, 66.09; H, 4.35; N, 7.09.
1.2.5. Cyclophane 10. 59%, Colourless solid, 249±2518C
decomp.; H NMR dH (300 MHz, DMSO-d6) 3.87 (s, 3H),
1
6.24 (s, 4H), 6.35 (s, 4H), 7.41 (s, 2H), 7.75 (s, 4H), 7.92 (d,
2H, Jˆ7.58 Hz), 8.03±8.13 (m, 6H); 13C NMR dC
(75.47 MHz, DMSO-d6) 53.8, 54.92, 55.67, 113.7, 114.0,
114.9, 115.9, 124.1, 131.4, 131.53, 133.9, 134.7, 135.2,
139.2, 152.0, 160.0; m/z (MALDI-MS, CCA) 475.9
(M122Br); Anal. Calcd for C28H25N7OBr2: C, 52.91; H,
3.94; N, 15.43; Found: C, 52.66; H, 3.81; N, 15.62.
1.2.12. Cyclophane 17. 69%, Colourless solid, 208±2108C
decomp.; H NMR dH (200 MHz, DMSO-d6) 5.03 (s, 4H),
1.2.6. Cyclophane 11. 52%, pale yellow solid, 202±2048C
decomp.; IR nmax(KBr); 3417; 1H NMR dH (400 MHz,
DMSO-d6) 6.25 (s, 4H), 6.32 (s, 4H), 7.92±8.41 (m 11H)
8.86 (s, 2H) 13C NMR dC (100.40 MHz, DMSO-d6) 51.9,
52.7, 113.8, 114.0, 114.9, 121.7, 124.6, 129.6, 130.2, 131.2,
131.5, 134.3, 134.5, 152.1, 152.2; m/z (FAB-MS, NBA) 586
(M12Br), 506 (M122Br); Anal. Calcd for C27H22N8O3Br2:
C, 48.65; H, 3.30; N, 16.82; Found: C, 48.55; H, 3.25; N,
16.99.
1
5.71 (s, 4H), 5.81 (s, 4H), 7.38±7.89 (m, 22H), 10.20 (s,
2H); 13C NMR dC (50.33 MHz. DMSO-d6) 48.24, 49.53,
68.46, 111.98, 112.29, 114.26, 119.50, 121.31, 123.98,
125.14, 128.33, 129.22, 129.68, 141.14, 151.19, 154.19,
156.82; m/z (FAB, NBA) 736 (M12Br), 656 (M122Br);
Anal. Calcd for C42H36N6O2Br2: C, 61.76; H, 4.41; N, 10.29;
Found: C, 61.65; H, 4.32; N, 10.45.
1.2.7. Cyclophane 12. 54%, Colourless solid, 300±3028C
decomp.; H NMR dH (400 MHz, DMSO-d6) 5.63 (s, 8H),
Acknowledgements
1
7.59 (d, 4H, Jˆ7.8 Hz), 7.64 (d, 4H, Jˆ1.5 Hz), 7.97 (t, 2H,
Jˆ7.8 Hz), 9.21 (s, 2H); 13C NMR dC (100.40 MHz.
DMSO-d6) 52.3, 122.5, 123.3, 137.0, 138.5, 153.3; m/z
(FAB-MS, NBA) 424 (M12Br), 344 (M122Br); Anal.
Calcd for C20H20N6Br2: C, 47.62; H, 3.97; N, 16.67;
Found: C, 47.51; H, 3.85; N, 16.88.
M. D. thanks DST for ®nancial assistance and Dr P.
Shanmugam, RRL, Trivandrum for spectral data.
References
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1.2.8. Cyclophane 13. 57%, Colourless solid, 284±2868C
decomp.; H NMR dH (400 MHz, DMSO-d6) 3.86 (s, 3H),
1
2. Hellier, P. C.; Bradshaw, J. S.; Young, J. J.; Zhang, X. X.;
Izatt, R. M. J. Org. Chem. 1996, 61, 7270.
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2H, Jˆ7.8 Hz), 7.79 (s, 2H), 7.83 (s, 2H), 8.07 (t, 3H,
Jˆ7.8 Hz), 9.32 (s, 2H); 13C NMR dC (100.40 MHz.
DMSO-d6) 51.4, 52.7, 55.6, 113.6, 115.5, 123.0, 123.5,
136.7, 137.9, 138.7, 153.6, 159.6; m/z (FAB-MS, NBA)
453 (M12Br), 373 (M122Br); Anal. Calcd for
C22H23N5OBr2: C, 49.53; H, 4.32; N, 13.33; Found: C,
49.13; H, 4.11; N, 13.55.
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1.2.9. Cyclophane 14. 45%, pale yellow solid, 228±2308C
decomp.; IR nmax(KBr); 3433; 1H NMR dH (400 MHz,
DMSO-d6) 5.49 (s, 4H), 5.62 (s, 4H), 7.64 (d, 2H,
Jˆ7.8 Hz), 7.70 (s, 2H), 7.79 (s, 2H), 7.96 (t, 1H,
Jˆ7.8 Hz), 8.36 (s, 2H), 8.87 (s, 2H); 13C NMR dC
(100.40 MHz. DMSO-d6) 48.8, 52.6, 113.7, 122.5, 123.2
123.5, 123.8, 129.0, 136.3, 138.8, 153.8, 217.7; m/z (FAB-
MS, NBA) 476 (M12Br), 396 (M122Br); Anal. Calcd for
C21H20N6O3Br2: C, 44.68; H, 3.55; N, 14.89; Found: C,
44.45; H, 3.33; N, 14.99.
È
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