Synthesis of chiral cyclophanes based on meta-terphenyl and pyridyl blocks

Article abstract of DOI:10.1016/S0040-4020(01)00966-8

Coupling of m-terphenyl dibromide with binol afforded the corresponding optically active cyclophane. Chiral cyclophanes were also obtained by the coupling of p-nitrophenol or 4,4″-bis(bromomethyl)-1,3-dibenzylbenzene with binol.

Full text of DOI:10.1016/S0040-4020(01)00966-8

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 9749±9754
Synthesis of chiral cyclophanes based on meta-terphenyl
and pyridyl blocks
Perumal Rajakumarp and Muthialu Srisailas
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai Tamil Nadu 600 025, India
Received 22 May 2001; accepted 5 October 2001
AbstractÐCoupling of m-terphenyl dibromide with binol afforded the corresponding optically active cyclophane. Chiral cyclophanes were
also obtained by the coupling of p-nitrophenol or 4,400-bis(bromomethyl)-1,3-dibenzylbenzene with binol. q 2001 Elsevier Science Ltd. All
rights reserved.
Extensive studies on the use of chiral binaphthol based
crown ethers as hosts for molecular recognition have been
carried out as early as 1970.1 Though the ®rst binaphthyl
crown ether was reported in 1973,2 the m-terphenyl and
pyridyl based cyclophanes are not known so far. Cyclo-
phanes based on m-terphenyl building blocks possess a
large non-collapsible rigid cavity.3 Hence, bisbinaphthyl
cyclophanes based on m-terphenyls would have a macro-
cyclic cavity and they could ®nd application in chiral
resolution and asymmetric induction. Further, when m-
terphenyl and pyridyl units are employed, the binol cyclo-
phanes could function as excellent receptors for chiral
molecules. Herein, we report the preparation of such cyclo-
phanes by a simple route and by using conventional
reagents.
obtained in 32% yield by the reaction of the bisalkylated
product 2b with one equivalent of the m-terphenyl ester
dibromide 1a. Similarly, the tetrabromide ethylene glycol
ester 1c on reaction with 2 equiv. of binaphthol gave the
intra-annularly linked bisbinaphthyl cycolphane 3d in
40% yield. All the chiral cyclophanes displayed two
doublets with the same coupling constant for the OCH2
protons attached with the binol unit. The reactions are
summarised in Scheme 1 and the optical rotations are
given in Table 1.
In order to explore the synthesis of cyclophanes based on
binol unit, the chiral cyclophane 5a and 5b were derived
from m-xylenyl dibromide and p-nitrophenol, respectively
as given in Scheme 2. The m-xylenyl dibromide was
bisalkylated using methyl p-hydroxybenzoate to give
diester, which was converted into the corresponding diol
using LAH. The dibromide 4a,5 obtained by treating the
diol with PBr3 in CH2Cl2, was coupled with 1 equiv. of
the binol in presence of K2CO3 in acetone for 120 h to
give the cyclophane 5a in 45% yield. Same strategy was
followed for the synthesis of dibromide 4b from 1,3-bis-
(bromomethyl),2-acetoxy,5-nitrobenzene,6 with a slight
modi®cation. Bisalkylation has been carried out using
p-hydroxybenzaldehyde and the resulting dialdehyde was
reduced with NaBH4 (Table 2).
Hart reaction4 affords a simple route for the synthesis of
various 20-substituted m-terphenyls in good yield. In order
to test whether m-terphenyl dibromides could be used
for coupling with binapthol, reaction of 2 equiv. of
(S)-binaphthol with 1 equiv. of m-terphenyl dibromide 1a
was carried out in acetone in the acetone in the presence of
K2CO3 at room temperature for 48 h. The bisalkylated
product 2a was obtained in 65% yield after usual work up.
1H NMR of 2a showed OCH2 protons at d 5.12 as singlet in
addition to the aromatic protons and the IR showed the OH
stretching at 3340 cm21. Further coupling of one more
equivalent of m-terphenyl dibromide under high dilution
conditions afforded the cyclophane 3a in 40% yield. By a
similar sequence the bisalkylated product 2b was obtained
in 57% yield from the m-terphenyl ester dibromide 1b
and binol. The bisalkylated product 2b has been converted
into cyclophane 3b by its further reaction with one more
equivalent of 1b. Unsymmetrical cyclophane 3c was
Binol based optically active pyridinophane 7 is derived
from 2,6-bisbromomethyl pyridine as shown in Scheme 3.
The dibromide 6 obtained by the reduction of respective
dialdehyde was treated with 1 equiv. of the binol in presence
of K2CO3 in acetone for 120 h to furnish the pyridinophane
8 in 42% yield as shown in Scheme 3.
Another optically active novel binol cyclophane 9 was
obtained from dibromide 8. The dibromide 8, which has
not been so far used for the synthesis of cyclophanes, was
prepared from isophthaloyl chloride and toluene in presence
Keywords: chiral cyclophanes; meta-terphenyl; pyridyl.
Corresponding author. Tel.: 191-44-2351265, ext. 213; fax: 191-44-
2352494; e-mail: perumalrajakumar@hotmail.com
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00966-8

9750
P. Rajakumar, M. Srisailas / Tetrahedron 57 ,2001) 9749±9754
Scheme 1.
Table 1.
Compound
Yield (%)
Mp (8C
) a]D25 ([c 0.1 CHCl3)
Table 2.
3a
3b
3c
3d
40
32
28
40
210
208
206
215
2140.0
Compound
X
Y
Yield (%)
Mp (8C
) a]D[25 (CHCl3)
2152.4
2146.7
2171.3
5a
5b
H
NO2
H
OAc
45
42
208
235
2212.5 (c 0.12)
2210.0 (c 0.10)

P. Rajakumar, M. Srisailas / Tetrahedron 57 ,2001) 9749±9754
9751
Scheme 2.
Scheme 3.

9752
P. Rajakumar, M. Srisailas / Tetrahedron 57 ,2001) 9749±9754
Scheme 4.
of AlCl3 to give diketone, followed by NBS bromination in
CCl4 in presence of benzoyl peroxide. Coupling of the
dibromide 8 with the binol in presence of K2CO3 in acetone
for 120 h at room temperature afforded the cyclophane 9 as
shown in Scheme 4.
residue, which was chromatographed over SiO2 using
CHCl3 afforded the corresponding precyclophane.
25
1.2.1. Precyclophane 2a. Yield 65%; mp 1728C ; a[ ]D
ˆ
214.68, (c 2.3, CHCl3); IR (cm21) 3340 (b, OH); 1H NMR
d 5.13 (s, 4H), 6.82 (bs, 2H, exchangeable with D2O), 7.08
(m, 6H), 7.25±7.54 (m, 22H), 7.86±8.02 (m, 8H), 13CNMR
71.4, 115.8, 120.6, 122.6, 123.4, 124.9, 125.2, 125.7, 125.9,
126.4, 127.2, 127.4, 128.1, 129.5, 130.8, 134.2, 136.6,
139.9, 141.2; Anal. Calcd for C60H42O4: C, 87.14, H, 5.12;
Found: C, 87.02; H, 5.01.
Reduction of the cyclophane 9 could result in the formation
of optically active diol. Synthesis of other binol based chiral
cyclophanes and other applications are under investigation.
1. Experimental
1.1. General
25
1.2.2. Precyclophane 2b. Yield 57%, mp 1658C ; a[ ]D
ˆ
217.2, (c 2, CHCl3); IR (cm21) 3340 (b, OH), 1722 (CO);
1H NMR (CDCl3) d 3.46 (s, 3H), 5.12 (s, 4H), 6.50 (bs, 2H,
exchangeable with D2O); 7.12±7.18 (m, 6H), 7.28±7.54 (m,
21 H); 7.88±8.04 (m, 8H); 13CNMR d 30.4, 71.4, 115.9,
120.2, 123.7, 125.5, 125.7, 126.6, 126.8, 127.1, 127.9,
128.8, 129.6, 129.8, 134.2, 136.6, 139.9, 142.4, 138.4,
143.2; Anal. Calcd for C62H44O6: C, 84.14; H 5.01;
Found: C, 84.07, H, 4.89.
All the melting points are uncorrected. The IR spectra were
recorded using Shimadzu FT-IR 8300 instrument. The H
1
and 13C NMR spectra of all compounds in CDCl3 were
recorded using Jeol GSX 400 (400 MHz) NMR spectro-
meter. The mass spectra were recorded using Jeol (EI,
70 eV and FAB-MS). The rotations were recorded using
Autopol II (Automatic Polarimeter) at 258C. The column
chromatography was performed using silica gel (100±200
mesh).
1.3. General procedure for the preparation of
cyclophanes
1.2. General procedure for the preparation of
precyclophanes
Precyclophane (0.5 mmol) and dibromide (0.5 mmol) were
stirred with K2CO3 in acetone at room temperature for 120 h
after which the reaction mixture was acidi®ed and evapo-
rated to dryness. The residue obtained was extracted with
CH2Cl2 (3£100 mL), washed with 10% NaOH (2£50 mL);
with water (3£100 mL) and dried (MgSO4). Evaporation of
the organic layer gave a residue which was chromato-
graphed over SiO2 using CHCl3/hexane (1:1) afforded the
corresponding cyclophane.
Dibromide (1 mmol) and (S)-binaphthol (2 mmol) were
stirred with K2CO3 in acetone at room temperature for
48 h after which the reaction mixture was acidi®ed and
evaporated to dryness. The residue obtained was extracted
with CH2Cl2 (3£100 mL), washed with water (3£100 mL)
and dried (MgSO4). Evaporation of the organic layer gave a

P. Rajakumar, M. Srisailas / Tetrahedron 57 ,2001) 9749±9754
9753
25
1.3.1. Cyclophane 3a. Yield 40%, mp 2108C ; a[ ]D
ˆ
C44H33NO8: C, 75.10; H, 4.73, N, 1.99; Found: C, 74.97;
H, 54.69, N, 1.91.
2140.0, (c 0.1, CHCl3); IR (cm21), 2964, 1590, 1263,
1118, 806, 748; 1H NMR (CDCl3) d 5.03 (d, 4H, Jˆ
12.7 Hz), 5.19 (d, 4H, Jˆ12.7 Hz), 6.97 (d, 4H, Jˆ8 Hz),
7.03 (d, 4H, Jˆ8 Hz), 7.06±7.35 (m, 30H), 7.47 (d, 2H,
Jˆ9.3 Hz), 7.89 (d, 4H, Jˆ8.3 Hz), 7.97 (d, 4H, Jˆ
8.8 Hz); 13CNMR 70.2, 115.5, 120.5, 123.5, 124.8, 125.4,
125.5, 126.4, 126.7, 127.2, 127.9, 128.6, 129.2, 129.3,
132.3, 134.3, 136.3, 139.8, 140.5, 148.3, 153.8; m/z (FAB-
MS) 1080 (M1); Anal. Calcd for C80H56O4: C, 88.86; H,
5.22; Found: C, 88.81, H, 5.12.
1.3.7. Cyclophane 7. Dibromide 6 (0.5 mmol) and
(S)-binaphthol (0.5 mmol); Yield 42%, mp 2138C;
25
1
[a]D ˆ275.47, (c 0.31, CHCl3); H NMR (CDCl3) 4.83
(d, 2H, Jˆ12.7 Hz), 4.96 (d, 2H, Jˆ12.7 Hz), 5.18 (d, 2H,
Jˆ14.2 Hz), 5.21 (d, 2H, Jˆ14.2 Hz), 6.57 (d, 4H, Jˆ
8.8 Hz), 6.82 (d, 4H, Jˆ8.8 Hz), 7.14±7.36 (m, 10H),
7.57 (t, 1H, Jˆ7.8 Hz), 7.82 (t, 4H, Jˆ6.8 Hz); 13CNMR
70.7, 70.9, 115.2, 116.6, 120.8, 121.2, 123.6, 125.3, 126.2,
127.8, 128.0, 128.9, 129.4, 129.6, 134.1, 137.7, 153.9,
156.9, 157.1; m/z (EI, 70 eV) 601 (M1); Anal. Calcd for
C41H31NO4: C, 81.84; H, 5.19; N, 2.33; Found: C, 81.81,
H, 5.15, N, 2.28.
25
1.3.2. Cyclophane 3b. Yield 32%, mp 2088C ; a[ ]D
ˆ
2152.4, (c 0.1, CHCl3); IR (cm21) 1722 (CO); H NMR
(CDCl3) 3.96 (s, 6H), 5.06 (d, 8H, Jˆ12.7 Hz), 5.16 (d,
8H, Jˆ12.7 Hz), 6.96±7.36 (m, 30H), 7.82±8.00 (m, 8H);
13CNMR 29.7, 70.6, 115.8, 120.6, 123.7, 125.5, 125.7,
126.4, 126.8, 127.0, 127.9, 128.9, 129.3, 129.4, 134.2,
136.6, 139.9, 140.9, 165.2; m/z (FAB-MS) 1096 (M1);
Anal. Calcd for C84H60O8: C, 84.26; H, 5.05; Found: C,
84.11, H, 4.94.
1
1.3.8. Cyclophane 9. Dibromide
(S)-binaphthol (1 mmol); yield 41%, mp 2138C ; a[ ]D
8 (1 mmol) and
25
ˆ
247.7, (c 0.5, CHCl3); IR (cm21)1660 (CO); H NMR
4.85 (d, 2H, Jˆ12.7 Hz), 5.19 (d, 2H, Jˆ12.7 Hz), 7.14
(d, 4H, Jˆ7.8 Hz), 7.24 (d, 2H, Jˆ8.3 Hz), 7.33 (s, 2H),
7.35 (s, 2H), 7.38 (d, 2H, Jˆ8.3 Hz), 7.55 (d, 4H,
J7.8 Hz), 7.63 (s, 1H), 7.71 (t, 1H, Jˆ7.8 Hz), 7.88 (t, 4H,
Jˆ9.3 Hz), 8.25 (d, 2H, Jˆ7.8 Hz); 13CNMR 70.7, 115.6,
120.5,123.8, 125.3, 126.5, 127.3, 127.9, 129.3, 129.4, 129.7,
132.9, 134.2, 135.8, 136.4, 136.8, 142.2, 153.8, 195.1; m/z
(EI, 70 eV) 596 (M1); Anal. Calcd for C42H28O4: C, 84.54;
H, 4.73; Found: C, 84.51, H, 4.68.
1
25
1.3.3. Cyclophane 3c. Yield 28%, mp 2068C ; a[ ]D
ˆ
2146.7, (c 0.1, CHCl3); IR (cm21) 1724 (CO); H NMR
3.84 (s, 3H), 5.08 (d, 8H, Jˆ12.7 Hz), 5.17 (d, 8H,
Jˆ12.7 Hz), 6.96±7.34 (m, 29H), 7.86±8.14 (m, 8H); 13C
NMR 29.5, 70.4, 115.8, 121.6, 123.7, 124.8, 124.9, 125.1,
125.3, 125.5, 125.9,126.1, 126.2, 127.0, 127.9, 128.7, 129.5,
129.4, 134.4, 136.8, 139.4, 140.1, 167.5; Anal. Calcd for
C82H58O6:C, 86.44, 5.13; Found: C, 86.31, H, 5.09.
1
1.3.9. Synthesis of dibromide 8. Isophthaloyl chloride
(2.03 g, 10 mmol) in toluene (100 mL) was added
anhydrous AlCl3 (13.34 g, 0.1 m) at 08C) in portions over
a period of 30 min after which the reaction mixture was
stirred at room temperature for 8 h. The reaction mixture
was then acidi®ed with 4N HCl and extracted with CH2Cl2,
washed with water, dried (MgSO4). Evaporation of the
solvent afforded the diketone in 67% yield. The diketone
(3.144 g, 10 mmol) and NBS (3.916 g, 22 mmol was
re¯uxed in CCl4 with benzoyl peroxide for 24 h, after
which the reaction mixture was ®ltered and evaporated to
dryness. The residue obtained was puri®ed by column
chromatography over SiO2 using CHCl3/hexane (1:1) to
furnish the dibromide 8. Yield 75%, mp 1768C; IR 1660
25
1.3.4. Cyclophane 3d. Yield 40%, mp 2158C ; a[ ]D
ˆ
1
2171.3, (c 0.1, CHCl3); IR 1722 (CO); H NMR 3.97 (s,
4H), 5.06 (d, 8H, Jˆ12.7 Hz), 5.18 (d, 8H, Jˆ12.7 Hz),
7.02±7.42 (m, 30H), 7.82±8.00 (m, 8H); 13CNMR
31.3, 71.6, 115.9, 121.6, 123.4, 124.5, 125.2, 125.4,
125.8, 126.4, 127.5, 128.9, 129.3, 129.4, 134.8, 137.6,
139.9, 141.5, 168.8; m/z (FAB-MS) 1194 (M1); Anal.
Calcd for C84H58O8: C, 84.40; H, 4.89; Found: C, 84.31,
H, 4.75.
1.3.5. Cyclophane 5a. Dibromide 4a (0.5 mmol) and
(S)-binaphthol (0.5 mmol); Yield 38%, mp 2088C;
1
25
1
(CO); H NMR 4.56 (s, 4H), 6.96 and 7.21 (d, 8H, Jˆ
[a]D ˆ2212.5, (c 0.12, CHCl3); H NMR (CDCl3) 4.84
(d, 2H, Jˆ12.7 Hz), 4.97 (d, 2H, Jˆ12.7 Hz), 5.05 (d, 2H,
Jˆ14.7 Hz), 5.12 (d, 4H, Jˆ14.7 Hz), 6.42 (d, 4H, Jˆ
8.8 Hz), 6.75 (d, 4H, Jˆ8.8 Hz), 7.16±7.36 (m, 12H),
7.82±7.85 (m, 4H); 13CNMR 69.5, 70.7, 115.4, 116.4,
120.8, 123.6, 125.3, 125.5, 125.7, 126.3, 127.8, 127.9,
128.9, 129.0, 129.4, 129.6, 134.1, 137.8, 153.9, 157.0; m/z
(EI, 70 eV) 600 (M1); Anal. Calcd for C42H32O4: C, 83.98;
H, 5.37; Found: C, 83.91, H, 5.25.
8.8 Hz), 7.14 (s, 1H), 7.34 (t, 1H, Jˆ4 Hz), 7.56 (d, 2H,
Jˆ4 Hz); Anal. Calcd for C22H16Br2O2: C, 55.96, H, 3.42;
Found: C, 55.72; H, 3.30.
Acknowledgements
M. S. thanks CSIR, New Delhi for ®nancial assistance. The
authors thank RSIC, IIT Madras for NMR spectra and UGC
SAP for ®nancial assistance.
1.3.6. Cyclophane 5b. Dibromide 4b (0.5 mmol) and
(S)-binaphthol (0.5 mmol); Yield 29%, mp 2088C;
25
1
[a]D ˆ2210, (c 0.1, CHCl3); H NMR (CDCl3) 1.77 (s,
3H); 4.85 (d, 2H, Jˆ12.7 Hz), 4.99 (d, 2H, Jˆ12.7 Hz), 5.12
(d, 2H, Jˆ14.7 Hz), 5.21 (d, 2H, Jˆ14.7 Hz), 6.46 (d, 4H,
Jˆ8.8 Hz), 6.82 (d, 4H, Jˆ8.8 Hz), 7.20±7.32 (m, 12H),
7.93 (s, 2H); 13CNMR 30.5, 69.8, 70.9, 115.7, 116.2,
120.8, 123.6, 125.5, 125.6, 126.3, 126.7, 127.8, 127.9,
128.9, 129.4, 129.6, 129.9, 134.1, 136.8, 153.0, 157.0,
170.4; m/z (EI, 70 eV) 703 (M1); Anal. Calcd for
References
1. (a) Pu, L. Chem. Rev. 1998, 98, 2405. (b) Cram, D. J.; Srgah,
D. Y. J. Am. Chem. Soc. 1985, 107, 830. (c) Cram, D. J. Science
1988, 240, 760. (d) Cram, D. J. Nature 1992, 356, 29.
2. Kyba, E. B.; Koga, K.; Sausa, L. L.; Siegel, M. G.; Cram, D. J.
J. Am. Chem. Soc. 1973, 95, 2692.
3. (a) Kannan, A.; Rajakumar, P.; Kabaleswaran, V.; Rajan, S. S.

9754
P. Rajakumar, M. Srisailas / Tetrahedron 57 ,2001) 9749±9754
J. Org. Chem. 1996, 61, 5090. (b). Rajakumar, P.; Srisailas, M.
Tetrahedron Lett. 1997, 38, 5323.
4. Jen, C.; Du, F.; Hart, H.; Ng, K. K. D. J. Org. Chem. 1986, 51,
5. Rajakumar, P.; Srisailas, M.; Dhanasekaran, M. Synth.
Commun. 2001, 31, 3517.
6. Kumar, S.; Hundal, G.; Paul, D.; Hundal, M. S.; Singh, H.
J. Org. Chem. 1999, 64, 7717.
3162.