Photochemical synthesis of cyclophanes containing tethered benzofuran rings

Full text of DOI:10.1021/jo0103165

6800
J . Org. Chem. 2001, 66, 6800-6802
of 1,3,6,8-tetrahydroxyanthraquinone4 or the 3-OH posi-
P h otoch em ica l Syn th esis of Cyclop h a n es
tion of 1,3-dihydroxyacridone5 was selectively alkylated.
It is well-known that o-alkoxybenzophenones photo-
cyclize readily to benzofuranols via intramolecular δ-hy-
drogen abstraction.6,7 The photocyclization of two o-alkox-
ybenzophenone moieties of 7a -f followed by dehydration
produced a novel type of cyclophane containing two
benzo[b]furan rings, 1a -f. A 1 mM benzene8 solution of
7a -f was irradiated under nitrogen with a 350 nm
mercury lamp using a RPR-100 photochemical reactor
in a Pyrex glass vessel. After 6-7 h of irradiation, the
reaction mixture showed virtually no starting material
remaining. Because so many stereoisomers are possible
for the dihydrobenzofuranol derivatives 8a -f, a dehydra-
tion reaction was carried out, without attempting the
isolation and separation of the intermediates, by treating
the concentrated reaction mixture with a few drops of 1
M HCl in acetone or DMF. Silica gel column chromatog-
raphy afforded the desired cyclophanes with 20-58%
yields. The results are summarized in Table 1. A lower
concentration of 7a in the photocyclization reaction gave
a better yield of 1a ; the yields in 16 mM, 10 mM, and 1
mM benzene solution were 21%,3 25%, and 50%, respec-
tively.
Con ta in in g Teth er ed Ben zofu r a n Rin gs
Kwanghee Koh Park,*,† In Kyu Han,† and
J oon Woo Park‡
Department of Chemistry, Chungnam National University,
Taejon 305-764, South Korea, and Department of Chemistry,
Ewha Womans University, Seoul 120-750, South Korea
khkoh@cnu.ac.kr
Received March 23, 2001
The design and synthesis of macrocyclic compounds
attract current interest in view of supramolecular chem-
istry.1 In particular, cyclophanes, macrocycles containing
aromatic groups, represent the central class of synthetic
receptors in molecular recognition because of the hydro-
phobicity and π-stacking interactions of their aromatic
groups.2 Recently, we prepared a novel class of cyclo-
phane containing two benzo[b]furan rings, 1a , based
upon the photocyclization reaction via intramolecular
δ-hydrogen abstraction.3 X-ray analysis of 1a has shown
that it has a rectangular cavity,3 rendering this cyclo-
phane as an attractive candidate for a synthetic receptor.
Thus, efficient preparation of this novel type of cyclo-
phane with various tethering groups and functionalities
would be interesting not only because it widens a pool of
artificial receptors but also because it broadens photo-
chemical synthetic applications. Here, we report the facile
synthetic procedure for the cyclophanes containing two
benzo[b]furan rings connected by various tethering groups,
1a -f (Scheme 1).
Reaction of 2,4-dihydroxybenzophenone, 2, with a 0.60
molar ratio of R,ω-dihaloalkane (X-R-X) in acetone at
room temperature in the presence of potassium carbonate
afforded the products 3-6 with ca. 80% yield, which
indicates that the alkylation occurs exclusively at the
p-hydroxyl group of 2. Further reaction of R,ω-bis(4-
benzoyl-3-hydroxyphenoxy)alkanes 3-6 with a slight
molar excess of R,ω-dihaloalkane (X-R′-X) in acetone
at reflux or in DMF at 80-90 °C in the presence of
potassium carbonate gave the macrocycles 7a -f with 30-
40% yield. The differential reactivity between the two
hydroxyl groups in 2,4-dihydroxybenzophenone, 2, seems
to arise from less reactivity of the o-hydroxyl group
because of its hydrogen bonding to the carbonyl, which
enables us to introduce a desired tethering group selec-
tively at the ortho or para position of 2. Similar selective
alkylation of the non-hydrogen-bonded phenolic hydroxyl
groups has been reported;4,5 the 3-OH and 6-OH positions
The structure of the cyclophanes 1a -f was character-
ized by 1H and 13C NMR spectrometry and elemental
1
analysis. The number of H and 13C NMR peaks con-
firmed the symmetrical nature of the compounds 1a -f.
The numbers of the peaks observed in their 13C NMR
spectra are included in Table 1, and they exactly match
with the expected numbers based on 2-fold symmetry of
the compounds except for 1e having one less peak
because of overlapping. The structure of 1a was further
determined by single-crystal X-ray analysis;3 the cyclo-
phane has 2-fold symmetry along the b-axis, the dihedral
angle between a benzofuran ring and the benzene ring
of p-xylyl group is 85.9°, and the two benzofuran rings
are almost parallel to each other with a dihedral angle
of 171.8°, making the molecule form a rectangular cavity.
In summary, we have developed a general facile route
for a novel type of cyclophane, 1a -f, having two benzo-
[b]furan rings connected through various tethering groups
by photocyclization of the macrocycles 7a -f followed by
a dehydration reaction. Macrocycles 7a -f were prepared
by utilizing differential reactivity between two hydroxyl
groups in 2,4-dihydroxybenzophenone; the first alkylation
occurs selectively at the p-hydroxyl group at room tem-
perature, and the second alkylation proceeds at the
o-hydroxyl group at higher temperature.
Exp er im en ta l Section
All reagents were purchased from Aldrich Chemical Co. and
* To whom correspondence should be addressed. Phone: 82-42-821-
5479. Fax: 82-42-823-1360.
1
used as received. Melting points are uncorrected. H NMR and
† Chungnam National University.
13C NMR spectra were obtained at 200/50 or 400/100 MHz using
tetramethylsilane as an internal standard. High-field NMR
‡ Ewha Womans University.
(1) Breitenbach, J .; Boosfeld, J .; Vo¨gtle, F. In Comprehensive Su-
pramolecular Chemistry; Vo¨gtle, F., Ed.; Elsevier Science: New York,
1996; Vol. 2, pp 29-67.
(2) Vo¨gtle, F. Cyclophane Chemistry; Wiley: Chichester, U.K., 1993.
(3) Park, K. K.; Seo, H.; Kim, J .-G.; Suh, I.-H., Tetrahedron Lett.
2000, 41, 1393.
(6) Wagner, P. J . Acc. Chem. Res. 1989, 22, 83.
(7) (a) Lappin, G. R.; Zannucci, J . S. J . Org. Chem. 1971, 36, 1808.
(b) Sumathi, T.; Balasubramanian, K. K. Tetrahedron Lett. 1992, 33,
2213. (c) Abdul-Aziz, M.; Auping, J . V.; Meador, M. A. J . Org. Chem.
1995, 60, 1303. (d) Sharshira, E. M.; Okamura, M.; Hasegawa, E.;
Horaguchi, T. J . Heterocycl. Chem. 1997, 34, 861.
(4) O′Malley, G. J .; Murphy, R. A., J r.; Cava, M. P. J . Org. Chem.
1985, 50, 5533.
(5) J olivet, C.; Rivalle, C.; Bisagni, E. J . Chem. Soc., Perkin Trans.
1 1995, 511.
(8) Benzene is a toxic solvent and should be handled with appropri-
ate care. Using toluene instead of benzene lowered the yields.
10.1021/jo0103165 CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/07/2001

Notes
J . Org. Chem., Vol. 66, No. 20, 2001 6801
Sch em e 1
Ta ble 1. Syn th esis of Cyclop h a n es 1a -f by P h otoir r a d ia tion a of 7a -f F ollow ed by Deh yd r a tion b
a
b
A 1 mM benzene solution of 7 was photoirradiated. Acetone (entries 1-5) or DMF (entry 6) was used as a solvent for dehydration.
c They exactly match with the expected numbers based on 2-fold symmetry of 1 except for 1e having one less peak because of overlapping.
The yields obtained from 16 mM (ref 3) and 10 mM benzene solution are 16% and 25%, respectively. e Reference 3.
d
measurements and elemental analyses were performed at the
Central Research Facilities of Chungnam National University.
Gen er a l P r oced u r e for th e Syn th esis of r,ω-Bis(4-ben -
zoyl-3-h yd r oxyp h en oxy)a lk a n es, 3-6. The procedure de-
scribed for 1,4-bis(4-benzoyl-3-hydroxyphenoxymethyl)benzene3
was followed with slight modification. An acetone solution (30
mL) of the corresponding R,ω-dihaloakane (5.60 mmol; R,R′-
dibromo-p-xylene, R,R′-dibromo-m-xylene, 1,6-diiodohexane, or
2,6-bis(bromomethyl)pyridine) was added slowly to a mixture
of 2,4-dihydroxybenzophenone (2.00 g, 9.34 mmol) and potassium
carbonate (3.87 g, 28.0 mmol) in 50 mL of acetone, and the
reaction mixture was stirred at room temperature for 25-70 h.
After the reaction was complete, distilled water (200 mL) was
added to dissolve the potassium carbonate. The remaining
precipitate was filtered and washed with acetone to afford the
corresponding R,ω-bis(4-benzoyl-3-hydroxyphenoxy)alkanes.
1,4-Bis(4-b en zoyl-3-h yd r oxyp h en oxym et h yl)b en zen e,
3: yield, 87%; mp 175-176 °C (lit.3 mp 175-176 °C).
(s, 4H, -OCH2-C6H4-CH2O-), 6.55-6.7 (m, 4H, Ar-H ortho
or para to -OH), 7.4-7.7 (m, 16H, Ar-H), 11.99 (br s, 2H,
Ar-OH).
1,6-Bis(4-ben zoyl-3-h yd r oxyp h en oxy)h exa n e, 5: yield,
79%; mp 148-149 °C; 1H NMR (CDCl3) δ 1.35-2.0 (m, 8H,
-OCH2(CH2)4CH2O-), 3.96 (t, 4H, J ) 6 Hz, -OCH2(CH2)4-
CH2O-), 6.25-6.45 (m, 4H, Ar-H ortho or para to -OH), 7.3-
7.65 (m, 12H, Ar-H), 12.59 (br s, 2H, Ar-OH).
2,6-Bis(4-b en zoyl-3-h yd r oxyp h en oxym et h yl)p yr id in e,
1
6: yield, 79%; mp 173-174 °C; H NMR (CDCl3) δ 5.19 (s, 4H,
-OCH2-C5H3N-CH2O-), 6.35-6.55 (m, 4H, Ar-H ortho or para
to -OH), 7.3-7.8 (m, 15H, Ar-H), 12.52 (br s, 2H, Ar-OH).
Gen er a l P r oced u r e for t h e Syn t h esis of Ma cr ocycles
7a -f. The procedure described for the macrocycle 7a 3 was
followed with slight modification. To the suspension of R,ω-bis-
(4-benzoyl-3-hydroxyphenoxy)alkane (2.00 mmol) and potassium
carbonate (1.66 g, 12.0 mmol) in acetone (200 mL) at reflux was
added a solution of the corresponding R,ω-dihaloalkane (2.10
mmol; 1,6-diiodohexane, 1,8-diiodooctane, or 1,12-dibromodode-
cane) in acetone (45 mL) very slowly, and reflux was continued
1,3-Bis(4-b en zoyl-3-h yd r oxyp h en oxym et h yl)b en zen e,
4: yield, 84%; mp 172-173 °C; 1H NMR (DMSO-d6) δ 5.23

6802 J . Org. Chem., Vol. 66, No. 20, 2001
Notes
for 48-72 h. In the case of 7e,f, DMF was used as a solvent
instead of acetone and the mixture was heated at 80-90 °C for
16-70 h. When the R,ω-dihaloakane is dibromide, a catalytic
amount of KI was added to the reaction mixture. After most of
the starting material, R,ω-bis(4-benzoyl-3-hydroxyphenoxy)-
alkane, was used up, potassium carbonate was removed by
filtration, and the concentrated filtrate was purified by silica
gel column chromatography eluting with dichloromethane and
then 40:1 dichloromethane/ethyl acetate to give macrocycles
7a -f.
for 1 h, and then neutralized with 5% KOH aqueous solution.
After removal of the solvent in vacuo, the residue was taken up
in water and extracted with ethyl ether. The ether layer was
purified by column chromatography (eluent: dichloromethane)
to give 1f.
Photoirradiation of a 10 mM benzene solution of 7a followed
by dehydration gave the product with 25% yield, much lower
yield compared with 50% obtained with a 1 mM solution.
1a : yield, 50%; mp 271 °C (lit.3 mp 271 °C).
1
1b: yield, 40%; mp 214-216 °C; H NMR (CDCl3) δ 1.1-1.3
7a : yield, 32%; mp 172 °C (lit.3 mp 172 °C).
(m, 4H, -(CH2)2-(CH2)2-(CH2)2-), 1.55-1.75 (m, 4H, -CH2CH2-
(CH2)2CH2CH2-), 2.75 (t, 4H, J ) 7 Hz, -CH2(CH2)4CH2-), 5.28
(s, 4H, -OCH2-C6H4-CH2O-), 6.70 (d, 2H, J ) 2 Hz, C7-H of
benzofuran ring), 6.99 (dd, 2H, J ) 9, 2 Hz, C5-H of benzofuran
ring), 7.3-7.5 (m, 16H, Ar-H); 13C NMR δ 26.31, 27.25, 28.72,
69.13, 96.17, 113.35, 117.08, 119.76, 121.94, 126.35, 126.84,
128.64, 129.00, 132.93, 136.85, 153.69, 154.47, 155.65. Anal.
Calcd for C42H36O4: C, 83.42; H, 6.00. Found: C, 83.28; H, 6.17.
1c: yield, 55%; mp 210 °C; 1H NMR (CDCl3) δ 1.70 (br s, 4H,
-CH2-(CH2)2-CH2-), 2.82 (br s, 4H, -CH2(CH2)2CH2-), 5.26
(s, 4H, -OCH2-C6H4-CH2O-), 6.70 (d, 2H, J ) 2 Hz, C7-H of
benzofuran ring), 6.97 (dd, 2H, J ) 8, 2 Hz, C5-H of benzofuran
ring), 7.3-7.5 (m, 16H, Ar-H); 13C NMR δ 25.80, 26.27, 70.58,
97.26, 113.72, 117.12, 119.53, 122.40, 124.19, 125.54, 126.84,
128.64, 128.96, 129.49, 132.92, 138.55, 153.32, 154.57, 156.05.
Anal. Calcd for C40H32O4: C, 83.31; H, 5.59. Found: C, 83.41;
H, 5.50.
7b: yield, 30%; mp 170 °C; 1H NMR (CDCl3) δ 1.0-1.2 (m.
8H, -O(CH2)2-(CH2)4-(CH2)2O-), 1.38 (quintet, 4H, J ) 7 Hz,
-OCH2CH2(CH2)4CH2CH2O-), 3.67 (t, 4H, J ) 7 Hz, -OCH2-
(CH2)6-CH2O-), 5.19 (s, 4H, -OCH2-C6H4-CH2O-), 6.32 (d,
2H, J ) 2 Hz, Ar-H ortho to -O(CH2)8-), 6.67 (dd, 2H, J ) 8,
2 Hz, Ar-H para to -O(CH2)8-), 7.3-7.55 (m, 12H, Ar-H), 7.7-
7.75 (m, 4H, Ar-H ortho to CdO in two benzoyl groups).
7c: yield, 40%; mp 124 °C; 1H NMR (CDCl3) δ 1.1-1.2 (m.
4H, -O(CH2)2-(CH2)2-(CH2)2O-), 1.4-1.55 (m, 4H, -OCH2CH2-
(CH2)2CH2CH2O-), 3.83 (t, 4H, J ) 7 Hz, -OCH2-(CH2)4-
CH2O-), 5.20 (s, 4H, -OCH2-C6H4-CH2O-), 6.53 (d, 2H, J )
2 Hz, Ar-H ortho to -O(CH2)6-), 6.62 (dd, 2H, J ) 8, 2 Hz,
Ar-H para to -O(CH2)6-), 7.3-7.55 (m, 11H, Ar-H), 7.65 (s,
1H, Ar-H ortho to both CH2- in the m-xylyl group), 7.72-7.76
(m, 4H, Ar-H ortho to CdO in two benzoyl groups).
7d : yield, 30%; mp 146-148 °C; 1H NMR (CDCl3) δ 1.05-1.3
(m. 16H, -O(CH2)2-(CH2)8-(CH2)2O-), 1.43 (quintet, 4H, J )
7 Hz, -OCH2CH2(CH2)8CH2CH2O-), 3.84 (t, 4H, J ) 7 Hz,
-OCH2-(CH2)10-CH2O-), 5.15 (s, 4H, -OCH2-C6H4-CH2O-
), 6.61 (d, 2H, J ) 2 Hz, Ar-H ortho to -O(CH2)12-), 6.65 (dd,
2H, J ) 8, 2 Hz, Ar-H para to -O(CH2)12-), 7.35-7.55 (m, 11H,
Ar-H), 7.67 (s, 1H, Ar-H ortho to both CH2- in the m-xylyl
group), 7.74 (d, 4H, J ) 7 Hz, Ar-H ortho to CdO in two benzoyl
groups).
1d : yield, 58%; mp 124-126 °C; 1H NMR (CDCl3) δ 1.15-
1.35 (m, 12H, -(CH2)2-(CH2)6-(CH2)2-), 1.71 (quintet, 4H, J
) 7 Hz, -CH2CH2(CH2)6CH2CH2-), 2.81 (t, 4H, J ) 7 Hz,
-CH2-(CH2)8-CH2-), 5.21 (s, 4H, -OCH2-C6H4-CH2O-), 6.92
(dd, 2H, J ) 8, 2 Hz, C5-H of benzofuran ring), 7.03 (d, 2H, J
) 2 Hz, C7-H of benzofuran ring), 7.3-7.5 (m, 16H, Ar-H); 13
C
NMR δ 26.61, 28.20, 28.60, 28.81, 29.39, 70.34, 97.88, 111.84,
116.68, 119.48, 122.64, 125.39, 126.02, 126.84, 128.64, 128.80,
128.94, 132.98, 137.91, 154.38, 154.69, 156.37. Anal. Calcd for
1
7e: yield, 33%; mp 123-125 °C; H NMR (CDCl3) δ 1.1-2.0
(m, 20H, -OCH2-(CH2)6-CH2O- and -OCH2-(CH2)4-CH2O-
), 3.83 (t, 4H, J ) 7 Hz, -OCH2-(CH2)nCH2O-), 4.07 (t, 4H, J
) 6 Hz, -OCH2-(CH2)nCH2O-), 6.47 (d, 2H, J ) 2 Hz, Ar-H
ortho to -O(CH2)12-), 6.56 (dd, 2H, J ) 8, 2 Hz, Ar-H para to
-O(CH2)12-), 7.3-7.55 (m, 8H, Ar-H), 7.71-7.76 (m, 4H, Ar-H
ortho to CdO in two benzoyl groups).
C
46H44O4: C, 83.60; H, 6.71. Found: C, 83.81; H, 6.67.
1e: yield, 32%; mp 134-136 °C; H NMR (CDCl3) δ 1.3-1.4
1
(m, 4H, -(CH2)2-(CH2)2-(CH2)2-), 1.5-1.6 (m, 4H, -O(CH2)2-
(CH2)2-(CH2)2O-), 1.75-1.85 (m, 8H, two -CH2-CH2-(CH2)2-
CH2-CH2-), 2.81 (t, 4H, J ) 7 Hz, -CH2-(CH2)4-CH2-), 4.09
(t, 4H, -OCH2-(CH2)4-CH2O-), 6.85 (dd, 2H, J ) 8, 2 Hz,
C5-H of benzofuran ring), 7.02 (d, 2H, J ) 2 Hz, C7-H of
benzofuran ring), 7.3-7.5 (m, 12H, Ar-H); 13C NMR δ 24.93,
26.20, 27.15, 28.09, 68.35, 97.67, 111.57, 116.74, 119.39, 122.30,
126.81, 128.64, 128.95, 133.06, 154.00, 154.86, 156.62. Anal.
Calcd for C40H40O4: C, 82.16; H, 6.89. Found: C, 82.32; H, 6.96.
1f: yield, 20%; mp 179 °C; 1H NMR (CDCl3) δ 1.2-1.4 (m.
12H, -(CH2)2-(CH2)6-(CH2)2), 1.73 (quintet, 4H, J ) 7 Hz,
-CH2CH2-(CH2)6-CH2CH2-), 2.79 (t, 4H, J ) 7 Hz, -CH2-
(CH2)8-CH2-), 5.38 (s, 4H, -OCH2-C5H3N-CH2O-), 7.02 (dd,
2H, J ) 8, 2 Hz, C5-H of benzofuran ring), 7.06 (d, 2H, J ) 2
Hz, C7-H of benzofuran ring), 7.3-7.5 (m, 14H, Ar-H), 7.63 (t,
1H, J ) 8 Hz, C4-H of the pyridine ring); 13C NMR δ 26.78,
28.32, 28.55, 28.71, 29.07, 71.23, 96.73, 113.20, 116.48, 119.64,
119.75, 122.52, 126.89, 128.71, 128.93, 132.96, 137.61, 154.47,
154.64, 156.19, 157.39. Anal. Calcd for C45H43NO4: C, 81.67; H,
6.55; N, 2.12. Found: C, 81.53; H, 6.58; N, 2.31.
7f: yield, 31%; mp 126-129 °C; 1H NMR (CDCl3) δ 1.05-
1.25 (m, 16H, -O(CH2)2-(CH2)8-(CH2)2O-), 1.41 (quintet, 4H,
J ) 7 Hz, -OCH2CH2(CH2)8CH2CH2O-), 3.81 (t, 4H, J ) 7 Hz,
-OCH2-(CH2)10-CH2O-), 5.28 (s, 4H, -OCH2-C5H3N-CH2O-
), 6.61 (d, 2H, J ) 2 Hz, Ar-H ortho to -O(CH2)12-), 6.69 (dd,
2H, J ) 8, 2 Hz, Ar-H para to -O(CH2)12-), 7.35-7.55 (m, 10H,
Ar-H), 7.71-7.75 (m, 4H, Ar-H ortho to CdO in two benzoyl
groups), 7.83 (t, 1H, J ) 7 Hz, C4-H of the pyridine ring).
Gen er a l P r oced u r e for th e Syn th esis of Ben zofu r a n -
Con ta in in g Cyclop h a n es, 1a -f. A 1 mM benzene8 solution
of macrocycle 7 (350 mL) contained in a Pyrex glass vessel was
purged with nitrogen for 1 h and then irradiated under nitrogen
with a 350 nm mercury lamp for 6-7 h using a RPR-100
photochemical reactor (Southern New England Ultraviolet
Company). After the reaction was complete, the solvent was
removed under reduced pressure, and the residue was dissolved
in 10 mL of acetone. The acetone solution was treated with a
few drops of 1 M HCl, stirred for 1 h, and then concentrated
and subjected to silica gel column chromatography (eluent, 1:1
CH2Cl2/hexane) to afford the cyclophanes.
Ack n ow led gm en t. This work was supported by
Grant No. 2000-0-123-003-3 from the Basic Research
Program of the Korea Science and Engineering Founda-
tion.
For the cyclophane 1f, dehydration and workup procedures
were modified. DMF was used instead of acetone as a solvent
for dehydration; the residue obtained from the photoreaction was
dissolved in DMF, treated with a few drops of 1 M HCl, stirred
J O0103165