Preparation of mono-, di- and trisubstituted resorcinol macrocycles

Article abstract of DOI:10.1055/s-1998-1613

The synthesis of four new partially substituted resorcinarene macrocycles by a mixed resorcinol-aldehyde condensation method is described.

Full text of DOI:10.1055/s-1998-1613

February 1998
SYNLETT
139
Preparation of Mono-, Di- and Trisubstituted Resorcinol Macrocycles
Gerardo Cortes-Lopez and Linda M. Gutierrez Tunstad*
Department of Chemistry and Biochemistry, California State University, Los Angeles, CA 90032, USA
Received 24 September 1997
17
Abstract: The synthesis of four new partially substituted resorcinarene
macrocycles by a mixed resorcinol-aldehyde condensation method is
described.
good yield as reported by Sorrell and thus provides a good platform
for making mono-, di- and trifunctionalized macrocycles and larger
dimeric hosts derived from these resorcinarenes.
21,22
Other substituted
resorcinols are currently being used in "mixed" condensations to
provide analogous substituted products. Hexanal was used as the
aldehyde in our condensation reactions as it provides desirable
lipophilic solubility for the octols and subsequent hosts.
Tetrameric resorcinarenes which possess eight hydroxyl groups, 1, are
of interest as hosts which bind guest molecules through hydrogen bonds
1-3
and CH-π interactions,
and as precursors to more synthetically
4-8
A 1:1 ratio of the two resorcinols in the condensation reaction provided
the greatest yields of the desired disubstituted macrocycles with lower
yields for the mono- and trisubstituted compounds. The reaction
proceeded smoothly with five product spots visible by thin-layer
chromatography, representing the six predicted products: unsubstituted
resorcinarene, mono-, 1,3-di-, 1,2-di-, tri- and tetramethyl
resorcinarenes. Separation for all compounds except the two dimethyl
substituted resorcinarenes was achieved using silica gel thin layer
radially accelerated chromatography. The dimethyl substituted
resorcinarenes were subsequently separated with high performance
liquid chromatography using a silica gel column and solvent conditions
similar to that for the radial chromatographic separation. The 1,3-
dimethyl resorcinarene eluted first, followed immediately by the 1,2-
elaborated macrocycles. Of particular interest in host-guest work is
the construction of host molecules which possess more than one type of
substituent, "A" in Scheme 1. We report here the synthesis of four new
mono-, di- and trimethyl resorcinarenes which will serve as hosts and as
precursors to multiply substituted hosts.
Literature precedent for these partially substituted resorcinarenes is
scant although many tetrasubstituted resorcinarenes have been
3,4,7,9
reported.
There are several examples of Mannich-type
10-12
tetrasubstitutions directly on the resorcinarene.
Recently, Konishi
reported the yields of partially brominated resorcinarenes prepared by
reaction of the resorcinarene with two equivalents of N-
13
bromosuccinimide. Several disubstituted cavitands (rigid cavity-
1
dimethyl resorcinarene. All new compounds gave satisfactory H NMR
containing molecules) derived from resorcinarenes possessing alkyl
spanners between neighboring oxygens have been reported, although in
23
spectra, mass spectroscopic results and elemental analyses.
Typical yields for the isolated resorcinarenes from the 1:1 resorcinols
mixture were as follows: tetramethyl, 3%; trimethyl, 16%; 1,3- and 1,2-
dimethyl, 12% and 8%, respectively; monomethyl, 14%; unsubstituted
resorcinarene, 4% for an overall yield of 55-60%, somewhat lower than
8,14,15
relatively low yield for their four to five step syntheses.
16
Reinhoudt has recently reported the synthesis of partially substituted
cavitands which are phthalimido derivatives of the tetrasubstituted
17
benzylic bromide compounds originally prepared by Sorrell.
9
that reported for simple condensations of this type. Other
We report here the first synthesis of partially substituted resorcinarenes
1b-1e by incorporation of one or more 2-substituted resorcinol units into
stoichiometric combinations of the resorcinols in the "mixed"
condensation reaction resulted in predictably lower yields of the
disubstituted methyl resorcinarenes and higher yields of the other
products.
the forming arene tetramer. Resorcinarenes are obtained as
a
thermodynamic product of a reversible, acid-catalyzed, high-yielding
resorcinol-aldehyde condensation which precludes sequential building
The reversibility of the resorcinol cyclooligomerization also formed the
basis for a second study on the preparation of partially substituted
tetrameric resorcinarenes. We investigated reactions in which
9,18-20
of the tetramer as is known with calixarenes.
Our approach takes
advantage of the high-yielding condensation step to produce a mixture
of substituted macrocycles by combining two different resorcinols along
with the aldehyde (Scheme 1) to obtain the desired mono- and
disubstituted resorcinarenes along with smaller amount of tri- and
tetrasubstituted resorcinarenes. Conditions were chosen to maximize the
1
4
unsubstituted resorcinarene 1f (A - A = H) and 2-methylresorcinol
were combined under the reversible reaction conditions of the
condensation reaction with no additional aldehyde added (Scheme 2).
While we were able to isolate the desired partially substituted hosts,
yields were ~10% less overall for this step than for the "mixed"
condensation reactions, due primarily to the loss of material to
polymerization.
9
cis-cis-cis stereoisomeric products.
Resorcinol and 2-methylresorcinol were chosen as starting materials for
the condensation reaction as each individually provides high yields of
the tetraresorcinol macrocycle (octol). The benzylic methyl group of
We are currently utilizing the isolated mono- and disubstituted
resorcinarenes in the preparation of more elaborate host molecules
whose studies will be reported elsewhere.
9
methylene-spanned tetramethyl resorcinarenes is readily brominated in

140
LETTERS
SYNLETT
in vacuo for 8h to provide 18.9g of a crude mixture. The t.l.c R
Acknowledgements. This work was supported by NIH MBRS grant
GM08101. G. C.-L. thanks the NIH for support through a MARC
fellowship (GM08228). NMR spectra were recorded on a Bruker
instrument supported by NSF (9151268).
f
values of the macrocycles (8:2:1 CH Cl :hexanes:MeOH) were:
2
2
0.29 for the tetramethyl, 0.25 for the trimethyl, 0.23 for the
dimethyls, 0.18 for monomethyl and 0.14 for the unsubstituted
resorcinarene. The separation of 0.210 g of the above mixture by
radial chromatography was accomplished using a solvent mixture of
References
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2
2
1)
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3)
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52
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3,7 9,13 15,19
pentacyclo[19.3.1.1 .1 .1
]octacosa-1(25),3,5,-7(28),9,11,-
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5)
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33.7mg (16%), mp 245-247 °C (dec): H NMR (CD OD) δ 0.91 (t, J
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= 6.79 Hz, 12 H, CH ), 1.22 - 1.42 (bm, 24 H, CH (CH ) CH ),
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2
4 9
J = 7.50 Hz, 2H, methine), 6.26 (s, 1H, ArH, ortho to OH), 7.02 (s,
1H, ArH, meta to OH), 7.09 (s, 2H, ArH, meta to OH), 7.16 (s, 1H,
ArH, meta to OH), 7.91 (s, 8H, OH); FAB-MS (16 eV) m / e 811
8)
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+
+
(M , 30.1), 739 (M
-
C H
72.9). Anal. Calcd. for
5
11,
C
H
O •CH OH: C, 74.08; H, 8.85. Found (dried at 80 °C, 2 mm
Tunstad, L. M.; Tucker, J. A.; Dalcanale, E.; Weiser, J.; Bryant, J.
51 70
8
3
Hg, 8h): C, 74.00; H, 8.64.
1,3-Dimethyl macrocycle.
tetrapentylpentacyclo[19.3.1.1 .1 .1
A.; Sherman, J. C.; Helgeson, R. C.; Knobler, C. B.; Cram, D. J. J.
5,17-Dimethyl-2,8,14,20-
] octacosa-1(25),3,5,-
1989, , 1305-1312.
54
Org. Chem.
3,7 9,13 15,19
10) Matsushita, Y.-i.; Matsui, T. Tetrahedron Lett. 1993, 34, 7433-7436.
7(28),9,11,13(27),15,17,19(26), 21,23-dodecaene-4,6,10,12,16,18,-
11) Konishi, H.; Yamaguchi, H.; Miyashiro, M.; Kobayashi, K.;
22,24-octol. Stereoisomer 1d. 24.3mg (12%), mp 248-252 °C
Morikawa, O. Tetrahedron Lett. 1996, 37, 8547-8548.
1
(dec): H NMR ((CD ) CO) δ 0.88 (t, J = 6.58 Hz, 12 H, CH ), 1.2 -
3 2
3
12) Yanagihara, R.; Tominaga, M.; Aoyama, Y. J. Org. Chem. 1994, 59,
1.4 (bm, 24 H, CH (CH ) CH ), 1.86 (s, 6H, CH ortho to OH), 2.2
2
2 3
3
3
6865-6867.
- 2.4 (bm, 8 H, CH C H ), 4.30 (t, J = 7.79 Hz, 4H, methine), 6.41
2
4 9
13) Konishi, H.; Nakamaru, H.; Nakatani, H.; Ueyama, T.; Kobayashi,
(s, 2H, ArH, ortho to OH), 7.42 (s, 2H, ArH, meta to OH), 7.45 (s,
K.; Morikawa, O. Chem. Lett. 1997, 185-186.
2H, ArH, meta to OH), 7.68 (bs, 8H, OH); FAB-MS (16 eV) m / e
+
+
796 (M , 16.9), 725 (M
- C H , 100). Anal. Calcd. for
5 11
14) Sorrell, T. N.; Richards, J. L. Synlett 1992, 2, 155-156.
C
H
O •H O: C, 73.68; H, 8.66. Found (dried at 80 °C, 2mm Hg,
50 68
8
2
15) Lukin, O. V.; Pirozhenko, V. V.; Shivanyuk, A. N. Tetrahedron
8h): C, 73.37; H, 8.67.
1,2-Dimethyl macrocycle.
tetrapentylpentacyclo[19.3.1.1 .1 .1
1995, , 7725-7728.
36
Lett.
5,11-Dimethyl-2,8,14,20-
] octacosa-1(25),3,5,-
16) Boerrigter, H.; Verboom, W.; Vanhummel, G. J.; Harkema, S.;
3,7 9,13 15,19
Reinhoudt, D. N. Tetrahedron Lett. 1996, 37, 5167-5170.
7(28),9,11,13(27),15,17,19(26), 21,23-dodecaene-4,6,10,12,16,18,-
17) Sorrell, T. N.; Pigge, F. C. J. Org. Chem. 1993, 58, 784-5.
18) Niederl, J.; Vogel, H. J. J. Am. Chem. Soc. 1940, 62, 2512-2514.
19) Högberg, A. G. S. J. Org. Chem. 1980, 45, 4498-500.
1
22,24-octol. Stereoisomer 1c. 17.4 mg (8%), mp 251 °C (dec):
H
NMR ((CD ) CO) δ 0.88 (t, J = 6.81 Hz, 12 H, CH ), 1.25 -1.4 (bs,
3 2
3
24 H, CH (CH ) CH ), 1.98 (s, 6H, CH ortho to OH), 2.24 - 2.38
2
2 3
3
3
(m, 8 H, CH C H ), 4.28 (t, J = 7.76 Hz, 1H, methine), 4.30 (t, J =
20) Casnati, A.; Domiano, L.; Pochini, A.; Ungaro, R.; Carramolino, M.;
Magrans, J. O.; Nieto, P. M.; Lopezprados, J.; Prados, P.;
Demendoza, J.; Janssen, R. G.; Verboom, W.; Reinhoudt, D. N.
2 4 9
7.93 Hz, 2H, methine), 4.36 (t, J = 7.83 Hz, 1H, methine), 6.27 (s,
2H, ArH, ortho to OH), 7.38 (s, 2H, ArH, meta to OH), 7.55 (s, 2H,
ArH, meta to OH), 7.91 (bs, 8H, OH); FAB-MS (16 eV) m / e 796
1995, , 12699-12720.
51
Tetrahedron
+
+
(M , 30.9), 725 (M
-
C H
100). Anal. Calcd. for
11,
5
21) Cram, D. J.; Tanner, M. E.; Knobler, C. B. J. Am. Chem. Soc. 1991,
113, 7717-7727.
C
H
O •2H O: C, 72.09; H, 8.71. Found (dried at 80 °C, 2 mm
50 68
8
2
Hg, 8h): C, 72.41; H, 8.51.
22) Timmerman, P.; Boerrigter, H.; Verboom, W.; Vanhummel, G. J.;
Harkema, S.; Reinhoudt, D. N. J. Inclusion Phenom. 1994, 19, 167-
191.
Monomethyl macrocycle. 5-Methyl-2,8,14,20- tetrapentylpenta-
3,7 9,13 15,19
cyclo[19.3.1.1 .1 .1
]
octacosa-1(25),3,5,7(28),9,11,13-
(27),15,17,19(26), 21,23-dodecaene-4,6,10,12,16,18,22,24-octol.
23) Mixed Condensation. This procedure was a modification of that
Stereoisomer 1e. 28.9mg (14 %) , mp 263 °C (dec);
9
1
followed by Cram and coworkers designed to minimize other
H NMR ((CD ) CO) δ 0.89 (t, J = 6.75 Hz, 12 H, CH ), 1.21-1.43
3 2
3
stereoisomeric products. Resorcinol (5.94 g, 53.9 mmol) and 2-
methylresorcinol (6.70 g, 53.9 mmol) were dissolved in 244 mL of a
(bm, 24 H, CH (CH ) CH ), 1.91 (s, 3H, CH ortho to OH), 2.21-
2
2 3
3
3
2.38 (bm, 8 H, CH C H ), 4.30 (t, J = 7.87 Hz, 2H, methine), 4.32
2
4 9
solvent mixture of MeOH, H O and concentrated HCl (9:0.75:3).
2
(t, J = 7.61 Hz, 2H, methine), 6.19 (s, 1H, ArH, ortho to OH), 6.34
(s, 2H, ArH, ortho to OH), 7.42 (s, 1H, ArH, meta to OH), 7.52 (s,
2H, ArH, meta to OH), 7.59 (s, 1H, ArH, meta to OH), 8.46 (bs, 8H,
The solution was cooled to 10 °C, and hexanal (10.8 g, 108 mmol,
dissolved in 100 mL of the same solvent mixture) was added
dropwise with stirring over a period of 95 min. The solution was
then stirred at 60 °C for 8 days. The reaction mixture was
precipitated with brine, cooled, filtered, rinsed with hot water, dried
+
+
OH); FAB-MS (16 eV) m / e 782 (M , 27.6), 711 (M - C H
5
11,
96.4). Anal. Calcd. for C
H O •0.5H O: C, 74.30; H, 8.53. Found
49 66 8 2
(dried at 80 °C, 2mm Hg, 8h): C, 74.07; H, 8.57.