Calixarene Anhydrides as Useful Synthetic Intermediates

Full text of DOI:10.1021/jo962044p

2280
J . Org. Chem. 1997, 62, 2280-2284
can be introduced onto the top rim of the calixarene to
give, for example, 8b and 8c.
Ca lixa r en e An h yd r id es a s Usefu l Syn th etic
In ter m ed ia tes1
The carboxyl groups in 6-8 can, in turn, be converted
to other functional groups, e.g., esters and amides, to
produce a variety of difunctionalized calixarenes. This
has been explored in two particular cases, one in which
the second group is both structurally and stereochemi-
cally identical with the first and the other in which the
second group is structurally identical but stereochemi-
cally enantiomeric with the first. Thus, introduction of
a second phenylglycine methyl ester moiety into 8a , using
the dicyclohexylcarbodiimide method for amide formation
from a carboxylic acid and an amine, yields the (R,R)
compound 9a when the (R)-(-) enantiomer of the R-amino
ester is used and the (R,S) compound 9b when its (S)-
Dejian Xie and C. David Gutsche*
Department of Chemistry, Texas Christian University,
Fort Worth, Texas 76129
Received October 31, 1996
The introduction of functionality into calixarenes con-
tinues to be one of the major goals in the rapidly
expanding chemistry of the these compounds,2 and a
number of methods have been devised for the synthesis
of calixarenes containing two or more different functional
groups on the upper rim.3 The present work adds to this
list, making use of calixarene anhydrides for achieving
this goal.
The starting compound for these syntheses is 5,17-
bis(cyanomethyl)-11,23-di-tert-butylcalix[4]arene-25,26,-
27,28-tetrol (1),4 prepared by the quinone methide route.5
Brosylation of 1 (i.e., treatment with p-bromobenzene-
sulfonyl chloride) to give 2 was chosen to fix the calix-
[4]arene in the cone conformation, because benzylation
is known to also involve the R-carbons of the cyanomethyl
groups.6 Acid-catalyzed hydrolysis of the cyano groups
of 2 proceeds smoothly to yield the dicarboxylic acid 3
without disruption of the brosylate moieties (Scheme 1).
Treatment of 3 with oxalyl chloride leads to the diacid
chloride 5, the anhydride 4, or a mixture thereof depend-
ing on the reaction conditions. If oxalyl chloride is used
as both reagent and solvent the diacid chloride 5 is
obtained in 95% yield along with a small amount of
anhydride. However, if a dilute solution of 3 (lower than
0.01 M) in CH2Cl2 is treated with oxalyl chloride the
anhydride 4 is obtained in quantitative yield.
1
(+) enantiomer is used. The H NMR spectra of 9a and
9b present an interesting comparison (Figure 1). The
optically active (R,R) compound 9a contains a C2 sym-
metry axis. The methylene groups of the calixarene ring
in 9a labeled 1 and 3 are equivalent; those labeled 2 and
4 are equivalent; but, the 1,3-set is diastereotopic with
the 2,4-set. As a consequence, two sets of pairs of
1
doublets are observed in the H NMR spectrum arising
from the ArCH2Ar groups, one centered near δ 3.75 and
the other at δ 2.47. Similarly, the CH2CONH methylene
groups are equivalent but their hydrogens are diaste-
reotopic, giving rise to a pair of very close-lying doublets
at δ 2.87. The CO2Me groups are equivalent and appear
as a sharp singlet at δ 3.69, and the p-tert-butyl groups
also are equivalent and appear as a singlet at δ 1.22. The
optically inactive (R,S) compound 9b is a meso structure
with a plane of symmetry. The methylene groups of the
calixarene ring in 9b labeled 1 and 2 are enantiotopic;
those labeled 3 and 4 are enantiotopoic; but, the 1,2 -set
is diastereotopic with the 3,4-set. Thus, just as with the
(R,R) compound, two sets of doublets are observed at δ
3.73 and 2.48. The CH2CONH groups are enantiotopic,
but their hydrogens are diastereotopic and should appear
as a pair of doublets. The apparent singlet at δ 2.86
must, therefore, be the result of accidental overlap. In
contrast to 9a , the tert-butyl groups in 9b are not
equivalent but are diastereotopic, and a pair of singlets
is observed at δ 1.26 and 1.20.
The anhydride 4 is stable at room temperature and
undergoes only very slow decomposition upon standing
in a humid atmosphere. However, it reacts smoothly
with a variety of nucleophiles such as alcohols to give
half esters 6a -d , and amines to give half amides 7a -e.
A particularly useful aspect of the latter is the reaction
of 4 with R-amino esters to give calixarenes carrying a
chiral moiety on the upper rim. For example, (R)-(-)-2-
phenylglycine methyl ester hydrochloride reacts with 4
in the presence of Et3N in refluxing CH2Cl2 to afford a
95% yield of the half amide 8a , a compound in which
The bisanhydride, prepared7 from the 1,3-alternate
conformer of the tetrabenzyl ether of p-(carboxymethyl)-
calix[4]arene, forms much less easily than does the
monoanhydride 4. The reactions of the bisanhydride will
be described in a subsequent paper.
1
groups that are H NMR-equivalent in 7a -e (e.g., meth-
ylenes, tert-butyls) now become diastereotopic, as re-
flected in the increased multiplicity of the 1H NMR
spectrum. In a similar fashion, other amino acid moieties
Exp er im en ta l Section 8
5,17-Bis(cya n om eth yl)-11,23-d i-ter t-bu tyl-25,26,27,28-tet-
r a k is[[(p-br om op h en yl)su lfon yl]oxy]ca lix[4]a r en e (2). To
a solution of 2.15 g (3.5 mmol) of 5,17-bis(cyanomethyl)-11,23-
(1) Calixarenes. 46. Part 45: Sharma, S. K.; Gutsche, C. D. J . Org.
Chem. 1996, 61, 25l1.
(2) Bo¨hmer, V. Angew. Chem., Int. Ed. Engl. 1995, 34, 713. Gutsche,
C. D. Aldrichim. Acta 1995, 28, 3. Calixarenes: A Versatile Class of
Macrocyclic Compounds; Bo¨hmer, V., Vicens, J ., Eds.; Kluwer Aca-
demic Publishers: Dordrecht, 1991. Gutsche, C. D. Calixarenes. In
Monographs in Supramolecular Chemistry; Stoddart, J . F., Ed.; Royal
Society of Chemistry: London, 1989.
(3) (3) Cf. for example: Timmerman, P.; Verboom, W.; Reinhoudt,
D. N.; Arduini, A.; Grandi, S.; Sicuri, A. R.; Pochini, E.; Ungaro, R.
Synthesis 1994, 185. Shu, C.-m.; Yuan, T.-s.; Ku, M.-c.; Ho, Z.-c.; Liu,
W.-c.; Tang, F.-s.; Lin, L.-g. Tetrahedron 1996, 52, 9805. For a review
of the prior literature cf.: van Loon, J .-D.; Verboom, W.; Reinhoudt,
D. N. Org. Prep. Proced. Int. 1992, 24, 437.
(4) Kanamathareddy, S.; Gutsche, C. D. J . Org. Chem. 1995, 60,
6070.
(5) Gutsche, C. D.; Nam, K. C. J . Am. Chem. Soc. 1988, 110, 6153.
(6) Sharma, S. K.; Gutsche, C. D. Tetrahedron Lett. 1993, 34, 5389;
Tetrahedron 1994, 50, 4087.
(7) Sharma, S. K.; Gutsche, C. D. Unpublished observations.
(8) Unless otherwise noted, starting materials were obtained from
commercial suppliers and used without further purification. THF was
freshly distilled from Na benzophenone. The melting points of all
compounds melting above 250 °C were taken in sealed and evacuated
capillary tubes on a Mel-Temp apparatus (Laboratory Devices, Cam-
bridge, MA) using a 500 °C thermometer calibrated against a ther-
mocouple. 1H NMR and 13C NMR spectra9 were recorded on a Varian
XL-300 spectrometer at 300 and 75 MHz, respectively. TLC analyses
were carried out on Analtech silica gel plates (absorbent thickness 250
µm) containing a fluorescent indicator. Chromatography was carried
out with J . T. Baker silica gel no. J T7042-2 (40-64 µm particles) on
columns filled to a height of ca. 6 in. Elution rates were 2 in./min.
Analytical samples were dried at least 36 h at 100-140 °C and 1-2
mmHg of pressure.
S0022-3263(96)02044-0 CCC: $14.00 © 1997 American Chemical Society

Notes
J . Org. Chem., Vol. 62, No. 7, 1997 2281
Sch em e 1
di-tert-butylcalix[4]arene-25,26,27,28-tetrol (1) in 100 mL of THF
was added 2.25 g of NaH (60% oil dispersion, 56 mmol). The
reaction mixture was stirred for 30 min, treated with 4.48 g (18.2
mmol) of p-bromobenzenesulfonyl chloride, and allowed to stir
at rt for 3 h. The solvent was removed under vacuum, and the
residue was treated with 80 mL of CHCl3 and poured into 80 g
of crushed ice. The organic layer was separated, washed with
H2O and brine, and dried over Na2SO4 and the solvent removed
by evaporation, leaving a residue that was triturated with
hexane and recrystallized from CH2Cl2-MeOH to give 4.5 g
(87%) of 2 as white crystals: mp 280-281.5 °C; 1H NMR (CDCl3)
δ 7.93 (d, 4, J ) 8.5 Hz), 7.80 (d, 4, J ) 8.6 Hz), 7.66 (m, 8), 7.04
(s, 4), 6.08 (s, 4), 3.80 (d, 4, J ) 14.3 Hz), 3.26 (s, 4), 2.54 (d, 4,
J ) 14.5 Hz,), 1.35 (s, 18); 13C NMR (CDCl3) δ 150.46, 143.58,
143.46, 135.60, 134.54, 134.44, 134.17, 132.87, 132.39, 131.24,
130.60, 129.70, 129.37, 127.87, 127.81, 127.18, 117.72, 34.49 ,
31.46 , 31.30, 22.87 Anal. Calcd for C64H54N2O12Br4S4: C, 51.55;
H, 3.62. Found: C, 51.63; H, 3.69.
The white precipitate was collected by suction filtration and
dried to give a quantitative yield of 3. An analytical sample
was obtained by recrystallization from CH2Cl2-hexane: mp >
1
307 °C dec; H NMR (CDCl3) δ 7.96 (d, 4, J ) 8.7 Hz), 7,83 (d,
4, J ) 8.6 Hz), 7.62 (d, 4, J ) 8.6 Hz), 7.54 (d, 4, J ) 8.6 Hz),
7.05 (s, 4), 6.57 (s, 4), 3.92 (d, 4, J ) 13.8 Hz), 3.03 (s, 4), 2.57
(d, 4, J ) 14.0 Hz), 1.30 (s, 18); 13C NMR (CDCl3 + 1 drop of
DMSO-d6) δ 172.6, 149.5, 142.8, 142.6, 134.9, 134.3, 134.0, 133.8,
132.4, 132.1, 132.0, 130.9, 130.5, 129.1, 129.0, 126.4, 40.1, 34.1,
31.0; IR (KBr) 1712.9 cm-1 (CO2H). Anal. Calcd for
C64H56O16Br4S4: C, 50.28; H, 3.69. Found: C, 50.58; H, 3.75.
An h yd r id e of 5,17-Bis(ca r boxym eth yl)-11,23-d i-ter t-bu -
tyl-25,26,27,28-tetr akis[[(p-br om oph en yl)su lfon yl]oxy]calix-
[4]a r en e (4). A 0.46 g (0.3 mmol) sample of 3 in 30 mL of dry
CH2Cl2 containing 1 mL of (COCl)2 (11.5 mmol) was refluxed
under N2 for 2 h. Evaporation of the solvent and excess (COCl)2
gave a white solid in quantitative yield. An analytical sample
of 4 was obtained by recrystallization from CH2Cl2-hexane: mp
5,17-Bis(ca r boxym eth yl)-11,23-d i-ter t-bu tyl-25,26,27,28-
tetr a k is[[(p-br om op h en yl)su lfon yl]oxy]ca lix[4]a r en e (3).
A suspension of 2 g of 2 in 30 mL of HOAC, 3 mL of concd
H2SO4, and 3 mL of H2O was refluxed for 24 h, the solution
clearing after 3 h but then depositing a precipitate after 12 h.
The mixture was cooled to rt, and 40 mL of cold water was added.
1
305-306.5 °C; H NMR (CDCl3) δ 7.95 (d, 4, J ) 8.6 Hz), 7.82
(d, 4, J ) 8.2 Hz), 7.59-7.68 (4 lines, 8), 7.02 (s, 4), 6.00 (s, 4),
3.81 (d, 4, J ) 14.2 Hz), 3.18 (s, 4), 2.51 (d, 4, J ) 14.5 Hz), 1.35
(s, 18); 13C NMR (CDCl3) δ 165.3, 150.2, 143.6, 143.0, 135.7,
134.5, 134.2, 132.9, 132.8, 132.4, 132.3, 131.3, 130.6, 129.6, 129.3,
128.9, 127.0 (Ar: Calcd, 16; found, 16), 42.0, 34.4, 31.4, 31.3
(sp3: Calcd, 4; found, 4); IR (KBr) 1714.8, 1760.0 cm-1 (CO).
Anal. Calcd for C64H54O15Br4S4: C, 50.87; H, 3.60. Found: C,
50.89; H, 3.68.
(9) For the 13C NMR spectra of compounds 4-9 the calculated and
found numbers of aromatic carbons and sp3 carbons are included in
parantheses. In all cases but one, the number of lines found is equal
to or less than the calculated value, ascribable to accidental overlaps.
In the case of 7c one more Ar line than the calculated number appears,
the reason for this being unknown.
5,17-Bis[(ch lor oca r bon yl)m eth yl]-11,23-d i-ter t-bu tyl-25,-
26,27,28-t et r a k is[[(p -b r om op h en yl)su lfon yl]oxy]ca lix[4]-
a r en e (5). A 0.23 g (0.15 mmol) sample of 3 in 15 mL of (COCl)2

2282 J . Org. Chem., Vol. 62, No. 7, 1997
Notes
F igu r e 1. 1H NMR spectra of 9a and 9b in CDCl3 at 300 MHz at room temperature.
was refluxed under N2 for 2 h. Evaporation of the (COCl)2
furnished the diacid chloride 5 as pale yellow solid in
solution becoming clear after 0.5 h. Upon cooling, 0.15 g (95%)
of 6b precipitated as white crystals: mp 180-182 °C; H NMR
1
a
quantitative yield. The product decomposes to the diacid 3 on
prolonged storage in the atmosphere: 1H NMR (CDCl3) δ 7.88
(d, 4, J ) 8.5 Hz), 7.79 (d, 4, J ) 8.6 Hz), 7.64 (d + d, 8, J ) 8.5
Hz and 8.2 Hz), 6.92 (s, 4), 6.26 (s, 4), 3.83 (d, 4, J ) 14.0 Hz),
3.59 (s, 4), 2.52 (d, 4, J ) 14.4 Hz), 1.25 (s, 18); 13C NMR (CDCl3)
δ 170.9, 150.1, 143.5, 143.1, 135.0, 134.7, 134.4, 134.0, 132.8,
132.4, 131.2, 130.8, 129.7, 129.6, 129.4, 129.0, 126.8 (Ar: Calcd,
16; found, 16) , 52.0, 34.4, 31.3 (sp3: Calcd 4; found 3); IR (KBr)
(CDCl3) δ 7.88 (d, 4, J ) 8.7 Hz), 7.78 (d, 4, J ) 8.6 Hz), 7.60-
7.67 (m, 8), 6.95 (d, 2, J ) 2.3 Hz), 6.90 (d, 2, J ) 2.2 Hz), 6.23
(s, 2), 6.10 (s, 2), 4.98 (5 peaks, 1, J ) 6.3 Hz), 3.80 (d + d, 4, J
) 14.0 Hz), 3.16 (s, 2), 2.96 (s, 2), 2.50 (dd, 4, J ) 14.0 Hz), 1.26
(s, 18), 1.21 (d, 6, J ) 6.3 Hz); 13C NMR (CDCl3) δ 172.8, 172.1,
149.8, 143.1, 142.7, 142.5, 135.4, 135.3, 134.5, 134.2, 134.1, 134.0,
132.7, 132.3, 132.2, 131.6, 131.2, 130.9, 130.8, 129.6, 129.5, 129.4,
129.3, 128.0, 126.8, 126.6 (Ar: Calcd, 24; found, 24), 68.9, 40.5,
39.6, 34.3, 31.3, 31.2, 21.7 (sp3: Calcd, 8; found, 7). Anal. Calcd
for C67H62O16Br4S4: C, 51.22; H, 3.98. Found: C, 51.12; H, 4.13.
5-(Ca r b oxym et h yl)-17-[(ter t-b u t oxyca r b on yl)m et h yl]-
11,23-d i-ter t-bu tyl-25,26,27,28-tetr a k is[[(p-br om op h en yl)-
su lfon yl]oxy]ca lix[4]a r en e (6c) was prepared by the proce-
dure described for 6b, with tert-butyl alcohol and 12 h reflux,
and was obtained in 92% yield as white crystals: mp >180 °C
1796 (CO) cm-1
.
5-(Ca r b oxym et h yl)-17-[(m et h oxyca r b on yl)m et h yl]-11,-
23-d i-t er t -b u t yl-25,26,27,28-t e t r a k is[[(p -b r om op h e n yl)-
su lfon yl]oxy]ca lix[4]a r en e (6a ). A 0.151 g (0.1 mmol) sample
of the anhydride 4 was dissolved in 15 mL of CH2Cl2. A few
drops of MeOH (excess) were added, and the solution was stirred
at rt for 3 h. Removal of the solvent gave a quantitative yield
of the 6a as a white solid: mp 180-182 °C; 1H NMR (CDCl3) δ
7.87 (d, 4, J ) 8.7 Hz), 7.77 (d, 4, J ) 8.7 Hz), 7.67 (m, 8), 6.91
(d, 2, J ) 2.4 Hz), 6.98 (d, 2, J ) 2.4 Hz), 6.26 (s, 2), 6.14 (s, 2),
3.80 (d + d, 4, J ) 14.0 Hz and 14.1 Hz), 3.66 (s, 3), 3.00 (s, 2),
2.51 (d + d, 4, J ) 14.1, 14.0 Hz), 1.25 (s, 18); 13C NMR (CDCl3)
δ 172.8, 149.8, 143.1, 142.8, 142.7, 135.2, 134.5, 134.3, 134.2,
134.1, 132.7, 132.3, 131.6, 131.3, 131.2, 130.9, 130.8, 129.6, 129.5,
129.3, 128.2, 126.8, 126.6 (Ar: Calcd, 24; found, 22), 52.3, 40.3,
39.3, 34.4, 31.3, 31.2 (sp3 Calcd, 7; found, 6); IR (KBr) 1739.9
1
dec; H NMR (CDCl3) δ 7.89 (d, 4, J ) 8.6 Hz), 7.79 (d, 4, J )
8.6 Hz), 7.56-7.66 (m, 8), 6.97 (d, 2, J ) 2.3 Hz), 6.92 (d, 2, J )
2.3 Hz), 6.24 (s, 2), 6.10 (s, 2), 3.82 (d + d, 4, J ) 14.2, 14.3 Hz),
3.18 (s, 2), 2.94 (s, 2), 2.50 (d + d, 4, J ) 14.0, 14.1 Hz), 1.44 (s,
9), 1.28 (s, 18); 13C NMR(CDCl3) δ 172.9, 171.2, 149.9, 143.2,
142.5, 135.4, 134.6, 134.3, 134.2, 133.9, 133.7, 132.8, 132.2, 132.1,
132.0, 131.2, 130.9, 130.8, 129.7, 129.5, 129.4, 129.2, 127.7, 126.9,
126.6 (Ar: Calcd, 24; found, 23), 82.3, 40.7, 40.1, 34.4, 31.4, 31.2,
28.0 (sp3: Calcd, 8; found 7). Anal. Calcd for C67H64O16Br4S4:
C, 51.16; H, 4.10; Found: C, 51.26; H, 4.04.
5-(Ca r boxym eth yl)-17-[[(p-ter t-bu tylp h en oxy)ca r bon yl]-
m e t h yl]-11,23-d i-ter t -b u t yl-25,26,27,28-t e t r a k is[[(p -b r o-
m op h en yl)su lfon yl]oxy]ca lix[4]a r en e (6d ). A mixture of
0.30 g (0.2 mmol) of the anhydride 4, 0.034 g (0.22 mmol) of
p-tert-butylphenol, 1 drop of Et3N, and 20 mL of CH2Cl2 was
(CO2Me), 1718.7 cm-1 (CO2H). Anal. Calcd for C65H58O16
Br4S4: C, 50.60; H, 3.79. Found: C, 50.41, H, 3.80.
-
5-(Ca r b oxym et h yl)-17-[(isop r op oxyca r b on yl)m et h yl]-
11,23-d i-ter t-bu tyl-25,26,27,28-tetr a k is[[(p-br om op h en yl)-
su lfon yl]oxy]ca lix[4]a r en e (6b). A suspension of 0.151 g (0.1
mmol) of 4 in 10 mL of 2-propanol was refluxed for 2 h, the

Notes
J . Org. Chem., Vol. 62, No. 7, 1997 2283
refluxed for 12 h. The mixture was cooled, washed with 0.2 N
HCl, water, and brine, and dried over Na2SO4 and the solvent
removed by evaporation, leaving a residue that was chromoto-
graphed (eluant 4% acetone-CH2Cl2 (v/v)) to give 0.30 g (90%)
of 6d as a white solid: mp > 170 °C dec; 1H NMR (CDCl3) δ
7.88 (d, 4, J ) 8.6 Hz), 7.78 (d, 4, J ) 8.7 Hz), 7.64 (m, 8), 7.38
(d, 2, J ) 8.7 Hz), 6.90 (m, 6), 6.20 (s, 4), 3.81 and 3.80 (dd, 4, J
) 14.1 Hz), 3.34 (s, 2), 2.96 (s, 2), 2.51 (d, 4, J ) 14.5 Hz), 1.32
(s, 9), 1.20 (s, 18); 13C NMR (CDCl3) δ 173.8, 170.3, 149.8, 149.1,
147.9, 143.1, 143.0, 142.9, 135.3, 135.2, 134.4, 134.2, 132.7, 132.3,
131.2, 131.0, 130.8, 130.6, 129.5, 129.4, 129.3, 128.6, 126.8, 126.6,
126.3, 120.4 (Ar: Calcd, 28; found, 24), 40.1, 39.7, 34.5, 34.3,
95% yield according to the procedure described for 7a , using
diethylamine and a reflux time of 3 h, and obtained as a colorless
solid: mp 273.5-275.5 °C; 1H (CDCl3) δ 7.93 (d, 4, J ) 8.7 Hz),
7.82 (d, 4, J ) 8.7 Hz), 7.50-7.64 (m, 8), 7.03 (d, 2, J ) 2.3 Hz),
6.95 (d, 2, J ) 2.3 Hz), 6.25 (s, 2), 6.01 (s, 2), 3.93 (d, 2, J ) 14.1
Hz), 3.74 (d, 2, J ) 14.0 Hz), 3.38 (m, 4), 3.01 (q, 2, J ) 7.0 Hz),
2.92 (s, 2), 2.53 (d, 2, J ) 14.1 Hz), 2.47 (d, 2, J ) 14.4 Hz), 1.33
(s, 18), 1.17 (t, 3, J ) 7.0 Hz), 1.02 (t, 3, J ) 7.0 Hz); 13C NMR
(CDCl3) δ 172.5, 171.5, 150.1, 143.2, 141.9, 135.6, 135.4, 134.7,
134.3, 134.1, 133.9, 133.1, 133.0, 132.8, 132.3, 132.0, 131.2, 130.8,
130.7, 129.8, 129.4, 129.2, 127.1, 127.0, 126.6 (Ar: Calcd, 24;
found, 23), 42.6, 41.7, 40.2, 36.7, 34.4, 31.5,31.2, 31.3 (sp3: Calcd,
10; found 8); IR (KBr) 1718 (CO2H), 1604.9 cm-1 (CONR2). Anal.
Calcd for C68H65O15NBr4S4: C, 51.56; H, 4.14. Found: C, 51.56;
H, 4.16.
31.3, 31.2 (sp3: Calcd, 8; found, 6). Anal. Calcd for C74H68O16
Br4S4: C, 53.50; H, 4.13. Found: C, 53.86; H, 4.18.
-
5-(Car boxym eth yl)-17-[[(N-octylam in o)car bon yl]m eth yl]-
11,23-d i-ter t-bu tyl-25,26,27,28-tetr a k is[[(p-br om op h en yl)-
su lfon yl]oxy]ca lix[4]a r en e (7a ). To a solution of 0.30 g (0.2
mmol) of the anhydride 4 in 15 mL of dry CH2Cl2 was added
0.029 g (0.22 mmol) of octylamine. The reaction mixture was
refluxed for 6 h, cooled, washed with 0.2 N HCl, water, and brine,
and dried over Na2SO4 and the solvent removed by evaporation
5-(Car boxym eth yl)-17-[[N,N-bis[2-(3,5-dim eth ylpyr azolyl)-
et h yl]a m in o]ca r b on yl]m et h yl]-11,23-d i-ter t-b u t yl-25,26,-
27,28-t e t r a k is[[(p -b r om op h e n yl)su lfon yl]oxy]ca lix[4]-
a r en e (7e) was prepared in 95% yield following the procedure
described for 7a , using bis[2-(3,5-dimethyl-1-pyrazoyl)ethyl]-
amine10 and a reflux time of 3 h. An analytical sample of 7e
1
to give 0.3 g (92%) of 7a as a white solid: mp > 210 °C dec; H
was obtained as
a white solid by recrystallization from
CH2Cl2-MeOH: mp >180 °C dec; 1H NMR (CDCl3) δ 7.94 (d, 4,
J ) 8.7 Hz), 7.81 (d, 4, J ) 8.5 Hz), 7.56-7.65 (m, 8), 6.97 (d, 2,
J ) 2.2 Hz), 6.95 (d, 2, J ) 2.2 Hz), 6.11 (s, 2), 5.88 (s, 2), 5.80
(s, 2), 4.08 (t, 2, J ) 5.6 Hz), 3.84 (d, 2, J ) 14.4 Hz), 3.66-3.80
(m, 6), 3.10 (t, 2, J ) 7.4 Hz), 3.00 (s, 4), 2.51 (d + d, 4, J ) 14.4
Hz), 2.23 (s, 3) 2.182 (s, 3), 2.178 (s, 3), 1.88 (s, 3), 1.23 (s, 18);
13C NMR (CDCl3) δ 172.0, 171.9, 149.7, 148.1, 148.0, 143.6,
142.5, 142.2, 140.4, 139.4, 135.9, 135.8, 134.7, 134.3, 133.5, 133.1,
132.9, 132.8, 132.2, 132.1, 131.8, 131.2, 130.7, 129.4, 129.2, 129.1,
128.9, 126.9, 126.8, 105.8, 105.0 (Ar: Calcd, 30; found, 29), 48.8,
47.7, 45.6, 45.3, 39.8, 37.3, 34.3, 31.5, 31.4, 31.2, 13.5, 12.8, 10.6
and 10.5 (sp3: Calcd 14; found, 14); IR (KBr) 1718.7 (CO2H),
1653.1 cm-1 (CONR2). Anal. Calcd for C78H77O15N5Br4S4: C,
52.86; H, 4.38. Found: C, 53.02; H, 4.46.
5-(Ca r b oxym e t h yl)-17-[[[N -[(ca r b om e t h oxyp h e n yl)-
m eth yl]a m in o]ca r bon yl]m eth yl]-11,23-d i-ter t-bu tyl-25,26,-
27,28-t e t r a k is[[(p -b r om op h e n yl)su lfon yl]oxy]ca lix[4]-
a r en e (8a ). A mixture of 0.60 g (0.4 mmol) of anhydride 4, 0.088
g (0.44 mmol) of (R)-(-)-2-phenylglycine methyl ester hydro-
chloride, 0.1 g of Et3N, and 20 mL of CH2Cl2 was refluxed for 3
h. The mixture was cooled and washed with 0.2 N HCl (2 × 3
mL), water, and brine and the solvent removed by evaporation
to give 0.64 g (95%) of 8a as a white solid: mp > 172 °C dec; 1H
NMR (CDCl3) δ 7.94 (d, 4, J ) 8.7 Hz), 7.82 (d, 4, J ) 8.7 Hz),
7.68 (s, 4), 7.62 (d, 2, J ) 8.2 Hz), 7.53 (d, 2, J ) 8.6 Hz), 7.36-
7.41 (m, 3). 7.24-7.26 (m, 2), 7.0 (d + d, 2, J ) 2.3 Hz), 6.93 (d,
1, J ) 2.3 Hz), 6.88 (d, 1, J ) 7.0 Hz), 6.51 (d, 1, J ) 2.3 Hz),
6.24 (d, 1, J ) 2.2 Hz), 6.15 (d, 1, J ) 2.3 Hz), 6.05 (d, 1, J ) 2.2
Hz), 5.79 (d, 1, J ) 2.0 Hz), 5.53 (d, 1, J ) 7.0 Hz), 3.92 (d, 1, J
) 13.7 Hz), 3.89 (d, 1, J ) 13.9 Hz), 3.73 (s, 3), 3.71 (d, 1, J )
14.4 Hz), 3.57 (d, 1, J ) 14.2 Hz), 3.36 (d, 1, J ) 16.7 Hz), 3.20
(d, 1, J ) 16.2 Hz), 2.98(d, 1, J ) 13.4), 2.81 (d, 1, J ) 13.4 Hz),
2.65 (d, 1, J ) 14.5 Hz), 2.50 (d, 1, J ) 14.5 Hz), 2.39 (d, 1, J )
14.0 Hz), 2.25 (d, 1, J ) 14.0 Hz), 1.32 (s, 9), 1.16 (s, 9); 13C
NMR (CDCl3) δ 172.1, 171.6, 171.4, 149.9, 143.2, 142.2, 142.1,
135.5, 135.4, 135.3, 134.6, 134.3, 134.1, 134.0, 133.8, 133.25,
133.18, 132.8, 132.4, 132.2, 132.1, 131.7, 131.3, 130.8, 130.7,
129.6, 129.4, 129.2, 129.1, 128.7, 127.6, 127.4, 127.0, 126.8, 126.7
(Ar: Calcd, 40; found, 32), 53.2, 52.6, 41.1, 40.3, 37.7, 34.4, 31.4,
31.3, 31.2, 31.0 (sp3: Calcd, 12; found, 10); IR (KBr) 1740.0 (CO2-
Me), 1686.5 (CO2H), 1637.7 cm-1 (CONHR). Anal. Calcd for
NMR (CDCl3) δ 7.91 (d, 4, J ) 8.6 Hz), 7.81 (d, 4, J ) 8.7 Hz),
7.48-7.68 (m, 8), 6,98 (d, 2, J ) 2.1 Hz), 6.94 (d, 2, J ) 2.1 Hz),
6.23 (s, 2), 6.06 (s, 2), 5.77 (br t, 1), 3.92 (d, 2, J ) 14.0 Hz), 3.70
(d, 2, J ) 14.0 Hz), 3.24 (m, 4), 2.89 (s, 2), 2.56 (d, 2, J ) 14.0
Hz), 2.43 (d, 2, J ) 14.1 Hz), 1.25-1.52 (m, 30), 0.89 (t, 3, J )
7.0 Hz); 13C NMR (CDCl3) δ 172.1, 171.9, 150.0, 143.2, 142.0,
141.8, 135.4, 134.6, 134.4, 133.9, 133.7, 133.0, 132.9, 132.8, 132.6,
132.2, 132.1, 131.2, 130.8, 130.7, 129.8, 129.5, 129.2, 127.2, 127.1,
126.7 (Ar: Calcd, 24; found, 24), 41.5, 40.2, 39.9, 34.4, 31.8, 31.3,
31.26, 31.1, 29.3, 29.2, 26.8, 22.6, 14.1 (sp3: Calcd, 14; found
13); IR (KBr) 1734.1 (CO2H), 1722.5 (sh), 1624.2 cm-1 (CONHR).
Anal. Calcd for C72H73NO15Br4S4: C, 52.72; H, 4.49. Found:
C, 52.68; H, 4.48.
5-(Ca r boxym eth yl)-17-[[(N-a d a m a n tyla m in o)ca r bon yl]-
m e t h yl]-11,23-d i-ter t -b u t yl-25,26,27,28-t e t r a k is[[(p -b r o-
m op h en yl)su lfon yl]oxy]ca lix[4]a r en e (7b) was prepared in
90% yield following the procedure described above for 7a using
1-adamantanamine. An analytical sample of 7b was obtained
as white crystals by recrystallization from CH2Cl2-hexane: mp
>200 °C dec; 1H NMR (CDCl3) δ 7.90 (d, 4, J ) 8.7 Hz), 7.80 (d,
4, J ) 8.7 Hz), 7.73 (d, 2, J ) 8.8 Hz), 7.66 (d, 2, J ) 8.8 Hz),
7.61 (d, 2, J ) 8.6 Hz), 7.48 (d, 2, J ) 8.7 Hz), 7.01 (d, 2, J ) 2.3
Hz), 6.97 (d, 2, J ) 2.4 Hz), 6.22 (s, 2), 6.01 (s, 2), 5.31 (s, 1),
3.97 (d, 2, J ) 14.0 Hz), 3.70 (d, 2, J ) 14.1 Hz), 3.20 (s, 2), 2.88
(s, 2), 2.60 (d, 2, J ) 14.0 Hz), 2.43 (d, 2, J ) 14.1 Hz), 2.11 (br,
3), 2.00 (br, 3), 2.00 (bt, 6), 1.69 (br, 3), 1.33 (s, 18); 13C NMR
(CDCl3) δ 172.1, 171.6, 150.1, 143.2, 141.9, 141.6, 135.6, 135.5,
134.7, 134.5, 134.0, 133.8, 133.0, 132.7, 132.1, 131.2, 130.9, 130.7,
129.8, 129.4, 129.1, 127.1, 126.6 (Ar: Calcd, 24; found, 21), 52.8,
41.6, 41.3, 41.0, 36.1, 34.4, 31.5, 31.2, 31.17, 29.3 (sp3: Calcd,
10; found, 10); IR (KBr) 1714.8 (CO2H), 1630 cm-1 (CONHR).
Anal. Calcd for C74H71NO15Br4S4: C, 53.47; H, 4.31. Found:
C, 53.56; H, 4.42.
5-(Ca r b oxym e t h yl)-17-[[(N -p h e n yla m in o)ca r b on yl]-
m e t h yl]-11,23-d i-ter t -b u t yl-25,26,27,28-t e t r a k is[[(p -b r o-
m op h en yl)su lfon yl]oxy]ca lix[4]a r en e (7c) was prepared in
90% yield following the procedure described above for 7a , using
aniline and a 16 h reflux time. An analytical sample of 7c was
obtained as a white solid by column chromotography using 1.5%
1
MeOH-CHCl3 as eluent: mp >175 °C dec; H NMR (CDCl3) δ
7.95 (s, 1), 7.88 (d, 4, J ) 8.7 Hz), 7.79 (d, 4, J ) 8.6 Hz), 7.59-
7.73 (m, 8), 7.48 (dd, 2, J ) 7.4, 8.6 Hz), 7.32 (dd, 2, J ) 7.6, 8.0
Hz), 7.17 (t, 1, J ) 7.4 Hz), 6.99 (d, 2, J ) 2.2 Hz), 6.90 (d, 2, J
) 2.2 Hz), 6.23 (s, 2), 6.11 (s, 2), 3.95 (d, 2, J ) 14.2 Hz), 3.68 (d,
2, J ) 14.2 Hz), 3.34 (s, 2), 2.93 (s, 2), 2.57 (d, 2, J ) 14.0 Hz),
2.44 (d, 2, J ) 14.4 Hz), 1.28 (s, 18); 13C NMR (CDCl3) δ 172.2,
170.6, 150.1, 143.1, 142.0, 141.9, 136.9, 135.5, 135.4, 134.5, 134.2,
134.1, 133.9, 133.2, 132.7, 132.6, 132.3, 132.1, 131.2, 130.8, 130.7,
129.7, 129.6, 129.5, 129.2, 129.0, 127.3, 127.0, 126.7, 125.2, 120.1
(Ar: Calcd, 28; found, 29), 41.3, 41.2, 34.3, 31.3, 31.2, 31.1 (sp3:
Calcd, 6; found 6); IR (KBr) 1719 (CO2H), 1601 cm-1 (CONR2).
Anal. Calcd for C70H61O15NBr4S4: C. 52.41; H, 3.83. Found:
C, 52.74; H, 3.90.
C
73H65O17NBr4S4: C, 52.31; H, 3.91. Found: C, 52.12; H, 3.86.
5-(C a r b o x y m e t h y l)-17-[[[N -[(c a r b o m e t h o x y b e n zy l)
m eth yl]a m in o]ca r bon yl]m eth yl]-11,23-d i-ter t-bu tyl-25,26,-
27,28-t e t r a k is[[(p -b r om op h e n yl)su lfon yl]oxy]ca lix[4]-
a r en e (8b ) was prepared by the procedure described for 8a ,
using L-phenylalanine methyl ester hydrochloride, and was
obtained in 95% yield as a white solid: mp > 160 °C dec; 1H
NMR (CDCl3) δ 7.90-7.93 (4 lines, 4), 7.78-7.82 (4 lines, 4),
7.52-7.63 (5 lines, 8), 7.27 (m, 3), 7.01 (m, 4), 6.93 (d, 1, J ) 2.2
Hz), 6.90 (d, 1, J ) 2.2 Hz), 6.21 (s, 2), 6.13 (d, 1, J ) 7.0 Hz),
6.02 (s, 1), 5.96 (s, 1), 4.84 (m, 1), 3.71-3.91 (m, 7), 3.01-3.23
(m, 4), 2.90 (s, 2), 2.44-2.56 (m, 4), 1.314 (s, 9), 1.307 (s, 9); 13
C
5-(Ca r b oxym et h yl)-17-[[(N,N-d iet h yla m in o)ca r b on yl]-
m e t h yl]-11,23-d i-ter t -b u t yl-25,26,27,28-t e t r a k is[[(p -b r o-
m op h en yl)su lfon yl]oxy]ca lix[4]a r en e (7d ) was prepared in
(10) Sorrell, T. N.; Malachowski, M. R. Inorg. Chem. 1983, 22, 1883.

2284 J . Org. Chem., Vol. 62, No. 7, 1997
Notes
NMR (CDCl3) δ 172.1, 171.6, 171.4, 149.9, 143.2, 142.2, 142.1,
135.5, 135.4, 135.3, 134.6, 134.3, 134.1, 134.0, 133.8, 133.2, 132.8,
132.4, 132.2, 132.1, 131.7, 131.3, 130.8, 130.7, 129.6, 129.4, 129.2,
129.1, 128.7, 127.6, 127.4, 127.0, 126.8, 126.7 (Ar: Calcd, 40;
found, 31), 53.2, 52.6, 41.1, 40.3, 37.7, 34.3, 31.4, 31.3, 31.2, 31.0
(sp3: Calcd, 13; found, 10). Anal. Calcd for C74H67O17NBr4S4:
C, 52.59; H, 4.0. Found: 52.41; H, 4.05.
brine and dried over Na2SO4 and the solvent removed by
evaporation under reduced pressure. The residue was chroma-
tagraphed (0.5% acetone-CHCl3, v/v) and recrystallized from
CH2Cl2-MeOH to yield 0.18 g (85%) of 9a as tiny needles: mp
242-244 °C; 1H NMR (CDCl3) δ 7.91 (d, 4, J ) 8.7 Hz), 7.79
(d, 4, J ) 8.6 Hz), 7.64 (m, 8), 7.33 (m, 3), 7.19 (m, 2), 6.93(d,
2, J ) 2.2 Hz), 6.85 (d, 2, J ) 2.2 Hz), 6.33 (d, 2, J ) 7.1 Hz),
5.96 (d, 2, J ) 2.0 Hz), 5.92 (d, 2, J ) 2.0 Hz), 5.41 (d, 2, J )
7.1 Hz), 3.76 (d, 2, J ) 14.2 Hz), 3.74 (d, 2, J ) 14.5 Hz), 3.69
(s, 6), 2.87 (dd, 4, J ) 15.9 Hz), 2.51 (d, 2, J ) 14.6 Hz), 2.45 (d,
2, J ) 14.6 Hz), 1.22 (s, 18); 13C NMR (CDCl3) δ 171.1, 170.0,
149.9, 143.5, 143.2, 136.2, 135.7, 135.6, 134.7, 134.6, 134.5, 134.2,
132.7, 132.4, 131.9, 131.2, 130.7, 129.5, 129.3, 129.1, 129.0, 128.9,
128.6, 127.0, 126.9, 126.8 (Ar: Calcd, 24; found, 24), 56.2, 52.8,
42.1, 34.3, 31.4, 31.2 (sp3: Calcd, 7; found, 6). Anal. Calcd for
C85H74O18N2Br4S4: C, 54.02; H, 4.09. Found: C, 53.93; H, 4.07
5-(Car boxym eth yl)-17-[[[N-(1-car bom eth oxy-2-im idazolyl-
et h yl)a m in o]ca r b on yl]m et h yl]-11,23-d i-ter t-b u t yl-25,26,-
27,28-t e t r a k is[[(p -b r om op h e n yl)su lfon yl]oxy]ca lix[4]-
a r en e (8c). A mixture of 0.5 g (0.34 mmol) of the anhydride 4,
0.096 g (0.40 mmol) of L-histidine methyl ester dihydrochloride,
0.16 g of Et3N, and 20 mL of CH2Cl2 was refluxed for 3 h. The
mixture was cooled and washed with 1 N HCl (2 × 2 mL), water,
and brine and the solvent removed by evaporation to give a white
solid. Further purification by chromatography (eluant, 5%
MeOH-CHCl3, v/v) followed by recrystallization from CHCl3-
MeOH gave 0.39 g (70%) of 8c as white crystals: mp > 180 °C;
1H NMR (CDCl3) δ 8.05 (d, 1), 7.91 (m, 4), 7.79 (m, 4), 7.51-
7.65 (m, 9), 7.09 (s, 1), 6.99 (s, 2), 6.93 (s, 1), 6.83 (s, 1), 6.31 (s,
1), 6.26 (s, 1), 6.14 (s, 1), 5.81(s, 1), 4.53 (m, 1), 3.94 (d, 1, J )
14.1 Hz), 3.92 (d, 1, J ) 14.0 Hz), 3.69-3.74 (m, 4), 3.54 (d, 1, J
) 14.5 Hz), 2.78-3.19 (m, 6), 2.26-2.60 (m, 4), 1.29 (s, 9), 1.27
(s, 9); 13C NMR (CDCl3) δ 173.8, 171.5, 171.0, 149.9, 149.8, 143.6,
143.5, 142.2, 141.9, 136.4, 136.2, 135.4, 135.0, 134.8, 134.7, 134.5,
134.2, 134.1, 133.5, 133.4, 133.2, 133.1, 132.74, 132.66, 132.6,
132.3, 132.2, 131.2, 130.7, 129.8, 129.5, 129.4, 129.24, 129.20,
129.1, 128.8, 128.2, 127.3, 126.5, 114.8 (Ar: Calcd, 39; found,
37), 53.8, 52.3, 40.5, 40.2, 34.3, 31.9, 31.7, 31.3, 31.2, 31.1, 28.2
(sp3: Calcd, 13; found, 11). Anal. Calcd for C71H65Br4O17N3S4‚
1.67CHCl3: C, 46.45; H, 3.58. Found: C, 46.67. H, 3.68.
(R,R)-5,17-Bis[[[N-[(car bom eth oxyph en yl)m eth yl]am in o]-
ca r bon yl]m eth yl]-11,23-d i-ter t-bu tyl-25,26,27,28-tetr a k is-
[[(p-br om op h en yl)su lfon yl]oxy]ca lix[4]a r en e (9a ). A 0.2 g
(0.12 mmol) sample of 8a was mixed with 0.03 g (0.18 mmol) of
(R)-(-)-2-phenylglycine methyl ester, 0.036 g (0.18 mmol) of
dicyclohexylcarbodimide, and 0.024 g (0.18 mmol) of 1-hydroxy-
benzotriazole in 15 mL of dry CH2Cl2. The mixture was stirred
at rt for 1 day. After removal of the precipitate by filtration,
the solution was treated with 2 mL of 0.1 N HCl, water, and
(R,S)-5,17-Bis[[[N-[(car bom eth oxyph en yl)m eth yl]am in o]-
ca r bon yl]m eth yl]-11,23-d i-ter t-bu tyl-25,26,27,28-tetr a k is-
[[(p-br om op h en yl)su lfon yl]oxy]ca lix[4]a r en e (9b) was pre-
pared by the procedure described for 9a , using (S)-(+)-2-
phenylglycine methyl ester, and was obtained in 85% yield as
tiny needles: mp 249.5-251.5 °C; 1H NMR (CDCl3) δ 7.91 (d, 4,
J ) 8.6 Hz), 7.79 (d, 4, J ) 8.6 Hz), 7.64 (m, 8), 7.33 (m, 3), 7.19
(m, 2), 6.94 (s, 2), 6.85(s, 2), 6.29 (d, 2, J )7.3 Hz), 5.99 (s, 2),
5.91 (s, 2), 5.41 (d, 2, J ) 7.2 Hz), 3.73 (dd, 2, J ) 14.0 Hz), 3.69
(s, 6), 2.86 (s, 4), 2.48(dd, 2, J ) 15.0 Hz), 1.26 (s, 9), 1.20 (s, 9);
13C NMR (CDCl3) δ 171.1, 170.0, 149.9, 143.5, 143.48, 143.3,
136.2, 135.7, 135.64, 135.60, 134.7, 134.6, 134.5, 134.1, 132.8,
132.4, 131.9, 131.2, 130.7, 129.5, 129.3, 129.2, 129.0, 128.6, 127.0,
126.9, 126.8 (Ar: Calcd, 28; found, 25), 56.2, 52.8, 42.2, 34.39,
34.34, 31.44, 31.28, 31.23 (sp3: Calcd, 9; found 8). Anal. Calcd
for C85H74O18N2Br4S4: C, 54.02; H, 4.09. Found: C, 53.83; H,
4.07.
Ack n ow led gm en t. We are indebted to the National
Science Foundation and the Robert A. Welch Founda-
tion for generous support of this work.
J O962044P