Synthesis and reactions of calix[4]arene bisanhydrides

Article abstract of DOI:10.1021/jo9822636

The tetrabenzyl ether, tetra-p-bromobenzenesulfonate, and tetra-p- methylbenzenesulfonate of p-carboxymethylcalix[4]arene in the 1,3-alternate conformation have been converted to the corresponding bisanhydrides. Reactions of the bisanhydrides with alcohols or amines afford calix[4]arenes carrying two carboxymethyl and two carboalkoxymethyl or two amidomethyl groups on the upper rim positions. The substitution pattern that is established confers molecular chirality on the calixarenes.

Full text of DOI:10.1021/jo9822636

J . Org. Chem. 1999, 64, 3507-3512
3507
Syn th esis a n d Rea ction s of Ca lix[4]a r en e Bisa n h yd r id es1
Shiv Kumar Sharma and C. David Gutsche*
Department of Chemistry, Texas Christian University, Fort Worth, Texas 76129
Received November 13, 1998
The tetrabenzyl ether, tetra-p-bromobenzenesulfonate, and tetra-p-methylbenzenesulfonate of
p-carboxymethylcalix[4]arene in the 1,3-alternate conformation have been converted to the
corresponding bisanhydrides. Reactions of the bisanhydrides with alcohols or amines afford calix-
[4]arenes carrying two carboxymethyl and two carboalkoxymethyl or two amidomethyl groups on
the upper rim positions. The substitution pattern that is established confers molecular chirality
on the calixarenes.
1
Calixarenes are cavity-containing macrocyclic com-
pounds2 that are of interest, inter alia, for their potential
to serve as catalysts when appropriately substituted on
the lower and/or upper rims. Among the numerous
methods that have been fashioned for effecting upper rim
functionalization are those employing anhydride inter-
mediates, the first example of which was reported by Xie
and Gutsche for a calix[4]arene monoanhydride.3 The
present paper extends these studies to calix[4]arene
bisanhydrides and provides compounds that are useful
precursors to upper rim-substituted calix[4]arenes pos-
sessing molecular chirality.
The starting material for the present study is p-cyano-
methylcalix[4]arene (1),4 prepared from the readily avail-
able p-tert-butylcalix[4]arene5 by removal of the tert-butyl
groups followed by application of the p-quinonemethide
reaction sequence6 (amino-methylation with HCHO and
R2NH, methylation with MeI, and treatment with CN-).
Subsequent functional group alteration was then carried
out by two routes, one involving hydrolysis of the cyano
groups before O-functionalization (1 f 2 f 3 f 4 f 5)
and the other involving hydrolysis of the cyano groups
after O-functionalization (1 f 6 f 7 f 5). In the first
route acid-catalyzed hydrolysis of the tetracyano com-
pound 1 followed by esterification with MeOH produced
the previously reported7 tetraester 2 which was treated
with benzyl bromide and a large excess of K2CO3 to afford
the tetrabenzyl ether 3 in 83% yield. The appearance of
a singlet at δ 3.63 in the H NMR spectrum and a line at
δ 37.48 in the 13C NMR spectrum8 established the
conformation as 1,3-alternate, and this conformation is
retained throughout the remaining transformations. Hy-
drolysis of 3 with aqueous alcoholic KOH gave the
tetracarboxylic acid 4 which, however, resisted conversion
to an anhydride upon treatment with (COCl)2 or SOCl2
in CH2Cl2. Prolonged treatment with refluxing Ac2O did
produce the desired bisanhydride 5a , but in only 8%
yield. Therefore, an alternative route to the bisanhy-
drides was sought which started with the conversion of
1 to an arylsulfonate by treatment with p-toluenesulfonyl
chloride (tosylation) or p-bromobenzenesulfonyl chloride
(brosylation) in the presence of 1-methylimidazole, pro-
ducing the 1,3-alternate conformers of 6b and 6a . Acid-
catalyzed hydrolysis of the arylsulfonates gave the tet-
raacids 7a and 7b which reacted with (COCl)2 under high
dilution conditions to afford the bisanhydrides 5b and
5c in 61% and 34% yields, respectively. (Scheme 1).
The bisanhydrides 5a -c reacted with alcohols (MeOH,
EtOH, n-PrOH, i-PrOH) to give the half esters 8a -h and
with amines (PhCH2CH2NH2, Et2NH, Me2CHNH2) and
bis[(3,5-dimethyl-1-pyrazoyl)ethyl]amine to give the half
amides 10a -d in quantitative yields (Chart 1). The
products of these reactions all possess molecular chirality,
1
and as a consequence display rather complex H NMR
spectral patterns. When the half esters 8a -h are con-
verted to the corresponding tetraesters 9a -h , however,
the 1HNMR spectra became much less complex as the
result of the transformation from chiral to achiral
molecules (Scheme 2). In like fashion, the complexity of
the H NMR spectra of the half amides 10b and 12 were
markedly reduced when converted to the tetraamides 11a
and 11b, respectively. A representative example of the
(1) Paper 51 in a series entitled Calixarenes. For paper 50, cf.:
Sharma, S. K.; Gutsche, C. D. J . Org. Chem. 1999, 64, 998-1003.
(2) (a) Gutsche, C. D. Calixarenes Revisited; Stoddart, F. J ., Ed.;
Monographs in Supramolecular Chemistry: The Royal Society of
Chemistry, 1998. (b) Bo¨hmer, V. Calixarene, Macrocycles with (Almost)
Unlimited Possibilities. Angew. Chem., Int. Ed. Engl. 1995, 34, 713-
745. (c) Gutsche, C. D. Calixarenes. Aldrichimica Acta 1995, 28, 3-9.
(d) Calixarenes: A Versatile Class of Macrocyclic Compounds; Vicens,
J ., Bo¨hmer, V., Eds.; Kluwer Academic Publishers: Dordrecht, The
Netherlands, 1991. (e) Gutsche, C. D. Calixarenes; Stoddart, F. J ., Ed.;
Monographs in Supramolecular Chemistry: The Royal Society of
Chemistry, 1989.
(3) Xie, D.; Gutsche, C. D. J . Org. Chem. 1997. 62, 2280.
(4) The term “calixarene” is variously employed in different contexts.
In colloquial usage (as employed in the Discussion Section), it implies
the presence of oxygens on the lower rim. In the more precise and
complete specification of a compound (as used in the Experimental
Section), it implies only the basic skeleton to which the substituents,
including the O-containing groups, are attached at positions designated
by appropriate numbers.
1
1
contrasting H NMR spectra for the chiral and achiral
molecules is shown in Figure 1. The half amide 10d and
the tetraamides 11b,c are of interest in connection with
our ongoing study of copper-containing calixarenes as
oxidation catalysts.9
Exp er im en ta l Section 10
5,11,17,23-Tetr a k is(ca r bom eth oxym eth yl)-25,26,27,28-
tetr a k is(ben zyloxy)ca lix[4]a r en e (3) (1,3-Alter n a te Con -
for m er ). A mixture of 54.0 g (0.4 M) of anhydrous K2CO3 and
(5) Gutsche, C. D.; Iqbal, M. Org. Synth. 1990, 68, 234.
(6) Gutsche, C. D.; Nam, K. C. J . Am. Chem. Soc. 1988, 110, 6153.
(7) Sharma, S. K.; Kanamathareddy, S.; Gutsche, C. D. Synthesis
1997, 1268.
(8) J aime, C.; deMendoza, J .; Prados, P.; Nieto, P. M.; Sanchez, C.
J . Org. Chem. 1991, 56, 3372.
(9) Xie, D.; Gutsche, C. D. J . Org. Chem. 1999, 63, 9270.
10.1021/jo9822636 CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/24/1999

3508 J . Org. Chem., Vol. 64, No. 10, 1999
Sharma and Gutsche
Sch em e 1
Ch a r t 1
2.5 g of NaI was suspended in 200 mL of Me2CO in a 500 mL
round-bottomed flask, and 7.0 g (10 mmol) of the tetraester
27 was added. The reaction mixture was stirred for 5 min, and
27.5 g (0.15 M) of benzyl bromide was added. The reaction
mixture was stirred for 36 h at room temperature. The solvent
was removed by evaporation, and the residue was poured into
ice-cold water and neutralized with 20% HCl to give a light
yellow precipitate. The precipitate was removed by filtration,
and the product was purified by column chromatography (CH2-
Cl2 eluent) to give 8.90 g (83%) of the tetrabenzyl ether 3 as a
white powder: mp 255-56 °C; 1H NMR (CDCl3) δ 7.41 (bs,
12), 7.08 (d, 8, J ) 6.0 Hz), 6.57 (s, 8), 4.80 (s, 8), 3.63 (s, 8),
3.54 (s, 12), 2.89 (s, 8); 13C NMR (CDCl3) δ 172.57, 155.02,
138.32, 133.98, 131.90, 128.08, 127.34, 127.01, 126.36, 71.61,
51.73, 40.00, 37.48. Anal. Calcd for C68H64O12: C, 76.10; H,
6.01. Found: C, 75.84; H, 6.03.
of KOH in 100 mL of EtOH, and 20 mL of H2O was refluxed
for 48 h, and progress of the reaction was monitored with 1H
NMR. After completion, most of the EtOH was removed under
reduced pressure, and the residue was dissolved in ice-cold
water and neutralized with 50% HCl to give a white precipi-
tate. This was removed by filtraton, washed thoroughly with
cold water, and dried at 80-90 °C for 2 days to give 2.71 g
(72%) of the tetraacid 4. An analytical sample was obtained
by trituration with MeOH: mp 260-62 °C; 1H NMR (CDCl3)11
δ 7.52-7.39 (m, 12), 7.10 (d, 8, J ) 6.3 Hz), 6.57 (s, 8), 4.78 (s,
8H), 3.61 (s, 8H), 2.85 (s, 8); 13C NMR (CDCl3 + 1 drop DMSO-
d6) δ 174.27, 154.99, 138.35, 133.91, 132.14, 128.21, 128.03,
127.16, 126.61, 71.86, 40.37, 37.59. Anal. Calcd for C64H56O12
H2O: C, 74.26; H, 5.65. Found: C, 74.36; H, 5.59.
‚
Bisa n h yd r id e of 5,11,17,23-Tetr a k is(ca r boxym eth yl)-
25,26,27,28-t et r a k is(b en zyloxy)ca lix[4]a r en e (5a ) (1,3-
Alter n a te Con for m er ). A slurry of 3.5 g (3.5 mmol) of the
tetraacid 4 in 200 mL ofAc2O was stirred for 4 h at room
temperature and then refluxed for 18 h in an oil bath at 135-
5,11,17,23-Tetr akis(car boxym eth yl)-25,26,27,28-tetr akis-
(ben zyloxy)ca lix[4]a r en e (4) (1,3-Alter n a te Con for m er ).
A mixture of 4.0 g (4 mmol) of tetraester 3, 4.0 g (large excess)

Synthesis and Reactions of Calix[4]arene Bisanhydrides
J . Org. Chem., Vol. 64, No. 10, 1999 3509
F igu r e 1. 1H NMR spectra of the diethyl ester 8d and tetraethyl ester 9a of the tetrabenzyl ether of p-carboxymethylcalix[4]-
arene.
Sch em e 2
40 °C. The reaction mixture was poured into cold water, and
the yellow semisolid precipitate was extracted into CH2Cl2. The
organic layer was separated, the solvent was removed under
reduced pressure, and the residue was triturated with n-
hexane. The hexane-insoluble material was the major product
and proved to be starting material. Evaporation of the hexane
produced a light yellow solid which was subjected to column
chromatography (CHCl3 eluent) to give 0.28 g (8%) of the
bisanhydride 5a as a white powder. An analytical sample was
Bisa n h yd r id e of 5,11,17,23-Tetr a k is(ca r boxym eth yl)-
25,26,27,28-t et r a k is(4′-b r om ob en zen esu lfon yl)ca lix[4]-
a r en e (5b) (1,3-Alter n a te Con for m er ). A mixture of 2.0 g
(1.33 mmol) of 7a in 150 mL of HPLC grade dry CH2Cl2
containing 6 mL of (COCl)2 was refluxed under N2 for 6 h.
Evaporation of the solvent and excess (COCl)2 under vacuum
gave a white solid which was stirred with n-hexane, and the
insoluble material was removed by filtration and dried. The
product was flash chromatographed (HPLC grade CH2Cl2
eluent) to give 1.2 g (61%)12 of 5b as a white powder: mp 270-
72 °C; 1H NMR (CDCl3) δ 7.90 (d, 8, J ) 8.7 Hz), 7.84 (d, 8, J
) 8.4 Hz), 6.70 (s, 8), 3.37 (s, 8), 3.30 (s, 8); 13C NMR (CDCl3)
δ 166.24, 145.30, 135.74, 133.67, 133.36, 130.92, 130.59,
1
prepared by trituration with cold MeOH: mp 265-66 °C; H
NMR (CDCl3) δ 7.47-7.40 (m, 20), 6.79 (s, 8), 4.82 (s, 8H),
3.53 (s, 8H), 3.13 (s, 8); 13C NMR (CDCl3) δ 167.54, 155.58,
138.15, 133.72, 131.46, 128.85, 128.37, 125.19, 75.29, 42.55,
35.46. Anal. Calcd for C64H52O10‚0.5 H2O: C, 77.64; H, 5.40.
Found: C, 77.46; H, 5.33.
129.84, 129.63, 42.43, 34.31. Anal. Calcd for C60H40S4Br4O18
C, 48.14; H, 2.69. Found: C, 47.77; H, 2.52.
:

3510 J . Org. Chem., Vol. 64, No. 10, 1999
Sharma and Gutsche
Bisa n h yd r id e of 5,11,17,23-Tetr a k is(ca r boxym eth yl)-
25,26,27,28-t et r a k is(4′-m et h ylb en zen esu lfon yl)ca lix[4]-
a r en e (5c) (1,3-Alter n a te Con for m er ). A mixture of 4.0 g
(4 mmol) of 7b in 300 mL of dry CH2Cl2 containing 6 mL of
(COCl)2 was refluxed under N2 for 10 h. The product was
worked up and purified according to the procedure of 5b as a
white powder: yield 1.4 g (34%);11 mp 287-88 °C; 1H NMR
(CDCl3) δ 7.91 (d, 8, J ) 8.4 Hz), 7.48 (d, 8, J ) 8.1 Hz), 6.67
(s, 8), 3.51 (s, 8), 3.31 (s, 8), 2.52 (s, 12); 13C NMR (CDCl3) δ
166.45, 146.34, 145.41, 134.09, 133.80, 130.93, 130.49, 129.15,
128.34, 42.36, 34.23, 21.86. Anal. Calcd for C64H52S4O18: C,
62.12; H, 4.24. Found: C, 62.08; H, 4.54.
reaction mixture was poured over 400 mL of ice-cold water to
give a white precipitate which was removed by filtration and
washed thoroughly with water to remove unreacted acid. The
product was dried at 80-90 °C for 2 days to give 7.20 g (94%)
of 7a as a colorless powder. An analytical sample was obtained
by triturating with MeOH: mp 156-57 °C; 1H NMR (CDCl3)11
δ 7.79 (s, 16), 6.82 (s, 8), 3.38 (s, 8), 3.28 (s, 8); 13C NMR (CDCl3)
δ 173.28, 144.90, 135.86, 134.58, 134.23, 133.41, 132.11,
131.25, 130.78, 40.56, 35.61. Anal. Calcd for C60H44S4Br4O20:
C, 47.01; H, 2.89. Found: C, 47.17; H, 2.76.
5,11,17,23-Tetr akis(car boxym eth yl)-25,26,27,28-tetr akis-
(4′-m eth ylben zen esu lfon yl)ca lix[4]a r en e (7b) (1,3-Alter -
n a te Con for m er ). Following the procedure described above
for the preparation of 7a , a 0.6 g (5 mmol) sample of 6b was
converted to 5.8 g (93%) of 7b which was obtained as a colorless
5,11,17,23-Tetr a k is(cya n om eth yl)-25,26,27,28-tetr a k is-
(4′-br om oben zen esu lfon yl)ca lix[4]a r en e (6a ) (1,3-Alter -
n a te Con for m er ). A slurry of 4.35 g (7.5 mmol) of p-cyano-
methylcalix[4]arene (1) in 200 mL of anhydrous MeCN was
treated, with stirring, with 15 mL of 1-methylimidazole (clear
yellow solution) followed by portionwise addition of 25.0 g (0.1
mol) of 4-bromobenzenesulfonyl chloride. The reaction mixture
was stirred at room temperature for 4 days (progress of the
reaction monitored by 1H NMR). After completion, it was
poured into ice-cold H2O and neutralized with 50% HCl to give
a light yellow precipitate.This was separated by filtration and
purified by column chromatography (CH2Cl2 eluent) to give
9.6 g (88%) of 6a as a pale yellow powder. An analytical sample
was obtained by trituration with MeOH: mp 273-274 °C
1
solid after trituration with MeOH: mp 286-87 °C; H NMR
(DMSO-d6)11 δ 8.10 (d, 8, J ) 8.4 Hz), 7.66 (d, 8, J ) 8.1 Hz),
6.39 (s, 8), 3.53 (s, 8), 2.89 (s, 8), 2.51 (s, 12); 13C NMR (DMSO-
d6) δ 172.39, 147.19, 144.05, 133.43, 133.34, 131.99, 131.24,
131.11, 128.48, 40.27, 34.23, 21.78. Anal. Calcd for C64H56
S4O20: C, 60.37; H, 4.43. Found: C, 60.31; H, 4.56.
-
5,11-Bis(ca r b oxym et h yl)-17,23-b is(m et h oxyca r b om e-
t h yl)-25,26,27,28-t et r a k is(b en zyloxy)ca lix[4]a r en e (8a )
(1,3-Alter n a te Con for m er ). A mixture of 80 mg (0.08 mmol)
of the bisanhydride 5a in 50 mL of HPLC grade MeOH was
refluxed for 4 h under N2. The MeOH was removed under
reduced pressure, and the residue was triturated with n-
hexane to leave a quantitative yield of 8a as a white powder:
mp 255-57 °C; 1H NMR (CDCl3)11 δ 7.47-7.39(m, 12), 7.12
(b, 8). 6.61 (s,4), 6.49 (s, 4), 4.84-4.70 (m, 8), 3.70-3.47 (m,
14), 3.06 (s, 4), 3.00 (s, 4). Anal. Calcd for C66H60O12‚MeOH C,
74.70; H, 5.98. Found: C, 74.78; H, 5.73.
1
(softening at 240 °C); H NMR (CDCl3) δ 7.86 (s, 16), 6.87 (s,
8), 3.58 (s, 8), 3.36 (s, 8); 13C NMR (CDCl3) δ 146.24, 135.91,
134.23, 133.69, 130.92, 130.73, 130.06, 128.39, 118.27, 35.18,
23.02. Anal. Calcd for C60H40N4S4Br4O12: C, 49.47; H, 2.77.
Found: C, 50.03; H, 2.48.
5,11,17,23-Tetr a k is(cya n om eth yl)-25,26,27,28-tetr a k is-
(4′-m eth ylben zen esu lfon yl)ca lix[4]a r en e (6b) (1,3-Alter -
n a te Con for m er ). Following the procedure described above
for 6a , a 5.81 g (10 mmol) sample of 1 was converted (5 day
reaction time) to 8.10 g (67%) of 6b as an almost colorless
powder from which an analytical sample was obtained by
5,11-Bis(ca r b oxym et h yl)-17,23-b is(m et h oxyca r b om e-
th yl)-25,26,27,28-tetr a k is(4′-br om oben zen esu lfon yloxy)-
ca lix[4]a r en e (8b) (1,3-a lter n a te con for m er ) was obtained
in quantitative yield as a white powder by refluxing l.0 g of
5b with anhydrous MeOH and working up the reaction
mixture as described above for 8a : mp 140-41 °C (softening),
151-53 °C; 1H NMR (CDCl3)11 δ 7.82-7.68 (m, 16), 6.84-6.63
(m, 8), 3.91-3.80 (m, 6), 3.52-3.20 (m, 16). Anal. Calcd for
1
trituration from MeOH: mp 266-68 °C; H NMR (CDCl3) δ
7.84 (d, 8, J ) 8.4 Hz), 7.49 (d, 8, J ) 8.4 Hz), 6.82 (s, 8), 3.46
(s, 8), 3.36 (s, 8), 2.54 (s, 12); 13C NMR (CDCl3) δ 146.74, 146.43,
134.44, 134.23, 130.84, 128.76, 128.55, 127.88, 118.21, 35.14,
22.92, 22.20. Anal. Calcd for C64H52N4 S4O12: C, 64.20; H, 4.38.
Found: C, 65.04; H, 4.46.
C
62H48S4Br4O20: C, 47.70; H, 3.10. Found: C, 47.63; H, 3.23.
5,11-Bis(ca r b oxym et h yl)-17,23-b is(m et h oxyca r b om e-
th yl)-25,26,27,28-tetr a k is(4′-m eth ylben zen esu lfon yloxy)-
ca lix[4]a r en e (8c) (1,3-a lter n a te con for m er ) was obtained
in quantitative yield as a white powder from the reaction of
5,11,17,23-Tetr akis(car boxym eth yl)-25,26,27,28-tetr akis-
(4′-br om oben zen esu lfon yl)ca lix[4]a r en e (7a ) (1,3-Alter -
n a te Con for m er ). A slurry of 7.32 g (5 mmol) of the tetraester
6a in 150 mL of acetic acid was treated with 12 mL of H2O
and 12 mL of concentrated H2SO4 with careful stirring at room
temperature. The reaction mixture was refluxed for 10 h, and
1
l.1 g of 5c with anhydrous MeOH: mp 240-42 °C; H NMR
(CDCl3)11 δ 7.89-7.80 (m, 8), 7.47-7.43 (m, 8), 6.83-6.57 (m,
8), 3.89-3.74 (m, 12), 3.51-3.10 (m, 16), 2.52 (m, 6). Anal.
Calcd for C66H60S4O20: C, 60.91; H, 4.64. Found: C, 60.71; H,
4.46.
1
the progress of the reaction was monitored with H NMR. The
5,11-Bis(car boxym eth yl)-17,23-bis(eth oxycar bom eth yl)-
25,26,27,28-tetr a k is(ben zyloxy)ca lix[4]a r en e (8d ) (1,3-
a lter n a te con for m er ) was prepared in quantitative yield by
refluxing 50 mg of 5a with absolute EtOH and was obtained
as a white powder: mp 154-56 °C; 1H NMR (CDCl3)11 δ 7.40
(bs, 12), 7.14-7.08 (m, 8). 6.62-6.48 (m, 8), 4.80-4.70 (m, 8),
4.11-3.99 (2q, 4), 3.62-3.46 (m, 8), 3.10-2.86 (m, 8), 1.26-
1.15 (2t, 6). Anal. Calcd for C68H64O12‚H2O: C, 74.84; H, 6.09.
Found: C, 74.69; H, 5.75.
5,11-Bis(car boxym eth yl)-17,23-bis(eth oxycar bom eth yl)-
25,26,27,28-tetr a k is(4′-br om oben zen esu lfon yloxy)ca lix-
[4]a r en e (8e) (1,3-a lter n a te con for m er ) was obtained in
quantitative yield by refluxing 0.21 g of 5b with absolute EtOH
as a white powder: mp 159-61 °C; 1H NMR (CDCl3) δ 7.87-
7.41 (m, 16), 6.83-6.52 (m, 8), 4.38-4.15 (m, 4), 3.62-2.98
(m, 16), 1.41-1.26 (m, 6). Anal. Calcd for C64H52S4Br4O20: C,
48.37; H, 3.29. Found: C, 48.28; H, 3.48.
5,11-Bis(car boxym eth yl)-17,23-bis(eth oxycar bom eth yl)-
25,26,27,28-tetr a k is(4′-m eth ylben zen esu lfon yloxy)ca lix-
[4]a r en e (8f) (1,3-a lter n a te con for m er ) was obtained in
quantitative yield by refluxing 0.12 g of 5c with absolute EtOH
as a white powder: mp 265-67 °C (softening at 255-6 °C);
1H NMR (CDCl3)11 δ 7.87-7.81 (m, 8), 7.46-7.42 (m, 8), 6.78-
6.57 (m, 8), 4.36-4.18 (m, 4), 3.46-3.15 (m, 16), 2.5 (bs, 12),
1.39-1.32 (m, 6).
(10) Unless otherwise noted, starting materials were obtained from
commercial suppliers and used without further purification. The HPLC
grade of N,N-dimethylformamide (DMF), dichloromethane, acetonitrile,
and acetone were used. Tetrahydrofuran (THF) was dried over
benzophenone/Na and distilled before using. Column chromatography
was carried out with Aldrich 70-230 mesh, 60 Å silica gel. Thin-layer
chromatography (TLC) was performed on 250 µm silica gel plates
containing a fluorescent indicator. Melting points were measured in
sealed and evacuated capillary tubes on
a MEL-Temp apparatus
(Laboratory Devices, Cambridge, MA) using a 400 °C thermometer
calibrated against a thermocouple and are uncorrected. The 1H NMR
and 13C NMR spectra were recorded on a Varian XL-300 spectrometer,
and the chemical shifts are reported as δ values with units of parts
per million (ppm). 1H NMR spectra are referenced to tetramethylsilane
(TMS) at 0.00 ppm as an internal standard and recorded at room
temperature (20 ( 1 °C), and 13C NMR spectra are referenced to CDCl3
(77.00 ppm), DMSO-d6 (40.0 ppm), or TMS (0.00 ppm) and also
recorded at room temperature (20 ( 1 °C). Microanalytical samples
were dried for at least 48-72 h at 111 °C (refluxing toluene) or at 140
°C (refluxing xylene) at 1-2 mm, and the analyses were carried out
by Desert Laboratories, Tucson, AZ. In cases where the solvent of
crystallization affected the elemental analysis, appropriate increments
of the solvents were used to obtain the best fit between the observed
and calculated values.
(11) The CO2H resonances are not reported in the 1H NMR spectra.
(12) Further elution gave a mixture of starting material and an
unidentified intermediate from which additional bisanhydride can be
obtained by retreatment with (COCl)2 as described.

Synthesis and Reactions of Calix[4]arene Bisanhydrides
J . Org. Chem., Vol. 64, No. 10, 1999 3511
5,11-Bis(ca r b oxym et h yl)-17,23-b is(n -p r op oxyca r b o-
m eth yl)-25,26,27,28-tetr akis(ben zyloxy)calix[4]ar en e (8g)
(1,3-a lter n a te con for m er ) was prepared in quantitative yield
from 80 mg of 5a and n-propanol as a white powder: mp 181-
84 °C; 1H NMR (CDCl3)11 δ 7.38 (b, 12), 7.11 (b, 8). 6.60 (s, 8),
4.77-4.74 (m, 8), 3.99-3.90 (m, 4), 3.60-3.49 (m, 8), 3.02 (s,
4), 2.94 (s, 4), 1.62-1.54 (m, 4), 0.90-0.86 (m, 6). Anal. Calcd
for C70H68O12‚3H2O: C, 72.77; H, 6.46. Found: C, 72.98; H,
6.55.
9a using absolute EtOH to give a quantitative yield of 9e as
a white powder: mp 216-17 °C; 1H NMR (CDCl3) δ 7.71 (d, 8,
J ) 8.3 Hz), 7.42 (d, 8, J ) 8.3 Hz), 6.74 (s, 8), 4.07 (q, 8, J )
6.9 Hz), 3.45 (s, 8), 3.05 (s, 8), 2.51 (s, 12), 1.31 (t, 12, J ) 7.1
Hz); 13C NMR (CDCl3) δ 170.86, 145.73, 145.17, 133.93, 133.72,
131.56, 131.22, 130.16, 128.04, 60.90, 40.15, 35.00, 21.79,
14.27. Anal. Calcd for C72H72S4O20‚H2O: C, 61.61; H, 5.31.
Found: C, 61.68; H, 5.12. The tetraethyl ester 9e was also
obtained when the diethyl ester 8f was refluxed with absolute
EtOH containing a drop of concentrated H2SO4.
5,11,17,23-Tet r a k is(ca r bo-n -p r op yloxym et h yl)-25,26,-
27,28-tetr akis(4′-br om oben zen esu lfon yl)calix[4]ar en e (9f)
(1,3-a lter n a te con for m er ) was prepared as described above
for 9a using anhydrous n-PrOH to give a quantitative yield of
9f as a white powder: mp 155-57 °C; 1H NMR (CDCl3) δ 7.77
(d, 8, J ) 8.4 Hz), 7.42 (d, 8, J ) 8.7 Hz), 6.84 (s, 8), 4.05 (t, 8,
J ) 6.6 and 6.9 Hz), 3.62 (s, 8), 2.99 (s, 8), 1.65 (m, 8), 0.94 (t,
12, J ) 7.2 and 7.5 Hz); 13C NMR (CDCl3) δ 170.73, 145.48,
135.69, 134.04, 132.79, 132.35, 132.19, 129.57, 129.09, 66.60,
39.83, 36.01, 21.95, 10.38. Anal. Calcd for C72H68S4Br4O20: C,
50.83; H, 4.04. Found: C, 50.52; H, 4.05. The tetra-n-propyl
ester 9f was also obtained when the di-n-propyl ester 8h was
refluxed with n-PrOH containing a drop of concentrated H2-
SO4.
5,11-Bis(ca r b oxym et h yl)-17,23-b is(n -p r op oxyca r b o-
m et h yl)-25,26,27,28-t et r a k is(4′-b r om ob en zen esu lfon yl-
oxy)ca lix[4]a r en e (8h ) (1,3-a lter n a te con for m er ) was
prepared in quantitative yield from 0.21 g of 5b and 2-propanol
as a white powder: mp. 118-19 °C; 1H NMR (CDCl3)11 δ 7.87-
7.62 (m, 16), 6.84-6.51 (m, 8), 4.29-4.09 (m, 4), 3.55-3.17
(m, 16), 1.78-1.70 (m, 4), 1.02-0.95 (m, 6). Anal. Calcd for
C
66H56S4Br4O20: C, 49.02; H, 3.49. Found: C, 48.63; H, 3.34.
5,11,17,23-Tet r a k is(ca r b oet h oxym et h yl)-25,26,27,28-
tetr a kis(ben zyloxy)ca lix[4]a r en e (9a ) (1,3-Alter n a te Con -
for m er ). A mixture of 0.20 g (0.2 mmol) of tetraacid 4 and
100 mL of absolute EtOH containing 2 drops of concentrated
H2SO4 was refluxed for 4 h. After completion of the reaction
(as revealed by TLC), the EtOH was removed under reduced
pressure and the residue was poured over ice-cold water to
give a white precipitate. The product was removed by filtration
to give 0.22 g (100%) of a white powder which was purified by
chromatography (CH2Cl2 eluent) followed by trituration with
MeOH: mp 150-52 °C (softening at 118 °C); 1H NMR (CDCl3)
δ 7.39 (m, 12), 7.10 (m, 8), 6.58 (s, 8), 4.79 (s, 8), 4.00 (q, 8, J
) 6.9 Hz), 3.62 (s, 8), 2.88 (s, 8), 1.16 (t, 12, J ) 4.0 Hz); 13C
NMR (CDCl3) δ 172.53, 155.32, 138.69, 134.25, 132.18, 128.39,
127.82, 127.30, 126.76, 71.98, 60.79, 40.51, 37.82, 14.51. Anal.
Calcd for C72H74O12: C, 76.44; H, 6.59. Found: C, 76.23; H,
6.46. The tetraethyl ester 9a was also obtained by refluxing
8a with EtOH containing a drop of concentrated H2SO4.
5,11,17,23-Tetr a k is(ca r bom eth oxym eth yl)-25,26,27,28-
tetr akis(4′-br om oben zen esu lfon yl)calix[4]ar en e (9b) (1,3-
Alter n a te Con for m er ). A slurry of 0.20 g (0.13 mmol) of the
dimethyl ester 8b in 50 mL of anhydrous MeOH was treated
wth 2 drops of concentrated H2SO4 with stirring at room
temperature. The reaction mixture was refluxed (after 30 min
clear solution) for 3 h and worked up as described above for
9a to give 9b in quantitative yield. An analytical sample was
obtained by column chromatography (CH2Cl2 eluent): mp
5,11,17,23-Tet r a k is(ca r bo-n -p r op yloxym et h yl)-25,26,-
27,28-t et r a k is(4′-m et h yl-ben zen esu lfon yl)ca lix[4]a r en e
(9g) (1,3-a lter n a te con for m er ) was prepared as described
above for 9a using anhydrous MeOH to give a 90% yield of 9g
1
as a white powder: mp 178-80 °C; H NMR (CDCl3) δ 7.69
(d, 8, J ) 8.4 Hz), 7.42 (d, 8, J ) 7.8 Hz), 6.75 (s, 8), 4.08 (t, 8,
J ) 6.6 Hz), 3.45 (s, 8), 3.08 (s, 8), 2.51 (s, 12), 1.69 (m, 8),
0.95 (t, 12, J ) 7.5 Hz); 13C NMR (CDCl3) δ 170.91, 145.71,
145.16, 133.72, 131.59, 131.29, 130.13, 128.05, 66.49, 40.15,
35.00, 21.98, 21.79, 10.39. Anal. Calcd for C76H80S4O20
63.31; H, 5.59. Found: C, 62.96; H, 5.49.
: C,
5,11,17,23-Tetr a k is(ca r boisop r op ylm eth yl)-25,26,27,28-
tetr akis(4′-br om oben zen esu lfon yl)calix[4]ar en e (9h ) (1,3-
a lter n a te con for m er ) was prepared as described above for
9a using anhydrous i-PrOH to give an 87% yield of 9h as a
white powder: mp 192-94 °C; 1H NMR (CDCl3) δ 7.77 (d, 8, J
) 6.9 Hz), 7.40 (d, 8, J ) 6.6 Hz), 6.85 (s, 8), 5.02 (m, 4), 3.64
(s, 8), 2.94 (s, 8), 1.25 (d, 24, J ) 6.0 Hz); 13C NMR (CDCl3) δ
170.22, 145.47, 135.67, 134.08, 132.76, 132.54, 132.19, 68.44,
40.07, 36.07, 21.82. Anal. Calcd for C72H68S4Br4O20‚0.5CH2-
Cl2: C, 49.94; H, 3.94. Found: C, 49.95; H, 3.53.
1
216-18 °C; H NMR (CDCl3) δ 7.78 (d, 8, J ) 8.58 Hz), 7.45
(d, 8, J ) 8.73 Hz), 6.82 (s, 8), 3.72 (s, 12), 3.60 (s, 8), 3.02 (s,
8); 13C NMR (CDCl3) δ 171.08, 145.52, 135.66, 134.01, 132.84,
132.39, 132.12, 129.66, 129.15, 52.24, 39.65, 35.96. Anal. Calcd
for C64H52S4Br4O20: C, 48.38; H, 3.30. Found: C, 48.57; H, 3.48.
5,11,17,23-Tetr a k is(ca r bom eth oxym eth yl)-25,26,27,28-
tetr akis(4′-m eth ylben zen esu lfon yl)calix[4]ar en e (9c) (1,3-
a lter n a te con for m er ) was prepared as described above for
9a using anhydrous MeOH to give a quantitative yield of 9c
5,11-Bis(ca r boxym eth yl)-17,23-bis(N,N-d ieth yla m id o-
m eth yl)-25,26,27,28-tetr akis(ben zyloxy)calix[4]ar en e (10a)
(1,3-Alter n a te Con for m er ). A mixture of 0.2 g (0.2 mmol)
of the bisanhydride 5a and 0.11 g of diethylamine in 30 mL of
CH2Cl2 was refluxed 3 h under N2, and the reaction mixture
was worked up to give 0.21 g (100%) of 10a as a light yellow
powder: mp 215-17 °C; 1H NMR (CDCl3) δ 7.39-7.24 (m, 20),
6.78 (d, 4, J ) 6.6 Hz), 6.44 (d, 4, J ) 6.0 Hz), 4.74-4.70 (m,
8), 3.57-3.48 (m, 8), 3.30 (s, 4), 3.09-3.00 (m, 12), 1.15 (t, 6,
J ) 7.0 Hz), 1.01 (t, 6, J ) 6.6 Hz).
5,11-Bis(ca r boxym eth yl)-17,23-bis(N,N-isop r op yla m i-
d o m e t h y l)-25,26,27,28-t e t r a k is (b e n zy lo x y )c a lix [4]-
a r en e (10b) (1,3-Alter n a te Con for m er ). A mixture of 50 mg
(0.05 mmol) of 5a and 40 mg of diisopropylamine in 20 mL of
CH2Cl2 was refluxed 2 h under N2, and the reaction mixture
was worked up to give 54 mg (100%) of 10b as a white
powder: mp 156-58 °C; 1H NMR (CDCl3 + 1 drop of DMSO-
d6) δ 7.52-7.33 (m, 12), 7.18-7.10 (m, 8), 6.56-6.31 (m, 8),
4.73 (m, 8), 3.56, 3.46-3.33 (m, 8), 2.98 (m, 8), 1.02(d, 48, J )
6.3 Hz). The diisopropylamide 10b was converted to the
tetraisopropyl amide 11 by using DCC/1-HOBt (vide infra).
5,11-Bis(ca r boxym eth yl)-17,23-bis(N-p h en yleth yla m i-
d o m e t h y l)-25,26,27,28-t e t r a k is (b e n zy lo x y )c a lix [4]-
a r en e (10c) (1,3-Alter n a te Con for m er ). A mixture of 98 mg
(0.99 mmol) of the bisanhydride 5a and 0.2 g of 2-phenylethy-
lamine in 40 mL of HPLC grade CH2Cl2 was refluxed for 2 h
under N2. After completion of the reaction, the CH2Cl2 was
removed under reduced pressure, and the concentrated mate-
rial was triturated with n-hexane to leave a light yellow
precipitate which was removed by filtration and purified to
1
as a white powder: mp 231-33 °C; H NMR (CDCl3) δ 7.73
(d, 8, J ) 8.31 Hz), 7.43 (d, 8, J ) 8.04 Hz), 6.72 (s, 8), 3.74 (s,
12), 3.44 (s, 8), 3.09 (s, 8), 2.51 (s, 12); 13C NMR (CDCl3) δ
171.26, 145.82, 145.22, 133.93, 133.70, 131.54, 131.03, 130.19,
128.06, 52.12, 39.95, 34.99, 21.80. Anal. Calcd for C68H64
S4O20: C, 61.43; H, 4.85. Found: C, 61.08; H, 4.95.
-
5,11,17,23-Tet r a k is(ca r b oet h oxym et h yl)-25,26,27,28-
tetr akis(4′-br om oben zen esu lfon yl)calix[4]ar en e (9d) (1,3-
a lter n a te con for m er ) was prepared as described above for
9a using absolute EtOH to give a quantitative yield of 9d as
1
a white powder: mp 205-6 °C; H NMR (CDCl3) δ 7.77 (d, 8,
J ) 8.70 Hz), 7.44 (d, 8, J ) 8.70 Hz), 6.83 (s, 8), 4.16 (dd, 8,
J ) 7.0 Hz), 3.62 (s, 8), 2.99 (s, 8), 1.29 (t, 12, J ) 7.2 Hz); 13
C
NMR (CDCl3) δ 170.68, 145.47, 135.66, 134.03, 132.81, 132.29,
132.15, 129.60, 129.13, 61.05, 39.83, 36.00, 14.24. Anal. Calcd
for C68H60S4Br4O20: C, 49.64; H, 3.67. Found: C, 49.38; H, 3.83.
The tetraethyl ester 9d was also obtained by refluxing the
diethyl ester 8e with absolute EtOH containing a drop of
concentrated H2SO4.
5,11,17,23-Tet r a k is(ca r b oet h oxym et h yl)-25,26,27,28-
tetr akis(4′-m eth ylben zen esu lfon yl)calix[4]ar en e (9e) (1,3-
a lter n a te con for m er ) was prepared as described above for

3512 J . Org. Chem., Vol. 64, No. 10, 1999
Sharma and Gutsche
give 100 mg (100%)) of 10c as a light yellow powder: mp 110-
su lfon yloxy)calix[4]ar en e (11b) (1,3-Alter n ate Con for m er ).
A mixture of 300 mg (0.05 mmol) of the bisanhydride 5b, 0.50
g of bis[(3,5-dimethyl-1-pyrazoyl)ethyl]amine, 0.5 g of DCC,
and 0.1 g of 1-HOBT in 100 mL of HPLC grade CH2Cl2 was
stirred at room temperature for 2 days. The white precipitate
of DCU and unreacted DCC was removed by filtration, and
the filtrate was concentrated under reduced pressure and
stirred with CH2Cl2. Again, the precipitate was removed by
filtration, and this procedure repeated until the product was
free of DCC and DCU. Further puricifation was effected by
trituration with MeOH to give 280 mg (56%) of 11b as a white
powder: mp 99-101 °C (softening at 90-91 °C); 1H NMR
(DMSO-d6) δ 7.88 (d, 8, J ) 7.8 Hz), 7.43 (d, 8, J ) 8.4 Hz),
6.72 (s, 8), 5.76 (s, 4), 5.74 (s, 4), 4.01 (bs, 8), 3.85 (bs, 8), 3.65
(bs, 8), 3.42 (bs, 16), 3.12 (bs, 8), 2.07 (s, 24), 2.05 (s, 12), 1.98
(s, 12). Anal. Calcd for C116H128N20S4Br4O16: C, 55.59; H, 5.14.
Found: C, 55.64; H, 5.15.
1
12 °C; H NMR (CDCl3)13 δ 7.37-7.35 (m, 12), 7.29-7.20 (m,
6), 7.13-7.06 (m, 12), 6.60 (s, 4), 6.44 (s, 4), 5.45 (t, 2), 4.73-
4.48 (m, 8), 3.45-3.38 (m, 12), 3.10 (s, 4), 3.01(s, 4), 2.77-
2.72 (m, 4). Anal. Calcd for C80H74N2O10‚2H2O: C, 76.29; H,
6.24. Found: C, 76.22; H, 6.11.
5,11-Bis(ca r boxym eth yl)-17,23-bis((bis[(3,5-d im eth yl-
1-p yr a zoyl)et h yl]a m id om et h yl)-25,26,27,28-t et r a k is(4-
br om oben zen esu lfon yloxy)ca lix[4]a r en e (10d ) (1,3-Al-
ter n a te Con for m er ). A mixture of 150 mg (0.01 mmol) of
bisanhydride 5b and 0.06 g of bis[(3,5-dimethyl-1-pyrazoyl)-
ethyl]amine in 50 mL of CH2Cl2 was refluxed for 4 h under
N2. After completion of the reaction, the CH2Cl2 was removed
under reduced pressure and the residue was triturated with
n-hexane followed by MeOH to give 200 mg (100%) of 10d as
a white powder: mp 162-64 °C (softening at 152-54 °C); 1H
NMR (CDCl3) δ 7.90-7.59 (m, 16), 6.83-6.54 (m, 8), 5.87 (s,
2), 5.78 (s, 2), 4.29 (m, 4), 4.10 (m, 4), 3.79-3.76 (m, 6), 3.55-
3.22 (m, 16), 3.00-2.90 (m, 4), 2.33 (s, 6), 2.24 (s, 6), 2.21 (s,
6), 2.16 (s, 6). Anal. Calcd for C88H86N10S4Br4O18: C, 52.34; H,
4.29. Found: C, 51.50; H, 4.14.
5,11,17,23-Tetr a k is(N,N-d iisop r op yla m id om eth yl)-25,-
26,27,28-tetr a k is(ben zyloxy)ca lix[4]a r en e (11a ) (1,3-Al-
ter n a te Con for m er ). A mixture of 500 mg (0.5 mmol) of the
tetraacid 4, 0.4 g of isopropylamine, 0.5 g of dicyclohexyl-
carbodimide (DCC), and 0.1 g of 1-hydroxybenzotriazole (1-
HOBT) in 60 mL of HPLC grade CH2Cl2 and 10 mL of THF
was stirred at room temperature for 18 h and worked up to
give 0.42 g (62%) of 11a as a white powder: mp 265-67 °C
(softening at 135 °C); 1H NMR (DMSO-d6) δ 7.41 (b, 12), 7.10
(bs, 8), 6.50 (s, 8), 4.70 (s, 8), 3.51 (s, 8), 3.05 (m, 8), 2.62 (s, 8),
1.12 (d, 48). Anal. Calcd for C88H108N4O8‚CHCl3: C, 72.76; H,
7.48. Found: C, 72.93; H, 6.95.
5,11,17,23-Te t r a k is(b is(3,5-d im e t h yl-1-p yr a zoyle t h -
yl)a m id om eth yl)-25,26,27,28-tetr a k is(4′-m eth ylben zen e-
su lfon yloxy)calix[4]ar en e (11c) (1,3-Alter n ate Con for m er ).
A mixture of 0.38 g (0.05 mmol) of bisanhydride 5c, 0.50 g of
bis[(3,5-dimethyl-1-pyrazoyl)ethyl]amine, 0.5 g of DCC, and
0.1 g of 1-HOBT in 90 mL of HPLC grade CH2Cl2 and 10 mL
of THF was stirred at room temperature for 2 days and worked
up to give 0.42 g (62%) of 11c as white powder: mp 82-4 °C
1
(softening at 71-2 °C); H NMR (DMSO-d6) δ 7.82 (d, 8, J )
8.1 Hz), 7.44 (d, 8, J ) 7.5 Hz), 6.70 (s, 8), 5.80 (s, 4), 5.72 (s,
4), 3.99 (bs, 8), 3.81 (bs, 8), 3.56 (bs, 8), 3.43 (bs, 16), 3.09 (bs,
8), 2.44 (s, 12), 2.12 (s, 12), 2.07 (s, 24), 1.94 (s, 12). Anal. Calcd
for C120H140N20S4O16‚0.5CH2Cl2: C, 62.33; H, 6.14. Found: C,
62.62; H, 6.51.
5,11,17,23-Te t r a k is(b is(3,5-d im e t h yl-1-p yr a zoyle t h -
yl)a m id om eth yl)-25,26,27,28-tetr a k is(4′-br om oben zen e-
Ack n ow led gm en t. We are indebted to the National
Science Foundation and the Robert A. Welch Founda-
tion for gererous support of this work.
(13) The CO2H and NH resonances are not reported in the 1H NMR
spectra.
J O9822636