Conformationally restricted calix[8]arenes substituted at all methylene bridges

Article abstract of DOI:10.1021/jo2009643

Reaction under S_N1 conditions of the octabromocalix[8]arene derivative 2d with alcohols proceeds in nonstereoselective fashion, but all-cis octaryl derivatives are the single major products in the reaction with arenes. The incorporation of aryl substituents at the bridges rigidifies the calix[8]arene skeleton.

Full text of DOI:10.1021/jo2009643

NOTE
pubs.acs.org/joc
Conformationally Restricted Calix[8]arenes Substituted at All
Methylene Bridges
Katerina Kogan and Silvio E. Biali*
Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
S Supporting Information
b
ABSTRACT: Reaction under SN1 conditions of the octa-
bromocalix[8]arene derivative 2d with alcohols proceeds in
nonstereoselective fashion, but all-cis octaryl derivatives are the
single major products in the reaction with arenes. The incor-
poration of aryl substituents at the bridges rigidifies the calix-
[8]arene skeleton.
he introduction of substituents at the methylene bridges of
suggesting that the bromination of each bridge did not proceed
beyond the monobromination stage. On this basis, the complex
pattern of signals is ascribed to a mixture of stereoisomers of 2d.
Replacing the solvent in the bromination reaction by CH2Cl2
resulted in a nearly identical product composition.
The major component in the isomeric mixture (as judged by
1H NMR) was isolated in nearly pure form by overnight
trituration of the crude mixture with hot i-PrOH. The compound
displayed in the 1H NMR spectrum two t-Bu and two methoxy
singlets, three singlets (in a 2:4:2 ratio) for the methine protons,
and four doublets for the aromatic signals, a pattern consistent
with C2v symmetry. Assuming that the molecule is conforma-
tionally flexible on the NMR time scale at room temperature, this
pattern is consistent with only one isomer out of the 18 isomeric
forms, namely, the rt3ct3 form (in blue in Figure 1).
T
the calixarenes (1)1,2 is of interest as a means to modify the
properties of the calixarene scaffold, while keeping all the lower-
rim binding groups intact. This structural modification can alter
the intrinsic conformational preferences of the scaffold and
increase the rigidity and preoganization of the calix macrocycle.3
In this Note we report such structural modification in the
notoriously conformationally flexible calix[8]arene scaffold.
Bromocalixarenes derivatives 2aÀc, readily available via
photochemical bromination of the corresponding calixarene
methyl ether derivatives 1aÀc,4 are useful synthetic intermedi-
ates for the preparation of methylene-functionalized calixarenes.5
Typically, the replacement of the bromine atoms by O-, N-, and
C-nucleophiles is conducted under SN1 conditions in an ionizing
solvent such as TFE or hexafluoroisopropanol (HFIP).
One of the components of the isomeric mixture (in magenta in
Figure 2) displayed a relative simple signal pattern (two singlets
for the aromatic protons, one singlet for the methine protons)
consistent only with the rct2c2t2 form of D2d symmetry (in
magenta in Figure 1). From the signal pattern of the isomer
colored in green (two doublets and two singlets for the aromatic
protons, two singlets for the methine protons), it could be
deduced that this isomer possesses C2h symmetry, but since
two different isomers possess this symmetry (marked in green in
Figure 1), only a partial configurational assignment could be
made. The fourth isomer displayed an even complex pattern of
signals (six doublets and two singlets for the aromatic protons
and four singlets for the methine protons, shown in red in
Figure 2). The signals pattern is consistent with a structure
possessing either a C2 axis or mirror plane bisecting a pair of
opposite rings as the single symmetry element. The four isomeric
forms with those symmetries are shown in red in Figure 1. The
composition of the crude product consisted of about 31% of the
rt3ct3 isomer, 9% of the rct2c2t2 and 8% and 7% of two additional
isomers of Cs (or C2) and C2h symmetry, respectively, and 45% of
additional isomers. Although the spectrum of the crude product
A calix[8]arene with eight bridges identically monofunctiona-
lized possesses eight stereocenters, and 18 diastereomeric forms
are possible arising from the possible cis/trans arrangements of
the substituents. The 18 forms, their symmetry elements, and
their point group symmetries are shown in Figure 1. Each form is
characterized by a configurational descriptor describing in a
sequential clockwise fashion the cis (c) or trans (t) relationship
of the substituents relative to a reference substituent (r).6
It has been reported that photochemical bromination of
octamethoxycalix[8]arene 1d in CCl4 with excess NBS (28
equiv) affords a single product.4b The simplicity of the NMR
data reported is consistent with either the rc7 (i.e, all-cis) or
the rtctctct (i.e., all-trans) forms. However, in our hands the
photochemical bromination using the experimental conditions
yielded, as judged from 1H NMR analysis, a mixture of products
(Figure 2), none of them possessing the simple spectrum
reported in the literature. Photochemical bromination using 8
equiv of NBS yielded a nearly identical mixture of products
Received: May 12, 2011
Published: August 09, 2011
r
2011 American Chemical Society
7240
dx.doi.org/10.1021/jo2009643 J. Org. Chem. 2011, 76, 7240–7244
|

The Journal of Organic Chemistry
NOTE
Figure 1. The 18 diastereomeric forms of a calix[8]arene possessing eight bridges identically monosubstituted. Assuming fast rotations of the rings,
the macrocycle is represented by a planar regular octagon where each corner represents a monosubstituted bridge. Isomers are grouped according to
the number of hashed wedged bonds (none, one, two, three, or four). For the chiral isomers only one enantiomer is shown.
(Figure 1) indicated a complex mixture, a “simpler” spectrum
showing the nearly exclusive presence of the four isomers was
obtained when the crude product was recrystallized from hexane
(Figure S1, Supporting Information).7
Upon heating of a sample of 2d (rt3ct3 isomer) in tetrachlor-
oethane-d2 to 348 K, an extensive isomerization was observed
after 10 min, as judged by 1H NMR spectroscopy (see Figure S2,
Supporting Information). Further heating did not result in
any appreciable change in the spectrum, suggesting that an
equilibrium mixture has been reached. The equilibrium mixture
at 348 K consisted of ca. 22% of the rt3ct3 form, ca. 8% of the
rct2c2t2 form, and additional isomers. Compound 2d (rt3ct3
isomer) also slowly isomerizes upon standing in CDCl3 solution
at room temperature. Such behavior was not observed in the
smaller bromocalixarenes analogues 2aÀc, suggesting that 2d is
substantially more reactive than its smaller analogues. The
increased reactivity suggested by the relative ease by which 2d
undergoes isomerization (a process that involves heterolytic
7241
dx.doi.org/10.1021/jo2009643 |J. Org. Chem. 2011, 76, 7240–7244

The Journal of Organic Chemistry
NOTE
Figure 2. 1H NMR spectrum (low-field region) of a mixture of
octabromocalix[8]arene derivatives 2d (crude mixture). Blue, rt3ct3
isomer; magenta, rct2c2t2 isomer; green, isomer of C2h symmetry, red,
isomer of Cs or C2 symmetry.
Figure 3. Crystal structure of the octamethoxycalix[8]arene 3b.
cleavage of the CÀBr bonds) is probably a result of the larger
conformationally flexibility of the calix[8]arene scaffold. This
flexibility enables in the transition state a better orbital overlap of
the two geminal aryl rings with the developing cationic orbital on
the bridge, thus facilitating the CÀBr bond cleavage.
proceeds in nonstereospecific fashion. No mutual interconver-
sion was observed after heating to reflux a methanolic solution of
3a or 3b for 18 h, and therefore we conclude that the isomeric
mixture was formed under kinetic control. Examination of the
crude product of the reaction of 2d (mixture of isomers) with
EtOH indicated also the formation of a complex mixture of
products, but small amounts of a single isomer could be obtained
via slow recrystallization of the mixture. To this isomer is
1
assigned the rct2c2t2 configuration (4) on the basis of its H
NMR spectrum, which is remarkable similar to that of 3a.
Crystallization of 3b from acetone afforded a single crystal
suitable for X-ray diffraction. The structural determination by
X-ray diffraction confirmed the rt3ct3 configurational assignment
(Figure 3). In contrast to the reported structure of the parent
calix[8]arene 1d (with unsubstituted bridges), which adopts a nearly
square-shaped conformation of approximately C4v symmetry,9 3b
adopts in the crystal a conformation of approximately C2 symmetry
with the two unique methoxy groups at the bridges (the pair of
opposite groups in a trans relationship to the six methoxy groups in a
cis arrangement) pointing toward the molecular cavity.
m-Xylyl groups were incorporated at the bridges of the calix
scaffold by means of a solvolytic FriedelÀCrafts reaction.10 The
reaction was conducted by heating to reflux the mixture of
stereoisomers of 2d and m-xylene in a mixture of CHCl3 and
HFIP. Although under analogous conditions the reaction also
proceeds with p-xylene or mesitylene, replacement of the ioniz-
ing solvent (HFIP) by AgClO4 afforded a cleaner product.11
Starting from either pure 2d (rt3ct3) or the isomeric mixture
afforded in both cases in nearly stereoselective fashion a single
major product, 6 or 7, respectively.
Heating overnight a heterogeneous mixture of the crude
product obtained in the bromination of 2d with MeOH in the
presence of propylene oxide (a scavenger of HBr) yielded a
complex mixture, but filtration of the solid that precipitated
yielded a single isomer of the octamethoxy derivative.8 This
1
isomer displayed in the H NMR spectrum a simple signal
pattern (single singlets for the methine, methoxy group at the
bridges, and pair of singlets for the t-Bu, aromatic protons, and
lower rim methoxy groups). The isomer is ascribed to 3a
possessing the rct2c2t2 configuration of D2d symmetry. A second
octamethoxy derivative was isolated after several recrystalliza-
tions of the filtrate from acetone. This isomer is ascribed to 3b
possessing the rt3ct3 configuration. The 1H NMR spectrum of 3b
displayed two singlets each for the lower rim methoxy and t-Bu
groups, three singlets for the methoxy groups at the bridges, three
singlets for the methine protons, and four doublets for the
aromatic signals. Since the configuration of 3b is identical to
the configuration of the major isomer obtained in the bromina-
tion and it is a major product (41%) in the crude mixture of
octamethoxy isomers, we examined whether 3b is formed via a
stereospecific reaction of 2d (rt3ct3). Due to the poor solubility in
MeOH of pure 2d (rt3ct3), the reaction was conducted in a
mixture of CHCl3/MeOH. Examination of the crude product
showed a very complex mixture, essentially identical to the one
obtained in the reaction of crude 2d (i.e., a mixture of isomers)
indicating that under the reaction conditions the reaction
Single crystals of 6 and 7 were obtained by slow evaporations
of solutions in CHCl3/acetonitrile and p-xylene, respectively.
The X-ray structures of 6 and 7 indicate that the configuration of
7242
dx.doi.org/10.1021/jo2009643 |J. Org. Chem. 2011, 76, 7240–7244

The Journal of Organic Chemistry
NOTE
the stereocenters is rc7 (i.e, all-cis, Figure S3, Supporting
Information).12 The crystal conformations of both molecules
are very similar. Six anisole rings of the calix macrocycle are
twisted relative to the mean macrocyclic plane while the two
remaining rings (at 12 and 6 o’clock positions) are nearly parallel
to that plane (Figure S3, Supporting Information). The pair of
rings at 3 and 9 o’clock positions direct their t-Bu groups toward
the center of the macrocycle. Ideally, this conformation possesses
C2v symmetry, with the two mutually perpendicular mirror
planes bisecting pairs of opposite rings at 3 and 9 o’clock and
at 12 and 6 o’clock positions. Pairs of geminal anisole rings are
oriented syn, with the mesityl group located in an equatorial-like
position of the bridge connected to the two rings. Notably, the
three rings of a given triarylmethyl subunits are all twisted in the
same sense relative to the plane defined by the three ipso carbons
(a propeller conformation).13
(s, 12H), 1.25 (s, 36H), 1.19 (s, 36H) ppm. 13C NMR (126 MHz,
CDCl3) δ 150.8, 150.7, 147.2, 146.9, 134.7, 134.4, 133.7, 133.3, 128.5,
127.8, 127.6, 127.0, 61.7, 61.4, 42.9, 42.3, 42.1, 34.7, 34.6, 31.5, 31.3, 31.2
ppm. HRMS (ESI) m/z, 2042.2475 [(M + H)+, calcd for C96H121Br8O8,
2042.2480].
5,11,17,23,29,35,41,47-Octa-tert-butyl-2,8,14,20,26,32,38,
44,49,50,51,52,53,54,55,56-hexadecamethoxycalix[8]arene
(rct2c2t2 Isomer 3a and rt3ct3 Isomer 3b). A mixture of 200 mg of
2d (isomeric mixture), 20 mL of methanol, and 0.5 mL of 1,2-
epoxybutane was heated to reflux overnight. The solid product was
filtered to give 18 mg (11%) of the rct2c2t2 isomer 3a, mp 354À356 °C.
Evaporation of the filtrate and repeated recrystallizations from acetone
afforded the rt3ct3 isomer 3b (53 mg, 33%), mp 340À342 °C (dec).
1
rct2c2t2 isomer (3a): H NMR (400 MHz, CDCl3) δ 7.60 (s, 8H),
7.06 (s, 8H), 5.85 (s, 8H), 3.81 (s, 12H), 3.33 (s, 24H), 3.14 (s, 12H),
1.37 (s, 36H), 1.06 (s, 36H) ppm. 13C NMR (126 MHz, CDCl3) δ
154.9, 153.9, 146.4, 146.1, 133.7, 133.5, 125.5, 123.6, 74.4, 62.2, 60.7,
57.1, 34.6, 34.3, 31.6, 31.1 ppm. HRMS (ESI) m/z, 1673.0380 [(M +
1
Compounds 5À7 display in the H NMR spectrum a signal
pattern indicating that the calix macrocycle possesses three types
of symmetry nonequivalent anisole rings (the aromatic protons
of those rings appear as two singlets and a pair of doublets) and
two types of symmetry nonequivalent aryl substituents at the
bridges. In the case of 7, pairs of ortho methyls appear as separate
signals. The signal pattern at rt is consistent only with a single
preferred conformation of C2v symmetry, which is rigid at rt on
the NMR time scale. Most likely, this rigid conformation
corresponds to the conformation present in the crystal. Upon
raising the temperature, signals coalesced and the spectrum
became simpler. For example, the spectrum of 5 at 410 K (in
tetrachloroethane-d2) displayed only single average signals for
the t-Bu, OMe, and methine protons (Figure S4, Supporting
Information).
1
Na)+, calcd for C104H144NaO16, 1673.0386]. rt3ct3 isomer (3b): H
NMR (500 MHz, CDCl3) δ 7.62 (d, J = 2.5 Hz, 4H), 7.30 (d, J = 2.6 Hz,
4H), 7.29 (d, J = 2.6 Hz, 4H), 6.92 (d, J = 2.4 Hz, 4H), 6.13 (s, 2H), 6.02
(s, 4H), 5.63 (s, 2H), 3.84 (s, 12H), 3.47 (s, 6H), 3.42 (s, 12H), 3.00
(s, 12H), 2.78 (s, 6H), 1.28 (s, 36H), 1.05 (s, 36H) ppm.13C NMR (126
MHz, CDCl3) δ 154.5, 154.3, 146.5, 146.1, 134.0, 133.7, 133.4, 133.0,
125.1, 124.8, 124.2, 123.8, 73.9, 73.8, 73.2, 62.3, 61.1, 57.4, 56.0, 50.7,
34.6, 34.3, 31.4, 31.1. HRMS (ESI) m/z, 1673.0381 [(M + Na)+, calcd
for C104H144NaO16, 1673.0386].
5,11,17,23,29,35,41,47-Octa-tert-butyl-2,8,14,20,26,32,38,
44-octaethoxy-49,50,51,52,53,54,55,56-octamethoxycalix-
[8]arene (4). A mixture of 200 mg of 2d (isomeric mixture), 20 mL of
ethanol and 0.5 mL of 1,2-epoxybutane were heated to reflux overnight.
After evaporation of the solvent, the residue was recrystallized from
ethanol to give 23 mg (13%) of 4 (rct2c2t2 isomer), mp 322À324 °C. 1H
NMR (500 MHz, CDCl3) δ 7.61 (s, 8H), 7.03 (s, 8H), 5.94 (s, 8H), 3.79
(s, 12H), 3.47 (m, 16H), 3.15 (s, 12H), 1.37 (s, 36H), 1.20 (t, J = 7.0 Hz,
24H), 1.04 (s, 36H) ppm.13C NMR (126 MHz, CDCl3) δ 154.9, 153.9,
146.1, 145.7, 134.3, 133.8, 125.7, 123.7, 72.7, 64.6, 62.1, 60.7, 34.6, 34.3,
31.6, 31.3, 31.1, 15.5 ppm. HRMS (ESI) m/z, 1785.1632 [(M + Na)+,
calcd for C112H160NaO16, 1785.1638].
5,11,17,23,29,35,41,47-Octa-tert-butyl-49,50,51,52,53,54,
55,56-octamethoxy-2,8,14,20,26,32,38,44-octakis-(2,4-dim-
ethylphenyl)calix[8]arene (rc7 isomer, 5). A mixture of 2d
(isomeric mixture, 0.10 g, 0.049 mmol), 8 mL of chloroform, 2 mL of
HFIP, and 1 mL of m-xylene was refluxed overnight. After evaporation of
the solvents, the residue was recrystallized from CHCl3/MeOH to yield
25 mg (23%) of 5, mp 300 °C (dec). 1H NMR (500 MHz, C2D2Cl4)
δ 7.00 (d, J = 2.1 Hz, 4H), 6.95 (s, 4H), 6.88 (overlapping peaks, 16H),
6.81 (d, J = 8.2 Hz, 4H), 6.74 (d, J = 8.0 Hz, 4H), 6.67 (s, 4H), 6.35 (d, J =
7.9 Hz, 4H), 6.31 (s, 4H), 6.13 (s, 4H), 3.34 (s, 12H), 3.00 (s, 6H), 2.71
(s, 6H), 2.28 (s, 12H), 2.25 (s, 12H), 2.03 (s, 12H), 2.02 (s, 12H), 1.05
(s, 36H), 1.00 (s, 18H), 0.82 (s, 18H) ppm. 13C NMR (126 MHz,
CDCl3) δ 154.0, 153.8, 145.8, 145.4, 144.6, 141.10, 140.7, 137.8, 136.5,
136.3, 136.2, 135.7, 135.0, 133.8, 131.2, 131.1, 129.9, 128.1, 127.2, 127.0,
126.4, 126.0, 126.0, 125.8, 125.0, 101.5, 60.5, 60.4, 59.8, 40.9, 39.8, 34.3,
34.2, 34.1, 31.3, 31.2, 31.1, 21.0, 20.9, 19.4, 19.2 ppm. HRMS (ESI) m/z,
2265.4543 [(M + Na)+, calcd for C160H192NaO8, 2265.4548].
5,11,17,23,29,35,41,47-Octa-tert-butyl-49,50,51,52,53,54,
55,56-octamethoxy-2,8,14,20,26,32,38,44-octakis-(2,5-dim-
ethylphenyl)calix[8]arene (rc7 isomer, 6). A suspension of 2d
(isomeric mixture, 0.20 g, 0.10 mmol) and AgClO4 (0.17 g, 0.82 mmol)
in 3 mL of p-xylene was stirred in the dark for 30 min at 0 °C. The
reaction was quenched by adding water (20 mL) and CH2Cl2 (20 mL).
The AgBr was filtered, and the organic phase was washed twice
with water, dried (MgSO4), and evaporated. The crude product was
The preferred formation of all-syn products in the reaction of
2d with arenes was previously observed also in the analogous
reaction of the smaller bromocalixarenes 2aÀc. Although the
possibility of transannular anchimeric assistance of the hetero-
lytic cleavage of the C-Br groups cannot be ruled out (in
particular in the large calix[8]arene macrocycle),14 it may be
possible that this stereoselectivity is connected to the conforma-
tional preferences of bulky substituents on the bridges to avoid
axial or axial-like positions.
In summary, the reaction of octabromocalixarene 2d with
alcohols proceeds in nonstereoselective fashion. However, a
single major product is obtained in the reaction with aromatic
rings, thus providing a facile and convenient synthetic entry into
conformationally restricted calix[8]arene systems.
’ EXPERIMENTAL SECTION
2,8,14,20,26,32,38,44-Octabromo-5,11,17,23,29,35,41,47-
octa-tert-butyl-49,50,51,52,53,54,55,56-octamethoxycalix-
[8]arene (2d). A mixture of 1d (2.00 g, 1.42 mmol), NBS (2.07 g,
11.41 mmol), and dichloromethane (100 mL) was stirred overnight at
room temperature while being irradiated with a spotlight (100 W).
Aqueous NaHSO3 was added, and after phase separation the organic
phase was washed with water, dried (MgSO4), and evaporated. After
treatment of the residue with 40 mL of hexanes, a mixture of octabromo
calix[8]arene derivatives 2d precipitated (1.97 g, 68%). Overnight
trituration with 60 mL of 2-propanol and 0.5 mL of 1,2-epoxybutane
yielded the rt3ct3 octabromo isomer in almost pure form (0.35 g, 12%).
Mp 280 °C (dec). 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 2.3 Hz,
4H), 7.68 (d, J = 2.3 Hz, 4H), 7.54 (d, J = 2.3 Hz, 4H), 7.36 (d, J = 2.3 Hz,
4H), 7.09 (s, 2H), 7.00 (s, 4H), 6.67 (s, 2H), 3.91 (s, 12H), 3.38
7243
dx.doi.org/10.1021/jo2009643 |J. Org. Chem. 2011, 76, 7240–7244

The Journal of Organic Chemistry
NOTE
recrystallized from CHCl3/acetonitrile, giving 56 mg of 6 (25%), mp
305 °C (dec). 1H NMR (500 MHz, CDCl3) δ 7.01 (s, 8H), 6.96 À 6.82
(overlapping signals, 20H), 6.74 (s, 4H), 6.63 (s, 4H), 6.34 (s, 4H), 6.29
(s, 4H), 6.16 (s, 4H), 3.33 (s, 12H), 2.76 (s, 6H), 2.73 (s, 6H), 2.18
(s, 12H), 2.14 (s, 12H), 2.04 (s, 12H), 1.96 (s, 12H), 1.07 (s, 36H), 1.01
(s, 18H), 0.87 (s, 18H) ppm. 13C NMR (126 MHz, CDCl3) δ 154.1,
153.9, 153.5, 145.9, 145.6, 144.8, 143.8, 143.7, 136.5, 136.3, 134.7, 134.2,
134.0, 133.8, 133.7, 133.0, 130.1, 129.3, 129.2, 128.9, 128.0, 126.9, 126.6,
126.4, 126.1, 125.1, 60.4, 60.1, 59.7, 41.3, 40.4, 34.3, 34.2, 34.1, 31.3,
31.2, 31.0, 21.2, 21.1, 18.82, 18.78 ppm. HRMS (ESI) m/z, 2243.4724
[(M + H)+, calcd for C160H193O8, 2243.4729].
5,11,17,23,29,35,41,47-Octa-tert-butyl-49,50,51,52,53,54,
55,56-octamethoxy-2,8,14,20,26,32,38,44-octakis-(2,4,6-tri-
methylphenyl)calix[8]arene (rc7 isomer, 7). A suspension of 2d
(isomeric mixture, 0.40 g, 0.2 mmol) and AgClO4 (0.5 g, 2.41 mmol) in
7 mL of mesitylene was stirred in dark for 30 min at 0 °C. The reaction
was quenched by adding water (20 mL) and CH2Cl2 (20 mL). The AgBr
was filtered, and the organic phase was washed twice with water, dried
(MgSO4), filtered, and evaporated. The residue was treated with 20 mL
of cold acetone to yield 170 mg (36%) of the pure octamesityl derivative
7, mp 312 °C (dec). 1H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 2.3 Hz,
4H), 7.18 (d, J = 2.4 Hz, 4H), 7.10 (s, 4H), 6.90 (s, 4H), 6.74 (s, 8H),
6.63 (s, 4H), 6.58 (s, 4H), 6.36 (s, 4H), 6.30 (s, 4H), 3.10 (s, 12H), 2.89
(s, 6H), 2.48 (s, 6H), 2.28 (s, 6H), 2.26 (s, 6H), 2.17 (s, 12H), 2.11
(s, 6H), 2.06 (s, 6H), 1.55 (s, 6H), 1.12 (s, 36H), 1.10 (s, 18H), 0.72
(s, 18H) ppm. 13C NMR (126 MHz, CDCl3) δ 155.6, 154.0, 153.5,
146.7, 145.4, 143.0, 138.58, 138.55, 138.2, 138.0, 137.7, 136.7, 136.1,
135.7, 135.3, 135.0, 134.7, 133.7, 131.2, 131.1, 129.6, 129.5, 128.3, 127.1,
126.0, 61.5, 60.1, 60.0, 41.4, 40.8, 34.3, 34.2, 33.8, 31.3, 31.2, 31.0,
24.3, 22.2, 21.1, 21.0, 20.7, 20.6 ppm. HRMS (ESI) m/z, 2377.5795
[(M + H)+, calcd for C168H209O8, 2377.5800].
Predeus, A. V.; Huang, R. H.; Wulff, W. D. J. Am. Chem. Soc. 2009,
131, 18018. (g) Gruber, T.; Gruner, M.; Fischer, C.; Seichter, W.;
Bombicz, P.; Weber, E. New J. Chem. 2010, 34, 250.
(3) For selected examples of conformationally restricted calix-
[8]arenes, see: (a) Cunsolo, F.; Piatelli, M.; Neri, P. J. Chem. Soc., Chem.
Commun. 1994, 1917. (b) Mascal, M.; Naven, R. T.; Warmuth, R.
Tetrahedron Lett. 1995, 36, 9361. (c) Arduini, A.; Pochini, A.; Secchi, A.;
Ungaro, R. J. Chem. Soc., Chem. Commun. 1995, 879. (d) Cunsolo, F.;
Consoli, G. M. L.; Piatelli, M.; Neri, P. Tetrahedron Lett. 1996, 37, 715.
(e) Mascal, M.; Warmuth, R.; Naven, R. T.; Edwards, R. A.; Hursthouse,
M. B.; Hibbs, D. E. J. Chem. Soc., Perkin Trans. 1 1999, 3435. (f) Gloede,
J.; Ozegowski, S.; Matt, D.; De Cian, A. Tetraedron Lett. 2001, 42, 9139.
(g) Consoli, G. M. L.; Cunsolo, F.; Geraci, C.; Gavuzzo, E.; Neri, P. Org.
Lett. 2002, 4, 2649.
(4) (a) Klenke, B.; N€ather, C.; Friedrichsen, W. Tetrahedron Lett.
1998, 39, 8967. (b) Kumar, S. K.; Chawla, H. M.; Varadarajan, R.
Tetrahedron Lett. 2002, 43, 7073.
(5) (a) Columbus, I.; Biali, S. E. Org. Lett. 2007, 9, 2927. (b)
Columbus, I.; Biali, S. E. J. Org. Chem. 2008, 73, 2598. (c) Kogan, K.;
Columbus, I.; Biali, S. E. J. Org. Chem. 2008, 73, 7327. (d) Kogan, K.;
Biali, S. E. J. Org. Chem. 2009, 74, 7172. (e) Kogan, K.; Itzhak, N.; Biali,
S. E. Supramol. Chem. 2010, 22, 704. (f) Kuno, L.; Biali, S. E. J. Org.
Chem. 2011, 76, 3664.
(6) Each descriptor unambiguously characterizes each isomer. Sev-
eral descriptors are possible for some structures, depending on the
identity of the substituent chosen as reference and whether a clockwise
or counterclockwise sequencing order is used. Arbitrarily, one of the
more “compact” descriptors (e.g., rt7, instead of rc6t) is the one chosen
for each structure. See ref 5c.
(7) This mixture consisted of 58% of the rt3ct3 isomer, 14% of the
rct2c2t2 form, and 16% and 12% of Cs (or C2) and C2h symmetry forms,
respectively.
(8) For simplicity, we refer to 3a and 3b as octamethoxy derivatives,
disregarding the eight additional methoxy groups at the lower rim.
(9) Bolte, M.; Brusko, V.; B€ohmer, V. J. Supramol. Chem. 2002, 2, 57.
A less symmetric conformation was found in the crystal structure of the
p-Br derivative of 1d. See:Baudry, R.; Felix, C.; Bavoux, C.; Perrin, M.;
Vocanson, F.; Dumazet-Bonnamour, I.; Lamartine, R. New J. Chem.
2003, 9, 1540. Bolte, M.; Brusko, V.; B€ohmer, V. Acta Crystallogr. 2003,
E59, 1691.
’ ASSOCIATED CONTENT
Supporting Information. 1H and 13C spectra for 2d, 3À7
S
b
and crystallographic information file (CIF) of 3b, 6, and 7. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(10) Hofmann, M.; Hampel, N.; Kanzian, T.; Mayr, H. Angew Chem.,
Int. Ed. 2004, 43, 5402.
’ AUTHOR INFORMATION
(11) For examples of silver-mediated substitutions in bromodienone
calixarene derivatives, see: (a) Troisi, F.; Pierro, T.; Gaeta, C.; Neri, P.
Org. Lett. 2009, 11, 697. (b) Troisi, F.; Pierro, T.; Gaeta, C.; Carratu, M.;
Neri, P. Tetrahedron Lett. 2009, 50, 4436.
Corresponding Author
*E-mail: silvio@vms.huji.ac.il.
(12) The all-cis configuration of stereocenters may not be immedi-
ately obvious by inspection of the crystal conformation, but it is clearly
visible in a molecular model once the rings of the macrocycle are rotated
into a cone-like conformation (a process that does not affect the
configuration of the stereocenters).
(13) Gust, D.; Mislow, K. J. Am. Chem. Soc. 1973, 95, 1535.
(14) It has been experimentally demonstrated that the calix[8]arene
scaffold is sufficiently large to allow for the formation of a transannular
spiro CÀO spiro bond. See: Gaeta, C.; Martino, M.; Neri, P. Tetrahedron
Lett. 2003, 44, 9155.
’ ACKNOWLEDGMENT
We thank Shmuel Cohen for the crystal structure determina-
tions. This research was supported by the Israel Science Founda-
tion (grant No. 104/10).
’ REFERENCES
(1) For reviews on calixarenes see: (a) Calixarenes in Action;
Mandolini, L., Ungaro, R., Eds.; Imperial College Press: London,
2000. (b) B€ohmer, V. In The Chemistry of Phenols; Rappoport, Z.,
Ed.,; Wiley: Chichester, 2003; Chapter 19. (c) Gutsche, C. D. Calixar-
enes: An Introduction; Royal Society of Chemistry: Cambridge, 2008.
(2) Several different approaches have been developed to synthesize
calixarenes with a single, several, or all methylene bridges functionalized.
See for example: (a) Scully, P. A.; Hamilton, T. M.; Bennett, J. L. Org.
Lett. 2001, 3, 2741. (b) Tabatabai, M.; Vogt, W.; B€ohmer, V. Tetrahedron
Lett. 1990, 31, 3295. (c) Middel, O.; Greff, Z.; Taylor, N. J.; Verboom,
W.; Reinhoudt, D. N.; Snieckus, V. J. Org. Chem. 2000, 65, 667. (d)
Agbaria, K.; Biali, S. E. J. Am. Chem. Soc. 2001, 123, 12495. (e) Kuno, L.;
Seri, N.; Biali, S. E. Org. Lett. 2007, 9, 1577. (f) Gopalsamuthiram, V.;
7244
dx.doi.org/10.1021/jo2009643 |J. Org. Chem. 2011, 76, 7240–7244