Broad functionalization of deep-cavity cavitands by directed ortho metalation

Article abstract of DOI:10.1002/ejoc.200800206

The endo- and exo-rim positions of deep-cavity cavitand 1 were functionalized by directed ortho metalation (DoM) procedures. A range of electrophilic quenchers led to hosts with ester, phenol and thioether functionality. In each case, a combination of host pre-organization and reaction control resulted in far fewer products than the theoretical sixty-nine. In addition to the nature of the lithiate, functionalization patterns were also dependent on the electrophile, with a general trend that the non-carbon electrophiles examined gave higher degrees of substitution. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800206

FULL PAPER
DOI: 10.1002/ejoc.200800206
Broad Functionalization of Deep-Cavity Cavitands by Directed ortho
Metalation
Kannupal Srinivasan,[a] Zachary R. Laughrey,[b] and Bruce C. Gibb*[a]
Keywords: Cavitands / Lithiation / Receptors / Supramolecular chemistry
The endo- and exo-rim positions of deep-cavity cavitand 1
were functionalized by directed ortho metalation (DoM) pro-
cedures. A range of electrophilic quenchers led to hosts with
In addition to the nature of the lithiate, functionalization pat-
terns were also dependent on the electrophile, with a general
trend that the non-carbon electrophiles examined gave
ester, phenol and thioether functionality. In each case, a com- higher degrees of substitution.
bination of host pre-organization and reaction control re-
sulted in far fewer products than the theoretical sixty-nine.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
with the cavity wall termed “exo” (Figure 1). We report here
on the extension of this DoM strategy for functionalizing
deep-cavity cavitands. These results illustrate the generality
Introduction
“Concavity” and “functionality” are two basic qualities
that warrant consideration in designing enzyme mimics.
Concavity is required for selectivity (the “specific sub-site”
in the parlance of biochemists), while the functionality en-
genders catalysis (the “reaction sub-site”). Resorcinarene-
based cavitands[1–3] are attractive tools in this context, as
they possess a pre-organized cavity that can be tuned to
selectively bind substrates,[4] and they possess suitable sites
for the attachment of functional groups around their cavity.
Combining these two facets have therefore led to some
promising results.[5]
The commonly employed protocols for introducing func-
tionalities to the concave surface of simple methylene-
bridged cavitands involve halogen–metal exchange pro-
cedures[1c,6] or nucleophilic substitution on inherent halo-
methyl groups.[7] The deep-cavity cavitand 1 (Figure 1, a)
reported from our laboratory functions as a versatile host
for a variety of guests.[4f,8] To expand its scope to supra-
molecular catalysis, we are in search of ways to introduce
suitable functionalities to its concave surface. Towards this,
we recently reported two protocols, namely, directed ortho
metalation (DoM)[9] and electrophilic substitution[10] to in-
corporate a range of functional groups to the rim of such
cavitands. The former,[9] demonstrated that 1 possesses two
kinds of weakly acidic rim positions: four positions
pointing inward termed “endo” and four positions pointing
[a] Department of Chemistry, University of New Orleans,
New Orleans, LA 70148, USA
Fax: +1-504-280-6860
E-mail: bgibb@uno.edu
[b] Department of Chemistry, The University of North Carolina at
Chapel Hill,
Figure 1. (a) Chemical structure and (b) space-filling model of cavi-
tand 1, showing the endo and exo positions. (c) Representation of
a di-substituted cavitand to illustrate the nomenclature used (see
text).
Chapel Hill, NC 27599, USA
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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K. Srinivasan, Z. R. Laughrey, B. C. Gibb
FULL PAPER
of the DoM strategy, and demonstrate how the procedure labeled A–D in a clockwise manner. The endo positions are
can lead to a wide variety of functionalized hosts with un- labeled similarly, starting at the position immediately clock-
precedented substitution patterns.
wise to the exo-A position. The substitutions are given the
lowest possible alphabetical designation. Thus, the di-sub-
stituted cavitand in Figure 1, c is termed A-exo, B-endo,
whereas its enantiomer is named A-exo, C-endo (not
Results and Discussion
Cavitand 1 is available in three steps from commercially shown).
available materials, although we chose a four step process
The first electrophile examined was methyl chloro-
for economic reasons.[8a,8b] When 1 was treated with vary- formate, a quencher that converts the lithiates generated
ing equivalents of butyllithium compounds and quenched from 1 into their corresponding methyl esters; ester groups
with electrophiles, it afforded the corresponding function- subsequently provide access to carboxylic acids, function-
alized cavitands. The following nomenclature is used to de- ality that is repeatedly utilized by nature in enzyme cataly-
scribe the various products (Figure 1, c). Looking down sis. When 2.2 equiv. of nBuLi was used as a base, in ad-
into the cavity, the exo positions are given priority and are dition to the starting material, the mono-endo ester 2 and
Figure 2. Chemical structures of products arising from this study.
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Eur. J. Org. Chem. 2008, 3265–3271

Functionalization of Deep-Cavity Cavitands
the mono-exo ester 3 were obtained (Table 1 and Figure 2). the individual tri- or tetra-phenols. As expected, switching
With 5.5 equiv. of nBuLi, the A/C-endo diester 4, the chiral the base to sBuLi gave higher substitution patterns. Unex-
A-exo, B-endo diester 5 (and its enantiomer) and the two pected however, was the observation of penta-phenol prod-
(inseparable) A/C- and A/B-exo diesters 6 and 7 were also ucts. Thus, the use of 5 equiv. of sBuLi afforded 14, an in-
isolated. Using 10 equiv. of base did not change the nature separable mixture of tri-substituted products, tetra-exo phe-
of the products, but did influence their yields. Switching nol 16,[11] and an inseparable mixture of penta-substituted
the base to sBuLi resulted in a different functionalization products. The observation of penta-substituted products
pattern. For example, 5.5 equiv. afforded the A/B-exo, C- confirms that the nature of the electrophile does influence
endo triester 8, the A/B/C-exo triester 9 and the tetra-exo the product distribution in these DoM reactions. When the
ester 10. Using 10 equiv. gave the same three products, but number of equivalents of sBuLi was increased to ten, tri-
increased the yield of the tetra-ester 10 to a remarkable exo phenol 15, tetra-exo phenol 16 and the penta-substi-
70%. The use of tBuLi gave little in the way of mono-sub- tuted tetra-exo, mono-endo phenol 17 were formed. Both
stitution; with 5.5 equiv. di-, tri-, and tetra esters were phenols 15 and 17 contained respectively Ͻ 2% and ca. 5%
formed, whilst 10 equiv. produced tri- and tetra-esters. To impurities; a reminder that it is often difficult to separate
sum up, paralleling dimethylformamide,[9] methyl chloro- poly-functionalized molecules.
formate gave a range of ten esters, from mono- through to
tetra-substitutions, with nBuLi giving mono- and di-substi-
tution, sBuLi giving tri- and tetra-, and tBuLi giving di-,
Table 2. Range and yield of products arising from treatment of 1
with different butyllithium compounds and quenching with
B(OMe)3 followed by oxidation with alkaline H2O2.[a]
tri-, and tetra-substitution.
Base Equiv.
Range and yield (%) of products
[b]
1
11 12
*
14
15
16
17
Table 1. Range and yield of products arising from treatment of 1
with different butyllithium compounds and quenching with
ClCO2Me.[a]
nBuLi
sBuLi
2
5
10
5
8
–
–
–
18 35 19
2
8
2
8
–
–
–
[c]
[c]
2
1
–
2
1
–
40
17
–
*
*
(15%)
(31%)
43
Base Equiv.
Range and yield (%) of products
[d]
[e]
*
*
1
2
3
4
5[b] 6/7[c]
8
9
10
(13%)
(9%)
10
–
–
–
–
–
10[f]
33
21[g]
nBuLi 2.2
28
12
2
–
–
29
12
4
–
–
28
22
10
–
–
8
10
–
–
10
–
–
14
28
–
–
23
22
–
–
–
–
30
12
14
20
–
–
–
–
–
–
5.5
[a] All reactions were run in THF at –78 °C; Yields are the average
of at least two reactions. [b] A mixture of di-substituted products,
from which 13 could be isolated in trace amounts by repetitive
chromatography. [c] Two inseparable mixtures of tri- and tetra-sub-
stituted products. [d] A mixture of tri-substituted products. [e] A
mixture of penta-substituted products. [f] Contained Ͻ 2% impuri-
ties. [g] Contained ca. 5% impurities.
10
sBuLi 5.5
10
27 37
12 70
22 11
13 62
–
–
–
tBuLi 5.5
10
–
–
–
–
–
–
18
–
15
–
[a] All reactions were run in THF at –78 °C; yields are the average
of at least two reactions. [b] Product is chiral and was isolated as
racemate. [c] Compounds 6 and 7 could not be separated by col-
umn chromatography.
We also examined incorporating thioether groups to 1 as
potential precursors to their corresponding sulfonic acids.
Thus, dimethyl disulfide (MeSSMe) was used as an electro-
phile to quench the lithiate mixtures of 1. With 5 equiv. of
nBuLi, it afforded the A/C-endo dithioether 18, chiral A-
exo, B-endo dithioether 19 (containing ca. 8% isomeric im-
purities), the A/C-exo dithioether 20, the A/B-exo, C-endo
trithioether 21 and the A/B/C-exo trithioether 22 (Table 3
and Figure 2). Increasing the amount of base to 10 equiv.
altered the yields somewhat, but gave the same range of
products. The use of 5 equiv. of sBuLi gave 21, an insepa-
rable mixture containing 22 and unknown tetra-substituted
With similar product distributions seen for dimethyl-
formamide[9] and methyl chloroformate, we were also inter-
ested in examining other, non-carbon electrophiles. As a
first example, we chose trimethyl borate, the resulting bo-
rate cavitands being oxidized with alkaline H2O2 in situ to
yield a range of phenols. With this electrophile, the extent
of substitution with nBuLi increased to four groups whilst
five could be introduced with sBuLi. Thus, the use of
2 equiv. of nBuLi gave in addition to starting material the
readily separable mono-endo phenol 11 and the mono-exo-
phenol 12, a mixture of di-substituted products, and the
A/B-exo diphenol 14 (Table 2 and Figure 2). The mixture
of di-substituted products proved difficult to separate, but
repetitive chromatography did yield trace amounts of the
A/C-exo diphenol 13. It is noteworthy that this method of-
fers an alternative route to the mono-endo phenol 11, which
was previously obtained in a low yielding, multi-step pro-
cedure.[8c] With 5 equiv. of nBuLi, di-, tri- and tetra-substi-
tuted products were isolated, whereas 10 equiv. increased
the amounts of tri- and tetra-substituted products at the
expense of di-phenols. In both cases, although it was pos-
sible to separate the tri-phenol from the tetra-phenol prod-
Table 3. Range and yield of products arising from treatment of 1
with different butyllithium compounds and quenching with
Me2S2.[a]
Base
Equiv.
Range and yields (%) of products
18 19[b] 20
21
22
23[d]
24 25
nBuLi
sBuLi
5
10
5
17
10
–
35
24
–
12
14
–
8
9
21
–
2
–
–
–
–
2
–
–
12
[c]
*
(27%)
22
22
13 31
10
–
–
–
–
[a] All reactions were run in THF at –78 °C; yields are the average
of at least two reactions. [b] Contained ca. 8% isomeric impurities.
[c] A mixture of 22 and unknown tetra-substituted product(s)
ucts, flash chromatography did not allow the separation of (44:56). [d] Contained ca. 7% impurities.
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K. Srinivasan, Z. R. Laughrey, B. C. Gibb
FULL PAPER
column chromatography, a mobile phase of 50% DCM/hexane
changing to 70% DCM/hexane was used. Both starting material
(1, 28%) and products (2 and 3) are colorless solids.
compound(s) (44:56), the penta-substituted tetra-exo,
mono-endo thioether 24 and tetra-exo thioether 25. With
10 equiv. of sBuLi, a new penta-substituted product, A/B/C-
tri-exo, C/D-di-endo 23 (containing ca. 7% impurities) was
also isolated along with 24 and 25.
Reactions adding between one and eight functional
groups to the rim of 1 can lead to theoretically sixty-nine
products. Why are relatively few formed? The answer ap-
pears to be that functionalization patterns containing A,B-
endo or A-exo, A-endo motifs (Figure 3) must necessarily
involve high energy di- (or poly) anions. With the carbon
electrophiles DMF or chloroformate, only one product has
ever been observed with such patterning.[9] With non-car-
bon electrophiles this rule is violated more frequently (17,
23 and 24), but when compared to the total range of prod-
ucts this “no proximal dianions” rule seems a useful guiding
principle.
Mono-endo Ester 2: Yield 29%, m.p. above 250 °C. 1H NMR
(500 MHz, CDCl3, 25 °C): δ = 2.58 (m, 16 H), 3.44 (s, 3 H), 4.59
(s, 2 H), 4.65 (s, 2 H), 4.85 (m, 4 H), 6.00 (s, 2 H), 6.09 (s, 1 H),
6.13 (s, 1 H), 6.52 (br. s, 2 H), 6.54 (m, 4 H), 6.58 (br. s, 2 H), 6.61
(br. s, 2 H), 6.64 (t, J = 2.0 Hz, 1 H), 6.96 (m, 4 H), 7.13 (m, 8 H),
7.19–7.26 (m, 24 H), 7.58 (m, 3 H), 7.64 (t, J = 8.0 Hz, 1 H) ppm.
13C NMR (100 MHz, CDCl3, 25 °C): δ = 32.98, 33.04, 34.55, 36.81,
36.83, 52.47, 105.89, 106.69, 106.77, 107.60, 108.15, 109.52, 110.04,
115.54, 115.60, 115.71, 116.07, 120.73, 120.81, 120.84, 121.10,
122.19, 122.49, 122.70, 126.42, 128.57, 128.88, 131.45, 132.74,
136.81, 136.91, 137.01, 137.06, 139.40, 139.57, 141.58, 141.61,
153.49, 156.63, 156.65, 156.72, 156.74, 156.76, 156.86, 157.04,
160.64, 161.04, 161.2, 161.37, 164.35 ppm. MS (MALDI-TOF):
calcd. for [C114H82O18
+
Ag]+ 1847.73; found 1846.49.
C114H82O18·1/2CH2Cl2 (1782.33): calcd. C 77.24, H 4.68; found C
77.28, H 4.52.
Mono-exo Ester 3: Yield 28%, m.p. above 250 °C. 1H NMR
(500 MHz, CDCl3, 25 °C): δ = 2.58 (m, 16 H), 3.99 (s, 3 H), 4.54
(m, 3 H), 4.56 (s, 1 H), 4.85 (m, 4 H), 5.98 (s, 2 H), 6.01 (s, 2 H),
6.50 (br. s, 2 H), 6.53 (m, 4 H), 6.60 (s, 2 H), 6.65 (t, J = 2.0 Hz,
2 H), 6.68 (t, J = 2.0 Hz, 2 H), 6.99 (t, J = 2.0 Hz, 2 H), 7.01 (t, J
= 2.0 Hz, 1 H), 7.12 (m, 8 H), 7.19–7.26 (m, 24 H), 7.59 (t, J =
8.0 Hz, 4 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 32.99,
34.55, 36.82, 53.14, 105.66, 105.78, 105.85, 106.24, 107.80, 107.90,
109.44, 109.89, 115.00, 115.49, 115.61, 115.95, 120.75, 120.87,
121.17, 122.30, 122.37, 126.43, 128.55, 128.88, 131.43, 131.46,
136.92, 137.01, 137.13, 139.32, 140.36, 141.50, 156.48, 156.53,
156.70, 156.73, 156.78, 156.83, 158.15, 161.36, 161.42, 165.41 ppm.
MS (MALDI-TOF): calcd. for [C114H82O18 + Ag]+ 1847.73; found
1846.77. C114H82O18·H2O (1757.88): cacld. C 77.89, H 4.82; found
C 77.77, H 4.84.
Figure 3. Rarely observed functionalization patterns.
Conclusions
Although the primary driving force for the product dis-
tribution during the DoM strategy to functionalize the cavi-
tand 1 is the high preorganization of the cavitand, the na-
ture of the electrophile does indeed influence the outcome.
This would tend to suggest a mechanism more complex
than a kinetic quenching of a pool of equilibrated carban-
ions. We are currently exploring this point, as well as study-
ing a number of possibilities engendered by the now wide
range of functionalized cavitands.
5.5 Equiv. of n-BuLi: For this reaction, 0.4 mL (0.99 mmol) of
nBuLi and 0.21 mL (2.7 mmol) of methyl chloroformate were used.
For column chromatography, a mobile phase of 100% DCM
changing to 5% EtOAc/DCM was used. All products are colorless
solids. In addition to the starting material 1 (12%), the mono-endo
ester 2 (12%) and the mono-exo ester 3 (22%), the products 4 and
5 and inseparable 6/7 were isolated (see Table 1 for yields).
A/C-endo Diester 4: Yield 8%, m.p. above 250 °C. 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 2.58 (m, 16 H), 3.37 (s, 6 H), 4.65
(s, 4 H), 4.86 (t, J = 8.0 Hz, 4 H), 6.00 (s, 2 H), 6.10 (s, 2 H), 6.51
(t, J = 2.4 Hz, 2 H), 6.54 (br. s, 4 H), 6.59 (br. s, 4 H), 6.49 (br. s,
4 H), 7.13 (m, 8 H), 7.18–7.32 (m, 24 H), 7.58 (t, J = 8.0 Hz, 2 H),
7.66 (t, J = 8.0 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C):
δ = 33.01, 34.56, 36.83, 52.33, 106.20, 106.29, 107.72, 109.64,
115.44, 115.63, 115.83, 120.89, 121.67, 122.17, 122.32, 122.92,
126.42, 128.58, 128.89, 131.51, 132.50, 136.93, 137.04, 139.39,
141.60, 153.59, 156.61, 156.71, 156.82, 160.91, 161.09, 164.00 ppm.
MS (MALDI-TOF): calcd. for [C116H84O20 + Ag]+ 1905.76; found
1906.06. C116H84O20·1/2CH2Cl2 (1840.37): calcd. C 76.11, H 4.64;
found C 76.30, H 4.84.
Experimental Section
General Lithiation Procedure: A solution of 1 (0.3 g; 0.178 mmol)
in dry THF (20 mL) was cooled to –78 °C with a dry ice/acetone
bath. The alkyllithium (n-/sec-/tert-butyllithium) was added drop-
wise and the solution was stirred for 20 min. A solution of the
electrophile (methyl chloroformate/trimethyl borate/dimethyl disul-
fide) in THF (1 mL) was added dropwise and stirred at –78 °C for
2 h. The solution was then brought to room temp. and acidified
with 10% HCl (in the case of trimethyl borate, before acidification,
the reaction mixture was treated with excess alkaline hydrogen per-
oxide and stirred at room temp. for 6 h). THF was evaporated,
water added and extracted with CHCl3 (3ϫ). The organic layers
were combined, dried with anhydrous Na2SO4 and filtered. The
solvent was evaporated and the resulting solid was purified by col-
umn chromatography.
Racemate A-exo, B(C) endo Diester 5 (and its enantiomer): Yield
1
14%, m.p. above 250 °C. H NMR (500 MHz, CDCl3, 25 °C): δ =
2.58 (m, 16 H), 3.47 (s, 3 H), 3.98 (s, 3 H), 4.58 (m, 2 H), 4.64 (s,
2 H), 4.85 (m, 4 H), 5.97 (s, 1 H), 6.00 (s, 1 H), 6.06 (s, 1 H), 6.13
(s, 1 H), 6.52 (m, 2 H), 6.55 (t, J = 2.0 Hz, 1 H), 6.58 (m, 5 H),
6.61 (m, 2 H), 6.69 (t, J = 2.0 Hz, 1 H), 6.97 (m, 3 H), 7.13 (m, 8
H), 7.19–7.30 (m, 24 H), 7.58 (m, 3 H), 7.64 (t, J = 8.0 Hz, 1 H)
ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 33.03, 34.56, 36.83,
Methyl Esters
2.2 Equiv. of nBuLi: For this reaction, 0.16 mL (0.4 mmol) of nBuLi
and 83 µL (1.08 mmol) of methyl chloroformate were used. For
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Functionalization of Deep-Cavity Cavitands
52.63, 53.11, 105.76, 105.86, 106.37, 106.53, 106.81, 107.63, 108.18,
108.24, 109.50, 109.56, 110.06, 114.82, 115.55, 115.63, 115.74,
116.07, 120.71, 120.83, 121.04, 121.14, 122.19, 122.28, 122.49,
122.81, 126.44, 128.59, 128.90, 131.47, 132.70, 136.87, 136.97,
137.01, 137.08, 139.34, 139.36, 139.53, 140.59, 141.60, 153.44,
156.47, 156.59, 156.63, 156.70, 156.82, 157.04, 157.08, 158.04,
158.19, 160.62, 160.70, 161.01, 161.06, 161.25, 161.35, 164.36,
165.50 ppm. MS (MALDI-TOF): calcd. for [C116H84O20 + Ag]+
1905.76; found 1906.01. C116H84O20 (1797.90): calcd. C 77.49, H
4.71; found C 77.19, H 4.76.
cation conditions were as per reaction with 5.5 equiv. of sBuLi. The
same products formed with 5.5 equiv. of sBuLi were isolated (see
Table 1 for yields).
5.5 Equiv. of tBuLi: For this reaction, 0.58 mL (0.99 mmol) of
tBuLi and 0.21 mL (2.7 mmol) of methyl chloroformate were used.
Purification conditions were as per reaction with 5.5 equiv. of
sBuLi (see above). Products 4–10 were isolated (see Table 1 for
yields).
10 Equiv. of tBuLi: For this reaction, 1.12 mL (1.8 mmol) of tBuLi
and 0.42 mL (5.4 mmol) of methyl chloroformate were used. Purifi-
cation conditions were as per reaction with 5.5 equiv. of sBuLi (see
above). Products 8–10 were isolated (see Table 1 for yields).
10 Equiv. of n-BuLi: For this reaction, 0.72 mL (1.8 mmol) of nBuLi
and 0.42 mL (5.4 mmol) of methyl chloroformate were used. Purifi-
cation conditions were as per reaction with 5.5 equiv. of nBuLi.
The same products formed with 5.5 equiv. of nBuLi were isolated
(see Table 1 for yields).
Phenols
2 Equiv. of nBuLi: For this reaction, of nBuLi (0.15 mL,
0.357 mmol), trimethyl borate (0.2 mL, 1.78 mmol) and excess al-
kaline hydrogen peroxide [10% NaOH (2.5 mL) and 50% H2O2
(5 mL)] were used. For column chromatography, a mobile phase of
70% DCM/hexane changing to 100% DCM and then 2.5% EtOAc/
DCM was used. Both starting material (1, 8%) and products 11–
14 are colorless solids.
5.5 Equiv. of sBuLi: For this reaction, 0.71 mL (0.99 mmol) of
sBuLi and 0.21 mL (2.7 mmol) of methyl chloroformate were used.
For column chromatography, a mobile phase of 100% DCM fol-
lowed by 5% EtOAc/DCM and then 10% EtOAc/DCM was used.
All products are colorless solids.
A/B-exo, C-endo Triester 8: Yield 30%, m.p. above 250 °C. 1H
NMR (500 MHz, CDCl3, 25 °C): δ = 2.57 (m, 16 H), 3.48 (s, 3 H),
3.98 (s, 6 H), 4.58 (s, 2 H), 4.63 (s, 2 H), 4.85 (t, J = 8.0 Hz, 4 H),
5.97 (s, 2 H), 6.02 (s, 1 H), 6.13 (s, 1 H), 6.58 (m, 10 H), 6.73 (m,
1 H), 6.97 (m, 2 H), 7.12 (m, 8 H), 7.18–7.28 (m, 24 H), 7.58 (m,
3 H), 7.64 (t, J = 8.0 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3,
25 °C): δ = 33.00, 34.56, 36.85, 52.77, 53.10, 106.24, 106.30, 106.54,
106.80, 108.23, 109.57, 114.82, 115.55, 115.65, 116.05, 120.71,
121.05, 121.12, 122.26, 122.37, 122.47, 122.90, 126.45, 128.56,
128.89, 131.46, 132.63, 136.94, 137.00, 139.30, 140.51, 141.53,
153.40, 156.45, 156.53, 156.60, 156.68, 157.05, 158.05, 158.11,
160.66, 161.01, 164.33, 165.41 ppm. MS (MALDI-TOF): calcd. for
[C118H86O22 + Ag]+ 1963.80; found 1962.93. C118H86O22·CH2Cl2
(1940.86): calcd. C 73.64, H 4.57; found C 73.46, H 4.76.
Mono-endo Phenol 11: Yield 18%, m.p. above 250 °C. 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 2.47–2.63 (m, 16 H), 4.52 (s, 2 H),
4.57 (s, 2 H), 4.81–4.86 (m, 4 H), 4.89 (s, 1 H), 5.99 (s, 1 H), 6.00
(s, 2 H), 6.01 (s, 1 H), 6.48 (m, 2 H), 6.52 (m, 2 H), 6.58–6.59 (m,
4 H), 6.60 (t, J = 2.4 Hz, 1 H), 6.66 (t, J = 2.2 Hz, 2 H), 6.98 (t, J
= 2.2 Hz, 2 H), 7.07–7.12 (m, 14 H), 7.18–7.25 (m, 20 H), 7.55–
7.60 (m, 4 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 33.01,
34.56, 36.84, 104.40, 105.69, 105.74, 106.41, 107.30, 107.79, 109.81,
109.92, 115.46, 115.61, 115.79, 115.96, 120.74, 120.88, 122.09,
122.31, 126.44, 128.58, 128.89, 131.43, 136.96, 137.02, 139.36,
139.52, 141.54, 142.06, 142.62, 156.59, 156.73, 156.76, 156.82,
156.92, 160.58, 161.42, 161.51 ppm. MS (MALDI-TOF): calcd. for
[C112H80O17 + Ag]+ 1805.69; found 1805.36. C112H80O17 (1697.82):
calcd. C 79.23, H 4.75; found C 79.18, H 4.90.
A/B/C-exo Triester 9: Yield 27%, m.p. above 250 °C. 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 2.62 (m, 16 H), 4.07 (s, 9 H), 4.60
(m, 4 H), 4.92 (m, 4 H), 6.02 (s, 2 H), 6.05 (s, 2 H), 6.57 (br. s, 2
H), 6.64 (br. s, 4 H), 6.68 (br. s, 2 H), 6.78 (m, 2 H), 6.81 (m, 2 H),
7.08 (br. s, 1 H), 7.20 (m, 8 H), 7.27–7.35 (m, 24 H), 7.67 (t, J =
8.0 Hz, 4 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 32.97,
34.52, 36.82, 53.13, 105.70, 106.03, 106.08, 106.26, 107.85, 109.47,
109.94, 114.96, 115.01, 115.44, 115.57, 116.01, 116.04, 120.82,
121.15, 121.23, 122.38, 122.45, 126.47, 128.55, 128.90, 131.45,
131.49, 136.91, 137.04, 137.12, 137.14, 139.27, 140.30, 141.48,
156.40, 156.47, 156.50, 156.56, 156.57, 156.76, 156.79, 158.14,
158.16, 158.22, 161.42, 165.38 ppm. MS (MALDI-TOF): calcd. for
Mono-exo Phenol 12: Yield 35%, m.p. above 250 °C. 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 2.47–2.63 (m, 16 H), 4.53 (s, 1 H),
4.54 (s, 3 H), 4.83 (m, 4 H), 5.82 (br. s, 1 H), 6.00 (s, 4 H), 6.51–
6.53 (m, 6 H), 6.55 (br. s, 2 H), 6.63 (t, J = 2.2 Hz, 2 H), 6.66 (t,
J = 2.2 Hz, 2 H), 6.99 (t, J = 2.0 Hz, 3 H), 7.10–7.12 (m, 8 H),
7.18–7.27 (m, 24 H), 7.55–7.61 (m, 4 H) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 33.06, 34.57, 36.85, 105.75, 105.87, 105.92,
106.47, 107.87, 107.93, 109.92, 110.05, 115.60, 115.91, 115.95,
120.90, 121.12, 122.34, 122.39, 126.45, 128.15, 128.60, 128.92,
131.48, 131.54, 135.77, 136.95, 137.03, 137.04, 139.40, 139.47,
141.60, 148.23, 156.59, 156.74, 156.76, 156.82, 156.86, 161.35,
[C118H86O22
+
Ag]+ 1963.80; found 1962.90. C118H86O22·
161.41, 161.45 ppm. MS (MALDI-TOF): calcd. for [C112H80O17
+
1/2CH2Cl2 (1898.40): calcd. C 74.97, H 4.62; found C 75.14, H
4.74.
Ag]+ 1805.69; found 1805.44. C112H80O17·H2O (1715.84): calcd. C
78.40, H 4.82; found C 78.05, H 4.83.
Tetra-exo Ester 10: Yield 37%, m.p. above 250 °C. 1H NMR
(500 MHz, CDCl3, 25 °C): δ = 2.57 (m, 16 H), 4.01 (s, 12 H), 4.53
(s, 4 H), 4.85 (t, J = 8.0 Hz, 4 H), 5.95 (s, 4 H), 6.58 (s, 8 H), 6.76
(t, J = 2.0 Hz, 4 H), 7.13 (m, 8 H), 7.21–7.30 (m, 24 H), 7.61 (t, J
= 8.0 Hz, 4 H) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 33.00,
34.54, 36.84, 53.14, 106.07, 109.51, 114.99, 115.49, 116.10, 121.18,
122.43, 126.48, 128.55, 128.91, 131.48, 137.08, 140.25, 141.44,
156.42, 156.56, 158.15, 165.35 ppm. MS (MALDI-TOF): calcd. for
[C120H88O24 + Ag]+ 2021.84; found 2020.79. C120H88O24 (1913.97):
calcd. C 75.30, H 4.63; found C 75.46, H 4.83.
A/C-exo Diphenol (13): Obtained in trace amounts from a mixture
of di-substituted phenols by repetitive column chromatography;
1
m.p. above 250 °C. H NMR (400 MHz, CDCl3, 25 °C): δ = 2.47–
2.63 (m, 16 H), 4.53 and 4.54 (2ϫs, 4 H), 4.83 (2ϫt, J = 7.9 Hz, 4
H), 5.85 (br. s, 2 H), 6.00 (s, 4 H), 6.52 (d, J = 2.4 Hz, 4 H), 6.55
(s, 4 H), 6.67 (t, J = 2.2 Hz, 4 H), 6.99 (t, J = 2.2 Hz, 2 H), 7.10–
7.12 (m, 8 H), 7.18–7.28 (m, 24 H), 7.59 (t, J = 8.0 Hz, 4 H) ppm.
13C NMR (100 MHz, CDCl3, 25 °C): δ = 32.98, 33.03, 34.55, 34.52,
36.80, 36.84, 105.83, 106.44, 108.00, 109.88, 109.99, 115.56, 115.88,
120.88, 121.09, 122.33, 126.43, 128.14, 128.56, 128.89, 131.52,
135.70, 136.93, 137.00, 139.50, 141.54, 148.20, 156.57, 156.70,
156.72, 156.80, 161.31 ppm. MS (MALDI-TOF): calcd. for
10 Equiv. of sBuLi: For this reaction, 1.29 mL (1.8 mmol) of sBuLi
and 0.42 mL (2.7 mmol) of methyl chloroformate were used. Purifi-
Eur. J. Org. Chem. 2008, 3265–3271
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3269

K. Srinivasan, Z. R. Laughrey, B. C. Gibb
FULL PAPER
[C112H80O18 + Ag]+ 1821.69; found 1820.91. C112H80O18·H2O
1
A/C-endo Dithioether 18: Yield 17%, m.p. above 250 °C. H NMR
(1731.84): calcd. C 77.67, H 4.77; found C 77.60, H, 5.01.
(400 MHz, CDCl3, 25 °C): δ = 2.26 (s, 6 H), 2.46–2.63 (m, 16 H),
4.56 (s, 4 H), 4.83 (t, J = 7.8 Hz, 4 H), 5.95 (s, 2 H), 6.01 (s, 2 H),
6.39 (s, 4 H), 6.55 (s, 4 H), 6.78 (s, 2 H), 7.04 (s, 4 H), 7.10–7.12
(m, 8 H), 7.15–7.25 (m, 20 H), 7.28 (s, 2 H), 7.30 (s, 2 H), 7.52 (t,
J = 8.0 Hz, 2 H), 7.57 (t, J = 8.0 Hz, 2 H) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 18.29, 33.00, 34.57, 36.82, 104.58,
105.70, 107.15, 109.81, 115.49, 115.62, 116.23, 120.95, 122.17,
122.31, 122.36, 125.44, 126.41, 128.55, 128.87, 130.11, 131.35,
136.93, 136.97, 139.21, 141.57, 156.59, 156.72, 156.85, 156.97,
161.06, 161.49 ppm. MS (MALDI-TOF): calcd. for [C114H84O16S2
+ Ag]+ 1881.88; found 1881.95. C114H84O16S2·H2O (1792.02):
calcd. C 76.41, H 4.84, S 3.58; found C 76.60, H 4.90, S 3.45.
A/B-exo Diphenol 14: Yield 2%, m.p. above 250 °C. 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 2.47–2.63 (m, 16 H), 4.53 (s, 2 H),
4.55 (s, 2 H), 4.83 (2ϫt, J = 7.7 Hz, 4 H), 5.86 (br. s, 2 H), 5.99 (s,
4 H), 6.50 (distorted d, 2 H), 6.52 (distorted d, 2 H), 6.54 (s, 2 H),
6.56 (s, 2 H), 6.64 (t, J = 2.2 Hz, 1 H), 6.67 (t, J = 2.2 Hz, 2 H),
6.70 (t, J = 2.2 Hz, 1 H), 6.99 (t, J = 2.2 Hz, 2 H), 7.10–7.12 (m,
8 H), 7.17–7.29 (m, 24 H), 7.56–7.63 (m, 4 H) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 33.00, 33.04, 34.54, 36.81, 105.76,
105.93, 106.37, 106.53, 107.93, 109.87, 110.02, 115.56, 115.83,
115.88, 115.92, 120.85, 121.12, 122.34, 126.44, 128.18, 128.57,
128.89, 131.46, 131.53, 131.60, 135.78, 136.92, 136.95, 136.99,
137.02, 139.43, 141.55, 148.10, 148.17, 156.54, 156.56, 156.73,
156.82, 156.85, 161.35, 161.41 ppm. MS (MALDI-TOF): calcd. for
[C112H80O18 + Ag]+ 1821.69; found 1821.65. C112H80O18·3H2O
(1767.87): calcd. C 76.09, H 4.90; found C 76.03, H 4.97.
1
A/C-exo Dithioether 20: Yield 12%, m.p. above 250 °C. H NMR
(400 MHz, CDCl3, 25 °C): δ = 2.47–2.63 (m, 22 H), 4.52 (s, 2 H),
4.55 (s, 2 H), 4.80–4.85 (m, 4 H), 5.97 (s, 4 H), 6.50 (d, J = 2.4 Hz,
4 H), 6.58 (s, 4 H), 6.62 (t, J = 2.2 Hz, 4 H), 6.97 (t, J = 2.2 Hz, 2
H), 7.09–7.12 (m, 8 H), 7.18–7.27 (m, 24 H), 7.59 (t, J = 8.4 Hz, 4
H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 18.18, 32.95,
33.01, 34.52, 36.78, 36.82, 105.57, 106.55, 107.58, 109.60, 109.97,
115.57, 115.82, 120.78, 120.99, 122.35, 126.45, 128.56, 128.90,
131.51, 136.99, 137.01, 137.99, 139.30, 141.51, 156.60, 156.70,
156.80, 157.03, 161.16, 161.46 ppm. MS (MALDI-TOF): calcd.
For [C114H84O16S2 + Ag]+ 1881.88; found 1881.08. C114H84O16S2
(1774.01): C 77.18, H 4.77, S 3.62; found C 76.95, H 4.72, S 3.57.
5 Equiv. of nBuLi: For this reaction, nBuLi (0.37 mL, 0.892 mmol),
trimethyl borate (0.2 mL, 1.78 mmol) and excess alkaline hydrogen
peroxide [10% NaOH (2.5 mL) and 50% H2O2 (5 mL)] were used.
For column chromatography, a mobile phase of 70% DCM/hexane
changing to 100% DCM, then 5% EtOAc/DCM and finally 5%
MeOH/CHCl3 was used. The products 11, 12, 14 and two insepa-
rable mixtures of tri- and tetra-substituted products were isolated
(see Table 2 for yields).
1
A/B-exo, C-endo Trithioether 21: Yield 8%, m.p. above 250 °C. H
10 Equiv. of nBuLi: For this reaction, nBuLi (0.74 mL, 1.78 mmol),
trimethyl borate (0.4 mL, 3.57 mmol) and excess alkaline hydrogen
peroxide [10% NaOH (2.5 mL) and 50% H2O2 (5 mL)] were used.
Purification conditions were as per reaction with 5 equiv. of nBuLi
(see above). The same products formed with 5 equiv. of nBuLi were
isolated (see Table 2 for yields).
NMR (400 MHz, CDCl3, 25 °C): δ = 2.27 (s, 3 H), 2.47–2.63 (m,
22 H), 4.55 (s, 2 H), 4.56 (s, 2 H), 4.81–4.86 (m, 4 H), 5.95 (s, 1
H), 5.96 (s, 1 H), 5.99 (s, 2 H), 6.39 (s, 2 H), 6.55 (s, 4 H), 6.60 (s,
3 H), 6.70 (t, J = 2.2 Hz, 2 H), 7.05 (t, J = 2.4 Hz, 2 H), 7.10–7.12
(m, 8 H), 7.17–7.31 (m, 24 H), 7.52 (t, J = 8.2 Hz, 1 H), 7.57–7.63
(m, 3 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 18.20,
33.00, 34.55, 36.83, 104.60, 105.75, 106.21, 106.40, 107.25, 109.64,
109.84, 115.47, 115.60, 115.65, 115.79, 115.92, 120.76, 120.92,
120.99, 122.26, 122.36, 125.33, 126.44, 128.55, 128.89, 130.16,
131.45, 131.57, 136.92, 137.00, 137.07, 137.92, 139.18, 141.51,
141.54, 156.60, 156.63, 156.69, 156.76, 156.82, 156.92, 156.96,
161.07, 161.12, 161.17, 161.46 ppm. MS (MALDI-TOF): calcd. for
[C115H86O16S3 + Ag]+ 1927.97; found 1928.60. C115H86O16S3·H2O
(1838.12): calcd. C 75.14, H 4.83, S 5.23; found C 75.17, H 4.93, S
5.57.
A/B/C-exo Trithioether 22: Yield 2%, m.p. above 250 °C. 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 2.47–2.63 (m, 25 H), 4.52 (s, 1 H),
4.54 (m, 3 H), 4.80–4.85 (m, 4 H), 5.94 (s, 2 H), 5.97 (s, 2 H), 6.50
(d, J = 1.6 Hz, 2 H), 6.57 (m, 6 H), 6.62 (t, J = 2.2 Hz, 2 H), 6.63
(t, J = 2.2 Hz, 2 H), 6.98 (t, J = 2.0 Hz, 1 H), 7.09–7.12 (m, 8 H),
7.17–7.27 (m, 24 H), 7.57–7.63 (m, 4 H) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 18.17, 32.97, 34.52, 36.78, 105.60, 106.21,
106.37, 106.42, 107.65, 109.63, 109.97, 115.54, 115.58, 115.66,
115.81, 120.82, 120.94, 121.01, 122.35, 126.46, 128.56, 128.90,
131.51, 131.57, 136.96, 137.00, 137.07, 137.86, 137.92, 139.27,
141.49, 156.63, 156.72, 156.80, 156.87, 156.94, 156.98, 161.18,
161.45 ppm. MS (MALDI-TOF): calcd. for [C115H86O16S3 + Ag]+
1927.97; found 1928.01. C115H86O16S3·H2O (1838.12): calcd. C
75.14, H 4.83, S 5.23; found C 75.39, H 5.04, S 5.04.
5 Equiv. of sBuLi: For this reaction, sBuLi (0.69 mL, 0.892 mmol),
trimethyl borate (0.2 mL, 1.78 mmol) and excess alkaline hydrogen
peroxide [10% NaOH (2.5 mL) and 50% H2O2 (5 mL)] were used.
For column chromatography, a mobile phase of 1% MeOH/CHCl3
changing to 5% MeOH/CHCl3 was used. All products are colorless
solids. Phenol 14, an inseparable mixture of tri-substituted prod-
ucts, 16 and another inseparable mixture of penta-substituted prod-
ucts were isolated (see Table 2 for yields).
Tetra-exo Phenol 16: Yield 43%, m.p. above 250 °C. 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 2.47–2.63 (m, 16 H), 4.53 (s, 4 H),
4.83 (t, J = 7.8 Hz, 4 H), 5.89 (br. s, 4 H), 5.99 (s, 4 H), 6.55 (s, 8
H), 6.71 (t, J = 2.2 Hz, 4 H), 7.10–7.12 (m, 8 H), 7.17–7.22 (m, 16
H), 7.26–7.29 (m, 8 H), 7.61 (t, J = 8.2 Hz, 4 H) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 33.04, 34.56, 36.85, 106.51, 109.99,
115.53, 115.79, 121.08, 122.35, 126.42, 128.21, 128.55, 128.86,
131.58, 135.86, 136.93, 141.54, 148.09, 156.57, 156.71 ppm. MS
(MALDI-TOF): calcd. for [C112H80O20 + Ag]+ calcd, 1853.69;
found, 1853.87. C112H80O20·2H2O (1781.85): calcd. C 75.49, H
4.75; found C 75.31, H 4.79.
10 Equiv. of sBuLi: For this reaction, sBuLi (1.37 mL, 1.78 mmol),
trimethyl borate (0.4 mL, 3.57 mmol) and excess alkaline hydrogen
peroxide [10% NaOH (2.5 mL) and 50% H2O2 (5 mL)] were used.
Purification conditions were as per reaction with 5 equiv. of sBuLi
(see above). Products 15–17 were isolated (see Table 2 for yields).
10 Equiv. of nBuLi: For this reaction, nBuLi (0.74 mL, 1.78 mmol)
and dimethyl disulfide (0.32 mL, 3.57 mmol) were used. Purifica-
tion conditions were as per reaction with 5 equiv. of nBuLi (see
above). The same products formed with 5 equiv. of nBuLi were
isolated (see Table 3 for yields).
Thioethers
5 Equiv. of nBuLi: For this reaction, nBuLi (0.37 mL, 0.892 mmol)
and dimethyl disulfide (0.16 mL, 1.78 mmol) were used. For col-
umn chromatography, a mobile phase of 70% DCM/hexane chang-
ing to 100% DCM was used. Products 18–22 were isolated and all
are colorless solids.
5 Equiv. of sBuLi: For this reaction, sBuLi (0.69 mL, 0.892 mmol),
and dimethyl disulfide (0.16 mL, 1.78 mmol) were used. For col-
3270
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3265–3271

Functionalization of Deep-Cavity Cavitands
ich, Bull. Chem. Soc. Jpn. 2002, 75, 393–413; f) S. M. Biros, J.
Rebek Jr, Chem. Soc. Rev. 2007, 36, 93–104.
umn chromatography, a mobile phase of 70% DCM/hexane chang-
ing to 100% DCM was used. All products are colorless solids.
A/B-exo, C-endo trithioether 21 (21%), an inseparable mixture of
22 and unknown tetra-substituted products (27%), the penta-
substituted tetra-exo, mono-endo thioether 24 and tetra-exo thio-
ether 25 were isolated.
[2] For non-covalent assemblies of cavitands, see: a) T. Heinz,
D. M. Rudkevich, J. Rebek Jr, Nature 1998, 394, 764–766; b)
C. L. D. Gibb, B. C. Gibb, J. Am. Chem. Soc. 2006, 128, 16498–
16499; c) A. Lützen, A. Renslo, C. Schalley, B. M. O’Leary,
J. Rebek Jr, J. Am. Chem. Soc. 1999, 121, 7455–7456; d) K.
Kobayashi, T. Shirasaka, K. Yamaguchi, S. Sakamoto, E.
Horn, N. Furukawa, Chem. Commun. 2000, 41–42; e) P. Jaco-
pozzi, E. Dalcanale, Angew. Chem. Int. Ed. Engl. 1997, 36, 613–
615; f) O. D. Fox, M. G. B. Drew, E. J. S. Wilkinson, P. D. Beer,
Chem. Commun. 2000, 391–392; g) T. Haino, M. Kobayashi, Y.
Fukazawa, Chem. Eur. J. 2006, 12, 3310–3319.
[3] For covalent assemblies of cavitands, see: a) E. S. Barrett, J. L.
Irwin, A. J. Edwards, M. S. Sherburn, J. Am. Chem. Soc. 2004,
126, 16747–16749; b) D. A. Makeiff, J. C. Sherman, J. Am.
Chem. Soc. 2005, 127, 12363–12367; c) X. Liu, Y. Liu, G. Li,
R. Warmuth, Angew. Chem. Int. Ed. 2006, 45, 901–904; d) Y.
Liu, X. Liu, R. Warmuth, Chem. Eur. J. 2007, 13, 8953–8959.
[4] a) P. Soncini, S. Bonsignore, E. Dalcanale, E. Ugozzoli, J. Org.
Chem. 1992, 57, 4608–4612; b) D. M. Rudkevich, G. Hilmers-
son, J. Rebek Jr, J. Am. Chem. Soc. 1997, 119, 9911–9912; c)
F. C. Tucci, D. M. Rudkevich, J. Rebek Jr, J. Org. Chem. 1999,
64, 4555–4559; d) A. Renslo, J. Rebek Jr, Angew. Chem. Int.
Ed. 2000, 39, 3281–3283; e) P. Ballester, A. Shivanyuk, A. R.
Far, J. Rebek Jr, J. Am. Chem. Soc. 2002, 124, 14014–14016; f)
Z. R. Laughrey, C. L. D. Gibb, T. Senechal, B. C. Gibb, Chem.
Eur. J. 2003, 9, 130–139; g) S. M. Biros, E. C. Ullrich, F. Hof,
L. Trembleau, J. Rebek Jr, J. Am. Chem. Soc. 2004, 126, 2870–
2876.
[5] a) B. W. Purse, J. Rebek Jr, Proc. Natl. Acad. Sci. USA 2005,
102, 10777–10782; b) F. H. Zelder, J. Rebek Jr, Chem. Commun.
2006, 753–754; c) R. J. Hooley, S. M. Biros, J. Rebek Jr, Angew.
Chem. Int. Ed. 2006, 45, 3517–3519; d) T. Iwasawa, E. Mann,
J. Rebek Jr, J. Am. Chem. Soc. 2006, 128, 9308–9309; e) T. Iwa-
sawa, R. Hooley, J. Rebek Jr, Science 2007, 317, 493–496.
[6] a) J. L. Irwin, M. S. Sherburn, J. Org. Chem. 2000, 65, 602–
605; b) J. L. Irwin, M. S. Sherburn, J. Org. Chem. 2000, 65,
5846–5848; c) J. L. Irwin, M. S. Sherburn, Org. Lett. 2001, 3,
225–227; d) O. Hass, A. Schierholt, M. Jordan, A. Lützen, Syn-
thesis 2006, 519–527.
[7] a) H. Boerrigter, W. Verboom, G. van Hummel, S. Harkema,
D. N. Reinhoudt, Tetrahedron Lett. 1996, 37, 5167–5170; b) H.
Boerrigter, W. Verboom, D. N. Reinhoudt, J. Org. Chem. 1997,
62, 7148–7155; c) M. Flauaus, M. Herzing, A. Kollhofer, M.
Laly, H. Plenio, Eur. J. Org. Chem. 2001, 1061–1068; d) T. Vor-
falt, H. Plenio, Synthesis 2007, 565–571.
Tetra-exo, Mono-endo Thioether 24: Yield 2%, m.p. above 250 °C.
1H NMR (400 MHz, CDCl3, 25 °C): δ = 2.39 (s, 3 H), 2.46–2.62
(m, 28 H), 4.55 (s, 4 H), 4.80–4.83 (m, 4 H), 5.89 (s, 1 H), 5.95 (s,
1 H), 5.96 (s, 2 H), 6.45 (m, 2 H), 6.55 (m, 2 H), 6.57–6.59 (m, 5
H), 6.70 (t, J = 2.2 Hz, 2 H), 7.09–7.11 (m, 8 H), 7.16–7.29 (m, 22
H), 7.33 (s, 1 H), 7.35 (s, 1 H), 7.55–7.63 (m, 4 H) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 18.01, 18.15, 19.29, 32.96, 34.51,
36.78, 114.91, 115.46, 115.51, 115.61, 115.77, 115.86, 120.85,
120.95, 122.30, 122.39, 105.01, 106.07, 106.17, 106.36, 109.59,
109.66, 124.81, 126.45, 128.55, 128.89, 130.81, 131.52, 136.98,
137.04, 137.84, 137.89, 141.50, 156.56, 156.66, 156.69, 156.85,
157.00, 157.02, 157.98, 161.15, 161.19, 161.53 ppm. MS (MALDI-
TOF): calcd. for [C117H90O16S5 + Ag]+ 2020.16; found 2020.04.
C117H90O16S5·H2O (1930.30): calcd. C 72.80, H 4.80, S 8.31; found
C 72.75, H 4.93, S 8.22.
Tetra-exo Thioether 25: Yield 22%, m.p. above 250 °C. 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 2.47–2.63 (m, 28 H), 4.53 (s, 4 H),
4.82 (t, J = 7.8 Hz, 4 H), 5.95 (s, 4 H), 6.57 (s, 8 H), 6.63 (t, J =
2.2 Hz, 4 H), 7.09–7.12 (m, 8 H), 7.18–7.28 (m, 24 H), 7.61 (t, J =
8.0 Hz, 4 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 18.18,
33.01, 34.53, 36.81, 106.29, 109.69, 115.56, 115.60, 115.81, 120.95,
122.39, 126.48, 128.58, 128.92, 131.59, 137.04, 137.87, 141.51,
156.69, 156.93, 161.18 ppm. MS (MALDI-TOF): calcd. for
[C116H88O16S4 + Ag]+ 1974.06; found 1974.89. C116H88O16S4·H2O
(1884.21): C 73.94, H 4.81, S 6.81; found C 73.95, H 4.68, S 6.72.
10 Equiv. of sBuLi: For this reaction, sBuLi (1.37 mL, 1.78 mmol)
and dimethyl sulfide (0.32 mL, 3.57 mmol) were used. Purification
conditions were as per reaction with 5 equiv. of sBuLi (see above).
Products 23–25 were isolated (see Table 3 for yields).
Supporting Information (see also the footnote on the first page of
this article): The general experimental methods and data for in-
separable compounds 6/7 and compounds with inseparable impuri-
ties 15, 17, 19 and 23. NMR and mass spectra for products 2–25.
Acknowledgments
[8] a) C. L. D. Gibb, E. D. Stevens, B. C. Gibb, J. Am. Chem. Soc.
2001, 123, 5849–5850; b) C. L. D. Gibb, H. Xi, P. A. Politzer,
M. Concha, B. C. Gibb, Tetrahedron 2002, 58, 673–681; c)
C. L. D. Gibb, X. Li, B. C. Gibb, Proc. Natl. Acad. Sci. USA
2002, 99, 4857–4862; d) Z. R. Laughrey, T. G. Upton, B. C.
Gibb, Chem. Commun. 2006, 970–972.
This work was supported by the National Science Foundation
(CHE-0718461). We thank Prof. Richard B. Cole and the New Or-
leans Center for Mass Spectrometry Research for mass analysis.
[9] Z. R. Laughrey, B. C. Gibb, J. Org. Chem. 2006, 71, 1289–1294.
[10] K. Srinivasan, B. C. Gibb, Org. Lett. 2007, 9, 745–748.
[11] We note in passing that tetrol 16 is reminiscent of the cavitand
subunits used with such great effect by Cram and subsequently
Sherman for the formation of carceplexes.[1a,1c]
[1] a) D. J. Cram, J. M. Cram, in Container Molecules and Their
Guests (Ed.: J. F. Stoddart), Royal Society of Chemistry, Cam-
bridge, 1994; b) P. Timmerman, W. Verboom, D. N. Reinhoudt,
Tetrahedron 1996, 52, 2663–2704; c) A. Jasat, J. C. Sherman, J.
C, Chem. Rev. 1999, 99, 931–968; d) D. M. Rudkevich, J. Re-
bek Jr, Eur. J. Org. Chem. 1999, 1991–2005; e) D. M. Rudkev-
Received: February 22, 2008
Published Online: April 29, 2008
Eur. J. Org. Chem. 2008, 3265–3271
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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