Synthesis of hydroxyl-footed cavitands

Full text of DOI:10.1021/jo951633c

J . Org. Chem. 1996, 61, 1505-1509
1505
Syn th esis of Hyd r oxyl-F ooted Ca vita n d s
Sch em e 1. Syn th esis of Silicon -Br id ged Ca vita n d s
a a n d 5b. Syn th esis of Meth ylen e-Br id ged
5
Ca vita n d 4a via a Silicon Br id ge P r otection /
Bruce C. Gibb, Robert G. Chapman, and
J ohn C. Sherman*
a
Dep r otection Rou te
Department of Chemistry, 2036 Main Mall,
University of British Columbia,
Vancouver, British Columbia, Canada V6T 1Z1
Received September 6, 1995
a
MDT, methylene ditosylate.
In tr od u ction
be converted into a nucleophile or an electrophile and
(2) can be incorporated close to the bowl. We report here
the synthesis of several short-chained hydroxyl-footed
cavitands (i.e., methylene-bridged) and include a discus-
sion of the key bridging reaction. We also present an
alternative, milder route to the preparation of bridged
cavitands, which may be particularly useful when the
pendant groups contain even more sensitive funtionali-
ties.
Methylene-bridged resorcin[4]arene cavitands such as
have been used for a variety of purposes because of
11
their rigidity, enforced cavities, and synthetic viability.
For example, these cavitands have served as precursors
2
3
to carceplexes, as binders of neutral guest molecules,
and as agents to form monolayers.4 The interest in
resorcinarene-based cavitands is still on the rise as new
5
uses in materials science and biological chemistry arise.
Thus, the incorporation of new functionalities into the
pendant groups of these compounds would expand their
versatility toward future applications. For example, use
of the pendant groups to covalently link cavitands
6
(
remote from the enforced cavity) to each other, to solid
supports, or to other species could lead to new materials,
while short water-solubilizing pendant groups could pave
the way toward biological applications such as drug
delivery. One problem is that functionalities in the
pendant groups often interfere with the bridging reaction
that incorporates the rigidity into the molecule and
enforces the cavity. To be synthetically useful, the ideal
pendant group should contain a functionality that (1) can
Resu lts
Butanol-footed dodecol 2a has been prepared by Cram
in 80% yield.7 We prepared propanol-footed dodecol 2b
in a similar manner in 61% yield (Scheme 1) so that we
can eventually probe the effect of chain length in the
applications mentioned above.8 Compounds 2a and 2b
were brominated using N-bromosuccinimide to give
bromo dodecols 3a (90% yield) and 3b (82% yield),
respectively (Scheme 1).
(
1) (a) Moran, J . R.; Karbach, S.; Cram, D. J . J . Am. Chem. Soc.
1
982, 104, 5826-5828. (b) Cram, D. J .; Karbach, S.; Kim, H. E.;
Knobler, C. B.; Maverick, E. F.; Ericson, J . L.; Helgeson, R. C. J . Am.
Chem. Soc. 1988, 110, 2229-2237. For a review of unbridged resor-
cinarenes, see: Schneider, H.-J .; Schneider, U. J . Inclusion Phenom.
Mol. Recognit. Chem. 1994, 19, 67-83.
(
2) (a) Sherman, J . C. Tetrahedron 1995, 51, 3395-3422. (b)
Timmerman, P.; Nierop, K. G. A.; Brinks, E. A.; Verboom, W.; van
Veggel, F. C. J . M.; van Hoorn, W. P.; Reinhoudt, D. N. Chem. Eur.
1
995, 1, 132-143. (c) Helgeson, R. C.; Knobler, C. B.; Cram. D. J . J .
Chem. Soc., Chem. Commun. 1995, 307-308. (d) Kurdistani, S. K.;
Robbins, T. A.; Cram. D. J . J . Chem. Soc., Chem. Commun. 1995,
1
259-1260.
3) (a) Tucker, J . A.; Knobler, C. B.; Trueblood, K. N.; Cram, D. J .
(
J . Am. Chem. Soc. 1989, 111, 3688-3699. (b) Timmerman, P.; Brinks,
E. A.; Verboom, W.; Reinhoudt, D. N. J . Chem. Soc., Chem. Commun.
1
995, 417-418.
4) (a) van Velzen, E. U. T.; Engbersen, J . F. J ; de Lange, P. J .; Mahy,
J . W. G.; Reinhoudt, D. N. J . Am. Chem. Soc. 1995, 117, 6853-6862.
b) Schierbaum, K. D.; Weiss, T.; van Velzen, E. U. T.; Engbersen, J .
(
(
F. J ; Reinhoudt, D. N.; G o¨ pel, W. Science 1994, 265, 1413-1415. For
formation of monolayers using unbridged resorinarenes, see: (c)
Kurihara, K.; Ohto, K.; Tanaka, Y.; Aoyama, Y.; Kunitake, T. J . Am.
Chem. Soc. 1991, 113, 444-450. (d) Adams, H.; Davis, F.; Stirling, C.
J . M. J . Chem. Soc., Chem. Commun. 1994, 2527-2529. (e) Weib, T.;
Schierbaum, K. D.; van Velzen, U. T.; Reinhoudt, D. N.; G o¨ pel, W.
Sensors Actuat. B 1995, 26-27, 203-207.
(
5) For uses of resorcinarene-based cavitands that contain non-
Methylene bridges were incorporated into dodecol 3a
to form the rigid cavitand 4a both via direct bridging
methylene bridges, see: (a) Lippmann, T.; Wilde, H.; Dalcanale, E.;
Mavilla, L.; Mann, G.; Heyer, U.; Spera, S. J . Org. Chem. 1995, 60,
(
Scheme 2) and via a protection/deprotection route
2
2
35-242. (b) Vincenti, M.; Dalcanale, E. J . Chem. Soc., Perkin Trans.
1995, 1069-1076. (c) Xu, W.; Vittal, J . J .; Puddephatt, R. J . J . Am.
(Scheme 1). As this bridging is often the most difficult
step in the formation of resorcinarene cavitands, we
Chem. Soc. 1993, 115, 6456-6457. (d) Vincenti, M.; Pelizzetti, E.;
Dalcanale, E.; Soncini, P. Pure Appl. Chem. 1993, 65, 1507-1512. (e)
Sonicini, P.; Bonsignore, S.; Dalcanale, E.; Ugozzoli, F. J . Org. Chem.
1
992, 57, 4608-4612. (f) Dalcanale, E.; Costantini, G.; Soncini, P. J .
(7) Compound 2a has been reported previously, but was not fully
characterized, see: Tunstad, L. M.; Tucker, J . A.; Dalcanale, E.; Weiser,
J .; Bryant, J . A.; Sherman, J . C.; Helgeson, R. C.; Knobler, C. B.; Cram,
D. J . J . Org. Chem. 1989, 54, 1305-1312.
(8) For the incorporation of alcohols of different chain length into
the lower rim of calixarenes, see: Moran, J . K.; Georgiev, E. M.;
Yordanov, A. T.; Mague, J . T.; Roundhill, D. M. J . Org. Chem. 1994,
59, 5990-5998.
Inclusion Phenom. Mol. Recognit. Chem. 1992, 13, 87-92. (g) Xu, W.;
Vittal, J . J .; Puddephatt, R. J . J . Am. Chem. Soc. 1995, 117, 8362-
8
371.
(
6) For linkage of cavitands to each other via their rims, see ref 2
and (a) Cram, D. J .; Tunstad, L. M.; Knobler, C. B. J . Org. Chem. 1992,
7, 528-535. (b) von dem Bussche-H u¨ nnefeld, C.; B u¨ hring, D.; Knobler,
C. B.; Cram, D. J . J . Chem. Soc., Chem. Commun. 1995, 1085-1086.
5
0
022-3263/96/1961-1505$12.00/0 © 1996 American Chemical Society

1
506 J . Org. Chem., Vol. 61, No. 4, 1996
Notes
Sch em e 2. Syn th esis of Ca vita n d s 4a , 4b, 6a , a n d
b via Dir ect Meth ylen e Br id gin ga
sensitive functional groups. Table 1 summarizes the
conditions and yields for a variety of bridging reactions.
6
The bridging reaction entails the organization of
fluxional molecules into highly rigid molecules.1
b,12
Each
bridge requires the attack of a phenol (or phenoxide) on
a bis-electrophile (i.e., CH XY), followed by attack of a
second phenol (or phenoxide) on a singly-electrophilic
intermediate (i.e., ArOCH X). As successive bridges
2
2
a
MDT, methylene ditosylate.
form, the molecules become more rigid, which slows down
subsequent bridging substantially. By examination of
CPK models, the phenols appear to be highly accessible
to attack on the electrophiles during the formation of the
first two bridges due to the flexibility of the molecules.
When there are three bridges or even two that oppose
each other (“A,C”), the molecules become very rigid and
the phenols lose their access to electrophilic attack. This
notion is supported experimentally by the common
observation of the “tris-bridged” and “A,C-bis-bridged”
explored a variety of conditions for direct bridging of
various dodecols, including 3a , as detailed in the Discus-
sion section. The protection/deprotection route from
dodecol 3a toward cavitand 4a entailed silicon bridging/
9
protection of dodecol 3a using Me
2
SiCl
2
to yield silicon
cavitand 5a (82% yield), whose alcohols were protected
with methoxymethyl (MOM) groups to yield the MOM-
protected silicon cavitand 5c (75% yield). The silicon
bridges of 5c were removed with HF to yield octol 3c (82%
yield), which was bridged with methylene ditosylate
intermediates, which form in the presence of limited
1b, 12
bridging reagent
or when the solvent is too nucleo-
1
0
(
MDT) to yield methylene-bridged cavitand 4c (41%
philic and consumes the bridging reagent at the temper-
1
1
yield). Removal of the MOM group of 4c with catalytic
HCl in refluxing methanol/THF (1:1) gave butanol-footed
cavitand 4a (95% yield). Dodecol 3a was also bridged
12
atures needed for final bridging. The base most likely
13
deprotonates one set of four of the eight phenols, which
are much more acidic than the second set, due to the
formation of charged hydrogen bonds. Although this
hydrogen-bonding network should rigidify the molecules,
there is still enough flexibility to allow early bridges to
form faster than the later bridges.
directly with MDT or CH
and 3b, to yield hydroxyl-footed cavitands 4a (55%), 6a
35%), 6b (30%), and 4b (57%), respectively, as indicated
in Table 1.
2
BrCl as were dodecols 2a , 2b,
(
The effect of preorganization on bridging is further
illustrated by the reaction of dodecols 3a and 3b with
Me
2
SiCl
2
versus trimethylsilyl chloride (TMSCl), using
SiCl as a
pyridine as the base and solvent. Use of Me
2
2
bridging reagent9 gave 82 and 74% yields of silicon-
bridged cavitands 5a and 5b, respectively. In contrast,
reaction of dodecols 3a and 3b with TMSCl gave only
mixtures with TMS groups on both the phenols and the
alcohols.14 These results may be rationalized as follows.
The preorganization of the macrocycle allows the ArO-
2
SiMe Cl intermediates to bridge readily with the adjacent
phenols (to complete the eight-membered rings), such
that the relative nucleophilicity of the pendant alcohols
is low. Each silicon bridge may further preorganize the
macrocycle, thereby enhancing formation of the eight-
membered rings, whereas the ArOTMS groups render the
remaining phenols comparable in nucleophilicity (or even
less so) than the pendant alcohols. The ArOTMS groups
likely create steric hindrance to nucleophilic attack by
the adjacent phenols and may reduce the nucleophilicity
of the distal phenols by disrupting the cyclic array of
charged hydrogen bonds: the cooperative formation of
the charged hydrogen bonds is likely to be diminished
Discu ssion
by each ArOTMS group, whereas each ArOSiMe
2
OAr
bridge is likely to strengthen the cyclic hydrogen-bonded
network.
The incorporation of methylene bridges into resor-
cinarenes is often difficult due to oligomerization, and
in the case of resorcinarenes 2 and 3, the bridging
reaction is complicated by the competitive reactions
caused by the pendant hydroxyl groups. In an effort to
alleviate these problems, we probed the bridging reaction
and hoped that some guidelines might be formulated that
could be applied to derivatives that contain even more
Several trends regarding the methylene bridging in the
formation of cavitands can be observed from Table 1. The
yields for the hydroxyl-footed cavitands are lower than
for the phenethyl-footed cavitands,15 and there is an
optimal amount of bridging reagent for the hydroxyl-
footed cavitands (data shown in Table 1 for cavitand 6b
(
9) For bridging of resorcinarenes with Me
2
SiCl
2
, see: Cram, D. J .;
(12) Timmerman, P.; Boerrigter, H.; Verboom, W.; van Hummel, G.
J .; Harkema, S.; Reinhoudt, D. N. J . Inclusion Phenom. Mol. Recognit.
Chem. 1994, 19, 167-191.
Stewart, K. D.; Goldberg, I.; Trueblood, K. N. J . Am. Chem. Soc. 1985,
1
07, 2574-2575.
(
(
10) Emmons, W. D.; Ferris, A. F. J . Am. Chem. Soc. 1953, 75, 2257.
11) The 41% yield in the methylene bridging of octol 3c would likely
(13) (a) Schneider, H.-J .; G u¨ ttes, D.; Schneider, U. J . Am. Chem.
Soc. 1988, 110, 6449-6454. (b) Sorrell, T. N.; Pigge, F. C.; White, P.
S. Inorg. Chem. 1994, 33, 632-635.
increase if the MOM groups were replaced by a more robust protective
group such as (methoxyethoxy)methyl.
1
(14) TMS derivatives of 3a and 3b were characterized by H NMR.

Notes
J . Org. Chem., Vol. 61, No. 4, 1996 1507
Ta ble 1. Con d ition s a n d Yield s for Meth ylen e-Br id gin g Rea ction sa
starting
material
bridging
reagentb
entry
product
equiv time/tempc
yield (%)
1
1
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
2a
2a
3a
3a
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
3b
3b
3b
3b
3b
3c
3c
2d
2d
3d
3d
3d
3d
3d
6a
6a
4a
4a
6b
6b
6b
6b
6b
6b
6b
6b
6b
6b
6b
4b
4b
4b
4b
4b
4c
4c
6d
6d
4d
4d
4d
4d
4d
BCM
MDT
BCM
MDT
BCM
BCM
MDI
MDT
MDT
MDT
MDT
MDT
MDT
MDT
MDT
BCM
BCM
MDI
MDT
MDT
BCM
MDT
BCM
MDT
BCM
MDT
MDT
MDT
MDT
4.5d 2 d rt, 4.5 1 d 40 °C, 4.5 3 d 65 °C
4.5 2 d rt, 4.5 2 d 60 °C
26e
35
55
f
4.5 d 2 d rt, 1 d rt, 4.5 1 d 40 °C, 4.5 3 d 65 °C
4.5 2 d rt, 4.5 2 d 60 °C
40
12
d
e
4.5 2 d rt, 1 d rt, 4.5 1 d 40 °C, 4.5 3 d 65 °C
4.5 2 d rt, 4.5 2 d 60 °C
4.5 2 d rt, 4.5 2 d 60 °C
2.0 2 d rt, 2.5 2 d 60 °C
2.5 2 d rt, 2.5 2 d 60 °C
3.5 2 d rt, 3.5 2 d 60 °C
4.0 2 d rt, 4.0 2 d 60 °C
4.5 2 d rt, 4.5 2 d 60 °C
6.5 2 d rt, 5.0 2 d 60 °C
4.5 1 d rt, 4.5 1 d 60 °C
3.5 2 d rt
5
12
18
23
30
24
16
5
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
14
0
57
d
f
4.5 2 d rt, 1 d rt, 4.5 1 d 40 °C, 4.5 3 d 65 °C
4.5 2 d rt, 4.5 2 d 60 °C
4.5 2 d rt, 4.5 2 d 60 °C
4.5 1 d rt, 4.5 1 d 60 °C
4.5 2 d rt, 4.5 2 d 60 °C
7
13
18
30
g
e
4.5 1 d rt, 1 d rt, 4.6 1 d 40 °C, 4.5 3 d 65 °C
1
3.5 2 d rt, 3.5 2 d 60 °C
41
45
g
e
4.5 1 d rt, 1 d rt, 4.5 1 d 40 °C, 4.5 3 d 65 °C
4.5 1 d rt, 4.5 1 d 60 °C
4.6g 1 d rt, 1 d rt, 4.5 1 d 40 °C, 4.5 3 d 65 °C
4.6 2 d rt, 4.6 2 d 60 °C
4.5 1 d rt, 4.5 1 d 60 °C
4.5 1 d 0 °C, 4.6 1 d 60 °C
4.6 1 d 60 °C, 4.6 1 d 60 °C
82
60
e
70
27
8
18
a
All reactions were run using ca. 50 mg of starting material, K2CO3 as the base, and dimethylacetamide as the solvent, unless noted
otherwise. BCM, bromochloromethane; MDI, methylene diiodide; MDT, methylene ditosylate. c Number of equivalents refers to the
bridging reagent. All reagents were added at once unless noted otherwise. rt, room temperature; d, days. The starting material was
b
d
e
added via syringe pump over 48 h; all other reagents were added at once. Subsequent additions of bridging reagent were all at once. The
reaction was run on a 0.5 g scale. f The reaction was run on a 10 g scale. g The starting material was added via syringe pump over 24 h;
all other reagents were added at once. Subsequent additions of bridging reagent were all at once.
only, entries 8-13). These results indicate that the
pendant alcohols can react with excess bridging reagent
as expected, which diminishes the yields of cavitands.
This side-reaction was further evident by an experiment
in which methylene-bridged cavitand 4b was subjected
to optimal bridging conditions (3.5 equiv, 2 d at rt; 3.5
equiv, 2 d at 60 °C) using MDT as the bridging reagent.
Only 49% of the cavitand was recovered, whereas under
the same conditions, but omitting the MDT, 73% of 4b
was recovered. Thus, under these conditions, 24% of the
hydroxyl-footed material is lost to intermolecular reaction
at the pendant alcohols. Interestingly, in contrast to the
methylene bridging, the silicon bridging of dodecols 3a
and 3b proceeds very efficiently, indicating that the side
reactions with the pendant hydroxyls is not a problem.
This high selectivity with silicon bridging may be due to
the milder conditions used for the reaction (pyridine as
base and lower temperature). In fact, significantly longer
reaction times were required to form TMS ethers at the
and 14; 19 and 20; 26, 27, and 28), which is consistent
with the later bridges being slow to form.12 Initial
reaction at 60 °C lowers the yields (entries 27, 28, and
29), perhaps due to an increase in polymerization with
the less preorganized, unbridged species. Finally, the
presence of a bromine in the 2-position of the resorcinols
slows the bridging reaction as is evident by the extra time
required to achieve a high yield when the pendant groups
are phenethyl (entries 24, 26, and 27). Furthermore,
2
when CH BrCl is used as the bridging reagent and the
reaction is stirred at 65 °C for 3 days, the yields are
higher with bromine versus hydrogen (entries 1 and 3; 5
and 16; 23 and 25); the bromine most likely hinders
intermolecular bridging between the phenols. Interest-
ingly, this differential in yields between bromine versus
hydrogen in the 2-position is not observed using the
bulkier MDT as the bridging reagent (entries 2 and 4;
12 and 20; 24 and 26).
pendant alcohols than for bridging the phenols with Me
SiCl . Unfortunately, a stronger base (K CO ) is required
2
-
Con clu sion s
2
2
3
for the methylene bridging of the resorcinarenes, even
with MDT as the bridging reagent (see below).
Other trends concerning the bridging reaction are the
following. The reactivity of the bridging reagents ap-
We have prepared several hydroxyl-footed cavitands.
The short three- and four-carbon chains may be useful
in tail-to-tail coupling of cavitands, the incorporation of
water-solubilizing groups distal to the enforced cavity of
cavitands, and in the formation of monolayers where the
bowls are held close to a solid surface. The factors
involved in the bridging of the resorcinarenes are mani-
fold, but conditions can be rationally adjusted to optimize
the yields of the methylene-bridged cavitands. For
example, MDT is more effective at methylene bridging
under milder conditions. We have also developed an
alternative route to methylene-bridged cavitands that
pears to decrease in the order MDT > CH
2
I
2
2
> CH BrCl
(
see entries 6, 7, and12 and 17, 18, and 20), which follows
the order of leaving group abilities. The reaction yields
are often improved by a second day at 60 °C (entries 12
(
15) Cavitand 4d has been prepared previously in 52% yield on a
1 g scale using similar conditions to entry 25 in Table 1, see:
Sherman, J . C.; Knobler, C. N.; Cram, D. J . J . Am. Chem. Soc. 1991,
13, 2194-2204.
2
1

1
508 J . Org. Chem., Vol. 61, No. 4, 1996
Notes
involves an unusual use of silicon bridges as protective
groups. This route may be useful to incorporate meth-
ylene bridges into resorcinarenes that contain reactive
funtionalities in the pendant groups.
Anal. Calcd for C40
6.75; H, 4.64.
Ca vita n d 4a . Dodecol 3a (10.92 g, 10.0 mmol) was dissolved
in 50 mL of DMA and added via syringe pump over 2 days to a
stirred mixture of 350 mL of DMA, potassium carbonate (18 g,
H
44
O
12Br
4
: C, 46.36; H, 4.28. Found: C,
4
1
30 mmol), and BCM (3.0 mL, 45 mmol). After stirring for
another day at rt, BCM (3.0 mL, 45 mmol) was added, and the
reaction mixture was stirred at 45 °C for 1 day. Additional BCM
(3.0 mL, 45 mmol) was added, and the reaction mixture was
stirred at 65 °C for 3 days. The reaction mixture was then cooled
to rt, and the solvent was removed in vacuo. The solid residue
was sonicated in 300 mL of water followed by slow addition of 2
M HCl until the carbonate salts were neutralized. The resulting
mixture was filtered, and the solid was washed with water (3 ×
Exp er im en ta l Section
Gen er a l.16 Acetonitrile and pyridine were dried over 4 Å
molecular sieves. DMF and dimethylacetamide (DMA) were
stirred over BaO, then distilled in vacuo onto 4 Å molecular
2
sieves, and stored under N . Mass spectra were obtained using
a Kratos Concept IIH32 using LSIMS+ (unless noted otherwise)
with thioglycerol (TG) and m-nitrobenzyl alcohol (NBA) as the
matrices as noted. All products were dried overnight at rt at
.1 Torr unless otherwise noted.
Dod ecol 2a .7 Resorcinol (20 g, 182 mmol) was dissolved in
5
0 mL), dissolved in 300 mL of THF, and dried with MgSO4.
The solvent was removed in vacuo and purified by silica gel
column chromatography using 9:1 CHCl :methanol (v/v). The
product was recrystallized from THF/acetonitrile to give 6.3 g
0
3
1
2
50 mL of 4:1 methanol/37% HCl under N . 3,4-Dihydro-2H-
1
6
of 4a (55%) as a white solid: mp >250 °C; H NMR (DMSO-d )
pyran (16.6 mL, 182 mmol) was then added via syringe pump
over 4 h. After an additional 4 h of stirring at rt, the mixture
was heated to 50 °C. After 7 days a considerable amount of
precipitate was formed and the reaction mixture was allowed
to cool to rt. The solid was filtered off and then taken up in 1 L
of cold distilled water and sonicated. The solid was again filtered
off and dried at 0.1 Torr at rt overnight. After this period the
product was taken up in dry THF. The insoluble material was
filtered off and dried to give 22.8 g (65%) of the desired C4v
δ 7.60 (s, 4 H), 5.99 (d, 4 H, J ) 7.6 Hz), 4.69 (t, 4 H, J ) 8.2
Hz), 4.38 (broad, 4 H), 4.30 (d, 4 H, J ) 7.6 Hz), 3.40 (m, 8 H),
2
.39 (m, 8 H), 1.54 (m, 8 H), 1.33 (m, 8 H); MS (LSIMS, NBA)
+
-
+
-
m/z 1139 ((M - H ) , 50), 1293 ((M - H + NBA) , 100). Anal.
Calcd for C48 : C, 50.55; H, 4.60. Found: C, 50.24; H,
.58.
Ca vita n d 4b. Dodecol 3b (10.36 g, 10.0 mmol) was dissolved
52 4
H O12Br
4
in 50 mL of DMA and added via syringe pump over 2 days to a
stirred mixture of 350 mL of DMA, potassium carbonate (18 g,
1
isomer 2a as an off-white solid: mp >250 °C; H NMR (DMSO-
1
30 mmol), and BCM (3.0 mL, 45 mmol). After stirring for
d
5
1
6
) δ 8.90 (s, 8 H), 7.22 (s, 4 H), 6.13 (s, 4 H), 4.29 (t, 4 H, J )
another day at rt, BCM (3.0 mL, 45 mmol) was added and the
reaction mixture was stirred at 45 °C for 1 day. Additional BCM
.1 Hz), 4.18 (t, 4 H, J ) 7.8 Hz), 3.30 (m, 8 H), 2.08 (m, 8 H),
+
.44 (m, 8 H), 1.18 (m, 8 H); MS (NBA) m/z 776 (M , 100). Anal.
(3.0 mL, 45 mmol) was added, and the reaction mixture was
Calcd for C44
Dod ecol 2b. Resorcinol (20 g, 182 mmol) was dissolved in
50 mL of 4:1 methanol/37% HCl under N . 2,3-Dihydrofuran
13.8 mL, 182 mmol) was then added via syringe pump over 4
56
H O12: C, 68.02; H, 7.27. Found: C, 67.98; H, 7.27.
stirred at 65 °C for 3 days. The reaction mixture was then cooled
to rt, and the solvent was removed in vacuo. The solid residue
was sonicated in 300 mL of water followed by slow addition of 2
M HCl until the carbonate salts were neutralized. The resulting
mixture was filtered, and the solid was washed with water (3 ×
1
(
2
h. After an additional 4 h of stirring at rt, the mixture was
heated to 50 °C. After 7 days a considerable amount of
precipitate was formed and the reaction mixture was allowed
to cool to rt. The solid was filtered off and taken up in 1 L of
cold distilled water and sonicated. The solid was again filtered
off and dried at 0.1 Torr at rt overnight. The solid was then
taken up in dry THF, and the insoluble material was filtered
5
0 mL), dissolved in 300 mL of THF, and dried with MgSO4.
The solvent was removed in vacuo and purified by silica gel
column chromatography using 9:1 CHCl :methanol (v/v). The
product was recrystallized from THF/acetonitrile to give 6.2 g
3
1
6
of 4b (57%) as a white solid: mp >250 °C; H NMR (DMSO-d )
δ 7.65 (s, 4 H), 5.99 (d, 4 H, J ) 7.6 Hz), 4.69 (t, 4 H, J ) 8.3
off and dried to give 20.0 g (61%) of the desired C4v isomer 2b
Hz), 4.50 (broad, 4 H), 4.30 (d, 4 H, J ) 7.6 Hz), 3.50 (m, 8 H),
1
as an off-white solid: mp >250 °C; H NMR (DMSO-d
6
) δ 8.88
+
2
.46 (m, 8 H), 1.44 (m, 8 H); MS (NBA) m/z 1085 (M , 100). Anal.
(
4
8
s, 8 H), 7.22 (s, 4 H), 6.13 (s, 4 H), 4.29 (t, 4 H, J ) 5.1 Hz),
Calcd for C44
H, 4.20.
H
44
O
12Br
4
2
‚H O: C, 47.94; H, 4.21. Found: C, 47.95;
.18 (t, 4 H, J ) 7.8 Hz), 3.40 (m, 8 H), 2.08 (m, 8 H), 1.33 (m,
+
+
H); MS (TG) m/z 720 (M , 60) 661 ((M - HO(CH
2
)
3
) , 100).
Silicon Ca vita n d 5a . Dodecol 3a (40 g, 36.6 mmol) was
dissolved in 1.2 L of pyridine. To this solution was rapidly added
Me SiCl (44.4 mL, 366 mmol), and the reaction mixture was
2 2
Anal. Calcd for C40
H, 6.66.
48
H O12: C, 66.65; H, 6.71. Found: C, 66.29;
Dod ecol 3a . Dodecol 2a (10 g, 12.9 mmol) was added to 190
mL of 30% methanol in butanone. N-Bromosuccinimide (NBS,
0.3 g, 57.9 mmol) was added to this suspension, and the
reaction mixture was stirred at rt in the dark for 5 h. Additional
NBS (4.58 g, 25.7 mmol) was added, and the reaction mixture
was stirred overnight. The reaction mixture was filtered, and
the solid was washed with 100 mL of cold butanone. The solid
stirred for 2 h at rt. The solvent was removed in vacuo, giving
a solid that was taken up in methanol to destroy the remaining
reagent. The methanol was removed in vacuo, and the resulting
solid was suspended in methanol, filtered, and dried to give 39.5
1
1
g of 5a as a white solid (82% yield): mp >250 °C; H NMR
(
6
DMSO-d ) δ 7.77 (s, 4 H), 4.50 (t, 4 H, J ) 8.0 Hz), 4.36 (t, 4 H,
J ) 5.1 Hz), 3.36 (m, 8 H), 2.35 (m, 8 H), 1.49 (m, 8 H), 1.23 (m,
8
1
was dried to give 12.7 g (90%) of 3a as an off-white solid: mp
+
H), 0.55 (s, 12 H), -0.62 (s, 12 H); MS (NBA) m/z 1316 (M ,
1
2
4
8
1
27 °C dec; H NMR (DMSO-d
6
) δ 9.14 (s, 8 H), 7.41 (s, 4 H),
00). Anal. Calcd for C52 Si C, 47.42; H, 5.20.
H
68
O
12Br
4
4
:
.32 (m, 8 H), 3.34 (t, 8 H, J ) 6.6 Hz), 2.21 (m, 8 H), 1.47 (m,
Found: C, 47.49; H, 5.27.
Silicon Ca vita n d 5b. Dodecol 3b (500 mg, 0.48 mmol) was
dissolved in 20 mL of pyridine. To this solution was rapidly
2 2
added Me SiCl (0.66 mL, 5.4 mmol), and the reaction mixture
was stirred for 2 h at rt. The solvent was removed in vacuo,
giving a solid that was taken up in methanol to destroy the
remaining reagent. The methanol was removed in vacuo, and
the resulting solid was suspended in methanol, filtered, and
+
-
H), 1.19 (m, 8 H); MS (LSIMS-, NBA) m/z 1091 ((M - H ) ,
00). Anal. Calcd for C44 : C, 48.37; H, 4.80. Found:
52 4
H O12Br
C, 48.36; H, 5.00.
Dod ecol 3b. Dodecol 2b (10 g, 13.9 mmol) was added to 190
mL of 30% methanol in butanone. N-Bromosuccinimide (NBS,
1.1 g, 62.4 mmol) was added to this suspension, and the
reaction mixture was stirred at rt in the dark for 5 h. Additional
NBS (4.93 g, 27.7 mmol) was added, and the reaction mixture
was stirred overnight. The reaction mixture was filtered, and
the solid was washed with 100 mL of cold butanone. The solid
1
dried to give 450 mg of 5b as a white solid (74% yield): mp >250
1
°
4
C; H NMR (DMSO-d
6
) δ 7.80 (s, 4 H), 4.50 (t, 4 H, J ) 8.0 Hz),
.41 (t, 4 H), 3.45 (t, 8 H, J ) 6.4 Hz), 2.39 (m, 8 H), 1.37 (m, 8
was dried to give 11.8 g (82%) of 3b as an off-white solid: mp
+
H), 0.55 (s, 12 H), -0.61 (s, 12 H); MS (NBA) m/z 1260 (M ,
00). Anal. Calcd for C48 Si C, 45.72; H, 4.80.
Found: C, 45.46; H, 4.91.
1
2
4
8
20 °C dec; H NMR (DMSO-d
6
) δ 9.11 (s, 8 H), 7.40 (s, 4 H),
1
H
60
O
12Br
4
4
:
.34 (br, 8 H), 3.43 (t, 8 H, J ) 6.5 Hz), 2.21 (m, 8 H), 1.34 (m,
+
+
H); MS (TG) m/z 1036 (M , 50) 977 ((M - HO(CH ) ) , 100).
2 3
Silicon Ca vita n d 5c. Silicon cavitand 5a (10 g, 7.60 mmol)
was suspended in 150 mL of DMF. While vigorous stirring was
maintained, diisopropylethylamine (20 mL, 115 mmol) and
MOM-Cl (5.8 mL, 76 mmol) were added. Within 1 h full
dissolution had occurred, and the reaction was stirred overnight
(
16) For further general experimental details, see: Fraser, J . R.;
Borecka, B.; Trotter, J .; Sherman, J . C. J . Org. Chem. 1995, 60, 1207-
213.
1

Notes
J . Org. Chem., Vol. 61, No. 4, 1996 1509
at rt. The solvent was removed in vacuo, and the crude product
was taken up in ethyl acetate. The organic layer was washed
with dilute HCl, then saturated potassium carbonate, and finally
purified by silica gel column chromatography using 9:1 CHCl
3
:
methanol (v/v) to give 19 mg (35%) of 6a as a white solid: mp
1
6
>250 °C; H NMR (DMSO-d ) δ 7.57 (s, 4 H), 6.50 (s, 4 H), 5.70
distilled water. The organic layer was dried (MgSO
4
), and the
(d, 4 H, J ) 7.8 Hz), 4.56 (t, 4 H, J ) 8.1 Hz), 4.38 (d, 4 H, J )
7.6 Hz), 4.36 (t, 4 H, J ) 5.0 Hz), 3.40 (m, 8 H), 2.36 (m, 8 H),
solvent was removed in vacuo to give a solid that was recrystal-
lized from acetone and dried to give 8.5 g (75%) of 5c as a white
+
1.54 (m, 8 H), 1.32 (m, 8 H); MS (TG) m/z 825 (M , 100). Anal.
1
1
solid: mp >250 °C; H NMR (CDCl
3
) δ 7.20 (s, 4 H), 4.64 (t, 4
Calcd for C48
H, 7.04.
H
56
O
12‚ /
2
H
2
O: C, 69.13; H, 6.89. Found: C, 69.13;
H, J ) 8.1 Hz), 4.57 (s, 8 H), 3.84 (t, 8 H, J ) 6.5 Hz), 3.32, (s,
2 H), 2.20 (m, 8 H), 1.66 (m, 8 H), 1.34 (m, 8 H), 0.60 (s, 12 H),
0.53 (s, 12 H); MS (NBA) m/z 1492 (M , 100). Anal. Calcd for
Si : C, 48.26; H, 5.67. Found: C, 48.10; H, 5.65.
Octol 3c. Silicon cavitand 5c (5 g, 3.35 mmol) was dissolved
1
Ca vita n d 6b. Dodecol 2b (46 mg, 0.064 mmol), potassium
carbonate (90 mg, 0.65 mmol), and MDT (80 mg, 0.22 mmol)
were added to 2 mL of DMA, and the solution was stirred at rt
for 2 days. Additional MDT (80 mg, 0.22 mmol) was added, and
the reaction mixture was stirred at 60 °C for 2 days. The solvent
was removed in vacuo and the ensuing solid was sonicated in
50 mL of water for 10 min followed by slow addition of 2 M HCl
until the carbonate salts were neutralized. The resulting
mixture was filtered, and the solid was washed with water (3 ×
15 mL), dissolved in 50 mL of THF, and dried with MgSO4. The
solvent was removed in vacuo, and the solid was purified by
+
-
60
C
H
84
O
16Br
4
4
in 180 mL of DMF in a polypropylene flask. To this stirring
solution was added HF (1.39 mL of a 48% solution, 33.4 mmol).
The reaction mixture was stirred overnight at rt, the solvent
was removed in vacuo (T < 40 °C), and the crude product was
taken up in ethyl acetate. The organic layer was washed three
4
times with distilled water before being dried (MgSO ). The
solvent was removed in vacuo, giving a solid that was recrystal-
lized from acetone and dried at 0.1 Torr at 77 °C for 24 h to give
silica gel column chromatography using 9:1 CHCl
v) to give 15 mg (30%) of 6b as a white solid: mp >250 °C; H
NMR (DMSO-d ) δ 7.60 (s, 4 H), 6.49 (s, 4 H), 5.70 (d, 4 H, J )
3
:methanol (v/
1
1
3
.5 g (82%) of 3c as a white solid: mp 230 °C dec; H NMR
(
acetone-d
6
) δ 8.25 (s, 8 H), 7.62 (s, 4 H), 4.52 (s, 4 H), 4.47 (t, 4
6
H, J ) 7.8 Hz), 3.45 (t, 8 H, J ) 6.5 Hz), 3.25 (s, 12 H), 2.34 (m,
8
H
7.6 Hz), 4.55 (t, 4 H, J ) 8.1 Hz), 4.43 (t, 4 H, J ) 5.0 Hz), 4.34
H), 1.62 (m, 8 H), 1.36 (m, 8 H); MS (TG) m/z 1286 ((M +
(d, 4 H, J ) 7.6 Hz), 3.50 (m, 8 H), 2.40 (m, 8 H), 1.45 (m, 8 H);
+
+
+
+
2
O) , 100) 1268 (M , 65) 1206 ((M - MOMOH) , 60). Anal.
: C, 49.23; H, 5.40. Found: C, 49.00; H,
MS (TG) m/z 769 (M , 100). Anal. Calcd for C44
H
48
O
12: C,
Calcd for C52
.40.
Ca vita n d 4c. Octol 3c (500 mg, 0.394 mmol), potassium
H
68
O
16Br
4
68.74; H, 6.29. Found: C, 68.82; H, 6.45.
5
Ca vita n d 6d . Octol 2d 17 (50 mg, 0.055 mmol) was dissolved
in 1 mL of DMA and added via syringe pump over 4 h to a
mixture of potassium carbonate (90 mg, 0.65 mmol) and MDT
(89 mg, 0.25 mmol) in 2.5 mL of DMA. The reaction mixture
was stirred for 1 day at rt, before MDT (89 mg, 0.25 mmol) was
added, and the reaction mixture was stirred at 60 °C for 1 day.
The reaction mixture was then cooled to rt, and the solvent was
removed in vacuo. The solid residue was stirred in water and
carbonate (900 mg, 6.5 mmol), and MDT (505 mg, 1.42 mmol)
were added, with stirring, to 15 mL of DMA. The reaction
mixture was stirred for 2 days before additional MDT (505 mg,
1
7
.42 mmol) was added, and the temperature was increased to
0 °C. After 2 days, the solvent was removed in vacuo, and the
residue was taken up in THF and filtered. The filtrate was
evaporated in vacuo, and the residue was purified by silica gel
colunm chromatography (3:1 THF:hexanes) and dried at 0.1 Torr
extracted with CHCl
purified by silica gel column chromatography (3:1 CHCl
hexanes) to give 43 mg (82%) of 6d as a white solid: mp >250
3
. The solvent was removed in vacuo and
3
:
at 77 °C for 24 h to give 210 mg (41%) of 4c as a white solid:
1
1
mp 193 °C dec; H NMR (CDCl
)
3
) δ 7.01 (s, 4 H) 5.94 (d, 4 H, J
3
°C; H NMR (CDCl ) δ 7.23-7.12 (m, 24 H), 6.52 (s, 4 H), 5.75
7.3 Hz), 4.87 (t, 4 H, J ) 8.1 Hz), 4.60 (s, 8 H), 4.37 (d, 4 H,
(d, 4 H, J ) 7.1 Hz), 4.82 (t, 4 H, J ) 7.9 Hz), 4.45 (d, 4 H, J )
+
J ) 7.3 Hz), 3.52 (t, 8 H, J ) 6.5 Hz), 3.33 (s, 12 H), 2.23 (m, 8
7.1 Hz), 2.65 (m, 8 H), 2.51 (m, 8 H); MS (TG) m/z 953 (M , 100).
+
1
H), 1.71 (m, 8 H), 1.44 (m, 8 H); MS (NBA) m/z 1316 (M , 100).
Anal. Calcd for C48
C, 79.95; H, 5.95.
H
56
O
12‚ /
2
H
2
O: C, 79.89; H, 5.97. Found:
Anal. Calcd for C56
1.07; H, 5.19.
Ca vita n d 6a . Dodecol 2a (50 mg, 0.064 mmol), potassium
68 4
H O16Br : C, 51.08; H, 5.21. Found: C,
5
Ack n ow led gm en t. We thank the Natural Sciences
and Engineering Research Council of Canada (NSERC)
for financial support. R.G.C. thanks NSERC for a
graduate fellowship. Acknowledgment is made to the
donors of The Petroleum Research Fund, administered
by the American Chemical Society, for partial support
of this research.
carbonate (90 mg, 0.65 mmol), and MDT (103 mg, 0.29 mmol)
were added to 2 mL of DMA, and the solution was stirred at rt
for 2 days. Additional MDT (103 mg, 0.29 mmol) was added,
and the reaction mixture was stirred at 60 °C for 2 days. The
solvent was removed in vacuo, and the ensuing solid was
sonicated in 50 mL of water for 10 min followed by slow addition
of 2 M HCl until the carbonate salts were neutralized. The
resulting mixture was filtered, and the solid was washed with
water (3 × 15 mL), dissolved in 50 mL of THF, and dried with
J O951633C
MgSO
4
.
The solvent was removed in vacuo, and solid was
(17) For the preparation of octol 2d , see ref 7.