Improved synthesis of functional CTVs and cryptophanes using Sc(OTf) 3 as catalyst

Article abstract of DOI:10.1021/jo050495g

Functional cyclotriveratrylene (CTV) and cryptophane derivatives are synthesized in the presence of scandium triflate [Sc(OTf)₃]. This route allows the preparation of new derivatives that could not be prepared or easily obtained by using the previously reported experimental procedures. With a catalytic amount of scandium triflate (1% mol), CTVs were obtained with yields similar to or higher than those reported previously in reactions run under strong acidic conditions. Cryptophanes were also synthesized in fairly good yields by performing the ring-closure step in the presence of a stoichiometric amount of Sc(OTf)₃. Interestingly, this novel approach strongly reduces the formation of side products and gives rise to novel functionalized molecules for the construction of supramolecular host-guest systems.

Full text of DOI:10.1021/jo050495g

Improved Synthesis of Functional CTVs and Cryptophanes Using
Sc(OTf)3 as Catalyst
Thierry Brotin,* Vincent Roy, and Jean-Pierre Dutasta*
Laboratoire de Chimie (UMR CNRS 5182), EÄ cole Normale Supe´rieure de Lyon, 46 Alle´e d’Italie,
F-69364 Lyon 7, France
thierry.brotin@ens-lyon.fr; dutasta@ens-lyon.fr
Received March 11, 2005
Functional cyclotriveratrylene (CTV) and cryptophane derivatives are synthesized in the presence
of scandium triflate [Sc(OTf)3]. This route allows the preparation of new derivatives that could not
be prepared or easily obtained by using the previously reported experimental procedures. With a
catalytic amount of scandium triflate (1% mol), CTVs were obtained with yields similar to or higher
than those reported previously in reactions run under strong acidic conditions. Cryptophanes were
also synthesized in fairly good yields by performing the ring-closure step in the presence of a
stoichiometric amount of Sc(OTf)3. Interestingly, this novel approach strongly reduces the formation
of side products and gives rise to novel functionalized molecules for the construction of supramo-
lecular host-guest systems.
Introduction
despite their increasing development, the current meth-
ods of preparation of CTVs still refer to old protocols,
which usually require strong dehydrating reagents.
These include perchloric acid in methanol,7 phosphorus
pentaoxide in diethyl ether,8 sulfuric acid in acetic acid,9
concentrated hydrochloric acid,10 trifluoroacetic acid in
chloroform,11 and BF3-etherate in benzene.12 However,
these conditions are often incompatible with the synthe-
sis of new CTV derivatives bearing acid-sensitive func-
tions, and it is therefore desirable to examine mild
reagents which could provide new routes to functional
CTVs. Recently, Raston et al. described the synthesis of
a tri(O-allyl)-CTV obtained in good yield under mild
conditions using an ionic liquid.13 Their approach appears
The cup-shape cyclotriveratrylene derivatives (CTV)
are among the key structures, with, e.g., calixarenes and
cavitands, which have been exploited for many years for
the design of molecular hosts.1 They still represent
interesting starting compounds for the construction of
new supramolecular architectures such as solid inclusion
complexes,2 chiral scaffolds for triple helix formation,3 or
more recently, coordination polymer networks4 and self-
assembled monolayers on gold surface.5 A second but not
least point of interest of the CTV derivatives is their use
in the synthesis of cryptophane hosts.6 Surprisingly,
(1) Collet, A. Tetrahedron 1987, 43, 5725-5739.
(2) Hardie, M. J.; Raston, C. L.; Wells, B. Chem. Eur. J. 2000, 6,
3293-3298.
(3) Rump, E. T.; Rijkers, D. T. S.; Hilbers, H. W.; De Groot, P. G.;
Liskamp, R. M. J. Chem. Eur. J. 2002, 8, 4613-4621.
(4) Hardie, M. J.; Sumby, C. J. Inorg. Chem. 2004, 43, 6872-6874.
(5) Zhang, S.; Echegoyen, L. J. Am. Chem. Soc. 2004, 127, 2006-
2011.
(7) Collet, A.; Jacques, J. Tetrahedron Lett. 1978, 1265-1268.
(8) Cram, D. J.; Tanner, M. E.; Keipert, S. J.; Knobler, C. B. J. Am.
Chem. Soc. 1991, 113, 8909-8916.
(9) Lindsey, A. S. J. Chem. Soc. 1965, 1685-1692.
(10) Carre´, M. M. P.; Libermann, D. Bull. Soc. Chim. Fr. 1935, 291-
295.
(6) (a) Collet, A.; Dutasta, J. P.; Lozach, B.; Canceill, J. Top. Curr.
Chem. 1993, 165, 103-129. (b) Collet, A. In Comprehensive Supramo-
lecular Chemistry; Vo¨gtle, F., Ed.; Pergamon Press: 1996; Vol. 2, pp
425-365.
(11) Atwood, J. L.; Orr, G. W.; Means, N. C.; Hamada, F.; Zhang,
H.; Bott, S. G.; Robinson, K. D. Inorg. Chem. 1992, 31, 603-606.
(12) Umezawa, B.; Hoshino, O.; Hara, H.; Ohyama, K.; Mitsuba-
yashi, S.; Sakakibara, J. Chem. Pharm. Bull. 1969, 17, 2240-2244.
10.1021/jo050495g CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/06/2005
J. Org. Chem. 2005, 70, 6187-6195
6187

Brotin et al.
TABLE 1. Formation of CTVs 2a-f from the
very promising even though ionic solvents are not still
of common use in many laboratories and their price as
solvent may be prohibitive for the production of large
amounts of compounds. Moreover, for the same reason,
the use of ionic liquids seems inappropriate for the
synthesis of cryptophanes because dilute conditions are
usually required. Konishi et al. reported an elegant
synthesis of protected calixarenes obtained in good yields,
using scandium triflate, Sc(OTf)3, as Lewis acid.14 This
strong Lewis acid gained considerable interest for the last
15 years and was found to catalyze numerous organic
reactions of prime importance like Friedel-Crafts alky-
lation reactions.15 We recently reported the synthesis of
monoprotected cryptophane16 and hemicryptophane17
obtained in fairly good yields using Sc(OTf)3 as Lewis
acid. These findings led us to investigate further scan-
dium triflate as a potent reagent for the preparation of
CTV and cryptophane derivatives. In this paper, we
demonstrate the ability of Sc(OTf)3 to promote the
synthesis of CTVs with satisfactory yields. In addition,
we show that the experimental procedure reported herein
allows the formation of new compounds, which cannot
be prepared, or properly purified, by using the previous
methods. In a second part, we report that under dilute
conditions, the reaction of a stoichiometric amount of
Sc(OTf)3 with the proper precursor leads to the formation
of cryptophane derivatives. The yields obtained under
these new conditions are in most cases similar, or even
higher, than those reported in the literature for known
compounds. Interestingly, we note that the simplicity of
this approach, combined with a significant decrease of
the side products of the reaction, and easier purification
of the expected compounds, allow the synthesis of new
cryptophanes, which cannot be prepared or easily purified
by following the previous synthetic procedures.
Corresponding Benzyl Alcohols 1a-h Using Catalytic
Amounts of Sc(OTf)3 (1% mol) in Acetonitrile or
Dichloromethane at 60 °C Overnight
compd
R1
R2
R3
solvent
CTV
yield (%)
1a
1b
1c
1c
1d
1d
1e
1f
OMe
OMe
OMe
OMe
OMe
OEt
H
CH3CN
CH3CN
CH3CN
CH2Cl2
CH3CN
CH2Cl2
CH3CN
CH3CN
CH3CN
CH3CN
2a
2b
2c
2c
2d
2d
2e
2e
2f
44
48
50
55
43
47
48
31
37
33
OEt
H
O-allyl
O-allyl
O-allyl
O-allyl
OMe
SMe
O-allyl
O-allyl
H
H
H
OEt
H
SMe
OMe
OBn
OBn
H
H
1g
1h
H
THP
2f
group is replaced by an ethyl group (1b), compound 2b
is obtained with similar yield (48%) under the present
experimental conditions, whereas it dropped to 10% when
run in 65% HClO4/methanol at 20 °C, due to an increase
of its solubility in the medium.20 In acetonitrile, benzyl
alcohols 1c and 1d bearing O-allyl protective groups gave
rise to the expected CTVs 2c and 2d in 50% and 43%
yields, respectively (Table 1). By exchanging acetonitrile
for dichloromethane, similar yields were obtained for
compounds 2c (55%) and 2d (47%). Again, these results
are better than those reported for 2c prepared in HCLO4/
methanol solution.21 Thus, this method provides a new
efficient approach to easily synthesize CTV 2c, which is
an important intermediate in the synthesis of cryp-
tophanes and related compounds.6 These satisfactory
results clearly demonstrate that Sc(OTf)3 is an efficient
catalysis for the improved synthesis of CTV derivatives
and represent an important alternative to the former
procedures requiring large amount of acids. Additionally,
it is noteworthy that this new route strongly facilitates
the purification steps by reducing significantly the for-
mation of side products. Compounds 1e and 1f prepared,
respectively, in five steps from vanillin and isovanillin
using a Newman-Kwart reaction also provided the
corresponding CTV 2e in 48% and 31% yields, respec-
tively.22 In this case, the yields are lower than those
reported by Garcia et al., who performed the ring closure
reaction in formic acid (70% from 1e and 60% from 1f).
However, as noted previously, the present procedure is
still attractive as the purification step is facilitated.
Results and Discussion
Synthesis of CTVs. A series of differently substituted
CTVs were prepared by treating the parent benzyl
alcohols with Sc(OTf)3 in catalytic amount (1% mol); the
results are summarized in Table 1. Because only strongly
activated benzyl alcohols provide the CTV derivatives,
only O- or S-substituted phenyl compounds have been
allowed to react with Sc(OTf)3 in acetonitrile or in
dichloromethane. In all cases, the procedure given in the
Experimental Section provided CTVs with satisfactory
yields. For instance, in acetonitrile compound 1a gave
rise to the corresponding CTV 2a in 44% yield after
purification. This result is better than those reported for
the reactions run with 60% perchloric acid (35% yield)12
or with trifluoroacetic acid in chloroform (19% yield),18
but less than for the method using sulfuric acid in hot
acetic acid (87% yield).19 Interestingly, when one methyl
To demonstrate the utility of this method to promote
the formation of CTVs that could not be easily obtained
(13) Scott, J. L.; MacFarlane, D. R.; Raston, C. L.; Teoh, C. M. Green
Chem. 2000, 2, 123-126.
(19) Lindsey, A. S. J. Chem. Soc. 1965, 1685-1692.
(20) Compound 2b has been obtained in 51% yield in HClO4/
methanol solution by performing the reaction in a fridge in order to
precipitate the product and to avoid partial decomposition (see ref 37).
This procedure appears however very inconvenient and the use of
scandium triflate as a catalyst is thus preferred for the synthesis of
2b.
(14) Konishi, H.; Sakakibara, H.; Kobayashi, K.; Morikawa, O. J.
Chem. Soc., Perkin Trans. 1 1999, 2583-2584.
(15) Tsuchimoto, T.; Tobita, K.; Hiyama, T.; Fukuzawa, S. J. Org.
Chem. 1997, 62, 6997-7005.
(16) Darzac, M.; Brotin, T.; Bouchu, D.; Dutasta, J. P. Chem.
Commun. 2002, 48-49
(17) Gautier, A.; Mulatier, J. C.; Crassous, J.; Dutasta, J. P. Org.
Lett. 2005, 7, 1207-1210.
(21) Canceill, J.; Gabard, J.; Collet, A. J. Chem. Soc., Chem.
Commun. 1983, 122-123.
(18) Al-Farhan, E.; Keehn, P. M.; Stevenson, R. Tetrahedron Lett.
1992, 33, 3591-3594.
(22) Garcia, C.; Andraud, C.; Collet, A. Supramol. Chem. 1992, 1,
31-45.
6188 J. Org. Chem., Vol. 70, No. 16, 2005

Functional CTVs and Cryptophanes
SCHEME 1
by following already known procedures, we performed the
reaction of compound 1g with Sc(OTf)3. Benzyl alcohol
1g was synthesized in three steps from 3,4-dihydroxy-
benzyl alcohol 3 (Scheme 1). Monoallylation was achieved
according to a known method to give compound 4 in 56%
yield.23 Monoprotected derivative 4 was then reacted with
benzyl bromide in acetone in the presence of potassium
carbonate to give compound 5 in 97% yield. Reduction of
5 with NaBH4 in methanol gave the benzyl alcohol
derivative 1g in 96% yield after purification. Attempts
to prepare CTV 2f from compound 1g in HClO4/methanol
mixture failed. The presence of many side products did
not allow purifying properly the small amount of CTV
detected by 1H NMR spectroscopy in the crude material.
The situation is somewhat different when Sc(OTf)3 in
acetonitrile was used to promote the formation of com-
pound 2f, which was easily obtained in 37% yield after
purification. Protected benzyl alcohols are usually re-
quired to purify properly some cryptophane precursors
(see below). It was thus interesting to attempt the
cyclization reaction with the O-THP-protected benzyl
alcohol 1h, which was prepared in 84% yield by treating
1g with dihydropyran in the presence of PPTS. As
expected, the reaction of 1h with Sc(OTf)3 in CH2Cl2
afforded CTV 2f in 33% yield, a yield similar to that
obtained from 1g. This demonstrates that under these
conditions the O-THP protection of the benzyl alcohol
function does not affect significantly the yield of the
cyclization reaction. CTV 2f was fully characterized by
usual spectroscopic techniques, and it represents an
important building block for the elaboration of new
derivatives, such as multiprotected cryptophanes. Indeed,
both protecting groups can be selectively cleaved at
different stage of the synthesis. For instance, reaction of
2f with palladium catalyst afforded the trihydroxy CTV
6 in 81% yield (Scheme 1).23
Synthesis of Cryptophanes. The satisfactory results
obtained with CTV derivatives prompted us to investigate
scandium triflate as new potent reagent for the synthesis
of cryptophane derivatives. Cryptophanes are molecular
receptors usually synthesized in formic acid as solvent.
This procedure gave satisfactory results, but this ap-
proach appeared inappropriate for the design of new
molecules bearing protecting groups. Indeed, when we
tried to perform in formic acid the synthesis of cryp-
tophanes bearing several benzyl or allyl substituents,
most of these attempts failed and a complex mixture of
compounds was observed at the end of the reaction. An
additional difficulty arose from the purification steps,
which were particularly critical when only tiny amounts
of cryptophanes were detected in the crude reaction
mixtures. It thus became obvious that the use of Sc(OTf)3
as a mild reagent might be an interesting option to
synthesize cryptophane hosts. However, optimal reaction
conditions require dilute solutions (∼10-3 M) when the
so-called template method is applied in order to avoid
polymerization side reactions.24 Consequently, catalytic
amounts of Sc(OTf)3 would be inappropriate to achieve
the formation of cryptophanes in satisfactory yield, and
we thus used Sc(OTf)3 in stoichiometric amounts to
perform these syntheses. We should mention that the use
of larger amounts of reagents still presents interest as
(23) Brotin, T.; Devic, T.; Lesage, A.; Emsley, L.; Collet, A. Chem.
Eur. J. 2001, 7, 1561-1573.
(24) Gabard, J.; Collet, A. J. Chem. Soc., Chem. Commun. 1981,
1137-1139.
J. Org. Chem, Vol. 70, No. 16, 2005 6189

Brotin et al.
TABLE 2. Formation of Cryptophanes 8a-c from Their
Precursors 7a-c Using a Stoichiometric Amount of
Sc(OTf)3 in Acetonitrile or Dichloromethane at 60 °C for
72 h
proposed to prepare 11. In a first approach, the phenol
groups in 9 could be removed by hydrogenolysis of the
tris(2-phenyl-1-tetrazolyl) derivative to give 11 in 90%
yield.31 A second route used Raney-Ni desulfuration of
2e.22 Both methods gave satisfactory results, but the
present novel procedure is more appropriate to give
sizable amounts of compound 11. Removal of the three
methyl groups in 11 was easily achieved using BBr3 in
dichloromethane to give the cyclotriphenolene 12 in 66%
yield.32 The cryptophane precursor 14 was obtained in
70% yield from 12, and protected benzyl alcohol 13 in
the presence of cesium carbonate in DMF. Compound 14
was then allowed to react with Sc(OTf)3 for 72 h to give
anti-cryptophane-C 15a and syn-cryptophane-D 15b in
50% and 8% yields, respectively. Compound 15a is known
for its interesting binding properties toward chiral ha-
logenomethanes.33
The syntheses of 15a and 15b have been previously
reported with 25% and 5% yields, respectively.34 The
results presented herein enlighten the simplicity of both
the method and the purification procedure that make this
approach very attractive for the design and purification
of cryptophanes 15a,b. These CTVs and cryptophane
derivatives were characterized by usual analytical tech-
niques. To our knowledge, cryptophane-D 15b is the only
syn-isomer with OCH2CH2O bridges, which has been
unambiguously isolated and characterized; its 500 MHz
1H NMR spectrum is given in Figure 1. Thus, the
obtaining of sizable amounts of 15b is crucial for further
spectroscopic investigations including the studies of
encapsulation processes within the molecular cavity of
the host. For instance, cryptophane-D 15b is suitable for
complexation of xenon guest, which is accessible through
NMR experiments using laser-polarized 129Xe.35
In an attempt to further improve the capability of
Sc(OTf)3 in the formation of cryptophanes, we synthesize
the new cryptophane 17 bearing three benzyl protecting
groups (Scheme 3). Cryptophane precursor 16 was ob-
tained in 88% yield from CTV 6 and compound 13 in the
presence of cesium carbonate. Attempts to obtain 17 from
16 dissolved in a mixture of formic acid and chloroform
at 55 °C were unsuccessful. Although 17 was clearly
detected in tiny amount in the crude reaction mixture,
the purification by column chromatography was inef-
ficient as several side-products were eluted with the
desired cryptophane. When compound 16, was allowed
to react with Sc(OTf)3 in CH2Cl2, the expected cryp-
tophane 17 was isolated as the anti-isomer in 42% yield.
Figure 2 shows the 500 MHz 1H NMR spectrum of
cryptophane 17. We observed a signal at 3.4 ppm,
corresponding to the three methoxy groups, high-field
shifted by 0.4 ppm with respect to the usual chemical
shift observed for methoxy groups in cryptophane-A 8a,
a consequence of the shielding effect of the benzyl
moieties on the facing CTV unit. Once again, the forma-
precursor
n
m
R
solvent cryptophane yield (%)
7a
7a
7b
7c
2
2
3
2
2
2
3
3
OTHP CH3CN
OTHP CH2Cl2
OTHP CH2Cl2
8a (A)
8a (A)
8b (E)
8c (223)
36
51
28
33
H
CH2Cl2
Sc(OTf)3 can be easily recovered from the aqueous layer
and reused for subsequent experiments.25
Substituted CTV precursors 7a-c leading to the
formation of known cryptophanes were reacted with
Sc(OTf)3, and results are summarized in Table 2. For
instance, when precursor 7a23 was allowed to react with
a stoichiometric amount of Sc(OTf)3 in acetonitrile, the
expected cryptophane-A 8a was obtained in 36% yield.
The yield increased to 51% when dichloromethane was
used instead of acetonitrile. The present yields for 8a are
lower than those obtained by using formic acid (80%
yield).26 However, once again, this new procedure made
easier the purification steps by column chromatography.
Similar observations were made with precursors 7b and
7c. Compound 7b afforded the expected anti-cryp-
tophane-E 8b in 28% yield,27 and compound 7c gave anti-
cryptophane-223 8c in 33% yield.28 These last two
experiments gave yields similar to those reported in
previous syntheses using formic acid.
We then explored further the advantages of Sc(OTf)3
reagent over the usual procedures using strong acidic
conditions by performing the synthesis of cryptophane
15 from the substituted cyclotriphenolene 14. Compound
14 was prepared in four steps from CTV 9 using a novel
and efficient synthetic approach described in Scheme 2.
Deprotection of CTV 2c with a palladium catalyst fol-
lowing a known procedure gave compound 9,29 which was
then allowed to react with triflic anhydride in pyridine
to afford 10 in 85% yield. The reduction step was achieved
with a palladium catalyst, and compound 11 was ob-
tained in 71% yield.30 Compound 11 is very useful and
has been involved in the studies of the optical properties
of CTVs or in the synthesis of anti-cryptophane-C 15a.
To our knowledge, two different approaches have been
(25) Kobayashi, S. Eur. J. Org. Chem. 1999, 15-27.
(26) Canceill, J.; Collet, A.; Gottarelli, G.; Palmieri, P. J. Am. Chem.
Soc. 1987, 109, 6454-6464.
(31) Canceill, J.; Collet, A.; Gottarelli, G. J. Am. Chem. Soc. 1984,
106, 5997-6003.
(27) Canceill, J.; Ce´sario, M.; Collet, A.; Guilhem, J.; Lacombe, L.;
Lozach, B.; Pascard, C. Angew. Chem., Int. Ed. Engl. 1989, 28, 1246-
1248.
(32) Canceill, J.; Collet, A. J. Chem. Soc., Chem. Commun. 1983,
1145-1147.
(33) Costante-Crassous, J.; Hecht, L.; Polaravapu, P. L.; Collet, A.;
Barron, L. D. Angew. Chem., Int. Ed. Engl. 1997, 36, 885-886.
(34) Canceill, J.; Lacombe, L.; Collet, A. J. Am. Chem. Soc. 1985,
107, 6993-6996.
(35) Desvaux, H.; Huber, J. G.; Brotin, T.; Dutasta, J. P.; Berthault,
P. ChemPhysChem 2003, 4, 384-387.
(28) Brotin, T.; Dutasta, J. P. Eur. J. Org. Chem. 2003, 973-984.
(29) Gosse, I.; Dutasta, J. P.; Perrin, M.; Thozet, A. New J. Chem.
1999, 23, 545-548.
(30) Saa`, J. M.; Dopico, M.; Martorell, G.; Garcia-Raso, A. J. Org.
Chem. 1990, 50, 991-995.
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Functional CTVs and Cryptophanes
SCHEME 2
tion of this new cryptophane exemplifies the synthetic
possibilities of Sc(OTf)3 in the design of more complex
cryptophane derivatives, which cannot be easily obtained
or even purified using previously reported procedures.
Furthermore, such multiprotected molecules are key
compounds for achieving the optical resolution of new
cryptophanes36 and the construction of new supramo-
lecular structures.
catalyst strongly reduced the formation of side-products
and thus made the purification steps easier. On the other
hand, the mild conditions reported herein allowed the
synthesis of new functionalized CTV derivatives such as
2g bearing both allyl and benzyl moieties as protecting
groups. We also reported the synthesis of new CTV
derivatives 6 and 10 in good yields, which are important
precursors for the preparation of new functional CTVs
or cryptophanes. In a second part, we showed that
Sc(OTf)3 used in stoichiometric amount in diluted solu-
tion, provided the expected cryptophanes from their re-
spective precursors. In most cases the yields obtained are
similar to those reported for other methods. Several
parameters such as solvent, temperature, and dilution
may influence the formation of the cryptophanes, and
some experimental conditions could be optimized. How-
ever, the yields reported herein and the procedure given
in the Experimental Section lead to very satisfactory
results. The following criteria can be retained to under-
line the advantages of Sc(OTf)3 in the synthesis of CTVs
Conclusion
Scandium triflate Sc(OTf)3 was used for the prepara-
tion of various CTVs and cryptophanes. We showed
that Sc(OTf)3 used in catalytic amounts (1% mol) pro-
moted the formation of CTVs 2a-g in moderate yields
(30-55%). These values are similar to those reported in
previous works using strong acids such as perchloric or
formic acids. Interestingly, we noted that using this
(36) Brotin, T.; Barbe, R.; Darzac, M.; Dutasta, J. P. Chem. Eur. J.
2003, 9, 5784-5792.
J. Org. Chem, Vol. 70, No. 16, 2005 6191

Brotin et al.
1
FIGURE 1. 500 MHz H NMR spectrum of syn-cryptophane-D 15b (CDCl3).
1
FIGURE 2. 500 MHz H NMR spectrum of anti-cryptophane 17 (CDCl3).
SCHEME 3
and cryptophanes: Sc(OTf)3 is an environmentally safe
Lewis acid and reduces the amount of solvents in the
preparation of cryptophane by the template method (both
catalyst and solvent can be easily recovered and reused).
Importantly, the use of Sc(OTf)3 catalyst, strongly re-
duces the formation of side-products and facilitates the
purification steps. This was exemplified by the formation
and the purification of syn-cryptophane-D 15b pre-
pared in moderate yield from compound 14. Furthermore,
Sc(OTf)3 allowed the formation of new cryptophanes,
which could not be easily prepared or purified by the
previous procedures. For instance, cryptophane 17 was
isolated in fairly good yield, but could not be obtained
when formic acid was used as solvent. Sc(OTf)3 appears
therefore as a very promising reagent for the formation
of more complex cryptophanes derivatives such as mul-
tiprotected cryptophanes and will probably contribute
significantly to the design of new original molecules.
Experimental Section
General Methods. 1H and 13C NMR spectra were recorded
at 499.83 and 125.7 MHz, respectively. Chemical shifts are in
δ values from Me4Si (1H, 13C). Multiplicities are as follows: s,
singlet; d, doublet; t, triplet; q, quadruplet; m, multiplet;
Ha,e, H axial, equatorial. High-resolution mass analyses were
recorded using LSIMS. Column chromatographic separations
were carried out over silica gel 60 (0.040-0.063 mm). Analyti-
cal thin-layer chromatography (TLC) was performed on silica
6192 J. Org. Chem., Vol. 70, No. 16, 2005

Functional CTVs and Cryptophanes
gel TLC plates with F-254 indicator. Melting points were
measured using differential scanning calorimeter. Solvents
were distilled prior to use: DMF from CaH2, CH2Cl2 from
CaCl2, THF from Na/benzophenone and NEt3 from KOH. All
other commercially available compounds were used without
further purification.
3,4-Dimethoxybenzyl alcohol 1a was commercially available.
Benzyl alcohol 1b was commercially available or was easily
prepared from vanillyl alcohol.37 Benzyl alcohols 1c,31 1d,37 and
1e,f22 were prepared as described. Compounds 4,23 7a,23 9,29
12,32 and 1323 were synthesized according to known proce-
dures.
Addition of AcOEt allows the precipitation of 2a, which was
collected on a frit and washed with a small amount of AcOEt
and diethyl ether. The solid was then recrystallized from
CH2Cl2/pentane mixture to give 2a as a white solid (2.0 g,
44%): mp (DSC) 230.5 °C (lit.12 232 °C).
2,7,12,-Triethoxy-3,8,13-trimethoxy-10,15-dihydro-5H-
tribenzo[a,d,g]cyclononene 2b. According to method A,
4-ethoxy-3-methoxybenzyl alcohol 1b (2.0 g, 11.8 mmol) and
scandium triflate (0.051 g, 0.12 mmol) in acetonitrile gave
compound 2b (0.92 g, 48%) after purification by column
chromatography (AcOEt/CH2Cl2: 80/20): mp (DSC) 172 °C
(lit.37 172 °C).
(4-Allyloxy-3-benzyloxyphenyl)methanol (1g). Sodium
borohydride (1.62 g, 0.043 mol) was added in small portions
to an ice-cooled solution of 5 (8.17 g, 0.031 mol) in methanol
(50 mL). After complete addition, the solution was stirred at
room temperature for 5 h. Then, most of the solvent was
removed by rotary evaporation under reduced pressure. Water
(100 mL) was added, and the solution was slowly acidified with
a concd HCl solution at 0 °C. The white precipitate was then
extracted twice with ethyl acetate. The combined organic
layers were then washed with brine and dried over sodium
sulfate. Evaporation of the solvent gave a residue, which was
purified by column chromatography (AcOEt). The combined
fractions were evaporated under reduced pressure to give 1g
as a white crystalline compound (7.9 g, 94%): mp (DSC) 61
°C; TLC Rf 0.83 (AcOEt); 1H NMR (CDCl3, 20 °C) δ 7.435 (m,
2H, Ar), 7.35 (m, 2H, Ar), 7.28 (m, 1H, Ar), 6.95 (s, 1H, Ar),
6.865 (m, 2H, Ar), 6.05 (m, 1H), 5.395 (m, 1H), 5.34 (m, 1H),
5.13 (m, 2H), 4.60 (m, 2H, OCH2), 4.55 (d, 2H, OCH2, 3J ) 6.0
2,7,12-Triallyloxy-3,8,13-trimethoxy-10,15-dihydro-
5H-tribenzo[a,d,g]cyclononene 2c. (a) Procedure Using
Acetonitrile as Solvent. According to general procedure A,
4-allyloxy-3-methoxybenzyl alcohol 1c (20.0 g, 104.0 mmol) and
scandium triflate (0.45 g, 1.04 mmol) in acetonitrile (50 mL)
gave compound 2c (9.0 g, 50%) after purification by column
chromatography (CH2Cl2/Et2O: 95:5). (b) Procedure Using
Dichloromethane as Solvent. According to general proce-
dure A, 1c (5.0 g, 25.8 mmol) and scandium triflate (0.127 g,
0.26 mmol) in dichloromethane (50 mL) gave compound 2c
(2.5 g, 55%) after purification by column chromatography
(CH2Cl2/Et2O: 95/5): mp (DSC) 168 °C (lit.21 172 °C).
2,7,12-Triallyloxy-3,8,13-triethoxy-10,15-dihydro-
5H-tribenzo[a,d,g]cyclononene 2d. (a) Procedure Using
Acetonitrile as Solvent. According to method A, 4-allyloxy-
3-ethoxybenzyl alcohol 1d (2.0 g, 9.15 mmol) and scandium
triflate (0.047 g, 0.1 mmol) in acetonitrile (20 mL) gave
compound 2d (0.8 g, 43%) after purification by column chro-
matography (CH2Cl2/Et2O: 95/5): mp (DSC) 116 °C (lit.37 116
°C); 1H NMR (CDCl3, 20 °C) δ 6.83 (s, 3H, Ar), 6.79 (s, 3H,
Ar), 6.03 (m, 3H, Ar), 5.35 (m, 3H), 5.21 (m, 3H), 4.69 (d, 3H,
3
Hz), 1.58 (t, 1H, OH, J ) 6.0 Hz); 13C NMR (CDCl3, 20 °C) δ
148.69, 148.09, 137.10, 134.07, 133.38, 128.39 (2C), 127.69,
127.18 (2C), 119.94, 117.45, 114.23, 113.64, 70.90, 69.97, 64.91.
Anal. Calcd for C17H18O3 (270.327): C, 75.53; H, 6.71. Found:
C, 75.54; H, 6.84.
2
Ha, J ) 14.0 Hz), 4.54 (m, 6H), 4.03 (m, 6H, OCH2), 3.47 (d,
3H, He, 2J ) 14.0 Hz), 1.38 (t, 9H, CH3, 2J ) 7.0 Hz); 13C NMR
(CDCl3, 20 °C) δ 147.64 (3C), 147.30 (3C), 134.02 (3C), 132.61
(3C), 132.09 (3C), 117.03 (3C), 116.58 (3C), 114.94 (3C), 70.49
(3C, OCH2), 64.84 (3C, OCH2), 36.43 (3C, Ca,e), 14.92 (3C, CH3).
Anal. Calcd for C36H42O6 (570.724): C, 75.76; H, 7.41. Found:
C, 75.48; H, 7.52. (b) Procedure Using Dichloromethane
as Solvent. According to method A, 1d (2.0 g, 9.15 mmol) and
scandium triflate (0.048 g, 0.11 mmol) in CH2Cl2 (20 mL) gave
compound 2d (0.86 g, 47%) after purification by column
chromatography (CH2Cl2/Et2O: 95/5).
2-(4-Allyloxy-3-benzyloxybenzyloxy)tetrahydro-
pyran (1h). A solution of PPTS (0.64 g, 0.026 mol) dissolved
in CH2Cl2 (10 mL) was added in one portion to a stirred
solution of 1g (6.9 g, 0.026 mol) and DHP (3.22 g, 0.038 mol)
in THF (100 mL) at room temperature. The solution was
stirred overnight at room temperature. The solvent was then
evaporated under reduced pressure, and the residue was
extracted with diethyl ether. The organic layer was washed
twice with brine and then dried over sodium sulfate. The
solvent was evaporated under reduced pressure to leave a
residue, which was purified by chromatography (Et2O/pen-
tane: 50/50). Evaporation of the solvent gave white crystals
of compound 1h (7.74 g, 84%): mp (DSC) 46.5 °C; TLC Rf 0.83
2,7,12,-Trimethoxy-3,8,13-trimethylthio-10,15-dihydro-
5H-tribenzo[a,d,g]cyclononene 2e. (a) From 1e. According
to method A, 4-methoxy-3-methylthiobenzyl alcohol 1e (2.2 g,
12.0 mmol) and scandium triflate (0.052 g, 0.12 mmol) in
acetonitrile (40 mL) gave compound 2e (0.95 g, 48%) after
purification by column chromatography (CH2Cl2/hexane: 99/
1): mp (DSC) 242 °C (lit.22 238 °C). (b) From 1f. According to
general procedure A, 3-methoxy-4-methylthiobenzyl alcohol 1f
(1.0 g, 5.4 mmol) and scandium triflate (0.023 g, 0.05 mmol)
in acetonitrile gave compound 2e (0.28 g, 31%) after purifica-
tion by column chromatography (CH2Cl2/hexane: 99/1).
1
(Et2O/pentane 50/50); H NMR (CDCl3, 20 °C) δ 7.43 (m, 2H,
Ar), 7.34 (m, 2H, Ar), 7.27 (m, 1H, Ar), 6.94 (s, 1H, Ar), 6.86
(m, 2H, Ar), 6.05 (m, 1H), 5.39 (m, 1H), 5.25 (m, 1H), 5.14 (m,
2H, OCH2), 4.65 (d, 1H, 2J ) 11.5 Hz), 4.60 (m, 3H), 4.375 (d,
2
1H, J ) 11.5 Hz), 3.85 (m, 1H), 3.49 (m, 1H), 1.86-1.74 (m,
1H), 1.72-1.63 (m, 1H), 1.62-1.44 (m, 4H); 13C NMR (CDCl3,
20 °C) δ 148.66, 148.25, 137.29, 133.53, 131.31, 128.38 (2C),
127.65, 127.19 (2C), 121.03, 117.38, 114.76, 114.25, 97.39,
71.08, 70.07, 68.48, 62.10, 31.52, 25.42, 19.35. Anal. Calcd for
C22H26O4 (254.445): C, 74.55; H, 7.39. Found: C, 74.65; H,
7.45.
2,7,12-Triallyloxy-3,8,13-tribenzyloxy-10,15-dihydro-
5H-tribenzo[a,d,g]cyclononene 2f. (a) From 1g. Scandium
triflate (0.016 g, 0.037 mmol) was added in one portion to a
stirred solution of benzyl alcohol 1g (0.93 g, 3.45 mmol) in
acetonitrile (20 mL). The solution was stirred at 60 °C for 18
h under argon. The solvent was then removed under reduced
pressure and the remaining residue extracted twice with
dichloromethane. The combined organic layers were then
washed with brine and dried over sodium sulfate. Filtration
and removal of the solvent by rotary evaporation afforded a
residue, which was then purified by column chromatography
(CH2Cl2/pentane: 50/50, then gradient 60/40, 70/30, 80/20).
Removal of the solvent gave compound 2f as a white crystalline
solid (0.32 g, 37%): mp (DSC) 122 °C; TLC Rf 0.94 (CH2Cl2/
General Method for the Synthesis of CTV Derivatives
with Sc(OTf)3. Method A. 2,3,7,8,12,13-Hexamethoxy-
10,15-dihydro-5H-tribenzo[a,d,g]cyclononene 2a. A solu-
tion of scandium triflate (0.128 g, 0.3 mmol) and 3,4-
dimethoxybenzyl alcohol 1a (5.0 g, 30 mmol) in acetonitrile
(30 mL) was stirred at 60 °C for 18 h under argon. Acetonitrile
was removed by rotary evaporation and the residue extracted
twice with CH2Cl2. The combined organic layers were washed
with brine and dried over sodium sulfate. The solvent was
removed under reduced pressure to leave a yellow residue.
1
Et2O: 95/5); H NMR (CDCl3, 20 °C) δ 7.40 (m, 6H, Ar), 7.33
(m, 6H, Ar), 7.27 (m, 3H, Ar), 6.83 (s, 3H, Ar), 6.73 (s, 3H,
Ar), 6.03 (m, 1H), 5.23 (m, 3H), 5.07 (s, 6H, OCH2), 4.65 (d,
(37) Canceill, J.; Collet, A.; Gabard, J.; Gottarelli, G.; Spada, G. P.
J. Am. Chem. Soc. 1985, 107, 1299-1308.
J. Org. Chem, Vol. 70, No. 16, 2005 6193

Brotin et al.
2
3H, Ha, J ) 14.0 Hz), 4.47 (m, 6H, OCH2), 3.425 (d, 3H, He,
3.49 (d, 3H, He, 2J ) 14.0 Hz), 2.78 (q, 3H, CH2, 3J ) 7.0 Hz),
3
2J ) 14.0 Hz); 13C NMR (CDCl3, 20 °C) δ 147.69, 147.56,
137.55, 133.82, 132.68, 132.41, 128.49 (2C), 127.75, 127.06
(2C), 117.25, 116.92, 116.47, 71.74, 70.34, 36.45. Anal. Calcd
for C51H48O6 (756, 9366): C, 80.93; H, 6.39. Found: C, 80.93;
H, 6.67. (b) From 1h. Scandium triflate (0.025 g, 0.056 mmol)
dissolved in acetonitrile (5 mL) was added in one portion to a
stirred solution of 1h (2.0 g, 0.0056 mol) in acetonitrile (25
mL). The solution was stirred at 60 °C for 48 h under argon.
Acetonitrile was then removed in a vacuum to give a residue,
which was extracted twice with dichloromethane. The com-
bined organic layers were then washed with water and dried
over sodium sulfate. The solvent was evaporated under
reduced pressure to give an oily residue, which was purified
by column chromatography (CH2Cl2). Crystallization from
CH2Cl2/pentane mixture gave white crystals, which were
collected on a frit and washed with a mixture of diethyl ether
and pentane (0.47 g, 33%).
2.66 (q, 3H, CH2, J ) 7.0 Hz), 1.90-1.80 (m, 3H), 1.74-1.67
(m, 3H), 1.64-1.48 (m, 12H); 13C NMR (CDCl3, 20 °C) δ 149.31
(3C), 148.13 (3C), 147.76 (3C), 146.83 (3C), 132.12 (3C), 131.77
(3C), 130.98 (3C), 120.51 (3C), 115.09 (3C), 113.55 (3C), 112.86
(3C), 111.70 (3C), 97.46 (3C), 68.69 (3C, OCH2), 65.84 (3C,
OCH2), 65.58 (3C, OCH2), 62.24 (3C, OCH2), 56.01 (3C, OCH3),
55.78 (3C, OCH3), 36.35 (3C), 30.55 (3C), 29.06 (3C), 19.43 (3C);
HRMS calcd for C72H90O18 (M•+) 1242.6127, found 1242.6131.
[4-[2-(12-[2-(4-hydroxymethyl-2-methoxyphenoxy)-
ethoxy]-3,8,13-trimethoxy-7-[3-[2-methoxy-4-(tetrahydro-
pyran-2-yloxymethyl)phenoxy]propoxy]-10,15-dihydro-
5H-tribenzo[a,d,g]cyclononene-2-yloxy)ethoxy]-3-
methoxyphenyl]methanol (7c). This compound was prepared
according to a known procedure from 7,12-bis[2-(4-hydroxym-
ethyl-2-methoxyphenoxy)ethoxy]-3,8,13-trimethoxy-10,15-di-
hydro-5H-tribenzo[a,d,g]cyclononen-2-ol (0.5 g, 0.65 mmol),38
2-[4-(3-iodopropoxy)-3-methoxybenzyloxy]tetrahydropyran (0.33
g, 0.81 mmol),28 and cesium carbonate (0.32 g, 0.98 mmol) in
DMF (30 mL). Purification by column chromatography (AcOEt/
EtOH: 98/2) gave compound 7c as a glassy solid (0.48 g,
70%): TLC Rf 0.31 (AcOEt/EtOH: 98:2); 1H NMR (CDCl3, 20
°C) δ 6.985 (s, 1H, Ar), 6.98 (s, 1H, Ar), 6.92 (s, 1H, Ar), 6.90-
6.84 (m, 8H, Ar), 6.81-6.77 (m, 4H, Ar), 4.71 (d, 2H, Ha, 2J )
4-Allyloxy-3-benzyloxybenzaldehyde 5. Benzyl bromide
(6.34 g, 0.037 mol) was added in one portion to a stirred
mixture of potassium carbonate (5.11 g, 0.037 mol) and
compound 4 (6.0 g, 0.034 mol) in DMF (70 mL). The mixture
was stirred overnight at 80 °C under argon and then poured
into water. The product was then extracted three times with
ethyl acetate. The combined organic layers were then washed
five times with brine to remove DMF and then dried over
sodium sulfate. Evaporation of the solvent under reduce
pressure gave a residue, which was purified by column
chromatography (AcOEt/pentane: 50/50). Evaporation of the
solvent afforded compound 5 as a slight yellow crystalline
compound (8.72 g, 97%): mp (DSC) 49 °C; TLC Rf 0.88 (AcOEt/
pentane: 50/50); 1H NMR (CDCl3, 20 °C) δ 9.80 (s, 1H, CHO),
2
2
14.0 Hz), 4.709 (d, 1H, Ha, J ) 14.0 Hz), 4.685 (d, 1H, J )
11.5 Hz), 4.652 (m, 1H), 4.585 (d, 4H, OCH2, 3J ) 6.0 Hz),
4.411 (d, 1H, J ) 11.5 Hz), 4.40-4.30 (m, 8H, OCH2), 4.26-
2
4.14 (m, 4H, OCH2), 3.90 (m, 1H), 3.82 (s, 3H, OCH3), 3.75 (s,
3H, OCH3), 3.73 (s, 6H, OCH3), 3.67 (s, 3H, OCH3), 3.66 (s,
3H, OCH3), 3.52 (m, 1H), 3.505 (d, 2H, He, 2J ) 14.0 Hz), 3.50
(d, 1H, He, 2J ) 14.0 Hz), 2.285 (q, 1H, CH2, 3J ) 6.0 Hz), 2.27
(q, 1H, CH2, 3J ) 6.0 Hz), 1.88-1.78 (m, 1H), 1.73 (t, 1H, OH,
3J ) 6.0 Hz), 1.72 (t, 1H, OH, 3J ) 6.0 Hz), 1.76-1.68 (m, 1H),
1.64-1.48 (m, 4H); 13C NMR (CDCl3, 20 °C) δ 149.82 (2C),
149.51, 148.59 (2C), 148.28, 147.89, 147.59 (2C), 147.02, 146.89
(2C), 134.68 (2C), 133.14 (2C), 132.23, 132.01, 131.89 (2C),
131.19, 120.56, 119.37 (2C), 116.97 (2C), 115.46, 114.19 (2C),
114.02 (2C), 113.83, 113.22, 111.96, 111.13 (2C), 97.57, 68.74
(1C, OCH2), 68.32 (2C, OCH2), 67.96 (2C, OCH2), 66.08 (1C,
OCH2), 65.79 (1C, OCH2), 65.14 (1C, OCH2), 62.26 (1C, OCH2),
56.17 (3C, OCH3), 55.88 (1C, OCH3), 55.78 (2C, OCH3), 36.38
(3C, Ca,e), 30.59, 29.22 (1C, CH2), 25.45, 19.46; HRMS calcd
for C60H70O16 (M•+) 1046.4664, found 1046.4663.
4
7.45 (d, 1H, Ar, J ) 2.0 Hz), 7.44 (m, 2H, Ar), 7.42 (dd, 1H,
4
3
Ar, J ) 2.0 Hz, J ) 8.0 Hz), 7.36 (m, 2H, Ar), 7.30 (m, 1H,
3
Ar), 6.98 (d, 1H, Ar, J ) 8.0 Hz), 6.06 (m, 1H), 5.44 (m, 1H),
5.31 (m, 1H), 5.18 (s, 2H, OCH2), 4.69 (m, 2H, OCH2); 13C NMR
(CDCl3, 20 °C) δ 154.06, 148.90, 136.43, 132.32, 130.06, 128.48
(2C), 127.92, 127.23 (2C), 126.54, 118.07, 112.44, 112.07, 70.80,
69.57. Anal. Calcd for C17H16O3 (268,3116): C, 76.10; H, 6.0.
Found: C, 76.10; H, 6.07.
3,8,13-Tribenzyloxy-10,15-dihydro-5H-tribenzo[a,d,g]-
cyclononene-2,7,12-triol 6. Compound 2f (0.175 g, 0.23
mmol), PPh3 (0.010 g, 0.38 mmol), THF (4 mL), diethylamine
(1.6 mL), palladium acetate (0.005 g, 0.022 mmol), and water
(0.8 mL) were mixed in a 25 mL flask. The mixture was stirred
at 80 °C for 4 h 30 under argon. The solvent was then removed
under reduced pressure and the residue extracted three times
with AcOEt. The combined organic layers were washed with
brine and dried over sodium sulfate. Evaporation of the solvent
afforded a residue, which was purified by column chromatog-
raphy (CH2Cl2/EtOH: 99/1). Evaporation of the solvent gave
6 as a white crystalline compound (0.120 g, 81%): mp (DSC)
144.5 °C (first polymorph crystalline structure); TLC Rf 0.71
General Method for the Synthesis of Cryptophanes
Using Sc(OTf)3. Method B. anti-Cryptophane-A 8a. A
solution of cryptophane precursor 7a (0.5 g, 0.42 mmol) in
CH2Cl2 (130 mL) was added at 60 °C over a period of 25-30 h
to a stirred suspension of scandium triflate (0.180 g, 0.42
mmol) in CH2Cl2 (30 mL). After complete addition, the solution
was stirred at 60 °C for 48 h. The solution was then poured
into water and the organic layer extracted once with water
and dried over sodium sulfate. The solvent was removed under
vacuum to give a residue, which was purified by column
chromatography (CH2Cl2/acetone: 90/10). Evaporation of the
solvent afforded compound 8a (0.18 g, 51%). The 500 MHz 1H
NMR spectrum is identical to that previously reported.36
anti-Cryptophane-E 8b. According to method B, cryp-
tophane precursor 7b (0.5 g, 0.4 mmol) and scandium triflate
(0.174 g, 0.4 mmol) in CH2Cl2 (160 mL) gave derivative 8b
(0.105 g, 28%) after purification by column chromatography
1
(CH2Cl2/ethanol: 99/1); H NMR (CDCl3, 20 °C) δ 7.40-7.33
(m, 15H, Ar), 6.85 (s, 3H, Ar), 6.82 (s, 3H, Ar), 5.42 (s, 3H,
OH), 6.02 (m, 6H, OCH2), 4.77 (d, 3H, Ha, 2J ) 14.0 Hz), 3.45
(d, 3H, He, 2J ) 14.0 Hz); 13C NMR (CDCl3, 20 °C) δ 144.66 (3
C), 144.59 (3 C), 136.60 (3 C), 133.07 (3 C), 131.21 (3 C), 128.74
(3 C), 128.37 (6 C), 127.88 (6 C), 115.74 (3 C), 114.12 (3 C),
71.53 (3 C), 36.36 (3 C); HRMS calcd for C42H36O6 (M•+
)
1
(CH2Cl2/acetone: 90/10). The 500 MHz H NMR spectrum is
636.2512, found 636.2514. Anal. Calcd for C42H36O6, 0.5 H2O
(645.7504): C, 78.06; H, 5.78. Found: C, 78.12; H, 5.66.
identical to that previously reported.26
anti-Cryptophane-223 8c. According to method B, cryp-
tophane precursor 7c (0.39 g, 0.37 mmol) and scandium triflate
(0.161 g, 0.37 mmol) in CH2Cl2 (160 mL) gave compound 8c
(0.11 g, 33%) after purification by column chromatography
Compound 7b. This compound was prepared according to
a known procedure from 2-[4-(3-iodopropoxy)-3-methoxyben-
zyloxy]tetrahydropyran (2.51 g, 6.17 mmol),28 CTV 9 (0.7 g,
1.71 mmol), and cesium carbonate (3.35 g, 10.3 mmol) in DMF
(30 mL). Purification by column chromatography gave 7b as
a glassy solid (1.6 g, 75%): 1H NMR (CDCl3, 20 °C) δ 6.91 (s,
3H, Ar), 6.88 (s, 3H, Ar), 6.86-6.82 (m, 9H, Ar), 4.71 (d, 3H,
1
(CH2Cl2/acetone: 90:10). The 500 MHz H NMR spectrum is
identical to that previously reported.28
Compound 10. A solution of triflic anhydride (1.5 mL) was
slowly added under argon to an ice-cooled solution of 9 (1.0 g,
2
2
Ha, J ) 14.0 Hz), 4.69 (d, 3H, J ) 11.5 Hz), 4.65 (m, 3H),
2
4.41 (d, 3H, J ) 11.5 Hz), 4.26-4.12 (m, 12H, OCH2), 3.90
(38) Darzac, M.; Brotin, T.; Rousset-Arzel, L.; Bouchu, D.; Dutasta,
J. P. New J. Chem. 2004, 28, 502-512.
(m, 3H), 3.82 (s, 9H, OCH3), 3.71 (s, 9H, OCH3), 3.53 (m, 3H),
6194 J. Org. Chem., Vol. 70, No. 16, 2005

Functional CTVs and Cryptophanes
2.45 mmol) in a mixture of pyridine (8 mL) and CH2Cl2 (15
mL). After addition, the solution was allowed to warm to room
temperature and stirred for 18 h. Water was then added, and
the mixture was extracted three times with CH2Cl2. The
combined organic layers were washed with water and dried
other sodium sulfate. Filtration and evaporation of the solvent
afforded a residue, which was purified by column chromatog-
raphy (CH2Cl2). Evaporation of the solvent gave compound 10
as a slight yellow solid (1.5 g, 85%): mp (DSC) 210 °C; TLC
for compound 15a: 13C NMR (CDCl3, 20 °C) δ 156.55 (3C),
148.54 (3C), 147.34 (3C), 141.06 (3C), 132.84 (3C), 132.18 (3C),
131.75 (3C), 130.83 (3C), 119.40 (3C), 116.76 (3C), 114.91 (3C),
111.78 (3C), 66.90 (3C, OCH2), 65.43 (3C, OCH2), 56.54 (3C,
OCH3), 36.24 (3C, Ca,e), 36.02 (3C, Ca,e); additional information
for compound 15b: 13C NMR (CDCl3, 20 °C) δ 157.14 (3C),
150.01 (3C), 140.83 (3C), 134.70 (3C), 132.29 (3C), 131.92 (3C),
130.80 (3C), 121.20 (3C), 119.03 (3C), 114.10 (3C), 113.34 (3C),
71.46 (3C, OCH2), 66.05 (3C, OCH2), 56.13 (3C, OCH3), 36.29
(3C, Ca,e), 36.03 (3C, Ca,e).
1
Rf 0.93 (CH2Cl2); H NMR (CDCl3, 20 °C) δ 7.17 (s, 3H, Ar),
2
6.89 (s, 3H, Ar), 4.73 (d, 3H, Ha, J ) 15.0 Hz), 3.86 (s, 9H,
Compound 16. Compound 13 (0.4 g, 1.15 mmol) was added
in one portion to a stirred solution of CTV 6 (0.205 g, 0.32
mmol) and cesium carbonate (0.415 g, 1.28 mmol) in DMF (9
mL). The mixture was stirred at 80 °C for 18 h under argon
and then poured into water and extracted three times with
AcOEt. The combined organic layers were washed five times
with water to remove the remaining DMF and then dried over
sodium sulfate. Filtration and evaporation of the solvent gave
a yellow residue, which was purified by column chromatog-
raphy (AcOEt/pentane: 50/50, then AcOEt/pentane: 70/30).
Evaporation of the solvent under vacuum afforded 16 as a
yellow oil (0.39 g, 85%): TLC Rf 0.55 (AcOEt/pentane: 50/50);
1H NMR (CDCl3, 20 °C) δ 7.34-7.32 (m, 6H, Ar), 7.30-7.22
(m, 9H, Ar), 6.88-6.78 (m, 12H, Ar), 6.81-6.79 (m, 3H, Ar),
2
OCH3), 3.64 (d, 3H, He, J ) 15.0 Hz); 13C NMR (CDCl3, 20
°C) δ 150.66 (3C), 140.88 (3C), 137.90 (3C), 131.67 (3C),
1
124.29 (3C), 119.28 (q, 3C, CF3, JCF ) 321.6 Hz), 115.01
(3C), 56.81 (3C, OCH3), 36.70 (3C, Ca,e); HRMS calcd for
C27H21O12S3F9 (M•+) 804.0051, found 804.0051. Anal. Calcd for
C27H21O12S3F9‚CH2Cl2 (889.566): C, 37.80; H, 2.60; S, 10.81.
Found: C, 37.57; H, 2.51; S, 10.81.
Compound 11. Compound 10 (1.45 g, 1.79 mmol), dppp
(0.33 g, 0.8 mmol), tributylamine (7.18 g, 1.55 mmol), dichlo-
robis(triphenylphosphine)palladium (0.391 g, 0.56 mmol),
formic acid (0.94 mL), and DMF (9.5 mL) were mixed in a 25
mL three-neck flask. The solution was heated at 100 °C for
18 h under argon. Then, water was added, and the product
was extracted with CH2Cl2. The organic layer was washed
several times with water and dried over sodium sulfate.
Filtration and evaporation of the solvent under reduced
pressure gave a residue, which was purified by column
chromatography (CH2Cl2/pentane: 70/30). Evaporation of the
solvent gave compound 11 as a white solid (0.460 g, 71%). The
1H NMR spectrum is identical to that previously reported.31
Compound 14. Compound 13 (0.91 g, 2.63 mmol) was
added to a solution of CTV 12 (0.209 g, 0.73 mmol) and cesium
carbonate (0.95 g, 2.92 mmol) in DMF (15 mL). The mixture
was stirred at 80 °C for 18 h under argon. The mixture was
then poured into water and extracted twice with chloroform.
The combined organic layers were dried over sodium sulfate.
Filtration and evaporation of the solvent under vacuum gave
a very insoluble solid, which was washed on a frit with diethyl
ether to afford 14 (0.57 g, 70%) as a white solid: mp (DSC)
111 °C; 1H NMR (CDCl3, 20 °C) δ 7.24 (d, 3H, Ar, 3J ) 8.0
Hz), 6.91 (d, 3H, Ar, 4J ) 2.0 Hz), 6.90-6.86 (m, 9H, Ar), 6.64
2
5.01 (s, 6H), 4.69-4.64 (m, 9H, CH2 + Ha), 4.40 (d, 3H, J )
11.5 Hz), 4.36-4.22 (m, 12 H, OCH2), 3.90 (m, 1H), 3.77 (s,
9H, OCH3), 3.52 (m, 1H), 3.45 (d, 3H, He, 2J ) 14.0 Hz), 1.88-
1.78 (m, 3H), 1.74-1.66 (m, 3H), 1.64-1.46 (m, 12 H); 13C NMR
(CDCl3, 20 °C) δ 149.60 (3C), 147.89 (3C), 147.78 (3C), 147.73
(3C), 137.52 (3C), 132.92 (3C), 132.81 (3C), 131.56 (3C), 128.38
(6C), 127.62 (3C), 127.22 (6C), 120.51 (3C), 117.30 (3C), 117.22
(3C), 113.83 (3C), 112.0 (3C), 97.52 (3C), 71.81 (3C), 68.68 (3C),
68.49 (3C), 67.94 (3C), 62.22 (3C), 55.80 (3C), 36.37 (3C), 30.57
(3C), 25.44 (3C), 19.44 (3C); ESI MS m/z [M + H]+ 1123.3.
Cryptophane 17. According to method B, a solution of
cryptophane precursor 16 (0.45 g, 0.32 mmol) in CH2Cl2 (130
mL) was added at 60 °C over a period of 25-30 h to a stirred
suspension of scandium triflate (0.136 g, 0.32 mmol) in
CH2Cl2 (30 mL). After complete addition, the solution was
stirred at 60 °C for 48 h. The solution was then poured into
water and the organic layer extracted once with water and
dried over sodium sulfate. The solvent was removed under
reduced pressure to give a residue, which was purified by
column chromatography (CH2Cl2/acetone: 98/2). Evaporation
of the solvent afforded compound 17 as a white solid (0.15 g,
42%), which was then washed on a frit with small amounts of
diethyl ether and pentane: mp (DSC) dec above 310 °C; 1H
NMR (CDCl3, 20 °C) δ 7.49 (m, 6H, Ar), 7.44 (m, 6H, Ar), 7.35
(m, 3H, Ar), 6.81 (s, 3H, Ar), 6.78 (s, 3H, Ar), 6.72 (s, 3H, Ar),
6.58 (s, 3H, Ar), 5.02 (d, 3H, OCH2, 2J ) 11.5 Hz), 4.98 (d, 3H,
OCH2, 2J ) 11.5 Hz), 4.55 (d, 6H, Ha, 2J ) 13.5 Hz), 4.30-
3
4
2
(dd, 3H, Ar, J ) 8.0 Hz, J ) 2.0 Hz), 4.73 (d, 3H, Ha, J )
13.5 Hz), 4.70 (d, 3H, 2J ) 12.0 Hz), 4.65 (m, 3H), 4.42 (d, 3H,
2J ) 12.0 Hz), 4.31-4.22 (m, 12 H, OCH2), 3.91 (m, 3H), 3.83
2
(s, 9H, OCH3), 3.61 (d, 3H, He, J ) 12.0 Hz), 3.53 (m, 3H),
1.88-1.79 (m, 3H), 1.75-1.68 (m, 3H), 1.64-1.47 (m, 12H);
13C NMR (CDCl3, 20 °C) δ 157.26 (3C), 149.57 (3C), 147.50
(3C), 141.01 (3C), 131.78 (3C), 131.63 (3C), 131.00 (3C), 120.45
(3C), 116.09 (3C), 113.78 (3C), 112.84 (3C), 111.89 (3C), 68.68
(3C, OCH2), 67.62 (3C, OCH2), 66.23 (3C, OCH2), 62.25 (3C,
OCH2), 55.85 (3C, OCH3), 36.48 (3C, Ca,e), 30.56 (3C), 25.41
(3C), 19.45 (3C); HRMS calcd for C66H78O15 (M•+) 1110.5441,
found 1110.5449. Anal. Calcd for C66H78O15 (1111.333): C,
71.33; H, 7.07. Found: C, 71.06; H, 7.18.
Cryptophanes 15a and 15b. According to method B,
cryptophane precursor 14 (0.413 g, 0.37 mmol) and scandium
triflate (0.160 g, 0.37 mmol) in acetonitrile (160 mL) gave a
mixture of cryptophanes 15a (0.13 g, 50%) and 15b (0.021 g,
8%) after purification by column chromatography (CH2Cl2/
acetone: 90/10). Spectral data of compound 15a and 15b are
identical to those previously reported.34 Additional information
2
4.16 (m, 12 H, OCH2), 3.41 (s, 9H, OCH3), 3.37 (d, 3H, He, J
2
) 13.5 Hz), 3.36 (d, 3H, He, J ) 13.5 Hz); 13C NMR (CDCl3,
20 °C) δ 149.71 (3C), 149.14 (3C), 147.79 (3C), 146.64 (3C),
137.28 (3C), 134.31 (3C), 134.07 (3C), 132.78 (3C), 131.60 (3C),
128.55 (6C), 127.86 (3C), 126.96 (6C), 122.103 (3C), 120.63
(3C), 117.71 (3C), 114.30 (3C), 71.71 (3C), 69.63 (3C), 69.31
(3C), 55.81 (3C), 36.13 (6C); HRMS calcd for C72H66O12 (M•+
1122.4554, found 1122.4549.
)
JO050495G
J. Org. Chem, Vol. 70, No. 16, 2005 6195