Highly selective palladium-catalyzed aminocarbonylation and cross-coupling reactions on a cavitand scaffold

Article abstract of DOI:10.1016/j.tet.2012.01.065

Palladium-catalyzed aminocarbonylation and cross-coupling reactions (Suzuki-, Sonogashira-, Stille-coupling) served as highly efficient synthetic tools for the synthesis of novel, functionalized deepened cavitands. Unexpectedly high chemoselectivities tow

Full text of DOI:10.1016/j.tet.2012.01.065

Tetrahedron 68 (2012) 2657e2661
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Highly selective palladium-catalyzed aminocarbonylation and cross-coupling
reactions on a cavitand scaffold
a
,
b
a,
*
*
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
Zsolt Csok , Aniko Takatsy , Laszlo Kollar
a
ꢀ
ꢀ
Department of Inorganic Chemistry, University of Pecs, H-7624 Pecs, PO Box 266, Hungary
Department of Biochemistry and Medical Chemistry, Medical School, University of Pecs, H-7624 Pecs, PO Box 266, Hungary
b
ꢀ
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
Palladium-catalyzed aminocarbonylation and cross-coupling reactions (Suzuki-, Sonogashira-, Stille-
coupling) served as highly efficient synthetic tools for the synthesis of novel, functionalized deepened
cavitands. Unexpectedly high chemoselectivities towards tetrafunctionalized cavitands have been ob-
served for all of these reactions even using coupling partners much below the stoichiometric amount. No
significant formation of either the mono-, di- or trifunctionalized products was observed.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 16 November 2011
Received in revised form 3 January 2012
Accepted 23 January 2012
Available online 28 January 2012
Keywords:
Cavitand
Aminocarbonylation
Cross-coupling
Carbon monoxide
Palladium
1. Introduction
iodoarenes) can readily be converted into the corresponding car-
boxamides by using carbon monoxide and various amines as nu-
Cavitands1 are a class of molecular hosts representing a con-
formationally rigid, bowl-shaped structure. Enlarging the inner
cavity of such molecular containers is essential considering their
potential applications as sensors, nanoreactors and drug delivery
systems.2 Deepening the molecular pocket of cavitands was prin-
cipally accomplished by conventional organic reactions3; never-
theless homogeneous catalytic cross-coupling reactions were
sparsely employed as well.4 In a previous paper, we described
a methodology based on Williamson etherification that provided
easy access to a wide variety of deepened cavitands, including
a tetraiodo derivative.5 Tetraiodocavitand (1), bearing four excel-
lent leaving groups, served as a key intermediate for further ex-
tension of the cavitand structure as demonstrated in its utilization
in a Suzuki-reaction. In this study, we aimed to broaden the scope
of palladium-catalyzed homogeneous catalytic reactions on this
cavitand scaffold.
cleophiles, in the presence of a
palladium(0) catalyst.8 The
synthetic applicability of these catalytic reactions is due to the ease
in structural variation of amides both on the amide nitrogen and on
the carboxylic acid moieties. That is, instead of the conventional
carboxylic aciddacyl chloridedamide route, the direct carbonyla-
tion of haloaromatics or haloalkenes as well as those of the corre-
sponding triflate surrogates can be used.9 It is worth mentioning
that aminocarbonylation has shown high tolerance towards both
the structure of the primary and secondary amine and that of the
organic halide derivative. This straightforward synthetic method
has been successfully applied to a range of substrates, including
simple model compounds, heterocyclic compounds10 and bi-
ologically important skeletons such as tropane11 and steroidal
backbones.12 However, to the best of our knowledge, there are no
examples of palladium-catalyzed carbonylation reactions per-
formed on cavitands or related macrocycles.
Carboxamide functionalities were previously introduced into
the cavitand skeleton by acylation of the corresponding amino-
cavitands.6 Palladium-catalyzed carbonylation reactions serve as an
important synthetic tool in the hands of organic chemists.7 In
aminocarbonylation, organohalides (preferably iodoalkenes and
2. Results and discussion
Aminocarbonylation as well as cross-coupling (Suzuki-, Sono-
gashira-, Stille-coupling) reactions were chosen to introduce vari-
ous functionalities on the rim of the cavitand scaffold in the
presence of Pd(OAc)2þ2PPh3 in situ catalytic systems (Scheme 1).
The tetraiodo-cavitand (1), used as a substrate, was synthesized by
an improved methodology (see Experimental).
ꢀ
* Corresponding authors. E-mail addresses: zscsok@gamma.ttk.pte.hu (Z. Csok),
ꢀ
kollar@ttk.pte.hu (L. Kollar).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.01.065

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Z. Csok et al. / Tetrahedron 68 (2012) 2657e2661
Table 1
R1 R2
N
R1 R2
N
Palladium-catalyzed aminocarbonylation of 1a
R1 R2
N
R1 R2
N
Entry Amine
Amine p[CO] Conversionb Chemoselectivityc Isolated
O
(mol
(bar) (%)
(%)
yieldd
(%)
O
n
n
O
O
n
equiv)
n
R1 R2
n
1
2
3
4
5
6
7
8
t-Bu-amine
4
1
1
55
100
46g
89
22h
83
2a (100)
2a (70), 2b (30)
2a (100)
2b (100)
2a (100)
2b (100)
3a (100)
3a (87), 3b (13)
3a (29), 3b (71)
3a (40), 3b (60)
3b (100)
32 (2a)
n.d.
2a
2b
3a
3b
4a
4b
1
H
t-Bu
t-Bu
t-Bu-amine 18
t-Bu-amine
t-Bu-amine 18
t-Bu-amine
t-Bu-amine 18
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
2
1
2
1
2
H
O
O
2
30
30
90
90
1
18 (2a)
65 (2b)
13 (2a)
78 (2b)
56 (3a)
n.d.
n.d.
n.d.
69 (3b)
25 (3b)
85 (3b)
n.d.
(CH2)5
(CH2)5
O
O
CH2
H2C
CH2
O
H2C
O
1
O
O
O
O
O
O
H
H
CH(CH3)COOCH3
CH(CH3)COOCH3
4
18
18
2
18
18
18
4
96
100
1
H
H
9
30
90
90
30
30
1
30
30
30
90
30
90
42g
80
29
90
H
H
CH3
CH3
CH3
H3C
10
11
12e
13f
14
15
16
17
18
CO, HNR1R2
Pd(OAc)2 + 2 PPh3
Yields: 32-85%
3b (100)
3b (100)
D
D
D
D
D
D
-AlaeOMe
-AlaeOMe
-AlaeOMe
-AlaeOMe 16
-AlaeOMe
-AlaeOMe
100
4a (86), 4b (14)
4a (76), 4b (24)
4a (52), 4b (48)
4a (9), 4b (91)
4a (49), 4b (51)
4a (44), 4b (56)
4
8
100
100
100
100
29
n.d.
n.d.
n.d.
n.d.
I
I
I
I
8
8
e
19
n.d.
a
Reaction conditions: 1/Pd(OAc)2/PPh3/base¼1:0.15:0.3:12, 60 ꢀC.
(Moles of converted 1)/(moles of initial 1)ꢁ100.
O
O
O
b
c
O
CH2
Determined on the crude reaction mixture by means of 1H and 13C NMR spec-
H2C
CH2
O
H2C
O
O
O
O
O
O
troscopy (before column chromatography) as described in Experimental (4.3).
O
d
Isolated yields of pure products.
Tris(2,4,6-trimethoxyphenyl)phoshine was used as ligand.
Tributylphosphine tetrafluoroborate was used as a ligand precursor.
In the case of selective tetrasubstitution the highest conversion that could be
e
f
H
H
H
H
g
CH
CH3
3 H3C
CH3
achieved is 50%.
1
h
In the case of selective tetrasubstitution the highest conversion that could be
achieved is 25%.
RX
Pd(OAc)2 + 2 PPh3
Yields: 42-82%
N-nucleophile was used, only the same tetrafunctionalized products
(2ae4a and 2be4b) could be isolated along with unreacted starting
tetraiodocavitand (1) (entries 3, 5 and 10). Therefore, during the
course of the reactions, the composition of the reaction mixtures was
carefully checked both by in situ 1H and 13C NMR. Again, neither the
formation of mono-, di- or trifunctionalized products nor that of the
‘mixed-substituted’ carboxamido-ketocarboxamido-cavitands was
observed even at lower amine/substrate molar ratios. Hence, it has
been proved by detailed NMR investigations, carried out on crude
reaction mixtures, that two types of tetrafunctionalised amino-
carbonylated products such as carboxamidocavitands 2ae4a and
ketocarboxamidocavitands 2be4b were almost exclusively formed.
The total of the side products (that is, the total amount of the ‘mixed-
substituted’ iodo-carboxamido-cavitands or that of the carboxamido-
ketocarboxamido-cavitands) was less than 3% according to the NMR
analyses.
R
R
R
R
R
O
5a Ph
O
O
O
5b 4-OH-C6H4
5c 4-Ph-C6H4
CH2
H2C
CH2
O
H2C
O
O
O
O
O
O
O
6
C
C-Ph
7
CH CH2
H
H
H
H
CH
CH3
3 H3C
CH3
Scheme 1. Selective functionalization of 1 via aminocarbonylation and cross-coupling
reactions.
Besides a primary (tert-butyl-amine) and a secondary amine
A
catalytic system containing bulkier ligand (tris(2,4,6-
(piperidine), a chiral amino acid (D-alanine methyl ester hydro-
trimethoxyphenyl)phosphine) provided even higher chemo-
selectivity towards 3b, however, it showed less catalytic activity
compared to the Pd(OAc)2þ2PPh3 catalyst system (entries 9 and
12). Very good activity and excellent chemoselectivity were ob-
served in the presence of the catalyst containing the more basic
tributylphosphine (added as a tetrafluoroborate salt)13 instead of
PPh3 (entry 13).
chloride) was employed as N-nucleophile for the preparation of the
novel carboxamidocavitands (n¼1, 2ae4a) in aminocarbonylation.
Depending on the reaction conditions, the insertion of a second CO
also permits the formation of ketocarboxamides (n¼2, 2be4b).
We noticed that increasing the molar equivalents of the amine
reagents resulted in the preferential formation of tetrakis(2-
ketocarboxamide)cavitands (n¼2) in the product distribution
(Table 1, entries 1 and 2 for 2b, 7 and 8 for 3b, and entries 15e17 for
4b, respectively). Furthermore, higher COpressure generated also, as
expected, a superior chemoselectivity towards these derivatives
(entries 2, 4, 6 for 2b, entries 8, 9, 11 for 3b, and entries 14, 15 for 4b,
respectively). Generally, both higher molar equivalents of the amine
reactants and higher CO pressure provided better yields. It is im-
portant to note that none of these tetrakis(2-ketocarboxamide) de-
rivatives contained any mono-, bis- or tris(carboxamide) impurities.
Tooursurprise, whenthemolarequivalentsof theaminereactants
were decreased below 4, i.e., less than a stoichiometric amount of the
The structure of carboxamides 2ae4a was confirmed by 1H and
13C NMR spectroscopy and MS measurements, all other novel
cavitands were isolated as pure compounds and fully characterized
(Experimental). Cavitands 4a and 4b could only be isolated as
mixtures. Tetrakis(amidocavitands) bearing amide NeH protons
(2 and 4) showed remarkably different 1H NMR spectra in DMSO-d6
and in CDCl3 (see Fig. 1 for 4). The 1H NMR spectrum of the mixture
of 4a and 4b in DMSO-d6, a media competitive for hydrogen bonds,
clearly indicated a monomeric, C4 symmetrical species, where the
NeH doublet appeared at 8.58 and 9.28 ppm, respectively. In con-
trast, the spectrum, in the less polar CDCl3, no longer showed the

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Z. Csok et al. / Tetrahedron 68 (2012) 2657e2661
2659
monoxide results in the formation of the arylglyoxyloyl complex
(E), which provides ketocarboxmides (b). It should be noted that
the formation of the latter product via reductive elimination from
acylecarbamoylepalladium(II) species cannot be excluded.14
It has been proved that neither carboxamides can be carbony-
lated to 2-ketocarboxamides nor 2-ketocarboxamides decarbony-
lated to carboxamides under the reaction conditions used. That is,
the chemoselectivity of the reaction is determined during the car-
bon monoxide insertion steps (B/C, and D/E) followed by
aminolysis.
We have previously described
a Suzuki-reaction using
PhB(OH)2,5 and now we have broadened the scope of cross-
coupling reactions on this cavitand platform. Besides two novel
deepened cavitands obtained by Suzuki-coupling (5b and 5c),
Sonogashira- (6) and Stille-reactions (7) were also exploited
(Scheme 1). It should be noted that 5c exhibits very low solubilities
in most organic solvents. As described for aminocarbonylation,
decreasing the molar equivalents of the coupling reagents (boronic
acids, phenylacetylene or tributylvinylstannane) below 4, the ex-
clusive formation of tetrafunctionalized products (5a, 5b, 5c, 6, 7)
was observed while the corresponding amount of unreacted
starting tetraiodocavitand (1) was recovered.
To find a reasonable explanation for the very high chemo-
selectivities towards tetrafunctionalized products, some novel cat-
alytic features of the palladium-catalyst have to be supposed. It is
worth noting, that Reinhoudt and Sherburn reported on various
organic reactions between cavitands having appropriate function-
alities and less than 4 mol equiv of reactants. As expected, these
reactions resulted in the generation of statistical mixtures of up to
five partially substituted products.15 In contrast, we noticed un-
expectedly high chemoselectivities towards tetrafunctionalized
cavitands in homogeneous palladium-catalyzed reactions. Although
these selectivities have been proved by in situ NMR and catalytic
investigations, as well as by the isolation of two-component mix-
tures and analytically pure compounds in high yields, the ration-
alisation of the formation of ‘well-defined cavitands’ needs further
investigations. Quantum chemical calculations, kinetic and co-
ordination chemistry studies are in progress.
Fig. 1. 1H NMR spectra of the mixture of 4a and 4b in CDCl3 (top) and in DMSO-d6
(bottom), ꢁ and o denote the protons of 4a and 4b, respectively (* stands for the
protons of the corresponding NMR solvents, # designates residual EtOAc).
features of a symmetrical structure. This suggests the presence of
hydrogen bonded dimeric forms of 2 or 4 in nonpolar solvents.4a
Furthermore, the 1H NMR spectra of 3 in both DMSO-d6 and in
CDCl3 displayed highly symmetrical, monomeric species owing to
the absence of amide NeH protons capable of making in-
termolecular hydrogen bonds. The characteristic, low-field ArC]O
chemical shifts appeared in all 13C NMR spectra of the tetra(2-
ketocarboxamide)cavitands (188.89 ppm for 2b, 190.31 ppm for
3b and 188.57 ppm for 4b) along with the signal for N(H)C]O
(165.73 ppm for 2b, 165.55 ppm for 3b and 165.52 ppm for 4b).
The formation of the mono and double-carbonylated products
(a and b, respectively) can be rationalized as follows (Scheme 2).
The iodoarene substrate is oxidatively added to the Pd(0) centre
forming the aryl-iodo intermediate (A), which is able to coordinate
carbon monoxide as a terminal carbonyl ligand (B). The insertion
of carbon monoxide provides the palladium(II)eacyl intermediate
(C), which undergoes aminolysis forming carboxamides (a). A
further carbon monoxide could also be coordinated forming an
acylecarbonyl complex (D). The insertion of the ‘second’ carbon
3. Conclusion
Palladium-catalyzed cross-coupling reactions (Suzuki-, Sono-
gashira-, Stille-coupling) served as highly efficient synthetic tools
for the synthesis of electron-rich, extended cavitands. Furthermore,
the easily available and varied amine reactants make amino-
carbonylation a powerful synthetic methodology for the function-
alization of deepened cavitands. Remarkable chemoselectivities
were achieved towards tetracarboxamido- and tetrakis(keto-
carboxamido)cavitands, which exhibit great stability and good
solubility in most organic solvents. All of these deepened cavitands
might serve as flexible binding pockets in ‘hosteguest’ chemistry.
4. Experimental
4.1. General procedures
All reagents and solvents were purchased from Aldrich and used
as received. Toluene and THF were distilled from sodium/benzo-
phenone. 1H and 13C NMR spectra were recorded at 25 ꢀC in CDCl3
(or in DMSO-d6) on a Varian Inova 400 spectrometer at 400.13 MHz
and 100.62 MHz, respectively. The 1H chemical shifts (
d), reported
in parts per million (ppm) downfield, are referenced to the residual
protons (7.26 ppm for CDCl3 and 2.50 for DMSO-d6). The 13C
chemical shifts are referenced to the carbon resonance of CDCl3
(77.00 ppm) or to that of DMSO-d6 (39.52 ppm), respectively.
MALDI-TOF spectra were obtained on an Autoflex II TOF/TOF
Scheme 2. A simplified catalytic cycle of mono and double-carbonylation leading to
a and b, respectively.

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Z. Csok et al. / Tetrahedron 68 (2012) 2657e2661
2660
spectrometer (Bruker Daltonics) in positive ion modes, using
a 337 nm pulsed nitrogen laser (accelerating voltage: 20.0 kV,
matrix: 2,5-dihydroxybenzoic acid). Cavitand 5a was prepared as
previously described.5
4.5. A typical procedure for Stille (7) cross-coupling reaction
Into a Schlenk-tube, 1 (250 mg, 0.164 mmol), Pd(OAc)2 (5.6 mg,
0.025 mmol), PPh3 (13.1 mg, 0.05 mmol), CuI (31 mg, 0.164 mmol)
and KF (115 mg, 1.97 mmol) were weighed, and placed under an
inert atmosphere. Anhydrous DMF (15 mL) and tributyl(vinyl)tin
4.2. Improved synthesis of tetrakis(4-iodo-phenoxymethyl)-
cavitand (1)
(383 mL, 1.312 mmol) were added, and then the reaction mixture
was stirred at 70 ꢀC for 2 days. The precipitation was filtered, the
filtrate was evaporated to dryness, and the residue was treated with
MeOH (5 mL). The resulting precipitate was collected by filtration,
and purified by column chromatography (silica gel; eluent: ben-
zene; Rf¼0.68).
To a solution of 4-iodophenol (10.4 g, 0.047 mol) in THF (60 mL)
was added a solution of aqueous NaOH (0.47 M, 100 mL), then the
solution was stirred for 30 min. This solution was then slowly
added to
a solution of tetrakis(bromomethyl)cavitand (5.2 g,
5.37 mmol) in THF (100 mL).16 The reaction mixture was stirred at
70 ꢀC for 16 h, then the precipitated product was collected by fil-
tration and dried in vacuo. Yield: 5.302 g (65%). The spectroscopic
data corresponded to those reported.5
4.6. Characterizations of the products
4.6.1. Cavitand 2a. Viscous material (75 mg, 32%). Found: C, 71.22;
H, 6.71, N, 3.77. C84H92N4O16 requires C, 71.37; H, 6.56; N, 3.96%. Rf
4.3. A typical procedure for aminocarbonylation experiments
(CH2Cl2) 0.95; nmax(KBr): 1655 cmꢂ1
; dH (400.1 MHz, DMSO-d6):
1.36 (36H, s, t-Bu),1.90 (12H, d, J 7.2 Hz, CH3CH), 4.48 (4H, d, J 7.2 Hz,
inner of OCH2O), 4.82e4.96 (12H, br m, CHCH3 overlapping with
ArCH2O), 5.81 (4H, d, J 7.2 Hz, outer of OCH2O), 6.92 (8H, d, J 8.4 Hz,
Ar), 7.52 (4H, s, NH), 7.74 (8H, d, J 8.4 Hz, Ar), 7.91 (4H, s, Ar). dC
(100.6 MHz, DMSO-d6): 16.1 (CH3CH), 28.7 ((CH3)3C), 31.3 (CH3CH),
50.6 ((CH3)3C), 60.5 (ArCH2O), 99.4 (OCH2O), 113.7, 122.1, 122.5,
128.4, 129.1, 139.1, 153.1, 160.3, 165.6 (C]O). MS: 1435.49 [Mþ23]þ.
Method
A (for cavitands 2, 3): Compound 1 (250 mg,
0.164 mmol), Pd(OAc)2 (5.6 mg, 0.025 mmol), PPh3 (13.1 mg,
0.05 mmol) and K2CO3 (272 mg, 1.97 mmol) were weighed and
placed under an inert atmosphere into a 100 mL autoclave. Dry
toluene (20 mL) and the corresponding amount of amine (given in
Table 1) were added, and then the reaction mixture was placed
under CO pressure. The reaction mixture was stirred at 60 ꢀC for
40 h, the precipitate was filtered, and the filtrate was evaporated to
dryness. The residue was treated with MeOH (5 mL), the resulting
precipitate was collected by filtration and dried in vacuo. An ana-
lytically pure sample of 3b was obtained by column chromatogra-
phy (silica gel; eluent: CH2Cl2/EtOAc¼1:1, Rf¼0.51). Method B (for
cavitands 4): Compound 1 (250 mg, 0.164 mmol), Pd(OAc)2 (5.6 mg,
0.025 mmol), and PPh3 (13.1 mg, 0.05 mmol) were weighed and
placed under an inert atmosphere into a 100 mL autoclave. Dry
4.6.2. Cavitand 2b. White powder (195 mg, 78%), mp 273e277 ꢀC.
Found: C, 69.42; H, 5.98; N, 3.38. C88H92N4O20 requires C, 69.28; H,
6.08; N, 3.67%. Rf (CH2Cl2) 0.86; nmax(KBr): 1662 cmꢂ1
; dH
(400.1 MHz, DMSO-d6): 1.36 (36H, s, t-Bu), 1.90 (12H, d, J 7.2 Hz,
CH3CH), 4.47 (4H, d, J 7.2 Hz, inner of OCH2O), 4.90 (4H, q, J 7.2 Hz,
CHCH3), 4.94 (8H, s, ArCH2O), 5.82 (4H, d, J 7.2 Hz, outer of OCH2O),
7.11 (8H, d, J 8.4 Hz, Ar), 7.86 (8H, d, J 8.4 Hz, Ar), 7.92 (4H, s, Ar), 8.40
(4H, s, NH). dC (100.6 MHz, DMSO-d6): 16.1 (CH3CH), 28.3 ((CH3)3C),
31.3 (CH3CH), 51.1 ((CH3)3C), 60.8 (ArCH2O), 99.4 (OCH2O), 114.8,
122.1, 122.7, 126.0, 132.0, 139.1, 153.2, 163.1, 165.7 (N(H)C]O), 188.9
(ArC]O). MS: 1547.60 [Mþ23]þ.
DMF (20 mL), NEt3 (275
amount of -alanine methyl ester hydrochloride (given in Table 1)
mL, 1.97 mmol) and the corresponding
D
were added. The reaction mixture was then placed under CO
pressure. The reaction mixture was stirred at 60 ꢀC for 40 h, the
precipitate was filtered, and the filtrate was evaporated to dryness.
The residue was treated with MeOH (5 mL), the resulting pre-
cipitate was collected by filtration, and purified by column chro-
matography (silica gel; eluent: CH2Cl2/EtOAc¼1:1; Rf¼0.80).
4.6.3. Cavitand 3a. Viscous material (135 mg, 56%). Found: C,
72.17; H, 6.44; N, 3.59. C88H92N4O16 requires C, 72.31; H, 6.34; N,
3.83%. Rf (50% EtOAc/CHCl3) 0.42; nmax(KBr): 1607 cmꢂ1
; dH
(400.1 MHz, CDCl3): 1.52e1.72 (24H, br m, (CH2)3), 1.82 (12H, d, J
7.2 Hz, CH3CH), 3.53 (16H, br s, N(CH2)2), 4.64 (4H, d, J 7.2 Hz, inner
of OCH2O), 4.92 (8H, s, ArCH2O), 5.09 (4H, q, J 7.2 Hz, CHCH3), 5.76
(4H, d, J 7.2 Hz, outer of OCH2O), 6.91 (8H, d, J 8.0 Hz, Ar), 7.33 (8H, d,
J 8.0 Hz, Ar), 7.40 (4H, s, Ar). dC (100.6 MHz, CDCl3): 16.1 (CH3CH),
24.6, 26.2 (br), 31.2 (CH3CH), 43.3 (br), 48.8 (br), 60.6 (ArCH2O),
100.0 (OCH2O), 114.2, 120.7, 122.3, 128.8, 129.2, 138.9, 154.0, 159.5,
170.0 (C]O). MS: 1483.60 [Mþ23]þ.
4.4. A typical procedure for Suzuki (5) and Sonogashira (6)
cross-coupling reactions
Compound
1
(250 mg, 0.164 mmol), Pd(OAc)2 (5.6 mg,
0.025 mmol), PPh3 (13.1 mg, 0.05 mmol) and 1.31 mmol of the
corresponding coupling reagent (4-hydroxyphenylboronic acid for
5b, 4-biphenylboronic acid for 5c and phenylacetylene for 6) were
weighed, placed under an inert atmosphere into a Schlenk-tube,
and deoxygenated THF (10 mL) was added. (For the synthesis of
6, CuI (31 mg, 0.164 mmol) was also added.) K2CO3 (272 mg,
1.97 mmol) was dissolved in deoxygenated water (5 mL), and was
added to the reaction mixture. The reaction mixture was then
stirred at 70 ꢀC for 16 h. (During the preparation of 5c, the product
precipitated from the reaction mixture, thus no further purification
was required.) The reaction mixture was partitioned between
CH2Cl2 (10 mL) and water (10 mL). The organic phase was sepa-
rated, and the aqueous phase was extracted with another portion of
CH2Cl2 (10 mL). The combined organic phases were washed with
water (10 mL), dried over MgSO4, and evaporated to dryness. The
residue was treated with MeOH (5 mL), the resulting precipitate
was collected by filtration, and dried in vacuo. An analytically pure
sample of 6 was obtained by column chromatography (silica gel;
eluent: benzene; Rf¼0.90).
4.6.4. Cavitand 3b. White powder (219 mg, 85%), mp 190e193 ꢀC.
Found: C, 70.43; H, 5.81; N, 3.31. C92H92N4O20 requires C, 70.21; H,
5.89; N, 3.56%. Rf (50% CH2Cl2/EtOAc) 0.51; nmax(KBr): 1635,
1672 cmꢂ1
; dH (400.1 MHz, CDCl3): 1.54 (8H, br s, CH2), 1.68 (16H, br
s, (CH2)2), 1.82 (12H, d, J 7.2 Hz, CH3CH), 3.28 (8H, br s, NCH2), 3.68
(8H, br s, NCH2), 4.59 (4H, d, J 7.2 Hz, inner of OCH2O), 4.98 (8H, s,
ArCH2O), 5.07 (4H, q, J 7.2 Hz, CHCH3), 5.75 (4H, d, J 7.2 Hz, outer of
OCH2O), 6.98 (8H, d, J 8.8 Hz, Ar), 7.41 (4H, s, Ar), 7.89 (8H, d, J
8.8 Hz, Ar). dC (100.6 MHz, CDCl3): 16.1 (CH3CH), 24.3, 25.4, 26.2,
31.2 (CH3CH), 42.1, 47.1, 60.9 (ArCH2O), 99.8 (OCH2O), 114.6, 121.0,
121.7, 126.8, 132.1, 139.1, 153.9, 163.5, 165.5 (NC]O), 190.3 (ArC]O).
MS: 1595.68 [Mþ23]þ.
4.6.5. Cavitand 4a (isolated as a mixture of 4a and 4b). White
powder (180 mg, ca. 68% (combined yield)). Rf (50% CH2Cl2/EtOAc)
0.80; nmax(KBr): 1661, 1774 cmꢂ1
; dH (400.1 MHz, DMSO-d6): 1.38

ꢀ
Z. Csok et al. / Tetrahedron 68 (2012) 2657e2661
2661
(12H, d, J 7.2 Hz, COOCH3), 1.90 (12H, d, J 7.2 Hz, CH3CH), 3.63 (12H,
s, NC(H)CH3), 4.40e4.54 (8H, m, inner of OCH2O overlapping with
NCH(CH3)), 4.91 (4H, q, J 7.2 Hz, CHCH3), 4.96 (8H, s, ArCH2O), 5.83
(4H, d, J 7.2 Hz, outer of OCH2O), 6.99 (8H, d, J 8.8 Hz, Ar), 7.82 (8H,
d, J 8.4 Hz, Ar), 7.92 (4H, s, Ar), 8.58 (4H, d, J 6.8 Hz, NH). MS:
1555.28 [Mþ23]þ.
with CH]CHaHb), 5.60 (4H, d, J 17.6 Hz, CH]CHaHb), 5.76 (4H, d, J
7.2 Hz, outer of OCH2O), 6.65 (4H, dd, J 17.6, 10.8 Hz, CH]CH2), 6.86
(8H, d, J 8.7 Hz, Ar), 7.30 (8H, d, J 8.7 Hz, Ar), 7.40 (4H, s, Ar). dC
(100.6 MHz, CDCl3): 16.2 (CH3CH), 31.2 (CH3CH), 60.6 (ArCH2O),
100.1 (OCH2O), 111.8, 114.6, 120.6, 122.7, 127.4, 130.9, 136.1, 138.9,
154.0, 158.5. MS: 1142.6 [Mþ22]þ.
4.6.6. Cavitand 4b (isolated as a mixture of 4a and 4b). White
powder (180 mg, ca. 68% (combined yield)). Rf (50 % CH2Cl2/EtOAc)
Acknowledgements
0.80; nmax(KBr): 1661, 1774, 970, 1254 cmꢂ1
;
dH (400.1 MHz, DMSO-
The authors thank the Hungarian Research Fund (CK78553) and
Developing Competitiveness of Universities in the South Trans-
danubian Region (SROP-4.2.1.B-10/2/KONV-2010-0002) for the fi-
nancial support and Johnson Matthey for the generous gift of
palladium(II) acetate. Z.C. thanks the Bolyai Grant of the Hungarian
Academy of Sciences.
d6): 1.37 (12H, d, J 7.2 Hz, COOCH3), 1.90 (12H, d, J 7.2 Hz, CH3CH),
3.69 (12H, s, NCH(CH3)), 4.40e4.54 (8H, m, inner of OCH2O over-
lapping with NCH(CH3)), 4.91 (4H, q, J 7.2 Hz, CHCH3), 4.96 (8H, s,
ArCH2O), 5.83 (4H, d, J 7.2 Hz, outer of OCH2O), 7.12 (8H, d, J 8.8 Hz,
Ar), 7.92 (4H, s, Ar), 7.96 (8H, d, J 8.4 Hz, Ar), 9.28 (4H, d, J 5.2 Hz,
NH). dC (100.6 MHz, DMSO-d6): 16.0 (CH3CH), 16.5 (NC(H)CH3), 31.3
(CH3CH), 47.5 (NC(H)CH3), 52.1 (COOCH3), 60.8 (ArCH2O), 99.4
(OCH2O), 114.8, 122.7, 125.9, 132.2, 139.1, 153.1, 160.8, 163.4,
165.5 (N(H)C]O), 172.3 (COOCH3), 188.6 (ArC]O); MS: 1667.68
[Mþ23]þ.
Supplementary data
1H and 13C NMR spectra (as pdf files) are available via the In-
ternet at http://www.journals.elsevier.com/tetrahedron for all iso-
lated cavitands. Supplementary data related to this article can be
found in the online version, at doi:10.1016/j.tet.2012.01.065.
4.6.7. Cavitand 5b. White powder (96 mg, 42%), mp >350 ꢀC (dec).
Found: C, 76.42; H, 5.12. C88H72O16 requires C, 76.29; H, 5.24%.
nmax(KBr): 973, 1244 cmꢂ1
; dH (400.1 MHz, DMSO-d6): 1.91 (12H, d,
References and notes
J 7.2 Hz, CH3CH), 4.56 (4H, d, J 7.2 Hz, inner of OCH2O), 4.82e5.02
(12H, m, CHCH3 overlapping with ArCH2O), 5.82 (4H, d, J 7.2 Hz,
outer of OCH2O), 6.79 (8H, d, J 8.0 Hz, Ar), 6.95 (8H, d, J 8.4 Hz, Ar),
7.35 (8H, d, J 8.0 Hz, Ar), 7.43 (8H, d, J 8.4 Hz, Ar), 7.92 (4H, s, Ar),
9.50 (4H, s, OH). dC (100.6 MHz, DMSO-d6): 16.1 (CH3CH), 31.3
(CH3CH), 60.4 (ArCH2O), 99.4 (OCH2O), 115.0, 115.7, 122.3, 122.9,
127.0, 127.1, 130.5, 133.0, 139.0, 153.1, 156.6, 157.3. MS: 1407.45
[Mþ23]þ.
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Helgeson, R. C. J. Am. Chem. Soc. 1988, 110, 2229e2237.
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Found: C, 82.96; H, 5.28. C112H88O12 requires C, 82.74; H, 5.46%.
nmax(KBr): 974, 1260 cmꢂ1
; dH (400.1 MHz, CDCl3): 1.86 (12H, d, J
7.2 Hz, CH3CH), 4.76 (4H, d, J 7.2 Hz, inner of OCH2O), 5.00 (8H, s,
ArCH2O), 5.13 (4H, q, J 7.2 Hz, CHCH3), 5.82 (4H, d, J 7.2 Hz, outer of
OCH2O), 6.99 (8H, d, J 9.2 Hz, Ar), 7.30e7.60 (48H, m, Ar). MS:
1647.60 [Mþ23]þ.
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Weinheim, 1998; Vol. IeII; (b) Modern Carbonylation Methods; Kollar, L., Ed.;
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4.6.9. Cavitand 6. White powder (125 mg, 54%), mp >300 ꢀC (dec).
Found: C, 81.62; H, 4.98. C96H72O12 requires C, 81.34; H, 5.12%. Rf
4114e4133; (c) Cornils, B.; Herrmann, W. A. In Applied Homogeneous Catalysis
with Organometallic Compounds; Wiley-VCH: Weinheim, 1996; (d) Beller, M.;
Bolm, C. Transition Metals for Organic Synthesis; Wiley-VCH: Weinheim, 1998;
Vols. IeII; (e) Arcadi, A. Carbonylation of enolizable ketones (enol triflates) and
(benzene) 0.90; nmax (KBr): 975, 1246 cmꢂ1
; dH (400.1 MHz, CDCl3):
1.85 (12H, d, J 7.2 Hz, CH3CH), 4.66 (4H, d, J 7.2 Hz, inner of OCH2O),
4.96 (8H, s, ArCH2O), 5.11 (4H, q, J 7.2 Hz, CHCH3), 5.79 (4H, d, J
7.2 Hz, outer of OCH2O), 6.88 (8H, d, J 8.5 Hz, Ar), 7.28e7.53 (32H, m,
Ar). dC (100.6 MHz, CDCl3): 16.2 (CH3CH), 31.2 (CH3CH), 60.6
(ArCH2O), 88.3 (C^C), 89.1 (C^C), 100.1 (OCH2O), 114.6, 116.0,
120.7, 122.5, 123.5, 127.9, 128.3, 131.5, 133.2, 139.0, 154.0, 158.6. MS:
1440.81 [Mþ23]þ.
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4.6.10. Cavitand 7. White powder (150 mg, 82%), mp >270 ꢀC
(dec). Found: C, 77.38; H, 5.58. C72H64O12 requires C, 77.12; H, 5.75%.
Rf (benzene) 0.68; nmax(KBr): 972, 1246 cmꢂ1
; dH (400.1 MHz,
CDCl3): 1.83 (12H, d, J 7.5 Hz, CH3CH), 4.67 (4H, d, J 7.2 Hz, inner of
OCH2O), 4.92 (8H, s, ArCH2O), 5.07e5.15 (8H, m, CHCH3 overlapping
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