Directing the Cation Recognition Ability of Calix[4]arenes toward Asymmetric Phase-Transfer Catalysis

Article abstract of DOI:10.1002/ejoc.201700912

The recognition abilities of chiral calixarene hosts toward alkali cation guests have been exploited for the first time in asymmetric phase-transfer catalysis. The binding affinities of a series of chiral α-methylbenzylamine-derived calix[4]arene-amides toward Na⁺ guest have been determined by ¹H NMR spectroscopic titration experiments. The good apparent association constant values are consistent with the macrocycles' catalytic efficiency in the asymmetric alkylation reaction of N-(diphenylmethylene)glycine esters under phase-transfer conditions.

Full text of DOI:10.1002/ejoc.201700912

A Journal of
Accepted Article
Title: Directing the Cation Recognition Ability of Calix[4]arenes Toward
Asymmetric Phase-Transfer Catalysis
Authors: Nicola Alessandro De Simone, Rosaria Schettini, Carmen
Talotta, Carmine Gaeta, Irene Izzo, Giorgio Della Sala, and
Placido Neri
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700912
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10.1002/ejoc.201700912
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Directing the Cation Recognition Ability of Calix[4]arenes Toward
Asymmetric Phase-Transfer Catalysis
Nicola Alessandro De Simone,[a] Rosaria Schettini,[a] Carmen Talotta,[a] Carmine Gaeta,[a] Irene
Izzo,[a] Giorgio Della Sala,*[a] and Placido Neri*[a]
Abstract: The recognition abilities of chiral calixarene hosts toward
alkali cation guests have been exploited for the first time in
asymmetric phase-transfer catalysis. The binding affinities of a
series of chiral -methylbenzylamine-derived calix[4]arene-amides
toward Na+ guest have been determined by 1H NMR titration
experiments. The good apparent association constant values are
consistent with the macrocycles’ catalytic efficiency in the
asymmetric alkylation of N-(diphenylmethylene)-glycine esters under
phase-transfer conditions.
Introduction
Calix[n]arenes[1] are
a
well-known class of macrocyclic
compounds which have been largely exploited in the last
decades due to their particular three-dimensional shape and
ease of functionalization.[2] The synthetic versatility of calixarene
macrocycles makes them suitable for
a wide range of
applications including molecular recognition and sensing,[3]
synthesis of interpenetrated architectures,[4] biomolecular
recognition,[5] and catalysis.[6] It has long been known that
calix[4]arene-amide hosts show a high affinity towards alkali
metal cations.[7,8] The studies conducted by Arnaud-Neu et al.[8]
showed that, among the alkali metal cations series, Na+ was the
best extracted cation (Figure 1a).[7] These cation-recognition
abilities of calixarene-amides have been particularly exploited in
sensing devices[7a,c-e] for the detection of metal ions and for the
extraction of alkali picrates,[8] whereas their employment in
phase transfer catalysis has surprisingly remained elusive.
About thirty years ago, in pioneering works, Shinkai[9] and
Taniguchi[10] reported some examples of PTC[11] exploiting the
cation-complexing abilities of calixarene-ether derivatives
(Figure 1b). Since then, however, this approach has been
neglected.[12] Surprisingly, even if calix[4]arene-tetramides are
better hosts for alkali-metal cations with respect to calixarene-
ethers,[7,8] the PTC abilities of calix-amide derivatives have been
totally disregarded.
Figure 1. Examples of calix[4]arene-based phase-transfer catalysts.
Recently, through a different approach, some examples of
calixarene-based PTC have been proposed,[6b,13] in which the
macrocycle acts as a scaffold bearing quaternary ammonium
groups, that are the actual phase-transfer catalysts (Figure
1c).[13a-f]
The development of enantioselective reactions using a
PTC protocol is a task of great importance because of the
possibility to obtain optically active molecules of biological and
pharmaceutical interest.[14] In this regard, the synthesis of
optically active -amino acids via an asymmetric PTC protocol
with chiral calixarene-ammonium catalysts has been
investigated in the last decade.[15] Thus, Sirit[15a] and co-workers
designed a chiral calix[4]arene, bearing at the lower rim two
ammonium pendant groups derived from cinchona alkaloid, as a
phase–transfer catalyst for the enantioselective synthesis of -
amino acids. Analogously, Su[15d] and Shimizu[15b,c] reported
calix[4]arene-based phase-transfer catalysts, bearing cationic
pendant groups at the lower and the upper rim respectively, for
the enantioselective -functionalization of glycine. Surprisingly,
no examples of asymmetric phase-transfer catalysis exploiting
[a]
Dipartimento di Chimica e Biologia “A. Zambelli”
Università di Salerno
Via Giovanni Paolo II 132, I-84084 Fisciano (Salerno), Italy
E-mail: gdsala@unisa.it, neri@unisa.it,
http://docenti.unisa.it/004471/en/home,
http://docenti.unisa.it/003773/en/home
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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the cation-recognition abilities of chiral calixarene-amide hosts
have been reported to date.
Synthesis of calix[4]arene-amides 1-7. Calixarene-amide
derivatives 1 and 2 (Figure 2) were obtained following the
procedures reported by Stibor and coworkers.[17] Calixarene-
monohydroxy-triamide 3 (Figure 2) was obtained following the
procedure reported in Scheme 1a. In details, the known
calix[4]arene-tri-carboxylic acid 9[18] was converted into the
corresponding acyl chloride and then coupled with (S)--
methylbenzylamine to give
3 in 20 % yield, which was
characterized by HR ESI(+)-MS, 1H and 13C NMR
spectroscopy.[19]
Calixarene-monomethoxy-triamide
4
was
obtained
following a synthetic route similar to 3 (Scheme 1a). The
methylation of the free OH group of 8 in the presence of
potassium
carbonate
afforded
25-methoxy-26,27,28-tris-
((ethoxycarbonyl)methoxy)-5,11,17,23-tetra-tert-butyl-
calix[4]arene 10[20] in 70 % yield. Derivative 10 was suspended
in a mixture of EtOH/H2O and hydrolyzed in the presence of
NaOH to give triacid 11[20] in 96 % yield, which was converted
into the corresponding acyl chloride and coupled with (S)--
methylbenzylamine to give 4[19] in 57 % yield.
Figure 2. Calix[4]arene-amides employed in this study.
The synthesis of calix-dimethoxy-diamide 5 is outlined in
Scheme 1b. The known diacid derivative 12[21] was converted
into the corresponding diacyl chloride and then directly coupled
with (S)--methylbenzylamine to give 5 in 80 % yield, which was
characterized by HR ESI(+)-MS, 1H and 13C NMR
Prompted by these considerations we designed chiral
calix[4]arene-amides 1-7 (Figure 2) and, in continuation of our
research on macrocycle catalyzed phase-transfer reactions,[16]
we wish to report here on their abilities as phase-transfer
catalysts in the asymmetric alkylation of N-(diphenylmethylene)-
glycine esters. In particular, in all cases we have designed
calixarenes catalysts 1−7 bearing secondary amides at lower rim
thanks to their ease of synthesis and good complexing abilities.
spectroscopy.[19] Calix-trimethoxy-monoamide
6 was easily
obtained (Scheme 1c) by transformation of the known monoacid
derivative 13[22] into the corresponding acyl chloride by treatment
with oxalyl chloride, and subsequent coupling with (S)--
methylbenzylamine to give 6 in 60 % yield.[19] Finally, calix-
monomethoxy-naphthyl-triamide 7 was obtained in 76 % yield,
by coupling the acyl chloride of 11 (Scheme 1a) with (S)-1-(2-
naphthyl)ethylamine.[19]
Results and Discussion
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Scheme 1. Synthesis of derivatives 3-6. Conditions a): dry CH2Cl2, dry NEt3, (S)-α-methylbenzylamine, 15 h, room temperature. Conditions b): dry CH2Cl2, dry
NEt3, (S)-1-(2-naphthyl)ethylamine, 3 d (63 h), room temperature.
introduction of (S)--methylnapthylamine residues in place of
Asymmetric PTC Catalysis. With the calix[4]arene-amides 1-7
in our hands we decided to test their catalytic performances in
the phase-transfer alkylation of N-(diphenylmethylene)-glycine t-
butyl ester 14 with benzyl bromide in a liquid-liquid system
NaOH 50 %/toluene at 0 °C, with a catalyst loading of 5 mol-%
(Table 1, entries 1-7). The alkylation catalyzed by tetramide 1
led to the (R)-benzylated product 15a with a good yield but with
disappointing enantioselectivity (Table 1, entry 1). Comparable
yields and faster reactions were obtained with phenolic amides 2
and 3, but the resulting enantioselectivities were even lower
(Table 1, entries 2 and 3).
As the phenolic groups on the lower rim might be involved in
side alkylation reactions leading to the transformation of the
catalyst during the process,[23] we directed our attention to calix-
methoxy-amides 4-6. A significant improvement of both yield
and enantioselectivity was achieved with triamide 4 (Table 1,
entry 4); enantioselectivities decreased by reducing the number
of chiral amide appendages (entries 5 and 6). Scarce catalytic
activity and enantioselectivity are especially shown by
monoamide 6, which led to racemic product and incomplete
conversion even after 20 h; in this case, presumably, the
presence of only one chiral amide group results in reduced
cation-complexing and stereodifferentiating abilities. The
(S)--methylbenzylamine slowed down the reaction and led to a
decrease in enantioselectivity (Table 1, entry 7).
A comparison of the yields obtained in the presence of
calixarene-amides 1-7 with the low conversion observed in the
uncatalyzed reaction (8 % yield after 24 h, Scheme 2a)
confirmed the catalytic activity of these macrocycles. In order to
assess the effect of calixarene scaffold on catalytic activity and
enantioselectivity, we conducted the reaction in the presence of
chiral monoamide 16 (0.20 equiv., Scheme 2b). Racemic
benzylated product 15a was obtained in 9 % yield, presumably
as a result of the background reaction. The achiral tetramide 17,
albeit less active than its chiral analogue 1, also showed a
moderate catalytic activity (5 mol-% cat., 40 % yield, Scheme
2c). We assumed that the calixarene scaffold plays an essential
role in phase-transfer catalysis activity by preorganizing and
orienting properly the amide groups in such a way as to favor
the complexation of Na+ cation. To support this hypothesis, the
recognition abilities of calix[4]arene amides toward Na+ cation
were then assessed (see the next section).
Successively, we evaluated the effect of the ester group in the
substrate, using the best catalyst 4. As expected,[16a,24a,25] the
presence of less hindered ester groups, such as ethyl and
benzyl, proved to be detrimental for the stereoselectivity of
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10.1002/ejoc.201700912
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alkylation (Table 1, entries 8 and 9). Slightly lower ee was
achieved starting from cumyl ester 20 (Table 1, entry 10). A
disappointing result was also observed with the benzhydryl ester
21, with an unexpected inversion of enantioselectivity (Table 1,
entry 11).
Table 1. Phase-transfer benzylation of N-(diphenylmethylene)-glycine
esters promoted by calix[4]arene-amides 1-7.[a]
Entry
Catalyst
Substrate
Time [h]
Yield[b] [%]
ee[c,d]
[%]
Scheme 2. Phase-transfer benzylation of N-(diphenylmethylene)-glycine t-
butyl ester 14 catalyzed by amide 16 and calixarene-tetramide 17.
Comparison with the uncatalyzed process.
1
2
1
2
3
4
5
6
7
4
4
4
4
tBu– (14)
20
4
77
71
83
92
92
48
97
77
80
84
74
13
7
tBu– (14)
tBu– (14)
After screening of the catalysts and the ester groups of the
the substrates, our attention was directed towards examining the
effect of other parameters, such as solvent, base, catalyst
loading, and temperature, on the benzylation of t-butyl ester 14.
Good yields but poor enantioselectivities were obtained in
different reaction media such as chlorinated solvents, ether,
chlorobenzene, and xylenes (Table 2, entries 2-8). Gratifyingly,
a significant improvement, up to 35 % ee, was achieved in
mesitylene (Table 2, entry 9). A decrease of ee was observed
with a 10 mol-% amount of CH2Cl2 in mesitylene (Table 2, entry
10). The use of inorganic bases other than aqueous NaOH 50 %
3
4
5
4
tBu– (14)
5
28
13
rac
9
5
tBu– (14)
4
6
tBu– (14)
20
20
3
7
tBu– (14)
8
Et– (18)
4
9
Bn– (19)
7
rac
24
6 (S)
resulted in low values and
a startling inversion of the
10
11
Ph(Me)2C– (20)
Ph2CH– (21)
6
enantioselectivity (Table 2, entries 11-14). By replacing sodium
with the larger potassium or cesium cation, a change of the host-
guest tridimensional structure is anticipated, with specific
reference to the cation position into the binding site. This may
affect the mode of association with the carbanion and hence the
reaction enantioselectivity.[26] At -20 °C the reaction proceeded
slowly and, even after prolonged reaction time, low conversion
and enantioselectivity resulted (Table 2, entry 15). Lower
enantioselectivities were also obtained with smaller or higher
catalyst loadings (Table 2, entries 16 and 17). While examples
erosion of enantioselectivity with increasing amount of catalyst
has been frequently described,[27,28] much less common is the
opposite effect.[29] Presumably, at higher concentrations,
aggregation of the host-guest complex can explain the influence
on enantioselectivity.
5
[a] All reactions were performed in a liquid-liquid system with 0.08 mmol of
substrate 14,18-21, benzyl bromide (1.2 equiv.), and catalyst (5 mol-%) in
toluene (0.8 mL) and NaOH 50 % aq (0.5 mL). [b] Isolated yields. [c]
Determined by HPLC using a Chiralcel OD-H chiral stationary phase. [d]
The absolute configuration of the products were determined by
comparison of the HPLC retention times and optical rotations with
literature values.[15a,16a,24]
Table 2. Optimization of phase-transfer benzylation of 14 promoted by
calix[4]arene-triamide 4.[a]
Yield[b]
ee[ [c,d]
Entry
Solvent
Base
Time
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[h]
5
[%]
92
[%]
28
3
4-(t-butyl)benzyl
15c
20
79
44
1
toluene
NaOH 50 % aq.
4
2-methylbenzyl
allyl
15d
15e
7
75
75
15
15
5 [e]
20
2
3
4
Et2O
CH2Cl2
CHCl3
NaOH 50 % aq.
NaOH 50 % aq.
NaOH 50 % aq.
5
7
87
83
78
4
6
5
[a] All reactions were performed in a liquid-liquid system with 0.08 mmol of
14, benzyl bromide (1.2 equiv.), and catalyst (5 mol-%) in toluene (0.8 mL)
and NaOH 50 % aq (0.5 mL). [b] Isolated yields. [c] Determined by HPLC
30
chlorobenzen
e
5
NaOH 50 % aq.
5
90
rac
using
a Chiralcel OD-H chiral stationary phase. [d] The absolute
6
7
8
9
m-xylene
p-xylene
NaOH 50 % aq.
NaOH 50 % aq.
NaOH 50 % aq.
NaOH 50 % aq.
20
7
82
84
88
86
3
configuration of the product was determined by comparison of the HPLC
retention time and optical rotation with literature values.[16b,24a,28,30] [e] 1.5
equiv. of allyl bromide were used.
rac
17
35
o-xylene
5
mesitylene
7
mesitylene/
CH2Cl2 9:1
10
NaOH 50 % aq.
6
89
26
Recognition abilities of calix[4]arene-amides toward Na+
cation. The complexation of Na+ by calix[4]arene-amide catalyst
is a requisite step in the phase-transfer alkylation of glycine
ester 14 with benzyl bromide (see Schemes in Tables 1-3). With
the aim to explore the recognition abilities of the most active
calix[4]arene-amides catalysts toward Na+ guest we performed
1H NMR titration experiments[31] of a solution of host in CDCl3
11
12
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
NaOH (s)
KOH 50 % aq.
KOH (s)
92
92
44
44
92
7
75
76
79
72
12
73
73
4 (S)
10 (S)
15 (S)
11 (S)
14
13
14
CsOH (s)
15 [e]
16 [f]
17 [g]
NaOH 50 % aq.
NaOH 50 % aq.
NaOH 50 % aq.
28
with
Na+
as
the
TFPB−
[tetrakis[3,5-
20
13
bis(trifluoromethyl)phenyl]borate][32] salt. The hydrophobic
TFPB−, that is known to be a weakly coordinating anion,[32a] was
chosen as counteranion due to the good solubility of its sodium
salt in organic solvents.[32b] As previously shown by us,[3a,4b,c] the
good solubility of the TFPB− salts in CDCl3 enable the
determination of the apparent association constant of the
complex by direct integration of its 1H NMR signals with respect
to those of the free host.
[a] Reactions were performed in a liquid-liquid system with 0.08 mmol of 14,
benzyl bromide (1.2 equiv.), and catalyst (5 mol-%) in toluene (0.8 mL) and
NaOH 50 % aq (0.5 mL), except where otherwise noted. [b] Isolated yields.
[c] Determined by HPLC using a Chiralcel OD-H chiral stationary phase. [d]
The absolute configuration of the product was determined by comparison of
the HPLC retention time and optical rotation with literature values.[24a] [e]
Reaction performed at -20 °C. [f] 10 mol-% of catalyst loading was used. [g]
2.5 mol-% of catalyst loading was used.
Finally, we carried out this calix[4]arene-amide catalysed
reaction with other alkylating agents, under optimized conditions
(NaOH 50 % aq., 5 mol-% of triamide 4, in mesitylene, Table 3).
Good yields of alkylated products were obtained in all cases.
Higher enantioselectivities were achieved with p-alkyl
substituted benzyl substrates (Table 3, entries 2 and 3),
whereas with a ortho-substituted substrate and with allyl
bromide a 15 % ee resulted (Table 3, entries 4 and 5).
Table 3. Phase-transfer alkylation of 14 promoted by calix[4]arene-
triamide 4.[a]
Figure 3. Expansion of the 1H NMR spectra (400 MHz, CDCl3, 298 K) of: (a)
tetramide 1 (1.9 mM) (b) a mixture of 1 (1.0 equiv., 1.9 mM) and NaTFPB (0.5
equiv., 0.95 mM) after mixing; (c) an equimolar solution (1.9 mM) of 1 and
NaTFPB after equilibration for 3 d at 298 K.
Time
[h]
Yield[b]
[%]
ee[ [c,d]
[%]
Entry
Product
R
1
2
benzyl
15a
15b
7
7
86
85
35
47
4-methylbenzyl
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Initially, we studied the recognition abilities of calixarene-
tetramide 1 toward NaTFPB in CDCl3. The 1H NMR spectrum of
1 in CDCl3 (Figure 3a) undergoes drastic changes after addition
of NaTFPB. After the addition of 0.5 equiv of NaTFPB, a new AX
system (4.25 and 3.26 ppm, J = 12.0 Hz) emerged in the 1H
NMR spectrum (in red in Figure 3b), which was attributable to
the ArCH2Ar groups of the Na+1 complex in slow exchange
with those of the free host 1 on the NMR time scale. The OCH2
protons of the free host 1, which resonate in CDCl3 at 4.33 ppm
(AB system), form a new AX system (4.52 and 3.89 ppm, J =
13.2 Hz) after complexation with Na+ (in magenta in Figure 1b).
After a further addition of 0.5 equiv of NaTFPB, the Na+1
complex was formed in 74 % after 3 d at 298 K, as determined
by 1H NMR signal integration of both complexed and free host 1
(Figure 3c; the NMR signal areas were obtained by using a
fitting program, see supporting information for further details).
From the percentage of formation of the Na+1 complex an
apparent association constant of 1.22±0.04×104 M-1 was
obtained.
Successively, we studied the binding affinity of calixarene-
monomethoxy-triamide 4 toward NaTFPB in CDCl3 (Figure 4).
Free 4 adopts a cone conformation in CDCl3 as indicated by the
presence in its 1H NMR spectrum (CDCl3, 298 K) of four AX
systems at 4.49/3.24, 4.31/2.94, 4.11/3.24, and 4.08/3.24 ppm
(COSY spectrum, see supporting information) which correlate in
the HSQC spectrum with CH2 carbon signals at 31.6, 31.5, and
31.8 (x2) ppm, respectively. By the known Gutsche's and de
Mendoza's rules,[33] these data were only compatible with a cone
conformation of 4. In addition, the presence in the 1H NMR
spectrum of 4 in CDCl3 (600 MHz, 298 K) of shielded aromatic
signals in the 6.40-6.47 ppm region (integrating for 4 H)
evidenced that the calixarene skeleton of 4 adopts a pinched
conformation. The pinched-cone conformation adopted by 4 in
solution was studied by DFT calculations at the B3LYP/6-
31G(d,p) level of theory and by 1D and 2D NMR spectroscopy.
A close inspection of the DFT-optimized structure of 4 (Figure 5)
reveals the presence of two intramolecular H-bonding
interactions between amide groups at the lower rim, which
stabilize the pinched conformation of 4.
Figure 4. 1H NMR spectra (400 MHz, CDCl3, 298 K) of: (a) triamide 4 (1.9
mM) (b) an equimolar solution (1.9 mM) of 4 and NaTFPB after mixing; (c) an
equimolar solution (1.9 mM) of 4 and NaTFPB after equilibration for 3 d (72 h)
at 298 K.
At this point the 1:1 stoichiometry of the Na+4 complex
was determined by spectral integration (with respect to the
1
TFPB−ArH signal), while the assignment of its H and 13C NMR
spectra was obtained by means of 1D and 2D NMR studies (2D
HSQC and COSY spectra; 600 MHz, CDCl3).[19] Interestingly, the
formation of the Na+4 complex was easily followed by the
1
disappearence of the H NMR ArH signals of 4 between 6.40-
6.47 ppm, which are attributable to the aromatic rings of the
pinched-cone inwardly oriented with respect to the calix-cavity.
This result clearly indicated that upon Na+ complexation, 4
switches from the pinched-cone to a cone conformation in which
the ArH resonate between 7.01 and 7.39 ppm. After the
formation of the Na+4 complex, the destruction of the
intramolecular H-bonds between amide groups occurs, which
was evidenced by the upfield shift (see green signals in Figures
2b and 2c) of the N-H signals. The analysis of the complexation
When NaTFPB salt (0.5 equiv) was added to a CDCl3
solution of 4 a new set of signals emerged in the 1H NMR
spectrum attributable to the formation of the Na+4 complex,
which was in slow exchange on the NMR time scale (Figure 4b).
After a further addition of 0.5 equiv of NaTFPB salt, the
formation of the Na+4 complex was complete after 3 d (72 h)
at 298 K (1H NMR analysis; Figure 4c).
1
induced shifts of H NMR signals of 4, clearly showed that the
Na+ cation is encapsulated inside the cavity delimited by the
oxygen atoms at the lower rim to establish ion-dipole
interactions. Thus, the 1H NMR signals attributable to the OCH2
groups at the lower rim of 4 are downfield shifted upon
complexation of Na+, whereas the singlet at 3.74 ppm
attributable to the OCH3 group of 4 is upfield shift at 3.65 ppm.
A close inspection of the DFT-optimized structure of the Na+4
complex at the B3LYP/6-31G(d,p) theory level, indicates that the
OCH3 group is positioned right at the top of a close phenyl ring
to establish a C-H···π interaction, with a C-H···πcentroid distance
1
of 2.81 Å (Figure 5*). This result is fully in accord with the H
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NMR upfield shift observed for the OMe signal of 4 in the Na+ 4
complex against the trend observed for the other OCH2 groups
at the lower rim of 4.
spectrum at 233 K reveals the presence of an AX system at 4.12
and 3.20 ppm, attributable to ArCH2Ar groups, which correlates
in the 2D HSQC spectrum with a signal at 31.2 ppm. From the
known Gutsche's and de Mendoza's rules,[33] these data were
only compatible with a cone conformation of 5. Upon addition of
NaTFPB (1 equiv) to a CDCl3 solution of 5 at 298 K, a new set of
slowly exchanging signals attributable to the Na+5 complex
emerged in the 1H NMR spectrum. A close inspection of the 1D
and 2D NMR spectra of the NaTFPB/5 mixture (1:1 in CDCl3,
298 K) revealed the presence of two Na+5 complexes in which
the two calix[4]arene macrocycles adopted different
conformations (Figure 6). In details, four doublets were present
at 4.06, 3.95, 3.33, and 3.31 ppm which correlated with carbon
resonances at 29.8 and 30.0 ppm, attributable to ArCH2Ar
groups between syn oriented Ar-rings, and compatible with a
calixarene in a cone conformation (Na+5cone). In addition, the
OCH2 groups belonging to the Na+5cone complex were observed
at 4.52 and 4.40 ppm, while the OCH3 singlet was present at
3.52 ppm. Surprisingly, a close inspection of the 1D and 2D
NMR spectra revealed the presence of a Na+5 complex in
Figure 5. DFT-optimized structures of free 4, in the pinched-cone
conformation, and Na+4 complex at the B3LYP/6-31G(d,p) theory level
(some H atoms have been omitted for clarity). Dotted lines in yellow indicate
intramolecular H-bonds stabilizing the pinched conformation (average N-
H···O=C distance 2.87 Å). Inset (*): particular of the C-H···π interaction
between methyl group and phenyl ring in the Na+4 complex.
which the calixarene adopts
a partial-cone conformation
(Na+5paco) in a 1:1 ratio with respect to Na+5cone complex (by
1
integration of the H NMR signlas). In fact, two AB systems at
In a similar way, when NaTFPB (0.5 equiv) was added to a
CDCl3 solution of naphthyl-triamide 7, a new set of signals
emerged. In particular, four new AX systems (4.04 and 3.19 ppm,
J = 11.8 Hz; 4.14 and 3.30 ppm, J = 11.8 Hz; 4.17 and 3.37 ppm,
J = 12.4 Hz; 4.21 and 3.22 ppm, J = 12.0 Hz) which was
attributable to ArCH2Ar groups of Na+7 complex in slow
exchange on the NMR time scale. In addition, three AX systems
(4.33 and 3.85 ppm, J = 14.8 Hz; 4.37 and 4.05 ppm, J = 11.6
Hz and 4.60 and 4.44 ppm, J = 13.6 Hz) were attributable to the
OCH2 groups of Na+7 complex. Finally, the OCH3 group was
present as a singlet at 3.60 ppm. Upon a further addition of 0.5
equiv of NaTFPB salt, the formation of the Na+7 complex was
complete (1H NMR analysis) after equilibration for 3 d (72 h) at
298 K. A percentage of formation of 78 % was calculated by
integration of the OCH3 singlets for free and complexed 7, which
gave an apparent association constant of 9.16±0.04×103 M−1.
Also in this case the NMR signal areas were obtained by using a
fitting program (see supporting information for further details).
The apparent association constant of the Na+ 4 complex
could not be determined by direct signal integration because the
3.76 and 3.82 ppm, which correlated with carbon resonances at
37.5 and 37.9 ppm, were indicative of ArCH2Ar groups between
anti oriented Ar-rings. In addition, two AB systems attributable
to OCH2 groups were observed at 4.51/4.26 and 4.60/4.28 ppm.
Finally, a singlet attributable to OCH3 group of the Na+5paco
complex was present at 3.30 ppm, while the OCH3 group
belonging to the inverted Ar-ring was found at 1.97 ppm.
1
intensities of the H NMR signals (Figure 4c) of the free host 4
were below the reliable 10 % limit. Therefore, Kass evaluation
was carried out by means of a competition experiment[31]
between calix-triamides 4 and 7[19] by mixing them with NaTFPB
in a 1:1:1 ratio. After equilibration for 3 d (72 h), the Na+4
complex was preferentially formed over the Na+7 one with a
percentage of formation of 56 and 44 %, respectively. From
these data, an apparent association constant of 1.26±0.09×104
M−1 was calculated for the formation of Na+4 complex in CDCl3.
Interstingly when the competition experiment was carried out
between hosts 4 and 1 for NaTFPB guest, the calculated
association constant value of 1.30±0.06×104 M−1 was consistent
with previously determined value.
Figure 6. Expansion of the 1H NMR spectra (400 MHz, CDCl3, 298 K) of: (a)
derivative 5 (1.9 mM) (b) an equimolar solution (1.9 mM) of 5 and NaTFPB
after equilibration for 3 d at 298 K.
The good binding affinities determined for calix[4]arene-
amides 1, 4, and 7 toward Na+ guest support a phase-transfer
catalytic role for these macrocycles. We suggest a mechanism
involving the interfacial formation of a tight ion pair between
Na+calixarene-amide complex and the enolate anion generated
VT 1H NMR studies showed that calix-dimethoxy-diamide 5
adopts in solution a cone conformation. In fact, its 1H NMR
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10.1002/ejoc.201700912
European Journal of Organic Chemistry
FULL PAPER
0.80 mmol) in 10 mL of dry CHCl3 at 0 °C. The reaction mixture was
stirred for 15 h at room temperature under nitrogen atmosphere, then
was washed with a 1N aqueous solution of HCl (2 × 5 mL). The aqueous
phase was extracted with CHCl3 (3 × 5 mL). The collected organic layers
were washed with H2O (10 mL), dried over Na2SO4 and evaporated
under reduced pressure. The crude product was purified by column
chromatography (SiO2, CHCl3) to give the compound 3 as a white solid
after deprotonation of 14. The chiral lipophilic ion pair can diffuse
into the organic layer and undergo enantioselective alkylation.[34]
Conclusions
20
(0.060 g, 20 % yield): mp 126−128 °C; [α]D = −38.5±0.7 (c = 0.100,
For the first time, the cation recognition abilities of chiral calix-
amide hosts have been exploited in asymmetric phase transfer
catalysis. In particular, α-methylbenzylamine and 1-(2-
naphthyl)ethylamine-derivatives 1-7 turned out to be effective
catalysts in the asymmetric alkylation of N-(diphenylmethylene)-
glycine esters under PTC conditions. The recognition abilities of
catalysts 1, 4, 5, and 7 toward Na+ guest have been investigated
CHCl3); 1H NMR (400 MHz, CDCl3, 298 K): δ 8.06 (d, J = 8.2 Hz, NH, 1H),
7.48 – 7.07 (overlapped ArH + NH, 21H), 6.79 (d, J = 8.2 Hz, NH, 1H),
6.52 (s, ArH, 1H), 6.51 (s, ArH, 1H), 6.48 (s, ArH, 1H), 6.44 (s, ArH, 1H),
5.31 – 5.28 (overlapped, CHPhCH3 + OH, 3H), 5.09 (m, CHPhCH3, 1H),
4.66 (d, J = 14.6 Hz, OCH2CO, 1H), 4.37 (d, J = 13.8 Hz, OCH2CO, 1H),
4.29 (d, J = 13.3 Hz, ArCH2Ar, 1H), 4.23 (d, J = 14.6 Hz, OCH2CO, 1H),
4.19 (d, J = 13.1 Hz, ArCH2Ar, 1H), 4.14 (d, J = 13.8 Hz, OCH2CO, 1H),
4.07 (d, J = 12.9 Hz, ArCH2Ar, 1H), 3.75 (d, J = 13.1 Hz, ArCH2Ar, 1H),
3.50 (d, J = 13.7 Hz, OCH2CO, 1H), 3.38 (d, J = 13.3 Hz, ArCH2Ar, 1H),
3.17 (d, J = 13.1 Hz, ArCH2Ar, 2H), 3.12 (d, J = 13.7 Hz,, OCH2CO, 1H)
3.03, (d, J = 12.9 Hz, ArCH2Ar, 1H), 1.74 (d, J = 7.0 Hz, CHPhCH3, 3H),
1.67 (d, J = 7.0 Hz, CHPhCH3, 3H), 1.58 (d, J = 6.9 Hz, CHPhCH3, 3H),
1.37 (s, C(CH3)3, 9H), 1.36 (s, C(CH3)3, 9H), 0.83 (s, C(CH3)3, 9H), 0.77
(s, C(CH3)3, 9H). 13C NMR (100 MHz, CDCl3, 298 K): δ 168.9, 167.9,
167.5, 151.9, 151.6, 151.5, 149.8, 147.6, 146.7, 146.5, 143.3, 143.0,
142.8, 142.7, 135.4, 135.2, 131.6, 131.1, 130.8, 130.4, 128.9, 128.8,
128.7, 128.4, 128.3, 128.0, 127.8, 127.6, 126.9, 126.7, 126.6, 125.8,
125.7, 125.5, 125.5, 125.3, 75.8, 75.7, 74.0, 49.5, 49.0, 48.9, 34.4, 34.2,
33.9, 33.8, 32.1, 31.9, 31.8, 31.5, 31.3, 31.1, 21.9, 21.3, 20.1. IR (KBr): ṽ
= 2962, 2868, 1657, 1538, 1480, 1454, 1393, 1362, 1300, 1219, 1196,
1123, 1048, 872, 771, 699 cm-1. HRMS (ESI+) m/z [M]+ calcd for
C74H90N3O7, 1132.6773; found 1132.6778.
1
by H NMR titration experiments. The good calculated apparent
association constant values for Na+X (X = 1, 4, and 7)
complexes are consistent with the remarkable catalytic activity
exhibited by calixarene-amides 1-7 in the above-mentioned PTC
process. This finding opens up new scenarios in phase-transfer
catalysis, with the view to designing novel macrocyclic catalysts
based on calixarene scaffolds decorated with chiral cation-
coordinating moieties. Further studies developing this concept
are in progress and will be reported in due course.
Experimental Section
General Information. HR MALDI mass spectra were acquired on a FT-
ICR mass spectrometer equipped with a 7T magnet. All chemicals were
reagent grade and were used without further purification. Compounds
16[35] and 17[36] were prepared as reported in the literature. Anhydrous
solvents were used as purchased from the supplier. When necessary
compounds were dried in vacuo over CaCl2. Reaction temperatures were
measured externally. Reactions were monitored by TLC silica gel plates
(0.25 mm) and visualized by UV light, or by spraying with H2SO4-
Ce(SO4)2. Flash chromatography was performed on silica gel 60 (particle
size: 0.040−0.063 mm) and the solvents employed were of analytical
grade. Enantiomeric excesses of products 15a-e were determined by
chiral HPLC using Chiralcel OD-H columns with an UV detector set at
260 nm. Optical rotation values were measured at λ = 589 nm,
corresponding to the sodium D line, at the temperatures indicated. NMR
spectra were recorded on a 600 [600 (1H) and 150 MHz (13C)], 400 MHz
spectrometer [400 (1H) and 100 MHz (13C)] or 300 MHz spectrometer
[300 (1H) and 75 MHz (13C)]. Chemical shifts are reported relative to the
residual solvent peak (CHCl3: δ 7.26, CDCl3: δ 77.23; TCDE: δ 6.0,
TCDE: δ 74.0). Standard pulse programs, provided by the manufacturer,
were used for 2D COSY and 2D HSQC experiments. One-dimensional
1H and 13C spectra, and two-dimensional COSY-45 and heteronuclear
single quantum correlation (HSQC) were used for NMR peak assignment.
COSY-45 spectra were taken using a relaxation delay of 2 s with 30
scans and 170 increments of 2048 points each. HSQC spectra were
performed with gradient selection, sensitivity enhancement, and phase-
Compound 4. Oxalyl chloride (1.5 mL, 18 mmol) was slowly added to a
stirred solution of 11 (0.38 g, 0.46 mmol) in 20 mL of dry CHCl3 at 0 °C.
The reaction mixture was refluxed under nitrogen atmosphere for 13 h,
then was cooled at room temperature and the solvent was removed
under reduced pressure to give a dark solid. The crude product was
dissolved in 13 mL of dry CHCl3 and added dropwise to a stirred solution
of (S)-α-methylbenzylamine (0.18 mL, 1.4 mmol) and dry Et3N (0.19 mL,
1.4 mmol) in 23 mL of dry CHCl3 at 0 °C. The reaction mixture was stirred
for 22 h at room temperature under nitrogen atmosphere, then was
washed with a 1N aqueous solution of HCl (2 × 15 mL). The aqueous
phase was extracted with CHCl3 (3 × 10 mL). The collected organic
layers were washed with H2O (20 mL), dried over Na2SO4 and
evaporated. The crude product was purified by column chromatography
(SiO2, CHCl3/hexane from 6/4 to 9/1 (v/v)) to give the derivative 4 as a
20
white solid (0.22 g, 57 %): mp 140 −143 °C; [α]D = − 26.4 ± 0.4 (c =
1.00, CHCl3); 1H NMR (400 MHz, CDCl3, 298 K): δ 7.73 (broad, NH, 1H),
7.70 (d, J = 8.4 Hz, NH, 1H), 7.46 (d, J = 7.2 Hz, ArH, 2H), 7.40 (d, J, =
7.2 Hz, ArH, 2H), 7.28 – 7.02 (overlapped, ArH, 15H), 6.78 (broad, NH,
1H), 6.47 – 6.45 (overlapped, ArH, 3H), 6 40 (s, ArH, 1H), 5.35 – 5.27 (m,
NCHPhCH3, 2H), 5.04 – 5.00 (m, NCHPhCH3, 1H), 4.69 – 4.60
(overlapped, OCH2CO, 2H), 4.49 (d, J = 13.2 Hz, ArCH2Ar, 1H), 4.30 (d,
J = 13.2 Hz, ArCH2Ar, 1H), 4.22 (s, OCH2CO, 2H), 4.13 (s, OCH2CO, 2H),
4.11 (d, J = 12.4 Hz, ArCH2Ar, 1H), 4.08 (d, J = 12.4 Hz, ArCH2Ar, 1H),
3.74 (s, OCH3, 3H), 3.24 (overlapped, ArCH2Ar, 3H), 2.94 (d, J = 13.2 Hz,
ArCH2Ar, 1H), 1.65 (d, J = 6.8 Hz, CHPhCH3, 3H), 1.58 (d, J = 7.2 Hz,
CHPhCH3, 3H), 1.41 (d, J = 6.8 Hz, CHPhCH3, 3H), 1.34 (s, C(CH3)3,
9H), 1.33 (s, C(CH3)3, 9H), 0.86 (s, C(CH3)3, 9H), 0.85 (s, C(CH3)3, 9H).
13C NMR (100 MHz, CDCl3, 298 K): δ 168.33, 168.28, 168.1, 154.9,
153.1, 152.0, 145.8, 145.6, 145.2, 145.1, 143.3, 143.1, 142.8, 134.9,
134.7, 134.7, 131.3, 131.3, 130.8, 128.5, 128.4, 127.2, 126.5, 126.3,
126.2, 126.1, 125.8, 125.1, 124.7, 124.6, 74.7, 74.6, 60.2, 48.7, 48.5,
48.3, 34.1, 33.6, 31.6, 31.5, 31.2, 31.0, 21.8, 21.5, 21.2. IR (KBr): ṽ =
3286, 3036, 2963, 2868, 1659, 1544, 1480, 1393, 1362, 1300, 1219,
sensitive mode using Echo/Antiecho-TPPI procedure.
A
typical
experiment comprised 20 scans with 113 increments of 2048 points each.
Compound 3. Oxalyl chloride (0.88 mL, 10 mmol) was slowly added to a
stirred solution of 9[18] (0.22 g, 0.27 mmol) in 10 mL of dry CHCl3 at 0 °C.
The reaction mixture was refluxed under nitrogen atmosphere for 15 h,
then was cooled at room temperature and the solvent was removed
under reduced pressure to give a dark solid. The crude product was
dissolved in 5 mL of dry CHCl3 and added dropwise to a stirred solution
of (S)-α-methylbenzylamine (0.10 mL, 0.80 mmol) and dry Et3N (0.11 mL,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700912
European Journal of Organic Chemistry
FULL PAPER
1195, 1124, 1047, 1021, 949, 871, 772, 698 cm-1. HRMS (ESI+) m/z [M +
dissolved in 7 mL of dry CHCl3 and added dropwise to a stirred solution
of (S)-1-(2-naphthyl)ethylamine (0.22 g, 1.3 mmol) and dry Et3N (0.18
mL, 1.3 mmol) in 13 mL of dry CHCl3 at 0 °C. The reaction mixture was
stirred for 63 h at room temperature under nitrogen atmosphere, then
was washed a 1N aqueous solution of HCl (2 × 10 mL). The aqueous
phase was extracted with CHCl3 (3 × 10 mL). The collected organic
layers were washed with H2O (25 mL), dried over Na2SO4 and
evaporated. The crude product was purified by column chromatography
(SiO2, CH2Cl2/Et2O 96/4 (v/v)) to afford compound 7 as white solid (0.24
g, 76 %): mp 138-139 °C; [α]D20 = − 424 ± 4 (c = 0.0938, CHCl3); 1H NMR
(600 MHz, CDCl3, 298 K): δ 7.88 (s, ArH, 1H), 7.85 (broad, NH, 1H), 7.83
(broad, NH, 1H), 7.81 (s, ArH, 1H), 7.75 – 7.63 (overlapped, ArH, 7H),
7.58 (s, ArH, 1H), 7.57 (s, ArH, 1H), 7.51 (s, ArH, 1H), 7.50 (s, ArH, 1H),
7.47 (broad, NH, 1H), 7.55 – 7.37 (overlapped, ArH, 6H), 7.13 (d, J = 1.8
Hz, ArH, 1H), 7.12 (d, J = 1.8 Hz, ArH, 1H), 7.09 (s, ArH, 2H), 7.06 (d, J
= 2.4 Hz, ArH, 1H), 6.94 (d, J = 2.4 Hz, ArH, 1H), 6.50 (broad, ArH, 1H),
6.47 (broad, ArH, 1H), 6.45 (d, J = 2.4 Hz, ArH, 1H), 6.36 (d, J = 1.8 Hz,
ArH, 1H), 5.49 – 5.43 (overlapped, COCHPhCH3, 2H), 5.11 – 5.08 (m,
COCHPhCH3, 1H), 4.75-4.71 (overlapped, OCH2CO, 2H), 4.53 (d, J =
13.2 Hz, ArCH2Ar, 1H), 4.34 (d, J = 12.6 Hz, ArCH2Ar, 1H), 4.25 (broad,
OCH2CO, 2H), 4.17 – 4.12 (overlapped, OCH2CO, 2H), 4.10 – 4.06
(overlapped, ArCH2Ar, 2H), 3.73 (s, OCH3, 3H), 3.23 – 3.21 (overlapped,
ArCH2Ar, 2H), 3.17 (d, J = 13.2 Hz, ArCH2Ar, 1H), 2.87 (d, J = 12.6 Hz,
ArCH2Ar, 1H), 1.74 (d, J = 7.2 Hz, CHPhCH3, 3H), 1.60 (d, J = 7.2 Hz,
CHPhCH3, 3H), 1.39 (d, J = 6.6 Hz, CHPhCH3, 3H), 1.31 (s, CCH3, 9H),
1.30 (s, CCH3, 9H), 0.87 (s, CCH3, 9H), 0.84 (s, CCH3, 9H). 13C NMR
(150 MHz, CDCl3, 298 K): δ 168.6, 155.1, 152.3, 145.4, 145.2, 140.9,
140.6, 140.3, 134.8, 134.6, 133.4, 133.3, 132.8, 132.7, 131.5, 131.1,
128.5, 128.4, 128.3, 128.1, 128.0, 128.0, 127.7, 127.7, 126.2, 126.1,
126.0, 125.9, 125.8, 125.4, 125.2, 125.0, 124.9, 124.8, 74.8, 60.4, 48.8,
48.6, 34.2, 34.2, 33.8, 33.7, 31.7, 31.2, 21.8, 21.4, 21.3. IR (KBr): ṽ =
3282, 3055, 2963, 2868, 1652, 1602, 1543, 1480, 1393, 1362, 1299,
1219, 1195, 1124, 1050, 1019, 949, 871, 855, 816, 772 cm-1. HRMS
(ESI+) m/z [M + Na]+ calcd for C87H98N3NaO7, 1319.7297; found
1319.7256.
Na]+ calcd for C75H91N3NaO7, 1168.6749; found 1168.6756.
Compound 5. Oxalyl chloride (0.27 mL, 3.2 mmol) was slowly added to
a stirred solution of 12 (0.097 g, 0.12 mmol) in 5 mL of dry CHCl3 at 0 °C.
The raction mixture was refluxed under nitrogen atmosphere for 16 h,
then was cooled at room temperature and the solvent removed under
reduced pressure to give a white solid. The crude product was dissolved
in 1 mL of dry CHCl3 and added dropwise to a stirred solution of (S)-α-
methylbenzylamine (0.03 mL, 0.2 mmol) and dry Et3N (0.03 mL, 0.2
mmol) in 3 mL of dry CHCl3 at 0 °C. The reaction mixture was stirred for
64 h at room temperature under nitrogen atmosphere, then was washed
with a 1N aqueous solution of HCl (2 × 5 mL). The aqueous phase was
extracted with CHCl3 (3 × 5 mL). The collected organic layers were
washed with H2O (5 mL), dried over Na2SO4 and evaporated. The crude
product was purified by column chromatography (SiO2, CHCl3) to afford 5
as a white solid (0.096 g, 80 % ): mp 237-239 °C; [α]D20 = − 34.68 ± 0.04
(c = 0.997, CHCl3); 1H NMR (600 MHz, CDCl3, 298 K): δ 7.30 – 7.20
(overlapped, NH + ArH, 12H), 7.12 (s, ArH, 4H), 6.42 (s, ArH, 4H), 5.31
(overlapped, COCHPhCH3, 2H), 4.27-4.21 (overlapped, OCH2CO, 4H),
4.11 (broad, ArCH2Ar, 4H), 3.69 (s, OCH3, 6H), 3.20 (broad, ArCH2Ar,
4H), 1.49 (d, J = 6.6 Hz, CHPhCH3, 6H), 1.32 (s, C(CH3)3, 18H), 0.81 (s,
C(CH3)3, 18H). 13C NMR (150 MHz, CDCl3, 298 K): δ 168.4, 154.8, 146.3,
145.5, 142.6, 135.3, 131.1, 131.0, 128.9, 127.7, 126.1, 125.0, 74.3, 60.3,
48.0, 34.3, 33.7, 31.8, 31.1, 21.7. IR (KBr): ṽ = 3414, 3201, 3032, 2962,
2868, 2819, 1671, 1603, 1525, 1480, 1455, 1393, 1362, 1301, 1282,
1241, 1218, 1210, 1197, 1122, 1051, 1021, 955, 912, 871, 833, 815, 771,
699 cm-1. HRMS (ESI+) m/z [M+H]+ calcd for C66H83N2O6, 999.6246;
found 999.6260.
Compound 6. Oxalyl chloride (0.26 mL, 3.1 mmol) was slowly added to
a stirred solution of 13 (0.18 g, 0.24 mmol) in 10 mL of dry CHCl3 at 0 °C.
The reaction mixture was refluxed under nitrogen atmosphere for 19 h,
then was cooled at room temperature and the solvent was removed
under reduced pressure to give a white solid. The crude product was
dissolved in 6 mL of dry CHCl3 and added dropwise to a stirred solution
of (S)-α-methylbenzylamine (0.03 mL, 0.2 mmol) and Et3N (0.03 mL, 0.2
mmol) in 3 mL of dry CHCl3 at 0 °C. The reaction mixture was stirred for
16 h at room temperature under nitrogen atmosphere, then was washed
with a 1N aqueous solution of HCl (2 × 5 mL). The aqueous phase was
extracted with CHCl3 (3 × 5 mL). The collected organic layers were
washed with H2O (10 mL), dried over Na2SO4 and evaporated. The crude
product was purified by column chromatography (SiO2, CH2Cl2) to afford
6 as a white solid (0.12 g, 60 %): mp 106 −107 °C; [α]D20 = − 15.4 ± 0.8
(c = 1.00, CHCl3); 1H NMR (600 MHz, TCDE, 353 K): δ 7.22 (s, ArH, 5H),
7.13 (s, NH, 1H), 6.94 – 6.87 (overlapped, ArH, 4H), 6.65 (s, ArH, 2H),
6.51 (s, ArH, 2H), 5.16 (broad, COCHPhCH3, 1H), 4.15 (broad, OCH2CO,
2H), 4.00 (broad, ArCH2Ar, 2H), 3.88 (broad, ArCH2Ar, 4H), 3.33 (s,
OCH3, 3H), 3.20 (s, OCH3, 6H), 3.14 (broad, ArCH2Ar, 2H), 1.45 (broad,
CHPhCH3, 3H), 1.17 (s, C(CH3)3 9H), 1.14 (s, C(CH3)3, 9H), 0.98 (s,
C(CH3)3, 9H), 0.83 (s, C(CH3)3, 9H). 13C NMR (150 MHz, TCDE, 353 K):
δ 168.5, 155.1, 154.8, 152.0, 145.3, 144.3, 143.0, 134.6, 134.3, 132.7,
131.7, 128.7, 127.4, 126.2, 126.1, 125.5, 125.4, 125.3, 74.2, 60.4, 60.1,
49.6, 48.3, 34.0, 34.0, 33.7, 33.7, 31.7, 31.6, 31.4, 31.2, 29.7, 21.3. IR
(KBr): ṽ = 2961, 2928, 2867, 2819, 1734, 1684, 1659, 1653, 1540, 1521,
1507, 1481, 1458, 1447, 1392, 1362, 1300, 1219, 1122, 1048, 1023, 847,
870, 772 cm-1. HRMS (ESI+) m/z [M + Na]+ calcd for C57H73NNaO5,
874.5381; found 874.5391.
Compound 10.[20] CH3I (0.38 mL, 6.09 mmol) was added to
a
suspension of 8 (0.55 g, 0.61 mmol) and K2CO3 (0.34 g, 2.44 mmol) in
CH3CN (15 mL) at 0 °C. The reaction mixture was refluxed for 15 h. The
solvent was evaporated under reduced pressure and the crude product
was suspended in CH2Cl2 (30 mL) and washed with a 1N aqueous
solution of HCl (2 × 15 mL). The aqueous layer was extracted with
CH2Cl2 (3 × 10 mL). The collected organic layers were washed with H2O,
dried over Na2SO4 and evaporated. The crude product was triturated with
methanol, filtered and the solid was washed with cold methanol to give
the derivative 10 as a white solid (0.39 g, 70 % yield). Spectroscopic data
were consistent with those previously reported:[20] mp >250 °C dec; 1H
NMR (600 MHz, TCDE, 353 K): δ 6.96 (s, ArH, 2H), 6.88 (s, ArH, 2H),
6.64 (broad, ArH, 1H), 6.48 (broad, ArH, 1H), 6.43 (s, ArH, 2H), 4.64 –
4.62 (overlapped, OCH2 + ArCH2Ar, 4H), 4.54 (d, J = 12.6 Hz, ArCH2Ar,
2H), 4.37 (s, OCH2CO, 2H), 4.29 (s, OCH2CO, 2H), 4.12 (q, J = 7.2 Hz,
OCH2CH3, 4H), 4.00 (q, J = 7.2 Hz, OCH2CH3, 2H), 3.65 (s, OCH3, 3H),
3.05 (d, J = 12.6 Hz, ArCH2Ar, 4H), 1.18 – 1.16 (overlapped, C(CH3)3, +
OCH2CH3, 24H), 1.09 (t, J = 6.6 Hz, OCH2CH3, 3H), 0.81 (s, C(CH3)3,
18H). 13C NMR (150 MHz, TCDE, 353 K): δ 171.0, 169.7, 156.2, 156.1,
153.4, 145.5, 145.2, 135.1, 133.7, 132.5, 132.1, 132.0, 126.0, 125.7,
125.5, 125.3, 74.5, 72.3, 71.8, 60.7, 60.2, 51.5, 34.2, 34.1, 33.8, 32.4,
31.8, 31.6, 31.5, 14.4, 14.3, 14.3. (ESI+) m/z [M+Na]+: 943.5 Anal. Calcd
for C57H76O10: C, 74.32; H, 8.32. Found: C, 74.30; H, 8.34.
Compound 7. Oxalyl chloride (0.78 mL, 9.3 mmol) was slowly added to
a stirred solution of 11 (0.20 g, 0.24 mmol) in 10 mL of dry CHCl3 at 0 °C.
The reaction mixture was refluxed under nitrogen atmosphere for 15 h,
then was cooled at room temperature and the solvent was removed
under reduced pressure to give a white solid. The crude product was
Compound 11. [20] A suspension of NaOH (0.57 g, 14 mmol) in EtOH (4
mL) and H2O (3 mL) was added to a solution of 10 (0.44 g, 0.47 mmol) in
EtOH (14 mL). The reaction mixture was refluxed for 14 h. Then the
solvent was evaporated under reduced pressure and the crude product
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10.1002/ejoc.201700912
European Journal of Organic Chemistry
FULL PAPER
was triturated with a 1N aqueous solution of HCl, filtered and the solid
washed with cold H2O and dried in vacuo to give the derivative 11 as a
white solid (0.38 g, 96 %). Spectroscopic data were consistent with those
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a) P. Neri, J. L. Sessler, M.-X. Wang B., Eds., Calixarenes and Beyond,
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1
previously reported:[20] mp 248 −250 °C; H NMR (400 MHz, CDCl3, 298
K): δ 9.06 (broad, COOH, 3H), 7.16 (overlapped, ArH, 4H), 6.61
(overlapped, ArH, 4H), 4.86 – 4.75 (overlapped, ArCH2Ar + OCH2COOH,
6H), 4.56 (broad s, OCH2COOH, 2H), 4.28 (d, J = 12.8 Hz, ArCH2Ar, 2H),
3.79 (s, OCH3, 3H), 3.28 – 3.21 (overlapped, ArCH2Ar, 4H), 1.32 (s,
C(CH3)3, 18H), 0.85 (s, C(CH3)3, 18H). 13C NMR (100 MHz, CDCl3, 298
K): δ 173.4, 171.0, 151.0, 149.7, 147.0, 146.3, 145.8, 134.5, 134.1, 132.9,
131.9, 131.7, 125.9, 125.8, 125.4, 125.2, 72.0, 71.7, 63.3, 34.0, 33.6,
31.5, 31.3, 31.2, 30.9, 30.9, 30.5. HRMS (ESI+) m/z [M + K]+ calcd for
C51H64NaO10, 859.3818; found 859.4391.
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General procedure for the phase-transfer alkylation of N-
(diphenylmethylene)glycine tert-butyl ester (14) catalyzed by chiral
calix[arene]-amide 4. To a solution of N-(diphenylmethylene)glycine
tert-butyl ester 14 (148 mg, 0.50 mmol) and chiral catalyst 4 (28.8 mg,
0.025 mmol) in mesitylene (5.0 mL) under inert athmosphere, the alkyl
bromide (1.2-1.5 equiv.) was added. The mixture was degassed and then
brought to 0° C. Degassed 50 % aqueous NaOH (0.5 mL) was then
added. The reaction mixture was stirred at 0 °C until TLC disappearance
of the starting material. Then the suspension was diluted with CH2Cl2 (25
mL) and water (15 mL), and the organic layer was taken. The aqueous
layer was extracted twice with CH2Cl2 (25 mL × 2) and the combined
organic phases were dried over Na2SO4, filtered, and concentrated in
vacuo. Purification of the residue by flash column chromatography on
silica gel (petroleum ether−ethyl acetate: 98:2 to 90:10) afforded the pure
alkylated products. The characterization data of the known products 19a-
e matched those previously reported.[24a,28,30]
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Determination of Kassoc value Na+4 complex by competition
experiment. 1H NMR competition experiments were carried out on a
1:1:1 mixture of hosts 4 (1.9×10–3 M-1), 7 (1.9×10–3 M-1) and guest
NaTFPB (1.9×10–3 M-1) in CDCl3. The mixture was equilibrated for 3 days
at 298 K. Accordingly, a Ka value of 1.06±0.06×104 M‒1 was calculated for
Na+4 complex following a recently reported procedure (see supporting
information for further details).
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Acknowledgements
The authors acknowledge the Regione Campania (POR
CAMPANIA FESR 2007/2013 O.O.2.1, CUP B46D14002660009,
for the FT-ICR mass spectrometer facilities, and Farma-BioNet –
CUP B25C13000230007), the ‟Centro di Tecnologie Integrate
per la Salute” (CITIS, Project PONa3_00138), Università di
Salerno, for the 600 MHz NMR facilities.
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Keywords: Asymmetric catalysis • Alkylation • Calixarenes •
Cation recognition • Phase-transfer catalysis
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Entry for the Table of Contents
FULL PAPER
The recognition abilities of chiral
calixarenes hosts toward alkali
cation guests have been exploited
for the first time in asymmetric
phase-transfer catalysis. The
binding affinities of a series of α-
methylbenzylamine-derived
Supramolecular catalysis
Nicola Alessandro De Simone,
Rosaria Schettini, Carmen Talotta,
Carmine Gaeta, Irene Izzo, Giorgio
Della Sala,* and Placido Neri*
Page No. – Page No.
calix[4]arene-amides toward Na+
guest are consistent with their
catalytic efficiency in the
Directing the Cation Recognition
Ability of Calix[4]arenes Toward
Asymmetric Phase-Transfer
Catalysis
asymmetric alkylation of N-
(diphenylmethylene)-glycine esters
under phase-transfer conditions.
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