Synthesis of a calixarene-based chiral phase-transfer catalyst derived from cinchonine and its application in asymmetric alkylation

Article abstract of DOI:10.3184/174751912X13418247519819

The synthesis of a novel calixarene-based chiral phase-transfer catalyst derived from cinchonine has been achieved in four steps from p-t-butylcalix[4]arene. Its catalytic properties were evaluated over a range of conditions by carrying out the phase-tran

Full text of DOI:10.3184/174751912X13418247519819

532 RESEARCH PAPER
SEPTEMBER, 532–535
JOURNAL OF CHEMICAL RESEARCH 2012
Synthesis of a calixarene-based chiral phase-transfer catalyst derived
from cinchonine and its application in asymmetric alkylation
Li Huang, Can Jin and Weike Su*
Key Laboratory of Green PharmaceuticalTechnologies and Related Equipment of Ministry of Education, College of Pharmaceutical
Sciences, Zhejiang University ofTechnology, Hangzhou 310014, P. R. China
The synthesis of a novel calixarene-based chiral phase-transfer catalyst derived from cinchonine has been achieved
in four steps from p-t-butylcalix[4]arene. Its catalytic properties were evaluated over a range of conditions by carry-
ing out the phase-transfer alkylation of N-(diphenylmethylene)glycine t-butyl ester with benzyl bromide. Under the
optimal conditions the alkylated product was formed in 96% yield with 91% ee.
Keywords: calixarene, cinchonine, phase transfer catalyst, asymmetric alkylation reaction, chiral α-amino acids
The development of novel and efficient catalytic methodolo-
gies for asymmetric alkylation is important and asymmetric
phase transfer catalysts (APTC) have proved useful for the
successful achievement of that goal.1,2 There are many reports
of the use of simple derivatives of quinoline alkaloids as
APTCs, e.g. O’Donnells N-benzyl-cinchonine 6 (Fig. 1),2 and
recently cinchonine has been attached to a polymeric support
for the synthesis of α-amino acids.3,4 Furthermore, to achieve a
dual mode of phase-transfer catalysis, quinoline alkaloids have
been attached to an achiral catalyst such as a crown ether
to increase the enantiomeric excess, at the same time decreas-
ing the quantity required of the asymmetric phase transfer
catalyst.5
add 1,2-dibromoethane to 1 in the presence of NaH, LiH or
K2CO3 to produce 4 directly failed. When 1 was treated with
1.2 equiv. of 1,2-dibromoethane in MeCN using K2CO3 as
the base, unexpectedly, the known9 dimeric calixarene 10 was
produced (Scheme 2).
In order to investigate the catalytic activity of the calixarene-
based chiral phase-transfer catalyst derived from cinchonine 5,
we compared its performance with that of the chiral quaternary
ammonium salt6 under various conditions in the catalyst
for asymmetric benzylation of benzophenone derivative 7
(Scheme 3). The results are summarised in Table 1.
Compared with 62 or a mixture of calixarene and 6 (entries
7 and 8), the result at 0 °C was better when 5 was used as
APTC (entry 4). An initial attempt was made with 1 mol% of
5 in a biphasic system formed by a mixture of toluene/CHCl3
(7:3 v/v) and 50% aqueous KOH solution at 0 °C which yielded
the benzylated product 9 in 88% yield, but afforded low enan-
tioselectivity 32% ee (entry 1). When, the inorganic base was
changed to NaOH, the yield increased to 91% of 9 with 71%
ee (entry 2). This result showed that the enantioselectivity was
sensitive to the cation of the base and that the chelating ability
of 5 towards the sodium cation presumably plays a key role in
making the sodium chelate complex extract efficiently into the
organic phase as well as achieving enantiofacial differentiation
in the transition state. Maybe the sodium ion radius is similar
to that of the cavity present in calix[4]arene.
When, the amount of 5 was increased to 5%, 96% of 9 was
obtained with 91% of ee under the same reaction conditions
(entry 4). By contrast, with 20 mol% of 6 as the APTC, the
enantioselectivity was poor (entry 7). We used the binary
phase-transfer catalyst systems with the chiral phase-transfer
catalyst 6 and the calixarene as an achiral cocatalyst as the
PTC in the same reaction. When 20 mol% of 6 and 10 mol% of
calix[4]arene were used as the catalyst systems, it produced a
91% yield with 84% ee under the same reaction conditions
(entry 9). The result was better than when using 20 mol%
of 6 and 10 mol% of calix[6]arene as the catalytic systems
(compare entry 8 with entry 9). We surmised that the size of
the calixarene cavity played a vital role in the catalytic activity
and the enantioselectivity.
As is known, calixarenes possess phase transfer properties6
and both the phenolic (lower) rim and the non-phenolic (upper)
rim are easily functionalised.7 We therefore decided to design
a novel APTC consisting of two parts, one component being
a quinoline alkaloid as the functional chiral phase transfer
catalyst, and the other the scaffold of calixarene, as an achiral
phase transfer catalyst. The structure of the calixarene-based
chiral phase-transfer catalyst derived from cinchonine 5 that
we synthesized and tested as an APTC is shown in Fig. 1.
The synthetic route to the calixarene-based chiral phase-
transfer catalyst 5 is shown in Scheme 1. First, three phenolic
hydroxyl groups at the lower rim of 1 were protected through
benzyl groups to give known8 compound 2, which reacted with
1,2-dibromoethane in the presence of LiH in DMF/CH3CN
(2:1) easily to give the product 3 in good yield (70%). removal
of the benzyl ether groups of 3 by hydrogenolysis gave 4
successfully. Subsequent reaction of 4 with an excess of cin-
chonine was carried out in xylene at 140 °C for 8 h. Compound
5, a tetraethylammonium was bromide, was purified by column
chromatography and recrystallisation (yield 45%). Attempts to
The reaction temperature also affected the yield and the
enantioselectivity of the product. Lowering the reaction tem-
perature to –20 °C resulted in lower enantioselectivity and
a worse yield (entry 5), as did raising the reaction mixture
to 25 °C (entry 3). The reactions could not be improved by
prolonging the reaction time, but lead to more and more side
products. Finally, the enantioselectivity is related to the
concentration of the aqueous NaOH solution too. When the
concentration of the aqueous NaOH solution was reduced to
25%, the yield was almost unchanged but the ee was decreased
to 5% (entry 6).
Fig. 1 Chiral phase-transfer catalysts 5 and 6.
* Correspondent. E-mail: pharmlab@zjut.edu.cn

JOURNAL OF CHEMICAL RESEARCH 2012 533
Scheme 1 The synthesis of a calixarene-based chiral phase-transfer catalyst 5.
Scheme 2 The synthesis of a dimeric calixarene 10.
Scheme 3 Synthesis of α-alkyl-α-amino acid esters.
In summary, we have prepared a novel type of binary inte-
Experimental
grative phase-transfer catalyst that comprises p-t-butycalix[4]
arene and a cinchonine ammonium salt. This chiral super
molecule was successfully used as a catalyst for asymmetric
alkylation of an α-glycine derivative. The use of calixarene-
based cinchonine ammonium salts as chiral phase-transfer
catalysts may usefully be extended to other types of asymmet-
ric transformations.
All reagents were purchased from commercial suppliers and were
used without further purification. Melting points were measured on a
Buchi B-540 capillary melting point apparatus and are uncorrected.
The NMR spectra were measured with a Varian 400 instrument
(1H NMR at 400 Hz, 13C NMR at 100 Hz) using CDCl3 as solvent with
TMS as internal standard. IR spectra were recorded using KBr pellets
on a Nicolet Aviatar-370 instrument. Mass spectra were measured
with a Thermo Finnigan LCQ-Advantage. High resolution mass

534 JOURNAL OF CHEMICAL RESEARCH 2012
Table 1 Catalytic enantioselective phase-transfer benzylation
of 7 to 9 with chiral phase-transfer catalysts (PTC)
151.7, 145.5, 144.7, 144.2, 138.0, 137.4, 135.4, 135.2, 131.9, 131.9,
129.8, 129.2, 128.4, 127.9, 127.8, 127.5, 125.3, 124.6, 124.3, 78.0,
72.8, 34.2, 34.1, 33.7, 31.9, 31.8, 31.5, 31.2, 31.2, 31.1; MS (ESI):
m/s = 1047.3 [M+Na]+. HRMS-ESI: m/z (M++Na) Calcd for
C67H77BrNaO4: 1047.4903; found: 1047.4914.
Entry
PTC/mol%
T/°C
Base Yield of %eeb
/50%
9/%a (configc)
1
2
3
4
5
6
7
8
9
5(1)
0
0
25
0
KOH
NaOH
NaOH
NaOH
NaOH
NaOHd
NaOH
NaOH
NaOH
88
91
92
96
87
92
92
93
91
32(R)
71(R)
81(R)
91(R)
89(R)
86(R)
72(R)
79(R)
84(R)
Synthesis of 5,11,17,23-tetra-t-butyl-25-O-(2-bromoethyl)-calix[4]
arene (4); general procedure
5(1)
5(5)
5(5)
5(5)
5(5)
6(20)
Pd/C (10% w/w, 80 mg) was added to a solution of compound 3
(0.4 g, 0.39 mmol) in acetic acid (0.04 mL) and MeOH/THF (10mL:
5mL) and the resulting suspension stirred under a hydrogen atmo-
sphere (1 atm) for 24 h at 50 °C. The mixture was filtered through a
pad of Celite®, eluting with THF (50 mL), and the combined filtrates
were evaporated to provide compound 4 (0.28 g, 94%) as a white
solid: m.p. 172–173 °C; IR: νmax = 3335, 2961, 1485, 1204, 872 cm−1;
1H NMR δ 10.11 (s, 1H), 9.24 (s, 2H), 7.07 (s, 2H), 7.04–7.02 (m,
4H), 6.97 (m, 2H), 5.22 (s, 1H), 4.47 (t, J = 5.9, 2H), 4.38 (s, 1H), 4.35
(s, 1H), 4.28 (s, 1H), 4.24 (s, 1H), 3.99 (t, J = 5.9, 2H), 3.45 (s, 2H),
3.41 (s, 2H), 1.22–1.21 (m, 27H), 1.18 (s, 9H); 13C NMR δ 148.6,
148.3, 148.2, 147.5, 143.4, 143.0, 133.1, 128.1, 127.6, 127.4, 126.5,
125.7, 125.6, 125.5, 76.0, 34.3, 34.1, 34.0, 33.1, 32.3, 31.6, 31.3, 29.5;
MS (ESI): m/s=753.2 [M-H]−; HRMS-ESI: m/z (M++H) Calcd for
C46H60BrO4: 755.3675; found: 755.3603.
–20
0
0
6(20) Calix[6]arene(10)
6(20) Calix[4]arene(10)
0
0
a Isolated yields.
b Enantiomeric excess was determined by HPLC analysis using
a chiral column (Daicel Chiralcel OD-H) using hexane/isopropa-
nol (99:1) as an eluent.
c The absolute configuration was determined by comparison of
the measured specific rotation values of product 9 with that
given in the literature.
d The concentration of the aqueous NaOH solution was 25%.
spectral (HRMS) analysis was determineded on a Bruker micrOTOF-
QII using ESI techniques. The HPLC analyses were carried out
using an Agilent 1100 apparatus equipped with Daicel Chiralcel
OD-H column (conditions: n-hexane/isopropanol (99:1), flow rate:
0.6 mL min−1, detection λ = 250 nm). A racemic sample was prepared
using n-tetrabutylammonium bromide as a phase-transfer catalyst for
HPLC analysis.
Synthesis of 5; general procedure
A mixture of cinchonine (1.48 g, 5 mmol) with 4 (0.38 g, 0.5 mmol)
in xylene (7 mL) was stirred at 140 °C for 8 h. After cooling the reac-
tion mixture to room temperature, the suspension was filtered off and
the solid dissolved in MeOH (30 mL) after which the turbid solution
was filtered over a pad of Celite®. The solvent was then distilled off,
and the oily residue was subjected to column chromatography
(CH2Cl2/MeOH = 30:1 eluent). The crude product was recrystallised
from Et2O/CH2Cl2 to afford 5 (0.24 g, 45%) as a dark brown solid:
m.p. 203–204 °C; IR: νmax = 3426, 2953, 1620, 1462, 773 cm−1; [α]2D5 =
+180 (c = 0.2, MeOH); 1H NMR δ 8.85 (d, J = 4.4, 2H), 8.05 (d, J =
8.2, 2H), 7.94 (d, J = 8.4, 2H), 7.70 (d, J = 4.4, 2H), 7.48 (d, J = 8.1,
2H), 7.26–7.20 (m, 5H), 6.45 (s, 2H), 6.11–5.99 (m, 2H), 5.24–5.13
(m, 3H), 4.13 (d, J = 9.3, 2H), 3.27 (m, 6H), 3.02 (m, 2H), 2.50 (d, J
= 8.9, 2H), 2.41–2.28 (m, 2H), 1.93 (s, 1H), 1.82 (s, 2H), 1.70–1.57
(m, 2H), 1.35 (s, 9H), 1.33 (s, 18H), 1.31 (s, 9H), 1.06 (s, 2H); 13C
NMR δ 149.9, 149.8, 149.7, 149.4, 146.9, 143.6, 142.6, 137.6, 129.7,
129.5, 128.2, 127.6, 125.8, 125.0, 124.2, 123.8, 120.7, 115.7, 80.3,
65.9, 65.7, 63.9, 61.2, 53.3, 41.3, 38.9, 31.4, 30.5, 26.3, 23.9, 19.8;
MS (ESI): m/s = 1047.2 [M-H]−; HRMS-ESI: m/z (M−-H) Calcd for
C65H80BrN2O5: 1047.5251; found: 1047.5259.
synthesis of 5,11,17,23-tetra-t-butyl-26,27,28-tri-O-benzyloxycalix[4]
arene (2); general procedure
p-t-Butyl-calix[4]arene 1 (1.0 g, 1.5 mmol), BaO (1.6 g, 10.5 mmol)
and Ba(OH)2·8H2O (1.7 g, 5.39 mmol) were dissolved under nitrogen
in DMF (20 mL) for 30 min. Then (chloromethyl)benzene (3.78 g,
30 mmol) was added and the mixture was stirred under nitrogen for
8 h. H2O (60 mL) was added and the mixture was stirred for 10 more
minutes. The aqueous layer was extracted by CH2Cl2 (3×30 mL).
The organic layer was washed with brine (30 mL) and with H2O
(2×20 mL) (pH 9), dried over Na2SO4, filtered and evaporated. The
obtained solid was dissolved in ethyl acetate (20 mL) and filtered. The
filtrate was evaporated to give the crude product which was purified
by recrystallisation from CH2Cl2/MeOH to give 2 (1.17 g, 85%) as
white crystals: TLC: eluant (n-hexane/ethyl acetate: 30:1); m.p. 200–
203 °C, [lit.8 207–209 °C]; 1H NMR δ 7.45 (d, J = 7.0, 2H), 7.30–7.22
(m, 12H), 7.19 (dd, J = 12.8, 5.4, 3H), 7.02 (d, J = 35.5, 4H), 6.55 (d,
J = 1.6, 2H), 6.50 (d, J = 1.6, 2H), 6.32 (s, 1H), 4.92 (s, 2H), 4.62 (q,
J = 11.6, 4H), 4.15 (dd, J = 15.2, 13.0, 4H), 3.03 (d, J = 13.2, 2H),
2.96 (d, J = 12.8, 2H), 1.31 (s, 9H), 1.29 (s, 9H), 0.83 (s, 18H); 13C
NMR δ 153.0, 150.7, 150.6, 145.3, 145.1, 140.9, 138.2, 137.3, 135.6,
132.3, 132.0, 129.2, 128.6, 128.5, 128.0, 127.6, 127.4, 126.9, 125.3,
124.7, 77.5, 75.9, 34.1, 33.8, 33.7, 31.8, 31.7, 31.6, 31.3, 31.1.
MS(ESI): m/s = 917.4 [M-H]−.
Synthesis of a dimeric calixarene; general procedure
10: 1 (1.0 g, 1.5 mmol) and K2CO3 (0.69 g, 5 mmol) were dissolved
under nitrogen in MeCN (20 mL) for 30 min. Then 1,2-dibromoeth-
ane (0.34 g, 1.8 mmol) was added and the mixture was stirred at 80 °C
under nitrogen for 8 h. H2O (60 mL) was added and the mixture was
stirred for 10 more minutes. The aqueous layer was extracted by
CH2Cl2 (3×30 mL). The organic layer was then washed with brine
(30 mL) and with H2O (2×20 mL), dried over Na2SO4, filtered and
evaporated. The obtained solid was dissolved in CH2Cl2 (20 mL) and
filtered. The filtrate was evaporated to give a crude product that was
purified by recrystallisation from CH2Cl2/MeOH to give 10 (0.51 g,
50%) as white crystals: TLC: eluant: n-hexane/ethyl acetate 30:1;
m.p. > 400 °C, [lit.9 > 300 °C]; 1H NMR δ 7.64 (s, 4H), 6.99 (s, 8H),
6.85 (s, 8H), 4.60 (s, 8H), 4.51 (d, J = 12.8, 8H), 3.36 (d, J = 12.9,
8H), 1.26 (s, 36H), 0.99 (s, 36H); 13C NMR δ 151.3, 150.9, 146.5,
146.3, 140.7, 132.3, 127.7, 125.5, 124.8, 77.2, 75.9, 34.0, 33.9, 32.5,
31.8, 31.5, 31.2; MS (ESI): m/s = 1387.1 [M+K]+.
Synthesis of 5,11,17,23-tetra-t-butyl-25-O-(2-bromoethyl)-26,27,28-
tri-O-benzyloxycalix[4]arene (3); general procedure
LiH (0.006 g, 0.75 mmol) was added to a suspension of 2 (0.59 g,
0.645 mmol) in DMF (15 mL) and the reaction mixture was stirred at
55 °C for l h until a clear solution was obtained. Then 1,2-dibromoeth-
ane (1.21 g, 6.45 mmol, 10 eq.) was added and the mixture was stirred
for 10 h at the same temperature. H2O (40 mL) was added and the
mixture was stirred for 10 more minutes. The aqueous layer was
extracted by CH2Cl2 (3×30 mL). The organic layer was then washed
with brine (30 mL) and with H2O (2×20 mL), dried over Na2SO4,
filtered and evaporated. After evaporation of the solvent the residue
was submitted to column chromatography (SiO2, CHCl3-n-hexane =
l:3) to yield some starting compound 2 (0.05 g) and 3 (0.46 g, 70%)
as white crystals: m.p. 188.7–190.1 °C; IR: νmax = 2961, 1479, 1193,
696 cm−1; 1H NMR δ 7.34 (s, 10H), 7.19 (t, J = 7.4, 3H), 7.08 (d, J =
7.7, 2H), 7.03 (d, J = 8.6, 4H), 6.49 (d, J = 2.0, 2H), 6.35 (d, J = 1.9,
2H), 4.80 (s, 2H), 4.63 (d, J = 10.8, 2H), 4.53 (d, J = 10.8, 2H), 4.18
(s, 1H), 4.16 (s, 1H), 4.15 (s, 1H), 4.13 (s, 1H), 4.06–4.06 (m, 2H),
3.90–3.86 (m, 2H), 2.98 (s, 1H), 2.96 (s, 1H), 2.94 (s, 1H), 2.93 (s,
1H), 1.33 (s, 9H), 1.29 (s, 9H), 0.82 (s, 18H); 13C NMR δ 153.5, 153.1,
Synthesis of t-butyl 2-(diphenylmethyleneamino)-3-phenylpropanoate
(9); general procedure
To t-butyl-2-(diphenylmethyleneamino) acetate 7 (50 mg, 0.17 mmol),
and 5 (8.9mg, 8.5×10−3 mmol) were added toluene/CHCl3 (7:3 v/v)
(0.40 mL) and benzyl bromide 8 (34 mg, 0.2 mmol, 1.2 equiv.). Then,
a 1.5 cm egg-shaped magnetic stir bar was placed in the vial which
was then transferred to a cold room at 0 °C. The reaction mixture was
allowed to equilibrate for at least 1 h with stirring. Lastly, 50% aq.
NaOH (0.02 mL) was added and the mixture was stirred at 0 °C for
2 h. The suspension was diluted with ether (20 mL), washed with
water (2×5 mL), dried over MgSO4, filtered, and solvent evaporated

JOURNAL OF CHEMICAL RESEARCH 2012 535
under reduced pressure; thereby excess benzyl bromide was also
removed. The crude product was passed through a short silica column
using n-hexane/ethyl acetate (45:1) as an eluent to remove chiral
catalysts to afford the desired product 9 as a colourless oil. 1H NMR
δ 7.55 (d, J = 7.2, 2H), 7.37–7.25 (m, 9H), 7.37–7.27 (m, 3H), 7.03 (d,
J = 7.3, 2H), 6.58 (d, J = 6.6, 2H), 4.09 (dd, J = 9.2, 4.2, 1H), 3.28–
3.10 (m, 2H), 1.44 (s, 9H); 13C NMR δ 170.6, 170.1, 139.4, 138.2,
136.2, 129.9, 129.7 (2C), 128.6 (2C), 128.0, 127.9 (2C), 127.9 (2C),
127.8 (2C), 127.5 (2C), 126.0, 81.1, 67.9, 39.7, 28.2 (3C); MS (APCI):
m/s = 386.0 [M+H]+. The enantiomeric excess of the product was
determined by chiral HPLC analysis [Daicel Chiralcel OD-H column,
hexane:isopropanol (99:1), flow rate = 0.6 mL min−1, 23°C, λ = 250 nm,
retention times R (major) 12.31 min, S (minor) 16.26 min and found
to be 91% ee.
Received 12 May 2012; accepted 17 June 2012
Paper 1201306 doi: 10.3184/174751912X13418247519819
Published online: 28 August 2012
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for financial support.

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