The Synthesis of Hydrobenzoin-Based Monoaza Crown Ethers and Their Application as Recyclable Enantioselective Catalysts

Article abstract of DOI:10.1007/s10562-019-03013-0

Abstract: New recyclable monoaza-15-crown ethers have been synthesized starting from (R,R)-(+)- and (S,S)-(?)-hydrobenzoin. These macrocycles proved to be efficient and reusable phase transfer catalysts in a few asymmetric reactions under mild conditions.

Full text of DOI:10.1007/s10562-019-03013-0

Catalysis Letters
https://doi.org/10.1007/s10562-019-03013-0
The Synthesis of Hydrobenzoin‑Based Monoaza Crown Ethers
and Their Application as Recyclable Enantioselective Catalysts
1
1
1
1
1
1
Tamás Nemcsok · Zsolt Rapi · Péter Bagi · Attila Oláh · György Keglevich · Péter Bakó
Received: 17 July 2019 / Accepted: 15 October 2019
©
The Author(s) 2019
Abstract
New recyclable monoaza-15-crown ethers have been synthesized starting from (R,R)-(+)- and (S,S)-(−)-hydrobenzoin. These
macrocycles proved to be eꢀcient and reusable phase transfer catalysts in a few asymmetric reactions under mild conditions.
The asymmetric epoxidation of trans-chalcone took place with up to 81% ee, while using other chalcone derivatives, the
products were formed with 68–88% ee. The hydrobenzoin-based lariat ethers were also tested in the cyclopropanation of
a few electron deꢁcient oleꢁns using diethyl bromomalonate to aꢂord the product with good enantioselectivities (54–75%
ee). The catalysts were recovered by salt formation, followed by extraction, and were reused without the loss of the activity
and eꢂect on the enantioselectivity.
Graphic Abstract
The synthesis of hydrobenzoin-based monaza crown ethers and their application as recyclable enantioselective catalysts.
O
O
∗
Ar1
∗
O
O
Ar2
∗
∗
Ph
Ph
O
O
ee
6
8-88%
N
R
O
COOEt
COOEt
∗
crown
recyclable
catalysts
Ph
O
up to 75% ee
1
Introduction
shortcomings that the recovery of the catalyst is not solved,
or cumbersome puriꢁcation (e.g. chromatography) has to be
used. Recently, in response to economy and sustainability con-
cerns, an increasing attention has been paid to process intensi-
ꢁcation, elimination of harmful substances, waste reduction,
and recycling of the solvents and catalysts. Therefore, the
design of recyclable chiral phase transfer catalyst is a challeng-
ing area in current organic chemistry. For this purpose, sev-
eral polymer-supported chiral ammonium salt-type catalysts
derived mostly from cinchona alkaloids have been synthesized
Asymmetric phase transfer catalysis has become a topic of
great scientiꢁc interest in the last 30 years. A great num-
ber of chiral catalysts have been synthesized and used with
excellent enantioselectivities in different reactions [1–8].
Despite all advantages, most of the applied methods have the
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s10562-019-03013-0) contains
supplementary material, which is available to authorized users.
[
9–16]. However, the enantioselectivity achieved by most of
*
Péter Bakó
these catalysts decreased as compared to the nonsupported
derivatives. To avoid this decrease in the selectivity, a few
recyclable homogenous catalysts have also been developed. A
binaphthyl-based ꢃuorous phase transfer catalyst has been used
pbako@mail.bme.hu
1
Department of Organic Chemistry and Technology,
Budapest University of Technology and Economics, PO
Box 91, 1521 Budapest, Hungary
Vol.:(0
1
123456789)
3

T. Nemcsok et al.
by Maruoka et al. in the synthesis of a few amino acids with
high enantioselectivities [17]. This ꢃuorinated catalyst was
regenerated by extraction with a ꢃuorous solvent, however,
the scale up of this method is problematic due to the high price
of the ꢃuorinated reagents and solvents. Nájera et al. applied a
cinchona-derived dimeric ammonium salt that provided a good
enantioselectivity, and it was possible to recover the catalyst
almost quantitatively by precipitation in ether [18].
(R,R)- and (S,S)-hydrobenzoin (Scheme 1) [41, 42]. The
vicinal hydroxy groups of diol 1 were alkylated with bis(2-
chloroethyl) ether in the presence of 50% aq. NaOH and
tetrabutylammonium hydrogensulphate to give intermediates
(R,R)-2 and (S,S)-2 in 64% and 68% yield after chroma-
tography. The exchange of chlorine to iodine in bischloro
compounds (R,R)-2 and (S,S)-2 was accomplished by reac-
tion with NaI in boiling acetone in excellent yields (93%
and 95%, respectively). Bisiodo compound (R,R)-3 was
then cyclized with four diꢂerent amines (3-aminopropan-
1-ol, 3-methoxypropylamine, 2-(2-methoxyphenyl)ethyl-
amine and 2-(3,4-diethoxyphenyl)ethylamine, respectively)
in boiling acetonitrile in the presence of Na CO to aꢂord
Chiral crown ethers have also been used in enantioselective
syntheses as phase transfer catalysts [19]. Macrocycles derived
from binaphtol, [20, 21] carbohydrates, [22–26] spirobiindane
[
27] and other chiral diols [28–31] have all been used eꢀ-
ciently in diꢂerent asymmetric reactions. In our group, mono-
aza-15-crown-5-type lariat ethers incorporating a carbohydrate
unit were synthesized [32, 33]. These macrocycles generated
high asymmetric induction in certain model reactions [34–37].
Although chiral crown compounds have been widely used as
phase transfer catalysts, to the best of our knowledge, none
of these catalysts were reusable. Monoaza crown ethers have
the advantage that they can be regenerated by salt formation,
followed by extraction. This recovery technique is known for
achiral monoaza crown ethers [38]. Our most eꢀcient mon-
oaza-type catalysts all had acid sensitive functional groups,
therefore, this type of recovery attempt has not been successful
so far. We intended to develop new chiral crown ether cata-
lysts, which can be recovered by the simple method mentioned.
Herein, we wish to report the synthesis and application of
a few recyclable hydrobenzoin-based monoaza-15-crown-5
ethers. Enantiopure (R,R)- and (S,S)-hydrobenzoin have been
extensively used in asymmetric syntheses as chiral ligands,
auxiliaries, and chiral building blocks because of their easy
availability and relatively low price, as compared to other
chiral diols [39] We assumed that a diol with bulky aro-
matic groups would be the best choice as a starting mate-
rial, since both steric and π-π interactions may enhance the
enantioselectivity of the catalyst. Crown ethers derived from
hydrobenzoin have already been reported [40]. These macro-
cycles generated good enantioselectivites in the asymmetric
reduction of aromatic ketones with ammonia-borane com-
plexes [30, 31], but only moderate results were obtained
in a Michael addition [29]. As monoaza-type crown ethers
starting from hydrobenzoin have not been prepared so far,
we intended to synthesize a few such derivatives, with vari-
ous side arms, and test their catalytic eꢂect, and also their
reusability.
2
3
azacrown ethers (R,R)-4a-d after chromatography in yields
of 52–68%. Previously, these side arms proved to be eꢀ-
cient in terms of enantioelectivity when they were attached
to carbohydrate-based monoaza crown ethers [43, 44]. The
(S,S)-3 intermediate was reacted only with 3-aminopropan-
1-ol and 2-(3,4-diethoxyphenyl)ethylamine, because these
two side chains proved to be the most eꢂective according
to experiments with macrocycles (R,R)-4a-d. Thus, six new
hydrobenzoin-based monoaza crown ethers have been syn-
thesized, of which (S,S)-4a and (R,R)-4a and also (S,S)-4c
and (R,R)-4c are pairs of enantiomers, therefore the outcome
of the asymmetric reactions may be inꢃuenced by choosing
the proper enantiomer of the catalyst.
2.2 Asymmetric Reactions Catalyzed by Lariat
Ethers
The new hydrobenzoin-based catalysts were applied in a few
asymmetric reactions to test their ability to induce enanti-
oselectivity. Besides synthesizing the products in high opti-
cal purity, we also tried to turn these model reactions more
eco-friendly by choosing green solvents, using minimum
amounts of the reagents and catalyst, and by recycling the
catalyst after the reactions. The crude products were puriꢁed
by preparative TLC. Enantiomeric excess of the products
was determined by chiral HPLC analysis.
One of the model reactions was the asymmetric epoxida-
tion of trans-chalcone (5a) and its derivatives. Chiral epox-
ides are useful intermediates in organic synthesis, prone
to react with a variety of nucleophilic reagents aꢂording
intermediates and precursors in the preparation of enanti-
omerically pure bioactive compounds [45–48]. Although the
asymmetric synthesis of epoxides 6 was reported applying
diꢂerent catalysts [49, 50], only a part of these methods used
a recyclable catalyst [51–54], and even less examples can be
found, when the activity of the catalyst did not decrease after
the recyclings [55–57].
2
Results and Discussion
2.1 Synthesis of Hydrobenzoin‑Based Lariat Ethers
First, we tested the new hydrobenzoin-based catalysts
(R,R)-4a-d under the reaction conditions reported by our
group using carbohydrate-based crown ethers [58] with
The synthesis of monoaza-15-crown ethers was performed
according to the protocol elaborated earlier, starting from
1
3

The Synthesis of Hydrobenzoin-Based Monoaza Crown Ethers and Their Application as Recyclable…
Scheme 1 The synthesis of
hydrobenzoin-based crown
ethers ((R,R)-4a–d, (S,S)-4a and
(
S,S)-4c)
some modiꢁcations (Table 1, entries 1–4). Less catalyst
the enantioselectivities and/or the yields were signiꢁcantly
lower as compared to tBuOOH. Among catalysts (R,R)-
4a–d, only crown ether (R,R)-4a with hydroxypropyl side
arm generated a signiꢁcant asymmetric induction (80% ee).
Using the other three derivatives ((R,R)-4b–d), product 6a
(
(
5 mol%), and only 1.3 equivalents of the oxidizing agent
tert-butylhydroperoxide) were used in a toluene—20% aq.
NaOH two phase system. Other oxidizing agents such as
H O , NaOCl and mCPBA were tested earlier, however,
2
2
Table 1 Optimization of the reaction conditions and screening the catalyst in the asymmetric epoxidation of trans-chalcone (5a)
solvent
tBuOOH (1.3 eqv.)
O
O
O ∗
∗
2
0% aq.NaOH
catalyst (5 mol%)
5
a
6a
Entry
Catalyst
Time (h)
Solvent
T (°C)
Yield (%)
ee (%)a
1
2
3
4
5
6
7
8
9
(R,R)-4a
(R,R)-4b
(R,R)-4c
(R,R)-4d
(R,R)-4a
(R,R)-4a
(R,R)-4a
(R,R)-4a
(S,S)-4a
4
4
5
6
5
5
4
10
4
Toluene
Toluene
Toluene
Toluene
CH Cl
25
25
25
25
25
25
25
0
89
81
90
85
81
83
88
83
90
80 (2S,3R)
15 (2S,3R)
8 (2S,3R)
6 (2S,3R)
56 (2S,3R)
77 (2S,3R)
81 (2S,3R)
81 (2S,3R)
79 (2R,3S)
2
2
Et O
2
MTBE
MTBE
MTBE
25
aBased on chiral HPLC, the absolute conꢁguration was assigned by comparison of the speciꢁc rotations with literature data [59]
1
3

T. Nemcsok et al.
was obtained with low enantioselectivities (6–15%). In all
cases complete diastereoselectivity was observed. The sig-
niꢁcant diꢂerence between the catalytic activities is cur-
rently unclear. Similar phenomenon has been observed ear-
lier in the case of other crown compounds when catalysts
with hydroxypropyl side chain performed better than their
methoxypropyl analogues [33, 37, 43].
It can be concluded from Table 2 that neither the yield
(71–93%), nor the enantioselectivity (68–88% ee) changed
drastically, and in a few cases even slightly better results
were obtained as compared to those observed with the
unsubstituted chalcone (88% yield, 81% ee). The chloro-
substituted products were formed in good yields and with
70–88% ee (Table 2, entries 1–5). The degree of asymmet-
ric induction was slightly inꢃuenced by the position of the
Thereafter, we tested the inꢃuence of diꢂerent solvents
using catalyst (R,R)-4a (Table 1, entries 5–7). In dichlo-
romethane, the enantioselectivity was lower (56%), while
the experiments carried out in diethyl ether or methyl tert-
butyl ether (MTBE) led to similar results (77% ee and 81%
ee, respectively) obtained in toluene (80% ee). The yield
of epoxyketone 6a was not signiꢁcantly inꢃuenced by the
solvent. Considering the green chemical principles, MTBE
was chosen as the solvent in the next experiments. Finally,
we investigated the eꢂect of the temperature on the course of
the reaction (Table 1, entry 8). When the reaction was per-
formed at 0 °C, an increased reaction time of 10 h (instead
of 4 h) was needed, but this change did not increase the
enantioselecivity (81%). Using the other enantiomer (S,S)
of catalyst 4a, almost the same enantiomeric excess (79%)
was observed, but, as expected, this occasion the other enan-
tiomer (2R,3S) of the product was formed (Table 1, entry 9).
After exploring the optimized protocol for the enanti-
oselective epoxidation, we investigated the generality and
the scope of this methodology. The oxidation of a variety
2
chlorine atom in the phenyl ring (Ar ). When the Cl atom
was in ortho position, the enantioselectivity was somewhat
lower (6b: 75% ee, 6e: 70% ee) as compared to the meta
and para substituted derivatives (6c: 85% ee, 6d: 83% ee).
The highest enantioselectivity (88% ee) was observed in
case of product 6f, when the Cl atom was in the other phe-
1
nyl ring (Ar ) in para position. The methyl group did not
have an inꢃuence on the outcome of the reaction (Table 2,
1
2
entries 6, 7). Product 6g (Ar = Ph, Ar = 3-Me-C H ) and
6
4
1
2
6h (Ar = 4-Me-C H , Ar = Ph) were both formed with
6
4
79% ee. The experiment with para nitro substituted chal-
2
cone 5i (Ar = 4-NO –C H ) resulted with an ee value of
2
6
4
74% (Table 2, entry 8). Somewhat weaker enantioselectiv-
1
ity (68%) was observed in case of chalcone 5j (Ar = Ph,
2
Ar = piperonyl) (Table 2, entry 9). The enantioselective
epoxidation catalyzed by (R,R)-4a was also performed
with the structurally similar, but cyclic 2-benzylidene-
1-indanone (5k) and 2-benzylidene-1-tetralone (5l). High
enantiomeric excess (86%) was observed in case of the
oxidation of 2-benzylidene-1-tetralone (5l), while the
experiment with 2-benzylidene-1-indanone (5k) led to
1
of chalcone derivatives with diꢂerent substituents (Ar or
2
Ar ) in the aromatic rings (5b–k) were studied (Table 2).
Table 2 Generality of catalyst (R,R)-4a in the asymmetric epoxidation of chalcone derivatives (5b–m)
MTBE
tBuOOH (1.3 eqv.)
O
O
O ∗
Ar1
Ar2
Ar1
2
0% aq. NaOH
∗
Ar2
(
R,R)-4a (5 mol%)
5b-m
6b-m
Entry
Ar1
Ar2
Time (h)
Yield (%)
ee (%)a
1
2
3
4
5
6
7
8
9
C H
2-Cl-C H
10
7
5
3
5
6
8
24
10
24
24
6b: 76
6c: 88
6d: 93
6e: 85
6f: 89
6g: 79
6h: 86
6i: 80
6j: 86
6k: 71
6l: 75
75 (2S,3R)
85 (2S,3R)
83 (2S,3R)
70 (−)
88 (2S,3R)
79 (2S,3R)
79 (2S,3R)
74 (2S,3R)
68 (+)
6
5
5
5
5
6
4
4
4
C H
3-Cl-C H
6
6
C H
4-Cl-C H
6
6
C H
2,6-diCl-C H
6
6
3
4-Cl-C H
C H
6
4
6
5
C H
3-Me-C H
6
5
6
4
4-Me-C H
C H
6
4
6
5
C H
4-NO -C H
6
5
2
6
4
C H
Piperonyl
6
5
10
1
2-benzylidene-1-indanone
2-benzylidene-1-tetralone
76 (+)
86 (2S,3′R)
1
aBased on chiral HPLC, the absolute conꢁgurations were assigned by comparison of the speciꢁc rotations with literature data [60–62]
1
3

The Synthesis of Hydrobenzoin-Based Monoaza Crown Ethers and Their Application as Recyclable…
somewhat lower selectivity (76% ee) (Table 2, entries 11,
2).
The reusability of catalyst (R,R)-4a was also investigated
Table 3 Recycling of catalyst (R,R)-4a in the asymmetric epoxidation
of trans-chalcone (5a)
1
Number of uses
1
2
3
4
5
in the epoxidation of chalcone 5a. The recovery technique
was summarized in Scheme 2. After completion of the reac-
tions, the monoaza crown ether (R,R)-4a was transformed
to its hydrochloride salt with 10% aq. HCl, and extracted
several times with HCl solution. Then, sodium hydroxide
was added to the aqueous layer until the pH turned basic (pH
Yield (%)
ee (%)
87
80
89
81
88
81
90
78
86
81
a
aBased on chiral HPLC
8
–9), and the liberated azacrown ether was extracted with
S conꢁguration in all cases, was formed with moderate
enantioselectivities (55–63%), and in good yields (74–83%)
regardless of the side chain. The best result was obtained
using crown ether (R,R)-4c with a 3,4-diethoxyphenethyl
side arm (Table 4, entry 3), therefore the further experiments
were carried out with this catalyst. Next, the eꢂect of the sol-
vent was investigated (Table 4, entry 5–9). After testing six
diꢂerent solvents, it may be concluded that the nature of the
solvent has a strong inꢃuence on the asymmetric induction.
MTBE. Finally, the organic layer was concentrated, and the
catalyst was dried in a desiccator for 24 h. The recovered
catalyst was then reused in the next experiment.
The results of the repeated uses are summarized in
Table 3, from which one can see that neither the enantiose-
lectivity (78–81%) nor the yields (86–90%) changed much
even after the ꢁfth cycle. Applying the above-mentioned
method, catalyst (R,R)-4a was recovered with good yields
1
(
95–98%) and high purity (checked by H NMR). The slight
Ether type solvents (Et O and MTBE) proved to be the best
2
loss of the catalyst was compensated with the addition of
unused (R,R)-4a.
(63% and 64% ee), whereas in dichloromethane, hexane or
ethyl acetate, the enantioselectivities were much lower (30%,
40% and 44%, respectively). However, the yield of cyclo-
propane 9 did not depend much on the diꢂerent solvents
(78–86%). Again, considering green chemical principles,
MTBE was chosen for further investigations.
Thereafter, the hydrobenzoin-based crown compounds
(
4) were tested in some MIRC (Michael-initiated ring clo-
sure) reactions, in which an electron deꢁcient oleꢁn reacts
with diethyl bromomalonate (8) aꢂording cyclopropane
derivatives. Chiral cyclopropanes are prevalent in natural
products and bioactive compounds [63–66]. Moreover, they
can be easily transformed to other important optically active
compounds as the consequence of the easy ring cleavage of
the strained cyclopropane moiety [67–69]. Recently, much
attention was payed to the enantioselective synthesis of
cyclopropanes, [70–72] however, only a few of the reported
methods applied chiral phase transfer catalysts [73–77].
First, the reaction conditions were optimized, and the
eꢂect of catalysts was evaluated. The MIRC reaction of
Eventually, the reaction was performed at 0 °C (Table 4,
entry 10), resulting in spiro compound 9 with a better enan-
tiomeric excess (75%). Carrying out the reaction at −20 °C
the conversion remained incomplete (Table 4, entry 11).
While in the presence of lariat ether (R,R)-4c the S isomer
of cyclopropane derivative 9 was formed in 75% ee, catalyst
(S,S)-4c induced the formation of the opposite R isomer with
almost the same enantiomeric excess (72%). This method-
ology seems to be superior as compared to the previously
reported synthetic method of compound 9, [77–79] since
less catalyst was used (5 mol % instead of 10 mol % and
50 mol %), slightly better ee values were observed, and the
recovery of the catalyst may be solved.
2
-benzylidene-1,3-indandione (7) and diethyl bromom-
alonate (8) was chosen as the model reaction to test the
utility of catalysts (R,R)-4a–d (Table 4, entries 1–4) [78,
7
9]. The reactions took place in diethyl ether using Na CO
After the cyclopropanation of starting material 7, the
recovery of catalyst 4c was also investigated using the
above described method. The experiment was repeated ꢁve
times with the recovered catalyst (the loss was compen-
sated), and the results conꢁrmed that macrocycle 4c can
2
3
as the base, and 5 mol % of the catalyst in 1–2 h. In this
instance, the side arm of lariat ethers (R,R)-4a–d did not
have a signiꢁcant eꢂect on the enantioselectivity as com-
pared to the above-mentioned epoxidation. Product 9, with
Scheme 2 Recovery of catalyst
(
R,R)-4a by salt formation fol-
lowed by extraction
1
3

T. Nemcsok et al.
Table 4 Optimization of the reaction conditions and screening the catalyst in the asymmetric MIRC reaction of 2-benzylidene-1,3-indandione
(
7) and diethyl bromomalonate (8)
O
O
O
COOEt
COOEt
EtOOC
COOEt
Solvent
+
Ph
Na CO3
Br
2
O
Ph
catalyst (5 mol%)
7
8
9
Entry
Catalyst
Solvent
T (°C)
Time (h)
Yield (%)
ee (%)a
1
2
3
4
5
6
7
8
9
(R,R)-4a
(R,R)-4b
(R,R)-4c
(R,R)-4d
(R,R)-4c
(R,R)-4c
(R,R)-4c
(R,R)-4c
(R,R)-4c
(R,R)-4c
(R,R)-4c
(S,S)-4c
Et O
25
25
25
25
25
25
25
25
25
0
2
2
1
1
2
3
2
6
1
3
24
3
83
81
80
74
81
78
86
78
82
83
28
81
58 (S)
55 (S)
63 (S)
58 (S)
30 (S)
55 (S)
44 (S)
40 (S)
64 (S)
75 (S)
78 (S)
72 (R)
2
Et O
2
Et O
2
Et O
2
CH Cl
2
2
toluene
EtOAc
hexane
MTBE
MTBE
MTBE
MTBE
1
1
1
0
1
2
−20
0
aBased on chiral HPLC, the absolute conꢁguration was assigned by comparison of the speciꢁc rotations with literature data [78]
be reused without any decrease in its activity or selectivity.
Product 9 was obtained in a yield of 75–84% and with an ee
of 71–75%. At the same time, the yield of the recovery was
somewhat lower (73–83%) for catalyst 4c as compared to
species 4a, that can be explained by the higher lipophilicity
of macrocycle 4c.
respectively). Both lower and higher enantioselectivities
were reported earlier for the preparation of compound 11a
[36, 77]. A 80% ee was described by Cobb et al. for the syn-
thesis of the dimethyl analogue of product 11c [80]. How-
ever, in these cases, the catalyst could not be reused; moreo-
ver, halogenated solvents, or solvent mixtures were used,
that make these methods less valuable from the point of
view of scaling up. Using the appropriate catalyst ((S,S)-4c
or (R,R)-4c), the desired enantiomer of the product could be
prepared with approximately the same enantiomeric excess
and yield.
Having the optimized reaction conditions in hand, addi-
tional, less studied MIRC reactions were performed [77,
8
0, 81]. Electron deꢁcient oleꢁns 10a–c were reacted with
diethyl bromomalonate (8) using both enantiomers of cata-
lyst 4c to aꢂord chiral cyclopropanes 11a–c (Table 5). The
reactions were complete within one day (5–24 h), and the
products were isolated in good yields (86–94%) and with
moderate enantioselectivities (54–72%). The best result
3 Conclusions
(
72% ee) was achieved in the cyclopropanation of ethyl (E)-
-cyano-3-phenylacrylate (10b) (Table 5, entries 2 and 5).
2
In conclusion, new hydrobenzoin-based monoaza-15-crown-5
ethers with various side arms have been synthesized, and
applied as recyclable phase transfer catalysts in a few asym-
metric reactions. To the best of our knowledge, this is the
ꢁrst time that a chiral crown ether phase transfer catalyst was
reused in an eꢀcient way. For the epoxidation of trans-chal-
cone, a scalable and green method was elaborated using recy-
clable catalyst 4a and MTBE as the solvent. The product was
formed with good yield (90%) and enantiomeric excess (81%).
Macrocycle 4a was reused ꢁve times without any decrease in
The corresponding product (11b) was obtained in a some-
what lower enantiomeric excess (72%) than reported by
Feng et al. (89% ee) [81], however, in our method less cata-
lyst was used (5 mol % instead of 10 mol %), furthermore,
the hydrobenzoin-based catalyst may be recycled, thus, this
methodology is more robust.
Slightly lower enantioselectivities were observed in the
reaction of benzylidenemalononitrile (10a) and (E)-3-phe-
nyl-2-(phenylsulfonyl)acrylonitrile (10c) (59% and 54%,
1
3

The Synthesis of Hydrobenzoin-Based Monoaza Crown Ethers and Their Application as Recyclable…
Table 5 Asymmetric MIRC reaction of electron deꢁcient oleꢁns 10a–c and diethyl bromomalonate (8) using catalyst 4c
0
°C
EtOOC COOEt
R
EtOOC
COOEt
MTBE
∗
∗
R
+
CN
Br
Na CO
2 3
catalyst (5 mol%)
CN
11a-c
1
0a-c
8
Entry
Catalyst
R
Time (h)
Yield (%)
ee (%)a
1
2
3
4
5
6
(S,S)-4c
(S,S)-4c
(S,S)-4c
(R,R)-4c
(R,R)-4c
(R,R)-4c
CN
COOEt
5
11a: 86
11b: 90
11c: 93
11a: 89
11b: 88
11c: 94
59 (R)
24
24
5
24
24
72 (2S,3S)
54 (2S,3R)
56 (S)
72 (2R,3R)
51 (2R,3S)
SO Ph
2
CN
COOEt
SO Ph
2
a
Based on chiral HPLC, the absolute conꢁguration was assigned by comparison of the speciꢁc rotations with literature data [77, 81] The abso-
lute conꢁguration of 11c was determined based on analogy with the dimethyl analogue [80]
the yield and enantioselectivity. The method developed has a
general value, as it could be extended also to other chalcone
derivatives. Neither the yield (71–93%), nor the enantiomeric
excess (68–86%) of the products decreased drastically by the
eꢂect of the substituents in the aromatic ring of the chalcone.
In the asymmetric MIRC reaction of 2-benzylidene-1,3-in-
dandione, crown ether 4c with a 3,4-diethoxyphenylethyl side
arm generated the highest enantiomeric excess (75%). The
experiments with benzylidenemalonitrile, ethyl (E)-2-cyano-
was vigorously stirred with 50% aq. NaOH solution at room
temperature for 10 h. Then, the mixture was poured on a
mixture of CH Cl and water 1:1 (3 times the volume of
2
2
the reaction mixture), and the phases were separated. The
water layer was extracted twice with CH Cl , the combined
2
2
organic layer was washed with water, and dried (Na SO ),
2
4
then the solvent was evaporated. The remaining bis(2-chlo-
roethyl)ether was removed by vacuum distillation. The crude
product was puriꢁed by column chromatography on silica
gel to give the pure product.
3
-phenylacrylate, (E)-3-phenyl-2-(phenylsulfonyl)acryloni-
trile resulted in good yields (85–94%) and moderate ee values
54–72%). This methodology for the synthesis of these chiral
(
4.2 General Procedure for Preparation of Bisiodo
cyclopropanes seems to be superior from the point of view
green chemistry and scaling up, as compared to previously
reported methods. These promising results encourage us to
perform further investigations with the hydrobenzoin-based
crown ethers by substituting the aromatic ring of hydroben-
zoin. We hope that these modiꢁcations will improve the selec-
tivity of our catalysts, and even enantiopure products may be
obtained. We believe that the applied recovery technique can
help to expand the sphere of application of chiral monoaza
crown ethers in asymmetric catalysis by eliminating the draw-
back regarding the high price and poor recyclability.
Compounds (R,R)‑3 and (S,S)‑3
A mixture of bischloro compound and NaI (4 equivalent) in
dry acetone was stirred under reꢃux for 40 h. After cooling,
the precipitate was ꢁltered, and washed with acetone. The
combined acetone solutions were evaporated in vacuum. The
residue was dissolved in a mixture of CHCl and water (1:1),
3
the layers were separated, and the organic phase was washed
with water and dried (Na SO ). Evaporation of the solvent
2
4
aꢂorded the products.
4
.3 General Procedure for the Preparation of Crown
Ethers 4a–d
4
Experimental
Bisiodo podand (R,R)-3 or (S,S)-3 was dissolved in dry
4
.1 General Procedure for Preparation of Bischloro
CH CN and anhydrous Na CO (6 equivalent), and the
3
2
3
Compounds (R,R)‑2 and (S,S)‑2
appropriate amine (1 equivalent) was added under Ar.
The mixture was reꢃuxed for 50 h. Then, the solvent was
A solution of hydrobenzoin (R,R-1 or S,S-1) and tetrabu-
removed, the residue was dissolved in a mixture of CHCl
3
tylammonium hydrogensulphate in bis(2-chloroethyl)ether
and water, the layers were separated, and the organic phase
1
3

T. Nemcsok et al.
was washed with water, dried, then concentrated. The crude
product was puriꢁed by column chromatography.
Development and Innovation Fund (TUDFO/51757/2019-ITM, The-
matic Excellence Program).
Open Access This article is distributed under the terms of the Creative
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mons.org/licenses/by/4.0/), which permits unrestricted use, distribu-
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credit to the original author(s) and the source, provide a link to the
Creative Commons license, and indicate if changes were made.
4
.4 General Procedure for the Asymmetric
Epoxidations
trans-Chalcone derivative (0.5 mmol) and crown catalyst
5 mol %) were dissolved in MTBE (3 ml), then 0.12 ml (1.3
equivalent) tert-butylhydroperoxide (5.5 M in decane) and
0% aq. NaOH solution (1 ml) were added. The mixture was
(
2
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with 10% aq. HCl solution (3×10 ml), dried (Na CO and
1
2
.
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Acknowledgements Open access funding provided by Budapest Uni-
versity of Technology and Economics (BME). Zsolt Rapi is grate-
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