New enantiopure binaphthyl-cinchona thiosquaramides: synthesis and application for enantioselective organocatalysis

Article abstract of DOI:10.1039/C8NJ06451B

This work presents the first successful applications of cinchona-thiosquaramides in asymmetric reactions. Binaphthyl-cinchona squaramides and thiosquaramides were synthesised, and then used as organocatalysts to promote the catalytic enantioselective Mich

Full text of DOI:10.1039/C8NJ06451B

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J. Kupai, New J. Chem., 2019, DOI: 10.1039/C8NJ06451B.
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The role of atropisomers on the photo-reactivity and fatigue of
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DOI: 10.1039/C8NJ06451B
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New enantiopure binaphthyl-cinchona thiosquaramides: synthesis
and application for enantioselective organocatalysis†
Sándor Nagy,a Gyula Dargó,a Péter Kisszékelyi,a Zsuzsanna Fehér,a András Simon,b Júlia Barabás,b
Tibor Höltzl,b,c Béla Mátravölgyi,a Levente Kárpáti,d László Drahos,e Péter Huszthy,a and József
Kupai*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
This work presents the first successful applications of cinchona-thiosquaramides in asymmetric reactions. Binaphthyl-
cinchona squaramides and thiosquaramides were synthesised, and then used as organocatalysts to promote the catalytic
enantioselective Michael addition reaction of pentane-2,4-dione to trans-β-nitrostyrene with excellent yields (up to 99%)
and enantioselectivities (up to 99% ee) at as low as 0.2 mol% catalyst loadings. Thiosquaramides gave higher
enantioselectivities (up to 92% ee) in conjugate addition reaction of lawsone to -unsaturated -keto ester than its oxo
analogue, with high yields (up to 100%). Also, only thiosquaramide could catalyse the aza-Diels–Alder addition reaction of
2-siloxydiene to benzylideneacetone. Furthermore, quantum chemical computations showed that the geometrical structure
of binaphthyl-cinchona thiosquaramide is similar to that of the squaramide.
(Fig. 1) have been found beneficial in asymmetric Michael
addition.13-16
Introduction
Over the last 20 years an explosive growth of research in the
field of asymmetric synthesis has taken place.1-5 The aim of
enantioselective synthesis or catalysis is to produce
enantiopure products (a single enantiomer as the ultimate goal)
starting from achiral substrates by chiral reagents, catalysts or
auxiliaries. The role of these chiral reagents or catalysts is to
generate diastereomeric transition states leading to the
formation of two enantiomers so that one of them is
preferentially formed. In recent years binaphthyl compounds
have found frequent applications in the design of various
asymmetric organocatalysts,6-12 since the binaphthyl structure
is an attractive platform for catalyst development, particularly
in the light of their axially chiral characteristic. The enantiomeric
atropisomers of 2,2’-substituted binaphthyls have been
developed to exploit the axial dissymmetry induced by the
restricted rotation about the biaryl bond.8 Application of
binaphthyl units as a chiral scaffold is well-established in
asymmetric catalysis, especially the binaphthyl-based
bifunctional mono-, bisthioureas, and cinchona-squaramides
Fig. 1 Binaphthyl-based bifunctional squaramides.
Nowadays, squaramides have become a dominant core among
hydrogen bond catalysts,17-21 thanks to their rigid four-
membered ring, the appropriate distance between the donor
hydrogens, and higher acidity. Very recently, Rawal et al.
published22 the first application of thiosquaramides, the thio
analogues of squaramides, as asymmetric catalysts. In a recent
review, the main benefits of thio analogues compared to those
of squaramides, like increased aromaticity, higher acidity and
greater solubility in non-polar solvents, were summarized.23
Bifunctional thiosquaramides are a promising new class of
catalysts, and their simple preparation procedure is expected to
further expand the scope of reactions in hydrogen bonding
catalysis.24
Stereodivergence in cooperative asymmetric catalysis with
simultaneous involvement of two chiral catalysts is a persistent
challenge in asymmetric catalysis. Depending on whether the
orientation of the two chiral attachments is complimentary or
opposed, stereochemical enhancement or stereochemically
destructive interference might occur. The question of how two
chiral catalytic units work in concert, surmounting the chiral
match−mismatch issue, is profoundly important.25, 26 Chirality
transfer from two catalysts to the product can be particularly
complex. Sunoj et al. revealed the origin of high
enantioselectivities in a reaction catalysed by axially chiral
binaphthyl and cinchona units through transition-state
modelling.26 Besides applying theoretical studies, it can be
a.Department of Organic Chemistry & Technology, Budapest University of
Technology & Economics, Szent Gellért tér 4, Budapest, 1111, Hungary.
E-mail: jkupai@mail.bme.hu; Tel: 0036-1463-2229
b.Department of Inorganic & Analytical Chemistry, Budapest University of
Technology & Economics, Szent Gellért tér 4, Budapest, 1111, Hungary.
c. Furukawa Electric Institute of Technology, Késmárk utca 28/A, Budapest, 1157,
Hungary.
d.Laboratory of Plastics & Rubber Technology, Budapest University of Technology
& Economics, Műegyetem rkp. 3., Budapest, 1111, Hungary.
e. MS Proteomics Research Group, Research Centre for Natural Sciences,
Hungarian Academy of Sciences, Magyar Tudósok körútja 2, Budapest, 1117,
Hungary.
† Electronic Supplementary Information (ESI) available: FT-IR, 1H, 13C, 2D NMR and
MS spectra of new compounds, thermoanalytical measurements (TGA, DSC) of
catalysts 1a and 1b, chiral HPLC profiles of Michael and conjugate adducts and data
of theoretical calculations. See DOI: 10.1039/x0xx00000x
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proved experimentally if stereodivergence could be achieved by In our recent publications,28, 29 we used hydroquinine (4a
View Article O)nlianes
30
inverting the configuration of the chiral catalysts that are starting material to form its amino derivative (
involved in the activation of the reactants. quinine (4b) is a cheaper source of the cinchona scaffold.
Herein we report the synthesis of new binaphthyl-cinchona Considering that this method contained catalytic
squaramides and their thio analogues, which are good multiple hydrogenation step, the ethyl derivative was synthesized by
6
DOI: 10.103)9,/C8hNoJ0w6e4v51eBr
a
6
hydrogen bond donor organocatalysts, and the comparison of reducing the vinyl and the azide group in the same step (Scheme
their application in asymmetric Michael addition of pentane- 3). Applying the latter procedure, the intermediates were used
2,4-dione to trans-β-nitrostyrene, in asymmetric conjugate without any purification.
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addition reaction of lawsone and ,-unsaturated -keto ester
and, moreover, in aza-Diels–Alder addition reaction of 2-
siloxydiene and benzylideneacetone is presented. Furthermore,
the effect of the configuration of the axially chiral binaphthyl
unit and match-mismatch of chiralities with the cinchona unit
was studied.
Scheme 3 Synthesis of cinchona amine 6.
The binaphthyl-cinchona squaramide 1a was gained by reacting
Results and discussion
Planning the synthesis of catalysts 1a and 1b has begun with a
retrosynthetic analysis (Scheme 1). Based on this, a convergent
synthetic route starting from commercially available 2,2’-
half-squaramides HSq
binaphthalene (R)- . Application of methyl ester HSq
reagent is advantageous due to the higher yield (91% vs. 66%),
and the easier separation of 1a from the excess of HSq , than
from HSq during column chromatography.
-
M
or HSq
-
B
with the aminomethyl
2
-M
as
-
M
-
B
dimethyl-1,1’-binaphthalene [(R)-
and cinchona alkaloids (4a and 4b) was designed for the
preparation of catalysts 1a and 1b
3], squaric esters (Sq-M, Sq-B)
The synthesis of binaphthyl-cinchona thiosquaramide 1b was
attempted in many ways (see Scheme 4 and Scheme S1, ESI†),
but it was successful only by thionation of its dioxo form 1a
using P4S10·pyridine complex.31,32 In this synthetic route, the
purification of the intermediates is easier than in those that
apply thionated starting materials or intermediates, due to
decomposition of thiosquaramide-derivatives on silica gel. We
note here that all compounds were characterised by well-
established methods including low- and high-resolution MS, IR,
1D and 2D NMR (see Experimental section and ESI†). The
binaphthyl-cinchona squaramide 1a was gained by reacting
.
half-squaramides HSq
binaphthalene (R)-
-M or HSq-B with the aminomethyl
2
.
Scheme 1 Retrosynthetic analysis of 1a and 1b.
Amine fragment (R)-
2
was prepared through bromination of
dimethyl binaphthalene followed by substitution (Scheme 2).
The monobromo derivative (R)-
5 was synthesized using N-
bromosuccinimide (NBS) as brominating agent and benzoyl
peroxide (BPO) as initiator.27 This product was converted into
amine (R)-2 in two different ways (Scheme 2): reacting with
sodium azide, and reducing the corresponding azide by catalytic
hydrogenation (Method A), or applying large excess of aqueous
ammonia (Method B). The latter was the preferred procedure,
because it is a one-step, easily implemented method providing
Scheme 4 Synthesis of binaphthyl-cinchona squaramide 1a and thiosquaramide 1b
organocatalysts.
The catalytic activity of binaphthyl-cinchona (thio)squaramides
1a and 1b was tested in Michael addition reaction using trans-
β-nitrostyrene (7) and pentane-2,4-dione (8) (Table 1).
The highest yields and enantiomeric excesses were reached in
ethyl acetate and toluene. Following solvent selection
guidelines33-35 – based on properties of solvents such as boiling
point, health hazard, aquatic and air impact – ethyl acetate was
chosen to optimise the amount of catalysts and to decrease the
reaction time of the Michael addition reaction from 48 hours to
24 hours. The results are shown in Table 2.
amine (R)-2 with the same yield. Also, in comparison to Pd/C
and H2; aqueous ammonia solution is an easy to handle reagent.
Scheme 2 Synthesis of the axially chiral binaphthalene precursor (R)-2.
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Table 1 Test of catalysts 1a and 1b in the Michael reaction using trans-β-nitrostyrene (7)
and pentane-2,4-dione (8)a.
22% higher enantiomeric excesses when thiosquaramides were
used, demonstrating the superior performance of this new type
View Article Online
DOI: 10.1039/C8NJ06451B
of bifunctional catalysts. Also, the higher acidity of aryl
thiosquaramides allowed their application as Brønsted acids in
aza-Diels–Alder reaction. In this reaction, the corresponding
thiourea, oxo-, and thiosquaramides were applied. Product was
only afforded, when thiosquaramide was used.
Thus, we applied 1a and 1b organocatalysts in the
aforementioned two asymmetric reactions (Table 3 and Table 4).
In the conjugate addition (Table 3), high yields were achieved
by the application of catalysts 1a and 1b, even with 5% catalyst
loadings. In all cases, thiosquaramide (1b) gave higher
enantioselectivity than its dioxo analogue (1a). These results
also prove the noted high catalytic activity of thiosquaramides.
5
6
7
8
Entry
1
2
3
4
5
6
7
8
Catalyst
Solvent
Yield [%]b
ee [%]c
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
DCM
toluene
EtOAc
MTBE
MeOH
H2O
56
80
83
70
52
42
59
44
85
76
63
51
71
52
95
96
98
97
61
93
98
80
96
98
98
67
98
100
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
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42
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neat
DCM
9
toluene
EtOAc
MTBE
MeOH
H2O
10
11
12
13
14
Table 3 The application of catalysts 1a and 1b in the conjugate addition of lawsone (10)
to ,-unsaturated -keto ester 11a.
neat
a
Reaction conditions: pentane-2,4-dione (8) (0.41 mmol) was added to the solution of
trans-β-nitrostyrene (7) (0.16 mmol) and 5 mol% of catalyst 1a or 1b in 1 mL of solvent,
b
then the resulting mixture was stirred at room temperature for 48 hours. Isolated
yields. c Determined by chiral HPLC (S enantiomer).
Entry
Catalyst
Amount of
catalyst [mol%]
Yield
[%]b
ee
Table 2 The optimisation of the amount of catalysts 1a and 1b in the Michael reaction
using trans-β-nitrostyrene (7) and pentane-2,4-dione (8)a.
[%]c
1
2
3
4
5
6
7
1a
1a
1a
1b
1b
10
5
1
10
5
1
93
98
74
89
93
46
44
79
83
83
91
92
88
0
1b
DBU
10
Entry
Catalyst
Amount of
catalyst [mol%]
Yield
[%]b
ee
[%]c
a
Reaction conditions: -unsaturated -keto ester (11) (0.11 mmol) was added to the
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
5
1
0.5
0.2
0.1
5
85
93
93
90
88
81
92
90
91
88
98
98
96
93
88
98
97
97
98
77
solution of lawsone (10) (0.10 mmol) and catalyst 1a or 1b or DBU in 0.5 mL of DCM,
c
then stirred at room temperature for 1 hour. b Isolated yields. Determined by chiral
HPLC (R enantiomer).
Following the preliminary studies of Rawal et al.,22 both
organocatalysts (1a and 1b) were also applied in aza-Diels–Alder
reaction (Table 4). Similarly to their observation, only
thiosquaramide (1b) was able to act as Brønsted acid, therefore
adduct 15 was only afforded in the reaction when it was
catalysed by 1b. Adduct 15 was obtained with 80% yield in a
diastereomeric ratio of 5.4 to 1 (major diastereomer shown in
Table 4). Using catalyst 1a, only the unreacted starting materials
were detected.
1
0.5
0.2
0.1
10
a
Reaction conditions: pentane-2,4-dione (8) (0.41 mmol) was added to the solution of
trans-β-nitrostyrene (7) (0.16 mmol) and catalyst 1a or 1b in 1 mL of ethyl acetate, then
b
the reaction mixture was stirred at room temperature for 24 hours. Isolated yields.
c Determined by chiral HPLC (S enantiomer).
The yields and enantiomeric excesses have not changed
significantly by decreasing the reaction time from 48 hours to
24 hours in the presence of 5 mol% of catalysts 1a or 1b
Table 4 The application of catalysts 1a and 1b in aza-Diels–Alder reaction of 2-siloxydiene
13 and N-benzylideneaniline (14)a.
.
Comparing these two catalysts (1a and 1b), the differences
between the yields and enantiomeric excesses were only
relevant, when less than 0.5 mol% of catalysts were applied.
However, in the presence of 0.1 mol% catalyst, in both cases, a
decrease was noticed in these values, mainly in enantiomeric
excesses. No reaction took place in the absence of a catalyst.
For thiosquaramide 1b 0.2 mol% was the minimum catalyst
loading, that gave the Michael adduct with high yield and
enantiomeric excess, however the ee was only 5% lower when
its dioxo analogue (1a) was used.
Entry
Catalyst
Yield [%]b
drc
[%]b
1
2
1a
1b
0
80
-
5.4:1
a
Reaction conditions: 2-siloxydiene 13 (0.20 mmol) was added to the solution of
N-benzylideneaniline (14) (0.24 mmol) and 20 mol% of catalyst 1a or 1b in 1 mL of
toluene, stirred at room temperature for 12 hours. b Isolated yields. c Determined by 1
NMR.
H
The first, preliminary studies of bifunctional aryl
thiosquaramides have been reported by Rawal et al.22 They
applied and compared oxo- and the corresponding
thiosquaramides in the conjugate addition reaction of lawsone
Containing two chiral fragments, namely the cinchona and the
binaphthyl unit, 1a and 1b could either act as a cooperating (matched
pair) or an uncooperating (mismatched pair) multistereogenic
catalyst system. Hence, after the successful utilization of catalysts 1a
and 1b, the application of the “the opposite” catalysts (1c and 1d)
(
10) to ,-unsaturated -keto ester (11), and they achieved 9–
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synthesized from (S)-3, the enantiomer pair of (R)-dimethyl
binaphthalene [(R)-3], was investigated in the same asymmetric
transformations.
taken place when thiosquaramide 1b was used. Therefore, the
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optimisation of the reaction conditions is stilDl OinI:p1r0o.1g0r3e9s/sC. 8NJ06451B
Table 6 The application of catalysts 1c and 1d in the conjugate addition of lawsone (10)
to ,-unsaturated -keto ester 11a.
8
9
10
11
12
13
14
15
16
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Entry
Catalyst
Amount of
catalyst [mol%]
Yield
[%]b
ee
Scheme 5 Synthesis of the opposite catalysts 1c and 1d.
[%]c
The synthesis of the “opposite” catalysts (1c and 1d) was
accomplished by the same route (Scheme S2, ESI†) as catalysts 1a
and 1b.
First, we tested them in Michael addition reaction using trans-β-
nitrostyrene (7) and pentane-2,4-dione (8) (Table 5).
1
2
3
4
5
1c
1c
1c
1d
1d
10
5
1
10
5
100
100
73
100
100
100
83
84
79
88
89
6
1d
1
90
a
Reaction conditions: -unsaturated -keto ester 11 (0.11 mmol) was added to the
solution of lawsone (10) (0.10 mmol) and catalyst 1c or 1d in 0.5 mL of DCM, stirred at
room temperature for 1 hour. Isolated yields. Determined by chiral HPLC (R
Table 5 The optimisation of the amount of catalysts 1c and 1d in the Michael reaction
using trans-β-nitrostyrene (7) and pentane-2,4-dione (8)a.
b
c
enantiomer).
Theoretical calculations
The distance between the two NH groups of the squaramide or
thiosquaramide unit and the H-bond angle has a significant
effect on the enantioselectivity of the reaction.36, 37 Therefore,
we analysed the differences in the 3D geometric structure of
the binaphthyl-cinchona squaramide (1a) and thiosquaramide
Entry
Catalyst
Amount of
catalyst [mol%]
Yield
[%]b
ee
[%]c
1
2
3
4
5
6
7
8
9
1c
1c
1c
1c
1c
1d
1d
1d
1d
1d
5
1
0.5
0.2
0.1
5
96
93
83
62
56
93
96
91
86
83
96
94
95
90
81
98
97
97
91
84
(
1b) catalysts (Fig. 2) using quantum chemical calculations.
The calculated distances between the NH groups (4.12 Å and
4.14 Å) and also the N-N-H angles (70.3° and 71.4°) are very
similar in both the thiosquaramide and in squaramide catalysts
(Fig. 2). Furthermore, a hydrogen bond is formed between the
quinuclidine and the squaramide part. Also, only minor
differences are observed in the geometry of the four membered
rings.
Thus, the molecular geometries of thiosquaramide and
squaramide do not imply
enantioselectivities.
1
0.5
0.2
0.1
10
a
Reaction conditions: pentane-2,4-dione (8) (0.41 mmol) was added to the solution of
trans-β-nitrostyrene (7) (0.16 mmol) and catalyst 1c or 1d in 1 mL of ethyl acetate, then
b
c
the reaction mixture was stirred at room temperature for 24 hours. Isolated yields.
Determined by chiral HPLC (S enantiomer).
a significant difference in their
In this Michael addition 1c and 1d gave the same enantiomer [S)] of
9 in excess as was given by using 1a and 1b. Comparing oxo-catalysts
1a and 1c, the yields were significantly lower (up to 32% difference)
when 1c was used, in cases of 0.5 mol% or lower catalyst loadings,
but the enantiomeric excesses have not changed considerably.
Notable difference in the efficiency and selectivity between thio-
analogues 1b and 1d was not noticed. Between 1c and 1d, the yields
were up to 27% higher when thio-squaramide (1d) was used, but the
selectivity of these catalysts is comparable.
The conjugate addition of lawsone (10) to ,-unsaturated -
keto ester (11) proved the noted high catalytic activity of
thiosquaramides22 (Table 3), therefore, we tested the catalysts 1c
and 1d in this reaction as well. The results are shown in Table 6.
In this conjugate addition, both the yield and selectivity were
higher in the presence of only 1% of thiosquaramide (1d). Comparing
these results to the outcomes of conjugate addition catalysed by 1a
and 1b, the same tendency was observed: the enantiomeric excess
is approximately 5–10% higher when thiosquaramide is applied. By
applying 1a and 1b or 1c and 1d, the same enantiomer [(R)] of the
adduct 12 was obtained.
Finally we tested 1c and 1d catalysts in aza-Diels–Alder reaction,
although, none of them gave product; however the reaction has
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58
59
60
Fig. 2 Optimised geometries and schematic structures of binaphthyl-cinchona thiosquaramide 1b (a, b) and binaphthyl-cinchona squaramide 1a (c, d) catalysts with the calculated
distances and angles. The hydrogen bond between the NH group and the quinuclidine part is shown by red dashed arrows.
experimentally observed similar yield and ee values. These findings
Conclusions
significantly expand the scope of applications of thiosquaramide
derivatives in asymmetric syntheses.
In conclusion, the synthesis of a new class of chiral cinchona
(thio)squaramide organocatalysts containing axially chiral binaphthyl
moiety was demonstrated. We have addressed a fundamental
problem of chiral induction in asymmetric catalysis when two chiral
catalytic units act together in a reaction. Cinchona-thiosquaramides
Experimental
General
(1b and 1d) were first applied as enantioselective organocatalyst in
Infrared spectra were recorded on a Bruker Alpha-T FT-IR
asymmetric Michael addition of pentane-2,4-dione (8) to trans-β-
spectrometer. Optical rotations were measured on a Perkin-
nitrostyrene (7) performing a thorough solvent screening and
Elmer 241 polarimeter that was calibrated by measuring the
parameter optimisation. Compared to their oxo analogues,
optical rotations of both enantiomers of menthol. NMR spectra
thiosquaramide catalyst 1b gave Michael adduct 9 with almost the
were recorded at Directorate of Drug Substance Development,
same yield (90% and 91%) and 1d gave the adduct with significantly
Egis Pharmaceuticals Plc., on a Bruker Avance III HD (at 600 MHz
higher yield, than its oxo analogue (86% vs. 62%). Thiosquaramide 1b
for H and at 150 MHz for 13C spectra) or at Department of
1
gave slightly higher enantioselectivity (98% ee vs. 93% ee) with even
0.2 % of catalyst loading in ethyl acetate. In the conjugate addition
reaction of lawsone (10) to unsaturated -keto ester 11, the
adduct 12 was gained with high yields (up to 100%), even when 1%
of catalyst loadings was applied. In this conjugate addition, the
application of 1b and 1d thio derivatives resulted in up to 12% higher
enantioselectivities (up to 92%) than by using the corresponding
oxosquaramides 1a or 1c. Our results demonstrated clearly that
there is no considerable effect of the match-mismatch pair of (R) and
(S) binaphthyl cinchona (thio)squaramide diastereomers (1a vs. 1c
and 1b vs. 1d) on the selectivity. The Brønsted acid activity of the
squaramides and their thio analogues were tested in aza-Diels–Alder
addition of 2-siloxydiene 13 to N-benzylideneaniline (14). In this
reaction the adduct (15) was only obtained when thiosquaramide 1b
was used, with dr of 5.4 (trans):1 (cis). Quantum chemical
computations showed that the geometric structures of binaphthyl-
cinchona thiosquaramide and squaramide are similar, in line with the
Inorganic & Analytical Chemistry, Budapest University of
Technology and Economics, on a Bruker DRX-500 Avance
spectrometer (at 500 MHz for 1H and at 125 MHz for 13C spectra)
or on a Bruker 300 Avance spectrometer (at 300 MHz for 1H and
at 75 MHz for 13C spectra) at temperatures given. Mass spectra
were recorded on CAMAG LCMS Interface (HPLC pump:
Shimadzu LC-20AD Prominence SQ MS: Shimadzu LCMS-2020
MS settings: Detector Voltage: 1.10 kV, m/z: 105-1000, Scan
speed: 1075 u·sec-1, DL temperature: 250 °C, Nebulizing Gas
Flow: 1.5 L·min-1, Drying Gas Flow: 15 L·min-1. eluent:
acetonitrile: 0.1% (v/v) formic acid 95:5, 1.5 mL·min-1). The
exact mass measurements were performed using Q-TOF
Premier mass spectrometer (Waters Corporation, 34 Maple St,
Milford, MA, USA) in positive electrospray ionisation mode. The
enantiomeric ratios of the samples were determined by chiral
high-performance
liquid
chromatography
(HPLC)
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measurements using reversed phase mode (Thermo Finnigan 60.6, 124.8, 125.0, 125.0, 125.4, 126.3, 127.6, 127.7, 128.0,
View Article Online
Surveyor LC System. Elemental analyses were performed in the 128.2, 128.7, 131.6, 131.8, 132.1, 132.4D, O1I3: 210.4.1,03193/C3.82N,J1063445.10B,
Microanalytical Laboratory of the Department of Organic 138.0; MS-ESI+ (m/z): the ionization was not feasible of this
Chemistry, Institute for Chemistry, Eötvös Loránd University, compound under the circumstances of the applied methods (ESI
Budapest, Hungary. Melting points were taken on a Boetius H+ addition or Na+ addition). Anal. calc. for C22H17Br (%): C,
micro-melting point apparatus and they were uncorrected. 73.14; H, 4.74; Br, 22.12. Found: C, 73.11; H, 4.77; Br, 22.09.
Starting materials were purchased from Aldrich Chemical To the best of our knowledge the synthesis of (R)-
Company unless otherwise noted. Silica gel 60 F254 (Merck) reported.
plates and aluminium oxide 60 F254 (Merck) were used for TLC.
5 has not been
10
11
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16
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The spots of materials on TLC plates were visualised by UV light
at 254 nm. Silica gel 60 (70–230 mesh, Merck) was used for
column chromatography. Silica gel 60 with particle size of 0.063
mm was used for dry column vacuum chromatography
(DCVC).38 Ratios of solvents for the eluents are given in
milliliters. PerkinElmer TGA 6 was used to determine the
(S)-2-(Bromomethyl)-2'-methyl-1,1'-binaphthalene [(S)-5]
White waxy oil (396 mg, 62%). [푎]퐷20 -121.2 (c 1.00, CHCl3), the
other spectroscopic data of this product are the same as those
thermal stability of the catalysts with nitrogen purging. The
beginning of thermal degradation was determined at 95%
(w/w) of the measured sample. A 10 °C min-1 heating rate was
used from 30 to 700 °C, then the sample was kept at 700 °C for
10 min. PerkinElmer DSC 7 was used to measure melting point
of the catalysts with nitrogen purging.
The computations were carried out using Density Functional Theory
applying the ωB97X-D functional39 and 6-31G* basis set,40 as it is
implemented in the Q-Chem 5.2. quantum chemical software
package.41 This functional includes long range and dispersion
corrections and the accuracy of this method has been tested for
similar systems in our previous studies.29,42,43 The (75,302)
integration grid was applied in all cases. The geometries of the
catalysts were optimised both in the gas phase and in ethyl acetate
solvent using SM8 continuum solvation method.44 Molecules were
visualised using the PyMol program.45
of (R)-5.
To the best of our knowledge the synthesis of (S)-5 has not been
reported.
(R)-2,2'-Bis(bromomethyl)-1,1'-binaphthalene [(R)-5b] (the
by-product of the preparation of (R)-5)
White crystals (157 mg, 20%). TLC (SiO2; hexane : DCM = 2:1,
Rf=0.74). M.p. 161–165 °C. [푎]퐷20 +161.9 (c 1.00, CHCl3); IR νmax
3048, 3010, 2966, 2917, 2849, 1912, 1773, 1719, 1507, 1463,
1212, 1025, 821, 756, 722, 686 cm-1; 1H NMR δ (ppm, 600 MHz,
DMSO-d6, 25 °C) 4.33 (2 H, d, JH,H 10.0 Hz), 4.37 (2 H, d, JH,H 10.0
Hz), 6.89 (2 H, d, JH,H 8.6 Hz), 7.33 (2 H, t, JH,H 7.5 Hz), 7.55 (2 H,
t, JH,H 7.5 Hz), 7.84 (2 H, d, JH,H 8.6 Hz), 8.06 (2 H, d, JH,H 8.3 Hz),
8.17 (2 H, d, JH,H 8.6 Hz); 13C NMR δ (ppm, 75 MHz, DMSO-d6, 25
°C) 33.2, 126.4, 127.1, 127.2, 128.2, 128.4, 129.5, 132.0, 133.1,
133.8, 134.2; MS-ESI+ (m/z): the ionization was not feasible of
this compound under the circumstances of the applied
methods(ESI H+ addition or Na+ addition).
General procedure for the preparation of 2-(bromomethyl)-2'-
methyl-1,1'-binaphthalenes, and their by-products 2,2'-
bis(bromomethyl)-1,1'-binaphthalenes
To the best of our knowledge the NMR assignment of (R)-5b has
not been reported.
A stirred mixture of 2,2'-dimethyl-1,1'-binaphthalene [(R)-
3 or
(S)- ] (500 mg, 1.77 mmol), N-bromosuccinimide (334 mg, 1.86
3
mmol) and BPO (22 mg, 0.09 mmol) were heated at reflux
temperature in cyclohexane (13 mL) with irradiation of infrared
light (250 Watt) for 6 h. After the reaction was completed, the
solvent was removed under reduced pressure. The crude
product was purified by dry column vacuum chromatography38
(4 mL of hexane was passed through a silica pad with 2 cm of
diameter and
7 cm of height) to afford mono-, and
(S)-2,2'-Bis(bromomethyl)-1,1'-binaphthalene [(S)-5b] (the by-
product of the preparation of (S)-5)
dibrominated products.
White crystals (151 mg, 19%). M.p. 161–165 °C. [푎]퐷20 -161.9 (c
1.00, CHCl3), the other spectroscopic data of this product are
(R)-2-(Bromomethyl)-2'-methyl-1,1'-binaphthalene [(R)-5]
White waxy oil (383 mg, 60%). TLC (SiO2; hexane : DCM = 2:1,
Rf=0.67). [푎]퐷20 +121.2 (c 1.00, CHCl3); IR νmax 3046, 1506, 1212,
812, 751 cm-1; 1H NMR δ (ppm, 300 MHz, DMSO-d6, 25 °C) 1.96
(3 H, s), 4.04 (1 H, d, JH,H 14.0 Hz), 4.13 (1 H, d, JH,H 14.0 Hz), 6.85
(1 H, d, JH,H 8.5 Hz), 6.86 (1H, d, JH,H 8.3 Hz), 7.23 (1 H,
overlapped), 7.26 (1H, overlapped), 7.42 (1 H, overlapped), 7.45
(1 H, overlapped), 7.58 (1 H, d, JH,H 8.4 Hz), 7.90 (1 H, d, JH,H 8.6
Hz), 7.97 (2 H, overlapped), 8.00 (1 H, overlapped), 8.07 (1 H, d,
JH,H 8.5 Hz); 13C NMR δ (ppm, 75 MHz, DMSO-d6, 25 °C) 19.8,
the same as those of (R)-5b
.
To the best of our knowledge the NMR assignment of (S)-5b has
not been reported.
6 | J. Name., 2012, 00, 1-3
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(R)-2-(Azidomethyl)-2'-methyl-1,1'-binaphthalene [(R)-16]
(R)-2-Bromomethyl-2'-methyl-1,1'-binaphthalene [(R)-
mg, 0.556 mmol), was dissolved in DCM (1 mL), then acetone (4
mL), sodium azide (72.2 mg, 1.11 mmol) and water (10 μL) was
under reduced pressure. Further purification was not necessary
to obtain the pure product.
View Article Online
DOI: 10.1039/C8NJ06451B
5
] (200
(R)-2-(Aminomethyl)-2'-methyl-1,1'-binaphthalene [(R)-2]
added. The mixture was stirred until the reaction was Pale-yellow crystals (165 mg, 99%). TLC (SiO2 TLC; hexane:DCM
completed. The acetone was removed under reduced pressure, = 2:1, Rf=0.77); M.p. 69–71 °C; [푎]퐷20 +12.7 (c 0.99, CHCl3); IR νmax
and the remaining material was dissolved in a mixture of DCM 3371, 3051, 3007, 2917, 2856, 1593, 1506, 812, 744 cm-1; H
1
10
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and water (2 mL of each). The phases were shaken well and NMR δ (600 MHz; DMSO-d6) 1.97 (3 H, s), 3.28 (1 H, d, JH,H 14.8
separated. The organic phase was dried over anhydrous MgSO4 Hz), 3.37 (1 H, d, JH,H 14.9 Hz), 6.85 (1 H, d, JH,H 8.6 Hz), 6.87 (1H,
and the solvent was removed under reduced pressure. Further d, JH,H 8.6 Hz), 7.24 (1 H, overlapped), 7.25 (1H, overlapped),
purification was not necessary to afford the pure product as 7.42 (1 H, overlapped), 7.44 (1 H, overlapped), 7.59 (1 H, d, JH,H
white waxy oil (179 mg, quantitative yield). TLC (SiO2 TLC; 8.5 Hz), 7.92 (1 H, d, JH,H 8.6 Hz), 7.97 (1 H, overlapped), 7.99 (1
hexane: DCM = 2:1, Rf=0.49). [푎]퐷20 +60.5 (c 1.00, CHCl3); IR νmax H, overlapped), 8.00 (1 H, overlapped), 8.06 (1 H, d, JH,H 8.6 Hz);
1
3053, 3010, 2918, 2805, 2090, 810, 742 cm-1; H NMR δ (ppm, 13C NMR δ (ppm, 150 MHz, DMSO-d6, 25°C) 20.1, 43.4, 125.1,
300 MHz, DMSO-d6, 25°C) 1.99 (3 H, s), 4.07 (1 H, d, JH,H 13.5 Hz), 125.1, 125.3, 125.5, 126.3, 126.5, 126.6, 127.8, 127.9, 128.3,
4.12 (1 H, d, JH,H 13.6 Hz), 6.83 (1 H, d, JH,H 8.4 Hz), 6.92 (1H, d, 128.3, 128.9, 131.9, 132.0, 132.4, 132.5, 133.2, 133.9, 134.3,
JH,H 8.5 Hz), 7.25 (1 H, ddd, J1,H,H 8.4 Hz, J2,H,H 6.9 Hz, J3,H,H 1.4 Hz), 139.5; MS-ESI+ (m/z): [M+H+] calcd for C22H20N: 298.16, found:
7.31 (1H, ddd, J1,H,H 8.5 Hz, J2,H,H 6.9 Hz, J3,H,H 1.3 Hz), 7.44 (1 H, 298.20. Anal. calc. (%): C, 88.85; H, 6.44; N, 4.71. Found: C,
ddd, J1,H,H 8.2 Hz, J2,H,H 6.9 Hz, J3,H,H 1.4 Hz), 7.525 (1 H, ddd, J1,H,H 88.84; H, 6.45; N, 4.71.
To the best of our knowledge the synthesis of (R)-2 has not been
reported.
8.2 Hz, J2,H,H 6.9 Hz, J3,H,H 1.3 Hz), 7.61 (1 H, d, JH,H 8.5 Hz), 7.77
(1 H, d, JH,H 8.5 Hz), 7.99 (1 H, overlapped), 8.02 (1 H,
overlapped), 8.06 (1 H, d, JH,H 8.4 Hz), 8.13 (1 H, d, JH,H 8.5 Hz);
13C NMR δ (ppm, 125 MHz, DMSO-d6, 25°C) 19.8, 52.1, 124.7,
125.2, 125.3, 126.4, 126.4, 126.8, 126.9, 128.1, 128.1, 128.3,
128.3, 128.6, 131.7, 131.8, 132.3, 132.5, 133.0, 134.5, 135.6;
MS-ESI+ (m/z): [M+H+-N2] calcd for C22H18N: 296.14, found:
296.20. Anal. calc. for C22H17N3 (%): C, 81.71; H, 5.30; N, 12.99.
Found: C, 81.70; H, 5.33; N, 12.96.
(S)-2-(Aminomethyl)-2'-methyl-1,1'-binaphthalene [(S)-2]
Pale-yellow crystals (165 mg, 99%). [푎]퐷20 -12.7 (c 0.99, CHCl3), the
other spectroscopic data of this product are the same as those of (R)-
2.
To the best of our knowledge the synthesis of (S)-2 has not been
reported.
To the best of our knowledge the synthesis of (R)-16 has not
been reported.
General procedure for the preparation of 2-(aminomethyl)-2'-
methyl-1,1'-binaphthalenes
(1S)-[(2S,4S,5R)-5-Ethylquinuclidin-2-yl)(6-methoxyquinolin-4-
yl)]methanamine (6)
Method A: (R)-2-Azidomethyl-2'-methyl-1,1'-binaphthalene
[(R)-16] (150 mg, 0.464 mmol), was dissolved in a mixture of
DCM (2 mL) and methanol (5 mL). 20 % Pd/C catalyst (15 mg)
was used for the catalytic hydrogenation of the azide (R)-16. The
hydrogenation was carried out at room temperature in
atmospheric pressure using hydrogen gas. The catalyst was
filtered through a pad of Celite®, then the solvent was removed
under reduced pressure. Further purification was not necessary
to obtain the pure product as pale-yellow crystals (137 mg,
99%).
This compound was synthesized as described in the literature46
with some minor modifications. To a solution of triethylamine
(4.1 mL, 2.97 g, 29.4 mmol), and quinine (4b) (2.00 g, 6.2 mmol)
in THF (35 mL) mesyl chloride (1.9 mL, 2.81 g, 24.5 mmol) was
added at 0 °C. The reaction mixture was stirred at room
temperature for 4 h. The solvent was removed under reduced
pressure, subsequently DCM (50 mL) and saturated aq. NaHCO3
solution (50 mL) were added to the residue. The phases were
shaken well and separated. The organic phase was dried over
anhydrous MgSO4 and the solvent was removed. This mesylate
intermediate was dissolved in DMF (50 mL), and sodium azide
(1.6 g, 24.7 mmol) was added. The reaction mixture was stirred
overnight. After the reaction was completed, the solvent was
removed under reduced pressure. The crude product was
dissolved in methanol (50 mL). 20% Pd/C catalyst (200 mg) was
used for the catalytic hydrogenation of the azide intermediate.
The hydrogenation was carried out at room temperature in
atmospheric pressure using hydrogen gas. After the reaction
Method B: 2-Bromomethyl-2'-methyl-1,1'-binaphthalene [(R)-
5
or (S)- ]] (200 mg, 0.556 mmol), was dissolved in a mixture of
5
chloroform and methanol (2 mL of each), then it was added
dropwise to a solution of ammonia (4.3 mL of methanol in 8.6
mL 25% aq. NH3), and this reaction mixture was stirred for 12 h.
After the reaction was completed, the organic solvents were
removed under reduced pressure. The remaining aqueous
mixture was extracted using chloroform (5 mL). The organic
phase was dried over MgSO4 and the solvent was removed
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was completed, the catalyst was filtered through a pad of 144.2, 147.8, 157.9, 170.8, 177.8, 181.4, 189.9; MS-ESI+ (m/z):
View Article Online
Celite®, then the solvent was removed under reduced pressure. [M+H+] calcd for C25H30N3O4: 436.22, fouDndO:I:4103.610.3309/.CA8nNaJl0.6c4a5l1cB.
Further purification was not necessary to obtain the pure (%): C, 68.95; H, 6.71; N, 9.65. Found: C, 68.92; H, 6.74; N, 9.65.
To the best of our knowledge the synthesis of HSq-M has not been
reported.
product as a yellow oil (1.61 g, 70% overall yield). Spectral data
were fully consistent with those reported in the literature.46 TLC
(SiO2 TLC; DCM: methanol:NH3 (25% aq. solution)=10:1:0.01,
Rf=0.19). [푎]퐷20 +63.6 (c 0.97, CHCl3, lit.: [푎]2퐷0 +71.8 (c 0.97,
CHCl3);47 IR νmax 3371, 3299, 2926, 2859, 2119, 1918, 1620,
1588, 1506, 1473, 1454, 1431, 1355, 1317, 1259, 1228, 1174,
10
11
12
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1
1133, 1076, 1028, 977, 916, 851, 826, 741, 712, 635 cm-1; H
NMR δ (ppm, 500 MHz, DMSO-d6, 80 °C) 0.71 (1 H, dd, J1,H,H 7.6,
J1,H,H 13.2), 0.81 (3 H, t, JH,H 7.3 Hz), 1.23 (1 H, m, overlapped),
1.27 (2H, m, overlapped), 1.40 (1 H, m, overlapped), 1.44 (1 H,
m, overlapped), 1.52 (1 H, m, overlapped), 1.54 (1 H, m,
overlapped), 2.45 (1 H, m), 2.68 (1 H, m, overlapped), 3.00 (1 H,
m, overlapped), 3.20 (1 H, m, overlapped), 3.24 (1 H, m,
overlapped), 3.96 (3 H, s), 4.59 (1 H, d, JH,H 10.1 Hz), 7.41 (1 H,
dd, J1,H,H 2.5, J2,H,H 9.2), 7.56 (1 H, d, JH,H 4.5 Hz), 7.83 (1 H, s), 7.95
(1 H, d, JH,H 9.2 Hz), 8.70 (1 H, d, JH,H 4.5 Hz); 13C NMR δ (ppm,
125 MHz, DMSO-d6, 80 °C) 11.4, 24.8, 25.1, 26.6, 28.0, 36.8,
40.1, 52.5, 55.2, 57.1, 60.9, 102.9, 119.9, 120.4, 128.2, 130.8,
143.9, 147.2, 147.4, 156.6; MS-ESI+ (m/z): [M+H+] calcd for
C20H28N3O: 326.22, found: 326.22.
3-(((1S)-((2S,4S,5R)-5-Ethylquinuclidin-2-yl)(6-methoxyquinolin-4-
yl)methyl)amino)-4-butoxycyclobut-3-ene-1,2-dione (HSq-B)
White crystals (287 mg, 62%). TLC (SiO2 TLC; DCM:methanol =
10:1, Rf=0.38). M.p. 120 °C (decomposed) [푎]퐷20 -129 (c 1.00,
chloroform); IR νmax 3234, 3075, 3034, 2956, 2932, 2870, 1802,
1706, 1606, 1509, 1475, 1433, 1359, 1297, 1259, 1229, 1171,
1
1084, 1029, 919, 853 cm-1; H NMR δ (600 MHz; DMSO-d6, 60
°C) 0.80 (3 H, t, JH,H 7.4), 0.85 (3 H, overlapped), 1.29 (2 H,
broad), 1.33 (2 H, overlapped), 1.39 (1 H, overlapped), 1.42 (1
H, overlapped), 1.52 (1 H, overlapped), 1.54 (1 H, overlapped),
1.67 (1 H, broad), 2.43 (1 H, broad), 2.64 (1 H, broad), 3.14 (1 H,
overlapped), 3.17 (1 H, overlapped), 3.35 (1 H, broad), 3.96 (3
H, s), 4.56 (2 H, broad), 7.46 (1 H, d, JH,H 9.1), 7.63 (1 H, d, JH,H 4.5
Hz, overlapped), 7.72 (1 H, broad), 7.98 (1 H, d, JH,H 9.1), 8.77 (1
H, d, JH,H 4.5), 9.02 (1 H, broad); 13C NMR δ (150 MHz; DMSO-d6,
60 °C) 11.8, 13.2, 17.9, 24.9, 25.5, 26.9, 28.1, 31.3, 36.9, 40.3,
53.3, 55.6, 57.0, 58.7, 72.6, 101.1, 120.1, 121.4, 127.4, 131.5,
143.2, 144.2, 147.7, 157.8, 171.2, 177.3, 181.6, 189.5; MS-ESI+
(m/z): [M+H+] calcd for C28H36N3O4: 478.27, found: 478.30. Anal.
calc. (%): C, 70.42; H, 7.39; N, 8.80. Found: C, 70.40; H, 7.40; N,
8.79.
General procedure for the preparation of cinchona half-
squaramides
A solution of cinchona amine
mL) was added in three portions to a solution of dimethyl
squarate (Sq-M) (193 mg, 1.36 mmol) or dibutyl squarate (Sq-B
6 (400 mg, 1.23 mmol) in DCM (0.5
)
To the best of our knowledge the synthesis of HSq-B has not
been reported.
(308 mg, 1.36 mmol) in DCM (0.5 mL). This mixture was stirred
overnight at room temperature. The solvent was removed
under reduced pressure, then the crude product was purified by
column chromatography (SiO2; DCM:methanol = 10:1) to obtain
HSq-M or HSq-B
.
(((1S)-((2S,4S,5R)-5-Ethylquinuclidin-2-yl)(6-methoxyquinolin-4-
yl)methyl)amino)-4-methoxycyclobut-3-ene-1,2-dione (HSq-M)
General procedures for the preparation of binaphthyl cinchona-
oxosquaramides
Pale-yellow crystals (375 mg, 70%). TLC (SiO2 TLC;
DCM:methanol = 10:1, Rf=0.28). M.p. 120 °C (decomposed)
[푎]퐷20 -60 (c 1.00, chloroform); IR νmax 3186, 3078, 2954, 2932,
2870, 1802, 1705, 1667, 1622, 1606, 1552, 1509, 1475, 1434,
A solution of aminomethyl binaphthalene [(R)-2 or (S)-2] (200
mg, 0.67 mmol) in chloroform (0.7 mL) was added to a solution
of cinchona half squaramide (HSq-M: 322 mg, 0.74 mmol or
HSq-B: 353 mg, 0.74 mmol) in chloroform (1.5 mL). This mixture
was stirred for 5 h at room temperature. The solvent was
removed under reduced pressure, then the crude product was
purified by column chromatography on silica gel using
DCM:methanol: NH3 (40:1:0.01) mixture as an eluent to obtain
the pure product.
1
1392, 1224 cm-1; H NMR δ (ppm, 500 MHz, DMSO-d6, 80 °C)
0.61 (1 H, m), 0.79 (3 H, t, JH,H 12.0 Hz), 1.27 (2H, overlapped),
1.31 (1 H, overlapped), 1.41 (1 H, overlapped), 1.43 (1 H,
overlapped), 1.53 (1 H, overlapped), 1.56 (1 H, overlapped),
2.46 (1 H, d, JH,H 13.5 Hz), 2.66 (1 H, m), 3.15 (1 H, overlapped),
3.19 (1 H, overlapped), 3.39 (1 H, overlapped), 3.95 (3 H, s), 4.25
(3 H, s), 5.75 (1 H, broad), 7.45 (1 H, d, JH,H 9.0 Hz), 7.64 (1 H, d,
JH,H 4.0 Hz, overlapped), 7.66 (1 H, overlapped), 7.97 (1 H, d, JH,H
9.0 Hz), 8.77 (1 H, d, JH,H 4.0 Hz); 13C NMR δ (ppm, 125 MHz,
DMSO-d6, 80 °C) 12.0, 24.8, 25.6, 27.0, 28.0, 36.7, 40.2, 52.0,
55.6, 57.1, 58.5, 60.1, 101.1, 119.9, 121.9, 127.3, 131.6, 142.9,
3-(((1S)-((2S,4S,5R)-5-Ethylquinuclidin-2-yl)(6-
methoxyquinolin-4-yl)methyl)amino)-4-(R)-(((2'-methyl-[1,1'-
binaphthalen]-2-yl)methyl)amino)cyclobut-3-ene-1,2-dione
(1a)
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Pale-yellow crystals (427 mg, 91% with reagent HSq-M and 310 HRMS-ESI+ (m/z): [M+H+] calcd for C46H45N4O3: 701.3492,
View Article Online
DOI: 10.1039/C8NJ06451B
mg, 66% with reagent HSq-B). M.p. 170 °C (DSC), TLC (SiO2 TLC; found: 701.3501.
DCM:methanol: NH3 = 40:1:0.01, Rf=0.31). [푎]퐷20 -44,7 (c 1.00,
CHCl3); IR νmax 3234, 3051, 3004, 2930, 2860, 1794, 1676, 1621,
To the best of our knowledge the synthesis of 1c has not been
reported.
1
2589, 1530, 1508, 1458, 1359, 1260, 1241, 1224 cm-1; H NMR
δ (ppm, 500 MHz, DMSO-d6, 60 °C) 0.70 (1 H, m), 0.81 (3 H, t,
JH,H 7.4 Hz), 1.36 (2 H, overlapped), 1.53 (1 H, overlapped), 1.54
(2 H, overlapped), 1.64 (1 H, overlapped), 1.65 (1 H,
overlapped), 1.75 (3 H, s), 2.57 (1 H, m), 2.77 (1 H, wide), 3.28
(1 H, overlapped), 3.45 (1 H, overlapped), 3.66 (1 H,
overlapped), 3.96 (3 H, s), 4.31 (1 H, dd, J1,H,H 5.2 Hz, J2,H,H 14.9
Hz), 4.40 (1 H, dd, J1,H,H 6.8 Hz, J2,H,H 14.9 Hz), 5.98 (1 H, wide),
7.19 (1 H, ddd, J1,H,H 1.3 Hz, J2,H,H 6.7 Hz, J3,H,H 14.9 Hz), 7.26 (2 H,
overlapped), 7.37 (1 H, ddd, J1,H,H 1.0 Hz, J2,H,H 6.7 Hz, J3,H,H 14.9
Hz), 7.46 (1 H, overlapped), 7.48 (1 H, overlapped), 7.59 (1 H, d,
JH,H 4.6 Hz), 7.69 (1 H, d, JH,H 8.6 Hz), 7.78 (1 H, d, JH,H 2.7 Hz),
7.84 (1 H, d, JH,H 7.2 Hz), 7.90 (1 H, d, JH,H 8.1 Hz), 7.99 (2 H,
overlapped), 8.04 (1 H, d, JH,H 8.6 Hz), 8.78 (1 H, d, JH,H 4.6 Hz);
13C NMR δ (ppm, 125 MHz, DMSO-d6, 60 °C) 11.4, 19.4, 24.5,
25.1, 26.1, 26.7, 35.9, 40.2, 45.1, 53.0, 55,6, 56.5, 58.7, 101.6,
121.6, 124.3, 124.7, 124.9, 125.8, 125.8, 126.2, 126.5, 127.2,
127.6, 127.8, 127.9, 128.0, 128.1, 131.3, 131.6, 131.7, 132.0,
132.3, 132.5, 133.5, 134.0, 134.5, 144.2, 147.4, 157.8, 165.9,
167.6, 181.3, 182.2; HRMS-ESI+ (m/z): [M+H+] calcd for
C46H45N4O3: 701.3492, found: 701.3501.
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General procedure for the preparation of binaphthyl cinchona-
thiosquaramides
A solution of binaphthyl-cinchona squaramide (1a or 1c, 80 mg,
0.114 mmol) in acetonitrile (1 mL) was added to the pyridine
complex of phosphorus pentasulfide (87 mg, 0.228 mmol). The
reaction mixture was stirred at 80 °C for 4 hours. After the
reaction was completed, the mixture was poured onto water
(10 mL), then the precipitated yellow crystals were filtered, and
dried on air. The crude product was dissolved in DCM and
filtered through a pad of aluminium oxide. The solvent was
evaporated, and this crude product was dissolved in DCM (0.5
mL), and hexane (5 mL) was added to this solution. The
precipitated orange crystals were filtered, washed with hexane
and dried under reduced pressure to obtain thiosquaramide
catalysts. The product can be used without further purification.
3-(((1S)-((2S,4S,5R)-5-Ethylquinuclidin-2-yl)(6-
To the best of our knowledge the synthesis of 1a has not been
reported.
methoxyquinolin-4-yl)methyl)amino)-4-(R)-(((2'-methyl-[1,1'-
binaphthalen]-2-yl)methyl)amino)cyclobut-3-ene-1,2-
dithione (1b)
Orange crystals (74 mg, 88%). TLC (aluminium oxide TLC;
chloroform:methanol: NH3 = 40:1:0.01 ) Rf=0.69; (SiO2 TLC;
chloroform:methanol = 40:1:0.01 NH3 ) Rf=0.23. M.p. 237 °C
(DSC), [푎]퐷20 -44.6 (c 0.25, CHCl3); IR νmax 3436, 3169, 3051, 2999,
2930, 2872, 1917, 1762, 1698, 1620, 1588, 1507, 1474, 1432,
3-(((1S)-((2S,4S,5R)-5-Ethylquinuclidin-2-yl)(6-
methoxyquinolin-4-yl)methyl)amino)-4-(S)-(((2'-methyl-[1,1'-
binaphthalen]-2-yl)methyl)amino)cyclobut-3-ene-1,2-dione
(1c)
1
1357, 1243, 1143, 1085, 1028, 812, 748 cm-1; H NMR δ (ppm,
600 MHz, DMSO-d6, 60 °C) 0.74 (3 H, t, JH,H 7.4 Hz), 0.94 (1 H, m,
JH,H 13.0 Hz), 1.28 (1 H, t, JH,H 7.4 Hz), 1.60 (1 H, t, JH,H 12.0 Hz),
1.74 (3 H, s), 1.81 (1 H, overlapped), 1.83 (3 H, overlapped), 3.09
(1 H, overlapped), 3.12 (1 H, overlapped), 3.57 (1 H, wide), 4.03
(1 H, s), 4.12 (1 H, overlapped), 4.43 (1 H, wide), 4.76 (3 H, d, JH,H
15.4 Hz), 5.16 (1 H, d, JH,H 15.4 Hz), 6.84 (2 H, d, JH,H 8.4 Hz), 7.16
(1 H, wide), 7.20 (2 H, overlapped), 7.24 (1 H, t, JH,H 7.6 Hz), 7.35
(1 H, t, JH,H 7.2 Hz), 7.45 (1 H, t, JH,H 7.1 Hz), 7.49 (1 H, dd, J1,H,H
2.7 Hz, J2,H,H 9.2 Hz), 7.82 (1 H, d, JH,H 8.4 Hz), 7.85 (1 H,
overlapped), 7.86 (1 H, overlapped), 7.92 (1 H, wide), 7.97 (1 H,
d, JH,H 8.3 Hz), 8.00 (1 H, overlapped), 8.02 (1 H, overlapped),
8.04 (1 H, d, JH,H 8.7 Hz), 8.86 (1 H, d, JH,H 4.6 Hz); 13C NMR δ
(ppm, 150 MHz, DMSO-d6, 60 °C) 11.2, 19.8, 23.3, 23.9, 24.5,
25.2, 34.5, 41.2, 44.9, 51.8, 55.2, 56.3, 59.8, 102.2, 120.7, 122.4,
124.6, 124.9, 124.9, 125.7, 125.9, 126.4, 126.6, 126.6, 127.9,
128.0, 128.1, 128.2, 128.3, 131.7, 131.8, 131.9, 132.1, 132.3,
132.6, 132.7, 134.2, 134.4, 141.1, 144.4, 147.8, 158.2, 169.6,
170.9, 202.4, 204.9; HRMS-ESI+ (m/z): [M+H+] calcd for
C46H45N4S2O: 733.3035, found: 733.3043.
Pale-yellow crystals (413 mg, 88% with reagent HSq-M). M.p.
204–206 °C, TLC (SiO2 TLC; DCM:methanol: NH3 = 40:1:0.01,
Rf=0.29). [푎]퐷20 -76,6 (c 1.00, CHCl3); IR νmax 3425, 2931, 1796,
1677, 1621, 1590, 1530, 1509, 1460, 1360, 1260, 1242, 1028,
813, 687 cm-1; 1H NMR δ (ppm, 400 MHz, DMSO-d6, 117 °C) 0.76
(1 H, b), 0.83 (3 H, t, JH,H 7.4 Hz), 1.07 (2 H, t, JH,H 7 Hz), 1.37 (2
H, q, JH,H 8 Hz), 1.53 (1 H, b), 1.65 (1 H, b), 1.69 (1 H, b), 1.94 (3
H,s), 2.67 (1 H, b), 3.76 (1 H, b), 3.37 (1 H, m), 3.47 (2 H, q, JH,H
=7 Hz), 3.94 (3 H, s), 4.39 (2 H, d, JH,H =5.2 Hz), 5.97 (1 H, d, JH,H
=10.6 Hz), 6.79 (1 H, d, JH,H =8.6 Hz), 6.88 (1 H, d, JH,H =8.6 Hz),
6.93 (1 H, t, JH,H 7 Hz), 7.04 (1 H, t, JH,H 7.6 Hz), 7.23 (1 H, t, JH,H
7.6 Hz), 7.44 (1 H, m), 7.45 (1 H, m), 7.46 (1 H, m), 7.54 (1 H, d,
JH,H 4.6 Hz), 7.67 (1 H, d, JH,H 8.6 Hz), 7.73 (1 H, m), 7.74 (1 H, m),
7.84 (1 H, d, JH,H 8.4 Hz), 7.96 (1 H, m), 7.98 (1 H, m), 8.00 (1 H,
m), 8.75 (1 H, d, JH,H =4.6 Hz); 13C NMR δ (ppm, 100 MHz, DMSO-
d6, 117 °C) 10.9, 17.9, 19.2, 24.3, 24.5, 25.7, 35.5, 45.1, 52.9,
55.5, 55.7, 56.3, 59.3, 101.9, 119.3, 121.4, 124.2, 124.3, 124.8,
125.5, 125.5, 125.6, 126.1, 127.0, 127.3, 127.4, 127.6, 127.7,
128.1, 131.1, 131.4, 131.6, 131.7, 132.0, 132.3, 132.5, 133.4,
133.8, 134.6, 144.2, 147.2, 157.8, 165.7, 168.0, 181.5, 182.3;
To the best of our knowledge the synthesis of 1b has not been
reported.
This journal is © The Royal Society of Chemistry 20xx
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NH4OAc in H2O = 40/60, isocratic mode; 0.6 mL·min-1; UV
View Article Online
detector 222 nm, 5 µL or 10 µL injection,D2O0I:°1C0..1R0e39te/Cn8tNioJn06t4im51Be
for (S)-9: 11.94 min, for (R)-9: 14.20 min.The applied solvents,
the amounts of the catalysts and reaction times are shown in
Table 1, 2 and 5.
8
9
3-(((1S)-((2S,4S,5R)-5-Ethylquinuclidin-2-yl)(6-
General procedure for conjugate addition reaction of lawsone to
-unsaturated -keto ester
methoxyquinolin-4-yl)methyl)amino)-4-(S)-(((2'-methyl-[1,1'-
binaphthalen]-2-yl)methyl)amino)cyclobut-3-ene-1,2-
dithione (1d)
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To a solution of lawsone (10) (17.4 mg, 0.10 mmol) in
dichloromethane (0.5 mL), organocatalyst 1a
, 1b, 1c or 1d was
Orange crystals (72 mg, 86%). TLC (aluminium oxide TLC;
chloroform:methanol: NH3 = 40:1:0.01 ) Rf=0.66; (SiO2 TLC;
chloroform:methanol = 40:1:0.01 NH3 ) Rf=0.25. M.p. 208–210
°C, [푎]퐷20 -93.3 (c 1.00, CHCl3); IR νmax 3431, 2929, 1698, 1566,
added. Then -unsaturated -keto ester (11) (22.5 mg, 0.11

,

mmol) was added to this solution and the resulting reaction
mixture was stirred 1 h at room temperature. After the reaction
was completed, the volatile components were removed under
reduced pressure. The crude product was purified by
preparative thin layer chromatography on silica gel using
hexane:ethyl acetate 2:1 mixture (Rf=0.30) as eluent to obtain
adduct 12 as yellow crystals. Yields and enantiomeric excess
(ee) values can be seen in Tables 3 and 6. These products had
the same spectroscopic data than those of reported (the
absolute configuration was determined by the optical rotation
of the products).48 HPLC: Phenomonex Lux Cellulose-1 column
(3 µm, 250 × 4.6 mm); eluent CH3CN/0.1% AcOH in H2O and =
40:60, isocratic mode; 0.8 mL·min-1; UV detector 222 nm ; 5 µL
or 10 µL injection, 25 °C. Retention time for (R)-12: 9.16 min,
for(S)-12: 10.87 min. The amounts of the catalysts are shown in
Table 3 and 6.
1508, 1474, 1244, 1145, 1086, 1029, 813, 746 cm-1; H NMR δ
1
(ppm, 600 MHz, DMSO-d6, 22 °C) 0.76 (3 H, t, JH,H 7.3 Hz), 1.25
(2H, b), 1.35 (2 H, m), 1.44 (1 H, b), 1.47 (1 H, b), 1.56 (1 H, b),
1.98 (3 H, s), 1.81 (1 H, b), 2.43 (1 H, b), 2.60 (1 H, b), 3.16 (1 H,
b), 3.67 (1 H, b), 4.00 (1 H, b), 4.02 (3 H, s), 4.89 (1 H, d, JH,H 14.6
Hz), 5.13 (1 H, d, JH,H 14.6 Hz), 6.73 (1 H, b), 6.82 (1 H, b), 6.86 (1
H, d, JH,H 8.5 Hz), 6.96 (1 H, b), 7.28 (1 H, m), 7.48 (1 H, m), 7.49
(1 H, m), 7.50 (1 H, m), 7.61 (1 H, b), 7.72 (1 H, b), 7.79 (1 H, d,
JH,H 8.5 Hz), 7.86 (1 H, d, JH,H 8.4 Hz), 8.00 (1 H, m), 8.01 (1 H, m),
8.02 (1 H, m), 8.10 (1 H, d, JH,H 8.5 Hz), 8.83 (1 H, d, JH,H 4.3 Hz);
13C NMR δ (ppm, 150 MHz, DMSO-d6, 22 °C) 12.0, 20.2, 22.3,
24.0, 25.4, 27.6, 36.5, 41.1, 44.9, 56.0, 56.4, 57.0, 102.7, 120.2,
122.5, 124.7, 124.7, 125.2, 125.4, 126.3, 126.6, 127.1, 127.3,
128.0, 128.2, 128.4, 128.6, 129.0, 131.6, 131.9, 132.1, 132.4,
132.5, 133.0, 134.4, 134.8, 135.5, 144.5, 147.9, 158.0, 168.8,
171.2, 201.0, 204.3; HRMS-ESI+ (m/z): [M+H+] calcd for
C46H45N4S2O: 733.3035, found: 733.3043.
General procedure for aza-Diels–Alder reaction of 2-siloxydiene to
N-benzylideneaniline
To the best of our knowledge the synthesis of 1d has not been
reported.
To a solution of N-benzylideneaniline (14) (18 mg, 0.10 mmol)
in toluene (0.5 mL), organocatalyst 1a, 1b, 1c or 1d was added.
Then 2-siloxydiene (13) (31 mg, 0.12 mmol) was added to this
solution and the resulting reaction mixture was stirred at room
temperature for 12 h. After the reaction was completed, the
volatile components were removed under reduced pressure.
The crude product was purified by preparative thin layer
chromatography on neutralised aluminium oxide gel using
hexane (Rf=0.40) as eluent to obtain aza-Diels–Alder adduct as
pale-yellow crystals. Yields and diastereomeric ratio (dr) values
can be seen in Table 4. These products had the same
spectroscopic data than those of reported.49
General procedure for Michael addition of pentane-2,4-dione to
trans-β-nitrostyrene
To a solution of trans-β-nitrostyrene (
in the corresponding solvent (1 mL), organocatalyst 1a
or 1d was added. Then pentane-2,4-dione ( ) (41.5 μL, 40.7 mg,
7
) (23.4 mg, 0.16 mmol)
,
1b 1c
,
8
0.41 mmol) was added to this solution and the resulting Conflicts of interest
reaction mixture was stirred at room temperature. After the
There are no conflicts to declare.
reaction was completed, the volatile components were
removed under reduced pressure. The crude product was
purified by preparative thin layer chromatography on silica gel
using hexane:ethyl acetate 2:1 mixture (Rf=0.36) as eluent to
Acknowledgements
This research was funded by the New National Excellence
obtain Michael adduct as pale-yellow crystals. Yields and
enantiomeric excess (ee) values can be seen in Tables 1, 2 and
5. These products had the same spectroscopic data than those
of reported (the absolute configuration was determined by the
optical rotation of the products).29 HPLC: Phenomonex Lux
Cellulose-3 column (3 µm, 250 × 4.6 mm), eluent CH3CN/20 mM
Program of the Ministry of Human Capacities, grant numbers
ÚNKP-18-4-BME-270 and ÚNKP-18-2-II-BME-243, and the Janos
Bolyai Research Scholarship of the Hungarian Academy of
Science. It was also supported by the National Research,
Development and Innovation office (former OTKA, grant
number K128473), the Servier-Beregi PhD Research Fellowship,
10 | J. Name., 2012, 00, 1-3
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and the Gedeon Richter's Talentum Foundation. The authors
are grateful to Zsófia Garádi from Budapest University of
Technology and Economics and to Dr. András Dancsó from Egis
Pharmaceuticals Plc., Directorate of Drug Substance
Development for their assistance with the NMR measurements.
25. M. P. Doyle, J. P. Morgan, J. C. Fettinger, VPie.wY.AZrtiaclveaOlinjl,inJe.
T. Colyer, D. J. Timmons and M. D. Carducci, J. Org. Chem.,
2005, 70, 5291-5301.
26. B. Bhaskararao and R. B. Sunoj, J. Am. Chem. Soc.,
2015, 137, 15712-15722.
27. P. C. B. Page, B. R. Buckley and A. J. Blacker, Org. Lett.,
2004, 6, 1543-1546.
28. S. Nagy, Z. Feher, P. Kisszekelyi, P. Huszthy and J.
Kupai, New J. Chem., 2018, 42, 8596-8602.
DOI: 10.1039/C8NJ06451B
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29. C. Didaskalou, J. Kupai, L. Cseri, J. Barabas, E. Vass, T.
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New enantiopure binaphthyl-cinchona thiosquaramides: synthesis and application for
enantioselective organocatalysis
Sándor Nagy, Gyula Dargó, Péter Kisszékelyi, Zsuzsanna Fehér, András Simon, Júlia Barabás, Tibor Höltzl, Béla
Mátravölgyi, Levente Kárpáti, László Drahos, Péter Huszthy, and József Kupai
Binaphthyl-cinchona squaramide and thiosquaramide were applied as organocatalysts in three types of
asymmetric reactions with excellent yields and enantioselectivities.
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