Enantioselective sulfa-Michael addition reaction of methyl thioglycolate to chalcones derivatives with sterically encumbered quinine squaramide organocatalyst

Article abstract of DOI:10.1016/j.tetlet.2018.02.068

Asymmetric organocatalytic sulfa-Michael reactions give access to enantiomerically enriched sulfur containing adducts that can be used as valuable chiral building blocks. A variety of chalcone derivatives were allowed to react with methyl thioglycolate under optimized conditions, in the presence of a bifunctional quinine derived sterically encumbered squaramide organocatalyst, giving rise to excellent stereoselectivities, up to 99% ee. The designed catalyst system proved to be efficient even at gram scale and under milder reaction conditions.

Full text of DOI:10.1016/j.tetlet.2018.02.068

Accepted Manuscript
Enantioselective sulfa-Michael addition reaction of methyl thioglycolate to
chalcones derivatives with sterically encumbered quinine squaramide organo-
catalyst
Deniz Hasılcıoğulları, Cihangir Tanyeli
PII:
S0040-4039(18)30266-1
https://doi.org/10.1016/j.tetlet.2018.02.068
TETL 49753
DOI:
Reference:
Tetrahedron Letters
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Accepted Date:
22 January 2018
19 February 2018
23 February 2018
Please cite this article as: Hasılcıoğulları, D., Tanyeli, C., Enantioselective sulfa-Michael addition reaction of methyl
thioglycolate to chalcones derivatives with sterically encumbered quinine squaramide organocatalyst, Tetrahedron
Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.02.068
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Enantioselective sulfa-Michael addition
reaction of methyl thioglycolate to chalcones
derivatives with sterically encumbered
quinine squaramide organocatalyst
Leave this area blank for abstract info.
Deniz Hasılcıoğulları, Cihangir Tanyeli

1
Tetrahedron Letters
Enantioselective sulfa-Michael addition reaction of methyl thioglycolate to chalcones
derivatives with sterically encumbered quinine squaramide organocatalyst
Deniz Hasılcıoğullarıa and Cihangir Tanyelia, 
aDepartment of Chemistry, Middle East Technical University, Ankara, 06800, Turkey
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Asymmetric organocatalytic sulfa-Michael reactions give access to enantiomerically enriched
sulfur containing adducts that can be used as valuable chiral building blocks. A variety of
chalcone derivatives were allowed to react with methyl thioglycolate under optimized
conditions, in the presence of a bifunctional quinine derived sterically encumbered squaramide
organocatalyst, giving rise to excellent stereoselectivities, up to 99% ee. The designed catalyst
system proved to be efficient even at gram scale and under milder reaction conditions.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Asymmetric catalysis
Asymmetric synthesis
Organocatalysis
Conjugate addition
Sulfa-Michael addition
of 2-aminoDMAP and quinine derived chiral bifunctional
Introduction
organocatalysts25a-e 1a-e and 2a-e, respectively (Figure 1) for the
sulfa-Michael addition of methyl thioglycolate to the
unsubstituted trans-chalcone (4a). Among the eleven
organocatalysts screened, catalysts containing adamantyl
moieties at their acidic part showed relatively better selectivities
with the best being the quinine based catalyst 2b (Table 1, entry
7), which gave the desired product with quantitative yield and
83% ee.
In the context of asymmetric synthesis, the use of
organocatalysts has profound advantages over transition metal
catalysts in terms of ease use and more importantly, compatibility
with the environment.1a-c Among the efforts in asymmetric
organocatalysis, Michael additions have attracted a great deal of
interest, being a valuable tool for C-C bond formation,2-3 using
aldehydes,4-5 ketones6-7and 1,3-dicarbonyl compounds8-10 as
donors. Despite giving rise to valuable building blocks for sulfur-
containing drug molecules11-13 by being a very important route
for C-S bond formation,14 sulfa-Michael reactions are yet a less
studied variant of Michael additions. While there are examples of
the addition of a large variety of thiols,15-20 thioglycolic esters are
a rather less popular choice as the nucleophile in asymmetric
sulfa-Michael additions.21-23 And only in a few studies chalcones
were employed as Michael acceptors, which were all based on
transition metal catalysis instead of organocatalysis.22-23 Thus, an
organocatalytic asymmetric study with the aforementioned
substrates would be a valuable contribution to the literature.
Herein, we describe the first asymmetric organocatalytic sulfa-
Michael addition of methyl thioglycolate to chalcones in the
presence of quinine derived sterically encumbered organocatalyst
with excellent yields and selectivities.
After choosing 2b as the best working organocatalyst, the
effect of solvent, catalyst loading, molarity, reactant ratios and
temperature were investigated as well to reach the optimal
working condition (Tables 1 and 2). Among the solvents
screened, nonpolar solvents were found to work better than polar
solvents. The best results were obtained with hexane, toluene,
chloroform, tert-butyl methyl ether and diethyl ether with small
differences in enantioselectivity output (Table 1, entries 12, 13,
15, 17 and 20, respectively). However, the reaction was sluggish
in hexane (6 h), chloroform (6 h) and diethyl ether (5 h) (entries
11, 14 and 19, respectively), compared to toluene (1 h) and tert-
butyl methyl ether (2 h) (entries 12 and 16, respectively). And of
the last two, toluene afforded the target product with both highest
yield and ee (>99% yield and 87% ee, versus 89% yield and 84%
ee, respectively). Hence, toluene was selected to be the best
working solvent.
Results and Discussion
The chalcone derivatives were synthesized using known
procedures.24 The study was started with the screening of a series
———
 Corresponding author. Tel.: +90-312-210-3222; e-mail: tanyeli@metu.edu.tr

2
Tetrahedron
The effect of catalyst loading on enantioselectivity was
investigated in the range of 1-10 mol % organocatalyst (Table 2,
entries 1-4). The best selectivity (91% ee) was obtained in the
presence of 10 mol % catalyst (entry 4). The chalcone
concentration was varied 0.05 - 0.4 M (Table 2, entries 4-7,
respectively). 92% of enantiomeric excess was attained when the
concentration was decreased to 0.1 M (Table 2, entry 6).
Decreasing the concentration had
a positive effect on
enantioselectivity, presumably due to lowering the possibility of
aggregation of the catalyst via hydrogen bonding. However,
decreasing the concentration further had a negative effect on ee
(entry 5).
Table 2. Further screening results for the addition of methyl
thioglycolate to trans-chalcone
Entry Load T (°C) Conc. (M) Time (h) Yieldb (%) eec (%)
1
2
1%
2%
0
0
0.2
0.2
0.2
0.2
0.05
0.1
0.4
0.1
0.1
0.1
0.1
0.1
0.1
23
1
76
48
87
89
91
88
92
91
91
79
93
94
97
90
Figure 1. Structures of the screened organocatalysts
>99
>99
>99
>99
>99
>99
86
3
5%
0
1
4
10%
10%
10%
10%
10%
10%
10%
10%
10%
1%
0
0.5
0.5
0.5
0.5
0.5
0.5
0.5
3
Table 1. Catalyst and solvent screening
5
0
6
0
7
0
8d
9e
10
11
12
13
0
Entrya Catalyst
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Hexane
Toluene
THF
Time (h) Yieldb (%) eec (%)
0
>99
>99
>99
>99
>99
1
2
1a
1b
1c
1d
1e
2a
2b
2c
2d
2e
2b
2b
2b
2b
2b
2b
2b
2b
2b
2
1
6
1
6
5
1
6
6
6
6
1
1
6
1
2
5
2
5
81
>99
83
40
68
5
RT
-20
-40
RT
3
25
1
4
>99
15
23
8
a
Unless stated otherwise, all reactions were performed with 1:2 ratio of
5
trans-chalcone to methyl thioglycolate in toluene, in the presence of
organocatalyst 2b at the indicated temperature. b Isolated yields. c Determined
by chiral HPLC analysis, AD-H column, 80:20 hexane / isopropanol, 1.0
mL/min, 254 nm. The reaction was carried out using 1:1 ratio of trans-
chalcone to methyl thioglycolate. The reaction was carried out using 1:3
6
80
50
83
14
9
7
>99
32
d
e
8
ratio of trans-chalcone to methyl thioglycolate.
9
86
10
11
12
13
14
15
16
17
18
19
70
15
86
87
22
84
45
84
26
15
84
Using an equimolar mixture of chalcone and methyl
thioglycolate resulted in a slight decrease in ee and a rather sharp
decrease in yield (86% yield, entry 8). Further increasing the
methyl thioglycolate ratio to 3 molar equivalents showed a
drastic decrease in selectivity (79% ee, entry 9). Finally the effect
of temperature was investigated. Enantioselectivity drastically
increased upon lowering the temperature to -20ºC and -40°C
(93% and 97% ee; entries 11 and 12, respectively). We also tried
employing a milder condition to test the efficiency of the system
by using only 0.1 mol % organocatalyst at room temperature and
managed to attain 90% ee for the unsubstituted chalcone (entry
13). However, the mild condition failed to maintain the high
selectivities for the substituted adducts. Thus, the optimal catalyst
loading and reaction temperature were selected to be 10 mol %
and -40°C, respectively.
54
>99
>99
99
Chloroform
Dioxane
TBME
EtOAc
MeCN
>99
89
96
92
Et2O
92
a Unless stated otherwise, all reactions were performed with 0.10 mmol trans-
chalcone and 0.20 mmol methyl thioglycolate in 0.5 mL of solvent, in the
presence of 2 mol % organocatalyst at 0°C. b Isolated yields. c Determined by
chiral HPLC analysis, AD-H column, 80:20 hexane/isopropanol, 1.0 mL/min,
254 nm.
With the optimized conditions in hand, the scope of the
reaction was extended to various substituted chalcones. All the

3
reactions were performed in toluene at -40°C, with 0.1 M
To demonstrate the efficiency of the asymmetric induction, a
concentration of 4a-v. The results are summarized in Table 3.
scale-up reaction was performed by using 4.9 mmol of 4a. The
gram-scale synthesis yielded 5a with >99% yield and 93% ee
(entry 21).
Table 3. Results for the addition of methyl thioglycolate to
trans-chalcone derivatives
The absolute configuration of chiral adduct 5a was assigned as
R by comparing the specific rotations and HPLC analyses given
in the literature.22 The rest were tentatively assigned by analogy.
A transition state model was proposed to elucidate the source of
enantioselectivity (Figure 2) which agrees with the model
calculated by Wong et al.26 The nucleophile is activated via the
activation of the nucleophile by squaramide hydrogens via
hydrogen bonding, whereas the chalcone is activated and the
newly forming alkoxide is stabilized by the quinuclidinium ion.
The nucleophilic attack occurs on the Re face of chalcones,
affording the R enantiomer.
Entrya
1
4
R1, R2
Ph, Ph
Product Time (h) Yieldb (%) eec (%)
4a
5a
5b
5c
5d
5e
5f
25
22
23
22
21
25
42
19
19
23
21
22
20
21
20
20
25
22
20
21
41
41
24
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
97
95
96
97
82
96
99
96
86
96
96
81
96
96
79
95
68
76
95
91
91
95
93
2
4b Ph, 3-MeC6H5
4c Ph, 4-MeC6H5
3
4
4d 4-MeC6H5, Ph
4e Ph, 2-MeOC6H5
4f Ph, 3-MeOC6H5
4g Ph, 4-MeOC6H5
5
6
7
5g
5h
5i
8
4h
4i
Ph, 3-FC6H5
Ph, 2-ClC6H5
Ph, 3-ClC6H5
Ph, 4-ClC6H5
Ph, 2-BrC6H5
Ph, 3-BrC6H5
4-BrC6H5, Ph
9
10
11
12
13
14
15
16
17
18
19
20
21
22
21d
4j
5j
4k
4l
5k
5l
Figure 2. A proposed transition state model
4m
4n
5m
5n
5o
5p
5q
5r
5s
In conclusion, we report the first highly enantioselective
organocatalytic sulfa-Michael additions of methyl thioglycolate
to trans-chalcones, in the presence of a quinine derived 2-
adamantyl squaramide containing organocatalyst. The excellent
enantioselectivity and yield were maintained in scale-up
synthesis, which proves that the designed catalyst system has
great efficiency. The newly formed enantiomerically enriched
adducts serve as valuable precursors for the design of sulfur-
containing drugs. Efforts to transform the products to
heterocycles via further reactions are ongoing.
4o Ph, 2-CF3C6H5
4p Ph, 4-CF3C6H5
4q Ph, 2-NO2C6H5
4r Ph, 3-NO2C6H5
4s Ph, 4-NO2C6H5
4t 4-NO2C6H5, Ph
5t
4u
4v Ph, 2-thiophenyl
4a Ph, Ph
Ph, 2-furyl
5u
5v
5a
Acknowledgments
a Unless stated otherwise, all reactions were performed with 0.10 mmol trans-
This study was financially supported by Scientific and
Technological Research Council of Turkey (113Z156), and
Middle East Technical University Scientific Research Projects
Center.
chalcone and 0.20 mmol methyl thioglycolate in 1.0 mL of solvent, in the
b
c
presence of 10 mol % 2b at -40°C. Isolated yields. Determined by chiral
HPLC analysis. d Performed with 4.9 mmol (1.02 g) of 4a, at gram-scale.
Among the chalcones derivatives, the best ee’s were obtained
with the ones having electron donating substituents at m- and p-,
giving rise to excellent ee’s ranging between 95-99% ee (Table 3,
entries 2, 3, 4, 6 and 7). Electron withdrawing substituents at the
m- (entries 8, 10 and 13) or p- positions (entries 11, 14, 16, 19
and 19) were also very well tolerated (91-96% ee), as well as 2-
furyl and 2-thiophenyl moieties (91-96% ee; entries 21 and 22,
respectively), with the exception being the 3-nitro substituted
chalcone (76% ee, entry 18). Chalcones having o- substituents,
however, gave rather lower ee’s ranging between 68-86% ee
(entries 5, 9, 12, 15, 17), presumably because of the steric
hindrance, since the detrimental effect was observed for
chalcones with both electron withdrawing and electron donating
substituents. The lowest ee was obtained with the 2-nitro
substituted chalcone (4q) (entry 17), which might be due to the
accelerated rate of background reaction in the presence of a
powerful electron withdrawing group in close proximity with the
reaction center, in addition to the steric hindrance.
References and notes
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4
Tetrahedron
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Supplementary Material
Experimental procedures, spectral and chromatographic data
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5



2-Adamantyl/quinine organocatalyst shows
remarkable enantioselectivity
Enantiomerically rich adducts can serve as
building blocks for drug synthesis
The first organocatalytic asymmetric
reaction of thioglycolic ester with chalcones