Bifunctional Amine-Squaramides as Organocatalysts in Michael/Hemiketalization Reactions of β,γ-Unsaturated α-Ketoesters and α,β-Unsaturated Ketones with 4-Hydroxycoumarins

Article abstract of DOI:10.1021/acs.joc.8b01847

The catalytic efficiency of various amine-squaramides was tested in Michael/hemiketalization reactions of 4-hydroxycoumarines with two types of enones. Tertiary amine-squaramide organocatalysts afforded the best results regarding both activity and enantio

Full text of DOI:10.1021/acs.joc.8b01847

Subscriber access provided by UNIV OF LOUISIANA
Article
Bifunctional Amine-Squaramides as Organocatalysts in Michael/
hemiketalization Reactions of #,#-Unsaturated #-Ketoesters
and #,#-Unsaturated ketones with 4-Hydroxycoumarins
Viktoria Modrocka, Eva Veverkova, Maria Meciarova, and Radovan Sebesta
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01847 • Publication Date (Web): 02 Oct 2018
Downloaded from http://pubs.acs.org on October 2, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Bifunctional AmineꢀSquaramides as Organocatalysts in
Michael/hemiketalization Reactions of β,γꢀUnsaturated αꢀ
Ketoesters and α,βꢀUnsaturated ketones with 4ꢀ
Hydroxycoumarins
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
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Viktória Modrocká, Eva Veverková, Mária Mečiarová, and Radovan Šebesta*
Comenius University in Bratislava, Faculty of Natural Sciences, Department of Organic Chemistry,
Mlynska dolina, Ilkovičova 6, SK-84215 Bratislava, Slovakia
Corresponding author: Radovan Šebesta; e-mail: radovan.sebesta@uniba.sk; tel.: +421 2 60296208.
Table of Contents/Abstract Graphic
Abstract
The catalytic efficiency of various amine-squaramides has been tested in Michael/hemiketalization
reactions of 4-hydroxycoumarines with two types of enones. Tertiary amine-squaramide
organocatalysts afforded the best results regarding both activity and enantioselectivity when β,γ-
unsaturated α-ketoesters were used as the Michael acceptors (yields up to 98%, enantioselectivities
up to 90% ee). On the other hand, the primary amine-squaramides are the best choice for related
reactions of 4-hydroxycoumarins with enones. The corresponding pyrano[3,2-c]chromen-5-on
products were obtained in high enantiomeric purities (up to 96%). The Michael addition of 4-
hydroxycoumarin to 4-phenylbut-3-en-2-on directly produced chiral anticoagulant drug (S)-warfarin
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 21
1
2
3
4
in 92% ee, when green solvent 2-MeTHF and catalyst (S,S)-C8 was used. Moreover, an enantiomeric
catalyst (R,R)-C8 gave (R)-warfarin in >99 % ee.
5
6
7
Introduction
Bifunctional amine-squaramides are effective hydrogen-bond donating catalysts for promoting many
asymmetric transformations.1-3 Since pioneering work of Rawal,4 these catalysts were utilized
successfully in a wide array of asymmetric Michael reactions, especially when nitroolefins were used
as Michael acceptors.5-10 On the other hand, Michael additions to β,γ-unsaturated α-keto esters
catalyzed by squaramides were reported less frequently. Xu and co-workers described the first
example of the ketoester activation by a squaramide organocatalyst.11 They presented Michael
addition of 4-hydroxycoumarins and related 4-hydroxy-6-methyl-2-pyrone to β,γ-unsaturated α-
oxoesters catalyzed by cinchona alkaloid-based squaramide. Amine-squaramide activation of α-
oxoesters was also used in Michael addition of 2-hydroxy-1,4-naphthoquinone,12 and cyclic
diketones.13
8
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
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The enantioselective Michael addition of 4-hydroxycoumarin to 4-phenylbut-3-en-2-one leads
directly to a chiral drug, (S)-warfarin, which is an effective anticoagulant for preventing thrombosis
and embolism. Jørgensen´s group described the first organocatalytic asymmetric Michael addition
that afforded warfarin and other Michael adducts in the presence of chiral imidazolidine catalysts.14
Later, Feng and co-workers used chiral amide catalyst derived from proline in warfarin synthesis.15
Primary amine-based organocatalysts were recognized as useful for Michael additions of
coumarins.16-17 Mlynarski, and recently, Zlotin described the synthesis of warfarin in water using (S,S)-
diphenylethylenediamine or quinoline-based 1,2-diamine organocatalysts.18-20 Primary amine
organocatalysts were also tagged with suitable ionic groups to ensure their recyclability.21-22 Warfarin
synthesis using quinine as a catalyst was also adopted for flow set-up.23 Several other efficient
asymmetric methods based on primary amine catalysts derived from cinchona and primary amine
thiourea catalysts have been introduced for the preparation of (S)-warfarin.24-25 Although bifunctional
amine-squaramide organocatalysts were used for activation of related compounds, they were not
used in the asymmetric synthesis of warfarin and its analogs.
In this context, we decided to study the applicability of various chiral bifunctional amine-
squaramides (Figure 1) in the Michael/hemiketalization reaction of 4-hydroxycoumarins with β,γ-
unsaturated α-oxo esters. We have also extended our study to Michael/hemiketalization reaction of
4-hydroxycoumarins with enones, which leads to warfarin. Furthermore, we would like to improve
sustainability profile of these syntheses by evaluating greener solvent alternatives.
Results and discussion
2
ACS Paragon Plus Environment

Page 3 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
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
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 1. Applied amine-squaramide organocatalysts.
In the first part of our study, we examined the reaction of 4-hydroxycoumarin (1a) to the α-oxoester
2a (Scheme 1). In our previous work, we have found that tertiary amine-squaramide catalysts
containing trans-cyclohexane-1,2-diamine chiral backbone were highly efficient for asymmetric
Michael addition of 4-hydroxycoumarin to nitrostyrenes.26 Therefore, we decided to exploit tertiary
amine catalysts C1 – C5 (Figure 1) in the reaction of 4-hydroxycoumarin (1a) with the α-oxoester 2a.
Scheme 1. Michael addition of 4-hydroxycoumarin to 4-phenyl-2-oxo-3-butenoate ethyl ester.
As shown in Table 1, all tested catalysts afforded the target product 3a without the formation of any
by-products. Catalyst C1 displayed high catalytic activity as the reaction was completed within 2 h
and afforded the product 3a in 98% yield. Product 3a is formed as a mixture of open (keto-3a) and
closed form (ketal-3a), which are in rapid equilibrium, as we observed only one set of signals on
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 21
1
2
3
4
5
6
7
8
9
HPLC. Keto and ketal isomers can, however, be observed by NMR. With catalyst C1, only moderate
enantiomeric purity (66% ee) of 3a was observed (Table 1, entry 1). In our previous works, catalyst C2
exhibited high stereo-control in related Michael additions.8,10 However, catalyst C2 showed only
moderate enantioselectivity in the reaction of 4-hydroxycoumarin (1a) with oxoester 2a (Table 1,
entry 2, 50% ee). Interestingly, catalyst C3 showed much higher stereo-control (90% ee) in this
transformation (Table 1, entry 3). The decrease of the catalyst loading to 2.5 mol% did not affect
enantioselectivity, but the yield decreased, so the reaction time had to be prolonged (Table 1, entry
4). Chiral catalyst C4 possessing binaphthol moiety afforded the product 3a as opposite (R)-
enantiomer in 60% yield and low enantiomeric purity (Table 1, entry 5). To compare the effects of
the configuration of the piperidinocyclohexylamine moiety on the studied reaction, we investigated
the catalyst C5 with both (S,R,R)- and (S,S,S)-configurations (Table 1, cf. entries 6 and 7). Catalyst C8,
bearing primary amine functionality afforded product 3a in only low enantiomeric purity (Table 1,
entry 8).
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
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Screening of catalysts in the Michael reaction of 1a and 2a.a
Yield of 3a
Entry
Catalyst
Time (h)
ee (%)e
(%)d
98
98
95
80
60
92
87
77
1
2
3
4
5
6
7
8
C1
C2
C3
C3b
2
2
1.5
4
4
2
66 (S)
50 (S)
90 (S)
90 (S)
46 (R)
82 (S)
76 (R)
33 (S)
(S,S,S)-C4
(S,R,R)-C5
(S,S,S)-C5
C8
2
4
a Unless noted otherwise, the reactions were carried out with 1a (0.2 mmol) and 2a (0.2 mmol) in the presence
of a catalyst (10 mol %) in DCM (1.0 mL) at ambient temperature for the time indicated. b 2.5 mol % of catalyst
was used. c Performed in dioxane. d Yield of isolated product. e Determined by HPLC analysis.
Solvents and reaction temperatures were assessed in the reaction of 4-hydroxycoumarin (1a) with
oxoester 2a using catalyst C3 (Table 2). This screening showed that the reaction works best in
dichloromethane at 20°C (Table 2, entry 1).
Table 2. Screening of solvents and temperatures in the reaction of 1a with 2a using catalyst C3.
Temp.
(°C)
20
30
0
Yield of 3a
Entry
Solvent
Time (h)
ee (%)e
(%)d
95
1
2
3
4
DCM
DCM
DCM
1,5
1,5
1,5
2
90
90
86
76
94
36
70
dioxane
20
4
ACS Paragon Plus Environment

Page 5 of 21
The Journal of Organic Chemistry
1
2
3
4
5
5
6
7
8
MeCN
THF
toluene
tBuOMe
3
2
4
4
30
30
30
30
58
98
20
10
84
84
60
n.d.
6
7
8
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
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Catalysts and conditions evaluation revealed that the reaction of hydroxycoumarins 1 with oxoesters
2 proceeds most efficiently in dichloromethane at room temperature using squaramide catalyst C3.
Under the optimized reaction conditions, the scope of the Michael addition/hemiketalization was
extended (Scheme 2). The reaction performed with catalyst C3 provided the corresponding products
3b-g in nearly quantitative yields (Scheme 2). It appears that the electronic properties of substituents
do not affect the efficiency of this reaction. In case of selectivity, no difference was observed with an
electron donor and electron acceptor substituents on the 4-hydroxycoumarin skeleton of products
3b and 3c. On the other hand, both derivatives of β,γ-unsaturated α-oxoesters resulted in a decrease
of enantioselectivity of the process. While the electron accepting chloro substituent caused only a
slight decrease of enantiomeric excess (88% for 3d, and 75 % for 3f), the electron donating methoxy
group led to a significant decrease of enantiomeric purities (58% ee for 3e, and 34 % ee for 3g). It
appears that higher electron density in the β,γ-unsaturated α-keto ester 2e have a negative effect on
the enantioselectivity of the process.
R2
OH
R1
HO
CO2Et
O
O
OH
O
O
O
catalyst C3
(10 mol%)
R1
R1
1
(S)
+
CO2Et
O
CH2Cl2
1.5 h, rt
R2
O
O
O
CO2Et
3
2
R2
HO
O
HO
O
HO
O
CO2Et
CO2Et
CO2Et
Me
Br
Ph
O
Ph
O
O
Cl
O
O
O
3f, 98%, 75% ee
3c, 94%, 90% ee
3b, 96%, 90% ee
HO
HO
HO
CO2Et
CO2Et
CO2Et
O
O
O
O
O
OMe
O
O
O
O
Cl
OMe
3g, 87%, 34% ee
3e, 97%, 58% ee
3d, 98%, 88% ee
Scheme 2. Substrate scope of the asymmetric reaction of coumarines 1 with α-oxoesters 2.
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 21
1
2
3
4
5
6
7
Because of swift action and high stereoselectivity of tertiary-squaramide catalysts tested above, we
also wanted to exploit them in Michael addition of 4-hydroxycoumarin (1a) to benzylideneacetone
(4a), a reaction that affords important anticoagulant, warfarin (5a). This type of Michael addition can
also afford anticoagulant rodenticide coumachlor (5d).
8
9
Catalysts C1 and C2 were either inactive or gave product 5a in racemic form (Table 3, entries 1 and
2). We have tried to enhance the reactivity of benzylidene acetone by covalent activation, imine
formation with (S)-proline as co-catalyst (Table 3, entries 3 and 4). Under these conditions, both
catalysts (S,S,S)-C4 as well as (S,R,R)-C5, afforded product 5a in good yields (79 and 70%, respectively)
but only in moderate enantiomeric purity (24 and 14% ee, respectively).
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
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Unsatisfactory results achieved with tertiary amine-squaramide organocatalysts prompted us to
investigate catalysts having ancillary secondary or primary amino groups. Secondary amine-
squaramide catalyst C6 afforded racemic warfarin (5a). Addition of basic additive led to a slight
increase of enantioselectivity (Table 3, cf. entries 5 and 6). It was reported that 4-hydroxycoumarin
can be activated by LiClO4 as a Lewis acid, so we applied it in the reaction with enones.27 We have
also replaced dichloromethane/methanol mixture with an aprotic solvent dioxane/acetonitrile,
because of the possible adverse effect of MeOH on the enantioselectivity of the process. However,
product 5a was still obtained in low yield and enantiomeric purity (Table 3, entry 7).
Interestingly, use of primary amine catalyst C7 resulted in increased enantioselectivity of the reaction
to 40% ee (Table 3, entry 8). This result encouraged us to use another primary amine catalyst C8 with
somewhat less rigid structure in comparison to catalyst C7. We were pleased to observe that catalyst
C8 afforded warfarin (5a) in 86% yield and high enantiomeric purity (90% ee) (Table 3, entry 9).
Table 3. Screening of catalysts and optimization of conditions in Warfarin synthesis.a
Yield of 5ae
Entry
Catalyst
Additived
-
Solvent
Time (d)
ee (%) f
(%)
52
-
79
70
26
60
44
23
86
1
2
3
4
5
6
7
8
9
C1
C2
DCM/MeOH
Dioxane
5
3
3
3
5
5
5
4
5
rac
-
24 (S)
14 (R)
rac
16 (R)
24 (R)
40 (R)
90 (R)
(S,S,S)-C4c
-
-
-
DCM/MeOH
DCM/MeOH
DCM/MeOH
DCM/MeOH
dioxane/MeCN
dioxane/MeCN
dioxane/MeCN
(S,R,R)-C5c
C6
C6
C6
C7
C8
NaOAc
LiClO4
LiClO4
LiClO4
a Unless noted otherwise, the reactions were carried out with 1a (0.25 mmol) and 4a (0.3 mmol) in the
presence of catalyst (10 mol %) in solvent (1.0 mL) at ambient temperature for the time indicated; b 50 mol %
of catalyst was used; c 10 mol % of (S)-proline was added; d 10 mol % of additive was used; e Yield of isolated
product; f Determined by HPLC analysis.
6
ACS Paragon Plus Environment

Page 7 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
7
Reaction solvent often dramatically influence reaction rate, yield, selectivity, as well as health and
environmental impact of the reaction.28 Therefore, we have screened several “green solvents” in the
asymmetric Michael addition of 4-hydroxycoumarin 1a to enone 4a.
8
9
Owing to the low solubility of starting material and catalysts in common organic solvents, we started
our study with ionic liquids and deep eutectic solvents. Room temperature ionic liquids are excellent
alternatives for traditional volatile organic solvents. Synthesis of warfarin proceeded in 1-ethyl-3-
methylimidazolium methyl sulfate ([Emim]OSO3Me) with 56% yield and 40% ee. Slightly better
results (65% yield and 72% ee) were obtained in 1-butyl-3-methylpyridinium
bis(trifluormethylsulfonyl)imide ([Bmpy]NTf2). The reaction in 1-ethyl-3-methylimidazolium 2-(2-
methoxyethoxy)ethylsulfate gave a product with 49% yield in racemic form (Table 4, entries 1–3).
Some other ionic liquids (see Supporting Information) have been tested, but they have not been
applicable for this reaction.
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
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Deep eutectic solvents (DESs) exhibit similar properties to ionic liquids while being cheaper, easier to
obtain, and its components often come from natural sources.29 When the reaction of 4-
hydroxycoumarin (1a) with ketone 4a was carried out in choline chloride/glycerol (1:2) mixture,
product 5a was obtained in 23% yield, but with only 35% ee. The reaction in choline chloride/urea
(1:2) and choline chloride/urea/water (1:2:4) has failed, and only traces of warfarin was detected in
the reaction mixture (Table 4, entries 4 and 5). Ethyl lactate is an environmentally benign solvent
with properties and applicability comparable to petroleum-based solvents.30 The reaction in chiral (-)-
L-ethyl lactate afforded the product 5a in 51% yield and reasonable optical purity of 76% ee (Table 4,
entry 6). Polyethyleneglycols (PEG), as well as glymes (glycol diethers), are non-toxic, inexpensive,
thermally stable, and recoverable media for organic reactions.31-32 Synthesis of warfarin in ethylene
glycol did not proceed well as the product was isolated only in 26% yield and 34% ee. The yield
increased to 40% in PEG 600 and warfarin was obtained with excellent enantiomeric purity (97 % ee).
Interestingly, monoglyme was one of the best solvents considering yield as well as enantiomeric
purity. The reaction led to warfarin in 78% yield and 88% ee (Table 4, entries 7–9).
Cyclopentyl(methyl)ether (CPME) and 2-methyltetrahydrofuran (2-MeTHF) are greener alternatives
to other ethereal solvents for many types of organic syntheses. Low peroxide formation, stability
under acidic and basic conditions, high boiling point and low heat of vaporization are their main
positive features.33 Furthermore, 2-MeTHF is derived from renewable resources.34 Warfarin synthesis
proceeded in CPME with 56% yield and 90% ee (Table 4, entry 10). The best solvent for
organocatalytic warfarin synthesis was 2-MeTHF with regard to the yield (81%) as well as
enantioselectivity (99% ee) (Table 4, entry 11).
Table 4. Green solvents screening in warfarin synthesis.a
Entry Solvent
Time (d) Yield of 5a (%)b
ee (%)c
40 (R)
72 (R)
rac
1
2
3
4
[Emim]OSO3Med
7
7
7
7
56
65
49
23
e
[Bmpy]NTf2
[Emim]OSO3Etf
Choline chloride/glycerol (1:2)
35 (R)
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 21
1
2
3
4
5
6
7
8
9
5
6
7
8
9
10
11
12h
Choline chloride/urea (1:2)
(-)-L-Ethyl lactate
Ethylene glycol
7
7
7
7
5
5
5
5
traces
51
26
40
78
n.d.
76 (R)
34 (R)
97 (R)
88 (R)
90 (R)
>99 (R)
92 (S)
PEG 600
1,2-Dimethoxyethane
Cyclopentyl(methyl)ether
2-Methyltetrahydrofurang
2-Methyltetrahydrofuran
56
81
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
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
84
a The reactions were carried out with 1a (0.25 mmol) and 4a (0.3 mmol) in the presence of catalyst (R,R)-C8 (10
mol%) and LiClO4 (10 mol%) at ambient temperature for the time indicated. b Yield of isolated product. c
Determined by HPLC analysis. d 1-ethyl-3-methylimidazolium methyl sulfate. e 1-butyl-3-methylpyridinium
bis(trifluormethylsulfonyl)imide. f 1-ethyl-3-methylimidazolium 2-(2-methoxyethoxy) ethyl sulfate. g For
comparison, the reaction in THF afforded product in 66% yield and 92% ee. h Catalyst (S,S)-C8 was used.
Optimized reaction conditions for the Michael addition/hemiketalization of hydroxycoumarins 1 to
enones 4 comprise 2-methyltetrahydrofuran as a solvent, room temperature, LiClO4 as an additive
and primary-amine squaramide catalyst C8. We have also extended the scope of Michael addition
reaction to various 4-hydroxycoumarines 1 and derivatives of benzylideneacetone 4 (Scheme 3). The
electronic properties of substituents on 4-hydroxycoumarin did not affect the enantioselectivities of
products 5b-i in comparison with product 5a. For benzylidene acetone with a substituted benzene
ring, electron-withdrawing substituent led to high enantioselectivities (5d, 5f, 5h). Electron-donating
substituent caused a slight decrease in enantioselectivity of product 5g (72% ee), and the yield
dropped as well (5e).
8
ACS Paragon Plus Environment

Page 9 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
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
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3. Substrate scope of the asymmetric reaction of coumarin derivatives 1 with α,β-
unsaturated ketones 4.
Absolute configuration of product (S)-3a, which was obtained with catalyst C3, was determined by
comparison of the order of peaks of enantiomers of 3a in chiral HPLC and sign of optical rotation with
literature values.11,13,35 Absolute configuration of compound (R)-5a (warfarin), which was synthesized
using catalyst (R,R)-C8, was determined by comparison of its optical rotation and circular dichroism
data with literature.36 Opposite absolute configuration of products 3a and 5a was unequivocally
ascertained by CD spectroscopy (Figure 2), which also strengthen assignement of series 3.
Configurations of other derivatives 3b-e and 5b-e were confirmed by CD spectroscopy too (see
Supporting information for more details).
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 21
1
2
3
4
5
6
7
8
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
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 2. CD spectra for (S)-3a (green line) and (R)-5a (red line).
With the help of quantum-chemical calculations, we have devised a stereomodel for the Michael
additions. The reaction of coumarin 1a with ketoester 2a was catalyzed by derivative C3. On the
other hand, in the reaction of coumarin 1a with enone 4a, the most effective primary amine C8 was
examined. DFT calculations were performed with dispersion corrected ωB97X-D functional using 6-
31G* basis set. Calculations support the notion that the reaction of coumarin 1a with ketoester 2a is
catalyzed via a hydrogen-bond-donating activation of catalyst C3. In this case, major (S)-configured
products 3 would originate via Si-attack of the coumarin to ketoester (Figure 3a). On the other hand,
in the reaction of enones 4, primary amine catalyst C8 promotes the reaction via an iminium
activation of the enone and concomitant hydrogen-bond activation of the coumarin moiety. Here,
Re-attack would afford (R)-5 as the major enantiomer (Figure 3b).
a)
O
O
O
HO
O
CO2Et
RO
F3C
(S)
N
N
H
Ph
H
=
N
H
O
O
O
O
O
C3
3a
(S)ꢀ
RO
Ph
O
O
Siꢀattack
b)
CF3
O
O
HO
O
Me
Ph
F3C
N
H
(R)
N
C8
Ph
H
Ph
Ph
=
O
HN
O
O
(R)ꢀ5a
Me
O
O
Reꢀattack
10
ACS Paragon Plus Environment

Page 11 of 21
The Journal of Organic Chemistry
1
2
3
4
Figure 3. Stereochemical model for Michael addition of coumarin 1a to oxoester 2a (Fig. 3a), and to enone 4a
(Fig. 3b); 3D-renderings obtained by DFT at ωB97XD/6-31G* level.
5
6
7
8
Conclusion
9
In conclusion, a series of chiral tertiary amine-squaramide catalysts, containing trans-cyclohexane-
1,2-diamine chiral backbone, was successfully applied to catalysis of the Michael/hemiketalization
reaction of 4-hydroxycoumarins with β,γ-unsaturated α-oxoesters in excellent yields (up to 98%) and
enantioselectivities (up to 90%). We found that primary amine-squaramides are highly effective
catalysts for Michael/hemiketalization reaction of 4-hydroxycoumarins with enones. Furthermore,
we developed an environmentally friendly Michael reaction affording warfarin and related Michael
adducts in high yields and enantioselectivities (up to 99% ee) when 2-methyltetrahydrofuran was
used as a green solvent.
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
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Experimental Section
General Information
The solvents were purified by standard methods. NMR spectra were recorded on NMR System 300
1
and 600 instruments (300 or 600 MHz for H, 151 MHz for 13C). Chemical shifts (δ) are given in ppm
relative to tetramethylsilane. Specific optical rotations were measured on Jasco P-2000 instrument
and are given in deg cm3 g–1 dm–1. Column chromatography was performed on Merck silica gel 60.
Thin-layer chromatography was performed on Merck TLC-plates silica gel 60, F-254. Enantiomeric
excesses were determined by HPLC using Chiralpak IA, IB (Daicel Chemical Industries) columns using
n-hexane/propan-2-ol as a mobile phase and detected by UV at 254 and 308 nm. HRMS spectra were
recorded on a hybrid ion trap/orbitrap mass spectrometer using HESI (heated electrospray
ionization) in positive mode. The squaramide organocatalysts C1,37 C2,38 C3,39 C4,40 C5,26 C6,41 C7,37
C842 were synthesized according to literature procedures.
General procedure for asymmetric Michael/hemiketalization reaction of 4-hydroxycoumarins and
(E)-ethyl 2-oxo-4-phenylbut-3-enoates
To a solution of 4-hydroxycoumarin (1, 0.2 mmol) and (E)-ethyl 2-oxo-4-arylbut-3-enoate (2, 0.2
mmol) in DCM (1 mL) the catalyst C3 (0.02 mmol) was added. The solution was stirred at room
temperature for 1.5 h. Then the solvent was removed in vacuo, and the crude product was purified
by column chromatography on silica gel, eluted by hexane-EtOAc (5:1 – 3:1).
(4S)-Etyl 4-phenyl-2-hydroxy-5-oxo-2,3,4,5-tetrahydropyrano[3,2-c]chromene-2-carboxylate (3a). 70
25
mg (95%), white solid, mp 166-168 °C; [α]D20 +6.0 (c = 0.93, CHCl3); lit35 [α]D –40.8 (c 0.93, CHCl3 for
(R)-enantiomer). 1H NMR (600 MHz, CDCl3) δ: 7.79 (dd, J = 7.9, 1.4 Hz, 1 H), 7.57-7.51 (m, 1 H), 7.33-
7.20 (m, 7 H), 4.64 (s, 1 H), 4.36 (q, J = 7.1 Hz, 2 H), 4.25 (t, J = 7.8 Hz, 1 H), 2.61-2.43 (m, 2 H); 1.35 (t,
J = 7.1 Hz, 3 H). Spectral data are consistent with those in the literature.11 Enantiomeric excess 90 %
ee determined by HPLC (Chiralpak IB, hexane/iPrOH 80:20, flow rate 1 mL/min, λ = 254 nm):
tR(minor) = 14.33 min, tR(major) = 26.57 min.
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 21
1
2
3
4
5
6
7
8
9
(4S)-Ethyl
9-bromo-4-phenyl-2-hydroxy-5-oxo-2,3,4,5-tetrahydropyrano[3,2-c]chromene-2-
20
carboxylate (3b). 86 mg (96%), white solid, mp 193-195 °C; [α]D +15.0 (c = 0.3, CHCl3). The product
was found to exist in rapid equilibrium with a pseudo-diastereomeric hemiketal form in solution. The
equilibrium is very rapid and therefore no pseudo-diastereomers are observed during HPLC analysis.
1H NMR (600 MHz, CDCl3) δ: 7.93 (d, J = 2.4 Hz, 0.3 H, ArH), 7.88 (d, J = 2.4 Hz, 0.7 H, ArH), 7.67-7.59
(m, 1H, ArH), 7.38-7.28 (m, 2.5 H, ArH), 7.25-7.16 (m, 3.5 H, ArH), 4.89 (s, 0.7 H, OH ketal), 4.63 (s, 0.3
H, OH keto), 4.42-4.30 (m, 2.3 H, CH2 ketal and keto, CH ketal), 4.22-4.16 (m, 0.7 H; CH2 keto), 2.80
(ddd, J = 14.3, 7.4, 1.2 Hz, 0.4 H, CH2 ketal), 2.52 (dd, J = 14.3, 3.3 Hz, 0.4 H, CH2 ketal), 2.44 (d, J = 8.8
Hz, 1.3 H, CH2 ketal), 1.45 (t, J = 7.1 Hz, 0.3 H, CH3 keto), 1.36 (dt, J = 7.1 3.3 Hz, 2.8 H, CH3 keto and
ketal). 13C NMR (151 MHz, CDCl3) δ: 168.3, 160.9, 160.0, 157.4, 156.9, 151.7, 142.0, 141.2, 134.9,
134.6, 129.2, 128.9, 128.7, 128.4, 127.4, 127.1, 126.9, 126.8, 125.5, 125.4, 118.4, 118.3, 116.9, 116.6,
105.9, 103.9, 96.2, 95.6, 63.7, 38.0, 35.4, 34.7, 33.8, 14.0. HRMS (ESI) m/z: [M+H]+ calcd for
C21H18BrO6 445.0288; found 445.0299. Enantiomeric excess 90% ee determined by HPLC (Chiralpak
IB, Hexane/iPrOH 75:25, flow rate 1 mL/min, λ = 254 nm): tR(minor) = 11.85 min, tR(major) = 34.13
min.
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
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(4S)-Ethyl 4-fenyl-2-hydroxy-9-metyl-5-oxo-2,3,4,5-tetrahydropyrano[3,2-c]chromene-2-carboxylate
(3c). 71 mg (94%), white solid, mp 191-193 °C; [α]D +23.6 (c 1.03, CHCl3); lit.35 [α]D –42.7 (c 1.03,
CHCl3 for (R)-enantiomer). The product was found to exist in rapid equilibrium with a pseudo-
diastereomeric hemiketal form in solution. The equilibrium is very rapid and therefore no pseudo-
20
25
1
diastereomers are observed during HPLC analysis. H NMR (600 MHz, CDCl3) δ: 7.60 (s, 0.4 H), 7.55
(s, 0.6 H, ArH); 7.38-7.27 (m, 3 H, ArH), 7.25-7.22 (m, 2 H, ArH), 7.19 (d, J = 8.4 Hz, 1 H, ArH), 4.68 (s,
0.7 H, OH ketal), 4.48 (s, 0.3 H, OH keto), 4.41-4.31 (m, 2.3 H, CH2 ketal and keto, CH ketal), 4.21-4.18
(m, 0.7 H, CH2 keto), 2.80 (dd, J = 13.2, 7.5 Hz, 0.4 H, CH2 ketal), 2.53 (dd, J = 14.3, 3.1 Hz, 0.4 H, CH2
ketal), 2.45-2.42 (m, 4 H, CH2 and CH3 ketal), 1.37-1.34 (m, 3 H, CH3 keto and ketal). Spectral data are
consistent with those in the literature.11 Enantiomeric excess 90% ee determined by HPLC (Chiralpak
IB, Hexane/iPrOH 75:25, flow rate 1 mL/min, λ = 254 nm): tR(minor) = 4.90 min, tR(major) = 18.49
min.
(4S)-Ethyl
2-hydroxy-4-(4-chlorophenyl)-5-oxo-2,3,4,5-tetrahydropyrano[3,2-c]
chromen-2-
carboxylate (3d). 78 mg (98%), white solid, mp 200-202 °C; [α]D +30.8 (c 1.07, CHCl3); lit.35 [α]D
–
20
25
51.7 (c 1.07, CHCl3 for (R)-enantiomer). The product was found to exist in rapid equilibrium with a
pseudo-diastereomeric hemiketal form in solution. The equilibrium is very rapid and therefore no
pseudo-diastereomers are observed during HPLC analysis. 1H NMR (600 MHz, CDCl3) δ: 7.79 (ddd, J =
13.3, 7.9, 1.5 Hz, 1 H, ArH), 7.56 (m, 1 H, ArH), 7.38-7.27 (m, 3.5 H, ArH), 7.20 (dt, J = 5.7, 4.5 Hz, 2.5
H, ArH), 4.73 (s, 0.6 H, OH ketal), 4.56 (s, 0.4 H, OH keto), 4.38 (q, J = 7.1 Hz, 2 H, CH2 ketal), 4.31 (dd,
J = 7.5, 2.7 Hz; 0.4 H, CH ketal), 4.18 (dd, J = 11.0, 7.6 Hz, 0.7 H, CH ketal), 2.80 (dd, J = 14.3, 7.5 Hz,
0.5 H, CH2 ketal), 2.50-2.38 (m, 1.7 H, CH2 ketal), 1.36 (td, J = 7.1, 2.6 Hz, 3 H, CH3 ketal and keto).
Spectral data are consistent with those in the literature.27 Enantiomeric excess 88% ee determined
by HPLC (Chiralpak IB, Hexane/iPrOH 85:15, flow rate 0.7 mL/min, λ = 254 nm): tR(minor) = 26.87 min,
tR(major) = 37.04 min.
(4S)-Ethyl
2-hydroxy-4-(4-metoxyphenyl)-5-oxo-2,3,4,5-tetrahydropyrano[3,2-c]
chromene-2-
carboxylate (3e). 77 mg (97 %), white solid, mp 164-166 °C; [α]D +35.6 (c 1.2, CHCl3); lit.35 [α]D
–
20
25
45.0 (c 1.2, CHCl3 for (R)-enantiomer). The product was found to exist in rapid equilibrium with a
12
ACS Paragon Plus Environment

Page 13 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
pseudo-diastereomeric hemiketal form in solution. The equilibrium is very rapid and therefore no
pseudo-diastereomers are observed during HPLC analysis. 1H NMR (600 MHz, CDCl3) δ: 7.80 (ddd, J =
16.7, 7.9, 1.5 Hz, 1 H, ArH), 7.59-7.50 (m, 1 H, ArH), 7.37-7.25 (m, 2 H, ArH), 7.18 (d, J = 8.5 Hz, 2 H,
ArH), 6.87-6.81 (m, 2 H, ArH), 4.73 (s, 0.6 H, OH ketal), 4.54 (s, 0.4 H, OH keto), 4.40-4.29 (m, 2.4 H,
CH2 ketal and keto, CH ketal), 4.16 (t, J = 9.2 Hz, 0.7 H, CH ketal), 3.78 (s, 1.9 H, CH3 ketal), 3.77 (s, 1.1
H, CH3 keto), 2.78 (dd, J = 14.3, 7.3 Hz, 0.5 H, CH2 ketal), 2.50 (dd, J = 14.3, 3.0 Hz, 0.5 H, CH2 ketal),
2.43 (d, J = 9,3 Hz, 1.3 H, CH2 ketal), 1.35 (t, J = 7.1 Hz, 2.8 H, CH3 ketal), 1.25 (t, J = 7.1 Hz, 0.2 H, CH3
keto). Spectral data are consistent with those in the literature.27 Enantiomeric excess 58% ee
determined by HPLC (Chiralpak IB, Hexane/iPrOH 80:20, flow rate 1.0 mL/min, λ = 254 nm): tR(minor)
= 9.96 min, tR(major) = 14.26 min.
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
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(4S)-Ethyl 4-(4-chlorophenyl)-2-hydroxy-9-methyl-5-oxo-2,3,4,5-tetrahydropyrano[3,2-c]chromene-2-
carboxylate (3f). 61 mg (98%), white solid, mp 204-206 °C; [α]D20 +49,2 (c = 1, CHCl3). The product was
found to exist in rapid equilibrium with a pseudo-diastereomeric hemiketal form in solution. The
equilibrium is very rapid and therefore no pseudo-diastereomers are observed during HPLC analysis.
1H NMR (600 MHz, CDCl3) δ: 8.09 (s, 0,2 H, ArH), 7.56 (d, J = 27.7 Hz, 1 H, ArH), 7.36(ddd, J = 22.4 Hz,
8.5 Hz, 1.8 Hz, 1 H, ArH), 7.29-7.26 (m, 1.5 H, ArH), 7.25-7.23 (m, 0.8 H, ArH), 7.20-7.17 (m, 2.5 H,
ArH), 4.71 (s, 0.6 H, OH ketal), 4.55 (s, 0.4 H, OH keto), 4.40-4.37 (m, 2 H, CH2 ketal), 4.29 (dd, J = 7.5,
2.8 Hz; 0.4 H, CH ketal), 4.17 (dd, J = 11.6, 7.0 Hz, 0.6 H, CH ketal), 2.80 (dd, J = 13.5, 6.8 Hz, 0.4 H, CH2
ketal), 2.47-2.40 (m, 3.6 H, CH2 and CH3 ketal), 1.37 (td, J = 7.1, 2.6 Hz, 3 H, CH3 ketal and keto) ppm.
13C NMR (151 MHz, CDCl3) δ: 168.5, 168.4, 161.7, 160.7, 158.5, 158.2, 151.0, 151.0, 141.1, 140.3,
133.8, 133.6, 133.2, 133.0, 132.4, 132.3, 129.5, 128.9, 128.5, 128.4, 122.4, 116.5, 116.4, 114.8, 114.6,
104.4, 102.4, 95.7, 95.2, 63.7, 37.9, 35.1, 34.1, 33.1, 30.6, 29.7, 29.0, 24.0, 22.9, 20.9, 14.0. HRMS
(ESI) m/z: [M+H]+ calcd for C22H20ClO6 415.0943; found 415.0944. IR (ATR): 3442, 2923, 1720, 1630,
1586, 1489, 1410, 1364, 1026, 920. Enantiomeric excess 75% ee determined by HPLC (Chiralpak IB,
Hexane/iPrOH 85:15, flow rate 0,8 mL/min, λ = 254 nm): tR(minor) = 12.28 min, tR(major) = 17.78
min.
(4S)-Ethyl 2-hydroxy-4-(4-methoxyphenyl)-9-methyl-5-oxo-2,3,4,5-tetrahydropyrano[3,2-c]chromene-
20
2-carboxylate (3g). 54 mg (87%), white solid, mp 182-184 °C; [α]D 36,8 (c = 1, CHCl3). The product
was found to exist in rapid equilibrium with a pseudo-diastereomeric hemiketal form in solution. The
equilibrium is very rapid and therefore no pseudo-diastereomers are observed during HPLC analysis.
1H NMR (600 MHz, CDCl3) δ: 8.09 (s, 0,3 H, ArH), 7.57 (d, J = 34.9 Hz, 1 H, ArH), 7.36 (dd, J = 8.5 Hz,
1.7 Hz, 0.6 H, ArH), 7.32 (d, J = 10.4 Hz, 0.4 H, ArH), 7.24 (s, 0.3 H, ArH), 7.19-7.16 (m, 2.4 H, ArH),
6.86-6.81 (m, 2 H, ArH), 4.73 (s, 0.6 H, OH ketal), 4.53 (s, 0.4 H, OH keto), 4.39-4.31 (m, 2.3 H, CH2
ketal and keto, CH ketal), 4.15 (t, J = 9.2 Hz, 0.7 H, CH ketal), 3.78 (s, 1.8 H, CH3 ketal), 3.76 (s, 1 H,
CH3 keto), 2.76 (dd, J = 14.9, 6.7 Hz, 0.5 H, CH2 ketal), 2.49 (dd, J = 14.3, 3.0 Hz, 0.5 H, CH2 ketal), 2.43-
2.41 (m, 3.6 H, CH2 and CH3 ketal), 1.35 (td, J = 7.1 Hz, 3.2 Hz, 3 H, CH3 keto and ketal) ppm. 13C NMR
(151 MHz, CDCl3) δ: 168.6, 168.5, 165.9, 161.8, 160.8, 158.3, 158.2, 157.8, 151.0, 150.9, 134.5, 134.2,
133.7, 133.6, 133.5, 133.0, 132.8, 129.5, 128.4, 128.1, 122.5, 122.3, 116.4, 116.3, 115.3, 114.7,
114.1, 113.9, 105.0, 103.0, 96.0, 95.3, 67.8, 63.5, 55.2, 38.9, 38.2, 35.5, 33.8, 32.8, 30.6, 29.7, 29.0,
24.0, 23.0, 20.9, 14.0. HRMS (ESI) m/z: [M+H]+ calcd for C23H23O7 411.1438; found 411.1436. IR (ATR):
3442, 2926, 1721, 1631, 1585, 1243, 1222, 1189, 1100, 1020. Enantiomeric excess 34% ee
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 21
1
2
3
determined by HPLC (Chiralpak IB, Hexane/iPrOH 80:20, flow rate 1 mL/min, λ = 254 nm): tR(minor) =
4
29.83 min, tR(major) = 45.63 min.
5
6
7
8
9
General procedure for asymmetric Michael/hemiketalization reaction of 4-hydroxycoumarins and
(E)-4-arylbut-3-en-2-one
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
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
To a solution of 4-arylbut-3-en-2-one (4, 0.3 mmol) in 2-MeTHF (1 mL) the catalyst C8 (13 mg, 0.025
mmol) was added and mixture was stirred at room temperature 5 min. Then 4-hydroxycoumarin (1,
0.25 mmol) and LiClO4 (2,7 mg, 0,025 mmol) was added. The reaction mixture was stirred at room
temperature for 4 d. Then the solution was loaded onto silica gel column to purify the desired
product by using hexane-EtOAc (3:1) eluent system. From other green solvents, the product was
isolated after extraction to DCM or EtOAc and purification by column chromatography with eluent
hexanes/EtOAc.
(4R)-4-Phenyl-2-hydroxy-2-methyl-3,4-dihydropyrano[3,2-c]chromene-5(2H)-one (5a). 63 mg (81%),
white solid, mp 160-161 °C; [α]D +10.0 (c 0.6, CH3CN); lit.43 [α]D20 +9.9 (c 0.46, CH2Cl2). The product
20
was found to exist in rapid equilibrium with a pseudo-diastereomeric hemiketal form in solution. The
equilibrium is very rapid and therefore no pseudo-diastereomers are observed during HPLC analysis.
1H NMR (600 MHz, CDCl3) δ: 9.45 (s, 0.2 H), 7.94 (dd, J = 8.0, 1.4 Hz; 0.2 H, ArH), 7.89 (dd, J = 8.0, 1.4
Hz, 0.5 H, ArH), 7.81 (dd, J = 8.2, 1.1 Hz, 0.5 H, ArH), 7.56 (ddd, J = 8.6, 7.3, 1.6 Hz, 0.5 H, ArH), 7.50-
7.46 (m, 0.6 H, ArH), 7.36-7.20 (m, 7 H, ArH), 4.70 (dd, J = 10.0, 2.4 Hz, 0.2 H, CH keto), 4.28 (dd, J =
6.8, 3.3 Hz, 0.5 H, CH ketal), 4.16 (dd, J = 11.4, 6.9 Hz, 0.6 H, CH ketal), 3.86 (dd, J = 19.4, 10.1 Hz, 0.3
H, CH2 keto), 3.34 (d, J = 2.3 Hz, 0.1 H, CH2 keto), 3.28-3.25 (m, 0.6 H, CH2 keto), 3.20 (s, 0.5 H, CH2
ketal), 2.57-2.38 (m, 1.7 H, CH2 keto), 2.29 (s, 0.5 H, CH3 ketal); 2.05-1.97 (m, 0.7 H, CH2 ketal), 1.71(s,
1.6 H, CH3 ketal), 1.67 (s, 1.4 H, CH3 ketal). Spectral data are consistent with those in the literature.44
Enantiomeric excess 99% ee determined by HPLC (Chiralpak IA, Hexane/iPrOH 80:20, flow rate 1
mL/min, λ = 308 nm): tR(major) = 15.76 min, tR(minor) = 49.29 min.
(4R)-9-bromo-2-hydroxy-2-methyl-4-phenyl-3,4-dihydropyrano[3,2-c]chromene-5(2H)-one (5b). 68 mg
25
(70 %), white solid, mp 181-183 °C, [α]D +28.6 (c 1.0, CH3CN). The product was found to exist in
rapid equilibrium with a pseudo-diastereomeric hemiketal form in solution. The equilibrium is very
rapid and therefore no pseudo-diastereomers are observed during HPLC analysis. 1H NMR (600 MHz,
CDCl3) δ: 9.63 (s, 0.2 H), 7.97 (dd, J = 47.9 Hz, 1.8 Hz, 1 H, ArH), 7.81 (dd, J = 8.6 Hz, 1.6 Hz, 0.5 H,
ArH), 7.65 (dd, J = 8.7 Hz, 2.0 Hz, 0.5 H, ArH), 7.34-7.15 (m, 6 H, ArH), 4.68 (d, J = 9.9 Hz, 0.2 H, CH
keto), 4.28 (dd, J = 6.6 Hz, 2.7 Hz, 0.5 H, CH ketal), 4.15 (dd, J = 11.4 Hz, 6.9 Hz, 0.7 H, CH ketal), 3.84
(dd, J = 15.6 Hz, 8.6 Hz, 0.3 H, CH2 keto), 3.32 (d, J = 20.1 Hz, 0.2 H, CH2 keto), 3.17 (s, 1 H, CH2 ketal),
2.56-2.39 (m, 1.7 H, CH2 keto), 2.30 (s, 0.5 H, CH3 ketal), 2.04-1.98 (m, 0.8 H, CH2 ketal), 1.74 (s, 1.6 H,
CH3 ketal), 1.69 (s, 1.4 H, CH3 ketal) ppm. 13C NMR (151 MHz, CDCl3) δ: 161.4, 160.5, 158.4, 157.4,
151.8, 151.7, 142.7, 141.1, 134.8, 134.3, 129.2, 128.7, 127.3, 127.0, 126.9, 126.6, 125.7, 125.3, 118.4,
118.3, 117.4, 116.8, 116.4, 105.3, 102.1, 100.8, 99.2, 42.3, 39.8, 35.4, 34.1, 28.3, 27.8. HRMS (ESI):
m/z 387.0233 calcd for C19H16BrO4 [M+H]+; found 387.0230. IR (ATR): 3363, 1683, 1609, 1558, 1479,
1412, 1373, 1066, 878, 780. Enantiomeric excess 94% ee determined by HPLC (Chiralpak IA,
Hexane/iPrOH 75:25, flow rate 0.5 mL/min, λ = 308 nm): tR(major) = 20.74 min, tR(minor) = 50.29
min.
14
ACS Paragon Plus Environment

Page 15 of 21
The Journal of Organic Chemistry
1
2
3
4
(4R)-2-hydroxy-2,9-dimethyl-4-phenyl-3,4-dihydropyrano[3,2-c]chromene-5(2H)-one (5c). 72 mg
25
(90%), white solid, mp 178-181 °C, [α]D +12.3 (c = 1.0, CH3CN). The product was found to exist in
5
6
7
8
rapid equilibrium with a pseudo-diastereomeric hemiketal form in solution. The equilibrium is very
rapid and therefore no pseudo-diastereomers are observed during HPLC analysis. 1H NMR (600 MHz,
CDCl3) δ: 9.41 (s, 0.2 H), 7.64 (d, J = 47.4 Hz, 1 H, ArH), 7.37-7.11 (m, 7 H, ArH), 4.70 (d, J = 10.1 Hz, 0.2
H, CH keto), 4.28 (dd, J = 6.9 Hz, 3.2 Hz, 0.5 H, CH ketal), 4.15 (dd, J = 11.3 Hz, 6.9 Hz, 0.5 H, CH ketal),
3.86 (dd, J = 19.4 Hz, 10.1 Hz, 0.2 H, CH2 keto), 3.31 (dd, J = 19.4 Hz, 2.4 Hz, 0.2 H, CH2 keto), 3.19 (d, J
= 13.3 Hz, 1 H, CH2 ketal), 2.54 (dd, J = 14.2 Hz, 3.3 Hz, 0.5 H, CH2 keto), 2.49-2.39 (m, 4 H, CH2 and
CH3 keto), 2.29 (s, 0.5 H, CH3 ketal), 2.04-1.98 (m, 0.6 H, CH2 ketal), 1.72 (s, 1.5 H, CH3 ketal), 1.68 (s,
1.5 H, CH3 ketal) ppm. 13C NMR (151 MHz, CDCl3) δ: 212.6, 177.9, 162.3, 161.4, 159.6, 158.6, 151.1,
151.1, 143.2, 141.5, 133.6, 133.3, 133.0, 132.5, 129.2, 128.6, 128.1, 127.9, 127.2, 127.0, 126.9, 126.5,
122.7, 122.3, 116.4, 116.3, 104.0, 101.0, 100.4, 98.9, 45.2, 42.5, 40,0, 35.3, 34.9, 34.1, 30.0, 28.3,
27.7, 20.9. HRMS (ESI): m/z 323.1279 calcd for C20H19O4 [M+H]+; found 323.1280. IR (ATR): 3428,
2926, 1687, 1610, 1577, 1492, 1379, 1064, 997, 764. Enantiomeric excess 96% ee determined by
HPLC (Chiralpak IA, Hexane/iPrOH 75:25, flow rate 1 mL/min, λ = 308 nm): tR(major) = 7.37 min,
tR(minor) = 22.31 min.
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
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(4R)-4-(4-chlorophenyl)-2-hydroxy-2-metyl-3,4-dihydropyrano[3,2-c]chromene-5(2H)-one (5d). 40 mg
25
(47 %), white solid, mp 177-179 °C (lit. 174-176 °C), [α]D +15.6 (c = 1.0, CH3CN). The product was
found to exist in rapid equilibrium with a pseudo-diastereomeric hemiketal form in solution. The
equilibrium is very rapid and therefore no pseudo-diastereomers are observed during HPLC analysis.
1H NMR (600 MHz, CDCl3) δ: 9.55 (s, 0.2 H), 7.88 (dd, J = 7.9 Hz, 1.4 Hz, 0.4 H, ArH), 7.82 (dd, J = 7.9
Hz, 1.4 Hz, 0.6 H, ArH), 7.57-7.51 (m, 1 H, ArH), 7.36-7.16 (m, 6 H, ArH), 4.64 (d, J = 8.3 Hz, 0.2 H, CH
keto); 4,21 (dd, J = 7,0 Hz, 2.5 Hz, 0.4 H, CH ketal), 4.14 (dd, J = 13.7 Hz, 6.8 Hz, 0.6 H, CH ketal), 3.88-
3.83 (m, 0.2 H, CH2 keto), 3.27 (d, J = 19.5 Hz, 0.2 H, CH2 keto), 2.99 (d, J = 42.3 Hz, 1 H, CH2 keto),
2.48-2.39 (m, 1.7 H, CH2 keto), 2.30 (s, 0.5 H, CH3 ketal), 2.04 (s, 0.3 H, CH2 ketal), 1.98-1.94 (m, 0.7 H,
CH2 ketal), 1.75 (s, 1.8 H, CH3 ketal), 1.70 (s, 1.2 H, CH3 ketal) ppm. Spectral data are consistent with
those in the literature.27 Enantiomeric excess 99% ee determined by HPLC (Chiralpak IA,
Hexane/iPrOH 80:20, flow rate 0.8 mL/min, λ = 308 nm): tR(major) = 18.85 min, tR(minor) = 52.11
min.
(4R)-4-(4-methoxyphenyl-2-hydroxy-2-methyl-3,4-dihydropyrano[3,2-c]chromene-5(2H)-one (5e). 41
25
mg (48 %), white solid, mp 167-169°C (lit. 164-166 °C), [α]D +18.9 (c 1.0, CH3CN). The product was
found to exist in rapid equilibrium with a pseudo-diastereomeric hemiketal form in solution. The
equilibrium is very rapid and therefore no pseudo-diastereomers are observed during HPLC analysis.
1H NMR (600 MHz, CDCl3) δ: 9.41 (s, 0.2 H), 7.86 (dd, J = 24.0 Hz, 7.4 Hz, 1 H, ArH), 7.59-7.48 (m, 1 H,
ArH), 7.37-7.13 (m, 4 H, ArH), 6.88-6.80 (m, 2 H, ArH), 4.65 (dd, J = 10.0 Hz; 2.1 Hz, 0.3 H, CH keto),
4.26 (dd, J = 6.6 Hz, 2.8 Hz, 0.5 H, CH ketal), 4.12 (dd, J = 11.3 Hz, 6.8 Hz, 0.6 H, CH ketal), 3.78 (s, 1.3
H, CH3 ketal), 3.77 (s, 1.7 H, CH3 keto), 3.26 (s, 0.5 H, CH2 keto), 3.09 (d, J = 1.9 Hz, 0.5 H, CH2 keto),
2.57-2.37 (m, 1.7 H, CH2 keto), 2.29 (s, 0.5 H, CH3 ketal), 2.04-1.96 (m, 0.7 H, CH2 ketal), 1.72 (s, 1.5 H,
CH3 ketal), 1.68 (s, 1.5 H, CH3 ketal) ppm. Spectral data are consistent with those in the literature.27
Enantiomeric excess 84% ee determined by HPLC (Chiralpak IA, Hexane/iPrOH 80:20, flow rate 0.6
mL/min, λ = 308 nm): tR(major) = 26.77 min, tR(minor) = 59.69 min.
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 21
1
2
3
4
5
6
7
8
9
(4R)-4-(4-chlorophenyl)-2-hydroxy-2,9-dimethyl-3,4-dihydropyrano[3,2-c]chromen-5(2H)-one (5f). 37
mg (69 %), yellow solid, mp 181-183 °C, [α]D25 +14.3 (c 0.6, CH3CN). The product was found to exist in
rapid equilibrium with a pseudo-diastereomeric hemiketal form in solution. The equilibrium is very
rapid and therefore no pseudo-diastereomers are observed during HPLC analysis. 1H NMR (600 MHz,
CDCl3) 9.49 (s, 0.2 H), 7.72 (s, 1 H, ArH), 7.66 (s, 0.5 H, ArH), 7.60 (s, 0.5 H, ArH), 7.54-7.52 (m, 1 H,
ArH), 7.38-7.32 (m, 1 H, ArH), 7.23-7.15 (m, 3 H, ArH), 4.63 (d, J = 10.2 Hz, 0.2 H, CH keto), 4.29 (d, J =
6.8 Hz, 1 H, CH ketal), 4.22-4.20 (m, 0.5 H, CH keto), 4.15 (dd, J = 11.5 Hz, 6.8 Hz, 0.5 H, CH keto), 3.85
(dd, J = 19.2 Hz, 10.5 Hz, 0.3 H, CH2 keto), 3.00 (s, 0.6 H, CH2 keto), 2.94 (s, 0.4 H, CH2 ketal), 2.47-2.40
(m, 4 H, CH2 and CH3 keto), 2.30 (s, 0.5 H, CH3 ketal), 1.75 (s, 1.7 H, CH3 ketal), 1.70 (s, 1.3 H, CH3
ketal) ppm. 13C NMR (151 MHz, CDCl3) δ: 212.5, 167.7, 162.1, 159.5, 158.8, 151.1, 151.1, 141.8,
140.5, 133.7, 133.4, 133.1, 132.7, 132.1, 130.9, 129.4, 129.0, 128.8, 128.6, 128.4, 128.2, 127.9, 127.2,
127.0, 126.9, 126.5, 122.6, 122.3, 116.5, 116.3, 103.7, 101.0, 100.7, 98.7, 66.2, 65.9, 45.2, 42.3, 39.9,
36.5, 34.9, 34.0, 28.3, 27.9, 20.9. HRMS (ESI): m/z 357.0888 calcd for C20H18ClO4 [M+H]+; found
357.0888. IR (ATR): 3375, 2927, 1678, 1617, 1571, 1488, 1376, 1110, 815, 782. Enantiomeric excess
86% ee determined by HPLC (Chiralpak IA, Hexane/iPrOH 80:20, flow rate 0.6 mL/min, λ = 308 nm):
tR(major) = 10.36 min, tR(minor) = 41.59 min.
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
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(4R)-2-hydroxy-4-(4-methoxyphenyl)-2,9-dimethyl-3,4-dihydropyrano[3,2-c]chromen-5(2H)-oneone
20
(5g). 44 mg (83 %), yellow solid, mp 186-188 °C, [α]D +5.3 (c 1, CH3CN). The product was found to
exist in rapid equilibrium with a pseudo-diastereomeric hemiketal form in solution. The equilibrium is
1
very rapid and therefore no pseudo-diastereomers are observed during HPLC analysis. H NMR (600
MHz, CDCl3) δ: 9.34 (s, 0.2 H), 7.72 (s, 1.6 H, ArH), 7.6 (s, 0.4 H, ArH), 7.54-7.52 (m, 1.6H, ArH), 7.22-
7.18 (m, 1.4H), 6,87-6,80 (m, 2H, ArH), 4.64 (dd, J = 9.9 Hz, 2.5 Hz, 0.2 H, CH keto), 4.31-4,28 (m, 1.8
H, CH ketal and CH keto), 4.13-4.10 (m, 0.5 H, CH2 ketal), 3.86 (m, 0.2 H, CH2 keto), 3.78 (s, 1.2 H, CH3
ketal), 3.77 (s, 1.8 H, CH3 keto), 3.23 (s, 0.5 H, CH2 keto), 2.53 (dd, J = 14.2 Hz, 2.9 Hz, 0.5 H, CH2 keto),
2.48-2.39 (m, 3,6 H, CH2 and CH3 ketal), 2.28 (s, 0.4 H, CH3 ketal), 2.04-1.99 (m, 0.6 H, CH2 ketal), 1.73
(s, 1.6 H, CH3 ketal), 1.68 (s, 1.4 H, CH3 ketal) ppm. 13C NMR (151 MHz, CDCl3) δ: 212.6, 167.7, 162.3,
159.4, 158.7, 158.1, 151.1, 151.1, 135.1, 133.6, 133.3, 132.9, 132.5, 130.9, 129.0, 128.8, 128.0, 123.5,
122.7, 122.3, 116.4, 116.3, 114.7, 114.1, 104.3, 101.2, 100.4, 98.9, 66.2, 65.9, 55.3, 45.5, 42.5, 39.8,
36.6, 36.5, 34.3, 33.1, 32.5, 29.2, 27.9, 26.8, 23.0, 20.9. HRMS (ESI): m/z 353.1384 calcd for C21H21O5
[M+H]+; found 353.1382. IR (ATR): 3386, 2930, 1681, 1607, 1575, 1376, 1248, 1113, 815, 784.
Enantiomeric excess 72% ee determined by HPLC (Chiralpak IA, Hexane/iPrOH 80:20, flow rate 0.6
mL/min, λ = 308 nm): tR(major) = 12.90 min, tR(minor) = 38.19 min.
(4R)-9-bromo-4-(4-chlorophenyl)-2-hydroxy-2-methyl-3,4-dihydropyrano[3,2-c]chromen-5(2H)-one
(5h). 61 mg (97 %), yellow solid, mp 215-217 °C, [α]D20 +24.6 (c 0.5, CH3CN). The product was found to
exist in rapid equilibrium with a pseudo-diastereomeric hemiketal form in solution. The equilibrium is
1
very rapid and therefore no pseudo-diastereomers are observed during HPLC analysis. H NMR (600
MHz, CDCl3) δ: 9.68 (s, 0.3 H), 8.09 (s, 0.3 H, ArH), 7.96 (dd, J = 38.5 Hz, 2.3 Hz, 1 H, ArH), 7.65 (dd, J =
11.0 Hz, 2.2 Hz, 0.4 H, ArH), 7.60 (dd, J = 8.8 Hz, 2.4 Hz, 0.6 H, ArH), 7.28-7.27 (m, 1.2 H, ArH), 7.25-
7.14 (m, 3.5 H, ArH), 4.62 (dd, J = 10.0 Hz; 1.8 Hz, 0.2 H, CH keto), 4.28-4.19 (m, 0.8 H, CH ketal), 4.13
(dd, J = 11.8 Hz, 6.8 Hz, 0.7 H, CH ketal), 3.84 (dd, J = 19.3 Hz, 10.6 Hz, 0.3 H, CH ketal), 3.06 (s, 0.6 H,
CH2 keto), 2.96 (s, 0.4 H, CH2 keto), 2.48-2.38 (m, 1.6 H, CH2 keto), 2.31 (s, 0.5 H, CH3 ketal), 2.04-1.92
(m, 1 H, CH2 ketal), 1.76 (s, 1.7 H, CH3 ketal), 1.71 (s, 1.3 H, CH3 ketal) ppm. 13C NMR (151 MHz, CDCl3)
δ: 161.3, 160.4, 158.4, 157.6, 141.3, 140.1, 134.9, 134.5, 132.3, 129.5, 129.0, 128.8, 128.6, 128.4,
128.3, 126.6, 125.6, 118.5, 118.3, 117.3, 117.0, 116.8, 116.5, 104.8, 102.1, 100.5, 99.2, 42.1, 39.7,
38.9, 34.9, 34.4, 34.1, 30.0, 29.7, 29.0, 28.3, 28.0. HRMS (ESI): m/z 420.9837 calcd for C19H15BrClO4
16
ACS Paragon Plus Environment

Page 17 of 21
The Journal of Organic Chemistry
1
2
3
4
5
[M+H]+; found 420.9836. IR (ATR): 3351, 2928, 1678, 1610, 1560, 1480, 1411, 1373, 1066, 878.
Enantiomeric excess >99% ee determined by HPLC (Chiralpak IA, Hexane/iPrOH 75:25, flow rate 0.8
mL/min, λ = 308 nm): tR(major) = 25.74 min, tR(minor) = 74.03 min.
6
7
8
(4R)-9-bromo-2-hydroxy-4-(4-methoxyphenyl)-2-methyl-3,4-dihydropyrano[3,2-c]chromen-5(2H)-one
20
(5i). 43 mg (69 %), white solid, mp 78-80 °C, [α]D +21.3 (c 0.5, CH3CN). The product was found to
9
exist in rapid equilibrium with a pseudo-diastereomeric hemiketal form in solution. The equilibrium is
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
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
very rapid and therefore no pseudo-diastereomers are observed during HPLC analysis. H NMR (600
MHz, CDCl3) δ: 9.60 (s, 0.2 H), 8.09 (s, 0.2 H, ArH), 8.05 (s, 0,1 H, ArH), 7.94 (dd, J = 61.0 Hz, 2.3 Hz, 0.7
H, ArH), 7.63 (dd, J = 8.5 Hz, 6.1 Hz, 0.4 H, ArH), 7.53 (dd, J = 8.7 Hz, 2.3 Hz, 0.6 H, ArH), 7.18 (dd, J =
20.0 Hz, 8.7 Hz, 1.5 H, ArH), 7.10 (dd, J = 19.8 Hz, 9.9 Hz, 1.5 H, ArH), 6.85-6.80 (m, 2 H, ArH), 4.62
(dd, J = 9.7 Hz; 1.8 Hz, 0.2 H, CH keto), 4.27-4.20 (m, 0.8 H, CH ketal), 4.11 (dd, J = 15.9 Hz, 8.7 Hz, 0.8
H, CH ketal), 3.77 (s, 1.6 H, CH3 ketal), 3.76 (s, 1.4 H, CH3 keto), 3.45 (s, 0.5 H, CH2 keto), 3.27 (dd, J =
19.4 Hz, 2.2 Hz, 0.3 H, CH2 keto), 2.52-2.35 (m, 1.7 H, CH2 keto), 2.28 (s, 0.5 H, CH3 ketal), 2.04-1.94
(m, 1 H, CH2 ketal), 1.68 (s, 1.6 H, CH3 ketal), 1.66 (s, 1.4 H, CH3 ketal) ppm. 13C NMR (151 MHz, CDCl3)
δ: 212.7, 166.0, 161.6, 160.7, 158.7, 158.4, 158.2, 157.5, 151.7, 151.6, 151.1, 134.8, 134.7, 134.2,
132.8, 129.5, 129.1, 128.0, 125.7, 125.3, 118.3, 118.2, 117.5, 117.1, 116.8, 116.4, 114.6, 114.1, 105.4,
102.4, 100.9, 99.5, 67.8, 60.4, 55.2, 45.4, 42.5, 39.8, 38.9, 34.6, 33.4, 30.5, 29.0, 28.0, 27.7, 24.0,
23.0. HRMS (ESI): m/z 417.0332 calcd for C20H18BrO5 [M+H]+; found 417.0332. IR (ATR): 3356, 2926,
1687, 1611, 1561, 1479, 1374, 1230, 1071, 877. Enantiomeric excess 86% ee determined by HPLC
(Chiralpak IA, Hexane/iPrOH 90:10, flow rate 1.0 mL/min, λ = 308 nm): tR(major) = 18.65 min,
tR(minor) = 36.47 min.
Supporting Information
Pictures of 1H and 13C NMR spectra, HPLC chromatograms, ECD spectra and DFT computational
details.
Acknowledgments
This work was supported by the Slovak Grant Agency VEGA, grant no. VEGA 1/0414/16. This
publication is the result of the project implementation: 262401200025 supported by the Research &
Development Operational Programme funded by the ERDF.
References
(1)
Zhao, B.-L.; Li, J.-H.; Du, D.-M. Squaramide-Catalyzed Asymmetric Reactions. Chem.
Rec. 2017, 17, 994-1018.
(2)
Chauhan, P.; Mahajan, S.; Kaya, U.; Hack, D.; Enders, D. Bifunctional Amine-
Squaramides: Powerful Hydrogen-Bonding Organocatalysts for Asymmetric Domino/Cascade
Reactions. Adv. Synth. Catal. 2015, 357, 253-281.
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 21
1
2
3
(3)
Alemán, J.; Parra, A.; Jiang, H.; Jørgensen, K. A. Squaramides: Bridging from Molecular
4
5
6
7
8
9
Recognition to Bifunctional Organocatalysis. Chem. Eur. J. 2011, 17, 6890-6899.
(4) Malerich, J. P.; Hagihara, K.; Rawal, V. H. Chiral Squaramide Derivatives are Excellent
Hydrogen Bond Donor Catalysts. J. Am. Chem. Soc. 2008, 130, 14416-14417.
(5) Min, C.; Han, X.; Liao, Z.; Wu, X.; Zhou, H.-B.; Dong, C. C3-Symmetrical Cinchonine-
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
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Squaramide as New Highly Efficient, and Recyclable Organocatalyst for Enantioselective Michael
Addition. Adv. Synth. Catal. 2011, 353, 2715-2720.
(6)
Yang, W.; Du, D.-M. Chiral Squaramide-Catalyzed Highly Enantioselective Michael
Addition of 2-Hydroxy-1,4-naphthoquinones to Nitroalkenes. Adv. Synth. Catal. 2011, 353, 1241-
1246.
(7)
Dong, Z.; Qiu, G.; Zhou, H.-B.; Dong, C. Chiral squaramide as multiple H-bond donor
organocatalysts for the asymmetric Michael addition of 1,3-dicarbonyl compounds to nitroolefins.
Tetrahedron: Asymmetry 2012, 23, 1550-1556.
(8)
Baran, R.; Veverková, E.; Škvorcová, A.; Šebesta, R. Enantioselective Michael addition
of 1,3-dicarbonyl compounds to a nitroalkene catalyzed by chiral squaramides - a key step in the
synthesis of pregabalin. Org. Biomol. Chem. 2013, 11, 7705-7711.
(9)
Highly Active Bifunctional Organocatalysts in Michael Addition. J. Org. Chem. 2015, 80, 828-835.
(10) Veverková, E.; Bilka, S.; Baran, R.; Šebesta, R. Squaramide-Catalyzed Michael Addition
as a Key Step for the Direct Synthesis of GABAergic Drugs. Synthesis 2016, 48, 1474-1482.
(11) Xu, D.-Q.; Wang, Y.-F.; Zhang, W.; Luo, S.-P.; Zhong, A.-G.; Xia, A.-B.; Xu, Z.-Y. Chiral
Işık, M.; Unver, M. Y.; Tanyeli, C. Modularly Evolved 2-AminoDMAP/Squaramides as
Squaramides as Highly Enantioselective Catalysts for Michael Addition Reactions of 4-
Hydroxycoumarins and 4-Hydroxypyrone to β,γ-Unsaturated α-Keto Esters. Chem. Eur. J. 2010, 16,
4177-4180.
(12)
Wang, Y.-F.; Zhang, W.; Luo, S.-P.; Zhang, G.-C.; Xia, A.-B.; Xu, X.-S.; Xu, D.-Q. Highly
Enantioselective Organocatalytic Michael Addition of 2-Hydroxy- 1,4-naphthoquinone to β,γ-
Unsaturated α-Oxo Esters. Eur. J. Org. Chem. 2010, 4981-4985.
(13)
Wang, Y.-F.; Wang, K.; Zhang, W.; Zhang, B.-B.; Zhang, C.-X.; Xu, D.-Q.
Enantioselective Asymmetric Michael Addition of Cyclic Diketones to β,γ-Unsaturated α-Keto Esters.
Eur. J. Org. Chem. 2012, 3691-3696.
(14)
Halland, N.; Hansen, T.; Jørgensen, K. A. Organocatalytic Asymmetric Michael
Reaction of Cyclic 1,3-Dicarbonyl Compounds and α,β-Unsaturated Ketones—A Highly Atom-
Economic Catalytic One-Step Formation of Optically Active Warfarin Anticoagulant. Angew. Chem.
Int. Ed. 2003, 42, 4955-4957.
18
ACS Paragon Plus Environment

Page 19 of 21
The Journal of Organic Chemistry
1
2
3
(15)
Dong, Z.; Wang, L.; Chen, X.; Liu, X.; Lin, L.; Feng, X. Organocatalytic Enantioselective
4
5
6
Michael Addition of 4-Hydroxycoumarin to α,β-Unsaturated Ketones: A Simple Synthesis of Warfarin.
Eur. J. Org. Chem. 2009, 5192-5197.
7
8
(16)
Zhu, X.; Lin, A.; Shi, Y.; Guo, J.; Zhu, C.; Cheng, Y. Enantioselective Synthesis of
9
Polycyclic Coumarin Derivatives Catalyzed by an in Situ Formed Primary Amine-Imine Catalyst. Org.
Lett. 2011, 13, 4382-4385.
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
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(17)
Zhu, L.; Zhang, L.; Luo, S. Catalytic Asymmetric β-C–H Functionalizations of Ketones
via Enamine Oxidation. Org. Lett. 2018, 20, 1672-1675.
(18)
Kucherenko, A. S.; Kostenko, A. A.; Zhdankina, G. M.; Kuznetsova, O. Y.; Zlotin, S. G.
Green asymmetric synthesis of Warfarin and Coumachlor in pure water catalyzed by quinoline-
derived 1,2-diamines. Green Chem. 2018, 20, 754-759.
(19)
analogues on water. Tetrahedron: Asymmetry 2014, 25, 813-820.
(20) Rogozińska, M.; Adamkiewicz, A.; Mlynarski, J. Efficient “on water” organocatalytic
protocol for the synthesis of optically pure warfarin anticoagulant. Green Chem. 2011, 13, 1155-1157.
(21) Kucherenko, A. S.; Siyutkin, D. E.; Nigmatov, A. G.; Chizhov, A. O.; Zlotin, S. G. Chiral
Rogozińska-Szymczak, M.; Mlynarski, J. Asymmetric synthesis of warfarin and its
Primary Amine Tagged to Ionic Group as Reusable Organocatalyst for Asymmetric Michael Reactions
of C-Nucleophiles with α,β-Unsaturated Ketones. Adv. Synth. Catal. 2012, 354, 3078-3086.
(22)
Kucherenko, A. S.; Lisnyak, V. G.; Chizhov, A. O.; Zlotin, S. G. Primary Amine Attached
to an N-(Carboxyalkyl)imidazolium Cation: A Recyclable Organocatalyst for the Asymmetric Michael
Reaction. Eur. J. Org. Chem. 2014, 3808-3813.
(23)
Porta, R.; Benaglia, M.; Coccia, F.; Rossi, S.; Puglisi, A. Enantioselective
Organocatalysis in Microreactors: Continuous Flow Synthesis of a (S)-Pregabalin Precursor and (S)-
Warfarin. Symmetry 2015, 7, 1395.
(24)
Xie, J.-W.; Yue, L.; Chen, W.; Du, W.; Zhu, J.; Deng, J.-G.; Chen, Y.-C. Highly
Enantioselective Michael Addition of Cyclic 1,3-Dicarbonyl Compounds to α,β-Unsaturated Ketones.
Org. Lett. 2007, 9, 413-415.
(25)
Mei, R.-Q.; Xu, X.-Y.; Li, Y.-C.; Fu, J.-Y.; Huang, Q.-C.; Wang, L.-X. Highly effective and
enantioselective Michael addition of 4-hydroxycoumarin to α,β-unsaturated ketones promoted by
simple chiral primary amine thiourea bifunctional catalysts. Tetrahedron Lett. 2011, 52, 1566-1568.
(26)
Modrocká, V.; Veverková, E.; Baran, R.; Šebesta, R. Enantioselective Synthesis of 2,3-
Dihydrofurocoumarins by Squaramide-Catalyzed Michael Addition/Cyclization of 4-
Hydroxycoumarins with β-Nitrostyrenes. ChemistrySelect 2018, 3, 1466-1471.
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 21
1
2
3
(27)
Yang, H.-M.; Li, L.; Jiang, K.-Z.; Jiang, J.-X.; Lai, G.-Q.; Xu, L.-W. Highly enantioselective
4
5
6
synthesis of warfarin and its analogs by means of cooperative LiClO4/DPEN-catalyzed Michael
reaction: enantioselectivity enhancement and mechanism. Tetrahedron 2010, 66, 9708-9713.
7
8
9
(28)
Solvents in Chemical Processes. Chem. Rev. 2018, 118, 747-800.
(29) Zhang, Q.; De Oliveira Vigier, K.; Royer, S.; Jerome, F. Deep eutectic solvents:
syntheses, properties and applications. Chem. Soc. Rev. 2012, 41, 7108-7146.
(30) Pereira, C. S. M.; Silva, V. M. T. M.; Rodrigues, A. E. Ethyl lactate as a solvent:
Properties, applications and production processes - a review. Green Chem. 2011, 13, 2658-2671.
(31) Pires, M. J. D.; Purificação, S. I.; Santos, A. S.; Marques, M. M. B. The Role of PEG on
Pd- and Cu-Catalyzed Cross-Coupling Reactions. Synthesis 2017, 49, 2337-2350.
(32) Tang, S.; Zhao, H. Glymes as versatile solvents for chemical reactions and processes:
from the laboratory to industry. RSC Adv. 2014, 4, 11251-11287.
(33) Karem, S.; Catharina, N.; Helmut, S. Green Solvents in Organic Synthesis: An Overview
II. Curr. Org. Chem. 2016, 20, 1576-1583.
Clarke, C. J.; Tu, W.-C.; Levers, O.; Bröhl, A.; Hallett, J. P. Green and Sustainable
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
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(34)
Pace, V.; Hoyos, P.; Castoldi, L.; Domínguez de María, P.; Alcántara, A. R. 2-
Methyltetrahydrofuran (2-MeTHF): A Biomass-Derived Solvent with Broad Application in Organic
Chemistry. ChemSusChem 2012, 5, 1369-1379.
(35)
Catalyzed by a Bifunctional Amine–Thiourea Catalyst. Chem. Eur. J. 2010, 16, 13068-13071.
(36) Regalado, E. L.; Sherer, E. C.; Green, M. D.; Henderson, D. W.; Thomas, W. R.; Joyce,
Gao, Y.; Ren, Q.; Wang, L.; Wang, J. Enantioselective Synthesis of Coumarins
L. A.; Welch, C. J. Chromatographic Separation and Assignment of Absolute Configuration of
Hydroxywarfarin Isomers. Chirality 2014, 26, 95-101.
(37)
Mailhol, D.; Duque, M. d. M. S.; Raimondi, W.; Bonne, D.; Constantieux, T.; Coquerel,
Y.; Rodriguez, J. Enantioselective Organocatalytic Michael Addition of Cyclobutanones to
Nitroalkenes. Adv. Synth. Catal. 2012, 354, 3523-3532.
(38)
enantioselective Friedel-Crafts reaction of indoles with imines. Chem. Commun. 2010, 46, 3004-3006.
(39) Kasaplar, P.; Riente, P.; Hartmann, C.; Pericàs, M. A. A Polystyrene-Supported, Highly
Qian, Y.; Ma, G.; Lv, A.; Zhu, H.-L.; Zhao, J.; Rawal, V. H. Squaramide-catalyzed
Recyclable Squaramide Organocatalyst for the Enantioselective Michael Addition of 1,3-Dicarbonyl
Compounds to β-Nitrostyrenes. Adv. Synth. Catal. 2012, 354, 2905-2910.
(40)
Vargová, D.; Baran, R.; Šebesta, R. Stereoselective synthesis of 4-methylpregabalin via
organocatalytic Michael addition to a racemic nitroalkene. Beilstein J. Org. Chem. 2018, 14, 553-559.
20
ACS Paragon Plus Environment

Page 21 of 21
The Journal of Organic Chemistry
1
2
3
(41)
Albrecht, Ł.; Dickmeiss, G.; Acosta, F. C.; Rodríguez-Escrich, C.; Davis, R. L.; Jørgensen,
4
5
6
K. A. Asymmetric Organocatalytic Formal [2 + 2]-Cycloadditions via Bifunctional H-Bond Directing
Dienamine Catalysis. J. Am. Chem. Soc. 2012, 134, 2543-2546.
7
8
(42)
Liu, Y.; Lu, A.; Hu, K.; Wang, Y.; Song, H.; Zhou, Z.; Tang, C. Bifunctional Primary
9
Amine-Squaramide Catalyzed Enantioselective Intramolecular Michael Addition of Keto-enones: A
Convenient Process to the Stereocontrolled Construction of trans-Dihydrobenzofuran Skeletons. Eur.
J. Org. Chem. 2013, 4836-4843.
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
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(43)
Liu, Y.; Liu, X.; Wang, M.; He, P.; Lin, L.; Feng, X. Enantioselective Synthesis of 3,4-
Dihydropyran Derivatives via Organocatalytic Michael Reaction of α,β-Unsaturated Enones. J. Org.
Chem. 2012, 77, 4136-4142.
(44)
Dong, J.; Du, D.-M. Highly enantioselective synthesis of Warfarin and its analogs
catalysed by primary amine-phosphinamide bifunctional catalysts. Org. Biomol. Chem. 2012, 10,
8125-8131.
21
ACS Paragon Plus Environment