Access to Spirocyclic Benzothiophenones with Multiple Stereocenters via an Organocatalytic Cascade Reaction

Article abstract of DOI:10.1021/acs.joc.0c00882

The present report describes an organocatalytic cascade reaction between 2-alkylidene benzo[b]thiophenone derivatives and enones in the presence of the Cinchona alkaloid amine. Spirobenzothiophenonic cyclohexane derivatives containing three stereocenters were prepared via one-step synthesis in yields ranging from 88 to 96% and in enantioselectivities (enantiomeric excess (ee)) ranging from 85 to 97%, with diastereoselectivities of approximately 14/2/1. Therefore, this method provides an efficient route for the synthesis of a new class of optically active 2-spirobenzothiophenones.

Full text of DOI:10.1021/acs.joc.0c00882

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Article
Access to spirocyclic benzothiophenones with multiple
stereocenters via an organocatalytic cascade reaction
Bed#ich Formánek, Ji#í Tauchman, Ivana Císa#ová, and Jan Vesely
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00882 • Publication Date (Web): 01 Jun 2020
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Page 1 of 13
The Journal of Organic Chemistry
Access to spirocyclic benzothiophenones with multiple stereocenters via
an organocatalytic cascade reaction
1
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Bedřich Formánek,† Jiří Tauchman,† Ivana Císařová,‡ Jan Veselý*†
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8
† Department of Organic Chemistry, Faculty of Science, Charles University, Hlavova 2030/8, 128 43, Prague 2, Czech
Republic
E-mail: jan.vesely@natur.cuni.cz
9
‡ Department of Inorganic Chemistry, Faculty of Science, Charles University, Hlavova 2030/8, 128 43, Prague 2, Czech
Republic
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Supporting Information Placeholder
N
EWG
R
N
O
S
(20 mol%)
O
NH2
O
yields 88-96%
~14/2/1
4-NO2C6H4CO2H (40 mol%)
O
dr
ee 85-97%
+
R
S
EWG
dioxane, RT, 36 h
The present report describes an organocatalytic cascade reaction between 2-alkylidene benzo[b]thiophenone derivatives
and enones in the presence of Cinchona alkaloid amine. Spirobenzothiophenonic cyclohexane derivatives containing three
stereocenters were prepared via one-step synthesis in yields ranging from 88 to 96% and in enantioselectivities (ee) ranging
from 85 to 97%, with diastereoselectivities of approximately 14/2/1. Therefore, this method provides an efficient route for the
synthesis of a new class of optically active 2-spirobenzothiophenones.
Nevertheless, these difficulties can be overcome through
asymmetric organocatalysis. Over the past decade, several
INTRODUCTION
Sulfur-containing heterocycles are common structural motifs
occurring in compounds with interesting physiochemical
properties and with various biological and pharmacological
activities.1 Interestingly, more than one third of the twenty
best-selling small molecule pharmaceuticals in 2018 contained
a sulfur atom in their structural motifs.2 In addition, sulfur-
bearing full-substituted carbon stereocenters stand out as
prominent structural fragments in natural products, bioactive
compounds and drugs. Such motifs (Figure 1) can be found in
plant metabolites, such as spirobrassinin A (anticancer
activity)3 and thiolactomycin B (antibacterial activity)4, and in
men-made molecules, such as spirolactam C (antiviral agent)5.
organocatalytic methods have been developed to construct
various sulfur-containing heterocycles with a tetrasubstitued
chiral carbon.7 Since the pioneering work by Córdova et al.8
based on the sulfa-Michael addition-initiated construction of
tetrahydrothioxanthones, various enantioselective sulfa-
Michael additions have been developed using electron-
deficient alkenes, such as enones9a,b, dienones9c, acrylates9d
and unsaturated amides9e. Other valuable protocols for the
synthesis of enantiomerically enriched, sulfur-bearing full-
substituted carbon stereocenters include Mannich reactions of
thiols into ketimines10 and electrophilic sulfenylation reactions
of α-branched aldehydes, β-keto esters, nitroacetates, oxindols,
benzofuran-2(3H)-ones, and oxazolones.7,11 An alternative
organocatalytic strategy for the preparation of such
enantiomerically enriched compounds containing a sulfur-
bearing full-substituted stereogenic center is based on the
stereoselective formation of C-C or C-N bonds using prochiral
sulfur-based substrates, such as α-sulfenylated acrylates and
enals, rhodanines, 3-thiooxindoles, and thiazolones.7,12 Yet,
MeS
O
COOH
O
N
S
N
S
S
O
H2N
AcHN
O
N
OH
H
C
influenza neuraminidase
inhibitor
A
B
thiolactomycin
spirobrassinin
only
a few reports on organocatalytic reactions on
Figure 1. Selected examples of biologically relevant compounds.
benzo[b]thiophene derivatives have been published to date13.
Considering the above and our interest in the enantioselective
preparation of heterocycles with full-substituted stereogenic
center bearing sulfur atom, we aimed to use an
enantioselective double Michael cascade reaction of
benzo[b]thiophenone derivatives14 with less reactive enones to
prepare such stereocenters.
Noticeably, the biological activities of these compounds may
be significantly affected by their optical purity. Thus, efficient
enantioselective methods must be developed to construct
structurally diverse, sulfur-bearing tetrasubstituted carbon
stereocenters. In general, the preparation of quaternary carbon
stereocenters is a challenging task considering the reduced
reactivity of their sterically demanding precursors and the
limited enantiocontrol of the newly formed stereocenters due
to the lowered steric dissimilarities of non-hydrogen
substituents on the prochiral carbon. In addition, the strong
coordinating and adsorptive properties of sulfur species may
cause additional difficulties by disrupting the catalytic
process.6
RESULTS AND DISCUSSION
At the outset, we chose alkylidene-benzothiophenone
derivative 1a as a suitable Michael acceptor and (E)-4-
phenylbut-3-en-2-one (2a) as a donor for our model cascade
reaction catalyzed by
a primary amine derived from
cinchonidine (I). In line with previous results15,16, the acid
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Page 2 of 13
additive was required to obtain the desired product in a high were fully converted in reduced times while increasing the
1
2
3
4
5
6
7
8
yield. As expected, the cyclization reaction proceeded
successfully in toluene, providing spiroproduct 3a in a high
yield with moderate enantioselectivity of the main
diastereomer (3aa), albeit with poor diastereoselectivity (entry
1, Table 1). Nevertheless, when screening various solvents, the
yield remained mostly unchanged (60-92%, entry 1-7, Table
1), whereas the reaction rate and stereochemical outcome were
notably affected, with a significantly slower conversion of
starting alkylidene derivative 1a in chlorinated and polar
protic solvents (entries 2 and 4, Table 1). Moreover,
compound 3a was obtained with low diastereo- and
enantiocontrol in both solvent systems.
yield of spirocompound 3a. However, the diastereoselectivity
of the reaction and the enantiomeric purity of the main
diastereomer 3aa decreased slightly. To modify the catalytic
centers in terms of electronic and steric properties, we used
diamines IV-VIII, readily available from the amino acids.17
Unfortunately, none of the aminocatalysts tested afforded
yields of 3a comparable to the yield determined when using
organocatalyst I. Full conversion of 1a was not reached even
after prolonged reaction times (entries 10-14). Subsequently,
we assess the effects of acid additives, additive-to-amine I
ratio, reactant ratio, catalyst loading and temperature on our
reaction (for details, please, see SI). In summary, in the
presence of 4-nitrobenzoic acid as an additive, we prepared
spirobenzothiophenone derivative 3a in a virtually quantitative
yield, with high diastereoselectivity and enantioselectivity
(entry 15, Table 1). Notably, the major diastereomer 3aa can
be easily isolated by column chromatography.
9
10
11
12
13
14
15
16
17
18
19
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22
23
24
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26
27
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32
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35
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42
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44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Screening of the chiral tertiary amine catalyst and
optimization studies.
CO Et
2
O
O
Catalyst (20 mol%)
2,4-DNBA (40 mol%)
O


O
O

S
S
Ph
CO2Et
solvent
RT
Ph
After completing the optimization tests, we focused our
attention on finding the scope and limitations of the method
developed in this study. Gratifyingly, the reaction proceeded
smoothly with various enones (2a-h) bearing an aromatic
moiety (Table 2). Both electron-withdrawing and electron-
donating groups can be present on the aromatic ring without
affecting the efficiency of the method. In addition, enones
bearing an heteroaromatic ring (2i-1j) also led to satisfactory
results (entries 9-10). In most cases, the diastereoselectivity of
the reaction and the enantiomeric purity of the isolated
spirocompounds 3aa-3aj remained high. A slight decrease in
stereoselectivity was observed only when introducing the
substituent in the ortho position of the aryl moiety (entry 5).
1a
2a
3a
(1 equiv.)
(2 equiv.)
CO Et
2
CO Et
2
CO Et
O
2
O
O
O
O
S
S
S
Ph
Ph
Ph
3aa
3'aa
3''aa
Yield [%]a 3aa/3´aa/3´´aab ee [%]c
Entry
Catalyst
Solvent
Time [d]
1
2
I
I
10.8/15.0/1
7.4/5.4/1
toluene
CHCl3
4
7
4
7
4
3
4
2
2
7
7
7
7
7
1.5
85
60
82
76
86
92
86
95
93
63
61
74
38
20
96
72
85
88
79
87
93
96
93
93
77
83
74
54
35
95
3
I
7.7/3.4/1
DMF
4
I
2.5/2.8/1
MeOH
5
I
12.8/5.6/1
7.6/2.3/1
MTBE
Table 2. Screening of various enone derivatives in
organocatalytic reaction.
6
I
THF
7
I
13.4/4.0/1
20.2/6.3/1
31.1/12.2/1
76.5/10.2/1
58.2/7.5/1
60.5/7.4/1
15.9/3.4/1
8.8/3.0/1
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
CO Et
2
O
O
I
(20 mol%)
8
II
O
4-NBA (40 mol%)
O
9
III
IV
V
VI
VII
VIII
I
S
S
CO2Et
R
1,4-dioxane
RT, 36 h
R
10
11
12
13
14
15d
1a
2
(1 equiv.)
(2 equiv.)
3
Yield [%]a
dr [%]b
ee [%]c
Entry
R
Product
1
2
Ph
71 (96)
65 (96)
63 (96)
52 (92)
47 (96)
63 (95)
62 (96)
75 (95)
69 (93)
55 (94)
54 (92)
25.4/3.1/1
11.4/1.5/.1
16.8/2.2/1
9.6/1.9/1
95
95
86
92
86
90
93
96
95
95
-87
3aa
3ab
2-naphthyl
4-NO2C6H4
3-NO2C6H4
2-NO2Ph
3
3ac
25.4/3.1/1
4
a
3ad
3aa 3'aa 3''aa
Isolated overall yield of diastereomers
,
,
after column chromatography.
b Determined by 1H NMR analysis of crude mixture. c Ee of diastereomer
determined by HPLC analysis. d 4-NO2C6H4CO2H was used as an additive.
3aa
5
26.5/7.4/1
10.1/2.1/1
13.8/1.9/1
12.7/1.2/1
9.6/1.3/1
3ae
R''
6
4-CF3C6H4
4-BrC6H4
4-CH3C6H4
2-thienyl
3af
N
R''
R'
OMe
7
3ag
N
R'''
NH2
N
N
NH2
R'''
8
IV R''=Cy, R'''=H
VII R''=R'''=Et
3ah
VI
R''=Cy,R'''=H
VIII R''=R'''=Et
NH2
NH2
9
3ai
N
N
Cy
NH2
N
10
11d
5-benzo[b]thiophenyl
5.5/1.1/1
I
II
R'=H
R'=OMe
III
3aj
N
H
NH2
Ph
11.0/1.5/1
ent-3aa
N
IX
V
a Isolated yield of main diastereomer (overall yield of all diastereomers) after column
chromatography. b Determined by 1H NMR analysis of crude mixture. c Ee of major
Model reactions performed in ethereal and dipolar aprotic
solvents afforded product 3a in shortened reaction times with
improved diastereoselectivity (entries 3, 5-6). Among the
solvents tested, 1,4-dioxane provided 3a with the highest
stereoselectivity (dr 13/4/1). Thus, we continued our
evaluation of various primary aminocatalysts I-III in dioxane
using 2,4-dinitrobenzoic acid as an additive. In the presence of
quinine-derived amine derivative II, the starting materials
diastereomer determined by HPLC analysis. d Catalyst
was used.
IX
Similarily, the presence of the EWG group in the para
position on the aromatic ring caused a small drop in the
enantioselectivity of the reaction (entries 3,6). Importantly,
access to the opposite enantiomer of spirocompounds 3 is
allowed when using pseudoenantiomeric catalyst IX, for
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The Journal of Organic Chemistry
exemple, with enone 2a, observing only a slight decrease in intermediate affording the major diastereoisomer 3 after
1
the enantiocontrol of the reaction (entry 11).
hydrolysis (Scheme 1).
2
3
4
5
6
7
8
9
Subsequently, we assessed the usability of spirocompounds 3
on the following set of transformations (Scheme 2). When
compound 3aa was treated with lithium hydroxide, under
standard saponification conditions, we observed epimerization
Then, we examined benzothiophenones with different
alkylidene moieties under optimized conditions (Table 3). The
presence of EWG on the alkylidene moiety (R1) was necessary
to drive the reaction to completion. When alkylidenes bearing
an aryl group (1b-1c) were mixed with 2a, the reaction did not
proceed. The result was also affected by the low solubility of
substrate 1c in dioxane. Nevertheless, when changing the
solvent system to DMF, trace amounts of 3ca were detected as
a result. Conversely, the best results were found when a cyano
group was attached to the alkylidene, most likely due to its
strong electron-deficient character. High diastereo- and
enantioselectivity levels were also observed with
benzothiophenone derivatives bearing a modified ester moiety
(entries 4-6). Similarily, the position of substitution on the
aromatic benzothiophenone ring (R2) only had a limited effect
on the efficiency of the reaction (entries 9-12). In all cases, the
level of stereocontrol was high, except when introducing an
electron-withdrawing substituent in 5-position (entry 8), which
caused a marked decrease in diastereoselectivity.
Scheme
1.
Proposed
reaction
mechanism.
+
I
Catalyst -H
2
3
-H2O
-H2O
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
N
N
H
H
O
O
H
EWG
NH
N
NH
S
S
EWG
N
Ar
Ar
H
N
H
O
H
NH
EWG
S
N
Ar
Table 3. Reaction scope of organocatalytic cyclization
between alkylidenes 1 and enones 2.
at the carbon center adjacent to the ethylcarboxylate group,
followed by hydrolysis, affording the acid 4 ’ ’ aa in a good
yield. To avoid epimerization, we used a metal-catalyzed
deesterification procedure for allyl ester 3fa, preparing the
corresponding acid 4aa in a high yield with an enantiomeric
excess equal to the starting material. Spirocompounds 3 can be
easily transformed into the corresponding sulfoxides 5. For
example, compound 3aa was converted by treatment with 1.1
equivalent of mCPBA into the diastereomerically pure
sulfoxide 5a. A higher excess of mCPBA and a prolonged
reaction time led to desired sulfone 6a without decreasing the
optical purity.
R1
O
O
R2
R2
I
(20 mol%)
O
4-NBA (40 mol%)
O
R1
S
S
Ph
1,4-dioxane
RT, 36 h
Ph
1
2a
(1 equiv.)
(2 equiv.)
3
R1
R2
Yield [%]a
dr [%]b
n.d.
ee [%]c
Entry
Product
1
2
3ba
3ca
3da
3ea
3aa
3fa
Ph
4-NO2C6H4
PhCO
H
H
n.r.
n.d.
n.d.
85
95
95
95
97
92
92
90
95
96
94
n.d.
22.8/3.4/1
44.9/4.1/1
25.4/3.1/1
14.6/2.0/1
16.7/1/0
<5
3
H
36 (90)
68 (90)
71 (96)
57 (96)
57 (96)
36 (96)
48 (96)
70 (88)
73 (96)
51 (94)
63 (93)
4
CO2Me
CO2Et
CO2allyl
CN
H
5
H
6
H
Scheme 2. Further transformations of spirocyclohexanone
derivatives.
7
3ga
3ha
3ia
H
1.3/1.3/1
8
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Me
5-Br
10.1/2.0/1
10.1/1.8/1
17.3/2.3/1
9.4/1.6/1
9
5-Me
4-Me
6-Me
7-Me
H
10
11
12
13d
3ja
3ka
3la
42.6/3.8/1
3ea
a Isolated yield of main diastereomer (overall yield of all diastereomers) after column
chromatography. b Determined by 1H NMR analysis of crude mixture. c Ee of major
diastereomer determined by HPLC analysis. d 1 g scale experiment (4.54 mmol of
.
1e)
To
ascertain
the
absolute
configuration
of
spirobenzothiophenones 3, we performed single-crystal X-ray
diffraction analysis of compound 3ag. All stereogenic centers,
including the spiroatom, have an (S)-configuration (for details,
please, see SI). That observation is in line with the generally
accepted mechanism of organocatalytic double Michael
addition cascade reaction of nitrogen- and oxygen-containing
analogs.15,16 In a proposed bifunctional mode of activation, the
enamine generated from enone and primary amine attacks
electron-deficient β-carbon of 1. The presence of protonated
quinuclidine moiety is crucial for the stereochemical outcome
due to hydrogen bonding. The following Michael addition of
generated enol to iminium ion leads to formation of enamine
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standard for 19F NMR. IR spectra were recorded on a Thermo
Nicolet AVATAR 370 FT-IR spectrometer with KBr tablets of
CO2Et
Ph
O
S
CO2H
Ph
O
S
inversion of the
1) LiOH, THF/H2O
2) HCl
configuration at
the carboxylate-
bearing stereogenic
center
1
2
3
4
5
6
7
8
O
O
O
O
the compounds using the DRIFT method. Melting points were
measured using a Büchi Melting Point B-545 apparatus. All
melting points were measured in an open glass capillary, and all
values are uncorrected. Chiral HPLC was performed using a
LC20AD Shimadzu liquid chromatograph with SPD-M20A diode
array detector with IA, IB and IC Daicel Chiralpak® columns.
High-resolution mass spectroscopic data were acquired using ESI
(TOF analyzer) at the Laboratory of mass spectrometry, Faculty
of Science, Department of Chemistry, Charles University.
a
b
3aa
ee 95%
4''aa
47% (77%) , dr 1/6.6/42.4, ee 82%
CO2allyl
O
CO2H
O
1) Pd(PPh3)4,
pyrrolidine
configuration
retained
O
S
DCM, RT
S
Ph
ee 95%
Ph
3fa
4aa
92%, ee 95%
CO2Et
O
9
CO2Et
O
1.1 equiv. mCPBA
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
O
General procedure for the synthesis of the aminoamide catalyst
(GP1)
DCM, RT
S
S
Ph
ee 95%
Ph
O
Following a slightly modified procedure18, DCC was slowly
added (0.87 g, 4.2 mmol) in dry DCM (4 mL) to a solution of N-
Boc-protected aminoacid (4.0 mmol) in dry DCM (6 mL) at 0 °C.
After stirring for 30 min, the corresponding amine (4.0 mmol), in
dry DCM (2 mL), was added portionwise (10 portions, 1h). Then,
the solution was stirred for another 1 h at room temperature. The
resulting white solid was filtered and washed with DCM, and the
organics were combined and concentrated under reduced pressure.
Column chromatography of the residue on silica gel
(DCM/acetone/NH4OH: 100/0/0 → 100/5/1) furnished N-Boc-
protected aminoamide, which was used directly in next step.
CH3COCl was added (1 mL) dropwise to the solution of N-Boc-
protected aminoamide in dry MeOH (0.5M) at 0°C. The solution
was refluxed for 1 h, then cooled to room temperature. The
solvent was evaporated under reduced pressure, adding DCM (12
mL) and H2O (8 mL), and the pH value was adjusted to 12 with
saturated K2CO3. The organic phase was separated, and the
aqueous phase was extracted with DCM (2 × 8 mL). The organics
were combined, dried (Na2SO4) and concentrated under reduced
pressure. Filtration through a pad of silica gel (5 cm layer,
DCM/MeOH/NH4OH: 100/1/1) furnished the corresponding
aminoamide, which was used as such in the following step (GP2).
3aa
5a
79%, dr 20/1, ee 95%
CO2Et
O
CO2Et
O
2.2 equiv. mCPBA
O
O
DCM, RT
S
S
O
O
Ph
Ph
3aa
3ha
6a
ee 95%
75 %, ee 95%
CO2Et
Ph
O
Pd(dppf)Cl2 (10 mol%)
O
S
CO2Et
Ph
Br
KOAc
4-tolyl
+
O
O
S
1,4-dioxane, 110 °C
B(OH)2
7a
97%, ee 92%
ee 92%
a Overall yield of all diastereomers after column chromatography. b Ee of major
diastereomer determined by HPLC analysis.
Furthermore, Suzuki coupling between bromoderivative 3ha
and tolylboronic acid proceeded well, with no deactivation of
the Pd catalyst by the sulfur-bearing starting molecule. The
desired product (7a) was obtained in high yield and
enantiopurity (ee 92%).
In summary, we have developed an organocatalytic cascade
reaction of benzothiophenone derivatives with enones
catalyzed by a Cinchona alkaloid amine derivative. The
corresponding spirocompounds were afforded in virtually
quantitative yields, and the main diastereomers were obtained
in high yields and with an excellent degree of enantiomeric
purity. Moreover, we demonstrated that enantiomerically
enriched benzothiophenones can be used in various
transformations, thereby leading to chiral molecules with a
high potential for applications in medicinal chemistry.
(S)-2-Amino-N-cyclohexyl-3-phenylpropanamide (IV‘)
The title compound was synthesized according to the general
procedure GP1. Analytically pure product was obtained after
column
chromatography
on
silica
gel
(50
g,
DCM/MeOH/NH4OH: 100/1/1). Off-white powder, yield 483 mg
(49% after two steps), m.p. 99 °C. [α]D = +26.6° (c 1.0;
1
96% EtOH). H NMR (400 MHz, CDCl3) δ 7.33 – 7.29 (m, 2H),
7.25 – 7.21 (m, 3H), 7.06 (d, J = 7.3 Hz, 1H), 3.80 – 3.70 (m,
1H), 3.56 (dd, J = 9.1, 4.3 Hz, 1H), 3.23 (dd, J = 13.7, 4.2 Hz,
1H), 2.70 (dd, J = 13.7, 9.1 Hz, 1H), 1.87 – 1.83 (m, 2H), 1.68
(dt, J = 13.1, 3.7 Hz, 2H), 1.59 (dt, J = 12.7, 3.9 Hz, 1H), 1.42 –
1.31 (m, 2H), 1.29 (s, 2H), 1.21 – 1.06 (m, 3H) ppm.
13C{1H}NMR (101 MHz, CDCl3) δ 173.0, 138.0, 129.30 (2C),
128.6 (2C), 126.7, 56.4, 47.5, 41.1, 33.1, 33.0, 25.5, 24.8 (2C)
ppm. IR (KBr): ν = 3297, 3061, 3034, 2938, 2851, 1548, 1449,
1251, 1240, 1150, 1093, 866 cm-1. HRMS (ESI) m/z: [M+H]+
calcd for C15H23N2O+ 247.1805; found 247.1803.
EXPERIMENTAL SECTION
Chemicals and solvents were either purchased from commercial
suppliers or purified using standard techniques. For thin-layer
chromatography (TLC), silica gel plates Merck 60 F254 were
used, visualizing the compounds by irradiation with UV light
and/or by treatment with a solution of phosphomolybdenic acid
(25 g), Ce(SO4)2·H2O (10 g), conc. H2SO4 (60 mL) and H2O (940
mL) followed by heating or treatment with a solution of ninhydrin
(2 g), AcOH (5 mL) and 96% EtOH (1000 mL) followed by
heating. Flash chromatography was performed using silica gel
Silicycle - Siliaflash® P 60 (particle size 40–63 μm, pore
diameter 60 Å).
General procedure for synthesis of diamine catalysts (GP2)
Following a slightly modified procedure18, LiAlH4 was added
(114 mg, 3.0 mmol) portionwise to a solution of aminoamide (1.0
mmol) in dry THF (0.2M) at 0°C. Then, the solution was refluxed
overnight. After cooling to room temperature, a saturated aqueous
solution of Na2SO4 was added dropwise until gas evolution
ceased. The resulting solid was filtered and washed with THF
several times. The organics were combined, dried (Na2SO4) and
concentrated under reduced pressure. Column chromatography of
the residue on silica gel (EtOAc/MeOH/NH4OH: 100/0/0 →
90/10/0 → 90/10/1) furnished the diamine catalyst.
1H, 13C, 19F NMR spectra were measured on FT-NMR
spectrometers Bruker AVANCE III 600 MHz or Bruker
AVANCE III HD 400. Chemical shifts are given in ppm relative
to tetramethylsilane and coupling constants J are given in Hz. The
spectra were recorded in CDCl3 as solvent at 25°C and served as
1
internal standards (δCDCl3 = 7.26 ppm) for H NMR and (δCDCl3
=
77.0 ppm) for 13C NMR, trifluoroacetic acid was used as external
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The catalysts I-III, IX were prepared using known procedures,
The title compound was synthesized according to the general
procedure GP3-b. Yellow powder, yield 248 mg (52%). Our
physical and spectroscopic data corroborated previously published
materials.22
1
2
and their spectral data matched previously published data.19
(S)-N1-Cyclohexyl-3-phenylpropane-1,2-diamine (IV)
3
4
5
6
7
8
9
The title compound was synthesized according to the general
procedure GP2. Yellow oil, yield 109 mg (47%). Our physical and
spectroscopic data corroborated previously published materials.18
(Z)-2-(4-Nitrobenzylidene)benzo[b]thiophen-3(2H)-one (1c)
The title compound was synthesized according to general
procedure GP3-b. Instead of column chromatography, residue was
suspended in 96% EtOH (5 mL), filtered on sintered funnel and
washed with Et2O (5 mL). Orange-yellow powder, yield 238 mg
(42%). Our physical and spectroscopic data corroborated
previously published material.23
(S)-N1-Cyclohexyl-4-methylpentane-1,2-diamine (V)
The title compound was synthesized according to the general
procedure GP2. Yellow oil, yield 131 mg (66%). [α]D = +13.5°
1
(c 1.0; 96% EtOH). H NMR (400 MHz, CDCl3) δ 2.85 – 2.79
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
(m, 1H), 2.66 (dd, J = 11.5, 3.6 Hz, 1H), 2.41 – 2.34 (m, 1H),
2.30 (dd, J = 11.5, 8.9 Hz, 1H), 1.88 – 1.85 (m, 2H), 1.75 – 1.67
(m, 3H), 1.61 – 1.58 (m, 1H), 1.42 – 1.38 (m, 3H), 1.29 – 1.12 (m,
5H), 1.10 – 1.01 (m, 2H), 0.90 (dd, J = 12.1, 6.6 Hz, 6H) ppm.
13C{1H} NMR (101 MHz, CDCl3) δ 57.0, 54.2, 49.2, 45.9, 33.9,
33.6, 26.2, 25.08, 25.06, 24.7, 23.5, 22.0 ppm. IR (KBr): ν =
3309, 2938, 2860, 2597, 2352, 1583, 1431, 1344, 1305, 1180, 890
(Z)-2-(2-Oxo-2-phenylethylidene)benzo[b]thiophen-3(2H)-one
(1d)
The title compound was synthesized according to general
procedure GP3-b. Orange powder, yield 53 mg (10%). Our
physical and spectroscopic data corroborated previously published
materials.13a
+
cm-1. HRMS (ESI) m/z: [M+H]+ calcd for C12H27N2 199.2169;
found = 199.2168.
Methyl
(1e)
(Z)-2-(3-oxobenzo[b]thiophen-2(3H)-ylidene)acetate
(S)-N1-Cyclohexyl-3,3-dimethylbutane-1,2-diamine (VI)
The title compound was synthesized according to the general
procedure GP2. Yellow oil, yield 40 mg (20 % after three steps).
Our physical and spectroscopic data corroborated previously
published materials.17
The title compound was synthesized according to general
procedure GP3-a. Yellow powder, yield 238 mg (54%). Our
physical and spectroscopic data corroborated previously published
materials.13a
Allyl (Z)-2-(3-oxobenzo[b]thiophen-2(3H)-ylidene)acetate (1f)
The title compound was synthesized according to the general
procedure GP3-b. Yellow powder, yield 365 mg, (74%). m.p. 101
°C. 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 7.7 Hz, 1H), 7.60
(td, J = 7.8, 1.3 Hz, 1H), 7.45 – 7.43 (m, 1H), 7.29 (t, J = 7.5 Hz,
1H), 7.05 (s, 1H), 5.99 (ddt, J = 17.2, 10.4, 5.8 Hz, 1H), 5.40 (dd,
J = 17.2, 1.5 Hz, 1H), 5.30 (dd, J = 10.4, 1.3 Hz, 1H), 4.76 (dt, J
= 5.8, 1.4 Hz, 2H) ppm. 13C{1H} NMR (101 MHz, CDCl3) δ
188.3, 165.8, 147.5, 147.4, 136.6, 131.5, 129.2, 127.2, 126.2,
124.2, 118.9, 118.0, 66.1 ppm. IR (KBr): ν = 1682, 1607, 1589,
1464, 1359, 1311, 1281, 1222, 1177, 1069, 1027, 991, 955, 940,
848, 737 cm-1. HRMS (ESI) m/z: [M+Na]+ calcd for
C13H10O3NaS+ 269.0243; found 269.0240.
(S)-N1,N1-Diethyl-3-phenylpropane-1,2-diamine (VII)
The title compound was synthesized according to the general
procedure GP2. Yellow oil, yield 60 mg (29% after three steps).
Our physical and spectroscopic data corroborated previously
published materials.18
(S)-N1,N1-Diethyl-3,3-dimethylbutane-1,2-diamine (VIII)
The title compound was synthesized according to the general
procedure GP2. Yellow oil, yield 21 mg (12% after three steps).
Our physical and spectroscopic data corroborated previously
published materials.20
General procedure for the synthesis of alkylidene-
benzo[b]thiophenones (GP3)
(Z)-2-(3-Oxobenzo[b]thiophen-2(3H)-ylidene)acetonitrile (1g)
The title compound was synthesized according to the general
procedure GP3-a. Yellow-brown powder, yield 161 mg (43%)
a) Following a slightly modified procedure13a, the corresponding
Wittig reagent (2.0 mmol) was added to
a solution of
benzo[b]thiophene-2,3-dione (2.0 mmol) in toluene (10 mL) at
room temperature and stirred overnight. The organics were
concentrated under reduced pressure. Column chromatography of
the residue on silica gel (hexanes/EtOAc or hexanes/toluene)
furnished the corresponding 2-alkylidene-benzo[b]thiophenones.
b) Following a slightly modified procedure21, a solution of n-BuLi
(2.5M in hexanes, 2.0 mmol) was added dropwise to a solution of
phosphonium salt (2.2 mmol) in dry THF (80 mL) at room
temperature and stirred for 30 min under argon atmosphere. Then,
benzo[b]thiophene-2,3-dione (2.0 mmol) was added at one portion
and sirred overnight. The organics were concentrated under
reduced pressure. Column chromatography of the residue on silica
gel (hexanes/EtOAc or hexanes/toluene) furnished the
corresponding 2-alkylidene-benzo[b]thiophenones.
(separated
from
2-(2-oxobenzo[b]thiophen-3(2H)-
ylidene)acetonitrile). m.p. 167 °C. 1H NMR (400 MHz, CDCl3) δ
7.89 (dd, J = 7.7, 0.7 Hz, 1H), 7.67 (td, J = 7.9, 1.4 Hz, 1H), 7.47
(d, J = 7.9 Hz, 1H), 7.35 (td, J = 7.6, 0.9 Hz, 1H), 6.54 (s, 1H)
ppm. 13C{1H} NMR (101 MHz, CDCl3) δ 185.4, 152.2, 144.1,
137.3, 129.0, 128.0, 126.8, 124.4, 115.7, 97.9 ppm. IR (KBr): ν =
3034, 2217, 1691, 1589, 1568, 1458, 1311, 1287, 1228, 1069,
1024, 842, 740 cm-1. HRMS (ESI) m/z: [M+Na]+ calcd for
C10H5ONNaS+ 209.9984; found 209.9982.
Ethyl
(Z)-2-(5-bromo-3-oxobenzo[b]thiophen-2(3H)-
ylidene)acetate (1h)
Following a slightly modified procedure24, a solution of DBU
(2.38 g, 15.7 mmol) in benzene (5 mL) was added dropwise to a
stirred solution of 4-bromobenzenethiol (2.84 g, 15.0 mmol) and
ethyl bromoacetate (2.61 g, 15.7 mmol) in benzene (5 mL) under
argon atmosphere and stirred for 2 h at reflux. The reaction
mixture was filtered through a sintered funnel, and the solid
residue was washed with benzene (2 × 5 mL). The organics were
concentrated under reduced pressure. Kugelrohr distillation
(200°C, 3 mbar) of the crude mixture furnished a transparent oil,
3.86 g.
Ethyl (Z)-2-(3-oxobenzo[b]thiophen-2(3H)-ylidene)acetate (1a)
The title compound was synthesized according to the general
procedure GP3-a. Orange powder, yield 117 mg (25%). Our
physical and spectroscopic data corroborated previously published
materials.13a
(Z)-2-Benzylidenebenzo[b]thiophen-3(2H)-one (1b)
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Following a slightly modified procedure25, the oil was dissolved
ppm. 13C{1H} NMR (101 MHz, CDCl3) δ 187.7, 166.2, 148.4,
1
2
3
4
5
6
in THF (15 mL), adding a solution of NaOH (1.80 g, 45.0 mmol)
in H2O (13 mL), and the reaction mixture was vigorously stirred
at room temperature overnight. Then, the mixture was poured into
H2O (50 mL) and acidified by adding 1M HCl. The precipitated
solid was filtered, washed with H2O (2 × 10 mL) and dried in
desiccator (silica gel) to yield 2-((4-bromophenyl)thio)acetic acid,
white plates, 3.35 g.
147.9, 147.5, 127.3, 127.1, 126.9, 124.5, 118.1, 61.5, 22.2, 14.2
ppm. IR (KBr): ν = 2980, 1700, 1685, 1598, 1571, 1404, 1371,
1362, 1308, 1281, 1234, 1186, 1072, 1024, 857 cm-1. HRMS
(ESI) m/z: [M+Na]+ calcd for C13H12O3NaS+ 271.0399; found
271.0397.
Ethyl
(Z)-2-(7-methyl-3-oxobenzo[b]thiophen-2(3H)-
Following a slightly modified procedure26, the crude thioacetic
acid derivative (1.24 g) was treated with SOCl2 (2 mL, excess)
and heated to reflux for 1 h under argon atmosphere. SOCl2 was
evaporated under reduced pressure. The residue was dissolved in
DCM (10 mL) and AlCl3 (0.80 g, 6 mmol) was added in one
portion at 0°C and stirred for 1 h under argon atmosphere at room
temperature. Subsequently, after adding crushed ice and then
water (10 mL), the resulting solution was extracted with DCM (3
× 10 ml). The organics were combined, washed with brine
(10 mL), dried (MgSO4) and concentrated under reduced pressure.
Crude 5-bromobenzo[b]thiophen-3(2H)-one was dissolved in
benzene (30 mL), subsequently adding a solution of ethyl
glyoxalate (50% w/w in toluene, 2 mL, excess), and then
piperidine (2 drops). The reaction mixture was stirred for 2 h at
room temperature. To the mixture, EtOAc (10 mL) was added,
and the organic phase was washed with 1M HCl (10 mL), H2O
(10 mL), Na2S2O3 (aq. 5% w/w, 10 mL), brine (10 mL), dried
(MgSO4) and concentrated under reduced pressure. Column
chromatography of the residue on silica gel (hexanes/EtOAc)
furnished the title compound.
ylidene)acetate (1l)
7
8
9
The title compound was synthesized according to the general
procedure GP3-a. Bright yellow powder, yield 293 mg (59%).
Our physical and spectroscopic data corroborated previously
published material.13a
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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48
49
50
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53
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59
60
General procedure for synthesis of enones (GP4)
Following
a
slightly modified procedure27, morpholinium
trifluoroacetate (1.0 mmol, 201 mg) was added to a solution of
corresponding aldehyde (5.0 mmol) in acetone (12.5 mL). The
reaction mixture was refluxed until reaching full conversion
(monitored by TLC, 1–2 d). The reaction mixture was carefully
concentrated (bumping) under reduced pressure, subsequently
adding EtOAc (10 mL) and a saturated NaHCO3 solution (20
mL). The organic phase was separated, and the aqueous phase
was extracted with EtOAc (2 × 10 mL). The organics were
combined, dried (Na2SO4) and concentrated under reduced
pressure. Column chromatography of the residue on silica gel
(hexanes/EtOAc) furnished enones.
Yellow-brown powder, yield 1.50 g, (32% after five steps). m.p.
(E)-4-(Naphthalen-2-yl)but-3-en-2-one (2b)
1
142 °C. H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 2.0 Hz, 1H),
The title compound was synthesized according to the general
procedure GP4. White solid, yield 461 mg (47%). Our physical
and spectroscopic data corroborated previously published
materials.27
7.69 (dd, J = 8.3, 2.0 Hz, 1H), 7.33 (d, J = 8.3 Hz, 1H), 7.02 (s,
1H), 4.33 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H) ppm.
13C{1H} NMR (101 MHz, CDCl3) δ 187.2, 166.0, 146.5, 146.4,
139.0, 130.9, 129.8, 125.5, 119.9, 119.3, 61.8, 14.2 ppm. IR
(KBr): ν = 3085, 2977, 1691, 1607, 1580, 1559, 1449, 1410,
1362, 1317, 1257, 1198, 1081, 1027, 896, 827, 773 cm-1. HRMS
(ESI) m/z: [M+Na]+ calcd for C12H9O3BrNaS+ 334.9348; found
334.9344.
(E)-4-(4-Nitrophenyl)but-3-en-2-one (2c)
The title compound was synthesized according to the general
procedure GP4. Yellow powder, yield 516 mg (54%). Our
physical and spectroscopic data corroborated previously published
materials.27
Ethyl
(Z)-2-(5-methyl-3-oxobenzo[b]thiophen-2(3H)-
ylidene)acetate (1i)
(E)-4-(3-Nitrophenyl)but-3-en-2-one (2d)
The title compound was synthesized according to general
procedure GP3-a. Orange powder, yield 99 mg (20%). Our
physical and spectroscopic data corroborated previously published
materials.13a
The title compound was synthesized according to the general
procedure GP4. Yellowish powder, yield 440 mg (46%). m.p. 97
1
°C. H NMR (400 MHz, CDCl3) δ 8.39 (t, J = 1.9 Hz, 1H), 8.23
(ddd, J = 8.2, 2.2, 1.0 Hz, 1H), 7.85 –7.84 (m, 1H), 7.59 (t, J = 8.0
Hz, 1H), 7.54 (d, J = 16.3 Hz, 1H), 6.82 (d, J = 16.3 Hz, 1H), 2.41
(s, 3H) ppm. 13C{1H} NMR (101 MHz, CDCl3) δ 197.5, 148.7,
140.1, 136.2, 133.7, 130.0, 129.3, 124.6, 122.5, 28.0 ppm. IR
(KBr): ν = 3076, 1670, 1527, 1353, 1296, 1266, 1216, 1108,
1012, 979, 815 cm-1. HRMS (ESI) m/z: [M+H]+ calcd for
C10H10NO3+ 192.0655; found 192.0654.
Ethyl
(Z)-2-(4-methyl-3-oxobenzo[b]thiophen-2(3H)-
ylidene)acetate (1j)
The title compound was synthesized according to the general
procedure GP3-a. Orange powder, yield 84 mg (17%). m.p. 118
1
°C. H NMR (400 MHz, CDCl3) δ 7.42 (t, J = 7.6 Hz, 1H), 7.25
(d, J = 7.2 Hz, 1H), 7.03 (d, J = 7.5 Hz, 1H), 6.94 (s, 1H), 4.32 (q,
J = 7.1 Hz, 2H), 2.66 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H) ppm.
13C{1H} NMR (101 MHz, CDCl3) δ 189.1, 166.4, 148.2, 147.4,
142.7, 135.5, 128.6, 126.7, 121.7, 117.5, 61.5, 19.0, 14.2 ppm. IR
(KBr): ν = 2977, 1700, 1679, 1607, 1577, 1380, 1362, 1305,
1257, 1222, 1195, 1177, 1027, 872, 851 cm-1. HRMS (ESI) m/z:
[M+Na]+ calcd for C13H12O3NaS+ 271.0399; found 271.0397.
(E)-4-(2-Nitrophenyl)but-3-en-2-one (2e)
The title compound was synthesized according to general
procedure GP4. Brownish powder, yield 287 mg (30%). Our
physical and spectroscopic data corroborated previously published
material.28
(E)-4-(4-(trifluoromethyl)phenyl)but-3-en-2-one (2f)
The title compound was synthesized according to the general
procedure GP4. White powder, yield 728 mg (68%). Our physical
and spectroscopic data corroborated previously published
materials.27
Ethyl
(Z)-2-(6-methyl-3-oxobenzo[b]thiophen-2(3H)-
ylidene)acetate (1k)
The title compound was synthesized according to the general
procedure GP3-a. Additionally, the product was recrystallized
from 96% EtOH/CHCl3 (2/1, v/v). Orange powder, yield 159 mg
1
(32%). m.p. 149 °C. H NMR (400 MHz, CDCl3) δ 7.73 (d, J =
(E)-4-(4-Bromophenyl)but-3-en-2-one (2g)
The title compound was synthesized according to the general
procedure GP4. White powder, yield 574 mg (51%). Our physical
7.9 Hz, 1H), 7.23 (s, 1H), 7.06 (d, J = 7.9 Hz, 1H), 6.98 (s, 1H),
4.31 (q, J = 7.1 Hz, 2H), 2.42 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H)
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and spectroscopic data corroborated previously published
65.0, 61.6, 48.0, 47.3, 43.2, 39.4, 13.7 ppm. IR (KBr): ν = 3072,
1
2
materials.29
2982, 1725, 1684, 1587, 1496, 1450, 1413, 1374, 1281, 1184,
1150, 918, 891, 870, 743 cm-1. HRMS (ESI) m/z: [M+Na]+ calcd
for C22H20O4NaS+ 403.0975; found 403.0977.
(E)-4-(4-Tolyl)but-3-en-2-one (2h)
3
4
5
6
The title compound was synthesized according to the general
procedure GP4. Yellow powder, yield 489 mg (61%). Our
physical and spectroscopic data corroborated previously published
materials.29
Ethyl
(2R,2'R,6'R)-3,4'-dioxo-6'-phenyl-3H-
spiro[benzo[b]thiophene-2,1'-cyclohexane]-2'-carboxylate
(ent-3aa)
7
8
9
(E)-4-(Thiophen-2-yl)but-3-en-2-on (2i)
The title compound was synthesized according to general
procedure GP5 with catalyst IX (reaction time: 36 hours),
affording the product as a diastereomeric mixture 11.0/1.5/1, yield
35 mg (92%). The major diastereomer, a yellowish wax, was
separated with a yield of 21 mg (54%) and 87% ee (IA column, n-
heptane:i-PrOH = 80:20; tR = 8.5 (major.), 9.2 (minor.) min), [α]D
= +37.6° (c 0.93; CHCl3). The other recorded spectral data
corroborated previously reported values for compound 3aa.
The title compound was synthesized according to the general
procedure GP4. Yellow wax, yield 449 mg (59%). Our physical
and spectroscopic data corroborated previously published
materials.27
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11
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59
60
(E)-4-(Benzo[b]thiophen-5-yl)but-3-en-2-one (2j)
Following
a a solution of
slightly modified procedure30,
iPrMgCl·LiCl (1.3M in THF, 27 mL, 35 mmol) was added
dropwise to an oven dried flask with a stirred solution of
5-bromobenzo[b]thiophene (2.131 g, 10 mmol) in dry THF (55
mL) at 25 °C under argon atmosphere. The resulting reaction
mixture was stirred at the same temperature for 20 h. Then,
freshly distilled dry DMF (6.0 mL, 77 mmol) was added
dropwise. After 30 min, the mixture was cooled to 0°C, adding
water (90 mL) and then 1M HCl until dissolving all solids. The
resulting solution was extracted with EtOAc (3 × 50 ml). The
organics were combined, washed with brine (50 mL), dried
(MgSO4) and concentrated under reduced pressure. Column
chromatography of the residue on silica gel (hexanes/EtOAc)
furnished benzo[b]thiophene-5-carbaldehyde, yellow solid, 560
mg, which was used as such. The title compound was synthesized
according to the general procedure GP4. Yellowish solid, yield
682 mg (96%). Our physical and spectroscopic data corroborated
previously published materials.31
Ethyl
(2S,2'S,6'S)-6'-(naphthalen-2-yl)-3,4'-dioxo-3H-
spiro[benzo[b]thiophene-2,1'-cyclohexane]-2'-carboxylate
(3ab)
The title compound was synthesized according to general
procedure GP5 (reaction time: 36 hours), affording the product as
a 11.4/1.5/1 diastereomeric mixture, with a yield of 41 mg (96%).
The major diastereomer, a off-white foam, was separated with a
yield of 28 mg (65%) and 95% ee (IA column, n-heptane:i-PrOH
= 80:20; tR = 11.1 (minor.), 16.6 (major.) min), [α]D = -40.5°
1
(c 0.58; CHCl3). H NMR (400 MHz, CDCl3) δ 7.72 – 7.67 (m,
2H), 7.63 – 7.58 (m, 3H), 7.41 – 7.36 (m, 2H), 7.34 – 7.30 (m,
1H), 7.29 – 7.27 (m, 1H), 7.11 (d, J = 8.1 Hz, 1H), 7.04 – 7.00
(m, 1H), 4.31 (dd, J = 11.8, 4.7 Hz, 1H), 4.20 – 4.08 (m, 2H),
3.72 (dd, J = 15.3, 11.6 Hz, 1H), 3.63 – 3.56 (m, 2H), 2.79 – 2.72
(m, 2H), 1.12 (t, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR (101 MHz,
CDCl3) δ 207.3, 201.9, 171.4, 150.8, 135.8, 134.6, 132.8, 132.6,
130.8, 128.6, 127.9, 127.4, 127.4, 127.1, 126.6, 126.0, 125.9,
124.9, 123.5, 65.0, 61.6, 48.0, 47.7, 43.5, 39.5, 13.8 ppm. IR
(KBr): ν = 3055, 2977, 2929, 1739, 1718, 1691, 1592, 1452,
1401, 1284, 1266, 1240, 1219, 1189, 1111, 1021, 863, 740 cm-1.
HRMS (ESI) m/z: [M+Na]+ calcd for C26H22O4NaS+ 453.1131;
found 453.1132.
General procedure for organocatalytic reaction (GP5)
The corresponding enone 2 (0.20 mmol, 2.0 equiv.) was added to
a homogeneous solution of catalyst I (5.9 mg, 0.02 mmol, 0.2
equiv.) and 4-nitrobenzoic acid (6.7 mg, 0.04 mmol, 0.4 equiv.) in
1,4-dioxane (0.5 mL). The mixture was stirred for 10 minutes at
room temperature. Then, the corresponding alkylidene compound
1 (0.10 mmol, 1.0 equiv.) was added to the reaction mixture. The
reaction was stirred for the indicated time. After completing the
reaction (monitored on TLC), the solvent was evaporated under
reduced pressure. Column chromatography of the residue on silica
gel (hexanes/EtOAc) furnished corresponding spiro compounds 3.
Racemates for chiral HPLC analysis were prepared according to a
similar method using the catalyst 9-amino(9-deoxy)epi-
cinchonidine (I) (2.9 mg, 0.01 mmol, 0.1 equiv.) and its
pseudoenantiomer 9-amino(9-deoxy)epi-cinchonine (IX) (2.9 mg,
0.01 mmol, 0.1 equiv.).
Ethyl
(2S,2'S,6'S)-6'-(4-nitrophenyl)-3,4'-dioxo-3H-
spiro[benzo[b]thiophene-2,1'-cyclohexane]-2'-carboxylate
(3ac)
The title compound was synthesized according to the general
procedure GP5 (reaction time: 36 hours), affording the product as
a 16.8/2.2/1 diastereomeric mixture, with a yield of 41 mg (96%).
The major diastereomer, a yellowish wax, was separated with a
yield of 27 mg (63%) and 86% ee (IC column, n-heptane:i-PrOH
= 80:20; tR = 47.5 (major.), 55.4 (minor.) min), [α]D = -27.3°
1
(c 0.11; CHCl3). H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.8
Hz, 2H), 7.63 (d, J = 7.8 Hz, 1H), 7.46 – 7.41 (m, 1H), 7.37 (d, J
= 8.8 Hz, 2H), 7.16 (d, J = 7.9 Hz, 1H), 7.14 – 7.11 (m, 1H), 4.35
(dd, J = 12.5, 4.6 Hz, 1H), 4.21 – 4.09 (m, 2H), 3.68 – 3.51 (m,
3H), 2.72 (ddd, J = 15.6, 5.1, 1.6 Hz, 1H), 2.64 (ddd, J = 15.2,
4.6, 1.6 Hz, 1H), 1.14 (t, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR
(101 MHz, CDCl3) δ 206.0, 201.5, 171.4, 150.6, 147.3, 144.3,
136.4, 130.5, 130.3 (2C), 126.8, 125.4, 123.6, 122.9 (2C), 64.1,
61.9, 47.8, 47.2, 42.5, 39.3, 13.8 ppm. IR (KBr): ν = 3079, 2980,
2929, 1724, 1679, 1586, 1518, 1449, 1347, 1278, 1219, 1186,
1150, 1111, 1066, 1015, 857, 755 cm-1. HRMS (ESI) m/z:
[M+Na]+ calcd for C22H19O6NNaS+ 448.0822; found 448.0825.
Ethyl
(2S,2'S,6'S)-3,4'-dioxo-6'-phenyl-3H-
spiro[benzo[b]thiophene-2,1'-cyclohexane]-2'-carboxylate
(3aa)
The title compound was synthesized according to the general
procedure GP5 (reaction time: 36 hours), affording the product as
a 25.4/3.1/1 diastereomeric mixture, with a yield of 37 mg (96%).
The major diastereomer, a yellowish wax, was separated with a
yield of 27 mg (71%), 95% ee (IA column, n-heptane:i-PrOH =
80:20; tR = 8.5 (minor.), 9.2 (major.) min), [α]D = -40.3° (c 0.62;
1
CHCl3). H NMR (600 MHz, CDCl3) δ 7.60 (d, J = 7.2 Hz, 1H),
7.40 (td, J = 7.7, 1.3 Hz, 1H), 7.17 – 7.14 (m, 3H), 7.12 – 7.07 (m,
4H), 4.16 – 4.04 (m, 3H), 3.60 (t, J = 6.5 Hz, 1H), 3.58 – 3.49 (m,
2H), 2.75 – 2.67 (m, 2H), 1.07 (t, J = 7.2 Hz, 3H) ppm. 13C{1H}
NMR (151 MHz, CDCl3) δ 207.4, 201.7, 171.2, 150.7, 136.8,
135.7, 130.9, 129.2 (2C), 127.8 (2C), 127.7, 126.6, 124.9, 123.4,
Ethyl
(2S,2'S,6'S)-6'-(3-nitrophenyl)-3,4'-dioxo-3H-
spiro[benzo[b]thiophene-2,1'-cyclohexane]-2'-carboxylate
(3ad)
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Page 8 of 13
The title compound was synthesized according to the general
Ethyl
(2S,2'S,6'S)-2'-(4-bromophenyl)-3,4'-dioxo-3H-
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5
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procedure GP5 (reaction time: 36 hours), affording the product as
a 9.6/1.9/1 diastereomeric mixture, with a yield of 39 mg (92%).
The major diastereomer, a yellow wax, was separated with a yield
of 22 mg (52%) and 92% ee (IA column, n-heptane:i-PrOH =
80:20; tR = 14.5 (minor.), 16.5 (major.) min), [α]D = -19.0°
(c 0.53; CHCl3). 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.94
(dd, J = 8.2, 1.3 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 7.8
Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.29 (t, J = 7.9 Hz, 1H), 7.14 (d,
J = 8.1 Hz, 1H), 7.09 (t, J = 7.5 Hz, 1H), 4.36 (dd, J = 12.7, 4.6
Hz, 1H), 4.23 – 4.10 (m, 2H), 3.70 – 3.60 (m, 2H), 3.54 – 3.51
(m, 1H), 2.72 (ddd, J = 15.8, 5.1, 1.7 Hz, 1H), 2.65 (ddd, J = 15.2,
4.6, 1.7 Hz, 1H), 1.16 (t, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR
(101 MHz, CDCl3) δ 206.1, 201.6, 171.5, 150.6, 147.4, 138.9,
136.3, 135.2, 130.7, 128.7, 126.8, 125.3, 124.4, 123.5, 122.8,
64.1, 61.9, 47.7, 47.1, 42.4, 39.4, 13.8 ppm. IR (KBr): ν = 3076,
2983, 2935, 1724, 1679, 1586, 1527, 1449, 1347, 1308, 1278,
1222, 1189, 1147, 1099, 1018, 905, 806, 746 cm-1. HRMS (ESI)
m/z: [M+Na]+ calcd for C22H19O6NNaS+ 448.0826; found
448.0825.
spiro[benzo[b]thiophene-2,1'-cyclohexane]-6'-carboxylate
(3ag)
The title compound was synthesized according to the general
procedure GP5 (reaction time: 36 hours), affording the product as
a 13.8/1.9/1 diastereomeric mixture, with a yield of 44 mg (96%).
The major diastereomer, a yellowish wax, was separated with a
yield of 29 mg (62%) and 93% ee (IB column, n-heptane:i-PrOH
= 80:20; tR = 9.4 (major.), 10.8 (minor.) min), [α]D = -32.2°
1
(c 0.45; CHCl3). H NMR (600 MHz, CDCl3) δ 7.61 (d, J = 7.7
Hz, 1H), 7.45 – 7.42 (m, 1H), 7.23 (d, J = 8.5 Hz, 2H), 7.18 (d, J
= 8.0 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H), 7.04 (d, J = 8.5 Hz, 2H),
4.15 – 4.08 (m, 3H), 3.57 – 3.50 (m, 3H), 2.72 – 2.67 (m, 1H),
2.63 (ddd, J = 15.4, 4.6, 1.3 Hz, 1H), 1.09 (t, J = 7.1 Hz, 3H)
ppm. 13C{1H} NMR (151 MHz, CDCl3) δ 206.9, 201.7, 171.3,
150.7, 136.1, 135.9, 130.9 (2C+2C overlapped), 130.7, 126.7,
125.1, 123.5, 121.7, 64.6, 61.7, 47.5, 47.1, 43.0, 39.3, 13.8 ppm.
IR (KBr): ν = 3067, 2989, 2905, 1727, 1673, 1583, 1485, 1446,
1332, 1281, 1216, 1186, 1150, 1009, 869, 824 cm-1. HRMS (ESI)
m/z: [M+Na]+ calcd for C22H19O4BrNaS+ 481.0080; found
481.0081.
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Ethyl
(2S,2'S,6'S)-6'-(2-nitrophenyl)-3,4'-dioxo-3H-
spiro[benzo[b]thiophene-2,1'-cyclohexane]-2'-carboxylate
(3ae)
Ethyl
(2S,2'S,6'S)-3,4'-dioxo-6'-(p-tolyl)-3H-
spiro[benzo[b]thiophene-2,1'-cyclohexane]-2'-carboxylate
(3ah)
The title compound was synthesized according to the general
procedure GP5 (reaction time: 36 hours), affording the product as
a 26.5/7.4/1 diastereomeric mixture, with a yield of 41 mg (96%).
The major diastereomer, yellowish wax, was separated with a
yield of 20 mg (47%) and 86% ee (IA column, n-heptane:i-PrOH
= 80:20; tR = 15.9 (minor.), 19.5 (major.) min), [α]D = +141.4°
(c 0.49; CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.72 (dd, J = 8.1,
1.5 Hz, 1H), 7.64 – 7.62 (m, 1H), 7.47 – 7.43 (m, 1H), 7.39 – 7.35
(m, 1H), 7.31 – 7.25 (m, 2H), 7.21 (d, J = 7.9 Hz, 1H), 7.16 –
7.12 (m, 1H), 5.17 (dd, J = 10.3, 5.2 Hz, 1H), 4.16 – 4.08 (m,
2H), 3.55 – 3.43 (m, 3H), 2.84 – 2.74 (m, 2H), 1.10 (t, J = 7.1 Hz,
3H) ppm. 13C{1H} NMR (101 MHz, CDCl3) δ 206.2, 201.6,
170.5, 150.7, 150.3, 136.1, 132.2, 131.9, 130.8, 129.4, 128.5,
126.7, 125.3, 124.7, 123.7, 64.5, 62.0, 47.4, 42.7, 40.8, 39.7, 13.7
ppm. IR (KBr): ν = 3085, 2989, 2926, 1718, 1679, 1583, 1530,
1446, 1353, 1278, 1222, 1180, 1156, 1138, 1015, 851, 756 cm-1.
HRMS (ESI) m/z: [M+Na]+ calcd for C22H19O6NNaS+ 448.0825;
found 448.0825.
The title compound was synthesized according to the general
procedure GP5 (reaction time: 36 hours), affording the product as
a 12.7/1.2/1 diastereomeric mixture, with a yield of 38 mg (95%).
The major diastereomer, an off-white wax, was separated with a
yield of 30 mg (75%) and 96% ee (IC column, n-heptane:i-PrOH
= 80:20; tR = 18.1 (minor.), 22.0 (major.) min), [α]D = -34.0°
1
(c 0.53; CHCl3). H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 9.2
Hz, 1H), 7.44 – 7.41 (m, 1H), 7.20 (d, J = 8.1 Hz, 1H), 7.13 –
7.09 (m, 1H), 7.01 (d, J = 8.2 Hz, 2H), 6.93 (d, J = 7.7 Hz, 2H),
4.15 – 4.05 (m, 2H), 4.01 (dd, J = 11.4, 5.2 Hz, 1H), 3.62 – 3.58
(m, 1H), 3.54 – 3.45 (m, 2H), 2.75 – 2.68 (m, 2H), 2.19 (s, 3H),
1.07 (t, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR (101 MHz, CDCl3) δ
207.6, 201.7, 171.2, 150.7, 137.3, 135.7, 134.0, 130.9, 129.1 (2C),
128.6 (2C), 126.7, 124.9, 123.5, 65.2, 61.5, 47.8, 47.2, 43.6, 39.6,
20.9, 13.7 ppm. IR (KBr): ν = 3058, 2980, 2929, 1718, 1679,
1586, 1512, 1449, 1308, 1281, 1216, 1189, 1150, 1060, 1024,
869, 737 cm-1. HRMS (ESI) m/z: [M+Na]+ calcd for
C23H22O4NaS+ 417.1131; found 417.1132.
Ethyl (2S,2'S,6'S)-3,4'-dioxo-6'-(4-(trifluoromethyl)phenyl)-
3H-spiro[benzo[b]thiophene-2,1'-cyclohexane]-2'-carboxylate
(3af)
Ethyl
(2R,2'S,6'S)-3,4'-dioxo-6'-(thiophen-2-yl)-3H-
spiro[benzo[b]thiophene-2,1'-cyclohexane]-2'-carboxylate
(3ai)
The title compound was synthesized according to the general
procedure GP5 (reaction time: 36 hours), affording the product as
a 10.1/2.1/1 diastereomeric mixture, with a yield of 43 mg (95%).
The major diastereomer, a white foam, was separated with a yield
of 28 mg (63%) and 90% ee (IA column, n-heptane:i-PrOH =
90:10; tR = 14.8 (major.), 17.5 (minor.) min), [α]D = -27.5°
The title compound was synthesized according to the general
procedure GP5 (reaction time: 36 hours), affording the product as
a 9.6/1.3/1 diastereomeric mixture, with a yield of 36 mg (93%).
The major diastereomer, a yellow wax, was separated with a yield
of 27 mg (69%) and 95% ee (IC column, n-heptane:i-PrOH =
80:20; tR = 18.5 (minor.), 21.4 (major.) min), [α]D = -20.8°
(c 0.51; CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.64 (dd, J = 7.8,
0.7 Hz, 1H), 7.49 – 7.45 (m, 1H), 7.27 – 7.25 (m, 1H), 7.14 (t, J =
7.5 Hz, 1H), 7.02 (dd, J = 5.1, 1.2 Hz, 1H), 6.85 – 6.84 (m, 1H),
6.77 (dd, J = 5.1, 3.5 Hz, 1H), 4.43 (dd, J = 11.5, 4.9 Hz, 1H),
4.18 – 4.06 (m, 2H), 3.60 – 3.47 (m, 3H), 2.81 (ddd, J = 15.3, 4.9,
1.5 Hz, 1H), 2.68 (ddd, J = 15.8, 6.1, 1.5 Hz, 1H), 1.11 (t, J = 7.1
Hz, 3H) ppm. 13C{1H} NMR (101 MHz, CDCl3) δ 206.3, 201.5,
171.3, 150.9, 139.8, 135.9, 130.7, 126.9, 126.9, 126.2, 125.1,
124.7, 123.6, 64.7, 61.7, 47.6, 44.7, 43.4, 39.3, 13.8 ppm. IR
(KBr): ν = 3064, 2980, 2929, 1721, 1682, 1583, 1446, 1371,
1332, 1284, 1192, 1120, 1063, 1021, 878, 740 cm-1. HRMS (ESI)
1
(c 0.46; CHCl3). H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 7.8
Hz, 1H), 7.45 – 7.41 (m, 1H), 7.37 (d, J = 8.2 Hz, 2H), 7.29 (d, J
= 8.3 Hz, 2H), 7.17 (d, J = 7.9 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H),
4.23 (dd, J = 12.2, 4.6 Hz, 1H), 4.20 – 4.07 (m, 2H), 3.64 – 3.53
(m, 3H), 2.75 – 2.69 (m, 1H), 2.66 (dd, J = 15.3, 4.6 Hz, 1H),
1.12 (t, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR (101 MHz, CDCl3) δ
206.6, 201.6, 171.4, 150.6, 141.0, 136.1, 130.7, 129.9 (q, J = 32.3
Hz, 1C), 129.7 (2C), 126.8, 125.2, 124.7 (q, J = 3.8 Hz, 2C),
123.8 (q, J = 272.7 Hz, 1C), 123.6, 64.5, 61.7, 47.6, 47.5, 42.8,
39.4, 13.8 ppm. 19F NMR (376 MHz, CDCl3) δ -62.75 (s, 3F)
ppm. IR (KBr): ν = 3064, 2956, 2920, 1730, 1682, 1586, 1452,
1419, 1329, 1281, 1171, 1126, 1069, 1018, 833, 767 cm-1. HRMS
(ESI) m/z: [M+Na]+ calcd for C23H19O4F3NaS+ 471.0844; found
471.0848.
+
m/z: [M+Na]+ calcd for C20H18O4NaS2 409.0539; found
409.0541.
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The Journal of Organic Chemistry
Ethyl (2S,2'S,6'S)-2'-(benzo[b]thiophen-5-yl)-3,4'-dioxo-3H-
The title compound was synthesized according to the general
1
2
3
4
5
6
7
8
spiro[benzo[b]thiophene-2,1'-cyclohexane]-6'-carboxylate
(3aj)
procedure GP5 (reaction time: 36 hours), affording the product as
a 14.6/2.0/1 diastereomeric mixture, with a yield of 38 mg (96%).
The major diastereomer, a yellowish wax, was separated with a
yield of 22 mg (57%) and 95% ee (IA column, n-heptane:i-PrOH
= 90:10; tR = 12.0 (minor.), 14.1 (major.) min), [α]D = -35.8°
The title compound was synthesized according to the general
procedure GP5 (reaction time: 36 hours), affording the product as
a 5.5/1.1/1 diastereomeric mixture, with a yield of 41 mg (94%).
The major diastereomer, a yellow wax, was separated with a yield
of 24 mg (55%) and 95% ee (IC column, n-heptane:i-PrOH =
80:20; tR = 23.6 (minor.), 26.1 (major.) min), [α]D = -56.4°
1
(c 0.69; CHCl3). H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 7.8
Hz, 1H), 7.42 – 7.38 (m, 1H), 7.18 – 7.07 (m, 7H), 5.77 – 5.67
(m, 1H), 5.22 (dd, J = 17.2, 1.4 Hz, 1H), 5.16 (dd, J = 10.4, 1.2
Hz, 1H), 4.55 (dt, J = 5.9, 1.3 Hz, 2H), 4.09 (dd, J = 11.8, 4.7 Hz,
1H), 3.65 – 3.52 (m, 3H), 2.77 – 2.67 (m, 2H) ppm. 13C{1H}
NMR (151 MHz, CDCl3) δ 207.3, 201.7, 171.1, 150.7, 136.8,
135.8, 131.0, 130.9, 129.3 (2C), 127.8 (2C), 127.7, 126.7, 124.9,
123.5, 119.2, 66.2, 64.9, 48.0, 47.5, 43.2, 39.5 ppm. IR (KBr): ν =
3061, 3025, 2956, 2920, 1718, 1679, 1586, 1449, 1422, 1332,
1308, 1284, 1263, 1216, 1177, 1150, 1075, 988, 934, 761 cm-1.
HRMS (ESI) m/z: [M+Na]+ calcd for C23H20O4NaS+ 415.0975;
found 415.0975.
1
(c 1.14; CHCl3). H NMR (400 MHz, CDCl3) δ 7.62 – 7.60 (m,
3H), 7.38 – 7.34 (m, 2H), 7.21 (d, J = 4.6 Hz, 1H), 7.14 (d, J = 8.1
Hz, 2H), 7.05 (t, J = 7.5 Hz, 1H), 4.24 (dd, J = 11.7, 4.6 Hz, 1H),
4.18 – 4.06 (m, 2H), 3.69 – 3.53 (m, 3H), 2.74 (dd, J = 16.1, 5.2
Hz, 2H), 1.10 (t, J = 7.2 Hz, 3H) ppm. 13C{1H} NMR (101 MHz,
CDCl3) δ 207.4, 201.9, 171.4, 150.8, 139.2, 139.0, 135.8, 133.3,
130.8, 126.7, 126.6, 125.6, 124.9, 124.3, 123.8, 123.5, 121.8,
65.2, 61.6, 47.8, 47.6, 43.7, 39.5, 13.8 ppm. IR (KBr): ν = 3067,
2977, 2926, 1724, 1682, 1586, 1449, 1419, 1371, 1278, 1213,
1183, 1156, 1051, 1018, 899, 815, 740, 704 cm-1. HRMS (ESI)
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+
m/z: [M+Na]+ calcd for C24H20O4NaS2 459.0693; found
(2S,2'S,6'S)-3,4'-Dioxo-6'-phenyl-3H-spiro[benzo[b]thiophene-
2,1'-cyclohexane]-2'-carbonitrile (3ga)
459.0695.
The title compound was synthesized according to the general
procedure GP5 (reaction time: 36 hours), affording the product as
a 16.7/1/0 diastereomeric mixture, with a yield of 32 mg (96%).
The major diastereomer, a yellow foam, was separated with a
yield of 19 mg (57%) and 97% ee (IC column, n-heptane:i-PrOH
= 60:40; tR = 17.5 (major.), 26.0 (minor.) min), [α]D = +10.3°
(2S,2'S,6'S)-2'-Benzoyl-6'-phenyl-3H-
spiro[benzo[b]thiophene-2,1'-cyclohexane]-3,4'-dione (3da)
The title compound was synthesized according to the general
procedure GP5 (reaction time: 36 hours), affording the product as
a 22.8/3.4/1 diastereomeric mixture, with a yield of 37 mg (90%).
The major diastereomer, a yellow-orange wax, was separated with
1
(c 0.44; CHCl3). H NMR (400 MHz, CDCl3) δ 7.69 – 7.67 (m,
a
yield of 15 mg (36%) and 85% ee (IA column,
1H), 7.49 – 7.45 (m, 1H), 7.21 – 7.10 (m, 7H), 3.85 (dd, J = 11.7,
5.0 Hz, 1H), 3.71 – 3.59 (m, 3H), 2.82 – 2.75 (m, 2H) ppm.
13C{1H} NMR (101 MHz, CDCl3) δ 203.7, 200.3, 150.1, 136.7,
136.2, 130.6, 128.8 (2C), 128.2, 128.1 (2C), 127.0, 125.6, 123.8,
118.2, 64.1, 48.8, 43.2, 39.6, 36.8 ppm. IR (KBr): ν = 3061, 3025,
2926, 2241, 1715, 1682, 1586, 1449, 1407, 1329, 1311, 1278,
1219, 1156, 1081, 1018, 967, 887, 758 cm-1. HRMS (ESI) m/z:
[M+Na]+ calcd for C20H15O2NNaS+ 356.0716; found 356.0717.
n-heptane:i-PrOH = 80:20; tR = 10.1 (major.), 12.3 (minor.) min),
1
[α]D = -110.7° (c 0.28; CHCl3). H NMR (600 MHz, CDCl3) δ
7.88 (d, J = 7.0 Hz, 2H), 7.64 (d, J = 7.8 Hz, 1H), 7.58 (t, J = 7.4
Hz, 1H), 7.45 (t, J = 7.8 Hz, 2H), 7.34 (t, J = 7.6 Hz, 1H), 7.25 (d,
J = 6.9 Hz, 2H), 7.10 – 7.03 (m, 5H), 4.54 (dd, J = 13.0, 4.8 Hz,
1H), 4.43 (dd, J = 7.5, 2.8 Hz, 1H), 3.84 – 3.75 (m, 2H), 2.68 (dd,
J = 14.9, 2.9 Hz, 1H), 2.56 (d, J = 15.3 Hz, 1H) ppm. 13C{1H}
NMR (151 MHz, CDCl3) δ 207.1, 203.0, 199.9, 151.4, 137.0,
135.9, 135.4, 133.9, 131.1, 129.5 (2C), 128.9 (4C), 127.6 (3C),
126.6, 124.8, 123.5, 64.6, 48.0, 47.5, 43.0, 39.5 ppm. IR (KBr): ν
= 3058, 3028, 2956, 2920, 1718, 1676, 1586, 1449, 1308, 1278,
1222, 1201, 1180, 1078, 1006, 985, 758 cm-1. HRMS (ESI) m/z:
[M+Na]+ calcd for C26H20O3NaS+ 435.1025; found 435.1026.
Ethyl
(2S,2'S,6'S)-5-bromo-3,4'-dioxo-6'-phenyl-3H-
spiro[benzo[b]thiophene-2,1'-cyclohexane]-2'-carboxylate
(3ha)
The title compound was synthesized according to the general
procedure GP5 (reaction time: 36 hours), affording the product as
a 1.3/1.3/1 diastereomeric mixture, with a yield of 44 mg (96%).
The major diastereomer, an off-white foam, was separated with a
yield of 17 mg (36%) and 92% ee (IA column, n-heptane:i-PrOH
= 80:20; tR = 8.6 (major.), 9.6 (minor.) min), [α]D = -8.8° (c 0.46;
Methyl
(2S,2'S,6'S)-3,4'-dioxo-6'-phenyl-3H-
spiro[benzo[b]thiophene-2,1'-cyclohexane]-2'-carboxylate
(3ea)
1
The title compound was synthesized according to the general
procedure GP5 (reaction time: 36 hours), affording the product as
a 44.9/4.1/1 diastereomeric mixture, with a yield of 33 mg (90%).
The major diastereomer, a yellow wax, was separated with a yield
of 25 mg (68%) and 95% ee (IA column, n-heptane:i-PrOH =
90:10; tR = 12.1 (minor.), 14.5 (major.) min), [α]D = -33.6°
CHCl3). H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 2.0 Hz, 1H),
7.50 (dd, J = 8.4, 2.0 Hz, 1H), 7.16 – 7.10 (m, 5H), 7.07 (d, J =
8.4 Hz, 1H), 4.15 – 4.08 (m, 2H), 4.05 (dd, J = 11.4, 4.8 Hz, 1H),
3.60 (t, J = 6.5 Hz, 1H), 3.54 – 3.46 (m, 2H), 2.75 – 2.68 (m, 2H),
1.11 (t, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR (101 MHz, CDCl3) δ
207.0, 200.4, 171.1, 149.5, 138.4, 136.5, 132.5, 129.22, 129.18
(2C), 128.0 (2C), 127.9, 124.9, 118.5, 66.1, 61.7, 48.1, 47.2, 43.2,
39.5, 13.8 ppm. IR (KBr): ν = 3064, 2977, 2926, 1721, 1676,
1583, 1446, 1407, 1368, 1290, 1251, 1195, 1144, 1084, 1018,
872, 701 cm-1. HRMS (ESI) m/z: [M+Na]+ calcd for
C22H19O4BrNaS+ 481.0076; found 481.0080.
1
(c 0.60; CHCl3). H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 7.8
Hz, 1H), 7.42 – 7.38 (m, 1H), 7.17 – 7.07 (m, 7H), 4.12 (dd, J =
11.8, 4.7 Hz, 1H), 3.66 (s, 3H), 3.62 – 3.53 (m, 3H), 2.75 – 2.66
(m, 2H) ppm. 13C{1H} NMR (101 MHz, CDCl3) δ 207.3, 201.8,
172.0, 150.7, 136.9, 135.8, 130.8, 129.3 (2C), 127.8 (2C), 127.7,
126.7, 124.9, 123.5, 64.8, 52.4, 47.9, 47.5, 43.2, 39.5 ppm. IR
(KBr): ν = 3094, 3058, 3025, 2956, 2905, 1721, 1676, 1586,
1446, 1428, 1362, 1284, 1204, 1174, 1153, 1054, 994, 887 cm-1.
HRMS (ESI) m/z: [M+Na]+ calcd for C21H18O4NaS+ = 389.0818;
found 389.0820.
Ethyl
(2S,2'S,6'S)-5-methyl-3,4'-dioxo-6'-phenyl-3H-
spiro[benzo[b]thiophene-2,1'-cyclohexane]-2'-carboxylate
(3ia)
The title compound was synthesized according to the general
procedure GP5 (reaction time: 36 hours), affording the product as
a 10.1/2.0/1 diastereomeric mixture, with a yield of 38 mg (96%).
The major diastereomer, a yellowish wax, was separated with a
yield of 19 mg (48%) and 92% ee (IA column, n-heptane:i-PrOH
= 80:20; tR = 16.2 (major.), 17.2 (minor.) min), [α]D = -22.1°
Allyl
(2S,2'S,6'S)-3,4'-dioxo-6'-phenyl-3H-
spiro[benzo[b]thiophene-2,1'-cyclohexane]-2'-carboxylate
(3fa)
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The Journal of Organic Chemistry
Page 10 of 13
(c 0.91; CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.42 (s, 1H), 7.23
(101 MHz, CDCl3) δ 207.5, 202.1, 171.3, 150.5, 136.9, 135.8,
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(dd, J = 8.1, 1.2 Hz, 1H), 7.14 – 7.09 (m, 5H), 7.07 (d, J = 8.1 Hz,
1H), 4.16 – 4.04 (m, 3H), 3.60 – 3.47 (m, 3H), 2.74 – 2.68 (m,
2H), 2.28 (s, 3H), 1.09 (t, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR
(101 MHz, CDCl3) δ 207.5, 201.7, 171.3, 147.7, 137.1, 137.1,
134.9, 131.0, 129.3 (2C), 127.8 (2C), 127.6, 126.6, 123.2, 65.3,
61.5, 48.0, 47.4, 43.4, 39.5, 20.7, 13.8 ppm. IR (KBr): ν = 3061,
3031, 2977, 2926, 1724, 1682, 1601, 1562, 1470, 1413, 1371,
1275, 1186, 1144, 1090, 1048, 1024, 818, 755 cm-1. HRMS (ESI)
m/z: [M+Na]+ calcd for C23H22O4NaS+ 417.1132; found
417.1131.
132.7, 130.8, 129.2 (2C), 127.7 (2C), 127.6, 125.2, 124.1, 65.2,
61.5, 48.1, 47.3, 43.3, 39.6, 18.5, 13.7 ppm. IR (KBr): ν = 3067,
2974, 2920, 1721, 1679, 1571, 1473, 1452, 1407, 1269, 1180,
1150, 1048, 767 cm-1. HRMS (ESI) m/z: [M+Na]+ calcd for
C23H22O4NaS+ 417.1135; found 417.1131.
Large scale synthesis of 3ea
The enone 2a (1.324 g, 9.08 mmol) was added to a homogeneous
solution of catalyst I (0.261 g, 0.91 mmol) and 4-nitrobenzoic
acid (0.302 g, 1.82 mmol) in 1,4-dioxane (22.5 mL). The mixture
was stirred for 10 minutes at room temperature. Then, the
alkylidene derivative 1e (1.008 g, 4.54 mmol) was added to the
reaction mixture. The reaction was stirred for the indicated time.
After completing the reaction (monitored on TLC), the solvent
was evaporated under reduced pressure. Column chromatography
of the residue on silica gel (hexanes/EtOAc) affording the product
3ea as a 42.6/3.8/1 diastereomeric mixture, with a yield of 1.560 g
(93%). The major diastereomer, a yellow wax, was separated with
a yield of 1.057 g (63%) and 94% ee.
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Ethyl
(2S,2'S,6'S)-4-methyl-3,4'-dioxo-6'-phenyl-3H-
spiro[benzo[b]thiophene-2,1'-cyclohexane]-2'-carboxylate
(3ja)
The title compound was synthesized according to the general
procedure GP5 (reaction time: 36 hours), affording the product as
a 10.1/1.8/1 diastereomeric mixture, with a yield of 35 mg (88%).
The major diastereomer, a yellow wax, was separated with a yield
of 28 mg (70%) and 90% ee (IA column, n-heptane:i-PrOH =
80:20; tR = 7.3 (minor.), 7.7 (major.) min), [α]D = -4.2° (c 1.32;
Physical and spectroscopic data corroborated with above
mentioned experiment in small scale.
1
CHCl3). H NMR (400 MHz, CDCl3) δ 7.22 (t, J = 7.6 Hz, 1H),
7.15 – 7.07 (m, 5H), 6.99 (d, J = 7.9 Hz, 1H), 6.81 (d, J = 7.4 Hz,
1H), 4.13 – 3.97 (m, 2H), 3.99 (dd, J = 11.7, 4.6 Hz, 1H), 3.67
(dd, J = 7.7, 5.9 Hz, 1H), 3.55 – 3.45 (m, 2H), 2.76 – 2.65 (m,
2H), 2.50 (s, 3H), 1.04 (t, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR
(101 MHz, CDCl3) δ 207.7, 202.5, 171.2, 151.3, 141.7, 136.8,
134.6, 129.1 (2C), 128.0, 127.7 (2C), 127.6, 127.1, 121.0, 64.0,
61.4, 48.4, 47.2, 42.9, 39.5, 19.1, 13.7 ppm. IR (KBr): ν = 3061,
3031, 2977, 2923, 1718, 1676, 1586, 1571, 1461, 1413, 1374,
1293, 1260, 1228, 1180, 1147, 1051, 1015, 857, 773 cm-1. HRMS
(ESI) m/z: [M+Na]+ calcd for C23H22O4NaS+ 417.1131; found
417.1128.
(2S,2'R,6'S)-3,4'-Dioxo-6'-phenyl-3H-
spiro[benzo[b]thiophene-2,1'-cyclohexane]-2'-carboxylic acid
(4‘‘aa)
Following
a a solution of
slightly modified procedure32,
LiOH·nH2O (105 mg, 2.50 mmol) in H2O (1 mL) was added
dropwise to a stirred solution of 3aa (38.0 mg, 0.10 mmol) in
THF (1 mL) at 0°C. The reaction mixture was vigorously stirred
at room temperature until no starting material was present
(monitored by TLC, approximately 2 h). Then, EtOAc (5 mL) and
1M HCl (4 mL) were added, and the aqueous phase was saturated
with solid NaCl and extracted with EtOAc (3 × 5 ml). The
organics were combined, dried (MgSO4) and concentrated under
reduced pressure. Column chromatography of the residue on silica
Ethyl
(2S,2'S,6'S)-6-methyl-3,4'-dioxo-6'-phenyl-3H-
spiro[benzo[b]thiophene-2,1'-cyclohexane]-2'-carboxylate
(3ka)
gel (DCM/MeOH/AcOH: 200/2/1) furnished product as
a
The title compound was synthesized according to the general
procedure GP5 (reaction time: 36 hours), affording the product as
a 17.3/2.3/1 diastereomeric mixture, with a yield of 38 mg (96%).
The major diastereomer, a yellow wax, was separated with a yield
of 29 mg (73%) and 95% ee (IA column, n-heptane:i-PrOH =
80:20; tR = 8.2 (minor.), 9.8 (major.) min), [α]D = -39.9° (c 1.36;
1.0/6.6/42.4 diastereomeric mixture, with a yield of 27 mg (77%).
The major diastereomer of acid 4‘‘aa, a white wax, was separated
with a yield of 17 mg (47%) and 82% ee (for HPLC analysis, the
product was treated with an excess of a diethylether solution of
diazomethane and compared with a diastereomeric mixture of
methyl ester 3ea; IA column, n-heptane:i-PrOH = 90:10; tR = 25.4
1
1
CHCl3). H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 8.0 Hz, 1H),
(major.), 31.7 (minor.) min), [α]D = +25.8° (c 0.16; CHCl3). H
7.17 – 7.09 (m, 5H), 6.96 (s, 1H), 6.89 (d, J = 8.0 Hz, 1H), 4.17 –
4.05 (m, 3H), 3.63 – 3.50 (m, 3H), 2.73 – 2.64 (m, 2H), 2.30 (s,
3H), 1.10 (t, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR (101 MHz,
CDCl3) δ 207.5, 201.2, 171.4, 151.1, 147.4, 137.1, 129.3 (2C),
128.7, 127.8 (2C), 127.6, 126.4, 126.4, 123.6, 65.0, 61.5, 47.9,
47.6, 43.3, 39.4, 22.0, 13.8 ppm. IR (KBr): ν = 3058, 3031, 2977,
2923, 1730, 1676, 1595, 1452, 1404, 1371, 1278, 1222, 1180,
1150, 1030, 887, 770, 701 cm-1. HRMS (ESI) m/z: [M+Na]+
calcd for C23H22O4NaS + 417.1131; found 417.1127.
NMR (600 MHz, CDCl3) δ 7.43 (d, J = 7.6 Hz, 1H), 7.30 (t, J =
7.6 Hz, 1H), 7.19 – 7.15 (m, 3H), 7.02 – 6.96 (m, 4H), 3.91 – 3.89
(m, 1H), 3.64 (dd, J = 14.3, 3.1 Hz, 1H), 3.12 (t, J = 14.7 Hz, 1H),
3.02 – 3.00 (m, 1H), 2.79 (t, J = 14.7 Hz, 1H), 2.61 (d, J = 14.7
Hz, 1H) ppm. 13C{1H} NMR (151 MHz, CDCl3) δ 205.6, 201.6,
172.7, 149.9, 135.0, 134.9, 131.9, 128.8 (2C), 128.0, 127.5 (2C),
126.4, 125.0, 123.5, 68.5, 49.9, 49.3, 44.7, 41.0 ppm. IR (KBr): ν
= 3159, 3058, 3028, 2956, 2920, 2851, 1739, 1705, 1586, 1446,
1365, 1308, 1284, 1225, 1195, 1132, 1066, 890, 842 cm-1. HRMS
(ESI) m/z: [M+Na]+ calcd for C20H16O4NaS+ 375.0662; found
375.0663.
Ethyl
(2S,2'S,6'S)-7-methyl-3,4'-dioxo-6'-phenyl-3H-
spiro[benzo[b]thiophene-2,1'-cyclohexane]-2'-carboxylate
(3la)
(2S,2'S,6'S)-3,4'-Dioxo-6'-phenyl-3H-spiro[benzo[b]thiophene-
2,1'-cyclohexane]-2'-carboxylic acid (4aa)
The title compound was synthesized according to the general
procedure GP5 (reaction time: 36 hours), affording the product as
a 9.4/1.6/1 diastereomeric mixture, with a yield of 37 mg (94%).
The major diastereomer, a yellowish wax, was separated with a
yield of 20 mg (51%) and 96% ee (IB column, n-heptane:i-PrOH
= 80:20; tR = 7.0 (minor.), 8.5 (major.) min), [α]D = -45.7° (c 0.99;
Following a slightly modified procedure33, pyrrolidine (7.5 mg,
0.105 mmol) was added dropwise to a stirred solution of 3fa (39.2
mg, 0.10 mmol), Ph3P (1.3 mg, 0.005 mmol) and Pd(Ph3P)4
(2.9 mg, 0.0025 mmol) in DCM (0.5 mL) at 0°C. The reaction
mixture was stirred at room temperature until no starting material
was present (monitored by TLC, approx. 1 h). Then, 1M HCl (4
mL) was added, and the organic phase was separated. The
aqueous phase was extracted with EtOAc (3 × 5 ml), and the
organics were combined, dried (MgSO4) and concentrated under
1
CHCl3). H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 7.2 Hz, 1H),
7.22 (d, J = 7.3 Hz, 1H), 7.15 – 7.07 (m, 5H), 7.02 (t, J = 7.5 Hz,
1H), 4.18 – 4.05 (m, 3H), 3.61 – 3.51 (m, 3H), 2.76 – 2.68 (m,
2H), 2.18 (s, 3H), 1.08 (t, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR
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Page 11 of 13
The Journal of Organic Chemistry
reduced pressure. Column chromatography of the residue on silica
(m, 2H), 7.75 – 7.71 (m, 1H), 7.16 – 7.15 (m, 3H), 7.03 – 7.00 (m,
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gel (DCM/MeOH/AcOH: 200/2/1) furnished compound 4aa, an
off-white wax, with a yield of 32 mg (92%) and 95% ee (for
HPLC analysis 4aa was treated with an excess of a diethylether
solution of diazomethane and compared with methyl ester 3ea; IA
column, n-heptane:i-PrOH = 90:10; tR = 12.1 (minor.), 14.5
(major.) min), [α]D = -30.3° (c 0.50; CHCl3). 1H NMR (600 MHz,
CDCl3) δ 7.62 (d, J = 7.7 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.17 –
7.14 (m, 3H), 7.13 – 7.08 (m, 4H), 4.11 (dd, J = 11.7, 4.7 Hz,
1H), 3.65 – 3.58 (m, 3H), 2.76 (dd, J = 15.5, 4.9 Hz, 1H), 2.70
(dd, J = 15.3, 4.5 Hz, 1H) ppm. 13C{1H} NMR (151 MHz,
CDCl3) δ 207.6, 201.7, 175.1, 150.7, 136.8, 135.9, 130.8, 129.3
(2C), 127.8 (2C), 127.8, 126.8, 125.0, 123.6, 64.3, 47.9, 47.4,
43.2, 39.4 ppm. IR (KBr): ν = 3162, 3058, 3031, 2920, 2848,
1718, 1682, 1586, 1449, 1410, 1359, 1308, 1275, 1219, 1186,
1147, 1120, 1075, 890 cm-1. HRMS (ESI) m/z: [M+Na]+ calcd
for C20H16O4NaS+ 375.0662; found 375.0664.
2H), 4.38 (dd, J = 7.8, 5.8 Hz, 1H), 4.04 (q, J = 7.1 Hz, 2H), 3.98
(dd, J = 11.0, 5.2 Hz, 1H), 3.46 (dd, J = 17.0, 5.2 Hz, 1H), 3.17
(dd, J = 16.0, 5.8 Hz, 1H), 3.08 (dd, J = 17.1, 11.0 Hz, 1H), 3.04
(dd, J = 16.0, 7.7 Hz, 1H), 0.99 (t, J = 7.1 Hz, 3H) ppm. 13C{1H}
NMR (101 MHz, CDCl3) δ 206.4, 190.9, 169.7, 144.5, 137.0,
136.7, 134.2, 132.3, 129.4 (2C), 128.3 (2C), 128.0, 124.4, 121.6,
70.0, 62.0, 44.4, 44.3, 43.7, 39.2, 13.4 ppm. IR (KBr): ν = 3064,
3028, 2980, 2923, 1727, 1583, 1455, 1419, 1305, 1225, 1186,
1153, 1018, 884, 764 cm-1. HRMS (ESI) m/z: [M+Na]+ calcd for
C22H20O6NaS+ 435.0873; found 435.0877.
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Ethyl
(2S,2'S,6'S)-3,4'-dioxo-6'-phenyl-5-(p-tolyl)-3H-
spiro[benzo[b]thiophene-2,1'-cyclohexane]-2'-carboxylate (7a)
p-Tolyl boronic acid (8.2 mg, 0.06 mmol), 3ha (23.0 mg, 0.05
mmol),
[1,1′-bis(diphenylphosphino)ferrocene]dichloro
palladium(II) (3.7 mg, 0.005 mmol), and anhydrous KOAc (19.6
mg, 0.20 mmol) were added to a flame-dried Schlenk flask under
a stream of argon, dissolved in dry 1,4-dioxane (0.5 mL). The
mixture was carefully degassed in three vacuum-argon cycles.
The reaction mixture was stirred at 110°C under argon
atmosphere overnight. Then, the reaction mixture was filtered
Ethyl
(2S,2'S,6'S)-3,4'-dioxo-6'-phenyl-3H-
spiro[benzo[b]thiophene-2,1'-cyclohexane]-2'-carboxylate 1-
oxide (5a)
mCPBA (77% w/w, 24.6 mg, 0.11 mmol) was added to a stirred
solution of 3aa (38.0 mg, 0.10 mmol) in DCM (2 mL) at room
temperature. The reaction mixture was stirred at the same
temperature until no starting material was present (monitored by
TLC, for approximately 1 h). Then, DCM (5 mL) was added, and
the organic phase was washed with saturated NaHCO3 (2 × 5 ml),
dried (Na2SO4) and concentrated under reduced pressure. Column
chromatography of the residue on silica gel (hexanes/EtOAc: 2/1
→ 1/1) furnished compound 5a, a white wax, with a yield of
31 mg (79%) and 95% ee (the racemic mixture for HPLC analysis
was prepared under the same conditions from the racemate of
compound 3aa; our attempts to prepare (by oxidation of 3aa with
H2O2 in AcOH) an equimolar mixture of sulfoxide diastereomers
(contrary configurations on sulfur atom) gave inconsistent results
due to the instability of the second diastereomer on silica gel or
chiral stationary phase; IA column, n-heptane:i-PrOH = 70:30; tR
= 11.7 (minor.), 18.0 (major.) min), [α]D = +59.4° (c 0.35;
through
a plug of cotton wool. The organic phase was
concentrated under reduced pressure. Column chromatography of
the residue on silica gel (hexanes/EtOAc: 10/1) furnished
compound 7a, a white solid, with a yield of 23 mg (97%) and
92% ee (IA column, n-heptane:i-PrOH = 80:20; tR = 12.1
1
(major.), 14.5 (minor.) min), [α]D = +30.0° (c 0.20; CHCl3). H
NMR (400 MHz, CDCl3) δ 7.83 (d, J = 1.3 Hz, 1H), 7.67 (dd, J =
8.3, 2.0 Hz, 1H), 7.43 (d, J = 8.2 Hz, 2H), 7.25 – 7.23 (m, 3H),
7.18 – 7.09 (m, 5H), 4.18 – 4.06 (m, 3H), 3.66 – 3.50 (m, 3H),
2.77 – 2.71 (m, 2H), 2.39 (s, 3H), 1.10 (t, J = 7.1 Hz, 3H) ppm.
13C{1H} NMR (101 MHz, CDCl3) δ 207.5, 201.7, 171.3, 149.3,
138.3, 137.8, 137.0, 136.2, 134.6, 131.5, 129.7 (2C), 129.3 (2C),
127.9 (2C), 127.8, 126.6 (2C), 124.4, 123.8, 65.8, 61.6, 48.2,
47.4, 43.4, 39.6, 21.1, 13.8 ppm. IR (KBr): ν = 3031, 2977, 2920,
1730, 1700, 1682, 1598, 1464, 1422, 1374, 1263, 1189, 1144,
1093, 1024, 911, 812, 749 cm-1. HRMS (ESI) m/z: [M+Na]+
calcd for C29H26O4NaS+ 493.1444; found 493.1441.
1
CHCl3). H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 7.6 Hz, 1H),
7.63 (dd, J = 6.4, 1.3 Hz, 2H), 7.58 – 7.54 (m, 1H), 7.03 – 6.96
(m, 5H), 4.97 (dd, J = 13.3, 4.6 Hz, 1H), 4.31 – 4.18 (m, 2H),
3.86 (dd, J = 15.3, 7.9 Hz, 1H), 3.53 (dd, J = 7.8, 2.6 Hz, 1H),
3.40 (dd, J = 14.7, 13.2 Hz, 1H), 2.84 (dt, J = 15.4, 2.2 Hz, 1H),
2.65 (ddd, J = 14.7, 4.6, 1.8 Hz, 1H), 1.28 (t, J = 7.1 Hz, 3H)
ppm. 13C{1H} NMR (101 MHz, CDCl3) δ 206.9, 200.5, 172.7,
149.9, 136.5, 135.7, 134.7, 132.8, 128.44 (2C), 128.39 (2C),
128.3, 127.4, 126.0, 72.8, 61.9, 44.3, 43.5, 42.9, 40.6, 13.9 ppm.
IR (KBr): ν = 3061, 3031, 2977, 2932, 1724, 1697, 1586, 1452,
1371, 1329, 1275, 1225, 1186, 1147, 1066, 1042, 979, 872, 758
cm-1. HRMS (ESI) m/z: [M+H]+ calcd for C22H21O5S+ 397.1104;
found 397.1111.
ASSOCIATED CONTENT
Supporting Information
1
Spectral data for all prepared compounds with copies of the H
NMR, 13C NMR and 19F NMR and HPLC chromatograms are
available online from http://xxxxxxxxxxx.
CIF file for compound 3ag. (CIF)
Accession codes
CCDC 1978776 contains the supplementary crystallographic data
of this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
Ethyl
(2S,2'S,6'S)-3,4'-dioxo-6'-phenyl-3H-
spiro[benzo[b]thiophene-2,1'-cyclohexane]-2'-carboxylate 1,1-
dioxide (6a)
mCPBA (77% w/w, 49.3 mg, 0.22 mmol) was added to a stirred
solution of 3aa (38.0 mg, 0.10 mmol) in DCM (2 mL) at room
temperature. The reaction mixture was stirred at the same
temperature until no sulfoxide 5a was present (monitored by TLC,
approx. 30 h). Then, DCM (5 mL) was added, and the organic
phase was washed with saturated NaHCO3 (2 × 5 ml), dried
(Na2SO4) and concentrated under reduced pressure. Column
chromatography of the residue on silica gel (hexanes/EtOAc: 2/1)
furnished compound 6a, a transparent wax, with a yield of 31 mg
AUTHOR INFORMATION
Corresponding Author
* E-mail: jan.vesely@natur.cuni.cz
ORCID
Jan Veselý: orcid.org/0000-0001-5198-8950
(75%) and 95% ee (IA column, n-heptane:i-PrOH = 70:30; tR
=
Notes
13.4 (minor.), 18.4 (major.) min), [α]D = -106.7° (c 0.30; CHCl3).
The authors declare no competing financial interests.
1H NMR (400 MHz, CDCl3) δ 7.94 – 7.92 (m, 1H), 7.88 – 7.84
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Page 12 of 13
heterocyclic carbene as a non-covalent organocatalyst Chem. Sci.
ACKNOWLEDGMENT
1
2
3
4
5
6
7
8
2015, 6, 4184−4189. (c) Tian, X.; Liu, Y.; Melchiorre, P.
Aminocatalytic Enantioselective 1,6 Additions of Alkyl Thiols to
Cyclic Dienones: Vinylogous Iminium Ion Activation Angew. Chem.,
Int. Ed. 2012, 51, 6439−6442. (d) Lu, H.-H.; Zhang, F.-G.; Meng, X.-
G.; Duan, S.-W.; Xiao, W.-J. Enantioselective Michael Reactions of
β,β-Disubstituted Nitroalkenes: A New Approach to β2,2-Amino Acids
with Hetero-Quaternary Stereocenters Org. Lett. 2009, 11,
3946−3949. (e) Chen, W.; Jing, Z.; Chin, K. F.; Qiao, B.; Zhao, Y.;
Yan, L.; Tan, C.-H.; Jiang, Z. Catalytic asymmetric conjugate
Jan Veselý gratefully acknowledges the Czech Science
Foundation (No 20-29336S) for the financial support. Bedřich
Formánek thanks the Charles University Grant Agency (No
393615) for the financial support. We also thank Dr. Simona
Petrželová and Jan Ulč for the NMR service provided, Dr. Martin
Štícha for his MS analysis and Dr. Carlos V. Melo for
proofreading the manuscript.
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