Catalytic Enantioselective Synthesis of 3,4-Unsubstituted Thiochromenes through Sulfa-Michael/Julia-Kocienski Olefination Cascade Reaction

Article abstract of DOI:10.1021/acs.joc.7b00579

A highly enantioselective cascade sulfa-Michael/Julia-Kocienski olefination reaction between 2-mercaptobenzaldehydes and β-substituted vinyl PT-sulfones has been realized for the synthesis of 3,4-unsubstituted 2H-thiochromenes. This reaction, catalyzed by diphenylprolinol TMS ether, proceeds through an aromatic iminium intermediate and furnishes a wide range of 2-substiuted 2H-thiochromenes with excellent enantioselectivities (up to 99:1 er).

Full text of DOI:10.1021/acs.joc.7b00579

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Article
Catalytic Enantioselective Synthesis of 3,4-Unsubstituted Thiochromenes
through Sulfa-Michael/Julia-Kocienski Olefination Cascade Reaction
AMIT KUMAR SIMLANDY, and Santanu Mukherjee
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00579 • Publication Date (Web): 07 Apr 2017
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Catalytic Enantioselective Synthesis of 3,4-Unsubstituted Thiochromenes
through Sulfa-Michael/Julia-Kocienski Olefination Cascade Reaction
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Amit Kumar Simlandy and Santanu Mukherjee*
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Eꢀmail: sm@orgchem.iisc.ernet.in
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Fax: +91ꢀ80ꢀ2360ꢀ0529; Tel: +91ꢀ80ꢀ2293ꢀ2850
ABSTRACT
A highly enantioselective cascade sulfaꢀMichael/JuliaꢀKocienski olefination reaction
between 2ꢀmercaptobenzaldehydes and βꢀsubstituted vinyl PTꢀsulfones has been realized for
the synthesis of 3,4ꢀunsubstituted 2Hꢀthiochromenes. This reaction, catalyzed by
diphenylprolinol TMS ether, proceeds through an aromatic iminium intermediate and
furnishes a wide range of 2ꢀsubstiuted 2Hꢀthiochromenes with excellent enantioselectivities
(up to 99:1 er).
INTRODUCTION
Thiochromenes, thiochromanes and their derivatives are valuable compounds due to their
potential applications in pharmaceutical industries (Figure 1).1 As a result, a number of
strategies have been devised for the enantioselective synthesis of such heterocycles.2ꢀ4
Catalytic enantioselective sulfaꢀMichaelꢀinitiated cascade reactions are possibly the most
efficient ways of constructing these and related heterocycles.2ꢀ5
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Figure 1. Bioactive thiochromenes and thiochromanes
The first report by Wang et al. in 20062 triggered the development of a large number of
sulfaꢀMichaelꢀinitiated cascade reactions. However in all these reactions, 2Hꢀthiochromenes
are formed invariably containing an electronꢀwithdrawing substituent at the C3 position
(Scheme 1A).4 Enantioselective synthesis of 3,4ꢀunsubstituted 2Hꢀthiochromenes remained
an unmet challenge until very recently. While the present study was nearing completion,
Birman et al. reported an elegant strategy for the first enantioselective synthesis of 3,4ꢀ
unsubstituted thiochromenes via an acylꢀtransferꢀinitiated cascade reaction (Scheme 1B).6
With our interest in thiochromenes, we aimed to develop a facile and enantioselective
route to 3,4 unsubstituted thiochromenes.
Scheme 1. Catalytic enantioselective routes to 2ꢀsubstituted thiochromenes
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In 2013, our laboratory has reported a sulfaꢀMichael/HornerꢀWadsworthꢀEmmons
cascade reaction between 2ꢀmercaptobenzaldehydes and αꢀcarboxylato vinylphosphonates for
the enantioselective synthesis of 2Hꢀthiochromenes bearing an ester moiety at C3 (Scheme
1A).4c While the phosphonate group acts as a traceless activator of α,βꢀunsaturated ester in
this reaction, vinyl phosphonate itself was found to be unreactive under our reaction
conditions and thereby eliminates the possibility of constructing 3,4ꢀunsubstituted 2Hꢀ
thiochromenes through this route.
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Nucleophilic addition to vinyl sulfones followed by JK olefination as a metalꢀfree
strategy for formal allylic alkylation is known through the seminal works of Cid and coꢀ
workers.7 We reasoned that a related sulfaꢀMichael addition of 2ꢀmercaptobenzaldehyde to
vinyl sulfones could set the stage for a JuliaꢀKocienski (JK) olefination8 (Scheme 1B).
Controlling enantioselectivity of the initial sulfaꢀMichael step would of course be the key to
success of this cascade reaction, which would result in 3,4ꢀunsubstituted 2Hꢀthiochromenes
containing a stereogenic center at the C2 position. The successful implementation of this
strategy is presented here.
RESULTS AND DISCUSSION
Earlier studies by our group9 and the Cid group7a confirmed vinyl(1ꢀphenylꢀ1Hꢀtetrazolꢀ
5ꢀyl)sulfone7 (vinyl PTꢀsulfone) to be more reactive compared to the corresponding vinyl
phenyl sulfone. Accordingly, the reaction between 2ꢀmercaptobenzaldehyde 1a and vinyl PTꢀ
sulfone 2a was chosen for the optimization of catalyst and reaction conditions (Table 1). The
success of bifunctional tertiary aminoꢀ(thio)urea catalysts in vinylogous nucleophilic addition
to vinyl PTꢀsulfones9 encouraged us to probe similar catalysts for this cascade reaction.
However, slow reaction rates and low enantioselectivities observed10 with these catalysts
prompted us to seek an alternative catalytic strategy.
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Table 1. Reaction optimizationa
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Entry Cat.
Solvent
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhCF3
tꢀBuPh
tꢀBuPh
Coꢀcat.
t/h
24
48
72
96
48
48
48
48
72
48
48
46
48
48
48
48
48
48
Yield (%)b erc
1
ꢀ
ꢀ
<5
37
ꢀ
2
ꢀ
80:20
55:45
78:22
48:52
60:40
56:44
85:15
51:49
90:10
93:7
94:6
93:7
91:9
97:3
98:2
99:1
99:1
I
3d
ꢀ
33
II
III
IV
V
VI
VII
VIII
I
4
ꢀ
n.d.
n.d.
n.d.
n.d.
19
5
ꢀ
6
ꢀ
7
ꢀ
8
ꢀ
9
ꢀ
42
10e
11e
12e
13e
14e
15e
16e,f
17 e,f,g
18f,g
ꢀ
33
ꢀ
46
I
ꢀ
74
I
PhCO2H
56
I
tꢀBuPh 2ꢀFC6H4CO2H
46
I
tꢀBuPh
tꢀBuPh
tꢀBuPh
tꢀBuPh
(PhO)2PO2H
(PhO)2PO2H
(PhO)2PO2H
(PhO)2PO2H
42
I
65
I
79
I
80
I
a Reactions were performed using 1.1 equiv of 1a and 1.0 equiv of 2a. b Yields
c
correspond to the isolated yield. n.d. = not determined. Enantiomeric ratio
(er) as determined by HPLC analysis on a chiral stationary phase. d Using 1.2
equiv of 1a. e Reaction at 0.25 M conc. fUsing 1.8 equiv of 1a. g With 4Å MS.
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Activation of aromatic aldehydes of type 1a by amine catalyst through iminium
intermediate (A in Scheme 3) is first reported by Xu et al.11 This type of aromatic iminium
activation, despite its obvious potential, remains largely underdeveloped.12 We surmised that
the iminium intermediate formed from 2ꢀmercaptobenzaldehyde 1a with a suitable amine
catalyst should facilitate the enantioselective sulfaꢀMichael addition to 2a. The subsequent
ring closure through intramolecular JK olefination13 should then generate the desired
thiochromene 3aa.
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The reaction between 1a and 2a, when carried out in the presence of 10 mol % of
diphenylprolinol TMS ether14 (I) in toluene at room temperature, 2ꢀphenylꢀ2Hꢀthiochromene
3aa was indeed found to form, albeit in rather low yield and with modest enantioselectivity
(Table 1, entry 2). Variation of the aryl group or the silyl protecting group on oxygen of the
catalyst (IIꢀVII) either did not improve the enantioselectivity or did so marginally at the
expense of the reaction rate (entries 3ꢀ8). Likewise, nearly racemic product was obtained
using bifunctional secondary aminoꢀthiourea VIII15 as the catalyst. Product with improved er
was observed when the reaction was carried out at higher concentration (entry 10). Solvent,
however, was found to play the vital role: the reaction in tertꢀbutylbenzene using I as the
catalyst furnished the product with significantly improved er of 94:6 (entry 12).
Enantioselectivity could be further improved by using 10 mol % an acid coꢀcatalyst, with
diphenyl phosphate proved to be the optimum (entries 13ꢀ15).16 Susceptibility of 1a toward
oxidation appeared to be the reason for low yield, which could be overcome by using an
excess of 1a (entry 16). Finally, superior product yield was obtained in the presence of 4Å
molecular sieves: under these conditions, 3aa was formed in 79% yield with 99:1 er (entry
17). Considering the operational simplicity, we decided to carry out the reaction at 0.1 M
concentration when the same level of yield and enantioselectivity was maintained (entry 18).
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Table 2. Scope with respect to vinyl sulfonea
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Entry
1
R
t/h
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26
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72
48
Yieldb (%) erc
3
Ph
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99:1
98:2
98:2
99:1
99:1
97:3
96:4
97:3
98:2
97:3
96:4
98:2
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
3aj
3ak
3al
2
2ꢀMeC6H4
4ꢀMeC6H4
4ꢀ(iꢀPr)C6H4
4ꢀOMeC6H4
2ꢀFC6H4
3ꢀClC6H4
4ꢀClC6H4
4ꢀBrC6H4
4ꢀCF3C6H4
3ꢀNO2C6H4
2ꢀNapthyl
3
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73
99:1
3am
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3,4ꢀ(OMe)2C6H3
3,4ꢀCl2C6H3
2ꢀThienyl
PhCH=CH
Me
90
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86
66
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40
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99:1
3an
3ao
3ap
3aq
3ar
3as
3at
98:2
98:2
97:3
95:5
iꢀBu
97.5:2.5
99:1
cꢀHex
a Reactions were performed on a 0.1 mmol scale. b Yields correspond to
c
the isolated yield. Enantiomeric ratio (er) as determined by HPLC
analysis on a chiral stationary phase.
Application of reaction conditions optimized for 2ꢀmercaptobenzaldehyde 1a and vinyl
PTꢀsulfone 2a (Table 1, entry 18) to a range of similar substrates was then undertaken. The
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scope of vinyl sulfones (2) was first examined and the results are outlined in Table 2. Our
reaction conditions proved to be general for a range of vinyl PT sulfones bearing both
aromatic and aliphatic substituents at the βꢀposition. Irrespective of the steric or electronic
nature of the substituents on different positions of the aryl ring, 2Hꢀthiochromenes (3) were
obtained with excellent enantioselectivities in moderate to high yields (entries 2ꢀ15). The
same selectivity trend was observed for βꢀheteroaryl or βꢀalkenyl substituted vinyl PTꢀ
sulfones, although in the latter case the product was formed with low yield (entries 16ꢀ17).
We were delighted to find that βꢀalkyl substituted vinyl PT sulfones were not only tolerated,
but furnished the products with good to excellent enantioselectivities (entries 18ꢀ20).
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Table 3. Scope with respect to aldehydea
Entry
R1
R2
H
t/h
72
47
48
69
41
72
90
Yieldb (%)
erc
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7
Me
OMe
Ph
46
75
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56
96:4
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98:2
3ba
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3ha
H
H
Br
H
tꢀBu
H
H
Me
Br
H
a Reactions were performed on 0.1 mmol scale. b Yields correspond
c
to the isolated yield. Enantiomeric ratio (er) as determined by
HPLC analysis on a chiral stationary phase.
In addition to the examples shown in Table 2, we surveyed the scope of the aldehyde
component (1) with respect to the substituents on the aryl ring. As portrayed in Table 3,
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various substituents on either 4ꢀ or 5ꢀposition of the aryl ring could be accommodated. In all
these cases, the products were obtained with good to excellent enantioselectivities.
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Absolute configuration of 3ai and 3ak was established by Xꢀray crystallography and
found to be R (Figure 2).17 The stereochemistry of the remaining examples was assigned by
analogy.
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3ai
3ak
(CCDC 1506906)
(CCDC 1506907)
Figure 2. Xꢀray structure of 3ai and 3ak showing their absolute configuration with thermal ellipsoids at 50%
and 30% probability, respectively
Having successfully demonstrated the scope of the sulfaꢀMichael/JK olefination cascade
reaction, the product 2ꢀphenylꢀ2Hꢀthiochromene 3aa was subjected to a few synthetic
elaborations (Scheme 2). Hydrogenation under Pd/C afforded (R)ꢀ2ꢀphenylthiochromane 4 in
excellent yield. Enantioselective synthesis of 3,4ꢀunsubstituted thiochromanes has not been
explored previously except for a solitary report by Pfaltz et al.18 Therefore, ours is only the
second example of the enantioselective synthesis of 4. 2ꢀArylthiochromenꢀ4ꢀones
(thioflavones) and their derivatives are known to display a broad spectrum of biological
activities including anticancer, antitumor and antibacterial activities.19 Thioflavone 5 could
easily be prepared from 3aa through its exposure to OsO4 catalyzed oxidation conditions.
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Scheme 2. Derivatization of the cascade product 3aa
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Based on a number of experimental evidences collected during the course of this
investigation, we propose a catalytic cycle as presented in Scheme 3 for the formation of 3aa.
The aromatic iminium intermediate
A
generated from the catalyst (I) and
2ꢀmercaptobenzaldehyde (1a) leads to nucleophilic activation, presumably via general base
catalysis by the phosphate anion (X–).11,12 Approach of the vinyl PTꢀsulfone 2a to the catalyst
bound iminium A then takes place from the face opposite to the bulky diphenylmethanolꢀ
TMS ether substituent. The Siꢀface selective sulfaꢀMichael addition to vinyl PTꢀsulfone
results in intermediate B. Hydrolysis of B regenerates the catalyst and releases the sulfaꢀ
Michael product C. The formation of A, B and C could be detected by high resolution ESIꢀ
MS analysis of the reaction mixture. Intramolecular JK olefination of C then furnishes 2Hꢀ
thiochromene 3aa. The role (or the absence of it) of catalyst in JK olefination remains
unknown at this stage as C appeared to be rather unstable and our attempts to isolate C in
reasonable quantity proved futile.
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Scheme 3. Proposed catalytic cycle
CONCLUSION
In summary, a highly enantioselective synthesis of 3,4ꢀunsubstituted 2Hꢀthiochromenes
has been realized through a catalytic cascade sulfaꢀMichael/JuliaꢀKocienski olefination
reaction between 2ꢀmercaptobenzaldehydes and βꢀsubstituted vinyl PTꢀsulfones. Our
approach is complementary to that of Birman and coꢀworkers,6 and only the second example
of the enantioselective synthesis of 3,4ꢀunsubstituted 2Hꢀthiochromenes. This operationally
simple reaction, catalyzed by diphenylprolinol TMS ether, proceeds through an aromatic
iminium intermediate and furnishes a wide range 2ꢀsubstituted 2Hꢀthiochromenes with good
to excellent enantioselectivities.
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EXPERIMENTAL SECTION
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General information
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Infrared (FTꢀIR) spectra were recorded on Perkin Elmer Spectrum BX
spectrophotometer and Bruker alfa FTꢀIR, νmax in cmꢀ1. NMR spectra were recorded on
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1
Bruker Ultrashield spectrometer at 400 MHz (for HꢀNMR) and 100 MHz (for 13CꢀNMR).
Chemical shifts are reported in ppm from tetramethylsilane with the solvent resonance as
internal standard (CDCl3: δ 7.26 for HꢀNMR and CDCl3: δ 77.00, for 13CꢀNMR). For Hꢀ
NMR, data are reported as follows: chemical shift, multiplicity (s = singlet, br s = broad
singlet, d = doublet, dd = double doublet, t = triplet, q = quartet, dt = doublet of triplets, m =
multiplet), coupling constants (Hz) and integration. High resolution mass spectrometry was
performed on Micromass QꢀTOF Micro instrument. Optical rotations were measured on
JASCO Pꢀ2000 polarimeter. Melting points were measured using ANALAB ꢁꢀThermocal 10
melting point apparatus. All melting points were measured in open glass capillary and values
are uncorrected. Enantiomeric ratios were determined by Shimadzu LCꢀ20AD HPLC
instrument and SPDꢀ20A UV/Vis detector using stationary phase chiral columns (25 cm ×
0.46 cm) in comparison with authentic racemic compounds.
1
1
Unless stated otherwise, all reactions were carried out with distilled and dried solvents
under an atmosphere of argon in oven (120 °C) dried glassware with standard vacuum line
techniques. Organic solvents used for carrying out reactions were dried using standard
methods. All work up and purification were carried out with reagent grade solvents in air.
Thin layer chromatography was performed using Merck silica gel 60 F254 preꢀcoated plates
(0.25 mm). Column chromatography was performed using silica gel (230ꢀ400 or 100ꢀ200
mesh).
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Catalyst preparation and characterization
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Catalyst I was synthesized according to previously reported procedure.14d
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General procedure for the catalytic enantioselective sulfa-Michael/Julia-Kocienski
olefination cascade reaction
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In an oven and vacuum dried Schlenk tube, 100 mg 4Å MS (activated by heating at 200 °C
under high vacuum for 20 min prior to use) was taken. Diphenylphosphate (2.5 mg, 0.010
mmol, 0.1 equiv), catalyst I (3.3 mg, 0.010 mmol, 0.1 equiv) and thiosalicylaldehyde 1
(0.180 mmol, 1.8 equiv) were added along with 1.0 mL tertꢀbutylbenzene. Vinyl sulfone 2
(0.100 mmol, 1.0 equiv) was added to the reaction mixture after stirring for 10 min at room
temperature. The reaction was continued until TLC revealed the complete consumption of 2.
The reaction mixture was purified by column chromatography to obtain the desired product.
(R)ꢀ2ꢀPhenylꢀ2Hꢀthiochromene (3aa)
Purified by silica gel (100ꢀ200 mesh) column chromatography (10% CH2Cl2/Petroleum ether)
to afford a colorless oil (18.0 mg, 0.080 mmol, 80% yield). FTꢀIR (Thin film): 3727, 3587,
1
2919, 2850, 1634, 1023 cmꢀ1; HꢀNMR (400 MHz, CDCl3): δ 7.35ꢀ7.33 (m, 2H), 7.31ꢀ7.22
(m, 3H), 7.15ꢀ7.05 (m, 4H), 6.65 (dd, J = 10.2 Hz, 1.3 Hz, 1H), 6.00 (dd, J = 10.2 Hz, 5.2 Hz,
1H), 4.88 (dd, J = 5.2 Hz, 1.3 Hz, 1H); 13CꢀNMR (100 MHz, CDCl3): δ 141.8, 131.0, 130.6,
128.74, 128.70, 128.4, 128.1, 127.7, 127.6, 126.8, 125.6, 125.5, 43.0; HRMS (ESI+): Calcd.
for C15H12KS ([M+K]+): 263.0297, Found: 263.0299; Optical rotation: [α]D24 –145.1 (c 1.0,
CHCl3) for an enantiomerically enriched sample with 99:1 er. The enantiomeric ratio was
determined by HPLC analysis using Daicel Chiralpak IF column (80:20 nꢀHexane/MTBE,
1.0 mL/min, 20 °C, 254 nm, τminor = 5.4 min, τmajor = 6.2 min).
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(R)ꢀ2ꢀ(oꢀTolyl)ꢀ2Hꢀthiochromene (3ab)
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8
Purified by silica gel (100ꢀ200 mesh) column chromatography (8% CH2Cl2/Petroleum ether)
to afford a colorless oil (19.0 mg, 0.080 mmol, 80% yield). FTꢀIR (Thin film): 2922, 2854,
1601, 1019 cmꢀ1; 1HꢀNMR (400 MHz, CDCl3): δ 7.44ꢀ7.42 (m, 1H), 7.18ꢀ7.11 (m, 7H), 6.71
(d, J = 10.1 Hz, 1H), 5.99 (dd, J = 10.2 Hz, 4.9 Hz, 1H), 5.18 (d, J = 3.8 Hz, 1H), 2.45 (s,
3H); 13CꢀNMR (100 MHz, CDCl3): δ 139.1, 135.2, 131.2, 130.9, 130.7, 129.3, 128.3, 128.1,
127.6, 126.9, 126.4, 125.8, 125.5, 39.2, 19.4; HRMS (ESI+): Calcd. for C16H14KS ([M+K]+):
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15
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18
19
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24
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277.0453, Found: 277.0448; Optical rotation: [α]D –254.4 (c 1.0, CHCl3) for an
enantiomerically enriched sample with 98:2 er. The enantiomeric ratio was determined by
HPLC analysis using Daicel Chiralpak IB column (80:20 nꢀHexane/MTBE, 1.0 mL/min, 20
°C, 254 nm, τmajor = 6.7 min, τminor = 7.6 min).
(R)ꢀ2ꢀ(pꢀTolyl)ꢀ2Hꢀthiochromene (3ac)
Purified by silica gel (100ꢀ200 mesh) column chromatography (7% CH2Cl2/Petroleum ether)
to afford a colorless oil (20.0 mg, 0.084 mmol, 84% yield). FTꢀIR (Thin film): 3760, 3655,
2921, 2376, 1591, 1436, 1021 cmꢀ1; 1HꢀNMR (400 MHz, CDCl3): δ 7.23 (d, J = 7.7 Hz, 2H),
7.14ꢀ7.05 (m, 6H), 6.63 (d, J = 10.2 Hz, 1H), 5.99 (dd, J = 10.2 Hz, 5.2 Hz, 1H), 4.85 (d, J =
5.0 Hz, 1H), 2.30 (s, 3H); 13CꢀNMR (100 MHz, CDCl3): δ 138.9, 137.5, 131.1, 130.7, 129.4,
128.6, 128.3, 128.1, 127.5, 126.8, 125.8, 125.4, 42.7, 21.1; HRMS (ESI+): Calcd. for
24
C16H14KS ([M+K]+): 277.0453, Found: 277.0451; Optical rotation: [α]D –134.5 (c 1.0,
CHCl3) for an enantiomerically enriched sample with 98:2 er. The enantiomeric ratio was
determined by HPLC analysis using Daicel Chiralpak IF column (80:20 nꢀHexane/ MTBE,
1.0 mL/min, 20 °C, 254 nm, τminor = 5.7 min, τmajor = 6.4 min).
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(R)ꢀ2ꢀ(4ꢀIsopropylphenyl)ꢀ2Hꢀthiochromene (3ad)
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6
7
8
Purified by silica gel (100ꢀ200 mesh) column chromatography (6% CH2Cl2/Petroleum ether)
to afford a colorless oil (20.0 mg, 0.075 mmol, 75% yield). FTꢀIR (Thin film): 2959, 1510,
1158, 1019 cmꢀ1; 1HꢀNMR (400 MHz, CDCl3): δ 7.26 (d, J = 8.0 Hz, 2H), 7.16ꢀ7.05 (m, 6H),
6.63 (d, J = 10.3 Hz, 1H), 6.00 (dd, J = 10.2 Hz, 5.2 Hz, 1H), 4.86 (d, J = 5.1 Hz, 1H), 2.90ꢀ
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2.83 (m, 1H), 1.21 (d, J = 6.9 Hz, 6H); CꢀNMR (100 MHz, CDCl3): δ 148.4, 139.2, 131.1,
130.8, 128.5, 128.3, 128.1, 127.5, 126.8, 125.8, 125.4, 42.7, 33.8, 23.9; HRMS (ESI+):
Calcd. for C18H18KS ([M+K]+): 305.0766, Found: 305.0765; Optical rotation: [α]D24 –108.4
(c 1.0, CHCl3) for an enantiomerically enriched sample with 99:1 er. The enantiomeric ratio
was determined by HPLC analysis using Phenomenex Celluloseꢀ3 column (97:3 nꢀHexane/iꢀ
PrOH, 1.0 mL/min, 20 °C, 254 nm, τminor = 8.0 min, τmajor = 10.0 min).
(R)ꢀ2ꢀ(4ꢀMethoxyphenyl)ꢀ2Hꢀthiochromene (3ae)
Purified by silica gel (100ꢀ200 mesh) column chromatography (20% CH2Cl2/Petroleum ether)
to afford a colorless oil (17.0 mg, 0.067 mmol, 67% yield). FTꢀIR (Thin film): 3780, 2922,
1
2852, 1605, 1019 cmꢀ1; HꢀNMR (400 MHz, CDCl3): δ 7.25 (d, J = 8.7 Hz, 2H), 7.14ꢀ7.05
(m, 4H), 6.82 (d, J = 8.7 Hz, 2H), 6.63 (dd, J = 10.2 Hz, 1.4 Hz, 1H), 5.98 (dd, J = 10.2 Hz,
5.2 Hz, 1H), 4.85 (dd, J = 5.2 Hz, 1.4 Hz, 1H), 3.76 (s, 3H); 13CꢀNMR (100 MHz, CDCl3): δ
159.2, 133.9, 131.0, 130.7, 128.7, 128.5, 128.3, 128.1, 126.8, 125.9, 125.4, 114.1, 55.2, 42.4;
HRMS (ESI+): Calcd. for C16H14KOS ([M+K]+): 293.0402, Found: 293.0406; Optical
rotation: [α]D24 –145.3 (c 1.0, CHCl3) for an enantiomerically enriched sample with 99:1 er.
The enantiomeric ratio was determined by HPLC analysis using Daicel Chiralpak IB column
(95:5 nꢀHexane/iꢀPrOH, 1.0 mL/min, 20 °C, 254 nm, τmajor = 5.8 min, τminor = 6.2 min). See
Supporting Information: Part B for HPLC chromatograms.
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(R)ꢀ2ꢀ(2ꢀFluorophenyl)ꢀ2Hꢀthiochromene (3af)
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8
Purified by silica gel (100ꢀ200 mesh) column chromatography (6% CH2Cl2/Petroleum ether)
to afford a colorless oil (18.0 mg, 0.074 mmol, 74% yield). FTꢀIR (Thin film): 2923, 1638,
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1485, 1161, 1021 cmꢀ1; HꢀNMR (400 MHz, CDCl3): δ 7.34 (td, J = 7.8 Hz, 1.4 Hz, 1H),
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7.25ꢀ7.19 (m, 1H), 7.17ꢀ7.10 (m, 4H), 7.08ꢀ7.01 (m, 2H), 6.74 (d, J = 10.2 Hz, 1H), 5.99 (dd,
J = 10.2 Hz, 5.9 Hz, 1H), 5.18 (d, J = 5.9 Hz, 1H); 13CꢀNMR (100 MHz, CDCl3): δ 160.3,
157.8, 130.8, 130.1, 129.4, 129.3 (d, J = 3.1 Hz), 129.2, 129.1, 128.8, 128.6, 128.5, 128.2,
127.1, 125.6, 124.3 (d, J = 3.8 Hz), 123.8, 115.6, 115.3, 34.6 (d, J = 3.7 Hz); HRMS (ESI+):
Calcd. for C15H11FKS ([M+K]+): 281.0203, Found: 281.0200; Optical rotation: [α]D24 –239.6
(c 1.0, CHCl3) for an enantiomerically enriched sample with 97:3 er. The enantiomeric ratio
was determined by HPLC analysis using Daicel Chiralpak IB column (80:20 nꢀ
Hexane/MTBE, 1.0 mL/min, 20 °C, 254 nm, τminor = 4.8 min, τmajor = 5.9 min).
(R)ꢀ2ꢀ(3ꢀChlorophenyl)ꢀ2Hꢀthiochromene (3ag)
Purified by silica gel (100ꢀ200 mesh) column chromatography (7% CH2Cl2/Petroleum ether)
to afford a colorless oil (19.0 mg, 0.073 mmol, 73% yield). FTꢀIR (Thin film): 3766, 2923,
2856, 1720, 1589, 1472, 1219, 1023 cmꢀ1; 1HꢀNMR (400 MHz, CDCl3): δ 7.34 (s, 1H), 7.23
(d, J = 1.3 Hz, 3H), 7.16ꢀ7.08 (m, 4H), 6.89 (dd, J = 10.2 Hz, 1.2 Hz, 1H), 5.99 (dd, J = 10.2
Hz, 5.5 Hz, 1H), 4.83 (dd, J = 5.4 Hz, 1.2 Hz, 1H); 13CꢀNMR (100 MHz, CDCl3): δ 143.8,
134.4, 130.8, 130.0, 129.9, 129.2, 128.6, 128.3, 127.8, 127.7, 126.8, 125.8, 125.7, 124.5,
42.3; HRMS (ESI+): Calcd. for C15H11ClKS ([M+K]+): 296.9907, Found: 296.9910; Optical
rotation: [α]D24 –134.6 (c 1.0, CHCl3) for an enantiomerically enriched sample with 96:4 er.
The enantiomeric ratio was determined by HPLC analysis using Daicel Chiralpak IF column
(97:3 nꢀHexane/iꢀPrOH, 1.0 mL/min, 20 °C, 254 nm, τminor = 4.6 min, τmajor = 5.1 min).
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(R)ꢀ2ꢀ(4ꢀChlorophenyl)ꢀ2Hꢀthiochromene (3ah)
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Purified by silica gel (100ꢀ200 mesh) column chromatography (8% CH2Cl2/Petroleum ether)
to afford a colorless oil (14.0 mg, 0.054 mmol, 54% yield). FTꢀIR (Thin film): 2921, 2851,
1640, 1158, 1020 cmꢀ1; 1HꢀNMR (400 MHz, CDCl3): δ 7.28ꢀ7.23 (m, 4H), 7.14ꢀ7.08 (m, 4H),
6.67 (dd, J = 10.2 Hz, 1.2 Hz, 1H), 5.98 (dd, J = 10.2 Hz, 5.5 Hz, 1H), 4.81 (dd, J = 5.4 Hz,
1.2 Hz, 1H); 13CꢀNMR (100 MHz, CDCl3): δ 140.4, 133.5, 130.9, 130.1, 129.1, 128.9, 128.8,
128.5, 128.2, 126.9, 125.7, 124.9, 42.1; HRMS (ESI+): Calcd. For C15H12ClS ([M+H]+):
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259.0348, Found: 259.0346; Optical rotation: [α]D –146.6 (c 1.0, CHCl3) for an
enantiomerically enriched sample with 97:3 er. The enantiomeric ratio was determined by
HPLC analysis using Daicel Chiralpak IB column (99:1 nꢀHexane/iꢀPrOH, 1.0 mL/min, 20
°C, 254 nm, τmajor = 6.6 min, τminor = 7.1 min).
(R)ꢀ2ꢀ(4ꢀBromophenyl)ꢀ2Hꢀthiochromene (3ai)
Purified by silica gel (100ꢀ200 mesh) column chromatography (10% CH2Cl2/Petroleum ether)
to afford a solid (21.0 mg, 0.069 mmol, 69% yield). m.p. 87ꢀ88 °C (CHCl3:nꢀHexane = 1:10).
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FTꢀIR (Thin film): 2921, 1642, 1159, 1019 cmꢀ1; HꢀNMR (400 MHz, CDCl3): δ 7.42ꢀ7.40
(m, 2H), 7.22ꢀ7.20 (m, 2H), 7.15ꢀ7.08 (m, 4H), 6.68 (dd, J = 10.2 Hz, 1.4 Hz, 1H), 5.99 (dd,
J = 10.2 Hz, 5.5 Hz, 1H), 4.80 (dd, J = 5.6 Hz, 1.2 Hz, 1H); 13CꢀNMR (100 MHz, CDCl3): δ
140.9, 131.8, 130.9, 130.0, 129.2, 129.1, 128.5, 128.2, 126.9, 125.7, 124.8, 121.6, 42.1;
HRMS (ESI+): Calcd. for C15H12BrS ([M+H]+): 302.9843, Found: 302.9826; Optical
rotation: [α]D24 –138.3 (c 1.0, CHCl3) for an enantiomerically enriched sample with 98:2 er.
The enantiomeric ratio was determined by HPLC analysis using Daicel Chiralpak IB column
(97:3 nꢀHexane/iꢀPrOH, 1.0 mL/min, 20 °C, 254 nm, τmajor = 5.7 min, τminor = 6.1 min). The
absolute stereochemistry of the product 3ai was assigned in single crystal XꢀRay diffraction
analysis.
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(R)ꢀ2ꢀ(4ꢀ(Trifluoromethyl)phenyl)ꢀ2Hꢀthiochromene (3aj)
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Purified by silica gel (100ꢀ200 mesh) column chromatography (6% CH2Cl2/Petroleum ether)
to afford colorless oil (21.0 mg, 0.072 mmol, 72% yield). FTꢀIR (Thin film): 3777, 2937,
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1647, 1407, 1174, 1126, 998 cmꢀ1; HꢀNMR (400 MHz, CDCl3): δ 7.55 (d, J = 8.1 Hz, 2H),
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7.45 (d, J = 8.1 Hz, 2H), 7.17ꢀ7.10 (m, 4H), 6.72 (dd, J = 10.2 Hz, 1.0 Hz, 1H), 6.02 (dd, J =
10.2 Hz, 5.6 Hz, 1H), 4.87 (d, J = 5.5 Hz, 1H); 13CꢀNMR (100 MHz, CDCl3): δ 145.8, 130.8,
130.0, 129.8, 129.7, 129.4, 128.7, 128.3, 127.8, 126.9, 125.8, 125.7 (q, J = 3.8 Hz), 125.4,
124.4, 122.7, 42.2; HRMS (ESI+): Calcd. for C16H11F3S ([M]+): 292.0534, Found: 292.0505;
Optical rotation: [α]D24 –168.8 (c 1.0, CHCl3) for an enantiomerically enriched sample with
97:3 er. The enantiomeric ratio was determined by HPLC analysis using Daicel Chiralpak IB
column (99:1 nꢀHexane/iꢀPrOH, 1.0 mL/min, 20 °C, 254 nm, τmajor = 6.8 min, τminor = 7.4
min).
(R)ꢀ2ꢀ(3ꢀNitrophenyl)ꢀ2Hꢀthiochromene (3ak)
Purified by silica gel (100ꢀ200 mesh) column chromatography (25% CH2Cl2/Petroleum ether)
to afford a solid (15.5 mg, 0.058 mmol, 58% yield). m.p. 99ꢀ100 °C (CHCl3:nꢀHexane = 1:4).
FTꢀIR (Thin film): 3726, 3588, 3395, 3294, 2923, 2853, 2313, 1643, 1525, 1349, 1018 cmꢀ1;
1HꢀNMR (400 MHz, CDCl3): δ 8.19 (t, J = 1.8 Hz, 1H), 8.11ꢀ8.08 (m, 1H), 7.68 (d, J = 7.7
Hz, 1H), 7.45 (t, J = 8.0 Hz, 1H), 7.19ꢀ7.16 (m, 1H), 7.14ꢀ7.11 (m, 3H), 6.78 (d, J = 10.2 Hz,
1H), 6.05 (dd, J = 10.2 Hz, 5.8 Hz, 1H), 4.89 (d, J = 5.8 Hz, 1H); 13CꢀNMR (100 MHz,
CDCl3): δ 148.4, 144.0, 133.7, 130.7, 129.9, 129.6, 129.3, 128.8, 128.4, 127.0, 126.0, 123.6,
122.6, 122.4, 41.7; HRMS (ESI+): Calcd. for C15H11NaNO2S ([M+Na]+): 292.0408, Found:
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292.0408; Optical rotation: [α]D –158.6 (c 1.0, CHCl3) for an enantiomerically enriched
sample with 96:4 er. The enantiomeric ratio was determined by HPLC analysis using Daicel
Chiralpak IB column (80:20 nꢀHexane/MTBE, 1.0 mL/min, 20 °C, 254 nm, τmajor = 17.8 min,
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τminor = 20.3 min). The absolute stereochemistry of the product 3ai was assigned in single
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crystal XꢀRay diffraction analysis.
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(R)ꢀ2ꢀ(Naphthalenꢀ2ꢀyl)ꢀ2Hꢀthiochromene (3al)
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Purified by silica gel (100ꢀ200 mesh) column chromatography (10% CH2Cl2/Petroleum ether)
to afford a colorless oil (22.0 mg, 0.080 mmol, 80% yield). FTꢀIR (Thin film): 2922, 2853,
1
1643, 1434, 1362, 1158, 1020 cmꢀ1; HꢀNMR (400 MHz, CDCl3): δ 7.82ꢀ7.77 (m, 3H), 7.75
(s, 1H), 7.53 (dd, J = 8.5 Hz, 1.8 Hz, 1H), 7.49ꢀ7.44 (m, 2H), 7.19ꢀ7.10 (m, 4H), 6.74 (dd, J =
10.3 Hz, 1.1 Hz, 1H), 6.11 (dd, J = 10.2 Hz, 5.3 Hz, 1H), 5.07 (dd, J = 5.2 Hz, 1.0 Hz, 1H);
13CꢀNMR (100 MHz, CDCl3): δ 139.0, 133.2, 132.9, 131.0, 130.5, 129.0, 128.7, 128.4, 128.2,
128.0, 127.6, 126.8, 126.2, 126.0, 125.8, 125.6, 125.3, 43.1; HRMS (ESI+): Calcd. for
C19H15S ([M+H]+): 275.0894, Found: 275.0895; Optical rotation: [α]D24 –84.0 (c 1.0, CHCl3)
for an enantiomerically enriched sample with 98:2 er. The enantiomeric ratio was determined
by HPLC analysis using Daicel Chiralpak IB column (99:1 nꢀHexane/iꢀPrOH, 1.0 mL/min,
20 °C, 254 nm, τmajor = 8.1 min, τminor = 8.9 min).
(R)ꢀ5ꢀ(2HꢀThiochromenꢀ2ꢀyl)benzo[d][1,3]dioxole (3am)
Purified by silica gel (100ꢀ200 mesh) column chromatography (20% CH2Cl2/Petroleum ether)
to afford a colorless oil (19.5 mg, 0.073 mmol, 73% yield). FTꢀIR (Thin film): 3766, 3159,
2901, 1644, 1404, 1247, 1035, 999 cmꢀ1; 1HꢀNMR (400 MHz, CDCl3): δ 7.16ꢀ7.07 (m, 4H),
6.85 (d, J = 1.4 Hz, 1H), 6.79 (dd, J = 8.0 Hz, 1.5 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 6.64 (d,
J = 10.2 Hz, 1H), 5.97 (dd, J = 10.3 Hz, 5.3 Hz, 1H), 5.92 (d, J = 1.9 Hz, 2H), 4.81 (d, J =
5.1 Hz, 1H); 13CꢀNMR (100 MHz, CDCl3): δ 147.8, 147.2, 135.8, 130.8, 130.5, 128.6, 128.4,
128.2, 126.8, 125.5, 120.8, 108.2, 108.1, 101.1, 42.8; HRMS (ESI+): Calcd. for C16H12KO2S
([M+K]+): 307.0195, Found: 307.0196; Optical rotation: [α]D24 –138.0 (c 1.0, CHCl3) for an
enantiomerically enriched sample with 99:1 er. The enantiomeric ratio was determined by
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HPLC analysis using Daicel Chiralpak IB column (97:3 nꢀHexane/iꢀPrOH, 1.0 mL/min, 20
°C, 254 nm, τmajor = 7.0 min, τminor = 7.6 min).
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(R)ꢀ2ꢀ(3,4ꢀDimethoxyphenyl)ꢀ2Hꢀthiochromene (3an)
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60
Purified by silica gel (100ꢀ200 mesh) column chromatography (8% EtOAc/Petroleum ether)
to afford a colorless oil (18.5 mg, 0.065 mmol, 65% yield). FTꢀIR (Thin film): 3583, 2932,
1679, 1592, 1513, 1463, 1142, 1025 cmꢀ1; 1HꢀNMR (400 MHz, CDCl3): δ 7.16ꢀ7.06 (m, 4H),
6.90ꢀ6.86 (m, 2H), 6.78 (d, J = 8.1 Hz, 1H), 6.65 (dd, J = 10.2 Hz, 1.1 Hz, 1H), 6.00 (dd, J =
10.2 Hz, 5.1 Hz, 1H), 4.86 (dd, J = 5.1 Hz, 1.4 Hz, 1H), 3.85 (s, 3H), 3.80 (s, 3H); 13CꢀNMR
(100 MHz, CDCl3): δ 149.0, 148.7, 134.2, 131.1, 130.7, 128.6, 128.3, 128.0, 126.8, 125.9,
125.5, 119.8, 111.1, 110.7, 55.9, 55.7, 42.8; HRMS (ESI+): Calcd. for C17H16KO2S
([M+K]+): 323.0508, Found: 323.0506; Optical rotation: [α]D24 –41.3 (c 1.0, CHCl3) for an
enantiomerically enriched sample with 99:1 er. The enantiomeric ratio was determined by
HPLC analysis using Daicel Chiralpak ASꢀH column (97:03 nꢀHexane/EtOH, 1.0 mL/min,
20 °C, 254 nm, τmajor = 8.6 min, τminor = 9.6 min).
(R)ꢀ2ꢀ(3,4ꢀDichlorophenyl)ꢀ2Hꢀthiochromene (3ao)
Purified by silica gel (100ꢀ200 mesh) column chromatography (8% CH2Cl2/Petroleum ether)
to afford a colorless oil (20.0 mg, 0.068 mmol, 68% yield). FTꢀIR (Thin film): 2921, 1635,
1158, 1020 cmꢀ1; 1HꢀNMR (400 MHz, CDCl3): δ 7.42ꢀ7.41 (m, 1H), 7.35 (d, J = 8.3 Hz, 1H),
7.18ꢀ7.09 (m, 5H), 6.71 (d, J = 10.2 Hz, 1H), 5.98 (dd, J = 10.2 Hz, 5.6 Hz, 1H), 4.77 (d, J =
5.6 Hz, 1H); 13CꢀNMR (100 MHz, CDCl3): δ 142.0, 132.6, 131.7, 130.7, 130.6, 129.6, 129.5,
128.7, 128.3, 126.94, 126.89, 125.9, 124.0, 41.6; HRMS (ESI+): Calcd. for C15H11Cl2S
([M+H]+): 292.9959, Found: 292.9962; Optical rotation: [α]D24 –153.8 (c 1.0, CHCl3) for an
enantiomerically enriched sample with 98:2 er. The enantiomeric ratio was determined by
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Page 20 of 32
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HPLC analysis using Daicel Chiralpak IB column (99:1 nꢀHexane/iꢀPrOH, 1.0 mL/min, 20
°C, 254 nm, τmajor = 8.0 min, τminor = 8.7 min).
7
8
(R)ꢀ2ꢀ(Thiophenꢀ2ꢀyl)ꢀ2Hꢀthiochromene (3ap)
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
Purified by silica gel (100ꢀ200 mesh) column chromatography (8% CH2Cl2/Petroleum ether)
to afford a colorless oil (14.5 mg, 0.063 mmol, 63% yield). FTꢀIR (Thin film): 2920, 2069,
1631, 1019 cmꢀ1; 1HꢀNMR (400 MHz, CDCl3): δ 7.20ꢀ7.17 (m, 2H), 7.16ꢀ7.15 (m, 1H), 7.14ꢀ
7.09 (m, 2H), 6.95ꢀ6.94 (m, 1H), 6.89 (dd, J = 5.1 Hz, 3.6 Hz, 1H), 6.66 (d, J = 10.1 Hz,
1H), 6.14 (dd, J = 10.1 Hz, 5.8 Hz, 1H), 5.07 (d, J = 5.8 Hz, 1H); 13CꢀNMR (100 MHz,
CDCl3): δ 145.4, 130.9, 130.1, 128.6, 128.4, 128.2, 127.2, 126.8, 125.7, 125.2, 125.1, 37.7;
HRMS (ESI+): Calcd. for C13H10S2 ([M]+): 230.0224, Found: 230.0223; Optical rotation:
24
[α]D –217.5 (c 1.0, CHCl3) for an enantiomerically enriched sample with 98:2 er. The
enantiomeric ratio was determined by HPLC analysis using Daicel Chiralpak IF column (97:3
nꢀHexane/iꢀPrOH, 1.0 mL/min, 20 °C, 254 nm, τminor = 4.8 min, τmajor = 5.2 min.
(S,E)ꢀ2ꢀStyrylꢀ2Hꢀthiochromene (3aq)
Purified by silica gel (100ꢀ200 mesh) column chromatography (6% CH2Cl2/Petroleum ether)
to afford a colorless oil (7.0 mg, 0.028 mmol, 28% yield). FTꢀIR (Thin film): 2922, 1744,
1639, 1406, 1073, 962 cmꢀ1; 1HꢀNMR (400 MHz, CDCl3): δ 7.33ꢀ7.31 (m, 2H), 7.28ꢀ7.24 (m,
2H), 7.22ꢀ7.18 (m, 2H), 7.13ꢀ7.06 (m, 3H), 6.60 (d, J = 10.1 Hz, 1H), 6.46 (d, J = 15.7 Hz,
1H), 6.23 (dd, J = 15.7 Hz, 8.0 Hz, 1H), 5.96 (dd, J = 10.1 Hz, 6.0 Hz, 1H), 4.29ꢀ4.26 (m,
1H); 13CꢀNMR (100 MHz, CDCl3): δ 136.5, 131.3, 130.8, 130.0, 128.6, 128.5, 128.18,
128.15, 127.8, 127.7, 127.4, 126.6, 125.5, 124.1, 40.6; HRMS (ESI+): Calcd. for C17H14S
24
([M]+): 250.0816, Found: 250.0817; Optical rotation: [α]D –190.4 (c 0.5, CHCl3) for an
enantiomerically enriched sample with 97:3 er. The enantiomeric ratio was determined by
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The Journal of Organic Chemistry
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HPLC analysis using Daicel Chiralpak IF column (80:20 nꢀHexane/ MTBE, 1.0 mL/min,
20 °C, 254 nm, τminor = 6.4 min, τmajor = 7.1 min).
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(S)ꢀ2ꢀMethylꢀ2Hꢀthiochromene (3ar)
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10
11
12
13
14
15
16
17
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23
24
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Purified by silica gel (100ꢀ200 mesh) column chromatography (6% CH2Cl2/Petroleum ether)
to afford a colorless oil (6.5 mg, 0.040 mmol, 40% yield). FTꢀIR (Thin film): 3733, 3589,
1
2922, 2314, 1744, 1668, 1513, 1101, 1020 cmꢀ1; HꢀNMR (400 MHz, CDCl3): δ 7.22ꢀ7.20
(m, 1H), 7.12ꢀ7.06 (m, 3H), 6.45 (d, J = 10.1 Hz, 1H), 5.89 (dd, J = 10.1 Hz, 5.3 Hz, 1H),
3.75ꢀ3.68 (m, 1H), 1.38 (d, J = 7.0 Hz, 3H); 13CꢀNMR (100 MHz, CDCl3): δ 131.4, 130.8,
128.3, 127.9, 127.5, 127.3, 125.3, 33.6, 21.7; HRMS (ESI+): Calcd. for C10H10KS ([M+K]+):
24
201.0140, Found: 201.0124; Optical rotation: [α]D +74.7 (c 0.5, CHCl3) for an
enantiomerically enriched sample with 95:5 er. The enantiomeric ratio was determined by
HPLC analysis using Daicel Chiralpak ID column (95:5 nꢀHexane/MTBE, 1.0 mL/min,
20 °C, 254 nm, τminor = 4.9 min, τmajor = 5.2 min).
(S)ꢀ2ꢀIsobutylꢀ2Hꢀthiochromene (3as)
Purified by silica gel (100ꢀ200 mesh) column chromatography (6% CH2Cl2/Petroleum ether)
to afford a colorless oil (12.6 mg, 0.062 mmol, 62% yield). FTꢀIR (Thin film): 2922, 1642,
1117, 1019 cmꢀ1; 1HꢀNMR (400 MHz, CDCl3): δ 7.23ꢀ7.21 (m, 1H), 7.12ꢀ7.05 (m, 3H), 6.46
(d, J = 10.2 Hz, 1H), 5.92 (dd, J = 10.1 Hz, 5.6 Hz, 1H), 3.64ꢀ3.59 (m, 1H), 1.95ꢀ1.85 (m,
1H), 1.62ꢀ1.49 (m, 2H), 0.91 (d, J = 6.6 Hz, 3H), 0.89 (d, J = 6.6 Hz, 3H); 13CꢀNMR (100
MHz, CDCl3): δ 131.8, 130.8, 127.9, 127.8, 127.6, 127.5, 127.4, 125.3, 44.8, 36.7, 24.5, 22.7,
21.9; HRMS (ESI+): Calcd. For C13H16KS ([M+K]+): 243.0610, Found: 243.0611; Optical
rotation: [α]D24 +80.2 (c 1.0, CHCl3) for an enantiomerically enriched sample with 97.5:2.5
er. The enantiomeric ratio was determined by HPLC analysis using Daicel Chiralpak IF
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column (95:5 nꢀHexane/MTBE, 1.0 mL/min, 20 °C, 254 nm, τminor = 4.8 min, τmajor = 5.2
5
6
min).
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(S)ꢀ2ꢀCyclohexylꢀ2Hꢀthiochromene (3at)
9
10
11
12
13
14
15
16
17
18
19
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22
23
24
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26
27
28
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35
36
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Purified by silica gel (100ꢀ200 mesh) column chromatography (6% CH2Cl2/Petroleum ether)
to afford a colorless oil (14.0 mg, 0.061 mmol, 61% yield). FTꢀIR (Thin film): 3764, 2924,
1643, 1020 cmꢀ1; 1HꢀNMR (400 MHz, CDCl3): δ 7.19 (d, J = 7.2 Hz, 1H), 7.11ꢀ7.06 (m, 1H),
7.04ꢀ7.02 (m, 2H), 6.50 (d, J = 10.3 Hz, 1H), 5.90 (dd, J = 10.3 Hz, 6.0 Hz, 1H), 3.43 (t, J =
6.1 Hz, 1H), 1.91ꢀ1.88 (m, 1H), 1.76ꢀ1.71 (m, 3H), 1.63ꢀ1.61 (m, 1H), 1.57ꢀ1.50 (m, 1H),
13
1.20ꢀ1.01 (m, 5H); CꢀNMR (100 MHz, CDCl3): δ 131.7, 128.1, 127.9, 127.8, 126.8, 125.3,
125.0, 124.97, 44.9, 44.0, 29.5, 29.2, 26.4, 26.15, 26.11; HRMS (ESI+): Calcd. for C15H18KS
([M+K]+): 269.0766, Found: 269.0753; Optical rotation: [α]D24 +106.6 (c 1.0, CHCl3) for an
enantiomerically enriched sample with 99:1 er. The enantiomeric ratio was determined by
HPLC analysis using Daicel Chiralpak IE column (99:01 nꢀHexane/MTBE, 1.0 mL/min, 20
°C, 254 nm, τmajor = 10.3 min, τminor = 11.6 min).
(R)ꢀ6ꢀMethylꢀ2ꢀphenylꢀ2Hꢀthiochromene (3ba)
Purified by silica gel (100ꢀ200 mesh) column chromatography (8% CH2Cl2/Petroleum ether)
to afford a colorless oil (11.0 mg, 0.046 mmol, 46% yield). FTꢀIR (Thin film): 2921, 2852,
1639, 1158, 1021 cmꢀ1; 1HꢀNMR (400 MHz, CDCl3): δ 7.35ꢀ7.33 (m, 2H), 7.31ꢀ7.22 (m, 3H),
7.03 (d, J = 7.8 Hz, 1H), 6.95ꢀ6.92 (m, 2H), 6.61 (d, J = 10.2 Hz, 1H), 6.00 (dd, J = 10.2 Hz,
5.2 Hz, 1H), 4.85 (dd, J = 5.2 Hz, 1.2 Hz, 1H), 2.29 (s, 3H); 13CꢀNMR (100 MHz, CDCl3): δ
141.9, 135.2, 131.0, 129.2, 128.9, 128.8, 128.7, 127.7, 127.6, 127.0, 126.7, 125.7, 43.0, 20.9;
HRMS (ESI+): Calcd. for C16H14KS ([M+K]+): 277.0453, Found: 277.0455; Optical rotation:
24
[α]D –153.5 (c 1.0, CHCl3) for an enantiomerically enriched sample with 96:4 er. The
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The Journal of Organic Chemistry
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enantiomeric ratio was determined by HPLC analysis using Daicel Chiralpak IF column
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6
(80:20 nꢀHexane/MTBE, 1.0 mL/min, 20 °C, 254 nm, τminor = 5.3 min, τmajor = 6.6 min).
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(R)ꢀ6ꢀMethoxyꢀ2ꢀphenylꢀ2Hꢀthiochromene (3ca)
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10
11
12
13
14
15
16
17
18
19
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21
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23
24
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27
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31
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Purified by silica gel (100ꢀ200 mesh) column chromatography (22% CH2Cl2/Petroleum ether)
to afford a yellow oil (19.0 mg, 0.075 mmol, 75% yield). FTꢀIR (Thin film): 3777, 3660,
2922, 1636, 1595, 1472, 1270, 1028 cmꢀ1; 1HꢀNMR (400 MHz, CDCl3): δ 7.34ꢀ7.32 (m, 2H),
7.30ꢀ7.22 (m, 3H), 7.06 (d, J = 8.3 Hz, 1H), 6.73ꢀ6.69 (m, 2H), 6.62 (d, J = 10.2 Hz, 1H),
6.07 (dd, J = 10.2 Hz, 5.3 Hz, 1H), 4.83 (dd, J = 5.6 Hz, 1.2 Hz, 1H), 3.79 (s, 3H); 13CꢀNMR
(100 MHz, CDCl3): δ 157.9, 141.6, 132.2, 128.9, 128.7, 127.8, 127.7, 127.5, 126.7, 121.3,
114.2, 113.7, 55.4, 43.0; HRMS (ESI+): Calcd. for C16H14KOS ([M+K]+): 293.0402, Found:
24
293.0405; Optical rotation: [α]D –176.0 (c 1.0, CHCl3) for an enantiomerically enriched
sample with 98:2 er. The enantiomeric ratio was determined by HPLC analysis using Daicel
Chiralpak IB column (97:03 nꢀHexane/ iꢀPrOH, 1.0 mL/min, 20 °C, 254 nm, τmajor = 7.4 min,
τminor = 8.8 min).
(R)ꢀ2,6ꢀDiphenylꢀ2Hꢀthiochromene (3da)
Purified by silica gel (100ꢀ200 mesh) column chromatography (10% CH2Cl2/Petroleum ether)
to afford a colorless oil (17.0 mg, 0.057 mmol, 57% yield). FTꢀIR (Thin film): 2922, 1726,
1
1593, 1462, 1163, 1074, 758, 696 cmꢀ1; HꢀNMR (400 MHz, CDCl3): δ 7.60ꢀ7.58 (m, 2H),
7.45ꢀ7.43 (m, 2H), 7.40ꢀ7.31 (m, 7H), 7.30ꢀ7.28 (m, 1H), 7.23 (d, J = 8.8 Hz, 1H), 6.74 (d, J
= 10.2 Hz, 1H), 6.08 (dd, J = 10.2 Hz, 5.3 Hz, 1H), 4.93 (dd, J = 5.2 Hz, 1.1 Hz, 1H); 13Cꢀ
NMR (100 MHz, CDCl3): δ 141.8, 140.4, 138.6, 131.3, 129.7, 128.81, 128.79, 128.7, 127.8,
127.6, 127.3, 127.1, 127.0, 126.8, 126.7, 125.9, 43.1; HRMS (ESI+): Calcd. for C21H16NaS
([M+Na]+): 323.0870, Found: 323.0867; Optical rotation: [α]D24 –270.4 (c 1.0, CHCl3) for an
enantiomerically enriched sample with 97:3 er. The enantiomeric ratio was determined by
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HPLC analysis using Daicel Chiralpak IB column (97:03 nꢀHexane/ iꢀPrOH, 1.0 mL/min, 20
°C, 254 nm, τmajor = 6.5 min, τminor = 7.3 min).
7
8
(R)ꢀ6ꢀBromoꢀ2ꢀphenylꢀ2Hꢀthiochromene (3ea)
9
10
11
12
13
14
15
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17
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23
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26
27
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35
36
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Purified by silica gel (100ꢀ200 mesh) column chromatography (6% CH2Cl2/Petroleum ether)
to afford a colorless oil (20.5 mg, 0.068 mmol, 68% yield). FTꢀIR (Thin film): 3583, 2919,
1645, 1458, 1021 cmꢀ1; 1HꢀNMR (400 MHz, CDCl3): δ 7.31ꢀ7.25 (m, 6H), 7.23ꢀ7.20 (m, 1H),
7.00 (d, J = 8.3 Hz, 1H), 6.59 (d, J = 10.3 Hz, 1H), 6.07 (dd, J = 10.2 Hz, 5.3 Hz, 1H), 4.86
(d, J = 5.3 Hz, 1H); 13CꢀNMR (100 MHz, CDCl3): δ 141.3, 132.7, 131.0, 130.6, 129.6, 128.8,
128.2, 127.9, 127.8, 127.5, 126.8, 118.6. 42.8; HRMS (ESI+): Calcd. for C15H12BrS
([M+H]+): 302.9843, Found: 302.9851; Optical rotation: [α]D24 –189.2 (c 1.0, CHCl3) for an
enantiomerically enriched sample with 96:4 er. The enantiomeric ratio was determined by
HPLC analysis using Daicel Chiralpak IB column (97:03 nꢀHexane/ iꢀPrOH, 1.0 mL/min, 20
°C, 254 nm, τmajor = 5.9 min, τminor = 6.5 min).
(R)ꢀ6ꢀ(tertꢀButyl)ꢀ2ꢀphenylꢀ2Hꢀthiochromene (3fa)
Purified by silica gel (100ꢀ200 mesh) column chromatography (8% CH2Cl2/Petroleum ether)
to afford a colorless oil (19.0 mg, 0.068 mmol, 68% yield). FTꢀIR (Thin film): 2953, 2860,
1634, 1591, 1474, 1194, 1020 cmꢀ1; 1HꢀNMR (400 MHz, CDCl3): δ 7.38ꢀ7.36 (m, 2H), 7.33ꢀ
7.28 (m, 3H), 7.18ꢀ7.15 (m, 2H), 7.08 (d, J = 7.9 Hz, 1H), 6.65 (d, J = 10.3 Hz, 1H), 6.00
(dd, J = 10.2 Hz, 5.1 Hz, 1H), 4.91 (dd, J = 5.0 Hz, 1.3 Hz, 1H), 1.32 (s, 9H); 13CꢀNMR (100
MHz, CDCl3): δ 148.6, 142.0, 130.6, 129.2, 128.7, 127.7, 127.2, 126.3, 125.6, 125.4, 125.3,
43.1, 34.3, 31.2; HRMS (ESI+): Calcd. for C19H20S ([M]+): 280.1286, Found: 280.1287;
Optical rotation: [α]D24 –129.9 (c 1.0, CHCl3) for an enantiomerically enriched sample with
95:5 er. The enantiomeric ratio was determined by HPLC analysis using Phenomenex
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Celluloseꢀ1 column (97:03 nꢀHexane/ iꢀPrOH, 1.0 mL/min, 20 °C, 254 nm, τminor = 5.2 min,
τmajor = 5.6 min).
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(R)ꢀ7ꢀMethylꢀ2ꢀphenylꢀ2Hꢀthiochromene (3ga)
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10
11
12
13
14
15
16
17
18
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Purified by silica gel (100ꢀ200 mesh) column chromatography (10% CH2Cl2/Petroleum
ether) to afford a colorless oil (15.0 mg, 0.063 mmol, 63% yield). FTꢀIR (Thin film): 2920,
1
1645, 1599, 1487, 1451, 1267, 1071, 1028, 899 cmꢀ1; HꢀNMR (400 MHz, CDCl3): δ 7.35ꢀ
7.24 (m, 5H), 7.02 (d, J = 7.7 Hz, 1H), 6.96 (s, 1H), 6.89 (d, J = 7.7 Hz, 1H), 6.63 (d, J =
10.2 Hz, 1H), 5.95 (dd, J = 10.2 Hz, 5.3 Hz, 1H), 4.85 (d, J = 5.1 Hz, 1H), 2.26 (s, 3H); 13Cꢀ
NMR (100 MHz, CDCl3): δ 142.0, 138.4, 130.3, 128.7, 128.6, 128.4, 128.0, 127.7, 127.5,
127.3, 126.4, 124.4, 43.0, 21.2; HRMS (ESI+): Calcd. for C16H14KS ([M+K]+): 277.0453,
24
Found: 277.0452; Optical rotation: [α]D –76.9 (c 1.0, CHCl3) for an enantiomerically
enriched sample with 97:3 er. The enantiomeric ratio was determined by HPLC analysis
using Daicel Chiralpak IC column (80:20 nꢀHexane/ MTBE, 1.0 mL/min, 20 °C, 254 nm,
τminor = 4.4 min, τmajor = 4.7 min).
(R)ꢀ7ꢀBromoꢀ2ꢀphenylꢀ2Hꢀthiochromene (3ha)
Purified by silica gel (100ꢀ200 mesh) column chromatography (8% CH2Cl2/Petroleum ether)
to afford a colorless oil (17.0 mg, 0.056 mmol, 56% yield). FTꢀIR (Thin film): 2918, 2849,
1
1645, 1537, 1458, 1317, 1018 cmꢀ1; HꢀNMR (400 MHz, CDCl3): δ 7.33ꢀ7.27 (m, 6H), 7.21
(dt, J = 8.1 Hz, 1.0 Hz, 1H), 6.99 (d, J = 8.2 Hz, 1H), 6.62 (d, J = 10.2 Hz, 1H), 6.04 (dd, J =
10.2 Hz, 5.3 Hz, 1H), 4.86 (d, J = 5.2 Hz, 1H); 13CꢀNMR (100 MHz, CDCl3): δ 141.3, 132.8,
129.8, 129.2, 128.8, 128.5, 127.94, 127.92, 127.5, 125.8, 121.6, 42.8; HRMS (ESI+): Calcd.
for C15H12BrS ([M+H]+): 302.9843, Found: 302.9849; Optical rotation: [α]D24 –23.9 (c 1.0,
CHCl3) for an enantiomerically enriched sample with 98:2 er. The enantiomeric ratio was
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determined by HPLC analysis using Daicel Chiralpak IB column (99:01 nꢀHexane/ iꢀPrOH,
1.0 mL/min, 20 °C, 254 nm, τminor = 6.2 min, τmajor = 6.5 min).
7
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Procedure for the hydrogenation of 3aa
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To a solution of 3aa (18.0 mg, 0.080 mmol, 1.0 equiv) in EtOAc (1.0 mL), 10% PdꢀC (9.0
mg, 0.008 mmol, 0.1 equiv) was added. The resulting mixture was degassed and stirred under
H2 balloon pressure for 20 h at 25 °C. The reaction mixture was filtered over Celite®. The
filtrate was concentrated under reduced pressure to obtain an oil.
(R)ꢀ2ꢀphenylthiochroman (4)
Purified by silica gel (100ꢀ200 mesh) column chromatography (10% CH2Cl2/ Petroleum
ether) to obtain 4 as a colorless oil (16.5 mg, 0.073 mmol, 91% yield). FTꢀIR (Thin film):
2924, 1593, 1437, 1219, 1021 cmꢀ1; 1HꢀNMR (400 MHz, CDCl3): δ 7.43 (d, J = 7.3 Hz, 2H),
7.38ꢀ7.34 (m, 2H), 7.31ꢀ7.28 (m, 1H), 7.14ꢀ7.10 (m, 3H), 7.04ꢀ7.01 (m, 1H), 4.48 (dd, J =
10.6 Hz, 3.1 Hz, 1H), 2.98ꢀ2.95 (m, 2H), 2.46ꢀ2.40 (m, 1H), 2.30ꢀ2.20 (m, 1H); 13CꢀNMR
(100 MHz, CDCl3): δ 141.9, 134.1, 133.1, 129.8, 128.6, 127.65, 127.60, 126.5, 126.0, 124.0,
46.3, 31.2, 30.0; HRMS (ESI+): Calcd. for C15H14KS ([M+K]+): 265.0453, Found: 265.0456;
Optical rotation: [α]D24 –142.4 (c 1.0, CHCl3) for an enantiomerically enriched sample with
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98:2 er [Lit.4 [α]D –98.5 (c 0.4, CHCl3) for an enantiomerically enriched sample with
95.5:4.5 er]. The enantiomeric ratio was determined by HPLC analysis using Daicel
Chiralpak IB column (97:3 nꢀHexane/iꢀPrOH, 1.0 mL/min, 20 °C, 254 nm, τmajor = 5.2 min,
τminor = 5.7 min).
Procedure for the oxidation of 3aa
In a oven dried 10 mL round bottom flask, 3aa (17.0 mg, 0.076 mmol, 1.0 equiv) was taken
in 0.5 mL THF, followed by addition of H2O (0.030 mL, 0.0017 mmol, 0.0017 equiv), NMO
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(12.0 mg, 0.1 mmol, 1.25 equiv) and OsO4 (0.5 mg, 0.0019 mmol, in 0.5 mL THF, 0.025
equiv). The resulting mixture was stirred at room temperature for 16 h. Saturated aqueous
Na2SO3 solution (3.0 mL) was added to the reaction mixture. Aqueous layer was extracted
with EtOAc (3 × 5 mL). The combined organic layer was washed with brine (5.0 mL), dried
over anhydrous Na2SO4, concentrated under reduced pressure to obtain yellow oil.
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2ꢀphenylthiochromenꢀ4ꢀone (5)
Purification by silica gel (230ꢀ400 mesh) column chromatography (10% EtOAc/Petroleum
ether) afforded 5 as a yellow solid (12.0 mg, 0.050 mmol, 66% yield). m.p. 112ꢀ113 °C; FTꢀ
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IR (Thin film): 2922, 1617, 1336, 1102 cmꢀ1; HꢀNMR (400 MHz, CDCl3): δ 8.56 (dd, J =
7.8 Hz, 1.0 Hz, 1H), 7.71ꢀ7.68 (m, 2H), 7.67ꢀ7.61 (m, 2H), 7.58ꢀ7.54 (m, 1H), 7.52ꢀ7.48 (m,
3H) 7.26 (s, 1H); 13CꢀNMR (100 MHz, CDCl3): δ 180.8, 153.1, 137.7, 136.6, 131.6, 130.9,
130.8, 129.3, 128.6, 127.8, 127.0, 126.5, 123.4; HRMS (ESI+): Calcd. For C15H10NaOS
([M+Na]+): 261.0350, Found: 261.0351.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at
DOI: 10.1021/acs.joc.XXXXXXX.
1
Copies of H and 13C NMR spectra of products, HPLC spectra of products, and Xꢀray
crystallographic data (ORTEP) of 3ai and 3ak
CIF data for 3ai
CIF data for 3ak
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AUTHOR INFORMATION
Corresponding Author
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*E-mail: sm@orgchem.iisc.ernet.in
Fax: +91ꢀ80ꢀ2360ꢀ0529; Tel: +91ꢀ80ꢀ2293ꢀ2850
ORCID
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Amit Kumar Simlandy: 0000ꢀ0002ꢀ8792ꢀ4825
Santanu Mukherjee: 0000ꢀ0001ꢀ9651ꢀ6228
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work is funded by the DAEꢀBRNS [Grant No. 2013/37C/56/BRNS/2440] and
SERB [Grant No. SB/S1/OCꢀ63/2013]. A.K.S. thanks the Council of Scientific and Industrial
Research (CSIR), New Delhi for a doctoral fellowship. We thank Mr. Soumya Jyoti Singha
Roy for helpful discussion. We wish to thank Mr. Rupak Saha (Department of Inorganic and
Physical Chemistry, IISc, Bangalore) and Mr. Amar A. Hosamani (Solid State and Structural
Chemistry Unit, IISc, Bangalore) for their help with the Xꢀray structure analysis.
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