A convenient one-pot synthesis of 2-(alkylthio)isoflavones from deoxybenzoins using a phase transfer catalyst

Article abstract of DOI:10.1016/S0040-4039(02)01342-4

A convenient phase transfer catalysis procedure for the synthesis of 2-(alkylthio)isoflavones is described. A number of compounds of potential pharmaceutical interest can be prepared in a single step at ambient conditions from various, easily accessible d

Full text of DOI:10.1016/S0040-4039(02)01342-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6113–6115
A convenient one-pot synthesis of 2-(alkylthio)isoflavones from
deoxybenzoins using a phase transfer catalyst
Young-Woo Kim and Robert W. Brueggemeier*
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, 500 West 12th Avenue,
Columbus, OH 43210-1291, USA
Received 18 June 2002; accepted 3 July 2002
Abstract—A convenient phase transfer catalysis procedure for the synthesis of 2-(alkylthio)isoflavones is described. A number of
compounds of potential pharmaceutical interest can be prepared in a single step at ambient conditions from various, easily
accessible deoxybenzoins using this method. © 2002 Elsevier Science Ltd. All rights reserved.
The 4H-1-benzopyran-4-one ring system (1, Fig. 1) is
widely found in a number of natural products such as
flavonoids. These natural products have demonstrated
numerous biological activities such as antiviral, anti-
inflammatory, antiallergic, antimutagenic and anticar-
cinogenic activities.1
convenient and efficient synthesis of 2-(alkylthio)-
isoflavones under ambient conditions using a phase
transfer catalyst.
Several years ago a phase transfer catalysis procedure
was reported for the synthesis of O-alkyl-S-methyl
dithiocarbonates (3) in high yields (Scheme 1).5 We
investigated this procedure for the synthesis of 2-
(alkylthio)isoflavones (2) from deoxybenzoins since we
envisioned that the O-aryl-S-alkyl dithiocarbonates
would be good intermediates. More importantly,
because deoxybenzoins have an active methylene group,
it was expected that the O-aryl-S-alkyl dithiocarbon-
ates 3% would undergo further cyclization reaction in
this reaction condition, thereby directly generating the
desired 2-(alkylthio)isoflavones 2 in a single step
(Scheme 2).
This fact has led us to investigate novel 4H-1-benzopy-
ran-4-one derivatives as new therapeutic agents for
hormone-dependent breast cancer.2 As part of this
effort, we have been interested in 3-aryl-2-alkylthio-4H-
1-benzopyran-4-ones, or 2-(alkylthio)isoflavones (2,
Fig. 1), as potential drug candidates in this area. How-
ever, only a few methods have been reported for the
synthesis of 2-alkylthio-4H-1-benzopyran-4-ones.3 Fur-
thermore, these methods suffer several disadvantages
such as low yields, multiple steps, and harsh conditions.
Recently, a high yielding one-pot synthesis of 2-
methylthio-4H-1-benzopyran-ones has been reported
using KHMDS as a base.4 However, this method also
requires skillful handling of the base, low temperature,
and anhydrous reaction conditions. Herein we report a
Deoxybenzoins 6 were prepared by Friedel–Crafts
acylation of resorcinol with corresponding arylacetic
acids followed by Mitsunobu reaction for the selective
methylation of 4-hydroxyl group (Scheme 3).6
O
O
As expected, when the deoxybenzoin 6a, carbon
disulfide, and methyl iodide in a THF7/water two-phase
system were treated with aqueous NaOH solution at
room temperature in the presence of 10 mol% of tetra-
butylammonium hydrogensulfate (n-Bu4N·HSO4), the
R
3
2
R
O
O
SR
4H-1-benzopyran-4-one, 1
2-(alkylthio)isoflavone, 2
O
C
3
n-Bu4NHSO4
Figure 1.
ROH + CS2 + MeI
RO
SMe
50% aq. NaOH
* Corresponding author. Tel.: +1-614-292-5231; fax: +1-614-292-2435;
e-mail: brueggemeier.1@osu.edu
Scheme 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01342-4

6114
Y.-W. Kim, R. W. Brueggemeier / Tetrahedron Letters 43 (2002) 6113–6115
H
O
O
O
O
R
R
2
R
S
MeO
OH
O
6a
SMe
deoxybenzoins
3'
A
fast
Scheme 2.
H
O
O
R1
O
R1
O
a
MeO
MeS
SMe
HO
7
HO
OH
B
slow
O
4a: R1 = H
4b: R1 = Me
4c: R1 = OMe
5a: R1 = H (77%)
5b: R1 = Me (83%)
5c: R1 = OMe (85%)
b
MeO
O
SMe
2a (87%)
R1
O
Scheme 4. Reagents and conditions: CS2, R2X, n-Bu4N·HSO4,
aq. NaOH, THF, rt, 3 h.
MeO
OH
6a: R1 = H (88%)
6b: R1 = Me (93%)
6c: R1 = OMe (81%)
R1
R1
O
O
O
MeO
SR2
MeO
OH
Scheme 3. Reagents and conditions: (a) resorcinol, BF3·OEt2,
100°C, 2 h; (b) PPh3, DIAD, MeOH, THF, rt, 5 min; (c) CS2,
R2X, n-Bu4N·HSO4, aq. NaOH, THF, rt, 3–7 h.
6a: R1 = H
6b: R1 = Me
6c: R1 = OMe
2a: R1 = H, R2 = Me (87%)
2b: R1 = Me, R2 = Me (90%)
2c: R1 = OMe, R2 = Me (85%)
2d: R1 = H, R2 = allyl (96%)
2e: R1 = H, R2 = benzyl (97%)
desired 2-(methylthio)isoflavone 2a was obtained in
87% yield (Scheme 4). The reaction apparently occurred
in a stepwise manner as monitored by TLC. Interest-
ingly, the spectral data of the intermediate indicated
that the reaction proceeded not via the O-alkyl-S-
methyl dithiocarbonate but via a-oxoketene dithioac-
etal (7).8 This could be explained by the intramolecular
hydrogen bond of the starting deoxybenzoin, which
might facilitate the enolate formation. In addition, the
formation of a-oxoketene dithioacetal intermediate
(step A, Scheme 3) is very fast; all the starting material
was converted into the intermediate as soon as the
aqueous NaOH solution was added. However, when
the reaction is done at 0°C, intermediate 7 can be
obtained within 5 min in a high yield (>90%). In
contrast, the subsequent cyclization (step B, Scheme 3)
is the rate-determining step, and thereby requires a
longer reaction time (3–4 h) to be completed pre-
sumably because the intramolecular hydrogen bond of
intermediate 7 is still rigid. However, this reaction can
be completed within an hour when the reaction mixture
is warmed at ꢀ50°C.
Scheme 5. Reagents and conditions: CS2, R2X, n-Bu4N·HSO4,
aq. NaOH, THF, rt, 3–7 h.
halides were used as an alkylating agent, indicating
diverse alkylthio groups can be directly introduced at
the 2-position using this process.
In summary, we have described a convenient phase
transfer catalysis procedure allowing the efficient con-
version of deoxybenzoins into 2-(alkylthio)isoflavones
in a single step at ambient reaction conditions. This
method can be very useful to generate a number of
drug-like compounds from easily available deoxyben-
zoins in a short period of time. Extended studies on
reaction scopes and applications of this method are
currently underway.
General experimental procedure
To a stirred mixture of a deoxybenzoin (1 mmol),
carbon disulfide (0.6 mL, 10 mmol), alkyl halide (2.2
mmol), and tetrabutylammonium hydrogensulfate (34
mg, 0.1 mmol) in THF (3 mL) and water (1 mL) was
slowly added aqueous NaOH solution (1.2 mL, 12
mmol, 10 M) at room temperature. A slight exothermic
reaction and a color change of the mixture were
observed. The resulting mixture was vigorously stirred
Similar results were obtained when deoxybenzoin 6b
and 6c were used as starting materials (Scheme 5).
Therefore, this method proved to be efficient to prepare
the 2-(methylthio)isoflavones, which can be used as
useful intermediates to introduce various nucleophiles
at the 2-position. In addition, as shown in Scheme 5,
this process was also efficient when different alkyl

Y.-W. Kim, R. W. Brueggemeier / Tetrahedron Letters 43 (2002) 6113–6115
6115
1
at room temperature for several hours, and the product
was extracted with ethyl acetate (2×10 mL). The sepa-
rated organics were washed with water (10 mL) and
then with brine (10 mL), dried over MgSO4, and
filtered. The filtrate was concentrated under reduced
pressure, and the residue was purified by silica gel
column chromatography (eluting with EtOAc/hexane
or MeOH/CHCl3) to give the product as a white solid.
All the products were recrystallized from EtOAc/
hexane.9
8. NMR data for compound 7: H NMR (400 MHz, CDCl3)
l 12.37 (s, 1H), 7.56 (d, J=8.6 Hz, 1H), 7.43–7.45 (m,
2H), 7.27–7.35 (m, 3H), 6.39–6.43 (m, 2H), 3.80 (s, 3H),
2.27 (s, 3H), 2.25 (s, 3H); 13C NMR (100 MHz, CDCl3) l
199.21, 166.71, 166.46, 143.82, 137.06, 136.34, 134.11,
129.21, 128.96, 128.83, 113.88, 108.40, 101.43, 56.03, 18.05,
17.28.
9. Physical and spectral data for compounds 2: (a) 2a: mp
140–142°C; IR (KBr) 1629, 1619, 1584, 1541, 1499, 1431,
1
1373, 1349, 1252, 1201 cm−1; H NMR (400 MHz, CDCl3)
l 8.13 (d, J=8.9 Hz, 1H), 7.32–7.44 (m, 5H), 6.96 (dd,
J=8.9, 2.4 Hz, 1H), 6.84 (d, J=2.3 Hz, 1H), 3.91 (s, 3H),
2.53 (s, 3H); 13C NMR (62.9 MHz, CDCl3) l 173.96,
164.41, 164.01, 158.52, 132.64, 131.05, 128.88, 128.68,
128.34, 122.29, 117.66, 114.62, 100.10, 56.30, 14.12;
HRMS calcd for C17H15O3S (M+H)+ 299.0742, found
299.0735. (b) 2b: mp 188–189.5°C; IR (KBr) 1632, 1612,
Acknowledgements
This work was financially supported in part by a
USAMRMC Breast Cancer Program grant DMAD
17-00-1-0388.
1544, 1510, 1433, 1368, 1287, 1265 cm−1 1H NMR (400
;
MHz, CDCl3) l 8.14 (d, J=8.9 Hz, 1H), 7.20–7.26 (m,
4H), 6.95 (dd, J=8.9, 2.3 Hz, 1H), 6.83 (d, J=2.3 Hz,
1H), 3.90 (s, 3H), 2.53 (s, 3H), 2.37 (s, 3H); 13C NMR
(62.9 MHz, CDCl3) l 174.08, 164.20, 163.96, 158.51,
138.50, 130.84, 129.68, 129.58, 128.36, 122.24, 117.66,
114.55, 100.08, 56.28, 21.85, 14.14; HRMS calcd for
C18H16NaO3S (M+Na)+ 335.0718, found 335.0721. (c) 2c:
mp 169–170°C; IR (KBr) 1616, 1540, 1437, 1374, 1348,
References
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1252 cm−1; H NMR (400 MHz, CDCl3) l 8.12 (d, J=8.8
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J=2.3 Hz, 1H), 3.90 (s, 3H), 3.82 (s, 3H), 2.52 (s, 3H); 13C
NMR (62.9 MHz, CDCl3) l 174.15, 164.31, 163.95,
159.90, 158.50, 132.24, 128.32, 124.69, 121.82, 117.61,
114.57, 114.40, 100.07, 56.28, 55.65, 14.15; HRMS calcd
for C18H16NaO4S (M+Na)+ 351.0667, found 351.0668. (d)
2d: mp 117–118°C; IR (KBr) 1635, 1615, 1585, 1546, 1503,
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1
1435, 1373, 1345, 1252, 1197 cm−1; H NMR (400 MHz,
CDCl3) l 8.13 (d, J=8.9 Hz, 1H), 7.30–7.44 (m, 5H), 6.96
(dd, J=8.9, 2.4 Hz, 1H), 6.81 (d, J=2.3 Hz, 1H), 5.83–
5.94 (m, 1H), 5.27 (dd, J=16.9, 1.2 Hz, 1H), 5.14 (dd,
J=10.1, 0.8 Hz, 1H), 3.91 (s, 3H), 3.70 (d, J=6.9 Hz, 2H);
13C NMR (62.9 MHz, CDCl3) l 174.21, 164.12, 163.40,
158.50, 133.20, 132.61, 131.08, 128.82, 128.68, 128.39,
123.35, 119.27, 117.69, 114.51, 100.13, 56.31, 34.54;
HRMS calcd for C19H16NaO3S (M+Na)+ 347.0718, found
347.0705. (e) 2e: mp 153–154°C; IR (KBr) 1636, 1617,
4. Lee, G. H.; Pak, C. S. Synth. Commun. 1999, 29, 2539.
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6. (a) For the reaction conditions for the synthesis of com-
pounds 5, see: Wa¨ha¨la¨, K.; Hase, T. A. J. Chem. Soc.,
Perkin Trans. 1 1991, 3005; (b) Compounds 6a and 6c are
commercially available; (c) Physical and spectral data for
compound 6b: mp 71–72°C; IR (KBr) 1639, 1623, 1516,
1508, 1439, 1388, 1355, 1268, 1231, 1205, 1131 cm−1 1H
;
1586, 1546, 1502, 1438, 1373, 1341, 1252, 1205 cm−1 1H
;
NMR (250 MHz, CDCl3) l 12.72 (s, 1H), 7.73 (d, J=8.6
Hz, 1H), 7.14–7.24 (m, 4H), 6.43–6.40 (m, 2H), 4.15 (s,
2H), 3.81 (s, 3H), 2.31 (s, 3H); 13C NMR (62.9 MHz,
CDCl3) l 202.63, 166.56, 166.28, 137.14, 132.47, 131.71,
129.87, 129.61, 113.60, 108.20, 101.43, 55.98, 44.89, 21.48;
HRMS calcd for C16H16NaO3 (M+Na)+ 279.0997, found
279.0989.
NMR (400 MHz, CDCl3) l 8.12 (d, J=8.9 Hz, 1H),
7.22–7.41 (m, 10H), 6.95 (dd, J=8.9, 2.4 Hz, 1H), 6.81 (d,
J=2.3 Hz, 1H), 4.30 (s, 2H), 3.91 (s, 3H); 13C NMR (62.9
MHz, CDCl3) l 174.22, 164.10, 163.54, 158.48, 136.51,
132.52, 131.04, 129.32, 129.17, 128.81, 128.66, 128.39,
128.17, 122.97, 117.70, 114.49, 100.19, 56.31, 36.17;
HRMS calcd for C23H18NaO3S (M+Na)+ 397.0874, found
397.0856.
7. We have modified the original reaction condition by using
THF as an organic solvent instead of carbon disulfide.