New Synthesis of Thioflavanones by the Regioselective Cyclization of 1-(2-Benzylthio)phenyl-3-phenyl-2-propen-1-ones with Hydrobromic Acid

Full text of DOI:10.1002/bkcs.11989

Note
DOI: 10.1002/bkcs.11989
BULLETIN OF THE
J. In Lee
KOREAN CHEMICAL SOCIETY
New Synthesis of Thioflavanones by the Regioselective Cyclization
of 1-(2-Benzylthio)phenyl-3-phenyl-2-propen-1-ones with
Hydrobromic Acid
*
Jae In Lee
Department of Chemistry, College of Natural Science, Duksung Women’s University, Seoul 01369,
Republic of Korea. *E-mail: jilee@duksung.ac.kr
Received September 5, 2019, Accepted January 29, 2020
Keywords: Thioflavanones, Condensation, 6-Endo cyclization
Thioflavanones have a skeleton of a thiochroman-4-one ring
with aryl groups in the 2-position and unlike flavanones are
not found naturally. Their pharmacological activities have
recently been investigated in anticipation of improved bio-
availability compared to flavanones. They inhibit the cellu-
lar proliferation of human breast cancer with weak
cytotoxicity1 and exhibit antioxidative activity2 against nit-
ric oxide (NO). They also have antileishmanial activity3
against Leishmania panamensis and show better antifungal
activity4 against fungi, such as Cryptococcus neoformans
and Epidermophyton floccosum than fluconazole.
Several methods for synthesizing thioflavanones have been
described through the construction of thiochroman-4-one ring
as a key step.5 The reaction of thiophenols and cinnamic acids
afforded 3-(phenylthio)-3-phenylpropanoic acids, which
were converted to the corresponding acid chlorides with
oxalyl chloride, followed by cyclization with SnCl4 to give
the thioflavanones (Scheme 1 (a)).6 The treatment of 20-
halochalcones, which were prepared from 1-(2-halophenyl)
ethanones and benzaldehydes using NaOH, with NaSH7 or
potassium ethyl xanthogenate/10 mol % Cu(OAc)28 produced
the corresponding 3-phenyl-1-(2-sulfanylphenyl)propenones
in situ, followed by intramolecular 1,4-addition to afford the
thioflavanones under heating conditions (Scheme 1 (b)).
Alternatively, the reaction of oxathiolone-fused chalcones,
which were prepared by the condensation of 4-acetyl-2-oxo-
benz[1,3]oxathiole with benzaldehydes using H2SO4, with
NaOH afforded 8-hydroxythioflavanones in low-to-moderate
yields by the deprotection and subsequent cyclization in
refluxing CH3OH (Scheme 1 (c)).9
thioflavanones were also synthesized by the 1,4-addition of
phenylzinc chloride12 or diarylcuprates13 to thiochromones
in the presence of [Rh(COD)Cl]2 catalyst or 2 equiv. of
TMSCl, respectively (Scheme 1 (e)).
Thus far, several methods for synthesizing thioflavanones
have been reported, but some suffer from a lack of
regioselectivity toward intramolecular cyclization, use of excess
reagent, and multiple steps. Furthermore, there are few reports
on the synthesis of thioflavanones by the cyclization of 20-
mercaptochalcones or S-protected thiochalcones and the scope
of the reaction has not been fully investigated. Although the
cyclization of thiolatechalcone intermediates, produced from
p-methoxybenzylmercaptochalcones and AgNO3 in refluxing
EtOH, with p-toluenesulfonic acid gave thioflavanones, five
steps are needed, resulting in low yields together with
thioflavones as side products.14 20-Mercaptochalcones were
not readily isolated because the thiol group was oxidized
easily to give the corresponding disulfide.15 Initially, our
attempt to prepare 20-mercaptochalcone by the condensation
of 20-mercaptoacetophenone and benzaldehyde using KOH
or BF3ꢀEt2O were also unsuccessful. Thus, protection of
the thiol group by avoiding oxidation was essential for the
synthesis of thiochalcones. This article reports the efficient
synthesis of thioflavanones by the regioselective cyclization
of 1-(2-benzylthio)phenyl-3-phenyl-2-propen-1-ones with
hydrobromic acid.
Initially, 1-(2-benzylthio)phenylethanone (2) was pre-
pared in two steps: (1) The reaction of 2-mercaptobenzoic
acid (1) and 3 equiv. of methyllithium in THF afforded 20-
mercaptoacetophenone in 81% yield. (2) The subsequent
reaction of 20-mercaptoacetophenone with benzyl chloride
using KOH in THF afforded 2 in 92% yield. On the other
hand, 2 was prepared conveniently by the treatment of
1 with 3 equiv. of methyllithium and successive addition of
benzyl chloride in THF in a one-pot operation (Scheme 2).
The sulfur atom of the resulting lithium thiophenolate inter-
mediate was benzylated selectively after 4 h at room tem-
perature. The mixture was quenched with a 1 N HCl
solution and the THF evaporated off. After the usual acidic
The direct condensation of 20-mercaptoacetophenone and
benzaldehydes using 2 equiv. of lithium diisopropylamide
(LDA) afforded thioflavanones through the attack of a sul-
fur atom to the corresponding chalcone intermediates
(Scheme 1 (d)).10 The combination of 2-(tert-butylthio)
benzaldehyde and arylacetylenes using
5
mol
%
Rh(nbd)2BF4/dcpm afforded β’-(tert-butylthio)enone inter-
mediates in situ, which underwent intramolecular S-
conjugate addition to give thioflavanones after deprotection
with an excess of CF3COOH (Scheme 1 (e)).11 Recently,
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BULLETIN OF THE
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KOREAN CHEMICAL SOCIETY
S
OH
(entry 4). When HOAc, ClCH2CH2Cl, and DME were
employed as solvents using 1.5 equiv. of 48% HBr, 4h was
obtained in 92, 84, and 0% yield, respectively, after 1.5,
24, and 24 h, respectively, at 70 ꢁC (entries 5–7).
(COCl)2; SnCl4
R1
(a)
(b)
R2
O
R2
S
R1
X
NaSH or
S
R1
R2
O
Thus, the 6-endo cyclization of 3 was accomplished suc-
cessfully with 1.5 equiv. of 48% HBr in CH3CN at 70 ꢁC and
the competitive 5-exo cyclized products were not observed.
The reaction appeared to proceed through the debenzylation of
the benzylthio group in 3 by HBr with the liberation of benzyl
bromide to produce the corresponding 20-mercaptochalcone
intermediates, which underwent rapid 1,4-addition to give
thioflavanones (4). The 6-endo-digonal cyclization was ener-
getically favorable compared to 5-exo-digonal cyclization as
Baldwin’s rule.16 This synthetic method of thioflavanones via
S-protected chalcone intermediates showed the advantage
of the short steps, the exclusive 6-endo cyclization, and
the high yields compared with those using oxathiolone-
fused chalcones9 and p-methoxybenzylmercaptochalcones.14
The characteristic 1H NMR spectra of the synthesized
thioflavanones appeared as a doublet of doublets for the C2
proton signals in the range of 4.67–5.22 ppm and two doublets
of doublets for two C3 protons signals in the range of 3.27–-
3.36 ppm and 3.13–3.26 ppm, respectively.
As presented in Table 2, various thioflavanone derivatives
were synthesized from 1-(2-benzylthio)phenyl-3-phenyl-
2-propen-1-ones and 48% HBr in high overall yields
(48–61%). The selective 6-endo cyclization of 3a-l proceeded
well regardless of the types and the positions of electron-
donating (4b, 4c, 4g–4j) and electron-withdrawing (4d-4f)
substituents on the 2-substituted phenyl rings to give the
corresponding thioflavanones under the described conditions.
Furthermore, the reaction of 3 containing the heteroaromatic
groups, 2-furyl (3k) and 2-thienyl (3l), proceeded equally
well to give the corresponding 2,3-dihydro-2-(2-heteroaryl)-
4H-thiopyran-4-ones in 90% and 88% yield, respectively.
In conclusion, a regioselective method was developed for
the synthesis of thioflavanones from 1-(2-benzylthio)phe-
nyl-3-phenyl-2-propen-1-ones using 48% HBr in CH3CN
in high yields.
O
O
X = Cl, Br, I
KS
OEt
OH
R2
O
S
S
NaOH; aq HCl
R1
R1
R2
(c)
(d)
O
O
O
SH
2 eq LDA
H
+
CH3
R
R
R
S
O
S-t-Bu
Rh(nbd)2BF4;
CF3COOH
(e)
(f)
O
+
H
O
S
R2
S
PhZnCl / [Rh(COD)Cl]2 or
Ar2CuM / 2 eq TMSCl
M = Li, MgCl
R1
R1
O
O
Scheme 1. General method for synthesizing thioflavanones.
work-up and purification by recrystallization, 2 was
obtained in 76% yield.
The condensation of 2 with arylaldehydes was carried
out using 0.5 N KOH in THFꢁ. The reaction proceeded
smoothly for 2–5 h between 0 C and room temperature
regardless of the type and position of substituents on the
phenyl rings under the present conditions. The mixture was
neutralized with a 0.5 N HCl solution and evaporated of
THF. After the usual aqueous work-up and purification by
recrystallization, 3a-l were obtained as yellow solids in
77–90% yields.
To investigate the optimal conditions for the cyclization
of 3, the effect of acids and solvents for the reaction
of 1-(2-benzylthio)phenyl-3-(4-methoxyphenyl)-2-propen-
1-one (3h) was examined (Table 1). The cyclization of 3h
with HOAc solvent did not proceeded for 24 h at 65 ꢁC and
the starting material was recovered in 96% yield (entry 1).
The cyclization of 3h with CF3COOH solvent and 5 equiv.
of 70% HClO4 in THF afforded 40-methoxythioflavanone
(4 h) in 90% and 45% yield, respectively, in 4 h/70 ꢁC and
24 h/65 ꢁC, respectively (entries 2–3). On the other hand,
the cyclization of 3h proceeded well with 1.5 equiv. of 48%
HBr in CH3CN to give 4h in 93% yield after 1 h at 70 ꢁC
Experimental
Preparation of 1-(2-Benzylthio)phenylethanone (2).
Methyllithium (1.5 M in Et2O, 11.0 mL, 16.5 mmol) was
O
R
S
Ph
CH3
Ph
SH
OH
S
S
a, b
d
R
H
R
c
PhCH2Br
O
O
O
O
1
2
3a-l
4a-l
R = C6H5 (a); 2-CH3O-C6H4 (b); 3-HO-C6H4 (c); 3-O2N-C6H4 (d);
4-F-C6H4 (e); 4-Cl-C6H4 (f); 4-CH3-C6H4 (g); 4-CH3O-C6H4 (h);
3,4-(CH3O)2-C6H3 (i); 3,4,5-(CH3O)3-C6H2 (j); 2-furyl (k); 2-thienyl (l)
Scheme 2. Reagents and conditions: (a) 3 equiv. CH3Li, THF, 0 ꢁC, 15 min; (b) PhCH2Cl, rt, 4 h in one-pot; 1 N HCl; (c) 0.5 N KOH,
THF, 0 ꢁC-rt, 2–5 h; (d) 1.5 equiv. 48% HBr, CH3CN, 70 ꢁC, 1–4 h.
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BULLETIN OF THE
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KOREAN CHEMICAL SOCIETY
Table 1. Effect of acids and solvents for the cyclization of 1-(2-benzylthio)phenyl-3-(4-methoxyphenyl)-2-propen-1-one (3h)
OCH3
Ph
S
OCH3
S
O
4h
3h
O
.
Entry
Acids
HOAc
Solvents
Temp (ꢁC); time (h)
Yields of 4h, %a
1
2
3
4
5
6
7
-
-
65; 24
70; 4
65; 24
70; 1
70; 1.5
70; 24
70; 24
0 (96)
90
45
93
92
CF3COOH
70% HClO4
48% HBrc
48% HBrc
48% HBrc
48% HBrc
b
THF
CH3CN
HOAc
ClCH2CH2Cl
DME
84
0
a The number in parenthesis indicates the recovery yield of 3h.
b 5 equiv. was used.
c 1.5 equiv. was used.
Table 2. Synthesis of 3 and thioflavanones 4.a
Yields, %b
Yields, %b
Entry
Thioflavanones
3 4
Entry
Thioflavanones
3 4
a
82 87 (54)
g
88 90 (60)
83 93 (59)
85 91 (59)
88 82 (55)
CH3
S
S
O
S
O
S
b
c
87 93 (61)
77c 82 (48)
84 83 (53)
h
i
OCH3
OCH3
O
S
O
S
O
O
S
OCH3
OCH3
OH
O
d
j
OCH3
OCH3
NO2
S
OCH3
O
e
f
86 81 (53)
90 83 (57)
k
l
86 90 (59)
87 88 (58)
F
S
O
S
O
S
O
Cl
S
S
O
O
a The conversion of 3 to 4 was carried out using 1.5 equiv. of 48% HBr in CH3CN at 70 ꢁC.
b The numbers in parentheses indicate the overall yields from 2-mercaptobenzoic acid 1.
c 2 equiv. of 0.5 N KOH were used.
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added slowly to a solution of 2-mercaptobenzoic acid
(1, 771 mg, 5.0 mmol) in THF (20 mL) under argon atmo-
sphere at 0 ꢁC. After stirring for 15 min, benzyl chloride
(633 μL, 5.5 mmol) was added to the resulting yellow
lithiophenylthiolate solution and stirred for 4 h at room
temperature. The reaction mixture was quenched with a
1 N HCl solution (5 mL) and THF was evaporated. The
mixture was poured into a 0.1 N HCl solution (50 mL) and
extracted with methylene chloride (3 x 20 mL). The organic
layer was dried over anhydrous MgSO4, filtered, and con-
centrated in vacuo. The crude residue was recrystallized
twice in 10% EtOAc/n-hexane to give 2 (921 mg, 76%).
mp 147–148 ꢁC; 1H NMR (300 MHz, CDCl3) δ 7.80
(d, J = 7.8 Hz, 1H), 7.36–7.42 (m, 4H), 7.29–7.34 (m, 2H),
7.24–7.29 (m, 1H), 7.17–7.23 (m, 1H), 4.13 (s, 2H), 2.59
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 199.4, 140.8, 136.3,
135.5, 132.1, 130.8, 129.1, 128.6, 127.3, 126.7, 124.2,
Acknowledgments. This research was supported by the
Duksung Women’s University Research Grants 300000
3404 (2019).
Supporting Information. Additional supporting informa-
tion may be found online in the Supporting Information
section at the end of the article.
REFERENCES
1. E. J. Choi, J. I. Lee, G.-H. Kim, Int. J. Mol. Med. 2012,
29, 252.
2. J. I. Lee, J.-H. Lee, Food Sci. Biotechnol. 2014, 23, 957.
3. (a) E. Vargas, F. Echeverri, I. D. Velez, S. M. Robledo,
W. Quinones, Molecules 2017, 22, 2041. (b) E. Vargas,
F. Echeverri, Y. A. Upegui, S. M. Robledo, W. Quinones,
Molecules 2018, 23, 70.
4. Y.-L. Song, F. Wu, C.-C. Zhang, G.-C. Liang, G. Zhou, J.-
J. Yu, Bioorg. Med. Chem. Lett. 2015, 25, 259.
5. S. Bondock, M. A. Metwally, J. Sulfur Chem. 2008, 29, 623.
6. (a) G. S. Ponticello, M. B. Freedman, C. N. Habecker,
M. K. Holloway, J. S. Amato, R. S. Conn, J. J. Baldwin,
J. Org. Chem. 1988, 53, 9. (b) D. K. Bates, K. Li, J. Org.
Chem. 2002, 67, 8662.
7. (a) K. Kobayashi, A. Kobayashi, M. Tanmatsu, Heterocycles
2012, 85, 919. (b) J. I. Lee, Bull. Kor. Chem. Soc. 2013,
34, 1253.
8. S. Sangeetha, P. Muthupandi, G. Sekar, Org. Lett. 2015,
17, 6006.
37.8, 28.5; FTIR (KBr) 1670 (C O) cm−1
.
Preparation of 1-(2-Benzylthio)phenyl-3-(4-methoxyphe-
yl)-2-propen-1-one (3h). Potassium hydroxide (0.5 N in
CH3OH, 6.0 mL, 3.0 mmol) was added to a mixture solu-
tion of 2 (727 mg, 3.0 mmol) and 4-methoxybenzaldehyde
(409 mg, 3.0 mmol) in THF (10 mL) at 0 ꢁC. Stirring was
continued for 5 h between 0 ꢁC and room temperature and
the mixture was then quenched with a 0.5 N HCl solution
(6 mL). After evaporating the solvent, the mixture was
poured into a 0.1 N HCl solution (40 mL), extracted with
methylene chloride (3 × 20 mL), and washed with a satu-
rated NaHCO3 solution (40 mL). The concentrated residue
was recrystallized twice in 50% EtOAc/n-hexane to give
1
3h (898 mg, 83%). mp 144–145 ꢁC; H NMR (300 MHz,
9. W. Konieczny, M. Konieczny, Synthesis 2009, 2009, 1811.
10. (a) J. I. Lee, Bull. Kor. Chem. Soc. 2008, 29, 1263.
(b) M. Basooti, N. Saadatjoo, F. Nemati, G. Shirvani,
M. A. A. Faghih, M. Javaheri, J. Label. Compd. Radiopharm.
2017, 60, 550.
CDCl3) δ 7.57 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 9.0 Hz,
2H), 7.34–7.44 (m, 3H), 7.19–7.32 (m, 6H), 7.09
(d, J = 15.8 Hz, 1H), 6.91 (d, J = 8.8 Hz, 2H), 4.11
(s, 2H), 3.84 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 194.1,
161.7, 145.5, 140.2, 136.8 (overlapped), 130.8, 130.3,
129.8, 129.0, 128.9, 128.5, 127.4, 127.2, 125.6, 123.4,
11. A. Bouisseau, J. Glancy, M. C. Willis, Org. Lett. 2016,
18, 5676.
114.4, 55.4, 39.2; FTIR (KBr) 1635 (C O) cm−1
.
12. L. Meng, M. Y. Jin, J. Wang, Org. Lett. 2016, 18, 4986.
13. (a) F. Guo, M. C. Jeffries, B. N. Graves, S. A. Graham,
D. A. Pollard, G. Pang, H. Y. Chen, Tetrahedron 2017, 73,
5745. (b) S. A. Bass, D. M. Parker, T. J. Bellinger,
A. S. Eaton, A. S. Dibble, K. L. Koroma, S. A. Sekyi,
D. A. Pollard, F. Guo, Molecules 2018, 23, 1728.
14. M. T. Konieczny, B. Horowska, A. Kunikowski, J. Konopa,
K. Wierzba, Y. Yamada, T. Asao, J. Org. Chem. 1999,
64, 359.
15. (a) M. A. Zolfigol, K. Niknam, M. Bagherzadeh,
A. Ghorbani-Choghamarani, N. Koukabi, M. Hajjami,
E. Kolvari, J. Chin. Chem. Soc. 2007, 54, 1115.
(b) S. E. Clayton, C. D. Gabbutt, J. D. Hepworth,
B. M. Heron, Tetrahedron 1993, 49, 939.
Preparation of 40-Methoxythioflavanone (4 h). Hydro-
bromic acid (48 wt % in H2O, 340 μL, 3.0 mmol) was
added to a solution of 3h (721 mg, 2.0 mmol) in CH3CN
(8 mL) and stirred for 1 h at 70 ꢁC. Acetonitrile was then
evaporated under reduced pressure. The mixture was
poured into a saturated NaHCO3 solution (30 mL) and
extracted with methylene chloride (3 x 20 mL). The organic
layer was dried over anhydrous MgSO4, filtered, and con-
centrated in vacuo. Benzyl bromide was evaporated further
under high vacuum and the residue was then recrystallized
twice in 10% EtOAc/n-hexane to give 4h (502 mg, 93%)
as a pale yellow solid. Physical and spectral data for the
thioflavanone compounds associated with this article can be
found in the Supporting Information.
16. K. Nakatani, A. Okamoto, I. Saito, Tetrahedron 1996,
52, 9427.
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