One-pot synthesis of 2H-thiochromenes via TiCl4-promoted reaction of 2-tert-butylthiobenzaldehydes with activated alkenes

Article abstract of DOI:10.1002/jhet.182

(Chemical Equation Presented) A facile synthesis of 2H-thiochromenes through TiCl₄-promoted reaction of 2-tert-butylthiobenzaldehydes with activated alkenes is described.

Full text of DOI:10.1002/jhet.182

September 2009
One-Pot Synthesis of 2H-Thiochromenes via TiCl4-Promoted
Reaction of 2-tert-Butylthiobenzaldehydes with
Activated Alkenes
1023
Chang Hoon Lee and Kee-Jung Lee*
Organic Synthesis Laboratory, Department of Chemical Engineering,
Hanyang University, Seoul 133-791, Korea
*E-mail: leekj@hanyang.ac.kr
Received February 13, 2009
DOI 10.1002/jhet.182
Published online 3 September 2009 in Wiley InterScience (www.interscience.wiley.com).
A facile synthesis of 2H-thiochromenes through TiCl4-promoted reaction of 2-tert-butylthiobenzalde-
hydes with activated alkenes is described.
J. Heterocyclic Chem., 46, 1023 (2009).
INTRODUCTION
2-tert-butylthiobenzaldehydes with activated alkenes,
which serves as a facile method for the synthesis of 2H-
thiochromenes.
Thiochromenes are of considerable pharmacological
and material interest because they display a wide range
of biological activities [1] and are occasionally used as
scaffolds [2] or synthetic intermediates of functional
dyes [3]. In recognition of their importance, several
efforts have been made to synthesize this class of mole-
cules so far, but the development of more efficient and
general method still remains a continuing challenge. The
main synthetic routes involve an initial condensation of
thiophenols with acrylic acid derivatives, followed by
reduction and dehydration [4], and a magnesium amide-
induced sequential conjugate addition-aldol type conden-
sation reaction between 2-mercaptoacetophenone and
a,b-unsaturated carboxylic acid derivatives and subse-
quent dehydration [5]. A similar method to produce chi-
ral 2H-thiochromenes through tandem Michael-aldol
reactions between 2-mercaptobenzaldehyde and a,b-un-
saturated aldehydes has been reported [6]. In addition,
several other synthetic methods are available such as the
cyclization of 3-(2-tert-butylthiophenyl)-prop-2-en-1-ols
[7] and the Baylis-Hillman (BH) reaction of 2,20-dithio-
dibenzaldehyde with activated alkenes [8]. However,
most of these routes suffer from main drawbacks such
as multistep processes, the poor availability of starting
material, and the limited scope of substrates. Recently,
we also reported a tandem SN20 and SNAr reaction of
BH acetates having an ortho-leaving group with sodium
sulfide, leading to the formation of 2H-thiochromenes,
which gave unsatisfactory product yields [9]. In continu-
ation of our ongoing studies on the synthesis of hetero-
cycles, including thiochromenes, using BH methodology
[10], we herein describe TiCl4-promoted reaction of
RESULTS AND DISCUSSION
The chalcogeno-Baylis-Hillman reaction [11] is well
known as a coupling reaction of activated alkenes with
electrophiles such as aldehydes [12], activated ketones
[13], and acetals [14] catalyzed by a mixture of Lewis
acid and base, typically using titanium (IV) chloride
(TiCl4)/methyl sulfide [12,13] to give highly functional-
ized olefins. We envisioned that the reactions of 2-tert-
butylthiobenzaldehydes with activated alkenes in the
presence of TiCl4 could produce the thiochromenes
alone or together with the BH adducts, after loss of the
tert-butyl group under acidic conditions without addition
of extra Lewis base such as sulfide, because aldehydes
have a chalcogenyl group which might serve as a Lewis
base (Scheme 1).
Accordingly, we first synthesized 2-tert-butylthioben-
zaldehydes 2a–e as starting materials, following a
slightly modified literature procedure [15,16]. The reac-
tion of benzaldehydes 1a–e with 1.2 equiv of tert-
butylthiol in the presence of 1 equiv of potassium car-
bonate in N,N-dimethylformamide at reflux temperature
gave 2-tert-butylthiobenzaldehydes 2a–e in 64–97%
yields. Treatment of 2a–e with 2 equiv of methyl vinyl
ketone (MVK) in the presence of 1 equiv of TiCl4 in
1,2-dichloroethane at reflux temperature gave the
expected 3-acetyl-2H-thiochromenes 4a–e in low to ac-
ceptable yields (8–51%) without the production of BH
adducts. The spectral data of 4a were identical to the
1
reported infrared, H, 13C NMR spectral values [8]. As
C
V
2009 HeteroCorporation

1024
C. H. Lee and K.-J. Lee
Vol 46
Scheme 1
CONCLUSIONS
In conclusion, a new method for the synthesis of
2H-thiochromenes has been developed through TiCl4-
promoted reaction of 2-tert-butylthiobenzaldehyde deriv-
atives with activated alkenes. Although some products
were obtained in low yields, compared with other
routes, this synthetic method apparently allows a facile
approach to 2H-thiochromenes.
EXPERIMENTAL
Silica gel 60 (70–230 mesh ASTM) used for column chro-
matography was supplied by E. Merck. Analytical thin layer
chromatography (TLC) was performed on Merck silica gel 60
F254 TLC plates. Melting points were measured by an electro-
thermal melting point apparatus and were uncorrected. Micro-
analyses were obtained using a Thermo Electron Corporation
Flash EA 1112 element analyzer. Mass spectra were obtained
using a ThermoQuest Polaris Q mass spectrometer operating at
70 eV. Infrared spectra were recorded on a Nicolet Magna 550
shown in Table 1, the presence of electron-withdrawing
chloro- or nitro-substituents in benzene ring of aldehyde
2 demanded a prolonged reaction time to afford the cor-
responding thiochromenes. For instance, the synthesis of
4b and 4c (Entries 7 and 8) having chloro-substituent
required longer reaction time than that of 4a (Entry 6)
(2–4 h vs. 0.5 h). Nitro-substituted aldehyde 2d with
MVK also gave desired thiochromene 4d in low yield
(8%) after relatively long reaction time (4 h). We
consider that the reduced nucleophilicity of the sulfur
atom in aldehyde 2 by electron-withdrawing chloro- or
nitro-substituent decelerated the reaction. Next, we
examined the reaction of 2a–e with methyl acrylate or
acrylonitrile. Using 2 equiv of methyl acrylate, the cor-
responding thiochromenes 4f–h and 4j were produced in
35–70% yields. However, the reaction of 2d having
nitro-substituent with methyl acrylate was unsuccessful,
and very complex mixture of unidentified products was
observed by thin layer chromatography. The spectral
data of 4f–h and 4j were identical to the reported infra-
1
FTIR spectrometer. The H and 13C NMR spectra were meas-
ured on a Gemini 300 spectrometer using deuteriochloroform.
All chemical shifts are reported in parts per million relative to
tetramethylsilane. The coupling constants (J) are expressed in
Hertz.
Preparation of 2-tert-butylthiobenzaldehyde derivatives
2: General procedure. To a stirred solution of aldehyde 1
(40 mmol) and tert-butyl thiol (5.40 mL, 48 mmol) in dime-
thylformamide (40 mL) was added potassium carbonate (5.53
g, 40 mmol) and the mixture was heated to reflux temperature
for 1–7 days. After cooling to room temperature, the reaction
mixture was diluted with water (300 mL) and extracted
with diethyl ether (3 ꢀ 100 mL). The combined organic layer
was dried over anhydrous magnesium sulfate, and the solvent
was evaporated in vacuo. The resulting mixture was
Table 1
1
red, H, 13C NMR spectral values [9]. In the cases of
Aldehydes 2a–d and 2H-thiochromenes 4a–j.
acrylonitrile, thiochromenes 4k and 4l were produced in
relatively low yields (25 and 18%, respectively) and
were taken long reaction times (Entries 16 and 17).
Because of low yields, additional reactions of 2c–e with
acrylonitrile were not undertaken. A plausible mecha-
nism based on Kataoka’s work [12] is shown in
Scheme 2. A b-sulfonium-TiCl4-stabilized enolate 3a is
produced by conjugate addition of sulfur atom in alde-
hyde 2 to TiCl4-activated Michael acceptor, followed by
carbon–carbon bond formation through transition state
3b to give the TiCl4-stabilized alkoxide 3c and subse-
quent proton migration to afford 3d, which gives 2H-thi-
ochromene 4 by dehydration and loss of the tert-butyl
group. A similar Michael-aldol process catalyzed by
Lewis acid/chalcogenide [11(b)], amine [17], and
bifunctional thiourea [18] is well known. It is also
known that the tert-butyl thioethers are easily cleaved
under Lewis [19] or Brønsted [20] acidic conditions.
Reaction
time
Yield
(%)
Entry
Reactant
Olefin
Product
1
2
1a
1b
1c
1d
1e
2a
2b
2c
2d
2e
2a
2b
2c
2d
2e
2a
2b
–
–
1 day
4 days
7 days
6 h
2a
2b
2c
2d
2e
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
84
97
94
64
73
51
22
24
8
3
4
–
–
5
6
–
4 d
MVK
MVK
MVK
MVK
MVK
MA
MA
MA
MA
MA
AN
AN
0.5 h
2 h
4 h
7
8
9
4 h
10
11
12
13
14
15
16
17
0.5 h
0.5 h
2.5 h
4 h
32
69
70
42
–
35
25
18
3 days
1 h
4.5 h
4 days
MVK, methyl vinyl ketone; MA, methyl acrylate; AN, acrylonitrile.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2009 One-Pot Synthesis of 2H-Thiochromenes via TiCl4-Promoted Reaction of 2-tert-
Butylthiobenzaldehydes with Activated Alkenes
1025
Scheme 2
chromatographed on silica gel eluting with hexane/ethyl
acetate (20:1) to produce 2 as an oil or a solid.
The physical and spectral data of 2 prepared by this general
method are as follows.
m/z (%) 239 (Mþ, 8), 210 (9), 183 (100), 182 (14), 136 (43).
Anal. Calcd. for C11H13NO3S: C, 55.21; H, 5.48; N, 5.85; S,
13.40. Found: C, 55.32; H, 5.60; N, 5.84; S, 13.26.
2-tert-Butylthio-5-methoxybenzaldehyde (2e). Yellow oil;
1
2-tert-Butylthiobenzaldehyde (2a). [15] Yellow oil; yield:
yield: 73%; IR (neat): 1683, 1589, 1473, 1375 cmꢁ1; H NMR
1
84%; IR (neat): 1692, 1583, 1455, 1363 cmꢁ1; H NMR (deu-
(deuteriochloroform): d 1.27 (s, 9H), 3.88 (s, 3H), 7.13 (dd,
J ¼ 8.5 and 3.1 Hz, 1H), 7.49 (d, J ¼ 3.1 Hz, 1H), 7.54 (d, J
¼ 8.5 Hz, 1H), 10.73 (s, 1H); 13C NMR (deuteriochloroform):
d 30.7, 47.1, 55.5, 110.9, 121.1, 128.0, 140.3, 141.3, 160.5,
193.7; ms: m/z (%) 224 (Mþ, 100), 222 (3), 221 (2), 220 (2)
168 (2), 167 (1). Anal. Calcd. for C12H16O2S: C, 64.25; H,
7.19; S, 14.29. Found: C, 64.41; H, 7.22; S, 14.03.
Preparation of 3-substituted 2H-thiochromenes 4: Gen-
eral procedure. To a stirred solution of aldehyde 2 (3 mmol)
and alkene (6 mmol) in 1,2-dichloroethane (10 mL) was added
TiCl4 (0.33 mL, 3 mmol) at room temperature, and then the
mixture was heated to reflux temperature for 0.5–96 h. After
cooling to room temperature, the reaction mixture was
quenched by aqueous saturated NaHCO3 solution (50 mL),
diluted with water (150 mL), and extracted with dichlorome-
thane (2 ꢀ 150 mL). The combined organic layer was dried
over anhydrous magnesium sulfate, and the solvent was evapo-
rated in vacuo. The resulting mixture was chromatographed on
silica gel eluting with hexane/ethyl acetate (10:1) to produce 4
as an oil or a solid.
teriochloroform): d 1.30 (s, 9H), 7.50–7.65 (m, 3H), 7.98–8.01
(m, 1H), 10.80 (s, 1H); 13C NMR (deuteriochloroform): d
30.8, 47.5, 128.0, 129.5, 133.5, 136.5, 139.4, 139.9, 193.6; ms:
m/z (%) 194 (Mþ, 100), 138 (14), 137 (6), 109 (12), 104 (8).
2-tert-Butylthio-3-chlorobenzaldehyde (2b). [16] White
solid; yield: 97%; mp: 52–54ꢂC; IR (potassium bromide):
1
1680, 1571, 1458, 1366 cmꢁ1; H NMR (deuteriochloroform):
d 1.32 (s, 9H), 7.46 (t, J ¼ 7.9 Hz, 1H), 7.78 (dd, J ¼ 7.9 and
1.5 Hz, 1H), 7.91 (dd, J ¼ 7.9 and 1.5 Hz, 1H), 10.77 (s, 1H);
13C NMR (deuteriochloroform): d 31.1, 50.7, 126.7, 130.3,
135.0, 135.5, 142.0, 143.4, 193.5; ms: m/z (%) 230 (Mþ, 41),
228 (Mþ, 100), 173 (5), 172 (7), 171 (6).
2-tert-Butylthio-5-chlorobenzaldehyde (2c). Yellow oil;
1
yield: 94%; IR (neat): 1695, 1570, 1454, 1363 cmꢁ1; H NMR
(deuteriochloroform): d 1.29 (s, 9H), 7.52–7.59 (m, 2H), 7.96
(d, J ¼ 2.1 Hz, 1H), 10.71 (s, 1H); 13C NMR (deuteriochloro-
form): d 30.8, 47.9, 128.1, 133.5, 134.8, 136.3, 140.4, 141.2,
192.4; ms: m/z (%) 230 (Mþ, 39), 228 (Mþ, 100), 227 (6), 226
(7), 225 (8). Anal. Calcd. for C11H13ClOS: C, 57.76; H, 5.73;
S, 14.02. Found: C, 57.59; H, 5.55; S, 13.87.
The physical and spectral data of 4 prepared by this general
method are as follows.
2-tert-Butylthio-5-nitrobenzaldehyde
(2d). Yellow
oil;
yield: 64%; IR (neat): 1696, 1598, 1525, 1458, 1345 cmꢁ1; H
NMR (deuteriochloroform): d 1.38 (s, 9H), 7.85 (d, J ¼ 8.5
Hz, 1H), 8.39 (dd, J ¼ 8.5 Hz and 2.7 Hz, 1H), 8.78 (d, J ¼
2.7 Hz, 1H), 10.75 (s, 1H); 13C NMR (deuteriochloroform): d
31.0, 49.5, 123.2, 126.9, 139.9, 140.1, 144.6, 148.2, 191.0; ms:
3-Acetyl-2H-thiochromene (4a). [8] Yellow oil; yield: 51%;
IR (neat): 1641, 1616, 1439, 1378, 1305, 1281, 1235, 1217
1
1
cmꢁ1; H NMR (deuteriochloroform): d 2.47 (s, 3H), 3.72 (d,
J ¼ 0.9 Hz, 2H), 7.12–7.31 (m, 4H), 7.40 (s, 1H); 13C NMR
(deuteriochloroform): d 22.8, 25.3, 125.7, 127.3, 130.5, 130.8,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1026
C. H. Lee and K.-J. Lee
Vol 46
131.4, 131.7, 135.0, 137.8, 196.7; ms: m/z (%) 190 (Mþ, 63),
189 (62), 149 (8), 148 (23), 147 (100).
form): d 3.73 (d, J ¼ 0.9 Hz, 2H), 3.85 (s, 3H), 7.16–7.23 (m,
3H), 7.48 (s, 1H); 13C NMR (deuteriochloroform): d 23.9,
52.3, 124.3, 128.1, 129.8, 129.9, 131.2, 132.3, 132.7, 136.1,
166.0; ms: m/z (%) 242 (Mþ, 25), 241 (20), 240 (Mþ, 67), 239
(22), 227 (38), 225 (100), 183 (15), 181 (42).
3-Acetyl-8-chloro-2H-thiochromene (4b). Yellow oil; yield:
1
22%; IR (neat): 1656, 1625, 1412, 1372, 1238, 1214 cmꢁ1; H
NMR (deuteriochloroform): d 2.49 (s, 3H), 3.76 (d, J ¼ 0.9
Hz, 2H), 7.09 (t, J ¼ 7.6 Hz, 1H), 7.20 (dd, J ¼ 7.6 and 1.2
Hz, 1H), 7.33 (dd, J ¼ 7.6 and 1.2 Hz, 1H), 7.39 (s, 1H); 13C
NMR (deuteriochloroform): d 22.9, 25.4, 125.7, 129.0, 131.2,
131.6, 131.9, 132.9, 134.8, 137.5, 196.5; ms: m/z (%) 226
(Mþ, 23), 225 (20), 224 (Mþ, 59), 223 (25), 183 (37), 181
(100), 146 (11), 145 (25). Anal. Calcd. for C11H9ClOS: C,
58.80; H, 4.04; S, 14.27. Found: C, 58.71; H, 3.87; S, 14.04.
3-Acetyl-6-chloro-2H-thiochromene (4c). Yellow solid;
yield: 24%; mp: 85–86ꢂC; IR (potassium bromide): 1662,
3-Carbomethoxy-6-methoxy-2H-thiochromene (4j). [9] Yel-
low solid; yield: 35%; mp: 38–39ꢂC; IR (potassium bromide):
1
1704, 1628, 1599, 1561, 1236 cmꢁ1; H NMR (deuteriochloro-
form): d 3.70 (d, J ¼ 1.2 Hz, 2H), 3.80 (s, 3H), 3.85 (s, 3H),
6.75–6.82 (m, 2H), 7.18–7.21 (m, 1H), 7.53 (s, 1H); 13C NMR
(deuteriochloroform): d 24.2, 52.2, 55.4, 115.6, 116.3, 124.0,
124.5, 128.0, 132.3, 137.4, 157.8, 166.3; ms: m/z (%) 236
(Mþ, 86), 235 (25), 221 (100), 205 (4), 177 (20), 134 (12).
3-Cyano-2H-thiochromene (4k). [8] Yellow solid; yield:
25%; mp: 87–88ꢂC; IR (potassium bromide): 2208, 1616,
1
1632, 1461, 1369, 1235, 1208 cmꢁ1; H NMR (deuteriochloro-
1
1461, 1436, 1415, 1254 cmꢁ1; H NMR (deuteriochloroform):
form): d 2.48 (s, 3H), 3.71 (d, J ¼ 0.9 Hz, 2H), 7.18–7.27 (m,
3H), 7.33 (s, 1H); 13C NMR (deuteriochloroform): d 22.8,
25.4, 128.3, 130.1, 130.2, 131.2, 132.7, 132.8, 133.3, 136.6,
196.5; ms: m/z (%) 226 (Mþ, 28), 225 (27), 224 (Mþ, 78), 223
(27), 183 (38), 181 (100), 146 (12), 145 (18). Anal. Calcd. for
C11H9ClOS: C, 58.80; H, 4.04; S, 14.27. Found: C, 58.67; H,
3.87; S, 14.03.
d 3.58 (d, J ¼ 0.9 Hz, 2H), 7.15–7.26 (m, 5H); 13C NMR
(deuteriochloroform):
d 25.8, 103.7, 118.3, 126.3, 127.5,
130.06, 130.11, 130.9, 132.7, 142.2; ms: m/z (%) 173 (Mþ,
64), 172 (100), 147 (7), 146 (4), 145 (10).
3-Cyano-8-chloro-2H-thiochromene (4l). Yellow solid;
yield: 18%; mp: 116–117ꢂC; IR (potassium bromide): 2202,
1620, 1442, 1413, 1282 cmꢁ1; H NMR (deuteriochloroform):
3-Acetyl-6-nitro-2H-thiochromene (4d). [3(a)] Yellow solid;
yield: 8%; mp: 143–144ꢂC; IR (potassium bromide): 1662,
1
d 3.64 (d, J ¼ 1.2 Hz, 2H), 7.10–7.18 (m, 3H), 7.32–7.35 (m,
1H); 13C NMR (deuteriochloroform): d 26.0, 104.1, 117.9,
126.2, 128.4, 131.5, 131.7, 132.1, 132.8, 141.9; ms: m/z (%)
209 (Mþ, 22), 208 (38), 207 (Mþ, 59), 206 (51), 181 (5), 172
(100). Anal. Calcd. for C10H6ClNS: C, 57.83; H, 2.91; N,
6.74; S, 15.44. Found: C, 57.91; H, 2.70; N, 6.56; S, 15.28.
1
1598, 1558, 1510, 1336, 1226 cmꢁ1; H NMR (deuteriochloro-
form): d 2.52 (s, 3H), 3.81 (d, J ¼ 0.9 Hz, 2H), 7.42 (d, J ¼
8.5 Hz, 1H), 7.45 (s, 1H), 8.06 (dd, J ¼ 8.5 Hz and 2.4 Hz,
1H), 8.15 (d, J ¼ 2.4 Hz, 1H); 13C NMR (deuteriochloroform):
d 22.8, 25.4, 124.6, 125.0, 127.5, 131.6, 132.6, 135.9, 144.4,
145.5, 196.2; ms: m/z (%) 235 (Mþ, 68), 234 (8), 192 (90),
176 (19), 146 (100).
Acknowledgments. This study was supported in part by Brain
Korea 21 program, Republic of Korea.
3-Acetyl-6-methoxy-2H-thiochromene (4e). Yellow solid;
yield: 32%; mp: 100–102ꢂC; IR (potassium bromide): 1653,
1
1620, 1485, 1459, 1316, 1247, 1223 cmꢁ1; H NMR (deuterio-
chloroform): d 2.48 (s, 3H), 3.69 (d, J ¼ 0.9 Hz, 2H), 3.81 (s,
3H), 6.82–6.85 (m, 2H), 7.21–7.24 (m, 1H), 7.37 (s, 1H); 13C
NMR (deuteriochloroform): d 23.1, 25.4, 55.5, 115.7, 116.7,
125.5, 128.2, 132.4, 132.7, 137.9, 157.8, 196.8; ms: m/z (%)
220 (Mþ, 87), 219 (33), 177 (100), 162 (8), 134 (33). Anal.
Calcd. for C12H12O2S: C, 65.43; H, 5.49; S, 14.56. Found: C,
65.62; H, 5.47; S, 14.31.
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3-Carbomethoxy-2H-thiochromene (4f). [8,9] Yellow solid;
yield: 69%; mp: 34–35ꢂC; IR (potassium bromide): 1704,
1
1628, 1586, 1552, 1438, 1239 cmꢁ1; H NMR (deuteriochloro-
form): d 3.73 (d, J ¼ 0.9 Hz, 2H), 3.84 (s, 3H), 7.09–7.28 (m,
4H), 7.54 (s, 1H); 13C NMR (deuteriochloroform): d 24.0,
52.2, 123.0, 125.8, 127.1, 130.2, 130.6, 131.3, 134.0, 137.4,
166.4; ms: m/z (%) 206 (Mþ, 73), 205 (62), 191 (100), 175
(8), 147 (35).
3-Carbomethoxy-8-chloro-2H-thiochromene (4g). [9] Yel-
low solid; yield: 70%; mp: 94–95ꢂC; IR (potassium bromide):
1
1699, 1641, 1436, 1415, 1247, 1220 cmꢁ1; H NMR (deuterio-
chloroform): d 3.78 (d, J ¼ 1.2 Hz, 2H), 3.86 (s, 3H), 7.06 (t,
J ¼ 7.6 Hz, 1H), 7.15 (dd, J ¼ 7.6 and 1.5 Hz, 1H), 7.29 (dd,
J ¼ 7.6 and 1.5 Hz, 1H), 7.53 (s, 1H); 13C NMR (deuterio-
chloroform): d 24.2, 52.3, 123.2, 125.7, 128.8, 130.9, 131.7,
132.8, 133.9, 137.0, 166.0; ms: m/z (%) 242 (Mþ, 21), 241
(23), 240 (Mþ, 56), 239 (31), 227 (39), 225 (100), 183 (12),
181 (34).
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September 2009 One-Pot Synthesis of 2H-Thiochromenes via TiCl4-Promoted Reaction of 2-tert-
Butylthiobenzaldehydes with Activated Alkenes
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