Synthesis of 2-mercaptobenzaldehyde, 2-mercaptocyclohex-1- enecarboxaldehydes and 3-mercaptoacrylaldehydes

Article abstract of DOI:10.1002/cjoc.201200433

A novel one-pot approach for the preparation of 2-mercaptobenzaldehyde, 2-mercaptocyclohex-1-enecarboxaldehydes and 3-mercaptoacrylaldehydes [(Z)-3-mercapto-2-methyl-3-phenylacrylaldehyde, 3-mercapto-3-(o-tolyl) acrylaldehyde)] starting from ortho-bromobenzaldehyde, 2-chlorocyclohex-1- enecarbaldehydes, (Z)-3-chloro-2-methyl-3-phenylacrylaldehyde and 3-chloro-3-(o-tolyl)acrylaldehyde is reported. The reaction of sulfur with the Grignard reagent of the acetal for the protection of the aldehyde group affords the title compounds through hydrolysis with dilute hydrochloric acid in high yields. One-pot synthesis of 2-mercaptobenzaldehyde, 2-mercaptocyclohex-1- enecarboxaldehydes and 3-mercaptoacrylaldehydes was developed by the reaction of the Grignard reagent with sulfur. The novel procedure showed high yields of the desired products, easy work-up, short reaction time, no catalyst, no hazardous phosphine ligands, no strong and foul smell sulfur-containing reagents, no environmental problem and mild reaction conditions in comparison with other methods, which are the strong points of the present procedure. Copyright

Full text of DOI:10.1002/cjoc.201200433

FULL PAPER
DOI: 10.1002/cjoc.201200433
Synthesis of 2-Mercaptobenzaldehyde, 2-Mercaptocyclohex-
1-enecarboxaldehydes and 3-Mercaptoacrylaldehydes
Niu, Qingfen(牛庆芬)
Sun, Hongjian(孙宏建)
Xu, Xiaofeng(徐晓峰)
Li, Xiaoyan*(李晓燕)
School of Chemistry and Chemical Engineering, Shandong University, Jinan, Shandong 250100, China
A novel one-pot approach for the preparation of 2-mercaptobenzaldehyde, 2-mercaptocyclohex-1-enecarboxal-
dehydes and 3-mercaptoacrylaldehydes [(Z)-3-mercapto-2-methyl-3-phenylacrylaldehyde, 3-mercapto-3-(o-tolyl)-
acrylaldehyde)] starting from ortho-bromobenzaldehyde, 2-chlorocyclohex-1-enecarbaldehydes, (Z)-3-chloro-2-
methyl-3-phenylacrylaldehyde and 3-chloro-3-(o-tolyl)acrylaldehyde is reported. The reaction of sulfur with the
Grignard reagent of the acetal for the protection of the aldehyde group affords the title compounds through hydroly-
sis with dilute hydrochloric acid in high yields.
Keywords
2-mercaptobenzaldehyde, 2-mercaptocyclohex-1-enecarboxaldehydes, 3-mercaptoacrylaldehydes,
Grignard reagent, sulfur, aldehyde
Introduction
benzaldehydes from substituted aldehydes by successive
action of n-butyllithium, sulfur and hydrochloric acid
with yields of 72%—94% arriving at moderate levels of
purities (79%—94%). Due to lack of crystallization the
crude products proved difficult to purify.[30] Pariza re-
leased a complicated process for the synthesis of
2-mercaptobenzaldehydes from ortho-halogeno benzal-
Sulfur-containing heterocycles have a wide range of
biological activities which usually exist in proteins, en-
zyme, coenzyme, and so on. The S-ligation molecules
and pharmaceuticals such as thiochromanes[1-9] are re-
ported to exhibit anti-inflammatory, anti-bacteria, anti-
psychiatric, anti-hyperplasia, anti-cancer, and analgesic
activities.[10-15] The synthesis of the substituted thio-
chromanes can be conducted by using a cupreine-cata-
lyzed reaction from Zhao’s group[16,17] or by using an
enantioselective domino-Michael aldol reaction from
Wang’s group.[18-20] In all these reactions thiosalicylal-
dehydes serve as starting materials.
In organometallics, the chemistry of thiosalicylalde-
hydes attracts much attention of researchers through the
replacement of the oxygen atom in salicylaldehydes by
a sulfur atom which has good coordination abilities with
several kinds of transition metal centers which have
been widely investigated in syntheses, mechanisms, and
catalytics.[21-27]
dehydes[31] similar to that of a Japanese patent.[32]
A
Chinese patent gives a preparation of 5-nitro-2-mer-
captobenzaldehyde from 5-nitro-salicyl-aldehyde which
is not reproducable.[33] However, these syntheses are
obviously accompanied by poor yields, strict operations,
vigorous reaction conditions, long reaction time, unde-
sired side products, difficult purifications and tedious
work-up. Furthermore, some of these methods are asso-
ciated with the use of hazardous phosphine ligands, the
use of sulfur-containing reagents such as benzenethiols
which generally have such a strong, foul smell that
working with them can be extremely unpleasant and in
some cases the poor reproducibility of the yields.
The literature methods for the preparation of
2-mercaptobenzaldehyde are shown in Scheme 1.
A derivative of 2-mercaptobenzaldehyde was pre-
pared from the corresponding salicylaldehyde in three
steps with a total yield of about 40%.[28] 2-Mercapto-
benzaldehydes could be obtained in yields of 37%—
43% by trapping organolithium intermediates, formed
by directed ortho-lithiation of the precursors.[29] Pardoe
reported a synthetic method for substituted 2-mercapto-
2-Mercaptocyclohex-1-enecarbaldehyde was pre-
pared by treating 2-cholrocyclohex-1-enecarbaldehyde
with NaSH or from 2-thiocyanatocyclohex-1-enecarbal-
dehyde in the yield of 40%—65%.[34] (Z)-3-Mercapto-
2-methyl-3-phenylacrylaldehyde was prepared by treat-
ing (Z)-3-chloro-2-methyl-3-phenylacrylaldehyde with
Na2S which is not reproducible.[35]
As a consequence, the introduction of new methods
and/or further work on technical improvements to
*
E-mail: xli63@sdu.edu.cn; Fax: 0086-0531-88564464
Received May 3, 2012; accepted June 3, 2012; published online XXXX, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.20120433 or from the author.
Chin. J. Chem. 2012, XX, 1—6 © 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Niu et al.
FULL PAPER
Scheme 1 Literature methods for preparation of 2-mercaptobenzaldehyde
SH
1. n-BuLi, hexane, TMEDA, -78 oC
2. DMF 3. H3O+
1. DABCO, DMF, 2 h, 55 - 60 oC
2. Me2NC(=S)Cl, PhMe, reflux,
overnight
Red-Al, THF, benene
SH
CHO
OH
CON(Me)Ph
3. NaOH, MeOH
4. HCl, H2O, 4 - 5 h, reflux
CHO
SH
1. Na2S, S, H2O, 1 h, 55 oC
2. EtOH, 4 h, 55 oC
1. n-BuLi, TMEDA,
THF, -78 oC
CHO
Cl
CHO
2. S8 3. HCl, H2O
3. NaOH, H2O, 2 h, 0 oC
4. HCl, H2O, 0 oC, pH=4
1. LiAlH4, Et2O-THF 2. PCC, CH2Cl2
3. Ph3P, MeOH, H2O, DMF, r.t.; reflux
COOH
SH
overcome the limitations is still an important experi-
mental challenge. Herein, we have presented our new
strategy, a novel procedure for the first time that the
reaction of sulfur with the Grignard reagent of the acetal
for the protection of the aldehyde group affords the title
compounds through hydrolysis with dilute hydrochloric
acid in high yields.
tion anhydrous ethylene glycol (12.4 g, 0.20 mol) and
p-toluenesulfonic acid (258 mg, 1.50 mmol). The re-
sulting solution mixture was refluxed until the theoreti-
cal yield of water had been collected in a Dean-Stark
trap. After 6 h the mixture was cooled, washed with
10% aqueous sodium hydroxide (30 mL×2), followed
by deionized water (30 mL×2), brine (30 mL×1) and
the organic layer was dried over anhydrous MgSO4. The
solvent was removed in vacuo to give 24.4 g (86%) of a
colorless oil, 2-(2-chlorocyolohex-1-en-1-yl)-1,3-dioxo-
lane (2b). m.p. 8.2—9.0 ℃; b.p. 78 ℃/9 mbar; IR
(KBr) ν: 1668, 1442, 1389, 1216, 1127, 1057, 952, 819
Experimental
General procedures and materials
Standard vacuum techniques were used in manipula-
tions of volatile and air-sensitive materials. Infrared
spectra (4000—400 cm－1), as obtained from Nujol
mulls between KBr disks, were recorded on an ALPHA
－
1
cm ; 1H NMR (300 MHz, 295 K, C6D6) δ: 6.08 (s, 1H),
3.61—3.79 (m, 2H), 3.45—3.58 (m, 2H), 2.18—2.24
(m, 4H), 1.33—1.43 (m, 4H); 13C NMR (75 MHz, 297
K, C6D6) δ: 132.8, 130.7, 101.4, 65.1, 34.3, 23.5, 21.5;
HRMS calcld for C9H13ClO2: 189.0638, found
189.0677.
1
FT-IR Spectrometer. H and 13C NMR spectra were re-
corded on a Bruker Avance 300 spectrometer. Melting
points were measured in capillaries and are uncorrected.
MS were obtained from Agilent 6510 Accurate-Mass
Q-TOF LC/MS system.
2-(2-Chloro-5-methylcyclohex-1-en-1-yl)-1,3-di-
oxolane (2c) In a 250 mL one-necked round-bottomed
flask, a solution of 2-chloro-5-methylcyclohex-1-ene-
carbaldehyde (1c) (23.8 g, 0.15 mol) in 40 mL of
toluene was added in one portion anhydrous ethylene
glycol (12.4 g, 0.20 mol) and p-toluenesulfonic acid
(258 mg, 1.50 mmol). The resulting solution mixture
was refluxed until the theoretical yield of water had
been collected in a Dean-Stark trap. After 6.5 h, the
mixture was cooled, washed with 10% aqueous sodium
hydroxide (30 mL×2), followed by deionized water (30
mL×2), brine (30 mL×1) and the organic layer was
dried over anhydrous MgSO4. The solvent was removed
in vacuo to give 25.5 g (84%) of a colorless liquid, 2-(2-
chloro-5-methylcyclohex-1-en-1-yl)-1,3-dioxolane (2c).
2-Chlorocyclohex-1-enecarbaldehyde[36] (1b) from
cyclohexanone, 2-chloro-5-methylcyclohex-1-enecarb-
aldehyde[37] (1c) from 4-methylcyclohexanone, 5-(tert-
butyl)-2-chlorocyclohex-1-enecarbaldehyde[38]
(1d)
from 4-(tert-butyl)mcyclohexanone, (Z)-3-chloro-2-
methyl-3-phenylacrylaldehyde[39] (1e) from propiophe-
none and 3-chloro-3-(o-tolyl)acrylaldehyde[40] (1f) from
1-(o-tolyl)methanone were synthesized according to the
literature.
2-(2-Chlorocyolohex-1-en-1-yl)-1,3-dioxolane (2b)
In a 250 mL one-necked round-bottomed flask, a solu-
tion of 2-chlorocyclohex-1-enecarbaldehyde (1b) (22.0
g, 0.15 mol) in 40 mL of toluene was added in one por-
2
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Chin. J. Chem. 2012, XX, 1—6

Synthesis of 2-Mercaptobenzaldehyde, 2-Mercaptocyclohex-1-enecarboxaldehyde
m.p. 18.5—19.0 ℃; b.p. 106 ℃/14 mbar; IR (KBr) ν:
2951, 2924, 1666, 1455, 1433, 1382, 1347, 1304, 1214,
1126, 1050, 1028, 1012, 946, 905, 877, 799, 711, 640,
128.1, 129.0, 101.3, 64.7, 13.1; HRMS calcd for
C12H13ClO2: 225.0638, found 225.0690.
2-(2-Chloro-2-(o-tolyl)vinyl)-1,3-dioxolane
(2f)
－
554 cm ; 1H NMR (300 MHz, C6D6, 295 K) δ: 6.07 (s,
1H), 3.48—3.54 (m, 2H), 3.32—3.47 (m, 2H), 2.38—
2.43 (m, 1H), 2.14—2.37 (m, 2H), 1.79—1.88 (m, 1H),
1.20—1.40 (m, 2H), 0.89—0.99 (m, 1H), 0.75 (d, J＝
6.6 Hz, 3H, CH3); 13C NMR (75 MHz, C6D6, 297 K) δ:
132.2, 129.5, 100.9, 64.6, 33.9, 31.9, 30.8, 27.2, 20.5;
HRMS calcld for C10H15ClO2: 203.0794, found
203.0838.
1
In a 250 mL one-necked round-bottomed flask, a solu-
tion of 3-chloro-3-(o-tolyl)acrylaldehyde (1f) (27.1 g,
0.15 mol) in 40 mL of toluene was added in one portion
anhydrous ethylene glycol (12.4 g, 0.20 mol) and
p-toluenesulfonic acid (258 mg, 1.50 mmol). The re-
sulting solution mixture was refluxed until the theoreti-
cal yield of water had been collected in a Dean-Stark
trap. After 5 h, the mixture was cooled, washed with
10% aqueous sodium hydroxide (30 mL×2), followed
by deionized water (30 mL×2), brine (30 mL×1) and
the organic layer was dried over anhydrous MgSO4. The
solvent was removed in vacuo and the residue distilled
(b.p.: 168 ℃/19 mbar) to give the product (30.0 g, 89%)
2-(5-(tert-Butyl)-2-chlorocyclohex-1-en-1-yl)-1,3-
dioxolane (2d) In a 250 mL one-necked round-
bottomed flask, a solution of 5-(tert-butyl)-2-chlorocy-
clohex-1-enecarbaldehyde (1d) (30.0 g, 0.15 mol) in 40
mL of toluene was added in one portion anhydrous
ethylene glycol (12.4 g, 0.20 mol) and p-toluenesulfonic
acid (258 mg, 1.50 mmol). The resulting solution mix-
ture was refluxed until the theoretical yield of water had
been collected in a Dean-Stark trap. After 7 h, the mix-
ture was cooled, washed with 10% aqueous sodium hy-
droxide (30 mL×2), followed by deionized water (30
mL×2), brine (30 mL×1) and the organic layer was
dried over anhydrous MgSO4. The solvent was removed
in vacuo to give 30.4 g (83%) of a colorless liquid, 2-
(5-(tert-butyl)-2-chlorocyclohex-1-en-1-yl)-1,3-dioxo-
lane (2d). m.p. 23.8—25 ℃; b.p. 125 ℃/12 mbar; IR
(KBr) ν: 2956, 1714, 1675, 1626, 1469, 1388, 1305,
1219, 1130, 1082, 1023, 954, 889, 822, 766, 719, 549,
1
as a pale-yellow oil as a 22∶78 mixture (by H NMR
analysis) of E/Z isomers, 2-(2-chloro-2-(o-tolyl)vinyl)-
1,3-dioxolane (2f). b.p.: 168 ℃/19 mbar; IR (KBr) ν:
2955, 2886, 1656, 1599, 1485, 1456, 1386, 1285, 1228,
1148, 1071, 1027, 944, 876, 762, 726, 665, 606, 520,
－
1
449 cm ; 1H NMR (300 MHz, C6D6, 295 K) E isomer δ:
7.31 (d, J＝7.5 Hz, 1H), 7.08—7.00 (m, 3H), 6.29 (q,
J＝4 Hz, 1H), 5.10 (q, J＝6 Hz, 1H), 3.66 (d, J＝3 Hz,
1H), 3.60 (d, J＝2.1 Hz, 1H), 3.21 (d, J＝7.2 Hz, 2H),
2.41 (s, 3H, CH3); Z isomer δ: 7.19—7.24 (m, 1H), 6.93
—7.03 (m, 3H), 6.08 (q, J＝6.8 Hz, 1H), 5.89 (q, J＝
6.8 Hz, 1H), 3.59—3.66 (m, 2H), 3.45 (d, J＝2.1 Hz,
2H), 2.32 (s, 3H, CH3); 13C NMR (75 MHz, C6D6, 297
K) δ: 139.1, 138.1, 136.4, 130.9, 129.6, 129.5, 128.1,
126.3, 100.9, 65.3, 19.9; HRMS calcld for C12H13ClO2:
225.0638, found 225.0670.
－
1
439 cm ; 1H NMR (300 MHz, C6D6, 295 K) δ: 6.07 (s,
1H), 3.49—3.58 (m, 2H), 3.34—3.43 (m, 2H), 2.40—
2.47 (m, 1H), 1.95—2.19 (m, 3H), 1.35—1.39 (m, 1H),
0.86—1.06 (m, 2H) 0.73 (s, 9H, 3CH3); 13C NMR (75
MHz, C6D6, 297 K) δ: 132.4, 129.8, 101.1, 64.5, 42.4,
35.0, 31.3, 26.5, 24.5, 24.2; HRMS calcld for
C13H21ClO2: 245.1264, found 245.1324.
2-Mercaptobenzaldehyde (5a) A 500 mL three-
necked flask was charged with magnesium (2.6 g, 0.11
mol) and 100 mL of anhydrous THF. 2-(2-bromophe-
nyl)-1,3-dioxolane (2a)[41] (22.9 g, 0.10 mol) was added
dropwise at 0 ℃. The mixture was allowed to warm to
ambient temperature and refluxed for 1 h. At 0 ℃ sub-
limed sulfur (3.2 g, 0.10 mol) was added to the mixture.
The solution was stirred overnight at room temperature.
1 mol/L of HCl was used to quench the reaction until
the mixture was acidic. After refluxing for 2 h the mix-
ture was extracted with diethyl ether (50 mL×3) and
the organic phase was dried over anhydrous Na2SO4.
After filtration and concentration to 50 mL product 5a
was obtained at －30 ℃ as bright yellow solid (12.6 g,
yield 91%). m.p.: 43—44 ℃; IR (KBr) ν: 1690 (s, C＝
(Z)-2-(1-Chloro-1-phenylprop-1-en-2-yl)-1,3-dioxo-
lane (2e) In a 250 mL one-necked round-bottomed
flask, a solution of (Z)-3-chloro-2-methyl-3-phenyl-
acrylaldehyde (1e) (27.1 g, 0.15 mol) in 40 mL of tolu-
ene was added in one portion anhydrous ethylene glycol
(12.4 g, 0.20 mol) and p-toluenesulfonic acid (258 mg,
1.50 mmol). The resulting solution mixture was re-
fluxed until the theoretical yield of water had been col-
lected in a Dean-Stark trap. After 5.5 h, the mixture was
cooled, washed with 10% aqueous sodium hydroxide
(30 mL×2), followed by deionized water (30 mL×2),
brine (30 mL×1) and the organic layer was dried over
anhydrous MgSO4. The solvent was removed in vacuo
to give 29.3 g (87%) of light yellow liquid, (Z)-2-(1-
chloro-1-phenylprop-1-en-2-yl)-1,3-dioxolane (2e). m.p.
6.8—7.3 ℃; b.p. 110 ℃/16 mbar; IR (KBr) ν: 2954,
2887, 1673, 1650, 1487, 1442, 1390, 1256, 1216, 1100,
－
1
O), 2561 (m, S—H) cm ; 1H NMR (300 MHz, CDCl3,
295 K) δ: 10.05 (s, 1H), 7.72 (dd, J＝7.2, 1.2 Hz, 1H),
7.27—7.32 (m, 2H), 7.36—7.42 (m, 1H), 5.52 (s, 1H,
SH); 13C NMR (75 MHz, CDCl3, 297 K) δ: 192.8, 137.9,
136.1, 133.4, 131.3, 131.1, 125.0.
2-Mercaptocyclohex-1-enecarbaldehyde[34] (5b)
A 500 mL three-necked round-bottomed flask was
charged with magnesium (1.6 g, 0.066 mol) and 100 mL
of anhydrous THF. 2-(2-Chlorocyclohex-1-en-1-yl)-1,3-
dioxolane (2b) (11.9 g, 0.063 mol) was added dropwise
at 0 ℃. The mixture was allowed to warm to ambient
－
1
1027, 993, 945, 894, 764, 700, 625, 517 cm ; 1H NMR
(300 MHz, C6D6, 295 K) δ: 7.51 (q, J＝9 Hz, 2H), 7.09
(q, J＝13.5 Hz, 3H), 5.40 (s, 1H), 3.53 (q, J＝7.5 Hz,
2H), 3.24 (t, J＝6 Hz, 2H), 2.21 (s, 3H, CH3); 13C NMR
(75 MHz, C6D6, 297 K) δ:137.4, 134.4, 131.8, 128.5,
Chin. J. Chem. 2012, XX, 1—6
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3

Niu et al.
FULL PAPER
temperature and refluxed for 2 h. At 0 ℃ sublimed
sulfur (2.0 g, 0.063 mol) was added to the mixture and
stirred for 1 h. The solution was stirred overnight at
room temperature. At 0 ℃ 1 mol/L of HCl was used to
quench the reaction, then the solution was stirred for 2 h
until the mixture was acidic. Then the mixture was ex-
tracted with diethyl ether (50 mL×3) and the organic
phase was dried over anhydrous Na2SO4. After filtration
and concentration 2-mercaptocyclohex-1-enecarbalde-
hyde (5b) was obtained at －20 ℃ as yellow needle
m.p.: 14.6—16.8 ℃; IR (KBr) ν: 3337 (w, C＝O(H)),
－
1
1
1678 (s, C＝O), 1625 (s, C＝C) cm ; H NMR (300
MHz, CDCl3, 295 K) δ: 10.18 (s, 1H), 2.60 (q, J＝22.1
Hz, 2H), 1.18—1.95 (m, 2H), 0.91—1.42 (m, 3H), 0.91
(s, 9H, 3×CH3), 0.88 (s, 1H, SH); 13C NMR (75 MHz,
CDCl3, 297 K) δ: 191.7, 151.7, 133.8, 43.4, 37.5, 32.7,
27.6, 25.8, 25.0; HRMS calcld for C11H18OS: 199.1112,
found 199.2176.
(Z)-3-Mercapto-2-methyl-3-phenylacrylaldehyde
(5e) A 500 mL three-necked flask was charged with
magnesium (2.6 g, 0.11 mol) and 100 mL of anhydrous
THF. (Z)-2-(1-Chloro-1-phenylprop-1-en-2-yl)-1,3-di-
oxolane (2e) (22.5 g, 0.10 mol) was added dropwise at 0
℃. The mixture was allowed to warm to ambient tem-
perature and refluxed for 4 h. At 0 ℃ sublimed sulfur
(3.2 g, 0.10 mol) was added to the mixture. The solution
was stirred overnight at room temperature. 1 mol/L of
HCl was used to quench the reaction until the mixture
was acidic. After refluxing for 2 h the mixture was ex-
tracted with diethyl ether (50 mL×3) and the organic
phase was dried over anhydrous Na2SO4. The solvent
was removed in vacuo and the yellow oil was purified
by chromatography using petroleum ether/ethyl acetate
(25∶1) as eluent to afford the product (Z)-3-mercapto-
2-methyl-3-phenylacrylaldehyde (5e) (15.3 g, yield 86%)
crystal (8.6 g, yield 96%). m.p.: 7.8—8.2 ℃; IR (KBr) ν:
－
1
1
1679 (s, C＝O), 1623 (s, C＝C) cm ; H NMR (300
MHz, 295 K, CDCl3) δ: 10.20 (s, 1H), 2.57 (t, J＝6, 3
Hz, 2H), 2.28 (t, J＝6 Hz, 2H), 1.75 (t, J＝12, 3 Hz,
2H), 1.66 (t, J＝12, 3 Hz, 2H), 1.58 (s, 1H, SH); 13C
NMR (75 MHz, CDCl3, 297 K) δ: 190.5, 150.8, 132.9,
35.3, 23.2, 22.7, 20.5; HRMS calcld for C7H10OS:
143.0486, found 143.0629.
2-Mercapto-5-methylcyclohex-1-enecarbaldehyde
(5c) A 500 mL three-necked flask was charged with
magnesium (2.6 g, 0.11 mol) and 100 mL of anhydrous
THF. 2-(2-Chloro-5-methylcyclohex-1-en-1-yl)-1,3-di-
oxolane 2c (20.3 g, 0.10 mol) was added dropwise at 0
℃. The mixture was allowed to warm to ambient tem-
perature and refluxed for 2 h. At 0 ℃ sublimed sulfur
(3.2 g, 0.10 mol) was added to the mixture. The solution
was stirred overnight at room temperature. 1 mol/L of
HCl was used to quench the reaction until the mixture
was acidic. After refluxing for 2 h the mixture was ex-
tracted with diethyl ether (50 mL×3) and the organic
phase was dried over anhydrous Na2SO4. After filtration
and concentration 2-mercapto-5-methylcyclohex-1-ene-
carbaldehyde (5c) was obtained at －20 ℃ as yellow
tidy crystal (13.8 g, yield 88%). m.p.: 13.8—15.0 ℃; IR
as a pale-yellow oil. IR (KBr) ν: 3329 (w, C＝O(H)),
－
1
1
1674 (s, C＝O), 1608 (s, C＝C) cm ; H NMR (300
MHz, CDCl3, 295 K) δ: 9.48 (s, 1H), 7.48—7.40 (m,
5H), 2.09 (s, 3H, CH3) 1.85 (s, 1H, SH); 13C NMR (75
MHz, CDCl3, 297 K) δ: 198.8, 153.9, 153.8, 135.3,
129.9, 129.6, 127.9, 12.8; HRMS calcld for C10H10OS,
179.0486, found 179.0681.
3-Mercapto-3-(o-tolyl)acrylaldehyde (5f) A 500
mL three-necked flask was charged with magnesium
(2.6 g, 0.11 mol) and 100 mL of anhydrous THF.
2-(2-Chloro-2-(o-tolyl)vinyl)-1,3-dioxolane (2f) (22.5 g,
0.10 mol) was added dropwise at 0 ℃. The mixture
was allowed to warm to ambient temperature and re-
fluxed for 4 h. At 0 ℃ sublimed sulfur (3.2 g, 0.10 mol)
was added to the mixture. The solution was stirred
overnight at room temperature. 1 mol/L of HCl was
used to quench the reaction until the mixture was acidic.
After refluxing for 2 h the mixture was extracted with
diethyl ether (50 mL×3) and the organic phase was
dried over anhydrous Na2SO4. The solvent was removed
in vacuo and the yellow oil was purified by chromatog-
raphy using petroleum ether/ethyl acetate (25∶1) as
eluent to afford the product (15.8 g, yield 89%) as a
(KBr) ν: 3334 (w, C＝O(H)), 1677 (s, C＝O), 1622 (s,
－
1
1
C＝C) cm ; H NMR (300 MHz, CDCl3, 295 K) δ:
10.19 (s, 1H), 2.60—2.66 (m, 2H), 2.50—2.59 (m, 1H),
1.69—1.85 (m, 3H), 1.39—1.43 (m, 1H), 1.25 (s, 1H,
SH), 1.02 (d, J＝6 Hz, 3H, CH3); 13C NMR (75 MHz,
CDCl3, 297 K) δ: 191.6, 151.6, 133.4, 36.3, 32.2, 31.6,
27.9, 21.4; HRMS calcld for C8H12OS: 157.0642, found
157.0866.
5-(tert-Butyl)-2-mercaptocyclohex-1-enecarbalde-
hyde (5d) A 500 mL three-necked flask was charged
with magnesium (2.6 g, 0.11 mol) and 100 mL of anhy-
drous THF. 2-(5-(tert-Butyl)-2-chlorocyclohex-1-en-1-
yl)-1,3-dioxolane (2d) (24.5 g, 0.10 mol) was added
dropwise at 0 ℃. The mixture was allowed to warm to
ambient temperature and refluxed for 2 h. At 0 ℃ sub-
limed sulfur (3.2 g, 0.10 mol) was added to the mixture.
The solution was stirred overnight at room temperature.
1 mol/L of HCl was used to quench the reaction until
the mixture was acidic. After refluxing for 2 h the mix-
ture was extracted with diethyl ether (50 mL×3) and
the organic phase was dried over anhydrous Na2SO4.
After filtration and concentration 5-(tert-butyl)-2-mer-
captocyclohex-1-enecarbaldehyd-e (5d) was obtained at
－20 ℃ as yellow tidy crystal (17.2 g, yield 87%).
1
pale-yellow oil as a 40∶60 mixture (by H NMR
analysis) of E/Z isomers. IR (KBr) ν: 3342 (w, C＝
－
1
1
O(H)), 1681 (s, C＝O), 1613 (s, C＝C) cm ; H NMR
(300 MHz, CDCl3, 295 K ) E isomer δ: 10.20 (d, J＝9
Hz, 1H), 7.35—7.25 (m, 4H), 6.25 (d, J＝6 Hz, 1H),
2.42 (s, 3H, CH3),1.59 (s, 1H, SH); Z isomer δ: 9.21 (d,
J＝9 Hz, 1H), 7.35—7.25 (m, 4H), 6.55 (d, J＝9 Hz,
13
1H), 2.38 (s, 3H, CH3), 1.25 (s, 1H, SH); C NMR (75
MHz, CDCl3, 297 K) E isomer δ: 190.3, 158.4, 136.6,
135.0, 132.0, 131.3, 130.9, 129.9, 126.5, 19.9; Z isomer
4
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Chin. J. Chem. 2012, XX, 1—6

Synthesis of 2-Mercaptobenzaldehyde, 2-Mercaptocyclohex-1-enecarboxaldehyde
δ: 191.4, 153.0, 137.8, 135.1, 131.5, 130.8, 129.2, 128.9,
126.6, 20.5; HRMS calcld for C10H10OS: 179.0486,
found 179.0683.
reaction whereby 5a can be obtained in a reproducible
high yield of 91% (for 5b: 96%, 5c: 88%, 5d: 87%, 5e:
86%, 5f: 89%). As the second improvement no column
chromatography for the purification of the crude prod-
ucts as described in the literature is necessary because
the pure product 5a, 5b, 5c or 5d is conveniently ob-
tained as bright yellow solid by crystallization from di-
ethyl ether while this procedure made hardly damage to
the environment and easy work-up. Furthermore, we
have been successfully involved in a program aimed at
the use of odorless starting materials which can substi-
tute for malodorous reagents such as benzenethiol, and
other sulfur-containing reagents, however, this feature
has greatly improved the environmental working condi-
tions.
Results and Discussion
Our strategy for developing a convenient one-pot
synthesis of 2-mercaptobenzaldehyde 5a, 2-mercapto-
cyclohex-1-enecarbaldehyde 5b, 2-mercapto-5-methyl-
cyclohex-1-enecarbaldehyde 5c, 5-(tert-butyl)-2-mer-
captocyclohex-1-enecarbaldehyde 5d, (Z)-3-mercapto-
2-methyl-3-phenylacrylaldehyde 5e and 3-mercapto-3-
(o-tolyl)acrylaldehyde 5f can be illustrated in Scheme 2.
The corresponding novel intermediates (2b—2f) and
the title compounds (5a—5f) were isolated in high
yields (Tables 1 and 2).
At first the aldehyde group of ortho-bromobenzal-
dehyde 1a, 2-chlorocyclohex-1-enecarbaldehyde 1b, 2-
chloro-5-methylcyclohex-1-enecarbaldehyde 1c, 5-(tert-
butyl)-2-chlorocyclohex-1-enecarbaldehyde 1d, (Z)-3-
chloro-2-methyl-3-phenylacrylaldehyde 1e or 3-chloro-
3-(o-tolyl)acrylaldehyde 1f is protected from the attack
of the basic Grignard reagent by conversion to the acetal
2 with p-toluenesulfonic acid (PTSA) as catalyst.[13]
Acetal 2 transforms to the Grignard compound 3 in THF.
The reaction of Grignard reagent 3 with sulfur gives rise
to the magnesium halide 4. The acetal and the SMgX
groups of compound 4 can be simultaneously hydro-
lyzed by treatment with acid to form the corresponding
expected compounds 5a, 5b, 5c, 5d, 5e and 5f. In order
to get high yields in this acidification refluxing for at
least 2 h is necessary until the acetal was completely
hydrolyzed. Comparing with the literature methods,
however, there are several remarkable advantages of
this novel method. First, the transformation from the
acetal 2 to the end product 5 is a convenient one-pot
Table 1 Yields for novel intermediates 2b—2f
Novel intermediates 2b—2f
Yield of 2b—2f/%
2b
2c
2d
2e
2f
86
84
83
87
89
Table 2 Yields for the title compounds 2b—2f
Title compounds 5a—5f
Yield of 5a—5f/%
5a
5b
5c
5d
5e
5f
91
96
88
87
86
89
Scheme 2 Our strategy for the synthetic route
O
O
R1
CHO
R1
PTSA, ethylene glycol
R1
O
O
Mg, THF
R2
X
toluene
R2
MgX
R2
X
1
3
2
S8, THF
ONE-POT
CHO
O
R1
R1
R2
O
HCl, THF
R2
SMgX
SH
5
4
R1
R2
H
H3C
=
(o-Me)C6H4
C6H5
Cl
Cl
Cl
Br
1a
2a
5a
Cl
Cl
X =
1
2
5
1e
1f
2f
1c
2c
5c
1b
2b
5b
1d
2d
5d
2e
5e
5f
Chin. J. Chem. 2012, XX, 1—6
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
5

Niu et al.
FULL PAPER
Marucci, G.; Carrieri, A.; Carotti, A.; Poggesi, E.; Leonardi, A.;
Melchiorre, C. J. Med. Chem. 2002, 45, 1633.
Conclusions
In summary, we have demonstrated the remarkable
effect of one-pot approach for the first time for the
preparation of 2-mercaptobenzaldehyde (5a), 2-mer-
captocyclohex-1-enecarbaldehydes (5b — 5d) and
3-mercaptoacrylaldehydes (5e—5f) starting from ortho-
bromobenzaldehyde (1a), the derivatives (1b—1d) of
2-chlorocyclohex-1-enecarbaldehydes, and the deriva-
tives (1e—1f) of acrylaldehydes. The reaction of sulfur
with the Grignard reagent of the acetal for the protection
of the aldehyde group afforded the title compounds in
high yields of 86%—96% through hydrolysis with di-
lute hydrochloric acid that is facile, efficient, and highly
selective. Surprisingly, the pure products 5a, 5b, 5c and
5d are conveniently isolated as bright yellow micro-
crystals. The novel procedure showed high yields of the
desired products, easy work-up, short reaction time, no
catalyst, no hazardous phosphine ligands, no strong and
foul smell sulfur-containing reagents, no environmental
problem and mild reaction conditions in comparison
with other methods, which are the strong points of the
present procedure.
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6
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Chin. J. Chem. 2012, XX, 1—6