Cyanuric chloride-catalyzed thioacetalization for organocatalytic synthesis of thioacetals

Article abstract of DOI:10.1080/10426507.2015.1054934

The thioacetalization of aromatic aldehydes has been realized with broad diversity in the presence of various thiols and thiophenols using cyanuric chloride as an organocatalyst.

Full text of DOI:10.1080/10426507.2015.1054934

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Cyanuric chloride-catalyzed thioacetalization for
organocatalytic synthesis of thioacetals
Yaqin Liu
To cite this article: Yaqin Liu (2015): Cyanuric chloride-catalyzed thioacetalization for
organocatalytic synthesis of thioacetals, Phosphorus, Sulfur, and Silicon and the Related
Elements, DOI: 10.1080/10426507.2015.1054934
To link to this article: http://dx.doi.org/10.1080/10426507.2015.1054934
Accepted online: 06 Oct 2015.
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Date: 09 October 2015, At: 23:34

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CYANURIC CHLORIDE-CATALYZED THIOACETALIZATION FOR
ORGANOCATALYTIC SYNTHESIS OF THIOACETALS
Yaqin Liu*,a
a Department of Chemistry, Zhejiang University, Hangzhou, 310027, P. R. China
Email: maldi@zju.edu.cn.
Abstract The thioacetalization of aromatic aldehydes has been realized with broad diversity in
the presence of various thiols and thiophenols using cyanuric chloride as an organocatalyst.
Key words: Thioacetalization, organocatalysis, cyanuric chloride
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INTRODUCTION
Thioacetalization is a fundamental transformation in organic synthesis. It is one of the most
useful strategies for the protection of carbonyl groups in linear synthesis owing to the stability of
thioacetals and thioketals in both conventional acidic and basic atmosphere as well as their easy
deprotection.1 More notably, thioacetals are important precursors of carbon anions which have
exhibited tremendous utilities in the construction of C-H and C-heteroatom bonds.2-4 Therefore,
catalytic methods towards efficient thioacetalization have been an issue of everlasting interest in
organic synthesis. During the past decade, a variety of different catalytic conditions and/or agents
have been developed for practical thioacetalization transformation. The typical examples such as
hafnium triflate,5 HCl,6 BF3·Et2O,7 AlCl3,8 InCl3,9 acidic ionic liquid,10 trichloroisocyanuric
acid,11 silica supported sulfonic acid,12 1,3-dibromo-5,5-dimethylhydantoin (DBH),13 SBA-15
functionalized sulfonic acid,14 sulfonated polyanthracene,15 graphene oxide16 and glycerol,17 to
name but a few, have contributed significantly to the preparation of thioacetals. On the other
hand, despite the benefits provided by these known protocols, one or more of the limits such as
the dependence on metal catalyst, harsh reaction conditions or unsatisfactory substrate tolerance
have been suffered. In this context, developing alternative catalytic approaches of improved
sustainability with facile operation is still an issue of significance in the chemistry of thioacetals.
Cyanuric chloride, also named 2,4,6-trichloro-1,3,5-triazine (TCT), is a useful organocatalyst
showing ability in catalyzing or promoting a vast array of important organic reactions.18-22 Some
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particular reactions involving the condensation of aldehydes such as acetalization,23
transacetalization24 and the deprotection of thioacetals have been also realized with TCT
catalysis.25 However, to the best of our knowledge, no report on TCT-catalyzed thioacetalization
has been described. Herein, we present a mild, economical and highly efficient method of
thioacetalization which tolerates the transformation of both thiols and thiophenols by using TCT
as the catalyst.
RESULTS AND DISCUSSION
Originally, the model transformation on forming thioacetal 3a via the condensation of
benzaldehyde 1a with ethanethiol 2a was run in the presence of TCT. The tentative examination
using 50 mol% TCT and heating at 80oC under solvent free-condition gave a good yield of the
target product (entry 1, Table 1). Subsequently, experiments on varying the loading of TCT
indicated that 30 mol% TCT was the optimal loading (entries 2-3, Table 1). When the model
reaction was run at different temperatures, in room temperature provided an equally good yield
as elevated temperatures. Lower temperature showed a negative impact on the result (entries 4-6,
Table 1). Finally, a further improved yield of product was obtained when dichloromethane was
used as the reaction medium (entry 7, Table 1). In addition, a blank experiment performed at
room temperature without using the catalyst gave a low yield of 3a (entry 8, Table 1).
With the optimized reaction conditions, we then examined the application scope of this mild
thioacetalization protocol. A class of different aromatic aldehydes and thiols/thiophenols were
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employed, respectively. As shown in Table 2, aldehydes containing various functional groups
such as alkyl, halogen, nitro and cyano etc. were successfully converted to the corresponding
thioacetals in the presence of either linear or branched alkyl thiols as reaction partners (3a-3l,
Table 2). More notably, benzylthiol and thiophenols also took part in the thioacetalization
transformation to give the corresponding product with good yield (3m and 3n-3p, Table 2).
Generally good to excellent yields of products were provided, and no evident impact of the
reactant structure on the results was observed. Notably, the cyclic thioacetal 3q was obtained
with almost quantitative yield when ethane-1,2-dithiol was used (entry 17, Table 2). The results
from this section clearly demonstrate a general applicability of this organocatalytic method for
the preparation of thioacetals.
On the basis of the results on thioacetal synthesis in the presence of TCT, we propose a
tentative reaction mechanism shown in Scheme 1. The electrophilic CCl bond of TCT could
initially activate the formyl group by forming transition state I, which facilitates the subsequent
nucleophilic attack of the thiol to give intermediate 4 and releasing HCl as an acid co-catalyst for
the thioacetalization process. The nucleophilic substitution of another molecule of thiol to 4 then
produces the thioacetal 3, and 1,3,5-triazine-2,4,6-triol 5 is formed simultaneously as side
product. Based on this mechanism, TCT is not only the source of HCl, but more importantly the
scavenger of water formed during the thioacetalization. This assumption can also explain the
excellent effect of TCT in promoting this thioacetalization process.
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CONCLUSIONS
In conclusion, we have developed a facile new organocatalytic method for the
thioacetalization transformation using TCT as organocatalyst. The present protocol consists of
mild reaction conditions and economical reagents. Together with the satisfactory substrate
tolerance, this method will reasonably be a useful complementary route of thioacetalization to
known methods.
EXPERIMENTAL
General
All chemicals and reagents used in the experiments were obtained from commercial sources
and used directly without further treatment. The NMR spectra were recorded in CDCl3 solution
at 600 MHz (1H) and 150 MHz (13C), respectively. Chemical shifts  are reported in ppm (TMS
as internal standard). The HRMS data for new compounds were obtained under ESI model.
General procedure for the TCT-catalyzed synthesis of thioacetals
The aldehyde (1.0 mmol), the thiol (2.0 mmol) and TCT (0.3 mmol) in CH2Cl2 (2 mL) were
filled into a 25 mL round bottomed. The mixture was stirred at room temperature for 12 h (open
air, TLC). Upon completion, water (5 mL) was added and the resulting mixture was extracted
with EtOAc (3 × 10 mL). The organic extracts were combined and dried over anhydrous Na2SO4.
After filtration and removing the solvent under reduced pressure, and the resulting residue was
subjected to silica gel column chromatography to provide the pure product by using mixed
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petroleum ether and ethyl acetate (VPET : VEA = 200:1). The Supplemental Materials contains
sample 1H and 13C spectra of the products 3a-3h (Figures S 1 – S 16)
1
(Phenylmethylene)bis(ethylsulfane) (3a).5 Pale yellow liquid; H NMR: δ 1.27 (t, 6 H, J = 6.0
Hz), 2.49-2.83 (m, 4 H), 4.97 (s, 1 H), 7.25 (t, 1 H, J = 6.0 Hz), 7.32 (t, 2 H, J = 6.0 Hz), 7.43 (d,
2 H, J = 6.0 Hz); 13C NMR: δ 16.9, 28.9, 55.1, 130.3, 130.4, 131.1, 143.1.
1
[(4-Bromophenyl)methylene]bis(ethylsulfane) (3b).5 Pale yellow liquid; H NMR: δ 1.21 (t, 6
H, J = 6.0 Hz), 2.48-2.60 (m, 4 H), 4.86 (s, 1 H), 7.32 (d, 2 H, J = 6.0 Hz), 7.44 (d, 2 H, J = 6.0
Hz); 13C NMR: δ 16.9, 28.9, 54.4, 124.2, 132.1, 134.3, 142.2.
[(4-Bromophenyl)methylene]bis(octylsulfane) (3c). Pale yellow liquid; 1H NMR: δ 0.87 (t, 6 H,
J = 6.0 Hz), 1.24-1.32 (m, 20 H), 1.51-1.53 (m, 4 H), 2.45-2.57 (m, 4 H), 4.81 (s, 1 H), 7.32 (d, 2
H, J = 6.0 Hz), 7.44 (d, 2 H, J = 6.0 Hz); 13C NMR: δ 16.2,16.9, 23.8, 25.2, 28.9, 36.9, 54.8, 55.2,
55.5, 130.2, 131.8, 140.1, 140.2; ESI-HRMS Calcd. for C23H40BrS2 [M+H]+ 459.1749; found
459.1746.
1
(p-Tolylmethylene)bis(octylsulfane) (3d). Pale yellow liquid; H NMR: δ 0.88 (t, 6 H, J = 6.0
Hz), 1.25-1.33 (m, 20 H), 1.53-1.54 (m, 4 H), 2.33 (s, 1 H), 2.47-2.59 (m, 4 H), 4.85 (s, 1 H),
7.13 (d, 2 H, J = 6.0 Hz), 7.32 (d, 2 H, J = 6.0 Hz); 13C NMR: δ 16.7, 23.7, 25.3, 31.5, 31.8, 34.4,
35.0, 55.6, 130.2, 131.8, 140.0, 140.3; ESI-HRMS Calcd. for C24H43S2 [M+H]+ 395.2801; found
395.2801.
1
[(4-Bromophenyl)methylene]bis(sec-butylsulfane) (3e). Pale yellow liquid; H NMR: δ
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0.89-0.95 (m, 6 H), 1.21-1.22 (m, 6 H), 1.46-1.50 (m, 2 H), 1.55-1.58 (m, 2 H), 2.64-2.81 (m, 2
13
H), 4.87 (s, 1 H), 7.35 (d, 2 H, J = 6.0 Hz), 7.44 (d, 2 H, J = 6.0 Hz); C NMR: δ 13.8, 23.3,
32.2, 45.0, 52.7, 123.9, 132.1, 134.1, 143.0; ESI-HRMS Calcd. for C15H24BrS2 [M+H]+
347.0497; found 347.0512.
(p-Tolylmethylene)bis(propylsulfane) (3f). Pale yellow liquid; 1H NMR: δ 0.93-0.96 (m, 6 H),
1.54-1.59 (m, 4 H), 2.33 (s, 1 H), 2.45-2.57 (m, 2 H), 4.83 (s, 1 H), 7.12 (d, 2 H, J = 6.0 Hz),
7.32 (d, 2 H, J = 6.0 Hz); 13C NMR: δ 16.2, 23.8, 25.2, 37.0, 55.5, 130.2, 131.8, 140.1, 140.3.0;
ESI-HRMS Calcd. for C14H23S2 [M+H]+ 255.1236; found 255.1244.
1
[(2-Chlorophenyl)methylene]bis(ethylsulfane) (3g). Pale yellow liquid; H NMR: δ 1.24 (t, 6
H, J = 6.0 Hz), 2.52-2.66 (m, 4 H), 5.49 (s, 1 H), 7.16-7.18 (m, 1 H), 7.26-7.28 (m, 1 H),
7.32-7.34 (m, 1 H), 7.74-7.75 (m, 1 H); 13C NMR: δ 17.1, 29.1, 50.6, 129.9, 131.4, 132.0,132.3,
135.2, 140.9.0; ESI-HRMS Calcd. for C11H16ClS2 [M+H]+ 247.0376; found 247.0371.
1
[(2-bromophenyl)methylene]bis(ethylsulfane) (3h).5 Pale yellow liquid; H NMR: δ 1.25 (t, 6
H, J = 6.0 Hz), 2.51-2.66 (m, 4 H), 5.46 (s, 1 H), 7.09-7.12 (m, 1 H), 7.31-7.33 (m, 1 H),
7.51-7.52 (m, 1 H), 7.751-7.76 (m, 1 H) ; 13C NMR: δ 17.1, 29.1, 53.4, 126.0, 130.6, 131.7,132.5,
135.3, 142.5.
4-[Bis(ethylthio)methyl]-N,N-dimethylbenzenamine (3i).5 Pale yellow liquid; 1H NMR: δ 1.21
(t, 6 H, J = 6.0 Hz), 2.49-2.60 (m, 4 H), 2.94 (s, 6 H),4.90 (s, 1 H), 6.68 (d, 2 H, J = 6.0 Hz), 7.32
(d, 2 H, J = 6.0 Hz); 13C NMR: δ 17.0, 28.9, 43.2, 54.7, 114.9, 131.2, 152.7.
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[(4-Nitrophenyl)methylene]bis(ethylsulfane) (3j).5 Pale yellow liquid; 1H NMR: δ 1.23 (t, 6 H,
J = 6.0 Hz), 2.55-2.67 (m, 4 H), 5.76 (s, 1 H), 7.39 (t, 1 H, J = 6.0 Hz), 7.60 (t, 1 H, J = 6.0 Hz),
7.82 (d, 1 H, J = 6.0 Hz), 7.98 (d, 1 H, J = 6.0 Hz); 13C NMR: δ 16.9, 29.5, 48.8, 126.9,
131.0,133.2, 135.8, 138.6,150.5.
4-[Bis(ethylthio)methyl]benzonitrile (3k).5 Pale yellow liquid; 1H NMR: δ 1.21 (t, 6 H, J = 6.0
13
Hz), 2.47-2.62 (m, 4 H), 4.90 (s, 1 H), 7.55 (d, 2 H, J = 6.0 Hz), 7.61 (d, 2 H, J = 6.0 Hz); C
NMR: δ 16.9, 29.0, 54.7, 114.2, 131.1, 131.2, 135.0, 148.8.
[(4-Chlorophenyl)methylene]bis(ethylsulfane) (3l).5 Colorless liquid; 1H NMR: δ 1.21 (t, 6 H,
J = 6.0 Hz), 2.47-2.61 (m, 4 H), 4.88 (s, 1 H), 7.28 (d, 2 H, J = 6.0 Hz), 7.38 (d, 2 H, J = 6.0 Hz);
13C NMR: δ 16.9, 28.9, 54.4, 131.3, 131.7, 136.0, 141.8; ESI-HRMS Calcd. for C11H16ClS2
[M+H]+ 247.0382; found 247.0329.
1
(Phenylmethylene)bis(benzylsulfane) (3m).26 Pale yellow liquid; H NMR: δ 3.60 (d, 2 H, J =
12.0 Hz), 3.82 (d, 2 H, J = 12.0 Hz), 4.53 (s, 1 H), 7.20 (d, 4 H, J = 6.0 Hz), 7.28-7.30 (m, 7 H),
7.34-7.39 (m, 4 H); 13C NMR: δ 39.1, 53.7, 129.7, 130.7, 131.2, 131.3, 140.4, 142.3.
1
(Phenylmethylene)bis[(4-isopropylphenyl)sulfane] (3n). Colorless liquid; H NMR: δ 1.24 (d,
12 H, J = 12.0 Hz), 2.86-2.90 (m, 2 H), 5.37 (s, 1 H), 7.12 (d, 4 H, J = 12.0 Hz), 7.27-7.30 (m, 7
13
H), 7.38 (d, 2 H, J = 6.0 Hz); C NMR: δ 26.6, 36.5, 63.9, 129.6, 129.7, 130.5, 130.6, 131.1,
134.1, 135.5, 142.8, 151.4; ESI-HRMS Calcd. for C25H29S2 [M+H]+ 393.1705; found 393.1730.
1
(Phenylmethylene)bis(phenylsulfane) (3o).5 Colorless liquid; H NMR: δ 7.37-7.35 (m, 6 H),
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7.28-7.24 (m, 9 H), 5.44 (s, 1 H); C NMR: δ 139.8, 134.6, 132.6, 128.9, 128.6, 128.1, 128.0,
127.9.
1
(Phenylmethylene)bis[(4-fluorophenyl)sulfane] (3p).27 Colorless liquid; H NMR: δ 7.32-7.30
(m, 4 H), 7.25-7.22 (m, 5 H), 6.95-6.92 (m, 4 H), 5.23 (s, 1 H); 13C NMR: δ 166.2, 164.5, 141.9,
138.3, 131.7, 131.1, 130.8, 130.3, 118.7, 118.5, 64.6.
2-Phenyl-1,3-dithiolane (3q).5 Colorless liquid; 1H NMR: δ 7.52 (d, 2 H, J = 6.0 Hz), 7.31 (t, 2
H, J = 6.0 Hz), 7.25 (d, 1 H, J = 6.0 Hz), 5.64 (s, 1 H), 3.52-3.47 (m, 2 H), 3.38-3.32 (m, 2 H);
13C NMR: δ 142.9, 134.1, 130.7, 130.6, 58.9, 42.8.
Funding The work was supported by the Zhejiang University.
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Table 1 Condition optimization on TCT-catalyzed thioacetalizationa
Entry TCT loading (%) T (oC) Yield (%)b
1
2
50
30
10
30
30
30
30
0
80
80
80
60
rt
83
84
64
82
84
55
88
37
3
4
5
6
7c
10
rt
8
rt
aGeneral conditions: benzaldehyde 1a (1.0 mmol) and EtSH (2 mmol) with TCT, stirred for 12 h.
bYield of isolated product. c2 mL CH2Cl2 was used.
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Table 2 Scope of TCT-catalyzed thioacetalizationa
Entry R1
R2
Product Yield (%)b
1
H
Et
88
84
76
81
76
86
88
84
81
73
71
76
74
79
91
93
99
3a
3b
3c
3d
3e
3f
2
4-Br
4-Br
4-Me
4-Br
4-Me
2-Cl
2-Br
Et
3
n-Oct
n-Oct
sec-Bu
n-Pr
Et
4
5
6
7
3g
3h
3i
8
Et
9
4-NMe2 Et
10
11
12
13
14
15
16
17
4-NO2
4-CN
4-Cl
H
Et
3j
Et
3k
3l
Et
PhCH2
4-i-PrC6H4
Ph
3m
3n
3o
3p
3q
H
H
H
4-FC6H4
CH2CH2SH
H
a General conditions: Aldehyde 1 (1.0 mmol), TCT (0.3 mmol) and thiol 2 (2.0 mmol) in CH2Cl2
(2 mL), stirred at room temperature for 12 h. bYield of isolated product.
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Scheme 1 The proposed reaction mechanism
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