Ethyl lactate mediated thioacetalization of aldehydes at ambient temperature

Article abstract of DOI:10.1080/10426507.2016.1209504

Dithioacetalization reactions of aldehydes with thiols/thiophenols have been successfully achieved at room temperature by employing the green, bio-based ethyl lactate as the reaction medium. By means of this sustainable approach, a class of dithioacetals has been acquired with high diversity and efficiency.

Full text of DOI:10.1080/10426507.2016.1209504

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Ethyl lactate mediated thioacetalization of
aldehydes at ambient temperature
Jie-Ping Wan, Yanfeng Jing & Yunyun Liu
To cite this article: Jie-Ping Wan, Yanfeng Jing & Yunyun Liu (2016) Ethyl lactate mediated
thioacetalization of aldehydes at ambient temperature, Phosphorus, Sulfur, and Silicon and
the Related Elements, 191:10, 1302-1305, DOI: 10.1080/10426507.2016.1209504
To link to this article: http://dx.doi.org/10.1080/10426507.2016.1209504
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Date: 16 October 2016, At: 00:16

PHOSPHORUS, SULFUR, AND SILICON
, VOL. , NO. , –
http://dx.doi.org/./..
SHORT COMMUNICATION
Ethyl lactate mediated thioacetalization of aldehydes at ambient temperature
Jie-Ping Wan, Yanfeng Jing, and Yunyun Liu
College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, P.R. China
ABSTRACT
ARTICLE HISTORY
Received  June 
Accepted  June 
Dithioacetalization reactions of aldehydes with thiols/thiophenols have been successfully achieved at room
temperature by employing the green, bio-based ethyl lactate as the reaction medium. By means of this
sustainable approach, a class of dithioacetals has been acquired with high diversity and efficiency.
KEYWORDS
Ambient temperature;
bio-based solvent;
dithioacetalization; ethyl
lactate; green
GRAPHICAL ABSTRACT
dithioacetals themselves are known as highly versatile build-
ing blocks in organic synthesis.8–12 Owing to the significance of
dithioacetal synthesis, extensive efforts have been made to the
dithioacetalization reactions of carbonyl substrates which have
led to the occurrence of numerous catalytic methods enabling
efficient dithioacetal synthesis.13–22 While these known meth-
ods contribute significantly to the advances of dithioacetaliza-
tion chemistry, the reliance of toxic catalyst(s) and/or volatile
organic solvent as reaction medium demonstrate the require-
ment of developing complementary catalytic approaches with
further improved sustainability and cleanness.
In continuation of our longstanding endeavor in exploring
alternative green organic synthesis employing bio-based sol-
vents as reaction medium and the synthesis of sulfur-containing
products,23,24 we report herein an alternative method allowing
ambient dithioacetalization reaction of aldehydes by employing
EL as the green medium.
Introduction
Upon the daily increasing concern to sustainable develop-
ment all around the world, discovering and making use of
renewable and environmentally benign resources have attracted
unprecedentedly high attention in the area of chemical indus-
try.1,2 Among the numerous renewable resources, the bio-mass
derived chemicals are inarguably one of the most important
classes of candidates because of their inherent advantages of low
cost, high environment tolerance and broad application.3 Ethyl
lactate (EL) is a biomass available chemical that can be used as
platform compound in the generation of many organic products.
In addition, EL has also exhibited application in food additive,
perfume flavor, and solvent in coating industry, etc.4 In recent
years, EL has attracted renewed interests by acting as reaction
medium in organic synthesis because of its intrinsic advantages
of non-toxicity, full degradability, good stability and solubility
to both water and organic compounds. Although not a research
topic of long history, the research work in recent several years
discloses the high potential of EL as green solvent in mediat-
ing important organic reactions,5,6 and these results indicate the
broad space of EL in the designation of much more sustainable
green syntheses.
Results and discussion
To start the work, the reaction of p-chlorobenzaldehyde 1a with
ethanethiol 2a was selected as model reaction, and a series of
optimization experiments were first conducted. According to
the results, EL was an ideal medium for the reaction which
The formation of dithioacetals is one of the most classi-
cal strategies in the group protection chemistry.7 In addition,
CONTACT Yunyun Liu
chemliuyunyun@jxnu.edu.cn
College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang , P.R. China.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/gpss.
Supplemental data for this article can be accessed on the publisher’s website at http://dx.doi.org/./...
© Jiangxi Normal University

PHOSPHORUS, SULFUR, AND SILICON
1303
Table . Optimization of reaction conditions.a
Entry
Solvent
t(°C)
Yield (%)b

EL
EL
EL
EL
EL
rt





rt











Figure . The proposed activation model of EL to both aldehydes and thiols.
EL

HO
CHCN
p-xylene
NR
trace
trace


rt
rt
containing different substituents, heteroaryl and alkyl aldehy-
des also displayed smooth applicability in the synthesis of the
corresponding thioacetals (3j and 3q, Table 2). On the other
hand, general application of different alkyl thiols (3a–3i, 3o–
3p, Table 2), dithiols (3k–3n, Table 2), and thiophenols (3j,
3q–3s, Table 2) were also well tolerated. The dithioacetals were
generally obtained with good to excellent yields without being
evidently effected by the functional group in either compo-
nent. On the basis of the aldehyde-based dithioacetalization
with the present protocol, corresponding reactions employing
ketones, including aliphatic methyl ketone (acetone) and aro-
matic methyl ketone (acetophenone) were also subjected for
potential reactions with ethyl thiol, respectively. However, no
transformation was observed.
To illustrate the unique function of EL in mediating the
dithioacetalization reaction, a possible model of substrate acti-
vation has been proposed. As outlined in Figure 1, upon the
analysis to the structural features of EL and the reactants, it
is plausible that both aldehyde and thiol are activated by EL.
At first, the slightly acidic hydroxyl group in EL activates alde-
hyde via the O–H–O hydrogen bond; simultaneously, the oxy-
gen atom of the ethoxy group in EL could activate the thiol sub-
strate via the O–H–S interaction. Besides the activation effect,
this activation model is also beneficial in keeping the aldehyde
and thiol close to each other and facilitating the final reaction of
the two reactants.
aGeneral conditions: a (. mmol), a (. mmol) in  mL solvent, stirred for  h.
bYield of isolated product.
allowed the formation of dithioacetal 3a with excellent yield at
different temperatures without using any catalyst or additive. In
the range of room temperature to 80 °C, no evident difference
in the product yield was observed (entries 1-6, Table 1). In cor-
responding comparing experiments, other solvents of different
properties and polarity such as water, acetonitrile and p-xylene
were all found inapplicable in enabling the production of 3a,
suggesting the unique advantage of EL for this dithioacetaliza-
tion reaction (entries 7-9, Table 1).
After optimizing the reaction conditions, the scope of this
EL-mediated synthetic protocol was subsequently investigated
by employing different alkyl thiols, thiophenols, and aldehy-
des as starting materials. As shown in Table 2, broad applica-
tion and good functional group tolerance were demonstrated
by the experimental results acquired in this section. For the
aldehyde component, besides conventional aromatic aldehydes
Table . Application of the dithioacetalization reaction in EL.a
R
R
Product
Yield(%)b
Conclusions
-ClCH
Ph
Et
Et
Et
Et
Et
Et
Et
Et
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r




In conclusion, we have developed a new biomass-based EL-
mediated method for the dithioacetalization reactions of alde-
hydes with thiols/thiophenols. Besides the inherent greenness
of EL, the present method is also advantageous and practical
because no additional catalyst is required and the reaction is run
at room temperature operation. The sustainability, broad appli-
cation scope and satisfactory yields of products reasonably make
the method a useful complement to known methodologies of
dithioacetalization.
-MeCH
-MeOCH
-BrCH
-CNCH
-NOCH
-ClCH
-NOCH
furyl--yl
-ClCH
Ph
-MeOCH
,-(MeO)CH
-ClCH
-NOCH
n-propyl
Ph











Et
Ph
HSCHCH
HSCHCH
HSCHCH
HSCHCH
n-Bu
n-Bu
Ph
Ph
Ph
Experimental




General information
-MeCH
s
All reactions were performed under air atmosphere. Chemi-
cals were obtained from commercial sources and used directly
aGeneral conditions: aldehyde 1 (. mmol), thiol 2 (. mmol) in  mL EL, stirred
at rt for  h.
bYield of isolated product.
1
without further treatment. H NMR spectra were recorded at

1304
J.-P. WAN ET AL.
2-Phenyl-1,3-dithiolane (3l).13 1H NMR: δ 7.51 (d, J = 7.6 Hz,
2 H), 7.32–7.22 (m, 3 H), 5.63 (s, 1 H), 3.52–3.44 (m, 2 H),
3.37–3.29 (m, 2 H).
400 MHz (Bruker Avance 400 apparatus) using CDCl3 as sol-
vent. The chemical shifts δ are reported in ppm with TMS as
internal standard. The structures of all products were confirmed
by comparing their 1H NMR data with those reported in the lit-
erature. The Supplemental Materials contains sample 1H NMR
of 3a-3s (Figures S1–S19).
2-(4-Methoxyphenyl)-1,3-dithiolane (3m).18 1H NMR: δ 7.46
(d, J = 8.4 Hz, 2 H), 6.84 (d, J = 9.2 Hz, 2 H), 5.64 (s, 1 H),
3.79 (s, 3 H), 3.52–3.46 (m, 2 H), 3.38–3.31 (m, 2H).
2-(3,4-Dimethoxyphenyl)-1,3-dithiolane (3n).14 1H NMR: δ
7.11 (s, 1 H), 7.05 (d, J = 10.4 Hz, 1 H), 6.78 (d, J = 8.4 Hz,
1H), 5.64 (s, 1 H), 3.90 (s, 3 H), 3.87 (s, 3 H), 3.53–3.47 (m, 2
H), 3.39–3.32 (m, 2 H).
General procedure for the thioacetalization reaction in EL
A 25 mL round bottom flask was charged with the aldehyde
1 (1.0 mmol) and the thiol 2 (2.0 mmol) and EL (2 mL). The
resulting mixture was stirred at rt for 12 h (TLC). Upon com-
pletion, water (5 mL) was added, and the resulting suspension
was extracted with ethyl acetate (3 × 10 mL). The combined
organic phases were further washed with water (3 × 5 mL). The
organic solution was then dried with anhydrous Na2SO4. After
filtration, the organic solvent was removed under reduced pres-
sure. The residue was subjected to silica gel column chromatog-
raphy to provide pure products with elution of mixed petroleum
ether and ethyl acetate (v/v = 200 : 1).
1-[Bis(n-propylthio)methyl]-4-chlorobenzene (3o).14 1H NMR:
δ 8.12 (d, J = 8.8 Hz, 2 H), 7.55 (d, J = 8.4 Hz, 2 H), 4.84 (s,
1 H), 2.56–2.41 (m, 4 H), 1.51–1.43 (m, 2 H), 1.35–1.26 (m,
2 H), 0.81 (t, J = 7.2 Hz, 6 H).
1-[Bis(n-propylthio)methyl]-4-nitrobenzene (3p).14 1H NMR: δ
7.39 (d, J = 8.4 Hz, 2 H), 7.29 (d, J = 7.6 Hz, 2 H), 4.84 (s, 1
H), 2.60–2.46 (m, 4 H), 1.56–1.49 (m, 2 H), 1.41–1.32 (m, 2
H), 0.88 (t, J = 7.6 Hz, 6 H).
1-[Bis(phenylthio)methyl]ethane (3q).19 1H NMR: δ 7.45 (d,
J = 7.4, 4 H), 7.30–7.19 (m, 6 H), 4.35 (t, J = 6.8 Hz, 1 H),
1.91–1.84 (m, 2 H), 1.12 (t, J = 7.2 Hz, 3 H).
1-[Bis(ethylthio)methyl]-4-chlorobenzene (3a).13 1H NMR: δ
7.39 (d, J = 8.4 Hz, 2 H), 7.29 (d, J = 8.8 Hz, 2 H), 4.89 (s,
1 H), 2.63–2.47 (m, 4 H), 1.22 (t, J = 7.6 Hz, 6 H).
1-[Bis(ethylthio)methyl]benzene (3b).13 1H NMR: δ 7.44 (d, J =
7.2 Hz, 2 H), 7.32 (t, J = 7.6 Hz, 2 H), 7.25 (t, J = 7.6 Hz, 1
H), 4.92 (s, 1 H), 2.64–2.47 (m, 4 H), 1.21 (t, J = 7.6 Hz, 6 H).
1-[Bis(ethylthio)methyl]-4-methylbenzene (3c).16 1H NMR: δ
7.33 (d, J = 8.0 Hz, 2 H), 7.13 (d, J = 8.0 Hz, 2 H), 4.91 (s,
1 H), 2.64–2.47 (m, 4 H), 2.33 (s, 3 H), 1.22 (t, J = 7.6 Hz,
6 H).
1-[Bis(phenylthio)methyl]benzene (3r).13 1H NMR (400 MHz,
CDCl3): δ 7.36–7.32 (m, 6 H), 7.23–7.17 (m, 9 H), 5.43 (s, 1
H).
1-(Bis(phenylthio)methyl)-4-methylbenzene (3s).25 1H NMR: δ
7.51 (d, J = 7.6, 4 H), 7.39 (d, J = 7.2Hz, 2 H), 7.32–7.17 (m,
6 H), 7.04 (d, J = 7.6Hz, 2 H), 5.43 (s, 1 H), 2.26 (s, 3 H).
Funding
This work was financially supported by the Natural Science Foundation of
Jiangxi Province (20142BAB213007).
1-[Bis(ethylthio)methyl]-4-methoxybenzene (3d).13 1H NMR:
δ 7.37 (d, J = 8.8 Hz, 2 H), 6.85 (d, J = 8.8 Hz, 2 H), 4.91
(s, 1 H), 3.79 (s, 3 H), 2.63–2.46 (m, 4 H), 1.22 (t, J = 7.6 Hz,
6 H).
References
1-[Bis(ethylthio)methyl]-4-bromobenzene (3e).13 1H NMR: δ
7.45 (d, J = 7.6 Hz, 2 H), 7.33 (d, J = 8.4 Hz, 2 H), 4.88 (s,
1 H), 2.64–2.46 (m, 4 H), 1.22 (t, J = 7.6 Hz, 6H).
1-[Bis(ethylthio)methyl]-4-cyanobenzene (3f).13 1H NMR: δ
7.64 (d, J = 8.4 Hz, 2 H), 7.58 (d, J = 8.4 Hz, 2 H), 4.94 (s,
1 H), 2.66–2.48 (m, 4 H), 1.23 (t, J = 7.6 Hz, 6 H).
1-[Bis(ethylthio)methyl]-4-nitrobenzene (3g).13 1H NMR: δ
8.20 (d, J = 8.8 Hz, 2 H), 7.63 (d, J = 8.8 Hz, 2 H), 4.98 (s,
1 H), 2.66–2.51 (m, 4 H), 1.24 (t, J = 7.6 Hz, 6 H).
1-[Bis(ethylthio)methyl]-2-chlorobenzene (3h).15 1H NMR: δ
7.75 (d, J = 8.0 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 7.28 (t,
J = 7.6 Hz, 1 H), 7.18 (t, J = 7.2 Hz, 1 H), 5.49 (s, 1 H), 2.68–
2.49 (m, 4 H), 1.24 (t, J = 7.6 Hz, 6 H).
1. Rostrup-Nielsen, J. R. Sci. 2005, 308, 1421-1422.
2. Shams, S. S.; Zhang, L. S.; Hu, R.; Zhang, R.; Zhu, J. Mater. Lett. 2015,
161, 476-479.
3. Huber, G. W.; Iborra, S.; Corma, A. Chem. Rev. 2006, 106, 4044-4098.
4. Pereira, C. S. M.; Silva, V. M. T. M.; Rodrigues, A. E. Green Chem. 2011,
13, 2658-2671.
5. Wei, L.; Chen, X.; Liu, Y.; Wan, J.-P. Chin. J. Org. Chem. 2016, 36, 954-
961.
6. Wan, J.-P.; Zhong, S.; Xie, L.; Cao, X.; Liu, Y.; Wei, L. Org. Lett. 2016,
18, 584-587.
7. Sartori, G.; Ballini, R.; Bigi, F.; Bosica, G.; Maggi, R.; Righi, Paolo.
Chem. Rev. 2004, 104, 199-250.
8. Luh, T.-Y. Acc. Chem. Res. 1991, 24, 257-263.
9. Luh, T.-Y.; Lee, C.-F. Eur. J. Org. Chem. 2005, 3875-3885.
10. Chou, C.-M.; Chen, W.-Q.; Chen, J.-H.; Lin, C.-L.; Tseng, J.-C.; Lee,
C.-F.; Luh, T.-Y. Chem. Asian J. 2006, 1-2, 46-55.
11. Takeda, T.; Fujiwara, T. Rev. Heteroatom Chem. 1999, 21, 93-115.
12. Corey, E. J.; Seebach, D. Angew. Chem. Int. Ed. 1965, 4, 1075-1077.
13. Wu, Y.-C.; Zhu, J. J. Org. Chem. 2008, 73, 9522-9524.
14. Saraswathy, V. G.; Sankararaman, S. J. Org. Chem. 1994, 59, 4665-4670.
15. Liu, Y. Phosphorus Sulfur Silicon Relat. Elem. 2016, 191, 679-682.
16. Hajipour, A. R.; Pourmousavi, S. A.; Ruoho, A. E. Synth. Commun.
2008, 38, 2548-2566.
17. Madabhushi, S.; Mallu, K. K. R.; Chinthala, N.; Beeram, C. R.; Vangipu-
ram, V. S. Tetrahedron Lett. 2012, 53, 697-701.
18. Naik, S.; Gopinath, R.; Goswami, M.; Patel, B. K. Org. Biomol. Chem.
2004, 2, 1670-1677.
1-[Bis(ethylthio)methyl]-3-nitrobenzene (3i).16 1H NMR: δ
8.24 (s, 1 H), 8.05 (d, J = 10.4 Hz, 1H), 7.75 (d, J = 7.6 Hz,
1 H), 7.45 (t, J = 8.0 Hz, 1 H), 4.93 (s, 1 H), 2.62–2.42 (m, 4
H), 1.16 (t, J = 7.2 Hz, 6 H).
2-[Bis(phenylthio)methyl]furan (3j).17 1H NMR: δ 7.37–7.32
(m, 5 H), 7.24–7.21 (m, 6 H), 6.20 (dd, 1 H, J = 3.2 Hz, 1.6
Hz), 6.13 (d, 1 H, J = 3.2 Hz).
2-(4-Chlorophenyl)-1,3-dithiolane (3k).16 1H NMR: δ 7.43 (d, 2
H, J = 8.4 Hz), 7.25 (d, 2 H, J = 8.4 Hz), 5.57 (s, 1 H), 3.48–
3.40 (m, 2 H), 3.34–3.28 (m, 2 H).

PHOSPHORUS, SULFUR, AND SILICON
1305
19. Kumar, A.; Rao, M. S.; Rao, V. K. Aust. J. Chem. 2010, 63, 135140.
20. Yadav, J. S.; Reddy, B. V. S.; Pandey, S. K. Synth. Commun. 2002, 32,
715-719.
21. (a)Huang, L.-F.; Lee, C.-F.; Tseng, J.-C.; Luh, T.-Y. Synlett 2006, 3173-
3175. (b)Leung, M.-K.; Luh, T.-Y. Sci. Synth. 2007, 30, 221-349
22. Yu, J.-S.; Wu, W.-B.; Zhou, F. Org. Biomol. Chem. 2016, 14, 2205-2209.
23. Liu, Y.; Huang, B. Phosphorus Sulfur Silicon Relat. Elem. 2016, 191, 926-
929.
24. Liu, Y.; Wang, H.; Zhang, J.; Wan, J.-P.; Wen, C. RSC Adv. 2014, 4,
19472-19475.
25. Zhang, H.; Wang, H.; Yang, H.; Fu, H. Org. Biomol. Chem. 2015, 13,
6149-6153.