CuCl-catalyzed cleavage of S-triphenylmethyl thioether: a new detritylation method for thio group

Article abstract of DOI:10.1016/j.tetlet.2006.12.090

A new method for the deprotection of trityl thioethers using CuCl as the catalyst under ultrasonic conditions is described.

Full text of DOI:10.1016/j.tetlet.2006.12.090

Tetrahedron Letters 48 (2007) 1095–1097
CuCl-catalyzed cleavage of S-triphenylmethyl thioether: a new
detritylation method for thio group
Ming Ma, Xiu Zhang, Lingling Peng and Jianbo Wang*
Beijing National Laboratory of Molecular Sciences (BNLMS), Green Chemistry Center (GCC) and Key Laboratory of
Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry, Peking University,
Beijing 100871, China
Received 25 October 2006; revised 13 December 2006; accepted 15 December 2006
Available online 19 December 2006
Abstract—A new method for the deprotection of trityl thioethers using CuCl as the catalyst under ultrasonic conditions is described.
Ó 2006 Elsevier Ltd. All rights reserved.
Triphenylmethyl (trityl) is a common S-protecting group
used to avoid disulfide formation and prevent the thiol
group from reacting with other sensitive functional
groups.1 Thus, the methods that are able to cleave the
S-trityl group under mild conditions are very important
for the thiol group containing molecules. Classical ways
for detritylation usually employ acidic conditions, either
with protonic acid2 (e.g., hydrogen chloride, hydrogen
bromide, trifluoroacetic acid) or Lewis acid3 (e.g.,
AlBr3). Besides, some oxidative protocols have been
developed for the deprotection of trityl thioethers.4–8
Among them, iodinolysis in a protic solvent such as
methanol is most commonly used.7,8 On the other hand,
due to the affinity of sulfur atom with heavy metals, such
as mercury(II) and silver(I), the S-trityl group can be
removed easily with heavy metal salts at room
temperature.9–12 Obviously, these methods suffer some
drawbacks such as strongly acidic conditions and heavy
metal pollutions.13 Herein we report a new and efficient
detritylation method for thioethers, in which CuCl is uti-
lized as an efficient catalyst under ultrasonic conditions.
CO2Me
Ph
Ph
S
S
Cu(CH3CN)4PF6
(200 mol %)
SCPh3
CO2Me
74%
2a
+
Ph
CO2Me
1a
H2O (200 mol %)
CH2Cl2, r.t., 24 h
Ph3COH
3
71%
Scheme 1.
Following this primary result, we proceeded to
examine other copper salts with 1a as the substrate.
The data are collected in Table 1. It was concluded that
Cu(CH3CN)4PF6 and CuCl similarly mediated detrityla-
tion reactions (entries 1 and 2). However, with other
copper salts, such as CuBr, CuI, and CuSO4, the
detritylation did not proceed well (entries 3–5).
To further improve the reaction, we studied the reaction
of thioether 1b with CuCl under different conditions
During our study on [2,3]-r rearrangement of sulfur
ylide generated from Cu(I) carbene,14 we unexpectedly
found that the reaction of trityl thioether 1a and
Cu(CH3CN)4PF6 (200 mol %) at room temperature in
CH2Cl2 containing H2O (200 mol %) afforded disulfide
2a in a 74% yield, together with triphenylmethol in a
71% yield (Scheme 1).
Table 1. Effect of different copper salts on the reaction of 1a
Entry
Copper salta
Reaction time (h)
Yieldb (%)
1
2
3
4
5
Cu(CH3CN)4PF6
CuCl
CuBr
CuI
CuSO4Æ5H2O
24
24
24
24
24
74
86
Trace
NRc
NR
a 2.0 equiv of copper salt was used.
b Isolated yield by column chromatography.
c No reaction occurred as judged by TLC.
Keywords: Deprotection; Thiol; CuCl-catalyzed; Trityl.
*
Corresponding author. E-mail: wangjb@pku.edu.cn
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.090

1096
M. Ma et al. / Tetrahedron Letters 48 (2007) 1095–1097
Table 2. Detritylation of 1b using CuCl under various conditions
(Table 2). The results demonstrated that the reaction
could be only slightly accelerated by raising the reaction
temperature (entry 2). To our delight, under ultrasonic
conditions, the reaction could complete within 3 h (entry
3). Furthermore, the amount of CuCl could be reduced
to 20 mol % under ultrasonic conditions. Thus, the det-
ritylation could be performed with catalytic CuCl.
CuCl
S
H2O (200 mol %)
S
SCPh3
CH2Cl2
1b
Entry Reaction condition
2b
Copper salt Reaction Yielda
(mol %)
timeb (h) (%)
The scope of the detritylation procedure is demonstrated
by the reaction with a series of thioether substrates 1a–k
(Table 3). For comparison, the data both for reactions
under ultrasonic conditions with catalytic amount of
CuCl and the reactions under non-ultrasonic conditions
with 200 mol % CuCl were collected in the table. The
data indicate a remarkable increase in the rate of the
reactions under ultrasonic conditions in general. A com-
plete detritylation of thioethers 1a–h under ultrasonic
conditions (Condition B) took 2.5–7 h, and the yields
1
2
3
4
5
rt
200
200
18
16
3
3
3
83
85
89
93
88
rt ꢀ reflux
Ultrasonic rt ꢀ 30 °Cc 200
Ultrasonic rt ꢀ 30 °C
Ultrasonic rt ꢀ 30 °C
50
20
a Isolated yield after column chromatography.
b Thioether 2b completely disappeared by TLC.
c The water bath was used and the temperature of the water bath kept
30 °C during ultrasonic irradiation.
Table 3. Detritylation of thioethers 1a–k with CuCl15
Condition A or B
RSCPh3
S
R
+
Ph3COH
R
S
1a-k
2a-k
Condition Aa
Reaction time
Entry
Thioether 1
Condition Bb
Reaction time (h)
Yieldc (%)
90
Yield (%)
89
SCPh3
1
1a
3 days
4
Ph
CO2CH3
2
3
4
1b
1c
1d
SCPh3
SCPh3
18 h
12 h
18 h
83
85
83
3
88
90
94
2.5
3
Cl
SCPh3
SCPh3
5
1e
12 h
86
3.5
88
6
7
1f
3 days
3 days
88
86
5
5
7
89
90
83
Ph
SCPh3
SCPh3
1g
Ph
Ph
8
9
1h
1i
5 days
36 h
78
76
SCPh3
d
d
—
—
—
—
SCPh3
10
11
1j
CH3(CH2)8CH2SCPh3
5 days
5 days
63
—
—
57e
(
)
6
1k
Ph3CS
SCPh3
a Condition A: 200 mol % CuCl, 200 mol % H2O, CH2Cl2, rt.
b Condition B: 20 mol % CuCl, 200 mol % H2O, CH2Cl2, ultrasonic, rt ꢀ 30 °C.
c Isolated yield after column chromatography when thioether 1 completely disappeared by TLC.
d Reaction gave complex mixture.
e Yield of a mixture of dimer and trimer.

M. Ma et al. / Tetrahedron Letters 48 (2007) 1095–1097
1097
2. (a) Zervas, L.; Photaki, I. J. Am. Chem. Soc. 1962, 84,
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of the isolated disulfide products ranged from 83% to
94% (Table 3, entries 1–8). The reaction under condition
A (200 mol % CuCl, non-ultrasonic), gave comparable
yields. However, the reaction took much longer time.
The detritylation was found to be general. In addition
to aryl thioethers, the thio ether substrates containing
benzyl, allyl, and propargyl group all worked well and
gave the corresponding disulfides in good yields. Thio-
ether substrates 1i–k, which contain alkyl substituents,
also worked well under non-ultrasonic conditions (Con-
dition A). However, under ultrasonic conditions the
reaction resulted in a complex mixture (entries 9–11).
In summary, we have developed a mild and efficient
reaction for the deprotection of trityl thioethers to their
corresponding disulfide compounds with CuCl. Because
the conditions is virtually neutral, acid-sensitive groups
could tolerate the reaction. Although the reaction mech-
anism is not clear at present, it is likely that the reaction
proceeds through electron-transfer process with radical
species as a reactive intermediate.
11. Gregg, D. C.; Iddles, H. A.; Stearns, P. W., Jr. J. Org.
Chem. 1951, 16, 246.
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2178.
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Hiskey, R. G.; Mizoguchi, T.; Smithwick, E. L. J. Org.
Chem. 1967, 32, 97; (b) Mairanovsky, V. G. Angew.
Chem., Int. Ed. Engl. 1976, 15, 281; (c) Pearson, D. A.;
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15. General procedure for the detritylation of thioethers to
Acknowledgements
The project is generously supported by Natural Science
Foundation of China (Grant Nos. 20572002, 20521202,
20225205, 20390050) and the Ministry of Education of
China (Cheung Kong Scholars Program).
disulfides under condition B. Thioether
1
(60 mg,
0.16 mmol) was dissolved in CH2Cl2 (1.5 mL), and to this
solution was successively added CuCl (3 mg, 0.03 mmol)
and H2O (6 mg, 0.32 mmol), then the reaction bottle was
sealed with a rubber plug. The reaction was conducted
under ultrasonic irradiation for 3–7 h until detritylation
was complete as judged by TLC. Removal of the solvent
afforded a crude product, which was purified by column
chromatography to give pure disulfide product 2.
References and notes
1. For comprehensive reviews on protecting groups, see: (a)
Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 2nd ed.; Wiley: New York, 1991; (b)
´
Kocienski, P. J. Protecting Group, 3rd ed.; Georg Thieme
Verlag: Stuttgart, 2005.