An efficient and chemoselective method for protection of thiols catalyzed by aluminumdodecatungstophosphate (AlPW12O40), as a highly water tolerant Lewis acid catalyst

Article abstract of DOI:10.1016/j.tetlet.2005.02.071

Protection of various thiols with diphenylmethanol was achieved in high yields at room temperature using catalytic amounts of AlPW₁₂O ₄₀ in CH₂Cl₂. In the presence of this catalyst, protection of SH versus OH was achieved with high chemoselectivity and yields. The catalyst can be easily recovered and reused. Deprotection of DPM thioethers was also achieved using molecular iodine at reflux in CH₂Cl ₂ in high yields.

Full text of DOI:10.1016/j.tetlet.2005.02.071

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2683–2686
An efficient and chemoselective method for protection of thiols
catalyzed by aluminumdodecatungstophosphate (AlPW12O40),
as a highly water tolerant Lewis acid catalyst
Habib Firouzabadi,* Nasser Iranpoor* and Abbas Ali Jafari
Department of Chemistry, Shiraz University, Shiraz 71454, Iran
Received 1 November 2004; revised 2 February 2005; accepted 10 February 2005
Abstract—Protection of various thiols with diphenylmethanol was achieved in high yields at room temperature using catalytic
amounts of AlPW12O40 in CH2Cl2. In the presence of this catalyst, protection of SH versus OH was achieved with high chemo-
selectivity and yields. The catalyst can be easily recovered and reused. Deprotection of DPM thioethers was also achieved using
molecular iodine at reflux in CH2Cl2 in high yields.
Ó 2005 Published by Elsevier Ltd.
1. Introduction
Fe(NO3)3Æ9H2O.10 Most of these methods require a high
catalyst to substrate ratio and also require long reaction
times. Some of the above mentioned catalysts are not
easily available and they require special precautions
and some require harsh reaction conditions. However,
to the best of our knowledge, a general method for pro-
tection of SH groups with diphenylmethanol has not
been reported.
Protection of one functional group in the presence of
other groups is an essential task for the synthesis of
complex molecules. The protection of the SH functional
group is important because of the reactivity of this func-
tionality as a nucleophile and also its sensitivity to oxi-
dation both by dimerization and S-oxide formation.1,2
We have examined the selective protection of SH versus
OH groups. The methods reported for the protection of
SH groups are rather limited.2
Heteropolyacids (HPAs) have been extensively studied
as acid and oxidation catalysts for many reactions and
have found industrial application in several processes.11
HPAs are promising solid acids and can replace environ-
mentally harmful liquid acid catalysts such as
H2SO4.11c–f The Keggin type H3PW12O40 is more ac-
tive than conventional solid acids such as SiO2–Al2O3,
H3PO4–SiO2, and zeolites.11c–f Solid acid catalysts are
harmless to the environment with respect to corrosive-
ness, safety, quantity of waste, and separability.
Aluminumdodecatungstophosphate (AlPW12O40) is pre-
pared easily from commercially available H3PW12O40 and
Al(NO3)3 in water.12a,13 This salt is water-stable and
nonhygroscopic. In continuation of our interest on the
catalytic activities of heteropolyacids,12,13 we describe
the use of AlPW12O40 as an effective catalyst for the pro-
tection of thiol groups as DPM thioethers. The catalyst
used in this protocol was easily separated and reused in
several runs without losing its catalytic activity. The re-
sults of this study are shown in Table 1. Various ali-
phatic and aromatic thiols and acid-sensitive substrates
like furfurylmercaptan were converted efficiently into
The triphenylmethyl, diphenylmethyl, and benzyl
groups are frequently used for the protection of alcohol,
amine and carboxylic acid functional groups. Protection
of alcohols as their diphenylmethyl ethers (DPM) is of
value from different points of view.3 DPM ethers are
inexpensive and show high stability toward different re-
agents and conditions. DPM ethers are also found as
parts of the structures of several pharmacologically ac-
tive compounds.4 Protection of OH groups as DPM
ethers is usually achieved using diphenylmethyl chloride
or bromide in the presence of a base,5 diphenylmethyl
diazomethane or diphenylmethyl phosphate–trifluoro-
acetic acid,6 diphenylmethanol in the presence of con-
centrated sulfuric acid7 or p-toluenesulfonic acid,8
xenon difluoride,9 ytterbium triflate–ferric chloride3 or
*
Corresponding authors. Tel.: +711 2284822; fax: +711 2280926;
e-mail: firouzabadi@susc.ac.ir
0040-4039/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.02.071

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H. Firouzabadi et al. / Tetrahedron Letters 46 (2005) 2683–2686
Table 1. Protection of thiols with DPM in the presence of catalytic amounts of AlPW12O40 (7 mol%) in CH2Cl2 at room temperature
AlPW12O40, 7 mol%
RSH
+
Ph2CHOH
Ph2HCSR + H2O
CH2Cl2, r.t.
Entry
Substrate
Product
Ph2CHSPh
Time (h)
Isolated yield (%)
1
2
3
4
5
PhSH
p-MeC6H4SH
PhCH2SH
2
4
92
96
90
81
86
p-MeC6H4SCHPh2
Ph2CHSCH2Ph
4
CH3CH2CH2SH
CH3(CH2)6CH2SH
Ph2CHSCH2CH2CH3
Ph2CHSCH2 (CH2)6CH3
24
16
6
7
5.5
95
92
SH
Ph2CHS
O
O
9
Ph2CHS
SH
Ph2CHS
SCHPh2
92a
90a
HS
8
9
6
4
SH
SH
HS
Ph2CHS
SCHPh2
a Ratio of dithiol to diphenylmethanol was 1:2.
diphenylmethyl thioethers in high yields at room
temperature in CH2Cl2. This catalyst effects protection
of thiols very selectively and efficiently in the presence
of hydroxyl groups. Thus, 2-thioethanol (1.1 mmol)
and diphenylmethanol (1 mmol) in the presence of
AlPW12O40 (4 mol%) produced 2-benzhydrylsulfanyl
ethanol in 95% yield at room temperature (Scheme 1).
water tolerant, heterogeneous, reusable, and environ-
mentally benign catalyst. The operational simplicity,
high yields of the products, high selectivity, and reus-
ability of the catalyst are the advantages of the present
protocol. Deprotection of the thioethers was achieved
using molecular iodine in CH3CN at room temperature
in high yields.
This selectivity was also demonstrated in competition
experiments as shown in Scheme 2.
2. Preparation of diphenylmethyl phenyl thioether as a
typical procedure
Protection of functional groups is only of value if a
deprotection protocol is available. We present here a
facile and simple procedure for deprotection of thio-
ethers using molecular iodine in refluxing CH2Cl2. The
reaction proceeded smoothly and the deprotected thiols
were isolated as their disulfides in high yields. The iso-
lated disulfides can be easily cleaved to their thiols by
the traditional method using Zn powder/HOAc.14
A mixture of thiophenol (1.1 mmol, 0.121 g), diphenyl-
methanol (1 mmol, 0.184 g) and AlPW12O40 (0.07 mmol,
0.2 g) in CH2Cl2 (3 ml) was stirred at room temperature
for 2 h. After completion of the reaction (monitored by
TLC), CH2Cl2 (10 ml) was added in order to precipitate
the catalyst which was removed by filtration. The excess
thiol in the filtrate was neutralized by the addition of a
solution of NaOH (5%, 10 ml). The organic phase was
separated washed with water (10 ml) and dried over
anhydrous MgSO4. After evaporation of the solvent,
the pure product was isolated in 92% yield (0.25 g).
In conclusion, we have developed a selective and effi-
cient protocol for the protection of SH groups in the
presence of OH groups catalyzed by AlPW12O40 as a
3. Deprotection of diphenylmethyl cyclohexyl thioether as
a typical procedure
AlPW12O40, 4 mol%
HS
Ph2HCS
+ Ph2CHOH
OH
OH
CH2Cl2, r.t.
95% Yield
1 h
+
H2O
To a solution of diphenylmethyl cyclohexyl thioether
(0.282 g, 1 mmol) in CH2Cl2 (5 ml), I2 (0.152 g,
0.6 mmol) was added and the mixture stirred at reflux
for 2 h. After completion of the reaction (monitored
by TLC), a solution of 10% Na2S2O3 (5 ml) was added
to the mixture until the color of unreacted iodine disap-
peared. To the mixture, CH2Cl2 (10 ml) was added and
the organic phase was separated, washed with water
(10 ml) and dried over anhydrous MgSO4. After evapo-
ration of the solvent, further purification was achieved
by column chromatography (eluent: petroleum ether/
EtOAc (95/5)) to afford the corresponding disulfide in
89% yield.
Scheme 1.
PhSH
AlPW12O40, 7 mol%
Ph2HCSPh
+
H2O
100%
0%
+ Ph2CHOH
+ Ph2CHOH
CH2Cl2, r.t.
2.5 h
PhOH
Ph2HCOPh + H2O
PhCH2SH
PhCH2OH
AlPW12O40, 7 mol%
Ph2HCSCH2Ph
+
H2O
100%
0%
CH2Cl2, r.t.
4 h
Ph2HCOCH2Ph + H2O
Scheme 2.

H. Firouzabadi et al. / Tetrahedron Letters 46 (2005) 2683–2686
2685
3.1. Spectral data of DPM thioethers
1610 (m), 1490 (s), 1450 (s), 1330 (w), 1260 (m), 1200
(m), 1070 (m), 1030 (m), 740 (s), 700 (s). MS (EI, 70
ev), m/e: M+ = 282; Anal. Calcd for (C19H22S): C,
80.80; H, 7.85. Found: C, 80.79; H, 7.83.
3.1.1. Ph2CHSPh. 1H NMR (250 MHz, CDCl3,
TMS): d (ppm) = 5.52 (s, 1H), 7.01–7.23 (m, 11H),
7.38 (d, 4H, J = 7.5); 13C NMR (63 MHz, CDCl3,
TMS): d (ppm) = 58.5, 128, 128.6, 129.3, 129.5, 129.8,
131.2, 137.3, 142.1; IR: m (cmÀ1) = 3060 (s), 3030 (s),
2935 (w), 1580 (s), 1475 (s), 1440 (s), 1170 (m), 1070
(s), 1015 (s), 920 (m), 850 (m), 750 (s) and 690 (s); MS
(EI, 70 eV), m/e: M+ = 276; Anal. Calcd for (C19H16S):
C, 82.57; H, 5.83. Found: C, 82.43; H, 5.81.
3.1.7. Ph2CHSC5H5O. 1H NMR (250 MHz, CDCl3,
TMS): d 3.52 (s, 2H), 5.09 (s, 1H), 6.02 (s, 1H), 6.18
(s, 1H), 7.17–7.31 (m, 7H), 7.69 (d, 4H, J = 7.5) ppm;
13C NMR (63 MHz, CDCl3, TMS): 29.2, 54.2, 109.7,
111, 127.8, 129, 129.1, 141.4, 142.7, 151.9 ppm; IR: m
(cmÀ1) = 3060 (s), 3040 (s), 2950 (m), 1610 (s), 1500
(s), 1450 (s), 1415 (w), 1250 (m), 1200 (s), 1160 (s),
1080 (s), 1015 (s), 920 (s), 730 (s), 700 (s). MS (EI, 70
ev), m/e: M+ = 280; Anal. Calcd for (C18H16OS): C,
77.11; H, 5.75. Found: C, 77.30; H, 5.75.
3.1.2. Ph2CHSC6H4–Me-p. 1H NMR (250 MHz,
CDCl3, TMS): d 2.19 (s, 3H), 5.45 (s, 1H), 6.92 (d,
2H, J = 7.75), 7.11–7.26 (m, 8H), 7.38 (d, 4H, J = 7.5)
ppm; 13C NMR (63 MHz, CDCl3, TMS): 21.8, 58.8,
128.0, 129.3, 130.3, 132.2, 137.6, 142.0 ppm; IR (neat):
m 3060 (s), 3030 (s), 2935 (m), 1580 (s), 1475 (s), 1440
(s), 1170 (m), 1070 (s), 1015 (s), 920 (m), 850 (m), 750
(s), 690 (s) cmÀ1. MS (EI, 70 eV), m/e: M+ = 290; Anal.
Calcd for (C20H18S): C, 82.71; H, 6.25. Found: C, 82.60;
H, 6.23.
3.1.8. Ph2CHSCH2CH2SCHPh2. 1H NMR (250 MHz,
CDCl3, TMS): d 2.51 (s, 4H), 5.05 (s, 2H), 7.09–7.24 (m,
12H), 7.32 (d, 8H, J = 7.5) ppm; 13C NMR (63 MHz,
CDCl3, TMS): 32.6, 54.7, 127.2, 128.1, 128.3,
141.7 ppm; IR: m (cmÀ1) = 3060 (s), 3010 (s), 2900 (s),
1610 (m), 1500 (s), 1450 (s), 1415 (w), 1250 (m), 1200
(s), 1160 (s), 1080 (s), 1015 (s), 920 (s), 730 (s), 700 (s).
MS (EI, 70 ev), m/e: M+ = 426; Anal. Calcd for
(C28H26S2): C, 78.83; H, 6.14. Found: C, 78.85; H, 6.16.
3.1.3. Ph2CHSCH2Ph. 1H NMR (250 MHz, CDCl3,
TMS): d 3.49 (s, 2H), 5.01 (s, 1H), 7.14–7.25 (m, 11H),
7.34 (d, 4H, J = 7.5) ppm; 13C NMR (63 MHz, CDCl3,
TMS): 37.2, 53.9, 127.6, 127.8, 129.0, 129.6, 138.6,
141.7 ppm; IR: m (cmÀ1) = 3060 (s), 3030 (s), 2935 (m),
1580 (s), 1475 (s), 1440 (s), 1170 (m), 1070 (s), 1015
(s), 920 (m), 850 (m), 750 (s), 690 (s). MS (EI, 70 ev),
m/e: M+ = 290; Anal. Calcd for (C20H18S): C, 82.71;
H, 6.25. Found: C, 82.61; H, 6.24.
3.1.9.
Ph2CHSCH2CH2CH2SCHPh2. 1H
NMR
(250 MHz, CDCl3, TMS): d 1.71 (t, 2H, J = 7), 2.34 (t,
4H, J = 7), 5.03 (s, 2H), 7.09–7.23 (m, 12H), 7.32 (d,
8H, J = 7.5) ppm; 13C NMR (63 MHz, CDCl3, TMS):
29.2, 31.86, 54.7, 127.2, 128.1, 128.3, 141.7 ppm; IR: m
(cmÀ1) = 3060 (s), 3010 (s), 2900 (s), 1610 (m), 1500
(s), 1450 (s), 1415 (w), 1250 (m), 1200 (s), 1160 (s),
1080 (s), 1015 (s), 920 (s), 730 (s), 700 (s). MS (EI, 70
ev), m/e: M+ = 440; Anal. Calcd for (C29H28S2): C,
79.04; H, 6.40. Found: C, 78.99; H, 6.41.
3.1.4. Ph2CHSCH2CH2CH3. 1H NMR (250 MHz,
CDCl3, TMS): d 0.86 (t, 3H, J = 5), 1.52 (m, 2H), 2.34
(t, 2H, J = 7.3), 5.12 (s, 1H), 7.11–7.26 (m, 6H), 7.39
(d, 4H, J =7.5) ppm; 13C NMR (63 MHz, CDCl3,
TMS): 14.7, 23.2, 34.6, 54.8, 127.6, 128.4, 128.8,
142.2 ppm; IR: m (cmÀ1) = 3040 (m), 3020 (m), 2925
(m), 2860 (m), 1610 (m), 1490 (s), 1450 (s), 1090 (m),
1030 (m), 740 (s), 700 (s). MS (EI, 70 ev), m/e:
M+ = 242; Anal. Calcd for (C16H18S): C, 79.29; H,
7.49. Found: C, 79.30; H, 7.48.
3.1.10. Ph2CHSCH2CH2OH. 1H NMR (250 MHz,
CDCl3, TMS): d 2.45 (t, 2H, J = 6.15), 2.88 (s, 1H),
3.51 (t, 2H, J = 6.15), 5.14 (s, 1H), 7.10–7.24 (m, 6H),
7.36 (d, 4H, J = 7.5) ppm; 13C NMR (63 MHz, CDCl3,
TMS): 34.8, 53.5, 60.3, 127.2, 128.1, 128.3, 141.7 ppm;
IR: m (cmÀ1) = 3200–3600 (b), 3060 (s), 3010 (s), 2900
(s), 1610 (m), 1500 (s), 1450 (s), 1415 (w), 1250 (m),
1200 (s), 1160 (s), 1080 (s), 1015 (s), 920 (s), 730 (s), 700
(s). MS (EI, 70 ev), m/e: M+ = 244; Anal. Calcd for
(C15H16OS): C, 73.73; H, 6.60. Found: C, 73.70; H, 6.58.
3.1.5. Ph2CHSCH2(CH2)6CH3. 1H NMR (250 MHz,
CDCl3, TMS): d 0.86 (t, 3H, J = 5), 1.22–1.26 (m,
10H), 1.50 (m, 2H), 2.34 (t, 2H, J = 7.27), 5.12 (s, 1H),
7.11–7.26 (m, 6H), 7.39 (d, 4H, J = 7.5) ppm; 13C
NMR (63 MHz, CDCl3, TMS): 14.7, 23.2, 29.0, 29.6,
32.4, 33.0, 34.6, 54.8, 127.6, 128.4, 128.8, 142.2 ppm;
IR (neat): m (cmÀ1) = 3040 (m), 3020 (m), 2925 (s),
2860 (s), 1610 (m), 1490 (s), 1450 (s), 1090 (m), 1030
(m), 740 (s), 700 (s). MS (EI, 70 eV), m/e: M+ = 312;
Anal. Calcd for (C21H28S): C, 80.71; H, 9.03. Found:
C, 80.68; H, 9.00.
Acknowledgements
Financial support from Iran Chapter of TWAS based at
ISMO and Shiraz University Research Council are
highly appreciated.
3.1.6. Ph2CHSC6H11. 1H NMR (250 MHz, CDCl3,
TMS): d 1.09–1.18 (m, 3H), 1.29–1.37 (m, 2H),1.42–
1.46 (m, 1H), 1.65–1.67 (m, 2H), 1.84–1.89 (m, 2H),
2.45 (m, 1H), 5.22 (s, 1H), 7.10–7.26 (m, 6H), 7.40 (d,
4H, J = 7.5) ppm; 13C NMR (63 MHz, CDCl3, TMS):
26.6, 33.8, 44.0, 58.6, 127.6, 128.4, 128.8, 142.6 ppm;
IR: m (cmÀ1) = 3060 (m), 3030 (m), 2940 (s), 2860 (s),
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