Efficient chemoselective mild deprotection of S,S-and S,O-acetals and ketals with electrophilic halogens

Article abstract of DOI:10.1080/10426500500326305

A novel and simple method for the chemoselective deprotection of S,S- and S,O-acetals and ketals in the presence of their O,O-analogs with electrophilic halogens to their corresponding carbonyl compounds is described using N-bromosuccinimide, N-chlorosuccinimide, 2,4,4,6-tetrabromo-2,5-cyclohexen-1- one, trichlorocyanuric acid, or molecular bromine in aqueous acetonitrile. The use of these reagents in the presence of hydrated silica gel provide efficient, novel, and mild procedures for the deprotection of cyclic and acyclic O,O-, S,S-, and S,O-acetals and ketals in excellent yields in short reaction times. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426500500326305

Phosphorus, Sulfur, and Silicon, 181:1059–1071, 2006
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500500326305
Efficient Chemoselective Mild Deprotection of S,S-
and S,O-Acetals and Ketals with Electrophilic Halogens
Hamid Reza Shaterian
Hassan Hadadzadeh
Department of Chemistry, University of Sistan and Baluchestan,
Zahedan, Iran
A novel and simple method for the chemoselective deprotection of S,S- and
S, O-acetals and ketals in the presence of their O,O-analogs with electrophilic
halogens to their corresponding carbonyl compounds is described using N-
bromosuccinimide, N-chlorosuccinimide, 2,4,4,6-tetrabromo-2,5-cyclohexen-1-one,
trichlorocyanuric acid, or molecular bromine in aqueous acetonitrile. The use of
these reagents in the presence of hydrated silica gel provide efficient, novel, and mild
procedures for the deprotection of cyclic and acyclic O,O-, S,S-, and S,O-acetals and
ketals in excellent yields in short reaction times.
Keywords Chemoselective; deprotection; electrophilic halogens; hydrated silica gel; S,O-
acetals and ketals; S,S-acetals and ketals
Thioacetals and ketals as important intermediates in multistep natu-
ral product synthesis1,2 are stable compounds in both acidic and basic
conditions, and their deprotection to carbonyl groups, especially under
mild reaction conditions, are considered an important transformation
reaction in organic synthesis.
The methods employed for the deprotection of S,S-acetals include
(a) hydrolysis in the presence of different transition-metal ions,3−10 (b)
oxidation of sulfur to a higher oxidation state with various oxidizing
agents,11−18 and (c) hydrolysis19−21 and use of alkylating agents.21b
A review has been published on the methods of preparation and cleav-
age of 1,3-dithiolanes.22
Although some of the reported methods in the literature can be ap-
plied for the chemoselective deprotection of O,O- acetals and ketals in
Received May 1, 2005; accepted June 18, 2006.
We are thankful to the Sistan and Baluchestan University Research Council for their
partial support of this work.
Address correspondence to Hamid Reza Shaterian, University of Sistan and
Baluchestan, Department of Chemistry, Faculty of Science, PO Box 98135-674, Zahedan,
Iran. E-mail: hrshaterian@hamoon.usb.ac.ir
1059

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H. R. Shaterian and H. Hadadzadeh
the presence of S,S- and S,O- analogs, to the best of our knowledge, there
is no report available in the literature concerning reverse chemoselec-
tivity. In our previous research, we reported catalytic and chemoselec-
tive deprotection of S,S- and S,O-acetals and ketals in the presence of
their O,O-analogs with electrophilic halogens under neutral conditions
using DMSO as oxygen transfer.23
Now we report a novel and a highly chemoselective protocol for
the deprotection of S,S- and S,O- acetals and ketals in the presence
of their O,O- analogs. In this method, N-Bromosuccinimide (NBS),
N-Chlorosuccinimide (NCS), 2,4,4,6-Tetrabromo-2,5-Cyclohexadien-1-
One (TABCO), Trichlorocyanuric Acid (TCCA), or bromine are used as
sources of electrophilic halogens in aqueous acetonitrile. Halogens car-
ried by these reagents interact with the soft sulfur atom in S,S- and
S,O- acetals and ketals and water as a hydrolyzing agent and source
of oxygen. The ease of halogenation of the sulfur atom in S,S- and S,O-
acetals and ketals in comparison with the oxygen in the O,O-analogs
let the reaction occur with high chemoselectivity for the deprotection of
S,S- and S,O-acetals and ketals at r.t. (Scheme 1).
SCHEME 1
We first performed the deprotection reaction of 2-phenyl-1,3-dithiane
using NBS, NCS, TABCO, TCCA, and Br2 reagent in aqueous acetoni-
trile (Scheme 1, condition A) at r.t. It was observed that the rate of
the reactions and the molar ratio of dithiane/reagent (1/1.3) with these
reagents were nearly the same and the reactions were completed af-
ter 15 min to produce benzaldehyde in a 91–95% yield. Therefore, we
applied similar reaction conditions to other S,S- and S,O- acetals and ke-
tals. Experimentally it was observed that at least one molar equivalent
of electrophilic halogens for S,S- acetals and ketals and half an equimo-
lar amount for S,O- acetals and ketals were required. The results of this
investigation are shown in Table I. By these methods, cyclic and acyclic
thioacetals and also 1,3-oxathiolanes carrying electron-withdrawing or
electron-donating groups on their aromatic rings were converted into
their corresponding carbonyl compounds easily at r.t. within 10–80 min.
2,2-diphenyl-1,3-dithiane, and mono-1,3-dithiane of camphor quinone

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Efficient Chemoselective Mild Deprotection
1063
as examples of hindered dithioacetals were also converted into ben-
zophenone and camphor quinone, respectively, with good yields (Table I,
Entries 11, 12). In the case of S,S- and S,O-acetals and ketals carrying
enolizable hydrogens, the addition of pyridine (1.5 equimolar) to the re-
action mixture greatly reduced the formation of α-brominated carbonyl
compounds in the reaction mixtures (Table I, entries 10, 13, and 14).
The deprotection of structurally different thioacetals produced the
corresponding aldehydes or ketones together with structurally differ-
ent organo-sulfur compounds. The production of disulfides from acyclic
dithioacetals in the presence of electrophilic halogens were also de-
tected and isolated in high yields from the reaction mixtures under
this study. The structure of the isolated disulfides (II) was identified by
comparison of their physical data with authentic samples.24,25 We have
proposed a mechanism for the production of the disulfides and carbonyl
compounds from acyclic dithioacetals (Scheme 2).
SCHEME 2
Easily polymerizable 1,2-dithiacyclopentane, which is stable in
dilute solutions, is produced in the reaction of 1,3-dithianes in the
presence of electrophilic halogens. The structure of this compound was
1
identified by comparison of its H and 13C NMR spectral data with
those reported in the literature24 and also by the synthesis of

1064
H. R. Shaterian and H. Hadadzadeh
1,2-dithiacyclopentane by an intramolecular coupling of 1,3-
propanedithiol by the known procedure.25
Cyclic 1,3-oxathiolanes under similar reaction conditions, in addi-
tion to carbonyl compounds, bis(2-hydroxyethyl) disulfide, was also pro-
duced in high yields. The structures of the isolated bis(2-hydroxyethyl)
disulfide was identified by comparison of its physical data with those
reported in the literature24,25 and also by its synthesis from 2-
mercaptoethanol by the reported procedure.26
1,3-dithiolanes in the process of deprotection reactions produce
a cyclic compound with four sulfur atoms. Easily polymerizable
1,2,5,6-tetrathiacylooctane was detected in the reaction mixture and
identified by spectroscopic data and also by its synthesis from the
coupling reaction of 1,2-ethanedithiol.24,25 In this mechanism, 1,2,5,6-
tetrathiacylooctane can be produced either by the intermolecular re-
action between (I) and a molecule of 1,3-dithiolane or through the
formation of unstable intermediate 1,2-dithiacyclopentane24,25 that is
produced in the reaction by intramolecular coupling of (I).
We have also studied the possibility of using these reagents for
the chemoselective deprotection of S,S-, and S,O-acetals and ketals in
the presence of their O,O-analogs in aqueous acetonitrile in the pres-
ence of pyridine as an acid scavenger. Pyridine does not show a consider-
able effect on the rate of the reactions but greatly prevents deprotection
of O,O-acetals and ketals in the presence of their S,S- and S,O-analogs
by the removal of the produced acid. The results of this investigation
using TABCO as a representative reagent are shown in Table II. By
this method, 2-phenyl-1,3-dithiane was deprotected in the presence of
benzaldehyde dimethyl acetal with the ratio of 100/8 (Table II, entry 1).
When we used 2-phenyl-1,3-dioxane that is more stable than benzalde-
hyde dimethyl acetal, excellent chemoselectivity was observed with the
ratio of 100/5, and in the presence of even more stable 4-nitrophenyl-
1,3-dioxane, the ratio of 100/2 was obtained (Table II, entries 2, 4). The
deprotection of the S,S-acetal and S,O-acetal in the presence of O,O-
ketals also can be performed with excellent chemoselectivity (Table II,
entries 5–9).
In order to extend the applicability of these reagents for the depro-
tection of O,O-acetals and ketals, we developed a very simple method
and used these reagents in the presence of hydrated silica gel in
dichloromethane. In this procedure, silica gel (2.5 g) and water (1.5 mL)
were stirred vigorously until a free-flowing powder was obtained. A
solution of O,O- , O,S-, or S,S-acetals or ketals (1.0 mmol) in CH2Cl2
(5 mL) was added to the resulting silica gel. To this mixture, a solution
of TABCO, NBS, NCS, TCCA, or Br2 (Table III) in CH2Cl2 (5 mL) was
added and stirred at r.t. for 10 min. During this period, TLC and GC

Efficient Chemoselective Mild Deprotection
1065
TABLE II Selective Deprotection of Cyclic and Acyclic O,O-Acetals
and Ketals in the Presence of S,S- and S,O-Acetals and Ketals with
TABCO in Aqueous Acetonitrile at r.t.
Substrate 1
Substrate 2
Product 1
Product 2
Time
(min)
Yield
Entry
1
(%)a,b,c
8
100
8
2
12
100
5
3
4
5
12
25
25
100
7
100
2
100
1
(Continued on next page)

1066
H. R. Shaterian and H. Hadadzadeh
TABLE II Selective Deprotection of Cyclic and Acyclic O,O-Acetals
and Ketals in the Presence of S,S- and S,O-Acetals and Ketals with
TABCO in Aqueous Acetonitrile at R. T. (Continued)
Substrate 1
Substrate 2
Product 1
Product 2
Time
(min)
Yield
Entry
6
(%)a,b,c
30
100
0
7
8
25
98
2
35
40
98
5
9
97
7
aYields based on analysis by NMR and GC (n-heptane was used as internal
standard).
bThe ratio of S,S-acetal/O,O-acetal/TABCO is 1/1/1.2.
cThe reaction was performed in the presence of two molar equivalents of pyridine.
analysis confirmed the complete disappearance of the reactant. Simple
filtration and chromatography on a short silica gel column afforded the
corresponding carbonyl compounds in excellent yields. The results of
this study are also shown in Table III.

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Efficient Chemoselective Mild Deprotection
1069
We believe hydrated silica gel plays the following important roles in
the reactions we have studied: (a) Silica gel acts as an acid scavenger,
and by the absorption of hydrogen halides, enolization of the carbonyl
compounds is minimized; consequently, the amount of α-halogenated
carbonyl compounds is drastically reduced; (b) the water in the hy-
drated silica gel acts as an oxygen an transfer source and hydrolyzes the
sulfonium intermediate easily; (c) deprotection of S,S- and S,O-acetals
and ketals in the presence of hydrated silica gel occurs much faster
than that observed in aqueous acetonitrile but with a lack of selectiv-
ity; and (d) using this method, the efficient mild deprotection of cyclic
and acyclic O,O-, S,S-, and S,O-acetals and ketals to their carbonyl com-
pound was achieved in excellent yields at r.t. High yields of desired
products, short reaction times, and easy work up in comparison with
aqueous acetonitrile media are the advantage of this system (Tables I
and III).
In conclusion, high chemoselectivity that has been observed in the
presence of pyridine using NBS, NCS, TCCA, TABCO, and Br2 in aque-
ous acetonitrile is an excellent practical achievement in organic syn-
thetic methods. The use of NBS, NCS, TCCA, TABCO, and Br2 as
sources of electrophilic halogens in the presence of hydrated silica gel
in CH2Cl2 provide efficient, novel, and mild procedures for the de-
protection of cyclic and acyclic O,O-, S,S-, and S,O-acetals and ketals.
In addition, in both of procedures, cheapness and availability of the
reagents, simplicity of the procedures, short reaction times, and excel-
lent yields can be considered strong practical points for the presented
protocols.
EXPERIMENTAL
All yields refer to isolated products. The products were purified by col-
umn chromatography and the purity determination of the products
were accomplished by GLC on a Shimadzu model GC-8A instrument
or by TLC on Silica-gel polygram SIL G/UV 254 plates. Mass spectra
were run on a Shimadzu GC MS-QP 1000EX at 75 eV. IR spectra were
recorded on a Perkin-Elmer 781 spectrophotometer. The NMR spectra
were recorded on a Bruker Avance DPX 250 MHz instrument.
General Procedure for the Deprotection of Cyclic and Acyclic
Dithioacetals and 1,3-Oxathiolanes to Their Parent Carbonyl
Compounds Using Electrophilic Halogens in Aqueous CH3CN
To a solution of dithioacetals or 1,3-oxathiolanes (1.0 mmol) in 20%
aqueous acetonitrile (5 mL) a solution of TABCO, NBS, NCS, TCCA, or

1070
H. R. Shaterian and H. Hadadzadeh
Br2 (Table I) in CH3CN (5 mL) was added. The resulting mixture was
stirred at room temperature for 30–50 min (Table II). The progress of
the reaction was monitored by TLC and GC analysis. Upon completion
of the reaction, CH2Cl2 (25 mL) was added to the reaction mixture.
The solution was washed in an aqueous solution of NaOH (5%, 20 mL)
followed with brine solution (10 mL) and water (2 × 10 mL). The organic
phase was separated and dried over anhydrous sodium sulfate. After
evaporation of the solvent followed by chromatography on short silica
gel column (hexane/EtOAc 8/2), the desired carbonyl compound(s) was
obtained in excellent yield(s) (Table I).
General Procedure for the Deprotection of Cyclic and Acyclic
Dithioacetals and 1,3-Oxathiolanes to Their Parent Carbonyl
Compounds Using Electrophilic Halogens and Hydrated Silica
Gel in Dichloromethane
Silica gel (2.5 g) was placed in a round-bottom flask (100 mL) equipped
with a magnetic stirrer and a loosely fitted rubber septum. Water (1.5 g)
was added to the vigorously stirred silica gel. After complete addition
of water, stirring continued until a free-flowing powder was obtained
(5 min). A solution of dithioacetals or 1,3-oxathiolanes (1.0 mmol) in
CH2Cl2 (5 mL) was added to the hydrated silica gel. To this mixture,
a solution of TABCO, NBS, NCS, TCCA, or Br2 (Table III) in CH2Cl2
(5 mL) was added. The mixture was stirred at r.t. for 10 min. The mix-
ture was then filtered through a sintered glass funnel, and the solid
residue was washed with CH2Cl2 (5 × 10 mL). Removal of the solvent
under vacuum gave the crude product(s). After chromatography on sil-
ica gel using n-hexane/EtOAc 8/2 as eluent, the carbonyl compound(s)
were obtained in excellent yield(s). The product was characterized by
comparison of its physical data (m.p. or b.p.), IR, and 1HNMR spectral
data with those of known aldehydes and ketones.
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