Simple and efficient deprotection of 1,3-dithianes and 1,3-dithiolanes by copper(II) salts under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2007.06.160

Aerobic solid state deprotection of 1,3-dithianes and 1,3-dithiolanes of aromatic and aliphatic aldehydes and ketones has been performed in excellent yields by Cu(NO₃)₂·2.5H₂O in the presence of montmorillonite K10 clay and sonic waves at room temperature. These dethioacetalizations proceed more slowly but efficiently under catalytic conditions by using 20% of the copper(II) salt with K10 clay and sonication.

Full text of DOI:10.1016/j.tetlet.2007.06.160

Tetrahedron Letters 48 (2007) 6150–6154
Simple and efficient deprotection of 1,3-dithianes and
1,3-dithiolanes by copper(II) salts under solvent-free conditions
*
´
Gabriela Oksdath-Mansilla and Alicia B. Penenory
˜ ˜
INFIQC, Departamento de Quı´mica Orga´nica, Facultad de Ciencias Quı´micas, Universidad Nacional de Co´rdoba,
Ciudad Universitaria, 5000 Co´rdoba, Argentina
Received 11 June 2007; accepted 26 June 2007
Available online 5 July 2007
Abstract—Aerobic solid state deprotection of 1,3-dithianes and 1,3-dithiolanes of aromatic and aliphatic aldehydes and ketones has
been performed in excellent yields by Cu(NO3)2Æ2.5H2O in the presence of montmorillonite K10 clay and sonic waves at room tem-
perature. These dethioacetalizations proceed more slowly but efficiently under catalytic conditions by using 20% of the copper(II)
salt with K10 clay and sonication.
Ó 2007 Elsevier Ltd. All rights reserved.
The protection of a carbonyl group is often a necessary
step in organic synthesis, especially in the total synthesis
of natural products and multifunctional organic com-
pounds. Thioacetals and cyclic thioacetals (1,3-dithianes
and 1,3-dithiolanes) are protecting groups commonly
used due to their easy access and high stability under
both acidic and basic conditions.1 Furthermore, cyclic
thioacetals are versatile synthetic reagents as acyl anion
equivalents for C–C bond formation;2 which is a com-
mon and successful strategy for the construction of com-
plex natural products.3
also been used in solution. Nevertheless, these methods
have some disadvantages such as long reaction times,
strong acids, toxic reagents and solvents, expensive cata-
lysts or not readily available reactives, and unwanted
side reactions.
Recently, an increased interest has been observed in
reactions under solvent-free conditions to reduce con-
tamination, lower costs, and simplify the process.13
These procedures usually combine supported reagents
and microwave14 (MW) or ultrasonic irradiation15 to
carry out a wide range of reactions in shorter times
and with high conversion and selectivity. Few examples
of solid state dethioacetalization have been reported to
use Clayfen/MW,16 ammonium persulfate on wet K10
under MW,17 Fe(NO3)3Æ9H2O/H3PMo12O40ÆxH2O,18
acidic ionic liquid [bmim]HSO4/MW,19 mercury(II)
nitrate trihydrate20 and benzyltriphenylphosphonium
peroxymonosulfate21 in the presence of AlCl3.
Many procedures are available for the preparation of
thioacetal; dethioacetalization, however, is not always
an easy step.1 Traditionally, deprotection of thioacetals4
has required drastic conditions, stoichiometric or an
excess amount of toxic reactives such as Hg2+ salts
and other heavy metal salts from Bi3+, Zn2+, Zr2+
V
,
5+, Ce3+, Ta5+, SbCl55 or SeO2. In addition, there
are methods under heterogeneous conditions which
use montmorillonite K10 supported Fe(NO3)3 and
Cu(NO3)2 (Clayfen and Claycop, respectively),6 or
NH4NO3 (Clayan);7 Cu(NO3)2 supported on silica
gel,8 Fe(NO3)3/K10/hexane.9 FeCl3Æ6H2O,10 Fe(phen)3-
(PF6)3,11 and other recent non-metallic reagents12 have
Therefore, it is still necessary to develop alternative
milder methods for dethioacetalization using inexpen-
sive, not toxic and accessible reagents. Thus, we report
herein a simple and convenient aerobic solvent-free
deprotection of thioketals/thioacetals by copper(II) salts
in the presence of montmorillonite K10 clay under ultra-
sonic irradiation (Scheme 1).
Keywords: Thioacetals; Solid state synthesis; Copper(II) salts; Oxida-
tion; Cleavage; Ultrasound.
We have selected 2-phenyl-1,3-dithiolane (1a) as a model
compound to examine the deprotection reaction by
copper(II) salts under a variety of reaction conditions.
*
Corresponding author. Tel.: +54 351 4334170; fax: +54 351
4333030; e-mail: penenory@fcq.unc.edu.ar
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.06.160

G. Oksdath-Mansilla, A. B. Pen˜e´n˜ory / Tetrahedron Letters 48 (2007) 6150–6154
6151
lar solid mixture of 1a and Cu(NO3)2Æ2.5H2O afforded
benzaldehyde in 92% yield after 3 h under sonic wave
irradiation. The small amount of salt employed did
not allow an efficient contact between both reagents
and, due to a poor homogenization of the reaction sys-
tem, the reaction was slower and consequently difficult
to be reproduced (Table 1, entries 1–3). There was no
reaction in the absence of Cu(NO3)2Æ2.5H2O, or in the
n
O
S
S
R2
Cu(NO3)2. 2.5 H2O / K10
air, rt,
R1
R2
R1
1
2
R1 = alkyl, aryl; R2 = H, alkyl, aryl; n = 1, 2
Scheme 1.
23
presence of NH4NO3 or CuSO4, and dithiane 1a was
Before studying the solvent-free reaction, a comparative
deprotection was performed in solvent media. Thus, the
reaction of 1a with Cu(NO3)2Æ2.5H2O (1 equiv) in
MeCN at rt in an open-air vessel afforded 92% of benz-
aldehyde after 180 min of stirring. With an excess of the
Cu(II) salt (3 equiv) the reaction is quantitative after
15 min of stirring (Eq. 1). In CH2Cl2 this reaction was
slower and was completed after 135 min. Comparable
results were obtained under nitrogen atmosphere, indi-
cating that in solution the presence of molecular oxygen
is not necessary. The different reactivity observed in
both solvents can be ascribed to a higher solubility of
the copper salt in MeCN. In comparison, the dethioace-
talization reported by Claycop (2 equiv) under heteroge-
neous conditions which employs a large excess of
CH2Cl2 requires 5 h for a complete conversion.6
recovered in 93–98% yields (Table 1, entries 4–6). The
acetate salt was also non reactive and the bromide gave
only 44% of benzaldehyde after 3 h of sonication (Table
1, entries 7 and 8). Thus, coordinating ligands decrease
or eliminate catalytic activity in Cu(II) salts, specifically
SO24ꢀ or OAcꢀ.24 A catalytic amount of HCl accelerates
the reaction by Cu(NO3)2, even though its sole presence
does not cause deprotection (Table 1, entries 9 and 10).
These results clearly show that the nature of the ligand
in the copper salt is essential, being the nitrate and, to
a lesser extent, the bromide, only reactive for the dethi-
oacetalization. K10 clay behaves only as an acidic sup-
port to favor the homogenization of both reagents.
When washed sand was used instead of K10, a complete
deprotection was also obtained. Finally, when the reac-
tion was performed under nitrogen atmosphere, only a
7% yield of benzaldehyde was quantified. This indicates
that the presence of air is required for a complete dep-
rotection of the dithiane by the copper salt (Table 1,
entry 11).
O
S
S
Cu(NO3)2.2.5 H2O (3 equiv)
MeCN, 15 min, air, rt
ð1Þ
H
Ph
2a (98%)
Ph
1a
H
A series of conditions were found to affect the solvent-
free deprotection reaction by Cu(II) salts with the results
illustrated in Table 1. The deprotection of 1a was
explored using a solid state mixture of both Cu(NO3)2Æ
2.5H2O and montmorillonite K10.22 In the absence of
sonic waves only 1% yield of benzaldehyde was achieved
after 3 h at room temperature, whereas ultrasonic irradi-
ation enhanced the deprotection reaction rate and dethi-
oacetalization of 1a was completed after 2 h of
sonication. Without the solid support K10, an equimo-
A variety of 1,3-dithianes and 1,3-dithiolanes of aro-
matic and aliphatic aldehydes and ketones were subject
to the optimized deprotection conditions (Table 1, entry
2) as described in Table 2. This method provides a gen-
eral and benign removal of thioacetals and thioketals on
substrates which bear different functional groups,
including electron acceptor and electron donor groups.
Thioacetals are more reactive than thioketals, and the
presence of EWG on the phenyl ring apparently acceler-
ates the reaction in comparison with electron donor
groups (Table 2, entries 8 and 9). Furthermore, a higher
reactivity is observed for 1,3-dithiane derivatives in rela-
tion to the corresponding 1,3-dithiolanes.
Table 1. Solvent-free deprotection of thioacetal 1a by copper(II) saltsa
Entry
Conditions
Time
(min)
Product
yieldb (%)
1c
2
3
4
5
6
7e
8
Cu(NO3)2Æ2.5H2O/K10/air
Cu(NO3)2Æ2.5H2O/K10/air
Cu(NO3)2Æ2.5H2O/air
K10/air
NH4NO3/K10/air
CuSO4/K10/air
Cu(OAc)2/K10/air
CuBr2/K10/air
Cu(NO3)2Æ2.5H2O/K10/air/HCl
(0.6 equiv)
HCl (0.6 equiv)/air
Cu(NO3)2Æ2.5H2O/K10/N2
180
120
180
180
180
180
180
180
25
1
94
92
0d
0d
0d
0f
For environmental reasons, it is fundamental to reduce
the use of copper salts under catalytic conditions. There-
fore, only 0.2 equiv of Cu(NO3)2 was employed to per-
form the cleavage of thiolane 1a (Eq. 2).25
O
S
S
Cu(NO3)2. 2.5 H2O (0.2 equiv)/K10
air, rt,
44g
92
ð2Þ
H
Ph
2a (92%)
Ph
H
9
1a
10
11
180
180
0d
7d
As illustrated in Table 3, very good to excellent depro-
tection is achieved by these mild conditions; the general
process is slowed down providing a major selectivity.
Thus, the ketone derivatives are markedly less reactive
than the aldehyde derivatives, probably as a result of
steric hindrance in the oxidation pathway.
a All reactions run at room temperature, with 1 mmol of 1a and
1 mmol of the inorganic salt and/or 1.3 g of K10, under sonication.
b Isolated yield.
c In the absence of sonic waves.
d 93–98% of unreacted 1a was recovered.
e Dithiane of 4-cyanobenzaldehyde (1b).
f 98% of unreacted 1b was recovered.
To gain insight into the reaction mechanism we exam-
ined the possibility of a one-electron oxidation pathway
g 54% of unreacted 1a was recovered.

6152
G. Oksdath-Mansilla, A. B. Pen˜e´n˜ory / Tetrahedron Letters 48 (2007) 6150–6154
Table 2. Deprotection of 1,3-dithiolanes/1,3-dithianes (1) with Cu(NO3)2Æ2.5H2O/K10 under solvent-free conditionsa
Entry
Substrate
R1
Time (h)
Yieldb (%)
n
R2
1
2
3
4
5
1
1
1
1
1
1a
1b
1c
1d
1e
Ph
H
H
Me
Ph
3
98
p-NCC6H4
Ph
1.5
5.5
3.5
4.5
97c
84
Ph
98c
92
R1–R2 = –(CH2)5–
S
S
6
1
1f
11
90
Me
7
8
9
10
11
12
2
2
2
2
2
2
1g
1h
1i
Ph
H
H
H
Me
Ph
Me
2.5
0.8
2
4
2
99
p-NCC6H4
p-MeOC6H4
Ph
Ph
Et
S
99c
95
1j
93
1k
1l
93c
93
1
13
2
1m
6
95
HO
S
a All reactions run at room temperature, with 1 mmol of 1 and 1 mmol of the inorganic salt and 1.3 g of K10, under sonication.
b Isolated yield by extraction with n-hexane.
c Isolated yield by extraction with CH2Cl2.
for this dethioacetalization. Cu(OAc)2 and Cu(OTf)2
CH2
+ PhS
Ph
SPh
salts are one-electron oxidants for the generation of
radical from lithium enolates and silyl enolether, respec-
tively.26 Aliphatic and aromatic dithianes and dithiol-
anes have oxidation potentials typically between 1.0–
1.6 V (vs SCE).27 Since trisphenanthroline iron(III)
hexafluorophosphate, (E1/2 = 0.69 V) has proved to be
a one-electron oxidant able to deprotect 1,3-dithianes
in solution,11 an ET oxidation of dithiane or dithiolane
by Cu(II) is also likely to be a favorable process
(Cu(OTf)2, E1/2 = 0.67 V).28 The ability of Cu(NO3)2
to oxidize sulfur compounds by an ET pathway was
assessed by means of cinammyl phenyl sulfide (3) as a
model compound to test the intermediacy of sulfur-
centered radical cation. It is known that 3Å+ affords the
thiyl radical and the stabilized cinnamyl cation by frag-
mentation of the C–S bond. These intermediates finally
render the disulfide and cinnamyl alcohol. Further oxi-
dation of alcohol 4 yields cinnamaldehyde and benzalde-
hyde, the latter by oxidative cleavage of the double bond
(Scheme 2).29
Ph
Ph
Ph
2x
3
H2O
+ Ph2S2
OH
O
4
6
5
+ PhCHO
7
Scheme 2.
The aerobic oxidation of sulfide 3 by the Cu(II) salt in
solid state rendered the fragmentation products 5, 6,
and 7 after 4 h under sonication (Eq. 3).30 This reaction
was strongly inhibited by the presence of a good electron
donor such as 1,2,4,5-tetramethoxybenzene31 (TMB,
1 equiv), and 91% of the sulfide 3 was recovered after
sonication.
Cu(NO3)2. 2.5 H2O / K10
4h, air, r.t.
5
+
6
+ 7
3
ð3Þ
(28%) (30%) (38%)
A similar result was observed when the deprotection
reaction of 1a was performed in the presence of the
TMB (1 equiv) and 93% of 1a was recovered after 2 h
under sonic wave irradiation. When 1b (1 mmol) was
treated with a different amount of Cu(NO3)2 (1 mmol,
0.2 mmol and 0.1 mmol), conversion to 2b was
completed after 1.5 h, 2 h and 3.5 h of sonication,
respectively. This suggests a catalytic cycle for the
dethioacetalization. The strong inhibition by a better
electron donor found, and the fragmentation products
observed in the reaction of 3, evidence an ET process
followed by fragmentation of the sulfur-centered radical
cation in the deprotection reaction by Cu(NO3)2. A
plausible mechanism is outlined in Scheme 3.32 After
ET, the sulfur radical cation can follow two competi-
tive pathways: (a) C–S bond fragmentation to render
the carbon radical 8; this radical can be captured by
Table 3. Catalytic deprotection of 1,3-dithiolanes/1,3-dithianes (1)
with Cu(NO3)2Æ2.5H2O/K10 under solvent-free conditionsa
Entry
Substrate
Time (h)
Yieldb (%)
1
2
3
4
5
6
1a
1b
1d
1h
1k
1e
4.5
2.5
24
4
24
48
92c
98
91
96
95
80
a All reactions run at room temperature, with a ratio substrate:
Cu(NO3)2Æ2.5H2O of 1.0:0.2 and 0.6 g of K10, at room temperature
under sonication.
b Isolated yield by extraction with CH2Cl2.
c Isolated yield by extraction with n-hexane.

G. Oksdath-Mansilla, A. B. Pen˜e´n˜ory / Tetrahedron Letters 48 (2007) 6150–6154
6153
of K10 under sonication. After 2.5 h under sonic wave
irradiation, the reaction mixture was extracted with n-
hexane affording benzophenone (11) and 4-cyanobenzal-
dehyde (13) in 65% and 38% yields, respectively (Eq. 5).
This example clearly shows the difference in reactivity
for both compounds at the initiation (oxidative ET pro-
cess) and propagation cycle. Seemingly, the C–S bond
cleavage would govern the reactivity observed.
n
S
n
S
n
S
Cu(NO3)2
ET,
(a)
S
S
S
Ph
H
Ph
H
Ph
H
1
1
8
(b)
O2
n
n
S
S
S
S
O O
Ph
H
10
H2O
Ph
H
9
O
O
O
Cu(NO3)2.2.5 H2O
/K10
+ e
Ph
+ e
Ph
H
Ph
1b
1k
+
+
ð5Þ
H
air, rt,
NC
11 (65%)
13 (38%)
Scheme 3.
In conclusion, we have developed a very simple and effi-
cient method for deprotection of dithianes and dithiol-
anes, which involves the use of a catalytic amount of
Cu(NO3)2 under air atmosphere, sonication and sol-
vent-free conditions. This protocol is a valuable alterna-
tive to the existing deprotection methods for economical
and environmental reasons. Finally, the participation of
the Cu(NO3)2 as one-electron oxidant was established.
To the best of our knowledge this is the first report of
oxidation of sulfur compounds by Cu(II) salts involving
an ET process.
molecular oxygen to give the peroxy radical 9, which
rearranges to the carbonyl compounds through another
ET step. (b) C–S bond fragmentation to afford a thiyl
radical and the carbocation 10; this cation can be
attacked by water and finally converted to the carbonyl
compounds.33 The observation of dethioacetalization
only in the presence of molecular oxygen in the solid
state conditions, suggests the participation of pathway
(a) for the formation of the carbonyl compound.34 In
contrast, the dethioacetalization reaction in homo-
geneous solution was not sensible to the atmosphere.
This can be more adequately attributed to the occurrence
of both competitive pathways, (a) and (b), Scheme 3.35
Representative experimental procedure for the general
solvent-free deprotection: approximately 1.3 g of K10
was placed in an Erlenmeyer (50 mL). After the addition
of Cu(NO3)2Æ2.5H2O (1 mmol) and thioacetal (1 mmol),
the reaction mixture was then lowered into a sonication
bath (Ultrasonik 28X, 45–49 kHz) and sonicated at
room temperature for the time specified in Table 2,
which was optimized to achieve a complete conversion.
After sonication, the mixture was washed with n-hexane,
filtered, and the extract was analyzed by GC and GC–
MS. Evaporation of the solvent under reduced pressure
afforded the crude product that was purified by radial
thin layer chromatography. The identity of all the prod-
In general, the lower reactivity observed for 1,3-dithiol-
anes compared with 1,3-dithianes (for example, entries 2
and 8, Table 2) is in agreement with the oxidation poten-
tial 300–400 mV more positive than the corresponding
dithiane. On the other hand, 1f requires longer times
of deprotection than 1d. This cannot be ascribed to a
less efficient ET process, since both substrates should
have similar oxidation potential. Instead, the C–S bond
fragmentation step and the subsequent ET pathways can
be responsible for the difference in the global reactivity.
Thus, for 1dÅ+ the C–S bond cleavage is faster since it
renders a more stable diphenylmethyl radical. When
an equimolar mixture of 1d and 1f was treated with
1 equiv of Cu(NO3)2/K10 under sonication for 3.5 h,
and the resulting reaction mixture was extracted by
n-hexane, benzophenone (11) and 1-adamantylmethyl-
ketone (12) were isolated in 88% and 90% yields, respec-
tively (Eq. 4). An equilibration of both radical cations
followed by a fast C–S bond fragmentation for 1dÅ+ trig-
gers a faster dethioacetalization for both dithiolanes.
1
ucts was confirmed by H and 13C NMR and MS spec-
trometry. The data for known compounds are in good
agreement with those reported. Spectroscopic data for
1m are provided.36
Acknowledgments
This work was supported in part by the Consejo Nac-
´
´
ional de Investigaciones Cientıficas y Tecnicas (CONI-
´
´
CET), Secretarıa de Ciencia y Tecnologıa (SECyT)-
O
Cu(NO3)2.2.5 H2O
/K10
O
´
Universidad Nacional de Cordoba (UNC) and Fondo
´
´
´
1f
para la Investigacion Cientıfica y Tecnologica (FON-
CyT). GOM gratefully acknowledges receipt of a fellow-
ship from CONICET.
1d
+
+
Ph
Ph
Me
12 (90%)
ð4Þ
air, rt,
11 (88%)
As previously mentioned, the presence of a more reac-
tive thio-derivative in the propagation cycle accelerates
the deprotection reaction of a less reactive sulfur com-
pound (Eq. 4). The deprotection of 1d or 1k under cat-
alytic conditions is expected to be faster in the presence
of 1b or 1h. Therefore, an equimolar mixture of 1b and
1k was treated with Cu(NO3)2 (0.4 equiv) in the presence
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cinnamaldehyde affords a mixture of cinnamaldehyde and
benzaldehyde. The oxidative cleavage of the cinnamalde-
hyde by Cu(II) was not avoided even at shorter reaction
times.
31. Epox (TMB) = 0.77 V, versus SCE in MeCN (Ref. 5).
32. The absence of reaction in the presence of NH4NO3/K10
only, and the reactivity observed by CuBr2 in our
experimental conditions allow us to attribute the forma-
tion of the sulfide radical cation to a reaction with the
Cu(II) ion. Nevertheless, a co-oxidation by NO2 could not
be entirely disregarded due to the formation of NO2
(brown gas) observed at the end of the reaction. Bosch and
Kochi reported that NO2 can catalyze the O2 oxidation of
sulfides via the formation of an electron donor–acceptor
(EDA) complex ½sulfide;NOþꢁNO3ꢀ, followed by ET to
produce a sulfur radical cation. Bosch, E.; Kochi, J. J.
Org. Chem. 1995, 60, 3172–3183, Further electrochemical
studies are required to elucidate the role of nitrate.
33. Pathway (a) has been proposed for the PET deprotection
of dithiane by pyrilium salts under O2 atmosphere
Kamata, M.; Kato, Y.; Hasegawa, E. Tetrahedron Lett.
1991, 32, 4349-4352; whereas pathway (b) has been
suggested for the dethioacetalization induced by visible
light and dyes (Epling, G. A.; Wang, Q. Tetrahedron Lett.
1992, 33, 5909–5912) and indirect electrochemical oxida-
tion, (Platen, M.; Steckhan, E. Tetrahedron Lett. 1980, 21,
511–514).
´
43, 6250–6284; (c) de la Hoz, A.; Dıaz-Ortiz, A.; Moreno,
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2623–2624.
17. Ganguly, N. C.; Datta, M. Synlett 2004, 659–662.
18. Zolfigol, M. A.; Mohammadpoor-Baltork, I.; Khazae, A.;
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305–308.
34. Another possibility would be a fast interconversion
between the two distonic radical cations 10 and 8, the
former a carbocation with a thiyl radical, and the latter a
carbon radical with a sulfur cation moiety.
19. Gupta, N.; Sonu; Kad, G. L.; Singh, J. Catal. Commun.
2007, 1323–1328.
20. Habibi, M. H.; Tangestaninejad, S.; Montazerozohori,
M.; Mohamadpoor-Baltork, I. Molecules 2003, 8, 663–
669.
21. Hajipour, A. R.; Mallakpour, S. E.; Mohamadpoor-
Baltork, I.; Adibi, H. Molecules 2002, 7, 674–680.
22. This procedure avoids a previous synthesis of Claycop.
23. However, NH4NO3 supported on K10 (Clayan) has been
reported as a reagent for deprotection of thioacetals and
thioketals, using a ratio substrate/Clayan of 1:7 (Ref. 7).
24. A similar result was reported for the aerobic sulfoxidation
by heterogeneous catalysis with cupric decamolybdodiva-
35. The deprotection of dithianes with Fe(phen)3(PF6) com-
plexes and SbCl5 requires an excess of the oxidant. Thus,
the mechanism proposed to account for this dethioacetal-
ization involves one-electron oxidation of a sulfur radical
to a sulfonium ion as a key step. This intermediate by a
second oxidative ET process affords a dication responsible
for the formation of the ketone. Refs. 11 and 5.
36. Spectral data for 1,3-dithiolane 1m: white solid. Mp
144.5–145.4°C, (petroleum ether). 1H NMR (200 MHz,
CDCl3, 30 °C): d = 1.44–1.51 (m, 3H), 1.59 (d, 2H), 1.71
(s, 2H), 1.92–1.95 (m, 2H), 2.13 (s, 1H), 2.40–2.51 (m, 6H),
2.79–2.83 (m, 4H). 13C NMR (50 MHz, CDCl3, 30 °C):
d = 25.1, 25.7, 26.0, 29.9, 31.4, 38.3, 40.3, 48.0, 57.5, 67.7.