Cleavage of 1,3-dithianes via acid-catalyzed hydrolysis of the corresponding 1,3-dithianemonooxides

Article abstract of DOI:10.1055/s-2008-1067164

The hydrolysis of 1,3-dithianes to their parent carbonyl compounds via their corresponding monosulfoxides was systematically investigated. The oxidation of the 1,3-dithianes was carried out in high yields using tert-butyl hydroperoxide. Acid-catalyzed hydrolysis of the monosulfoxides to the carbonyl compounds was then performed in excellent yields. The cleavage reactions were monitored by gas chromatography and kinetics were investigated on substrates varying in electron density and steric requirements. Neither effect prevented high overall yields in the cleavage reaction. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067164

PAPER
2369
Cleavage of 1,3-Dithianes via Acid-Catalyzed Hydrolysis of the Corresponding
1,3-Dithianemonooxides
Acid-Catalyzed
H
y
a
drolysis of
r
1, 3-Dith
s
ianemono
t
oxide
s
en Krohn,* Stephan Cludius-Brandt
Department Chemie, Universität Paderborn, Warburger Str. 100, 33098 Paderborn, Germany
Fax +49(5251)603245; E-mail: k.krohn@uni-paderborn.de
Received 30 January 2008; revised 23 April 2008
acetonitrile, is shown in Scheme 1. In the fist series of ex-
Abstract: The hydrolysis of 1,3-dithianes to their parent carbonyl
compounds via their corresponding monosulfoxides was systemati-
cally investigated. The oxidation of the 1,3-dithianes was carried
out in high yields using tert-butyl hydroperoxide. Acid-catalyzed
periments, a number of 1,3-dithianes 1a–g were synthe-
sized using known methods by reaction of the
corresponding carbonyl compounds with 1,3-pro-
hydrolysis of the monosulfoxides to the carbonyl compounds was panedithiol.6,7 As substrates, we selected aromatic, olefin-
then performed in excellent yields. The cleavage reactions were
monitored by gas chromatography and kinetics were investigated
on substrates varying in electron density and steric requirements.
Neither effect prevented high overall yields in the cleavage reac-
ic and aliphatic aldehydes and ketones 3a–g. Table 1
summarizes the synthesized dithianes and sulfoxides.
tion.
O
S
R1
S
R2
S
R1
S
R2
Key words: 1,3-dithianes, dithioacetals, 1,3-dithiane-1-oxides,
cleavage, dethioacetalization
R1
R2
O
1
2
3
R1 , R2 = alkyl, aryl, or H
Scheme 1 Hydrolysis of 1,3-dithianes 1 via their monosulfoxides 2
Table 1 Summary of Synthesized Dithianes and Sulfoxides
Dithioacetals are important protecting groups for carbon-
yl compounds due to their ease of formation and their sta-
bility under acidic and basic conditions.1 In addition, their
well known umpolung reactivity makes them extremely
useful reagents.2 Unfortunately, the regeneration of the
carbonyl groups often leads to unexpected difficulties. In
spite of the large number of deprotection methods,3 many
of these procedures have considerable drawbacks such as
the use of toxic reagents, long reaction times, harsh reac-
tion conditions, expensive catalysts, or the occurrence of
undesired side reactions. Therefore, there is still a need for
generally applicable and mild methods for the cleavage of
dithioacetals to their parent carbonyls.
Dithiane Yield Mp
Ref. mp Sulfoxide Yield Mp
Ref. mp
(%)
85
86
96
91
83
91
86
84
80
98
(°C)
(°C)
7413
6512
(%)
76
70
75
79
70
90
79
86
66
80
(°C) (°C)
1a
1b
1c
1d
1e
1f
72
2a
2b
139
152
88
–
63
–
bp 63 bp 62–6517 2c
–
112
178
107
108
31
11214
1814b
–
2d
2e
2f
144
203
119
140
82
2034b
–
1374b
In 1961, Kuhn et al. reported that the monosulfoxides of
1,3-dithianes undergo easy cleavage to the carbonyl com-
pounds in acidic methanol.4 Later, Krohn and Behnke
modified this method by transformation of photochemi-
cally generated 1,3-dithiane-1-oxides into the correspond-
ing dimethyl acetals, which were subsequently cleaved to
the carbonyl compound.5 However, neither of these very
convenient methods found many applications and were
not included in the latest review article on deprotecting
methods for 1,3-dithianes.3a Therefore, we initiated a sys-
tematic investigation with a selected number of 1,3-
dithianes varying in steric demand and electronic proper-
ties in order to probe the scope and limitations of the Kuhn
dithiane cleavage methodology.
1g
1h
1i
10815
3511
4216
–
2g
2h
2i
8110
–
–
–
40
76
1j
97
2j
171
The subsequent oxidation to the corresponding monosulf-
oxides 2a–g was carried out using tert-butyl hydroper-
oxide (TBHP) in dichloromethane and catalytic amounts
of camphorsulfonic acid (CSA).8 The yields in this trans-
formation were nearly quantitative and the formation of
higher oxidation products (sulfones or disulfoxides) was
not observed.
The straightforward hydrolysis of 1,3-dithianes 1, via
their oxidation to the monosulfoxides 2 and subsequent
cleavage to their parent carbonyl compounds 3 in acidic
The acidic hydrolysis reactions (see Table 2) were per-
formed in acetonitrile (1 mmol substrate in 10 mL aceto-
nitrile to which 0.5 mL of 6 N HCl was added) and
conducted overnight for reasons of convenience and in or-
der for the reactions to reach completion. Alternatively,
SYNTHESIS 2008, No. 15, pp 2369–2372
x
x.
x
x
.
2
0
0
8
Advanced online publication: 08.07.2008
DOI: 10.1055/s-2008-1067164; Art ID: T01408SS
© Georg Thieme Verlag Stuttgart · New York

2370
K. Krohn, S. Cludius-Brandt
PAPER
HO
complete conversion could also be observed by heating at
30 °C for 12 hours. The conversions were quantitative by
TLC comparison and no side products were formed ex-
cept the expected 1-(hydroxythio)-3-mercaptopropane
(see Scheme 2).4b The isolated yields were in the range of
91–95%; some losses in the workup procedure occurred in
the case of the volatile benzaldehyde 3a and ketone 3f.
The polar 1-(hydroxythio)-3-mercaptopropane or the
polymeric ethylenedisulfide were easily separated by fil-
tration over a short silica gel column (see Experimental).
O
HO
S
S
S
S
S
S
H+
R
R
R
R
R
R
O
H
H
HO
R
R
S
S
R
OH
OH
O
+
HS
S
– H+
R
Scheme 2 Assumed mechanism for the cleavage of 1,3-dithiane-1-
oxides in acidic acetonitrile
Table 2 Acidic Cleavage of 1,3-Dithiane-1-oxides in Acetonitrile
the beginning, the concentration increases more or less
exponentially and, after a short time, asymptotically when
approaching the termination of the cleavage reaction. The
formation of by-products was not observed in the GC. The
very polar 1-(hydroxythio)-3-mercaptopropane was easi-
ly separated by filtration over a short silica gel column.
Substrate
Time Product
(h)
Yield
(%)
O
O
S
S
2a 38
3a 83
O
O
O
S
S
S
O
O
2b 12
2c 12
2d 12
3b 94
3c 91
3d 95
S
S
S
O
Figure 1 Cleavage reaction of 2e (see Table 2) monitored by gas
chromatography. The formation of the product 3e is detected.
O
S
S O
2e 12
2f 12
3e 95
3f 86
Table 3 shows the calculated rate constants for a range of
substrates. For the kinetic investigation, the substrates
were selected according to steric and electronic para-
meters. Thus, the steric effects on the reaction rate should
be evaluated by comparison of compounds 2h and 2i in
Table 2, whereas electronic effects are exemplified by
compounds 2g and 2j. The results from the calculated rate
constants showed that increased steric hindrance did not
decrease the reaction rate. By contrast, the rate was even
larger in a sterically more hindered substrate (compounds
2h and 2i). This is in accord with the putative reaction
mechanism (Scheme 2) in which more stabilized carbeni-
um ions should enhance the reaction rate. The destabiliza-
tion of the carbenium ions by introduction of electron-
withdrawing groups (compound 2j), causing a small de-
crease in the reaction rate as seen by comparison of com-
pounds 2g and 2j, is in agreement with this assumption.
O
S
O
S
O
S
S O
8
2g
3g 93
min
Scheme 2 shows the assumed mechanism for the cleavage
reaction in acidic acetonitrile.4 In the first step, the addi-
tion of a proton to the oxygen atom of the sulfoxide leads
to the formation of a sulfonium ion. Subsequent ring-
cleavage gives an open-chain sulfur-stabilized carbenium
ion, which is then transformed into the corresponding car-
bonyl compound by nucleophilic attack by water.
In summary, we have shown for a representative number
of examples that the two-step Kuhn cleavage of 1,3-
dithianes via the corresponding monosulfoxides is a
straightforward and high-yielding process.
In order to gain insight into the kinetics of the cleavage re-
action, the formation of the desired product was moni-
tored by gas chromatography and the rate constants were
determined. A typical graph obtained by monitoring the
reactions by gas chromatography is shown in Figure 1. At
The method does not seem to be restricted by electronic or
steric effects and can be considered as an economic and
environmentally friendly alternative to existing methods.
Synthesis 2008, No. 15, 2369–2372 © Thieme Stuttgart · New York

PAPER
Acid-Catalyzed Hydrolysis of 1,3-Dithianemonooxides
2371
2,2-Bis(4-chlorophenyl)-[1,3]-dithiane (1j)19
Yield: 98%; mp 97 °C.
Table 3 Cleavage Reactions Monitored by Gas Chromatography
Substrate
Time
(min)
Rate constant
(min–1)
IR (KBr): 2892, 1486, 1396, 1272, 1087, 1014, 794, 788 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.02–2.13 (m, 2 H), 2.77–2.83 (m,
4 H), 7.30–7.39 (m, 4 H), 7.62–7.68 (m, 4 H).
O
1.6 × 10–3
0.07
S
S
13C NMR (50 MHz, CDCl3): d = 24.9, 29.8, 63.5, 129.0, 131.1,
2a
2h
2i
38 h
12
134.1, 141.2.
MS (EI): m/z (%) = 341 (58) [M]+, 265 (100), 230 (60), 199 (70),
154 (68), 110 (10), 75 (8), 44 (10).
S
S
HRMS: m/z calcd for C16H14S2Cl2: 341.3434; found: 340.99078.
O
t-Bu
S
2-Phenyl-1,3-dithiane-1-oxide (2a)
Yield: 76%; mp 138 °C (Lit.9 137 °C).
40 h
9.5 × 10–3
S
O
2-Styryl-1,3-dithiane-1-oxide (2b)
Yield: 70%; mp 152 °C.
IR (KBr): 2965, 2911, 1652, 1508, 1452, 1428, 1261, 1035 (S=O),
802, 698 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.30–2.94 (m, 5 H), 3.46–3.52 (m,
1 H), 4.37 (d, J = 7.7 Hz, 1 H), 6.27 (dd, J = 15.8, 7.7 Hz, 1 H), 6.86
(d, J = 15.8 Hz, 1 H), 7.17–7.44 (m, 5 H).
13C NMR (50 MHz, CDCl3): d = 30.1, 30.4, 49.7, 68.3, 122.1, 126.8,
127.2, 128.9, 130.6, 136.5.
S
S O
2g
2j
8
0.25
0.2
S
S O
15
MS (EI): m/z (%) = 238 (52) [M]+, 147 (64), 123 (72), 115 (100),
106 (17), 90 (27), 77 (15), 57 (13), 43 (25).
Cl
Cl
HRMS: m/z calcd for C12H14S2O: 238.0500; found: 238.0486.
However, the substrates have to be stable to the TBHP ox-
idation and the mild acidic cleavage conditions.
2-Phenylethyl-1,3-dithiane-1-oxide (2c)
Yield: 75%; mp 88 °C.
IR (KBr): 2906, 1718, 1558, 1448, 1033, 752, 703 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.97–2.01 (m, 2 H), 2.38–2.95 (m,
7 H), 3.41 (m, 1 H), 3.58 (t, J = 7.6 Hz, 1 H), 7.16–7.28 (m, 5 H).
13C NMR (50 MHz, CDCl3): d = 29.4, 29.9, 30.4, 31.7, 54.1, 65.53,
126.4, 128.6, 129.3, 137.2.
Column chromatography was performed on silica gel 60 (particle
size 0.040–0.063 mm). Melting points were measured on a Büchi
SMP-20 melting point apparatus using one-side-open capillary
tubes, and are uncorrected. NMR spectra were recorded at r.t. on a
Bruker ARX 200 or ARX 500 instrument. Chemical shift values (d)
are given in ppm relative to TMS. IR spectra were measured on a
Nicolet 510P FT-IR Spectrometer. GC analyses were carried out on
a Hewlett–Packard 5890 Series II instrument. Solvents were puri-
fied if necessary by standard methods.
MS (EI): m/z (%) = 240 (10) [M]+, 224 (15), 150 (15), 123 (92), 117
(98), 91 (100), 65 (38), 51 (10), 41 (23).
HRMS: m/z calcd for C12H16S2O: 240.3937; found: 240.0642.
Oxidation of 1,3-Dithianes to 1,3-Dithiane-1-oxides; General
Procedure
2-(Napthalene-6-yl)-1,3-dithiane-1-oxide (2d)
Yield: 79%; mp 144 °C.
A stirred solution of dithiane 1 (1 mmol) in CH2Cl2 (5 mL) was
treated with a tert-butyl hydroperoxide (TBHP) solution in CH2Cl2
(1 mL, 2 mmol) and a catalytic amount of CSA (0.1 mmol). The re-
action mixture was stirred at r.t. and monitored by TLC until com-
plete (8–12 h). The mixture was then poured directly onto a short
silica gel column (10 g) and eluted with CH2Cl2 (50 mL) to afford
the pure sulfoxide from the nonpolar fraction after evaporation of
the solvent.
IR (KBr): 2981, 2908, 1596, 1432, 1272, 1149, 1033, 825, 759
cm–1.
1H NMR (200 MHz, CDCl3): d = 2.42–3.06 (m, 5 H), 3.65 (m, 1 H),
4.79 (s, 1 H), 7.43–7.58 (m, 3 H), 7.79–8.01 (m, 4 H).
13C NMR (50 MHz, CDCl3): d = 30.1, 31.4, 49.8, 69.6, 124.9, 126.3,
128.0, 128.5, 128.6, 131.1, 133.7, 135.9.
MS (EI): m/z (%) = 262 (100) [M]+, 171 (57), 141 (16), 106 (20), 90
(23), 57 (20).
9-Phenyl-1,5-dithiaspiro[5,5]undecane (1f)18
Yield: 91%; mp 107 °C.
HRMS: m/z calcd for C14H14S2O: 262.4003; found: 262.0486.
IR (KBr): 2923, 1596, 1488, 1417, 1270, 1099, 991, 900, 759, 700
cm–1.
1H NMR (200 MHz, CDCl3): d = 1.73–2.11 (m, 8 H), 2.49–2.55 (m,
3 H), 2.79–2.98 (m, 4 H), 7.22–7.35 (m, 5 H).
13C NMR (50 MHz, CDCl3): d = 26.1, 26.7, 29.9, 38.4, 44.5, 50.1,
126.5, 127.3, 128.8, 147.0.
MS (EI): m/z (%) = 264 (100) [M]+, 189 (60), 145 (50), 104 (16), 91
2,2-Diphenylene-1,3-dithiane-1-oxide (2e)
Yield: 70%; mp 203 °C (Lit.4b 203 °C).
1H NMR (200 MHz, CDCl3): d = 2.73–2.96 (m, 2 H), 3.17–3.21 (m,
4 H), 7.32–8.05 (m, 8 H).
13C NMR (50 MHz, CDCl3): d = 26.0, 45.9, 67.8, 125.8, 127.1,
128.4, 130.4, 141.3, 142.5.
(20), 41 (10).
9-Phenyl-1,5-dithiaspiro[5,5]undecane-1-oxide (2f)
Yield: 90%; mp 119 °C.
HRMS: m/z calcd for C15H20S2: 264.4590; found: 264.1006.
Synthesis 2008, No. 15, 2369–2372 © Thieme Stuttgart · New York

2372
K. Krohn, S. Cludius-Brandt
PAPER
Reaction Conditions and Sampling for the GC Analyses
IR (KBr): 2925, 1596, 1492, 1438, 1234, 1098, 1037, 991, 902, 759,
700 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.87–3.18 (m, 15 H), 7.24–7.35
(m, 5 H).
13C NMR (50 MHz, CDCl3): d = 24.7, 28.4, 32.9, 43.8, 48.6, 63.1,
126.7, 127.2, 128.9, 146.3.
MS (EI): m/z (%) = 280 (100) [M]+, 263 (80), 189 (70), 157 (60),
129 (30), 106 (35), 90 (70), 77 (10), 41 (15).
Sulfoxides 2 (0.15 mmol) were dissolved in MeCN (2 mL), 6 N HCl
(0.05 mL) was added and the solution was stirred at r.t. At one
minute intervals a sample (0.2 mL) was taken and neutralized with
a small amount (15 mg) of basic ion exchange resin III (Merck
104767, OH– form). The suspension was poured onto a small silica
gel column (1.5 cm long, 0.4 mm diameter) and eluted with hexane
(1 mL) to remove the polar 1-(hydroxythio)-3-mercaptopropane.
The filtrate was made up to a total volume of 2 mL to obtain the
standard solution for GC analysis [He, 0.4 bar; Split/splitless-inj.,
260 °C, 1 mL injection; Column: DB 5, 30 m, 0.25 mm ID, 0.25 mm;
Temp.: 80 °C, 1 min; 5 °C/min, 250 °C; Detector: FID, 260 °C].
HRMS: m/z calcd for C15H20S2O: 280.4583; found: 280.0955.
2,2-Diphenyl-1,3-dithiane-1-oxide (2g)
Yield: 79%; mp 141 °C (Lit.4b 137 °C).
Prior to measuring the reaction samples, the GC was calibrated by
measuring a dilution series of the respective carbonyl compounds
(3; 0.05 mg/mL, 0.07 mg/mL, 1 mg/mL, 3 mg/mL). For sample
measurements, a volume of 1 mL was injected; each sample was
measured three times.
1H NMR (200 MHz, CDCl3): d = 2.14–2.74 (m, 5 H), 3.01 (m, 1 H),
7.37–7.55 (m, 10 H).
13C NMR (50 MHz, CDCl3): d = 24.8, 29.9, 39.2, 70.3, 128.7, 129.4,
130.4, 142.3.
Acknowledgment
2-tert-Butyl-2-methyl-1,3-dithiane-1-oxide (2h)
Yield: 86%; mp 82 °C (Lit.10 81 °C).
We thank Dr Heinz Weber for professional help with the GC analy-
sis and Mariola Zukowski for the MS measurements. Furthermore
we thank Prof van Ree for checking the manuscript.
1,5-Dithiaspiro[5,5]undecane-1-oxide (2i)
Yield: 66%; mp 76 °C.
IR (KBr): 2917, 2856, 1442, 1228, 1145, 1097, 1033, 941, 860, 738
cm–1.
References
1H NMR (200 MHz, CDCl3): d = 1.13–3.04 (m, 15 H), 3.69 (m,
(1) (a) Wuts, P. G. M.; Greene, T. W. Greene's Protective
Groups in Organic Synthesis, 4th ed.; Wiley: New York,
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Thieme Verlag: Stuttgart, 2004.
1 H).
13C NMR (50 MHz, CDCl3): d = 23.8, 25.8, 26.1, 26.8, 39.8, 53.2,
59.8.
MS (EI): m/z (%) = 204 (91) [M]+, 187 (100), 145 (20), 122 (40),
106 (37), 81 (98), 79 (36), 57 (23), 41 (43).
(2) Seebach, D. Synthesis 1969, 17.
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Synthesis 1977, 357.
HRMS: m/z calcd for C9H16S2O: 204.3603; found: 204.0642.
(4) (a) Kuhn, R.; Baschang-Bister, W.; Dafeldecker, W. Justus
Liebigs Ann. Chem. 1961, 641, 160. (b) Kuhn, R.;
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2,2-Bis(4-chlorophenyl)-1,3-dithiane-1-oxide (2j)
Yield: 80%; mp 171 °C.
IR (KBr): 2915, 1654, 1490, 1400, 1268, 1093, 1035, 1014, 852,
790 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.25–2.93 (m, 5 H), 3.13 (m, 1 H),
7.21–7.48 (m, 4 H), 7.81–7.95 (m, 4 H).
13C NMR (50 MHz, CDCl3): d = 26.6, 29.5, 45.9, 72.1, 129.9, 131.5,
135.3, 137.4.
MS (EI): m/z (%) = 357 (10) [M]+, 344 (10), 308 (30), 261 (60), 250
(68), 200 (36), 155 (32), 141 (58), 138 (100), 110 (62), 106 (10), 75
(30), 50 (10), 41 (20).
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1974, 767.
HRMS: m/z calcd for C16H14S2Cl2O: 357.3428; found: 356.9905.
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Cleavage of 1,3-Dithiane-1-oxides in Acidic Acetonitrile; Gen-
eral Procedure
A solution of sulfoxide (1 mmol) in MeCN (10 mL) was treated
with 6 N HCl (0.5 mL) and the solution was stirred at r.t. overnight.
When the reaction was complete (TLC monitoring), the solution
was neutralized by addition of an equivalent amount of basic ion
exchange resin III (Merck 104767, OH– form) and stirred for sever-
al minutes. The suspension was filtered and the ion exchanger was
washed with MeCN (5 mL). The filtrate was evaporated to dryness
under reduced pressure and the residue was dissolved in a minimum
amount of MeCN and purified by filtration through a short column
of silica gel (1.5 cm long, 0.4 mm diameter) using petroleum ether
as the eluent to remove the polar 1-(hydroxythio)-3-mercaptopro-
pane.
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Lett. 2003, 44, 919.
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Synthesis 2008, No. 15, 2369–2372 © Thieme Stuttgart · New York