Oxidative deprotection of 1,3-dithiane group using NaClO2 and NaH2PO4 in aqueous methanol

Article abstract of DOI:10.1055/s-2004-829558

The 1,3-dithiane group was oxidatively deprotected under the conditions of sodium chlorite, sodium dihydrogenphosphate, and 2-methyl-2-butene in 3:1 methanol-water at room temperature in good yield.

Full text of DOI:10.1055/s-2004-829558

1686
LETTER
Oxidative Deprotection of 1,3-Dithiane Group Using NaClO2 and NaH2PO4 in
Aqueous Methanol
O
xidative Depr
a
otection of
k
1, 3-Dithiane
a
G
roup hiro Ichige,a Annu Miyake,a Naoki Kanoh,a,b Masaya Nakata*a
a
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku,
Yokohama 223-8522, Japan
Fax +81(45)5661551; E-mail: msynktxa@applc.keio.ac.jp
b
Antibiotics Laboratory, Discovery Research Institute, RIKEN (The Institute of Physical and Chemical Research), 2-1 Hirosawa, Wako,
Saitama 351-0198, Japan
Received 17 May 2004
We selected silyl ether 3a, prepared from 1,3-propanediol
via alcohol 3b as shown in Scheme 2, as the model com-
pound. First, solvent (0.2 M for 3a) optimization was in-
vestigated (Table 1) using 6 molar amounts of NaClO2,9 2
molar amounts of NaH2PO4,10 and 10 molar amounts of 2-
methyl-2-butene at room temperature for the indicated re-
action time. As shown in Table 1, alcoholic solvents were
suitable for this reaction (entries 7–10); among them, 3:1
MeOH–H2O was the best choice (entry 10, 84% yield of
4a).
Abstract: The 1,3-dithiane group was oxidatively deprotected
under the conditions of sodium chlorite, sodium dihydrogenphos-
phate, and 2-methyl-2-butene in 3:1 methanol–water at room tem-
perature in good yield.
Key words: thioacetals, sodium chlorite, sodium dihydrogenphos-
phate, protecting groups, deprotection
1,3-Dithiane derivatives are versatile intermediates in or-
ganic synthesis. Since the introduction by Corey and See-
bach in 1965,1 the 2-metallo-1,3-dithiane derivatives have
been used as excellent acyl anion equivalents for carbon-
carbon bond formation.2,3 Moreover, the 1,3-dithiane
group is widely used as an important carbonyl protecting
group because of its stability in both acidic and basic con-
ditions.4 However, it is necessary to use special conditions
for deprotection of the 1,3-dithiane group to generate the
parent carbonyl group.4,5 Therefore, the development of
new deprotection methods is still of continuous concern
by synthetic organic chemists.6 During the course of our
synthetic studies on biscembranoid marine natural prod-
ucts, we found that dithiane aldehyde 17 was converted to
keto carboxylic acid 2 under normal oxidation conditions,
i.e., NaClO2, NaH2PO4, and 2-methyl-2-butene in 3:1 t-
BuOH–H2O at room temperature (Scheme 1).8 We con-
sidered that this oxidation method would be a new, facile,
and mild alternative for the deprotection of the 1,3-
dithiane group. We describe in this letter the results of this
research.
1) Me(CH2)4MgBr,
THF, –78 to 0 °C, 2.5 h
2) TPAP, NMO,
MS4AP, CH2Cl2,
r.t., 1 h
1) TrCl, Et3N,
CH2Cl2,
0 °C, 3 h
HO
OH
TrO
CHO
3) CSA, CH2Cl2-
2) TPAP, NMO,
MeOH, r.t., 1.5 h
MS4AP, CH2Cl2,
r.t., 1 h, 60% (2 steps)
4) 1,3-propanedithiol,
BF3·OEt2, CH2Cl2,
r.t., 5 h, 51% (4 steps)
S
S
S
S
HO
Me
RO
Me
2
4
2
4
3b
to 3a: TBDMSCl, imidazole, CH2Cl2, 99% 3a: R = TBDMS
to 3c: TrCl, Et3N, CH2Cl2, 75%
to 3d: PMBCl, NaH, DMF, 49%
to 3e: Ac2O, Et3N, DMAP, CH2Cl2, 85%
3c: R = Tr
3d: R = PMB
3e: R = Ac
Scheme 2 Preparation of 1,3-dithiane derivatives 3a–e
Next, the substrate concentration was examined in 3:1
MeOH–H2O. Data in Table 2 show that the lower the con-
centration for 3a, the better the isolated yield of 4a. From
a synthetic point of view, the 0.1 M substrate
concentration is suitable; therefore, the following experi-
ments were conducted in the 0.1 M concentration.
NaClO2
(10 mol amt),
NaH2PO4
Me
Me
Me
Me
O
O
S
S
O
H
HO
(5 mol amt),
CO2Me
CO2Me
2-methyl-2-butene
(10 mol amt),
3:1 t-BuOH-H2O (0.2 M
for 1), r.t., 1 h, 47%
Under these optimized conditions, several 1,3-dithiane
derivatives, 3b–e (Scheme 2) and 3f–r (Figure 1; the
preparation of 3f–r is shown in Scheme 3),11 were sub-
jected to the deprotection reactions. These results are
compiled in Table 3.
MeO2C
1 (1 mol amt)
MeO2C
2
Scheme 1
The 2,2-dialkyl-1,3-dithiane derivatives, 3b–h, afforded
the corresponding parent carbonyl compounds, 4b–h, in
good yields (entries 1–7). No a-epimerization occurred in
the case of 3f (entry 5). 2,2-Diphenyl-1,3-dithiane (3i) and
SYNLETT 2004, No. 10, pp 1686–1690
Advanced online publication: 15.07.2004
DOI: 10.1055/s-2004-829558; Art ID: U14304ST
© Georg Thieme Verlag Stuttgart · New York
0
9
.0
8
.2
0
0
4

LETTER
Oxidative Deprotection of 1,3-Dithiane Group
1687
Table 1 Solvent Optimization for Deprotection of 3a
TBDMSO
OH
NaClO2 (6 mol amt),
NaH2PO4 (2 mol amt),
S
S
S
S
PMBO
O
Me
S
S
TBDMSO
Me
TBDMSO
Me
Me
OPMB
Me
Me
2-methyl-2-butene
(10 mol amt),
3f
3g
2
4
2
4
3a (1 mol amt)
4a
solvent (0.2 M for 3a), r.t.
S
S
S
S
S
S
S
S
Entry
Solvent
Time (h)
Yield (%) of 4aa
TBDPSO
Me
Me
2
4
1
2
3:1 EtOAc–H2O
3:1 THF–H2O
2
29
30
31
39
42
55
54
67
77
84
3h
3i
3j
2
3
3:1 CH2Cl2–H2O
3:1 Acetone–H2O
3:1 DMF–H2O
2.5
2.5
2
S
S
S
S
Me
Me
Me
4
4
4
4
5
HO
3k
MeO
3l
O2N
S
3m
6
3:1 MeCN–H2O
3:1 t-BuOH–H2O
3:1 i-PrOH–H2O
3:1 EtOH–H2O
3:1 MeOH–H2O
3
7
1
S
S
Me
5
TBDPSO
EtO2C
S
8
2
4
3n
3o
9
4
10
2
S
S
H
S
S
H
S
S
H
a Isolated yield after silica-gel column chromatography.
3p
MeO
3q
MeO
3r
OMe
Table 2 Effect of Substrate Concentration for Deprotection of 3a
Figure 1
NaClO2 (6 mol amt),
NaH2PO4 (2 mol amt),
O
S
S
TBDMSO
Me
TBDMSO
Me
2-methyl-2-butene
(10 mol amt),
A possible rationale for the substituent dependence on the
success of the reaction is as follows (Scheme 4). When the
first mono-oxidized intermediate I is opened to give the
intermediate II (path a),12 deprotection smoothly proceeds
to afford the parent carbonyl compound. However, when
the intermediate I is further oxidized to give the interme-
diate III (path b), deprotection does not proceed under the
given reaction conditions.2b The critical point is the elec-
tronic nature of the substituents at the C2 position of the
1,3-dithiane derivatives. Ketone-derived 1,3-dithiane de-
rivatives prefer the path a route because the two substitu-
ents can stabilize the intermediate II. The electron-
withdrawing ester substituent (3n) would prevent the path
a route and only one alkyl or phenyl substituent (3o or 3p)
would be insufficient for the path a route.
2
4
2
4
3a (1 mol amt)
4a
3:1 MeOH-H2O, r.t., 2 h
Entry
Concentration (M) for 3a
Yield (%) of 4aa
1
2
3
0.2
84
92
97
0.1
0.05
a Isolated yield after silica-gel column chromatography.
the 2-aryl-2-pentyl-1,3-dithiane derivatives, 3j–m, also
gave the corresponding parent carbonyl compounds, 4i–
m, in good yields. The electronic nature of the substituent
on the phenyl ring had only a small influence on the yields
of 4i–m (entries 8–12). In contrast, in the case of the ester-
substituted 1,3-dithiane derivative 3n, ketone 4n was iso-
lated in less than 10% yield (entry 13). Only a complex
mixture was obtained when the aliphatic aldehyde- and
benzaldehyde-derived 1,3-dithiane derivatives, 3o and
3p, were subjected to our conditions (entries 14 and 15).
Interestingly and expected, the aromatic aldehyde-derived
1,3-dithiane derivatives having the methoxy substituent,
3q and 3r, gave a mixture of the carboxylic acids and their
methyl esters in good yields (entries 16 and 17).
It is noteworthy that the methyl esters were obtained in the
case of 3q and 3r (Table 3, entries 16 and 17). With 3q,
an interesting disulfide 6 (Scheme 5) was also isolated in
12% yield. The structure of 6 was confirmed by 1H NMR,
13C NMR, and MS spectra. In addition, the following re-
sults also support the structure; reduction of 6 with Bu3P
gave thiol 8 (6:1 CH2Cl2–H2O, r.t., 0.5 h, quantitative
yield, Scheme 6) and thiol 8 was oxidized to 6 by treat-
ment with I2 (MeOH, Et3N, r.t., 10 min, 77%). We consid-
ered that this S-alkyl thioate 6 would be the precursor of
methyl ester 5. To rationalize this assumption, we con-
ducted an experiment using a 1 molar amount of 3q and 2
molar amounts of NaClO2, giving a 57:12:19:12 mixture
Synlett 2004, No. 10, 1686–1690 © Thieme Stuttgart · New York

1688
T. Ichige et al.
LETTER
Table 3 Deprotection of Several 1,3-Dithiane Derivatives 3b–r
n-BuLi, THF, r.t., 5 min,
TBDMSO
3f
NaClO2 (6 mol amt), NaH2PO4 (2 mol amt),
2-methyl-2-butene (10 mol amt),
S
S
O
then
in THF, r.t., 3 h, 76%
3b–3r
(1 mol amt)
4b–4r
Me
3:1 MeOH-H2O (0.1 M for 3), r.t.
OPMB
Entry
1
Substrate
3b
3c
Time (h)
Yield (%) of 4a
1) PMBCl, NaH, DMF, 0 °C, 2 h
2) SeO2, TBHP, salicylic acid, CH2Cl2, r.t., 48 h
3) PDC, MS4AP, CH2Cl2, r.t., 1 h
2
61
80
geraniol
3g
2
2
4) 1,3-propanedithiol, BF3·OEt2, CH2Cl2, 0 °C, 1.5 h
5) n-BuLi, THF, –30 °C, 5 min, then MeI,
–30 to 0 °C, 1.5 h, 12% (5 steps)
3
3d
3e
2
85
1,3-propanedithiol,
4
2
88
O
3h
TBDPSO
5
3f
1
87
LiClO4, ether, r.t., 48 h
98%
Me
2
6
3g
3.5
2
85b
75
1,3-propanedithiol, BF3·OEt3,
7
3h
3i
benzophenone
O
3i
CH2Cl2, 0 °C to r.t., 24 h, 43%
8
2
96
9
3j
3
94
1,3-propanedithiol, BF3·OEt3,
Me
3j
10
11
12
13
14
15
16
17
3k
3l
3
93
4
CH2Cl2, 0 °C to r.t., 21 h, 67%
4.5
4
97
1,3-propanedithiol,
CH2N2,
MeOH,
O
3m
3n
3o
89
BF3·OEt3,
Me
3k
3l
3
<10
4
CH2Cl2, 0 °C to r.t.,
19 h, 99%
r.t., 36 h
67%
c
HO
4
–
c
3p
3q
3r
2
–
1) Me(CH2)4MgBr in ether,
ZnCl2 in ether, THF, –30 °C, 1 h
2) PDC, MS4AP, CH2Cl2, r.t., 14 h
83d
94e
CHO
2
3m
2
O2N
3) 1,3-propanedithiol, BF3·OEt3,
a Isolated yield after silica gel column chromatography.
b The reaction temperature was 0 °C.
CH2Cl2, 0 °C to r.t., 19 h, 46% (3 steps)
c Complex mixture was obtained.
d Carboxylic acid (68%) and its methyl ester (15%) were obtained.
e Carboxylic acid (68%) and its methyl ester (26%) were obtained.
n-BuLi, HMPA, THF, –78 °C, 0.5 h
S
S
3n
then hexyl iodide, –78 °C to r.t., 2 h, 78%
CO2Et
1) TBDPSCl, imidazole, DMF, r.t., 1 h
2) PDC, MS4AP,CH2Cl2, r.t., 12 h
CO2H
CO2Me
CHO
1,5-pentanediol
3o
MeO
MeO
3) 1,3-propanedithiol, BF3·OEt3,
CH2Cl2, 0 °C to r.t., 3 h, 40% (3 steps)
NaClO2 (6 or 2 mol amt),
NaH2PO4 (2 mol amt),
4q
5
2
S
3q
CHO
2-methyl-2-butene
(10 mol amt),
3:1 MeOH-H2O
1,3-propanedithiol,
O
3p: R1 = R2 = H (84%)
3q: R1 = OMe, R2 = H (91%)
3r: R1 = R2 = OMe (99%)
BF3·OEt3, CH2Cl2,
MeO
R1
7
S
(0.1 M for 3q), r.t., 4 h
0 °C to r.t., 12 h
R2
6
MeO
Scheme 3 Preparation of 1,3-dithiane derivatives 3f–r
Scheme 5
S
HO Cl
O
H
+ H
a
OH
O
R1
R2
S
of 3q, 4q, 6, and 7 (Scheme 5).13 A possible mechanism
for the formation of 6 is depicted in Scheme 6. The highly
reactive sulfenic acid II14 is attacked by 3q to give the di-
sulfide intermediate IV that is oxidized with NaClO2,
affording S-alkyl thioate 6 via the intermediate V. The
isolated 6 was subjected to the deprotection conditions,
quantitatively giving a 76:24 mixture of carboxylic acid
a
II
b
S
S O
a
a
R1 R2
b
O
S
R1
S
R2
I
– H
III
Scheme 4
Synlett 2004, No. 10, 1686–1690 © Thieme Stuttgart · New York

LETTER
Oxidative Deprotection of 1,3-Dithiane Group
1689
2
S
S
S
S
2
NaClO2
O
R
H
S
R
H
S
S
O
S
R
S
H
2
Cl
O
II
IV
OH
R
H
R
S
6
+
3q
H
V
SH
O
(R = p-methoxyphenyl)
Bu3P, 6:1 CH2Cl2-H2O,
r.t., 0.5 h
under the reaction
conditions (NaClO2)
or
NaClO2,
NaH2PO4,
I2, MeOH, Et3N, r.t., 10 min
R
S
H2O
NaClO2
8
2-methyl-2-butene,
3:1 MeOH-H2O,
r.t., 4 h
O
R
OH
under the reaction
conditions (NaClO2)
or
NaClO2,
NaH2PO4,
2-methyl-2-butene,
3:1 MeOH-H2O,
r.t., 4 h
4q
2
S
S
O
NaH2PO4,
H2O or
MeOH
2-methyl-2-butene,
3:1 MeOH-H2O,
r.t., 8 h
O
R
H
7
R
O
O
VI
R
OMe
5
Scheme 6 Proposed mechanism for formation of 4q and 5
4q and methyl ester 5. The probable intermediate in this
case must be the acyl sulfoxide VI. Moreover, p-methoxy-
benzaldehyde (7) itself afforded carboxylic acid 4q as the
only oxidation product under the deprotection conditions,
while 4q itself did not afford methyl ester 5 under the
deprotection conditions without NaClO2. These facts
indicate that S-alkyl thioate 6 must be the precursor of not
only carboxylic acid 4q but also methyl ester 5 in our
deprotection reaction.
References
(1) (a) Corey, E. J.; Seebach, D. Angew. Chem., Int. Ed. Engl.
1965, 4, 1075. (b) Seebach, D.; Corey, E. J. J. Org. Chem.
1975, 40, 231.
(2) For reviews, see: (a) Seebach, D. Synthesis 1969, 17.
(b) Gröbel, B.-T.; Seebach, D. Synthesis 1977, 357.
(c) Page, P. C. B.; van Niel, M. B.; Prodger, J. C.
Tetrahedron 1989, 45, 7643. (d) Kolb, M. In Encyclopedia
of Reagents for Organic Synthesis, Vol. 5; Paquette, L. A.,
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(3) Our recent examples, see: (a) Ide, M.; Yasuda, M.; Nakata,
M. Synlett 1998, 936. (b) Ide, M.; Nakata, M. Bull. Chem.
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Gaunt, M. J.; Sfouggatakis, C.; Moser, W. H. J. Am. Chem.
Soc. 2003, 125, 14435.
In summary, we developed new, facile, and mild depro-
tection conditions for 1,3-dithiane derivatives using 6 mo-
lar amounts of NaClO2, 2 molar amounts of NaH2PO4, and
10 molar amounts of 2-methyl-2-butene in 3:1 MeOH–
H2O at room temperature. These conditions are suitable
for the ketone-derived 1,3-dithiane derivatives and aro-
matic aldehyde-derived 1,3-dithiane derivatives. In the
latter case, the products are a mixture of carboxylic acids
and their methyl esters.15
(4) (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 3rd ed.; John Wiley and Sons: New
York, 1999. (b) Kocienski, P. J. Protecting Groups, 3rd ed.;
Thieme: Stuttgart, 2003.
Acknowledgment
This research was supported by a Grant-in-Aid for Scientific
Research on Priority Areas (A) ‘Exploitation of Multi-Element
Cyclic Molecules’ and partially supported by a Grant-in-Aid for the
21st Century COE program ‘KEIO Life Conjugate Chemistry’ from
the Ministry of Education, Culture, Sports, Science and Technolo-
gy, Japan.
(5) Most widely used procedures, see: (a) N-Halosuccinimide:
Corey, E. J.; Erickson, B. W. J. Org. Chem. 1971, 36, 3553.
(b) Hg(ClO4)2: Fujita, E.; Nagao, Y.; Kaneko, K. Chem.
Pharm. Bull. 1978, 26, 3743. (c) PhI(CF3CO2)2: Stork, G.;
Zhao, K. Tetrahedron Lett. 1989, 30, 287.
(6) For recent examples, see: (a) Cu(NO3)2·N2O4 or
Fe(NO3)3·1.5N2O4: Firouzabadi, H.; Iranpoor, N.; Zolfigol,
M. A. Bull. Chem. Soc. Jpn. 1998, 71, 2169. (b) Cray
supported ammonium nitrate, microwave: Meshram, H. M.;
Reddy, G. S.; Sumitra, G.; Yadav, J. S. Synth. Commun.
1999, 29, 1113. (c) VOCl3, O2: Kirihara, M.; Ochiai, Y.;
Arai, N.; Takizawa, S.; Momose, T.; Nemoto, H.
Synlett 2004, No. 10, 1686–1690 © Thieme Stuttgart · New York

1690
T. Ichige et al.
LETTER
Tetrahedron Lett. 1999, 40, 9055. (d) Natural kaolinitic
clay, microwave: Bandgar, B. P.; Kasture, S. P. Green
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N.; Hazarkhani, H.; Karimi, B. J. Org. Chem. 2002, 67,
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V. S., Raghavendra S., Satyanarayana M.; Tetrahedron
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D.; Mahajan, V. A.; Wakharkar, R. D. Tetrahedron Lett.
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Lett.; 2002, 43: 6443. (l) NaNO2, AcCl: Khan, A. T.;
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(9) The starting material 3a remained when less than 6 molar
amounts of NaClO2 were used.
(10) In the absence of NaH2PO4, no reaction occurred.
(11) (a) 3f: see ref.3b (b) 3h: Tietze, L. F.; Weigand, B.; Wulff, C.
Synthesis 2000, 69. (c) 3m: Kulkarni, S. N.; Bhamare, N. K.;
Kamath, H. V. Ind. J. Chem., Sect. B 1987, 26, 168. (d) 3n:
Yuan, W.; Berman, R. J.; Gelb, M. H. J. Am. Chem. Soc.
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Strieter, E. R.; Burke, S. D. Org. Lett. 2002, 4, 467.
(12) The sulfenic acid part in II is a transient structure because of
its high reactivity. See ref.14
(13) The ratio was based on 1H NMR analysis of the crude
product. Methyl ester 5 was obtained in only a trace amount.
(14) Davis, F. A.; Rizvi, S. Q. A.; Ardecky, R.; Gosciniak, D. J.;
Friedman, A. J.; Yocklovich, S. G. J. Org. Chem. 1980, 45,
1650.
(15) Representative Experimental Procedure (Table 2, Entry
2):
To a mixture of 3a (57.0 mg, 0.163 mmol) in MeOH (1.2
mL) and H2O (0.400 mL) were added at r.t. 2-methyl-2-
butene (0.172 mL, 1.630 mmol) and NaH2PO4 (39.0 mg,
0.326 mmol). After cooling to 0 °C, 86% NaClO2 (103.0 mg,
0.978 mmol) was added and the resulting suspension was
stirred at r.t. for 2 h. Then H2O (1.5 mL) was added and the
mixture was extracted with EtOAc (1.5 ml × 3); the extracts
were washed with sat. aq NaCl, dried with Na2SO4, and
concentrated. The residue was chromatographed on silica
gel with 3:1 hexane–EtOAc to afford 4a (38.7 mg, 92%) as
a colorless oil. Compound 4a: 1H NMR (300 MHz, CDCl3,
CHCl3 = 7.26): d = 0.04 (6 H, s), 0.87 (9 H, s), 0.88 (3 H, t,
J = 7.0 Hz), 1.18–1.40 (4 H, m), 1.57 (2 H, quint, J = 7.5
Hz), 2.44 (2 H, t, J = 7.5 Hz), 2.59 (2 H, t, J = 7.0 Hz), 3.88
(2 H, t, J = 7.0 Hz). 13C NMR (75 MHz, CDCl3 = 77.16):
d = –5.35, 14.04, 18.34, 22.59, 23.34, 25.98, 31.52, 43.99,
45.70, 59.07, 210.42. HRMS (EI): m/z calcd for C10H21O2Si
[M – t-Bu]+ 201.1311; found: 201.1318.
(7) Total synthesis of biscembranoid marine natural product,
methyl sarcoate, and the synthesis of 1 will be reported
elsewhere.
(8) (a) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27,
888. (b) Kraus, G. A.; Taschner, M. J. J. Org. Chem. 1980,
45, 1175.
Synlett 2004, No. 10, 1686–1690 © Thieme Stuttgart · New York