A mild and efficient method for the preparation of 1,3-dithianes from aldehydes and ketones

Article abstract of DOI:10.1055/s-2000-6226

A mild method for the preparation of 1,3-dithianes from aldehydes and ketones is described. By using lithium perchlorate as Lewis acid and propane- 1,3-dithiol even highly acid-labile β-hydroxy aldehydes can be transformed into the corresponding thioaceta

Full text of DOI:10.1055/s-2000-6226

SHORT PAPER
69
A Mild and Efficient Method for the Preparation of 1,3-Dithianes from
Aldehydes and Ketones
Lutz F. Tietze,* Berthold Weigand, Christian Wulff
Institut für Organische Chemie, Georg-August-Universität Göttingen, Tammannstr. 2, D-37077 Göttingen, Germany
Fax +49(551)399476, E-mail: ltietze@gwdg.de
Received 11 August 1999
Table 1 Formation of Dithiane 3a from 1a
Abstract: A mild method for the preparation of 1,3-dithianes from
Reaction Conditionsb
Yield of 3a
(%)
aldehydes and ketones is described. By using lithium perchlorate as
Lewis acid and propane-1,3-dithiol even highly acid-labile b-hy-
droxy aldehydes can be transformed into the corresponding thio-
acetals. The desired products were obtained in 41-98% yield.
Dithiol 2
(Equiv)
2a: 1.5
2a: 1.5
2b: 1.5
2b: 1.2
2b: 3.0
2a: 3.0
2a: 3.0
2a: 2.0
2a: 1.5
BF3∑OEt2 (2.0 equiv), CH2Cl2, 0°C
Zn(OTf)2 (1.5 equiv),CH2Cl2, r.t.
Zn(OTf)2 (1.5 equiv), CH2Cl2, r.t.
LiClO4 (5 M), Et2O, r.t.
LiClO4 (5 M), Et2O, r.t.
LiClO4 (5 M), Et2O, r.t.
LiClO4 (5 M), Et2O, 0°C
LiClO4 (2 M), Et2O, r.t.
LiClO4 (0.23 M), Et2O, r.t.
0c
10
10
0d
Key words: 1,3-dithianes, lithium perchlorate, aldehydes, ketones,
Lewis acid, thiols, deprotection, sulfur
0d
61
30
90
90
Since the introduction of 1,3-dithianes as nucleophilic
acylating reagents by Corey and Seebach,1 they have be-
come widely used tools for the formation of C-C bonds.
Lithiation of 1,3-dithianes followed by reaction with a
broad variety of electrophiles1-3 is now a common method
in organic chemistry, as has also been demonstrated in
several syntheses of natural products.2 In view of their
utility, several methods for the preparation of thioacetals
from aldehydes with propane-1,3-dithiol using HCl gas,4
sulfur dioxide,5 trimethylsilyl chloride,6 zinc or magne-
sium triflate,7 TeCl4,8 TiCl4,9 SOCl2/SiO2,10 boron
trifluoride11 or aq trifluoroacetic acid12 have been reported
in the literature.
a 1 Equivalent of the substrate 1 was used in all reactions.
b Reaction time: 24 h.
c Decomposition of aldehyde.
d No conversion.
Literature reports have demonstrated that solutions of lith-
ium perchlorate in Et2O14 could be successfully used for
[1,3]-sigmatropic rearrangements,15 alkylations of allyl
esters and quinones,16 additions of allyl stannanes to alde-
hydes,17 the addition of trimethylsilyl cyanide and silyl
ketene acetals to aldehydes18 as well as for the formation
of 1,3-dithiolanes and acyclic dithioacetals.19 In addition,
LiBr has also been used for some of these transforma-
tions.20 Here we describe the application of lithium per-
chlorate for the synthesis of 1,3-dithianes of aldehydes
and ketones, with a special emphasis for highly sensitive
substrates.
For the synthesis of complex diterpenes we wanted to
transform the sensitive hydroxyaldehyde 1 into the corre-
sponding dithiane 3a and further into the MOM-protected
3b (Scheme 1). Reaction of 1 and propane-1,3-dithiol (2a)
in the presence of BF3∑OEt2 led to decomposition of 1.
Zinc triflate, known as a mild reagent, which usually pre-
vents b-elimination,7 gave only 10% of the desired prod-
uct 3a. Also, employing the silylated derivative 2b of
propane-1,3-dithiol13 did not lead to any significant im-
provement (see Table 1).
Reaction of 1 with propane-1,3-dithiol (2a) in the pres-
ence of a 2 M or even 0.23 M solution of lithium perchlo-
rate in anhydrous diethyl ether led to the dithiane 3a in
remarkable 90% yield. In contrast, the use of a 5 M solu-
tion of lithium perchlorate caused decomposition of 1 to a
high extent; with 2b as a reagent a transformation did not
take place.
O
S
S
2a: HS
SH
or
Encouraged by the excellent results, we carried out further
investigations on the preparation of 1,3-dithioacetals 5a-
i of aromatic, α,β-unsaturated, aliphatic and functional-
ized aldehydes and ketones 4a-i (Scheme 2). The results
are listed in Table 2.
OH
OR
SiMe3
SiMe3
S
2b:
S
TIPSO
TIPSO
1
R = H
R = MOM
3a
3b
MOMCl, iPr2NEt,
CH2Cl2, DMAP,
NaI, 40 °C, 79%
In one case, e.g. the dithiane 5i was deprotected with tet-
rabutylammonium fluoride to give the alcohol 6 (Scheme
3).
Scheme 1
Synthesis 2000, No. 1, 69–71 ISSN 0039-7881 © Thieme Stuttgart · New York

70
L F. Tietze et al.
SHORT PAPER
Spectroscopic data for the dithianes 5a,1 5b,21 5c,22 5d,23 5e24 and
5f24 and 5h25 match with those reported in the literature.
2 eq.
HS
SH
O
LiClO4, Et2O, r.t., 24-120 h
41-98 %
S
R1
S
R2
R1
R2
Preparation of 1,3-Dithianes, General Procedures
Method 1: Aromatic Carbonyl Compounds
4a-i
5a-i
A solution of anhyd LiClO4 (1.28 g, 12 mmol) in anhyd Et2O (2 mL)
was added dropwise to a solution of the carbonyl compound (2
mmol) and propane-1,3-dithiol (433 mg, 4 mmol) in anhyd Et2O
(0.4 mL) under dry argon. The mixture was stirred for 120 h at r.t.
H2O (4 mL) was added and the aqueous phase was extracted with
Et2O (3 î 5 mL). The combined organic layers were dried
(MgSO4) and the solvent was evaporated under vacuum. The crude
product was purified on silica gel (pentane/Et2O); yield 76-90%.
Scheme 2
2 eq. TBAF, THF, r.t.
S
S
S
S
80%
TBDPSO
HO
5i
6
Method 2: Aliphatic Carbonyl Compounds
Scheme 3
A solution of anhyd LiClO4 (426 mg, 4 mmol) in anhyd Et2O (1.5
mL) was added dropwise to a solution of the carbonyl compound (2
mmol) and propane-1,3-dithiol (433 mg, 4 mmol) in anhyd Et2O
(0.5 mL) under dry argon and stirred for 24 h. The workup was car-
ried out as described above; yield 41-98%.
In conclusion, a wide range of all classes of aldehydes and
even ketones could be transformed into the corresponding
1,3-dithianes in good yield by the present method. The
method is mild enough to tolerate even α- and b-hydroxy
carbonyl functionalities without the formation of the cor-
responding alkenes. We think that the described proce-
dure is a valuable and highly useful alternative to the
known techniques especially if one uses sensitive sub-
strates.
MOM-Protected Dithiane 3b
The dithiane 3a was prepared from 1 and 2a according to Method 2
in 90% yield and the crude product immediately transformed into
3b.
Compound 3a
1H NMR (200 MHz, CDCl3): d = 1.06 (s, 1 H, OH), 1.10 (s, 21 H,
TIPS-H), 1.32 (s, 3 H, 2’-CH3), 1.64-1.98 (m, 5 H, 5-Ha, 1’-H2, 3’-
H2), 1.98-2.19 (m, 1 H, 5-Hb), 2.74-3.06 (m, 4 H, 4-H2, 6-H2), 4.00
(t, J = 5.5 Hz, 2 H, 4’-H2), 4.24 (t, J = 5.5 Hz, 1 H, 2-H).
13C NMR (50.3 MHz, CDCl3): d = 11.72 (Si-C), 17.97 (TIPS-CH3),
25.36 (C-5), 26.95 (2’-CH3), 30.89 (C-4), 30.95 (C-6), 42.14 (C-3’),
42.29 (C-2), 47.94 (C-1’), 60.90 (C-4’), 72.52 (C-2’).
Melting points were determined in open capillary tubes using a
Mettler FP 61 capillary melting point apparatus and are corrected.
1H and 13C NMR spectra: Varian XL 200, Varian VXR 200; chem-
ical shifts (δ) are relative to TMS. IR spectra: Bruker IFS 25. UV-
spectra: Perkin-Elmer Lamda 2. Mass spectra: Varian MAT 311a,
Varian MAT 731. Optical rotations: Perkin-Elmer Polarimeter 241.
MS (70 eV, DCI): m/z (%) = 396 (100) [M+18+], 379 (75) [M+H+].
Compound 3b
MOMCl (1.61 g, 20 mmol) was added to a suspension of the alcohol
3a (378 mg, 1 mmol), NaI (2.7 g, 18 mmol), i-Pr2NEt (2.84 g, 22
mmol) and DMAP (6 mg, 0.05 mmol) in CH2Cl2 (30 mL) at r.t. The
mixture was stirred for 30 min at r.t. and further for 3 d at reflux.
Satd aq Na2CO3 solution (15 mL) was added and the mixture was
extracted repeatedly with CH2Cl2. The organic phases were dried,
the solvent was evaporated and the crude product was purified by
chromatography on silica gel (pentane/Et2O) to give 3b (334 mg,
79%) as a colourless oil.
1H NMR (200 MHz, CDCl3): d = 1.07 (s, 21 H, TIPS-H), 1.35 (s, 3
H, 2’-CH3), 1.70-2.00 (m, 3 H, 3’-H2, 5-Ha), 1.92 (d, J = 5.8 Hz, 2
H, 1’-H2), 2.00-2.20 (m, 1 H, 5-Hb), 2.65-3.04 (m, 4 H, 4-H2, 6-
H2), 3.38 (s, 3 H, OCH3), 3.81 (t, J = 7.0 Hz, 2 H, 4’-H2), 4.20 (t,
J = 5.8 Hz, 1 H, 2-H), 4.72 (s, 2 H, OCH2O).
Table 2 Formation of Dithianes 5 from Aldehydes and Ketones 4
4
R1
R2 Time Lewis Acid Yield
(h)
of 5
(%)
4a Ph
4b 4-MeOC6H4
4c Ph
H
H
120
120
5 M LiClO4 5a: 76a
5 M LiClO4 5b: 90a
5 M LiClO4 5c: 89a
2 M LiClO4 5d: 75b
Me 120
Me 48
4d Propyl
4e
4f
H
H
H
24
24
24
2 M LiClO4 5e: 93b
2 M LiClO4 5f: 41b
2 M LiClO4 5g: 78b
13C NMR (50.3 MHz, CDCl3): d = 11.76 (Si-C), 17.89 (TIPS-CH3),
24.21 (2’-CH3), 25.22 (C-5), 31.01 (C-4), 31.05 (C-6), 42.01
(OCH3), 42.47 (C-3’), 45.71 (C-1’), 55.27 (C-2), 59.22 (C-4’),
76.95 (C-2’), 90.72 (OCH2O).
O
+
MS (70 eV, EI): m/z (%) = 422 (1) [M+], 407 (4) [M - CH3 ] 317
4g
(100) [M - SCH2CH2S + H+].
O
HRMS: m/z calcd for C20H42O3S2Si (422.76): 422.2344, found:
422.2344.
4h
Me 24
Me 48
2 M LiClO4 5h: 82b
2 M LiClO4 5i: 98b
2-Methylpropyl 4-(1,3-Dithian-2-yl)butanoate (5g)
Prepared by Method 2; yield: 78%.
1H NMR (200 MHz, CDCl3): δ = 0.94 (d, J = 7 Hz, 6 H, 2’’-CH3,
3’’-H3), 1.74-2.04 (m, 7 H, 1’-H2, 2’-H2, 2’’-H, 5-H2), 2.35 (t, J = 7
Hz, 2 H, 3’-H2), 2.58-2.94 (m, 4 H, 4-H2, 6-H2), 3.88 (d, J = 7 Hz,
2 H, 1’’-H2), 4.04 (t, J = 7 Hz, 1 H, 2-H).
OH
TBDPSO
4i
a Method 1.
b Method 2.
Synthesis 2000, No. 1, 69–71 ISSN 0039-7881 © Thieme Stuttgart · New York

SHORT PAPER
A Mild and Efficient Method for the Preparation of 1,3-Dithianes from Aldehydes and Ketones
71
13C NMR(50.3 MHz, CDCl3): δ = 18.83 (2’’-CH3, C-3’’), 23.26 (C-
2’), 27.35 (C-2’’), 28.00 (C-3’), 29.97 (C-4, C-6), 33.39 (C-5),
34.39 (C-1’), 51.39 (C-2), 70.11 (C-1’’), 172.68 (C-5’).
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1994, 511.
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MS (70 eV, EI): m/z (%) = 262 (100) [M+], 205 (20) [M+ - C4H9],
189 (40) [M+ - C4H9O].
HRMS: m/z calcd for C12H22S2O2 (262.11): 262.1061, found:
262.1062.
2-(2-Methyl-1,3-dithian-2-yl)ethanol (6)
The dithiane 5i was prepared from 4i according to Method 2 in 98%
yield and deprotected with TBAF to give the alcohol 6. Spectro-
scopic data of 6 match with those reported in literature.26
5i
1H NMR (200 MHz, CDCl3): δ = 1.06 (s, 9 H, t-C4H9), 1.55 (s, 3 H,
2-CH3), 1.78-2.09 (m, 2 H, 5-H2), 2.24 (t, J = 7.0 Hz, 2 H, 1’-H2),
2.53-2.88 (m, 4 H,, 4-H2, 6-H2), 2.84 (t, J = 7.0 Hz, 2 H, 2’-H2),
7.32-7.78 (m, 10 H, C6H5).
13C NMR (50.3 MHz, CDCl3): δ = 19.09 [(CH3)3C], 26.43 (2-CH3),
26.83 [(CH3)3C], 28.27 (C-5), 42.87 (C-1’), 47.30 (C-2), 60.77 (C-
2’), 127.61, 129.57, 133.66, 135.56 (C6H5).
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+
MS (70 eV, DCI): m/z (%) = 434 (100) [M + NH4 ], 850 (10)
[2 î M + NH4 ]
+
Deprotection of 5i
TBAF (523 mg, 2 mmol) was added to a solution of 5i (416 mg, 1
mmol) in THF (4 mL) and the mixture stirred for 2 h at r.t. H2O (4
mL) was added and the mixture was extracted with Et2O (4 î 10
mL). The combined organic phases were dried, the solvent evapo-
rated and the crude product was purified by chromatography on sil-
ica gel (pentane/Et2O) to give 6 (142 mg, 80%).
Acknowledgement
Support from the Fonds der Chemischen Industrie is gratefully ack-
nowledged.
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Article Identifier:
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Synthesis 2000, No. 1, 69–71 ISSN 0039-7881 © Thieme Stuttgart · New York