Synthesis of 1,2,4-Trithiolanes from Thione S-Oxides and Lawesson Reagent at Room Temperature

Article abstract of DOI:10.1246/bcsj.77.187

The reaction of 2,2,4,4-tetramethyl-3-thioxocyclobutanone S-oxide with Lawesson reagent (L. R.) afforded the corresponding 1,2,4-trithiolane. Thiopivalophenone and thiopivalophenone S-oxides reacted with L. R. at rt to give the corresponding S-sulfide, which further reacted with thiones to afford the corresponding cis-1,2,4-trithiolanes.

Full text of DOI:10.1246/bcsj.77.187

Short Articles
Bull. Chem. Soc. Jpn., 77, 187–188 (2004)
187
S
O
S
S
Synthesis of 1,2,4-Trithiolanes from
Thione S-Oxides and Lawesson
Reagent at Room Temperature
+
O
O P4S10
5a
5b
+
reflux, 1 h
Pyridine
S
S
S
S
2a
S
1a
Ph
Ph
S
S
ꢀ
Shinji Shibata, and Kosei Shioji
Kentaro Okuma, Toshiyuki Shigetomi,
S
Ph
Ph
O
S
1b
S
5c
+
80°C
S
O
O
+
5a
Department of Chemistry, Faculty of Science,
Fukuoka University, Jonan-ku, Fukuoka 814-0180
- N2
S
1c
Ph
Ph
+ PhN3
+
N
Received September 1, 2003; E-mail: kokuma@fukuoka-u.ac.jp
Ph
7
Scheme 1.
The reaction of 2,2,4,4-tetramethyl-3-thioxocyclobuta-
none S-oxide with Lawesson reagent (L. R.) afforded the cor-
responding 1,2,4-trithiolane. Thiopivalophenone and thiopi-
valophenone S-oxides reacted with L. R. at rt to give the cor-
responding S-sulfide, which further reacted with thiones to af-
ford the corresponding cis-1,2,4-trithiolanes.
P4S10
S
2a
C
S
reflux, 12 h
Pyridine
S
8
S
P4S10
heat
S
2a
S
1,2,4-Trithiolanes (1) are well-known heterocycles, some of
which are obtained from natural products.1 Although many
methods for the formation of 1 have been reported,2 there are
a few reports on the direct synthesis of 1 from ketones (2) by
using thiation reagents.3 We have reported on the isolation of
cis- and trans-1 from pivalophenone and P4S10 in refluxing pyr-
idine.4 While the intermediacy of the thiosulfines (3) and the di-
thiiranes (4) has been proposed to explain the reaction mech-
anisms leading to 1, Huisgen and Rapp have clearly shown that
the reaction of 3 prepared from tetraaryl-1,2,4-trithiolanes with
acetylenes or thiones (5) gave the corresponding cycloadducts.5
The isolation of a series of stable 4 was accomplished by Ishii
and Nakayama.6 Recently, Shimada et al. reported the synthesis
of sterically crowded 4 by the reaction of thioketone S-oxides
(6) with Lawesson reagent (L. R.).7 These results prompted
us to investigate the synthesis of 1 from ketones 2 via thiosul-
fine 3 or dithiirane 4 under mild conditions.
Elam and Davis reported the synthesis of 2,2,4,4-tetrameth-
yl-3-thioxocyclobutanone (5a) and 1,3-dithione (5b) by the
reaction of 2,2,4,4-tetramethyl-1,3-cyclobutanedione (2a) with
P4S10. They isolated trithiolane (1a) as a side product (2.8%).8
Mloston and Heimgartner reported that the reaction of thioben-
zophenone (5c) with PhN3 in the presence of 5a gave 1,2,4-tri-
thiolanes (1b, 1c) and imine (7) (Scheme 1).9
9
Scheme 2.
R
R
S
L. R.
rt
R
O
R
S
S
6a
4a
S
L. R.
rt
O
O
2a
6b
Scheme 3.
formation of trithiolane 1c by the reaction of 2,2,4,4-tetrameth-
yl-3-thioxocyclobutanone S-oxide (6b) with L. R. was unsuc-
cessful, and only desulfurated product 2a could be detected
(Scheme 3).11 We have been interested in this reaction because
a possible formation of trithiolane 1 or dithiirane 4 at room tem-
perature. When sulfine 6b was treated with L. R. in the presence
of monothione 5a at room temperature for
7 days,
1,1,3,3,7,7,9,9-octamethyl-5,10,11-trithiadispiro[3.1.3.2]unde-
cane-2-thione-8-one (1d) was obtained in 7% yield along with
monothione 5a and dione 2a, suggesting that the intermediates
should be thiosulfine 3a or dithiirane 4b (Scheme 4).
Since the yield of 1d was low, we then applied this method to
the synthesis of 1 from thiopivalophenone S-oxides. The treat-
ment of p-methylthiopivalophenone S-oxide (6c) with L. R.,
followed by the addition of p-methylthiopivalophenone (5d)
for 72 h, resulted in the formation of cis-trithiolane 1e4 in
79% yield. Another isomer (trans-trithiolane 1e) was not ob-
tained. When thione 5d was treated with L. R. at rt for 19 days,
cis-1e was obtained in 26% yield, suggesting that a prolonged
reaction time was required for completion. Additionally, the re-
When dione 2a was treated with P4S10 in refluxing pyridine
for 12 h, the corresponding dithioester (8) was produced almost
quantitatively, whereas the reaction of 2a with P4S10 up to 200
ꢁC under reduced pressure resulted in the formation of 3,3,5,5-
tetramethyl-4-thioxothiolane-2-thione (9) in 72% yield
(Scheme 2). Since 9 was previously prepared by the irradiation
of dithione 5b in methanol via radical species,10 the reaction
might proceed through a similar radical intermediate.
Recently, Shimada et al. reported the synthesis of sterically
crowded dithiirane (4a) by the reaction of thioketone S-oxide
(6a) with L. R.7 Mloston et al. have reported that the attempted
Published on the web January 13, 2004; DOI 10.1246/bcsj.77.187

188 Bull. Chem. Soc. Jpn., 77, No. 1 (2004)
Ó 2004 The Chemical Society of Japan
Room Temperature. To a solution of S-oxide 6c (208 mg, 1.0
mmol) in dichloromethane (15 mL) was added a solution of L.
R. (136 mg, 3.4 mmol) at rt. After stirring for 1 h, 5e (192 mg,
1.0 mmol) was added to this solution. After stirring for 72 h, the
reaction mixture was evaporated to give pale-blue oily crystals.
The resulting mixture was chromatographed over silica gel by elu-
tion from hexane, hexane–dichloromethane (2:1), and hexane–di-
chloromethane (1:1) to give cis-trithiolane 1e (328 mg, 0.79
mmol), 5d (29 mg, 0.14 mmol), and p-methylpivalophenone
(2b) (12 mg, 0.07 mmol). cis-Trithiolane 1c; mp 134–135 ꢁC.
The spectral data were identical with the reported value.4 Found:
C, 68.82; H, 7.52%. Calcd for C24H32OS3: C, 69.17; H, 7.74%.
Similarly, reaction of S-oxide 6c (30 mg, 0.14 mmol) with L. R.
(68 mg, 0.17 mmol) in the presence of thione 5e (38 mg, 0.14
mmol) was carried out. Unsymmetrical cis-trithiolane 1f (28 mg,
0.059 mmol, 42%) and a mixture of p-methyl- and p-phenoxythio-
pivalophenone (5d:5e = 1:1 by 1H NMR, 16 mg, 0.07 mmol) were
obtained. cis-3,5-Di-tert-butyl-3-p-methylphenyl-5-p-phenoxy-
phenyl-1,2,4-trithiolane 1f: colorless crystals. Mp 124–125 ꢁC.
1H NMR (400 MHz, CDCl3) ꢀ 1.22 (s, 9H, tert-Bu), 1.24 (s, 9H,
tert-Bu), 2.23 (s, 3H, Me), 6.65 (d, 2H, J ¼ 9 Hz, Ar), 6.81 (d,
2H, J ¼ 8 Hz, Ar), 6.85 (d, 2H, J ¼ 7 Hz, Ar), 7.05 (t, 1H, J ¼
7 Hz, Ph), 7,29 (d, 2H, J ¼ 8 Hz), 7.40. 13C NMR (100 M Hz,
CDCl3) ꢀ 20.90, 26.65, 29.44, 34.97, 36.53, 37.73, 38.78, 39.71,
40.20, 90.68 (S–C–S), 98.81 (S–C–S), 126.87, 130.52, 136.04,
139.37. Found: C, 70.03; H, 6.99%. Calcd for C29H34OS3: C,
70.40; H, 6.93%.
S
O
O
S
3a
O
L. R.
rt
S
O
S
6b
S
4b
S
5a
S
O
S
S
1d
Scheme 4.
S
S
C
C S
S
3b
L. R.
rt
C S
p
-Tol
p-Tol
O
4c
p
-Tol
6c
C
S
5d
p
-Tol
S
S
S
Tol-
p
p
-Tol
cis-1e
C
S
p
-PhOC6H4
L. R.
5e
S
6c
S
S
C6H4-OPh-
p
p
-Tol
rt
cis-1f
Financial support from Dojindo Laboratories is gratefully
acknowledged.
Scheme 5.
action of S-oxide 6c with L. R., followed by addition of p-phen-
oxythiopivalophenone (5e), gave unsymmetrical cis-trithiolane
(1f) in 42% yield (Scheme 5).
References
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mL) was added L. R. (242 mg, 0.6 mmol). After being stirred
for 10 min, thioxocyclobutanone 5a (94 mg, 0.6 mmol) was added
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0.028 mmol). Mp 72–74.5 ꢁC; 1H NMR (CDCl3) ꢀ 1.45 (s, 3H,
Me), 1.49 (s, 3H, Me), 1.50 (s, 3H, Me), 1.56 (s, 3H, Me).
13C NMR (CDCl3) ꢀ 21.45 (Me), 25.25 (Me), 26.07 (Me), 30.18
(Me), 66.76 (quaternary C), 69.72 (quaternary C), 85.67 (S–C–
S), 89.59 (S–C–S), 218.73 (C=O), 278.89 (C=S). Found: C,
53.88; H, 7.03%. Calcd for C16H24OS4: C, 53.29; H, 6.71%. A cor-
rect elemental analysis of 1d was not obtained, but its 13C NMR
clearly shows the trithiolane structure. Thioxocyclobutaone 5a
(55 mg, 0.35 mmol) and 2a (35 mg, 0.25 mmol) were also isolated.
Reaction of S-Oxide 6c with L. R. in the Presence of 5d at
5
6
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9
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