Double Michael addition of dithiols to acetylenic carbonyl compounds under the influence of molecular sieve and dimethyl sulfoxide

Article abstract of DOI:10.1016/j.tetlet.2009.11.002

Double Michael addition of dithiols such as 1,3-propanedithiol and 1,2-ethanedithiol to α,β-acetylenic carbonyl compounds in the presence of molecular sieve and dimethyl sulfoxide proceeds very smoothly to afford the corresponding β-keto 1,3-dithianes and

Full text of DOI:10.1016/j.tetlet.2009.11.002

Tetrahedron Letters 51 (2010) 290–292
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Double Michael addition of dithiols to acetylenic carbonyl compounds
under the influence of molecular sieve and dimethyl sulfoxide
*
Tomoko Kakinuma, Takeshi Oriyama
Department of Chemistry, Faculty of Science, Ibaraki University, 2-1-1 Bunkyo, Mito 310-8512, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Double Michael addition of dithiols such as 1,3-propanedithiol and 1,2-ethanedithiol to
carbonyl compounds in the presence of molecular sieve and dimethyl sulfoxide proceeds very smoothly
to afford the corresponding b-keto 1,3-dithianes and b-keto 1,3-dithiolanes, respectively, in good to high
yields.
a,b-acetylenic
Received 18 September 2009
Revised 22 October 2009
Accepted 2 November 2009
Available online 5 November 2009
Ó 2009 Elsevier Ltd. All rights reserved.
b-Keto cyclic dithioacetals, such as b-keto 1,3-dithiolanes and
1,3-dithianes, are well known as versatile synthetic intermedi-
ates.1 For example, b-keto 1,3-dithianes can be converted to 1,3-
dicarbonyl compounds by deprotection of the 1,3-dithiane
moiety.2
A number of methods are available for generating b-keto 1,3-
dithiolanes and b-keto 1,3-dithianes, including a-alkylation of car-
The reaction of 1,3-diphenyl-2-propyn-1-one with 1,3-propane-
dithiol was selected to optimize the reaction conditions. First, we
tried double Michael addition of 1,3-propanedithiol (0.30 mmol)
to 1,3-diphenyl-2-propyn-1-one (0.30 mmol) in the presence of
MS 4A in various solvents (Table 1). We found that aprotic polar
solvents (DMSO, dimethylformamide) were suitable for this reac-
tion and 1-pheny-2-(2-phenyl-1,3-dithian-2-yl)ethan-1-one(1a)
was obtained in 90% and 88% yields, respectively (entries 1
and 2). When using MeOH as a solvent, we obtained the desired
product in moderate yield (entry 3). Dichloromethane, tetrahydro-
furan, and hexane were found to be ineffective for this reaction
(entries 4–6). We have already reported the silylation of alcohols
with trialkylsilyl chloride under the influence of DMSO (3 equiv)
in hexane without using a catalyst.14 Therefore, we expected that
the amount of DMSO could be reduced in hexane as a solvent.
Thus, we investigated the equivalent of DMSO to 1,3-diphenyl-2-
propyn-1-one in hexane (Table 2). We found that 5 equiv
bonyl compounds with 1,3-dithiolane and 1,3-dithiane or its deriv-
atives,3 nucleophilic addition of 1,3-dithiane to epoxides followed
by oxidation,4 conjugate reduction of
a
-oxoketene dithioacetals,5
and double Michael addition of 1,2-ethanedithiol and 1,3-propane-
dithiol to
a
,b-acetylenic carbonyl compounds.6 The double Michael
addition of dithiols needs a catalyst [Al2O3, n-Bu3P, ionic liquid,
(MgCO3)4Mg(OH)2, and NaOMe]2,6 to proceed smoothly. Further-
more, some reactions must be carried out at a lower tempera-
ture.6b,d These conventional methods, therefore, have much room
for improvement toward simpler operations and milder reaction
conditions. For example, in the case of Al2O3-catalyzed double Mi-
chael addition, the activation of Al2O3 is unavoidable before use.
In recent years, dimethyl sulfoxide (DMSO) has received re-
newed attention as a polar solvent and a promoter of efficient or-
ganic reactions.7 We developed several effective reactions in the
presence of molecular sieves (MS) 4A in DMSO during the course
of our intensive work. For example, cyanobenzoylation of alde-
hydes,8 cyanocarbonation of aldehydes,9 trifluoromethylation of
carbonyl compounds,10 Henry reaction,11 and Knoevenagel reac-
tion12 were documented. Moreover, we investigated Michael addi-
tion in the presence of MS 4A in DMSO, and the desired reaction
occurred readily to yield the corresponding 1,4-addition prod-
ucts.13 These results suggested that a similar double Michael addi-
tion of dithiols could be performed in DMSO.
Table 1
Effect of solventa
O
Solvent
O
+
HS
SH
S
S
Ph
MS 4A / rt / 4 h
Ph
Ph
Ph
1a
Entry
Solvent (2 mL)
Yieldb (%)
1
2
3
4
5
6
DMSO
DMF
MeOH
CH2Cl2
THF
90
88
45
4
3
5
Hexane
a
Reactions were carried out using 1,3-diphenyl-2-propyn-1-one (0.3 mmol) and
1,3-propanedithiol (0.3 mmol) in solvent in the presence of MS 4A (100 mg).
* Corresponding author. Tel.: +81 29 228 8368; fax: +81 29 228 8403.
E-mail address: tor@mx.ibaraki.ac.jp (T. Oriyama).
b
Isolated yield of the purified product.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.002

T. Kakinuma, T. Oriyama / Tetrahedron Letters 51 (2010) 290–292
291
Table 2
Table 4
Screening of the amount of DMSOa
Double Michael addition to various
a
,b-acetylenic carbonyl compoundsa
X equiv.
MS 4A / DMSO
O
O
n
S
R2
MS 4A / DMSO
O
O
R1
+
+
HS
SH
S
HS
SH
S
S
Ph
n
hexane / rt / 12 h
hexane / rt / 4 h
R1
R2
Ph
Ph
Ph
n = 0, 1
1a
Entry
R1
R2
Yieldb (%) (n = 0)
Yieldb (%) (n = 1)
Enrty
X (equiv)
Yieldb (%)
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
93
63
90
73
83
95c
86
72
72
64
97
88
89
63
63
89c
74
61
55
44
1
2
3
4
94 (2 mL)
10
5
90c
90
90
73
4-BrC6H4
4-MeC6H4
4-MeOC6H4
3
Ph
CH2OTBDMS
2-Furyl
Me
Ph
Ph
Ph
n-Bu
Ph
H
a
Reactions were carried out using 1,3-diphenyl-2-propyn-1-one (0.3 mmol) and
1,3-propanedithiol (0.3 mmol) in hexane (2 mL) in the presence of MS 4A (100 mg).
b
Isolated yield of the purified product.
H
EtO
10
a
The reactions were performed using
a,b-acetylenic carbonyl compounds
(0.3 mmol) and dithiols (0.3 mmol) in hexane (2 mL) in the presence of MS 4A
(150 mg) and DMSO (1.5 mmol).
(1.5 mmol) of DMSO in hexane (2 mL) improved the yield of the
desired product (entry 3).
b
Isolated yield of the purified product.
c
The reaction was carried out in DMSO (2 mL).
Next, we tested double Michael addition in the presence of var-
ious dehydrating reagents as an additive (Table 3). When the
experiment was performed without an additive, no reaction oc-
curred (entry 1). On the other hand, the reaction in the presence
of MS 4A (100 mg) proceeded very smoothly to yield the desired
product in 90% yield (entry 3). Other additives such as MS 5A,
MS 13X, Drierite, and MgSO4 were less effective than MS 4A15 (en-
tries 4–7). A screening of the amount of MS 4A showed that double
Michael addition proceeded smoothly, when MS 4A (150 mg) was
used. The reaction with 1,2-ethanedithiol instead of 1,3-propane-
dithiol also occurred readily, producing the corresponding b-keto
1,3-dithiolane in good yields. However, thioacetalization of the
carbonyl group could not be detected.
O
Ph SnBu
SnBu
MS 4A / DMSO
hexane / rt / 12 h
O
nBuSH
+
Ph
Ph
Ph
Ph
0.3 mmol
0.6 mmol
trace
O
SnBu
Ph
94%
Scheme 1. Michael addition of n-BuSH.
The scope of the present reaction was investigated using a vari-
ety of
Michael addition of 1,2-ethanedithiol and 1,3-propanedithiol was
uniformly successful for various ,b-acetylenic ketones (entries
1–8). The ketone having a trialkylsilyloxy group afforded the corre-
sponding product in good yield (entry 5). Moreover, we found that
a
,b-acetylenic carbonyl compounds (Table 4).16,17 Double
5 g
5 equiv.
O
a
MS 4A / DMSO
O
+
HS
SH
S
S
Ph
hexane / rt / 12 h
67 mL
Ph
Ph
Ph
10 mmol
10 mmol
87%
a,b-acetylenic aldehyde and a,b-acetylenic ester also gave the cor-
purified by recrystallization
responding adducts in good yields (entries 9 and 10).
mp121-122oc
We examined the addition reaction of 1,3-diphenyl-2-propyn-
1-one with monothiol, n-BuSH, instead of dithiol; however, we ob-
tained the single Michael adduct predominantly in 94% yield
Scheme 2. Double Michael addition performed in a large scale.
(Scheme 1). In addition, we could obtain the corresponding b-keto
dithiane in larger scale after purification by recrystallization
(10 mmol scale, Scheme 2). The detailed role of DMSO and MS
4A in not made clear at present, the combination of DMSO and
MS 4A is indispensable for this double Michael addition.
In conclusion, we have developed a convenient double Michael
addition of 1,3-propanedithiol and 1,2-ethanedithiol to a,b-acety-
lenic carbonyl compounds to give b-keto 1,3-dithianes and b-keto
1,3-dithiolanes, respectively. The reaction can proceed smoothly in
hexane in the presence of MS 4A and DMSO. The reaction has the
following synthetic advantages: (1) in contrast to known methods,
this procedure does not need an additional base or Lewis acid, (2) a
Table 3
Effect of additivea
5 equiv.
Additive / DMSO
O
O
+
HS
SH
S
S
Ph
hexane / rt / 4 h
Ph
Ph
Ph
1a
Entry
Additive
None
Yieldb (%)
1
2
3
4
5
6
7
8
9
Trace
86
90
5
42
7
6
93
76
MS 3A (100 mg)
MS 4A (100 mg)
MS 5A (100 mg)
MS 13X (100 mg)
Drierite (100 mg)
MgSO4 (100 mg)
MS 4A (150 mg)
MS 4A (200 mg)
wide range of
a,b-acetylenic carbonyl compounds can be em-
ployed, (3) not only 1,3-propanedithiol but also 1,2-ethanedithiol
as a nucleophile are available, (4) this method is very simple, con-
venient, and practical, and (5) atom economy is extremely high.
Acknowledgment
a
Reactions were carried out using 1,3-diphenyl-2-propyn-1-one (0.3 mmol) and
1,3-propanedithiol (0.3 mmol) in hexane (2 mL) in the presence of DMSO
(1.5 mmol).
This work was supported by a Grant-in-Aid for Scientific Re-
search on Priority Areas ‘Advanced Molecular Transformations of
b
Isolated yield of the purified product.

292
T. Kakinuma, T. Oriyama / Tetrahedron Letters 51 (2010) 290–292
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used without further purification. Typical experimental procedure is as
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were added to a solution of 1,3-diphenyl-2-propyn-1-one (61.8 mg, 0.3 mmol)
in hexane (2 mL) in the presence of MS 4A (150 mg) at room temperature
under argon atmosphere. The resultant mixture was stirred for 12 h at room
temperature and the reaction was quenched with a phosphate buffer (pH 7).
The organic materials were extracted with AcOEt and dried over MgSO4. The
solvent was evaporated and 1-pheny-2-(2-phenyl-1,3-dithian-2-yl)ethan-1-
one (89.5 mg, 97%) was isolated by thin-layer chromatography on silica gel
(AcOEt/hexane = 1:5). The product gave satisfactory NMR and IR spectra.