Fe(III)-catalyzed intermolecular C(sp2)-C(sp3) dehydration coupling reaction of ketene dithioacetals and propargyl alcohols: Synthesis of novel gem-dialkylthiopenten-4-ynes and further conversion into methyl pent-4-ynoates

Article abstract of DOI:10.1055/s-0030-1260333

We report an iron(III)-catalyzed intermolecular C(sp²)-C(sp ³) dehydration coupling reaction between ketene dithioacetals and propargyl alcohols, leading to the synthesis of gem-dialkylthiopenten-4-ynes in high efficiency. The produc

Full text of DOI:10.1055/s-0030-1260333

LETTER
2551
Fe(III)-Catalyzed Intermolecular C(sp2)–C(sp3) Dehydration Coupling
Reaction of Ketene Dithioacetals and Propargyl Alcohols: Synthesis of Novel gem-
Dialkylthiopenten-4-ynes and Further Conversion into Methyl Pent-4-ynoates
D
ehydrati
i
on
C
ou
n
pling Reactio
-
n
of
K
e
N
tene
D
ithioacetals
a
a
nd Propargyl
A
l
S
cohols ong,*a Zhongxue Fang,b Ying Liu,b Ran Li,a Lixin Xu,a Badru-Deen Barry,b Qun Liu,b Xihe Bi,b,c
Peiqiu Liao*b
a
School of Biological and Agricultural Engineering, Jilin University, Changchun 130022, P. R. of China
Fax +86(431)85099759; E-mail: songjn2010@jlu.edu.cn
Department of Chemistry, Northeast Normal University, Changchun 130024, P. R. of China
State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai University, Tianjin 300071, P. R. of China
b
c
E-mail: liaopq774@nenu.edu.cn
Received 29 June 2011
iron-catalyzed intramolecular aromatic C–H alkenylation
Abstract: We report an iron(III)-catalyzed intermolecular C(sp2)–
C(sp3) dehydration coupling reaction between ketene dithioacetals
and propargyl alcohols, leading to the synthesis of gem-dialkylthio-
penten-4-ynes in high efficiency. The products could be trans-
formed into methyl pent-4-ynoates in high yields.
of arenes, the [4C+1N] tandem cyclization of 4-acetylenic
ketones with primary amines, and the aminolysis of b-car-
bonyl 1,3-dithianes.7 In this context, the iron-catalyzed in-
termolecular C(sp2)–C(sp3) dehydration coupling reaction
between ketene dithioacetals and propargyl alcohols was
developed; the approach possessed several advantages be-
cause it was applicable to a wide range of substrates with
admirable reaction efficiencies, and led to the generation
of penten-4-ynes bearing a characteristic dialkylthio
group at the terminal of the alkenyl group.
Key words: iron, dehydration, coupling reactions, alkynes, thioac-
etals
Transition-metal-catalyzed C–C coupling reactions have
attracted great attention over the last decades.1 Among the
many kinds of C–C coupling reactions, intermolecular de-
hydration processes are alluring because water is the ex-
clusive by-product. Ketene dithioacetals are versatile
synthetic intermediates in organic synthesis.2 One of their
major structural features is the high electrophilicity of the
a-carbon adjacent to the electron-withdrawing group
(EWG) due to the push–pull effect of the alkylthio group
and the EWG at either side of the double bond. As part of
our continuing studies on ketene dithioacetal chemistry,3
we have previously reported a copper-catalyzed dehydra-
tion coupling reaction between ketene dithioacetals with
benzylic alcohols.4 In view of the electron-rich character
of penten-4-ynes and the lack of any significant synthetic
explorations on their use,5 we herein report a new C(sp2)–
C(sp3) dehydration coupling reaction between ketene
dithioacetals and propargyl alcohols catalyzed by iron
salts, which leads to the synthesis of gem-dialkylthiopen-
ten-4-ynes with high efficiency. Furthermore, the synthet-
ic potential of the products was also exploited, resulting in
the preparation of substituted methyl pent-4-ynoates in
high yields.
Table 1 Optimization of Reaction Conditionsa
O
S
Ph
S
Ph
[Fe], solvent
r.t.
H
S
+
HO
Ph
Ph
S
O
1a
2a
3a
Entry
[Fe]b
Solvent
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
toluene
MeOH
DMSO
1,4-dioxane
Time (h)
Yield (%)c
1
2
3
4
5
6
7
8
9
FeCl3
25 min
87
80
88
0
Fe(OTf)3
FeBr3
Fe(acac)3
FeCl2
Fe
30 min
20 min
5
5
5
2
1
5
5
0
0
FeCl3
FeCl3
FeCl3
FeCl3
85
81
0
Over the past few years, the development of iron-cata-
lyzed reactions has gained prominence because, com-
pared with precious metal catalysts (e.g., Pt, Rh, Ru, Pd, 10
Au, and Ag), iron is less expensive, nontoxic, and abun-
dant.6 In our continuing interest in exploiting iron salts as
0
a Reagents and conditions: 1a (1 mmol), 2a (1.2 mmol), solvent
(2 mL), r.t.
b [Fe] (30 mol%) was used as catalyst.
catalysts in organic reactions, we previously reported the
c Isolated yield.
SYNLETT 2011, No. 17, pp 2551–2554
x
x
.x
x
.2
0
1
1
Advanced online publication: 27.09.2011
DOI: 10.1055/s-0030-1260333; Art ID: W14711ST
© Georg Thieme Verlag Stuttgart · New York
This study commenced with an exploration of the optimal
conditions using substrate 1a and propargyl alcohol 2a as

2552
J.-N. Song et al.
LETTER
a model reaction; the results are summarized in Table 1. dithioacetals 1b–e with various EWG substituents, such
Using 30 mol% FeCl3 or Fe(OTf)3, the reaction of 1a with as acyl, aminoacyl, and cyano groups, were utilized in the
2a proceeded smoothly and reached completion in a short coupling reaction with propargyl alcohol 2a, and the cor-
time at room temperature in acetonitrile (MeCN), afford- responding products 3b–e were obtained in good yields
ing the desired product 3a in 87 and 80% yield, respec- (Table 2, entries 1–4). Next, a range of propargyl alcohols
tively (Table 1, entries 1 and 2). In comparison, the 2b–i, with systematically varied R1 and R2 substituents,
reaction catalyzed by FeBr3 needed a slightly shorter reac- were reacted with a-acetyl ketene dithioacetal (1a) to fur-
tion time, and offered a comparably high yield (Table 1, nish the gem-dialkylthiopenten-4-ynes 3f–m in good to
entry 3). Other iron species, such as Fe(acac)3, FeCl2 as high yields (Table 2, entries 5–12). Furthermore, ketene
well as zero-valent iron (Fe) failed as catalysts in this re- dithioacetal 1¢, containing a 1,3-dithian-2-ylidene struc-
action, even with prolonged reaction time (Table 1, en- tural unit, was applied to the coupling reaction with prop-
tries 4–6). The choice of solvent had significant influence argyl alcohols. As shown in Table 3, all reactions
on the reaction. For example, when nonpolar toluene or proceeded smoothly and delivered the corresponding
protic MeOH were used, the reaction required slightly products 3¢ in good to high yields, albeit after slightly
longer reaction times, but gave similar yields of 3a (85 longer reaction time compared to the reactions of ketene
and 81%, respectively), whereas polar and aprotic sol- dithioacetals 1.
vents, such as DMSO and 1,4-dioxane, did not give any
products after five hours, and only starting materials were
recovered (Table 1, entries 7–10). Consequently, the con-
ditions listed in Table 1, entry 2 were chosen for subse-
It is known that a thioacetal-transferring reaction can take
place with a-ketene dithioacetals in the presence of anhy-
drous protic acid to remove the thioacetal group.9 There-
fore, we tested the possible transformation of 3 and 3¢
using a combination of acetyl chloride and methanol as
quent investigations.
With the optimal conditions in hand (Table 1, entry 3),8 the HCl source. To our delight, we found that substituted
we studied the scope of the reaction for substrate applica- methyl pent-4-ynoate 4a was produced as the sole product
bility; the results are summarized in Table 2. Ketene using 3¢a as the starting reactant.
Table 2 Synthesis of gem-Dialkylthiopenten-4-ynes 3a
R1
R1
S
S
H
EWG
S
HO
FeBr3 (30 mol%)
S
+
R2
R2
MeCN, r.t.
0.5–1.0 h
EWG
1
2
3
Entry
1
1
EWG
2
R1
R2
3
Yield (%)b
1b
1c
1d
1e
1a
1a
1a
1a
1a
1a
1a
1a
EtCO
2a
2a
2a
2a
2b
2c
2d
2e
2f
Ph
Ph
Ph
Ph
Ph
3b
3c
3d
3e
3f
82
62
85
77
84
89
80
82
87
71
90
84
2
PhCO
H2NCO
CN
Ph
3
Ph
4
Ph
5
MeCO
MeCO
MeCO
MeCO
MeCO
MeCO
MeCO
MeCO
4-MeOC6H4
4-ClC6H4
2-ClC6H4
2-FC6H4
2-thienyl
1-naphthyl
Ph
Ph
6
Ph
3g
3h
3i
7
Ph
8
Ph
9
Ph
3j
10
11
12
2g
2h
2i
Ph
3k
3l
4-MeC6H4
4-BrC6H4
Ph
3m
a Reagents and conditions: FeBr3 (30 mol%), 1 (1 mmol), 2 (1.2 mmol), MeCN (2 mL), r.t.
b Isolated yield.
Synlett 2011, No. 17, 2551–2554 © Thieme Stuttgart · New York

LETTER
Dehydration Coupling Reaction of Ketene Dithioacetals and Propargyl Alcohols
2553
Table 3 Synthesis of gem-Dialkylthiopenten-4-ynes 3¢a
pent-4-ynoate 4. In contrast, the 1,3-dithiolane fragment
of 3 was stable under the same conditions.11
S
H
In summary, we have developed a novel and efficient in-
termolecular C(sp2)–C(sp3) dehydration coupling reaction
between ketene dithioacetals and propargyl alcohols us-
ing inexpensive and environmentally friendly iron salts as
catalyst, leading to the synthesis of gem-dialkylthiopen-
ten-4-ynes in good to high yields. The conversion of these
products into methyl pent-4-ynoates was also explored.
Further investigations on the synthetic application of
these readily available gem-dialkylthiopenten-4-ynes are
ongoing, and will be reported in due course.
S
O
S
R1
O
1'
FeBr3 (30 mol%)
+
S
MeCN, r.t.
2–3 h
R1
R2
HO
3'
R2
2
Entry
2
R1
R2
Ph
Ph
Ph
3¢
Yield (%)b
1
2
3
2a
2d
2c
Ph
3¢a
3¢h
3¢g
89
80
75
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
2-ClC6H4
4-ClC6H4
Acknowledgment
a Reagents and conditions: FeBr3 (30 mol%), 1¢ (1 mmol), 2 (1.2
mmol), MeCN (2 mL), r.t.
This work was supported by the Specialized Research Fund for the
Doctoral Program of Higher Education (20100061120071), the
Young Scientific Research Foundation of Jilin Province
(201101068), the Natural Science Foundation of Jilin University
(201003051), the NSFC (31101010) and the Science Foundation for
Young Teachers of Northeast Normal University (09QNJJ013).
b Isolated yield.
In contrast, no reaction was observed when substrate 3a
(n = 1) was reacted under these conditions (Scheme 1).
Subsequently, some representative substrates 3¢ (Table 3)
were submitted to this transformation reaction to yield
methyl pent-4-ynoates 4a–c in good to high yields. Meth-
yl pent-4-ynoates are useful synthetic intermediates that
have been used to generate pharmaceutically relevant
compounds.10 Therefore, we present here an efficient ap-
proach to this type of compound.
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For mechanistic consideration, the coupling reaction be-
tween ketene dithioacetals 1 or 1¢ and propargyl alcohol 2
possibly proceeds first through the formation of a propar-
gyl carbocation, which then reacts with the nucleophilic
a-carbon of the ketene dithioacetal to give the coupled
product 3 or 3¢. In the subsequent ring-opening reaction in
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observed between the two thioacetal compounds (3 and
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n = 1
R1
S
no reaction
( )n
MeCOCl (2 equiv)
S
R1
O
MeOH, reflux
1–2 h
n = 2
R2
OMe
O
R2
4
3 (n = 1) or
3' (n = 2)
Cl
O
O
Cl
O
OMe
OMe
OMe
4a (97%)
4b (90%)
4c (95%)
Scheme 1 Synthetic conversion of gem-dialkylthiopenten-4-ynes 3¢ into methyl pent-4-ynoates 4
Synlett 2011, No. 17, 2551–2554 © Thieme Stuttgart · New York

2554
J.-N. Song et al.
LETTER
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(s, 3 H), 3.63–3.40 (m, 2 H), 3.42–3.45 (m, 2 H), 5.68 (s,
1 H), 7.25–7.31 (m, 1 H), 7.32–7.37 (m, 5 H), 7.49–7.53 (m,
4 H). 13C NMR (CDCl3, 125 Hz): d = 28.4, 35.9, 39.32, 41.9,
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(8) Synthesis of gem-dialkylthiopenten-4-ynes (3); Typical
procedure with 3a: To a solution of 1-(1,3-dithiolan-2-
ylidene)propan-2-one (1a; 160 mg, 1.0 mmol) and 1,3-
diphenylprop-2-yn-1-ol (2a; 250 mg, 1.2 mmol) in MeCN
(2.0 mL), FeBr3 (88 mg, 0.3 mmol) was added, and the
mixture was stirred at r.t. for 20 min. After completion of the
reaction (progress monitored by TLC), the mixture was
poured into ice-water and extracted with CH2Cl2 (3 × 15
mL). The combined organic layers were dried with MgSO4,
filtered, evaporated in vacuum, and the residue was purified
by column chromatography (petroleum ether–diethylether =
10:1) to give product 3a (308 mg, 88% yield) as a white
solid. Mp 170–171 °C. 1H NMR (CDCl3, 500 Hz): d = 2.17
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Synlett 2011, No. 17, 2551–2554 © Thieme Stuttgart · New York

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