Base-Promoted Sulfur-Mediated Carbonylative Cyclization of Propargylic Amines

Article abstract of DOI:10.1002/ejoc.201701717

A tBuOK-mediated carbonylative cyclization of propargylic amines with elemental sulfur has been developed. With benzene-1,3,5-triyl triformate (TFBen) as a convenient CO surrogate, various substituted 1,3-thiazolidin-2-ones were produced in good to excellent yields.

Full text of DOI:10.1002/ejoc.201701717

A Journal of
Accepted Article
Title: Base-Promoted Sulfur-Mediated Carbonylative Cyclization of
Propargylic Amines
Authors: Jun Ying, Hai Wang, Xinxin Qi, Jin-Bao Peng, and Xiao-Feng
Wu
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701717
Link to VoR: http://dx.doi.org/10.1002/ejoc.201701717
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201701717
COMMUNICATION
Base-Promoted Sulfur-Mediated Carbonylative Cyclization of
Propargylic Amines
[
a]+
[a]+
[a]
[a]
[a,b]
Jun Ying, Hai Wang, Xinxin Qi, Jin-Bao Peng, and Xiao-Feng Wu*
t
Abstract: A BuOK mediated carbonylative cyclization of propargylic
8
known sulfuration agents, elemental sulfur (S ) is obviously
amines with elemental sulfur has been developed. With benzene-
the most desirable raw material due to its inexpensive, non-
8
1,3,5-triyl triformate (TFBen) as a convenient CO surrogate, various
toxic, inodorous and stable characters. Sulfur-involved
8
,9
substituted 1,3-thiazolidin-2-ones were produced in good to excellent
yields.
carbonylation is an intriguing but difficult research topic.
Not surprisingly, to date there is no research on the
carbonylative cyclization of propargylic amines with S been
8
reported. Herein, we disclose a novel procedure for the
synthesis of 1,3-thiazolidin-2-ones via a BuOK-mediated
carbonylative cyclization of propargylic amines with S . It is
8
noteworthy that the reaction undergoes smoothly under
metal-free conditions to afford the desired 4-alkylidene-
thiazolidin-2-ones in good to excellent yields with TFBen as
the solid CO source.
In nowadays, carbonylation reaction has already been
accepted as a class of potent transformations in modern
organic chemistry. Notably, many carbonylation related
processes have been industrialized, such as Fischer-
t
1
Tropsch process, Cativa process, and hydroformylations.
However, transition-metal catalysts are usually obligatory in
most of the achieved procedures. Besides the risk of metals
contamination on the terminal products, the using metal
catalysts will definitely increases the costs of the process.
Although metal-free radical mediated carbonylation reactions
have been established as well, relative high CO pressure (>
2
5
0 bar) is mandatory. Additionally, even though carbon
monoxide is a cheap and ideal C1 source for large scale
carbonylation chemistry, its high toxicity and smell-less
properties lead the related procedures are reluctant to be
applied by synthetic chemists in laboratories. Hence, the
development of CO surrogates and 3their applications
exploration become a new research topic.
On the other hand, sulfur-containing heterocyclic
compounds are one of the central chemicals due to their
unusual physical properties and versatile biological activities
4
Scheme 1. Selected examples of bio-active sulfur-containing motifs.
(Scheme 1).
Among the various sulfur-containing
heterocycles, 1,3-thiazolidin-2-ones are useful and valuable
motifs in various areas. Consequently, much attention has
5
The initial model reactions were carried out using the
propargylic amine 1aa as a substrate, and the results are
summarized in Table 1. When 1aa was treated with TFBen
10
been focused on the development of new synthetic
6
procedures towards thiazolidinones. Various sulfuration
(
(
2 equiv; benzene-1,3,5-triyl triformate) and sulfur powder
agents including thiols, sulfides, and their oxidized
derivatives and so on have been applied. However,
challenging such as relative harsh reaction conditions, low
reaction efficiency and limited substrates scope still exist.
Additionally, the compatibility of transition metal catalysts
o
0.5 equiv) in the presence of DBU at 35 C, the reaction
afforded the corresponding cyclized product 2aa in 91% yield
Table 1, entry 1). Then, a series of bases were examined
Table 1, entries 2-5). A slightly reduced yield (88%) of 2aa
(
(
7
was obtained with NaOH as the promotor (Table 1, entry 2).
with sulfuration agents is usually problematic as well. This
t
We were delighted to find that the using of BuOK and
property makes the development of new methodology for
sulfur incorporation more challenge. Moreover, among the
DABCO improved the yield to 96% and 93%, respectively
Table 1, entries 3 and 4). A significantly decreased yield
47%) was observed when DMAP was employed (Table 1,
(
(
entry 5). When the solvent of reaction was changed from
DMF to DMSO, over 99% yield was achieved, while MeCN,
toluene, 1,4-dioxane, and DCM lead to the formation of a
trace or no desired product (Table 1, entries 6-10). Excellent
yields (over 99%) were still maintained when the amounts of
[
a]
Dr. J. Ying, H. Wang, Dr. X. Qi, Dr. J.-B. Peng, Prof. Dr. X.-F. Wu
Department of Chemistry, Zhejiang Sci-Tech University, Xiasha
Campus, Hangzhou 310018, People’s Republic of China
E-mail: xiao-feng.wu@catalysis.de
https://www.catalysis.de/mitarbeiter/wu-xiao-feng/
[
b]
Prof. Dr. X.-F. Wu
8
TFBen (1 equiv) and S (0.375 equiv) were decreased (Table
Leibniz-Institut für Katalyse e. V. an der Universität Rostock, Albert-
Einstein-Straβe 29a, 18059 Rostock, Germany
J. Ying and H. Wang contributed equally to this work.
1
, entries 11 and 12). Further reducing the amount of S
8
+
t
(0.25 equiv) or BuOK (1.5 equiv) slightly decreased the
reaction yields (Table 1, entries 13 and 14). It was found that
the yield was dramatically decreased to 53% with the use of
Supporting information for this article is given via a link at the end of
the document.
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European Journal of Organic Chemistry
10.1002/ejoc.201701717
COMMUNICATION
0
.5 equivalent of TFBen (Table 1, entry 15). Moreover, in the
crystallography as shown in Figure 1 (see the Supporting
Information).
reaction temperature variations, low conversion of the
substrate was observed at room temperature while higher
temperature gives no better results.
a
Scheme 2. Substrate Scope.
a
Table 1. Reaction Optimization.
b
Entry
S
8
TFBen
Base
Solvent
Yield
1
2
3
4
0.5 eq
0.5 eq
0.5 eq
0.5 eq
2.0 eq
2.0 eq
2.0 eq
2.0 eq
2.0 eq DBU
DMF
DMF
DMF
DMF
91%
88%
96%
93%
2.0 eq NaOH
t
2.0 eq BuOK
2.0 eq
DABCO
5
6
7
8
0.5 eq
0.5 eq
0.5 eq
0.5 eq
2.0 eq
2.0 eq
2.0 eq
2.0 eq
2.0 eq DMAP
DMF
DMSO
MeCN
Toluen
e
dioxan
e
DCM
DMSO
DMSO
47%
>99%
Trace
0
t
2.0 eq BuOK
t
2.0 eq BuOK
t
2.0 eq BuOK
t
9
0.5 eq
2.0 eq
2.0 eq BuOK
0
t
10
11
12
0.5 eq
0.5 eq
0.375 eq
2.0 eq
1.0 eq
1.0 eq
2.0 eq BuOK
0
t
2.0 eq BuOK
>99%
>99%c
t
2.0 eq BuOK
(
92%)
96%
95%
53%
t
13
14
15
0.25 eq
0.5 eq
0.375 eq
1.0 eq
1.0 eq
0.5 eq
2.0 eq BuOK
DMSO
DMSO
DMSO
t
1.5 eq BuOK
t
2.0 eq BuOK
a
b
Reaction conditions: 1aa (0.2 mmol), solvent (1 mL). The yield of 2aa was
c
determined by GC analysis using n-dodecane as internal standard. Isolated
yield.
The optimal reaction conditions (Table 1, entry 12)
were successfully applied to various propargylic amines as
follows (Scheme 2). It shows that the propargylic amines
bearing both electron-donating and electron-withdrawing
substituents underwent cyclization smoothly to give the
corresponding products (2ab-2ah) in 70-93% yields. The
reactions of substrates containing benzyl and alkyl groups on
the nitrogen atom afforded the products (2ba-2bg, 2c) in
high yields. When the propargylic amine with a N-cyclohexyl
substituent was subjected to the same reaction conditions,
only a trace of the desired product 2d was observed, which
could be explained by the steric property on the nitrogen
atom. Compounds having a carbocycle on the triple bond
were converted to the desired products (2e-2h) in moderate
to good yields (41-94%). It should be noted that the reaction
with a thiophene substituted propargylic amine led to the
formation of product 2i in 94% yield. For compounds
containing alkyl groups on the triple bond, good yields of the
desired products (2j-2m) were obtained under higher
a
8
Reaction conditions: substrate (0.2 mmol), S (0.375 eq), TFBen (1.0 eq),
t
o
b
o
BuOK (2.0 eq), DMSO (1 mL), 35 C, 24 h, isolated yields. 60 C.
Figure 1. X-ray structures of products 2bg (CCDC: 1586022), and TFBen
CCDC: 1562894).
o
(
temperature (65 C). Interestingly, primary propargylic amine
can be successfully transformed to the product 2n in 88%
In order to get some insight into the reaction pathway,
control experiments of this carbonylative cyclization of
propargylic amine and sulfur were performed as well
yield as well. In addition, we tested the cyclization of
2
substrates with aryl and alkyl substituents (R = aryl, alkyl
3
and R = H), 45-95% yields of the corresponding products
(
Scheme 3). First, propargylic amine 1aa was subjected to
2
o-2t were achieved. It was found that a compound without
t
2
3
the standard reaction conditions in the absence of BuOK. No
substituents (R , R = H) can also undergo carbonylative
cyclization to provide the product 2u in a moderate yield. The
structure of product 2bg was confirmed by X-ray
product 2aa could be observed and the formamide 3 was
t
obtained in 85% yield, which indicated that BuOK is
8
essential to activate S in this sulfur-involved carbonylative
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European Journal of Organic Chemistry
10.1002/ejoc.201701717
COMMUNICATION
cyclization. On the other hand, it was found that carbonyl
sulfide (COS), prepared from KSCN and H SO , can react
2 4
with 1aa to give product 2aa in 60% yield. This result
be obtained under mild conditions. Further synthetic
applications of this method and more detailed study of the
reaction mechanism are under progress.
suggested that COS or analogues, which formed from
t
8
BuOK-mediated reaction between S and CO, could be a
possible intermediate in this reaction. Additionally, possibility Experimental Section
of the involvement of radical intermediates can be excluded
by the addition of TEMPO and BHT (2,6-di-tert-butyl-p-kresol) S (0.375 equiv.), TFBen (1.0 equiv.) and tBuOK (2.0 equiv.) were added
8
to the model system which gave the same yields of the
desired product.
to a 15 mL tube equipped with a magnetic stirrer which was then placed
under vacuum and refilled with nitrogen three times. A solution of
propargylamine (0.2 mmol) in DMSO (1.0 mL) was added to the reaction
o
tube, then the tube was sealed and the mixture was stirred at 35 C for
2
4 h. After the reaction was completed, the reaction mixture was diluted
with 50 mL water and extracted with 30 mL EtOAc three times. The
combined organic phases were dried with anhydrous Na SO
concentrated and purified by silica gel column chromatography
PE/EtOAc=10/1) to obtain desired (Z)-5-benzylidene-3-butyl-4,4-
2
4
,
(
dimethylthiazolidin-2-one.
Acknowledgements
Scheme 3. Mechanistic Investigations.
The authors thank the financial supports from NSFC (21472174),
Zhejiang Natural Science Fund for Young Scholars
(LQ18B020008) and Zhejiang Natural Science Fund for
Distinguished Young Scholars (LR16B020002). We also
appreciate the general supports from Professors Matthias Beller
and Armin Börner in LIKAT.
8
,9
On the basis of previous works and our preliminary
mechanistic studies, a postulated pathway is proposed to
account for carbonylative cyclization of propargylic amine
and sulfur as follows (Scheme 4). Elemental sulfur is
t
activated in the treatment of BuOK, producing the sulfur
anion 4. The reaction of 4 with carbon monoxide, generated
in situ from TFBen, gives the carbonyl sulfide 5. Elimination
of 5 leads to the formation of the key intermediate COS. In
Keywords: carbonylation • metal-free • sulfur • heterocycle
synthesis • cyclization
t
the presence of BuOK, the nucleophilic attack of the
propargylic amine 1 to COS generates the thiocarbamate 6.
The desired product 2 is obtained through an intramolecular
annulation of 6. The stereoselectivity of product 2 (Z-isomer)
can be explained by a trans addition of sulfur anion to a
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solid CO source, various desired 1,3-thiazolidin-2-ones were
produced in a straightforward manner. Moderate to excellent
yields (45-96%) and broad functional groups tolerance can
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European Journal of Organic Chemistry
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COMMUNICATION
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European Journal of Organic Chemistry
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COMMUNICATION
COMMUNICATION
Jun Ying, Hai Wang, Xinxin Qi, Jin-Bao
Peng, and Xiao-Feng Wu*
Page No. – Page No.
Base-Promoted Sulfur-Mediated
Carbonylative Cyclization of
Propargylic Amines
t
A BuOK mediated carbonylative cyclization of propargylic amines with elemental sulfur has been
developed. With benzene-1,3,5-triyl triformate (TFBen) as a convenient CO surrogate, various
substituted 1,3-thiazolidin-2-ones were produced in good to excellent yields.
This article is protected by copyright. All rights reserved.