Copper-Catalyzed Thioannulation of Propynamides with Sodium Sulfide for the Synthesis of Isothiazol-3-ones

Article abstract of DOI:10.1002/adsc.201801579

A method for the copper-catalyzed thioannulation of propynamides with sodium sulfide was developed for the synthesis of isothiazol-3-ones. The reaction involves a nucleophilic addition and an intramolecular cross-dehydrogenative coupling reaction. The thi

Full text of DOI:10.1002/adsc.201801579

Title: Copper-catalyzed Thioannulation of Propynamides with Sodium
Sulfide for the Synthesis of Isothiazol-3-ones
Authors: Sui-Quan Wang, Bo-Lun Hu, and Xing-Guo Zhang
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10.1002/adsc.201801579
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial sttaff))
Copper-Catalyzed Thioannulation of Propynamides with
Sodium Sulfide for the Synthesis of Isothiazol-3-ones
Sui-Qian Wang,a Bo-Lun Hu,a and Xing-Guo Zhang a,*
a College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, China
Tel./Fax: (+86)-577-8668-9615; e-mail: zxg@wzu.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######. ((Please
delete if not appropriate))
ynamides could undergo sulfur addition and intramolecular
cross-dehydrogenative coupling reactions[11] with metal
sulfides to produce isothiazol-3-ones. Herein, we report a
method for the copper-catalyzed thioannulation of
propynamides using sodium sulfide, which is inexpensive
and odorless, for the concise, one-pot synthesis of
isothiazol-3-one derivatives (Scheme 1, b).
Abstract:
A
method for the copper-catalyzed
thioannulation of propynamides with sodium sulfide was
developed for the synthesis of isothiazol-3-ones. The
reaction involves
intramolecular cross-dehydrogenative coupling reaction.
The thioannulation features the use of an inexpensive and
odorless sulfur source and easily prepared propynamides
with excellent functional group tolerance.
a
nucleophilic addition and an
The reaction between N,3-diphenylpropanamide 1a and
sodium sulfide was selected as a model reaction to
Keywords: Annulation; sulfur heterocycles; hydrogen optimize the reaction conditions, and the results are
migration; cross-dehydrogenative coupling.
Table 1. Optimization of reaction conditions.[a]
Sulfur-containing
heterocycles
have
received
considerable interest due to their wide application in
pharmaceuticals, natural products, and functional
materials.[1] Among them, isothiazol-3-ones are a class of
privileged structural motifs found in many heterocyclic
compounds with remarkable biological activities, including
anti-inflammatories,[2] biocides[3] and inhibitors of
telomerase,[4] histone acetyl transferase,[5] and cytokine-
induced cartilage destruction.[6] However, applications of
isothiazol-3-ones are limited by the insufficient methods
available for their efficient preparation. The few reported
approaches suffer from multistep reactions, unavailable
reactants and poor atom-economic sulfur surrogates.[7]
Entry Catalyst Oxidant
Ligand
Solvent Yield(%)
1
2
Cu(OAc)2
Cu(OAc)2 K2S2O8
-
-
-
-
-
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
31
30
32
35
51
52
48
48
60
43
33
61
62
70
82
71
NR
33
3
4
5
6
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuBr2
TBHP
BQ
I2
-
-
-
-
-
-
I2
Therefore,
a simple and efficient protocol for the
7
CuCl2
I2
construction of the isothiazol-3-one framework is highly
desirable. In 2017, Reddy and coworkers reported the
synthesis of five isothiazol-3-ones from the decyanative
cyclization of ynamides with 4 equiv of KSCN (Scheme 1,
8
CuO
I2
9
10
Cu(OTf)2
-
I2
I2
a).[8] As part of our continued interest in sulfur-containing
I2
I2
I2
I2
I2
I2
I2
I2
11 Cu(OTf)2
12 Cu(OTf)2
13 Cu(OTf)2
14 Cu(OTf)2
15 Cu(OTf)2
16 Cu(OTf)2
17 Cu(OTf)2
18[b] Cu(OTf)2
bipyridine
DMEDA
TMEDA
1,10-Phen MeCN
1,10-Phen DMF
1,10-Phen DMSO
1,10-Phen Toluene
1,10-Phen
[9]
molecules
and inspired by the synthesis of S-
heterocycles from metal sulfides,[10] we questioned whether
DMF
[a] Reaction conditions: 1a (0.2 mmol), Na2S (2.5 equiv),
Cu(OTf)2 (10 mol %), ligand (20 mol %), oxidant (1.0
equiv), solvent (2 mL) under N2 atmosphere at 100 °C
for 12 h, isolated yield.
Scheme 1. Construction of isothiazol-3-ones.
[b] Na2S (1.8 equiv); NR = no reaction.
1
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10.1002/adsc.201801579
Advanced Synthesis & Catalysis
summarized in Table 1. First, treatment of 1a with 2.5 diphenylpropionamide 4 was used as a substrate under
equiv of Na2S and 10 mol% Cu(OAc)2 in MeCN afforded standard conditions, neither product 2a nor 5-methyl-N-
the desired product 2a in 31% yield (Table 1, entry 1). phenylisothiazol-3(2H)-one could be detected (Eq. 2).
Next, we investigated oxidants, and I2 was found to be the Moreover, the N-deuterated ynamide 5 was prepared in situ
best oxidant to provide product 2a in 51% yield (entries 2- through a deuterium-hydrogen exchange of substrate 1a
5). To further improve the yield of the reaction, several with CD3OD in the presence of NaH. Then, the
copper catalysts were tested, including CuBr2, CuCl2, CuO, thioannulation of 5 was carried out immediately in one pot
and Cu(OTf)2 (entries 6-9). The results indicated that
Table 2. Synthesis of isothiazol-3-ones.[a]
Cu(OTf)2 was the best catalyst and a 60% yield was
obtained (entry 9). Only 43% yield was isolated in the
absence of the copper catalyst (entry 10). Encouraged by
these results, we continued to examine various N,N-
didentate ligands, and 1,10-Phen proven to be the best
ligand, affording product 2a in 70% yield (entries 11-14).
Subsequently, various solvents were used in the reaction,
such as DMF, DMSO, and toluene (entries 15-17). We
were pleased to find that product 2a could be isolated in
82% yield in the presence of DMF (entry 15). Lower yields
were observed when the loading of Na2S was reduced to
1.8 equiv, indicating that Na2S not only acted as a sulfur
source but also as a weak base in the reaction (entry 18).
With the optimal reaction conditions in hand, we
explored the substrate scope of this thioannulation by
testing the reaction of a variety of propionamides with
Na2S (Table 2). First, 4-substituented phenyl groups of the
alkyne moiety (R) were examined, and the results showed
that both the electron-rich methyl, methoxy and the
electron-poor F, Cl, Br and CF3 were suitable for providing
the corresponding products 2b-2g in 53-73% yield. The
bulky o-tolyl and naphthalen-1-yl provided products 2h
and 2i in 65% and 48% yield, respectively. It is noteworthy
that the reaction of an aliphatic propynamide also
proceeded smoothly, and the product 2j was isolated in
44% yield. Subsequently, we investigated a series of N-
substituents (R'). As expected, para-substituted phenyl
groups including Me, OMe, t-Bu, F, Cl, Br and CF3, are all
compatible in providing the corresponding isothiazoles 2k-
2q in 53-84% yield. The structure of product 2o was
confirmed by single-crystal X-ray diffraction analysis. o-
Tolyl,
propionamides 1 delivered products 2r-2t in 54-72% yield.
Propionamide with sterically hindered mesityl
m-tolyl
and
m-chlorophenyl-substituted
1
[a]
Reaction conditions: 1 (0.2 mmol), Na2S (2.5 equiv),
Cu(OTf)2 (10 mol %), 1,10-Phen (20 mol %), I2 (1.0
equiv), DMF (2 mL) under N2 atmosphere at 100 °C for
12 h.
successfully provided product 2u in 53% yield. During the
examination of polycyclic aryls and heteroaryls,
naphthalene-2-yl and pyridi-3-yl were found to be tolerated
well in this cyclization reaction, albeit products 2v and 2w
were produced in low yields. Finally, we examined some
N-alkyl substituents, such as benzyl, n-butyl, and
cyclopentyl. We were pleased to find that the
thioannulation of these N-aliphatic alkyl substituted amides
proceeded smoothly under standard conditions to give the
corresponding products 2x-2z in 26-44% yield.
To elucidate the mechanism of this transformation,
several control experiments were carried out and the results
are shown in Scheme 2. First, the reaction of ynamide 1a
with Na2S was conducted in anhydrous DMF and 0.1 mL
D2O under standard conditions. Product 2a was isolated in
62% yield, while the deuterated product 3 could not be
detected (Eq. 1). The results indicated that the hydrogen
atom in the 4-position of the isothiazol-3-one was not
provided by the water in the solvent. When N-methyl-N, 3-
Scheme 2. Control experiments.
2
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10.1002/adsc.201801579
Advanced Synthesis & Catalysis
by adding Na2S, Cu(OTf)2, 1,10-phen, I2 and anhydrous 155.4, 136.6, 131.4, 129.5, 129.4, 129.3, 127.0, 125.8,
DMF under standard conditions. We were pleased to find 124.1, 110.4. LRMS (EI 70 eV) m/z (%): 253 (M+, 68), 180
that the mixture of deuterated product 3 and 2a were (16), 129 (100), 77 (12). HRMS (ESI) Calcd for
isolated in a 64% yield and a 29:71 ratio, and the structure C15H12NOS + ([M + H]+) 254.0634, Found: 254.0634.
of product 3 was identified by NMR and HRMS (Eq. 3).
These results indicated that the 4-position hydrogen of the
isothiazol-3-one 2a might come from the intramolecular
hydrogen migration of the N-monosubstituted propynamide.
X-Ray structure: Supplementary crystallographic data
was deposited at the Cambridge Crystallographic Data
Centre (CCDC) under the numbers CCDC-1879120 (2o)
and can be obtained free of charge from via
www.ccdc.cam.ac.uk/data_request.cif.
Acknowledgements
We thank the National Natural Science Foundation of
China (No. 21272177) and Natural Science Foundation of
Zhejiang Province (No. LR15B020002) for financial
support.
Scheme 3. Possible mechanism.
References
Based on the observed results and the reported
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outlined in Scheme 3. In the presence of Lewis acid
Cu(OTf)2, a nucleophilic addition reaction of sodium
sulfide with ynamide 1a yields the sulfide anion
intermediate A. Then, intermediate A undergoes a [1,3]-
hydrogen migration to produce intermediate B. The anion
exchange of Cu(OTf)2 with intermediate B provides
cyclocopper complex C. The final reductive elimination
gives product 2a and Cu(0), which can be oxidated to
regenerate Cu(II) in the presence of iodine.
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A
variety of N-monosubstituted propynamides can undergo
the thioannulation with sodium sulfide to produce
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Experimental Section
Typical Experimental Procedure for the Synthesis of 2a:
To a flame-dried Schlenk tube with a magnetic stirring bar
was charged 1a (44.2 mg, 0.2 mmol), Na2S (39.0 mg, 2.5
eq), Cu(OTf)2 (7.2 mg, 10 mol %), 1,10-phen (7.2 mg, 20
mol %), I2 (50.8 mg, 1.0 equiv ) in DMF (2 mL) under N2
atmosphere. The reaction mixture was stirred at 100 °C for
12 hours. After the reaction was finished, the mixture was
poured into ethyl acetate, which was washed with saturated
brine (2 x 15 mL). After the aqueous layer was extracted
with ethyl acetate, the combined organic layers were dried
over anhydrous Na2SO4 and evaporated under vacuum. The
residue was purified by flash column chromatography
(petroleum ether/ethyl acetate) to afford the desired product
2a. Pale yellow solid (41.5 mg, 82% Yield), mp 90-92 ºC;
1H NMR (500 MHz, DMSO-d6) δ 7.76-7.74 (m, 2H), 7.68
(d, J = 7.5 Hz, 2H), 7.58-7.50 (m, 5H), 7.39-7.36 (m, 1H),
6.96 (s, 1H). 13C NMR (125 MHz, DMSO-d6) δ 166.8,
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10.1002/adsc.201801579
Advanced Synthesis & Catalysis
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4
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10.1002/adsc.201801579
Advanced Synthesis & Catalysis
UPDATE
Copper-catalyzed Thioannulation of Propynamides
with Sodium Sulfide for the Synthesis of
Isothiazol-3-ones
Adv. Synth. Catal. Year, Volume, Page – Page
Sui-Qian Wang, Bo-Lun Hu, Xing-Guo Zhang
5
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