I2-Promoted [3+2] Cyclization of 1,3-Diketones with Potassium Thiocyanate: a Route to Thiazol-2(3H)-One Derivatives

Article abstract of DOI:10.1002/adsc.202100228

An I₂-promoted strategy has been developed for the synthesis of thiazol-2(3H)-one derivatives from 1,3-diketones with potassium thiocyanate. This [3+2] cyclization reaction involves C?S and C?N bond formation and exhibits good functional group tolerance. A series of thiazol-2(3H)-one derivatives are obtained in moderate to good yields. (Figure presented.).

Full text of DOI:10.1002/adsc.202100228

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DOI: 10.1002/adsc.202100228
I2-Promoted [3+2] Cyclization of 1,3-Diketones with Potassium
Thiocyanate: a Route to Thiazol-2(3H)-One Derivatives
Zhenyu An,a Yafeng Liu,b Pengbo Zhao,a and Rulong Yana,*
a
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University,
Lanzhou 730000, Gansu, People’s Republic of China
E-mail: yanrl@lzu.edu.cn
Chemical Science and Engineering College, North Minzu University, Yinchuan 750000, People’s Republic of China
b
Manuscript received: February 19, 2021; Revised manuscript received: May 24, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100228
2(3H)-one derivatives by nucleophilic addition of
Abstract: An I2-promoted strategy has been devel-
hydroxylamines to allenyl isothiocyanates (Sche-
oped for the synthesis of thiazol-2(3H)-one deriva-
tives from 1,3-diketones with potassium thiocya-
me 1b). In 2016, Sheng[9] disclosed an efficient organo-
catalytic enantioselective Michael addition of substi-
tuted isorhodanines with α,β-unsaturated aldehydes for
the synthesis of 4,5-disubstituted thiazol-2(3H)-ones
nate. This [3+2] cyclization reaction involves CÀ S
and CÀ N bond formation and exhibits good func-
tional group tolerance. A series of thiazol-2(3H)-
(Scheme 1c). Despite these advances, there are very
one derivatives are obtained in moderate to good
few examples for the synthesis of 4,5-disubstituted
yields.
thiazol-2(3H)-ones from KSCN through intermolecular
cyclization reaction.
Potassium thiocyanate (KSCN), which is inexpen-
sive, low toxicity, and easy availability, has been
Keywords: 1,3-Diketones; Potassium thiocyanate;
Thiazol-2(3H)-ones; Transition-metal-free; Cycliza-
tion
widely used to construct N,S-containing heterocyclic
compounds.[10] For instance, some researches of KSCN
to synthesize 2-aminothiazoles have been reported by
Zhang, Liu, and Duan.[11] In 2017, Reddy reported a
The thiazolone skeletons, as important N,S-heterocy- catalyst-free cyclization to access thiazine-2-thiones
clic compounds, are ubiquitous in natural products and from KSCN and ynones.[12] Recently, Cui and Yan
pharmacologically active molecules.[1] Particularly, respectively developed I2-promoted one-pot three-
thiazol-2(3H)-one derivatives present promising phar- component strategies for the construction of thiadia-
macological profiles and broad biological activities zoles using KSCN as sulfur source.[13] Inspired by
including antitumor, anticancer, antimycobacterial ac- these elegant works, we disclosed an I2-promoted
tivities and so on.[2] For instance, compound I[3] is
druggable and has potential to be developed into
inhibitor of acetyllysine-bromodomain interaction
(Figure 1). Furthermore, sibenadet (II)[4] is known to
act as β2-adrenoceptor agonist for the treatment of
airway diseases (Figure 1). Pioglitazone (III)[5] is a
prototypical antidiabetic agent which has been eval-
uated for possible clinical development (Figure 1).
In the past few years, thiazol-2(3H)-one derivatives
have attracted considerable attentions and significant
efforts have been devoted to construct this scaffolds.[6]
The group of Yoon, Zhu, and Yu developed some
strategies to synthesize benzo[d]thiazol-2(3H)-ones
through reactions of o-substituted aniline derivatives
with CO source or S source (Scheme 1a).[7] In 2014,
Figure 1. Pharmaceutical and bioactive compounds containing
thiazol-2(3H)-one.
Banert[8] reported an approach to synthesize thiazol-
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Table 1. Optimization of reaction conditions.[a]
[b]
°
Entry I2 (eq.) [O] (eq.)
Solvent Temp ( C) Yield (%)
1
2
3
4
5
6
7
8
0.5
0.5
0.5
0.5
0.5
0.5
0.5
–
1.0
1.5
2.0
2.0
2.0
2.0
2.0
2.0
2.0
air
air
air
air
air
air
air
air
air
air
air
DMSO 120
37
NMP
DMF
DMA
120
120
120
50
42
30
CH3NO2 120
trace
35
NMP
NMP
NMP
NMP
NMP
NMP
100
140
140
140
140
140
140
140
140
140
140
140
55
n.d.[c]
60
9
10
11
12
13
14
15
66
70
30
75
TBHP (2) NMP
K2S2O8 (2) NMP
Oxone® (2) NMP
Scheme 1. Synthesis of substituted thiazol-2(3H)-ones.
79
O2
O2
O2
NMP
NMP
NMP
90
protocol for the construction of thiazol-2(3H)-ones via 16
[3+2] cyclization of 1,3-diketones and KSCN.
85[d]
76[e]
17
Initially, the model reaction of 1,3-diphenylpro-
pane-1,3-dione 1a and KSCN 2a was undertaken.
When the reaction was performed employing KSCN
[a] Reaction conditions: 1a (0.2 mmol), KSCN (0.6 mmol), I2,
oxidant, and solvent (2 mL) for 10 h.
[b] Isolated yield.
[c] n.d.=not detected
°
(3 equiv.) and I2 (0.5 equiv.) in DMSO at 120 C for
[d] NaSCN (3.0 equiv.) was used.
10 h, target product 4-benzoyl-5-phenylthiazol-2(3H)-
one 3a was obtained in 37% yield (Table 1, entry 1).
The structure of 3a was confirmed by X-ray crystal-
lography (see the Supporting Information for
details).[14] Several solvents, such as NMP, DMF,
DMA, and CH3NO2, were evaluated and it was found
[e] NH4SCN (3.0 equiv.) was used. Entry in bold highlights
optimized reaction conditions, and the reaction time was
monitored by TLC.
that NMP was better than others (Table 1, entries 2–5). reacted well with KSCN, affording 3g in excellent
°
When the temperature was raised to 140 C, the yield of 94%. The steric effect was clearly observed in
reaction proceeded well and gave the expected product this transformation, in which the substrate 1h led to
3a in 55% yield (Table 1, entries 6–7). No reaction the desired product 3h only in 38% yield. To evaluate
occurred in the absence of I2 (Table 1, entry 8). Never- the feasibility of the protocol with unsymmetrical 1,3-
theless, the yield of product 3a was improved to 70% diketones, substrate 1i was used as reactive partner. As
by increasing the amount of I2 (Table 1, entries 9–11). expected, the mixture of two regioisomeric products 3i
Subsequently, several oxidants, such as TBHP, K2S2O8, and 3i’ was isolated in 78% yield with a ratio of 1.2:1.
Oxone®, and O2, were investigated, and O2 was found Unfortunately, pentane-2,4-dione 1j failed to undergo
to be the most effective oxidant to furnish the desired this process and no desired product was detected.
product in 90% yield (Table 1, entries 12–15). Finally,
To further examine the scope and limitations of the
when different thiocyanating reagents (NaSCN and reaction, substrate 4a was subjected to the optimized
NH4SCN) were examined, no improvement was conditions, only 36% yield of product 5a was obtained
afforded in this reaction system (Table 1, entries 16– (Table S1, entry 1, see the ESI†). Therefore, the
17). So the optimized reaction system was established reaction conditions were re-optimized and the yield of
as Table 1, entry 15.
5a was increased to 72% when the reaction was
Based on the optimal reaction conditions, we carried out using Oxone® (4.0 equiv.) as the oxidant in
°
investigated the substituent scope of this protocol, and NMP/CH3NO2 (1:1) at 140 C for 10 h (Table S1,
the results are summarized in Table 2. Substrates 1b– entry 17, ESI†). Upon optimization of the reaction
1f with para substituents (Me, MeO, F, Cl, and Br) on conditions, the substrate scope for this transformation
the phenyl ring underwent the cyclization reaction was surveyed. As shown in Table 3, this procedure was
smoothly and generated the desired products 3b–3f in slightly affected by electronic property of the substitu-
good yields. Notably, 1g with CF3 group on the phenyl ents on the aromatic ring of 1,3-diketones. For
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Table 2. Scope of substituted 1,3-diphenylpropane-1,3-dione.[a]
Table 3. Scope of substituted 1-phenylbutane-1,3-dione.[a]
[a] Reaction conditions: 1 (0.2 mmol), 2 a (0.6 mmol), I2
°
(0.4 mmol) in NMP (2 mL) at 140 C under O2 (balloon)
for 10 h.
example, para-substituted 1-phenylbutane-1,3-diones
4b–4g bearing electron-donating groups (Me, Et, iPr,
OMe, OEt, N,N-diMe) gave corresponding products
5b–5g in 61–80% yields. However, 4h–4k with
electron-withdrawing groups (F, Cl, Br, and CF3) were
converted to corresponding products 5h–5k in lower
yields. What’s more, meta- and ortho-substituted 1-
phenylbutane-1,3-diones 4m–4r provided desired thia-
zol-2(3H)-ones 5m–5r in moderate yields. These
results indicated that the reaction efficiency was not [a] Reaction conditions: 4 (0.2 mmol), 2a (0.6 mmol), I2
(0.2 mmol), Oxone® (0.8 mmol) in NMP/CH3NO2 (1 mL/
significantly affected by steric hindrance effect. Dis-
ubstituted substrates 4s–4u were also tolerated to
afford 5s–5u in good yields. To explore the effect of
°
1 mL) at 140 C under Ar for 10 h.
fused rings on reactivity, naphthyl 1,3-diketones 4v–
4x were investigated, providing target products 5v–5x 2a to afford the corresponding products 5z-1 and 5z-2
in 55–76% yields. Importantly, 1-(furan-2-yl)butane- in 45% and 37% yields, respectively. Unfortunately,
1,3-dione 4y could also be transformed into the desired this method could not be extended to substrate 4z-3,
product 5y in 57% yield. Besides 1,3-diketones and only a trace amount of 5z-3 was detected.
bearing methyl, 4z-1 and 4z-2 reacted smoothly with
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To probe the mechanism of this transformation,
some control experiments were carried out in
Scheme 2. Initially, the addition of radical scavengers
like 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)
and 2,6-di-tert-butyl-4-methyl phenol (BHT) did not
inhibit the cyclization reactions. The results indicated
that this reaction maybe proceed through an ionic
pathway (Scheme 2a-2b). In addition, compound A
was obtained in 40% yield when 1a was operated
under the standard conditions without KSCN (Sche-
me 2c). Thereafter, compound A was employed to react
with KSCN without I2 under argon and the desired
product 3a was isolated in 94% yield, which suggested
Scheme 3. Proposed mechanism.
that compound A was the intermediate for this reaction see the Supporting Information for details), suggesting
(Scheme 2d). When compound 6 was subjected to the that the hydrolytic pathway was involved in this
standard conditions, no desired product 3a was reaction.
detected (Scheme 2e). The result indicated that com-
On the basis of the above results and previous
pound 6 was not the intermediate for this trans- reports,[11,15] a possible mechanism is proposed in
formation. In addition, an O18-labeling experiment was Scheme 3. Initially, 1,3-diphenylpropane-1,3-dione 1a
conducted in the presence of H2O18 (10 equiv.) under reacts with I2 to give intermediate A. The nucleophilic
the standard conditions, producing 3a and O18-labeled addition reaction between intermediate A and KSCN
product 3a-[O18] with a molar ratio of 1:11 in 86% occurs and results in the formation of intermediate B.
yield. 3a-[O18] was detected by GCMS (Scheme 2f, Next, intermediate C, which is formed through intra-
molecular nucleophilic cyclization of intermediate B,
undergoes hydrolytic process to deliver intermediate
D. Finally, intramolecular nucleophilic attack of inter-
mediate D leads to intermediate E, which generates the
product 3a by dehydration.
In conclusion, we have demonstrated an I2-medi-
ated annulation reaction for preparing thiazol-2(3H)-
ones from 1,3-diketones and potassium thiocyanate
under transition-metal-free conditions. This protocol
shows a broad scope and great compatibility with
functional groups, affording a series of substituted
thiazol-2(3H)-ones in moderate to good yields.
Experimental Section
General procedure for the preparation of substituted thiazol-
2(3H)-ones 3 exemplified by the synthesis of compound 3a. A
Schlenk tube was charged with 1,3-diphenylpropane-1,3-diones
1a (44.8 mg, 0.2 mmol), 2a (58.2 mg, 0.6 mmol), I2 (101.6 mg,
0.4 mmol), NMP (1-methyl-2-pyrrolidinone) (2 mL). The mix-
°
ture was stirred at 140 C under O2 for 10 h (monitored by
TLC). Upon completion, the mixture was cooled to room
temperature. The reaction mixture was diluted with water
(30 mL) and extracted with ethyl acetate (3×30 mL). The
combined organic layers were washed with saturated Na2S2O3
aqueous solution and brine, dried over Na2SO4 and filtered. The
solvent was removed under vacuum. The crude product was
purified by flash column chromatography on silica gel (petro-
leum ether/ethyl acetate=4:1, Rf=0.28) to afford the desired
product 3a.
Scheme 2. Control experiments.
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[6] a) A. Khalil, G. A. Elsayed, H. A. Mohamed, A. Raafat,
Acknowledgements
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Zhang, W. Zeng, H. Huang, Y. Liang, RSC Adv. 2014, 4,
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This work was supported by National Natural Science
Foundation of China (21672086).
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I2-Promoted [3+2] Cyclization of 1,3-Diketones with
Potassium Thiocyanate: a Route to Thiazol-2(3H)-One Deriv-
atives
Adv. Synth. Catal. 2021, 363, 1–6
Z. An, Y. Liu, P. Zhao, R. Yan*