Transition Metal-Free Synthesis of Substituted Isothiazoles via Three-Component Annulation of Alkynones, Xanthate and NH4I

Article abstract of DOI:10.1002/adsc.202001179

A protocol was described to access diverse isothiazoles with functionalization potential via transition metal-free three-component annulation of alkynones, potassium ethylxanthate (EtOCS₂K) and ammonium iodide (NH₄I). A sequential regioselective hydroamination/thiocarbonylation/intramolecular cyclization cascade achieved the efficient formation of consecutive C?N, C?S and N?S bonds in a one-pot process. (Figure presented.).

Full text of DOI:10.1002/adsc.202001179

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DOI: 10.1002/adsc.202001179
Transition Metal-Free Synthesis of Substituted Isothiazoles via
Three-Component Annulation of Alkynones, Xanthate and NH4I
Jian Li,a Jiaming Li,a Xiaoliang Ji,a Qiang Liu,a, b Lu Chen,a Yubing Huang,a,*
and Yibiao Lia,*
a
School of Biotechnology and Health Sciences,
Wuyi University, Jiangmen, Guangdong Province 529090, People’s Republic of China.
Fax: +86 3299391,
Tel: +86 3299391
E-mail: wyuchemhyb@126.com; leeyib268@126.com
Center of Basic Molecular Science, Department of Chemistry,
b
Tsinghua University, Beijing 100084, People’s Republic of China
Manuscript received: September 25, 2020; Revised manuscript received: November 28, 2020;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202001179
Abstract: A protocol was described to access diverse isothiazoles with functionalization potential via
transition metal-free three-component annulation of alkynones, potassium ethylxanthate (EtOCS2K) and
ammonium iodide (NH4I). A sequential regioselective hydroamination/thiocarbonylation/intramolecular
cyclization cascade achieved the efficient formation of consecutive CÀ N, CÀ S and NÀ S bonds in a one-pot
process.
Keywords: Isothiazole; Sulfur heterocycle; Xanthate; Cyclization; Regioselective
Introduction
formed α,β-usaturated N-sulfonylimines and K2S, in
which only a few conventional isothiazole products
Isothiazole is a valuable five-membered heterocycle, were listed with low yields (Scheme 1a, i). Reddy[8b]
extensively found in natural products, synthetic inter- described the synthesis of isothiazole from ynones and
mediates and functional materials as a key structural KSCN by two-step conversions, where the positions of
unit.[1–2] Substituted isothiazoles with special structures S and N atoms are determined by the thiocyanative/
have medical value due to their biological and
therapeutic activities[3] as well as commercial impor-
tance due to various industrial applications.[4] Among
them, the 3,5-disubstituted isothiazole skeletons have
appeared in a variety of pharmaceutical active mole-
cules, such as GPR agonists, mGluR1 antagonists.[5]
As a consequence, the value of substituted isothiazoles
has prompted more attention to their synthesis and
application, and several effective synthesis methods
have been reported.[6–7] Though transition metal-cata-
lyzed reactions have proven to be highly efficient,[7]
the use of expensive metal catalysts or specially
designed ligands can increase the cost of the reactions
and limit their applications. By comparison, metal-free
strategies have been more extensively studied as being
[8]
considered environmentally friendly.
For example,
*
Wang and Ji et al.[8c] developed a cascade S3
À
Scheme 1. Methods to Synthesize Substituted Isothiazoles.
addition/electron detosylation reaction of in situ
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Table 1. Optimization of reaction conditions.[a]
decyanative cyclization in the first step (Scheme 1a,
ii). As most of methods for constructing substituted
isothiazoles are still have limitations, it’s urgently
needed to develop novel metal-free reactions to
efficien tly construct substituted isothiazoles by using
eco-friendly conditions and inexpensive and easily
available substrates.
Entry “N” source
(equiv.)
“S” source
(equiv.)
Solvent Yield
(%)
As versatile precursors, xanthates can be applied to
a variety of organic transformations,[9] and their
reactive exploration has attracted our long-standing
attention.[10] Recently, our group had achieved one-pot
synthesis of 4-substituted isothiazoles through a
cascade annulation of isopropene derivatives, NH4I
and EtOCS2K (Scheme 1b),[11] in which EtOCS2K/
NH4I was first discovered to be an excellent combina-
tion for isothiazole synthesis. The continuation to
explore the reactivity of EtOCS2K/NH4I combination
for the synthesis of diverse substituted isothiazoles is
1
2
NH4I (3)
NH4I (3)
thioacetamide (2) DMF 52
isopropylxanthic DMF 68
disulphide (2)
3
4
5
6
7
8
9
10
NH4I (3)
NH4I (3)
NH4I (3)
NH4I (3)
NH4Cl (3)
NH4Br (3)
thiourea (2)
S8 (2)
DMF 54
DMF 53
DMF 57
DMF 73
DMF <5
DMF 32
DMF 28
DMF <5
DMSO 33
DMAc 53
xylenes <5
DMF 82
DMF 89
DMF 73
DMF 68
DMF 54
DMF 51
Na2S (2)
EtOCS2K (2)
EtOCS2K (2)
EtOCS2K (2)
CH3COONH4 (3) EtOCS2K (2)
NH3·H2O (3)
NH4I (3)
NH4I (3)
NH4I (3)
NH4I (4)
NH4I (4)
EtOCS2K (2)
EtOCS2K (2)
EtOCS2K (2)
EtOCS2K (2)
EtOCS2K (2)
EtOCS2K (1.2)
EtOCS2K (1.2)
EtOCS2K (1.2)
EtOCS2K (1.2)
EtOCS2K (1.2)
valuable and challenging. Herein, we propose a 11
12
13
14
15
transition metal-free synthesis of substituted isothia-
zoles via three-component annulation of alkynones and
EtOCS2K/NH4I combination (Scheme 1c). The pro-
posal is highly reliable because alkynones required are
readily accessible and the reaction system is simple
and efficient. Notably, consecutive CÀ N, NÀ S and
CÀ S bonds can be formed efficiently and regioselec-
tively through a one-pot method, and the structure of
obtained isothiazoles is inconsistent with that reported
by Reedy.
16[b] NH4I (4)
17[c] NH4I (4)
18[d] NH4I (4)
19[e] NH4I (4)
[a] Reaction conditions: 1,3-diphenylprop-2-yn-1-one 1 a
(0.5 mmol), “N” source, “S” source and H2O (0.5 mmol) in
solvent (2.0 mL), 130 C, 12 h. Isolated yield.
°
[b]
°
130 C, 8 h.
[c]
Results and Discussion
°
110 C, 12 h.
[d]
°
90 C, 12 h.
We commenced to use 1,3-diphenylprop-2-yn-1-one
(1a) as the model substrate for condition optimization
(Table 1). Initially, a series of investigations were
conducted to determine the most suitable combination
[e] under a N2 atmosphere.
of “N” and “S” sources (entries 1–9). With NH4I as the conditions were 0.5 mmol 1a, 2.0 mmol NH4I and
°
“N” source, a series of sulfur-containing compounds 0.6 mmol of EtOCS2K in 2.0 mL DMF at 130 C for
were tested, including thioacetamide, thiourea, Na2S 12 h.
(entries 1–6). The results showed that the dimer of
Under the optimized conditions, we subsequently
xanthates is effective (entry 2), and the reaction investigated the substrate scope of this three-compo-
proceeded best when EtOCS2K was used as the “S” nent annulation reaction as shown in Scheme 2. Firstly,
source to give the product 2a in the yield of 73% we explored reactivities of alkynones by changing the
(entry 6). With EtOCS2K as “S” source, the examina- substituents on the R2 group. The reactions of alkynone
tion of different ammonium salts showed that NH4I substrates bearing different substituents (halo-,
was the best choice of “N” sources (entries 6–10). trifluoromethoxy- and nitro-) on the R2 group pro-
Other solvents, such as DMSO, DMAc and xylenes, ceeded smoothly, and the desired products (2a–2f)
could not increase the yield of 2a (entries 11–13). were produced in good to excellent yields. We also
Pleasingly, an excellent yield of 89% was obtained studied the preparation of isothiazole 2a on a
when NH4I was increased to 4 equivalents while 1.0 mmol-scale, obtaining 3,5-diphenylisothiazole in
EtOCS2K was decreased to 1.2 equivalents (entry 15). 83% yield, which confirmed the practicability of this
Furthermore, reducing the reaction time or lowering cyclization reaction (See experimental section). Re-
the reaction temperature led to a decrease in yield placing R1 group with 4-methoxyphenyl, both electron-
(entries 16–18). Under a N2 atmosphere, the yield of rich substituents (methoxy-) or electron-poor substitu-
the reaction decreased to 51%, indicating that the ents (halo- and cyano-) were well tolerated, the
presence of air promotes the cyclization reaction. reactions delivered the target products (2g–2k) in 68–
Based on the above results, the optimized reaction 78% yields. Subsequently, the reactivities of alkynones
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Figure 1. Molecular Structures of 2z by X-ray Crystallographic
Analysis.
Next, A series of alkyl alkynones were investigated
and the results were shown in Scheme 3. When the R1
group was a phenyl group and the R2 group was H or
an alkyl group (Me or tBu), the corresponding
substrates had good reactivities, and the target products
(2aa–2ac) were formed in excellent yields. The R1
group was subsequently substituted with a 2-thiophene
group, and the reaction gave 2ad in 67% yield. The
dialkyl ynones such as pentadec-8-yn-7-one also
successfully completed the cyclization reaction to give
the corresponding product 2ae in 61% yield. Unfortu-
nately, the reaction of terminal alkynones, such as 1-
phenylprop-2-yn-1-one, produced a mixture of prod-
ucts (Scheme 3, 2af).
Other special transformations were discovered
during the reaction process, as shown in Scheme 2.
The reaction of the alkyne containing a 2-meth-
oxyphenyl group under optimal conditions gave 2ag in
72% yield, which could be converted to 2ah by further
demethylation with a yield of 87% (Scheme 4, eq. a).
Interestingly, when using 1,3-bis(2-fluorophenyl)prop-
2-yn-1-one as a substrate, the reaction gave the
Scheme 2. Substrate scope of alkynones. Reaction conditions:
alkynones
1
(0.5 mmol), NH4I (2.0 mmol), EtOCS2K
°
(0.6 mmol) and H2O (0.5 mmol) in DMF (2.0 mL), 130 C,
12 h. a) Reaction carried on 1.0 mmol-scale.
with different substituents on the R1 groups were benzothiophene product (3a) in 84% yield instead of
investigated. Among them (2l–2p), product containing the isothiazole product (Scheme 4, eq. b). The alkynols
a methyl substituent on the R1 group produced higher such as 1,3-diphenylprop-2-yn-1-ol successfully com-
yield (87%) than those containing a halo substituent. pleted the cyclization reaction to give the isothiazole
When R1 group was the same as R2 group, the reaction 2a in 81% yield (Scheme 4, eq. c). When a chalcone
of alkynone bearing 3-methylphenyl, 2-chlorophenyl, was used as reaction substrate, the cyclization reaction
4-chlorophenyl or 2-fluorophenyl substituent pro- also gave the corresponding isothiazole 2a in 69%
ceeded smoothly to produce the isothiazole products yield. (Scheme 4, eq. d).
(2q–2t) in 83–88% yields, proving that halo substitu-
ents were tolerated in the reaction system. The
naphthalene substrate (1u) was also suitable for this
annulation reaction and was converted to 2u in 87%
yield. By comparison, the conversion of 2-thiophene
substrate (1x) was better than that of 3-thiophene
substrate (1w), probably because the 3-thiophene
substituent contained active sites for side reactions,
resulting in a lower yield. Particularly, the alkynone
substrates with a complex R1 group, such as 4,4-
dimethylthiochroman, 4-dioxaborolanephenyl or 4-car-
bazolephenyl moiety, also participated well in the
reactions, delivering the desired isothiazoles (2v, 2y–
Scheme 3. Substrate scope of alkyl alkynones. Reaction con-
ditions: alkyl alkynones 1 (0.5 mmol), NH4I (2.0 mmol),
EtOCS2K (0.6 mmol) and H2O (0.5 mmol) in DMF (2.0 mL),
2z) in good yields. The structure of 2z was further
confirmed by X-ray crystallographic analysis (Fig-
ure 1, CCDC: 2025711).
°
130 C, 12 h.
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nylisothiazole (5a), which could then be effectively
transformed into the desired products 6a and 7a by
Suzuki-Miyaura and Miyaura boronation reactions,
respectively (eq. f–g).
In order to get insight into the reaction mechanism,
several control experiments were then carried out, as
shown in Scheme 6. First, it was noteworthy that when
using DMF/D2O (4:1) as a solvent mixture, 83% of 4-
deuterio-3,5-diphenylisothiazole (2a–D) was obtained,
which indicated that a protonation process happened in
the reaction (Scheme 6, eq. a). Since 1,3-diphenylprop-
2-yn-1-one could react with NH4I be converted to
°
enamine 8a in 42% yields under 60 C for 1 hours,
Scheme 4. Other Transformations.
respectively, they were considered to be possible
reaction intermediates (Scheme 6, eq. b). Then, the
reaction was conducted with enamine 8a as a
As important type of building blocks, the newly substrate, EtOCS2K as “S” source and NH4I as an
formed isothiazoles could be utilized in various addition to obtain the target product (2a) in 73% yield,
synthetic transformations (scheme 5). First, 4-deuterio- from which we speculated that enamine 8a might be
3,5-diphenylisothiazole (2a–D) could be obtained the reaction intermediate. At the same time, we can
through base-catalyzed deuteration reaction in 91% detect thioketone 9a by ESI-HRMS, but it cannot be
yield (eq. a). Forthermore, 3,5-diphenylisothiazole isolated independently. (Scheme 6, eq. c). In the
could undergo Rh(III)-catalyzed annulative coupling absence of NH4I, the reaction of enamine 8a with
with alkynes smoothly and converted into different EtOCS2K did not gave the envisaged intermediate
isoquinoline-isothiochromene conjugates (4a and 4b) thioketone 9a or desired isothiazole 2a, instead of
in 89% and 87% yields, respectively.[12] The trans- recycled raw material 8a. It shows that in the absence
formation above was also applicable to 2-thiophene- of NH4I, it is difficult for EtOCS2K to react with
substituted and 3-thiophene-substituted alkynones, and carbonyl to obtain thioketones intermediates.
their reactions with 1,2-diphenylethyne furnished com- (Scheme 6, eq. d). When replacing NH4I with I2, gave
pounds (4c and 4d) with novel structures in 77% and the 2a in 68% yield, proving that NH4I not only acted
81% yields, respectively (eq. b–d). The bromination of as a “N” source, its iodine element could also
3,5-diphenylisothiazole prepared 4-bromo-3,5-diphe- effectively promote the reaction for synthesis of
isothiazole 2a (Scheme 6, eq. e). When try to use the
Scheme 5. Synthetic Utilization.
Scheme 6. Control Experiments.
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Lawesson’s reagent as thionating agent for preparation
of thioketone 9a, the reaction direct gave the
Conclusions
isothiazole products 2a in 73% yields. It shows that In conclusion, a one-pot synthesis protocol for the
the sulfur cyclization of thioketone 9a can be efficient synthesis of substituted isothiazoles through
completed spontaneously without catalyst under high- three-component annulation of alkynones, EtOCS2K
temperature conditions (Scheme 6, eq. f).
and NH4I has been established. Under transition metal-
On the basis of observed experimental results and free conditions, the reaction delivers a series of
the previous work,[11] the plausible mechanism for isothiazoles in moderate to excellent yields through the
transition metal-free synthesis of substituted isothia- efficient formation of CÀ N, NÀ S and CÀ S bonds,
zoles is proposed in Scheme 7. As described in basing on a sequential regioselective hydroamination/
published work, the thermal decomposition of NH4I thiocarbonylation/intramolecular cyclization cascade
can release NH3, which will preferentially undergo reaction. Simple operations, inexpensive and readily
nucleophilic addition to alkynone through regioselec- available substrates, broad substrate scopes and syn-
tive hydroamination to form enamine intermediate thetic utilization of diversity make the method highly
A.[13] After undergoing the nucleophilic attack of feasible in application. Further efforts are currently
EtOCS2K on the carbonyl group with the aid of HI to underway to further elucidate the mechanism and
form thioketone intermediate H.[14] Alternative, the further expand the synthetic applications of isothiazole
thioketone intermediate H may be formed through a compounds in advanced materials.
process similar to Lawesson’s reaction.[15] The reaction
underg a nucleophilic attack of EtOCS2K on the
carbonyl group and subsequent intramolecular cycliza-
Experimental Section
tion, intermediate G is formed with an unstable four- General information
membered heterocycle, followed by the instantaneous
departure of EtOCSOH to form thioketone intermedi-
ate H. Subsequently, the thioketone intermediate H
Chemicals and solvents were purchased from commercial
suppliers and used as received unless noted. All products were
1
purified by flash chromatography on silica gel. H NMR and
13C NMR spectra were recorded on 500 MHz Bruker spectrom-
undergoes an intramolecular nucleophilic attack of
sulfur on the imine nitrogen (C=NH), forming the NÀ
S bond to generate dihydroisothiazole intermediate
1
eters. Chemical shifts of H were reported in part per million
relative to the CDCl3 residual peak (δ 7.260). Chemical shifts of
I.[6c,8a] Subsequent aerial or I2 oxidation of intermediate 13C NMR were reported relative to CDCl3 (δ 77.00). The used
abbreviations are as follows: s (singlet), d (doublet), t (triplet),
quart. (quartet), quint (quintet), m (multiplet), br (broad).
Multiplets which arise from accidental equality of coupling
constants of magnetically non-equivalent protons are marked as
virtual (virt.). High resolution mass spectra (HRMS) data were
measured on a ESI- microTOF II. Melting points were
measured on a SGW® X-4B and are not corrected. Reactions
were monitored by TLC analysis using silica gel 60 Å F-254
thin layer plates and compounds were visualized with a UV
light at 254 nm or 365 nm. All the other chemicals were
purchased from Aldrich Chemicals, Energy Chemical and
Leyan Chemical. Commercial reagents were used without
further purification.
I gives the desired product 2, in which I2 is obtained
by decomposition of NH4I.[16]
General procedures for synthesis of 1,3-diphenylprop-2-yn-
1-one: In a nitrogen atmosphere, add PdCl2(PPh3)2 (23 mg,
5 mol%), CuI (9.5 mg, 4 mol%), THF (15 mL), terminal
alkynes (2.5 mmol) and acid chloride (3 mmol). After stirring
for 2 minutes, Et3N (5 mL) was added and the reaction was
stirred at room temperature for 5 h. After the reaction was
completed, the reaction was diluted with ethyl acetate and
washed with saturated brine (10 mL*3). The organic layer was
then extracted, all organics were combined and dried with
Na2SO4, The organic phase is concentrated and purified by flash
chromatography to afford the 1,3-diphenylprop-2-yn-1-one.
General procedures for synthesis of 3,5-diphenylisothiazole:
A mixture of 1,3-diphenylprop-2-yn-1-one (0.5 mmol), NH4I
(2.0 mmol, 290 mg), EtOCS2K (0.6 mmol, 96 mg), H2O
(0.5 mmol), DMF (2.0 ml) was added successively in a 20 mL
Schlenk tube. The Schlenk tube was then immersed in an oil
Scheme 7. Possible Reaction Mechanism.
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°
bath at 130 C stirring for 12 h. After cooling down to room
temperature, the solution was filtered through a small amount of
silica gel. Then the residue was concentrated in vacuo and the
crude was purified by flash chromatography with n-hexane/
ethyl acetate (20/1, v/v) to afford the 3,5-diphenylisothiazole
(2a) as a white solid in 89% yield.
affording the3,5-diphenylisothiazole (2a) as a white solid in
83% yield (196.7 mg).
3,5-diphenylisothiazole (2a). White solid (105 mg, 89% yield);
MP: 82–84 C; Rf =0.48 (Hexane/EtOAc=30:1); 1H NMR
°
(500 MHz, CDCl3) δ 8.03–7.98 (m, 2H), 7.76 (s, 1H), 7.69–
7.63 (m, 2H), 7.51–7.41 (m, 6H); 13C NMR (125 MHz, CDCl3)
δ 168.2, 168.19, 134.8, 130.9, 129.6, 129.2 (3 C), 128.8 (2 C),
126.8 (2 C), 126.5 (2 C), 117.5. HRMS (ESI-TOF) (m/z): [M+
H]+ calcd for C15H12NS, 238.0685, found 238.0685.
General procedures for synthesis of 3a-3d:[12] To an oven-
dried Schlenk tube were added isothiazole 2 (0.2 mmol), 1,2-
diphenylethyne (0.4 mmol), [Cp*Rh(MeCN)3] [SbF6]2 (6.6 mg,
4.0 mol%), and Cu(OAc)2 (72.6 mg, 0.4 mmol). The tube was
flushed with N2, and DCE (3.0 mL) was added via syringe. The
5-(3-chlorophenyl)-3-phenylisothiazole (2b). Light yellow
°
solid (92 mg, 68% yield); MP: 85–87 C; Rf = 0.6 (Hexane
°
mixture was hated with oil bath at 100 C for 18 h. The resulting
/EtOAc=30:1); 1H NMR (500 MHz, CDCl3) δ 8.00 (d, J=
2.0 Hz, 1H), 7.87 (dt, J=6.7, 2.1 Hz, 1H), 7.73 (s, 1H), 7.65
(dd, J=8.1, 1.4 Hz, 2H), 7.49–7.43 (m, 3H), 7.43–7.37 (m,
2H); 13C NMR (125 MHz, CDCl3) δ 168.8, 166.7, 136.4, 134.8,
130.8, 130.1, 129.8, 129.3 (2 C), 129.2, 127.0, 126.6 (2 C),
124.9, 117.5. HRMS (ESI-TOF) (m/z): [M+H]+ calcd for
C15H11NSCl, 272.0295, found: 272.0294.
suspension was diluted with water and was extracted with
EtOAc (10 mL*3). The combined organic layer was dried over
Na2SO4 and concentrated in vacuo.The crude material was
subjected to silica gel chromatography give the corresponding
coupling product 3a–3d.
General procedures for synthesis of 4a: A mixture of 3,5-
diphenylisothiazole 2a (0.5 mmol), NBS (1.2 eq, 107 mg),
DMF (2.0 ml) was added successively in a 20 mL Schlenk tube.
5-(3,5-dichlorophenyl)-3-phenylisothiazole (2c). Black solid
°
(110 mg, 72% yield); MP: 110–112 C; Rf = 0.6 (Hexane/
°
The Schlenk tube was then immersed in an oil bath at 130 C
EtOAc=5:1); 1H NMR (500 MHz, CDCl3) δ 7.98 (d, J=
8.4 Hz, 2H), 7.74 (s, 1H), 7.52 (d, J=1.8 Hz, 2H), 7.50–7.40
(m, 4H); 13C NMR (125 MHz, CDCl3) δ 168.5, 165.0, 135.9
(2 C), 134.4, 133.6, 129.5, 129.2, 128.9 (2 C), 126.8 (2 C),
124.9 (2 C), 118.7. HRMS (ESI-TOF) (m/z): [M+H]+ calcd
for C15H10NSCl2, 305.9906, found:305.9902.
stirring for 8 h. After cooling down to room temperature, the
solution was filtered through a small amount of silica gel. Then
the residue was concentrated in vacuo and the crude was
purified by flash chromatography with n-hexane/ethyl acetate
(20/1, v/v) to afford the 4a as a white solid in 92% yield.
General procedures for synthesis of 5a: A mixture of 4a
(0.5 mmol), PhB(OH)2 (1.5 eq, 92 mg), Cs2CO3 (1.2
eq,196 mg), THF (2.0 ml), H2O (0.2 ml) was added successively
in a 20 mL Schlenk tube. The Schlenk tube was then immersed
5-(4-fluorophenyl)-3-phenylisothiazole (2d). Yellow solid
°
(89 mg, 70% yield); MP: 112–114 C; Rf =0.6 (Hexane /EtOAc
=15:1); 1H NMR (500 MHz, CDCl3) δ 7.98 (d, J=7.3 Hz, 2H),
7.70 (s, 1H), 7.64 (dd, J=8.6, 5.2 Hz, 2H), 7.54–7.33 (m, 3H),
7.16 (t, J=8.5 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 168.4,
167.0, 163.4 (d, J=248.7 Hz, 1 C), 134.7, 129.3, 128.8, 128.5,
128.5 (d, J=8.2 Hz, 2 C), 127.3 (d, J=3.5 Hz, 1 C), 126.8,
117.7, 116.3 (d, J=23 Hz, 2 C); HRMS (ESI-TOF) (m/z): [M+
H]+ calcd for C15H11NSF, 256.0591, found: 256.0591.
°
in an oil bath at 60 C stirring for 10 h. After cooling down to
room temperature, the solution was filtered through a small
amount of silica gel. Then the residue was concentrated in
vacuo and the crude was purified by flash chromatography with
n-hexane/ethyl acetate (4/1, v/v) to afford the 5a as a white
solid in 82% yield.
3-phenyl-5-(4-(trifluoromethoxy)phenyl)isothiazole(2e). Yel-
General procedures for synthesis of 6a: A mixture of 4a
(0.5 mmol), CH3COOK (2 eq, 98 mg), [1,1’Bis(diphenylphos-
phino)ferrocene]dichloropalladium(II) (3 mol%, 11 mg), Bis
(pinacolato)diboron (1 equiv, 127 mg), DMF (3 ml) was added
successively in a 20 mL Schlenk tube. The Schlenk tube was
°
low solid (133 mg, 83% yield); MP: 108–110 C; Rf =0.45
(Hexan/EtOAc =30:1); H NMR (500 MHz, CDCl3) δ 8.02 (d,
1
J=8.7 Hz, 2H), 7.73 (s, 1H), 7.70–7.63 (m, 2H), 7.60–7.41 (m,
3H), 7.32 (d, J=8.3 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ
168.8, 166.8, 149.8 (d, J=3.0 HZ, 1 C), 133.4, 130.7, 129.8,
129.3 (2 C), 128.3 (2 C), 126.6(2 C), 122.4 (q, J=256.1 HZ,
1 C), 121.2 (2 C), 117.4. HRMS (ESI-TOF) (m/z): [M+H]+
calcd for C16H11F3NOS, 322.0508, found: 322.0506.
°
then immersed in an oil bath at 90 C stiring for 12 h. After
cooling down to room temperature, the solution was filtered
throu-gh a small amount of silica gel. Then the residue was
concentrated in vacuo and the crude was purified by flash
chromatography with n-hexane/ethyl acetate (20/1, v/v) to
afford the 6a as a yellow liquid in 93% yield.
5-(3-nitrophenyl)-3-phenylisothiazole (2f). Yellow solid
°
(93 mg, 66% yield); MP: 162–164 C; Rf =0.5 (Hexane /EtOAc
=4:1); 1H NMR (500 MHz, CDCl3) δ 8.51 (s, 1H), 8.28 (d, J=
8.2 Hz, 1H), 8.00 (d, J=7.0 Hz, 3H), 7.86 (s, 1H), 7.67 (t, J=
8.0 Hz, 1H), 7.59–7.38 (m, 3H); 13C NMR (125 MHz, CDCl3) δ
168.7, 165.2, 148.7, 134.3, 132.6, 132.4, 130.4, 129.6, 128.9
(2 C), 126.9 (2 C), 124.0, 121.3, 118.9. HRMS (ESI-TOF) (m/
z): [M+H]+ calcd for C15H11N2O2S, 283.0536, found:
283.0531.
Synthesis of 3,5-diphenylisothiazole (2a) in mmol-scale: A
25 mL Schlenk tube was charged with 1,3-diphenylprop-2-yn-
1-one 1a (1.0 mmol, 206 mg), potassium xanthate (1.2 mmol,
190 mg, 1.2 equiv), NH4I (4.0 mmol, 580 mg), H2O (1.0 mmol,
18 mg), DMF (3.0 ml) and a magnetic stirring bar. The Schlenk
°
tube was then immersed in an oil bath at 130 C stirring for
12 h. After the reaction finished, the reaction mixture was
diluted with ethyl acetate and passed through Celite. After
evaporation of the solvent the residue was adsorbed on silica
gel and the crude product was purified by column chromatog-
raphy using n-hexane/ethyl acetate (20/1, v/v) the eluent,
3,5-bis(4-methoxyphenyl)isothiazole (2g). Yellow solid
°
(107 mg, 72% yield); MP: 183–185 C; Rf =0.6 (Hexane/EtOAc
=2:1); 1H NMR (500 MHz, CDCl3) δ 7.94 (dd, J=17.9,
8.8 Hz, 2H), 7.66–7.52 (m, 3H), 6.98 (dd, J=8.6, 6.4 Hz, 4H),
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3.87 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 167.9, 167.8,
160.6, 160.4, 129.1, 128.2 (2 C), 127.9 (2 C), 123.8, 116.2,
114.5 (2 C), 114.1 (2 C), 55.4, 55.3. HRMS (ESI-TOF) (m/z):
[M+H]+ calcd for C17H16NO2S, 298.0896, found:298.0895.
5-(4-chlorophenyl)-3-(p–tolyl)isothiazole (2n). Yellow solid
°
(94 mg, 66% yield); MP: 169–171 C; Rf =0.55 (Hexane
/EtOAc=20:1); 1H NMR (500 MHz, CDCl3) δ 7.93 (d, J=
8.5 Hz, 2H), 7.68 (s, 1H), 7.54 (d, J=8.0 Hz, 2H), 7.44 (d, J=
8.5 Hz, 2H), 7.27(d, J=9.5 Hz, 2H), 2.41 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 168.8, 166.9, 140.0, 135.2, 133.3, 129.9
(2 C), 129.0 (2 C), 128.1 (2 C), 128.0, 126.5 (2 C), 116.9, 21.4.
HRMS (ESI-TOF) (m/z): [M+H]+ calcd for C16H13ClNS,
286.0452, found: 286.0455
5-(2-chlorophenyl)-3-(4-methoxyphenyl)isothiazole
(2h).
°
Yellow solid (102 mg, 68% yield); MP: 91–93 C; Rf =0.45
(Hexane/EtOAc=5:1); H NMR (500 MHz, CDCl3) δ 7.79 (d,
1
J=2.8 Hz, 1H), 7.74 (s, 1H), 7.59 (d, J=8.8 Hz, 2H), 7.49 (d,
J=9.3 Hz, 1H), 7.36 (d, J=3.7 Hz, 2H), 6.98 (d, J=8.8 Hz,
2H), 3.87 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 167.2, 166.2,
160.7, 134.5, 132.0, 131.4, 130.2, 130.0, 128.0 (2 C), 127.0,
123.6, 120.3, 114.6 (2 C), 55.4. HRMS (ESI-TOF) (m/z): [M+
H]+ calcd for C16H13ONSCl, 302.0401, found: 302.0402.
3-(4-fluorophenyl)-5-(p–tolyl)isothiazole (2o). Yellow solid
°
(95 mg, 71% yield); MP: 158–160 C; Rf =0.55 (Hexane
/EtOAc=20:1); H NMR (500 MHz, CDCl3) δ 7.97 (dd, J=
1
8.6, 5.5 Hz, 2H), 7.67 (s, 1H), 7.54 (d, J=8.0 Hz, 2H), 7.27(d,
J=8.5 Hz, 2H), 7.15 (t, J=8.6 Hz, 2H), 2.41 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 168.6, 167.1, 163.3 (d, J=247.4 Hz, 1 C),
139.9, 131.2 (d, J=3.8 Hz, 1 C), 129.9, 128.7 (d, J=8.8 Hz,
2 C), 128.0, 126.4, 116.8, 115.8 (d, J=21.2 Hz, 2 C), 21.4.
HRMS (ESI-TOF) (m/z): [M+H]+ calcd for C16H13FNS,
270.0747, found: 270.0746.
5-(4-chlorophenyl)-3-(4-methoxyphenyl)isothiazole (2i). Pink
°
solid (110 mg, 73% yield); MP: 152–154 C; Rf =0.6 (Hexane/
EtOAc=2:1); 1H NMR (500 MHz, CDCl3) δ 7.92 (d, J=
8.7 Hz, 2H), 7.65 (s, 1H), 7.57 (d, J=8.4 Hz, 2H), 7.43 (d, J=
8.4 Hz, 2H), 6.98 (d, J=8.7 Hz, 2H), 3.87 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 168.1, 166.5, 160.5, 135.4, 129.5, 129.4
(2 C), 128.2 (2 C), 127.8 (2 C), 127.7, 117.4, 114.1 (2 C), 55.3.
HRMS (ESI-TOF) (m/z): [M+H]+ calcd for C16H13ONSCl,
302.0401, found: 302.0401.
3-(4-bromophenyl)-5-(p–tolyl)isothiazole (2p). Yellow solid
°
(112 mg, 68% yield); MP: 186–188 C; Rf =0.55 (Hexane
/EtOAc=3:1); 1H NMR (500 MHz, CDCl3) δ 7.87 (d, J=
8.1 Hz, 2H), 7.70 (s, 1H), 7.59 (d, J=8.4 Hz, 2H), 7.51 (d, J=
8.4 Hz, 2H), 7.28 (d, J=8.3 Hz, 2H), 2.41 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 168.5, 166.6, 139.4, 132.4 (2 C), 132.0,
129.9, 129.5 (2 C), 128.0 (2 C), 126.7 (2 C), 123.6, 117.7, 21.4.
HRMS (ESI-TOF) (m/z): [M+H]+ calcd for C16H13BrNS,
329.9946, found: 329.9948.
5-(3,5-dichlorophenyl)-3-(4-methoxyphenyl)isothiazole (2j).
°
Brown solid (126 mg, 75% yield); MP: 146–148 C Rf =0.55
(Hexane /EtOAc=5:1); H NMR (500 MHz, CDCl3) δ 7.87 (d,
1
J=1.9 Hz, 2H), 7.64–7.54 (m, 3H), 7.39 (t, J=1.9 Hz, 1H),
6.98 (d, J=8.8 Hz, 2H), 3.87 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 168.2, 164.7, 160.7, 135.8 (2 C), 133.7, 129.2, 128.3
(2 C), 127.4, 124.9 (2 C), 118.3, 114.2 (2 C), 55.4. HRMS (ESI-
TOF) (m/z): [M+H]+ calcd for C16H12ONSCl2, 336.0011,
found: 336.0009.
3,5-di-m–tolylisothiazole (2q). Yellow solid (117 mg, 88%
1
°
yield); MP: 117–119 C Rf =0.5 (Hexane /EtOAc=10:1); H
NMR (500 MHz, CDCl3) δ 7.86 (s, 1H), 7.79 (d, J=7.7 Hz,
1H), 7.74 (s, 1H), 7.47 (d, J=9.1 Hz, 2H), 7.36 (dt, J=12.5,
7.6 Hz, 2H), 7.27–7.21 (m, 2H), 2.44 (d, J=11.4 Hz, 6H); 13 C
NMR (125 MHz, CDCl3) δ 168.3, 168.2, 138.9, 138.4, 134.7,
130.8, 130.3, 129.9, 129.0, 128.6, 127.4, 127.1, 123.9, 123.6,
117.4, 21.4, 21.3. HRMS (ESI-TOF) (m/z): [M+H]+ calcd for
C17H16NS, 266.0998, found: 266.0994.
4-(3-(4-methoxyphenyl)isothiazol-5-yl)benzonitrile (2k). Yel-
°
low solid (114 mg, 78% yield); MP: 103–105 C; Rf =0.35
(Hexane/EtOAc=2:1); H NMR (500 MHz, CDCl3) δ 7.92 (d,
1
J=8.8 Hz, 2H), 7.75 (s, 5H), 6.99 (d, J=8.8 Hz, 2H), 3.87 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 168.4, 165.4, 160.7, 135.2,
133.0 (2 C), 128.3 (2 C), 127.3, 127.1 (2 C), 118.4, 118.3, 114.2
(2 C), 112.9, 55.4. HRMS (ESI-TOF) (m/z): [M+H]+ calcd for
C17H13N2OS, 293.0743, found: 293.0742.
3,5-bis(2-chlorophenyl)isothiazole (2r). Yellow solid (130 mg,
°
85% yield); MP: 77–79 C; Rf =0.6 (Hexane /EtOAc=10:1);
1H NMR (500 MHz, CDCl3) δ 7.99 (s, 1H), 7.83 (dd, J=7.2,
2.1 Hz, 1H), 7.70–7.64 (m, 1H), 7.56–7.52 (m, 1H), 7.49 (dd,
J=7.3, 1.8 Hz, 1H), 7.39–7.32 (m, 4H); 13C NMR (125 MHz,
CDCl3) δ 164.7, 163.2, 134.1, 132.3, 132.0, 131.5, 130.7, 130.3,
130.2, 130.2, 130.1, 129.9, 127.2, 127.0, 124.7. HRMS (ESI-
TOF) (m/z): [M+H]+ calcd for C15H10Cl2NS, 305.9906, fuond:
305.9902.
3,5-di-p–tolylisothiazole (2l). White solid (115 mg, 87%
yield); MP: 124–126 C; Rf =0.5 (Hexane/EtOAc=15:1); 1H
°
NMR (500 MHz, CDCl3) δ 7.88 (d, J=8.1 Hz, 2H), 7.69 (s,
1H), 7.54 (d, J=8.1 Hz, 2H), 7.29–7.25 (m, 4H), 2.41 (s, 6H);
13C NMR (125 MHz, CDCl3) δ 168.3, 168.1, 139.7, 139.2,
132.2, 129.8 (2 C), 129.5 (2 C), 128.2, 126.7 (2 C), 126.4 (2 C),
117.0, 21.3 (2 C). HRMS (ESI-TOF) (m/z): [M+H]+ calcd for
C17H16NS, 266.0998, found: 266.0999.
3,5-bis(4-chlorophenyl)isothiazole (2s). Yellow solid (127 mg,
°
83% yield); MP: 137–139 C; Rf =0.6 (Hexane /EtOAc=5:1);
3-(2-chlorophenyl)-5-(p–tolyl)isothiazole (2m). Yellow solid
1H NMR (500 MHz, CDCl3) δ 7.91 (d, J=8.5 Hz, 2H), 7.68 (s,
1H), 7.57 (d, J=8.5 Hz, 2H), 7.44 (d, J=8.4 Hz, 4H); 13C
NMR (125 MHz, CDCl3) δ 167.2, 167.1, 135.7, 135.3, 133.1,
129.5 (2 C), 129.2, 129.0 (2 C), 128.1 (2 C), 127.8 (2 C), 117.6.
HRMS (ESI-TOF) (m/z): [M+H]+ calcd for C15H10Cl2NS,
305.9906, found: 305.9905.
°
(90 mg, 63% yield); MP: 61–63 C; Rf =0.55 (Hexane
/EtOAc=20:1); 1H NMR (500 MHz, CDCl3) δ 7.89 (d, J=
8.1 Hz, 2H), 7.85 (s, 1H), 7.66 (d, J=9.4 Hz, 1H), 7.54 (d, J=
9.3 Hz, 1H), 7.36 (d, J=7.3 Hz, 2H), 7.28 (d, J=8.0 Hz, 2H),
2.41 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 167.0, 164.0,
139.2, 132.3, 132.1, 130.7, 130.3, 130.1, 130.1, 129.5 (2 C),
127.2, 126.8 (2 C), 121.1, 21.4. HRMS (ESI-TOF) (m/z): [M+
H]+ calcd for C16H13ClNS, 286.0452, found 286.0446.
3,5-bis(4-fluorophenyl)isothiazole (2t). Yellow solid (115 mg,
84% yield); Rf =0.6 (Hexane /EtOAc=5:1); 1H NMR
(500 MHz, CDCl3) δ 7.94 (dd, J=8.5, 5.6 Hz, 2H), 7.62 (dd,
J=8.5, 5.3 Hz, 2H), 7.16 (t, J=8.5 Hz, 2H), 7.10 (t, J=8.6 Hz,
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2H), 6.03 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 188.63, 165.4
(d, J=57.5 Hz, 1 C), 163.4 (d, J=57.5 Hz, 1 C), 161.9, 136.3,
136.3, 133.6, 133.6, 129.4 (d, J=8.8 Hz, 1 C), 128.4 (d, J=
8.6 Hz, 1 C), 116.1 (d, J=21.6 Hz, 1 C), 115.2 (d, J=21.5 Hz,
1 C), 91.5. HRMS (ESI-TOF) (m/z): [M+H]+ calcd for
C15H10F2NS, 274.0496,found: 274.0495.
NMR (125 MHz, CDCl3) δ 168.7, 167.3, 140.6, 138.4, 133.7,
130.8, 129.7, 129.3, 128.3, 127.2 (2 C), 126.6 (2 C), 126.0
(2 C), 123.5 (2 C), 120.3 (2 C), 120.1 (2 C), 117.5 (2 C), 109.8
(2 C). HRMS (ESI-TOF) (m/z): [M+H]+ calcd for C27H19N2S,
403.1263, found: 403.1253.
3-phenylisothiazole (2aa). Brown solid (65 mg, 81% yield);
MP: 45–47 C; Rf =0.6 (Hexane /EtOAc=10:1); 1H NMR
°
3,5-di(naphthalen-2-yl)isothiazole
(2u).
Yellow
solid
°
(147 mg, 87% yield); MP: 116–118 C; Rf =0.35 (Hexane
/EtOAc=20:1); 1H NMR (500 MHz, CDCl3) δ 8.62 (d, J=
8.3 Hz, 1H), 8.29 (d, J=9.7 Hz, 1H), 7.98 (dt, J=6.2, 3.1 Hz,
4H), 7.87 (d, J=7.0 Hz, 1H), 7.75 (s, 1H), 7.71 (d, J=6.1 Hz,
1H), 7.65–7.53 (m, 6H); 13C NMR (125 MHz, CDCl3) δ 168.0,
165.5, 133.9, 133.7, 133.1, 131.1, 130.8, 129.8, 129.5, 128.6,
128.5, 128.4, 127.9, 127.6, 127.1, 126.8, 126.4, 126.0, 125.7,
125.7, 125.2, 125.2, 125.0. HRMS (ESI-TOF) (m/z): [M+H]+
calcd for C23H16NS, 338.0998, found: 338.0999.
(500 MHz, CDCl3) δ 8.47 (d, J=1.6 Hz, 1H), 7.63–7.58 (m,
2H), 7.47–7.37 (m, 4H); 13C NMR (125 MHz CDCl3) δ 167.3,
158.2, 130.7, 129.5, 129.2 (2 C), 126.7 (2 C), 119.8. HRMS
(ESI-TOF) (m/z): [M+H]+ calcd for C9H8NS, 162.0372, found:
162.0371.
5-methyl-3-phenylisothiazole (2ab). Brown solid (75 mg, 86%
yield); MP: 67–69 C; Rf =0.6 (Hexane /EtOAc=5:1); 1H
°
NMR (500 MHz, CDCl3) δ 7.58 (d, J=6.8 Hz, 2H), 7.41 (dd,
J=12.8, 7.2 Hz, 3H), 7.20 (s, 1H), 2.53 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 167.9, 167.4, 131.0, 129.4, 129.2 (2 C),
126.5 (2 C), 19.1. HRMS (ESI-TOF) (m/z): [M+H]+ calcd for
C10H10NS, 176.0528, fund: 176.0530.
3-(4,4-dimethylthiochroman-6-yl)-5-phenylisothiazole (2v).
Yellow liquid (104 mg, 62% yield); Rf =0.4 (Hexane /EtOAc=
1
10:1); H NMR (500 MHz, CDCl3) δ 7.99 (d, J=7.1 Hz, 2H),
7.69 (s, 1H), 7.61 (d, J=1.9 Hz, 1H), 7.50–7.39 (m, 3H), 7.32
(dd, J=8.2, 2.0 Hz, 1H), 7.17 (d, J=8.2 Hz, 1H), 3.08 (d, J=
12.2 Hz, 2H), 1.99 (d, J=12.2 Hz, 2H), 1.40 (s, 6H); 13C NMR
(125 MHz, CDCl3) δ 168.4, 168.2, 142.8, 134.9, 134.5, 129.2,
128.8 (2 C), 127.3, 126.8 (2 C), 126.7, 124.4, 124.1, 116.8,
37.1, 33.1, 30.0 (2 C), 23.1. HRMS (ESI-TOF) (m/z): [M+H]+
calcd for C20H20NS2, 338.1032, found: 338.1026.
5-(tert-butyl)-3-phenylisothiazole (2ac). Yellow liquid
(87 mg, 80% yield); Rf = 0.6 (Hexane /EtOAc=5:1); H NMR
1
(500 MHz, CDCl3) δ 7.59 (d, J=7.1 Hz, 2H), 7.41 (dt, J=14.6,
7.0 Hz, 3H), 7.33 (s, 1H), 1.42 (s, 9H). 13C NMR (125 MHz,
CDCl3) δ 180.4, 167.1, 131.2, 129.2, 129.1 (2 C), 126.5 (2 C),
117.4, 36.6, 30.1 (3 C); HRMS (ESI-TOF) (m/z): [M+H]+
calcd for C13H16NS, 218.0998, found: 218.0993.
3,5-di(thiophen-3-yl)isothiazole (2w). Yellow solid (83 mg,
5-(tert-butyl)-3-(thiophen-2-yl)isothiazole (2ad). Brown
liquid (75 mg, 67% yield); Rf =0.6 (Hexane /EtOAc=5:1); H
°
67% yield); MP: 117–119 C; Rf =0.4 (Hexane /EtOAc=10:1);
1
1H NMR (500 MHz, CDCl3) δ 7.80 (d, J=2.7 Hz, 1H), 7.64 (d,
J=5.0 Hz, 1H), 7.59 (d, J=2.6 Hz, 1H), 7.53 (s, 1H), 7.48–
7.42 (m, 1H), 7.39 (dd, J=5.0, 3.0 Hz, 1H), 7.33 (d, J=5.0 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ 163.7, 162.0, 137.2, 131.6,
127.2, 126.4, 126.4, 126.1, 123.7, 122.9, 117.8. HRMS (ESI-
TOF) (m/z): [M+H]+ calcd for C11H8NS3, 249.9813, found:
249.9813.
NMR (500 MHz, CDCl3) δ 7.37–7.33 (m, 1H), 7.29–7.26 (m,
1H), 7.19 (s, 1H), 7.06 (dd, J=5.1, 3.7 Hz, 1H), 1.39 (s, 9H);
13C NMR (125 MHz, CDCl3) δ 180.2, 159.4, 133.1, 128.1,
126.6, 126.1, 117.9, 36.6, 30.0 (3 C); HRMS (ESI-TOF) (m/z):
[M+H]+ calcd for C11H14NS2, :224.0562, found: 224.0561.
3,5-dihexylisothiazole (2ae). Yellow liquid (77 mg, 61%
1
yield); Rf =0.7 (Hexane /EtOAc=30:1); H NMR (500 MHz,
3,5-di(thiophen-2-yl)isothiazole (2x). Brown solid (111 mg,
CDCl3) δ 6.75 (s, 1H), 2.86 (t, J=7.7 Hz, 2H), 2.81–2.68 (m,
2H), 1.73–1.65 (m, 4H), 1.32 (ddt, J=10.6, 6.8, 5.4 Hz, 12H),
0.88 (q, J=6.7 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 171.9,
169.3, 121.4, 33.32, 31.6, 31.4, 30.9, 29.0, 28.96, 28.8, 27.9,
22.5, 22.5, 14.04, 14.01. HRMS (ESI-TOF) (m/z): [M+H]+
calcd for C15H28NS, 254.1937, found: 254.1938.
°
89% yield); MP: 85–87 C; Rf =0.6 (Hexane /EtOAc=20:1);
1H NMR (500 MHz, CDCl3) δ 7.53–7.48 (m, 2H), 7.39 (dd, J=
10.6, 5.1 Hz, 2H), 7.33 (d, J=3.5 Hz, 1H), 7.10 (q, J=4.4 Hz,
2H); 13C NMR (125 MHz, CDCl3) δ 162.3, 160.4, 138.7, 132.3,
128.2, 127.7, 127.2, 127.2, 126.6, 125.9, 117.1 HRMS (ESI-
TOF) (m/z): [M+H]+ calcd for C11H8NS3, 249.9813, found:
249.9812.
3-(2-methoxyphenyl)-5-phenylisothiazole (2ag). Yellow solid
°
(96 mg, 72% yield) MP: 110–112 C; Rf =0.5 (Hexane
5-phenyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)
/EtOAc=20:1); 1H NMR (500 MHz, CDCl3) δ 8.02 (d, J=
7.2 Hz, 2H), 7.97 (s, 1H), 7.85 (d, J=7.8 Hz, 1H), 7.48 (t, J=
7.5 Hz, 2H), 7.44–7.36 (m, 2H), 7.11–7.03 (m, 2H), 4.03 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 165.6, 162.5, 155.9, 135.0,
130.4, 128.9, 128.7 (2 C), 127.0, 126.8 (2 C), 121.1, 120.2,
116.9, 111.5, 55.6; HRMS (ESI-TOF) (m/z): [M+H]+ calcd for
C16H14NOS, 268.0791, found: 268.0784.
phenyl)isothiazole (2y). Yellow liquid (118 mg, 65% yield); Rf
1
= 0.5 (Hexane /EtOAc=5:1); H NMR (500 MHz, CDCl3) δ
8.11 (s, 1H), 8.03 (d, J=7.3 Hz, 2H), 7.88 (d, J=7.4 Hz, 1H),
7.84 (s, 1H), 7.77 (d, J=7.8 Hz, 1H), 7.53–7.43 (m, 4H), 1.41
(s, 12H); 13C NMR (125 MHz, CDCl3) δ 168.2, 136.0 (2 C),
134.8, 132.6 (2 C), 130.4, 129.4, 129.2, 128.8 (2 C), 128.6,
126.9 (2 C), 117.7, 84.2 (2 C), 24.9 (4 C). HRMS (ESI-TOF)
(m/z): [M+Na]+ calcd for C21H22BNNaO2S, 385.1393, found
385.1394.
2-(5-phenylisothiazol-3-yl)phenol (2ah). Yellow solid
(110 mg, 87% yield); MP: 80–82 C; Rf =0.5 (Hexane/EtOAc=
20:1); H NMR (500 MHz, Acetone) δ 11.6 (s, 1H), 8.38-8.37
(m, 1H), 8.02 (d, J=7.5 Hz, 1H), 7.79-7.86 (m, 2H), 7.56-7.51
(m, 3H), 7.36-7.33 (m, 1H), 7.02-6.96 (m, 2H); 13C NMR
(125 MHz, Acetone) δ 170.4, 167.8, 158.7, 132.2, 131.2, 130.4
(2 C), 129.2, 127.6 (2 C), 120.2 118.7, 118.3. HRMS (ESI-
°
1
3-(4-(9H-carbazol-9-yl)phenyl)-5-phenylisothiazole (2z). Yel-
°
low solid (149 mg, 74% yield); MP: 138–140 C, Rf = 0.5
(Hexane /EtOAc=5:1); H NMR (500 MHz, CDCl3) δ 8.24 (d,
J=8.4 Hz, 2H), 8.17 (d, J=7.8 Hz, 2H), 7.84 (s, 1H), 7.74–
1
7.66 (m, 4H), 7.54–7.42 (m, 7H), 7.33 (t, J=7.4 Hz, 2H); 13C
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TOF) (m/z): [M+H]+ calcd for C15H12NOS, 254.0634,
found:254.0629.
7.05 (t, J=7.6 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 149.5,
143.8, 139.0, 138.3, 137.7, 137.2, 135.3, 132.3, 131.2, 131.1
(2 C), 130.5 (2 C), 130.3, 130.3, 130.1 (2 C), 130.0 (2 C),
129.5, 128.7 (2 C), 128.3 (2 C), 127.9, 127.9 (2 C), 127.8,
127.8, 127.3 (2 C), 127.2, 127.2, 126.7, 126.0, 125.4, 124.2,
122.0, 107.8. HRMS (ESI-TOF) (m/z): [M+H]+ calcd for
C39H25NS3, 604.1222, found: 604. 604.1215.
benzo[b]thiophen-2-yl(2-fluorophenyl)methanone (3a). Pink
°
solid (108 mg, 84% yield); MP: 127–129 C; Rf =0.4 (Hexane
/EtOAc=4:1); 1H NMR (500 MHz, CDCl3) δ 8.55 (d, J=
8.0 Hz, 1H), 7.63 (d, J=3.3 Hz, 2H), 7.55 (m, J=5.4 Hz, 2H),
7.47 (m, J=7.5 Hz, 1H), 7.27 (m, J=11.3 Hz, 2H), 7.24–7.16
(m, 2H).13C NMR (125 MHz, CDCl3) δ 180.4, 159.1 (d, J=
251.3 Hz, 1 C), 147.0, 138.0, 132.0 (d, J=8.4 Hz, 1 C), 131.6,
130.7, 130.0 (d, J=1.8 Hz, 1 C), 128.6, 127.8, 1126.8 (d, J=
3.8 Hz, 1 C), 126.3, 124.7 (d, J=3.8 Hz, 1 C), 124.3 (d, J=
12.5 Hz, 1 C), 1116.7 (d, J=21.2 Hz, 1 C). HRMS (ESI-TOF)
(m/z): [M+H]+ calcd for C15H10FOS, 257.0431, found:
257.0430.
[2d]
4-bromo-3,5-diphenylisothiazole (5a).
White solid
°
(144 mg, 92% yield); MP: 127–129 C; Rf =0.5 (Hexane
/EtOAc=20:1) 1H NMR (500 MHz, CDCl3) δ 7.85 (dd, J=7.8,
1.8 Hz, 2H), 7.67 (dd, J=7.9, 1.6 Hz, 2H), 7.58–7.43 (m, 6H);
13C NMR (125 MHz, CDCl3) δ 167.0, 162.9, 134.7, 130.1,
129.8, 129.4, 129.0 (2 C), 128.9 (2 C), 128.8 (2 C), 128.2 (2 C),
106.0. HRMS (ESI-TOF) (m/z): [M+H]+ calcd for
C15H11BrNS, 315.9790, found: 315.9788.
(Z)-1-((3,4-diphenyl-1H-isothiochromen-1-ylidene)methyl)-
3,4-diphenylisoquinoline (4a).[12] Yellow solid (263 mg, 89%
3,4,5-triphenylisothiazole (6a).
Yellow solid (128 mg, 82%
1
[2d]
1
°
yield); Rf =0.5 (Hexane /EtOAc=10:1); H NMR (500 MHz,
yield); MP: 217–219 C; Rf =0.5 (Hexane /EtOAc=3:1); H
NMR (500 MHz, CDCl3) δ 7.39 (d, J=6.9 Hz, 2H), 7.37–7.26
(m, 7H), 7.26–7.20 (m, 4H), 7.09 (d, J=6.3 Hz, 2H); 13C NMR
(125 MHz, CDCl3) δ 167.6, 164.0, 135.7, 134.2, 134.1, 131.0,
130.6 (2 C), 128.9 (2 C), 128.8, 128.7 (2 C), 128.7 (2 C), 128.6
(2 C), 128.4, 128.0 (2 C), 127.5; HRMS (ESI-TOF) (m/z): [M+
H]+ calcd for C21H16NS, 314.0998, found: 314.0997.
CDCl3) δ 8.45 (d, 1H), 8.06 (d, J=7.0 Hz, 2H), 7.82–7.49 (m,
5H), 7.48–7.26 (m, 9H), 7.24–7.04 (m, 12H); 13C NMR
(125 MHz, CDCl3) δ 152.8, 140.1, 138.4, 137.6, 137.5, 136.6,
135.3, 132.1, 131.5 (2 C), 131.4 (2 C), 130.9 (2 C), 130.8,
130.4, 130.13, 129.9, 129.3 (2 C), 129.1, 128.3 (2 C), 128.2,
128.1 (2 C), 128.0, 127.8 (2 C), 127.4, 127.3, 127.2 (2 C),
127.0, 126.8, 126.7, 126.4, 125.7, 125.6, 124.6, 116.1.
3,5-diphenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)
Z)-1-((3,4-bis(4-methoxyphenyl)-1H-isothiochromen-1-
ylidene)methyl)-3,4-bis(4-methoxyphenyl)isoquinoline
(4b).[12] Yellow solid (309 mg, 87% yield); Rf =0.5 (hexane/
isothiazole (7a). Brown liquid (136 mg, 75% yield); Rf =0.5
(Hexane /EtOAc=5:1); H NMR (500 MHz, CDCl3) δ 7.80 (d,
1
J=7.8 Hz, 2H), 7.63–7.60 (m, 2H), 7.42 (dd, J=8.0, 2.2 Hz,
6H), 1.19 (s, 12H); 13C NMR (125 MHz, CDCl3) δ 174.3,
172.4, 136.7, 131.9, 129.3, 128.8, 128.7 (2 C), 128.5 (2 C),
128.5 (2 C), 128.2 (2 C), 127.5, 84.4 (2 C), 24.7 (4 C). HRMS
(ESI-TOF) (m/z): [M+H]+ calcd for C21H23BNO2S, 363.1573,
found: 363.1563.
1
EtOAc=3:1); H NMR (500 MHz, CDCl3) 8.40–8.43 (m, 1H),
8.01–8.05 (m, 2H), 7.71–7.73 (m, 1H), 7.57–7.59 (m, 2H), 7.51
(d, J=9 Hz, 2H), 7.41–7.44 (m, 1H), 7.30–7.33 (m, 1H), 7.18–
7.20 (m, 2H), 7.12–7.14 (m, 3H), 7.04 (d, J=8.5 Hz, 2H), 6.93
(d, J=8.5 Hz, 2H), 6.80 (d, J=8.5 Hz, 2H), 6.70 (d, J=
8.5 Hz, 2H), 6.64 (d, J=8.5 Hz, 2H), 3.86 (s, 3H), 3.79 (s, 3H),
3.75 (s, 3H), 3.746 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
158.7, 158.6, 158.5, 158.2, 152.5, 137.0, 135.6, 132.5 (2 C),
132.4 (2 C), 132.2 (2 C), 130.9, 130.9, 130.7, 130.7 (2 C),
130.2, 130.1, 129.0, 128.0, 127.9, 127.8, 126.3, 126.27, 125.6,
125.5, 124.7, 115.9, 113.9 (2 C), 113.5 (2 C), 113.2 (2 C), 112.8
(2 C), 55.2, 55.12, 55.09, 55.05.
3,5-diphenylisothiazole-4-d (2a-D). White solid (108 mg, 91%
1
yield); Rf =0.5 (Hexane /EtOAc=30:1); H NMR (500 MHz,
CDCl3) δ 8.01 (d, J=7.5 Hz, 2H), 7.66 (d, J=7.3 Hz, 2H),
7.46 (dq, J=20.4, 7.3 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ
168.2, 168.1, 134.8, 130.9, 129.6, 129.2 (3 C), 128.8 (2 C),
126.8 (2 C), 126.5 (2 C), 117.3 (t, J=27.5 Hz, 1 C); HRMS
(ESI-TOF) (m/z): [M+H]+ calcd for C15H11DNS, 239.0748,
found: 239.0746.
(Z)-7-((4,5-diphenyl-7H-thieno[2,3-c]thiopyran-7-ylidene)
methyl)-4,5-diphenylthieno[2,3-c]pyridine (4c). Yellow solid
(E)-3-amino-1,3-diphenylprop-2-en-1-one (8a).[17] Yellow
liquid (47 mg, 42% yield); 1H NMR (500 MHz, CDCl3) δ 10.44
(s, 1H), 7.95 (d, J=7.8 Hz, 2H), 7.65 (d, J=7.6 Hz, 2H), 7.58–
7.40 (m, 6H), 6.16 (s, 1H), 5.47 (s, 1H); 13C NMR (125 MHz,
CDCl3) δ 190.2, 162.9, 140.3, 137.6, 131.04, 130.7, 129.0
(2 C), 128.3 (2 C), 127.2 (2 C), 126.3 (2 C), 91.9. HRMS (ESI-
TOF) (m/z): [M+H]+ calcd for C15H14NO, 224.1070, found:
224.1065.
1
°
(256 mg, 85% yield); MP: 269–271 C; H NMR (500 MHz,
CDCl3) δ 7.64–7.59 (t, J=7.0 Hz, 3H), 7.34 (dt, J=15.3,
7.6 Hz, 6H), 7.30–7.25 (m, 4H), 7.25–7.22 (m, 2H), 7.22–7.17
(m, 5H), 7.13 (t, J=7.3 Hz, 1H), 7.09 (s, 1H), 7.04 (t, J=
7.6 Hz, 2H), 6.83 (d, J=5.4 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 149.7, 148.8, 145.9, 139.9, 139.6, 138.8, 138.3, 137.3,
136.8, 136.4, 134.1, 132.2, 130.9 (2 C), 130.7 (2 C), 130.6
(2 C), 130.1 (2 C), 129.6, 128.8, 128.3 (2 C), 128.1 (2 C),
128.0, 127.8 (2 C), 127.8, 127.2 (2 C), 127.1, 127.0, 126.9,
125.8, 125.4, 124.4, 106.7. HRMS (ESI-TOF) (m/z): [M+H]+
calcd for C39H25NS3, 604.1222, found: 604.1215.
CCDC-2025711 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
(Z)-4-((6,7-diphenyl-4H-thieno[3,4-c]thiopyran-4-ylidene)
methyl)-6,7-diphenylthieno[3,4-c]pyridine (4d). Yellow solid
1
°
(244 mg, 81% yield); MP: 177–179 C; H NMR (500 MHz,
Acknowledgements
CDCl3) δ 7.73 (d, J=5.6 Hz, 1H), 7.69 (d, J=5.5 Hz, 1H), 7.65
(d, J=7.2 Hz, 2H), 7.52–7.47 (m, 2H), 7.42–7.34 (m, 6H),
7.31–7.26 (m, 7H), 7.22–7.19 (m, 3H), 7.14 (t, J=7.3 Hz, 1H),
This work was supported by the Foundation of the De-partment
of Education of Guangdong Province (2019KZDXM052,
Adv. Synth. Catal. 2020, 362, 1–11
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asc.wiley-vch.de
2017KZDXM085 and 2018KZDXM070), Science Foundation
for Young Teachers of Wuyi University (2019td06), the
Foundation for Young Talents (2019KQNCX159 and
2019KQNCX160), the Foundation of Guangdong Basic and
Applied Basic Research (2019 A1515110516) and Chemical
Industry Collaborative Innovation Center of Yueshan Town
2017(368).
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Böhlmann, M. Findeisen, T. Gelbrich, H. Holmann, B.
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Transition Metal-Free Synthesis of Substituted Isothiazoles
via Three-Component Annulation of Alkynones, Xanthate
and NH4I
Adv. Synth. Catal. 2020, 362, 1–11
J. Li, J. Li, X. Ji, Q. Liu, L. Chen, Y. Huang*, Y. Li*