Synthesis of Bicyclic Isothiazoles through an Intramolecular Rhodium-Catalyzed Transannulation of Cyanothiadiazoles

Article abstract of DOI:10.1021/acs.joc.7b02077

An intramolecular rhodium-catalyzed transannulation of readily available cyanothiadiazoles containing an ester, amide, or ether as a linker is described. It provides a wide range of bicyclic isothiazoles in good to excellent yields together with the release of molecular nitrogen. These results indicate that the carbon atom in the α-thiavinyl carbene is nucleophilic and that the sulfur atom is electrophilic.

Full text of DOI:10.1021/acs.joc.7b02077

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Article
Synthesis of Bicyclic Isothiazoles through an Intramolecular
Rhodium-Catalyzed Transannulation of Cyanothiadiazoles
Boram Seo, Hyunseok Kim, Ya Gob Kim, Yonghyeon Baek, Kyusik Um, and Phil Ho Lee
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02077 • Publication Date (Web): 09 Sep 2017
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Synthesis of Bicyclic Isothiazoles through an Intramolecular
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Rhodium-Catalyzed Transannulation of Cyanothiadiazoles
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Boram Seo,† Hyunseok Kim,† Ya Gob Kim,† Yonghyeon Baek, Kyusik Um, and Phil Ho Lee*
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Department of Chemistry, Kangwon National University, Chuncheon 24341, Republic of Korea
Eꢀmail: phlee@kangwon.ac.kr
Table of Contents
ABSTRACT: An intramolecular rhodiumꢀcatalyzed transannulation of readily available
cyanothiadiazoles containing an ester, amide, or ether as a linker is described. It provides a wide
range of bicyclic isothiazoles in good to excellent yields together with the release of molecular
nitrogen. These results indicate that the carbon atom in the αꢀthiavinyl carbene is nucleophilic and
that the sulfur atom is electrophilic.
■
INTRODUCTION
Bicyclic isothiazole ring systems are privileged structural motifs found in many pharmaceutical
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compounds and functional materials.1 They have been widely used as significant privileged
scaffolds in a myriad of areas, such as organic electroluminescent materials, semiconductors,
pesticides, anticancer drugs, and ligands (Figure 1).1 Thus, the development of an efficient synthetic
method for functionalized bicyclic isothiazoles is highly desired.
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Figure 1. Important compounds containing bicyclic isothiazole scaffolds
In recent years, many metalꢀcatalyzed transannulation reactions via metalꢀcarbenoid
intermediates from Nꢀsulfonylꢀ1,2,3ꢀtriazoles2 and pyridotriazoles3 have been reported. More
recently, Gevorgyan and coꢀworkers described the Rhꢀcatalyzed transannulation of 1,2,3ꢀ
thiadiazoles with alkynes for the synthesis of thiophenes via an αꢀthiavinyl carbene as a 1,3ꢀdipole
equivalent.4 In addition, we developed the intermolecular Rhꢀcatalyzed transannulation of 1,2,3ꢀ
thiadiazoles with nitriles5 and alkenes6 to produce isothiazoles and 4ꢀsubstituted dihydrothiophenes,
respectively. These results are in obvious contrast with earlier findings of Gevogyan and coꢀworkers
from the point of view of regioselectivity.4 Stimulated by these results and interested in the latent
uses of bicyclic isothiazoles in medicinal chemistry, electronic material chemistry, and
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pharmaceuticals, we report an efficient intramolecular Rhꢀcatalyzed transannulation of
cyanothiadiazoles containing an ester, amide, or ether as a linker, leading to the straightforward
preparation of bicyclic isothiazoles (Scheme 1).
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Scheme 1. Synthesis of Bicyclic Isothiazoles via the Intramolecular Rh-Catalyzed
Transannulation of Cyanothiadiazoles
■
RESULTS and DISCUSSION
First, we investigated the intramolecular transannulation of cyanothiadiazole (1a) in the presence of
a variety of transition metal catalysts and ligands (Table 1). A wide range of ligands, including 1,2ꢀ
bis(diphenylphosphino)ethane (DPPE), 1,3ꢀbis(diphenylphosphino)propane (DPPP), 1,4ꢀ
bis(diphenylphosphino)butane (DPPB), bis[(2ꢀdiphenylphosphino)phenyl] ether (DPEPhos), 4,5ꢀ
bis(diphenylphosphino)ꢀ9,9ꢀdimethylxanthene (XantPhos), and bis(diphenylphosphino)biphenyl
(BIPHEP) in the presence of [Rh(COD)Cl]2, were examined. To our delight, DPPE and DPPP gave
the desired bicyclic isothiazole 2a in 59% and 43% yields, respectively (entries 1 and 2). The
structure of 2a was confirmed by Xꢀray crystallography (see the Supporting Information).7
Although XantPhos is inefficient, DPPB, DPEPhos, and BIPHEP provided 2a in 95%, 92% and
98% yield (entries 3ꢀ6). DPPF was the ligand of choice, affording 2a in quantitative yield (99%
NMR yield, 92% isolated yield, entry 7). Next, many catalysts including Rh2(oct)4, [Cp*RhCl2]2,
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[Ir(COD)Cl]2, and [Rh(COD)Cl]2 were examined to disclose that [Rh(COD)Cl]2 (5.0 mol %) was
the most effective catalyst (entries 7ꢀ10). Although Rh2(oct)4 and [Ir(COD)Cl]2 were not useful, the
catalytic activity of [Cp*RhCl2]2 is comparable to that of [Rh(COD)Cl]2, leading to the formation of
2a in 93% yield. Control experiments without [Rh(COD)Cl]2 or DPPF did not proceed, indicating
that this catalyst and ligand are essential for the intramolecular transannulation reaction (entries 11
and 12).
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Table 1. Reaction Optimizationa
entry cat.
ligandb
DPPE
DPPP
DPPB
DPEPhos
XantPhos
BIPHEP
DPPF
DPPF
DPPF
DPPF
ꢀ
time (h)
yield (%)c
59 (34)
43 (45)
95
1
[Rh(COD)Cl]2
5
2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
Rh2(oct)4
5
3
1
4
3
92
5
5
0 (52)
98
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1
7
1
99 (92)d
0 (24)
93
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5
9
[Cp*RhCl2]2
[Ir(COD)Cl]2
[Rh(COD)Cl]2
ꢀ
2
10
11
12
5
0 (15)
0 (＞99)
0 (＞99)
14
14
DPPF
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aReaction conditions: 1a (0.2 mmol) in the presence of 5.0 mol % catalyst and 12.0 mol % ligand in
PhCl (1.0 mL) under a nitrogen atmosphere. bDPPE: 1,2ꢀBis(diphenylphosphino)ethane. DPPP: 1,3ꢀ
Bis(diphenylphosphino)propane. DPPB: 1,4ꢀBis(diphenylphosphino)butane. DPEPhos: Bis[(2ꢀ
diphenylphosphino)phenyl] ether. Xantphos: 4,5ꢀBis(diphenylphosphino)ꢀ9,9ꢀdimethylxanthene.
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c
BIPHEP: Bis(diphenylphosphino)biphenyl. DPPF: 1,1′ꢀBis(diphenylphosphino)ferrocene. Yields
were determined by NMR using CH2Br2 as an internal standard. Numbers in parenthesis indicate
the recovered yield of 1a. dIsolated yield of 2a.
With these optimized conditions in hand, we investigated the scope and limitation of the Rhꢀ
catalyzed intramolecular transannulation of many cyanothiadiazoles (1), which are readily accessed
from the esterification of isothiazoleꢀ4ꢀcarboxylic acid with 3ꢀhydroxypropanenitrile (Scheme 2).4,8
The electronic variation of the substituents on the aryl group of 2ꢀcyanoethyl 5ꢀarylisothiazoleꢀ4ꢀ
carboxylate did not influence the reaction efficiency. Electronꢀdonating methyl, methoxy, and
methylenedioxy groups gave the desired bicyclic isothiazoles in excellent yields varying from 91%
to 96%. The conditions of the Rhꢀcatalyzed intramolecular transannulation reaction were
compatible with bromo and nitro groups, providing 2e and 2f in 90% and 92% yields, respectively.
2ꢀFurylꢀsubstituted cyanothiadiazole 1g tolerated the optimized conditions and afforded the
corresponding 2ꢀfurylꢀsubstituted bicyclic isothiazole 2g in 91% yield. 2ꢀ or 3ꢀThiophenylꢀ
substituted cyanothiadiazoles (1h and 1i) also provided the desired bicyclic isothiazoles (2h and 2i)
in 80% to 90% yields, respectively. The present method worked equally well even with methylꢀ and
cyclohexylꢀsubstituted cyanothiadiazoles (1j and 1k), leading to the facile construction of bicyclic
isothiazoles 2j (95%) and 2k (91%).
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Scheme 2. Substrate Scope of Thiadiazoles Bearing a Cyanoethoxycarbonyl Groupa
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4
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9
O
O
5.0 mol % [Rh(COD)Cl]2
12.0 mol % DPPF
O
CN
O
N
PhCl, 130 oC, 1 h
N
N
N
R
R
S
S
1
2
O
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O
O
O
N
S
S
Me
2b (96%)
2a (92%)
O
O
O
O
O
O
N
N
O
O
N
S
S
S
MeO
Br
2c (96%)b
2e (90%)b
2d (91%)
O
O
O
O
O
O
N
S
N
N
S
S
O2N
O
S
2f (92%)
2g (91%)
2h (80%)
O
O
O
O
O
O
N
N
S
S
N
Me
S
S
2i (90%)
2j (95%)
2k (91%)
aReaction conditions: 1 (0.2 mmol) in the presence of 5.0 mol % [Rh(COD)Cl]2 and 12.0 mol %
b
DPPF in PhCl (1.0 mL) under a nitrogen atmosphere at 130 °C for 1 h. The reaction was carried
out at 80 °C.
Encouraged by these results, we examined the effect of the chain length and substituents on the
cyanoalkyl group on the Rhꢀcatalyzed transannulation (Scheme 3). Thiadiazoles (1l, 1m, and 1n)
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with cyanomethyl groups obtained from αꢀhydroxynitriles, including 2ꢀhydroxypropanenitrile, 2ꢀ
hydroxyꢀ2ꢀmethylpropanenitrile, and 1ꢀhydroxycyclohexanecarbonitrile, underwent the Rhꢀ
catalyzed transannulation, producing the desired bicyclic thiazoles (2l, 2m, and 2n) in excellent
yields ranging from 91% to 93%. The structure of 2n was confirmed by Xꢀray crystallography (see
the Supporting Information).7 Thiadiazoles (1o, 1p, and 1q) generated from the esterification
reaction of 5ꢀphenyl isothiazoleꢀ4ꢀcarboxylic acid with 3ꢀhydroxyheptanenitrile, 3ꢀhydroxyꢀ3ꢀ
phenylpropanenitrile, and 3ꢀhydroxyꢀ3ꢀpꢀtolylpropanenitrile were compatible with the reaction
conditions to furnish the desired thiazoles (2o, 2p, and 2q) in quantitative yields. The present
method worked equally well with thiadiazole 1r accessed from 2ꢀhydroxycyclohexanecarbonitrile,
resulting in the formation of tricyclic isothiazole 2r in 98% yield. We were pleased to obtain a
tricyclic isothiazole (2s) in 90% yield from thiadiazole 1s derived from 2ꢀhydroxybenzonitrile.
Variation of the substituents on the aryl group in the 2ꢀhydroxybenzonitriles did not influence the
efficiency in the syntheses of isothiazoles (2t and 2u), and therefore, methyl and bromo substituents
were readily employed. Thiadiazole 1v generated from 2ꢀhydroxyꢀ1ꢀnaphthonitrile took part in the
Rhꢀcatalyzed transannulation reaction to afford tetracyclic isothiazole 2v in 74% yield. Next, we
investigated the Rhꢀcatalyzed transannulation of cyanoalkyl 5ꢀphenylꢀ1,2,3ꢀthiodiazolylꢀ4ꢀ
carboxylates (1) with an enlarged alkyl chain. Although thiadiazole 1w prepared from 4ꢀ
hydroxybutanenitrile was less reactive, the desired bicyclic thiazole 2w was obtained in acceptable
yield. When thiadiazole 1x obtained from 2ꢀ(2ꢀhydroxyphenyl)acetonitrile was treated with the Rh
catalyst, tricyclic isothiazole 2x was obtained in 70% yield. Moreover, thiadiazole 1y bearing a 3ꢀ
(2ꢀhydroxynaphthalenꢀ1ꢀyl)propanenitrile moiety was compatible with the reaction conditions,
resulting in the production of tetracyclic isothiazole 2y in 66% yield.
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Scheme 3. Substrate Scope of Thiadiazoles Bearing a Cyanoalkoxycarbonyl Groupa
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4
5
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R2 R3
R2 R3
R4
R4
m
5.0 mol % [Rh(COD)Cl]2
12.0 mol % DPPF
m
O
O
m = 0, 1
n = 0, 1, 2
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8
PhCl, 130 oC, 1 h
n
n
O
CN
O
N
1
2
9
N
N
R1
R1
S
S
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Me
Me
O
O
S
O
O
Me
O
O
N
N
N
Ph
Ph
Ph
S
S
2l (91%)b
2m (92%)b
2n (93%)
n-Bu
Ph
p-Tol
O
O
O
O
O
O
N
N
N
Ph
S
Ph
Ph
S
S
2o (96%)
2p (99%)
2q (99%)
O
O
Me
O
O
O
O
N
S
2s (90%)
N
N
S
Ph
Ph
Ph
S
2t (99%)
2r (98%)
O
O
O
Br
O
O
O
N
N
N
S
Ph
Ph
2w (40%)b
Ph
S
S
2u (90%)
2v (74%)
O
O
O
O
N
N
S
Ph
Ph
S
2x (70%)
2y (66%)
aReaction conditions: 1 (0.2 mmol) in the presence of 5.0 mol % [Rh(COD)Cl]2 and 12.0 mol %
DPPF in PhCl (1.0 mL) under a nitrogen atmosphere bThe reaction was carried out at 80 °C.
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To demonstrate the efficiency and scope of the present method, we next applied
cyanothiadiazoles 3 bearing an amide or ether group as a linker between the thiadiazole ring and the
nitrile group to the Rhꢀcatalyzed transannulation (Scheme 4). Cyanothiadiazoles 3a and 3b with 2oꢀ
and 3oꢀamide group as a linker were smoothly converted to the corresponding bicyclic isothiazoles
4a and 4b in excellent yields. Cyanothiadiazole 3c with an ether linker obtained from (5ꢀphenylꢀ
1,2,3ꢀthiadiazolꢀ4ꢀyl)methanol and 3ꢀbromopropanenitrile was applied to the present transformation,
providing the corresponding bicyclic isothiazole 4c in 84% yield. Cyanothiadiazoles 3d and 3e with
4ꢀbromobutanenitrile and 5ꢀbromopentanenitrile moieties were subjected to the Rh catalyst, and the
transannulation reaction occurred, producing the corresponding bicyclic isothiazoles 4d and 4e in
65% and 50% yields, respectively.
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Scheme 4. Substrate Scope of Cyanothiadiazoles Bearing Amide or Ether Linkersa
X
X
5.0 mol % [Rh(COD)Cl]2
12.0 mol % DPPF
Y
Y
CN
n
n
N
PhCl, 130 oC, 1 h
N
N
Ph
Ph
S
S
3
n = 1, 2, 3
X = NH, NMe, O Y = O, H2
4
Me
N
HN
O
O
N
N
Ph
Ph
S
S
4a (95%)b
4b (94%)
O
O
O
N
N
N
Ph
Ph
Ph
S
S
S
4c (84%)
4d (65%)
4e (50%)
aReaction conditions: 3 (0.2 mmol) in the presence of 5.0 mol % [Rh(COD)Cl]2 and 12.0 mol %
b
DPPF in PhCl (1.0 mL) under a nitrogen atmosphere. 12.0 mol % DPPBz was used as a ligand
o
instead of DPPF. Reactions were carried out at 130 C under microwave irradiation for 10 min in
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sealed microwave vial (SPS mode, 200 W).
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A plausible reaction mechanism for the Rhꢀcatalyzed intramolecular transannulation of
cyanothiadiazoles is suggested in Scheme 5. First, a reversible ringꢀchain tautomerization of the
thiadiazole moieties in cyanothiadiazoles 1 and 3 provides the cyanoꢀsubstituted αꢀdiazo
thiocarbonyl A. The corresponding αꢀthiavinyl Rhꢀcarbenoid B is then generated from the
denitrogenation of A in the presence of the Rh calalyst.9 The [2 + 1] intramolecular cycloaddition of
B affords the thiocarbonyl azirine intermediate C,10 which then cycloisomerizes to form bicyclic
isothiazole 2 and 4 (path a). However, path a might be excluded in the catalytic cycle due to ring
strain. On the other hand, the intermediate B might be subjected to intramolecular nucleophilic
attack by the nitrile (path c) to furnish the nitrilium cation D, which subsequently cyclizes to afford
the zwitterionic intermediate E. In the end, E regenerates the Rh catalyst to provide bicyclic
isothiazoles 2 and 4. On the other hand, the zwitterionic intermediate E can be obtained through an
intramolecular [3 + 2] cycloaddition of the nitrile group with the αꢀthiavinyl Rhꢀcarbenoid B (path
b). Based on the selective formation of the isothiazole (2 and 4), the nitrilium cation F is ruled out
in the catalytic cycle due to an unfavorable geometry (path d). Confirmation of the comprehensive
mechanism of the present method must wait for further investigation.
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Scheme 5. A Plausible Mechanism
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■
CONCLUSION
In summary, we developed an intramolecular Rh(I)ꢀcatalyzed transannulation of readily available
cyanothiadiazoles containing an ester, amide, or ether as a linker, serving as an efficient platform
for the construction of a wide range of biꢀ, triꢀ, and tetracyclic isothiazoles in good to excellent
yields together with the release of molecular nitrogen. These results suggest that the carbon atom in
the αꢀthiavinyl carbene is nucleophilic and that the sulfur atom is electrophilic.
Experimental Section
General: Reactions were carried out in ovenꢀdried glassware under air atmosphere. [Rh(COD)Cl]2,
Rh2(oct)4, [Cp*RhCl2]2, [Ir(COD)Cl]2, DPPF, DPPP, DPPE, Xantphos, DPEPhos, DPPB, and
BIPHEP were purchased and was used as received. All commercially available reagents were used
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as received. Commercial available reagents were used without purification. Chlorobenzene was
purified by distillation from CaCl2 under nitrogen. All reaction mixtures were stirred magnetically
and were monitored by thinꢀlayer chromatography using silica gel preꢀcoated glass plates, which
were visualized with UV light and then, developed using either iodine or a solution of anisaldehyde.
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1
Flash column chromatography was carried out using silica gel (230ꢀ400 mesh). H NMR (400
MHz) and 13C{1H} NMR (100 MHz) spectra were recorded on NMR spectrometer. Deuterated
chloroform was used as the solvent and chemical shift values (δ) are reported in parts per million
relative to the residual signals of this solvent (δ 7.26 for H and δ 77.2 for 13C{1H}). Infrared
1
spectra were recorded on FTꢀIR spectrometer as either a thin film pressed between two sodium
chloride plates or as a solid suspended in a potassium bromide disk. High resolution mass spectra
(HRMS) were obtained by fast atom bombardment (FAB) using a double focusing magnetic sector
mass spectrometer and electron impact (EI) ionization technique (magnetic sectorꢀelectric sector
double focusing mass analyzer) from the KBSI (Korea Basic Scienece Institute). Melting points
were determined in open capillary tube. The reaction temperature under microwave irradiation was
monitored by external surface sensor.
Preparation of Cyanothiadiazoles 1 and 3a
To a solution of the alcohol or amine (6)11 (1.0 mmol), 4ꢀdimethylaminopyridine (DMAP, 36.7 mg,
0.10 mmol), and thiadiazoleꢀ4ꢀcarboxylic acid (5)12 (822.8 mg, 1.3 mmol) in dry 1,2ꢀdichloroethane
o
(DCE, 10 mL) at 0 C under a nitrogen atmosphere was added N,N’ꢀdicyclohexylcarbodiimide
(DCC, 823.3 mg, 1.3 mmol) in one portion. After stirring for 30 min at the same temperature, the
reaction mixture was allowed to warm up to room temperature followed by stirring for additional 3
h. Then, reaction mixture was filtered by Celite and the mixture was washed with dichloromethane
(3 x 10 mL). The combined filtrate was evaporated under reduced pressure to give the crude
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product, which was purified by silica gel chromatography (EtOAc:Hexane = 1:2) to provide the
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pure product 1 and 3a.13
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2-Cyanoethyl 5-phenyl-1,2,3-thiadiazole-4-carboxylate (1a): 212.6 mg, 82%, White solid, Meltin
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9
o
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g point: 79ꢀ80 C, Rf = 0.3 (EtOAc:Hx = 1:2), H NMR (400 MHz, CDCl3)
δ 7.55ꢀ7.51 (m,
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5H), 4.56 (t, J = 6.4 Hz, 2H), 2.78 (t, J = 6.4 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3)
δ
163.2,
159.8, 147.4, 131.1, 129.8, 129.0, 125.9, 116.4, 60.1, 18.0; IR (film) 1731, 1623, 1324, 1173, 1002,
834, 751, 694 cmꢀ1; HRMS (EI) m/z [M]+ Calcd for C12H9N3O2S: 259.0415, Found: 259.0413.
2-Cyanoethyl 5-(p-tolyl)-1,2,3-thiadiazole-4-carboxylate (1b): 177.7 mg, 65%, White solid, Melti
o
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ng point: 98ꢀ100 C, Rf = 0.3 (EtOAc:Hx = 1:2), H NMR (400 MHz, CDCl3)
δ 7.44 (dt, J =
8.2, 1.8 Hz, 2H), 7.31 (dd, J = 8.4, 0.6 Hz, 2H), 4.58 (t, J = 6.5 Hz, 2H), 2.81 (t, J = 6.5 Hz, 2H),
2.44 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ
163.6, 160.0, 147.0, 141.7, 129.78, 129.69,
122.8, 116.4, 60.1, 21.6, 18.0; IR (film) 2252, 1735, 1329, 1280, 1173 cmꢀ1; HRMS (EI) m/z
[M]+ Calcd for C13H11N3O2S: 273.0572, Found: 273.0569.
2-Cyanoethyl 5-(4-methoxyophenyl)-1,2,3-thiadiazole-4-carboxylate (1c): 193.8 mg, 67%,
o
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White solid, Melting point: 87ꢀ89 C, Rf = 0.2 (EtOAc:Hx = 1:2), H NMR (400 MHz, CDCl3)
δ
7.52 (dt, J = 9.7,. 2.5 Hz, 2H), 7.01 (dt, J = 9.7, 2.5 Hz, 2H), 4.59 (t, J = 6.5 Hz, 2H), 3.88 (s, 3H),
2.84 (t, J = 6.5 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3)
δ
163.5, 162.0, 160.2, 146.6, 131.6,
117.7, 116.5, 114.5, 60.1, 55.6, 18.1; IR (film) 2252, 1732, 1605, 1257, 1173 cmꢀ1; HRMS (EI) m
/z [M]+ Calcd for C13H11N3O3S: 289.0521, Found: 289.0522.
2-Cyanoethyl 5-(benzo[d][1,3]dioxol-5-yl)-1,2,3-thiadiazole-4-carboxylate (1d): 88.0 mg, 29%,
1
Yellow oil, Rf = 0.2 (Et2O:DCM:Hx = 1:3:5), H NMR (400 MHz, CDCl3)
δ 7.05ꢀ7.03 (m, 2H),
6.91 (d, J = 8.5 Hz, 1H), 6.08 (s, 2H), 4.60 (t, J = 6.5 Hz, 2H), 2.85 (t, J = 6.5 Hz, 2H); 13C{1H} N
MR (100 MHz, CDCl3)
δ
163.0, 160.0, 150.1, 148.1, 146.8, 124.6, 118.7, 116.5, 109.9, 108.7,
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102.0, 80.0, 17.9; IR (film) 2915, 1731, 1624, 1471, 1320, 1141, 1036, 930, 783, 620 cmꢀ1; HRMS
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(EI) m/z [M]+ Calcd for C13H9N3O4S: 303.0314, Found: 303.0312.
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2-Cyanoethyl 5-(4-bromophenyl)-1,2,3-thiadiazole-4-carboxylate (1e): 209.7 mg, 62%, White so
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lid, Melting point: 116ꢀ118 C, Rf = 0.3 (EtOAc:Hx = 1:2), H NMR (400 MHz, CDCl3)
δ
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7.65 (dt, J = 9.0, 2.2 Hz, 2H), 7.42 (dt, J = 9.0, 2.2 Hz, 2H), 4.58 (t, J = 6.4 Hz, 2H), 2.83 (t, J = 6.4
Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3)
δ
162.1, 159.7, 147.4, 132.3, 131.3, 125.8, 124.7,
116.4, 60.2, 18.0; IR (film) 2252, 1734, 1273, 1175, 1071 cmꢀ1; HRMS (EI) m/z [M]+ Calcd for
C12H879BrN3O2S: 336.9521, C12H881BrN3O2S: 338.9500, Found: 336.9519, 338.9507.
2-Cyanoethyl 5-(4-nitrophenyl)-1,2,3-thiadiazole-4-carboxylate (1f): 200.8 mg, 66%, White soli
o
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d, Melting point: 121ꢀ122 C, Rf = 0.2 (Et2O:DCM:Hx = 1:3:5), H NMR (400 MHz, CDCl3)
δ
8.37 (td, J = 9.1, 2.1 Hz, 2H), 7.73 (td, J = 9.1, 2.1 Hz, 2H), 4.59 (t, J = 6.3 Hz, 2H), 2.84 (t, J =
6.3 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3)
δ
160.4, 159.4, 149.3, 148.1, 132.4, 131.0, 124.0,
116.4, 60.4, 18.1 cmꢀ1; HRMS (EI) m/z [M]+ Calcd for C12H8N4O4S: 304.0266, Found:
304.0262.
2-Cyanoethyl 5-(furan-2-yl)-1,2,3-thiadiazole-4-carboxylate (1g): 59.8 mg, 24%, White solid, M
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elting point: 137ꢀ138 C, Rf = 0.2 (EtOAc:Hx = 1:2), H NMR (400 MHz, CDCl3)
δ 7.87 (dd,
J = 3.7, 0.6 Hz, 1H), 7.67ꢀ7.66 (m, 1H), 6.67 (q, J = 1.8 Hz, 1H), 4.71 (t, J = 6.6 Hz, 2H), 2.96 (t, J
= 6.6 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3)
δ
160.4, 151.9, 147.1, 143.7. 142.9, 117.9,
116.5, 113.7, 60.1, 18.2; IR (film) 1725, 1575, 1484, 1277, 1177, 1146, 881, 767, 591 cmꢀ1; HRM
S (EI) m/z [M]+ Calcd for C10H7N3O3S: 249.0208, Found: 249.0207.
2-Cyanoethyl 5-(thiophen-2-yl)-1,2,3-thiadiazole-4-carboxylate (1h): 217.6 mg, 82%, White soli
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d, Melting point: 116ꢀ118 C, Rf = 0.2 (Et2O:DCM:Hx = 1:3:5), H NMR (400 MHz, CDCl3)
δ
7.75 (dd, J = 3.8, 1.2 Hz, 1H), 7.67 (dd, J = 5.1, 1.2 Hz, 1H), 7.20 (dd, J = 5.1, 3.8 Hz, 1H), 4.68
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(t, J = 6.6, 2H), 2.93 (t, J = 6.6, 2H); 13C{1H} NMR (100 MHz, CDCl3)
δ 160.3, 156.5, 145.2,
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133.7, 132.5, 128.7, 125.8, 116.4, 60.3, 18.1; IR (film) 3106, 3062, 2251, 1726, 1167, 734 cmꢀ1; H
RMS (FAB) m/z [M + H]+ Calcd for C10H8N3O2S2: 266.0058, Found: 266.0060.
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2-Cyanoethyl 5-(thiophen-3-yl)-1,2,3-thiadiazole-4-carboxylate (1i): 212.2 mg, 80%, White soli
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d, Melting point: 101ꢀ102 C, Rf = 0.2 (Et2O:DCM:Hx = 1:3:5), H NMR (400 MHz, CDCl3)
δ
8.07(dd, J = 3.0, 1.3 Hz, 1H), 7.48 (dd, J = 5.1, 3.0 Hz, 1H), 7.38 (dd, J = 5.1, 3.0 Hz, 1H), 4.65 (t,
J = 6.5 Hz, 2H), 2.89 (t, J = 6.5 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3)
δ
160.3, 157.6,
146.4, 129.8, 129.2, 127.3, 125.1, 116.5, 60.2, 18.1; IR (film) 3104, 1730, 1529, 1306, 1196, 1028,
947, 779, 627 cmꢀ1; HRMS (EI) m/z [M]+ Calcd for C10H7N3O2S2: 264.9980, Found: 264.9981.
2-Cyanoethyl 5-methyl-1,2,3-thiadiazole-4-carboxylate (1j): 195.2 mg, 99%, White solid, Meltin
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g point: 85ꢀ86 C, Rf = 0.3 (EtOAc:Hx = 1:2), H NMR (400 MHz, CDCl3)
δ 4.65 (t, J = 6.4
Hz, 2H), 2.93ꢀ2.91 (m, 5H); 13C{1H} NMR (100 MHz, CDCl3)
δ
161.3, 160.3, 149.4, 116.6,
60.0, 18.2, 11.3; IR (film) 2969, 2253, 1729, 1497, 1385, 1212, 1183, 906, 862, 530 cmꢀ1; HRMS
(EI) m/z [M]+ Calcd for C7H7N3O2S: 197.0259, Found: 197.0257.
2-Cyanoethyl 5-cyclohexyl-1,2,3-thiadiazole-4-carboxylate (1k): 225.5 mg, 85%, Yellow solid,
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Melting point: 94ꢀ95 C, Rf = 0.1 (Et2O:DCM:Hx = 1:3:5), H NMR (400 MHz, CDCl3)
δ
4.65 (t, J = 6.5 Hz, 2H), 3.73 (tt, J = 3.4, 17.5 Hz, 1H), 2.92 (t, J = 6.5 Hz, 2H), 2.13 (t, J = 6.2 Hz,
2H), 1.88ꢀ1.77 (m, 3H), 1.53ꢀ 1.42 (m, 2H), 1.38ꢀ1.23 (m, 3H); 13C{1H} NMR (100 MHz, CDCl
)
δ 174.0, 160.2, 147.4, 116.6, 59.9, 37.2, 36.2, 26.3, 25.5, 18.2; IR (film) 2931, 2853, 1730, 1488,
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1316, 1132, 1005, 892, 847, 653 cmꢀ1; HRMS (EI) m/z [M]+ Calcd for C12H15N3O2S: 265.0885,
Found: 265.0887.
1-Cyanoethyl 5-phenyl-1,2,3-thiadiazole-4-carboxylate (1l): 189.3 mg, 73%, White solid, Meltin
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g point: 82ꢀ83 C, Rf = 0.5 (EtOAc:Hx = 1:3), H NMR (400 MHz, CDCl3)
δ 7.58ꢀ7.52(m,
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5H), 5.61 (q, J = 6.9 Hz, 1H), 1.72 (d, J = 6.9 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ
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164.1, 158.8, 146.6, 131.3, 129.9, 129.0, 125.6, 116.9, 58.6, 18.8; IR (film) 1739, 1472, 1276,
1164, 1043, 845, 749, 692, 553 cmꢀ1; HRMS (EI) m/z [M]+ Calcd for C12H9N3O2S: 259.0415, F
ound: 259.0417.
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2-Cyanopropan-2-yl 5-phenyl-1,2,3-thiadiazole-4-carboxylate (1m): 96.7 mg, 35%, Ivory solid,
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Melting point: 82ꢀ83 C, Rf = 0.5 (EtOAc:Hx = 1:3), H NMR (400 MHz, CDCl3)
δ 7.56ꢀ
7.27(m, 5H), 1.82 (d, J = 0.4 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3)
δ
163.3, 158.4, 147.4,
131.0, 129.8, 129.0, 125.8, 118.8, 70.2, 26.9; IR (film) 1743, 1470, 1389, 1348, 1179, 987, 848,
754, 695 cmꢀ1; HRMS (EI) m/z [M]+ Calcd for C13H11N3O2S: 273.0572, Found: 273.0575.
1-Cyanocyclohexyl 5-phenyl-1,2,3-thiadiazole-4-carboxylate (1n): 150.4 mg, 48%, Yellow solid,
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Melting point: 90ꢀ91 C, Rf = 0.4 (EtOAc:Hx = 1:2), H NMR (400 MHz, CDCl3)
7.45(m, 5H), 2.31ꢀ2.28 (m, 2H), 1.91ꢀ1.85 (m, 2H), 1.72ꢀ, 1.57 (m ,5H), 1.35ꢀ1.29 (m, 1H); 13C
{1H} NMR (100 MHz, CDCl3)
δ 7.54ꢀ
δ
163.0, 158.1, 147.5, 130.9, 129.7, 128.9, 125.8, 117.9, 74.5,
35.0, 24.4, 22.0; IR (film) 2941, 2863, 1742, 1470, 1334, 1279, 1028, 951, 844, 754 cmꢀ1; HRMS
(EI) m/z [M]+ Calcd for C16H15N3O2S: 313.0885, Found: 313.0882.
1-Cyanohexan-2-yl 5-phenyl-1,2,3-thiadiazole-4-carboxylate (1o): 227.1 mg, 72%, Orange oil,
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Rf = 0.6 (EtOAc:Hx = 1:2), H NMR (400 MHz, CDCl3)
δ 7.56ꢀ7.50 (m, 5H), 5.26 (dq, J = 8.1,
5.4 Hz, 1H), 2.74 (ddd, J = 48.1, 17.0, 5.5 Hz, 2H), 1.81ꢀ1.63 (m, 2H), 1.35ꢀ1.19 (m, 4H), 0.87 (t, J
= 7.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ
162.7, 159.7, 148.1, 130.9, 129.8, 128.8,
126.0, 116.1, 70.9, 33.0, 27.1, 23.0, 22.3, 13.9; IR (film) 2251, 1733, 1177 cmꢀ1; HRMS (EI) m/z
[M]+ Calcd for C16H17N3O2S: 315.1041, Found: 315.1044.
2-Cyano-1-phenylethyl 5-phenyl-1,2,3-thiadiazole-4-carboxylate (1p): 218.0 mg, 65%, White so
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lid, Melting point: 124ꢀ126 C, Rf = 0.5 (EtOAc:Hx = 1:2), H NMR (400 MHz, CDCl3)
δ
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7.56ꢀ7.46 (m, 5H), 7.35ꢀ7.26 (m, 5H), 6.23 (t, J = 6.3 Hz, 1H), 2.94 (d, J = 6.4 Hz, 2H); 13C{1H} N
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4
5
MR (100 MHz, CDCl3)
δ 163.0, 159.1, 147.8, 136.4, 130.9, 129.8, 129.6, 129.1, 128.0, 126.4,
126.0, 115.9, 72.4, 25.6; IR (film) 2252, 1736, 1172, 1002 cmꢀ1; HRMS (EI) m/z [M]+ Calcd for
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C18H13N3O2S: 335.0728, Found: 335.0726.
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2-Cyano-1-(p-tolyl)ethyl 5-phenyl-1,2,3-thiadiazole-4-carboxylate (1q): 223.6 mg, 64%, Ivory
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solid, Melting point: 107ꢀ109 C, Rf = 0.6 (EtOAc:Hx = 1:2), H NMR (400 MHz, CDCl3)
7.56ꢀ7.46 (m, 5H), 7.18ꢀ7.13 (m, 4H), 6.20 (t, J =6.4 Hz, 1H), 2.93ꢀ2.91 (m, 2H), 2.33 (s, 3H); 13C
{1H} NMR (100 MHz, CDCl3)
δ
δ
162.9, 159.0, 147.8, 139.5, 133.4, 130.8, 129.8, 129.7, 128.9,
126.4, 126.0, 116.0, 72.3, 25.6, 21.3; IR (film) 2251, 1736, 1172 cmꢀ1; HRMS (EI) m/z [M]+
Calcd for C19H15N3O2S: 349.0885, Found: 349.0883.
2-(Cyanomethyl)cyclohexyl 5-phenyl-1,2,3-thiadiazole-4-carboxylate (1r): 188.0 mg, 60%,
1
Orange oil, Rf = 0.4 (EtOAc:Hx = 1:4), H NMR (400 MHz, CDCl3)
δ 7.56ꢀ7.48 (m, 5H),
5.20(dt, J = 3.9, 9.0 Hz, 1H), 2.68 (dt, J = 4.0, 9.7 Hz, 1H), 2.20ꢀ2.07 (m, 2H), 1.77ꢀ1.64 (m, 3H),
1.53ꢀ1.38 (m, 2H), 1.34ꢀ1.26 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3)
δ
162.7, 159.2, 148.0,
130.8, 129.8, 128.8, 126.1, 119.8, 73.1, 33.5, 30.1, 27.8, 23.4, 22.7; IR (film) 2243, 1733, 1178
cmꢀ1; HRMS (EI) m/z [M]+ Calcd for C16H15N3O2S: 313.0885, Found: 313.0883.
2-Cyanophenyl 5-phenyl-1,2,3-thiadiazole-4-carboxylate (1s): 298.1 mg, 97%, White solid, Rf =
o
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0.3 (EtOAc:Hx = 1:2), Melting point: 76ꢀ77 C, H NMR (400 MHz, CDCl3)
δ 7.73ꢀ7.69 (m,
13
1H), 7.67ꢀ7.65 (m, 1H), 7.64ꢀ7.62 (m, 2H), 7.54ꢀ 7.46 (m, 3H), 7.42ꢀ7.38 (m, 2H); C{1H} NMR
(100 MHz, CDCl3) 165.0, 158.0, 151.8, 146.2, 134.4, 133.6, 131.2, 129.9, 129.0, 127.1, 125.4,
δ
123.3, 115.1, 107.5; IR (film) 2233, 1756, 1449, 1324, 1224, 1136, 947, 845, 694 cmꢀ1; HRMS
(EI) m/z [M]+ Calcd for C16H9N3O2S: 307.0415, Found: 307.0417.
2-Cyano-4-methylphenyl 5-phenyl-1,2,3-thiadiazole-4-carboxylate (1t): 181.9 mg, 57%, Light
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o
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orange solid, Melting point: 124ꢀ126 C Rf = 0.3 (EtOAc:Hx = 1:4), H NMR (400 MHz, CDC
3
4
5
13
l3)
δ
7.63ꢀ7.61 (m, 2H), 7.54ꢀ7.44 (m, 5H), 7.26 (d, J = 8.4 Hz, 1H), 2.40 (s, 3H); C{1H} NMR
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7
(100 MHz, CDCl3)
δ
164.9, 158.3, 149.7, 146.4, 137.4, 135.1, 133.7, 131.2, 130.0, 129.0, 125.5,
8
9
123.0, 115.3, 107.2, 20.8; IR (film) 2233, 1754, 1205, 1138 cmꢀ1; HRMS (EI) m/z [M]+ Calcd
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for C17H11N3O2S: 321.0572, Found: 321.0569.
4-Bromo-2-cyanophenyl 5-phenyl-1,2,3-thiadiazole-4-carboxylate (1u): 77.2 mg, 20%, Yellow
o
1
solid, Melting point: 93ꢀ94 C, Rf = 0.4 (EtOAc:Hx = 1:2), H NMR (400 MHz, CDCl3)
δ
7.83 (d, J = 2.4 Hz, 1H), 7.77 (dd, J = 2.4, 8.8 Hz, 1H), 7.62ꢀ7.59 (m, 2H), 7.53ꢀ7.4 (m, 3H), 7.29
(d, J = 8.8 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3)
δ
165.2, 157.6, 150.9, 145.9, 137.5, 135.9,
131.3, 129.9, 129.0, 125.3, 124.9, 119.8, 113.7, 109.3; IR (film) 2236, 1755, 1468, 1329, 1280,
1176, 1133, 854, 694 cmꢀ1; HRMS (EI) m/z [M]+ Calcd for C16H879BrN3O2S: 384.9521, C16H8
81
BrN3O2S: 386.9501, Found: 384.9521, 386.9494.
1-Cyanonaphthalen-2-yl 5-phenyl-1,2,3-thiadiazole-4-carboxylate (1v): 164.4 mg, 46%,
o
1
Organge solid, Melting point: 116ꢀ118 C, Rf = 0.3 (EtOAc:Hx = 1:4), H NMR (400 MHz, C
DCl3)
δ 8.22, (d, J = 8.1 Hz, 1H), 8.13 (d, J = 9.0 Hz, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.74 (ddd, J =
7.0, 8.3, 1.2 Hz, 1H), 7.68ꢀ7.61 (m, 3H), 7.54ꢀ7.46 (m, 4H); 13C{1H} NMR (100 MHz, CDCl3)
δ
165.1, 158.1, 152.3, 146.4, 134.8, 132.9, 131.28, 131.22, 130.0, 129.6, 129.0, 128.8, 127.7, 125.5,
125.3, 121.0, 114.2, 103.6; IR (film) 2232, 1754, 1216, 1133 cmꢀ1; HRMS (EI) m/z [M]+ Calcd
for C20H11N3O2S: 357.0572, Found: 357.0569.
3-Cyanopropyl 5-phenyl-1,2,3-thiadiazole-4-carboxylate (1w): 153.1 mg, 56%, Ivory solid, Melt
o
1
ing point: 50ꢀ52 C, Rf = 0.4 (EtOAc:Hx = 1:2), H NMR (400 MHz, CDCl3)
δ 7.59ꢀ7.49 (m,
5H), 4.45 (t, J = 5.9 Hz, 2H), 2.29 (t, J = 7.2 Hz, 2H), 2.08ꢀ2.01 (m, 2H); 13C{1H} NMR (100 MH
z, CDCl3)
δ
162.4, 160.1, 148.2, 130.9, 129.7, 128.9, 126.2, 118.7, 63.5, 24.8, 14.2; IR (film)
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2249, 1733, 1336, 1180 cmꢀ1; HRMS (EI) m/z [M]+ Calcd for C13H11N3O2S: 273.0572, Found:
3
4
5
273.0572.
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7
2-(Cyanomethyl) phenyl-5-phenyl-1,2,3-thiadiazole-4-carboxylate (1x): 196.0 mg, 61%, White s
8
9
o
1
olid, Melting point: 96ꢀ98 C, Rf = 0.4 (EtOAc:Hx = 1:2), H NMR (400 MHz, CDCl3)
δ
10
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7.62ꢀ7.59 (m, 2H), 7.56ꢀ7.47 (m, 4H), 7.43ꢀ7.39 (m, 1H), 7.35ꢀ7.30 (m, 2H), 3.67 (s, 2H); 13C{1H}
NMR (100 MHz, CDCl3)
δ 164.3, 158.2, 148.2, 147.0, 131.2, 130.0, 129.8, 129.7, 129.0, 127.2,
125.6, 122.7, 122.6, 116.9, 19.1; IR (film) 2251, 1751, 1215, 1171, 1145 cmꢀ1; HRMS (EI) m/z
[M]+ Calcd for C17H11N3O2S: 321.0572, Found: 321.0574.
1-(2-Cyanoethyl)naphthalen-2-yl 5-phenyl-1,2,3-thiadiazole-4-carboxylate (1y): 289.1 mg, 75%,
o
1
Pink solid, Melting point: 112ꢀ113 C, Rf = 0.4 (EtOAc:DCM:Hx = 1:2:5), H NMR (400 MHz,
CDCl3)
3H), 7.55ꢀ7.47 (m, 4H), 7.40 (d, J = 8.9 Hz, 1H), 3.39 (t, J = 8.0 Hz, 2H), 2.59 (t, J = 8.0 Hz, 2H); 1
3C{1H} NMR (100 MHz, CDCl3)
δ 7.96 (d, J = 8.5 Hz, 1H), 7.89 (d, J = 7.7 Hz, 1H), 7.84 (d, J = 9.0 Hz, 1H), 7.65ꢀ7.58 (m,
δ
164.2, 159.1, 147.3, 146.4, 132.3, 132.0 131.2, 130.0, 129.4,
129.3, 129.0, 127.6, 126.1, 125.8, 124.7, 123.1, 121.2, 119.2, 22.3, 17.4; IR (film) 2247, 1745,
1207, 1146 cmꢀ1; HRMS (FAB) m/z [M + H]+ Calcd for C22H16N3O2S: 386.0963, Found:
386.0964.
N-(2-Cyanoethyl)-5-phenyl-1,2,3-thiadiazole-4-carboxamide (3a): 90.4 mg, 35%, White solid,
o
1
Melting point: 87ꢀ89 C, Rf = 0.1 (DCM), H NMR (400 MHz, CDCl3)
δ 8.12 (br s, 1H), 7.65ꢀ
7.62 (m, 2H), 7.54ꢀ7.46 (m, 3H), 3.75 (q, J = 6.5 Hz, 2H), 2.75 (t, J = 6.6 Hz, 2H); 13C{1H} NMR
(100 MHz, CDCl3)
δ 161.3, 160.2, 149.0, 130.9, 130.2, 128.7, 125.8, 117.9, 36.0, 18.5; IR (film)
3347, 3061, 2932, 2250, 1672, 1535, 1503, 1075 cmꢀ1; HRMS (EI) m/z [M]+ Calcd for C12H10N4
OS: 258.0575, Found: 258.0577.
Preparation of 3b14
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The solution of thiadiazoleꢀ4ꢀcarboxylic acid (5a)12 (412.44 mg, 2.0 mmol) and SOCl2 (2.0 mmol)
3
4
5
o
was stirred at 60 C for 3 h. After stirring for 3 h, the redundant SOCl2 was evaporated under
6
7
8
9
reduced pressure and then dropwised amine in DCM (0.2 M) (6) and strred at room temperature for
1 h. The organic phase was washed with aqueous HCl and aqueous K2CO3, then dried by anhydrous
MgSO4. After evaporating the DCM, the Nꢀ(2ꢀcyanoethyl)ꢀNꢀmethylꢀ5ꢀphenylꢀ1,2,3ꢀthiadiazoleꢀ4ꢀ
carboxamide was obtained and used in the next step directly.
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N-(2-Cyanoethyl)-N-methyl-5-phenyl-1,2,3-thiadiazole-4-carboxamide (3b): 60 mg, 11%,
o
1
White solid, Melting point: 104ꢀ105 C, Rf = 0.2 (EtOAc:Hx=1:2), H NMR (400 MHz, CDCl3)
δ
7.57ꢀ7.47 (m, 5H), 3.85 (t, J = 6.5 Hz, 1.5 H), 3.61 (t, J = 7.0 Hz, 0.5 H), 3.26 (s, 1H), 3.04 (s,
2H), 2.80 (t, J = 6.5 Hz, 1.5 H), 2.72 (t, J = 7.0 Hz, 0.5 H); 13C{1H} NMR (100 MHz, CDCl3)
δ
163.6, 162.7, 157.8, 156.2, 151.5, 151.3, 131.1, 131.0, 129.7, 129.5, 129.4, 129.0, 126.2, 126.1,
117.9, 117.3, 47.3, 44.9, 38.1, 34.1, 17.7, 15.9; IR (film) 2233, 1756, 1471, 1449, 1329, 1136, 947,
845, 694 cmꢀ1; HRMS (EI) m/z [M]+ Calcd for C13H12N4OS: 272.0732, Found: 272.0734.
Preparation of 3c, 3d, and 3e
To an ovenꢀdried roundꢀbottom flask equipped with a magnetic stirring bar under a nitrogen
atmosphere was added (1,2,3ꢀthiadiazolꢀ4ꢀyl)methanol (7)15 (3.0 mmol) and DMF (9.0 mL). Dry
sodium hydride (95%) (216 mg, 9.0 mmol) was added and the mixture was stirred at room
temperature for 30 min. 8 (15.0 mmol) was added and the mixture was stirred at 100 oC for 2 h. All
volatiles were removed in vacuo and the resulting residue was partitioned between water and
EtOAc. The layers were separated and the aqueous layer was extracted with ethyl acetate. The
combined organic layers were washed with brine, and then dried over MgSO4. The solvent was
removed in vacuo, and purified by silica gel chromatography (EtOAc:Hexane = 1:5) to provide the
product 3.16
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3-((5-Phenyl-1,2,3-thiadiazol-4-yl)methoxy)propanenitrile (3c): 264.9 mg, 36%, Yellow solid, M
3
4
5
o
1
elting point: 54ꢀ56 C, Rf = 0.5 (Et2O:Hx = 1:1), H NMR (400 MHz, CDCl3)
δ 7.64ꢀ7.62 (m,
2H), 7.54ꢀ7.52 (m, 3H), 4.97 (s, 2H), 3.89 (t, J = 6.2 Hz, 2H), 2.67 (t, J = 6.2 Hz, 2H); 13C{1H} N
6
7
8
9
MR (100 MHz, CDCl3)
δ 156.6, 154.3, 130.5, 129.7, 129.6, 127.3, 117.8, 65.1, 64.2, 19.1; IR (fi
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lm) 3061, 2918, 2873, 2251, 1245, 1100 cmꢀ1; HRMS (FAB) m/z [M + H]+ Calcd for
C12H12N3OS: 246.0701, Found: 246.0702.
4-((5-Phenyl-1,2,3-thiadiazol-4-yl)methoxy)butanenitrile (3d): 116.7 mg, 15%, Yellow oil, Rf =
1
0.3 (Et2O:DCM:Hx = 1:1:1), H NMR (400 MHz, CDCl3)
δ 7.61ꢀ7.56 (m, 2H), 7.55ꢀ7.51 (m,
3H), 4.94 (s, 2H), 3.74 (t, J = 5.7 Hz, 2H), 2.44 (t, J = 7.1 Hz, 2H), 2.00ꢀ1.93 (m, 2H); 13C{1H} N
MR (100 MHz, CDCl3) 155.9, 154.8, 130.4, 129.55, 129.51, 127.5, 119.4, 68.0, 64.3, 25.8,
δ
14.2; IR (film) 3062, 2931, 2869, 2249, 1104, 697 cmꢀ1; HRMS (FAB) m/z [M + H]+ Calcd for
C13H14N3OS: 260.0858, Found: 260.0860.
5-((5-Phenyl-1,2,3-thiadiazol-4-yl)methoxy)pentanenitrile (3e): 599 mg, 73%, Yellow oil, Rf =
1
0.6 (Et2O:DCM:Hx = 1:1:1), H NMR (400 MHz, CDCl3)
δ 7.61ꢀ7.58 (m, 2H), 7.58ꢀ7.50 (m,
3H), 4.91 (s, 2H), 3.66 (t, J = 5.7 Hz, 2H), 2.35 (t, J = 6.8 Hz, 2H), 1.82ꢀ1.70 (m, 4H); 13C{1H} N
MR (100 MHz, CDCl3) 155.7, 155.1, 130.4, 129.6, 129.5, 127.6, 119.7, 69.5, 64.1, 28.7, 22.6,
δ
17.1; IR (film) 3062, 2244, 1245, 1094, 834, 768, 697 cmꢀ1; HRMS (FAB) m/z [M + H]+ Calcd
for C14H16N3OS: 274.1014, Found: 274.1016.
General Procedure for the Intramolecular Transannulation
To a test tube were added [Rh(COD)Cl]2 (4.9 mg, 0.01 mmol), DPPF (13.3 mg, 0.024 mmol), and
cyanothiadiazoles (1) (0.2 mmol) in chlorobenzene (1.0 mL). The resulting mixture was stirred at
130 oC for 1 h under a nitrogen atmosphere. After Celite filtration and evaporation of the solvents in
vacuo, the crude product was purified by silica gel column chromatography (EtOAc:Hexane = 1:4)
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to provide the product 2 and 4.
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4
5
3-Phenyl-6,7-dihydro-4H-pyrano[4,3-c]isothiazol-4-one (2a): 42 mg, 91%, White solid, Melting
6
7
8
9
1
point: 70ꢀ71 °C, Rf = 0.3 (EtOAc:Hx = 1:2), H NMR (400 MHz, CDCl3)
δ 7.71ꢀ7.69 (m, 2H),
7.50ꢀ7.46 (m, 3H), 4.60ꢀ4.57 (m, 2H), 3.24ꢀ3.21 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3)
δ
10
11
12
13
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176.6, 168.3, 161.0, 131.0, 129.3, 128.9, 128.7, 119.4, 67.0, 29.3; IR (film) 1729, 1533, 1274, 1082,
751, 601, 550, 514 cmꢀ1; HRMS (EI) m/z [M]+ Calcd for C12H9NO2S: 231.0354, Found: 231.0354.
3-(p-Tolyl)-6,7-dihydro-4H-pyrano[4,3-c]isothiazol-4-one (2b): 47 mg, 96%, White solid,
Melting point: 119ꢀ120 °C, Rf = 0.3 (EtOAc:Hx = 1:3), 1H NMR (400 MHz, CDCl3)
2H), 7.29 (d, J = 7.9 Hz, 2H), 4.58 (t, J = 6.0 Hz, 2H), 3.22 (t, J = 6.0 Hz, 2H), 2.42 (s, 3H); 13C
{1H} NMR (100 MHz, CDCl3)
δ 7.63ꢀ7.60 (m,
δ
176.9, 168.3, 161.2, 141.5, 129.6, 129.2, 125.9, 119.1, 67.0, 29.4,
21.6; IR (film) 1730, 1527, 1433, 1374, 1157, 1036, 808, 701 cmꢀ1; HRMS (EI) m/z [M]+ Calcd for
C13H11NO2S: 245.0510, Found : 245.0511.
3-(4-Methoxyphenyl)-6,7-dihydro-4H-pyrano[4,3-c]isothiazol-4-one (2c): 50 mg, 96%,; White
1
solid, Melting point: 131ꢀ132 °C, Rf = 0.2 (EtOAc:Hx = 1:3), H NMR (400 MHz, CDCl3)
δ 7.71
(td, J = 2.2, 9.7 Hz, 2H), 6.99 (dd, J = 1.6, 7.0 Hz, 2H), 4.57 (t, J = 6.0Hz, 2H), 3.87 (s, 3H), 3.20 (t,
J = 6.0 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3)
δ
176.6, 168.4, 162.0, 161.4, 131.0, 121.1,
118.5, 114.4, 67.0, 55.6, 29.4; IR (film) 2929, 1729, 1536, 1433, 1254, 1083, 825, 702, 591 cmꢀ1;
HRMS (EI) m/z [M]+ Calcd for C13H11NO3S: 261.0460, Found: 261.0462.
3-(Benzo[d][1,3]dioxol-5-yl)-6,7-dihydro-4H-pyrano[4,3-c]isothiazol-4-one (2d): 50 mg, 91%,
Yellow oil, Rf = 0.7 (EtOAc:Hx = 1:2), 1H NMR (400 MHz, CDCl3)
= 8.0 Hz, 1H), 6.05 (s, 2H), 4.57 (t, J = 6.0 Hz, 2H), 3.21 (t, J = 6.0 Hz, 2H); 13C{1H} NMR (100
δ 7.26ꢀ7.22 (m, 2H), 6.89 (d, J
MHz, CDCl3)
δ 176.4, 168.3, 161.2, 150.2, 148.2, 124.1, 122.4, 118.9, 109.7, 108.7, 101.9, 67.0,
29.4; IR (film) 1728, 1534, 1487, 1234, 1109, 1036, 930, 864 cmꢀ1; HRMS (EI) m/z [M]+ Calcd for
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C13H9NO4S: 275.0252, Found : 275.0250.
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3-(4-Bromophenyl)-6,7-dihydro-4H-pyrano[4,3-c]isothiazol-4-one (2e): 56 mg, 90%, White
6
7
8
9
1
solid, Melting point: 143ꢀ144 °C, Rf = 0.3 (EtOAc:Hx = 1:2), H NMR (400 MHz, CDCl3)
δ 7.63ꢀ
7.58 (m, 4H), 4.60 (t, J = 6.0 Hz, 2H), 3.24 (t, J = 6.0 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3)
δ
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175.1, 168.4, 161.0, 132.2, 130.8, 127.6, 125.7, 119.6, 67.1, 29.3; IR (film) 1727, 1531, 1486, 1280,
1083, 1009, 812, 606, 522 cmꢀ1; HRMS (EI) m/z [M]+ Calcd for C12H879BrNO2S: 308.9459,
C12H881BrNO2S: 310.9439, F ound: 308.9458, 310.9446.
3-(4-Nitrophenyl)-6,7-dihydro-4H-pyrano[4,3-c]isothiazol-4-one (2f): 51 mg, 92%, White solid,
Melting point: 121ꢀ122 °C, Rf = 0.3 (EtOAc:Hx = 1:3), 1H NMR (400 MHz, CDCl3)
2.1, 6.9 Hz, 2H), 7.88 (dd, J = 2.1, 6.9 Hz, 2H), 4.63 (t, J = 6.1 Hz, 2H), 3.28 (t, J = 6.0 Hz, 2H); 13
C{1H} NMR (100 MHz, CDCl3)
δ 8.34 (dd, J =
δ
173.1, 168.6, 160.7, 149.1, 134.8, 130.5, 124.0, 120.7, 67.3,
29.2; IR (film) 1735, 1514, 1348, 1279, 1348, 1279, 1084, 825, 746 cmꢀ1; HRMS (EI) m/z [M]+
Calcd for C12H8N2O4S: 276.0205, Found : 276.0205.
3-(Furan-2-yl)-6,7-dihydro-4H-thieno[3,4-c]pyran-4-one (2g): 40 mg, 91%, White solid, Melting
point: 150ꢀ151 °C, Rf = 0.5 (EtOAc:Hx = 1:2), 1H NMR (400 MHz, CDCl3)
1H), 7.58 (d, J = 7.6 Hz, 1H), 7.27 (s, 1H), 4.56 (t, J = 6.1 Hz, 2H), 3.18 (t, J = 6.1 Hz, 2H); 13C
{1H} NMR (100 MHz, CDCl3)
δ 7.98 (d, J = 3.6 Hz,
δ
167.8, 163.0, 161.5, 145.4, 145.3, 117.0, 116.2, 113.5, 67.0, 29.0;
IR (film) 1723, 1578, 1528, 1381, 1278, 1141, 1034, 870, 782, 700, 509 cmꢀ1; HRMS (EI) m/z [M]+
Calcd for C10H7NO3S: 221.0147, Found : 221.0147.
3-(Thiophen-2-yl)-6,7-dihydro-4H-pyrano[4,3-c]isothiazol-4-one (2h): 38.1 mg, 80%, Yellow so
o
1
lid, Melting point: 72ꢀ74 C, Rf = 0.4 (Et2O:DCM:Hx = 1:1:2), H NMR (400 MHz, CDCl3)
δ
7.94 (dd, J = 3.8, 1.1 Hz, 1H), 7.60 (dd, J = 5.1, 1.1 Hz, 1H), 7.17 (dd, J = 5.1, 3.8 Hz, 1H), 4.56 (t,
J = 6.0 Hz, 2H), 3.19 (t, J = 6.1 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3)
δ 168.4, 168.3,
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161.4, 131.7, 131.4, 129.5, 128.3, 117.7, 66.9, 29.3; IR (film) 3104, 1725, 1536, 1278, 1220, 1153,
3
4
5
1084, 702 cmꢀ1; HRMS (EI) m/z [M]+ Calcd for C10H7NO2S2: 236.9918, Found: 236.9915.
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7
3-(Thiophen-3-yl)-6,7-dihydro-4H-pyrano[4,3-c]isothiazol-4-one (2i): 43 mg, 90%, White solid,
8
9
Melting point: 126ꢀ127 °C, Rf = 0.4 (EtOAc:Hx = 1:2),1H NMR (400 MHz, CDCl3)
δ 8.47 (dd, J =
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1.3, 3.0 Hz, 1H), 7.52 (dd, J = 1.3, 5.1 Hz, 1H), 7.42 (dd, J = 3.0, 5.1 Hz, 1H), 4.56 (t, J = 6.0 Hz,
2H), 3.21 (t, J = 6.0 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3)
δ
169.9, 168.5, 161.5, 129.4, 128.7,
128.0, 126.8, 118.5, 66.9, 29.3; IR (film) 1720, 1540, 1378, 1269, 1145, 1036, 982, 800, 780 cmꢀ1;
HRMS (EI) m/z [M]+ Calcd for C10H7NO2S2: 236.9918, Found : 236.9921.
3-Methyl-6,7-dihydro-4H-pyrano[4,3-c]isothiazol-4-one (2j): 32 mg, 95%, White solid, Melting
point: 89ꢀ90 °C, Rf = 0.5 (EtOAc:Hx = 1:2), 1H NMR (400 MHz, CDCl3)
3.15 (t, J = 6.1 Hz, 2H), 2.86 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ
4.53 (t, J = 6.1 Hz, 2H),
174.5, 167.4, 162.0,
δ
121.5, 67.5, 29.0, 13.4; IR (film) 2919, 1725, 1540, 1264, 1074, 1053, 1009, 781, 701cmꢀ1; HRMS
(EI) m/z [M]+ Calcd for C7H7NO2S: 169.0197, Found : 169.0199.
3-Cyclohexyl-6,7-dihydro-4H-pyrano[4,3-c]isothiazol-4-one (2k): 43 mg, 91%, White solid,
Melting point: 101ꢀ102 °C, Rf = 0.7 (EtOAc:Hx = 1:2), 1H NMR (400 MHz, CDCl3)
δ 4.52 (t, J =
6.1 Hz, 2H), 3.72 (tt, J = 3.4, 17.4 Hz, 1H), 3.15 (t, J = 6.1 Hz, 2H), 2.17ꢀ2.14 (m, 2H), 1.87ꢀ1.76
(m, 3H), 1.55ꢀ1.23 (m, 5H); 13C{1H} NMR (100 MHz, CDCl3)
δ
187.4, 167.3, 161.7, 119.6, 67.1,
38.6, 34.7, 28.9, 26.3, 25.8; IR (film) 2927, 1728, 1536, 1261, 1123, 1071, 1023, 786, 706 cmꢀ1;
HRMS (EI) m/z [M]+ Calcd for C12H15NO2S: 237.0823, Found : 237.0826.
6-Methyl-3-phenylfuro[3,4-c]isothiazol-4(6H)-one (2l): 42 mg, 91%, White solid, Melting point:
125ꢀ136 °C, Rf = 0.4 (EtOAc:Hx= 1:2), 1H NMR (400 MHz, CDCl3)
(m, 3H), 5.46 (q, J = 6.7 Hz, 1H), 1.72 (d, J = 6.7 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ 8.12ꢀ8.10 (m, 2H), 7.52ꢀ7.50
δ
182.7, 171.8, 161.9, 132.0, 130.0, 128.6, 128.4, 122.5, 76.1, 19.3; IR (film) 1757, 1551, 1466, 1303,
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1117, 1048, 936, 759, 687 cmꢀ1; HRMS (EI) m/z [M]+ Calcd for C12H9NO2S: 231.0354, Found:
3
4
5
231.0356.
6
7
6,6-Dimethyl-3-phenylfuro[3,4-c]isothiazol-4(6H)-one (2m): 45 mg, 92%, White solid, Melting
8
9
1
point: 134ꢀ135 °C, Rf = 0.5 (EtOAc:Hx = 1:2), H NMR (400 MHz, CDCl3)
δ
8.13ꢀ8.11 (m, 2H),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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29
30
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43
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45
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47
48
49
50
51
52
53
54
55
56
57
58
59
60
7.52ꢀ7.49 (m, 3H), 1.74 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3)
δ 185.5, 171.8, 161.4, 131.9,
129.6, 128.6, 128.4, 122.0, 83.9, 26.1; IR (film) 1747, 1547, 1446, 1363, 1280, 1182, 1106, 900,
789, 686 cmꢀ1; HRMS (EI) m/z [M]+ Calcd for C13H11NO2S: 245.0510, Found: 245.0512.
3'-Phenyl-4'H-spiro[cyclohexane-1,6'-furo[3,4-c]isothiazol]-4'-one (2n): 53 mg, 93%, White
1
solid, Melting point: 119ꢀ120 °C, Rf = 0.6 (EtOAc:Hx = 1:2), H NMR (400 MHz, CDCl3)
δ 8.13ꢀ
8.11 (m, 2H), 7.52ꢀ7.49 (m, 3H), 2.05ꢀ1.79 (m, 8H), 1.67ꢀ1.55 (m, 2H); C{1H} NMR (100 MHz,
13
CDCl3)
δ 185.4, 171.3, 161.7, 131.8, 129.6, 128.7, 128.4, 122.4, 85.8, 35.2, 24.7, 22.1; IR (film)
2937, 1760, 1497, 1288, 1163, 1031, 943, 866, 711 cmꢀ1; HRMS (EI) m/z [M]+ Calcd for
C16H15NO2S: 285.0823, Found: 285.0821.
6-Butyl-3-phenyl-6,7-dihydro-4H-pyrano[4,3-c]isothiazol-4-one (2o): 55.3 mg, 96%, Colorless
1
oil, Rf = 0.5 (EtOAc:Hx = 1:4), H NMR (400 MHz, CDCl3)
δ 7.73ꢀ7.68 (m, 2H), 7.51ꢀ7.44 (m,
3H), 4.62ꢀ4.56 (m, 1H), 3.20 (dd, J = 16.5, 3.2 Hz, 1H), 2.98(dd, J = 16.5, 11.4 Hz, 1H), 1.97ꢀ1.88
(m, 1H), 1.80ꢀ1.72 (m, 1H), 1.62ꢀ1.52 (m, 1H), 1.51ꢀ1.34 (m, 3H), 0.94 (t, J = 7.2 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3)
δ 176.0, 168.6, 161.0, 130.9, 129.3, 128.8, 128.7, 119.3, 78.9, 34.52,
34.46, 27.2, 22.5, 14.0; IR (film) 1731, 1536, 1286, 1170 cmꢀ1; HRMS (EI) m/z [M]+ Calcd for
C16H17NO2S: 287.0980, Found: 287.0981.
3,6-Diphenyl-6,7-dihydro-4H-pyrano[4,3-c]isothiazol-4-one (2p): 61.1 mg, 99%, Yellow solid,
o
1
Melting point: 147ꢀ149 C, Rf = 0.4 (EtOAc:Hx = 1:4), H NMR (400 MHz, CDCl3)
δ 7.76ꢀ
7.73 (m, 2H), 7.53ꢀ7.37 (m, 8H), 5.65 (dd, J = 11.2, 3.8 Hz, 1H), 3.46 (dd, J = 3.9, 16.8 Hz, 1H),
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3.38 (dd, J = 16.6, 11.2 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3)
δ 176.5, 168.2, 160.6, 137.8,
3
4
5
131.0, 129.4, 129.06, 128.98, 128.94, 128.7, 126.3, 119.4, 79.9, 36.6; IR (film) 1731, 1534, 1287,
1162 cmꢀ1; HRMS (EI) m/z [M]+ Calcd for C18H13NO2S: 307.0667, Found: 307.0665.
6
7
8
9
3-Phenyl-6-(p-tolyl)-6,7-dihydro-4H-pyrano[4,3-c]isothiazol-4-one (2q): 63.6 mg, 99%, White s
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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27
28
29
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45
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48
49
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55
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58
59
60
o
1
olid, Melting point: 148ꢀ150 C, Rf = 0.4 (EtOAc:Hx = 1:4), H NMR (400 MHz, CDCl3)
δ
7.75ꢀ7.73 (m, 2H), 7.53ꢀ7.47 (m, 3H), 7.37 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 7.9 Hz, 2H), 5.62 (dd, J
= 10.6, 4.2 Hz, 1H), 3.44 (dd, J = 16.7, 4.4 Hz, 1H), 3.38 (dd, J = 16.8, 10.8, 1H), 2.38 (s, 3H); 13C
{1H} NMR (100 MHz, CDCl3)
δ 176.4, 168.4, 160.8, 139.0, 134.8, 131.0, 129.6, 129.4, 128.9,
128.7, 126.3, 119.5, 80.0, 36.5, 21.4; IR (film)1732, 1534, 1286, 1161 cmꢀ1; HRMS (EI) m/z
[M]+ Calcd for C19H15NO2S: 321.0823, Found: 321.0823.
3-Phenyl-5a,6,7,8,9,9a-hexahydro-4H-chromeno[4,3-c]isothiazol-4-one (2r): 55.9 mg, 98%,
o
1
White solid, Melting point: 156ꢀ158 C, Rf = 0.5 (EtOAc:Hx = 1:4), H NMR (400 MHz, CD
Cl3) 7.72ꢀ7.69 (m, 2H), 7.52ꢀ7.45 (m, 3H), 4.19 (td, J = 17.1, 4.3 Hz, 1H), 2.86 (td, J = 17.0, 4.1
δ
Hz, 1H), 2.73ꢀ 2.69 (m, 1H), 2.31ꢀ2.27 (m, 1H), 1.99ꢀ1.90 (m, 2H), 1.80ꢀ1.70 (m, 1H), 1.53ꢀ1.38
(m, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ
176.2, 171.8, 161.0, 130.9, 129.3, 128.9, 128.8,
119.6, 81.8, 44.0, 31.4, 26.3, 24.7, 24.3; IR (film) 1728, 1533, 1274, 1173 cmꢀ1; HRMS (EI) m/z
[M]+ Calcd for C16H15NO2S: 285.0823, Found: 285.0822
3-Phenyl-4H-chromeno[4,3-c]isothiazol-4-one (2s)17: 46 mg, 84%, White solid, Melting point:
1
158ꢀ159 °C, Rf = 0.3 (EtOAc:Hx= 1:2), H NMR (400 MHz, CDCl3)
δ 8.31 (d, J = 8.2 Hz, 1H),
7.80ꢀ7.78 (m, 2H), 7.59ꢀ7.52 (m, 4H), 7.40ꢀ7.36 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3)
δ
178.3, 162.8, 156.7, 152.7, 132.2, 131.2, 129.6, 129.0, 128.4, 125.0, 124.4, 117.5, 117.3, 117.1; IR
(film) 1732, 1591, 1483, 1293, 1156, 896, 750, 639 cmꢀ1.
8-Methyl-3-phenyl-4H-chromeno[4,3-c]isothiazol-4-one (2t) : 58.1 mg, 99%, White solid, Meltin
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2
o
1
g point: 157ꢀ159 C, Rf = 0.6 (EtOAc:Hx = 1:4), H NMR (400 MHz, CDCl3)
δ 8.10 (dd, J =
3
4
5
6
7
1.4, 0.5 Hz, 1H), 7.80ꢀ7.78 (m, 2H), 7.56ꢀ7.52 (m, 3H), 7.36 (ddd, J = 8.4, 2.2, 0.5 Hz, 1H), 7.27 (d,
J = 9.7 Hz, 1H), 2.47(s, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ
178.3, 163.0, 156.9, 150.9,
8
9
134.8, 133.1, 131.2, 129.6, 129.0, 128.5, 117.2, 117.1, 21.0; IR (film) 1743, 1532, 1484, 1111 cmꢀ
10
11
12
13
14
15
16
17
18
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20
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22
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42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1; HRMS (EI) m/z [M]+ Calcd for C17H11NO2S: 293.0510, Found: 293,0508.
8-Bromo-3-phenyl-4H-chromeno[4,3-c]isothiazol-4-one (2u): 64 mg, 90%, White solid, Melting
point: 188ꢀ189 °C, Rf = 0.7 (EtOAc:Hx = 1:2), 1H NMR (400 MHz, CDCl3)
δ 8.45 (d, J = 2.4 Hz,
1H), 7.80ꢀ7.77 (m, 2H), 7.65 (dd, J = 8.8, 2.4 Hz, 1H), 7.58ꢀ7.53 (m, 3H), 7.28 (d, J = 8.8 Hz, 1H);
13C{1H} NMR (100 MHz, CDCl3)
δ
178.7, 161.4, 156.0, 151.4, 134.8, 131.3, 129.4, 128.9, 128.0,
127.0, 119.0, 118.9, 117.7, 116.8; IR (film) 1755, 1583, 1458, 1274, 1250, 1003, 902, 855, 746, 536
cmꢀ1; HRMS (EI) m/z [M]+ Calcd for C16H879BrNO2S: 356.9459, C16H881BrNO2S: 356.9439,
Found: 356.9456, 356.9426.
3-Phenyl-4H-benzo[5,6]chromeno[4,3-c]isothiazol-4-one (2v): 59.3 mg, 90%, White solid, Melti
o
1
ng point: 238ꢀ240 C, Rf = 0.9 (Et2O:DCM:Hx = 1:3:3), H NMR (400 MHz, CDCl3)
δ 10.10
(d, J = 8.5 Hz, 1H), 8.02 (d, J = 8.9 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.82ꢀ7.76 (m, 3H), 7.62ꢀ7.50
(m, 5H); 13C{1H} NMR (100 MHz, CDCl3)
δ
177.2, 163.9, 156.8, 152.8, 133.5, 131.11, 131.06,
129.8, 129.7, 129.1, 129.0, 128.8, 128.5, 126.9, 126.2, 118.1, 117.4, 111.0; IR (film) 2919, 1730,
1273, 813, 747, 729, 691 cmꢀ1; HRMS (EI) m/z [M]+ Calcd for C20H11NO2S: 329.0510, Found:
329.0511.
3-Phenyl-7,8-dihydro-4H,6H-oxepino[4,3-c]isothiazol-4-one (2w): 20.6 mg, 40%, Rf = 0.3
(EtOAc:Hx = 1:4); ivori solid; Melting point: 206ꢀ208 °C; 1H NMR (400 MHz, CDCl3)
(m, 5H), 4.35 (dd, J = 5.3, 4.8 Hz, 2H), 3.32 (t, J = 8.08, 2H), 2.21ꢀ2.15 (m, 2H); 13C{1H} NMR
δ 7.47ꢀ7.43
(100 MHz, CDCl3)
δ
173.9, 170.2, 163.2, 130.2, 129.9, 129.0, 128.6, 125.6, 65.3, 31.6, 29.2; IR
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(film) 2956, 2921, 1712, 1522, 1481, 1193, 1033 cmꢀ1; HRMS (EI) m/z [M]+ Calcd for
3
4
5
C13H11NO2S: 245.0510, Found : 245.0512.
6
7
3-Phenylbenzo[6,7]oxepino[4,3-c]isothiazol-4(10H)-one (2x): 41 mg, 70%, White solid, Melting
8
9
1
point: 119ꢀ120 °C, Rf = 0.8 (EtOAc:Hx = 1:2), H NMR (400 MHz, CDCl3)
δ
7.54ꢀ7.52 (m, 2H),
177.5,
10
11
12
13
14
15
16
17
18
19
20
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60
7.49ꢀ7.44 (m, 3H), 7.37ꢀ7.20 (m, 4H), 4.26 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3)
δ
168.8, 160.0, 151.0, 130.7, 129.6, 129.5, 129.0, 128.9, 126.6, 121.8, 121.6, 36.6; IR (film) 1734,
1525, 1485, 1276, 1221, 1060, 955, 800, 754, 692 cmꢀ1; HRMS (EI) m/z [M]+ Calcd for
C17H11NO2S: 293.0510, Found: 293.0512.
3-Phenyl-12,13-dihydro-4H-naphtho[2',3':7,8]oxocino[4,3-c]isothiazol-4-one (2y): 47.4 mg,
o
1
66%, White solid, Melting point: 195ꢀ196 C, Rf = 0.5 (EtOAc:DCM:Hx = 1:2:5), H NMR (40
0 MHz, CDCl3) 8.03 (d, J = 8.5 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H),
δ
7.62ꢀ7.58 (m, 1H), 7.50ꢀ7.46 (m, 6H), 7.26 (d, J = 8.7 Hz, 1H), 3.65 (t, J = 7.2 Hz, 2H), 3.51 (t, J =
7.3 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3)
δ
169.1, 165.8, 164.9, 148.1, 132.3, 131.8, 130.3,
129.4, 129.2, 129.0, 128.1, 127.6, 126.2, 126.1, 125.6, 123.5, 119.1, 32.5, 21.3; IR (film) 1747,
1265, 1214, 1162, 1066 cmꢀ1; HRMS (EI) m/z [M]+ Calcd for C22H15NO2S: 357.0823, Found :
357.0820.
3-Phenyl-6,7-dihydroisothiazolo[4,3-c]pyridin-4(5H)-one (4a): 43.9 mg, 95%, Light brown solid,
1
Melting point: 184ꢀ185 °C, Rf = 0.4 (Acetone:Hx = 1:2), H NMR (400 MHz, CDCl3)
δ 7.73ꢀ7.71
(m, 2H), 7.44ꢀ7.44 (m, 3H), 5.90 (s, 1H), 3.61 (dt, J = 2.7, 6.5 Hz, 2H), 3.15 (t, J = 6.5 Hz, 2H);
13C{1H} NMR (100 MHz, CDCl3)
δ
172.8, 168.8, 163.2, 130.3, 129.6, 129.4, 128.6, 123.0, 40.2,
29.4; IR (film) 3189, 3064, 2917, 1671, 1546, 1330, 1063 cmꢀ1; HRMS (EI) m/z [M]+ Calcd for
C12H10N2OS: 230.0514, Found: 230.0512.
5-Methyl-3-phenyl-6,7-dihydroisothiazolo[4,3-c]pyridin-4(5H)-one (4b): 46 mg, 94%, White
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1
2
1
solid, Melting point: 126ꢀ127 °C, Rf = 0.5 (EtOAc:Hx = 2:1), H NMR (400 MHz, CDCl3)
δ 7.69ꢀ
3
4
5
6
7.67 (m, 2H), 7.46ꢀ7.43 (m, 3H), 3.66 (t, J = 6.6 Hz, 2H), 3.11 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) 172.2, 168.3, 161.7, 130.0, 129.6, 128.4, 123.5, 77.4, 48.3, 34.5, 29.0; IR (film) 1650,
δ
7
8
9
1541, 1495, 1447, 1390, 1329, 1086, 816, 693 cmꢀ1; HRMS (EI) m/z [M]+ Calcd for C13H12N2OS:
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
244.0670, Found: 244.0670.
3-Phenyl-6,7-dihydro-4H-pyrano[4,3-c]isothiazole (4c): 36.5mg, 84%, White solid, Melting po
o
1
int: 54ꢀ56 C, Rf = 0.4 (Et2O:Hx = 1:1), H NMR (400 MHz, CDCl3)
δ 7.49ꢀ7.37 (m, 5H),
4.93 (s, 2H), 4.04 (t, J = 5.9 Hz, 2H), 3.04 (t, J = 5.9 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3)
δ
164.5, 159.8, 130.9, 129.4, 129.3, 127.9, 127.8, 66.8, 65.3, 30.6; IR (film) 3057, 1397, 1227,
1095, 759, 720, 693 cmꢀ1; HRMS (EI) m/z [M]+ Calcd for C12H11NOS: 217.0561, Found:
217.0560.
3-Phenyl-4,6,7,8-tetrahydrooxepino[4,3-c]isothiazole (4d): 30.1 mg, 65%, Yellow oil, Rf = 0.5
1
(Et2O:Hx = 1:1), H NMR (400 MHz, CDCl3)
δ 7.48ꢀ7.40 (m, 3H), 7.36ꢀ7.33 (m, 2H), 4.64 (s,
2H), 4.07 (t, J = 5.1 Hz, 2H), 3.18ꢀ3.15 (m, 2H), 1.96ꢀ1.90 (m, 2H); 13C{1H} NMR (100 MHz, C
DCl3) 172.5, 163.0, 133.7, 130.8, 129.3, 129.15, 129.10, 75.7, 66.2, 34.0, 28.7; IR (film) 3058,
δ
2943, 2846, 1252, 1108, 911, 697 cmꢀ1; HRMS (EI) m/z [M]+ Calcd for C13H13NOS: 231.0718,
Found: 231.0715.
3-Phenyl-6,7,8,9-tetrahydro-4H-oxocino[4,3-c]isothiazole (4e): 24.5 mg, 50%, Yellow oil, Rf =
1
0.4 (Et2O:Hx = 1:1), H NMR (400 MHz, CDCl3)
δ 7.52ꢀ7.40 (m, 5H), 4.70 (s, 2H), 3.75 (t, J =
4.9, 2H), 3.19 (t, J = 6.3, 2H), 1.89ꢀ1.83 (m, 2H), 1.77ꢀ1.72 (m, 2H); 13C{1H} NMR (100 MHz,
CDCl3) 171.8, 164.0, 131.2, 130.8, 129.3, 129.2, 128.8, 69.9, 63.7, 32.1, 27.7, 27.6; IR (film)
δ
3058, 2923, 2856, 1132, 1079, 750, 696 cmꢀ1; HRMS (EI) m/z [M]+ Calcd for C14H15NOS:
245.0874, Found : 245.0872.
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