Rhodium-Catalyzed Intramolecular Transannulation Reaction of Alkynyl Thiadiazole Enabled 5,n-Fused Thiophenes

Article abstract of DOI:10.1021/acs.joc.6b02614

A method for the synthesis of a wide range of fused thiophenes, including those fused with lactams, lactones, or cyclic ethers, was developed from a rhodium-catalyzed intramolecular transannulation reaction of alkynyl thiadiazoles. This transannulation reaction provides an efficient platform for the construction of a variety of 5,n-fused thiophenes from readily available starting materials together with the release of molecular nitrogen.

Full text of DOI:10.1021/acs.joc.6b02614

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Article
Rhodium-Catalyzed Intramolecular Transannulation Reaction
of Alkynyl Thiadiazoles Enabled 5,n-Fused Thiophenes
Ji Eun Kim, Jinsub Lee, Hyunsik Yun, Yonghyeon Baek, and Phil Ho Lee
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02614 • Publication Date (Web): 11 Jan 2017
Downloaded from http://pubs.acs.org on January 11, 2017
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Rhodium-Catalyzed Intramolecular Transannulation Reaction of
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Alkynyl Thiadiazoles Enabled 5,n-Fused Thiophenes
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Ji Eun Kim, Jinsub Lee, Hyunsik Yun, Yonghyeon Baek, and Phil Ho Lee*
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National Creative Research Initiative Center for Catalytic Organic Reactions, Department of
Chemistry, Kangwon National University, Chuncheon 24341, Republic of Korea
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E-mail: phlee@kangwon.ac.kr
Table of Contents
R2
( )n
X
X
S
[Rh(COD)Cl]2 (5 mol %)
DPPF (12 mol %)
O
R2
R3
Modular synthesis of 5,n-fused thiophene
Versatile ring size and type
( )n
O
N
N
PhCl, 130 oC, 30 min
- N2
R3
R1
R1
Simple operation
Short time
S
X = O, NH n = 1, 2, 3, 4
35 examples
up to 98% yields
R1 = alkyl, aryl, heteroaryl R2 = H, alkyl
R3 = H, alkyl, aryl, TMS
ABSTRACT: A method for the synthesis of a wide range of fused thiophenes, including those
fused with lactams, lactons, or cyclic ethers, was developed from a rhodium-catalyzed
intramolecular transannulation reaction of alkynyl thiadiazoles. This transannulation reaction
provides an efficient platform for the construction of a variety of 5,n-fused thiophenes from readily
available starting materials together with the release of molecular nitrogen.
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INTRODUCTION
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Fused thiophenes have been recognized as very important scaffolds in the fields of
pharmaceutical and functional materials sciences.1 For this reason, the development of an efficient
synthetic method for functionalized fused thiophenes is highly attractive and poses a significant
challenge. To date, various synthetic methods of fused thiophenes from easily available compounds
have been reported (Scheme 1a-1g): (a) one-pot three step reaction of 3,4-dibromothiophene using
n-BuLi, 1-benzylpiperidin-4-one, CO2, and Ac2O,2 (b) basic hydrolysis and subsequent ring closure
of dicarboxylic acid after Rosenmund-von Braun reaction of 3,4-dibromothiophene,3 (c) Pd-
catalyzed carbonylative amidation of 3,4-dibromothiophene,4 (d) condensation reaction of
thiophene dicarbaldehydes and aromatic amines in the presence of 2-mercaptoethanol,5 (e) Friedel-
Crafts acylation of thiophene-3,4-dicarbonyl dichloride and benzene,6 (f) Suzuki-Miyaura cross-
coupling of bromo arylcarboxylate and o-hydroxyarylboronic acid,7 (g) reaction of o-
hydroxyacetophenone with ethyl cyanoacetate and elemental sulfur under microwave condition.8
However, because the previously reported some synthetic methods demand a strong base, long
reaction times, and vigorous reaction conditions, development of efficient synthtic approachs to
overcome these shortcomings has been continuously required.
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Scheme 1. Synthesis of the Fused Thiophenes
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Bn
MeO2C
Br
N
O
Br
Br
O
HO
n-BuLi
Ac2O
(f)
(a)
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NaOAc
1) Benzyl
piperidinone
2) CO2
(HO)2B
MW
S
S
S
cat. Pd
R
N
1) CuCN
160 oC
2) KOH
200 oC
3) Ac2O
O
O
O
O
O
O
O
1) RNH2
2) SOCl2
(b)
S
S
R
N
S
O
O
cat. Pd
(c)
OEt
R-NH2, CO
HO
O
(g)
S
R
NC
N
OHC
CHO
R-NH2
O
O
OH
HS
MW
S
(d)
(e)
S
S
O
O
ClCl
O
O
+
AlCl3
H2N
O
O
S
S
S
previous work
this work
R2
( )n
X
X
S
O
R2
( )n
O
cat. Rh
- N2
(h)
N
R3
R1
R3
N
R1
S
X = O, NH n = 1, 2, 3, 4
R1 = alkyl, aryl, heteroaryl R2 = H, alkyl
R3 = H, alkyl, aryl, TMS
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Recently, N-sulfonyl-1,2,3-triazoles were easily prepared through a Cu-catalyzed [3 + 2]
cycloaddition reaction from 1-alkynes and N-sulfonyl azides9 and have been used as α-imino
carbene precursors.10 These results exhibited that the α-imino carbene functions as a 1,3-dipole
equivalent in transannulation reactions with diverse unsaturated compounds possessing carbon-
carbon or carbob-heteroatom multiple bonds. Thus, intermolecular, as well as intramolecular,
transannulation reactions using N-sulfonyl-1,2,3-triazoles have become a valuable method for
preparing a wide variety of heterocyclic compounds.11 More recently, Gevorgyan and co-workers
developed Rh-catalyzed intermolecular transannulation reactions of 1,2,3-thiadiazoles with alkynes
to produce thiophenes (Schem 2a).12a In addition, Rh-catalyzed intermolecular transannulation
reactions of 1,2,3-thiadiazoles with alkenes (b and c) and nitriles (d) were developed to produce
sulfur-containing five-membered heterocyclic compounds, including thiophenes, dihydrothiophenes,
and isothiazoles, through an α-thiavinyl carbene.12b,c
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Scheme 2. Rh-Catalyzed Intermolecular Transannulation Reactions of 1,2,3-Thiadiazoles
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R2
R1
R3
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S
cat. Rh
R3
b
- N2
one-pot
1) cat. Rh
R3, - N2
2) [O]
R2
R1
R2
R2
R1
R3
cat. Rh
N
N
S
R3
- N2
a
R3
R1
S
S
c
cat. Rh
R3
d
N
- N2
R2
R1
R3
N
S
On the basis of these results and facts, we envisioned that if alkynyl thiadiazoles possessing a
variety of linkers between the alkynyl group and the thiadiazole ring were treated with a transition
metal catalyst, an intramolecular transannulation reaction would occur, producing a large number of
fused thiophenes together with the release of molecular nitrogen. Herein, we report for the first time
that rhodium-catalyzed intramolecular transannulation reactions of alkynyl thiadiazoles including
esters, amides, or ethers as linkers afford an excellent platform for the preparation of a wide range
of 5,n-fused thiophenes (Scheme 1h).
RESULTS AND DISCUSSION
First, we commenced our study by optimizing an intramolecular transannulation reaction of
alkynyl thiadiazole (1a) in the presence of a transition metal catalyst (Table 1). Rh2(oct)4 (5 mol %)
and RhCl3·H2O (5 mol %)/DPPF (12 mol %) were totally ineffective for the transannulation (entries
2 and 3). However, Rh(PPh)3Cl and [Ir(COD)Cl]2 (5 mol % each) in the presence of DPPF (12
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mol %) afforded, gratifyingly, the desired transannulated product 2a in 42% and 16% yields,
respectively (entries 1 and 5). The quantitative yield of 2a was obtained with [Rh(COD)Cl]2 (5
mol %) and DPPF (12 mol %) together with the release of nitrogen gas (entry 4). The efficiency of
the present transannulation was not greatly influenced by solvents. The desired product 2a was
produced in 65% yield in chloroform (entry 8). Moreover, the fused thiophene 2a was obtained in
good to excellent yields ranging from 87% to 90% in the solvents dichloromethane (DCM),
dichloroethane (DCE), and toluene (entries 6, 7, and 9). The reaction temperature effected on the
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o
transannulation efficiency. The higher transannulation reaction took place at 130 C (entries 4, 10,
and 11). Use of a lesser amount of [Rh(COD)Cl]2 (2 mol %) and DPPF (5 mol %) provided an
inferior result (entry 12). Control experiments demonstrated that both [Rh(COD)Cl]2 and DPPF
were essential for the transannulation reaction (entries 13-15).
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Table 1. Reaction Optimizationa
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O
O
O
O
cat. (5 mol %)
N
N
ligand (12 mol %)
n-Bu
Ph
n-Bu
Ph
S
S
1a
2a
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temp (oC)
yieldb (%)
entry cat. (mol %)
ligand (mol %) solvent
time (h)
Rh(PPh3)Cl (5)
Rh2(oct)4 (5)
DPPF (12)
PhCl
1
2
130
130
12
12
42
0
PhCl
PhCl
PhCl
PhCl
DCM
DCE
-
.
RhCl3 H2O (5)
DPPF (12)
3
4
5
6
7
130
130
130
40
12
0.5
12
12
12
0
99 (95)c
[Rh(COD)Cl]2 (5) DPPF (12)
[Ir(COD)Cl]2 (5)
[Rh(COD)Cl]2 (5)
DPPF (12)
DPPF (12)
16
89
[Rh(COD)Cl]2 (5) DPPF (12)
[Rh(COD)Cl]2 (5) DPPF (12)
[Rh(COD)Cl]2 (5) DPPF (12)
[Rh(COD)Cl]2 (5) DPPF (12)
[Rh(COD)Cl]2 (5) DPPF (12)
[Rh(COD)Cl]2 (2) DPPF (5)
60
90
8
60
12
12
12
12
12
2
65
87
29
5
CHCl3
toluene
PhCl
9
130
60
10
11
12
13
25
PhCl
130
130
36
0
PhCl
[Rh(COD)Cl]2 (5)
-
PhCl
-
-
DPPF (12)
14
15
130
130
2
2
0
0
PhCl
PhCl
-
aReaction conditions: 1a (0.2 mmol) was placed in solvent (1.0 mL) under N2. NMR yields using
b
dibromomethane as an internal standard. cIsolated yield.
To demonstrate the efficiency and scope of the Rh-catalyzed transannulation reaction, we
applied this catalytic system to a wide range of alkynyl thiadiazoles 1 with ester or amide group as
linkers between the thiadiazole ring and the alkynyl group, and the results are summarized in
Scheme 3. The corresponding alkynyl thiadiazoles 1 were easily obtained from the coupling
reactions of acids derived from the hydrolysis of ethyl 5-aryl-1,2,3-thiadiazole-4-carboxylate with
alkynyl alcohols and amines (see the Supporting Information). Alkynyl thiadiazole 1b, having a
propargyl group, which is a terminal alkyne, was smoothly transannulated to give the fused
thiophene 2b in 72% yield. Alkynyl thiadiazoles (1c, 1d, and 1e) obtained from 2-butyn-1-ol, 2-
pentyn-1-ol, and 3-phenyl-2-propyn-1-ol underwent the transannulation reaction, affording the
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fused thiophenes (2c, 2d, and 2e) in high yields ranging from 87% to 89% yields. The structure of
2d was confirmed by X-ray crystallography (see the Supporting Information). In particular, it is
noteworthy that a trimethylsilyl group was compatible with the present reaction. Namely,
trimethylsilyl-substituted propargyl thiadiazole 1f is applicable to the present transannulation
reaction, providing 2f in quantitative yield. Alkynyl thiadiazoles (1g and 1h) generated from
internal alkynyl alcohols having a methyl substituent on the propargylic carbon worked equally well
to give the fused thiophenes 2g (98%) and 2h (72%). To our satisfaction, amide linked-alkynyl
thiadiazoles (1i and 1j), which are easily prepared from the coupling reaction of a thiadiazolyl acid
with 2-pentyn-1-amine and 3-phenyl-2-propyn-1-amine, turned out to be compatible with the
reaction conditions, leading to the formation of -lactam fused thiophenes 2i and 2j in good yields.
Moreover, thiadiazolylmethyl octynoate (1k) was compatible with the reaction conditions,
producing 5,5-fused thiophene 2k in 74% yield. Thiadiazolylmethyl 2-pentyn-1-yl ether (1l) took
part in the transannulation reaction to afford 2l in 62% yield.
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Scheme 3. Scope of Alkynyl Groups in the Transannulation of Alkynyl Thiadiazolesa
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R1
X
X
O
R1
R2
[Rh(COD)Cl]2 (5 mol %)
DPPF (12 mol %)
PhCl, 130 oC, 30 min
O
N
8
9
R2
N
Ph
Ph
S
S
- N2
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1
2
X = O, NH
O
S
O
O
O
O
O
Ph
Ph
Ph
Me
Ph
Et
S
S
2b (72%)
2c (87%)
2d (89%)
O
O
O
O
O
O
Ph
Ph
Ph
n-Bu
SiMe3
2f (98%)
S
S
S
2a (95%)
2e (89%)
H
N
H
O
S
O
S
N
O
Me
O
Me
O
O
Ph
Ph
Ph
Ph
n-Bu
Ph
Et
Ph
S
S
2g (98%)
2h (72%)
2i (79%)
2j (71%)
O
O
O
Ph
Ph
n-Pent
2k (74%)
Et
S
S
2l (62%)
aReaction conditions: 1 (0.2 mmol) was used in the presence of [Rh(COD)Cl]2 (5 mol %) and DPPF
(12 mol %) in PhCl (1.0 mL) under N2 at 130 °C.
Encouraged by these results, we investigated the scope of a wide range of ester-linked alkynyl
thiadiazoles (1) in the Rh-catalyzed intramolecular transannulation reaction (Scheme 4). Electronic
variation of the thiadiazolyl ring did not largely affect the efficiency of the transannulation reaction.
Alkynyl thiadiazoles having an electron-donating methyl group on the 5-phenylthiadiazolyl ring
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efficiently underwent the intramolecular transannulation reaction to afford the desired fused
thiophenes 2m and 2n, in 98% and 84% yields, respectively, under the optimized conditions.
Substrates (1o and 1p) obtained from 4-methoxyphenyl-substituted thiadiazolyl acid and 2-pentyn-
1-ol and 3-phenyl-2-propyn-1-ol were smoothly converted to give the fused thiophenes 2o (84%)
and 2p (98%). Methylenedioxy-substituted alkynyl thiadiazoles were efficiently subjected to the
transannulation reaction, producing the desired fused thiophenes 2q and 2r in quantitative yields.
Substrates possessing an electron-withdrawing bromo group on the 5-phenylthiadiazolyl ring
delivered the desired -lactone fused thiophenes (2s and 2t) in good to excellent yields.
Heteroaryl-substituted alkynyl thiadiazoles were easily transformed to the corresponding fused
thiophenes. For example, furan-2-yl- and thiophen-2-yl-substituted alkynyl thiadiazoles are
applicable to the present transannulation reaction, affording the corresponding fused thiophenes (2u,
2v, 2w, and 2x) in good to excellent yields ranging from 88% to 95%. To our delight, cyclohexyl-
substituted substrates took part in the transannulation reaction to afford 2y and 2z in 84% yields.
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Scheme 4. Scope of Thiadiazolyl and Alkynyl Groups in the Transannulation of Alkynyl
Thiadiazolesa
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7
8
9
O
O
O
O
[Rh(COD)Cl]2 (5 mol %)
DPPF (12 mol %)
PhCl, 130 oC, 30 min
N
R2
R1
R1
N
R2
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S
S
- N2
1
2
O
O
O
O
O
O
Et
Ph
S
Et
S
S
Me
Me
MeO
2m (98%)
2n (84%)
2o (84%)
O
O
O
O
O
O
O
O
Ph
Et
S
Ph
S
S
O
O
MeO
2p (98%)
2q (96%)
2r (97%)
O
O
O
O
O
O
Et
Ph
S
Et
S
S
Br
Br
O
2s (97%)
2t (78%)
2u (95%)
O
O
O
O
O
O
Ph
Et
S
Ph
S
S
O
S
S
2v (88%)
2w (95%)
2x (89%)
O
S
O
O
O
Et
Ph
S
2y (84%)
2z (84%)
aReaction conditions: 1 (0.2 mmol) was used in the presence of [Rh(COD)Cl]2 (5 mol %) and DPPF
(12 mol %) in PhCl (1.0 mL) under N2 at 130 °C.
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With these results in hand, we next examined the Rh-catalyzed transannulation reaction of
alkynyl thiadiazoles (3) in the case where the alkynyl chain was largely extended by carbon
(Scheme 5). Alkynyl thiadiazole (3a), obtained from the coupling reaction of 5-phenylthiadiazolyl
acid with 3-butyn-1-ol, was exposed to the rhodium catalyst, leading to the formation of -lactone
fused thiophene 4a in 51% yield. Alkynyl thiadiazole (3b), derived from 3-hexyn-1-ol, was
converted to the desired product 4b in 87% yield. Substrate 3c was less reactive and then the
corresponding -lactone fused diphenyl-substituted thiophene 4c was produced in 62% yield in
chlorobenzene at 130 oC after 3 h. Alkynyl thiadiazole (3d), prepared from the coupling reaction of
5-phenylthiadiazolyl acid with 2-(hex-1-ynyl)phenol, has been engaged in the Rh-catalyzed
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transannulation reaction, producing 4d in 90% yield (130 C, 5 h). When alkynyl thiadiazole (3e)
was employed, the desired product 4e was obtained in 75% yield. Substrate (3f), possessing a 4-
chlorophenyl group, was employed in the Rh-catalyzed transannulation reaction, providing 4f in
83% yield. In addition, thiadiazolyl alkynyl ethers (3g and 3h) were compatible with the reaction
conditions, producing 5,7-fused thiophene (4g and 4h) in moderate yield. To our delight, 5,8-fused
thiophene 4i was obtained in 52% yield.
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Scheme 5. Synthesis of 5,n-Fused Thiophenes via Transannulation of Alkynyl Thiadiazolesa
4
5
R1
R1
6
7
8
9
( )n
( )n
O
O
[Rh(COD)Cl]2 (5 mol %)
DPPF (12 mol %)
PhCl, 130 oC, 30 min
- N2
( )m
R2
( )m
O
O
N
R2
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N
Ph
Ph
S
S
3
4
O
O
O
O
O
O
Ph
4a
Ph
Ph
Et
Ph
S
S
S
b
4b
(51%)
(87%)
4c
(62%)
O
O
O
Cl
O
O
O
Ph
Ph
Ph
n-Bu
Ph
Ph
4f
(83%)
S
S
S
c
4d
4e
(90%)
(75%)
O
O
O
Ph
Ph
Ph
4i
Ph
S
(54%)
S
S
4g
4h
(55%)
(52%)
aReaction conditions: 1 (0.2 mmol) was used in the presence of [Rh(COD)Cl]2 (5 mol %) and DPPF
(12 mol %) in PhCl (1.0 mL) under N2 at 130 °C. b3 h. c5 h.
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The present method applied in the synthesis of spirocyclic fused thiophene, which has been
known as ligands to interact with 1 receptor protein and modulate the 1 receptor activity for the
treatment of neurological disorders (Scheme 6).13 The corresponding alkynyl thiadiazole 7 was
prepared from the esterification reaction of acid (5) derived from the hydrolysis of ethyl 5-phenyl-
1,2,3-thiadiazole-4-carboxylate with alkynyl alcohol (6) in 81% yield. Alkynyl thiadiazole 7 was
transannulated under the optimized reaction conditions, producing the desired product 8 in 52%
yield.2
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Scheme 6. Synthetic Application of Spirocyclic Fused Thiophene
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A plausible reaction mechanism for the Rh-catalyzed intramolecular transannulation of alkynyl
thiadiazoles is proposed in Scheme 7. First, a reversible ring-chain tautomerization of thiadiazole
moieties in alkynyl thiadiazoles 1 and 3 provides the alkynyl-substituted α-diazo thiocarbonyl I.
Next, exposure of α-diazo thiocarbonyl I to the Rh(I) catalyst affords the α-thiavinyl Rh-carbenoid
II together with the release of nitrogen gas.12,14 The fused thiophenes 2 and 4 might be produced
through cyclopropene intermediate III generated from the intramolecular [2 + 1] cycloaddition of II
(path a). However, path a is ruled out in the catalytic cycle due to Bredt’s rule and ring strain. In
addition, the Rh-carbenoid II reacts with the intramolecular triple bond to afford the zwitterionic
intermediate IV, which then cyclizes to intermediate VI (path c). Alternatively, intermediate VI can
be produced through the intramolecular [3 + 2] cycloaddition of the α-thiavinyl Rh-carbenoid II
(path b). A mechanism involving rhodium carbene-alkyne metathesis don’t favor in the catalytic
cycle due to an efficient intramolecular transannulation reaction of internal alkynyl thiadiazoles
(path d). The elucidation of the detailed mechanism of the intramolecular transannulation reaction
awaits further investigation.
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Scheme 7. A Proposed Mechanism
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R2
( )n
X
R2
R3
X
O
( )n
O
R3
N2
I
[Rh]
R2
R1
R1
S
S
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2, 4
R2
( )n
X
X
O
( )n
O
N2
N
R1
R3
path a
[2 + 1]
R3
R1
N
S
S
III
1, 3
R2
( )n
X
O
R2
R3
( )n
X
X
path b
[3 + 2]
[Rh]
R1
O
R3
[Rh]
S
R1
VI
S
II
X
O
R2
R3
( )n
path c
[Rh]
R1
S
IV
path d
metathesis
mechanism
X
O
R2
( )n
R1
[Rh]
S R3
V
CONCLUSION
In summary, a method for the synthesis of a wide range of thiophenes fused to lactams,
lactones, and cyclic ethers was developed employing a Rh-catalyzed intramolecular transannulation
reaction of alkynyl thiadiazoles. This method provides an efficient platform for the construction of a
wide range of 5,n-fused thiophenes from readily accessible starting materials.
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Experimental section
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General. Reactions were carried out in oven-dried glassware under air atmosphere. [Rh(COD)Cl]2,
Rh2(oct)4, RhCl3•H2O, Rh(PPh3)3Cl, [Ir(COD)Cl]2, and DPPF were purchased and was used 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 thin-layer chromatography using silica gel pre-coated glass plates, which
were visualized with UV light and then, developed using either iodine or a solution of anisaldehyde.
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Flash column chromatography was carried out using silica gel (230-400 mesh). H NMR (400
13
MHz) and C{1H} NMR (100 MHz) spectra were recorded on NMR spectrometer. Deuterated
chloroform was used as the solvent and chemical shift values () are reported in parts per million
relative to the residual signals of this solvent [δ 7.26 for 1H (chloroform-d), δ 2.50 for 1H (DMSO-
d6), δ 77.2 for 13C{1H} (chloroform-d) and δ 39.25 for 13C{1H} (DMSO-d6)]. Infrared spectra were
recorded on FT-IR 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 electron impact (EI) ionization technique (magnetic sector - electric sector double
focusing mass analyzer). Melting points were determined in open capillary tube.
1. Preparation of alkynyl thiadiazoles (1a-1z): Thiadiazoles15 (4.4 mmol, 1.03 g) was added to
10% aqueous-methanolic solution (9.0 mL) of potassium hydroxide (8.8 mmol, 494.0 mg) and
mixture was heated for 2 h under reflux. After the solvent was evaporated, 10 mL of water was
added to the residue and the mixture was acidified with dilute hydrochloric acid under vigorous
stirring. The precipitate was filtered off, dried in air, and recrystallized from water. To a solution of
the alcohol or amine (1.0 mmol), 4-dimethylaminopyridine (DMAP, 0.10 mmol, 36.7 mg), and
o
thiadiazole-4-carboxylic acid (5)16 (1.3 mmol, 822.8 mg) in dry DCE (10 mL) at 0 C under a
nitrogen atmosphere was added N,N’-dicyclohexylcarbodiimide (DCC, 1.3 mmol, 823.3 mg) in one
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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 another 3 h. Then, reaction mixture was filtered by
Celite and the mixture was washed by CH2Cl2 (3 x 10 mL). The combined filtrate was evaporated
under reduced pressure to give the crude product, which was purified by silica gel chromatography
(EtOAc:CH2Cl2:Hexane = 1:5:15) to provide the pure product 1.17
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Hept-2-yn-1-yl 5-phenyl-1,2,3-thiadiazole-4-carboxylate (1a): Yield: 180.0 mg (75%); Rf = 0.3
1
(EtOAc:Hexane = 1:9); Yellow oil; H NMR (400 MHz, CDCl3) δ 7.56-7.46 (m, 5H), 4.95 (t, J =
2.2 Hz, 2H), 2.21 (tt, J = 10.4 Hz, 2.2 Hz, 2H), 1.52-1.45 (m, 2H), 1.43-1.34 (m, 2H), 0.90 (t, J =
13
7.2 Hz, 3H); C{1H} NMR (100 MHz, CDCl3) δ 162.6, 160.0, 147.8, 130.9, 130.0, 128.8, 126.0,
88.7, 73.2, 54.4, 30.5, 22.0, 18.6, 13.7; IR (film): 2932, 2236, 1736, 1325, 1171, 984 cm-1; HRMS
(EI): m/z calcd for C16H16N2O2S: 300.0932; found: 300.0928.
Prop-2-yn-1-yl 5-phenyl-1,2,3-thiadiazole-4-carboxylate (1b): Yield: 102.6 mg (57%); Rf = 0.3
(EtOAc:Hexane = 1:9); White Solid; Melting point: 62-64 oC; 1H NMR (400 MHz, CDCl3) δ 7.56-
7.46 (m, 5H), 4.95 (d, J = 2.4 Hz, 2H), 2.53 (t, J = 2.4 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ
162.9, 159.6, 147.3, 130.9, 129.9, 128.8, 125.7, 76.8, 75.8, 53.2; IR (film): 3287, 2948, 1737, 1281,
1172, 693 cm-1; HRMS (EI): m/z calcd for C12H8N2O2S: 244.0306; found: 244.0306.
But-2-yn-1-yl 5-phenyl-1,2,3-thiadiazole-4-carboxylate (1c): Yield: 140.5 mg (68%); Rf = 0.3
o
1
(EtOAc:Hexane = 1:9); Ivory Solid; Melting point: 112-114 C; H NMR (400 MHz, CDCl3) δ
13
7.57-7.46 (m, 5H), 4.93(q, J = 2.4 Hz, 2H), 1.85 (t, J = 2.4 Hz, 3H); C{1H} NMR (100 MHz,
CDCl3) δ 162.7, 160.0, 147.7, 130.9, 130.0, 128.8, 125.9, 84.2, 72.4, 54.3, 3.8; IR (film): 2910,
2238, 1731, 1326, 1172, 984 cm-1; HRMS (EI): m/z calcd for C13H10N2O2S: 258.0463; found:
258.0466.
Pent-2-yn-1-yl 5-phenyl-1,2,3-thiadiazole-4-carboxylate (1d): Yield: 736 mg (90%); Rf = 0.3
1
(EtOAc:Hexane = 1:9); Orange oil; H NMR (400 MHz, CDCl3) δ 7.56-7.46 (m, 5H), 4.95 (t, J =
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2.2 Hz, 2H), 2.21 (qt, J = 12.5 Hz, 2.2 Hz, 2H), 1.13 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 162.6, 160.0, 147.8, 130.9, 130.0, 128.8, 126.0, 89.9, 72.6, 54.3, 13.6, 12.6; IR (film):
2975, 2236, 1731, 1273, 1167, 934 cm-1; HRMS (EI): m/z calcd for C14H12N2O2S: 272.0619; found:
272.0621.
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3-Phenylprop-2-yn-1-yl 5-phenyl-1,2,3-thiadiazole-4-carboxylate (1e): Yield: 240.3 mg (75%);
Rf = 0.3 (EtOAc:Hexane = 1:9); White solid; Melting point: 83-85 oC; 1H NMR (400 MHz, CDCl3)
δ 7.58-7.55 (m, 2H), 7.53-7.43 (m, 5H), 7.37-7.29 (m, 3H), 5.20 (s, 2H); 13C{1H} NMR (100 MHz,
CDCl3) δ 162.9, 159.9, 147.7, 132.1, 131.0, 130.0, 129.0, 128.9, 128.5, 125.9, 122.1, 87.4, 82.2,
54.3; IR (film): 3061, 2949, 2360, 2342, 1734, 1473, 1325, 1168, 690 cm-1; HRMS (EI): m/z calcd
for C18H12N2O2S: 320.0619; found: 320.0617.
3-(Trimethylsilyl)prop-2-yn-1-yl 5-phenyl-1,2,3-thiadiazole-4-carboxylate (1f): Yield: 167.7 mg
(53%); Rf = 0.5 (EtOAc: CH2Cl2:Hexane = 1:5:15); Yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.39-
13
7.28 (m, 5H), 4.78 (s, 2H), 0.00 (s, 9H); C{1H} NMR (100 MHz, CDCl3) δ 162.7, 159.7, 147.6,
130.9, 129.9, 128.8, 125.9, 98.0, 93.1, 54.1, 0.3; IR (film): 3063, 2960, 2899, 2359, 2186, 1737,
1474, 1328, 1251, 1172, 1034, 846, 753, 694 cm-1; HRMS (EI): m/z calcd for C15H16N2O2SSi:
316.0702; found: 316.0704.
Oct-3-yn-2-yl 5-phenyl-1,2,3-thiadiazole-4-carboxylate (1g): Yield: 213.8 mg (68%); Rf = 0.6
(EtOAc:CH2Cl2:Hexane = 1:5:15); Colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.55-7.45 (m, 5H),
5.68 (qt, J = 6.7 Hz, 2.0 Hz, 1H), 2.19 (td, J = 7.0 Hz, 1.9 Hz, 2H), 1.52 (d, J = 6.6 Hz, 3H), 1.49-
13
1.33 (m, 4H), 0.90 (t, J = 7.2 Hz, 3H); C{1H} NMR (100 MHz, CDCl3) δ 162.1, 159.6, 148.4,
130.7, 129.9, 128.7, 126.2, 86.7, 77.8, 62.9, 30.5, 22.6, 21.7, 18.5, 13.7; IR (film): 2957, 2934, 2871,
2247, 1733, 1472, 1330, 1280, 1182, 1165, 1058, 984, 846, 694 cm-1; HRMS (EI): m/z calcd for
C17H18N2O2S: 314.1089; found: 314.1092
4-Phenylbut-3-yn-2-yl 5-phenyl-1,2,3-thiadiazole-4-carboxylate (1h): Yield: 217.4 mg (65%); Rf
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= 0.6 (EtOAc:CH2Cl2:Hexane = 1:5:15); Cololess oil; 1H NMR (400 MHz, CDCl3) δ 7.57-7.54 (m,
2H), 7.52-7.41 (m, 5H), 7.35-7.28 (m, 3H), 5.93 (q, J = 6.7 Hz, 1H), 1.65 (d, J = 6.7 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 162.3, 159.6, 148.3, 132.0, 130.8, 129.9, 128.9, 128.8, 128.4,
126.1, 122.2, 86.6, 85.6, 62.8, 21.4; IR (film): 3060, 2989, 2935, 2359, 1733, 1473, 1443, 1328,
1280, 1175, 1084, 845, 755, 691 cm-1; HRMS (EI): m/z calcd for C19H14N2O2S: 334.0776; found:
334.0778.
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N-(Pent-2-yn-1-yl)-5-phenyl-1,2,3-thiadiazole-4-carboxamide (1i): Yield: 168.2 mg (62%); Rf =
0.4 (EtOAc:CH2Cl2:Hexane = 1:5:15); White solid, Melting point : 109-111 oC, 1H NMR (400 MHz,
CDCl3)  7.75 (brs, 1H), 7.66-7.63 (m, 2H), 7.52-7.44 (m, 3H), 4.25-4.23 (m, 2H), 2.19 (qt, J =
13
12.5 Hz, 2.3 Hz, 2H), 1.14 (t, J = 7.5 Hz, 3H); C{1H} NMR (100 MHz, CDCl3)  160.8, 159.0,
149.3, 130.6, 130.2, 128.5, 125.9, 85.9, 74.1, 29.8, 13.7, 12.4; IR (film) 3311, 2979, 1661, 1277,
1530, 826 cm-1; HRMS (EI) m/z calcd. for C14H13N3OS: 271.0779; found: 271.0779.
5-Phenyl-N-(3-phenylprop-2-yn-1-yl)-1,2,3-thiadiazole-4-carboxamide (1j): Yield: 174.8 mg
(71%); Rf = 0.3 (EtOAc:CH2Cl2: Hexane = 1:5:15); Orange oil; 1H NMR (400 MHz, CDCl3) δ 7.89
(brs, 1H), 7.67-7.65 (m, 2H), 7.51-7.43 (m, 5H), 7.33-7.29 (m, 3H), 4.51 (d, J = 5.4 Hz, 1H);
13C{1H} NMR (100 MHz, CDCl3) δ 160.9, 159.1, 149.2, 131.8, 130.7, 130.2, 128.6, 128.5, 128.3,
125.9, 122.5, 84.1, 83.8, 30.1 ; IR (film): 3331, 3059, 1674, 1270, 756, 691 cm-1; HRMS (EI): m/z
calcd for C18H13N3OS: 319.0779; found: 319.0782.
(5-Phenyl-1,2,3-thiadiazol-4-yl)methyl oct-2-ynoate (1k): Yield: 236.0 mg (97%); Rf = 0.5
1
(EtOAc: CH2Cl2:Hexane = 1:5:15); Pale yellow oil; H NMR (400 MHz, CDCl3) δ 7.52-7.46 (m,
5H), 5.56 (s, 2H), 2.33 (t, J = 7.1 Hz, 2H), 1.62-1.54 (m, 2H), 1.42-1.27 (m, 4H), 0.90 (t, J = 7.1 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 156.4, 153.3, 152.2, 130.6, 129.6, 129.5, 126.9, 91.4, 72.6,
58.8, 31.1, 27.2, 22.2, 18.8, 14.0; IR (film): 2932, 2861, 2232, 1715, 1238, 1072, 696 cm-1; HRMS
(EI): m/z calcd for C17H18N2O2S: 314.1089; found: 314.1093.
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Pent-2-yn-1-yl 5-(p-tolyl)-1,2,3-thiadiazole-4-carboxylate (1m): Yield: 277.8 mg (97%); Rf = 0.6
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(EtOAc:CH2Cl2:Hexane = 1:5:15); White solid; Melting point: 68-70 C; H NMR (400 MHz,
CDCl3) δ 7.47-7.44 (m, 2H), 7.30-7.28 (m, 2H), 4.95 (t, J = 2.2 Hz, 2H), 2.43 (s, 3H), 2.26-2.20 (m,
2H), 1.14 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.9, 160.1, 147.5, 141.4, 129.9,
129.6, 122.9, 89.9, 72.7, 54.3, 21.6, 13.6, 12.6; IR (film): 2920, 2227, 1735, 1478, 1442, 1375, 1324,
1281, 1166, 990, 829, 691 cm-1; HRMS (EI): m/z calcd for C15H14N2O2S: 286.0776; found:
286.0777.
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3-Phenylprop-2-yn-1-yl 5-(p-tolyl)-1,2,3-thiadiazole-4-carboxylate (1n): Yield: 317.7 mg (95%);
Rf = 0.5 (EtOAc:CH2Cl2: Hexane = 1:5:15); Yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.48-7.43 (m,
4H), 7.37-7.28 (m, 5H), 5.20 (s, 2H), 2.39 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.1, 160.0,
147.4, 141.5, 132.0, 129.9, 129.6, 129.0, 128.4, 122.8, 122.1, 87.3, 82.2, 54.2, 21.5; IR (film): 2920,
2231, 1735, 1478, 1442, 1375, 1324, 1280, 1166, 990, 757, 691 cm-1; HRMS (EI): m/z calcd for
C19H14N2O2S: 334.0776; found: 334.0776.
Pent-2-yn-1-yl 5-(4-methoxyphenyl)-1,2,3-thiadiazole-4-carboxylate (1o): Yield: 124.0 mg
(41%); Rf = 0.5 (EtOAc:CH2Cl2: Hexane = 1:5:15); White solid; Melting point: 71-73 oC; 1H NMR
(400 MHz, CDCl3) δ 7.56-7.52 (m, 2H), 7.01-6.97 (m, 2H), 4.97 (t, J = 2.2 Hz, 2H), 3.87 (s, 3H),
2.27-2.20 (m, 2H), 1.14 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.8, 161.9, 160.2,
147.0, 131.7, 117.9, 114.4, 89.8, 72.7, 55.6, 54.2, 13.6, 12.6; IR (film): 2976, 2938, 2839, 2239,
1732, 1605, 1476, 1257, 1168, 985, 835, 784 cm-1; HRMS (EI): m/z calcd for C15H14N2O3S:
302.0725; found: 302.0728.
3-Phenylprop-2-yn-1-yl 5-(4-methoxyphenyl)-1,2,3-thiadiazole-4-carboxylate (1p): Yield: 332.9
o
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mg (95%); Rf = 0.5 (EtOAc:CH2Cl2:Hexane = 1:5:15); Orange solid; Melting point: 87-89 C; H
NMR (400 MHz, CDCl3) δ 7.57-7.53 (m, 2H), 7.46-7.44 (m, 2H), 7.37-7.29 (m, 3H), 7.00-6.95 (m,
2H), 5.21 (s, 2H), 3.82 (s, 3H); C{1H} NMR (100 MHz, CDCl3) δ 163.0, 161.9, 160.2, 146.9,
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132.1, 131.7, 129.0, 128.4, 122.2, 117.8, 114.4, 87.3, 82.3, 55.5, 54.2; IR (film): 2936, 2837, 2233,
1732, 1604, 1475, 1294, 1256, 1165, 1030, 835, 691 cm-1; HRMS (EI): m/z calcd for C19H14N2O3S:
350.0725; found: 350.0723.
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Pent-2-yn-1-yl 5-(benzo[d][1,3]dioxol-5-yl)-1,2,3-thiadiazole-4-carboxylate (1q): Yield: 230.9
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mg (73%); Rf = 0.4 (EtOAc: CH2Cl2:Hexane = 1:5:15); White solid; Melting point: 88-90 C; H
NMR (400 MHz, CDCl3) δ 7.08-7.05 (m, 2H), 6.90-6.88 (m, 1H), 6.06 (s, 2H), 4.97 (t, J = 2.2 Hz,
2H), 2.27-2.21 (m, 2H), 1.14 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.5, 160.1,
150.1, 148.2, 147.3, 124.9, 119.1, 110.2, 108.7, 102.0, 89.9, 72.6, 54.3, 13.6, 12.6; IR (film): 2977,
2938, 2907, 2239, 1732, 1509, 1471, 1316, 1243, 1175, 1037, 973, 815 cm-1; HRMS (EI): m/z calcd
for C15H12N2O4S: 316.0518; found: 316.0515.
3-Phenylprop-2-yn-1-yl
5-(benzo[d][1,3]dioxol-5-yl)-1,2,3-thiadiazole-4-carboxylate
(1r):
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Yield: 164.0 mg (45%); Rf = 0.4 (EtOAc:CH2Cl2:Hexane = 1:5:15); Colorless Oil; H NMR (400
MHz, CDCl3) δ 7.48-7.44 (m, 2H), 7.37-7.29 (m, 3H), 7.09-7.05 (m, 2H), 6.89-6.87 (m, 1H), 6.00
(s, 2H), 5.21 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.8, 160.0, 150.2, 148.2, 147.2, 132.1,
129.0, 128.4, 124.8, 122.1, 119.0, 110.2, 108.7, 102.0, 87.4, 82.2, 54.3; IR (film): 2902, 2782, 2237,
1733, 1509, 1470, 1316, 1244, 1172, 1036, 963, 757 cm-1; HRMS (EI): m/z calcd for
C19H12N2O4S: 364.0518; found: 364.0515.
Pent-2-yn-1-yl 5-(4-bromophenyl)-1,2,3-thiadiazole-4-carboxylate (1s): Yield: 277.5 mg (79%);
o
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Rf = 0.5 (EtOAc:CH2Cl2: Hexane = 1:5:15); Yellow solid; Melting point: 91-93 C; H NMR (400
MHz, CDCl3) δ 7.64-7.61 (m, 2H), 7.44-7.41 (m, 2H), 4.95 (t, J = 2.2 Hz, 2H), 2.27-2.20 (m, 2H),
1.14 (t, J = 7.5 Hz, 3H); C{1H} NMR (100 MHz, CDCl3) δ 161.4, 159.8, 147.9, 132.1, 131.5,
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125.6, 124.9, 90.1, 72.4, 54.5, 13.6, 12.6; IR (film): 2976, 2937, 2239, 1732, 1587, 1470, 1375,
1320, 1172, 1071, 984, 831 cm-1; HRMS (EI): m/z calcd for C14H1179BrN2O2S: 349.9725,
C14H1181BrN2O2S: 351.9705; found: 349.9724, 351.9703.
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mg (42%); Rf = 0.5 (EtOAc: CH2Cl2:Hexane = 1:5:15); Yellow oil; H NMR (400 MHz, CDCl3) δ
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7.63-7.59 (m, 2H), 7.46-7.42 (m, 4H), 7.37-7.30 (m, 3H), 5.19 (s, 2H); C{1H} NMR (100 MHz,
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CDCl3) δ 161.5, 159.7, 147.8, 132.1, 132.0, 131.4, 129.1, 128.5, 125.6, 124.8, 122.0, 87.5, 82.0,
54.4; IR (film): 3057, 2938, 2234, 1734, 1587, 1470, 1321, 1271, 1169, 981, 756, 691 cm-1; HRMS
(EI): m/z calcd for C18H1179BrN2O2S: 397.9725, C18H1181BrN2O2S: 399.9705; found: 397.9723,
399.9709.
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Pent-2-yn-1-yl 5-(furan-2-yl)-1,2,3-thiadiazole-4-carboxylate (1u): Yield: 175.7 mg (67%); Rf =
0.5 (EtOAc:CH2Cl2:Hexane = 1:5:15); White solid; Melting point: 105-107 oC; 1H NMR (400 MHz,
CDCl3) δ 7.90 (dd, J = 3.6 Hz, 0.6 Hz, 1H), 7.65 (dd, J = 1.8 Hz, 0.6 Hz, 1H), 6.65 (dd, J = 3.7 Hz,
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1.8 Hz, 1H), 5.07 (t, J = 2.2 Hz, 2H), 2.29-2.23 (m, 2H), 1.16 (t, J = 7.5 Hz, 3H); C{1H} NMR
(100 MHz, CDCl3) δ 160.4, 151.3, 146.9, 144.4, 143.2, 117.6, 113.6, 90.1, 72.8, 54.4, 13.6, 12.7; IR
(film): 3147, 2981, 2938, 2247, 1717, 1573, 1480, 1310, 1219, 1029, 981, 774 cm-1; HRMS (EI):
m/z calcd for C12H10N2O3S: 262.0412; found: 262.0409.
3-Phenylprop-2-yn-1-yl 5-(furan-2-yl)-1,2,3-thiadiazole-4-carboxylate (1v): Yield: 214.1 mg
o
(69%); Rf = 0.5 (EtOAc:CH2Cl2: Hexane = 1:5:15); Pale yellow solid; Melting point: 88-90 C; 1H
NMR (400 MHz, CDCl3) δ 7.92 (dd, J = 3.7 Hz, 0.6 Hz, 1H), 7.65 (dd, J = 1.8 Hz, 0.7 Hz, 1H),
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7.50-7.46 (m, 2H), 7.37-7.29 (m, 3H), 6.65 (dd, J = 3.6 Hz, 1.8 Hz, 1H), 5.32 (s, 2H); C{1H}
NMR (100 MHz, CDCl3) δ 160.3, 151.5, 147.0, 144.3, 143.1, 132.1, 129.0, 128.4, 122.1, 117.8,
113.7, 87.5, 82.4, 54.4; IR (film): 3050, 2938, 2233, 1725, 1488, 1312, 1223, 1172, 1031, 964, 879,
754 cm-1; HRMS (EI): m/z calcd for C16H10N2O3S: 310.0412; found: 310.0415.
Pent-2-yn-1-yl 5-(thiophen-2-yl)-1,2,3-thiadiazole-4-carboxylate (1w): Yield: 264.4 mg (95%);
o
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Rf = 0.6 (EtOAc:CH2Cl2: Hexane = 1:5:15); Ivory solid; Melting point: 75-77 C; H NMR (400
MHz, CDCl3) δ 7.78 (dd, J = 3.8 Hz, 1.2 Hz, 1H), 7.64 (dd, J = 5.2 Hz, 1.2 Hz, 1H), 7.19-7.17 (m,
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1H), 5.05 (t, J = 2.2 Hz, 2H), 2.28-2.22 (m, 2H), 1.15 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 160.3, 155.8, 145.7, 133.5, 132.2, 128.5, 126.0, 90.0, 72.7, 54.5, 13.5, 12.6; IR (film):
3106, 2975, 2313, 2238, 1721, 1513, 1463, 1298, 1175, 1147, 959, 732, 652 cm-1; HRMS (EI): m/z
calcd for C12H10N2O2S2: 278.0184; found: 278.0184.
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3-Phenylprop-2-yn-1-yl 5-(thiophen-2-yl)-1,2,3-thiadiazole-4-carboxylate (1x): Yield: 320.0 mg
(98%); Rf = 0.6 (EtOAc: CH2Cl2:Hexane = 1:5:15); White solid; Melting point: 85-87 oC; 1H NMR
(400 MHz, CDCl3) δ 7.79 (dd, J = 3.8 Hz, 1.2 Hz, 1H), 7.64 (dd, J = 5.1 Hz, 1.2 Hz, 1H), 7.49-7.46
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(m, 2H), 7.36-7.29 (m, 3H), 7.18-7.16 (m, 1H), 5.30 (s, 2H); C{1H} NMR (100 MHz, CDCl3) δ
160.3, 156.0, 145.6, 133.6, 132.3, 132.1, 129.0, 128.6, 128.4, 126.0, 122.1, 87.5, 82.3, 54.5; IR
(film): 2920, 2850, 2330, 2230, 1726, 1466, 1273, 1210, 1165, 965, 755, 690 cm-1; HRMS (EI): m/z
calcd for C16H10N2O2S2: 326.0184; found: 326.0181.
Pent-2-yn-1-yl 5-cyclohexyl-1,2,3-thiadiazole-4-carboxylate (1y): Yield: 192.1 mg (69%); Rf =
1
0.6 (EtOAc:CH2Cl2:Hexane = 1:5:15); Yellow Oil; H NMR (400 MHz, CDCl3) δ 5.03 (t, J = 2.2
Hz, 2H), 3.84-3.76 (m, 1H), 2.29-2.22 (m, 2H), 2.18-2.14 (m, 2H), 1.89-1.78 (m, 3H), 1.54-1.43 (m,
2H), 1.39-1.24 (m, 3H), 1.15 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 173.4, 160.3,
148.0, 89.8, 72.8, 54.1, 37.1, 36.2, 26.3, 25.6, 13.6, 12.6; IR (film): 2976, 2931, 2852, 2240, 2117,
1725, 1486, 1313, 1193, 1130, 997, 786 cm-1; HRMS (EI): m/z calcd for C14H18N2O2S: 278.1089;
found: 278.1093.
3-Phenylprop-2-yn-1-yl 5-cyclohexyl-1,2,3-thiadiazole-4-carboxylate (1z): Yield: 267.7 mg
(82%); Rf = 0.6 (EtOAc:CH2Cl2:Hexane = 1:5:15); Yellow Oil; 1H NMR (400 MHz, CDCl3) δ 7.48-
7.46 (m, 2H), 7.36-7.29 (m, 3H), 5.27 (s, 2H), 3.85-3.78 (m, 1H), 2.17 (d, J = 11.5 Hz, 2H), 1.89-
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1.78 (m, 3H), 1.55-1.43 (m, 2H), 1.39-1.23 (m, 3H); C{1H} NMR (100 MHz, CDCl3) δ 173.6,
160.2, 147.8, 132.0, 128.9, 128.4, 122.1, 87.2, 82.4, 54.0, 37.1, 36.1, 26.3, 25.5; IR (film): 2929,
2852, 2235, 1727, 1488, 1444, 1313, 1192, 1129, 997, 757, 691 cm-1; HRMS (EI): m/z calcd for
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C18H18N2O2S: 326.1089; found: 326.1086.
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2. Preparation of alkynyl thiadiazoles (3a-3f) : To a solution of the alcohol18 (1.0 mmol), 4-
dimethylaminopyridine (DMAP, 0.10 mmol, 36.7 mg), and thiadiazole-4-carboxylic acid (5)16 (1.3
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mmol, 822.8 mg) in dry DCE (10 mL) at 0 C under a nitrogen atmosphere was added N,N’-
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dicyclohexylcarbodiimide (DCC, 1.3 mmol, 823.3 mg) 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 another 3 h. Then, reaction mixture was filtered by Celite and the mixture was
washed by CH2Cl2 (3 x 10 mL). The combined filtrate was evaporated under reduced pressure to
give the crude product, which was purified by silica gel chromatography (EtOAc:CH2Cl2:Hexane =
1:5:15) to provide the pure product 3.17
But-3-yn-1-yl 5-phenyl-1,2,3-thiadiazole-4-carboxylate (3a): Yield: 155.0 mg (60%); Rf = 0.5
(EtOAc:CH2Cl2:Hexane = 1:5:15); Colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.55-7.46 (m, 5H),
4.47 (t, J = 7.0 Hz, 2H), 2.60 (td, J = 7.0 Hz, 2.7 Hz, 2H), 2.00 (t, J = 2.7 Hz, 1H); 13C{1H} NMR
(100 MHz, CDCl3) δ 162.4, 160.1, 148.0, 130.8, 129.8, 128.8, 126.0, 79.5, 70.5, 63.6, 18.9; IR
(film): 3288, 2963, 2918, 1731, 1474, 1330, 1281, 1178, 1003, 840, 751, 694 cm-1; HRMS (EI): m/z
calcd for C13H10N2O2S: 258.0463; found: 258.0459.
Hex-3-yn-1-yl 5-phenyl-1,2,3-thiadiazole-4-carboxylate (3b): Yield: 203.3 mg (71%); Rf = 0.5
1
(EtOAc:CH2Cl2:Hexane = 1:5:15); Yellow oil; H NMR (400 MHz, CDCl3) δ 7.56-7.46 (m, 5H),
4.42 (t, J = 7.2 Hz, 2H), 2.55 (tt, J = 7.2 Hz, 2.4 Hz, 2H), 2.13 (qt, J = 12.5 Hz, 2.4 Hz, 2H), 1.09 (t,
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J = 7.5 Hz, 3H); C{1H} NMR (100 MHz, CDCl3) δ 162.2, 160.2, 148.2, 130.8, 129.9, 128.7,
126.1, 83.9, 74.3, 64.3, 19.2, 14.1, 12.4; IR (film): 2974, 2936, 1733, 1474, 1388, 1330, 1281, 1179,
1005, 845, 752, 694 cm-1; HRMS (EI): m/z calcd for C15H14N2O2S: 286.0776; found: 286.0779.
4-Phenylbut-3-yn-1-yl 5-phenyl-1,2,3-thiadiazole-4-carboxylate (3c): Yield: 210.7 mg (63%); Rf
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= 0.4 (EtOAc:CH2Cl2:Hexane = 1:5:15); Yellow oil; H NMR (400 MHz, CDCl3) δ 7.54-7.43 (m,
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5H), 7.38-7.36 (m, 2H), 7.29-7.27 (m, 3H), 4.55 (t, J = 7.0 Hz, 2H), 2.82 (t, J = 7.0 Hz, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ 162.4, 160.2, 148.2, 131.7, 130.8, 129.9, 128.8, 128.3, 128.1,
126.1, 123.3, 85.0, 82.5, 63.8, 19.9; IR (film): 3059, 2961, 2916, 2360, 2341, 1732, 1474, 1330,
1281, 1177, 1004, 755, 692 cm-1; HRMS (EI): m/z calcd for C19H14N2O2S: 334.0776; found:
334.0778.
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2-(Hex-1-yn-1-yl)phenyl 5-phenyl-1,2,3-thiadiazole-4-carboxylate (3d): Yield: 235.6 mg (65%);
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Rf = 0.4 (EtOAc:Hexane = 1:15); Yellow oil, H NMR (400 MHz, CDCl3)  7.66-7.64 (m, 2H),
7.52-7.44 (m, 4H), 7.33-7.29 (m, 1H), 7.23 (m, 2H), 2.29 (t, J = 6.9 Hz, 2H), 1.39-1.25 (m, 4H),
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0.76 (t, J = 7.2 Hz, 3H); C{1H} NMR (100 MHz, CDCl3) ; 163.6, 158.4, 151.1, 147.1, 133.1,
130.9, 130.0, 128.8, 128.7, 126.3, 125.7, 121.9, 118.2, 96.2, 75.5, 30.5, 21.8, 19.2, 13.5; IR (film)
3062, 2957, 2232, 1752, 1186, 752 cm-1; HRMS (EI) m/z calcd. For C21H18N2O2S: 362.1089,
found : 362.1087.
2-(Phenylethynyl)phenyl 5-phenyl-1,2,3-thiadiazole-4-carboxylate (3e): Yield: 290.6 mg (76%);
Rf = 0.2 (EtOAc:CH2Cl2:Hexane = 1:1:20); Yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.61-7.59 (m,
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1H), 7.55-7.53 (m, 2H), 7.45-7.39 (m, 1H), 7.38-7.33 (m, 3H), 7.31-7.21 (m, 7H); C{1H} NMR
(100 MHz, CDCl3) δ 163.9, 158.5, 151.2, 147.1, 133.1, 131.5, 130.9, 129.9, 129.6, 128.7, 128.6,
128.3, 126.5, 125.6, 122.7, 122.2, 117.6, 94.9, 84.3; IR (film): 3060, 2220, 1752, 1195, 754, 691
cm-1; HRMS (EI): m/z calcd for C23H14N2O2S: 382.0776; found: 382.0776.
4-Chloro-2-(phenylethynyl)phenyl 5-phenyl-1,2,3-thiadiazole-4-carboxylate (3f): Yield: 219.2
o
1
mg (58%); Rf = 0.3 (Ether:Hexane = 1:4); White solid; Melting point: 127-129 C; H NMR (400
MHz, CDCl3) δ 7.59 (d, J = 2.5 Hz, 1H), 7.55-7.53 (m, 2H), 7.49-7.45 (m, 1H), 7.41-7.34 (m, 3H),
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7.31-7.26 (m, 5H), 7.21 (d, J = 8.7 Hz, 1H); C{1H} NMR (100 MHz, CDCl3) δ 164.1, 158.2,
149.7, 146.8, 132.6, 131.9, 131.6, 131.0, 129.9, 129.5, 128.9, 128.8, 128.4, 125.4, 123.4 122.2,
119.2, 96.0, 83.0; IR (film): 3060, 2223, 1753, 1140, 864, 690 cm-1; HRMS (EI): m/z calcd for
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C23H13ClN2O2S: 416.0386; found: 416.0384
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3. General procedure for alkynyl thiadiazoles (1l, 3g-3i): Compounds (1l, 3g-3i) were prepared
from thiadiazoles15 as shown. Thiadiazole was reacted with DIBAL-H to give (1,2,3-thiadiazol-4-
yl)methanol19 in THF. To an oven-dried round-bottom flask equipped with a magnetic stirring bar
under a nitrogen atmosphere was added (1,2,3-thiadiazol-4-yl)methanol (1.0 mmol) and DMF (3.0
mL). Sodium hydride was added as a 95% suspension in mineral oil (3.0 mmol, 72 mg) and the
mixture was let stir at room temperature for 30 min. Alkynyl halide (5.0 mmol , 0.51 mL) was
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added and the mixture was stirred at 100 C for 2 h. All volatiles were removed in vacuo and the
resulting residue was partitioned between water and ethyl acetate. 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 1 and 3.
4-((Pent-2-yn-1-yloxy)methyl)-5-phenyl-1,2,3-thiadiazole (1l): Yield: 194.1 mg (75%); Rf = 0.5
(EtOAc:Hexane = 1:5); Orange oil; 1H NMR (400 MHz, CDCl3) δ 7.65-7.63 (m, 2H), 7.51-7.49 (m,
3H), 4.98 (s, 2H), 4.33 (t, J = 2.2 Hz, 2H), 2.21 (qt, J = 12.5 Hz, 2.1 Hz, 2H), 1.13 (t, J = 7.5 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 156.0, 154.8, 130.3, 129.8, 129.4, 127.6, 89.4, 74.8, 62.6,
58.6, 13.9, 12.6; IR (film): 3063, 2976, 2936, 1245, 1074, 697 cm-1; HRMS (EI): m/z calcd for
C14H14N2OS: 258.0827; found: 258.0830.
4-((Pent-4-yn-1-yloxy)methyl)-5-phenyl-1,2,3-thiadiazole (3g): Yield: 240.3 mg (93%); Rf = 0.6
(EtOAc:Hexane = 1:5); Yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.64-7.61 (m, 2H), 7.52-7.49 (m,
3H), 4.91 (s, 2H), 3.74 (t, J = 6.1 Hz, 2H), 2.29 (td, J = 10.5 Hz, 2.7 Hz, 2H), 1.94 (t, J = 2.7 Hz,
1H), 1.85 (quintet, J = 6.5 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 155.9, 155.2, 130.3, 129.6,
129.4, 127.7, 83.7, 68.86, 68.80, 64.1, 28.6, 15.3; IR (film): 3294, 3062, 2867, 1102, 697, 637 cm-1;
HRMS (EI): m/z calcd for C14H14N2OS: 258.0827; found: 258.0823.
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5-Phenyl-4-(((5-phenylpent-4-yn-1-yl)oxy)methyl)-1,2,3-thiadiazole (3h): Yield: 138.2 mg
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5
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(41%); Rf = 0.4 (EtOAc:Hexane = 1:10); Yellow oil; H NMR (400 MHz, CDCl3) δ 7.64-7.62 (m,
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2H), 7.50-7.47 (m, 3H), 7.37-7.34 (m, 2H), 7.29-7.26 (m, 3H), 4.93 (s, 2H), 3.79 (t, J = 6.1 Hz, 2H),
2.52 (t, J = 7.0 Hz, 2H), 1.93 (quintet, J = 6.5 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 155.9,
155.2, 131.7, 130.3, 129.6, 129.4, 128.3, 127.74, 127.69, 124.0, 89.3, 81.2, 69.1, 64.1, 28.9, 16.4;
IR (film): 3059, 2865, 2233, 1101, 757, 693 cm-1; HRMS (EI): m/z calcd for C20H18N2OS:
334.1140; found: 334.1142.
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4-((Hex-5-yn-1-yloxy)methyl)-5-phenyl-1,2,3-thiadiazole (3i): Yield: 239.7 mg (88%); Rf = 0.6
1
(EtOAc:Hexane = 1:5); Pale Yellow oil; H NMR (400 MHz, CDCl3) δ 7.64-7.61 (m, 2H), 7.51-
7.49 (m, 3H), 4.89 (s, 2H), 3.65 (t, J = 6.3 Hz, 2H), 2.20 (td, J = 10.6 Hz, 2.6 Hz, 2H), 1.94 (t, J =
13
2.6 Hz, 1H), 1.80-1.73 (m, 2H), 1.65-1.57 (m, 2H); C{1H} NMR (100 MHz, CDCl3) δ 155.7,
155.3, 130.3, 129.6, 129.4, 127.7, 84.3, 70.2, 68.6, 64.0, 28.8, 25.2, 18.3; IR (film): 3294, 2939,
2865, 1092, 697, 635 cm-1; HRMS (EI): m/z calcd for C15H16N2OS: 272.0983; found: 272.0984.
4. General procedure for transannulation of alkynyl thiadiazoles for the synthesis of 5,5-fused
thiophenes: To a test tube were added [Rh(COD)Cl]2 (0.01 mmol, 4.9 mg), DPPF (0.024 mmol,
13.3 mg), and alkynyl thiadiazoles (1) (0.2 mmol) in chlorobenzene (1.0 mL). The resulting mixture
o
was stirred at 130 C for 30 min under nitrogen atmosphere. After celite filtration and evaporation
of the solvents in vacuo, the crude product was purified by column chromatography on silica gel
using Et2O:Hexane = 1:4.
4-Butyl-6-phenylthieno[3,4-c]furan-1(3H)-one (2a): Yield: 51.7 mg (95%); Rf = 0.4
o
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(Ether:Hexane = 1:4); Ivory solid; Melting point: 72-74 C; H NMR (400 MHz, CDCl3) δ 8.02-
7.99 (m, 2H), 7.44-7.40 (m, 2H), 7.37-7.33 (m, 1H), 5.13 (s, 2H), 2.74 (q, J = 7.6 Hz, 2H), 1.71-
13
1.64 (m, 2H), 1.47-1.38 (m, 2H), 0.97 (t, J = 7.3 Hz, 3H); C{1H} NMR (100 MHz, CDCl3) δ
164.3, 145.1, 144.1, 133.0, 131.7, 129.2, 129.0, 127.9, 125.7, 66.2, 32.8, 27.9, 22.4, 13.9; IR (film):
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2955, 2929, 1751, 1090, 1020, 754 cm-1; HRMS (EI): m/z calcd for C16H16O2S: 272.0871; found:
272.0868.
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6-Phenylthieno[3,4-c]furan-1(3H)-one (2b)12c: Yield: 31.1 mg (72%); Rf = 0.4 (Ether:Hexane =
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1:4); Ivory solid; Melting point: 124-126 C; H NMR (400 MHz, CDCl3) δ 8.07-8.04 (m, 2H),
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7.47-7.43 (m, 2H), 7.41-7.37 (m, 1H), 6.98 (t, J = 1.4 Hz, 1H), 5.21 (d, J = 1.4 Hz, 2H); C{1H}
NMR (100 MHz, CDCl3) δ 164.0, 148.6, 148.0, 131.1, 129.6, 129.0, 128.0, 126.1, 112.7, 66.5; IR
(film): 3105, 2945, 1751, 1115, 1053, 756 cm-1; HRMS (EI): m/z calcd for C12H8O2S: 216.0245;
found: 216.0241.
4-Methyl-6-phenylthieno[3,4-c]furan-1(3H)-one (2c): Yield: 40.1 mg (87%); Rf = 0.4
(Ether:Hexane = 1:4); Ivory solid; Melting point: 111-113 oC; 1H NMR (400 MHz, CDCl3) δ 8.01-
7.99 (m, 2H), 7.44-7.40 (m, 2H), 7.37-7.33 (m, 1H), 5.11 (d, J = 1.1 Hz, 2H), 2.40 (t, J = 1.0 Hz,
3H); C{1H} NMR (100 MHz, CDCl3) δ 164.4, 145.3, 144.8, 131.6, 129.3, 129.0, 127.8, 127.0,
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125.8, 66.1, 13.0; IR (film): 3064, 2919, 1752, 1342, 1113, 756 cm-1; HRMS (EI): m/z calcd for
C13H10O2S: 230.0402; found: 230.0400.
4-Ethyl-6-phenylthieno[3,4-c]furan-1(3H)-one (2d): Yield: 43.5 mg (89%); Rf = 0.4
o
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(Ether:Hexane = 1:4); Ivory solid; Melting point: 78-80 C; H NMR (400 MHz, CDCl3) δ 8.01-
7.99 (m, 2H), 7.43-7.40 (m, 2H), 7.36-7.33 (m, 1H), 5.14 (s, 2H), 2.78 (q, J = 7.5 Hz, 2H), 1.32 (t, J
= 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 164.3, 144.9, 143.7, 134.3, 131.6, 129.2, 129.0,
127.8, 125.7, 66.2, 21.7, 15.0; IR (film): 2973, 2959, 1746, 1588, 1454, 1116 cm-1; HRMS (EI): m/z
calcd for C14H12O2S: 244.0558; found: 244.0561.
4,6-Diphenylthieno[3,4-c]furan-1(3H)-one (2e)20: Yield: 52.0 mg (89%); Rf = 0.4 (Ether:Hexane =
o
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1:4); Yellow solid; Melting point: 139-141 C; H NMR (400 MHz, CDCl3) δ 8.08-8.06 (m, 2H),
7.46-7.40 (m, 4H), 7.39-7.32 (m, 4H), 5.35 (s, 2H); C{1H} NMR (100 MHz, CDCl3) δ 163.9,
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146.1, 143.6, 132.1, 131.5, 131.2, 129.7, 129.5, 129.1, 128.3, 128.1, 127.0, 126.0, 67.2; IR (film):
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