Temperature-Controlled Thiation of α-Cyano-β-Alkynyl Carbonyl Derivatives for de Novo Synthesis of 2-Aminothiophenes and Thieno[2,3- c]isothiazoles

Article abstract of DOI:10.1021/acs.joc.8b01866

Making use of temperature-controlled thiation as a key operation, a simple route to 2-aminothiophenes or thieno[2,3-c]isothiazoles has been newly developed wherein the 2-aminothiophene nucleus was formed through an initial formation of thioamide followed

Full text of DOI:10.1021/acs.joc.8b01866

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Note
Temperature-Controlled Thiation of #-Cyano-#-Alkynyl Carbonyl Derivatives
for De Novo Synthesis of 2-Aminothiophenes and Thieno[2,3-c]isothiazoles
Tzu-Ting Kao, Bo-Kai Peng, Min-Chieh Liang, Chia-Jui Lee, I-Chia Chen, Kak-Shan Shia, and Yen-Ku Wu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01866 • Publication Date (Web): 02 Oct 2018
Downloaded from http://pubs.acs.org on October 2, 2018
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The Journal of Organic Chemistry
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Temperature-Controlled Thiation of α-Cyano-β-Alkynyl Carbonyl
Derivatives for De Novo Synthesis of 2-Aminothiophenes and
Thieno[2,3-c]isothiazoles
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Tzu-Ting Kao†, Bo-Kai Peng‡, Min-Chieh Liang‡, Chia-Jui Lee†, I-Chia Chen§, Kak-Shan Shia*† and
Yen-Ku Wu*‡
† Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli 35053, Taiwan
‡ Department of Applied Chemistry, National Chiao Tung University, 1001 University Road, Hsinchu 30010, Taiwan
§ Department of Cosmetic Applications and Management, Cardinal Tien Junior College of Healthcare and Management, New
Taipei City 23143, Taiwan
Supporting Information Placeholder
P4S10, EtOH
80 °C; then
EWG
CN
Ar
S
EWG
NH2
P4S10, EtOH
R
R
80 °C, air
LR, p-xylene
130 °C, air
S
S
N
R
14 examples
up to 95% yield
EWG = COR, CO2R, CN, SO2R
R = aryl, alkyl, H, TMS, CH2OBn
15 examples
up to 73% yeild
ABSTRACT: Making use of temperature-controlled thiation as a key operation, a simple route to 2-aminothiophenes or thieno[2,3-
c]isothiazoles has been newly developed wherein the 2-aminothiophene nucleus was formed through an initial formation of thioam-
ide followed by a 5-exo-dig addition to the tethered alkyne; however, under harsher thermal conditions, excess sulfur-transferring
reagents
enabled
further
oxidative
thiation
to
generate
the
corresponding
thieno[2,3-c]isothiazoles.
Heterocycles are common structural motifs in marketed
pharmaceutical drugs.1 The search and identification of small
heterocyclic molecules with desirable pharmacological proper-
ties are therefore essential for the progress in medicinal chem-
istry. Over the past decades, the practice of drug discovery has
revealed that selected heterocycles seem to occupy biological-
ly relevant regions of vast chemical space.2 Accordingly, those
prominent structures have been collectively coined as the priv-
ileged scaffold.3 In the subset of sulfur-containing structures,
the 2-aminothiophene core has received considerable attention
because an increasing number of drug candidates, agrochemi-
cals, and dyestuffs based on this modality has been widely
developed (Figure 1).4 To expand the sulfur chemistry in this
field, facile synthetic approaches to novel 2-aminothiophene
analogs are evidently in high demand.
Scheme 1. Thiation Reactions of Activated Nitriles
a) The Gewald reaction:
R1
R2
EWG
NH2
N
S
EWG
O
CN
EWG
R1
S8
+
amine
R2
S
P
R1
R2
S
b) Pedersen and Lawesson:
Ar
Lawesson's
reagent (LR)
Ar
S
S
O
P
LR =
P
O
NH
S
S
Ar
CN
Ph
toluene, 110 °C
Ph
S
Ar = 4-MeOPh
c) This work:
EWG CN
Ar
EWG
NH2
thiation agent
solvent, temp.
R
or
R
S
S
N
S
O
O
1
R
3
4 (EWG = COAr)
Me
Me
NH2
NH
Cl
CF3
Me
N
NH2
S
S
F
Several methods have been documented for the de novo as-
sembly of 2-aminothiophenes from acyclic precursors.5 A pio-
neering example was published by Gewald and co-workers in
1966 wherein the authors discovered that amine-mediated
three-component coupling of ketones, activated nitriles, and
sulfur resulted in the formation of functionalized 2-
aminothiophenes (Scheme 1a).6 Arguably, the Gewald reaction
and its variants constitute the most widely used protocols for
N
NH2
PD81723
TPCA-1
O
O
N
O
N
OMe
NH2
S
Cl
H
N
Bn
olanzepine
(Zyprexa®)
NH2
T-62
S
S
tinoridine
Figure 1. Bioactive 2-Aminothiophene Derivatives
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,
the preparation of 2-aminothiophenes.7 8 Alternative strategies
for 2-aminothiophene syntheses mainly relied on various cy-
Table 1. Screening of Reaction Conditions
1
2
,
, ,
clization reactions of activated thioamides.9 10 11 12
O
O
S
Ph
3
4
5
6
7
8
9
Ph
NH2
As illustrated in Scheme 1b, Pedersen and Lawesson report-
ed that α-cyano acetophenone could be efficiently converted
into an oxazaphosphorine derivative under the treatment with
Lawesson’s reagent (LR).13 This work together with Gewald’s
thiophene synthesis inspired us to probe a potential new reac-
tion via the treatment of alkyne-appended β-ketonitriles with
various sulfur-transferring reagents (Scheme 1c). During the
course of the investigation, we found that a complete control
over creating either 2-aminothiophene 3 or thieno[2,3-
c]isothiazole 4 could be readily fulfilled by tuning the reaction
parameters as detailed in the following.
Ph
O
NH2
S
[S]
CN
Ph
2a
3a
Ph
solvent
temp., air
Ph
Ph
1a
Ph
≡
S
S
N
4a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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25
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50
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57
58
59
60
solvent/temp.
(°C)
yield%
yield% yield%
entry
[S]
of 2aa
of 3aa
of 4aa
−
1
P4S10
LR
EtOH/rt
23
46b
−
−
Scheme 2. Preparation of Alkyne-Appended Nitriles
2
THF/rt
−
−
3
P4S10
LR
EtOH/80
83
36
−
−
L-proline
Hantzsch ester
EWG
CN
O
4
EtOH/80
−
−
EWG
CN
+
5
P4S10
LR
p-xylene/130
p-xylene/130
p-xylene/130
toluene/100
dioxane/100
−
22
58
44
−
EtOH, 70 °C
R
1
R
6
−
−
7c
8d
9e
LR
−
−
1a: EWG = C(O)Ph; R = Ph
1b: EWG = C(O)Ph; R = 4-MePh
1c: EWG = C(O)Ph; R = 4-ClPh
1l: EWG = SO2Tol; R = Ph
1m: EWG = CN; R = Ph
1n: EWG = C(O)2-thienyl; R = 4-MePh
S8
−
−
1d: EWG = C(O)2-MeOPh; R = Ph 1o: EWG = C(O)4-MeOPh; R = 4-ClPh
1e: EWG = C(O)4-MeOPh; R = Ph 1p: EWG = C(O)4-ClPh; R = 4-ClPh
NaSH
−
−
−
1f: EWG = C(O)2-furyl; R = Ph
1g: EWG = C(O)2-thienyl; R = Ph
1h: EWG = C(O)Ph; R = 2-thienyl
1q: EWG = C(O)4-MePh; R = Ph
1r: EWG = C(O)4-ClPh; R = Ph
1s: EWG = C(O)Ph; R = TMS
aYield of the isolated product. A significant amount of starting
material 1a could be recovered. Under N2 atmosphere. No reac-
tion. Mixture of unidentifiable products. LR = Lawesson’s rea-
b
c
d
e
S1: EWG = C(O)2-NO2Ph; R = TMS 1t: EWG = C(O)Ph; R = Et
1j: EWG = CO2Et; R = Ph
1k: EWG = C(O)t-Bu; R = Ph
1u: EWG = C(O)Ph; R = CH2OBn
1v: EWG = C(O)Et; R = Ph
gent.
From a mechanistic point of view (Scheme 3), the direct
conversion of 1a into 4a calls for the action of an oxidant.
Since the reactions were conducted under air, we wondered
whether oxygen is an essential factor in this process. However,
when we performed the reaction under nitrogen atmosphere,
thieno[2,3-c]isothiazole 4a was still generated in only slightly
lower yield (entry 7: 44% versus entry 6: 58%); hence, LR is
supposed to be responsible for the oxidation event. The em-
ployment of other standard thiation reagents such as octasulfur
and sodium sulfide failed to give the desired product 4a (en-
tries 9 and 10). Taken together, a plausible mechanism is pro-
posed in Scheme 3 to account for the formation of 3a and 4a.20
A series of alkyne-appended nitriles 1 were readily prepared in
good yields by a reductive condensation reaction (Scheme 2).
Compound 1a was chosen as a model substrate to study a series of
thiation reactions under air (Table 1). At room temperature, reac-
tions of 1a with either phosphorus decasulfide or Lawesson’s
reagent could deliver thioamide 2a as the sole product (entries 1
and 2).14 Notably, the sulfur-transferring reagents were found to
chemoselectively target the cyano group instead of the ketone
moiety. When the reaction was conducted with P4S10 in refluxing
ethanol,15 we observed that 2-aminothiophene 3a was formed in
good yield (83%, entry 3). At elevated temperatures (130 °C), the
LR-mediated reaction in p-xylene could furnish an unexpected
product 4a in 58% yield (entry 6), the structure of which was
unambiguously determined by X-ray crystallographic analysis as
a substituted thieno[2,3-c]isothiazole.16 To our knowledge, only a
few synthetic approaches were reported to synthesize thieno[2,3-
Scheme 3. Proposed Reaction Mechanism
,
,
18 19
c]isothiazole scaffolds. 17
Among them, Gewald and co-
O
NH2
S
O
5-exo-
dig
NH2
S
LR
workers had described the first synthesis of thieno[2,3-
c]isothiazoles involving a three-step sequence through an oxida-
tive ring closure of 2-amino-3-thioamidethiophenes.17 Serendipi-
tously, our method enables the one-pot conversion of various
alkyne-appended β-ketonitriles into thieno[2,3-c]isothiazoles in
the presence of LR (vide infra).
Ph
Ph
1a
80 °C
4a
2a
Ph
Ph
±H
LR
-H2O
±H
S
S
Ar
H
P
Ar
P
S
O
NH2
S
O
N
H
S
S
3a
Ph
Ph
S
-ArP=S
Ar = 4-OMe
130 °C
CH2Ph
CH2Ph
With the optimized reaction conditions, we first evaluated
the scope of the thiation reactions transforming α-cyano ke-
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The Journal of Organic Chemistry
alkynes also furnished the cyclized products 4k-n in 40~61%
tones 1 to 2-aminothiophenes 3 (Table 2). In general, sub-
1
2
3
4
5
6
7
8
strates with an electron-deficient and electron-rich aryl sub-
stituent afforded the cyclized products 3a-e in moderate to
good yields. The presence of heteroaromatic group was also
well tolerated (see 3f-h). 4-Alkyl-substituted thiophene 3i and
3j could be prepared from the substrate possessing a suitable
alkyne (R = H or CH2CH2OBn). In addition to aryl ketone
precursors, the method is applicable to other alkynyl carbonyl
derivatives. Ester 3k was obtained in good yield, but those
cases with the pivaloyl (see 3l) or sulfonyl (see 3m) function-
ality are less efficient due to a complex mixture formed in the
reaction. Intriguingly, the reaction of malononitrile 1m result-
ed in the formation of thienyl thioamide 3n, clearly indicating
that both nitrile groups could participate in the P4S10-mediated
thiation reaction as illustrated in Scheme 4.
yields. The modest yield of 4o was due to the labile character-
istic of alkyl ketone 1v. Although the yields are generally in a
moderate range, this protocol offers a rapid access to
thieno[2,3-c]isothiazole scaffold that would be otherwise dif-
ficult to synthesize by any existing methods.
Table 3. Scope of Thieno[2,3-c]isothiazole Synthesis via the
One-Pot Procedurea
9
R1
S
O
P4S10 (2 equiv)
EtOH, 80 °C, 3 h; then
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
R2
CN
R1
LR (1.2 equiv), p-xylene
130 °C, 1 h, air
S
N
1
4
R2
R
Table 2. Scope of 2-Aminothiophene Synthesisa
Me
MeO
Ph
S
S
EWG
NH2
EWG
CN
P4S10 (2 equiv)
Ph
S
R
S
S
N
EtOH, 80 °C, 3 h
S
N
S
N
S
3
air
R
R = H: 4a, 62% yield
R = Me: 4b, 52% yield
R = Cl: 4c, 40% yield
1
2-OMe: 4d, 60% yield
4-OMe: 4e, 55% yield
4f, 74% yield
O
O
O
X
R
OMe
Ph
R
R
Ph
NH2
Cl
Ph
NH2
NH2
S
S
S
NO2
Ph
R = H: 3a, 83% yield
R = Me: 3b, 95% yield
R = Cl: 3c, 46% yield
2-OMe: 3d, 60% yield
4-OMe: 3e, 76% yield
X = O: 3f, 89% yield
X = S: 3g, 65% yield
Me
S
S
S
S
N
S
N
S
N
O2N
O
R = Cl: 4g, 55% yield
R = OMe: 4h, 43% yield R = Cl: 4j, 56% yield
R = Me: 4i, 50% yield
4k, 41% yield
O
O
Ph
Ph
S
Me
BnO
NH2
3j, 68% yield
NH2
S
Me
NH2
3i, 89% yield
Ph
Ph
S
S
R = CH2OBn: 4l, 61% yield
S
R
R = SiMe3: 4m, 40% yieldb
3h, 76% yield
S
N
S
R = Et: 4n, 43% yield
S
N
4o, 15% yield
EWG
NH2
EWG = CO2Et: 3k, 60% yield
EWG = COt-Bu: 3l, 19% yield
EWG = SO2Tol: 3m, 9% yield
aUnless otherwise noted, all reactions were conducted following
the one-pot, two-step procedure. Yields refer to isolated products.
bOnly LR was used at 110 °C.
Ph
S
aReactions were conducted following the optimized procedure
(Table 1, entry 3). Yields refer to isolated products.
Scheme 5. Strategic Transformation of Compound 4k
Scheme 4. Reaction of Alkynyl Malononitrile 1m
I
S
NIS, DMF
NO2
NO2
NC
CN
P4S10 (2 equiv)
NH2
NH2
Me
S
Me
S
80 °C, 3 h
Ph
S
N
S
N
EtOH, 80 °C, 3 h
S
air
4k
5, 73% yield
Ph
1m
3n, 46% yield
Pd(PPh3)4 (2 mol %) PhMe/EtOH/H2O
K2CO3, 4-BrPhB(OH)2 80 °C, 16 h
For the synthesis of thieno[2,3-c]isothiazoles from 1, we
later found that a one-pot, two-step procedure gave better and
more consistent results than those solely employing Lawes-
son’s reagent in p-xylene at 130 °C (See the Experimental
Section). The reaction conditions as shown in Table 3 were
applied to examine the scope of the process. Substrates with
various substitution patterns on the aryl units (R1 and R2) were
successfully converted to the desired products 4a-j (40~74%).
The thiation reaction of terminal and alkyl- or silyl-capped
Br
Br
Fe, 2 N HCl
NH2
NO2
CHCl3/EtOH/H2O
reflux, 1.5 h
Me
S
Me
S
S
N
S
N
7, 86% yield
6, 88% yield
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tolyl)propiolaldehyde (302 mg, 2.09 mmol), L-proline (32 mg,
To showcase the utility of the method, a few advanced de-
rivatives of 4k were prepared (Scheme 5). An iodo substituent
was introduced to the thieno[2,3-c]isothiazole framework by
the treatment of 4k with N-iodosuccinimide (NIS). The result-
ing heteroaryl iodide 5 could efficiently undergo the Suzuki
coupling reaction in a co-solvent system (PhMe/EtOH/H2O) to
give an extended polyaromatic product 6 (88%). The
chemoselective reduction of the nitro group afforded 7 in good
yield (86%). Conceivably, these sample transformations might
open new opportunities for further exploring the structure-
activity relationship of a library of structurally diverse thio-
phene-derived compounds.21
1
2
3
4
5
6
7
8
0.28 mmol) and Hantzsch ester (350 mg, 1.38 mmol) in 44% yield
(190 mg) as a brown solid. 1b: IR (neat) 3029, 2923, 2244, 1698,
1596, 1510 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.03 (dd, J = 8.4,
1.2 Hz, 2H), 7.67 (tt, J = 7.4, 1.2 Hz, 1H), 7.54 (t, J = 7.8 Hz,
2H), 7.26 (d, J = 8.4 Hz, 2H), 7.09 (dd, J = 8.0, 0.4 Hz, 2H), 4.59
(t, J = 7.2 Hz, 1H), 3.14 (d, J = 7.8 Hz, 2H), 2.33 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 188.9, 138.5, 134.7, 133.9, 131.6,
129.1, 129.0, 128.9, 119.9, 116.4, 84.5, 82.7, 39.1, 21.4, 20.6;
HRMS (ESI, [M+Na]+) calcd. for C19H15NNaO: 296.1046, found:
296.1044; Rf = 0.2 (9% EtOAc/hexanes); mp 59-60 oC.
9
2-Benzoyl-5-(4-chlorophenyl)pent-4-ynenitrile (1c). According
to the procedure for the preparation of 1a, compound 1c was syn-
thesized from benzoylacetonitrile (92 mg, 0.63 mmol), 3-(4-
chlorophenyl)propiolaldehyde (150 mg, 0.91 mmol), L-proline
(14 mg, 0.12 mmol) and Hantzsch ester (154 mg, 0.61 mmol) in
68% yield (137 mg) as a brown solid. 1c: IR (neat) 3062, 2943,
2357, 2241, 1703, 1487 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.03
(d, J = 8.4 Hz, 2H), 7.68 (t, J = 7.2 Hz, 1H), 7.55 (t, J = 7.2 Hz,
2H), 7.30-7.24 (m, 4H), 7.09-7.02 (m, 2H), 4.59 (t, J = 7.2 Hz,
1H), 3.14 (d, J = 7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
188.7, 134.8, 134.5, 133.8, 132.9, 129.2, 128.9, 128.6, 120.9,
116.2, 84.5, 83.3, 38.9, 20.4; HRMS (EI, [M]+) calcd. for
C18H12NClO: 293.0602, found: 293.0600; Rf = 0.39 (25%
EtOAc/hexanes); mp 85-86 oC.
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
In conclusion, we have developed a new method to synthe-
size 2-aminothiophenes and thieno[2,3-c]isothiazoles from the
common linear alkynyl nitriles using phosphorus decasulfide
and/or Lawesson’s reagent as a sulfur-transferring reagent.
The reaction course was governed by the setting of solvent and
temperature. The thiation processes could be carried out with
ease under air and required no sophisticated experimental
techniques. Studies directed toward the design and synthesis
of bioactive 2-aminothiophene-based compounds are under-
way, and results will be reported in due course.
EXPERIMENTAL SECTION
2-(2-Methoxybenzoyl)-5-phenylpent-4-ynenitrile (1d). Accord-
ing to the procedure for the preparation of 1a, compound 1d was
synthesized from 2-methoxybenzoylacetonitrile (311 mg, 1.78
mmol), 3-phenylpropiolaldehyde (341 mg, 2.62 mmol), L-proline
(41 mg, 0.36 mmol) and Hantzsch ester (443 mg, 1.75 mmol) in
58% yield (298 mg) as a brown oil. 1d: IR (neat) 2945, 2360,
General Information. All reactions were performed under air
unless otherwise stated. All solvents (ACS grade) were used as
received. Commercially available reagents were used as received
without further purification. Thin layer chromatography (TLC)
analysis was conducted on glass plates precoated with 0.25 mm
silica gel, visualized with 254 nm UV lamp and stained with po-
tassium permanganate followed by heating until development of
color. Flash chromatography was performed on 230-400 mesh
silica gel with the indicated eluents. Nuclear magnetic resonance
(NMR) spectra were recorded in indicated deuterated solvents and
are reported in ppm with residual protiated solvent used as a ref-
erence. Coupling constants (J) are reported in Hertz (Hz). Infrared
(IR) spectra were recorded neat and reported in cm-1. Mass spectra
were recorded on a TOF mass spectrometer by using FD, ESI or
FI as specified in each case.
1
2341, 1682, 1597, 1486, 1291 cm-1; H NMR (400 MHz, CDCl3)
δ 7.79 (dd, J = 7.6, 2.0 Hz, 1H), 7.57 (td, J = 7.6, 2.0 Hz, 1H),
7.41-7.39 (m, 2H), 7.30-7.26 (m, 3H), 7.09-7.02 (m, 2H), 4.73(dd,
J = 8.0, 5.6 Hz, 1H), 4.01 (s, 3H), 3.09 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 190.4, 158.8, 135.5, 131.7, 131.6, 128.2, 128.2,
124.6, 122.8, 121.4, 117.0, 111.8, 84.1, 83.7, 55.9, 44.1, 20.2;
HRMS (ESI, [M+Na]+) calcd. for C19H15NO2Na: 312.0995,
found: 312.0991; Rf = 0.38 (25% EtOAc/hexanes).
2-(4-Methoxybenzoyl)-5-phenylpent-4-ynenitrile (1e). Accord-
ing to the procedure for the preparation of 1a, compound 1e was
synthesized from 4-methoxybenzoylacetonitrile (306 mg, 1.75
mmol), 3-phenylpropiolaldehyde (341 mg, 2.62 mmol), L-proline
(40 mg, 0.35 mmol) and Hantzsch ester (442 mg, 1.74 mmol) in
99% yield (504 mg) as a brown solid. 1e: IR (neat) 3057, 2935,
Procedure for the Synthesis of 2-Benzoyl-5-phenylpent-4-
ynenitrile (1a). Benzoylacetonitrile (1.03 g, 7.10 mmol), L-
proline (159 mg, 1.38 mmol) and Hantzsch ester (1.74 g, 6.87
mmol) were added to a round-bottom flask charged with a mag-
netic bar, and then the flask was sealed with a rubber septum and
purged with nitrogen (N2). Ethanol (70 mL) and 3-
phenylpropiolaldehyde (1.34 g, 10.30 mmol) were sequentially
added to the mixture. The resulting mixture was stirred for 10 min
at room temperature. Next, the reaction was stirred at 70 °C (oil
bath) until completion as indicated by TLC (typically for 4 h).
After cooling to room temperature, the crude reaction mixture was
concentrated in vacuo. The residue was purified by flash column
chromatography over silica gel (15% EtOAc/hexanes) to give the
desired compound 1a (1.51 g, 82% yield) as a yellow oil. 1a: IR
(neat) 3063, 2923, 1608, 1571, 1527, 1485, 1345, 1270, 1250,
1
2243, 2340, 1686, 1599, 1512 cm-1; H NMR (400 MHz, CDCl3)
δ 8.02 (d, J = 8.8 Hz, 2H), 7.39-7.36 (m, 2H), 7.30-7.27 (m, 3H),
7.38-7.36 (m, 2H), 6.99 (d, J = 8.8 Hz, 2H), 4.54 (t, J = 7.2 Hz,
1H), 3.90 (s, 3H), 3.13 (dd, J = 7.2, 2.8 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ 187.0, 164.8, 131.7, 131.4, 128.3, 128.2, 126.8,
122.5, 116.6, 114.4, 84.2, 83.7, 55.7, 38.6, 20.5; HRMS (ESI,
[M+Na]+) calcd. for C19H15NNaO2: 312.0995, found: 312.0997;
Rf = 0.38 (25% EtOAc/hexanes); mp 72-73 oC.
2-(Furan-2-carbonyl)-5-phenylpent-4-ynenitrile (1f). Accord-
ing to the procedure for the preparation of 1a, compound 1f was
synthesized from 3-(furan-2-yl)-3-oxopropanenitrile (243 mg,
1.80 mmol), 3-phenylpropiolaldehyde (326 mg, 2.50 mmol), L-
proline (38 mg, 0.33 mmol) and Hantzsch ester (423 mg, 1.67
mmol) in 74% yield (330 mg) as a brown oil. 1f: IR (neat) 3134,
1
1070, 1008, 954, 808 cm-1; H NMR (400 MHz, CDCl3) δ 8.05-
8.03 (m, 2H), 7.68 (td, J = 7.2, 1.6 Hz, 1H), 7.57-7.53 (m, 2H),
7.38-7.36 (m, 2H), 7.31-7.26 (m, 3H), 4.60 (t, J = 7.6 Hz, 1H),
3.16 (d, J = 7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 188.8,
134.8, 133.9, 131.7, 129.2, 128.9, 128.4, 128.2, 122.4, 116.3,
84.4, 83.4, 39.0, 20.5; HRMS (ESI, [M+Na]+) calcd. for
1
2958, 2925, 2247, 1795, 1723, 1598, 1567, 1462, 1288 cm-1; H
NMR (400 MHz, CDCl3) δ 7.71 (dd, J = 1.6, 0.8 Hz, 1H), 7.48
(dd, J = 3.6, 0.8 Hz, 1H), 7.39-7.35 (m, 2H), 7.31-7.27 (m, 3H),
6.66 (dd, J = 3.6, 1.6 Hz, 1H), 4.45 (t, J = 0.8 Hz, 1H), 3.15 (d, J
= 7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 177.3, 150.2,
148.1, 131.7, 128.4, 128.2, 122.4, 120.3, 115.9, 113.4, 84.4, 83.0,
C18H13NNaO: 282.0889, found: 282.0888; Rf
EtOAc/hexanes).
= 0.2 (9%
2-Benzoyl-5-p-tolylpent-4-ynenitrile (1b). According to the
procedure for the preparation of 1a, compound 1b was synthe-
sized from benzoylacetonitrile (227 mg, 1.56 mmol), 3-(p-
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The Journal of Organic Chemistry
39.3, 20.4; HRMS (EI, [M]+) calcd. for C16H11NO2: 249.0784,
found: 249.0788; Rf = 0.26 (20% EtOAc/hexanes).
145.0, 135.2, 134.3, 131.9, 128.0, 124.6, 115.7, 77.7, 72.8, 43.6,
19.5; HRMS (ESI, [M+Na]+) calcd. for C12H8N2O3Na: 251.0427,
found: 251.0425; Rf = 0.17 (25% EtOAc/hexanes).
1
2
3
4
5
6
7
8
5-Phenyl-2-(thiophene-2-carbonyl)pent-4-ynenitrile (1g). Ac-
cording to the procedure for the preparation of 1a, compound 1g
was synthesized from 2-thenoylacetonitrile (150 mg, 0.99 mmol),
3-phenylpropiolaldehyde (185 mg, 1.42 mmol), L-proline (23 mg,
0.20 mmol) and Hantzsch ester (251 mg, 0.99 mmol) in 83% yield
(218 mg) as a brown oil. 1g: IR (neat) 3094, 2957, 2923, 2247,
Ethyl 2-cyano-5-phenylpent-4-ynoate (1j). According to the
procedure for the preparation of 1a, compound 1j was synthesized
from ethyl cyanoacetate (526 mg, 4.65 mmol), 3-
phenylpropiolaldehyde (897 mg, 6.89 mmol), L-proline (108 mg,
0.94 mmol) and Hantzsch ester (1.18 g, 4.66 mmol) in 53% yield
(557 mg) as a brown oil. 1j: IR (neat) 2957, 2925, 2252, 1745,
1599, 1464, 1377, 1211 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.43-
7.41(m, 2H), 7.32-7.28 (m, 3H), 4.31 (q, J = 7.2 Hz, 2H), 3.76 (t,
J = 6.8 Hz, 1H), 3.07 (d, J = 6.8 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 165.4, 132.5, 129.0, 129.2, 123.2,
116.3, 85.2, 83.4, 64.0, 38.1, 21.8, 14.8; HRMS (EI, [M]+) calcd.
for C14H13NO2: 227.0941, found: 227.0944; Rf = 0.25 (30%
EtOAc/hexanes).
1
1717, 1597, 1571, 1490, 1442 cm-1; H NMR (400 MHz, CDCl3)
δ 7.95 (d, J = 4 Hz, 1H), 7.81 (d, J = 5.2 Hz, 1H), 7.38-7.34 (m,
2H), 7.33-7.25 (m, 3H), 7.21 (t, J = 4.8 Hz, 1H), 4.44 (t, J = 7.2
Hz, 1H), 3.16 (d, J = 7.6 Hz, 2H)；13C NMR (100 MHz, CDCl3)
δ 181.5, 140.6, 136.8, 134.4, 131.7, 128.9, 128.5, 128.3, 122.4,
116.4, 84.6, 83.4, 39.9, 21.0; HRMS (EI, [M]+) calcd. for
C16H11NOS: 265.0556, found: 265.0560; Rf = 0.34 (20%
EtOAc/hexanes).
9
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
5-Phenyl-2-pivaloylpent-4-ynenitrile (1k). According to the
procedure for the preparation of 1a, compound 1k was synthe-
sized from pivaloylacetonitrile (500 mg, 3.99 mmol), 3-
phenylpropiolaldehyde (743 mg, 5.71 mmol), L-proline (92 mg,
0.80 mmol) and Hantzsch ester (1.01 g, 3.99 mmol) in 87% yield
(831 mg) as a light yellow solid. 1k: IR (neat) 3035, 2972, 2873,
2-Benzoyl-5-(thiophen-2-yl)pent-4-ynenitrile (1h). According
to the procedure for the preparation of 1a, compound 1h was syn-
thesized from benzoylacetonitrile (127 mg, 0.88 mmol), 3-
(thiophen-2-yl)propiolaldehyde (170 mg, 1.25 mmol), L-proline
(20 mg, 0.17 mmol) and Hantzsch ester (222 mg, 0.88 mmol) in
59% yield (137 mg) as a brown oil. 1h: IR (neat) 3106, 2957,
1
2243, 1723, 1598, 1477, 1442, 1370 cm-1; H NMR (400 MHz,
1
2923, 2244, 1697, 1596, 1492, 1448 cm-1; H NMR (400 MHz,
CDCl3) δ 7.39-7.37 (m, 2H), 7.30-7.28 (m, 3H), 4.11 (t, J = 7.6
Hz, 1H), 3.04-2.93 (m, 2H), 1.26 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ/ppm: 203.9, 131.6, 128.5, 128.4, 122.5, 116.3, 84.0,
83.8, 45.5, 36.3, 25.9, 20.8; HRMS (EI, [M]+) calcd. for
CDCl3) δ 8.05-8.02 (m, 2H), 7.68 (tt, J = 7.4, 1.2 Hz, 1H), 7.54 (t,
J = 8.0 Hz, 2H), 7.23 (dd, J = 5.2, 1.2 Hz, 1H), 7.15 (dd, J = 3.6,
1.2 Hz, 1H), 6.94 (dd, J = 5.2, 3.6 Hz, 1H), 4.59 (t, J = 7.2 Hz,
1H), 3.17 (d, J = 7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
188.8, 134.9, 133.8, 132.3, 129.2, 129.0, 127.2, 126.9, 122.4,
116.3, 87.5, 77.6, 38.8, 20.7; HRMS (EI, [M]+) calcd. for
C16H17NO: 239.1305, found: 239.1307; Rf
= 0.59 (30%
EtOAc/hexanes); mp 57-58 oC.
C16H11NOS: 265.0556, found: 265.0555; Rf
EtOAc/hexanes).
= 0.4 (20%
5-Phenyl-2-tosylpent-4-ynenitrile (1l). According to the proce-
dure for the preparation of 1a, compound 1l was synthesized from
4-(methylphenyl)sulfonylacetonitrile (200 mg, 1.02 mmol), 3-
phenylpropiolaldehyde (191 mg, 1.47 mmol), L-proline (24 mg,
0.21 mmol) and Hantzsch ester (260 mg, 1.02 mmol) in 94% yield
(297 mg) as a brown oil. 1l: IR (neat) 3055, 2925, 2248, 1722,
1596, 1442, 1337, 1154 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.91
(d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.0 Hz,
2H), 7.30-7.24 (m, 3H), 4.28 (dd, J = 9.0, 5.2 Hz, 1H), 3.26 (dd, J
= 17.0, 5.2 Hz, 1H), 3.10 (dd, J = 16.8, 9.2 Hz, 1H), 2.38 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 147.2, 132.1, 131.8, 130.4, 129.9,
128.7, 128.3, 122.1, 113.4, 85.2, 80.9, 56.4, 21.8, 19.2.; HRMS
(EI, [M]+) calcd. for C18H15NO2S: 309.0818, found: 309.0817; Rf
= 0.46 (30% EtOAc/hexanes).
Procedure for the Synthesis of Compound S1. According to the
procedure for the preparation of 1a, compound S1 was synthe-
sized from 3-(2-nitrophenyl)-3-oxopropanenitrile (6.80 g, 35.76
mol), 3-(Trimethylsilyl)propiolaldehyde (8.70 mL, 58.86 mmol)
L-proline (0.82 g, 7.12 mol) and Hantzsch ester (9.00 g, 35.53
mol) in 58% yield (6.28 g) as a yellow oil. S1: IR (neat) 2958,
1
2924, 2182, 1724, 1532, 1347 cm-1; H NMR (400 MHz, CDCl3)
δ 8.29 (dd, J = 8.0, 0.8 Hz, 1H), 7.83 (td, J = 7.6, 1.2 Hz, 1H),
7.76-7.71 (m, 1H), 7.52 (dd, 1H, J = 7.6, 1.2 Hz, 1H), 4.12 (dd, J
= 7.2, 5.6 Hz, 1H), 3.11-2.99 (m, 2H), 0.16 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 192.4, 145.1, 135.0, 134.6, 131.8, 128.1,
124.5, 115.8, 99.5, 89.8, 43.8, 21.0, -0.2; HRMS (ESI, [M+Na]+)
calcd. for C15H16N2NaO3Si 323.0822, found: 323.0821; Rf = 0.36
(25% EtOAc/hexanes).
2-(3-Phenylprop-2-yn-1-yl)malononitrile (1m). According to
the procedure for the preparation of 1a, compound 1m was syn-
thesized from malononitrile (300 mg, 4.54 mmol), 3-
phenylpropiolaldehyde (844 mg, 6.49 mmol), L-proline (105 mg,
0.91 mmol) and Hantzsch ester (1.15 g, 4.54 mmol) in 89% yield
(724 mg) as a brown solid. 1m: IR (neat) 3058, 2958, 2918, 2259,
2242, 1719, 1598, 1490 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.50-
7.47 (m, 2H), 7.37-7..31 (m, 3H), 3.98 (t, J = 6.4 Hz, 1H), 3.14 (d,
J = 6.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 131.9, 129.1,
128.5, 121.6, 111.8, 86.4, 80.3, 23.3, 22.8; HRMS (EI, [M]+)
calcd. for C12H8N2: 180.0682, found: 180.0681; Rf = 0.44 (30%
EtOAc/hexanes); mp 59-60 oC.
Procedure for the Synthesis of Compound 1i. To a round-
bottom flask charged with a magnetic bar, S1 (1.61 g, 5.36 mmol)
and methanol (53 mL) was sequentially added at room tempera-
ture. The flask was sealed with a rubber septum and purged with
nitrogen (N2). The solution was cooled down to 0 °C (ice/water).
K2CO3 (1.50 g, 10.85 mmol) was added, and then the reaction was
allowed to warm to room temperature. After 16 h, the flask was
placed in an ice/water bath, and then the reaction was neutralized
with 2N aqueous HCl. The reaction mixture was then transferred
to a separatory funnel and extracted with EtOAc (15 mL×3), and
the combined organic layers were washed with brine, dried over
MgSO4, filtered, and then concentrated in vacuo to give a black
crude oil. The residue was purified by flash column chromatog-
raphy over silica gel (10% EtOAc/hexanes) to afford 1i (1.15 g,
94% yield) as a yellow oil. 1i: IR (neat)：3293, 3106, 2926, 2251,
2-(Thiophene-2-carbonyl)-5-(p-tolyl)pent-4-ynenitrile
(1n).
According to the procedure for the preparation of 1a, compound
1n was synthesized from 3-oxo-3-(thiophen-2-yl)propanenitrile
(300 mg, 1.98 mmol), 3-(p-tolyl)propiolaldehyde (435 mg, 3.02
mmol), L-proline (46 mg, 0.40 mmol) and Hantzsch ester (503
mg, 1.99 mmol) in 57% yield (314 mg) as a brown oil. 1n: IR
1722, 1530, 1347 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.29 (dd, J
= 8.4, 0.8 Hz, 1H), 7.85 (td, J = 8.4, 1.2 Hz, 1H), 7.74 (td, J = 7.6,
1.2 Hz, 1H), 7.52 (dd, J = 7.6, 1.2 Hz, 1H), 4.14 (dd, J = 7.2, 6.0
Hz, 1H), 3.05 (t, J = 2.8 Hz, 1H), 3.03 (dd, J = 2.8, 1.2 Hz, 1H),
2.22 (t, J = 2.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 192.1,
1
(neat) 2923, 2359, 2340, 1673, 1510, 1412 cm-1; H NMR (400
MHz, CDCl3) δ 7.95 (d, J = 4.0 Hz, 1H), 7.81 (d, J = 4.8 Hz, 1H),
7.26-7.20 (m, 3H), 7.08 (d, J = 8.0 Hz, 2H), 4.42 (t, J = 7.2 Hz,
1H), 3.15 (d, J = 7.2 Hz, 2H), 2.33 (s, 3H); 13C NMR (100 MHz,
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The Journal of Organic Chemistry
Page 6 of 11
CDCl3) δ 181.4, 138.6, 136.6, 134.2, 131.6, 129.1, 129.0, 128.8,
(400 MHz, CDCl3) δ 8.01 (d, J = 7.6 Hz, 2H), 7.67 (t, J = 7.4 Hz,
1
2
3
4
5
6
7
8
119.3, 116.3, 84.7, 82.4, 40.0, 21.4, 20.9; HRMS (ESI, [M+Na]+)
calcd. for C17H13NNaOS: 302.0616, found: 302.0610; Rf = 0.34
(20% EtOAc/hexanes).
1H), 7.54 (t, J = 8.0 Hz, 2H), 4.50 (t, J = 7.4 Hz, 1H), 2.95 (d, J =
7.2 Hz, 2H), 0.12 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 188.9,
134.8, 133.9, 129.1, 128.9, 116.2, 99.9, 89.6, 38.8, 20.9, -0.2;
HRMS (EI, [M]+) calcd. for C15H17NOSi: 255.1074, found:
255.1069; Rf = 0.55 (30% EtOAc/hexanes).
5-(4-Chlorophenyl)-2-(4-methoxybenzoyl)pent-4-ynenitrile
(1o). According to the procedure for the preparation of 1a, com-
pound 1o was synthesized from 4-methoxybenzoylacetonitrile
(110 mg, 0.63 mmol), 3-(4-chlorophenyl)propiolaldehyde (150
mg, 0.91 mmol), L-proline (15 mg, 0.13 mmol) and Hantzsch
ester (160 mg, 0.63 mmol) in 95% yield (193 mg) as a brown
solid. 1o: IR (neat) 2958, 2926, 2241, 1722, 1599, 1173, 827 cm-1;
1H NMR (400 MHz, CDCl3) δ 8.01 (dd, J = 8.8, 1.6 Hz, 2H), 7.30
(dd, J = 8.4, 1.6 Hz, 2H), 7.25 (dd, J = 8.4, 1.6 Hz, 2H), 7.00 (dd,
J = 7.2, 1.6 Hz, 2H), 4.55-4.51 (m, 1H), 3.90 (dd, J = 8.4, 1.6 Hz,
2H), 3.14-3.11 (dd, J = 8.4, 1.6 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 187.4, 165.4, 135.0, 133.5, 132.0, 129.2, 127.3, 121.6,
117.2, 115.0, 85.4, 83.7, 56.3, 39.1, 21.0; HRMS (EI, [M]+) calcd.
for C19H14ClNO2: 323.0708, found: 323.0703; Rf = 0.35 (30%
EtOAc/hexanes); mp 119-120 oC.
2-Benzoylhept-4-ynenitrile (1t). According to the procedure for
the preparation of 1a, compound 1t was synthesized from ben-
zoylacetonitrile (397 mg, 2.73 mmol), 2-pentynal (321 mg, 3.91
mmol), L-proline (63 mg, 0.55 mmol) and Hantzsch ester (693
mg, 2.74 mmol) in 62% yield (359 mg) as a yellow oil. 1t: IR
9
1
(neat) 3086, 2976, 2935, 2242, 1694, 1595, 1448 cm-1; H NMR
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
(400 MHz, CDCl3) δ 8.00 (d, J = 8.0 Hz, 2H), 7.67 (t, J = 7.4 Hz,
1H), 7.54 (t, J = 7.8 Hz, 2H), 4.47 (t, J = 7.2 Hz, 1H), 2.88 (d, J =
7.2 Hz, 2H), 2.17-2.10 (m, 2H), 1.08 (t, J = 7.6 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 189.3, 134.7, 133.9, 129.1, 128.9,
116.6, 86.2, 73.2, 39.4, 20.1, 13.8, 12.3; HRMS (EI, [M]+) calcd.
for C14H13NO: 211.0992, found: 211.0998; Rf = 0.38 (20%
EtOAc/hexanes).
2-(4-Chlorobenzoyl)-5-(4-chlorophenyl)pent-4-ynenitrile (1p).
According to the procedure for the preparation of 1a, compound
1p was synthesized from 4-chlorobenzoylacetonitrile (350 mg,
1.95 mmol), 3-(4-chlorophenyl)propiolaldehyde (480 mg, 2.92
mmol), L-proline (50 mg, 0.43 mmol) and Hantzsch ester (490
mg, 1.93 mmol) in 79% yield (504 mg) as a brown solid. 1p: IR
2-Benzoyl-6-(benzyloxy)hex-4-ynenitrile (1u). According to the
procedure for the preparation of 1a, compound 1u was synthe-
sized from benzoylacetonitrile (233 mg, 1.61 mmol), 4-
(benzyloxy)but-2-ynal (400 mg, 2.30 mmol), L-proline (37 mg,
0.32 mmol) and Hantzsch ester (407 mg, 1.61 mmol) in 71% yield
(344 mg) as a brown oil. 1u: IR (neat) 3086, 3062, 2952, 2923,
1
1
(neat) 2923, 2357, 2244, 1697, 1589, 1489 cm-1; H NMR (400
2243, 1696, 1595, 1450, 1263, 1071 cm-1; H NMR (400 MHz,
MHz, CDCl3) δ 7.97 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H),
7.30-7.25 (m, 4H), 4.52 (t, J = 7.2 Hz, 1H), 3.13 (d, J = 7.2 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 187.5, 141.6, 134.6, 132.9,
132.1, 130.3, 129.6, 128.6, 120.8, 115.9, 84.2, 83.4, 38.9, 20.3;
HRMS (EI, [M]+) calcd. for C18H11NOCl2: 327.0212, found:
327.0210; Rf = 0.46 (20% EtOAc/hexanes); mp 149-150 oC.
CDCl3) δ 8.02-8.00 (m, 2H), 7.68 (t, J = 7.6 Hz, 1H), 7.54 (t, J =
8.0 Hz, 2H), 7.38-7.32 (m, 4H), 7.31-7.27 (m, 1H), 4.57 (s, 2H),
4.50 (t, J = 7.2 Hz, 1H), 4.15 (t, J = 2.0 Hz, 2H), 2.99 (dt, J = 7.2,
1.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 188.7, 137.3, 134.8,
133.7, 129.2, 128.9, 128.4, 128.2, 127.9, 116.3, 80.8, 80.2, 71.6,
57.3, 38.9, 19.8; HRMS (EI, [M]+) calcd. for C20H17NO2:
303.1254, found: 303.1253; Rf = 0.37 (30% EtOAc/hexanes).
2-(4-Methylbenzoyl)-5-phenylpent-4-ynenitrile (1q). According
to the procedure for the preparation of 1a, compound 1q was syn-
thesized from 4-methylbenzoylacetonitrile (368 mg, 2.31 mmol),
3-phenylpropiolaldehyde (300 mg, 2.31 mmol), L-proline (43 mg,
0.37 mmol) and Hantzsch ester (477 mg, 1.88 mmol) in 99% yield
(511 mg) as a brown . 1q: IR (neat) 3060, 2923, 2243, 2190,
5-Phenyl-2-propionylpent-4-ynenitrile (1v). According to the
procedure for the preparation of 1a, compound 1v was synthe-
sized from 3-oxopentanenitrile (2.60 g, 26.77 mmol), 3-
phenylpropiolaldehyde (4.98 g, 38.26 mmol), L-proline (616 mg,
5.35 mmol) and Hantzsch ester (6.73 g, 26.57 mmol) in 64% yield
(3.63 g) as a brown oil. 1v: IR (neat) 3057, 2981, 2941, 2245,
1
1606, 1489 cm-1; H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.0
1
Hz, 2H), 7.40-7.36 (m, 2H), 7.34 (d, J = 8.4 Hz, 2H), 7.31-7.28
(m, 3H), 4.57 (t, J = 7.2 Hz, 1H), 3.14 (d, J = 7.2 Hz, 2H), 2.45 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 188.3, 146.1, 133.3, 131.7,
129.9, 129.1, 128.4, 128.2, 122.5, 116.5, 84.3, 83.6, 38.9, 21.8,
20.5; HRMS (ESI, [M+H]+) calcd. for C19H16NO: 274.1226,
found: 274.1227; Rf = 0.33 (25% EtOAc/hexanes).
1729, 1490, 1287 cm-1; H NMR (400 MHz, CDCl3) δ 7.42-7.40
(m, 2H), 7.31-7.27 (m, 3H), 3.67 (t, J = 6.6 Hz, 1H), 3.07-2.96
(m, 2H), 2.90 (dq, J = 18.8, 7.2 Hz, 1H), 2.78 (dq, J = 18.8, 7.2
Hz, 1H), 1.16 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
168.9, 158.1, 149.7, 138.8, 138.3, 128.8, 128.7, 126.9, 111.4,
38.5, 21.0, 15.2.; HRMS (FD, [M]+) calcd. for C14H13NO:
211.0992, found: 211.0997; Rf = 0.55 (30% EtOAc/hexanes).
2-(4-Chlorobenzoyl)-5-phenylpent-4-ynenitrile (1r). According
to the procedure for the preparation of 1a, compound 1r was syn-
thesized from 4-chlorobenzoylacetonitrile (500 mg, 2.78 mmol),
3-phenylpropiolaldehyde (515 mg, 3.96 mmol), L-proline (64 mg,
0.56 mmol) and Hantzsch ester (705 mg, 2.78 mmol) in 47% yield
(381 mg) as a brown solid. 1r: IR (neat) 2924, 2245, 1697, 1589,
Procedure for the Synthesis of Compound 2a. To a round-
bottom flask, 1a (99 mg, 0.38 mmol), Lawesson’s reagent
(251mg, 0.62 mmol) and THF (7.7 mL) were sequentially added.
The resulting solution was stirred under air at room temperature
for 72 h. The reaction was concentrated in vacuo, and the crude
residue was purified by flash column chromatography over silica
gel (10% EtOAc/hexanes) to give the desired substrate 2a (52 g,
46% yield) as an orange solid. 2a: IR (neat) 3373, 3173, 2958,
1
1490 cm-1; H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.4 Hz,
2H), 7.52 (d, J = 8.4 Hz, 2H), 7.37-7.35 (m, 2H), 7.31-7.26 (m,
3H), 4.54 (t, J = 7.2 Hz, 1H), 3.15 (d, J = 7.2 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 187.7, 141.5, 132.2, 131.7, 130.3, 129.5,
128.5, 128.3, 122.3, 116.0, 84.5, 83.2, 39.0, 20.4; HRMS (ESI,
[M+H]+) calcd. for C18H13NClO: 294.0680, found: 294.0680; Rf
= 0.45 (25% EtOAc/hexanes); mp 85-86 oC.
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2925, 1721, 1664, 1615, 1443, 1276 cm-1; H NMR (400 MHz,
CDCl3) δ 8.23 (s, 1H), 8.10 (d, J = 7.2 Hz, 2H), 7.63 (t, J = 7.6
Hz, 2H), 7.51 (t, J = 7.6 Hz, 2H), 7.24-7.21 (m, 3H), 5.29 (t, J =
6.8 Hz, 1H), 3.17 (d, J = 6.8 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 202.2, 198.4, 136.1, 134.4, 131.5, 129.0, 128.9, 128.2,
128.1, 122.7, 84.7, 84.4, 59.9, 25.4; HRMS (EI, [M]+) calcd. for
C18H15NOS: 293.0869, found: 293.0870; Rf = 0.28 (30% EtO-
Ac/hexanes); mp 127-128 oC.
2-Benzoyl-5-(trimethylsilyl)pent-4-ynenitrile (1s). According to
the procedure for the preparation of 1a, compound 1s was synthe-
sized from benzoylacetonitrile (330 mg, 2.27 mmol), 3-(4-
(trimethylsilyl)phenyl)propiolaldehyde (410 mg, 3.25 mmol), L-
proline (52 mg, 0.45 mmol) and Hantzsch ester (575 mg, 2.27
mmol) in 95% yield (554 mg) as a yellow oil. 1s: IR (neat) 3063,
Procedure for the Synthesis of (2-Amino-5-benzylthiophen-3-
yl)(phenyl)methanone (3a). To a flask charged with a magnetic
bar, 1a (70 mg, 0.27 mmol), phosphorus decasulfide (360 mg,
1
2958, 2245, 2181, 1700, 1596, 1448, 1250, 843 cm-1; H NMR
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The Journal of Organic Chemistry
0.81 mmol) and ethanol (3 mL) were sequentially added at room
(2-Amino-5-benzylthiophen-3-yl)(furan-2-yl)methanone
(3f).
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temperature, and then the flask was sealed with a rubber septum.
After 10 min, the reaction was stirred at 80 °C (oil bath) until
completion as indicated by TLC (typically for 5 h). After cooling
to room temperature, the crude reaction mixture was concentrated
in vacuo. The residue was purified by flash column chromatog-
raphy over silica gel (15% EtOAc/hexanes) to give the desired
substrate 3a (66 g, 83% yield) as an orange solid. 3a: IR (neat)
According to the procedure for the preparation of 3a, compound
3f was synthesized from 1f (200 mg, 0.80 mmol) and phosphorus
decasulfide (670 mg, 1.51 mmol) in 89% yield (202 mg) as an
orange solid. 3f: IR (neat) 3439, 3370, 2956, 2923, 1578, 1557,
1468, 1307 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.58 (dd, J = 1.6,
0.8 Hz, 1H), 7.35-7.31 (m, 3H), 7.21 (dd, J = 3.2, 0.8 Hz, 1H),
7.08 (br, 2H), 6.54 (dd, J = 3.6, 1.6 Hz, 1H), 3.98 (s, 2H); 13C
NMR (100 MHz, CDCl3) δ 175.7, 167.8, 153.9, 144.9, 139.8,
128.6, 128.5, 126.7, 124.8, 123.1, 116.5, 112.8, 111.9, 36.23;
HRMS (EI, [M]+) calcd. for C16H13NO2S: 283.0662, found:
283.0654; Rf = 0.34 (25% EtOAc/hexanes); mp 98-99 oC.
1
3382, 3273, 2961, 2926, 1720, 1566, 1451, 1366, 1276 cm-1; H
NMR (400 MHz, CDCl3) δ 7.69-7.66 (m, 2H), 7.51-7.42 (m, 3H),
7.32-7.28 (m, 2H), 7.24-7.20(m, 3H), 6.90 (br, 2H), 6.64 (t, J =
1.0 Hz, 1H), 3.90 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 190.8,
166.2, 166.1, 141.0, 139.7, 130.6, 128.6, 128.4, 128.1, 128.1,
126.7, 124.5, 124.3, 114.4, 36.1; HRMS (ESI, [M+H]+) calcd. for
C18H16NOS 294.0947, found: 294.0950; Rf = 0.28 (20% EtO-
Ac/hexanes); mp 113-114 oC.
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(2-Amino-5-benzylthiophen-3-yl)(thiophen-2-yl)methanone
(3g). According to the procedure for the preparation of 3a, com-
pound 3g was synthesized from 1g (70 mg, 0.26 mmol) and phos-
phorus decasulfide (235 mg, 0.53 mmol) in 65% yield (51 mg) as
a brown oil. 3g: IR (neat) 3437, 3385, 2956, 2924, 1565, 1453 cm-
1; 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 3.6 Hz, 1H), 7.56 (d,
J = 4.8 Hz, 1H), 7.34-7.31 (m, 2H), 7.25-7.24 (m, 3H),7.12 (dd, J
= 4.8, 3.6 Hz, 1H), 6.99 (s, 1H), 6.87 (br, 2H), 3.96 (s, 2H); 13C
NMR (100 MHz, CDCl3) δ 181.0, 166.2, 145.3, 139.6, 131.0,
130.6, 128.6, 128.4, 127.4, 126.7, 125.0, 123.3, 113.8, 36.1;
HRMS (EI, [M]+) calcd. for C16H13NOS2: 299.0433, found:
299.0429; Rf = 0.42 (25% EtOAc/hexanes).
(2-Amino-5-(4-methylbenzyl)thiophen-3-yl)(phenyl)methanone
(3b). According to the procedure for the preparation of 3a, com-
pound 3b was synthesized from 1b (31 mg, 0.11 mmol) and phos-
phorus decasulfide (100 mg, 0.22 mmol) in 95% yield (33 mg) as
an orange solid. 3b: IR (neat) 3376, 3272, 2956, 2924, 1725,
1
1567, 1451, 1274 cm-1; H NMR (400 MHz, CDCl3) δ 7.68-7.66
(m, 2H), 7.51-7.42 (m, 3H), 7.11 (s, 4H), 6.90 (br, 2H), 6.63 (s,
1H), 3.86 (s, 2H), 2.32 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
190.8, 166.0, 141.0, 136.7, 136.2, 130.6, 129.3, 128.2, 128.1,
128.1, 124.7, 124.3, 114.4, 35.7, 21.0; HRMS (EI, [M]+) calcd.
for C19H17NOS: 307.1025, found: 307.1021; Rf = 0.47 (25%
EtOAc/hexanes); mp 129-130 oC.
(2-Amino-5-(thiophen-2-ylmethyl)thiophen-3-
yl)(phenyl)methanone (3h). According to the procedure for the
preparation of 3a, compound 3h was synthesized from 1h (140
mg, 0.53 mmol) and phosphorus decasulfide (500 mg, 1.12 mmol)
in 76% yield (120 mg) as a brown oil. 3h: IR (neat) 3387, 3283,
(2-Amino-5-(4-chlorobenzyl)thiophen-3-yl)(phenyl)methanone
(3c). According to the procedure for the preparation of 3a, com-
pound 3c was synthesized from 1c (100 mg, 0.34 mmol) and
phosphorus decasulfide (303 mg, 0.68 mmol) in 46% yield (51
mg) as an orange oil. 3c: IR (neat) 3378, 3276, 3146, 2957, 2924,
1
2956, 2922, 1728, 1585, 1435, 1307 cm-1; H NMR (400 MHz,
CDCl3) δ 7.68-7.66 (m, 2H), 7.51-7.42 (m, 3H), 7.17 (dd, J = 5.2,
1.2 Hz, 2H), 6.98 (br, 2H), 6.93 (dd, J = 3.4, 1.5 Hz, 1H), 6.87-
6.85 (m, 1H), 6.69 (t, J = 1.0 Hz, 1H), 4.09 (t, J = 1.0 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 190.9, 166.1, 142.7, 140.9, 130.7,
128.1, 128.1, 126.9, 125.2, 124.7, 124.4, 123.4, 114.4, 30.3;
HRMS (EI, [M]+) calcd. for C16H13NOS2: 299.0433, found:
299.0428; Rf = 0.4 (25% EtOAc/hexanes).
1
1719, 1567, 1451, 1367, 1275, 700 cm-1; H NMR (400 MHz,
CDCl3) δ 7.68-7.65 (m, 2H), 7.50-7.42 (m, 3H), 7.28-7.25 (m,
2H), 7.13 (d, J = 8.0 Hz, 2H), 7.05 (br, 2H), 6.63 (s, 1H), 3.85 (s,
2H); 13C NMR (100 MHz, CDCl3) δ 190.8, 166.3, 140.9, 138.2,
132.4, 130.7, 129.7, 128.7, 128.2, 128.1, 124.8, 123.5, 114.3,
35.4; HRMS (EI, [M]+) calcd. for C18H14ClNOS: 327.0479,
found: 327.0472; Rf = 0.35 (20% EtOAc/hexanes).
(2-Amino-5-methylthiophen-3-yl)(2-nitrophenyl)methanone(3i).
According to the procedure for the preparation of 3a, compound
3i was synthesized from 1i (0.91 g, 3.99 mmol) and phosphorus
decasulfide (3.50 g, 7.87 mmol) in 89% yield (933 mg) as an or-
(2-Amino-5-benzylthiophen-3-yl)(2-methoxyphenyl)methanone
(3d). According to the procedure for the preparation of 3a, com-
pound 3d was synthesized from 1d (30 mg, 0.10 mmol) and phos-
phorus decasulfide (89 mg, 0.20 mmol) in 60% yield (20 mg) as
an orange oil. 3d: IR (neat) 3439, 3380, 2960, 2929, 1599, 1457,
1
ange solid. 3i: IR (neat) 3444, 1585, 1526, 1456 cm-1; H NMR
(400 MHz, CDCl3) δ 8.14 (d, J = 8.0 Hz, 1H), 7.70 (t, J = 7.6 Hz,
1H), 7.58 (t, J = 7.6 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 6.86 (br,
2H), 5.96 (s, 1H), 2.16 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
186.7, 165.7, 146.2, 137.1 133.7, 129.7, 128.6, 124.3, 122.2,
121.0, 114.5, 14.8; HRMS (ESI, [M+Na]+) calcd. for
C12H10N2O3SNa 285.0304, found: 285.0309; Rf = 0.24 (25%
EtOAc/hexanes); mp 114-115 oC.
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1246, 1025 cm-1; H NMR (400 MHz, CDCl3) δ 7.40-7.36 (m,
1H), 7.33-7.28 (m, 3H), 7.23-7.17 (m, 3H), 7.02-6.98 (m, 1H),
6.96 (d, J = 8.0 Hz, 1H), 6.90 (br, 1H), 6.29 (s, 1H), 3.84 (s, 2H),
3.80 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 190.2, 165.2, 156.2,
139.8, 130.9, 130.7, 128.6, 128.5, 128.3, 126.6, 124.7, 123.9,
120.3, 116.0, 111.3, 55.6, 36.0; HRMS (EI, [M]+) calcd. for
C19H17NO2S: 323.0975, found: 323.0980; Rf = 0.33 (25% EtO-
Ac/hexanes).
(2-amino-5-(2-(benzyloxy)ethyl)thiophen-3-
yl)(phenyl)methanone (3j). According to the procedure for the
preparation of 3a, compound 3j was synthesized from 1u (200
mg, 0.66 mmol) and phosphorus decasulfide (600 mg, 1.35 mmol)
in 68% yield (158 mg) as an yellow oil. 3j: IR (neat) 3399, 3283,
(2-Amino-5-benzylthiophen-3-yl)(4-methoxyphenyl)methanone
(3e). According to the procedure for the preparation of 3a, com-
pound 3e was synthesized from 1e (58 mg, 0.20 mmol) and phos-
phorus decasulfide (178 mg, 0.40 mmol) in 76% yield (49 mg) as
an orange oil. 3e: IR (neat) 3442, 3394, 3284, 2959, 2931, 1565,
1
2924, 2855, 1724, 1584, 1452, 1278 cm-1; H NMR (400 MHz,
CDCl3) δ 7.65 (d, J = 8.0 Hz, 2H), 7.49-7.40 (m, 3H), 7.36-7.27
(m, 5H), 6.91 (br, 2H), 6.60 (s, 1H), 4.53 (s, 2H), 3.62 (t, J = 6.4
Hz, 2H), 2.86 (t, J = 6.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
190.9, 165.8, 141.1, 138.1, 130.6, 128.4, 128.1, 128.1, 127.7,
124.6, 121.8, 114.6, 73.2, 70.4, 30.6.; HRMS (EI, [M]+) calcd. for
C20H19NO2S: 337.1131, found: 337.1118; Rf = 0.27 (20% EtO-
Ac/hexanes).
1
1452, 1253, 1168 cm-1; H NMR (400 MHz, CDCl3) δ 7.71-7.67
(m, 2H), 7.33-7.28 (m, 2H), 7.25-7.21 (m, 3H), 6.96-6.93 (m,
2H), 6.84 (br, 1H), 6.68 (t, J = 1.2 Hz, 1H), 3.91 (s, 2H), 3.86 (s,
3H)； 13C NMR (100 MHz, CDCl3) δ 189.9, 165.6, 161.7, 139.8,
133.5, 130.3, 128.6, 128.4, 126.6, 124.6, 124.2, 114.5, 113.4,
55.4, 36.1; HRMS (EI, [M]+) calcd. for C19H17NO2S: 323.0975,
found: 323.0974; Rf = 0.34 (25% EtOAc/hexanes).
Ethyl 2-amino-5-benzylthiophene-3-carboxylate (3k). Accord-
ing to the procedure for the preparation of 3a, compound 3k was
synthesized from 1j (367 mg, 1.61 mmol) and phosphorus deca-
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The Journal of Organic Chemistry
Page 8 of 11
sulfide (1.44 g, 3.23 mmol) in 60% yield (251 mg) as an orange
oil. 3k: IR (neat) 3441, 3335, 2957, 2922, 1721, 1565, 1499, 1263
cm-1; 1H NMR (400 MHz, CDCl3) δ 7.34-7.30 (m, 2H), 7.26-7.23
(m, 3H), 6.72 (s, 1H), 5.84 (s, 2H), 4.26 (q, J = 7.2 Hz, 2H), 3.92
(s, 2H), 1.34 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
165.4, 162.2, 139.9, 128.6, 128.5, 126.6, 125.2, 122.8, 106.2,
59.7, 36.0, 14.6; HRMS (EI, [M]+) calcd. for C14H15NO2S
261.0818, found: 261.0816; Rf = 0.57 (30% EtOAc/hexanes).
calcd. for C18H14NS2: 308.0562, found: 308.0566; Rf = 0.48 (9%
EtOAc/hexanes); mp 91-92 oC.
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5-(4-Methylbenzyl)-3-phenylthieno[2,3-c]isothiazole (4b). Ac-
cording to the procedure for the preparation of 4a, compound 4b
was synthesized from 1b (100 mg, 0.37 mmol), phosphorus deca-
sulfide (374 mg, 0.84 mmol) and Lawesson’s reagent (178 mg,
0.44 mmol) in 52% yield (61 mg) as a yellow solid. 4b: IR (neat)
1
2923, 2854, 1513, 1445, 1337, 1268 cm-1; H NMR (400 MHz,
1-(2-Amino-5-benzylthiophen-3-yl)-2,2-dimethylpropan-1-one
(3l). According to the procedure for the preparation of 3a, com-
pound 3l was synthesized from 1k (625 mg, 2.61 mmol) and
phosphorus decasulfide (2.32 g, 5.22 mmol) in 19% yield (133
mg) as an orange solid. 3l: IR (neat) 3399, 3284, 2966, 2924,
CDCl3) δ 7.63 (d, J = 7.6 Hz, 2H), 7.48 (t, J = 7.4 Hz, 2H), 7.41
(t, J = 7.2 Hz, 1H),7.19 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz,
2H), 6.86 (s, 1H), 4.12 (s, 2H), 2.35 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 169.6, 154.0, 152.4, 137.3, 136.6, 135.2, 131.1, 129.4,
129.4, 129.2, 128.6, 127.2, 112.2, 38.3, 21.1; HRMS (ESI,
[M+H]+) calcd. for C19H16NS2: 322.0719, found: 322.0712; Rf =
0.68 (25% EtOAc/hexanes); mp 88-89 oC.
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1725, 1563, 1439 cm-1; H NMR (400 MHz, CDCl3) δ 7.35-7.31
(m, 2H), 7.26-7.24 (m, 3H), 6.92 (br, 2H), 6.91 (s, 1H), 3.94 (s,
2H), 1.33 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 201.9, 166.3,
139.8, 128.6, 128.4, 126.7, 123.3, 123.2, 112.1, 43.5, 36.2, 27.9;
HRMS (EI, [M]+) calcd. for C16H19NOS: 273.1182, found:
273.1184; Rf = 0.58 (30% EtOAc/hexanes); mp 99-100 oC.
5-(4-Chlorobenzyl)-3-phenylthieno[2,3-c]isothiazole (4c). Ac-
cording to the procedure for the preparation of 4a, compound 4c
was synthesized from 1c (68 mg, 0.23 mmol), phosphorus deca-
sulfide (205 mg, 0.46 mmol) and Lawesson’s reagent (94 mg,
0.23 mmol) in 40% yield (32 mg) as a yellow solid. 4c: IR (neat)
3062, 2924, 1595, 1487, 1093 cm-1; 1H NMR (400 MHz, DMSO-
d6) δ 7.80 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.35-7.32
(m, 5H), 7.26 (br, 1H), 4.23 (s, 2H); 13C NMR (100 MHz, CDCl3)
δ 169.7, 152.6, 152.6, 138.1, 137.5, 135.2, 129.6, 128.8, 128.8,
128.3, 127.1, 112.1, 38.7; HRMS (EI, [M]+) calcd. for
C18H12NS2Cl: 341.0094, found: 341.0099; Rf = 0.64 (25% EtO-
Ac/hexanes); mp 87-88 oC.
5-Benzyl-3-tosylthiophen-2-amine (3m). According to the pro-
cedure for the preparation of 3a, compound 3m was synthesized
from 1l (169 mg, 0.55 mmol) and phosphorus decasulfide (485
mg, 1.09 mmol) in 9% yield (16 mg) as an orange solid. 3m: IR
(neat) 3450, 3346, 2958, 2925, 1721, 1598, 1515, 1286, 1138,
1
1087 cm-1; H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.0 Hz,
2H), 7.34-7.27 (m, 4H), 7.24-7.19 (m, 1H), 7.16 (d, J = 7.2 Hz,
2H), 6.51 (s, 1H), 5.43 (s, 2H), 3.84(s, 2H), 2.41 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 157.4, 143.6, 140.3, 139.1, 129.7,
128.6, 128.5, 127.6, 126.8, 126.3, 121.5, 112.5, 35.8, 21.6; HRMS
(EI, [M]+) calcd. for C18H17NO2S2: 343.0695, found: 343.0695; Rf
= 0.38 (30% EtOAc/hexanes); mp 110-111 oC.
5-Benzyl-3-(2-methoxyphenyl)thieno[2,3-c]isothiazole
(4d).
According to the procedure for the preparation of 4a, compound
4d was synthesized from 1d (112 mg, 0.39 mmol), phosphorus
decasulfide (470 mg, 1.06 mmol) and Lawesson’s reagent (188
mg, 0.47 mmol) in 60% yield (78 mg) as a yellow solid. 4d: IR
2-Amino-5-benzylthiophene-3-carbothioamide (3n). According
to the procedure for the preparation of 3a, compound 3n was syn-
thesized from 1m (300 mg, 1.66 mmol) and phosphorus decasul-
fide (1.48 mg, 3.33 mmol) in 46% yield (190 mg) as an orange
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(neat) 3025, 2926, 2362, 1597, 1504, 1462, 1252 cm-1; H NMR
(400 MHz, CDCl3) δ 7.86 (dd, J = 7.6, 1.2 Hz, 1H), 7.40-7.27 (m,
5H), 7.10 (t, J = 7.6 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 7.01 (s,
1H), 4.18 (s, 2H), 4.00 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
167.6, 155.7, 150.4, 149.1, 138.5, 137.1, 129.9, 128.7, 128.7,
127.7, 126.9, 121.1, 120.9, 113.6, 111.4, 55.6, 38.7; HRMS (ESI,
[M+H]+) calcd. for C19H16NOS2 338.0668, found: 338.0673; Rf =
0.66 (25% EtOAc/hexanes); mp 124-125 oC.
1
solid. 3n: IR (neat) 3439, 2997, 2912, 1654, 1437 cm-1; H NMR
(400 MHz, DMSO-d6) δ 8.57 (br, 2H), 8.36 (d, J = 26.4 Hz, 2H),
7.32-7.29 (m, 2H), 7.23-7.20 (m, 3H), 6.95 (s, 1H), 3.84 (s, 2H);
13C NMR (100 MHz, DMSO-d6) δ 189.1, 164.8, 140.5, 128.9,
128.7, 126.8, 121.8, 121.2, 110.9, 35.6; HRMS (EI, [M]+) calcd.
for C12H12N2S2: 248.0436, found: 248.0441; Rf = 0.28 (30%
EtOAc/hexanes); mp 59-60 oC.
5-Benzyl-3-(4-methoxyphenyl)thieno[2,3-c]isothiazole
(4e).
According to the procedure for the preparation of 4a, compound
4e was synthesized from 1e (198 mg, 0.68 mmol), phosphorus
decasulfide (553 mg, 1.24 mmol) and Lawesson’s reagent (332
mg, 0.82 mmol) in 55% yield (127 mg) as a yellow solid. 4e: IR
Procedure for the Synthesis of 5-Benzyl-3-phenylthieno[2,3-
c]isothiazole (4a). To an oven-dried flask charged with a magnet-
ic bar, 1a (143 mg, 0.55 mmol), phosphorus decasulfide (490 mg,
1.10 mmol) and ethanol (10 mL) were sequentially added at room
temperature, and then the flask was sealed with a rubber septum.
After 10 min, the reaction was stirred at 80 °C until completion as
indicated by TLC (typically for 3 h). After cooling to room tem-
perature, the volatiles were removed in vacuo [NOTE: the remov-
al of ethanol at this stage is essential for the use of Lawesson’s
reagent in the next step]. To the flask containing the residue, p-
xylene (10 mL) and Lawesson’s reagent (334 mg, 0.83 mmol)
were sequentially introduced. The reaction flask was then placed
in a 130 °C oil bath. After the completion of reaction that was
indicated by TLC, typically 1 h, the reaction was quenched by
water (10 mL). The resulting biphasic mixture was stirred vigor-
ously at 60 °C for 15 min, and then concentrated in vacuo. The
crude residue was purified by flash column chromatography over
silica gel (15% EtOAc/hexanes) to afford compound 4a (105 mg,
62% yield) as a yellow solid. 4a: IR (neat) 3060, 3027, 2338,
1601, 1492, 1336, 1270 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.64
(d, J = 7.2 Hz, 2H), 7.48 (t, J = 7.4 Hz, 2H), 7.43 (d, J = 7.2 Hz,
1H), 7.40-7.28 (m, 5H), 4.16 (s, 2H); 13C NMR (100 MHz,
CDCl3) δ 169.6, 154.1, 152.0, 138.2, 137.3, 131.1, 129.4, 129.2,
128.8, 128.7, 127.2, 127.0, 112.4, 38.7; HRMS (ESI, [M+H]+)
1
(neat) 3027, 2925, 2836, 1605, 1504, 1453, 1252 cm-1; H NMR
(400 MHz, CDCl3) δ 7.56 (d, J = 8.4 Hz, 2H), 7.36-7.26 (m, 5H),
6.99 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 0.8 Hz, 1H), 4.14 (s, 2H),
3.86 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.5, 160.4, 154.2,
151.2, 138.3, 136.6, 128.8, 128.7, 128.6, 128.5, 127.0, 123.7,
114.8, 112.4, 55.4, 38.7; HRMS (ESI, [M+H]+) calcd. for
C19H16NOS2 338.0668, found: 338.0673; Rf = 0.5 (25% EtO-
Ac/hexanes); mp 110-111 oC.
5-(4-Methylbenzyl)-3-(thiophen-2-yl)thieno[2,3-c]isothiazole
(4f). According to the procedure for the preparation of 4a, com-
pound 4f was synthesized from 1n (74 mg, 0.26 mmol), phospho-
rus decasulfide (250 mg, 0.56 mmol) and Lawesson’s reagent
(113 mg, 0.28 mmol)) in 74% yield (64 mg) as a yellow solid. 4f:
IR (neat) 2921, 2853, 2219, 1539, 1213, 1427, 1330, 1218 cm-1;
1H NMR (400 MHz, DMSO-d6) δ 7.82 (d, J = 5.2 Hz, 1H), 7.60
(dd, J = 1.4, 1.2 Hz, 1H), 7.25-7.23 (m, 1H), 7.21 (d, J = 8.0 Hz,
2H), 7.18 (s, 1H), 7.13 (d, J = 8.0 Hz, 2H), 4.16 (s, 2H), 2.26 (s,
3H); 13C NMR (100 MHz, DMSO-d6) δ 168.6, 152.9, 146.5,
136.4, 136.0, 135.6, 131.0, 129.3, 129.0, 128.9, 128.6, 127.5,
112.6, 37.4, 20.7; HRMS (EI, [M]+) calcd. for C17H13NS3:
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The Journal of Organic Chemistry
327.0205, found: 327.0204; Rf = 0.67 (25% EtOAc/hexanes); mp
79-80 oC.
5-(2-(Benzyloxy)ethyl)-3-phenylthieno[2,3-c]isothiazole (4l).
According to the procedure for the preparation of 4a, compound
4l was synthesized from 1u (100 mg, 0.33 mmol), phosphorus
decasulfide (293 mg, 0.66 mmol) and Lawesson’s reagent (133
mg, 0.33 mmol) in 61% yield (37 mg) as a yellow oil. 4l: IR (ne-
at) 2954, 2918, 1727, 1455, 1285, 1097 cm-1; 1H NMR (400 MHz,
DMSO-d6) δ 7.64 (d, J = 7.2 Hz, 2H), 7.47 (t, J = 7.2 Hz, 2H),
7.43-7.25 (m, 6H), 6.92 (s, 1H), 4.57 (s, 2H), 3.79 (t, J = 6.2 Hz,
2H), 3.13 (t, J = 6.2 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ
169.7, 153.8, 149.7, 137.9, 137.3, 131.2, 129.3, 129.2, 128.4,
127.8, 127.7, 127.2, 112.7, 69.5, 33.2; HRMS (EI, [M]+) calcd.
for C20H17NOS2: 351.0712, found: 351.0726; Rf = 0.53 (20%
EtOAc/hexanes).
1
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3
4
5
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7
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5-(4-Chlorobenzyl)-3-(4-chlorophenyl)thieno[2,3-c]isothiazole
(4g). According to the procedure for the preparation of 4a, com-
pound 4g was synthesized from 1p (70 mg, 0.21 mmol), phospho-
rus decasulfide (189 mg, 0.43 mmol) and Lawesson’s reagent (86
mg, 0.21 mmol) in 55% yield (44 mg) as a yellow solid. 4g: IR
1
(neat) 3029, 2924, 2853, 1896, 1594, 1488, 1403 cm-1; H NMR
(400 MHz, CDCl3) δ 7.55-7.51 (m, 2H), 7.45-7.41 (m, 2H), 7.32-
7.29 (m, 2H), 7.22 (d, J = 8.4 Hz, 2H), 6.79 (s, 1H), 4.11 (s, 2H);
13C NMR (100 MHz, CDCl3) δ 169.5, 152.9, 151.8, 137.3, 136.5,
135.3, 133.0, 130.1, 129.6, 129.4, 128.9, 128.3, 112.3, 38.0;
HRMS (ESI, [M+H]+) calcd. for C18H12Cl2NS2: 375.9783, found:
375.9788; Rf = 0.77 (25% EtOAc/hexanes); mp 113-114 oC.
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Procedure
for
the
Synthesis
of
3-Phenyl-5-
((trimethylsilyl)methyl)thieno[2,3-c]isothiazole (4m). To an oven-
dried flask charged with a magnetic bar, 1s (107 mg, 0.42 mmol)
and Lawesson’s reagent (508 mg, 1.26 mmol) and toluene (5 mL)
were added sequentially and the flask was sealed with a rubber
septum. The reaction flask was stirred in a 110 °C oil bath until
the reaction was complete as indicated by TLC (typically for 12
h). After cooling to room temperature, the mixture was concen-
trated in vacuo. The crude residue was purified by flash column
chromatography over silica gel (15% toluene/hexanes) to give the
desired compound 4m (37 mg, 40% yield) as a yellow solid. 4m:
5-(4-Chlorobenzyl)-3-(4-methoxyphenyl)thieno[2,3-
c]isothiazole (4h). According to the procedure for the preparation
of 4a, compound 4h was synthesized from 1o (150 mg, 0.46
mmol), phosphorus decasulfide (412 mg, 0.93 mmol) and Lawes-
son’s reagent (225 mg, 0.56 mmol) in 43% yield (74 mg) as a
yellow solid. 4h: IR (neat) 2957, 2925, 1725, 1505, 1285, 1253
cm-1; 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 8.8 Hz, 2H), 7.31
(d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 6.99 (d, J = 8.8 Hz,
2H), 6.81 (s, 1H), 4.10 (s, 2H), 3.86 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 169.4, 160.5, 154.5, 150.4, 136.7, 136.5, 132.9, 130.1,
128.9, 128.5, 123.6, 114.8, 112.6, 55.4, 38.0; HRMS (EI, [M]+)
calcd. for C19H14NOS2Cl 371.0200, found: 371.0191; Rf = 0.61
(25% EtOAc/hexanes); mp 131-132 oC.
1
IR (neat) 2953, 2922, 1727, 1529, 1490, 851 cm-1; H NMR (400
MHz, CDCl3) δ 7.65-7.62 (m, 2H), 7.50-7.46 (m, 2H), 7.42-7.38
(m, 1H), 6.63 (t, J = 1.2 Hz, 1H), 2.31 (d, J = 0.8 Hz, 2H), 0.12 (t,
J = 3.4 Hz, 9H), 3.86 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
169.3, 151.4, 151.4, 138.1, 131.5, 129.3, 128.9, 127.1, 109.7,
24.0, -1.6; HRMS (EI, [M]+) calcd. for C15H17NS2Si 303.0566,
found: 303.0564; Rf = 0.59 (10% EtOAc/hexanes).
5-Benzyl-3-p-tolylthieno[2,3-c]isothiazole (4i). According to
the procedure for the preparation of 4a, compound 4i was synthe-
sized from 1q (100 mg, 0.42 mmol), phosphorus decasulfide (374
mg, 0.84 mmol) and Lawesson’s reagent (178 mg, 0.44 mmol) in
50% yield (59 mg) as a yellow solid. 4i: IR (neat) 2995, 2911,
3-Phenyl-5-propylthieno[2,3-c]isothiazole (4n). According to
the procedure for the preparation of 4a, compound 4n was synthe-
sized from 1t (100 mg, 0.47 mmol), phosphorus decasulfide (420
mg, 0.95 mmol) and Lawesson’s reagent (230 mg, 0.57 mmol) in
43% yield (53 mg) as a yellow oil. 4n: IR (neat) 2955, 2921,
1
1659, 1437, 1407, 1310 cm-1; H NMR (400 MHz, DMSO-d6) δ
7.66 (d, J = 8.0 Hz, 2H), 7.37-7.32 (m, 7H), 7.26 (s, 1H), 4.21 (s,
2H), 2.37 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 169.4,
154.3, 152.3, 140.1, 139.2, 136.8, 130.7, 129.1, 127.7, 127.3,
127.2, 113.6, 38.2, 21.4 ; HRMS (EI, [M]+) calcd. for C19H15NS2:
321.0640, found: 321.0647; Rf = 0.69 (25% EtOAc/hexanes); mp
112-113 oC.
1
1727, 1460, 1284 cm-1; H NMR (400 MHz, CDCl3) δ 7.66-7.64
(m, 2H), 7.51-7.46 (m, 2H), 7.43-7.39 (m, 1H), 6.84 (s, 1H), 2.82
(t, J = 7.8 Hz, 2H), 1.77 (qt, J = 7.4, 7.4 Hz, 2H), 1.02 (t, J = 7.4
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.5, 153.6, 153.3,
137.5, 131.3, 129.3, 129.1, 127.2, 111.4 34.6, 23.6, 13.6; HRMS
(EI, [M]+) calcd. for C14H13NS2: 259.0484, found: 259.0484; Rf =
0.61 (25% EtOAc/hexanes).
5-Benzyl-3-(4-chlorophenyl)thieno[2,3-c]isothiazole (4j). Ac-
cording to the procedure for the preparation of 4a, compound 4j
was synthesized from 1r (32 mg, 0.11 mmol), phosphorus deca-
sulfide (97 mg, 0.22 mmol) and Lawesson’s reagent (44 mg, 0.11
mmol) in 56% yield (21 mg) as a yellow solid. 4j: IR (neat) 3061,
5-Benzyl-3-ethylthieno[2,3-c]isothiazole (4o). According to the
procedure for the preparation of 4a, compound 4o was synthe-
sized from 1v (250 mg, 1.18 mmol), phosphorus decasulfide (1.05
g, 2.37 mmol) and Lawesson’s reagent (480 mg, 1.19 mmol) in
15% yield (45 mg) as a yellow oil. 4o: IR (neat) 2956, 2924,
1728, 1454, 1378, 1284 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.36-
7.32 (m, 2H), 7.30-7.25 (m, 3H), 6.55 (t, J = 1.2 Hz, 1H), 4.10 (s,
2H), 3.05 (q, J = 7.6 Hz, 2H), 1.40 (q, J = 7.6 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 168.9, 158.1, 149.7, 138.8, 138.3, 128.8,
128.7, 126.9, 111.4, 38.5, 21.0, 15.2; HRMS (FD, [M]+) calcd. for
C14H13NS2: 259.0484, found: 259.0483; Rf = 0.68 (30% EtO-
Ac/hexanes).
1
3028, 2923, 2853, 1600, 1488, 1453, cm-1; H NMR (400 MHz,
DMSO-d6) δ 7.82-7.78 (m, 2H), 7.64-7.60 (m, 2H), 7.37-7.32 (m,
5H), 7.28-7.24 (m, 1H), 4.23 (s, 2H); 13C NMR (100 MHz,
CDCl3) δ 169.6, 152.6, 152.5, 138.1, 137.4, 135.2, 129.6, 129.5,
128.8, 128.7, 128.3, 127.1, 112.0, 38.7; HRMS (ESI, [M+H]+)
calcd. for C18H13ClNS2: 342.0172, found: 342.0172; Rf = 0.70
(25% EtOAc/hexanes); mp 117-118 oC.
5-Methyl-3-(2-nitrophenyl)thieno[2,3-c]isothiazole (4k). Ac-
cording to the procedure for the preparation of 4a, compound 4k
was synthesized from 1i (400 mg, 1.75 mmol), phosphorus deca-
sulfide (1.56 g, 3.51 mmol) and Lawesson’s reagent (1.06 g, 2.62
mmol) in 41% yield (197 mg) as a yellow solid. 4k: IR (neat)
Procedure for the Synthesis of Compound 5. To an oven-dried
flask charged with a magnetic bar, 4k (97 mg, 0.35 mmol), DMF
(1.1 mL) and N-iodosuccinimide (158 mg, 0.70 mmol) was se-
quentially added. The flask was sealed with a rubber septum,
purged with nitrogen (N2) and wrapped with aluminium foil. The
reaction mixture was stirred at room temperature for 30 min, and
then heated to 80 °C (oil bath) for 3 h. The reaction was quenched
with sodium thiosulfate at 0 °C (water/ice bath), and extracted
with DCM. The combined organic layers were washed with brine,
dried over anhydrous magnesium sulfate, filtered and concentrat-
ed under reduced pressure. The residue was purified by flash
3065, 2919, 2855, 2357, 1605, 1569, 1526, 1437, 1350 cm-1; H
1
NMR (400 MHz, CDCl3) δ 8.00 (dd, J = 8.0, 1.2 Hz, 1H), 7.69
(td, J = 7.4, 1.2 Hz, 1H), 7.63-7.57 (m, 2H), 6.37 (d, J = 1.2 Hz,
1H), 2.49 (d, J = 1.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
168.4, 149.2, 148.5, 146.6, 140.6, 132.8, 132.7, 130.0, 125.4,
124.9, 111.5, 18.1; HRMS (ESI, [M+H]+) calcd. for
C12H9N2O2S2: 277.0100, found: 277.0101; Rf = 0.48 (25% EtO-
Ac/hexanes); mp 81-82 oC.
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The Journal of Organic Chemistry
Page 10 of 11
chromatography (15% EtOAc/hexanes) to afford 5 (103 mg, 73%
Corresponding Author
1
2
3
4
5
6
7
8
yield) as a yellow solid. 5: IR (neat): 3065, 2920, 2855, 2359,
1609, 1571, 1525, 1343, 1323, 1264, 1247, 1158, 1068, 953 cm-1;
1H NMR (400 MHz, CDCl3) δ 8.25-8.23 (m, 1H), 7.75-7.68 (m,
2H), 7.53-7.51 (m, 1H), 2.43 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 165.7, 150.4, 149.1, 146.0, 139.9, 134.0, 132.6, 130.8,
125.0, 124.1, 66.7, 20.4; HRMS (ESI, [M+H]+) calcd. for
C12H8N2O2S2I: 402.9066, found: 402.9074; Rf = 0.59 (25% EtO-
Ac/hexanes); mp 109-110 oC.
*E-mail: ksshia@nhri.org.tw (K.-S.S.).
*E-mail: yenkuwu@nctu.edu.tw (Y.-K.W.).
ORCID
Kak-Shan Shia: 0000-0001-9560-2466
Yen-Ku Wu: 0000-0002-9269-7444
ACKNOWLEDGMENT
We thank the National Health Research Institutes and the Ministry
of Science and Technology, Taiwan for financial support.
Procedure for the Synthesis of Compound 6. To an oven-dried
flask charged with a magnetic bar, 5 (242 mg, 0.60 mmol), 4-
bromophenylboronic acid (181 mg, 0.90 mmol), Pd(PPh3)4 (35
mg, 0.03 mmol) and K2CO3 (208 mg, 1.50 mmol) were sequen-
tially added. The flask was sealed with a rubber septum and
purged with argon (Ar). A co-solvent (PhMe/EtOH/H2O = 20/5/1;
2 mL) was introduced to the flask at room temperature. After 10
min, the reaction was stirred at 80 °C for 16 h. After cooling to
room temperature, the reaction was extracted with DCM (10
mL×3). The combined organic layers were washed with brine,
dried over anhydrous magnesium sulfate, filtered and concentrat-
ed under reduced pressure. The residue was purified by flash col-
umn chromatography over silica gel (10% EtOAc/hexanes) to
afford 6 (229 mg, 88% yield) as a yellow solid. 6: IR (neat): 3063,
2923, 1608, 1571, 1527, 1485, 1345, 1270, 1250, 1070, 1008,
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REFERENCE
1 (a) Gomtsyan, A. Heterocycles in drugs and drug discovery. Chem.
Heterocycl. Compd. 2012, 48, 7-10. (b) Heterocyclic Chemistry in
Drug Discovery; Li, J., Ed.; Wiley: Hoboken, 2013.
2 Rabal, O.; Oyarzabal, J. Biologically Relevant Chemical Space
Navigator: From Patent and Structure–Activity Relationship Analysis
to Library Acquisition and Design. J. Chem. Inf. Model. 2012, 52,
3123-3137.
3 Welsch, M. E.; Snyder, S. A.; Stockwell, B. R. Privileged scaffolds
for library design and drug discovery. Curr. Opin. Chem. Biol. 2010,
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4 For reviews, see: (a) Sabnis, R. W. The Gewald reaction in dye
chemistry. Colora. Technol. 2016 132, 49-82. (b) Bozorov, K.; Nie, L.
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ical and pharmacological attributes in medicinal chemistry. Eur. J.
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1
954, 808 cm-1; H NMR (400 MHz, CDCl3) δ 7.84-7.81 (m, 1H),
7.48-7.45 (m, 2H), 7.23-7.21 (m, 1H), 7.15 (d, J = 4.0 Hz, 2H),
6.77 (d, J = 4.0 Hz, 2H), 2.37 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 166.3, 148.6, 148.0, 143.2, 139.7, 132.8, 132.4, 131.6,
131.0, 130.8, 129.9, 124.9, 124.5, 121.3, 15.8; HRMS (ESI,
[M+H]+) calcd. for C18H12N2O2S2Br 430.9518, found: 430.9516;
Rf = 0.65 (25% EtOAc/hexanes); mp 181-182 oC.
Procedure for the Synthesis of Compound 7. To a round-bottom
flask charged with a magnetic bar, 6 (61 mg, 0.14 mmol), a co-
solvent (CHCl3/EtOH/H2O = 1/4/1; 3 mL) and iron powder (50
mg, 0.89 mmol) were sequentially added. The flask was sealed
with a rubber septum and purged with nitrogen (N2). The reaction
mixture was stirred at 0 °C (ice/water) bath for 10 min, and then
2N aqueous HCl (0.132 mL) was added to the flask. The resulting
mixture was stirred at 80 °C for 1.5 h. After cooling to room tem-
perature, the suspension was filtered through a pad of celite. The
filtrate was neutralized with saturated aqueous NaHCO3, and then
extracted with EtOAc (20 mL×3). The combined organic layers
were washed with brine, dried over anhydrous magnesium sulfate,
filtered and concentrated under reduced pressure. The residue was
purified by flash column chromatography over silica gel (10%
EtOAc/hexanes) to afford 7 (49 mg, 86% yield) as a white solid.
5 Gewald, K. Methods for the synthesis of 2-aminothiophenes and
their reactions (review). Chem. Heterocycl. Compd. 1976, 12, 1077-
1090.
6 Gewald, K.; Schinke, E.; Böttcher, H. Heterocyclen aus CH‐aciden
Nitrilen, VIII. 2‐Amino‐thiophene aus methylenaktiven Nitrilen,
Carbonylverbindungen und Schwefel. Chem. Ber. 1966, 99, 94-100.
7 For reviews, see: (a) Forero, J. S. B.; Jones, J.; da Silva, F. M. The
Synthetic Potential and Chemical Aspects of the Gewald Reaction: Appli-
cation in the Preparation of 2-Aminothiophenes and Related Heterocycles.
Curr. Org. Synth. 2013, 10, 347-365. (b) Huang, Y.; Dömling, A. The
Gewald multicomponent reaction. Mol. Diversity 2011, 15, 3-33. (c)
Sabnis, R. W.; Rangnekar, D. W.; Sonawane, N. D. 2‐
aminothiophenes by the gewald reaction. J. Heterocycl. Chem. 1999,
36, 333-345.
8
For selected recent examples, see: (a) Han, Y.; Tang, W.-Q.; Yan,
1
7: IR (neat): 3443, 3355, 2923, 1615, 1487 cm-1; H NMR (400
C.-G. Gewald-type reaction of double activated 2,3-
diarylcyclopropanes with elemental sulfur for synthesis of polysubsti-
tuted 2-aminothiophenes. Tetrahedron Lett. 2014, 55, 1441-1443. (b)
Abaee, M. S.; Hadizadeh, A.; Mojtahedi, M. M.; Halvagar, M. R.
Exploring the scope of the Gewald reaction: Expansion to a four-
component process. Tetrahedron Lett. 2017, 58, 1408-1412. (c)
Thomas, J.; Jana, S.; Sonawane, M.; Fiey, B.; Balzarini, J.; Liekens,
S.; Dehaen, W. A new four-component reaction involving the Mi-
chael addition and the Gewald reaction, leading to diverse biological-
ly active 2-aminothiophenes. Org. Biomol. Chem. 2017, 15, 3892-
3900.
9 For miscellaneous examples, see: (a) Lugovik, K. I.; Eltyshev, A. K.;
Benassi, E.; Belskaya, N. P. Synthesis of 5‐Acyl‐2‐Amino‐3‐
Cyanothiophenes: Chemistry and Fluorescent Properties. Chem. Asian
J. 2017, 12, 2410-2425. (b) Zali-Boeini, H.; Fadaei, N. Novel Route
to Thiophene-2,4-diamines. Synlett 2015, 26, 1819-1822. (c)
Moghaddam, F. M.; Boinee, H. Z. A versatile one-pot synthesis of
2,3,5-tri-substituted thiophenes from thiomorpholides. Tetrahedron
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MHz, CDCl3) δ 7.19-7.16 (m, 2H, ArH), 7.07 (td, J = 7.6, 1.2 Hz,
1H, ArH), 6.89-6.86 (m, 3H, ArH), 6.59 (td, J = 7.6, 1.2 Hz, 1H,
ArH), 6.43 (d, J = 8.0 Hz, 1H, ArH), 3.44 (s, 2H, NH2), 2.43 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 167.1, 151.6, 144.4, 142.1,
138.3, 131.7, 130.8, 130.5, 130.4, 125.4, 121.1, 117.9, 115.1,
113.9, 16.0; HRMS (ESI, [M+H]+) calcd. for C18H14N2S2Br
400.9776, found: 400.9781; Rf = 0.47 (25% EtOAc/hexanes); mp
141-142 oC.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
1H and 13C NMR spectra and an ORTEP diagram of 4a (PDF)
Crystallographic data for 4a (CIF)
10 For selected examples of the base-mediated coupling of β-
ketothioamides and carbonyl compounds bearing a α-leaving group,
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16 CCDC 1532241 (4a) contains the supplementary crystallographic
data for this paper. The data can be obtained free of charge from The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/structures.
17 Gewald, K.; Hentschel, M.; Heikel, R. 2‐Amino‐thieno [2,3‐d]
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20 To further support the proposed mechanism, we showed that 2-
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in 49% isolated yield with LR in p-xylene at 130 °C.
21 Cinar, E. M.; Ozturk, T. Thienothiophenes, Dithienothiophenes,
and Thienoacenes: Syntheses, Oligomers, Polymers, and Properties.
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