Molecular Iodine-Promoted [3 + 2] Oxidative Cyclization for the Synthesis of Heteroarene-Fused [1,2,4] Thiadiazoles/Selenadiazoles

Article abstract of DOI:10.1021/acs.joc.0c00421

Two new classes of heteroarene-fused [1,2,4]thiadiazole and [1,2,4]selenadiazole are synthesized through the iodine-mediated [3 + 2] oxidative cyclization of 2-aminoheteroarenes and isothiocyanates/isoselenocyanates. This oxidative [3 + 2] annulation stra

Full text of DOI:10.1021/acs.joc.0c00421

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Article
Molecular Iodine-Promoted [3 + 2] Oxidative Cyclization for the
Synthesis of Heteroarene-Fused [1,2,4] Thiadiazoles/Selenadiazoles
Jin-Yu Chen, Manikandan Selvaraju, Yen-Tzu Lin, Sandip Dhole, Chih-Yu Lin, and Chung-Ming Sun*
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ABSTRACT: Two new classes of heteroarene-fused [1,2,4]thiadiazole and
[1,2,4]selenadiazole are synthesized through the iodine-mediated [3 + 2] oxidative
cyclization of 2-aminoheteroarenes and isothiocyanates/isoselenocyanates. This
oxidative [3 + 2] annulation strategy is highly regiospecific to proceed a selective
C−N bond formation at the endo-nitrogen of 2-aminoheteroarenes followed by an
intramolecular oxidative N−S/N−Se bond formation. It is the first example of an
I2-mediated oxidative nitrogen−selenium (N−Se) bond formation.
class of fused heteroarenes containing the benzimidazole/
oxazole/thiazole cores and 1,2,4-thiadiazole/selenadiazole
rings.
An in-depth literature review disclosed that only a few
methods for the synthesis of heteroarene-fused [1,2,4]-
thiadiazoles are documented (Scheme 1). Accordingly, the
INTRODUCTION
■
Heteroarene is the most prominent entity in many marketed
drugs.1 In the subset of heteroarene compounds, fused
heteroarene is recognized as a significant scaffold in medicinal
chemistry and drug discovery program because these templates
have occurred in several natural and biologically active
molecules. They have exhibited promising biological profiles
(Figure 1). For example, benzthiazole-fused imidazole (YM-
Scheme 1. Previous Work on the Synthesis of Heteroarene-
Fused [1,2,4] Thiadiazole
pioneering strategy was reported by Potts and Kane in 1986,
wherein the synthesis of benzthiazole-fused [1,2,4]thiadiazole
was achieved from 2-aminobenzthiazole and sulfonyl chlor-
ide.7a Later, the same group described the synthesis of
thiadiazolo[3,4-b]benzthiazole by the reaction of 2-amino-
benzthiazole with 1,1,1-trichloromethanesulfenyl chloride
followed by cyclization using aromatic and heteroaromatic
amines.7b In 2014, Samanta prepared benzimidazole-fused
1,2,4-thiadiazoles using a methanesulfonyl chloride through a
multistep cyclization between carbodiimide and thiourea.7c
Nevertheless, these methods suffer from some limitations such
Figure 1. Biological importance of fused heteroarenes and 1,2,4-
thiadiazole/selenadiazole.
201627) (I) is a potent and an orally active antitumor agent for
human lung cancer.2 Benzoxazole-fused triazole derivative (II)
possesses antibacterial activity.3 Moreover, benzoimidazo[1,2-
a]imidazole (III) has shown antianxiety activity in the
treatment of neuropsychiatric disorders.4 On the other hand,
sulfur- and selenium-containing five-membered 1,2,4-thiadia-
zole/selenadiazole are the key core structures of many
functionalized molecules which show neuroprotective (IV)5
and antibacterial activities (V).6 Accordingly, their diverse
pharmacological activities stimulated us to synthesize a novel
Received: February 18, 2020
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a
Table 1. Study of Reaction Conditions
Entry
oxidant (equiv)
base (equiv)
solvent
yields (%) 3aa
b
1
CH2I2 (5.0)
I2 (0.5)
I2 (1.0)
I2 (2.0)
I2 (2.0)
I2 (2.0)
K2CO3 (3.0)
K2CO3 (3.0)
K2CO3 (3.0)
K2CO3 (3.0)
Na2CO3 (3.0)
Cs2CO3 (3.0)
NaH (3.0)
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
DMF
10
40
55
80
73
70
0
2
3
4
5
6
7
I2 (2.0)
8
9
I2 (2.0)
I2 (2.0)
I2 (2.0)
I2 (2.0)
I2 (2.0)
I2 (2.0)
PIDA (0.5)
NIS (0.5)
CuI (0.5)
TBAI (0.5)
I2 (2.0)
NEt3 (3.0)
DBU (3.0)
CHCl3
CHCl3
CHCl3
ACN
toluene
DMF
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
0
15
50
60
37
48
20
0
0
0
0
80
10
11
12
13
14
15
16
17
DABCO (3.0)
K2CO3 (3.0)
K2CO3 (3.0)
K2CO3 (3.0)
K2CO3 (3.0)
K2CO3 (3.0)
K2CO3 (3.0)
K2CO3 (3.0)
K2CO3 (3.0)
K2CO3 (3.0)
c
18
19
d
I2 (2.0)
a
Reaction conditions unless otherwise specified: 1a (1.0 equiv), 2a (2.0 equiv), I2 (2.0 equiv), base (3.0 equiv), and solvent (3.0 mL) at 60 °C for
b
c
d
12 h. 4aa was obtained in 30% yield. At 25 °C. At 100 °C.
as difficulty in accessing starting materials, low reaction yields,
narrow substrate scope, and stepwise and harsh reaction
conditions owing to the use of high temperatures or strong
acids. Thus, more practical and new synthetic strategies to
construct novel bioscaffolds are still in high demand and attract
great attention.
of unexpected products in 10% yield without the incorporation
of CH2I2 along with benzimidazole-linked thiazetidine 4aa in
30% yield and the unreacted starting material 1a (Table 1,
entry 1). Initially, this unknown product was analyzed by the
1H and 13C NMR studies where the corresponding −CH2 peak
of the thiadiazine ring disappeared, and the mass was reduced
by 14 m/z. In addition, structure of the unknown product 3aa
was further analyzed by the X-ray crystallography study, and it
revealed that the existence of the N−S bond and the
benzimidazole moiety and the five-membered [1,2,4] thiadia-
zole ring are fused perpendicularly to each other (see
Supporting Information, S184).
From the literature evidence, we assumed that the aged
CH2I2 may dissociate into the corresponding radicals (•CH2)
and iodine.14 These traces of I2 in the current reaction may
assist in the oxidative N−S bond formation to deliver the
unexpected benzo[4,5]imidazo[2,1-c][1,2,4]thiadiazole 3aa.
Accordingly, to test this hypothesis, we performed the reaction
in the presence of molecular iodine (0.5 equiv) and K2CO3 in
chloroform for 12 h, and the benzo[4,5]imidazo[2,1-c][1,2,4]-
thiadiazole 3aa was obtained in 40% yield (Table 1, entry 2).
This interesting result encouraged us to explore the possibility
of a new mechanism through which iodine plays a key role in
the formation of 3aa. Subsequently, we continued the
optimization and found that the desired product 3aa was
obtained in 80% yield with the utilization of two equivalents of
iodine (Table 1, entries 3−4). Further evaluation of various
solvents and bases revealed that CHCl3 and K2CO3 were a
more appropriate combination for this transformation (Table
1, entries 5−13). Interestingly, the reaction in the presence of a
In recent years, cascade cyclization involving the carbon−
carbon/carbon−heteroatom bond formation followed by
heteroatom−heteroatom bond formation has gained tremen-
dous momentum.8 As a consequence, a plethora of methods
have been documented for the N−S and N−Se bond
formation.9,10 Over the past several years, 2-aminoheteroarenes
are frequently used as reactants or reaction intermediates to
access new classes of azole-fused heterocycles. Many protocols
were developed for the synthesis of various fused-azole
derivatives utilizing the bis-nucleophilic nature of 2-amino-
benzazoles, that is, an endo-ring nitrogen or free exo-NH2
group.11 In this regard, we also developed several novel
strategies to synthesize benzimidazole-fused heterocycles by 2-
aminobenzimidazole as a valuable building block.12 As a part of
our efforts to develop an expeditious synthesis of a new class of
fused heterocycles, we report, herein, our new results of the
metal-free synthesis of benzimidazole-fused [1,2,4] thiadiazoles
from the reaction of 2-aminobenzimidazole and the
isothiocyanates.
RESULTS AND DISCUSSION
■
In the beginning, we studied the three-component reaction of
2-aminobenzimidazole 1a, phenyl isothiocyanate 2a, and
diiodomethane in refluxing chloroform13 to deliver a mixture
B
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a
Table 2. Scope of 2-Amino Heteroarenes 1 and Isothiocyanate 2
a
Reaction conditions unless otherwise specified: 1a (1.0 equiv), 2a (2.0 equiv), I2 (2.0 equiv), K2CO3 (3.0 equiv), CHCl3 (3.0 mL), 60 °C, 12.0 h.
strong base such as NaH in dimethylformamide (DMF)
enhances nucleophilicity of the exo-nitrogen atom of 2-amino
benzimidazole 1a and undergoes the thiourea 5aa formation
which subsequently reacts with phenyl isothiocyanate 2a and
rearranges to 2-guanidinobenzoimiodazole 6aa by the
elimination of CS2 (see Supporting Information, page S2,
Scheme S1). The structure of the 2-guanidino benzoimioda-
zole 6ba was confirmed by the X-ray crystallographic study
(see Supporting Information, page S192). Afterward, we tested
the effect of other oxidants such as phenyliodine(III) diacetate
(PIDA), N-iodosuccinimide (NIS), CuI, and tetrabutylammo-
nium iodide (TBAI), and only PIDA provided the oxidized
product 3aa in 20% yield (Table 1, entries 14−17). No
product formation was observed at 25 °C, whereas the yield of
the product remained the same at 100 °C (Table 1, entries
18−19). The best reaction conditions for the construction of
benzoimidazo[2,1-c][1,2,4]thiadiazole 3aa included 2-amino
benzimidazole (1a, 1.0 equiv), isothiocyanate (2a, 2.0 equiv),
I2 (2.0 equiv), and K2CO3 (3.0 equiv) in CHCl3 at 60 °C for
12 h (Table1, entry 4).
The scope of the iodine-promoted C−N and N−S bond
formation reaction was studied using various type 2-amino
heteroarenes 1 and isothiocyanates 2 (Table 2). A series of 2-
amino benzimidazole bearing electron-withdrawing and
electron-rich substituents on the benzimidazole ring and
various substituents at endo-nitrogen (N2) atoms (1a−j)
were reacted well with phenyl isothiocyanate 2a to afford the
desired products 3 in good to excellent yields (3aa−3ga, 3hb,
and 3if). Moreover, the generality of isothiocyanates 2 was also
tested. The aliphatic isothiocyanate (2b, 2c), cyclic isothio-
cyanate (2d), and aromatic isothiocyanate having electron-
donating (2f) or withdrawing (2e) groups were well-tolerated
to furnish the corresponding products (3ac−ae, 3ib, and 3jf)
in moderate to good yields. Surprisingly, the 1H-benzo[d]-
imidazol-2-amine 1j which contains the three nucleophilic
nitrogen atoms has shown the inherent reactivity with
isothiocyanates 2a−c. This reaction yielded the products 3ja,
C
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a
Table 3. Scope of Isoselenocyanates
a
Reaction conditions unless otherwise specified: 1a (1.0 equiv), 7a (2.0 equiv), I2 (2.0 equiv), K2CO3 (3.0 equiv), CHCl3 (3.0 mL), 60 °C, 12.0 h.
Obtained N-alkylated products 9′cc and 9′db.
b
3jb, and 3jc in 52, 45, and 55% yields, respectively,
amino benzimidazoles 1 to furnish the benzimidazo[2,1-
c][1,2,4]selenadiazoles (8aa, 8ab, 8ba, 8fa, and 8fc) in
moderate to good yields.
accompanied with the undesired product benzimidazo[1,2-
c][1,3,5]thiadiazine 12ja−jc. Because of the presence of three
nucleophilic sites of 1H-benzo[d]imidazol-2-amine 1j, the
reaction proceeded through the generation of the dithiourea
intermediate which further underwent cyclization via desulfur-
ization to deliver the benzimidazo[1,2-c][1,3,5]thiadiazine.
Furthermore, the reaction of 2-amino benzoxazole 1′a with
phenyl isothiocyanate 2a provided the expected product 3′aa
in an excellent yield, whereas the 2-amino-oxazolo[5,4-
b]pyridine 1′b furnished the product 3′ab in poor (13%)
yield because the electron-deficient pyridine ring decreases
nucleophilicity. The 2-aminobenzthiazole 1′c and methoxy
substituted 2-aminobenzthiazole 1′d reacted smoothly with
phenyl isothiocyanate 2a and 3-methoxypropyl isothiocyanate
2g to offer the corresponding products 3′ca, 3′cg, and 3′da in
76, 80, and 89% yields, respectively. The structure of the
compounds 3′aa and 3′cg was confirmed by the single X-ray
crystal analysis (see Supporting Information, page S186 and
S188).
Next, we explored the substrate scope of 2-aminobenzox-
azole (1′a) and 2-aminobenzthiazole (1′c, 1′d). The 2-
aminobenzoxazole (1′a) transformed smoothly into their
corresponding products 8′aa and 8′ac in good yields (75
and 60%). Moreover, the more reactive 2-aminobenzthiazole
has shown an influence in product formation. The reaction of
2-aminobenzthiazoles (1′c) with phenyl isoselenocynate (7a)
afforded the desired product 8′ca in 70% yield. Whereas with
aliphatic (7c) and cyclic (7b) isoselenocyanates delivered the
expected products 8′cb, and 8′dc in good yield along with the
N-alkylated products 9′cc and 9′db in 17 and 12% yields,
respectively. We proposed that the N-alkylated product was
generated by the activation of isoselenocyanates 7 through the
coordination of the nitrogen atom with iodine followed by SN2
displacement (R3 = aliphatic/cyclic) of selenocyanate15 (see
Supporting Informtion, page S2, Scheme S2). Furthermore, the
reaction of 2-amino benzimidazole 1a or 2-amino benzthiazole
1′d with phenyl isocyanate 7d gave the urea 10ad and 10′dd
in 40 and 55% yields, respectively, instead of the expected
products 8ad or 8′dd. The structure of benzimidazole-fused
[1,2,4]selenadiazole 8ab and N-(3-phenylpropyl)benzo[d]-
To further expand the substrate scope, we synthesized the
heteroarene-fused [1,2,4]selenadiazoles 8 using isoselenocya-
nates 7 as a coupling partner (Table 3). A variety of
isoselenocyanates 7 such as aromatic (7a), aliphatic (7b),
and cyclic (7c) isoselenocyanates smoothly reacted with 2-
D
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Scheme 2. Several Control Experiments
Scheme 3. Possible Reaction Mechanism for the Synthesis of Heteroarene-Fused [1,2,4]-Thiadiazoles 3
thiazol-2-amine 9′cc was unambiguously ascertained by X-ray
crystallography (see Supporting Information, S190, S194).
To investigate the possible reaction mechanism, the reaction
between 2-aminobenzthiazole 1′d and phenyl isothiocyanate
2a was carried out in the absence of the iodine catalyst which
gave the thiourea 5′da in 15% yield along with the unreacted
starting material (Scheme 2a). Next, the treatment of thiourea
5′da in the standard reaction conditions undergoes inter-
molecular C−S bond formation followed by desulfurization16
to afford product 11′da in 55% yield without observation of
the possible regioisomer product 3″da (Scheme 2b). Then, the
reaction of 2-aminobenzimidazole 1a with phenyl isothiocya-
nate 2a using TEMPO as a radical scavenger under optimal
reaction conditions furnished the desired product 3aa in 70%
yield which suggested that the reaction did not proceed
through a radical pathway (Scheme 2c).
On the basis of the experimental results and previous reports
on oxidative cyclization through heteroatom−heteroatom
bond formation,9,17 the plausible mechanism for the synthesis
of heteroarene-fused [1,2,4]-thiadiazole 3 is proposed (Scheme
3). Initially, the electron-rich (CS) site of isothiocyanate 2
reacts with molecular iodine to generate activated isothiocya-
nate species I.18 Subsequently, the highly nucleophilic sp2
endo-nitrogen atom (−N3) of 2-aminoheteroarenes 1 attacks
on the activated isothiocyanate species I to form the C−N
bond followed by oxidative iodination to give the possible
iodo-intermediates II and III. Next, the intermediate III
undergoes S−N bond formation to give the ammonium ion
intermediate IV by intramolecular nucleophilic attack of exo-
nitrogen (−N1) on the sulfur to cleave the S−I bond. Finally,
the base-mediated deprotonation affords the desired product 3.
CONCLUSIONS
■
We have reported molecular iodine-promoted [3 + 2]
annulation reaction of 2-aminoheteroerenes with isothiocya-
nate/isoselenocyanates to construct heteroarene-fused [1,2,4]-
thiadiazoles and [1,2,4]selenadiazole. This iodine-mediated
cyclization involves regioselective C−N bond formation
followed by the oxidative N−S/N−Se bond formation. This
versatile synthetic approach is widely applicable to a variety of
2-amino heteroarenes and isothiocyanates to offer novel
heteroarene-fused [1,2,4]thiadiazoles in good to excellent
yields. The strategy was further successfully extended to the
synthesis of heteroarene-fused [1,2,4]selenadiazoles using
isoselenocyanates as a coupling partner. The accessibility and
generality of this process make it highly valuable because of the
medicinal importance of these fused heterocycles.
EXPERIMENTAL SECTION
■
General Information. All the solvents were distilled before use.
All reactions were performed with unpurified reagents and dry
solvents. Analytical thin-layer chromatography was performed using
0.25 mm silica gel-coated plates. Flash chromatography was
performed using the indicated solvent and silica gel 60 (230−400
E
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mesh). 1H NMR, 13C NMR, and NOE spectra were recorded at
ambient temperature using 300, 400, and 600 MHz spectrometers.
Chemical shifts are reported in parts per million (ppm) on the δ scale
from an internal standard (TMS). Low-resolution mass spectra and
high-resolution mass spectra (HRMS) were recorded in the
electrospray ionization (ESI) mode using the time-of-flight mass
spectrometer. Melting points were measured with a Fargo melting
point apparatus and are uncorrected. 2-Aminoheteroarene (1/1′)12b
and isoselenocyanates (7a−c)19 were prepared by established
methods. All isothiocyanates 2 and phenyl isocyanate 7d were
purchased from commercial suppliers and used without further
purification unless otherwise specified.
General Procedure for the Synthesis of Heteroarene-Fused
[1,2,4]-Thiadiazole/Selenadiazole (3/3′/8/8′). To a solution of
methyl 2-amino-1-(4-methoxybenzyl)-1H-benzo[d]imidazole-5-car-
boxylate 1a (100 mg, 0.321 mmol) in CHCl3 (10 mL), phenyl
isothiocyanate 2a (86 mg, 0.643 mmol), K2CO3 (128 mg, 0.964
mmol), and I2 (162 mg, 0.643 mmol) were added. The resulting
reaction mixture was placed in a preheated 60 °C oil bath and stirred
for 12 h. After completion of the reaction, the reaction mixture was
diluted with EtOAc (20 mL) and filtered through the celite. The
solvent was removed under vacuum, and the residue was purified by
silica gel chromatography (EA/Hex = 1:9) to afford the desired
product 3aa (114 mg, 80%) as a white solid. A similar general
procedure was followed for the synthesis of another type of
heteroarene-fused [1,2,4]-thiadiazoles/selenadiazoles (3/3′/8/8′)
using various 2-aminoheteroarene 1/1′ and isothiocyanates/isosele-
nocyanates 2/7.
108.9, 52.3; MS (ESI) [M + H]+ m/z: 401; HRMS (ESI) m/z: [M +
H]+ calcd for C22H17N4O2S, 401.1067; found, 401.1067.
(Z)-6-Methoxy-9-(2-methoxyethyl)-N-phenyl-3H,9H-benzo[4,5]-
imidazo[2,1-c][1,2,4]thiadiazol-3-imine (3ea). White solid; yield:
112 mg, 70%; mp 122−124 °C; 1H NMR (400 MHz, CDCl3): δ 7.78
(d, J = 2.4 Hz, 1H), 7.39 (t, J = 8.1 Hz, 2H), 7.17−7.09 (m, 3H), 7.06
(d, J = 8.8 Hz, 1H), 6.86 (dd, J = 8.8, 2.4 Hz, 1H), 4.12 (t, J = 5.3 Hz,
2H), 3.88 (s, 3H), 3.76 (t, J = 5.3 Hz, 2H), 3.35 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ 155.9, 155.4, 151.3, 149.2, 131.1, 129.4,
125.1, 124.1, 121.1, 111.2, 109.4, 99.3, 70.1, 59.1, 56.2, 42.8; MS
(ESI) [M + H]+ m/z: 355; HRMS (ESI) m/z: [M + H]+ calcd for
C18H19N4O2S, 355.1223; found, 355.1228.
(Z)-9-(Furan-2-ylmethyl)-N-phenyl-6-(trifluoromethyl)-3H,9H-
benzo[4,5]imidazo[2,1-c] Z[1,2,4]Thiadiazol-3-imine (3fa). White
1
solid; yield: 119 mg, 81%; mp 170−172 °C; H NMR (400 MHz,
CDCl3): δ 8.37 (S, 1H), 7.57 (d, J = 8.6 Hz, 1H), 7.47−7.34 (m, 3H),
7.26 (d, J = 8.6 Hz, 1H), 7.19−7.00 (m, 3H), 6.47 (dd, J = 3.3, 0.8
Hz, 1H), 6.36 (dd, J = 3.3, 1.9 Hz, 1H), 5.16 (s, 2H); 13C{1H} NMR
(100 MHz, CDCl3): δ 155.0, 150.1, 148.6, 147.5, 143.3, 138.9, 129.5,
124.5, 124.5 (q, JC−F = 33.0 Hz), 124.4, 124.1 (q, JC−F = 271 Hz),
122.3 (q, JC−F = 4.0 Hz), 121.0, 110.8, 110.1 (q, JC−F = 3.9 Hz), 109.9,
108.6, 39.2; MS (ESI) [M + H]+ m/z: 415; HRMS (ESI) m/z: [M +
H]+ calcd for C20H14F3N4OS, 415.0835; found, 415.0848.
(Z)-8-Methyl-N-phenyl-9-propyl-3H,9H-benzo[4,5]imidazo[2,1-
c][1,2,4]thiadiazol-3-imine (3ga). Brown solid; yield: 127 mg, 75%;
mp 102−104 °C; 1H NMR (400 MHz, CDCl3): δ 8.06 (d, J = 7.8 Hz,
1H), 7.40 (t, J = 8.0 Hz, 2H), 7.21−6.96 (m, 5H), 4.09 (t, J = 7.8 Hz,
2H), 2.57 (s, 3H), 1.87 (p, J = 7.6 Hz, 2H), 1.03 (t, J = 7.4 Hz, 3H);
13C{1H} NMR (101 MHz, CDCl3): δ 156.0, 151.4, 149.1, 134.6,
Characterization Data of Heteroarene-Fused [1,2,4]-
Thiadiazole 3/3′. Methyl (Z)-9-(4-Methoxybenzyl)-3-(phenylimi-
no)-3H,9H-benzo[4,5]imidazo[2,1-c][1,2,4]thiadiazole-6-carboxy-
129.4, 128.0, 124.9, 123.9, 121.5, 121.1, 119.7, 110.9, 45.7, 23.4, 18.2,
11.0; MS (ESI) [M + H]+ m/z: 323; HRMS (ESI) m/z: [M + H]+
calcd for C18H19N4S, 323.1325; found, 323.1322.
1
late (3aa). White solid; yield: 114 mg, 80%; mp 160−162 °C; H
(Z)-N-Butyl-9-(4-methoxybenzyl)-7-methyl-3H,9H-benzo[4,5]-
imidazo[2,1-c][1,2,4]thiadiazol-3-imine (3hb). Yellow solid; yield:
106 mg, 75%; mp 152−154 °C; 1H NMR (600 MHz, CDCl3): δ 7.74
(d, J = 8.0 Hz, 1H), 7.28 (d, J = 8.6 Hz, 2H), 6.91 (d, J = 8.0 Hz, 1H),
6.85 (d, J = 8.7 Hz, 2H), 6.73 (s, 1H), 5.01 (s, 2H), 3.77 (s, 3H), 3.12
(t, J = 7.0 Hz, 2H), 2.36 (s, 3H), 1.71 (p, J = 7.2 Hz, 2H), 1.54−1.38
(m, 2H), 0.96 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (151 MHz, CDC3):
δ 159.3, 154.5, 151.7, 136.5, 134.2, 128.8, 127.3, 122.6, 122.1, 114.2,
111.8, 108.9, 55.2, 55.0, 45.4, 32.9, 21.8, 20.5, 13.9; MS (ESI) [M +
H]+ m/z: 381; HRMS (ESI) m/z: [M + H]+ calcd for C21H25N4OS,
381.1744; found, 381.1750.
NMR (400 MHz, CDCl3): δ 8.67 (s, 1H), 7.97 (d, J = 8.3 Hz, 1H),
7.40 (t, J = 7.4 Hz, 2H), 7.30 (d, J = 7.9 Hz, 2H), 7.24−7.09 (m, 3H),
6.98 (d, J = 8.3 Hz, 1H), 6.86 (d, J = 7.9 Hz, 2H), 5.07 (s, 2H), 3.92
(s, 3H), 3.76 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 166.5,
159.7, 155.2, 150.8, 148.9, 140.2, 129.5, 129.1, 127.4, 126.4, 124.4,
124.4, 124.0, 121.0, 114.4, 113.9, 108.2, 55.3, 52.2, 46.0; MS (ESI)
[M + H]+ m/z: 445; HRMS (ESI) m/z: [M + H]+ calcd for
C24H21N4O3S, 445.1329; found, 445.1341.
Methyl (Z)-3-(Phenylimino)-9-propyl-3H,9H-benzo[4,5]imidazo-
[2,1-c][1,2,4]thiadiazole-6-carboxylate (3ba). White solid; yield:
111 mg, 70%; mp 150−152 °C; 1H NMR (400 MHz, CDCl3): δ 8.71
(d, J = 1.7 Hz, 1H), 8.06 (dd, J = 8.4, 1.7 Hz, 1H), 7.39 (t, J = 7.7 Hz,
2H), 7.22−7.10 (m, 3H), 7.08 (d, J = 8.4 Hz, 1H), 3.99−3.93 (m,
5H), 1.96−1.85 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3): δ 166.5, 155.2, 150.8, 148.9, 140.6, 129.5, 127.3,
124.3, 124.2, 123.7, 121.0, 113.9, 107.6, 52.2, 44.5, 21.4, 11.3; MS
(ESI) [M + H]+ m/z: 367; HRMS (ESI) m/z: [M + H]+ calcd for
C19H19N4O2S, 367.1223; found, 367.1228.
Methyl (Z)-3-(Benzylimino)-9-(4-methoxybenzyl)-3H,9H-benzo-
[4,5]imidazo[2,1-c][1,2,4]thiadiazole-6-carboxylate (3ac). Orange
1
solid; yield: 97 mg, 68%; mp 157−159 °C; H NMR (400 MHz,
CDCl3): δ 8.56 (d, J = 1.7 Hz, 1H), 7.95 (dd, J = 8.4, 1.7 Hz, 1H),
7.46 (d, J = 7.2 Hz, 2H), 7.37 (t, J = 7.6 Hz, 2H), 7.30 (m, 3H), 6.97
(d, J = 8.4 Hz, 1H), 6.87 (d, J = 8.7 Hz, 2H), 5.09 (s, 2H), 4.42 (s,
2H), 3.91 (s, 3H), 3.78 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3):
δ 166.5, 159.6, 155.6, 151.3, 140.1, 139.3, 129.1, 128.4, 127.6, 127.0,
126.9, 126.5, 124.5, 123.9, 114.4, 113.4, 108.0, 58.3, 55.3, 52.2, 45.9;
MS (ESI) [M + H]+ m/z: 459; HRMS (ESI) m/z: [M + H]+ calcd for
C25H23N4O3S, 459.1485; found, 459.1485.
Methyl (Z)-9-(Furan-2-ylmethyl)-3-(phenylimino)-3H,9H-benzo-
[4,5]imidazo[2,1-c][1,2,4]thiadiazole-6-carboxylate (3ca). White
1
solid; yield: 110 mg, 74%; mp 161−162 °C; H NMR (400 MHz,
Methyl (Z)-3-(Cyclohexylimino)-9-(4-methoxybenzyl)-3H,9H-
CDCl3): δ 8.71 (d, J = 1.6 Hz, 1H), 8.06 (dd, J = 8.4, 1.6 Hz, 1H),
7.45−7.33 (m, 3H), 7.22 (d, J = 8.4 Hz, 1H), 7.19−7.08 (m, 3H),
6.47 (d, J = 3.3 Hz, 1H), 6.36 (dd, J = 3.3, 1.9 Hz, 1H), 5.16 (s, 2H),
3.94 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 166.5, 155.1,
150.3, 148.9, 147.6, 143.3, 140.0, 129.5, 127.4, 124.4, 124.2, 121.0,
113.9, 110.7, 109.8, 108.3, 52.3, 39.1; MS (ESI) [M + H]+ m/z: 405;
HRMS (ESI) m/z: [M + H]+ calcd for C21H17N4O3S, 405.1016;
found, 405.1021.
benzo[4,5]imidazo[2,1-c][1,2,4]thiadiazole-6-carboxylate (3ad).
1
White solid; yield: 94 mg, 65%; mp 146−149 °C; H NMR (400
MHz, CDCl3): δ 8.49 (d, J = 1.7 Hz, 1H), 7.91 (dd, J = 8.4, 1.7 Hz,
1H), 7.29 (d, J = 8.7 Hz, 2H), 6.92 (d, J = 8.4 Hz, 1H), 6.86 (d, J =
8.7 Hz, 2H), 5.06 (s, 2H), 3.92 (s, 3H), 3.77 (s, 3H), 2.72 (m, 1H),
1.93−1.75 (m, 4H), 1.65 (m, 1H), 1.57−1.43 (m, 2H), 1.42−1.30
(m, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 166.6, 159.6, 151.8,
151.3, 140.1, 129.0, 126.7, 126.6, 124.7, 123.7, 114.4, 113.3, 107.8,
64.9, 55.3, 52.2, 45.8, 33.3, 25.8, 24.7; MS (ESI) [M + H]+ m/z: 451;
HRMS (ESI) m/z: [M + H]+ calcd for C24H27N4O3S, 451.1798;
found, 451.1800.
Methyl (Z)-9-Phenyl-3-(phenylimino)-3H,9H-benzo[4,5]imidazo-
[2,1-c][1,2,4]thiadiazole-6-carboxylate (3da). Brown solid; yield:
130 mg, 86%; mp 222−223 °C; 1H NMR (400 MHz, CDCl3): δ 8.81
(d, J = 1.7 Hz, 1H), 8.05 (dd, J = 8.5, 1.7 Hz, 1H), 7.71−7.65 (m,
2H), 7.63−7.56 (m, 2H), 7.52−7.44 (m, 1H), 7.44−7.36 (m, 2H),
7.25 (d, J = 8.3 Hz, 1H), 7.20−7.11 (m, 3H), 3.96 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ 166.4, 154.9, 149.8, 148.9, 139.9, 133.4,
130.1, 129.5, 128.6, 127.4, 124.9, 124.8, 124.5, 124.4, 121.0, 114.1,
Methyl (Z)-9-(4-Methoxybenzyl)-3-((4-nitrophenyl)imino)-
3H,9H-benzo[4,5]imidazo[2,1-c][1,2,4]thiadiazole-6-carboxylate
1
(3ae). Yellow solid; yield: 115 mg, 73%; mp 240−242 °C; H NMR
(400 MHz, CDCl3): δ 8.72 (d, J = 1.6 Hz, 1H), 8.28 (d, J = 8.9 Hz,
2H), 8.05 (dd, J = 8.4, 1.6 Hz, 1H), 7.33 (d, J = 8.5 Hz, 2H), 7.27 (d,
F
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J = 8.9 Hz, 2H), 7.09 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 8.5 Hz, 2H),
5.16 (s, 2H), 3.95 (s, 3H), 3.79 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 166.3, 159.8, 158.0, 154.6, 150.7, 143.7, 140.3, 129.2,
127.9, 126.1, 125.5, 124.3, 124.0, 121.6, 114.5, 114.3, 108.6, 55.3,
52.4, 46.2; MS (ESI) [M + H]+ m/z: 490; HRMS (ESI) m/z: [M +
H]+ calcd for C24H20N5O5S, 490.1180; found, 490.1175 (M + H)+.
Methyl (Z)-9-Cyclopentyl-3-((4-methoxyphenyl)imino)-3H,9H-
benzo[4,5]imidazo[2,1-c][1,2,4]thiadiazole-6-carboxylate (3if).
J = 8.2, 1.3 Hz, 1H), 7.43−7.34 (m, 2H), 7.29 (dd, J = 8.2, 5.2 Hz,
1H), 7.20−7.10 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
152.6, 152.1, 148.7, 144.7, 144.5, 141.0, 129.6, 125.1, 120.7, 118.5;
MS (ESI) [M + H]+ m/z: 269; HRMS (ESI) m/z: [M + H]+ calcd for
C13H9N4OS, 269.0492; found, 269.0491.
(Z)-N-Phenyl-3H-benzo[4,5]thiazolo[2,3-c][1,2,4]thiadiazol-3-
imine (3′ca). White solid; yield: 143 mg, 76%; mp 107.1−109.9 °C;
1H NMR (400 MHz, CDCl3): δ 8.68 (dd, J = 8.1, 1.4 Hz, 1H), 7.53−
1
7.30 (m, 5H), 7.18−7.11 (m, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 156.9, 156.0, 149.3, 132.5, 129.7, 127.7, 126.9, 125.7,
124.6, 122.9, 120.7, 115.2; MS (ESI) [M + H]+ m/z: 284; HRMS
(ESI) m/z: [M + H]+ calcd for C14H10N3S2, 284.0311; found,
284.0321.
White solid; yield: 102 mg, 68%; mp 216−219 °C; H NMR (400
MHz, CDCl3): δ 8.73 (d, J = 1.7 Hz, 1H), 8.04 (dd, J = 8.5, 1.7 Hz,
1H), 7.18−7.05 (m, 3H), 6.94 (d, J = 8.9 Hz, 2H), 4.76−4.66 (m,
1H), 3.95 (s, 3H), 3.83 (s, 3H), 2.40−2.20 (m, 2H), 2.17−2.07 (m,
2H), 2.04−1.96 (m, 2H), 1.86−1.68 (m, 2H); 13C{1H} NMR (100
MHz, CDCl3): δ 166.6, 156.4, 154.1, 150.3, 142.3, 140.0, 127.0,
124.4, 123.4, 122.1, 114.6, 113.7, 108.2, 55.9, 55.5, 52.2, 29.0, 24.6;
MS (ESI) [M + H]+ m/z: 423; HRMS (ESI) m/z: [M + H]+ calcd for
C22H23N4O3S, 423.1485; found, 423.1482.
(Z)-N-(3-Methoxypropyl)-3H-benzo[4,5]thiazolo[2,3-c][1,2,4]-
thiadiazol-3-imine (3′cb). Brown solid; yield: 149 mg, 80%; mp
1
159−161 °C; H NMR (400 MHz, CDCl3): δ 8.34 (dd, J = 8.1, 1.4
Hz, 1H), 7.36−7.25 (m, 2H), 7.18 (t, J = 7.7 Hz, 1H), 3.53 (t, J = 6.3
Hz, 2H), 3.34 (s, 1H), 3.15 (t, J = 6.6 Hz, 2H), 1.99 (p, J = 6.5 Hz,
2H); 13C{1H} NMR (101 MHz, CDCl3): δ 156.4, 155.5, 132.4,
127.4, 126.6, 125.1, 122.6, 114.3, 70.4, 58.6, 52.1, 30.8; MS (ESI) [M
+ H]+ m/z: 280; HRMS (ESI) m/z: [M + H]+ calcd for
C12H14N3OS2, 280.0573; found, 280.0571.
(Z)-N-Phenyl-3H,9H-benzo[4,5]imidazo[2,1-c][1,2,4]thiadiazol-3-
1
imine (3ja). White solid; yield: 104 mg, 52%; mp 145−147 °C; H
NMR (600 MHz, acetone-d6): δ 8.10 (d, J = 7.8 Hz, 1H), 7.43−7.37
(m, 2H), 7.34−7.20 (m, 4H), 7.16−7.09 (m, 3H); 13C{1H} NMR
(151 MHz, acetone-d6): δ 151.05, 149.43, 136.46, 129.34, 125.17,
125.06, 123.78, 121.28, 120.98, 112.26, 110.47. MS (ESI) [M + H]+
m/z: 267; HRMS (ESI) m/z: [M + H]+ calcd for C14H11N4S,
267.0699; found, 267.0693.
(Z)-7-Methoxy-N-phenyl-3H-benzo[4,5]thiazolo[2,3-c][1,2,4]-
thiadiazol-3-imine (3′da). White solid; yield: 155 mg, 89%; mp
1
146−148 °C; H NMR (400 MHz, CDCl3): δ 8.55 (d, J = 8.9 Hz,
1H), 7.46−7.35 (m, 2H), 7.16−7.10 (m, 3H), 7.00 (d, J = 2.5 Hz,
1H), 6.95 (dd, J = 8.9, 2.5 Hz, 1H), 3.86 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ 157.6, 156.8, 149.4, 129.6, 129.0, 126.4, 124.4,
120.7, 115.8, 112.6, 110.0, 108.4, 55.9; MS (ESI) [M + H]+ m/z: 314;
HRMS (ESI) m/z: [M + H]+ calcd for C15H12N3OS2, 314.0416;
found, 314.0414.
Diphenyl-4H-benzo[4,5]imidazo[1,2-c][1,3,5]thiadiazine-
2,4(1H)-diimine (12ja). White solid; yield: 69 mg, 25%; mp 120−122
1
°C; H NMR (400 MHz, acetone-d6): δ 8.97 (d, J = 8.2 Hz, 0H),
7.78−7.10 (m, 13H); 13C{1H} NMR (151 MHz, acetone-d6): δ
173.6, 149.3, 148.3, 145.3, 136.9, 131.1, 130.6, 130.3, 129.9, 128.4,
125.9, 125.3, 124.1, 121.1, 117.9, 116.1; MS (ESI) [M + H]+ m/z:
370; HRMS (ESI) m/z: [M + H]+ calcd for C21H16N5S, 370.1121;
found, 370.1128.
Characterization Data of Heteroarene-Fused [1,2,4]-
Selenadiazole 8/8′. Methyl (Z)-9-(4-Methoxybenzyl)-3-(phenyl-
imino)-3H,9H-benzo[4,5]imidazo[2,1-c][1,2,4]selenadiazole-6-car-
boxylate (8aa). White solid; yield: 118 mg, 75%; mp 165−168 °C;
1H NMR (400 MHz, CDCl3): δ 9.34 (d, J = 1.6 Hz, 1H), 8.06 (d, J =
8.1 Hz, 1H), 7.95 (dd, J = 8.3, 1.6 Hz, 1H), 7.91 (d, J = 7.8 Hz, 1H),
7.48 (t, J = 7.6 Hz, 1H), 7.31−7.25 (m, 2H), 7.21 (d, J = 8.6 Hz, 2H),
6.96 (d, J = 8.3 Hz, 1H), 6.87 (d, J = 8.6 Hz, 2H), 5.01 (s, 2H), 3.97
(s, 3H), 3.77 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 166.8,
159.7, 155.1, 151.4, 150.4, 136.0, 135.0, 128.3, 128.1, 126.7, 126.2,
125.7, 124.3, 124.2, 123.9, 123.5, 115.7, 114.7, 106.6, 55.3, 52.3, 45.6;
MS (ESI) m/z: 493 (M + H)+; HRMS (ESI) m/z: (M + H)+ calcd
for C24H21N4O3Se, 493.0775; found, 493.0778.
(Z)-N-Butyl-3H,9H-benzo[4,5]imidazo[2,1-c][1,2,4]thiadiazol-3-
1
imine (3jb). White solid; yield: 83 mg, 45%; mp 114−116 °C; H
NMR (400 MHz, CDCl3): δ 8.29 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.0
Hz, 1H), 7.16 (t, J = 7.8 Hz, 1H), 7.07 (t, J = 8.3 Hz, 1H), 3.33 (t, J =
7.2 Hz, 2H), 1.83 (p, J = 7.3 Hz, 2H), 1.56−1.32 (m, 2H), 0.99 (t, J =
7.4 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ 151.6, 136.0,
126.1, 123.3, 121.5, 113.3, 111.6, 52.3, 31.0, 20.3, 13.7; MS (ESI) [M
+ H]+ m/z: 247; HRMS (ESI) m/z: [M + H]+ calcd for C12H15N4S,
247.1012; found, 247.1009.
N2,N4-Dibutyl-4H-benzo[4,5]imidazo[1,2-c][1,3,5]thiadiazine-
2,4(1H)-diimine (12jb). White solid; yield: 69 mg, 28%; mp 183−185
°C; 1H NMR (400 MHz, CDCl3): δ 9.05 (d, J = 8.3 Hz, 1H), 7.61 (d,
J = 8.0 Hz, 1H), 7.43 (t, J = 7.7 Hz, 1H), 7.34−7.18 (m, 1H), 6.33 (s,
1H), 4.64 (s, 2H), 3.57 (q, J = 6.6 Hz, 2H), 1.85 (p, J = 8.0 Hz, 2H),
1.65 (p, J = 7.5 Hz, 2H), 1.44−1.33 (m, 4H), 0.97 (t, J = 7.4 Hz, 3H),
0.89 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ
172.04, 149.8, 148.3, 130.6, 126.4, 121.7, 117.2, 116.4, 46.8, 42.4,
30.9, 28.3, 20.1, 19.8, 13.7, 13.7; MS (ESI) [M + H]+ m/z: 330;
HRMS (ESI) [M + H]+ m/z: calcd for C17H24N5S, 330.1747; found,
330.1750.
Methyl (Z)-3-(Cyclohexylimino)-9-(4-methoxybenzyl)-3H,9H-
benzo[4,5]imidazo[2,1-c][1,2,4]selenadiazole-6-carboxylate (8ab).
1
White solid; yield: 112 mg, 70%; mp 181−183 °C; H NMR (400
MHz, CDCl3): δ 8.54 (d, J = 1.6 Hz, 1H), 7.88 (dd, J = 8.4, 1.7 Hz,
1H), 7.29 (d, J = 8.5 Hz, 2H), 6.86−6.83 (m, 3H), 5.06 (s, 2H), 3.91
(s, 3H), 3.76 (s, 3H), 2.48−2.41 (m, 1H), 1.88−1.81 (m, 4H), 1.65−
1.58 (m, 3H), 1.39−1.31 (m, 3H); 13C{1H} NMR (101 MHz,
CDCl3): δ 166.7, 159.4, 151.2, 146.7, 140.2, 128.9, 126.9, 126.7,
124.6, 123.3, 114.2, 113.4, 107.3, 69.7, 55.2, 52.1, 45.4, 33.4, 25.7,
24.5; MS (ESI) m/z: 499 (M + H)+; HRMS (ESI) m/z: (M + H)+
calcd for C24H27N4O3Se, 499.1244; found, 499.1252.
(Z)-N-Benzyl-3H,9H-benzo[4,5]imidazo[2,1-c][1,2,4]thiadiazol-3-
1
imine (3jc). Yellow solid; yield: 116 mg, 55%; mp 190−192 °C; H
NMR (400 MHz, acetone-d6): δ 10.54 (s, 1H), 7.95 (d, J = 7.8 Hz,
1H), 7.49 (d, J = 7.5 Hz, 2H), 7.39−7.33 (m, 2H), 7.30−7.13 (m,
4H), 4.34 (s, 2H); 13C{1H} NMR (101 MHz, CDCl3): δ 151.4,
135.7, 128.6, 128.3, 128.1, 127.7, 125.6, 121.8, 113.2, 111.0, 34.2; MS
(ESI) [M + H]+ m/z: 281; HRMS (ESI) m/z: [M + H]+ calcd for
C15H13N4S, 281.0855; found, 281.0854.
(Z)-N-Phenyl-3H-benzo[4,5]oxazolo[2,3-c][1,2,4]thiadiazol-3-
imine (3′aa). Brown solid; yield: 164 mg, 82%; mp 134−136 °C; 1H
NMR (400 MHz, CDCl3): δ 8.01 (d, J = 6.9 Hz, 1H), 7.45−7.29 (m,
5H), 7.19−7.08 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
153.7, 153.0, 150.6, 148.1, 129.6, 126.0, 125.5, 125.0, 124.7, 120.9,
113.0, 111.3; MS (ESI) [M + H]+ m/z: 268; HRMS (ESI) m/z: [M +
H]+ calcd for C14H10N3OS, 268.0539; found, 268.0543.
Methyl (Z)-3-(Phenylimino)-9-propyl-3H,9H-benzo[4,5]imidazo-
[2,1-c][1,2,4]selenadiazole-6-carboxylate (8ba). White solid; yield:
117 mg, 66%; mp 140−142 °C; 1H NMR (400 MHz, CDCl3): δ 8.75
(d, J = 1.6 Hz, 1H), 8.05 (dd, J = 8.4, 1.7 Hz, 1H), 7.46−7.34 (m,
2H), 7.20−7.11 (m, 3H), 7.01 (d, J = 8.4 Hz, 1H), 3.97−3.93 (m,
5H), 1.90 (h, J = 7.4 Hz, 2H), 1.03 (t, J = 7.4 Hz, 3H); 13C{1H}
NMR (101 MHz, CDCl3): δ 166.6, 152.4, 150.9, 150.8, 140.7, 129.8,
127.4, 124.9, 124.2, 123.4, 119.8, 113.9, 107.1, 52.1, 44.1, 21.3, 11.3;
MS (ESI) m/z: 415 (M + H)+; HRMS (ESI) m/z: [M + H]+ calcd for
C19H19N4O2Se, 415.0669; found, 415.0678.
(Z)-9-(Furan-2-ylmethyl)-N-phenyl-6-(trifluoromethyl)-3H,9H-
benzo[4,5]imidazo[2,1-c][1,2,4]selenadiazol-3-imine (8fa). Yellow
1
solid; yield: 106 mg, 65%; mp 190−193 °C; H NMR (400 MHz,
acetone-d6): δ 8.36 (d, J = 1.8 Hz, 1H), 7.69 (dd, J = 8.4, 1.8 Hz, 1H),
7.52 (s, 1H), 7.47−7.43 (m, 2H), 7.21−7.14 (m, 2H), 6.60 (dd, J =
3.3, 1.9 Hz, 1H), 6.42 (dd, J = 3.3, 1.9 Hz, 1H), 5.32 (s, 2H);
N-Phenyl-3H-[1,2,4]thiadiazolo[3′,4′:2,3]oxazolo[5,4-b]pyridin-
3-imine (3′ba). White solid; yield: 25 mg, 13%; mp 154−156 °C; 1H
NMR (400 MHz, CDCl3): δ 8.40 (dd, J = 5.2, 1.3 Hz, 1H), 7.61 (dd,
G
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13C{1H} NMR (101 MHz, acetone-d6): δ 152.6, 150.6, 150.2, 148.6,
N-Cyclohexyl-6-methoxybenzo[d]thiazol-2-amine (9′db). White
solid; yield: 21 mg, 12%; mp 82−85 °C; 1H NMR (400 MHz,
acetone-d6): δ 7.31 (d, J = 8.7 Hz, 1H), 7.22 (d, J = 2.6 Hz, 1H), 6.84
(dd, J = 8.7, 2.6 Hz, 1H), 3.79−3.72 (m, 4H), 2.10−2.07 (m, 2H),
1.80−1.74 (m, 2H), 1.65−1.59 (m, 1H), 1.49−1.25 (m, 5H);
13C{1H} NMR (101 MHz, acetone-d6): δ 164.0, 154.9, 147.2, 131.5,
118.6, 112.8, 105.1, 55.1, 53.3, 32.7, 25.5, 24.7; MS (ESI) m/z: 263
(M + H)+; HRMS (ESI) m/z: [M + H]+ calcd for C14H19N2OS,
263.1213, found, 263.1216.
Methyl-1-(4-methoxybenzyl)-2-(3-phenylureido)-1H-benzo[d]-
imidazole-5-carboxylate (10ad). White solid; yield: 55 mg, 40%; mp
113−115 °C; 1H NMR (600 MHz, acetone-d6): δ 11.92 (s, 1H), 8.51
(s, 1H), 8.13 (s, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 8.0 Hz,
2H), 7.42 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.4 Hz, 1H), 7.26 (t, J = 7.7
Hz, 2H), 6.94 (t, J = 7.5 Hz, 1H), 6.89 (d, J = 8.3 Hz, 2H), 5.28 (s,
2H), 3.86 (s, 3H), 3.75 (s, 3H); 13C{1H} NMR (151 MHz, CDCl3):
δ 166.7, 162.4, 159.3, 154.5, 139.4, 133.2, 128.8, 128.7, 128.6, 127.3,
124.7, 124.5, 122.6, 118.7, 114.2, 111.3, 108.5, 55.2, 52.1, 44.8; MS
(ESI) m/z: 263 (M + H)+; HRMS (ESI) m/z: [M + H]+ calcd for
C24H23N4O4, 431.1714; found, 431.1717.
143.2, 139.7, 129.8, 125.0, 124.4, 123.2, 123.0, 122.6, 122.4, 122.3,
122.3, 122.2, 119.8, 110.5, 109.4, 109.1, 38.6; MS (ESI) m/z: 463 (M
+ H)+; HRMS (ESI) m/z: [M + H]+ calcd for C20H14F3N4OSe,
463.0280; found, 463.0300.
(Z)-9-(Furan-2-ylmethyl)-N-(3-phenylpropyl)-6-(trifluoromethyl)-
3H,9H-benzo[4,5]imidazo[2,1-c][1,2,4]selenadiazol-3-imine (8fc).
1
Brown solid; yield: 130 mg, 73%; mp 162−165 °C; H NMR (400
MHz, CDCl3): δ 8.21 (d, J = 1.8, 1H), 7.58−7.44 (m, 1H), 7.37 (d, J
= 1.8, Hz, 1H), 7.33−7.26 (m, 2H), 7.25−7.15 (m, 3H), 7.13 (d, J =
8.4 Hz, 1H), 6.44 (d, J = 3.3 Hz, 1H), 6.35 (dd, J = 3.2, 1.9 Hz, 1H),
5.12 (s, 2H), 3.15 (t, J = 6.7 Hz, 2H), 2.79 (t, J = 6.7 Hz, 2H), 2.09 (t,
J = 6.7 Hz, 2H); 13C{1H} NMR (101 MHz, CDCl3): δ 150.6, 149.5,
148.0, 143.0, 141.8, 138.8, 128.5, 128.3, 125.8, 125.6, 124.5, 124.1,
123.8, 122.9, 121.8, 121.8, 121.7, 121.7, 110.6, 109.6, 109.5, 109.5,
109.5, 107.9, 58.5, 38.7, 33.5, 32.1; MS (ESI) [M + H]+ m/z: 505;
HRMS (ESI) m/z: [M + H]+ calcd for C23H20F3N4OSe, 505.0750;
found, 505.0752.
(Z)-N-Phenyl-3H-benzo[4,5]oxazolo[2,3-c][1,2,4]selenadiazol-3-
1
imine (8′aa). White solid; yield: 175 mg, 75%; mp 115−117 °C; H
1-(6-Methoxybenzo[d]thiazol-2-yl)-3-phenylurea (10′dd). White
NMR (400 MHz, CDCl3): δ 8.63 (d, J = 7.8 Hz, 1H), 8.01 (d, J = 8.1
Hz, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.59−7.18 (m, 6H); 13C{1H}
NMR (101 MHz, CDCl3): δ 154.6, 152.3, 150.8, 142.04, 135.4, 128.1,
126.4, 124.9, 124.9, 124.8, 124.2, 123.9, 123.7, 115.2, 110.0; MS
(ESI) [M + H]+ m/z: 315; HRMS (ESI) m/z: [M + H]+ calcd for
C14H10N3OSe, 315.9984; found, 315.9997.
1
solid; yield: 91 mg, 55%; mp 129−131 °C; H NMR (400 MHz,
CDCl3): δ 7.66 (d, J = 8.9 Hz, 1H), 7.50 (d, J = 8.1 Hz, 2H), 7.34 (t, J
= 7.7 Hz, 2H), 7.22 (d, J = 2.5 Hz, 1H), 7.12 (t, J = 7.3 Hz, 1H), 7.00
(dd, J = 9.0, 2.5 Hz, 1H), 3.85 (s, 3H); 13C{1H} NMR (101 MHz,
CDCl3): δ 156.6, 152.2, 137.4, 129.0, 124.2, 120.6, 120.3, 114.8,
104.7, 55.8; MS (ESI) m/z: 300 (M + H)+; HRMS (ESI) m/z: [M +
H]+ calcd for C15H14N3O2S, 300.0801; found, 300.0794.
(Z)-N-(3-Phenylpropyl)-3H-benzo[4,5]oxazolo[2,3-c][1,2,4]-
selenadiazol-3-imine (8′ac). Brown solid; yield: 170 mg, 64%; mp
1
Characterization Data of 2-Guanidinobenzoimiodazole 6.
Methyl-2-((bis(phenylamino)methylene)amino)-1-(4-methoxyben-
zyl)-1H-benzo[d]imidazole-5-carboxylate (6aa). White solid; yield:
64−66 °C; H NMR (400 MHz, CDCl3): δ 7.89−7.74 (m, 1H),
7.42−7.16 (m, 8H), 3.13 (t, J = 6.6 Hz, 2H), 2.80 (t, J = 7.6 Hz, 2H),
2.07 (p, J = 7.6 Hz, 2H); 13C{1H} NMR (101 MHz, CDCl3): δ 153.0,
150.0, 147.1, 141.7, 128.6, 128.5, 128.5, 128.4, 128.3, 126.5, 126.4,
125.8, 124.8, 124.5, 112.6, 110.8, 57.5, 33.4, 32.1; MS (ESI) [M +
H]+ m/z: 358; HRMS (ESI) m/z: [M + H]+ calcd for C17H16N3OSe,
358.0454; found, 358.0453.
1
123 mg, 76%; mp 162−165 °C; H NMR (400 MHz, acetone-d6): δ
8.07 (d, J = 1.5 Hz, 1H), 7.77 (dd, J = 8.4, 1.6 Hz, 1H), 7.57−7.51
(m, 4H), 7.42−7.33 (m, 6H), 7.26−7.20 (m, 2H), 7.20−7.13 (m,
2H), 6.84 (d, J = 8.7 Hz, 2H), 5.37 (s, 2H), 3.85 (s, 3H), 3.73 (s,
3H); 13C{1H} NMR (101 MHz, CDCl3): δ 168.0, 158.8, 157.7,
151.9, 140.9, 136.7, 129.3, 128.3, 123.0, 122.6, 118.4, 113.9, 107.8,
55.2, 51.8, 45.29; MS (ESI) m/z: 428 (M + H)+.
(Z)-N-Phenyl-3H-benzo[4,5]thiazolo[2,3-c][1,2,4]selenadiazol-3-
1
imine (8′ca). White solid; yield: 168 mg, 70%; mp 230−232 °C; H
NMR (400 MHz, CDCl3): δ 8.71 (d, J = 7.9 Hz, 1H), 7.46−7.36 (m,
4H), 7.32 (d, J = 7.9 Hz, 1H), 7.19 (t, J = 7.4 Hz, 1H), 7.14−7.09 (m,
2H); 13C{1H} NMR (101 MHz, CDCl3): δ 156.0, 155.3, 151.6,
132.8, 130.0, 127.5, 126.7, 125.6, 125.2, 122.7, 119.6, 115.4; MS
(ESI) [M + H]+ m/z: 332; HRMS (ESI) m/z: [M + H]+ calcd for
C14H10N3SSe, 331.9760; found, 331.9752.
Methyl 2-((Bis(phenylamino)methylene)amino)-1-propyl-1H-
benzo[d]imidazole-5-carboxylate (6ba). White solid; yield: 146
mg, 80%; mp 179−181 °C; 1H NMR (400 MHz, acetone-d6): δ 8.07
(d, J = 1.5 Hz, 1H), 7.81 (dd, J = 8.4, 1.6 Hz, 1H), 7.59−7.55 (m,
4H), 7.45−7.36 (m, 5H), 7.20−7.15 (m, 2H), 4.18 (t, J = 7.4, 2H),
3.86 (s, 3H), 1.82 (t, J = 7.4, 2H), 0.97 (t, J = 7.4 Hz, 3H); 13C{1H}
NMR (101 MHz, CDCl3): δ 168.1, 157.7, 151.7, 140.7, 136.8, 128.6,
122.7, 122.4, 121.3, 118.4, 107.4, 51.8, 44.0, 22.68, 11.5; MS (ESI)
m/z: 428 (M + H)+.
Characterization Data of Compound 10′da. 1,1′-Thiobis(N-
(6-methoxybenzo[d]thiazol-2-yl)-N′-phenylmethanedimine)
(10′da). White solid; yield: 103 mg, 55%; 1H NMR (400 MHz,
CDCl3): δ 7.75−7.40 (m, 8H), 7.27−7.22 (m, 3H), 7.13−6.97 (m,
3H), 6.91 (d, J = 2.4 Hz, 1H), 6.78 (dd, J = 8.8, 2.4 Hz, 1H), 3.85 (s,
3H), 3.76 (s, 3H); MS (ESI) [M + H]+ m/z: 595; HRMS (ESI) m/z:
[M + H]+ calcd for C30H23N6O2S3, 595.1039; found, 595.1045.
(Z)-N-(3-Phenylpropyl)-3H-benzo[4,5]thiazolo[2,3-c][1,2,4]-
selenadiazol-3-imine (8′cc). White solid; yield: 154 mg, 62%; mp
68−70 °C; 1H NMR (400 MHz, CDCl3): δ 8.53 (d, J = 8.6 Hz, 2H),
7.43−7.06 (m, 8H), 3.10 (t, J = 6.6 Hz, 2H), 2.79 (t, J = 7.6 Hz, 2H),
2.09 (p, J = 7.6 Hz, 2H); 13C{1H} NMR (101 MHz, CDCl3): δ 156.5,
152.2, 141.7, 133.0, 128.5, 128.4, 128.3, 127.4, 126.6, 125.8, 125.2,
122.6, 114.9, 59.3, 33.5, 32.2, 30.8; MS (ESI) [M + H]+ m/z: 374;
HRMS (ESI) m/z: [M + H]+ calcd for C17H16N3SSe, 374.0225;
found, 374.0229.
N-(3-Phenylpropyl)benzo[d]thiazol-2-amine (9′cc). Yellow solid;
1
yield: 30 mg, 17%; mp 95−97 °C; H NMR (400 MHz, CDCl3): δ
7.58 (dd, J = 7.8, 1.6 Hz, 1H), 7.52 (dd, J = 8.1, 1.9 Hz, 1H), 7.31−
7.26 (m, 3H), 7.23−7.17 (m, 3H), 7.08 (dd, J = 8.0, 7.3 Hz, 1H), 3.44
(t, J = 7.0 Hz, 2H), 2.73 (t, J = 7.0 Hz, 2H), 2.03 (t, J = 7.2 Hz, 2H);
13C{1H} NMR (101 MHz, CDCl3): δ 167.5, 152.3, 140.9, 130.3,
128.5, 128.4, 128.3, 128.3, 126.1, 125.9, 121.4, 120.7, 120.5, 118.8,
44.9, 33.0, 31.0; MS (ESI) [M + H]+ m/z: 269; HRMS (ESI) m/z:
[M + H]+ calcd for C16H17N2S, 269.1107; found, 269.1108.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c00421.
■
sı
X-ray crystallographic data, plausible mechanisms, and
spectral data (PDF)
X-ray crystallographic data of compound 3aa (CIF)
X-ray crystallographic data of compound 3′aa (CIF)
checkCIF/PLATON report of 3aa(PDF)
checkCIF/PLATON report of 3′aa (PDF)
X-ray crystallographic data of compound 3′cg (CIF)
checkCIF/PLATON report of 3′cg (PDF)
X-ray crystallographic data of compound 6ba (CIF)
(Z)-N-Cyclohexyl-7-methoxy-3H-benzo[4,5]thiazolo[2,3-c]-
[1,2,4]selenadiazol-3-imine (8′db). Yellow semi-solid; yield: 138 mg,
1
68%; H NMR (400 MHz, acetone-d6): δ 8.34 (d, J = 8.9 Hz, 1H),
7.31 (d, J = 2.5 Hz, 1H), 7.00 (dd, J = 8.9, 2.6 Hz, 1H), 3.85 (s, 3H),
2.72 (tt, J = 9.2, 3.6 Hz, 1H), 1.87−1.78 (m, 4H), 1.66−1.24 (m,
6H); 13C{1H} NMR (101 MHz, acetone-d6): δ 157.5, 156.3, 152.9,
128.5, 126.4, 114.8, 112.6, 108.6, 65.0, 55.3, 33.0, 25.6, 24.1; MS
(ESI) [M + Na]+ m/z: 389; HRMS (ESI) m/z: [M + Na]+ calcd for
C15H18N3OSSe, 368.0330; found, 368.0335.
H
https://dx.doi.org/10.1021/acs.joc.0c00421
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
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checkCIF/PLATON report of 6ba (PDF)
X-ray crystallographic data of compound 8ab (CIF)
checkCIF/PLATON report of 8ab (PDF)
X-ray crystallographic data of compound 9′cc (CIF)
checkCIF/PLATON report of 9′cc (PDF)
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AUTHOR INFORMATION
Corresponding Author
Chung-Ming Sun − Department of Applied Chemistry, National
Chiao Tung University, Hsinchu 300-10, Taiwan; Department
of Medicinal and Applied Chemistry, Kaohsiung Medical
University, Kaohsiung 807-08, Taiwan; orcid.org/0000-
0002-1804-1578; Email: cmsun@nctu.edu.tw
■
Authors
Jin-Yu Chen − Department of Applied Chemistry, National
Chiao Tung University, Hsinchu 300-10, Taiwan
Manikandan Selvaraju − Department of Medicinal Chemistry,
University of Kansas, Lawrence, Kansas 66045, United States
Yen-Tzu Lin − Department of Applied Chemistry, National
Chiao Tung University, Hsinchu 300-10, Taiwan
Sandip Dhole − Department of Applied Chemistry, National
Chiao Tung University, Hsinchu 300-10, Taiwan
Chih-Yu Lin − Department of Applied Chemistry, National
Chiao Tung University, Hsinchu 300-10, Taiwan
(8) (a) Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reactions in
Organic Synthesis; Wiley-VCH: Weinheim, 2006. (b) Pellissier, H.
Stereocontrolled Domino Reactions. Chem. Rev. 2013, 113, 442.
(c) Tietze, L. F. Domino Reactions: Concepts for Efficient Organic
Synthesis; Wiley-VCH: Weinheim, 2014. (d) Guru, M. M.;
Punniyamurthy, T. Copper(II)-Catalyzed Aerobic Oxidative Syn-
thesis of Substituted 1,2,3- and 1,2,4-Triazoles from Bisarylhydrazones
via C-H Functionalization C−C/N−N/C−N Bonds Formation. J.
Org. Chem. 2012, 77, 5063. (e) Yu, W.; Huang, Y.; Li, J.; Tang, X.;
Wu, W.; Jiang, H. Copper-Catalyzed Aerobic Oxidative [3+2]
Annulation for the Synthesis of 5-Amino/Imino-Substituted 1,2,4-
Thiadiazoles through C−N/N−S Bond Formation. J. Org. Chem.
2018, 83, 9334. (f) Teslenko, F. E.; Churakov, A. I.; Larin, A. A.;
Ananyev, I. V.; Fershtat, L. L.; Makhova, N. N. Route to 1,2,4- and
1,2,5-oxadiazole ring assemblies via a one-pot condensation/oxidation
protocol. Tetrahedron Lett. 2020, 61, 151678.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c00421
Notes
The authors declare no competing financial interest.
(9) (a) Song, L.; Tian, X.; Lv, Z.; Li, E.; Wu, J.; Liu, Y.; Yu, W.;
Chang, J. I2/KI-Mediated Oxidative N−N Bond Formation for the
Synthesis of 1,5-Fused 1,2,4-Triazoles from N-Aryl Amidines. J. Org.
Chem. 2015, 80, 7219. (b) Xie, H.; Cai, J.; Wang, Z.; Huang, H.;
Deng, G.-J. A Three-Component Approach to 3,5-Diaryl-1,2,4-
thiadiazoles under Transition-Metal-Free Conditions. Org. Lett.
2016, 18, 2196. (c) Fan, W.; Li, Q.; Li, Y.; Sun, H.; Jiang, B.; Li,
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Zhou, Y.; Ren, L.; Wu, J.; Yu, W.; Chang, J. Synthesis of 5-Amino and
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N−S Bond Formation. J. Org. Chem. 2017, 82, 5898. (e) Wang, Z.;
Xie, H.; Xiao, F.; Guo, Y.; Huang, H.; Deng, G.-J. Palladium-
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ACKNOWLEDGMENTS
■
The authors thank the Ministry of Science and Technology
(MOST) of Taiwan for financial assistance and the authorities
of the National Chiao Tung University for providing the
laboratory facilities.
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