Three Component Divergent Reactions: Base-Controlled Amphiphilic Synthesis of Benzimidazole-Linked Thiazetidines and Fused Thiadiazines

Article abstract of DOI:10.1021/acs.joc.6b01586

A divergent reaction of 2-aminobenzimidazole with isothiocyanates and dihalomethanes has been developed for the selective synthesis of benzoimidazothiazetidine and benzoimidazothiadiazine. A single-pot reaction of 2-aminobenzimidazole in the presence of s

Full text of DOI:10.1021/acs.joc.6b01586

Article
pubs.acs.org/joc
Three Component Divergent Reactions: Base-Controlled Amphiphilic
Synthesis of Benzimidazole-Linked Thiazetidines and Fused
Thiadiazines
Manikandan Selvaraju,† Sandip Dhole,† and Chung-Ming Sun*,†,‡
†Department of Applied Chemistry, National Chiao-Tung University, 1001 Ta-Hseuh Road, Hsinchu 300-10, Taiwan, ROC
‡Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, 100 Shih-Chuan First Road, Kaohsiung 807-08,
Taiwan, ROC
S
* Supporting Information
ABSTRACT: A divergent reaction of 2-aminobenzimidazole with isothiocyanates and dihalomethanes has been developed for
the selective synthesis of benzoimidazothiazetidine and benzoimidazothiadiazine. A single-pot reaction of 2-aminobenzimidazole
in the presence of sodium hydride delivers benzoimidazothiazetidine, whereas triethylamine promotes the formation of
benzoimidazothiadiazine via a sequential stepwise fashion. The reaction sequence involves the initial formation of thiourea
followed by regioselective nucleophilic addition and intramolecular ring-closing with dihalo electrophiles. The observed
regioselectivity of this reaction is governed by the nature of bases and the reaction sequence.
number of synthetic steps to meet the higher demand in
chemical genetics and drug discovery.7 In this context,
multicomponent reactions (MCRs) constitute a significant
role due to their high synthetic efficiency to construct a high
level of molecular diversity in a step- and atom-economic
manner.8 However, most MCRs follow a single reaction
pathway to furnish only one type of molecular scaffold.
Consequently, development of novel MCRs for the selective
formation of divergent products from the same participants is a
worthy and challenging goal.9,10
Hence, we report herein the first systematic approach for the
synthesis of benzimidazole-linked thiazetidine or fused
thiadiazine through a three component reaction of 2-amino-
benzimidazole, isothiocyanate, and diiodomethane. The present
strategy explores the amphiphilic reactivity of 2-amino-
benzimidazoles with isothiocyanates and dihalogen electro-
philes (Scheme 1). Benzimidazole-linked thiazetidine 8 was
obtained when the reaction was carried out in a single-pot
operation using diiodomethane as a one carbon electrophile
with sodium hydride. Both aromatic and aliphatic isothiocya-
nates were reacted successfully to deliver the product under
these conditions. On the other hand, the reaction of isolated
thiourea 7 with diiodomethane or dichloromethane in the
presence of triethylamine yielded benzimidazole-fused thiadia-
INTRODUCTION
■
Benzimidazoles are a class of important heterocycles that have
attracted considerable attention because of their widespread
applications in various domains.1 In particular, polycyclic
benzimidazole derivatives represent the range of eminent
biologically and therapeutically active molecules, organic
materials, and significant natural products.2 A vast number of
small molecules containing thiazetidine and thiadiazine
skeletons have shown prominent biological and pharmaceutical
applications as depicted in Figure 1. 1,3-Thiazetidin-2-ylidene
directly linked with triazine (I) acts as a valuable herbicide.
Similarly, 1,3-thiazetidine bearing oxadiazole core (II) exhibits
promising antifungal and antibacterial activities.3
Likewise, six-membered 1,3,5-thiadiazines have been identi-
fied to possess significant applications in medicine and
agriculture applications. 1,2,4-Triazole-fused thiadiazine (III)
and its derivatives are recognized as antibacterial agents and
insecticides.4 Buprofezin(IV), a potent insecticide, was found as
an active growth regulator on greenhouse whitefly and the
brown planthopper.5 Hence, we assumed that incorporating
these scaffolds in a single molecule might be an effective
strategy to discover novel entities with unusual biological
properties. However, the synthesis of thiazetidines is very
limited, and there is no report for the synthesis of
benzoimidazothiazetidine or benzoimidazothiadiazine.6 Diver-
sity-oriented synthesis is a powerful tool for generating a
collection of structurally complex molecules in a limited
Received: July 1, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.6b01586
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Figure 1. Biologically important thiazetidine and thiadiazine scaffolds.
Scheme 1. Regioselective Synthesis of Benzimidazole-Linked Thiazetidine 8 and Benzimidazole-Fused Thiadiazine 10
Scheme 2. Facile Synthesis of 2-Aminobenzimidazoles 4
zine 10. Notably, only aliphatic isothiocyanates were feasible to
furnish product 10 under this protocol. Under the strong basic
conditions (NaH), the parent amine nitrogen is flanked
exocyclic to the thiazetidine core and the other nitrogen is a
part of thiazetidine. In contrast, the parent amine nitrogen is
involved in a thiadiazine ring, and the other nitrogen stays
exocyclic to thiadiazine in weak basic conditions (NEt3).
Hence, the product selectivity is dictated by the basicity of the
parent amine and the reaction conditions (substrates and base)
employed.
To our delight, desired product 8a and thiourea 7a were
isolated in 35 and 20% yields, respectively. Encouraged by the
results of the model reaction, the task of reaction optimization
to improve the yield of 8a was undertaken by varying the bases
and solvents. The results for various optimization experiments
are summarized in Table 1. Screening of various bases such as
CS2CO3, K2CO3, Et3N, and NaH under various solvents
revealed that NaH in DMF gave the highest 69% yield (Table
1, entry 5). Next, we evaluated the suitability of different
dihaloelectrophiles such as CH2Br2 and CH2Cl2 on the
reactivity of 4a in the presence of NaH. However, CH2Br2
was less reactive than that of CH2I2, and the product was
obtained in a relatively lower yield (entries 7 and 8). It should
be noted that, when employing dichloromethane as a reagent or
solvent, the reaction did not generate any desired products
(entries 9−11). With the optimized reaction conditions in hand
(Table 1, entry 5), we first evaluated the scope for the
formation of compound 8 by employing several substituted 2-
aminobenzimidazoles and isothiocyanates. The reaction
efficiency was not affected by the substituent groups on both
RESULTS AND DISCUSSION
■
Our work started with the facile synthesis of variously
substituted 2-aminobenzimidazole 4 from 1-fluoro-2-nitro-
benzene 1 by following the literature methods as represented
in Scheme 2.11
Then, we carried out a three component reaction of 4a with
1-isothiocyanato-3-methoxypropane 5a and diiodomethane 6a
in the presence of Cs2CO3 in refluxing acetonitrile.
B
DOI: 10.1021/acs.joc.6b01586
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
Table 1. Optimization of Reaction Conditions for the Synthesis of 8a
b
yield (%)
entry
electrophile
base
solvent
temperature (°C)
time (h)
7a
8a
1
2
3
4
5
6
7
8
9
CH2I2
Cs2CO3
K2CO3
NEt3
CH3CN
CH3CN
CH3CN
acetone
CH2I2
reflux
reflux
reflux
rt
12
12
12
12
0.4
1
20
15
15
0
35
28
0
CH2I2
CH2I2
CH2I2
NEt3
0
CH2I2
CH2I2
NaH
rt
0
69
36
28
52
0
NaH
THF
rt
12
22
0
CH2Br2
CH2Br2
CH2Cl2
CH2Cl2
CH2Cl2
CH2I2
Cs2CO3
NaH
CH3CN
DMF
reflux
rt
12
0.4
12
0.4
12
12
NaH
CH2Cl2
DMF
rt
0
c
10
NaH
90
50
10
20
0
11
12
NEt3
CH2Cl2
CH2I2
reflux
rt
0
KOtBu
31
a
b
Reaction conditions: 4a (0.3 mmol), 5a (0.45 mmol), CH2I2 (0.9 mmol), base (0.9 mmol), solvent (2 mL) at the specified temperature. Isolated
c
yield. Under microwave irradiation.
benzimidazole and isothiocyanates. The electron-withdrawing
and -donating groups were well tolerated under these reaction
conditions and proceeded smoothly to give the corresponding
derivatives in good yields. In particular, both aromatic as well as
aliphatic isothiocyanates furnished the products smoothly with
moderate yields (Scheme 3). Further, the substrate scope of
this three component reaction was expanded by employing
substituted 2-aminobenzoxazoles as a suitable substrate
(Scheme 3, entries 8m and 8n).
In addition to the spectroscopic analysis, the structure of 8c
is assured by X-ray crystallographic analysis, and the ORTEP
diagram is represented in Figure 2.13 The benzimidazole and
the four-membered thiazetidine were tethered through an
exocyclic imine bridge in an angular orientation.
Further, we carried out this multicomponent one-pot
reaction in a sequential stepwise pathway to understand its
unique mechanism (Table 2). Hence, we performed a model
reaction using isolated urea 7i and CH2Cl2 in the presence of
various bases as shown in Table 2. Employing inorganic bases
such as K2CO3, Cs2CO3, or NaH did not give any product
formation. Surprisingly, when we treated triethylamine as a
base, no thiazetidines 8 was isolated, but an unprecedented
benzimidazole-fused thiadiazine 10i accompanied by unreactive
7i were obtained (entry 5). The conversion was improved to
95% when diiodomethane was used as an electrophile (entry
9). Interestingly, treatment of NaH as a base delivered only
thiazetidines 8 under this stepwise protocol (entry 7). Hence,
the optimized conditions to selectively obtain product 10 are
identified as the employment of triethylamine as a base and
CH2I2 as an electrophile in acetone for 24 h at room
temperature (entry 9).
Next we focused on the substrate scope for the formation of
benzimidazole-fused thiadiazines 10 (Scheme 4). All of the
aliphatic isothiocyanates smoothly delivered product 10 with
moderate to high yields. On the contrary, aromatic
isothiocyanates (entries 8o and 8p) were converted to
thiazetidines 8 with lower yields under these conditions.
Notably, no product formation was observed when 4-
nitrophenyl isothiocyanate was employed (entry 8j). Hence,
in this stepwise protocol, using triethylamine as a base, the
product outcome is dictated by the electronic nature of
isothiocyanates; aliphatic isothiocyanates delivered thiadiazines
10 and aromatic isothiocyanates furnished thiazetidines 8.
In contrast, sodium hydride selectively promotes the
formation of thiazetidines 8 in both one-pot and stepwise
protocols irrespective of the electronic nature of isothiocyanates
(both aromatic and aliphatic). On the basis of the experimental
observation, a plausible mechanism for the formation of
benzoimidazothiazetidine and benzoimidazothiadiazine is out-
lined in Scheme 5.6
The first step is the formation of thiourea 7 through the
reaction of 2-aminobenzimidazole 4 and isothiocyanate 5 in a
one-pot or stepwise fashion. This preformed thiourea 7 acts as
a common intermediate for the S-alkylation with diiodo-
methane under the basic conditions to obtain compound 9,
which shows base-controlled divergent cyclization. In the
presence of NaH, the subsequent intramolecular ring closure of
9 is aided by the selective deprotonation of parent amine
nitrogen to furnish four membered thiazetidines 8. On the
other hand, employing triethylamine in acetone promotes the
formation of six-membered thiadiazines 10. Hence, the main
difference in reactivity is probably caused by the ability of a base
to abstract slightly acidic hydrogen in 9 as represented in
C
DOI: 10.1021/acs.joc.6b01586
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 3. One-Pot Synthesis of Benzimidazothiazetidine 8
Figure 2. ORTEP diagram of 8c.
D
DOI: 10.1021/acs.joc.6b01586
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
Table 2. Optimization of Reaction Conditions for the Synthesis of 10i
b
yield (%)
a
entry
electrophile
base (equiv)
temperature (°C)
time (h)
10i
8i
1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2I2
K2CO3(5)
Cs2CO3(5)
NaH(5)
40
40
rt
24
24
8
0
0
0
0
2
3
0
0
4
NEt3(5)
rt
24
8
12
49
0
0
5
NEt3(10)
K2CO3(5)
NaH(5)
rt
0
6
rt
24
0.5
24
24
48
48
0
7
CH2I2
CH2I2
rt
rt
0
92
0
8
NEt3(3)
67
95
0
9
CH2I2
CH2I2
NEt3(7)
rt
rt
0
10
11
Pyridine
0
CH2I2
DIPEA(10)
rt
0
0
a
b
CH2Cl2 is used as solvent and reagent. Acetone is used as a solvent when CH2I2 (1.5 equiv) is employed as an electrophile. Isolated yields.
silica gel 60 (230−400 mesh). 1H NMR, 13C NMR, and NOE spectra
Scheme 5. Although the strong base NaH could form a more
reactive and nucleophilic anion, much weaker triethylamine
could assist only as a general base catalyst. In addition, a
possible driving force for the observed selectivity could be the
resonance stabilization of the resulting anion with the aromatic
group on isothiocyanates. All of the prepared compounds of 8
and 10 were characterized by proton NMR (the characteristic
−CH2 proton resonates at 4.6 ppm for compound 8 and
compound 10 shows at 5.9 ppm, and C-13 carbon NMR (the
characteristic −CH2 carbon resonates at 46.5 ppm for
compound 8 and compound 10 shows at 52.8 ppm).
In addition, the structure of 10f was unambiguously
confirmed by X-ray crystallographic analysis as shown in Figure
3.12 The thiadiazine skeleton is twisted and fused with the
benzimidazole ring, which brought the characteristic methylene
protons in close proximity to account for the deshielding effect
consistently observed in all compounds 10.13
were recorded at ambient temperature using 300, 400, and 600 MHz
spectrometers. Chemical shifts are reported in parts per million (ppm)
on the scale from an internal standard. IR spectra were recorded on an
FT-IR instrument and are reported in wavenumbers (inverse
centimeters). High-resolution mass spectra were recorded in ESI
mode using a magnetic sector mass analyzer and TOF mass
spectrometer.
Experimental Procedure for the Synthesis of Methyl 1-(2-
(Cyclohex-1-en-1-yl)ethyl)-2-((3-(3-methoxypropyl)-1,3-thiazetidin-
2-ylidene)amino)-1H-benzo[d]imidazole-5-carboxylate (8a). To a
solution of methyl 2-amino-1-(2-(cyclohex-1-en-1-yl)ethyl)-1H-benzo-
[d]imidazole-5-carboxylate 4a (0.1 g, 0.334 mmol) and 1-isothiocya-
nato-3-methoxypropane 5a (0.065 g, 0.501 mmol) in DMF (8 mL)
were added NaH (0.024 g, 1.002 mmol) followed by the addition of
diiodomethane (0.268 g, 1.002 mmol). The resulting reaction mixture
was stirred at room temperature for 15 min. After completion of the
reaction, the reaction mixture was quenched with cold water (10 mL),
extracted with EtOAc (2 × 20 mL), and washed with brine solution
(30 mL). The combined organic extracts were dried over MgSO4,
filtered, and concentrated under reduced pressure. The crude product
was purified by column chromatography (10% EtOAc in hexane) to
afford methyl 1-(2-(cyclohex-1-en-1-yl)ethyl)-2-((3-(3-methoxyprop-
yl)-1,3-thiazetidin-2-ylidene)amino)-1H-benzo[d]imidazole-5-carboxy-
late 8a as an off-white solid (0.102 g, 69%).
Experimental Procedure for the Synthesis of Methyl 10-Isobutyl-
2-(isopropylimino)-4,10-dihydro-2H-benzo[4,5]imidazo[1,2-c]-
[1,3,5]thiadiazine-7-carboxylate (10a). To a solution of methyl 2-
amino-1-isobutyl-1H-benzo[d]imidazole-5-carboxylate 4a (0.2 g, 0.808
mmol) and 2-isothiocyanatopropane (0.122 g, 1.212 mmol) in DMF
(8 mL) was added NaH (0.058 g, 2.424 mmol), and the resulting
reaction mixture was stirred at room temperature for 15 min. After
completion of the reaction, the reaction mixture was quenched with
cold water (10 mL), extracted with EtOAc (2 × 20 mL), and washed
with brine solution (30 mL). The combined organic extracts were
dried over MgSO4, filtered, and concentrated under reduced pressure.
The crude product was purified by column chromatography (5%
EtOAc in hexane) to afford methyl 1-isobutyl-2-(3-isopropylthiour-
eido)-1H-benzo[d]imidazole-5-carboxylate 7a (0.259 g, 92%) as a
white solid. In the next step, to a solution of methyl 1-isobutyl-2-(3-
isopropylthioureido)-1H-benzo[d]imidazole-5-carboxylate 7a (0.1 g,
0.287 mmol) in acetone (10 mL) were added triethylamine (0.203 g,
2.011 mmol) and diiodomethane (0.115 g, 0.430 mmol). The resulting
reaction mixture was allowed to stir at room temperature for 30 min.
CONCLUSIONS
■
In conclusion, we have developed a three component reaction
of 2-aminobenzimidazole, isothiocyanate, and diiodomethane
for the regioselective synthesis of benzoimidazothiazetidine and
benzoimidazothiadiazine. In this selective protocol, the one-pot
conditions resulted in the formation benzoimidazothiazetidine,
whereas a stepwise sequential reaction furnished benzoimida-
zothiadiazine. The salient features of this strategy include
milder reaction conditions, inexpensive reagents, high-atom
economy, and efficacy of forming consecutive C−S and C−N
bonds and two different unique heterocycles in a single
synthetic operation. Further studies on the detailed reaction
mechanism and their utility on other heterocycles for biological
applications are underway.
EXPERIMENTAL SECTION
■
General Information. All of the solvents were distilled before use.
All reactions were performed under an inert atmosphere with
unpurified reagents and dry solvents. Analytical thin-layer chromatog-
raphy (TLC) was performed using 0.25 mm silica gel-coated plates.
Flash chromatography was performed using the indicated solvent and
E
DOI: 10.1021/acs.joc.6b01586
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 4. Synthesis of Benzimidazothiadiazine 10 via a Stepwise Protocol
After completion of the reaction, the solvent was evaporated, diluted
with ethyl acetate (15 mL), and washed with water (2 × 20 mL)
followed by brine solution (10 mL). The organic extract was dried
over MgSO4, filtered, and concentrated under reduced pressure The
crude product was purified by column chromatography (10% EtOAc
in hexane) to afford methyl 10-isobutyl-2-(isopropylimino)-4,10-
dihydro-2H-benzo[4,5]imidazo[1,2-c][1,3,5]thiadiazine-7-carboxylate
10a as a white solid (0.084 g, 82%).
5H), 7.18 (d, J = 8.4 Hz, 1H), 5.24 (t, J = 6.9 Hz, 1H), 4.60 (s, 2H),
4.45 (s, 2H), 4.17 (t, J = 7.4 Hz, 2H), 3.89 (s, 3H), 2.35 (t, J = 7.4 Hz,
2H), 1.97 (d, J = 6.8 Hz, 2H), 1.83−1.72 (m, 2H), 1.62−1.50 (m,
2H), 1.46−1.38 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 22.1, 22.8,
25.1, 28.2, 37.4, 41.2, 49.4, 50.3, 51.7, 107.9, 119.6, 122.3, 123.0, 124.0,
128.1, 128.7, 128.9, 133.8, 134.8, 137.1, 141.6, 156.6, 164.0, 168.0; FT-
IR (neat) 2993, 1709, 1503, 1438, 1296, 816, 787 cm−1; MS (ESI) m/
z 461 (MH+); HRMS (ESI, m/z) calcd C26H28N4O2S [M + H]+
461.2006, found 461.2013.
Methyl 1-(2-(Cyclohex-1-en-1-yl)ethyl)-2-((3-(3-methoxypropyl)-
1,3-thiazetidin-2-ylidene)amino)-1H-benzo[d]imidazole-5-carboxy-
Methyl 2-((3-Cyclohexyl-1,3-thiazetidin-2-ylidene)amino)-1-(3-
1
late 8a. White solid; yield = 0.12 g, 69%; mp 65−67 °C; H NMR
phenylpropyl)-1H-benzo[d]imidazole-5-carboxylate 8c. White
1
(400 MHz, CDCl3) δ 8.23 (d, J = 1.6 Hz, 1H), 7.82 (dd, J = 8.4, 1.6
Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 5.23 (t, J = 6.9 Hz, 1H), 4.55 (s,
2H), 4.13 (t, J = 6.9, Hz, 2H), 3.88 (s, 3H), 3.50 (t, J = 6.9 Hz, 2H),
3.45 (t, J = 6.9 Hz, 2H), 3.32 (s, 3H), 2.32 (t, J = 7.3 Hz, 2H), 1.97 (t,
J = 7.3 Hz, 2H), 1.95−1.89 (m, 2H), 1.89−1.77 (m, 2H), 1.61−1.51
(m, 2H), 1.50−1.40 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 22.1,
22.8, 25.1, 27.7, 28.2, 37.3, 41.14, 43.9, 50.2, 51.7, 58.7, 69.6, 107.8,
119.6, 122.2, 122.9, 123.9, 133.8, 37.16, 141.6, 156.7, 163.7, 168.0; FT-
IR (neat) 2873, 1709, 1503, 1438, 1113, 767, 749 cm−1; MS (ESI) m/
z 443 (MH+); HRMS (ESI, m/z) calcd C23H30N4O3S [M + H]+
443.2111, found 443.2124.
solid; yield = 0.097 g, 65%; mp 165−167 °C; H NMR (400 MHz,
CDCl3) δ 8.27 (s, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.51−6.82 (m, 6H),
4.52 (s, 2H), 4.13 (t, J = 7.1 Hz, 2H), 3.91 (s, 3H), 2.66 (m, 1H), 2.13
(t, J = 7.6 Hz, 2H), 2.00 (d, J = 11.1 Hz, 2H), 1.83 (d, J = 12.2 Hz,
2H), 1.68 (d, J = 12.7 Hz, 2H), 1.17 (t, J = 12.3 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 24.9, 24.9, 25.3, 29.9, 29.94, 30.5, 33.0, 41.8,
41.8, 46.8, 51.8, 55.3, 107.7, 119.5, 122.2, 123.0, 126.0, 126.0, 128.2,
128.3, 128.3, 128.4, 137.2, 141.1, 141.7, 157.1, 162.9, 168.1; FT-IR
(neat) 2933, 2855, 1711, 1627, 1505, 1296, 1218, 1003, 819, 768
cm−1; MS (ESI) m/z 463 (MH+); HRMS (ESI, m/z) calcd
C26H31N4O2S [M + H]+ 463.2162, found 463.2165.
Methyl 2-((3-Benzyl-1,3-thiazetidin-2-ylidene)amino)-1-(2-(cyclo-
Methyl 1-Isobutyl-2-((3-phenethyl-1,3-thiazetidin-2-ylidene)-
amino)-1H-benzo[d]imidazole-5-carboxylate 8d. Off-white solid;
yield = 0.112 g, 66%; mp 149−150 °C; 1H NMR (400 MHz,
CDCl3) δ 8.26 (d, J = 1.6 Hz, 1H), 7.83 (dd, J = 8.4, 1.6 Hz, 1H), 7.31
hex-1-en-1-yl)ethyl)-1H-benzo[d]imidazole-5-carboxylate 8b. Pale
1
yellow solid; yield = 0.102 g, 67%; mp 122−124 °C; H NMR (400
MHz, CDCl3) δ 8.26 (s, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.44−7.26 (m,
F
DOI: 10.1021/acs.joc.6b01586
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
White solid; yield = 0.097 g, 65%; mp 200−201 °C; H NMR (400
MHz, CDCl3) δ 8.32 (d, J = 1.6 Hz, 1H), 7.88 (dd, J = 8.4, 1.6 Hz,
1H), 7.62 (d, J = 8.4 Hz, 1H), 7.38 (t, J = 7.8 Hz, 2H), 7.29 (m, 1H),
7.11 (t, J = 7.8 Hz, 2H), 5.32 (t, J = 7.4 Hz, 1H), 4.95 (s, 2H), 4.25 (t,
J = 7.4 Hz, 2H), 3.91 (s, 3H), 2.42 (t, J = 7.4 Hz, 2H), 2.01 (t, J = 7.4
Hz, 2H), 1.93−1.78 (m, 2H), 1.51−1.36 (m, 4H); 13C NMR (100
MHz, CDCl3) δ 22.0, 22.8, 25.2, 28.3, 37.6, 41.8, 48.4, 51.8, 108.1,
116.0, 120.1, 122.7, 123.3, 123.7, 124.3, 129.1, 133.8, 137.0, 139.8,
141.4, 156.0, 167.9; FT-IR (neat) 2922, 2851, 1713, 1623, 1494, 1296,
1089, 766, 689 cm−1; MS (ESI) m/z 447 (MH+); HRMS (ESI, m/z)
calcd C25H26N4O2S [M + H]+ 447.1849, found 447.1845.
Scheme 5. Plausible Mechanism for the Formation of 8 and
10
Methyl 1-Cyclopentyl-2-((3-phenyl-1,3-thiazetidin-2-ylidene)-
amino)-1H-benzo[d]imidazole-5-carboxylate 8g. Off-white solid;
1
yield = 63%; mp 116−118 °C; H NMR (400 MHz, CDCl3) δ 8.30
(d, J = 1.6 Hz, 1H), 7.85 (dd, J = 8.4, 1.6 Hz, 1H), 7.53 (d, J = 8.4 Hz,
2H), 7.43−7.32 (m, 2H), 7.30−7.10 (m, 2H), 5.11 (p, J = 8.9 Hz,
1H), 4.87 (s, 2H), 3.90 (s, 3H), 2.27−2.20 (m, 2H), 2.19−1.94 (m,
4H), 1.81−1.76 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 25.1, 30.1,
48.6, 51.8, 55.2, 109.3, 116.1, 120.2, 122.4, 123.1, 123.7, 129.2, 136.1,
139.8, 141.6, 156.1, 159.8, 167.9; FT-IR (neat) 2997, 2871, 1711,
1623, 1580, 1492, 1362, 1300, 767, 688 cm−1; MS (ESI) m/z 407
(MH+); HRMS (ESI, m/z) calcd C22H22N4O2S [M + H]+ 407.1536,
found 407.1538.
Methyl 1-Isobutyl-2-((3-(4-methoxyphenyl)-1,3-thiazetidin-2-
ylidene)amino)-1H-benzo[d]imidazole-5-carboxylate 8h. Off-white
1
solid; yield = 0.105 g, 61%; mp 141−144 °C; H NMR (400 MHz,
CDCl3) δ 8.30 (d, J = 1.6 Hz, 1H), 7.86 (dd, J = 8.4, 1.6 Hz, 1H), 7.48
(d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 8.9 Hz, 2H),
4.86 (s, 2H), 3.94 (d, J = 7.3 Hz, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 2.27
(m, 1H), 0.95 (d, J = 6.7 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ
20.4, 29.0, 48.6, 50.0, 51.8, 55.5, 108.2, 114.3, 117.4, 119.9, 122.6,
123.2, 133.6, 137.5, 141.4, 155.9, 156.5, 159.1, 167.9; FT-IR (neat)
2955, 2870, 1710, 1625, 1500, 1324, 1245, 894, 750, 768 cm−1; MS
(ESI) m/z 425 (MH+); HRMS (ESI, m/z) calcd C22H24N4O3S [M +
H]+ 425.1645, found 425.1647.
(d, J = 8.4 Hz, 1H), 7.27−7.19 (m, 4H), 7.16 (d, J = 8.4 Hz, 1H), 4.31
(s, 2H), 3.90 (d, J = 7.0 Hz, 2H), 3.88 (s, 3H), 3.64 (t, J = 7.0 Hz,
2H), 2.98 (t, J = 7.0 Hz, 2H), 2.22 (m, 1H), 0.92 (d, J = 6.7 Hz, 6H);
13C NMR (100 MHz, CDCl3) δ 20.3, 28.8, 33.9, 48.2, 49.7, 50.6, 51.7,
108.0, 119.6, 122.2, 22.9, 126.8, 128.5, 128.8, 137.6, 138.2, 141.5,
157.0, 163.4, 168.0; FT-IR (neat) 2955, 2870, 1710, 1588, 1439, 1297,
1109, 768, 750 cm−1; MS (ESI) m/z 423 (MH+); HRMS (ESI, m/z)
calcd C23H26N4O2S [M + H]+ 423.1849, found 423.1849.
N-(1-(Furan-2-ylmethyl)-5-(trifluoromethyl)-1H-benzo[d]-
imidazol-2-yl)-3-(m-tolyl)-1,3-thiazetidin-2-imine 8i. White solid;
1
yield = 65%; mp 187−190 °C; H NMR (400 MHz, CDCl3) δ 7.87
(s, 1H), 7.43−7.30 (m, 6H), 6.95 (d, J = 7.5 Hz, 1H), 6.31−6.27 (m,
2H), 5.36 (s, 2H), 4.92 (s, 2H), 2.39 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 21.6, 39.2, 48.5, 108.37, 109.0, 110.5, 113.4, 116.7, 115.4 (q,
3JC−F = 4.5 Hz), 118.0 (q, 3JC−F = 3.02 Hz), 124.7, 129.1, 135.5, 139.2,
2
139.7, 141.46, 142.5, 149.6, 155.9, 124.1 (q, JC−F = 31.7 Hz), 160.2;
Methyl 1-Isobutyl-2-((3-phenyl-1,3-thiazetidin-2-ylidene)amino)-
FT-IR (neat) 2916, 2849, 1625, 1446, 1324, 735, 685, 661 cm−1; MS
(ESI) m/z 443 (MH+); HRMS (ESI, m/z) calcd C22H17F3N4OS [M +
H]+ 443.1148, found 443.1152.
1H-benzo[d]imidazole-5-carboxylate 8e. Brown solid; yield = 0.094
1
g, 59%; 167−170 °C; H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H),
7.88 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.38 (t, J = 7.8 Hz,
2H), 7.29 (m, 1H), 7.11 (t, J = 7.5 Hz, 2H), 4.93 (s, 2H), 3.99 (d, J =
7.3 Hz, 2H), 3.90 (s, 3H), 2.29 (m, 1H), 0.97 (d, J = 6.7 Hz, 6H); 13C
NMR (100 MHz, CDCl3) δ 20.4, 29.0, 29.6, 48.5, 50.1, 51.8, 108.3,
116.0, 120.1, 122.7, 123.3, 123.7, 129.2, 137.5, 139.9, 141.3, 156.3,
159.6, 167.9; FT-IR (neat) 2955, 1710, 1625, 1500, 1324, 1245, 894,
768, 750 cm−1; MS (ESI) m/z 395 (MH+); HRMS (ESI, m/z) calcd
C21H22N4O2S [M + H]+ 395.1536, found 395.1538.
N-(1-(Furan-2-ylmethyl)-N-(3-(4-nitrophenyl)-1,3-thiazetidin-2-
ylidene)-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-amine 8j. Yel-
low solid; yield = 67%; mp 199−202 °C; 1H NMR (400 MHz,
CDCl3) δ 8.30 (d, J = 8.7 Hz, 2H), 7.90 (s, 1H), 7.73 (d, J = 8.7 Hz,
2H), 7.42−7.24 (m, 3H), 6.27 (dd, J = 2.1, 1.3, 1H), 6.19 (d, J = 3.2,
1H), 5.39 (s, 2H), 5.03 (s, 2H); 13C NMR (150 MHz, CDCl3) δ 39.4,
3
49.2, 108.5, 109.3, 110.5, 115.8, 115.9, 124.3, 118.6 (q, JC−F = 3.01
Hz), 125.4, 126.2, 135.4, 141.1, 142.8, 143.0, 144.2, 149.1, 154.9,
160.6; FT-IR (neat) 2917, 2850, 1629, 1583, 1330, 1103, 812, 747,
Methyl 1-(2-(Cyclohex-1-en-1-yl)ethyl)-2-((3-phenyl-1,3-thiazeti-
din-2-ylidene)amino)-1H-benzo[d]imidazole-5-carboxylate 8f.
Figure 3. ORTEP diagram of compound 10f.
G
DOI: 10.1021/acs.joc.6b01586
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
664 cm−1; MS (ESI) m/z 474 (MH+); HRMS (ESI, m/z) calcd
C21H14F3N5O3S [M + H]+ 474.0845, found 474.0842.
1297, 749 cm−1; MS (ESI) m/z 465 (MH+); HRMS (ESI, m/z) calcd
C25H25FN4O2S [M + H]+ 465.1755, found 465.1737.
Methyl 10-Isobutyl-2-(isopropylimino)-4,10-dihydro-2H-benzo-
N-(3-Benzyl-1,3-thiazetidin-2-ylidene)-1-(furan-2-ylmethyl)-5-(tri-
fluoromethyl)-1H-benzo[d]imidazol-2-amine 8k. White solid; yield
= 67%; mp 123−125 °C; 1H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H),
7.39−7.30 (m, 8H), 6.27 (dd, J = 3.2, 1.8 Hz, 1H), 6.19 (d, J = 3.2 Hz,
1H), 5.31 (s, 2H), 4.64 (s, 2H), 4.47 (s, 2H); 13C NMR (150 MHz,
[4,5]imidazo[1,2-c][1,3,5]thiadiazine-7-carboxylate 10a. White
1
solid; yield = 0.084 g, 82%; mp 227−230 °C; H NMR (400 MHz,
CDCl3) δ 8.43 (d, J = 1.4 Hz, 1H), 8.10 (dd, J = 8.5, 1.4 Hz, 1H), 7.37
(d, J = 8.5 Hz, 1H), 5.82 (s, 2H), 4.48 (sept, J = 6.6 Hz, 1H), 3.99 (d, J
= 7.4 Hz, 2H), 3.95 (s, 3H), 2.20 (m, 1H), 1.44 (d, J = 6.6 Hz, 6H),
1.00 (d, J = 6.7 Hz, 6H); 13C NMR (100 MHz, CD3OD) δ 18.9, 20.5,
28.2, 40.3, 46.3, 49.9, 51.6, 111.1, 111.9, 126.1, 126.6, 128.1, 133.4,
151.1, 161.7, 165.9; FT-IR (neat) 2960, 2916, 1708, 1547, 1497, 1297,
1202, 1014, 807, 721 cm−1; MS (ESI) m/z 361 (M + H)+; HRMS
(ESI, m/z) calcd C18H24N4O2S [M + H]+ 361.1693, found 361.1698.
Methyl 10-Isobutyl-2-((3-methoxypropyl)imino)-4,10-dihydro-
2H-benzo[4,5]imidazo[1,2-c][1,3,5]thiadiazine-7-carboxylate 10b.
3
CDCl3) δ 39.0, 49.5, 50.4, 108.2, 108.8, 110.4, 115.0 (q, JC−F = 4.5
3
Hz), 117.6 (q, JC−F = 3.01 Hz), 128.2, 128.8, 129.0, 134.7, 135.5,
2
141.6, 142.4, 149.7, 156.5, 123.7 (q, JC−F = 31.7 Hz), 164.6; FT-IR
(neat) 2918, 2850, 1629, 1583, 1371, 796, 701 cm−1; MS (ESI) m/z
443 (MH+); HRMS (ESI, m/z) calcd C22H17F3N4OS [M + H]+
443.1148, found 443.1149.
N-(3-Cyclohexyl-1,3-thiazetidin-2-ylidene)-1-(furan-2-ylmethyl)-
5-(trifluoromethyl)-1H-benzo[d]imidazol-2-amine 8l. White solid;
1
White solid; yield = 0.081 g, 79%; mp 212−214 °C; H NMR (300
1
yield = 69%; mp 161−163 °C; H NMR (400 MHz, CDCl3) δ 7.79
MHz, CDCl3) δ 8.51 (d, J = 1.4 Hz, 1H), 8.12 (dd, J = 8.5, 1.4 Hz,
1H), 7.41 (d, J = 8.5 Hz, 1H), 5.97 (s, 2H), 4.03 (d, J = 7.4 Hz, 2H),
3.97 (s, 3H), 3.80 (t, J = 6.6 Hz, 2H), 3.52 (t, J = 6.6 Hz, 2H), 3.35 (s,
3H), 2.29 (m, 1H), 2.09 (quint, J = 6.6 Hz, 2H), 1.02 (d, J = 6.7 Hz,
6H); 13C NMR (100 MHz, CDCl3) δ 165.8, 162.8, 150.9, 132.9,
128.2, 127.0, 126.6, 113.0, 110.1, 69.8, 58.6, 52.6, 50.4, 41.7, 41.2, 28.6,
28.3, 20.1, 20.1; FT-IR (neat) 2922, 1728, 1566, 1519, 1253, 1017, 784
cm−1; MS (ESI) m/z 391 (MH+); HRMS (ESI, m/z) calcd
C19H26N4O3S [M + H]+ 391.1798, found 391.1805.
(s, 1H), 7.29 (m, 3H), 6.27 (dd, J = 3.2, 1.8 Hz, 1H), 6.20 (d, J = 3.2
Hz, 1H), 5.27 (s, 2H), 4.52 (s, 2H), 3.99−3.58 (m, 1H), 2.06−1.98
(m, 2H), 1.88−1.79 (m, 2H), 1.74−1.62 (m, 2H), 1.51−1.16 (m, 4H);
13C NMR (150 MHz, CDCl3) δ 24.9, 25.2, 29.9, 39.0, 46.9, 55.4,
3
3
108.1, 108.6, 110.4, 114.8 (q, JC−F = 4.1 Hz), 117.3 (q, JC−F = 3.8
2
Hz), 135.5, 141.7, 142.3, 149.9, 156.8, 123.5 (q, JC−F = 32.0), 163.3,
125.1 (q, 1JC−F = 271.8); FT-IR (neat) 2937, 2856, 1624, 1509, 1252,
1109, 1049, 679, 660 cm−1; MS (ESI) m/z 435 (MH+); HRMS (ESI,
m/z) calcd C21H21F3N4OS [M + H]+ 435.1465, found 435.1461.
5-Chloro-N-(3-phenethyl-1,3-thiazetidin-2-ylidene)benzo[d]-
oxazol-2-amine 8m. Off-white solid; yield = 0.13 g, 64%; mp 170−
173 °C; 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 2.1 Hz, 1H), 7.31
(t, J = 8.5 Hz, 1H), 7.28−7.18 (m, 5H), 7.09 (dd, J = 8.5, 2.1 Hz, 1H),
4.26 (s, 2H), 3.71 (t, J = 7.0 Hz, 2H), 2.99 (t, J = 7.0 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 33.9, 48.3, 50.2, 110.1, 117.7, 122.4, 126.9,
128.5, 128.9, 129.0, 137.8, 143.4, 146.9, 165.2, 166.1; FT-IR (neat)
2917, 2849, 1629, 1529, 1445, 1400 cm−1; MS (ESI) m/z 344 (MH+);
HRMS (ESI, m/z) calcd C17H14ClN3OS [M + H]+ 344.0619, found
344.0612.
Methyl 10-(Furan-2-ylmethyl)-2-(propylimino)-4,10-dihydro-2H-
benzo[4,5]imidazo[1,2-c][1,3,5]thiadiazine-7-carboxylate 10c. Pale
1
yellow; yield = 0.082 g, 80%; mp 205−207 °C; H NMR (300 MHz,
CDCl3) δ 8.42 (s, J = 1.4 Hz 1H), 8.11 (dd, J = 8.5, 1.4 Hz, 1H), 7.57
(d, J = 8.5 Hz, 1H), 7.39 (dd, J = 2.4, 1.9 Hz, 1H), 6.48 (dd, J = 3.3,
1.9 Hz, 1H), 6.38 (dd, J = 3.3, 1.9 Hz, 1H), 5.90 (s, 2H), 5.39 (s, 2H),
3.94 (s, 3H), 3.74 (t, J = 7.4, 2H), 1.92−1.80 (m, 2H), 1.03 (t, J = 7.4
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 11.6, 22.0, 39.4, 41.7, 45.8,
52.5, 110.4, 110.6, 110.8, 112.7, 126.7, 127.1, 128.1, 132.3, 143.6,
146.6, 150.6, 162.9, 165.8; FT-IR (neat) 2915, 2948, 1718, 1552, 1458,
1251, 767, 637 cm−1; MS (ESI) m/z 385 (MH+); HRMS (ESI, m/z)
calcd C19H20N4O3S [M + H]+ 385.1329, found 385.1334.
5-Chloro-N-(3-isopropyl-1,3-thiazetidin-2-ylidene)benzo[d]-
oxazol-2-amine 8n. Off-white solid; yield = 0.103 g, 62%; mp 140−
141 °C; 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 2.2 Hz, 1H), 7.21
(d, J = 8.5 Hz, 1H), 7.06 (dd, J = 8.5, 2.2 Hz, 1H), 4.49 (s, 2H), 4.19
(sept, J = 6.7 Hz, 1H), 1.23 (d, J = 6.7 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ 19.6, 19.6, 45.6, 48.0, 110.0, 117.6, 122.2, 128.9, 143.4,
146.8, 165.4; FT-IR (neat) 2981, 2906, 1604, 1448, 1287, 997, 801
cm−1; MS (ESI) m/z 282 (MH+); HRMS (ESI, m/z) calcd
C12H12ClN3OS [M + H]+ 282.0462, found 282.0466.
Methyl 10-(2-(Cyclohex-1-en-1-yl)ethyl)-2-((3-methoxypropyl)-
imino)-4,10-dihydro-2H-benzo[4,5]imidazo[1,2-c][1,3,5]-
thiadiazine-7-carboxylate 10d. White solid; yield = 0.083 g, 81%; mp
199−203 °C; 1H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 1.5 Hz, 1H),
8.09 (dd, J = 8.5, 1.4 Hz, 1H), 7.37 (d, J = 8.5 Hz, 1H), 5.91 (s, 2H),
5.15 (t, J = 3.5 Hz, 1H), 4.25 (t, J = 7.0 Hz, 2H), 3.93 (s, 3H), 3.77 (t,
J = 7.2 Hz, 2H), 3.48 (t, J = 7.2 Hz, 2H), 3.30 (s, 3H), 2.40 (t, J = 7.2
Hz, 2H), 1.99−2.08 (m, 4H), 1.85−1.72 (m, 2H), 1.59−1.35 (m, 4H);
13C NMR (100 MHz, CDCl3) δ 21.8, 22.6, 25.1, 28.0, 28.5, 36.3, 41.3,
Methyl 1-(2-(Cyclohex-1-en-1-yl)ethyl)-2-((3-(m-tolyl)-1,3-thiaze-
41.7, 41.8, 52.5, 58.6, 69.8, 110.0, 113.2, 125.6, 126.5, 127.0, 128.1,
132.3, 132.4, 150.7, 162.6, 165.9; FT-IR (neat) 2923, 2853, 1719,
1555, 1251, 1193, 765, 734 cm−1; MS (ESI) m/z 443 (MH+); HRMS
(ESI, m/z) calcd C23H30N4O3S [M + H]+ 443.2111, found 443.2116.
Methyl 2-(Benzylimino)-10-(2-(cyclohex-1-en-1-yl)ethyl)-4,10-di-
hydro-2H-benzo[4,5]imidazo[1,2-c][1,3,5]thiadiazine-7-carboxylate
tidin-2-ylidene)amino)-1H-benzo[d]imidazole-5-carboxylate 8o.
1
Off-white solid; yield = 0.034 g, 22%; mp 170−171 °C; H NMR
(400 MHz, CDCl3) δ 8.32 (d, J = 1.5 Hz, 1H), 7.88 (dt, J = 8.4, 1.1
Hz, 1H), 7.45 (s, 1H), 7.37 (dd, J = 8.1, 2.1 Hz, 1H), 7.29−7.19 (m,
4H), 6.94 (d, J = 7.5 Hz, 1H), 5.33 (s, 1H), 4.92 (s, 2H), 4.25 (dd, J =
8.2, 6.7 Hz, 2H), 3.91 (s, 3H), 2.42 (t, J = 7.6 Hz, 2H), 2.01 (s,3H),
1.87 (d, J = 5.0 Hz, 2H), 1.57−1.50 (m, 2H), 1.47 (ddt, J = 7.8, 5.7,
2.3 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 167.9, 159.6, 156.1,
141.4, 139.8, 139.2, 137.1, 133.8, 128.9, 124.5, 124.1, 123.2, 122.7,
120.1, 116.7, 113.1, 108.1, 51.8, 48.4, 41.7, 37.5, 28.3, 25.1, 22.7, 22.1,
21.6; FT-IR (neat) 2926, 1712, 1629, 1504, 1297, 749 cm−1; MS (ESI)
m/z 461 (MH+); HRMS (ESI, m/z) calcd C26H29N4O2S [M + H]+
461.2006, found 461.2005.
1
10e. White solid; yield = 0.086 g, 84%; mp 212−213 °C; H NMR
(400 MHz, CDCl3) δ 8.45 (d, J = 1.3 Hz, 1H), 8.09 (dd, J = 8.6, 1.4
Hz, 1H), 7.52−7.43 (m, 2H), 7.35 (d, J = 8.9 Hz, 1H), 7.30−7.22 (m,
2H), 7.20 (d, J = 7.0 Hz, 1H), 5.83 (s, 2H), 5.18 (s, 1H), 4.82 (s, 2H),
4.19 (t, J = 7.2 Hz, 2H), 3.94 (s, 3H), 2.32 (t, J = 7.2 Hz, 2H), 1.92−
1.82 (m, 4H), 1.63−1.35 (m, 4H); 13C NMR (100 MHz, CDCl3) δ
22.6, 25.1, 28.2, 36.1, 41.6, 41.9, 47.1, 52.6, 110.1, 113.0, 125.3, 126.6,
127.1, 127.5, 128.0, 128.3, 128.5, 132.3, 132.4, 136.5, 150.5, 162.9,
165.8, 21.8; FT-IR (neat) 2924, 2853, 1719, 1551, 1252, 1193, 798,
698 cm−1; MS (ESI) m/z 461 (MH+); HRMS (ESI, m/z) calcd
C26H28N4O2S [M + H]+ 461.2006, found 461.2013.
Methyl 1-(2-(Cyclohex-1-en-1-yl)ethyl)-2-((3-(4-fluorophenyl)-1,3-
thiazetidin-2-ylidene)amino)-1H-benzo[d]imidazole-5-carboxylate
1
8p. White solid; yield = 0.046 g, 30%; mp 159−162 °C; H NMR
(400 MHz, CDCl3) δ 8.32 (d, J = 1.6 Hz, 1H), 7.89 (dd, J = 8.4, 1.6
Hz, 1H), 7.58 (dd, J = 9.1, 4.5 Hz, 2H), 7.24 (s, 2H), 7.12−7.02 (m,
2H), 5.30 (d, J = 3.8 Hz, 1H), 4.93 (s, 2H), 4.25 (t, J = 7.4 Hz, 2H),
3.90 (s, 3H), 2.40 (t, J = 7.4 Hz, 2H), 1.99 (d, J = 7.2 Hz, 2H), 1.91−
1.78 (m, 2H), 1.51−1.42 (m, 4H); 13C NMR (100 MHz, CDCl3) δ
22.0, 22.8, 25.2, 28.3, 37.5, 41.7, 48.6, 51.8, 108.17, 109.9, 115.8, 116.0,
117.5, 117.5, 120.1, 122.7, 123.3, 124.3, 133.7, 137.0, 141.3, 155.9,
158.8 (d, 1JC−F = 244.4) 167.9; FT-IR (neat) 2995, 1712, 1629, 1504,
Methyl 2-(Cyclohexylimino)-10-(3-phenylpropyl)-2,10-dihydro-
4H-benzo[4,5]imidazo[1,2-c][1,3,5]thiadiazine-7-carboxylate 10f.
1
White solid; yield = 0.083 g, 81%; mp 219−221 °C; H NMR (400
MHz, CDCl3) δ 8.43 (d, J = 1.4 Hz, 1H), 8.07 (dd, J = 8.5, 1.4 Hz,
1H), 7.45−6.90 (m, 6H), 5.85 (s, 2H), 4.20 (t, J = 7.2 Hz, 2H), 4.07
(dtd, J = 11.2, 7.2, 3.6 Hz, 1H), 3.94 (s, 3H), 2.75 (t, J = 7.3 Hz, 2H),
2.24 (p, J = 7.3 Hz, 2H), 2.07−1.91 (m, 2H), 1.96−1.52 (m, 6H), 1.28
(tt, J = 8.7, 5.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 24.9, 25.1,
H
DOI: 10.1021/acs.joc.6b01586
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
29.1, 31.6, 32.9, 41.5, 42.8, 52.6, 54.5, 109.7, 112.9, 126.5, 126.9, 128.0,
128.2, 128.5, 132.4, 139.5, 150.6, 161.4, 165.9; FT-IR (neat) 2916,
2849, 1732, 1625, 1445, 1324, 1109, 881, 735 cm−1; MS (ESI) m/z
463 (MH+); HRMS (ESI, m/z) calcd C26H31N4O2S [M + H]+
463.2162, found 463.2165.
ACKNOWLEDGMENTS
■
The authors thank the Ministry of Science and Technology of
Taiwan for financial support and the authorities of the National
Chiao Tung University for providing the laboratory facilities.
This study was particularly supported by the “Centre for
bioinformatics research of aiming for the Top University Plan”
of the National Chiao Tung University and Ministry of
Education, Taiwan.
Methyl 10-Isobutyl-2-(phenethylimino)-4,10-dihydro-2H-benzo-
[4,5]imidazo[1,2-c][1,3,5]thiadiazine-7-carboxylate 10g. White
1
solid; yield = 0.079 g, 77%; mp 208−210 °C; H NMR (400 MHz,
CDCl3) δ 8.50 (d, J = 1.5 Hz, 1H), 8.07 (dd, J = 8.6, 1.5 Hz, 1H), 7.36
(d, J = 8.6 Hz, 1H), 7.29−7.19 (m, 4H), 7.15 (m, 1H), 5.96 (s, 2H),
3.94 (d, J = 7.0 Hz, 2H), 3.92 (s, 3H), 3.88 (t, J = 7.9 Hz, 2H), 3.14 (t,
J = 7.9 Hz 2H), 2.21 (m, 1H), 0.96 (d, J = 6.7 Hz, 6H); 13C NMR
(100 MHz, CDCl3) δ 20.2, 28.3, 35.0, 41.7, 45.2, 50.4, 52.6, 76.7, 77.0,
77.3, 110.2, 113.1, 126.4, 126.6, 127.0, 128.1, 128.5, 128.8, 132.8,
138.4, 150.9, 162.9, 165.8; FT-IR (neat) 2952, 2925, 1719, 1553, 1458,
1183, 765 cm−1; MS (ESI) m/z 423 (MH+); HRMS (ESI, m/z) calcd
C23H26N4O2S [M + H]+ 423.1849, found 423.1851.
REFERENCES
■
(1) (a) Lai, M. Y.; Chen, C. H.; Huang, W. S.; Lin, J. T.; Ke, T. H.;
Chen, L. Y.; Tsai, M. H.; Wu, C. C. Angew. Chem., Int. Ed. 2008, 47,
581. (b) Jin, Z. Nat. Prod. Rep. 2011, 28, 1143. (c) Gulevich, A. V.;
Dudnik, A. S.; Chernyak, N.; Gevorgyan, V. Chem. Rev. 2013, 113,
3084. (d) Fahsi, K.; Dutremez, S. G.; Vioux, A.; Viau, L. J. Mater.
Chem. A 2013, 1, 4451.
(2) (a) Hauel, N. H.; Nar, H.; Priepke, H.; Ries, U.; Stassen, J.;
Wienen, W. J. Med. Chem. 2002, 45, 1757. (b) Hranjec, M.; Piantanida,
I.; Kralj, M.; Suman, L.; Pavelic, K.; Karminski-Zamola, G. J. Med.
Chem. 2008, 51, 4899. (c) Hamdy, N. A.; Eldeen, A. M. G; Aziz, H. A.
A.; Fakhr, I. M. I. Eur. J. Med. Chem. 2010, 45, 463. (d) Yuan, G.; Liu,
H.; Gao, J.; Yang, K.; Niu, Q.; Mao, H.; Wang, X.; Lv, X. J. Org. Chem.
2014, 79, 1749.
(3) (a) Field, L.; Sweetman, B. J.; Bellas, M. J. Med. Chem. 1969, 18,
624. (b) Heimer, N. E.; Field, L. J. Org. Chem. 1970, 35, 1668.
(c) Gordeev, M. F.; Gordon, E. M.; Patel, D. V. J. Org. Chem. 1997, 62,
8177. (d) Nakayama, J.; Ishii, A. Adv. Heterocycl. Chem. 2000, 77, 221.
(4) (a) Coburn, R. A.; Ho, C. H.; Bronstein, M. L. J. Med. Chem.
1982, 25, 481. (b) Shobana, N.; Farid, P. Comprehensive Heterocyclic
Chemistry III; Pergamon: Oxford, 2008; Vol. 9, p 457. (c) Dotsenko,
V. V.; Frolov, K. A.; Pekhtereva, T. M.; Papaianina, O. S.; Suykov, S.
Y.; Krivokolysko, S. G. ACS Comb. Sci. 2014, 16, 543.
N-(10-(Furan-2-ylmethyl)-7-(trifluoromethyl)-4,10-dihydro-2H-
benzo[4,5]imidazo[1,2-c][1,3,5]thiadiazin-2-ylidene)-
cyclohexanamine 10h. White solid; yield = 0.088 g, 86%; mp 252−
1
254 °C; H NMR (400 MHz, CD3OD) δ 8.15 (d, J = 1.4 Hz, 1H),
7.94 (dd, J = 8.6, 1.4 Hz, 1H), 7.35 (d, J = 8.6 Hz, 1H), 7.46 (dd, J =
1.9, 0.8 Hz, 1H), 6.58 (dd, J = 3.3, 0.8 Hz, 1H), 6.40 (dd, J = 3.3, 0.8
Hz, 1H), 5.69 (s, 2H), 5.55 (s, 2H), 4.33 (m, 1H), 2.12−2.05 (m, 2H),
1.90−1.78 (m, 2H), 1.79 (m, 1H), 1.40−1.38 (m, 4H), 1.35 (m, 1H);
13C NMR (100 MHz, CD3OD) δ 24.3, 24.5, 24.9, 31.5, 32.3, 39.0,
40.4, 53.5, 108.4, 109.8, 110.3, 111.9, 121.7, 122.6, 126.9, 128.2, 131.9,
143.4, 147.4, 150.9, 162.1; FT-IR (neat) 2934, 2856, 1556, 1507, 1487,
1063, 1012, 742 cm−1; MS (ESI) m/z 435 (MH+); HRMS (ESI, m/z)
calcd C21H21F3N4OS [M + H]+ 435.1461, found 435.1467.
Methyl 2-(Cyclohexylimino)-10-isopropyl-4,10-dihydro-2H-
benzo[4,5]imidazo[1,2-c][1,3,5]thiadiazine-7-carboxylate 10i.
1
White solid; yield = 0.085 g, 83%; mp 191−194 °C; H NMR (400
MHz, CDCl3) δ 8.61 (d, J = 1.4 Hz, 1H), 8.06 (dd, J = 8.7, 1.4 Hz,
1H), 7.48 (d, J = 8.6 Hz, 1H), 5.87 (s, 2H), 4.97 (p, J = 7.0 Hz, 1H),
4.10 (m, 1H), 3.93 (s, 3H), 1.21−1.90 (m, 4H), 1.80−1.71(m, 2H),
1.66 (d, J = 7.0 Hz, 6H), 1.40−1.17 (m, 4H); 13C NMR (100 MHz,
CDCl3) δ 20.5, 24.9, 25.0, 30.8, 31.6, 41.4, 48.2, 52.5, 54.5, 110.9,
112.9, 126.2, 126.6, 128.5, 131.5, 150.1, 161.2, 165.9; FT-IR (neat)
2931, 2854, 1720, 1550, 1478, 1292, 971, 890, 817 cm−1; MS (ESI) m/
z 387 (MH+); HRMS (ESI, m/z) calcd C20H26N4O2S [M + H]+
387.1849, found 387.1853.
(5) (a) Kanno, H. Pure Appl. Chem. 1987, 59, 1027. (b) Wang, Z. Y.;
You, T. P.; Shi, H. J.; Shi, H. X. Molecules 1996, 1, 89. (c) Wang, Z. Y.;
Shi, H. X.; Shi, H. J. Synth. Commun. 2001, 31, 2841.
(6) (a) Ried, W.; Mosinger, W. M. O. Justus Liebigs Ann. Chem. 1973,
̈
1973, 1362. (b) Okajima, N.; Okada, Y. J. Heterocycl. Chem. 1991, 28,
177.
(7) (a) Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43,
46. (b) O’Connor, C. J.; Beckmann, H. S. G.; Spring, D. R. Chem. Soc.
Rev. 2012, 41, 4444. (c) Ibbeson, B. M.; Laraia, L.; Alza, E.; O'Connor,
C. J.; Tan, Y. S.; Davies, H. M. L.; McKenzie, G.; Venkitaraman, A. R.;
Spring, D. R. Nat. Commun. 2014, 5, 4155.
Methyl 2-(Cyclopentylimino)-10-isobutyl-4,10-dihydro-2H-
benzo[4,5]imidazo[1,2-c][1,3,5]thiadiazine-7-carboxylate 10j.
1
White solid; yield = 0.086 g, 84%; mp 232−234 °C; H NMR (400
MHz, CDCl3) δ 8.47 (s, 1H), 8.08 (d, J = 8.5 Hz, 1H), 7.36 (d, J = 8.6
Hz, 1H), 5.88 (s, 2H), 4.51 (p, J = 6.8 Hz, 1H), 3.99 (d, J = 7.4 Hz,
2H), 3.94 (s, 3H), 2.26 (m, 1H), 2.09−2.01 (m, 4H), 1.98−1.90 (m,
2H), 1.62−1.56 (m, 2H), 0.99 (d, J = 6.7 Hz, 6H); 13C NMR (100
MHz, CDCl3) δ 20.2, 24.2, 28.4, 29.6, 32.2, 41.5, 50.4, 52.6, 56.5,
110.0, 112.9, 126.5, 127.0, 128.2, 132.9, 150.8, 161.6, 165.8; FT-IR
(neat) 2954, 2872, 1722, 1547, 1501, 1251, 878, 736 cm−1; MS (ESI)
m/z 387 (MH+); HRMS (ESI, m/z) calcd C20H26N4O2S [M + H]+
387.1849, found 387.1855.
(8) (a) Ruijter, E.; Scheffelaar, R.; Orru, R. V. A. Angew. Chem., Int.
Ed. 2011, 50, 6234. (b) Yu, J.; Shi, F.; Gong, L. Z. Acc. Chem. Res.
2011, 44, 1156. (c) Domling, A.; Wang, W.; Wang, K. Chem. Rev.
̈
2012, 112, 3083. (d) de Graaff, C.; Ruijter, E.; Orru, R. V. A. Chem.
Soc. Rev. 2012, 41, 3969.
(9) (a) Zhu, Y. G.; Zhai, C. W.; Yang, L. P.; Hu, W. H. Eur. J. Org.
Chem. 2011, 2011, 1113. (b) Jing, C.; Xing, D.; Qian, Y.; Shi, T.; Zhao,
Y.; Hu, W. Angew. Chem., Int. Ed. 2013, 52, 9289. (c) Selvaraju, M.;
Sun, C. M. ACS Comb. Sci. 2015, 17, 182. (d) Dhole, S.; Selvaraju, M.;
Maiti, B.; Chanda, K.; Sun, C. M. ACS Comb. Sci. 2015, 17, 310.
(10) Xu, X. F.; Doyle, M. P. Chin. Chem. Lett. 2015, 26, 227.
(11) (a) Chen, C. H.; Yellol, G. S.; Lin, P. T.; Sun, C. M. Org. Lett.
2011, 13, 5120. (b) Selvaraju, M.; Shiu, W. S.; Kulkarni, M. V.; Sun, C.
M. RSC Adv. 2013, 3, 22314.
(12) Compound 10f was directly obtained as a hydrochloride salt
when dichloromethane was employed as an electrophile during the
optimization studies.
(13) CCDC 849746 and 1463873 contain the supplementary
crystallographic data for compounds 8c and 10f, respectively. This
data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b01586.
■
S
1H, 13C, LRMS, HRMS, and IR spectra (PDF)
X-ray crystal data of 8c (CIF)
X-ray crystal data of 10f (CIF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: cmsun@mail.nctu.edu.tw.
■
Notes
The authors declare no competing financial interest.
I
DOI: 10.1021/acs.joc.6b01586
J. Org. Chem. XXXX, XXX, XXX−XXX