Synthesis of 1,3,4-Thiadiazoles and 1,4,2-Oxathiazoles from α-Enolic Dithioesters and Active 1,3-Dipoles

Article abstract of DOI:10.1021/acs.joc.1c00156

The synthesis of two kinds of five-membered organosulfur heterocycles (i.e., 1,4,2-oxathiazoles and 1,3,4-thiadiazoles) from α-enolic dithioesters with active 1,3-dipoles (nitrile oxides and nitrilimines) generated in situ was achieved under mild reaction

Full text of DOI:10.1021/acs.joc.1c00156

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Article
Synthesis of 1,3,4-Thiadiazoles and 1,4,2-Oxathiazoles from α‑Enolic
Dithioesters and Active 1,3-Dipoles
Bin Cheng,* Hui Li,∥ Jianguo Sun,∥ Xinping Zhang, Yixuan He, Haiyan Sun, Wei Xu, Taimin Wang,*
and Hongbin Zhai*
Cite This: J. Org. Chem. 2021, 86, 5265−5273
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ABSTRACT: The synthesis of two kinds of five-membered organosulfur heterocycles (i.e.,
1,4,2-oxathiazoles and 1,3,4-thiadiazoles) from α-enolic dithioesters with active 1,3-dipoles
(nitrile oxides and nitrilimines) generated in situ was achieved under mild reaction
conditions. This transformation further expands the synthetic application of α-enolic
dithioesters as the sulfur-containing building blocks.
quinolines via site-selective coupling of o-aminoaryl ketones
(i.e., C and CS vs C and CO, eqs b and c) with α-enolic
dithioesters.3f Recently, the two nucleophilic reactive sites (i.e.,
C and S, eq c) were applied in the formal (3+3) annulation
reaction with 1,3,5-triazinanes to access 3,4-dihydro-2H-1,3-
thiazines by us.3g Despite these great advances, the develop-
ment and application of this kind of versatile synthon with
multiple reactive sites are still highly desired.
An extensive literature search of α-enolic dithioesters
revealed that only two documents referred to dipole
equivalents generated in situ from epoxides or donor−acceptor
cyclopropanes.3h,i Therefore, we were motivated to further
explore whether nitrile oxides and nitrilimines, two different
active dipoles, could react with α-enolic dithioesters and which
reactive sites of α-enolic dithioesters will be involved. Nitrile
oxides and nitrilimines are commonly generated in situ from
hydroximoyl halides and hydrazonoyl halides and inclined to
be dimerized, which made the designed plan very challenging.
Herein, we will present our preliminary results on this subject.
INTRODUCTION
■
Sulfur is one of the essential elements in life and exists in most
biomolecules (e.g., protein), which play a crucially important
role in life. In addition, organosulfur compounds constitute a
large family of natural products, pharmaceutical molecules,
perfumes, and others. Moreover, some organosulfur molecules,
such as sulfones, sulfoxides, and trialkylsulfoniums, are often
used as useful synthetic reagents or intermediates in organic
synthesis. As a consequence, considerable effort has been
devoted to the development of practical and efficient
approaches to access these functional molecules.1 Tradition-
ally, in addition to elemental sulfur, the incorporation of sulfur
atoms into organic frameworks is accomplished by using
inorganic sulfur compounds (e.g., sulfites and sulfides) or
organosulfur small molecules (e.g., thiols and sulfoxides).2
Among the latter, α-enolic dithioesters A have been proven to
be a class of useful and versatile synthons, and their synthetic
applications have been extensively studied to access various
sulfur-containing heterocyclic compounds (e.g., thiopyrans,3b
isothiazoles,3c and thiazoles3d) in the past decades.3
Continuing our ongoing interest in sulfur-containing
building block,3g,4 we were also attracted to α-enolic
dithioesters, because α-enolic dithioesters, structurally, possess
two electrophilic and three nucleophilic reactive sites and
could react with suitable reaction partners in a regioselective
manner (Scheme 1). For example, Junjappa reported a
cyclocondensation reaction of arylhydrazines with α-enolic
dithioesters to afford substituted pyrazoles using two electro-
philic sites (CO and CS, eq a).3e Singh disclosed an acid-
controlled chemodivergent synthesis of differently substituted
Received: January 20, 2021
Published: March 23, 2021
https://doi.org/10.1021/acs.joc.1c00156
© 2021 American Chemical Society
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a
Scheme 1. Previous Applications of the α-Enolic Dithioester
Scheme 2. Substrate Scope of 1,3,4-Thiadiazole
and This Work
RESULTS AND DISCUSSION
■
To be economic, equimolar α-enolic dithioester 1a and
benzohydrazonoyl chloride 2a were chosen and mixed in
dichloromethane at room temperature, using Et3N (1.5 equiv)
as the base. Delightfully, 1,3,4-thiadiazole derivative 3a was
obtained as a single Z geometrical isomer in almost
quantitative yield (99%).5 The exact structure of 3a was
confirmed by X-ray diffraction.6 In addition, a smaller amount
of Et3N resulted in a long reaction time. In view of the high
efficiency of this annulation reaction, we decided to directly
explore the substrate scope of this transformation without
further optimization, and the results are summarized in
Scheme 2. Generally, various hydrazonoyl chlorides tested in
this reaction were well-tolerated and gave excellent yields. The
substituents on the phenyl ring of R3 could be electron-
donating or electron-withdrawing groups, and the position of
the substituents made no difference to the yields (3a−3h).
The ethoxycarbonyl and tert-butyl group-substituted hydrazo-
noyl chlorides were also investigated, and their annulation
reactions proceeded smoothly (3i and 3j). The substituents of
the phenyl group in the Ar and R1 moiety had no influence on
the yields (3k−3n). α-Enolic dithioester with a heteroaryl
group (e.g., 3-pyridyl) or a methyl group in R1 also performed
well, delivering high yields (3o and 3p). The scale-up
experiment for 3a was conducted, and no corrosion in the
yield was observed. It is worth noting that all of the substrates
exhibited exclusive Z selectivity, and the geometrical
configuration of the products was determined by analogy
with 3a.
a
Reaction conditions: 1 (0.3 mmol), 2 (1 equiv), and Et3N (1.5
b
equiv) in DCM (3 mL) at rt. The reaction was conducted on a gram
scale.
exposed to the standard conditions for accessing 1,3,4-
thiadiazole. Unexpectedly, two 1,4,2-oxathiazole derivatives of
5a and 6a were obtained. Possibly, the 5-(methylthio)-1,4,2-
oxathiazole 6a was the precursor for the formation of 5a via the
elimination of the methylthio moiety. To gain a better
selectivity between two 1,4,2-oxathiazole products, the
optimization of reaction conditions was elaborately conducted,
and the detailed results are listed in Table 1. In general, the
solvent and the equivalent of the base seemed to be the key
parameters for product selectivity. For example, testing of a
series of common solvents (e.g., DCM, CHCl3, DMF, etc.,
entries 1−8) indicated that methanol gave the highest yield of
5a (entry 8), while variant of the equivalent of Et3N from 2 to
1.5 made no difference in the formation of this product (entry
9). It is worth noting that ether solvents, such as THF and
dioxane, could significantly suppress the formation of 5a
(entries 5 and 6, respectively), and prolonging the reaction
time was detrimental for the formation of 6a (entries 10 and
11 vs entries 5 and 6). Finally, it was found that decreasing the
amount of Et3N was effective (entries 12 and 13), and dioxane
gave the highest yield of 6a (entry 13).
With the optimal conditions (Table 1, entries 9 and 13) in
hand, a survey of the generality and scope of this divergent
synthesis was then conducted. As demonstrated in Scheme 3,
methanol was used as the solvent to access 1,4,2-oxathiazole 5.
Like the annulation reaction of nitrilimine, the electronic
property and position of the substituent on the phenyl ring of
Encouraged by the initial success with nitrilimine, we hoped
to extend this strategy to access 1,4,2-oxathiazoles, another
important class of five-membered organosulfur heterocycles,
which are structural analogues of 1,3,4-thiadiazoles. Thus, α-
enolic dithioester 1a and tolyl hydroximoyl chloride 4a were
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investigated, delivering the desired 1,4,2-oxathiazole in 90%
yield (5m). Finally, the reaction of methyl (Z)-3-hydroxybut-
2-enedithioate was investigated, which proceeded smoothly to
afford 5n in 80% yield. It should be mentioned that
hydroximoyl chloride was consumed within 30 min normally,
much faster than the reaction of hydrazonoyl chloride, which
resulted in the remnant of dithioester in some cases. Thus,
additional hydroximoyl chloride needed to be replenished to
improve the yield. The Z/E selectivity was also perfect,7 as no
any E isomers were detected.
Table 1. Optimization of the Product Selectivity between
1,4,2-Oxathiazole Derivatives of 5a and 6a
a
b
yield (%)
entry
1a/4a/Et3N
solvent
time (min)
5a
60
54
83
83
22
30
39
95
95
6a
43
50
14
10
63
68
55
trace
trace
30
To selectively access 5-(methylthio)-1,4,2-oxathiazole 6,
dioxane was selected as the solvent (Scheme 4). The substrate
1
2
3
4
5
6
7
8
1:1:2
1:1:2
1:1:2
1:1:2
1:1:2
1:1:2
1:1:2
1:1:2
1:1:1.5
1:1:2
1:1:2
1:1:1
1:1:1
DCM
CHCl3
DMF
CH3CN
THF
dioxane
PhCH3
MeOH
MeOH
THF
dioxane
THF
dioxane
10
10
40
50
50
50
50
10
10
90
90
50
50
a
Scheme 4. Substrate Scope of 1,4,2-Oxathiazole 6
9
10
11
12
13
61
60
6
trace
30
83
90
a
Reaction conditions: 1a (0.1 mmol), 4a, and Et3N in solvent (1 mL)
b
at rt. The yield was determined by 1H NMR using 1,3,5-
trimethoxybenzene as the internal standard.
a
Scheme 3. Substrate Scope of 1,4,2-Oxathiazole 5
a
Reaction conditions: 1 (0.3 mmol), 4 (1 equiv), and Et3N (1 equiv)
b
in dioxane (3 mL) at rt, unless otherwise noted. 4 (1.2 equiv) and
Et3N (1.2 equiv) were used instead. 4 (1.5 equiv) and Et3N (1.5
equiv) were used instead. 4 (2 equiv) and Et3N (2 equiv) were used
instead. 4 (2.2 equiv) and Et3N (2.2 equiv) were used instead.
c
d
e
compatibility also proved to be satisfactory. The substituents of
R3 in hydroximoyl chlorides could be an aryl (6a−6i), an
alkenyl (6j), an alkyl (6k and 6l), or an ethoxylcarbonyl (6m)
group. Among them, the yields of alkyl and ethoxylcarbonyl
group-substituted substrates were relatively lower. In addition,
the R1 group in α-enolic dithioester could be phenyl (6a−6m)
and methyl (6n) groups. Likewise, additional hydroximoyl
chloride needed to be replenished for improving the yield in
some cases.
On the basis of previous works,3 a possible mechanism was
proposed as shown in Scheme 5. Nucleophilic attack of the
sulfur of the thiocarbonyl moiety in α-enolic dithioester 1 on
the active 1,3-dipole derived from hydrazonoyl chloride 2 or
hydroximoyl chloride 4 in situ provides β-dithioenone B,
which undergoes intramolecular 1,4-addition of oxygen or
nitrogen anion to deliver enolate C. At this junction, enolate C
can be quenched by a proton in the case of nitrile oxide (Y =
O) to give 5-(methylthio)-1,4,2-oxathiazole 6, while elimi-
nation (i.e., retro-S-Michael addition) of the methylthio moiety
affords 3 and 5. Alternative pathways, for example, synergetic
1,3-dipolar cycloaddition of nitrile oxide and the CS bond of
α-enolic dithioester 1 to afford 5-(methylthio)-1,4,2-oxathia-
a
Reaction conditions: 1 (0.3 mmol), 4 (1 equiv), and Et3N (1.5
b
equiv) in MeOH (3 mL) at rt, unless otherwise noted. 4 (1.2 equiv)
was used instead. 4 (1.5 equiv) was used instead.
c
the R3 group were tested, and all of the substrates worked well,
giving high yields of 1,4,2-oxathiazoles (5a−5h). Hydroximoyl
chlorides with an alkenyl or alkyl substituent were also viable
(see 5i and 5j), albeit 1,4,2-oxathiazole 5j was obtained in a
moderate yield of only 55%. α-Enolic dithioester with a methyl
group or bromo group at position 4 of the phenyl ring afforded
high yields of 87% or 93%, respectively (5k and 5l). Heteroaryl
(e.g., 2-thienyl) group-substituted α-enolic dithioester was also
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monitored by TLC, the solvent was evaporated and the resulting
crude product was directly purified by silica gel column chromatog-
raphy (50:1 to 20:1 PE/EtOAc) to afford the corresponding 1,4,2-
oxathiazole. Additional hydroximoyl chloride (0.2 equiv) needed to
be replenished after 30 min to improve the yield of 1,4,2-oxathiazoles
5d−5i. Additional hydroximoyl chloride (0.5 equiv) was needed for
1,4,2-oxathiazole 5l.
Scheme 5. Proposed Mechanism
General Procedure for the Preparation of 1,4,2-Oxathia-
zoles 6a−6n. To a solution of α-enolic dithioester (0.3 mmol, 1.0
equiv) in 1,4-dioxane (3 mL) were added hydroximoyl chloride (0.3
mmol, 1.0 equiv) and NEt3 (0.3 mmol, 1.0 equiv), and then the
mixture was stirred at rt. After completion of the reaction as
monitored by TLC, the solvent was evaporated and the resulting
crude product was directly purified by silica gel column chromatog-
raphy (50:1 to 20:1 PE/EtOAc) to afford the corresponding 1,4,2-
oxathiazole. Additional hydroximoyl chloride (0.2 equiv) and NEt3
(0.2 equiv) needed to be replenished after 30 min to improve the
yield of 1,4,2-oxathiazoles 6b, 6h, 6i, and 6n. For the preparation of
1,4,2-oxathiazoles 6c, 6j, and 6l, additional hydroximoyl chloride (0.5
equiv) and NEt3 (0.5 equiv) were divided into two equivalent parts
and added with an interval of 30 min. For the preparation of 1,4,2-
oxathiazoles 6d, 6e, 6g, and 6m, additional hydroximoyl chloride (1.0
equiv) and NEt3 (1.0 equiv) were divided into four equivalent parts
and added with an interval of 30 min. For the preparation of 1,4,2-
oxathiazole 6f, additional hydroximoyl chloride (1.2 equiv) and NEt3
(1.2 equiv) were divided into six equivalent parts and added with an
interval of 30 min.
zole 6, could not be excluded. Possibly, the intramolecular
noncovalent S···O interaction determine the stereoselectivity
of elimination products 3 and 5, because the single-crystal X-
ray structure of 5i revealed a S···O distance of ∼2.597 Å, which
is shorter than the sum of the van der Waals radii of the
respective atoms (3.32 Å).7
CONCLUSIONS
■
In summary, a cyclocondensation of α-enolic dithioesters with
two types of active 1,3-dipoles generated in situ to access
various 1,3,4-thiadiazoles and 1,4,2-oxathiazoles was achieved
under mild reaction conditions. This approach facilitates
diversity-oriented synthesis of sulfur-containing heterocycles
and expands the new synthetic applications of α-enolic
dithioester. The other intriguing explorations of an α-enolic
dithioester in our laboratory are in progress and will be
reported in due course.
Characterization Data of Products. (Z)-1-Phenyl-2-[3-phenyl-5-
(p-tolyl)-1,3,4-thiadiazol-2(3H)-ylidene]ethan-1-one. Compound 3a
[110 mg, 99% yield, Rf = 0.35 (5:1 PE/EA)] was isolated as a
1
yellow solid: mp 151−152 °C; H NMR (400 MHz, CDCl3) δ 7.88
(d, J = 6.4 Hz, 2H), 7.78 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 7.2 Hz, 2H),
7.59 (t, J = 7.2 Hz, 2H), 7.49 (t, J = 7.2 Hz, 1H), 7.45−7.35 (m, 3H),
7.27 (d, J = 8.0 Hz, 2H), 6.71 (s, 1H), 2.40 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 183.8, 160.2, 155.0, 141.4, 139.6, 139.0, 131.1,
129.9 (2C), 129.1, 128.4, 127.3, 127.0, 126.7, 125.6, 85.7, 21.6; ESI-
HRMS m/z calcd for C23H19N2OS [M + H]+ 371.1213, found
371.1216.
EXPERIMENTAL SECTION
General Information. All isolated compounds were characterized
on Bruker 400 spectrometers in CDCl3 or (CD3)2CO. Chemical shifts
■
1
are reported as δ values relative to internal CHCl3 (δ 7.26 for H
NMR and δ 77.16 for 13C NMR) and (CH3)2CO (δ 2.05 for H
1
(Z)-2-[3,5-Diphenyl-1,3,4-thiadiazol-2(3H)-ylidene]-1-phenylethan-1-
one. Compound 3b [106 mg, 99% yield, Rf = 0.36 (5:1 PE/EA)] was
NMR and δ 29.84 for 13C NMR). 19F NMR chemical shifts were
determined as δ values relative to external standard PhCF3 at δ
−63.50. High-resolution mass spectra (HRMS) were recorded on a
4G mass spectrometer using electrospray ionization (ESI) analyzed by
a quadrupole time-of-flight (QTof) instrument. All melting points
were measured with the samples after column chromatography and
uncorrected. Column chromatography was performed on silica gel.
Solvents (analytical reagent) were used as obtained from commercial
sources without further purification and drying. α-Enolic dithioesters,8
hydrazonoyl chlorides,9 and hydroximoyl chlorides10 were all known
and prepared according to the literature.
1
isolated as a yellow solid: mp 154−155 °C; H NMR (400 MHz,
CDCl3) δ 7.95−7.86 (m, 4H), 7.68−7.64 (m, 2H), 7.61 (t, J = 7.8
Hz, 2H), 7.55−7.37 (m, 7H), 6.74 (s, 1H); 13C{1H} NMR (100
MHz, CDCl3) δ 183.9, 160.2, 154.8, 139.6, 139.0, 131.2, 130.9, 129.9,
129.8, 129.2 (2C), 128.4, 127.3, 126.8, 125.6, 85.8; ESI-HRMS m/z
calcd for C22H17N2OS [M + H]+ 357.1056, found 357.1058.
(Z)-2-(5-(4-Chlorophenyl)-3-phenyl-1,3,4-thiadiazol-2(3H)-ylidene)-
1-phenylethan-1-one. Compound 3c [116 mg, 99% yield, Rf = 0.44 (5:1
1
PE/EA)] was isolated as a yellow solid: mp 165−166 °C; H NMR
(400 MHz, CDCl3) δ 7.86 (d, J = 7.6 Hz, 2H), 7.77 (d, J = 8.4 Hz,
2H), 7.66−7.54 (m, 4H), 7.50 (t, J = 7.2 Hz, 1H), 7.45−7.34 (m,
5H), 6.71 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 183.7, 159.8,
153.4, 139.4, 138.7, 136.8, 131.1, 129.8, 129.4, 129.1, 128.3, 128.2,
127.8, 127.2, 125.4, 85.9; ESI-HRMS m/z calcd for C22H16ClN2OS
[M + H]+ 391.0666, found 391.0669.
General Procedure for the Preparation of 1,3,4-Thiadia-
zoles 3a−3p. To a solution of α-enolic dithioester 1 (0.3 mmol, 1.0
equiv) in DCM (3 mL) was added hydrazonoyl chloride 2 (0.3 mmol,
1.0 equiv), and then the mixture was stirred at rt. After completion of
the reaction as monitored by TLC, the solvent was evaporated and
the resulting crude product was directly purified by silica gel column
chromatography (10:1 to 3:1 PE/EtOAc) to afford the corresponding
1,3,4-thiadiazole.
Scale-up Experiment for 3a. To a solution of α-enolic dithioester
1a (4.75 mmol, 1.0 equiv) in DCM (48 mL) was added 4-methyl-N-
phenylbenzohydrazonoyl chloride 2a (4.75 mmol, 1.0 equiv), and
then the mixture was stirred at rt. After completion of the reaction as
monitored by TLC, the solvent was evaporated and the resulting
crude product was directly purified by silica gel column chromatog-
raphy (10:1 to 3:1 PE/EtOAc) to afford 1,3,4-thiadiazole 3a as a
yellow solid (1.72 g, 98%).
(Z)-2-[5-(4-Fluorophenyl)-3-phenyl-1,3,4-thiadiazol-2(3H)-ylidene]-
1-phenylethan-1-one. Compound 3d [111 mg, 99% yield, Rf = 0.36
1
(5:1 PE/EA)] was isolated as a yellow solid: mp 142−143 °C; H
NMR (400 MHz, CDCl3) δ 7.92−7.84 (m, 4H), 7.66−7.57 (m, 4H),
7.51 (t, J = 7.2 Hz, 1H), 7.45−7.36 (m, 3H), 7.16 (t, J = 8.8 Hz, 2H),
6.72 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 183.9, 164.3 (d, J
= 250.4 Hz), 160.1, 153.7, 139.5, 138.9, 131.2, 129.9, 129.2, 128.8 (d,
J = 8.6 Hz), 128.4, 127.3, 126.1 (d, J = 3.3 Hz), 125.6, 116.4 (d, J =
22.0 Hz), 85.9; 19F{1H} NMR (376 MHz, CDCl3) δ −109.2; ESI-
HRMS m/z calcd for C22H16FN2OS [M + H]+ 375.0962, found
375.0963.
General Procedure for the Preparation of 1,4,2-Oxathia-
zoles 5a−5n. To a solution of α-enolic dithioester 1 (0.3 mmol, 1.0
equiv) in MeOH (3 mL) were added hydroximoyl chloride 4 (0.3
mmol, 1.0 equiv) and NEt3 (0.45 mmol, 1.5 equiv), and then the
mixture was stirred at rt. After completion of the reaction as
(Z)-2-[5-(4-Nitrophenyl)-3-phenyl-1,3,4-thiadiazol-2(3H)-ylidene]-1-
phenylethan-1-one. Compound 3e [118 mg, 98% yield, Rf = 0.41 (3:1
1
PE/EA)] was isolated as a yellow solid: mp 201−202 °C; H NMR
(400 MHz, CDCl3) δ 8.28 (d, J = 8.8 Hz, 2H), 8.00 (d, J = 8.4 Hz,
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2H), 7.85 (d, J = 7.2 Hz, 2H), 7.68−7.60 (m, 4H), 7.58−7.51 (m,
1H), 7.47−7.35 (m, 3H), 6.75 (s, 1H); 13C{1H} NMR (100 MHz,
CDCl3) δ 184.1, 159.8, 152.0, 148.8, 139.2, 138.4, 135.6, 131.5, 130.0,
129.5, 128.5, 127.4, 127.3, 125.5, 124.4, 86.5; ESI-HRMS m/z calcd
for C22H16N3O3S [M + H]+ 402.0907, found 402.0909.
(Z)-2-[5-(3-Methoxyphenyl)-3-phenyl-1,3,4-thiadiazol-2(3H)-yli-
dene]-1-phenylethan-1-one. Compound 3f [112 mg, 97% yield, Rf =
0.48 (5:1 PE/EA)] was isolated as a yellow solid: mp 156−157 °C;
1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 6.8 Hz, 2H), 7.64 (d, J =
7.6 Hz, 2H), 7.59 (t, J = 7.6 Hz, 2H), 7.53−7.32 (m, 7H), 7.00 (d, J =
5.6 Hz, 1H), 6.72 (s, 1H), 3.83 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 183.7, 160.1, 160.0, 154.6, 139.5, 138.8, 131.0, 130.8, 130.2,
129.8, 129.1, 128.3, 127.2, 125.5, 119.3, 117.3, 111.2, 85.7, 55.4; ESI-
HRMS m/z calcd for C23H19N2O2S [M + H]+ 387.1162, found
387.1162.
128.4, 127.3, 126.7, 125.8, 123.4, 86.0; ESI-HRMS m/z calcd for
C22H16ClN2OS [M + H]+ 391.0666, found 391.0668.
(Z)-1-(4-Methoxyphenyl)-2-[3-phenyl-5-(p-tolyl)-1,3,4-thiadiazol-
2(3H)-ylidene]ethan-1-one. Compound 3m [119 mg, 99% yield, Rf =
0.35 (5:1 PE/EA)] was isolated as a yellow solid: mp 120−121 °C;
1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.8 Hz, 2H), 7.78 (d, J =
8.0 Hz, 2H), 7.68−7.57 (m, 4H), 7.54−7.47 (m, 1H), 7.28 (d, J = 7.6
Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 6.68 (s, 1H), 3.83 (s, 3H), 2.41 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 182.8, 162.0, 159.6, 154.7,
141.2, 139.6, 131.6, 129.8 (2C), 129.1, 128.9, 126.9, 126.6, 125.5,
113.5, 85.2, 55.3, 21.5; ESI-HRMS m/z calcd for C24H21N2O2S [M +
H]+ 401.1318, found 401.1316.
(Z)-1-(4-Bromophenyl)-2-[3-phenyl-5-(p-tolyl)-1,3,4-thiadiazol-
2(3H)-ylidene]ethan-1-one. Compound 3n [133 mg, 99% yield, Rf =
0.26 (20:1 PE/EA)] was isolated as a yellow solid: mp 213−214 °C;
1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 7.6 Hz, 2H), 7.72 (d, J =
8.0 Hz, 2H), 7.66−7.56 (m, 4H), 7.54−7.47 (m, 3H), 7.26 (d, J = 8.0
Hz, 2H), 6.62 (s, 1H), 2.40 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 182.3, 160.5, 155.2, 141.5, 139.4, 137.8, 131.5, 129.9, 129.2,
128.8, 126.8, 126.7, 125.7, 125.6, 85.3, 21.6 (1C peak is merged with
other peaks); ESI-HRMS m/z calcd for C23H18BrN2OS [M + H]+
449.0318, found 449.0319.
(Z)-2-[5-(2-Fluorophenyl)-3-phenyl-1,3,4-thiadiazol-2(3H)-ylidene]-
1-phenylethan-1-one. Compound 3g [110 mg, 98% yield, Rf = 0.46 (3:1
1
PE/EA)] was isolated as a yellow solid: mp 178−179 °C; H NMR
(400 MHz, CDCl3) δ 8.02 (t, J = 7.6 Hz, 1H), 7.88 (d, J = 7.2 Hz,
2H), 7.67−7.55 (m, 4H), 7.50 (t, J = 7.2 Hz, 1H), 7.45−7.32 (m,
4H), 7.24−7.14 (m, 2H), 6.71 (s, 1H); 13C{1H} NMR (100 MHz,
CDCl3) δ 183.6, 160.5 (d, J = 7.0 Hz) 160.0 (d, J = 252.9 Hz), 149.8
(d, J = 5.5 Hz), 139.3, 138.8, 132.3 (d, J = 8.4 Hz), 131.0, 129.8,
129.1, 128.6 (d, J = 2.4 Hz), 128.3, 127.2, 125.5, 124.6 (d, J = 3.3
Hz), 117.8 (d, J = 11.7 Hz), 116.6 (d, J = 21.2 Hz), 85.6; 19F{1H}
NMR (376 MHz, CDCl3) δ −111.8; ESI-HRMS m/z calcd for
C22H16FN2OS [M + H]+ 375.0962, found 375.0962.
(Z)-2-[3-Phenyl-5-(p-tolyl)-1,3,4-thiadiazol-2(3H)-ylidene]-1-(pyri-
din-3-yl)ethan-1-one. Compound 3o [102 mg, 92% yield, Rf = 0.18
1
(2:1 PE/EA)] was isolated as a yellow solid: mp 134−135 °C; H
NMR (400 MHz, CDCl3) δ 9.02 (s, 1H), 8.64 (d, J = 3.2 Hz, 1H),
8.19 (dt, J = 8.0, 2.0 Hz, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.67−7.58 (m,
4H), 7.56−7.50 (m, 1H), 7.35 (dd, J = 8.0, 4.8 Hz, 1H), 7.28 (d, J =
8.0 Hz, 2H), 6.65 (s, 1H), 2.41 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 181.2, 160.7, 155.3, 151.4, 148.5, 141.6, 139.2, 134.9, 134.3,
129.9 (2C), 129.4, 126.7, 126.6, 125.5, 123.5, 85.5, 21.6; ESI-HRMS
m/z calcd for C22H18N3OS [M + H]+ 372.1165, found 372.1165.
(Z)-1-[3-Phenyl-5-(p-tolyl)-1,3,4-thiadiazol-2(3H)-ylidene]propan-2-
one. Compound 3p [85 mg, 92% yield, Rf = 0.27 (5:1 PE/EA)] was
(Z)-2-[5-(Naphthalen-2-yl)-3-phenyl-1,3,4-thiadiazol-2(3H)-yli-
dene]-1-phenylethan-1-one. Compound 3h [112 mg, 92% yield, Rf = 0.5
1
(5:1 PE/EA)] was isolated as a yellow solid: mp 148−149 °C; H
NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 8.02 (d, J = 8.4 Hz, 1H),
7.95−7.80 (m, 5H), 7.68 (d, J = 7.8 Hz, 2H), 7.61 (t, J = 7.8 Hz, 2H),
7.57−7.48 (m, 3H), 7.48−7.37 (m, 3H), 6.76 (s, 1H); 13C{1H} NMR
(100 MHz, CDCl3) δ 183.7, 160.0, 154.7, 139.5, 138.9, 134.3, 133.0,
131.1, 129.8, 129.0, 128.9, 128.6, 128.3, 127.9, 127.6, 127.2 (2C),
127.1, 127.0, 125.5, 123.1, 85.9; ESI-HRMS m/z calcd for
C26H19N2OS [M + H]+ 407.1213, found 407.1215.
1
isolated as a yellow solid: mp 179−180 °C; H NMR (400 MHz,
CDCl3) δ 7.74 (d, J = 7.6 Hz, 2H), 7.59−7.52 (m, 4H), 7.50−7.43
(m, 1H), 7.25 (d, J = 8.0 Hz, 2H), 6.00 (s, 1H), 2.39 (s, 3H), 2.16 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 190.4, 158.3, 154.3, 141.2,
139.5, 129.8, 129.7, 128.9, 127.0, 126.7, 125.5, 88.7, 28.6, 21.6; ESI-
HRMS m/z calcd for C18H17N2OS [M + H]+ 309.1056, found
309.1056.
Ethyl (Z)-5-(2-Oxo-2-phenylethylidene)-4-phenyl-4,5-dihydro-1,3,4-
thiadiazole-2-carboxylate. Compound 3i [99 mg, 94% yield, Rf =
0.41 (5:1 PE/EA)] was isolated as a yellow solid: mp 165−166 °C;
1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 6.8 Hz, 2H), 7.63−7.51
(m, 5H), 7.47−7.36 (m, 3H), 6.71 (s, 1H), 4.47 (q, J = 7.2 Hz, 2H),
1.42 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 184.3,
160.8, 158.9, 146.4, 138.7, 138.2, 131.4, 129.9, 129.8, 128.4, 127.3,
125.7, 87.2, 63.0, 14.2; ESI-HRMS m/z calcd for C19H17N2O3S [M +
H]+ 353.0954, found 353.0954.
(Z)-2-[5-(tert-Butyl)-3-phenyl-1,3,4-thiadiazol-2(3H)-ylidene]-1-phe-
nylethan-1-one. Compound 3j [98 mg, 97% yield, Rf = 0.14 (10:1 PE/
EA)] was isolated as a yellow solid: mp 128−129 °C; 1H NMR (400
MHz, CDCl3) δ 7.86 (d, J = 6.0 Hz, 2H), 7.60−7.51 (m, 4H), 7.47−
7.33 (m, 4H), 6.66 (s, 1H), 1.45 (s, 9H); 13C{1H} NMR (100 MHz,
CDCl3) δ 183.5, 166.7, 160.7, 139.6, 139.2, 130.8, 129.7, 128.7, 128.2,
127.1, 125.4, 85.1, 35.8, 30.0; ESI-HRMS m/z calcd for C20H21N2OS
[M + H]+ 337.1369, found 337.1370.
(Z)-1-Phenyl-2-[3-(p-tolyl)-1,4,2-oxathiazol-5-ylidene]ethan-1-one.
Compound 5a [81 mg, 91% yield, Rf = 0.33 (10:1 PE/EA)] was
1
isolated as a white solid: mp 117−118 °C; H NMR (400 MHz,
CDCl3) δ 8.01 (d, J = 6.8 Hz, 2H), 7.71 (d, J = 8.0 Hz, 2H), 7.58−
7.46 (m, 3H), 7.31 (d, J = 8.0 Hz, 2H), 7.17 (s, 1H), 2.43 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 186.4, 176.2, 160.8, 143.1,
137.5, 132.6, 130.2, 128.8, 127.9, 127.8, 123.2, 90.9, 21.7; ESI-HRMS
m/z calcd for C17H14NO2S [M + H]+ 296.0740, found 296.0745.
(Z)-2-[3-(4-Methoxyphenyl)-1,4,2-oxathiazol-5-ylidene]-1-phenyle-
than-1-one. Compound 5b [84 mg, 90% yield, Rf = 0.31 (5:1 PE/EA)]
was isolated as a white solid: mp 100−101 °C; 1H NMR (400 MHz,
CDCl3) δ 8.00 (d, J = 7.6 Hz, 2H), 7.75 (d, J = 8.4 Hz, 2H), 7.50 (m,
3H), 7.15 (s, 1H), 6.99 (d, J = 8.4 Hz, 2H), 3.86 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 186.4, 176.2, 162.8, 160.3, 137.6, 132.5,
129.6, 128.7, 127.8, 118.3, 114.9, 90.8, 55.6; ESI-HRMS m/z calcd for
C17H14NO3S [M + H]+ 312.0689, found 312.0694.
(Z)-1-Phenyl-2-[5-phenyl-3-(p-tolyl)-1,3,4-thiadiazol-2(3H)-ylidene]-
ethan-1-one. Compound 3k [106 mg, 95% yield, Rf = 0.22 (10:1 PE/
EA)] was isolated as a yellow solid: mp 149−150 °C; 1H NMR (400
MHz, CDCl3) δ 7.94−7.86 (m, 4H), 7.51 (d, J = 8.4 Hz, 2H), 7.47−
7.35 (m, 8H), 6.70 (s, 1H), 2.46 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 183.6, 160.2, 154.5, 139.2, 138.9, 136.9, 131.0, 130.7, 130.3,
129.7, 129.1, 128.3, 127.2, 126.6, 125.3, 85.7, 21.3; ESI-HRMS m/z
calcd for C23H19N2OS [M + H]+ 371.1213, found 371.1216.
(Z)-2-[3-(3-Chlorophenyl)-5-phenyl-1,3,4-thiadiazol-2(3H)-ylidene]-
1-phenylethan-1-one. Compound 3l [114 mg, 97% yield, Rf = 0.2 (10:1
(Z)-1-Phenyl-2-(3-phenyl-1,4,2-oxathiazol-5-ylidene)ethan-1-one.
Compound 5c [75 mg, 89% yield, Rf = 0.31 (10:1 PE/EA)] was
isolated as a white solid: mp 92−93 °C; 1H NMR (400 MHz, CDCl3)
δ 8.01 (d, J = 7.2 Hz, 2H), 7.83 (d, J = 7.2 Hz, 2H), 7.59−7.46 (m,
6H), 7.19 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 186.5, 176.0,
160.9, 137.5, 132.6, 132.4, 129.5, 128.8, 128.0, 127.8, 126.2, 91.0;
ESI-HRMS m/z calcd for C16H12NO2S [M + H]+ 282.0583, found
282.0588.
(Z)-2-[3-(4-Chlorophenyl)-1,4,2-oxathiazol-5-ylidene]-1-phenylethan-
1-one. Compound 5d [80 mg, 84% yield, Rf = 0.44 (10:1 PE/EA)]
was isolated as a yellow solid: mp 122−123 °C; 1H NMR (400 MHz,
CDCl3) δ 8.00 (d, J = 7.6 Hz, 2H), 7.77 (d, J = 8.0 Hz, 2H), 7.60−
7.45 (m, 5H), 7.20 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ
1
PE/EA)] was isolated as a yellow solid: mp 165−166 °C; H NMR
(400 MHz, CDCl3) δ 7.91−7.84 (m, 4H), 7.68 (t, J = 2.0 Hz, 1H),
7.57 (dt, J = 8.0, 1.6 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.48−7.37 (m,
7H), 6.74 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 184.0, 159.6,
155.0, 140.5, 138.7, 135.5, 131.2, 131.0, 130.7, 129.4, 129.2, 129.1,
5269
https://doi.org/10.1021/acs.joc.1c00156
J. Org. Chem. 2021, 86, 5265−5273

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
186.5, 175.7, 160.0, 138.7, 137.4, 132.7, 129.9, 129.2, 128.8, 127.8,
124.6, 91.2; ESI-HRMS m/z calcd for C16H10ClNO2SNa [M + Na]+
338.0013, found 338.0017.
HRMS m/z calcd for C17H13BrNO2S [M + H]+ 373.9845, found
373.9850.
(Z)-1-(Thiophen-2-yl)-2-[3-(p-tolyl)-1,4,2-oxathiazol-5-ylidene]-
ethan-1-one. Compound 5m [81 mg, 90% yield, Rf = 0.31 (20:1 PE/
EA)] was isolated as a yellow solid: mp 128−129 °C; 1H NMR (400
MHz, CDCl3) δ 7.74 (d, J = 3.6 Hz, 1H), 7.69 (d, J = 7.6 Hz, 2H),
7.62 (d, J = 5.2 Hz, 1H), 7.31 (d, J = 8.0 Hz, 2H), 7.16 (t, J = 4.4 Hz,
1H), 6.99 (s, 1H), 2.43 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
179.5, 175.4, 160.9, 144.8, 143.2, 132.8, 130.2, 130.1, 128.3, 127.9,
123.1, 91.1, 21.8; ESI-HRMS m/z calcd for C15H12NO2S2 [M + H]+
302.0304, found 302.0306.
(Z)-2-[3-(4-Bromophenyl)-1,4,2-oxathiazol-5-ylidene]-1-phenylethan-
1-one. Compound 5e [86 mg, 80% yield, Rf = 0.16 (10:1 PE/EA)] was
1
isolated as a white solid: mp 110−111 °C; H NMR (400 MHz,
CDCl3) δ 8.01 (dd, J = 8.6, 1.6 Hz, 2H), 7.72−7.64 (m, 4H), 7.60−
7.54 (m, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.20 (s, 1H); 13C{1H} NMR
(100 MHz, CDCl3) δ 186.5, 175.7, 160.1, 137.4, 132.8, 132.8, 129.3,
128.8, 127.9, 127.2, 125.1, 91.2; ESI-HRMS m/z calcd for
C16H11BrNO2S [M + H]+ 359.9688, found 359.9697.
Methyl (Z)-4-[5-(2-Oxo-2-phenylethylidene)-1,4,2-oxathiazol-3-yl]-
benzoate. Compound 5f [77 mg, 76% yield, Rf = 0.18 (10:1 PE/
EA)] was isolated as a yellow solid: mp 140−141 °C; 1H NMR (400
MHz, CDCl3) δ 8.18 (d, J = 8.0 Hz, 2H), 8.01 (d, J = 7.2 Hz, 2H),
7.90 (d, J = 8.0 Hz, 2H), 7.57 (t, J = 7.2 Hz, 1H), 7.50 (t, J = 7.6 Hz,
2H), 7.21 (s, 1H), 3.96 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
186.5, 175.6, 166.0, 160.2, 137.4, 133.5, 132.8, 130.6, 130.1, 128.8,
128.0, 127.9, 91.2, 52.7; ESI-HRMS m/z calcd for C18H14NO4S [M +
H]+ 340.0638, found 340.0644.
(Z)-1-[3-(p-Tolyl)-1,4,2-oxathiazol-5-ylidene]propan-2-one. Com-
pound 5n [56 mg, 80% yield, Rf = 0.15 (10:1 PE/EA)] was isolated
as a white solid: mp 95−96 °C; 1H NMR (400 MHz, CDCl3) δ 7.66
(d, J = 8.4 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 6.43 (s, 1H), 2.40 (s,
3H), 2.29 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.6, 173.8,
160.5, 143.0, 130.1, 127.8, 123.2, 94.2, 29.3, 21.7; ESI-HRMS m/z
calcd for C12H12NO2S [M + H]+ 234.0583, found 234.0588.
2-[5-(Methylthio)-3-(p-tolyl)-1,4,2-oxathiazol-5-yl]-1-phenylethan-1-
one. Compound 6a [94 mg, 91% yield, Rf = 0.17 (10:1 PE/EA)] was
isolated as a yellow solid: mp 93−94 °C; 1H NMR (400 MHz,
CDCl3) δ 8.02 (d, J = 6.8 Hz, 2H), 7.67−7.58 (m, 3H), 7.51 (t, J =
7.6 Hz, 2H), 7.23 (d, J = 7.6 Hz, 2H), 4.47 (d, J = 17.6 Hz, 1H), 3.97
(d, J = 17.6 Hz, 1H), 2.39 (s, 3H), 2.29 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 194.1, 157.9, 141.8, 136.0, 134.2, 129.7, 129.0, 128.4,
127.8, 124.9, 109.2, 49.9, 21.6, 13.9; ESI-HRMS m/z calcd for
C18H17NO2S2Na [M + Na]+ 366.0593, found 366.0599.
(Z)-1-Phenyl-2-[3-(m-tolyl)-1,4,2-oxathiazol-5-ylidene]ethan-1-one.
Compound 5g [82 mg, 92% yield, Rf = 0.39 (10:1 PE/EA)] was
1
isolated as a yellow solid: mp 108−109 °C; H NMR (400 MHz,
CDCl3) δ 8.00 (d, J = 7.2 Hz, 2H), 7.66−7.58 (m, 2H), 7.54 (t, J =
7.6 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.41−7.33 (m, 2H), 7.16 (s,
1H), 2.41 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 186.4, 176.0,
160.9, 139.4, 137.5, 133.2, 132.5, 129.3, 128.7, 128.5, 127.8, 125.9,
125.1, 90.9, 21.4; ESI-HRMS m/z calcd for C17H14NO2S [M + H]+
296.0740, found 296.0746.
2-[3-(4-Methoxyphenyl)-5-(methylthio)-1,4,2-oxathiazol-5-yl]-1-phe-
nylethan-1-one. Compound 6b [93 mg, 86% yield, Rf = 0.26 (5:1 PE/
1
(Z)-2-[3-(Naphthalen-2-yl)-1,4,2-oxathiazol-5-ylidene]-1-phenyle-
than-1-one. Compound 5h [89 mg, 90% yield, Rf = 0.33 (10:1 PE/
EA)] was isolated as a yellow solid: mp 109−110 °C; 1H NMR (400
MHz, CDCl3) δ 8.22 (s, 1H), 8.02 (d, J = 7.2 Hz, 2H), 7.98−7.86 (m,
4H), 7.64−7.53 (m, 3H), 7.50 (t, J = 7.6 Hz, 2H), 7.20 (s, 1H);
13C{1H} NMR (100 MHz, CDCl3) δ 186.4, 176.0, 160.9, 137.5,
135.0, 132.9, 132.6, 129.4 (2C), 128.9, 128.8, 128.5, 128.1, 127.8,
127.5, 123.5 (2C), 91.0; ESI-HRMS m/z calcd for C20H13NO2S [M +
H]+ 332.0740, found 332.0747.
EA)] was isolated as a yellow solid: mp 95−96 °C; H NMR (400
MHz, CDCl3) δ 8.02 (d, J = 7.2 Hz, 2H), 7.71−7.58 (m, 3H), 7.51 (t,
J = 7.5 Hz, 2H), 6.93 (d, J = 8.4 Hz, 2H), 4.47 (d, J = 17.6 Hz, 1H),
3.96 (d, J = 17.6 Hz, 1H), 3.84 (s, 3H), 2.28 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 194.1, 162.0, 157.6, 136.0, 134.2, 129.5, 129.0,
128.4, 120.1, 114.4, 108.9, 55.6, 49.7, 13.9; ESI-HRMS m/z calcd for
C18H17NO3S2Na [M + Na]+ 382.0542, found 382.0549.
2-[5-(Methylthio)-3-phenyl-1,4,2-oxathiazol-5-yl]-1-phenylethan-1-
one. Compound 6c [84 mg, 85% yield, Rf = 0.27 (10:1 PE/EA)] was
1
(Z)-1-Phenyl-2-[3-(E)-styryl-1,4,2-oxathiazol-5-ylidene]ethan-1-one.
Compound 5i [83 mg, 90% yield, Rf = 0.30 (10:1 PE/EA)] was
isolated as a yellow solid: mp 126−127 °C; H NMR (400 MHz,
CDCl3) δ 8.02 (d, J = 7.6 Hz, 2H), 7.72 (d, J = 6.8 Hz, 2H), 7.63 (t, J
= 7.6 Hz, 1H), 7.56−7.39 (m, 5H), 4.48 (d, J = 17.6 Hz, 1H), 3.98 (d,
J = 17.6 Hz, 1H), 2.29 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
194.0, 157.9, 135.9, 134.2, 131.3, 129.0, 128.4, 127.8, 127.7, 109.4,
49.9, 13.8 (the 1C peak is merged with other peaks); ESI-HRMS m/z
calcd for C17H15NO2S2Na [M + Na]+ 352.0436, found 352.0444.
2-[3-(4-Chlorophenyl)-5-(methylthio)-1,4,2-oxathiazol-5-yl]-1-phenyl-
ethan-1-one. Compound 6d [95 mg, 87% yield, Rf = 0.19 (10:1 PE/
EA)] was isolated as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 8.01
(d, J = 7.2 Hz, 2H), 7.68−7.58 (m, 3H), 7.52 (t, J = 7.6 Hz, 2H), 7.40
(d, J = 8.8 Hz, 2H), 4.48 (d, J = 17.6 Hz, 1H), 3.97 (d, J = 17.6 Hz,
1H), 2.28 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.9, 157.0,
137.4, 135.9, 134.3, 129.3, 129.0 (2C), 128.4, 126.2, 109.8, 49.8, 13.9;
ESI-HRMS m/z calcd for C17H14ClNO2S2Na [M + Na]+ 386.0047,
found 386.0052.
1
isolated as a white solid: mp 107−108 °C; H NMR (400 MHz,
CDCl3) δ 8.00 (d, J = 6.8 Hz, 2H), 7.59−7.46 (m, 5H), 7.45−7.38
(m, 3H), 7.19 (s, 1H), 7.19 (s, 1H), 7.15 (s, 1H); 13C{1H} NMR
(100 MHz, CDCl3) δ 186.5, 175.2, 160.4, 142.4, 137.5, 134.5, 132.6,
130.5, 129.2, 128.8, 127.8, 127.7, 113.6, 90.9; ESI-HRMS m/z calcd
for C18H14NO2S [M + H]+ 308.0740, found 308.0745.
(Z)-2-[3-(tert-Butyl)-1,4,2-oxathiazol-5-ylidene]-1-phenylethan-1-one.
Compound 5j [43 mg, 55% yield, Rf = 0.20 (10:1 PE/EA)] was
isolated as a yellow solid: mp 69−70 °C; 1H NMR (400 MHz,
CDCl3) δ 7.98 (dd, J = 8.2, 1.6 Hz, 2H), 7.57−7.51 (m, 1H), 7.50−
7.45 (m, 2H), 7.10 (s, 1H), 1.44 (s, 9H); 13C{1H} NMR (100 MHz,
CDCl3) δ 186.6, 176.6, 171.3, 137.7, 132.5, 128.8, 127.8, 90.5, 35.5,
29.6; ESI-HRMS m/z calcd for C14H16NO2S [M + H]+ 262.0896,
found 262.0899.
(Z)-1-(p-Tolyl)-2-[3-(p-tolyl)-1,4,2-oxathiazol-5-ylidene]ethan-1-one.
Compound 5k [81 mg, 87% yield, Rf = 0.35 (20:1 PE/EA)] was
isolated as a white solid: mp 108−109 °C; H NMR (400 MHz,
2-[3-(4-Bromophenyl)-5-(methylthio)-1,4,2-oxathiazol-5-yl]-1-phenyl-
ethan-1-one. Compound 6e [105 mg, 86% yield, Rf = 0.31 (10:1 PE/
EA)] was isolated as a yellow solid: mp 98−99 °C; H NMR (400
1
1
CDCl3) δ 7.91 (d, J = 8.0 Hz, 2H), 7.70 (d, J = 8.0 Hz, 2H), 7.30 (d, J
= 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 7.15 (s, 1H), 2.42 (s, 6H);
13C{1H} NMR (100 MHz, CDCl3) δ 186.2, 175.7, 160.8, 143.3,
143.1, 134.9, 130.1, 129.5, 127.9, 127.8, 123.3, 90.8, 21.7, (the 1C
peak is merged with other peaks); ESI-HRMS m/z calcd for
C18H16NO2S [M + H]+ 310.0896, found 310.0896.
MHz, CDCl3) δ 8.01 (d, J = 6.8 Hz, 2H), 7.64 (t, J = 7.6 Hz, 1H),
7.60−7.54 (m, 4H), 7.52 (t, J = 8.0 Hz, 2H), 4.47 (d, J = 17.6 Hz,
1H), 3.97 (d, J = 17.6 Hz, 1H), 2.28 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 193.9, 157.1, 135.9, 134.3, 132.3, 129.2, 129.0, 128.4,
126.7, 125.7, 109.9, 49.8, 13.9; ESI-HRMS m/z calcd for
C17H14BrNO2S2Na [M + Na]+ 429.9542, found 429.9549.
Methyl 4-[5-(Methylthio)-5-(2-oxo-2-phenylethyl)-1,4,2-oxathiazol-3-
yl]benzoate. Compound 6f [100 mg, 86% yield, Rf = 0.15 (10:1 PE/
(Z)-1-(4-Bromophenyl)-2-[3-(p-tolyl)-1,4,2-oxathiazol-5-ylidene]-
ethan-1-one. Compound 5l [104 mg, 93% yield, Rf = 0.41 (20:1 PE/
1
1
EA)] was isolated as a white solid: mp 122−123 °C; H NMR (400
EA)] was isolated as a white solid: mp 119−120 °C; H NMR [400
MHz, CDCl3) δ 7.85 (d, J = 8.8 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H),
7.61 (d, J = 8.8 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.10 (s, 1H), 2.42
(s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 185.3, 176.8, 160.9,
143.3, 136.3, 132.0, 130.2, 129.3, 127.9, 127.5, 123.1, 90.6, 21.8; ESI-
MHz, (CD3)2CO] δ 8.14 (d, J = 7.2 Hz, 2H), 8.12 (d, J = 6.8 Hz,
2H), 7.88 (d, J = 8.4 Hz, 2H), 7.71 (t, J = 7.2 Hz, 1H), 7.59 (t, J = 7.6
Hz, 2H), 4.77 (d, J = 17.6 Hz, 1H), 4.09 (d, J = 18.0 Hz, 1H), 3.92 (s,
3H), 2.25 (s, 3H); 13C{1H} NMR [100 MHz, (CD3)2CO] δ 194.7,
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Article
166.4, 157.8, 137.0, 134.8, 133.3, 132.8, 130.8, 129.7, 129.2, 128.5,
110.6, 52.7, 49.5, 13.7; ESI-HRMS m/z calcd for C19H17NO4S2Na [M
+ Na]+ 410.0491, found 410.0496.
1-[5-(Methylthio)-3-(p-tolyl)-1,4,2-oxathiazol-5-yl]propan-2-one.
Compound 6n [71 mg, 84% yield, Rf = 0.28 (10:1 PE/EA)] was
isolated as a yellow oil: 1H NMR [400 MHz, (CD3)2CO] δ 7.59 (d, J
= 8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 4.02 (d, J = 18.0 Hz, 1H),
3.56 (d, J = 17.6 Hz, 1H), 2.38 (s, 3H), 2.30 (s, 3H), 2.21 (s, 3H);
13C{1H} NMR [100 MHz, (CD3)2CO] δ 202.6, 158.2, 142.6, 130.5,
128.2, 125.8, 108.7, 53.3, 30.6, 21.4, 13.5; ESI-HRMS m/z calcd for
C13H15NO2S2Na [M + Na]+ 304.0436, found 304.0439.
2-[3-(2-Chlorophenyl)-5-(methylthio)-1,4,2-oxathiazol-5-yl]-1-phenyl-
ethan-1-one. Compound 6g [94 mg, 86% yield, Rf = 0.18 (10:1 PE/
EA)] was isolated as a yellow oil: 1H NMR [400 MHz, (CD3)2CO] δ
8.14 (d, J = 8.0 Hz, 2H), 7.74−7.68 (m, 2H), 7.64−7.53 (m, 4H),
7.48 (t, J = 7.6 Hz, 1H), 4.74 (d, J = 17.6 Hz, 1H), 4.11 (d, J = 17.6
Hz, 1H), 2.31 (s, 3H); 13C{1H} NMR [100 MHz, (CD3)2CO] δ
194.8, 156.1, 137.0, 134.8, 133.4, 133.1, 132.0, 131.6, 129.7, 129.2,
128.4, 127.9, 110.9, 49.8, 13.8; ESI-HRMS m/z calcd for
C17H14ClNO2S2Na [M + Na]+ 386.0047, found 386.0054.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00156.
■
sı
2-[5-(Methylthio)-3-(naphthalen-2-yl)-1,4,2-oxathiazol-5-yl]-1-phe-
nylethan-1-one. Compound 6h [104 mg, 91% yield, Rf = 0.22 (10:1
1
Copies of 1H and 13C NMR spectra for all new
compounds (PDF)
PE/EA)] was isolated as a yellow solid: mp 111−112 °C; H NMR
[400 MHz, (CD3)2CO] δ 8.22 (s, 1H), 8.16 (d, J = 7.2 Hz, 2H),
8.12−8.06 (m, 1H), 8.04−7.90 (m, 3H), 7.71 (t, J = 7.6 Hz, 1H),
7.66−7.55 (m, 4H), 4.78 (d, J = 17.6 Hz, 1H), 4.08 (d, J = 17.6 Hz,
1H), 2.27 (s, 3H); 13C{1H} NMR [100 MHz, (CD3)2CO] δ 194.8,
158.7, 137.1, 135.4, 134.8, 134.0, 129.7, 129.6 (3C), 129.2, 128.7,
128.0, 126.3, 124.2, 109.8, 49.4, 13.7 (the 1C peak is merged with
other peaks); ESI-HRMS m/z calcd for C21H17NO2S2Na [M + Na]+
402.0593, found 402.0599.
Accession Codes
CCDC 2041487 and 2041852 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
2-[5-(Methylthio)-3-(m-tolyl)-1,4,2-oxathiazol-5-yl]-1-phenylethan-1-
one. Compound 6i [96 mg, 93% yield, Rf = 0.38 (10:1 PE/EA)] was
isolated as a yellow oil: 1H NMR [400 MHz, (CD3)2CO] δ 8.14 (d, J
= 7.2 Hz, 2H), 7.70 (t, J = 7.2 Hz, 1H), 7.63−7.50 (m, 4H), 7.43−
7.34 (m, 2H), 4.73 (d, J = 17.6 Hz, 1H), 4.03 (d, J = 18.0 Hz, 1H),
2.40 (s, 3H), 2.24 (s, 3H); 13C{1H} NMR [100 MHz, (CD3)2CO] δ
194.8, 158.6, 139.8, 137.1, 134.8, 132.8, 129.8, 129.7, 129.2, 128.8,
128.7, 125.5, 109.6, 49.4, 21.2, 13.7; ESI-HRMS m/z calcd for
C18H17NO2S2Na [M + Na]+ 366.0593, found 366.0598.
AUTHOR INFORMATION
Corresponding Authors
■
Bin Cheng − State Key Laboratory of Applied Organic
Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou 730000, China; Institute of
Marine Biomedicine/Hoffmann Institute of Advanced
Materials, Shenzhen Polytechnic, Shenzhen 518055, China;
orcid.org/0000-0002-8276-6653; Email: chengbin@
szpt.edu.cn
(E)-2-[5-(Methylthio)-3-styryl-1,4,2-oxathiazol-5-yl]-1-phenylethan-1-
one. Compound 6j [90 mg, 84% yield, Rf = 0.15 (10:1 PE/EA)] was
1
isolated as a white solid: mp 117−118 °C; H NMR [400 MHz,
(CD3)2CO] δ 8.13 (d, J = 7.2 Hz, 2H), 7.74−7.67 (m, 3H), 7.58 (t, J
= 7.6 Hz, 2H), 7.48−7.35 (m, 3H), 7.16 (d, J = 16.4 Hz, 1H), 7.10 (d,
J = 16.4 Hz, 1H), 4.71 (d, J = 17.6 Hz, 1H), 3.98 (d, J = 18.0 Hz, 1H),
2.22 (s, 3H); 13C{1H} NMR [100 MHz, (CD3)2CO] δ 194.8, 158.8,
141.0, 137.1, 136.2, 134.7, 130.4, 129.8, 129.7, 129.2, 128.3, 116.4,
109.0, 49.2, 13.7; ESI-HRMS m/z calcd for C19H17NO2S2Na [M +
Na]+ 378.0593, found 378.0601.
Taimin Wang − Institute of Marine Biomedicine/Hoffmann
Institute of Advanced Materials, Shenzhen Polytechnic,
Shenzhen 518055, China; Email: wangtm@szpt.edu.cn
Hongbin Zhai − Institute of Marine Biomedicine/Hoffmann
Institute of Advanced Materials, Shenzhen Polytechnic,
Shenzhen 518055, China; State Key Laboratory of Chemical
Oncogenomics, Shenzhen Engineering Laboratory of Nano
Drug Slow-Release, Peking University Shenzhen Graduate
School, Shenzhen 518055, China; orcid.org/0000-0003-
2198-1357; Email: zhaihb@pkusz.edu.cn
2-[3-(tert-Butyl)-5-(methylthio)-1,4,2-oxathiazol-5-yl]-1-phenylethan-
1-one. Compound 6k [70 mg, 76% yield, Rf = 0.28 (10:1 PE/EA)]
1
was isolated as a yellow solid: mp 95−96 °C; H NMR [400 MHz,
(CD3)2CO] δ 8.10 (d, J = 6.8 Hz, 1H), 7.69 (t, J = 7.2 Hz, 1H), 7.57
(t, J = 7.6 Hz, 2H), 4.62 (d, J = 17.6 Hz, 1H), 3.88 (d, J = 17.6 Hz,
1H), 2.18 (s, 3H), 1.29 (s, 9H); 13C{1H} NMR [100 MHz,
(CD3)2CO] δ 194.8, 168.4, 137.2, 134.6, 129.7, 129.2, 108.8, 49.4,
35.8, 29.4, 13.6; ESI-HRMS m/z calcd for C15H19NO2S2Na [M +
Na]+ 332.0749, found 332.0754.
Authors
Hui Li − State Key Laboratory of Applied Organic Chemistry,
College of Chemistry and Chemical Engineering, Lanzhou
University, Lanzhou 730000, China; Institute of Marine
Biomedicine/Hoffmann Institute of Advanced Materials,
Shenzhen Polytechnic, Shenzhen 518055, China
Jianguo Sun − State Key Laboratory of Chemical
Oncogenomics, Shenzhen Engineering Laboratory of Nano
Drug Slow-Release, Peking University Shenzhen Graduate
School, Shenzhen 518055, China
Xinping Zhang − State Key Laboratory of Applied Organic
Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou 730000, China; Institute of
Marine Biomedicine/Hoffmann Institute of Advanced
Materials, Shenzhen Polytechnic, Shenzhen 518055, China
Yixuan He − State Key Laboratory of Applied Organic
Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou 730000, China; Institute of
Marine Biomedicine/Hoffmann Institute of Advanced
Materials, Shenzhen Polytechnic, Shenzhen 518055, China
2-[5-(Methylthio)-3-propyl-1,4,2-oxathiazol-5-yl]-1-phenylethan-1-
one. Compound 6l [71 mg, 80% yield, Rf = 0.18 (10:1 PE/EA)] was
isolated as a yellow oil: 1H NMR [400 MHz, (CD3)2CO] δ 8.10 (d, J
= 6.8 Hz, 2H), 7.69 (t, J = 7.6 Hz, 1H), 7.57 (t, J = 7.6 Hz, 2H), 4.63
(d, J = 17.6 Hz, 1H), 3.89 (d, J = 17.6 Hz, 1H), 2.61−2.47 (m, 2H),
2.19 (s, 3H), 1.71−1.60 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H); 13C{1H}
NMR [100 MHz, (CD3)2CO] δ 194.7, 159.8, 137.1, 134.6, 129.7,
129.2, 108.6, 49.2, 30.2, 21.8, 13.7, 13.6; ESI-HRMS m/z calcd for
C14H17NO2S2Na [M + Na]+ 318.0593, found 318.0597.
Ethyl 5-(Methylthio)-5-(2-oxo-2-phenylethyl)-1,4,2-oxathiazole-3-car-
boxylate. Compound 6m [64 mg, 66% yield, Rf = 0.14 (10:1 PE/EA)]
was isolated as a yellow oil: 1H NMR [400 MHz, (CD3)2CO] δ 8.11
(d, J = 7.2 Hz, 2H), 7.70 (t, J = 7.6 Hz, 1H), 7.58 (t, J = 7.6 Hz, 2H),
4.69 (d, J = 18.0 Hz, 1H), 4.37 (q, J = 7.2 Hz, 2H), 4.12 (d, J = 18.0
Hz, 1H), 2.24 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H); 13C{1H} NMR [100
MHz, (CD3)2CO] δ 194.5, 158.7, 152.6, 136.8, 134.9, 129.7, 129.2,
112.6, 63.7, 49.9, 14.2, 13.5; ESI-HRMS m/z calcd for
C14H15NO4S2Na [M + Na]+ 348.0335, found 348.0339.
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Article
Synthesis of Three Differently Substituted Quinolines via Site
Selective Coupling of orthoAminoaryl Ketones with a-Enolic
Dithioesters. Adv. Synth. Catal. 2016, 358, 1195. (g) Cheng, B.; Li,
H.; Hou, J.; Zhang, X.; He, Y.; Sun, H.; Xu, W.; Wang, T.; Zhai, H.
Synthesis of 3,4-Dihydro-2H-1,3-thiazines from α-Enolic Dithioesters
and 1,3,5-Triazinanes via a Formal (3 + 3) Annulation Reaction. J.
Org. Chem. 2020, 85, 13339. (h) Wang, S.-W.; Guo, W.-S.; Wen, L.-
R.; Li, M. Yb(OTf)3 Catalyzed [3 + 2] Annulations of D-A
Cyclopropanes with β-Oxodithioesters: a Regioselective Synthesis of
Tetrahydrothiophenes. RSC Adv. 2015, 5, 47418. (i) Shukla, G.;
Nagaraju, A.; Srivastava, A.; Verma, G. K.; Raghuvanshi, K.; Singh, M.
S. Regioselectivity in the Ring Opening of Epoxides: A Metal-Free
Cascade C-S/C-O Bond Formation Approach to 1,3-Oxathiolan-2-
ylidenes through Heteroannulation of α-Enolic Dithioesters at Room
Temperature. Synthesis 2014, 46, 1815.
Haiyan Sun − Institute of Marine Biomedicine/Hoffmann
Institute of Advanced Materials, Shenzhen Polytechnic,
Shenzhen 518055, China
Wei Xu − Institute of Marine Biomedicine/Hoffmann Institute
of Advanced Materials, Shenzhen Polytechnic, Shenzhen
518055, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00156
Author Contributions
∥H.L. and J.S. contributed equally to this work.
Notes
The authors declare no competing financial interest.
(4) (a) Cheng, B.; Li, Y.; Wang, T.; Zhang, X.; Li, H.; Li, Y.; Zhai, H.
Pyridinium 1,4-Zwitterionic Thiolates as a Useful Class of Sulfur-
Containing Synthons: Application to the Synthesis of 2,5-Dihydro-
1,4,5-thiadiazepines. Chem. Commun. 2019, 55, 14606. (b) Zhai, S.;
Zhang, X.; Cheng, B.; Li, H.; Li, Y.; He, Y.; Li, Y.; Wang, T.; Zhai, H.
Synthesis of Tetrasubstituted Thiophenes via a [3 + 2] Cascade
Cyclization Reaction of Pyridinium 1,4-Zwitterionic Thiolates and
Activated Allenes. Chem. Commun. 2020, 56, 3085. (c) Cheng, B.;
Duan, X.; Li, Y.; Zhang, X.; Li, H.; Wu, F.; Li, Y.; Wang, T.; Zhai, H.
Development and Application of Pyridinium 1,4-Zwitterionic
Thiolates: Synthesis of Polysubstituted Thiophenes. Eur. J. Org.
Chem. 2020, 2020, 1896. (d) Cheng, B.; Bao, B.; Xu, W.; Li, Y.; Li,
H.; Zhang, X.; Li, Y.; Wang, T.; Zhai, H. Synthesis of Fully
Substituted Pyrazoles from Pyridinium 1,4-Zwitterionic Thiolates and
Hydrazonoyl Chlorides via a [[3 + 3] - 1] Pathway. Org. Biomol.
Chem. 2020, 18, 2949−2955. (e) Cheng, B.; Li, H.; Duan, S.; Zhang,
X.; He, Y.; Li, Y.; Li, Y.; Wang, T.; Zhai, H. Synthesis of Indolizines
from Pyridinium 1,4-Zwitterionic Thiolates and Propiolic Acid
Derivatives via a Formal [4 + 1] Pathway. Org. Biomol. Chem.
2020, 18, 6253. (f) Cheng, B.; Li, Y.; Wang, T.; Zhang, X.; Li, H.; He,
Y.; Li, Y.; Zhai, H. Application of Pyridinium 1,4-Zwitterionic
Thiolates: Synthesis of Benzopyridothiazepines and Benzothiophenes.
J. Org. Chem. 2020, 85, 6794. (g) Cheng, B.; Zhang, X.; Li, Y.; Li, H.;
He, Y.; Li, Y.; Wang, T.; Zhai, H. Synthesis of Indolizines from
Pyridinium 1,4-Zwitterionic Thiolates and α-Functionalized Bromoal-
kanes via a Stepwise [(5 + 1)-1] Pathway. Chem. Commun. 2020, 56,
8396. (h) Cheng, B.; Li, Y.; Zhang, X.; Duan, S.; Li, H.; He, Y.; Li, Y.;
Wang, T.; Zhai, H. Two Reaction Modes of Pyridinium 1,4-
Zwitterionic Thiolates with Sulfenes: Synthesis of 3H-1,2-Dithiole
2,2-Dioxides, 1,9a-Dihydropyrido[2,1-c][1,4]thiazines, and Indoli-
zines. Org. Lett. 2020, 22, 5817. (i) Cheng, B.; Zhang, X.; Li, H.;
He, Y.; Li, Y.; Sun, H.; Wang, T.; Zhai, H. Synthesis of
Pyridothiazepines via a 1,5-Dipolar Cycloaddition Reaction between
Pyridinium 1,4-Zwitterionic Thiolates and Activated Allenes. Adv.
Synth. Catal. 2020, 362, 4668.
ACKNOWLEDGMENTS
■
The authors thank the NSFC (21971092, 21901014,
21472072, 21871018, 21732001, and 21672017), the Charac-
teristic Innovation Project of Guangdong Provincial Education
Department (2020KTSCX295), and the Shenzhen Science and
T e c h n o l o g y I n n o v a t i o n C o m m i t t e e
(JCYJ20170818114529521) for financial support.
REFERENCES
■
(1) (a) Acton, A. Q., Ed. Sulfur Compounds: Advances in Research and
Application; Scholarly: Atlanta, 2012. (b) Jiang, X., Ed. Sulfur
Chemistry, Topics in Current Chemistry; Springer: Cham, Switzerland,
2019. (c) Wang, N.; Saidhareddy, P.; Jiang, X. Construction of Sulfur-
Containing Moieties in the Total Synthesis of Natural Products. Nat.
Prod. Rep. 2020, 37, 246. (d) Feng, M.; Tang, B.; Liang, S. H.; Jiang,
X. Sulfur Containing Scaffolds in Drugs: Synthesis and Application in
Medicinal Chemistry. Curr. Top. Med. Chem. 2016, 16, 1200. (e) Fan,
R.; Tan, C.; Liu, Y.; Wei, Y.; Zhao, X.; Liu, X.; Tan, J.; Yoshida, H. A
Leap Forward in Sulfonium Salt and Sulfur Ylide Chemistry. Chin.
Chem. Lett. 2021, 32, 299.
(2) For reviews, see: (a) Liu, H.; Jiang, X. Transfer of Sulfur: From
Simple to Diverse. Chem. - Asian J. 2013, 8, 2546. (b) Metzner, P.;
Thuillier, A. Sulfur Reagents in Organic Synthesis; Academic Press:
̈
New York, 1994. (c) Tan, W.; Jänsch, N.; Ohlmann, T.; Meyer-
Almes, F.-J.; Jiang, X. Thiocarbonyl Surrogate via Combination of
Potassium Sulfide and Chloroform for Dithiocarbamate Construction.
Org. Lett. 2019, 21, 7484. For selected examples, see: (d) Tan, W.;
Wang, C.; Jiang, X. Green Carbon Disulfide Surrogate via a
Combination of Potassium Sulfide and Chloroform for Benzothia-
zine-thione and Benzothiazole-thione Construction. Org. Chem. Front.
2018, 5, 2390.
(3) For some selected examples, see: (a) Yadav, D.; Ansari, M. A.;
Kumar, M.; Singh, M. S. Metal- and Catalyst-Free One-Pot Cascade
Coupling of α-Enolic Dithioesters with in Situ Generated 4-Chloro-3-
Formylcoumarin: Access to Thioxothiopyrano[3,2-c]chromen-5(2H)-
ones. Adv. Synth. Catal. 2020, 362, 512 and references cited therein.
(b) Soni, S.; Koley, S.; Ansari, M. A.; Singh, M. S. Site-Specific S-
Allylation of α-Enolic Dithioesters with Morita-Baylis-Hillman
Acetates at Room Temperature: Precursor for Thiopyrans. Adv.
Synth. Catal. 2019, 361, 4091. (c) Shukla, G.; Srivastava, A.; Singh, M.
S. Metal- and Catalyst-Free, Formal [4 + 1] Annulation via Tandem C
= O/C = S Functionalization: One-Pot Access to 3,5-Disubstituted/
Annulated Isothiazoles. Org. Lett. 2016, 18, 2451. (d) Srivastava, A.;
Shukla, G.; Yadav, D.; Singh, M. S. Access to Fully Substituted
Thiazoles and 2,3-Dihydrothiazoles via Copper-Catalyzed [4 + 1]
Heterocyclization of α-(N-Hydroxy/aryl)imino-β-Oxodithioesters
with α-Diazocarbonyls. J. Org. Chem. 2017, 82, 10846. (e) Peruncher-
alathan, S.; Khan, T. A.; Ila, H.; Junjappa, H. Regioselective Synthesis
of 1-Aryl-3,4-substituted/annulated-5-(methylthio)pyrazoles and 1-
Aryl-3-(methylthio)-4,5-substituted/annulated Pyrazoles. J. Org.
Chem. 2005, 70, 10030. (f) Koley, S.; Chanda, T.; Ramulu, B. J.;
Chowdhury, S.; Singh, M. S. Acid-Controlled Chemodivergent
(5) For some related works, see: (a) Pocar, D.; Rossi, L. M.;
Trimarco, P. Reactions of β-keto thioacide anilides with Acyl Chloride
Aryl-Hydrazones. J. Heterocycl. Chem. 1975, 12, 401. (b) Mloston, G.;
́
Urbaniak, K.; Utecht, G.; Lentz, D.; Jasinski, M. Trifluoromethylated
2,3-Dihydro-1,3,4-thiadiazoles via the Regioselective (3 + 2)-Cyclo-
additions of Fluorinated Nitrile Imines with Aryl, Hetaryl, and
Ferrocenyl Thioketones. J. Fluorine Chem. 2016, 192, 147. (c) Hegab,
M. I.; El-Gazzar, A.-R. B. A.; Gad, F. A.; Ellithey, M. Regioselective
Synthesis and Pharmacological Activities of Spirodibenzo[a,d]-
cycloheptene-5,2′-[1,3,4]thiadiazole Derivatives. J. Sulfur Chem.
2007, 28, 101. (d) Abdelhamid, A. O.; Ismail, Z. H.; Abdel-Gawad,
S. M.; Ghorab, M. M.; Abdel-Aziem, A. Synthesis of Some New
Thieno[2,3-b]pyridines, Pyrimidino[4′,5′:4,5]thieno[2,3-b]-pyridines,
and 2,3-Dihydro-1,3,4-thiadiazoles. Phosphorus, Sulfur Silicon Relat.
Elem. 2008, 184, 58.
(6) The X-ray structural data were deposited at the Cambridge
Crystallographic Data Center. CCDC 2041487 (3a) and CCDC
2041852 (5i) contain the supplementary crystallographic data for this
paper.
5272
https://doi.org/10.1021/acs.joc.1c00156
J. Org. Chem. 2021, 86, 5265−5273

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(7) Beno, B. R.; Yeung, K.-S.; Bartberger, M. D.; Pennington, L. D.;
Meanwell, N. A. A Survey of the Role of Noncovalent Sulfur
Interactions in Drug Design. J. Med. Chem. 2015, 58, 4383.
(8) (a) Kumar, L.; Lal, N.; Kumar, V.; Sarswat, A.; Jangir, S.; Bala,
V.; Kumar, L.; Kushwaha, B.; Pandey, A. K.; Siddiqi, M. I.; Shukla, P.
K.; Maikhuri, J. P.; Gupta, G.; Sharma, V. L. Azole-carbodithioate
Hybrids as Vaginal Anti-Candida Contraceptive Agents: Design,
Synthesis and Docking Studies. Eur. J. Med. Chem. 2013, 70, 68.
(b) Ramulu, B. J.; Chowdhury, S.; Nagaraju, A.; Koley, S.; Anand, N.;
Singh, M. S. Iodine-Mediated Annulation of S-Allylated α-Enolic
Dithioesters: Rapid Access to 2-Alkylidene-1,3-dithiolanes at Room
Temperature. Synthesis 2015, 47, 1510.
(9) Giustiniano, M.; Meneghetti, F.; Mercalli, V.; Varese, M.;
Giustiniano, F.; Novellino, E.; Tron, G. C. Synthesis of Amino-
carbonyl N-Acylhydrazones by a Three-Component Reaction of
Isocyanides, Hydrazonoyl Chlorides, and Carboxylic Acids. Org. Lett.
2014, 16, 5332.
(10) (a) Yang, K.; Zhang, F.; Fang, T.; Zhang, G.; Song, Q.
Stereospecific 1,4-Metallate Shift Enables Stereoconvergent Synthesis
of Ketoximes. Angew. Chem., Int. Ed. 2019, 58, 13421. (b) Dubrovskiy,
A. V.; Larock, R. C. Synthesis of Benzisoxazoles by the [3 + 2]
Cycloaddition of in situ Generated Nitrile Oxides and Arynes. Org.
Lett. 2010, 12, 1180.
5273
https://doi.org/10.1021/acs.joc.1c00156
J. Org. Chem. 2021, 86, 5265−5273