Hydrogen Peroxide-Mediated Rapid Room Temperature Metal-Free C(sp2)-H Thiocyanation of Amino Pyrazoles, Amino Uracils, and Enamines

Article abstract of DOI:10.1021/acs.joc.0c01738

A rapid metal-and additive-free room temperature method for C(sp2)-H thiocyanation of aminopyrazoles, aminoisoxazole, aminoisothiazole, amino uracils, and aliphatic enamines has been developed in an aqueous medium using hydrogen peroxide as a benign oxidant and ammonium thiocyanate as a thiocyanating agent. On the other hand, the reaction of hydrogen peroxide and ammonium thiocyanate followed by one-pot addition of NaOH provides the corresponding disulfides in the case of amino azoles, and pyrimidine-fused 2-amino thiazoles were observed in the case of aminouracils. The salient features of this method are the use of an eco-friendly oxidant, reaction tunability to access different products, wide substrate scope, and good to very good yields.

Full text of DOI:10.1021/acs.joc.0c01738

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Hydrogen Peroxide-Mediated Rapid Room Temperature Metal-Free
C(sp2)‑H Thiocyanation of Amino Pyrazoles, Amino Uracils, and
Enamines
Danish Ali, Anoop Kumar Panday, and Lokman H. Choudhury*
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ABSTRACT: A rapid metal- and additive-free room temperature
method for C(sp2)-H thiocyanation of aminopyrazoles, amino-
isoxazole, aminoisothiazole, amino uracils, and aliphatic enamines
has been developed in an aqueous medium using hydrogen
peroxide as a benign oxidant and ammonium thiocyanate as a
thiocyanating agent. On the other hand, the reaction of hydrogen
peroxide and ammonium thiocyanate followed by one-pot addition
of NaOH provides the corresponding disulfides in the case of
amino azoles, and pyrimidine-fused 2-amino thiazoles were
observed in the case of aminouracils. The salient features of this
method are the use of an eco-friendly oxidant, reaction tunability to
access different products, wide substrate scope, and good to very
good yields.
(Scheme 1f).11 Similarly, molecular oxygen in the TFA
medium has been used for thiocyanation of 4-aminocoumarins
in the presence of visible light.12 Despite these useful methods
for thiocyanation, very few methods are known in the literature
for the C(sp2)-H thiocyanation of heterocycles using readily
available and environmentally benign reagents.
Aminopyrazole and aminouracils are found in diverse drugs
and bioactive molecules, and they act as valuable starting
materials for the construction of fused N-heterocycles.13
Although a plethora of methods are known in the literature
for thiocyanation of arenes, indoles, carbazoles, pyrroles, and
imidazopyridines, however, till now, only limited methods are
known for the thiocyanation of the pyrazole moiety.14
Hydrogen peroxide is a popular and benign oxidizing agent
used in various organic transformations.15 Recently, Cheng et
al. have reported hydrogen peroxide-mediated iodide-catalyzed
sulfenylation and selenylation of unprotected uracil deriva-
tives.16 To the best of our knowledge, H2O2 has not been used
under additive- and metal-free conditions for the thiocyanation
reactions. In continuation of our work on new methodology
development,17 we wanted to develop a metal-free thiocyana-
INTRODUCTION
■
Thiocyanation is one of the popular and very useful
transformations for the incorporation of C−S bonds in organic
synthesis.1 Organic thiocyanates can be easily transformed into
various thiol derivatives such as thiols, disulfides, thioethers,
thiocarbamates, and phosphonothioates and for diverse sulfur-
containing heterocycles.2 In addition to these, organic
thiocyanates possess diverse medicinal properties such as
antiparasitic, antifungal, and antibacterial.3 Considering their
enormous applications, over the years, numerous methods for
the formation of the C−SCN bond have been developed.4
Recently, thiocyanation of C(sp2)-H bond has gained
considerable attention, and different catalysts and thiocyanat-
ing agents are being used for this purpose.5 As for example,
Jiang and Wu et al. reported an oxidative thiocyanation
method for aromatic and heteroaromatic compounds using
KSCN and molecular oxygen in the presence of Cu(OTf)2 as
the catalyst (Scheme 1a).6 Wan et al. reported thiocyanation of
C−H bonds of enaminones using NH4SCN and visible light in
the presence of rose bengal or Ru(bpy)3Cl2·6H2O as
photocatalysts (Scheme 1b).7 Chen and Liu et al. developed
an NBS-mediated synthesis of 2-aminothiazole derivatives
from the reaction of enaminones with KSCN (Scheme 1c).8
Subsequently, Duan et al. reported thiocyanation reaction of
enaminones using NBS and KSCN either in DMF or ethanol
medium to prepare thiocyanated products and aminothiazoles,
as shown in Scheme 1d.9 Recently, K2S2O8 in combination
with NH4SCN has been explored for the thiocyanation of N-
substituted pyrazolone (Scheme 1e)10 and pyrazolin-5-ones
Received: July 21, 2020
https://dx.doi.org/10.1021/acs.joc.0c01738
© XXXX American Chemical Society
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Scheme 1. Few Recent Methods for Thiocyanation and Our Work
tion method for the sp2(C−H) bond using readily available
encouraging result, next, we focused on the optimization of the
reaction conditions by screening this reaction in different
solvents such as THF, DMF, MeOH, EtOH, and H2O (Table
1, entries 3−7). From this screening, we observed that the
water medium provided the highest yield among all the
screened solvents (Table 1, entry 7). Considering this
outcome, then we tried to improve the yield of the reaction
by increasing the amount of H2O2 and thiocyanating agent
NH4SCN. Interestingly, using 4.0 equiv of H2O2 and 3.0 equiv
of NH4SCN, 65% yield of 3e was observed within 30 min. The
best result was obtained using 8.0 equiv of H2O2 and 3.0 equiv
of NH4SCN within 15 min (Table 1, entry 10). We also
screened NaSCN and KSCN as thiocyanating agents under
H2O2 as a benign oxidizing agent.
RESULTS AND DISCUSSION
■
We started our preliminary investigation on thiocyanation by
taking 3-methyl-1-phenyl-1H-pyrazol-5-amine (1e) and
NH4SCN (2) as model substrates. The reaction of 1e with 2
in acetonitrile medium in the absence of any catalyst or
oxidizing agent did not provide our expected product 3e even
after 12 h of room temperature stirring. Interestingly, when we
performed the same reaction in the presence of 2 equiv of
H2O2 within 2 h, the corresponding thiocyanated product 3e
was obtained in 35% yield (Table 1, entry 2). With this
B
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a
Table 1. Optimization of Reaction Conditions
b
entry
oxidizing agent (equiv)
MSCN (equiv)
solvent
time
yield (%)
1
2
3
4
5
6
7
8
NH4SCN (1)
NH4SCN (2)
NH4SCN (2)
NH4SCN (2)
NH4SCN (2)
NH4SCN (2)
NH4SCN (2)
NH4SCN (3)
NH4SCN (3)
NH4SCN (3)
NaSCN (3)
MeCN
MeCN
THF
DMF
MeOH
EtOH
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
12 h
2 h
2 h
2 h
2 h
2 h
2 h
30 min
20 min
15 min
20 min
20 min
15 min
15 min
15 min
15 min
6 h
NR
35
40
30
45
52
58
65
70
81
78
75
77
74
72
75
trace
H2O2 (2)
H2O2 (2)
H2O2 (2)
H2O2 (2)
H2O2 (2)
H2O2 (2)
H2O2 (4)
H2O2 (6)
H2O2 (8)
H2O2 (8)
H2O2 (8)
K2S2O8 (8)
Na2S2O8 (8)
oxone (8)
TBHP (8)
O2
9
10
11
12
13
14
15
16
17
KSCN (3)
NH4SCN (3)
NH4SCN (3)
NH4SCN (3)
NH4SCN (3)
NH4SCN (3)
a
b
Reactions were carried out using 0.5 mmol (1.0 equiv) of 1e at room temperature. Yield of the isolated product.
similar reaction conditions, and relatively lower yields were
observed than those of NH4SCN (Table 1, entries 11−12).
Next, various oxidants such as K2S2O8, Na2S2O8, oxone, and
TBHP were screened in the presence of 3.0 equiv of NH4SCN
at room temperature. In all these cases, the observed yield was
lower than that of entry 10. We also tried a reaction using
molecular oxygen as the oxidant, keeping all other parameters
constant, and to our surprise, only a trace amount of our
desired product 3e was observed even after 6 h of reaction
time (Table 1, entry 17). Thus, considering all these, 3.0 equiv
of NH4SCN and 8.0 equiv of H2O2 in water as a reaction
medium were chosen as the optimum reaction conditions for
this transformation (Table 1, entry 10).
With these optimized reaction conditions at hand, we then
turned our attention to check the generality and scope of this
method. A wide variety of aminopyrazole derivatives with R1 =
methyl, tertiary butyl, phenyl, and p-tolyl groups and R2 = H,
Me, and Ph were found suitable for thiocyanation by this
method, and the corresponding thiocyanated products were
obtained in good to very good yields (Table 2). Then, we tried
to explore 5-amino-3-methylisoxazole and 5-amino-3-methyl-
isothiazole under similar reaction conditions, and the
corresponding products 3i and 3j were obtained with 85 and
78% yields, respectively. We also tried thiocyanation of 3,5-
dimethyl-1-phenyl-1H-pyrazole, a pyrazole derivative without
having any amino substituent under similar reaction con-
ditions. To our surprise, the reaction was very slow, and only
20% yield of 3k was obtained even after 6 h of stirring. Similar
to aminopyrazoles, 6-aminouracil also provided the corre-
sponding thiocyanation product 5a in very good yield under
the standard reaction conditions. Likewise, monosubstituted
and disubstituted 6-aminouracils with alkyl groups such as
methyl, ethyl, and propyl were reacted, and the corresponding
products 5b−5e were prepared in good to very good yields.
This method is also applicable to electron-rich pyrimidine-like
2,4,6-triaminopyrimidine, and the corresponding product 5f
was obtained with relatively lower yield (60%). It is
noteworthy to mention that all these reactions were completed
within 15−20 min time. All the products were fully
1
characterized by H & 13C NMR and by recording HRMS.
Next, we tried this methodology to acyclic enamine derivatives
having the ketone or ester functionality. Under the standard
reaction conditions, 4-amino-3-penten-2-one provided the
corresponding product 7a in 81% yield within 20 min. The
scope of acyclic enamine derivatives was studied by preparing
7b−7e, and the results are summarized in Table 3. Cyclic
enamines such as 3-aminocyclohex-2-en-1-one and 3-amino-
5,5-dimethyl cyclohex-2-en-1-one were reacted under the
standard reaction conditions, and the corresponding products
7f (78%) and 7g (76%), respectively, were obtained. Likewise,
5,5-dimethyl-3-morpholinocyclohex-2-en-1-one, a cyclic enam-
ine derivative having the tertiary amine functionality, provided
the corresponding product 7h in 73% yield. Interestingly, in all
the cases, we did not observe any intramolecular cyclization
product. However, when cyclic enaminone, 3-(cyclohexylami-
no)-5,5-dimethylcyclohex-2-en-1-one, having a secondary
amine group was treated with NH4SCN under the standard
reaction conditions, we observed thiocyanation followed by
intramolecular cyclized product 9a.
Next, the feasibility of gram-scale synthesis of thiocyanated
products was checked. For this purpose, we took amino-
pyrazole 1e in 8.0 mmol and 3.0 equiv of NH4SCN and 8.0
equiv of H2O2 in 40 mL of water and kept under room
temperature stirring for 20 min. After completion of the
reaction, the corresponding thiocyanated product 3e was
obtained in 78% yield (Scheme 2a). Similarly, aminouracil 4c
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a b
,
Table 2. Substrate Scope for the H2O2-Mediated Thiocyanation of Aminopyrazole and Amino Uracils
a
b
Reaction conditions: NH4SCN (1.5 mmol), 1 or 4 (0.5 mmol), and 30% H2O2 (4.0 mmol) in H2O (3.0 mL), rt, 15−20 min. Yield of the
c
isolated product. For 3k, the reaction time was 6 h.
also provided 79% yield of 5c when performed in 8.0 mmol
scale reaction, as shown in Scheme 2b.
prepared, and the results are summarized in Table 4. Similar to
aminopyrazoles, 5-amino-3-methyl-isothiozole also provided
the corresponding disulfide 10e in good yield. All the products
After developing this methodology for thiocyanation of
diverse aminopyrazole, aminouracil, and enamine derivatives,
next, we wanted to examine the outcome of a one-pot reaction
of aminopyrazole with NH4SCN in the presence of H2O2
followed by treatment with NaOH solution. For this purpose,
we initially took 5-amino-1,3-dimethyl-1H-pyrazole (0.5
mmol), H2O2 (4.0 mmol), and NH4SCN (1.5 mmol) in 3.0
mL of water, and the resultant reaction mixture was stirred for
20 min at room temperature; to this solution, 5.0% (w/v)
NaOH solution (0.3 mL) was added, and the resultant solution
was kept under room temperature stirring for another 1.0 h.
Interestingly, in this reaction, we observed product 10a, a
disulfide of an aminopyrazole derivative, in good yield. Next,
with this interesting observation, we focused to generalize this
one-pot method for the formation of disulfides by varying
aminopyrazole derivatives under similar reaction conditions.
Different aminopyrazole derivatives with alkyl or aryl
substitutes were found suitable for this one-pot disulfide
formation reaction. Next, using this one-pot two-step process,
a set of disulfides of aminopyrazoles such as 10b−10d were
1
were fully characterized by H & 13C NMR and HRMS. In
addition to these, for the unambiguous structure determi-
nation, we recorded single-crystal XRD of 10d.
After having these interesting observations, next we tried to
see the outcome of our one-pot two-step procedure in amino
uracils. To our surprise, when 6-amino-1,3-dimethyluracil was
taken as a substrate and the same reaction procedure was
followed, we observed the corresponding fused aminothiazole
derivative 11a in very good yield instead of any disulfide.
Similar to 6-amino-1,3-dimethyluracil, other aminouracil
derivatives also provided the corresponding uracil-fused 2-
aminobenzothiazoles 11b and 11c in good yields (Table 5).
Six-membered cyclic enaminone, 3-aminocyclohex-2-enone,
also behaved similar to aminouracils and provided the
corresponding fused 2-aminothiazole 11d in good yield.
Finally, we tried to utilize our thiocyanated products for the
preparation of various sulfur-containing products. Thus, first,
we took compound 3e and reacted with an excess amount of
phenyl magnesium bromide, and the corresponding phenyl
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a b
,
Table 3. Substrate Scope for Thiocyanation of Enamine Derivatives
a
b
Reaction conditions: NH4SCN (1.5 mmol), 6 or 8 (0.5 mmol), and 30% H2O2 (8.0 equiv) in H2O (3.0 mL), rt, 15−20 min. Yield of the isolated
product.
Scheme 2. Controlled Experiment for Gram-Scale Synthesis of 3e and 5b
thioether of aminopyrazole 13 was obtained in 65% yield
(Scheme 3a). Then, we performed a reaction of 3e with
sodium azide in the presence of ZnCl2 to prepare a hybrid
thioether having aminopyrazole linked with tetrazole (14), as
shown in Scheme 3a. Next, we have used acyclic enamine
derivative 7a to prepare cyclic product 15a in the presence of
sulfuric acid in the water medium. Likewise, 7b was treated
with sulfuric acid in the water medium, and within 3 h, the
corresponding thiazolone 15b was obtained in 72% yield.
Mechanistically, we believe that H2O2-mediated thiocyana-
tion can go through either path I or path II, as shown in
Scheme 4a. The hydroxyl radical (HO•) generated from H2O2
can abstract one electron from the −SCN anion to form the
SCN radical (I) or dimerized intermediate (II). In the case of
path I, 3-position of aminopyrazole, which acts as a C-
nucleophilic site, attacks intermediate II to form intermediate
III. Finally, a hydroxide ion (generated from abstracting one
electron from the reaction of thiocyanate anion by the
hydroxyl radical) abstracts one H+ from III to provide our
desired product 3e. On the other hand, reaction can also follow
path II. In this case, reaction goes via intermediates IV and V
to provide the desired product 3e. Synthesis of symmetrical
disulfides from the organic thiocyanates in the presence of
bases is known in the literature.18 Based on the literature
reports,18,19 we propose that disulfide formation in the case of
amino pyrazoles takes place by the nucleophilic attack of the
hydroxide ion on the CN functionality of SCN in 3e, which
will provide the thiolate anion. This resultant thiolate anion
subsequently attacks another molecule of thiocyanate to form
an S−S bond, as shown in Scheme 4b.
CONCLUSIONS
■
In summary, we have developed an efficient rapid room
temperature additive- and metal-free methodology for the C−
H thiocyanation of diverse amino (pyrazoles, isothaizole,
isoxazole, and aminouracils) and enamine derivatives using
H2O2 as a benign oxidizing agent. Interestingly, one-pot two-
step reaction of NH4SCN and H2O2 followed by NaOH
addition provides the corresponding disulfides by amino-
pyrazoles, whereas aminouracil and cyclic enamines provide
the corresponding fused 2-aminothiazole derivatives. The
salient features of this work are simple procedure, short
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a b
,
Table 4. One-Pot Two-Step Synthesis of Disulfides
a
Reaction conditions: 1 (0.5 mmol), NH4SCN (1.5 mmol) (i) 30% H2O2 (8.0 equiv) in H2O (3.0 mL), rt, 20−30 min. (ii) NaOH (5%) rt, 1 h.
b
Yield of the isolated product.
a b
,
Table 5. One-Pot Two-Step Synthesis of Fused 2-Aminothiazoles
a
Reaction conditions: NH4SCN (1.5 mmol, 3.0 equiv), 4 (0.5 mmol, 1.0 equiv), (i) H2O2 (8.0 equiv) in H2O (3.0 mL), rt, 20−30 min. (ii) NaOH
b
(5%) rt, 1 h. Yield of the isolated product.
Scheme 3. Synthetic Utility of Thiocyanated Products
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Scheme 4. Plausible Reaction Mechanism for Thiocyanation and Disulfide Formation
{1H} NMR (100 MHz, DMSO-d6): δ 156.9, 136.3, 112.3, 78.9, 38.6.
HRMS (ESI) m/z: [M + H]+ calcd for C5H7N4S, 155.0386; found,
155.0381.
reaction time, wide substrate scope with good to very good
yields, use of H2O2 as a readily available eco-friendly oxidizing
agent, and tunability of the method for the one-pot preparation
of disulfides and aminothiazoles. Gram-scale thiocyanation is
also possible by this method.
1,3-Dimethyl-4-thiocyanato-1H-pyrazol-5-amine (3b). It was
purified by column chromatography [eluent hexane/ethyl acetate =
1
17:3 (v/v)]. Yield 71 mg (84%); white solid; mp 180−182 °C. H
NMR (400 MHz, DMSO-d6): δ 6.14 (s, 2H), 3.47 (s, 3H), 2.07 (s,
3H). 13C {1H} NMR (100 MHz, DMSO-d6): δ 150.6, 148.5, 112.5,
72.8, 34.6, 11.8. HRMS (ESI) m/z: [M + H]+ calcd for C6H9N4S,
169.0542; found, 169.0545.
EXPERIMENTAL SECTION
■
General Information. All the reagents were procured from
commercial sources (Sigma-Aldrich, Merck, and Alfa-Aesar) and used
as such without further purification. Organic extracts were dried over
anhydrous sodium sulfate. Solvents were removed using a rotary
evaporator under reduced pressure. Reactions were monitored by
TLC. Column chromatographic separations were performed using
Merck silica gel (60−120 mesh). Melting points were recorded using
an SRS EZ-Melt automated melting point apparatus by capillary
methods and uncorrected. NMR spectra were recorded in a Bruker
400 MHz spectrometer in CDCl3 or DMSO-d6 with tetramethylsilane
as the internal standard. Chemical shift values are reported in δ values
(ppm) downfield from tetramethylsilane. HRMS analysis was carried
out using a Bruker Impact HD mass spectrometer (Impact HD UHR-
TOF, ESI with positive mode), Agilent 6520 Q-TOF, and XEVO G2-
XS QTOF mass spectrometer. Single-crystal XRD was recorded in a
Bruker AXS (D8 Quest system) X-ray diffractometer.
Experimental Procedure. General Procedure for the Synthesis
of 3a−3j and 5a−5f. In a 10.0 mL round-bottom flask, 0.5 mmol of
aminopyrazole/isoxazole/isothiazole or amino uracil, 1.5 mmol of
NH4SCN, and 3.0 mL of H2O were transferred. To this mixture, 4.0
mmol of 30% H2O2 was added, and the resultant mixture was kept
under constant stirring at ambient temperature. The progress of the
reaction was monitored by TLC. After completion of the reaction, the
reaction mixture was transferred to a separating funnel, and 10.0 mL
of water was added and extracted three times with dichloromethane
(3 × 10.0 mL) for 3a−3j, and for 5a−5f, 3 × 10.0 mL of ethyl acetate
was used. The resultant organic layer was dried over anhydrous
sodium sulfate and concentrated using a rotavap. The crude product
was purified by silica gel column chromatography using a mixture of
hexane−ethyl acetate as the eluent.
3-(tert-Butyl)-1-methyl-4-thiocyanato-1H-pyrazol-5-amine (3c).
It was purified by column chromatography [eluent hexane/ethyl
acetate = 9:1 (v/v)]. White solid; yield 84 mg (80%); mp 101−103
1
°C. H NMR (400 MHz, DMSO-d6): δ 6.11 (s, 2H), 3.49 (s, 3H),
1.32 (s, 9H). 13C {1H} NMR (100 MHz, DMSO-d6): δ 158.5, 152.3,
113.3, 70.8, 35.2, 33.3, 29.6. HRMS (ESI) m/z: [M + H]+ calcd for
C9H15N4S, 211.1012; found, 211.1014.
1-Methyl-3-phenyl-4-thiocyanato-1H-pyrazol-5-amine (3d). It
was purified by column chromatography [eluent hexane/ethyl acetate
1
= 9:1 (v/v)]. Brown solid; yield 98 mg (85%); mp 124−126 °C. H
NMR (400 MHz, DMSO-d6): δ 7.76 (d, J = 8.0 Hz, 2H), 7.47 (t, J =
8.0, 2H), 7.40 (t, J = 8.0 Hz, 1H), 6.36 (s, 2H), 3.62 (s, 3H). 13C
{1H} NMR (100 MHz, DMSO-d6): δ 151.8, 149.7, 132.2, 128.5,
128.2, 127.2, 112.8, 71.9, 35.2. HRMS (ESI) m/z: [M + H]+ calcd for
C11H11N4S, 231.0699; found, 231.0695.
3-Methyl-1-phenyl-4-thiocyanato-1H-pyrazol-5-amine (3e). It
was purified by column chromatography [eluent hexane/ethyl acetate
1
= 9:1 (v/v)]. White solid; yield 93 mg (81%); mp 108−110 °C. H
NMR (400 MHz, DMSO-d6): δ 7.51−7.48 (m, 4H), 7.40−7.34 (m,
1H), 6.32 (s, 2H), 2.19 (s, 3H). 13C {1H} NMR (100 MHz, DMSO-
d6): δ 150.5, 150.3, 138.3, 129.3, 127.1, 123.4, 112.3, 75.1, 11.9.
HRMS (ESI) m/z: [M + H]+ calcd for C11H11N4S, 231.0699; found,
231.0706.
1,3-Diphenyl-4-thiocyanato-1H-pyrazol-5-amine (3f). It was
purified by column chromatography [eluent hexane/ethyl acetate =
19:1 (v/v)]. Saddle brown solid; yield 114 mg (78%) mp 80−82 °C.
1H NMR (400 MHz, CDCl3): δ 7.89 (d, J = 8.0 Hz, 2H), 7.58−7.41
(m, 8H), 4.56 (s, 2H). 13C {1H} NMR (100 MHz, CDCl3): δ 152.9,
149.6, 137.8, 131.4, 129.9, 129.1, 128.7, 128.1, 124.2, 111.3,76.2.
HRMS (ESI) m/z: [M + H]+ calcd for C16H13N4S, 293.0855; found,
293.0857.
1-Methyl-4-thiocyanato-1H-pyrazol-5-amine (3a). It was purified
by column chromatography [eluent hexane/ethyl acetate = 17:3 (v/
v)]. White solid; yield 63 mg (82%); mp 105−107 °C. 1H NMR (400
MHz, DMSO-d6): δ 7.87 (s, 1H), 5.28 (s, 2H), 3.60 (s, 3H). 13C
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1-Phenyl-4-thiocyanato-3-(p-tolyl)-1H-pyrazol-5-amine (3g). It
was purified by column chromatography [eluent hexane/ethyl acetate
= 19:1(v/v)]. Saddle brown semisolid; yield 124 mg (81%). 1H NMR
(400 MHz, DMSO- d6): δ 7.79 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 8.0
Hz, 2H), 7.49 (t, J = 8.0 Hz, 2H), 7.40 (t, J = 8.0 Hz, 1H), 7.29 (d, J =
8.0 Hz, 2H), 4.56 (s, 2H), 2.39 (s, 3H). 13C {1H} NMR (100 MHz,
CDCl3): δ 152.8, 149.6, 138.9, 137.8, 129.8, 129.3, 128.5, 128.4,
127.9, 124.1, 111.4, 75.9, 21.4. HRMS (ESI) m/z: [M + H]+ calcd for
C17H15N4S, 307.1012; found, 307.1014.
1.57−1.48 (m, 2H), 0.84 (q, J = 8 Hz, 6H). 13C {1H} NMR (100
MHz, DMSO-d6): δ 173.3, 156.7, 155.9, 151.4, 92.7, 46.4, 42.6, 21.4,
21.2, 11.6, 11.3. HRMS (ESI) m/z: [M + H]+ calcd for C11H17N4O2S,
269.1067; found, 269.1075.
5-Thiocyanatopyrimidine-2,4,6-triamine (5f). It was purified by
just washing with methanol. Yield 55 mg (60%) white solid; mp 208−
210 °C. 1H NMR (400 MHz, DMSO-d6): δ 6.55 (br s, 4H), 6.02 (br
s, 2H). 13C {1H} NMR (100 MHz, DMSO-d6): δ 163.2, 159.6, 111.8,
63.5 ppm. HRMS (ESI) m/z: [M + H]+ calcd for C5H7N6S,
183.0447; found, 183.04454.
5-Methyl-N-phenyl-4-thiocyanato-1H-pyrazol-3-amine (3h). It
General Procedure for the Synthesis of 7a−h and 9a. In a 10.0
mL round-bottom flask, 0.5 mmol of enamine derivatives (6), 1.5
mmol of NH4SCN, and 3.0 mL of H2O were transferred. To this
mixture, 4.0 mmol of 30% H2O2 was added, and the resultant mixture
was kept under constant stirring at ambient temperature. The
progress of the reaction was monitored by TLC. After completion of
reaction, the reaction mixture was transferred to a separating funnel,
and 10.0 mL of water was added and extracted with 3 × 10.0 mL of
ethyl acetate. The resultant organic layer was dried over anhydrous
sodium sulfate and concentrated using rotavap. Finally, the crude
product was purified by silica gel column chromatography using a
mixture of hexane and ethyl acetate as the eluent.
was purified by column chromatography [eluent hexane/ethyl acetate
= 4:1 (v/v)]. Yield 86 mg (75%), white solid; mp 171−173 °C. H
1
NMR (400 MHz, DMSO- d6): δ 12.60 (s, 1H), 8.25 (s, 1H), 7.54 (d,
J = 8.0 Hz, 2H), 7.20 (t, J = 8.0 Hz, 2H), 6.79 (t, J = 8.0 Hz, 1H),
2.33 (s, 3H). 13C {1H} NMR (100 MHz, DMSO- d6): δ 152.3, 146.8,
144.2, 142.7, 128.5, 119.1, 116.0, 112.1, 81.6, 40.2, 9.7. HRMS (ESI)
m/z: [M + H]+ calcd for C11H11N4S, 231.0699; found, 231.0693.
3-Methyl-4-thiocyanatoisoxazol-5-amine (3i). It was purified by
column chromatography [eluent hexane/ethyl acetate = 9:1(v/v)].
1
Yield 66 mg (85%), white solid; mp 160−162 °C; H NMR (400
MHz, CDCl3): δ 5.29 (br s, 2H), 2.29 (s, 3H). 13C {1H} NMR (100
MHz, CDCl3): δ 170.4, 162.2, 109.9, 70.1, 10.5 ppm. HRMS (ESI)
m/z: [M + H]+ calcd for C5H6N3OS, 156.0226; found, 156.0228.
3-Methyl-4-thiocyanatoisothiazol-5-amine (3j). It was purified by
column chromatography [eluent hexane/ethyl acetate = 9:1 (v/v)].
(E)-4-Amino-3-thiocyanatopent-3-en-2-one (7a). It was purified
by column chromatography [eluent hexane/ethyl acetate = 9:1 (v/
1
v)]. White solid. Yield 115 mg (81%), mp 152−154 °C. H NMR
1
(400 MHz, DMSO-d6): δ 10.56 (br s, 1H), 8.92 (br s, 1H), 2.34 (s,
3H), 2.30 (s, 3H). 13C {1H} NMR (100 MHz, DMSO-d6): δ 195.7,
170.3, 113.8, 84.8, 28.7, 22.4. HRMS (ESI) m/z: [M + H]+ calcd for
C6H9N2OS, 157.0430; found, 157.0433.
Yield 67 mg (78%) brownish solid; mp 104−106 °C. H NMR (400
MHz, CDCl3 + DMSO-d6): δ 6.58 (br s, 2H), 2.32 (s, 3H). 13C {1H}
NMR (100 MHz, CDCl3 + DMSO-d6): δ 175.6, 166.1, 109.8, 88.6,
18.2. HRMS (ESI) m/z: [M + H]+ calcd for C5H6N3S2, 171.9998;
found, 172.0002.
(E)-Methyl 3-Amino-2-thiocyanatobut-2-enoate (7b). It was
purified by column chromatography [eluent hexane/ethyl acetate =
3,5-Dimethyl-1-phenyl-4-thiocyanato-1H-pyrazole (3k). It was
purified by column chromatography [eluent hexane/ethyl acetate =
32:1 (v/v)]. Yield 23 mg (20%) white solid; mp 96−98 °C. 1H NMR
(400 MHz, CDCl3): δ (7.52−7.39 m, 5H), 2.44 (s, 3H), 2.43 (s, 3H).
13C {1H} NMR (100 MHz, CDCl3): δ 152.1, 144.5, 139.2, 129.5,
128.8, 125.1, 110.9, 96.7, 12.1, 11.6. HRMS (ESI) m/z: [M + H]+
calcd for C12H12N3S, 230.0746; found, 230.0755.
1
9:1 (v/v)]. Yield 66 mg (77%); white solid; mp 101−103 °C. H
NMR (400 MHz, CDCl3): δ 9.27 (br s, 1H), 5.72 (br s, 1H), 3.78 (s,
3H), 2.39 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3): δ 168.9,
168.7, 113.5, 75.9, 52.1, 23.5. HRMS (ESI) m/z: [M + H]+ calcd for
C6H9N2O2S, 173.0379; found, 173.0378.
Ethyl 3-Amino-3-phenyl-2-thiocyanatoacrylate (7c). It was
purified by column chromatography [eluent hexane/ethyl acetate =
6-Amino-5-thiocyanatopyrimidine-2,4(1H,3H)-dione (5a). It was
1
19:1 (v/v)]. Yield 92 mg (74%), white solid; mp 98−100 °C. H
purified by washing with methanol. Yield 76 mg (82%) white solid;
1
NMR (400 MHz, CDCl3): δ 9.34 (br s, 1H), 7.51−7.46 (m, 3H),
7.43−741 (m, 2H), 5.61 (br s, 1H), 4.30 (q, J = 8.0 Hz, 2H), 1.39 (t,
J = 8.0 Hz, 3H). 13C {1H} NMR (100 MHz, CDCl3): δ 169.7, 168.8,
136.9, 130.5, 128.9, 127.4, 114.1, 77.5, 61.3, 14.5. HRMS (ESI) m/z:
[M + H]+ calcd for C12H13N2O2S, 249.0692; found, 249.0693.
(E)-3-Amino-1,3-diphenyl-2-thiocyanatoprop-2-en-1-one (7d). It
was purified by column chromatography [eluent hexane/ethyl acetate
mp 358−360 °C. H NMR (400 MHz, DMSO-d6): δ 10.85 (s, 1H),
10.68 (s, 1H), 7.25 (br s, 2H). 13C {1H} NMR (100 MHz, DMSO-
d6): δ 162.1, 157.6, 149.5, 112.5, 65.8. HRMS (ESI) m/z: [M + H]+
calcd for C5H5N4O2S, 185.0128; found, 185.0122.
6-Amino-1-methyl-5-thiocyanatopyrimidine-2,4(1H,3H)-dione
(5b). It was purified by column chromatography [eluent hexane/ethyl
acetate = 7:3 (v/v)]. Yield 83 mg (83%) white solid; mp 312−314
1
1
= 9:1 (v/v)]. Yield 103 mg (73%), white solid; mp 94−96 °C. H
°C. H NMR (400 MHz, DMSO-d6): δ 11.03 (s, 1H), 7.86 (s, 2H),
3.27 (s, 3H). 13C {1H} NMR (100 MHz, DMSO-d6): δ 160.6, 158.6,
149.9, 112.5, 66.2, 30.0. HRMS (ESI) m/z: [M + H]+ calcd for
C6H7N4O2S, 199.0284; found, 199.0287.
NMR (400 MHz, CDCl3): δ 11.18 (br s, 1H), 7.61−7.59 (m, 2H),
7.55−7.52 (m, 5H), 7.46−7.44 (m, 3H), 6.23 (s, 1H). 13C {1H}
NMR (100 MHz, CDCl3): δ 197.7, 172.9, 141.1, 136.8, 130.8, 130.2,
129.1, 128.2, 127.4, 127.1, 114.5, 87.2. HRMS (ESI) m/z: [M + H]+
calcd for C16H13N2OS, 281.0743; found, 281.0745.
6-Amino-1,3-dimethyl-5-thiocyanatopyrimidine-2,4(1H,3H)-
dione (5c). It was purified by column chromatography [eluent
hexane/ethyl acetate = 7:3 (v/v)]. Yield 90 mg (85%) white solid; mp
(E)-Isopropyl 3-Amino-2-thiocyanatobut-2-enoate (7e). It was
purified by column chromatography [eluent hexane/ethyl acetate =
1
302−304 °C. H NMR (400 MHz, DMSO-d6): δ 7.88 (s, 2H), 3.34
1
(s, 3H), 3.15 (s, 3H). 13C {1H} NMR (100 MHz, DMSO-d6): δ
160.2, 157.3, 150.3, 112.4, 66.2, 31.0, 28.3. HRMS (ESI) m/z: [M +
H]+ calcd for C7H9N4O2S, 213.0441; found, 213.0446.
19:1 (v/v)]. Yield 81 mg (81%), white solid; mp 100−102 °C. H
NMR (400 MHz, CDCl3): δ 9.27 (br s, 1H), 5.62 (br s, 1H), 5.03
(sep, J = 8.0 Hz, 1H), 2.37 (s, 3H), 1.32 (d, J = 8.0 Hz, 6H). 13C {1H}
NMR (100 MHz, CDCl3): δ 168.14, 168.10, 113.6, 76.5, 68.4, 23.5,
22.1. HRMS (ESI) m/z: [M + H]+ calcd for C8H13N2O2S, 201.0692;
found, 201.0693.
6-Amino-1,3-diethyl-5-thiocyanatopyrimidine-2,4(1H,3H)-dione
(5d). It was purified by column chromatography [eluent hexane/ethyl
acetate = 8:2 (v/v)]. Yield 95 mg (79%) white solid; mp 172−174
°C. 1H NMR (400 MHz, DMSO-d6): δ 7.91 (s, 2H), 3.95 (q, J = 8.0
Hz, 2H), 3.81 (q, J = 8.0 Hz, 2H), 1.12 (t, J = 8.0 Hz, 3H), 1.07 (t, J =
8.0 Hz, 3H). 13C {1H} NMR (100 MHz, DMSO-d6): δ 159.8, 156.4,
149.7, 112.6, 66.6, 38.9, 36.5, 13.1, 12.9. HRMS (ESI) m/z: [M + H]+
calcd for C9H13N4O2S, 241.0754; found, 241.0756.
3-Amino-2-thiocyanatocyclohex-2-enone (7f). It was purified by
column chromatography [eluent hexane/ethyl acetate = 1:1 (v/v)].
1
Yield 66 mg (78%) white solid; mp 188−190 °C. H NMR (400
MHz, DMSO-d6): δ 8.20 (s, 1H), 7.80 (s, 1H), 2.60 (t, J = 8.0 Hz,
2H), 2.30 (t, J = 8.0 Hz, 2H), 1.83−1.77 (m, 2H). 13C {1H} NMR
(100 MHz, DMSO-d6): δ 189.9, 171.2, 112.5, 86.3, 36.7, 29.9, 20.1.
HRMS (ESI) m/z: [M + H]+ calcd for C7H9N2OS, 169.0430; found,
169.0429.
6-Amino-1,3-dipropyl-5-thiocyanatopyrimidine-2,4(1H,3H)-
dione (5e). It was purified by column chromatography [eluent
hexane/ethyl acetate = 8:2 (v/v)]. Yield 105 mg (78%) white solid;
1
mp 152−154 °C. H NMR (400 MHz, DMSO-d6): δ 8.52 (s, 2H),
3-Amino-5,5-dimethyl-2-thiocyanatocyclohex-2-enone (7g). It
was purified by column chromatography [eluent hexane/ethyl acetate
3.92 (t, J = 8.0 Hz, 2H), 3.77 (m, 2H), 1.66−1.58 (m, 7.5 Hz, 2H),
H
https://dx.doi.org/10.1021/acs.joc.0c01738
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Article
1
= 1:1(v/v)]. Yield 75 mg (76%), white solid; mp 180−182 °C. H
NMR (400 MHz, DMSO-d6): δ 7.91 (br s, 1H), 7.03 (br s, 1H), 2.42
(s, 2H), 2.21 (s, 2H), 0.96 (s, 6H). 13C {1H} NMR (100 MHz,
DMSO-d6): δ 189.8, 168.8, 111.3, 85.9, 50.1, 42.9, 31.1, 27.3. HRMS
(ESI) m/z: [M + H]+ calcd for C9H13N2OS, 197.0743; found,
197.0754.
General Procedure for the Synthesis of 11a−11d. A mixture of
the 6-amino uracil derivative (0.5 mmol), NH4SCN (1.5 mmol), and
3.0 mL of water was transferred to a 25 mL round-bottom flask. To
this mixture, 4.0 mmol of 30% H2O2 was added, and the resultant
mixture was stirred for 20 min. Then, 5% sodium hydroxide solution
(0.3 mL) was added to the reaction mixture and stirred for another
1.0 h. After the completion of the reaction, as monitored by the TLC,
the reaction mixture was filtered off, and the residue was washed with
5.0 × 2.0 mL of water, followed by washing with 2.0 mL of methanol.
Compound 11d was also prepared by the same method just by
replacing 6-aminouracil with 3-aminocyclohex-2-enone.
5,5-Dimethyl-3-morpholino-2-thiocyanatocyclohex-2-enone
(7h). It was purified by column chromatography [eluent hexane/ethyl
acetate = 1:1 (v/v)]. Yield 97 mg (73%), white solid; mp 105−107
°C. 1H NMR (400 MHz, CDCl3): δ 3.83 (t, J = 4.0 Hz, 4H), 3.72 (t, J
= 4.0 Hz, 4H), 2.47 (s, 2H), 2.36 (s, 2H), 1.07 (s, 6H). 13C {1H}
NMR (100 MHz, CDCl3): δ 192.0, 168.2, 112.1, 92.9, 67.1, 50.7,
50.1, 44.8, 31.7, 28.5. HRMS (ESI) m/z: [M + H]+ calcd for
C13H19N2O2S, 267.1162; found, 267.1169.
2-Amino-4,6-dimethylthiazolo[4,5-d]pyrimidine-5,7(4H,6H)-
dione (11a). It was purified by filtration, and the residue was washed
with 5.0 × 2 mL of water, followed by washing with 2.0 mL of
methanol. Yield 88 mg (83%); white solid; mp 362−364 °C. 1H
NMR (400 MHz, DMSO-d6): δ 8.50 (s, 2H), 3.42 (s, 3H), 3.18 (s,
3H). 13C {1H} NMR (100 MHz, DMSO-d6): δ 172.6, 156.4, 155.6,
151.5, 91.9, 31.5, 27.7. HRMS (ESI) m/z: [M + H]+ calcd for
C7H9N4O2S, 213.0441; found, 213.0446.
3-Cyclohexyl-2-imino-5,5-dimethyl-2,3,5,6-tetrahydrobenzo[d]-
thiazol-7(4H)-one (9a). It was purified by column chromatography
[eluent hexane/ethyl acetate = 1:1 (v/v)]. Yield 77 mg (55%), yellow
1
solid; mp 198−200 °C. H NMR (400 MHz, CDCl3): δ 2.61 (br s,
2H), 2.34 (s, 2H), 1.90−1.69 (m, 6H), 1.43−1.34 (m, 2H), 1.26−
1.19 (m, 3H), 1.15 (s, 6H). 13C {1H} NMR (100 MHz, CDCl3): δ
188.2, 164.3, 153.2, 109.3, 60.5, 50.3, 39.4, 34.8, 29.8, 28.7, 26.4, 25.3.
HRMS (ESI) m/z: [M + H]+ calcd for C15H23N2OS, 279.1526;
found, 279.1534.
2-Amino-4,6-diethylthiazolo[5,4-d]pyrimidine-5,7(4H,6H)-dione
(11b). It was purified by filtration, and the residue was washed with
5.0 × 2 mL of water, followed by washing with 2.0 mL of methanol.
1
Yield 92 mg (76%); white solid; mp 172−174 °C. H NMR (400
MHz, DMSO-d6): δ 8.50 (s, 2H), 4.00 (q, J = 8.0 Hz, 2H), 3.84 (q, J
= 8.0 Hz, 2H), 1.17 (t, J = 8.0 Hz, 3H), 1.08 (t, J = 8.0 Hz, 3H). 13C
{1H} NMR (100 MHz, DMSO-d6): δ 173.0, 156.2, 155.3, 150.7, 92.5,
39.9, 35.9, 13.41, 13.23. HRMS (ESI) m/z: [M + H]+ calcd for
C9H13N4O2S, 241.0754; found, 241.0760.
General Procedure for the Synthesis of 10a−10e. A mixture of
aminopyrazole/isothiazole (0.5 mmol), NH4SCN (1.5 mmol), and
3.0 mL of water was transferred to a 15 mL round-bottom flask. To
this mixture, 4.0 mmol of 30% H2O2 was added, and the resultant
mixture was stirred for 20 min. Then, 5% sodium hydroxide solution
(0.3 mL) was added to the reaction mixture and stirred for another
1.0 h. After the completion of the reaction, as monitored by the TLC,
the reaction mixture was filtered off and washed with 5.0 × 2 mL of
water followed by 10.0 mL of methanol. All the compounds were
purified by silica gel column chromatography.
2-Amino-4,6-dipropylthiazolo[5,4-d]pyrimidine-5,7(4H,6H)-
dione (11c). It was purified by filtration, and the residue was washed
with 5.0 × 2 mL of water, followed by washing with 2.0 mL of
1
methanol. Yield 103 mg (77%); white solid mp 152−154 °C. H
NMR (400 MHz, DMSO-d6): δ 8.50 (s, 2H), 3.91 (t, J = 8.0 Hz, 2H),
3.77 (t, J = 8.0 Hz, 2H), 1.67−1.58 (m, 2H), 1.57−1.47 (m, 2H),
0.84 (q, J = 8.0 Hz, 6H). 13C {1H} NMR (100 MHz, DMSO-d6): δ
172.9, 156.3, 155.5, 151.0, 92.3, 46.0, 42.2, 21.0, 20.8, 11.2, 10.9.
HRMS (ESI) m/z: [M + H]+ calcd for C11H17N4O2S, 269.1067;
found, 269.1072.
4,4′-Disulfanediylbis(1,3-dimethyl-1H-pyrazol-5-amine) (10a). It
was purified by column chromatography [eluent hexane/ethyl acetate
= 17:3 (v/v)]. Yield 103 mg (72%); saddle brown solid; mp 140−142
1
°C. H NMR (500 MHz, DMSO-d6): δ 5.51 (s, 4H), 3.44 (s, 6H),
1.70 (s, 6H). 13C {1H} NMR (125 MHz, DMSO-d6): δ 149.9, 149.1,
90.3, 34.5, 11.4. HRMS (ESI) m/z: [M + H]+ calcd for C10H17N6S2,
285.0951; found, 285.0947.
2-Amino-5,6-dihydrobenzo[d]thiazol-7(4H)-one (11d). It was
purified by filtration, and the residue was washed with 5.0 × 2 mL
of water, followed by washing with 2.0 mL of methanol. Yield 68 mg
4,4′-Disulfanediylbis(3-(tert-butyl)-1-methyl-1H-pyrazol-5-
amine) (10b). It was purified by column chromatography [eluent
hexane/ethyl acetate = 17:3 (v/v)]. Yield 68 mg (74%); reddish solid;
1
(81%); white solid; mp 262−264 °C. H NMR (400 MHz, DMSO-
d6): δ 8.09 (br s, 2H), 2.66 (t, J = 8.0 Hz, 2H), 2.35 (t, J = 8.0 Hz,
2H), 2.06−1.87 (m, 2H). 13C {1H} NMR (100 MHz, DMSO-d6): δ
189.7, 173.6, 168.3, 118.6, 36.8, 26.8, 22.5. HRMS (ESI) m/z: [M +
H]+ calcd for C7H9N2OS, 169.0430; found, 169.0432.
1
mp 155−157 °C. H NMR (400 MHz, CDCl3): δ 3.70 (br s, 4H),
3.56 (s, 6H), 1.37 (s, 18H). 13C {1H} NMR (100 MHz, CDCl3): δ
160.7, 150.2, 92.2, 34.7, 33.8, 29.9 ppm. HRMS (ESI) m/z: [M + H]+
calcd for C16H29N6S2, 369.1890; found, 369.1891.
Procedure for the Synthesis of 3-Methyl-1-phenyl-4-(phenyl-
thio)-1H-pyrazol-5-amine (13). 3-methyl-1-phenyl-4-thiocyanato-
1H-pyrazol-5-amine 3e (115 mg, 0.5 mmol) and 3.0 mL of dry
THF were transferred to a two-neck 25 mL round-bottom flask fitted
with a condenser and airtight septums. The temperature of the
reaction mixture was kept as 0 °C using an ice bath. Phenyl
magnesium bromide (1.0 M) in THF (1.46 mL, 3.0 equiv) was
transferred dropwise using a syringe to the reaction mixture under
constant stirring conditions. After addition, the ice bath was removed,
and temperature was allowed to reach 25 °C. The mixture was kept
under stirring conditions at this temperature for 6.0 h. After
completion of the reaction, saturated solution of ammonium chloride
(5.0 mL) was added to the reaction mixture and extracted with
dichloromethane (3 × 5.0 mL). The combined organic layers were
dried over anhydrous sodium sulfate and filtered, and the solvent was
evaporated under reduced pressure. The residue was purified by
column chromatography [eluent hexane/ethyl acetate = 19:1 (v/v)].
Yield 92 mg (65%); dark red semisolid. 1H NMR (400 MHz,
CDCl3): δ 7.60 (d, J = 8.0 Hz, 2H), 7.49 (t, J = 8.0 Hz, 2H), 7.35 (t, J
= 8.0 Hz, 1H), 7.24 (t, J = 8.0 Hz, 2H), 7.12−7.10 (m, 3H), 4.22 (s,
2H), 2.24 (s, 3H). 13C {1H} NMR (100 MHz, CDCl3): δ 153.3,
148.6, 138.8, 138.4, 129.7, 129.1, 127.6, 125.2, 125.1, 123.5, 87.9,
12.4. HRMS (ESI) m/z: [M + H]+ calcd for C16H16N3S, 282.1059;
found, 282.1061.
4,4′-Disulfanediylbis(1-methyl-3-phenyl-1H-pyrazol-5-amine)
(10c). It was purified by column chromatography [eluent hexane/
ethyl acetate = 17:3 (v/v)]. Yield 80 mg (78%); saddle brown solid;
1
mp 176−178 °C. H NMR (400 MHz, CDCl3): δ 7.49−7.43 (m,
8H), 7.34 (t, J = 8.0 Hz, 2H), 4.20 (s, 4H), 2.17 (s, 6H). 13C {1H}
NMR (100 MHz, CDCl3): δ 152.7, 148.7, 138.5, 129.8, 127.7, 123.5,
94.2, 12.1. HRMS (ESI) m/z: [M + H]+ calcd for C20H21N6S2,
409.1264; found, 409.1278.
4,4′-Disulfanediylbis(3-methyl-1-phenyl-1H-pyrazol-5-amine)
(10d). It was purified by column chromatography [eluent hexane/
ethyl acetate = 17:3 (v/v)]. Yield 77 mg (75%); saddle brown solid;
1
mp 140−142 °C. H NMR (400 MHz, CDCl3): δ 7.50−7.43 (m,
8H), 7.34 (t, J = 8.0 Hz, 2H), 4.19 (s, 4H), 2.18 (s, 6H). 13C {1H}
NMR (100 MHz, CDCl3): δ 152.7, 148.8, 138.5, 129.8, 127.7, 123.5,
94.21, 12.11 ppm. HRMS (ESI) m/z: [M + H]+ calcd for
C20H21N6S2, 409.1264; found, 409.1276.
4,4′-Disulfanediylbis(3-methylisothiazol-5-amine) (10e). It was
purified by column chromatography [eluent hexane/ethyl acetate =
1
17:3 (v/v)] yield 50 mg (69%); yellow solid; mp 222−224 °C. H
NMR (400 MHz, DMSO-d6): δ 7.16 (s, 4H), 1.82 (s, 6H). 13C {1H}
NMR (100 MHz, DMSO-d6): δ 175.4, 167.4, 103.6, 17.7 ppm.
HRMS (ESI) m/z: [M + H]+ calcd for C8H11N4S4, 290.9861; found,
290.9867.
I
https://dx.doi.org/10.1021/acs.joc.0c01738
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Article
Procedure for the Preparation of 4-((2H-Tetrazol-5-yl)thio)-3-
methyl-1-phenyl-1H-pyrazol-5-amine (14). 3-methyl-1-phenyl-4-
thiocyanato-1H-pyrazol-5-amine 3e (115 mg, 0.5 mmol), ZnCl2
(0.5 mmol), and NaN3 (0.6 mmol) were taken in an oven-dried
10.0 mL round-bottom flask and flushed with N2 gas. To this mixture,
2.0 mL of isopropanol was then injected using a syringe. The resulting
mixture was heated to 50 °C using an oil bath and kept under
constant stirring for 3 h. After cooling to room temperature, the
solvent was evaporated under reduced pressure. After that, 5% NaOH
(5.0 mL) was added, and the mixture was stirred for 20 min, until all
the precipitates had dissolved and a suspension of Zn(OH)2 had
formed. The suspension was filtered, and the solid was washed with
5% NaOH (5.0 mL). Next, pH of the filtrate was adjusted to 1.0 by
adding conc. HCl, which caused the tetrazole product to precipitate.
The tetrazole was filtered, washed with 9% HCl (2 × 5.0 mL)
followed by 2 × 5.0 mL of water, and dried. Yield 112 mg (82%);
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c01738
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Authors are grateful to IIT Patna for providing the general
facilities to carry out this work. D.A. and A.K.P. are thankful to
IIT Patna for their research fellowships. We are also thankful to
SAIF IIT Patna for the single-crystal XRD facility and
Chemical and Biochemical Department of IIT Patna and
Chemistry Department, IIT Ropar, for providing us HRMS
data.
1
white solid, mp 201−203 °C. H NMR (400 MHz, DMSO-d6): δ
7.68 (d, J = 8.0 Hz, 2H), 7.37−7.28 (m, 3H), 6.05 (br s, 2H), 3.65 (s,
3H). 13C {1H} NMR (100 MHz, DMSO-d6): δ 152.6, 150.3, 133.4,
128.7, 128.3, 127.4 76.3, 35.6. HRMS (ESI) m/z: [M + H]+ calcd for
C11H12N7S, 274.0869; found, 274.0873.
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Yield 57 mg (72%) white solid; mp 211−213 °C. H NMR (400
MHz, DMSO-d6): δ 11.91 (s, 1H), 2.39 (s, 3H), 2.35 (s, 3H). 13C
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c01738.
■
sı
NMR spectra for all product compounds and crystal
structure information of 10d (PDF)
Crystal structure information of the products (CIF)
AUTHOR INFORMATION
Corresponding Author
■
Lokman H. Choudhury − Department of Chemistry, Indian
Institute of Technology Patna, Patna 801106, India;
orcid.org/0000-0003-1735-1985; Email: lokman@
iitp.ac.in, lokman.iitp@gmail.com
Authors
Danish Ali − Department of Chemistry, Indian Institute of
Technology Patna, Patna 801106, India
Anoop Kumar Panday − Department of Chemistry, Indian
Institute of Technology Patna, Patna 801106, India
J
https://dx.doi.org/10.1021/acs.joc.0c01738
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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