Hypervalent Iodine(III) Mediated Synthesis of 3-Substituted 5-Amino-1,2,4-thiadiazoles through Intramolecular Oxidative S-N Bond Formation

Article abstract of DOI:10.1021/acs.joc.6b01199

An efficient synthesis of 3-substituted-5-arylamino-1,2,4-thiadiazoles through intramolecular oxidative S-N bond formation of imidoyl thioureas by phenyliodine(III) bis(trifluoroacetate) is reported. The protocol features a metal-free approach, broad subs

Full text of DOI:10.1021/acs.joc.6b01199

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Article
Hypervalent Iodine(III) Mediated Synthesis of 3-Substituted 5-Amino-1,2,4-
thiadiazoles through Intramolecular Oxidative S-N Bond Formation
Arumugam Mariappan, Kandasamy Rajaguru, Noufal Merukan
Chola, Shanmugam Muthusubramanian, and Nattamai Bhuvanesh
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01199 • Publication Date (Web): 05 Jul 2016
Downloaded from http://pubs.acs.org on July 7, 2016
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Hypervalent Iodine(III) Mediated Synthesis of
3-Substituted 5-Amino-1,2,4-thiadiazoles through Intramolecular
Oxidative S-N Bond Formation
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Arumugam Mariappan,† Kandasamy Rajaguru,† Noufal M C,† Shanmugam
Muthusubramanian,†,* and Nattamai Bhuvanesh#
†Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University,
Madurai - 625 021, India.
#X-ray Diffraction Laboratory, Department of Chemistry, Texas A & M University,
College Station, Texas, TX 77842, USA.
Abstract
An efficient synthesis of 3-substituted-5-arylamino-1,2,4-thiadiazoles through
intramolecular oxidative S-N bond formation of imidoyl thioureas by phenyliodine(III)
bis(trifluoroacetate) is reported. The protocol features metal free approach, broad substrate scope
and very short reaction times, good to excellent yields and simple starting materials.
Keywords: 1,2,4 -Thiadiazole; phenyliodine(III) bis(trifluoroacetate); hypervalent iodine(III); oxidative
cyclisation.
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Introduction
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Efficient and convenient procedures for the synthesis of heterocycles through the
heteroatom-heteroatom bond [N-X bond (X= N, O, S)] formation are still in high demand as only
limited examples are available in the literature for the N-X1-3 bond formation compared to C-C and
C-X bond formation processes. The available metal catalyzed protocols for N-X bond formation
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have their own disadvantages, the metal contamination in the desired product and harsh reaction
1d, 5
conditions being the main limitations.4 Some metal free approaches
have been developed for
the N-X bond formation, in which hypervalent iodine (III) reagents have turned out to be good
candidates owing to their environmentally benign nature, low cost and strong oxidizing power.6
Hypervalent iodine (III) reagents have been employed in the construction of C-C,7 C-X8 and
N-X1a, b, 9-11 (X= N, O, S) bond formation protocols. A careful literature survey reveals that only
very few reports describe the synthesis of heterocycles through the S-N bond formation using
iodine(III) reagents.11
1,2,4-Thiadiazole is an important heterocyclic core with a broad spectrum of applications as
a pharmacophore and its derivatives serve as pesticides and corrosion inhibitors.12 In particular, the
substituted 1,2,4-thiadiazoles have been reported to have a wide spectrum of biological activity
including antibacterial,13 anti-inflammatory,14 antiulcerative,15 anti-rheumatic16 and antidiabetic.17
In view of this importance, numerous methodologies have been developed to construct this
skeleton. Among them, the simple oxidative dimerization of thio amides using various oxidants is
very common.18 Smith et al. reported the synthesis of 1,2,4-Thiadiazoles by thermolysis of N3-
thiocarbamoylamidrazone ylides.19 Dürüst et al. reported a cyclocondensation reaction of
amidoximes with N-substituted thioureas in the presence of KF/Al2O3, but the reaction required
more time even at reflux temperature.20 Wehn et al. reported the synthesis of 3-amino-1,2,4-
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thiadiazoles via a palladium catalyzed Suzuki-Miyaura coupling reaction.21 Many approaches have
been reported to construct 1,2,4-thiadiazole skeleton from imidoyl thioureas.22-26 Kurzer and Tertiak
have employed hydrogen peroxide to prepare 3-alkyl(or aryl)-5-alkyl(or aryl)-amino-1,2,4-
thiadiazoles from imidoyl thioureas.27 Kim et al. developed a copper catalyzed synthesis of 3-
substituted-5-amino-1,2,4-thiadiazoles through intramolecular oxidative cyclisation.28 In
continuation of our efforts on the development of useful synthetic methodologies for the
construction of heterocycles through mild and eco-friendly protocols using hypervalent iodine (III)
reagents,29 we present an efficient and mild approach for the synthesis of 3-substituted-5-
arylamino-1,2,4-thiadiazoles in a very short reaction time at room temperature.
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Scheme 1. Synthesis of 3-substituted-5-amino-1,2,4-thiadiazoles.
Results and Discussion
We initially tested hypervalent iodine (III) reagent, phenyl iodine(III) diacetate (PIDA), for
the oxidative cyclisation of imidoyl thiourea 1a, which has been obtained by the reaction of amidine
and phenylisothiocyanate. To our delight, the reaction got completed in 5 minutes yielding the
expected product 2 (Scheme 1) in 70 % yield in THF (Table 1, entry 1). Encouraged by this result,
we studied this conversion with different hypervalent iodine reagents such as 2-iodoxy benzoic
acid, Dess Martin periodinane and phenyliodine(III) bis(trifluoroacetate) (Table 1, entries 2, 3 & 4).
We also employed other oxidants such as ceric ammonium nitrate, DDQ, potassium perdisulfate
and oxone. The yields were good with oxone and DDQ (Table 1, entries 5 & 8), but relatively poor
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Table 1. Optimisation of reaction conditions.a
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Entry
oxidant
solventb
Time
(mins)
5
Yield (%)c
1
2
PIDA
DMP
IBX
THF
THF
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76
73
80
68
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47
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65
70
83
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3
5
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THF
4
PIFA
Oxone
CAN
K2S2O8
DDQ
PIFAd
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
THF
5
THF
6
THF
7
THF
8
THF
9
THF
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DMF
MeOH
DCE
MeCN
1,4-Dioxane
TFA
aReaction conditions: Reactant 1 (1.0 mmol), oxidant 2 (1.1 mmol), solvent (3 mL) - stirred at room
temperature for 3-5 mins. bAbbreviations used in the table: PIDA = phenyl iodine(III) diacetate; DMP = Dess
Martin periodinane; IBX = 2-iodoxy benzoic acid; PIFA = phenyliodine(III) bis(trifluoroacetate); CAN = ceric
ammonium nitrate; DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; DCE = 1,2-dichloroethane; THF =
tetrahydrofuran; MeCN = acetonitrile; DMF = N, N-dimethylformamide; TFA = trifluroacetic acid.
cIsolated yield. dOxidant 2 (2.2 mmol).
with ceric ammonium nitrate and potassium perdisulfate (Table 1, entries 5 & 6). Among all the
oxidants investigated, PIFA was found to be the best choice (Table 1, entry 4), though the yield
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Table 2. Synthesised compounds: 2a-2z.
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was equally good with DMP (Table 1, entry 2). Increasing the oxidant amount had negative
impact on the reaction (Table 1, entry 9) resulting in decreased yield of the product. Though the
yield was relatively good with all the polar solvents (Table 1, entry 10, 11, 13 & 15), the best
solvent identified was dichloroethane (Table 1, entry 12). With the optimized reaction conditions in
hand, we explored the substrate scope of the reaction. The reaction proceeded well with substrates
having both electron-withdrawing as well as electron-donating groups in the aryl rings.
Subsequently, we varied the amidine part with heteroaryl rings as well resulting in good yields of 2.
A library of synthesized compounds is listed in Table 2. The structure of products 2 were
unambiguously assigned by spectral and analytical data, and that of 2f was confirmed by single
crystal X-ray analysis (See supporting information).30
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The scalability of the reaction has been tested with three compounds (Scheme 2) and the
results are encouraging.
Scheme 2. Gram- scale synthesis.
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Scheme 3. One-pot synthesis of 3-substituted-5-amino-1,2,4-thiadiazoles.
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An attempt to carry out this oxidative cyclisation in a one pot fashion by allowing amidine 3
to react with phenylisothiocyanate 4 followed by the addition of the hypervalent iodine (III) reagent
in the same reaction vessel did not affect the yield significantly (Scheme 3). Under the optimized
reaction conditions, when the control experiments were carried out with radical scavengers like
TEMPO (2,2,6,6-tetramethylpiperdine-1-oxide) and hydroquinone, no considerable effect was
observed ruling out the radical mechanism favoring the ionic mechanism (Scheme 4).
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Scheme 4. Control experiments
Radical scavenger (mmol)
TEMPO(1.5)
Yield (%)
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Hydroquinone(1.5)
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Based on this and the previous literature report,1c a mechanism has been proposed for the
formation of 2 as depicted in Scheme 5. The imidoyl thiourea reacts with PIFA to form an
intermediate A, followed by the nucleophilic attack on the sulfur atom by the NH-group with the
removal of trifluoro acetic acid and iodobenzene resulting in the required product 2.
Scheme 5. Proposed mechanism for the intramolecular oxidative S-N bond formation.
Conclusion
In summary, we have developed an efficient protocol for the synthesis of 3-substituted-5-
amino-1,2,4-thiadiazoles through intramolecular oxidative S-N bond formation by hypervalent
iodine (III) reagent, PIFA.
Experimental Section
General methods
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All solvents were purchased from commercial sources and used without further purification. The
melting points were measured in open capillary tubes and are uncorrected. Nuclear Magnetic
Resonance (1H and 13C NMR) spectra were recorded on a 300 MHz spectrometer in CDCl3 and
DMSO-D6 using TMS as an internal standard. Chemical shifts are reported in parts per million (),
coupling constants (J values) are reported in Hertz (Hz) and spin multiplicities are indicated by the
following symbols: s (singlet), d (doublet), t (triplet), sept (septet), m (multiplet), bs (broad singlet),
bd (broad doublet). 13C NMR spectra were routinely run with broadband decoupling. Pre coated
silica gel on aluminum plates were used for TLC analysis with a mixture of petroleum ether (60-
80oC) and ethyl acetate as eluent. Elemental analyses were performed on an Elemental CHNS
analyzer.
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Synthesis of N-(pyridin-2-yl)benzo[d]thiazol-2-amines (2a-2z):
General procedure
A mixture of N-(phenylcarbamothioyl)benzimidamide 1a ( 255 mg, 1.0 mmol) and PhI(OCOCF3)2
(430 mg, 1.1 mmol) was taken in a 10 ml round bottom flask in 1,2-dichloroethane (3 mL) and
stirred at room temperature for 3 minutes. The completion of the reaction was monitored by TLC.
After the completion of the reaction, the solvent was removed. Then the reaction mass was washed
with sodium bicarbonate solution and extracted with dichloromethane (3 times). After drying over
sodium sulfate, dichloromethane was removed under vacuum. Crude product was purified by
column chromatography using petroleum ether − ethyl acetate (70: 30) as the eluent to afford
compound 2a.
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Characterization data for compounds (2a-2z)
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N,3-Diphenyl-1,2,4-thiadiazol-5-amine (2a).26 Isolated as white solid ( 210 mg, 83% ); mp 170 –
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173oC; IR (KBr): ν = 3231, 2967, 1602, 1566, 1453 cm-1; H NMR (300 MHz, CDCl3) δ 8.64 (s,
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1H), 8.22 – 8.20 (m, 2H), 7.45 – 7.41 (m, 3H), 7.39 – 7.36 (m, 2H), 7.21 (d, J = 7.7 Hz, 2H), 7.15
13
(t, J = 7.4 Hz, 1H). C NMR (75 MHz, CDCl3) δ 180.8, 169.3, 139.1, 132.8, 130.1, 129.8, 128.6,
128.0, 124.3, 118.4. ESI-MS m/z calcd [M+H]+ 253.07, found 254.12.
N-(4-Chlorophenyl)-3-phenyl-1,2,4-thiadiazol-5-amine (2b).26 Isolated as white solid (232 mg,
o
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81% ); mp 194 – 196 C; IR (KBr): ν = 3222, 3080, 1604, 1560, 1490 cm-1; H NMR (300 MHz,
CDCl3) δ 10.31 (s, 1H), 8.26 – 8.22 (m, 2H), 7.58 (d, J = 8.8 Hz, 2H), 7.47- 7.44 (m, 3H), 7.35 –
7.32 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 178.9, 168.9, 138.4, 132.8, 129.5, 128.7, 128.0, 127.5,
127.0, 118.8.
N-(4-Iodophenyl)-3-phenyl-1,2,4-thiadiazol-5-amine (2c). Isolated as light brown solid ( 302 mg,
o
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80% ) ; mp 180 – 183 C; IR (KBr): ν =3220, 3068, 1594, 1551, 1458, 714 cm-1; H NMR (300
MHz, CDCl3+DMSO-D6) δ 10.17 (s, 1H), 8.24 – 8.21 (m, 2H), 7.66 (d, J = 8.8 Hz, 2H), 7.46 – 7.44
(m, 3H), 7.38 (d, J = 8.6 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 178.8, 168.9, 139.5, 137.5, 132.7,
129.5, 128.0, 127.5, 119.5, 84.9. Anal. Calcd for: C14H10IN3S: C, 44.34; H, 2.66; N, 11.08 %.
Found: C, 44.32; H, 2.69; N, 11.11%. ESI-MS m/z calcd [M+H]+ 379.96, found 380.01.
N-(4-Fluorophenyl)-3-phenyl-1,2,4-thiadiazol-5-amine (2d). Isolated as white solid ( 207 mg, 79%
1
); mp 170 – 173oC; IR (KBr): ν =3228, 3080, 1597, 1548, 1466 cm-1; H NMR (300 MHz,
CDCl3+DMSO-D6) δ 10.17 (s, 1H), 8.25 – 8.22 (m, 2H), 7.60 – 7.55 (m, 2H), 7.47 – 7.44 (m, 3H),
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7.08 (t, J = 8.7 Hz, 2H). C NMR (75 MHz, CDCl3) δ 179.9, 169.2, 158.4(d, JC-F = 241.5Hz)
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136.2, 133.1, 129.6, 127.9, 119.6(d, JC-F = 8.5Hz), 115.6 (d, JC-F = 22.5Hz). Anal. Calcd for:
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C14H10FN3S: C, 61.98; H, 3.72; N, 15.49 %. Found: C, 61.89; H, 3.68; N, 15.42 %.
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3-Phenyl-N-(p-tolyl)-1,2,4-thiadiazol-5-amine (2e). Isolated as off-white solid (225 mg, 85% ); mp
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o
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120 – 123 C; IR (KBr): ν = 3234, 3085, 1605, 1564, 1512 cm-1; H NMR (300 MHz, CDCl3) δ
8.69 (s, 1H), 8.20 – 8.17 (m, 2H), 7.43 – 7.41 (m, 3H), 7.17 (d, J = 8.2 Hz, 2H), 7.10 (d, J = 8.3 Hz,
13
2H), 2.34 (s, 3H). C NMR (75 MHz, CDCl3) δ 181.7, 169.3, 136.7, 134.4, 132.9, 130.3, 130.1,
128.5, 127.9, 119.0, 20.8. Anal. Calcd for: C15H13N3S: C, 67.39; H, 4.90; N, 15.72 %. Found: C,
67.43; H, 4.87; N, 15.76 %. ESI-MS m/z calcd [M+H]+ 268.08, found 268.14.
3-Phenyl-N-(o-tolyl)-1,2,4-thiadiazol-5-amine (2f).26 Isolated as white solid ( 228 mg, 86% ); mp
168 – 171oC; IR (KBr): ν = 3218, 3078, 1605, 1559, 1486 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.17
– 8.13 (m, 2H), 8.04 (bs, 1H), 7.46 (d, J = 7.6 Hz, 2H), 7.41 – 7.39 (m, 2H), 7.35 – 7.26 (m, 2H),
13
7.18 (t, J = 7.4 Hz, 1H), 2.34 (s, 3H). C NMR (75 MHz, CDCl3) δ 183.0, 169.4, 137.8, 132.8,
131.4, 130.7, 130.0, 128.4, 127.8, 127.5, 126.2, 121.2, 17.6.
3-Phenyl-N-(m-tolyl)-1,2,4-thiadiazol-5-amine (2g). Isolated as off-white solid ( 220 mg, 83% );
mp 110 – 113 oC; IR (KBr): ν = 3228, 3089, 1596, 1548, 1476 cm-1; 1H NMR (300 MHz, CDCl3) δ
8.54 (s, 1H), 8.10 (dd, J = 8.7, 0.9 Hz, 2H), 7.47 (d, J = 7.9 Hz, 1H), 7.38 – 7.31 (m, 4H), 7.25 –
7.27 (m, 1H), 7.20 – 7.15 (m, 1H), 2.29 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 181.1, 169.2, 139.9,
139.1, 132.8, 130.1, 129.5, 128.5, 128.0, 125.1, 119.5, 115.2, 21.4. Anal. Calcd for C15H13N3S: C,
67.39; H, 4.90; N, 15.72 %. Found: C, 67.42; H, 4.95; N, 15.69 %.
N-(4-Ethylphenyl)-3-phenyl-1,2,4-thiadiazol-5-amine (2h). Isolated as white solid ( 223 mg, 80% );
mp 140 – 143 oC; IR (KBr): ν = 3223, 3070, 1596, 1555, 1513 cm-1; 1H NMR (300 MHz, CDCl3) δ
8.32 (s, 1H), 8.22 – 8.19 (m, 2H), 7.68 – 7.44 (m, 3H), 7.24 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.5 Hz,
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2H), 2.66 (q, J=7.5 Hz, 2H), 1.26 (t, J = 7.6 Hz, 3H). C NMR (75 MHz, CDCl3) δ 181.2, 169.4,
140.8, 136.9, 133.1, 130.0, 129.1, 128.5, 128.0, 118.9, 28.0, 15.2. Anal. Calcd for C16H15N3S: C,
68.30; H, 5.37; N, 14.93 %. Found: C, 68.27; H, 5.39; N, 14.97 %. ESI-MS m/z calcd [M+H]+
282.10, found 282.33.
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N-(4-Isopropylphenyl)-3-phenyl-1,2,4-thiadiazol-5-amine (2i). Isolated as white solid ( 246 mg,
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84% ); mp 130 – 132 C; ν = 3216, 3092, 1601, 1560, 1520, 1453 cm-1; H NMR (300 MHz,
CDCl3) δ 8.42 (s, 1H), 8.19 (d, J = 5.3 Hz, 2H), 7.43 (d, J = 2.1 Hz, 3H), 7.26 (d, J = 7.8 Hz, 2H),
7.16 (d, J = 8.0 Hz, 2H), 2.98 – 2.83 (m, 1H), 1.26 (d, J = 6.7 Hz, 6H). 13C NMR (75 MHz, CDCl3)
δ 181.4, 169.1, 145.4, 136.9, 132.7, 130.1, 128.5, 128.0, 127.7 119.0, 33.5, 23.9. Anal. Calcd for:
C17H17N3S: C, 69.12; H, 5.80; N, 14.22 %. Found: C, 69.16; H, 5.77; N, 14.27 %. ESI-MS m/z
calcd [M+H]+ 296.11, found 296.33.
N-(2,5-Dimethylphenyl)-3-phenyl-1,2,4-thiadiazol-5-amine (2j). Isolated as white solid ( 234 mg,
o
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80% ); mp 135 – 137 C; IR (KBr): ν = 3227, 3026, 1586, 1548, 1442 cm-1; H NMR (300 MHz,
CDCl3) δ 8.43 (s, 1H), 8.10 (dd, J = 7. 9, 1.6 Hz, 2H), 7.42 – 7.31 (m, 4H), 7.14 (d, J = 7.7 Hz, 1H),
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6.99 (d, J = 7.6 Hz, 1H), 2.37 (s, 3H), 2.25 (s, 3H). C NMR (75 MHz, CDCl3) δ 183.1, 169.6,
137.5, 137.5, 132.9, 131.3, 129.9, 128.4, 127.8, 127.5, 127.0, 121.9, 21.1, 17.2. Anal. Calcd for:
C16H15N3S: C, 68.30; H, 5.37; N, 14.93 %. Found: C, 68.33; H, 5.39; N, 14.90 %. ESI-MS m/z
calcd [M+H]+ 282.10, found 282.17.
N-(4-Methoxyphenyl)-3-phenyl-1,2,4-thiadiazol-5-amine (2k). Isolated as white solid ( 196 mg,
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73% ); mp 116 – 118 C; IR (KBr): ν = 3230, 3079, 1603, 1548, 1512, 1421 cm-1; H NMR (300
MHz, CDCl3+DMSO-D6) δ 9.94 (s, 2H), 8.22 – 8.20 (m, 2H), 7.46 – 7.43 (m, 5H), 6.93 (d, J = 8.9
Hz, 2H), 3.82 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 181.3, 169.3, 156.2, 133.1, 129.7, 128.2,
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127.8, 127.1, 120.8, 114.6, 55.4. Anal. Calcd for: C15H13N3OS : C, 63.58; H, 4.62; N, 14.83 %.
Found: C, 63.52; H, 4.66; N, 14.78 %.
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4-((3-Phenyl-1,2,4-thiadiazol-5-yl)amino)benzonitrile (2l). Isolated as white solid ( 196 mg, 71% );
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mp 208 – 210 C; IR (KBr): ν = 3230, 3091, 2234, 1602, 1560, 1428 cm-1; H NMR (300 MHz,
CDCl3+DMSO-D6) δ 10.91 (s, 1H), 8.23 – 8.21 (m, 2H), 7.80 (d, J = 8.7 Hz, 2H), 7.63 (d, J = 8.7
Hz, 2H), 7.45 – 7.42 (m, 3H). 13C NMR (75 MHz, CDCl3) δ 178.2, 169.3, 143.4, 133.1, 132.7,
129.8, 128.2, 127.7, 119.0, 117.4, 104.4. Anal. Calcd for: C15H10N4S: C, 64.73; H, 3.62; N, 20.13
%. Found: C, 64.70; H, 3.66; N, 20.08 %. ESI-MS m/z calcd [M+H]+ 279.06, found 279.14.
3-((3-Phenyl-1,2,4-thiadiazol-5-yl)amino)benzonitrile (2m).26 Isolated as yellow solid ( 213 mg,
77% ); mp 223 – 226 C; IR (KBr): ν = 3236, 2238, 1599, 1540, 1449 cm-1; H NMR (300 MHz,
CDCl3+DMSO-D6) δ 10.61 (s, 1H), 8.27 - 8.24 (m, 2H), 8.10 (s, 1H), 7.91 (dd, J = 7.9, 1.7 Hz,
1H), 7.50 – 7.45 (m, 4H), 7.33 (d, J = 6.3 Hz, 1H). 13C NMR (75 MHz, CDCl3+DMSO-D6) δ 178.6,
169.1, 140.5, 132.6, 129.7, 129.7, 128.2, 127.6, 125.5, 121.5, 120.3, 118.5, 112.4.
o
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Methyl 4-((3-phenyl-1,2,4-thiadiazol-5-yl)amino)benzoate (2n). Isolated as white solid ( 216 mg,
70% ); mp 179 – 182oC; IR (KBr): ν = 3228, 3068, 1720, 1602, 1556, 1432 cm-1; H NMR (300
1
MHz, CDCl3) δ 10.62 (s, 1H), 8.27 – 8.26 (m, 2H), 8.07 (d, J = 7.4 Hz, 2H), 7.69 (d, J = 7.5 Hz,
13
2H), 7.48 – 7.46 (m, 3H), 3.91 (s, 3H). C NMR (75 MHz, CDCl3) δ 178.2, 168.6, 165.8, 143.4,
132.4, 130.3, 129.3, 127.8, 127.2, 123.0, 116.2, 51.2. Anal. Calcd for C16H13N3O2S: C, 61.72; H,
4.21; N, 13.50 %. Found: C, 61.76; H, 4.24; N, 13.46 %.
3-(4-Bromophenyl)-N-(4-chlorophenyl)-1,2,4-thiadiazol-5-amine (2o). Isolated as pale yellow solid
( 307 mg, 84% ); mp 174 – 176oC; IR (KBr): ν = 3226, 3080, 1606, 1557, 1491, 1440 cm-1; H
1
NMR (300 MHz, CDCl3+DMSO-D6) δ 10.50 (s, 1H), 8.11 (d, J = 8.1 Hz, 2H), 7.59 (d, J = 8.2 Hz,
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4H), 7.34 (d, J = 8.3 Hz, 2H). 13C NMR (75 MHz, CDCl3+DMSO-D6) δ 178.6, 167.1, 137.8, 131.3,
130.6, 128.6, 128.1, 126.3, 123.2, 118.3. Anal. Calcd for: C14H9BrClN3S: C, 45.86; H, 2.47; N,
11.46 %. Found: C, 45.82; H, 2.49; N, 11.40 %.
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N, 3-Bis(4-bromophenyl)-1,2,4-thiadiazol-5-amine (2p). Isolated as pale yellow solid ( 331 mg,
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81% ); mp 179 – 181oC; IR (KBr): ν = 3231, 3080, 1600, 1554, 1493, 1443 cm-1; H NMR (300
MHz, CDCl3+DMSO-D6) δ 10.60 (s, 1H), 8.13 (d, J = 8.5 Hz, 2H), 7.62 – 7.57 (m, 4H), 7.50 (d, J
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= 6.9 Hz, 2H). C NMR (75 MHz, CDCl3+DMSO-D6) δ 179.0, 167.8, 138.8, 131.8, 131.5, 131.1,
129.0, 123.7, 119.2, 114.6. Anal. Calcd for: C14H9Br2N3S : C, 40.90; H, 2.21; N, 10.22 %. Found:
C, 40.96; H, 2.18; N, 10.18 %.
3-(4-Bromophenyl)-N-(p-tolyl)-1,2,4-thiadiazol-5-amine (2q). Isolated as white solid ( 286 mg,
1
83% ); mp 241 – 243oC; IR (KBr): ν = 3224, 3054, 1592, 1565, 1438 cm-1; H NMR (300 MHz,
CDCl3+DMSO-D6) δ 10.30 (s, 1H), 8.11 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.5 Hz, 2H), 7.42 (d, J =
8.3 Hz, 2H), 7.19 (d, J = 8.1 Hz, 2H), 2.28 (s, 3H). 13C NMR (75 MHz, CDCl3+DMSO-D6) δ 180.3,
168.3, 138.2, 132.9, 132.8, 132.1, 130.2, 130.1, 124.3, 118.7, 21.2. Anal. Calcd for: C15H12BrN3S:
C, 52.03; H, 3.49; N, 12.14 %. Found: C, 52.07; H, 3.44; N, 12.17 %.
N-(2-Methoxyphenyl)-3-phenyl-1,2,4-thiadiazol-5-amine (2r). Isolated as white solid ( 281 mg,
1
78% ); mp 120 – 123oC; IR (KBr): ν = 3237, 3065, 1600, 1570, 1439 cm-1; H NMR (300 MHz,
CDCl3) δ 8.39 (s, 1H), 8.12 – 8.10 (m, 2H), 7.60 – 7.57 (m, 3H), 7.11 – 7.08 (m, 2H), 6.96 (d, J =
13
7.2 Hz, 1H), 3.94 (s, 3H). C NMR (75 MHz, CDCl3) δ 179.6, 168.4, 148.0, 132.0, 131.7, 129.6,
128.7, 124.5, 123.7, 121.3, 116.4, 110.7, 55.8. Anal. Calcd for: C15H12BrN3OS : C, 49.74; H, 3.34;
N, 11.60 %. Found: C, 49.68; H, 3.30; N, 11.65 %.
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N-Benzyl-3-phenyl-1,2,4-thiadiazol-5-amine (2s).26 Isolated as white solid ( 223 mg, 84% ); mp 101
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– 104oC; IR (KBr): ν = 3218, 3098, 1594, 1570, 1436, 1353 cm-1; H NMR (300 MHz, CDCl3) δ
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8.15-8.12 (m, 2H), 7.40-7.38 (m, 2H), 7.34-7.26 (m, 6H), 7.01 (s, 1H), 4.47 (d, J = 5.3 Hz, 2H). 13C
NMR (75 MHz, CDCl3) δ 184.7, 169.8, 136.1, 133.1, 129.9, 128.9, 128.4, 128.1, 127.9, 127.6,
50.4. ESI-MS m/z calcd [M+H]+ 268.08, found 268.15.
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N-Cyclohexyl-3-phenyl-1,2,4-thiadiazol-5-amine (2t).22b Isolated as white solid ( 218 mg, 85% );
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mp 113 – 115 C; IR (KBr): ν = 3190, 3062, 2985,1577, 1503, 1450 cm-1; H NMR (300 MHz,
CDCl3) δ 8.17 – 8.14 (m, 2H), 7.43 – 7.41 (m, 3H), 5.91 (d, J = 7.7 Hz, 1H), 3.28 – 3.18 (m, 1H),
2.17 – 2.09 (m, 2H), 1.82 – 1.75 (m, 2H), 1.42 – 1.25 (m, 6H). 13C NMR (75 MHz, CDCl3) δ 183.4,
169.8, 133.2, 129.8, 128.4, 127.9, 56.2, 32.5, 25.2, 24.5. ESI-MS m/z calcd [M+H]+ 260.11, found
260.33.
3-(5-Bromopyridin-2-yl)-N-(4-chlorophenyl)-1,2,4-thiadiazol-5-amine (2u). Isolated as brown solid
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( 285 mg, 78% ); mp 228 – 231oC; IR (KBr): ν = 3179, 3063, 3027, 1590, 1490, 1445 cm-1; H
NMR (300 MHz, CDCl3+DMSO-D6) δ 10.54 (s, 1H), 8.80 (s, 1H), 8.19 (d, J = 8.3 Hz, 1H), 8.01 –
7.96 (m, 1H), 7.57 (d, J = 8.8 Hz, 2H), 7.34 (d, J = 8.8 Hz, 2H). 13C NMR (75 MHz,
CDCl3+DMSO-D6)) δ 179.3, 166.8, 150.1, 148.6, 138.8, 138.0, 128.4, 126.9, 124.2, 121.0, 118.7.
Anal. Calcd for C13H8BrClN4S: C, 42.47; H, 2.19; N, 15.24 %. Found: C, 42.50; H, 2.13; N, 15.28
%.
N-Benzyl-3-(5-bromopyridin-2-yl)-1,2,4-thiadiazol-5-amine (2v). Isolated as white solid ( 283 mg,
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82% ); mp 221 – 224 C; IR (KBr): ν = 3233, 3088, 3032, 1601, 1534, 1498 cm-1; H NMR (300
MHz, CDCl3+DMSO-D6) 8.64 (d, J = 2.1 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.89 (dd, J = 8.5, 2.3
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Hz, 1H), 7.37 (m, 5H), 4.56 (d, J = 5.5 Hz, 2H). C NMR (75 MHz, CDCl3+DMSO-D6)) δ 183.0,
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166.2, 149.2, 148.5, 138.2, 136.4, 127.4, 126.6, 126.4, 123.7, 120.1, 48.2. Anal. Calcd for
C14H11BrN4S: C, 48.43; H, 3.19; N, 16.14 %. Found: C, 48.40; H, 3.21; N, 16.11 %.
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N-(3-Chlorophenyl)-3-(1H-pyrazol-1-yl)-1,2,4-thiadiazol-5-amine (2w). Isolated as off-white solid
( 235 mg, 85% ); mp 220 – 222 oC; IR (KBr): ν = 3267, 3148, 3087, 1614, 1544, 1473, 1432 cm-1;
1H NMR (300 MHz, CDCl3+DMSO-D6) 10.85 (s, 1H), 8.36 (bd, J = 2.1 Hz, 1H), 7.76 (s, 1H),
7.64 (s, 1H), 7.45 – 7.44 (m, 1H), 7.31 (t, J = 8.1 Hz, 1H), 7.07 (d, J = 7.8 Hz, 1H), 6.47 (s, 1H).
13C NMR (75 MHz, CDCl3+DMSO-D6) δ 179.5, 157.4, 142.3, 140.2, 134.3, 129.9, 129.5, 122.9,
117.9, 115.9, 107.3. Anal. Calcd for C11H8ClN5S : C, 47.57; H, 2.90; N, 25.22 %. Found: C, 47.53;
H, 2.93; N, 25.27 %.
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N-(4-Bromophenyl)-3-(1H-pyrazol-1-yl)-1,2,4-thiadiazol-5-amine (2x). Isolated as white solid ( 259
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mg, 81% ); mp 221 – 224 C; IR (KBr): ν = 3226, 3060, 3025, 1615, 1490, 1430 cm-1; H NMR
(300 MHz, CDCl3+DMSO-D6) 10.72 (s, 1H), 8.35 (bd, J = 2.4 Hz, 1H), 7.75 (s, 1H), 7.47 (s, 4H),
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6.47 – 6.45 (m, 1H). C NMR (75 MHz, CDCl3+DMSO-D6) δ 178.9, 156.9, 141.8, 137.8, 131.2,
129.1, 119.1, 114.7, 106.9. Anal. Calcd for C11H8BrN5S : C, 41.01; H, 2.50; N, 21.74 %. Found: C,
41.06; H, 2.47; N, 21.69 %.
3-(1H-Pyrazol-1-yl)-N-(p-tolyl)-1,2,4-thiadiazol-5-amine (2y). Isolated as Pale yellow solid ( 219
o
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mg, 86% ); mp 180 – 183 C; IR (KBr): ν = 3220, 3073, 1606, 1548, 1457 cm-1; H NMR (300
MHz, CDCl3) 8.98 (s, 1H), 8.30 (s, 1H), 7.57 (s, 1H), 7.24 – 7.15 (m, 4H), 6.41 (s, 1H), 2.37 (s,
3H). 13C NMR (75 MHz, CDCl3) 182.7, 158.1, 142.3, 136.6, 135.3, 130.1, 129.1, 120.9, 107.9,
20.9. Anal. Calcd for C12H11N5S : C, 56.01; H, 4.31; N, 27.22 %. Found: C, 56.06; H, 4.34; N,
27.16 %.
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3-(Methylthio)-N-phenyl-1,2,4-thiadiazol-5-amine (2z). Isolated as white solid ( 184 mg, 83% ); mp
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6
1
80 – 83oC; IR (KBr): ν = 3223, 2968, 1592, 1545, 1451 cm-1; H NMR (300 MHz, CDCl3) δ 9.83
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(s, 1H), 7.42 – 7.37 (m, 2H), 7.34 – 7.31 (m, 2H), 7.14 (t, J = 7.2 Hz, 1H), 2.63 (s, 3H). 13C NMR
(75 MHz, CDCl3) 180.2, 168.1, 139.4, 129.4, 123.8, 118.5, 14.3. Anal. Calcd for C9H9N3S2 : C,
48.41; H, 4.06; N, 18.82 %. Found: C, 48.46; H, 4.03; N, 18.78 %.
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ASSOCIATED CONTENT
Supporting Information
1H, 13C NMR, ESI-Mass spectra (PDF) and X-ray crystal data of compound 2f (CIFs). This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: muthumanian2001@yahoo.com.
ACKNOWLEDGMENTS
We thank DST, New Delhi, for assistance under the IRHPA program for the NMR facility and financial support
from UGC MRP (major research project) F. No. 41-265/2012(SR), New Delhi. A.M. gratefully acknowledges
UGC for the award of a Junior Research Fellowship.
References
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E.; SanMartin, R. J. Org. Chem. 2006, 71, 3501. (b) Correa, A.; Tellitu, I.; Dominguez, E.; San
Martin, R. Tetrahedron 2006, 62, 11100. (c) Zheng, Z.; Ma, S.; Tang, L.; Zhang-Negrerie, D.; Du,
Y.; Zhao, K. J. Org. Chem. 2014, 79, 4687. (d) Song, L.; Tian, X.; Lv, Z.; Li, E.; Wu, J.; Liu, Y.;
Yu, W.; Chang, J. J. Org. Chem. 2015, 80, 7219. (e) Hirayama, T.; Ueda, S.; Okada, T.; Tsurue, N.;
Okuda, K.; Nagasawa, H. Chem. Eur. J. 2014, 20, 4156.
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(2) For examples of N−O bond forming heterocycles, see: (a) Asao, N.; Sato, K.; Yamamoto, Y.
Tetrahedron Lett. 2003, 44, 5675. (b) Stokes, B. J.; Vogel, C. V.; Urnezis, L. K.; Pan, M.; Driver,
T. G. Org. Lett. 2010, 12, 2884. (c) Chauhan, J.; Fletcher, S. Tetrahedron Lett. 2012, 53, 4951. (d)
Otley, K. D.; Ellman, J. A. J. Org. Chem. 2014, 79, 8296. (e) Prakash, O.; Saini, R. K.; Singh, S. P.;
Varma, R. S. Tetrahedron Lett. 1997, 38, 3147.
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(3) For examples of N−S bond forming heterocycles, see: Ma, W. B.; Li, S. N.; Zhou, Z. H.; Shen,
H. S.; Li, X.; Sun, Q.; He, L.; Xue, Y. Eur. J. Org. Chem. 2012, 1554.
(4) (a) Kuram, M. R.; Kim, W. G.; Myung, K.; Hong, S. Y. Eur. J. Org. Chem. 2016, 438. (b)
Neumann, J. J.; Suri, M.; Glorius, F. Angew. Chem. Int. Ed. 2010, 49, 7790. (c) Bartels, B.; Bolas,
C. G.; Cueni, P.; Fantasia, S.; Gaeng, N.; Trita, A. S. J. Org. Chem. 2015, 80, 1249. (d) Stokes, B.
J.; Vogel, C. V.; Urnezis, L. K.; Pan, M.; Driver, T. G. Org. Lett. 2010, 12, 2884. (e) Ueda, S.;
Nagasawa, H. J. Am. Chem. Soc. 2009, 131, 15080.
(5) (a) Counceller, C. M.; Eichman, C. C.; Wray, B. C.; Stambuli, J. P. Org. Lett. 2008, 10, 1021.
(b) Kale, A.; Chennapuram, M.; Bingi, C.; Nanubolu, J. B.; Atmakur, K. Org. Biomol. Chem. 2016,
14, 582.
(6) See for example: (a) Dohi, T.; Kita, Y. Chem. Commun. 2009, 16, 2073. (b) Zhdankin, V. V. J.
Org. Chem. 2011, 76, 1185. (c) Dohi, T.; Nakae, T.; Ishikado, Y.; Kato, D.; Kita, Y. Org. Biomol.
Chem. 2011, 9, 6899. (d) Manna, S.; Matcha, K.; Antonchick, A. P. Angew. Chem. Int. Ed. 2014,
53, 8163. (e) Qian, G.; Liu, B.; Tan, Q.; Zhang, S.; Xu, B. Eur. J. Org. Chem. 2014, 4837. (f) Dohi,
T.; Kita, Y. Chem. Rec. 2015, 15, 886. (g) Yoshimura, A.; Zhdankin, V. V. Chem. Rev. 2016, 116,
3328.
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(7) For examples of C−C bond forming heterocyles using hypervalent iodine (III) reagents, see: (a)
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(30) CCDC No. 1478589 contains the supplementary crystallographic data for the compound 2f.
These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
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