I2-Catalyzed Oxidative N-S Bond Formation: Metal-Free Regiospecific Synthesis of N-Fused and 3,4-Disubstituted 5-Imino-1,2,4-thiadiazoles

Article abstract of DOI:10.1021/acs.joc.7b00646

A novel and expeditious approach for the synthesis of N-fused and 3,4-disubstituted 5-imino-1,2,4-thiadiazole derivatives has been achieved through the molecular iodine-catalyzed oxidative cyclization of 2-aminopyridine/amidine and isothiocyanate via N-S

Full text of DOI:10.1021/acs.joc.7b00646

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Article
I2-Catalyzed Oxidative N-S Bond Formation: Metal-Free Regiospecific
Synthesis of N-Fused and 3,4-Disubstituted 5-Imino-1,2,4-Thiadiazoles
Nagaraju Tumula, Nagesh Jatangi, Radha Krishna
Palakodety, Sridhar Balasubramanian, and Mangarao Nakka
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 27 Apr 2017
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I2-Catalyzed Oxidative N-S Bond Formation: Metal-Free Regiospecific Synthesis of N-
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Fused and 3,4-Disubstituted 5-Imino-1,2,4-Thiadiazoles
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Nagaraju Tumula,† Nagesh Jatangi,† Radha Krishna Palakodety,† Sridhar Balasubramanian,‡
Mangarao Nakka *,†
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†Organic and Bimolecular Chemistry Division, CSIR-Indian Institute of Chemical Technology,
Hyderabad-500007, India.
‡Center for X-ray Crystallography, CSIR-Indian Institute of Chemical Technology, Hyderabad-
500007, India.
A novel and expeditious approach for the synthesis of N-fused and 3,4-disubstituted 5-imino-
1,2,4-thiadiazole derivatives has been achieved through the molecular iodine-catalyzed oxidative
cyclization of 2-aminopyridine/amidine and isothiocyanate via N-S bond formation at ambient
temperature. The present one-pot transition-metal-free protocol provides the facile and highly
efficient regiospecific synthesis of various 1,2,4-thiadiazole derivatives in a scaled-up manner
with good to excellent yields using inexpensive I2 as a catalyst.
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INTRODUCTION
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N-Containing heterocyclic compounds are important structures found in natural and
synthetic compounds. Development of new synthetic protocols for the synthesis of biologically
active N-heterocyclic compounds through various N-N, N-O and N-S bond formations is still in
high demand. As a result, a plethora of methods were developed for heteroatom-heteroatom bond
formation. Amongst these, metal-catalyzed protocols for N-N, N-O and N-S bond construction
have limitations, such as the metal contamination, drastic reaction conditions, cost-factors, air-
sensitivity and scalability issues.1 Earlier, metal free protocols were developed for N-N, N-O and
N-S bond connection,2 of all these iodine catalyzed reactions played a major role owing to its
environmentally friendly nature, oxidizing ability, inexpensive, easily available in solid form and
easy to handle. Recently, iodine-catalyzed approaches were found during C-X (X = C, N, O, S)
bond formation and as well as in N-N, N-S bonds.3 As a catalyst, iodine has been extensively
used in organic transformations, such as esterification, acylation, and allylation as well as for
Michael addition and aldol reaction.4 It can also mediate domino, iodocyclization and one-pot
multicomponent reactions.5a However, it is very interesting to note that iodine could substitute
for transition metal as catalysts.2a, 5b
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1,2,4-Thiadiazoles are an important class of organic molecules for medicinal chemistry
and are associated with a broad range of biological activity,6a including antibacterial,6b
antiulcerative,7 antidiabetic,8 antirheumatic,9 anti-inflammatory,10 anti-microbial agents.11
A
family of 1,2,4-thiadiazole derivatives also exhibit fungicidal,12 and herbicidal activity. 13 Despite
their wide applications in pharmacology and organic synthesis, few methods was developed for
the synthesis of 1,2,4-thiadiazoles. The general methods for the synthesis of 1,2,4-thiadiazoles
mainly involve oxidative cyclization of primary thioamides with a variety of oxidizing
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reagents.14 Recently, Wehn et al. invoked a palladium-catalyzed Suzuki-Miyaura coupling
reaction for ready access to 3-amino-1,2,4-thiadiazoles.15a Independently, Khosropour and co-
workers obtained 1,2,4-thiadiazoles from aryl nitriles in the presence of (NH4)2S and TCT–
DMSO.15b On the other hand, 1,2,4-thiadiazole scaffold was also obtained from imidoyl
thioureas.16 Intramolecular oxidative S-N bond formation under copper catalysis was developed
by Kim et al. for ready access to 3-substituted-5-amino-1,2,4-thiadiazoles.17a Muthusubramanian
and co-workers developed a phenyliodine(III) bis(trifluoroacetate) catalyzed oxidative
cyclization for the synthesis of 3,5-disubstituted 1,2,4-thiadiazoles.17b
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However, some of these protocols suffer from the limitations such as prefunctionalization
of starting materials, require strong oxidative reaction conditions, tedious work-up, and harsh
reaction conditions. More importantly, these methods are mainly suitable for preparation of 3,5-
disubstituted 1,2,4-thiadiazoles. Thus, it is desirable to develop an efficient protocol for the
synthesis of fully substituted 1,2,4-thiadiazoles using readily available raw materials in one pot.
However, there seems to be no reports in the literature on I2-catalyzed N-S bond formation
reactions for the synthesis of 1,2,4-thiadiazoles. Encouraged by our previous work on the
development of efficient synthetic methods for various biologically active heterocycles,18 in this
paper, we envisioned for the first time the construction of N-S bond by employing molecular
iodine as a catalyst to synthesize the biologically important N-fused 1,2,4-thiadiazole and 3,4-
disubstituted 5-imino-1,2,4-thiadiazole scaffolds (Scheme 1).
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Scheme 1. Synthesis of N-fused 1,2,4-thiadiazoles and 3,4-disubstituted 5-imino-1,2,4-
thiadiazoles
RESULTS AND DISCUSSION
Our initial study started with the reaction of isothiocyanate 1a with 2-aminopyridine (2a)
in the presence of iodine (0.2 equiv) with no solvent (neat) at room temperature. We were
delighted to observe the formation of the expected 1,2,4-thiadiazole 3a, although in low yields
(Table 1, entry 1). The poor yield of 3a might be due to the low solubility of the reactants. Next,
we optimized the reaction conditions with various solvents, forward yield improvement and the
results are summarized in Table 1. Amongst all acetonitrile proved to be a better solvent in terms
of the reaction time and yield of the product (Table 1, entry 4). The replacement of iodine with
other oxidizing catalysts, including KI, TBAI, and NIS resulted in a decrease yield of 3a (Table
1, entries 8-10). Having established the suitable catalyst for synthesis of 1,2,4-thiadiazoles, we
then focused on the quantity of iodine. Raising the loading of iodine resulted in the desired
product 3a in high yields (Table 1, entries 11 and 12), and the use of 50 mol% of catalyst gave
the best result (Table 1, entry 12). With the further increasing of iodine from 0.5 to 1.0 equiv, the
yield of 3a not augmented (Table 1, entry 13). Thus, the standardized conditions for this reaction
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are summarized as follows: 1a (3 mmol, 1equiv), 2a (3 mmol, 1 equiv), and I2 (50 mol%), at rt in
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CH3CN in 1-2 h.
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Table 1. Optimization of reaction conditionsa
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entry
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catalyst (mol%)
I2 (20)
solvent
-
yield (%)
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2
I2 (20)
DCE
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I2 (20)
1,4-dioxane
CH3CN
DMF
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I2 (20)
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I2 (20)
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I2 (20)
EtOH
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I2 (20)
DMSO
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
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KI (20)
TBAI (20)
NIS (20)
I2 (30)
trace
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I2 (50)
91
I2 (100)
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aReaction conditions: 1a (3 mmol, 1 equiv), 2a (3 mmol, 1 equiv),
catalyst (x mol%) and solvent (1 mL) at rt for 1 to 2 h.
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Next, we investigated the generality of the oxidative synthesis of N-fused 1,2,4-
thiadiazoles (Scheme 2). A variety of isothiocyanates with different substituents were tested. As
expected, all the isothiocyanates gave the corresponding N-fused 1,2,4-thiadiazoles in good to
excellent yields. Phenyl isothiocyanate (1a) gave the desired product 3a in 91% yield. Further
structural confirmation of 3a was ascertained by X-ray studies (see the Supporting Information).
Arylisothiocyanates containing groups like -methyl, -methoxy at para-, meta-, and ortho-
positions gave better reactivity and provided the corresponding products in good to excellent
yields (3b, 3c, 3h and 3i). Conversely, arylisothiocyanates with electron-withdrawing groups
such as -chloro, and -fluoro at para-, and meta-positions furnished corresponding products in
moderate to good yields (3d, 3e and 3j). It should be noted that arylisothiocyanates with strong
electron-withdrawing groups, including -NO2, and -CF3, were well tolerated under the reaction
conditions and the desired N-fused 1,2,4-thiadiazole products were obtained in good yields (3f
and 3g). It was worth mentioning that steric hindrance (3b, 3c and 3h-3j) and electronic factors
(3a-3j) of phenyl isothiocyanates seemingly exerted a negligible influence on the reaction rate or
the yields of the products. An alicyclic isothiocyanate such as cyclopropyl isothiocyanate was
also tolerated under these reaction conditions, and the corresponding product 3k was isolated in
79% yield. Aliphatic isothiocyanates including cyclohexyl methyl, propyl and isopropyl
underwent the oxidative reaction to give the corresponding products in good yields (3l-3n). To
further examine the scope and limitations of the reaction, we studied various 2-aminopyridines
with phenyl isothiocyanate (Scheme 2). Methyl substituted 2-aminopyridine was well tolerated
and the position of the methyl substituent at 4, 5, and 6 did not bear any significant affect on the
reaction yield (3o-3q). Electron-withdrawing groups such as chloro and bromo were compatiable
and gave the corresponding products 3r and 3s in 87% and 86% yields, respectively. When a
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strong electron-withdrawing nitro group was used, the desired product 3t was obtained in 84%
yield (3t). It should be noted that the catalytic transformation was successfully conducted in
gram scale without any difficulty (Scheme 2, 3a).
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Scheme 2. Synthesis of N-fused 1,2,4-thiadiazolesa
3a, X = H, 91% (89%)b
3b, X = Me, 90%
3c, X = OMe, 95%
3d, X = Cl, 88%
3e, X = F, 88%
3f, X = NO2, 85%
3g, X = CF3, 82%
3h, 82%
3i, 82%
3k, 79%
3j, 86%
3n, 76%
3q, 86%
3m, 76%
3l, 78%
3o, 86%
3p, 86%
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3s, 86%
3t, 84%
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3r, 87%
aReaction conditions: 1a (3 mmol, 1 equiv), 2a (3 mmol, 1 equiv), I2 (50
mol%) and CH3CN (1 mL) at rt for 1to 2 h. bThe reaction was conducted on
gram-scale.
In light of successful oxidative cyclization process for the synthesis of N-fused 1,2,4-
thiadiazoles, we sought to further extend the scope of this practical approach by replacing 2-
aminopyridine (2) with N-phenylbenzamidines (4) to prepare 3,4-disubstituted 5-imino-1,2,4-
thiadiazoles under the optimal reaction conditions. Gratifyingly, following the above protocol,
we were able to prepare 3,4-disubstituted 5-imino-1,2,4-thiadiazoles very efficiently. As shown
in Scheme 3, this protocol tolerates a variety of arylisothiocyanates with different N-
phenylbenzamidines. No significant substituent effect was observed, excellent yields were
obtained for arylisothiocyanates having both electron-donating and electron-withdrawing
substituents with different N-phenylbenzamidines. This methodology worked equally well with
alicyclic isothiocyanate such as cyclopropyl and good yield was observed (5l). Fortunately, the
reaction worked equally well with aliphatic isothiocyanates including butaryl, isopropyl and
propyl gave corresponding 3,4-disubstituted 5-imino-1,2,4-thiadiazoles in good yields (5i, 5k
and 5m). Compound 5k was fully characterized by X-ray analysis (Please see SI).
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Scheme 3. Synthesis of 3,4-disubstituted 5-imino-1,2,4-thiadiazolesa
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5a, X = H, 89%
5b, X = Me, 90%
5c, X = OMe, 90%
5d, X = Cl, 87%
5e, X = NO2, 86%
5f, X = CF3, 82%
S
N
N
OMe
N
5g, 82%
5h, 87%
5i, 74%
5j, 76%
S
N
N
N
Me
5k, 75%
5l, 76%
5m, 73%
aReaction conditions: 1a (1.5 mmol, 1 equiv), 2a (1.5 mmol, 1 equiv), I2 (50
mol%) and CH3CN (1 mL) at rt for 1to 2 h.
To further probe the mechanism, we attempted control experiments as shown in scheme
4. When the phenyl isothiocyanate (1a) with 2-amino pyridine (2a) under optimized conditions
in inert atmosphere gave the desired 3a in 91% (Scheme 4a). It is highly likely that I2 plays a role
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of oxidant. As expected, when 2,2,6,6-tetramethylpiperdine-1-oxide (TEMPO, a well-known
radical inhibitor) was added to the reaction, no considerable effect was observed (Scheme 4b),
demonstrating that a radical mechanism was ruled out. When the phenyl isothiocyanate (1c) was
reacted with 2-amino pyridine (2a) in the absence of I2 intermediate C' (Scheme 4c) was
obtained, which was confirmed by 1H, 13C NMR, HRMS and X-ray analysis (see the SI).
However C' did not produce 3c' in the presence of I2 (Scheme 4d). Thus, it maybe deduced that
the present protocol is highly regiospecific and affords 3c exclusively.
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Scheme 4. Control experiments
Based on results presented above, and previous reports,19 a plausible mechanism was
proposed and shown in Scheme 5. First step for the formation of product 3a involves a
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nucleophilic attack of activated 2-amino pyridine (A) on phenyl isothiocyanate (1a) to form
intermediate B. Finally, the intermolecular nucleophilic attack of the NH group on the sulfur
atom gave the corresponding derivative 3a. However, when the same reaction was performed in
the absence of I2, nucleophilic addition of free amine on isothiocyanate gave stable thiourea
derivative C', which was isolated and characterized by its 1H, 13C NMR, HRMS as well as X-
ray analysis. Independently when C' upon treatment with I2 did not afford the cyclized
regioisomer 3c' (Scheme 4d). Thus it conclusively proves the intermediacy of B and its
conversion into product 3a.
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Scheme 5. A plausible mechanism for the preparation of 3a
CONCLUSION
In summary, a novel and convenient iodine catalyzed oxidative protocol for the N-S bond
formation towards the regiospecific synthesis of N-fused 1,2,4-thiadiazole and 3,4-disubstituted
5-imino-1,2,4-thiadiazole derivatives was developed for the first time. This versatile and
transition-metal-free one-pot protocol features a broad substrate scope, inexpensive and nontoxic
molecular iodine as the catalyst, no addition of any ligand, base, or additive is need and with
easy workup procedure. The developed synthetic approach can be easily scaled up to gram scale,
thereby providing the possibility for the scaled production of diverse N-fused 1,2,4-thiadiazole
and 3,4-disubstituted 5-imino-1,2,4-thiadiazole derivatives.
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EXPERIMENTAL SECTION
General information:
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Unless otherwise noted, common reagents and substrates were obtained from commercial
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suppliers and used without further purification. H-NMR was measured on Bruker Avance-300,
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Varian Unity-400 MHz and Avance New-500 MHz, and C-NMR was measured with Varian
Unity-400 MHz (100 MHz) and with Avance New-500 MHz (125 MHz), as specified and
referred as the internal standard to TMS (tetramethylsilane). High Resolution Mass Spectra
(HRMS) were performed on a high resolution magnetic sector mass spectrometer. Melting points
were recorded on Büchi 535 melting point apparatus and are uncorrected. TLC analysis was
performed on Merck silica gel 60 F254 plates. Column chromatography was performed on silica
gel (100-200 mesh) from Merck.
Typical procedure for the synthesis of N-fused 1,2,4-thiadiazoles 3a-3t:
A mixture of isothiocyanate (1) (3 mmol), 2-aminopyridine (2) (3 mmol), I2 (50 mol%,
202 mg, 1.5 mmol) in CH3CN (1 mL) at room temperature. After completion of the reaction as
monitored by TLC, the reaction mixture was quenched with a saturated aqueous solution of
Na2S2O3. The organic and aqueous layers were then separated and the aqueous layer was
extracted with ethyl acetate twice. The combined organic layers were dried over anhydrous
Na2SO4 and concentrated under reduced pressure to get crude. The crude was purified by silica
gel column chromatography using EtOAc : hexane as eluents to afford corresponding product 3.
(Z)-N-(3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)aniline (3a):20 Yield: 91% (659 mg); pale
yellow solid; Mp 124-126 °C; eluent: hexane/ethyl acetate 95:5; 1H NMR (500 MHz, CDCl3): δ
= 8.21 (d, J = 7.17 Hz, 1H), 7.42-7.37 (m, 2H), 7.22-7.10 (m, 4H), 7.06-7.03 (m, 1H), 6.46 (dd, J
= 0.92 Hz, J = 5.34 Hz, 1H); 13C{1H}NMR (100 MHz, CDCl3): δ = 159.2, 151.6, 148.5, 133.4,
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129.5, 126.1, 124.3, 121.1, 119.4, 109.6; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C12H10N3S
228.0512; Found 228.0520.
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(Z)-N-(3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)-4-methylaniline (3b):21 Yield: 90% (692
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mg); pale yellow solid; Mp 104-106 °C; eluent: hexane/ethyl acetate 95:5; H NMR (500 MHz,
CDCl3): δ = 8.20 (d, J = 7.17 Hz, 1H), 7.21-7.16 (m, 3H), 7.07-7.02 (m, 3H), 6.46-6.42 (m, 1H),
2.35 (s, 3H); C{1H}NMR (100 MHz, CDCl3): δ = 158.5, 151.6, 145.9, 133.8, 133.3, 130.1,
13
126.1, 120.9, 119.4, 109.5, 21.0; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C13H12N3S
242.0745; Found 242.0746.
(Z)-N-(3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)-4-methoxyaniline (3c):22 Yield: 95% (779
1
mg); pale yellow solid; Mp 125-127 °C; eluent: hexane/ethyl acetate 94:6; H NMR (400 MHz,
CDCl3): δ
= 8.20 (d, J = 7.21 Hz, 1H), 7.21-7.16 (m, 1H), 7.11-7.06 (m, 2H), 7.05-7.01 (m,
1H), 6.96-6.91 (m, 2H), 6.44 (dd, J = 5.38 Hz, J = 0.97 Hz, 1H), 3.82 (s, 3H); C{1H}NMR
(125 MHz, CDCl3): δ = 157.9, 156.3, 151.6, 141.6, 133.4, 126.1, 122.2, 119.4, 114.7, 109.5,
55.5; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C13H12N3OS 258.0654; Found 258.0663.
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(Z)-N-(3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)-4-chloroaniline (3d):22 Yield: 88% (733
1
mg); pale yellow solid; Mp 144-146 °C; eluent: hexane/ethyl acetate 95:5; H NMR (400 MHz,
CDCl3): δ = 8.19 (d, J = 7.17 Hz, 1H), 7.36-7.32, (m, 2H), 7.24-7.20 (m, 1H), 7.09-7.06 (m, 3H),
6.49 (dd, J = 1.06 Hz, J = 5.34 Hz, 1H); C{1H}NMR (125 MHz, CDCl3): δ = 159.7, 151.6,
13
147.1, 133.4, 129.6, 129.1, 125.9, 122.4, 119.4, 109.9; HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C12H9ClN3S 262.0137; Found 262.0142.
(Z)-N-(3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)-4-fluoroaniline (3e):22 Yield: 88% (688
1
mg); pale yellow solid; Mp 148-150 °C; eluent: hexane/ethyl acetate 95:5; H NMR (400 MHz,
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CDCl3): δ = 8.19 (d, J = 7.17 Hz, 1H), 7.23-7.19 (m, 1H), 7.12-7.05 (m, 5H), 6.48 (dd, J = 1.06
Hz, J = 5.34 Hz, 1H); 13C{1H}NMR (125 MHz, CDCl3): δ = 159.9 (d, J = 102 Hz), 158.5, 151.6,
144.7, 133.4, 125.9, 122.4 (d, J = 7 Hz), 119.4, 116.2 (d, J = 18 Hz), 109.7; HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C12H9FN3S 246.0493; Found 246.0495.
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(Z)-N-(3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)-4-nitroaniline (3f):22 Yield: 85% (737
1
mg); orange solid; Mp 189-191 °C; eluent: hexane/ethyl acetate 92:8; H NMR (400 MHz,
CDCl3): δ = 8.30-8.25 (m, 3H), 7.33-7.28 (m, 1H), 7.26-7.22 (m, 2H), 7.19-7.15 (m, 1H), 6.63-
13
6.58 (m, 1H); C{1H}NMR (125 MHz, CDCl3): δ = 161.7, 154.3, 151.6, 143.5, 133.6, 125.8,
125.5, 121.5, 119.5, 110.7; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C12H9N4O2S 273.0435;
Found 273.0441.
(Z)-N-(3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)-4-(trifluoromethyl)aniline (3g): Yield:
1
82% (772 mg); pale yellow solid; Mp 158-160 °C; eluent: hexane/ethyl acetate 93:7; H NMR
(500 MHz, CDCl3): δ = 8.24-8.20 (m, 1H), 7.64 (d, J = 8.55 Hz, 2H), 7.27-7.20 (m, 3H), 7.13-
13
7.08 (m, 1H), 6.55-6.50 (m, 1H); C{1H}NMR (125 MHz, CDCl3): δ = 158.2, 149.1, 130.9,
125.0, 124.2 (d, J = 2 Hz), 123.4, 123.3 (q, J = 48.1 Hz), 121.8 (d, J = 216 Hz), 118.7, 116.9,
107.6; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C13H9F3N3S 296.0460; Found 296.0464.
(Z)-N-(3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)-3-methylaniline (3h): Yield: 82% (631
1
mg); pale yellow liquid; eluent: hexane/ethyl acetate 95:5; H NMR (500 MHz, CDCl3): δ =
8.23-8.19 (m, 1H), 7.30-7.25 (m, 1H), 7.20 (dd, J = 1.37 Hz, J = 5.04 Hz, 1H), 7.07-7.03 (m,
1H), 6.98-6.92 (m, 3H), 6.49-6.44 (m, 1H), 2.37 (s, 3H); 13C{1H}NMR (100 MHz, CDCl3): δ =
159.0, 151.6, 148.5, 139.5, 133.3, 129.4, 126.1, 125.1, 121.9, 119.4, 117.7, 109.6, 21.5; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C13H12N3S 242.0745; Found 242.0746.
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(Z)-N-(3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)-2-methoxyaniline (3i): Yield: 82% (672
5
6
1
mg); pale yellow liquid; eluent: hexane/ethyl acetate 91:9; H NMR (500 MHz, CDCl3): δ =
7
8
9
8.26-8.23 (m, 1H), 7.19 (dd, J = 1.37 Hz, J = 5.04 Hz, 1H), 7.14-7.09 (m, 2H), 7.03 (d, J = 9.46
Hz, 1H), 7.00-6.96 (m, 2H), 6.48-6.44 (m, 1H), 3.87 (s, 3H); 13C{1H}NMR (100 MHz, CDCl3):
δ = 160.4, 151.6, 151.4, 138.1, 133.1, 126.2, 125.3, 121.3, 120.6, 119.4, 112.0, 109.6, 55.7;
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C13H12N3OS 258.0694; Found 258.0695.
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(Z)-N-(3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)-3-chloroaniline (3j): Yield: 86% (716
1
mg); pale yellow solid; Mp 107-109 °C; eluent: hexane/ethyl acetate 95:5; H NMR (500 MHz,
CDCl3): δ = 8.20-8.17 (m, 1H), 7.30 (t, J = 7.93 Hz, 1H), 7.22 (dd, J = 1.37 Hz, J = 5.04 Hz,
1H), 7.14 (t, J = 1.98 Hz, 1H), 7.11-7.05 (m, 2H), 7.02 (dd, J = 1.37 Hz, J = 8.08 Hz, 1H), 6.51-
13
6.47 (m, 1H); C{1H}NMR (125 MHz, CDCl3): δ = 160.2, 151.5, 149.8, 135.0, 133.4, 130.5,
125.9, 124.2, 121.7, 119.4, 119.1, 110.0; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C12H9ClN3S 262.0154; Found 262.0159.
(Z)-N-(3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)cyclopropanamine (3k): Yield: 79% (481
1
mg); pale yellow liquid; eluent: hexane/ethyl acetate 90:10; H NMR (400 MHz, CDCl3): δ =
7.90-7.86 (m, 1H), 7.15-7.10 (m, 1H), 6.99-6.95 (m, 1H), 6.35-6.31 (m, 1H), 2.49-2.42 (m, 1H),
0.86-0.83 (m, 2H), 0.69-0.65 (m, 2H); 13C{1H}NMR (100 MHz, CDCl3): δ = 161.4, 152.2,
133.2, 125.7, 119.3, 108.9, 36.0, 7.1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C9H10N3S
192.0543; Found 192.0551.
(Z)-N-(3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)-1-cyclohexylmethanamine (3l): Yield:
1
78% (614 mg); pale yellow liquid; eluent: hexane/ethyl acetate 90:10; H NMR (500 MHz,
CDCl3): δ = 7.95 (d, J = 7.17 Hz 1H), 7.13-7.09 (m, 1H), 6.94 (d, J = 9.46 Hz, 1H), 6.32 (t, J =
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7.02 Hz, 1H), 2.96 (d, J = 6.56 Hz, 2H), 1.87-1.80 (m, 2H), 1.78-1.64 (m, 4H), 1.33-1.26 (m,
2H), 1.23-1.16 (m, 1H), 1.08-0.96 (m, 2H); 13C{1H}NMR (125 MHz, CDCl3): δ = 158.3, 152.3,
133.3, 126.1, 119.3, 108.6, 61.7, 39.4, 31.5, 26.6, 26.1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C13H18N3S 248.1208; Found 248.1215.
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(Z)-N-(3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)propan-1-amine (3m): Yield: 76% (468
1
mg); pale yellow liquid; eluent: hexane/ethyl acetate 90:10; H NMR (300 MHz, CDCl3): δ =
7.98-7.94 (m, 1H), 7.16-7.09 (m, 1H), 6.98-6.93 (m, 1H), 6.37-6.31 (m, 1H), 3.11 (t, J = 6.87
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Hz, 2H), 1.82-1.68 (m, 2H), 1.01 (t, J = 7.43 Hz, 3H); C{1H}NMR (125 MHz, CDCl3): δ =
158.6, 152.3, 133.3, 126.0, 119.3, 108.7, 56.7, 23.9, 12.0; HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C9H12N3S 194.0756; Found 194.0759.
(Z)-N-(3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)propan-2-amine (3n): Yield: 76% (468
1
mg); pale yellow liquid; eluent: hexane/ethyl acetate 90:10; H NMR (500 MHz, CDCl3): δ =
7.94 (d, J = 7.32 Hz, 1H), 7.13-7.08 (m, 1H), 6.92 (d, J = 9.46 Hz, 1H), 6.31 (t, J = 7.02 Hz, 1H),
13
3.19-3.10 (m, 1H), 1.24 (d, J = 6.26 Hz, 6H); C{1H}NMR (100 MHz, CDCl3): δ = 157.1,
152.3, 133.3, 126.2, 119.2, 108.6, 56.4, 22.9; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C9H12N3S 194.0745; Found 194.0746.
(Z)-N-(7-methyl-3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)aniline (3o): Yield: 86% (575
1
mg); pale yellow solid; Mp 104-106 °C; eluent: hexane/ethyl acetate 93:7; H NMR (400 MHz,
CDCl3): δ = 8.11 (d, J = 7.34 Hz, 1H), 7.41-7.36 (m, 2H), 7.16-7.08 (m, 3H), 6.82-6.79 (m, 1H),
13
6.30 (dd, J = 1.46 Hz, J = 7.34 Hz, 1H), 2.26 (d, J = 1.22 Hz, 3H); C{1H}NMR (125 MHz,
CDCl3): δ = 159.3, 151.8, 148.6, 144.8, 129.5, 124.9, 124.2, 121.1, 116.8, 112.8, 21.5; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C13H12N3S 242.0756; Found 242.0759.
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(Z)-N-(6-methyl-3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)aniline (3p): Yield: 86% (575
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6
1
mg); pale yellow solid; Mp 147-149 °C; eluent: hexane/ethyl acetate 94:6; H NMR (500 MHz,
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CDCl3): δ = 8.00 (s, 1H), 7.39 (t, J = 7.78 Hz, 2H), 7.18-7.05 (m, 4H), 7.01-6.97 (m, 1H), 2.22
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(s, 3H); C{1H}NMR (125 MHz, CDCl3): δ = 159.5, 151.2, 148.7, 136.8, 129.5, 124.1, 122.7,
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121.1, 119.4, 118.6, 17.6; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C13H12N3S 242.0767;
Found 242.0773.
(Z)-N-(5-methyl-3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)aniline (3q): Yield: 86% (575
1
mg); pale yellow solid; Mp 98-100 °C; eluent: hexane/ethyl acetate 93:7; H NMR (500 MHz,
CDCl3): δ = 7.38 (t, J = 7.78 Hz, 2H), 7.11 (t, J = 7.47 Hz, 1H), 7.04 (d, J = 7.47 Hz, 2H), 6.90
(dd, J = 6.56 Hz, J = 9.46 Hz, 1H), 6.79 (d, J = 9.31 Hz, 1H), 5.99 (d, J = 6.56 Hz, 1H), 2.96 (s,
13
3H); C{1H}NMR (125 MHz, CDCl3): δ = 163.0, 154.0, 150.2, 141.9, 132.6, 129.7, 124.2,
120.3, 118.1, 110.7, 21.9; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C13H12N3S 242.0753;
Found 242.0758.
(Z)-N-(8-chloro-3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)aniline (3r): Yield: 87% (532
1
mg); pale yellow solid; Mp 136-138 °C; eluent: hexane/ethyl acetate 95:5; H NMR (500 MHz,
CDCl3): δ = 8.20 (dd, J = 1.06 Hz, J = 7.17 Hz, 1H), 7.42-7.38 (m, 2H), 7.34 (dd, J = 1.06 Hz, J
= 7.02 Hz, 1H), 7.16-7.11 (m, 3H), 6.43 (t, J = 7.02 Hz, 1H); 13C{1H}NMR (100 MHz, CDCl3):
δ = 158.9, 148.4, 147.9, 131.9, 129.6, 125.1, 124.8, 124.6, 121.0, 109.0; HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C12H9ClN3S 262.0145; Found 262.0149.
(Z)-N-(6-bromo-3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)aniline (3s): Yield: 86% (456
1
mg); pale yellow solid; Mp 147-149 °C; eluent: hexane/ethyl acetate 92:8; H NMR (500 MHz,
CDCl3): δ = 8.37 (dd, J = 0.85 Hz, J = 1.95 Hz, 1H), 7.43-7.37 (m, 2H), 7.21 (dd, J = 1.98 Hz, J
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= 9.76 Hz, 1H), 7.16-7.10 (m, 3H), 6.95 (dd, J = 0.76 Hz, J = 9.92 Hz, 1H); 13C{1H}NMR (100
MHz, CDCl3): δ = 157.6, 149.6, 147.9, 136.7, 129.6, 125.8, 124.5, 121.0, 119.9, 104.1; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C12H9BrN3S 305.9691; Found 305.9695.
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(Z)-N-(6-nitro-3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)aniline (3t): Yield: 84% (493 mg);
orange solid; Mp 180-182 °C; eluent: hexane/ethyl acetate 91:9; 1H NMR (500 MHz, CDCl3): δ
= 9.38-9.35 (m, 1H), 7.91 (dd, J = 2.32 Hz, J = 10.27 Hz, 1H), 7.46-7.41 (m, 2H), 7.20 (t, J =
7.46 Hz, 1H), 7.16-7.13 (m, 2H), 7.08 (d, J = 10.27 Hz, 1H); 13C{1H}NMR (100 MHz, CDCl3):
δ = 155.8, 149.2, 146.7, 135.1, 129.7, 127.9, 126.9, 125.5, 121.1, 119.3; HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C12H9N4O2S 273.0451; Found 273.0458.
Typical procedure for the synthesis of 3,4-disubstituted 5-imino-1,2,4-thiadiazoles 5a-5m:
A mixture of isothiocyanate (1) (1.5 mmol), N-phenylbenzamidines (4) (1.5 mmol), I2 (50 mol%,
97 mg, 0.75 mmol) in CH3CN (1 mL) at room temperature for 1 to 2 h. After completion of the
reaction as monitored by TLC, the reaction mixture was quenched with a saturated aqueous
solution of Na2S2O3. The organic and aqueous layers were then separated and the aqueous layer
was extracted with ethyl acetate twice. The combined organic layers were dried over anhydrous
Na2SO4 and concentrated under reduced pressure to get crude. The crude was purified by silica
gel column chromatography using EtOAc : hexane as eluents to afford corresponding product 5.
(Z)-N-(3,4-diphenyl-1,2,4-thiadiazol-5(4H)-ylidene)aniline (5a):23 Yield: 89% (448 mg); white
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1
solid; Mp 196-198 °C; eluent: hexane/ethyl acetate 95:5; H NMR (500 MHz, CDCl3): δ = H
NMR (400 MHz, CDCl3) δ 7.44-7.27 (m, 10H), 7.26-7.19 (m, 2H), 7.10-6.99 (m, 3H);
13C{1H}NMR (100 MHz, CDCl3): δ = 164.5, 157.1, 150.6, 136.6, 130.3, 130.1, 129.53, 129.47,
128.8, 128.6, 128.3, 124.0, 121.0; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H16N3S
330.1034; Found 330.1037.
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(Z)-N-(3,4-diphenyl-1,2,4-thiadiazol-5(4H)-ylidene)-4-methylaniline (5b): Yield: 90% (472 mg);
white solid; Mp 192-194 °C; eluent: hexane/ethyl acetate 95:5; 1H NMR (500 MHz, CDCl3): δ =
7.42-7.27 (m, 8H), 7.25-7.21 (m, 2H), 7.12 (d, J = 8.08 Hz, 2H), 6.91 (d, J = 8.24 Hz, 2H), 2.31
(s, 3H); 13C{1H}NMR (125 MHz, CDCl3): δ = 164.1, 157.1, 148.2, 136.6, 133.4, 130.2, 130.15,
130.06, 129.4, 128.76, 128.72, 128.6, 128.3, 120.7, 20.9; HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C21H18N3S 344.1209; Found 344.1215.
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(Z)-N-(3,4-diphenyl-1,2,4-thiadiazol-5(4H)-ylidene)-4-methoxyaniline (5c): Yield: 90% (494
1
mg); white solid; Mp 207-209 °C; eluent: hexane/ethyl acetate 94:6; H NMR (500 MHz,
CDCl3): δ = 7.43-7.26 (m, 8H), 7.25-7.20 (m, 2H), 6.98-6.93 (m, 2H), 6.89-6.83 (m, 2H), 3.79
13
(s, 3H); C{1H}NMR (125 MHz, CDCl3): δ = 164.0, 157.1, 156.2, 144.1, 136.7, 130.3, 130.1,
129.4, 128.76, 128.72, 128.6, 128.3, 121.9, 114.6, 55.5; HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C21H18N3OS 360.1161; Found 360.1165.
(Z)-4-chloro-N-(3,4-diphenyl-1,2,4-thiadiazol-5(4H)-ylidene)aniline (5d): Yield: 87% (483 mg);
white solid; Mp 170-172 °C; eluent: hexane/ethyl acetate 95:5; 1H NMR (400 MHz, CDCl3): δ =
13
7.44-7.21 (m, 12H), 6.98-6.92 (m, 2H); C{1H}NMR (125 MHz, CDCl3): δ = 164.9, 157.2,
149.3, 136.5, 130.4, 129.9, 129.55, 129.48, 128.9, 128.7, 128.6, 128.3, 122.4; HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C20H15ClN3S 364.0641; Found 364.0645.
(Z)-N-(3,4-diphenyl-1,2,4-thiadiazol-5(4H)-ylidene)-4-nitroaniline (5e): Yield: 86% (492 mg);
1
pale yellow solid; Mp 180-182 °C; eluent: hexane/ethyl acetate 93:7; H NMR (300 MHz,
CDCl3): δ = 8.20(d, J = 9.07 Hz, 2H), 7.48-7.23 (m, 10H), 7.12 (d, J = 9.07 Hz, 2H);
13C{1H}NMR (125 MHz, CDCl3): δ = 166.2, 157.4, 156.4, 143.6, 136.2, 130.6, 129.6, 129.5,
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129.3, 128.8, 128.5, 128.4, 125.5, 121.5; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C20H15N4O2S 375.0838; Found 375.0842.
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(Z)-N-(3,4-diphenyl-1,2,4-thiadiazol-5(4H)-ylidene)-4-(trifluoromethyl)aniline (5f): Yield: 82%
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(528 mg); white solid; Mp 227-229 °C; eluent: hexane/ethyl acetate 94:6; H NMR (300 MHz,
CDCl3): δ = 7.57 (d, J = 8.53 Hz, 2H), 7.47-7.22 (m, 10H), 7.10 (d, J = 8.53 Hz, 2H);
13C{1H}NMR (125 MHz, CDCl3): δ = 165.5, 157.2, 153.7, 136.4, 130.5, 129.7, 129.5, 129.0,
128.7, 128.6, 128.3, 126.7 (d, J = 3 Hz), 125.7 (d, J = 26 Hz), 123.3, 121.2; HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C21H15F3N3S 398.0929; Found 398.0933.
(Z)-N-(3,4-diphenyl-1,2,4-thiadiazol-5(4H)-ylidene)-2-methoxyaniline (5g): Yield: 82% (450
1
mg); white solid; Mp 132-134 °C; eluent: hexane/ethyl acetate 94:6; H NMR (500 MHz,
CDCl3): δ = 7.42 (m, 2H), 7.36-7.27 (m, 6H), 7.26-7.20 (m, 2H), 7.08-7.03 (m, 1H), 6.99-6.95
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(m, 1H), 6.93-6.88 (m, 2H), 3.80 (s, 3H); C{1H}NMR (125 MHz, CDCl3): δ = 165.1, 156.9,
151.1, 140.1, 136.6, 130.2, 130.1, 129.4, 128.76, 128.70, 128.6, 128.2, 124.9, 121.5, 121.3,
112.4, 55.8; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H18N3OS 360.1157; Found
360.1162.
(Z)-3-chloro-N-(3,4-diphenyl-1,2,4-thiadiazol-5(4H)-ylidene)aniline (5h): Yield: 87% (483 mg);
white solid; Mp 164-166 °C; eluent: hexane/ethyl acetate 95:5; 1H NMR (400 MHz, CDCl3): δ =
7.45-7.20 (m, 11H), 7.06-7.01 (m, 2H), 6.94-6.89 (m, 1H); C{1H}NMR (100 MHz, CDCl3): δ
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= 165.3, 157.2, 151.8, 136.4, 134.9, 130.5, 130.4, 129.8, 129.5, 128.9, 128.7, 128.6, 128.3,
123.9, 121.6, 119.0; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H15ClN3S 364.0669; Found
364.0669.
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(Z)-N-(3,4-diphenyl-1,2,4-thiadiazol-5(4H)-ylidene)butan-1-amine (5i): Yield: 74%(349 mg);
white solid; Mp 120-122 °C; eluent: hexane/ethyl acetate 92:8; 1H NMR (300 MHz, CDCl3): δ =
7.40-7.14 (m, 10H), 3.11 (t, J = 7.15 Hz, 2H), 1.66-1.54 (m, 2H), 1.44-1.30 (m, 2H), 0.92 (t, J =
9
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7.43 Hz, 3H); C{1H}NMR (100 MHz, CDCl3): δ = 162.4, 157.5, 136.7, 130.4, 130.1, 129.3,
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128.7, 128.6, 128.5, 128.2, 55.6, 32.4, 20.6, 14.0; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C18H20N3S 310.1362; Found 310.1367.
(Z)-N-(4-phenyl-3-(p-tolyl)-1,2,4-thiadiazol-5(4H)-ylidene)aniline (5j): Yield: 76% (372 mg);
white solid; Mp 175-177 °C; eluent: hexane/ethyl acetate 95:5; 1H NMR (400 MHz, CDCl3): δ =
7.45-7.27 (m, 7H), 7.21-7.16 (m, 2H), 7.09-6.99 (m, 5H), 2.30 (s, 3H); 13C{1H}NMR (100 MHz,
CDCl3): δ = 164.5, 157.2, 150.7, 143.0, 140.6, 136.7, 129.5, 129.4, 128.9, 128.62, 128.67, 127.2,
123.9, 121.0, 21.4; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H18N3S 344.1221; Found
344.1224.
(Z)-N-(4-phenyl-3-(p-tolyl)-1,2,4-thiadiazol-5(4H)-ylidene)propan-2-amine (5k): Yield: 75%
1
(331 mg); white solid; Mp 164-166 °C; eluent: hexane/ethyl acetate 92:8; H NMR (400 MHz,
CDCl3): δ = 7.36-7.26 (m, 3H), 7.18-7.10 (m, 4H), 7.00 (d, J = 8.06 Hz, 2H), 3.08-2.98 (m, 1H),
13
2.27 (s, 3H), 1.14 (d, J = 6.23 Hz, 6H); C{1H}NMR (125 MHz, CDCl3): δ = 160.1, 157.5,
140.2, 137.1, 129.1, 128.8, 128.7, 128.6, 128.1, 127.7, 57.4, 23.2, 21.4; HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C18H20N3S 310.1332; Found 310.1336.
(Z)-N-(4-phenyl-3-(p-tolyl)-1,2,4-thiadiazol-5(4H)-ylidene)cyclopropanamine (5l): Yield: 76%
1
(333 mg); white solid; Mp 166-168 °C; eluent: hexane/ethyl acetate 91:9; H NMR (500 MHz,
CDCl3): δ = 7.36-7.28 (m, 3H), 7.16-7.12 (m, 4H), 7.01 (d, J = 8.08 Hz, 2H), 2.45-2.39 (m, 1H),
2.28 (s, 3H), 0.75-0.70 (m, 2H), 0.57-0.53 (m, 2H); 13C{1H}NMR (125 MHz, CDCl3): δ = 166.4,
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157.6, 140.4, 136.7, 129.3, 128.8, 128.62, 128.58, 128.4, 127.5, 36.3, 21.4, 7.1; HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C18H18N3S 308.1124; Found 308.1131.
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(Z)-N-(4-phenyl-3-propyl-1,2,4-thiadiazol-5(4H)-ylidene)propan-1-amine (5m): Yield: 73%
(352 mg); liquid; eluent: hexane/ethyl acetate 90:10; 1H NMR (500 MHz, CDCl3): δ = 7.54-7.48
(m, 2H), 7.47-7.41 (m, 1H), 7.28-7.23 (m, 2H), 3.00 (t, J = 7.02 Hz, 2H), 2.24 (t, J = 7.47 Hz,
2H), 1.65-1.53 (m, 4H), 0.89-0.85 (m, 6H); 13C{1H}NMR (100 MHz, CDCl3): δ = 163.1, 159.0,
136.3, 129.9, 129.1, 128.6, 57.8, 32.8, 23.5, 19.1, 13.6, 11.9; HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C14H20N3S 262.1367; Found 262.1372.
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AUTHOR INFORMATION
Corresponding Author
* E-mail: drmangarao@gmail.com
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We gratefully acknowledge SERB, New Delhi, India (PDF/2016/000177) for financial support in
the form of NPDF. The authors T. N and J. N thank the CSIR and UGC, New Delhi for financial
support in the form of fellowships.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
Copies of 1H and 13C NMR spectral data for all the products and X-ray crystallographic data for
3a, 5k and C'. (PDF)
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