Sulfur-carbon bond formation through ring-opening of triazolothiadiazole with organometallics

Article abstract of DOI:10.1002/ejoc.201400151

An efficient and convenient method was developed for the formation of S-substituted thiotriazoles through an unprecedented organometallic addition and subsequent ring-opening sequence of 3-substituted [1,2,4]triazolo[3,4-b][1,3,4] thiadiazole. The method is applicable to a wide range of substrates containing different functional groups and furnishes excellent yields of the corresponding N-unsubstituted 3- or 5-alkyl, aryl, alkynyl and alkenyl sulfanyl-1,2,4-triazole products. Copyright

Full text of DOI:10.1002/ejoc.201400151

FULL PAPER
DOI: 10.1002/ejoc.201400151
Sulfur–Carbon Bond Formation through Ring-Opening of Triazolothiadiazole
with Organometallics
Raja Ben Othman,[a,b] Stéphane Massip,[c] Mathieu Marchivie,[c] Christian Jarry,[c]
Johnny Vercouillie,[d] Sylvie Chalon,[d] Gérald Guillaumet,[a] Franck Suzenet,*[a] and
Sylvain Routier*[a]
Keywords: Synthetic methods / Domino reactions / Sulfur heterocycles / Nitrogen heterocycles / Grignard reagents
An efficient and convenient method was developed for the
strates containing different functional groups and furnishes
formation of S-substituted thiotriazoles through an unprece- excellent yields of the corresponding N-unsubstituted 3- or
dented organometallic addition and subsequent ring-open- 5-alkyl, aryl, alkynyl and alkenyl sulfanyl-1,2,4-triazole
ing sequence of 3-substituted [1,2,4]triazolo[3,4-b][1,3,4]thia- products.
diazole. The method is applicable to a wide range of sub-
propargylic acid.[4] It is therefore of great interest to develop
Introduction
efficient methods for the synthesis and functionalization of
During the past decade, C–S bond formation reactions
1,2,4-triazoles, especially because several of its fellows are
have received considerable attention. Their creation is chal-
known to possess a wide range of biological activities, for
lenging because thiols can dimerize or complex transition
example against cancer, tuberculosis, convulsion, inflam-
metals.[1] As a result, catalytic reactions involving organo-
metallic reagents are seldom used compared to more versa-
tile methods generating C–C, C–O, and C–N bonds.[2] Nev-
ertheless, despite these drawbacks, methods leading to C–S
bonds are becoming increasingly prevalent. Among them,
metal-catalyzed reactions involving copper, palladium, rho-
dium, iron, and gold, are widely employed.[3]
Despite numerous efforts, limitations occur in hetero-
cyclic series especially when an acidic proton is present. For
example, when triazole nitrogen atoms are not substituted,
access to such heterocycles is restricted to nucleophilic sub-
stitutions without involving any transition metals. Organo-
metallic methods are, in this case, inefficient and useful elec-
trophiles are limited to nitrobenzenes, halogenoalkyls, and
mation, pain, depression, bacterial growth or ulcers.[5]
Interestingly, working with sulfur-containing hetero-
cycles may provide unexpected results. Ethylene was acci-
dentaly proved to be released during the cryogenic reaction
of organolithium derivatives with imidazothiazolines. Al-
though this method led to free-nitrogen 1,2,4-triazoles, its
extrapolation to other Grignard reagents seemed uncertain.
Improvements were, however, considered possible,[6] and we
report herein unprecedented results in the pursuit of this
objective.
Results and Discussion
In a continuation of our research programs on novel re-
actions of rare heterocycles, we focused on building a li-
brary of [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives 2
(Scheme 1), which are readily available from the parent
thiones 1 through a classical protocol.[7]
[a] Institut de Chimie Organique et Analytique, Université
d’Orléans, UMR CNRS 7311,
BP 6759, 45067 Orléans Cedex 2, France
E-mail: franck.suzenet@univ-orleans.fr
sylvain.routier@univ-orleans.fr
http://www.univ-orleans.fr/icoa/
[b] École Supérieure des Sciences et de Technologie de Hammam
Sousse (ESST), Laboratoire d’Application de la Chimie aux
Ressources et Substances Naturelles et à l’Environnement
(LACReSNE), Faculté des Sciences de Bizerte,
Rue Lamine Abassi 4011 Hammam Sousse, 7021 Zarzouna,
Bizerte Tunisie
[c] Université Bordeaux Segalen, CNRS FRE 3396,
Pharmacochimie,
146 Rue Léo Saignat, 33000 Bordeaux, France
[d] Inserm U930 Imagerie et cerveau, U INSERM 930, UFR des
Sciences Pharmaceutiques,
31 avenue Monge, 37200 Tours, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201400151.
Scheme 1. Synthesis of starting material 3-substituted [1,2,4]tri-
azolo[3,4-b][1,3,4]thiadiazoles.
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We first prepared 2a as a model with which to examine Table 1. Copper iodide-catalyzed reactions of triazolo-thiadiazole
CH activation.[8] To this end, we carried out a reaction with
2a with aryl iodides.
2a and p-iodotoluene in the presence of CuI (10 mol-%),
phenanthroline, and tBuOK, however, only 3-phenyl-5-
thioaryl-1H-1,2,4-triazole (4a) was isolated in very low yield
(7%; Scheme 2). Because CH arylation of 2a was not pos-
sible, irrespective of the conditions used, we decided to fo-
cus on increasing the yield in 4a. By omitting phenanthrol-
ine from the reaction mixture, the reaction reached comple-
tion and the desired product 4a was isolated in 90% yield;
the 6-arylated derivative 3 was never detected.
Scheme 2. First reactions leading to 3-phenyl-5-thioaryl-1H-1,2,4-
triazole (4a). Reagents and conditions: (i) tBuOK (2.5 equiv.), CuI
(10 mol-%), DMF, argon, 36 h, 140 °C; Yield: 6% (with 0.1 equiv.
phenanthroline) or 90% (without phenanthroline).
A survey of the literature did not reveal any reports of
thiadiazole ring opening concomitant with the reaction of
a halogenoaryl derivative under copper catalysis. The high
yield and novelty of this tandem transformation, which
seems to imply cyanide release, compelled us to investigate
its scope and limitations as well as to seek a realistic mecha-
nism. We report herein a novel and efficient protocol for
the preparation of a collection of 5-thioether triazoles 4
from readily available [1,2,4]triazolo[3,4-b][1,3,4]thiadi-
azoles derivatives of type 2.
[a] Yield of isolated product after column chromatography on silica
gel. [b] When the reaction was carried out under microwave irradia-
tion, after 1 h only degradation products were observed. [c] The
position of the NH group is based on the ORTEP diagram of 4c
(Figure 1).
The use of the optimized reaction conditions [i.e., CuI
(cat.), tBuOK, N,N-dimethylformamide (DMF), 140 °C]
with 2a and a series of aryl iodides (Table 1) led, in all cases,
to the expected products 4.
Reactions involving electron-rich or -deficient phenyl
iodides proceeded smoothly and efficiently and afforded the
desired products 4b–f in excellent yields after 36 h. When
the reaction was carried out under microwave irradiation,
only degradation products were observed.
Figure 1. ORTEP diagram of 4c.
Several functional groups were tolerated and the reaction
afforded S-substituted thiotriazoles 4bЈ–p in good to very
The structure of 4c was solved by single-crystal X-ray good yields (Table 2). Vinyl and acetylenyl moieties were
diffraction analysis. The ORTEP depiction in Figure 1 con- also good substrates (Table 2, entries 8, 12, 13), with the
firms that the aromatic part originating from the organo- exception of 4m, which was isolated but was too unstable
metallic reagent is bonded to the sulfur atom. Crystalline to be stored (Table 2, entry 9). The use of phenylmagnesium
cohesion is reinforced through an internal H bond (HN(1)– bromine or phenyllithium led to the formation of 4bЈ in
N(4) 2.845 Å) that leads to an infinite chain along the c- yields similar to those obtained using cuprate formed in situ
axis.[9]
(Compare Table 2 entries 1 and 10 with Table 1, entry 1).[10]
Reasoning that the reaction proceeded through an nu- In all cases, condenstations of organometallics are achieved
cleophilic organocopper species generated in situ, we then in less than 1 h.
decided to investigate the effect of various organometallic
The structure of 4bЈ was solved by single-crystal X-ray
compounds, i.e., Grignard reagents, at room temperature, diffraction. The given ORTEP representations confirm that
and organolithium derivatives at low temperature, with sub- the aromatic part originating from the organocuprate is
strate 2a.
bonded to the sulfur atom (Figure 2). Compound 4bЈ crys-
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Sulfur-Carbon Bond Formation with Triazolothiadiazole
Table 2. Reactions of triazolothiadiazole 2a with Grignard reagents These independent molecules are linked by two successive
RMgX and organolithiums RLi.[a] (All reactions required 2 equiv.
H bonds (HN(22)–N(4) 2.816 Å and N(21)–HN(2) 3.012 Å
of organometallic reagent. A stoichiometric amount led to incom-
with N–H–N angles close to 170°) to form a tetramer.[9]
plete reactions).
Figure 2. ORTEP diagram of 4bЈ.
This novel method clearly represents an improvement
over existing reactions because it furnishes unconventional
aryl, vinyl, and acetylenyl sulfides[11] on unsubstituted ni-
trogen triazoles. The reaction occurs in a single step
through cyanide ejection in situ,[12] irrespective of the
organometallic compound used. In addition, the system is
compatible with both small and large Grignard reagents.
To the best of our knowledge, this is the first example of
the direct introduction of vinyl groups on the sulfur atom
with a good yield; at present, these vinyl sulfides are only
accessible from acetylenic thioethers.[13] To examine the cy-
anide moiety removal in more detail and to gain further
insight into the mechanism, we reacted 2b in the presence
of iPrMgBr (Scheme 3). Ring opening was achieved as ex-
pected and the reaction provided a stoichiometric amount
of benzylcyanide concomitant with 4j.
Scheme 3. Examining nitrile elimination.
Based on of these results, we are now able to propose a
plausible mechanism and explain the formation of S-substi-
tuted 5-thiotriazoles and 3-thiotriazoles (Scheme 4). A nu-
cleophilic attack of the organometallic reagent on the sulfur
atom initiates ring opening, leading to the elimination of
the cyanide moiety. The desired products were obtained in
different tautomeric forms of the 1,2,4-triazole ring after
hydrolysis.
[a] Argon atmosphere, conducted at room temp. [b] Argon atmo-
sphere, conducted at –78 °C to room temp. [c] Yield of isolated
product after column chromatography on silica gel. [d] The posi-
tion of the NH group based on the ORTEP diagram of 4bЈ.
tallizes with two independent molecules that show a slight
difference in the N(1)–C(5)–S(12)–C(13) torsion angle. thiotriazoles.
Scheme 4. Proposed mechanism for the formation of S-substituted
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F. Suzenet, S. Routier et al.
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To complete the study, we explored the scope of this reac-
tion. To our satisfaction, the reaction took place easily
using a range of 3-substituted triazolothiadiazoles 2
(Table 3) and gave good yields in the presence of vinyl and
isopropylmagnesium bromides. A methyl group at C(3) of 2
was well tolerated (entries 2 and 6) despite its mildly acidic
character, whereas reactions with C(3)-substituted pyrid-
inyl-triazolothiadiazole-specific optimization was required
(entries 4 and 8). Access to the previously isolated (see
above) compounds 4j and 4m from triazolothiadiazole 2d
(entries 3 and 7) is consistent with the proposed mecha-
nism.
Experimental Section
General: 1H and 13C NMR spectra were recorded with a Bruker
DPX 250 MHz or 400 MHz spectrometer using CDCl3 or [D6]-
DMSO. The chemical shifts are reported in parts per million (ppm,
δ scale) and coupling constant (J) values are in Hertz [Hz]. The
following abbreviations are used for multiplicities: s (singlet), d
(doublet), t (triplet), q (quartet), m (multiplet), dd (doublet doub-
let), and ddd (doublet doublet doublet). For some compounds, only
13C DEPT 135 spectra are described because we were unable to
observe the Cq signals in 13C NMR spectra even with high concen-
tration of product or by changing the nature of the solvent. Melting
points are uncorrected. IR absorption spectra were obtained with
a Perkin–Elmer PARAGON 1000 PC spectrometer and values are
reported in cm–1. HRMS were recorded with a Bruker maXis mass
spectrometer. The progress of the reactions were monitored by
using TLC with silica gel plates (silica Merck 60 F254). Spots were
visualized by UV light at 254 and 356 nm. Column chromatog-
raphy was performed by using silica gel 60 (0.063–0.200 mm,
Merck). Reactions requiring anhydrous conditions were performed
under argon. All solvents were freshly distilled under argon prior
to use. Petroleum ether (PE) had a boiling range of 45–65 °C.
Chemicals were obtained from Aldrich and Acros organics. Micro-
wave irradiation was carried out in sealed 2–5 mL vessels placed in
a Biotage Initiator system using a standard absorbance level
(300 W maximum power). The temperatures were externally mea-
sured by an IR probe, which gave the temperature on the surface
of the vial. The reaction time was measured from the point at which
the reaction mixture reached the stated temperature for tempera-
ture-controlled experiments. Pressure was measured by a non-in-
vasive sensor integrated into the cavity lid.
Table 3. Reactions of other triazolothiadiazoles with Grignard rea-
gents, RMgX.
Copper Iodide Catalysis with Aryl Iodides; General Procedure A: In
a sealed tube, copper iodide (10 mol-%) was added under argon
to a solution of 2a (1.0 equiv., 0.50 mmol, 101.0 mg), aryl iodide
(2.0 equiv., 1.00 mmol), and tBuOK (2.5 equiv., 1.25 mmol) in
DMF (2 mL). The mixture was stirred at 140 °C for 48 h, then the
crude material was evaporated under reduced pressure. The residue
was dissolved in water (20 mL), and the mixture was extracted with
CH2Cl2 (2ϫ 20 mL). The combined organic layers was dried with
magnesium sulfate, filtered, and concentrated in vacuo. The residue
was purified by flash column chromatography on silica gel (PE/
EtOAc).
[a] Yield of isolated product after column chromatography on silica
gel. [b] Reaction carried out in a very high concentration.
General Procedure B: In a 25 mL flask, RMgX (see Table 2;
2.0 equiv., 1.0 mmol, 2.5 m solution in THF) was added dropwise
under argon at room temperature to a solution of 2a–e (1.0 equiv.,
0.5 mmol) in THF (5 mL), and the mixture was stirred for 25–
60 min. At the end of the reaction, an aqueous solution of satu-
rated NH4Cl (10 mL) was added and the mixture was extracted
with CH2Cl2 (2ϫ 20 mL). The combined organic layers were dried
with magnesium sulfate, filtered, and concentrated in vacuo. The
residue was purified by flash column chromatography on silica gel
(PE/EtOAc).
Conclusions
A simple, efficient, practical, and convenient protocol
has been developed for the synthesis of S-substituted thio-
triazoles through the in situ generation of the cyanide com-
pound and tandem ring-opening of triazolothiazole with
various organometallic compounds including cuprates
formed in situ, lithiated species, and a wide range of Grig-
nard reagents. The direct introduction of alkyl, aryl, alk-
ynes, and vinyl groups on the sulfur atom with high yield
was achieved in only a few minutes by using organometallic
reagents. A mechanism has been proposed that involves nu-
cleophilic action of organometallic reagents onto the sulfur
atom of the thiazolotriazole core. This unprecedented
method could offer new perspectives for building triazole
libraries and for access to nonclassical molecules.
General Procedure C: In a 25 mL flask, n-BuLi (2.0 equiv.,
1.0 mmol, 2.5 m in n-hexane) was added dropwise under argon at
–78 °C to a solution of phenylethyne or propylethyne (2.0 equiv.,
1.0 mmol) in THF (5 mL), and the mixture was stirred at –78 °C
for 0.5 h. Compound 2a (1.0 equiv., 0.5 mmol) was added and the
reaction mixture was allowed to reach room temperature for 25 to
30 min. Upon completion, the reaction was quenched with aqueous
saturated NH4Cl (10 mL), and extracted with CH2Cl2 (2ϫ 20 mL).
The combined organic layers were dried with magnesium sulfate,
filtered, and concentrated in vacuo. The residue was purified by
flash column chromatography on silica gel (PE/EtOAc).
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Sulfur-Carbon Bond Formation with Triazolothiadiazole
General Procedure D: In a 10 mL flask, isopropylmagnesium brom-
ide or vinylmagnesium bromide (2.0 equiv., 1.0 mmol, 2.5 m solu-
tion in THF) was added dropwise under argon at room tempera-
ture to 2d (1.0 equiv., 0.5 mmol), and the mixture was stirred for
70 min. At the end of the reaction, the mixture was quenched with
aqueous saturated NH4Cl (10 mL), and the mixture was extracted
with CH2Cl2 (2ϫ 20 mL). The combined organic layers were dried
with magnesium sulfate, filtered, and concentrated in vacuo. The
residue was purified by flash column chromatography on silica gel
(PE/EtOAc).
3-Phenyl[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (2a):[7c] 1H NMR
(400 MHz, [D6]DMSO): δ = 9.48 (s, 1 H), 8.27–8.20 (m, 2 H), 7.65–
7.53 (m, 3 H) ppm. 13C NMR (101 MHz, [D6]DMSO): δ = 157.1
(Cq), 155.1 (2 CHAr), 145.6 (2 CHAr), 130.7 (CHAr), 129.6 (Cq),
126.2 (Cq), 126.0 (CH) ppm. HRMS (EI-MS): m/z calcd. for
C9H6N4S [M + H]+ 203.03859; found 203.03876.
3-Phenyl-5-(o-tolylthio)-1H-1,2,4-triazole (4c): Compound 4c was
obtained as a white solid in 98% yield (General Procedure A). Rf
= 0.61 (PE/EtOAc, 6:4); m.p. 159–161 °C. IR (ATR diamond): ν=
˜
3049, 2916, 2849, 2712, 1509, 1441, 1393, 1321, 1258, 1158, 1072,
1
1024, 971, 787, 728 cm–1. H NMR (400 MHz, CDCl3): δ = 11.95
(br. s, 1 H), 7.89 (d, J = 7.1 Hz, 2 H), 7.44 (d, J = 7.7 Hz, 1 H),
7.41–7.30 (m, 3 H), 7.22–7.04 (m, 3 H), 2.39 (s, 3 H) ppm. 13C
DEPT NMR (101 MHz, CDCl3): δ = 133.8 (CHAr), 131.0 (CHAr),
130.0 (CHAr), 129.3 (CHAr), 128.7 (2 CHAr), 127.0 (CHAr), 126.5
(2 CHAr), 20.7 (CH3) ppm. HRMS (EI-MS): m/z calcd. for
C15H13N3S [M + H]+ 268.09029; found 268.09059.
3-Phenyl-5-{[4-(trifluoromethyl)phenyl]thio}-1H-1,2,4-triazole (4d):
Compound 4d was obtained as a white solid in 95% yield (General
Procedure A). Rf = 0.61 (PE/EtOAc, 6:4); m.p. 161–163 °C. IR
(ATR diamond): ν = 3049, 2916, 2851, 2782, 1605, 1459, 1400,
˜
1
1326, 1259, 1154, 1101, 1063, 981, 828, 692. H NMR (400 MHz,
CDCl3): δ = 12.53 (br. s, 1 H), 7.88 (d, J = 7.5 Hz, 2 H), 7.55–7.41
(m, 5 H), 7.41–7.32 (m, 2 H) ppm. 13C DEPT NMR (101 MHz,
CDCl3): δ = 130.8 (CHAr), 130.1 (2 CHAr), 129.0 (2 CHAr), 126.5
(2 CHAr), 125.9 (q, 3JCH–F = 4.0 Hz, 2 CH) ppm. HRMS (EI-MS):
m/z calcd. for C15H10F3N3S [M + H]+ 322.06202; found 322.06221.
6-Benzyl-3-phenyl[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (2b):[7b] 1H
NMR (400 MHz, CDCl3): δ = 8.36–8.32 (m, 2 H), 7.60–7.33 (m, 8
H), 4.35 (s, 2 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 169.7
(Cq), 154.9 (Cq), 146.3 (Cq), 134.2 (Cq), 130.3 (CHAr), 129.3
(2CHAr), 129.0 (2CHAr), 128.9 (2CHAr), 128.3 (CHAr), 126.4
(2CHAr), 125.6 (Cq), 38.6 (CH2) ppm. HRMS (EI-MS): m/z calcd.
for C16H13N4S [M + H]+ 293.08554; found 293.08591.
3-Methyl[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole: (2c).[7g,14] 1H NMR
(400 MHz, CDCl3): δ = 8.74 (s, 1 H), 2.76 (s, 3 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 152.6 (Cq), 151.9 (CH), 144.7 (Cq), 10.3
(CH3) ppm. HRMS (EI-MS): m/z calcd. for C4H4N4S [M + H]+
141.02294; found 141.02316.
6-Methyl-3-phenyl[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (2d):[15] 1H
NMR (400 MHz, [D6]DMSO): δ = 8.27–8.18 (m, 2 H), 7.66–7.49
(m, 3 H), 2.80 (s, 3 H) ppm. 13C NMR (101 MHz, [D6]DMSO): δ
= 167.4 (Cq), 155.5 (Cq), 145.4 (Cq), 130.6 (CHAr), 129.5 (2CHAr),
126.1 (2CHAr), 126.0 (Cq), 18.5 (CH3) ppm.
Ethyl 4-[(3-Phenyl-1H-1,2,4-triazol-5-yl)thio]benzoate (4e): Com-
pound 4e was obtained as a white solid in 67% yield (General
Procedure A). Rf = 0.50 (PE/EtOAc, 6:4); m.p. 108–110 °C. IR
(ATR diamond): ν= 3052, 2968, 2850, 2723, 1719, 1593, 1459,
˜
1399, 1286, 1276, 1257, 1176, 1123, 1016, 981, 848, 705, 685 cm–1.
1H NMR (400 MHz, CDCl3): δ = 12.82 (br. s, 1 H), 7.98–7.83 (m,
4 H), 7.46–7.33 (m, 5 H), 4.34 (q, J = 7.1 Hz, 2 H), 1.36 (t, J =
7.1 Hz, 3 H) ppm. 13C DEPT NMR (101 MHz, CDCl3): δ = 130.6
(CHAr), 130.2 (2 CHAr), 129.4 (CHAr), 128.9 (2 CHAr), 126.5 (3
CHAr), 61.2 (CH2), 14.2 (CH3) ppm. HRMS (EI-MS): m/z calcd.
for C17H15N3O2S [M + H]+ 326.09577; found 326.09581.
5-[(4-Methoxyphenyl)thio]-3-phenyl-1H-1,2,4-triazole (4f): Com-
pound 4f was obtained as a white solid in 79% yield (General Pro-
cedure A) and 82% yield (General Procedure B). Rf = 0.42 (PE/
3-(4-Pyridyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole
(2e):[16]
1H
NMR (250 MHz, [D6]DMSO): δ = 9.56 (s, 1 H), 8.88–8.77 (m, 2
H), 8.20–8.10 (m, 2 H) ppm. 13C NMR (63 MHz, [D6]DMSO): δ
= 159.5 (CH), 157.8 (Cq), 152.6 (2CHAr), 145.1 (Cq), 134.3 (Cq),
121.2 (2CHAr) ppm. HRMS (EI-MS): m/z calcd. for C8H6N5S [M
+ H]+ 204.03384; found 204.03438.
EtOAc, 6:4); m.p. 142–144 °C. IR (ATR diamond): ν= 3068, 2916,
˜
2842, 2664, 1719, 1590, 1493, 1467, 1341, 1246, 1183, 1175, 1022,
976, 825, 728, 691 cm–1. 1H NMR (400 MHz, CDCl3): δ = 11.32
(br. s, 1 H), 8.00–7.87 (m, 2 H), 7.61–7.51 (m, 2 H), 7.36–7.41 (m,
3 H), 6.93–6.79 (m, 2 H), 3.77 (s, 3 H) ppm. 13C DEPT NMR
(101 MHz, CDCl3): δ = 135.8 (2 CHAr), 129.9 (CHAr), 128.7 (2
CHAr), 126.4 (2 CHAr), 115.3 (2 CHAr), 55.4 (CH3) ppm. HRMS
(EI-MS): m/z calcd. for C15H13N3OS [M + H]+ 284.08521; found
284.08532.
3-Phenyl-5-(p-tolylthio)-1H-1,2,4-triazole (4a): Compound 4a was
obtained as a white solid in 90% yield by following General Pro-
cedure A. Rf = 0.61 (PE/EtOAc, 6:4); m.p. 125–127 °C. IR (ATR
diamond): ν = 3075, 2978, 2920, 2850, 2783, 1557, 1491, 1260,
˜
1142, 1019, 976, 806, 775, 687, 634 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 12.54 (br. s, 1 H), 7.86 (d, J = 6.8 Hz, 2 H), 7.40–7.28
(m, 5 H), 7.02 (d, J = 8.0 Hz, 2 H), 2.23 (s, 3 H) ppm. 13C DEPT
NMR (101 MHz, CDCl3): δ = 132.9 (2 CHAr), 130.3 (2 CHAr),
130.0 (CHAr), 128.7 (2 CHAr), 126.5 (2 CHAr), 21.1 (CH3) ppm.
HRMS (EI-MS): m/z calcd. for C15H13N3S [M + H]+ 268.09029;
found 268.09061.
3-{[4-(Phenoxymethyl)phenyl]thio}-5-phenyl-1H-1,2,4-triazole (4g):
Compound 4g was obtained as a viscous liquid in 75% yield (Gene-
ral Procedure B). Rf = 0.46 (PE/EtOAc, 6:4). IR (ATR diamond):
ν= 3063, 2928, 2865, 1588, 1476, 1462, 1324, 1224, 1141, 1072,
˜
1
1023, 777, 728, 691 cm–1. H NMR (400 MHz, CDCl3): δ = 10.63
(br. s, 1 H), 7.92–7.81 (m, 2 H), 7.37–7.22 (m, 8 H), 7.11–7.04 (m,
2 H), 6.99 (dt, J = 7.9, 1.3 Hz, 1 H), 6.76 (ddd, J = 8.4, 2.4, 1.1 Hz,
1 H), 4.86 (s, 2 H) ppm. 13C DEPT NMR (101 MHz, CDCl3): δ =
130.2 (CHAr), 130.2 (CHAr), 128.8 (2 CHAr), 128.5 (2 CHAr), 128.0
(CHAr), 127.5 (2 CHAr), 126.5 (2 CHAr), 124.1 (CHAr), 117.8
(CHAr), 115.0 (CHAr), 70.0 (CH2) ppm. HRMS (EI-MS): m/z
calcd. for C21H17N3OS [M + H]+ 360.11651; found 360.11665.
3-(Methylthio)-5-phenyl-1H-1,2,4-triazole (4h):[17] Compound 4h
was obtained as a white solid in 93% yield (General Procedure B).
Rf = 0.42 (PE/EtOAc, 6:4); m.p. 160–162 °C. IR (ATR diamond):
3-Phenyl-5-(phenylthio)-1H-1,2,4-triazole (4b): Compound 4b was
obtained as a white solid in 83% (General Procedure A), 83% (Ge-
neral Procedure B), and 93% (General Procedure C). Rf = 0.61
(PE/EtOAc, 6:4); m.p. 125–127 °C. IR (ATR diamond): ν = 3061,
˜
2917, 2782, 1556, 1488, 1465, 1417, 1327, 1271, 1258, 1004, 778,
704, 682 cm–1. 1H NMR (400 MHz, CDCl3): δ = 12.19 (br. s, 1 H),
7.91 (d, J = 6.6 Hz, 2 H), 7.53–7.45 (m, 2 H), 7.43–7.32 (m, 3 H),
7.31–7.22 (m, 3 H) ppm. 13C DEPT NMR (101 MHz, CDCl3): δ =
132.2 (CHAr), 130.2 (CHAr), 129.5 (2 CHAr), 128.8 (2 CHAr), 128.6 ν= 2974, 2840, 2773, 2649, 1548, 1463, 1338, 1267, 1139, 1027, 976,
˜
(CHAr), 126.5 (3 CHAr) ppm. HRMS (EI-MS): m/z calcd. for 780, 726, 692 cm–1. 1H NMR (250 MHz, [D6]DMSO): δ = 14.28
C14H11N3S [M + H]+ 254.07464; found 254.07492.
(br. s, 1 H), 8.04–7.91 (m, 2 H), 7.60–7.40 (m, 3 H), 2.63 (s, 3
3229
Eur. J. Org. Chem. 2014, 3225–3231
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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F. Suzenet, S. Routier et al.
FULL PAPER
H) ppm. 13C DEPT NMR (63 MHz, [D6]DMSO): δ = 129.8
= 13.00 (br. s, 1 H), 8.06–7.89 (m, 2 H), 7.48–7.29 (m, 3 H), 3.23–
(CHAr), 128.5 (2 CHAr), 126.0 (2 CHAr), 14.7 (CH3) ppm. HRMS 3.07 (m, 2 H), 1.70–1.42 (m, 2 H), 1.50–1.31 (m, 2 H), 0.89 (t, J =
(EI-MS): m/z calcd. for C9H9N3S [M + H]+ 192.05899; found 7.3 Hz, 3 H) ppm. 13C DEPT NMR (101 MHz, CDCl3): δ = 130.0
192.05929.
(CHAr), 128.8 (2 CHAr), 126.5 (2 CHAr), 32.7 (CH2), 31.6 (CH2),
21.7 (CH2), 13.5 (CH3) ppm. HRMS (EI-MS): m/z calcd. for
C12H15N3S [M + H]+ 234.10594; found 234.10643.
3-(Ethylthio)-5-phenyl-1H-1,2,4-triazole (4i):[17a] Compound 4i was
obtained as a white solid in 91% yield (General Procedure B). Rf
= 0.46 (PE/EtOAc, 6:4); m.p. 85–87 °C. IR (ATR diamond): ν=
5-Phenyl-3-[(phenylethynyl)thio]-1H-1,2,4-triazole (4o): Compound
4o was obtained as a white solid in 96% yield (General Procedure
C). Rf = 0.56 (PE/EtOAc, 6:4); m.p. 148–150 °C. IR (ATR dia-
˜
3068, 2978, 2848, 2776, 1556, 1463, 1335, 1263, 1143, 1027, 977,
726, 690 cm–1. 1H NMR (400 MHz, CDCl3): δ = 11.31 (br. s, 1 H),
8.03–7.89 (m, 2 H), 7.45–7.31 (m, 3 H), 3.16 (q, J = 7.3 Hz, 2 H), mond): ν= 2992, 2921, 1863, 1796, 1560, 1464, 1328, 1286, 1274,
˜
1.36 (t, J = 7.3 Hz, 3 H) ppm. 13C DEPT NMR (101 MHz,
CDCl3): δ = 130.0 (CHAr), 128.8 (2 CHAr), 126.5 (2 CHAr), 27.3
(CH2), 14.9 (CH3) ppm. HRMS (EI-MS): m/z calcd. for C10H11N3S
[M + H]+ 206.07464; found 206.07486.
1146, 1008, 837, 775, 754, 718, 686 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 14.27 (br. s, 1 H), 7.87–7.75 (m, 2 H), 7.42–7.30 (m, 3
H), 7.24–7.18 (m, 1 H), 7.15–7.08 (m, 4 H) ppm. 13C DEPT NMR
(101 MHz, CDCl3): δ = 132.0 (2 CHAr), 130.6 (CHAr), 129.3
(CHAr), 128.8 (2 CHAr), 128.2 (2 CHAr), 126.5 (2 CHAr) ppm.
HRMS (EI-MS): m/z calcd. for C16H11N3S [M + H]+ 278.07464;
found 278.07514.
3-(Isopropylthio)-5-phenyl-1H-1,2,4-triazole (4j): Compound 4j was
obtained as a white solid by following General Procedure B, in
98% yield (from 2a), 86% yield (from 2c), and 88% yield (from
2e). Rf = 0.46 (PE/EtOAc, 6:4); m.p. 128–130 °C. IR (ATR dia-
3-(Pent-1-yn-1-ylthio)-5-phenyl-1H-1,2,4-triazole (4p): Compound
4p was obtained as a white solid in 97% yield (General Procedure
C). Rf = 0.60 (PE/EtOAc, 6:4); m.p. 122–124 °C. IR (ATR dia-
mond): ν= 3073, 2926, 2864, 1556, 1460, 1442, 1460, 1328, 1240,
˜
1154, 1055, 1019, 980, 783, 726, 690 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 12.79 (br. s, 1 H), 8.06–7.92 (m, 2 H), 7.44–7.34 (m, 3 mond): ν= 3129, 3069, 2930, 2868, 2797, 1558, 1464, 1407, 1329,
˜
H), 3.84–3.75 (m, 1 H), 1.38 (s, 3 H), 1.36 (s, 3 H) ppm. 13C DEPT 1283, 1272, 1140, 1008, 878, 828, 776, 720, 688 cm–1. 1H NMR
NMR (101 MHz, CDCl3): δ = 130.0 (CHAr), 128.8 (2 CHAr), 126.6
(400 MHz, CDCl3): δ = 13.78 (br. s, 1 H), 8.01–7.87 (m, 2 H), 7.49–
(2 CHAr), 38.9 (CH), 23.5 (2 CH3) ppm. HRMS (EI-MS): m/z 7.32 (m, 3 H), 2.08–2.01 (m, 2 H), 1.47–1.29 (m, 2 H), 0.86 (t, J =
calcd. for C11H13N3S [M + H]+ 220.09029; found 220.09059.
7.3 Hz, 3 H) ppm. 13C DEPT NMR (101 MHz, CDCl3): δ = 130.5
(CHAr), 128.9 (2 CHAr), 126.5 (2 CHAr), 22.0 (CH2), 21.6 (CH2),
13.4 (CH3) ppm. HRMS (EI-MS): m/z calcd. for C13H13N3S [M +
H]+ 244.09029; found 244.09076.
3-(tert-Butylthio)-5-phenyl-1H-1,2,4-triazole (4k): Compound 4k
was obtained as a white solid in 95% yield (General Procedure B).
Rf = 0.60 (PE/EtOAc, 6:4); m.p. 139–141 °C. IR (ATR diamond):
ν= 2988, 2967, 2921, 2858, 2773, 2652, 1557, 1465, 1415, 1342,
3-(Isopropylthio)-5-methyl-1H-1,2,4-triazole (5a): Compound 5a
was obtained as a yellow solid in 96% yield (General Procedure
B). Rf = 0.33 (PE/EtOAc, 6:4); m.p. 70–72 °C. IR (ATR diamond):
˜
1258, 1221, 1160, 1143, 975, 927, 906, 782, 693 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 13.06 (br. s, 1 H), 8.13–8.03 (m, 2 H), 7.43–
7.33 (m, 3 H), 1.44 (s, 9 H) ppm. 13C DEPT NMR (101 MHz, ν= 3156, 3026, 2927, 2864, 2654, 1765, 1588, 1435, 1376, 1322,
˜
CDCl3): δ = 129.9 (CHAr), 128.7 (2 CHAr), 126.6 (2 CHAr), 31.2 (3 1268, 1242, 1156, 1060, 883, 703, 641 cm–1. 1H NMR (400 MHz,
CH3) ppm. HRMS (EI-MS): m/z calcd. for C12H15N3S [M + H]+
CDCl3): δ = 13.83 (br. s, 1 H), 3.77–3.67 (m, 1 H), 2.56 (s, 3 H),
1.38 (s, 3 H), 1.36 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ
= 157.5 (Cq), 156.0 (Cq), 38.3 (CH), 23.5 (2CH3), 12.6 (CH3) ppm.
HRMS (EI-MS): m/z calcd. for C6H11N3S [M + H]+ 158.07464;
found 158.07509.
234.10594; found 234.10637.
5-Phenyl-3-(vinylthio)-1H-1,2,4-triazole (4l):[18] Compound 4l was
obtained as a white solid by following General Procedure B, in
94% yield (from 2a), 75% yield (from 2c), and 87% yield (from
2e). Rf = 0.46 (PE/EtOAc, 6:4); m.p. 181–183 °C. IR (ATR dia-
3-(Isopropylthio)-5-pyridinyl-1H-1,2,4-triazole (5b): Compound 5b
was obtained as a white solid in 10% yield (General Procedure B)
and 62% yield (General Procedure D). Rf = 0.23 (PE/EtOAc, 3:7);
mond): ν= 3076, 2928, 2859, 1590, 1556, 1442, 1328, 1259, 1138,
˜
1071, 1025, 981, 906, 780, 724, 705, 690 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 12.66 (br. s, 1 H), 7.99–7.89 (m, 2 H), 7.46–7.36 (m, 3 m.p. 157–159 °C. IR (ATR diamond): ν= 3396, 2962, 2494, 1846,
˜
H), 6.85 (dd, J = 16.9, 9.7 Hz, 1 H), 5.53 (d, J = 16.9 Hz, 1 H), 5.46 1613, 1427, 1337, 1308, 1240, 1009, 991, 836, 746, 721 cm–1. 1H
(d, J = 9.7 Hz, 1 H) ppm. 13C DEPT NMR (101 MHz, CDCl3): δ NMR (400 MHz, CDCl3): δ = 13.87 (br. s, 1 H), 8.75 (d, J =
= 130.5 (CHAr), 128.9 (2 CHAr), 127.3 (CH), 126.5 (2 CHAr), 117.8 6.1 Hz, 2 H), 8.08 (d, J = 6.2 Hz, 2 H), 3.80–3.92 (m, 1 H), 1.45
(CH2) ppm. HRMS (EI-MS): m/z calcd. for C10H9N3S [M + H]+
204.05899; found 204.05934.
(s, 3 H), 1.43 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 160.3
(Cq), 153.8 (Cq), 149.5 (2CHAr), 138.9 (Cq), 120.9 (2CHAr), 39.5
(CH), 23.5 (2CH3) ppm. HRMS (EI-MS): m/z calcd. for
C10H12N4S [M + H]+ 221.08554; found 221.08610.
3-(Ethynylthio)-5-phenyl-1H-1,2,4-triazole (4m): Compound 4m
was obtained as a brown solid in 89% yield (General Procedure B).
Rf = 0.38 (PE/EtOAc, 6:4); m.p. 87–89 °C. This product was not
very stable and was only characterized by 1H NMR analysis. IR
5-Methyl-3-(vinylthio)-1H-1,2,4-triazole (5c):[13b] Compound 5c was
obtained as a white solid in 92% yield (General Procedure B). Rf
(ATR diamond): ν= 3127, 3104, 2922, 1555, 1467, 1455, 1441,
= 0.58 (PE/EtOAc, 6:4); m.p. 133–135 °C. IR (ATR diamond): ν=
˜
˜
1
1324, 1276, 1134, 1068, 977, 846, 789, 965, 757, 696, 683 cm–1. H
3156, 3028, 2927, 2873, 2802, 2655, 1712, 1588, 1427, 1372, 1329,
1266, 1059, 955, 888, 864, 728, 713, 701 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 13.36 (br. s, 1 H), 6.79 (dd, J = 16.8, 9.7 Hz, 1 H),
5.52 (d, J = 16.8 Hz, 1 H), 5.46 (d, J = 9.7 Hz, 1 H), 2.55 (s, 3
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 157.4 (Cq), 155.6 (Cq),
127.7 (CH), 117.1 (CH2), 12.4 (CH3) ppm. HRMS (EI-MS): m/z
calcd. for C5H7N3S [M + H]+ 142.04334; found 142.04366.
NMR (250 MHz, CDCl3): δ = 10.94 (br. s, 1 H), 7.98–7.72 (m, 2
H), 7.52–7.44 (m, 3 H), 3.31 (s, 1 H) ppm. HRMS (EI-MS): m/z
calcd. for C10H7N3S [M + H]+ 202.04334; found 202.04351.
3-(n-Butylthio)-5-phenyl-1H-1,2,4-triazole (4n): Compound 4n was
obtained as a white solid in 84% yield (General Procedure C). Rf
= 0.58 (PE/EtOAc, 6:4); m.p. 83–85 °C. IR (ATR diamond): ν=
˜
3059, 2922, 2857, 2789, 1552, 1465, 1418, 1335, 1265, 1139, 1008,
3-(Vinylthio)-5-pyridinyl-1H-1,2,4-triazole (5d): Compound 5d was
obtained as a white solid in 7% yield (General Procedure B) and
1
980, 922, 853, 775, 720, 685 cm–1. H NMR (400 MHz, CDCl3): δ
3230
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 3225–3231

Sulfur-Carbon Bond Formation with Triazolothiadiazole
Khan, A. Khan, M. I. J. Choudhary, Enz. Inhib. Med. Chem.
2010, 25, 572–576.
in 63% yield (General Procedure D). Rf = 0.16 (PE/EtOAc, 3:7);
m.p. 160–162 °C. IR (ATR diamond): ν= 3031, 2452, 1873, 1612,
˜
[6] J. Sisko, J. A. Kassick, B. S. Shetzline, Org. Lett. 2000, 2, 2877–
1427, 1333, 1301, 1009, 968, 836, 750, 707, 980, 678 cm–1. 1H NMR
(250 MHz, CDCl3): δ = 13.71 (br. s, 1 H), 8.75 (d, J = 6.2 Hz, 2
H), 8.08 (d, J = 6.2 Hz, 2 H), 6.85 (dd, J = 16.8, 9.6 Hz, 1 H), 5.60
(d, J = 16.8 Hz, 1 H), 5.55 (d, J = 9.6 Hz, 1 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 159.6 (Cq), 153.1 (Cq), 149.4 (2CHAr),
138.6 (Cq), 126.5 (CH), 121.0 (2CHAr), 118.7 (CH2) ppm. HRMS
(EI-MS): m/z calcd. for C9H8N4S [M + H]+ 205.05424; found
205.05488.
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Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C and 13C DEPT NMR spectra for all compounds.
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Acknowledgments
This research was supported by grants from the Région Centre and
the Labex IRON (ANR-11-LABX-0018-01).
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Received: January 29, 2014
Published Online: April 8, 2014
Eur. J. Org. Chem. 2014, 3225–3231
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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