Synthesis of 1,2,4-triazoles employing isocyanides

Article abstract of DOI:10.1016/j.tet.2013.01.039

A conceptually new, two-step synthesis of medicinally important 1,2,4-triazoles from isocyanides and thiosemicarbazones was developed. The method is based on the recently discovered TMSCl-promoted reaction of isocyanides that yields rare N¹,N³-disubstututed formamidrazones.

Full text of DOI:10.1016/j.tet.2013.01.039

Tetrahedron 69 (2013) 2289e2295
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Synthesis of 1,2,4-triazoles employing isocyanides
*
Pakornwit Sarnpitak, Mikhail Krasavin
Eskitis Institute for Cell and Molecular Therapies, Griffith University, Nathan, Queensland 4111, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
A conceptually new, two-step synthesis of medicinally important 1,2,4-triazoles from isocyanides and
thiosemicarbazones was developed. The method is based on the recently discovered TMSCl-promoted
reaction of isocyanides that yields rare N1,N3-disubstututed formamidrazones.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 6 November 2012
Received in revised form 14 December 2012
Accepted 7 January 2013
Available online 21 January 2013
Keywords:
Isocyanides
TMSCl-promoted reaction
Formamidrazones
1,2,4-Triazoles
Convergent synthesis
Dehydrogenation
1. Introduction
isocyanide NeH insertion followed by the elimination of iso-
thiocyanic acid (Scheme 2). Given the novelty of this reaction and
The synthetic utility of isocyanides extends far beyond the
an intriguing arrangement of potentially reactive electrophilic
hydrazone and nucleophilic amidine moieties in 9, we became in-
terested in identifying the utility of the latter for ring-forming
processes.16 Herein we described the application of isocyanide-
derived formamidrazones 9 toward facile preparation of diversely
substituted 1,2,4-triazoles.
preparation of
a-acyloxy and a-acylaminocarboxamides via the
‘classical’ Passerini1 and Ugi2 reactions, respectively, as this reagent
class continues to prove instrumental in de novo heterocycle con-
struction. The unique reactivity of a-acidic p-toluenesulfonylme-
thylisocyanide (TosMIC) enabled the van Leusen imidazole3 and
oxazole4 syntheses; numerous cases of successful use of bi-
functional reagents5 and post-condensational modifications6 in
conjunction with the Ugi reaction clearly attest to the power of
isocyanide chemistry to reach into new areas of heterocyclic
chemical space, aromatic and saturated alike (Scheme 1).
2. Results and discussion
As we reported earlier,15 in some cases formamidrazone hy-
drochlorides 9 precipitate from the reaction mixture and can be
conveniently isolated and characterized. Their free-base counter-
parts 10, however, exist as a mixture of tautomers (presumably, 100
and 1000) that complicate their spectroscopic characterization. In
principle, ring tautomer 10000 could also exist in equilibrium with
the open-chain tautomers 100 and 1000 (although only two major
tautomers could be detected by 1H NMR spectroscopy). We rea-
soned that if this was the case, 2,3-dihydro-1,2,4-triazole 10000 could
be aromatized under appropriate dehydrogenation conditions and
thus provide a convenient access to 1,2,4-triazoles 11 (Scheme 3).
A model formamidrazone hydrochloride 9a (R1¼3-chlorophenyl,
R2¼t-Bu) that was prepared in high yield (90%) and isolated, in an-
alytically pure form, from the TMSCl-promoted reaction of t-BuNC
with 3-chlorobenzaldehyde thiosemicarbazone15 was converted to
the free-base formamidrazone (10a) and subjected to a number of
dehydrogenation conditions. Treatmentof10a with DDQ17 in toluene
or acetonitrile (at reflux temperatures) as well as with silica gel
1,2,4-Triazoles constitute an important class of heterocycles and
have been reported as key to a number of pharmacologically active
compounds: potent 5HT antagonist 1,7 arginine vasopressin V1A re-
ceptor antagonist 2,8 Ras farnesyl transferase inhibitor 3,9
d opioid
receptor antagonist 4,10 tubulin polymerization inhibitor 5,11 high-
affinity ligand to the human ghrelin receptor 612 and glycine trans-
porter 1 inhibitor 713 are only a few examples illustrating the privi-
leged character14 of the 1,2,4-triazole core for the drug design (Fig.1).
Recently, we described a new reaction of isocyanides with al-
dehyde thiosemicarbazones 8 that yields rare N1,N3-disubstituted
formamidrazone hydrochlorides 9.15 The reaction is promoted by
chlorotrimethylsilane (TMSCl) and is thought to proceed via
* Corresponding author. E-mail address: m.krasavin@griffith.edu.au (M.
Krasavin).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.01.039

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P. Sarnpitak, M. Krasavin / Tetrahedron 69 (2013) 2289e2295
Scheme 1. Isocyanides in heterocycle synthesis: (a) van Leusen azole syntheses; examples of (b) a bifunctional ketocarboxylic acid use in the Ugi reaction and (c) a post-Ugi
modification leading to a novel heterocyclic framework.
Fig. 1. Examples of pharmacologically active 1,2,4-triazoles.
supported KMnO418 (acetonitrile, rt) gave a complex mixture of un-
identified products. However, a promising result was obtained upon
treatmentof10a with10%Pdonactivatedcharcoal(toluene,110ꢀC).19
Under these conditions, 10a underwent a steady (albeit somewhat
slow) conversion to a more polar product that was isolated chro-
matographically in 72% yield and its identity as the desired 1,2,4-
triazole 11a was established by 1H and 13C NMR spectroscopy,
LCMS,andhigh-resolution mass-spectrometry. Incontrast, underthe
same reaction conditions, hydrochloride 9a remained unchanged
upon extended heating (7 days). This observation appears to be
consistent with the formamidrazone hydrochloride being ‘locked’ as
open-chain tautomer 100 (as was earlier established by X-ray crys-
tallography),15 which renders it unavailable for the formation of the
postulated ring tautomer 10000 and subsequent dehydrogenation.
The newly established synthetic approach was applied to
a diverse range of free-base formamidrazones 10bez that were
also prepared via the TMSCl-promoted reaction of thio-
semicarbazones 8 with aliphatic isocyanides, followed by basic
work-up of the reaction mixture. In principle, the crude for-
mamidrazones could be used in the dehydrogenative cyclization
step directly (Scheme 4). However, better yields and easier puri-
fication of the target 1,2,4-triazoles were obtained from for-
mamidrazones that were briefly fractionated by silica gel
chromatography to achieve at least 80% purity (as judged by LC
MS analysis). The isolated yields of the 1,2,4-triazoles 11bez from
thiosemicarbazones 8, were fair to excellent (Table 1).20 Notably,
when we repeated the synthesis of 11a without the isolation of 9a
and proceeded with the basic work-up of the reaction mixture
and fractionation of the free-base product, the yield of 11a was
even slightly higher (76%) than that obtained via isolation of the
formamidrazone hydrochloride by filtration (possibly due to
a partial solubility of 9a in acetonitrile).

P. Sarnpitak, M. Krasavin / Tetrahedron 69 (2013) 2289e2295
2291
3. Conclusion
In conclusion, we have described a conceptually new prepara-
tion of 1,2,4-triazoles and the first practical application of the rare,
isocyanide-derived N1,N3-disubstituted formamidrazones in het-
erocycle synthesis. Our convergent and technically simple ap-
proach significantly extends the modern arsenal of methods to
prepare this important class of heterocyclic compounds.
4. Experimental section
4.1. General
Dry acetonitrile (MeCN) was obtained by passing commercially
available predried, oxygen-free formulations through activated
alumina columns. All other compounds were used as received from
the suppliers. The crude reaction mixtures were concentrated un-
Scheme
2. TMSCl-promoted
reaction
of
isocyanides
with
aldehyde
thiosemicarbazones.15
Scheme 3. The rationale for the formation of 1,2,4-triazoles.
der reduced pressure by removing organic solvents on rotary
evaporator. Column chromatography was performed using silica
gel 60 (particle size 0.040e0.063 mm, 230e400 mesh ASTM). An-
alytical thin-layer chromatography (TLC) was performed with silica
gel 60 F254 aluminum sheets. Chemical shifts for nuclear magnetic
resonance (NMR) spectra were reported in parts per million
(ppm, d) using the residual solvent peaks as internal standard.
Splitting patterns are described as singlet (s), doublet (d), triplet (t),
quartet (q), multiplet (m), doublet of doublet (dd), triplet of triplet
(tt), and quartet of doublet (qd). High-resolution mass spectra
(HRMS) were acquired using a Fourier Transform Ion Cyclotron
Resonance spectrometer fitted with an electrospray source and
operating in positive ion mode.
4.2. Typical procedure: synthesis of 1,2,4-triazoles 11
Scheme 4. 1,2,4-Triazole synthesis developed in this work.
A stirred suspension (solution) of a thiosemicarbazone (1 mmol)
in dry acetonitrile (10 mL) was treated with TMSCl (1 mmol) and
stirred for 10 min at rt. An isocyanide (1.1 mmol) was added, the
reaction flask was purged with argon and the reaction mixture was
stirred at rt for 3e16 h, until TLC analysis indicated a complete dis-
appearance of the starting thiosemicarbazone. The reaction mixture
was partitioned between EtOAc and satd aq NaHCO3, the organic
phasewas dried overanhydrous MgSO4, filtered and concentrated to
provide the crude formamidrazone 10. The latter was briefly frac-
tionated on a short silica gel column (using an appropriate mixture
of EtOAc in hexanes or MeOH in DCM) to provide >80% pure for-
mamidrazone (as judged by LC MS analysis). The latter was com-
bined, in a sealed tube, with 10% palladium on activated charcoal
(equal amount w/w) in toluene (5 mL) and the resulting mixture was
heated, under vigorous stirring, at 110 ꢀC for 72 h. The cooled
This conceptually new methodology for constructing the 3,4-
disubstituted 1,2,4-triazoles complements the earlier described
synthetic strategies21 and is suitable for convenient synthesis of
diverse representatives of this medicinally important chemical
class (for example, compound 11y was reported as a potent P2X7
ion channel blocker).22 1,2,4-Triazoles with a wide range of 3-
(hetero)aromatic as well as stiryl-type substituents are easily ac-
cessible by the new synthetic route. The latter, however, does not
appear to be applicable to the preparation of 3-alkyl- and/or 4-aryl-
substituted 1,2,4-triazoles as free-base formamidrazones 12aed
(reported by us earlier15) failed to give the anticipated products on
treatment with Pd/C (Fig. 2).23

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P. Sarnpitak, M. Krasavin / Tetrahedron 69 (2013) 2289e2295
Table 1
3,4-Disubstituted 1,2,4-triazoles 11 synthesized in this work
Compound
R1
R2
m/z of 10 by LC MS ([MþH]þ
)
Yield of 11 (%)
11a
t-Bu
t-Bu
194.4
76 (72)a
11b
11c
238.4
283.5
69
64
Cyclohexyl
11d
t-Bu
243.5
54
11e
11f
Cyclohexyl
260.5
234.4
78
70
t-Bu
11g
11h
Cyclohexyl
t-Bu
269.2
229.5
61
58
11i
11j
t-Bu
210.5
318.5
38
73
11k
11l
294.5
302.5
278.6
63
79
61
11m
11n
11o
11p
11q
11r
Cyclohexyl
236.5
226.5
220.5
246.6
336.6
52
29
70
71
47
t-Bu
Cyclohexyl
11s
288.6
54

P. Sarnpitak, M. Krasavin / Tetrahedron 69 (2013) 2289e2295
2293
Table 1 (continued )
Compound
R1
R2
m/z of 10 by LC MS ([MþH]þ
)
Yield of 11 (%)
11t
308.7
314.3
66
33
11u
Cyclohexyl
11v
11w
11x
307.7
298.6
308.7
72
74
77
11y
357.6
232.4
38
63
11z
t-Bu
a
Yield in parentheses obtained with the isolation of formamidrazone 9a by filtration, prior to its conversion to free-base 10a.
7.54 (dd, J¼1.9, 0.8 Hz, 1H), 6.81 (dd, J¼3.4, 0.8 Hz, 1H), 6.49 (dd,
J¼3.4, 1.9 Hz, 1H), 1.50 (s, 9H); 13C NMR (125 MHz, CDCl3)
d 145.3,
143.5, 142.1, 141.6, 113. 9, 111.5, 57.4, 30.0; HRMS m/z [MþNaþ] calcd
for C10H13N3NaO 214.0951, found 214.0941.
4.3.3. 2-(4-Cyclohexyl-4H-1,2,4-triazol-3-yl)-1-methyl-1H-indole
(11c). Light yellow oil. 1H NMR (500 MHz, CDCl3)
d 8.50 (s, 1H), 7.70
(d, J¼7.8 Hz, 1H), 7.44 (d, J¼7.8 Hz, 1H), 7.35 (t, J¼7.8 Hz, 1H), 7.20 (t,
J¼7.8 Hz, 1H), 6.70 (s, 1H), 4.25 (tt, J¼12.1, 3.7 Hz, 1H), 3.90 (s, 3H),
2.12e2.07 (m, 2H), 1.94e1.85 (m, 2H), 1.80e1.63 (m, 3H), 1.43e1.21
(m, 3H); 13C NMR (125 MHz, CDCl3)
d 141.4,138.3,127.1,124.9,123.5,
121.3, 120.4, 110.1, 104.4, 55.4, 34.6, 31.4, 25.4, 24.9; HRMS m/z
[MþNaþ] calcd for C17H20N4Na 303.1580, found 303.1583.
Fig. 2. Examples of formamidrazones that failed to give 1,2,4-triazoles.
4.3.4. 2-(4-tert-Butyl-4H-1,2,4-triazol-3-yl)-1H-indole (11d). Light
orange solid, mp¼198e199 ꢀC; 1H NMR (500 MHz, CDCl3)
d 10.57 (s,
reaction mixture was diluted with an equal volume of methanol and
sonicated for 3 min. It was then filtered through a plug of Celite and
the latter was washed again with copious amounts of methanol. The
combined filtrate and washings were concentrated in vacuo to
provide the crude product. The latter was purified by chromatog-
raphy on silica gel using an appropriate gradient of MeOH in CH2Cl2
to provide the analytically pure 1,2,4-triazole 11.
1H), 8.25 (s, 1H), 7.64 (d, J¼7.8 Hz, 1H), 7.48 (d, J¼7.8 Hz, 1H), 7.22 (t,
J¼7.8 Hz, 1H), 7.12 (t, J¼7.8 Hz, 1H), 6.84 (s, 1H), 1.59 (s, 9H); 13C
NMR (125 MHz, CDCl3) d 147.7,142.1,136.3,127.6,124.6,123.3,120.8,
120.1, 111.9, 105.8, 57.5, 30.2; HRMS m/z [MþHþ] calcd for C14H17N4
241.1448, found 241.1448.
4.3.5. 4-Cyclohexyl-3-(4-methoxyphenyl)-4H-1,2,4-triazole
4.3. Analytical data for the obtained compounds
(11e). Pale yellow solid, mp¼96e98 ꢀC; 1H NMR (500 MHz, CDCl3)
d
8.21 (s, 1H), 7.41 (d, J¼8.7 Hz, 2H), 6.95 (d, J¼8.7 Hz, 2H), 3.92 (tt,
4.3.1. 4-tert-Butyl-3-(3-chlorophenyl)-4H-1,2,4-triazole (11a). Pale
J¼12.0, 3.7 Hz, 1H), 3.79 (s, 3H), 2.01e1.93 (m, 2H), 1.84e1.76 (m,
yellow solid, mp¼123e126 ꢀC; 1H NMR (500 MHz, CDCl3)
d 8.34 (s,
2H), 1.70e1.49 (m, 3H), 1.31e1.09 (m, 3H); 13C NMR (125 MHz,
1H), 7.47 (dd, J¼7.8, 1.0 Hz, 1H), 7.45e7.42 (m, 1H), 7.38 (t, J¼7.8 Hz,
CDCl3) d 160.7, 153.2, 140.9, 130.1, 119.3, 114.2, 55.2, 54.9, 34.3, 25.2,
1H), 7.33 (dd, J¼7.8, 1.0 Hz, 1H), 1.48 (s, 9H); 13C NMR (125 MHz,
24.7; HRMS m/z [MþHþ] calcd for C15H20N3O 258.1601, found
CDCl3)
d
141.9,134.2,131.9,130.7,130.1,129.5,128.8,128.1, 57.6, 31.0;
258.1595.
HRMS m/z [MþNaþ] calcd for C12H1435ClN3ONa 258.0768, found
258.0750.
4.3.6. 4-tert-Butyl-3-(4-methoxyphenyl)-4H-1,2,4-triazole
(11f). White solid, mp¼173e175 ꢀC; 1H NMR (500 MHz, CDCl3)
4.3.2. 4-tert-Butyl-3-(furan-2-yl)-4H-1,2,4-triazole (11b). Pale yel-
d
8.24 (s, 1H), 7.33 (d, J¼8.7 Hz, 2H), 6.90 (d, J¼8.7 Hz, 2H), 3.79 (s,
low solid, mp¼108e110 ꢀC; 1H NMR (500 MHz, CDCl3)
d
8.27 (s,1H),
3H), 1.42 (s, 9H); 13C NMR (125 MHz, CDCl3)
d 160.5, 153.5, 141.6,

2294
P. Sarnpitak, M. Krasavin / Tetrahedron 69 (2013) 2289e2295
131.8, 122.0, 113.5, 57.0, 55.2, 30.8; HRMS m/z [MþNaþ] calcd for
J¼12.0, 3.7 Hz, 1H), 2.17e2.11 (m, 2H), 1.97e1.88 (m, 2H), 1.82e1.74
(m, 1H), 1.66 (qd, J¼12.5, 3.3 Hz, 2H), 1.48e1.34 (m, 2H), 1.34e1.21 (m,
C13H17N3NaO 254.1264, found 254.1261.
1H); 13C NMR (125 MHz, CDCl3)
d 148.3, 141.3, 128.3, 128.1, 127.8,
4.3.7. 2-(4-Cyclohexyl-4H-1,2,4-triazol-3-yl)-1H-indole (11g). Brown
127.7, 55.5, 34.4, 25.4, 24.9; HRMS m/z [MþNaþ] calcd for
solid, mp¼223e225 ꢀC; 1H NMR (500 MHz, CDCl3)
d
11.20 (s, 1H),
C12H15N3NaS 256.0879, found 256.0878.
8.35 (s, 1H), 7.69 (d, J¼7.8 Hz, 1H), 7.63 (d, J¼7.8 Hz, 1H), 7.27 (t,
J¼7.8 Hz, 1H), 7.15 (t, J¼7.8 Hz, 1H), 6.79 (s, 1H), 4.50 (tt, J¼11.9,
3.5 Hz,1H), 2.33e2.27 (m, 2H), 2.05e1.98 (m, 2H),1.97e1.83 (m,1H),
1.77e1.67 (m, 2H), 1.64e1.49 (m, 2H), 1.41e1.27 (m, 1H); 13C NMR
4.3.15. Methyl
2-(3-(thiophen-2-yl)-4H-1,2,4-triazo-4-yl)acetate
(11o). Yellow solid, mp¼120e122 ꢀC; 1H NMR (500 MHz, CDCl3)
d
8.25 (s, 1H), 7.53e7.51 (m, 1H), 7.36e7.34 (m, 1H), 7.20e7.13 (m,
(125 MHz, CDCl3)
d
147.6, 141.2, 136.8, 128.0, 123.8, 123.8, 120.9,
1H), 4.88 (s, 2H), 3.81 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 166.7,
120.3, 112.2, 101.5, 55.7, 34.0, 25.5, 25.0; HRMS m/z [MþHþ] calcd for
149.1, 144.8, 128.9, 128.4, 127.9, 126.6, 53.25, 46.1; HRMS m/z
C16H19N4 267.1604, found 267.1604.
[MþNaþ] calcd for C9H9N3NaO2S 246.0308, found 246.0306.
4.3.8. 4-(4-tert-Butyl-4H-1,2,4-triazol-3-yl)benzonitrile (11h). Pale
4.3.16. (E)-4-tert-Butyl-3-(2-(furan-2-yl)vinyl)-4H-1,2,4-triazole
yellow solid, mp¼247e250 ꢀC; 1H NMR (500 MHz, CDCl3)
d
8.33 (s,
(11p). Brown solid, mp¼139e140 ꢀC; 1H NMR (500 MHz, CDCl3)
1H), 7.75 (d, J¼8.4 Hz, 2H), 7.58 (d, J¼8.4 Hz, 2H), 1.47 (s, 9H); 13C
d
8.17 (s, 1H), 7.50 (d, J¼15.6 Hz, 1H), 7.43 (d, J¼1.4 Hz, 1H), 6.96 (d,
NMR (125 MHz, CDCl3)
d
151.9, 142.2, 135.1, 131.9, 131.4, 117.8, 114.0,
J¼15.6 Hz, 1H), 6.49e6.42 (m, 2H), 1.68 (s, 9H); 13C NMR (125 MHz,
57.6, 31.1; HRMS m/z [MþNaþ] calcd for C13H14N4Na 249.1111, found
CDCl3) d 151.9, 151.8, 143.2, 141.4, 123.1, 112.1, 112.0, 110.8, 56.2, 30.4;
249.1109.
HRMS m/z [MþNaþ] calcd for C12H15N3NaO 240.1107, found
240.1106.
4.3.9. 4-tert-Butyl-3-(thiophen-2-yl)-4H-1,2,4-triazole
(11i). Pale
8.35 (s,
yellow solid, mp¼99e101 ꢀC; 1H NMR (500 MHz, CDCl3)
d
4.3.17. (E)-4-Cyclohexyl-3-(2-(furan-2-yl)vinyl)-4H-1,2,4-triazole
1H), 7.53 (d, J¼5.1 Hz, 1H), 7.31 (d, J¼3.5 Hz, 1H), 7.13 (dd, J¼5.1,
(11q). Brown solid, mp¼158e160 ꢀC; 1H NMR (500 MHz, CDCl3)
3.5 Hz, 1H), 1.57 (s, 9H); 13C NMR (125 MHz, CDCl3)
d
147.7, 142.5,
d
8.14 (s, 1H), 7.55 (d, J¼15.7 Hz, 1H), 7.43 (d, J¼1.1 Hz, 1H), 6.66 (d,
131.8, 129.2, 128.0, 127.0, 58.56, 30.7; HRMS m/z [MþNaþ] calcd for
J¼15.7 Hz, 1H), 6.47 (d, J¼3.3 Hz, 1H), 6.43 (dd, J¼3.3, 1.8 Hz, 1H),
3.96 (tt, J¼11.9, 3.7 Hz, 1H), 2.12e2.06 (m, 2H), 1.96e1.88 (m, 2H),
1.81e1.74 (m, 1H), 1.60 (qd, J¼12.4, 3.2 Hz, 2H), 1.50e1.38 (m, 2H),
C10H13N3NaS 230.0722, found 230.0720.
4.3.10. 3-(4-Methoxyphenyl)-4-(naphthalen-1-ylmethyl)-4H-1,2,4-
1.30e1.18 (m, 1H); 13C NMR (125 MHz, CDCl3)
d 151.7, 151.0, 143.3,
triazole (11j). White solid, mp¼136e138 ꢀC; 1H NMR (500 MHz,
140.5, 123.3, 112.2, 112.0, 107.8, 54.6, 34.0, 25.4, 24.9; HRMS m/z
CDCl3)
d
8.01 (s, 1H), 7.88 (d, J¼7.4 Hz, 1H), 7.84 (d, J¼8.3 Hz, 1H),
[MþHþ] calcd for C14H18N3O 244.1444, found 244.1442.
7.64 (d, J¼8.3 Hz, 1H), 7.55 (d, J¼8.8 Hz, 2H), 7.53e7.44 (m, 2H),
7.42e7.36 (m, 1H), 7.06 (d, J¼7.4 Hz, 1H), 6.91 (d, J¼8.8 Hz, 2H), 5.59
4.3.18. 4-(4-Bromophenethyl)-3-(thiophen-2-yl)-4H-1,2,4-triazole
(s, 2H), 3.77 (s, 3H); 13C NMR (125 MHz, CDCl3)
d
160.9, 154.0, 144.3,
(11r). Yellow oil; 1H NMR (500 MHz, CDCl3)
d 7.93 (s) and 7.90 (s) e
133.6, 130.5, 130.0, 129.9, 129.3, 129.0, 127.0, 126.3, 125.3, 125.0,
121.9, 118.7, 114.3, 55.2, 46.7; HRMS m/z [MþHþ] calcd for
C20H18N3O 316.1444, found 316.1446.
total 1H, 7.50 (d, J¼5.1 Hz,1H), 7.41e7.33 (m, 2H), 7.30e7.23 (m,1H),
7.15 (dd, J¼6.4, 2.2 Hz, 1H), 7.03 (d, J¼7.7 Hz) and 6.88 (d, J¼7.7 Hz)
e total 2H, 4.40e4.30 (m, 2H), 3.04 (t, J¼7.2 Hz) and 2.99 (t,
J¼7.2 Hz) e total 2H (biaryl restricted rotation conformers); 13C
4.3.11. 4-(Naphthalen-1-ylmethyl)-3-(thiophen-2-yl)-4H-1,2,4-
NMR (125 MHz, CDCl3) d 148.6, 144.3, 144.2, 136.1, 135.1, 132.0,
triazole (11k). Yellow solid, mp¼122e123 ꢀC; 1H NMR (500 MHz,
130.3, 129.0, 128.6, 128.4, 128.4, 128.2, 128.1, 127.8, 127.7, 127.3,
127.2, 121.3, 46.6, 46.3, 36.7, 36.1 (biaryl restricted rotation con-
formers); HRMS m/z [MþHþ] calcd for C14H1379BrN3S 334.0008,
found 334.0006.
CDCl3)
d
8.01 (s, 1H), 7.97e7.91 (m, 1H), 7.88 (d, J¼8.3 Hz, 1H),
7.78e7.72 (m, 1H), 7.60e7.52 (m, 2H), 7.45e7.39 (m, 2H), 7.28 (dd,
J¼3.7, 1.0 Hz, 1H), 7.06e7.01 (m, 2H), 5.74 (s, 2H); 13C NMR
(125 MHz, CDCl3)
d 149.3, 144.6, 133.7, 130.1, 129.8, 129.5, 129.1,
128.6, 127.9, 127.8,127.4, 127.3, 126.5, 125.5, 125.0, 121.9, 47.0; HRMS
4.3.19. 4-(3-Methoxyphenethyl)-3-(thiophen-2-yl)-4H-1,2,4-triazole
m/z [MþHþ] calcd for C17H14N3S 292.0903, found 292.0904.
(11s). Yellow oil; 1H NMR (500 MHz, CDCl3)
d 7.92 (s, 1H), 7.49 (d,
J¼5.1 Hz, 1H), 7.38 (d, J¼3.7 Hz, 1H), 7.19 (t, J¼8.1 Hz, 1H), 7.15 (dd,
J¼5.1, 3.7 Hz, 1H), 6.78 (dd, J¼8.1, 2.4 Hz, 1H), 6.62 (d, J¼7.5 Hz, 1H),
6.54 (s, 1H), 4.35 (t, J¼7.1 Hz, 2H), 3.73 (s, 3H), 3.01 (t, J¼7.1 Hz, 2H);
4.3.12. 4-(2-Chlorobenzyl)-3-(4-methoxyphenyl)-4H-1,2,4-triazole
(11l). Pale yellow solid, mp¼143e146 ꢀC; 1H NMR (500 MHz,
CDCl3)
d
8.12 (s, 1H), 7.48 (d, J¼8.8 Hz, 2H), 7.40 (dd, J¼8.0, 1.1 Hz,
13C NMR (125 MHz, CDCl3)
d 160.0, 148.6, 144.3, 137.6, 130.0, 128.4,
1H), 7.28 (td, J¼7.7, 1.3 Hz, 1H), 7.22 (td, J¼7.7, 1.3 Hz, 1H), 6.94 (d,
J¼8.8 Hz, 2H), 6.85 (dd, J¼8.0, 1.1 Hz, 1H), 5.26 (s, 2H), 3.81 (s, 3H);
128.1, 127.7, 127.4, 120.8, 114.4, 112.6, 55.2, 46.5, 36.7; HRMS m/z
[MþHþ] calcd for C15H16N3OS 286.1008, found 286.1002.
13C NMR (125 MHz, CDCl3)
d 161.0, 154.2, 144.2, 132.8, 132.8, 130.1,
130.0, 129.9, 128.4, 127.6, 118.6, 114.4, 55.3, 46.5; HRMS m/z [MþHþ]
4.3.20. (E)-4-(3-Methoxyphenethyl)-3-styryl-4H-1,2,4-triazole
calcd for C16H1535ClN3O 300.0898, found 300.0893.
(11t). Pale yellow oil; 1H NMR (500 MHz, CDCl3)
d 7.89 (s, 1H), 7.67
(d, J¼16.1 Hz, 1H), 7.44 (d, J¼7.2 Hz, 2H), 7.39e7.28 (m, 3H), 7.17 (t,
J¼7.7 Hz,1H), 6.73 (dd, J¼8.3, 2.4 Hz,1H), 6.59 (d, J¼7.7 Hz,1H), 6.55
(s, 1H), 6.51 (d, J¼16.1 Hz, 1H), 4.23 (t, J¼6.7 Hz, 2H), 3.69 (s, 3H),
4.3.13. 4-(2-Chlorobenzyl)-3-(thiophen-2-yl)-4H-1,2,4-triazole
(11m). Pale yellow solid, mp¼89e92 ꢀC; 1H NMR (500 MHz, CDCl3)
d
8.14 (s, 1H), 7.46e7.40 (m, 2H), 7.29 (t, J¼7.6 Hz, 1H), 7.25e7.18 (m,
3.00 (t, J¼6.7 Hz, 2H); 13C NMR (125 MHz, CDCl3)
d 160.0, 151.7,
2H), 7.06 (dd, J¼5.0, 3.8 Hz, 1H), 6.81 (d, J¼7.6 Hz, 1H), 5.40 (s, 2H);
143.4, 137.9, 136.4, 135.6, 130.0, 129.0, 128.7, 127.0, 120.8, 114.5,
112.6,109.5, 55.1, 45.7, 37.2; HRMS m/z [MþHþ] calcd for C19H20N3O
306.1601, found 306.1593.
13C NMR (125 MHz, CDCl3)
d 149.0, 144.5, 132.6, 132.1, 129.9, 129.9,
128.5, 128.0, 127.8, 127.7, 127.5, 127.0, 46.5; HRMS m/z [MþHþ] calcd
for C13H1135ClN3S 276.0357, found 276.0351.
4.3.21. 3-(4-Bromothiophen-2-yl)-4-cyclohexyl-4H-1,2,4-triazole
4.3.14. 4-Cyclohexyl-3-(thiophen-2-yl)-4H-1,2,4-triazole(11n). Yellow
(11u). Pale yellow solid, mp¼122e124 ꢀC; 1H NMR (500 MHz,
1
oil; H NMR (500 MHz, CDCl3)
d
8.27 (s, 1H), 7.51 (dd, J¼5.1, 1.0 Hz,
CDCl3)
d
8.30 (s, 1H), 7.42 (s, 1H), 7.29 (s, 1H), 4.18 (tt, J¼11.9, 3.6 Hz,
1H), 7.41 (dd, J¼3.6, 1.0 Hz, 1H), 7.17 (dd, J¼5.1, 3.6 Hz, 1H), 4.22 (tt,
1H), 2.18e2.11 (m, 2H), 2.00e1.94 (m, 2H), 1.84e1.77 (m, 1H), 1.68

P. Sarnpitak, M. Krasavin / Tetrahedron 69 (2013) 2289e2295
2295
(qd, J¼12.5, 3.2 Hz, 2H), 1.51e1.37 (m, 2H), 1.35e1.22 (m, 1H); 13C
Eskitis Institute is thanked for high-resolution mass spectrometry
measurements.
NMR (125 MHz, CDCl3) d 147.1, 141.6, 130.0, 129.4, 125.5, 110.4, 55.6,
34.3, 25.3, 24.8; HRMS m/z [MþHþ] calcd for C12H1579BrN3S
312.0164, found 312.0161.
Supplementary data
4.3.22. 4-(4-(4-Methoxyphenethyl)-4H-1,2,4-triazol-3-yl)benzoni-
The supplementary data containing NMR spectra of the reaction
products is available on http://www.sciencedirect.com. Supple-
mentary data related to this article can be found online at http://
dx.doi.org/10.1016/j.tet.2013.01.039.
trile (11v). Yellow solid, mp¼115e118 ꢀC; 1H NMR (500 MHz,
CDCl3)
d
8.09 (s, 1H), 7.72 (d, J¼8.5 Hz, 2H), 7.53 (d, J¼8.5 Hz, 2H),
6.79 (d, J¼8.7 Hz, 2H), 6.74 (d, J¼8.7 Hz, 2H), 4.26 (t, J¼6.7 Hz, 2H),
3.76 (s, 3H), 2.92 (t, J¼6.7 Hz, 2H); 13C NMR (125 MHz, CDCl3)
d
159.0, 152.4, 144.6, 132.5, 131.3, 129.5, 129.2, 127.6, 118.0, 114.4,
References and notes
113.8, 55.2, 47.0, 36.3; HRMS m/z [MþNaþ] calcd for C18H16N4NaO
327.1216, found 327.1209.
1. Banfi, L.; Riva, R. Org. React. 2005, 65, 1e140.
€
2. Ugi, I.; Meyr, R.; Fetzer, U.; Steinbruckner, C. Angew. Chem. 1959, 71, 386.
3. Van Leusen, A. M.; Wildeman, J.; Oldenziel, O. H. J. Org. Chem. 1977, 42,
1153e1159.
4.3.23. (E)-3-(2-(Furan-2-yl)vinyl)-4-(4-methoxyphenethyl)-4H-
1,2,4-triazole (11w). Brown oil; 1H NMR (500 MHz, CDCl3)
d 7.78 (s,
4. Van Leusen, A. M.; Hoogenboom, B. E.; Siderius, H. Tetrahedron Lett. 1972, 13,
2369e2372.
5. (a) Hulme, C.; Dietrich, J. Mol. Diversity 2009,13,195e207; (b) Ilyin, A. P.; Trifilenkov,
A. S.; Kurashvili, I. D.; Krasavin, M.; Ivachtchenko, A. V. J. Comb. Chem. 2005, 7,
360e363.
6. (a) Akritopoulou-Zanze, I.; Djuric, S. W. Heterocycles 2007, 73, 125e147; (b)
Tsirulnikov, S.; Nikulnikov, M.; Kysil, V.; Ivachtchenko, A.; Krasavin, M. Tetra-
hedron Lett. 2009, 50, 5529e5531.
7. Street, L. J.; Baker, R.; Davey, W. B.; Guiblin, A. R.; Jelley, R. A.; Reeve, A. J.;
Routledge, H.; Sternfeld, F.; Watt, A. P.; Beer, M. S.; Middlemiss, D. N.; Noble, A.
J.; Stanton, J. A.; Scholey, K.; Hargreaves, R. J.; Sohal, B.; Graham, M. I.; Matassa,
V. G. J. Med. Chem. 1995, 38, 1799e1810.
8. Kakefuda, A.; Suzuki, T.; Tobe, T.; Tahara, A.; Sakamoto, S.; Tsukamoto, S. Bioorg.
Med. Chem. 2002, 10, 1905e1912.
9. Saha, A. K.; Liu, L.; Simoneaux, R.; DeCorte, B.; Meyer, C.; Skrzat, S.; Breslin, H. J.;
Kukla, M. J.; End, D. W. Bioorg. Med. Chem. Lett. 2005, 15, 5407e5411.
10. Zhang, Q.; Keenan, S. M.; Peng, Y.; Nair, A. C.; Yu, S. J.; Howells, R. D.; Welsh, W.
J. J. Med. Chem. 2006, 49, 4044e4047.
1H), 7.44 (d, J¼15.8 Hz, 1H), 7.41 (s, 1H), 6.89 (d, J¼8.5 Hz, 2H), 6.75
(d, J¼8.5 Hz, 2H), 6.48 (d, J¼15.8 Hz, 1H), 6.45e6.39 (m, 2H), 4.14 (t,
J¼6.8 Hz, 2H), 3.67 (s, 3H), 2.93 (t, J¼6.8 Hz, 2H); 13C NMR
(125 MHz, CDCl3)
d 158.7, 151.5, 151.4, 143.4, 143.2, 129.5, 128.2,
123.1, 114.2, 112.0, 111.9, 107.3, 55.0, 45.8, 36.1; HRMS m/z [MþHþ]
calcd for C17H18N3O2 296.1394, found 296.1389.
4.3.24. (E)-4-(4-Methoxyphenethyl)-3-styryl-4H-1,2,4-triazole
(11x). Yellow solid, mp¼73e75 ꢀC; 1H NMR (500 MHz, CDCl3)
d
7.86 (s, 1H), 7.68 (d, J¼16.1 Hz, 1H), 7.44 (d, J¼8.2 Hz, 2H),
7.41e7.28 (m, 3H), 6.91 (d, J¼8.3 Hz, 2H), 6.78 (d, J¼8.3 Hz, 2H), 6.50
(d, J¼16.1 Hz, 1H), 4.20 (t, J¼6.6 Hz, 2H), 3.67 (s, 3H), 2.98 (t,
J¼6.6 Hz, 2H); 13C NMR (126 MHz, CDCl3)
d 158.9, 151.7, 143.4, 136.4,
11. Zhang, Q.; Peng, Y.; Wang, X. I.; Keenan, S. M.; Arora, S.; Welsh, W. J. J. Med.
135.6, 129.7, 129.0, 128.7, 128.3, 127.1, 114.4, 109.6, 55.1, 46.1, 36.4;
Chem. 2007, 50, 749e754.
HRMS m/z [MþHþ] calcd for C19H20N3O 306.1601, found 306.1600.
12. Demange, L.; Boeglin, D.; Moulin, A.; Mousseaux, D.; Ryan, J.; Berge, G.; Gagne,
D.; Heitz, A.; Perrissoud, D.; Locatelli, V.; Torsello, A.; Galleyrand, J.-C.; Fehrentz,
J.-A.; Martinez, J. J. Med. Chem. 2007, 50, 1939e1957.
13. Sugane, T.; Tobe, T.; Hamaguchi, W.; Shimada, I.; Maeno, K.; Miyata, J.; Suzuki,
T.; Kimizuka, T.; Kohara, A.; Morita, T.; Doihara, H.; Saita, K.; Aota, M.; Furutani,
M.; Shimada, Y.; Hamada, N.; Sakamoto, S.; Tsukamoto, S. J. Med. Chem. 2011, 54,
387e391.
4.3.25. 3-(2,3-Dichlorophenyl)-4-(naphthalen-1-ylmethyl)-4H-1,2,4-
triazole (11y). Yellow oil; 1H NMR (500 MHz, CDCl3)
d 8.10 (s) and
8.08 (s) e total 1H, 7.93 (m) and 7.87 (m) e total 2H, 7.69e7.59 (m,
2H), 7.59e7.43 (m, 2H), 7.39 (t, J¼7.6 Hz,1H), 7.35e7.23 (m, 2H), 7.17
(d, J¼7.0 Hz) and 7.13 (d, J¼7.0 Hz) e total 1H, 5.66 (s) and 5.45 (s) e
total 2H (biaryl restricted rotation conformers); 13C NMR (125 MHz,
14. Evans, B. E. J. Med. Chem. 1988, 31, 2235e2246.
15. Sarnpitak, P.; Tsirulnikov, S.; Krasavin, M. Tetrahedron Lett. 2012, 53, 6540e6543.
16. Encouragingly, preparation of 1,3,5-trisubstituted 1,2,4-triazoles, via aerobic
activation of amidrazones was recently described: El Kaim, L.; Gizzi, M.; Grimaud,
L. Synlett 2010, 1771e1774.
17. Sharma, S.; Kundu, B. J. Comb. Chem. 2009, 11, 720e731.
18. Mohammadpoor-Baltork, I.; Zolfigol, M. A.; Abdollahi-Alibeik, M. Tetrahedron
Lett. 2004, 45, 8687e8690.
19. (a) Amemiya, Y.; Miller, D. D.; Hsu, F. L. Synth. Commun. 1990, 20, 2483e2489; (b)
Anastassiadou, M.; Baziard-Mouysset, G.; Payard, M. Synthesis 2000, 1814e1816.
20. Compounds synthesized in this work have been deposited with the Queens-
land Compound Library (Griffith University) and are available for collaborative
discovery projects.
CDCl3)
d 151.6, 144.8, 143.9, 133.9, 133.8, 133.0, 132.6, 130.6, 130.5,
130.4, 130.2, 129.9, 129.8, 129.3, 129.2, 129.1, 129.0, 128.8, 127.8,
127.3, 127.2, 127.1, 126.6, 126.4, 125.6, 125.4, 125.2, 122.0, 121.9, 47.1,
47.0 (biaryl restricted rotation conformers); HRMS m/z [MþNaþ]
calcd for C19H1379Cl2N3Na 376.0379, found 376.0381.
4.3.26. 4-tert-Butyl-3-(3,4-dimethylphenyl)-4H-1,2,4-triazole
(11z). Light orange solid, mp¼167e169 ꢀC; 1H NMR (500 MHz,
21. Holm, S. C.; Straub, B. F. Org. Prep. Proced. Int. 2011, 43, 319e347.
22. (a) Carroll, W. A.; Kalvin, D. M.; Perez Medrano, A.; Florjancic, A. S.; Wang, Y.;
CDCl3)
d 8.32 (s, 1H), 7.22e7.09 (m, 3H), 2.30 (s, 3H), 2.27 (s, 3H),
1.47 (s, 9H); 13C NMR (125 MHz, CDCl3)
d 141.6, 138.5, 136.5, 131.6,
ꢀ
Donnelly-Roberts, D. L.; Namovic, M. T.; Grayson, G.; Honore, P.; Jarvis, M. F.
129.3, 128.0, 127.4, 57.27, 31.0, 19.6, 19.6; HRMS m/z [MþNaþ] calcd
Bioorg. Med. Chem. Lett. 2007, 17, 4044e4048; (b) Carroll, W. A.; Florjancic, A. S.;
Perez-Medrano, A.; Peddi, S. U.S. Pat. Appl. Publ. US20070105842A1, p 50;
Chem. Abstr. 2007, 146, 507509.
for C14H19N3Na 252.1471, found 252.1462.
23. Under the 1,2,4-triazole synthesis conditions, formamidrazones derived from
aliphatic aldehydes (12aeb) decomposed while those derived from aromatic
isocyanides (12ced) remained largely unchanged. The latter observation ap-
pears to be consistent with the expected lower nucleophilicity of the aryl-
substituted formamidrazone and its lower propensity to participate in the
ring-forming process.
Acknowledgements
Mikhail Krasavin acknowledges support from Griffith University
(New Researcher Grant 2012, project 215586). Dr. Hoan Vu of