A coupling reaction of 4-amino-5-mercapto-3-substituted-1,2,4-triazoles to generate symmetrically substituted hydrazines

Article abstract of DOI:10.1007/s00706-005-0372-1

A novel coupling reaction of 4-amino-5-mercapto-3-substituted-1,2,4- triazoles to generate symmetrically substituted hydrazines, N,N′-bis(5- mercapto-3-substituted-1,2,4-triazol-4-yl)hydrazines was unexpectedly observed. Five examples are presented to dem

Full text of DOI:10.1007/s00706-005-0372-1

Monatshefte f€ur Chemie 136, 2045–2049 (2005)
DOI 10.1007/s00706-005-0372-1
A Coupling Reaction of 4-Amino-5-mercapto-
3-substituted-1,2,4-triazoles to Generate
Symmetrically Substituted Hydrazines
Ming Li1;ꢀ, Guilong Zhao1, Lirong Wen1, Xiao Wang1,
Xiaomao Zou2, and Huazheng Yang2
1
College of Chemistry and Molecular Engineering, Qingdao University of Science
and Technology, Qingdao 266042, P.R. China
2
State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin
300071, P.R. China
Received March 11, 2005; accepted (revised) March 29, 2005
Published online November 14, 2005 # Springer-Verlag 2005
Summary. A novel coupling reaction of 4-amino-5-mercapto-3-substituted-1,2,4-triazoles to generate
symmetrically substituted hydrazines, N,N0-bis(5-mercapto-3-substituted-1,2,4-triazol-4-yl)hydrazines
was unexpectedly observed. Five examples are presented to demonstrate this reaction. All isolated
products were unambiguously characterized.
Keywords. Triazole; Coupling reaction; Acetal; Synthesis.
Introduction
Triazole derivatives have been reported as a class of useful heterocyclic com-
pounds, and have found widespread applications in the fields of agrochemicals and
pharmaceuticals [1–3]. During the course of our investigation directed towards the
synthesis of biologically active triazole compounds, we have unexpectedly discov-
ered a novel coupling reaction of 4-amino-5-mercapto-3-substituted-1,2,4-triazoles 1
[4] to give rise to N,N0-bis(5-mercapto-3-substituted-1,2,4-triazol-4-yl)hydrazines 3.
Thus, the reaction of 1 with ꢀ-hydroxy-ꢀ-methylthioacetophenone 2 [5] in refluxing
glacial acetic acid or pyridine did not produce the anticipated compounds 4; instead,
it yielded the novel coupling products 3 in satisfactory isolated yields (Scheme 1).
Results and Discussion
This novel coupling reaction was first observed in the case of 1a. Initially, the
reaction of 1a with the acetophenone 2 was carried out in refluxing dry ethanol
ꢀ
Corresponding author. E-mail: liming928@263.net

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M. Li et al.
Scheme 1
with several drops of concentrated hydrochloric acid. However, 2 was readily
transformed into a new compound, while 1a was not consumed at all. The new
compound was isolated and identified as the hemiacetal, ꢀ-ethoxy-ꢀ-hydroxyace-
tophenone 5, resulting from the substitution of the methylthio group in 2 by the
ethoxyl group ethanol. In fact, the hemiacetal was observed when 2 was recrys-
tallized from absolute ethanol.
The reaction of 1a with 2 was subsequently performed in refluxing glacial
acetic acid, and the coupling product 3a was unexpectedly isolated in a satisfactory
yield. This reaction was also performed in refluxing pyridine, where we expected to
obtain the initially anticipated product 4 (R ¼ CH3), only to find that the reaction
also gave rise to the coupling product 3a in a lower yield than that obtained in
refluxing glacial acetic acid. This reaction might well be extended to develop other
similar protocols for the synthesis of such symmetrically substituted hydrazines
starting from other commonly encountered amines, such as aliphatic amines and
aniline derivatives. Encouraged by the novel structure of 3a and especially the
above-mentioned great potential, we thus tested the generality of the reaction of
1a with 2. The substituents at C-3 of the triazole ring were extended to both al-
iphatic and aromatic moieties with both electron-withdrawing and electron-donat-
ing groups attached to them (Scheme 1). To our surprise, all these substrates 1 gave
satisfactory results, and the ready isolation of the coupling products 3 proved the
expected generality of this reaction. Further extension of the generality of this
reaction is now in progress in our laboratory, with great expectation to develop
a more general procedure for the coupling reaction of commonly encountered

A Coupling Reaction to Generate Hydrazines
2047
amines, such as aliphatic amines and other aromatic amines. Preliminary results
have shown that the reactions involving aromatic amines, such as aniline, did not
proceed chemoselectively under the above-mentioned reaction conditions and a
large number of products was generated. Therefore, the optimization of the re-
action conditions for these unsatisfactory reactions is now under investigation. It is
also worth noting that when R ¼ H, the coupling reaction of 1 was not observed
under the aforementioned reaction conditions, and this reaction may require more
vigorous conditions.
It is obvious that the reaction mechanism is considerably interesting and chal-
lenging. Also, the role played by 2 in this reaction is not very clear; nonetheless, it
is clear that 2 does not function as a catalyst, since a catalytic amount of 2 in this
reaction has proved useless to the transformation of 1 to 3 and one equivalent of 2
is required in each case. The investigation into this mechanism is now under way.
The work-up procedure was also optimized. The use of chloroform in the pro-
cedure was remarkably effective in the simplification of the work-up, since it could
dissolve practically all the other components in the residue except the coupling
product 3a, due to the poor solubility of 3a in chloroform. However, in the case of
3d, acetonitrile was employed instead of chloroform. An attempt to use column
chromatography to purify the product was successful but considerably tedious,
owing to the existence of impurities that possess similar polarity to that of the
target molecule.
Compound 3 actually exists as a tautomeric form, 1,2,4-triazol-5-thione 3-1
(Scheme 1), with the H atom in the mercapto group having been transferred
to the N-1 position. The absence of the absorption band of S–H (usually at
2550–2600 cmꢁ1) in the IR spectrum of 3 provided proof for the thione form [6].
In conclusion, we have discovered a novel coupling reaction of 4-amino-5-
mercapto-3-substituted-1,2,4-triazoles 1 to generate the symmetrically substituted
hydrazines 3 providing great potential to extend this reaction to other substrates,
such as aliphatic and aromatic amines.
Experimental
Melting points were determined on a RY-1 apparatus and are uncorrected. H NMR spectra were re-
corded on a JEOL JNM-ECP 600 M spectrometer at 600 MHz and 13C NMR spectra were at 150 MHz,
with DMSO-d6 as solvent and TMS as internal standard. IR spectra were obtained on a Nicolet 501P
FT-IR spectrophotometer from KBr discs. Mass spectra were recorded on a VG ZAB-HS mass
spectrometer at 8 KV using fast-atom bombardment technique. Elemental analyses were carried out
with an ELEMENTO EL-III CHNS analyzer and gave satisfactory results.
In a typical procedure for the synthesis of 3, 0.547g 2 (3mmol) and 0.391 g 1a (3mmol) were
dissolved in 20 cm3 glacial acetic acid, and the resulting solution was then refluxed for ꢂ6 h. On
cooling, the solvent was evaporated to dryness on a rotary evaporator to furnish a solid residue, which
was transferred into a flask containing 40cm3 CHCl3. The obtained suspension solution was subse-
quently stirred for ꢂ5 h and the solid was collected, which upon recrystallization from absolute ethanol
yielded 3a as colorless needles.
N,N0-Bis(5-mercapto-3-methyl-1,2,4-triazol-4-yl)hydrazine (3a, C6H10N8S2)
Yield 65%; mp 273–275ꢃC; 1H NMR: ꢁ ¼ 2.17 (s, 3Hꢄ2, CH3ꢄ2), 13.05 (br, s, 1Hꢄ2, NHꢄ2, NH-1
or NH-6), 13.17 (br, s, 1Hꢄ2, NHꢄ2, NH-6 or NH-1) ppm; 13C NMR: ꢁ ¼ 10.85 (CH3), 148.87 (C-3),

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M. Li et al.
165.88 (C-5) ppm; IR (KBr): ꢂꢀ¼ 3119 (N-H), 1462, 1548, 1608 (aromatic skeleton), 1249 (C¼S),
1391 (CH3) cmꢁ1; FAB-MS (8kV): m=z ¼ 259 (Mþ 1).
N,N0-Bis(3-ethyl-5-mercapto-1,2,4-triazol-4-yl)hydrazine (3b, C8H14N8S2)
Colorless needles; yield 70%; mp 254–256ꢃC; 1H NMR: ꢁ ¼ 1.14–1.70 (t, 3Hꢄ2, CH3ꢄ2, J ¼ 7.7 Hz),
2.51–2.55 (q, 2Hꢄ2, CH2, J ¼ 7.7 Hz), 13.10 (br, s, 1Hꢄ2, NHꢄ2, NH-1 or NH-6), 13.19 (br, s, 1Hꢄ2,
NHꢄ2, NH-6 or NH-1) ppm; 13C NMR: ꢁ ¼ 10.12 (CH3), 15.74 (CH2), 148.87 (C-3), 165.88 (C-5)
ppm; IR (KBr): ꢂꢀ¼ 3125 (N-H), 1464, 1552, 1602 (aromatic skeleton), 1248 (C¼S), 1389 (CH3)
cmꢁ1; FAB-MS (8kV): m=z ¼ 287 (Mþ 1).
N,N0-Bis(5-mercapto-3-phenyl-1,2,4-triazol-4-yl)hydrazine (3c, C16H14N8S2)
1
Colorless needles; yield: 59%; mp 259–260ꢃC; H NMR: ꢁ ¼ 7.51–7.53, 7.90–7.92 (mm, (3H þ
2H)ꢄ2, Ph-H), 13.70 (br, s, 1Hꢄ2, NHꢄ2, NH-1 or NH-6), 13.87 (br, s, 1Hꢄ2, NHꢄ2, NH-6 or
NH-1) ppm; 13C NMR: ꢁ ¼ 125.42, 125.62, 129.10, 130.60 (C of Ph), 150.16 (C-3), 166.97 (C-5) ppm;
IR (KBr): ꢂꢀ¼ 3123 (N-H), 1464, 1550, 1600 (aromatic skeleton), 1249 (C¼S), 1380 (CH3) cmꢁ1
FAB-MS (8kV): m=z ¼ 383 (Mþ 1).
;
N,N0-Bis[5-mercapto-3-(p-methoxyphenyl)-1,2,4-triazol-4-yl]hydrazine (3d, C18H18N8O2S2)
Colorless needles; yield: 68%; mp 253–255ꢃC; 1H NMR: ꢁ ¼ 3.82 (s, 3H, CH3), 7.06–7.08, 7.84–7.86
(dd, 2Hꢄ2 each, J ¼ 9.2 Hz), 13.57 (br, s, 1Hꢄ2, NHꢄ2, NH-1 or NH-6), 13.71 (br, s, 1Hꢄ2, NHꢄ2,
NH-6 or NH-1) ppm; 13C NMR: ꢁ ¼ 55.37 (CH3), 114.53, 117.85, 127.30, 160.98 (C of Ph), 150.10
(C-3), 166.60 (C-5) ppm; IR (KBr): ꢂꢀ¼ 3129 (N-H), 1450, 1568, 1599 (aromatic skeleton), 1257
(C¼S), 1384 (CH3) cmꢁ1; FAB-MS (8kV): m=z ¼ 443 (Mþ 1).
N,N0-Bis[5-mercapto-3-(p-trifluoromethylphenyl)-1,2,4-triazol-4-yl]hydrazine
(3e, C18H12F6N8S2)
Colorless needles; yield: 73%; mp 273–274ꢃC; 1H NMR: ꢁ ¼ 7.91–7.92, 8.12–8.14 (dd, 2Hꢄ2 each,
J ¼ 8.3 Hz), 13.89 (br, s, 2Hꢄ2, NHꢄ2, NH-1 and NH-6) ppm; 13C NMR: ꢁ ¼ 122.97, 124.77, 126.11,
126.42 (C of Ph), 129.30 (CF3), 149.08 (C-3), 167.49 (C-5) ppm; IR (KBr): ꢂꢀ¼ 3134 (N-H), 1460,
1545, 1601 (aromatic skeleton), 1245 (C¼S), 1380 (CH3) cmꢁ1; FAB-MS (8kV): m=z ¼ 519 (Mþ 1).
The Preparation of Hemiacetal 5
In the above-mentioned procedure for the synthesis of 3, the solvent was displaced by dry ethanol with
several drops of conc HCL. The mixture was then stirred while refluxing for 3–4 h. The new compound
as monitored by TLC was isolated using column chromatography as a colorless oil. 1H NMR:
ꢁ ¼ 8.06–8.07, 7.64–7.66, 7.52–7.55 (m each, 2Hþ 1Hþ 2H, Ph–H), 6.99 (br, s, 1H, OH), 5.53 (s,
1H, CH), 3.79–3.84, 3.60–3.65 (qþ q each, 1H each, CH2, 2J ¼ 9.8 Hz, 3J ¼ 7.0 Hz), 1.15–1.17 (t, 3H,
J ¼ 7.0 Hz) ppm. The prochirality of the CH2 group can be observed from the above spectral data,
owing to the existence of the chiral center at the ꢀ-C; IR (neat): ꢂꢀ¼ 3423 (OH), 1692 (C¼O), 1227,
1283 (C–O) cmꢁ1
.
Acknowledgements
The authors express sincere gratitude to the Natural Science Foundation of China (No. 20572057) and
the Natural Science Foundation of Shandong Province (No. Y2003B01) for financial support.
References
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[2] Chiara BV, Maurizio M, Augusto CA, Mario G (1998) J Heterocyclic Chem 35: 29

A Coupling Reaction to Generate Hydrazines
2049
[3] Couderchet M, Schmalfub J, Boger P (1998) Pestic Sci 52: 381
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[6] This conclusion has been verified unambiguously by X-ray diffraction method. Please see our
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