Synthesis of 3-(phenylazo)-1, 2, 4-triazoles by a nucleophilic reaction of primary amines with 5-chloro-2, 3-diphenyltetrazolium salt via mesoionic 2, 3-diphenyltetrazolium-5-aminides

Article abstract of DOI:10.3762/bjoc.5.8

The reactions of a 5-chloro-2, 3-diphenyltetrazolium salt with amines have been examined. In the presence of an inorganic base such as NaHCO₃, primary and secondary amines undergo a nucleophilic substitution to give the corresponding 5-aminotet

Full text of DOI:10.3762/bjoc.5.8

Synthesis of 3-(phenylazo)-1,2,4-triazoles by a
nucleophilic reaction of primary amines with
5-chloro-2,3-diphenyltetrazolium salt via mesoionic
2,3-diphenyltetrazolium-5-aminides
Shuki Araki*, Satoshi Hirose, Yoshikazu Konishi, Masatoshi Nogura
and Tsunehisa Hirashita
Full Research Paper
Open Access
Address:
Beilstein Journal of Organic Chemistry 2009, 5, No. 8.
Omohi College, Graduate School of Engineering, Nagoya Institute of
Technology, Gokiso-cho, Showa-ku, Nagoya 466-8555, Japan
doi:10.3762/bjoc.5.8
Received: 22 December 2008
Accepted: 08 February 2009
Published: 02 March 2009
Email:
Shuki Araki* - araki.shuki@nitech.ac.jp
* Corresponding author
Associate Editor: J. Murphy
Keywords:
© 2009 Araki et al; licensee Beilstein-Institut.
License and terms: see end of document.
formazan; mesoionic compounds; nucleophilic substitution;
tetrazolium; 1,2,4-triazole
Abstract
The reactions of a 5-chloro-2,3-diphenyltetrazolium salt with amines have been examined. In the presence of an inorganic base such
as NaHCO3, primary and secondary amines undergo a nucleophilic substitution to give the corresponding 5-aminotetrazolium salts.
When triethylamine is used as a base, primary amines give 3-phenylazo-1,2,4-triazoles. A plausible dual-path mechanism is
proposed for the formation of the triazoles via Type B mesoionic tetrazolium-5-aminides.
Introduction
Mesoionic compounds can be classified into two families, type preparation of this chlorotetrazolium salt 2 and its reactions
A and type B mesoions, according to their electronic arrange- with amines, which involve the unexpected formation of
ments [1-5]. Type B mesoionic compounds are less common 3-(phenylazo)-1,2,4-triazole derivatives.
compared with type A mesoions. The 5-chloro-1,3-diphenyltet-
razolium salt (1) has been proved to be a versatile precursor to Results and Discussion
several type A 1,3-diphenyltetrazolium mesoionic compounds, The 5-chloro-2,3-diphenyltetrazolium salt 2 was prepared in an
because the chlorine atom is a good leaving group and easily analogous manner to the corresponding 1,3-diphenyl isomer 1
replaced by a variety of nucleophiles [6,7]. Although the corres- [6,7]. Thus, the treatment of 2,3-diphenyltetrazolium-5-olate
ponding 5-chloro-2,3-diphenyltetrazolium salt 2 is not yet with phosphorus oxychloride gave 2 in high yield as stable crys-
known, it is expected that 2 is also useful for the synthesis of tals, after an anion exchange to tetrafluoroborate.
type B tetrazolium mesoions. In this paper, we disclose the first
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Beilstein Journal of Organic Chemistry 2009, 5, No. 8.
Next, the reactions of 2 with various amines were examined. sodium hydrogencarbonate 5-aminotetrazolium 4b was formed.
When 2 was treated with benzylamine in dichloromethane in Other primary amines, such as ethanolamine and ethyl glycinate
the presence of triethylamine, 1,5-diphenyl-3-(phenylazo)-1H- gave the corresponding triazoles 3c and 3d. Interestingly, steric-
1,2,4-triazole (3a) was formed in 50% yield. The expected ally bulky primary amines as well as secondary amines gave the
substitution product, 2,3-diphenyl-5-(benzylamino)tetrazolium respective 5-aminotetrazolium salts 4d–h. It is worthy to note
salt 4a, was not found in the reaction mixture. Interestingly, that the reaction of isopropylamine/triethylamine gave 3-(isop-
when the base was changed to solid sodium carbonate or ropylideneamino)-1,5-diphenylformazan as the major product.
sodium hydrogencarbonate, 4a was obtained exclusively
(Scheme 1).
As a representative tertiary amine, triethylamine was also
subjected to the reaction with 2. The reaction proceeded under
The results with other amines are summarized in Table 1. The reflux in dichloromethane to afford 5-(diethylamino)tetrazolium
reaction of butylamine showed a similar tendency: with the salt 4h in 60% yield, presumably via an Arbuzov-type reaction
triethylamine base triazole 3b was obtained, whereas with (Scheme 2). The reactions with other nucleophiles than amines
Scheme 1: Reaction of chlorotetrazolium 2 with benzylamine.
Table 1: Reaction of chlorotetrazolium 2 with various amines.
Entry
R1R2NH (equiv)
Base (equiv)
Time (h)
Yield (%)
3
4
1a,b
2c
PhCH2NH2
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.4
0.83
1.0
1.0
Et3N
3.0
1.0
1.0
2.0
1.0
3.0
4.0
1.0
1.0
1.0
2.0
1.0
1.0
2.5
22
19
72
20
3.5
4
3a 50 (R' = Ph)
0
PhCH2NH2
PhCH2NH2
n-BuNH2
NaHCO3
Na2CO3
Et3N
0
4a 68 (R1 = CH2Ph, R2 = H)
4a 39
3
0
4
3b 23 (R' = n-Pr)
0
5
n-BuNH2
NaHCO3
Et3N
0
4b 34 (R1 = n-Bu, R2 = H)
4c 2 (R1 = CH2CH2OH, R2 = H)
0
6a,b,c
7a,b,c
8b,e
9
HOCH2CH2NH2
NH2CH2CO2Etd
i-PrNH2
3c 50 (R' = CH2OH)
Et3N
3d 39 (R' = CO2Et)
Et3N
20
20
2
0
0
0
0
0
0
4d 38 (R1 = i-Pr, R2 = H)
4d 22
i-PrNH2
NaHCO3
Et3N
10a,c
11
t-BuNH2
4e 55 (R1 = t-Bu, R2 = H)
4f 73 (R1 = R2 = CH2Ph)
4g 96 (R1 = R2 = n-Bu)
4h 41 (R1 = R2 = Et)
(PhCH2)2NH
n-Bu2NH
Et3N
3
12
Et3N
4
13
Et2NH
NaHCO3
18
aThe reaction was conducted under reflux. bUnder air. cMeCN was used as a solvent. dThe hydrochloride salt was used. e3-(Isopropylideneamino)-1,5-
diphenylformazan was obtained (48% yield).
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Beilstein Journal of Organic Chemistry 2009, 5, No. 8.
Scheme 2: Reaction of chlorotetrazolium 2 with triethylamine.
such as alcohols and thiols did not give the corresponding oxa- However, the desired formazan 5a was not obtained at all.
and thiadiazole derivatives.
Then, a nucleophilic substitution of 3-chloroformazan 6 with
benzylamine was undertaken. The chlorotetrazolium salt 2 was
easily converted to 6 with NaBH4 (43% yield) or p-(dimethyl-
Reaction mechanism
The reaction mechanism for the formation of triazole 3 was amino)aniline (73% yield). The reaction of 6 with benzylamine
investigated. First, the 5-(benzylamino)tetrazolium salt 4a was in ethanol, however, did not give the expected 5a, but triazole
treated with triethylamine in dichloromethane at room temper- 3a was formed in 30% yield. In this reaction, 3a is considered
ature. Triazole 3a was obtained in 16% yield. Although the to be formed via initially produced formazan 5a, which is spon-
yield is not high, this fact shows that 3a is derived, at least taneously oxidized in situ. As these results imply that formazan
partially, from 4a (Scheme 3).
5a is too unstable to be isolated, the preparation of
3-(butylamino)formazan 5b was next planned. Fortunately, the
reaction of 6 with butylamine proceeded and the desired 5b
could be isolated in 22% yield. As expected, aerobic oxidation
of 5b in ethanol gave triazole 3b in 69% yield, though the reac-
tion took 10 d (Scheme 4).
On the basis of these experimental results, the most plausible
reaction mechanism is illustrated in Scheme 5. Nucleophilic
substitution of the chlorine atom of 2 by amine gives
5-aminotetrazolium salt 4. Deprotonation of 4 affords
Scheme 3: Conversion of benzylaminotetrazolium 4a to 1,2,4-triazole
3a.
Next, the possibility that 3 is formed by the oxidation of tetazolium-5-aminide A, which is in the equilibrium with the
3-amino-1,5-diphenylformazan 5 was examined. In order to acyclic tautomer B. Further deprotonation from B followed by
synthesize 3-(benzylamino)formazan 5a, the reduction of 4a an intramolecular ring-closure gives C, which is oxidized by air
with reductants such as NaBH4 and DIBAL was attempted. to furnish triazole 3. The sterically demanding primary amines
Scheme 4: Synthesis of chloroformazan 6 and its reaction with benzylamine and butylamine.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 8.
Scheme 5: Plausible reaction mechanism for the formation of 1,2,4-triazole 3.
Experimental
(isopropylamine and tert-butylamine) are considered to be diffi-
cult to give the cyclized intermediate C. The less efficient beha- General
viour of the carbonates in the deprotonation process may be Melting points were measured with a hot-stage apparatus
attributed to the heterogeneous reaction system. In the last oxid- Yanaco MP 50533 and are uncorrected. Elemental analyses
ation stage from C to 3, aminotetrazolium 4 is considered also were carried out with a Perkin Elmer 2400 II CHNS/O. IR
to act as a hydride acceptor and 4 itself is transformed to spectra were taken as KBr discs on a JASCO A-102 spectro-
3-aminoformazan 5. Thus, the formation of triazole 3 is meter. Electronic spectra were measured on a Hitachi U-3500 or
considered to be a dual-path process: via oxidation of the inter- a Shimadzu UV-2450 spectrophotometer. 1H NMR spectra
mediate C and formazan 5. It is worthy to note here that a were obtained using a Varian Mercury 200 (200 MHz) or a
similar 1,5-dipolar ring closure of type B mesoionic thiocar- Varian Mercury 300 (300 MHz), and 13C NMR spectra were
bonyl ylides is known to furnish thiadiazolines [8].
obtained using a Varian Mercury 200 (50 MHz). Chemical
shifts are recorded in ppm downfield from tetramethylsilane. J
values are given in Hz. Mass spectra were taken with a Hitachi
Conclusion
It has now been revealed that the 5-chlorotetrazolium salt 2 M-2000 spectrometer (EI, 70 eV). For TLC, Merck Silica gel
reacts with primary and secondary amines to give the corres- 60 F254 Plate was used. For column chromatography, Merck
ponding 5-aminotetrazolium salts 4. When triethylamine is Silica gel 60 (0.063–0.200 mm) was used.
employed as a base in the reaction with primary amines, depro-
5-Chloro-2,3-diphenyltetrazolium tetra-
tonation from 4 proceeds readily to give tetrazolium-5-amin-
ides A. Contrary to the stable type A mesoionic tetrazolium-5- fluoroborate (2)
aminides [6,7], type B mesoionic aminide A undergoes further A mixture of 2,3-diphenyltetrazolium-5-olate (1.0 g, 4.2 mmol)
transformations from its acyclic tautomer B to furnish 1,2,4- and phosphorus oxychloride (2.2 ml, 24 mmol) was heated at
triazoles 3.
110 °C for 16 h. The excess phosphorus oxychloride was
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Beilstein Journal of Organic Chemistry 2009, 5, No. 8.
removed under reduced pressure and the residue was mixed N) and water. After being dried over Na2SO4, the solvent was
with 42% fluoroboric acid (4.4 ml) and ultrasonicated for 30 removed and the residue (72 mg) was purified by column chro-
min. The mixture was filtered, and the solid was washed with matography on silica gel (eluent: CH2Cl2→MeCN) to give a
cold THF to give 2 (1.0 g, 72%). From the filtrate and wash- crude product. Recrystallization from ethanol gave 3a (21 mg,
ings, a further amount (0.27 g, 18%) of 2 was obtained; total 16%).
1.27 g, 90%. mp 208–212 °C (EtOH); IR (KBr) νmax 3060,
3045, 1482, 1462, 1388, 1362, 1300, 1158, 1122, 1082, 1036, Reduction of chlorotetrazolium salt 2
1000, 788, 780, 764, 692, 684; 1H NMR (200 MHz, CD3CN) δ 1. With NaBH4
7.67–7.70 (m, 8H), 7.75–7.87 (m, 2H), 13C NMR (50 MHz, To a solution of 2 (176 mg, 0.51 mmol) in dichloromethane (5
CD3CN) δ 126.29 (o-Ph), 131.08 (m-Ph), 133.00 (i-Ph), 135.14 ml) was added NaBH4 (7 mg, 0.18 mmol) and the mixture was
(p-Ph), 158.10 (C+); UV/VIS (MeCN): λmax (log ε) = 243.0 stirred for 4 h. Additional NaBH4 (2 mg, 0.053 mmol) was
(3.41), 272.0 (3.57). Anal. calcd for C13H10BClF4N4 (344.5): added and the reaction was continued further for 4 h. Water was
C, 45.32; H, 2.93; N, 16.26. Found: C, 45.32; H, 3.10; N, 16.52. added and the product was extracted with dichloromethane. The
extract was washed with water and diluted hydrochloric acid (1
1,5-Diphenyl-3-(phenylazo)-1H-[1,2,4]triazole
N). After being dried over Na2SO4, the solvent was removed to
(3a)
give 6 (56 mg, 43%).
A mixture of 2 (345 mg, 1.0 mmol), benzylamine (110 μl, 1.0
mmol), and triethylamine (0.42 ml, 3.0 mmol) in dichloro- 2. With p-(dimethylamino)aniline
methane (6 ml) was heated at reflux for 2.5 h. The reaction m i x t u r e o f ( 3 4 5 m g , 1 . 0 m m o l ) a n d
A
2
mixture was poured into water, and the product was extracted p-(dimethylamino)aniline (140 mg, 1.0 mmol) in dichloro-
with dichloromethane. The extract was washed with water and methane (5 ml) was stirred overnight at room temperature. The
diluted hydrochloric acid (1 N). After being dried over Na2SO4, solvent was evaporated and the residue was dissolved in
the solvent was removed and the residue (334 mg) was purified acetone. Hexane was added and the resultant black solid was
by column chromatography on silica gel (eluent: dichloro- filtered off. Evaporation of the solvent from the filtrate left 6
methane, then acetonitrile) to give 3a (163 mg, 50%).
(190 mg, 73%) as orange crystals.
Reaction of 3-chloroformazan 6 with
Orange needles, mp 146.7–148.0 °C (EtOH); IR (KBr) νmax
3070, 1594, 1496, 1448, 1380, 1362, 1300, 1178, 1150, 1076, benzylamine
1020, 990, 924, 916, 800, 770, 740, 718, 690; 1H NMR (200 A mixture of 3-chloroformazan 6 (130 mg, 0.50 mmol) and
MHz, CDCl3) δ 7.35–7.62 (m, 13H), 8.10–8.15 (m, 2H, benzylamine (0.30 ml, 2.5 mmol) in ethanol (3 ml) was stirred
o-PhN=N-); 13C NMR (50 MHz, CDCl3) δ 123.5, 125.1, 126.8, at room temperature for 5 h. The precipitated solid
128.2, 128.8, 129.0, 129.0, 129.2, 130.3, 132.1, 137.4, 152.4, (benzylamine hydrochloride) was filtered off and the filtrate
155.0, 168.1; MS (EI, 70 eV) m/z 325 (M+, 3), 220 (4), 180 was concentrated. The residue was washed several times with
(100), 117 (24), 77 (53), 31 (13), 27 (54); UV-vis (MeCN) λmax ether. The washings were poured into water and extracted with
(log ε)/nm: 325 (3.3); Anal. calcd. for C20H15N5 (325.37): C, dichloromethane. The extract was washed with diluted hydro-
73.82; H, 4.65; N, 21.53. Found: C, 73.73; H, 4.44; N, 21.58. chloric acid (1 N). After being dried over Na2SO4, the solvent
was removed and the residue (141 mg) was purified by column
Reaction of 2 with triethylamine
chromatography on silica gel (eluent: CH2Cl2→MeCN) to give
The salt 2 (175 mg, 0.51 mmol) was treated with triethylamine a brown solid (57 mg). This product was further purified by
(140 μl, 1.0 mmol) in dichloromethane (6 ml) under reflux for column chromatography on silica gel (eluent: CH2Cl2) to give
16 h. The reaction mixture was poured into water, and the triazole 3a (49 mg, 30%).
product was extracted with dichloromethane. The extract was
washed with diluted hydrochloric acid (1 N). After being dried 3-(Butylamino)-1,5-diphenylformazan (5b)
over Na2SO4, the solvent was removed to give 4h (115 mg, A mixture of 6 (85 mg, 0.33 mmol) and butylamine (100 μl, 1.0
60%).
mmol) in dichloromethane (5 ml) was stirred overnight at room
temperature. Diluted hydrochloric acid (1 N) was added and the
product was extracted with dichloromethane. After being dried
Conversion of 4a to 3a
A mixture of 4a (167 mg, 0.40 mmol) and triethylamine (112 over Na2SO4, the solvent was removed and the residue (80 mg)
μl, 0.80 mmol) in dichloromethane (4 ml) was stirred at room was purified by column chromatography on silica gel (eluent:
temperature for 21 h under argon. The reaction mixture was CH2Cl2→MeOH) to give a mixture of E/Z isomer of 5b (21
diluted with ether, and washed with diluted hydrochloric acid (1 mg, 22%) as a green solid. This compound was easily oxidized
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Beilstein Journal of Organic Chemistry 2009, 5, No. 8.
by air, and satisfactory elemental analysis data and mass spec-
trum were not obtained.
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1H NMR (300 MHz, CDCl3) δ 0.90–1.00 (m, 3H), 1.40–1.69
(m, 4H), 3.12 (q), 3.41 (q), 4.90 (br, NH), 5.26 (br, NH), 6.99
(br, NH), 7.15–7.60 (m), 7.78–7.82 (m), 7.89–7.92 (m), 8.08 (s,
NH), 9.42 (s, NH).
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
13C NMR (50 MHz, CDCl3) δ 14.0, 14.2, 20.1, 20.5, 31.7, 33.1,
41.7, 43.7, 113.9, 117.9, 121.2, 123.0, 125.3, 128.8, 129.0,
130.6, 143.3, 147.6, 148.0, 151.1, 154.1.
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Oxidation of 5b to triazole 3b
The definitive version of this article is the electronic one
which can be found at:
A solution of 5b (139 mg, 0.47 mmol) in ethanol (20 ml) was
allowed to stand at room temperature for 10 d. The solvent was
evaporated and the residue was column chromatographed on
silica gel (eluent: CH2Cl2) to give 3b (94 mg, 69%).
doi:10.3762/bjoc.5.8
Supporting Information
Supporting Information File 1
Experimental details for Table 1, entries 2–13
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-5-8-S1.doc]
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