Novel process for synthesis of 1,2,4-triazoles: Ytterbium triflate-catalyzed cyclization of hydrazonyl chlorides with nitriles

Article abstract of DOI:10.1081/SCC-200057976

A series of 1,3,5-trisubstituted 1,2,4-triazoles were synthesized via the intermolecular cyclization of hydrazonyl chlorides with nitriles catalyzed by ytterbium triflate [Yb(OTf)₃]. The amount of catalysis was discussed and Yb(OTf)₃ could be reused without loss of activity. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1081/SCC-200057976

This article was downloaded by: [University of Cambridge]
On: 16 October 2014, At: 06:10
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,
UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic
Organic Chemistry
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Novel Process for Synthesis
of 1,2,4‐Triazoles: Ytterbium
Triflate–Catalyzed Cyclization
of Hydrazonyl Chlorides with
Nitriles
Weike Su a , Dianwen Yang a & Jianjun Li a
a College of Pharmaceutical Sciences, Zhejiang
University of Technology , Hangzhou, China
Published online: 17 Dec 2010.
To cite this article: Weike Su , Dianwen Yang & Jianjun Li (2005) Novel Process for
Synthesis of 1,2,4‐Triazoles: Ytterbium Triflate–Catalyzed Cyclization of Hydrazonyl
Chlorides with Nitriles, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 35:11, 1435-1440, DOI: 10.1081/
SCC-200057976
To link to this article: http://dx.doi.org/10.1081/SCC-200057976
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the
information (the “Content”) contained in the publications on our platform.
However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness,
or suitability for any purpose of the Content. Any opinions and views
expressed in this publication are the opinions and views of the authors, and

are not the views of or endorsed by Taylor & Francis. The accuracy of the
Content should not be relied upon and should be independently verified with
primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages,
and other liabilities whatsoever or howsoever caused arising directly or
indirectly in connection with, in relation to or arising out of the use of the
Content.
This article may be used for research, teaching, and private study purposes.
Any substantial or systematic reproduction, redistribution, reselling, loan,
sub-licensing, systematic supply, or distribution in any form to anyone is
expressly forbidden. Terms & Conditions of access and use can be found at
http://www.tandfonline.com/page/terms-and-conditions

Synthetic Communicationsw, 35: 1435–1440, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200057976
Novel Process for Synthesis of
1,2,4-Triazoles: Ytterbium
Triflate–Catalyzed Cyclization of
Hydrazonyl Chlorides with Nitriles
Weike Su, Dianwen Yang, and Jianjun Li
College of Pharmaceutical Sciences, Zhejiang University of Technology,
Hangzhou, China
Abstract: A series of 1,3,5-trisubstituted 1,2,4-triazoles were synthesized via the inter-
molecular cyclization of hydrazonyl chlorides with nitriles catalyzed by ytterbium
triflate [Yb(OTf )3]. The amount of catalysis was discussed and Yb(OTf )3 could be
reused without loss of activity.
Keywords: Cyclization, hydrazonyl chlorides, nitriles, triazoles, ytterbium triflate
It is reported that 1,2,4-triazoles have been a topic of research interest because
molecules with these structural features have been found to display a wide
range of potent biological activities, such as antifungal[1] and antibacterial
activities.[2] Because of the important biological properties of 1,2,4-triazole
compounds, several kinds of methods have been reported for the preparation
of triazoles. Initially most of the 1,2,4-triazoles were synthesized by the
reaction of hydrazonyl chlorides with aromatic or aliphatic nitriles in the
presence of AlCl3.[3] Synthesis of 1,2,4-triazoles were accomplished by cycli-
zation of 1,2,4-triazene employing oxidizing agents such as Ag2CO3,[4,5]
H2O2/KOH,[6] NaClO, Ca(ClO)2, Dess–Martin periodinane, and Ley’s
oxidizing agent (TPAP/NMO).[7] However, these methods required more
than stoichiometric amounts of reagents and these reagents were difficult to
Received in Japan December 16, 2004
Address correspondence to Weike Su, College of Pharmaceutical Sciences,
Zhejiang University of Technology, Hangzhou 310014, China. Fax: (0086)
57188320752; E-mail: suweike@zjut.edu.cn
1435

1436
W. Su, D. Yang, and J. Li
handle. Therefore, it is necessary to explore a convenient and environmentally
friendly method for the prepatation of 1,2,4-triazoles.
In recent years, Yb(OTf )3 has attracted attention as catalyst for a wide
range of reactions in organic synthesis.[8] A catalytic amount of Yb(OTf )3
was enough to complete the reactions in most cases. It was demonstrated
that the catalysts were easily recovered after the reaction and could be reused
without loss of activity. Until now, there were no reports on the reaction of
hydrazonyl chlorides and nitriles catalyzed by Yb(OTf )3. Herein we report
the preparation of 1,2,4-triazoles from hydrazonyl chlorides and nitriles in
the presence of Yb(OTf )3 (Scheme 1).
RESULTS AND DISCUSSION
Yb(OTf )3, as a reusable Lewis acid, can catalyze the cyclizations of hydra-
zonyl chlorides with nitriles in chlorobenzene at reflux (Scheme 1). The
results are summarized in Table 1.
As shown in Table 1, the reactions were run well with the catalytic
amounts of Yb(OTf )3. The yields were not obviously affected by different
amounts of Yb(OTf )3 0.1 equiv. of catalyst was enough to complete the
reaction (entries 2–4) and excessive amounts of Yb(OTf )3 did not increase
the yields. We also found that the reactions of aliphatic nitriles with hydrazo-
nyl chlorides were quicker than that of aromatic nitriles (entries 2, 5–8).
Furthermore, comparision of the yields (entries 4–7) shows that aliphatic
nitriles got better results than aromatic nitriles under similar conditions. Unfor-
tunately, when p-nitrobenzonitrile was used as substrate in the same conditions
(entry 8), the desired product was not detected even for a long time. On the
other hand, by prolonging the reaction time and increasing the reaction temp-
erature, 1,3,4,6-tetraphenyl-1,4-dihydro-1,2,4,5-tetrazine was obtained.
In addition, we investigated the recycling of Yb(OTf )3. It was found that
the reaction proceeded smoothly with recovered Yb(OTf )3 and gave good
yields of the corresponding products. The results are summarized in Table 2.
In summary, in the presence of catalytic amount of Yb(OTf )3, hydrazonyl
chlorides can react with nitriles to obtain the corresponding 1,2,4-triazoles in
good yields. Ten percent mol of ytterbium triflate is enough to complete the
reaction, and it can be recovered and reused easily.
Scheme 1.

a
Table 1. Preparation of triazoles catalyzed by Yb(OTf)3
Entry
Yb(OTf)3 (equiv.)
Time (h)
R1
R2
R3
Product
Yield (%)b
1
2
None
0.1
0.5
1.0
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
4
4
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
CH3
CH3
3a
3a
3a
3a
3b
3c
3d
—
3e
3f
NDc
82
3
4
CH3
CH3
85
84
4
4
C6H5
C6H5
5
4
H5C2OOCCH2
C6H5
80
72
6
6
C6H5
C6H5
C6H5
7
6
p-H3COC6H4
p-O2NC6H4
CH3
70
8
10
4
NDc
80
9
p-O2NC6H4
p-O2NC6H4
p-O2NC6H4
C6H5
10
11
12
6
C6H5
H5C2OOCCH2
CH3
70
80
4
3g
3h
4
p-H3CC6H4
83
aThe reaction were carried out using 1.2 equiv. of nitriles and 1 equiv. of hydrazonyl chlorides.
bIsolated yields based on hydrazonyl chlorides.
cNot detected.

1438
W. Su, D. Yang, and J. Li
Table 2. Catalyst recovery and its catalytic activitya using N-phenylbenzhydrazonyl
chloride and acetonitrile
Use
Reaction time/h
Yield/%
Cat. recovered/%
1st
4
4
4
4
82
81
80
80
95
94
93
94
2nd
3rd
4th
aRecovered catalyst.
EXPERIMENTAL
1H NMR spectra was recorded on a Varian-400 MHz instrument using
CDCl3 as the solvent with TMS as an internal standard. IR spectra was
recorded on a AVATAR-370 Infrared Spectrophotometer. MS spectra was
determined on a Thermo Finnigan LCQ-Advantage (ESI) instrument.
Melting points were determined on a Digital Melting Point Apparatus WRS-
1B and are uncorrected. Microanalysis was carried out on a Carlo-Erba
1106 instrument. All reactions were carried out under a dry nitrogen atmos-
phere. Hydrazonyl chlorides were synthesized by the literature procedure;[9]
Yb(OTf )3 was prepared from ytterbium oxide and trifluoromethanesulfonic
acid in water according to the literature.[10] All reagents used are commercial
available.
General Procedure for the Preparation of 1,3,5-Trisubstituted
1,2,4-Triazoles
Nitrile (2.4 mmol), Yb(OTf)3 (0.2 mmol), hydrazonyl chloride (2 mmol), and
dry chlorobenzene (10 mL) were subsequently added into a dry three-neck
flask under nitrogen atmosphere. The reaction mixture was refluxed for 4 h
and turned dark, then the mixture was washed with water (10 mL), the organic
layer was isolated, and the aqueous layer was extracted by ethyl acetate
(10 mL 3). Yb(OTf )3 can be recovered by removing the water and can then
be reused after recrystallization from CH3CN/CH2Cl2. The combined
organic layer was dried by anhydrous MgSO4, filtered, and concentrated in
vacuo, which was purified by preparative TLC (ethyl acetate–petroleum
ether ¼ 3:1) to obtain the product.
3a: Mp 92–938C (Lit.[3], 95–968C); IR (cm21) 1633, 1599, 1516, 1500,
1
1469, 1356, 1456, 1444, 1115; H NMR (CDCl3) ppm d: 2.56 (3H, s, CH3),
7.40–7.52 (8H, m, ArH), 8.14–8.16 (2H, m, ArH); MS (ESI) m/z: 236.2
(Mþ þ 1).
3b: Mp 46–478C (Lit.[3], 478C); IR (cm21) 1746, 1599, 1500, 1446,
1397, 1370, 1335, 1260, 1197, 1097, 1027; 1H NMR (CDCl3) ppm d:

Synthesis of 1,2,4-Triazoles
1439
1.27(3H, t, CH3), 3.95 (2H, s, CH2), 4.20–4.26 (2H, q, CH2), 7.40–7.46 (6H,
m, ArH), 7.51–7.55 (2H, m, ArH), 8.12–8.15 (2H, m, ArH); MS (ESI) m/z:
308.2 (Mþ þ 1).
3c: Mp 102–1038C (Lit.[3], 103–1048C); IR (cm21) 1594, 1516, 1498,
1480, 1461, 1446, 1378; 1H NMR (CDCl3) ppm d: 7.34–7.56 (11H, m, ArH),
7.62 (2H, m, ArH), 8.24–8.26 (2H, m, ArH); MS (ESI) m/z: 298.3 (Mþ þ 1).
3d: Mp 105–1068C (Lit.[11], 105–1068C); IR (cm21) 1607, 1595, 1576,
1459, 1461, 1440, 1388; 1H NMR (CDCl3) ppm d: 3.80 (3H, s, CH3O), 6.94
(2H, m, ArH), 7.40–7.58 (10H, m, ArH), 8.22 (2H, m, ArH); MS (ESI) m/z:
328.3 (Mþ þ 1).
3e: Mp 140–1428C (Lit.[6], 140–1428C); IR (cm21) 1633, 1599, 1516,
1
1499, 1469, 1444, 1342, 1115; H NMR (CDCl3) ppm d: 2.71 (3H, s, CH3),
7.46 (2H, d, J ¼ 6.4, ArH), 7.59–7.63 (1H, m, ArH), 7.81 (2H, d,
J ¼ 8.6 Hz, ArH), 8.15 (2H, d, J ¼ 6.4 Hz, ArH), 8.42 (2H, d, J ¼ 8.6 Hz,
ArH); MS (ESI) m/z: 281.1 (Mþ þ 1).
3f: Mp 160–1628C (Lit.[6], 160–1628C); IR (cm21) 1595, 1517, 1480,
1461, 1446, 1379, 1338; 1H NMR (CDCl3) ppm d: 7.42–7.53 (6H, m,
ArH), 7.53 (2H, m, ArH), 7.57–7.62 (2H, m, ArH), 8.21 (2H, m, ArH),
8.22–8.25 (2H, m, ArH); MS (ESI) m/z: 343.2 (Mþ þ 1).
3g: Mp 113–1158C; IR (cm21) 1736, 1612, 1597, 1469, 1528, 1500,
1
1447, 1345, 1212, 1174, 1112, 1026; 855,724; H NMR (CDCl3) ppm d:
1.33 (3H, t, J ¼ 7.2 Hz, CH3), 4.11 (2H, s, CH2), 4.28 (2H, q, J ¼ 7.2 Hz,
CH2), 7.53–7.55 (3H, m, ArH), 7.92 (2H, q, J ¼ 8.6 Hz, ArH), 8.21–8.23
(2H, q, ArH), 8.49 (2H, q, J ¼ 8.6 Hz, ArH); MS (ESI) m/z: 353.1
(Mþ þ 1); Anal. calcd. for C18H16N4O4: C, 61.36; H, 4.58; N, 15.90; found,
C, 61.39; H, 4.53; N, 15.82.
3h: Mp 102–1038C (Lit.[12], 103–1048C); IR (cm21) 1599, 1514, 1500,
1
1455, 1400, 1346, 1112, 1020; H NMR (CDCl3) ppm d: 2.39 (3H, s, CH3),
2.57 (3H, s, CH3), 7.25 (2H, d, J ¼ 8.0 Hz, ArH), 7.45–7.52 (5H, m, ArH),
8.03 (2H, d, J ¼ 8.0 Hz, ArH); MS (ESI) m/z: 250.2 (Mþ þ 1).
ACKNOWLEDGMENTS
We are grateful to the National Natural Science Foundation of China (No.
20276072), National Basic Research Program (No.2003CB114400), and
National Natural Science Foundation of Zhe Jiang Province (No. 2002095)
for financial support.
REFERENCES
1. Tanoury, G. J.; Senanayake, C. H.; Hett, R.; Kuhn, A. M.; Kessler, D. W.;
Wald, S. A. Pd-catalyzed aminations of aryl triazolones: Effective synthesis of
hydroxyitraconazole enantiomers. Tetrahedron Lett. 1998, 39, 6845–6848.

1440
W. Su, D. Yang, and J. Li
2. Sui, Z.; Guan, J.; Hlasta, D. J.; Macielag, M. J.; Foleno, B. D.; Goldschmidt, R. M.;
Loeloff, M. J.; Webb, G. C.; Barrett, J. F. SAR studies of diaryltriazoles against
bacterial two-component regulatory systems and their antibacterial activities.
Bioorg. Med. Chem. Lett. 1998, 8, 1929–1934.
3. Conde, S.; Corral, C.; Madronero, R. Synthesis of 1H-1,2,4-triazoles via nitrilium
salts. Synthesis 1974, 28–29.
4. Broggini, G.; Bruche, L.; Garanti, L.; Zecchi, G. J. Chem. Soc., Perkin Trans. 1
1994, 433.
5. Paulvannan, K.; Chen, T.; Hale, R. An improved synthesis of 1,2,4-triazoles using
Ag2CO3. Tetrahedron 2000, 56, 8071–8076.
6. Buzykin, B. I.; Bredikhina, Z. A. An approach to 1-aryl-1,2,4-triazoles. Synthesis
1993, 59–61.
7. Paulvannan, K.; Hale, R.; Sedehi, D.; Chen, T. Cyclization of 1,2,4-triazenes to
1,2,4-triazoles using oxidizing reagents—NaClO, Ca(ClO)2, Dess–Martin
periodinane and Ley’s TPAP/NMO. Tetrahedron 2001, 57, 9677–9682.
8. Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W.-L. Rare-earth metal triflates in
organic synthesis. Chem. Rev. 2002, 102, 2227–2302.
9. Patel, H. V.; Vyas, K. A.; Pandey, S. P.; Fernandes, P. S. Facile synthesis of hydra-
zonyl halides by reaction of hydrazones with N-halosuccinimide-dimethyl sulfide
complex. Tetrahedron 1996, 52, 661–668.
10. Osberg, J. H.; Spaziano, V. T.; Balasubramanian, T. M.; Liu, G. K.; Kinsley, S. A.;
Duckworth, C. A.; Poteruca, J. J.; Brown, P. S.; Miller, J. L. Use of lanthanide(III)
ions as catalysts for the reactions of amines with nitriles. J. Org. Chem. 1987, 52,
1017–1021.
11. Bojilova, A. 1,3-Dipolar cycloadditions of 1-(N-arylidene)amino-1,2,3-triazoles
with Diphenylnitrilimine. J. Chem. Soc., Perkin Trans. 1 1998, 3233–3237.
12. Mansurul Hoque, A. K. M.; Albert, C. K.; Wang, K. L.; Henry, J. S. 1,3-Dipolar
cycloadditions induced by cation radicals. Formation of 1,2,4-triazoles from
oxidative addition of 1,4-diphenylazomethane and aryl aldehyde phenylhydra-
zones to nitriles. Tetrahedron Lett. 1985, 26, 5655–5658.