Microwave-assisted and efficient one-pot synthesis of substituted 1,2,4-triazoles

Article abstract of DOI:10.3987/COM-05-10415

An efficient microwave-assisted one-pot and three-component synthesis of substituted 1,2,4-triazoles has been achieved utilizing substituted primary amines.

Full text of DOI:10.3987/COM-05-10415

HETEROCYCLES, Vol. 65, No. 8, 2005
1957
HETEROCYCLES, Vol. 65, No. 8, 2005, pp. 1957 - 1962
Received, 1st April, 2005, Accepted, 19th May, 2005, Published online, 20th May, 2005
MICROWAVE-ASSISTED AND EFFICIENT ONE-POT SYNTHESIS OF
SUBSTITUTED 1,2,4-TRIAZOLES
*
Daliang Li, Hongli Bao, and Tianpa You
Chemistry Department, University of Science & Technology of China, Hefei 230026,
P. R. China; Tel.: +86-551-3606944; Fax: +86-551-3606168; E-mail:
ytp@ustc.edu.cn.
Abstract –An efficient microwave-assisted one-pot and three-component synthesis of
substituted 1,2,4-triazoles has been achieved utilizing substituted primary amines.
INTRODUCTION
,2,4-Triazoles are attractive constructs because of their unique chemical properties and structure. They
1
have been found many applications in organic, organometallic, and medicinal chemistry, as well as in
1
materials chemistry and biology. As a consequence, a number of synthetic methods have been
1
, 2
3
developed to construct this ring system. The three-component procedure developed by Stocks was the
first one-pot synthesis reported for preparation of 1,2,4-triazoles, though it provided an efficient
procedure and the possible reaction pathway to prepare 1,2,4-triazoles. There remains a drawback of low
yield in the synthesis of 4-alkyl-substituted 1,2,4-triazoles. As well-known, microwave induced has
emerged as a powerful technique to promote a variety of organic reactions under solvent-free conditions
4
offering reduced pollution and low cost together with simplicity in processing and handling. These
promote us to carry out this one-pot, three-component reaction with microwave assisted.
RESULTS AND DISCUSSION
In our initial studies, N’-acetyl-N,N-dimethylhydrazonoformamide (1) was generated by combining acetic
hydrazide with DMF-DMA(dimethylformamide dimethylacetal) in CH
then acidic Al
no desired product was obtained under microwave irradiation.
2
Cl
2
under refluxing(Scheme 1);
5
2
O
3
was used as a carrier and was catalyst in the acid-catalyzed ring closure step. However,

1958
HETEROCYCLES, Vol. 65, No. 8, 2005
O
a) CH Cl ,
OCH3
OCH3
2
2
NH2
reflux, 30 min
O
N
N
N
+
N
H
N
H
1
b) BuNH2
c) Al O , MW, 2-3 min
N
N
N
2
3
Scheme 1 Initial Results Employing Butylamine with MW
Since the desired products were not obtained under solvent-free condition, acetic acid was used as solvent
also as catalyst instead of acidic Al . The mixture reacted under microwave irradiation for 2-3 min to
2
O
3
prepare the substituted 1,2,4-triazoles. Fortunately, satisfactory results were obtained (Table 1).
Table 1 Microwave-assisted one-pot synthesis of substituted 1,2,4-triazoles
2
a R= Ph
2
h R=
i R=
2j R=
OMe
2
b R= Bu
O
a) CH Cl ,
O
COEt
OCH3
OCH3
2
2
NH2
O
reflux, 30 min
2
N
N
N
2c R=
+
N
H
N
Et
N
H
N
O
1
b) RNH2
2d R=
N
N
N
R
2
k R=
l R=
OMe
2e R= t-Bu
c) acetic acid, MW, 2-3 min
2
2f R= -CH2Ph
g R=
2
F
2
Me
a
Entry
R-NH2
aniline
butylamine
Product Yield(%)
Yield(%)
1
2
2a
2b
2c
2d
2e
2f
2g
2h
2i
77
68
95
72
66
81
98
97
55
98
72
82
64
/
/
52
3
4
5
6
7
8
9
2-aminomethyl-1-ethylpyrrolidine
cyclohexylamine
b
tert-butylamine
benzylamine
4-methylaniline
4-methoxyaniline
/
39
/
87
43
/
22
68
ethyl 4-aminobenzoate
N-(3-aminopropyl)morpholine
4-methoxybenzylamine
4-fluorobenzylamine
1
0
2j
2k
2l
1
1
1
2
a
b
Note: This yield was provided by reference 3. This yield was achieved by using
N-dimethoxymethyl-N,N’,N’-trimethylethane-1,2-diamine instead of DMF-DMA.
Our microwave-assisted procedure is more efficient than that without microwave-assisted with higher
yield and shorter reaction time.

HETEROCYCLES, Vol. 65, No. 8, 2005
1959
EXPERIMENTAL
1
Melting points were determined with an XT-4 apparatus and were uncorrected. The HNMR spectra
were measured with BRUKER AV-300 spectrometers.
General Prcedure for the synthesis of substituted 1,2,4-triazoles:
In an open vessel (25 mL), acetic hydrazide (222 mg, 3 mmol) was dissolved in dichloromethane (2 mL)
and dimethylformamide dimethyl acetal (3 mmol) was added. The reaction mixture was refluxing for 30
2
min, evaporated in vacuo and RNH (2.8 mmol) was added followed by acetic acid (1.5 mL). The
reaction mixture was standed under microwave irradiation for 2-3 min, then cooled, concentrated and the
residue was purified by chromatography on silica gel.(Eluent: MeOH: Ethyl Acetate=20:1 to MeOH:
Ethyl Acetate=1:1).
3
Entry 1: 3-Methyl-4-phenyl-1,2,4-triazole (2a)
o
o
1
Prepare in 77% yield as a white solid. mp 101-103 C, 102-103 C(lit.). HNMR(CDCl
3
, 300 MHz) δ:
, 75 MHz) δ: 150.5,
9 3
H N , calcd: 159.0796, find: 159.0793.
1
3
8
1
.22(1H, s), 7.60-7.49(3H, m), 7.32-7.28(2H, m), 2.44(3H, s) ppm; CNMR(CDCl
43.2, 134.1, 130.0, 129.4, 125.3, 10.7 ppm; HRMS(EI): C
3
9
Entry 2: 4-Butyl-3-methyl-1,2,4-triazole (2b)
1
Prepare in 68% yield as yellow oil. HNMR(CDCl , 300 MHz) δ: 8.05(1H, s), 3.89(2H, t, J=7.1 Hz),
3
1
3
2
1
.49(3H, s), 1.74(2H, m), 1.38(2H, m), 0.95(3H, t, J=7.2 Hz) ppm; CNMR(CDCl
3
, 75 MHz) δ: 150.3,
43.1, 44.2, 32.4, 19.7, 13.6, 10.3 ppm; HRMS(EI): C , calcd: 139.1109, find: 139.1116; Anal.
7
13 3
H N
Calcd for C H N C, 60.40; H, 9.41; N, 30.19. Found: C, 60.07; H, 9.65; N, 29.98.
7
13
3
Entry 3: 1-Ethyl-2-(3-methyl-1,2,4-triazole-4-methyl)pyrrolidine (2c)
1
Prepare in 95% yield as yellow oil. HNMR(CDCl
3
, 300 MHz) δ: 8.22(1H, s), 3.95(2H, d, J=5.5 Hz),
3
1
6
1
.19(1H, t, J=6.9 Hz), 2.78(1H, m), 2.63(1H, m), 2.48(3H, s), 2.25-2.41(2H, m), 1.89(1H, m),
1
3
.58-1.80(2H, m), 1.48(1H, m), 1.07(3H, t, J=7.1 Hz) ppm; CNMR(CDCl , 75 MHz) δ: 151.0, 144.0,
3
3.5, 53.5, 49.3, 48.0, 28.7, 23.2, 21.5, 13.8, 10.6 ppm; HRMS(EI): C H N , calcd: 194.1531, find:
1
0
18
4
94.1526; Anal. Calcd for C10
H
18
N
4
C, 61.82; H, 9.34; N, 28.84. Found: C, 61.49; H, 9.54; N, 28.62.
3
Entry 4: 4-Cyclohexyl-3-methyl-1,2,4-triazole (2d)
o
o
1
Prepare in 72% yield as a white solid. mp 99-100 C, 100-101 C(lit.). HNMR(CDCl
3
, 300 MHz) δ:
8
1
5
.15(1H, s), 3.86(1H, m), 2.48(3H, s), 2.08-2.04(2H, m), 1.98-1.93(2H, m), 1.82-1.77(1H, m),
1
3
.68-1.59(2H, m), 1.55-1.43(2H, m), 1.38-1.26(1H, m) ppm; CNMR(CDCl
3
, 75 MHz) δ: 150.0, 140.4,
4.8, 33.7, 25.3, 24.8, 10.5 ppm; HRMS(EI): C , calcd: 165.1266, find: 165.1260.
9 15 3
H N

1960
HETEROCYCLES, Vol. 65, No. 8, 2005
Entry 5: 4-tert-Butyl-3-methyl-1,2,4-triazole (2e)
o
1
Prepare in 66% yield as a white solid. mp 90-92 C. HNMR(CDCl
3
, 300 MHz) δ: 8.16(1H, s), 2.63(3H,
1
3
s), 1.65(9H, s) ppm; CNMR(CDCl
, calcd: 139.1109, find: 139.1118; Anal. Calcd for C
C, 60.11; H, 9.61; N, 29.92.
Entry 6: 4-Benzyl-3-methyl-1,2,4-triazole (2f)
3
, 75 MHz) δ: 150.2, 141.6, 56.0, 29.9, 14.1 ppm; HRMS(EI):
C
7
H
13
N
3
7 13 3
H N C, 60.40; H, 9.41; N, 30.19. Found:
3
o
o
1
Prepare in 81% yield as a white solid. mp 65-67 C, 66-69 C(lit.). HNMR(CDCl
3
, 300 MHz) δ: 8.10(1H,
s), 7.40-7.33(3H, m), 7.12-7.09(2H, m), 5.10(2H, s), 2.37(3H, s) ppm; CNMR(CDCl , 75 MHz) δ: 151.0,
43.7, 134.3, 129.3, 128.6, 127.0, 48.1, 10.4 ppm; HRMS(EI): C10 , calcd: 173.0953, find: 173.0952.
Entry 7: 3-Methyl-4-(4-methylphenyl)-1,2,4-triazole (2g)
1
3
3
1
11 3
H N
o
1
3
Prepare in 98% yield as a white solid. mp 42-44 C. HNMR(CDCl , 300 MHz) δ: 8.22(1H, s), 7.35(2H, d,
1
3
J=8.0 Hz), 7.18(2H, d, J=8.0 Hz), 2.47(3H, s), 2.43(3H, s) ppm; CNMR(CDCl
3
, 75 MHz) δ: 151.0,
1
1
43.5, 139.9, 131.4, 130.6, 125.2, 21.3, 21.2, 10.7 ppm; HRMS(EI): C10H N , calcd: 173.0953, find:
11 3
73.0944; Anal. Calcd for C10
H
11
N
3
C, 69.34; H, 6.40; N, 24.26. Found: C, 69.01; H, 6.59; N, 23.95.
3
Entry 8: 4-(4-Methoxyphenyl)-3-methyl-1,2,4-triazole (2h)
o
o
1
Prepare in 97% yield as a white solid. mp 110-111 C, 112-113 C(lit.). HNMR(CDCl
3
, 300 MHz) δ:
8.21(1H, s), 7.25(2H, dd, J=2.0, 4.6 Hz), 7.05 (2H, dd, J=2.0, 4.6 Hz), 3.90(3H, s), 2.42(3H, s) ppm;
1
3
CNMR(CDCl
3
, 75M Hz) δ: 160.4, 151.2, 143.6, 126.8, 126.5, 115.1, 55.6, 10.6 ppm; HRMS(EI):
C H N O, calcd: 189.0902, find: 189.0908.
1
0
11
3
3
Entry 9: Ethyl 4-(3-methyl-1,2,4-triazole-4-yl)benzoate (2i)
o
o
1
Prepare in 55% yield as a white solid. mp 101-102 C, 103-104 C(lit.). HNMR(CDCl
3
, 300 MHz) δ:
8
1
1
.28(1H, s), 8.24(2H, dd, J=2.0, 8.4 Hz), 7.44(2H, dd, J=2.0, 8.4 Hz), 4.44(2H, q, J=7.2 Hz), 2.48(3H, s),
1
3
.43(3H, t, J=7.2 Hz) ppm; CNMR(CDCl , 75 MHz) δ: 165.0, 150.4, 143.0, 137.6, 131.4, 125.1, 61.6,
3
4.3, 10.9 ppm; HRMS(EI): C H N O , calcd: 231.1008, find: 231.1002.
1
2
13
3
2
Entry 10: 4-(3-N-Morpholine-propyl)-3-methyl-1,2,4-triazole (2j)
1
Prepare in 98% yield as yellow oil. HNMR(CDCl
3
, 300 MHz) δ: 8.15(1H, s), 4.01(2H, t, J=6.9 Hz),
1
3
3
.74-3.70(4H, m), 2.48-2.44(7H, m), 2.33(2H, t, J=6.5 Hz), 2.00-1.91(2H, m) ppm; CNMR(CDCl , 75
3
MHz) δ: 150.7, 143.4, 66.5, 54.1, 53.2, 41.8, 26.2, 10.0 ppm; HRMS(EI): C10
H N
18 4
O, calcd: 210.1481,
18 4
find: 210.1484; Anal. Calcd for C10H N O C, 57.12; H, 8.63; N, 26.64. Found: C, 56.80; H, 8.77; N,
2
6.37.

HETEROCYCLES, Vol. 65, No. 8, 2005
1961
3
Entry 11: 4-(4-Methoxybenzyl)-3-methyl-1,2,4-triazole (2k)
o
o
1
Prepare in 72% yield as a white solid. mp 86-88 C, 88-90 C(lit.). HNMR(CDCl
3
, 300 MHz) δ: 8.07(1H,
s), 7.05(2H, dd, J= 8.8, 2.0 Hz), 6.90(2H, dd, J= 8.8, 2.0 Hz), 5.02(2H, s), 3.80(2H, s), 2.38(3H, s) ppm;
1
3
CNMR(CDCl
3
, 75 MHz) δ: 159.8, 150.9, 143.5, 128.7, 126.0, 114.6, 55.3, 47.8, 10.3 ppm; HRMS(EI):
11 13 3
C H N O, calcd: 203.1059, find: 203.1061.
3
Entry 12: 4-(4-Fluorobenzyl)-3-methyl-1,2,4-triazole (2l)
1
Prepare in 82% yield as an oil. HNMR(CDCl
3
, 300 MHz) δ: 8.09(1H, s), 7.12-7.06(4H, m), 5.10(2H, s),
, 75MHz) δ: 164.4, 161.1, 150.8, 143.6, 130.2, 128.9(d, J=8.3 Hz),
16.4(d, J=21.8 Hz), 47.5, 10.4 ppm; HRMS(EI): C10 F, calcd: 191.0859, find: 191.0857.
1
3
2
.37(3H, s) ppm; CNMR(CDCl
3
1
10 3
H N
ACKNOWLEDGEMENTS
We thank the National Natural Science Foundation of China (No. 20172049) and our university for
financial support.
REFERENCES
1
. J. Y. Hwang, H. -S. Choi, D. -H. Lee, S. -E. Yoo, and Y. -D. Gong, J. Comb. Chem., 2005, 7, 136; S. K.
Samanta and J. Yli-Kauhaluoma, J. Comb. Chem., 2005, 7, 142; R. D. Armour, A. D. Baxter, J. S.
Bryans, K. N. Dack, P. S. Johnson, R. A. Lewthwaite, J. Newman, D. J. Rawson, and T. Ryckmans,
WO2004037809, 2004 (Chem. Abstr., 2004, 140, 391283); I. Cho, H. -J. Park, J. Noh, H. -C. Ryu, S. -W.
Park, S. Jung, S. Lee, J. -H. Kim, J. -W. Lim, C. Lyu, D. -H. Kim, Y. -H. Kim, K. -J. Yeon, M. -Y. Chae,
I. Min, H. Jin, and K. Kang, WO2004014878, 2004 (Chem. Abstr., 2004, 140, 181455); M. Krueger, O.
Petrov, K. -H. Thierauch, and G. Siemeister, WO2002094814, 2002 (Chem. Abstr., 2002, 138, 4620); M.
Geslin, D. Gully, J. -P. Maffrand, and P. Roger, WO2001044207, 2001 (Chem. Abstr., 2001, 135, 46184);
S. Borg, G. Estenne-Bouhtou, K. Luthman, I. Csoregh, W. Hessellink, and U. Hacksell, J. Org. Chem.,
1
995, 60, 3112.
. P. J. Garratt, ‘Comprehensive Heterocyclic Chemistry II’, Vol. 4, ed. by R. C. Storr, Elsevier, Oxford,
996, pp. 127-163, 905-1006; K. Turnbull, ‘Progress in Heterocyclic Chemistry’, Vol. 10, Elsevier,
Oxford, 1998, p. 153; M. Balasubramanian, J.G. Keay, E. F. V. Scriven, and N. Shobana, Heterocycles,
994, 37, 1951; T. Vanek, V. Velkova, and T. Gut, Collect. Czech. Chem. Commun., 1984, 249, 2492; A.
R. Dunstan, H. -P. Weber, G. Rihs, H. Widner, and E. K. Dziadulewicz, Tetrahedron Lett., 1998, 39,
2
1
1

1962
HETEROCYCLES, Vol. 65, No. 8, 2005
7983; J. J. Vanden Eynde, L. Estievenart, and Y. V. Haverbeke, Heterocycl. Commun., 2000, 6, 412; C.
H. Lee and K. -J. Lee, J. Heterocycl. Chem., 2002, 39, 845; S. W. Martin, J. L. Romine, L. Chen, G.
Mattson, I. A. Antal-Zimanyi, and G. S. Poindexter, J. Comb. Chem., 2004, 6, 35.
3
4
. M. J. Stocks, D. R. Cheshire, and R. Reynolds, Org. Lett., 2004, 6, 2969 and its references.
. B. L. Hayes, ‘Microwave Synthesis: Chemistry at the Speed of Light’, CEM Publishing, Matthews, NC,
2
002; S. Caddick, Tetrahedron, 1995, 51, 10403; L. Perreux and A. Loupy, Tetrahedron, 2001, 57, 9199;
P. Lidstrŏm, J. Tierney, B. Wathey, and J. Westman, Tetrahedron, 2001, 57, 9225; M. Larhed and A.
Hallberg, Drug Discovery Today, 2001, 6, 406; A. Fini and A. Breccia, Pure Appl. Chem., 1999, 71, 573;
A. de la Hoz, A. Díaz-Ortis, A. Moreno, and F. Langa, Eur. J. Org. Chem., 2000, 65, 3659; M. Alterman
and A. Hallberg, J. Org. Chem., 2000, 65, 7984.
5
. H. Bartsch and T. Erker, J. Heterocycl. Chem., 1990, 27, 991.