An environmentally benign and solvent-free synthesis of 3-aryl[1,2,4]triazolo[4,3-a]pyridines and 1-aryl-5-methyl[1,2,4]triazolo[4,3-a] quinolines using phenyliodine bis(trifluoroacetate) or iodobenzene diacetate

Article abstract of DOI:10.1007/s10593-012-0899-0

A simple, solvent-free and effective method for oxidative cyclization of 2-pyridyl- and 2-quinolylhydrazones with phenyliodine bis(trifluoroacetate) and iodobenzene diacetate to the corresponding 3-aryl[1,2,4]triazolo[4,3-a]pyridines and 1-aryl[1,2,4]tria

Full text of DOI:10.1007/s10593-012-0899-0

Chemistry of Heterocyclic Compounds, Vol. 47, No. 10, January, 2012 (Russian Original Vol. 47, No. 10, October, 2011)
AN ENVIRONMENTALLY BENIGN AND SOLVENT-FREE
SYNTHESIS OF 3-ARYL[1,2,4]TRIAZOLO[4,3-a]PYRIDINES
AND 1-ARYL-5-METHYL[1,2,4]TRIAZOLO[4,3-a]QUINOLINES
USING PHENYLIODINE BIS(TRIFLUOROACETATE) OR
IODOBENZENE DIACETATE
P. Kumar1
A simple, solvent-free and effective method for oxidative cyclization of 2-pyridyl- and 2-quinolyl-
hydrazones with phenyliodine bis(trifluoroacetate) and iodobenzene diacetate to the corresponding
3-aryl[1,2,4]triazolo[4,3-a]pyridines and 1-aryl[1,2,4]triazolo[4,3-a]quinolines is described. All
reactions were characterized by short reaction times and high yields at room temperature. All reactions
were carried out by just grinding the reaction components.
Keywords: bridgehead triazoles, hydrazones, iodobenzene diacetate, phenyliodine bis(trifluoroacetate),
grinding, oxidative cyclization, solvent-free reactions.
In the last few decades, the chemistry of 1,2,4-triazoles and their fused heterocyclic derivatives have
received considerable attention owing to their synthetic and biological importance [1–11]. 1,2,4-Triazole makes
up the core structure of numerous biologically active compounds, including blockbuster drugs such as conazole
fungicides (Fluconazole, Hexaconazole), triazolobenzodiazepines (Estazolam, Triazolam, Alprazolam),
Rizatriptan, and Ribavirin, which find a wide range of applications in pharmaceutical and agrochemical industry
[12]. Triazole fused with other ring systems is also found to possess diverse applications in medicine [12–18],
i.e., as antitumor [12], anticancer, and antimicrobial agents [13, 15].
The principle underlying green chemistry entails testing the necessity of use of organic solvents and
reducing the energy requirements. Because many organic solvents are ecologically harmful, strategies to
minimize their use make up part of the developments toward environmentally benign chemical technologies.
Hypervalent iodine reagents have gained much importance as oxidants in the attempts to avoid the use of toxic
transition metals in oxidizing processes [19–27]. Recent literature survey shows the development of new
hypervalent iodine reagents that can be used as "green" oxidants [28–29]. The poor solubility of hypervalent
iodine reagents in most common organic solvents has led to the development of solvent-free reactions [30–31].
_______
* To whom correspondence should be addressed, e-mail: drpkawasthignkc@rediffmail.com.
1Department of Chemistry, Kurukshetra University, Kurukshetra, Haryana 136119, India.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1499-1312, October, 2011.
Original article submitted October 11, 2010.
0009-3122/12/4710-1237©2012 Springer Science+Business Media, Inc.
1237

Many exothermic reactions can be accomplished by just grinding solids together in a mortar with a
pestle. Reactions are initiated by the transfer of very small amounts of energy through friction. It brings
advantages from the environmental point of view, as well as rate enhancement, less waste products, and higher
yields [32].
F
Cl
H
N
N
F
N
N
N
N
N
Cl
N
OH
N
N
Me
N
N
N
Me
OH
N
Me
Rizatriptan
Hexaconazole
Fluconazole
R1
N
N
R
OH
N
O
N
HO
NH2
N
O
HO
N
Cl
N
Estazolam R = R1 = H;
Triazolam R = Cl, R1 = Me;
Alprazolam R = H, R1 = Me
Ribavirin
In continuation of our previous work [16, 33–37] on biologically active heterocyclic compounds and
development of novel synthetic methodologies and because of the biological significance of 1,2,4-triazole, a
solvent-free oxidative cyclization of 2-pyridyl- and 2-quinolylhydrazones with phenyliodine bis(trifluoroace-
tate) (PIFA) or iodobenzene diacetate (IBD) to the corresponding 3-aryl-[1,2,4]triazolo[4,3-a]pyridines and 1-aryl-
5-methyl-[1,2,4]triazolo[4,3-a]quinolines is reported here.
Two series of 2-pyridyl- and 2-quinolylhydrazones were synthesized to study their oxidative cyclization
to the analogous triazole derivatives. The reaction of 2-(2-benzylidenehydrazinyl)pyridine (1a) with IBD was
taken as a model reaction. In a preliminary experiment, 1.0 eqv. of 2-(2-benzylidenehydrazinyl)pyridine (1a)
was ground with 1.2 eqv. of IBD at room temperature. As expected, 3-phenyl-[1,2,4]triazolo[4,3-a]pyridine (2a)
was obtained in 75% yield in 20 min. The same reaction with PIFA (1.2 eqv.) yielded compound 2a in 89% in
6 min. However, the oxidative cyclization reaction of 2-quinolylhydrazones 3a–d with IBD did not proceed at
room temperature and required some heating (40–50°C), whereas with PIFA, the reaction occurred at room
temperature. Thus the oxidative efficiency of PIFA was higher in terms of yield and time (Table 1).
Me
Me
PIFA
PIFA
N
Ar
N
Ar
Grinding
Grinding
N
N
N
N
N
N
N
N
H
H
N
N
Ar
3a–h
1a–i
Ar
4a–h
2a–i
1–4 a Ar = Ph, b Ar = 4-MeC6H4, c Ar = 4-ClC6H4, d Ar = 4-MeOC6H4, e Ar = 5-O2N-2-furyl,
f Ar = 2-thienyl; 1, 2 g Ar = 4-FC6H4, h Ar = 2-MeOC6H4, i Ar = 2-furyl;
3, 4 g Ar = 4-O2NC6H4, h Ar = 3,4-(MeO)2C6H3
1238

TABLE 1. Solvent-free Synthesis of 3-Aryl-[1,2,4]triazolo[4,3-a]pyri-
dines 2a–i and 1-Aryl-5-methyl-[1,2,4]triazolo[4,3-a]quinolines 4a–h
Grinding time, min
Yield, %
Product
PIFA
IBD
PIFA
IBD
6
6
20
20
25
15
18
16
20
15
16
15
15
15
15
15
15
15
15
89
86
87
85
90
88
84
86
85
90
86
85
85
81
80
86
85
75
70
68
64
68
65
64
66
65
65
64
66
64
65
61
65
65
2a
2b
2c
2d
2e
2f
8
5
8
5
5
2g
2h
2i
6
7
6
4a
4b
4c
4d
4e
4f
8
10
5
10
8
5
4g
4h
7
TABLE 2. Characteristics of Compounds 2a–i and 4a–h
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °C
lit. mp, °C [38]
C
H
N
2a
2b
2c
C12H9N3
73.98
73.83
74.56
74.62
4.55
4.65
5.26
5.30
3.46
3.51
21.33
21.52
20.22
20.08
18.22
18.30
174-75
155-56
173-75
154-55
C13H11N3
C12H8ClN3
189-91
190-91
62.88
62.76
2d
2e
2f
C13H11N3O
C10H6N4O3
C10H7N3S
69.44
69.32
52.32
52.18
59.58
59.68
5.03
4.92
2.77
2.63
18.53
18.66
24.22
24.34
123-25
256-58
113-14
124-26
254-56
112-114
3.62
3.51
20.74
20.88
2g
2h
2i
C12H8FN3
C13H11N3O
C10H7N3O
C17H13N3
67.51
67.60
69.41
69.32
64.69
64.86
78.88
78.74
78.98
79.10
69.44
69.51
74.59
74.72
61.26
61.22
3.72
3.78
4.81
4.92
3.87
3.81
4.99
5.05
5.43
5.53
4.15
4.12
5.28
5.23
3.36
3.43
19.61
19.71
18.71
18.66
22.60
22.69
16.31
16.20
15.45
15.37
14.41
14.30
14.45
14.52
18.97
19.04
161-162
161-62
189-91
153-55
211-12
200-02
160-62
183-185
165-166
281-282
224-235
—
—
—
4a
4b
4c
4d
4e
4f
152-153
213-214
201-202
162-163
182-183
164-165
—
C18H15N3
C17H12ClN3
C18H15N3O
C15H10N4O3
C15H11N3S
C17H12N4O2
C19H17N3O2
68.02
67.90
66.98
67.10
71.27
71.46
4.05
4.18
4.05
3.97
5.26
5.37
15.69
15.84
18.56
18.41
12.99
13.16
4g
4h
—
1239

The mechanistic pathway could include initial electrophilic attack of hypervalent iodine(III) at the
hydrazone nitrogen of compound 3, giving N-iodine(III) adduct, followed by reductive elimination of
iodobenzene, resulting in the intermediate which on elimination of proton affords nitrile imine that undergoes
intramolecular cyclization to yield the product 4. The results in Table 1 clearly indicate the advantage of PIFA
over IBD: a) time required for oxidative cyclization of 2-pyridyl- and 2-quinolylhydrazones is shorter;
b) oxidative cyclization takes place at room temperature; c) yields are higher. Solvent-phase oxidative
cyclization of 2-pyridyl- and 2-quinolylhydrazones using IBD in dichloromethane has already been used for this
reaction [38], but the reaction time was long and yields were low.
Me
Me
PIFA
Ar
– CF3CO2H
– PhI
Ar
N
N
N
N
N
N
I
H
OCOCF3
3
Me
N
Me
Me
N
Ar
Ar
N
N+
N
N+
–
N
– CF3CO2H
N
H
–
CF3CO2
N
Ar
4
In conclusion, a rapid and environmentally benign method for oxidative cyclization of 2-pyridyl- and
2-quinolylhydrazones to a triazole derivative is demonstrated. In terms of reaction time and yields, PIFA is a
more efficient oxidant than IBD. The mild experimental conditions, solvent-free synthesis, operational
simplicity, rapid conversions, and high yields of the product are attractive features of the present protocol. These
results, therefore, could contribute to the development of sustainable methods in organic synthesis.
EXPERIMENTAL
1
IR spectra were recorded on a Perkin-Elmer 1600 FTIR spectrophotometer in KBr pellets. H NMR
spectra were recorded on a Bruker Avance spectrometer (300 MHz) using TMS as internal standard. The
elemental analyses were performed on a Carlo Erba 1106 instrument. Melting points were determined on a
Buchi oil-heated melting apparatus and are uncorrected.
2-Pyridyl- and 2-quinolylhydrazones were prepared as reported previously [38], not additionally
purified, and used directly in oxidative cyclization. All chemicals used in this study were of the highest purity
available and purchased from Lancaster, Merck, and Fluka.
The Oxidative Cyclization of 2-Pyridyl- and 2-Quinolylhydrazones with PIFA (General Method).
A mixture of the correspoding hydrazone (1.0 mmol) and PIFA (516 mg, 1.2 mmol) was blended thoroughly in
a mortar. The resulting homogeneous mixture was ground with a pestle at room temperature for 5-10 min. The
progress of reaction was monitored by TLC (benzene–acetone, 4:1). After completion of the reaction as
indicated by the appearance of liquid in the reaction mixture, 20 ml of 5% solution of sodium bicarbonate was
added. The reaction mixture was filtered, and the solid collected on the filter was recrystallized from ethanol to
afford the respective cyclized product 3 or 4.
1240

TABLE 3. 1H NMR and IR Spectra of Compounds 2a–i and 4a–h
Com-
pound
IR, ν, cm-1
1H NMR (CDCl3), δ, ppm (J, Hz)
3071, 3042, 1620, 1588, 1497, 1370,
1064, 780, 750, 710
6.86-6.90 (1H, m, H Ar); 7.30 (1H, m, H Ar);
7.55-7.65 (3H, m, H Ar); 7.80-7.85 (3H, m, H Ar);
8.30 (1H, d, J = 7.2, H Ar)
2a
3074, 3036, 2988, 1628, 1502, 1375,
1005, 847, 744
2.43 (3H, s, CH3); 7.23 (2H, d, J = 7.8, H Ar);
7.37 (1H, m, H Ar); 7.43 (2H, d, J = 7.8, H Ar);
7.83 (2H, m, H Ar); 8.31 (1H, m, H Ar)
2b
2c
2d
2e
2f
3033, 3022, 1631, 1475, 1406, 1367,
1312, 1090, 1060, 985, 827, 754, 741, 7.52 (1H, m, H Ar); 7.84 (1H, m, H Ar);
716
7.21 (1H, m, H Ar); 7.27-7.49 (4H, m, H Ar);
8.30 (1H, d, J = 7.2, H Ar)
3055, 3033, 1629, 1578, 1511, 1475,
1243, 1052, 830, 755
3.89 (3H, s, OCH3); 6.98 (2H, d, J = 8.1, H Ar);
7.45-7.51 (4H, m, H Ar); 7.81 (1H, m, H Ar);
8.29 (1H, d, J =7.2, H Ar).
3098, 3067, 1631, 1598, 1533, 1490,
1341, 1101, 1023, 755
7.40-7.41 (1H, m, H Ar); 7.59-7.64 (2H, m, H Ar);
7.85-8.05 (2H, m, H Ar);
8.35 (1H, d, J = 7.2, H Ar)
3122, 3051, 1635, 1598, 1494, 1110,
1066, 791, 752, 722
6.90-6.96 (1H, m, H Ar); 7.20-7.30 (2H, m, H Ar);
7.52 (1H, d, J = 3.2, H Ar);
7.65-7.80 (2H, m, H Ar);
8.38 (1H, d, J = 8.0, H Ar)
3068, 3014, 1580, 1487, 1461, 1212,
837, 734
6.86-6.90 (1H, m, H Ar); 7.25-7.30 (3H, m, H Ar);
7.80-7.90 (3H, m, H Ar);
8.27 (1H, d, J = 7.2, H Ar)
2g
2h
3066, 3016, 1605, 1556, 1502, 1457,
1233, 1025, 752, 710
3.83 (3H, s, OCH3); 6.80-6.85 (1H, m, H Ar);
7.10-7.20 (2H, m, H Ar); 7.30-7.35 (1H, m, H Ar);
7.55-7.60 (1H, m, H Ar); 7.70-7.90 (2H, m, H Ar);
8.29 (1H, d, J = 7.2, H Ar)
3122, 3051, 1635, 1598, 1494, 1110,
1066, 791, 752, 722
6.65-6.70 (1H, m, H Ar); 6.90-6.95 (1H, m, H Ar);
7.25-7.35 (2H, m, H Ar); 7.65-7.80 (2H, m, H Ar);
8.31 (1H, d, J = 7.2, H Ar)
2i
3058, 3033, 1613, 1577, 1490, 1366,
1027, 743, 713
2.59 (3H, s, CH3); 7.28-7.82 (10H, m, H Ar).
4a
4b
4c
4d
3068, 3054, 3011, 2917, 1607, 1592,
1503, 1464, 1046, 833, 782
2.48 (3H, s, CH3); 2.60 (3H, s, CH3);
7.14-7.85 (9H, m, H Ar)
3073, 3022, 3009, 1617, 1585, 1503,
1470, 828, 785
2.60 (3H, s, CH3); 7.31-7.92 (9H, m, H Ar)
3072, 3032, 3006, 2966, 2897, 1632,
1598, 1505, 1442, 1258, 1103, 841,
744
2.61 (3H, s, CH3); 3.85 (3H, s, OCH3);
7.05-7.95 (9H, m, H Ar)
3095, 3066, 3022, 2905, 1622, 1600,
1537, 1510, 1445, 1353, 1260, 860,
837, 722
2.62 (3H, s, CH3); 7.27-8.00 (7H, m, H Ar)
4e
3103, 3077, 3021, 2955, 1619, 1602,
1472, 1119, 1023, 789, 747
2.60 (3H, s, CH3); 7.31-7.98 (8H, m, H Ar)
2.68 (3H, s, CH3); 7.32-8.42 (9H, m, H Ar)
4f
4g*
4h
3058, 3027, 2912, 1622, 1592, 1548,
1461, 1361, 1023, 862, 828, 739
3079, 3041, 3011, 2952, 2887, 1603,
1588, 1499, 1262, 1198, 1023, 902,
852, 752
2.64 (3H, s, CH3); 3.82 (3H, s, OCH3);
3.95 (3H, s, OCH3); 7.00-7.92 (8H, m, H Ar)
_______
*1H NMR spectra were recorded in DMSO-d6.
The Oxidative Cyclization of 2-Pyridyl- and 2-Quinolylhydrazones with IBD (General Method). A
mixture of a 2-pyridyl- (1) or 2-quinolylhydrazone (3) (1.0 mmol) and IBD (1.2 mmol) was blended thoroughly
with a pestle in a mortar. The resulting homogeneous mixture was ground at room temperature for 15-25 min. In
the case of the oxidative cyclization of 2-quinolylhydrazones, the reaction mass was first kept in the oven for
4-5 min at 40-50°C to initiate the reaction and then ground for 15 min. The progress of the reaction was
monitored by TLC (benzene–acetone, 4:1). After completion of the reaction as indicated by the appearance of
1241

liquid in the reaction mixture, 20 ml of 5% solution of sodium bicarbonate was added. The reaction mixture was
filtered, and the solid collected on the filter was recrystallized from ethanol to afford the respective cyclized
product 3 or 4.
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