Microwave assisted synthesis of novel 1,2,4-triazines in dry media

Article abstract of DOI:10.1081/SCC-100103982

An efficient facile and solventless synthesis of 1,2,4-triazines using microwave is described. A non conventional synthetic procedure has been developed where solid inorganic support is used as energy transfer medium under microwave irradiation (MWI) which devoids hazards of solution phase reactions. The reaction time has been brought down from hours to seconds with improved yield as compared to conventional heating.

Full text of DOI:10.1081/SCC-100103982

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MICROWAVE ASSISTED
SYNTHESIS OF NOVEL 1,2,4-
TRIAZINES IN “DRY MEDIA”
Mazaahir Kidwai a , Pooja Sapra a , Kumar Ranjan
Bhushan a & Preeti Misra a
a Department of Chemistry, University of Delhi,
Delhi, 110007, India
Published online: 09 Nov 2006.
To cite this article: Mazaahir Kidwai , Pooja Sapra , Kumar Ranjan Bhushan &
Preeti Misra (2001) MICROWAVE ASSISTED SYNTHESIS OF NOVEL 1,2,4-TRIAZINES
IN “DRY MEDIA”, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 31:11, 1639-1645, DOI: 10.1081/
SCC-100103982
To link to this article: http://dx.doi.org/10.1081/SCC-100103982
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SYNTHETIC COMMUNICATIONS, 31(11), 1639–1645 (2001)
MICROWAVE ASSISTED SYNTHESIS OF
NOVEL 1,2,4-TRIAZINES IN ‘‘DRY MEDIA’’
Mazaahir Kidwai,* Pooja Sapra,
Kumar Ranjan Bhushan, andPreeti Misra
Department of Chemistry, University of Delhi,
Delhi 110007, India
ABSTRACT
An efficient facile and solventless synthesis of 1,2,4-triazines
using microwave is described. A non conventional synthetic
procedure has been developed where solid inorganic support
is used as energy transfer medium under microwave irradia-
tion (MWI) which devoids hazards of solution phase reac-
tions. The reaction time has been brought down from hours
to seconds with improved yield as compared to conventional
heating.
Key Words: Alumina; Montmorillonite; Silica gel; Micro-
wave irradiation; Triazines.
The use of microwave irradiation has become an established tool
in organic synthesis for achieving better selectivity, rate enhancement and
reduction of thermally degradative by products.1–2 However, these pro-
cedures are practically limited as the solvents in microwave oven at ele-
vated temperatures create high pressures, which may cause explosion.3
* Corresponding author.
1639
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

1640
KIDWAI ET AL.
To circumvent these problems, there is a need for the development of newer
methods which proceed under mild and solvent free4 conditions. One of the
advances in this area, where substantial progress has been made, is the
inorganic5–6 solid supported organic synthesis which attracted attention
because of enhanced selectivity, milder reaction conditions and associated
case of manipulation. The main advantage being that solid supports do not
absorb microwave at 2450 MHz, so are not an obstacle for the transition of
microwaves to the reactants. More ever they also provide an opportunity
to work with open vessels and an enhanced possibility of upscaling the
reactions on a preparative scale.7–8
1,2,4-Triazines have been associated with diverse pharmacological
activities such as antihypertension and inhibition of platelets,9 antileuke-
mic,10 antiinflammatory11 and are potent neuro-protective agents.12
Naturally occuring antibiotics fervenulin, toxoflavin and reurhycin contains
1,2,4-triazine moiety. Tetrazoles13 and indoles14 are also well known for
their significant biological activities.
In view of the above mentioned limitations of the reported methods,15
pharmacological importance of heterocycles and our ongoing endeavours
to conduct organic synthesis under solvent free conditions,16–18 we now
describe
a expeditious solventless microwave accelerated solid-state
approach for the rapid assembly of 6-(40-chloro/aminophenyl)-3-[tetrazol-
20-yl/indole-30-yl/phenoxy/undecyl]methyl-1,2,4-triazines.
Hydrazides (2a–d, 0.02 mol) on reaction with phenacyl bromide/
4-chloro phenacyl bromide/4-aminophenacyl bromide (1a–c, 0.01 mol) using
MWI under dry conditions yielded corresponding 1,2,4-triazines (Scheme).
Scheme.
The structure of these products were established from their physical
and spectral data. In IR spectra of all the synthesised compounds bands at

NOVEL 1,2,4-TRIAZINES IN DRY MEDIA
1641
3260–3320 of NH2 and at 1630–1640 cm–1 due to CONH were missing
which confirm the product formation. Further the appearance of a band
at 1580–1600 cm–1 of C ¼ N group elucidated the structure of compounds.
1
In H-NMR spectra disappearance of singlet at d 4.4–5.0 due to CH2 of
4-chloro/amino phenacyl bromide and of hump at d 4.3–4.5 due to NH2 and
at d 8.7–8.8 due to NH of hydrazides further confirm the product formation.
Since we were interested in investigating the facile, rapid and expedi-
tious solventless methodology for triazines, we tried the reaction on three
different inorganic solid supports viz. neutral alumina, silica gel and mon-
tmorillonite K 10 clay. The same reaction was also carried out in solution
phase under microwave irradiation and by conventional method. The results
summarised in the Table demonstrate the versatality of the process as con-
siderable reaction rate enhancement has been observed by bringing down
the reaction time from hours to seconds with improved yield as compared to
conventional heating19 and also show that neutral alumina is the best sup-
port as compared to silica gel and montmorillonite in terms of yield and
time for the synthesis of 1,2,4-triazines as there is a chance of protonation of
hydrazides in acidic support such as silica gel and montmorillonite which
retard the reaction rate and lower the yield of product.
This is the first report on the synthesis of 1,2,4-triazines under dry
conditions using microwaves. In short, the salient feature of our approach
Table. Physical Data of Compounds 3a–l
Method C
Silica
Gel
a(s)/b
Montmorillonite
K 10 Clay
a(s)/b
Neutral
Alumina
a(s)/b
Compound
No.
Method A
a(h)/b
Method B
a(s)/b
3a
3b
3c
3d
3e
3f
3g
3h
3i
18/50
20/55
25/57
23/59
20/52
19/54
21/56
23/58
25/55
24/56
22/54
20/52
300/60
360/62
330/61
420/60
390/64
420/62
300/61
390/64
360/60
420/63
330/61
360/63
115/75
120/74
100/78
110/75
110/79
100/72
110/70
90/72
115/71
100/70
120/73
120/74
120/70
115/72
120/70
110/74
115/70
120/70
100/72
110/73
95/70
75/90
70/93
95/92
90/90
60/90
75/92
90/89
85/95
65/91
70/88
85/93
70/91
3j
100/72
120/71
110/70
3k
3l
a ¼ Time, b ¼ Yield (%)

1642
KIDWAI ET AL.
is coupling microwaves with solvent free technique keeping modernisation
and simplification of classical procedures, avoiding volatile and toxic organic
solvents, which make it a clean, efficient and economical technology to
obtain various useful heterocyclic compound for organic synthesis.
EXPERIMENTAL
Melting points were taken on Thomas Hoover apparatus and
1
are uncorrected. H NMR spectra were recorded in CDCl3 on FT NMR
R 32 (90 MHz) using TMS as internal standard (d in ppm). IR (KBr) spectra
were obtained on
a
Perkin-Elmer FTIR-1710 spectrophotometer.
Microwave irradiations were carried out in Padmini Essentia oven, Model
Brownie at 2450 MHz(using energy output 0.56 kw). Elemental analysis
were performed on a Heraeus CHN-Rapid Analyser. The purities of
the compounds were checked on silica gel coated Aluminium plates
(Merck).
General Procedure for the Synthesis of Phenacyl Bromide/4-Chloro
Phenacyl Bromide/4-Amino Phenacyl Bromide 1a–c
These were prepared according to the literature method.20
General Procedure for the Synthesis of Hydrazides 2a–d
2a, 2c, 2d were prepared according to the literature method.21 2b
purchased from Aldrich.
General Procedure for Synthesis of 6-(4-Chloro/aminophenyl)-
3-[tetrazol-20-yl/indole-30-yl/phenoxy/undecyl]methyl-1,2,
4-triazines 3a–l
Method A: Solution Phase Conventional
To a solution of substituted hydrazides (2a–d, 0.02 mol) in ethanol
added, phenacyl bromide/4-chloro phenacyl bromide/4-amino phenacyl
bromide (1a–c, 0.01 mol) and mixture was refluxed for 18–25 hr. After com-
pletion of the reaction as followed by the TLC examination, the reaction

NOVEL 1,2,4-TRIAZINES IN DRY MEDIA
1643
mixture was cooled and poured over crushed ice, the solid was separated,
filtered, washed with water, and recrystallised with DMF-ethanol mixture.
Method B: Solution Phase MWI
To a solution of substituted hydrazides (2a–d, 0.02 mol) in ethanol
(15 ml), taken in an Erlenmeyer flask (250 ml), added phenacyl bromide/4-
chloro phenacyl bromide/4-amino phenacyl bromide (1a–c, 0.01 mol). The
reaction mixture was subjected to microwave irradiation for 5–7 minutes
with an interval after every 20–30 seconds. The reaction mixture was worked
up as in method A.
Method C: Solid Phase MWI
To a solution of substituted hydrazides (2a–d, 0.02 mol) in ethanol
added inorganic solid support (10 g) at room temperature. Similarly inor-
agnic support (8 g) was added in the solution of phenacyl bromide/4-chloro
phenacyl bromide/4-amino phenacyl bromide (1a–c, 0.01 mol) in dichloro
methane. Adsorbed material was mixed properly, kept inside alumina bath22
and subjected to microwave irradiation for 60–120 sec. On completion of
the reaction as followed by TLC examination, the mixture was cooled to
room temperature and then product was extracted into ethanol (2 ꢀ15 ml).
The filtrate was concentrated and recovering the solvent under reduced
pressure afforded the product which was purified through recrystallization
from ethanol-DMF mixture.
3a: m.p.: 115–117ꢁC; 1H NMR (CDC13): d ¼ 5.15 (s, 1H, 5-CH),
5.91(s, 2H, 3-CH2), 7.23–7.64 (m, 5H, Ar-H), 8.75 (s, 1H, H-5 of tetrazol);
ꢀ (KBr)/cm–1 1585 (C ¼ N); Anals. Calcd. for C11H9H7: C 55.23; H 3.76;
N 4.00. Found: C 55.21; H 3.74; N 4.02.
3b: m.p.: 130–132ꢁC; H NMR (CDC13): d ¼ 5.20 (s, 1H, 5-CH), 3.52
1
(s, 2H, 3-CH2), 7.33–7.82 (m, 9H, Ar-H), 8.15 (s, 1H, 2-CH of indole), 9.15
(brs, 1H, NH of indole); ꢀ (KBr)/cm–1 1590 (C ¼ N); Anals. Calcd. for
C18H14N4: C 75.52; H 4.89; N 19.58. Found: C 75.50; H 4.87; N 19.56.
3c: m.p.: 140–142ꢁC; H NMR (CDC13): d ¼ 5.10 (s, 1H, 5-CH), 5.40
1
(s, 2H, 3-CH2), 7.43–7.95 (m, 10H, Ar-H); ꢀ (KBr)/cm–1 1590 (C ¼ N):
Anals. Calcd. for C16H13N3O: C 73.0–0; H 4.94; N 15.96. Found: C
73.03; H 4.92; N 15.94.
3d: m.p.: 79–81ꢁC; H NMR (CDC13): d ¼ 0.87 (t, 3H, J ¼ 8 Hz , 11-
CH3), 1.25 (m, 16H, 8 ꢀ CH2), 1.60 (m, 2H, 20-CH2); 2.30 (t, 2H, J ¼ 7 Hz ,
3-CH2), 5.15 (s, 1H, 5-CH), 7.35–7.81 (m, 5H, Ar-H); ꢀ (KBr)/cm–1 1590
1
0

1644
KIDWAI ET AL.
(C ¼ N); Anals. Calcd. for C20H29N3: C 77.17; H 9.32; N 13.50. Found: C
77.15; H 9.30; 13.52.
3e: m.p.: 122–124ꢁC; H NMR (CDC13): d ¼ 5.25 (s, 1H, 5-CH), 6.01
1
(s, 2H, 3-CH2), 7.47–7.82 (m, 4H, Ar-H), 8.84 (s, 1H, H-5 of tetrazole);
ꢀ (KBr)/cm–1 1595 (C ¼ N); Anals. Calcd. for C11H18N7C1: C 48.35; H
2.93; N 35.89. Found: C 48.33; H 2.91; 35.87.
3f: m.p.: 135–137ꢁC; H NMR (CDC13): d ¼ 5.21 (s, 1H, 5-CH), 3.53
1
(s, 2H, 3-CH2), 7.35–7.71 (m, 8H, Ar-H), 8.25 (s, 1H, 2-CH of indole), 9.00
(brs, 1H, NH of indole); ꢀ (KBr)/cm–1 1585 (C ¼ N); Anals. Calcd. for
C18H13N4C1: C 67.50; H 4.06; N 17.50. Found: C 67.52; H 4.04; N 17.52.
3g: m.p.: 146–148ꢁC; H NMR (CDC13): d ¼ 5.20 (s, 1H, 5-CH), 5.45
1
(s, 2H, 3-CH2), 7.43–8.05 (m, 9H, Ar-H), ꢀ (KBr)/cm–1 1660 (C ¼ N); Anals.
Calcd. for C16H12N3C1O: C 64.64; H 4.04; N 14.14. Found: C 64.66; H 4.06;
N 14.12.
3h: m.p.: 83–85ꢁC; H NMR (CDC13): d ¼ 0.88 (t, 3H, J ¼ 8 Hz , 11-
CH3), 1.27 (m, 16H, 8ꢀCH2), 1.61 (m, 2H, 20-CH2), 2.32 (5, 2H, J ¼ 7 Hz ,
3-CH2), 5.21 (s, 1H, 5-CH), 7.31–7.75 (m, 4H, Ar-H); ꢀ (KBr)/cm–1 1595
(C ¼ N); Anals. Calcd. for C20H28N3C1: C 69.56; H 8.11; N 12.17. Found: C
69.54; H 8.13; N 12.19.
1
0
3i: m.p.: 110–112ꢁC; 1H NMR (CDC13): d ¼ 4.55 (brs, 2H, NH2), 5.11
(s, 1H, 5-CH), 5.73 (s, 2H, 3-CH2), 7.72–8.03 (m, 4H, Ar-H), 8.75 (s, 1H,
H-5 of tetrazole); ꢀ (KBr)/cm–1 1590 (C ¼ N); Anals. Calcd. for C11H10N8:
C 51.96; H 3.93; N 44.04. Found: C 51.98; H 3.91; N 44.05.
3j: m.p.: 128–130ꢁC; 1H NMR (CDC13): d ¼ 4.40 (brs, 2H, NH2), 3.55
(s, 1H, 5-CH), 5.81 (s, 2H, 3-CH2), 7.53–7.75 (m, 8H, Ar-H), 8.13 (s, 1H,
2-CH of indole), 9.14 (brs, 1H, NH of indole); ꢀ (KBr)/cm–1 1580 (C ¼ N);
Anals. Calcd. for C18H15N5C1: C 71.76; H 4.98; N 23.25. Found: C 71.75; H
4.97; N 23.23.
3k: m.p.: 137–139ꢁC; 1H NMR (CDC13): d ¼ 4.53 (brs, 2H, NH2), 5.25
(s, 1H, 5-CH), 5.56 (s, 2H, 3-CH2), 7.56–8.13 (m, 9H, Ar-H), ꢀ (KBr)/cm–1
1585 (C ¼ N); Anals. Calcd. for C16H14N4O: C 69.06; H 5.03; N 20.14.
Found: C 69.08; H 5.03; N 20.12.
3l: m.p.: 75–77ꢁC; H NMR (CDC13): d ¼ 0.89 (t, 3H, J ¼ 8 Hz , 11-
CH3), 1.26 (m, 16H, 8ꢀCH2), 1.62 (m, 2H, 20-CH2), 2.34 (t, 2H, J ¼ 7 Hz ,
3-CH2), 4.55 (brs, 2H, NH2), 5.27 (s, 1H, 5-CH), 7.47–7.91 (m, 4H, Ar-H);
ꢀ (KBr)/cm–1 1590 (C ¼ N); Anals. Calcd. for C20H30N4: C 73.61; H 9.20;
N 17.17. Found: C 73.63; H 9.22; N 17.18.
1
0
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Received in Japan June 13, 2000