A novel three-component synthesis of triazinothiazolones

Article abstract of DOI:10.1081/SCC-200048903

A series of 4-arylidene-2-methyloxazol-5-ones 1 were condensed with thiosemi-carbazide to yield 6-arylmethyl-3-mercapto-1,2,4-triazin-5-ones 2. The resulting mercapto triazinones 2 were condensed with monochloroacetic acid and 5-aryl-furan-2-carboxaldehydes 3 in a one-pot three-component reaction in the presence of acetic anhydride, acetic acid, and sodium acetate to yield 4-substituted-5-oxo-7-(5-aryl-2-furfurylidene)-1,2,4-triazino[3,4-b] -thiazol-6-ones 4. Some of the newly synthesized compounds were tested for their antibacterial activity against Gram (+)ve and Gram (-)ve bacteria. The results of such studies are discussed in this paper. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1081/SCC-200048903

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A Novel Three‐Component
Synthesis of
Triazinothiazolones
Bantval Shivarama Holla a , Kani Veetil Malini a
Balladka Kunhanna Sarojini a b & Boja Poojary a
,
a Department of Post‐Graduate Studies and Research
in Chemistry, Mangalore University, Mangalagangotri,
574 199, India
b Department of Chemistry, P.A. College of
Engineering, Nadupadavu, Mangalore, 574133, D.K.,
India
Version of record first published: 28 Jul 2007.
To cite this article: Bantval Shivarama Holla, Kani Veetil Malini, Balladka
Kunhanna Sarojini & Boja Poojary (2005): A Novel Three‐Component Synthesis of
Triazinothiazolones, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 35:3, 333-340
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Synthetic Communicationsw, 35: 333–340, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200048903
A Novel Three-Component Synthesis of
Triazinothiazolones
Bantval Shivarama Holla, Kani Veetil Malini,
Balladka Kunhanna Sarojini,† and Boja Poojary
Department of Post-Graduate Studies and Research in Chemistry,
Mangalore University, Mangalagangotri, India
Abstract: A series of 4-arylidene-2-methyloxazol-5-ones 1 were condensed with
thiosemi-carbazide to yield 6-arylmethyl-3-mercapto-1,2,4-triazin-5-ones 2. The
resulting mercapto triazinones 2 were condensed with monochloroacetic acid and
5-aryl-furan-2-carboxaldehydes 3 in a one-pot three-component reaction in the
presence of acetic anhydride, acetic acid, and sodium acetate to yield 4-substituted-5-
oxo-7-(5-aryl-2-furfurylidene)-1,2,4-triazino[3,4-b]-thiazol-6-ones 4. Some of the
newly synthesized compounds were tested for their antibacterial activity against Gram
(þ)ve and Gram (2)ve bacteria. The results of such studies are discussed in this paper.
Keywords: Three component reaction, triazinothiazolones, MCRs, antibacterial
activity
INTRODUCTION
Multicomponent reactions (MCRs) are fundamentally different from two-
component reactions in several aspects. The convergent synthetic pathways
of MCRs show advantages over linear or divergent approaches with respect
to speed, time, yield, and reproducibility. Among organic reactions,
multi-component reactions are highly convergent.[1] They constitute a
†Present address: Balladka Kunhanna Sarojini, Department of Chemistry, P.A.
College of Engineering, Nadupadavu, Mangalore 574133 D.K., India.
Received in the USA October 24, 2004
Address correspondence to Bantval Shivarama Holla, Department of Chemistry,
Mangalore University, Mangalagangotri 574 199, India. E-mail: hollabs@yahoo.com

334
B. S. Holla et al.
superior tool for diversity-oriented and complexity-generating synthesis for
drug discovery.[2] MCRs being one-pot reactions, they are practically
single-step conversions and are easier to carry out than multistep synthesis.
Thus, MCRs come close to the idea of an “ideal synthesis.”
Several triazinones and their condensation products find important appli-
cations in medicinal and agricultural fields.[3] The synthesis of triazinones
have already been reported in the literature.[4–8] Synthesis of aza-uracils
and their thio and thioalkyl derivatives having antidiuretic and neurodepre-
mant activities were reported by Timar et al.[9] Some of the S-alkylated
mercaptotriazinones exhibited herbicidal activities. Among them 4-amino-3-
methylthio-6–t-butyl-1,2,4-triazin-5(4H)-one is being used as a commercial
herbicide for control of weeds in potato crops.[10] The 4-amino-3-mercapto-
1,2,4-triazin-5(4H)-ones were used for the synthesis of several N-bridged
heterocycles.[11,12]
Prompted by these observations, it was contemplated to synthesize a new
series of 4-substituted-5-oxo-7-(5-aryl-2-furfurylidene)-1,2,4-triazino[3,4-b]-
thiazol-6-ones 4 by the condensation of appropriate 6-arylmethyl-3-
mercapto-1,2,4-triazin-5-ones 2 with appropriate 5-aryl-furan-2-carboxalde-
hyde and monochloroacetic acid in the presence of acetic anhydride, acetic
acid, and anhydrous sodium acetate in a multicomponent synthesis, which
provide a maximum of structural complexity and diversity in a minimum
number of steps and to screen them for antibacterial properties.
RESULTS AND DISCUSSION
6-Arylmethyl-3-mercapto-1,2,4-triazin-5-ones 2 were synthesized according
to the procedure reported in the literature[13] by the reaction of the respective
4-arylidene-2-methyloxazol-5-ones 1 with thiosemicarbazide. Acetyl glycine
was prepared by the acetylation of glycine using acetic anhydride. 5-Aryl-
furan-2-carboxaldehydes 3 were prepared through Meerwein reaction.[14]
6-Arylmethyl-3-mercapto-1,2,4-triazin-5-ones 2 were condensed with mono-
chloroacetic acid and 5-aryl-furan-2-carboxaldehydes 3 in the presence
of anhydrous sodium acetate, acetic anhydride, and acetic acid to obtain 4-sub-
stituted-5-oxo-7-(5-aryl-2-furfurylidene)-1,2,4-triazino[3,4-b]-thiazol-6-ones
4 (Scheme 1).
The newly synthesized compounds 4 were characterized by spectral and
1
analytical data. The 300 MHz H NMR spectrum of compound 4a showed
a singlet at d 4.12 integrating for two protons, which is attributed to the
methylene protons of the arylmethyl group. The b-protons of furan ring
resonated as two doublets at d 6.91 and 7.11 with a coupling constant of
J ¼ 3.8 Hz. The signal due to exocyclic vinylic proton appeared as a singlet
1
at d 7.93. The H NMR spectra of compounds 4b, 4g, and 4m were also
recorded, and the triazinothiazolone structure assigned to the condensation

Three-Component Synthesis of Triazinothiazolones
335
Scheme 1.
product 4 was confirmed. Further evidence for the formation of compound 4
was obtained by recording their mass spectra. The spectral data are given in
the experimental section.
EXPERIMENTAL SECTION
The melting points were recorded in open capillaries and are uncorrected. IR
spectra were recorded on a JASCO(FT-IR) Spectrophotometer. 1H NMR

336
B. S. Holla et al.
spectra were recorded on a Bruker AC 300/400 MHz spectrometer using
TMS as internal standard. The mass spectra were recorded on a VG 70-S
mass spectrometer operating at 70eV or JEOL JMS D-300 mass spectrometer.
Purity of the compounds was checked by thin layer chromatography on silica
gel plates using a mixture of benzene and methanol (8 : 2) as an eluting
solvent. Iodine was used as a visualizing agent.
Preparation of Acetyl Glycine[15]
Glycine (75 g, 1 mol) in water was placed in an Erlenmeyer flask. The mixture
was stirred vigorously until glycine dissolved completely. Acetic anhydride
(215 g, 2 mol) was added in one portion. Vigorous stirring was continued
for 15–20 min. The solution was kept overnight in a refrigerator to
effect complete crystallization. It was collected by filtration and dried at
100–1108C. The filtrate was evaporated to dryness under reduced pressure
on a water bath at 50–608C. The residue was recrystallized from boiling
water to obtain a second crop of acetylglycine, m.p. 2078C (Lit. m.p.
207–2088C) yield 89%.
Preparation of 4-Arylidence-2-methyloxazol-5-one (1)
General procedure: A mixture of acetyl glycine (58.5 g, 0.5 mol), anhydrous
sodium acetate (30 g, 0.34 mol), substituted benzaldehyde (0.5 mol), and
95% acetic anhydride (134 g, 1.25 mol) was taken in a loosely stoppered
Erlenmeyer flask and warmed on a steam bath with occasional stirring until
the solution became clear. The reaction mixture was refluxed on a water
bath for 2–3 h, cooled and left overnight in a refrigerator. The solid mass
thus obtained was filtered and washed with cold water. The crude
oxazolone was dried in a vacuum desiccator over phosphorous pentoxide.
Preparation of 6-Arylmethyl-3-mercapto-triazin-5(4H)-one (2)
General procedure: A mixture of 4-aryl-2-methyloxazol-5-one (1, 0.1 mol),
KOH (5 g) in 150 mL water was refluxed for 6 hrs. To the clear solution
obtained, thiosemicarbazide(0.1mol) was added and the mixture was refluxed
for another 4 h. Activated charcoal was added to the solution and filtered.
The filtrate was acidified to pH 3-4 with acetic acid to give 6-arylmethyl-3-
mercapto-triazin-5 (4H)-ones.
2a: 6-benzyl-3-mercapto-triazin-5(4H)-one, m.p.1958C(Lit.,[12] 195)
yield 85%.

Three-Component Synthesis of Triazinothiazolones
337
2b: 6-(4-chlorobenzyl)-3-mercapto-triazin-5(4H)-one, m.p. 2028C,
yield 72%.
2c: 6-(2,4-dichlorobenzyl)-3-mercapto-triazin-5(4H)-one, m.p. 1858C,
yield 70%, 1H NMR (DMSO-d6 þ CDCl3) d: 4.0 (s, 2H, CH2), 7.19 (dd, 1H,
Ar-H, J ¼ 8.6 Hz, J ¼ 2.0 Hz), 7.24 (d, 1H, Ar-H, J ¼ 8.6 Hz), 7.36 (d, 1H,
Ar-H, J ¼ 2.0 Hz), EIMS: m/z 288 (45.1%, Mþ), 290 (34.1%, M þ 2), 292
(7%, M þ 4), 253 (100%, Mþ-Cl), 125 (53%, p-chlorobenzyl cation).
2d: 6-(3,4-methylenedioxybenzyl)-3-mercapto-triazin-5(4H)-one, m.p.
2108C, yield 64%.
Preparation of 5-Aryl-furan-2-carboxaldehyde (3)
General procedure: A mixture of substituted aniline (0.1 mol), dilute hydro-
chloric acid (15%, 60 mL), and water (90 mL) was heated to get a clear
solution. The solution was cooled to 08C and was diazotised by the addition
of sodium nitrite solution (30%, 24 mL). The cold clear solution of the
diazonium salt was collected by filtration and was treated with 2-furfuralde-
hyde (0.1 mol) and water (50 mL). To this an aqueous solution of cupric
chloride (2.5 g in 10 mL of water) was added dropwise with stirring.
Stirring was continued for 4 h and the precipitated solid was collected by
filtration. The crude compound was recrystallized from a mixture of ethanol
and dioxane.
3a: 5-(2-nitrophenyl)-furan-2-carboxaldehyde, m.p.988C [Lit.,[16] 988C]
yield 74%.
3b: 5-(4-chlorophenyl)-furan-2-carboxaldehyde, m.p. 1288C [Lit.,[17]
1298C] yield 70%.
,
3c: 5-(2,4-dichlorophenyl)-furan-2-carboxaldehyde, m.p. 1468C [Lit.,[18]
1468C] yield 64%.
3d: 5-(4-bromohenyl)-furan-2-carboxaldehyde, m.p. 1588C [Lit.,[16]
1588C] yield 63%.
,
Preparation of 4-Substituted–5-oxo-7-(5-aryl-2-furylidene)–1,2,4-
triazino-(3,4,-b)-thiazol-6-one (4)
General procedure: A mixture of appropriate mercapto triazinone (2,
0.01 mol), monochloroacetic acid (0.015 mol), anhydrous sodium acetate
(2 g), glacial acetic acid (20 mL), acetic anhydride (15 mL), and 5-aryl-
furan-2-Carboxaldehyde (0.01 mol) was heated to reflux for 4–6 h. The
reaction mixture was cooled and poured into crushed ice with vigorous
stirring. The solid obtained was filtered, washed with water, dried and
recrystallised from a mixture ethanol and dimethyl formamide (Table 1).
4a: 4-benzyl-5-oxo-7-(5-(2-nitrophenyl)-2-furylidene)–1,2,4-triazino-
1
(3,4,-b)-thiazol-6-one, H NMR (DMSO-d6 þ CDCl3) d: 4.12 (s, 2H, CH2),

338
B. S. Holla et al.

Three-Component Synthesis of Triazinothiazolones
339
6.9 (d, 1H, furan H, J ¼ 3.8 Hz), 7.1 (d, 1H, furan H, J ¼ 3.8 Hz), 7.22–7.33
(m, 4H, Ar-H), 7.44 (m, 2H, Ar-H), 7.59 (m, 1H, Ar-H), 7.74 (m, 1H, Ar-H,
Jortho ¼ 6.7 Hz, Jmeta ¼ 3.3 Hz, Jpara ¼ 1.2 Hz), 7.86 (m, 1H, Ar-H), 7.9 (s.1H,
exocyclic vinylic H).
4b: 4-benzyl–5-oxo-7-(5-(4-chlorophenyl)-2-furylidene)–1,2,4-triazino-
1
(3,4,-b)-thiazol-6-one, H NMR (DMSO-d6 þ CDCl3) d: 4.12 (s, 2H, CH2),
6.9 (d,1H, furan H, J ¼ 3.7 Hz), 7.1 (d,1 Hz, furan H, J ¼ 3.7 Hz), 7.3
(m, 4H, Ar-H), 7.48 (m, 3H, Ar-H), 7.7 (d, 2H, Ar-H, J ¼ 8 Hz), 7.94
(s, 1H, exocyclic vinylic H).
4d:
triazino-(3,4,-b)-thiazol-6-one, IR nmax (KBr disc): 3042 (C-H), 2900
(exocyclic vinylic C-H), 1737 (C55O), 1526 (C55N), 799 (C-Cl) cm21
4g: 4-(4-chlorobenzyl)–5-oxo-7-(5-(4-bromophenyl)-2-furylidene)–
4-benzyl–5-oxo-7-(5-(2,4-dichlorophenyl)-2-furylidene)–1,2,4-
.
1,2,4-triazino-(3,4,-b)-thiazol-6-one, IR nmax (KBr disc): 3045 (C-H), 2923
(exocyclic vinylic C-H), 1743 (C55O), 1521 (C55N), 817 (p-substituted
Ar-H), 792 (C-Cl), 529 (C-Br) cm21
.
1H NMR (DMSO-d6 þ CDCl3) d:
4.09 (s, 2H, CH2), 7.96 (s,1H, exocyclic vinylic H), 6.9 (d, 1H, furan H,
J ¼ 3.8 Hz), 7.18 (d,1H, furan H, J ¼ 3.8 Hz), 7.28 (m, 2H, Ar-H),
7.39(d, 2H, Ar-H), 7.66 (m, 4H, Ar-H).
4m: 4-(3,4-methylenedioxybenzyl)–5-oxo-7-(5-(2-nitrophenyl)-2-furyli-
dene)–1,2,4-triazino-(3,4,-b)-thiazol-6-one (4m), 1H NMR (DMSO-
d6 þ CDCl3): d 4.0 (s, 2H, CH2), 5.9 (s, 2H, -O-CH2-O-protons),6.7 (d, 1H,
Ar-H, J ¼ 3.2 Hz), 6.95 (m, 3H, 2 Ar-H & Furan H), 7.1 (d, 1H, Furan H,
J ¼ 3.6 Hz), 7.61 (m, 1H, Ar-H), 7.72 (m, 1H, Ar-H),7.84 (m, 1H, Ar-H),
7.93 (s, 1H, exocyclic vinylic H). MS m/z (%): 458 (38.3, Mþ), 245 (5.2,
(5-phenyl-2-furfuryl)-1-thioethylene radical cation), 160 (4.4, 2-(4-nitrophe-
nyl)-cyclopropenyl cation), 122 (6.6, (2-nitrophenyl cation), 116 (100,
C6H5CHþCN).
CONCLUSION
In summary, we have demonstrated the application of multicomponent
reaction for the synthesis of a series of triazinothiazolones in good yield.
The newly synthesized compounds also showed moderate to excellent
antibacterial activity. Although no conclusive structure-activity relationship
has emerged from the antibacterial activity studies, it appears that the destruc-
tion of free SH group of compounds 2 into a rigid core in compounds 4 has
brought about this decrease in antibacterial activity.
ACKNOWLEDGMENT
The authors are thankful to the Director, RSIC, Punjab University, Chandi-
garh, The Head RSIC, CDRI Lucknow and the Head, RSIC, IIT Chennai

340
B. S. Holla et al.
for elemental and spectral analysis. The authors are also thankful to
Dr. N. Suchetha Kumari, K.S. Hegde Medical Academy, Deralakatte,
Mangalore for arranging the antibacterial activity studies reported in this
paper. One of the authors K.V. Malini is thankful to UGC, New Delhi for
the award of Teacher Fellowship under Faculty Improvement Programme.
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