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Acta Chim. Slov. 2005, 52, 88–92
Short Communication
Ecofriendly Synthesis of Novel Antifungal (Thio)Barbituric
Acid Derivatives
Mazaahir Kidwai,* Ruby Thakur, and Richa Mohan
Department of Chemistry, University of Delhi, Delhi-110007, India E-mail: kidwai_chemistry@yahoo.co.uk; Fax: (91 11) 27666235
Received 17-07-2004
Abstract
An expeditious solventless synthesis of novel Mannich bases of thiobarbiturates and barbiturates using montmo-rillonite clay under microvvaves are herein described. This methodologv eliminates the use of excess of solvent during the course of reaction. The reaction tirne is brought down from hours to minutes along with yield enhancement. The rate enhancement and high yield is attributed to the coupling of MWS with solventless conditions. Further, the role of montmorillonite K-10 clay is studied in the reaction and it is concluded that microvvave as-sisted montmorillonite clay catalyzed reaction is the best in terms of catalysis as well as reaction and yield. Ali the compounds synthesized were screened for their antifungal activity against A. niger and A. flavus and found to possess good activity.
Key words: Thiobarbiturates, Barbiturates, Mannich base, Montmorillonite, Mcrovvave, Antifungal
Introduction
Mannich reaction is widely used for the construc-tion of nitrogen containing molecule.1 In this three component transformation, compounds possessing (3-hydrogen atom, an aldehyde and an amine react to form (3-aminoketone derivatives. In addition it has been reported2 that insertion of aryl amino methyl moiety at 5th-position of TBA/BA enhances the antidepressant activities of the resultant compounds. Best example of the heterocycles containing active methylene group is TBA/BA. Several Mannich bases possess diverse biological activities viz. antimicrobial,3 antitubercular and antiviral activities.4 Also TBA and BA derivatives are well known to possess antibacterial,5 sedatives,6 herbicides,7 fungicides8 and antiviral agents.9
The coupling of microwave irradiation (MWI) with solid supported reagents is well known for the synthesis of variety of compounds1016 where in chemical reaction are accelerated because of selective adsorption of microwaves by the polar molecules. Montmorillonite clay, a class of inexpensive and non-corrosive solid acids, has reacted great development in different areas of organic synthesis17~18 due to their environmental compatibility. These dry media reactions1921 catalyzed by montmorillonite clay, under microwave activation results in unique chemical processes with special at-tribute such as enhanced reaction rate, higher yield, greater selectivity and ease of manipulation.
In the view of above mentioned biological
activity of thiobarbiturates and Mannich bases and in continuation of our interest in the development of environmentally benign protocols,2224 we herein report, a facile, rapid, one pot synthesis of Ar-pyridyl/Ar-anti-pyryl-1 -furyl/indolyl-1 -[thiobarbituric acid/barbituric acid]aminomethane (5a-h) using montmorillonite clay in dry media under MWI. Moreover, novel reactions were also performed using NaOEt in ethanol and glacial acetic acid under conventional heating, and we developed a new synthetic procedure for the synthesis of (thio)barbituric acid derivatives. These derivatives were screened for their antifungal activity against A. niger and A. flavus (Table 2).
Results and Discussion
Condensation of Aldehyde 1 with amine 2 in the presence of glacial acetic acid (Method C) with ethanol as solvent was carried out under conventional heating. On formation of intermediate 3, TBA/BA 4 dissolved in NaOEt solution was added to it. The final product 5a-h was obtained in 10-12 hrs of heating with mod-erate yield. In an attempt to “greenfiy” the synthetic procedure and increase its rate and yield experiments were done under microwaves (MWs).
Aldehyde la-b and amine 2a-b was reacted with TBA/BA over montmorillonite K-10 clay25b under MWI to give Mannich reaction products 5a-h at C-5 position of TBA/BA (Method A, Scheme 1). The structural assignment of 5a-h is based on elemental analysis and
Kidwai et al. Synthesis of Barbituric Acid Derivatives
Acta Chim. Slov. 2005, 52, 88–92
89
RCHO    +   ArNH2 1a-b             2a-b
|1V
Acidic Alumina
RCH=N-Ar (3)
O      R
|1V, K-10clay
O
HN'
H  4a-b (TBA/BA)
TBA/BA
HN'
X^N^ ^ H
5a-h
A
|1V
Basic alumina supported 4a-b
CH-NH-Ar
1a
/
O.
W    //
1b
,N.
\      2a
2b
O
Ph
isrCH3
CH3
4a X = S     4b X = O
Scheme 1. Microwave assisted synthesis of thiobarbituric acid and barbituric acid derivatives using different solid supports.
spectroscopic data. The molecular formulae were con-firmed by elemental analysis. In JH NMR the appear-ance of doublet at 3.0-3.8 due to C-H group introduced by Mannich reaction was observed. Also broad signal at 5 4.9-5.2 and doublet at 5 4.5-4.8 due to N-H and C5-H of TBA/BA respectively of the synthesized compounds 5a-h in XH NMR spectra confirmed the formation of products 5a-h.
In order to study the versatility of different solid support and on observing the fact that aldehyde reacts with amine in acidic condition. The reaction was also tried with acidic alumina25a (Method B, Scheme 1). Upon formation of intermediate, TBA/BA adsorbed separately over basic alumina250 was added to the above reaction bath without eluting the intermediate in be-tween. Now the resulting reaction mkture was subjected to microwaves, final product 5a-h, so obtained was in good yield (Table 1).
Reactions betvveen 1, 2, and 4 under conventional heating (Method C) were completed in 10-12 hrs with moderate yield (Table 1), whereas the same reactions under MWs (Method A and B) gave excellent yield with in few minutes of irradiation. Further, on moving from two pot, alumina supported (Method B) synthesis, to the reactions catalyzed by montmorillonite K-10 clay (Method A), we observed reduction in reaction time and improvement in yield (Table 1). This result can be attributed to the ditopic nature23b of montmorillonite K-10 clay.
Ali compounds synthesized were screened for their antifungal activity against A niger and A. flavus by paper disc diffusion method.19 The zone of inhibition was measured in millimeters. The antifungal activities of the test compounds were compared to standard salicylic acid20 (17-21 mm). DMF was used as solvent. AH compounds have shown good activity against both fungi. However, thiobarbituric acid derivatives 5a, 5c, and 5g have shown excellent antifungal activity (20-22 mm) against both A niger and A. flavus. Compounds 5b, 5f showed better activity (16-18 mm) against A. niger as compared to activity (11-13 mm) against A. flavus (Table 2).
Table 2. Antifungal activity of compounds (5a-h).
Compound
Inhibition of A niger (50 ug/mL)
Inhibition of A. flavus (50 ug/mL)
5a	+++++
5b	++++
5c	+++++
5d	+++
5e	++++
5f	++++
5g	+++++
5h	+++
Salicylic acid	+++++
+++++
+++
+++++
++
+++
+++
+++++
++++
++++++
+  : 3-9 mm;  ++  :  10-12 mm;  + + +   :  13-15 mm; ++++ : 16-21 mm; +++++ : >21 mm.
H
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Table 1. Comparison of reaction times and yields for compounds 5a-h.
Compound       X
5a
R
Ar                             MethodA                             Method Bb                          Method C
Time (min'sec")/Yield (%)      Time (min'sec")/Yield (%)        (hr.min')/Yield (%)
O
i    }
4'50"/96
14V85
10.20765
5b             O
O
i    /l
^
3'40"/94
12V85
11.10762
5c
/
CX
W    //
Ph
H
CH3
3'20"/97
11781
10.30766
5d             O
O
i }
O;
Ph
|\TCH3 CH3
3'50'795
9779
11.30/58
5e
5f
5g
sf
H
/
H
/
H
/
O;
Ph
N IN-N-CH3
CH3
3'40'795
3'20'792
4'30'797
8782
T50788
10'20'784
10.40759
10.10761
12.20756
5h
H
/
O;
Ph
^TCH3
CH3
3'50'791
10'50'783
12.40754
b Total time for the synthesis (5+x) min, 5 min is the time required for the synthesis of intermediate 3 over acidic alumina. ‘X’ is the
additional time required for the synthesis of 5a-h from intermediate 3.
Conclusions
In conclusion we have modified and developed a facile and convenient synthetic procedure for preparation of novel Mannich bases ((3-amino ketone derivative) of thio(barbiturates) by coupling microwaves with motmorillonite K-10 clay. The procedure clearly highlights the versatility of solid supports when coupled with microwaves. The advantages of this ecofriendly and safe protocol include a simple reaction set up,
good product yield, short reaction time and above ali the use of volatile and toxic solvents is eliminated. Ali the compounds synthesized were found to possess good antifungal activity.
Experimental Section
Melting points were determined by Electrother-mal melting point apparatus and are uncorrected.
N
S

N

S
N
N
S

N
O
s
o
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IR spectra (in KBr) were recorded on 1710 Perkin Elmer FT infrared spectrophotometer. JH NMR spectra were recorded on FT NMR Hitachi R-600 (60 MHz) spectrometer. Elemental Analyses were performed on Hareaus CHN-Rapid Analyser. For microwave ir-radiation (MWI) Kenstar microwave oven, Model No. OM9925E (2450 MHz, 800 W) was used. The purity of the compounds was checked on silica gel coated Al plates (Merck). The approximate temperature of the reaction mkture (as measured by AZ, mini Non-Contact Infrared Thermometer, Model No. 8868), was 90-120 °C (800 W).
General Procedure for the Svnthesis of N-pyridyl/N-antipyryl-l-furyl/indolyl-l-[thiobarbituric acid/barbi-turic acid]aminomethane (5a-h). Method A:
Montmorillonite K-10 clay25b 18 g was added to the equimolar mkture of la-b (0.01 mol), 2a-b (0.01 mol) and 4a-b (0.01 mole) in ethanol. The reaction mixture was stirred well and dried in air. Then the reaction mixture was placed in alumina bath26 inside the microwave oven at 560 W for 3.2-4.5 minutes. Progress of the reaction was monitored through TLC at the interval of 30 sec. On completion of the reaction, mixture was cooled at room temperature the product was extracted using ethanol and solvent was removed under reduced pressure, which yield the corresponding title compounds 5a-h, which were recrystallized from the appropriate solvents.
Method B:
Acidic alumina25a was added to the equimolar mkture of 1 and 2 (0.01 mol) in ethanol. The reaction mkture was stirred well, dried in air and placed in alumina bath26 inside the microwave oven for 5 min on formation of intermediate 3 as checked by TLC examination, an-other reactant 4a-b which was already adsorbed over basic alumina250 was added to the above reaction bath without eluting the intermediate in betvveen. Now the resulting reaction mkture 3 and 4a-b formed were again irradiated under microwaves for specified time. Progress of reaction was monitored through TLC at the interval of 30 sec. On completion of reaction, mkture was cooled at room temperature the product was extracted using ethanol and solvent was removed under pressure. The final product 5a-h so obtained was recrystallized using appropriate solvent.
Method C:
An equimolar amount of 1 and 2 (0.01 mol) were put in a round-bottomed flask. To this, glacial acetic acid in ethanol was added and the reaction mkture is refluxed for 30 min gently with stirring on a magnetic stirrer equipped with an air condenser. Then, on forma-
tion of intermediate 3 as checked by TLC examination, another reactant 4 dissolved in NaOEt in EtOH was added to the above reaction mkture and refluxed for 10-12 hr. On formation of product as monitored by TLC the product was filtered through Hirsch Funnel and the solid so obtained was recrystallized with the appropriate solvent.
5a: Mp 295-296 °C (Petroleum ether). JH NMR (CDCI3+DMSO) 58.1-8.5 (m, 5H, C-H-pyridine), 4.5^1.8 (d, 1H, / 7.5 Hz, C5HTBA), 5.0 (brs, 1H, NH), 6.2-6.4 (m, 3H, C-H furan ring), 3.0 (d, 1H, / 7.4 Hz, C-H). IR (KBr): 1030 (C=S), 1600 (C=C), 1650 (C=0), 2960 (C-H), 3050 (Py C-H), 3390 (N-H) cm4. Anal. Calcd for C14HnN403S: C 53.33, H 3.49, N 17.77. Found: C 53.35, H 3.48, N 17.79.
5b: Mp 252-253 °C (Methanol). JH NMR (CDCl3+DMSO) 5 8.1-8.5 (m, 5H, C-H-pyridine), 4.5-4.8 (d, lH,/7.8 Hz, C5HBA), 5.2 (brs, 1H, NH), 6.2-6.4 (m, 3H, C-H furan), 3.1 (d, lH,/7.8 Hz, CH). IR (KBr): 1650 (C=0), 2960 (C-H), 3050 (Py C-H), 3320 (N-H) cm4. Anal. Calcd for C14HnN404: C 56.18, H 3.67, N 18.72. Found: C 56.16, H 3.65, N 18.71.
5c: Mp 310-311 °C (Petroleum ether). JH NMR (CDCI3+DMSO) 52.0 (s, 3H, CH3), 2.6 (s, 3H, NCH3), 7.8 (m, 5H, N-Ph), 4.9 (brs, 1H, NH), 6.2-6.4 (m, 3H, CH furan), 4.7-4.8 (d, 1H,/8.0 Hz, C5HTBA), 3.2 (d, lH,/7.9 Hz, C-H). IR (KBr): 1030 (C=S), 1550 (C=0 antipyrine), 1630 (C=C antipyrine), 1650 (C=0), 3340 (N-H) cm4. Anal. Calcd for C20H19N5O4S: C 56.47, H 4.47, N 16.47. Found: C 56.45, H 4.45, N 16.45.
5d: Mp 302-303 °C (Ethanol). JH NMR (CDCI3+DMSO) 5 2.1 (s, 3H, CH3), 2.5 (s, 3H, NCH3), 7.8 (m, 5H, N-Ph), 5.1 (brs, 1H, NH), 6.2-6.4 (m, 3H, C-H furan), 4.7-4.9 (d, 1H, / 8.1 Hz, C5HBA), 3.0 (d, 1H, / 8.0 Hz, C-H). IR (KBr): 1550 (C=0 antipyrine), 1630 (C=C antipy-rine), 1650 (C=0), 3340 (N-H) cm4. Anal. Calcd for C20H19N5O5: C 58.67, H 4.64, N 17.18. Found: C 58.69, H 4.66, N 17.19.
5e: Mp 286-287 °C (Chloroform). 1H NMR (CDCl3+DMSO) 5 5.2 (brs, 1H, NH), 4.6^1.8 (d, 1H,/ 7.6 Hz, C5HTBA), 7.0-7.2 (NH-indole), 8.1-8.5 (s, 1H, C6Hpyridine), 6.7-6.9 (d, 1H, / 1.5 Hz, C5Hpyridine), 6.5 (s, 1H, C2Hindole), 3.4 (d, 1H, C-H). IR (KBr): 1030 (C=S), 1650 (C=0), 2960 (C-H), 3050 (Py-C-H), 3390 (N-H) cm4. Anal. Calcd for C18H14N502S: C 59.34, H 3.84, N 19.23. Found: C 59.36, H 3.86, N 19.26.
5f: Mp 293-294 °C (Methanol). 1H NMR (CDCl3+DMSO) 5 5.2 (brs, 1H, NH), 7.0-7.2 (NH-indole), 8.1-8.5 (s, 1H, C6Hpyridine), 6.7-6.9 (d, 2H, / 1.5 Hz, C5Hpyridine), 6.5 (s, 1H, C2Hindole), 4.8-4.9 (d, 1H, / 7.6 Hz, C5HBA), 3.8 (d, 1H, / 7.5 Hz, C-H). IR (KBr): 1640 (C=0), 2950 (C-H), 3040 (Py-C-H),
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3390 (N-H) cm 1. Anal. Calcd for C18H14N503: C 62.06, H 4.02, N 20.11. Found: C 62.09, H 4.06, N 20.14.
5g: Mp 264-265 °C (Petroleum ether). JH NMR (CDCI3+DMSO) 5 2.1 (s, 3H, CH3), 2.5 (s, 3H, CH3), 7.8 (m, 5H, NPh), 5.0 (brs, 1H, NH), 7.0-7.2 (N-H in-dole), 6.5 (s, 1H, C2Hindole), 4.3-4.5 (d, 1H, / 8.2 Hz, C5HTBA), 3.4-3.5 (d, 1H, / 8.1 Hz, C-H). IR (KBr): 1030 (C=S), 1550 (C=0 antipyrine), 1630 (C=C anti-pyrine), 1640 (C=0), 3370 (N-H) cm4. Anal. Calcd for C14H22N503S: C 62.06, H 4.78, N 15.21. Found: C 62.64, H 4.79, N 15.24.
5h: Mp 154—155 °C (Ethanol). ^NMR (CDCl3+DMSO) 5 2.1 (s, 3H, CH3), 2.5 (s, 3H, NCH3), 7.8 (m, 5H, NPh), 5.0 (brs, 1H, NH), 7.0-7.2 (N-H indole), 6.5 (s, 1H, C2Hindole), 4.1^.2 (d, lH,/7.7 Hz, C5HBA), 3.6-3.8 (d, 1H, / 7.6 Hz, C-H). IR (KBr): 1550 (C=0 antipyrine), 1630 (C=C antipyrine), 1640 (C=0), 2960 (C-H), 3350 (N-H) cm-1. Anal. Calcd for C24H22N504: C 64.86, H 4.25, N 15.76. Found: C 64.82, H 4.93, N 15.74.
Acknowledgements
Authors are thankful to the University Grants Commission, New Delhi for their financial assistance.
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Povzetek
Opisana je sinteza novih Mannichovih baz iz barbituratov in tiobarbituratov s pomočjo montmorillonita in mikrovalov. Sintesa je hitra in poteka brez topil. Ta metoda, v primerjavi s klasičnim segrevanjem, zmanjša reakcijske čase iz ur na minute, povečani pa so tudi izkoristki. Vsem pripravljenim spojinam smo testirali aktivnost na A. niger in A. flavus.

Kidwai et al. Synthesis of Barbituric Acid Derivatives