pyrimidinones have been paid increasing attention , due to their various therapeutic and pharmacological properties , such as antiviral , antibacterial , antihypertensive , and antitumor effects .
more recently , they emerged as integral backbones of several calcium blockers , antihypertensive agents , -1a - antagonists , and neuropeptide y ( npy ) antagonists .
pyrimidinone derivatives are found as core units in many marine alkaloids ( batzelladine and carambine ) , which have been found to be potent to hiv - gp-120 cd4 inhibitors . due to the remarkable biological utilization ,
the pyrimidinones attract many researchers as well as academicians . recently , several methods improved the procedure using phosphorus pentoxide - methanesulfonic acid , potassium ter - butoxide ( t - buok ) , ammonium dihydrogen phosphate , silica - gel , mesoporous molecular sieve mcm-41 , cyanuric chloride , nano - bf3sio2 , silica gel - supported polyphosphoric acid , zirconium(iv ) chloride , and indium(iii ) bromide   as catalysts .
however , some of these one - pot procedures generally require strong protic or lewis acids , prolonged reaction times , and high temperature .
consequently , there is a scope for further modification towards mild reaction condition , increased variation of the substituents , and improved yields .
microwave promoted solvent - free reactions   are well known as environmentally benign methods that also usually provide improved selectivity , enhanced reaction rates , cleaner products , and manipulative simplicity . however , these procedures are practically limited as the solvents in microwave oven at elevated temperatures create high pressures , which may cause explosion . to circumvent these problems , there is a need for the development of newer methods which proceed under mild and solvent free condition .  
nowadays solvent - free reactions gained much importance in organic synthesis because of the high yields and shorter reaction times .
earlier reported procedures for the synthesis of pyrimidine derivatives typically involved longer reaction time and fewer yields . in the present communication , we would like to describe the advantages of dry reaction techniques coupled with microwave activation and their applications to organic synthesis .
reactions were routinely monitored by thin layer chromatography ( tlc ) on silica gel ( precoated f 254 merck plates ) and visualized the products under uv light ( 254  nm ) .
h nmr spectra were determined in cdcl3 or dmso - d6 solutions with a bruker advance ii 400  mhz spectrometer and signals recorded in parts per million (  ) downfield from tetramethylsilane as internal standard .
ir spectra were recorded on perkin elmer ft - ir spectrometer ( spectrum rx i ) using kbr pellet technique .
melting points were recorded in open capillaries on labindia melting point apparatus and were uncorrected .
anti - inflammatory activity has been carried out in institute of pharmacy , vikram university , ujjain .  
a mixture of aldehyde 1 ( 1  mmol ) , ethyl cyanoacetate 2 ( 1.2  mmol ) , guanidine nitrate 3 ( 1.5  mmol ) , and 2 - 3 drops of piperidine was subjected to microwave irradiation at 60% power in 600  w microwave oven for 5  min .
( successive irradiation of 3040  sec with cooling intervals of time , the temperature being 90100c ) . on completion of reaction , indicated by tlc ,
the mixture was cooled and quenched with water ( 3  10  ml ) .
white crystals ; mp : 218220c ; ir ( kbr vmax / cm ) : 3478 ( nh ) , 3090 ( c  h ) , 2260 ( cn ) , 1690 ( c = o ) , 1617 ( c =
h nmr ( 300  mhz , cdcl3 )  8.56 , 2.0 ( s , 2h nh ) , 7.277.40 ( m , 5h , ar ) , 4.1 ( d , ch , j = 8.4  hz ) , 3.97 ( d , ch , j = 11.5  hz ) .
c nmr ( cdcl3 )  : 168.4 , 153.3 , 143.5 , 128.5 , 126.9 , 126.7 , 116.8 , 43.2 , 42.4 .
molecular weight : 214.22 ; mass ( m / z ) : 214 ( m ) ; c11h10n4o ( 214.09 ) ; cacld .
c , 61.67 ; h , 4.71 ; n , 26.15 ; o , 7.47 ; found .
c , 60.07 ; h , 4.13 ; n , 25.87 ; o , 7.08 . 
 2-amino-6-(4-methoxyphenyl)-4-oxo-1,4,5,6-tetrahydropyrimidine-5-carbonitrile 
 ( 4b ) .
light yellow crystals ; mp : 110112c ; ir ( kbr vmax / cm ) : 3318 ( nh ) , 3055 ( c  h ) , 2190 ( cn ) , 1710 ( c = o ) , 1620
h nmr ( 300  mhz , cdcl3 )  : 8.32 ( s , 2h , nh2 ) , 6.947.18 ( m , 4h , ar ) , 3.9 ( d , ch , j = 14.4  hz ) , 3.72 ( d , ch , j = 11.5  hz ) , 3.50 ( s , 3h , och3 ) , 2.0 ( s , 2h nh ) .
c nmr ( cdcl3 )  : 166.7 , 159.1 , 153.5 , 136.2 , 127.4 , 116.3 , 115.0 , 56.1 , 43.6 , 44.8 .
molecular weight : 244 ; mass ( m / z ) : 243 ( m ) ; c12h12n4o2 ( 244.10 ) ; cacld .
c , 59.01 ; h , 4.95 ; n , 22.94 ; o , 13.10 ; found .
c , 58.87 ; h , 4.63 ; n , 22.65 , o , 12.72 . 

yellow crystals ; mp : 127 - 128c ; ir ( kbr vmax / cm ) : 3460 ( nh ) , 3080 ( arom .
c  h ) , 2943 ( methyl c  h ) , 1590 ( c = c ) , 1290 ( aryl och3 ) , 1670 ( c = o ) , 1567 ( c = n ) , 2310 ( cn).h nmr
( 300  mhz , cdcl3 )  : 6.746.96 ( m , 3h , ar ) , 2.0 , 8.56 ( s , 2h , nh ) , 3.97 ( d , ch , j = 8.4  hz ) , 4.1 ( d , ch , j = 11.5  hz ) , 3.83 ( s , 2h , methylene proton ) .
c nmr ( cdcl3 )  : 168.4 , 153.3 , 149.6 , 147.8 , 136.8 , 121.9 , 118.9 , 116.8 , 109.8 , 43.2 , 42.7 , 56.1 .
molecular weight : 274.28 ; mass ( m / z ) : 248 ( m ) ; c13h14n4o3 ( 274.11 ) ; cacld .
c , 56.93 ; h , 5.14 ; n , 20.43 ; o , 17.50 ; found .
c , 56.14 ; h , 5.04 ; n , 21.98 ; o , 17.19 . 
 2-amino-6-(4-nitrophenyl)-4-oxo-1,4,5,6-tetrahydropyrimidine-5-carbonitrile 
  ( 4d ) .
yellow crystals ; mp : 162164c ; ir ( kbr vmax / cm ) : 3440 ( nh ) , 3080 ( c  h ) , 2327 ( cn ) , 1640 ( c = o ) , 1560 ( c = n ) , 1567 ( c = c ) , 1523 ( n = o ) .
h nmr ( 300  mhz , cdcl3 )  : 7.558.21 ( dd , 4h , ar ) , 2.0 , 8.56 ( s , 2h , nh ) , 3.97 ( d , ch , j = 11.5  hz ) , 4.1 ( d , ch , j = 8.4  hz ) .
c nmr ( cdcl3 )  : 168.4 , 153.3 , 149.6 , 145.9 , 123.7 , 123.4 , 116.8 , 43.2 , 42.4 .
molecular weight : 259.22 ; mass ( m / z ) : 259 ( m ) ; c11h9n5o3 ( 259.07 ) ; cacld .
c , 50.97 ; h , 3.50 ; n , 27.02 ; o , 18.52 ; found .
c , 50.73 ; h , 3.24 ; n , 26.92 ; o , 18.32 .  

yellow crystals ; mp : 9395c ; ir ( kbr vmax / cm ) : 3420 ( nh ) , 3111 ( ar c  h ) , 2360 ( cn ) , 1720 ( c = o ) , 1593 ( c = n ) .
h nmr ( 300  mhz , cdcl3 )  : 5.726.69 ( m , 3h , ar ) , 2.0 , 8.56 ( s , 2h , nh ) , 3.02 ( m , 1h , ch ) , 3.9 ( m , 1h , ch ) .
c nmr ( cdcl3 )  : 168.4 , 153.3 , 130.5 , 118.0 , 116.8 , 108.5 , 107.7 , 43.9 , 42.8 .
molecular weight : 203.20 ; mass ( m / z ) : 203 ( m ) ; c9h9n5o ( 203.08 ) ; cacld .
c , 53.20 ; h , 4.46 ; n , 34.47 ; o , 7.87 ; found .
n , 33.94 ; o , 7.59 .  
 2-amino-6-(furan-2-yl)-4-oxo-1,4,5,6-tetrahydropyrimidine-5-carbonitrile ( 4f ) . light yellow crystals ; mp : 7678c ir ( kbr vmax / cm ) : 3427 ( nh ) , 3121 ( c  h ) , 2230 ( cn ) , 1690 ( c = o ) , 1615 ( c =
h nmr ( 300  mhz , cdcl3 )  : 7.92 ( s , 2h , nh2 ) , 6.547.67 ( m , 3h , ar ) , 4.1 ( d , ch , j = 11.5  hz ) , 3.82 ( d , ch , j = 8.4  hz ) , 2.0 ( s , 2h , nh ) .
c nmr ( cdcl3 )  : 164.5 , 153.6 , 149.9 , 142.1 , 116.5 , 111.1 , 110.4 , 44.3 , 40.7 .
molecular weight : 204 ; mass ( m / z ) : 203 ( m ) ; c9h8n4o2 ( 204.06 ) ; cacld .
c , 52.94 ; h , 3.95 ; n , 27.44 ; o , 15.67 ; found .
c , 52.81 ; h , 3.78 ; n , 26.97 ; o , 15.41 .  

yellow crystals ; mp : 190192c ; ir ( kbr vmax / cm ) : 3450 ( nh ) , 3120 ( c  h ) , 2310 ( cn ) , 1690 ( c = o ) , 1590 ( c =
h nmr ( 300  mhz , cdcl3 )  : 10.8 ( s , 1h , nh ) , 8.22 ( s , 2h , nh2 ) , 7.117.69 ( m , 5h , ar ) , 3.7 ( d , ch , j = 14.0  hz ) , 3.4 ( d , ch , j = 8.0  hz ) , 2.0 ( s , 2h , nh ) .
c nmr ( cdcl3 )  : 164.3 , 154.1 , 133.2 , 126.4 , 124.3 , 122.5 , 120.6 , 114.7 , 117.1 , 110.9 , 43.1 , 45.4 .
molecular weight : 253 ; mass ( m / z ) : 252 ( m ) ; c13h11n5o ( 253.10 ) ; cacld .
c , 61.65 ; h , 4.38 ; n , 27.65 ; o , 6.32 ; found .
c , 61.16 ; h , 3.99 ; n , 27.34 ; o , 5.89 . 

yellow crystals ; mp : 148150c ; ir ( kbr vmax / cm ) : 3470 ( nh ) , 3111 ( arom .
c  h ) , 2360 ( cn ) , 1720 ( c = o ) , 1542 ( c = c ) , 1593 ( c =
h nmr ( 300  mhz , cdcl3 )  : 5.726.69 ( m , 3h , ar ) , 2.0 , 8.56 ( s , 2h , nh ) , 3.90 ( s , 1h , ch3 ) , 3.97 ( d , ch , j = 8.4  hz ) , 4.1 ( d , ch , j = 11.5  hz ) .
c nmr ( cdcl3 )  : 168.4 , 153.3 , 132.1 , 122.5 , 116.8 , 108.6 , 108.4 , 44.2 , 40.3 , 35.2 .
molecular weight : 217.23 ; mass ( m / z ) : 217 ( m ) ; c10h11n5o ( 217.10 ) ; cacld .
c , 55.29 ; h , 5.10 ; n , 32.24 ; o , 7.37 ; found .
c , 54.94 ; h , 4.92 ; n , 31.91 ; o , 7.03 .
colony bred healthy rats of wistar strain and albino mice procured from local market from ujjain were used for the study .
they were housed in standard polypropylene cages under room temperature ( 24  2c ) , relative humidity ( 60%70% ) , and exposed to 12  :  12 hours light  :  dark cycle .
the rats were fed nutrilab rodent feed and drinking water filtered through an aqua guard water filter system adlibitum .
the anti - inflammatory activity was determined in vivo   using the carrageenan - induced rat paw edema test [ 5 , 11 ] . a solution of 0.1  ml of 1% carrageenan ( sigma - aldrich , dorset , uk ) in saline was injected subplantarly in the right hind paw of the rats 1  h after ip administration of compounds .
the paw thickness was measured from the ventral to the dorsal surfaces using a dial caliper immediately prior to carrageenan injection and then at each hour , up to 4  h after the subplanar injection .
the edema was calculated as the thickness variation between the carrageenan and saline treated paw .
anti - inflammatory activity was expressed as the percent of inhibition of the edema when compared with the control group .
the data was statistically analyzed by one way analysis of variance ( anova ) followed by tukey multicomparison test .
antibacterial activity of the prepared compounds 4d , 4e , 4f , 4 g , and 4h were tested by the disk diffusion method .
the sterile disks were impregnated with the test compounds ( 250  mg / ml ) .
agar plates were uniformly surface inoculated with fresh broth culture of staphylococcus aureus , basillus subtilis , escherichia coli , and pseudomonas aeruginosa .
the impregnated disks were placed on the medium suitably spaced apart , and the plates were incubated at 30c for 1  h to permit good diffusion and were then transferred to an incubator at 37  2c for 24  h. the zones of inhibition were measured on mm scale . the results of antimicrobial activity tests are listed in table 3 .
antifungal susceptibility test was done by disk diffusion method   using sabouraud 's dextrose agar medium .
after sterilization , the medium was inoculated with candida albicans , aspergillus flavus , and aspergillus niger .
the standard antifungal agent clotrimazole ( 100  g / ml ) , solvent control ( 0.5% v / v tween 80 ) , and the newly synthesized compounds 4d , 4e , 4f , 4 g , and 4h in a concentration of 100  g / ml were then added by sterile micropipette .
the plates were then incubated at 37c for 24  h and the diameter of zone of inhibition was measured and recorded in table 3 .
in the view of the above mentioned limitations of the reported method , pharmacological importance of dihydropyrimidinones and our ongoing endeavors to conduct organic synthesis under solvent free conditions , we describe an expeditious solvent less microwave accelerated approach for the rapid assembly of 2-amino dihydropyrimidinones .
aromatic aldehydes ( 1a  h , 1  mmol ) on reaction with ethyl cyanoacetate ( 2 , 1.2  mmol ) and guanidine nitrate ( 3 , 1.5  mmol ) using dry conditions yielded corresponding 2-amino dihydropyrimidinones ( scheme 1 ) . as far as our interest in investigating the facile , rapid , and expeditious solvent - less methodology for 2-amino dihydropyrimidinone
, we tried the reaction of benzaldehyde ( 1a , 1  mmol ) , with ethyl cyanoacetate ( 2 , 1.2  mmol ) and guanidine nitrate ( 3 , 1.5  mmol ) by varying microwave power from 150 watts to 750 watts .
it was observed that by increase in power up to 600 watts , there was increase in yield and shortened reaction time . beyond the 600 watts
there was no significant change in reaction time and yield .   in order to evaluate the generality of this model reaction
, we then prepared a range of 2-amino dihydropyrimidinone derivatives under the optimized reaction conditions . in all cases , aryl aldehydes and heteroaryl aldehydes with substituents carrying either electron - donating or electron - withdrawing groups reacted successfully and gave the expected products in good to excellent yields in relatively short reaction times .
the formation of the product takes place when aryl aldehydes were reacted with ethyl cyanoacetate to form arylmethylene ethylcyanoacetate , which subsequently added with guanidine followed by cyclization and tautomerization to form the desired product .  
the results of the anti - inflammatory activity of compounds 4d , 4e , 4f , 4 g , and 4h were summarized in table 2 . from the results ,
it is evident that compounds 4c , 4f , and 4h as well as indomethacin as the reference drug induced significant anti - inflammatory activity after 3 and 4  h in comparison to control and almost all of the tested compounds were shown moderate to good anti - inflammatory activity .  
the mic values of the test solutions are recorded in table 3 which is recorded in zones of inhibition in mm for the bacteria and fungi .
the antimicrobial screening has shown that compounds 4d , 4f , 4 g , and 4f have displayed moderate activity against gram + ve bacteria tested , that is , s. aureus and b. subtilis .
compounds 4d and 4h have shown broad spectrum activity against gram ve bacteria tested , that is , e. coli and p. aeruginosa while compound 4e has shown poor activity against both gram + ve and gram ve bacteria tested .
compound 4d has shown good antifungal activity against all the tested fungi , that is , c. albicans , a. flavus , and a. niger while the remaining compounds 4e and 4f have shown good activity , and compounds 4 g and 4h have shown moderate activity against all fungi tested .
  in summary , we have described one - pot synthesis of 2-amino dihydropyrimidinone derivatives via a three component cycloaddition reaction under microwave irradiation .
another advantage of this method is excellent yields in shorter reaction time with high purity of the products .
the synthesized compounds have shown good anti - inflammatory , antibacterial , and antifungal activities .
 a simple protocol for the efficient preparation of aryl and heteroaryl substituted dihydropyrimidinone has been achieved via initial knoevenagel , subsequent addition , and final cyclization of aldehyde , ethylcyanoacetate , and guanidine nitrate in the presence of piperidine as a catalyst in solvent - free under microwave irradiation . 
 the synthesized compounds showed a good anti - inflammatory , antibacterial , and antifungal activity . 
1. Introduction
2. Experimental
3. Results and Discussion
4. Conclusion