Molecular Diversity 7: 153–159.KLUWER/ESCOM© 2003 Kluwer Academic Publishers. Printed in the Netherlands.

153

Full paper

A one-pot microwave-assisted synthesis of pyrido[2,3-d]pyrimidines

Nuria Mont1, Jordi Teixido1, C. Oliver Kappe2 & Jose I. Borrell1∗1 Grup d’Enginyeria Molecular, Institut Quımic de Sarria, Universitat Ramon Llull, Barcelona, Spain;2 Institute of Chemistry, Karl-Franzens-University Graz, Graz, Austria(∗ Author for correspondence, E-mail: j.i.borrell@iqs.url.edu, Fax: +34 932 056 266)

Received 3 May 2003; Accepted 26 June 2003

Key words: microwave synthesis, multicomponent reactions, pyrido[2,3-d]pyrimidines

Summary

A high yield multicomponent reaction providing multifunctionalized pyrido[2,3-d]pyrimidines with up to fourdiversity centers in a one-pot microwave-assisted cyclocondensation of α,β-unsaturated esters, amidine systemsand malononitrile (or ethyl cyanoacetate) is described.

Introduction

Pedro Victory (Madrid, 1928–Barcelona, 1994)spent most of his scientific career studying thesynthetic applications of 2-methoxy-6-oxo-1,4,5,6-tetrahydropyridin-3-carbonitriles 3 (Scheme 1), ob-tained by reaction of an α,β-unsaturated ester 1 andmalononitrile 2 (G = CN) in NaOMe/MeOH [1]. Thepresence in pyridones 3 of a methoxy group linkedto a sp2 carbon atom that is the end of an α,β-unsaturated cyano group, which is also conjugatedwith the lactam NH, render such compounds ex-cellent substrates for nucleophilic substitution. Thisapproach allowed us to describe general proceduresfor the synthesis of bicyclic heterocycles such aspyrazolo[3,4-b]pyridines, 1,6-naphthyridines, and 4-amino-pyrido[2,3-d]pyrimidines 6 (R3 = NH2) bytreatment of pyridones 3 with amidine systems 5 (R4

= NH2, H, Me, Ph) [1]. More recently, we describedan acyclic variation of the above protocol for the syn-thesis of pyridopyrimidines 6 (R3 = NH2) based on theisolation of the corresponding Michael adduct 4 (G =CN), that also allowed us to obtain 4-oxopyrido[2,3-d]pyrimidines 6 (R3 = OH) by treatment of intermedi-ates 4 (G = CO2Me), synthesised by Michael additionof acrylate 1 and methyl cyanoacetate 2 (G = CO2Me),with an amidine building block 5 (Scheme 1) [2, 3].

Pyrido[2,3-d]pyrimidines are heterocyclic ringsystems of considerable interest due to several bio-logical activities associated with this scaffold: someanalogues have been found to act as antitumor agentsinhibiting dihydrofolate reductases or tyrosine kinases[4], while others are known antiviral agents [5]. Con-sequently, we decided to try to convert the aforemen-tioned methodologies in a multicomponent reaction.

Multicomponent reactions (MCRs) are of increas-ing importance in organic and medicinal chemistry.In times where a premium is put on speed, diversity,and efficiency in the drug discovery process, MCRstrategies offer significant advantages over conven-tional linear-type syntheses [6]. MCRs leading tointeresting heterocyclic scaffolds are particularly use-ful for the creation of diverse chemical libraries of‘drug-like’ molecules for biological screening, sincethe combination of three or more small molecularweight building blocks in a single operation leads tohigh combinatorial efficacy.

Now, we wish to report that pyrido[2,3-d]pyrimi-dines 6 can be rapidly obtained in a single stepby a 3 component microwave-assisted cyclocondens-ation of an α,β-unsaturated ester (1), amidine (5)and malononitrile/cyanoacetate building blocks (2)(termed as the ‘Victory’ reaction to honour Prof. Vic-tory; for a prelimminary account of this work seeRef. 7).

154

Scheme 1.

Results and discussion

Our initial efforts were carried out using conventionalheating by treating methyl crotonate (1{1}, R1 = H,R2 = Me), methyl methacrylate (1{2}, R1 = Me, R2

= H) or methyl acrylate (1{3}, R1 = R2 = H) withmalononitrile (2{1}, G = CN) and guanidine (5{1},R4 = NH2) in MeOH. Using a 1:1.2:1.2 molar ratio ofbuilding blocks 1/2/5, we observed that reflux for 24 hin an oil-bath was required in order for this multi-stepsequence to afford 55% of pyrido[2,3-d]pyrimidine6{1,1,1}, 43% of 6{2,1,1}, and 48% of 6{3,1,1}. Suchencouraging results lead us to study the influence ofmicrowaves in this reaction.

Under microwave irradiation conditions our firstinvestigations involved treatment of a mixture ofmethyl acrylate (1{3}, R1 = R2 = H), malononitrile(2{1}, G = CN) and guanidine (5{1}, R4 = NH2) ina variety of different solvents. Using sealed vesselmicrowave heating technology [8] at temperatures of100–140 ◦C full conversions were generally achievedwithin 10 min. A variety of different solvents such asMeOH, EtOH, THF and MeCN were utilised in ourearly optimisation studies. In general the strongly mi-crowave absorbing MeOH provided the highest yieldsof the desired products. First of all, a molar ratio1:1.2:1.2 of building blocks 1/2/5 was considered,but relatively low yields of pyrido[2,3-d]pyrimidine6{3,1,1} were obtained.

In previous studies [2], we found that treat-ment of Michael adduct 8 in MeOH with an

equimolar amount of guanidine 5{1} in absence ofsodium methoxyde afforded a mixture of the ex-pected pyrido[2,3-d]pyrimidine 10 and the corres-ponding 2-methoxy-6-oxo-1,4,5,6-tetrahydropyridin-3-carbonitrile 9 (Scheme 2). We interpreted such resultby postulating that guanidine (pKa = 13.40; guan-idinium form) firstly act as a base causing the disso-ciation of MeOH (pKa = 15.00) thus favouring theintramolecular cyclization that leads to pyridone 9.In other words, pyridone 9 is in fact the intermedi-ate of the transformation of adduct 8 to pyrido[2,3-d]pyrimidine 10.

Assuming that the behaviour could be similar dur-ing the three component reaction and, consequently,pyridones 3 would be formed in situ, we decided toincrease the amount of guanidine 5{1} in our modelreaction. Then, treatment of methyl acrylate 1{3} withmalononitrile 2{1} and guanidine 5{1} in MeOH us-ing a 1:1.2:3 molar ratio yielded compound 6{3,1,1}in 98% yield. Although the reaction can be conductedin the absence of additional base, a catalytic amountof. NaOMe (5%) was used to perform all ulteriorcyclocondensation reactions.

Considerable experimentation with respect to themolar equivalents of reagents was done arriving atconditions that utilised a 1:1.2:3 molar ratio of build-ing blocks 1/2/guanidine (5{1}, R4 = NH2) and1:1.2:2.2 molar ratio of building blocks 1/2/benz-amidine (5{2}, R4 = Ph), which gave the most satis-factory results in terms of product yields and purity.Such reaction conditions were extended to the altern-

155

Scheme 2.

Table 1. Yields of pyrido[2,3-d]pyrimidines 6

Compound R1 R2 R3 R4 Yield (%)

6{1,1,1} H Me NH2 NH2 >98

6{2,1,1} Me H NH2 NH2 >98

6{3,1,1} H H NH2 NH2 >98

6{4,1,1} H Ph NH2 NH2 96

6{1,2,1} H Me OH NH2 >98

6{2,2,1} Me H OH NH2 >98

6{3,2,1} H H OH NH2 87

6{4,2,1} H Ph OH NH2 >98

6{1,1,2} H Me NH2 Ph 90

6{2,1,2} Me H NH2 Ph 88

6{3,1,2} H H NH2 Ph 59

6{4,1,2} H Ph NH2 Ph 35

6{1,2,2} H Me OH Ph 53

6{2,2,2} Me H OH Ph 52

6{3,2,2} H H OH Ph 15

6{4,2,2} H Ph OH Ph 26

ative use of methyl cyanoacetate 2{2} (G = COOMe)to afford 4-oxopyrido[2,3-d]pyrimidines 6 (here de-picted as the hydroxytautomer, R3 = OH).

Using those conditions a set of α,β-unsaturatedesters 1{1-4} were employed for the synthesis of asmall library of pyrido[2,3-d]pyrimidines (Table 1).In all cases using guanidine (5{1}, R4 = NH2) andbenzamidine (5{2}, R4 = Ph) as amidine buildingblocks the products simply crystallised in high yieldafter cooling of the reaction mixture to room tem-perature and were collected by filtration. The purityof all pyridopyrimidines was higher than 98% basedon HPLC and 1H NMR measurements. For those ex-amples involving benzamidine 5{2} purification byflash chromatography was required and the isolatedyields were somewhat lower.

It is particularly remarkable that using this one-pot methodology we were able to obtain pyrido[2,3-d]pyrimidines 6 in which R1 = R2 = H starting frommethyl acrylate 1{3}. Such compounds were almost

impossible to be obtained using the stepwise cyclicand acyclic strategies (Scheme 1), due to the lowyields of the corresponding intermediates 3{3} and4{3}.

In summary, we have developed a new, rapid andsimple multicomponent cyclocondensation protocolfor the synthesis of pyrido[2,3-d]pyrimidines with upto four diversity centres.

Materials and methods

General

All melting points were determined with a Büchi530 capillary apparatus and are uncorrected. Infraredspectra were recorded in a Nicolet Magna 560 FTIRspectrophotometer. 1H and 13C NMR spectra were de-termined in a Varian Gemini-300 operating in a fieldstrength of 300 and 75.5 MHz, respectively. Chemicalshifts are reported in parts per million (δ) and couplingconstants (J ) in Hz, using in the case of 1H NMR, so-dium 2,2,3,3-tetradeuteriotrimethylsilylpropionate asan internal standard and setting, in the case of 13CNMR, the references at the signal of the solvent(163.8 ppm, CF3COOD, TFA-d). Standard and peakmultiplicities are designated as follows: s, singlet;d, doublet; dd, doublet of doublets; t, triplet; br,broad signal; m, multiplet. Elemental microanalyseswere obtained in a Carlo-Erba CHNS-O/EA 1108 ana-lyser and gave results for the elements stated with±0.4% of the theoretical values. Thin layer chroma-tography (TLC) was performed on precoated sheetsof silica 60 Polygram SIL N-HR/UV254 (MachereyNagel art. 804023). High performance liquid chro-matography (HPLC) were performed on A ShimadzuLC-10 system, that included LC-10AT(VP) pumps, anautosampler (S-10AXL), and a dual wavelength UVdetector set at 215 and 280 nm was used. Separationswere carried out using a C18 reversed phase analyticalcolumn, LiChrospher 100 (E. Merck, 100 × 3 mm,particle size 5 µm) at 25 ◦C and a mobile phase from

156

(A) 0.1%TFA in 90:10 water/ACN and (B) 0.1% TFAacid in ACN (all solvents were HPLC grade, Acros;TFA was analytical reagent grade, Aldrich). The fol-lowing gradients were applied at a flow rate of 0.5 mlmin−1: linear increase from solution 30% B to 100%solution B in 7 min, hold at 100% solution B for 1 min.

Microwave Chemistry was performed in an EmrysSynthesiser (Personal Chemistry, AB). The instrumentcomprises a monomode (sometimes also called single-mode) microwave cavity operating at a frequencyof 2.45 GHz with continuous microwave irradiationpower from 0 to 300 W. Reaction vials are glass-based ∼10 ml closed tubes, sealed with Teflon septaand an aluminum crimp top and provided with mag-netic stirring bars. The process vials are moved intoand out of the cavity in an automated fashion by agripper incorporated into the platform. Inside the mi-crowave cavity these vessels can be exposed to 20 barof pressure and 250 ◦C. Temperature is measuredwith an IR sensor (infrared thermometry) on the outersurface of the process vial. The software algorithmregulates the microwave output power so that the pre-selected maximum temperature is maintained for thedesired reaction/irradiation time. Reagents can eitherbe poured manually into the vials before capping orbe dispensed through the Teflon septum via the liquidhandler incorporated into the platform. After the ir-radiation period the reaction vessel is cooled rapidly(20–80 s) to ambient temperature by compressed air(gas jet cooling).

Synthesis

Synthesis of 2,4-diamino-5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine 6{1,1,1} usingconventional heatingGuanidine carbonate (180 mg, 3.0 mmol) was addedto a fresh solution of NaOMe prepared by additionof 3.0 ml of MeOH to Na (70 mg, 3,05 mmol). Themixture was heated at reflux for 15 min. After cool-ing to room temperature the mixture was filtered toremove Na2CO3. To the so prepared solution of guan-idine 5{1} in MeOH methyl crotonate 1{1} (100 mg,1.0 mmol) and malononitrile 2{1} (79 mg, 1.2 mmol)were added. This mixture was heated for 24 h at re-flux. Then it was cooled to room temperature andthe formed precipitate was collected by filtration andwashed thoroughly with water, EtOH and Et2O toyield an off-white powder (106 mg, 55%, purity>98%). Recrystallization from AcOH produced thepyridopyrimidine 6{1,1,1} (R1 = H, R2 = Me, R3 = R4

= NH2) in analytical purity. The spectral and analyticaldata were in agreement with authentic material [1c, 2,3].

Synthesis of 2,4-diamino-6-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine 6{2,1,1} usingconventional heatingAs above for 6{1,1,1} but using 100 mg (1.0 mmol) ofmethyl methacrylate 1{2} to give an off-white powder(83 mg, 43%, purity >98%). Recrystallization fromAcOH produced the pyridopyrimidine 6{2,1,1} (R1 =Me, R2 = H, R3 = R4 = NH2) in analytical purity. Thespectral and analytical data were in agreement withauthentic material [1c, 2, 3].

Synthesis of 2,4-diamino-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine 6{3,1,1} usingconventional heatingAs above for 6{1,1,1} but using 86 mg (1.0 mmol)of methyl acrylate 1{3} to give an off-white powder(86 mg, 48%, purity >98%). Recrystallization fromAcOH produced the pyridopyrimidine 6{3,1,1} (R1 =H, R2 = H, R3 = R4 = NH2) in analytical purity. Thespectral and analytical data were in agreement withauthentic material [1c, 3, 9].

Synthesis under microwave conditions

Synthesis of 2,4-diamino-5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine 6{1,1,1}Guanidine carbonate (180 mg, 3.0 mmol) was addedto a fresh solution of NaOMe prepared by additionof 3.0 ml of MeOH to Na (70 mg, 3.05 mmol). Themixture was heated at reflux for 15 min. After cool-ing to room temperature the mixture was filtered toremove Na2CO3. The so prepared solution of guanid-ine 5{1}in MeOH was placed in a microwave processvial containing a stir bar. After addition of methylcrotonate 1{1} (100 mg, 1.0 mmol) and malononi-trile 2{1} (79 mg, 1.2 mmol), the vial was sealedand subjected to microwave irradiation for 10 min at140 ◦C. After gas jet cooling to room temperature(2 min) the formed precipitate was collected by fil-tration and washed thoroughly with water, EtOH andEt2O providing an off-white powder (193 mg, 98%,purity >98%). Recrystallization from AcOH producedthe pyridopyrimidine 6{1,1,1} (R1 = H, R2 = Me, R3 =R4 = NH2) in analytical purity. The spectral and ana-lytical data were in agreement with authentic material[1c, 2, 3].

157

Synthesis of 2,4-diamino-6-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine 6{2,1,1}As above for 6{1,1,1} but using 100 mg (1.0 mmol) ofmethyl methacrylate 1{2} to give an off-white powder(193 mg, 98%, purity >98%). Recrystallization fromAcOH produced the pyridopyrimidine 6{2,1,1} (R1 =Me, R2 = H, R3 = R4 = NH2) in analytical purity. Thespectral and analytical data were in agreement withauthentic material [1c, 2, 3].

Synthesis of 2,4-diamino-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine 6{3,1,1}As above for 6{1,1,1} but using 86 mg (1.0 mmol)of methyl acrylate 1{3} to give an off-white powder(179 mg, 98%, purity >98%). Recrystallization fromAcOH produced the pyridopyrimidine 6{3,1,1} (R1 =H, R2 = H, R3 = R4 = NH2) in analytical purity. Thespectral and analytical data were in agreement withauthentic material [1c, 3, 9].

Synthesis of 2,4-diamino-5-phenyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine 6{4,1,1}As above for 6{1,1,1} but using 162 mg (1.0 mmol)of methyl cinnamate 1{4} to give an off-white powder(245 mg, 96%, purity >98%). Recrystallization fromAcOH produced the pyridopyrimidine 6{4,1,1} (R1 =H, R2 = Ph, R3 = R4 = NH2) in analytical purity. Thespectral and analytical data were in agreement withauthentic material [1a, 1c, 2, 3].

Synthesis of 2-amino-5-methyl-4,7-dioxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidine 6{1,2,1}Guanidine carbonate (180 mg, 3.0 mmol) was addedto a fresh solution of NaOMe prepared by additionof 3.0 ml of MeOH to Na (70 mg, 3,05 mmol). Themixture was heated at reflux for 15 min. After cool-ing to room temperature the mixture was filtered toremove Na2CO3. The so prepared solution of guanid-ine 5{1} in MeOH was placed in a microwave processvial containing a stir bar. After addition of methylcrotonate 1{1} (100 mg, 1.0 mmol) and methyl cyano-acetate 2{2} (119 mg, 1.2 mmol), the vial was sealedand subjected to microwave irradiation for 10 min at140 ◦C. After gas jet cooling to room temperature(2 min) the formed precipitate was collected by fil-tration and washed thoroughly with water, EtOH andEt2O providing an off-white powder (194 mg, 98%,purity >98%). Recrystallization from AcOH producedthe pyridopyrimidine 6{1,2,1} (R1 = H, R2 = Me, R3

= R4 = OH) in analytical purity. The spectral and ana-

lytical data were in agreement with authentic material[1c, 3].

Synthesis of 2-amino-6-methyl-4,7-dioxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidine 6{2,2,1}As above for 6{1,2,1} but using 100 mg (1.0 mmol) ofmethyl methacrylate 1{2} to give an off-white powder(194 mg, 98%, purity >98%). Recrystallization fromAcOH produced the pyridopyrimidine 6{2,2,1} (R1 =Me, R2 = H, R3 = R4 = OH) in analytical purity. Thespectral and analytical data were in agreement withauthentic material [1c, 3, 9].

Synthesis of 2-amino-4,7-dioxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidine 6{3,2,1}As above for 6{1,2,1} but using 86 mg (1.0 mmol)of methyl acrylate 1{3} to give an off-white powder(157 mg, 87%, purity >98%). Recrystallization fromAcOH produced the pyridopyrimidine 6{3,2,1} (R1 =H, R2 = H, R3 = R4 = OH) in analytical purity. Thespectral and analytical data were in agreement withauthentic material [1c, 3, 9].

Synthesis of 2-amino-5-phenyl-4,7-dioxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidine 6{4,2,1}As above for 6{1,2,1} but using 162 mg (1.0 mmol)of methyl cinnamate 1{4} to give an off-white powder(256 mg, 96%, purity >98%). Recrystallization fromAcOH produced the pyridopyrimidine 6{4,2,1} (R1 =H, R2 = Ph, R3 = R4 = OH) in analytical purity. Thespectral and analytical data were in agreement withauthentic material [1c, 3].

Synthesis of 4-amino-5-methyl-2-phenyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine 6{1,1,2}A fresh solution of NaOMe is prepared by additionof 3.0 ml of MeOH to Na (2 mg, 0.1 mmol). The soprepared solution was placed in a microwave processvial containing a stir bar. After addition of methyl cro-tonate 1{1} (100 mg, 1.0 mmol), malononitrile 2{1}(79 mg, 1.2 mmol) and benzamidine 5{2} (264 mg,2.2 mmol), the vial was sealed and subjected to mi-crowave irradiation for 10 min at 100 ◦C. After gasjet cooling to room temperature (2 min) the formedprecipitate was collected by filtration and washed thor-oughly with water, EtOH and Et2O providing anoff-white powder. Flash chromatography produced thepyridopyrimidine 6{1,1,2} (R1 = H, R2 = Me, R3 =R4 = NH2) (227 mg, 90%) in analytical purity. Thespectral and analytical data were in agreement withauthentic material [1c, 3].

158

Synthesis of 4-amino-6-methyl-2-phenyl -7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine 6{2,1,2}

As above for 6{1,1,2} but using 100 mg (1.0 mmol) ofmethyl methacrylate 1{2} to give an off-white powder.Flash chromatography produced the pyridopyrimidine6{2,1,2} (R1 = Me, R2 = H, R3 = R4 = NH2) (224 mg,88%) in analytical purity. The spectral and analyticaldata were in agreement with authentic material [1c, 3].

Synthesis of 4-amino-2-phenyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine 6{3,1,2}

As above for 6{1,1,2} but using 86 mg (1.0 mmol)of methyl acrylate 1{3} to give an off-white powder.Flash chromatography produced the pyridopyrimidine6{2,1,3} (R1 = H, R2 = H, R3 = R4 = NH2) (142 mg,59%) in analytical purity. IR (KBr), ν (cm−1): 3490–3100 (N-H), 1702, 1651 (C=O), 1562, (C=C, C=N).1H-NMR (300 MHz, DMSO-d), δT MS (ppm): 10.31(s, 1H, H8), 8.23 (m, 2H, o-Ph), 7.43 (m, 3H, p-Ph,m-Ph), 6.72 (s, 2H, NH2), 2.66 (t, 3J = 6.3 Hz, 2H, H5),2.54 (t, 3J= 6.3 Hz, 2H, H6). 13C-NMR (75.5 MHz,TFA-d), δ (ppm): 177.3 (C7), 159.8 (C4), 158.3 (C8a),156.8 (C2), 136.5 (ipso-Ph), 131.4 (m-Ph), 130.1 (p-Ph), 129.3 (o-Ph), 96.4 (C4a), 29.8 (C6), 18.0 (C5).MS (70 eV): [M+], 241. Anal. Calcd. for C13H12N4O:C, 64.99; H, 5.03; N, 23.32. Found: C, 65.26; H, 4.99;N, 23.23.

Synthesis of 4-amino-2,5-diphenyl -7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine 6{4,1,2}

As above for 6{1,1,2} but using 162 mg (1.0 mmol)of methyl cinnamate 1{4} to give an off-white powder.Flash chromatography produced the pyridopyrimidine6{4,1,2} (R1 = H, R2 = Ph, R3 = R4 = NH2) (111 mg,35%) in analytical purity. IR (KBr), ν (cm−1): 3491-3177 (N-H), 1705, 1634 (C=O), 1558, 1460 (C=C,C=N). 1H-NMR (300 MHz, DMSO-d), δT MS (ppm):10.5 (s, 1H, NH), 8.28 (m, 2H, o-Ph (C2)), 7.46–7.15 (m, 8H, Ph), 6.75 (s, 2H, NH2), 4.36 (d, 3J

= 6.0 Hz, 1H, H5), 3.12 (dd, 2J= 17.4 Hz,3J =6.0 Hz, 1H, H6), 2.62 (d, 2J = 17.4 Hz, 1H, H6). 13C-NMR (75.5 MHz, TFA-d), δ (ppm): 176.0 (C7), 160.2(C4), 158.7 (C8a), 157.0 (C2), 138.3 (ipso-Ph(C5)),140.6 (ipso-Ph(C2)), 136.7 (p-Ph(C2)), 131.8 (m-Ph(C2)), 131.5 (m-Ph(C5)), 130.0 (p-Ph(C5)), 129.5(o-Ph(C5)), 127.9 (o-Ph(C2)), 98.9 (C4a), 39.7 (C6),36.7 (C5). MS (70 eV): [M+], 316. Anal. Calcd. forC13H12N4O: C, 72.14; H, 5.10; N, 17.71. Found: C,71.92; H, 5.06; N, 17.58.

Synthesis of 5-methyl-2-phenyl-4,7-dioxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidine 6{1,2,2}A fresh solution of NaOMe is prepared by additionof 3.0 ml of MeOH to Na (2 mg, 0.1 mmol). Theso prepared solution was placed in a microwave pro-cess vial containing a stir bar. After addition of methylcrotonate 1{1} (100 mg, 1.0 mmol), methyl cyanoacet-ate 2{2} (119 mg, 1.2 mmol) and benzamidine 5{2}(264 mg, 2.2 mmol), the vial was sealed and subjectedto microwave irradiation for 10 min at 100 ◦C. Aftergas jet cooling to room temperature (2 min) the formedprecipitate was collected by filtration and washed thor-oughly with water, EtOH and Et2O providing anoff-white powder. Flash chromatography produced thepyridopyrimidine 6{1,2,2} (R1 = H, R2 = Me, R3 = R4

= OH) (135 mg, 53%) in analytical purity. The spectraland analytical data were in agreement with authenticmaterial [1c, 3].

Synthesis of 6-methyl-2-phenyl-4,7-dioxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidine 6{2,2,2}As above for 6{1,2,2} but using 100 mg (1.0 mmol) ofmethyl methacrylate 1{2} to give an off-white powder.Flash chromatography produced the pyridopyrimidine6{2,2,2} (R1 = Me, R2 = H, R3 = R4 = OH) (133 mg,52%) in analytical purity. The spectral and analyticaldata were in agreement with authentic material [1c, 3].

Synthesis of 2-phenyl-4,7-dioxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidine 6{3,2,2}As above for 6{1,2,2} but using 86 mg (1.0 mmol)of methyl acrylate 1{3} to give an off-white powder.Flash chromatography produced the pyridopyrimidine6{3,2,2} (R1 = H, R2 = H, R3 = R4 = OH) (36 mg,15%) in analytical purity. The spectral and analyticaldata were in agreement with authentic material [1c, 3,9].

Synthesis of 2,5-diphenyl-4,7-dioxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidine 6{4,2,2}As above for 6{1,2,2} but using 162 mg (1.0 mmol)of methyl cinnamate 1{4} to give an off-white powder.Flash chromatography produced the pyridopyrimidine6{4,2,2} (R1 = H, R2 = Ph, R3 = R4 = OH) (83 mg,26%) in analytical purity. IR (KBr), ν (cm−1): 3200–3050 (N-H), 1710, 1636 (C=O), 1611, 1558, 1518(C=C, C=N). 1H-NMR (300 MHz, DMSO-d), δT MS

(ppm): 10.47 (s, 1H, NH), 8.13–7.21 (m, 10H,Ph), 4.30 (d, 3J = 6.17 Hz, 1H, H5), 3.05 (dd,2J = 13.6 Hz,3J = 6.17 Hz, H6), 3.17 (d, 2J =13.6 Hz, H6). 13C-NMR (75.5 MHz, TFA-d), δ (ppm):

159

175.4 (C7), 166.8 (C4), 166.3 (C2), 160.5 (C8a),139.1 (p−Ph(C2)), 138.1 (ipso-Ph(C5)), 132.2 (m-Ph(C2)), 131.7 (m-Ph(C5)), 131.6 (o-Ph(C5)), 131.6(p-Ph(C5)), 128.2 (o-Ph(C2)), 137.5 (ipso-Ph(C2)),94.5 (C4a), 40.2 (C6), 36.9 (C5). MS (70 eV): [M+],318. Anal. Calcd. for C19H15N3O2: C, 71.91; H, 4.76;N, 13.24. Found: C, 71.66; H, 4.75; N, 13.12.

Acknowledgements

This work was supported by a grant from Generalitatde Catalunya (Grant 2001FI 00540, Borsa de Viatge-BV: 2003BV 00013). N.M. is grateful to Generalitatde Catalunya for a fellowship. We also thank PersonalChemistry AB for the use of their instrument.

References

1. (a) Victory, P. and Diago J., Contribution to the synthesis ofglutarimides, Afinidad, 35 (1978) 154–158.(b) Victory, P. and Diago J., Contribution to the synthesis ofglutarimides. II, Afinidad, 35 (1978) 161–165.(c) Victory, P., Nomen, R., Colomina, O., Garriga, M.and Crespo, A., New synthesis of pyrido[2,3-d]pyrimidines.1. Reaction of 6-alkoxy-5-cyano-3,4-dihydro-2-pyridones withguanidine and cyanamide, Heterocycles, 23 (1985) 1135–1141.(d) Victory, P., Teixidó, J., and Borrell, J. I., Heterocycles, 34(1992) 1905–1916.(e) Victory, P. and Borrell, J. I., ‘6-Alkoxy-5-cyano-3,4-dihydro-2-pyridones as Starting Materials for the Synthesisof Heterocycles’, in J. Menon (ed.), Trends in HeterocyclicChemistry, Vol. 3, Council of Scientific Research Integration,Trivandrum, India, 1993, pp. 235–247 and references therein.

2. Borrell, J. I., Teixidó, J., Martínez-Teipel, B.,Serra, B., Matallana, J. L., Costa, M., and Batllori,X., An unequivocal synthesis of 4-amino-1,5,6,8-tetrahydropyrido[2,3-d]pyrimidine-2,7-diones and2-amino-3,5,6,8-tetrahydropyrido[2,3-d]pyrimidine-4,7-diones, Collect. Czech. Chem. Commun., 61 (1996)901–909.

3. Borrell, J. I., Teixidó, J., Matallana, J. L., Martínez-Teipel, B., Colominas, C., Costa, M., Balcells, M.,Schuler, E. and Castillo, M. J., Synthesis and biologicalactivity of 7-oxo substituted analogues of 5-deaza-5,6,7,8-tetrahydrofolic acid (5-DATHF) and 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF), J. Med. Chem., 44 (2001)2366–2369.

4. Dihydrofolate reductases inhibitors:(a) Gangjee, A., Adair, O. and Queener, S. F., Pneumo-cystis carinii and Toxoplasma gondii dihydrofolate re-ductase inhibitors and antitumor agents: synthesis and biolo-gical activities of 2,4-diamino-5-methyl-6-[(monosubstitutedanilino)methyl]-pyrido[2,3-d]pyrimidines, J. Med. Chem., 42(1999) 2447–2455.(b) Gangjee, A., Vasudevan, A., Queener, S. F. andKisliuk, R. L., 2,4-Diamino-5-deaza-6-substituted pyrido[2,3-d]pyrimidine antifolates as potent and selective nonclas-sical inhibitors of dihydrofolate reductases J. Med. Chem.,39(1996), 1438–1446.Tyrosine kinase inhibitors:(c) Hamby, J. M., Connolly Cleo, J. C., Schroeder, M. C.,Winters, R. T., Showalter, H. D. H., Panek, R. L., Major,T. C., Olsewski, B., Ryan, M. J., Dahring, T., Lu, G. H.,Keiser, J. A., Aneesa, S. C., Kraker, A. J., Slintak, V., Nel-son, J. M., Fry, D. W., Bradford, L., Hallak, H. and Doherty,A. M., Structure-activity relationships for a novel series ofpyrido[2,3-d]pyrimidine tyrosine kinase inhibitors, J. Med.Chem., 40 (1997) 2296–2303.

5. Nasr, M. N. and Gineinah, M. M., Pyrido[2,3-d]pyrimidinesand pyrimido[5’,4’,5,6]pyrido[2,3-d]pyrimidines as new an-tiviral agents: Synthesis and biological activity, Arch. Pharm.,335 (2002) 289–295.

6. (a) Weber, L., Multi-component reactions and evolutionarychemistry, Drug Discov. Today, 7 (2002) 143–147.(b) Dömling, A., Recent advances in isocyanide-based mul-ticomponent chemistry, Current Opinion in Chemical Biology,6 (2002) 306–313.

7. Mont, N., Teixidó, J., Borrell, J. I. and Kappe, C. O., Athree-component synthesis of pyrido[2,3-d]pyrimidines, Tet-rahedron Lett., 44 (2003) 5385–5387.

8. For general references on microwave-assisted organic syn-thesis, see the following:(a) Hayes, B. L. Microwave Synthesis: Chemistry at the Speedof Light, CEM Publishing, Matthews, NC, 2002.(b) ‘Microwaves in Organic Synthesis’, A. Loupy (ed.), Wiley-VCH, 2002.(c) Lidström, P., Tierney, J., Wathey, B. and Westman, J., Mi-crowave assisted organic synthesis: A review, Tetrahedron, 57(2001) 9225–9283.(d) For more information on microwave-assisted organic syn-thesis, see: http://www.maos.net.

9. Schoffstall, A. M., Synthesis of 5,6-dihydropyrido[2,3-d]pyrimidine derivatives directly from acyclic precursors, J.Org. Chem., 36 (1971) 2385–2387.