One-Pot Four Component Reaction of Unsymmetrical 1-Methylbarbituric Acid with Brcn and Various Aldehydes in the Presence of Et3n And/Or Pyridine

Home , Spiro compound

Journal of the Korean Chemical Society 2011, Vol. 55, No. 6 Printed in the Republic of Korea http://dx.doi.org/10.5012/jkcs.2011.55.6.940

One-pot Four Component Reaction of Unsymmetrical 1-Methylbarbituric Acid with BrCN and Various Aldehydes in the Presence of Et3N and/or Pyridine

Mohammad Jalilzadeh and Nader Noroozi Pesyan* Department of Chemistry, Faculty of Science, Urmia University, 57159, Urmia, Iran. *E-mail: [email protected], [email protected] (Received May 29, 2011; Accepted August 4, 2011)

ABSTRACT. Reaction of 1-methylpyrimidine-(1H,3H,5H)-2,4,6-trione (1-MBA 1) as an unsymmetrical barbituric acid with cyanogen bromide and various aldehydes in the presence of triethylamine and/or pyridine afforded diastereomeric mixtures of new class of heterocyclic stable 5-aryl-1,1'-dimethyl- and 5-aryl-3,1'-dimethyl-1H,1'H-spiro[furo[2,3-d]pyrimidine-6,5'- pyrimidine]2,2',4,4',6'(3H,3'H,5H)-pentaones which are dimeric forms of 1-methyl barbiturate at the range of 0 oC to room temperature. In the reaction of some aldehydes with 1-MBA and BrCN were afforded a mixture of diastereomers. Another two aldehydes such as 4-cyano- and 2-hydroxybenzaldehydes gave exclusively two diastereomers in which binded to the salt of triethylammonium hydrobromide by intermolecular H-bond in ratio of 1:1. 4-Hydroxybenzaldehyde and 2-pyridinecarbaldehyde gave exclusively one diastereomer under the same condition. Aldehydes possessing strong electron-donor were produced exclusively two geometric isomers of Knoevenagel adduct (E- and Z-isomers). The structures of compounds were deduced by 1H NMR, 13C NMR and FT-IR spectroscopy. Mechanism of the formation is discussed. Key words: 1-Methyl barbituric acid, Spiro barbiturate, Biological effect, Cyanogen bromide, Diastereomer

INTRODUCTION (DMBA) derivatives.25 On the other hand, although the cyanogen bromide is Many of heterocyclic furo[2,3-d]pyrimidines,1-5 spirobar- toxic but it is very useful reagent in organic synthesis.26,27 bituric acids6-9 and fused uracils10-12 are well known as It is a capable reagent for the synthesis of cyanamides,26 wide varieties of pharmaceutical and biological effects. cyanates,27 and also used to selective cleavage of the Barbituric acid reacted with cyanogen bromide in the methionyl peptide bonds in ribonuclease28 and etc. None- presence of pyridine derivatives as König reaction. In this theless this compound also is useful brominating and reaction, the pyridine derivative reacts with cyanogen bro- cyanating agent as; the bromination and cyanation of imi- mide and is afterwards coupled with an active methylene dazoles,29 free radical reaction with alkanes that result in to give a polymethine dye.13 For example; determinations bromination of alkanes30 and α-bromination of β-ami- of nikethamide14 and niacinamide15 by the reaction of bar- noenones.31 More recently, we have reported the reaction bituric acid and cyanogen bromide have been used. Bar- of (thio)barbituric acids (as a symmetrical barbituric acids) bituric acids and their 2-thio analogues, both substituted with aldehydes32 and ketones33 in the presence of cyan- and unsubstituted at nitrogens, were most often studied as ogen bromide and triethylamine. Nonetheless, there is no C-nucleophiles of pyrimidine character. Their reaction report about the reaction of 1-methylbarbituric acid (1- with carbonyl compounds, with aromatic or aliphatic alde- MBA) as an unsymmetrical barbituric acid with cyano- hydes gives rise to 5-aryl or 5-alkylmethylenebarbituric gen bromide and aldehydes in the literature. Based on acids commonly in a high yield.16,17 Barbituric acids can these concepts, in this research, we have investigated the also act as a nucleophile attack to the various electro- one-pot and four component reaction of 1-MBA with philes e.g. carbodiimides,18 benzophenone derivatives,19 cyanogen bromide and various aldehydes in the presence 2,2'-bipyridil to form 5,5'-(2-pyrilidine)bisbarbituric acid,20,21 of triethylamine and/or pyridine. 22 C60 molecules, erythrolactol to obtain spiro barbituric deoxyribonucleoside,23 to form spiro-linked condensed RESULTS AND DISCUSSION [1,2-a]quinolines24 and to form π-conjugated systems contain- ing barbituric acid (BA) and 1,3-dimethyl barbituric acid Herein, we describes the new one-pot reaction of 1-methyl

-940- One-pot Four Component Reaction of Unsymmetrical 1-Methylbarbituric Acid 941

Scheme 1. One-pot reaction of 1-MBA (1) with BrCN and various aldehydes (2a-s) in the presence of Et3N and/or pyridine (The chiral centers are assigned with an asterisk in 5 as representative). barbituric acid (1) as an unsymmetrical barbituric acid with cyanogen bromide and various aldehydes in the presence of Et3N and/or pyridine afforded diastereomeric mixtures of new class of stable heterocyclic spiro barbi- turates (Scheme 1). Representatively, the reaction of 1 with cyanogen bromide and benzaldehyde (2a) in the presence of triethylamine and/or pyridine in methanol afforded the salt of triethylammonium-5-bromo-2,4,6-trioxohexahydro-1-methylpyrimidin-5-ide (3) and/or pyridinium 5-bromo-1-methyl-2,4,6-trioxohexahydropyrimidin- 5-ide (4), respectively and diastereomeric mixtures max- imum of four new class of heterocyclic stable compounds (5S,5'S)-1,1'-dimethyl- (5a), (5S,5'R)-1,1'-dimethyl- (6a), (5S,5'S)-1',3-dimethyl- (7a) and (5S,5'R)-1',3-dimethyl-5- phenyl-1H,1'H-spiro[furo[2,3-d]pyrimidine-6,5'-pyrimi- 2. 3 4 dine]-2,2',4,4',6'(3H,3'H,5H)-pentaone (8a) in good yield, Scheme Proposed mechanism for the formation of and/or . respectively (and also their corresponding four enanti- omers) (Scheme 1). On the basis of the well established chemistry of barbi- As a part of our current studies on barbituric acids and turic acid35 it is reasonable to assume that the enol form of its reaction with cyanogen bromide 32-34 and our interest in 1 reacts directly with cyanogen bromide to form inter- the chemistry of cyanogen bromide we have investigated mediate A through intermediates triethylammonium- the unexpected bromination of 1 by cyanogen bromide. 2,4,6-trioxohexahydro-1-methylpyrimidin-5-ide (9) and/ The bromination of 1-MBA by cyanogen bromide is or pyridinium-2,4,6-trioxohexahydro-1-methylpyrimidin-5- unexpected and was resulted as salts of 3 and/or 4. We ide (10) (path a). Intramolecular rearrangement of this found that the bromination of 1-MBA in the presence of intermediate produces 5-bromo-1-methylpyrimidine-(1H, triethylamine and/or pyridine occurred smoothly with 3H,5H)-2,4,6-trione (11) followed by loss of HCN to form adding cyanogen bromide and produced the salts of 3 and/ the salts of 3 and/or 4 (obtained from triethylamine and or 4 in methanol at the range of 0 oC to room temperature pyridine as a base, respectively) according to similar bro- (Scheme 2). The schematic mechanism for the reaction mination of 1-alkyl-imidazoles with BrCN29 and bromi- between 1 and cyanogen bromide is depicted in Scheme 2. nation of symmetric (thio)barbituric acids.32,33 No 1-methyl-

2011, Vol. 55, No. 6 942 Mohammad Jalilzadeh and Nader Noroozi Pesyan

Scheme 3. Tautomeric and mesomeric forms of 10.

2,4,6-trioxohexahydropyrimidine-5-carbonitrile (12) and the salts of triethylammonium-5-cyano-2,4,6-trioxohexahydro-1-methylpyrimidin-5-ide (13) and/or pyridinium-5- cyano-1-methyl-2,4,6-trioxohexahydropyrimidin-5-ide (14) were observed (path b) (Scheme 2). The salt of triethylammonium hydrobromide was also observed. Unfortu- nately, all attempts failed to separate or characterize 9 and 11. In contrast, the intermediate salt of 10 was trapped as a pink solid precipitate, separated and characterized (Its 1. 1 13 lifetime is about five minutes in the solution of reaction Fig. H NMR (a) and C NMR spectra (b) of an equilibrium mixture of tautomers 10A-E. mixture and to be disappeared after formation during five minutes). 1H NMR spectrum of 10 shows a singlet at δ 2.06 ppm and a multiplet at the range of 2.94-3.13 ppm E- (15) and Z-isomers (16). Michael addition of 3 and/or 4 correspond to C5-H and methyl groups on barbituric acid to 15 and 16 obtained intermediates 17-24, respectively. ring moiety of the equilibrium mixture of 10A-E tau- Unfortunately, all attempts failed to separate or charac- tomers, respectively (Scheme 3). Two triplets at δ 8.08, terize these intermediates (17-24). Finally, intramolecular 8.60 ppm and a doublet at 8.93 ppm correspond to pyri- nucleophilic attack of oxygen anion to the carbon atom dinium ring moiety (Fig. 1a). The 13C NMR spectrum of (O-attack) afforded 5-8 in good yield. In this reaction, the 10 indicated the existence of at least four tautomers and salts of 3 and/or 4 and triethylammonium hydrobromide show four distinct peaks for methyl group on barbituric were also obtained (Schemes 1 and 4). 5-Bromo barbitu- acid ring moiety in aliphatic region (Fig. 1b). This com- ric acids such as 5-bromo-1,3-dimethylpyrimidine-(1H, pound shows an equilibrium mixture of different tau- 3H,5H)-2,4,6-trione, 28 (in Fig. 4) have been reacted with tomers (at least four tautomers) (Scheme 3). The isolation unsaturated carbon-carbon double bond and formed 5- and characterization of 10 confirms that it is an interme- spirobarbiturate system under basic condition.22,36 diate for the formation of 4 and also confirms the pro- Aldehydes possessing strong electron-donor substitu- posed mechanism in (Scheme 2). ents in the reaction with 1 and BrCN in basic media typ- The proposed mechanism for the formation of possible ically afforded only Knoevenagel products 15 and 16. We four diastereomers 5-8 is shown in Scheme 4. First, the performed this reaction with 4-dimethylamino benzalde- Knoevenagel condensation16,17 of 1 as an unsymmetric hyde (2n) and anthracen-9-carbaldehyde (2r) under the barbituric acid with aldehyde was afforded two geometric same condition and the corresponding Knoevenagel con-

Journal of the Korean Chemical Society One-pot Four Component Reaction of Unsymmetrical 1-Methylbarbituric Acid 943

8 (consists of eight stereoisomers). The carbon atoms C5 and C6 are of chiral centre and were assigned with asterisk in the formula structures of 5-8 (Scheme 1). The separation of each diastereomer from diastereomeric mixture was unsuccessful. The structures of diastereomeric mixture of 5-8 were characterized by their IR, 1H NMR, 13C NMR spectra (see experimental). Representatively, the 1H NMR spectrum of the diastereomeric mixtures of 5a-8a consists of at least three singlets at the range of δ 4-5 ppm for methine hydrogen on C5. This observation revealed that there are three diastereomers were formed with judg- ing to appearance of a singlet for C5-H in each isomer (The C5-H show a singlet in the similar spiro compounds derived from symmetric (thio)barbituric acids32) (Scheme 1 and Fig. 2). At least, three singlets at δ 4.96, 4.92 and 4.87 ppm with integration ratio of 1.0:4.4:2.8 were found and corresponded to three diastereomers among of 5a-8a (Fig. 2a). In the reaction of 2k three diastereomers were found and corresponding C5-H peaks were observed at δ 4.88, 4.85 and 4.83 ppm (Fig. 2b) and obviously, three distinct diastereomers also were obtained from the reaction of 2m under the same condition (Fig. 2c). In the reaction Scheme 4. Knoevenagel condensation, Michael addition and of 2f, exclusively one distinct diastereomer was obtained cyclization mechanism for the formation of possible four dias- (Fig. 2d). It seems the formation of diastereomers is not tereomers of 5-8. equal in 5a-8a, 5k-8k and 5m-8m as representative (Fig. 2). All attempts failed in results for the separation of each diastereomer due to their equal polarity, approximately by means of high performance liquid chromatography (HPLC) (Fig. 3). Nonetheless, the identification and clarification of each peak to corresponding diastereomeric structure was unsuccessful. Barbituric acids and their 2-thio analogs, both substituted and unsubstituted at nitrogens, were most often studied as C-nucleophiles of pyrimidine character. Their reaction with carbonyl compounds, with aromatic or aliphatic aldehydes gives rise to 5-aryl or 5-alkylmethylene barbituric acids in the absence of cyanogen bromide.17 5. Scheme Knoevenagel condensation of some aldehydes pos- Barbituric acids also give mono- and bis-condensation sessing strong electron donor substituents. products with aldehydes.38-42 Therefore, according to Scheme 2, the cyanogen bromide plays a major role in densation products only were found (the mixture of geo- these reactions32,33 through intermediate A and 11 to form metric isomers 15 and 16). The reason of this, was arose 3 and/or 4. We believe that the compound 3 and/or 4 is the from decreasing the Lewis acidity of vinyl group in 15 key reactant for the synthesis of 5-8. No 3, 4 and 5-8 were and/or 16 by strong electron donor ability of substituent observed in the absence of cyanogen bromide under the (Scheme 5).37 However, no explanation was offered for same condition. The experimental results indicated that the production of spiro adduct in 3,4,5-trimethoxybenzal- the yield of reaction in the presence of pyridine is higher dehyde (2k) case. than that of triethylamine. In comparison, the reactivity of The reaction of various aldehydes with 1 and cyanogen aromatic aldehydes turned out to be higher than that of ali- bromide afforded the racemic mixture of diastereomers 5- phatics. Also, the aromatic aldehydes possessing electron-

2011, Vol. 55, No. 6 944 Mohammad Jalilzadeh and Nader Noroozi Pesyan

Fig. 2. Expanded 1H NMR spectra of C5-H region in diastereomeric mixture of spiro compounds derived from 2a (a), 2k (b), 2m (c) and 2f (d) as representative (2f gave exclusively one diastereomer).

Fig. 3. HPLC chromatograms of the elution of diastereomeric mixture derived from 2k by the solvent mixture of DMSO:H2O (90:10, v:v) (a) and DMSO:H2O (10:90, v:v) (b). withdrawing substituent are more reactive than that of electron-donating substituent. Owing to the aromatic nature of BA (25) the nucleophile ability of 25 is less than that of DMBA (26) due to amide resonance dominates over the aromaticity in barbituric acids.21 Therefore, the nucleophilicity and reactivity of 1 is more than 25 and less than that of 26. The structures of (thio)barbituric acids (25-27) Fig. 4. Structures of (thio)barbituric acids (25-27), their some and their some derivatives (28-31) are shown in Fig. 4. derivatives (28-31), dimeric 1,1',3,3',5,5'-hexamethylspiro[furo More recently, we have investigated the reaction of [2,3-d]pyrimidine-6(5H),5'-pyrimidine]-2,2',4,4',6'(1H,3H,1'H,3'H,5'H)- pentaone (32),34 trimeric form of barbiturate (33),33,43-45 1,3-indan- symmetric barbituric acids 25-27 with cyanogen bromide 46 32 33 dione (34) and 5-alkyl- and/or 5-aryl spiro[furo[2,3-d]pyrimi- and various aldehydes and ketones in the presence of dine-6,5'-pyrimidine]2,2',4,4',6'(3H,3'H,5H)-pentaones (35a' and 32 Et3N. It has been found that the salts of 29-31, 5-alkyl- 35b') and their sulfur analog (35c').

Journal of the Korean Chemical Society One-pot Four Component Reaction of Unsymmetrical 1-Methylbarbituric Acid 945 and/or 5-aryl spiro[furo[2,3-d]pyrimidine-6,5'-pyrimidine]2, 2',4,4',6'(3H,3'H,5H)-pentaones (dimeric forms of barbiturate, 35a'-c')32 were formed in the reaction of 25-27 with aldehydes in the presence of cyanogen bromide and triethylamine (Fig. 4). And of trimeric form of barbiturate, 5,6-dihydro-l,3-dimethyl-5,6-bis-[l',3'-dimethyl-2',4',6'-tri- oxo-pyrimid(5',5')yl]furo[2,3-d]uracil (33) derived from DMBA 26 in the reaction with ketone in the presence of cyanogen bromide and triethylamine by new chemical method33 Dryhurst et al. reported the synthesis of 33 by electrochemical method 43-45. We also reported the crystal structure of dimeric barbiturate form (32) derived from the reaction of 26 with acetone in the presence of cyanogen bromide and triethylamine.33,34 Previously, the trimeric form of indandione (34) has also been reported by Barba et al. by cathodic reduction of 2,2-dibromo-1,3- 46 indandione in dichloromethane-Bu4NBF4. In contrast, in comparison of the reactivity of 1 with 26, in the present research, no trimeric diastereomers of 36-41 (possible trimeric model forms of 1) were found from the reaction of 1 with cyanogen bromide and triethylamine and/or pyridine under the same condition (Scheme 6 and Fig. 5). Our observations indicated that the salt of 31 plays a major role33 and its nucleophilicity is stronger than that of

Scheme 7. Possible tautomeric and mesomeric forms of 3, 4 and 29-31.32,33

3 (this aspect is similar to the property of the salt with pyridinium moiety, 4). The salt of 3 has semi-aromatic nature with tautomerization of the proton on nitrogen atom with two neighbor’s carbonyl groups while 31 have not. The Scheme 6. No trimeric forms of 1-MBA 1 (36-41) were found in the reaction with BrCN in comparison with DMBA 26.33 nucleophilicity should be decreased due to aromatic nature of pyrimidine ring moiety (Scheme 7).21,32,33 One of the most interesting phenomenons in this research is the binding of triethylammonium hydrobromide salt to some obtained spiro compounds derived from 2c, 2d, 2e and 2h by intermolecular H-bonding in ratio of 1:1. The 1H NMR spectra confirms the binding of triethylammonium hydrobromide salt to these spiro compounds. Rep- resentatively, this phenomenon is shown for spiro compounds derived from 2h in Fig. 6. First, one can unambiguously think that the salt of triethylammonium hydrobromide is of impurity into spiro compound therefore it was washed with methanol and then consequently with water twice. The mother liquid did not show the salt of triethylammo- 1 13 Fig. 5. Possible trimeric model diastereomers of 1. nium hydrobromide. The H and C NMR spectra of spiro

2011, Vol. 55, No. 6 946 Mohammad Jalilzadeh and Nader Noroozi Pesyan

Fig. 6. 1H NMR spectrum of the mixture of two diastereomers among of 5h-8h and the binding of Et3NHBr (Two diastereomers are assigned with A and A').

Fig. 8. 1H NMR (a) and 13C NMR spectra (b) of the formation of exclusively one distinct diastereomer among of 5f-8f.

and 2-pyridinecarbaldehyde (2q) with 1 and cyanogen bromide in the presence of triethylamine and/or pyridine exclusively were obtained one distinct diastereomer under the same condition! No triethylammonium hydrobromide salt was binded to these spiro compounds (Fig. 8 and see experimental section). However, no explanation was offered for this case. On the other hand, other spiro compounds did not show these behaviors. Fig. 7. 13C NMR spectrum of the mixture of two diastereomers The reaction of 2c, 2d, 2e and 2f with 1 in the presence among of 5h-8h and the binding of Et3NHBr. of BrCN and triethylamine is shown in Scheme 8. In the reaction of 2c with 1 the Knoevenagel condensation and compounds derived from 2h are shown in Figs. 6 and 7, consequently Michael adduct of 6-hydroxy-5-((6-hydroxy- respectively. Figs. 6 and 7 indicates the formation of only 1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)(2- two diastereomers equals in ratio, approximately (assigned nitrophenyl)methyl)-3-methylpyrimidine-2,4(1H,3H)-dione with A and A'). Fig. 6 also indicated the binding of tri- (42c) exclusively were found (yield 100%). The reaction ethylammonium hydrobromide salt to both diastereomers of 4-cyanobenzaldehyde (2d) with 1 were afforded exclu- (integration ratio of C5-H and C5'-H to methyl protons on sively one diastereomer as a minor product (spiro com- triethylammonium moiety is 0.92:9.0, respectively). Sur- pound assigned with B in Fig. 9, 34%) and also Michael prisingly, in the reaction of 4-hydroxybenzaldehyde (2f) adduct of 4-((6-hydroxy-1-methyl-2,4-dioxo-1,2,3,4-tet-

Journal of the Korean Chemical Society One-pot Four Component Reaction of Unsymmetrical 1-Methylbarbituric Acid 947

Scheme 8. Comparison of the reaction of 2c-f with 1 in the presence of BrCN and triethylamine (Hb: H-bonding, Hf: H-free in 42c-f).

Table 1. The effect of substituent in the reaction pathway for the formation of two different products Compd. Substituent Michael Product (%) Spiro product(s) (%) 42c o-NO2 100 0 42d p-CN 66 34 42e p-Br 30 70 42f p-OH 0 100

consequently followed spiro compounds while possessing of strong electron-withdrawing substituents obtain Michael adduct37 (42c, 100% versus 42f, 0% in Scheme 8 and Table 1). The only exception being 4-nitrobenzaldehyde (2b) that afford spiro adduct. However, no explanation was offered for the production of spiro adduct in the later case. Another most interesting phenomenon is shown in 42c that binded to triethylammonium salt moiety by intermo- Fig. 9. 1H NMR spectrum of one diastereomer (B) from among lecular H-bonding. Surprisingly, in this compound one of of 5d-8d and the binding of triethylammonium hydrobromide exchangeable proton appeared in extra low field at δ 16.2 salt. (This salt is binded to diastereomer that assigned with B as a minor product). ppm that indicating the intramolecular H-bonding (Scheme 8 and see experimental section). The eight-membered intramolecular H-bonding was observed in 42c-d. Recently, rahydropyrimidin-5-yl)(6-hydroxy-3-methyl-2,4-dioxo- the formation of some eight-membered intramolecular H- 1,2,3,4-tetrahydropyrimidin-5-yl)methyl)benzonitrile (42d) bonding has been reported.47 as a major product (66%) under the same condition (Scheme 8). The reaction of 4-bromobenzaldehyde (2e) with 1 were CONCLUSION obtained spiro compound (70% exclusively one diastereomer) in which binded to triethylammonium hydrobro- In summary, the reaction of 1-MBA as an unsymmet- mide salt in ratio of 1:1 and other Michael adduct as a rical BA with cyanogen bromide and various aldehydes in minor product, 5-((4-bromophenyl)(6-hydroxy-1-methyl- the presence of triethylamine was used to develop an effi- 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)methyl)-6- cient synthetic procedure to prepare new dimeric stable hydroxy-3-methylpyrimidine-2,4(1H,3H)-dione (42e, 30%) barbiturate diastereomers 1,1'-dimethyl- and 3,1'-dime- under the same condition (Scheme 8). All these obtained thyl-1H,1'H-spiro[furo[2,3-d]pyrimidine-6,5'-pyrimidine] results are summarized in Table 1. It seems that it has a 2,2',4,4',6'(3H,3'H,5H)-pentaones. The experimental results correlation between substituent effect and reaction path- indicated that the aromatic aldehydes are more reactive way. Aldehydes possessing of strong electron-donating than that of aliphatic. The aromatic aldehydes possessing substituents typically afford Knoevenagel products then strong electron-withdrawing substituent produced both

2011, Vol. 55, No. 6 948 Mohammad Jalilzadeh and Nader Noroozi Pesyan spiro compound(s) and Michael aduct (except 2-nitroben- from 5a-s through 8a-s, 15, 16 and 42 are follows. zaldehyde that exclusively produced Michael aduct). Alde- hydes possessing electron-donating substituent exclusively 5-Phenyl-1,1'-dimethyl-1H,1'H-spiro[furo[2,3-d]pyri- produced spiro compound(s). All the obtained spiro bar- midine-6,5'-pyrimidine]-2,2',4,4',6'(3H,3'H,5H)-pent- biturates were the racemic mixtures. Many of aldehydes aone (5a-8a) in the reaction with 1-methyl barbituric acid and cyano- In a 10 mL with Teflon-faced screw cap tube equipped gen bromide gave at least three diastereomers with excep- by a magnetically stirrer, dissolved 0.06 g (0.48 mmol) tion of 4-cyanobenzaldehyde and salicylaldehyde in which cyanogen bromide (BrCN), 0.15 g (0.96 mmol) 1-methyl gave two diastereomers. 4-Hydroxybenzaldehyde and 2- barbituric acid and 0.015 g (0.48 mmol) benzaldehyde in pyridinecarbaldehyde exclusively gave only one distinct 10 mL methanol and then 0.8 mL triethylamine was added diastereomer in detail. Triethylammonium salt moiety is into solution at 0 oC. The reaction mixture was stirred for binded to some these compounds by intermolecular H- 3 h at 0 oC to room temperature. (Caution! The cyanogen bonding. All of Michael adducts showed eight-membered bromide is highly toxic. Reactions should be carried out in intramolecular H-bond. a well-ventilated hood). The Teflon-faced screw cap tube prevented the vaporization of cyanogen bromide during EXPERIMENTAL SECTION the reaction time. The progression of reaction was monitored by thin layer chromatography (TLC). After a few General minutes, the crystalline white solid precipitate, filtered The drawing and nomenclature of compounds is pro- off, washed with few mL methanol and dried. (0.12 g, ceeded by ChemBioDraw Ultra 12.0 version software. 70% yield). The reaction procedure in the presence of Melting points were measured with a digital melting point pyridine (in place of triethylamine) was similar to trieth- apparatus (Electrothermal) and were uncorrected. IR ylamine. Initially, the salt of pyridinium 1-methyl-2,4,6- spectra were determined in the region 4000- 400 cm-1 on a trioxohexahydropyrimidin-5-ide (10) precipitated (its life NEXUS 670 FT IR spectrometer by preparing KBr pel- time is about 5 minutes) then disappeared with dissolving lets. The 1H and 13C NMR spectra were recorded on Bruker in the reaction mixture progression. White solid; m.p. 210 oC 300 FT-NMR at 300 and 75 MHz, respectively (Urmia (decomps.); FT-IR (KBr) 3407 (NH), 3200 (NH), 3038 University, Urmia, Iran). 1H and 13C NMR spectra were (CH-ar.), 2819 (CH-aliph.), 1707 (C=O), 1657 (C=O), 1536 -1 1 obtained on solution in DMSO-d6 and/or CDCl3 as sol- (C=C), 1438, 1376 cm ; H NMR (DMSO-d6, 300 MHz) vent using TMS as internal standard. The data are reported δ 2.49 (s, 3H, NMe), 3.32 (s, 3H, NMe, overlapped with as (s=singlet, d=doublet, t=triplet, q=quartet, m=multip- water of DMSO), 4.87, 4.92, 4.96 (3s, 1H, 3CH-aliph.), let or unresolved, bs=broad singlet, coupling constant(s) 7.10 (m, 2H, Ph), 7.29 (m, 3H, Ph), 11.13 (s, 1H, NH), 13 in Hz, integration). All reactions were monitored by TLC 11.90 (bs, 1H, NH); C NMR (DMSO-d6, 75 MHz) δ with silica gel-coated plates (AcOEt:AcOH/80:20/v:v). 166.2, 164.4, 159.1, 155.0, 151.0, 149.9, 134.8, 129.0, 128.5, The mass analysis performed using mass spectrometer 127.0, 90.5, 86.2, 56.8, 29.2, 27.3. (Agilent Technology (HP) type, MS Model: 5973 network Mass selective detector Electron Impact (EI) 70 eV), ion 1-Methylpyrimidine-(1H,3H,5H)-2,4,6-trione (1) source temperature was 230 ºC (Tehran University, Tehran, White solid; m.p. 132 oC; FT-IR (KBr) 3423 (NH), Iran). LC system: Agilent 1200-Series HPLC; column: 3194 (NH), 3084 (CH-ar.), 2922 (CH-aliph.), 2850 (CH- Zorbax-C18; follow rate: 1 ml/min; detector: Diode Array aliph.), 1759 (C=O), 1687 (C=O), 1455, 1376, 1356, 1281 -1 1 Detector (DAD); pump: Quaternary pump; temperature cm ; H NMR (DMSO-d6, 300 MHz) δ 3.03 (s, 3H, NMe), 13 fixed at 60 ºC by thermostatted compartment. Compounds 2.57 (s, 2H, COCH2CO), 11.30 (s, 1H, NH); C NMR 48 49 1 and cyanogen bromide was synthesized based on (DMSO-d6, 75 MHz) δ 167.4, 166.9, 152.3, 77.7, 27.3. reported references. Aromatic aldehydes, triethylamine, pyridine and used solvents purchased from Merck and Pyridinium 1-methyl-2,4,6-trioxohexahydropyrimi- Aldrich without further purification. din-5-ide (10) Violet solid, m.p. 224 oC (decomps.); FT-IR (KBr) 3437 General Procedures for the Preparation of 5a-s (NH), 3093 (CH-ar.), 2965 (CH-aliph.), 2802 (CH-aliph.), through 8a-s, 15, 16 and 42 1682 (C=O), 1622 (C=C), 1563 (C=C), 1487, 1440, 1383 -1 1 The physical and spectral data of the selected compounds cm ; H NMR (DMSO-d6, 300 MHz) δ 2.06 (s, 1H,

Journal of the Korean Chemical Society One-pot Four Component Reaction of Unsymmetrical 1-Methylbarbituric Acid 949

COCHCO), 2.94, 3.04, 3.06, 3.07, 3.08, 3.10 (s, 3H, NMe, 131.7, 131.4, 131.2, 130.6, 129.5, 122.2, 117.7, 91.1, 90.2, equilibrium mixture of six tautomers), 8.05 (t, 2H, J = 6.6 86.1, 55.6, 46.2, 32.5, 29.2, 27.4 (Mixture of one diaste- Hz, CH-ar.), 8.58 (t, 1H, J = 7.8 Hz, CH-ar.), 8.93 (d, 2H, J reomer of spiro compound (70%) and 42e (30%)). = 6.0 Hz, CH-ar.), 9.94, 10.33, 10.41, 11.44, 11.53, 11.72, 11.93 (s, 1H, NH, equilibrium mixture of six tautomers); 5-(4-Hydroxyphenyl)-1,1'-dimethyl-1H,1'H-spiro[furo 13 C NMR (DMSO-d6, 75 MHz) δ 168.5, 166.0, 162.0, 157.4, [2,3-d]pyrimidine-6,5'-pyrimidine]-2,2',4,4',6'(3H,3'H, 156.3, 152.1, 150.6, 148.0, 146.8, 143.7, 142.6, 127.7, 127.1, 5H)-pentaone (5f-8f) 85.7, 31.2, 28.1, 28.0, 26.8 (equilibrium mixture of six White solid; m.p. 335 oC (decomps.); FT-IR (KBr) 3434 tautomers). (OH), 3300 (NH), 3016 (CH-ar.), 2813 (CH-aliph.), 1706 (C=O), 1652 (C=O), 1517, 1447, 1374 cm-1; 1H NMR 5-(4-Nitrophenyl)-1,1'-dimethyl-1H,1'H-spiro[furo[2,3-d] (DMSO-d6, 300 MHz) δ 2.40 (s, 3H, NMe), 3.30 (s, 3H, pyrimidine-6,5'-pyrimidine]-2,2',4,4',6'(3H,3'H,5H)- NMe), 4.79 (s, 1H, CH-aliph.), 6.63 (d, 2H, J = 7.5 Hz, Ph), pentaone (5b-8b) 6.88 (d, 2H, J = 7.5 Hz, Ph), 9.49 (s, 1H, OH), 11.11 (s, 1H, o 13 White solid; m.p. 242 C (decomps.); FT-IR (KBr) 3426 NH), 11.86 (s, 1H, NH); C NMR (DMSO-d6, 75 MHz) δ (NH), 3020 (CH-ar.), 2816 (CH-aliph.), 1708 (C=O), 1657 166.3, 164.4, 164.1, 159.1, 158.0, 151.0, 150.0, 130.1, 124.7, -1 1 (C=O), 1528, 1441, 1353 cm ; H NMR (DMSO-d6, 300 115.2, 90.6, 86.5, 56.6, 29.2, 27.4 (Exclusively one dias- MHz) δ 2.37, 3.07, 3.15, 3.33 (4s, 6H, 2Me), 5.22, 5.26, tereomer). 5.27 (3s, 1H, 3CH-aliph.), 7.60-7.72 (m, 2H, Ph), 8.08-8.18 (m, 2H, Ph), 11.17, 11.35, 11.95, 13.07 (4s, 2H, 4NH). 5-(2-Hydroxyphenyl)-1,1'-dimethyl-1H,1'H-spiro[furo [2,3-d]pyrimidine-6,5'-pyrimidine]-2,2',4,4',6'(3H,3'H, 5-(4-Cyanophenyl)-1,1'-dimethyl-1H,1'H-spiro[furo 5H)-pentaone (5h-8h) [2,3-d]pyrimidine-6,5'-pyrimidine]-2,2',4,4',6'(3H,3'H,5H)- White solid; m.p. 310 oC (decomps.); FT-IR (KBr) 3438 pentaone (5d-8d) (OH), 3221 (NH), 3000 (CH-ar.), 2998 (CH-aliph.), 2812 White solid; m.p. 264 oC (decomps.); FT-IR (KBr) 3433 (CH-aliph.), 1700 (C=O), 1632 (C=O), 1588 (C=C), 1448, -1 1 (NH), 3050 (CH-ar.), 2229 (CN), 1702 (C=O), 1630 1381 cm ; H NMR (DMSO-d6, 300 MHz) δ 1.10 (t, 9H, -1 1 (C=O), 1465 cm ; H NMR (DMSO-d6, 300 MHz) δ 1.15 J = 6.9 Hz, 3CH3CH2NH), 2.48 (s, 3H, NMe), 2.80 (s, 3H, (t, 9H, J = 7.2 Hz, 3Me), 2.38 (s, 3H, NMe), 3.08 (s, 3H, NMe), 3.00 (q, 6H, J = 6.9 Hz, 3CH3CH2NH), 5.11, 5.24 NMe), 3.11 (q, 6H, NHCH2- Overlapped with water of (2s, 1H, 2CH-aliph.), 6.74-6.84 (m, 3H, Ph), 7.04 (t, 1H, J DMSO), 5.12 (s, 1H, CH-aliph.), 7.38 (d, 2H, J = 8.1 Hz, = 6.6 Hz, Ph), 8.87 (bs, 1H, NHEt3), 9.25, 9.29 (2s, 1H, Ph), 7.78 (d, 2H, J = 8.1 Hz, Ph), 9.0 (bs, 1H, NH of tri- 2OH), 11.11, 11.27 (2bs, 1H, 2NH); 13C NMR (DMSO- ethylammonium salt moiety), 10.39 (s, 1H, NH), 11.19 (s, d6, 75 MHz) δ 170.1, 169.0, 167.4, 166.5, 163.8, 163.7, 13 1H, NH); C NMR (DMSO-d6, 75 MHz) δ 165.9, 165.1, 163.0, 159.4, 152.7, 150.9, 150.8, 129.0, 128.8, 127.1, 164.7. 164.0, 162.7, 159.1, 152.0, 151.4, 151.0, 149.9, 140.8, 127.0, 124.4, 124.0, 121.1, 120.9, 109.2, 109.1, 90.3, 132.4, 131.9, 130.3, 128.2, 119.9, 119.0, 111.7, 107.6, 78.2, 54.9, 54.5, 46.0, 28.5, 28.1, 26.5, 26.4, 9.0 (mixture 90.8, 90.1, 86.0, 55.4, 46.2, 33.4, 29.3, 27.3, 9.1 (Mixture of two diastereomers binded to triethylammonium hydro- of exclusively one diastereomer binded to triethylammo- bromide salt moiety). nium hydrobromide salt (34%) and 42d (66%)). 5-(4-Hydroxy-3-methoxyphenyl)-1,1'-dimethyl-1H, 5-(4-Bromophenyl)-1,1'-dimethyl-1H,1'H-spiro[furo 1'H-spiro[furo[2,3-d]pyrimidine-6,5'-pyrimidine]-2,2', [2,3-d]pyrimidine-6,5'-pyrimidine]-2,2',4,4',6'(3H,3'H, 4,4',6'(3H,3'H,5H)-pentaone (5i-8i) 5H)-pentaone (5e-8e) Yellow solid; m.p. 268 oC (decomps.); FT-IR (KBr) White solid; m.p. 251 oC (decomps.); FT-IR (KBr) 3406 3454 (OH), 3200 (NH), 3019 (CH-ar.), 2814 (CH-aliph.), (NH), 3051 (CH-ar.), 2868 (CH-aliph.), 2816 (CH-aliph.), 1733 (C=O), 1707 (C=O), 1650 (C=O), 1518, 1442, 1377, -1 1 1736 (C=O), 1706 (C=O), 1658 (C=O), 1589 (C=C), 1526, 1274 cm ; H NMR (DMSO-d6, 300 MHz) δ 2.39 (s, 3H, -1 1 1459, 1375 cm ; H NMR (DMSO-d6, 300 MHz) δ 2.47 NMe), 3.00 (s, 3H, NMe), 3.66 (s, 3H, OMe), 4.80 (s, 1H, (s, 3H, NMe), 3.04 (s, 3H, NMe), 4.95 (s, 1H, CH-aliph.), CH-aliph.), 6.47 (d, 1H, J = 5.7 Hz, Ph), 6.64 (d, 2H, J = 7.08 (m, 2H, Ph), 7.47 (m, 2H, Ph), 10.30 (bs, 1H, NH), 6.6 Hz, Ph), 9.09 (s, 1H, OH), 11.11 (s, 1H, NH), 11.85 13 13 11.13 (s, 1H, NH); C NMR (DMSO-d6, 75 MHz) δ 166.1, (bs, 1H, NH); C NMR (DMSO-d6, 75 MHz) δ 166.4, 165.1, 164.5, 164.1, 159.1, 151.4, 151.0, 149.9, 144.7, 134.4, 164.4, 164.1, 159.1, 151.0, 150.1, 147.6, 147.3, 125.1,

2011, Vol. 55, No. 6 950 Mohammad Jalilzadeh and Nader Noroozi Pesyan

121.6, 115.5, 113.2, 90.7, 86.3, 56.1, 29.2, 27.5. White solid; m.p. 272 oC (decomps.); FT-IR (KBr) 3433 (NH), 3186 (NH), 3046 (CH-ar.), 2793 (CH-aliph.), 1721 5-(3-Hydroxy-4-methoxyphenyl)-1,1'-dimethyl-1H, (C=O), 1653 (C=O), 1515, 1378 cm-1; 1H NMR (DMSO- 1'H-spiro[furo[2,3-d]pyrimidine-6,5'-pyrimidine]-2,2', d6, 300 MHz) δ 2.40 (s, 3H, NMe), 3.30 (s, 3H, NMe), 4,4',6'(3H,3'H,5H)-pentaone (5j-8j) 4.84 (s, 1H, CH-aliph.), 7.20 (m, 1H, Pyr.), 7.30 (m, 1H, Yellow solid; m.p. 210 oC (decomps.); FT-IR (KBr) Pyr.), 7.73 (m, 1H, Pyr.), 8.43 (s, 1H, Pyr.), 11.21 (s, 1H, 13 3600 (OH), 3446 (NH), 3206 (NH), 3016 (CH-ar.), 2819 NH), 11.96 (s, 1H, NH); C NMR (DMSO-d6, 75 MHz) δ (CH-aliph.), 1707 (C=O), 1654 (C=O), 1516, 1445, 1379 166.3, 164.7, 164.0, 159.3, 154.8, 151.0, 150.0, 149.3, -1 1 cm ; H NMR (DMSO-d6, 300 MHz) δ 2.43 (s, 3H, NMe), 137.3, 123.84, 123.78, 89.4, 85.3, 58.7, 29.2, 27.4 (Exclu- 2.47 (s, 3H, NMe), 3.71 (s, 3H, OMe), 4.74 (s, 1H, CH- sively one diastereomer). aliph.), 6.47 (s, 2H, Ph), 6.78 (s, 1H, Ph), 8.96 (s, 1H, OH), 11.15 (s, 1H, NH), 11.85 (s, 1H, NH); 13C NMR (DMSO- (E)-(15r) and (Z)-5-(Anthracen-9-ylmethylene)-1- d6, 75 MHz) δ 166.4, 164.3, 164.1, 159.1, 151.0, 150.0, methylpyrimidine-2,4,6(1H,3H,5H)-trione (16r) 148.3, 146.6, 127.0, 119.9, 115.9, 112.0, 90.6, 86.5, 56.6, Red solid; m.p. 303 oC (decomps.); FT-IR (KBr) 3188 56.1, 29.2, 27.5. (CH-ar.), 3056 (CH-ar.), 2857 (CH-aliph.), 1706 (C=O), 1675 (C=O), 1582 (C=C), 1444, 1379 cm-1; 1H NMR (DMSO- 5-(3,4,5-trimethoxyphenyl)-1,1'-dimethyl-1H,1'H-spiro d6, 300 MHz) δ 2.89 (s, 3H, NMe), 3.26 (s, 3H, NMe), [furo[2,3-d]pyrimidine-6,5'-pyrimidine]-2,2',4,4',6'(3H, 7.50 (t, 4H, J = 7.8 Hz, Anthranyl), 7.92 (t, 2H, J = 7.5 Hz, 3'H,5H)-pentaone (5k-8k) Anthranyl), 8.11 (d, 2H, J = 8.1 Hz, Anthranyl), 8.64 (s, White solid; m.p. 294 oC (decomps.); FT-IR (KBr) 3432 1H, Anthranyl), 9.00, 9.01 (2s, 1H, 2CH=C), 11.29 (s, 1H, 13 (NH), 3009 (CH-ar.), 2841 (CH-aliph.), 1706 (C=O), 1653 NH), 11.74 (s, 1H, NH); C NMR (DMSO-d6, 75 MHz) δ -1 1 (C=O), 1124 cm ; H NMR (DMSO-d6, 300 MHz) δ 2.39 162.6, 161.7, 160.6, 160.0, 152.4, 152.3, 151.32, 151.27, (s, 3H, NMe), 3.06 (s, 3H, NMe), 3.14 (s, 3H, NMe), 3.61 131.0, 130.1, 129.9, 129.1, 128.3, 128.1, 128.0, 126.7, 126.0, (s, 3H, OMe), 3.67 (s, 6H, 2OMe), 4.83, 4.85, 4.88 (3s, 125.7, 28.1, 27.3 (Mixture of two Z- and E-isomers). 1H, 3CH-aliph.), 6.42 (s, 2H, Ph), 11.13, 11.32, 11.88, 13 13.00 (4s, 2H, 2NH); C NMR (DMSO-d6, 75 MHz) δ 167.0, 6-Hydroxy-5-((6-hydroxy-1-methyl-2,4-dioxo-1,2,3,4- 166.2, 166.1, 164.4, 163.7, 163.1, 159.6, 159.1, 152.9, tetrahydropyrimidin-5-yl)(2-nitrophenyl)methyl)-3- 151.3, 151.0, 150.2, 138.2, 130.4, 130.3, 130.1, 107.0, methylpyrimidine-2,4(1H,3H)-dione (42c) 106.6, 90.1, 85.8, 85.3, 84.8, 60.4, 57.1, 56.4, 29.2, 28.6, White solid; m.p. 282 oC (decomps.); FT-IR (KBr) 3200 27.5, 27.3 (Mixture of three diastereomers). (NH), 3068 (CH-ar.), 2993 (CH-aliph.), 1690 (C=O), 1610 -1 1 (C=C), 1527, 1461, 1363 cm ; H NMR (DMSO-d6, 300 5-(4-Methoxyphenyl)-1,1'-dimethyl-1H,1'H-spiro[furo MHz) δ 1.15 (t, 9H, J = 7.2 Hz, 3CH3-CH2NH), 3.03 (s, 6H, [2,3-d]pyrimidine-6,5'-pyrimidine]-2,2',4,4',6'(3H,3'H, 2NMe), 3.09 (q, 6H, J = 7.2 Hz, 3CH3-CH2NH), 6.18 (s, 5H)-pentaone (5m-8m) 1H, CH-aliph.), 7.23 (m, 2H, Ph), 7.42 (m, 2H, Ph), 8.80 o White solid; m.p. 234 C (decomps.); FT-IR (KBr) 3435 (bs, 1H, Et3NH), 10.28 (s, 2H, 2NH), 16.20 (bs, 1H, OH); 13 (NH), 3055 (CH-ar.), 2845 (CH-aliph.), 1705 (C=O), 1657 C NMR (DMSO-d6, 75 MHz) δ 164.4, 162.6, 151.4, 150.3, -1 1 (C=O), 1514, 1446, 1371 cm ; H NMR (DMSO-d6, 300 138.0, 131.1, 130.0, 126.5, 123.6, 90.4, 46.2, 30.9, 27.2, MHz) δ 2.37, 2.39 (2s, 3H, 2NMe), 3.06, 3.10 (2s, 3H, 9.1 (Triethylammonium salt moiety binded to 42c). 2NMe), 3.72 (s, 3H, OMe), 4.82, 4.87, 4.92 (3s, 1H, 3CH- aliph.), 6.83 (d, 2H, J = 7.5 Hz, Ph), 6.98-7.10 (m, 2H, Ph), Acknowledgements. We gratefully acknowledge finan- 11.09, 11.11, 11.30, 11.86, 12.95 (5s, 2H, NH); 13C NMR cial support by the Research Council of Urmia University (DMSO-d6, 75 MHz) δ 166.5, 166.3, 164.2, 159.8, 159.1, (Grant Research no. #9-10523). The authors also grate- 151.0, 150.0, 130.6, 130.2, 127.1, 126.6, 113.9, 85.2, 56.3, fully acknowledge to Prof. Dr. Dabbagh H. A. of Isfahan 55.6, 55.5, 29.2, 28.6, 27.4, 27.2 (Mixture of three dias- University of Technology (IUT) from Iran for his helpful tereomers). discussion and guidance.

5-(2-Pyridinyl)-1,1'-dimethyl-1H,1'H-spiro[furo[2,3-d] Supplementary data: Full characterization data of dias- pyrimidine-6,5'-pyrimidine]-2,2',4,4',6'(3H,3'H,5H)- tereomers among 5a-s through 8a-s and 15n, 15r, 16n, pentaone (5q-8q) 16r are available.

Journal of the Korean Chemical Society One-pot Four Component Reaction of Unsymmetrical 1-Methylbarbituric Acid 951

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