Bismuth (III) nitrate catalyzed one-pot synthesis of 3,4-dihydro-pyrimidin-2-(1 H )-ones: an improved protocol for the Biginelli reaction

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Introduction
Dihydropyrimidinones (DHPMs) and their derivatives exhibit wide range of biological activities such as antibacterial, antiviral, antitumor and anti-inflamatory actions. 1 Biginelli compounds exhibit pharmacological activities as calcium channel blockers, antihypertensive agents, α -1aantagonists, and neuropeptide Y(NPY) antagonists. 2Several biologically active marine alkaloids were also found to contain the dihydropyrimidinone-5-carboxylate core. 3Most notable among them are batezelladine alkaloids, which have been found to be potent HIV gp-120-CD4 inhibitors. 4Consequently, syntheses of these compounds have gained importance.Biginelli (1893) reaction 5 is a simple one pot condensation of an aldehyde, ketoester and urea or thiourea in the presence of a catalytic amount of acid to produce 3,4-dihydropyrimidin-2-(1H)-ones and which often suffer from low yields, especially in the case of substituted aromatic and aliphatic aldehydes. 6Even though high yields could be achieved by following complex multi-step procedures, 7 these methods lack the simplicity of the original one-pot Biginelli protocol.Therefore, Biginelli reaction continues to attract attention of researchers searching for a milder and more efficient procedure for the synthesis of dihydropyrimidinones.
In recent years, several synthetic procedures for the preparation of DHPMs have been reported including classical conditions with microwave irradiation 8 and by using Lewis acids, as well as protic acids, as promoters.Such promoters as conc.HCl, 9 BF 3 •OEt 2 , 10a PPE, 10b KSF clay, 10c InCl 3 , 10d LaCl 3 , 10e,f lanthanide triflate, 10g H 2 SO 4 , 10h ceric ammonium nitrate (CAN), 10i Mn(OAc) 3 , 10j ion-exchange resin, 10k 1-n-butyl-3-methyl imidazolium tetrafluoroborate (BMImBF 4 ), 10l BiCl 3 , 10m LiClO 4 , 10n InBr 3 , 10o FeCl 3 , 10p ZrCl 4 , 10q Cu(OTf) 2 , 10r Bi(OTf) 3 , 10s LiBr, 10t ytterbium triflates, 10u NH 4 Cl, 10v SiO 2 /NaHSO 4 , 10x CdCl 2 , 10y etc. have been found to be effective.However, some of these methods require the use of toxic reagents in combination with Bronsted acids, such as hydrochloric acid and acetic acid, as additives.Many of these methods involve expensive reagents, stoichiometric amounts of catalysts, strongly acidic conditions, long reaction times, unsatisfactory yields and incompatibility with other functional groups.Therefore, the development of a neutral alternative would extend the scope of the Biginelli reaction.In view of this, we have utilized bismuth nitrate as an efficient catalyst for the Biginelli three-component one-pot synthesis in our laboratory.We are particularly interested in bismuth nitrate, because it is inexpensive and can be easily available in a laboratory.Bi(NO 3 ) 3 is an oxidizing agent which has a wide variety of utility in different chemical transformations, like bismuth nitrate catalyzed addition of amines, imidazoles and thiols to enones. 11We wish to report here a simple and efficient method for the synthesis of DHPMs using Bi(NO 3 ) 3 as a catalyst.

Results and Discussion
Initially, we have studied the Biginelli's one-pot condensation reaction of benzaldehyde (1.0 mmol) with urea (1.2 mmol) and ethyl acetoacetate (1.2 mmol) using 5-mol% of bismuth (III) nitrate in acetonitrile (5 ml) as solvent at ambient temperature (Scheme 1).The reaction is very fast and 90% conversion was observed in 1.5 h.

Scheme 1
Encouraged by these results, we examined several aromatic and aliphatic aldehydes under the optimized conditions (Table 1).It seems that acetonitrile is a much better solvent in terms of yields (93%) than all other tested solvents such as methanol (85%), dichloromethane (72%), tetrahydrofuran (55%), water (25%), H 2 O-THF (50%), toluene (32%).Furthermore, the use of just 5-mol% of bismuth (III) nitrate in acetonitrile is sufficient to promote the reaction.There are no improvements in the reaction rates and yields by increasing the amount of the bismuth (III) nitrate from 5-mol% to 10-mol%.The best results were achieved when the reactions were carried out at room temperature for 1.5-2.5 h in the presence of catalytic amount Bi(NO 3 ) 3 .The results are listed in Table 1.Another important feature of this procedure is the stability of a variety of functional groups, such as ether, hydroxy, halides, nitro, etc., under these reaction conditions.Most importantly, aromatic aldehydes carrying either electron-donating or electronwithdrawing substituents all reacted very well, giving excellent yields of products.Many of the pharmacologically relevant substitution patterns on the aromatic ring were introduced with high efficiency.Thiourea has been used with similar success to provide the corresponding dihydropyrimidin-2-(1H)-thiones in high yields, which are also of much interest with regard to biological activity.An acid sensitive aldehyde worked well without formation of any side product.Especially noteworthy is the survival of a variety of functional groups, such as ether, hydroxy, halides, nitro, double bond, etc., under the reaction conditions.

Conclusions
In summary, we have developed a new methodology for the synthesis of DHPMs by a threecomponent condensation in one pot using a catalytic amount of Bi(NO 3 ) 3 .By using Bi(NO 3 ) 3 as a catalyst at ambient temperature, the yields of the one-pot Biginelli reaction can be increased from 25-55% to 56-95% while the reaction time is shortened from 18 to 1-4 h.Thus, bismuth (III) nitrate mediated one-pot synthesis of DHPMs is a simple, high yielding, time saving, and eco-friendly process.