An enantioselective approach to the Biginelli dihydropyrimidinone condensation reaction using CeCl 3 and InCl 3 in the presence of chiral ligands

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Introduction
In recent times, dihydropyrimidinone derivatives have attracted considerable attention owing to their high activity as antihypertensive, antiviral, antitumor and anti-inflammatory agents, and as calcium channel blockers. 1The original procedure for the preparation of this type of compounds was reported by Biginelli in 1893, involving one-pot condensation of ethyl acetoacetate (1), benzaldehyde (2), and urea (3) under strongly acidic conditions (Scheme 1). 2  A serious limitation of this protocol is that it produces low yields of the desired heterocycle when substituted aromatic and aliphatic aldehydes are used.Of course, the original Biginelli methodology does not have any enantiocontrol during formation of the new stereocenter. 3lthough in the last years the development of alternative multi-step strategies to produce higher overall yields of the dihydropyrimidonone heterocycle has been met with success, 4 the art of performing efficient enantioselective coupling of three or more components in a single operation still represents a fundamental target in modern organic synthesis. 5harmacological studies concerning the structure-activity relationship for various dihydropyrimidinones have established that calcium channel modulation (antagonist vs agonist activity) depends on the absolute configuration in C(4) (Scheme 2).For this reason, the control of the stereochemistry of the substituent at C(4) has essential importance since it acts like a molecular gear of chiral regulation during drug-receptor recognition. 6Nevertheless, the absence of any general asymmetric synthesis of this heterocyclic system, chemical resolution and enzymatic strategies have been the most practical methods to obtain enantiomerically pure dihydropyrimidinone derivatives. 7ecently, cerium(III) chloride and indium(III) chloride have emerged as powerful catalysts imparting high regio-and chemoselectivity in various chemical transformations. 8Here we wish to report in full detail the development of conditions for performing enantioselective Biginelli condensation reactions catalyzed with InCl 3 or CeCl 3 in the presence of chiral ligands.

Results and Discussion
Our initial attempts focused on the use of Lewis acids such as Ce(III) and In(III) as activators of the Biginelli reaction for the preparation of dihydropyrimidinones such as compound 6 in racemic form.For this goal, we explored the effect of both equimolar and catalytic amounts of the Lewis acid.Furthermore, two different solvents were tested in order to find the best Lewis acid/solvent combination in terms of efficiency of the reaction.The results obtained in these preliminary experiments are shown in Table 1.1).(2) In toluene, the Biginelli condensation proceeds in slightly lower yields relative to THF solvent.Also, increased reaction times are required to achieve complete consumption of the starting materials.(Compare for example, entries 5 and 6 in Table 1).In toluene, the lower yields attained with both Lewis acids are presumably due to lower solubility of the chloride salts.(3) Comparison of entries 1 and 2, 3 and 4, 5 and 6, and 7 and 8 (diminution of the amount of Lewis acid to 20 %) confirmed that the process could be performed under catalytic conditions.Of course, this proved to be an advantage when chiral ligands were used.(See below).
Once we had established suitable conditions for the Biginelli reaction promoted by CeCl 3 and InCl 3 , and taking into account that one of the useful methodologies in asymmetric synthesis is based on the use of chiral ligands, we decided to use chiral amines 7-9 and amide 10 incorporating the (S)-α-phenylethylamino group 9,10 in order to explore the potential stereoinduction in this reaction.(-)-Sparteine was also included as chiral test ligand in this reaction since this chiral diamine has received considerable attention in the area of enantioselective synthesis (Scheme 3). 11Based on the results obtained in our initial studies (see Table 1), we decided to use THF as solvent and 20% of the Lewis acid as activator, as well as 20% of the chiral ligands.The results obtained in this reactions are shown in Table 2.   Table 2 collects the results of the Biginelli condensation in the presence of chiral ligands 7-11.The enantioselectivities were generally poor, presumably because of the high temperature required for the reaction (70 o C).In some cases (see, entries 1-3 and 6-8 in Table 2), the reaction yields were low, probably because a side reaction between benzaldehyde and the aminocontaining chiral ligands affords the corresponding iminium ion, that inhibits the mechanism operative for the desired reaction.Support for this lateral reaction (Scheme 4) was gained from 13 C NMR examination of a mixture of benzaldehyde and chiral ligand (S)-7 in THF with InCl 3 as activator.The formation of compound 12 seems to be confirmed by the appearance of a signal at δ = 163.8ppm, which is reasonable for the iminium carbon. 13n the other hand, the enantioselectivities and yields improved slightly when the condensation reaction was carried out in the presence of triamide (S,S,S)-10 and (-)-sparteine 11 (entries 4-5 and 9-10 in Table 2. Interestingly, triamide (S,S,S)-10 provided the best yields and enantioselectivities in comparison with other amine ligands, including (-)-sparteine.

O
We then decided to explore the use of other chiral ligands that would not be prone to iminium ion formation (Scheme 5).The results obtained with these ligands are shown in Table 3.The experiments performed with chiral ligands, 13-15 afforded good efficiencies both with regard the yield of 6, as well as a moderate increase in the enantioselectivity of the reaction.(In particular, entries 4, 6, 10 and 12 in Table 3 compare favorably with most enantiomeric relations presented in Table 2).Interestingly, the enantioselectivities observed in both THF and toluene solvents were quite similar.Looking for another alternative to increase the enantiomeric excess of the reaction, benzylidene urea 16, presumably one of key intermediates in the mechanism, 17 was synthesized according to the reaction shown in Scheme 6.Furthermore, in order to carry out the condensation reaction at low temperature, preformation of the enolate derived from methyl acetoacetate was accomplished by use of Lewis acids.The subsequent reaction between freshly prepared enolate 17 with the chiral ligands 13 and 14 at low temperature was anticipated to facilitate the transfer of the chiral information, necessary to make the process enantioselective.It was expected that the addition of benzyldene urea 16 to the preformed enolate 17 could, under kinetic control, increase the enantioselectivity of the overall process (Scheme 7).The results of this modification are collected in Table 4.The enantiomeric ratios obtained by this experimental modification (Table 4) reveal that stereoselectivity is indeed higher when the temperature of the reaction is lower (compare entries 1, 3, 5 and 7 with entries 2, 4, 6 and 8 in Table 4).Although this experimental modification to the normal Biginelli conditions presents some disadvantages such as longer reaction times, the encouraging enantiomeric excesses (up to 40 % ee in entry 1, Table 4), pave the road for further improvements in this important reaction.

Conclusions
CeCl 3 and InCl 3 Lewis acid activators can efficiently catalyze the Biginelli condensation reaction, both in THF and toluene as solvent.The use of chiral ligands 7-9, incorporating active amino groups, did not induce good enantioselectivities in the product, and actually proceeded in low yield owing to undesired condensation of the ligand with benzaldehyde.When the reaction was performed with chiral ligands 10-15, it was possible to improve the enantiomeric excesses to values in the 18 to 28 % ee range.An experimental modification based in the preformation of the key precursors and subsequent reaction under kinetic control (low temperature) gave enantiomeric excesses as high as 40 %.This modification of the Biginelli condensation reaction offers a promising alternative for the preparation of enantiomerically enriched dihydropyrimidinones. General procedure for the synthesis of dihydropyrimidinone 6 by the modified Biginelli protocol.A solution of methyl acetoacetate (260 mg, 2 mmol) in 15 mL of anhydrous THF was placed in a round bottom flask, treated with 2 mmol of InCl 3 and was stirred at 70 o C for 1 h.Following this, the chiral ligand (2 mmol) dissolved in 2 mL of the same solvent was added dropwise.The reaction mixture was stirred for 30 minutes at room temperature and then left standing at -78 o C for 30 min.At this point, benzylidene urea 16 (0.3 g, 2 mmol) suspended in 10 mL of the same solvent was slowly added to the indium enolate.The reaction is allowed to 12

Experimental Section
Determination of the absolute configuration and measurement the enantiomeric purity of dihydropyrimidinone 6.The determination of the enantiomeric excess was performed by means of HPLC, which was standardized and validated with the data reported by Kappe et al. 7c The separation of the corresponding enantiomers was obtained with a chiral column Chirobiotic T and using a mixture of acetonitrile:water (70:30) as mobile phase with 1.0 flow of ml/min.The retention time of the (R) enantiomer was 3.20 min and the retention time of for the (S) enantiomer was 5.35 min.

Scheme 3 .
Scheme 3. Chiral ligands used in this work.

Scheme 4 .
Scheme 4. Formation of iminium ion (S)-12 in the reaction of benzaldehyde with chiral amine (S)-7 in the presence of InCl 3 Lewis acid.

Scheme 5 .
Scheme 5. Additional chiral ligands used in this work.

Table 1 .
Solvent and Lewis acid effect on the yield of the racemic dihydropyrimidinone 6

Table 2 .
Enantioselectivity in the asymmetric Biginelli reactions promoted by CeCl 3 or InCl 3 and chiral ligands 7-11 a Quantified by HPLC.b)The assignment of the absolute configuration was carried out by comparison with the retention times reported in ref.12.

Table 3 .
Asymmetric Biginelli reaction in the presence of chiral ligands 13-15 a Quantified by HPLC.bThe assignment of the absolute configuration was carried out by comparison with the retention times reported in ref.12.

Table 4 .
Enantioselectivity and yields of modified Biginelli reaction in the presence of chiral ligands 13 and 14 a Quantified by HPLC.bThe assignment of the absolute configuration in product 6 was carried out by comparison with retention time data reported in ref.12.
18ocedures.All reactions were carried out with reagent grade solvents.Commercially available reagents were used without further purification.CeCl 3 and InCl 3 were dried at 130 o C at 25 mmHg for 3 h.Melting points were obtained on a melting point apparatus with capillary tubes and are uncorrected.1HNMRand13CNMRspectrawere recorded on 400 MHz for 1 H, 100 MHz for 13 C) NMR spectrometers in DMSO-d 6 solutions.Chemical shifts are given as δ values (ppm) and coupling constants (J) in Hz.HPLC: instrument fitted with UV-Vis detector and a chiral stationary phase of chirobiotic T for the determination of the enantiomeric ratios.THF or toluene was heated at 70 °C in the presence of 20 mol % of the Lewis acid under nitrogen atmosphere until consumption of the methyl acetoacetate and benzaldehyde reagents (between 12-24 h).Following this, the reaction was left standing at room temperature and then at 0 o C until formation of a precipitate that was filtered and recrystallized from hot ethanol and washed with 20 mL of cold water to give the pure product 6 (494 mg, 92% yield), mp.211-212 °C (lit.1amp.209-212°C).-toluensulfonic acid in 40 mL of toluene.The reaction mixture was heated for 4 h until no additional water formation was observed.The reaction mixture was concentrated and the resulting solid was filtered to give 1,04 g (77 % yield) of the desired product 16, with mp.202-205 o C. (lit.18mp.204-205 o C).This product was dried in the oven with vacuum during 4 h (50 o C at 20 mmHg) before its use.IR (KBr) 3440, 3300, 1677, 1450, 1381, 1315, 1145, 1052, 866 cm -1 . 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.8 (s, 5H), 6.8 (d, J = 8 Hz, 2H), 3.4 (s, 1H).DMSO-d 6 , 100 MHz): δ 160.3, 158.3, 143.1, 128.7, 127.6, 126.5.