Superparamagnetic Iron Oxide as an Efficient Catalyst for the One-Pot , Solvent-Free Synthesis of 5 , 5-Disubstituted Hexahydropyrimidines and Their Spiro Analogues

Superparamagnetic Fe3O4 is shown to act as a very efficient catalyst for the one-pot, three-component synthesis of 5,5-disubstituted hexahydropyrimidines and their spiropiperidines. e catalyst is easily recovered by the use of an external magnet and reused in several reactions without any noticeable loss of activity. e products are obtained in short time and good purity upon separation of the catalyst and evaporation of the volatiles of the reaction mixture.


Introduction
Hexahydropyrimidines are biologically important.N,N-Bisarylhexahydropyrimidines are effective against Ehrlichcarcinoma, LK lymphoma, and Staphylococcus aureus [1,2].e hexahydropyrimidine skeleton occurs in alkaloids such as verbamethine and verbametrine [3].N-Substituted hexahydropyrimidines are synthetic intermediates for recently discovered spermidine-nitroimidazole drugs for the treatment of A549 lung carcinoma [4] and structural units in new trypanothion ereductase inhibiting ligands for the regulation of oxidative stress in parasite cells [5].Benzo-fused hexahydropyrimidines or 1,2,3,4-tetrahydroquinazolines are potential R-adrenergic blockers [6] and possess antiplatelet activity [7].Hexahydropyrimidines are prepared classically by condensations of substituted propane-1,3-diamines with aldehydes and ketones [8,9].Liang and coworkers synthesized this type of compounds using cyclic ketone, amine, and formaldehyde [10].ere are also a few reports in literature describing the synthesis of hexahydropyrimidine derivatives either by using lewis acids and heteropolyacid as catalyst [11,12].In recent years multicomponent reactions (MCR) have become a powerful tool for atom efficient and waste-free synthesis of complex building blocks of "drug-like" motifs [13,14].Generally MCR strategy affords time and cost advantageous, environmentally benign pathways leading to the synthesis of a library of compounds.
In this letter, we report the multicomponent treaction of 1,3-dicarbonyl compounds, amines, and formaldehyde react in one step in the presence of superparamagnetic Fe 3 O 4 particles at 80 ∘ C (Scheme 1).e Fe 3 O 4 NPs were prepared as reported in the literature [15].
Although this important carbon-carbon bond forming reaction has witnessed much recent progress, [16][17][18][19][20] there are still demands for the development of efficient procedures involving inexpensive, recyclable catalytic systems under solvent-free conditions.

Results and Discussion
Table 1 summarizes the results of the Fe 3 O 4 -catalyzed reaction of 1,3-dicarbonyl compounds, amines, and formaldehyde.Initial experiments were carried out under solvent-free conditions involving the reaction of ethylacetoacetate,aniline and formaldehyde, at 80 ∘ C catalyzed by Fe 3 O 4 (Table 1) [12].
A series of catalysts were reported with the standard reaction of ethylacetoacetate, aniline, and formaldehyde.e results are depicted in Table 2.Among various Lewis acids  including different metal salts [13,14], Fe 3 O 4 was found to be the best catalyst (yield 90%, Table 1, entry 1) for the reaction.
In the presence of strong acid like HCl only trace amount of the product was detected in TLC.is could be due to decomposition of the product in the presence of strong acid.Complete disappearance of the aniline and formation of the product were monitored by TLC.e use of various amounts of the Lewis acid was investigated to optimize the reaction conditions.A catalytic quantity of Fe 3 O 4 (10 mol %) proved to be effective for complete conversion of the starting materials to the desired product 4a within 2.5 h(entry 1).e use of lower amounts of the catalyst (down to 2 mol%) prolonged the reaction time up to 5 h whilst still giving an almost quantitative yield of 4a.Omission of Fe 3 O 4 from the reaction medium led to formation of only trace quantities of 4a aer several hours indicating the crucial role of the catalyst.Similar reactions of ethylacetoacetate with other amines were conducted under the same conditions affording high yields of the respective products within the same time period.Other aromatic amines bearing electron-releasing groups reacted equally well with various 1,3-dicarbonyl compounds under the same conditions (entries 2-11).Upon completion of the reactions, the catalyst was recovered from the reaction mixture simply by applying an external permanent magnet and the products were isolated in good purity by removing the volatiles under reduced pressure.Further, the recovered Fe 3 O 4 was reused successfully in 10 subsequent reactions without signi�cant loss of catalytic performance.
e stoichiometric ratio of 1 : 2 : 3 (1,3-dicarbonyl compound: amine: formaldehyde) in the presence of 10 mol % of Fe 3 O 4 in solvent-free condition at 80 ∘ C was found to be the optimum condition for the maximum yield of hexahydropyrimidines.Under these reaction conditions, T 3: Synthesis of bis-spiropiperidines using dimedone, aromatic amines, and formaldehyde.the product 4a was obtained in a very good yield of 90% in 2.5 h.Aer the standardization of the reaction condition, a variety of b-keto esters and 1,3-dicarbonyl compounds like methylacetoacetate, ethylacetoacetate, allylacetoacetate, and 1-benzoyl acetone were used.A tentative mechanism for the reaction is proposed in Scheme 2. e 1,3-diketone or -keto ester undergoes twice -aminomethylation reactions in succession on the same -carbon of carbonyl-catalyzed by Fe 3 O 4 .e condensation of the resulting substituted propane-1,3-diamine with formaldehyde furnishes the desired spirohexahydropyrimidine.Using Mannich bases instead of -keto estersas reactants can also generate the desired products.Here the acidic nature of Fe 3 O 4 may facilitate both the enolization steps of the 1,3-diketone or -ketoestr.

Entry
When dimedone was used as 1,3-dicarbonyl compound instead of hexahydropyrimidines, spiro-substituted piperidines were obtained (Scheme 3) with the same methodology.One of the advantages of this methodology is that 3methylaniline also gives the desired product (Table 3, entry 2) which was not possibly using the methodology of Kozlov and Kadutskii [21].is may happen due to the high reactivity of dimedone.Here maximum yield of the piperidine compound was obtained when dimedone, aromatic amine, and formaldehyde were taken in the ratio of 2 : 1 : 3. Probable mechanism for the formation of the bisspiropiperidine is outlined in Scheme 4.

General Procedure for the Synthesis of Hexahydropyrimidines and eir Spiro Analogue.
A mixture of -keto ester (1 mmol), aniline (2 mmol), formaldehyde (3 mmol, 37-41% aqueous solution), and a catalytic amount of Fe 3 O 4 (10 mol %) was stirred at 80 ∘ C for 2.5 hours.e progress of the reaction was monitored by TLC.Upon completion of the reactions, the catalyst was recovered from the reaction mixture simply by applying an external permanent magnet and the products were puri�ed by column chromate-graphy.All products are known compounds.e identity of the products was con�rmed by comparison of their spectroscopic data with literature data.e isolated yields of the products were 70-94%.stirred at 80 ∘ C for 3 hours.e progress of the reaction was monitored by TLC.Aer the completion of the reaction Fe 3 O 4 was removed from the reaction mixture by external magnet e solvent was removed under reduced pressure.e crude product mixture was then puri�ed directly by crystallization from etylacetate.Spectroscopie and analytical data of several compounds have been reported.

The Spectral and Analytical Data of
a Few Compounds Reported in Tables 1 and 3 4.1.5-Acetyl-