DOI: 10.1002/adsc.200800089

Unmodified Nano-Powder Magnetite Catalyzes a Four-Component Aza-Sakurai Reaction

Ricardo Martnez,a Diego J. Ram�n,a,* and Miguel Yusa,*a Instituto de Sntesis Org�nica (ISO), and Departamento de Qumica Org�nica, Facultad de Ciencias, Universidad deAlicante, Apdo. 99, 03080 Alicante, SpainFax: (+35)-965-9035; e-mail: djramon@ua.es or yus@ua.es

Received: February 11, 2008; Published online: May 9, 2008

Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.

Abstract: A new catalyst for an old material: mag-netite is an excellent Lewis acid catalyst for thefour-component aza-Sakurai reaction. The processcould be repeated up to 15-times without losing ef-fectiveness, with the catalyst recycling being as easyas the use of a simple magnet. The catalyst is selec-tive and could discriminate between aldehyde andketone functionalities, catalyzing first the reactionwith the higher electrophilic aldehyde.

Keywords: heterogeneous catalysis; iron; Lewisacids; magnetic properties; multicomponent reac-tions; synthetic methods

Magnetic nano- and microparticles are of great inter-est for a wide range of disciplines, and their develop-ment is highly demanded nowadays,[1] with the suc-cessful applications of such particles dependingstrongly on their stability. So, for many applications,the protection of the naked magnetic particle, includ-ing grafting or coating with new organic or inorganiclayers, is crucial,[2] and permits their further function-alization.[3]

Among the different magnetic nanoparticles, Fe3O4

is the most important one, and although naked mag-netite seems to play a capital role in pre-bioticchemistry,[4] its use as a catalyst has been quite limitedto only a few examples, including carbon-carbondouble bond isomerization,[5] modified Fischer–Tropsch reaction,[6] water-gas shift reaction,[7] dehy-drogenation[8] and epoxidation[9] processes, many ofthem performed under very extreme reaction condi-tions.On the other hand, multicomponent reactions allow

one to create complicated molecules using only oneprocess in a very fast, efficient and time-savingmanner,[10] albeit with the higher the number of start-

ing reagents and catalysts the more difficult is the suc-cess of the reaction. Very recently, a new four-compo-nent aza-Sakurai reaction catalyzed by substoichio-metric amounts of FeSO4 and using aldehyde deriva-tives has been published, the results being in generalmoderate.[11]

With this study we would like to show the first ex-ample in which the unmodified commercial nano-powder magnetite can be used (and re-used) as a typi-cal heterogeneous Lewis acid catalyst in usual andmild organic synthetic protocols.Our starting point is the known surface of the mag-

netite Fe3O4 (111), which is terminated by a hexago-nal oxygen layer covered by one quarter monolayerof iron cations.[12] These Lewis acid centres on the sur-face could catalyze the reaction. So, the multicompo-nent reaction outlined in Table 1 was used as standardfor the reaction condition optimization. The reactionusing 40 mol% of commercial nanopowder magnetitegave the expected carbamate 5a with a good result,whereas the reaction under similar conditions in theabsence of catalyst did not take place, even after alonger reaction time (compare entries 1 and 2 inTable 1). The reaction using a lower amount of cata-lyst provoked an appreciable and unusual increase onthe result (entry 3 in Table 1), whereas further de-creases resulted in a continuous decline of the results(Table 1, entries 5 and 6). The reaction could be alsoperformed without the stirring bar and without a sig-nificant effect (Table 1, entry 4). The reaction usingFe2O3, which presents a similar atom surface distribu-tion to magnetite only changing Fe(II) by FeACHTUNGTRENNUNG(III),failed (entry 7). However, the reaction using FeO inwhich, excluding imperfections, the last surface layeris terminated purely by oxygen atoms, gave a signifi-cant result (entry 8). These results pointed out thatthe reaction seems to be catalyzed by Fe(II) and notby Fe ACHTUNGTRENNUNG(III) centres. The reaction performed at roomtemperature took a longer times in order to obtainsimilar results (Table 1, entries 9 and 10). Other reac-

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tion conditions or solvents did not improve the prece-dent result (entries 11–15).After completing the optimization study, we exam-

ined the reaction’s scope, starting by changing thenature of chloroformate 2. The reaction using differ-ent substituted chloroformates gave practically thesame results (Table 2, entries 1–6). These results aresimilar using benzoyl chloride or even using pivaloylchloride, which is clearly a more hindered compound(entries 7 and 8). Unfortunately, the reaction usingN,N-dimethylcarbamoyl chloride failed (entry 9).Then, we followed with a study using different sour-ces of the silylated nucleophile 3. Whereas the reac-tion with trimethylsilyl cyanide (3b) gave the expect-ed amido nitrile 5j with a very low yield, the reactionusing the corresponding allyltrimethylsilane (3c) gavethe expected carbamic compound 5k in high yield(compare entries 2, 10 and 11). Similar allylation pro-cess using a chiral chloroformate did not show anydiastereoselectivity (entry 14).The nature of the carbonyl compound 1 has a cer-

tain impact on the results. So, whereas aromatic ora,b-unsaturated aldehydes gave excellent results, ali-phatic aldehydes gave only good chemical yields(compare entries 2, 11–13, 15–19 in Table 2). In thecase of using acetophenone or 2-hexanone (en-tries 20–22) the reaction time had to be increased inorder to improve on the previous results. However,the expected carbamate 5u and v were obtained using

cyclohexanone in only two hours (entries 23 and 24).Finally, it is worthy of note that the catalyst is selec-tive and could discriminate between an aromatic alde-hyde and the related ketone. Thus, the reaction with4-acetylbenzaldehyde gave only the product resultingfrom the reaction with the aldehyde group even whenusing two equivalents of compounds 2, 3 and 4, therelated one resulting from the reaction with theketone group not being detected (entry 25).Once the catalytic activity of the unmodified mag-

netite was demonstrated, we faced the problem of re-use, finding that the chemical yields were constant ina range between 83 and 98%, after 15 cycles of reac-tion, for the preparation of compound 5a (Figure 1),with the magnetite being maintained inside the flaskby the help of a magnet.In order to explore the possible degradation of the

naked magnetite under the reaction conditions, theBET surface area was determined at the beginning ofthe process (52.69 m2g�1) and after 15 cycles(50.43 m2g�1), with this concordant result showingthat there is no significant sinterization process underthe assayed reaction conditions. A similar result couldbe extracted from the observation of TEM microscop-ic images, which did not show any difference betweenthe unmodified magnetite and the 15-fold reused one(Figure 2).To finish with the study on the stability of the mag-

netite nanopowder, we studied the obtained liquidphase after one cycle of the reaction for the prepara-tion of compound 5a. The magnetite was isolated by amagnet and washed with toluene; the resulting liquidmixture without filtration was used as medium for thepreparation of compound 5m in the absence of mag-netite, affording the expected allyl carbamate in only21% yield. This result indicated that the isolation pro-cesses permitted the presence of iron species in themedium. In a parallel experiment, after the standardpreparation of compound 5a and isolation of magnet-ite as above, the resulting mixture without filtrationwas concentrated and re-dissolved in methanol. Theflame atomic absorption spectroscopy (FAAS)showed the presence of around 6 mg of iron in themethanolic solution (less than 2% of initial magnetiteadded). However, if prior to the concentration, asimple filtration is done, the FAAS did not show thepresence of iron atoms, excluding the presence of ho-mogeneous iron species. Therefore, we believe thatthe possible degradation of magnetite is not true, andthe initial catalytic and FAAS results only showed thecapacity of the magnet used to trap the nanoparticles.The above protocol could be expanded to the relat-

ed ketals 6, as depicted in Scheme 1. The reactionusing the masked benzaldehyde derivative 6a gavethe corresponding carbamate 5b in 90% yield, whichis a similar result to that obtained using benzaldehyde(compare to entry 2 in Table 2). In order to study the

Table 1. Reaction-conditions optimization.

Entry Solvent T [8C] Catalyst [mol%] t [h] Yield [%][a]

1 PhMe 110 - 8 02 PhMe 110 Fe3O4 [40] 2 753 PhMe 110 Fe3O4 [20] 2 854 PhMe 110 Fe3O4 [20] 2 80[b]

5 PhMe 110 Fe3O4 [10] 2 796 PhMe 110 Fe3O4 [1] 2 <57 PhMe 110 Fe2O3 [20] 2 08 PhMe 110 FeO [20] 2 409 PhMe 25 Fe3O4 [20] 24 6510 CH2Cl2 25 Fe3O4 [20] 72 7511 CH2Cl2 110[c] Fe3O4 [20] 2 3012 THF 110[c] Fe3O4 [20] 2 5513 DMF 110 Fe3O4 [20] 2 1114 DMSO 110 Fe3O4 [20] 2 015 MeCN 110 Fe3O4 [20] 2 38

[a] Isolated yields after column chromatography (silica gel:hexane/ethyl acetate).

[b] Reaction performed without stirring bar.[c] Reaction performed in a sealed tube.

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Table 2. Magnetite catalyzes the four-component aza-Sakurai reaction.

Entry R1 R2 R3 Nu Product Yield [%][a]

1 Ph H OCH2Ph H[b] 5a 852 Ph H OCH2CH=CH2 H[b] 5b 983 Ph H OCH2C�CH H[b] 5c 934 Ph H OPh H[b] 5d 705 Ph H OEt H[b] 5e 706 Ph H (�)-menthyloxy H[b] 5f 807 Ph H Ph H[b] 5g 818 Ph H t-Bu H[b] 5h 569 Ph H NMe2 H[b] 5i 010 Ph H OCH2CH=CH2 CN 5j <511 Ph H OCH2CH=CH2 CH2CH=CH2 5k 9612 4-ClC6H4 H OCH2CH=CH2 CH2CH=CH2 5l 9413 4-MeOC6H4 H OCH2CH=CH2 CH2CH=CH2 5m 8414 Ph H (�)-menthyloxy CH2CH=CH2 5n 82[c]

15 PhCH=CH H OCH2CH=CH2 H[b] 5o 7116 PhCH=CH H OCH2CH=CH2 CH2CH=CH2 5p 8517 i-Pr H OCH2CH=CH2 H[b] 5q 6118 c-C6H11 H OCH2CH=CH2 H[b] 5r 5519 c-C6H11 H OCH2CH=CH2 CH2CH=CH2 5s 6620 Ph Me OCH2CH=CH2 H[b] 5t 71[d]

21 n-Bu Me OCH2C�CH H[b] 5u 89[d]

22 n-Bu Me OCH2C�CH CH2CH=CH2 5v 45[d]

23 -(CH2)5- OCH2C�CH H[b] 5w 5324 -(CH2)5- OCH2C�CH CH2CH=CH2 5x 4925 4-MeCOC6H4 H OCH2CH=CH2 CH2CH=CH2 5y 93

[a] Isolated yields after column chromatography (silica gel: hexane/ethyl acetate).[b] Reaction performed using Et3SiH.[c] 1:1 Mixture of diastereoisomers.[d] Yield after 16 h of reaction time.

Figure 1.

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possible selectivity between the free aldehyde groupand the masked one, the reaction was performedusing compound 6b, giving the biscarbamate deriva-tive 7 with a poor yield when only one equivalent ofreagents 2b, 3a and 4 were used and a higher yieldwhen two equivalents were added.Finally, we tried to identify some aspects of the pos-

sible catalytic pathway and therefore we performedseveral parallel reactions with different reagents.Firstly, we performed the reaction of compounds 4and 2b in toluene at 110 8C finding that after only onehour the carbamate 8 was formed, independently ofthe presence or absence of magnetite [Eq. (1) inScheme 2], the chemical yield being increased aftertwo hours. To the above mixture of the carbamate 8and the silyl derivative 9 was added benzaldehyde(1a) and, as in the previous case, the formation ofimine derivative 10 [Eq. (2) in Scheme 2] was inde-pendent on the presence of magnetite. This step waspreviously described as the only Fe(II)-catalyzed stepunder homogeneous conditions.[11] However, underhigher temperature conditions the catalyst seems tobe unnecessary. Finally, the isolated carbamate 10 was

submitted to reaction under different catalyst condi-tions. Compound 10 was alternatively prepared in aclassical two-step reaction[13] using benzaldehyde, lith-

Figure 2. TEM microscopic images of commmercial nanopowder magnetite (left) and the same magnetite after being used in15 cycles (right).

Scheme 2. Possible reaction pathway.

Scheme 1. Multicomponent reaction using ketals 6.

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ium hexamethyldisilylamide to form the correspond-ing imine and then reaction with the correspondingallyl chloroformate.The reaction of the imine compound 10 with tri-

ACHTUNGTRENNUNGethylsilane (3a) at 110 8C in toluene [Eq. (3) inScheme 2] failed after two hours. The parallel reactionusing one equivalent of hydrochloric acid-free trime-thylsilyl chloride also failed under the same condi-tions. The reaction using only 20 mol% of magnetitegave the expected product 5b, but with a low chemicalyield (<10%). However, the reaction using oneequivalent of hydrochloric acid-free trimethylsilylchloride and 20 mol% of magnetite gave the expectedproduct 5b in the usual chemical yields (90%). Finally,and in order to avoid the hypothesis that trimethyl-silyl chloride reacted with magnetite to form solubleFeCl2 and this was the true catalyst, the final reactionof compounds 10 and 3a was repeated using 0.3mol% of FeCl2 (which is a higher amount of iron thanwas found in an FAAS experiment without filtration;see above) giving the compound 5b in a miserableyield (<5%). After these experiments, we concludedthat the reaction pathway seems to follow the equa-tions outlined in Scheme 2, with the magnetite cata-lyst being only important in the reaction of silyl deriv-ative 3 with the imine intermediate 10, the nature ofthe true catalyst is still elusive.In conclusion, unmodified commercial magnetite

nanopowder has been shown to be an active, stableand highly selective catalyst for the uncommon four-component aza-Sakurai reaction. This is the first timethat unmodified magnetite is used as catalyst innormal organic reactions. The simple recyclabilitymakes this catalyst suitable for continuous industrialprocesses.

Experimental Section

General Procedure for the Four-Component Aza-Sakurai Reaction Catalyzed by Magnetite

To a solution of the carbonyl compound (1, 4 mmol) in drytoluene (5 mL) were added chloroformate derivative (2,4.8 mmol), silyl derivative (3, 4.8 mmol), hexamethyldisila-zane (4, 4.8 mmol, 1.01 mL) and Fe3O4 (0.86 mmol, 0.2 g)under an argon atmosphere. The reaction mixture washeated at 110 8C and stirred for 2 h. Then, the catalyst andstirrer bar were removed with a magnet. The solvent was re-moved under reduced pressure and the resulting residue waspurified by flash chromatography on silica gel (hexane/ethylacetate) to give the corresponding product 5.

Supporting Information

Experimental procedure and characterization data for allcompounds are given in the Supporting Information.

Acknowledgements

We are grateful to the Spanish Ministerio de Educaci n yCiencia (Consolider Ingenio 2010 CSD2007–00006) as wellas to the Generalitat Valenciana (GV; grant no. GRUPOS03/135) for the financial support. R.M. thanks GV for a predoc-toral grant.

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