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First application of hexaaquaaluminium(III) tetrafluoroborate as a mild, recyclable, non-hygroscopic acid catalyst in organic synthesis: a simple and efficient protocol for the multigram scale synthesis of 3,4-dihydropyrimidinones by Biginelli

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First application of hexaaquaaluminium(III) tetrafluoroborate as a mild, recyclable, non-hygroscopic acid catalyst in organic synthesis: a simple and efficient protocol for the multigram scale synthesis of 3,4-dihydropyrimidinones by Biginelli
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  First application of hexaaquaaluminium(III) tetrafluoroborate as a mild,recyclable, non-hygroscopic acid catalyst in organic synthesis: a simple andefficient protocol for the multigram scale synthesis of 3,4-dihydropyrimidinonesby Biginelli reaction Mladen Litvic´  a , * , Ivana Vecˇ enaj a , Zrinka Mikuldasˇ  Ladisˇ ic´  a , Marija Lovric´  a , y ,Vladimir Vinkovic´  b , Mirela Filipan-Litvic´  a , * a BELUPO Pharmaceuticals, Inc., R&D, Danica 5, 48 000 Koprivnica, Croatia b Institute Ru C  er Bosˇ kovic ´, Bijenic ˇ ka c. 54, 10002 Zagreb, Croatia a r t i c l e i n f o  Article history: Received 12 November 2009Received in revised form 18 February 2010Accepted 8 March 2010Available online 12 March 2010 Keywords: 3,4-DihydropyrimidinoneBiginelli reactionHeterocyclesCondensationHexaaquaaluminium(III) tetrafluoroborate a b s t r a c t For the first time hexaaquaaluminium(III) tetrafluoroborate has been used as a mild acid catalyst inorganic synthesis. A simple method of its preparation based on the reaction of aluminium triisoprop-oxide and tetrafluoroboric acid in isopropanol afforded catalyst of high purity and activity. The three-component Biginelli condensation of acetoacetate esters, urea and aldehydes catalyzed by 10 mol% of [Al(H 2 O) 6 ](BF 4 ) 3  in refluxing acetonitrile afforded 3,4-dihydropyrimidonones in good to high yields onmultigram scales. The tolerance to acid sensitive reactants such as thienyl and furyl carbaldehydes,applicability to sterically hindered  b -ketoesters and simple recyclability without losing catalytic activitymake this catalyst as good replacement to literature methods. The mechanism of the reaction includesformation of the so called ‘ureido-crotonate’ rather than corresponding acylimino intermediate as foundwith Brønsted type catalysts.   2010 Elsevier Ltd. All rights reserved. 1. Introduction The Biginelli reaction 1 is a well-known, simple and straightfor-wardprocedureforthesynthesisof3,4-dihydropyrimidinones(3,4-DHPMs) by the three-component condensation of an aliphatic oraromaticaldehyde, b -ketoesterandaurea.Thesrcinalreactionwasfirst reported by Pietro Biginelli in 1893 2 and was catalysed bymineral acids. This simple procedure has been successful ina number of Biginelli reactions involving substrates lackingsterically-demanded groups. By the three-component Biginellicondensation many 3,4-DHPMs have been synthesized to exhibitvariety of pharmacological activity such as calcium channel mod-ulation, 3 mitotic kinesin Eg5 inhibition (monastrol, Fig. 1), 4 antivi-ral, 5 antibacterial and antifungal activity, 6 anticancer 7 (MAL3-101,Fig. 1) etc. 8 3,4-DHPMs are also used as starting material for thesynthesis of so called ‘superstatin’ rosuvastatin selective and com-petitive inhibitor of HMG-CoA reductase, 9 the enzyme responsibleforthebiosynthesisofcholesterol.Moreover,the3,4-DHPMmotifispresent in many products isolated from natural material such asseveral species of sponges. The representatives such as batzella-dines, ptilomycalines and crambescidines 10 (Fig. 1) exhibit manybiological activities such as anticancer, antifungal, anti HIV etc.During the last few years, numerous catalytic methods havebeen developed in order to improve the reaction yield or the scopeof the Biginelli reaction. A recent review article shows the interestof the synthetic chemists in order to find better and more selectivecatalysts for Biginelli 3,4-DHPM synthesis. 11 Most of the methodsare based on employing Brønsted or Lewis acid type catalysts. 12–29 Probably the most effective methods involve the reagent(s), whichare stoichiometric dehydrating agents in the presence of  protic or Lewis acids: ethyl polyphosphate, 30 TMSCl, 31 TMSCl/NaI, 32 FeCl 3 /Si(OEt) 4 , 33 etc. However these methods suffer from cumbersomework-upofthereactionmixtureandproductionofwaterwasteandthus are suitable for the synthesis only on a small scale. In therecent years, catalysts, which are recyclable and capable of per-forming the reaction under mild condition have gained particularattention. 11,22,34,35 Those characteristics of the catalyst are essentialin the case of the enantioselective version of Biginelli reaction. 36 From that point there is still need to find catalyst, which arecapable to perform reaction under milder reaction conditions. *  Corresponding authors. Tel.:  þ 385 48 65 24 57; fax: þ 385 48 65 28 94; e-mailaddresses: mladen.litvic@belupo.hr (M. Litvic´), mirela.filipan-litvic@belupo.hr(M. Filipan-Litvic´). y Present address: GlaxoSmithKline research center Zagreb d.o.o., Prilaz BarunaFilipovic´a 29, 10000 Zagreb, Croatia. Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ – see front matter    2010 Elsevier Ltd. All rights reserved.doi:10.1016/j.tet.2010.03.024 Tetrahedron 66 (2010) 3463–3471  Despite the plethora of different catalysts published so far andprovedtobean efficientin Biginellireaction thesynthetic chemistsmay encounter the problem in finding the right one if reactionshould be performed on larger scale. Moreover, most of them areexotic, expensive, complex, unavailable, harmful and sometimesineffective in reaction with more complex reactants. Therefore,development of more selective and greener methods employingrecyclable catalysts in Biginelli 3,4-DHPM synthesis is stilldemanded. 2. Results and discussion In continuation of our research on chemistry of 3,4-DHPMs werequired multigram scale samples as a starting material for thestudy of their aromatization to the corresponding pyrimidines(similarly to chemistry of Hantzsch 1,4-dihydropyridines 37,38 ).From our previous experience 12,33 we have found Lewis acidssuperior over Brønsted acids due to better selectivity and higheryields of the products. Thus we were guided to choose one suitablefrom the literature available on large scale, nonexpensive andrecyclable. Interestingly, not many of them fulfilled the aboverequirements. Metallic triflates such as Cu(OTf) 235 Zn(OTf) 234 andYb(OTf) 322 as very efficient easily recyclable catalysts are notavailable in multigram quantities. Other, although readily availableas laboratory chemicals such as NiCl 2 $ 6H 2 O, 13 FeCl 3 $ 6H 2 O, 13 CuCl 2 $ 2H 2 O, 14 CeCl 3 $ 7H 2 O, 15 Mn(OAc) 3 $ 2H 2 O 16 are not easilyrecyclable and thus not appropriate for our study. From basicorganic synthesis it is known that aluminium halides such as AlCl 3 and AlBr 3  act as a strong Lewis acid catalyst in many organictransformationssuch asFriedel–Crafts acylations 39 andalkylations,rearrangements etc. A literature survey revealed that AlCl 3 , 40 AlBr 340 and Al(HSO 4 ) 321 have already been used as a catalysts inBiginelli reaction. That encouraged us to find appropriate alterna-tive to mentioned aluminium salt equally efficient but more watertolerant and recyclable.Oneofthe bestalternativeto aluminiumhalidesiswatertolerantand recyclable aluminium triflate (Al(OTf) 3 ), which has found its useas a catalyst for acetal formation, 41 ring opening of epoxides byalcohols, 42 synthesisofdiethyl-1-aminophosphonates, 43 etc. 44 Tothebest of our knowledge Al(OTf) 3  has not been used as a catalyst inBiginelli 3,4-DHPM synthesis although it is expected to be at leastequally active as other metallic triflates employed in the samereaction. 11,22,34,35 However, Al(OTf) 3  is not easily available and thusnotappropriateascatalystcandidateformultigramscalesynthesisof 3,4-DHPMs. 45 A much less expensive alternative to Al(OTf) 3  is thecorresponding tetrafluoroborate salt. Literature survey revealed thataluminium tetrafluoroborate has been used as heterogenous cata-lyst 46 (impregnatedtoaluminosilicatesorAl 2 O 3 )forisomerizationof tricyclic naphthenes into adamantanes, 47 dealkylation of alkylphe-nols 48 oralkylaromatics 49 andrecentlyasanadditiveinproductionof nonaqueous electrolyte batteries. 50 To our surprise aluminium tet-rafluoroborate has not been prepared in pure form without a solidcarrierandnotusedsofarinclassicalorganicsynthesis.Inordertotestit in Biginelli reaction a few grams of catalyst was needed. The liter-ature method of preparation was not convenient due to the difficultevaporation of the aqueous solution obtained by the treatment of Al(OH) 3 andboricacidinwaterwithhydrofluoricacid. 47,48a Thereforewe developed new simple and practical method for preparation of pure [Al(H 2 O) 6 ](BF 4 ) 3  according to Scheme 1. NNCO 2 Et SCH 3 HH NHN + NHOOCO 2 HHNOH 2 NH 2 NHNNOCO 2 BnONONH AcOCO 2 Me MAL3-101 OH Monastrol(–)-Ptilomycalin A NNNFCH 3 SOH 3 COCOO - OHOH2Ca 2+ Rosuvastatin calcium Figure 1.  Al(O i- Pr) 3  + 3HBF 4  (50% aq)1. i -PrOH, rt2. evaporation [Al(H2O)6](BF4)3 Scheme 1. M. Litvic ´ et al. / Tetrahedron 66 (2010) 3463–3471 3464  By the treatment of commercial aluminium triisopropoxidedissolved in isopropanol at room temperature with stoichiometricamount of tetrafluoroboric acid (48% in water), evaporation of solvent and drying under vacuum, pure [Al(H 2 O) 6 ](BF 4 ) 3  was pre-paredon0.1 molscale.Theanalysisofwatercontentondrycatalystby the Karl–Fisher method revealed that corresponding hexahy-drateisobtained([Al(H 2 O) 6 ](BF 4 ) 3 ).Thecatalystisnon-hygroscopicand stable for a period of several months at room temperature.According to X-ray diffraction data (XRD) the [Al(H 2 O) 6 ](BF 4 ) 3  ismainly amorphous substance characterized by the presence of broad background signal as depicted from Figure 2. 51 The re-crystallization of [Al(H 2 O) 6 ](BF 4 ) 3  (‘hexahydrate’) from waterafforded a literature new salt [Al(H 2 O) 6 ](BF 4 ) 3 $ 3H 2 O (‘non-ahydrate’) with presumably similar structure as correspondinghexaaquaaluminium(III) bromate trihydrate. 52 The FT-IR spectra of [Al(H 2 O) 6 ](BF 4 ) 3  is characterized by the presence of strong water-stretching region (3200–3600 cm  1 ) and low intensive bands at1060 and 530 cm  1 characteristic for BF 4  anion. 53 The thus obtained catalyst has been tested in the three-com-ponent condensation of benzaldehyde ( 1a ), methyl-acetoacetate( 2a ) and urea in acetonitrile at reflux temperature according toScheme 2. 54 After carrying out the reaction during 20 h and work-up of re-action mixture the product  3a  was isolated in 81% yield ona 10 mmol scale. For the comparison the same reaction has beenperformed with 16 different catalysts and the obtained results areoutlined in Table 1. According to the obtained results [Al(H 2 O) 6 ](BF 4 ) 3  is not only superior over other aluminium salts(Table 1, entries 1–3) but also to all other tested catalysts from the literature such as CeCl 3 $ 7H 2 O, ZnCl 2 , CuCl 2 $ 2H 2 O, FeCl 3 $ 6H 2 O etc.(Table 1, entries 5–13). The obtained results suggest that the non- coordinating counter ion BF 4  plays an important role in activityof [Al(H 2 O) 6 ](BF 4 ) 3  presumably by increasing acidity of [Al(H 2 O) 6 ] 3 þ cation.Next, we wanted to test the effect of the solvent on the reactionin order to find the optimal reaction condition. As presented inTable 2, acetonitrile emerged as the most convenient (entry 3)although in toluene the yield of   3a  (77%) is also high (entry 1). Thisis probably due to much higher boiling point of toluene (111   C)compared to acetonitrile (82  C).Interestingly,thereactionperformedundersolventlessmediaat100   C during 24 h (Table 2, entry 5) afforded product  3a  in only61% yield. It seems that coordination of solvent at coordinationsphere of cation determines the activity of catalyst, therebyimproving the yield of the product. Finally, the last parameterneeded to improve the reaction condition was the influence of theamount of the catalyst on the yield of   3a , Table 3. The modelreactionwithoutacatalystduring48 hatrefluxinacetonitrilegivesby TLC analysis only traces of the product (Table 3, entry 1). Theincremental amount of catalyst from 1 to 50 mol% increasesthe conversion and yield of the product, (with shortening of thereaction times) from 32 to almost quantitative (Table 3, entries2–5). However, 10 mol% of catalyst has been choosen for furtherstudies because of satisfactory yield of the product (81%) in rea-sonably short time (‘reflux overnight‘). Moreover, the isolation of the product in case if reaction is carried out with 50 mol% of cat-alyst is somehow difficult due to coprecipitation of the catalyst andproduct. Figure 2.  XRD pattern of [Al(H 2 O) 6 ](BF 4 ) 3.  Table 1 Catalyst effect (10 mol%) in the model Biginelli reaction (Scheme 1) on the yield of model 3,4-DHPM  3a  (10 mmol scale). Comparative study with literature catalystsEntry Catalyst Reaction time a Yield b (%) Ref.1 AlCl 3 $ 6H 2 O 24 48  d 2 Al 2 SO 4 $ 16H 2 O 24 34  d 3 AlCl 3  20 64 384 [Al(H 2 O) 6 ](BF 4 ) 3  20 81 This article5 NiCl 2 $ 6H 2 O 20 73 136 CeCl 3 $ 7H 2 O 20 64 157 ZnCl 2  20 52 198 ZnI 2  20 60 559 CuCl 2 $ 2H 2 O 16 71 1410 CuSO 4 $ 5H 2 O 24 69 1411 Mn(OAc) 3 $ 2H 2 O 24 70 1612 FeCl 3  18 73  d 13 FeCl 3 $ 6H 2 O 24 71 13 a Determined by TLC analysis. b Isolated yield.  Table 2 The influence of the solvent on the yield of model 3,4-DHPM  3a Entry Solvent Time Yield c (%)1 Toluene a 24 772 EtOH a 24 643 CH 3 CN a 20 814 THF a 48 535 – b 24 61 a Reflux temperature. b 100   C, solventless media. c Isolated yield. NNCO 2 MeO CH 3 3a CHO 1a +ONH 2 H 2 N+ CH 3 CO 2 Me O 2a HH MeCN / ∆ / 20 h / 81%catalyst Scheme 2.  Table 3 The influence of the amount of catalyst [Al(H 2 O) 6 ](BF 4 ) 3  on the synthesis of model3,4-DHPM  3a Entry [Al(H 2 O) 6 ](BF 4 ) 3a (mol%) Time a [h] Yield b (%)1 No catalyst 48 Traces of the product2 1 48 323 5 24 584 10 20 815 50 19 98 a Determined by TLC analysis. b Isolated yield. M. Litvic ´ et al. / Tetrahedron 66 (2010) 3463–3471  3465  With optimized conditions in hand we decided to explore thescope and limitations of this method. Thus, series of Biginelli3,4-DHPMs with significant steric, electron withdrawing and do-nating substituents, were synthesized and the obtained results aresummarized in Table 4. While preliminary investigation (includingoptimization) has beenperformedon 10 mmol scaleall preparativeexperiments were conducted on 200 mmol scale affording 40–50 gof the products depending on the molecular weights.The main characteristics of the reaction are good to excellentyields (80–95%) of the products obtained after simple work-up,ability to tolerate the variation in all the two components( b -ketoesters and aldehydes), reuse of the catalyst without loosingof activityand mostof all possibilityof scale-up of reaction in orderto prepare the products on multigram amounts. Both electronicwithdrawing (F, Cl, NO 2 ) and donating substituents (CH 3 , OCH 3 ) onthe aldehyde reactant are well tolerated in reaction withoutsignificant impact on the yield of the product. Moreover, acidsensitive aldehydes such as thienyl ( 1f  ), 5-bromothienyl ( 1g  ) andfuryl carbaldehydes ( 1e ) furnished products in yields of 80%, 87%and 83%, respectively. Interestingly, freshly distilled  1e  and  1f   usedinreactionhaveshownanimprovementinyieldof theproductsforalmost 10% (Table 4, entries 5, 6 and 9). However, this was not thecase for other usually stable aldehydes used in reaction. Mostimportantly, the reaction with sterically hindered methyl iso-butyrylacetate (entries 8and 9),ethyl butyrylacetate(entry14) andethyl benzoylacetate (entry 15) proceeded unexpectedly well andthe valuable literature unknown products usually prepared withdifficulty were isolated in excellent yield ( > 80%). As mentionedabove, the catalyst as well as the excess of urea are easily recycledby extraction of residue obtained after evaporation of ethanolicmother liquor (see Experimental Section) with hot water andevaporation of thus formed catalyst solution. The recycled catalystwas used over four times without loss of activity when ethyl-acetoacetate ( 2c ),  m -chlorobenzaldehyde ( 1k  ) and urea were con-densedinBiginellireactiontogive 3k  ,Table5.Thisfeatureprovides a significant benefit (environmental and cost) over traditionalLewis and Brønsted acids.In order to provide a reasonable explanation of obtained results(tolerance to variety of substituted reactants) we performed a fewexperiments regarding determination of possible mechanisticpathways of the reaction.According to the literature three possible mechanisms are pro-posed but generally accepted Biginelli reaction mechanism in-cludes the acid-catalysed formation of C ] N bond from thebenzaldehyde ( 1a ) and urea, followed byaddition of   b -ketoester  2a to the arylidene–urea  4  and cyclodehydration of intermediatesyielding dihydropyrimidinone  3a  (Scheme 3, pathway A). 56–58 However, this mechanism is probably characteristic only forprotic acids but not for other types of acid catalysts including me-tallic salts. This conclusion comes from our results obtained withSbCl 3 -catalysed synthesis of 3,4-DHPMs where pathway C(Scheme 3) is dominant to yield the product 12 while other two(pathway A and B) surprisingly do not participate in reaction at all.In order to clarify the role of [Al(H 2 O) 6 ](BF 4 ) 3  three separated  Table 4 Three component synthesis of substituted 3,4-DHPMs  3a – q  catalyzed by [Al(H 2 O) 6 ](BF 4 ) 3  (10 mol%) in acetonitrile at reflux temperature NNRCO 2 R 1 OR 2 ROH+ONH 2 H 2 N+R 2 CO 2 R 1 O10 mol% [Al(H2O) 6 ](BF4)3 MeCN / ∆ HH 3a - 3q1a - 1n 2a - 2g Entry 3,4-DHPM R R  1 ; R  2 t   (h) Yield (%) a,b 1  3a  Ph Me; Me 20 852  3b  p -FC 6 H 4  Me; Me 22 843  3c  2,4-(CH 3 ) 2 C 6 H 4  Me; Me 18 934  3d  o -OC 2 H 5 C 6 H 4  Me; Me 20 925  3e  2-Furyl Me; Me 22 83 (92) c 6  3f   2-Thienyl Me; Me 20 80 (89) c 7  3g   2-(5-Br-thienyl) Me; Me 20 878  3h  p -ClC 6 H 4  Me;  i -Pr 21 819  3i  2-Thienyl Me;  i -Pr 20 83 (90) c 10  3j  o -ClC 6 H 4  Et; Me 20 8811  3k   m -ClC 6 H 4  Et; Me 20 9512  3l  p -ClC 6 H 4  Et; Me 21 8113  3m  p -NO 2 C 6 H 4  Et; Me 20 8514  3n  Ph Et;  n -Pr 24 8115  3o  Ph Et; Ph 24 8016  3p  p -OCH 3 C 6 H 4  i -Pr; Me 20 8317  3q  p -CH 3 C 6 H 4  CH 2 Ph; Me 21 82 a Isolated yield. b All products were characterized by  1 H NMR,  13 C NMR, IR and MS spectra. Literature known compounds were compared with authentic samples. c Yield obtained with freshly distilled aldehyde.  Table 5 [Al(H 2 O) 6 ](BF 4 ) 3  recycling experiments on Biginelli  3k   synthesisRun a Yield b (%)1 952 943 934 93 a The yield of isolated mixture of catalyst and unreacted urea is about 95% aftereach run. b Isolated yield of   3k   on 10 mmol scale. M. Litvic ´ et al. / Tetrahedron 66 (2010) 3463–3471 3466  reactions were conducted (Scheme 3, pathways A–C) under theoptimized reactioncondition(10 mol%of[Al(H 2 O) 6 ](BF 4 ) 3  at refluxtemperature during 24 h).The prolonged heating of benzaldehyde ( 1a ) and methyl ace-toacetate ( 2a ) did not undergo the expected reaction (pathway C)to yield a mixture ( E  /  Z  ) of Knoevenagel products ( 5 ). The reactionof benzaldehyde ( 1a ) and urea furnished only a trace (conversion < 10%) of the arylidene–urea  4  (pathway A) whereas the conden-sation of methyl acetoacetate ( 2a ) and urea smoothly furnished N  -(1-ethoxycarbonyl-propen-2-yl)urea ( 6 ), which upon additionof benzaldehyde ( 1a ) was easily converted to dihydropyr-imidinone  3a  (Scheme 3, pathway C). The isolation of intermediate 6  is possible by the chromatographic method described in ourprevious article. 12 These findings clearly indicate that Biginellireaction catalysed by [Al(H 2 O) 6 ](BF 4 ) 3  proceeds predominatelythrough ureido-crotonate intermediate  6  (pathway C), whichsomewhat supports prediction that Biginelli reaction catalysed byother types of acid catalysts such as metallic salts does not includeformation of arylidene–urea  4  as in Brønsted type catalysis. 58 According to these results [Al(H 2 O) 6 ](BF 4 ) 3  acts as a Lewis acidin reaction. Furthermore, this is also supported by the fact thatureido-crotonate intermediate  6  in Biginelli reaction catalysed byBrønsted type catalysts is regarded as unlikely. 58 Despite this ob-servation, it is well-known from the literature that the[Al(H 2 O) 6 ] 3 þ cation in water solution acts as a weak proton donor(p K  a ¼ 4.97), 59 of comparable acidity to acetic acid (p K  a ¼ 4.76). 60 The dissociation of [Al(H 2 O) 6 ] 3 þ cation and possible action of a catalyst as Brønsted acid is presented in Scheme 4.In order to determine whether the [Al(H 2 O) 6 ](BF 4 ) 3  acts asa Lewis or Brønsted acid catalyst (or both) a series of experimentswere carried out employing glacial acetic acid (Brønsted acid) andanhydrous AlCl 3  (Lewis acid) as a catalysts. The reactions wereperformed under the same reaction condition as outlined inScheme 3. As expected, none of the catalysts was capable of performing the reaction between benzaldehyde ( 1a ) and methylacetoacetate ( 2a ) to give  5  (pathway B). The condensation of ureaand methyl acetoacetate ( 2a ) catalysed by 10 mol% of glacial aceticacid did not undergo formation of   6 , which is in accordance toliterature results for this type of reaction. 58 Interestingly, the con-densationofureaandbenzaldehyde( 1a )evenafter48 hatrefluxinacetonitrile furnished only a traces of condensation product  4 ,presumably as corresponding ‘bisureide’ 58 obtained by addition of second molecule of urea to  4 . As already mentioned[Al(H 2 O) 6 ](BF 4 ) 3  with similar p K  a  value as the acetic acid reachedalmost 10% conversion in the same reaction. Therefore, along withanactivityasaBrønstedacid(protondonor)thecoordinationofthereactants on a coordination sphere of aluminium (Lewis acidactivity) should not be neglected. The condensation of urea andmethyl acetoacetate ( 2a ) catalysed by 10 mol% of anhydrous AlCl 3 inacetonitrileatroomtemperatureafforded 6 in80%yieldwhereasurea and benzaldehyde ( 1a ) did not react under the same reactioncondition. If the latter reaction was carried out at reflux tempera-ture roughly 15% conversionwas reached, probably by the action of HClreleased bydecompositionof thecatalystwithwaterformedinreaction.AccordingtoobtainedresultsthepathwayA(Scheme3)ischaracteristic for the Brønsted type of catalysts whereas Lewis acidtype of catalysts follow the pathway C (ureido-crotonate mecha-nism). Although without a free orbital (main characteristic of a Lewis acid) the aluminium in [Al(H 2 O) 6 ](BF 4 ) 3  similarly to anhy-drous AlCl 3  efficiently catalyzed reaction of urea and methylacetoacetate ( 2a ) to give  6  in high yield (Scheme 3, path C).To explain this observation the substitution of water molecules incoordination spheresof aluminium is requiredto allow satisfactoryactivity of the catalyst. Recently, Katakura and co-workers havepublished the one-step synthesis of aluminium(III) acetylacetonatefrom mineral Boehmite ([AlO(OH)] n ) and acetylacetone in water atroom temperature. 61 They have shown how by simple mixing of reactantssubstitutionofligandssuchashydroxideionsandoxygenbridges in mineral are replaced by organic bidentate ligand at mildreaction condition. We believe that substitution of two watermolecules in [Al(H 2 O) 6 ](BF 4 ) 3  by  b -ketoester is even more facili-tated at elevated temperature (reflux of acetonitrile).As a result of a detailed experimental mechanistic investigationplausible simplified mechanism of [Al(H 2 O) 6 ](BF 4 ) 3 -catalysedBiginelli 3,4-DHPM synthesis is proposed to include activation of reactants by the dual action of the catalyst (Lewis and Brønstedacid) according to Scheme 5.The presented mechanism on 3,4-DHPM  3j  having sterically-demanded groups is used to explain low sensitivity of reaction toelectronicandstericalnatureofsubstituents(Table4).Thecatalyticcycle begins with a complexation of methyl isobutyrylacetate  2b and urea on a catalyst to form  7  with elimination of three watermolecules and HBF 4 . The formation of more stable complexbetween catalyst and methyl isobutyrylacetate  2b  (bidentateligand) than with aldehyde  1j  (monodentate ligand) allows intra-molecular nucleophilic attack (Michael addition) of urea to acti-vated C ] C double bond followed by tautomerisation andelimination of HBF 4  to give a complexed hemiaminal  8 . The intra-molecular tautomerization and elimination of water produce so CHOH 2 NCONH 2 NCONH 2 1a4 NON 3a CH 3 CO 2 MeH 2 NCONH 2 Pathway C  i CO 2 MeCH 3 NCONH 2 6 1a2a i : 10 mol% [Al(H 2 O) 6 ](BF 4 ) 3  / MeCN / refluxCHO i 1aPathway B CO 2 MeOCH 3 2a OCO 2 MeCH 3 CO 2 MeOCH 3 2a5 urea i Pathway A HHH Scheme 3. [Al(H 2 O) 6 ] 3+ [Al(OH)(H 2 O) 5 ] 2+ + H + Scheme 4. M. Litvic ´ et al. / Tetrahedron 66 (2010) 3463–3471  3467
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