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1有机合成化学复习思考题及答案

Meldrum’s Acids as Acylating Agents in the Catalytic

Intramolecular Friedel -Crafts Reaction

Eric Fillion,*Dan Fishlock,Ashraf Wilsily,and Julie M.Goll

Department of Chemistry,University of Waterloo,Waterloo,Ontario N2L 3G1,Canada

efillion@uwaterloo.ca

Received September 14,2004

The intramolecular Friedel -Crafts acylation of aromatics with Meldrum’s acid derivatives catalyzed by metal trifluoromethanesulfonates is reported.Meldrum’s acids are easily prepared,functionalized,handled,and purified.The synthesis of polysubstituted 1-indanones from benzyl Meldrum’s acids was investigated thoroughly,and it was shown that a variety of catalysts were effective,while accommodating a diversity of functional groups under mild conditions.The scope,limitations,and functional group tolerance (terminal alkene and alkyne,ketal,dialkyl ether,dialkyl thioether,aryl methyl ether,aryl TIPS and TBDPS ethers,nitrile-and nitro-substituted aryls,alkyl and aryl halides)for a variety of 5-benzyl (enolizable Meldrum’s acids)and 5-benzyl-5-substituted Meldrum’s acids (quaternized Meldrum’s acids),forming 1-indanones and 2-substituted-1-indanones,respec-tively,are delineated.This method was further applied to the synthesis of 1-tetralones,1-benzo-suberones,and the potent acetylcholinesterase inhibitor donepezil.Rate of cyclization as a function of ring size was established for various benzocyclic ketones via competition experiments:1-tetralones form faster than both 1-indanones and 1-benzosuberones,and 1-benzosuberones cyclize faster than 1-indanones.

Introduction

The intramolecular Friedel -Crafts acylation is the most powerful carbon -carbon forming reaction in syn-thetic organic chemistry for the synthesis of benzocyclic ketones,which comprise 1-indanones,1-tetralones,1-ben-zosuberones,and related compounds.1These structural motifs have proven synthetic utility in numerous biologi-cally active natural products 2and play a major role in medicinal chemistry and the development of pharma-ceuticals.3As illustrated in Figure 1,the antihyperten-sive drug (+)-indacrinone,4the norditerpene taiwan-iaquinol B,5and the acetylcholinesterase inhibitor

(1)For monographs on the Friedel -Crafts acylation reaction,see:(a)Heaney,H.In Comprehensive Organic Synthesis ;Trost,B.M.,Fleming,I.,Eds.;Pergamon Press:Oxford,UK,1991;Vol.2,pp 733-752.(b)Olah,G.A.Friedel -Crafts Chemistry ;John Wiley and Sons:New York,1973.(c)For reviews on the intramolecular Friedel -Crafts acylation reaction,see:(d)Heaney,H.In Comprehensive Organic Synthesis ;Trost,B.M.,Fleming,I.,Eds.;Pergamon Press:Oxford,UK,1991;Vol.2,pp 753-768.(e)Sethna,S.In Friedel -Crafts and Related Reactions ;Olah,G.A.,Ed.;Interscience:New York,1964;Vol.3,pp 911-1002.(f)Gore,P.H.

Chem.Rev.1955,55,229-281.(g)Johnson,https://www.wendangku.net/doc/a815199116.html,.React.1944,2,114-177.

(2)(a)Wipf,P.;Jung,https://www.wendangku.net/doc/a815199116.html,.Chem.2000,65,6319-6337.(b)Ollero,L.;Castedo,L.;Dominguez,D.Tetrahedron Lett.1998,39,1413-1416.(c)Danheiser,R.L.;Helgason,A.L.J.Am.Chem.Soc.1994,116,9471-9479.(d)Tori,M.;Sono,M.;Nishigaki,Y.;Na-(3)(a)Catoen-Chackal,S.;Facompre ′,M.;Houssin,R.;Pommery,N.;Goossens,J.-F.;Colson,P.;Bailly,C.;He ′nichart,J.-P.J.Med.Chem.2004,47,3665-3673.(b)Musso,D.L.;Cochran,F.R.;Kelley,J.L.;McLean,E.W.;Selph,J.L.;Rigdon,G.C.;Orr,G.F.;Davis,R.G.;Cooper,B.R.;Styles,V.L.;Thompson,J.B.;Hall,W.R.J.Med.Chem.2003,46,399-408.(c)Musso,D.L.;Orr,G.F.;Cochran,F.R.;Kelley,J.L.;Selph,J.L.;Rigdon,G.C.;Cooper,B.R.;Jones,M.L.J.Med.Chem.2003,46,409-416.(d)Bauta,W. E.;Lovett, D.P.;Cantrell,W.R.,Jr.;Burke,https://www.wendangku.net/doc/a815199116.html,.Chem.2003,68,5967-5973.(e)Caro,Y.;Masaguer,C.F.;Ravin ?a,E.Tetrahedron :Asymmetry 2003,14,381-387.(f)Ghatak,A.;Dorsey,J.M.;Garner,C.M.;Pinney,K.G.Tetrahedron Lett.2003,44,4145-4148.(g)Adams,D.R.;Duncton,https://www.wendangku.net/doc/a815199116.html,mun.2001,31,2029-2036.(h)Shiraishi,M.;Aramaki,Y.;Seto,M.;Imoto,H.;Nishikawa,Y.;Kanzaki,N.;Okamoto,M.;Sawada,H.;Nishimura,O.;Baba,M.;Fujino,M.J.Med.Chem.2000,43,2049-2063.(i)Bo ¨s,M.;Jenck,F.;Martin,J.R.;Moreau,J.-L.;Sleight,A.J.;Wichmann,J.;Widmer,U.J.Med.Chem.1997,40,2762-2769.

(4)(a)Dolling,U.-H.;Davis,P.;Grabowski,E.J.J.J.Am.Chem.Soc.1984,106,446-447.(b)deSolms,S.J.;Woltersdorf,O.W.,Jr.;Cragoe,E.J.,Jr.J.Med.Chem.1978,21,437-443.

(5)For studies on the synthesis of members of this family of natural products,see:(a)Lomberget,T.;Bentz,E.;Bouyssi,D.;Balme,https://www.wendangku.net/doc/a815199116.html,.Lett.2003,5,2055-2057.(b)Banerjee,M.;Makhopadhyay,R.;Achari,B.;Banerjee,https://www.wendangku.net/doc/a815199116.html,.Lett.2003,5,3931-3933.Isolation,see:(c)

donepezil hydrochloride (Aricept),6used for the treatment of Alzheimer’s disease,all contain a 1-indanone core.7

Conditions for the mild and catalytic acylation of aromatic compounds with broad functional group toler-ance have been elusive.Existing procedures work well with simple substrates but are rarely applicable to functionalized precursors.The classical intramolecular Friedel -Crafts acylation involves the reaction of an acyl halide or carboxylic acid with a tethered arene promoted by either Lewis or Br?nsted acids.8Reacting an aromatic with an acyl chloride in combination with a strong Lewis acid such as AlCl 3,TiCl 4,or SnCl 4is one of the most common acylation procedures.However,due to catalyst inhibition by the product,via formation of a stable Lewis acid -aromatic ketone complex,stoichiometric or excess amounts of the oxophilic promoter are necessary.Fur-thermore,decomposition of this complex by aqueous workup renders product isolation tedious.Additional drawbacks of this protocol include the moisture sensitiv-ity of acyl chlorides and the generation of hydrogen chloride.Alternatively,the reaction of acyl chlorides with stoichiometric quantities of trifluromethanesulfonic acid provides good yields of benzocyclic ketones via highly reactive sulfocarboxylic acid anhydride intermediates.9Lewis acid-catalyzed intramolecular Friedel -Crafts acylation procedures with acyl halides have not been reported.10

Complementary intramolecular acylation methods that directly use carboxylic acids as the electrophile suffer from the poor leaving group ability of the -OH moiety and thus require forcing conditions.Friedel -Crafts de-hydrative acylation with carboxylic acids have been promoted by polyphosphoric acid,11methanesulfonic acid,HF,or dehydrating agents such as P 2O 5,trifluoroacetic anhydride,and trifluoromethanesulfonic anhydride.8Nafion-H,an immobilized perfluorinated sulfonic acid,does not form stable complexes with aryl ketones in the acylation with acyl chlorides or carboxylic acids.12Al-though Nafion-H has been reported to effectively promote intramolecular dehydrative Friedel -Crafts acylations to yield tetralones at moderate temperature,it was inef-fective for preparing the synthetically more challenging indanones.Generally,1-tetralones are the easiest ben-zocyclic ketones to form by intramolecular Friedel -Crafts acylation.Difficulties are associated with 1-indanone synthesis and rigorous conditions are typically required for their preparation,including high temperatures and long reaction times.13

The synthetic importance of the Friedel -Crafts acylation has generated interest in the development of a catalytic version under mild reaction conditions.Progress has been made toward intermolecular Lewis acid-catalyzed protocols with use of rare-earth metal triflates but cyclization precursors are still essentially limited to acid halides and anhydrides.14The intermolecular acylation of aromatics with carboxylic acids at moderate temperature by the combined use of perfluoroalkanoic acid anhydride and Bi(OTf)3or Sc(OTf)3,via the in situ generation of an anhydride intermediate,was de-scribed.15,16Dehydrative cyclization protocols catalyzed by Bi(NTf 2)3and Tb(OTf)3were reported,but elevated temperatures were required,between 180and 200°C for the synthesis of 1-tetralones 17and 250°C for the prepa-ration of 1-indanones.18,19

Rather than examining reaction conditions,little at-tention has been paid to the elaboration of novel acylating agents.Operationally simple intramolecular Friedel -(6)Sugimoto,H.;Iimura,Y.;Yamanishi,Y.;Yamatsu,K.

J.Med.Chem.1995,38,4821-4829.

(7)For other natural products containing a 1-indanone core,see;(a)Ito,T.;Tanaka,T.;Iinuma,M.;Nakaya,K.;Takahashi,Y.;Sawa,R.;Murata,J.;Darnaedi,D.J.Nat.Prod.2004,67,932-937.(b)Nagle,D.G.;Zhou,Y.-D.;Park,P.U.;Paul,V.J.;Rajbhandari,I.;Duncan,C.J.G.;Pasco,D.S.J.Nat.Prod.2000,63,1431-1433.

(8)Larock,https://www.wendangku.net/doc/a815199116.html,prehensive Organic Transformations ,2nd ed.;Wiley-VCH:New York,1999;pp 1422-1433.

(9)(a)Hulin,B.;Koreeda,https://www.wendangku.net/doc/a815199116.html,.Chem.1984,49,207-209.Trifluoromethanesulfonic acid has been reported to catalyze intermo-lecular Friedel -Crafts acylation of aromatics with acyl chlorides,see:(b)Effenberger,F.;Epple,G.Angew.Chem.,Int.Ed.Engl.1972,11,299-300.(c)Effenberger,F.;Epple,G.Angew.Chem.,Int.Ed.Engl.1972,11,300-301.

(10)Intermolecular catalytic Friedel -Crafts acylations with acyl chlorides have been reported,see:(a)ZnO-Catalyzed:Sarvari,M.H.;Sharghi,https://www.wendangku.net/doc/a815199116.html,.Chem.2004,69,6953-6956.(b)Metal bis-{(trifluoromethyl)sulfonyl }amide complexes catalyzed:Earle,M.J.;Hakala,U.;McAuley,B.J.;Nieuwenhuyzen,M.;Ramani,A.;Seddon,https://www.wendangku.net/doc/a815199116.html,mun.2004,1368-1369.(c)SbCl 5-benzyltriethylam-monium chloride complex:Huang,A.;Liu,X.;Li,L.;Wu,X.;Liu,W.;Liang,Y.Adv.Synth.Catal.2004,346,599-602and references therein.(d)Ga(ONf)3catalyzed:Matsuo,J.;Odashima,K.;Kobayashi,

S.Synlett 2000,403-405.(e)Bi(OTf)3catalyzed:Re

′pichet,S.;Le Roux,(11)Popp,F.D.;McEwen,W.E.Chem.Rev.1958,58,321-401.(12)(a)Olah,G.A.;Mathew,T.;Farnia,M.;Prakash,G.K.S.Synlett 1999,1067-1068.(b)Yamato,T.;Hideshima,C.;Prakash,G.K.S.;Olah,https://www.wendangku.net/doc/a815199116.html,.Chem.1991,56,3955-3957.

(13)For other approaches to 1-indanone,see:(a)Rendy,R.;Zhang,Y.;McElrea,A.;Gomez,A.;Klumpp,https://www.wendangku.net/doc/a815199116.html,.Chem.2004,69,2340-2347.(b)Gagnier,S.V.;Larock,R.C .J.Am.Chem.Soc.2003,125,4804-4807.(c)Prakash,G.K.S.;Yan,P.;To ¨ro ¨k,B.;Olah,G.A.Catal.Lett.2003,87,109-112.(d)Pletnev,A.A.;Larock,https://www.wendangku.net/doc/a815199116.html,.Chem.2002,67,9428-9438.

(14)For a review on Sc(OTf)3in synthesis,see:(a)Kobayashi,S.;Sugiura,M.;Kitagawa,H.;Lam,W.W.-L.Chem.Rev.2002,102,2227-2302.(b)Kawada,A.;Mitamura,S.;Matsuo,J.;Tsuchiya,T.;Kobayashi,S.Bull.Chem.Soc.Jpn.2000,73,2325-2333.(c)Yon-ezawa,N.;Hino,T.;Ikeda,T.Recent https://www.wendangku.net/doc/a815199116.html,.Chem.1998,1,213-223.

(15)Matsushita,Y.;Sugamoto,K.;Matsui,T.Tetrahedron Lett.2004,45,4723-4727and references therein.

(16)Intermolecular catalytic Friedel -Crafts acylations with car-boxylic acids have been reported,see:(a)Eu(NTf 2)3catalyzed:Kawa-mura,M.;Cui,D.-M.;Hayashi,T.;Shimada,S.Tetrahedron Lett.2003,44,7715-7717and references therein.(b)Sc(OTf)3catalyzed:Koba-yashi,S.;Moriwaki,M.;Hachiya,I.Tetrahedron Lett.1996,37,4183-4186.

(17)Cui,D.-M.;Kawamura,M.;Shimada,S.;Hayashi,T.;Tanaka,M.Tetrahedron Lett.2003,44,4007-4010.

(18)Cui,D.-M.;Zhang,C.;Kawamura,M.;Shimada,S.Tetrahedron Lett.2004,45,1741-1745.

F IGURE 1.Bioactive 1-indanones

Meldrum’s Acids as Acylating Agents

Crafts reactions would be facilitated by the availability of a moisture-stable,highly electrophilic precursor20that is easily prepared,functionalized,and purified,preferably by recrystallization.Such a precursor should ideally provide aromatic ketones catalytically at moderate tem-peratures while generating only volatile and inert side products.This acylating agent should be sufficiently flexible for the facile and expedient modification and assembly of diverse polycyclic ring systems. Ketenes,21isocyanates,22isothiocyanates,23 -lactams,24 cyclic anhydrides,25azalactones,26carbamates,27and nitriles28have been exploited as electrophiles in intramo-lecular Friedel-Crafts acylations but with limited suc-cess and/or lack of generality.Esters and lactones have attracted little attention as acylating agents due to the predominant Friedel-Crafts alkylation pathway,29the carboxylate being an excellent leaving group when acti-vated by a Lewis acid.30A survey of the literature on intramolecular Lewis acid-promoted Friedel-Crafts acyl-ation with esters provided two examples.31Pinnick and co-workers reported a tandem Friedel-Crafts alkylation/ acylation of benzene with ethyl cyclopropanecarboxylate promoted by excess AlCl3at80°C to yield2-methyl-1-indanone in93%yield.32Gewald’s group described the formation of4-oxo-3-(1,4-dihydro-3-cinnoline)carbonitrile in64%yield from ethyl2-cyano-2-(2-phenylhydrazono)-acetate and excess AlCl3at reflux in chlorobenzene.33 In our hands,the application of Pinnick’s and Gewald’s work to a catalytic Friedel-Crafts acylation protocol with esters for the preparation of1-indanones was unfruitful. The methyl ester1,34bearing an electron-richπ-nucleo-phile,35was treated with a catalytic amount of BF3?OEt2. The formation of indanone2with only10%conversion directly reflected the quantity of Lewis acid used and the stoichiometric nature of the process(Scheme1).Since the primary objective was to devise a catalytic acylation reaction,metal trifluoromethanesulfonate catalysts were examined.Ester1was treated with Mg(OTf)2but the starting material was quantitatively recovered after24 h at reflux in CH3NO2.Mono-and dialkylated malonates 336and4were inert in the presence of Sc(OTf)3,and it was therefore concluded that methyl esters held little promise in metal-catalyzed intramolecular Friedel-Crafts acylation reactions.Efforts were then focused on the development of a potent electrophile for these reaction conditions.

Crow and McNab reported that Meldrum’s acid(2,2-dimethyl-1,3-dioxane-4,6-dione)could act as an electro-phile in Friedel-Crafts acylation;flash vacuum pyrolysis

(20)For a review on superelectrophiles,see:Olah,G.A.Angew. Chem.,Int.Ed.Engl.1993,32,767-788.

(21)(a)Intramolecular arylation of ketenium ions,see:Zhang,L.; Kozmin,S. A.J.Am.Chem.Soc.2004,126,10204-10205.(b) Intramolecular Friedel-Crafts acylation with chromium-carbene complex derived ketenes catalyzed by ZnCl2,see:Bueno,A.B.;Moser, W.H.;Hegedus,https://www.wendangku.net/doc/a815199116.html,.Chem.1998,63,1462-1466.

(22)Intramolecular acylation with isocyanates,see:(a)Bala′zs,L.; Nyerges,M.;Ka′das,I.;To¨ke,L.Synthesis1995,1373-1375.(b) Umezawa,B.;Hoshino,O.;Sawaki,S.;Mori,K.Chem.Pharm.Bull. 1980,28,1003-1005.(c)Tanaka,H.;Nagai,Y.;Irie,H.;Uyeo,S.; Kuno,A.J.Chem.Soc.,Perkin Trans.11979,874-878.(d)Umezawa, B.;Hoshino,O.;Sawaki,S.;Sashida,H.;Mori,K.Heterocycles1979, 12,1475-1478.(e)Davies,R.V.;Iddon,B.;Suschitzky,H.;Gittos,M. W.J.Chem.Soc.,Perkin Trans.11978,180-184.(f)Ohta,S.;Kimoto, S.Chem.Pharm.Bull.1976,24,2969-2976.(g)Tsuda,Y.;Isobe,K.; Toda,J.;Taga,J.Heterocycles1976,5,157-162.(h)Ohta,S.;Kimoto, S.Tetrahedron Lett.1975,16,2279-2282.(i)Hendrickson,J.B.; Bogard,T.L.;Fisch,M.E.;Grossert,S.;Yoshimura,N.J.Am.Chem. Soc.1974,96,7781-7789.

(23)Intramolecular acylation with isothiocyanates,see:(a)Smith,

P.A.S.;Kan,https://www.wendangku.net/doc/a815199116.html,.Chem.1964,29,2261-2265.(b)Smith,P.

A.S.;Kan,https://www.wendangku.net/doc/a815199116.html,.Synth.1964,44,91-94.(c)Smith,P.A.S.;Kan, R.O.J.Am.Chem.Soc.1960,82,4753-4754.

(24)Intramolecular acylation with -lactams,see:Anderson,K.W.; Tepe,https://www.wendangku.net/doc/a815199116.html,.Lett.2002,4,459-461.

(25)Intramolecular Friedel-Crafts acylation with cyclic anhydrides, see:(a)Fischer,W.;Kvita,V.Helv.Chim.Acta1985,68,854-859.

(b)Cannon,J.G.;Brubaker,A.N.;Long,J.P.;Flynn,J.R.;Verimer, T.;Harnirattisai,P.;Costall,B.;Naylor,R.J.;Nohria,V.J.Med.Chem. 1981,24,149-153.(c)Horton,W.J.;Johnson,H.W.;Zollinger,J.L. J.Am.Chem.Soc.1954,76,4587-4589.(d)Campbell,A.D.J.Chem. Soc.1954,3659-3669.(e)Lloyd,H.A.;Horning,E.C.J.Am.Chem. Soc.1954,76,3651-3653.(f)Urban,R.S.;Beavers,E.M.J.Am. Chem.Soc.1954,76,3042-3043.(g)Gensler,W.J.;Samour,C.M.; Wang,S.Y.J.Am.Chem.Soc.1954,76,315-316.(h)Campbell,K. N.;Cella,J.A.;Campbell,B.K.J.Am.Chem.Soc.1953,75,4681-4684.(i)Haworth,R.D.;Sheldrick,G.;Mavin,C.R.J.Chem.Soc. 1935,636-644.

(26)Intramolecular Friedel-Crafts acylation with azalactones, see:(a)Filler,R.;Rao,https://www.wendangku.net/doc/a815199116.html,.Chem.1962,27,2403-2406.(b) Awad,W.I.;Hafez,https://www.wendangku.net/doc/a815199116.html,.Chem.1961,26,2055-2057.

(27)Intramolecular acylation with carbamates(Bischler-Napier-alsky reaction),see:(a)Wang,Y.-C.;Georghiou,P.E.Synthesis2002, 2187-2190.(b)Wang,X.;Tan,J.;Grozinger,K.Tetrahedron Lett. 1998,39,6609-6612.(c)Angle,S.R.;Boyce,J.P.Tetrahedron Lett. 1995,36,6185-6188.(d)Banwell,M.G.;Bissett,B.D.;Busato,S.; Cowden,C.J.;Hockless,D.C.R.;Holman,J.W.;Read,R.W.;Wu,A. W.J.Chem.Soc.,https://www.wendangku.net/doc/a815199116.html,mun.1995,2551-2553.(e)Bandwell, M.G.;Cowden,C.J.;Gable,R.W.J.Chem.Soc.,Perkin Trans.11994, 3515-3518.(f)Bandwell,M.G.;Cowden,C.J.;Mackay,M.F.J.Chem. Soc.,https://www.wendangku.net/doc/a815199116.html,mun.1994,61-62.(g)Banwell,M.G.;Wu,A.W.J. Chem.Soc.,Perkin Trans.11994,2671-2672.(h)Martin,S.F.;Tu,

https://www.wendangku.net/doc/a815199116.html,.Chem.1981,46,3763-3764.

(28)For intramolecular versions of the Houben-Hoesch reaction (acylation with nitriles),see:(a)Sato,Y.;Yato,M.;Ohwada,T.;Saito, S.;Shudo,K.J.Am.Chem.Soc.1995,117,3037-3043.(b)Rama Rao, A.V.;Gaitonde,A.S.;Prakash,K.R.C.;Rao,S.P.Tetrahedron Lett. 1994,35,6347-6350.(c)Cameron,D.W.;Deutscher,K.R.;Feutrill,

(29)For an example of intramolecular Friedel-Crafts alkylation of π-nucleophiles withγ-lactones,see:Fillion,E.;Beingessner,R.L.J. Org.Chem.2003,68,9485-9488.

(30)For reviews on the Friedel-Crafts alkylation reaction,see:(a) Olah,G.A.;Krishnamurti,R.;Prakash,G.K.S.In Comprehensive Organic Synthesis;Trost,B.M.,Fleming,I.,Eds.;Pergamon Press: Oxford,UK,1991;Vol.3,pp293-339.(b)Roberts,R.M.;Khalaf,A.

A.Friedel-Crafts Alkylation Chemistry:A Century of Discovery;Marcel Dekker:New York,1984.Intermolecular Friedel-Crafts acylation with esters,see:(c)Karade,N.N.;Shirodkar,S.G.;Potrekar,R.A. J.Chem.Res.(S)2003,652-654.(d)Olah,G.A.;Nishimura,J.J. Am.Chem.Soc.1974,96,2214-2220and references therein.(e) Pepper,J.M.;Robinson,

B.P.Can.J.Chem.1966,44,1809-1816.(f) Pepper,J.M.;Robinson,B.P.Can.J.Chem.1963,41,2103-2106.

(g)Man,E.H.;Hauser,https://www.wendangku.net/doc/a815199116.html,.Chem.1952,17,397-403.(h) Takegami,Y.;Shingu,H.Bull.Inst.Chem.Res.,Kyoto Univ.1951, 24,84.(i)Illari,G.Gazz.Chim.Ital.1947,77,352-358.(j)Kursanov, D.N.;Zel’vin,https://www.wendangku.net/doc/a815199116.html,pt.Rend.Acad.Sci.URSS1942,36,17-21. (k)Norris,J.F.;Arthur,P.,Jr.J.Am.Chem.Soc.1940,62,874-877. (l)Simons,J.H.;Archer,S.;Randall,D.I.J.Am.Chem.Soc.1939, 61,1821-1822.(m)Norris,J.F.;Sturgis,B.M.J.Am.Chem.Soc. 1939,61,1413-1417.(n)Kursanov,D.N.;Zel’vin,R.R.Zh.Obshch. Khim.1939,9,2173-2178.(o)Berman,N.;Lowy,A.J.Am.Chem. Soc.1938,60,2596-2597.(p)Bowden,E.J.Am.Chem.Soc.1938, 60,645-647.(q)McKenna,J.F.;Sowa,F.J.J.Am.Chem.Soc.1937, 59,1204-1205.(r)Kashtanov,L.I.Zh.Obshch.Khim.1932,2,515-523.(s)Cox,E.H.J.Am.Chem.Soc.1930,52,352-358.(t)Cryer,J. Trans.R.Soc.Can.,Sect.III1925,19,29.

(31)Intramolecular Friedel-Crafts acylation with ethyl ester pro-moted by PPA,see:Poondra,R.R.;Fischer,P.M.;Turner,N.J.J. Org.Chem.2004,69,6920-6922.

(32)Pinnick,H.W.;Brown,S.P.;McLean,E.A.;Zoller,L.W.,III https://www.wendangku.net/doc/a815199116.html,.Chem.1981,46,3758-3760.

(33)Gewald,K.;Calderon,O.;Scha¨fer,H.;Hain,U.Liebigs Ann. Chem.1984,1390-1394.

(34)TenBrink,R.E.;McCall,J.M.J.Heterocycl.Chem.1981,18, 821-824.

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Fillion et al.

(FVP)of 2,2-dimethyl-5-phenoxy-1,3-dioxan-4,6-dione (5)at 450°C yielded benzofuran-2(3H )-one (6)in an unde-termined (N/A)yield (Scheme 2).37Starting from the analogous toluyl derivative 7,a 6%yield of the Friedel -Crafts acylation product 8was obtained and the authors proposed that the acylation proceeded via the interme-diacy of a phenoxyketene.Other than McNab’s work,the addition of carbon-based nucleophiles to Meldrum’s acid derivatives has not been exploited.38The high acidity of Meldrum’s acid and its propensity to enolize in the presence of weak Br?nsted or Lewis bases complicate nucleophilic addition to its highly electrophilic carbonyl groups.It was considered that neutral nonbasic π-nucleophiles would add to Mel-drum’s acid derivatives in the presence of a Lewis acid to further activate the carbonyl groups.39Recent work

from our laboratories has demonstrated that Meldrum’s acid derivatives are indeed effective acylating agents in intramolecular Friedel -Crafts reactions catalyzed by Sc(OTf)3under mild reaction conditions.40Meldrum’s acid is a versatile reagent,which offers several advantages over the conventional electrophiles:the precursors are readily prepared by mono-and difunctionalization at the 5-position,41easily purified,and frequently crystalline.Meldrum’s acids are highly stable with a long shelf life at room temperature.In addition,volatile byproducts,namely carbon dioxide and acetone,are generated in the acylation process.

We report herein the full account of our findings on the intramolecular Friedel -Crafts acylation of aromatics with Meldrum’s acid derivatives catalyzed by metal trifluoromethanesulfonates under mild reaction condi-tions (eq 1).The preparation of polysubstituted 1-in-

danones from benzyl Meldrum’s acids was investigated thoroughly,and it was shown that a diversity of catalysts can promote the reaction and many functional groups are tolerated by these relatively mild conditions in compari-son to conventional methods.The scope,limitations,and functional group tolerance for a variety of 5-benzyl (enolizable Meldrum’s acids)and 5-benzyl-5-substituted Meldrum’s acids (quaternized Meldrum’s acids),forming 1-indanones and 2-substituted-1-indanones,respectively,in good to excellent yields,are delineated.This method was further applied to the synthesis of 1-tetralones,1-benzosuberones,and the acetylcholinesterase inhibitor donepezil.

Results and Discussion

Substrate Preparation.To examine the proposed methodology of catalytic Friedel -Crafts acylation with Meldrum’s acid derivatives,a ready supply of substrates with appropriately tethered aromatics was required.Meldrum’s acid is a poor nucleophile,yet has a high propensity to overalkylate at the 5-position.Several approaches were therefore used to access substrates with variable tether length and substituents within both the aromatic and aliphatic portions of the molecule (Schemes 3and 4).5-Benzyl Meldrum’s acids unsubstituted at the benzylic position were procured on large scale by reduc-tive alkylation of Meldrum’s acid with benzaldehydes.Reductive alkylation methods,which proceed via a tandem Knoevenagel condensation/alkylidene reduction,were previously reported in the literature with sodium hydrogen telluride,42borane ?dimethylamine complex,43and triethylammonium formate 44as the reducing agents.45

(37)Crow,W.D.;McNab,H.

Aust.J.Chem.1979,32,111-121.(38)For a review on the FVP of Meldrum’s acid derivatives,see:(a)Gaber,A.E.-A.O.;McNab,H.Synthesis 2001,2059-2074.(b)Mahidol,C.;Pinyopronpanit,Y.;Radviroongit,S.;Thebtaranonth,C.;Thebtaranonth,Y.J.Chem.Soc.,https://www.wendangku.net/doc/a815199116.html,mun.1998,1382-1383.(39)Few examples of Meldrum’s acid derivatives activation by Lewis (40)For a communication of our initial work,see:Fillion, E.;Fishlock,https://www.wendangku.net/doc/a815199116.html,.Lett.2003,5,4653-4656.

(41)(a)Chen,B.-C.Heterocycles 1991,32,529-597.(b)McNab,H.Chem.Soc.Rev.1978,7,345-358.

(42)Huang,X.;Xie,https://www.wendangku.net/doc/a815199116.html,mun.1986,16,1701-1707.(43)Hrubowchak,D.M.;Smith,F.X.Tetrahedron Lett.1983,24,4951-4954.S CHEME 1.Intramolecular Friedel -Crafts Acylation with Esters and Malonates

S CHEME 2.

FVP of Meldrum’s Acid Derivatives

Meldrum’s Acids as Acylating Agents

5-Alkyl Meldrum’s acids have been prepared by reducing isopropylidene acylmalonates,via the intermediacy of an alkylidene,with either NaBH 3CN or NaBH 4in AcOH.46,47It was believed that these reported protocols could be combined such that the condensation/reduction sequence could be conveniently executed in one pot by using NaBH 3CN in a buffered medium.48Indeed,benzyl Mel-drum’s acids were successfully prepared from substituted benzaldehydes and Meldrum’s acid with NaBH 3CN at room temperature in the presence of a catalytic amount of piperidinium acetate in EtOH.In most cases,the highly crystalline products were purified,for convenience and practicality,by recrystallization from MeOH or EtOH.5-Benzyl Meldrum’s acid derivatives mono-and disub-stituted at the benzylic position were accessed via 1,4-conjugate addition of aryl Grignard’s to Meldrum’s alkylidenes following literature procedures.49,50Disub-stituted Meldrum’s alkylidenes were prepared by Knoevenagel condensation of Meldrum’s acid with ke-tones (cyclohexanone,tetrahydro-4H -pyran-4-one,tet-rahydrothiopyran-4-one,acetone)in pyridine in the presence of a catalytic amount of piperidine 51or molec-ular sieves,49a or via dehydrative condensation with TiCl 4in CH 2Cl 2.52The alkylidenes were unstable on silica gel and purified by recrystallization from MeOH or EtOH.These cyclization precursors could also be obtained by conjugate addition of alkyl and aryl Grignard’s or dialkyl-aluminum reagents 53to Meldrum’s acid arylidenes.The arylidenes were obtained by the condensation of Mel-drum’s acid with benzaldehydes in water,54or by the addition of aryl Grignards to methoxymethylene Mel-drum’s acid.

Substrates with longer tether length (5-ethylbenzyl and 5-propylbenzyl)were synthesized by using Tsuka-moto’s methodology.Carboxylic acids were coupled to Meldrum’s acid with use of DCC to form the isopropy-lidene acylmalonates that were subsequently reduced with NaBH 4in AcOH to the corresponding 5-alkyl Meldrum’s acids.47Symmetrical 5,5-dibenzyl substrates were prepared in one step by reacting Medrum’s acid with 2equivalents of the appropriate benzyl bromide,using K 2CO 3in DMF (Scheme 4).55Unsymmetrical 5-benzyl-5-substituted Mel-drum’s acids were produced from monosubstituted sub-strates in an analogous manner,by alkylation with iodomethane,allyl bromide,propargyl bromide,and various benzyl bromides.56Quaternized Meldrum’s acids were easily isolated in an analytically pure form by extraction and further purified by recrystallization from MeOH.

Friedel -Crafts Acylation with Enolizable Mel-drum’s Acids.To study the viability of the proposed intramolecular Friedel -Crafts strategy,substrate 9bear-ing an electron-rich π-nucleophile was selected as the initial and optimal cyclization precursor.Various reaction conditions,Lewis acids (Sc(OTf)3,Dy(OTf)3,Yb(OTf)3,and

(46)(a)Rosowsky,A.;Forsch,R.;Uren,J.;Wick,M.;Kumar,A.A.;Freisheim,J.

H.J.Med.Chem.1983,26,1719-1724.(b)Nutaitis,C.F.;Schultz,R.A.;Obaza,J.;Smith,https://www.wendangku.net/doc/a815199116.html,.Chem.1980,45,4606-4608.

(47)(a)Hin,B.;Majer,P.;Tsukamoto,https://www.wendangku.net/doc/a815199116.html,.Chem.2002,67,7365-7368.(b)Smrcina,M.;Majer,P.;Majerova,E.;Guerassina,T.A.;Eissenstat,M.A.Tetrahedron 1997,53,12867-12874.

(48)Following our initial publication,40a one-pot reductive alkyla-tion of Meldrum’s acid with benzaldehydes using NaBH 4was reported,see:Desai,U.V.;Pore,D.M.;Mane,R.B.;Solabannavar,S.B.;Wadgaonkar,https://www.wendangku.net/doc/a815199116.html,mun.2004,34,25-32.

(49)(a)Vogt,P.F.;Molino,B.F.;Robichaud,https://www.wendangku.net/doc/a815199116.html,mun.2001,31,679-684.(b)Davies,A.P.;Egan,T.J.;Orchard,M.G.;Cunningham,D.;McArdle,P.Tetrahedron 1992,48,8725-8738.(c)Larcheve ?que,M.;Tamagnan,G.;Petit,Y.J.Chem.Soc.,https://www.wendangku.net/doc/a815199116.html,mun.1989,31-33.(d)Huang,X.;Chan,C.-C.;Wu,Q.-L.Synth.React.Inorg.Met.-Org.Chem.1982,12,549-556.(e)Huang,X.;Chan,C.-C.;Wu,Q.-L.Tetrahedron Lett.1982,23,75-76.(f)Haslego,M.L.;Smith,https://www.wendangku.net/doc/a815199116.html,mun.1980,10,421-427.(g)For the (51)(a)Baty,J.D.;Jones,G.;Moore,https://www.wendangku.net/doc/a815199116.html,.Chem.1969,34,3295-3302.(b)For the synthesis of methyl alkylidene Meldrum’s acid,see:Ziegler,F.E.;Guenther,T.;Nelson,https://www.wendangku.net/doc/a815199116.html,mun.1980,10,661-665.

(52)Brown,R.F.C.;Coulston,K.J.;Eastwood,F.W.;Gatehouse,B.M.;Guddatt,L.W.;Luke,W.;Pfenninger,M.;Rainbow,I.Aust.J.Chem.1984,37,2509-2524.

(53)Maas,S.;Stamm,A.;Kunz,H.Synthesis 1999,1792-1798.(54)Bigi,F.;Carloni,S.;Ferrari,L.;Maggi,R.;Mazzacani,A.;Sartori,G.Tetrahedron Lett.2001,42,5203-5205.

(55)(a)Desai,D.G.;Mane,R.B.Chem.Ind.(London )1982,809.For alternative methods,see:(b)Dhuru,S.P.;Mohe,N.U.;Salunkhe,https://www.wendangku.net/doc/a815199116.html,mun.2001,31,3653-3657.(c)Shing,T.K.M.;Li,L.-H.;Narkunan,https://www.wendangku.net/doc/a815199116.html,.Chem.1997,62,1617-1622.(d)Chen,S CHEME 3.5-Monosubstituted Meldrum’s Acid

Synthesis

S CHEME 4.5,5-Disubstituted Meldrum’s Acid

Synthesis

Fillion et al.

TMSOTf),Br?nsted acids (TfOH and TFA),and solvents ation was catalyzed by Sc(OTf)(Table 1,entry 1).

T ABLE 1.Intramolecular Friedel -Crafts Acylation with Enolizable Benzyl Meldrum’s Acids

A 68%yield was obtained in CH 3CN (2h,8mol %catalyst),and a 72%yield in 1,2-dichloroethane (4.5h,12mol %catalyst).b 90%conversion.c The reaction was run in CH 3CN.d Powdered 5?MS (100wt %)were added to the reaction mixture.e The substrate was added by syringe pump,over approximately 8h,to a refluxing solution of Sc(OTf)3,followed by an additional ～1at reflux.The one-pot procedure yielded the indanone in 36%yield.f The slow addition protocol furnished the indanone in 73%.g The one-pot procedure failed to produce 1-indanone.h A yield of 57%was obtained when the slow addition procedure was used.

Meldrum’s Acids as Acylating Agents

reaction times.Short reaction times motivated the use of nitromethane as the standard solvent.

Yb(OTf)3and Dy(OTf)3provided indanone 10in lower yields (Table 1,entries 2and 3)compared to Sc(OTf)3,even though TLC and 1H NMR analysis of the crude reaction mixtures revealed clean material that could be easily purified by flash chromatography.When the acy-lation was conducted with 20mol %of TMSOTf,TFA,or TfOH in refluxing 1,2-dichloroethane,a 60%,37%,and 38%yield was obtained,respectively.Furthermore,com-plex mixtures of products were formed that made the indanone purification tedious.It is noteworthy that the electrophilic substitution proceeded in the absence of a catalyst within 6h in refluxing CH 3NO 2to yield indanone 10in 55%yield (Table 1,entry 4),consistent with thermal decomposition of 5-monosubstituted Meldrum’s acid derivatives.57Purification of indanone 10,generated thermally,was difficult due to the formation of numerous byproducts of similar polarity.

Considering the thermal instability of Meldrum’s acids and the potential background reaction,the development of a protocol requiring short reaction times would mini-mize side reactions.A typical acylation reaction was conducted by simple combination of the substrate,dried Sc(OTf)3,and distilled nitromethane in a round-bottom flask equipped with a reflux condenser.The resulting suspension was immediately immersed in an oil bath preheated to 100°C and consumption of the starting material was monitored by TLC.For practicality,no aqueous workup was performed,and nitromethane was removed under vacuum and the residue was purified by flash chromatography on silica gel.

A stoichiometric amount of acetone is produced in the Friedel -Crafts acylation with Meldrum’s acids.To as-certain whether acylation yields were affected by side reactions between the 1-indanones and acetone,a control experiment was conducted with equimolar amounts of 1-indanone (47)and acetone with a catalytic quantity of Sc(OTf)3in refluxing nitromethane.GC-MS and 1H NMR analysis of the crude reaction mixture showed no decom-position of the indanone,nor any formation of aldol products.

The scope of the intramolecular Friedel -Crafts acy-lation of 5-benzyl Meldrum’s acids has been fully defined by varying the pattern of substitution and electron-donating ability of the π-nucleophile unit,as well as substitution at the -position (in the tether)to generate a diversity of functionalized 1-indanones in yields ranging from 13%to 86%(eq 2).The results are compiled in Table 1.

Mixed results were obtained for the acylation with enolizable Meldrum’s acids.The electron-rich 3,5-dimeth-oxybenzyl Meldrum’s acid substrates (entries 1-11)provided good yields (73-86%)of 1-indanones,while yields were modestly lower (13-75%)with the less electron-rich π-nucleophiles (3,5-dimethylbenzyl,3,4-dimethoxybenzyl,2,5-dimethoxybenzyl,2,3-dimethoxy-benzyl,and benzyl).

Slow addition of the substrate over approximately 8h with a syringe pump to a suspension of Sc(OTf)3in nitromethane at 100°C improved the acylation yield.3,5-Dimethylbenzyl Meldrum’s acid (23)afforded indanone 24in a 36%yield with use of the standard protocol described above,yet the yield was increased to 52%via the slow addition technique (Table 1,entry 12).

The introduction of substituents at the benzylic posi-tion ( -position)had a profound influence upon the ease of acylation.Increased substitution slightly improved the efficiency of the acylation reaction for the electron-rich 3,5-dimethoxybenzyl and 3,4-dimethoxybenzyl Meldrum’s acid substrates (entries 5-7and entries 14-16).Sub-stantial yield enhancements were observed for cyclization precursors bearing a weak π-nucleophile like 3,5-di-methylbenzyl Meldrum’s acid substrate 25and benzyl Meldrum’s acids 48and 50(Table 1,entries 13,25,and 26).For the latter,the acylations were reasonably efficient and,for comparison,Meldrum’s acid 46did not provide 1-indanone (47)under the same reaction condi-tions (entry 24).The slow addition procedure failed to increase the yield when the -position was substituted.Acylation of substrate 38,with a methyl benzylic substitutent,provided a low yield of indanone 39in 38%(Table 1,entry 20).The disubstituted substrate 40produced only an intractable mixture of decomposition products.This surprising trend reversal (Table 1,entries 19-21)may be attributable to the unusual conformation adopted by these substrates compared with the other series of -substituted Meldrum’s acids.It is speculated that the conformation adopted by these substrates is unusual compared to other series of ( -substituted)benzyl Meldrum’s acids.That conformational difference is ap-parent from the remarkable chemical shift of the acidic hydrogen of Meldrum’s acid (the proton at the 5-position).The chemical shift is 5.38ppm for compound 40,in comparison to 3.46and 3.59ppm respectively for the analogous 3,4-dimethoxybenzyl and 3,5-dimethoxybenzyl Meldrum’s acids 30and 13.This chemical shift discrep-ancy is not seen with monomethyl substate 38,despite the lower acylation yield.Severe steric interactions between the methyl substituents at the -position and the methoxy group at the 2-position of the aromatics can be invoked.

A significant number of cases are described in the literature where intramolecular acylation of aryl ethers has proven difficult in the formation of 1-indanones.58Particularly challenging is the acylation of aromatics substituted with a methoxy group meta to the site of the electrophilic substitution,in which the methoxy induc-tively deactivates the π-nucleophile.Such a scenario is found in the 3,4-dimethoxybenzyl,2,5-dimethoxybenzyl,and 2,3-dimethoxybenzyl Meldrum’s acids.Despite the presence of an ortho (Table 1,entries 17and 18)or para directing methoxy group (Table 1,entries 14-16and 19-(57)At temperatures above 100°C,Meldrum’s acid derivatives tautomerize to the corresponding 6-hydroxydioxinones that further undergo retro-Diels -Alder reaction to furnish acylketenes.(a)For a review,see:Sato,M.;Iwamoto,K.

https://www.wendangku.net/doc/a815199116.html,.Chem.Jpn.1999,57,76-83.(b)Sato,M.;Ban,H.;Kaneko,C.Tetrahedron Lett.1997,Fillion et al.

21),the overallπ-nuclophilicity of the arene was reduced by the meta methoxy substituent and diminished the efficiency of the cyclization.The acylation of the3,4-dimethoxybenzyl substrates27,28,and30was regiose-lective(Table1,entries14-16)and analysis of the crude mixtures by1H NMR and GC-MS showed the exclusive formation of5,6-dimethoxy-1-indanones.

Functional Group Compatibility.A wide range of functional groups was compatible with this Friedel-Crafts acylation methodology.Accompanying aryl methyl ether cleavage by the Lewis acid catalyst has been observed previously in Friedel-Crafts acylation with use of the classical electrophiles and reaction conditions.58,59 This protocol was mild enough to not induce dealkylation of aryl methyl ether ortho and para to the newly introduced acyl group(Table1,entries1-11and14-23).In addition,dialkyl ethers(Table1,entry9)and aryl TBDPS and TIPS ethers(Table1,entries18,22,and23) were accommodated,but the reaction conditions were fine-tuned in some cases.For instance,the Lewis basic cyclic ether17,when treated with Sc(OTf)3,yielded a trace amount of indanone18but substantial decom-position was also observed(Table1,entry8).Gratify-ingly,spiro-indanone18was formed in79%yield with Yb(OTf)3(Table1,entry9).A similar result was obtained for the cyclization of dialkyl thioether19(Table 1,entry10).

The superior mildness of this Friedel-Crafts acylation protocol is illustrated by its compatibility with acid-labile 1,3-dioxolane.Submitting substrate21to the standard reaction conditions with use of Sc(OTf)3gave a40%yield, after20min,of a1.9:1mixture of ketal:ketone.The use of catalytic Dy(OTf)3,Yb(OTf)3,or BF3?OEt2improved substantially the acylation efficiency(77%(2.5:1),75% (2.9:1),and75%(1.7:1),respectively)but unsatisfactory deprotection was still observed.Running the acylation with a protic acid scavenger,DTBMP(1mol%),did not ameliorate the ratio of ketal to ketone,and furthermore, a low conversion was obtained.Mg(OTf)2furnished promising results after5h,giving an inseparable5.5:1 mixture of1,3-dioxolane:ketone,in45%yield.Despite rigorously drying the catalyst,substrate,and solvent,the presence of water in the reaction mixture was still suspected,and responsible for the cleavage of the1,3-dioxolane.It was finally found that addition of powdered 5?molecular sieves,along with catalytic Yb(OTf)3,gave a78%yield of indanone22in21h.60Analysis of the crude 1H NMR showed a28:1ratio of1,3-dioxolane:ketone.

It was anticipated that acylation of2-trialkylsilyloxy substrates34,42,and44would be problematic and could lead to the formation of2-chromanones(Table1,entries 18,22,and23).Aryltrimethylsilyl ethers have been shown to efficiently add to Meldrum’s acid at room temperature to produce monofunctionalized malonic silyl esters.39b In contrast to this reported reactivity of aryl-trimethylsilyl ethers,aryl TIPS and TBDPS ethers were tolerated by the Friedel-Crafts protocol and lactonization was not observed.

Alkyl chlorides were also compatible.Meldrum’s acid 50gave indanone51in52%yield(Table1,entry26). This observed reactivity is consistent with that of other unsubstituted benzylπ-nucleophiles.Alkyl halides are useful for further functionalization of the benzocyclic ketones and cannot be directly obtained by using classical Friedel-Crafts conditions.

Regioselectivity of the Friedel-Crafts Acylation with Enolizable Meldrum’s Acids.Having established the reactivity of Meldrum’s acid derivatives with disub-stituted and unsubstitutedπ-nucleophiles with metal triflate catalysis,the acylation protocol was applied to meta-substituted aromatics and the regioselectivity of the process determined.As discussed earlier,the importance of substitution at the benzylic position was prominent for substrates bearing a weakπ-nucleophilic moiety (Table2).Regioisomeric indanones were obtained from 3-methoxybenzyl and3-methylbenzyl Meldrum’s acids (Table2,entries1-4)in ratios comparable to classical Friedel-Crafts protocols.61

Interestingly,the deactivated3-chlorobenzyl Mel-drum’s acid substrate65provided a mixture of indanones 66and67in62%yield(Table2,entry6).Cyclization of the analogous substrate64unsubstituted at the benzylic position failed(Table2,entry5).

Influence of Substitution at the r-Position of Meldrum’s Acids:Intramolecular Friedel-Crafts Acylation with Quaternized Benzyl Meldrum’s Ac-ids.In pursuit of our objective of synthesizing polysub-stituted1-indanones,the influence of substitution at the R-position of Meldrum’s acid(C-5)was investigated(eq 3).

The acylation of quaternized Meldrum’s acid was conducted with substrate68,using the conditions devel-oped for the cyclization of enolizable benzyl Meldrum’s acids.Contrary to the enolizable substrates,no cycliza-tion occurred in the absence of a catalyst and the starting

(59)Coburn,C.E.;Anderson,D.K.;Swenton,J.S.

https://www.wendangku.net/doc/a815199116.html,.Chem.

1983,48,1455-1461.T ABLE2.Friedel-Crafts Acylation of

(3-Substituted)benzyl Meldrum’s Acids

entry substrate

reaction

time(h)

products

(para:ortho)a

yield

(%) 152,R1)OMe;R2)H153:54(5.5:1)52 255,R1)OMe;R2)-(CH2)5-256:57(3.4:1)71 358,R1)Me;R2)H159:60(1:1)48 461,R1)Me;R2)-(CH2)5-262:63(1:1)62 564,R1)Cl;R2)H2N/A 665,R1)Cl;R2)-(CH2)5-266:67(2:1)62

a Ratio determined by analysis of the crude1H NMR.

Meldrum’s Acids as Acylating Agents

material was recovered.Intuitively,increased substitu-tion at the position R to the carbonyls was anticipated to result in a decreased reactivity based on steric argu-ments.62The catalytic acylation of 68furnished smoothly 5,7-dimethoxy-2-methyl-1-indanone (69)within 45min yielding acylation of 5-methyl-5-(3,5-dimethylbenzyl)Meldrum’s acid (70).In comparison to the analogous 3,5-dimethylbenzyl Meldrum’s acid substrates 23(Table 1,entry 12),a substantial decrease in reaction time with a markedly increasing yield was observed.

T ABLE 3.Quaternized Benzyl Meldrum’s Acids in Friedel -Crafts Acylation

A 73%yield was obtained after 550min when the reaction was run with 11mol %of catalyst.b Determined by analysis of the crude 1H NMR.c The catalyst was added in two portions.The reaction was initially started with 7mol %of catalyst followed by an additional 10mol %after 23.5h.

Fillion et al.

into 2-alkyl-1-indanones.The preparation of this type of medicinally relevant structures usually requires several steps starting from 1-indanones.On the basis of these results,the scope of the intramolecular Friedel -Crafts acylation of quaternized Meldrum’s acids was subse-quently investigated by varying the pattern of substitu-tion and electron-donating ability of the π-nucleophile moiety,giving access to a diversity of functionalized 2-substituted-1-indanones in yields ranging from 66%to 94%(eq 3).

As shown in Table 3,excellent results were obtained for the Friedel -Crafts acylation with quaternized Mel-drum’s acids for a variety of substrates.π-Nucleophilicity was not as crucial as for the enolizable substrates and a range of aromatics including 3,4-dimethoxybenzyl,3,5-dimethoxybenzyl,2,5-dimethoxybenzyl,and 2,3-dimeth-oxybenzyl efficiently generated benzocyclic ketones (Table 3,entries 3-10and 13-17).The benzyl substrate 102provided a remarkable 66%yield of 2-benzyl-1-indanone (103)considering its inability to cyclize in the enolizable series (Table 3,entry 18versus Table 2,entry 24).In addition to a methyl group,various substituents (allyl,propargyl,aryl,and benzyl)could easily be introduced at the 2-position of the 1-indanones (Table 3,entries 4-10).

A route to 2,3-disubstituted-1-indanones by the C-alkylation of ( -methyl)benzyl Meldrum’s acid 11with iodomethane and benzyl bromide to form substrates 88and 90,respectively,was developed.Upon treatment with catalytic Sc(OTf)3,the synthesis of indanones 89and 91was achieved as diastereomeric mixtures in greater than 90%yield (Table 3,entries 11and 12).

An inherent limitation of this strategy is the inability to C-alkylate ( , -disubstituted)benzyl Meldrum’s acid.63Although acylation of these precursors would provide access to 2,3,3-trisubstituted-1-indanones,the generation of two contiguous all-carbon quaternary centers in these substrates was prohibitive.

Friedel -Crafts acylation of the electon-deficient 5,5-di(4-fluorobenzyl)Meldrum’s acid (104)and the analo-gous nitro compound 106failed (Table 4,entries 20and 21).In both cases,complete decomposition of starting material was observed without providing the desired indanones 105and 107.On the other hand,the aromatic substitution of 5,5-di(3-fluorobenzyl)Meldrum’s acid (108)resulted in a 93%yield of 1-indanones 109and 110in a 13:1regioisomeric mixture in favor of the para product (eq 4).64

Optimization of the Lewis Acid Catalyst.The excellent reactivity of quaternized Meldrum’s acid sys-tems prompted the reexamination of the reaction condi-tions initially developed for the acylation of enolizable substrates.To this end,several Lewis acids were sur-veyed with 5-(3,4-dimethoxybenzyl)-5-methyl Meldrum’s acid (72).As depicted in Table 4,in addition to Sc(OTf)3,numerous metal trifluoromethanesulfonates (aluminum,magnesium,copper,trimethylsilyl)successfully catalyzed the Friedel -Crafts acylation reaction.65Other excellent candidates were TfOH and magnesium bis(trifluo-romethanesulfonyl)amide (Table 4,entries 6,and 11).Unexpectedly,BF 3?OEt 2was shown to suitably catalyze the acylation reaction (Table 4,entry 10).This first example of BF 3?OEt 2-catalyzed Friedel -Crafts acylation appears not to suffer from the catalyst inhibition reported for conventional systems.

The Lewis acids TMSCl and AlCl 3were ineffective at promoting the acylation reaction (Table 4,entry 9).The former returned starting material while the latter yielded a trace amount of 1-indanone.With AlCl 3,the electro-philic aromatic substitution was sluggish and the main reaction pathway was formation of the acid chloride by the opening of the Meldrum’s acid moiety by a chloride ion,following complexation with the carbonyl group.Aqueous workup furnished the corresponding carboxylic acid.

Applying other Lewis acids than Sc(OTf)3to the dibenzyl Meldrum’s acid substrate (102)was unproduc-tive.A catalytic amount of BF 3?OEt 2led to trace forma-tion of 2-benzyl-1-indanone (103)and starting material recovery while Mg(OTf)2was unable to promote this transformation.From these results,the general superior-ity of Sc(OTf)3is obvious,particularly for weak π-nucleo-philes.Trifluoromethanesulfonic acid was found to be equally competent (Table 3,entry 19).

(62)Examples of intramolecular electrophilic aromatic substitution with R ,R -disubstituted electrophiles,see:(a)Schultz,A.G.;Macielag,M.;Podhorez,D.E.;Suhadolnik,J.

https://www.wendangku.net/doc/a815199116.html,.Chem.1988,53,2456-2464.(b)Newman,H.;Angier,https://www.wendangku.net/doc/a815199116.html,.Chem.1966,31,1456-(63)For C,O-dialkylation of Meldrum’s acid,see:Snyder,C.A.;Selegue,J.P.;Dosunmu,E.;Tice,N.C.;Parkin,https://www.wendangku.net/doc/a815199116.html,.Chem.2003,68,7455-7459.

(64)Rosenthal,J.;Schuster,https://www.wendangku.net/doc/a815199116.html,c.2003,80,679-T ABLE 4.Optimization of the Lewis Acid Catalyst

entry catalyst loading (mol %)reaction time (min)

yield (%)1Sc(OTf)31020852Al(OTf)31020693Mg(OTf)21020834Cu(OTf)21020825TMSOTf 1020906TfOH 1020867LiOTf 1070NR 8KOTf 20-6090NR 9TMSCl 10-3590NR 10BF 3?OEt 210209011

Mg(NTf 2)2

Meldrum’s Acids as Acylating Agents

Intramolecular Friedel -Crafts Acylation with Quaternized Benzyl Meldrum’s Acids:Functional Group Tolerance and Application to the Synthesis of Donepezil.Functional group compatibility was con-sistent with the results obtained in the enolizable Mel-drum’s acid series.Again,aryl methyl and aryl TBDPS and TIPS ethers were accommodated (Table 3,entries 14,16,and 17).The mild nature of the Friedel -Crafts acylation process was further demonstrated by reacting substrates containing a terminal alkyne or alkene (Table 3,entries 6and 7),as well as nitro-and nitrile-substituted aryl groups (Table 3,entries 8and 9).Prolonged reaction times were required for Lewis basic functional groups,likely due to partial deactivation of the catalyst.

The synthesis of the potent acetylcholinesterase inhibi-tor donepezil (Figure 1)was tackled,as it contains a tertiary amine within its structure.Attempts at acylating quaternized Meldrum’s acid 111with a catalytic amount of Sc(OTf)3failed (Table 5,entry 1).It was postulated that the catalyst was inhibited by the Lewis basic tertiary amine,66though Sc(OTf)3has been shown to be an effective catalyst in the presence of basic amines in certain transformations.67When substrate 111was treated with excess Sc(OTf)3,donepezil (112)was formed but the yield was undetermined due to its difficult isolation from the reaction mixture (Table 5,entry 2).Donepezil (112)was generated smoothly by the reaction of Meldrum’s acid 111with 120mol %of TfOH in a 61%yield (Table 5,entry 3).

The striking observations made with substrate 111led to the conclusion that the presence of a basic sp 3-hybridized amine was problematic.In an attempt to circumvent this issue,the synthesis of indanone 114from Meldrum’s acid 113was explored (Table 6).The sp 2-hybridized nitrogen in 113should be less prone to interact with the catalyst and reduce its activity.Fur-thermore,the transformation of indanone 114into done-pezil hydrochloride has been reported.68Unfortunately,all attempts to form 114under catalytic conditions were unsuccessful and starting material was recovered (Table 6,entries 1,2,6,and 8).Triflic acid cleanly promoted the formation of indanone 114in 77%yield (Table 6,

entry 3),but TFA or a 5:1mixture of TFA/TfOH failed.The decomposition of the starting material (Table 6,entry 7)was observed with excess BF 3?OEt 2.The volatile TMSOTf,when used in slight excess,induced the Friedel -Crafts acylation and indanone 114was isolated in a 62%yield (Table 6,entry 9).

In light of these results,it was concluded that nitrile and nitro groups are compatible with the catalytic protocol,while sp 2-and sp 3-hybridized nitrogen-contain-ing functionalities required excess TfOH or Lewis acid to proceed.

1-Tetralone and 1-Benzosuberone Synthesis:Rate of Cyclization as a Function of Ring Size.The use of Meldrum’s acid derivatives as the acylating agent in the synthesis of 1-tetralones and 1-benzosuberones was examined.Yield enhancement was significant for the enolizable Meldrum’s substrate 115that furnished te-tralone 116in 82%yield compared to 59%yield for its indanone counterpart 2(Table 7,entry 1and Table 1,entry 14).Quaternized Meldrum’s acid 117provided 6,7-dimethoxy-1-tetralone (118)in 82%yields (Table 7,entry 2).Moreover,1-benzosuberones were efficiently formed for both types of Meldrum’s acid precursors (Table 7,entries 3and 4).

In the Friedel -Crafts acylation,it is well established that 1-tetralones are readily formed in preference to the analogous 1-indanones and 1-benzosuberones.69Milder (66)Deactivation of La(OTf)3by DABCO,see:Aggarwal,V.K.;Mereu,A.;Tarver,G.J.;McCague,

https://www.wendangku.net/doc/a815199116.html,.Chem.1998,63,7183-7189.

(67)Fukuzawa,S.;Komuro,Y.;Nakano,N.;Obara,S.Tetrahedron T ABLE 5.Donepezil Synthesis

entry promotor loading (mol %)reaction time yield (%)1Sc(OTf)21528h NR 2Sc(OTf)31704h N/A 3

TfOH

120

30min

T ABLE 6.Acylation of Pyridine-Containing Substrate

113

entry promotor loading (mol %)reaction time (h)yield (%)1Sc(OTf)3100.33NR 2Sc(OTf)34014NR 3TfOH 1201774TFA

1203NR 5TFA/TfOH 100/2044NR 6BF 3?OEt 21019NR 7BF 3?OEt 212014N/A 8TMSOTf 2019NR 9

TMSOTf

120

1.5

T ABLE 7.Synthesis of 1-Tetralones and

1-Benzosuberones

entry substrate reaction time (min)

product yield (%)1115,R )H;n )145116,R )H;n )1822117,R )Me;n )115118,R )Me;n )1823119,R )H;n )245120,R )H;n )2784

121,R )Me;n )2

122,R )Me;n )2

Fillion et al.

toward formation of various ring sizes favors 6>5>7.1g Contrary to the expected order of reactivity,1-ben-zosuberone formation was facile for the enolizable Mel-drum’s substrate,(Table 4,entries 3)when compared to the analogous 1-indanone (Table 1,entry 14).To probe the effect of tether length on the relative rate of cycliza-tion,substrates that could give mixtures of products of various ring size were synthesized.The study was realized in the enolizable and non-enolizable Meldrum’s acid substrates series with Sc(OTf)3(10mol %)in nitromethane at 100°C.For each of the six models presented in Table 8,crude 1H NMR and GC-MS analysis showed the exclusive formation of a single benzocyclic ketone.Quaternized Meldrum’s acids were efficiently acylated (Table 8,entries 1-3)and 1-tetralones prefer-entially formed over 1-benzosuberones and 1-indanones.

This set of experiments also confirmed that 1-benzosub-erones are generated preferentially over 1-indanones (Table 8,entry 2).An identical trend was observed for the enolizable Meldrum’s acids 129,131,and 133(Table 8,entries 4-6).Therefore,for the intramolecular Friedel -Crafts acylation with Meldrum’s acid derivatives,the ring formation preference is 6>7>5.Summary

Exploitation of the exceptional electrophilicity and convenient functionalization of Meldrum’s acid provides benzocyclic ketones by catalytic intramolecular Friedel -Crafts https://www.wendangku.net/doc/a815199116.html,petition experiments determined that the rate of carbocyclization favors 1-tetralone cre-ation,while benzosuberones form in preference to 1-in-danones.The mild conditions of this method are com-patible with a very wide range of functional groups that would not survive the conditions of conventional Friedel -Crafts acylation reactions.The presence of sp 2-and sp 3-hybridized nitrogen within the substrate appears to inhibit catalyst activity,so stoichiometric promoters are required in these cases.

The operational simplicity and ready availability of all precursors should make this methodology a useful tool for the assembly of substituted 1-indanones,tetralones,and benzosuberones.Mechanistic studies investigating the distinct reactivity of the enolizable versus the quat-ernized Meldrum’s acid substrates are ongoing and will be disclosed in due course.

Acknowledgment.This work was funded by the Natural Sciences and Engineering Research Council of Canada (NSERC),the Canadian Foundation for In-novation,the Ontario Innovation Trust,the University of Waterloo,and a Boehringer Ingelheim Young Inves-tigator Award to E.F.D.F.thanks the Government of Ontario for a fellowship (OGSST),and J.M.G thanks NSERC for a NSERC-USRA.

Supporting Information Available:Detailed experi-mental procedures,full characterization data,and NMR spectra for all new compounds.This material is available free of charge via the Internet at https://www.wendangku.net/doc/a815199116.html,.JO0483724

(69)(a)v.Braun,J.;Manz,

G.Justus Liebigs Ann.Chem.1929,468,258-277.(b)Leuchs,H.Chem.Ber.Recl.1928,61,144-146.

T ABLE https://www.wendangku.net/doc/a815199116.html,petition Experiments

The acylation was carried out with Sc(OTf)3(10mol %)in CH 3NO 2at 100°C.b Reaction time is 45min.c The substrate was added by syringe pump,over approximately 8h,followed by an additional ～1h at reflux.

Meldrum’s Acids as Acylating Agents

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嵌入式习题答案Last revision on 21 December 2020

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SUBS R0，R0，#1 ；寻址方式：（立即寻址）。 MOV R0，R2，LSL#3 ；寻址方式：（寄存器移位寻址）。 SWP R1，R1，[R2] ；寻址方式：（寄存器间接寻址）。 LDR R2，[R3，#0x0C] ；寻址方式：（基址寻址）。汇编语言源程序中语句一般有（指令）、（伪指令）、（伪操作）和宏指令组成。对Flash存储器的编程可通过（JTAG仿真/调试器）、（ ISP ）和（IAP）3重方法来实现。异常向量表可以来自4个不同的存储器区域，分别是（片内Flash ）、（片内SRAM ）、（ Boot Block ）和片外存储器。系列的定时器主要用于3个方面：（对内部事件进行计数的间隔定时器）、（通过捕获输入实现脉宽解调器）、（自由运行的定时器）。二选择题可以表示微控制器的缩略词是（ B ） A. MPU B. MCU C. WDT 类存储器包括（ ABD ）

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各位：根据掌握要点认真复习，后面附有作业题答案。第1章掌握要点 1.1.1节嵌入式系统的概念 1.1．3节嵌入式系统的特点 1.3节嵌入式处理器 1.4节嵌入式系统的组成（看课件，有补充的内容）补：1.嵌入式系统开发过程？ 2.嵌入式系统调试常用的基本方法 3.交叉编译和交叉调试 4.嵌入式操作系统第2章掌握要点 2.1节计算机体系结构分类 2.3.1节 ARM和Thumb状态 2.3.2节 RISC技术 2.3.3节流水线技术 2.4.1 ARM存储系统 2.4.2 Cache:写通、写回、读操作分配cache、写操作分配cache、工作原理、地址映像 2.4.3节 ARM存储系统补充: (见课件) 1. ARM简介：ARM的命名方式、5种变形

2.理解片内Flash的3种编程方法。 3.理解ARM7芯片存储器存储空间分布。（8个bank，每个bank32MB）第3章掌握要点 3.1节ARM编程模式：处理器模式、处理器工作状态、寄存器组织、异常中断 3.2节指令格式和寻址方式 3.3节指令系统：掌握和熟练应用课件所讲的指令、可编程序段第5章掌握要点 5.1节键盘接口：行扫描法原理、掌握编写驱动程序 5.2节 LED显示器接口：理解工作原理，掌握编写驱动程序 5．5.1节 UART异步串行接口：异步通信格式、接收的4种错误类型、初始化、发送程序、接收程序第1章作业题答案： 1.什么是嵌入式系统？ ?第一种，根据IEEE（国际电气和电子工程师协会）的定义：嵌入式系统是“用于控制、监视或者辅助操作机器和设备的装置”（原文为devices used to control, monitor, or assist the operation of equipment, machinery or plants）。 ?第二种，嵌入式系统是以应用为中心、以计算机技术为基础、软件硬件可裁剪、功能、可靠性、成本、体积、功耗严格要求的专用计算机系统。

嵌入式原理与应用复习题

一.单项选择题 1. 下面哪项为错误的说法（Ａ） A. 冯·诺依曼结构共用数据存储空间和程序存储空间，不共享存储器总线 B. 哈佛结构有分离的数据和程序空间及分离的访问总线 C. 哈佛结构在指令执行时，取址和取数可以进行并行操作 D. 哈佛结构指令执行时效率更高 2. 下列关于/etc/fstab文件描述，正确的是（Ｄ） A. fstab文件只能描述属于linux的文件系统 B. CD_ROM和软盘必须是自动加载的 C. fstab文件中描述的文件系统不能被卸载 D. 启动时按fstab文件描述内容加载文件系统 3. ARM9和ARM7的重要区别是（Ａ） A . ARM9带有MMU功能 B . ARM9支持Thumb指令集 C . ARM9带有Cache功能 D . ARM9是哈佛结构 4. 如果数据的存储格式是大端模式，32bit宽的数0x12345678在大端模式下的CPU 内存中的存放（假设从地址0x4000开始）。内存地址为0x4001的内容是（Ａ） A.0x34 B.0x56 C.0x23 D.0x78 5. 文件exer1的访问权限为rw-r--r--，现要增加所有用户的执行权限和同组用户的写权限，下列命令正确的是（Ａ） A.c h m o d a+x g+w e x e r1 B.c h m o d765e x e r1 C.c h m o d o+x e x e r1 D.c h m o d g+w e x e r1 6. NAND FLASH和NOR FLASH的区别正确的是（Ｄ） A. NOR的读速度比NAND稍慢一些 B.NAND 的擦除速度远比NOR的慢 C.NAND的写入速度比NOR慢很多 D.大多数写入操作需要先进行擦除操作。 7. gcc使用下列哪个选项可以查看编译的详细过程（Ｂ） A. -o B. -v C.-E D. -g 8. Boot Loader 的stage2通常使用C语言实现，以完成复杂的功能，并增加可读性和可移植性，以下哪一步骤属于stage2的内容（Ｄ） A.为加载?Boot?Loader?的?stage2?准备?RAM?空间 B.设置好堆栈 C.硬件设备初始化 D.将?kernel?映像和根文件系统映像从?flash?上读到?RAM?空间中 9. 怎样新建一个新文件：（Ａ） A.touch hello.c B.mk hello.c C.rm hello.c D.new hello.c 10. 在vi编辑器的命令模式中，删除一行的命令是：（Ｂ） A.yy B.dd C.pp D.xx

解剖学思考题答案复习课程

形态解剖学思考题绪论 1.人体组织、器官和系统的概念。 2.掌握人体的标准解剖学姿势。 1、组织：在结构和机能上具有密切联系的细胞和细胞间质所组成的基本结构称为组织。（有许多形态和功能相同或相似的细胞和细胞间质组成的基本结构。）器官：由几种不同的组织按一定规律结合在一起，构成具有特定形态和功能的结构称为器官。系统：在结构和功能上具有密切联系的器官结合在一起，共同执行某种特定的生理活动，即构成系统。（人体可分为运动系统、循环系统、免疫系统、消化系统、呼吸系统、泌尿系统、生殖系统、内分泌系统、感觉器和神经系统等） 2、人体标准解剖学姿势为身体直立，两眼向前平视，上肢下垂至躯干两侧，掌心向前，两足并拢，足尖向前。第一章基本组织 3. 解释：内皮、间皮、骨单位内皮：内皮是分布在心、血管和淋巴管腔面的单层扁平上皮。内皮很薄，游离面光滑，有利于血和淋巴的流动及物质交换。间皮:间皮是分布在胸膜，腹膜和心包膜的单层扁平上皮。间皮细胞游离面湿润而光滑，便于内脏器官的活动和减少摩擦。骨单位：骨单位是位于内外环骨板之间，数量较多，呈圆筒状，

与骨干长轴平行排列。每个骨单位由1个位于骨单位中央的中央管和数层围绕中央管呈同心圆排列的骨单位骨板组成。 4．简述上皮组织的结构特点与分类，举例说明上皮组织的结构与机能的统一性。上皮组织的结构特点： ①上皮细胞排列紧密而规则； ②细胞间质少； ③上皮细胞具有明显的极性； ④一般没有血管和淋巴管，其营养物质是由深层结缔组织的血管提供。分类：①被覆上皮；②感觉上皮；③腺上皮；④生殖上皮。举例：分布于体表的上皮以保护功能为主，而小肠的黏膜上皮除了有保护作用外，还有吸收和分泌功能。 5．简述结缔组织的结构特点与分类。结构特点：①细胞种类多而排列松散； ②细胞形态多样； ③无极性； ④分散在细胞间质内； ⑤细胞间质多。分类：

周立功-ARM嵌入式系统基础教程课后习题答案11

第一章思考与练习 1、举出3个书本中未提到的嵌入式系统的例子。答:红绿灯控制,数字空调,机顶盒 2、什么叫嵌入式系统嵌入式系统：以应用为中心、以计算机技术为基础、软件硬件可裁剪、适应应用系统对功能、可靠性、成本、体积、功耗严格要求的专用计算机系统。 3、什么叫嵌入式处理器？嵌入式处理器分为哪几类？嵌入式处理器是为完成特殊的应用而设计的特殊目的的处理器。嵌入式微处理器(Embedded Microprocessor Unit, EMPU) 嵌入式微控制器(Microcontroller Unit, MCU) 嵌入式DSP 处理器(Embedded Digital Signal Processor, EDSP) 嵌入式片上系统(System On Chip) 4、什么是嵌入式操作系统？为何要使用嵌入式操作系统？是一段在嵌入式系统启动后首先执行的背景程序，首先，嵌入式实时操作系统提高了系统的可靠性。其次，提高了开发效率，缩短了开发周期。再次，嵌入式实时操作系统充分发挥了32 位CPU 的多任务潜力。第二章 1、嵌入式系统项目开发的生命周期分哪几个阶段？各自的具体任务是什么？项目的生命周期一般分为识别需求、提出解决方案、执行项目和结束项目4 个阶段。识别需求阶段的主要任务是确认需求，分析投资收益比，研究项目的可行性，分析厂商所应具备的条件。提出解决方案阶段由各厂商向客户提交标书、介绍解决方案。执行项目阶段细化目标，制定工作计划，协调人力和其他资源；定期监控进展，分析项目偏差，采取必要措施以实现目标。结束项目阶段主要包括移交工作成果，帮助客户实现商务目标；系统交接给维护人员；结清各种款项。 2、为何要进行风险分析？嵌入式项目主要有哪些方面的风险？在一个项目中，有许多的因素会影响到项目进行，因此在项目进行的初期，在客户和开发团队都还未投入大量资源之前，风险的评估可以用来预估项目进行可能会遭遇的难题。需求风险；时间风险；资金风险；项目管理风险 3、何谓系统规范？制定系统规范的目的是什么？规格制定阶段的目的在于将客户的需求，由模糊的描述，转换成有意义的量化数据。 4、何谓系统规划？为何要做系统规划系统规划就是拟定一个开发进程，使项目在合理的进程范围中逐渐建构完成。其目地是让客户可以进一步地掌握系统开发的进程，并确定检查点，以让双方确定项目是否如预期中的进度完成。 5、为什么在项目结束前需要进行项目讨论？项目的讨论一个项目进行的反馈机制。通过这一个程序，项目团队的经验才可以被记录下来，也就是说，这是一个撰写项目历史的过程。第三章 1、ARM7TDMI中的T、D、M、I的含义是什么？ 64 位乘法指令（带M 后缀的）、支持片上调试（带D 后缀的）、高密度16 位的Thumb 指令机扩展（带T 后缀的）和EmbededICE 观察点硬件（带I 后缀的） 2、ARM7TDMI采用几级流水线？使用何种存储器编址方式？三级流水线（取指译码执行）；使用了冯·诺依曼（V on Neumann ）结构，指令和数据共用一条 32 位总线。 3、ARM处理器模式和ARM处理器状态有何区别？处理器模式指的是处理器在执行程序时在不同时刻所处的不同状态，处理器状态指的是处理器当前所执行的指令集。 4、分别列举ARM的处理器模式和状态。状态： ARM 状态32 位，这种状态下执行的是字方式的ARM 指令

嵌入式系统原理及接口复习要点及思考题答案计

各位：根据掌握要点认真复习，后面附有作业题答案。第1章掌握要点 1.1.1节嵌入式系统的概念 1.1．3节嵌入式系统的特点 1.3节嵌入式处理器 1.4节嵌入式系统的组成（看课件，有补充的容）补：1.嵌入式系统开发过程？ 2.嵌入式系统调试常用的基本方法 3.交叉编译和交叉调试 4.嵌入式操作系统第2章掌握要点 2.1节计算机体系结构分类 2.3.1节ARM和Thumb状态 2.3.2节RISC技术 2.3.3节流水线技术 2.4.1 ARM存储系统 2.4.2 Cache:写通、写回、读操作分配cache、写操作分配cache、工作原理、地址映像 2.4.3节ARM存储系统补充: (见课件) 1. ARM简介：ARM的命名方式、5种变形

2.理解片Flash的3种编程方法。 3.理解ARM7芯片存储器存储空间分布。（8个bank，每个bank32MB）第3章掌握要点 3.1节ARM编程模式：处理器模式、处理器工作状态、寄存器组织、异常中断 3.2节指令格式和寻址方式 3.3节指令系统：掌握和熟练应用课件所讲的指令、可编程序段第5章掌握要点 5.1节键盘接口：行扫描法原理、掌握编写驱动程序 5.2节LED显示器接口：理解工作原理，掌握编写驱动程序 5．5.1节UART异步串行接口：异步通信格式、接收的4种错误类型、初始化、发送程序、接收程序第1章作业题答案： 1.什么是嵌入式系统？ ?第一种，根据IEEE（国际电气和电子工程师协会）的定义：嵌入式系统是“用于控制、监视或者辅助操作机器和设备的装置”（原文为devices used to control, monitor, or assist the operation of equipment, machinery or plants）。 ?第二种，嵌入式系统是以应用为中心、以计算机技术为基础、软件硬件可裁剪、功能、可靠性、成本、体积、功耗严格要求的专用计算机系统。

第四章感觉与知觉(复习稿练习与答案)

第四章感觉和知觉教学要求： 1.掌握感觉、知觉的概念。 2.了解感觉、知觉种类；感觉的一般规律、知觉的基本特征、直观教学的形式和特点、正确进行直观教学的措施。 3. 掌握青少年感知能力的培养方法。教学重点： 1. 感觉和知觉的概念； 2. 知觉的特性；教学重难点：感觉、知觉的特性，感受性与感觉阈限。第一节感觉和知觉的概述教学过程：导学提示感觉与知觉是最初级，也是最基本的认知过程。感觉是人类认识世界的第一步, 通过感觉, 我们从内外环境中获取信息, 通过知觉, 我们根据自己的知识经验对于从环境中输入的信息加以整合和识别, 使杂乱无章的刺激具有了意义。现实生活中，纯粹的感觉几乎是不存在的，感觉总是与知觉紧密结合在一起，因而也称感知觉。心理学对感知觉的研究有着最长的历史和最为丰富的内容。（一）、什么是感觉。 1 、感觉的概念。（1 ）导入：课堂小实验（2 ）定义：感觉是人脑对直接作用于感觉器官的客观事物的个别属性的反映。（区别于日常概念“感觉”。）【研究实例】美国普林斯顿大学做的剥夺感觉的实验。【心理点评】感觉虽然试一种简单的心理活动，但却十分重要。首先，感觉向大脑提供了内外环境的信息。通过感觉的人可以了解外界事物的各种属性，保证机体与环境的平衡。感觉是认识的开端，知识的源泉。而以上实验可以证明刺激和感觉对于任何人来说都是必不可少的。对于一个正常人来说，没有感觉的生活是不可忍受的。（二）感觉的特点

1 、感觉反映的是当前的事物。（不是过去的事物或间接的事物） 2 、感觉反映的是客观事物的个别属性。（不是事物的整体） 3 、感觉是客观内容和主观形式的统一。（以客观事物为根源，以主观解释为形式）（三）感觉的分类：根据感觉器官的不同，分为外部感觉和内部感觉。 1 、外部感觉：视觉、听觉、味觉、嗅觉、肤觉 2 、内部感觉：运动觉、平衡觉、机体觉。（略作解释）三、知觉的含义及其分类（一）什么是知觉， 1 、定义：知觉是人脑对直接作用于感觉器官的客观事物的整体属性的反映。 2 、分析：（1 ）“直接作用”。（2 ）“整体”。( 整体不是个别属性的简单相加，而是对多种个别属性和各个部分之间的关系的综合的反映。) （二）、知觉的种类。 1 、依据知觉活动时感受器的不同分为：视知觉、听知觉、嗅知觉、味知觉等。 2 、依据知觉的对象的不同分为：（1）物体知觉 ①空间知觉：对物体的形状、大小、远近、方位等特性的知觉。 ②时间知觉：对节奏、时间的估计。 ③运动知觉对物体空间位移的知觉。（2）社会知觉 ①个人知觉②人际知觉③自我知觉 3．根据知觉映象是否符合客观实际，可分为（补充内容）：（1）正确的知觉（2）错误的知觉（错觉）概念：～即对客观事物的一种不正确的、歪曲的知觉 ①对物的错觉（如视错觉、运动错觉、时间错觉、形重错觉） ②对人的错觉（首因效应、晕轮效应、近因效应、刻板印象）错觉在生活中的运用：错觉在我们的生活中并不完全是无益的，如果利用得法，我们是可以利用人们的错觉来达到一定的特殊效果的。四、感觉与知觉的关系（一）感觉和知觉的共同点： 1 、反映的对象相同：都是脑对直接作用于感觉器官的客观事物的反映。都属于感性认识阶

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周立功-ARM嵌入式系统基础教程课后习题答案11

嵌入式系统原理及接口复习要点及思考题答案计

第四章感觉与知觉(复习稿练习与答案)