化学药中特殊物质和基团检测方案

耐士科技400-188-0725www.rysstech.comTetrahedron Letters 55 (2014)6680-6683 www.rysstech.comS. Chatterjee et al./Tetrahedron Letters 55 (2014) 6680-6683耐士科技400-188-07256681 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage： www.elsevier.com/locate/tetlet Indium trichloride catalyzed sp’C-H bond functionalizationof 2-alkyl azaarenes under microwave irradiation CrossMark Sourav Chatterjee， Pinaki Bhattacharjee，Jagadeesh Temburu， Debkumar Nandi， Parasuraman Jaisankar* Laboratory of Catalysis and Chemical Biology， Department of Chemistry， CSIR-Indian Institute of Chemical Biology， Kolkata 700032， India ARTICLEINFO ABSTRACT Article history：Received 10 July 2014Revised 7 0ctober 2014Accepted 9 October 2014Available online 16 October 2014 Microwave promoted indium trichloride (10 mol%) catalyzed spc-H bond functionalization of2-alkylazaarenes 1 or 4 has been observed to construct C-C bond either with but-2-ene-1，4-diones 2 or (E)-3-(2-oxo-2-phenylethylidene)indolin-2-one (6) giving access to 2-((quinolin-2-yl)methyl)butane-1，4-diones3， 2-((pyridin-2-yl)methyl)butane-1，4-diones 5， or 3-(quinolin-2-yl)propan-2-yl)indolin-2-ones 7 ingood yields using 1，4-dioxane as solvent. @ 2014 Elsevier Ltd. All rights reserved. Keywords：Indium trichlorideMicrowave irradiationAzaareneEnedionesp'c-H bond functionalization Direct functionalization of sp’c-H bonds to undergo carbon-carbon bond formation attracts considerable attention in modernorganic synthesis due to simplicity of overall process. BenzylicspC-H bond functionalization of 2-alkyl azaarenes such as 2-alkylquinoline is a challengingtask due to inherent nature of lessreactivity of alkyl groups. Alkylazaarene derivatives are knownto possess a wide range of pharmacological activities， such asanti-tuberculosis，2a anti cancer，2b-danti-inflammatory，2eeandanti-HIV.2e They are also being used as self-organization and com-plex matter in supramolecular chemistry.2tg Microwave promotedorganic transformation has already been established as a reliabletool for getting higher yields of the products under milder reactionconditions and shorter reaction times. In recent time，sp’c-Hbond functionalization of 2-alkyl substituted azaarene catalyzedby transition metal catalysts，4 Lewis .acids， or Bronsted acidshas been reported. Many of these methods are associated with var-ious drawbacks such as use of tedious experimental procedures，unsatisfactory yields， long reaction times， and limited substratescope. Hence， it has become necessary to develop mild and effi-cient method and reagent to activate sp’C-H bond of 2-methylazaarene for further generation of C-C bond with suitable sub-strates.Although， indium belongs to the same group in the periodictable as boron and aluminum， indium salts have become popularamong the synthetic organic chemists due to its capability to ( * C orresponding author. Fax： +91 33 24735197. ) ( E-mail address： j a isank a r@iicb. r es. i n ( P . Jaisankar). ) ensure chemo- and regio-selectivity in various chemical transfor-mations such as Diels-Alder，7a aldol，7Friedel-Crafts，7and variousother reactions. It is generally considered to be nontoxic to nature，recyclable，and moisture tolerant. As part of our ongoing researchprogram to explore the application of indium chloride for the syn-thesis of various biologically active heterocyclic compounds， weare delighted to observe that InCls under MW irradiation (120℃，75 W) could functionalize sp’c-H bond of 2-methyl azaarenes，which underwent Michael addition with enedione or indoline-2-one affording alkyl azaarenyl substituted dicarbonyl derivativesin good yields. Our initial efforts focused on reacting 2-methyl quinoline (1a)and (E)-1，4-diphenylbut-2-ene-1，4-dione (2a) in the presence of10 mol % of InCl3 as a Lewis acid catalyst in THF under conventionalheating at 120C which afforded 65% of adduct 1，4-diphenyl-2-((quinolin-2-yl)methyl)butane-1，4-dione(3aa)，whereas，conductingthe same reaction under microwave (120℃，75 W) in the presenceof InCl3， afforded 3aa in 78% isolated yield (Table 1， entry 1).Hence it has become necessary to optimize the suitable reactionconditions for an easy access to a large number of synthesized prod-ucts. To investigate the role of solvent and Lewis acid as well asBronsted acid catalyst in the reaction， various solvents such asTHF，1，4-dioxane， CHCN， and toluene， Lewis acid catalysts such asIn(OTf)3， InCl3， ZnCl2， and FeCl， and Bronsted acid catalysts suchas acetic acid and TFA were screened (Table 1， entries 1-15). Thestudy revealed that 1，4-dioxane was the suitable solvent of choiceand InCl3 was found to be the best among the various catalysts used Solvent， Catalyst H2 MW， 30 min la 2a 3aa Entry Solvent Catalyst (10mol%) Yield (%) 1 THF InCls 78 2 Dioxane In(OTf)3 44 3 Dioxane InCls 87 4 Dioxane InBrs 83 5 Dioxane In(OAc)3 58 6 CH：CN InCls 49 7 'PrOH InCl3 73 DMF InCls 35 9 DCE InCl3 52 10 Toluene InCls 55 11 Dioxane FeCls 53 12 Dioxane RuCl3 47 13 Dioxane ZnCl， 59 14 Dioxane： water (9：1) AcOH 61 15 Dioxane： water (9：1) TFA 66 Reaction conditions： 0.75 mmol of 2-methyl quinoline， 0.5 mmol of (E)-1，4-diphenylbut-2-ene-1，4-dione， 1 mL of solvent， MW (120℃， 75 W)， 30 min.bIsolated yields. Hence， the ideal reaction conditions under MW irradiation(75W， 120℃) were found to be 10 mol% InCls as catalyst and1，4-dioxane as solvent.Using the optimized reaction conditions，the substrate scope of this reaction was investigated on a series ofsymmetrical as well as unsymmetrical enediones and the resultsare summarized in Table 2. Various substituents'effects on azaa-renes were also investigated. It seems that there is a correlationbetween the efficiency of reaction and electronic effect of substit-uents， since the presence of EWG in azaarene ring affordedslightly higher yield (91%， e.g.， NO2， Table 2， entry 3) in compari-son to EDG (e.g.， Cl， OCH3， CH3； Table 2， entry 2， 4， and 5).Similarly， when 2-ethyl quinoline (1f) was used as reactantinstead of 2-methyl quinoline (1a) it resulted in the expectedethyl azaarenyl substituted dicarbonyl derivative 3fa as diastereo-meric mixture (Table 2， entry 6). Other bulky substituentlike2-cyclohexyl quinoline (1g) also underwent C-H functionalizationwith (E)-1，4-diphenylbut-2-ene-1，4-dione (2a) to yield the desiredproduct 1，4-diphenyl-2-(1-(quinolin-2-yl)cyclohexyl)-butane-1，4-dione (3ga) in 42% yield upon microwave irradiation at 140°(100 W) for 30 min (Scheme 1) (see： Supporting information formicrowave irradiation profile). Prolonging the reaction time didnot improve the yield of 3ga. It is pertinent to mention that (E)-hex-3-ene-2，5-dione (2g) did not respond to the reaction， whenchosen as coupling partner (Table 2， entry 12). This is probablydue to the reduction of the electrophilic character on alkene bondof(E)-hex-3-ene-2，5-dione(2g) through hyper conjugative effectof two methyl groups which eventually prevents C-C bond forma-tion with 2-methyl azaarenes.Likewise， the electron deficientacetylenes as Michael acceptor did not undergo reaction withazaarenes. R R5 InCl (10mol%) H-R 0 1，4-dioxane， MW (75 watts) R4 120℃，30 min 34 R RR6 1a-f 2a-g 3aa-ag Entry R R R4 1 R5 R6 2 Product” Yield(%) 1 H H H Ph Ph a 3aa 87 2 H H C1 Ph Ph a 3ba 83 3 H H H Ph Ph a 3ca 91 4 H H OCH3 d Ph Ph a 3da 79 5 H CH3 H H Ph Ph a 3ea 73 6 CH3 H H H Ph Ph a 3fa 78 7 H H H H a p-np p-np b 3ab 79 8 H H H H a Ph OCHs c 3ac 85 9 H H H H a Ph CH： d 3ad 72 10 H H H H a p-BrC6H4 p-BrC6H4 e 3ae 82 11 H H H H a p-MeC6H4 p-MeC6H4 f 3af 78 12 H H H H a CH3 CH3 g 3ag n.r. dReaction conditions： 0.75 mmol of 2-methyl quinoline (1a)， 0.5 mmol of (E)-1，4-diphenylbut-2-ene-1，4-dione (2a)， InCls (10 mol%)， 1 mL of 1，4-dioxane， MW (75 W)，120°C，30 min. All products were characterized by NMR， HRMS analysis. ( The yields indicated ar e th e i so lated y i elds by column ch r omatography. ) ° Isolated as inseparable diastereomeric mixture. ° No reaction. www.rysstech.com Pleasingly the reaction could be extended to other 2-methylazaarenes. For instance， 2-picoline (4a) and 2，6-lutidine (4b) alsounderwent C-C bond formation reaction with (E)-1，4- diphenyl-but-2-ene-1，4-dione (2a) to afford the expected products 5a and5b in 72% and 63% yields， respectively (Scheme 2). In order to evaluate the effectiveness of this methodology，(E)-3-(2-oxo-2-phenylethylidene)indoline-2-one (6) Was alsoemployed in the reaction with 2-methyl quinolines 1a-c underidentical reaction conditions. As anticipated， these reactions pro-ceeded smoothly to afford desired products 7a-c in good yields(77-86%) (Table 3， entries 1-3). The structures of all the synthesized compounds have beendeduced mainly by NMR and high resolution mass. Further， thestructure of compound 3aa was determined unambiguously by Scheme 2. Reaction of 2-picoline (4a) and 2，6-lutidine (4b) with trans-1，2-dibenzoylethylene (2a). Table 3 sp’C-H bond functionalization of 2-methyl quinolines (1a-c) with (E)-3-(2-0x0-2-phenylethylidene)indoline-2-one (6) Reaction conditions： 0.75 mmol of 2-methyl quinoline (1a)， 0.5 mmol of (E)-3-(2-oxo-2-phenylethylidene)indoline-2-one (6)， InCls (10mol%)， 1 mL of 1，4-diox-ane， MW (75 W)， 120℃， 30 min. " All products were characterized by NMR， HRMS analysis. The yields indicated are the isolated yields by column chromatography Figure 1. X-ray crystal structure of 3aa.耐士科技 X-ray crystallographic analysis (Fig. 1) and resolving the racemicmixture by using chiral HPLC (see： Supporting information). In onclusion， we have developed a simple micr1CcrOWipromoted indium trichloride catalyzed synthetic methodology forsp’ C-H bond functionalization of 2-methyl azaarenes for theefficient construction of C-C bond with enediones and enamidesin good yields. The success of this reaction should broaden the syn-thetic utility of indium trichloride in the catalytic functionalizationof sp’c-H bonds in organic synthesis. Development of chiralorganocatalysts for enantioenrichment of these products is ongo-ing in our laboratory and the results will be communicated indue course. Acknowledgments This project was funded by the Council of Scientific andIndustrial Research (CSIR)， New Delhi， India in the form of NetworkProject (ORIGIN， CSC 0108). S.C. acknowledges UGC， New Delhi，India for award of a Research Fellowship. Supplementary data Supplementary data (spectroscopic data along with copies of 1Hand 13c NMR spectra of all compounds，chiral HPLC profile of 3aa，X-ray crystallographic data [CIF files] of 3aa， and microwave reac-tion profiles for the formation of 3aa and 3ga) associated with thisarticle can be found， in the online version， at http：//dx.doi.org/10.1016/j.tetlet.2014.10.058. These data include MOL files andInChiKeys of the most important compounds described in thisarticle. References and notes 1. For selected reviews on spc-H bonds transformations， see： (a) Chen， X.； Engle，M； Wang， D. H.； Yu， j. Q. Angew. Chem.， Int. Ed. 2009， 48，5094； (b) Jazzar， R.；Hitce，J：Renaudat， A.； Sofack-Kreutzer，J； Baudoin，O. Chem. Eur.J. 2010， 16，2654；(c)LyLyons，T. W.； Sanford， M. S. Chem. Rev. 2010，110，1147； (d) Li， H.； Li， B.Catal Sci. Technol. 2011， 1， 191. 2.For mycobacteriumtuberculosisactivity， see：(a)FHoughton， P. J.；Woldemariam， T. Z.； Watanabe， T.； Yates， M. Planta Med. 1999， 65， 250； fornti-cancer activity， see： (b) Michael， J. P. Nat. Prod. Rep. 2000， 17， 603； (c) Jacquemond-Collet，I.； Benoit-Vical， F.； Valentin， M. A.； Stanislas，E.； Mallie，M.；Fouraste， I. Planta Med. 2002，68，68；(d) Solomon， V.R.； Lee， H. Curr. Med. Chem.2011， 18， 148； for anti-inflammatory and anti-HIV activity，see： (e) Henry，G. 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PLoS ONE 2011， 6(12)， e28493. 11.G(eneral procedure for the InCls catalyzed formation of 1，4-diphenyl-2-((quinolin-2-yl)methyl)butane-1，4-dione (3aa) under microwave irradiation： Into a 2 mL (1a， 107 mg， 0.75 mmol)， (E)-1，4-diphenylbut-2-ene-1，4-dione (2a， 118 mg，0.5 mmol)，InCls (11 mg， 10 mol%)， and 1 mL of dry 1，4-dioxane. The mixturewas microwave irradiated (Biotage Initiator microwave system EXP EU， part no.355301)， at 120 C for 30 min. The mixture was filtered through a pad of Celitewhich was then washed with ethyl acetate and water. The organic phase wasseparated from the bilayer filtrate， washed with water， brine， and dried overanhydrous sodium sulphate. After evaporation， further purification wasperformed with flash chromatography (8-10% ethyl acetate in hexane) to getthe pure product 3aa (165 mg， 87% isolated yield) as pale yellow solid； H NMR(300 MHz， CDCl3)： 8 8.14(d，J=7.2Hz， 2H)， 8.02 (d，J=8.1 Hz， 1H)， 7.91 (d，J=7.8 Hz， 3H)， 7.74(d，J=8.1 Hz，1H)， 7.64(t，J=7.5 Hz， 1H)， 7.52-7.38(m，7H)，7.25 (d，J=7.2 Hz， 1H)， 4.89-4.85 (m， 1H)， 3.75 (dd，J=17.8 Hz， 8.5 Hz， 1H)，3.49 (dd，J=14.4 Hz， 6.0 Hz， 1H)，3.31 (dd，J=18.0 Hz， 4.2 Hz， 1H)， 3.18 (dd，J=14.4 Hz，8.1 Hz， 1H)； 1’C NMR(75 MHz， CDCl3)： 8 202.8， 198.3，158.9，147.8，136.6，136.5，136.4，133.1，132.9，129.4，128.9(2C)， 128.7(2C)， 128.6 (2C)，128.5(2C)， 128.1，127.4，126.8，126.0，121.7，41.2， 40.6， 40.5； HRMS (EI*)： calcdfor C26H21NO2[M]*： 379.1572， found 379.1573. For chiral resolution of racemicmixture of 3aa using HPLC： see Supporting information. 12.T1he information on crystal structure of 3aa (CCDC 983036) can be obtainedfree of charge from The Cambridge Crystallographic Data Centre vi.a http：//dx.doi.org/j.tetlet.O Elsevier Ltd. All rights reserved.士科技www.rysstech.com 耐士科技