an efficient, microwave-assisted, one-pot synthesis of indoles under sonogashira conditions

1、An efficient, microwave-assisted, one-pot synthesis of indoles under Sonogashira conditionsAn efficient, microwave-assisted, one-pot synthesis of indoles underSonogashira conditionsYu Chen, Nataliya A. Markina, Richard C. Larock*Department of Chemistry, Iowa State University, Ames, IA 50011, United

2、Statesa r t i c l e i n f oArticle history:Received 6 May 2009Received in revised form 24 June 2009Accepted 27 July 2009Available online 6 August 2009Keywords:Microwave-assistedOne-potThree-component couplingIndolesSonogashira couplinga b s t r a c tA microwave-assisted, one-pot, three-component cou

3、pling reaction for the synthesis of indoles has beendeveloped. The reaction is carried out in two steps under standard Sonogashira coupling conditions froman N-substituted/N,N-disubstituted 2-iodoaniline and a terminal alkyne, followed by the addition ofacetonitrile and an aryl iodide. A variety of

4、polysubstituted indoles have been prepared in moderate toexcellent yields using the present method.? 2009 Elsevier Ltd. All rights reserved.1. IntroductionTheindolenucleusisaubiquitousheterocyclicstructurefoundinnumerous natural and synthetic compounds with a wide variety ofbiological activities and

5、 considerable pharmaceutical importance.1The synthesis of indoles, therefore, has attracted enormous atten-tion from synthetic organic chemists and a substantial number ofmethods for the preparation of indoles have been developed.2Among the methods developed so far, palladium-catalyzed indolesynthes

6、es have received extraordinary attention due to the rela-tivelymild reaction conditionsemployedin these processesand thefact that they usually tolerate a wide variety of functional groups,thus avoiding protecting group chemistry. High regioselectivitiesand chemical yields are also generally achieved

7、.2bd,3Flynn pre-viously demonstrated a one-pot, two-step synthesis of indoles byconsecutive Sonogashira4and Cacchi5reactions. However, only oneexample of this process was reported.6Lu and co-workers later onreported a one-pot, three-component synthesis of indoles by thesame Sonogashira/Cacchi proces

8、s in which they replaced the aryliodide in the Cacchi cyclization with an aryl bromide.7However,asignificantsubstituenteffectinthethreestartingcomponentswasobserved on the rate of reaction. Sluggish reactions were observed,especially when an electron-withdrawing group was present at thepara-position

9、ofeithertheiodideortheamidemoietyofthestartingmaterial as in 20-iodo-trifluoroacetanilide.It is noteworthy that microwave technology has recentlyattracted more and more attention from synthetic organic chemistsdue to the many advantages microwave irradiation affords overconventional heating in chemi

10、cal transformations, particularly theenormous acceleration of the reaction rate, significant energysavings, as well as high chemical yields and cleaner reactions.8Ourgroup has been interested in developing newmethodologies forthesynthesis of functionalized indoles for almost two decades. Wehaveprevi

11、ouslydeveloped a palladium-catalyzedheteroannulationreaction of internal alkynes and 2-iodoanilines known as the Larockindole synthesis;9and the electrophilic cyclization of N,N-dialkyl-2-(1-alkynyl)anilines induced by halide,10sulfur or selenium elec-trophiles to generate indoles.11As a continuatio

12、n of our long-terminterest in indole synthesis, we hereby report a microwave-assis-ted, one-pot, three-component reaction to synthesize 2,3-di-substituted indoles under Sonogashira coupling conditions.2. Results and discussionOur group previously developed synthetic protocols for thepreparation of 3

13、-iodo-,103-sulfenyl-, and 3-selenylindoles11by theelectrophilic cyclization of N,N-dialkyl-2-(1-alkynyl)anilines byiodine or sulfenyl/selenyl chlorides. While preparing the startingN,N-dialkyl-2-(1-alkynyl)anilines for this process, we discovered aninteresting solvent effect during the Sonogashira c

14、oupling process.When the coupling of N,N-dialkyl-2-iodoanilines and terminal* Corresponding author. Tel.: t1 515 294 4660; fax: t1 515 294 0105.E-mail address: (R.C. Larock).Contents lists available at ScienceDirectContents lists available at ScienceDirectTetrahedronTetrahedronjour

15、nal homepage: homepage: see front matter ? 2009 Elsevier Ltd. All rights reserved.doi:10.1016/j.tet.2009.07.075Tetrahedron 65 (2009) 89088915alkynes was carried out in Et3N, the corresponding internal alkyneswere generally obtained as a single product in high chemical yield.On the otherhand, in the

16、presence of a polar solvent, such as CH3CNor DMF, with only 10 equiv of Et3N present, a significant amount ofan indole was obtained, alongside the desired N,N-dialkyl-2-(1-alkynyl)anilines. The indole is apparently generated by the palla-dium-catalyzed cyclization of the Sonogashira coupling product

17、and any unreacted N,N-dialkyl-2-iodoaniline.Cacchi has previously developed a similar cyclization between2-(1-alkynyl)trifluoroacetanilides and aryl iodides in the presenceof inorganic bases, such as K2CO3or Cs2CO3.5a,d,e,gIn the Cacchireaction, the reaction outcome was influenced by both the base a

18、ndthe nature of the nitrogen nucleophile. Employing Et3N as the basegave only low yields. On the other hand, a trifluoroacetamido groupplays a key role in this cyclization. When a free amino or acetamidogroup is used, no cyclization occurs and only the starting alkynesare recovered. In our case, due

19、 to the high nucleophilicity of theN,N-dialkylamino moiety, intramolecular cyclization takes placemore readily.In our view, this one-pot cyclization approach provides an idealprotocol for parallel library synthesis. Thus, a one-pot, three-com-ponent coupling reaction was carried out using N,N-dimeth

20、yl-2-iodoaniline,phenylacetyleneandethyl4-iodobenzoate(Table1,entry1). The Sonogashira coupling took place smoothly in Et3N at roomtemperature, while efficient further cyclization required a higherreactiontemperature (60as CH3CN. When a more bulky alkyne, such as 3,5-dimethoxy-phenylacetylene, and a

21、n electron-rich aryl iodide, such as 2-iodo-thiophene, were employed in this coupling, a considerably longerreaction time was needed for complete cyclization (Table 1, entry 2).In order to enhance the reaction rate of this one-pot coupling/cyclization process for the purpose of developing a high-thr

22、ough-put parallel synthetic protocol, microwave technology has beenemployed. To our delight, the entire process was dramatically ac-celerated by microwave irradiation. Both of the reactions werecompleted in less than an hour in yields comparable to thoseobtained previously.Encouraged by these result

23、s, we next explored the scope of thisone-pot, two-step approach to substituted indoles. Both the?C)andtheadditionof a polar solvent,suchSonogashira coupling and cyclization take place smoothly whenelectron-rich aryl acetylenes are used (Table 2; entries 2, 4, and 6).A longer reaction time is necessa

24、ry for complete conversion forboth the Sonogashira and cyclization steps, when an electron-de-ficient aryl acetylene is employed (Table 2, entry 3). Smooth cou-plings were also observed when aliphatic acetylenes are employed(Table 2, entries 5, 7, and 8). When 2-methoxyphenylacetylene isused, the st

25、eric bulkiness induced by the 2-methoxy group requiresa longer reaction time for cyclization (Table 2, entry 9). A free hy-droxyl group in the alkyne is not well accommodated by this cou-pling process as only a 33% yield of the desired indole product wasobtained (Table 2, entry 16).No significant el

26、ectronic effect has been observed in either the2-iodoanilines or the aryl iodides employed. Both electron-with-drawing and electron-releasing groups are readily accommodatedin these two components. An extra equivalent of aryl iodide wasemployed in the coupling processes utilizing N,N-dimethyl-4-brom

27、o-2-iodoaniline in order to suppress any interference by thebromo moiety in the cyclization step (Table 2, entries 1013). Bothbenzyl bromide and allyl acetate have been examined in this cou-pling process in place of the aryl iodide. However, none of the de-sired cyclization product was obtained in e

28、ither case. The two alkylgroups present on the aniline nitrogen play a crucial role in thesuccess of the overall process. Only Sonogashira coupling productwas obtained when either 2-iodoaniline or N-methyl-2-iodoanilinewas employed, which is in good agreement with our previousexperience with such So

29、nogashira processes.10,11BesidesN,N-dialkyl-2-iodoanilines,20-iodo-trifluoroacetanilidescan also be employed in the current microwave-irradiated process(Table 2, entries 1824). As described earlier using conventionalheating, the addition of an inorganic base is necessary for the suc-cess of this cyc

30、lization. In addition, a slightly higher reaction tem-perature is needed for efficient cyclization.As mentioned above, this overall process involves two steps(Scheme 1). The first step is a Sonogashira coupling to generate theN,N-dialkyl-2-(1-alkynyl)aniline A. The aryl iodide is added uponcompletio

31、n of the Sonogashira coupling. Oxidative addition of thearyl iodide to Pd(0) affords an electrophilic ArPdI species, whichactivates the alkyne triple bond of A by coordination to form aTable 1One-pot synthesis of indoles under Sonogashira coupling conditionsaNMeMeIR2+3 mol % PdCl2(PPh3)22 mol % CuI,

32、 Et3Nrt, 5 hNMeMeR2ArICH3CN, 60 CNMeR2ArR1R1R1123Entry1R1R2ArTime (h)3% YieldbStep 1Step 211aHC6H5CO2Et543a8221bBrMeOOMeS5123j83aRepresentative procedure: Step 1: 2-iodoaniline 1 (0.500 mmol), terminal alkyne 2 (0.525 mmol), PdCl2(PPh3)2(0.015 mmol), CuI (0.010 mmol), and 3 mL of Et3N weremixed in a

33、 sealed 4-dram vial. The reaction mixture was stirred at room temperature for the indicated time. Step 2: aryl iodide (0.550 mmol) and 3 mL of CH3CN were added tothe reaction mixture of Step 1. The resulting mixture was stirred at 60bIsolated yields of indole product after column chromatography.?C f

34、or the indicated time.Y. Chen et al. / Tetrahedron 65 (2009) 890889158909Table 2Microwave-assisted, one-pot synthesis of indoles under Sonogashira coupling conditionsaNR1R2IR4+3 mol % PdCl2(PPh3)22 mol % CuI, Et3NMW (300 W), 60 CNR1R2R4ArICH3CN, MW (300 W), 90 CNR1R4ArR3R3R3123Entry1R1R2R3R4ArTime (

35、min)3% YieldbStep 1Step 211aMeMeHC6H5CO2Et20303a8621aMeMeHOMeCO2Et20203b8631aMeMeHCNCO2Et30503c7741aMeMeHSCO2Et20303d7851aMeMeHNO220303e9161aMeMeHOMeC6H520303f9171aMeMeHCNNO220303g7281aMeMeHCNCO2Me20303h6391aMeMeHOMeCl20503i8710c1bMeMe4-BrMeOOMeS20303j7411c1bMeMe4-BrMeOOMeS20303k7612c1bMeMe4-BrSS203

36、03l85Y. Chen et al. / Tetrahedron 65 (2009) 890889158910p-palladium complex B, which subsequently undergoes intra-molecular trans-aminopalladation by a 5-endo-dig cyclization,affording the indolium species C. The latter undergoes methyl groupremoval via SN2 displacement by the in situ generated iodi

37、de anion,leading to the indole-containing Pd(II) intermediate D. The 2,3-di-substituted indole is generated after reductive elimination.Table 2 (continued)Entry1R1R2R3R4ArTime (min)3% YieldbStep 1Step 213c1bMeMe4-BrC6H5S20303m79141cMeMe4-MeC6H5CO2Et30303n68151cMeMe4-MeOMeCl30303o94161cMeMe4-MeOHOMeO

38、Me30303p33171dMeMe4-CO2MeOMeS30303q70181eHCF3OHC6H5CO2Et3030d3r93191eHCF3OHOMeOMe3030d3s82201fHCF3O4-MeOMeNO23030d3t88211fHCF3O4-MeCNC6H53030d3u66221fHCF3O4-MeSCl3030d3v67231gHCF3O4-CO2MeC6H5OMe3030d3w76241gHCF3O4-CO2MeOMeCO2Et3030d3x60aRepresentative procedure: Step 1: 2-iodoaniline 1 (0.500 mmol),

39、 terminal alkyne 2 (0.525 mmol), PdCl2(PPh3)2(0.015 mmol), CuI (0.010 mmol), and 3 mL of Et3N weremixed in a sealed 20 mL microwave vial. The reaction mixture was stirred at 60(0.550 mmol) and 3 mL of CH3CN were added to the reaction mixture of Step 1. The resulting mixture was stirred at 90indicate

40、d time.bIsolated yields of indole product after column chromatography.cAn extra equivalent of aryl iodide was employed in Step 2.dStep 2 was carried out at 100?C under microwave (300 W) irradiation for the indicated time. Step 2: aryl iodide?C under microwave irradiation (300 W) for the?C with the a

41、ddition of Cs2CO3(3 equiv).Y. Chen et al. / Tetrahedron 65 (2009) 8908891589113. ConclusionIn summary, an efficient, microwave-assisted, one-pot, three-component reaction for the synthesis of polysubstituted indoleshas been developed. Avariety of functionalities, such as nitro, ester,hydroxyl, cyano

42、, and halide groups are tolerated in this coupling/cyclization process. The desired indoles have been obtained inmoderate to excellent overall yields. This protocol provides an idealsynthetic approach for the parallel synthesis of an indole library.Due to the limited capacity of our current microwav

43、e equipment,these reactions have not been carried out on a larger scale. How-ever, we believe that the current method should be easily extendedto gram scale syntheses when appropriate microwave equipment isemployed. Further examination of the current reaction conditionsfor a one-pot, four-component

44、synthesis of indoles, as well as otherbiologically interesting heterocycles, is underway in our laboratory.4. Experimental4.1. General commentsAll microwave irradiation reactions were carried out on a Biot-age-EXP Microwave synthesis system, operating at a frequency of2450 MHz with continuous irradi

45、ation power from 0 to 300 W. Allreactions were carried out in 20 mL oven-dried Biotage microwavevials sealed with an aluminum/Teflon?crimp top, which can beexposed to a maximum of 250reaction temperature was measured by an IR sensor on the outersurface of the process vial. All commercially obtained

46、chemicalswere used as received without further purification unless other-wise indicated. The1H NMR and13C NMR spectra were recorded at400 MHz and 100 MHz, respectively, using CDCl3, acetone-d6orDMSO-d6as solvents. The chemical shifts of the1H NMR and13CNMR spectra are reported relative to the residu

47、al signal of CDCl3(d7.26 ppm for the1H NMR and d 77.23 ppm for the13C NMR), ace-tone-d6(2.05 ppm for the1H NMR and d 29.92 ppm for the13CNMR) or DMSO-d6(2.50 ppm for the1H NMR and d 39.51 ppm forthe13C NMR). The high resolution mass spectra were recorded ona double focusing magnetic sector mass spec

48、trometer using EI ata voltage of 70 eV. The melting points are uncorrected.?C and 20 bar internal pressure. The4.2. General procedure for preparation of the N,N-dimethyl-2-iodoanilinesThese compounds were prepared according to a procedurereported by Cadogan and co-workers.12To a solution of thecorre

49、sponding 2-iodoaniline (2.0 mmol) and iodomethane (0.85 g,6.0 mmol) in DMF (10 mL) was added K2CO3(0.55 g, 4.0 mmol). Theresulting mixture was stirred at room temperature for 48 h. Water(10 mL) was added to the reaction mixture and the resulting solu-tion was extracted with diethyl ether (3?10 mL).

50、The organic layerswere combined and washed with water to remove any remainingDMF and dried over anhydrous MgSO4. The solvent was removedunder vaccum and the residue was purified by flash column chro-matography on silica gel using ethyl acetate/hexanes as the eluent.4.2.1. N,N-Dimethyl-2-iodoanilineo

51、btained as a yellow oil in an 81% yield:1H NMR (400 MHz, CDCl3)d 2.76 (s, 6H), 6.77 (dt, J?7.6,1.5 Hz,1H), 7.09 (dd, J?7.8,1.5 Hz,1H),7.31 (dt, J?7.6, 1.5 Hz, 1H), 7.84 (dd, J?7.8, 1.5 Hz, 1H). The1H NMRspectral data are in good agreement with the literature data.10a(1a). Thiscompoundwas4.2.2. N,N-D

52、imethyl-4-bromo-2-iodoaniline (1b). This compoundwas obtained as a light red oil in an 81% yield:1H NMR (400 MHz,CDCl3) d 2.72 (s, 6H), 6.92 (d, J?8.5 Hz, 1H), 7.40 (dd, J?8.5, 2.4 Hz,1H), 7.94 (d, J?2.4 Hz, 1H). The1H NMR spectral data are in goodagreement with the literature data.114.2.3. N,N,4-Tr

53、imethyl-2-iodoanilineobtained as an orange liquid in a 91% yield:1H NMR (400 MHz,CDCl3) d 2.26 (s, 3H), 2.72 (s, 6H), 6.99 (d, J?8.1 Hz, 1H), 7.12 (d,J?8.1 Hz, 1H), 7.68 (s, 1H). The1H NMR spectral data are in goodagreement with the literature data.10b(1c). Thisproductwas4.3. Preparation of methyl 4

54、-dimethylamino-3-iodo-benzoate (1d)This compound was prepared according to a procedure reportedby Larock and co-workers.13The product was obtained as a color-less oil in a 44% yield:1H NMR (400 MHz, CDCl3) d 2.82 (s, 6H), 3.85(s, 3H), 6.98 (d, J?8.4 Hz, 1H), 7.92 (dd, J?8.4, 2.0 Hz, 1H), 8.46 (d,J?2

55、.0 Hz, 1H). The1H NMR spectral data are in good agreementwith the literature data.134.4. General procedure for preparation of theN-trifluoroacetyl-2-iodoanilinesThese compounds were prepared according to a procedurereported by Srinivasan and co-workers.14To a solution of the cor-responding 2-iodoani

56、line (4.3 mmol) and triethylamine (0.63 mL,4.55 mmol) in THF (11 mL) at ?15acetic anhydride (0.6 mL, 4.3 mmol) in 6.5 mL of THF. The resulting?C was slowly added trifluoro-NMeMeIR+NMeMeRArlNMeRPdArPd(0)/Cu(I)AArPdINRMe MeAr- MeIPd(0)NMeRArCBNMeRPdArMeIDPdIScheme 1. A proposed mechanism for the one-p

57、ot, two-step indole synthesis.Y. Chen et al. / Tetrahedron 65 (2009) 890889158912mixture was stirred for 1 h and then allowed to warm to roomtemperature and stirred for 16 h. The reaction mixture was thenpoured into a separatory funnel containing water (115 mL) andextracted with ethyl acetate (3?50

58、mL). The organic layers weredried over anhydrous MgSO4. The solvent was removed undervacuum and the residue was purified by flash column chromato-graphy on silica gel using ethyl acetate/hexanes as the eluent.4.4.1. N-Trifluoroacetyl-2-iodoanilineobtained as a white solid in a 96% yield: mp 105107(4

59、00 MHz, CDCl3) d 6.98 (t, J?7.0 Hz,1H), 7.42 (t, J?7.4 Hz,1H), 7.84(d, J?7.9 Hz, 1H), 8.21 (d, J?8.2 Hz, 1H), 8.29 (s, 1H). The1H NMRspectral data are in good agreement with the literature data.15(1e). Thisproduct?C;1H NMRwas4.4.2. N-Trifluoroacetyl-2-iodo-4-methylaniline (1f). This productwas obtained as a pink solid in a 95% yield: mp 8485(400 MHz, CDCl3) d 2.32 (s, 3H), 7.19 (d, J?8.1 Hz, 1H), 7.66 (s, 1H),8.01 (d, J?8.3 Hz, 1H), 8.21 (s, 1H).?C;1H NMR4.4.3. Methyl 4-(N-tr