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Twofold CH Functionalization: Palladium-Catalyzed Ortho Arylation of Anilides Citation Brasche, Gordon, Jorge Garcia-Fortanet, and Stephen L. Buchwald. “ Twofold CH Functionalization: Palladium-Catalyzed Ortho Arylation of Anilides.” Org. Lett. 10, no. 11 (June 2008): 2207–2210. © 2008 American Chemical Society. As Published http://dx.doi.org/10.1021/ol800619c Publisher American Chemical Society Version Final published version Accessed Wed Aug 27 20:34:49 EDT 2014 Citable Link http://hdl.handle
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  Twofold CH Functionalization: Palladium-Catalyzed Ortho Arylation of Anilides  Citation Brasche, Gordon, Jorge Garcia-Fortanet, and Stephen L.Buchwald. “ Twofold CH Functionalization: Palladium-CatalyzedOrtho Arylation of Anilides.” Org. Lett. 10, no. 11 (June 2008):2207–2210. © 2008 American Chemical Society. As Published http://dx.doi.org/10.1021/ol800619c Publisher American Chemical Society Version Final published version Accessed Wed Aug 27 20:34:49 EDT 2014 Citable Link http://hdl.handle.net/1721.1/87074 Terms of Use Article is made available in accordance with the publisher's policyand may be subject to US copyright law. Please refer to thepublisher's site for terms of use. Detailed Terms The MIT Faculty has made this article openly available. Please share  how this access benefits you. Your story matters.  Twofold C - H Functionalization:Palladium-Catalyzed  Ortho   Arylation ofAnilides Gordon Brasche, Jorge Garcı´a-Fortanet, and Stephen L. Buchwald*  Department of Chemistry, Massachusetts Institute of Technology,Cambridge, Massachusetts 02139sbuchwal@mit.edu Received March 17, 2008 ABSTRACT The  ortho   arylation of anilides to form biphenyls via a twofold C - H functionalization/C - C bond-forming process is described. The oxidativecoupling takes place in the presence of 5 - 10 mol % of Pd(OAc) 2 , 10 - 20 mol % of DMSO, and 4 - 11 equiv of the aryl substrate in TFA underan oxygen atmosphere. No metal-containing cocatalyst is required. Organic chemists are faced with the challenges of accessingcomplex organic molecules efficiently, producing a mini-mum amount of waste and handling nonrenewable ornatural resources as economically as possible. In thatcontext, the growing number of reports of catalytic, directfunctionalization of C - H bonds by transition metalsrepresents a promising advance. 1,2 The application of C - Hbond functionalization to the synthesis of biaryls, moleculeswith important applications in the polymer and pharmaceuti-cal sciences, illustrates the potential utility of these protocols. 3 As shown in Scheme 1, biaryl synthesis via C - H bondactivation has been achieved via simple 4 and, most recently,via twofold 5 C - H functionalization approaches. High regi-oselectivities have generally been observed only whenelectron-rich arenes 5c–e ordirecting groups (DG) 6 such as (1) For recent reviews of C - H functionalization, see: (a) Alberico, D.;Scott, M. E.; Lautens, M.  Chem. Re V  .  2007 ,  107  , 174. (b) Godula, K.; Sames,D.  Science  2006 ,  312 , 67. (c) Kakiuchi, F.; Chatani, N.  Ad  V  . Synth. Catal. 2003 ,  345 , 1077. (d) Ritleng, V.; Sirlin, C.; Pfeffer, M.  Chem. Re V  .  2002 , 102 , 1731 . (2) For selected examples using palladium as a catalyst, see: (a)Campeau, L.-C.; Schipper, D. J.; Fagnou, K.  J. Am. Chem. Soc.  2008 ,  130 ,3276. (b) Inamoto, K.; Saito, T.; Katsuno, M.; Sakamoto, T.; Hiroya, K. Org. Lett.  2007 ,  9 , 2931. (c) Cai, G.; Fu, Y.; Le, Y.; Wan, X.; Shi, Z.  J. Am. Chem. Soc.  2007 ,  129 , 7666. (d) Delcamp, J. H.; White, M. C.  J. Am.Chem. Soc.  2006 ,  128 , 15076. (e) Wan, X.; Ma, Z.; Li, B.; Zhang, K.; Cao,S.; Zhang, S.; Shi, Z.  J. Am. Chem. Soc.  2006 ,  128 , 7416. (f) Grimster,N. P.; Gauntlett, C.; Godfrey, C. R. A.; Gaunt, M. J.  Angew. Chem., Int. Ed.  2005 ,  44 , 3125. (g) Tsang, W. C. P.; Zheng, N.; Buchwald, S. L.  J. Am.Chem. Soc.  2005 ,  127  , 14560. (h) Boele, M. D. K.; van Strijdonck, G. P. F.;de Vries, A. H. M.; Kamer, P. C. J.; de Vries, J. G.; van Leeuwen,P. W. N. M.  J. Am. Chem. Soc.  2002 ,  124 , 1586 . (3) Bringmann, G.; Gu¨nther, C.; Ochse, M.; Schupp, O.; Tasler, S. In Progress in the Chemistry of Organic Natural Products ; Herz, W., Falk,H., Kirby, G. W., Moore, R. E., Eds.; Springer: New York, 2001; Vol. 82,pp 1 - 293 . (4) (a) Shi, Z.; Li, B.; Wan, X.; Cheng, J.; Fang, Z.; Cao, B.; Qin, C.;Wang, Y.  Angew. Chem., Int. Ed.  2007 ,  46  , 5554. (b) Yang, S.; Li, B.;Wan, X.; Shi, Z.  J. Am. Chem. Soc.  2007 ,  129 , 6066. (c) Chiong, H. A.;Pham, Q.-N.; Daugulis, O.  J. Am. Chem. Soc.  2007 ,  129 , 9879. (d) Daugulis,O.; Zaitsev, V. G.  Angew. Chem., Int. Ed.  2005 ,  44 , 4046 . Scheme 1 .  Palladium-Catalyzed Simple and twofold C - HFunctionalization in the Presence of a Directing Group ORGANICLETTERS 2008Vol. 10, No. 112207 - 2210 10.1021/ol800619c CCC: $40.75  ©  2008 American Chemical Society Published on Web 05/09/2008  anilides or pyridine are used as one of the coupling partners.Despite substantial practical advances, however, importantlimitations such as the need for Cu or Ag salts as cooxidants(oftentimes in stoichiometric amounts) 5a,4d and the require-ment of up to a 100 equivalent excess of arene couplingpartner limit the synthetic utility of these methods. Fewerexamples have been reported of palladium-catalyzed C - Hfunctionalization using molecular oxygen as the only oxi-dant. 7 In one elegant example, Stoltz and co-workersdescribed the oxidative annulation of indoles using a catalyticsystem of Pd(II)/ligand/O 2  (1 atm). 8 During our investigations in C - H activation-type reac-tions, we found that a twofold C - H functionalization occursbetween anilides and arenes to form substituted biaryls using5 - 10 mol % of Pd(OAc) 2  and 4 - 11 equiv of the arylcoupling partner in the presence of oxygen as the terminaloxidant.Initially, we studied the coupling of 2-methylpivalanilide( 1a ) with benzene ( 2a ) in the presence of Pd(OAc) 2  andoxygen (1 atm) to afford  3a  (Table 1). 9 The effects of different palladium sources, additives, and temperature weresystematically examined. Low conversion of   1a  to  3a  wasobserved in the presence of 5 mol % of Pd(OAc) 2  and 11equiv (1 mL) of benzene ( 2a ) under an oxygen atmosphereat 80  ° C (entry 1). Similar results were obtained when 5equiv of acetic acid (AcOH) were added (entry 2). Thesubstitution of trifluoroacetic acid (TFA) for AcOH resultedin better yields, but these results were not fully reproducible.After some experimentation we found that loss of activecatalyst through palladium black formation could be slowedby the addition of DMSO (10 mol %), thus affording theexpected biaryl in excellent yield (entry 4). The best resultswere finally obtained at 90  ° C, at which temperature  3a  wasisolated in 92% yield (entry 7).The reaction could also be carried out with only 4 equivof   2a  by increasing the amount of TFA to 10 equiv, althoughthe corresponding yield was lower. During the course of ourwork, an elegant related paper by Shi appeared. 5a In thisdisclosure, a single example of twofold C - H functionaliza-tion using 6 equiv of arene coupling partner was reported. 10 As shown in entry 9, oxygen could be replaced effectivelyby air, but lower conversions were generally achieved underthese conditions. Poor results were obtained if Pd(OAc) 2  wassubstituted by other palladium salts such as Pd(O 2 CCF 3 ) 2  orPdCl 2  (entries 5 and 6).Using these optimized conditions, we next explored thescope and generality of this process using benzene ( 2a ) asan arylating reagent. As shown in Table 2 (entry 1),acetanilides, as well as pivalanilides, can be efficientlyarylated using our protocol. Nonetheless, due to their greaterstability and selectivity at higher temperatures, we decidedto focus our attention on pivalanilides.Neutral or electron-rich substituents on the anilide affordedarylated products in good yields of up to 91% (entries 2 - 5).In the case of the slightly electron-deficient fluorinatedcompound  1g  the temperature had to be raised to 100  ° C toobtain a satisfactory yield of 68% (entry 6). However, even (5) (a) Li, B.-J.; Tian, S.-L.; Fang, Z.; Shi, Z.-J.  Angew. Chem., Int. Ed. 2008 ,  47  , 1115. (b) Hull, K. L.; Sanford, M. S.  J. Am. Chem. Soc.  2007 , 129 , 11904. (c) Stuart, D. R.; Villemure, E.; Fagnou, K.  J. Am. Chem. Soc. 2007 ,  129 , 12072. (d) Stuart, D. R.; Fagnou, K.  Science  2007 ,  316  , 1172.(e) Dwight, T. A.; Rue, N. R.; Charyk, D.; Josselyn, R.; DeBoef, B.  Org. Lett.  2007 ,  9 , 3137 . (6) (a) Yu, J.-Q.; Giri, R.; Chen, X.  Org. Biomol. Chem.  2006 ,  4 , 4041.(b) Daugulis, O.; Zaitsev, V. G.; Shabashov, D.; Pham, Q.-N.; Lazareva,A.  Synlett   2006 , 3382 . (7) (a) Beck, E. M.; Grimster, N. P.; Hatley, R.; Gaunt, M. J.  J. Am.Chem. Soc.  2006 ,  128 , 2528. (b) Stahl, S.  Angew. Chem., Int. Ed.  2004 , 43 , 3400. (c) Dams, M.; De Vos, D. E.; Celen, S.; Jacobs, P. A.  Angew.Chem., Int. Ed.  2003 ,  42 , 3512. (d) Hagelin, H.; Oslob, J. D.; Åkermark,B.  Chem. Eur. J.  1999 ,  5 , 2413. (e) Shue, R. S.  J. Chem. Soc. Chem.Commun.  1971 , 1510 . (8) (a) Ferreira, E. M.; Stoltz, B. M.  J. Am. Chem. Soc.  2003 ,  125 , 9578.(b) Ferreira, E. M.; Zhang, H.; Stoltz, B. M.  Tetrahedron  2008 , doi:10.1016/  j.tet.2008.01.052 . (9) Unsubstituted pivalanilide gave rise to a variable mixture of mono-and bis-ortho arylated products. Similar results were observed by Dauguliset al. See ref 4d for details .  (10) According to the Supporting Information of ref 5a, most of theexamples use 28 - 37 equiv of arene counterpart. Table 1.  Screening Results of the Arylation of 2-Methylpivalanilide with Benzene entry a 2a  (equiv) Pd catalyst additive(s) gas  T   ( ° C) convn b (%) yield b (%)1 11 Pd(OAc) 2  O 2  80 8 32 11 Pd(OAc) 2  5 equiv of HOAc O 2  80 11 33 c 11 Pd(OAc) 2  5 equiv of TFA O 2  80 66 644 11 Pd(OAc) 2  5 equiv of TFA, 10 mol % of DMSO O 2  80 91 875 11 Pd(O 2 CCF 3 ) 2  5 equiv of TFA, 10 mol % of DMSO O 2  80 20 166 11 PdCl 2  5 equiv of TFA, 10 mol % of DMSO O 2  80 87 11 Pd(OAc) 2  5 equiv of TFA, 10 mol % of DMSO O 2  90 100 92 d 8 4 Pd(OAc) 2  10 equiv of TFA, 10 mol % of DMSO O 2  100 97 789  e 11 Pd(OAc) 2  5 equiv of TFA, 10 mol % of DMSO air 80 82 76 a Reactions carried out on a 1.0 mmol scale.  b Corrected GC data with dodecane as internal standard.  c Reaction was carried out multiple times withsignificantly varying results.  d  Isolated yield: 90% (average of two runs).  e Reaction carried out on a 0.2 mmol scale. 2208  Org. Lett.,  Vol. 10, No. 11,  2008  with 10 mol % of Pd(OAc) 2 , this reaction could not be drivento completion. Furthermore, the arylated product  3h  couldbe isolated in only 59% yield after 96 h at 55  ° C (entry 7).In the case of the chlorinated example  1h , the reaction hadto be carried out at a lower temperature to prevent reductionof the aryl chloride and the immediate formation of palladiumblack. Electron-deficient substrates such as those substitutedby CF 3 , CO 2 Me, or NO 2  groups underwent either no or onlytrace amounts of arylation.Prompted by these results, we next examined the arylationof anilides with arenes other than benzene (Table 3). Eitherelectron-neutral or electron-rich arenes were equally effectiveusing 7.5 - 10 mol % of Pd(OAc) 2 . The use of toluene ascoupling partner, however, afforded a mixture of   ortho ,  meta ,and  para  regioisomers (Table 3, entry 1). The regioselectivitywas improved by employing anisole or arenes with severalsubstituents. In particular, the use of veratrole as the arenecoupling partner exclusively afforded the arylation product 4d  in excellent yield as the only regioisomer.Although the electronic effects of the substituents on thearene are considerable in determining the substitution patternof the product (Table 3, entries 1, 3, 5, 7 vs 2, 4, 6, 8), sterichindrance appears to play a more important role. Forexample, when 1,3-dimethoxybenzene was used as the arenecoupling partner (entry 6), the 1,2,3-regioisomer arising fromcoupling of the most electron-rich carbon, was not observed.Indeed, with all substrates tested, arylation at less hinderedpositions was observed almost exclusively. In line with theseresults, the arylation of 1,4-dimethoxybenzene was consis-tently sluggish. These results are in accord with the resultsrecently described by Sanford and co-workers. 5b Because of the excellent regioselectivity observed usingveratrole  2d  as the arene coupling partner, we next turnedour attention to the reaction of this substrate with pivalanil-ides with different substituents (Table 4). As expected, asingle regioisomer was observed in all cases, yielding thecorresponding biaryls in good yield.It is worth mentioning that reactions employing fluoroben-zene derivatives, such as 1,3-difluorobenzene or pentafluo-robenzene, as the arene coupling partner resulted in notablylow conversions under these conditions. The significantacidity of the  ortho  proton to the fluorine atom make thesesubstrates particularly reactive in a proton abstraction-typemechanism. Thereby, our results suggest that another mech-anism may be operative under our reaction conditions. 5b,11 Table 2.  Arylation of Anilides with Benzene a Isolated yield, average of two runs.  b Incomplete conversion of thestarting material.  c Reaction run for 96 h. Table 3.  Arylation of Anilides with Different Aryls a The ratio of the regioisomers was detemined by GC.  b Isolated yieldfor the mixture of all regioisomers, average of two runs.  c The ratio of theregioisomers was calculated by  1 H NMR.  d  Incomplete conversion.  e 5 equivof TFA were used. Org. Lett.,  Vol. 10, No. 11,  2008 2209
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