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In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains. www.rsc.org/chemcomm Page 1 of 4 Journal Name ChemComm Dynamic Article Links ► Cite this: DOI: 10.1039/c0xx00000x www.rsc.org/xxxxxx ARTICLE TYPE Palladium-Catalyzed Selective Aminoamidation and Aminocyanation of Alkenes Using Isonitrile as Amide and Cyanide Sources Hanling Gao, Bifu Liu, Wanqing Wu, Huanfeng Jiang* 5 Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX DOI: 10.1039/b000000x A mild and efficient palladium-catalyzed intermolecular an irreplaceable role over carbon monoxide for simple operation, aminoamidation and aminocyanation of alkenes with a broad an extra diversity point and possibilities for further elaboration 9 substrate scope has been developed. This cyclization process using convertible isocyanide. Therefore, it is not surprising that 10 provides a valuable synthetic tool for substituted indolines, large numbers of reactions with the insertion of isocyanides into 10 tetrahydroisoquinolines and pyrrolidines in good to excellent 45 the C-Pd bond have sprung up. Recently, we have developed yields. various methods for Pd-catalyzed isocyanides insertion to the synthesis of diversified amides and nitrogen heterocyclic 11 Manuscript The pursuit of concise strategies for the construction of nitrogen- compounds. To our knowledge, isocyanides can be utilized as a heterocyclic compounds continues to be a long sought after target source of both carbonyl and amino group to the formation of 11a,12 15 due to their wide existence in biological and medicinal chemistry. 50 synthetically useful amide and cyano compounds. Inspired 11g It was an attractive and challenging area of research in organic by our previous work and the related report about alkene 6b synthesis to get direct access to a final molecule from readily aminofunctionalization reaction, we herein report the first Pd- available substrates. In addition, alkene difunctionalization catalyzed aminoamidation and aminocyanation of alkenes with reactions are an attractive alternative means with significant isocyanide insertion to directly give 2-substituted indolines and 1 20 synthetic potential to rapidly increase molecular complexity. 55 pyrrolidines or tetrahydroisoquinolines (Scheme 1), which These reactions are particularly appealing and of fundamental function as versatile precursors of highly important building importance because they constituted a breakthrough in both blocks such as β-amino acids. On the other hand, these class of organic synthesis and green chemistry. 2 Recently, our group has scaffolds are embedded widely in natural products or designed Accepted 13 successfully developed a series of transition-metal-catalyzed compounds with a broad range of biological activities. 25 alkene difunctionalization reactions, such as diacetoxylation of 60 We began our investigation of the aminoamidation reaction alkenes and dehydrogenative aminohalogenation of unactivated focused on N-sulfonyl-2-allylaniline ( 1a ) with tert -butyl alkenes etc .3 Meanwhile, alkene aminofunctionalization reactions isocyanide ( 2a ) as the substrates to screen the reaction conditions. represent a highly versatile synthetic methods for the synthesis of When a solution of 1a and 2a in the presence of 10 mol % of valuable nitrogen-containing heterocycles and they are studied different catalysts with Cu(OAc) 2 as oxidant and NaHCO 3 as the 4 o 30 extensively as well. 65 base in dichloroethane at 100 C under air, the desired product 3a In the past decade, prosperous development of transition metal- could be achieved in 48% yield along with 10% of by-product (2- 14 catalyzed aminofunctionalization reactions have emerged as a methyl-1-tosyl-1H-indole) in the presence of Pd(TFA) 2 (Table very attractive branch of modern organic synthesis.(4g, 4h) Besides S1, entry 4; see the Supporting Information), which was superior palladium 5 catalysts, copper, 6 gold 7 and other metals 8 have also to any other catalysts. Then an extensive screening concerning 35 been employed successfully in this catalytic reactions. 70 copper salts, solvents, additives and temperature revealed that the o ChemComm use of Cu(TFA) 2 as oxidant in toluene at 100 C for 10 h turned out to be the best choice and resulted in 95% yield. With this optimized reaction conditions in hand, we then surveyed the generality of this aminoamidation reaction (Table 75 1). With a variety of para -substituted N-sulfonyl-2-allylanilines as the substrates, we were pleased to find that functional groups Scheme 1 Aminoamidation and aminocyanation of alkenes with both electron-donating (Me, OMe, i-Pr) and electron-withdrawing groups (CN, F, Cl, Br) could react smoothly with tert -butyl isocyanide. isocyanide, and the corresponding 2-acetamidated indolines ( 3a - 80 3h ) were obtained in good to excellent yields. Furthermore, Isocyanides, a class of unsaturated molecules acting as ortho - and meta -substituted of the aromatic ring could be also 40 isoelectronic species similar to carbon monoxide, which yet play effectively generated in good yields ( 3i and 3j ). In addition, a This journal is © The Royal Society of Chemistry [year] [journal] , [year], [vol] , 00–00 | 1 ChemComm Page 2 of 4 series of substituents on the nitrogen atom were found to be substrate could go smoothly in this reaction to give the efficiently to give the desired products 3k -3r in yields ranging corresponding products in moderate to good yields. Furthermore, from 68% to 93% under the standard conditions. Encouraged by different substituent on the nitrogen atom ( 4e ) was also well the aforementioned aminoamidation reaction, we extented this 40 tolerated and provide the desired product in moderate yield. 5 catalytic system to the aminoamidation of N-(2- Table 2. Scope of the Aminocyanation of Alkenes and Isocyanide allylbenzyl)methanesulfonamide and 4-pentenylsulfonamides for Insertion a the synthesis of corresponding substituted tetrahydroisoquinolin (3s ) and pyrrolidines (3u-3z ) in moderate to good yields. It was noteworthy that alkenes bearing methyl group at the allylic 10 olefinic carbon atoms (1t, 1v ) could not react with tert -butyl isocyanide ( 2a ) to give the corresponding product unless employing 2 equivalents of 2a and raising the temperature to 130 oC. Next, we turned our attention to test the reactivity of N- sulfonyl-2-allylaniline (1a ) and 4-methyl-N-(4-methyl-2,2- 15 diphenylpent-4-en-1-yl)benzenesulfonamide (1v ) with different isocyanides. Alkyl isocyanides such as n-butyl isocyanide, 1,1,3,3-tetramethylbutylisocyanide, and cyclohexylisocyanide (3v-3x , 3za -3zc ) were found to effectively undergo insertion whereas aromatic isocyanide was unable to provide the desired 20 product. Table 1. Scope of the Aminoamidation of Alkenes and Isocyanide Insertion a Reaction conditions: all reactions were performed with 1 (0.3 mmol), 2a Pd(TFA) (10 mol%), 45 (0.36 mmol), Pd(OAc) 2 (10 mol %), TFA (0.3 mmol), Cu(OAc) 2 (0.3 R2 2 R2 nNH Cu(TFA) (1.0 equiv), n N O (n=0,1) o 2 mmol), anhydrous toluene (2.0 mL ) at 100 C for 10 h Manuscript R1 + 3 R1 N R DABCO (2 equiv), R3 NH toluene, 100 oC, 10 h 1 2 3 To gain insight into the reaction mechanism, a control experiment was performed as shown in Scheme 215 . When N- Ts 3a, R = H, 95% F Ts Ts N 3b, R = Me, 76% N F N sulfonyl-2-allylaniline ( 1a ) and tert -butyl isocyanide (2a ) were 3c, R = OMe, 86% 18 NH 50 treated in anhydrous toluene in the presence of external H O R 3d, R = i-Pr, 85% NH NH 2 O 18 3e, R = F, 85% O O (5.0 equiv), 3a- O was was obtained nearly as the sole product. 3f, R = Cl, 91% 3i, 73% 3j, 73% 3g, R = Br, 90% This result indicated that the oxygen atom of the amide in the 3h, R = CN, 89% product was derived from H O. R 2 Ts N Ms 3k, R = Ms, 93% N O H N N 3l, R = CH CO, 70% NH 3 3m, R = PhCO, 84% N O H O Accepted 3s, 72% 3n, R = Boc, 68% 3t, 60%b 3o, R = p-MeOC6H4SO2, 93% 3p, R = p-CF3C6H4SO2, 92% 3q, R = 2,4,6-tri-MeC6H4SO2, 92% 55 Scheme 2. Mechanistic Studies. 3r, R = 2-naphthylSO2, 86% Ts 16 N Ph H O N Based on the above results and previous work , a possible Ph Ph NH R process of this reaction was proposed in Scheme 3. The reaction N 3v, R = t-Bu, 76%b N O Ph O N II H b Ts was initiated by the reaction of Pd with 1a to form the Ts 3w, R = n-Bu, 78% 3u, 68% 3x, R = cyclohexyl, 70%b 3y, 73% organometallic intermediate A. Followed by aminopalladation of Ts 60 N intermediate A generates the alkylpalladium species B, which Ts N O Ms O may undergo β-hydride elimination to give the by-product 5 (2- NH N NH N O R methyl-1-tosyl-1H-indole). Subsequent migratory insertion of 2a H 3za, R = n-Bu, 89% 3z, 82% 3zb, R = 1,1,3,3-tetramethylbutyl, 92% 3zd, 90% 3zc, R = cyclohexyl, 90% a Reaction conditions: all reactions were performed with 1 (0.3 mmol), 2 ChemComm 25 (0.36 mmol), Pd(OAc) 2 (10 mol %), DABCO (0.6 mmol), Cu(OAc) 2 (0.3 mmol), in toluene (2.0 mL ) at 100 oC for 10 h unless otherwise noted.