LETTER 3135 Catalytic Intermolecular Hydroamination of Vinyl Ethers HydroaminationNirmal of Vinyl Ethers K. Pahadi,* Jon A. Tunge* Department of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS 66045-7582, USA Fax +1(785)8645396; E-mail: [email protected] Received 30 July 2009 the concentration of vinyl ether to 1.6 M (4 equiv) slightly Abstract: This manuscript details the development of a palladium- catalyzed hydroamination of vinyl ethers. It is proposed that palla- lowers the yield (entry 5), while using just 2 equivalents dium catalyzes the hydroamination via Brønsted base catalysis, considerably lowered the yield of aminol (entry 6) and in- where palladium is protonated by the relatively acidic sulfonamide creased the time necessary for reaction completion. More- to generate a palladium hydride as well as the active anionic sul- over, substantial quantities of enamine 4a were formed. fonamide nucleophile. Thus, this process is distinct from known Further lowering the concentration of 2 to 0.5 M dramati- palladium-catalyzed hydroaminations of styrene derivatives that cally decreased the yield of 3, and only a trace amount of utilize less acidic amines. enamine 4 was observed. Dioxane, MeCN, DCE, and Key words: hydroamination, vinyl ether, palladium, sulfonamide THF were also tested as potential solvents; only dioxane provided any product. However, when 1,4-dioxane was used as solvent, a 1:1 mixture of 3a and 4a was obtained Transition-metal-catalyzed intermolecular hydroamina- Table 1 a tion of alkenes has attracted a great attention in recent Conditions for Hydroamination years.1 Much research in this line has centered on the in- PG OBu tramolecular hydroamination of simple alkyl-substituted N 2,3 Ph a-olefins. The analogous intermolecular hydroamina- PG 3a tion of alkenes has been most successful with electron- catalyst + N + 4 5 6 OBu Ph H deficient alkenes, dienes, and vinlyarenes. In contrast to 100 °C PG 1 these reactions, the related transition-metal-catalyzed 2a hydroaminations of vinyl ethers have not been extensively N Ph investigated. Electron-rich olefins, such as vinyl ethers, 4a undergo palladium-catalyzed intramolecular hydroamina- tion;7 intermolecular hydroaminations are catalyzed by Entry Catalyst PG Time Yield of Yield of (h) 3a (%) 4a (%) acid8 or bifunctional rhenium-oxo catalysts.9 b At the outset of our investigations, it was known that pal- 1 Pd(PPh3)4 Ac 24 <5 <5 ladium can catalyze the hydroamination of olefins by sev- b 2 Pd(PPh3)4 Me 24 <5 <5 eral mechanisms. For instance, palladium(II) catalyzes b the intramolecular hydroamination of vinyl ethers.7 This 3 Pd(PPh3)4 Bn 24 <5 <5 reaction is thought to occur via Lewis acid catalysis where 4Pd(PPh3)4 Ts 15 94 <5 palladium coordinates the olefin, thus polarizing it toward 7c,10 c nucleophilic attack by the amine. In addition, Hartwig 5 Pd(PPh3)4 Ts 12 82 <5 has developed a hydroamination of styrenes that is pro- d 6 Pd(PPh3)4 Ts 24 50 25 posed to go via acid-induced formation of p-benzyl com- Downloaded by: University of Kansas Libraries. Copyrighted material. 6 plexes. Herein we report a catalytic intermolecular 7PdCl2(PhCN)2 Ts 24 10 <5 hydroamination of vinyl ethers that we propose utilizes 8Pddba /BINAP Ts 24 80 <5 low-valent palladium as a specialized Brønsted base cata- 2 3 lyst. 9Pd2dba3/dppb Ts 24 72 <5 We began investigating the potential for hydroamination 10 Pd2dba3/dppf Ts 24 75 <5 of 1-(vinyloxy)butane 2a with a variety of aniline deriva- tives. Heating N-alkyl or N-acyl anilines in the presence of 11 none Ts 17 <5 <5 5 mol% Pd(PPh3)4 at 100 °C resulted in no product forma- 12 TfOH (5 mol%) Ts 12 <5 <5 tion. However, the more acidic N-tosyl aniline produced the corresponding addition product 3a, which was ob- 13 TfOH/Pd(PPh3)4 (5 mol%) Ts 12 <5 <5 tained in excellent yield (Table 1, entry 4) when the reac- 14 PhCO H/Pd(PPh ) (10 mol%) Ts 41 85 <5 tion was performed in excess, neat vinyl ether. Lowering 2 3 4 a Isolated yields of reactions carried out in a sealed vial with 1a (0.2 mmol) and neat 2a at 100 °C. SYNLETT 2009, No. 19, pp 3135–3138 xx.xx.2009 b Starting material was recovered. Advanced online publication: 21.10.2009 c 1.6 M olefin in toluene. DOI: 10.1055/s-0029-1218293; Art ID: S08709ST d Conditions: 2 equiv 2a. © Georg Thieme Verlag Stuttgart · New York 3136 N. K. Pahadi, J. A. Tunge LETTER as judged by 1H NMR spectroscopy. In addition, a variety Table 2 Scope of Hydroaminationa of other palladium catalysts were screened, but none was Ts OBu as effective at promoting the hydroamination as Pd(PPh3)4 N 1 (entries 7–10). Thus, reactions could be run in neat vinyl R Ts 3 Pd(PPh ) (5 mol%) 4 ether or in concentrated toluene solutions. For conve- 3 N + OBu 1 100 °C H nience, we chose to run reactions in neat vinyl ether for R + 1 2 examination of the scope of the hydroamination. Ts N Importantly, attempting to perform the same transforma- 1 R tion without the addition of Pd(PPh3)4 produced <5% 4 yield of 3a over 17 hours at 100 °C (entry 11). Further- 1 more, since such a transformation could potentially be Entry R 2 Time Yield of 3 Yield of 4 (equiv) (h) (%)b (%)b catalyzed by simple Brønsted acids,3,8 the reaction was run with 5 mol% TfOH with or without Pd(PPh3)4 and 1 4-BrC6H4 19 14 3b 67 – <5% product was observed (entries 12 and 13). Instead, 3c TfOH promoted the decomposition of the butyl vinyl 23-MeC6H4 19 12 92 – 11 ether to acetaldehyde dibutyl acetal. The reaction did 32-MeC6H4 19 20 – 4d 90 proceed with Pd(PPh3)4 and 10 mol% benzoic acid (entry 14), however, the acid additive inhibited the reaction, and 42-Me2C6H3 19 20 – 4e 45 longer times were required for completion of the reaction. 54-MeOC6H4 19 25 3f 80 – Importantly, the observed inhibition by acid contrasts b 64-MeOC6H4 4 25 3f 70 – with the Pd(PPh3)4-catalyzed hydroamination of vinylar- enes which requires strong acid additives.6 Thus, we pro- 73-MeOC6H4 19 24 3g 80 – pose that the mechanism of the palladium-catalyzed b hydroamination of vinyl ethers differs from that of vinyl 83-MeOC6H4 4 24 3g 60 – arenes. b 94-O2N-C6H4 4 15 3h 60 – Given the inhibition of the reaction by added acid, we hy- 10 4-NCC H 19 26 3i 93 – pothesized that the Pd catalyst was behaving as a Brønsted 6 4 base to facilitate the hydroamination. If this is the case, 11 4-EtO2CC6H4 19 15 3j 93 – then the triphenylphosphine that accompanies the palladi- b 3j 4j um may also be capable of acting as a base and catalyzing 12 4- EtO2CC6H4 4 15 50 50 8 the reaction. Indeed, the reaction also proceeded in the 13 CH2(CH2)3Me 19 24 3k 40 4k <20 presence of 20 mol% Ph3P as a Lewis base, however, the conversion was only 25% after extended reaction time. a All reactions were carried out in a sealed vial with 1 (0.2 mmol) and Thus, phosphine catalysis does not account for our ob- 2 in the presence of 5 mol% Pd(PPh3)4 at 100 °C unless otherwise in- served results. dicated. b In toluene solvent. Having the optimized conditions in hand, the scope and limitations of the hydroamination of butyl vinyl ether with Table 3 Scope of Vinyl Ethersa Ts a variety tosyl-protected amines was explored (Table 2). Ts Pd(PPh ) (5 mol%) 3 4 2 2 N OR + N Both electron-rich and electron-poor anilines are good OR 1 1 R R H substrates for the reaction and groups like esters, nitro 100 °C 1 2 groups, and nitriles are compatible with the reaction con- 3 Downloaded by: University of Kansas Libraries. Copyrighted material. ditions. Entry R1 R2 2 (equiv) Time (h) Yield of 3 (%)b Interestingly, ortho substitution of the aniline lead to ex- 1Ph n-Pr 19 36 3l 75 clusive formation of the enamine product (entries 3 and 4, b Table 2) in good to moderate yield. Unfortunately, high 24-FC6H4 n-Bu 8 14 3m 92 concentrations of the vinyl ether were often necessary to n b 3n promote formation of the aminol over the enamine. Last- 34-FC6H4 -Pr 4 14 87 ly, when an aliphatic amine was exposed, the anticipated 44-FC6H4 Et 19 26 3o 89 addition product 3k was isolated in moderate yield along with enamine 4k. 54-FC6H4 t-Bu 19 26 3p 82 b Next we turned our attention to investigating the vinyl 64-F3CC6H4 n-Bu 8 14 3q 82 ethers that were compatible reaction partners in the hy- 74-NCCH Cy 19 25 3r 30 droamination. Simple aliphatic vinyl ethers react smooth- 6 4 ly to afford the desired aminols except in the case of vinyl a All reactions were carried out in a sealed vial with 1 (0.2 mmol) in cyclohexyl ether, which gives only a low yield of aminol the presence of 5 mol% Pd(PPh3)4 at 100 °C. b In toluene. (Table 3, entry 7). Interestingly, the bulkier tert-butyl ether forms the aminol in good yield (Table 3, entry 5). Synlett 2009, No. 19, 3135–3138 © Thieme Stuttgart · New York LETTER Hydroamination of Vinyl Ethers 3137 Cyclic vinyl ethers undergo the palladium-catalyzed hy- General Procedure for the Hydroamination of Vinyl Ethers droamination as well.