Tetrahedron Letters 52 (2011) 6739–6742

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Tetrahedron Letters

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Palladium-catalyzed oxidation of vinyl ether to acetate with hydrogen peroxide

Yoshihiro Kon ⇑, Takefumi Chishiro, Daisuke Imao, Takuya Nakashima, Takashi Nagamine,Houjin Hachiya, Kazuhiko Sato ⇑National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba Central 5, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8565, Japan

a r t i c l e i n f o a b s t r a c t

Article history:Received 16 August 2011Revised 29 September 2011Accepted 5 October 2011Available online 12 October 2011

Keywords:OxidationPalladium catalystGreen chemistryAcetateHydrogen peroxide

0040-4039/$ - see front matter � 2011 Elsevier Ltd. Adoi:10.1016/j.tetlet.2011.10.015

⇑ Corresponding authors. Tel./fax: +81 29 861 4670E-mail addresses: y-kon@aist.go.jp (Y. Kon), k.sato@

The selective hydrogen peroxide oxidation of vinyl ethers to give acetates was developed using triphen-ylphosphine palladium and triethyl amine catalysts under mild reaction conditions.

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Pd-catalyzed oxidation processes that convert terminal olefinsto methyl ketones using molecular oxygen (O2) with Cu are wellknown and powerful methods applied to synthetic organic chem-istry in industry as well as in the laboratory.1–3 There are alsomany reports of Pd-catalyzed oxidation using hydrogen peroxide(H2O2) as an oxidant for the transformation of terminal alkenesto methyl ketones.4 In the application of these reactions to otheralkenes having various functional groups, Pd-catalyzed H2O2 oxi-dation of a,b-unsaturated carbonyl compounds to 1,3-dicarbonylcompounds has been reported.5 However, the Pd-catalyzed H2O2

oxidation of vinyl ether to acetate has rarely been reported.6 Vinylethers are known to undergo hydrolysis and a vinyl interchangereaction to produce alcohols and acetals under the Pd-catalyzedreaction conditions, respectively.7 Design of the process withoutgeneration of alcohols incidental to the cleavage of vinyl ethers isrequired for the syntheses of acetates in high yields. Previously,pyridinium chlorochromate (PCC) oxidation has been reported togenerate acetates from vinyl ethers in good yields.8 But this meth-od requires more than 2 equiv of PCC toward the substrate to formthe deoxygenated Cr by-products as waste. In a constant search fora cleaner oxidation reaction, H2O2 is a preferable oxidant becauseH2O2 can be used with high atom efficiency and water is a soleco-product.9 We have developed syntheses of various carbonylcompounds using Pd and/or Pt catalyst with aqueous H2O2 underorganic solvent-free conditions.10 Previously, it was well knownthat Pd–OOH species generated from H2O2 and Pd catalyst undergo

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(Y.K.), +81 3 5501 0604 (K.S.).aist.go.jp (K. Sato).

an oxygen transfer to terminal alkenes via peroxypalladation to af-ford methyl ketones.4,11 The addition of amines has also beenknown to affect a scavenger of free acids to suppress acetal forma-tion under a transfer vinylation reaction using Pd catalyst.7e Wetherefore thought that the addition of a catalytic amount of Pdcompound and amine would show good reactivity for the H2O2

oxidation of vinyl ethers to acetates. Here we report a uniqueand a convenient synthesis of acetates by the oxidation of variousvinyl ethers using H2O2 as an oxidant with triphenyl phosphinepalladium and triethylamine catalysts under mild reactionconditions.

We selected cyclohexyl vinyl ether as a screening substrate,which is known to generate cyclohexanol by the hydrolysis.7a

Table 1 shows the screening of various palladium catalysts withEt3N using H2O2 oxidation under organic solvent-free conditions.Cyclohexyl vinyl ether (2.0 mmol), a 0.02 molar amount ofPdCl2(PPh3)2, a 0.05 molar amount of Et3N, and a 2.0 molar amountof aqueous 30% H2O2 were stirred in open air at 30 �C for 2 h to givecyclohexyl acetate in 83% yield (86% conversion) and 97% selectiv-ity under organic solvent-free conditions (Table 1, entry 1).12

Hydrolysis of cyclohexyl vinyl ether was found to provide cyclo-hexanol in only 3% yield. Pd(PPh3)4 catalyst also showed good reac-tivity for the oxidation of cyclohexyl vinyl ether (66% yield, Table 1,entry 2). In the reaction using Pd(OAc)2 catalyst, cyclohexyl acetatewas produced in 20% yield (77% conversion), and cyclohexanol wasgiven in 49% yield (Table 1, entry 4). By the addition ofPd(OAc)2(PPh3)2 catalyst, cyclohexyl acetate was generated in60% yield (92% conversion) and cyclohexanol was given in 18%yield (Table 1, entry 3). In comparing entries 3 and 4, PPh3 ligands

Table 2Various amines tested for the oxidation of cyclohexyl vinyl ether using H2O2 withPdCl2(PPh3)2

a

Entry Amine Conversionb (%) Yieldb (%)

1 None 66 22 Et3N 86 833 n-Pr2NH 55 524 n-HexNH2 23 85 n-Hex3N 12 76 n-Oct3N 11 47 N-Methylpiperidine 82 808 N-Methylpyrrolidine 81 749 2,2,6,6-Tetramethylpiperidine 80 71

10 1,4-Diazabicyclo[2,2,2]octane 41 3711 4-Dimethylaminopyridine 59 5212 Pyridine 8 213 N-Methylpyrrole 10 314 2,20-Bipyridine 34 8

a Reaction conditions: cyclohexyl vinyl ether (2.0 mmol), 30% H2O2 (4.0 mmol),PdCl2(PPh3)2 (0.040 mmol), amine (0.10 mmol), 30 �C, 1500 rpm, 2 h, unlessotherwise stated.

b Yield and conversion on the basis of cyclohexyl vinyl ether, determined by GLCanalysis with biphenyl as an internal standard.

Table 1Various palladium catalysts tested for the oxidation of cyclohexyl vinyl ether using H2O2 with Et3Na

Entry Palladium catalyst Conversionb (%) Yieldb (%)

1 PdCl2(PPh3)2 86 832 Pd(PPh3)4 83 663 Pd(OAc)2(PPh3)2 92 604 Pd(OAc)2 77 205 Pd(OAc)2 + 4 PPh3 100 656 PdCl2(PCy3)2 0 07 [1,2-Bis(diphenylphosphino)ethane] palladium(II) dichloride 9 68 Bis[1,2-bis(diphenylphosphino)ethane] palladium 27 179 Pd(acac)2

c 0 010 PdCl2 18 211 Pd/C 0 012 Pd black 0 0

a Reaction conditions: cyclohexyl vinyl ether (2.0 mmol), 30% H2O2 (4.0 mmol), palladium catalyst (0.040 mmol), Et3N (0.10 mmol),30 �C, 1500 rpm, 2 h, unless otherwise stated.

b Yield and conversion on the basis of cyclohexyl vinyl ether, determined by GLC analysis with biphenyl as an internal standard.c acac = acetylacetonato.

6740 Y. Kon et al. / Tetrahedron Letters 52 (2011) 6739–6742

clearly accelerated the reaction and inhibited the generation ofcyclohexanol caused by the cleavage of vinyl ether. The reactionusing Pd catalyst with bulky phosphine ligands such as tricyclo-hexylphosphine (PCy3) and bidentate phosphine ligands such as1,2-bis(diphenylphosphino)ethane resulted in low yields due tosteric hindrance (0–17% yields, Table 1, entries 6–9). PdCl2 catalystalso showed low reactivity because of the lower solubility towardthe organic (substrate) phase (2% yield, Table 1, entry 10). Solid Pdcatalysts such as Pd/C and Pd black showed no reactivity due to thedecomposition of H2O2 catalyzed by Pd/C and Pd black with lowcontact with substrate under organic solvent-free conditions (Ta-ble 1, entries 11 and 12). The addition of Pd(OAc)2 catalyst andPPh3 also showed good catalytic activity to generate cyclohexylacetate in 65% yield (100% conversion) to the same extent as thatof Pd(OAc)2(PPh3)2 catalyst (Table 1, entry 5). The reactions ofother metal catalysts having PPh3 ligands such as Ni(PPh3)4 andPt(PPh3)4 did not proceed in contrast to that of Pd(PPh3)4 (0% yield(0% conversion) for Ni(PPh3)4 and 1% yield (2% conversion) forPt(PPh3)4).

Table 2 shows the screening of amines with PdCl2(PPh3)2 cata-lyst. When we carried out the reaction without amine, the cleavageof cyclohexyl vinyl ether occurred, cyclohexanol was given in 56%yield, and the desired cyclohexyl acetate was generated in only 2%yield (Table 2, entry 1). The addition of a 0.05 molar amount ofEt3N improved the selectivity to give cyclohexyl acetate in 83%yield (Table 1, entry 1 and Table 2, entry 2). In the case of usingn-Pr2NH and n-HexNH2, cyclohexyl acetate was provided in 52%yield for n-Pr2NH, and in 8% yield for n-HexNH2 (Table 2, entries3 and 4). These results indicate that the high basicity of an aminesuch as tertiary amine is required to accelerate the reaction. Hin-dered tertiary amines having long alkyl chains showed low reactiv-ities to give cyclohexyl acetate in 7% yield for n-Hex3N, and in 4%yield for n-Oct3N (Table 2, entries 5 and 6). N-methylpiperidine,N-methylpyrrolidine, and 2,2,6,6-tetramethylpiperidine showedhigh reactivity to give cyclohexyl acetate in 80%, 74%, and 71%yields, respectively (Table 2, entries 7–9). However, in the case of1,4-diazabicyclo[2,2,2]octane having less hindered tertiary amine,cyclohexyl acetate was produced in only 37% yield (Table 2, entry10). Cyclohexyl acetate was generated in 2%, 3%, and 8% yields forusing pyridine, N-methylpyrrole, and 2,20-bipyridine, respectively,(Table 2, entries 12–14). Aromatic amines are less effective for thisreaction, even in the case of 4-dimethylaminopyridine, which isknown as a strong base (Table 2, entry 11).

This process is well applicable to the oxidation of various vinylethers to give the corresponding acetates in good yields (Table 3).Oxidation of benzyl vinyl ether gave benzyl acetate in 71% yieldwith 91% selectivity (Table 3, entry 3). The reaction of cyclohexylvinyl ether and benzyl vinyl ether also proceeded under dimethyl-acetamide (DMA) solution to give the corresponding acetates in87% and 72% yields, respectively (Table 3, entries 2 and 4).3 How-ever, the oxidation of cyclohexyl vinyl ether under DMA solutionaccelerated the reactivity, and the selectivity of cyclohexyl acetatedecreased slightly compared to that under organic solvent-freeconditions (Table 2, entries 1 and 2). The reaction of cyclohexylm-ethyl vinyl ethers gave the corresponding acetates in 60% and 90%yields with excellent selectivities (>99% selectivities, Table 3, en-tries 5 and 6). On the other hand, it was difficult to oxidize alkyl

Table 3Catalytic H2O2 oxidation of various vinyl ethers with PdCl2(PPh3)2 and Et3Na

Entry Vinyl ether Acetate ester Conversionb (%) Yieldb (%)(isolated yield%) c

Selectivityd (%) H2O2 efficiencye (%)

12f

86100

83 (75)87

9787

4244

34f

78100

71 (70)72

9172

3636

5 60 60 (60) >99 30

6 90 90 (91)g >99 45

78f

7893

3466

4471

1733

910f

48100

3672

7572

1836

1112f

4188

2462

5970

1231

1314f

2782

849

3060

425

1516f

4087

2451

6059

1226

1718f

19h

0053

0053

00>99

0027

a Reaction conditions: vinyl ether (2.0 mmol), 30% H2O2 (4.0 mmol), PdCl2(PPh3)2 (0.040 mmol), Et3N (0.10 mmol), 30 �C, 1500 rpm, 2 h, unless otherwise stated.b Yield and conversion on the basis of cyclohexyl vinyl ether, determined by GLC analysis with biphenyl as an internal standard.c Acetates (mol)/vinyl ethers (mol) � 100 (%).d Yield/conversion (%).e Yield/2 (%) because the amount of H2O2 (mol) using this reaction was twice as much as that of vinyl ether (mol).f Using DMA (2 ml) as organic solvent at 60 �C.g Two gram-scale, isolated yield.h Using dichloromethane (0.5 ml) as organic solvent at 40 �C.

Y. Kon et al. / Tetrahedron Letters 52 (2011) 6739–6742 6741

vinyl ethers to generate the corresponding acetates in this catalyticsystem under organic solvent-free conditions. For example, theyields of n-propyl, n-butyl, i-butyl, and t-pentyl vinyl ethers were34%, 36%, 24%, and 8%, respectively (selectivities were 44%, 75%,59%, and 30%, respectively, Table 3, entries 7, 9, 11, and 13). Underthe reaction conditions with DMA solution at 60 �C, alkyl vinylethers were oxidized to generate acetates in good yields (66%,72%, 62%, and 49% for n-propyl, n-butyl, i-butyl, and t-pentyl vinylethers, respectively, Table 3, entries 8, 10, 12, and 14). Oxidation of2-chloroethyl vinyl ether gave 2-chloroethyl acetate in 51% yieldunder DMA solution (Table 3, entry 16). Oxidation of cholesteryl vi-nyl ether generated cholesteryl acetate in 53% yield with >99%selectivity under dichloromethane solution (Table 3, entry 19).

The reaction could be explained by the same mechanism of Pd-catalyzed H2O2 oxidation of terminal alkenes reported previously.4

The initial step was suggested to be the formation of the PdII–OOHspecies11 regardless of the valence of the employed Pd catalyst (Pd0

and/or PdII). Through the coordination of vinyl ether to Pd metal,Pd–OOH species underwent an oxygen transfer to vinyl ether viaperoxypalladation to afford the corresponding acetate. Deoxygen-ated Pd–OH species was reoxidized by H2O2 to regenerate thePd–OOH species. The addition of amine would work effectively toavoid the reduction of Pd–OH to metallic palladium by coordina-

tion to Pd–OH species and to scavenge the HCl produced by the re-leased Cl� from PdCl2(PPh3)2. The effect of PPh3 ligands might bethe stabilization of cationic Pd species through the catalytic cycleand the acceleration of vinyl ether coordination to Pd metal.

In summary, the oxidation of vinyl ether to acetate using 30%H2O2 aqueous solution with PdCl2(PPh3)2 and Et3N catalysts wascarried out. Cyclohexyl vinyl ether, cyclohexylmethyl vinyl ethers,and benzyl vinyl ether were effectively oxidized by this catalyticsystem to generate the corresponding acetates in good yields withexcellent selectivities under organic solvent-free conditions. Thiscatalytic system was also successfully applied to various alkyl vinylethers under DMA and/or dichloromethane solution in moderate togood yields.

Acknowledgment

This work was partially supported by the New Energy andIndustrial Technology Development Organization (NEDO), Japan.

Supplementary data

Supplementary data associated with this article can be found, inthe online version, at doi:10.1016/j.tetlet.2011.10.015.

6742 Y. Kon et al. / Tetrahedron Letters 52 (2011) 6739–6742

References and notes

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H2O2 oxidation of cyclohexyl vinyl ether resulted in 88% yield of cyclohexanolwith 12% yield of desired cyclohexyl acetate.

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11. Characterization of Pd–OOH complex and stoichiometric oxidation of ethyl vinylether to ethyl acetate with Pd–OOH complex has been reported: Miyaji, T.;Kujime, M.; Hikichi, S.; Moro-oka, Y.; Akita, M. Inorg. Chem. 2002, 41, 5286–5295.

12. The oxidation of cyclohexyl vinyl ether using O2 balloon with catalytic amountof PdCl2(PPh3)2 and Et3N at 30 �C for 2 h under organic solvent-free conditionsdid not proceed to give cyclohexyl acetate in 0% yield (0% conversion).