Published: April 06, 2011

r 2011 American Chemical Society 2457 dx.doi.org/10.1021/om2001958 |Organometallics 2011, 30, 2457–2460

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Driving Catalyst Reoxidation inWacker Cyclizations with Acetal-BasedMetal-Hydride AbstractorsNikki A. Cochrane, Maurice S. Brookhart,* and Michel R. Gagn�e*

Department of Chemistry, University of North Carolina at Chapel Hill, CB # 3290, Chapel Hill, North Carolina 27599, United States

bS Supporting Information

Wacker-like oxidative cyclization reactions have providednet-dehydrogenative routes to a broad variety of hetero-

cyles.1 The sequence of elementary steps leading to theseproducts typically involves activation of an alkene by an electro-philic metal center, attack of a carbon or heteronucleophile (e.g.,H2O, H2NAr), and β-H elimination of the resulting alkylcomplex to yield a metal hydride and product alkene. Thechallenge in rendering these processes catalytic has been toreturn the catalyst to its electrophilic state. In the case of Pd(II)catalysts, the resulting [Pd]-H typically undergoes reductiveelimination (deprotonation) to generate Pd(0), which is reox-idized to Pd(II).1,2 Early variants of these catalysts relied onoxidants such as CuCl2 or benzoquinone, although recentadvances have shown that O2 may also be used.1e,2

While Pt complexes display many of the same reactivityprofiles as Pd complexes, they have typically not been used forWacker-type transformations.3 The reasons include a loweracidity of the platinum hydride and the higher binding strengthof Pt(II) to counterions such as Cl�, which poison its electro-philic character. Previous efforts in our group on electrophilicdicationic Pt(II) complexes demonstrated that Wacker-likeactivity could be achieved with polyene substrates that propagatevia cation�olefin pathways.4 A terminating regioselective β-Helimination subsequently gave polycyclic structures with control ofelimination regiochemistry.3a,5b,5c Returning the resulting [Pt]-Hcations to the electrophilic Pt-dicationic state, however, was notachievable using conventional oxidants. Fortunately, trityl cation[Ph3C

þ][BF4�] was found to efficiently abstract the hydride to

form Ph3CH and regenerate Pt2þ free of coordinating anions.5b,c,6

Use of Ph3Cþ thus provides an approach to Pt(II) Wacker-

type catalysts and access to new transformations not available toPd variants.3a,5b,5c,7 Most convenient in this first-generationapproach was the use of Ph3COMe, which, upon reacting withHþ (the byproduct of the electrophilic activation), liberatedMeOH and the active Ph3C

þ. This served to keep the concen-tration of the reactive species at relatively low levels and

ultimately enabled the development of catalytic, enantio- andregioselective oxidative cascade cyclizations.

One disadvantage of this approach, however, was the conse-quent generation of a full equivalent of Ph3CH, which, combinedwith unreacted Ph3COMe, makes workup cumbersome. Resin-bound variants of the Ph3COMe were effective, but batch-to-batch variability was observed along with some reduction inactivity. To circumvent these issues, we sought alternative“oxidants” that could similarly abstract H�, but were more atomeconomical and conveniently removed from products. To thisend, we considered the possibility that acetals, ketals, and ortho-esters might be capable of hydride abstraction under acidicconditions (Scheme 1). Supporting this hypothesis were datareported by Bullock demonstrating that acetals in combinationwith strong acids could abstract hydrides from [Mo]-H complexes.8

Since most P2Pt2þ-catalyzed polyene cyclization reactions are

buffered with Ph2NH, we first tested whether its conjugate acid,Ph2NH2

þ, could generate the putative oxocarbenium ion. Ben-zaldehyde dimethyl acetal was therefore combined with CD3OD,and in <5 min complete exchange gives PhCH(OCD3)2, whichwas observed by 1H NMR spectroscopy (eq 1). This suggestedthat the putative oxocarbenium ion, 1, was readily accessibleunder conditions known to be compatible with the substrates forP2Pt

2þ-catalyzed cyclizations.

The ability of reactive intermediate 1 to abstract hydride froma catalytic [P2Pt-H]

þ intermediate was examined using a closemimic of this intermediate in our reaction mechanism, [(xylyl-phanephos)Pt(H)(NCC(CH3)3)][BF4], 2. Complex 2 could begenerated in situ from the corresponding P2PtI(H) by iodideabstraction with AgBF4 in the presence of 2 equiv of

Received: March 2, 2011

ABSTRACT: In traditional Wacker processes, Pd(II) becomes reduced toPd(0) after C�O bond formation and β-H elimination and must be reoxidizedto the electrophilic Pd(II) state via a stoichiometric oxidant such as benzoqui-none, CuCl2, or O2. We report herein a Pt-catalyzed Wacker-type process thatregenerates the electrophilic Pt2þ state by H� abstraction from a [Pt]-H usingan oxocarbenium ion generated from an acetal or ketal under acidic conditions.

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NCC(CH3)3. P2PtI(H) was obtained from the reaction of P2PtI2with polystyrene-bound triacetoxyborohydride (see SupportingInformation).

To look for hydride abstraction activity, a stoichiometricamount of 2 was added to a premixed solution of a 1:1 ratio ofbenzaldehyde dimethyl acetal and [Ph2NH2][BF4] in CD3NO2,the solvent of choice for catalysis (Scheme 2). Over the course of5 h, 2 cleanly converted to [(xylyl-phanephos)Pt(NCC-(CH3)3)2][(BF4)2], 3; no intermediates were observed by 1Hand 31P NMR spectroscopy. The predicted byproducts ofhydride abstraction, benzyl methyl ether and MeOH, wereconfirmed by 1H NMR spectroscopy and GC-MS (BnOMe),consistent with Scheme 1. Under identical conditions, reactionsof Ph3COMe with a stoichiometric amount of [Ph2NH2][BF4]and 2 resulted in >95% conversion to 3, and as expected, Ph3CHwas observed as the only byproduct (1H NMR and GC-MS).These baseline experiments were slightly faster than the acetalabstraction experiments.

With a reliable protocol in hand for testing the viability ofacetal-based hydride abstraction, other convenient commerciallyavailable aromatic, cyclic, and aliphatic acetals and ketals weretested. As shown in Table 1, themost successful aromatic hydrideabstractor candidates included benzaldehyde dimethyl acetal and4-methoxy benzaldehyde dimethyl acetal, each giving >95%conversion to 3 within 24 h. Noteworthy is the observation thatbenzaldehyde itself was equally effective and presumably paral-leled the protonated carbonyl reactivity reported by Bullock,Tilset, Norton, and others.8a,b,d,9�11

Aliphatic acetals were also examined and found to be viable(entries 7�11). Bullock has previously noted that secondarycarbenium ions are more reactive than tertiary ions, a trendfollowed by these aliphatic hydride abstractor candidates (seeTable 1).8d,12,13 Trioxane was not particularly effective, perhapsbecause fast reclosure results in a low steady concentration of the

oxocarbenium ion (entry 7). By contrast, the doubly stabilizeddioxocarbenium ion derived from trimethylorthoformate likelysuffers from a slow abstraction rate (entry 8). Encouraging wereresults obtained from the acetals derived from formaldehyde andacetaldehyde, especially dimethoxymethane, which generated 3in high yields. Since both the reaction products and dimethoxy-methane are volatile, workup using this reoxidant is particularlyattractive.

Tilset has previously demonstrated that hydride abstraction bytriflic acid in acetone is proportional to the steady-state concen-tration of (CH3)2CdOHþ.10 This observation reasonably sug-gests that the rate of the reactions described in Table 1 dependson a combination of factors including the steady-state concen-tration of the oxocarbenium ion along with its electrophilicity.More electrophilic ions will be present at lower concentrationsthan stabilized ions, but would compensate with higher reactiv-ities. In the event, the balance of forces tended to favor the morestabilized oxocarbenium ions (entries 2�4, 9, and 10). Althoughno intermediates were observed during the reaction in Scheme 2,both Bullock and Tilset have shown that hydride abstraction by

Scheme 1. Hydride Abstraction Reactions with [Pt-H]þ

Scheme 2. Predicted Pathway for Hydride Abstraction withBenzaldehyde Dimethyl Acetal

Table 1. Stoichiometric Pt-H Abstractor Candidatesa

aAcetal added to [Ph2NH2][BF4] in 0.1 mL of CD3NO2 for 5 min atRT; subsequently [Pt] in 0.2 mL CD2Cl2/0.3 mL CD3NO2 was added.b Percent conversion to 3 after 24 h as determined by 31P NMRspectroscopy.

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protonated ketones proceeds through a pathway wherein oxygencoordination to the metal immediately follows M�H breakageand yields alcohol adducts as the kinetic product.8a,b,d,9,10,14

On the basis of the reaction profiles displayed in Table 1, themost efficient hydride abstractor candidates were submitted tocatalytic reaction conditions using a biaryl xylyl-MeO-BIPHEP-based Pt(II) catalyst (Table 2).5a,b Our working mechanism forthis new protocol is thus shown in Scheme 3; the P2Pt dicationcoordinates to the least substituted alkene and initiates thecyclization of 4 to give an alkyl cation that regioselectively β-Heliminates to generate 5. Hydride abstraction by transientlygenerated oxocarbenium ions thus turns the catalytic cycle overby regenerating the electrophilic P2Pt

2þ initiator.15 Even withPh2NH as a buffer, acid buildup can initiate a Brønsted cycliza-tion to generate 6. As shown in Table 2, the acetals, whilegenerally more sluggish than Ph3COMe, were also less likely togenerate Brønsted products. Dimethoxymethane was especiallyselective, giving a high preponderance of the desired 5 over 6.Enantioselectivities were unchanged compared to experimentsusing Ph3COMe.5b Product isolation of 5 for entry 5 (Table 2)simply involved running the reaction mixture through a plugof silica gel to remove the catalyst, followed by removal ofthe methanol and dimethyl ether byproducts via vacuumconcentration.

In summary, these data indicate that the model hydrideabstraction studies outlined in Table 1 reliably track the catalyticefficiency of our oxidative cascade cyclizations. To our knowl-edge, these results demonstrate that acetals can, for the first time,

serve as stoichiometric oxidants in Wacker-type catalysis withconcomitant improvements in atom efficiency and ease of useover alternative oxidants (e.g., benzoquinone and Ph3COMe).

’ASSOCIATED CONTENT

bS Supporting Information. Synthesis of metal complexesand experimental information are available free of charge via theInternet at http://pubs.acs.org.

’AUTHOR INFORMATION

Corresponding Author*E-mail: mgagne@unc.edu.

’ACKNOWLEDGMENT

We thank the National Institute of General Medical Sciencesfor generous support (Grant GM-60578).

’REFERENCES

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Table 2. Catalytic Results Using Alternative HydrideAbstractorsa,

aAll reactions performed under standard catalytic conditions with a13 mM solution of 10mol % [(R)-(xylyl-MeO-BIPHEP)]Ptl2, 25 mol %AgBF4, 20 mol % Ph2NH, and 2.1 equiv of acetal in CH3NO2.

b Yieldsand % ee determined by chiral GC after 24 h. The mass balance wasunreacted 4. cResults after 48 h.

Scheme 3. Proposed Catalytic Cycle for OxocarbeniumHydride Abstractor

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