DOI: 10.1002/chem.201102937

Palladium-Catalyzed Allylic Sulfinylation and the Mislow–Braverman–EvansRearrangement

Jonatan Kleimark,[a] Guillaume Prestat,[b] Giovanni Poli,[b] and Per-Ola Norrby*[a]

Sulfoxides play important roles in organic and medicinalchemistry, as chiral handles,[1] ligands,[2] or bioisosteres.[3]

The most common method for sulfoxide preparation is con-trolled sulfide oxidation,[4] but a more convergent approachwould be to make them by formation of the C�S bond. Poli,Madec and co-workers recently disclosed a method fordirect sulfoxide formation involving a Pd-catalyzed allyla-tion or arylation of an intermediate sulfenate anion.[5]

This strategy is illustrated by the reaction between tert-butyl 3-p-tolylsulfinylpropionate and cinnamyl acetate,which gave the cinnamyl p-tolyl sulfoxide. In this reaction,the sulfenate anion and h3-allyl complex are generated insitu and react with each other to afford the final product.Herein, we disclose our theoretical results for the formationof the allyl sulfoxides (Scheme 1).

A simplified mechanistic scheme for the formation ofphenyl allyl sulfoxide is shown in Scheme 2. Sulfenate anionand h3-allyl Pd complexes are formed in situ and react bynucleophilic displacement. However, it is not a priori clearwhether initial attack occurs from the formally anionicoxygen atom or the formally neutral sulfur atom. The ob-served product is the allyl sulfoxide, but this would be ex-pected to be formed also from a rapid Mislow–Braverman–Evans (MBE) rearrangement[6] even if the allyl sulfenate

would be the initially formed product. Since the two mecha-nisms are closely linked, we initiated our investigation by adetailed computational study of the MBE rearrangement.

Our standard workhorse for computational investigationsof reaction mechanisms is DFT at the B3LYP level[7] with apolarized double-z basis set (6-31G*), augmented by vibra-tional corrections, ECP basis sets for heavy elements,[8] con-tinuum solvation,[9] and dispersion corrections.[10] However,Jorgensen and co-workers showed that even though trendsin the MBE rearrangement kinetics could be well repro-duced by similar methods, the equilibrium was erroneouslycalculated to favor the sulfenate product, not the sulfox-ide.[11] We could verify that the same problem exists alsowhen applying our standard methods to methyl allyl sulfox-ide. The correct preference for the sulfoxide could only bereproduced by using large basis sets. The results seemed rea-sonably well converged at the cc-PVDZ level, but due to aslight shift in energy when going to the cc-PVTZ basis[12] weselected the latter basis set for further studies. Geometrieswere well converged already at the 6-31G* level, as evi-denced by small differences in energy between cc-PVTZand cc-PVTZ//6-31G* calculations. Single-point cc-PVTZcalculations at 6-31G*-derived IRC points also revealed thatthe transition state of the rearrangement shifted by less than0.1 � with the larger basis set. Details of these investigationscan be found in the Supporting Information. In conclusion,to ensure proper energetics in our studies of the Pd-cata-lyzed process, we performed geometry optimizations at theB3LYP level with the lacvp* basis set,[8] validated all station-ary point by vibrational calculations, corrected to final freeenergies by adding contributions from vibrations, solvation,and basis set correction using cc-PVTZ basis set for the or-ganic moieties and lacv3p*+ for Pd.

We next turned our attention to the reaction between thesulfenate anion and h3-allyl Pd complexes, for three modelsystems. The methyl allyl sulfoxide 1 a was retained as a

[a] J. Kleimark, Prof. P.-O. NorrbyDepartment of Chemistry, University of GothenburgKemig�rden 4, #8076, 412 96 Gçteborg (Sweden)Fax: (+46) 31-7721394E-mail : pon@chem.gu.se

[b] Dr. G. Prestat, Prof. G. PoliInstitut Parisien de Chimie Mol�culaire (UMR CNRS 7201)UPMC Univ Paris 06FR2769, 4, Place Jussieu, 75252, case 183, 75005 Paris (France)

Supporting information for this article is available on the WWWunder http://dx.doi.org/10.1002/chem.201102937.

Scheme 1. Generation of sulfoxides via sulfenates.

Scheme 2. Sulfenate allylation mechanism.

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simple model product, but we also investigated the reactionsleading to the experimentally relevant phenyl allyl sulfoxide1 b and phenyl cinnamyl sulfoxide 1 c. For all resulting MBEpairs, our selected computational methodology correctlyidentifies the sulfoxide 1 a–c as being preferred over the cor-responding sulfenate 2 a–c, by 7–25 kJ mol�1. Since the reac-tion center is remote from the ligand, we selected diphosphi-noethane (DPE, H2PCH2CH2PH2) as a model for the exper-imentally competent DPPE ligand.

Looking first at the MBE rearrangement from allylsulfenate to sulfoxide[13] for the three model systems, we seemoderate barriers (82–104 kJ mol�1) for the free substrates,reduced to only 10–26 kJ mol�1 in the presence of the Pd0

DPE complex (Scheme 3).

In gas phase there is little difference between the free andcatalyzed processes, but the Pd-catalyzed process is stronglyfavored by solvation, indicating charge separation in thetransition state. As far as we know, the ability of Pd to in-crease the rate of the MBE rearrangement has previouslynot been shown, but Pd catalysis of the closely related Over-man rearrangement is well precedented.[14] A typical cata-lyzed MBE rearrangement transition state is depicted inFigure 1. The metal fragment is reminiscent of an (h3-al-

lyl)Pd complex, but with substantially longer distances fromPd to the terminal carbon atoms.

We next studied the O versus S nucleophilic trapping ofthe h3-allyl complex. NPA analysis[15] of the sulfenate ionsthemselves reveal a full negative charge on oxygen, but theHOMO still has a significant component on sulfur. Wetherefore assumed that both O and S could be competentnucleophiles. As seen before for nucleophilic attack on h3-allyl Pd complexes, the reaction in the gas phase is monoto-nous, without a transition state on the potential energy sur-face.[16] Location of transition states for this reaction thus re-quired optimization of the solvent. With our current resour-ces, this excludes calculation of the vibrational free energycomponent, but for relative energies of competing transitionstates, the influence of this factor should be minor. All rota-meric attack vectors utilizing either O or S as the nucleo-phile were considered. For the unsubstituted allyl, attack byeither S or O were virtually isoergic, differing only by1 kJ mol�1. However, for this substrate, the product will un-dergo rapid MBE rearrangement and only the sulfoxide willbe isolated (Scheme 2). The reaction surface is unusual; theaddition transition state does not lead directly to the prod-uct, but to another, lower saddle point that is also a transi-tion state for the MBE rearrangement (Figure 2). We notethat care must be taken in the search for the nucleophilicattack transition state, since the automatic search proce-dures more easily locate the lower energy transition statefor the MBE rearrangement (depicted in Figure 1). Thelatter transition state can also be located in vacuo.

Potential energy surfaces of the type depicted in Figure 2pose a particular problem in modeling. The standard proce-dure of following the minimum energy path from the transi-tion state to the minimum can only locate one possibleproduct in such cases, but ab initio dynamics reveals that de-pending on the trajectory of attack, both products can beformed.[17] However, in the current case, the rapid equilibra-tion of products over the very low second saddle point alle-viates the need for these more complex computational treat-ments.

For the cinnamyl substrate, the situation is more complex.The four possible types of attack (each with several rotamer-

Scheme 3. Uncatalyzed versus Pd-catalyzed MBE rearrangement.

Figure 1. Typical structure for Pd-catalyzed MBE rearrangement.

Figure 2. Pictorial representation of the potential energy surface forsulfenate attack on (h3-allyl)Pd.

www.chemeurj.org � 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eur. J. 2011, 17, 13963 – 1396513964

ic vectors) will lead to two manifolds of rapidly equilibratingproducts, of which only the sulfoxide will be observed(Scheme 4). The pathways leading to the manifold contain-ing the observed sulfoxide product were indeed lowest inenergy. Several different approach vectors were possible,and the one leading directly to the terminal sulfoxide waspreferred, but interestingly the oxygen attack at the internalposition was only 2 kJ mol�1 higher in energy. The pathsleading to the product manifold containing the internal sulf-oxide were at least 12 kJ mol�1 higher in energy. Since thelowest energy paths all lead to the observed product (direct-ly or through MBE rearrangement), the results are in excel-lent agreement with the experimental observation for thecorresponding p-tolyl sulfenate. The results can be under-stood in terms of steric effects and charge distribution. Thecationic charge is most highly concentrated at the benzylicposition, the preferred site of attack for the formally anionicoxygen atom, whereas the formally neutral, larger sulfuratom preferentially attacks the sterically least hindered posi-tion.

To summarize, the sulfenate has little difference in reac-tivity between the two potential nucleophilic sites, but sincethese two sites have opposite regiochemical preference, andthe products are in rapid, catalyzed equilibrium, the reactionshows a strong preference for one of the two possible sulfox-ide products. Furthermore, a catalytic effect of palladium onthe MBE rearrangement has been indicated.

Acknowledgements

We are grateful for the important work of Dr. David Madec on the initialsulfinylation. Support from COST Action D40 “Innovative Catalysis:New Processes and Selectivities” is also gratefully acknowledged.

Keywords: density functional calculations · Mislow–Braverman–Evans Rearrangement · palladium · reactionmechanisms · sulfinylation

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Received: September 19, 2011Published online: November 17, 2011

Scheme 4. Cinnamyl sulfinylation pathways.

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