Decarboxylative allylation using sulfones as surrogates of alkanes.

Recently, Craig reported an interesting decarboxylative sigmatropic rearrangement of allyl sulfonylacetic esters (Scheme 1).1 For all of its utility, the need for an α-hydrogen inherently limits the substrates for this transformation to α-unsubstituted1a or highly activated α-sulfonyl-β-ketoesters.1b Scheme 1 Our group and others have been interested in developing related catalytic decarboxylative couplings that facilitate C—C bond formations under neutral conditions.2,3 While a variety of nucleophilic reaction partners can be generated via decarboxylation, the generation of sp3-hybridized carbanion equivalents is thus far limited to the generation of nucleophiles with pKa’s < 25. Thus, simple unstabilized alkane nucleophiles do not undergo facile decarboxylative coupling. We surmised that merging the reaction chemistry of Craig with our catalytic decarboxylative coupling methodology would allow us to greatly extend the range of alkyl groups that undergo decarboxylative coupling. Specifically, we expected that the sulfone could be used to facilitate synthesis of pronucleophiles for decarboxylative coupling, accelerate decarboxylative coupling, and be readily cleaved to form allylated alkanes (Scheme 2). Scheme 2 Herein we report that palladium can be used to catalyze the decarboxylative coupling of sulfonylacetic esters and can be used for the coupling of α,α-disubstituted sulfones that are not viable reaction partners for the Carroll-like rearrangement developed by Craig.4 Moreover, the ability to readily cleave the sulfone allows the formal decarboxylative coupling of simple alkyl nucleophiles (Scheme 2). This allows us to circumvent the limitation that the nucleophilic components in decarboxylative allylations are currently restricted to relatively stabilized nucleophiles.2,3 To begin, allyl (phenylsulfonyl)acetate (1a) was chosen as a model substrate for reaction optimization. Substrate 1a is prepared by the straightforward dialkylation of the parent allyl(phenylsulfonyl) acetate. Initial attempts to effect the decarboxylative coupling using Pd(PPh3)4 in dry toluene resulted in successful coupling, however the reaction mixture contained a significant amount of 3a (Table 1). Despite rigorous removal of water from reagents and solvent, the generation of protonation product 3a could not be eliminated. Thus, a series of ligands were investigated for their ability to minimize the amount of product 3a. It was gratifying to find that use of (rac)-BINAP as a ligand with Pd2(dba)3 substantially reduced the amount byproduct with a concomitant increase in the yield of desired product. Table 1 Ligand screening. Next, we turned our attention to investigating the scope of this transformation. As can be seen in Table 2, simple α,α-dialkylsulfones undergo coupling to give good yields of product; the couplings of α,α-dialkyl sulfones generally take 12–15 h at 95 °C for completion. While fluorination of the α-center results in a reduced yield, α-chlorination is readily tolerated (entries 6–7). Interestingly, it appears that oxidative addition of the allylic C—O bond is more favorable than addition of the sterically hindered quaternary C—Cl bond. Moreover, the reactions of α-chloro substrates are somewhat accelerated and require only 3–4 h for completion. Table 2 Decarboxylative coupling of α-sulfonyl esters The decarboxylative couplings of substrates that contain an α-aryl group are further accelerated relative to alkyl- and chloro- substituted sulfones. This allows the reactions of α-arylsulfones to take place in ca. 10 minutes at room temperature rather than at 95 °C, which is required for α,α-dialkylsulfones. Moreover, the Pd(PPh3)4 is active enough to catalyze these reactions and the loading of catalyst can be lowered to 1–2 mol %. The fact that α-aryl substituted sulfones undergo more rapid decarboxylative coupling than alkyl analogs suggests that decarboxylation of the sulfone is rate-limiting. In such a scenario benzylic stabilization of the incipient anion can account for the observed rate acceleration. To further probe whether decarboxylation is rate-limiting, a conformationally constrained substrate 1o was prepared (Scheme 3). It is known that the most stable conformation of the α-sulfonyl anion has the lone pair situated antiperiplanar to the sulfonyl phenyl group (Figure 1).5 Since the cyclic nature of the anion derived from 1o cannot achieve this ideal conformation, decarboxylation is predicted to be very sluggish. Indeed, 1o does not undergo reaction under our standard conditions. However, heating the catalytic mixture in a microwave at 200 °C for 30 min. did allow the isolation of a modest yield of coupled product 2o (Scheme 3). We believe that this result further supports our hypothesis that decarboxylation is rate-limiting.6 Figure 1 Qualitative correlation of rate and stability Scheme 3 A variety of allyl groups are also compatible with the decarboxylative coupling (Table 2). For example, a monosubstituted allyl substrate reacts to give product with the standard preference for the linear product (entry 13). Disubstituted allyl alcohol derivatives also proceed in excellent yield, but occur with poor diastereoselectivity (entries 9–12). Lastly, dialkyl sulfones undergo decarboxylative coupling in high yield without any allylation at the activated benzylic position (Scheme 4). The fact that regioisomerization of the α-sulfonyl anion to the more stable anion does not take place indicates that the coupling is regiospecific with respect to the sulfone. Scheme 4 Similar regiospecificity is exhibited in the decarboxylative allylations of ketone enolates.2 Finally, we wanted to demonstrate the ability to remove the sulfone after using it to facilitate coupling. Toward this end, several substrates were subjected to decarboxylative coupling followed by reduction using Mg in methanol.7 In each case, clean reduction of the sulfone was achieved and the two-step decarboxylative coupling-reduction yields are good (Table 3). While reduction the α,α-dialkyl substrates expectedly gives rise to a tertiary carbon center, the α-chloro compounds undergo double reduction to provide the secondary carbon. Table 3 Decarboxylative coupling-reduction In addition to reductive cleavage, one can take advantage of the ability to eliminate the sulfinate,8 leading to skipped dienes (Scheme 5). Scheme 5 In conclusion, palladium-catalyzed decarboxylative coupling allows the synthesis of γ,δ-unsaturated sulfones. The sulfone facilitates i) alkylation reactions to construct a nucleophile for coupling and ii) the generation of α-sulfonyl anions under neutral conditions using decarboxylation as a driving force. Here there is a significant advantage to our method as compared to more traditional allylations of sulfones that take place under strongly basic conditions and often require toxic additives such as HMPA to achieve formation of quaternary C-C bonds.9,10 Finally, the sulfone can be reductively cleaved, making it a “traceless” activating group.11 Alternatively, the sulfone can facilitate many other reactions; in particular, the ability to couple α-chlorosulfones suggests our reaction as a precursor to Ramberg-Backlund olefin synthesis.