Biomolecular Chemistry Regiodivergent Lewis base-promoted O - to C -carboxyl transfer of furanyl carbonates †

Triazolinylidenes promote γ -selective C-carboxylation (up to 99 : 1 regioselectivity) in the O - to C -carboxyl transfer of furanyl carbonates in contrast to DMAP that promotes preferential α -C-carboxyl-ation with moderate regiocontrol (typically 60 : 40 regio-selectivity). The generality of this process is described and a simple mechanistic and kinetic model postulated to account for the observed regioselectivity of the α - and γ -regioisomeric products during the NHC-catalyzed reaction. These findings suggest that C-carboxy-lation with DMAP is irreversible in this system, with moderate, but preferential α -regiocontrol. Under NHC-catalysis reversible C-carboxylation is observed, with initial preferential formation of the γ -isomer, with subsequent equilibration leading to a mixture of α - : γ -products. These the C-carboxylation rearrangement


Introduction
The butenolide architecture is recognized as a privileged structure in synthetic chemistry, and is present in a variety of biologically active natural products. 1 The preparation of functionalized butenolides is commonly achieved by generation of the corresponding furanyl dienolate and reaction with an appropriate electrophile, with alkylations, vinylogous Mukaiyama-aldol, Mukaiyama-Michael and Mukaiyama-Mannich reactions all extensively explored, generally giving high levels of selectivity for γ-functionalization. 2 Limited catalytic methodologies have been developed with the formation of quaternary centers, although a number of organocatalytic 3 and metal-catalyzed processes show promise in this area. 4 As an alternative strategy to generate quaternary-functionalized butenolides, Vedejs et al. have investigated the Lewis base 5 -promoted regio-and enantioselective O-to C-carboxyl transfer of 5-aryl-3-methylfuranyl carbonates 1 using TADMAP 2. 6 In this process, the electronic characteristics of the C(5)-aryl substituent markedly affects the observed regioselectivity of this carboxyl transfer process. For example, while a C(5)-phenyl furanyl carbonate gave a 60 : 40 mixture of α : γ products, an electron-donating C(5)-4-MeOC 6 H 4 substituent favored α-functionalization (α : γ up to 92 : 8) while an electron-with-drawing C(5)-4-NCC 6 H 4 substituent favored γ-functionalization (α : γ up to 20 : 80) (Fig. 1).
Building upon our interest in Lewis base catalysis 7,8 and Oto C-carboxyl transfer rearrangements, 9 we have recently developed a catalyst selective regiodivergent O-to C-or N-carboxyl transfer reaction of pyrazolyl carbonates (Fig. 2, eqn (1)). 10 In this process, NHCs promote selective O-to C-carboxyl transfer, while DMAP promotes selective O-to N-transfer, with quantum mechanics calculations used to probe the observed catalyst selective divergence. In this manuscript we probe the generality of this principle by application to the O-to C-carboxyl transfer of furanyl carbonates. We sought to apply this catalyst selective 11 regiodivergence to promote γ-C-carboxylation in this process that would be independent of the electronic nature of furanyl substitution, allowing a direct comparison with the electronic bias observed by Vedejs. 12 In this manuscript ( Fig. 2, eqn (2)), triazolinylidene NHCs promote highly γ-selective C-carboxylation of furanyl carbonates in this rearrangement process (regioselectivity up to 1 : 99 α : γ), while DMAP gives preferential, but modest, α-selectivity (regioselectivity typically 60 : 40 α : γ).
These product distributions indicate that both DMAP 3 and NHC 8 are effective catalysts for this transformation, yet offer complementary product regioselectivities, with DMAP 3 favoring the α-isomer (with modest regiocontrol) and NHCs 8-10 the γ-isomer with excellent regiocontrol. To further investigate these mechanistic pathways, the individual regioisomeric products 6 and 7 were resubjected to the reaction conditions. Retreatment of both 6 and 7 with DMAP (17 mM, 5 mol%) for extended reaction times returned only the individual starting materials. However, treatment of the α-carboxyl product 6 with NHC 8 (17 mM, 4.5 mol%, five hour reaction time) returned a 16 : 84 ratio of α : γ products, consistent with significant regioisomeric exchange to favor the γ-carboxyl product 7 (Scheme 1, eqn (1)). Similarly, treatment of the γ-carboxyl regioisomer 7 with NHC 8 (17 mM, 4.5 mol%, five hour reaction time) delivered a 14 : 86 ratio of α : γ products (eqn (2)); both ratios within experimental error of the 14 : 86 ratio observed in Table 1 at higher catalyst loadings and concentration.
The variation in ratio of α-: γ-products with NHC concentration, catalyst loading, and reaction time, suggest the inter-  conversion of the αand γ-regioisomeric products during the NHC-catalyzed reaction. These findings suggest that C-carboxylation with DMAP is irreversible in this system, with moderate, but preferential α-regiocontrol. Under NHC-catalysis reversible C-carboxylation is observed, with initial preferential formation of the γ-isomer, with subsequent equilibration leading to a mixture of α-: γ-products. 15 These observations contrast the irreversible C-carboxylation process observed in the rearrangement of oxazolyl carbonates with NHC 8. 9a While the origin of the regioselectivity preference observed under either DMAP or NHC-mediated catalysis is currently unknown in this system, mechanistic studies indicate extensive carbonate crossover, consistent with rapid and reversible O-transcarboxylation as an initial reaction step as previously observed for oxazolyl carbonates. 16 A simple kinetic framework for this NHC-mediated process can be constructed and simulated (Fig. 3) by recognizing that the behavior of this system can be explained by invoking three coupled equilibria. The first process involves the rapid and reversible C-carboxylation of the NHC by the furanyl carbonate. This process is characterized by K i , which, in our kinetic model, is arbitrarily set at a large value of 1000. Additionally, the value for the forward rate constant for this process, k i , is the largest in the system. Formation of the αand γ-products proceeds though two further equilibria, characterized by two further equilibrium constants K γ and K α . The ratio of these two equilibrium constants (K γ /K α = 5.67) reflects the final ratio of the αand γ-products (∼85 : 15) reached at equilibrium. In this mechanism, free NHC is required both for reaction initiation from the furanyl carbonate and to allow equilibration of the C-carboxyl products. Since K i is large with respect to both K γ and K α , the concentration of free NHC will be low up to conversions in excess of 90% (based upon 10 mol% added NHC), leading to preferential kinetic formation of the γ-furanyl product. However, with increasing time and NHC concentration the αand γisomers can interconvert to generate the observed thermodynamic product ratio. Interestingly, for this model to mirror the observed selectivity for the γ-product at low conversions and/or low catalyst loadings, it is necessary to set k γ to be 100 × k α and for initiation (k i ) to be at least 10 × k γ . Using this parameter set, this model correctly predicts the behavior of the experimental systemat short reaction times and low NHC loading; the system is highly γ-selective (red areas in Fig. 3). As the reaction time increases, the reactivation of the product (by addition of the NHC to product 7) drives the system towards the thermodynamic distribution of αand γisomers (white area in Fig. 3). The reasons for the differential rates of transfer to the αand γpositions are unclear at this stage and in future work we intend to probe these issues computationally.

Reaction generality
The generality of this regiodivergent Lewis base-promoted process was next probed (Table 2). 17 A range of furanyl carbonates varying in substitution at both C(5)-and C(3)-positions, as well as the carbonate group, were each treated with DMAP 3 (34 mM, 10 mol%) and NHC 8 (34 mM, 9 mol% or 3.4 mM, 0.9 mol%) to assess the regioselectivity of the O-to C-carboxyl transfer process. In each case DMAP 3 favored the formation of the α-isomer with modest selectivity, while the NHC 8 favored the γ-isomer with good to excellent levels of regioselectivity independent of variation of the carbonate group, as well as C(5)-and C(3)-substitution. For example, phenyl, trichloroethyl and the sterically hindered but electronically activated β,β,β-trichloro-tert-butyl carbonate groups are tolerated, alongside variation at C(3) from Me to Et, Bn or allyl. In all cases, using NHC-mediated catalysis optimal γ-selectivity (up to  99 : 1) is observed at lower NHC concentrations and using short reaction times, allowing the isolation of the γ-isomer in 67-91% yield.

Conclusions
In conclusion, under kinetic control triazolinylidenes promote γ-selective C-carboxylation (up to 99 : 1 regioselectivity) in the O-to C-carboxyl transfer of furanyl carbonates, in contrast to DMAP that promotes preferential α-C-carboxylation with moderate regiocontrol. Current work from within our laboratory is focused upon demonstrating further applications of NHCmediated organocatalytic transformations in the construction of poly-functionalized building blocks for synthesis. a As shown by 1 H NMR spectroscopic analysis of the crude reaction product. b Isolated yield of major isomeric product.