Regiodivergent Palladium-Catalyzed Alkene Difunctionalization Reactions for the Construction of Methylene Cyclobutanes and Methylene Cyclopentanes

Abstract

Regiodivergent palladium-catalyzed alkene difunctionalization reactions between diethyl malonate and 1,5-dienes bearing a triflate group at C2 are described. Use of tris(2,4-di-tert-butylphenyl)phosphite as ligand leads to 4-exo-cyclization/functionalization to afford malonate-substituted methylene cyclobutanes. In contrast, the 1,2-bis(diphenylphosphino)benzene ligand provides methylene cyclopentanes via 5-endo-cyclization/functionalization. The 5-membered ring-forming reactions occur via anti-carbopalladation of the enolate nucleophile, whereas 4-membered ring-forming reactions proceed through syn-4-exo migratory insertion of the tethered alkene, followed by sp³C-sp³C bond-forming reductive elimination from a (alkyl)Pd(II)(malonate) complex.

Graphical Abstract

Palladium-catalyzed alkene difunctionalization reactions have emerged as powerful tools for the construction of heterocycles and carbocycles.¹ Our group has recently reported a series of palladium-catalyzed alkene difunctionalization reactions for the synthesis of functionalized methylene cyclopentanes.^2,3 In general, these transformations form carbocycles in good yield and diastereoselectivity through coupling reactions between 1,5-dien-2-yl triflates and amines,^2d–e alcohols/phenols,^2c indoles,^2b or enolates.³ For example, treatment of 1a with diethyl malonate in the presence of Pd(OAc)₂, BrettPhos, and LiO^tBu afforded 2a in 84% yield with >20:1 dr (Scheme 1, eq 1). In our prior studies, these transformations exclusively generated cyclopentane derivatives, except for one instance in which benzocyclobutane 4 was formed in low yield (23%) during the Pd-catalyzed coupling of 2-allylphenyltriflate and 3-methylin-dole (Scheme 1, eq 2).^2b

Scheme 1.

Prior studies

Given the generally high selectivity for 5-endo-cyclization, we were quite surprised to find that the coupling of gem-diester substrate 5a with di-tert-butyl malonate under standard conditions afforded an inseparable mixture of regioisomers 6a and 7a in 53% yield, with modest 4:1 selectivity for the cyclopentane product (Scheme 1, eq 3). Since cyclobutanes are synthetically useful compounds, and there are challenges associated with their synthesis,^4,5 we were curious as to whether a regiodivergent method to selectively afford either the 4- or 5-membered ring products could be achieved.⁶

In pursuit of this goal, we elected to take a two-pronged approach to optimization that involved an initial mechanistic experiment to test our working hypothesis, followed by rational ligand screening to optimize conditions. Given that 4-exo-migratory insertion processes are known to occur in Pd-catalyzed Heck reactions that afford cyclobutane products,⁷ it seemed plausible that 7a could be generated by migratory insertion of the tethered alkene into alkenylpalladium complex 9 or 12 followed by incorporation of the nucleophile (Scheme 2). To test the feasibility of the 4-exo-migratory insertion step, we carried out a simple experiment in which the nucleophile was omitted. When 9a was subjected to these conditions, intramolecular Heck product 8a (R = CO₂Et), which is formed via β-hydride elimination from 10, was obtained in approximately 51% NMR yield.⁸ This result is consistent with both the hypothesis outlined above, and Mulzer’s prior studies on intramolecular Heck reactions of related substrates.^7a

Scheme 2.

Possible mechanisms for cyclobutane formation

However, four different pathways involving alkene migratory insertion could potentially lead to the observed product (Scheme 2). Two pathways (a and b) involve initial syn-1,2-migratory insertion from 9 to 10.⁹ Intermediate 10 could then undergo a formal S_N2-reductive elimination with the malonate anion to afford the product 7 (path a). Alternatively, 10 could undergo 3-exo migratory insertion into the exocyclic alkene to form bicyclo[2.1.0]pentane intermediate 11 (path b).¹⁰ The bicycle can then be transformed to product 7 through S_N2’-like reductive elimination with the nucleophile. Two other pathways (c and d) would involve reductive elimination from the metal, rather than outer-sphere S_N2 substitution. Intermediate 10 could undergo transmetallation with the nucleophile to afford 13 (path c), which could then undergo C–C bond-forming reductive elimination with retention of configuration to provide 7’. Finally, intermediate 13 could also be generated by transmetallation of 9 with the malonate anion to provide 12, followed by subsequent migratory insertion (path d). Paths a and b should involve reductive elimination with inversion of configuration at the carbon bound to palladium to afford 7, whereas paths c and d should proceed via stereoretentive reductive elimination to give stereoisomeric product 7’.

Guided by this hypothesis, we set out to optimize conditions for regioselective formation of both the 4- and 5-membered ring products. It seemed that use of bidentate ligands should favor the formation of the cyclopentane derivatives, as migratory insertion reactions are known to proceed most rapidly when monodentate ligands are employed.¹⁰ After some screening, we found that use of bidentate ligands with small bite angles led to good regioselectivity for cyclopentane 6aa, and 1,2-bis(diphenylphosphino)benzene (dppBz) was selected as the optimal ligand (eq 4).¹¹ Additionally, use of five equivalents of nucleophile increased both the regioselectivity and the chemical yield in these transformations, but was not always required.

In contrast, it seemed that labile, monodentate ligands would accelerate the migratory insertion step,¹⁰ and therefore lead to increased selectivity for the 4-membered product. Several large and relatively electron-poor ligands were examined, and tris(2,4-di-tert-butylphenyl)phosphite provided the best yields and regioselectivities.¹² Additional improvement was achieved by conducting reactions for 12 h at a lower temperature of 60 °C in the presence of 5 equiv of the nucleophile (eq 5).

With conditions in hand for selective formation of either regioisomeric product, we turned our attention to exploring the scope of the reaction using a series of different alkenyl triflate derivatives. Substrates for these studies were prepared in 2–5 steps through formation and alkylation of the corresponding methyl ketone enolate, followed by enol triflate formation.¹¹ As shown in Scheme 3, substrate 5b gave excellent selectivity for the cyclobutane product 7b. However, analogous reactions of substrates with smaller alkyl substituents (5d-g) proceeded with lower regioselectivity for the cyclobutane product, which suggests the Thorpe-Ingold effect plays a significant role in the cyclobutane-forming reactions. In addition, the fact that gem-diester substrate 5a and gem-dimethoxy substrate 5c are transformed in much higher regioselectivity than gem-dialkylsubstrates 5d and 5e indicates that electronic effects also influence the regioselectivity of these transformations. Acetal-bearing substrate 5c was smoothly transformed to 7c in excellent regioselectivity and good chemical yield. In this case the cyclobutane 7c was easily separable from its cyclopentane regioisomer 6c.¹³ Substrates 5g-h were efficiently transformed to spirocyclic products 7g and 7j in good yield, but with moderate regioselectivity. Similarly, reactions of 1b-c afforded fused bicyclic products in good yield with low to moderate regioselectivity.

Scheme 3.

Synthesis of cyclobutanes^a–c

^aConditions: 1.0 equiv substrate, 5.0 equiv diethyl malonate, 5 equiv LiO^tBu, 4 mol % Pd(OAc)₂, 6 mol % P[O(2,4-^tBuC₆H₃)]₃, dioxane (0.1 M), 60 °C, 12 h. ^bYields are isolated yields (average of two or more experiments). ^cRegiosomeric ratios and diastereomeric ratios were determined by ¹H NMR analysis. ^dThe reaction was conducted on a 21.6 mmol scale. ^eThe reaction was conducted with 1 equiv of diethyl malonate. ^fEthyl Acetoacetate was used in place of diethyl malonate as the nucleophile. ^gDiethyl benzylmalonate was used in place of diethyl malonate as the nucleophile.

The optimized conditions for formation of methylene cyclopentanes were examined in reactions of 5a-g and 1b-c, and we were pleased to see high regioselectivity for the cyclopentane product in all cases except for 6b (Scheme 4, 77:23 rr). This further illustrates the dramatic impact of the steric and electronic effects on regioselectivity. In contrast to the cyclobutane-forming reactions, in which regioselectivity decreased with smaller alpha substituents, this was not observed in 5-membered ring-forming reactions. Although regioselectivity was excellent when dppBz was employed, diastereoselectivities were diminished as compared to those obtained with our original conditions³ that used Brettphos as ligand (6f, 6h, 15c). However, the diastereomers are separable by column chromatography. Functional group tolerance in these reactions was unaffected by these new conditions, and esters, alkenes, and acetals were well-tolerated.¹⁴

Scheme 4.

Synthesis of cyclopentanes^a–c

^aConditions: 1.0 equiv substrate, 5.0 equiv diethyl malonate, 5.0 equiv LiO^tBu, 4 mol % Pd(OAc)₂, 6 mol % dppBz, dioxane (0.1 M), 95 °C, 1 h. ^bYields are isolated yields (average of two or more experiments). ^cRegiosomeric ratios and diastereomeric ratios were determined by ¹H NMR analysis. ^dThe reaction was conducted with 1 equiv of diethyl malonate. ^eThe reaction was conducted with 2 equiv of diethyl malonate, 2 equiv of NaO^tBu as base, and toluene solvent (0.1 M). ^fThe reaction required 16 h to proceed to completion. ^gThe reaction was conducted on a 3 mmol scale.

To examine the stereochemical outcome of this reaction, we prepared a deuterated version of substrate 5b, as that substrate showed the highest inherent selectivity for generation of the methylene cyclobutane regioisomer. As such, Z-deuterioalkene substrate d-5b was prepared and subjected to our standard conditions. Product d-7b was generated in 62% yield as a single stereoisomer (>20:1 dr, eq 6).¹¹ To the best of our knowledge, this is the first example of sp3-sp3 C-C bond-forming reductive elimination from Pd(II) involving a malonate nucleophile.¹⁵ Although this experiment has provided key information about the mechanism of these reactions, it remains unclear whether the malonate binds to the Pd(II) complex before (path d) or after (path c) the migratory insertion step.^16,

Collectively, our data are consistent with a reaction mechanism that diverges towards one of the two products following the oxidative addition step in the catalytic cycle. As shown in Scheme 5, oxidative addition of d-5b to the Pd(0) catalyst affords d-9b, which can either undergo syn-migratory insertion and nucleophile coordination to afford d-13b, or anti-nucleopalladation to provide d-16b.¹⁷ Then, either d-13b or d-16b are transformed to products d-7b or d-6b respectively via C–C bond-forming reductive elimination. The observed ligand effects are consistent with this mechanistic hypothesis, as migratory insertion reactions are known to proceed most rapidly with coordinatively unsaturated, cationic palladium complexes. The observation that the chelating bis-phosphine ligand dppBz provides high selectivity for 5-membered ring product d-6b is likely due to the relatively slow rate of migratory insertion for a phosphine-ligated palladium complex that contains a chelating bis phosphine, rather than a labile, monodentate ligand.

Scheme 5.

Unified mechanistic picture

In contrast, the efficiency of the bulky phosphite ligand at promoting selective 4-exo carbopalladation to afford d-7b may be due to two different factors working simultaneously. First, the electron-deficiency of the ligand likely promotes ligand lability and accelerates the crucial migratory insertion step towards d-13b. In addition, the bulky tert-butyl groups of the phosphite appear to extend far from the metal center. This may serve to sterically shield the face of the coordinated olefin from attack by an exogenous nucleophile in a manner similar to that of some ligands used for asymmetric additions to allylpalladium complexes, thereby slowing the rate of conversion of d-9b to d-16b.¹⁸

In conclusion, we have developed a catalyst-controlled regiodivergent alkene difunctionalization reaction that selectively affords either methylene cyclobutanes or methylene cyclopentanes in good yield with high regioselectivities. Five-membered ring formation is favored when dppBz is used as ligand, whereas use of tris(2,4-di-tert-butylphenyl)phosphite facilitates generation of four-membered ring products. The methylene cyclobutane regioisomer is formed via a 4-exo migratory insertion process, followed by C-C bond-forming reductive elimination from the metal center. To our knowledge this is the first example of a transformation that involves sp³-sp³ C-C bond-forming reductive elimination from a Pd(alkyl)(malonate) complex, and future studies will be directed towards the application of this step to other metal-catalyzed reactions.

Data Availability Statement

The data underlying this study are available in the published article and its online supplementary material.