Distal Alkenyl C–H Functionalization via the Palladium/Norbornene Cooperative Catalysis

Abstract

A distal-selective alkenyl C–H arylation method is reported through a directed palladium/norbornene (Pd/NBE) cooperative catalysis. The key is to use an appropriate combination of the directing group and the NBE cocatalyst. A range of acyclic and cyclic cis-olefins are suitable substrates, and the reaction is operated under air with excellent site-selectivity. Preliminary mechanistic studies are consistent with the proposed Pd/NBE-catalyzed C–H activation instead of the Heck pathway. Initial success on distal alkylation has also been achieved using MeI and methyl bromoacetate as electrophiles.

Trisubstituted olefins are prevalent structural motifs found in numerous natural products¹ and other biologically active compounds;² they often serve as versatile synthetic intermediates to access various other functional groups, such as epoxides, aziridines, and cyclopropanes as well as tertiary stereocenters.³ Typically, trisubstituted olefins are prepared through olefination of carbonyls, hydrofunctionalization of alkynes, cross couplings, olefin metathesis, etc. (Scheme 1a). Despite the efficacy of these established approaches, it is nontrivial to control regio- and stereoselectivity for synthesis of unsymmetrical trisubstituted olefins (compared to disubstituted olefins) in the absence of steric or electronic bias.⁴ Alternatively, direct functionalization of an unactivated alkenyl C–H bond in 1,2-disubstiuted olefins represents an attractive approach for preparing unsymmetrical trisubstituted alkenes. In particular, the use of directing groups (DGs) offers a convenient approach to enhance reactivity and site-selectivity for the alkenyl C–H activation due to proximity effect (Scheme 1b).⁵ To date, a number of transition metal complexes, e.g., Ru,⁶ Pd,⁷ Rh,⁸ Ir,⁹ Fe,¹⁰ and Co,¹¹ have been reported to be efficient for functionalization of the proximal alkenyl C–H bonds. However, it would be attractive if a complementary approach could be developed to allow site-selective activation of the distal alkenyl C–H bonds, which would consequently enrich methods for regioselective synthesis of trisubstituted alkenes. Herein, we describe our initial development of a distal alkenyl C–H functionalization strategy via the palladium/norbornene (NBE) cooperative catalysis (Scheme 1c).

Scheme 1. Trisubstituted Olefins.

Recently, the Pd/NBE catalysis, originally discovered by Catellani, has emerged as a powerful tool for arene functionalization.¹² In 2015, the Yu¹³ and our¹⁴ groups independently reported complementary methods for the Pd/NBE-catalyzed meta-selective C–H activation initiated by directed ortho-palladation. An intriguing question is whether such a distal C–H functionalization strategy could be extended beyond aromatic substrates, such as alkenes (Scheme 1c). Starting with a directed C–H palladation at the proximal alkene position, followed by NBE insertion and a second C–H palladation at the distal position, an alkenyl–norbornyl palladacycle II would be formed, which could react with electrophiles to install a functional group at the distal carbon. Subsequent NBE extrusion and reprotonation at the proximal position complete the catalytic cycle.

However, compared with arenes, several challenges could be anticipated for activating alkene C–H bonds with the proposed pathway. The primary concern comes from the more reactive olefin π bond. Due to the lack of stability by aromaticity, the C=C bond in alkenes could easily undergo various π-breaking transformations, such as reactions with oxidants or electrophiles, leading to undesired background reactions. Second, the π bond of alkenes is typically considered to be a better ligand for Pd than arenes; thus a number of Pd-mediated side reactions, including 2π-insertion and nucleophilic attack of coordinated olefins, could compete with the desired C–H palladation step. Third, after NBE insertion, the alkyl–Pd intermediate is known to form cyclopropanes easily with the alkene via migratory insertion, instead of palladation with the distal C–H bond.¹⁵ Hence, limited examples are known for the Catellani-type reaction of regular alkenyl substrates.¹⁶

To address these challenges, it would be beneficial to realize fast and reversible proximal C–H palladation with appropriate DGs. In addition, the structure of NBE could also be important to minimize undesired side reactions by serving as a reactive ligand. Moreover, the DG should be easily installable and removable. To explore the proposed distal alkene C–H functionalization, cis-alkene 1a with an “exo”-type DG¹⁷ based on oxime ethers¹⁸ was chosen as the initial substrate and arylation was studied as the model reaction (Table 1). After careful evaluation of various reaction parameters, ultimately, the desired C–H arylation product (3a) was obtained in 76% yield with Pd(OAc)₂/N4 as the catalyst combination, 3-CF₃-2-pyridone as the additive,¹⁹ and AgOAc as the halide scavenger in CHCl₃ under air (see Supporting Information for detailed optimization). Other oxime ethers were also investigated as the DG (entry 2). While the aldehyde-derived ones (DG2–4) were much less reactive, the cyclohexanone-derived DG5 showed a comparable result. Control experiments indicate that both palladium and NBE are essential to this reaction, and diminished yield was observed in the absence of the pyridone additive (entries 3–5). Note that the normal Heck product (Z)-3a was formed dominantly in the absence of NBE (entry 5); in contrast, under the standard conditions the Heck reaction was significantly suppressed (vide infra, Scheme 2). In addition, simple NBE and other substituted NBEs also delivered the desired product (entry 6),²⁰ although the imide-based N4 was most reactive.²¹ Moreover, replacement of AgOAc with the corresponding cesium salt was not effective under the standard conditions (entry 7).

Table 1.

Selected Optimization for the C–H Arylation

^aUnless otherwise noted, reactions were run on a 0.2 mmol scale. Yields were determined by ¹H NMR analysis using CH₂Br₂ as the internal standard.

^b52% Heck product (Z)-3a observed.

Scheme 2. Mechanistic Studies.

With the optimized conditions in hand, the alkene scope was first investigated (Table 2). A range of styrenyl alkenes bearing both electron-deficient (3b) and -rich (3c) substituents afforded the desired products in good yields and excellent regio- and diastereoselectivity. Besides aliphatic alcohols, benzylic alcohol-derived substrates also reacted well. It is surprising that the phenyl-substituted substrate still gave the desired distal alkene-arylation product (3f) despite the potential side reaction on the arene, e.g., meta-arylation. It is likely that the chelation between the cis-alkene and the DG inhibited undesired ortho-palladation on the phenyl group. In addition, cis-1,2-dialkyl-substituted alkenes are competent substrates (3g–k). Apart from secondary alcohols, primary alcohol-derived substrates also reacted. Cyclic alkenes containing six- or eight-membered rings (3l, 3o) provided the desired products in moderate to good yields. Reactions with the more challenging linear alkenes derived from primary alcohols (3p, 3q) showed a slightly lower efficiency due to the flexibility of the substrates. Moreover, allylic and homoallylic protected amines (3r–t) worked well with a modified DG.

Table 2.

Alkene Scope^a

^aUnless otherwise noted, reactions were run on a 0.2 mmol scale in a 4 mL vial under the standard conditions. Numbers are the isolated yields, and E/Z ratio was determined by ¹H NMR analysis of the reaction crude.

^b36 h.

^c24 h.

^dDG6 = 3-methyl-2-pyridyl;

see Supporting Information for detailed conditions.

The scope of aryl iodides was then explored (Table 3). Aryl iodides with an ortho electron-withdrawing group proved to be most efficient, consistent with the typical Catellani arylation reaction.²² Interestingly, methyl 2,5-diiodobenzoate can be coupled to give the monoalkenylated product 4a in 63% yield, where the iodide ortho to the ester group reacted exclusively. Electron-deficient aryl iodides (4b–e, 4h) generally afforded the distal arylation products in good yield and excellent E/Z selectivity, while slightly electron-rich ones (4f and 4g) gave lower yields and moderate selectivity. Besides esters, other ortho groups, such as nitro (4d–f), ketone (4i), tertiary amide (4j), and Weinreb amide (4k), also delivered the desired products in good yields. Heteroarenes, such as thiophene (4g) and pyridine (4h), as well as iodide (4a), bromide (4e), and chloride (4c) substituents, were tolerated. Aryl iodides without an ortho electron-withdrawing group were much less reactive under the current conditions,²³ likely due to the difficulty of the oxidative addition step between the aryl electrophile and the alkenyl–norbornyl palladacycle. Beyond arylation, under slightly modified conditions, the distal C–H alkylation with methyl iodide and methyl bromoacetate can be achieved in moderate yields (4l–n).

Table 3.

Electrophile Scope^a

^aUnless otherwise noted, reactions were run on a 0.2 mmol scale in a 4 mL vial under the standard conditions. Numbers are the isolated yields, and E/Z ratio was determined by ¹H NMR analysis of the reaction crude.

^b110 °C.

^c24 h.

^dMeI was used.

^eMethyl bromoacetate was used.

A major competing reaction pathway is the directed Heck reaction (Scheme 2a). The aryl-Pd(II) species could undergo directed migratory insertion to the alkene followed by β-H elimination to give the Z-alkene product.²⁴ It was interesting to observe that, by increasing the loading of the NBE cocatalyst, the undesired Heck pathway was significantly inhibited (Scheme 2b). To gain insights into the reaction mechanism, deuterium labeling studies were carried out. In the absence of the aryl iodide, upon addition of 3.0 equiv of CD₃CO₂D, 81% of the alkene substrate was recovered with 20% and 22% deuterium incorporation at the distal and proximal vinyl positions, respectively (Scheme 2c). This indicates reversible formation of C–H palladation intermediates I and II (vide supra, Scheme 1c). In addition, a four-membered-ring side product²⁵ was obtained in 10% yield under these conditions, implying the formation of alkenyl–norbornyl palladacycle II. In the presence of the aryl iodide and CD₃CO₂D, deuterium incorporation was observed in the vinyl C–H bonds of both the arylation product and the recovered alkene substrate (Scheme 2c), which suggests protonation occurred at the proximal position. In addition, control experiments with the trans alkene substrate (E)-1n gave no desired arylation product, and Z/E isomerization was not observed under the standard reaction conditions (Scheme 2d), which rule out the pathways involving alkene isomerization-then-Heck or Heck-then-alkene isomerization.

From the view of practicality, the Pd loading can be reduced to 5 mol % on a larger scale (Scheme 3a). The arylation product can undergo various transformations (Scheme 3b). For example, the oxime-ether DG can be easily removed by treatment with Zn and acetic acid. The olefin moiety can be hydrogenated by Pd/C to deliver product 6. The Raney nickel-catalyzed condition can remove the DG and reduce the alkene simultaneously in a quantitative yield. Gratifyingly, the proximal position could undergo a further directed C–H/Heck coupling, which furnished an unsymmetrical tetrasubstituted alkene (7).²⁶ The linear arylation products after saponification can be converted to the corresponding substituted phthalides²⁷ in good yields (8–10, Scheme 3c). In addition, using methyl bromoacetate as the electrophile, a two-step 2-hydroxyethylation was realized in an efficient manner (Scheme 3d). Note that LiAlH₄ chemoselectively reduced the ester moiety instead of the oxime DG. Finally, an initial silver-free condition was identified for the allyl amine substrate (Scheme 3e), which replaced AgOAc with CsOAc using methyl tert-butyl ether (MTBE) as solvent.

Scheme 3. Synthetic Utility.

In summary, a Pd/NBE-catalyzed strategy for distal C–H functionalization of alkenes is developed, which provides a convenient way to prepare trisubstituted olefins. The reaction is regio- and stereoselective and can operate in air. The use of easily removable exo-DGs in alkene C–H activation could have implications beyond this transformation. Further optimization of the distal alkylation reaction and expansion of the electrophile scope are the topics of the ongoing investigation.