Transannular Functionalization of Multiple C(sp³)–H Bonds of Tropane via an Alkene-Bridged Palladium(I) Dimer

Abstract

This communication describes the Pd-catalyzed C(sp³)–H functionalization of a tropane derivative to generate products with functionalization at two (β/γ) or three (β/γ/β) different sites on the alicyclic amine core. These reactions proceed via an initial dehydrogenation to generate an alkene product that can react further to form a Pd(I) alkene-bridged dimer. Functionalization of this dimer affords β/γ/β-functionalized allylic arylation and allylic acetoxylation products.

Grahical Abstract

Six-membered alicyclic amines are the single most common heterocycle in pharmaceutically relevant architectures.^1–2 As such, there is significant interest in approaches for the selective C(sp³)–H functionalization of these scaffolds. To date, synthetic methods have been identified to target each of the individual C(sp³)–H sites on the core (Scheme 1a–c).^3–5 Most relevant to this report, our group has developed a Pd-catalyzed g-selective C(sp³)–H functionalization of alicyclic amines (Scheme 1c) in which the amine nitrogen and an appended directing group bind the catalyst and enable selective transannular C_γ–H activation.⁶ A complementary approach (Scheme 1d) would be to functionalize multiple sites on an alicyclic amine in a single transformation.⁷ This would enable the rapid generation of derivatives for biological evaluation.

Scheme 1.

(a-c) C(sp³)–H functionalization reactions that selectively target the α-, β-, and γ-C(sp³)–H bonds of 6-membered alicyclic amines. [R, R¹ = hydrogen, alkyl, aryl, or directing group (DG), depending on the transformation.] (d) This work: C(sp³)–H functionalization of the β/γ/β sites in a single transformation. [R = directing group, DG]

In this communication, we demonstrate the realization of this goal in the context of the Pd-catalyzed triple C–H functionalization of tropane substrate 1.⁸ We show that selective β/γ/β functionalization can be achieved by the transannular dehydrogenation of 1 followed by further functionalization of the resulting alkene. An alkene-bridged Pd(I) dimer was isolated from the stoichiometric reaction of 1 with Pd(OAc)₂, and this complex reacts with oxidants to form β/γ/β functionalized products in high yield and selectivity.

This work commenced with studies of the Pd(OAc)₂-catalyzed reaction between tropane substrate 1 and PhI using conditions previously reported by our group for C_γ–H arylation (Scheme 2).^6b The expected γ-arylation product 2 was obtained in 63% yield after 18 h at 140 °C. However, careful inspection of the crude reaction mixture revealed the minor side product 3, derived from functionalization at three different sites β/γ/β on the tropane core (9% yield). The structure and stereochemistry of 3 were confirmed by NMR spectroscopy and x-ray crystallography (see SI for details). Variation of the solvent, base, and picolinic acid derivative led to conditions where 3 is the major product (Scheme 2b). However, even under these optimized conditions, significant quantities of 2 were formed (~9%). Furthermore, the yield of 3 was variable, ranging from 27–64% from run-to-run.⁹

Scheme 2.

(a) Pd-catalyzed reaction of 1 with PhI affords products functionalized at the γ (2) and β/γ/β positions (3). (b) Optimized conditions afford 3 as the major product, but selectivity is modest, and yield is variable.

In an effort to address these issues, we interrogated the pathway to the β/γ/β functionalization product, 3. We hypothesized that 3 is formed via sequential Pd-catalyzed dehydrogenation followed by allylic arylation (Scheme 3a). Notably, Yu and coworkers have reported related Pd(OAc)₂-catalyzed oxazoline-¹⁰ and carboxylic acid-directed¹¹ dehydrogenations of alkanes to afford alkenes.¹² Furthermore, Pd-catalyzed Heck-type reactions between cyclic alkenes and aryl iodides to form allylic arylation products are well precedented.¹³

Scheme 3.

(a) Proposed pathway to 3. (b) Alkene 4 is formed in the absence of PhI. (c) Resubjecting 4 to the reaction conditions affords 3.

To test the feasibility of an initial dehydrogenation, we conducted the reaction from Scheme 2a in the absence of PhI, substituting trifluorotoluene as an inert aromatic solvent. This afforded alkene 4 as the major product in 48% yield (Scheme 3b). The conditions were optimized (by varying the solvent, base, temperature, and picolinic acid derivative) to afford alkene 4 in 63% isolated yield (see SI for details). An isolated sample of 4 was then re-subjected to the original Pd-catalyzed C–H arylation conditions. After 18 h at 140 °C, the reaction afforded 3 in 30% yield, consistent with 4 as an intermediate en route to 3.¹⁴

Our previous work has shown that transannular C_γ–H functionalization of related alicyclic amine substrates can be achieved in enhanced yield and selectivity via stoichiometric reactions of palladium-amine coordination complexes.¹⁵ For example, as shown in Scheme 4a, we demonstrated that Pd^II complex A forms under mild conditions from the reaction between Pd(OAc)₂/pyridine and alicyclic amines bearing fluoroarylamide directing groups. A then reacts with oxidants (FG in Scheme 4a) to afford γ-functionalized products.¹⁶ In some instances, the analogous organic products were formed in poor yield under catalytic conditions. Thus, we hypothesized that an analogous stoichiometric sequence might provide cleaner access to the target β/γ/β-functionalized product 3 and analogues thereof.

Scheme 4.

(a) Previous work on isolation and selective C–H functionalization of A. (b) Stoichiometric reaction of 1 with Pd(OAc)₂ forms alkene-bridged dimer C

In the event, the reaction of tropane substrate 1 with Pd(OAc)₂ and pyridine (identical conditions to those in Scheme 4a) did not afford the expected coordination complex B. Instead, it resulted in dehydrogenation of 1 and formation of the Pd^I alkene-bridged dimer C as the major distinguishable organometallic product.¹⁷ This dimer, which shows four diagnostic ¹H NMR resonances between 5.28 and 3.79 ppm, was formed in 17% yield as determined by ¹H NMR spectroscopic analysis of the crude reaction mixture. Modifying the reaction conditions (by changing the solvent from t-amyl alcohol to MeCN and removing the pyridine) resulted in a 36% crude yield of C. Purification by column chromatography on silica gel afforded an analytically pure sample of C in 35% isolated yield. X-ray quality crystals were obtained from a dichloromethane/hexanes solution at room temperature. The x-ray crystal structure is provided in Figure 1 and shows that this is a dimeric complex with the alkene ligands bridging two palladium(I) centers. The Pd–Pd distance is 2.445 Å, which is comparable to that in structurally similar Pd^I dimers.¹⁸

Figure 1.

X-ray crystal structure of C. Selected bond distances (Å): N1−Pd1 2.113, N2−Pd1 2.139, C34−Pd1 2.131, C35−Pd1 2.184, Pd1–Pd2 2.445. Hydrogen atoms are omitted for clarity.

With C in hand, we investigated stoichiometric reactions of this complex with oxidants to generate β/γ/β-functionalized products. As shown in Scheme 5, the treatment of C with phenyl iodide at 100 °C afforded 3 in 72% yield.^19a–b In contrast to the catalytic reactions in Schemes 1 and 2, this transformation was reproducible and high yielding. Analogous reactivity was observed using 3,5-dimethylphenyl iodide, providing 5 in 77% yield.^19a

Scheme 5.

High yielding functionalization of dimer C to form 3 and 5–7.

Based on literature reports from White²⁰ and others,²¹ we hypothesized that allylic oxygenation might also be feasible from C using carboxylic acids in conjunction with benzoquinone (BQ). Indeed, the treatment of C with benzoic acid and 2 equiv of BQ formed the allylic benzoylation product 6 in 71% yield.^19a This reaction proceeded similarly with propionic acid to afford 7 in 67% yield.^19a The structure and stereochemistry of the latter product was confirmed via x-ray crystallography (see SI for details). Overall, the stoichiometric formation and subsequent functionalization of C offers a clean, selective, reproducible, and high yielding route to the tri-functionalized products 3 and 5–7.

In summary, this report describes a route to β/γ/β-functionalized tropane derivatives via dehydrogenation/functionalization. The Pd(OAc)₂-catalyzed reaction requires high temperatures (≥140 °C) and exhibits poor reproducibility, yield, and product selectivity. To address these challenges, we developed a stoichiometric sequence involving initial dehydrogenation to form a dimeric Pd(I) intermediate followed by subsequent functionalization of this complex. This sequence proceeds under relatively mild conditions (60–100 °C) with high reproducibility. Furthermore, it provides a route to diverse C–C and C–O coupled products in good yield/selectivity. These studies highlight the value of interrogating stoichiometric reactions between metal and substrate as a pathway to achieving selective C–H functionalization reactions.