Aerobic Pd-Catalyzed sp³ C–H Olefination: A Route to Both N-Heterocyclic Scaffolds and Alkenes

Abstract

This communication describes a new method for the Pd/polyoxometalate-catalyzed aerobic olefination of unactivated sp³ C–H bonds. Nitrogen heterocycles serve as directing groups, and air is used as the terminal oxidant. The products undergo reversible intramolecular Michael addition, which protects the mono-alkenylated product from over-functionalization. Hydrogenation of the Michael adducts provides access to bicyclic nitrogen-containing scaffolds that are prevalent in alkaloid natural products. Additionally, the cationic Michael adducts undergo facile elimination to release α,β-unsaturated olefins, which can be elaborated in numerous C–C and C–heteroatom bond-forming reactions.

Transition metal catalyzed C–H olefination reactions have been the subject of tremendous research activity over the past 20 years.¹ These transformations provide atom economical methods for replacing simple carbon-hydrogen bonds with readily derivatizable alkene functional groups. A variety of different metals (for example, Pd, Cu, Ni, Co, Rh, and Ru) catalyze the olefination of arenes,² and these transformations have been applied to the synthesis and functionalization of biologically active target molecules.³ Pd-based catalysts have been particularly well studied and effectively promote the reaction of alkenes with diverse arene and heteroarene substrates.⁴

While the olefination of sp² C–H bonds is a reliable and widely-used synthetic method, analogous transformations at unactivated sp³ C–H sites remain extremely rare.^5,6 Expanding this chemistry to unactivated alkyl groups is challenging for several reasons. First, metal-mediated cleavage of sp³ C–H bonds is typically slow⁷ and is expected to be even slower in the presence of an alkene, which can compete for coordination sites at the metal center. Second, the key C–C bond-forming event requires carbometallation of a Pd-alkyl intermediate. Such reactions (particularly intermolecular variants) are difficult, because they are frequently plagued by competing β-hydride elimination.^8,9 Finally, the nucleophilic directing groups required to promote sp³ C–H activation can undergo intramolecular Michael addition to the olefinated products, thereby removing the versatile olefin functional group that was installed in the first step. Due to these challenges, there is currently only one report of the C–H olefination of unactivated sp³ C–H bonds.⁵ As shown in eq. 1, this study by Yu and coworkers described the Pd-catalyzed reaction of pentafluorophenyl-substituted amides with benzylacrylate (eq. 1).⁵ Although this was a landmark report, the transformation has a limited substrate scope, requires stoichiometric Cu^II and Ag^I salts as oxidants, and yields cyclic products derived from irreversible Michael addition of the amide to the alkene.

(1)

As part of a program aimed at developing Pd-catalyzed methods for the functionalization of unactivated C–H bonds,¹⁰ we report herein a new nitrogen heterocycle-directed sp³ C–H olefination reaction. This transformation utilizes air as the terminal oxidant and proceeds efficiently with a series of different 2-alkyl pyridines and α,β-unsaturated alkenes. The olefin-containing products can be elaborated using a variety of synthetic methods. In addition, this reaction provides a conceptually novel entry to 6,5-nitrogen heterocycles, which constitute the cores of numerous alkaloid natural products.

Our first efforts towards sp³ C–H olefination focused on the reaction of 2-tert-butylpyridine (2-tbp) with electron deficient alkenes (eq. 2). Extensive previous work from our group^10a,b and others¹¹ has shown that pyridine and quinoline derivatives are effective directing groups for the Pd-mediated cleavage of sp³ C–H bonds. The palladacyclic intermediates are generally slow to undergo β-hydride elimination (presumably due to the strong coordinating ability of pyridine), making them amenable to subsequent functionalization. In addition, we reasoned that a pyridine directing group could undergo reversible intramolecular Michael addition to the olefin product, thereby providing access to either olefin (A) or a cyclic pyridinium salt (B), depending on the reaction conditions (eq. 2).

(2)

Dioxygen is the most cost effective and environmentally benign terminal oxidant for this transformation. As such, we first examined the reaction of 2-tbp with ethyl acrylate under conditions reported by Ishii for the Pd/polyoxometalate co-catalyzed aerobic olefination of benzene derivatives.¹² Gratifyingly, the use of 10 mol % of Pd(OAc)₂ and 10 mol % of acetylacetone (acac) along with 3 mol % of H₄[PMo₁₁VO₄₀] in AcOH at 90 °C under 1 atm of O₂ provided 49% yield of product 1 (Table 1, entry 1). Increasing the temperature to 110 °C under 1 atm of O₂ significantly improved the yield to 81% (entry 2).

Table 1.

Optimization of Pd-Catalyzed Reaction between 2-tert-Butylpyridine and Ethylacrylate.

Entry	[Pd]	Conditions	Yield 1 (%)[a]
1	Pd(OAc)2	90 °C, O2, acac	49
2	Pd(OAc)2	110 °C, O2, acac	81
3	Pd(OAc)2	110 °C, air, acac	83
4	Pd(OAc)2	110 °C, air	89
5	Pd(MeCN)4(BF4)2	110 °C, air	92

^[a]Yield determined by ¹H NMR spectroscopic analysis.

We were pleased to find that ambient air could be used in place of 1 atm of O₂ without any detrimental effect on the overall yield (Table 1, entry 3). Finally, removing the acac ligand (entry 4) and replacing Pd(OAc)₂ with the cationic catalyst Pd(MeCN)₄(BF₄)₂¹³ (entry 5) both accelerated olefination and limited the formation of olefin-derived byproducts.¹⁴ Interestingly, despite the presence of an excess (5 equiv) of alkene, this reaction exclusively afforded the monofunctionalized product 1. This is in marked contrast to the C–H acetoxylation of 2-tbp with PhI(OAc)₂, which forms mixtures of mono-, di-, and triacetoxylated products.^10b In the current system, the intramolecular Michael addition appears to play a key role in protecting the product from over-functionalization.

As shown in Table 2, a variety of other 2-alkylpyridine derivatives participate in this sp³ C–H olefination/cyclization reaction. We found that replacing NaOAc with 1.1 equiv of NaOTf allowed for the olefination of substrates lacking geminal dimethyl groups; for example, both 2-ethyl and 2-iso-propylpyridine afforded high yields of the desired products (entries 1 and 2).

Table 2.

Pd-Catalyzed Olefination and Cyclization Between Various Pyridines and Ethyl Acrylate.

Entry	Substrate	Product	Yield
1 [a]			89%
2 [a]			81% (dr = 1.2 : 1)
3 [a]			55% (dr = 1.2 : 1)
4 [a]			43% (dr = 2.4 : 1)
5 [b]			70%
6 [b]			71%
7 [b]			75%
8 [b]			36%
9 [b]			49% (dr = 1 : 1)
10 [b]			39%

^[a]Conditions: 1.1 equiv of NaOTf, 10 mol % of Pd(MeCN)₄(BF₄)₂, 3 mol % of H₄[PMo₁₁VO₄₀], 5 equiv of ethyl acrylate, AcOH, air, 110 °C, 18 h.

^[b]Conditions: (i) 10 mol % of NaOAc, 10 mol % of Pd(MeCN)₄(BF₄)₂, 3 mol % of H₄[PMo₁₁VO₄₀], 5 equiv of ethyl acrylate , AcOH, air, 110 °C, 18 h; (ii) saturated aq. NaBF₄.

C–H activation/C–C coupling proceeded with >20:1 selectivity for 1° over 2° sp³ C–H bonds (for example, see entry 3). However, a 2° C–H bond on the cyclopropane ring of 2-cyclopropyl-3-methylpyridine could be functionalized to form tricyclic product 5 in modest yield (entry 4). Both electron withdrawing and electron donating substituents were tolerated on the pyridine ring (entries 5-7), and a tethered ester functional group was also compatible with the reaction conditions (entry 9). Remarkably, even 2-methyl-6-tert-butylpyridine provided moderate (36%) yield, despite the sterically crowded environment around the pyridine moiety (entry 8). Finally, quinoline was a useful directing group for sp³ C–H olefination under these conditions (entry 10).

The reaction of 2-tbp was also examined with a series of other olefinic substrates. As shown in Table 3, α,β-unsaturated esters, amides, and ketones were effective alkene coupling partners. Remarkably, the free carboxylic acid moiety of acrylic acid was also well tolerated (entry 4). In contrast, more electron rich olefins like styrene and 1-hexene exhibited low reactivity under the current conditions (entries 7 and 8). This is a common limitation of Pd-catalyzed arene C–H alkenylation reactions.⁴

Table 3.

Alkene Scope for C–H Bond Alkenylation.

Entry	R	Yield (%)
1	CO2Et	90[a]
2	CO2Bu	80[a]
3	CO2Bn	75[a]
4	CO2H	69[b]
5	CONMe2	55[b]
6	COEt	40[a]
7	Ph	<5[b]
8	Butyl	nr[c]

^[a]Isolated yield.

^[b]Yield determined by ¹H NMR spectroscopic analysis.

^[c]nr = no reaction detected

The cationic bicyclic products in Tables 1-3 are useful synthetic intermediates. For example, the PtO₂-catalyzed reduction of 2 with H₂ formed piperidine 12 in 75% yield as a 28 : 1 mixture of cis and trans isomers (Scheme 1).¹⁵ In addition, partial reduction of 2 with NaBH₄ in EtOH afforded 1,2,3,6-tetrahydropyridine 13 in 81% yield as a 2.3 : 1 mixture of readily separable cis and trans isomers (Scheme 1).¹⁶ This chemistry provides an expedient route to 6,5-nitrogen heterocycles, which are a common structural motif in naturally occurring alkaloids.

Scheme 1.

Reduction Reactions of 2

The pyridinium products of sp³ C–H olefination/cyclization can also be converted to the corresponding alkenes by treatment with base. For example, the reaction of 2 with 2 equiv of DBU in CH₂Cl₂ for 1 h afforded olefin 15 in 95% yield (eq 3).

(3)

The ability to readily generate the olefin-containing products allowed us to explore the further functionalization of these molecules. In particular, we sought to demonstrate that the pyridine moiety was compatible with various transition-metal mediated olefin functionalization reactions. As shown in Scheme 2, 15 underwent smooth and high yielding asymmetric dihydroxylation¹⁷ (to form 16 in 97% ee), Pd/C-catalyzed hydrogenation¹⁸ (to form 17), and Cu-catalyzed conjugate addition of EtMgBr¹⁹ (to form 18).

Scheme 2.

Functionalization of C–H Olefinated Product 15.^a

In conclusion, this communication describes a new Pd-catalyzed reaction for the pyridine-directed aerobic olefination of unactivated sp³ C–H sites. This transformation provides a convenient route to 6,5-N-fused bicyclic cores as well as readily functionalizable alkene products. Ongoing work is focused on expanding the scope of this transformation with respect to both directing group and alkene substrate, and these results will be reported in due course.