Allyl-Palladium Catalyzed Ketone Dehydrogenation Enables Telescoping with Enone α,β-Vicinal Difunctionalization

Abstract

The telescoping of allyl-palladium catalyzed ketone dehydrogenation with organocuprate conjugate addition chemistry allows for the introduction of aryl, heteroaryl, vinyl, acyl, methyl, and other functionalized alkyl groups chemoselectively to a wide variety of unactivated ketone compounds via their enone counterparts. The compatibility of the dehydrogenation conditions additionally allows for efficient trapping of the intermediate enolate with various electrophiles. The utility of this approach is demonstrated by comparison to several previously reported multistep sequences.

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Two for one: Zinc enolates are employed as intermediates in ketone dehydrogenation using allyl-palladium catalysis, which allows for telescoping with organocuprate conjugate addition chemistry.

The α,β-vicinal difunctionalization of enones is a standard tactic in organic synthesis utilized for the programmable, multicomponent assembly of readily available materials in a single synthetic step.^[1] While enone starting materials can be prepared from saturated ketones by a number of different methodologies,^[2] it would be advantageous to instead use the more inexpensive and readily available ketone oxidation state directly for α,β-vicinal difunctionalization in order to avoid discrete preparation and isolation of the enones in a separate synthetic operation.^[3]

While functionalization of acyclic carbonyl compounds at the β-position has been made possible by directed C-H activation, especially with palladium catalysis,^[4] derivatization of cyclic ketones by this same approach is geometrically challenging. Instead, methods to obtain cycloalkanones with the β-position functionalized^[5] have either relied on multistep sequences or more recently by conversion of ketones to activated intermediates such as enamines that can undergo oxidation to an allylic radical species^[6] or enones that can undergo conjugate addition.^[7,8] Through the use of palladium catalysis, Dong and co-workers were able to functionalize in situ generated enone intermediates with aryl halides^[7a] or diaryliodonium salts^[7b] to provide β-arylated ketones (Figure 1a). Su and co-workers reported the addition of latent, stabilized nucleophiles, including malonates and sulfonamides, to enone intermediates generated from propiophenone derivatives by a copper-catalyzed oxidation (Figure 1b).^[7c] Despite these advances, a method has not yet emerged that is applicable to unactivated, complex ketone starting materials, nor has a strategy been reported for the addition of unstabilized nucleophiles to modestly electrophilic enone intermediates.

Figure 1.

Development of Telescoped Ketone Dehydrogenation and α,β-Vicinal Difunctionalization.

In this report, the one-step dehydrogenation of classically challenging ketones is made possible through the use of allyl-palladium catalysis by way of a zinc enolate, which may reduce the dependency on two-step ketone dehydrogenation approaches.^[2] Furthermore, this dehydrogenation can be telescoped with organocuprate-mediated α,β-vicinal difunctionalization of the intermediate enones (Figure 1c).

Although organocuprates have been widely used for 1,4-addition due to their ease of preparation and their high degree of functional group compatibility, the basic and anhydrous conditions of organocuprate reactions have precluded telescoping^[9] with the most efficient and widely-used dehydrogenation methods,^[2] many of which require incompatible acidic or polar aprotic solvents. It was hypothesized that if our previously reported conditions for carboxylic acid derivative dehydrogenation^[10] could be adapted for the dehydrogenation of ketones, organocuprates could then be added to the same pot because dehydrogenation proceeds under basic conditions, uses a nonpolar solvent, and generates stoichiometric propene as the only oxidation byproduct.

To test this hypothesis, we chose (+)-nopinone (1a) as the model ketone substrate as it is a privileged chiral pool starting material,^[11,12] and dehydrogenation to form (+)-apoverbenone relies on two-step solutions involving α-bromination followed by elimination of HBr.^[13] Through considerable optimization, we found that successful ketone dehydrogenation requires the specific combination of Zn(TMP)₂,^[14] a commercial homoleptic zinc amide as base, and diethyl allyl phosphate as oxidant (Figure 2).^[15] These conditions allowed us to access the oxidized enone product of 1a in 70% isolated yield. We then explored the feasibility of telescoping the newly developed ketone dehydrogenation conditions with established organocuprate chemistry by sequentially adding a nucleophile and an electrophile to the same pot without work-up or isolation. Gratifyingly, we found that the introduction of the methyl Gilman reagent followed by hexamethylphosphoramide (HMPA) and methyl iodide afforded ketone 4a in 63% isolated yield (entry 1). When the reaction was conducted on a one-gram scale, the product was obtained without any erosion in yield (64%). Decreased yields were obtained when our previously disclosed transmetallation procedures were employed: LiTMP with ZnCl₂^[10a] provided product 4a in 10% yield while the use of LiCyan and ZnCl₂^[10b] was ineffective (entries 2–4). Employment of diethyl allyl phosphate as an oxidant was also critical for this transformation as use of allyl acetate as an oxidant only provided trace quantities of the product (entry 5).

Figure 2.

Optimization of Telescoped Ketone Dehydrogenation and α,β-Vicinal Difunctionalization.

^{[a] 1}H-NMR yield was determined using 1,3,5-trimethoxybenzene as an internal standard. ¹H-NMR yield of the enone intermediate is indicated in parentheses. ^[b] Isolated yield.

Under the optimized conditions, both vinyl and isopropenyl nucleophiles were diastereoselectively introduced to various ketones and afforded compounds 3a – 3c in moderate to good yields. Analogous to our previous report, the use of allyl-palladium catalysis allowed for the dehydrogenation of substrates containing readily oxidizable functionality, such as a tertiary amine (3b). The introduction of heterocycles was also tolerated, as demonstrated by the products containing pyridine (3f – 3h), furan (3i, 3j), benzofuran (3k), and thiophene (3l) functionality. Furthermore this method readily provided the protected enone 3i and represents a strategy to functionalize a synthetic equivalent of cyclopentadienone, an anti-aromatic and unstable compound.^[16]

To test the robustness of our methodological approach, we explored whether infrequently used metallated aldimines,^[17] generated by the insertion of an organolithium reagent into tert-butyl isocyanide, could be used as viable nucleophiles (Table 1b). Indeed, lithiated aldimines prepared from both commercial and halogen-derived organolithium reagents (3m – 3r), could be used to introduce acyl functionality to ketones. Unfortunately, limitations to the generation of metal aldimines prevented the incorporation of branched organolithium nucleophiles.

Table 1.

Scope of Ketones and Nucleophiles for Telescoped Ketone Dehydrogenation and Conjugate Addition.^a,b

^aReaction conditions: 1 (1.0 equiv), Zn(TMP)₂ (1.0 equiv), toluene (0.4 M), 0 °C, 10 min, then [Pd(allyl)Cl]₂ (2.5 mol%), diethyl allyl phosphate (1.0 equiv), 120 °C, 2 h; RCuL_n (2.0 – 3.0 equiv), −78 to 23 °C, 12 h.

^bIsolated yield.

^cOrganocuprates were derived from Grignard reagents.

^dOrganocuprates were derived from organolithium reagents.

^eOrganocuprates were derived from metal aldimine reagents.

^fOrganocuprates were derived from Negishi reagents.

Both primary (3s – 3x) and more hindered secondary cyclic and acyclic alkyl nucleophiles were also efficiently introduced with predictable diastereoselectivity and provided ketones with isopropyl (3y), cyclopropyl (3z), cyclopentyl (3aa, 3ab) and cyclohexyl (3ac) functionality. The telescoped process also tolerated acid-sensitive functional groups, thereby allowing for the formation of products 3u and 3aa. The functional group compatibility of Grignard-derived organocuprates was demonstrated through the installation of an acetal containing nucleophile (3af). The use of organozinc-derived organocuprates allowed for even greater functional group compatibility and was highlighted through the synthesis of products containing electron-withdrawing groups such as an ester (3ag), nitrile (3ah), and chloride (3ai).

In addition to the wide scope of nucleophiles, the enolate intermediates generated by conjugate addition were intercepted with various electrophiles to form α,β-functionalized products (Table 2). Primary and secondary (cyclic and acyclic) nucleophiles generated enolates that were efficiently methylated with methyl iodide in the presence of HMPA to afford products 4a – 4d. The use of other reactive electrophiles such as allyl (4e – 4g) and benzyl (4h, 4i) halides was also tolerated. The enolate intermediate could also participate in an aldol addition with monomeric formaldehyde as an electrophile and ZnCl₂ as a crucial promoter to give the α-hydroxymethyl ketone products 4j – 4l in high yields. It should be noted that this one-pot α,β-vicinal difunctionalization process proceeds with diastereoselectivity consistent with classical half-chair transition state theory.^[1]

Table 2.

Scope of Ketones, Nucleophiles, and Electrophiles for Telescoped Ketone Dehydrogenation and α,β-Vicinal Difunctionalization.^a,b

^aReaction conditions: 1 (1.0 equiv), Zn(TMP)₂ (1.0 equiv), toluene (0.4 M), 0 °C, 10 min, then [Pd(allyl)Cl]₂ (2.5 mol%), diethyl allyl phosphate (1.0 equiv), 120 °C, 2 h; RCuL_n (2.0 equiv), −78 to 23 °C, 3 – 6 h; then electrophile.

^bIsolated yield.

^cOrganocuprates were derived from Grignard reagents.

^dOrganocuprates were derived from organolithium reagents.

To demonstrate the synthetic utility of this method, various precursors to biologically active compounds were prepared more efficiently than in previous reports. With our telescoped process, ketones 3aj – 3al, which are intermediates en route to the bioactive compounds (–)-hibiscone C,^[12a] cyclobakuchiol B,^[12b] and 11-Nor-Δ⁸-THC methyl ester,^[12c] were obtained from (+)-nopinone in a single step with good yield, and compared favorably to previous preparations as indicated in Figure 3. Our method could also be utilized for the diastereoselective derivatization of a cis-decahydroquinoline ring system in a single step, affording 3am in 56% isolated yield, thus improving on the previous report which required three steps.^[18] Our one-pot dehydrogenation – conjugate addition sequence also provided steroid 3an after tetrahydropyranyl ether (OTHP) cleavage in 59% yield over two steps. The previously reported sequence accessed 3an in six steps with only a 35% overall yield.^[19] By increasing product yield while also reducing the number of synthetic steps, we hope this method will find broad utility in applications related to natural products synthesis and drug discovery.

Figure 3.

Application of Telescoped Process to Multistep Synthesis.

In conclusion, we have developed a methodology for ketone dehydrogenation that finds utility through its efficient telescoping with foundational organocuprate conjugate addition chemistry. The broad utility of this protocol arises from an allyl-palladium catalyzed ketone α,β-dehydrogenation that can be performed on diverse, unactivated ketone starting materials. The α,β-vicinal difunctionalization component capitalizes on the well-established scope and diastereoselectivity of organocuprate conjugate addition chemistry to introduce a wide selection of functionalities to ketones. We expect the broad generality of both the individual transformations and the step economy of the telescoped process to result in effortless translation to challenges in multistep synthesis.