Ligand-Enabled, Palladium-Catalyzed β-C(sp³)–H Arylation of Weinreb Amides

Abstract

We report the development of Pd(II)-catalyzed C(sp³)–H arylation of Weinreb amides. This work demonstrates the first example of using Weinreb amide as a directing group for transition metal-catalyzed C(sp³)–H activation. Both the inductive effect and the potential bidentate coordination mode of the Weinreb amides pose a unique challenge for this reaction development. A pyridinesulfonic acid ligand is designed to accommodate the weak, neutral coordinating property of Weinreb amides via preserving the cationic character of Pd center through zwitterionic assembly of Pd/ligand complexes. DFT studies of the C–H cleavage step indicate that the superior reactivity of 3-pyridinesulfonic acid ligand compared to pyridine, Ac-Gly-OH, and ligandless conditions originates from the stabilization of overall substrate-bound Pd species.

Graphical Abstract

Chelation-assisted, Pd-catalyzed C–H functionalization has been extensively developed in the past two decades.¹ One of the major advances include developing conditions and ligands to accommodate synthetically versatile weak-coordinating substrates (e.g. carbonyl compounds²). Despite these achievements, using native functional groups or common protecting groups as directing groups for C(sp³)–H activation is still highly limited.³ Traditionally, nitrogen-based, strong-coordinating groups have been most widely used as directing groups for C(sp³)–H activation, presumably due to the facile cyclometalation process that forms stable palladacycle intermediates.^4,5 On the other hand, utilizing oxygen-based neutral-coordinating groups such as tertiary amides, esters, and ketones to direct C(sp³)–H activation remains a significant challenge.⁶ These weak-coordinating functionalities have neither the basicity of nitrogen nor the anionic character of carboxylates/amidates that can stabilize the substrate-to-catalyst binding. Our group has shown that mono-protected amino acid (MPAA) ligands with Pd catalyst can enable the functionalization of C(sp²)–H bonds with a wide range of neutral carbonyl directing groups (Scheme 1, top).^2l The significant ligand effect observed for MPAA prompted us to develop a new class of ligands that can enable C(sp³)–H functionalization on these weak-coordinating substrates using Pd catalysis. Herein, we report the discovery of 3-pyridinesulfonic acid as a uniquely enabling ligand for Pd-catalyzed C(sp³)–H arylation using Weinreb amide as the directing group (Scheme 1, bottom). To the best of our knowledge, this work demonstrates the first example of Pd-catalyzed C(sp³)–H activation directed by a Weinreb amide group.

Scheme 1.

Pd-catalyzed C–H Functionalization Using Neutral, Carbonyl Directing groups

The broad synthetic utility of Weinreb amides as synthons for ketone/aldehyde synthesis⁷ prompted us to develop β-arylation of Weinreb amides. However, using Weinreb amide as directing group poses two unique challenges compared to simple amides (Scheme 1, bottom): First, the inductive effect of –OMe weakens the binding of the directing group with the Pd catalyst. Second, the unproductive bis-coordination with –OMe and carbonyl group can decelerate the catalysis. We postulated that these challenges can be addressed when an appropriate ligand is used to activate the Pd catalyst. However, examination of the corresponding pre-transition state structures suggests that the privileged pyridine/quinoline-type ligands⁸ would be incompatible with neutral-coordinating substrates, due to the lack of a free coordination site necessary for the agostic interaction with C–H bonds on the predominant Pd species A (Figure 1, top). Also, the dissociation of an acetate (or any counteranion) from complex A would be disfavored owing to the high energy associated with cationic complex B. To address this issue, we envisioned that installing a non-coordinating anion, such as sulfonate, into a pyridine ligand may promote the dissociation of an acetate anion from anionic complex C via electrostatic repulsion and thus stabilize the active Pd intermediate D as a zwitterionic species (Figure 1, bottom). Furthermore, the preserved cationic character of the Pd center would facilitate the binding of our weak-coordinating substrates. It is noteworthy that Carrow and coworkers recently reported that anionic thioether ligands can promote Pd-catalyzed C(sp²)–H olefination of electron-rich heterocycles.⁹

Figure 1.

Design Principle of Pyridinesulfonic acid Ligand.

To test our design principle, we chose Weinreb amide 1a as our model substrate for β-C–H arylation (Table 1). Under various conditions, we observed only trace amounts of product without using any ligand. Next, based on our hypothesis, we tested pyridine ligands bearing a sulfonate group at the 2- (L1), 3- (L2), and 4- (L3) positions. While L1 only gave trace amount of products, we were delighted to find that using L2 and L3 as ligands promoted arylation of 1a in high yields. To further support our design principle, we tested various classes of ligands that are known to promote Pd-catalyzed C–H activation. In accordance with our initial hypothesis, pyridine/quinoline-based ligands (L4-L7) only gave trace amounts of products. While pivalic acid¹⁰ (L8) showed similarly poor performance, MPAA ligands (L9-L10) afforded the products in 21 and 22% yields. Our recent finding of using electron-deficient 2-pyridones as ligands for C(sp³)–H¹¹ functionalization prompted us to try L11 as a ligand, but only slight improvement was observed compared to using no ligand. Interestingly, nicotinic acid (L12) and isonicotinic acid (L13) were completely ineffective ligands. We presume that the much stronger coordinating ability of carboxylate compared to sulfonate prevents the formation of the zwitterionic Pd/ligand assembly. Finally, we conducted simple control experiments to show that L2-L3 were not merely serving as sulfonic acid additives. First, using the sulfonic acid L14 only gave 8% yield of the arylated product. Second, using L4 and L14 together completely inhibited the reaction, showing the importance of having both the pyridine and the sulfonic acid moiety in the same molecule. Overall, Table 1 shows the uniquely enabling property of pyridinesulfonic acid ligands (L2, L3) and the importance of synergistic matching of the ligand and the directing group.¹²

Table 1.

Evaluation of Ligands for C(sp³)–H Arylation of Weinreb Amide^a,b

^aConditions: 1a (0.1 mmol), Pd(OAc)₂ (10 mol%), Ligand (12 mol%), methyl 4-iodobenzoate (0.2 mmol), AgOAc (0.2 mmol), HFIP (0.5 mL), 70 °C, under air, 24 h.

^bThe yield was determined by ¹H NMR analysis of the crude product using CH₂Br₂ as the internal standard.

^c80 °C.

We decided to use the commercially available and inexpensive L2 as the optimal ligand to evaluate the substrate scope of the arylation of Weinreb amides (Table 2). First, substrates with simple alkyl chains afforded the arylated products in good yields (2a-2d). Next, Weinreb amides containing heteroatoms (O, N, F) gave the corresponding products in moderate to good yields (2e-2g). Unfortunately, Weinreb amides with α-H did not yield any products (2h, 2i), presumably due to the lack of Thorpe-Ingold effect. However, it was interesting to find that the corresponding N,N-dimethylamide gave 2j in 34% yield. Weinreb amides derived from quaternary cyclopropanecarboxylic acids gave products 2k-2m in excellent yields. While an α-H containing cyclopropane substrate gave product 2n in only 18% yield, again the corresponding N,N-dimethylamide gave much higher 87% yield of 2o. Cyclopropane substrates bearing various aryl groups on the α-position were reactive (2p-2r) with exclusive selectivity towards cyclopropyl C(sp³)–H bond over C(sp²)–H bond. Moderate to good yields were obtained with cyclopropane substrates bearing aryl groups on more remote positions (2s-2v).

Table 2.

C(sp³)–H Arylation of Weinreb Amides: Substrate Scope^a,b,c

^aConditions: 1a-1v (0.1 mmol), Pd(OAc)₂ (10 mol%), L2 (12 mol%), methyl 4-iodobenzoate (0.2 mmol), AgOAc (0.2 mmol), HFIP (0.5 mL), 80 °C, under air, 24 h.

^bIsolated yield.

^cThe numbers in parentheses indicate the ratio of mono:di.

The high reactivity of the cyclopropane scaffold prompted us to examine the scope of aryl iodides with 1k as the substrate (Table 3). Aryl iodides with electron-withdrawing groups (3a-3c) and halides (3d-3f) at the para- position smoothly underwent the reaction to give products in high yields. While the reaction could tolerate p-Me group (3g), p-OMe group was not tolerated. Instead, aryl iodide with p-OTs group gave 3h in a very good yield. Substitution at the meta- and ortho- position of aryl iodides were well-tolerated with electron-withdrawing (3i-3l, 3o-3p) and electron-donating functional groups (3m-3n). A di-substituted aryl iodide also gave 3q in a good yield. Finally, heteroaryl iodides based on furan (3r), thiophene (3s), and pyridine (3t) also proved to be suitable coupling partners. To further test the utility of the developed β-C(sp³)–H arylation protocol, we conducted the reaction on gram scale of 1k with 5 mol% Pd(OAc)₂, and 1.85g (95% yield) of product 2k was isolated (Scheme 2, top). We were also delighted to find that reducing the catalyst loading to 1 mol% and increasing the reaction time can afford 2k in a synthetically useful yield (Scheme 2, bottom). Without using any ligand, 16% of 2k was obtained. With MPAA L9 as the ligand, 30% of 2k was obtained, again showcasing the superior ligand effect with L2. We believe that in this case the ligand effect is not as dramatic as with 1a due to the innate reactivity of the cyclopropane substrate 1k.

Table 3.

C(sp³)–H Arylation of Weinreb Amides: Aryl Iodide Scope^a,b

^aConditions: 1k (0.1 mmol), Pd(OAc)₂ (10 mol%), L2 (12 mol%), Ar–I (0.2 mmol), AgOAc (0.2 mmol), HFIP (0.5 mL), 70 °C, under air, 24 h.

^bIsolated yield.

^c80 °C.

^d48 h.

Scheme 2.

Gram Scale Reaction / 1 mol% Pd Loading

While our manuscript was being prepared, ligand-free β-arylation of N-alkyl pivalamides was reported by Lu and coworkers.⁶ Thus, we found it necessary to evaluate and compare Lu and coworkers’ ligand-free protocol (Conditions A) with our ligand-enabled protocol (Conditions B) on identical substrates and coupling partners (Table 4). First, Weinreb amide 1a showed sluggish reactivity under Conditions A albeit the high reaction temperature. In contrast, our protocol gave 2a in high yield, and the reaction is completely enabled by the ligand L2. Second, α-H-containing alkyl amide 1j showed no reactivity under Conditions A, but Conditions B can provide the product 2j albeit in low yield. Lastly, N-alkyl pivalamide 1w gave products 2w in 55% yield under Conditions A. Remarkably, our protocol can reduce the reaction temperature to 40 °C and still obtain 84% isolated yield of 2w. Overall, the results indicate that the pyridinesulfonic acid ligand effect is significant not only in Weinreb amides, but also in general amide substrates.

Table 4.

Comparison with Ligand-free Protocols^a

^aThe numbers in parentheses indicate the ratio of mono:di.

^bThe yield was determined by ¹H NMR analysis of the crude product using CH₂Br₂ as the internal standard.

^cIsolated yields.

^d40 °C, 48 h. For experimental details, see Supporting Information.

In order to achieve insight for the observed ligand effect with L2, a DFT study of the C(sp³)–H cleavage step (via CMD mechanism) with 1a was conducted (Figure 2). Quasi-harmonic Gibbs free energies of the substrate-bound-Pd complex (Int), C(sp³)–H-bound Pd complex (preTS), transition state for C(sp³)–H cleavage (TS), and the final palladacycle (Pdt) were calculated and compared for selected ligands. In each case, using AcO⁻ (i.e. no ligand), L2, L4, and L9 as the ligand were compared. Also, various conformations of both the amide substrate and the ligand binding were considered, and the pathways with the lowest TS free energies are presented in Figure 2 (For full details, see Supporting Information). First, the reaction pathway with simple pyridine L4 had the highest energy overall, showing the instability of the cationic species (Int A, preTS A, TS A) compared to neutral species. Next, the calculated free energy values of the Pd species on the ligandless pathway (preTS B, TS B) are too high to be reached under our reaction temperature (70 °C), which complies with the trace amount of product formed under these conditions. Also, the lower free energy for the pathway with L9 compared to ligandless pathway agrees with the minor ligand effect observed with L9. Lastly, the lowest TS free energy with L2 is nearly 5 kcal/mol lower than that with L9, which also qualitatively matches with the superior reactivity observed with L2. These results show that L2 enables the reaction via significantly lowering the free energy values of the corresponding substrate-bound Pd species (Int D, preTS D, and TS D). It also implies that the weak-coordinating ability of carbonyl moiety renders the binding of substrate to Pd center generally undesirable (i.e. preTS B, TS B have high energies), and the cationic character of Pd center generated with L2 is essential to accommodate such weak binding.

Figure 2.

Computed qh-G (T=343.15 K) Free Energy Profiles for the C(sp³)–H activation step at the M06/SDD, 6–311++G(d,p)(SMD)//ωB97X-D/SDD,6–31+G(d)(SMD) level of theory

In summary, a Weinreb amide-directed β-C(sp³)–H arylation using Pd catalysis has been developed. The reaction is enabled by the commercially available 3-pyridinesulfonic acid as the ligand. Computational studies indicate that the origin of ligand effect is the overall stabilization of the neutral substrate-bound Pd species, which is likely due to the enhanced cationic character of the Pd center. This is in accordance with our initial design principle of an anionic pyridine ligand that can stabilize the cationic Pd center via a zwitterionic assembly. Based on our finding that our new ligand can enable C(sp³)–H activation of α-H containing alkyl amides, our future work will focus on expanding the substrate scope towards more general substrates and different transformations.