A Neophyl Palladacycle as an Air- and Thermally Stable Precursor to Oxidative Addition Complexes

Abstract

The utilization of isolated Palladium Oxidative Addition Complexes (OACs) has had a significant impact on Pd-catalyzed and Pd-mediated cross-coupling reactions. Despite their importance, widespread utility of OACs has been limited by the instability of their precursor complexes. Herein, we report the use of Cámpora’s palladacycle as a new, more stable precursor to Pd OACs. Using this palladacycle, a series of biarylphosphine ligated OACs, including those with pharmaceutical-derived aryl halides and relevance to bioconjugation, were prepared.

Graphical Abstract

Palladium-catalyzed cross-coupling reactions are important for the synthesis of complex molecules. They have become mainstays in natural product synthesis,¹ materials science,² agrochemical synthesis,¹ and pharmaceutical development.³ Mechanistic studies utilizing stoichiometric Pd complexes have been valuable in expanding the generality of Pd catalysis by enabling each elementary step of the catalytic cycle to be probed (Figure 1A).⁴ Of these mechanistic inquiries, those focused on the generation and use of Pd oxidative addition complexes (OACs) are noteworthy. OACs have allowed for the study of different modes of catalyst deactivation,⁵ guided the synthesis of additional ligand scaffolds,⁶ been employed as an entry point to analyze other steps in the catalytic cycle,⁷ and been implemented as superior precatalysts for Pd-catalyzed carbon–heteroatom bond forming reactions.⁸

Figure 1.

(A) A general catalytic cycle for Pd⁰/Pd^II-catalyzed cross-coupling reactions highlighting the complexes of interest in this study. (B) Biarylphosphines utilized in this study.

The modularity and versatility of OACs have allowed them to be utilized stoichiometrically in Pd-mediated cross-coupling reactions as well.⁹ When catalytic cross-coupling methods are applied to complex aryl halides, they often fail to deliver any product.^9a In the context of drug discovery, this can lead to fewer potential drug candidates, and first-pass reaction success outweighs the cost of using stoichiometric quantities of Pd.^9a Additionally, Pd OACs have been applied to bioconjugation,^9c–f radioisotope incorporation,^9g and late-stage pharmaceutical diversification.^9a,b

Despite the aforementioned successes, accessing OACs still remain a challenge. While OACs are, themselves, often air-, moisture-, and thermally stable, they necessitate the use of unstable precursors. In order to access OACs with a broad ligand and aryl (pseudo)halide scope, either (cod)Pd(CH₂TMS)₂ (cod = 1,5-cyclooctadiene),¹⁰ a thermally sensitive Pd^II complex, or (L·Pd)₂(cod) (L = phosphine),¹¹ a series of air-sensitive Pd⁰ complexes that require manipulation in a glovebox, is often employed. While these complexes can be used to access a wider range of OACs than the commercial and more stable Pd₂(dba)₃,^5,12 their instability can limit their utility.

We sought to identify a more stable, user-friendly precursor to Pd OACs that would fulfill the following prerequisites: the new precursor should (1) display similar reactivity to (cod)Pd(CH₂TMS)₂, (2) be synthetically tractable, and (3) be stable at room temperature and under ambient atmosphere. With these goals in mind, we report the use of (cod)Pd(CH₂CMe₂C₆H₄) (P3), a five-membered palladacycle first reported by Cámpora,¹³ as a new precursor to OACs. Using P3, a series of OACs bearing a wide range of biarylphosphine ligands were accessible (Figure 1B). Palladacycle P3 was used to the generate (L·Pd)₂(cod) complexes in situ, which allowed for the synthesis of pharmaceutical-derived OACs without the use of a glovebox.

We sought to find a Pd^II complex that was air-, moisture-, and thermally stable with a labile ancillary ligand, such as cod, but could rapidly undergo reductive elimination upon ligand exchange with a phosphine ligand. This would generate a reactive L·Pd⁰ species that could subsequently undergo oxidative addition in the presence of an aryl (pseudo)halide to afford the desired OAC (Table 1). As a benchmark, (cod)Pd(CH₂TMS)₂ (P1) allowed for access to RuPhos-, XPhos-, and t-BuXPhos-ligated OACs in high yield in tetrahydrofuran (THF) at room temperature (entries 1–3). While stable dialkyl Pd complexes are underrepresented in the literature,^10a,14 reportedly stable polyfluorinated diaryl Pd complexes have been thoroughly studied.¹⁵ These complexes seemed like potential viable alternatives, as they are stable when ligated to cod, but have been shown to undergo reductive elimination in the presence of biarylphosphine ligands catalytically.¹⁶ However, complete conversion of (cod)Pd(2,4,6-F₃C₆H₂)₂ (P2) was only observed in the presence of smaller dicyclohexylbiarylphosphines (entries 4–6). We, thus, ultimately concluded that diaryl Pd complexes are too stable to be used as general precursors to OACs.

Table 1.

Investigation of Pd Precursors for OAC Formation^a

Entry	Pd Precursor	L	Temp (°C)	Yield A (%)	Yield B (%)
1b	P1	RuPhos	rt	n/a	99
2b	P1	XPhos	rt	n/a	97
3b	P1	t-BuXPhos	rt	n/a	99
4b	P2	RuPhos	rt	n/a	98
5b	P2	XPhos	rt	n/a	99
6b	P2	t-BuXPhos	rt	n/a	40
7	P3	RuPhos	rt	99	0
8	P3	XPhos	rt	70	0
9	P3	t-BuXPhos	rt	0	10
10	P3	t-BuBrettPhos	rt	0	0
11	P3	RuPhos	60	41	59
12	P3	XPhos	60	0	99
13	P3	t-BuXPhos	60	0	82
14	P3	t-BuBrettPhos	60	0	24

^aYields determined by ¹H NMR using 0.5 equiv of 1,3,5-trimethoxybenzene as an internal standard. Reaction conditions: Pd precursor (0.05 mmol), L (0.055 mmol), aryl bromide (0.075 mmol), and THF (0.50 mL, 0.10 M).

^bReactions run for 16 h.

Since the dialkyl Pd complex P1 afforded desired reactivity at the expense of stability and the diaryl Pd complex P2 had the desired stability at the cost of reactivity, we wondered whether the use of a mixed alkyl,aryl-Pd complex could combine the favorable aspects of each. While stable acyclic alkyl,aryl-Pd complexes without strong electron-withdrawing groups^7b remain rare, a series of air-stable 5-membered alkyl,aryl-palladacycles have been reported by Catellani,¹⁷ Echavarren,¹⁸ and Cámpora.¹³ Not only have these palladacycles been frequently invoked as intermediates in catalytic transformations¹⁹ and commonly utilized as mechanistic tools,^13,20 two reports have shown that they can undergo thermal reductive elimination from Pd^II complexes to generate Pd⁰ intermediates and the corresponding benzocyclobutene.²¹ In these cases, this reductive elimination was not used as a means to generate a Pd⁰ species. We, however, anticipated that the L·Pd⁰ intermediates generated in situ by this method could subsequently react with aryl halides to afford OACs.

Following a slightly modified literature procedure, the cod-bound Cámpora palladacycle P3 could be accessed in 79% isolated yield on 10 mmol scale and in a 65% average isolated yield on 25 mmol scale (Scheme 1). This synthesis employs a commercially available Grignard reagent, proceeds at ambient temperature, and has a predictable C–H activation/cyclization step. To determine the viability of P3 as a precursor to OACs, we treated it with a series of biarylphosphine ligands and 2-(trimethylsilyl)ethyl 4-bromobenzoate. In the presence of RuPhos at room temperature, we observed complete consumption of P3; however, no desired OAC was formed. Instead, formation of the RuPhos-ligated palladacycle was observed by LC/MS and ¹H NMR spectroscopy (Table 1, entry 7). When XPhos was utilized, partial conversion to the XPhos-ligated palladacycle was detected (entry 8). However, the analogous reaction with t-BuXPhos or t-BuBrettPhos resulted in trace or no OAC formation, respectively (entries 9–10). By heating each reaction mixture to 60 °C for 1 h, the RuPhos- and XPhos-ligated OACs could be formed in 59% and 100% yield, respectively (entries 11–12). In general, for dicyclohexylbiarylphosphines, the ligand exchange process is facile at room temperature, but the subsequent reductive elimination requires heating. In the case of di-tert-butylbiaryl-phosphines, the t-BuXPhos-ligated OAC was formed in 82% yield (entry 13), while the formation of the t-BuBrettPhos OAC was slower and resulted in 24% yield after 1 h at 60 °C (entry 14). Improved yields for the latter were obtained by heating the reaction mixture to 80 °C. Changing the reaction solvent from THF to n-hexane and heating each reaction mixture for 2 h allowed for isolation of the corresponding OAC by precipitation in excellent yield.

Scheme 1.

Synthesis of Palladacycle P3

^aAverage of 3 runs.

To expand on these preliminary studies, we investigated the scope of ligands that could form OACs using P3 (Figure 2A). Both the t-BuXPhos-bound and XPhos-bound OACs of 2-(trimethylsilyl)ethyl 4-bromobenzoate (1 and 2) were prepared in 90% and 68% isolated yield, respectively. Notably, the use of P3 that had been stored under ambient conditions for 1 year allowed for the isolation of 1 in 80% yield.²² By employing the same aryl halide, OACs bearing t-BuBrettPhos (3), RuPhos (4), Ad(Cy)BrettPhos (5), and GPhos (6) could be obtained. OACs ligated to the extremely bulky dialkylter-arylphosphine AlPhos were accessible, as both the bromide complex 7 and triflate complex 8 could be formed from P3. Additionally, OACs bearing electron-neutral (L = BrettPhos, 9) and electron-rich arenes (L = CPhos 10) could be generated in excellent yields. While some of these OACs have been utilized as precatalysts,⁸ we determined that P3 itself can also be used as a precatalyst (see SI for details).

Figure 2.

OAC scope from P3. Isolated yields shown. Reaction conditions: (A) P3 (0.50 mmol), L (0.53 mmol), aryl halide (0.60 mmol), and n-hexane (5.0 mL, 0.10 M); (B) P3 (0.60 mmol), L (0.72 mmol), aryl halide (0.60 mmol), 2-MeTHF (2.5 mL), and THF (5.0 mL). ^aIsolated yield using P3 stored under ambient conditions for 1 y. ^bCyclohexane (5.0 mL), 80 °C. ^c1.2 equiv of P3 and 1.0 equiv of aryl halide. ^d1.0 equiv of P3, 3.0 equiv of aryl halide, and 2-MeTHF (7.5 mL). See Supporting Information for details.

Much of the utility of Pd OACs arises from their versatility, with respect to both the ancillary ligand and the aryl halide. We were interested in determining if P3 could form OACs from more complex aryl halides, including pharmaceuticals. Formation of OACs from pharmaceutical-like aryl halides has a tremendous impact on first-pass reaction success.^9a However, accessing these OACs is often particularly challenging. Attempting to prepare OACs from (cod)Pd(CH₂TMS)₂ and pharmaceutical-derived aryl halides often leads to incomplete conversion and low yield of the product. Although preligating the desired ancillary ligand to the palladium center through the use of (L·Pd)₂(cod) complexes can lead to improved yields, these Pd⁰ complexes are oxygen sensitive and require storage and manipulation in a glovebox.

By simultaneously heating P3 with the desired ligand and aryl halide (conditions A), the protocol utilized with simple aryl halides, the t-BuXPhos-bound OAC derived from the “informer compound” X4^3b 11 was formed in 63% isolated yield (Figure 2B). However, these conditions were not general for other complex aryl halides, as they failed to deliver either the rivaroxaban-derived OAC 12 or the gefitinib-derived OAC 13. We postulated that by allowing P3 to react with t-BuXPhos prior to the addition of the aryl halide, we could generate [(t-BuXPhos)Pd]₂(cod) in situ. This may, in turn, increase the yield of OACs prepared from pharmaceutical-like aryl halides. By generating (L·Pd)₂(cod) before adding the desired aryl halide (conditions B), t-BuXPhos-bound 12 and 13 could be obtained in 80% and 88% isolated yield, respectively. Furthermore, this stepwise approach allowed for access to the XPhos-ligated 14 and BrettPhos-ligated 15, both derived from rivaroxaban.

Another application of Pd OACs involves their use as reagents for the selective delivery of arenes into densely functionalized molecules under mild conditions. These reagents have recently emerged as useful tools for the incorporation of radioisotopes^9g and for the functionalization of biomolecules (Figure 2C).^9c–f In this regard, we were able to synthesize the cationic RuPhos complex 16.^9c By allowing 4,4′-dibromobiphenyl to react with 2 equiv of P3, we were able to access the bis-Pd OAC 17, which has been used as a peptide stapling reagent.^9d While aryl iodides are not converted to product under conditions A,²³ we found that the BrettPhos-ligated Pd OAC of 1,4-diiodobenzene 18 could be prepared using conditions B with excess aryl halide. Additionally, OACs bearing orthogonal functional handles, including N-hydroxy-succinimide (19) and pentafluorophenoxy esters (20 and 21), could be prepared. In order to demonstrate that the chemistry was scalable, we also performed the synthesis of 19 on a 10 mmol scale, which resulted in 99% isolated yield. Complex 20 is also noteworthy, as amphiphilic sulfonated phosphine ligands have allowed for cross-coupling in aqueous conditions^9e and site-selective functionalization through ion-pairing interactions.²⁴

Prior to OAC formation, intermediate L·Pd⁰ and L·Pd^II complexes are generated in situ that are interesting to access in their own right (Figure 3). The t-BuXPhos-ligated 22 and BrettPhos-ligated 23 formed in the absence of aryl halides have been previously prepared from P1, although the protocol employed long reaction times, typically 48 h.¹¹

Figure 3.

Scope of other Pd⁰ and Pd^II complexes accessible via P3. Isolated yields shown. Reaction conditions: P3 (0.50 mmol), L (0.53 mmol), and CyH (5.0 mL, 0.10 M). Yields in parentheses are determined by ¹H NMR spectroscopy of the crude reaction mixture using 1,3,5-trimethoxybenzene as the internal standard. See Supporting Information for details. ^aL (0.50 mmol), Et₂O (5.0 mL, 0.05 M), 1 h. ^bL (0.50 mmol), pentane (5.0 mL, 0.05 M), 1 h.

With P3, each complex could be produced in 2 h. XPhos-bound 24 can also be accessed. Additionally, by allowing P3 to react with each ligand at room temperature, palladacycles bearing XPhos (25) and RuPhos (26) can be prepared. Although these complexes undergo reductive elimination at elevated temperatures, we found that samples of each showed no evidence of decomposition after 3 months in the solid state under ambient conditions.

In conclusion, we demonstrated that palladacycle P3 can be utilized as an air-, moisture-, and thermally stable precursor to a broad range of Pd OACs. Even after storing P3 under ambient conditions for a year, it showed no evidence of decomposition and allowed for access to a diverse array of biarylphosphine ligated OACs, including densely functionalized OACs relevant to pharmaceutical diversification and OACs bearing orthogonal functional handles for selective incorporation of Pd^II into biomolecules. OAC formation from P3 was found to be scalable, as P3 allowed for access to OACs on 10 mmol scale. We believe that the use of P3 will greatly expand the availability of OACs in both academic and industrial settings, which in turn will allow for the investigation of new chemical transformations and increase the accessible chemical space.