C–H Bond Activation at Palladium(IV) Centers

Abstract

This communication describes the first observation and study of C–H activation at a Pd^IV center. This transformation was achieved by designing model complexes in which the rate of reductive elimination is slowed relative to that of the desired C–H activation process. Remarkably, the C–H activation reaction can proceed under mild conditions and with complementary site selectivity to analogous transformations at Pd^II. These results provide a platform for incorporating this new reaction as a step in catalytic processes.

Over the past decade, high oxidation state palladium catalysis has found increasingly diverse applications in organic synthesis.¹ The development of new transformations in this area has been guided by fundamental studies of Pd^III and Pd^IV model complexes, which have provided key insights into the unique reactivity and mechanisms accessible at high valent palladium centers.^1,2 To date, these model studies have focused primarily on reductive elimination from Pd^III and/or Pd^IV species.^1,2 In contrast, the possibility of other organometallic transformations at high oxidation state Pd has not been explored in detail. This is likely due to the assumption that reductive elimination occurs much faster than competing reactions.

Very recently, several groups have proposed a new reaction – C–H activation at a transient Pd^IV intermediate – as a key step in catalysis.^3–7 This novel mode of reactivity has been implicated in four different catalytic contexts: (i) C–H oxidative coupling reactions,³ (ii) the carboamination of olefins,⁴ (iii) the acetoxylation of allylic C–H bonds,⁵ and (iv) the C–H arylation of naphthalene.^6,7 Remarkably, many of these catalytic reactions proceed under unusually mild conditions^3–5 and/or exhibit unprecedented site selectivities.^3,4,6 These results suggest that harnessing C–H activation at Pd^IV could provide opportunities for achieving distinct and complementary reactivity relative to analogous (and much more common) transformations at Pd^II centers.

While the reports described above have proposed C–H activation at Pd^IV during catalysis, there is currently no literature precedent for such a transformation. As such, we sought to design model systems to demonstrate the viability of this reaction and to probe reactivity and site selectivity in this context.^8,9 This communication demonstrates that, with appropriate choice of supporting ligands, C–H activation at a Pd^IV center can proceed rapidly at room temperature. Furthermore, we show that the site selectivity of this transformation can be dramatically different than that at analogous Pd^II complexes. These results provide a platform for incorporating this reaction as a step in new catalytic processes.

In order to observe and study C–H activation at Pd^IV, it is critical to slow competing C–X bond-forming reductive elimination (k_RE) while increasing the relative rate of the desired C–H activation process (k_C–H) (Scheme 1). On the basis of these considerations, we initiated investigations of oxidatively-induced C–H activation at complex 1 (Scheme 2). This Pd^II starting material contains a rigid bidentate sp² N-donor ligand [2,2’-bis(4-tert-butylbipyridine (dtbpy)] and a chloride. Both of these ligands are known to slow reductive elimination (k_RE) from high valent Pd intermediates,^11–13 often enabling detection/isolation of Pd^III or Pd^IV species.^1,2,11–13 In addition, the tethered aryl C–H bond could undergo sp² C–H activation to afford a 5-membered palladacycle. The intramolecular nature of this C–H cleavage event is expected to increase k_C–H.¹⁰

Scheme 1.

Competing Reductive Elimination versus C–H Activation at Pd^IV

Scheme 2.

Oxidation of 1 with PhCl₂: Formation of 2 and 3 (N~N = dtbpy)

We first examined the oxidation of 1 with PhICl₂, since this reagent is known to react with Pd^II starting materials to yield isolable Pd^IV products.¹³ As shown in Scheme 2, the reaction produced two major inorganic compounds: Pd^IICl₂(2, 83% yield) and complex 3 (16% yield). Both 2 and 3 are Pd^II species rather than the desired Pd^IV products; however, 3 is remarkable in that it contains a σ-aryl rather than a σ-alkyl ligand bound to Pd. We hypothesized that 2 and 3 might be formed from transient Pd^IV intermediate I, which could undergo competing sp³-C–Cl bond-forming reductive elimination (to liberate 2) and C–H activation/sp³-C–Cl bond-formation to generate 3. While these were promising initial results, complex 3 remained a minor side product under all conditions examined. Additionally, efforts to observe Pd^IV intermediates I and/or II were unsuccessful in this system.

The results in Scheme 2 suggest that k_RE is significantly faster than k_C–H for intermediate I. We reasoned that this problem could be addressed by: (1) replacing the chloride with an X-type ligand that is less prone to reductive elimination and (2) limiting the conformational flexibility of the tethered C–H substrate. As such, we next targeted Pd^II(CF₃)(2-PhC₆H₄)(dtbpy) (4) as our Pd^II starting material. The incorporation of the CF₃ ligand was a particularly important design feature, since several recent reports have shown that Pd^IV(CF₃)(Aryl) complexes can be stable to reductive elimination at or above room temperature.¹⁴ Complex 4 was prepared in 58% yield by the reaction of Pd^II(I)(2-PhC₆H₄)(dtbpy) with CsF/TMSCF₃ in THF.

The treatment of 4 with 1 equiv of PhICl₂ in MeCN at 25 °C for 35 min resulted in a color change from pale yellow to dark yellow along with the formation of products 5-Cl, 6, and 7 in 81%, 12%, and 11% yield as determined by ¹H NMR spectroscopic analysis of the crude reaction mixture (eq. 1). Complex 5-Cl was isolated in 77% yield by recrystallization from CH₂Cl₂/Et₂O. Characterization of 5-Cl by NMR spectroscopy, mass spectrometry, and X-ray crystallography (of a close analogue, vide infra) revealed that this is an octahedral Pd^IV complex containing a cyclometalated biphenyl ligand. This indicates that the desired C–H activation event has occurred.

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In order to gain insights into the mechanism of the C–H activation process, we monitored the reaction of 4 with d₅-PhICl₂ at −30 °C in CD₃CN (Scheme 3). ¹H and ¹⁹F NMR analysis showed fast consumption of starting material, and the formation of a transient intermediate 8.¹⁵ Upon warming to RT, this intermediate decayed over 35 min with 1^st order kinetics to form a mixture of 5-Cl and 6 (final ratio of 5-Cl : 6 = 1.0 : 0.27 under these conditions). Intermediate 8 shows resonances associated with 15 aromatic protons, and a ¹H-¹H COSY allowed assignment of five distinct protons on the pendant phenyl ring.¹⁶ This indicates that this ring is not yet cyclometalated (and also shows that rotation about the aryl-aryl bond is slow on the NMR timescale). ¹⁹F-¹³C HMBC further confirmed that 8 contains a single σ-aryl ligand, as the CF₃ fluorines showed only one correlation with an aromatic carbon. In contrast, two ¹⁹F-¹³C HBMC correlations were observed for the cyclometalated product 5-Cl. Finally, a DOSY experiment showed that 5-Cl and 8 have nearly identical diffusion coefficients at −15 °C, indicating that these complexes have similar hydrodynamic radii. This is consistent with the formulation of 8 as a monomeric octahedral complex.

Scheme 3.

Low temperature NMR study of reaction of 4 with d₅-PhICl₂

Mass spectrometry experiments provided further insights into the molecular structure of 8. ESI-MS showed a peak at 631.1312, which corresponds to the mass of [Pd(CF₃)(2-PhC₆H₄)(Cl)(dtbpy)]⁺. Notably, electrospray ionization commonly results in loss of one X-type ligand from Pd^IV complexes.^2g For example, ESI-MS of 5-Cl affords a peak at 595.1560, corresponding to the mass of [5-Cl–Cl]⁺. MALDI, a softer ionization technique, resulted in a peak at 667.1, which corresponds to [Pd(CF₃)(2-PhC₆H₄)(Cl)₂(dtbpy)+H]⁺.

All of the NMR and MS data presented above are consistent with formulation of intermediate 8 as a Pd^IV complex of general structure Pd^IV(CF₃)(2-PhC₆H₄)(Cl)₂(dtbpy). The diamagnetic nature of this complex clearly indicates that it is not a monomeric Pd^III species. The NMR diffusion experiment along with MALDI MS data provide evidence against alternative formulations as a Pd^III dimer or a square planar Pd^II complex.¹⁷ Overall, the characterization data are fully consistent with the C–H activation event occurring at Pd^IV intermediate 8, thereby representing the first demonstration that high oxidation state Pd can mediate this transformation.

We next explored the reaction of 4 with other 2e⁻ oxidants. While no reaction was observed with iodobenzene diacetate (PhI(OAc)₂, Table 1, entry 3),^2g both iodobenzene bistrifluoroacetate PhI(TFA)₂ and N-fluoro-2,4,6-trimethylpyridinium triflate (NFTPT)¹⁴ reacted with 4 within 10 min at rt to afford cyclometalated Pd^IV complexes where X = trifluoroacetate and triflate (5-TFA and 5-OTf, respectively). The structure of the trifluoroacetate complex was confirmed by X-ray crystallography, and an ORTEP picture of 5-TFA is shown in Figure 1. Consistent with the solution NMR data, the crystal structure shows an unsymmetrical ligand environment around the octahedral Pd^IV center, with the trifluoroacetate group trans to one σ-aryl ligand and the trifluoromethyl group trans to one N of the dtbpy (Figure 1).

Table 1.

Variation of Oxidant (N~N = dtbpy)

Entry	Oxidant	X (Product)	Yield (%)
1	PhICl2	Cl (5-Cl)	77
2	PhI(TFA)2	TFA (5-TFA)	73
3	PhI(OAc)2	OAc (5-OAc)	nr[a]
4	NFTPT	OTf (5-OTf)	86

^[a]No reaction observed after 12 h at 25 °C.

Figure 1.

ORTEP Plot of 5-TFA

Substrate 9 was also examined in order to probe the accessibility of a six-membered palladacycle (eq. 2). In this case, reaction with PhICl₂ for 10 min at 25 °C returned the ortho-chlorinated Pd^II product 10 in 95% yield. This result suggests that a 6-membered palladacycle was generated, but that the resulting Pd^IV intermediate underwent rapid C–Cl bond-forming reductive elimination under the reaction conditions.¹⁸

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Finally, we conducted a series of experiments to compare this C–H activation at Pd^IV to analogous transformations at Pd^II centers. A σ-aryl ligand derived from 2-iodo-3,5’-dimethyl-1,1’-biphenyl (ligand abbreviated σ-DMB) was used, since it contains two sterically and electronically differentiated sites for C–H activation (H_A and H_B). As shown in Scheme 4, the treatment of σ-DMB complex 11 with NFTPT at rt in MeCN produced a 1.7 : 1 mixture of two isomeric products 12-OTf and 13-OTf in 64% yield.^19,20 While 12-OTf/13-OTf could not be completely separated, the mixture was characterized using a variety of two-dimensional NMR experiments (see supporting information for details). In addition, treatment of 12-OTf/13-OTf with NaCl afforded the corresponding chloride complexes (12-Cl/13-Cl), and the structure of the major isomer was definitively established by X-ray crystallography. As shown in Figure 2, the X-ray structure confirms that 12-Cl (and by analogy 12-OTf) is the product of C–H activation at H_A.

Scheme 4.

Site Selectivity of C–H Activation at Pd^IV

Figure 2.

ORTEP Plot of 12-Cl

For comparison, we examined an analogous cyclopalladation reaction at the Pd^II σ-DMB complex 14-F (eq. 3), which was generated in situ by the treatment of 14-I with AgF. Cyclopalladation at 14-F was sluggish at room temperature and required heating to 60 °C in benzene for 4 h to proceed to completion. Furthermore, this reaction afforded >10 : 1 selectivity for activation of the less sterically hindered C–H bond (H_A).²¹ This selectivity is similar to that observed in numerous other cyclopalladation reactions at Pd^II centers, but very different from that observed in Scheme 4 (1.7 : 1).²² The significant difference in both rate and selectivity for this C–H activation at Pd^II versus Pd^IV highlights the dissimilarity of these processes, and highlights the potential value of Pd^IV-mediated C–H activation in catalysis.

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In summary, this communication describes the first observation and study of C–H activation at Pd^IV. This transformation was achieved by designing model complexes in which the rate of reductive elimination is slowed relative to that of the desired competing C–H activation process. Remarkably, the C–H activation reaction can proceed under mild conditions and with different site selectivity than analogous transformations at Pd^II. Investigations are underway to elucidate the mechanism of C–H activation at Pd^IV and to identify further intra- and intermolecular examples of this new reaction. We anticipate that such studies will ultimately enable the rational incorporation of Pd^IV-mediated C–H activation into Pd-catalyzed processes.