Mechanistic Basis for Efficient, Site-Selective, Aerobic Catalytic Turnover in Pd-Catalyzed C–H Imidoylation of Heterocycle-Containing Molecules

Abstract

A recently reported Pd-catalyzed method for oxidative imidoylation of C–H bonds exhibits unique features that have important implications for Pd-catalyzed aerobic oxidation catalysis: (1) The reaction tolerates heterocycles that commonly poison Pd catalysts. (2) The site selectivity of C–H activation is controlled by an N-methoxyamide group rather than a suitably positioned heterocycle. (3) A Pd⁰ source, Pd₂(dba)₃ (dba = dibenzylideneacetone), is superior to Pd(OAc)₂ as a precatalyst, and other Pd^II sources are ineffective. (4) The reaction performs better with air, rather than pure O₂. The present study elucidates the origin of these features. Kinetic, mechanistic, and in situ spectroscopic studies establish that Pd^II-mediated C–H activation is the turnover-limiting step. The ^tBuNC substrate is shown to coordinate more strongly to Pd^II than pyridine, thereby contributing to the lack of heterocycle catalyst poisoning. A well-defined Pd^II–peroxo complex is a competent intermediate that promotes substrate coordination via proton-coupled ligand exchange. The effectiveness of this substrate coordination step correlates with the basicity of the anionic ligands coordinated to Pd^II, and Pd⁰ catalyst precursors are most effective because they selectively afford the Pd^II–peroxo in situ. Finally, elevated O₂ pressures are shown to contribute to background oxidation of the isonitrile, thereby explaining the improved performance of reactions conducted with air rather than 1 atm O₂. These collective results explain the unique features of the aerobic C–H imidoylation of N-methoxybenzamides and have important implications for other Pd-catalyzed aerobic C–H oxidation reactions.

Graphical Abstract

INTRODUCTION

Catalytic carbonylation and imidoylation reactions provide an appealing strategy to introduce carbonyl and imine groups into organic compounds, and they are widely used in the preparation of pharmaceuticals and other industrial chemicals.¹ The importance of nitrogen-based functional groups in bioactive compounds contributes to the appeal of catalytic imidoylation reactions. Methods for C–H imidoylation could provide streamlined synthetic routes to versatile pharmacophores (e.g., Scheme 1),^2,3 and recent advances in Pd-catalyzed C–H imidoylation methods have led to methods for the following: preparation of 4-amino-substituted quinolines and quinazolines;^3a,g,i regioselective functionalization of indoles, including C2- and C3-cyanation^3d,e (via in situ loss of a tert-butyl group derived from ^tBuNC) and C3 amidation;^3f syntheses of 6-aminophenanthridines (following removal of a ^tBu group);^3h and preparation of iminoisoindolinones.^4–6

Scheme 1.

Arene C–H Imidoylation Reactions and Relevant Bioactive Molecules Containing Prospective Fragments Derived from Isonitriles

In 2014, Yu and co-workers reported Pd-catalyzed aerobic oxidative C–H imidoylation reactions for the conversion of N-methoxybenzamides to iminoisoindolinones (Scheme 2),⁴ which generate the N-substitution pattern in the product via in situ acyl migration, as depicted in Scheme 2B. The appealing synthetic utility of these reactions is complemented by a series of noteworthy mechanistic features that are not readily rationalized by earlier studies of Pd-catalyzed aerobic oxidation reactions (Scheme 3).⁷ First, the reactions exhibit unique tolerance to heterocycles that commonly poison Pd^II oxidation catalysts, and when the substrate contains a heterocycle that could chelate to the Pd center (e.g., a 2-pyridyl fragment in Scheme 3A), the site selectivity is controlled by the N-methoxyamide group rather than the heterocycle.⁸ Second, a Pd⁰ source, Pd₂(dba)₃ (dba = dibenzylideneacetone), is superior to Pd(OAc)₂ as a precatalyst, while other Pd^II sources [PdCl₂, Pd(TFA)₂, Pd(OTf)₂] are completely ineffective (Scheme 3B). Finally, the reactions proceed with higher yields when air, rather than pure O₂, is used as the source of oxidant (e.g., 94% versus 37%, respectively, in Scheme 3C). These observations have broad implications for the field of Pd-catalyzed aerobic oxidation reactions, if they could be generalized and applied to other reaction classes.

Scheme 2.

(A) Pd-Catalyzed Aerobic C–H Imidoylation of N-Methoxybenzamides and (B) 1,3-Acyl Migration Step That Leads to Product Formation

Scheme 3.

Key Observations from the Aerobic Oxidative C–H Imidoylation of N-Methoxybenzamides

In an effort to elucidate the mechanistic basis for the observations summarized in Scheme 3, we have undertaken an experimental study of this Pd-catalyzed aerobic oxidative imidoylation reaction.⁹ Our efforts focused on determining the catalytic rate law, the turnover-limiting step(s), and the catalyst resting state through a series of kinetic and mechanistic studies and through the use of various spectroscopic methods, including NMR spectroscopy, IR spectroscopy, and operando X-ray absorption spectroscopy (XAS). Stoichiometric and catalytic studies with well-defined Pd complexes probed the reactivity of possible catalytic intermediates. Collectively, the results described herein draw attention to beneficial as well as deleterious effects of using O₂ (or air) as the oxidant: the combination of O₂ and Pd⁰ promotes substrate coordination to the catalyst center; however, higher O₂ pressures contribute to background decomposition of the isonitrile substrate. The isonitrile plays an important role, not only as the substrate, but also as an ancillary ligand to prevent catalyst poisoning by heterocyclic substrates. These and other mechanistic data are presented and discussed within the broader context of Pd-catalyzed aerobic oxidation reactions.

RESULTS AND DISCUSSION

Kinetic Studies of the Catalytic Reaction

Initial-rate kinetic studies of the catalytic reactions were conducted as a first step in probing the mechanism of the reaction (Figure 1). The data show that the rate of product formation exhibits a first-order dependence on [Pd] (Figure 1A), a negligible kinetic dependence on [N-methoxybenzamide] from 13 to 100 mM (with 2.2 mM [Pd]), beyond which an inhibitory effect was observed (Figure 1B),¹⁰ and an inverse first-order dependence on [^tBuNC] (Figure 1C).

Figure 1.

Kinetic data of the Pd-catalyzed aerobic C–H imidoylation of N-methoxybenzamide, assessing the dependence on (A) [Pd] (B) [N-methoxybenzamide] (C) [1/^tBuNC]. Standard conditions: 1.1 mM Pd₂(dba)₃ ·CHCl₃ (2.2 mol% [Pd]), 50 mM N-methoxybenzamide, 150 mM ^tBuNC, 1 atm air, dioxane, 60 °C. Standard conditions were employed, except for the concentration of the component being varied. Error bars reflect typical standard deviations observed when multiple data points were obtained at an individual concentration.

Identical initial rates were observed under 1 atm O₂ and under air, reflecting a zero-order dependence of the reaction on pO₂ (see first 200 min in Figure 2 and complementary data in Figure S2). Gas uptake data, together with product quantitation, show that all four oxidizing equivalents of O₂ are used in the formation of organic products.¹¹ Full time-course data from the reactions in Figure 2 reveal, however, that ^tBuNC is consumed more rapidly under O₂ than under air at longer time periods.¹² The latter feature limits the product yield due to complete consumption of the ^tBuNC substrate and accounts for the lower yield observed with O₂ than with air. Isonitrile oxidation products include isocyanate ^tBuNCO and urea (^tBuNH)₂CO (see Figures S3–S5 in Supporting Information for further details). The urea byproduct derives from in situ hydrolysis of ^tBuNCO to afford ^tBuNH₂ and CO₂, followed by addition of ^tBuNH₂ to another 1 equiv of ^tBuNCO (Scheme 4).

Figure 2.

Time courses of the oxidative imidoylation reaction under O₂ (blue dashed lines) and under air (red solid lines). Reaction conditions: [N-methoxy-4-fluorobenzamide] = 101 mM, [^tBuNC] = 153 mM, [Pd] = 5.0 mM (2.5 mol% Pd₂(dba)₃ · CHCl₃), air or O₂ balloon, V_total = 8.0 mL, dioxane, 65 °C. The dashed gray line represents the concentration of starting material.

Scheme 4.

Isonitrile Oxidation under Catalytic Conditions

Measurement of the initial rates of reaction of N-methoxybenzamide and N-methoxybenzamide-d₅ revealed a significant deuterium kinetic isotope effect: k_H/k_D = 6.7 (±0.2) (Figure 3). This result supports C–H cleavage as the turnover-limiting step of the catalytic reaction.

Figure 3.

Independent initial-rate measurements of the reactions of N-methoxybenzamide (red circles) or N-methoxybenzamide-d₅ (blue squares). Conditions: 1.1 mM Pd₂(dba)₃ · CHCl₃ (2.2 mol% [Pd]), 50 mM N-methoxybenzamide, 150 mM ^tBuNC, 1 atm air, dioxane, 60 °C.

Reactivity Studies of a Well-Defined Pd^II–Peroxo Complex

Palladium(II)–peroxo complexes have been invoked as key intermediates in Pd-catalyzed aerobic oxidation reactions,^13,14 and such species were proposed in a recent computational study of the present reaction by Wang and coworkers.⁹ In 1969, Otsuka and co-workers reported the bis(isonitrile)-ligated complex (^tBuNC)₂Pd(O₂) (1),¹⁵ and this species is a plausible intermediate in the reaction. The peroxo compound 1 was prepared via addition of O₂ to (^tBuNC)₂Pd⁰, as originally described by Otsuka.¹⁵ Subsequent treatment of 1 with 2 equiv of N-methoxybenzamide and ^tBuNC (2 equiv) in dioxane resulted in formation of the iminoisoindolinone product in 47% yield together with the cyclopalladation products 2–4 (46% total yield) and trace (^tBuNH)₂CO (Scheme 5).¹⁶ Complex 2 was isolated and characterized by X-ray crystallography (Figure 4). Testing of 2 as a precatalyst for the reaction revealed a 3 h induction period followed by slow formation of the iminoisoindolinone product (Figures S11 and S12). These observations demonstrate that 2 is not a kinetically competent intermediate in the catalytic reaction. Inclusion of more ^tBuNC (10 equiv), in an effort to more closely mimic catalytic conditions, resulted in a similar yield of the iminoisoindolinone (48%); however, much less cyclopalladation was observed (2 was the only cyclopalladation species detected and was formed in only 7% yield). This observation suggests that ^tBuNC inhibits cyclopalladation, presumably by occupying requisite coordinate site(s) and provides additional evidence that product formation does not proceed via such intermediates (see further discussion below).

Scheme 5.

Reaction of (^tBuNC)₂Pd(O₂) 1 with N-Methoxybenzamide To Provide the Iminoisoindolinone Product and Several Cyclopalladated Pd^II Species

Figure 4.

Molecular drawing of (^tBuNC)₂Pd(C~N) 2. All atoms are shown as 90% thermal probability ellipsoids. All H atoms are omitted.

The Pd^II–peroxo compound 1 was then combined at low temperature with 2 equiv of N-methoxy-2,6-difluorobenzamide (HSub^F2), an amide substrate that cannot undergo cyclo-palladation (Figure 5A), and the reaction was probed by attenuated total reflectance (ATR) FTIR spectroscopy. The IR spectrum of 1 exhibits two N≡C bands at 2217 and 2195 cm^–1, corresponding to the symmetrical and unsymmetrical stretching modes (Figure 5A). The product also exhibits two bands, at 2249 and 2232 cm^–1 (Figure 5A), consistent with formation of the bisamidate product cis-(^tBuNC)₂Pd(Sub^F2)₂. Only one N≡C band would be expected for the corresponding trans product because the symmetrical stretch is IR-inactive in this species.¹⁷

Figure 5.

Stoichiometric reaction between (^tBuNC)₂Pd(O₂) 1 and N-methoxy-2,6-difluorobenzamide to afford the cis-bisamidate-Pd^II product 5^F (A) and in situ IR spectra of (^tBuNC)₂Pd(O₂) 1 and the product of the stoichiometric reaction between (^tBuNC)₂Pd(O₂) and N-methoxy-2,6-difluorobenzamide: cis-(^tBuNC)₂Pd(Sub^F2)₂ 5^F (B). The scaling of the absorbance of the spectrum of 5^F has been magnified by a factor of 3 to account for dilution relative to the sample used for the spectrum of 1.

Analysis of the Catalyst Resting State by X-ray Absorption and NMR Spectroscopy

Both Pd⁰ and Pd^II compounds have been used as precatalysts for the present catalytic reactions (cf. Scheme 3B),⁴ and Pd^I complexes are commonly observed in reactions with isonitriles.^18–20 For example, in the course of probing the reactivity of the Pd^II–peroxo compound 1 with carboxylic acids (in this case, benzoic acid), we observed formation of the tetrameric Pd^I compound [Pd^I(μ-^tBuNC)( μ-OBz)]₄ 6 (Figure 6).²¹ These considerations raised questions about the oxidation state of the catalyst resting state during catalytic turnover. Attempts to address this issue by using in situ NMR methods were complicated by the complexity of the spectral data (see further discussion below). However, palladium K-edge X-ray absorption spectroscopy, which involves excitation of Pd 1s electrons, has been shown to be an effective qualitative means of probing the oxidation state for a systematic series of Pd complexes.²² The Pd K-edge X-ray absorption near-edge structure (XANES) spectra were obtained for a series of Pd⁰, Pd^I, and Pd^II reference compounds, Pd₂(dba)₃ · CHCl₃, [Pd^I(μ-^tBuNC)( μ-OBz)]₄ (6), and Pd(TFA)₂, and the data in Figure 7 show a progressive increase in the edge energy with increasing oxidation state. A temperature-controlled XAS cell, constructed from PEEK, was used to obtain XAS data during operation of the catalytic reaction (see Supporting Information for details). The resulting operando Pd K-edge spectrum closely aligns with the spectrum observed with the Pd^II reference and supports a Pd^II catalyst resting state during the reaction.

Figure 6.

(A) Tetrameric Pd^I compound 6 obtained from the reaction of Pd^II–peroxo 1 with benzoic acid. (B) Molecular drawing (left) and ChemDraw (right) of 6. All atoms are shown as 90% thermal probability ellipsoids. All H atoms are omitted.

Figure 7.

Palladium K-edge XANES spectra of Pd⁰ (Pd₂(dba)₃ CHCl₃) (blue, solid), Pd^I ([Pd^I(μ-^tBuNC)( μ-OBz)]₄ 6) (red, long dash), Pd^II (Pd(TFA)₂) (black, short dash), and the catalyst resting state (green, long/short dash).

With these XANES data in hand, efforts were made to gain additional insights into the catalyst resting state by probing an active catalytic reaction by ¹H and ¹⁹F NMR spectroscopy using the 4-fluoro analogue of the substrate (HSub^4F). Two sets of prominent peaks were evident in the spectra. Definitive assignment of the structures of these species was not possible; however, the spectral data closely resemble the spectra obtained from a stoichiometric reaction of the amide substrate HSub^4F and ^tBuNC with the Pd^II–peroxo complex 1. The two species are tentatively assigned to bis-isonitrile Pd(amidinyl)(amidate) species on the basis of the spectroscopic data (eq 1; see Figures S20 and S21 and associated content in Supporting Information for further information).

(1)

Comparison of Pd⁰ and Pd^II Precatalysts

The superiority of a Pd⁰ source [Pd₂(dba)₃] over Pd(OAc)₂ as a precatalyst and the negligible reactivity with other Pd^II sources [e.g., PdCl₂, Pd(TFA)₂, Pd(OTf)₂] are distinctive features of these reactions (cf. Scheme 3B). To probe the origin of these observations, we compared the initial rates of catalytic reactions with Pd₂(dba)₃ and several different Pd^II precatalysts (Figure 8). In addition to aforementioned Pd^II salts, we tested the Pd^II–peroxo complex 1. The data in Figure 8 show that 1 exhibits excellent reactivity, nearly identical to that of Pd₂(dba)₃, while the other Pd^II precatalysts react with a trend that matches the relative basicity of the anionic ligand: Pd(OAc)₂ > Pd(OBz)₂ > Pd(TFA)₂ = PdCl₂ = 0.

Figure 8.

Initial rates of the oxidative imidoylation of N-methoxy-4-fluorobenzamide under air using different Pd precatalysts. Reaction conditions: [N-methoxy-4-fluorobenzamide] = 101 mM, [^tBuNC]_tot = 153 mM, [Pd] = 5.0 mM, dioxane (8.0 mL), 65 °C. Specific conditions: (a) 2.5 mM Pd₂(dba)₃ · CHCl₃; (b) 5.0 mM Pd(OAc)₂; (c) 5.0 mM Pd(OBz)₂; (d) 5.0 mM PdCl₂; (e) 5.0 mM Pd(TFA)₂; (f) 5.0 mM 1, 7.5 mM dba.

The data in Figure 8 are rationalized by substrate activation initiated by proton-coupled ligand exchange²³ between the anionic ligand on the Pd catalyst and amide substrate. As shown in Figure 5, Pd^II–peroxo 1 reacts with N-methoxy-2,6-difluorobenzamide to generate the Pd^II–bisamidate species 5^F. This ligand exchange reaction and the ensuing catalytic reaction is more favorable with more-basic anionic ligands. Direct observation of ligand effects on substrate activation was obtained by mixing trans-(^tBupy)₂Pd^IIX₂ complexes (^tBupy = 4-(tert-butyl)pyridine; X = OAc, OBz, TFA, or Cl) (Figure 9A) and 2 equiv of N-methoxy-2,6-difluorobenzamide in CDCl₃ and analyzing the equilibrium mixture of products by ¹H, ¹⁹F, ¹H–¹⁵N HMBC, and 1D NOESY NMR spectroscopic methods.²¹ The product mixtures obtained from these studies, together with the reactivity of Pd^II–peroxo complex 1 with the same substrate, are presented in Figure 9B. No amidate complexes were observed in the mixture containing nonbasic chloride ligands, while monoamidate and bisamidate complexes are formed in increasing quantities as the basicity of the carboxylate increases from TFA to OBz to OAc. As noted in Figure 5, reaction of Pd^II–peroxo complex 1 with the amide substrate exclusively forms the bisamidate complex. As shown in Figure 10, the ability of anionic ligands to promote formation of the bisamidate Pd^II in Figure 9 directly correlates with the observed catalytic rates with different PdX₂ precatalysts in Figure 8.

Figure 9.

(A) Reaction of (^tBupy)₂Pd^IIX₂ species with N-methoxy-2,6- difluorobenzamide to afford (a mixture of) ^tBupy-ligated Pd^II–amidate species. (B) Distribution of Pd^II species observed in mixtures of (^tBupy)₂Pd^IIX₂ and 2 equiv of N-methoxy-2,6-difluorobenzamide; the “O₂” complex corresponds to Pd^II–peroxo complex 1.

Figure 10.

Initial rate of product formation with different Pd^II precatalysts Pd^IIX₂ (cf. Figure 8) relative to that observed with Pd₂(dba)₃ plotted as a function of the equilibrium ratio of bisamidate species observed from the reaction of different PdX₂ sources with HSub^F2 in Figure 9. The number in parentheses corresponds to the aqueous pK_a of the corresponding conjugate acid of the anionic ligand, with the exception of O₂^2–, for which the pK_a corresponds to that of H₂O₂. For reference, the aqueous pK_a of the parent N- methoxybenzamide substrate is 8.9;²⁴ the 2,6-difluoro analogue will be more acidic owing to the inductive effect of the fluoro substituents.

Comparison of the Relative Binding Affinities of Isonitrile and Pyridine

The binding affinity of ^tBuNC relative to ^tBupy (as a representative substrate heterocycle) was qualitatively evaluated via titration of ^tBuNC into a solution of trans-(^tBupy)₂PdCl₂ in CDCl₃ (Figure 11). Analysis of the different mixtures by ¹H NMR spectroscopy shows sequential formation of trans-(^tBupy)(^tBuNC)PdCl₂ and a mixture of cis-and trans-(^tBuNC)₂PdCl₂. A clear preference for formation of the 1:1 Pd:^tBuNC adduct is evident when <1 equiv of ^tBuNC is present, and the data further show that very little ^tBupy ligand is bound to Pd when ≥2 equiv of ^tBuNC is present. Collectively, these results show that isonitrile coordination is strongly favored over ^tBupy.²⁵

Figure 11.

Plot of the ^tBupy speciation upon addition of ^tBuNC into a solution of trans-(^tBupy)₂PdCl₂ in CDCl₃ [initial concentration of (^tBupy)₂PdCl₂ = 56 mM].

Proposed Catalytic Mechanism

The data presented above provide valuable insights into the mechanism of Pd-catalyzed C–H imidoylation (Scheme 6). Oxidation of a Pd⁰ precatalyst or intermediate by O₂ in the presence of the isonitrile substrate is expected to afford (^tBuNC)₂Pd(O₂) 1 (step i).¹⁵ Protonolysis of the Pd–O bonds in 1 by the N-methoxybenzamide substrate will afford cis -(^tBuNC)₂Pd^II(amidate)₂ 5 (step ii), according to the reactivity shown above (cf. Figure 5). ^tBuNC insertion into a Pd–N bond and 1,3-acyl migration (cf. Scheme 2) accounts for formation of the three-coordinate monoisonitrile Pd^II(amidinyl)(amidate) species B (step iii). B is believed to be an on-cycle intermediate, but it will react rapidly with ^tBuNC to form the four-coordinate bisisonitrile complex A, proposed to be the catalyst resting state.²⁶ Dissociation of ^tBuNC from A to re-form B precedes turnover-limiting C–H activation of the substrate. The resulting cyclopalladated intermediate C (step iv) undergoes C–C reductive elimination (step v) to form the iminoisoindolinone product, together with release of 1 equiv of the substrate and regeneration of the (^tBuNC)₂Pd⁰ catalyst.

Scheme 6.

Proposed Mechanism for the Oxidative Imidoylation of N-Methoxybenzamide

Cyclopalladation of the substrate from the Pd^II(amidate)₂ intermediate 5 to afford the off-cycle species 2 does not lead to productive catalytic turnover and is inhibited by ^tBuNC in the same manner that ^tBuNC inhibits productive catalytic turnover via formation of A from B. The off-cycle equilibrium between A and B/^tBuNC and turnover-limiting C–H activation accounts for the kinetic data in Figures 1 and 2, which show that the catalytic rate law is first-order in [Pd], zero-order in [substrate], inverse first-order in [^tBuNC] (cf. Figure 1C) and exhibits a large deuterium KIE (k_H/k_D = 6.7). C–H activation is expected to proceed via a concerted metalation–deprotonation (CMD) mechanism,²⁷ in which case the N-methoxyamidate ligand in B will serve as the internal Brønsted base. The enhanced basicity of the amidate relative to typical carboxylates should promote this reaction.

Heterocycle Tolerance, Directing Groups, and Anionic Ligand Effects

^tBuNC is a better ligand for Pd^II than heterocycles such as ^tBupy (cf. Figure 11), and therefore L-type directing groups will be less effective in reactions of the type described here, which employ isonitriles as substrates.^8a This inhibition of L-type ligand directing-group effects is complemented by factors that favor X-type ligand directing groups. The use of a Pd⁰ catalyst precursor results in the generation of a basic peroxide ligand that undergoes facile exchange with the amide substrate to generate the active Pd^II–bisamidate species. Carboxylate ligands are also able to promote this exchange, but their utility correlates with their basicity. None of the carboxylates is as effective as peroxide, owing to their lower basicity and inability to promote complete formation of the Pd^II–bisamidate species (cf. Figure 9). The lack of effectiveness of Pd(TFA)₂ and PdCl₂ as catalyst precursors reflects the (nearly) complete inability of TFA and chloride to engage the N-methoxybenzamide substrate in proton-coupled ligand exchange. The enhanced acidity of the N-methoxyamide substrate N–H group relative to traditional amides contributes to the effectiveness of this ligand exchange. These collective effects are illustrated in Scheme 7.

Scheme 7.

Effects That Contribute to Site Selectivity in N-Methoxybenzamide C–H Functionalization

The imidoylation reaction rates are directly proportional to the quantity of Pd^II–bisamidate species formed in the ligand exchange experiments (cf. Figures 8–10). This correlation appears to arise from a thermodynamic effect, in which a higher concentration of amidate-ligated Pd^II species will favor the reaction, but also a kinetic effect, in which the availability of a second basic amidate ligand will favor the CMD C–H activation step relative to a Pd species with a less basic carboxylate ligand (Scheme 8). The importance of anionic ligand basicity in promoting CMD-type C–H activation has been directly addressed in a number of recent studies,²⁸ and amidate-mediated C–H activation has been the focus of considerable attention in recent Pd-catalyzed C–H oxidation reactions that feature monoprotected amino acid ligands.^29,30

Scheme 8.

C–H Activation with (top) an Amidate Ligand or (bottom) a Carboxylate Ligand

CONCLUSIONS

This study of Pd-catalyzed oxidative imidoylation of N-methoxybenzamides to iminoisoindolinones established a clear mechanistic framework for these reactions. Kinetic and mechanistic studies showed that Pd^II-mediated C–H activation is the turnover-limiting step of the reaction. The reaction does not show a kinetic dependence of the O₂ pressure, but elevated O₂ pressure contributes to background decomposition of the isonitrile substrate, resulting in the reaction performing better under ambient air, rather than under 1 atm O₂. Operando X-ray absorption spectroscopic data confirmed that the catalyst resting state is a Pd^II species, despite the presence of “soft” isonitrile ligands that commonly stabilize low-valent metal centers. Studies of stoichiometric reactions between the benzamide substrate and a well-defined Pd^II–peroxo complex and various Pd^II–carboxylate species provided valuable insights into the anionic ligand effects on the reaction.

The results highlight a number of factors that promote selectivity and activity in Pd-catalyzed aerobic C–H functionalization reactions. Anionic ligand effects, in particular, play a prominent role in these reactions. The Pd^II–peroxo species, generated as an intermediate during aerobic oxidation of the catalyst, can initiate substrate activation via proton-coupled ligand exchange between the peroxo group and the acidic N–H group of the N-methoxybenzamide. This step, in combination with strong ligand binding provided by isonitriles, accounts for the regioselectivity of C–H functionalization by promoting reactivity adjacent to the X-type directing group rather than L-type heterocycle directing groups and helps to prevent the formation of intermediates that lead to catalyst poisoning. The formation and kinetically beneficial role of a Pd^II–peroxo intermediate has important implications for other C–H functionalization reactions because the proton-coupled ligand exchange with other acidic functional groups could provide the basis for favorable reactions with diverse anionic nucleophiles and/or directing groups, while simultaneously helping to avoid poisoning by neutral heterocycles. Pd^II–carboxylate precatalysts are similarly capable of promoting proton-coupled ligand exchange, but the reduced basicity of carboxylates relative to the peroxo ligand results in competitive binding between the substrate-derived amidate and the carboxylate ligand. Although more-basic carboxylates are more effective, none is as effective as the Pd^II–peroxo. Use of a Pd⁰ precatalyst, such as Pd₂(dba)₃, provides a convenient means to generate the Pd^II–peroxo in situ. These insights provide a valuable foundation for efforts to discover new heterocycle-tolerant aerobic C–H oxidation reactions.