Enantioselective Remote Meta-C–H Arylation and Alkylation via a Chiral Transient Mediator

Abstract

Asymmetric C–H metalation has recently emerged as a promising approach for developing enantioselective C–H activation reactions. However, this approach is typically limited to 5- and 6-membered cyclometalation, thereby preventing the asymmetric functionalization of C–H bonds at positions remote to existing functional groups. Herein, we report the realization of enantioselective remote meta-C–H arylation of benzylamines, as well as arylation and alkylation of homobenzylamines. The desymmetrization and kinetic resolution are achieved using an achiral ligand and a catalytic amount of chiral transient mediator that relays an initial ortho-C–H activation to the meta position. The same chiral transient mediator affords comparable enantioselectivities with different classes of substrates containing either neutral σ-donor or anionic coordinating groups. This relay strategy could provide an alternative means to remote chiral induction, one of the most challenging problems in asymmetric catalysis.

Enantioselective C–H activation reactions via asymmetric metalation have the potential to open a new avenue for constructing chiral molecules owing to the diverse reactivity of chiral carbon–metal bonds^1–2. Efforts to achieve this goal have been met with tremendous difficulties due to the lack of appropriate catalytic redox manifolds and conceptual bases for effective chiral ligand design. Enantioselective activation of C(sp²)–H bonds has played an important role in developing chiral ligands and understanding chiral induction in the metalation of C–H bonds. For example, an early example of Ru(0)-catalyzed atropselective alkylation of 2-arylpyridine afforded only 49% ee³. In the past decade, the extensive search for suitable metal catalysts, chiral ligands and catalytic cycles that can achieve highly enantioselective C–H activation reactions has led to the finding that a Pd(II) catalyst bound to a chiral mono-protected amino acid ligand (MPAA) enables highly enantioselective C–H coupling via a Pd(II)/Pd(0) catalytic cycle^4–6, as well as C–H iodination and oxidation involving Pd(II)/Pd(IV) catalysis^7–8 (Figure 1a). In addition to point desymmetrizations, this class of chiral ligand is also competent in planar and axial desymmetrizations, as demonstrated by multiple research groups^9–12. Pd(0)-catalyzed intramolecular vinylation and arylation of C(sp²)–H bonds has also been rendered enantioselective by using chiral phosphine ligands^13–14. Recently, chiral rhodium^15–18 and iridium¹⁹ catalysts have been developed to enable enantioselective C(sp²)–H activation; however, these reactions are largely limited to either intramolecular silylations or pyridine-directed C–H olefinations. Hitherto, transition metal-catalyzed enantioselective remote meta-C(sp²)–H activation has not been reported.^20–23 Asymmetric metalation of remote sp²-C–H bonds presents a distinct challenge: the metal insertion event occurs too far from the carbon that becomes the chiral center. Remote C–H functionalization directed by a nitrile-template has been developed recently;²² however, the control of the stereochemistry through a conformationally flexible macro-cyclic transition state remains to be demonstrated (Figure 1b). In general, remote chiral induction remains one of the most challenging problems in asymmetric catalysis.^24–25

Figure 1. Enantioselective C(sp²)–H activation.

a, Enantioselective ortho-C–H activation. b, Enantioselective remote C–H activation (unsolved problem). c, Strategy for enantioselective remote C–H activation. d, Scope of enantioselective remote C–H activation.

Here we report a strategy using a catalytic amount of chiral norbornene as a transient mediator to achieve enantioselective remote C–H activation (Figure 1c). The norbornene plays a dual role: to relay C–H activation from the ortho position to the remote meta position^26–30; and to achieve chiral differentiation of the racemic ortho-C–H palladation intermediates, generated by an achiral catalyst, to ensure the formation of the enantio-enriched product. This approach has been successfully implemented in enantioselective remote meta-C–H activation reactions of benzyl and homobenzylamines, both of which are prevalent motifs in bioactive natural products, drug compounds, and chiral organic catalysts (Figure 1d). The chiral norbornene methyl (1S,4R)-bicyclo[2.2.1]hept-2-ene-2-carboxylate ((+)-NBE-CO₂Me) serves as a versatile chiral transient mediator (CTM) for both X- and L-type substrates. Kinetic resolution of homobenzylamines was also achieved using the same CTM to broaden the scope of the substrates.

Our experimental design was based on a previous finding that norbornene can intercept the ortho-palladation intermediate via migratory insertion and subsequently effect meta-C–H functionalizations^26–28. This reaction mechanism guided us to hypothesize that a chiral, enantioenriched norbornene might be able to differentiate the racemic ortho-palladate intermediate during the alkene insertion, or the subsequent alkene insertion intermediate (from the meta-C–H palladation step). We selected diarylmethylamine 1³¹, which contains a σ-donor coordinating group, as the model substrate to investigate the potential asymmetric arylation using chiral norbornene mediators (Figure 2a). While the chiral bicyclo[2.2.1]heptene derivatives CTM1 and CTM2 were effective mediators, both gave negligible enantioselectivity. Likewise, the lactam CTM3 failed to display any degree of stereoinduction. The use of chiral (+)-NBE-CO₂Me as the transient mediator led to a dramatic improvement in enantioselectivity to 88:12 (see Supplementary Information for optimization). While neither inorganic base nor carboxylic acid additives were effective, the phosphoric acid (PhO)₂PO₂H increased the er to 93:7. Pleasingly, (R)-BNDHP produced a 70% yield and an excellent enantioselectivity (97:3 er). Bulky substituents (like anthracenyl group) on the phosphoric acid proved detrimental to the reaction. To investigate the role of the chiral norbornene and phosphoric acid, we performed a number of control experiments. The use of racemic NBE-CO₂Me and (R)-BNDHP gave poor enantioselectivity (57:43). The use of (S)-BNDHP, (R)-phosphorylimide or chiral camphorsulfonic acid in combination with (+)-NBE-CO₂Me led to a slight drop in yield and enantioselectivity. These combined experiments suggest that (+)-NBE-CO₂Me is responsible for the chiral induction and the chiral phosphoric acid has a minor beneficial effect.

Figure 2. Enantioselective meta-C–H arylation of diarylmethylamines.

a, CTM and additive optimization. Reaction conditions: 10 mol% Pd(OAc)₂, 15 mol% pyridone-ligand, 50 mol% (+)-NBE-CO₂Me, 15 mol% additive, 3 equiv. methyl 4-iodobenzoate, 3 equiv. AgOAc, CHCl₃, 100 °C. For each entry number (in bold), data are reported as NMR yield. b, Scope of asymmetric arylation. Reaction conditions: 10 mol% Pd(OAc)₂, 15 mol% pyridone-ligand, 20 mol% (+)-NBE-CO₂Me, 15 mol% (R)-BNDHP, 3 equiv. Ar–I, 3 equiv. AgOAc, CHCl₃, 100 °C. ^*R¹ = Me. ^†15 mol% (PhO)₂PO₂H. ^‡1.5 equiv. Ar–I, 2 equiv. AgOAc. ^§80 °C. ^¶60 °C. ^**50 mol% (+)-NBE-CO₂Me. ^††R¹ = H. ^‡‡20 mol% Pd(OAc)₂, 30 mol% pyridone-ligand, 30 mol% (R)-BNDHP. ^§§15 mol% Pd(OAc)₂, 23 mol% pyridone-ligand. For each entry number (in bold), data are reported as isolated yield. The absolute configuration of 2ah was determined by X-ray crystallography. DG, directing group; Ar, aryl group; m-Tol, meta-tolyl group. Reducing the catalyst loading to 5 mol% produced comparable results for substrate 1a′ (see Table S6 in Supplementary Information).

Using the optimized conditions, we then tested the substrate scope with methyl 2-iodobenzoate (Figure 2b). Electron-neutral (2a, 2b), electron-donating (2c) and electron-withdrawing (2d to 2f) substituents were all well tolerated, providing enantioselectivities of up to 97:3. Substrate 1g bearing an alkyne group afforded a lower yield due to the instability of the C–C triple bond under the standard conditions. Substituents at the ortho-position (2h) reduced the reactivity via a presumed steric effect, but high enantioselectivity (91:9 er) was preserved. Bis-substituted arenes 2i and 2j, which contain heterocycles, were also compatible and afford consistently high enantioselectivity. The 5-membered heterocycle 2k gave lower selectivity, probably due to a coordinative effect.

We next surveyed the scope of aryl iodides (Figure 2b). The scope of ortho-substituted aryl iodides (2m to 2q) is broad, providing enantioselectivity in up to 97:3 er. Electronically diverse meta-substituted aryl iodides (2r to 2w) were tolerated, and produced enantiomeric ratios greater than 95:5 (2s to 2v). The scope of para-substituted aryl iodides is also broad, and electronic factors do not affect the enantioselectivity (2x to 2ac). Multi-substituted aryl iodides (2ad to 2ai) were also tolerated under the conditions, and the enantiomeric ratios all exceeded 95:5. The above scope of various aryl iodides features either halogens (as in 2t to 2v) or reactive groups (NHAc in 2m and 2r, phosphonate moiety in 2x, alkyl chloride 2z, and aldehyde in 2aa) that can serve as useful synthetic handles for subsequent chemical manipulation. Importantly, heterocyclic aryl iodides also proved successful in the reaction (2aj to 2au). Pyridine, quinoline, quinazoline, furan, thiophene, and indole derivatives were all suitable coupling partners, providing good to high enantioselectivities. The simple removal of directing group was demonstrated with product 2ae (see Supplementary Information for details).

We then investigated asymmetric meta-C–H activation of homobenzylamines³². Until now, no ortho-C–H activation method has achieved the construction of a homobenzylic chiral center. Considering that the challenge might be overcome by the CTM strategy, we tested different mediators and found that (+)-NBE-CO₂Me remained the most effective one, providing a 97:3 enantioselectivity with nosyl-protected homobenzylamine 3a, which contains an anionic coordinating group (see Supplementary Information for details). Notably, the use of a nosyl-protected (Ns) amino moiety as the directing group represents a practical advantage in synthetic applications. Further investigation revealed that this method covers a broad range of symmetric homobenzylamines (Figure 3a). Ortho-, meta-, and para-substituents were all well-tolerated, and provided the desired products (4a to 4f, 4h) in good to high enantioselectivities. Moreover, both naphthalene (4g) and the bis-substituted arene (4h) were amenable to the standard conditions.

Fig. 3. Enantioselective meta-C–H activation of homobenzylamines.

a, Scope of desymmetrization. Reaction conditions: 10 mol% Pd(OAc)₂, 20 mol% 3-methyl-5-phenylpyridine, 20 mol% (+)-NBE-CO₂Me, 3 equiv. R–I, 3 equiv. AgOAc, TBME, 90 °C. ^*Methyl 2-bromobenzoate (as arylation reagent). ^†50 mol% (+)-NBE-CO₂Me. ^‡15 mol% Pd(OAc)₂, 30 mol% 3-methyl-5-phenylpyridine. ^§1.4 equiv. Ar–I. ^¶15 mol% Pd(OAc)₂, 30 mol% 4-acetylpyridine (as ligand). ^**1.5 equiv. (+)-NBE-CO₂Me, DCM (as solvent). b, Scope of kinetic resolution. Reaction conditions: 10 mol% Pd(OAc)₂, 20 mol% 3-methyl-5-phenylpyridine, 20 mol% (+)-NBE-CO₂Me, 0.5 equiv. R–X, 2 equiv. AgOAc, TBME, 80 °C. ^††1.5 equiv. R–X. ^‡‡1 equiv. R–X. ^§§3 equiv. R–X, 3 equiv. AgOAc. ^¶¶20 mol% 4-acetylpyridine, DCM. ^***50 mol% (+)-NBE-CO₂Me. For each entry number (in bold), data are reported as isolated yield. The absolute configurations of 4m and 4n were determined by X-ray crystallography. TBME, tert-butylmethylether; o-Tol, ortho-tolyl group; DCM, dichloromethane. Reducing the catalyst loading to 5 mol% produced comparable results for substrate 3a (see Table S10 in Supplementary Information).

The reaction tolerated electronically diverse aryl iodides (4i to 4l) and provided enantioselectivities in up to 99:1 er. Heterocyclic aryl iodides such as pyridine, furan, and thiophene (4m to 4o) were also successful. In addition to aryl iodides, 2-bromobenzoate was also tested and provided moderate yield and excellent enantioselectivity (4a, >99:1 er). Likewise, the aliphatic coupling partner iodoacetate gave product 4p with 92:8 er.

In addition to desymmetrization, kinetic resolution of secondary amines was also realized (Figure 3b). (+)-NBE-CO₂Me successfully resolved a racemic mixture of amino esters providing meta-arylated products and recovered starting materials in good enantioselectivity with 2-bromo-benzoate (6a, 6b). These meta-arylated phenylalanines are central motifs in a family of bioactive natural products³³. Alkyl- and aryl-substituted homobenzylamines (6c to 6e) were also compatible with this system. Moreover, simple arene (6f), heterocycle (6g) and alkyl groups (6h, 6i) were all enantioselectively installed at the meta-position by this method. To showcase the synthetic utility of this reaction, a copper-catalyzed intramolecular amination of 6j yielded chiral indoline 7 with the 5-position substituted, a core structure of chemotherapy medication Vincristine.

Mechanistic studies of our previous enantioselective C–H activation reactions have established the asymmetric C–H metalation step as the enantio-determining step^34–35. Since the chiral mediator (+)-NBE-CO₂Me) is not involved in the ortho-C–H activation step, chiral differentiation should occur in one of the subsequent steps. A number of mechanistic experiments were thus carried out to provide further insights (see Supplementary Information for details). First, kinetic isotope effects (KIE) of 1.03 and 1.33 for the ortho- and meta-deuterated substrates respectively indicated that the C–H activation steps are likely not rate-limiting. First-order rate dependence observed for aryl iodide points to the oxidative addition of aryl iodide as rate-limiting (Figure 4a).³⁶ Second, substantial hydrogen/deuterium exchange at the ortho-position and the lack of such exchange at the meta-position suggests that the ortho-C–H activation step is fast and reversible while the meta-C–H activation is not readily reversible on the reaction time scale. These combined data suggest that the chiral differentiation by the chiral norbornene occurs at either the norbornene insertion into the ortho-palladation intermediate or subsequent meta-C–H activation step (Figure 4b).

Figure 4. Mechanistic studies.

a, Reaction rate dependence on aryl iodide. b, Proposed catalytic cycle.

In summary, remote enantioselective C–H activation reactions were realized by relaying ortho-C–H activation to remote meta-C–H activation using a chiral norbornene as the mediator. The chiral amplification is achieved by fast reversible non-asymmetric C–H activation followed by enantioselective norbornene insertion or meta-C–H activation. This approach is compatible with substrates containing either neutral σ-donor or anionic coordinating groups.

Methods Summary

General procedure for the Pd/(+)-NBE-CO₂Me catalyzed enantioselective meta-C–H activation

Arene (0.10 mmol, 1.0 equiv), Pd(OAc)₂ (2.2 mg, 10 μmol, 10 mol%), Ligand (15 mol% or 20 mol%), hydrogenphosphate (15 mol% for benzylamine substrate), aryl iodide (0.3 mmol, 3.0 equiv.), and AgOAc (50 mg, 0.30 mmol, 3.0 equiv.) were added into a 2-dram reaction vial. Solvent and (+)-NBE-CO₂Me (20 mol% or 50 mol%) were added to the mixture. The vial was flushed with N₂, and capped. The reaction mixture was then stirred at the given temperature for 12 to 24 hours. After cooling to room temperature, the mixture was filtered through Celite and eluted with EtOAc. The filtrate was evaporated under reduced pressure. Purification by preparative TLC chromatography afforded the desired product. Full experimental details and characterization of new compounds can be found in the Supplementary Information.