Pd^II-Catalyzed Site-selective β- and γ-C(sp³)−H Arylation of Primary Aldehydes Controlled by Transient Directing Groups

Abstract

Pd(II)-catalyzed site-selective β- and γ-C(sp³)−H arylation of primary aldehydes is developed by rational design of L,X-type transient directing groups (TDG). External 2-pyridone ligands are identified to be crucial for the observed reactivity. By minimizing the loading of acid additives, the ligand effect is enhanced to achieve high reactivities of the challenging primary aldehyde substrates. Site-selectivity can be switched from the proximate to the relatively remote position by changing the bite angle of TDG to match the desired palladacycle size. Experimental and computational investigations support this rationale for designing TDG to potentially achieve remote site-selective C(sp³)−H functionalizations.

Graphical Abstract

L,X-type transient directing groups (TDG) have emerged as a powerful tool in Pd(II)-catalyzed C−H functionalization since the first report in 2016.¹ Without the need of directing group installation and removal, the discovery and development of this class of TDG represents a significant advance for directed C−H activation reactions of amines,² ketones³ and aldehydes^4,5,6 that can form reversible imines with TDG. Our initial report using glycine as TDG for the C(sp³)−H arylation was limited to ketones or o-tolualdehydes.¹ Subsequently, other benzylic and ortho-functionalizations of benzaldehyde derivatives have been extensively investigated.^4,5 Amino acid-based TDG has also been developed for aliphatic aldehydes by the Ge group and others to achieve β- and γ-arylation (Scheme 1a).⁶ Despite these advances, substrates were limited to secondary or tertiary aldehydes. For primary aldehydes, only two individual examples have been reported to date by Li and Ge with 46% and 25% yield for methyl and methylene C(sp³)−H arylation, respectively.^6a In addition, β-methylene C−H functionalization of acyclic primary aldehydes remains to be developed.^6a,c,g Most importantly, controlling site-selectivity in C(sp³)−H activation by designing different TDG has not been demonstrated thus far. Notably, an alternative approach for β-arylation of aliphatic aldehydes have also been pursued via a radical pathway using cyanobenzene as coupling partners (Scheme 1b).⁷

Scheme 1.

Direct C(sp³)−H Arylation of Aliphatic Aldehydes

Herein, we report a combination of ligand and TDG that enabled site-selective Pd^II-catalyzed C(sp³)−H arylation of a broad range of primary aldehydes (Scheme 1c). With 3-amino-3-methylbutyric acid (TDG1) as transient directing group, β-methylene C−H arylation could be achieved with up to 83% yield. By simply employing a different TDG2, tert-Leucine, the regioselectivity could be switched to the relative remote γ-position. Mechanistic studies combined with density functional theory ( DFT ) calculations suggested that matching the TDG bite angle with the size of palladacycle could minimize the strain in the C−H activation transition state (TS), thereby controlling the site-selectivity. Considering the recent extensive examples of remote C(sp²)−H activation reactions developed using distance and geometry as the core parameters,⁸ this finding represents a promising step towards systematical development of remote site-selective C(sp³)−H activation.

To address the limitation of β- or γ-C−H functionalizations of aldehydes, we began to search for more effective ligands and TDG. Since the discovery of 2-pyridones as effective ligands for non-directed C−H activation of arenes,⁹ this class of ligands has also found applications in several TDG-mediated sp³ and sp² C−H activation reactions.¹⁰ However, for TDG-mediated reactions, large excess of carboxylic acid is usually required to catalyze the attachment and dissociation of TDG, hence, the carboxylate could compete with pyridone for coordination and reduce the ligand acceleration effect. Thus, we began to investigate the influence of the acid loading on the reaction.

In the mixture of HOAc/HFIP (1/5, v/v), model substrate decanal Pd(OAc)₂ (10 mol%), 3-amino-3-methylbutyric acid (TDG1, 30 mol%), 5-nitro-3-(trifluoromethyl)-2-pyridone (L8, 80 mol%), AgTFA (1.5 equiv) and Ag₂CO₃ (0.5 equiv) at 110 °C for 26 h. The reaction mixture was filtered through a short celite pad, followed by solvent removal to afford the β-C(sp³)−H arylation product 2a in 45% NMR yield (Table 1, entry 1). By lowering the acid loading to 5.7 equiv, the reaction mass balance improved significantly from 52% to 72%. When minimal amount (0.2 equiv) of acid was used, 54% desired product was observed with mass balance reaching its highest at 92%. Based on this finding, several other organic acids with lower pK_a were tested for their ability to promote the reversible imine formation with lower loading (entries 4–7). To our delight, replacing acetic acid with 0.2 equiv chloroacetic acid was found to be optimal, achieving 80% NMR yield of the product (entry 7). Notably, the reaction could occur without acid albeit with halved yield (entry 8). Presumably, the mild acidity of HFIP could catalyze the imine formation. Different pyridone ligands were also evaluated for this reaction. Among unfunctionalized 2-pyridone (L1, entry 9) and 5-substituted 2-pyridones (L2-L6, entries 10–14), 5-nitro-2-pyridone (L6) gave the highest yield of 41%. Moreover, replacing the trifluoromethyl group (CF₃) at the 3-position of L8 with a methyl or a nitro group (L7 and L9) proved to be inefficient (entries 16–17). Not surprisingly, no arylation product was obtained in the absence of pyridone (entry 17).

Table 1.

Evaluation of Acids and Ligands^a

Entry	Deviation from initial conditions	2a (%)
1	none	45 (52)c
2	HOAc (1/20, v/v, 5.7 equiv)	62 (72)c
3	HOAc (0.2 equiv)	54 (92)c
4	TFA (0.2 equiv) as acidb	57
5	F2CHCOOH (0.1 equiv) as acidb	53
6	CI3CCOOH (0.1 equiv) as acidb	36
7	CICH 2 COOH (0.2 equiv) as acid b	80 (96)c
8	No acid	46 (96)c
9	L1 instead of L8, CICH2COOH (0.2 equiv)	8
10	L2 instead of L8, CICH2COOH (0.2 equiv)	19
11	L3 instead of L8, CICH2COOH (0.2 equiv)	29
12	L4 instead of L8, CICH2COOH (0.2 equiv)	36
13	L5 instead of L8, CICH2COOH (0.2 equiv)	35
14	L6 instead of L8, CICH2COOH (0.2 equiv)	41
15	L7 instead of L8, CICH2COOH (0.2 equiv)	41
16	L9 instead of L8, CICH2COOH (0.2 equiv)	14
17	No Ligand, CICH2COOH (0.2 equiv)	n.d.

^aYield determined by ¹H NMR; CH₂Br₂ as internal standard.

^bLoading that gave the highest yield within a serial of concentrations. See SI for detailed screening.

^cMass balance (combined yields of product and unreacted starting material).

With the optimized conditions in hand, a variety of primary aldehydes with methylene β-C(sp³)−H bonds were tested using methyl 4-iodobenzoate as the coupling partner (Table 2). Linear aldehydes were functionalized at the β-position to furnish 2a-2c with good yields. Aldehyde bearing a large cyclohexyl group at the β-position showed inferior reactivity (2d, 41% yield), while cyclohexyl at the γ-position did not inhibit the reaction (2e). Arylation of benzylic β-C(sp³)−H was also compatible, providing 2f in a moderate yield. Substrates containing phenyl, fluoro, amide, acetate, ether, and N-oxyamide groups could all be functionalized with moderate to good yields (2g-2o). The reaction could be readily carried out in gram scale to provide 2a in 70% yield (1.22g isolated). Furthermore, when using pentanal (1b) as substrate, the loading of aryl iodide can be reduced to 1.2 equiv to provide 2b with 64% isolated yield.

Table 2.

Scope of Aldehydes for β-C(sp³)−H Arylation^a

^aIsolated yields.

^bWith methyl 4-iodobenzoate (1.2 equiv) and HFIP (0.6 mL).

^cReaction time 32 h.

^dReaction time 72 h.

Synthetic versatility of this reaction was further explored with the aryl iodide scope (Table 3). We selected the high boiling point decanal (1a) as the model substrate in order to readily determine mass balance and reaction time. The reaction was compatible with a broad scope of aryl iodides. Good to relatively high yields were acquired with para-substituted electron-deficient aryl iodides containing halogen, acetyl, trifluoromethyl and nitro groups (3a-3f). Surprisingly, the reaction also tolerated unprotected carboxylic acid functionality in the coupling partner to give 3g in 57% yield with longer reaction time. However, the reaction with para-cyano-substituted aryl iodide resulted in 3h with only 45% yield. The reactivities of electron-neutral iodides and iodides with election-donating groups were slightly lower, providing 3i-3k in good to moderate yields. For other aryl iodides containing a meta- ester, nitro, and trifluoromethoxy group, good yields were also obtained (3l-3n). The ortho-fluoro-substituted aryl iodide showed moderate reactivity due to steric hindrance (3o).

Table 3.

Scope of Aryl Iodide for β-C(sp³)−H Arylation^a

^aIsolated yields.

^bReaction time 24 h.

^cReaction time 36 h.

When this β-methylene C−H arylation protocol was extended to γ-C−H arylation of 3-methylbutanal (4a), less than 10% of the desired γ-methyl arylated product was obtained. We wondered whether the six-membered cyclopalladation of the γ-C−H bond could be promoted by a TDG chelating with Pd(II) via 5-membered ring due to a better match of the bite angles. To our delight, tert-Leucine (TDG2) efficiently directed γ-C(sp³)−H arylation of 3-methylbutanal, forming mono- and di-arylated products in 72% combined yield under slightly modified conditions. We then investigated other primary aldehydes to demonstrate the scope of compatible substrates (Table 4). The protocol tolerated a moderate to bulky substitution at the β-position. Substrates with pentyl, neopentyl, 4-methylpentyl, cyclohexyl or cyclopentyl groups could be transformed to the corresponding products in good yields (5b-5f). Acetoxy and phenyl groups were also shown to be compatible (5g-5h). Other primary aldehydes containing β-quaternary centers could be arylated at the γ-position efficiently, achieving good to moderate yields (5i-5k). At this stage, methylene γ-C(sp³)−H arylation is less efficient, affording low yield (5l).

Table 4.

Scope of Aldehydes for γ-C(sp³)−H Arylation^a

^aIsolated yields.

^bRatio of mono: di.

^cReaction time 36 h.

γ-C−H arylation reaction of 4c with a plethora of aryl iodides exhibited a good functional-group compatibility (Table 5). Aryl iodides with various electron-withdrawing groups at the para, meta or ortho positions were coupled to the desired γ-C(sp³)-H bonds in good yields (6a-6f). Coordinating groups such as nitro, acetyl, and cyano were also compatible (6g-6j). In addition, the reaction of fluorescent para-substituted N-(p-iodophenyl)-1,8-naphthalimide resulted in the fluorophore conjugate 6k with 56% yield. Furthermore, aryl iodides derived from natural products such as estrone and borneol were also effectively functionalized to afford the desired products in 65% and 57% yields, respectively (6l-6m). However, electron-neutral and electron-rich aryl iodides exhibited poor reactivity, with 22% and 36% yields observed using 4-iodotoluene and 4-iodoanisole as coupling partners, for instance (See SI for details).

Table 5.

Scope of Aryl Iodide for γ-C(sp³)−H Arylation^a

^aIsolated yields.

^bdr = 1:1.

To further illustrate the impact of the chelating ring size of TDG on site-selectivity, we attempted the challenging site-selective C(sp³)−H activation of a representative substrate containing both β-methylene and γ-primary C−H bonds (Scheme 2). To our delight, arylation of butanal 1p afforded over 77% yield of the desired product (2p) with an exclusive β-selectivity (β/γ >20:1) when 6-membered chelating TDG (TDG1) was used. In contrast, the selectivity was switched to γ-arylation (γ/β=9:1) in 62% yield with 5-membered chelating TDG (TDG2). Considering that previously reported C(sp³)−H activation reactions via a 6-membered palladacycle intermediate often needed substitutions at α/β positions to prevent β-C(sp³)−H activation, the impact of the TDG on site-selectivity is significant.⁶ However, when this protocol was extended to pentanal (1b) containing adjacent β- and γ-methylene sites, only β-arylated product was obtained with TDG2 (See SI for details).

Scheme 2. Site-selective β- and γ-C(sp³)−H Arylation^a,b.

^aIsolated yields. ^bratio determined by ¹H NMR of the crude mixture.

In 2019 we reported a single example of controlling γ/β selectivity in directed C(sp³)−H arylation of alcohols by designing different covalent L,X-type directing groups,⁷ and the origin of the selectivity was subsequently investigated computationally.⁸ The β-site-selectivity using amino acid-based TDG for C(sp³)−H activation of ketones has been rationalized through computational studies.⁹ This first example of TDG-controlled β- and γ-C(sp³)−H activation offers us a unique opportunity to probe the origin of switchable site-selectivity. We hence performed deuterium incorporation experiments in the presence of 2-chloroacetic acid-d and HFIP-OD (Scheme 3a). The absence of deuterium incorporation in the arylated products suggested that the C−H cleavage step was irreversible for both β- and γ-C(sp³)−H arylation. Moreover, kinetic isotope effect (KIE) studies revealed large primary KIE values (KIE_β of 7.8 and KIE_γ of 5.6) when using β- and γ-deuterated substrates (Scheme 3b). These results are consistent with the C−H cleavage being the rate- and site-selectivity-determining step for both β- and γ-C(sp³)−H arylation.

Scheme 3.

Mechanistic Studies

With these findings in hand, we began to investigate the influence of TDG on site-selectivity by DFT modeling of the corresponding C−H cleavage transition states (TS). We used 1p as the model substrate for our studies (please see the SI for computational details). With L8 as the ligand, 4 ensembles of TS were located from conformational search, corresponding to β- and γ-C(sp³)−H activation with TDG1 and TDG2 (Scheme 4, lowest TS shown with their relative Boltzmann-weighed activation free energies, ΔΔG^≠₃₈₃). Calculated β/γ- site-selectivity was obtained from the ratios of combined Boltzmann populations of the corresponding TS ensembles. β-C(sp³)−H activation was calculated to be favored over γ- by 2.29 kcal/mol with TDG1, while with TDG2 the selectivity was reversed with a free energy difference of 1.66 kcal/mol. These values correspond to 20:1 and 1:9 calculated β/γ- ratios, respectively, in excellent agreement with the experimental observations (Scheme 2). Our studies suggest that the site-selectivity of C−H cleavage is controlled by the bite angle of the TDG. Evidently, the 5,6-membered coordination (with O−Pd−C angle of around 175°) is preferred over the 5,5- or 6,6-membered coordination, where additional ring strain in the C−H cleavage TS renders them less favored. This finding is also consistent with the ring strain of fused carbocyclic rings.¹⁵

Scheme 4. DFT Modeling of The TDG Influence on Site-selectivity of C(sp3)−H Cleavage^a.

^aThe lowest TS for each TS ensemble with their relative Boltzmann-weighed activation free energies are shown. Calculated regioselectivity ratios were obtained at 383 K. Please see the SI for computational details.

In summary, we have developed a protocol for Pd^II-catalyzed site-selective β-methylene and γ-C(sp³)−H arylation of primary aldehydes. This reaction features broad substrate scope with good functional group compatibility, exemplified by successful C−H arylation of a range of readily oxidizable aldehydes under mild conditions. Moreover, this strategy highlighted the influence of TDG on site-selectivity through matching the bite angles between the palladacycle and the TDG chelation, providing a guidance for the future design of ligands or TDG. Efforts to develop TDG to achieve γ-methylene C−H activation using this principle are currently underway in our laboratory.