and Î´-CâH Arylation of Amines through Ligand Development

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Overcoming the Limitations of #, and #-C–H Arylation of Amines through Ligand Development Yan-Qiao Chen, Zhen Wang, Yongwei Wu, Steven R. Wisniewski, Jennifer X Qiao, William R Ewing, Martin D. Eastgate, and Jin-Quan Yu J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 30 Nov 2018 Downloaded from http://pubs.acs.org on November 30, 2018

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Journal of the American Chemical Society

Overcoming the Limitations of , and -C–H Arylation of Amines through Ligand Development Yan-Qiao Chen†,⊥, Zhen Wang†,⊥, Yongwei Wu†,⊥, Steven R. Wisniewski‖, Jennifer X. Qiao§, William R. Ewing§, Martin D. Eastgate‖, Jin-Quan Yu*,† †

Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla,

California 92037, United States ‖

Chemical & Synthetic Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, New Jersey

08903, United States §

Discovery Chemistry, Bristol-Myers Squibb, PO Box 4000, Princeton, New Jersey 08543, United States

*[email protected] RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required according to the journal that you are submitting your paper to) Abstract. L,X-type transient directing groups (TDG) based on a reversible imine linkage have emerged as broadly useful tools for C–H activation of ketones and free amines. However, competitive binding interactions among multiple reaction components (TDG itself, substrate, and substrate-TDG adduct) with the palladium catalyst often lead to the formation of multiple unreactive complexes, rendering ligand development extremely challenging. Herein we report the finding of versatile 2-pyridone ligands that addresses these problems and significantly improves the -methylene arylation of alkyl amines, extending the coupling partners to a wide range of medicinally important heteroaryl iodides and even previously ACS Paragon Plus Environment

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unreactive heteroaryl bromides. The combination of an appropriate transient directing group and pyridone ligand has also enabled the -arylation of alkyl amines. Notably, our transient directing group design reveals the importance of matching the size of the Pd-chelation with different transient directing groups and the size of palladacycles generated from - and -C–H bonds: TDGs that coordinate with Pd(II) to form a 6-membered chelate are selective toward -C–H bonds, whereas TDGs that coordinate with Pd(II) via a 5-membered chelate tend to activate -C–H bonds. These findings provide an avenue for developing protecting group free and selective C–H functionalization using the transient directing group strategy. 1. Introduction Transition metal-catalyzed C(sp3)–H functionalizations via the transient directing group strategy have attracted significant attention in recent years owing to its ability to employ innate functionalities to directly functionalize the targeted C–H bonds without installing and removing exogenous directing groups.1-4 This approach was first demonstrated in a number of pioneering examples involving Rh(I)catalyzed C(sp2)−H activations.5 Inspired by these works, we have studied various L,L-type chiral imine/oxazoline bidentate transient directing groups for asymmetric C−H activation of ketones and amines without success (Scheme 1).6 One exception of this L,L-type transient directing group design was recently reported by the Dong group, where the imine/pyridine L,L-type TDG generated from stoichiometric 8-formylquinoline can achieve arylation of free amines using highly active aryl iodonium Ar2IBF4 salts as coupling partners.4b Our earlier studies on monoprotected amino acid (MPAA) ligands7 and our recent advances utilizing amino acids as bidentate directing groups in C−H functionalizations of peptides8 guided us to successfully develop simple amino acids as transient directing groups toward Pdcatalyzed C(sp3)−H functionalization of aldehydes and ketones.2a Importantly, this work suggests that an in-situ generated bidentate imine and carboxylate L,X-type directing group is effective in promoting C−H functionalization. The readily reversible imine linkage and the weak coordination of the carboxylate are crucial advantages for developing versatile C–H activation reactions. Guided by this TDG design insight, we have subsequently developed -arylation of alkyl amines, diverse C(sp2)−H functionalizations of

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aldehydes, and methylene arylation of aliphatic ketones employing various appropriate L,X-type transient directing groups (Scheme 2).2e, 3a, 4a Furthermore, other groups have recently developed a variety of L,Xtype transient directing groups toward the same effort.2b, 2d, 2f, 2g, 3b, 3c, 4c, 4d Notably, other X-type binding moieties such as SO3H group is also effective.2h While transient directing groups open a new avenue towards practical and synthetically useful C−H activation reactions, this strategy is not without its intrinsic disadvantages and limitations. For instance, competitive binding interactions among multiple reaction components (TDG itself, substrate, and substrate-TDG adduct) with the palladium catalyst often lead to the formation of multiple unreactive complexes, thus deactivating the catalyst. An ideal solution to overcome this limitation would be the development of a suitable monodentate ligand that: (1) effectively stabilizes the palladium catalyst in the presence of other potentially catalyst-poisoning species, (2) but is not too strongly coordinating to outcompete the desired substrate-catalyst coordination, and (3) can promote and accelerate each step of the C−H activation catalytic cycle. Electron-deficient 2-pyridones were recently identified as exceptionally efficient ligands for both norbornene-mediated meta-C(sp2)−H functionalization and nondirected C(sp2)−H activation of arenes.9,10 Kinetic and density functional theory (DFT) studies suggest that pyridone is likely to serve as an X-type ligand, acting as an internal base to accelerate the C–H bond cleavage step.10 Palladium-pyridone complexes also exhibit enhanced reactivity and broader heterocycle scope compared to palladium acetate.9,10 Guided by this discovery, we envisioned that 2-pyridone could operate as an acetate surrogate to accelerate the C(sp3)−H bond cleavage step while preventing the undesired above-mentioned coordinations with the palladium catalyst.11 Herein, we report the first pyridone enabled methylene -C(sp3)–H heteroarylation and -C(sp3)–H arylation of alkyl amines using two different transient directing groups respectively (Scheme 3). The newly developed transient directing groups are selective toward their respective -methylene and -methyl C(sp3)–H bonds in the presence of other reactive C–H bonds. These findings indicate the importance of a cooperative effect between L,Xtype transient directing groups and external pyridone ligands.


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2. Results and Discussion Aliphatic amines are important substrates for C−H functionalization owing to their abundance and utility as valuable synthetic building blocks. Specifically, those amines bearing N-containing heterocycles at the -position are prevalent in bioactive molecules (Figure 1).12 Although previous reports showed a few less-coordinating heteroaryl iodides as effective coupling partners, these substrates are restricted to coupling with -methyl amines and no examples of methylene heteroarylation have been reported using transient directing groups to our knowledge. 4a,4c

Figure 1. Amine based bioactive molecules bearing N-containing heterocycles at the  position. ACS Paragon Plus Environment

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Driven to solve this problem, we began our investigation by conducting -methylene-arylation of cyclohexylamine. Under our previous reaction conditions using a simple phenol based TDG (TDG1), only 15% of the desired product was observed when 2-chloro-4-iodopyridine was used as the coupling partner at 150 ℃ (Table 1). Directed by our vision to replace acetate with other potentially superior acetate surrogates, we began screening different monodentate X-type ligands. To our delight, simply adding tBuCO2H (L1) improved the yield to 35%. Simple pyridones (L2−3) also demonstrated ligand effects. We next introduced various electron-withdrawing groups at the 3- and 5-positions of pyridone and were encouraged to find that 5-trifluoromethylpyridone provided the best yield of 56% (L4−9). Introducing another electron-deficient trifluoromethyl group or a coordinating NHAc group both lowered the yield. (L10−11). The reaction could be further optimized to 71% by increasing the silver salt loading to three equivalences (See Supporting Information). Table 1. Ligand Evaluation for -methylene-C(sp3)−H Heteroarylation of Free Aminesa,b

a

Experiments were performed with substrate 1a (0.2 mmol), 2-chloro-4-iodopyridine (0.4 mmol),

Pd(OAc)2 (10 mol%), TDG1 (20 mol%), Ligand (50 mol%), AgTFA (0.4 mmol), H2O (2.0 mmol), HFIP (1.0 mL), 150 °C, 12 h. bYields were determined by 1H NMR analysis of the crude product using CH2Br2 as an internal standard.


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With the best conditions and pyridone ligand identified, we next evaluated a series of transient directing groups in the presence of L7. Notably, simple 2-hydroxybenzaldehyde (TDG1) has been used to activate a tertiary C−H bond in hydroxylamine, albeit limited to a single substrate.13 We decided to further evaluate other variants of hydroxybenzaldehydes (Table 2). After systematically introducing different substituents of varying sizes and electronic properties such as fluoro, chloro, methoxy, and methyl groups to the 6- and 5-positions of TDG1 (TDG2−8), we were pleased to find that 6-chloro substituted hydroxybenzaldehyde (TDG3) performed best, providing the corresponding product in 76% yield. Next, we evaluated different 4,6-, 3,5-, and 3,6-di-substituted hydroxybenzaldehydes (TDG9−16) but found no further yield improvements. In addition, we also evaluated different 2hydroxynicotinaldehyde based transient directing groups (TDG17−18) which previously demonstrated superior reactivity but were ineffective for this reaction.4a Control experiment where only L7 was used in the absence of TDG gave no desired product. This result confirms that the pyridone ligand alone does not independently enable this reaction, thus highlighting the importance of the cooperative effect between an X-type pyridone ligand and an L,X-type TDG. Lastly, more control experiments were conducted to confirm that TDG17 does not also participate as a pyridone ligand (See Supporting Information). With the optimized conditions in hand, we next investigated the scope of the heteroaryl iodides using cyclohexylamine (1a) as the substrate (Table 3). For ease of analysis and separation, the arylated products were isolated in the form of the Boc-protected amines. Heteroarylation with various 2-substituted 4-iodopyridines proceeded smoothly regardless of their electronic properties (2a1-4). Equally good yields were achieved with numerous 3-iodopyridines (2a5-9). A wide range of 2-iodopyridines containing halogens, trifluoromethyl, ester, and even electron rich methoxy groups were excellent coupling partners (2a10-16). Importantly, strongly coordinating unsubstituted simple pyridines were also compatible coupling partners (2a17-19). 3- and 4-iodopyridines could provide the desired products in greater than 60% yields with further optimized conditions using DoE techniques (2a18-19). Notably, 2-, 3-, 6-iodoquinolines and even sterically demanding 4-iodoquinolines were competent coupling partners, providing the ACS Paragon Plus Environment

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Table 2. TDG Evaluation for -methylene-C(sp3)−H Heteroarylation of Free Aminesa,b

a

Experiments were performed with substrate 1a (0.2 mmol), 2-chloro-4-iodopyridine (0.4 mmol),

Pd(OAc)2 (10 mol%), TDG (20 mol%), L7 (50 mol%), AgTFA (0.6 mmol), H2O (2.0 mmol), HFIP (1.0 mL), 150 °C, 12 h. bYields were determined by 1H NMR analysis of the crude product using CH2Br2 as an internal standard. corresponding products in 34–64% yields (2a20-23). More importantly, other quinoxaline, benzothiazole, quinazoline, thiophene and pyrimidine based heteroaryl iodides were all successfully coupled at the position (2a24-30). Lastly, the reaction temperature could be lowered to 120 °C to achieve similar yields. (2a2, 2a11). The scope of amines was examined next (Table 4). Heteroarylation of trans-3-methylcyclohexylamine proceeded smoothly, whereas the cis isomer was completely unreactive (the substrate 3-methyl-cyclohexylamine was used as a cis and trans mixture and only the trans product was observed) presumably due to steric repulsion between the directing group and the methyl group (2b). Cyclooctylamine and cyclopentylamine were also compatible substrates with the former product as a single diastereomer while the latter product gave inseparable diastereomeric mixtures (2c−d). Notably, ACS Paragon Plus Environment

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two representative bridged cyclic amines afforded the desired products in good yields (2e−f), demonstrating this protocol’s potential to perform C–H functionalization on structurally more complex substrates. Importantly, medicinally relevant tetrahydro-2H-pyran-3-amine also provided the arylated tetrahydropyran derivatives in consistently good yield (2g). When the optimized conditions were applied Table 3. Scope of Heteroaryl Iodide Coupling Partnersa,b

a

Experiments were performed with substrate 1a (0.2 mmol), heteroaryl iodide (0.4 mmol), Pd(OAc)2 (10

mol%), TDG3 (20 mol%), L7 (50 mol%), AgTFA (0.6 mmol), H2O (2.0 mmol), HFIP (1.0 mL), 150 °C, 12 h. bIsolated yields. cReaction was run in 0.05 mmol scale. dReaction was run at 120 °C for 24 h. ACS Paragon Plus Environment

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Reactions were performed with substrate 1a (0.4 mmol), heteroaryl iodide (0.2 mmol), Pd(OAc)2 (10

mol%, 0.02mmol), TDG3 (10 mol%, 0.02mmol), L7 (0.2mmol), AgTFA (0.8 mmol), H2O (2.0 mmol), HFIP (1.0 mL), 130 °C, 48h. to acyclic amines, the reactivity dropped significantly. However, we were delighted to discover that simply replacing TDG3 with 2-hydroxynicotinaldehyde (TDG17) can enable -methylene-C(sp3)−H heteroarylation of linear alkyl amines with and without -quaternary centers in 39−61% yield (2h−m). Notably, this protocol is selective towards -methylene-C(sp3)−H bonds in the presence of -methylC(sp3)−H bonds (2h, 2l−m). Table 4. Scope of Alkyl Aminesa,b

a

Experiments were performed with alkyl amines 1b−m (0.2 mmol), 2-chloro-4-iodopyridine (0.4 mmol),

Pd(OAc)2 (10 mol%), TDG3 (20 mol%), L7 (50 mol%), AgTFA (0.6 mmol), H2O (2.0 mmol), HFIP (1.0 mL), 150 °C, 12 h. bIsolated yields. cTDG17 was used instead of TDG3. ACS Paragon Plus Environment

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While our protocol demonstrated exceptional compatibility with a wide range of aryl iodides, extending the coupling partner scope to the corresponding heteroaryl bromides is inherently preferred due to their availability and pricing.14 Zeng and coworkers have previously reported a protocol for -C(sp3)−H arylation of aliphatic acid derivatives with aryl bromides as coupling partners using an 8-aminoquinoline auxiliary.15 However, aryl bromides are less reactive coupling partners in Pd(II)/(IV) C−H activation manifold because of the intrinsically stronger C−Br bond strength relative to the corresponding C−I bond. Specifically, in the context of C−H activation using transient directing groups, no example of aryl bromides as the coupling partner has been reported to the best of our knowledge. Motivated to solve this long-standing problem, we wondered whether our newly developed conditions could enable aryl bromides to be effective coupling partners. After reaction optimizations, we were excited to discover that a range of 2-substituted heteroaryl bromides were suitable coupling partners for this reaction using TDG17 (Table 5). Simple 2-bromopyridine and various 6-substituted 2-bromopyridines such as 6-trifluoromethyl, Table 5. Scope of Heteroaryl Bromide Coupling Partnersa,b


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Experiments were performed with substrate 1a (0.2 mmol), heteroaryl bromide (0.4 mmol), Pd(OAc)2

(10 mol%), TDG17 (20 mol%), L7 (50 mol%), AgTFA (0.8 mmol), H2O (2.0 mmol), HFIP (1.0 mL), 160 °C, 12 h. bIsolated yields. 6-fluoro, 6-methyl, and 6-methoxy all proceeded smoothly to generate the corresponding products in good yields (2a17, 2a13, 2a31-32, 2a14). When 2,6-dibromopyridine was employed as the coupling partner, only one bromide was activated (2a12). A range of other 5- and 4-substituted 2-bromopyridines regardless of their electronic characters were also tolerated, affording consistently moderate to good yields (2a11, 2a3337).

Notably, 2-bromoquinoline and 3-bromoisoquinoline also afforded the desired product in 53% and

62% yield, respectively (2a20, 2a38).

Figure 2. Amine based pharmaceuticals bearing aromatic groups at the  position.

While electron-deficient 2-pyridones have enabled superior reactivity with respect to -methyleneC(sp3)–H heteroarylation of free amines, -C(sp3)–H functionalization of aliphatic amines remain underexplored.4b Amines bearing aryl groups at the  position are ubiquitous in important drug molecules (Figure 2).16 However, only one example has been reported by the Shi group on -C(sp3)–H alkenylation of simple alkyl amines with internal alkynes via the development of a bidentate directing group. 17 In general, C–H functionalizations of the more distal carbon center remains challenging due to the generation of the less favored six-membered palladacycle versus the kinetically favored five-membered palladacycle, and thus has had limited success.18 Cognizant of this challenge, we sought to design a new transient directing group that would perhaps favor the generation of the typically-less-favored six-membered palladacycle. Finding such transient directing groups would not only enable selective - and -C(sp3)–H


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functionalization of free amines, but also provide valuable insights into directing group designs for selective C(sp3)–H functionalizations of other substrates. Table 6. Development of the Transient Directing Group for -C(sp3)–H Arylation of Alkyl Aminesa,b

a

Experiments were performed with 3a (0.2 mmol), 4-CO2MePhI (0.4 mmol), Pd(OAc)2 (10 mol%), TDG

(40 mol%), AgTFA (0.4 mmol), HFIP (1.0 mL), H2O (2.0 mmol), 120 °C, 24 h. bYields were determined by 1H NMR analysis of the crude reaction mixture using CH2Br2 as an internal standard. cIsolated yield in a 4:1 mixture of mono and di-arylated products. We began our investigation by conducting -C(sp3)–H arylation of isopentylamine (3a) under similar conditions to our previous work of γ-C(sp3)–H arylation of free amines4a and found that 2hydroxynicotinaldehyde (TDG17) could afford the desired -C(sp3)–H arylated products in 17% yield as a mono and di-arylated mixture (Table 6). The simple phenol TDG1 which demonstrated good reactivity for γ-C(sp3)–H functionalization was not effective for this reaction. TDG3 which demonstrated superior reactivity for the above γ-C(sp3)–H heteroarylation was also ineffective for this reaction. Considering that the formation of a 6-membered chelate with our established phenol-based TDGs favors γ-C(sp3)–H activation, we wondered whether the formation of a 5-membered chelate with a different class of transient directing group would perhaps favor the desired -C(sp3)–H activation. Guided by this hypothesis, we next screened a range of -keto acids as the transient directing group, which were previously reported to be reactive towards γ-C(sp3)–H arylation by the Ge group.4c Indeed, simple glyoxylic acid TDG19 was reactive while the phenyl variant TDG20 afforded similar yields to TDG17. After extensive screening of ACS Paragon Plus Environment

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different substitution patterns on the phenyl group of TDG20, we identified that TDG21 could afford the product in 25% yield as a mono and di-arylated mixture. Unfortunately, further screening of other transient directing groups and reaction conditions failed to improve the efficiency of this reaction. Table 7. Ligand Development for -C(sp3)–H Arylation of Alkyl Aminesa,b

a

Experiments were performed with 3a (0.2 mmol), 4-CO2MePhI (0.4 mmol), Pd(OAc)2 (10 mol%),

TDG21 (40 mol%), Ligand (50 mol%), AgTFA (0.4 mmol), HFIP (1.0 mL), H2O (2.0 mmol), 120 °C, 24 h. bYields were determined by 1H NMR analysis of the crude reaction mixture using CH2Br2 as an internal standard. Inspired by our recent finding that pyridone ligands can accelerate both C(sp2)–H and C(sp3)–H activations and especially their ability to enable γ-C(sp3)–H heteroarylation of amines, we wondered whether pyridone would also enable the desired -C(sp3)–H arylation (Table 7). Encouragingly, ligand effects were immediately observed when 3- and 5-trifluoromethyl substituted pyridones were employed to generate the corresponding product in 44% yield (L6−7). Systematic evaluations of different 3- and 5trifluoromethyl substituted pyridones further increased the yield to above 50% (L10, L12−13). After evaluating more electron-deficient pyridones, we were excited to discover that 3- and 5-nitro substituted pyridones provided higher yields than those of the corresponding trifluoromethyl substituted pyridones (L8−9). Introducing more electron-withdrawing groups to L8 and L9 resulted in inferior reactivity (L14ACS Paragon Plus Environment

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16). Sterically hindered pyridone L17 significantly lowered the yield, presumably due to its ineffective binding to the palladium catalyst. As a control experiment, electron-deficient L-type pyridine L18 shutdown the reaction, indicating the importance of the X-type ligand for reaction acceleration. Furthermore, a series of control experiments were also conducted. The reaction did not proceed in the absence of TDG and pyridone. When only L9 was used in the absence of TDG21, trace product was observed, which precludes the possibility that pyridone alone enables this reaction. Only when both TDG21 and L9 were employed did we observe an increase in reaction yields, again underscoring the cooperative effort between the TDG and pyridone for the improved reactivity. With the optimal TDG and ligand identified and the best conditions established (See Supporting Information), we next investigated the scope of the aryl iodide coupling partners. Since isopentylamine (3a) afforded the products in a mixture of mono and di-arylated products and substrate 3b only provided the mono products in good diastereoselectivity, we decided to use 3b for the aryl iodide scope studies. We were pleased to find that -C(sp3)–H arylation of 3b with a vast variety of aryl iodides proceeded smoothly with moderate to good yields and diastereoselectivity (Table 8). Simple iodobenzene and various para- substituted electron-neutral to electron-rich aryl iodides, including methyl, methoxy, and OCF3 groups were well tolerated, affording the desired products in good yields (4b1-4). Electron-deficient para-substituted aryl iodides, including halogenated aryl iodides such as fluoro, chloro, bromo (4b5-7), and other aryl iodides bearing nitro, trifluoromethyl, acetyl, ester, OTs, phenyl, naphthyl, and even PO(OEt)2 groups all worked well (4b8-15), affording the corresponding products in 45−82% yields. In addition, aryl iodides with various meta substituents also proceeded smoothly regardless of their electronic properties (4b16-24). When 1,3-diiodobenzene was employed as the coupling partner, only one iodide was activated (4b19). A reactive aldehyde on the aryl iodide remained intact during the reaction (4b23). Multi-substituted aryl iodides containing several halogen and methyl groups were also well tolerated, providing consistently good yields (4b24-26). A sterically demanding aryl iodide bearing an ortho fluoro substituent afforded the corresponding product in 62% yield (4b27). Importantly, heteroaryl iodides ACS Paragon Plus Environment

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containing pyridines with different substitutions such as fluoro, chloro, bromo and trifluoromethyl groups at different positions are all compatible coupling partners, providing 31−58% yields (4c1-8). Strongly coordinating 2-iodopyridine was also successfully coupled (4c9). Coupling with other Table 8. Scope of Aryl Iodide Coupling Partnersa,b

a

Experiments were performed with 3a (0.2 mmol), ArI (0.4 mmol), Pd(OAc)2 (10 mol%), TDG21 (40

mol%), L9 (50 mol%), AgTFA (0.6 mmol), HFIP (1mL), H2O (1.0 mmol), 120 °C, 48 h. bIsolated yields.


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TDG21 (40 mol%), L9 (1.0 eq). dTDG21 (1.0 eq), L9 (50 mol%). eTDG21 (1.0 eq), L9 (1.0 eq). fIsolated

as the free amine. heteroaryl iodides containing thiophene and chromene groups (ethyl 6-iodo-4-oxo-4h-chromene-2carboxylate was used as the coupling partner and the corresponding ester was transformed to the free acid during the reaction in a one-pot fashion) were successfully accomplished with this protocol (4c10-11). Table 9. Scope of Alkyl Amines for -C(sp3)–H Arylationa,b

a

Experiments were performed with 3a-p (0.2 mmol), ArI (0.4 mmol), Pd(OAc)2 (10 mol%), TDG21 (40

mol%), L9 (50 mol%), AgTFA (0.6 mmol), HFIP (1mL), H2O (1.0 mmol), 120 °C, 48 h. bIsolated yields. c

TDG21 (40 mol%), L9 (1.0 eq), HFIP (0.5mL). dTDG21 (1.0 eq), L9 (1.0 eq). eTDG21 (1.0 eq), L9 (50

mol%). fTDG21 (40 mol%), L9 (1.0 eq). gTDG21 (1.0 eq), L9 (1.0 eq), HFIP (0.5mL). ACS Paragon Plus Environment

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Next, we surveyed the amine scope of this -C(sp3)–H arylation and were pleased to find that our protocol was applicable to a variety of aliphatic free amines (Table 9). The arylation of methyl C–H bonds in simple free aliphatic amines proceeded at the  position with moderate to good yields (4a, 4d−e). Aliphatic amines bearing quaternary center afforded the corresponding products in a mono- and diarylated mixture (4f). Notably, in the presence of other reactive benzylic and non-benzylic -methylene C−H bonds, our reaction was selective towards the more distal -C(sp3)–H bonds (4g−i). Cyclic amine substrates were also arylated selectively at the  position in good yields as a single diastereomer (4j-k). Furthermore, substrates containing oxygenated functionalities were tolerated as well (4l-m). In addition, our protocol is also effective towards benzylic C(sp3)–H bonds of 2-chloro-6-methylbenzylamine (4n). Encouragingly, our protocol enables −methylene-C(sp3)–H functionalization, albeit in lower yield (4o). Thus far, we have demonstrated the scope of our reaction for substrates where the  position is either blocked by one or two alkyl groups. Site-selectivity becomes more challenging between −methylC(sp3)–H bonds in the presence of the adjacent neighboring −methylene-C(sp3)–H bonds. Nonetheless, when 2-aminopentane was employed, we were surprised to discover that our protocol was almost exclusively selective towards the −methyl-C(sp3)–H bond in 20% yield and only 3% of the -C(sp3)–H arylated product was observed (4p). To demonstrate the synthetic utility of these reactions, we were pleased to find that the catalyst loading could be lowered to 3 mol% for -methylene-C(sp3)–H heteroarylation and 2 mol% for −methylC(sp3)–H arylation of alkyl amines, thus rendering our protocols highly efficient (Scheme 4a, c). The reaction temperature for -methylene-C(sp3)–H heteroarylation could be further lowered to 100 °C and 80 °C, obtaining 64% and 55% yield respectively. Furthermore, we successfully scaled up the reaction to 1.0 mmol and collected the pure arylated amine using simple acid−base extraction without further purifications in 70% isolated yield (Scheme 4d). Interestingly, C−H heteroarylation of 1e and 1f with 2fluoro-3-iodopyridine followed by SNAr of the amine to the pyridyl fluoride afforded the cyclized adducts 5e and 5f in a one-pot fashion (Scheme 4e), thus providing facile access to fused naphthyridine ACS Paragon Plus Environment

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derivatives. In addition, the structurally diverse arylated products illustrated in previous tables are potentially useful synthetic building blocks for drug discovery. Scheme 4. Catalyst Loading and Synthetic Applications

3. Conclusion In summary, we have demonstrated the feasibility of ligand development for imine-based transient directing groups. The strong cooperative effect between the ligand and the TDG has led to the development of Pd(II)-catalyzed -methylene-C(sp3)–H heteroarylation and -C(sp3)−H arylation of simple aliphatic amines with aryl iodides as the coupling partners. 5-Substituted trifluoromethyl- and nitro-2-pyridone were identified as the optimal X-type ligands for enabling this reaction. Our protocol features broad aliphatic amine and (hetero)aryl iodide scope, compatibility with aryl bromides as coupling partners, and low catalyst loading. Importantly, our transient directing group design revealed that the ACS Paragon Plus Environment

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formation of a 6-membered chelate with a phenol-based TDG favors -C(sp3)–H cleavage while the formation of a 5-membered chelate with a glyoxylic acid-based TDG favors -C(sp3)–H cleavage. The development of these L,X-type transient directing groups in combination with an X-type external ligand helps identify the match and mismatch effects between various sized palladium chelates with directing groups and palladacycle intermediate. This observation provides unique insights into directing group designs for efficient and selective C(sp3)–H functionalizations of other substrates. Efforts to develop other C(sp3)–H functionalizations of alkyl amines are currently underway in light of these findings.

4. Experimental Section General procedure for the ligand enabled -methylene-C(sp3)–H heteroarylation of aliphatic amines. To an oven dried microwave tube (10 mL) equipped with a magnetic stir bar was added Pd(OAc)2 (4.5 mg, 0.02 mmol, 10 mol%), transient directing group (TDG3 or TDG17, 0.02 mmol, 20 mol%), ligand (L7, 16.3 mg, 0.1 mmol, 50 mol%), HetArI (0.4 mmol), AgTFA (0.6 mmol) and solvent (HFIP, 1.0 mL and 2 mmol H2O), followed by the free amine substrate (0.2 mmol). Then the mixture was stirred at room temperature for 10 mins before heating to 150 °C for 12 h under vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature and the dark brown suspension was passed through a pad of Celite and washed with a mixture of methanol and chloroform (1:4, 2.0 mL × 3) The combined solutions were concentrated under vacuum. THF (1.0 mL) and HCl (2 M, 0.8 mL) were then added to the residue and the mixture was stirred at room temperature for 1 h. The mixture was subsequently basified with NaOH (10 M, 0.4 mL) (confirm with pH paper) and Boc2O (0.1 mL) was added. The brown solution was then stirred at room temperature for 4 h. Ethyl acetate (2.0 mL) was added and stirred for 5 mins. The top organic layer was separated and passed through a pad of silica (3 cm). The remaining aqueous layer was further extracted with ethyl acetate (2.0 mL×3) and each organic extract was passed through the above pad of silica. The combined solution was concentrated and purified by prep TLC in (Hex/EA) to afford


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the desired arylated product. Full experimental details and characterization of new compounds can be found in the Supplementary Information. General procedure for the ligand enabled -C(sp3)–H arylation of aliphatic amines. To an oven dried microwave tube (10 mL) equipped with a magnetic stir bar was added Pd(OAc)2 (0.02 mmol, 10 mol%), transient directing groups (TDG21, 0.04 mmol, 40 mol%), ligand (L9, 0.1 mmol, 50 mol%), ArI (0.4 mmol, 2.0 eq.), AgTFA (0.6 mmol, 3.0 eq.) and solvent (HFIP, 1.0 mL and 2 mmol H2O), followed by the free amine substrate (0.2 mmol). The tube was sealed and stirred at room temperature for 10 mins before heating to 120 °C for 48h under vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature and the dark brown suspension was passed through a pad of Celite and washed with DCM (1.0 mL × 3). The combined DCM solution was concentrated under vacuum. THF (1.0 mL) and HCl (2 M, 0.8 mL) were then added to the residue and the mixture was stirred at room temperature for 1 h. The mixture was subsequently basified with NaOH (10 M, 0.4 mL) (confirm with pH paper) and Boc2O (4.0 eq.) was added. The brown solution was then vigorously stirred at room temperature for 4 hr. Ethyl acetate (2.0 mL) was added and well mixed. The top organic layer was separated and passed through a pad of silica (3 cm). The remaining aqueous layer was further extracted with ethyl acetate (2.0 mL×3) and with each organic extract was passed through the above pad of silica. The combined solution was concentrated and purified by prep TLC to afford the desired arylated product. Full experimental details and characterization of new compounds can be found in the Supplementary Information. Corresponding author. *[email protected] Author Contributions. ⊥Y-Q.C., Z.W., and Y.W. contributed equally to this work. Notes. The authors declare no competing financial interest. Acknowledgements. We gratefully acknowledge The Scripps Research Institute, the NIH (NIGMS 5R01 GM084019), and Bristol-Myers Squibb for financial support. Y-Q. C. thanks the NSF Graduate Research ACS Paragon Plus Environment

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Fellowships for financial support. Dr. Jason Chen and Brittany Sanchez from the Scripps Automated Synthesis Center are acknowledged for guidance on analytical methods and DoE screening. Supporting Information Available. Detailed experimental procedures, characterization of new compounds. This material is available free of charge via the internet at http://pubs.acs.org.

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imine directing groups. Chem. Sci. 2017, 8, 4840. g) Chen, X.-Y. Y.; Ozturk, S.; Sorensen, E. J. Pd-Catalyzed Ortho C–H Hydroxylation of Benzaldehydes Using a Transient Directing Group. Org. Lett. 2017, 19, 6280. h) Chen, X.-Y.; Sorensen, E. J. Pd-Catalyzed, ortho C–H Methylation and Fluorination of Benzaldehydes Using Orthanilic Acids as Transient Directing Groups. J. Am. Chem. Soc. 2018, 140, 2789. 3. For ketone substrates: a) Hong, K.; Park, H.; Yu, J.-Q. Methylene C(sp3)–H Arylation of Aliphatic Ketones Using a Transient Directing Group. ACS Catal. 2017, 7, 6938. b) Xu, J.; Liu, Y.; Wang, Y.; Li, Y.; Xu, X.; Jin, Z. Pd-Catalyzed Direct ortho-C–H Arylation of Aromatic Ketones Enabled by a Transient Directing Group. Org. Lett. 2017, 19, 1562. c) Yao, Q.-J.; Zhang, S.; Zhan, B.-B.; Shi, B.-F. Atroposelective Synthesis of Axially Chiral Biaryls by Palladium-Catalyzed Asymmetric C-H Olefination Enabled by a Transient Chiral Auxiliary. Angew. Chem. Int. Ed. 2017, 56, 6617. 4. For amine substrates: a) Wu, Y.; Chen, Y.-Q.; Liu, T.; Eastgate, M. D.; Yu, J.-Q. Pd-Catalyzed γC(sp3)–H Arylation of Free Amines Using a Transient Directing Group. J. Am. Chem. Soc. 2016, 138, 14554. b) -C(sp3)−H arylation of 2-tert-butylaniline was demonstrated: Xu, Y.; Young, M. C.; Wang, C.; Magness, D. M.; Dong, G. Catalytic C(sp3)−H Arylation of Free Primary Amines with an exo Directing Group Generated In Situ. Angew. Chem. Int. Ed. 2016, 55, 9084. c) Liu, Y.; Ge, H. Nat. Chem. 2017, 9, 26. d) Yada, A.; Liao, W.; Sato, Y.; Murakami, M. Buttressing Salicylaldehydes: A Multipurpose Directing Group for C(sp3)−H Bond Activation. Angew. Chem. Int. Ed. 2017, 56, 1073. 5. For leading references, see: a) Jun, C. H.; Lee, H.; Hong, J. B. Chelation-Assisted Intermolecular Hydroacylation: Direct Synthesis of Ketone from Aldehyde and 1-Alkene. J. Org. Chem. 1997, 62, 1200. b) Bedford, R. B.; Coles, S. J.; Hursthouse, M. B.; Limmert, M. E. The Catalytic Intermolecular Orthoarylation of Phenols. Angew. Chem. Int. Ed. 2003, 42, 112. c) Lightburn, T. E.; Dombrowski, M. T.; Tan, K. L. Catalytic Scaffolding Ligands: An Efficient Strategy for Directing Reactions. J. Am. Chem. Soc. 2008, 130, 9210. d) Mo, F.; Dong, G. Regioselective ACS Paragon Plus Environment

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ketone α-alkylation with simple olefins via dual activation. Science. 2014, 345, 68. 6. Giri, R.; Chen, X.; Yu, J. -Q. Palladium-Catalyzed Asymmetric Iodination of Unactivated C−H Bonds under Mild Conditions. Angew. Chem. Int. Ed. 2005, 44, 2112. 7. Engle, K. M.; Yu, J. -Q. Developing Ligands for Palladium(II)-Catalyzed C–H Functionalization: Intimate Dialogue between Ligand and Substrate. J. Org. Chem. 2013, 78, 8927. 8. Gong, W.; Zhang, G.; Liu, T.; Giri, R.; Yu, J.-Q. Site-Selective C(sp3)–H Functionalization of Di, Tri-, and Tetrapeptides at the N-Terminus. J. Am. Chem. Soc. 2014, 136, 16940. 9. a) Wang, P.; Farmer, M. E.; Huo, X.; Jain, P.; Shen, P.-X.; Ishoey, M.; Bradner, J. E.; Wisniewski, S. R.; Eastgate, M. E.; Yu, J.-Q. Ligand-Promoted Meta-C–H Arylation of Anilines, Phenols, and Heterocycles. J. Am. Chem. Soc. 2016, 138, 9269. b) Li, G. C.; Wang, P.; Farmer, M. E.; Yu, J. Q. Ligand-Enabled Auxiliary-Free meta-C−H Arylation of Phenylacetic Acids. Angew. Chem. Int. Ed. 2017, 56, 6874. c) Farmer, M. E.; Wang, P.; Shi, H.; Yu, J.-Q. Palladium-Catalyzed meta-C– H Functionalization of Masked Aromatic Aldehydes. ACS Catal. 2018, 8, 7362. 10. Wang, P.; Verma, P.; Xia, G.; Shi, J.; Qiao, J. X.; Tao, S.; Cheng, P. T. W.; Poss, M. A.; Farmer, M. E.; Yeung, K. S.; Yu, J. -Q. Ligand-accelerated non-directed C–H functionalization of arenes. Nature 2017, 551, 489. 11. (The pyridone effect was first observed with TDG on -methylene-C(sp3)–H heteroarylation of free amines. It was later discovered that pyridone was also effective for ketone substrates as well) Zhu, R.-Y.; Li, Z.-Q.; Park, H. S.; Senanayake, C. H.; Yu, J.-Q. Ligand-Enabled γ-C(sp3)–H Activation of Ketones. J. Am. Chem. Soc. 2018, 140, 3564. 12. a) Burger, M. T.; Nishiguchi, G.; Han, W.; Lan, J.; Simmons, R.; Atallah, G.; Ding, Y.; Tamez, V.; Zhang, Y.; Mathur, M.; Muller, K.; Bellamacina, C.; Lindvall, M. K.; Zang, R.; Huh, K.; Feucht, P.; Zavorotinskaya, T.; Dai, Y.; Basham, S.; Chan, J.; Ginn, E.; Aycinena, A.; Holash, J.; Castillo, J.; Langowski, J. L.; Wang, Y.; Chen, M. Y.; Lambert, A.; Fritsch, C.; Kauffmann, A.; Pfister, E.; Vanasse,

K.

G.;

Garcia,

P.

D.

Identification

of

N-(4-((1R,3S,5S)-3-Amino-5-

methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide (PIM447), a Potent ACS Paragon Plus Environment

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and Selective Proviral Insertion Site of Moloney Murine Leukemia (PIM) 1, 2, and 3 Kinase Inhibitor in Clinical Trials for Hematological Malignancies. J. Med. Chem. 2015, 58, 8373. b) Pickarski, M.; Gleason, A.; Bednar, B.; Duong, L. T. Orally active αvβ3 integrin inhibitor MK0429 reduces melanoma metastasis. Oncol. Rep. 2015, 33, 2737. c) Zhou, X.; Zhang, J.; Haimbach, R.; Zhu, W.; Mayer-Ezell, R.; Garcia-Calvo, M.; Smith, E.; Price, O.; Kan, Y.; Zycband, E.; Zhu, Y.; Hoek, M; Cox, J. M.; Ma, L.; Kelley, D. E.; Pinto, S. An integrin antagonist (MK-0429) decreases proteinuria and renal fibrosis in the ZSF1 rat diabetic nephropathy model. Pharmacol. Res. Perspect. 2017, 5, e00354. d) Zwart, R.; Strotton, M.; Ching, J.; Astles, P. C.; Sher, E. Unique pharmacology of heteromeric α7β2 nicotinic acetylcholine receptors expressed in Xenopus laevis oocytes. Eur. J. Pharmacol. 2014, 726, 77. e) Hauser, T. A.; Kucinski, A.; Jordan, K. G.; Gatto, G. J.; Wersinger, S. R.; Hesse, R. A.; Stachowiak, E. K.; Stachowiak, M. K.; Papke, R. L.; Lippiello, P. M.; Bencherif, M. TC-5619: an alpha7 neuronal nicotinic receptor-selective agonist that demonstrates efficacy in animal models of the positive and negative symptoms and cognitive dysfunction of schizophrenia. Biochem. Pharmacol. 2009, 78, 803. 13. Ren, Z.; Dong, G. B. Direct Observation of C–H Cyclopalladation at Tertiary Positions Enabled by an Exo-Directing Group. Organometallics 2016, 35, 1057. 14. 2-Iodopyridine: 108USD/5g vs 2-bromopyridine: 30USD/25g from Sigma-Aldrich. 15. Wei, Y.; Tang, H.; Cong, X.; Rao, B.; Wu, C.; Zeng, X. Pd(II)-Catalyzed Intermolecular Arylation of Unactivated C(sp3)–H Bonds with Aryl Bromides Enabled by 8-Aminoquinoline Auxiliary. Org. Lett. 2014, 16, 2248. 16. a) Bellocq, C.; Wilders, R.; Schott, J. J.; Louerat-Oriou, B.; Boisseau, P.; Le Marec, H.; Escande, D.; Baro, I. A common antitussive drug, clobutinol, precipitates the long QT syndrome 2. Mol Pharmacol. 2004, 66, 1093. b) Kaplan, P. W.; Allen, R. P.; Buchholz, D. W.; Walters, J. K. A double-blind, placebo-controlled study of the treatment of periodic limb movements in sleep using carbidopa/levodopa and propoxyphene. Sleep. 1993, 16, 717. c) Gradman, A. H.; Schmieder, R. E.; Lins, R. L.; Nussberger, J.; Chiang, Y.; Bedigian, M. P. Aliskiren, a novel orally effective renin ACS Paragon Plus Environment

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