1-Aminopyridinium Ylides as Monodentate Directing Groups

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1‑Aminopyridinium Ylides as Monodentate Directing Groups for sp3 C−H Bond Functionalization Ky Khac Anh Le, Hanh Nguyen, and Olafs Daugulis* Department of Chemistry, University of Houston, Houston, Texas 77204-5003, United States

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S Supporting Information *

ABSTRACT: 1-Aminopyridinium ylides are efficient directing groups for palladium-catalyzed β-arylation and alkylation of sp3 C−H bonds in carboxylic acid derivatives. The efficiency of these directing groups depends on the substitution at the pyridine moiety. The unsubstituted pyridine-derived ylides allow functionalization of primary C−H bonds, while methylene groups are unreactive in the absence of external ligands. 4-Pyrrolidinopyridine-containing ylides are capable of C−H functionalization in acyclic methylene groups in the absence of external ligands, thus rivaling the efficiency of the aminoquinoline directing group. Preliminary mechanistic studies have been performed. A cyclopalladated intermediate has been isolated and characterized by X-ray crystallography, and its reactivity was studied.

1. INTRODUCTION Carbon−hydrogen bond activation and functionalization methodology has evolved from organometallic curiosity to applications in the synthesis of complex natural products.1 However, selective functionalization of unactivated (not benzylic or α to a heteroatom) sp3 C−H bonds still presents a challenge. Positional selectivity is usually achieved by employing a directing group that coordinates metal and positions it for cleavage of the desired C−H bond. Both monoand bidentate directing groups have been extensively used for this purpose. Monodentate directing groups can be broadly categorized as X or L type (Figure 1). Examples of X-type directing groups, sometimes categorized as weak, include carboxylates 1, polyfluoroanilides 2, and hydroxamic acids 3.2 L-Type monodentate auxiliaries (or strong directing groups) include pyridines, oxazolines, oxime derivatives, and tertiary amines.3 With few exceptions,3a,4 monodentate groups allow functionalization of only primary unactivated sp3 C−H bonds. Secondary C−H bonds in acyclic structures typically react only in the presence of added ligands, and transformations often require high loadings of palladium catalyst as well as forcing conditions. Reactivity in the presence of added external ligands has important practical consequences with respect to asymmetric C−H functionalization, since background reaction leading to erosion of enantioselectivity is suppressed.5 Bidentate, usually monoanionic, auxiliaries have been categorized as strong directing groups.1e,6 They allow for an efficient functionalization of both primary and secondary alkane C−H bonds. In some cases, even tertiary C−H bonds are reactive.7 The aminoquinoline, picolinamide, and 2thiomethyaniline auxiliaries were introduced in 2005 and 2010.8 Many similar directing groups have been found subsequently.9 Recently, C−H functionalizations have been rendered catalytic with respect to bidentate auxiliaries, and sometimes the formation of the directing groups can be © XXXX American Chemical Society

Figure 1. Directing groups for sp3 C−H functionalization.

performed in situ.10 The electron-rich, bidentate, monoanionic auxiliaries facilitate both the C−H activation and functionalReceived: June 22, 2019

A

DOI: 10.1021/jacs.9b06643 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

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Journal of the American Chemical Society

sodium tetrafluoroborate increased the yield (entries 3 and 4). Further improvement was observed when sodium triflate additive was used (entry 5). An increased amount of NaOTf did not result in higher reaction yield (entry 6). Highest yield was obtained at 90 °C (entry 8), while other temperatures gave lower yields (entries 7 and 9). Aryl bromides and aryl triflates are unreactive under these conditions. 2.2. Arylation of Primary C−H Bonds. The arylation of 1-(propionylamino)pyridinium ylide was conducted with a broad range of electron-rich (entries 1−5 and 15), electronpoor (entries 6−14), and heterocyclic (entries 15−18) aryl iodides. The products were obtained in good yields (Table 2). This reaction tolerates substituents at either para- or metapositions of the aryl iodides. No arylation products were observed if ortho-substituted aryl iodides were employed, consistent with results obtained with aminoquinoline amides. The reaction can accommodate a range of functional groups, such as methoxy (entry 2), alkyl (entries 1 and 3), bromo (entry 7), ether (entries 2, 5, and 15), ester (entry 6), trifluoromethyl (entries 9, 10, and 13), fluoro (entries 11 and 14), chloro (entry 14), and enolizable ketone (entry 17). Interestingly, even an aldehyde moiety is tolerated (entries 12 and 16). Some heterocycles, such as dihydrobenzofuran (entry 15), furan (entry 16), thiophene (entry 17), and protected indole (entry 18), are also compatible with reaction conditions. Introduction of strongly electron-withdrawing substituents decreases reaction yields (entries 8 and 9). Next, we investigated the possibility of room-temperature reaction and low catalyst loadings (Scheme 1). Arylation of ylide 16 was successful by using 1 mol % Pd(OAc)2 catalyst if an acetyl-protected aminoethyl phenyl thioether was added.2e Room-temperature arylation was also successful in the presence of this ligand. Reaction scope with respect to amide coupling component was investigated subsequently (Table 3). The arylation proceeded exclusively at the methyl group for the 2methylbutyric acid derivative (entry 1). The phenyl-substituted compound afforded product in 91% yield (entry 2). Arylation of isobutyric acid amide gave a mixture of diarylation and monoarylation products in 58% and 37% yields, respectively (entry 3). The reaction is compatible with trifluoromethyl and methoxy substitution on the amide (entries 4 and 6). More hindered substrates, such as cyclohexyl-substituted amide, are reactive as well, giving product in 83% yield (entry 5). Interestingly, the phthaloyl-protected alanine derivative affords arylation product in a reasonable yield, and no loss of enantiomeric excess was observed (entry 7). No arylation of secondary C(sp3)−H bonds was observed when the reaction was carried out under the standard conditions. 2.3. Arylation of Secondary C−H Bonds. Yu has shown that addition of mono-N-protected amino acid ligands allows palladium-catalyzed arylation of secondary, unactivated sp3 C− H bonds even when weak directing groups are used.5a Inspired by this precedent, we investigated the effect of mono-Nprotected amino acid ligands on secondary C(sp3)−H arylation. After considerable optimization, it was discovered that addition of N-acetyl-L-phenyalanine ligand afforded optimal reactivity. The results of secondary C(sp3)−H arylation are presented in Table 4. A higher loading of palladium acetate and use of silver trifluoroacetate additive is required to obtain good yields of products. The butanoic acid derivative afforded product in 67% isolated yield (entry 1). Cyclic substrates can be arylated as well. Cyclohexanecarbox-

ization steps, especially if high-valent transition metal intermediates are involved. There are cases, however, where weaker or monodentate coordination may be preferable. For example, development of catalytic, asymmetric transformations requires binding of external ligands to metal. Strong, bidentate auxiliaries may outcompete the chiral ligand, resulting in significant racemic background reaction. After the C−H activation step, the substrate coordinates to metal as a tridentate ligand, saturating its coordination sites (14). The decreased number of open sites at the metal and the stability of the intermediate palladacycles may interfere with the subsequent C−H functionalization step. Consequently, monodentate auxiliaries possessing efficiency of bidentate directing groups would have advantages in C−H bond functionalization, perhaps allowing for mild C−H functionalization and strong influence of added ligands. In 1974, McWhinnie and co-workers showed that benzoylated 1-aminopyridine ylides can be cyclometalated by palladium, rhodium, and platinum complexes.11 In the next 40 years, these ylides were used as substitutes for pyridine oxides, mostly for functionalization of the pyridine ring.12 We speculated that sp3 C−H functionalization could be achieved if aliphatic carboxylic acid amides of 1-aminopyridine were employed. We report here that 1-aminopyridine ylides are the first monodentate directing groups that allow for general functionalization of primary and secondary unactivated sp3 C− H bonds in the absence of external ligands. Properties of these auxiliaries can be easily tuned by substitution at the 4-position of the pyridine moiety. These new directing groups rival aminoquinoline in efficiency and may supplement it in the synthesis of complex natural products and multiple bond functionalization.13

2. RESULTS AND DISCUSSION 2.1. Reaction Optimization. The initial reaction optimization was based on previous results using monodentate directing groups for C−H functionalization (Table 1).14 However, conditions employing acetic acid solvent resulted in low yield of 17 (entry 1). Performing the reaction in hexafluoroisopropanol resulted in an improved 63% yield (entry 2). Addition of disodium hydrogen phosphate or Table 1. Optimization of Reaction Conditionsa

entry

T, °C

solvent

1 2 3 4 5 6b 7 8 9

100 110 110 110 110 110 100 90 80

AcOH HFIP HFIP HFIP HFIP HFIP HFIP HFIP HFIP

additive

yield, %

Na2HPO4 NaBF4 NaOTf NaOTf NaOTf NaOTf NaOTf

40 63 74 80 87 87 87 91 74

a

Amide 0.15 mmol, 4-iodotoluene 2.5 equiv, AgOAc 1.5 equiv, additive 1.0 equiv. Yields of 17 were determined by 1H NMR analysis using 1,1,2-trichloroethane internal standard. bNaOTf 1.2 equiv. AcOH = acetic acid, HFIP = hexafluoroisopropanol, OTf = triflate. B

DOI: 10.1021/jacs.9b06643 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

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Journal of the American Chemical Society Table 2. Arylation Scope with Respect to Aryl Iodidesa

a

Amide 0.5 mmol, hexafluoroisopropanol 3.5 mL. Yields are isolated yields. Py = 1-pyridyl. Please see Supporting Information for details.

single product diastereomer was obtained, consistent with results obtained with an aminoquinoline directing group.15 As shown above, unsubstituted iminopyridinium ylide auxiliary is about as efficient in directing C−H bond functionalization as Yu’s perfluoroarylamides,5a requiring added ligands to effect arylation of methylene groups. Assuming a catalytic cycle similar to that proposed for aminoquinoline amides,8b,15 it is likely that a more electron-

ylic acid amide gave two monoarylation diastereoisomers in 92% yield with a crude diastereomer ratio of 4:1 (entry 2). The cyclopentanecarboxylic acid derivative is monoarylated in 85% yield (entry 3), while cyclobutanecarboxylic acid amide reacts to produce diarylated product in 82% yield (entry 4). Interestingly, β-methylene C(sp3)−H bond arylation of a protected amino acid occurs in reasonable yield (entry 5), and C

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Journal of the American Chemical Society Table 3. Arylation Scope with Respect to Amidesa

Scheme 1. Reactions with Low Catalyst Loading and at Room Temperature

rich substrate/ligand will facilitate oxidation, forming Pd(III) (or Pd(IV)) species, irrespective of whether the reaction proceeds via Pd(IV) or dimeric Pd(III) complexes.16,17 Furthermore, while the electronic effect of coordinated ligand/substrate on the C−H activation step is unclear, in some cases strong σ-donor ligands allow for efficient cyclometalation.18 Consequently, a strongly donating auxiliary may increase the efficiency of C−H arylation. Functionalization of 1-aminopyridine ylide butyramides possessing an electron-donor substituent was investigated (Scheme 2). As predicted, strongly donating pyrrolidinopyridine-substituted ylide 50 gave the highest product yield, while methoxy- and dimethylamino-substituted 48 and 49 afforded lower conversions. Pyridine derivative 47 did not react under these conditions. The reactivities track the corresponding pyridine catalytic efficiencies in alcohol acylation reactions.19 After a short optimization, the scope of acylated 4pyrrolidinopyridine ylide arylation was investigated (Table 5). The butyryl derivative was arylated in a 68% yield (entry 1). Alkyl groups possessing a phenyl (entry 2), cyclohexyl (entry 3), or branched chains (entry 4) were arylated in good yields. For some substrates, increasing the palladium acetate loading to 10 mol % gives higher yields (entries 2 and 4). Cyclic structures, such as ylides derived from cyclohexane- and cyclobutanecarboxylic acids, are arylated in good yields (entries 5 and 6). In those cases, cis-products are obtained either predominately (entries 5 and 7) or exclusively (entry 6). Amide-containing substrates also react, albeit at higher palladium loading (entry 7). Fluoro- and trifluoromethyl functionalities are compatible with reaction conditions, and products were isolated in acceptable yields (entries 8 and 9). 2.4. Alkylation of C−H Bonds. Alkylation of C−H bonds was also successful (Scheme 3). Reactions require use of dibenzyl phosphate silver salt additive.20a Ethyl iodoacetate reacts with a propionic acid derivative to give an 82% yield of 62. Similarly, reactions with trifluoromethyl- and alkylsubstituted ylides afford products in acceptable to good yields (63 to 65). Benzyl ester gives alkylation product 66 in a reduced 14% yield. Methyl iodide is a competent alkylation agent, and 67 was obtained in 51% yield. 2.5. Directing Group Removal. The pyridinium moiety can be easily removed through zinc-mediated N−N bond cleavage. In the case of a 4-pyrrolidinopyridinium auxiliary, magnesium was used instead of zinc (Scheme 4). Additionally, the directing group can be cleaved by Lewis acid promoted

a

Amide 0.5 mmol, hexafluoroisopropanol 3.5 mL. Yields are isolated yields. Please see Supporting Information for details. bAr = 3,5Me2C6H3. Monoarylation product also isolated (37% yield). c Arylation of starting material (92% ee) gave 41 (92% ee).

methanolysis with no erosion of enantiomeric excess (41 to 70).20b 2.6. Mechanistic Considerations. A presumed C−H functionalization intermediate 72 was formed by reaction of amide 71 with palladium acetate in acetonitrile, isolated, and fully characterized (Scheme 5). It exists as a green-yellow solid that is soluble in hydroxylic solvents, is insoluble in acetonitrile, and decomposes in dichloromethane, forming a chloro-bridged complex. The structure of 72 was verified by single-crystal X-ray diffraction analysis. The ORTEP diagram D

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Journal of the American Chemical Society Table 4. N-Acetyl-L-phenyalanine-Enabled Secondary C(sp3)−H Arylationa

Table 5. Secondary C(sp3)−H Arylation without Added External Ligandsa

a

Amide 0.5 mmol, hexafluoroisopropanol 3.5 mL. Yields are isolated yields. Please see Supporting Information for details. Ar = 4-FC6H4. b Enantiomeric excess: 25%. cCis/trans 4.6/1. dEnantiomeric excess: 33% for the cis isomer. eEnantiomeric excess: 23%.

Scheme 2. Arylation of Substituted Ylides

of 72 is shown in Figure 2. Complex 72 crystallizes in monoclinic space group C2/c and exists as a dimer in the solid state with a Pd−Pd distance of 2.8821(3) Å, which is shorter than the van der Waals radii sum of 3.26 Å, signifying a Pd−Pd bonding interaction.21 The palladium−C(alkyl) bond length is 2.007(2) Å, while the palladium−N(amide) distance is 1.984(2) Å. The N(1)−Pd(1)−C(1) angle is 80.17(21)°, showing distortion from an idealized square-planar geometry at the palladium center. It appears that no transition metal complexes of acylated 1-aminopyridine ylides have been crystallographically characterized.22 Our attempts to oxidize 72 to a Pd(III) or Pd(IV) complex with a range of oxidants such as halogens and peroxides were not successful, and ligand loss from palladium was observed. Reactions with 4-fluorophenyl iodide were more informative. Complex 72 did not react with aryl iodide in methanol at 25 °C on a time scale of days. However, reactions in hexafluoroisopropanol were successful (Table 6).

a

Amide 0.5 mmol, hexafluoroisopropanol 3.5 mL. Yields are isolated yields. Please see Supporting Information for details. Ar = 4-FC6H4. b Ten mol % Pd(OAc)2. cCis/trans 5/1. dDiastereomer ratio: 1.6/1; 36 h, 110 °C. e36 h, 110 °C. fDiastereomer ratio: 1.5/1; 36 h, 110 °C. PPY = 4-pyrrolidino-1-pyridyl.

Reaction in hexafluoroisopropanol solvent for one hour gave a mixture of mono- and diarylation products (entry 1). After 24 h, some triarylation product was observed (entry 7). Addition of silver trifluoroacetate increased the rate of arylation (entry 2), while sodium trifluoroacetate and triflate had little effect on the reaction (entries 3 and 4). No arylation was observed in methanol solvent even in the presence of silver trifluoroacetate (entry 5). Addition of acetonitrile shut down E

DOI: 10.1021/jacs.9b06643 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

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Journal of the American Chemical Society Table 6. Reactivity of 72 with Aryl Iodidea

Scheme 3. Alkylation of C−H Bonds

Entry

solvent

additive

73 (%)

74 (%)

75 (%)

1 2 3 4 5 6 7b 8b

HFIP HFIP HFIP HFIP MeOH HFIP HFIP HFIP

none AgOCOCF3 NaOCOCF3 NaOTf AgOCOCF3 CH3CN AgOCOCF3 none AgOCOCF3

44 16 36 39 0 0 44 11

21 38 25 24 0 0 28 41

0 11 2 2 0 0 5 26

Scheme 4. Directing Group Removal a

Time: 1 h, trifluoroacetate or triflate additive: 1.2 equiv, acetonitrile additive: 7.5 equiv. Yield determined by NMR with 1,1,2,2tetrachloroethane internal standard. bTime: 24 h.

Scheme 6. H/D Exchange Experiments

Scheme 5. Cyclometalated Intermediate

recovered starting material. This is distinct from the corresponding reactivity of aminoquinoline amides, where H/D exchange is observed.8b,15 Furthermore, C−H functionalizations directed by bidentate, monoanionic auxiliaries proceed in coordinating solvents such as acetonitrile.8b While extensive mechanistic speculations are premature at this point, pyridine ylide-directed C−H functionalizations may proceed via dimeric species, as evidenced by the shutting down of the reaction when coordinating solvents are added.23

3. SUMMARY We report here that 1-aminopyridinium ylides are efficient directing groups for palladium-catalyzed β-arylation and alkylation of sp3 C−H bonds in carboxylic acid derivatives. The unsubstituted pyridine-derived ylides can direct functionalization of primary C−H bonds. Addition of external ligands allows for functionalization of methylene groups. Directing group efficiency is improved if electron-donor substituents are introduced at the 4-position of the pyridine ring. Thus, 4pyrrolidinopyridine-containing ylides are capable of C−H functionalization of acyclic methylene groups in the absence of external ligands. Preliminary mechanistic studies have been performed. A cyclopalladated intermediate was isolated, characterized by X-ray crystallography, and its reactions were studied. Aminopyridine ylide directing groups may find extensive use in new methodology development as well as in synthesis of natural products, supplementing current applications of bidentate, monoanionic auxiliaries.

Figure 2. ORTEP view of 72. Selected interatomic distances (Å) and angles (deg): Pd1−N1 1.984(2); Pd1−C1 2.007(2); Pd1−Pd1 2.8821(3); N1−N2 1.415(3); N1−Pd1−C1 80.17(10); C1−Pd1− O2 94.77(10).

the reaction completely (entry 6). Acetonitrile presumably breaks up the dimeric structure of 72. After 24 h, reaction with added silver salt gave a mixture of arylation products (entry 8). Furthermore, it appears that cyclometalation is irreversible (Scheme 6). No H/D exchange in the methyl group was observed if amide 76 was heated under the catalytic conditions with added acetic acid-d4. If amide 76 was arylated in HFIP-d2, deuterium was not incorporated in the methylene group of the F

DOI: 10.1021/jacs.9b06643 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

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Journal of the American Chemical Society

(2) (a) Giri, R.; Maugel, N.; Li, J.-J.; Wang, D.-H.; Breazzano, S. P.; Saunders, L. B.; Yu, J.-Q. Palladium-Catalyzed Methylation and Arylation of sp2 and sp3 C-H Bonds in Simple Carboxylic Acids. J. Am. Chem. Soc. 2007, 129, 3510−3511. (b) Wasa, M.; Engle, K. M.; Yu, J.Q. Pd(0)/PR3-Catalyzed Intermolecular Arylation of sp3 C-H Bonds. J. Am. Chem. Soc. 2009, 131, 9886−9887. (c) Wang, D.-H.; Wasa, M.; Giri, R.; Yu, J.-Q. Pd(II)-Catalyzed Cross-Coupling of sp3 C-H Bonds with sp2 and sp3 Boronic Acids Using Air as the Oxidant. J. Am. Chem. Soc. 2008, 130, 7190−7191. (d) Kapoor, M.; Liu, D.; Young, M. C. Carbon Dioxide-Mediated C(sp3)−H Arylation of Amine Substrates. J. Am. Chem. Soc. 2018, 140, 6818−6822. (e) Zhuang, Z.; Yu, C.-B.; Chen, G.; Wu, Q.-F.; Hsiao, Y.; Joe, C. L.; Qiao, J. X.; Poss, M. A.; Yu, J.-Q. Ligand-Enabled β-C(sp3)−H Olefination of Free Carboxylic Acids. J. Am. Chem. Soc. 2018, 140, 10363−10367. (3) (a) Desai, L. V.; Hull, K. L.; Sanford, M. S. Palladium-Catalyzed Oxygenation of Unactivated sp3 C−H Bonds. J. Am. Chem. Soc. 2004, 126, 9542−9543. (b) Giri, R.; Chen, X.; Yu, J.-Q. PalladiumCatalyzed Asymmetric Iodination of Unactivated C−H Bonds under Mild Conditions. Angew. Chem., Int. Ed. 2005, 44, 2112−2115. (c) Chen, X.; Goodhue, C. E.; Yu, J.-Q. Palladium-Catalyzed Alkylation of sp2 and sp3 C−H Bonds with Methylboroxine and Alkylboronic Acids: Two Distinct C−H Activation Pathways. J. Am. Chem. Soc. 2006, 128, 12634−12635. (d) Stowers, K. J.; Fortner, K. C.; Sanford, M. S. Aerobic Pd-Catalyzed sp3 C−H Olefination: A Route to Both N-Heterocyclic Scaffolds and Alkenes. J. Am. Chem. Soc. 2011, 133, 6541−6544. (e) He, C.; Gaunt, M. J. Ligand-Enabled Catalytic C−H Arylation of Aliphatic Amines by a Four-MemberedRing Cyclopalladation Pathway. Angew. Chem., Int. Ed. 2015, 54, 15840−15844. (f) Calleja, J.; Pla, D.; Gorman, T. W.; Domingo, V.; Haffemayer, B.; Gaunt, M. J. A Steric Tethering Approach Enables Palladium-Catalysed C−H Activation of Primary Amino Alcohols. Nat. Chem. 2015, 7, 1009−1016. (g) Desai, L. V.; Stowers, K. J.; Sanford, M. S. Insights into Directing Group Ability in PalladiumCatalyzed C−H Bond Functionalization. J. Am. Chem. Soc. 2008, 130, 13285−13293. (4) (a) Cabrera-Pardo, J. R.; Trowbridge, A.; Nappi, M.; Ozaki, K.; Gaunt, M. J. Selective Palladium(II)-Catalyzed Carbonylation of Methylene β-C−H Bonds in Aliphatic Amines. Angew. Chem., Int. Ed. 2017, 56, 11958−11962. (b) Gulia, N.; Daugulis, O. PalladiumCatalyzed Pyrazole-Directed sp3 C-H Bond Arylation for the Synthesis of beta-Phenethylamines. Angew. Chem., Int. Ed. 2017, 56, 3630−3634. (5) (a) Saint-Denis, T. G.; Zhu, R.-Y.; Chen, G.; Wu, Q.-F.; Yu, J.-Q. Enantioselective C(sp3)-H bond activation by chiral transition metal catalysts. Science 2018, 359, eaao4798. (b) Newton, C. G.; Wang, S.G.; Oliveira, C. C.; Cramer, N. Catalytic Enantioselective Transformations Involving C-H Bond Cleavage by Transition-Metal Complexes. Chem. Rev. 2017, 117, 8908−8976. (c) Chu, L.; Xiao, K.-J.; Yu, J.-Q. Room-temperature enantioselective C-H iodination via kinetic resolution. Science 2014, 346, 451−455. (6) (a) Daugulis, O.; Roane, J.; Tran, L. D. Bidentate, Monoanionic Auxiliary-Directed Functionalization of Carbon-Hydrogen Bonds. Acc. Chem. Res. 2015, 48, 1053−1064. (b) Rouquet, G.; Chatani, N. Catalytic functionalization of C(sp2)-H and C(sp3)-H bonds by using bidentate directing groups. Angew. Chem., Int. Ed. 2013, 52, 11726− 11743. (7) (a) Hoshiya, N.; Kobayashi, T.; Arisawa, M.; Shuto, S. Palladium-Catalyzed Arylation of Cyclopropanes via Directing Group-Mediated C(sp3)-H Bond Activation To Construct Quaternary Carbon Centers: Synthesis of cis- and trans-1,1,2-Trisubstituted Chiral Cyclopropanes. Org. Lett. 2013, 15, 6202−6205. (b) Parella, R.; Arulananda Babu, S. Palladium-catalyzed double activation and arylation of 2° and 3° C(sp3)-H bonds of the norbornane system: formation of a C-C bond at the bridgehead carbon and bridgehead quaternary stereocenter. Synlett 2014, 25, 1395−1402. (8) (a) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. Highly Regioselective Arylation of sp3 C-H Bonds Catalyzed by Palladium Acetate. J. Am. Chem. Soc. 2005, 127, 13154−13155. (b) Shabashov, D.; Daugulis, O. Auxiliary-Assisted Palladium-Catalyzed Arylation and

4. EXPERIMENTAL SECTION 4.1. General Procedure for the Arylation Directed by a 1Amino-4-pyrrolidinopyridine Auxiliary. A 8-dram vial equipped with a magnetic stir-bar was charged with amide (0.5 mmol), 1-fluoro4-iodobenzene (278 mg, 1.25 mmol), Pd(OAc)2 (5.7 mg, 5 mol %), AgOCOCF3 (133 mg, 1.2 equiv), NaOTf (86 mg, 1.0 equiv), and hexafluoroisopropanol (3.5 mL). The mixture was stirred at room temperature for 5 min, covered with aluminum foil, and then heated at 90 °C for 24 h. After completion, the reaction was cooled to room temperature and diluted with a CH2Cl2/MeOH mixture (5 mL, 9:1). The suspension was filtered through a pad of Celite, and the solid phase was washed with dichloromethane (2 × 20 mL). The filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel using an appropriate eluent. After purification, the product was dried under reduced pressure.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.9b06643. Crystallographic data for 72 (CIF) Detailed experimental procedures and characterization data for new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

*[email protected] ORCID

Olafs Daugulis: 0000-0003-2642-2992 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the Welch Foundation (Chair No. E-0044) and NIGMS (Grant No. R01GM077635) for supporting this research. We are grateful to Dr. Xiqu Wang for collecting and solving the X-ray structure of 72 and to Dr. Rana M. Kashif Khan for initial experiments with a 1-aminopyridine auxiliary.

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REFERENCES

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DOI: 10.1021/jacs.9b06643 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

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DOI: 10.1021/jacs.9b06643 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX