Olafs Daugulis

Palladium- and copper-catalyzed arylation of carbon-hydrogen bonds.

The transition-metal-catalyzed functionalization of C-H bonds is a powerful method for generating carbon-carbon bonds. Although significant advances to this field have been reported during the past decade, many challenges remain. First, most of the methods are substrate-specific and thus cannot be generalized. Second, conversions of unactivated (i.e., not benzylic or alpha to heteroatom) sp(3) C-H bonds to C-C bonds are rare, with most examples limited to t-butyl groups, a conversion that is inherently simple because there are no beta-hydrogens that can be eliminated. Finally, the palladium, rhodium, and ruthenium catalysts routinely used for the conversion of C-H bonds to C-C bonds are expensive. Catalytically active metals that are cheaper and less exotic (e.g., copper, iron, and manganese) are rarely used. This Account describes our attempts to provide solutions to these three problems. We have developed a general method for directing-group-containing arene arylation by aryl iodides. Using palladium acetate as the catalyst, we arylated anilides, benzamides, benzoic acids, benzylamines, and 2-substituted pyridine derivatives under nearly identical conditions. We have also developed a method for the palladium-catalyzed auxiliary-assisted arylation of unactivated sp(3) C-H bonds. This procedure allows for the beta-arylation of carboxylic acid derivatives and the gamma-arylation of amine derivatives. Furthermore, copper catalysis can be used to mediate the arylation of acidic arene C-H bonds (i.e., those with pK(a) values <35 in DMSO). Using a copper iodide catalyst in combination with a base and a phenanthroline ligand, we successfully arylated electron-rich and electron-deficient heterocycles and electron-poor arenes possessing at least two electron-withdrawing groups. The reaction exhibits unusual regioselectivity: arylation occurs at the most hindered position. This copper-catalyzed method supplements the well-known C-H activation/borylation methodology, in which functionalization usually occurs at the least hindered position. We also describe preliminary investigations to determine the mechanisms of these transformations. We anticipate that other transition metals, including iron, nickel, cobalt, and silver, will also be able to facilitate deprotonation/arylation reaction sequences.

Auxiliary-assisted palladium-catalyzed arylation and alkylation of sp2 and sp3 carbon-hydrogen bonds.

We have developed a method for auxiliary-directed, palladium-catalyzed beta-arylation and alkylation of sp(3) and sp(2) C-H bonds in carboxylic acid derivatives. The method employs a carboxylic acid 2-methylthioaniline- or 8-aminoquinoline amide substrate, aryl or alkyl iodide coupling partner, palladium acetate catalyst, and an inorganic base. By employing 2-methylthioaniline auxiliary, selective monoarylation of primary sp(3) C-H bonds can be achieved. If arylation of secondary sp(3) C-H bonds is desired, 8-aminoquinoline auxiliary may be used. For alkylation of sp(3) and sp(2) C-H bonds, 8-aminoquinoline auxiliary affords the best results. Some functional group tolerance is observed and amino- and hydroxy-acid derivatives can be functionalized. Preliminary mechanistic studies have been performed. A palladacycle intermediate has been isolated, characterized by X-ray crystallography, and its reactions have been studied.

Bidentate, Monoanionic Auxiliary-Directed Functionalization of Carbon–Hydrogen Bonds

In recent years, carbon-hydrogen bond functionalization has evolved from an organometallic curiosity to a tool used in mainstream applications in the synthesis of complex natural products and drugs. The use of C-H bonds as a transformable functional group is advantageous because these bonds are the most abundant functionality in organic molecules. One-step conversion of these bonds to the desired functionality shortens synthetic pathways, saving reagents, solvents, and labor. Less chemical waste is generated as well, showing that this chemistry is environmentally beneficial. This Account describes the development and use of bidentate, monoanionic auxiliaries for transition-metal-catalyzed C-H bond functionalization reactions. The chemistry was initially developed to overcome the limitations with palladium-catalyzed C-H bond functionalization assisted by monodentate directing groups. By the use of electron-rich bidentate directing groups, functionalization of unactivated sp(3) C-H bonds under palladium catalysis has been developed. Furthermore, a number of abundant base-metal complexes catalyze functionalization of sp(2) C-H bonds. At this point, aminoquinoline, picolinic acid, and related compounds are among the most used and versatile directing moieties in C-H bond functionalization chemistry. These groups facilitate catalytic functionalization of sp(2) and sp(3) C-H bonds by iron, cobalt, nickel, copper, ruthenium, rhodium, and palladium complexes. Exceptionally general reactivity is observed, enabling, among other transformations, direct arylation, alkylation, fluorination, sulfenylation, amination, etherification, carbonylation, and alkenylation of carbon-hydrogen bonds. The versatility of these auxilaries can be attributed to the following factors. First, they are capable of stabilizing high oxidation states of transition metals, thereby facilitating the C-H bond functionalization step. Second, the directing groups can be removed, enabling their use in synthesis and functionalization of natural products and medicinally relevant substances. While the development of these directing groups presents a significant advance, several limitations of this methodology are apparent. The use of expensive second-row transition metal catalysts is still required for efficient sp(3) C-H bond functionalization. Furthermore, the need to install and subsequently remove the relatively expensive directing group is a disadvantage.

A General Method for Copper-Catalyzed Arylation of Arene C−H Bonds

A general method for copper-catalyzed arylation of sp (2) C-H bonds with p K as below 35 has been developed. The method employs aryl halide as the coupling partner, lithium alkoxide or K 3PO 4 base, and DMF, DMPU, or mixed DMF/xylenes solvent. A variety of electron-rich and electron-poor heterocycles such as azoles, caffeine, thiophenes, benzofuran, pyridine oxides, pyridazine, and pyrimidine can be arylated. Furthermore, electron-poor arenes possessing at least two electron-withdrawing groups on a benzene ring can also be arylated. Two arylcopper-phenanthroline complex intermediates were independently synthesized.

Copper-Promoted Sulfenylation of sp2 C–H Bonds

An auxiliary-assisted, copper catalyzed or promoted sulfenylation of benzoic acid derivative β-C-H bonds and benzylamine derivative γ-C-H bonds has been developed. The method employs disulfide reagents, copper(II) acetate, and DMSO solvent at 90-130 °C. Application of this methodology to the direct trifluoromethylsulfenylation of C-H bonds was demonstrated.

Copper-Catalyzed Arylation and Alkenylation of Polyfluoroarene C−H Bonds

An efficient, copper-catalyzed method for the arylation, alkenylation, and benzylation of polyfluoroarenes has been developed. Arenes containing two or more fluorine substituents on the aromatic ring can be efficiently functionalized. The best results are obtained by using a combination of copper iodide catalyst, phenanthroline ligand, aryl bromide or aryl iodide coupling partner, and DMF or DMF/xylene mixed solvent.

Heterocycle Synthesis via Direct C–H/N–H Coupling

A method for five- and six-membered heterocycle formation by palladium-catalyzed C-H/N-H coupling is presented. The method employs a picolinamide directing group, PhI(OAc)(2) oxidant, and toluene solvent at 80-120 °C. Cyclization is effective for sp(2) as well as aliphatic and benzylic sp(3) C-H bonds.

Cobalt-Catalyzed, Aminoquinoline-Directed C(sp2)H Bond Alkenylation by Alkynes†

A method for cobalt-catalyzed, aminoquinoline- and picolinamide-directed C(sp(2))-H bond alkenylation by alkynes was developed. The method shows excellent functional-group tolerance and both internal and terminal alkynes are competent substrates for the coupling. The reaction employs a Co(OAc)2⋅4 H2O catalyst, Mn(OAc)2 co-catalyst, and oxygen (from air) as a terminal oxidant.

Directed Amination of Non‐Acidic Arene CH Bonds by a Copper–Silver Catalytic System

Amine meets arene: A method for direct amination of β-C(sp(2))-H bonds of benzoic acid derivatives and γ-C(sp(2))-H bonds of benzylamine derivatives has been developed. The reaction is catalyzed by Cu(OAc)2 and a Ag2CO3 cocatalyst, and shows high generality and functional-group tolerance, as well as providing a straightforward means for the preparation of ortho-aminobenzoic acid derivatives.

Nonnatural Amino Acid Synthesis by Using Carbon–Hydrogen Bond Functionalization Methodology

During the last years, transition-metal-catalyzed carbon-hydrogen bond functionalization has witnessed an explosive growth.[1] The use of C-H bond as a functional group is appealing because of shortening of reaction pathways and simplification of retrosynthetic analyses. However, most of the reports that deal with carbon-hydrogen bond conversion to carbon-carbon bonds involve either methodology development or mechanistic investigations. The applications in synthesis of natural products or their analogues are rare.[2] The limited use may be explained by the following issues. First, methods that result in functionalization of alkane C-H bonds are relatively rare.[3] Second, harsh reaction conditions are typically used that may be incompatible with sensitive functionalities. Third, methods often lack generality and require non-removable directing groups. We have reported the β-arylation of carboxylic acid and γ-arylation of amine derivatives by employing an 8-aminoquinoline or picolinic acid auxiliary, catalytic Pd(OAc)2, and an aryl iodide coupling partner (Scheme 1).[4a] Subsequently, several other auxiliaries were investigated for carboxylic acid β-arylation.[4b] Use of 2-thiomethylaniline auxiliary affords selective monoarylation of methyl groups. In contrast, use of 8-aminoquinoline auxiliary allows either diarylation of methyl or monoarylation of methylene groups. The arylation regioselectivity is determined by formation of double five-membered chelate 1. Scheme 1 Auxiliaries for C-H Bond Arylation Several other groups have recently used these directing groups in synthesis of natural products.[5] Corey has used the 8-aminoquinoline auxiliary to arylate sp3 C-H bonds in amino acid derivatives.[5a] However, monoarylation of alanine derivatives was not demonstrated and stereochemical integrity of arylation products as well as directing group removal was not reported. Developing new methodology for unnatural amino acid synthesis is important since they are used in drug discovery, protein engineering, peptidomimetics, glycopeptide synthesis, and click chemistry in biologically relevant systems.[6–7] Methods for preparation of chiral nonracemic unnatural α-amino acids involve synthesis of racemates followed by resolution, use of chiral auxiliaries, asymmetric hydrogenation, and biological approaches.[8] A general method for unnatural amino acid synthesis from chiral pool would expand the toolbox that is available for their preparation. We report here a method of palladium-catalyzed synthesis of protected unnatural amino acids by C-H bond functionalization that employs readily available starting materials derived from chiral pool. The functionalizaton of amino acid C-H bonds requires installation of a directing group and protection of the amino group. Phthaloyl group was chosen for protection of the amino functionality.[9] Directing group was installed by reacting phthaloylamino acid chlorides[10] with 8-aminoquinoline or 2-thiomethylaniline. N-Phthaloylalanine derivative 2 was arylated by PhI in the presence of a palladium catalyst and base. Subsequently, directing group was removed by treatment with BF3*Et2O in methanol at 100 °C (Table 1).[11] Nearly identical enantiomeric excess of 4 was observed by employing AgOAc, AgOCOCF3, or CsOAc bases at 60–70 °C (entries 3–8). Higher reaction temperatures resulted in erosion of product enantiomeric excess (entries 1, 4, 9), as did addition of pivalic acid (entry 2). The optimal combination of yield and enantiomeric excess was obtained by employing palladium acetate catalyst in combination with AgOAc at 60 °C (entry 5). Table 1 Reaction Optimization. Use of 2-thiomethylaniline derivative allows for a selective monoarylation of methyl group in 2 (Scheme 2). Arylation of 2 by iodobenzene affords 3 in 78% yield. 4-Methoxyiodobenzene is reactive and the arylation product 5 was isolated in 68% yield. 2-Iodonaphthalene and 2-iodobenzothiophene afforded the products in good yields. β-(2-Naphthyl)alanine-containing peptides are highly specific Pin1 inhibitors.[12] Interestingly, 3-iodo-1-methylindole can be coupled with 2 to give an N-methylated tryptophan derivative 8 in 61% yield. An azido functionality is tolerated and 3-azidophenylalanine derivative 9 was obtained in 81% yield. Thus, a wide variety of substituted phenylalanines can be made from a readily available, single starting material 2 in a convergent fashion. Two of the arylated derivatives were subjected to cleavage of directing group. N-Phthaloylphenylalanine methyl ester 4 was obtained in 87% yield and 90% ee. The benzothiophene derivative 10 was obtained in 80% yield. Scheme 2 Synthesis of Modified Phenylalanine Derivatives. 8-Aminoquinoline directing group can be used for diarylation of methyl and monoarylation of methylene functionalities (Scheme 3). Diarylation of 11 was accomplished by 3,4-dimethyl-1-iodobenzene and 4-iodobenzoic acid ethyl ester and the products 12 and 13 were isolated in excellent yields. Interestingly, arylation of methylene groups occurs with high diastereoselectivity favoring the anti diastereomers. Protected phenylalanine can be arylated by 4-iodoanisole to give 91% of the product 14 with crude diastereomer ratio 24:1. Similarly, arylation by 2-iodothiophene results in formation of a single diastereomer 15 in 95% yield. Protected lysine can be arylated by 4-iodoanisole and 2-iodothiophene in high yields and diastereoselectivities. Arylation of a leucine derivative affords products 18 and 19 in high yields. The reactions were typically run on a 0.5 mmol scale. A 5.55 mmol scale p-methoxyphenylation of the leucine derivative afforded 18 in 67% yield. Cleavage of directing group was investigated for 12 and 18. Methyl esters 20 and 21 were obtained in 80 and 58% yields, respectively. Compound 21 was produced in 86% ee that could be upgraded to 95% ee (85% recovery) by one recrystallization. Additionally, relative stereochemistry of 21, which is a derivative of highly constrained β-isopropyltyrosine,[13] was verified by X-ray crystallography. Scheme 3 Aminoquinoline Auxiliary. Preliminary results in alkylation and acetoxylation of amino acid C-H bonds are reported in Scheme 4. Thus, alanine derivative 11 was alkylated by 1-iodooctane affording 22 in 42% yield. Compound 22 is a derivative of a lipidic amino acid which has shown tumor cell growth inhibitor activity.[14] Acetoxylation of 23 gave 24 in 53% yield.[15–16] Scheme 4 Alkylation and Acetoxylation. The arylation diastereoselectivity is set either at the C-H activation or, less likely, at reductive elimination step.[17] The H/D exchange in 23 was examined by heating the substrate with catalytic Pd(OAc)2 in CD3CO2D-toluene-d8 mixture. (Scheme 5). After 5 hours at 100 °C, 64% of deuterium incorporation was observed at 3S position with minimal (<10%) incorporation at 3R position. A generalized reaction mechanism can be proposed. Formation of a palladium amide 23a is followed by the C-H activation that affords 23b. The complex 23b then can be protonated or deuterated leading to 25. Since protonation likely occurs with retention of configuration,[18] it can be assumed that 23b has a trans arrangement of phthaloyl and phenyl groups and that the diastereoselectivity of the arylation is set at the stage of palladation. Oxidative addition to give a high-valent[19] Pd intermediate 26 is followed by reductive elimination that proceeds with retention of configuration. Oxidative addition of aryl iodides to palladium(II) may be facilitated by the silver salts since they are known to complex aryl iodides.[20] Ligand exchange affords 27 and regenerates 23a. Scheme 5 Mechanistic Considerations. In conclusion, we have shown that synthesis of a number of substituted phenylalanine derivatives is possible by using C-H bond functionalization methodology. The syntheses are highly convergent and employ N-phthaloylalanine possessing a 2-thiomethylaniline directing group. The use of 8-aminoquinoline directing group allows for the diarylation of methyl and diastereoselective monoarylation of amino acid methylene groups. Acetoxylation and alkylation of amino acid derivative C-H bonds is also possible.