Alkylation

About: Alkylation is a research topic. Over the lifetime, 29915 publications have been published within this topic receiving 464944 citations. The topic is also known as: alkylation reaction.

Palladium-Catalyzed Picolinamide-Directed Alkylation of Unactivated C(sp3)–H Bonds with Alkyl Iodides

Abstract: We report an efficient method for the alkylation of γ-C(sp3)–H bonds of picolinamide-protected aliphatic amine substrates with primary alkyl iodides via palladium catalysis. Ag2CO3 and dibenzyl phosphate, (BnO)2PO2H, are critical promoters of this reaction. These reactions provide a convenient and straightforward method for the preparation of high-value N-containing products from readily available amine and alkyl iodide precursors.

Phase Transfer Catalysis in Organic Synthesis

Abstract: 1. Introduction and Principles.- 1.1 Introduction.- 1.2 Early Examples.- 1.3 The Coalescence of Ideas.- 1.4 The Principle of Phase Transfer Catalysis.- 1.5 Evidence for the Mechanism of Phase Transfer Catalysis.- 1.6 Charged Catalysts: Quaternary Ions.- 1.7 Uncharged Catalysts: The Amines.- 1.8 Uncharged Catalysts: The Crown Ethers.- 1.9 Uncharged Catalysts: The Cryptands.- 1.10 Catalyst Comparisons.- 1.11 Solvents.- 1.12 The Role of Water in Phase Transfer Catalysis.- 1.13 Summary.- References.- 2. The Reaction of Dichlorocarbene With Olefins.- 2.1 Introduction.- 2.2 The Mechanism of the Dichlorocyclopropanation Reaction.- 2.3 Catalytic Cyclopropanation.- 2.4 Dichlorocyclopropanation of Simple Olefins.- 2.5 Cyclopropanation of Enamines.- 2.6 Dichlorocyclopropanation Followed by Rearrangement.- 2.7 Carbene Addition to Indoles.- 2.8 Carbene Addition to Furans and Thiophenes.- 2.9 Carbene Addition to Polycyclic Aromatics.- 2.10 Carbene Addition to Conjugated Olefins.- 2.11 Michael Addition of the Trichloromethyl Anion.- 2.12 Dichlorocarbene Addition to Allylic Alcohols: A Cyclopentenone Synthon.- 2.13 Dichlorocarbene to Phenols: Reimer-Tiemann Reactions.- References.- 3. Reactions of Dichlorocarbene With Non-Olefinic Substrates.- 3.1 Introduction.- 3.2 C - H Insertion Reactions.- 3.3 Reaction With Alcohols: Synthesis of Chlorides.- 3.4 Carbene Addition to Imines.- 3.5 Addition to Primary Amines: Synthesis of Isonitriles...- 3.6 Reaction With Hydrazine, Secondary, and Tertiary Amines.- 3.7 Dehydration With Dichlorocarbene.- 3.8 Miscellaneous Reactions of Dichlorocarbene.- References.- 4. Dibromocarbene and Other Carbenes.- 4.1 Introduction.- 4.2 Dibromocarbene Addition to Simple Olefins.- 4.3 Dibromocarbene Addition to Strained Alkenes.- 4.4 Dibromocarbene Addition to Indoles.- 4.5 Dibromocarbene Addition to Michael Acceptors.- 4.6 Other Reactions of Dibromocarbene.- 4.7 Other Halocarbenes.- 4.8 Phenylthio- and Phenylthio(chloro)carbene.- 4.9 Unsaturated Carbenes.- References.- 5. Synthesis of Ethers.- 5.1 Introduction.- 5.2 Mixed Ethers: The Mechanism.- 5.3 Rate Enhancement in the Williamson Reaction.- 5.4 Methylation.- 5.5 Phenyl Ethers.- 5.6 Methoxymethyl Ethers of Phenol.- 5.7 Diethers From Dihalomethanes.- 5.8 The Koenigs-Knorr Reaction.- 5.9 Epoxides.- References.- 6. Synthesis of Esters.- 6.1 Introduction.- 6.2 Tertiary Amines and Quaternary Ammonium Salts.- 6.3 Noncatalytic Esterification in the Presence of Ammonium Salts.- 6.4 Polycarbonate Formation.- 6.5 Crown Catalyzed Esterification.- 6.6 Crown Catalyzed Phenacyl Ester Synthesis.- 6.7 Crown Catalyzed Esterification of BOC-Amino Acid to Chloromethylated Resins.- 6.8 Cryptate and Resin Catalyzed Esterifications.- 6.9 Synthesis of Sulfonate and Phosphate Esters by PTC.- References.- 7. Reactions of Cyanide Ion.- 7.1 Introduction.- 7.2 The Mechanism and General Features of the Cyanide Displacement Reaction.- 7.3 The Formation of Alkyl Cyanides.- 7.4 Formation of Acyl Nitriles.- 7.5 Synthesis of Cyanoformates.- 7.6 Cyanohydrin Formation.- 7.7 The Benzoin Condensation.- 7.8 Hydrocyanation, Cyanosilylation, and Other Reactions.- References.- 8. Reactions of Superoxide Ions.- 8.1 Introduction.- 8.2 Reactions at Saturated Carbon.- 8.3 Additions to Carbonyl Groups.- 8.4 Reactions With Aryl Halides.- References.- 9. Reactions of Other Nucleophiles.- 9.1 Introduction.- 9.2 Halide Ions.- 9.3 Azide Ions.- 9.4 Nucleophile Induced Elimination Reactions.- 9.5 Nitrite Ion.- 9.6 Hydrolysis Reactions.- 9.7 Anionic Polymerization Initiation.- 9.8 Organometallic Systems.- 9.9 Isotopic Exchange.- References.- 10. Alkylation Reactions.- 10.1 Introduction.- 10.2 The Substances Alkylated.- 10.3 Phase Transfer Alkylating Agents.- 10.4 Alkylation of Reissert's Compound.- References.- 11. Oxidation Reactions.- 11.1 Introduction.- 11.2 Permanganate Ion.- 11.3 Chromate Ion.- 11.4 Hypochlorite Ion.- 11.5 Catalytic Oxidation.- 11.6 Singlet Oxygen.- 11.7 Oxidation of Anions.- 11.8 Phosphorylation.- References.- 12. Reduction Techniques.- 12.1 Introduction.- 12.2 Borohydrides.- 12.3 Stoichiometric Reduction Systems.- 12.4 Other Catalytic Reductions.- 12.5 Altered Reactivity.- References.- 13. Preparation and Reactions of Sulfur Containing Substrates.- 13.1 Introduction.- 13.2 Preparation of Symmetrical Thioethers.- 13.3 Preparation of Mixed Sulfides.- 13.4 Preparation of Sulfides From Thiocyanates.- 13.5 Preparation of Alkylthiocyanates.- 13.6 Sulfides Resulting From Michael Additions.- 13.7 Synthesis of ?, ?-Unsaturated Sulfur Compounds.- 13.8 Other Phase Transfer Reactions of Sulfur Containing Substances.- References.- 14. Ylids.- 14.1 Introduction.- 14.2 Phase Transfer Wittig Reactions.- 14.3 The Wittig-Horner-Emmons Reaction.- 14.4 Sulfur Stabilized Ylids.- References.- 15. Altered Reactivity.- 15.1 Introduction.- 15.2 Cation Effects.- 15.3 Affected Anions.- 15.4 Ambident Nucleophiles.- References.- 16. Addendum: Recent Developments in Phase Transfer Catalysis.- Author Index.

A readily available chiral Ag-based N-heterocyclic carbene complex for use in efficient and highly enantioselective Ru-catalyzed olefin metathesis and Cu-catalyzed allylic alkylation reactions.

Abstract: A new chiral bidentate N-heterocyclic carbene (NHC) ligand has been designed and synthesized. The NHC ligand bears a chiral diamine backbone and an achiral biphenol group; upon metal complexation (derived from Ag(I), Ru(II), or Cu(II)), the diamine moiety induces >98% diastereoselectivity such that the biaryl unit coordinates to the metal center to afford the desired complex as a single atropisomer. Because the ligand does not require optically pure biaryl amino alcohols, its synthesis is significantly shorter and simpler than the related first generation ligands bearing a chiral binaphthyl-based amino alcohol. The chiral NHC ligand can be used in the preparation of highly effective Ru- and Cu-based complexes (prepared and used in situ from the Ag(I) carbene) that promote enantioselective olefin metathesis and allylic alkylations with scope that is improved from previously reported protocols. In many cases, transformations promoted by the chiral NHC-based complexes proceed with higher enantioselectivity and reactivity than was observed with previously reported complexes.

A Convenient Route to Functionalized Carbon Nanotubes

Abstract: Reductive alkylation of single-walled carbon nanotubes (SWNTs) using lithium and alkyl halides in liquid ammonia yields sidewall functionalized nanotubes that are soluble in common organic solvents. Atomic force microscopy (AFM) and high-resolution tunneling electron microscopy (HRTEM) of dodecylated SWNTs prepared from raw HiPco nanotubes show that extensive debundling has occurred. GC-MS analysis of the byproduct hydrocarbons demonstrates that alkyl radicals are intermediates in the alkylation step.

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

Abstract: 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.