Ortho Alkylation Research Articles

Kinetically stabilized 1,3-diarylisobenzofurans and the possibility of preparing large, persistent isoacenofurans with unusually small HOMO-LUMO gaps.

DFT calculations demonstrate that an isoacenofuran of any size possesses a smaller HOMO-LUMO gap than the corresponding acene bearing an isoelectronic π-system (i.e., the same total number of rings). Isoacenofurans show limited stability due in part to the highly reactive 1,3-carbons of the furan ring. Both 1,3-dimesitylisobenzofuran and 1,3-di(2',4',6'-triethylphenyl)isobenzofuran, each bearing sterically congesting ortho-alkyl groups on their phenyl substituents, have been synthesized and shown to adopt non-planar conformations with the ortho-alkyl groups located above and below the most reactive 1,3-carbons of the furan ring. These bulky substituents provide a strong measure of kinetic stabilization. Thus, 1,3-dimesitylisobenzofuran and 1,3-di(2',4',6'-triethylphenyl)isobenzofuran are significantly less reactive than 1,3-diphenylisobenzofuran toward the strong dienophiles DMAD and acrylonitrile. The insights gained here suggest that the synthesis of large, persistent, kinetically stabilized isoacenofurans with unusually small HOMO-LUMO gaps is achievable. As such, these molecules deserve increased attention as potential p-type organic semiconductors.

Rapid and Modular Access to Multifunctionalized 1,2-Azaborines via Palladium/Norbornene Cooperative Catalysis.

1,2-Azaborines, a unique class of BN-isosteres of benzene, have attracted great interest across several fields. While significant advancements have been made in the postfunctionalization of 1,2-azaborines, challenges still exist for the selective functionalization of the C4 position and access to 1,2-azaborines with five or six independently installed substituents. Here we report a rapid and modular method for C3 and C4 difunctionalization of 1,2-azaborines using the palladium/norbornene (Pd/NBE) cooperative catalysis. Enabled by the C2 amide-substituted NBE, diverse 3-iodo-1,2-azaborines can be used as substrates, showing broad functional group tolerance. Besides ortho arylation, preliminary success of ortho alkylation has also been realized. In addition, a range of alkenes and nucleophiles can be employed for ipso C3 functionalization. The reaction is scalable, and various postfunctionalizations, including forming hexa-substituted 1,2-azaborines, have been achieved.

Rh(III)‐Catalyzed Direct ortho Alkylation of Carbazoles with Nitroalkenes

AbstractThe Rh(III)‐catalyzed ortho alkylation of N‐pyridylcarbazoles with nitroalkenes has been developed, furnishing a wide range of 2‐(2‐nitroalkyl)carbazoles. Both aromatic and aliphatic nitroalkenes participated in this alkylation reaction successfully. This protocol also proceeded well with an indoline based substrate. Derivatization of the representative nitroalkane product was described.

Understanding photoenolization of O‐methyl acetophenone, and its subsequent [4 + 2] and 1,4 addition of its photoproduct from an aromaticity perspective

AbstractPhoton‐driven enolization of aromatic ketones and aldehydes with an ortho alkyl group has been suggested to proceed through triplet state surface after photoexcitation. We have investigated the photoexcitation of 2‐methoxy‐6‐methylacetophenone using time‐dependent density functional theory (TDDFT) and complete active space self‐consistent field (CASSCF) theory, following which we have studied excited state proton transfer on the triplet surface and have computed the aromaticity of both the ground and excited state intermediates and transition states using nucleus‐independent chemical shifts (NICSs) based on multi‐reference wavefunction. The barrier for the crucial proton transfer for photoenolization on ππ* lowest Triplet surface is predicted to be a paltry 3.7 kcal/mol, as compared to the prohibitively high barrier of 38 kcal/mol on the S0 surface at M06‐2X/6‐311++G(d,P) level of theory. We show that a favorable change from anti‐aromaticity to aromaticity on the ππ* triplet surface makes proton transfer facile, whereas in the ground state reaction, reduction of aromaticity along the reaction coordinate is responsible for a higher barrier. Moreover, it was found that the product arising from photoenolization can serve as a more efficient diene than traditional dienes such as 1,3‐butadiene, 1‐methoxy‐1,3‐butadiene for Diels–Alder‐based [4 + 2] cyclization and 1,4 addition due to the significant gain in aromaticity in the transition state of the former case as compared to those of the traditional ones.

Benzylic C−H Functionalisation by [Et3SiH+KOtBu] leads to Radical Rearrangements in o‐tolyl Aryl Ethers, Amines and Sulfides

AbstractReaction of Et3SiH+KOtBu with diaryl ethers, sulfides and amines that feature an ortho alkyl group leads to rearrangement products. The rearrangements arise from formation of benzyl radicals, likely formed through hydrogen atom abstraction by triethylsilyl radicals. The rearrangements involve cyclisation of the benzyl radical onto the partner arene, which, from computation, is the rate determining step. In the case of diaryl ethers, Truce‐Smiles rearrangements arise from radical cyclisations to form 5‐membered rings, but for diarylamines, cyclisations to form dihydroacridines are observed.magnified image

Nucleophilic Substitution at Tetracoordinate Sulfur. Kinetics and Mechanism of the Chloride-Chloride Exchange Reaction in Arenesulfonyl Chlorides: Counterintuitive Acceleration of Substitution at Sulfonyl Sulfur by ortho-Alkyl Groups and Its Origin.

The chloride-chloride exchange reaction in arenesulfonyl chlorides was investigated experimentally and theoretically by density functional theory (DFT) calculations. The second order rate constants and activation parameters of this identity reaction were determined for 22 variously substituted arenesulfonyl chlorides using radio-labeled Et4N36Cl. The chloride exchange rates of 11 sulfonyl chlorides bearing para-and meta-substituents (σ constants from −0.66 to +0.43) in the aromatic ring followed the Hammett equation with a ρ-value of +2.02. The mono- and di-ortho-alkyl substituted sulfonyl chlorides exhibit an enhanced reactivity although both inductive and steric effects lower the reaction rate. The DFT calculations of their structures together with X-ray data showed that an increased reactivity is mainly due to a peculiar, rigid, strongly compressed and sterically congested structure. The DFT studies of the title reaction revealed that it proceeds via a single transition state according to the SN2 mechanism. The analogous fluoride exchange reaction occurs according to the addition–elimination mechanism (A–E) and formation of a difluorosulfurandioxide intermediate. The reliability of the calculations performed was supported by the fact that the calculated relative rate constants and activation parameters correlate well with the experimental kinetic data.

Thiocarbamate‐Directed ortho C−H Bond Alkylation with Diazo Compounds

AbstractWe herein report a rhodium catalysed insertion of C(sp2)−H bond into diazo derived carbenes directed by a thiocarbamate group. This reaction provides a direct and efficient pathway to the ortho alkylation of phenol derivatives with a broad substrate scope. The C−H activation process is accomplished through a reversible electrophilic rhodation.magnified image

C―H···O hydrogen bonding interactions for sterically hindered phenols and their phenoxyl radicals

AbstractSterically hindered phenols have been widely used as chain‐breaking antioxidants in chemical and polymeric industries, and the remarkable stabilities of their phenoxyl radicals are generally attributed to the steric effects and resonance stabilization of the unpaired electron into the aromatic ring. Non‐covalent interaction (NCI) analysis shows that there are four intramolecular C―H···O hydrogen bonds between oxygen atom and the ortho t‐butyl C―H bonds for the sterically hindered phenoxyl radicals and their phenolic precursors. The C―H···O hydrogen bonds can be directly visualized and quantified from the reduced density gradient NCI isosurfaces and atoms‐in‐molecules analysis, respectively. Furthermore, the phenolic O―H bond strength decreases gradually with increasing volume of the ortho alkyl substituents in three different phenol model systems (Table 5). The nice linear correlation of the O―H bond dissociation enthalpies with the Taft's steric parameters (Figure 8) provides additional evidences to support formation of the intramolecular C―H···O hydrogen bonds between oxygen atom and the ortho t‐alkyl C―H bonds.

Palladium(II)-assisted ortho alkylation of C(sp2)-H bonds in substituted azobenzenes with simple alkyl halides

A new and relatively simple synthetic strategy has been described for Pd(II)-catalyzed C-C bond formation via alkylation of ortho C(sp2)-H bonds in substituted azobenzenes possessing (2-phenylamino)phenylazo directing group employing different alkyl iodides. The yields of various ortho alkylated products are found to be good to excellent (65%–85%). A palladocyclic intermediate complex has been isolated and fully characterized. Based on the experimental results and the isolation of the palladocyclic intermediate, a catalytic cycle involving a sequential C-H activation/oxidative addition followed by reductive elimination pathway has been proposed.

Sulfonium Salts as Alkylating Agents for Palladium-Catalyzed Direct Ortho Alkylation of Anilides and Aromatic Ureas.

A novel method for the ortho alkylation of acetanilide and aromatic urea derivatives via C-H activation was developed. Alkyl dibenzothiophenium salts are considered to be new reagents for the palladium-catalyzed C-H activation reaction, which enables the transfer of methyl and other alkyl groups from the sulfonium salt to the aniline derivatives under mild catalyticconditions.

Palladium-Catalyzed Arylation of Ketones and Acetonitrile with Ortho Alkylation of Aryl Rings: De Novo Synthesis of Tetralines and Benzocycloheptenes

Palladium-catalyzed α-arylation reactions of ketones with simultaneous ortho alkylation offer 1,2,3-substituted arenes. The reactions of 1,ω-dihaloalkanes also allow facile construction of medicinally important tetralines and benzocycloheptenes.

ChemInform Abstract: Palladium‐Catalyzed ortho C—H Bond Alkylation of Benzylamides with α‐Bromo Ketones.

A Pd-catalyzed alkylation of ortho C–H bonds in benzylamides possessing a bidentate-quinolinamide directing group with α-bromo ketones or nitrile is reported. α-Bromo aryl ketones, α-bromo alkyl ketone, and even α-bromo alkyl nitrile are competent reagents in this transformation, providing direct alkylated products with a pendant carbonyl or cyano group. Furthermore, direct alkylated products can be hydrolyzed under acidic conditions, providing a straightforward strategy for preparing high-value 3-arylisoquinoline derivatives.

N-H Imine as a Powerful Directing Group for Cobalt-Catalyzed Olefin Hydroarylation.

N-alkyl and N-aryl imines have been frequently used as directing groups in rhodium- and cobalt-catalyzed hydroarylation reactions of olefins and alkynes. However, the scope of such hydroarylation reactions has been limited by the difficulty of preparation of sterically hindered imines by condensation, and also by the steric bulkiness of the imine group itself. Reported herein is that an N-H imine serves as an alternative and highly effective directing group for cobalt-catalyzed hydroarylation of olefins, and unlocks many of the limitations associated with the previously employed N-aryl imine directing group. The power of this minimal nitrogen directing group is manifested in a fourfold ortho alkylation of benzophenone imine, and it occurs rapidly at ambient temperature.

N−H Imine as a Powerful Directing Group for Cobalt‐Catalyzed Olefin Hydroarylation

AbstractN‐alkyl and N‐aryl imines have been frequently used as directing groups in rhodium‐ and cobalt‐catalyzed hydroarylation reactions of olefins and alkynes. However, the scope of such hydroarylation reactions has been limited by the difficulty of preparation of sterically hindered imines by condensation, and also by the steric bulkiness of the imine group itself. Reported herein is that an N−H imine serves as an alternative and highly effective directing group for cobalt‐catalyzed hydroarylation of olefins, and unlocks many of the limitations associated with the previously employed N‐aryl imine directing group. The power of this minimal nitrogen directing group is manifested in a fourfold ortho alkylation of benzophenone imine, and it occurs rapidly at ambient temperature.

Palladium-catalyzed ortho C–H bond alkylation of benzylamides with α-bromo ketones

A Pd-catalyzed alkylation of ortho C–H bonds in benzylamides with α-bromo ketones or nitrile is reported. Furthermore, a straightforward strategy for preparing 3-arylisoquinoline derivatives is developed.

Regioselective ortho alkylation of nitro indole, carbazole, benzothiophene and benzofuran

Substituted indoles, carbazoles, benzothiophenes and benzofurans are important motifs in the pharmaceutical industry. Herein we report a novel, regioselective method to introduce alkyl substituents into position ortho of nitro groups by the addition of a Grignard reagent followed by subsequent oxidation with DDQ.

Palladium-Catalyzed Heteroarylation and Concomitant ortho-Alkylation of Aryl Iodides.

Three-component couplings were achieved from common aryl halides, alkyl halides, and heteroarenes under palladium and norbornene co-catalysis. The reaction forges hindered aryl-heteroaryl bonds and introduces ortho-alkyl groups to aryl rings. Various heterocycles such as oxazoles, thiazoles and thiophenes underwent efficient coupling. The heteroarenes were deprotonated in situ by bases without the assistance of palladium catalysts.

ChemInform Abstract: N‐Chlorophthalimide as a Mild and Efficient Chlorination Reagent in the Gassman ortho Alkylation of Aromatic Amines. Synthesis of 3‐(Methylthio)oxindoles.

AbstractThe modified mild conditions for Gassman ortho alkylation of aromatic amines allow the isolation of the intermediate α‐amidosulfides (III), which are cyclized to produce 3‐(methylthio)oxindoles.

Photoinduced Rearrangement of Aryl‐Substituted Acylcyclohexasilanes

AbstractIn the present study, we examined photochemical transformations of acylcyclohexasilanes (Me3Si)2Si6Me12(Me3Si)COR (compounds 1) with aromatic substituents attached to the carbonyl C atom. When photolyzed at wavelengths above 300 nm in hydrocarbon solvents, 1a–c (1a: R = o‐Tol; 1b: R = 2,3‐Me2C6H3; 1c: R = 2,4‐Me2C6H3) afforded the previously unknown eight‐membered heterocyclopolysilanes 3a–c, which feature endocyclic Si=C double bonds with remarkable selectivity. If two ortho‐alkyl groups are present at the aromatic ring (compounds 1d–f), the primary products of type 3 (3d: R = Mes; 3e: R = 1,6‐Me2C6H3; 3f: R = 2,4,6‐iPr3C6H2) are photochemically unstable and undergo intramolecular C–H‐bond addition reactions of a ortho‐CH3 group to the Si=C double bond, which leads to the formation of spirobenzocyclobutenes. When photolysis was performed in the presence of methanol, the expected 1,2‐addition products (compounds 4) of the Si=C double bond were obtained quantitatively in all cases. 4a (R = o‐Tol) and 4b (R = Mes) were isolated by crystallization from acetone and fully characterized spectroscopically and by single‐crystal X‐ray diffraction analysis. Interestingly 4b was obtained as an isomeric mixture arising from syn and anti addition of methanol to the endocyclic Si=C bond, whereas the syn addition was observed exclusively in the case of 4a.

Acridine Synthesis by the Reaction of 2-(Perfluoroalkyl)aniline with ortho-Alkyl-Substituted Aromatic Grignard Reagent: Mechanistic Studies

The reaction of 2-(perfluoroethyl)aniline and its higher perfluoroalkyl analogues with an arylmagnesium bromide substituted with a methyl or ethyl group at the ortho position furnishes an acridine containing a shorter perfluoroalkyl group at the 9-position and devoid of the methyl or ethyl group of the Grignard reagent. Yields are in the range of 46–93 %. The intermediary of a substituted aza-ortho-xylylene has been postulated for related transformations in the literature previously, but this intermediate product has never been isolated. As part of this work, the labile product E-27 (half-life of 6 h at 23°C) was isolated for the first time and characterized by infrared spectroscopy, electron impact mass spectrometry, fast atom bombardment mass spectrometry, and 1H NMR. Experimental evidence was also obtained regarding the elimination of the ortho-alkyl group of the Grignard reagent during the course of the reaction as an alcohol.