Ortho Metalation Research Articles

Transition-metal-free access to primary anilines from boronic acids and a common (+)NH2 equivalent.

Diversely substituted anilines are prepared by treatment of functionalized arylboronic acids with a common, inexpensive source of electrophilic nitrogen (H2N-OSO3H, HSA) under basic aqueous conditions. Electron-rich substrates are found to be the most reactive by this method. However, even moderately electron-poor substrates are well tolerated under the room temperature conditions. Sterically hindered substrates appear to be equally effective compared to unhindered ones. Highly electron-deficient substrates afford product in very low yields at room temperature, but moderate to good yields are obtained at refluxing temperatures. Our method is also amenable to electrophilic amination of several common boronic acid derivatives (e.g., pinacol esters). We demonstrate that it can be combined with metal-halogen exchange reactions or a variety of directed ortho metalation protocols in a "one-pot" sequence for the synthesis of aromatic amines with unique substitution patterns. DFT studies, in combination with experimental results, suggest that the reaction occurs via base-mediated activation of HSA, followed by 1,2 aryl B-N migration. This mode of activation appears to be critical for the success of the reaction and allows, for the first time, a general, electrophilic amination of boronic acids at ambient temperature.

Unprecedented pseudo-ortho and ortho metallation of [2.2]paracyclophanes--a methyl group matters.

The first example of a pseudo-ortho metallation on [2.2]paracyclophane is presented, giving easy access to enantiopure compounds of this type. By slight modification of the directing group, metallation of the ortho- and C2-positions is possible. The mechanism was further investigated by means of density functional theory (DFT) calculations.

Synthesis of 9-Phenylacridines via Ortho-Lithiation–Cyclization Sequence*

How to Cite Kinens, A.; Kalnins, T.; Suna E. Chem. Heterocycl. Compd. 201 5 , 50 , 1501. [ Khim. Geterotsikl. Soedin. 2014 , 1629.] For this article in the English edition see DOI 10.1007/s10593-014-1616-y

Ruthenium(II)-catalyzed <I>Ortho</I> C-O Bond formation of Substituted Aromatics with Oxygen Nucleophiles through C-H Bond Activation

The present review describes a ruthenium-catalyzed ortho C-O bond formation such as hydroxylation, benzoxylation and acetoxylation of substituted aromatics with oxygen nucleophiles via C-H bond activation. Various oxygen sources such as trifluoroacetic anhydride, aromatic carboxylic acids and acetic acid are used as nucleophiles in the reaction. Most of the reactions shown in the review mechanistically proceeds via a concerted deprotonation ortho metalation pathway. A fivemembered ruthenacycle intermediate was proposed in the reactions. These reactions provide an efficient route for the synthesis of ortho-hydroxy-, acetoxy- and benzoxy substituted aromatics in a highly regioselective manner in one pot.

ChemInform Abstract: Lithiation of N,N,N′,N′‐Tetraisopropylpyridine‐2,6‐dicarboxamide: Synthesis, Characterization and Single Crystal X‐Ray Studies of Chalcogen (Se/Te) Derivatives of N,N,N′,N′‐Tetraisopropylpyridine‐2,6‐dicarboxamide.

Abstract The lithiation of N,N,N′,N′-tetraisopropylpyridine-2,6-dicarboxamide (1) and its application in the synthesis of chalcogen (Se/Te) derivatives was investigated. It was found that the selectivity of the reaction changed with the change in the amount of n-BuLi used. The lithiation of 1 with 6.1 equiv of n-BuLi followed by subsequent reactions with selenium/tellurium and iodomethane exclusively afforded the monosubstituted chalcogen derivative (2a/2b) in excellent yield. However, the use of 2.1 or 4.2 equiv of n-BuLi gave two additional products along with 2a/2b. One of the isolated products corresponded to the double lithiation of 1 and the other to the ortho lithiation followed by nucleophilic addition of n-BuLi to the one of the two carbonyl moieties. The prepared compounds have been characterized by single crystal X-ray crystallography, NMR (1H, 13C, 77Se and 125Te), IR, UV–Visible and Mass spectroscopy. Crystal structure of N,N,N′,N′-tetraisopropyl-3,5-bis(methyltelluryl)pyridine-2,6-dicarboxamide (3b) reveals a strong intramolecular C O⋯Te secondary and intermolecular Te⋯π pyridyl interactions.

Solvent choice and kinetic isotope effects (KIEs) dramatically alter regioselectivity in the directed ortho metalation (DoM) of 1,5-dichloro-2,4-dimethoxybenzene.

The regioselective formation of the 6-lithio derivative of 1,5-dichloro-2,4-dimethoxybenzene (i.e., 12) by directed ortho metalation (DoM) with nBuLi in THF is described. Although literature reports suggest direct deprotonation at C6, a series of time-course and labelling studies has revealed that deprotonation rather occurs exclusively at C3 followed by isomerization of the anion to C6. By contrast, when DoM was performed in Et2 O, deprotonation again occurred selectively at C3, but now no isomerization occurs, and electrophilic capture produces the regioisomer of that produced in THF. In these labeling studies, it has been found that deuterium has an enormous kinetic isotope effect (KIE) that suppresses not only the original DoM reaction at C3 when deuterium is present there, but also suppresses isomerization to C6 when the label is at that site. Remarkably, this "protecting-group" role of the deuterium is unique to THF; in ether, full deprotonation of the deuterium at C3 was observed.

A bis-sulfonyl O,C,O aryl pincer ligand and its tin(II) complex: synthesis, structural studies, and DFT calculations.

The efficiency of the deprotonated aryl bis-sulfone [2,6-{(p-tolyl)SO2}2C6H3](-) as an O,C,O-coordinating pincer-type ligand was described. The bis-sulfone precursor was synthesized using a straightforward palladium-catalyzed cross-coupling reaction. As a result of directed ortho metalation (DoM) through sulfonyl groups, a selective lithiation of the aryl group was achieved and the corresponding carbanion was isolated and its structure determined by single-crystal X-ray diffraction analysis. A heteroleptic tin(II) complex has been prepared by a nucleophilic substitution reaction. Crystallographic analysis and DFT calculations indicate that the bis-sulfonyl moiety acts as a new O,C,O-coordinating pincer-type ligand with intramolecular S=O coordination to a tin(II) center. The cis form with the two nonbonded oxygen atoms of the sulfonyl groups on the same side is preferentially obtained.

A Bis‐Sulfonyl O,C,O Aryl Pincer Ligand and its Tin(II) Complex: Synthesis, Structural Studies, and DFT Calculations

AbstractThe efficiency of the deprotonated aryl bis‐sulfone [2,6‐{(p‐tolyl)SO2}2C6H3]− as an O,C,O‐coordinating pincer‐type ligand was described. The bis‐sulfone precursor was synthesized using a straightforward palladium‐catalyzed cross‐coupling reaction. As a result of directed ortho metalation (DoM) through sulfonyl groups, a selective lithiation of the aryl group was achieved and the corresponding carbanion was isolated and its structure determined by single‐crystal X‐ray diffraction analysis. A heteroleptic tin(II) complex has been prepared by a nucleophilic substitution reaction. Crystallographic analysis and DFT calculations indicate that the bis‐sulfonyl moiety acts as a new O,C,O‐coordinating pincer‐type ligand with intramolecular SO coordination to a tin(II) center. The cis form with the two nonbonded oxygen atoms of the sulfonyl groups on the same side is preferentially obtained.

ChemInform Abstract: Beyond Directed ortho Metalation: Ruthenium‐Catalyzed Amide‐Directed CAr—N Activation/C—C Coupling Reaction of Anthranilamides with Organoboronates.

AbstractSubstitution of the 2‐dimethylamino group in (I) by a 2‐diethylamino or a 2‐amino group leads to the corresponding analogues of (III) in significantly lower yield or no reaction, respectively.

Strong bases. Directed ortho-meta'- and meta-meta'-dimetalations: a template base approach to deprotonation.

The regioselectivity of deprotonation reactions between arene substrates and basic metalating agents is usually governed by the electronic and/or coordinative characteristics of a directing group attached to the benzene ring. Generally, the reaction takes place in the ortho position, adjacent to the substituent. Here, we introduce a protocol by which the metalating agent, a disodium-monomagnesium alkyl-amide, forms a template that extends regioselectivity to more distant arene sites. Depending on the nature of the directing group, ortho-meta' or meta-meta' dimetalation is observed, in the latter case breaking the dogma of ortho metalation. This concept is elaborated through the characterization of both organometallic intermediates and electrophilically quenched products.

ChemInform Abstract: Biomimetic Synthesis of (.+‐.)‐Merochlorin B.

A short total synthesis, guided by biosynthetic considerations, of racemic merochlorin B is presented. The formation of its isomer, merochlorin A, was not observed under the conditions. Key steps include a directed ortho-metalation (DoM), a selective demethylation, an ortho-allylation, and an oxidative [3 + 2]-cycloaddition mediated by an iodine(III) reagent.

Beyond directed ortho metalation: Ru-catalyzed CAr-O activation/cross-coupling reaction by amide chelation.

Disclosed is a new, catalytic, and general methodology for the chemical synthesis of biaryl, heterobiaryl, and polyaryl molecules by the cross-coupling of o-methoxybenzamides with aryl boroneopentylates. The reaction is based on the activation of the unreactive C-OMe bond by the proximate amide directing group using catalytic RuH2(CO)(PPh3)3 conditions. A one-step, base-free coupling process is thereby established that has the potential to supersede the useful two-step directed ortho metalation/cross-coupling reaction involving cryogenic temperature and strong base conditions. High regioselectivity, orthogonality with the Suzuki-Miyaura reaction, operational simplicity, minimum waste, and convenient scale-up make these reactions suitable for industrial applications.

Directed ortho Metalation of Naphthyl-2-carbamates

Directed ortho Metalation of Naphthyl-2-carbamates

ChemInform Abstract: A Practical in situ Generation of the Schwartz Reagent. Reduction of Tertiary Amides to Aldehydes and Hydrozirconation.

A new, highly efficient in situ protocol (Cp2ZrCl2/LiAlH(OBu-t)3) is described for the generation of the Schwartz reagent which provides a convenient method for the amide to aldehyde reduction and the regioselective hydrozirconation-iodination of alkynes and alkenes. Highlighted are chemoselective reductions of benzamides derived by directed ortho metalation (DoM) chemistry, allowing the synthesis of valuable 1,2,3-substituted benzaldehydes. The single-step, three-component process proceeds in a very short reaction time, shows excellent functional group compatibility, and uses inexpensive and long-storage stable reducing reagents.

Lithiation of N,N,N′,N′-tetraisopropylpyridine-2,6-dicarboxamide: synthesis, characterization and single crystal X-ray studies of chalcogen (Se/Te) derivatives of N,N,N′,N′-tetraisopropylpyridine-2,6-dicarboxamide

The lithiation of N,N,N′,N′-tetraisopropylpyridine-2,6-dicarboxamide (1) and its application in the synthesis of chalcogen (Se/Te) derivatives was investigated. It was found that the selectivity of the reaction changed with the change in the amount of n-BuLi used. The lithiation of 1 with 6.1 equiv of n-BuLi followed by subsequent reactions with selenium/tellurium and iodomethane exclusively afforded the monosubstituted chalcogen derivative (2a/2b) in excellent yield. However, the use of 2.1 or 4.2 equiv of n-BuLi gave two additional products along with 2a/2b. One of the isolated products corresponded to the double lithiation of 1 and the other to the ortho lithiation followed by nucleophilic addition of n-BuLi to the one of the two carbonyl moieties. The prepared compounds have been characterized by single crystal X-ray crystallography, NMR (1H, 13C, 77Se and 125Te), IR, UV–Visible and Mass spectroscopy. Crystal structure of N,N,N′,N′-tetraisopropyl-3,5-bis(methyltelluryl)pyridine-2,6-dicarboxamide (3b) reveals a strong intramolecular CO⋯Te secondary and intermolecular Te⋯π pyridyl interactions.

Biomimetic synthesis of (±)-merochlorin B.

A short total synthesis, guided by biosynthetic considerations, of racemic merochlorin B is presented. The formation of its isomer, merochlorin A, was not observed under the conditions. Key steps include a directed ortho-metalation (DoM), a selective demethylation, an ortho-allylation, and an oxidative [3 + 2]-cycloaddition mediated by an iodine(III) reagent.

CH Activation by Amide Chelation Control: Ruthenium‐ Catalyzed Direct Synthesis of 2‐Aryl‐3‐furanamides

AbstractA new, catalytic methodology for the synthesis of heterobiaryls by the ruthenium‐catalyzed CH activation/cross‐coupling of heterocyclic amides with aryl boroneopentylates is surveyed. From this survey, the highly regioselective reaction of furan‐3‐carboxamide to give 2‐aryl‐3‐furanamides is optimized and generalized in scope with respect to the aryl boroneopentylate coupling partners. Established thereby is a one‐step synthetic method which may supercede the broadly applied two‐step directed ortho metalation (DoM)–cross coupling reaction involving cryogenic and strong base conditions and which has potential for further ortho and remote metalation chemistry.magnified image

Directed ortho metalation strategies. Effective regioselective routes to 1,2-, 2,3-, and 1,2,3-substituted naphthalenes.

The regioselective synthesis of 2,3-di- and 1,2,3-trisubstituted naphthalenes via Directed ortho Metalation (DoM) strategies of N,N-diethyl-O-naphthyl-2-carbamate (1) is presented. Sequential LiTMP metalation-electrophile quench and s-BuLi/TMEDA (or t-BuLi)-electrophile quench of naphthyl-2-carbamate 1 provides a general route to contiguously substituted naphthalenes (6) with full regioselectivity. Further derivatization via ipso-halodesilylation and Suzuki-Miyaura cross-coupling leads ultimately to substituted halonaphthalenes and benzonaphthopyranones (9).

Cobalt PCP Pincer Complexes via an Unexpected Sequence of Ortho Metalations

The cobalt PCP pincer complexes [Co{2,6-(CH2PPh2-κP)2C6H3-κC1}(L)2], where L = PMe3 (1), CO (2), have been prepared. Complex 1 is obtained by a transmetalation reaction between 1-lithio-2,6-bis((diphenylphosphino)methyl)benzene and [CoCl(PMe3)3]. Subsequent exposure of 1 to CO gave complex 2. Complexes 1 and 2 can also be obtained from 1,3-bis((diphenylphosphino)methyl)benzene and [CoMe(PMe3)4]. Instead of ortho metalation occurring directly at the C2 (pincer) position of the diphosphine, ortho metalation first occurs at the C4 position to form [Co{2-(CH2PPh2-κP)-4-(CH2PPh2)-C6H3-κC1}(PMe3)3] (4). After reflux of the reaction mixture for 24 h, a rearrangement of 4 occurs to give pincer complex 1 with loss of PMe3 in ca. 50% yield; this rearrangement was accompanied by some decomposition. The mechanism for the conversion of 4 to 1 has been probed using 1-deuterio-2,6-bis((diphenylphosphino)methyl)benzene. Unexpectedly, the labeled ligand led to 15% deuterium enrichment of an ortho CH of the terminal PPh2 g...

Very Simple and Highly Modular Synthesis of Ferrocene-Based Chiral Phosphines with a Wide Variety of Substituents at the Phosphorus Atom(s)

Chiral ferrocene-based phosphines with a wide variety of substituents at the phosphorus atom(s) have been simply and modularly synthesized by ortho lithiation of Ugi’s amine and then reaction with PCl3 and finally treatment with Grignard or organolithium reagents.