Ortho Amination Research Articles

Beyond Tertiary Amines: Introducing Secondary Amines by Palladium/Norbornene-Catalyzed Ortho Amination.

Since the discovery of the palladium/norbornene (Pd/NBE)-catalyzed ortho amination in 2013, escaping the limitation of only yielding tertiary anilines has been a long-standing challenge. Here, we describe that, by carefully choosing the phosphine ligand and NBE mediator, the installation of a N-mono-alkylamino group becomes feasible. The reaction tolerates a wide range of aryl iodide substrates and various N-mono-tertiary alkylamine-derived electrophiles. Both ipso alkenylation and alkynylation can be realized. The synthetic utility of this method is exemplified by the formation of primary amino group via selective deprotection and streamlined access to N-heterocycles. Preliminary success of installing a bulky N-secondary alkylamino group and a mechanistic understanding of the decomposition pathways of mono N-alkylamine electrophiles have been obtained.

Beyond Tertiary Amines: Introducing Secondary Amines by Palladium/Norbornene‐Catalyzed Ortho Amination

AbstractSince the discovery of the palladium/norbornene (Pd/NBE)‐catalyzed ortho amination in 2013, escaping the limitation of only yielding tertiary anilines has been a long‐standing challenge. Here, we describe that, by carefully choosing the phosphine ligand and NBE mediator, the installation of a N‐mono‐alkylamino group becomes feasible. The reaction tolerates a wide range of aryl iodide substrates and various N‐mono‐tertiary alkylamine‐derived electrophiles. Both ipso alkenylation and alkynylation can be realized. The synthetic utility of this method is exemplified by the formation of primary amino group via selective deprotection and streamlined access to N‐heterocycles. Preliminary success of installing a bulky N‐secondary alkylamino group and a mechanistic understanding of the decomposition pathways of mono N‐alkylamine electrophiles have been obtained.

Simple and Efficient Method for Mono‐ and Di‐Amination of Polypyridine N‐Oxides

AbstractHerein we report a simple synthetic route towards both known and novel aminated polypyridyl ligands. The use of tosyl chloride in combination with potassium phthalimide followed by hydrolysis allows for chemo–selective ortho–amination of (poly)pyridyl mono‐ and di‐N‐oxides with good to excellent yield. The reactions are scalable and reproducible while using inexpensive, commercially available reagents.

Modular Entry to Functionalized Tetrahydrobenzo[b]azepines via the Palladium/Norbornene Cooperative Catalysis Enabled by a C7-Modified Norbornene.

Tetrahydrobenzo[b]azepines (THBAs) are commonly found in many bioactive compounds; however, the modular preparation of functionalized THBAs remains challenging to date. Here, we report a straightforward method to synthesize THBAs directly from simple aryl iodides via palladium/norbornene (Pd/NBE) cooperative catalysis. Capitalizing on an olefin-tethered electrophilic amine reagent, an ortho amination followed by 7-exo-trig Heck cyclization furnishes the seven-membered heterocycle. To overcome the difficulty with ortho-unsubstituted aryl iodide substrates, we discovered a unique C7-bromo-substituted NBE (N1) to offer the desired reactivity and selectivity. In addition to THBAs, synthesis of other benzo-seven-membered ring compounds can also be promoted by N1. Combined experimental and computational studies show that the C7-bromo group in N1 plays an important and versatile role in this catalysis, including promoting β-carbon elimination, suppressing benzocyclobutene formation, and stabilizing reaction intermediates. The mechanistic insights gained could guide future catalyst design. The synthetic utility has been demonstrated in a streamlined synthesis of tolvaptan and forming diverse pharmaceutically relevant THBA derivatives. Finally, a complementary and general catalytic condition to access C6-substituted THBAs from ortho-substituted aryl iodides has also been developed.

Regioselective Ortho Amination of an Aromatic C-H Bond by Trifluoroacetic Acid via Electrochemistry.

A trifluoroacetic acid-facilitated ortho amination of alkoxyl arene has been established via anodic oxidation in an undivided cell. In the absence of any additional metal or oxidant reagents, a series of aromatic and heteroaromatic amine derivatives have been synthesized in good to excellent yields. Our findings reveal the possibility of achieving complete ortho-selective amination of a simple arene, which emerges as an efficient route for facile and large-scale organic synthesis.

Modular ipso/ ortho Difunctionalization of Aryl Bromides via Palladium/Norbornene Cooperative Catalysis.

Palladium/norbornene (Pd/NBE) cooperative catalysis has emerged as a useful tool for preparing poly substituted arenes; however, its substrate scope has been largely restricted to aryl iodides. While aryl bromides are considered as standard substrates for Pd-catalyzed cross coupling reactions, their use in Pd/NBE catalysis remains elusive. Here we describe the development of general approaches for aryl bromide-mediated Pd/NBE cooperative catalysis. Through careful tuning the phosphine ligands and quenching nucleophiles, ortho amination, acylation and alkylation of aryl bromides have been realized in good efficiency. Importantly, various heteroarene substrates also work well and a wide range of functional groups are tolerated. In addition, the utility of these methods has been demonstrated in sequential cross coupling/ ortho functionalization reactions, consecutive Pd/NBE-catalyzed difunctionalization to construct penta-substituted aromatics and two-step meta functionalization reactions. Moreover, the origin of the ligand effect in ortho amination reactions has been explored through DFT studies. It is expected that this effort would significantly expand the reaction scope and enhance the synthetic potential for Pd/NBE catalysis in preparing complex aromatic compounds.

ChemInform Abstract: Copper‐Catalyzed Carboxamide‐Directed ortho Amination of Anilines with Alkylamines at Room Temperature.

AbstractSubstitution of the picolinamide moiety by picolinic acid, N‐methyl picolinamide, benzamide, or sulfonamides results in no reaction.

ChemInform Abstract: Synthesis of Anthranilic Acid Derivatives Through Iron‐Catalyzed ortho Amination of Aromatic Carboxamides with N‐Chloroamines.

Arenes possessing an 8-quinolinylamide group as a directing group are ortho aminated with N-chloroamines and N-benzoyloxyamines in the presence of an iron/diphosphine catalyst and an organometallic base to produce anthranilic acid derivatives in high yield. The reaction proceeds via iron-catalyzed C–H activation, followed by the reaction of the resulting iron intermediate with N-chloroamine. The choice of the directing group and diphosphine ligand is crucial for obtaining the anthranilic acid derivative with high yield and product selectivity.

Synthesis of Anthranilic Acid Derivatives through Iron-Catalyzed Ortho Amination of Aromatic Carboxamides with N-Chloroamines

Arenes possessing an 8-quinolinylamide group as a directing group are ortho aminated with N-chloroamines and N-benzoyloxyamines in the presence of an iron/diphosphine catalyst and an organometallic base to produce anthranilic acid derivatives in high yield. The reaction proceeds via iron-catalyzed C-H activation, followed by the reaction of the resulting iron intermediate with N-chloroamine. The choice of the directing group and diphosphine ligand is crucial for obtaining the anthranilic acid derivative with high yield and product selectivity.

Self Assembled Films of Porphyrins with Amine Groups at Different Positions: Influence of Their Orientation on the Corrosion Inhibition and the Electrocatalytic Activity

Self-assembled molecular films of two cobalt porphyrins with amine groups at different positions—(5,10,15,20-tetrakis-(2-aminophenyl) porphyrin-cobalt(II), [Co(II) (T(o-NH2)PP)] and (5,10,15,20-tetrakis-(4-aminophenyl) porphyrin-cobalt(II), [Co(II)(T(p-NH2)PP)]—were formed on a gold substrate. The functionalized surfaces were characterized using Raman spectroscopy, atomic force microscopy and electrochemical methods. Both modified gold surfaces completely mask the charge transfer of a [Fe(CN)6]3−/4− redox couple in solution, indicating the layer is highly resistive in behavior. Electrochemical impedance spectroscopy analyses revealed that the porphyrin film with amine groups at ortho positions shows a higher charge-transfer resistance with a better protective behavior compared to the para position modified surface. Raman, AFM and EIS data suggests that an ortho amine positioned molecule forms a more compact layer compared to the para-positioned molecule. This can be explained in terms of their orientation on the gold surface. [Co(II)(T(o-NH2)PP)] adopted a saddle shape orientation whereas [Co(II)(T(p-NH2)PP)] adopted a flat orientation on the gold surface. The porphyrin modified gold electrode catalyzes the oxygen reduction at lower potentials compared to the bare gold electrode. The shift in the overvoltage was higher in case of molecules with flat orientation compared to the saddle shaped oriented porphyrin molecules on the surface.

OrthoAmination of Naphthols by N-N Bond Cleavage of Hydrazines

Described is a simple thermal reaction of 2-naphthol, its analogues and quinoline derivatives 1 with N,N-disubstituted hydrazines 2 that leads to a general and efficient method for direct ortho amination to yield various α-aminated substituted naphthol and quinoline derivatives 3 and the corresponding secondary amines 4 in good to excellent yield. Only N-methyl-N-phenylhydrazine was employed on various naphthol analogues, whereas nine examples of N,N-disubstituted hydrazines were tested on 2-naphthol. The reaction proceeded well under solvent-free conditions. Reactions were also performed in methanol and chlorobenzene but required longer reaction times (15-60 h) for completion.

A New Method for N−N Bond Cleavage of N,N-Disubstituted Hydrazines to Secondary Amines and Direct Ortho Amination of Naphthol and Its Analogues

An unexpected reaction of N,N-disubstituted hydrazine with naphthol and its analogues under simply thermal conditions has been disclosed. 2-Naphthol reacted with various N,N-disubstituted hydrazines under argon to afford 1-amino-2-naphthol and the corresponding secondary amines in excellent yields. Ortho amination of 2-naphthols, hydroxyquinoline, and naphthalenamine occurred when they reacted with N-methyl-N-phenylhydrazine.

Chelated aryllithium reagent: ortho- and para-pyrrolidinomethylphenyllithium

Multinuclear NMR studies have been performed on two isomeric aryllithium reagents, one with an ortho amine chelating group (5-ring chelate, 4) and the second, a non-chelating model (5) with the same group in the para position. Both compounds were prepared isotopically enriched in 6 Li as solutions in THF or mixtures of THF with ethyl and/or methyl ether. Solution dynamics (aggregate interchange, chelation averaging) were measured by DNMR experiments. The model compound 5 is a mixture of dimer and monomer in THF (KMD = 180 M -1 ). Several bidentate chelating cosolvents (TMEDA, dimethyl-2-methoxyethylamine and 2-dimethylamino- methyltetrahydrofuran) interacted with 5 to give mono and bis complexes of the dimers as well as mono-complexed monomer, with only minimal changes in the monomer to dimer ratio. Compound 4 in THF solution forms a strong dimer as a single chelation isomer of the B-type. The dynamics of decoordination of the pyrrolidine groups was measured by DNMR coalescence of the diastereotopic pyrrolidine ring carbons ( ‡ 190 = 8.5 kcal/mol), and the dynamics of aggregate exchange were measured both by loss of C-Li coupling, and by exchange of 4 dimer with the mixed dimer 16 ( ‡ 246 = 12.5-13.0 kcal/mol). Compound 4 interacts only very weakly with TMEDA, but HMPA causes significant conversion of dimer to monomer. The Li/I exchange of 4 and the analogous iodide 17 was slower by 5 orders of magnitude than the PhLi/PhI exchange. A 119 Sn NMR study of a series of trimethylstannylaryl compounds with ortho substituents that could form a 5-membered chelate with an ether or amino group were weakly chelated.

Alkylidene-Centered Rearrangement of a Tantalum Alkylidene Alkoxide Species with the N,C,N-Bis-ortho-chelated 1,2,6-Trisubstituted Aryldiamine Ligand [C6H3(CH2NMe2)2-2,6]- to a Product with a C,N-Mono-ortho-chelated 1,2,4-Trisubstituted Aryldiamine Ligand. X-ray Molecular Structure of [TaCl(CH-t-Bu){C6H3(CH2NMe2)2-2,4}(O-t-Bu)

The reaction of 2 equiv of LiO-t-Bu with [TaCl2(CH-t-Bu){C6H3(CH2NMe2)2-2,6}] (1), in which there is an N,C,N-chelated 1,2,6-trisubstituted aryldiamine ligand, affords in a one-pot procedure at 80 °C the new rearranged product [Ta(CH-t-Bu){C6H3(CH2NMe2)2-2,4}(O-t-Bu)2] (2), in which there is a C,N-chelated 1,2,4-trisubstituted aryldiamine ligand. Complex 2 is a yellow solid that has been isolated in 69% yield. The reaction mechanism for the formation of 2 involves a crucial isomerization of the intermediate [TaCl(CH-t-Bu){C6H3(CH2NMe2)2-2,6}(O-t-Bu)] (3) to the rearranged intermediate [TaCl(CH-t-Bu){C6H3(CH2NMe2)2-2,4}(O-t-Bu)] (4). The intermediate complexes 3 and 4 have been independently prepared and characterized. The known complex 3 can be obtained by reaction of 1 with LiO-t-Bu at room temperature. Complex 4 is obtained exclusively, as revealed by 1H NMR spectroscopy, by heating a benzene solution of 3 to 80 °C and has been isolated as a purple solid in 77% yield. In solution 4 exists as two rotational isomers for the TaC(H)-t-Bu moiety; ΔG⧧ = 71 kJ mol-1. The X-ray molecular structure of 3 shows it to be a pentacoordinate Ta(V) species in which the aryl Cipso atom, the alkylidene functionality, and the alkoxide group define the meridional plane of a trigonal bipyramid, with one of the NMe2 nitrogen donors of the C,N-bidentate-bonded aryldiamine and the chloride occupying the axial positions. The lone pair of the N-donor atom of the second ortho amine substituent is oriented toward Ta (Ta···N = 2.629.4 Å), providing incipient η3(N,C,N) facial bonding of the aryldiamine ligand. The structure of 3 also shows a pseudo-parallel orientation of the alkylidene Cα−Hα bond and the Cipso−Ta bond that points to potential C−H activation via a four-membered metallacyclic ring that contains Ta, Cipso, Cα, and Hα. The involvement of the alkylidene functionality in the sequence of highly regiospecific C−H bond-making and -breaking processes necessary to produce complex 4 from 3 was confirmed by deuterium-labeling experiments. The mechanism probably involves an α-H abstraction from the alkylidene moiety in 3 (assisted by the weakly coordinated dimethylamino group) that leads to an intermediate which has a geometry similar to that of a known aryltantalum(V) zinc alkylidene adduct.

N‐Aryl‐O‐(α‐aminoacyl)hydroxylamine: Modellreaktionen zur Aktivierung von monocyclischen aromatischen Aminen zu ultimaten Carcinogenen durch α‐Aminosäuren

N‐Aryl‐O‐(α‐aminoacyl)hydroxylamines: Model Reactions for the Activation of Monocyclic Aromatic Amines into Ultimate Carcinogens with α‐Amino AcidsThe rearrangement of the new α‐aminohydroxamic acids 15 and 18 to the likewise new N‐(α‐aminoacyloxy)arylamines [“N‐(acyloxy)arylamines”] 19 and 20, respectively, is observed in amine‐catalyzed model reactions. N‐(acyloxy)arylamines such as 19 and 20 are indicated to be ultimate carcinogens of aromatic amines which are able to react with bionucleophiles such as the DNA bases. The formation of 19 and 20 was proven by trapping these reactive intermediates with the model nucleophile N‐methylaniline (21) to give the hydrazines 22 and‐depending on the substitutent in 19 and 20‐the so‐called ortho amination products 23. Analogous reactions of the aceto‐and pivalohydroxamic acids 24 and 25 lead also to the adducts 22 and 23, respectively, in comparable yields. These results demonstrate that the O‐α‐aminoacylation as shown here may be similarily used in model reactions for the activation of carcinogenic aromatic amines as the O‐acetylation.