Ullmann Condensation Research Articles

Cu‐promoted Access to 1,4‐Diazine‐fused Isoindoles Through Concomitant Csp3‐N and Csp2‐N Bonds Formation Starting from Constrained N,O‐acetals

Scarce dihydro‐1,4‐diazinoisoindole framework bearing two points of diversity was prepared through interesting cascade process based on concomitant Csp3‐N and Csp2‐N bonds formation. This approach consists on amidation in basic medium of tosyl group by nucleophilic substitution followed by Cu‐mediated Goldberg reaction in same operation. The required β‐bromoenamide bearing a tosyl group was obtained by tosylation of fused brominated N,O‐acetals for the first time in acidic medium using submolar amounts of PTSA. The obtained piperazines act as a powerful reaction intersection as illustrated by the formation of N‐heterocyclic system via the intramolecular interception of enamide function.

Kanamycin−Cu(II) Complex Catalyzed Ullmann Amine Synthesis at Room Temperature: A Tool for Mechanistic Insights into Methylene Blue Degradation

AbstractThis study highlights the significance of the Ullmann coupling reaction in modern organic synthesis and advances catalytic methodologies through the introduction of a kanamycin−copper complex as a highly efficient catalyst for the synthesis of diverse N−aryl compounds. We demonstrate the catalyst's versatility by synthesizing 20 diaryl−amine instances, 21 Ar(het)−N compounds, and 10 miscellaneous examples. NMR, IR, and UV spectroscopy offer insights into the catalyst's behaviour. Additionally, DFT studies support the catalyst's proficiency in generating SO4−⋅ radicals by stabilizing with amino sugar moieties. Ex‐situ NMR experiments confirm a ternary complex‐based mechanism at concentrations below 0.1 μM. Furthermore, we showcase the degradation of methylene blue to its precursor amine under optimized conditions. Overall, this research underscores the potential of Ullmann condensation reactions in contemporary organic synthesis and contributes significantly to the advancement of catalytic methodologies.

Atroposelective Chan-Evans-Lam Amination.

The synthetic control of atropoisomerism along C-N bonds is a major challenge, and methods that allow C-N atroposelective bond formation are rare. This is a problem because each atropoisomer can feature starkly differentiated biological properties. Yet, among the three most practical and applicable classical amination methods available: 1) the Cu-catalyzed Ullmann-Goldberg reaction, 2) the Pd-catalyzed Buchwald-Hartwig reaction, and 3) the Cu-catalyzed Chan-Evans-Lam reaction, none has truly been rendered atroposelective at the newly formed C-N bond. The first ever Chan-Evans-Lam atroposelective amination is herein described with a simple copper catalyst and newly designed PyrOx chiral ligand. This method should find important applications in asymmetric synthesis, in particular for medicinal chemistry.

Dual role of nitroarenes as electrophiles and arylamine surrogates in Buchwald–Hartwig-type coupling for C–N bond construction

A reductive and denitrative amination of nitroarenes has been developed, allowing the highly selective synthesis of various di- and triarylamines. The protocol employed synthetically upstream nitroarenes as both the electrophiles and amine sources.

Visible Light-Promoted Goldberg Reaction Driven by a Preponderant Facet of CuO Nanocrystals

Visible Light-Promoted Goldberg Reaction Driven by a Preponderant Facet of CuO Nanocrystals

Natural cellulose-based Cu(II) complex: An eco-friendly nanocatalyst for Ullmann condensations at room temperature

A bio-degradable and environmentally friendly heterogeneous Cu(II) complex have been synthesized from a jute nanocellulose-based poly(amidoxime) ligand for Ullmann condensation and synthesis of flexible liquid crystals. The bio-nanocellulose surface was modified via graft co-polymerization with acrylonitrile, and the poly(acrylonitrile) was converted into a bidentate poly(amidoxime) ligand via amidoximation. Further, this ligand was treated with an aqueous solution of CuSO4 resulted in strong complex formation (NCL-Cu(II)@PA) between the amidoxime ligands and Cu(II) species. This Cu(II) complex was successfully characterized and applied to the C–O bond formation via Ullmann condensation using ultra low loading (5–50 mol ppm of Cu) of metal species. A variety of alkyl/benzyl halides and 1-phenyl-2-bromoethanone were selectively forwarded the Ullmann condensation to afford the corresponding ethers quantitatively at room temperature. The NCL-Cu(II)@PA provided excellent catalytic performance in the condensation reaction with unrivalled TON 180000 and TOF 9000 h−1. The NCL-Cu(II)@PA was easily recovered from the reaction vessel and reused for up to seven cycles without a noteworthy drop in the respective ether. Furthermore, some azobenzene core flexible liquid crystal derivatives were also synthesized using the nanocellulose-based catalyst NCL-Cu(II)@PA. According to the STM results, the lengths of the bright aromatic disc-core and the azobenzene units were 0.77 ± 0.1 nm and 1.0 ± 0.2 nm.

Synthesis of MAPA Reagents and 2-Alkyl(aryl)aminopyridines from 2-Bromopyridine Using the Goldberg Reaction.

A short and economical synthesis of various 2-methylaminopyidine amides (MAPA) from 2-bromopyridine has been developed using the catalytic Goldberg reaction. The effective catalyst was formed in situ by the reaction of CuI and 1,10-phenanthroline in a 1/1 ratio with a final loading of 0.5–3 mol%. The process affords high yields and can accommodate multigram-scale reactions. A modification of this method provides a new preparation of 2-N-substituted aminopyridines from various secondary N-alkyl(aryl)formamides and 2-bromopyridine. The intermediate aminopyridine formamide is cleaved in situ through methanolysis or hydrolysis to give 2-alkyl(aryl)aminopyridines in high yields.

Efficient Synthesis of Polysubstituted 1,5-Benzodiazepinone Dipeptide Mimetics via an Ugi-4CR-Ullmann Condensation Sequence

AbstractAn efficient three-step synthesis towards 3-amino-1,4-benzodiazepin-2-one derivatives is presented. The versatile Ugi-4-component reaction (Ugi-4CR) and Boc deprotection is followed by a ligand-free Ullmann condensation. This protocol allows the rapid construction of a diverse array of substituted 1,5-benzodiazepinones. Since Ugi-based products are typically limited by their ‘inert’ C-terminal amides, the use of a convertible (‘cleavable’) isocyanide was envisaged and resulted in building blocks that can be made SPPS compatible. To demonstrate the potential of this novel synthetic route, the design and preparation of novel phenylurea-1,5-benzodiazepin-4(5H)-one dipeptide mimetics with potential CCK2-antagonist properties is reported.

Atom Transfer Radical Polymerization-Inspired Room Temperature (sp3)C-N Coupling.

A simple nonphotochemical procedure is reported for Cu(I)-catalyzed C-N coupling of aliphatic halides with amines and amides. The process is loosely based on the Goldberg reaction but takes place readily at room temperature. It uses Cu(I)Br, a commonly used and inexpensive atom transfer radical polymerization precatalyst, along with the cheap ligand N,N,N',N″,N″-pentamethyldiethylenetriamine, to activate the R-X bond of the substrate via inner-sphere electron transfer. The procedure brings about productive C-N bond formation between a range of alkyl halide substrates with heterocyclic aromatic amines and amides. The mechanism of the coupling step, which was elucidated through application of computational methods, proceeds via a unique Cu(I) → Cu(II) → Cu(III) → Cu(I) catalytic cycle, involving (a) inner-sphere electron transfer from Cu(I) to the alkyl halide to generate the alkyl radical; (b) successive coordination of the N-nucleophile and the radical to Cu(II); and finally reductive elimination. In the absence of a nucleophile, debrominative homocoupling of the alkyl halide occurs. Control experiments rule out SN-type mechanisms for C-N bond formation.

Preparation of Isodehydrodigallic Acid Using Ullmann Condensation.

Isodehydrodigallic acid, which is an important component of several ellagitannin compounds, was easily synthesized using a classical Ullmann condensation reaction.

Recent Advancement of Ullmann Condensation Coupling Reaction in the Formation of Aryl-Oxygen (C-O) Bonding by Copper-Mediated Catalyst

Transition metal-catalyzed chemical transformation of organic electrophiles and organometallic reagents belong to the most important cross coupling reaction in organic synthesis. The biaryl ether division is not only popular in natural products and synthetic pharmaceuticals but also widely found in many pesticides, polymers, and ligands. Copper catalyst has received great attention owing to the low toxicity and low cost. However, traditional Ullmann-type couplings suffer from limited substrate scopes and harsh reaction conditions. The introduction of homogeneous copper catalyst with presence of bidentate ligands over the past two decades has totally changed this situation as these ligands enable the reaction promoted in mild condition. The reaction scope has also been greatly expanded, rendering this copper-based cross-coupling attractive for both academia and industry. In this review, we will highlight the latest progress in the development of useful homogeneous copper catalyst with presence of ligand and heterogeneous copper catalyst in Ullmann type C-O cross-coupling reaction. Additionally, the application of Ullmann type C-O cross coupling reaction will be discussed.

Efficient Cu‐catalyzed Synthesis of Benzimidazoles Using Ammonia as Nitrogen Source in Water

AbstractIn present work, we have developed an efficient strategy for the synthesis of 2‐substituted benzimidazoles via Cu‐catalyzed Ullmann condensation reaction of o‐halobenzanilides with ammonia in water. This protocol is applicable to a wide variety of 2‐substituted benzimidazoles bearing functional groups tolerance, which features one‐pot, high yields, functional groups tolerable and green solvent.

Synthesis of a Regioregular Series of Poly(aryl ether carbonates) and Their Glass Transition Temperatures.

Bisphenol A polycarbonate (BPA-PC) is a remarkable high-performance engineering polymer, although it is susceptible to photo-Fries and hydrolytic degradation. New poly(aryl ether carbonates) were synthesized to address these limitations by replacing the chain backbone carbonate ester functionality with aryl ether functionality. The monomers for these new polymers were synthesized by a variation of the Ullmann condensation accelerated by 2,2,6,6-tetramethylheptane-3,5-dione and promoted by Cs2CO3 and 1-methyl-2-pyrrolidinone under mild conditions. Four such bisphenol A-based diarylether monomers containing different mass ratios of carbonate ester groups were prepared and polymerized with phosgene gas to give novel poly(aryl ether carbonates). Polymers were named as di-o-BPA-PC 9′, tri-o-BPA-PC 11′, tetra-o-BPA-PC 13′, and penta-o-BPA-PC 15′ where di-, tri-, tetra-, and penta- reflect the number of diphenylisopropylidene units in each of the respective polymers. The molecular weights of the resulting four poly(aryl ether carbonates) were measured by gel permeation chromatography. Differential scanning calorimetry was used to measure glass transition temperature (Tg). The polymers exhibited weight-average molecular weights up to 4.09 × 105 g/mol and Tg in the range of 136 to 149 °C with no melting temperature peak, indicative of their amorphous character. The new polymers formed transparent and flexible films by solution casting from chloroform solution.

Synthesis and Biological Evaluation of Acridine/Acridone Analogs as Potential Anticancer Agents.

The lack of efficacious therapy for advanced melanoma and neuroblastoma makes new approaches necessary. Therefore, many scientists seek new, more effective, more selective and less toxic anticancer drugs. We propose the synthesis of the new functionalized analogs of 1-nitroacridine/4- nitroacridone connected to tuftsin/retro-tuftsin derivatives as potential anticancer agents. Acridine and acridone analogues were prepared by Ullmann condensation and then cyclization reaction. As a result of nucleophilic substitution reaction 1-nitro-9-phenoxyacridine or 1- chloro-4-nitro-9(10H)-acridone with the corresponding peptides, the planned acridine derivatives (10a-c, 12, 17-a-d, 19) have been obtained. The cytotoxic activity of the newly obtained analogs were evaluated against melanotic (Ma) and amelanotic (Ab) melanoma cell lines and neuroblastoma SH-SY5Y by using the XTT method. Apoptosis and cell cycle were analyzed by flow cytometry. Among the investigated analogs compound 12 exhibited the highest potency comparable to dacarbazine action for amelanotic Ab melanoma cells. FLICA test (flurochrome-labeled inhibitors of caspases) showed that this analog significantly increased the content of cells with activated caspases (C+) among both neuroblastoma lines and only Ab melanoma line. Using phosphatidylserine (PS) externalization assay, 12 induced changes in the Ab melanoma plasma membrane structure as the externalization of phosphatidylserine (An+ cells). These changes in neuroblastoma cells were less pronounced. Analog 12 could be proposed as the new potential chemotherapeutic against amelanotic melanoma form especially.

Synthesis, cytotoxicity and antineoplastic activities of novel acridine-based platinum(II) organometallic complexes

Two new platinum(II) complexes incorporating acridine ligands with aniline moieties were successfully synthesised and characterised. The acridine-based ligands were synthesised by means of Ullmann's condensation. The reaction of cis-[PtCl2(DMSO)2] with the aforementioned ligand in a specified mol ratio gives 9-phenylaminoacridine cis-dichloro(dimethylsulfoxide)-platinum(II), 2a, and bis-[N-(3,5-dimethoxyphenyl) acridin-9-amine)]chloro platinum(II), 2b. Apparently, both complexes were slightly planar and in discrete asymmetrical units. Cytotoxicity and antineoplastic activity evaluations were conducted using WRL-68, MCF-7, HT-29, and HL60 cell lines. The novel complexes exhibited potent activity towards the cell lines. Concurrently, the MTT cytotoxicity assay revealed that all complexes significantly inhibited the proliferation of MCF-7 and HL60 cells.

An alternative synthesis of the non-small cell lung carcinoma drug afatinib

Afatinib (BIBW2992) is the anticancer drug developed by Boehringer Ingelheim. This work is reporting the synthesis of the afatinib using a new route by Ullmann-Goldberg reaction from corresponding 4-anilinoquinazoline iodide as the last step in the synthesis. This route was not described previously and it could be used for synthesis of afatinib analogues.

Optimization of diarylpentadienones as chemotherapeutics for prostate cancer

Our earlier studies indicate that (1E,4E)-1,5-bis(1-alkyl-1H-imidazol-2-yl)penta-1,4-diene-3-ones and (1E,4E)-1,5-bis(1-alkyl-1H-benzo[d]imidazol-2-yl)penta-1,4-diene-3-ones exhibit up to 121-fold greater antiproliferative potency than curcumin in human prostate cancer cell models, but only 2–10 fold increase in mouse plasma concentrations. The present study aims to further optimize them as anti-prostate cancer agents with both good potency and bioavailability. (1E,4E)-1,5-Bis(1H-imidazol-2-yl)penta-1,4-diene-3-one, the potential metabolic product of (1E,4E)-1,5-bis(1-alkyl-1H-imidazol-2-yl)penta-1,4-diene-3-ones, was synthesized and evaluated for its anti-proliferative activity. The promising potency of 1,5-bis(1-alkyl-1H-imidazol-2-yl)penta-1,4-diene-3-ones was completely abolished by removing the 1-alkyl group, suggesting the critical role of an appropriate group on the N1 position. We then envisioned that N-aryl substitution to exclude the C–H bond on the carbon adjacent to the N1 position (α-H) may increase the metabolic stability. Consequently, seven (1E,4E)-1,5-bis(1-aryl-1H-imidazol-2-yl)penta-1,4-dien-3-ones and three (1E,4E)-1,5-bis(1-aryl-1H-benzo[d]imidazol-2-yl)penta-1,4-dien-3-ones, as well as three (1E,4E)-1,5-bis(1-aryl-1H-pyrrolo[3,2-b]pyridine-2-yl)penta-1,4-dien-3-ones, were synthesized through a three-step transformation, including N-arylation via Ullmann condensation, formylation, and Horner-Wadsworth-Emmons reaction. Six optimal (1E,4E)-1,5-bis(1-aryl-1H-imidazol-2-yl)penta-1,4-dien-3-ones exhibit 24- to 375-fold improved potency as compared with curcumin. Replacement of the imidazole with bulkier benzoimidazole and 4-azaindole results in a substantial decrease in the potency. (1E,4E)-1,5-Bis(1-(2-methoxyphenyl)-1H-imidazol-2-yl)penta-1,4-dien-3-one (17d) was established as an optimal compound with both superior potency and good bioavailability that is sufficient to provide the therapeutic efficacy necessary to suppress in vivo tumor growth.

Combining Stereoselective Enzyme Catalysis with Chirality‐Assisted Synthesis in Tribenzotriquinacene Chemistry

The stereoselective synthesis of enantiomerically pure single‐wing‐functionalized tribenzotriquinacenes using the enzyme CAL‐B was successfully extended towards operating on a multi‐gram scale. Based on the (P)‐tribenzotriquinacene‐2‐carbaldehyde (P)‐6 obtained in >99 % ee, the hitherto unknown (P)‐2‐hydroxy‐ and (M)‐2‐hydroxy‐3‐iodo‐TBTQ derivatives (P)‐9 and (M)‐10 were prepared in optically pure form. The bowl‐shaped ortho‐iodophenol (M)‐10 was subjected to a twofold crosswise Ullmann‐type condensation to give, albeit in low yield (10 %), the 1,4‐dioxine 5, in which two TBTQ bowls are fused exclusively in a syn‐bi‐concave orientation, thus demonstrating a new example for a chirality‐assisted synthesis. The corresponding Ullmann condensation of the racemic TBTQ‐ortho‐iodophenol rac‐10 furnished the respective anti‐bis‐TBTQ‐dioxine 11 as the major diastereomer together with the syn‐isomer 5 in the same total yield and in a 11/5 ratio of at least 4. The two diastereomeric bis‐TBTQ‐dioxines show minor but significant differences in most of the characteristic 1H‐NMR chemical shifts. The solid‐state structure of the syn‐dimer 5, determined by X‐ray diffraction, was found to consist of pairs of host–guest complexes, [5·CH2Cl2]2, with pronounced face‐to‐face orientation of the bi‐concave host molecules.

Immobilized palladium nanoparticles on MNPs@A‐N‐AEB as an efficient catalyst for C‐O bond formation in water as a green Solvent

Palladium nanoparticles immobilized on the magnetic nanoparticles@2‐amino‐N‐(2‐aminoethyl) benzamide (MNPs@A‐N‐AEB.Pd0) have been presented as an efficient, and reusable magnetically heterogeneous catalyst for the C‐O coupling reaction, namely Ullmann condensation reactions in an aqueous medium. This heterogeneous catalyst shows superior reactivity for the C‐O arylation of different aryl halide (chloride, bromide, and iodide) with phenol derivatives to afford the desired products in good to excellent yields within short reaction time. Moreover, the catalyst can be easily recovered and reused for seven runs without loss of catalytic activity. The catalyst was characterized by several techniques, such as FT‐IR, SEM, TEM, EDS, XRD, TGA and ICP‐OES.

Syntheses, Characterizations, and Reactivity of Two Cu(I)-Amido Complexes: Proposed Intermediate in Cu(I)-Catalyzed Goldberg Reaction

Reactions between dichloro-bridged copper(I) complexes and amides with different carbonyl substituents (CF3, CH3, and Ph) were reported. Two neutral Cu(I)-amido complexes, [Cu(Dppf)(MOAA)] (I) and [Cu(Dppf)(MOTFAA)] (II) (Dppf = 1,1'-bis(diphenylphosphino)ferrocene, MOAA and MOTFAA = deprotonated N-(4-methoxyphenyl) acetamide and N-(4-methoxyphenyl) trifluoroacetamide, respectively), were synthesized in moderate to good yield and characterized by element analysis, 1H NMR and X-ray crystallography method (СIF file CCDC no. 1015222 (I)). The results showed that the production of Cu(I)- amido complxes were influenced by carbonyl substituent in the order of Ph > CF3 > CH3. The substituent effect also appeared in the N-arylation reactions of I and II with iodobenzene, which generated another copper(I) complex Cu(Dppf)I (III) and two amides products [N-methyl-N-(4-methoxyphenyl) acetamide] (А) and [N-methyl-N-(4-methoxyphenyl) trifluoroacetamide] (B) in different yield. The formation and transformation of the Cu(I)-amido complexes could indicate their dynamiccompetency as the intermediates of Goldberg reaction.