Base-sensitive Functional Groups Research Articles

N-Alkoxyphthalimides as Nitrogen Electrophiles to Construct C-N Bonds via Reductive Cross-Coupling.

N-Alkoxyphthalimides, one kind of phthalimide derivative, have great importance in synthesis, mainly used as free radical precursors. While the phthalimide unit, for a long time, was treated as part of the waste stream. Construction of C-N bonds has always been a hot spot, especially in reductive cross-coupling. Herein, a nickel-catalyzed reductive cross-coupling reaction of N-methoxyphthalimides with alkyl halides is described, where N-methoxyphthalimides serve as nitrogen electrophiles. This tactic provides a new approach to construct C-N bonds under mild neutral conditions. Alkyl chlorides, bromides, iodides, and sulfonates are all fit to this transformation. Moreover, the reaction could tolerate a broad substrate scope, especially base-sensitive functional groups (boron or silicon groups), as well as competitive nucleophilic groups (phenols and amides), which are incompatible with traditional Gabriel synthesis under basic conditions, demonstrating a complementary role of this work to Gabriel synthesis.

Synthesis of 3-Aminoalkylated Indoles Using Heterogeneous MgFe2O4 Nanoparticles Under Microwave Irradiation in One-Pot Three-Component System

AbstractA series of 3-aminoalkylated indoles are efficiently synthesised in a one-pot three-component reaction under microwave irradiation. Magnesium ferrite (MgFe2O4) nanoparticles (10 mol%) have been used as heterogeneous catalyst, which may easily be recovered by application of an external magnet and the recovered catalyst can be reused at least for five runs without affecting the efficiency of the catalyst. The solvent-free protocol developed has advantages of less reaction time, high yields, and easy workup, and the protocol is applicable to various acid base sensitive functional groups present in the substrate. The reported methodology is highly suitable especially for primary amines in addition to secondary amines as one of the components.

Co-catalytic borinate enables air-tolerant copper/oxalamide catalysis for cost-effective hydroxylation of aryl bromides

Copper/oxalamide-catalyzed hydroxylation of aryl bromides has been boosted with respect to air-tolerance and compatibility with cost-effective hydroxides by using co-catalytic dialkylborinates, making the important protocol for phenols more practical without loss of catalytic efficiency. Scope and limitations of the copper/boron co-catalyzed hydroxylation of aryl bromides with potassium hydroxide in air have been demonstrated by more than 20 examples, showing good tolerance to steric and electronic factors albeit low compatibility with base-sensitive functional groups. The boosting effects of co-catalytic dialkylborinates are tentatively attributed to prevention of the catalytically active copper species from deactivation by air and free hydroxide.

Selective Hydrolysis of Primary and Secondary Amides Enabled by Visible Light.

Amide hydrolysis is a fundamentally important transformation in organic chemistry. Developing hydrolysis procedures under mild conditions with a broad substrate scope is desirable. Herein, by leveraging a photoresponsive auxiliary o-nitroanilide, we established a mild two-step protocol for the hydrolysis of primary and secondary amides. This protocol is driven by visible light irradiation at room temperature under neutral conditions, which tolerates numerous acid- and base-sensitive functional groups. Various drugs, natural product-, and amino acid-derived amides can be selectively hydrolyzed.

Tandem Kumada-Tamao catalyst-transfer condensation polymerization and Suzuki-Miyaura coupling for the synthesis of end-functionalized poly(3-hexylthiophene).

Successive Kumada-Tamao catalyst-transfer condensation polymerization of 2-bromo-5-chloromagnesio-3-hexylthiophene and Suzuki-Miyaura end-functionalization with pinacol arylboronate in one pot afforded poly(3-hexylthiophene) (P3HT) with a base-sensitive functional group at both ends. The use of poly(methyl methacrylate) (PMMA) bearing a boronic acid ester moiety at one end enabled one-pot synthesis of PMMA-b-P3HT-b-PMMA triblock copolymer.

Regio- and Trans-Selective Ni-Catalyzed Coupling of Butadiene, Carbonyls, and Arylboronic Acids to Homoallylic Alcohols under Base-Free Conditions.

We herein report a Ni-catalyzed three-component coupling of 1,3-butadiene, carbonyl compounds, and arylboronic acids as a general synthetic approach to 1,4-disubstituted homoallylic alcohols, an important class of compounds, which have previously not been straightforward to access. The reaction occurs efficiently using a Ni(cod)2 catalyst without any external base and ligand at ambient temperature and allows a highly regioselective and trans-selective 1,4-dicarbofunctionalization of feedstock butadiene in a single operation. This simple and practical protocol could apply to a comprehensive scope of substrates. The neutral conditions show extraordinary tolerance for even highly base-sensitive functional groups.

Aryl Amination Using Soluble Weak Base Enabled by a Water-Assisted Mechanism

The amination of aryl halides has become one of the most commonly practiced C-N bond-forming reactions in pharmaceutical and laboratory syntheses. The widespread use of strong or poorly soluble inorganic bases for amine activation nevertheless complicates the compatibility of this important reaction class with sensitive substrates as well as applications in flow and automated synthesis, to name a few. We report a palladium-catalyzed C-N coupling using Et3N as a weak, soluble base, which allows a broad substrate scope that includes bromo- and chloro(hetero)arenes, primary anilines, secondary amines, and amide type nucleophiles together with tolerance for a range of base-sensitive functional groups. Mechanistic data have established a unique pathway for these reactions in which water serves multiple beneficial roles. In particular, ionization of a neutral catalytic intermediate via halide displacement by H2O generates, after proton loss, a coordinatively unsaturated Pd-OH species that can bind amine substrate triggering intramolecular N-H heterolysis. This water-assisted pathway operates efficiently with even weak terminal bases, such as Et3N. The use of a simple, commercially available ligand, PAd3, is key to this water-assisted mechanism by promoting coordinative unsaturation in catalytic intermediates responsible for the heterolytic activation of strong element-hydrogen bonds, which enables broad compatibility of carbon-heteroatom cross-coupling reactions with sensitive substrates and functionality.

Catalytic α-Hydroarylation of Acrylates and Acrylamides via an Interrupted Hydrodehalogenation Reaction.

The palladium-catalyzed, α-selective hydroarylation of acrylates and acrylamides is reported. Under optimized conditions, this method is highly tolerant of a wide range of substrates including those with base sensitive functional groups and/or multiple enolizable carbonyl groups. A detailed mechanistic study was undertaken, and the high selectivity of this transformation was shown to be enabled by the formation of a [PdII(Ar)(H)] intermediate, which performs selective hydride insertion into the β-position of α,β-unsaturated carbonyl compounds.

Nickel-Copper-Catalyzed Hydroacylation of Vinylarenes with Acyl Fluorides and Hydrosilanes.

The hydroacylation of vinylarenes with acyl fluorides and hydrosilanes was enabled by a synergistic bimetallic Ni/Cu-catalytic system, giving access to the corresponding branched ketone products. The reaction takes place under mild conditions at 25-80 °C and tolerates base-sensitive functional groups such as methoxycarbonyl and acetoxy groups.

Gold(i)-catalyzed Nicholas reaction with aromatic molecules utilizing a bifunctional propargyl dicobalt hexacarbonyl complex.

A benchtop-stable reagent for the catalytic Nicholas reaction was developed. By combining a propargyl dicobalt hexacarbonyl cluster with an ortho-alkynylbenzoate unit and a fluorous tag, introduction of a propargyl hexacarbonyl complex on various aromatic compounds having acid- or base-sensitive functional groups becomes possible by using a gold(i) catalyst. In addition, the presence of a fluorous tag facilitates convenient separation of the target products from byproducts.

Acyl/aroyl Meldrum’s acid as an enol surrogate for the direct organocatalytic synthesis of α,β-unsaturated ketones

The operationally simple, robust and straightforward organocatalytic protocol is developed for the synthesis of E-selective α,β-unsaturated ketones. The method utilizes simple and easily accessible starting materials such as Meldrum’s acid, carboxylic acid, aldehyde and simple bifunctional amine catalyst. The tandem organocatalytic process utilizes acyl/aroyl Meldrum’s acid as an enol surrogate for the effective Doebner-Knoevenagel type condensation reactions. A wide variety of aldehydes, carboxylic acids and base sensitive functional groups are well tolerated under the mild reaction conditions.

Breaking the Base Barrier: An Electron-Deficient Palladium Catalyst Enables the Use of a Common Soluble Base in C-N Coupling.

Due to the low intrinsic acidity of amines, palladium-catalyzed C-N cross-coupling has been plagued continuously by the necessity to employ strong, inorganic, or insoluble bases. To surmount the many practical obstacles associated with these reagents, we utilized a commercially available dialkyl triarylmonophosphine-supported palladium catalyst that facilitates a broad range of C-N coupling reactions in the presence of weak, soluble bases. The mild and general reaction conditions show extraordinary tolerance for even highly base-sensitive functional groups. Additionally, insightful heteronuclear NMR studies using 15N-labeled amine complexes provide evidence for the key acidifying effect of the cationic palladium center.

Mechanistic Insight Facilitates Discovery of a Mild and Efficient Copper-Catalyzed Dehydration of Primary Amides to Nitriles Using Hydrosilanes.

Metal-catalyzed silylative dehydration of primary amides is an economical approach to the synthesis of nitriles. We report a copper-hydride(CuH)-catalyzed process that avoids a typically challenging 1,2-siloxane elimination step, thereby dramatically increasing the rate of the overall transformation relative to alternative metal-catalyzed systems. This new reaction proceeds at ambient temperature, tolerates a variety of metal-, acid-, or base-sensitive functional groups, and can be performed using a simple ligand, inexpensive siloxanes, and low catalyst loading.

A General Protocol for the Broad-Spectrum Cross-Coupling of Nonactivated Sterically Hindered 1° and 2° Amines

While notable advances have been reported for the metal-catalyzed cross-coupling of bulky amines, to date no set of reported conditions has proven general for both hindered and unactivated primary and secondary amines. Examples that are reported with Pd catalysts invariably involve aggressive alkoxide bases in order to provide the necessary “push” required to couple these challenging substrates. Consequently, few, if any, base-sensitive functional groups (e.g., esters, ketones, cyano groups) are included in published reports involving such substrates. Herein we disclose the use of Pd-PEPPSI-IPentCl3-chloropyridine precatalyst with the mild, yet soluble base sodium butylated hydroxytoluene (NaBHT) in one single protocol that can couple a broad scope of hindered and unactivated primary and secondary amines to produce functionalized products in high yields.

Copper-catalyzed retro-aldol reaction of β-hydroxy ketones or nitriles with aldehydes: chemo- and stereoselective access to (E)-enones and (E)-acrylonitriles.

A copper-catalyzed transfer aldol type reaction of β-hydroxy ketones or nitriles with aldehydes is reported, which enables chemo- and stereoselective access to (E)-α,β-unsaturated ketones and (E)-acrylonitriles. A key step of the in situ copper(i)-promoted retro-aldol reaction of β-hydroxy ketones or nitriles is proposed to generate a reactive Cu(i) enolate or cyanomethyl intermediate, which undergoes ensuing aldol condensation with aldehydes to deliver the products. This reaction uses 1.2 mol% Cu(IPr)Cl (IPr denotes 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) as the catalyst in the presence of 6.0 mol% NaOtBu cocatalyst at room temperature or 70 °C. A range of aryl and heteroaryl aldehydes as well as acrylaldehydes are compatible with many useful functional groups being tolerated. Under the mild and weakly basic conditions, competitive Cannizzaro-type reaction of benzaldehydes and side reactions of base-sensitive functional groups can be effectively suppressed, which show synthetic advantages of this reaction compared to classic aldol reactions. The synthetic potential of this reaction is further demonstrated by the one-step synthesis of biologically active quinolines and 1,8-naphthyridine in excellent yields (up to 91%). Finally, a full catalytic cycle for this reaction has been constructed using DFT computational studies in the context of a retro-aldol/aldol two-stage mechanism. A rather flat reaction energy profile is found indicating that both stages are kinetically facile, which is consistent with the mild reaction conditions.

Gold-Catalyzed Proto- and Deuterodeboronation.

A mild gold-catalyzed protodeboronation reaction, which does not require acid or base additives and can be carried out in "green" solvents, is described. As a result, the reaction is very functional-group-tolerant, even to acid- and base-sensitive functional groups, and should allow for the boronic acid group to be used as an effective traceless directing or blocking group. The reaction has also been extended to deuterodeboronations for regiospecific ipso-deuterations of aryls and heteroaryls from the corresponding organoboronic acid. Based on density functional theory calculations, a mechanism is proposed that involves nucleophilic attack of water at boron followed by rate-limiting B-C bond cleavage and facile protonolysis of a Au-σ-phenyl intermediate.

Microwave-Assisted Condensation Reactions of Acetophenone Derivatives and Activated Methylene Compounds with Aldehydes Catalyzed by Boric Acid under Solvent-Free Conditions

We here disclosed a new protocol for the condensation of acetophenone derivatives and active methylene compounds with aldehydes in the presence of boric acid under microwave conditions. Implementation of the reaction is simple, healthy and environmentally friendly owing to the use of a non-toxic catalyst coupled to a solvent-free procedure. A large variety of known or novel compounds have thus been prepared, including with substrates bearing acid or base-sensitive functional groups.

Calcium Oxide Catalyzed Synthesis of Chalcone Under Microwave Condition

Calcium oxide was found to be an efficient solid base catalyst for synthesis of chalcone under microwave condition. We employed this method for the synthesis of various chalcone from various substituted ketone and aldehyde including o-hydroxy ketone and o-amino ketone. The merits of this method are inexpensive and easily available solid base catalyst, shorter reaction time, high yield compared to other reported methods, avoid use of toxic reagents and solvent free condition, and they are applicable to base sensitive functional groups. Keywords: Aldehyde, calcium oxide, chalcone, ecofriendly, ketone, microwave.

Efficient synthesis of oligosaccharyl 1,2-O-orthoesters from n-pentenyl glycosides and application to the pentaarabinofuranoside of the mycobacterial cell surface.

Complex oligosaccharide syntheses employ the use of more than one glycosyl donor and hence, methods for the interconversion of glycosyl donors are highly valuable for the overall synthesis plan. Herein, n-pentenyl glycosides are efficiently converted to glycosyl 1,2-O-orthoesters in the presence of both acid and base sensitive functional groups. The identified protocol was found to be suitable for the synthesis of trisaccharyl and tetrasaccharyl 1,2-O-orthoester as well. Furthermore, an iterative synthesis of pentaarabinofuranoside present on the Mycobacterium tuberculosis cell surface was accomplished using this method.

ChemInform Abstract: The Hexadehydro‐Diels—Alder Reaction: A New Chapter in Aryne Chemistry

AbstractReview: 22 refs.