Exploiting Nitroreductases for the Tailored Photoenzymatic Synthesis of Structurally Diverse Heterocyclic Compounds.

N-heterocyclic compounds have a broad range of applications and their selective synthesis is very appealing for the pharmaceutical and agrochemical industries. Herein we report the usage of the flavin-dependent nitroreductase BaNTR1 for the photoenzymatic synthesis of various anthranils and quinolines from retro-synthetically designed o-nitrophenyl-substituted carbonyl substrates, achieving high conversions (up to >99 %) and good product yields (up to 96 %). Whereas the effective production of anthranils required the inclusion of H2O2 in the reaction mixtures to accumulate the needed hydroxylamine intermediates, the formation of quinolines required the use of anaerobic or reducing conditions to efficiently generate the essential amine intermediates. Critical to our success was the high chemoselectivity of BaNTR1, performing selective reduction of the nitro group without reduction of the carbonyl moiety or the activated carbon-carbon double bond. The results highlight the usefulness of an innocuous chlorophyll- and nitroreductase-based photoenzymatic system for the tailored synthesis of diverse N-heterocycles from simple nitro compounds.

TBAI-Catalysed Formal [4+4]-Cycloaddition: Easy Access to Oxa-Bridged Eight-Membered Heterocycles.

TBAI-catalysed [4+4]-cyclization reaction of anthranils with hydrazones to deliver oxa-bridged eight-membered heterocycles in accepted yields was developed. Preliminary mechanistic studies indicated that the reaction involved the in situ generation of vinyldiazenes from readily available hydrazones followed by an aza-Michael addition of the anthranil substrates onto the vinyldiazenes and subsequent annulation. This transformation involved the formation of two new C-N bonds and C-O bond in one pot, overcoming the synthetic limitations of anthranils in organic chemistry. This strategy benefits from high efficiency and atomic economy with mild reaction conditions.

Gold-Catalyzed Iminations of Terminal Propargyl Alcohols with Anthranils with Atypical Chemoselectivity for C(1)-Additions and 1,2-Carbon Migration.

This work reports gold-catalyzed iminations of terminal propargyl alcohols with anthranils or isoxazoles to yield E-configured α-amino-2-en-1-ones and -1-als with complete chemoselectivity. These catalytic iminations occur exclusively with C(1)-nucleophilic additions on terminal alkynes, in contrast to a typical C(2)-route. For 3,3-dialkylprop-1-yn-3-ols, a methyl substituent is superior to long alkyl chains as the 1,2-migration groups toward α-imino gold carbenes. For secondary prop-1-yn-3-ols, phenyl, vinyl, and cyclopropyl substituents are better than hydrogen as the migrating groups, obviating typical gold carbene reactions. DFT calculations have been performed to rationalize the observed C(1)-regioselectivity and the preferable cyclopropyl migration based on gold carbene pathways.

Synthesis and process optimization of symmetric and unsymmetric barbiturates C5-coupled with 2,1-benzisoxazoles.

Benzisoxazoles represent an important pharmacophore in medicinal chemistry. Recently, an unexpected formation of symmetric 3-substituted 2,1-benzisoxazoles through reduction of 5-(2-nitrobenzylidene)barbiturates has been described. This reductive intramolecular heterocyclization probably involves a nitroso intermediary. To improve the previous reaction conditions, the nature of the reducing agent and additives, reaction time and solvents were evaluated. By applying the optimized conditions, several symmetric and unsymmetric barbiturates C5-coupled with 2,1-benzisoxazoles were prepared with an yield of 52-87%. From this set, seven compounds were novel and the unsymmetric nature of the (thio)barbituric acid moiety was explored. For that, the total synthesis, starting from the respective urea or thiourea, was successfully performed, and 11 thiobarbiturates, benzylidene barbiturate and thiobarbiturate precursors are described.

Gold(I)-Catalyzed Highly Diastereo- and Enantioselective Cyclization-[4+3] Annulation Cascades between 2-(1-Alkynyl)-2-alken-1-ones and Anthranils.

This work reports gold-catalyzed [4+3]-annulations of 2-(1-alkynyl)-2-alken-1-ones with anthranils to yield epoxybenzoazepine products with excellent exo-diastereoselectivity (dr>25:1). The utility of this new gold catalysis is manifested by applicable substrates over a broad scope. More importantly, the enantioselective versions of these [4+3]-cycloadditions have been developed satisfactorily with chiral gold catalysts under ambient conditions (DCM, 0 °C); the ee levels range from 88.0-99.9 %. With DFT calculations, we postulate a stepwise pathway to rationalize the preferable exo-stereoselection.

Acyl Migration versus Epoxidation in Gold Catalysis: Facile, Switchable, and Atom-Economic Synthesis of Acylindoles and Quinoline Derivatives.

We report a switchable synthesis of acylindoles and quinoline derivatives via gold-catalyzed annulations of anthranils and ynamides. α-Imino gold carbenes, generated in situ from anthranils and an N,O-coordinated gold(III) catalyst, undergo electrophilic attack to the aryl π-bond, followed by unexpected and highly selective 1,4- or 1,3-acyl migrations to form 6-acylindoles or 5-acylindoles. With the (2-biphenyl)di-tert-butylphosphine (JohnPhos) ligand, gold(I) carbenes experienced carbene/carbonyl additions to deliver quinoline oxides. Some of these epoxides are valuable substrates for the preparation of 3-hydroxylquinolines, quinolin-3(4H)-ones, and polycyclic compounds via facile in situ rearrangements. The reaction can be efficiently conducted on a gram scale and the obtained products are valuable substrates for preparing other potentially useful compounds. A computational study explained the unexpected selectivities and the dependency of the reaction pathway on the oxidation state and ligands of gold. With gold(III) the barrier for the formation of the strained oxirane ring is too high; whereas with gold(I) this transition state becomes accessible. Furthermore, energetic barriers to migration of the substituents on the intermediate sigma-complexes support the observed substitution pattern in the final product.

Pd-Catalyzed Dearomatization of Anthranils with Vinylcyclopropanes by [4+3] Cyclization Reaction.

Dearomatization of anthranils with vinylcyclopropanes (VCPs) by Pd-catalyzed [4+3] cyclization reaction has been realized. In the presence of a catalytic amount of borane as an activator, bridged cyclic products were obtained in good to excellent yields with excellent stereoselectivities. By introducing a chiral PHOX ligand (L5), asymmetric dearomatization reactions of anthranils with vinylcyclopropanes proceeded with excellent enantioselectivity. Borane plays a key role for the reactivity, likely owing to the formation of a borane-anthranil complex which has been confirmed by NMR experiments.

Gold-Catalyzed Regiospecific C-H Annulation of o-Ethynylbiaryls with Anthranils: π-Extension by Ring-Expansion En Route to N-Doped PAHs.

We describe a novel, short, and flexible approach to diverse N-doped polycyclic aromatic hydrocarbons (PAHs) through gold-catalyzed π-extension of anthranils with o-ethynylbiaryls as reagents. This strategy uses easily accessible starting materials, is simple due to high step and atom economy, and shows good functional-group compatibility as well as scale-up potential. Mechanistically, the tandem reaction is proposed to involve a nucleophilic addition/ring opening/regiospecific C-H annulation/protodeauration sequence terminated by a Friedel-Crafts-type cyclization. Photophysical studies of the products indicated violet-blue fluorescence emission with quantum yields up to 0.45.

Gold(III)-Catalyzed Site-Selective and Divergent Synthesis of 2-Aminopyrroles and Quinoline-Based Polyazaheterocycles.

A facile, site-selective, and divergent approach to construct 2-aminopyrroles and quinoline-fused polyazaheterocycles enabled by a simple gold(III) catalyst from ynamides and anthranils under mild reaction conditions is described. This one-pot strategy uses readily available starting materials, proceeds in a highly step- and atom-economical manner, with broad substrate scope and scale-up potential. The key element for success in this tandem reaction is a catalyst-directed preferred quenching of the in situ generated gold carbene intermediates by a nucleophilic benzyl/2-furylmethyl moiety on the ynamides as an alternative to the known C-H annulation leading to indoles.

Pd/C-Catalyzed Aminocarbonylation of Aryl Iodides with Anthranils in Water Using Mo(CO)6 as the CO Source.

A convenient procedure for the synthesis of N-(2-carbonylaryl)benzamides has been developed. Through Pd/C-catalyzed aminocarbonylation of anthranils with various hindered and functionalized aryl iodides, the desired amides were afforded in moderate to good yields. The protocol is advantageous due to the recyclable Pd/C catalyst, safe Mo(CO)6 as the solid CO source, and environmentally benign water as solvent. No inert atmosphere protection is needed.

Rh-Catalyzed Direct Amination of Unactivated C(sp(3) )-H bond with Anthranils Under Mild Conditions.

C-N Bond formation is of great significance due to the ubiquity of nitrogen-containing compounds. Here, a mild and efficient Rh(III) -catalyzed C(sp(3) )-H aryl amination reaction is reported. Anthranil is employed as the nitrogen source with 100 % atom efficiency. This C-H amination reaction exhibits broad substrate scope without using any external oxidants. Mechanistic studies including rhodacycle intermediates, H-D exchange, kinetic isotope effect (KIE) experiments, and in situ IR are presented.