Brønsted Acid-Catalyzed Synthesis of 4-Functionalized Tetrahydrocarbazol-1-ones from 1,4-Dicarbonylindole Derivatives.

A p-toluenesulfonic acid-catalyzed cascade reaction is reported for the synthesis of 4-functionalized tetrahydrocarbazolones via the reaction of 4-(indol-2-yl)-4-oxobutanal derivatives with a variety of nucleophiles in acetonitrile or hexafluoroisopropanol. After the initial intramolecular Friedel-Crafts hydroxyalkylation, the 3-indolylmethanol intermediate is subsequently activated and reacted with the external nucleophile. The reaction conditions are crucial to avoid alternative reaction pathways, allowing direct substitution reaction with thiols, (hetero)arenes, alkenes, or sulfinates. The procedure features high overall yields to access a diverse family of compounds bearing the tetrahydrocarbazole core.

Synthesis of 1,4-ketoaldehydes and 1,4-diketones by Mo-catalyzed oxidative cleavage of cyclobutane-1,2-diols.

A new two-step procedure for the synthesis of 1,4-dicarbonyls has been developed involving an efficient and clean Mo-catalyzed oxidative cleavage of cyclobutane-1,2-diols with DMSO, which is used as solvent and oxidant. The required starting glycols were prepared by nucleophilic additions of organolithiums and Grignard reagents to easily available 2-hydroxycyclobutanones.

Direct synthesis of haloaromatics from nitroarenes via a sequential one-pot Mo-catalyzed reduction/Sandmeyer reaction.

Herein, we report the direct synthesis of a wide variety of functionalized aromatic bromides, chlorides, iodides, and fluorides from nitroarenes in a sequential one-pot operation. This protocol is based on an air- and moisture-tolerant dioxomolybdenum-catalyzed reduction of nitroaromatics, employing pinacol as a reducing agent, which enables subsequent diazotization and halogenation steps. This methodology represents a step-economical, practical, and alternative procedure for synthesizing haloaromatics directly from nitroaromatics.

Transition Metal-Free Synthesis of Halobenzo[b]furans from O-Aryl Carbamates via o-Lithiation Reactions.

A straightforward and transition metal-free one-pot protocol to synthesize halobenzo[b]furans has been developed employing simple and easily available starting materials such as O-aryl carbamates and alkynylsulfones. The fine-tuning of the different steps involved was key to achieving a successful one-pot procedure. Initially, a directed ortho-lithiation process, which uses the carbamate as the directed metalation group, was crucial in providing access to O-2-alkynylaryl N,N-diethyl carbamates by a direct alkynylation of the o-lithiated carbamate, with arylsulfonylalkynes as electrophilic reagents. Cyclization of the generated o-alkynylaryl carbamates was successfully accomplished through a strategy involving in situ carbamate alkaline hydrolysis under conventional heating or microwave irradiation, coupled with a subsequent heterocyclization step delivering the desired benzo[b]furans. A wide variety of new halobenzo[b]furans has been synthesized and their utility has been demonstrated by their further transformation.

Asymmetric Gold(I)-Catalyzed Tandem Hydroarylation-Nazarov Cyclization: Enantioselective Access to Cyclopentenones.

The asymmetric synthesis of cyclopentachromenones from gold-catalyzed reaction of readily available skipped alkenynones is described. This cascade reaction involves an initial anti-Michael hydroarylation of the ynone moiety to form a gold-functionalized dialkenylketone intermediate, followed by a Nazarov cyclization that proceeds in an unprecedented enantioselective manner. Excellent enantiomeric ratios and chemical yields are obtained under mild reaction conditions.

Mo-Catalyzed One-Pot Synthesis of N-Polyheterocycles from Nitroarenes and Glycols with Recycling of the Waste Reduction Byproduct. Substituent-Tuned Photophysical Properties.

A catalytic domino reduction-imine formation-intramolecular cyclization-oxidation for the general synthesis of a wide variety of biologically relevant N-polyheterocycles, such as quinoxaline- and quinoline-fused derivatives, and phenanthridines, is reported. A simple, easily available, and environmentally friendly dioxomolybdenum(VI) complex has proven to be a highly efficient and versatile catalyst for transforming a broad range of starting nitroarenes involving several redox processes. Not only is this a sustainable, step-economical as well as air- and moisture-tolerant method, but also it is worth highlighting that the waste byproduct generated in the first step of the sequence is recycled and incorporated in the final target molecule, improving the overall synthetic efficiency. Moreover, selected indoloquinoxalines have been photophysically characterized in cyclohexane and toluene with exceptional fluorescence quantum yields above 0.7 for the alkyl derivatives.

From Propargylic Alcohols to Substituted Thiochromenes: gem-Disubstituent Effect in Intramolecular Alkyne Iodo/hydroarylation.

This work describes the 6-endo-dig cyclization of S-aryl propargyl sulfides to afford 2H-thiochromenes. The substitution at the propargylic position plays a crucial role in allowing intramolecular silver-catalyzed alkyne hydroarylation and N-iodosuccinimide-promoted iodoarylation. Additionally, a PTSA-catalyzed thiolation reaction of propargylic alcohols was developed to synthesize the required tertiary S-aryl propargyl ethers. The applicability of merging these two methods is demonstrated by synthesizing the retinoic acid receptor antagonist AGN194310.

Deoxygenation reactions in organic synthesis catalyzed by dioxomolybdenum(VI) complexes.

Dioxomolybdenum(VI) complexes have been applied as efficient, inexpensive and benign catalysts to deoxygenation reactions of a diverse number of compounds in the last two decades. Dioxomolybdenum complexes have demonstrated wide applicability to the deoxygenation of sulfoxides into sulfides and reduction of N-O bonds. Even the challenging nitro functional group was efficiently deoxygenated, affording amines or diverse heterocycles after reductive cyclization reactions. More recently, carbon-based substrates like epoxides, alcohols and ketones have been successfully deoxygenated. Also, dioxomolybdenum complexes accomplished deoxydehydration (DODH) reactions of biomass-derived vicinal 1,2-diols, affording valuable alkenes. The choice of the catalytic systems and reductant is decisive to achieve the desired transformation. Commonly found reducing agents involved phosphorous-based compounds, silanes, molecular hydrogen, or even glycols and other alcohols.

Unlocking the 5-exo Pathway with the AuI -Catalyzed Alkoxycyclization of 1,3-Dien-5-ynes.

The first general regio- and stereoselective 5-exo gold(I)-catalyzed alkoxycyclization of a specific class of 1,5-enynes such as 1,3-dien-5-ynes has been described, despite 1,5-enynes being known to almost invariably proceed via endo cyclizations under gold-catalysis. The configuration of the terminal alkene in the starting 1,3-dien-5-yne plays a crucial role on the regiochemical outcome of the reaction. A wide variety of interesting alkoxy-functionalized alkylidenecyclopentenes have been synthesized from 1-monosubstituted (E)-1,3-dien-5-ynes. On the contrary, the corresponding Z isomers evolve affording formal 6-endo cyclization products. In addition, mechanistic exploration supports a highly stabilized carbocation as a key intermediate instead of a highly constrained cyclopropyl gold carbene from E isomers, and also accounts for the well differentiated reactivity observed between both E/Z geometrical isomers as well as for the stereochemical outcome of the reaction.

Experimental and Computational Study of the 1,5-O → N Carbamoyl Snieckus-Fries-Type Rearrangement.

The reactions of o-lithiated O-aryl N,N-diethylcarbamates with different C-N multiple bond electrophiles have been thoroughly studied. A 1,5-O → N carbamoyl shift, a new variation of the anionic Fries-type rearrangement, takes place when nitriles, imines, or alkylcarbodiimides are employed. In these cases, the carbamoyl group plays a dual role as a directing group, building up a variety of functional groups through the 1,5-O → N carbamoyl migration. On the other hand, the use of iso(thio)cyanates and arylcarbodiimides led to non-rearranged o-functionalized O-arylcarbamates. This reactivity was further computationally explored, and the governing factor could be traced back to the relative basicity of the alternative products (migrated vs nonmigrated substrates). This exploration also provided interesting insights about the degree of complexation of the lithium cations onto these substrates. A new access to useful 2-hydroxybenzophenone derivatives has also been developed.

Gold(i)-catalyzed nucleophilic cyclization of ß-monosubstituted o-(alkynyl)styrenes: a combined experimental and computational study.

The stereospecific gold(i)-catalyzed nucleophilic cyclization of ß-monosubstituted o-(alkynyl)styrenes to produce C-1 functionalized 1H-indenes including challenging substrates and nucleophiles, such as ß-(cyclo)alkyl-substituted o-(alkynyl)styrenes and a variety of alcohols as well as selected electron-rich aromatics, is reported. DFT calculations support the stereochemical outcome of the process that involves the formation of a key cyclopropyl gold carbene intermediate through a regiospecific 5-endo cyclization.

Reductive Molybdenum-Catalyzed Direct Amination of Boronic Acids with Nitro Compounds.

The synthesis of aromatic amines is of utmost importance in a wide range of chemical contexts. We report a direct amination of boronic acids with nitro compounds to yield (hetero)aryl amines. The novel combination of a dioxomolybdenum(VI) catalyst and triphenylphosphine as inexpensive reductant has revealed to be decisive to achieve this new C-N coupling. Our methodology has proven to be scalable, air and moisture tolerant, highly chemoselective and engages both aliphatic and aromatic nitro compounds. Moreover, this general and step-economical synthesis of aromatic secondary amines showcases orthogonality to other aromatic amine syntheses as it tolerates aryl halides and carbonyl compounds.

Gold(i)-catalyzed diastereoselective synthesis of 1-α-oxybenzyl-1H-indenes.

The gold(i)-catalyzed oxycyclization of ß-aryl monosubstituted o-(alkynyl)styrenes gives rise to 1-α-methoxy or 1-α-hydroxybenzyl-1H-indenes in a diastereospecific way. In contrast to ß,ß-disubstituted o-(alkynyl)styrenes, the stereochemical outcome of this process, diastereospecific reaction supports the higher contribution of a gold intermediate with a cyclopropylcarbene-like character.

1,3-Dien-5-ynes: Versatile Building Blocks for the Synthesis of Carbo- and Heterocycles.

1,3-Dien-5-ynes have been extensively used as starting materials for the synthesis of a wide number of different carbo- and heterocycles. The aim of this review is to give an overview of their utility in organic synthesis, highlighting the variety of compounds that can be directly accessed from single reactions over these systems. Thus, cycloaromatization processes are initially commented, followed by reactions directed toward the syntheses of five-membered rings, other carbocycles and, finally, heterocycles. The diverse methodologies that have been developed for the synthesis of each of these types of compounds from 1,3-dien-5-ynes are presented, emphasizing the influence of the reaction conditions and the use of additional reagents in the outcome of the transformations.

Synthesis of Functionalized 1H-Indenes and Benzofulvenes through Iodocyclization of o-(Alkynyl)styrenes.

A convenient method for the preparation of synthetically useful 3-iodoindene derivatives has been developed. This protocol, based on the 5-endo iodocyclization reaction of o-(alkynyl)styrenes, represents one of the scarce examples of halocyclizations using olefins as nucleophilic counterparts and allows the synthesis of both 3-iodo-1H-indenes (from ß-alkyl-ß-alkyl/aryl-o-(alkynyl)styrenes) and 3-iodobenzofulvenes (from ß,ß-diaryl-o-(alkynyl)styrenes) in good yields under mild reaction conditions. In addition, related alkoxyiodocyclization processes are described, which are particularly interesting in their intramolecular version because they allow the synthesis of heteropolycyclic structures containing the indene core. Finally, the usefulness of the prepared 3-iodoindenes has been demonstrated by the synthesis of several polysubstituted indene derivatives through conventional palladium-catalyzed cross-coupling reactions and iodine-lithium exchange processes.

Exploring the Reactivity of α-Lithiated Aryl Benzyl Ethers: Inhibition of the [1,2]-Wittig Rearrangement and the Mechanistic Proposal Revisited.

By carefully controlling the reaction temperature, treatment of aryl benzyl ethers with tBuLi selectively leads to α-lithiation, generating stable organolithiums that can be directly trapped with a variety of selected electrophiles, before they can undergo the expected [1,2]-Wittig rearrangement. This rearrangement has been deeply studied, both experimentally and computationally, with aryl α-lithiated benzyl ethers bearing different substituents at the aryl ring. The obtained results support the competence of a concerted anionic intramolecular addition/elimination sequence and a radical dissociation/recombination sequence for explaining the tendency of migration for aryl groups. The more favored rearrangements are found for substrates with electron-poor aryl groups that favor the anionic pathway.

A Radical Mechanism for the Vanadium-Catalyzed Deoxydehydration of Glycols.

We propose a novel mechanism for the deoxydehydration (DODH) reaction of glycols catalyzed by a [Bu4N][VO2(dipic)] complex (dipic = pyridine-2,6-dicarboxylate) using triphenylphosphine as a reducing agent. Using density functional theory, we have confirmed that the preferred sequence of reaction steps involves reduction of the V(V) complex by phosphine, followed by condensation of the glycol into a [VO(dipic)(-O-CH2CH2-O-)] V(III) complex (6), which then evolves to the alkene product, with recovery of the catalyst. In contrast to the usually invoked closed-shell mechanism for the latter steps, where 6 suffers a [3+2] retrocycloaddition, we have found that the homolytic cleavage of one of the C-O bonds in 6 is preferred by 12 kcal/mol. The resulting diradical intermediate then collapses to a metallacycle that evolves to the product through an aromatic [2+2] retrocycloaddition. We use this key change in the mechanism to propose ways to design better catalysts for this transformation. The analysis of the mechanisms in both singlet and triplet potential energy surfaces, together with the location of the MECPs between them, showcases this reaction as an interesting example of two-state reactivity.

Synthesis of α-functionalized α-indol-3-yl carbonyls through direct SN reactions of indol-3-yl α-acyloins.

A new and efficient synthesis of α-functionalized α-indol-3-yl ketones from easily available indolyl α-acyloins is reported. This process, catalyzed by Brønsted or Lewis acids, involves an uncommon direct nucleophilic substitution reaction of a secondary α-carbonyl-substituted hydroxyl group. The described methodology allows the introduction of a variety of nucleophiles such as (hetero)arenes, thiophenols, nitroanilines and 1,3-dicarbonyl derivatives. The synthesized α-indol-3-yl carbonyl compounds are important synthetic targets also useful for accessing functionalized tryptophols and furan-3-yl indoles.

Brønsted Acid-Catalyzed Cascade Reactions Involving 1,2-Indole Migration.

A cascade reaction of indoles with propargylic diols involving an unprecedented metal-free 1,2-indole migration onto an alkyne was carried out. DFT calculations support a mechanism consisting of a concerted nucleophilic attack of the indole nucleus with loss of water, followed by the 1,2-migration and subsequent Nazarov cyclization. This Brønsted acid-catalyzed protocol affords indole-functionalized benzofulvene derivatives in high yields.

Gold(I)-catalyzed cycloisomerizations and alkoxycyclizations of ortho-(alkynyl)styrenes.

Indenes and related polycyclic structures have been efficiently synthesized by gold(I)-catalyzed cycloisomerizations of appropriate ortho-(alkynyl)styrenes. Disubstitution at the terminal position of the olefin was demonstrated to be essential to obtain products originating from a formal 5-endo-dig cyclization. Interestingly, a complete switch in the selectivity of the cyclization of o-(alkynyl)-α-methylstyrenes from 6-endo to 5-endo was observed by adding an alcohol to the reaction media. This allowed the synthesis of interesting indenes bearing an all-carbon quaternary center at C1. Moreover, dihydrobenzo[a]fluorenes can be obtained from substrates bearing a secondary alkyl group at the ß-position of the styrene moiety by a tandem cycloisomerization/1,2-hydride migration process. In addition, diverse polycyclic compounds were obtained by an intramolecular gold-catalyzed alkoxycyclization of o-(alkynyl)styrenes bearing a nucleophile in their structure. Finally, the use of a chiral gold complex allowed access to elusive chiral 1H-indenes in good enantioselectivities.