Recent strategies used in the synthesis of saturated four-membered heterocycles.

The importance and prevalance of O-, N-, and S-atom containing saturated four-membered ring motifs in biologically active molecules and potential therapeutics continues to drive efforts in their efficient synthetic preparation. In this review, general and recent strategies for the synthesis of these heterocycles are presented. Due to the limited potential bond disconnections, retrosynthetic strategies are broadly limited to cyclizations and cycloadditions. Nonetheless, diverse approaches for accessing cyclization precursors have been developed, ranging from nucleophilic substitution to C-H functionalization. Innovative methods for substrate activation have been developed for cycloadditions under photochemical and thermal conditions. Advances in accessing oxetanes, azetidines, and thietanes remain active areas of research with continued breakthroughs anticipated to enable future applications.

Clinical Scenario of Venerophobia in Patients Presenting in Outpatient Department.

BACKGROUND: Venereophobia is fear of getting sexually transmitted disease after first or repeated unprotected sexual activities with unsafe or safe partners. This study aims to study the epidemiological profile, varying clinical presentations and spectrum of psychiatric diagnoses among venereophobia patients Methods: A cross-sectional, prospective and observational study was conducted among 72 consecutive patients of venereophobia. Patients with symptoms of fear of sexually transmitted infections were evaluated with relevant history and genital examination. Additionally psychiatric evaluation was done for associated diagnoses. Patients with symptoms and clinical signs of sexually transmitted infections were excluded from the study. RESULTS: A total of 68 male and 4 females presented with the symptoms. The mean age of presentation was 25.85±5.15 years. Most of them were either servicemen (38.8%) followed by students (23.6%). After a mean time of 11±10.44 days of sexual activity, patients developed symptoms. Common presentations were genital papules (25%), slough (22.2%) and genital itchy sensation (15.3%). A total of 23(33.8%) patients visited to commercial sex workers with mean spells of visiting 3.2±2.67 times. Factors as regular use of condom and knowledge of overall STI was lacking; while self investigation and multiple doctor visit was common. Pearly penile papule 18(25%) was the commonest diagnosis made on clinical examination. A total of 43 (59.7%) cases were diagnosed with psychiatric conditions, most common being anxiety neurosis (58.1%). CONCLUSIONS: Venereophobia was commonly found to be associated with psychiatric illnesses. A proper anamnesis, genital and psychiatric evaluation of this common entity may prevent misdiagnosis and associated complications.

K2CO3-Catalyzed Synthesis of 2,5-Dialkyl-4,6,7-tricyano-Decorated Indoles via Carbon-Carbon Bond Cleavage.

We describe a novel method to synthesize 2,5-dialkyl-4,6,7-tricyanoindole derivatives from a base-catalyzed reaction of 1,3-diketones with fumaronitrile. The reaction proceeds by the condensation of two molecules of fumaronitrile and one molecule of 1,3-diketone in a remarkable process that involves the cleavage of one C(sp3)-C(sp2) bond in 1,3-diketones and the formation of one carbon-nitrogen bond and four carbon-carbon bonds to construct both the aryl and pyrrole rings of the indole in one step.

Nickel-Catalyzed α-Carbonylalkylarylation of Vinylarenes: Expedient Access to γ,γ-Diarylcarbonyl and Aryltetralone Derivatives.

We report a Ni-catalyzed regioselective α-carbonylalkylarylation of vinylarenes with α-halocarbonyl compounds and arylzinc reagents. The reaction works with primary, secondary, and tertiary α-halocarbonyl molecules, and electronically varied arylzinc reagents. The reaction generates γ,γ-diarylcarbonyl derivatives with α-secondary, tertiary, and quaternary carbon centers. The products can be readily converted to aryltetralones, including a precursor to Zoloft, an antidepressant drug.

Ni(I)-Catalyzed ß,δ-Vinylarylation of γ,δ-Alkenyl α-Cyanocarboxylic Esters via Contraction of Transient Nickellacycles.

We disclose a transmetalation-initiated Ni(I)-catalyzed regioselective ß,δ-vinylarylation of γ,δ-alkenyl α-cyanocarboxylic esters with vinyl triflates and arylzinc reagents. This reaction proceeds via contraction of six-membered nickellacycles to five-membered nickellacycles to form carbon-carbon bonds at the nonclassical homovicinal sites, and it provides expeditious access to a wide range of complex aliphatic α-cyanoesters, α-cyanocarboxylic acids, dicarboxylic acids, dicarboxylic acid monoamides, monocarboxylic acids, nitriles, and spirolactones. Control, deuterium labeling, and crossover experiments indicate that (i) the nickellacycle contraction occurs by ß-H elimination, followed by hydronickellation on transiently formed alkenes, and (ii) the Ni species are stabilized as Ni-enolates.

Synergistic Bimetallic Ni/Ag and Ni/Cu Catalysis for Regioselective γ,δ-Diarylation of Alkenyl Ketimines: Addressing ß-H Elimination by in Situ Generation of Cationic Ni(II) Catalysts.

We disclose unprecedented synergistic bimetallic Ni/Ag and Ni/Cu catalysts for regioselective γ,δ-diarylation of unactivated alkenes in simple ketimines with aryl halides and arylzinc reagents. The bimetallic synergy, which generates cationic Ni(II) species during reaction, promotes migratory insertion and transmetalation steps and suppresses ß-H elimination and cross-coupling, the major side reactions that cause serious problems during alkene difunctionalization. This diarylation reaction proceeds at remote locations to imines to afford, after simple H+ workup, diversely substituted γ,δ-diaryl ketones that are otherwise difficult to access readily with existing methods.

Ni-Catalyzed Regioselective Alkylarylation of Vinylarenes via C(sp3)-C(sp3)/C(sp3)-C(sp2) Bond Formation and Mechanistic Studies.

We report a Ni-catalyzed regioselective alkylarylation of vinylarenes with alkyl halides and arylzinc reagents to generate 1,1-diarylalkanes. The reaction proceeds well with primary, secondary and tertiary alkyl halides, and electronically diverse arylzinc reagents. Mechanistic investigations by radical probes, competition studies and quantitative kinetics reveal that the current reaction proceeds via a Ni(0)/Ni(I)/Ni(II) catalytic cycle by a rate-limiting direct halogen atom abstraction via single electron transfer to alkyl halides by a Ni(0)-catalyst.

Ni-Catalyzed Regioselective ß,δ-Diarylation of Unactivated Olefins in Ketimines via Ligand-Enabled Contraction of Transient Nickellacycles: Rapid Access to Remotely Diarylated Ketones.

We disclose a [(PhO)3P]/NiBr2-catalyzed regioselective ß,δ-diarylation of unactivated olefins in ketimines with aryl halides and arylzinc reagents. This diarylation proceeds at remote locations to the carbonyl group to afford, after simple H+ workup, diversely substituted ß,δ-diarylketones that are otherwise difficult to access readily with existing methods. Deuterium-labeling and crossover experiments indicate that diarylation proceeds by ligand-enabled contraction of transient nickellacycles.

Ni-catalysed regioselective 1,2-diarylation of unactivated olefins by stabilizing Heck intermediates as pyridylsilyl-coordinated transient metallacycles.

We report a Ni-catalysed diarylation of unactivated olefins in dimethylpyridylvinylsilane by intercepting Heck C(sp3)-NiX intermediates, derived from aryl halides, with arylzinc reagents. This approach utilizes a modifiable pyridylsilyl moiety as a coordinating group that plays a dual role of intercepting oxidative addition species to promote Heck carbometallation, and stabilizing the Heck C(sp3)-NiX intermediates as transient metallacycles to suppress ß-hydride elimination, and facilitate transmetalation/reductive elimination. This method affords 1,2-diarylethylsilanes, which can be readily oxidized to 1,2-diarylethanols that occur as structural motifs in 3-aryl-3,4-dihydroisocoumarin and dihydrostilbenoid natural products.

Transition Metal-Catalyzed Dicarbofunctionalization of Unactivated Olefins.

Transition metal (TM)-catalyzed difunctionalization of unactivated olefins with two carbon-based entities is a powerful method to construct complex molecular architectures rapidly from simple and readily available feedstock chemicals. While dicarbofunctionalization of unactivated olefins has a long history typically with the use of either carbon monoxide to intercept C(sp3 )-[M] (alkyl-TM) species or substrates lacking in ß-hydrogen (ß-Hs), development of this class of reaction still remains seriously limited due to complications of ß-H elimination arising from the in situ-generated C(sp3 )-[M] intermediates. Over the years, different approaches have been harnessed to suppress ß-H elimination, which have led to the development of various types of olefin dicarbofunctionalization reactions even in substrates that generate C(sp3 )-[M] intermediates bearing ß-Hs with a wide range of electrophiles and nucleophiles. In this review, these developments will be discussed both through the lens of historical perspectives as well as the strategies scrutinized over the years to address the issue of ß-H elimination. However, this review article by no means is designed to be exhaustive in the field, and is merely presented to provide the readers an overview of the key reaction developments.

Ni-Catalyzed Regioselective Dicarbofunctionalization of Unactivated Olefins by Tandem Cyclization/Cross-Coupling and Application to the Concise Synthesis of Lignan Natural Products.

We disclose a (terpy)NiBr2-catalyzed reaction protocol that regioselectively difunctionalizes unactivated olefins with tethered alkyl halides and arylzinc reagents. The reaction shows an excellent functional group tolerance (such as ketones, esters, nitriles, and halides) and a moderate to good level of diastereoselectivity. The current cyclization/cross-coupling also tolerates molecules containing base-sensitive racemizable stereocenters, which are preserved without racemization during the reaction. This cyclization/cross-coupling provides a rapid access to (arylmethyl)carbo- and heterocyclic scaffolds, which occur widely as structural cores in various natural products and bioactive molecules. In order to show synthetic utility and generality, we have applied this new method in gram-scale quantities to the concise synthesis of six lignan natural products containing three different structural frameworks. We further conducted mechanistic investigations with radical probes and selectivity studies, which indicated that the current reaction proceeds via a single electron transfer (SET) process.

Strategies toward Dicarbofunctionalization of Unactivated Olefins by Combined Heck Carbometalation and Cross-Coupling.

The use of combined Heck carbometalation and cross-coupling remains one of the most powerful ways for the difunctionalization of unactivated olefins with organometallic reagents and organohalides. This synopsis will provide an overview of this reaction developed in the last three and a half decades. Herein, both the three-component and the two-component cyclization/cross-coupling processes will be reviewed with a focus on strategies utilized to overcome the complications of ß-hydride elimination from Heck C(sp3)-[M] intermediates, which usually functions as a major side reaction.

Ni-Catalyzed Regioselective 1,2-Dicarbofunctionalization of Olefins by Intercepting Heck Intermediates as Imine-Stabilized Transient Metallacycles.

We disclose a strategy for Ni-catalyzed dicarbofunctionalization of olefins in styrenes by intercepting Heck C(sp3)-NiX intermediates with arylzinc reagents. This approach utilizes a readily removable imine as a coordinating group that plays a dual role of intercepting oxidative addition species derived from aryl halides and triflates to promote Heck carbometalation and stabilizing the Heck C(sp3)-NiX intermediates as transient metallacycles to suppress ß-hydride elimination and facilitate transmetalation/reductive elimination steps. This method affords diversely substituted 1,1,2-triarylethyl products that occur as structural motifs in various natural products.