Stereoselective Alder-Ene Reactions of Bicyclo[1.1.0]butanes: Facile Synthesis of Cyclopropyl- and Aryl-Substituted Cyclobutenes.

Bicyclo[1.1.0]butanes (BCBs), strained carbocycles comprising two fused cyclopropane rings, have become well-established building blocks in organic synthesis, medicinal chemistry, and chemical biology due to their diverse reactivity profile with radicals, nucleophiles, cations, and carbenes. The constraints of the bicyclic ring system confer high p-character on the interbridgehead C-C bond, leading to this broad reaction profile; however, the use of BCBs in pericyclic processes has to date been largely overlooked in favor of such stepwise, non-concerted additions. Here, we describe the use of BCBs as substrates for ene-like reactions with strained alkenes and alkynes, which give rise to cyclobutenes decorated with highly substituted cyclopropanes and arenes. The former products are obtained from highly stereoselective reactions with cyclopropenes, generated in situ from vinyl diazoacetates under blue light irradiation (440 nm). Cyclobutenes featuring a quaternary aryl-bearing carbon atom are prepared from equivalent reactions with arynes, which proceed in high yields under mild conditions. Mechanistic studies highlight the importance of electronic effects in this chemistry, while computational investigations support a concerted pathway and rationalize the excellent stereoselectivity of reactions with cyclopropenes.

Lewis acid-catalyzed one-pot thioalkenylation of donor-acceptor cyclopropanes using in situ generated dithiocarbamates and propiolates.

Lewis acid-catalyzed one-pot 1,3-thioalkenylation of donor-acceptor (D-A) cyclopropanes has been demonstrated employing in situ generated dithiocarbamates (from amines and CS2) as nucleophilic triggers and alkyl propiolates as electrophiles. This method addresses the limitations of previously known carbothiolation approach, eliminating the need for extra filtration prior to the subsequent trapping with electrophiles. The anticipated thioalkenylated products were obtained in good to excellent yields with a moderate to good E/Z ratio. Three new bonds (C-N, C-S, and C-C) are formed during this 1,3-bisfunctionalization reaction. Notably, employing enantiomerically pure D-A cyclopropanes resulted in enantiopure 1,3-thioalkenylated products, underscoring the stereospecific nature of the developed reaction.

Lewis Acid-Catalyzed Unusual (4+3) Annulation of para-Quinone Methides with Bicyclobutanes: Access to Oxabicyclo[4.1.1] octanes.

Over the past few years, there has been a surge of interest in the chemistry of bicyclobutanes (BCBs). Although BCBs have been used to synthesize bicyclo[2.1.1]hexanes and bicyclo[3.1.1]heptanes, the synthesis of bicyclo[4.1.1]octanes has remained elusive. Herein, we report the first Lewis acid-catalyzed unexpected (4+3) annulation of para-quinonemethides (p-QMs) with BCBs allowing the synthesis of oxabicyclo[4.1.1]octanes proceeding under mild conditions. With 5 mol % of Bi(OTf)3, the reaction afforded the (4+3) annulated product in high regioselectivity and good functional group compatibility via a simultaneous Lewis acid activation of BCBs and p-QMs. The reaction is likely initiated by the 1,6-addition of Lewis acid activated BCBs to p-QMs followed by the C2-selective intramolecular addition of the phenol moiety to the generated cyclobutyl cation intermediate. Moreover, detailed mechanistic studies provided insight into the mechanism of the reaction.

Ring-Opening 1,3-Carbothiolation of Donor-Acceptor Cyclopropanes Using Alkyl Halides and In Situ Generated Dithiocarbamates.

Two-step, ring-opening 1,3-carbothiolation of donor-acceptor (D-A) cyclopropanes employing alkyl halides and in situ generated dithiocarbamates (from amines and CS2) has been demonstrated under mild conditions. The reaction is operationally simple and works with good functional group compatibility. Three new bonds including C-N, C-S, and C-C are formed in this 1,3-bifunctionalization strategy. Electron-poor olefins can also be used as electrophiles instead of alkyl halides. The use of enantiomerically pure D-A cyclopropane afforded enantiopure 1,3-carbothiolated product, thus demonstrating the stereospecificity of the reaction.

An Observational Study on Metabolic Derangements in People Living with HIV.

BACKGROUND: HIV infection is a global pandemic. The adult HIV prevalence in India is 0.22%. Successful therapy is transforming HIV into a chronic medical condition, and there are many metabolic complications. This study aimed to evaluate the metabolic abnormalities in people living with HIV (PLHIV) who were on antiretroviral therapy (ART) for at least 2 years and compare it with ART-naïve patients as well as the effect of protease inhibitor-based (PI-based) and non-protease inhibitor-based (non-PI-based) ART was assessed. METHODOLOGY: Adult HIV-positive patients both ART-naïve and on ART for more than 2 years were included. Detailed history and clinical examination, including blood pressure and anthropometric measurements were done. This was followed by investigations like lipid profile including total cholesterol, triglyceride, high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), fasting plasma glucose, and hemoglobin A1c (HbA1C) estimation. Standard statistical tools were utilized to assess derangements and association to therapy. RESULTS: The study was conducted for 1.5 years in a tertiary care hospital. A total of 70% of the study population was male with mean age of participants being 43.2 years, 40% were ART-naïve, 37% received non-PI-based ART, and 23% PI-based ART. The mean total cholesterol level and mean triglyceride value were significantly higher in the PI-based ART group than in the therapy-naïve group. The ART-naïve group was seen to have more subjects with abnormally low HDL-C values. The PI-based ART study subjects were found to have a greater number of cases of glucose intolerance in relation to the rest of the two groups significantly (p-value <0.001). The LDL-C systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI), and waist circumference had no association with the different ART regimens or with the HIV infection itself. CD4 T cell count at diagnosis in the three study groups was compared with all the variables of metabolic syndrome and no association was found. CONCLUSION: Total cholesterol, triglycerides, and glucose levels are the main parameters found to be affected in PLHIV on therapy.

Transition-Metal-Free C2-Functionalization of Pyridines through Aryne Three-Component Coupling.

The direct C2-functionalization of pyridines through a transition-metal-free protocol by using aryne multicomponent coupling is demonstrated. The reaction allowed a broad-scope synthesis of C2-substituted pyridine derivatives bearing the -CF3 group in good yields with α,α,α-trifluoroacetophenones as the third component. Activated keto esters could also be employed as the third component in this formal 1,2-di(hetero)arylation of ketones. Performing the reaction under dilute conditions inhibited the competing pyridine-aryne polymerization pathway. Nucleophilic attack by the initially generated pyridylidene intermediate on the carbonyl followed by an SN Ar process resembling the Smiles rearrangement affords the desired products.

Selective Synthesis of N-H and N-Aryl Benzotriazoles by the [3 + 2] Annulation of Sodium Azide with Arynes.

The synthetic utility of NaN3 as the azide component in the [3 + 2] annulation with arynes generated from 2-(trimethylsilyl)aryltriflates resulting in the transition-metal-free synthesis of N-H and N-aryl benzotriazoles has been demonstrated. Using CsF as the fluoride source in CH3CN, the N-H benzotriazoles are formed in high selectivity instead of the expected azidobenzene. Interestingly, N-aryl benzotriazoles are formed using KF and THF as solvent in an open-flask reaction. Moreover, a method for the N1-arylation of benzotriazole is also presented.

Formal [4 + 2] benzannulation of 2-alkenyl indoles with aldehydes: a route to structurally diverse carbazoles and bis-carbazoles.

Construction of structurally diverse carbazoles and bis-carbazoles by protecting-group-free formal [4 + 2]-benzannulation of 2-alkenyl indoles and aldehydes is demonstrated. The sequence of four different reactions is executed in one-pot using readily available and cheap bottle reagents as catalysts rendering this method attractive. The incorporation of inexpensive and environmentally benign molecular oxygen as the oxidant into the final aromatization step enables tolerance of several functional groups.

Lewis acid-catalyzed diastereoselective formal ene reaction of thioindolinones/thiolactams with bicyclobutanes.

Bicyclo[1.1.0]butanes (BCBs), featuring two fused cyclopropane rings, have found widespread application in organic synthesis. Their versatile reactivity towards radicals, nucleophiles, cations, and carbenes makes them suitable for various reactions, including ring-opening and annulation strategies. Despite this versatility, their potential as enophiles in an ene reaction remains underexplored. Considering this and given the challenges of achieving diastereoselectivity in ring-opening reactions of BCBs, herein, we present a unique method utilizing BCBs as enophiles in a mild and diastereoselective Sc(OTf)3-catalyzed formal ene reaction with thioindolinones/thiolactams, delivering 1,3-disubstituted cyclobutane derivatives in high yields and excellent regio- and diastereoselectivity. Notably, structurally different thiolactam derivatives underwent diastereoselective addition to BCBs, affording the corresponding cyclobutanes. The synthesized thioindole-substituted cyclobutanes could serve as a versatile tool for subsequent functional group manipulations.

Benzotriazole-Triggered Three-Component Lewis Acid-Catalyzed Ring-Opening 1,3-Aminofunctionalization of Donor-Acceptor Cyclopropanes.

The use of benzotriazoles as nucleophilic triggers in the three-component Yb(OTf)3-catalyzed ring-opening 1,3-aminofunctionalization of donor-acceptor (D-A) cyclopropanes is presented. Using N-halo succinimide (NXS) as the third component, the reaction afforded the 1,3-aminohalogenation product in up to an 84% yield. Moreover, using alkyl halides or Michael acceptors as the third components, the 3,1-carboaminated products are formed in up to a 96% yield in a one-pot operation. Employing Selectfluor as the electrophile, the reaction furnished the 1,3-aminofluorinated product in a 61% yield.

Lewis acid-catalyzed diastereoselective carbofunctionalization of bicyclobutanes employing naphthols.

Traditional radical-mediated ring-opening of bicyclo[1.1.0]butanes (BCBs) for cyclobutane synthesis suffers from poor diastereoselectivity. Although few reports on BCB ring-opening via polar mechanisms are available, the Lewis acid-catalyzed diastereoselective ring-opening of BCBs using carbon nucleophiles is still underdeveloped. Herein, we report a mild and diastereoselective Bi(OTf)3-catalyzed ring-opening of BCBs employing 2-naphthols. The anticipated carbofunctionalized trisubstituted cyclobutanes were obtained via a bicoordinated bismuth complex and the products are formed in good to excellent yields with high regio- and diastereoselectivity. The scope of the reaction was further extended using electron-rich phenols and naphthylamine. The functionalization of the synthesized trisubstituted cyclobutanes shows the synthetic utility of the present method.

Synthesis of Trisubstituted Oxazoles via Aryne Induced [2,3] Sigmatropic Rearrangement-Annulation Cascade.

A transition-metal-free, [2,3] sigmatropic rearrangement-annulation cascade of 2-substituted thio/amino acetonitriles with arynes allowing the synthesis of 2,4,5-trisubstituted oxazoles under mild conditions has been demonstrated. The key sulfur/nitrogen ylides were generated by the initial S/N arylation followed by proton transfer, which was followed by the selective [2,3] sigmatropic rearrangement involving the -CN moiety and a subsequent annulation to afford the desired products in reasonable yields.

Three-Component, Diastereoselective [6 + 3] Annulation of Tropone, Imino Esters, and Arynes.

A transition-metal-free, three-component, and diastereoselective [6 + 3] annulation reaction employing tropone, imino esters, and arynes allowing the synthesis of bridged azabicyclo[4.3.1]decadienes is demonstrated. The key nitrogen ylides for the [6 + 3] annulation were generated by the addition of imino esters to the arynes followed by a proton transfer. The nitrogen ylides undergo a regioselective addition to tropone to furnish the desired products in moderate to good yields with good functional group tolerance under mild conditions.

An Umpolung Oxa-[2,3] Sigmatropic Rearrangement Employing Arynes for the Synthesis of Functionalized Enol Ethers.

An oxa-[2,3] sigmatropic rearrangement involving arynes is reported featuring the umpolung of ketones, where the C═O bond polarity is reversed. The in situ-generated sulfur ylides from ß-keto thioethers and arynes undergo efficient rearrangement allowing the facile and robust synthesis of functionalized enol ethers in high yields and excellent functional group compatibility. Preliminary mechanistic studies rule out the possibility of Pummerer-type rearrangement operating in this case.

Thiophenols as Protic Nucleophilic Triggers in Aryne Three-Component Coupling.

The synthetic potential of thiophenols as a protic nucleophilic trigger in the transition-metal-free and Grignard-reagent-free three-component coupling involving arynes is demonstrated. Employing aldehydes as the third component, the reaction allowed the mild and broad scope synthesis of 2-arylthio benzyl alcohol derivatives in good yields. Moreover, selenophenol could be used as the nucleophilic trigger, and activated ketones could be used as the third component in this reaction.

Lewis Acid Catalyzed Ring-Opening 1,3-Aminothiolation of Donor-Acceptor Cyclopropanes Using Sulfenamides.

Yb(OTf)3 catalyzed mild and regioselective ring-opening 1,3-aminothiolation of donor-acceptor (D-A) cyclopropanes using sulfenamides has been demonstrated. The insertion of the C-C σ-bond of D-A cyclopropanes into the S-N σ-bond of sulfenamides allows the synthesis of diverse γ-aminated α-thiolated malonic diesters in moderate to good yields (up to 87%) with good functional group compatibility. The stereospecificity of the reaction was demonstrated using enantiomerically pure D-A cyclopropane.

Iodide as a Nucleophilic Trigger in Aryne Three-Component Coupling for the Synthesis of 2-Iodobenzyl Alcohols.

The synthetic potential of KI as the iodide source in aryne three-component coupling has been demonstrated using aldehydes as the third component. This mild and transition-metal-free coupling reaction allowed the straightforward synthesis of 2-iodobenzyl alcohols in moderate to good yields with good functional group compatibility. Moreover, KBr and KCl could be used as the nucleophilic trigger in this aryne multicomponent coupling (MCC) and N-methylisatin and CO2 could be used as the electrophilic third components.

Three-Component Aminoselenation of Arynes.

The three-component coupling of tertiary amines, arynes, and aryl selenium bromide or diaryl diselenide as an electrophilic selenium source allowing the synthesis of 2-selanyl aniline derivatives is reported. This aminoselenation reaction of arynes installs a C-N and C-Se bond under mild conditions, and the products are formed in moderate to good yields. This reaction is compatible with various functional groups, and the preliminary studies on the mechanism of the reaction is also provided.