Deciphering substitution effects on reductive hydroalkoxylation of alkynyl aminols for stereoselective synthesis of morpholines and 1,4-oxazepanes: total synthesis of tridemorph and fenpropimorph.

Acid catalysed reductive etherification of N-propargyl amino alcohols for the stereoselective synthesis of cis-2,5/2,6-disubstituted morpholines and cis-2,6/2,7-disubstituted oxazepanes has been developed. Mechanistic studies revealed that terminal alkynols gave morpholines via a 6-exo-dig hydroalkoxylation-isomerization-reduction cascade. Interestingly, an alkyne hydration-cyclization-reduction sequence is found to be involved in the formation of oxazepanes from alkyl substituted internal alkynols. The strategy was used as a key step in the total synthesis of fungicides tridemorph and fenpropimorph.

Cu(II)/PTABS-Promoted, Regioselective SNAr Amination of Polychlorinated Pyrimidines with Mechanistic Understanding.

Regioselective amination of polyhalogenated heteroarenes (especially pyrimidines) has extensive synthetic and commercial relevance for drug synthesis applications but is plagued by the lack of effective synthetic strategies. Herein, we report the Cu(II)/PTABS-promoted highly regioselective nucleophilic aromatic substitution (SNAr) of polychlorinated pyrimidines assisted by DFT predictions of the bond dissociation energies of different C-Cl bonds. The unique reactivity of Cu(II)-PTABS has been attributed to the coordination/activation mechanism that has been known to operate in these reactions, but further insights into the catalytic species have also been provided.

Recent Advances in Small Molecule-Based Intracellular pH Probes.

Intracellular pH plays an important role in many biological and pathological processes. Small-molecule based pH probes are found to be the most effective for pH sensing because of ease of preparation, high sensitivity, and quick response. They have many advantages such as small perturbation to the functions of the target, functional adaptability, cellular component-specific localization, etc. The present review highlights the flurry of recent activity in the development of such probes. The probes are categorized based on the type of fluorophore used like quinoline, coumarin, BODIPY, rhodamine, indolium, naphthalimide, etc., and their analytical performance is discussed.

Protecting Group-Dependent Synthesis of Densely Substituted Dihydropyrroles v/s Pyrroles via 5-Exo-trig Cascade Radical Cyclization to Alkynyl Vinylogous Carbamates.

Densely substituted dihydropyrroles could be synthesized with excellent diastereoselectivity via 5-exo-trig cascade radical cyclization to alkynyl vinylogous carbamates. N-Alkyl/acyl protected alkynyl vinylogous carbamates upon radical cyclization using thiophenol gave substituted pyrroles as against dihydropyrroles, which were formed with N-sulfonyl protecting groups. This enabled a rare example wherein both dihydropyrrole and pyrrole rings are assembled in the same reaction. This strategy could be used for the synthesis of an unprecedented adjacent polyheterocyclic system having a furan-thiophene-pyrrole motif. When vinylogous carbamate is embedded in the isoindole moiety, a pyridoisoindole derivative was formed with excellent diastereoselectivity, instead of the expected pyrroloisoindole product.

Heteroatom-Assisted Regio- and Stereoselective Palladium-Catalyzed Carboxylation of 9-Allyl Adenine.

Strategy for the synthesis of acyclic nucleoside analogs of biological relevance via highly regio- and stereoselective C-H functionalization employing heteroatom-assisted palladium-catalyzed carboxylation of 9-allyl adenine is disclosed. Substrate scope with different carboxylic acids was performed giving decent to good yields of the desired products. The method also allowed for the synthesis of deuterated analogs.

TMSOTf-Mediated Formal [4 + 2] Cycloaddition-Retro-aza-Michael Cascade of Vinylogous Carbamates for the Synthesis of Highly Fluorescent Pyridocarbazoles.

Trimethylsilyl trifluoromethanesulfonate mediated dimerization reaction of vinylogous carbamates of carbazoles gave highly fluorescent pyridocarbazoles through a Povarov-type formal [4 + 2] cycloaddition-retro-aza-Michael cascade. The developed strategy was used to access indolo pyridocarbazole and quinolizinocarbazolone in an expeditious manner. Various coupling reactions were successfully performed on synthesized pyridocarbazoles to study the effect of electronics of substitution on photophysical properties. Synthesized carbazoles possess excellent photophysical properties with high quantum yields (ΦF). Fluorescent carbazole dicarboxylic acid showed potential as a pH probe to give a linear response to pH over a very wide range (7.0-3.0) reflecting high efficiency.

Recent advances in the synthesis of pyrrolo[1,2-a]indoles and their derivatives.

The pyrrolo[1,2-a]indole unit is a privileged heterocycle found in numerous natural products and has been shown to exhibit diverse pharmacological properties. Thus, recent years have witnessed immense interest from the synthesis community on the synthesis of this scaffold. In light of the ever-increasing demand for pyrrolo[1,2-a]indoles in drug discovery, this review provides an overview of recent synthesis methods for the preparation of pyrrolo[1,2-a]indoles and their derivatives. The mechanistic pathway and stereo-electronic factors affecting the yield and selectivity of the product are briefly explained. Furthermore, we have attempted to demonstrate the utility of the developed methods in the synthesis of bioactive molecules and natural products, wherever offered.

Design and Expeditious Synthesis of Quinoline-Pyrene-Based Ratiometric Fluorescent Probes for Targeting Lysosomal pH.

Intracellular pH plays a significant role in many pathological and physiological processes. A series of quinoline-pyrene probes were synthesized in one-step fashion through an oxonium-ion-triggered alkyne carboamination sequence involving C-C, C-O and C-N bond formation for intracellular pH sensing. The quinoline-pyrenes showed significant red shifts at low pH. Fluorescence lifetime decay measurements of the probes showed decreases in lifetime at pH 4. The probes showed excellent selectivity in the presence of various potential interfering agents such as amino acids and cations/anions. Furthermore, the probes were found to show completely reversible emission behaviour in the window between pH 4 and 7. A morpholine-substituted quinoline-pyrene probe efficiently stained lysosomes with high Pearson correlation coefficients (0.86) with Lysotracker Deep Red DND-99 as a reference. A co-localization study of the probe with Lysotracker DND-99 showed selective intracellular targeting and a shift in fluorescence emission due to acidic lysosomal pH.

Transition-Metal Acetate-Promoted Intramolecular Nitrene Insertion to Vinylogous Carbonates for Divergent Synthesis of Azirinobenzoxazoles and Benzoxazines.

Synthesis and isolation of highly unstable azirinobenzoxazole and benzoxazines in a chemodivergent fashion from aryl azido vinylogous carbonates by simple change in transition metal acetate is described. Thermal or rhodium(II) acetate-mediated decomposition of these azides gave dihydroazirino benzoxazole. Their nickel(II) acetate-promoted reaction gave 4-dihydro-2H-benzoxazines, whereas copper(II) acetate led to the corresponding oxidized imine derivatives. Benzaoxazine derivative could be kinetically resolved using a proline-catalyzed Mannich reaction. The benzoxazines were rapidly elaborated to angularly fused tetracyclic systems and coumarin-fused derivatives in a "one pot" fashion.

Expeditious diastereoselective synthesis of medium ring heterocycle-fused chromenes via tandem 8/9-endo-dig and 8-exo-dig hydroalkoxylation-formal-[4 + 2] cycloaddition.

The first examples of highly diastereoselective tandem 8/9-endo-dig and 8-exo-dig hydroalkoxylation-formal-[4 + 2] cycloaddition are described for the synthesis of medium ring heterocycle-fused chromenes. TMS-alkynols preferred the exo-dig mode of hydroalkoxylation over the endo-dig mode leading to spiro-cyclic chromenes. The method could be used for the synthesis of linearly-fused ladder-like polyethers. A thia-heterocycle-fused chromene could be transformed into a complex bridged tricyclic ketal by a tandem carbene-insertion-[2,3]-sigmatropic shift.

Metal-free Hydroalkoxylation-Formal [4+2] Cycloaddition Cascade for the Synthesis of Ketals.

A transition metal free, acid promoted cascade hydroalkoxylation-formal [4+2] cycloaddition of various alkynols with salicylaldehyde is demonstrated for the synthesis of tetrahydrofurano/pyrano-chromenes and spiroketals. In general, alkynols underwent hydroalkoxylations in an endo-dig manner when internal alkynes were used to furnish the heteroannular ketals, whereas terminal alkynes proceeded in an exo-dig fashion leading to spiroketals. The study revealed that intramolecular hydroalkoxylation of alkynols is a preferred path over a generation of oxonium ions when coupling partner is salicylaldehyde. This metal-free transformation provides a new avenue for the stereoselective synthesis of tetrahydrofurano- and pyrano-chromenes in an expeditious manner.

Lewis Acid Promoted Oxonium Ion Driven Carboamination of Alkynes for the Synthesis of 4-Alkoxy Quinolines.

Lewis acid mediated multisegment coupling cascade is designed for the synthesis of densely substituted 4-alkoxy quinolines via an oxonium ion triggered alkyne carboamination sequence involving C-C and C-N bond formations. Cyclic ether fused-quinolines could also be accessed using this fast, operationally simple, high yielding, chemoselective and functional group tolerant method. Versatility and utility of this methodology is demonstrated by postfunctionalization of products obtained and its use in synthesis of potent drug molecules.

Stereoselective synthesis of thiazino[4,3-a]indoles using the thia-Pictet-Spengler reaction of indoles bearing N-tethered thiols and vinylogous thiocarbonates.

An inter- as well as intra-molecular thia-Pictet-Spengler cyclization of N-tethered thiols and vinylogous thiocarbonates is described for the stereoselective synthesis of N-fused thiazinoindole derivatives. The strategy is extended to one-pot, sequential Friedel-Crafts alkylation - Pictet-Spengler cyclization and the synthesis of thiazino-oxepino-indole.

White Light Emission in Butadiyne Bridged Pyrene-Phenyl Hybrid Fluorophore: Understanding the Photophysical Importance of Diyne Spacer and Utilizing the Excited-State Photophysics for Vapor Detection.

Generation of white light emission (WLE) from a single organic fluorophore is challenging because of the need to get fluorescence covering the visible region (400-700 nm) upon excitation of the dye at near-ultraviolet wavelength. Herein, we report WLE from a butadiyne bridged pyrene-phenyl hybrid fluorophore in mixed-aqueous solvents as well as in polymer film matrices. The ability of the butadiynyl dye to emit from multiple excited states such as locally excited (LE; 400-500 nm), aggregate (excimer type; 475-600 nm), and charge transfer (CT; 500-750 nm) states spanning the emission almost throughout the visible range has made the generation of the white light to be possible. In highly polar solvent such as acetonitrile, the butadiynyl dye emits from the LE and CT states, and the WLE is achieved through a control of the dye concentration such that intermolecular CT (exciplex type) contributes along with the intramolecular CT and LE emissions. In mixed-aqueous systems such as water-acetonitrile and water-N,N-dimethylformamide, the CT emission is red-shifted (because of the high dielctric constant of water), and the contribution of the aggregate emission (originated because of the poor solvent water) is important in maintaining the relative distribution of the fluorescence intensities (LE, excimer, and CT) in the entire visible region. The significance of the diyne spacer in achieving the WLE is delineated through a control study with a single acetylenic analogue. The LE, aggregate, and CT emissions are involved in generating bluish-white light in a poly(vinyl alcohol) film matrix of the butadiynyl dye. Blue emission is noted in a poly(methyl methacrylate) (PMMA) film matrix of the dye with a major contribution from the LE and a minor contribution from the aggregate state. Exposure of the PMMA film of the dye to polar aprotic vapors assists in gaining the CT state emission such that the LE, aggregate, CT emissions cover the entire visible region to produce the WLE. This opens a new strategy for selective vapor sensing.

Photophysics of Diphenylbutadiynes in Water, Acetonitrile-Water, and Acetonitrile Solvent Systems: Application to Single Component White Light Emission.

Diacetylenes have been the subject of current research because of their interesting optoelectronic properties. Herein, we report that substituted diphenylbutadiynes exhibit locally excited (LE) and excimer emissions in water and multiple emissions from the LE, excimer, and intramolecular charge transfer (ICT) states in acetonitrile-water solvent systems. The LE, excimer, and ICT emissions are clearly distinguishable for a diphenylbutadiynyl derivative with push (-NMe2)-pull (-CN) substituents and those are closely overlapped for non-push-pull analogues. In neat acetonitrile, the excimer emission disappears and the LE and ICT emissions predominate. In the case of the push (-NMe2)-pull (-CN) diphenylbutadiyne, the intensity of the ICT emission increases with increasing the fluorophore concentration. This suggests that the ICT emission accompanies with intermolecular CT emission which is of exciplex type. As the LE and exciplex emissions of the push-pull diphenylbutadiyne together cover the visible region (400-700 nm) in acetonitrile, a control of the fluorophore concentration makes the relative intensities of the LE and exciplex emissions such that pure white light emission is achieved. The white light emission is not observed in those diphenylbutadiynyl analogues in which the peripheral substituents of the phenyl rings do not possess strong push-pull character.

Contrasting Solid-State Fluorescence of Diynes with Small and Large Aryl Substituents: Crystal Packing Dependence and Stimuli-Responsive Fluorescence Switching.

There has been a significant current interest in solid state luminescence of organic molecules and their stimuli responsive fluorescence switching behavior. Although small organic derivatives with olefinic, acetylenic, phenylenevinylenic, phenyleneethynylenic spacers are widely documented as solid state emitters in the literature, the solid state photophysics of organic derivatives with "butadiyne" spacer still remains unexplored. We provide detailed investigation on the solid state fluorescence properties of a series of butadiynyl fluorophores. Replacement of a phenyl ring, which is at periphery of the butadiyne bridge, with a large moiety such as pyrenyl group furnishes contrasting emissions in the solid state. While the butadiyne bridged phenyl derivatives show a blue shift of emission maxima in the solid powder with respect to monomer spectra in solution state, the butadiyne bridged pyrenyl derivatives exhibit a red shift in the solid state. The blue shift of the emission maxima of the butadiyne bridged phenyl derivatives in the solid powder is attributed to allowed excitonic transition in aggregates with nearly parallel transition dipoles. On the other hand, formation of pyrenyl excimer accounts for the red shift of the butadiyne bridged pyrenyl derivatives in the solid powder. In addition to that, the solid state fluorescence of the pyrenyl analogues is reversibly switched between two aggregate forms through external heating and rubbing stimuli.

Stereoselective synthesis of C-fused pyranoindoles, pyranobenzofurans and pyranobenzothiophene scaffolds using oxa-Pictet-Spengler type reaction of vinylogous carbonates.

C-fused pyranoheterocycles can be readily assembled using an intramolecular oxa-Pictet-Spengler type reaction of vinylogous carbonates in a highly stereoselective manner. Required indole and benzofuran rings tethered to vinylogous carbonates are prepared by a tandem Sonogashira coupling-nucleopalladation reaction. The entire process can also be carried out in a 'one-pot' manner starting from homopropargyl alcohol. The C-fused pyranoindoles could be converted to spirooxindoles as well as to ring expanded products under oxidative conditions.

Substituted diphenyl butadiynes: a computational study of geometries and electronic transitions using DFT/TD-DFT.

This work is aimed at theoretical understanding of electronic absorption and emission energies of a series of substituted diphenyl butadiynes through an assessment of several TDDFT functionals and a detailed study of solvent effects on their ground and excited state structures and properties. Out of a series of functionals examined, the coulomb attenuated DFT functional CAM-B3LYP is found to be most successful in predicting charge transfer absorption and emission energies of such derivatives. However, TDDFT potential energy surfaces obtained from hybrid functionals such as B3LYP and PBE0 are found to give a good description of the stability of locally excited (LE) and intramolecular charge transfer (ICT) states as a function of torsional angle, for the butadiynyl fluorophores. Interesting structural variations are observed in the ground and excited state optimized geometries of the fluorophores. The ICT emission of the butadiynyl fluorophores is observed to originate from the twisted state where the two phenyl rings in the diphenyl butadiyne get twisted around the butadiyne moiety. A bending of the butadiyne moiety is noted for some of the butadiynyl derivatives in the ICT emissive state. In addition, the direction of absorption and emission transition dipole moment vectors of the butadiynyl fluorophores is found to depend on the nature of substituents present at the periphery of the diphenyl butadiyne moiety.

Cascade radical cyclization on 3-propargyl-2-alkenyl indole gives stereoselective access to cyclohepta[b]indole over carbazole.

A protecting group-dependent diastereoselective synthesis of cyclohepta[b]indole over carbazole derivatives is developed. This strategy involves a regioselective 6-exo-trig radical cyclization-cyclopropanation-ring expansion cascade of 3-propargyl-2-alkenyl indole. The cascade radical cyclization was also performed on indole derivatives possessing alkyne, acrylate and vinylogous carbamate moieties, which delivered pyridocarbazole giving credence to the mechanistic hypothesis. Furthermore, cyclohepta[b]indole could be selectively converted to sulfone and sulfoxide as well as benzoazulenoindole via intramolecular Friedel-Crafts acylation.

Unlocking a reductive hydroalkoxylation cascade for the stereoselective synthesis of cyclic ethers: total synthesis of (±)-isolaurepan and (±)-cis-lauthisan.

A Lewis acid-mediated, 5/6/7/8-endo-dig reductive hydroalkoxylation cascade on enynols gives expeditious, diastereoselective access to small and medium ring cyclic ethers with a long aliphatic side chain. The brevity of the approach allowed a 4-step, stereoselective total synthesis of (±)-isolaurepan and (±)-cis-lauthisan.