Synthesis of Indolines via Base-Mediated C-H Activation and Defluorinative C-N Coupling, with no Need for Transition-Metals.

Syntheses of (partially) aromatic nitrogen heterocycles increasingly rely on transition-metal catalyzed C-C- and C-N-cross-coupling reactions. Here we describe a different approach to the synthesis of indolines by a domino C(sp)-H activation, 1,2-addition, and defluorinative SAr-cyclization sequence to provide the target 1,2-diarylindolines (1,2-diaryl-2,3-dihydroindoles) from ortho-fluorinated methyl-arenes and N-aryl imines (benzylidene anilines) in a cyclocondensation that is mediated by potassium hexamethyldisilazide (KHMDS) as base exclusively. This transition-metal-free process via C-H and C-F bond activation provides a one-step entry into a wide array of indoline scaffolds (43 examples, up to 96 % yield).

Rapid C-H Transformation: Addition of Diarylmethanes to Imines in Seconds by Catalytic Use of Base.

The addition of diarylmethanes or methylarenes activation of benzylic C(sp)-H bonds to -aryl imines proceeds under catalysis by alkali hexamethyldisilazide (HMDS) base to give -(1,2,2-triarylethyl)anilines or -(1,2-diarylethyl)anilines, respectively. In the presence of 10 mol % of LiHMDS at room temperature, the diarylmethane addition equilibrates within 20-30 s and is driven to near completion by cooling the reaction mixture to -25 °C, providing -(1,2,2-triarylethyl)aniline in a >90% yield.

Structure Elucidation of a Cryptic Condensation Product from Diacetyl and Arylamine - Then and Now.

Some 70 years ago, the reaction of diacetyl (1) and arylamines (2) in hot phosphoric acid was reported to give a new type of condensation products, but no structure was assigned to them. The case is presented to recapitulate the methods and rationales used in classical structure elucidation of organic molecules through reaction networks, before spectroscopic or crystallographic methods were generally available. The difficulties and limits of the classical approach are exemplified through this real-life problem, which could not be solved by the methodology of its time.

Generation of Organozinc Reagents by Nickel Diazadiene Complex Catalyzed Zinc Insertion into Aryl Sulfonates.

The generation of arylzinc reagents (ArZnX) by direct insertion of zinc into the C-X bond of ArX electrophiles has typically been restricted to iodides and bromides. The insertions of zinc dust into the C-O bonds of various aryl sulfonates (tosylates, mesylates, triflates, sulfamates), or into the C-X bonds of other moderate electrophiles (X=Cl, SMe) are catalyzed by a simple NiCl -1,4-diazadiene catalyst system, in which 1,4-diazadiene (DAD) stands for diacetyl diimines, phenanthroline, bipyridine and related ligands. Catalytic zincation in DMF or NMP solution at room temperature now provides arylzinc sulfonates, which undergo typical catalytic cross-coupling or electrophilic substitution reactions.

Stereochemistry of the Menthyl Grignard Reagent: Generation, Composition, Dynamics, and Reactions with Electrophiles.

Menthyl Grignard reagent 1 from either menthyl chloride (2) or neomenthyl chloride (3) consists of menthylmagnesium chloride (1a), neomenthylmagnesium chloride (1b), trans- p-menthane (4), 2-menthene (8), 3-menthene (9), and Wurtz coupling products including symmetrical bimenthyl 13. The diastereomeric ratio 1a/1b was determined in situ by C NMR or after DO quenching by H NMR analysis. Hydrolysis of the C-Mg bond proceeds with retention of configuration at C-1.

Is the tungsten(IV) complex (NEt)[WO(mnt)] a functional analogue of acetylene hydratase?

The tungsten(IV) complex (EtN)[W(O)(mnt)] (; mnt = maleonitriledithiolate) was proposed (Sarkar et al., , , 4315) to be a functional analogue of the active center of the enzyme acetylene hydratase from , which hydrates acetylene (ethyne; ) to acetaldehyde (ethanal; ). In the absence of a satisfactory mechanistic proposal for the hydration reaction, we considered the possibility of a metal-vinylidene type activation mode, as it is well established for ruthenium-based alkyne hydration catalysts with anti-Markovnikov regioselectivity.

Fiaud's Acid: A Brønsted Acid Catalyst for Enantioselective Friedel-Crafts Alkylation of Indoles with 2-Alkene-1,4-diones.

Fiaud's acid (trans-1-hydroxy-2,5-diphenylphospholane 1-oxide), a phospholane-based phosphinic acid, is introduced as an efficient chiral Brønsted acid catalyst that mediates the asymmetric Friedel-Crafts alkylation of indoles with 2-butene-1,4-diones. With a catalyst loading of 10 mol %, the reaction proceeded smoothly to afford 2-(indol-3-yl)butane-1,4-diones in high yield (up to 82%) and high enantioselectivity (up to 91% ee, one such product showed enhanced ee of 98% after recrystallization). The reaction conditions are sufficiently mild to tolerate sensitive functionality at room temperature and are therefore suitable for the synthesis of complex targets.

Oxyluciferin Derivatives: A Toolbox of Environment-Sensitive Fluorescence Probes for Molecular and Cellular Applications.

In this work, we used firefly oxyluciferin (OxyLH) and its polarity-dependent fluorescence mechanism as a sensitive tool to monitor biomolecular interactions. The chromophores, OxyLH, and its two analogues, 4-MeOxyLH and 4,6'-DMeOxyL, were modified trough carboxylic functionalization and then coupled to the N-terminus part of Tat and NCp7 peptides of human immunodeficiency virus type-1 (HIV-1). The photophysical properties of the labeled peptides were studied in live cells as well as in complex with different oligonucleotides in solution.

Bioinspired Molecular Lantern: Tuning the Firefly Oxyluciferin Emission with Host-Guest Chemistry.

Fireflies generate flashes of visible light via luciferase-catalyzed chemiexcitation of the substrate (luciferin) to the first excited state of the emitter (oxyluciferin). Microenvironment effects are often invoked to explain the effects of the luciferase active pocket on the emission; however, the exceedingly complex spectrochemistry and synthetic burdens have precluded elucidation of the nature of these interactions. To decipher the effects of microenvironment on the light emission, here the hydrophobic interior of cucurbit[7]uril (CB7) is used to mimic the nonpolar active pocket of luciferase.

A Sequential Homologation of Alkynes and Aldehydes for Chain Elongation with Optional (13)C-Labeling.

Terminal alkynes (RCCH) are homologated by a sequence of ruthenium-catalyzed anti-Markovnikov hydration of alkyne to aldehyde (RCH2CHO), followed by Bestmann-Ohira alkynylation of aldehyde to chain-elongated alkyne (RCH2CCH). Inverting the sequence by starting from aldehyde brings about the reciprocal homologation of aldehydes instead. The use of (13)C-labeled Bestmann-Ohira reagent (dimethyl ((1-(13)C)-1-diazo-2-oxopropyl)phosphonate) for alkynylation provides straightforward access to singly or, through additional homologation, multiply (13) C-labeled alkynes.

Structure of the Dioxygenase AsqJ: Mechanistic Insights into a One-Pot Multistep Quinolone Antibiotic Biosynthesis.

Multienzymatic cascades are responsible for the biosynthesis of natural products and represent a source of inspiration for synthetic chemists. The Fe(II)/α-ketoglutarate-dependent dioxygenase AsqJ from Aspergillus nidulans is outstanding because it stereoselectively catalyzes both a ferryl-induced desaturation reaction and epoxidation on a benzodiazepinedione. Interestingly, the enzymatically formed spiro epoxide spring-loads the 6,7-bicyclic skeleton for non-enzymatic rearrangement into the 6,6-bicyclic scaffold of the quinolone alkaloid 4'-methoxyviridicatin.

Asymmetric hydroalkoxylation of non-activated alkenes: titanium-catalyzed cycloisomerization of allylphenols at high temperatures.

The asymmetric catalytic addition of alcohols (phenols) to non-activated alkenes has been realized through the cycloisomerization of 2-allylphenols to 2-methyl-2,3-dihydrobenzofurans (2-methylcoumarans). The reaction was catalyzed by a chiral titanium-carboxylate complex at uncommonly high temperatures for asymmetric catalytic reactions. The catalyst was generated by mixing titanium isopropoxide, the chiral ligand (aS)-1-(2-methoxy-1-naphthyl)-2-naphthoic acid or its derivatives, and a co-catalytic amount of water in a ratio of 1:1:1 (5 mol % each).

Emission properties of oxyluciferin and its derivatives in water: revealing the nature of the emissive species in firefly bioluminescence.

The first systematic steady-state and time-resolved emission study of firefly oxyluciferin (emitter in firefly bioluminescence) and its analogues in aqueous buffers provided the individual emission spectra of all chemical forms of the emitter and the excited-state equilibrium constants in strongly polar environment with strong hydrogen bonding potential. The results confirmed the earlier hypothesis that excited-state proton transfer from the enol group is favored over proton transfer from the phenol group. In water, the phenol-keto form is the strongest photoacid among the isomers and its conjugate base (phenolate-keto) has the lowest emission energy (634 nm).

Vibrational spectra of chemical and isotopic variants of oxyluciferin, the light emitter of firefly bioluminescence.

The chemical complexity of oxyluciferin (OxyLH2), the light-emitting molecule in the bioluminescence of fireflies, originates from the possibility of keto/enol tautomerism and single or double deprotonation. Herein, we present detailed infrared spectroscopic analysis of OxyLH2 and several of its chemical isomers and isotopomers. To facilitate the future characterization of its biogenic forms, we provide accurate assignments of the solid-state and solution FTIR spectra of OxyLH2 based on comparison to six isotopically labeled variants ([2-(13)C]-OxyLH2, [3-(15)N]-OxyLH2, [4-(13)C]-OxyLH2, [5-(13)C]-OxyLH2, [2'-(13)C]-OxyLH2, [3'-(15)N]-OxyLH2), five closely related structural analogues, and theoretically computed spectra.

Synthesis of Soai aldehydes for asymmetric autocatalysis by desulfurative cross-coupling.

Palladium-catalyzed dehydrosulfurative Liebeskind-Srogl coupling of terminal alkynes with 2-mercapto-1,3-pyrimidine-5-carbaldehyde under base-free conditions provides 2-(alkynyl)-1,3-pyrimidine-5-carbaldehydes, which are substrates for autocatalytic amplification of chirality according to Soai et al. The mercapto aldehyde acceptor is obtained by condensation of Arnold's vinamidinium salt with thiourea.

Why is firefly oxyluciferin a notoriously labile substance?

The chemistry of firefly bioluminescence is important for numerous applications in biochemistry and analytical chemistry. The emitter of this bioluminescent system, firefly oxyluciferin, is difficult to handle. The cause of its lability was clarified while its synthesis was reinvestigated.

On the influence of water on the electronic structure of firefly oxyluciferin anions from absorption spectroscopy of bare and monohydrated ions in vacuo.

A complete understanding of the physics underlying the varied colors of firefly bioluminescence remains elusive because it is difficult to disentangle different enzyme-lumophore interactions. Experiments on isolated ions are useful to establish a proper reference when there are no microenvironmental perturbations. Here, we use action spectroscopy to compare the absorption by the firefly oxyluciferin lumophore isolated in vacuo and complexed with a single water molecule.

Inner workings of a cinchona alkaloid catalyzed oxa-Michael cyclization: evidence for a concerted hydrogen-bond-network mechanism.

Cinchona alkaloids catalyze the oxa-Michael cyclization of 4-(2-hydroxyphenyl)-2-butenoates to benzo-2,3-dihydrofuran-2-yl acetates and related substrates in up to 99% yield and 91% ee (ee = enantiomeric excess). Catalyst and substrate variation studies reveal an important role of the alkaloid hydroxy group in the reaction mechanism, but not in the sense of a hydrogen-bonding activation of the carbonyl group of the substrate as assumed by the Hiemstra-Wynberg mechanism of bifunctional catalysis. Deuterium labeling at C-2 of the substrate shows that addition of RO-H to the alkenoate occurs with syn diastereoselectivity of ≥99:1, suggesting a mechanism-based specificity.

Cyclization of ortho-hydroxycinnamates to coumarins under mild conditions: A nucleophilic organocatalysis approach.

(E)-Alkyl ortho-hydroxycinnamates cyclize to coumarins at elevated temperatures of 140-250 °C. We find that the use of tri-n-butylphosphane (20 mol %) as a nucleophilic organocatalyst in MeOH solution allows cyclization to take place under much milder conditions (60-70 °C). Several coumarins were prepared, starting from ortho-hydroxyarylaldehydes, by Wittig reaction with Ph(3)P=CHCO(2)Me to (E)-methyl ortho-hydroxycinnamates, followed by the phosphane catalyzed cyclization.

Reversible generation of metastable enols in the 1,4-addition of thioacetic acid to α,β-unsaturated carbonyl compounds.

Addition of thioacetic acid to reactive α,β-unsaturated carbonyl compounds like acrolein or crotonaldehyde in acetone-d(6) generates metastable (E)- and (Z)-1-alkenols, which tautomerize slowly at ambient temperature. The 1,4-addition of thioacetic acid and crotonaldehyde to (Z)-3-(acetylsulfanyl)-1-propen-1-ol is reversible with K(eq) = 5.5 ± 0.

Development of the titanium-TADDOLate-catalyzed asymmetric fluorination of β-ketoesters.

Titanium-based Lewis acids catalyze the α-fluorination of β-ketoesters by electrophilic N-F-fluorinating reagents. Asymmetric catalysis with TADDOLato-titanium(IV) dichloride (TADDOL = α,α,α',α'-tetraaryl-(1,3-dioxolane-4,5-diyl)-dimethanol) Lewis acids produces enantiomerically enriched α-fluorinated β-ketoesters in up to 91% enantiomeric excess, with either F-TEDA (1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.

Hidden Brønsted acid catalysis: pathways of accidental or deliberate generation of triflic acid from metal triflates.

The generation of a hidden Brønsted acid as a true catalytic species in hydroalkoxylation reactions from metal precatalysts has been clarified in case studies. The mechanism of triflic acid (CF(3)SO(3)H or HOTf) generation starting either from AgOTf in 1,2-dichloroethane (DCE) or from a Cp*RuCl(2)/AgOTf/phosphane combination in toluene has been elucidated. The deliberate and controlled generation of HOTf from AgOTf and cocatalytic amounts of tert-butyl chloride in the cold or from AgOTf in DCE at elevated temperatures results in a hidden Brønsted acid catalyst useful for mechanistic control experiments or for synthetic applications.

Mixed phosphane η5-CpRuCl(PR3)2 complexes as ambifunctional catalysts for anti-Markovnikov hydration of terminal alkynes.

The catalytic activity of [CpRu(L)(2)(MeCN)]PF(6) (L = 2-diphenylphosphinopyridine with bulky groups at C-6) for anti-Markovnikov hydration of terminal alkynes to aldehydes is retained when one heterocyclic ligand L is replaced by L' = PPh(3). Equal amounts of CpRuCl(PPh(3))(2) (1) and phosphane L in acetone solution equilibrate to a mixture of 1, CpRuCl(L)(PPh(3)) (2), and CpRuCl(L)(2) (3), which acts as highly active in situ catalyst for preparative anti-Markovnikov hydration of alkynes in water-rich media (2 mol % [Ru], 60 °C, 3-18 h in 4:1 (v/v) acetone/water). Reactions were completed in <15 min at 160 °C.

The AZARYPHOS family of ligands for ambifunctional catalysis: syntheses and use in ruthenium-catalyzed anti-Markovnikov hydration of terminal alkynes.

The family of AZARYPHOS (aza-aryl-phosphane) phosphane ligands, containing a phosphine unit and sterically shielded nitrogen lone pairs in the ligand periphery, is introduced as a tool for developing ambifunctional catalysis by the metal center and nitrogen lone pairs in the ligand sphere. General synthetic strategies have been developed to synthesize over 25 examples of structurally diverse (6-aryl-2-pyridyl)phosphanes (ARPYPHOS), (6-alkyl-2-pyridyl)phosphanes (ALPYPHOS), 4,6-disubsituted 1,3-diazin-2-ylphosphanes or 1,3,5-triazin-2-ylphosphanes, quinazolinylphosphanes, quinolinylphosphanes, and others. The scalable syntheses proceed in a few steps.

First stereoselective total synthesis of FD-594 aglycon.

Stereocontrolled access to the hexacyclic core of FD-594 has been achieved. The key steps include the intramolecular S(N)Ar reaction for construction of the densely functionalized xanthone skeleton, the stereoselective lactone cleavage using a chiral nucleophile to induce the axial stereochemistry, and the SmI(2)-mediated pinacol cyclization for the stereocontrolled conversion of axially chiral biaryl dialdehyde into the corresponding trans diol.