A Unified Continuous Flow Assembly‐Line Synthesis of Highly Substituted Pyrazoles and Pyrazolines

A rapid and modular continuous flow synthesis of highly functionalized fluorinated pyrazoles and pyrazolines has been developed. Flowing fluorinated amines through sequential reactor coils mediates diazoalkane formation and [3+2] cycloaddition to generate more than 30 azoles in a telescoped fashion. Pyrazole cores are then sequentially modified through additional reactor modules performing N ‐alkylation and arylation, deprotection, and amidation to install broad molecular diversity in short order. Continuous flow synthesis enables the safe handling of diazoalkanes at elevated temperatures, and the use of aryl alkyne dipolarphiles under catalyst‐free conditions. This assembly‐line synthesis provides a flexible approach for the synthesis of agrochemicals and pharmaceuticals, as demonstrated by a four‐step, telescoped synthesis of measles therapeutic, AS‐136A, in a total residence time of 31.7 min (1.76 g h⁻¹).     

Electrochemical Synthesis of gem-Difluoro- and γ-Fluoro-Allyl Boronates and Silanes

The electrochemical synthesis of fluorinated allyl silanes and boronates was disclosed. The addition of electrogenerated boryl or silyl radicals onto many α-trifluoromethyl or α-difluoromethylstyrenes in an undivided cell allowed the formation of a large panel of synthetically useful gem-difluoro and γ-fluoroallyl boronates and silanes (64 examples, from 31 % to 95 % yield). In addition, a scale up of the reactions under continuous flow was showcased using an electrochemical reactor with promising volumetric productivity (688 g.L⁻¹.h⁻¹ and 496 g.L⁻¹.h⁻¹). Moreover, the synthetic utility of these building blocks was highlighted through versatile transformations. Finally, plausible reaction mechanisms were suggested to explain the formation of the products.     

Stereoretentive N-Arylation of Amino Acid Esters with Cyclohexanones Utilizing a Continuous-Flow System

The N-arylation of chiral amino acid esters with minimal racemization is a challenging transformation because of the sensitivity of the α-stereocenter. A versatile synthetic method was developed to prepare N-arylated amino acid esters using cyclohexanones as aryl sources under continuous-flow conditions. The designed flow system, which consists of a coil reactor and a packed-bed reactor containing a Pd(OH)₂/C catalyst, efficiently afforded the desired N-arylated amino acids without significant racemization, accompanied by only small amounts of easily removable co-products (i. e., H₂O and alkanes). The efficiency and robustness of this method allowed for the continuous synthesis of the desired product in very high yield and enantiopurity with high space-time yield (74.1 g L⁻¹ h⁻¹) and turnover frequency (5.9 h⁻¹) for at least 3 days.     

Synthesis of 28-F-amphotericin B methyl ester

A fluorinated amphotericin B (AmB) derivative, 28-¹⁹F-AmB methyl ester (3), labeled at the polyene moiety, was synthesized by combining chemical synthesis with degradation of a natural product via cross-coupling reactions and macrolactonization. The fluorinated derivative 3 showed antifungal activity similar to that of AmB, and is expected to be a powerful tool for NMR-based investigation of the mechanism of ion-channel formation.     

Internally Reuse Waste: Catalytic Asymmetric One‐Pot Strecker Reaction of Fluoroalkyl Ketones,Anilines and TMSCN by Sequential Catalysis

We report a highly enantioselective one‐pot facile synthesis of fluorinated C^α‐tetrasubstituted amino nitriles from α‐fluoroalkyl α‐aryl ketones, anilines, and TMSCN through a sequential p‐TsOH catalyzed ketimine formation and chiral bifunctional tertiary amine mediated asymmetric Strecker reaction. This one‐pot approach has two important advantages. First, it greatly improves the overall yield of the synthesis of chiral C^α‐tetrasubstituted fluorinated aminonitriles from ketones, because the purification of α‐fluorinated ketimines by column chromatography suffers from great yield loss. Second, it represents the first example of asymmetric tandem reactions that can simultaneously reuse the by‐product and catalyst from the upstream step as a promoter and an additive to improve the reactivity and enantioselectivity of the subsequent catalytic enantioselective reaction, respectively. It could utilize the by‐product H₂O generated in‐situ from the ketimine formation step to activate TMSCN to form HCN, and concurrently reuse the remaining p‐TsOH acid as an additive to improve enantioselectivity.     

Continuous Flow Synthesis of Ketones from Carbon Dioxide and Organolithium or Grignard Reagents

We describe an efficient continuous flow synthesis of ketones from CO₂ and organolithium or Grignard reagents that exhibits significant advantages over conventional batch conditions in suppressing undesired symmetric ketone and tertiary alcohol byproducts. We observed an unprecedented solvent‐dependence of the organolithium reactivity, the key factor in governing selectivity during the flow process. A facile, telescoped three‐step–one‐flow process for the preparation of ketones in a modular fashion through the in‐line generation of organometallic reagents is also established.     

Synthesis of photocrosslinkable fluorinated polydimethylsiloxanes: Direct introduction of acrylic pendant groups via hydrosilylation

The synthesis of photocrosslinkable fluorinated polydimethylsiloxanes was achieved through direct hydrosilylation with copoly(dimethyl)(methyl‐hydrogen) siloxane. First, the hydrosilylation of a fluorinated olefin allowed the introduction of a fluorinated group onto the polysiloxane. Then, a second hydrosilylation of allyl methyl methacrylate led to the polysiloxane bearing both fluorinated and photocrosslinkable groups. This method, compared with a previous method of copolycondensation, is shown to be easier and more efficient. All the new products synthesized were characterized by IR, ¹H NMR, ¹⁹F NMR, and ²⁹Si NMR. A formulation containing the fluorosilicone was crosslinked after being coated on a mesoporous membrane and was evaluated as a vapor permeation membrane. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 3722–3728, 2000     

Iron-Catalyzed Cross-Coupling of Alkynyl and Styrenyl Chlorides with Alkyl Grignard Reagents in Batch and Flow

Transition-metal-catalyzed cross-coupling chemistry can be regarded as one of the most powerful protocols to construct carbon–carbon bonds. While the field is still dominated by palladium catalysis, there is an increasing interest to develop protocols that utilize cheaper and more sustainable metal sources. Herein, we report a selective, practical, and fast iron-based cross-coupling reaction that enables the formation of Csp−Csp³ and Csp²−Csp³ bonds. In a telescoped flow process, the reaction can be combined with the Grignard reagent synthesis. Moreover, flow allows the use of a supporting ligand to be avoided without eroding the reaction selectivity.     

Asymmetric Synthesis of Fluorinated Isoindolinones through Palladium‐Catalyzed Carbonylative Amination of Enantioenriched Benzylic Carbamates

The asymmetric synthesis of fluorinated isoindolinones has been achieved by a palladium‐catalyzed aminocarbonylation reaction of the corresponding α‐fluoroalkyl o‐iodobenzylamines. A base‐mediated anti β‐hydride elimination process was suggested to explain the partial erosion of the optical purity observed in some cases. This mechanistic rationale enabled the minimization of this partial racemization by fine‐tuning the pK_a of the base.     

The mechanism of cytotoxicity of methylmercury: Inhibition of progression through the S phase of the cell cycle

The effect of methylmercury (MeHg) on progression of the murine erythroleukemic cell (MELC) through the cell cycle was analyzed by flow cytometry (FCM). Exposure in vitro to 5.0-10.0 μmol dm^?3 MeHg for 6h resulted in a dose-dependent decrease in the rate of cell replication, apparently as a result of inhibition of DNA synthesis (rate of passage through the S phase of the cell cycle). Thus, only a modest accumulation of cells with a G₂/M (4n) DNA content was observed. At or above 10 μmol dm^?3 MeHg, progression through all phases of the cell cycle was blocked. FCM revealed a dose-dependent increase in cellular refractive index (90° light scatter), decrease in apparent cell volume (axial light loss), and increase in resistance to non-ionic detergent (NP-40)-mediated cytolysis indicative of fixation (protein denaturation, cross-linking, etc.) of the plasma membrane/cytoplasm complex. The data indicate DNA synthesis as the primary target of MeHg cytotoxicity.     

Synthesis of Novel Fluorinated [sgrave]-Conjugated Silicon-Containing Polymers: Polysilynes and Polysilanes

Abstract

The synthesis of fluorinated polysilynes, a new class of silicon-silicon network materials, has been achieved by reductive coupling of fluorinated trichlorosilanes with molten sodium in a mixture of toluene and diglyme (4:1) as a new synthetic route. Homopolysilynes containing fluorinated organogroups were insoluble in organic solvents due to side reactions. To improve solubility, copolysilynes were synthesized by co-polymerization of fluorinated trichlorosilanes with cyclohexyltrichlorosi-lane. All spectroscopic data indicate that the structure of the resulting fluorinated copolysilynes is a rigid, irregular network of monoalkyl sp ³-hybridized silicon units which exhibit extensive Si-Si [sgrave]-delocalization. They are more thermally stable than unfluorinated polysilynes. Upon exposure to deep-UV radiation in air, they undergo photooxidative crosslinking to give insoluble glass-like materials. This photooxidation process is accompanied by a large decrease in refractive index from n = 1.61 to n = 1.485. These results suggest that their potential applications include photoresists and optical waveguides. In order to understand the mechanism of reductive coupling of fluorinated trichlorosilanes, fluorinated linear polysilanes were also prepared.     

A Resin‐Linker‐Vector Approach to Radiopharmaceuticals Containing 18F: Application in the Synthesis of O‐(2‐[18F]‐Fluoroethyl)‐L‐tyrosine

A Resin‐linker‐vector (RLV) strategy is described for the radiosynthesis of tracer molecules containing the radionuclide ¹⁸F, which releases the labelled vector into solution upon nucleophilic substitution of a polystyrene‐bound arylsulfonate linker with [¹⁸F]‐fluoride ion. Three model linker‐vector molecules 7 a – c containing different alkyl spacer groups were assembled in solution from (4‐chlorosulfonylphenyl)alkanoate esters, exploiting a lipase‐catalysed chemoselective carboxylic ester hydrolysis in the presence of the sulfonate ester as a key step. The linker‐vector systems were attached to aminomethyl polystyrene resin through amide bond formation to give RLVs 8 a – c with acetate, butyrate and hexanoate spacers, which were characterised by using magic‐angle spinning (MAS) NMR spectroscopy. On fluoridolysis, the RLVs 8 a , b containing the longer spacers were shown to be more effective in the release of the fluorinated model vector (4‐fluorobutyl)phenylcarbamic acid tert‐butyl ester ( 9 ) in NMR kinetic studies and gave superior radiochemical yields (RCY≈60 %) of the ¹⁸F‐labelled vector. The approach was applied to the synthesis of the radiopharmaceutical O‐(2‐[¹⁸F]‐fluoroethyl)‐L ‐tyrosine ([¹⁸F]‐FET), delivering protected [¹⁸F]‐FET in >90 % RCY. Acid deprotection gave [¹⁸F]‐FET in an overall RCY of 41 % from the RLV.     

Continuous Consecutive Reactions with Inter‐Reaction Solvent Exchange by Membrane Separation

Pharmaceutical production typically involves multiple reaction steps with separations between successive reactions. Two processes which complicate the transition from batch to continuous operation in multistep synthesis are solvent exchange (especially high‐boiling‐ to low‐boiling‐point solvent), and catalyst separation. Demonstrated here is membrane separation as an enabling platform for undertaking these processes during continuous operation. Two consecutive reactions are performed in different solvents, with catalyst separation and inter‐reaction solvent exchange achieved by continuous flow membrane units. A Heck coupling reaction is performed in N,N‐dimethylformamide (DMF) in a continuous membrane reactor which retains the catalyst. The Heck reaction product undergoes solvent exchange in a counter‐current membrane system where DMF is continuously replaced by ethanol. After exchange the product dissolved in ethanol passes through a column packed with an iron catalyst, and undergoes reduction (>99 % yield).     

A scalable Nenitzescu synthesis of 2‐methyl‐4‐(trifluoromethyl)‐1H‐indole‐5‐carbonitrile

2‐Methyl‐4‐(trifluoromethyl)‐1H‐indole‐5‐carbonitrile is a key intermediate in the synthesis of selective androgen receptor modulators discovered in these laboratories. A practical and convergent synthesis of the title compound starting from 4‐nitro‐3‐(trifluoromethyl)phenol and tert‐butyl acetoacetate was developed, including a telescoped procedure for synthesis (without isolation) and Nenitzescu reaction of 2‐trifluoromethyl‐1,4‐benzoquinone. Conversion of the known Nenitzescu indole product to a novel triflate intermediate followed by palladium‐catalyzed cyanation afforded a penultimate carbonitrile. Removal of the C‐3 tert‐butyl ester group on the indole through a decarboxylative pathway completed the synthesis of the title compound in six steps (27% overall yield) from 4‐nitro‐3‐(trifluoromethyl)phenol (five steps, 37% overall yield from tert‐butyl acetoacetate). J. Heterocyclic Chem., (2011).     

Enantioselective Total Synthesis of (+)‐Plumisclerin A

The first and enantioselective total synthesis of (+)‐plumisclerin A, a novel unique complex cytotoxic marine diterpenoid, has been accomplished. Around the central cyclopentane anchorage, a sequential ring‐formation protocol was adopted to generate the characteristic tricycle[4.3.1.0^1,5]decane and trans‐fused dihyrdopyran moiety. Scalable enantioselective La^III‐catalyzed Michael reaction, palladium(0)‐catalyzed carbonylation and SmI₂‐mediated radical conjugate addition were successfully applied in the synthesis, affording multiple grams of the complex and rigid B/C/D‐ring system having six continuous stereogenic centers and two all‐carbon quaternary centers. The trans‐fused dihyrdopyran moiety with an exo side‐chain was furnished in final stage through sequential redox transformations from a lactone precursor, which overcome the largish steric strain of the dense multiring system. The reported total synthesis also confirms the absolute chemistries of natural (+)‐plumisclerin A.     

Addition of Electrophilic Radicals to 2‐Benzyloxyglycals: Synthesis and Functionalization of Fluorinated α‐C‐Glycosides and Derivatives

A new method for the synthesis of fluorinated α‐C‐glycosides is described. The reactions between highly electrophilic radicals (fluorinated or unfluorinated) and a 2‐benzyloxyglucal or galactal provide 2‐keto‐D ‐arabino‐ or 2‐keto‐D ‐lyxo‐hexopyranosides through an addition/fragmentation process. Sodium borohydride mediated or Meerwein–Ponndorf–Verley (MPV) reduction of these compounds provides α‐C‐glycosides that feature appropriate anchoring groups for further synthetic elaboration. The presence of CF₂CO₂iPr or CF₂Br groups at the pseudo‐anomeric position allows efficient reduction/olefination or Br/Li‐exchange/nucleophilic‐addition sequences. These transformations open the way for the synthesis of fluorinated C‐glycosidic analogues of glycoconjugates.     

An enzyme reactor electrode for urea determinations.

An enzyme reactor electrode system for the determination of urea is described. A buffer is pumped through an enzyme reactor (0.4 ml) containing urease immobilized with glutaraldehyde to glass. The effluent is mixed with sodium hydroxide pumped through a second channel and fed through an ammonia gas electrode. Samples are introduced via a third flow channel and mixed with the buffer. The conversion of urea to ammonia is quantitative for sample concentrations of less than 0.03 M for a flow rate of 40 ml h^-1. The reactor electrode shows a Nernstian slope of 57 mV/decade for 5·10^-5–3·10^-2 M urea. The response is independent of variations in the flow rate, enzyme activity or temperature of the reactor.     

Mapping Aldehyde Dehydrogenase 1A1 Activity using an [18F]Substrate-Based Approach

Aldehyde dehydrogenases (ALDHs) catalyze the oxidation of aldehydes to carboxylic acids. Elevated ALDH expression in human cancers is linked to metastases and poor overall survival. Despite ALDH being a poor prognostic factor, the non-invasive assessment of ALDH activity in vivo has not been possible due to a lack of sensitive and translational imaging agents. Presented in this report are the synthesis and biological evaluation of ALDH1A1-selective chemical probes composed of an aromatic aldehyde derived from N,N-diethylamino benzaldehyde (DEAB) linked to a fluorinated pyridine ring either via an amide or amine linkage. Of the focused library of compounds evaluated, N-ethyl-6-(fluoro)-N-(4-formylbenzyl)nicotinamide 4 b was found to have excellent affinity and isozyme selectivity for ALDH1A1 in vitro. Following ¹⁸F-fluorination, [¹⁸F] 4 b was taken up by colorectal tumor cells and trapped through the conversion to its ¹⁸F-labeled carboxylate product under the action of ALDH. In vivo positron emission tomography revealed high uptake of [¹⁸F] 4 b in the lungs and liver, with radioactivity cleared through the urinary tract. Oxidation of [¹⁸F] 4 b , however, was observed in vivo, which may limit the tissue penetration of this first-in-class radiotracer.     

Environmentally Compatible Access to α-Trifluoromethylseleno-Enones

α-Trifluoromethylselenolated enones constitute valuable building-blocks for further synthesis of innovative fluorinated compounds. Herein, we described an easy access to such compounds in green conditions through a Morita-Baylis-Hillman like reaction. These conditions have also been extended to higher fluorinated homologs.     

Influence of the Electromagnetic Forces on Momentum and Heat Transfer in a 3-Phase ac Plasma Reactor

A new 3-phase ac plasma reactor has been developed within the framework of research on hydrocarbon cracking for the production of carbon black and hydrogen. ^(1,2) One of the main characteristics of the system is related to the 3-phase, 50 Hz ac current plasma generator which induces a very particular arc motion affecting the heat and mass transfer inside the reactor. In a first step, the general flow inside the reactor in the absence of hydrocarbon injection has been studied. A simplified approach to characterize the heat and mass transfer inside the reactor is presented in this paper. The arc zone analysis is carried out simultaneously by a theoretical analysis of the electromagnetic forces and by an ultrahigh-speed cine-camera analysis. The flow in the reactor is modeled with a CFD commercial code. Results are compared with experimental temperature measurements.