Synthesis of γ‐Fluoro‐α, β‐unsaturated Carboxylic Esters from Saturated α‐Fluoro Aldehydes

γ‐Fluoro‐α, β‐unsaturated carboxylic esters 7a, 7b and 7d and 4‐fluoro‐4‐phenylbut‐3‐enoic ester ( 8 ) are obtained by two alternative pathways from 2‐fluoro aldehydes 5a—d , either by Horner—Wadsworth—Emmons reaction or by Wittig reaction. The aldehydes 5a—d are prepared by Swern oxidation of the corresponding fluorohydrins 4a—d . These are available from α‐olefins by bromofluorination, bromineby‐acetate replacement and subsequent hydrolysis.     

Microwave‐induced Fast Synthesis and Optical Resolution of 9H‐Carbazole‐2‐carboxylic Acids Enantiomers

Fast synthesis of a series 9H‐carabzole‐2‐carboxylic acids enantiomers 9—13 by N‐alkylation reaction of the carbazole and bromo ester under microwave irradiation is described using DMF as solvent. The HPLC optical resolution of these enantiomers were performed on amylose tris‐(phenylcarbamate)‐coated aminopropylated silica gel (ATPC) column.     

The Synthesis and Energetic Properties of 5,7‐Dinitrobenzo‐1,2,3,4‐tetrazine‐1,3‐dioxide (DNBTDO)

Energetic tetrazine‐1,3‐dioxide, 5,7‐dinitrobenzo‐1,2,3,4‐tetrazine‐1,3‐dioxide ( DNBTDO ), was synthesized in 45 % yield. DNBTDO was characterized as an energetic material in terms of performance (V_det 8411 m s⁻¹; p_{C J} 3.3×10¹⁰ Pa at a density of 1.868 g cm⁻³), mechanical sensitivity (impact and friction as a function of grain size), and thermal stability (T_dec 204 °C). DNBTDO exhibits a sensitivity slightly higher than that of RDX , and a performance slightly lower (96 % of RDX ).     

Synthese von Hetaryl‐pyridiniumsalzen und kondensierten 3‐Amino‐pyrid‐2‐onen

1‐(3‐Coumaryl)‐pyridinium salts 3 and 1‐(3‐coumaryl)‐tetrahydrothiophenium salts 5 were synthesized from 2‐acylphenyl chloro‐ or bromoacetates 2 . 2‐Chloro‐N¹‐(3,4‐dimethoxyphenyl)‐acetamide and substituted 2‐chloro‐N¹‐(2‐thienyl)‐acetamides 8 react with acetyl chloride and pyridine to yield the quinolinyl‐ and (thieno[2,3‐b]pyridin‐5‐yl)‐pyridinium salts 10 . Fused thieno[2,3‐b]pyridin‐ones 19 were formed from N‐chloroacetyl‐2‐aminothiophen‐3‐carbonitriles 16 with pyridine via Thorpe‐Ziegler cyclization and followed by cyclodehydrogenation. In presence of pyridine alkyl 2‐chloro‐acetylaminobenzoates 21 yield 3‐(1‐pyridinio)‐quinoline‐4‐olates 23 . Zincke‐cleavage of 10 and 23 with hydrazinium hydroxide leads to fused 3‐amino‐pyridine‐2‐ones 11 and 3‐amino‐4‐hydroxy‐quinoline‐2‐ones 24 , respectively. Oxazoloquinolines 25 were synthesized from 24 with acetic anhydride.     

Platinum‐Catalyzed Divergent Reactivity of α‐Hydroxyallenes: Synthesis of Dihydrofurans and α,β‐Unsaturated Ketones

α‐Allenols were catalytically transformed into dihydrofurans in the presence of platinum dichloride. Notably, using platinum dichloride along with silver triflate as the catalytic system, α,β‐unsaturated ketones were obtained. Therefore, the role of the silver salt may not just consist in the activation of the platinum precatalyst.

     

Using Conveniently Designed α‐Amino Ketones in Michael Reactions under Iminium Catalysis: Enantioselective Synthesis of γ‐Lactams and γ‐Amino‐δ‐keto Esters

The behaviour of aminoacetophenones as Michael donors in catalytic enantioselective Michael reactions with α,β‐unsaturated aldehydes under iminium activation has been studied. These compounds react with each other in the presence of catalytic amounts of a chiral secondary amine through a Michael/hemiaminal formation cascade process which proceeds with high yields and enantiocontrol. Elaboration of these adducts by oxidation allows the easy access to chiral disubstituted γ‐lactams and other synthetically useful chiral building blocks such as γ‐amino‐δ‐keto esters or β‐substituted δ‐oxoamides are accessible from the obtained adducts by simple transformations.     

Synthese potentieller Pflanzenschutzwirkstoffe auf 2, 3‐Dihydrothiazol‐2‐thion‐Basis. I. Strukturvariationen am N3 und C4

A considerable number of potential plant protecting compounds with the core structure of 2,3‐dihydrothiazol‐2‐thione has been prepared by the reaction of dithiocarbamates with halomethylcarbonyl compounds forming N‐substituted 4‐substituted 4‐hydroxythiazolidin‐2‐thiones 2—4 , which can split off water to yield 5 . The structural variability at N₃ is given either by the amine used for dithiocarbamate synthesis or by acylation of N‐unsubstituted 2,3‐dihydrothiazol‐2‐thiones like 4i . The variability at C₄ is either achieved by the kind of the halomethylcarbonyl compound or by reactions of 4‐chloromethyl derivatives 5 , which can be transformed by a number of nucleophilic reagents to derivatives like thioethers 8 , ethers 9 , amines 10 , nitriles 11 , azides 12a , thiocyanates 12b , the primary amine 14 and derived from that the amides 15 or the ureas 16 .     

Ring Transformations of Bicyclic Cycloalka[d]‐ to the Isomeric Cycloalka[c]isothiazolium Salts and their Oxidation to ω‐(2‐Aryl‐1,1,3‐trioxo‐2,3‐dihydro‐1H‐isothiazol‐4‐yl)‐alkanoic Acids

The synthesis of tetrahydro‐2,1‐benzisothiazolium salts 8 and cyclohepta[c] isothiazolium salts 11 by ring transformation of bicyclic isothiazolium perchlorates 2 , 3 is described and the by‐products 9 , 10 and 12 are characterized. Oxidation of the bicyclic salts 8 and 11 results in a new route to obtain ω‐(2‐aryl‐1,1,3‐trioxo‐2,3‐dihydro‐1H‐isothiazol‐4‐yl)‐alkanoic acids 17 and 18 by Criegee‐type‐rearrangement.     

Synthesis and Structure of Highly Enantio‐ and Diastereoenriched 1‐Aza‐4‐oxa‐7‐thiabicyclo[3.3.0]octan‐8‐ones Derived from Acyl‐Substituted S‐Benzyl Thiocarbamates

A convenient method for the synthesis of the title compounds 4a,b, 3a,b via an intramolecular condensation of thiourethanes, derived from the acylation of enantioenriched α‐thio benzyllithium compounds, is reported. The structure of one of the major diastereomers was elucidated by a singlecrystal X‐ray analysis and compared to semiempirical calculations.     

Oxidation of Acceptor‐substituted Isothiazolium‐2‐imines to Stable Cyclic Sulfin‐ and Sulfonamides with 3‐Hydroperoxy Function

The oxidation of isothiazolium 2‐imines 3,5 and their salts 4 to stable 3‐hydroperoxy‐2,3,4,5,6,7‐hexahydro‐1,2‐benzisothiazole 1‐oxides 7 and 1,1‐dioxides 8 and 9 as a new class of cyclic sultims and sultams is described. The formation of 3‐hydroxysultams 10 and isothiazol‐3(2H)one 1,1‐dioxides 11 is presented.     

A One‐Pot Synthesis of [1,2,4]Triazino[4,3‐b]‐[1,2,4,5]tetrazines

Reactions of hydrazonoyl halides 6 with either 4‐amino‐2,3‐dihydro‐6‐substituted‐3‐thioxo‐[1,2,4]‐triazin‐5(4H)ones 1 ( 2 ) or 4‐amino‐3‐methylthio‐6‐substituted‐[1,2,4]‐triazin‐5(4H)ones 3 ( 4 ) gave [1,2,4]‐triazino‐[4,3‐b][1,2,4,5]tetrazine derivatives 9 ( 10 ), respectively. The mechanism of the reactions studied is discussed.     

Microwave‐Enhanced Efficient Regioselective Synthesis of 1,3,4‐Trisubstituted 2‐Mercaptoimidazoles on a Soluble Support

A novel efficient synthetic method for regioselective synthesis of optically active 2‐mercaptoimidazoles with three points of structural diversity was investigated on a polyethylene glycol (PEG) support. The key synthetic steps involve (i) synthesis of thiourea derivatives of polymer‐supported amino acids with isothiocyanates and (ii) one‐pot regioselective condensation of PEG‐linked thiourea with α‐bromo ketones to furnish the 2‐mercaptoimidazole skeleton under microwave conditions. An excellent regioselectivity was observed during this one‐pot condensation reaction which was further supported by NOE studies. In addition to three sets of structural diversity, supplementary chirality at the α‐position of the 2‐mercaptoimidazole skeleton is the key feature of this synthesis. A representative set of 2‐mercaptoimidazoles was efficiently assembled on soluble support utilizing various L ‐amino acids, isothiocyanates and α‐bromoaryl ketones with good yields.     

Synthese potentieller Pflanzenschutzwirkstoffe auf 2,3‐Dihydrothiazol‐2‐thion‐Basis II [1] Strukturvariationen ausgehend von einer C 4 ‐Carbaldehydfunktion

Synthesis of Potential Plant Protecting Compounds on the Basis of 2,3‐Dihydrothiazol‐2‐thione. II: Structural Variations Derived from a C ₄ ‐Carbaldehyde Function 2‐Thioxo‐3‐(3‐trifluormethylphenyl)‐2,3‐dihydrothiazol‐ 4‐carbaldehyde ( 2 ) has been prepared from the corresponding chloromethyl compound 1 by a modified Kornblum oxidation. The aldehyde function has been reacted with aromatic and heterocyclic primary amines to yield the imino compounds 3 , with hydrazino compounds to yield hydrazones 4 and with hydroxylamine or O‐substituted hydroxylamines to form the oximes 7—10 , which could be separated into pure E and Z‐isomers. The unsubstituted oxime 7 could be transformed to the carbonitrile 11 with 3,5‐dinitrobenzoylchloride. 2 could be condensed in presence of a base with the CH‐acidic 5‐position of 3‐aminorhodanine derivatives to yield 12 .     

2‐Carbaborane‐3‐phenyl‐1H‐indoles—Synthesis via McMurry Reaction and Cyclooxygenase (COX) Inhibition Activity

Cyclooxygenase‐2 (COX‐2) inhibitors have been the focus of medicinal chemistry efforts for years, and many compounds that exhibit high selectivity and affinity have been developed. As carbaboranes represent interesting pharmacophores as phenyl mimetics in drug development, this paper presents the synthesis of carbaboranyl derivatives of COX‐2‐selective 2,3‐disubstituted indoles. Despite the lability of carbaboranes under reducing conditions, 2‐carbaborane‐3‐phenyl‐1H‐indoles could be synthesized by McMurry cyclization of the corresponding amides. Whereas the meta‐carbaboranyl‐substituted derivatives lacked COX inhibitory activity, an ortho‐carbaboranyl analogue was active, but showed a selectivity shift toward COX‐1.     

Synthesis of Functionalized Azetidines through Chemoselective Zinc‐Catalyzed Reduction of β‐Lactams with Silanes

An efficient method for the one‐step conversion of β‐lactams to their corresponding functionalized azetidines has been developed. This approach takes advantage of the selective reduction of the 2‐azetidinone nucleus with hydrosilanes in the presence of a zinc‐based catalyst. The methodology is tolerant towards sensitive groups such as allene, ester, and cyanohydrin moieties. In addition, the process allows the preparation of enantiopure azetidines without erosion of the stereochemical integrity. A catalytic cycle involving an azetidinium salt intermediate has been proposed.     

Copper‐Catalyzed N‐Aryl‐β‐enaminonitrile Synthesis Utilizing Isocyanides as the Nitrogen Source

A novel synthetic protocol for N‐aryl‐β‐enaminonitriles, which are useful building blocks for heterocycle synthesis, was developed using isocyanides as the nitrogen source. Using copper‐catalyzed one‐step reactions between isocyanides and benzyl cyanides under mild conditions, diverse N‐aryl‐β‐enaminonitriles could be synthesized in excellent yields and with high atom‐efficiency. N‐Alkyl‐β‐enaminonitriles were also synthesized in good yields. A mechanism involving an imidoyl‐copper intermediate was proposed based on mechanistic studies and previous reports. In addition, we demonstrated that a synthesized N‐aryl‐β‐enaminonitrile could be utilized for the synthesis of a β‐keto nitrile compound and 3‐aminopyrazole.

     

Synthesis and Structure–Activity Relationship Studies of 2‐(1,3,4‐Oxadiazole‐2(3H)‐thione)‐3‐amino‐5‐arylthieno[2,3‐b]pyridines as Inhibitors of DRAK2

In recent years, DAPK‐related apoptosis‐inducing protein kinase 2 (DRAK2) has emerged as a promising target for the treatment of a variety of autoimmune diseases and for the prevention of graft rejection after organ transplantation. However, medicinal chemistry optimization campaigns for the discovery of novel small‐molecule inhibitors of DRAK2 have not yet been published. Screening of a proprietary compound library led to the discovery of a benzothiophene analogue that displays an affinity constant (K_d) value of 0.25 μM . Variation of the core scaffold and of the substitution pattern afforded a series of 5‐arylthieno[2,3‐b]pyridines with strong binding affinity (K_d=0.008 μM for the most potent representative). These compounds also show promising activity in a functional biochemical DRAK2 enzyme assay, with an IC₅₀ value of 0.029 μM for the most potent congener. Selectivity profiling of the most potent compounds revealed that they lack selectivity within the DAPK family of kinases. However, one of the less potent analogues is a selective ligand for DRAK2 and can be used as starting point for the synthesis of selective and potent DRAK2 inhibitors.     

A Simple Copper‐Catalyzed Cascade Synthesis of 2‐Amino‐1H‐indole‐3‐carboxylate Derivatives

We have developed a simple and efficient copper‐catalyzed method for the synthesis of 2‐amino‐1H‐indole‐3‐carboxylate derivatives via cascade reactions of substituted N‐(2‐halophenyl)‐2,2,2‐trifluoroacetamide with alkyl 2‐cyanoacetate or malononitrile under mild conditions, and the method is of wide practical application.     

A Ring‐Closing Metathesis Approach to Cyclic α,β‐Dehydroamino Acids

A comprehensive study on the synthesis and ring‐closing metathesis (RCM) of α,β‐dehydroamino acids is described. This sequence has led to the formation of a range of biologically relevant functionalized nitrogen heterocycles. The incorporation of chiral building blocks in the RCM precursors eventually resulted in the formation of optically active 4‐substituted cyclic dehydroamino acids. In addition, olefin isomerization under metathesis conditions was observed for a number of compounds, which could be successfully inhibited either by the introduction of allylic substituents or by the addition of a ruthenium hydride scavenger.     

Catalysis by β‐Cyclodextrin Hydrate – Synthesis of 2,2‐Disubstituted 2H‐Chromenes in Aqueous Medium

A cost‐effective, operationally simple and eco‐compatible protocol for the one‐pot synthesis of photochromic pyrans by the reaction of propargyl alcohols as well as propargyl ethers with differently substituted phenols under ambient atmosphere in aqueous medium has been developed using β‐cyclodextrin hydrate as an efficient, recyclable and stable catalyst. This is the first report where β‐cyclodextrin hydrate acted as a catalyst for an organic transformation but β‐cyclodextrin alone failed.