Light-enabled scalable synthesis of bicyclo[1.1.1]pentane halides and their functionalizations.

In 2012, bicyclo[1.1.1]pentanes were demonstrated to be bioisosteres of the benzene ring.

SAr or Sulfonylation? Chemoselective Amination of Halo(het)arene Sulfonyl Halides for Synthetic Applications and Ultralarge Compound Library Design.

The chemoselectivity of halo(het)arene sulfonyl halide aminations is studied thoroughly under parallel synthesis conditions, and the scope and limitations of the method are established. It is shown that SAr-reactive sulfonyl halides typically undergo sulfonamide synthesis during the first step; the second amination is also possible provided that the SAr-active center is sufficiently reactive. On the contrary, sulfonyl fluorides bearing an arylating moiety undergo selective transformation at the latter reactive center under proper control.

Challenges for chemistry in Ukraine after the war: Ukrainian science requires rebuilding and support.

The unprovoked Russian invasion has created considerable challenges for Ukrainian science. In this article, we discuss actions needed to support and rebuild Ukrainian science and educational systems. The proposed actions take into account past Ukrainian scientific achievements including developments in organic chemistry.

The Ukrainian Factor in Early-Stage Drug Discovery in the Context of Russian Invasion: The Case of Enamine Ltd.

Ukrainian companies occupy an important niche in the global drug discovery process; however, before the Russian invasion, the role of Ukraine was not obvious. The biggest Ukrainian fine chemical supplier, Enamine Ltd, had to stop operation for more than a month, which significantly affected various early-stage drug discovery projects. The role of Enamine in drug discovery and the company's past and future in the context of the Russian invasion are described in this Viewpoint.

Synthesis of α--Stereochemically Pure Secondary Sulfonamides.

A convenient "green" stereoretentive approach to -enriched secondary sulfonamides bearing an asymmetric center at the α position to the sulfur atom is described. The method relies on the electrophilic amination of the corresponding stereochemically pure sulfinates with -alkylhydroxylamine sulfonic acids (in turn easily prepared from -alkylhydroxylamine and HSOCl). It is shown that the efficiency of the approach is governed mainly by steric factors; its tolerance to several functional groups (e.

Twisting and Turning the Sulfonamide Bond: A Synthetic, Quantum Chemical, and Crystallographic Study.

Structural restriction of the sulfonamide bond was used to design sultams with abnormal geometric parameters. Based on analysis of tertiary aliphatic sulfonamides published in the Cambridge crystallographic database, Paquette's sultams (i.e.

Sulfonimidamides and Imidosulfuric Diamides: Compounds from an Underexplored Part of Biologically Relevant Chemical Space.

Two novel solid reagents-1-sulfonimidoyl- and 1-sulfamimidoyl-3-methylimidazolium derivatives-for the synthesis of sulfonimidamides and imidosulfuric diamides, respectively, were developed. It is shown that these reagents are very effective in substitution reactions with various N- and O-nucleophiles; therefore, they significantly extend the accessibility to the chemical space covered by organosulfur(VI) compounds with S=N bonds. In addition, previously unknown imidosulfuric diamides with free imino nitrogen groups were prepared, and their physical and chemical properties were characterized (including molecular geometry, pK , Log P, microsomal stability, and reactivity towards typical electrophiles).

Ultra-large library docking for discovering new chemotypes.

Despite intense interest in expanding chemical space, libraries containing hundreds-of-millions to billions of diverse molecules have remained inaccessible. Here we investigate structure-based docking of 170 million make-on-demand compounds from 130 well-characterized reactions. The resulting library is diverse, representing over 10.

Photochemical In-Flow Synthesis of 2,4-Methanopyrrolidines: Pyrrolidine Analogues with Improved Water Solubility and Reduced Lipophilicity.

A practical synthesis of 2,4-methanopyrrolidines was elaborated. The key synthetic step was an intramolecular photochemical [2 + 2]-cycloaddition of an acrylic acid derivative in flow. In spite of a higher molecular weight, 2,4-methanopyrrolidines were shown to have higher solubility in water and lower lipophilicity than pyrrolidines, important characteristics of bioactive molecules in drug design.

Regioselective synthesis of isoxazole and 1,2,4-oxadiazole-derived phosphonates via [3 + 2] cycloaddition.

The results of the study on reactions of halogenoximes bearing (protected) functional groups or fluorinated substituents with various phosphorus-containing dipolarophiles are described. To control the regioselectivity of the reaction, vinylphosphonates bearing a leaving group (i.e.

Saturated Heterocyclic Aminosulfonyl Fluorides: New Scaffolds for Protecting-Group-Free Synthesis of Sulfonamides.

Cyclic saturated aminosulfonyl fluorides were synthesized as their HCl salts. The compounds were found to be stable upon storage and could be used for the protecting-group-free synthesis of sulfonamides. In the presence of the -SO F group, the nitrogen atom could be modified by means of acylation, arylation, or reductive amination to give products that have high potential for the synthesis of bioactive compounds.

[2+2]-Photocycloaddition of N-Benzylmaleimide to Alkenes As an Approach to Functional 3-Azabicyclo[3.2.0]heptanes.

A one-step synthesis of functionalized 3-azabicyclo[3.2.0]heptanes by [2+2]-photochemical intermolecular cycloaddition of N-benzylmaleimide to alkenes was elaborated.

Synthesis of Functionalized Difluorocyclopropanes: Unique Building Blocks for Drug Discovery.

Difluorocyclopropane-containing building blocks for drug discovery were synthesized from the functionalized alkenes and TMSCF /NaI. Novel fluorinated acids, amines, amino acids, alcohols, ketones and sulfonyl chlorides were obtained.

Expanding Synthesizable Space of Disubstituted 1,2,4-Oxadiazoles.

One-pot synthesis of 3,5-disubstituted 1,2,4-oxadiazoles from carboxylic acids and nitriles was optimized to parallel chemistry. The method was validated on a 141 member library; the desired products were recovered with a high success rate and in moderate yields. Practical application of the approach was demonstrated in the synthesis of bioactive compound pifexole and agonists of free fatty acid receptor 1.

2,2,2-Trifluoroethyl Chlorooxoacetate--Universal Reagent for One-Pot Parallel Synthesis of N(1)-Aryl-N(2)-alkyl-Substituted Oxamides.

A one-pot parallel synthesis of N(1)-aryl-N(2)-alkyl-substituted oxamides with 2,2,2-trifluoroethyl chlorooxoacetate was developed. The synthesis of a library of 45 oxamides revealed higher efficiency of this reagent over the known ethyl chlorooxoacetate. The reagent was successfully used to prepare the known oxamide-containing HIV entry inhibitors.

One-Pot Parallel Synthesis of Alkyl Sulfides, Sulfoxides, and Sulfones.

A simple and cost-effective one-pot parallel synthesis approach to sulfides, sulfoxides, and sulfones from thiourea was elaborated. The method combines two procedures optimized to the parallel synthesis conditions: alkylation of thiourea with alkyl chlorides and mono or full oxidation of in situ generated sulfides with H2O2 or H2O2-(NH4)2MoO4. The experimental set up required commonly used lab equipment: conventional oven and ultrasonic bath; the work up includes filtration or extraction with chloroform.

Crystal structure of (S)-1-(1,3-benzo-thia-zol-2-yl)-2,2,2-tri-fluoro-ethanol.

In the title compound, C9H6F3NOS, the 1,3-benzo-thia-zole ring system is essentially planar, with an r.m.s.

A one-pot parallel reductive amination of aldehydes with heteroaromatic amines.

A parallel reductive amination of heteroaromatic amines has been performed using a combination of ZnCl2-TMSOAc (activating agents) and NaBH(OAc)3 (reducing agent). A library of diverse secondary amines was easily prepared on a 50-300 mg scale.

Bis(2,2,2-trifluoroethyl) carbonate as a condensing agent in one-pot parallel synthesis of unsymmetrical aliphatic ureas.

One-pot parallel synthesis of unsymmetrical aliphatic ureas was achieved with bis(2,2,2-trifluoroethyl) carbonate. The procedure worked well for both the monosubstituted and functionalized alkyl amines and required no special conditions (temperature control, order, or rate of addition). A library of 96 diverse ureas was easily synthesized.

Sulfonyl fluorides as alternative to sulfonyl chlorides in parallel synthesis of aliphatic sulfonamides.

Two types of aliphatic sulfonyl halides (Cl versus F) were compared in parallel synthesis of sulfonamides derived from aliphatic amines. Aliphatic sulfonyl fluorides showed good results with amines bearing an additional functionality, while the corresponding chlorides failed. Both sulfonyl halides were effective in the reactions with amines having an easily accessible amino group.

Synthesis and reactivity of 5-polyfluoroalkyl-5-deazaalloxazines.

Reaction of 6-arylamino-1,3-dialkyluracils with anhydrides of polyfluorocarboxylic acids in the presence of pyridine and subsequent cyclization with concentrated H2SO4 gave the corresponding 1,3-dialkyl-5-(polyfluoroalkyl)pyrimido[4,5-b]quinoline-2,4(1H,3H)-diones (5-polyfluoroalkyl-5-deazaalloxazines). The reactivity of these compounds towards nucleophilic reagents, such as sodium cyanoborohydride, acetophenone, nitromethane, potassium cyanide, indole and p-thiocresol, as well as Suzuki and Sonogashira couplings are described. The nucleophilic addition takes place at the 5-position of the 5-deazaalloxazine system and is in many cases irreversible to give 5,10-dihydropyrimido[4,5-b]quinoline-2,4(1H,3H)-dione derivatives in good to excellent yields.

A solution-phase parallel synthesis of alkylated guanidines from thioisocyanates and amines.

An efficient solution-phase parallel synthesis of alkylated guanidines from commercial thioisocyanates and amines is described. In the first step, a thioisocyanate reacts with one equivalent of ammonia or a primary or secondary amine to give a thiourea intermediate. The latter is S-alkylated with n-dodecyl bromide resulting in the corresponding thiouronium bromide.

Conformational behaviour of peptides containing a 2-pyrrolidinemethanesulfonic acid (2PyMS) residue.

The conformational behaviour of model peptides containing a 2-pyrrolidinemethanesulfonic acid (2PyMS) residue was studied in both the crystalline state and in solution using X-ray, NMR and IR experiments. It was found that in crystals dipeptide PhC(O)-2PyMS-Phe-NHiPr adopted β-turn conformation, which was not stabilized by an intramolecular hydrogen bond and could be classified as a type IV β-turn. In the crystalline state tripeptide PhC(O)-Ala-2PyMS-Phe-NHiPr existed as an α-turn with uncommon cis-conformation of the amide bond formed by the pyrrolidine nitrogen atom of the 2PyMS residue, for which no close analogue can be envisaged among the tight turns identified so far.

The synthesis of low molecular weight pyrrolo[2,3-c]pyridine-7-one scaffold.

A facile method for the synthesis of substituted pyrrolo[2,3-c]pyridine-7-ones is developed that applies an acid-promoted intramolecular cyclization of 2-pyrrolecarboxylic acid amidoacetals as key step. The synthesis is easily scaled up to 1.5 mol quantity with no yield decrease.

Combinatorial synthesis of chemical building blocks 1. Azomethines.

128 Azomethines were synthesized through condensation of carbonyl compounds with various amines in pyridine in the presence of Me(3)SiCl as promoter and water scavenger in 58-98 % yield. Et(3)N was added to reaction mixtures before precipitating the product with H(2)O to prevent acid catalyzed hydrolysis of the C=N bond. The scope and limitation of the method are discussed.