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. Finally, the reaction of the thiouronium salt with a second equivalent of ammonia or a primary amine yields an alkylated guanidine. All three synthetic steps are easily combined in a one-pot high-yielding procedure with a simple work-up. Ca. 250 guanidine derivatives with high structural and functional diversity were synthesized by the developed method. 35 representatives reported in this study were fully characterized.

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. High yields and simple setup/workup procedure make this method suitable for the combinatorial synthesis of azomethines, which are suitable as starting materials for high throughput synthesis of various combinatorial libraries. The azomethines synthesized were used as starting materials in a one-pot combinatorial synthesis of amines and amides.

One-Pot Parallel Synthesis of 5-(Dialkylamino)tetrazoles.

Two protocols for the combinatorial synthesis of 5-(dialkylamino)tetrazoles were developed. The best success rate (67%) was shown by the method that used primary and secondary amines, 2,2,2-trifluoroethylthiocarbamate, and sodium azide as the starting reagents. The key steps included the formation of unsymmetrical thiourea, subsequent alkylation with 1,3-propane sultone and cyclization with azide anion. A 559-member aminotetrazole library was synthesized by this approach; the overall readily accessible (REAL) chemical space covered by the method exceeded 7 million feasible compounds.

An Old Story in the Parallel Synthesis World: An Approach to Hydantoin Libraries.

An approach to the parallel synthesis of hydantoin libraries by reaction of in situ generated 2,2,2-trifluoroethylcarbamates and α-amino esters was developed. To demonstrate utility of the method, a library of 1158 hydantoins designed according to the lead-likeness criteria (MW 200-350, cLogP 1-3) was prepared. The success rate of the method was analyzed as a function of physicochemical parameters of the products, and it was found that the method can be considered as a tool for lead-oriented synthesis. A hydantoin-bearing submicromolar primary hit acting as an Aurora kinase A inhibitor was discovered with a combination of rational design, parallel synthesis using the procedures developed, in silico and in vitro screenings.

(Chlorosulfonyl)benzenesulfonyl Fluorides-Versatile Building Blocks for Combinatorial Chemistry: Design, Synthesis and Evaluation of a Covalent Inhibitor Library.

Multigram synthesis of (chlorosulfonyl)benzenesulfonyl fluorides is described. Selective modification of these building blocks at the sulfonyl chloride function under parallel synthesis conditions is achieved. It is shown that the reaction scope includes the use of (hetero)aromatic and electron-poor aliphatic amines (e.g., amino nitriles). Utility of the method is demonstrated by preparation of the sulfonyl fluoride library for potential use as covalent fragments, which is demonstrated by a combination of in silico and in vitro screening against trypsin as a model enzyme. As a result, several inhibitors were identified with activity on par with that of the known inhibitor.

Facile One-Pot Parallel Synthesis of 3-Amino-1,2,4-triazoles.

A 1,2,4-triazole motif is present in numerous commercialized and investigational bioactive molecules. Despite its importance for medicinal chemistry, there is a lack of convenient combinatorial approaches toward this molecular core. Herein, we present a synthetic strategy suitable for the quick preparation of a library of structurally diverse 1,2,4-triazoles in a one-pot setting. The key steps include the formation of thioureas followed by S-alkylation using 1,3-propane sultone and consecutive ring closure leading to the desired 1,2,4-triazoles. Parallel synthesis yields thousands of 1,2,4-triazoles in a cost- and time-efficient manner from commercially available chemicals.

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. A library of 4 948 100 synthesizable drug-like 3,5-disubstituted 1,2,4-oxadiazoles was enumerated based on the method and available validated reagents.

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. The method was evaluated on an 81 member library of drug-like sulfides, sulfoxides, and sulfones yielding the compounds on a 30-300 mg scale. A small-scale synthesis of 2-(benzhydrylsulfinyl)acetamide (modafinil) utilizing our approach resulted in similar efficiency to the published procedures.

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.

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. Aliphatic sulfonyl chlorides reacted efficiently with amines bearing sterically hindered amino group while the corresponding fluorides showed low activity.

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.

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.

Combinatorial Knoevenagel reactions.

Chlorotrimethylsilane (TMSCl) has been utilized as an efficient promoter and water scavenger in the Knoevenagel condensations of aromatic aldehydes with various methylene active compounds. High yields and a simple workup of target compounds enables the facile generation of combinatorial libraries comprising 11,000 compounds of high structural and functional diversity.