ABSTRACT
The title compound, C(18)H(13)FN(2)OS, is the first structural example of a [6-5] fused ring incorporating the 2,3-dihydro-4H-imidazo[5,1-b][1,3]thiazin-4-one molecular scaffold. The six-membered 2,3-dihydro-1,3-thiazin-4-one ring adopts an envelope conformation, with the S-CH(2) C atom displaced by 0.761 (2) A from the five-atom plane (all within 0.05 A of the mean plane). The imidazole ring is planar. The phenyl ring is twisted from coplanarity with the imidazole ring by 23.84 (5) degrees and the 4-fluorophenyl ring is twisted by 53.36 (6) degrees , due to a close C(aryl)-H...O=C contact with the thiazin-4-one carbonyl O atom. The primary intermolecular interaction involves a CH(2) group with the F atom [C...F = 3.256 (2) A and C-H...F = 137 degrees ].
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemistry , Imidazoles/chemistry , Thiazines/chemistry , Crystallization , Crystallography, X-Ray , Hydrogen BondingABSTRACT
The solution-phase synthesis of a discovery library of 178 tricyclic pyrrole-2-carboxamides was accomplished in nine steps and seven purifications starting with three benzoyl-protected amino acid methyl esters. Further diversity was introduced by two glyoxaldehydes and 41 primary amines. The combination of Pauson-Khand, Stetter, and microwave-assisted Paal-Knorr reactions was applied as a key sequence. The discovery library was designed with the help of QikProp 2.1, and physicochemical data are presented for all pyrroles. Library members were synthesized and purified in parallel and analyzed by LC/MS. Selected compounds were fully characterized.
Subject(s)
Amides/chemical synthesis , Carboxylic Acids/chemistry , Heterocyclic Compounds, 3-Ring/chemical synthesis , Pyrroles/chemistry , Pyrroles/chemical synthesis , Combinatorial Chemistry Techniques , Computational Biology , Computer Simulation , Gas Chromatography-Mass Spectrometry , Molecular Structure , Pharmaceutical Preparations , StereoisomerismABSTRACT
Cascade reactions of internal and terminal alkynes, zirconocene hydrochloride, dimethylzinc, and phosphinoyl imines (prepared in one step from aldehydes and diphenylphosphinoyl amide) lead to allylic phosphinoyl amides after aqueous workup. Microwave acceleration allows the completion of this one-pot reaction sequence in 10 min. These allylic amides can be converted into a variety of derivatives, including carbamates and sulfonamides, or reacted prior to workup with diiodomethane to give novel C-cyclopropylalkylamides. A solution-phase "libraries from libraries" approach was used to generate an intermediate 20-member library which was subsequently expanded to a 100-member library by a series of N-functionalizations. The biological activity was evaluated in an assay for competitive binding to the estrogen receptor (ERalpha), revealing three potent lead compounds of a new structural type.
Subject(s)
Allyl Compounds/chemical synthesis , Amides/chemical synthesis , Combinatorial Chemistry Techniques/methods , Estrogen Receptor alpha/chemistry , Microwaves , Allyl Compounds/chemistry , Allyl Compounds/pharmacology , Amides/chemistry , Amides/pharmacology , Binding, Competitive , Molecular Structure , Structure-Activity RelationshipABSTRACT
An effective synthesis of the functionalized indole ring system has been developed from substituted o-aminostyrene starting material. Our methodology involves a novel cascade reaction sequence of alkyllithium addition to the styrene double bond and subsequent trapping of the intermediate organolithium with a suitable electrophile, followed by an in situ ring closure and dehydration to generate the indole ring. This new reaction sequence allows for the introduction of molecular diversity at all positions on the indole scaffold. The procedure was shown to be successful with a range of both C and N substituents on the o-aminostyrenes. The reaction sequence was tolerant to the reactivity range of alkyllithiums such as tert-, sec-, and n-butyllithium. The electrophiles used were DMF, which generated indole products with C-2 unsubstituted, and nitriles, which incorporated the nitrile substituent at C-2. The o-aminostyrene starting materials were generated by a Pd-catalyzed cross-coupling reaction of a vinyl boronic acid equivalent with the readily available substituted o-bromoanilines.
ABSTRACT
The molecule of the title compound, C(19)H(27)NO(3), is essentially planar, with all non-H atoms within 0.2 A of the nine-membered indole plane, except for the three tert-butyl C atoms. The C(5) pentyl chain is in an extended conformation, with three torsion angles of 179.95 (13), 179.65 (13) and -178.95 (15) degrees (the latter two angles include the C atoms of the C(5) chain only). Three intramolecular C-H.O=C contacts are present (C.O < 3.05 A and C-H.O > 115 degrees ), and an intermolecular C-H.O=C contact and pi-pi stacking complete the intermolecular interactions.
ABSTRACT
A novel synthetic approach to diversely functionalized indoles is described. Boc-protected ortho-aminostyrenes undergo an alkyllithium addition reaction, thereby generating a lithiated intermediate, which upon reaction with specific electrophiles sets up a cascade reaction process between the reacted electrophile and ortho-amino substituent, facilitating an in situ ring closure, followed by dehydration, to generate an indole ring system. This methodology is demonstrated by the synthesis of a range of 3,5-, 1,3,5-, and 2,3,5-substituted indoles.
Subject(s)
Indoles/chemical synthesis , Lithium/chemistry , Organometallic Compounds/chemistry , Styrenes/chemistryABSTRACT
A methodology for the microwave parallel synthesis of libraries is described. The procedure involves the use of an array of expandable reaction vessels, which can accommodate pressure buildup within the vessel due to heating without loss of volatile solvents or reagents. A demonstration 24-membered library of substituted 4(5)-sulfanyl-1H-imidazoles was generated by both conventional and microwave procedures, achieving a reduction from 12 h to 16 min in library generation time for the microwave approach.
