RESUMO
Advanced analogs of piperidine and smaller homologues of tropaneâ3-substituted 6-azabicyclo[3.1.1]heptanesâwere synthesized on a large scale using readily available bulk reagents. The key step of the approach involved the double alkylation reaction of malonate with cis-2,4-bis(mesyloxymethyl)azetidine-1-carboxylate, in turn easily prepared on up to 1 kg scale. After hydrolysis, N-Boc-6-azabicyclo[3.1.1]heptane-3,3-dicarboxylic acid was obtained (up to 400 g in a single run), which was used as a common intermediate for the preparation of all the title building blocks. In particular, Pb(OAc)4-mediated oxidative decarboxylation of this intermediate gave 2,6-methanopiperidone derivative (up to 400 g scale), while monodecarboxylation gave N-Boc-6-azabicyclo[3.1.1]heptane-3-carboxylic acids as an easily separatable mixture of cis and trans diastereomers (up to 100 g scale). Further functional group transformations gave diastereopure cis- and trans-N-Boc-monoprotected diamines and amino alcohols. Molecular structure analysis using exit vector parameters (EVP) revealed that cis isomers of 3-substituted 6-azabicyclo[3.1.1]heptanes are three-dimensional analogs of common 1,4-disubstituted piperidine chair conformer, whereas trans isomers can be considered as unusual "boat" piperidines.
RESUMO
This review disclosed synthetic approaches to sulfonyl amides from non-sulfonyl halogenated precursors. Known methods were systematized into groups and subgroups according to the type of starting organosulfur compound. Thiols, disulfides, and sulfonamides form a group of S(II)-containing precursors, which are used in oxidative amination reactions. An important and versatile group for oxidative amination is represented with S(IV)-containing compounds, i. e., sufinates, sulfinamides, DMSO, N-sulfinyl-O-(tert-butyl)hydroxylamine, etc. A series of S(VI)-containing precursors for amination reactions (except sulfonyl halides) include sulfonic acids, sulfonyl azides, thiosulfonates, and sulfones. All approaches are represented with the most prominent examples of the resulting sulfonamides, which could be obtained in high yields mostly via short reaction sequences. Promising electrochemical methods for the preparation of sulfonamides from thiols, disulfides, sulfonamides, sulfinic acid derivatives, and dimethyl sulfoxide under mild and green conditions are also highlighted.
RESUMO
Electrophilic double bond functionalization - intramolecular enolate alkylation sequence was used to obtain a series of bridged and fused bicyclo[m.n.k]alkane derivatives (i. e., bicyclo[4.1.1]octanes, bicyclo[2.2.1]heptanes, bicyclo[3.2.1]octanes, bicyclo[3.1.0]hexanes, and bicyclo[4.2.0]heptanes). The scope and limitations of the method were established, and applicability to the multigram synthesis of target bicyclic compounds was illustrated. Using the developed protocols, over 50 mono- and bifunctional building blocks relevant to medicinal chemistry were prepared. The synthesized compounds are promising isosteres of benzene and cycloalkane rings, which is confirmed by their physicochemical and structural characterization (pKa , LogP, and exit vector parameters (EVP)). "Rules of thumb" for the upcoming isosteric replacement studies were proposed.
RESUMO
A series of seven palladium-containing composites, i.e., four Pd/C and three Pd(OH)2/C (Pearlman's catalysts), was prepared using modified common approaches to deposition of Pd or hydrated PdO on charcoal. All the composites were tested in the catalytic hydrogenation of diene carboxylates with the isolated-ring scaffold, e.g., 5,6-dihydropyridine-1(2H)-carboxylates with 2-(alkoxycarbonyl)cyclopent-1-en-1-yl and hex-1-en-1-yl substituents at the C(4)-position. The performance of the composites was also studied via the hydrogenation of quinoline as a model reaction. The composites were characterized by transmission and scanning electron microscopy (TEM and SEM), powder X-ray diffraction, and low-temperature N2 adsorption. It was found that the composites containing Pd nanoparticles (NPs) of 5-40 nm size were the most efficient catalysts for the hydrogenation of dienes, providing the reduced products with up to 90% yields at p(H2) = 100 atm, T = 30 °C for 24 h. The method of Pd NPs formation had more effect on the catalyst performance than the size of the NPs. The catalytic performance of Pearlman's catalysts (Pd(OH)2/C) in the hydrogenation of dienes was comparable to or lower than the performance of the Pd/C systems, though the Pearlman's catalysts were more efficient in the hydrogenation of quinoline.
RESUMO
A scalable and efficient process for the preparation of 3-borylated pyrrolidines by 1,3-dipolar cycloaddition of N-benzyl azomethine ylide generated inâ situ has been developed. The optimized method included the use of LiF in DMSO at 110 °C and was suitable for α-mono-, α,ß-di-, and α,ß,ß-trialkyl-, ß,ß-(hetera)cycloalkylidene-, CO2 Et-, as well as most ß-(het)aryl-substituted alkenyl boropinacolates. The 1,3-dipolar reaction proceeded on a multigram scale providing 3-borylated pyrrolidines with diverse substitution patterns (including fused and spirocyclic ones) in a diastereoselective manner. The Pd(OH)2 -mediated N-debenzylation of pyrrolidine hydrochlorides was successfully performed to give the corresponding bifunctional building blocks on an up to 130â g scale, thus providing a substantial expansion of the synthetic and medicinal chemist's toolbox. Other reactions included the preparation of trifluoroborates, Zweifel-Aggarwal sp3 -sp2 coupling, and oxidative deborylation as an example of C-heteroatom bond formation.
Assuntos
Dióxido de Carbono , Dimetil Sulfóxido , Compostos Azo , Reação de Cicloadição , Pirrolidinas/química , TiossemicarbazonasRESUMO
An efficient synthesis (up to a 200 g scale) of 3-hydroxypyrrolidin-2-ones bearing alkyl substituents or functional groups at the C-5 position is described. The reaction sequence started from 1,3-dipolar cycloaddition of in situ generated nitrile oxides with (meth-)acrylates into 3-substituted isoxazoline-5-carboxylates. The catalytic hydrogenolysis of the isoxazoline N-O bond was optimal upon using H2 (1 atm) at rt, with the following order of the catalyst activity: Pd-C > Pd(OH)2-C > Pt-C. The reactions with Pt-C were more selective for the synthesis of pyrrolidones, while Pd-C provided the fastest conversion rates. The stirring efficiency had a positive impact on conversion rather than elevated temperatures (up to 40 °C) or pressure (up to 50 atm). The diastereoselectivity was governed mainly by steric factors, with a dr of 1:1 to 3:1 (cis- and trans-isomers could be separated). Higher homologues (isoxazolinylacetates and -propanoates) were suitable for the synthesis of 6- or 7-substituted 4-hydroxypiperidones and 5-hydroxyazepanones, respectively. The proposed methods are tolerant to functional groups, including CF3 (but not CHF2 or CH2Cl), ester, and most N-Boc-protected amines. The utility of hydroxyl groups in lactams was shown by functional group transformations. Hydrogenolysis of C(5)-functionalized isoxazolines, bearing trimethylsilyl, phosphonate, or sulfone groups, was also studied to demonstrate limitations.
Assuntos
Aminas , Lactamas , Catálise , Reação de Cicloadição , EstereoisomerismoRESUMO
One-pot intramolecular cyclization of novel sp3-enriched cyanoalkylsulfonyl fluorides into spirocyclic ß- or γ-sultams is disclosed. The method relies on nitrile group reduction followed by sulfonylation of amino group thus formed upon mild conditions (NaBH4, NiCl2·6H2O in MeOH). Cyclization proceeds smoothly with considerable efficiency (48-84%, 10 examples) on up to 30 g scale. The cyanoalkylsulfonyl fluoride intermediates can be obtained via S-nucleophilic substitution in ß-functionalized alkanenitriles or double alkylation of α-alkylthioacetonitrile, followed by oxidative chlorination with Cl2 and further reaction with KHF2. The title mono- and bifunctional sultams are advanced sp3-enriched building blocks for drug discovery and organic synthesis providing novel substitution patterns and frameworks mimicking saturated nitrogen heterocycles such as pyrrolidine/pyrrolidone.
RESUMO
The synthesis of 3-azabicyclo[3.2.0]heptyl boropinacolates and trifluoroborates via the [2 + 2] photocycloaddition of the corresponding alkenyl boronic derivatives and maleimides or maleic anhydride is described. Optimization of the reaction conditions (i.e., wavelength, concentration of the reagents, photosensitizer) was carried out, and the scope and limitations of the method were studied. Alkenyl boronic acid pinacolates were found to be more suitable for the [2 + 2] cycloaddition, providing better reaction outcomes compared to the trifluoroborates. The utility of this approach was shown by the preparation of bi- and trifunctional building blocks (21 examples), which could be easily synthesized on up to 60 g scale. These cycloadducts provide a convenient entry into the 3-azabicyclo[3.2.0]heptane scaffold through the C-C coupling or oxidative deborylation reactions.
RESUMO
An approach to 1,3-disubstitued bicyclo[2.1.0]pentane (housane) derivatives was developed. The method relied on lithium bis(trimethylsilyl)amide-mediated intramolecular cyclization of trisubstitued cyclopentane carboxylates bearing a leaving group (at the C-4 position) and an additional substituent (at the C-3 atom), in turn synthesized from cyclopent-3-ene carboxylate. The synthetic sequence allowed for the preparation of both cis- and trans-1,3-disubstituted housane-1-carboxylic acids in diastereoselective manner on up to 80 g scale. In particular, bicyclic γ-amino acids-γ-aminobutyric acid analogues-were synthesized. It was shown that the bicyclo[2.1.0]pentane did not significantly affect pKa of the corresponding derivatives and slightly increased their hydrophilicity (by 0.07-0.25 Log P units) as compared to cyclopentane. X-ray diffraction studies showed that cis- and trans-1,3-disubstituted housanes can be considered as flattened analogues of the corresponding cyclopentane derivatives with fixed envelope conformation of the five-membered ring.
RESUMO
A comprehensive study on the synthesis of 5-fluoroalkyl-substituted isoxazoles starting from functionalized halogenoximes is reported. One-pot metal-free [3 + 2] cycloaddition of CF3-substituted alkenes and halogenoximes bearing ester, bromo, chloromethyl, and protected amino groups was developed for the preparation of 5-trifluoromethylisoxazoles. The target 3,5-disubstituted derivatives were obtained in a regioselective manner in good to excellent yield on up to 130 g scale. 5-Fluoromethyl- and 5-difluoromethylisoxazoles were synthesized by late-stage deoxofluorination of the corresponding 5-hydroxymethyl or 5-formyl derivatives, respectively, in turn prepared via metal-free cycloaddition of halogenoximes and propargylic alcohol. An alternative approach based on nucleophilic substitution in 5-bromomethyl derivatives was found to be more convenient for the preparation of 5-fluoromethylisoxazoles. Reaction of isoxazole-5-carbaldehydes with the Ruppert-Prakash reagent was used for the preparation of (ß,ß,ß-trifluoro-α-hydroxyethyl)isoxazoles. Utility of described approaches was shown by multigram preparation of side-chain functionalized mono-, di-, and trifluoromethylisoxazoles, for example, fluorinated analogues of ABT-418 and ESI-09.
Assuntos
Isoxazóis/síntese química , Oximas/química , Ciclização , Isoxazóis/química , Estrutura Molecular , EstereoisomerismoRESUMO
An approach to di- and trihetera[3.3.n]propellanes (n = 2-4 ), advanced morpholine and piperazine analogues, is developed. The key step of the reaction sequence included a [3â¯+â¯2] cycloaddition reaction of unsaturated vicinal dicarboxylic acid derivatives and in situ generated azomethine ylide resulting in the formation of the pyrrolidine ring. One more heteroaliphatic ring (i.e., pyrrolidine or tetrahydrofuran) was annelated by nucleophilic cyclization of the appropriate 1,4-dielectrophilic intermediates. There were 11 examples of the title products obtained in 3-5 steps on a multigram scale with 10-72% overall yields. Additionally, molecular structures of homologous dihetera[3.3.n]propellanes, analogues of morpholine, were obtained from X-ray diffraction studies and analyzed using exit vector plots (EVPs). It was shown that the scaffolds obtained are somewhat larger as compared to the parent morpholine and bicyclic 3-oxa-7-azabicyclo[3.3.0]octane. Moreover, despite very similar chemical structures, they provide a very distinct spatial position of heteroatoms, which is clearly seen from the conformation adopted by a formal eight-membered ring including both N and O atoms (i.e., crown, boat-chair, twist chair-chair, and boat-boat for the oxaza[3.3.2]-, -[3.3.3]-, -[4.3.3]propellanes, and 3-oxa-7-azabicyclo[3.3.0]octane, respectively).