Saturated Heterocycles Research Articles

Heteroaliphatic Dimethylphosphine Oxide Building Blocks: Synthesis and Physico‐Chemical Properties

AbstractScalable synthesis of saturated heterocyclic dimethyl phosphine oxides (derivatives of azetidine, pyrrolidine, piperidine, and morpholine) is disclosed. The key steps of the synthesis relied on the reactions of HP(O)Me2, i. e. the phospha‐Mannich (the Kabachnik‐Fields‐type) condensation with cyclic imines or monoprotected diamines, palladium‐catalyzed reactions of alkenyl halides or trifltates (generated from cyclic ketones), as well as base‐mediated nucleophilic substitution, Michael addition, or oxirane ring opening. It was shown that introducing the P(O)Me2 group into the saturated heterocyclic core had very strong impact on the compound's basicity: the corresponding α‐, β‐, and γ‐isomeric derivatives were by ca. 4, 2, and 1.6 pKa units less basic, respectively, as compared to the parent saturated heterocycle. Meanwhile, the P(O)Me2‐substituted compound was more basic than its SO2i‐Pr and SO2NMe2‐containing isosteres (by ca. 1.2 and 0.4 pKa units, respectively). It was also demonstrated that the P(O)Me2 group typically increased the compound's hydrophilicity and aqueous solubility. In particular, the LogP values for the corresponding derivatives were by ca. 1.4–1.7 and 0.6 units lower than for the non‐substituted counterpart and sulfonamide/sulfone isosteres, respectively. Finally, a potential of the synthesized building blocks to generate lead‐like three‐dimensional compound libraries was confirmed using the Nelson's LLAMA tool.

DNA-encoded C[sbnd]H functionality via photoredox-mediated hydrogen atom transformation catalysis

We described a mode of catalytic activation that accomplished the α-alkylation of N-Boc saturated heterocycles with DNA-linked acrylamide via photoredox-mediated hydrogen atom transfer (HAT) catalysis. This C(sp3)-C(sp3) bond formation reaction tolerated five-, six- and seven-membered cyclic substrates, substantially streamline synthetic efforts to functionalize the α-position of heterocycles with native CH functional handle. This photoredox catalyzed CH functionalization proceeded in mild DNA-compatible condition, and suited for the construction of DNA-encoded libraries.

Non-Directed β- or γ-C(sp3)–H Functionalization of Saturated Nitrogen-Containing Heterocycles

AbstractReactions that take place via C–H functionalization are valuable tools in organic synthesis because they can be used for the synthesis of target compounds and for the late-stage functionalization of bioactive compounds. Among these, non-directed C(sp3)–H functionalization reactions of saturated nitrogen-containing heterocycles have been developed in recent years. However, most of these lead to functionalization at the α-position relative to the heteroatom, and reactions at the β- or γ-positions are limited since these bonds are stronger and less electron-rich. Hence, in this review, we will discuss non-directed β- or γ-C(sp3)–H functionalization reactions of saturated nitrogen-containing heterocycles, which are of recent interest to medicinal chemists. These methods are attractive in order to avoid the pre-functionalization of substrates, and to reduce the number of synthetic steps and the formation of byproducts. Such non-directed β- and γ-C(sp3)–H functionalization reactions can be divided into enamine-intermediate-mediated processes and other reaction types described in this review. 1 Introduction2 Non-Directed β-C(sp3)–H Functionalization of Saturated Nitrogen­-Containing Heterocycles via an Enamine Intermediate2.1 Non-Directed β-C(sp3)–H Functionalization of Saturated Nitrogen­-Containing Heterocycles under Acidic, Basic or Thermal Conditions2.2 Non-Directed β-C(sp3)–H Functionalization of Saturated Nitrogen­-Containing Heterocycles under Oxidative Conditions2.3 Non-Directed β-C(sp3)–H Functionalization of Saturated Nitrogen­-Containing Heterocycles under Redox-Neutral Conditions3 Strategies for Non-Directed β- or γ-C(sp3)–H Functionalization of Saturated Heterocycles Excluding Examples Proceeding via an Enamine Intermediate 4 Summary

Copper-Mediated Radical-Polar Crossover Enables Photocatalytic Oxidative Functionalization of Sterically Bulky Alkenes.

Oxidative heterofunctionalization reactions are among the most attractive methods for the conversion of alkenes and heteroatomic nucleophiles into complex saturated heterocycles. However, the state-of-the-art transition-metal-catalyzed methods to effect oxidative heterofunctionalizations are typically limited to unhindered olefins, and different nucleophilic partners generally require quite different reaction conditions. Herein, we show that Cu(II)-mediated radical-polar crossover allows for highly efficient and exceptionally mild photocatalytic oxidative heterofunctionalization reactions between bulky tri- and tetrasubstituted alkenes and a wide variety of nucleophilic partners. Moreover, we demonstrate that the broad scope of this transformation arises from photocatalytic alkene activation and thus complements existing transition-metal-catalyzed methods for oxidative heterofunctionalization. More broadly, these results further demonstrate that Cu(II) salts are ideal terminal oxidants for photoredox applications and that the combination of photocatalytic substrate activation and Cu(II)-mediated radical oxidation can address long-standing challenges in catalytic oxidation chemistry.

Zirconium Catalyzed Hydroaminoalkylation for the Synthesis of α-Arylated Amines and N-Heterocycles.

The zirconium catalyzed hydroaminoalkylation of alkenes with N-aryl- and sterically demanding N-alkyl-α-arylated secondary amines by using commercially available Zr(NMe2 )4 is reported. N-phenyl- and N-isopropylbenzylamine are used as amine substrates to establish the alkene substrate scope. Exclusively linear products are obtained in the presence of bulky vinylsilanes. Challenging α-heteroarylated amines and functionalized alkene substrates are compatible with this easy to use catalyst, affording a new disconnection strategy for the atom- and step-economic preparation of selectively substituted saturated α-arylated heterocycles.

One-photon VUV-MATI and two-photon IR+VUV-MATI spectroscopic determination of oxetane cation ring-puckering vibrations and conformation.

The conformational structures of heterocyclic compounds are of considerable interest to chemists and biochemists as they are often the constituents of natural products. Among saturated four-membered heterocycles, the conformational structure of oxetane is known to be slightly puckered in equilibrium because of a low interconversion barrier in its ring-puckering potential, unlike cyclobutane and thietane. We measured the one-photon vacuum ultraviolet mass-analyzed threshold ionization (VUV-MATI) and two-photon IR+VUV-MATI spectra of oxetane for the first time to determine the ring-puckering potential of the oxetane cation and hence its conformational structure in the D0 (ground) state. Remarkably, negative anharmonicity and large amplitudes were observed for the ring-puckering vibrational mode progression in the low-frequency region of the observed MATI spectra. We were able to successfully analyze the progression in the MATI spectra through the Franck-Condon simulations, using modeled potential energy functions for the ring-puckering modes in the S0 and D0 states. Considering that the interconversion barrier and puckered angle for the ring-puckering potential on the S0 state were found to be 15.5 cm-1 and 14°, respectively, the cationic structure is expected to be planar with C2v symmetry. Our results revealed that the removal of an electron from the nonbonding orbitals on the oxygen atom in oxetane induced the straightening of the puckered ring in the cation owing to an increase in ring strain. Consequently, we conclude that this change in the conformational structure upon ionization generated the ring-puckering vibrational mode progression in the MATI spectra.

Catalyst and Additive‐Free Selective Ring‐Opening Selenocyanation of Heterocycles with Elemental Selenium and TMSCN

AbstractA catalyst and additive‐free strategy for selective ring‐opening selenocyanation of saturated heterocycles with elemental selenium and TMSCN is developed, affording a series of aliphatic selenocyanates and selenaheterocycles. In the case of unprotected unstrained N‐heterocycles, the reactions offer ammonium selenonitriles that prove to be an efficient selenonitrile reagent.magnified image

Efficient Synthesis of Pharmaceutically Relevant Prochiral Heterocyclic Aminoketones

In this work, we report a practical method for alkylation of saturated heterocycles with chloroacetone yielding prochiral heterocyclic ketones, including previously not described molecules. The desired building blocks were obtained with high yields in hydrochloric salt forms, without the need for chromatographic purification.

A Stereoselective aza-Prins Reaction: Rapid Access to Enantiopure Piperidines and Pipecolic Acids

The aza-Prins reaction is a widely employed and highly efficient method for the preparation of saturated nitrogen-containing heterocycles. Its major drawback has always been a lack of diastereoselectivity and the formation of racemic products. Herein, we address these problems and report, for the first time, the synthesis of both diastereomerically and enantiopure multiply substituted piperidines via the aza-Prins reaction. This method is widely applicable for natural product synthesis and is exemplified here by the synthesis of enantiopure pipecolic acid derivatives.

Recent strategies used in the synthesis of saturated four-membered heterocycles.

The importance and prevalance of O-, N-, and S-atom containing saturated four-membered ring motifs in biologically active molecules and potential therapeutics continues to drive efforts in their efficient synthetic preparation. In this review, general and recent strategies for the synthesis of these heterocycles are presented. Due to the limited potential bond disconnections, retrosynthetic strategies are broadly limited to cyclizations and cycloadditions. Nonetheless, diverse approaches for accessing cyclization precursors have been developed, ranging from nucleophilic substitution to C-H functionalization. Innovative methods for substrate activation have been developed for cycloadditions under photochemical and thermal conditions. Advances in accessing oxetanes, azetidines, and thietanes remain active areas of research with continued breakthroughs anticipated to enable future applications.

Conformations of saturated five-membered heterocycles evaluated by MP2 calculations

The conformation of saturated heterocyclic rings is often a subject of computational investigations. In spite of their simple molecular structure, study of their conformation is often hindered by the high sensitivity for the type of the accepted potential of interactions and limitations inherent to introducing artificial constraints. Here we report the results of the MP2 calculations carried out within the aug-cc-pVTZ basis set and aimed to elucidate the basic conformational properties of a series of prototypic heterocyclic compounds, containing saturated five-membered rings. We have considered: oxolane, thiolane, pyrrolidine, 1,3-dioxolane, 1,2-oxathiolane, 1,3-oxathiolane pyrazolidine, imidazolidine, and cyclopentane (the latter included for comparative purposes). We have identified the local and global minima on the potential energy surface along the pseudorotation path. Moreover, the relative energies of structural and geometrical isomers were estimated. The results reveal a large degree of conformational heterogeneity of the studied compounds which always exhibit more than one type of conformation corresponding to the minimum of the energy. The information about the topology of the given compound is insufficient to predict its conformational properties, including the type of favorable ring shape. However, the magnitude of the out-of-plane deviations exhibit similar range of values for most of the studied compounds. The calculated puckering parameters will provide the essential data for the next stage of related studies exploiting the machine learning methodology.

Intramolecular C(sp₃)-H Bond Amination Strategies for the Synthesis of Saturated N-containing Heterocycles.

The selective functionalization of C(sp³)-H bonds via intramolecular amination reactions represents a very attractive strategy for the construction of saturated N-containing heterocycles (SNHets). Over the past de- cades, the chemical community has devoted its efforts towards expanding the synthetic toolbox with the aim of facilitating access to these key fragments in a controllable, reproducible and efficient manner. This review covers selected examples of the most recent advances in intramolecular C(sp³)-N bond-forming reactions by three main approaches: (1) the Hofmann-Löffler-Freytag (HLF) reaction; (2) transition-metal-catalyzed nitrene C(sp³)-H inser- tion; and (3) transition-metal-catalyzed ligand-assisted C(sp³)-N bond-forming reactions via a reductive elimination step. We will discuss reactivity, selectivity and the major mechanistic insights into these transformations.

Recent Advances in Homogeneous Catalysts for the Asymmetric Hydrogenation of Heteroarenes.

The asymmetric hydrogenation of heteroarenes has recently emerged as an effective strategy for the direct access to enantioenriched, saturated heterocycles. Although several homogeneous catalyst systems have been extensively developed for the hydrogenation of heteroarenes with high levels of chemo- and stereoselectivity, the development of mild conditions that allow for efficient and stereoselective hydrogenation of a broad range of substrates remains a challenge. This Perspective highlights recent advances in homogeneous catalysis of heteroarene hydrogenation as inspiration for the further development of asymmetric hydrogenation catalysts, and addresses underdeveloped areas and limitations of the current technology.

Fluorocyclization of Vinyl Azides for the Formation of 3-Azido Heterocycles.

3-Azido saturated heterocycles are important for therapeutic-development but challenging to prepare. Disclosed herein is a novel synthetic strategy for 3-azido heterocycles via fluorocyclization of the easily available vinyl azides. This transfor-mation proceeded under mild conditions and provided a wide range of 3-azido heterocycles in good to excellent yields. Notably, the azido group plays an indispensable role to promote rapid and regioselective fluorocyclization. Moreover, the protocol was highlighted by gram-scale synthesis and further synthetic transformations.

Synthesis of β-Diamine Building Blocks by Photocatalytic Hydroamination of Enecarbamates with Amines, Ammonia and N-H Heterocycles.

3‐Amino‐substituted saturated nitrogen heterocycles are an important subclass of β‐diamines, appearing in a number of clinical agents. Herein, we report a unified approach to these products based upon the regioselective photoredox‐mediated hydroamination of enecarbamates. The amine coupling partner can encompass diverse amine types under a single set of reaction conditions, including primary alkyl amines, ammonia, aryl and heteroaryl amines, and N−H heterocycles. The method enables the synthesis of a wide range of pharmaceutically relevant building blocks.

Photochemical Functionalization of Heterocycles with EBX Reagents: C-H Alkynylation versus Deconstructive Ring Cleavage*.

The development of novel methodologies for the functionalization of saturated heterocycles is highly desirable. Herein, we report a cheap and efficient photochemical method for the C-H functionalization of saturated O-heterocycles, as well as the deconstructive ring-cleavage of S-heterocycles, employing hypervalent iodine alkynylation reagents (ethynylbenziodoxolones, EBX). This photochemical alkynylation is performed utilizing phenylglyoxylic acid as the photoinitiator, leading to the corresponding products in good to high yields, under household fluorescent light bulb irradiation. When O-heterocycles were employed, the expected α-C-H alkynylation took place. In contrast, oxidative ring-opening to form a thioalkyne and an aldehyde was observed with S-heterocycles. Preliminary mechanistic experiments are presented to give first insights into this puzzling divergent reactivity.

Synthesis, density functional theory study and in vitro antimicrobial evaluation of new benzimidazole Mannich bases

The tri-component synthesis of novel chiral benzimidazole Mannich bases, by reaction between benzimidazole, aqueous 30% formaldehyde and an amine, the biological evaluation and DFT studies of the new compounds are reported here. The 1H-NMR, 13C-NMR, FTIR spectra and elemental analysis confirm the structures of the new compounds. All synthesized compounds were screened by qualitative and quantitative methods for their in vitro antibacterial activity against 4 bacterial strains. DFT studies were accomplished using GAMESS 2012 software and HOMO–LUMO analysis allowed the calculation of electronic and structural parameters of the chiral Mannich bases. The geometry of 1-methylpiperazine, the cumulated Mullikan atomic charges of the two heteroatoms and of the methyl, and the value of the global electrophilicity index (ω = 0.0527) of the M-1 molecule is correlated with its good antimicrobial activity. It was found that the presence of saturated heterocycles from the amine molecule, 1-methyl piperazine and morpholine, respectively, contributes to an increased biological activity, compared to aromatic amino analogs, diphenylamino-, 4-nitroamino- and 4-aminobenzoic acid. The planarity of the molecules, specific bond lengths and localization of HOMO–LUMO orbitals is responsible for the best biological activities of the compounds.

Structure-guided optimization of a novel class of ASK1 inhibitors with increased sp3 character and an exquisite selectivity profile

Apoptosis Signal-Regulating Kinase-1 (ASK1) is a known member of the Mitogen-Activated Protein Kinase Kinase Kinase (MAP3K) family and upon stimulation will activate the p38- and JNK-pathways leading to cardiac apoptosis, fibrosis, and hypertrophy. Using Structure-Based Drug Design (SBDD) in parallel with deconstruction of a published compound, a novel series of ASK1 inhibitors was optimized, which incorporated a saturated heterocycle proximal to the hinge-binding motif. This yielded a unique chemical series with excellent selectivity across the broader kinome, and desirable drug-like properties. The lead compound (10) is highly soluble and permeable, and exhibits a cellular EC50 = 24 nM and Kd < 1 nM. Of the 350 kinases tested, 10 has an IC50 ≤ 500 nM for only eight of them. This paper will describe the design hypotheses behind this series, key data points during the optimization phase, as well as a possible structural rationale for the kinome selectivity. Based on crystallographic data, the presence of an aliphatic cycle adjacent to the hinge-binder in the active site of the protein kinase showed up in <1% of the >5000 structures in the Protein Data Bank, potentially conferring the selectivity seen in this series.

Free radical sulfur ring-opening of thianaphthene in the presence of indene

Sulfur ring-opening of thiophenes present in heavy oils is a challenge, particularly for non-catalytic thermal processes. In this work, sulfur ring-opening of thianaphthene was studied in a thermal conversion process (400 °C, 2 MPa) in the absence of direct hydrogen supply, but in the presence of indan and indene, molecules that are capable of hydrogen transfer. Hydrogen transfer reactions resulted in the formation of 2,3-dihydrothianaphthene from thianaphthene and it was anticipated that ring-opening of the saturated heterocycle would readily take place. Yet, when thianaphthene reacted with indan, only trace evidence of ring-opening was found, but when thianaphthene reacted with indene, 2-methylbenzenethiol and 2-ethylbenzenethiol were found. Reaction pathways that involved homolytic bond dissociation of the saturated heterocycle in 2,3-dihydrothianaphthene were unimportant at 400 °C. Ring-opening appeared to be facilitated by the olefinic group, which interacted with the sulfur to weaken the carbon–sulfur bond and stabilize the reaction intermediate.

Synthesis of spirocyclic β- and γ-sultams by one-pot reductive cyclization of cyanoalkylsulfonyl fluorides.

One-pot intramolecular cyclization of novel sp3-enriched cyanoalkylsulfonyl fluorides into spirocyclic β- 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 β-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.