Common Synthon Research Articles

C3-Chlorination of C2-substituted benzo[b]thiophene derivatives in the presence of sodium hypochlorite.

Benzo[b]thiophene rings are common synthons for the development of novel drugs and materials, and thus, the discovery of facile ways for their functionalization is of value. In this work, a new method for the C3-chlorination of C2-substituted benzothiophene derivatives is described. The chlorine source is sodium hypochlorite pentahydrate (NaOCl·5H2O), and optimal transformations occur in aqueous acetonitrile at 65-75 °C to provide the corresponding C3-halogenated products in variable yields (30-65%). The reaction occurs in the presence of vinyl and alkyl groups, while the presence of alcohols leads to competing oxidation reactions at the heterobenzylic position. The presence of a carbonyl group at the C2-position inhibited the halogenation reaction, while the use of benzofuran led to a highly exothermic reaction, presumably via the formation of a peroxide intermediate. Reactions carried out at lower temperatures led to side reactions associated with competing oxidative processes. To gain a better understanding of the mechanism of the reaction, DFT calculations were carried out, where the heteroatom enables the formation of a hypochlorous acidium ion that serves to generate a C2-C3 chloronium ion intermediate in a step-wise manner, which in turn leads to the formation of an S-stabilized C2-carbocation that undergoes re-aromatization to the corresponding C3-chlorinated products. To probe potential synthetic applications, a model C3-chloro derivative was coupled with phenylboronic acid using standard Suzuki-Miyaura coupling conditions.

Asymmetric Divergent Synthesis of ent-Kaurane-, ent-Atisane-, ent-Beyerane-, ent-Trachylobane-, and ent-Gibberellane-type Diterpenoids.

A unified strategy toward asymmetric divergent syntheses of nine C8-ethano-bridged diterpenoids A1-A9 (candol A, powerol, sicanadiol, epi-candol A, atisirene, ent-atisan-16α-ol, 4-decarboxy-4-methyl-GA12, trachinol, and ent-beyerane) has been developed based on late-stage transformations of common synthons having ent-kaurane and ent-trachylobane cores. The expeditious assembly of crucial advanced ent-kaurane- and ent-trachylobane-type building blocks is strategically explored through a regioselective and diastereoselective Fe-mediated hydrogen atom transfer (HAT) 6-exo-trig cyclization of the alkene/enone and 3-exo-trig cyclization of the alkene/ketone, showing the multi-reactivity of densely functionalized polycyclic substrates with πC═C and πC═O systems in HAT-initiated reactions. Following the rapid construction of five major structural skeletons (ent-kaurane-, ent-atisane-, ent-beyerane-, ent-trachylobane-, and ent-gibberellane-type), nine C8-ethano-bridged diterpenoids A1-A9 could be accessed in the longest linear 8 to 11 steps starting from readily available chiral γ-cyclogeraniol 1 and known chiral γ-substituted cyclohexenone 2, in which enantioselective total syntheses of candol A (A1, 8 steps), powerol (A2, 9 steps), sicanadiol (A3, 10 steps), epi-candol A (A4, 8 steps), ent-atisan-16α-ol (A6, 11 steps), and trachinol (A8, 10 steps) are achieved for the first time.

Energetics of carboxylic acid–pyridine heterosynthon revisited: A computational study of intermolecular hydrogen bond domination on phenylacetic acid–nicotinamide cocrystals

Abstract Carboxylic acid–pyridine heterosynthon (CPHS) is one of the most common synthons found in cocrystal packing. Phenylacetic acid (PYC)–nicotinamide (NIC) (PYCNIC) cocrystals were used as a computational model to assess the most important factor in the emergence of the synthon. Geometry optimization was carried out on every possible two molecules of PYC–NIC conformation based on B3LYP-D3BJ/6-311G (d,p). Various energetic parameters, including total energy, interaction energy, and hydrogen bond energy, were used to compare the existing conformation to the putative conformation. The conformation with CPHS has −53.87 kJ mol−1 of single intermolecular hydrogen bond energy (EHB), which is the strongest of all. It turns out that there is no other parameter better than EHB to describe the superiority of CPHS in PYCNIC.

Asymmetric Alkynylation of Tertiary Carbon‐Centered Radical via Copper‐Catalyzed Radical Relay

Comprehensive SummaryAlkynes are frequently found in a high proportion of natural products and bioactive moleculars, as well as a common synthon in organic synthesis, which can be easily transformed to an alkenyl, alkyl, heteroaryl, or carboxylic acid group. The enantioselective construction of alkyne substituted all carbon quaternary stereocenters is rarely reported and still a big challenge. As part of our continuous effort on developing asymmetric radical transformations, we found introducing an amidyl group (CONHAr) adjacent to the tertiary carbon radical could enable the asymmetric radical coupling with alkyne reagents. The amidyl group may stabilize the tertiary carbon radical or coordination with the chiral copper catalyst. Herein, we communicate a copper‐catalyzed asymmetric trifluoromethyl‐alkynylation of α‐aryl substituted acrylamides, which provides a straightforward and efficient access to chiral quaternary all‐carbon centers bearing alkynyl groups in good yields and enantioselectivities. This reaction was also applied for the synthesis of chiral functionalized dipeptide.

Structural effects of halogen bonding in iodochalcones.

The structures of three iodochalcones, functionalized with fluorine or a nitro group, have been investigated to explore the impact of different molecular electrostatic distributions on the halogen bonding within each crystal structure. The strongly withdrawing nitro group presented a switch of the halogen bond from a lateral to a linear motif. Surprisingly, this appears to be influenced by a net positive shift in charge distribution around the lateral edges of the σ-hole, making the lateral I...I bonding motif less preferable. A channel of amphoteric I...I type II halogen bonds is observed for a chalcone molecule, which was not previously reported in chalcones, alongside an example of the common synthon involving extended linear chains of I...O2N donor-acceptor halogen bonds. This work shows that halogenated chalcones may be an interesting target for developing halogen bonding as a significant tool within crystal engineering, a thus far underexplored area for this common structural motif.

Benzobisoxazole Cruciforms: A Cross‐conjugated Platform for Designing Tunable Donor/Acceptor Materials

AbstractFour cross‐conjugated molecules based on the benzo[1,2‐d:4,5‐d’]bisoxazole (BBO) moiety have been synthesized from a common synthon. Theoretical studies indicated that these cruciforms had highly segregated HOMO and LUMO levels enabling semi‐autonomous tuning of the LUMO level from the HOMO through substitution along the 2,6‐axis. The experimental data confirms that the HOMO levels within these systems varied by 0.3 eV, whereas the LUMO levels varied by over 1.6 eV when the electron‐density along the 2,6‐axis was increased. The introduction of relatively electron‐deficient moieties along the 2,6‐axis resulted in a bathochromic shift in the absorption profiles concurrent with the stabilization of the LUMO. These substituents also prolonged the photoluminescent lifetimes owing to improved intramolecular charge transfer states between the 4,8‐ and 2,6‐ axis. The BBO cruciforms were evaluated as donor materials in organic solar cells (OSC)s, but the energy‐level mismatches and poor thin film morphology led to poor performance. These results indicate that benzobisoxazole cruciforms are a promising platform for the development of tunable materials for use in organic semiconductors, but improvements in the optical, electronic and film‐forming properties are needed to enable their use in efficient OSCs.

Synthesis of carboxy-polyethylene glycol-amine (CA (PEG)n ) and [1-14 C]-CA (PEG)n via oxa-Michael addition of amino-polyethylene glycols to propiolates vs to acrylates.

Synthesis of carboxy-polyethylene glycol-amine (CA (PEG)n ) via oxa-Michael addition of amino-polyethylene glycols to either acrylates or propiolates was investigated. Compared with the oxa-Michael addition to acrylates, the corresponding addition to propiolates was found to proceed under mild reaction conditions and afford the adducts in high yields from a broad scope of substrates. A two-step efficient and convenient synthesis of benzyl [1-14 C]-propiolate from 14 CO2 was therefore developed and utilized as a common synthon to afford practical and high yielding access to [1-14 C]-CA (PEG)n .

Identification and application of threonine aldolase for synthesis of valuable α-amino, β-hydroxy-building blocks

Chiral β-hydroxy α-amino acid structural motifs are interesting and common synthons present in multiple APIs and drug candidates. To access these chiral building blocks either multistep chemical syntheses are required or the application of threonine aldolases, which catalyze aldol reactions between an aldehyde and glycine. Bioinformatics tools have been utilized to identify the gene encoding threonine aldolase from Vanrija humicola and subsequent preparation of its recombinant version from E. coli fermentation. We planned to implement this enzyme as a key step to access the synthesis of our target API. Beyond this specific application, the aldolase was purified, characterized and the substrate scope of this enzyme further investigated. A number of enzymatic reactions were scaled-up and the products recovered to assess the diastereoselectivity and scalability of this asymmetric synthetic approach towards β-hydroxy α-amino acid chiral building blocks.

Diversity‐Oriented Synthesis of α‐Functionalized Acylborons and Borylated Heteroarenes by Nucleophilic Ring Opening of α‐Chloroepoxyboronates

AbstractThe ring‐opening reactions of N‐methyliminodiacetyl (MIDA) α‐chloroepoxyboronates with different nucleophiles allow the modular synthesis of a diverse array of organoboronates. These include seven types of α‐functionalized acylboronates and seven types of borylated heteroarenes, some of which are difficult‐to‐access products using alternative methods. The common synthons, α‐chloroepoxyboronates, could be viably synthesized by a two‐step procedure from the corresponding alkenyl MIDA boronates. Mild reaction conditions, good functional‐group tolerance, and generally good efficiency were observed. The utility of the products was also demonstrated.

Diversity-Oriented Synthesis of α-Functionalized Acylborons and Borylated Heteroarenes by Nucleophilic Ring Opening of α-Chloroepoxyboronates.

The ring-opening reactions of N-methyliminodiacetyl (MIDA) α-chloroepoxyboronates with different nucleophiles allow the modular synthesis of a diverse array of organoboronates. These include seven types of α-functionalized acylboronates and seven types of borylated heteroarenes, some of which are difficult-to-access products using alternative methods. The common synthons, α-chloroepoxyboronates, could be viably synthesized by a two-step procedure from the corresponding alkenyl MIDA boronates. Mild reaction conditions, good functional-group tolerance, and generally good efficiency were observed. The utility of the products was also demonstrated.

Enhancing Adamantylamine Solubility through Salt Formation: Novel Products Studied by X-ray Diffraction and Solid-State NMR

The reactivity of the neuroleptic drug adamantylamine toward aliphatic carboxylic acids, sulfone derivatives, and aromatic amino acids was screened for the first time using simple mechanochemical methods. Seven new molecular salt structures were reported exhibiting improved physicochemical properties. To carefully characterize these compounds, multiple complementary techniques were combined: single crystal and powder X-ray diffraction, 13C/15N solid-state NMR, and Fourier transform infrared-attenuated total reflectance spectroscopies, employed to solve cocrystal/salt ambiguities. In all molecular salts, the crystal packing is supported on a common synthon, a N–H+(ADA)···O–(coformer) charge assisted hydrogen bond. Different supramolecular arrangements were obtained induced by the size of the counterions as well as their complementary functional groups. Two salts, with glutaric and methanesulfonic acids, presented higher solubility than the commercially available pharmaceutical product.

Topology of Ladder Supramolecular Assemblies in Azahetorocyclic Phosphonates: A Structural and Computational Approach

Topologies of ladder packing arrangements in crystal structures of five azaheterocyclic phosphonates were characterized by four geometrical descriptors introduced in the paper. The structural analysis was augmented by detailed calculations on interactions stabilizing the molecular assemblies. Intermolecular energies were evaluated using PIXEL and DFT(M062x-GD3) methods. Additionally, fingerprint plots derived from the Hirshfeld surfaces were generated for each structure to characterize the crystal packing arrangement in detail. All structures are stabilized by the relatively weak hydrogen bonds and nonbonding interactions involving aromatic rings, i.e., π···π, C–H···π, and (lp)···π effects. Distribution of the molecular electrostatic potential demonstrates that positively charged, endocyclic sulfur atoms are prone to chalcogen–chalcogen (S···O) bonding. Analysis of the supramolecular motifs shows the lack of a common synthon responsible for the ladder packing arrangements. However, the striking geometry similarity of all molecules indicates that ladder packing is based on a shape oriented molecular recognition and mostly driven by the van der Waals forces. The intermolecular electrostatic effects are crucial for stabilizing and fixing geometry of the already formed molecular clusters.

The Construction of Anhydro Monosaccharides

AbstractAnhydro monosaccharide is a specific and distinctive category of carbohydrates, which is found in many naturally derived and artificial bioactive substrates. In the field of organic chemistry, some anhydro sugars can be used as common synthons to construct different carbohydrate structures. The development of efficient methodologies for the construction of various anhydro sugar fragments is very important in carbohydrate chemistry, which has attracted considerable attention in the past few years. This review mainly covers the development of new synthetic methods since 2000 and gives an overview of the development in the formation of anhydro monosaccharide structures. It systematically summarizes all methods to establish an intramolecular ether bridge in furanose and pyranose structures, which are the most commonly used monosaccharide fragments in carbohydrate chemistry.

Synthesis of a Small-Molecule Library with Skeletal Diversity from Hemslecin A via the Reaction-Discovery Strategy.

An efficient reaction tool box was developed for the synthesis of skeletally diverse and stereochemically complex templates for a small-molecule library based on the common synthon Q, which was prepared from hemslecin A in four steps. The reaction tool box comprises three acid-promoted rearrangements: semipinacol, Wagner-Meerwein, and cyclopropylmethyl cation rearrangements. More importantly, a Mn-mediated C-H oxidation was developed to achieve a high level of complexity, which provides a new entry for C-H functionalization of inert angular methyl groups in the chemistry of triterpenes. Our reaction-discovery strategy based on hemslecin A provides a basis for the inherent chemistry of triterpenes and could be applied for the further transformation of triterpenes.

ChemInform Abstract: A Versatile and Efficient Synthesis of Bithiophene‐Based Dicarboxaldehydes from a Common Synthon.

AbstractDibromide (I) is used as a convenient common synthon for the preparation of the title dicarboxaldehydes (IV), (VII), (X), and (XV), which represent promising electron‐rich building blocks for the development of arylenevinylene‐based organic semiconductors.

Pd-Catalyzed Diamination of 1,2,4-Triazinyl Complexant Scaffolds.

As part of ongoing efforts in this laboratory to design and synthesize multidentate soft-N-donors as effective complexants for chemoselective minor actinide extraction from used nuclear fuel, a series of aminated mono-1,2,4-triazinylpyridines were required. This study focuses on streamlining convergent access to a diverse array of functionalized N-donors using Pd-catalysis from a common synthon affording access to pyridinyl triazines as the 4,4'-amino derivatives which are commercially limited and unsuccessful in traditional condensation chemistry. A general Pd-catalyzed method for the double amination of functionalized pyridinyl-1,2,4-triazines with low catalyst/ligand loadings enabling the formation of 16 novel complexants is presented.

Synthesis of a Functionalized Benzofuran as a Synthon for Salvianolic Acid C Analogues as Potential LDL Antioxidants.

A palladium mediated synthesis of a common synthon for the syntheses of antioxidant analogues of naturally occurring salvianolic acids is presented. The synthetic route may be used to obtain analogues with a balanced lipophilicity/hydrophilicity which may result in potentially interesting LDL antioxidants for the prevention of cardiovascular diseases.

A versatile and efficient synthesis of bithiophene-based dicarboxaldehydes from a common synthon.

Bithiophene dicarboxaldehydes are promising electron-rich building blocks for the development of arylene vinylene-based organic semiconductors, but their use has been limited due to their synthetic inaccessibility. To facilitate the facile synthesis of these compounds we have prepared a novel functional bithiophene, namely 2,2'-(3,3'-dibromo-[2,2'-bithiophene]-5,5'-diyl)bis(5,5-dimethyl-1,3-dioxane) in two high yielding steps from 3,3',5,5'-tetrabromo-2,2'-bithiophene. This synthon is readily transformed into variety of bithiophene-based dicarboxaldehydes, also in high yields. The use of these functional molecules in the synthesis of arylene vinylene-linked donor-acceptor copolymers is demonstrated by the synthesis of two copolymers with electron deficient benzobisazoles.

ChemInform Abstract: Synthesis of Triazolo Isoquinolines and Isochromenes from 2‐Alkynylbenzaldehyde via Domino Reactions under Transition‐Metal‐Free Conditions.

We describe two simple straightforward syntheses of triazolo isoquinolines (3) and isochromenes (7) from 2-alkynylbenzaldehydes (1) as a common synthon. The synthetic strategy for 3 involves formation of the (E)-1-(2-nitrovinyl)-2-(alkynyl)benzene species 2 via condensation of synthon 1 with nitromethane followed by a [3 + 2] cycloaddition/extrusion of the nitro group/regioselective 6-endo cyclization domino sequence. In yet another strategy, the synthon 1 was condensed with nitromethane followed by electrophilic iodo cyclization of the resulting 2-nitro-1-(2-(alkynyl)phenyl)ethanol (6) to furnish iodo isochromene derivatives. The salient feature of the above two strategies involves formation of the corresponding heterocycles under metal-free conditions in good yields.

Synthesis of Triazolo Isoquinolines and Isochromenes from 2-Alkynylbenzaldehyde via Domino Reactions under Transition-Metal-Free Conditions

We describe two simple straightforward syntheses of triazolo isoquinolines (3) and isochromenes (7) from 2-alkynylbenzaldehydes (1) as a common synthon. The synthetic strategy for 3 involves formation of the (E)-1-(2-nitrovinyl)-2-(alkynyl)benzene species 2 via condensation of synthon 1 with nitromethane followed by a [3 + 2] cycloaddition/extrusion of the nitro group/regioselective 6-endo cyclization domino sequence. In yet another strategy, the synthon 1 was condensed with nitromethane followed by electrophilic iodo cyclization of the resulting 2-nitro-1-(2-(alkynyl)phenyl)ethanol (6) to furnish iodo isochromene derivatives. The salient feature of the above two strategies involves formation of the corresponding heterocycles under metal-free conditions in good yields.