One-pot Sequence Research Articles

(R)-(−)-2-[(5-Oxido-5-phenyl-5λ4-isoquino[4,3-c][2,1]benzothiazin-12-yl)amino]benzonitrile

Copper-catalyzed cross-coupling between (S)-S-methyl-S-phenylsulfoximine (1) and 2-iodobenzonitrile (2) resulted in the discovery of an unprecedented one-pot triple arylation sequence to give (R)-(−)-2-[(5-oxido-5-phenyl-5λ4-isoquino[4,3-c][2,1]benzothiazin- 12-yl)amino]benzonitrile (4). Here, we describe the synthesis of the title compound (R)-4 and the elucidation of its structure by means of various techniques.

Alkyl Substituent Effects on Molecular Packing and Optoelectronic Properties of 2,3-Dialkyltetracenes

Abstract A series of 2,3-dialkyltetracenes (alkyl = propyl to hexyl) were readily prepared from 2,3-dialkyl-5,12-tetracenequinone by a one-pot sequence involving hydride reduction with sodium borohydride and subsequent addition of tin(II) chloride in concd hydrochloric acid. X-ray diffraction patterns of their recrystallized powder samples demonstrated their crystalline nature. X-ray crystallographic analysis of the butyl derivative revealed that there were two disordered sets of butyl groups with 50% occupancies, and that in the molecular structure, one butyl group was coplanar with the tetracene core, while the other butyl group was perpendicular to the tetracene plane. Further, the crystal structure adopted a repeating bilayer structure of herringbone-packed tetracene cores and disordered alkyl groups. The conformational analysis demonstrated that there were a number of stable conformers, which would account for the occurrence of alkyl disorders. Flash-photolysis time-resolved microwave conductivity (FP-TRMC) measurements of 2,3-dialkyltetracenes exhibited an increase in the product of charge carrier mobility (3.0 × 10−5 to 3.5 × 10−4 cm2 V−1 s−1) and its generation efficiency with increase in the length of the alkyl side chains, suggesting that a longer alkyl side chain plays an important role in the degree of transfer integral and in the suppression of charge recombination or exciton quenching.

One-pot isomerization-cross metathesis-reduction (ICMR) synthesis of lipophilic tetrapeptides.

An efficient, versatile and rapid method toward homologue series of lipophilic tetrapeptide derivatives (herein, the opioid peptides H-TIPP-OH and H-DIPP-OH) is reported. High atom economy and a minimal number of synthetic steps resulted from a one-pot tandem isomerization-cross metathesis-reduction sequence (ICMR), applicable both in solution and solid phase methodology. The broadly applicable synthesis proceeds with short reaction times and simple work-up, as illustrated in this work for alkylated opioid tetrapeptides.

An economical and safe procedure to synthesize 2-hydroxy-4-pentynoic acid: A precursor towards 'clickable' biodegradable polylactide.

2-Hydroxy-4-pentynoic acid (1) is a key intermediate towards ‘clickable’ polylactide which allows for efficient introduction of a broad range of pendant functional groups onto polymers from a single monomer via convenient ‘click’ chemistry with organic azides. The incorporation of various pendant functional groups could effectively tailor the physicochemical properties of polylactide. The reported synthesis of 1 started from propargyl bromide and ethyl glyoxylate. However, both of starting materials are expensive and unstable; especially, propargyl bromide is shock-sensitive and subjected to thermal explosive decomposition, which makes the preparation of 1 impractical with high cost and high risk of explosion. Herein, we report a simple, economical and safe synthetic route to prepare 1 using cheap and commercially available diethyl 2-acetamidomalonate (4) and propargyl alcohol. The desired product 1 was obtained via alkylation of malonate 4 with propargyl tosylate followed by a one-pot four-step sequence of hydrolysis, decarboxylation, diazotization and hydroxylation of propargylic malonate 5 without work-up of any intermediate.

Tailoring 3,3'-dihydroxyisorenieratene to hydroxystilbene: finding a resveratrol analogue with increased antiproliferation activity and cell selectivity.

Four novel compounds were designed by "tailoring" 3,3'-dihydroxyisorenieratene (a natural carotenoid) based on an isoprene unit retention truncation strategy. Among them, the smallest molecule 1 (2,3,6,2',3',6'-hexamethyl-4,4'-dihydroxy-trans-stilbene) was concisely synthesized in a one-pot Stille-Heck tandem sequence, and surfaced as a promising lead molecule in terms of its selective antiproliferative activity mediated by blocking the NCI-H460 cell cycle in G1 phase. Additionally, theoretical calculations and cell uptake experiments indicate that the unique polymethylation pattern of compound 1 significantly induces a conformational change shift out of planarity and increases its cell uptake and metabolic stability. The observation should be helpful to rationally design resveratrol-inspired antiproliferative agents.

Combining photoredox-catalyzed trifluoromethylation and oxidation with DMSO: facile synthesis of α-trifluoromethylated ketones from aromatic alkenes.

Trifluoromethylated ketones are useful building blocks for organic compounds with a trifluoromethyl group. A new and facile synthesis of ketones with a trifluoromethyl substituent in the α-position proceeds through a one-pot photoredox-catalyzed trifluoromethylation-oxidation sequence of aromatic alkenes. Dimethyl sulfoxide (DMSO) serves as a key and mild oxidant under these photocatalytic conditions. Furthermore, an iridium photocatalyst, fac[Ir(ppy)3 ] (ppy=2-phenylpyridine), turned out to be crucial for the present photoredox process.

Regioselective synthesis of highly substituted enol esters from ketoketene dimer β-lactones

A method for the regioselective synthesis of highly substituted enol esters from ketoketene dimers β-lactones is described. Methylphenylketene dimer was subjected to a sequential one-pot reaction sequence involving ring-opening with an organolithium to give an enolate intermediate, followed by enolate acylation with an acyl chloride to give a highly substituted enol ester as the final product. Complete regioselectivity for O-acylation of the enolate was observed in all cases. Yields of up to 70% were obtained for the one-pot conversion of ketoketene dimers to highly substituted enol esters.

ChemInform Abstract: One‐Pot Zinc‐Promoted Asymmetric Alkynylation/Brook‐Type Rearrangement/Ene‐Allene Cyclization: Highly Selective Formation of Three New Bonds and Two Stereocenters in Acyclic Systems.

It's as easy as 1, 2, 3: In a one-pot sequence, two stereocenters and three new bonds were created with high selectivity through an asymmetric alkynylation of acyl silanes, a tandem Brook-type rearrangement and Zn-ene-allene cyclization, the addition of an electrophile, and finally oxidation. The straightforward nature of the synthetic procedure contrasts strongly with the complexity of the densely functionalized products obtained.

Nucleophilic Phosphine-Catalyzed Intramolecular Michael Reactions of N-Allylic Substituted α-Amino Nitriles: Construction of Functionalized Pyrrolidine Rings via 5-endo-trig Cyclizations

Pyrrolidine rings are common moieties for pharmaceutical candidates and natural compounds, and the construction of these skeletons has received much attention. α-Amino nitriles are versatile intermediates in synthetic chemistry and have been widely used in the generation of multiple polyfunctional structures. Herein, a novel nucleophilic phosphine-catalyzed intramolecular Michael reaction of N-allylic substituted α-amino nitriles has been developed for the efficient construction of functionalized 2,4-disubstituted pyrrolidines (N-heterocyclic α-amino nitriles) via 5-endo-trig cyclization. Furthermore, the one-pot sequence of the synthesis of pyrrolidine and the subsequent transformations of the functionalized products have also been demonstrated.

A New Synthesis and Process Development of Bis(fluoroalkyl)pyrazoles As Novel Agrophores

The synthesis of 3,5-bis(fluoroalkyl)-pyrazoles as novel agrophores is described. Commercially available fluoroacetoacetates are treated with BF3-activated TFEDMA affording in a straightforward one-pot sequence pyrazole carboxylates in good yields and with excellent regioselectivity. The carboxylate intermediates have been converted into the corresponding pyrazolic acids and submitted to decarboxylation, affording valuable building blocks for the design of novel bioactive ingredients. The found process is suitable for scale up and preparation of compounds in kilogram quantity.

Tetravinylethylene.

The first four-fold cross coupling reaction involving alkenic partners leads to the title hydrocarbon on multi-gram scale in one step from commercially available precursors. In stark contrast to its close structural relatives, tetravinylethylene is a remarkably robust, bench-stable compound. The π-bond rich hydrocarbon is shown to undergo one-pot sequences of pericyclic reactions leading to the formation of complex systems with four new rings, seven C-C bonds and ten stereocenters with a very high level of stereoselectivity. Insights into the reactivity of this and related systems is provided using the accurate composite ab initio MO G4(MP2) method.

Synthesis and optimization of an original V-shaped collection of 4-7-disubstituted Pyrido[3,2-d]pyrimidines as CDK5 and DYRK1A inhibitors

We here report the synthesis and biological evaluation of an original collection of 4,7-disubstituted pyrido[3,2-d]pyrimidines designed as potential kinase inhibitors. The collection was generated from a single starting material, 4,7-dichloropyrido[3,2-d]pyrimidine, which afforded the final compounds after two steps: a sequential or one-pot sequence including selective cross coupling reactions in C-4, followed by the second cross-coupling in C-7. In position C-4, a Suzuki-Miyaura type reaction led to monosubstituted derivatives whereas in position C-7, synthesis was achieved via a Suzuki or a Buchwald type reaction using commercially available or undescribed boron derivatives. The biological activity of the V-shaped family was measured in protein kinase assays. The structure activity relationship (SAR) revealed that some compounds selectively inhibited DYRK1A and CDK5 without affecting GSK3. Docking studies furnished possible explanations that correlate with the SAR data. The most active compound on the two biological targets was 27 which exhibited the following IC50: 110 nM for CDK5, 24 nM for DYRK1A and only 1.2 μM for GSK3. In the C-7 amino subfamily, the best derivative was indubitably compound 48 which led to a near selective action on DYRK1A and a remarkable IC50 of 60 nM.

ChemInform Abstract: One‐Pot Multistep Cascade Reactions over Multifunctional Nanocomposites with Pd Nanoparticles Supported on Amine‐Modified Mesoporous Silica.

Two kinds of multifunctional nanocomposites, SBA-15-NH2/Pd-p and SBA-15-NH2/Pd-f, with platelet-like and fiber-like morphologies, respectively, were fabricated by immobilizing Pd NPs onto amine-functionalized SBA-15. Some of the amino groups acted as anchoring sites for Pd NPs, whilst the remaining groups acted as Bronsted basic sites. As a result, the composites served as excellent multifunctional heterogeneous catalysts for one-pot multistep cascade reaction sequences. Moreover, when diffusion was the rate-determine step, SBA-15-NH2/Pd-p, with small mesopores, was superior to the fiber-like control sample, owing to its short diffusion length, a lower possibility of pore clogging, and better mass transportation for the reaction species during the catalysis.

A core–shell–satellite structured Fe3O4@MS–NH2@Pd nanocomposite: a magnetically recyclable multifunctional catalyst for one-pot multistep cascade reaction sequences

A hierarchical core-shell-satellite structured composite system Fe3O4@MS-NH2@Pd, which was composed of Pd nanoparticles well-dispersed on an amino group functionalized mesoporous silica (MS-NH2) nanosphere, and superparamagnetic Fe3O4 nanoparticles scattered inside the silica sphere, was prepared by using a facile procedure. The composite combined the catalytic properties of amino groups and Pd nanoparticles with superparamagnetic properties of magnetite into a single platform. This integrated nanosystem acted as an efficient magnetically recyclable noble metal-base multifunctional nanocatalyst and showed excellent catalytic activity, selectivity and stability for the direct synthesis of α-alkylated nitriles under mild conditions through facile one-pot multistep cascade reaction sequences.

Zinc-mediated addition of diethyl bromomalonate to alkynes for the cascade reaction towards polysubstituted pyranones and tetracarbonyl derivatives

The zinc-mediated regioselective addition reactions of diethyl bromomalonate and aromatic and aliphatic alkynes were investigated for the synthesis of vinyl malonates. When the vinyl organo-zinc intermediates were reacted with acid chlorides 2H-pyran-2-ones were obtained while the application of oxalyl chloride and an amine led to tetracarbonyl derivatives in a one-pot multi-step reaction sequence.

A one-pot process for palladium catalyzed direct C–H acylation of anilines in water using a removable ortho directing group

A new mild, practical method for the synthesis of aminobenzophenone derivatives through a three step one-pot reaction sequence involving acylation of anilines, palladium catalyzed cross-dehydrogenative coupling of the formed anilides and the hydrolytic cleavage is reported. The full reaction sequence was performed under aqueous conditions.

Core–shell structured MgAl-LDO@Al-MS hexagonal nanocomposite: an all inorganic acid–base bifunctional nanoreactor for one-pot cascade reactions

A core–shell structured nanocomposite, with hexagonal Mg–Al mixed oxide nanoplates derived from LDHs as the inner core and Al-containing mesoporous silica as the outer shell, was prepared using an inorganic, low cost and simple route. The mesoporous silica shell was not only capable of protecting the MgAl-LDO core, but also offered a high surface area for the derivation of functional acid catalytic sites. The MgAl-LDO@Al-MS nanocomposite served as an efficient acid–base bifunctional nanoreactor for one-pot multistep cascade reaction sequences, due to the good spatial separation of antagonistic sites via the core–shell structure design, confinement and enrichment effect of the reaction species endowed by the nanoreactor features.

Synthesis of heterocyclic-fused benzopyrans via the Pd(II)-catalyzed C-H alkenylation/C-O cyclization of flavones and coumarins.

An efficient and practical method for effecting a tandem C-H alkenylation/C-O cyclization has been achieved via the C-H functionalization of flavone derivatives. The synthetic utility of the one-pot sequence was demonstrated by obtaining convenient access to coumarin-annelated benzopyrans. The reaction scope for the transformation was found to be fairly broad, affording good yields of a wide range of flavone- or coumarin-fused benzopyran motifs, which are privileged structures in many biologically active compounds.

Autotandem Catalysis with Ruthenium: Remote Hydroesterification of Allylic Amides

A one-pot tandem sequence involving olefin isomerization and hydroesterification has been developed that enables the incorporation of a C1-unit at the remote terminal position of allylic amides. Key observations suggest that generation of an active ruthenium hydride, formed by addition of acetic acid, allows both processes to take place under mild conditions in an autotandem catalytic, cascading fashion, which is characterized by the use of a single catalytic entity capable of promoting multiple distinct steps without operator intervention.

Alkylation/elimination from azetidinium ylides: an entry to functionalized acrylonitriles

Azetidinium triflates were reacted in a one-pot two-steps sequence involving, generation of an azetidinium ylide, its alkylation with an halide, and final regioselective Hofmann elimination of the produced alkylated azetidinium ion to yield substituted α,β-unsaturated nitriles bearing an aminoethyl side-chain. The scope of this sequence was examined, and was found to depend both on the steric hindrance around the reactive center in the starting azetidinium salt, and on the nature of the reacting halide. Produced acrylonitriles were further used in DBU-catalyzed conjugate addition of amines, to yield 4-amino-2-aminomethyl-butyronitriles with fair diastereoselectivity, or, alternatively, to give C2 symmetrical cyclopropanes.