One-pot Sequence Research Articles

Sequential One-Pot Synthesis of 3-Arylbenzofurans from N-Tosylhydrazones and Bromophenol Derivatives.

A divergent and efficient one-pot sequence allowing direct access to 3-arylbenzofuran derivatives has been developed. The process, involving N-tosylhydrazones and bromophenols, proceeds via a palladium-catalyzed Barluenga-Valdés cross-coupling, followed by an aerobic, copper-catalyzed, radical cyclization to form Csp2-Csp2 and O-Csp2 bonds. 3-Arylated benzofurans bearing various substituents were obtained with good to excellent yields (up to 90%). Mechanistic investigation strongly supports a radical process for the cyclization step.

Next-Generation Total Synthesis of Vancomycin.

A next-generation total synthesis of vancomycin aglycon is detailed that was achieved in 17 steps (longest linear sequence, LLS) from the constituent amino acid subunits with kinetically controlled diastereoselective introduction of all three elements of atropisomerism. In addition to new syntheses of three of the seven amino acid subunits, highlights of the approach include a ligand-controlled atroposelective one-pot Miyaura borylation-Suzuki coupling sequence for introduction of the AB biaryl axis of chirality (>20:1 dr), an essentially instantaneous and scalable macrolactamization of the AB ring system nearly free of competitive epimerization (>30:1 dr), and two room-temperature atroposelective intramolecular SNAr cyclizations for sequential CD (8:1 dr) and DE ring closures (14:1 dr) that benefit from both preorganization by the preformed AB ring system and subtle substituent effects. Combined with a protecting group free two-step enzymatic glycosylation of vancomycin aglycon, this provides a 19-step total synthesis of vancomycin. The approach paves the way for large-scale synthetic preparation of pocket-modified vancomycin analogues that directly address the underlying mechanism of resistance to vancomycin.

Short Synthesis of Alkaloid (-)-205B.

The alkaloid (-)-205B has in the past served as a testing ground for novel approaches in nitrogen heterocycle synthesis. We herein report a highly straightforward synthesis of (-)-205B in just six synthetic steps, making it the shortest route currently known. The central steps of our approach are a vinylogous Mukaiyama-Mannich reaction to establish the first two stereogenic centers with excellent diastereo- and enantiocontrol followed by zinc-mediated Barbier allylation to set the third chiral center with high substrate control. Upon cyclization of the Barbier product to lactam and enolate methylation, the third ring is annulated by a one-pot sequence of lactam reduction and aza-Prins cyclization to directly set the final stereogenic center with complete cis-stereoselectivity. As the iminium ion undergoing the aza-Prins cyclization rapidly isomerized to a planar enamine intermediate, the alkaloid was eventually obtained as a 1:1 mixture of C6 diastereomers, which were readily separated by chromatography. Yet, the target natural product was obtained isomerically pure in an overall yield of 12%, which compares favorably with all previous syntheses.

N-Tosylcarboxamide in C–H Functionalization: More than a Simple Directing Group

C–H activation with transition metal catalysis has become an important tool in organic synthesis for the functionalization of low reactive bonds and the preparation of complex molecules. The choice of the directing group (DG) proves to be crucial for the selectivity in this type of reaction, and several different functional groups have been used efficiently. This review describes recent advances in C–H functionalization of aromatic rings directed by a N-tosylcarboxamide group. Results regarding alkenylation, alkoxylation, halogenation, and arylation of C–H in the ortho position to the tosylcarboxamide are presented. Moreover, the advantage of this particular directing group is that it can undergo further transformation and act as CO or CON fragment reservoir to produce, in sequential fashion or one-pot sequence, various interesting (hetero)cycles such as phenanthridinones, dihydroisoquinolinones, fluorenones, or isoindolinones.

Combined palladium/eosin Y-catalysed direct synthesis of anticancer biarylquinolinooxazocino-quinoxaline-1-ones under visible light in one-pot sequence: a revisited proof of concept

A novel, efficient, and green catalytic system under visible light irradiation has been introduced for the synthesis of anticancer biarylquinolooxazocino-quinoxaline-1-ones in one-pot sequence. The developed synthetic approach will be successfully utilized for the synthesis of various bioactive biarylquinolone in near future. Also, the cytotoxicity profile of these scaffolds has unveiled their superb cytoselectivity in HeLa and MCF-7 cell line compared to cisplatin.

Synthetic Approach to Fused Azasultams with 1,2,4-Thiadiazepine Framework

Synthetic approach to fused azasultams with 1,2,4-thiadi­azepine framework via base promoted protocols has been developed. 1H-Azole-2-carboxylates and N-(chloromethyl)-N-methylmethanesulfonamide were used as ambiphilic building blocks in the one-pot and two-step reaction sequences. Chemical behavior of the obtained azasultams in reactions with amines, hydrazine, DMFDMA, and NaBH4 was investigated. An enamino ketone derived from an azasultam was exploited in the synthesis of new pyrazole and pyrimidine heterocycles.

TANDEM REACTIONS OF THERMOLYSIS AND [3+2] CYCLOADDITION IN THE SYNTHESIS OF 3-HETARYL-4-NITROFUROXANS FROM 4-NITROFUROXANNITROLIC ACID

A tandem method of synthesis of 3-hetaryl-4-nitrofuroxans was developed based on the one-pot sequence of thermolysis of 4-nitrofuroxannitrolic acid to the corresponding 4-nitro-3-furoxancarbonitrile oxide and [3+2] cycloaddition of the latter to acetylenes and olefins. It was established that the synthesized 3-(isoxazol-3-yl)- and 3-(isoxazolin-3-yl)-4-nitrofuroxans are formed with high regioand diastereoselectivity.

Stereoselective Bromoboration of Acetylene with Boron Tribromide: Preparation and Cross-Coupling Reactions of (Z)-Bromovinylboronates.

The mechanism of acetylene bromoboration in neat boron tribromide was studied carefully by means of experiment and theory. Besides the syn-addition mechanism through a four-center transition state, radical and polar anti-addition mechanisms are postulated, both triggered by HBr, which is evidenced also to take part in the Z/E isomerization of the product. The proposed mechanism is well supported by ab initio calculations at the MP2/6-31+G* level with Ahlrichs' SVP all-electron basis for Br. Implicit solvation in CH2Cl2 has been included using the PCM and/or SMD continuum solvent models. Comparative case studies have been performed involving the B3LYP/6-31+G* with Ahlrichs' SVP for Br and MP2/Def2TZVPP levels. The mechanistic studies resulted in development of a procedure for stereoselective bromoboration of acetylene yielding E/Z mixtures of dibromo(bromovinyl)borane with the Z-isomer as a major product (up to 85%). Transformation to the corresponding pinacol and neopentyl glycol boronates and stereoselective decomposition of their E-isomer provided pure (Z)-(2-bromovinyl)boronates in 57-60% overall yield. Their reactivity in a Negishi cross-coupling reaction was tested. An example of the one-pot reaction sequence of Negishi and Suzuki-Miyaura cross-couplings for synthesis of combretastatin A4 is also presented.

Tandem Reactions of Thermolysis and [3+2] Cycloaddition in the Synthesis of 3-Hetaryl-4-Nitrofuroxans from 4-Nitrofuroxannitrolic Acid

A tandem method of synthesis of 3-hetaryl-4-nitrofuroxans was developed based on the one-pot sequence of thermolysis of 4-nitrofuroxannitrolic acid to the corresponding 4-nitro-3-furoxancarbonitrile oxide and [3+2] cycloaddition of the latter to acetylenes and olefins. It was established that the synthesized 3-(isoxazol-3-yl)- and 3-(isoxazolin-3-yl)-4-nitrofuroxans are formed with high regioand diastereoselectivity.

Application of Relay C−H Oxidation Logic to Polyhydroxylated Oleanane Triterpenoids

Summary Although clinical applications of abundant feedstock triterpenoids such as oleanolic acid are limited because of poor solubility and bioavailability, synthetic access to higher hydroxylated oleanane terpenoids is challenging. We now report the use of relay C−H oxidation logic to mimic the processes carried out in nature by P450 monooxygenase enzymes. To this end, we used the C-23-OH as natural handle for a hydrogen-atom transfer to access C-6, enabling the first syntheses of highly oxidized natural products uncargenin C and protobassic acid as well as uncovering the anti-leukemic activity of a synthetic intermediate.

Zirconium-Catalyzed Synthesis of Alkenylaminoboranes: From a Reliable Preparation of Alkenylboronates to a Direct Stereodivergent Access to Alkenyl Bromides.

A simple procedure has been optimized for the preparation of alkenylaminoborane from alkynes using diisopropylaminoborane and HZrCp2Cl. Coupled with a magnesium-catalyzed dehydrogenation, it allowed for the use of air- and moisture-stable diisopropylamine. This synthesis has been extended to a one-pot sequence leading directly to bromoalkenes with controlled stereochemistry. As such, it provides an easy, scalable, cheap process to access alkenylboronates and both (E)- and (Z)-bromoalkenes from commercially available alkynes.

Synthesis of Karrikinolide Using the Aldol-Type Acetal Addition Reaction.

A short step total synthesis of karrikinolide has been achieved. Both α and α' positions of O-acylated acetol were alkylated by the boron-mediated aldol-type acetal addition reaction. The one-pot sequence including the Arbuzov reaction, intramolecular Horner-Wadsworth-Emmons reaction, acidic hydrolysis of acetals, and pyran formation provided karrikinolide. This procedure was applicable to the gram-scale synthesis of karrikinolide.

Sulfa-Michael addition initiated one-pot tandem sequence: Construction of highly substituted 2-cyclopentenones from allylic cyanohydrins

A practical and facile one-pot protocol to construct highly substituted 2-vinyl 2-cyclopentenone derivatives from O-unsaturated acyl-substituted allylic cyanohydrins through a SMA triggered tandem sequence is described. In this process, a SMA triggered intramolecular aldol sequence, followed by a DBU-catalyzed intramolecular Aldol reaction and subsequent dehydroxylation were involved. This one-pot transformation proceeded smoothly under mild reaction conditions with efficiency.

Diversity-oriented approach to functional thiophene dyes by Suzuki coupling-lithiation one-pot sequences

Functional thiophenes, e.g. for organic metal-free dye sensitized solar cells (DSSC), are accessible efficiently via a divergent and diversity-oriented synthetic strategy.

Tandem Reaction Approaches to Isoquinolones from 2-Vinylbenzaldehydes and Anilines via Imine Formation–6π-Electrocyclization–Aerobic Oxidation Sequence

Two distinctive transition-metal-promoted aerobic oxidation protocols have been developed for the synthesis of isoquinolones from 2-vinylbenzaldehydes and aniline derivatives. Thus, the one-pot tandem reaction sequence of imine formation, thermal 6π-electrocyclization, followed by either Cu(OAc)2-mediated or Pd(OAc)2-catalyzed aerobic oxidation protocol allowed the ready access to isoquinolone derivatives. The control experiments revealed that the 1,2-dihydroisoquinoline intermediates from the 6π-electrocyclization of 1-azatrienes were aerobically oxidized to isoquinolones in the presence of either Cu(OAc)2 or Pd(OAc)2 catalyst.

Brønsted Base Catalyzed One-Pot Synthesis of Stereodefined Six-Member Carbocycles Featuring Transient Trienolates and a Key Intramolecular 1,6-Addition.

A catalyst-driven one-pot reaction sequence is developed for the enantio- and diastereoselective synthesis of tetrasubstituted cyclohexenes from simple unsaturated ketones or thioesters. The method involves a tertiary amine/squaramide-catalyzed α-selective addition of transiently generated trienolates to nitroolefins, subsequent base-catalyzed double bond isomerization, and an intramolecular (vinylogous) 1,6-addition reaction, a rare key carbocyclization step that proceeded with essentially perfect stereocontrol.

One-Pot Asymmetric Synthesis of Spiropyrazolone-Linked Cyclopropanes and Benzofurans through a General Michael Addition/Chlorination/Nucleophilic Substitution Sequence.

A sequential and general strategy has been successfully developed for the synthesis of spiropyrazolone scaffolds. This intriguing transformation of the asymmetric multicomponent catalysis process was realized with the combination of Michael addition/chlorination/nucleophilic substitution in a one-pot sequence, giving rise to a series of spiropyrazolones with fully substituted cyclopropanes and spiro-dihydrobenzofurans containing continuous stereogenic centers in good yields with excellent stereoselectivities.

Room-Temperature, Metal-Free, and One-Pot Preparation of 2H-Indazoles through a Mills Reaction and Cyclization Sequence.

The Mills reaction and cyclization of readily available 2-aminobenzyl alcohols and nitrosobenzenes using thionyl bromide provided 2H-indazoles in up to 88 % yields. In the metal-free process, acetic acid played a crucial role for the both Mills reaction and cyclization. A brominated 2H-indazole could also be obtained through the one-pot sequence.

Synthetic utility of one-pot chemoenzymatic reaction sequences.

In recent years, there has been a rapid and sustained increase in the development and use of one-pot chemoenzymatic reaction processes for the efficient synthesis of high-value molecules. This strategy can provide a number of advantages over traditional synthetic methods, including high levels of selectivity in reactions, mild and sustainable reaction conditions, and the ability to rapidly build molecular complexity in a single reaction vessel. Here, we present several examples of chemoenzymatic one-pot reaction sequences that demonstrate the diversity of transformations that can be incorporated in these processes.

One-pot synthesis of orthogonally protected sugars through sequential base-promoted/acid-catalyzed steps: A solvent-free approach with self-generation of a catalytic species

A varied set of solvent-free, one-pot synthetic sequences were developed to carry out the orthogonal protection of saccharide polyols. These sequences are composed of an initial regioselective benzylation, silylation or iodination (under mildly basic conditions), followed by an acid catalyzed protection of two further hydroxyl sites via the generation of a cyclic acetal. These processes allow recycling of the ammonium or pyridinium side products generated in the former step as effective catalytic species for the latter step.