Heterocyclic Ketones Research Articles

Controllable Synthesis of Oxa‐/Thia‐Spirohydroquinolines by [3+(2+1)] Annulation of Aromatic Amines with Bimolecular O/S‐Heterocyclic Ketones

Abstract[3+(2+1)] Annulation represents the most straightforward and atom‐economical strategies in organic synthesis for the efficient construction of diverse cyclic structural units and complex molecules. Herein, we present a Lewis acid Sc(OTf)3‐catalyzed controlled synthesis of two different regioselective oxa/thia‐spirohydroquinolines (C=C at the α/β‐site of O/S‐atom) from aromatic amines and bimolecular O/S‐heterocyclic ketones via intermolecular [3+(2+1)] annulation. This method features mild reaction conditions, high step economy and atom utilization, and the O/S‐heterocyclic ketone can act as both two‐ and one‐carbon synthons. Furthermore, density functional theory (DFT) calculations indicate that the intrinsic cause of this unique regioselectivity is caused by the proton abstraction step.

Unveiling the Reactivity of Part Per Million Levels of Cobalt-Salen Complexes in Hydrosilylation of Ketones.

A series of air-stable cobalt(III)salen complexes Co-1 to Co-4 have been synthesized and employed in the hydrosilylation of ketones. Notably, the most intricately tailored Co-3 pre-catalyst exhibited exceptional catalytic activity under mild reaction conditions. The developed catalytic hydrosilylation protocol proceeded with an unusual ppm level (5 ppm) catalyst loading of Co-3 and achieved a maximum turnover number (TON) of 200,000. A wide variety of aromatic, aliphatic, and heterocyclic ketones encompassing both electron-donating and electron-withdrawing substituents were successfully transformed into the desired silyl ethers or secondary alcohols in moderate to excellent yields.

Air-Stable Iron(III) Salen Complexes for Selective Hydroboration of Ketones and Unactivated Imines without Base Activation.

Herein, we designed and synthesized a series of air-stable, cost-effective, and readily synthesizable iron(III) salen complexes (Fe-1 and Fe-2) for facilitating the selective hydroboration of ketones and unactivated imines with pinacolborane in the absence of any additive. These catalyst systems exhibited good yields, chemoselectivity, high atom economy, and a broad substrate scope under mild reaction conditions with a minimal catalyst loading of 0.2 mol %. The catalytic efficiency of Fe-1 has been demonstrated through the hydroboration of diverse aromatic, aliphatic, and heterocyclic ketones and imines with a turnover number of up to 1000, highlighting its broad substrate scope. Ketones are chemoselectively hydroborated over other functional groups such as imines, alkenes, esters, nitriles, acids, and alcohols. Besides, the synthetic utility of this strategy has also been showcased by the construction of a natural chiral monoterpenoid carveol. This protocol can be readily scaled up for gram-scale synthesis of alcohols, which underscores the potential industrial applicability of our catalyst system in the synthesis of secondary alcohols on a larger scale.

Enhancing bread anti-staling with glucose-derived Maillard reaction products: In-depth analysis of starches, gluten networks, and moisture status

In this study, six types of amino acids (Ala, Phe, Glu, Gly, Ser, and Lys) were combined with glucose to produce Maillard reaction products (MRPs) named G-Ala, G-Phe, G-Glu, G-Gly, G-Ser and G-Lys. The effect of MRPs on bread staling was evaluated through texture and sensory analyses during storage. Furthermore, the study comprehensively analyzed the anti-staling mechanisms of MRPs by examining moisture content, starches, and gluten network changes. The results indicated that G-Gly and G-Glu delayed bread staling, with G-Gly showing the most significant effect. Compared with control, the staling rate and starch crystallinity of G-Gly bread decreased by 24.07% and 7.70%, respectively. Moreover, G-Gly increased the moisture content (3.48%), weakly bound water mobility (0.77%), and α-helix content (1.00%) of bread. Component identification and partial least squares regression further confirmed the aldonic acid, heterocyclic acids and heterocyclic ketones in MRPs inhibit water evaporation, gluten network loosening, and starch degradation, thereby delaying bread staling.

Engineering the substrate acceptance of l-amine dehydrogenase enables the collective biocatalytic synthesis of N-heterocyclic primary amines

Chiral N-heterocyclic primary amines are highly attractive synthons in the pharmaceutical industry. Amine dehydrogenases (AmDHs)-catalyzed direct asymmetric reductive amination of the readily available N-heterocyclic ketones represents a promising approach for synthesizing N-heterocyclic primary amines. However, the limited substrate acceptance of AmDHs restricts their application in biocatalytic synthesis. Here, we engineered the substrate acceptance of L-EsAmDH from Exiguobacterium sibiricum to access a panel of structurally diverse N-heterocyclic ketones. Through reverse substrate design and combining with substrate walking strategy, two active mutants with extended substrate specificity toward N-Boc-4-acetylpiperidine were identified, and two additional rounds of iterative site mutagenesis further increased the activity by 116.3-fold. The optimal mutant M4-2 (L49G/V303A/L307A/T143A) exhibited significantly expanded N-Boc, N-Bn, and N-Cbz-substituted heterocyclic ketones scope, and its practical biocatalytic synthesis performance was verified in the gram-scale synthesis of (R)-4-aminoethyl-1-Boc-piperidine, achieving 95 % conversion, >99 % ee, and an overall isolated yield of 86 % (9.8 g). Our study lays the foundation for the collective biocatalytic synthesis of structurally diverse N-heterocyclic primary amines and gives referable guidance for engineering AmDH family members into versatile biocatalysts.

Synthesis of 2-substituted quinoline derivatives using [RuCl2(p-cymene)]2-ferrocene thioamide catalytic system via acceptorless dehydrogenative coupling

The substituted quinolines were synthesized via acceptorless dehydrogenative coupling (ADC) of 2-aminobenzyl alcohol with ketones/secondary alcohols, which was accomplished using the in situ catalytic activity of [RuCl2(p-cymene)]2 and ferrocene thioamide (Fc-TA) ligands. The catalysis was extended to aromatic and heterocyclic ketones and secondary alcohols, with unsubstituted and chloro‑substituted 2-aminobenzyl alcohols. The Fc-TA ligands (L1-L3) were synthesized, and characterized using spectroscopic techniques such as FT-IR, UV–Vis, NMR and HRMS. The influence of ligands on the catalysis was studied. Overall, the synthesis of quinolines was accomplished with good to moderate yields, via both mono and double dehydrogenation reactions along with hydrogen and water as only by-products.

Efficient hydrogenation of ketones over the diaminophosphino manganese complex.

Herein, we synthesized new manganese(I) complexes coordinated with the tetradentate ligand PNNP. The complexes show higher activity and excellent substituent tolerance in contrast to their manganese counterparts and are applicable in the hydrogenation of a wide range of aromatic, aliphatic and heterocyclic ketones to their corresponding alcohols.

Multigram synthesis of β-fluorinated saturated heterocyclic methanamines

An efficient multigram synthesis of β-fluorinated saturated heterocyclic methanamines - promising building blocks for drug discovery, starting from the corresponding saturated heterocyclic ketones is described. The method includes Wittig olefination, bromofluorination, nucleophilic substitution with azide, and Staudinger reaction and works well for four- to seven-membered nitrogen- and oxygen-containing heterocyclic derivatives

Aza‐Prins Cyclization on Ketones to Access Piperidines with Tetrasubstituted Carbon Stereocenters

AbstractThe aza‐Prins cyclization in presence of a variety of aliphatic, aromatic, and heterocyclic ketones is disclosed. The developed method allows an access to diverse C‐2 functionalized piperidines, bearing a tetrasubstituted or spiranic carbon stereocenter, in a range of 30 to 87% yields. When diastereomers were formed, the trans isomer was identified as the major product.

The Reduction of Carbonyl Compounds with Dicyclopentylzinc: A New Example of Asymmetric Amplifying Autocatalysis

A previously unknown reduction of carbonyl compounds with dicyclopentylzinc is reported. Aldehydes react in mild conditions yielding corresponding primary alcohols and cyclopentene. Although cyclohexanone and acetophenone are inert to dicyclopentylzinc, a variety of heterocyclic ketones reacted readily, yielding reasonable to high yields of corresponding secondary alcohols. When the reaction was catalyzed with (–)-(1R,2S)-ephedrine, 3-acetylpyridine (10) resulted in a high yield of (S)-1-(pyridin-3-yl)ethanol (19) with >99% ee. 5-Acetyl-2-bromopyridine (11) also provided the corresponding optically active alcohol 20, albeit with a much lower optical yield. When 10% of 19 with 92% ee was used as an autocatalyst, 55% yield of the same compound was obtained, with 95% ee and 96% ee in two independent experiments. A three-stage reaction sequence starting from “no chirality” reaction yielded 19 with 6% ee. Thus, amplifying autocatalysis was detected in the reaction of ketone 10 with dicylopentylzinc.

Green Oxidation of Heterocyclic Ketones with Oxone in Water.

The recently reported efficient conversion of cyclic ketones to lactones by Oxone in neutral buffered water is extended to heterocyclic ketones, namely, cyclic N-Boc azaketones and oxoethers with the aim of obtaining N-protected azalactones and their analogues with oxygen in place of nitrogen. N-Boc-4-piperidinone and all the cyclic oxoethers were successfully oxidized to lactones, while the azacyclic ketones with nitrogen α-positioned to carbonyl were univocally transformed into N-Boc-ω-amino acids and N-Boc-N-formyl-ω-amino acids operating in alkaline water and DMF, respectively.

An efficient and green synthesis of multi‐heteroatom heterocycles via a three components reaction in acetic acid/aqueous condition

AbstractIn this research, the multi‐heteroatom heterocycles were effectively obtained via three components reactions from isatins, 3‐aminopyrazol‐5(4H)‐one, and the different heterocyclic ketones (kojic acid, ethyl 4‐oxopiperidine‐1‐carboxylate, and tetrahydro‐4H‐thiopyran‐4‐one) under acetic acid/aqueous condition for the first time. The advantages of the approach were easy to handle, excellent yields, a wide range of substrates and environmental friendliness. This study provided an alternative synthesis pathway for obtaining multi‐heteroatom heterocycle compounds.

Regulating the stereoselectivity of medium-chain dehydrogenase/reductase by creating an additional active pocket accommodating prochiral heterocyclic ketones.

Medium chain dehydrogenase/reductase (MDR) is a robust catalyst for the asymmetric synthesis of chiral heterocyclic alcohols, essential building blocks in pharmaceuticals. However, the regulatory mechanism of stereoselective complementary reduction of heterocyclic ketones by carbonyl reductase (CR) is unclear. Structure-guided creation of an additional substrate-binding active pocket inversed the stereoselectivity of SpCR from Spathaspora passalidarum. The mutant m48 showed improved catalytic activity towards the 12 tested heterocyclic ketones (conversion rate >99%, ee value > 99%). Hence, we regulated the stereoselectivity of MDR by creating an active pocket suitable for substrate localisation. This strategy has a guiding significance in addition to the conventional method for stereoselectivity modification of MDR.

One Pot Synthesis and Antimicrobial Evaluation of 8-Substituted-2,5-dihydro- 2-(2-nitrophenyl/4-nitrophenyl)-4-(2-thienyl)-1,5-benzothiazepines

The reaction of an α,β-unsaturated heterocyclic ketone, 3-(2-nitrophenyl/4-nitrophenyl)-1-(2-thienyl)- 2-propenone (3a-b) with 5-substituted-2-aminobenzenethiols (4a-d) with substituent -CH3, -Cl, -F and -Br was carried out in dry methanol containing trifluoroacetic acid (TFA) in catalytic amount as well as by swirling for 20 min in diethyl ether at room temperature. The yields of the products, 8-substituted- 2,5-dihydro-2-(2-nitrophenyl/4-nitrophenyl)-4-(2-thienyl)-1,5-benzothiazepines (5a-h), ranged from 60% to 75% by first method and 65% to 85% by second method. The synthesized compounds have been characterized by micro-estimation of C, H, N and 1H NMR, 13C NMR as well as mass spectral studies. All the synthesized compounds are tested for biological efficacy against, Gram-positive bacteria, Staphylococcus aureus, Gram-negative bacteria Escherichia coli and fungi, Candida albicans. All of the compounds demonstrated effective antibacterial and antifungal activities.

Photochemical Decarbonylation of Oxetanone and Azetidinone: Spectroscopy, Computational Models, and Synthetic Applications.

Photoexcitation of cyclic ketones leads to the expulsion of carbon monoxide and a mixture of products derived from diradical intermediates. Here we show that synthetic utility of this process is improved if strained heterocyclic ketones are used. Photochemistry of 3-oxetanone and N-Boc-3-azetidinone has not been previously described. Decarbonylation of these 4-membered rings proceeds through a step-wise Norrish type I cleavage of the C-C bond from the singlet excited state. Ylides derived from both compounds are high-energy species that are kinetically stable long enough to undergo [3+2] cycloaddition with a variety of alkenes and produce substituted tetrahydrofurans and pyrrolidines. The reaction has a sufficiently wide scope to produce scaffolds that were either previously inaccessible or difficult to synthesize, thereby providing experimental access to new chemical space.

Photochemical Decarbonylation of Oxetanone and Azetidinone: Spectroscopy, Computational Models, and Synthetic Applications**

AbstractPhotoexcitation of cyclic ketones leads to the expulsion of carbon monoxide and a mixture of products derived from diradical intermediates. Here we show that synthetic utility of this process is improved if strained heterocyclic ketones are used. Photochemistry of 3‐oxetanone and N‐Boc‐3‐azetidinone has not been previously described. Decarbonylation of these 4‐membered rings proceeds through a step‐wise Norrish type I cleavage of the C−C bond from the singlet excited state. Ylides derived from both compounds are high‐energy species that are kinetically stable long enough to undergo [3+2] cycloaddition with a variety of alkenes and produce substituted tetrahydrofurans and pyrrolidines. The reaction has a sufficiently wide scope to produce scaffolds that were either previously inaccessible or difficult to synthesize, thereby providing experimental access to new chemical space.

H3PO3/I2 mediated formation of N-benzyl benzo heterocyclic ketones from aromatic aldehydes and benzyl alcohol derivatives

We report a H3PO3/I2 mediated formation of N-benzyl benzo heterocyclic ketones from the reaction of benzo heterocyclic compounds with aromatic aldehydes or benzyl alcohol derivatives under metal-free conditions in one-pot. For the first time, aromatic aldehydes were used as benzylated reagents to synthesize benzo heterocyclic ketones in the presence of K2CO3. Control experiments indicated that the carbonyl oxygen most possibly originated from K2CO3. H3PO3 also played the dual role of promotor as well as hydrogen source. This novel method features a wide substrate scope, low-cost and simple condition.

Origin of the Unexpected Enantioselectivity in the Enzymatic Reductions of 5-Membered-Ring Heterocyclic Ketones Catalyzed by Candida parapsilosis Carbonyl Reductases

Candida parapsilosis carbonyl reductases (CpRCR) have been widely used for the reductive conversion of ketone precursors and chiral alcohol products in pharmaceutical industries. The enzymatic enantioselectivity is believed to be related to the shape complementation between the cavities in the enzymes and the substitutions of the ketone substrates. In this work, we reported an unexpected enantioselectivity in the enzyme reductions of dihydrofuran-3(2H)-one (DHF) to (S)-tetrahydrofuran-3-ol (DHF-ol, enantiomeric excess: 96.4%), while dihydrothiophen-3(2H)-one substrate (DHT) was unproductive under the same experimental conditions. To rationalize the exclusive S-configuration and the specific reactivity of DHF, we carried out molecular dynamics simulations for the reacting complexations of DHF with CpRCR, and DHT with CpRCR. Our calculations indicate that DHF preferentially binds to the small cavity near L119, F285, and W286, while the large cavity near the α1 helix was mainly occupied by solvent water molecules. Moreover, the pre-reaction state analysis suggests that the pro-S conformations were more abundant than the pro-R, in particular for DHF. This suggests that the non-polar interaction of substrate C4-C5 methylene contacting the hydrophobic side-chains of L119-F285-W286, and the polar interaction of funanyl oxygen exposing the solvent environment play important roles in the enantioselectivity and reactivity. The phylogenetic tree of CpRCR homologues implies that a variety of amino acid combinations at positions 285 and 286 were available and thereby potentially useful for redesigning enantioselective reductions of 5-membered-ring heterocyclic ketones.

Anti-tyrosinase, anti-elastase, and antioxidant activities of some symmetric bisthiocarbohydrazone compounds

Symmetric bisthiocarbohydrazone compounds (1, 2, 3) were obtained by the condensation of thiocarbohydrazide with carbonyl compounds such as isatin (a heterocyclic ketone) and two hydroxyl aldehydes (2-hydroxybenzaldehyde, 2-hydroxy-1-naphthaldehyde) respectively, according to the previously reported methods. These synthesized compounds were evaluated in terms of their anti-tyrosinase, anti-elastase and antioxidant potentials in vitro. All of the tested compounds exhibited anti-tyrosinase and anti-elastase activities. It was observed that the inhibition increased with the increase of bisthiocarbohydrazone concentrations. Compound 1 showed the highest anti-tyrosinase activity. The anti-tyrosinase activity is decreasing in the following order; 2<3<1 . Compound 1 showed also the highest anti-elastase activity. The anti-elastase activity is decreasing as 3<2<1 . As a result, the most effective compound in terms of anti-tyrosinase and anti-elastase activities is bisthiocarbohydrazone derived from isatin. Compounds 2 and 3 with the hydroxyl substitution showed antioxidant activity close to Trolox. These compounds were found to have significant reducing effects and to be effective scavengers of DPPH.

Electrochemical Cross-Dehydrogenative Aromatization Protocol for the Synthesis of Aromatic Amines.

The introduction of amines onto aromatics without metal catalysts and chemical oxidants is synthetically challenging. Herein, we report the first example of an electrochemical cross-dehydrogenative aromatization (ECDA) reaction of saturated cyclohexanones and amines to construct anilines without additional metal catalysts and chemical oxidants. This reaction exhibits a broad scope of cyclohexanones including heterocyclic ketones, affording a variety of aromatic amines with various functionalities, and shows great potential in the synthesis of biologically active compounds.