Continuous Synthesis of Aryl Amines from Phenols Utilizing Integrated Packed‐Bed Flow Systems

Aryl amines are important pharmaceutical intermediates among other numerous applications. Herein, an environmentally benign route and novel approach to aryl amine synthesis using dehydrative amination of phenols with amines and styrene under continuous‐flow conditions was developed. Inexpensive and readily available phenols were efficiently converted into the corresponding aryl amines, with small amounts of easily removable co‐products (i.e., H₂O and alkanes), in multistep continuous‐flow reactors in the presence of heterogeneous Pd catalysts. The high product selectivity and functional‐group tolerance of this method allowed aryl amines with diverse functional groups to be selectively obtained in high yields over a continuous operation time of one week.     

Stereoretentive N-Arylation of Amino Acid Esters with Cyclohexanones Utilizing a Continuous-Flow System

The N-arylation of chiral amino acid esters with minimal racemization is a challenging transformation because of the sensitivity of the α-stereocenter. A versatile synthetic method was developed to prepare N-arylated amino acid esters using cyclohexanones as aryl sources under continuous-flow conditions. The designed flow system, which consists of a coil reactor and a packed-bed reactor containing a Pd(OH)₂/C catalyst, efficiently afforded the desired N-arylated amino acids without significant racemization, accompanied by only small amounts of easily removable co-products (i. e., H₂O and alkanes). The efficiency and robustness of this method allowed for the continuous synthesis of the desired product in very high yield and enantiopurity with high space-time yield (74.1 g L⁻¹ h⁻¹) and turnover frequency (5.9 h⁻¹) for at least 3 days.     

Efficient double bond migration of allylbenzenes catalyzed by Pd(OAc)2-HFIP system with unique substituent effect

A novel catalyst system of Pd(OAc)₂-HFIP induces double-bond migration of allylbenzenes under mild conditions with low catalytic loading to afford 1-propenylbenzenes. The reaction shows a unique substituent effect that is highly dependent on the distance of substituents from the allylic moiety. Thus, the reactivity of substrates bearing a methyl group is ordered in para > meta > ortho, whereas it is entirely reversed as ortho > meta > para for methoxy and chloro substituents.     

Transacylation of alpha-aryl-beta-keto esters

The acyl group of an alpha-aryl-beta-keto ester was readily transferred to N-, O-, and S-nucleophiles. The transacylation from arylated diethyl 3-oxoglutarate to amines led to unsymmetrical malonic acid amide esters in high yields. The present reaction proceeded under mild conditions without formation of detectable byproducts. Only simple experimental manipulations were required. This reaction was also found to be sensitive to steric factors, which enabled the chemoselective monoacylation of diamines and amino alcohols without any modifications such as protection.     

New synthetic equivalent of nitromalonaldehyde treatable in organic media

beta-Nitroenamines having a formyl group at the beta-position behave as the synthetic equivalent of unstable nitromalonaldehyde, which is a useful synthon for syntheses of versatile nitro compounds. High solubility of the nitroenamines into general organic solvents enables us to conduct reactions in the organic media accompanied by easy experimental manipulations and considerable safety. When nitroenamines are treated with 1,2-bifunctional nucleophiles such as hydrazines, hydroxylamine and glycine ester, nitrated pyrazoles, isoxazole and pyrrole-2-carboxylate were readily prepared. This methodology was also applicable to guanidines and 1,2-diamines, leading to pyrimidines and 1,4-diazepines, respectively.     

Catalytic Enantioselective Addition of Nitro Compounds to Imines-A Simple Approach for the Synthesis of Optically Active beta-Nitro-alpha-Amino Esters

No AbstractSupporting information for this article is available on the WWW under http://www.angewandte.com or from the author.     

Safe cyano(nitro)methylating reagent—Michael addition of cyano-aci-nitroacetate leading to δ-functionalized α-nitronitriles

A practical, convenient, and safe cyano(nitro)methylation method was developed, in which cyano-aci-nitroacetate served as a synthetic equivalent of anionic nitroacetonitrile. A control of the single/double Michael additions was achieved, which enabled the synthesis of unsymmetrical double Michael adducts. Moreover, the Michael adducts can be used as precursors of pyridine and naphthyridine frameworks.     

Light‐Driven Rotary Molecular Motors on Gold Nanoparticles

We report the synthesis of unidirectional light‐driven rotary molecular motors based on chiral overcrowded alkenes and their immobilisation on the surface of gold nanoparticles through two anchors. Using a combination of ¹H and ¹³C NMR, UV/Vis and CD spectroscopy, we show that these motors preserve their photochemical and thermal behaviour after they have been attached to gold nanoparticles. Furthermore, we describe the synthesis of ²H‐ and ¹³C‐labelled derivatives that were used to verify the unidirectionality of the rotary cycle of these motors both in solution and while grafted to gold nanoparticles. Taken together, these data support the conclusion that these motors maintain their unidirectional rotary cycle when grafted to the surface of small (ca. 2 nm) gold nanoparticles. Thus, continuous irradiation of the system under appropriate conditions leads to unidirectional rotation of the upper half of the molecules relative to the entire nanoparticle.     

Synthesis of functionalized 4-nitroanilines by ring transformation of dinitropyridone with enaminones

2-Functionalized 4-nitroanilines were readily synthesized by ring transformation using 3,5-dinitro-2-pyridone and enaminones prepared from 1,3-dicarbonyl compounds and amines. Modification of the amino group and the ortho-position could be achieved by simply changing the enaminones. Using this strategy, functional groups such as acetyl, benzoyl, and ethoxycarbonyl groups could be introduced into the nitroaniline framework.