N-Dealkylation of Amines

N-dealkylation, the removal of an N-alkyl group from an amine, is an important chemical transformation which provides routes for the synthesis of a wide range of pharmaceuticals, agrochemicals, bulk and fine chemicals. N-dealkylation of amines is also an important in vivo metabolic pathway in the metabolism of xenobiotics. Identification and synthesis of drug metabolites such as N-dealkylated metabolites are necessary throughout all phases of drug development studies. In this review, different approaches for the N-dealkylation of amines including chemical, catalytic, electrochemical, photochemical and enzymatic methods will be discussed.     

Acetylation of alcohols with acetic anhydride promoted by N,N,N-trimethylanilinium tribromide

A wide variety of alcohols were reacted with acetic anhydride at room temperature in the presence of a catalytic amount of N,N,N-trimethylanilinium tribromide to produce the corresponding alkyl acetates in good to excellent yields. Following this procedure, acetylation of primary, secondary, and tertiary alcohols has been performed under neutral conditions.     

DDQ-promoted direct C–H amination of ethers with N-alkoxyamides under visible-light irradiation and metal-free conditions

A C(sp³)–N bond forming reaction between N-alkoxyamides and simple ethers has been developed. In the presence of commercially available 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), a variety of N-methoxyamides and ethers undergo this transformation smoothly to deliver the corresponding products in good yields under visible-light irradiation and metal-free conditions at room temperature.     

Synthesis of phthalan and phenethylamine derivatives via addition of alcohols to rhodium(II)-azavinyl carbenoids

1-Sulfonyl-1,2,3-triazoles undergo inter- and intramolecular 1,3-OH insertion with rhodium(II)-azavinyl carbenoid intermediates upon treatment with a rhodium(II) catalyst. Products of this transformation contain a synthetically versatile N-(2-alkoxyvinyl)sulfonamide, enabling divergent reactivity toward several N-protected phenethylamine derivatives under various conditions. Notably, products with a phthalan framework can be accessed directly from 4-aryl-1-sulfonyl-1,2,3-triazoles bearing a pendant alcohol.     

SmI2-promoted intra- and intermolecular C-C bond formation with chiral N-acyl oxazolidinones

The suitability of chiral oxazolidinones in the SmI₂-mediated C-C bond generation between the imide functionality of an N-acyl oxazolidinone unit and an olefinic radical acceptor, in both inter- and intramolecular reactions, was investigated. It was shown that the products from an Evans asymmetric alkylation can undergo direct carbon-carbon bond formation with an acrylamide providing chiral acyclic ketones in reasonable yields. These examples represent the first transformation of such N-acyl oxazolidinones where this chiral auxiliary is removed under the conditions for ketone formation. 5-exo-trig Cyclization studies were also undertaken with the same type of substrates, providing trans-2,5-disubstituted cyclopentanones in yields of approx. 50%. However, attempts to cyclize heteroatom-containing equivalents were less rewarding.     

Radical cyclizations to quinolone and isoquinolone systems under oxidative and reductive conditions

Radical cyclizations to quinolone and isoquinolone systems under Fenton-type and n-Bu₃SnH-mediated conditions are described. For N-iodoalkylquinolones, ca. 3:1 mixtures of oxidative cyclization products at C-2, and unexpectedly at C-8, were obtained under both conditions. Five- or six-membered oxidative cyclization products were obtained from N-iodoalkylisoquinolones under Fenton-type conditions, whereas n-Bu₃SnH-mediated reactions gave products of reductive cyclization in the five, six, and seven-membered series.     

P′CP′-Pincer palladium complex-catalyzed allylation of N,N-dimethylsulfamoyl-protected aldimines

The P′CP′-pincer palladium complex-catalyzed allylation of N,N-dimethylsulfamoyl-protected aldimines with allyl(tributyl)stannane is investigated for the preparation of N-homoallylic sulfamides. The desired N,N-dimethylsulfamoyl-protected products are obtained in moderate to high yields in DMF under very mild conditions and a high yielding and convenient deprotection of the N,N-dimethylsulfamoyl group is also demonstrated.     

A rapid and convergent synthesis of α,α-difluoro-β-hydroxyketones through regiospecific defluorinative alkylation reaction

Both the defluorinative alkylation reaction of trifluoroacetaldehyde N,O-acetals using alkyllithiums and the following C-C bond formation with carbonyls as electrophiles were accelerated by a suitable diamine additive such as (−)-sparteine to give α,α-difluoro-β-hydroxyketone N,O-acetal products in an excellent yield. We also found that N-benzyl-N,O-acetal group of the resultant products can be removed under palladium-catalyzed hydrogenolysis conditions giving rise to the corresponding α,α-difluoro-β-hydroxyketones. The present two-step procedure is a useful and novel synthetic approach for functionalized α,α-difluoroketones.     

Simple and Expedient Access to Novel Fluorinated Thiazolo- and Oxazolo[3,2-a]pyrimidin-7-one Derivatives and Their Functionalization via Palladium-Catalyzed Reactions

An efficient, versatile, and one-pot method for the preparation of novel fluorinated thiazolo- and oxazolo[3,2-a]pyrimidin-7-ones is described from 2-aminothiazoles or 2-amino-oxazoles and fluorinated alkynoates. This transformation, performed under transition-metal-free conditions, offers new fluorinated cyclized products with good to excellent yields. Moreover, the functionalization of these N-fused scaffolds via the Suzuki-Miyaura and Sonogashira cross-coupling reactions led to the synthesis of highly diverse thiazolo- and oxazolo[3,2-a]pyrimidin-7-ones.     

New insights into bromination process: effective preparation of Ambroxol

Ambroxol used as an expectorant in treating respiratory diseases was effectively prepared with a total yield of 62%, with o-toluidine as the feedstock via successive procedures of electrophilic bromination, acetylation, radical benzylic bromination, N-alkylation and hydrolysis processes. The addition of aqueous hydrogen peroxide could enhance the utilisation of liquid bromine in the electrophilic bromination of o-toluidine, avoiding the hazardous HBr generated as a by-product. In addition, liquid bromine promoted by MnO₂ was used efficiently for the radical benzylic bromination of N-acetyl-N-(2,4-dibromo-6-methylphenyl)acetamide under mild conditions.     

A Closed Concept of Extractive Whole Cell Microbial Transformation of Benzaldehyde into l-Phenylacetylcarbinol by Saccharomyces cerevisiae in Novel Polyethylene-Glycol-Induced Cloud-Point System

Extractive microbial transformation of benzaldehyde into l-phenylacetylcarbinol (l-PAC) by Saccharomyces cerevisiae (Baker’s yeast) has been carried out in a novel polyethylene-glycol-induced cloud-point system (PEG-CPS). The extractive microbial transformation in the PEG-CPS and a downstream process for stripping of the product from the microbial transformation broth with microemulsion extraction are demonstrated. The results indicate that the PEG-CPS maintains the advantage of CPS for in situ extraction of polar product in the microbial transformation. At the same time, the utilization of hydrophilic nonionic surfactant in the PEG-CPS is favorable for stripping of product from the nonionic surfactant in the microbial transformation broth by Winsor I microemulsion extraction. Thus, a closed concept of in situ extraction of polar product in microbial transformation and its downstream process of product recovery are fulfilled at the same time.     

Features of the reactions of β-aryl(heteryl)-α-nitroacrylates with N,N-, N,O-, and N,S-binucleophiles

The reactions of ??-aryl(heteryl)-??-nitroacrylates with N,N-, N,O-, and N,S-binucleophiles proceed regiospecifically through the initial formation of the Ad_N products, among which only the product from o-aminothiophenol was isolated. The conditions of converting the S-adducts into 2-aryl(heteryl)benzothiazole were found. The N-adducts formed in the reaction with hydrazine, o-phenylenediamine, and o-aminophenol undergo immediately the spontaneous transformation into the linear (azine, azomethine) or heterocyclic (benzimidazole) structures.     

Morita–Baylis–Hillman reactions of isatins with allenoates

4-(N,N-dimethylamino)pyridine (DMAP) was found to be a fairly efficient catalyst for the Morita–Baylis–Hillman reactions of isatins with α-substituted allenoates to give the corresponding products in good to high yields with moderate diastereoselectivities under mild conditions.     

Ring-closing metathesis in glycerol under microwave activation

Glycerol, a biodegradable and virtually non-toxic bio-sourced chemical can be used as an alternative, reusable, sustainable solvent, with so far limited application in the field of green organic chemistry. Herein, the reaction conditions have been screened for the ring-closing metathesis (RCM) of N,N-diallyltosylamine and diethyl diallylmalonate in glycerol, under microwave irradiation and in the presence of the most common commercially available RCM catalysts. The products were isolated in high yield after extraction and the catalyst could be recycled up to two times. Results with simultaneous cooling of the reaction vessel under microwave irradiation are also reported.     

General synthesis of mono-, di-, and tri-acetylated indoles from indolin-2-ones

Having developed the one-pot triacetylation of indolin-3-ones, we have now devised a simple two-step reaction sequences to produce di- and mono-acetylated indoles from indolin-2-ones. The indolin-2-ones were first subjected to acetylation in the presence of acetic anhydride and a catalytic amount of N,N-dimethylaminopyridine to give 2-acetoxy-1,3-diacetylindoles. Subsequently, an enzyme-assisted deacetylation resulted in the chemoselective deprotection of the acetoxy group to produce 1,3-diacetyl-2-hydroxyindoles. However, a chemical deacetylation of 2-acetoxy-1,3-diacetylinoles under mild basic or acidic conditions resulted in the formation of 3-acetyl-2-hydroxyindoles.     

Silica-bonded N-propyl sulfamic acid as an efficient catalyst for the formylation and acetylation of alcohols and amines under heterogeneous conditions

A simple and efficient procedure for the preparation of silica-bonded N-propyl sulfamic acid (SBNPSA) by the reaction of 3-aminopropylsilica (1) and chlorosulfonic acid in chloroform is described. This solid acid is employed as a new catalyst for the formylation of alcohols and amines with ethyl formate under mild and heterogeneous conditions at room temperature with good to excellent yields. Also, SBNPSA catalyzed acetylation of various alcohols and amines with acetic anhydride at room temperature.     

Oxidative transformation of <Emphasis Type="Italic">N</Emphasis>-substituted 3-aminopyrazoles to azopyrazoles using electrogenerated bromine as a mediator

The one-pot process of anodic transformation of N-alkyl-3-aminopyrazoles into azopyrazoles under conditions of membraneless electrolysis in an aqueous solution of NaBr was studied for the first time. It was found that under these conditions the aminopyrazoles, which do not have a substituent at position 4, transform into the corresponding 4,4´-dibromoazopyrazoles. The corresponding yield was in the interval of 28—80%, depending on the structure of the products. The transformation of 4-substituted aminopyrazoles resulted in the formation of azopyrazoles in the yields lying within 62—86% when this process was implemented under conditions with the anodically generated Br₂ acting as a mediator. A convenient method of anodic synthesis of azopyrazoles in an aqueous medium without the use of additives of chemical oxidants was proposed. The process is environmentally sound and is characterized by a high atom efficiency (>85%).     

Lipase-promoted kinetic resolution of racemic,P-chiral hydroxymethylphosphonates and phosphinates

Lipase-mediated acetylation of racemic P-chiral hydroxymethylphosphonates and phosphinates, and hydrolysis of their O-acetyl derivatives have been conducted under kinetic resolution conditions to give the enantiomerically enriched title products with up to 92% ee. Their absolute configuration has been determined by means of chemical correlation and CD measurements.     

Microbial transformation of (−)-Huperzine A

Five products were yielded from the transformation of (−)-Huperzine A (1) by Streptomyces griseus CACC 200300. Their structures were determined as 16-hydroxyl huperzine A (2), 14α-hydroxyl huperzine A (3), huperzine A 8α,15α-epoxide (4), 13N-formyl huperzine A (5), and 13N-acetyl huperzine A (6) on the basis of their chemical and physical data. It is the first report on the microbial transformation of (−)-Huperzine A and would facilitate further structural modification by chemo-enzymatic method.     

N-Dimethylphosphoryl-protected glucosamine trichloroacetimidate as an effective glycosylation donor

Glycosylation of a variety of alcohols with 3,4,6-tri-O-acetyl-2-N-dimethylphosphoryl-2-deoxy-α-d-glucopyranosyl trichloroacetimidate as a glycosyl donor provided the corresponding coupled products in high yields and good β-selectivity. N-Dimethylphosphoryl-protection stayed stable under acidic and basic conditions for further elaboration of the glucosamine-containing oligosaccharides.