Von Braun Reaction Research Articles

Ligand-Promoted Rosenmund–von Braun Reaction

AbstractTwo picolinamide ligands were found to have significant accelerating effect to classical Rosenmund–von Braun reaction, making the coupling of (hetero)aryl bromides with CuCN occur at 100–120 °C with good to excellent yields in most cases. A large number of functional groups and heterocycles were tolerated under these conditions, thereby providing a convenient and reliable approach for diverse synthesis of aryl nitriles.

Electron-Transfer Driven Cyanation of Aryl Iodides

Aryl cyanides are widely utilized as important intermediates in the research fields of pharmaceuticals, natural products and also organic materials, because the nitrile group can easily be transformed into a wide variety of functional groups, such as amides, carboxylic acids, imines, ketones, and amines. In the preparation of aryl cyanides, Rosenmund–von Braun reaction, in which an aryl halide reacts with copper cyanide, is often used; however, harsh reaction conditions are required, and the separation of cupper complexes in a workup process is often problematic, especially in a large-scale synthesis. We initiated our study to develop a copper free method to prepare aryl cyanides, and found that a catalytic amount of 1,10-phenanthroline nicely promoted the reaction of aryl iodides with tetraethylammonium cyanide to afford aryl cyanides (Scheme 1). 1,10-phenanthroline would work as a SET initiator on the first stage to generate radical anion. We next tried to use the electrochemical reaction for the initiation step. Electricity was simply passed to the mixed solution of aryl iodides and tetraethylammonium cyanide to afford the corresponding aryl cyanides in moderate yields. Notably, the reactions proceeded with a catalytic amount of electricity. Figure 1

Theoretical investigation of von Braun and von Braun‐like reactions

AbstractThe von Braun reaction, discovered at the dawn of the past century, consists of the reaction between a tertiary amine and cyanogen bromide. It leads to the cleavage of a C─N bond with the formation of an N‐dialkylcyanamide and an alkyl bromide and has been extensively used in organic synthesis. A detailed in silico study (PCM/density functional theory [DFT]/B3LYP/6‐31++G(d,p) calculations) of this venerable reaction has shown that in the first stage a zwitterionic adduct with a multibonded bromine atom is formed. The widely accepted mechanism involving an SN2 reaction occurs in the second step, thus accounting for its selectivity. Quantum chemical calculations were performed for the von Braun‐like reactions in systems formed by cyclic tertiary amines (N‐alkyl azetidines). In these cases, the first stage is almost the same as in the classical von Braun processes, and selective SN2 mechanisms can occur in the second step.

Biosynthetically Inspired Transformation of Iboga to Monomeric Post-iboga Alkaloids

Summary Organisms have evolved to produce various natural products from a common precursor as a means of maximizing the number of secondary metabolites, thus acquiring selectional advantages. By adopting nature's divergent biosynthetic strategy, we transformed (+)-catharanthine to various iboga and post-iboga alkaloids, including (−)-conodusine A, (+)-conodusines B and C, (−)-voatinggine, (−)-tabertinggine, and (+)-dippinine B. Well-orchestrated oxidations and reorganizations of catharanthine derivatives enabled chemical access to these natural products.

Heterocyclic analogs of 5,12-naphthacenequinone 15*. Synthesis of new anthra[2,3-b]thiophene-3(2)-carboxylic acids

Methods have been developed for the synthesis of anthra[2,3-b]thiophene-3(2)-carboxylic acids and their derivatives through modifications of 4,11-dibutoxy-3-methylanthra[2,3-b]thiophene-5,10-dione. A scheme involving methyl group transformations was proposed for the preparation of dibutoxyanthra[2,3-b]thiophene-3-carboxylic acid, including reactions of radical halogenation, hydrolysis, and oxidation of a 3-formyl derivative. 4,11-Dihydroxy-3-methylanthra[2,3-b]thiophene-2-carboxylic acid was synthesized from the appropriate carbonitrile, obtained by Rosenmund–von Braun reaction from 2-bromo-4,11-dibutoxy-3-methylanthra[2,3-b]-thiophene-5,10-dione.

The von Braun Reaction Applied to Azetidines

The von Braun reaction (the reaction of cyanogen bromide with tertiary amines) was applied to a series of functionalized N‐alkyl‐substituted azetidines. This reaction mainly led to the cleavage of the strained four‐membered ring to produce 3‐bromo N‐alkyl cyanamides in good yields with variable regioselectivity. The resulting cyanamide products were then employed as original building blocks for the synthesis of nitrogen heterocycles.

The Construction of X–CN (X=N, S, O) Bonds

AbstractThe cyano moiety is a common and important functional group that exists in a myriad of medicinal molecules and natural products. Moreover, nitriles serve as versatile precursors that can readily be converted into diverse functional groups as well as the nitrogen‐containing cyclic molecules. As a result, cyanation has become a significant type of transformation in organic chemistry. However, in comparison with the well‐developed C‐cyanation, few works have been reported dealing with the N‐, S‐ and O‐cyanation processes. Apart from the classical von Braun reaction, chemists have developed a number of methods with various cyanating reagents to achieve such X‐cyanations (X=N, S, O). In this review, recent advances (especially those after 2000) in the X–CN (X=N, S, O) bond formation are summarized with discussion and the outlooks are also listed.magnified image

Elucidation of reaction process through β-halogen elimination in CuCN-mediated cyanation of (E)-1-bromo-2-iodoalkene

The previously unknown reaction process involved with metal-mediated β-halogen elimination is described, including a description of a vinylic Rosenmund–von Braun reaction of (E)-(1-bromo-2-iodobut-1-en-1-yl)benzene. We investigated the product structures on the basis of crystallographic analyses and revealed that copper cyanide would form bifurcated paths to deliver the isomeric mixtures.

ChemInform Abstract: A Unique and Simple Preparative Method for α‐Arylpipecolinic Acid Esters via Base‐Induced Sommelet—Hauser Rearrangement.

AbstractTitle compounds such as (V) and (IX) are prepared via a new three‐step sequence including base‐induced Sommelet—Hauser rearrangement, subsequent von Braun reaction and intramolecular α‐alkylation.

A Unique and Simple Preparative Method for α-Arylpipecolinic Acid Esters via Base-Induced Sommelet–Hauser Rearrangement

Title compounds such as (V) and (IX) are prepared via a new three-step sequence including base-induced Sommelet—Hauser rearrangement, subsequent von Braun reaction and intramolecular α-alkylation.

Synthesis of Substituted 2-Aminoimidazoles

Looper and co-workers described a three-step synthesis of highly substituted 2-aminoimidazoles. The first step consists of the preparation of propargyl cyanamides by copper(I)-­catalyzed addition of an iminium generated from condensation of aldehydes (R² = alkyl or aryl) with secondary amines. Without further purification, the resulting tertiary amines are subjected to a von Braun reaction. The use of 4-methoxybenzyl-, 2,4- and 3,4-dimethoxybenzyl-substituted propargyl amines lead to the propargyl cyanamides in good yields whereas symmetric N,N-dialkylpropargyl amines give exclusively propargyl bromide. Screening of catalysts led to the use of La(OTf)3 for the final addition-hydroamination step. Both acyclic and cyclic secondary amines generated guanidine intermediates which underwent cyclization to the alkyne to afford 2-aminoimidazoles in good yields.

N-Demethylation of Alkaloids

The removal of an N-methyl group, or N-demethylation, is a useful chemical transformation in organic synthesis which has particular importance in the field of alkaloid chemistry. Historically, tertiary N-methyl alkaloids have been N-demethylated using the same methods as for N-dealkylating tertiary amines. Such methodologies have included the von Braun reaction, the use of chloroformate and azodicarboxylate reagents and the Polonovski reaction, amongst others. Photochemical and biochemical procedures have also been successfully employed. This review will examine these N-demethylation procedures, with special emphasis on their application to opiate alkaloids.

Efficient Microwave‐Assisted Cyanation of Aryl Bromide

Aryl nitriles were easily prepared from the corresponding bromides and copper cyanide in good yields through microwave‐accelerated Rosenmund–von Braun reaction in N‐methylpyrrolidinone (NMP) under ambient pressure.

Combined Directed Ortho Metalation/Cross-Coupling Strategies: Synthesis of the Tetracyclic A/B/C/D Ring Core of the Antitumor Agent Camptothecin

A convergent synthesis of the A/B/C/D ring fragment 5 of camptothecin using a combination of directed ortho metalation and Negishi cross-coupling is described. The key features of the synthetic sequence are an anionic ortho-Fries rearrangement (10 --> 12), a Negishi cross-coupling (7 --> 6), and a terminal modified von Braun reaction (16 --> 5) that leads to tetracyclic derivative 5 in 7 steps and 11% overall yield.

Efficient Microwave‐Assisted Cyanation of Aryl Bromide.

AbstractFor Abstract see ChemInform Abstract in Full Text.

High yield synthesis of aryl cyanides under microwave irradiation

Reaction of anhydrous cuprous cyanide with aryl bromides produced aryl cyanides (Rosenmund–von Braun reaction) under microwave irradiation in a short time and in high yield.

The synthesis of phthalocyanines containing both nitrile and non-peripheral alkyl or alkoxy side-chains

The synthesis of a number of phthalocyanines containing four or eight peripheral nitrile groups in addition to eight non-peripheral alkyl or alkoxyl side-chains is described. These materials are derived from the tetracyano- and tricyano-benzene derivatives prepared by the Rosenmund von Braun reaction of 1,2,4,5-tetrabromo-3,6-didodecylbenzene or 1,2,4,5-tetrabromo-3,6-hexyloxybenzene. Attempts to polymerise 1,2,4,5-tetracyano-3,5-didodecylbenzene to form a soluble polyphthalocyanine derivative failed.

Catalytic Rosenmund–von Braun reaction in halide-based ionic liquids

Ionic liquids based on 1- n-butyl-3-methylimidazolium halide salts (bmiX) have been used as an effective reusable reaction media in the Rosenmund–von Braun reaction of aryl halides and NaCN using copper(I) salts as catalysts. Product isolation is achieved by simple extraction using organic solvents. The copper catalysts immobilized in ionic liquid media can be reused continuously.

N-Demthylation Studies of Pavine Alkaloids

The N-norpavines, ring homologues of MK-801-a potent NMDA receptor antagonist, were prepared from N-methyl quaternary pavines by two nucleophilic reaction steps: N-methyl quaternary ammonium salts into tertiary amine by reacting with NaHTe (ethanolamine/Δ or OAc − salt/DMF, Δ); tertiary amine into N-norpavines by the von Braun reaction and subsequent hydrolysis

Synthesis of a Secondary N-Desmethyl and a Tertiary N-Cyclopropylmethyl Bridged Hexahydroaporphine as Precursors to Bicyclic Opioid Ligands

In an attempt to generate a bicyclic 5,8-ethano derivative of N-methylmorphinan, an isomeric bicyclic hexahydroaporphine 2 was synthesized. The phenolic analogue of 2 has demonstrated affinity for mu opioid receptors in vitro and, along with 2, provided weak, primarily nonopioid analgesic action when injected intracerebroventricularly in mice. It was of interest to assess the potential opioid antagonist action of bicyclic hexahydroaporphine analogues containing cyclopropylmethyl and allyl nitrogen substituents. As the first steps in the generation of these potential opioid antagonists, the secondary bicyclic hexahydroaporphine 3 and its N-cyclopropylmethyl congener 4 were synthesized. N-Demethylation of 2 was initially attempted via the von Braun reaction, but acid-catalyzed hydrolysis of the crude N-cyano intermediate resulted in product decomposition. A successful approach to 3 involved the hydrolysis of the N-formyl precursor 1 in ethanolic potassium hydroxide. Direct alkylation of the secondary amine 3 utilizing cyclopropylmethyl bromide and sodium bicarbonate successfully generated the alkylated derivative 4. Both products were purified in hydrochloride salt form and characterized by standard analytical and spectroscopic methods. The free base form of 3 was highly sensitive to photo-oxidation. Opioids are known to oxidize to 10-keto structures, and secondary amines can oxidize to hydroxylamines. Infrared analysis of the decomposition product indicated the presence of both hydroxy and carbonyl groups which were absent in the spectrum of the salt. Structures of potential oxidation products are proposed.