Electrophilic Bromination Research Articles

Corrigendum: Diastereo- and Enantioselective Intramolecular C(sp3)H Arylation for the Synthesis of Fused Cyclopentanes

Upon further investigations, the authors found out that the original X-ray structure of compound 2 k in their Communication was actually deduced from a crystal of the minor (R,R) enantiomer, present as 19 % in the enantiomeric mixture. As a consequence, the absolute configuration of all compounds in Scheme 2 should be inverted. The corrected version of Scheme 2 is presented below. In addition, corrected Figure 1 shows the X-ray structure of (S,S)-2k, which was proven to be the major enantiomer by HPLC analysis on a chiral stationary phase. The authors apologize for this error and for any inconvenience caused. We thank Mr. Philipp M. Holstein for additional experiments and Dr. Guillaume Pillet for the new X-ray structure. Scope of the stereoselective synthesis of indanes. Reaction conditions: Pd(OAc)2 (2.5 mol %), L11 (10 mol %), K2CO3 (2 equiv), DMSO, 140 °C. For each compound: yield of the isolated mixture of diastereoisomers, d.r. determined by 1H NMR analysis, e.r. determined by 19F NMR analysis of the Mosher amides prepared after reduction of the nitrile to the primary amine (2a–i) or by HPLC on a chiral phase (2 j). Absolute configurations of 2a–j were ascribed by analogy to 2 k. X-ray crystal structure of indane 2 k, obtained by electrophilic bromination of 2 d (ellipsoids are shown at 30 % probability).

ChemInform Abstract: Bromine‐Catalyzed Conversion of CO2 and Epoxides to Cyclic Carbonates under Continuous Flow Conditions.

A continuous method for the formation of cyclic carbonates from epoxides and carbon dioxide (CO2) is described. The catalysts used are inexpensive and effective in converting the reagents to the products in a residence time (t(R)) of 30 min. The cyclic carbonate products are obtained in good to excellent yield (51-92%). On the basis of a series of kinetics experiments, we propose a reaction mechanism involving epoxide activation by electrophilic bromine and CO2 activation by an amide.

Iridium-catalyzed isomerization/bromination of allylic alcohols: synthesis of α-bromocarbonyl compounds.

α-Brominated ketones and aldehydes, with two adjacent electrophilic carbon atoms, are highly valuable synthetic intermediates in organic synthesis, however, their synthesis from unsymmetrical ketones is very challenging, and current methods suffer from low selectivity. We present a new, reliable, and efficient method for the synthesis of α-bromocarbonyl compounds in excellent yields and with excellent selectivities. Starting from allylic alcohols as the carbonyl precursors, the combination of a 1,3-hydrogen shift catalyzed by iridium(III) with an electrophilic bromination gives α-bromoketones and aldehydes in good to excellent yields. The selectivity of the process is determined by the structure of the starting allylic alcohol; thus, α-bromoketones formally derived from unsymmetrical ketones can be synthesized in a straightforward and selective manner.

Copper(II)‐Catalyzed Aromatization Followed by Bromination of Cyclohexenones Leading to Phenols and Bromophenols

AbstractConversion of substituted cyclohexenones into the corresponding phenols can be achieved using copper acetate as the catalyst in the presence of LiBr and CF3COOH under oxygen. With the use of excess LiBr, electrophilic aromatic bromination afforded the corresponding bromophenol under similar catalytic conditions.

Regioselective Electrophilic Aromatic Bromination: Theoretical Analysis and Experimental Verification

Electrophilic aromatic bromination is the most common synthetic method used to prepare aryl bromides, which are very useful intermediates in organic synthesis. To understand the experimental results in electrophilic aromatic brominations, ab initio calculations are used here for a tentative analysis of the positional selectivity. The calculated results agree well with the corresponding experimental data, and the reliability of the resulting positional selectivity was verified by the corresponding experimental data.

Microwave‐Assisted One‐Pot Synthesis of Substituted 3‐Bromoimidazo[1,2‐a]pyridines and Imidazoheterocycles

Herein, an efficient, one‐pot microwave‐assisted synthesis of a diverse set of 3‐bromoimidazo[1,2‐a]pyridines is being reported with good yields (40–85%). The method involves electrophilic aromatic bromination using bromodimethylsulfonium ion generated in situ via oxidation of HBr salt by DMSO. This methodology was also applied to the synthesis of related imidazoheterocycles. Copyright © 2014 HeteroCorporation

ChemInform Abstract: N‐Bromoimide/DBU Combination as a New Strategy for Intermolecular Allylic Amination.

Allylic amination reactions of alkenes, with an NBP (N-bromophthalimide) or NBS (N-bromosuccinimide)/DBU combination, were developed, in which both internal and external nitrogen nucleophiles can be installed directly. Dual activation of NBS or NBP by DBU leads to more electrophilic bromine and more nucleophilic nitrogen atoms simultaneously. This protocol may provide a novel and complementary access to allylic amination under mild conditions.

Electrophilic Bromination of Nitrobenzene Using Barium Tetrafluorobromate (III)

It has been shown that Ba (BrF4)2 acted as a highly-active brominating agent. In case of interaction with nitrobenzene, the pure 3-bromo-nitrotoluene is formed. It has been shown that typical electrophilic bromination of the aromatic compound with electron-donating and electron-accepting substituents occurred without any catalysts or hard conditions.

On the ionizing properties of supercritical carbon dioxide: uncatalyzed electrophilic bromination of aromatics

scCO2, a non-polar solvent with a dielectric constant lower than n-pentane, promotes the electrophilic bromination of aromatics as efficiently as strongly ionizing solvents such as aqueous acetic and trifluoroacetic acids.

Bromine and iodine–cucurbit[6]uril complexes: preparation and applications in synthetic organic chemistry

Iodine and bromine inclusion compounds were easily prepared by gas diffusion of the halogens using finely powdered CB[6]. A brown powder consisting of I2–CB[6]·4H2O and an orange one of (Br2)4–CB[6]·10H2O were employed in several different reactions. I2–CB[6] can be used in catalytic reactions giving yields comparable to those reported in the literature. Br2–CB[6] was effectively applied in electrophilic bromination of benzene and formation of bromohydrin. However, the radical substitution at cyclohexene could not be performed. Overall, based on these results, several applications can be envisioned for these complexes.

Electrophilic bromination of substituted stilbenes and stilbazoles: a quantum-chemical investigation

In order to study the effect of substituents on the electrophilic bromination of stilbenes and stilbazoles, the geometries of the reaction intermediates were optimised at the MP2/6-31G(d,p) and M06-2X/6-31G(d,p) levels of theory. Stilbenes with two electron-withdrawing substituents are shown to favour bromonium ion intermediates, whereas the presence of an electron-donating substituent leads to a carbocation intermediate. These observations are rationalised by means of Hammett and Taft parameters. Localised molecular orbitals indicate that the bonding between the bromine atom and the carbon atoms in the stilbene varies from a σ-bond in a carbocation intermediate to a 3-centre-2-electron bond in a bromonium ion intermediate. Natural bond orbital (NBO) analyses reveal that carbocation intermediates are stabilised by resonance. The optimised geometries of charge-transfer complexes, the pre-reactive intermediates formed between molecular bromine and the stilbene, show that these species can be considered as halogen-bonded complexes with binding energies ranging from 14.5 to 20.1 kJ mol(-1).

Bromine-Catalyzed Conversion of CO2 and Epoxides to Cyclic Carbonates under Continuous Flow Conditions

A continuous method for the formation of cyclic carbonates from epoxides and carbon dioxide (CO2) is described. The catalysts used are inexpensive and effective in converting the reagents to the products in a residence time (t(R)) of 30 min. The cyclic carbonate products are obtained in good to excellent yield (51-92%). On the basis of a series of kinetics experiments, we propose a reaction mechanism involving epoxide activation by electrophilic bromine and CO2 activation by an amide.

N-Bromoimide/DBU Combination as a New Strategy for Intermolecular Allylic Amination

Allylic amination reactions of alkenes, with an NBP (N-bromophthalimide) or NBS (N-bromosuccinimide)/DBU combination, were developed, in which both internal and external nitrogen nucleophiles can be installed directly. Dual activation of NBS or NBP by DBU leads to more electrophilic bromine and more nucleophilic nitrogen atoms simultaneously. This protocol may provide a novel and complementary access to allylic amination under mild conditions.

A combination of directing groups and chiral anion phase-transfer catalysis for enantioselective fluorination of alkenes.

We report a catalytic enantioselective electrophilic fluorination of alkenes to form tertiary and quaternary C(sp3)-F bonds and generate β-amino- and β-aryl-allylic fluorides. The reaction takes advantage of the ability of chiral phosphate anions to serve as solid-liquid phase transfer catalysts and hydrogen bond with directing groups on the substrate. A variety of heterocyclic, carbocyclic, and acyclic alkenes react with good to excellent yields and high enantioselectivities. Further, we demonstrate a one-pot, tandem dihalogenation-cyclization reaction, using the same catalytic system twice in series, with an analogous electrophilic brominating reagent in the second step.

ChemInform Abstract: N‐Bromosuccinimide/1,8‐Diazabicyclo[5.4.1]undec‐7‐ene Combination: β‐Amination of Chalcones via a Tandem Bromoamination/Debromination Sequence.

A one-pot cascade transformation of chalcones into β-imidoketones has been developed, in which NBS provides both electrophilic bromine and nucleophilic nitrogen sources, and DBU functions as a nucleophilic reagent to activate NBS to be a more electrophilic bromine species and to further remove the bromine of α-bromoketones. The whole process involves tandem bromoamination and debromination, which represents a unique example of preparing β-aminoketones by the reaction of chalcones with the NBS/DBU combination.

Synthetic pathway for a new series of liquid crystal 2,6-disubstituted imidazo[2,1-b][1,3,4]thiadiazole

Herein, the synthesis of a novel series of liquid crystals 2,6-disubstituted imidazo[2,1-b]-1,3,4-thiadiazoles derivate is reported. These fused heterocyclic compounds were prepared through the cyclodehydration between 5-substituted-1,3,4-thiadiazole-2-amino derivatives and α-bromo aryl ketones. The derivates of 2-amino-thiadiazole were obtained from the condensation reaction between thiosemicarbazide and aryl/alkyl nitriles with good yields (60–83%). The α-bromination of aryl ketones was carried out using NBS as the source of electrophilic bromine, also with good yields (52–85%). For the final compounds, the liquid crystal behaviour was shown to be dependent on the number of chains. Mesomorphism was not observed for compounds without aliphatic chains, with more than two aliphatic chains or when the aliphatic chains are methoxy groups.

N-Bromosuccinimide/1,8-Diazabicyclo[5.4.1]undec-7-ene Combination: β-Amination of Chalcones via a Tandem Bromoamination/Debromination Sequence

A one-pot cascade transformation of chalcones into β-imidoketones has been developed, in which NBS provides both electrophilic bromine and nucleophilic nitrogen sources, and DBU functions as a nucleophilic reagent to activate NBS to be a more electrophilic bromine species and to further remove the bromine of α-bromoketones. The whole process involves tandem bromoamination and debromination, which represents a unique example of preparing β-aminoketones by the reaction of chalcones with the NBS/DBU combination.

Vanadate-dependent bromoperoxidases from Ascophyllum nodosum in the synthesis of brominated phenols and pyrroles.

Bromoperoxidases from the brown alga Ascophyllum nodosum, abbreviated as V(Br)PO(AnI) and V(Br)PO(AnII), show 41% sequence homology and differ by a factor of two in the percentage of α-helical secondary structures. Protein monomers organize into homodimers for V(Br)PO(AnI) and hexamers for V(Br)PO(AnII). Bromoperoxidase II binds hydrogen peroxide and bromide by approximately one order of magnitude stronger than V(Br)PO(AnI). In oxidation catalysis, bromoperoxidases I and II turn over hydrogen peroxide and bromide similarly fast, yielding in morpholine-4-ethanesulfonic acid (MES)-buffered aqueous tert-butanol (pH 6.2) molecular bromine as reagent for electrophilic hydrocarbon bromination. Alternative compounds, such as tribromide and hypobromous acid are not sufficiently electrophilic for being directly involved in carbon-bromine bond formation. A decrease in electrophilicity from bromine via hypobromous acid to tribromide correlates in a frontier molecular orbital (FMO) analysis with larger energy gaps between the π-type HOMO of, for example, an alkene and the σ*(Br,X)-type LUMO of the bromination reagent. By using this approach, the reactivity of substrates and selectivity for carbon-bromine bond formation in reactions mediated by vanadate-dependent bromoperoxidases become predictable, as exemplified by the synthesis of bromopyrroles occurring naturally in marine sponges of the genera Agelas, Acanthella, and Axinella.

Gold(i)-catalyzed enantioselective bromocyclization reactions of allenes

The enantioselective bromocyclization of allenes is accomplished through the use of a chiral dinuclear gold complex and/or chiral phosphate anions in the presence of an N-bromolactam as an electrophilic bromine source. This method provides access to heterocyclic vinyl bromides with an allylic stereocenter in excellent yield and enantioselectivity. These enantioenriched vinyl bromides may serve as a handle for further derivatization via cross-coupling reactions.

A Protocol forα-Bromination ofβ-Substituted Enones

α-Haloenone is an important building block in organic synthesis, especially in natural product synthesis. There are at least 4 different reaction modes of this class of compounds: 1, crossing coupling reactions at the α-position; 2, conjugate additions at the β-position; 3, deprotonation at the α'-position; 4, deprotonation at the γ-position. Representative examples of the utilities of α-haloenone include the syntheses of diversonol and the core structures of lomaiviticins and guanacastepenes. From a mechanistic perspective, two types of α-halogenation methods have been developed previously: one through a se- quential Baylis-Hillman-type Michael addition/α-halogenation/β-elimination process; the other one involving an electrophilic bromination followed by a β-elimination. The success of the former type of reactions highly depends on the formation of the transient enolate; the β-substituent on the enone substrates drastically slows down the rate of the first Michael addition step which is responsible for the enolate formation. The latter takes advantage of the strong electrophilicity of molecular bromine to overcome the steric effect of the substrates. However, quite a few side reactions including non-selective bromination often occur, resulting in modest to low yield and poor reproducibility of the desired product on a large scale. Here, we report a pro- tocol for α-bromination of β-substituted enones using pyridine hydrobromide perbromide as a brominating reagent. Cyclic enones prove to be suitable substrates for this reaction, and the corresponding products were obtained in >80% yield in general. Notably, β-phenyl cyclohexenone, a rather unreactive substrate due to both steric and electronic reasons, was bromi- nated smoothly. These bromination products may serve as useful synthon in organic synthesis. For acyclic enones and enoates, the reaction has to be performed at elevated temperature, which may be attributable to the rather poor acidity of the α-proton of the dibromo intermediate. The reaction is reliable on a large scale, and the reagents used are safe and low-toxic. Keywords conjugated enones; α-bromination; addition-elimination mechanism; pyridine hydrobromide perbromide; natural product synthesis