Electrophilic Halogenation Research Articles

ChemInform Abstract: Dearomatization Through Halofunctionalization Reactions

AbstractReview: [52 refs.

PH-controlled synthesis of an aromatic triazene and its copper(II) complexation accompanied by an unexpected aromatic ring halogenation

An isomeric triazene (H2L) and an azo dye (D1) were synthesized from the reaction between 2-amino-3-cyano-4-chloro-5-formylthiophene and 2-amino-5-nitrophenol under different pH values. Two Cu(II) complexes of the triazene H2L formulated as {[Cu(L′)(H2O)2]·DMF}n (C1) and [Cu2L2(DMF)2] (C2) were obtained by means of the reactions between deprotonated triazene ligand L2− and different copper salts (CuCl2·2H2O and Cu(OAc)2·H2O) at room temperature. It is noted that a new in situ formed chlorinated ligand L′2- was obtained via the unusual Cu(II) mediated phenyl halogenation of L2− evidenced by the formation of one-dimensional coordination polymer C1 in a high yield of 78%. A control experiment by using Cu(OAc)2·H2O as the metal source reveals the formation of a dinuclear Cu(II) complex C2 of ligand L2− without the occurrence of aromatic ring halogenation. It is suggested that the current study could present an effective approach to achieve the aromatic halogenation under a mild experimental condition with a high yield.

Halogenases: A Biotechnological Alternative for the Synthesis of Halogenated Pharmaceuticals.

The role of halogen atoms in pharmaceutical compounds has been recently revised, due to the weak interaction through the so called "halogen bond" between small molecules and proteins or other biomacromolecules, which could be fundamental for binding at a particular site within the macromolecule. Moreover, thousands of natural halogenated compounds have been described to date, pointing to a functional role of halogen atoms in these compounds, as well as a diversity of halogenating enzymes involved in the synthesis of these halogenated metabolites. In this mini-review the different halogenases described to date are presented, particularly those catalyzing halogenation reactions with potential applications in the pharmaceutical field. Oxidative halogenases following an electrophilic halogenation mechanism are the oldest and best characterized halogenases; however, novel halogenases following a nucleophilic halogenation mechanism have been recently described. The catalytic properties as well as the selectivity of some of these enzymes can be modulated through protein engineering, both by single point mutations or by directed evolution; on the other hand, metabolic pathway engineering has been used to improve the production of halogenated metabolites, as well as to produce novel halogenated compounds, potentially important in the pharmaceutical field. Recent advances and prospective on the field of enzymatic halogenation are covered.

ChemInform Abstract: Synthetic Applications of Carbohydrate‐Derived Donor—Acceptor Cyclopropanes

AbstractReview: [24 refs.

Halogen Bonding in Organic Synthesis and Organocatalysis.

Halogen bonding is a noncovalent interaction similar to hydrogen bonding, which is based on electrophilic halogen substituents. Hydrogen-bonding-based organocatalysis is a well-established strategy which has found numerous applications in recent years. In light of this, halogen bonding has recently been introduced as a key interaction for the design of activators or organocatalysts that is complementary to hydrogen bonding. This Concept features a discussion on the history and electronic origin of halogen bonding, summarizes all relevant examples of its application in organocatalysis, and provides an overview on the use of cationic or polyfluorinated halogen-bond donors in halide abstraction reactions or in the activation of neutral organic substrates.

Selective Claisen rearrangement and iodination for the synthesis of polyoxygenated allyl phenol derivatives

Allyl aryl ethers and allyl phenol derivatives were prepared starting from commercial or synthetized phenols. Either Williamson reaction or Et2AlCl catalyzed Claisen rearrangement was performed to obtain the polyoxygenated molecules. The pivotal allyl phenols were then modified by methylation, iodocyclization or electrophilic aromatic iodination to afford the polyoxygenated derivatives in good to excellent yields. Additionally, their antibacterial properties were also investigated against Gram-positive and Gram-negative bacteria.

Dearomatization through Halofunctionalization Reactions.

Recent advances in dearomatization through halofunctionalization reactions are summarized in this Minireview. Two general categories of strategies are currently employed in this field. On one hand, the reaction can be initiated with electrophilic halogenation at an alkyne or alkene moiety. The resulting halonium ion intermediate is then captured by a pendant aromatic ring at the ipso position, affording the dearomatization product. On the other hand, electrophilic halogenation can directly take place at a substituted arene, and the final dearomatization product is furnished by deprotonation or intramolecular nucleophilic trap. Highly enantioselective variants have been realized in the latter case by organocatalysis or transition metal catalysis. By applying these methods, various valuable halogenated polycyclic molecular architectures have been obtained from readily available starting materials.

Oxyresveratrol: Structural Modification and Evaluation of Biological Activities.

Oxyresveratrol (2,4,3′,5′-tetrahydroxystilbene, 1), a phytoalexin present in large amounts in the heartwood of Artocarpus lacucha Buch.-Ham., has been reported to possess a wide variety of biological activities. As part of our continuing studies on the structural modification of oxyresveratrol, a library of twenty-six compounds was prepared via O-alkylation, aromatic halogenation, and electrophilic aromatic substitution. The two aromatic rings of the stilbene system of 1 can be chemically modulated by exploiting different protecting groups. Such a strategy allows for selective and exclusive modifications on either ring A or ring B. All compounds were evaluated in vitro for a panel of biological activities, including free radical scavenging activity, DNA protective properties, antiherpetic activity, inhibition of α-glucosidase and neuraminidase, and cytotoxicity against some cancer cell lines. Several derivatives were comparably active or even more potent than the parent oxyresveratrol and/or the appropriate positive controls. The partially etherified analogs 5′-hydroxy-2,3′,4-trimethoxystilbene and 3′,5′-dihydroxy-2,4-dimethoxystilbene demonstrated promising anti-herpetic and DNA protective activities, offering new leads for neuropreventive agent research, whereas 5′-hydroxy-2,3′,4,-triisopropoxystilbene displayed anti-α-glucosidase effects, providing a new lead molecule for anti-diabetic drug development. 3′,5′-Diacetoxy-2,4-diisopropoxystilbene showed potent and selective cytotoxicity against HeLa cancer cells, but the compound still needs further in vivo investigation to verify its anticancer potential.

A Strategy towards the Multigram Synthesis of Uncommon Hexaarylbenzenes.

A novel rational synthetic pathway-the "functionalization of para-nitroaniline" (FpNA)-provides substituted hexaarylbenzenes (HABs) with uncommon symmetries that bear up to five different substituents, fully avoiding regioisomeric product distributions during the reactions. 4-Nitroaniline is functionalized by a cascade of electrophilic halogenations, Sandmeyer brominations, and Suzuki cross-coupling reactions, leading to 26 substitution geometries, of which 18 structures are not available by the current established techniques. Furthermore, we demonstrate that this method is applicable to the bulk production of such systems on a multigram scale. Regarding optoelectronic properties, we demonstrate how highly functionalized HABs can show strong luminescent behavior, making these molecules very attractive to organic electronic devices.

Asymmetric total synthesis of paecilomycin F, cochliomycin C, zeaenol, 5-bromo-zeaenol and 3,5-dibromo-zeaenol by Heck coupling and late stage macrolactonization approach

Asymmetric total synthesis of five structurally related naturally occurring 14-membered ring resorcylic acid lactones (RALs) have been described in this article through a concise and flexible way. The main highlight of the reported synthetic strategy involves successful application of an atom economical and highly stereoselective Heck reaction. Substrate directed Barbier propargylation, E-selective cross metathesis (CM) reaction, Mitsunobu esterification and late stage electrophilic halogenation reaction are the other key steps used for the total synthesis of the target molecules.

Mechanism of Oxidative Amidation of Nitroalkanes with Oxygen and Amine Nucleophiles by Using Electrophilic Iodine.

Recently, we developed a direct method to oxidatively convert primary nitroalkanes into amides that entailed mixing an iodonium source with an amine, base, and oxygen. Herein, we systematically investigated the mechanism and likely intermediates of such methods. We conclude that an amine-iodonium complex first forms through N-halogen bonding. This complex reacts with aci-nitronates to give both α-iodo- and α,α-diiodonitroalkanes, which can act as alternative sources of electrophilic iodine and also generate an extra equimolar amount of I(+) under O2. In particular, evidence supports α,α-diiodonitroalkane intermediates reacting with molecular oxygen to form a peroxy adduct; alternatively, these tetrahedral intermediates rearrange anaerobically to form a cleavable nitrite ester. In either case, activated esters are proposed to form that eventually reacts with nucleophilic amines in a traditional fashion.

Synthetic Applications of Carbohydrate‐derived Donor‐Acceptor Cyclopropanes

AbstractIn this account, we elaborate our group's contribution towards understanding the chemistry of carbohydrate‐derived donor‐acceptor (DA) cyclopropanes. Our work was mainly focused on the ring opening of these versatile chiral synthons under the influence of Lewis acid promoters like electrophilic halogen species, TMSOTf, BF3.OEt2, etc. We studied various modes of ring opening on these DA cyclopropanes, envisaging the access to intriguing molecular architectures. These modes of reaction of the DA cyclopropanes can be controlled by strategically introducing an electron‐withdrawing group (EWG) onto the cyclopropane ring, which could direct the ring cleavage by polarizing the cyclopropane C−C bond. Our studies also revealed that the ring opening is sluggish in the absence of an EWG. Using this concept, we demonstrated the synthesis of various biologically interesting molecular skeletons, viz., glycoamino acids (GAA), GAA nucleotides, α‐levoglucosan amino acid, and septano‐oligosaccharides, with high selectivity. We also applied our understanding to the first stereoselective synthesis of (S)‐(−)‐longianone and confirmed its absolute configuration. Apart from the inherently activated DA cyclopropanes, we introduced the in situ generation of DA cyclopropanes, starting from vinylcyclopropanes (VCPs). The ring‐opening and ring‐expansion chemistry of these easily accessible synthons was studied. The chemistry developed for carbohydrate‐fused cyclopropanes was also applied for carbohydrate‐derived spiro‐cyclopropanes. The Lewis‐acid‐mediated ring opening of spiro‐DA‐cyclopropanes enabled easy access to fused furopyrans and spirolactones.

Oxidative Coupling of Aryl Boron Reagents with sp(3)-Carbon Nucleophiles: The Enolate Chan-Evans-Lam Reaction.

Reported is a versatile new oxidative method for the arylation of activated methylene species. Under mild reaction conditions (RT to 40 °C), Cu(OTf)2 mediates the selective coupling of functionalized aryl boron species with a variety of stabilized sp(3) -nucleophiles. Tertiary malonates and amido esters can be employed as substrates to generate quaternary centers. Complementing either traditional cross-coupling or SN Ar protocols, the transformation is chemoselective in the presence of halogen electrophiles, including aryl bromides and iodides. Substrates bearing amide, sulfonyl, and phosphonyl groups, which are not amenable to coupling under mild Hurtley-type conditions, are suitable reaction partners.

Oxidative Coupling of Aryl Boron Reagents with sp3‐Carbon Nucleophiles: The Enolate Chan–Evans–Lam Reaction

AbstractReported is a versatile new oxidative method for the arylation of activated methylene species. Under mild reaction conditions (RT to 40 °C), Cu(OTf)2 mediates the selective coupling of functionalized aryl boron species with a variety of stabilized sp3‐nucleophiles. Tertiary malonates and amido esters can be employed as substrates to generate quaternary centers. Complementing either traditional cross‐coupling or SNAr protocols, the transformation is chemoselective in the presence of halogen electrophiles, including aryl bromides and iodides. Substrates bearing amide, sulfonyl, and phosphonyl groups, which are not amenable to coupling under mild Hurtley‐type conditions, are suitable reaction partners.

Halogen Bonding in Hypervalent Iodine Compounds.

Halogen bonds occur when electrophilic halogens (Lewis acids) attractively interact with donors of electron density (Lewis bases). This term is commonly used for interactions undertaken by monovalent halogen derivatives. The aim of this chapter is to show that the geometric features of the bonding pattern around iodine in its hypervalent derivatives justify the understanding of some of the longer bonds as halogen bonds. We suggest that interactions directionality in ionic and neutral λ(3)-iodane derivatives is evidence that the electron density distribution around iodine atoms is anisotropic, a region of most positive electrostatic potential exists on the extensions of the covalent bonds formed by iodine, and these positive caps affect, or even determine, the crystal packing of these derivatives. For instance, the short cation-anion contacts in ionic λ(3)-iodane and λ(5)-iodane derivatives fully match the halogen bond definition and geometrical prerequisites. The same holds for the short contacts the cation of ionic λ(3)-iodanes forms with lone-pair donors or the short contacts given by neutral λ(3)-iodanes with incoming nucleophiles. The longer and weaker bonds formed by iodine in hypervalent compounds are usually called secondary bondings and we propose that the term halogen bond can also be used. Compared to the term secondary bond, halogen bond may possibly be more descriptive of some bonding features, e.g., its directionality and the relationships between structure of interacting groups and interaction strength.

Electrophilic iodination: a gateway to high iodine compounds and energetic materials

A large number of iodine atoms can be introduced into a single molecule in a one-pot reaction using trifluoroperacetic acid-mediated electrophilic iodination methodology. The scope of this reaction was investigated extensively using several pyrazole substrates which resulted in nine polyiodo pyrazole compounds with iodine content as high as 80%. This synthetic methodology was also utilized successfully for iodination of benzimidazoles. Tetraiodobenzimidazole was nitrated with 100% nitric acid to give a high yield of 4,5,6,7-tetranitro-1H-benzimidazol-2(3H)-one (14). All of these materials were fully characterized and compounds 5, 9, 10 and 14 were confirmed further with single crystal X-ray analysis. High density, positive oxygen balance, and very good impact sensitivity values characterize 14. For the first time, two 1,2,5-oxadiazole-N-oxide rings were introduced into a benzimidazole ring (11) which remarkably improves the stability of oxadiazole-N-oxide compounds.

Eco-compatible zeolite-catalysed continuous halogenation of aromatics

Continuous iodobenzene chlorination reaction: experimental set-up and conversion – acid site density dependence.

ChemInform Abstract: Metal‐Free Synthesis of N‐Fused Heterocyclic Iodides via C—H Functionalization Mediated by tert‐Butylhydroperoxide.

Direct, regioselective and metal-free synthesis of fused N-heterocyclic iodides is reported. This regioselective C–H functionalization is mediated by tert-butylhydroperoxide (TBHP), via dual activation of molecular iodine and a heterocyclic substrate, resulting in the in situ generation of electrophilic iodine species (I+), and free radical(s) tBuO˙ or tBuOO˙, driving the iodination reaction.

Reactions of the halonium ions of carenes and pinenes: An experimental and theoretical study

The reactions of vinylcyclopropane (+)-2-carene (1) and vinylcyclobutanes (-)-β-pinene (7), (-)-α-pinene (11), and (-)-nopol (12) with electrophilic halogens in the presence of oxygen and nitrogen nucleophiles in various solvents have been investigated. The halonium ion intermediates that were presumably formed were very reactive and led to opening of the conjugated cyclopropane or cyclobutane. Reactions of chloramine-T trihydrate with compound 1 in acetonitrile gave amidine 13 and diazepine 14. Reactions of chloramine-T trihydrate with pinenes in methylene chloride gave allylic tosylamines 22, 16B and 24. Mechanisms to explain the observations are proposed and supported by ab initio and Density Functional Theory calculations on the carenes and pinenes in this report and their bromonium ion intermediates. For comparisons, the relative extent of conjugation with the bromonium ion moiety of these, as well as select cyclohexene and cyclohexadiene systems and their corresponding bromonium ions, were optimized at the B3LYP/cc-pVDZ level of theory, and then these geometries were analyzed using the absolute hardness index at the Hartree-Fock/aug-cc-pVDZ and B3LYP/aug-cc-pVDZ levels of theory. Additionally, Natural Population Analysis charges were calculated for these systems using Moller-Plessett Second-Order Perturbation Theory electron densities and the aug-cc-pVDZ basis set. Combining the results of these theoretical methods with analysis of structural details of their optimized geometries gives much electronic structure insight into the extent of conjugation of bromonium ions of the carenes and pinenes reported here, and places them in relative context of more traditional conjugated and non-conjugated bromonium ion systems. In particular, bromonium ions of compounds 1, 7, and 11 display structural distortions, charge delocalizations and hardness values comparable with those of traditional conjugated cyclohexadienes, with possible reasons for subtle differences presented.

ChemInform Abstract: One‐Pot Hydrogen Peroxide and Hydrohalic Acid Induced Ring Closure and Selective Aromatic Halogenation to Give New Ring‐Fused Benzimidazoles.

A new series of selectively dichlorinated and dibrominated five- to eight-membered-ring [1,2-a]-fused benzimidazoles and [1,4]oxazino[4,3-a]benzimidazoles are synthesized in mostly high yields of >80% using the reaction of hydrogen peroxide and hydrohalic acid with commercially available o-cyclic amine substituted anilines. Domestic bleach with HCl can also be used for a one-pot ring closure and chlorination.