Ultrafast Halogen Dance Reactions of Bromoarenes Enabled by Catalytic Potassium Hexamethyldisilazide.

Lochmann-Schlosser base, a stoichiometric combination of nBuLi and KOtBu, is commonly used as a superbase for deprotonating a wide range of organic compounds. In the present study, we report that catalytic potassium hexamethyldisilazide (KHMDS) exhibits higher catalytic activity than KOtBu for successive bromine-metal exchanges. Accordingly, 1-10 mol% of KHMDS dramatically enhances halogen dance reactions to introduce various electrophiles to bromopyridine, bromoimidazole, bromothiophene, bromofuran, and bromobenzene derivatives with the bromo group translocated from the original position. A dual catalytic cycle is proposed to explain the ultrafast bromine transfer.

High-Intensity Circular Dichroism of Head-To-Tail Regioregular Poly(1,4-Phenylene)s in the Aggregated State.

Circular dichroism (CD) studies on poly(1,4-phenylene)s bearing a chiral side chain in the aggregated conditions were carried out. Little CD was observed in a solution form, while addition of a poor solvent into the polyphenylene solution induced aggregation and a strong CD was observed, accordingly. Applying the controlled degree of polymerization (DP) of poly(1,4-phenylene) in the use of bidentate diphosphine Chiraphos as a ligand for the nickel catalyst, the relationship of DP with CD strength was studied to reveal to show the highest CD at the DP=84 (gabs=ca. 2×10-2). It was also found that the related aggregation was observed in good solvent 1,2-dichloroethane upon standing the solution at 4 °C for 3-23 days to observe gabs=ca. 10-1. Studies on the substituent effect of poly(1,4-phenylene) suggested that CD behaviors were dependent on the type of non-chiral substituent on the aromatic ring as well as the side-chain chirality.

Total Synthesis of Carbazomycins E and F.

Total synthesis of carbazomycins E and F was achieved by double functionalization of an aryne intermediate generated from a 2-aminobiphenyl derivative. The tethered amino group underwent nucleophilic addition to the aryne intermediate to construct the carbazole skeleton. The resulting carbanion was formylated to give the multiply substituted carbazole. This formyl group caused several problems. For example, it was difficult to perform regioselective demethylation of the methoxy group proximal to the formyl group without protecting the carbazole nitrogen. In addition, the formyl group was unexpectedly reduced to give a methoxymethyl group under heating conditions with copper iodide and sodium methoxide. Oxidation of this compound in the presence of water was effective for obtaining the formylated carbazole, leading to the first total synthesis of carbazomycin F.

A Ni0(cod)(dq) (COD: 1,5-cycloctadiene; DQ: duroquinone) complex as a catalyst precursor for oligothiophene and polythiophene synthesis.

Nickel-catalyzed syntheses of oligothiophene and polythiophene were carried out with Ni(cod)(dq) (COD: 1,5-cycloctadiene; DQ: duroquinone) as a catalyst precursor. Studies on the ligand exchange of Ni(cod)(dq) revealed that a high temperature was necessary to replace COD and DQ with PPh3 and N-heterocyclic carbene IPr. A coupling reaction of a metalated 3-hexylthiophene with 2-chloro-3-hexylthiophene employing Ni(cod)(dq) with IPr proceeded with a remarkably reduced amount of homocoupling byproduct. Polymerization of 2-chloro-3-hexylthiophene with Ni(cod)(dq)/DPPP also resulted in the reduction of the regioregularity defect.

"Snapshot" Trapping of Multiple Transient Azolyllithiums in Batch.

Invited for the cover of this issue is Kentaro Okano and co-workers at Kobe University. The image depicts that the 'dancing' transient organolithiums in the 'halogen dance' are successfully trapped in a batch reactor as if their individual snapshots were taken. Read the full text of the article at 10.1002/chem.202101256.

"Snapshot" Trapping of Multiple Transient Azolyllithiums in Batch.

Recent developments in flow microreactor technology have allowed the use of transient organolithium compounds that cannot be realized in a batch reactor. However, trapping the transient aryllithiums in a "halogen dance" is still challenging. Herein is reported the trapping of such short-lived azolyllithiums in a batch reactor by developing a finely tuned in situ zincation using zinc halide diamine complexes. The reaction rate is controlled by the appropriate choice of diamine ligand. The reaction is operationally simple and can be performed at 0 °C with high reproducibility on a multigram scale. This method was applicable to a wide range of brominated azoles allowing deprotonative functionalization, which was used for the concise divergent syntheses of both constitutional isomers of biologically active azoles.

Total Synthesis of Lamellarins G, J, L, and Z Using One-Pot Halogen Dance/Negishi Coupling.

A bottom-up synthesis of lamellarins G, J, L, and Z was achieved via one-pot halogen dance/Negishi coupling of a lithiated dibromopyrrole derivative. The easily accessible dibromopyrrole bearing an ester moiety underwent halogen dance smoothly at -78 °C within 10 min. The resultant α-pyrrolyllithium was transmetalated to the corresponding organozinc species, which was then coupled with an aryl iodide in the presence of catalytic palladium to provide the fully substituted pyrrole. Subsequent halogen-lithium exchange was performed to incorporate a boronate group exclusively at the ß position proximal to the ester moiety. This synthetic intermediate allowed stepwise diarylation for the total synthesis of lamellarins G, J, L, and Z.

Dehalogenative or Deprotonative? The Preparation Pathway to the Organometallic Monomer for Transition-Metal-Catalyzed Catalyst-Transfer-Type Polymerization of Thiophene Derivatives.

Due to a wide range of applications in electronic materials, polythiophenes attract considerable attention in organic and polymer syntheses as well as in materials science. For the purpose of developing the practical synthetic protocol, this review focuses on the deprotonative pathway in the preparation of thiophene organometallic monomer, which was shown to be effective employing 2-halo-3-substituted thiophene as a monomer precursor. The thus metallated thiophene monomer was shown to undergo polymerization by nickel(II) complex catalysis, with which highly regioregular head-to-tail (HT)-type polythiophenes were obtained with controlled molecular weight and molecular weight distribution. Several polythiophene derivatives with modified thiophene-ring and side-chain structures were shown to be designed in order to achieve the designed functionality as materials.

Convergent Total Synthesis of Lamellarins and Their Congeners.

A convergent total synthesis of lamellarins S and Z is described. The synthesis features a halogen dance of an easily accessible α,ß-dibromopyrrole promoted by an ester moiety. The resultant ß,ß'-dibromopyrrole undergoes a ligand-controlled Suzuki-Miyaura coupling to provide a range of diarylated pyrrole derivatives. The established synthetic method was also applicable to the synthesis of ningalin B and lukianols A and B.

Formal preparation of regioregular and alternating thiophene-thiophene copolymers bearing different substituents.

Differently substituted thiophene-thiophene-alternating copolymers were formally synthesized employing a halo-bithiophene as a monomer. Nickel-catalyzed polymerization of bithiophene with substituents at the 3-position, including alkyl-, fluoroalkyl-, or oligosiloxane-containing groups, afforded the corresponding copolymers in good to excellent yield. The solubility test in organic solvents was performed to reveal that several copolymers showed a superior solubility. X-ray diffraction analysis of the thin film of the alternating copolymers composed of methyl and branched oligosiloxane substituents was also performed, and the results suggested the formation of a dual-layered film structure.

Unprecedented Regioregular Poly(1,4-arylene)s Prepared by Nickel(II)-Catalyzed Cross-Coupling Polymerization of 2,5-Disubstituted Bromo(chloro)arylene.

The unprecedented synthesis of regioregular head-to-tail-type poly(1,4-arylene)s bearing different substituents at the 2- and 5-positions is described. They were prepared by the polymerization of 2,5-disubstituted bromo(chloro)arylenes by selective halogen-metal exchange with a Grignard reagent and subsequent cross-coupling polymerization with a nickel catalyst [NiCl2 (dppp)]. Formation of the regioregular poly(1,4-arylene)s were confirmed by NMR spectroscopy, and showed remarkable differences to those polymers having uncontrolled regioregularity. Polymerization of bromo(chloro)arylenes with a chiral alkoxy substituent also led to the regioregular head-to-tail-type polyarylene, which demonstrated circular dichroism, thus suggesting formation of a structure with higher-order regularity.

Regiocontrolled Halogen Dance of Bromothiophenes and Bromofurans.

The LDA (lithium diisopropylamide)-promoted regiocontrolled halogen dance of α-bromothiophenes and α-bromofurans is described. Bromothiophenes bearing a diethyl acetal moiety undergo selective deprotonation at the ß-position adjacent to the bromo group. In contrast, oxazoline, ester, and amide groups act as directing groups in the initial lithiation step to generate a carbanion at the ß-position neighboring the directing group to exclusively give the other regioisomer. These results can be applied to the regiocontrolled halogen dance of bromofuran derivatives.

Nosyl (2-Nitrobenzenesulfonyl) Annulation Strategy toward Winding Vine-Shaped Bithiophenes.

Winding vine-shaped bithiophene was synthesized through the nosyl (2-nitrobenzenesulfonyl) cyclization protocol. The reaction of bithiophene bearing bromomethyl groups at the 3,3'-positions with nosylated 1,2-ethylenediamine in the presence of potassium carbonate afforded the annulated product in excellent yield. The obtained bithiophene was found to contain a 10-membered ring, which was confirmed by X-ray analysis. The related nosyldiamine bearing a tri- or tetramethylene group also reacted in a similar manner, affording an 11- or 12-membered macrocycle, respectively.

One-Pot Halogen Dance/Negishi Coupling of Dibromothiophenes for Regiocontrolled Synthesis of Multiply Arylated Thiophenes.

One-pot halogen dance/Negishi cross-coupling of readily available 2,5-dibromothiophenes is described. A lithium diisopropylamide (LDA)-mediated halogen dance reaction resulted in the formation of thermodynamically stable α-lithiodibromothiophenes, which were transmetalated with ZnCl2 and subjected to Negishi cross-coupling to provide the corresponding arylated dibromothiophenes in one pot. The resultant ß-bromo group was much less reactive than the remaining α-bromo group, which was used in a one-pot double Suzuki-Miyaura cross-coupling, enabling facile synthesis of multiply arylated thiophenes.

Enantioselective synthesis of macrocyclic heterobiaryl derivatives of molecular asymmetry by molybdenum-catalyzed asymmetric ring-closing metathesis.

Winding vine-shaped molecular asymmetry is induced by enantioselective ring-closing metathesis with a chiral molybdenum catalyst. The reaction proceeds under mild conditions through an E-selective ring-closing metathesis leading to macrocyclic bisazoles with enantioselectivities of up to 96% ee.

Murahashi coupling polymerization: nickel(II)-N-heterocyclic carbene complex-catalyzed polycondensation of organolithium species of (hetero)arenes.

Revisiting Murahashi coupling, we found that it effectively allows polymerization of lithiated (hetero)arenes by nickel(II)-catalyzed polycondensation. Deprotonative polymerization of 2-chloro-3-substituted thiophene with n-butyllithium gave head-to-tail-type poly(3-substituted thiophene). Poly(1,4-arylene)s were obtained by the reaction of the corresponding dibromides through lithium-bromine exchange. A lithiated thiophene derivative obtained via deprotonative halogen dance also underwent polymerization to afford a bromo-substituted polythiophene.

Concise synthesis of well-defined linear and branched oligothiophenes with nickel-catalyzed regiocontrolled cross-coupling of 3-substituted thiophenes by catalytically generated magnesium amide.

The synthesis of linear and branched oligothiophenes of well-defined structures is performed with regioselective deprotonation of 3-substituted thiophenes and nickel-catalyzed cross-coupling of the thus formed metalated species with a bromothiophene. The reaction of 3-hexylthiophene with EtMgCl and 2,2,6,6-tetramethylpiperidine (TMP-H, 10 mol%) induces the metalation selectively at the 5-position by use of the catalytically generated hindered magnesium amide (TMPMgCl) and the subsequent reaction of a 2-halo-3-hexylthiophene (bromide or chloride) in the presence of a nickel catalyst affords a head-to-tail (HT)-type dimer. By repeating the same sequence, the linear oligothiophene up to a 4-mer is synthesized in good yield. The reaction of 3-hexylthiophene with 2,3-dibromothiophene also takes place to afford a branched oligothiophene 3-mer in quantitative yield. The obtained 3-mer is also metalated at the sterically less-hindered position in a regioselective manner furnishing a 7-mer in >99% yield after a further coupling reaction with 2,3-dibromothiophene. These dendrimers react with several multifunctionalized organic electrophiles, leading to a variety of branched oligothiophenes.

Formal Halogen Transfer of Bromoarenes via Stepwise Reactions.

A two-step halogen transfer of bromoarenes is reported. Mono-, di-, and tribromoaryllithiums generated through deprotonative lithiation were converted into organozinc species by in situ zincation, which were then subjected to bromination to provide the corresponding di-, tri-, and tetrabromoarenes, respectively, in 41-95% yields. Regioselective bromine-magnesium exchange with ethylmagnesium chloride followed by electrophilic trapping afforded benzene, pyridine, quinoline, pyrimidine, and thiazole derivatives with the bromo group translocated from the original position in 28-86% yields.

Regiocontrolled halogen dance of 2,5-dibromopyrroles using equilibrium between dibromopyrrolyllithiums.

A regiocontrolled halogen dance reaction of 2,5-dibromopyrroles is described. An N,N-dimethylsulfamoyl group on the pyrrole nitrogen was especially effective for facilitating interconversion of the resulting 2,3- and 2,4-dibromopyrrolyllithiums, rendering the smooth halogen dance reaction. This method was applicable to the formal synthesis of atorvastatin.

Formal Synthesis of Dictyodendrin B.

A formal synthesis of dictyodendrin B is described. Regiocontrolled functionalization of the α,ß-dibromopyrrole derivative provided the fully substituted pyrrole bearing an indole moiety. Subsequent reductive cyclization using a combination of sodium dispersion and triethylsilyl chloride enabled the formation of the benzene ring in the characteristic tetracyclic pyrrolo[2,3-c]carbazole skeleton, while the ethyl ester remained untouched. Further chemical transformation of the ester moiety and functional group manipulation completed the formal synthesis of dictyodendrin B.