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.

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.

A Cell-Targeted Non-Cytotoxic Fluorescent Nanogel Thermometer Created with an Imidazolium-Containing Cationic Radical Initiator.

A cationic fluorescent nanogel thermometer based on thermo-responsive N-isopropylacrylamide and environment-sensitive benzothiadiazole was developed with a new azo compound bearing imidazolium rings as the first cationic radical initiator. This cationic fluorescent nanogel thermometer showed an excellent ability to enter live mammalian cells in a short incubation period (10 min), a high sensitivity to temperature variations in live cells (temperature resolution of 0.02-0.84 °C in the range 20-40 °C), and remarkable non-cytotoxicity, which permitted ordinary cell proliferation and even differentiation of primary cultured cells.

Structural Determination of (-)-SCH 64874 and Hirsutellomycin by Semisynthesis.

The structure of a C2-symmetric epidithiodiketopiperazine alkaloid, SCH 64874, was determined by semisynthesis. The relative stereochemistry of the ß-hydroxy carboxylic acid chain having three chiral centers was determined by comparison of the NMR data of the four possible diastereomeric ß-hydroxy carboxylic acid fragments with those of SCH 64874. Condensation of the (-)-deacetylaranotin core with two enantiomeric ß-hydroxy carboxylic acids revealed the relative stereochemistry of SCH 64874. The relative stereochemistry of the ß-keto carboxylic acid chain of the analogous alkaloid hirsutellomycin was determined in a stepwise manner. The C4'-C6' syn relationships were predicted by comparing the NMR data of the corresponding ester fragments with that of hirsutellomycin. The relative stereochemistry of the whole molecule, including the epimerizable C2' stereocenter, was determined by introduction of four possible side chains into the bisdethiodi(methylthio)deacetylaranotin core. We found that the stereochemistry of C2' converged with that of the thermodynamically stable form influenced by the core structure.

Total Synthesis of (-)-Histrionicotoxin through a Stereoselective Radical Translocation-Cyclization Reaction.

Stereoselective total syntheses of (-)-histrionicotoxin and (-)-histrionicotoxin 235A are described. The 1-azaspiro[5.5]undecane skeleton was constructed diastereoselectively by a radical translocation-cyclization reaction involving a chiral cyclic acetal; the use of tris(trimethylsilyl)silane was crucial for the high diastereoselectivity. The cyclization product was converted into (-)-histrionicotoxin 235A through a one-pot partial-reduction-allylation reaction of a derivative containing an unprotected lactam. Finally, two terminal alkenes were transformed into enynes with the 1,3-amino alcohol protected as an oxathiazolidine oxide to complete the total synthesis of (-)-histrionicotoxin.

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.

Total Synthesis of (+)-MPC1001B.

The first total synthesis of an epidithiodiketopiperazine alkaloid, (+)-MPC1001B, was accomplished. This synthesis features a tetra-n-butylammonium fluoride mediated intramolecular aldol reaction for forming the 15-membered macrolactone ring, and the construction of an epidithiodiketopiperazine substructure through a stepwise sulfenylation reaction involving a novel trityl trisulfide (TrSSS)-group transfer.

Synthesis of a human urate transporter-1 inhibitor, an arginine vasopressin antagonist, and a 17ß-hydroxysteroid dehydrogenase type-3 inhibitor, using ring-expansion of cyclic ketoximes with DIBALH.

Synthesis of three clinical candidates for medicines, a human urate transporter-1 inhibitor, an arginine vasopressin antagonist, and a 17ß-hydroxysteroid dehydrogenase type-3 inhibitor, is described. These compounds were synthesized via construction of their 3,4-dihydro-2H-benzo[b][1,4]oxazine, dibenzodiazepine, and dibenzazocine skeletons, respectively, using the reductive ring-expansion reaction of the corresponding bicyclic or tricyclic oximes with diisobutylaluminum hydride.

Total synthesis of (-)-haouamine B pentaacetate and structural revision of haouamine B.

The enantiocontrolled total synthesis of (-)-haouamine B pentaacetate was accomplished via an optically active indane-fused ß-lactam, which was prepared by a newly developed Friedel-Crafts reaction. Subsequent cleavage of the ß-lactam and an intramolecular McMurry coupling reaction provided the core indane-fused tetrahydropyridine, which led to the elucidation of the structure, as proposed by Trauner and Zubía.

Enantiocontrolled total synthesis of (-)-mersicarpine.

A racemic synthesis of mersicarpine (1) was achieved by the Mizoroki-Heck reaction and a DIBALH-mediated reductive ring-expansion reaction. Based on a first-generation synthesis, a second-generation enantiocontrolled total synthesis of (-)-mersicarpine (1) was achieved by an 8-pot/11-step sequence in 21% overall yield from commercially available 2-ethylcyclohexanone. Subjection of a ketoester, which was prepared by an asymmetric Michael addition (according to the protocol by d'Angelo and Desmaële), and phenylhydrazine to modified Fischer indole conditions provided a six-membered tricyclic indole. Benzylic oxidation and subsequent oxime formation provided a ketoxime, which was treated with diisobutylaluminum hydride (DIBALH) to construct the characteristic azepinoindole skeleton in good yield. In the DIBALH-mediated reductive ring-expansion reaction, gradually increasing the reaction temperature and in situ-protection of the nitrogen in an oxygen-sensitive azepinoindole with a benzyloxycarbonyl (Cbz) group were crucial for the high-yielding process. With these methodologies, the short-step and efficient synthesis of (-)-mersicarpine was accomplished. Several synthetic efforts are also described.