Controlling Cyclic Dienamine Reactivity in Radical tert-Alkylation for Molecular Diversity to Synthesize Multicyclic Compounds Possessing a Quaternary Carbon.

Synthesis of diverse sterically congested molecules from a single important intermediate is one of the ideal synthetic strategies in organic synthesis. In this paper, we found that γ-oxoalkyl substituted cyclohexenone derivatives (OAC) possessing a quaternary carbon are a useful key intermediate to derive both congested fused [5,6] rings and spirocycles. For this purpose, we have established an efficient synthetic method to obtain OAC by tertiary alkylation of ß-methylcyclohexenone derivatives using α-bromocarbonyl compounds as a tertiary alkyl source. The key to the success of this reaction is controlling the reactivity of the dienamine intermediate. While there have been many reports on enamine reactions, dienamine reactions have not been well studied. Herein, we report controlling reactivity of dienamines and molecular diversification from OAC.

Sterically Congested Protecting Group for a Boronyl Group in Iterative Aminations.

In this study, we found that the sterically bulky α-hydroxycarboxamide moiety is a suitable framework for protecting the boronyl group of boron reagents during aminations. Condensation of α-hydroxycarboxamide with ArB(OH)2 produced aryloxazaborolidinone (ArOxB). The reactivity of the C-B bond in ArOxB is easily controlled by the steric and weak electronic effects of the backbone. H2N-(or Br-)ArOxB underwent Chan-Evans-Lam (C-E-L) or Buchwald-Hartwig (B-H) amination with retaining the C-B bond. On the other hand, direct C-E-L amination of ArOxB was also possible in an oxidative atmosphere, in which the C-B bond was activated by CuII species. Our methodology is effective for the precise synthesis of two or more arylamino group substituted arenes.

Oxazaborolidinones: Steric Coverage Effect of Lewis Acidic Boron Center in Suzuki-Miyaura Coupling Reactions.

It was demonstrated that α-hydroxycarboxamide is an excellent boron-protecting group. The reaction between α-hydroxycarboxamide and organoboronic acids produced stable oxazaborolidinones (OxBs), in which the sp 2 ${{_{{\rm sp}{^{2}}}}}$ -hybridized boron atom was sterically protected by α-hydroxycarboxamide. The alkyl groups of the α-hydroxycarboxamide moiety can dynamically cover the p-orbital of the sp 2 ${{_{{\rm sp}{^{2}}}}}$ -hybridized boron center, creating a small space around the boron atom, allowing for smooth transmetalation by a Pd catalyst and easy deprotection by water. This protecting phenomenon is effective for readily purification, Suzuki-Miyaura coupling reactions with unstable boronic acids and iterative cross-couplings.

Interaction between Divalent Copper Fluoride and Carboxamide Group Enabling Stereoretentive Fluorination of Tertiary Alkyl Halides.

Herein, we report a copper-catalyzed stereospecific fluorination involving CsF and α-bromocarboxamides as tertiary alkyl sources that, unlike traditional stereospecific routes involving stereoinversive SN 2 reactions, proceeds with retention of stereochemistry. The developed stereospecific Cu-catalyzed reaction is among the most efficient methods for synthesizing fluorinated molecules that possess highly congested stereogenic carbon centers. Mechanistic studies revealed that the combined reactivity of CuF2 and Cs salt is essential for completing the catalytic cycle. Our catalytic system underwent fluorination exclusively with tertiary alkyl bromides and did not react with primary alkyl bromides, indicating that this stereospecific fluorination methodology is suitable for synthesizing fluorinated building blocks possessing stereo-defined F-containing tertiary carbon stereogenic center.

Radical/Iminium Domino Strategy (RIDS) for Rapid Construction of Sterically Congested γ-Lactam-Based Multiheterocycles.

Cu-Catalyzed radical/iminium domino strategy (RIDS) for the efficient synthesis of quaternary-carbon-containing γ-lactam-based multiheterocyclic structures from α-bromocarboxamides is reported. This domino reaction strategy enables the construction of multiheterocycles in one step. Mechanistic studies showed that two catalytically generated iminiums are likely to be key intermediates in the catalytic cycle. The developed method can be used in a chemoselective manner to produce multicyclic products in the reaction with ketones possessing two different carbonyls.

Direct α-Tertiary Alkylations of Ketones in a Combined Copper-Organocatalyst System.

Herein, we report an efficient method for the tertiary alkylation of a ketone by using an α-bromocarbonyl compound as the tertiary alkyl source in a combined Cu-organocatalyst system. This dual catalyst system enables the addition of a tertiary alkyl radical to an enamine. Mechanistic studies revealed that the catalytically generated enamine is a key intermediate in the catalytic cycle. The developed method can be used to synthesize substituted 1,4-dicarbonyl compounds containing quaternary carbons bearing various alkyl chains.

Chemistry of Tertiary Carbon Center in the Formation of Congested C-O Ether Bonds.

Nucleophilic substitutions, including SN 1 and SN 2, are classical and reliable reactions, but a serious drawback is their intolerance for both bulky nucleophiles and chiral tertiary alkyl electrophiles for the synthesis of a chiral quaternary carbon center. An SRN 1 reaction via a radical species is another conventional method used to carry out substitution reactions of bulky nucleophiles and alkyl halides, but chiral tertiary alkyl electrophiles cannot be used. Therefore, a stereospecific nucleophilic substitution reaction using chiral tertiary alkyl electrophiles and bulky nucleophiles has not yet been well studied. In this paper, we describe the reaction of tertiary alkyl alcohols and non-chiral or chiral α-bromocarboxamides as a tertiary alkyl source for the formation of congested ether compounds possessing two different tertiary alkyl groups on the oxygen atom with stereoretention.

Amino Acid Schiff Base Bearing Benzophenone Imine As a Platform for Highly Congested Unnatural α-Amino Acid Synthesis.

Unnatural α-amino acids are invaluable building blocks in synthetic organic chemistry and could upgrade the function of peptides. We developed a new mode for catalytic activation of amino acid Schiff bases, serving as a platform for highly congested unnatural α-amino acid synthesis. The redox active copper catalyst enabled efficient cross-coupling to construct contiguous tetrasubstituted carbon centers. The broad functional group compatibility highlights the mildness of the present catalysis. Notably, we achieved successive ß-functionalization and oxidation of amino acid Schiff bases to afford dehydroalanine derivatives bearing tetrasubstituted carbon. A three-component cross-coupling reaction of an amino acid Schiff base, alkyl bromides, and styrene derivatives demonstrated the high utility of the present method. The diastereoselective reaction was also achieved using menthol derivatives as a chiral auxiliary, delivering enantiomerically enriched α-amino acid bearing α,ß-continuous tetrasubstituted carbon. The synthesized highly congested unnatural α-amino acid could be derivatized and incorporated into peptide synthesis.

Copper-Catalyzed Tertiary Alkylative Cyanation for the Synthesis of Cyanated Peptide Building Blocks.

In this paper, we report efficient cyanation of various peptides containing the α-bromocarbonyl moiety using a Cu-catalyzed radical-based methodology employing zinc cyanide as the cyanide source. Mechanistic studies revealed that in situ formed CuCN was a key intermediate during the catalytic cycle. Our method could be useful for the synthesis of modified peptides containing quaternary carbons.

Hybrid Reaction Systems for the Synthesis of Alkylated Compounds Based upon Cu-Catalyzed Coupling of Radicals and Organometallic Species.

A transition metal catalyzed alkylation with an alkyl halide is one of the most difficult reactions to achieve, because of the difficult oxidative addition of an alkyl-halogen bond to a metal, and the tendency of the resulting alkylmetal intermediate to undergo a ß-hydride elimination reaction to give an olefin. In this review, we discuss hybrid reaction systems involving Cu catalyzed combination of radicals and organometallic species, which enable facile alkylation reactions to construct C-C and C-heteroatom bonds. This paper highlights recent progress in arylation, alkenylation, alkynylation, cyclization, addition and introduction of heteroatoms via these hybrid reaction systems.

Controlling alkyne reactivity by means of a copper-catalyzed radical reaction system for the synthesis of functionalized quaternary carbons.

A terminal alkyne is one of the most useful reactants for the synthesis of alkyne and alkene derivatives. Because an alkyne undergoes addition reaction at a C-C triple bond or cross-coupling at a terminal C-H bond. Combining those reaction patterns could realize a new reaction methodology to synthesize complex molecules including C-C multiple bonds. In this report, we found that the reaction of 3 equivalents of terminal alkyne 1 (aryl substituted alkyne) and an α-bromocarbonyl compound 2 (tertiary alkyl radical precursor) undergoes tandem alkyl radical addition/Sonogashira coupling to produce 1,3-enyne compound 3 possessing a quaternary carbon in the presence of a copper catalyst. Moreover, the reaction of α-bromocarbonyl compound 2 and an alkyne 4 possessing a carboxamide moiety undergoes tandem alkyl radical addition/C-H coupling to produce indolinone derivative 5.

Facile Synthesis of Single α-tert-Alkylated Acetaldehydes by Hydroxyalkylation of Enamides in Aqueous Solution.

In this work, we established a general protocol to synthesize single α-tert-alkylated acetaldehydes via Cu-catalyzed hydroxyalkylation of enamides in aqueous solutions. The yields of the products were very high and there was excellent functional group compatibility. Our reaction allows easy access to highly functionalized acetaldehydes that can be used to synthesize further useful compounds including spirocycles. The control experiments revealed that this reaction includes hydroxyalkylation processes via radical reactions.

Copper-Catalyzed Amination of Congested and Functionalized α-Bromocarboxamides with either Amines or Ammonia at Room Temperature.

There are several reports on the synthesis of alkylamines, but most of the reported methods are not suitable for the synthesis of hindered amines. In this research, we found that a copper catalyst is effective for the formation of congested C-N bonds at room temperature. Control experiments revealed that a copper amide is a key intermediate. Moreover, when a chiral amine was used, a quaternary carbon stereogenic center was created with good selectivity.

Site-Selective Tertiary Alkyl-Fluorine Bond Formation from α-Bromoamides Using a Copper/CsF Catalyst System.

A copper-catalyzed site-selective fluorination of α-bromoamides possessing multiple reaction sites, such as primary and secondary alkyl-Br bonds, using inexpensive CsF is reported. Tertiary alkyl-F bonds, which are very difficult to synthesize, can be formed by this fluorination reaction with the aid of an amide group. Control experiments revealed that in situ generated CuF2 is a key fluorinating reagent that reacts with the tertiary alkyl radicals generated by the reaction between an α-bromocarbonyl compound and a copper(I) salt.

Cationic Pd(II)-catalyzed C-H activation/cross-coupling reactions at room temperature: synthetic and mechanistic studies.

Cationic palladium(II) complexes have been found to be highly reactive towards aromatic C-H activation of arylureas at room temperature. A commercially available catalyst [Pd(MeCN)4](BF4)2 or a nitrile-free cationic palladium(II) complex generated in situ from the reaction of Pd(OAc)2 and HBF4, effectively catalyzes C-H activation/cross-coupling reactions between aryl iodides, arylboronic acids and acrylates under milder conditions than those previously reported. The nature of the directing group was found to be critical for achieving room temperature conditions, with the urea moiety the most effective in promoting facile coupling reactions at an ortho C-H position. This methodology has been utilized in a streamlined and efficient synthesis of boscalid, an agent produced on the kiloton scale annually and used to control a range of plant pathogens in broadacre and horticultural crops. Mechanistic investigations led to a proposed catalytic cycle involving three steps: (1) C-H activation to generate a cationic palladacycle; (2) reaction of the cationic palladacycle with an aryl iodide, arylboronic acid or acrylate, and (3) regeneration of the active cationic palladium catalyst. The reaction between a cationic palladium(II) complex and arylurea allowed the formation and isolation of the corresponding palladacycle intermediate, characterized by X-ray analysis. Roles of various additives in the stepwise process have also been studied.

A Copper-Catalyzed Formal [3 + 2]-Cycloaddition for the Synthesis of All Different Aryl-Substituted Furans and Thiophenes.

A highly efficient formal [3 + 2]-cycloaddition was established using a copper catalyst. The resulting dihydrofurans were subjected to oxidation followed by arylations to produce tetraarylfurans. In addition, the dihydrofuran can be converted to diaryldihydrothiophene by using Lawesson's reagent. This protocol will facilitate the synthesis of all different aryl-substituted furans and thiophenes.

α-Halocarbonyls as a Valuable Functionalized Tertiary Alkyl Source.

This review introduces the synthetic organic chemical value of α-bromocarbonyl compounds with tertiary carbons. This α-bromocarbonyl compound with a tertiary carbon has been used primarily only as a radical initiator in atom transfer radical polymerization (ATRP) reactions. However, with the recent development of photo-radical reactions (around 2010), research on the use of α-bromocarbonyl compounds as tertiary alkyl radical precursors became popular (around 2012). As more examples were reported, α-bromocarbonyl compounds were studied not only as radicals but also for their applications in organometallic and ionic reactions. That is, α-bromocarbonyl compounds act as nucleophiles as well as electrophiles. The carbonyl group of α-bromocarbonyl compounds is also attractive because it allows the skeleton to be converted after the reaction, and it is being applied to total synthesis. In our survey until 2022, α-bromocarbonyl compounds can be used to perform a full range of reactions necessary for organic synthesis, including multi-component reactions, cross-coupling, substitution, cyclization, rearrangement, stereospecific reactions, asymmetric reactions. α-Bromocarbonyl compounds have created a new trend in tertiary alkylation, which until then had limited reaction patterns in organic synthesis. This review focuses on how α-bromocarbonyl compounds can be used in synthetic organic chemistry.

Catalytic tert-alkylation of enamides via C-C bond cleavage under photoredox conditions.

Efficient C-C bond cleavage is recognized as a persistent challenge in the field of synthetic methodology. In this study, we found that tertiary alkyl radicals are smoothly formed from tertiary alkylated dienones (BHT adducts) via SET, using PDI as a photocatalyst. Resulting tert-alkyl radicals could be applied to the tert-alkylation of enamides. The driving force of this C-C bond cleavage reaction is the mesolytic cleavage of the BHT adducts. The mechanistic study revealed that PDI anion radical is the key active species during the catalytic cycle.

An efficient generation of a functionalized tertiary-alkyl radical for copper-catalyzed tertiary-alkylative Mizoroki-Heck type reaction.

α-Halocarbonyl compounds undergo ß-hydrogen elimination to give conjugated olefins in the presence of a transition-metal catalyst. However, a copper/triamine catalyst system can induce the alkylative Mizoroki­Heck reaction of styrenes with tertiary-alkyl halides possessing a withdrawing group under very mild conditions. This reaction provides an efficient synthetic methodology for tertiary-alkylated styrenes.

Synthesizing Complex Quaternary Carbons by the Sequence-Regulated Additions of tert-Alkyl Radicals to Two Different Olefins.

We report the sequence-regulated radical additions of tert-alkyl radicals to two different olefins controlled by a Cu catalyst, which we term the "atom-transfer radical addition-substitution" reaction. The reactions of α-bromocarbonyl compounds, such as tert-alkyl radical sources, with methacrylates and styrenes occur in a sequence-regulated manner to give the corresponding three-component product possessing skipped quaternary carbon centers. Our method provides new insight into how to control the reactivities of tert-alkyl radicals during the synthesis of regulated aliphatic chains.