Review

. 2024 Oct;13(10):e202400108.

doi: 10.1002/open.202400108. Epub 2024 Jul 11.

α-Halocarbonyls as a Valuable Functionalized Tertiary Alkyl Source

Takashi Nishikata¹

Affiliations

PMID: 38989712
PMCID: PMC12056945
DOI: 10.1002/open.202400108

Review

α-Halocarbonyls as a Valuable Functionalized Tertiary Alkyl Source

Takashi Nishikata. ChemistryOpen. 2024 Oct.

. 2024 Oct;13(10):e202400108.

doi: 10.1002/open.202400108. Epub 2024 Jul 11.

Author

Takashi Nishikata¹

Affiliation

¹ Graduate School of Science and Engineering, Yamaguchi University, 2-16-1 Tokiwadai, Ube, Yamaguchi, 755-8611, Japan.

PMID: 38989712
PMCID: PMC12056945
DOI: 10.1002/open.202400108

Abstract

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.

Keywords: addition; asymmetric reaction; cross-coupling; tertiary alkyl radical; tertiary alkylation.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

**Figure 1**
Value of an α‐bromocarbonyl compound.

**Scheme 1**
Lei's Ni‐catalyzed tert‐alkylation with terminal olefin.

**Scheme 2**
Nishikata's Cu‐catalyzed *tert*‐alkylation with terminal olefin.

**Scheme 4**
ATRA of [1.1.1]propellane **4.1**.

**Scheme 7**
The reaction of α‐bromocarbonyl, vinyl ether and methanol.

**Scheme 10**
Carboamination with maleimide.

**Scheme 14**
Three‐component reaction with 1,3‐butadiene.

**Scheme 15**
Ni‐catalyzed three‐component reaction with arylzinc reagents.

**Scheme 16**
Co‐catalyzed three‐component reaction with arylzinc reagents.

**Scheme 17**
Ag‐mediated three‐component reaction with heteroaromatic C−H bonds.

**Scheme 18**
Cu‐catalyzed three‐component reaction with aromatic C−H bonds.

**Scheme 19**
In‐catalyzed three‐component reaction with heteroaromatic C−H bonds.

**Scheme 20**
Three‐component reaction with vinyl cyclopropanes.

**Scheme 21**
Ru‐catalyzed three‐component reaction with *meta*‐aromatic C−H bonds.

**Scheme 22**
Ru‐catalyzed three‐component reaction with *meta*‐aromatic C−H bonds.

**Scheme 23**
Cu‐catalyzed three‐component reaction with vinylic C−H bonds.

**Scheme 24**
Three‐component reaction via 1,5‐HAT.

**Scheme 25**
Cu‐catalyzed three‐component reaction for ligand screening.

**Scheme 26**
Cu‐catalyzed three‐component reaction with alkynes.

**Scheme 27**
Ni‐catalyzed three‐component reaction with alkynes.

**Scheme 31**
Ni‐catalyzed intramolecular C−H cyclization.

**Scheme 32**
Cu‐catalyzed intra‐ and intermolecular cyclization.

**Scheme 33**
Pd‐catalyzed intermolecular cyclization.

**Scheme 34**
Highly efficient Cu‐catalyzed intermolecular cyclization.

**Scheme 35**
Cu‐catalyzed diastereoselective intermolecular cyclization.

**Scheme 36**
Ni‐catalyzed intermolecular cyclization with carboxamide.

**Scheme 37**
Fe‐catalyzed intermolecular cyclization.

**Scheme 38**
Cu‐catalyzed intermolecular cyclization via water addition

**Scheme 39**
Cu‐catalyzed intermolecular cyclization with allene.

**Scheme 40**
Ag‐catalyzed intermolecular cyclization.

**Scheme 41**
Fe‐catalyzed intermolecular cyclization.

**Scheme 42**
Cu‐catalyzed cascade intermolecular cyclization.

**Scheme 43**
Hydroalkylation of alkyne catalyzed by a Cu salt.

**Scheme 44**
Three‐component reaction to give trisubstituted alkenes.

**Scheme 45**
Cu‐catalyzed ATRA/ATRC reaction.

**Scheme 46**
Cu‐catalyzed cascade intermolecular cyclizations of alkynylated arenes.

**Scheme 47**
Cu‐catalyzed cascade intermolecular cyclizations of alkynylated arenes.

**Scheme 48**
Cu‐catalyzed cascade intermolecular cyclization reaction of alkyne.

**Scheme 49**
Rh‐catalyzed cascade intermolecular cyclization reaction.

**Scheme 50**
Cu‐catalyzed intermolecular cyclization reaction to give a lactam.

**Scheme 51**
Cu‐catalyzed C−S bond formation in intermolecular cyclization reaction.

**Scheme 52**
Cu‐catalyzed intermolecular cyclization reaction with internal alkyne.

**Scheme 53**
Cu‐catalyzed homodimerization reaction.

**Scheme 54**
Intermolecular cyclization reaction with [60]fullerene.

**Scheme 55**
Cu‐mediated aryl rearrangement.

**Scheme 56**
Mechanochemical Cu‐catalyzed aryl rearrangement

**Scheme 57**
Pd‐catalyzed aryl rearrangement.

**Scheme 59**
Cu‐catalyzed ATRS in the presence of a bidentate ligand.

**Scheme 60**
Cu‐catalyzed directed tert‐alkylation.

**Scheme 64**
Co‐catalyzed ATRS and lactonization.

**Scheme 65**
Cu‐catalyzed ATRS with conjugated diene.

**Scheme 66**
Cu‐catalyzed decarboxylative *tert*‐alkylation.

**Scheme 67**
Cu‐catalyzed *tert*‐alkyl exchanging reaction.

**Scheme 68**
Pd‐catalyzed Ph‐rearrangement reaction.

**Scheme 69**
Cu‐catalyzed γ‐tert‐alkylation of silyl enol ethers.

**Scheme 70**
Cu‐catalyzed α‐tert‐alkylation of silyl enol ethers.

**Scheme 71**
Cu‐catalyzed ATRS to form external olefins.

**Scheme 72**
Cu‐catalyzed ATRS with E/Z‐mixed internal olefins.

**Scheme 73**
Pd‐catalyzed ATRS with cyclic enamides.

**Scheme 74**
Cu‐catalyzed ATRS with enamides.

**Scheme 75**
Fe‐mediated ATRS with enamides.

**Scheme 76**
Cu‐catalyzed α‐tert‐alkylation of ketones.

**Scheme 77**
Fe‐catalyzed tert‐alkylation of 1,4‐quinone.

**Scheme 78**
Cu‐catalyzed tert‐alkylation of cyclic olefin

**Scheme 79**
Cu‐catalyzed Suzuki‐Miyaura type coupling.

**Scheme 80**
Co‐catalyzed Negishi type coupling.

**Scheme 81**
Cu‐catalyzed α‐alkylation of nitroalkane.

**Scheme 83**
Cu‐catalyzed alkynylation.

**Scheme 84**
Cu‐catalyzed reactions with O‐ or S‐nucleophiles.

**Scheme 85**
Pd‐catalyzed congested C−O bond formations.

**Scheme 87**
Cu‐mediated double amination.

**Scheme 88**
Cu‐catalyzed amination with a nitroso compound.

**Scheme 89**
Cu‐catalyzed amination with hydrazine.

**Scheme 90**
Amination under Cu/PPh₃ catalyst system.

**Scheme 91**
Ni‐catalyzed furan C−H bond *tert*‐alkylation.

**Scheme 92**
Fe‐catalyzed furan C−H bond *tert*‐alkylation.

**Scheme 93**
Cucatalyzed furan C−H bond *tert*‐alkylation.

**Scheme 94**
Ru‐catalyzed remote C6‐selective C−H tert‐alkylation.

**Scheme 95**
Ru‐catalyzed naphthalene C5 *tert*‐alkylation.

**Scheme 96**
Frost's Ru‐catalyzed *meta*‐*tert*‐alkylation.

**Scheme 97**
Ackermann's Ru‐catalyzed *meta*‐*tert*‐alkylation.

**Scheme 98**
Ru‐catalyzed *para*‐*tert*‐alkylation.

**Scheme 99**
Ru‐catalyzed tandem cyclization/*meta*‐C−H alkylation.

**Scheme 100**
Cu‐catalyzed tandem *ortho*‐C−H *tert*‐alkylation/intramolecular amidation.

**Scheme 101**
Cu‐catalyzed Br/Cl exchange reaction with α‐bromocarbonyl compound.

**Scheme 102**
Cu‐catalyzed Br/F exchange reaction with α‐bromocarbonyl compound.

**Scheme 103**
Mn‐catalyzed addition with α‐iodocarbonyl compound.

**Scheme 104**
Ru‐catalyzed addition/rearrangement reaction.

**Scheme 105**
Ir‐catalyzed formyloxylation.

**Scheme 106**
Ir‐catalyzed ATRA with [1.1.1]‐propellane.

**Scheme 107**
Ir‐catalyzed three‐component reaction using indoles.

**Scheme 108**
Ru‐catalyzed three‐component reaction using aniline derivatives.

**Scheme 109**
Ir‐catalyzed three‐component reaction using arylboronic acids.

**Scheme 110**
Ir‐catalyzed three‐component reaction using [1.1.1]‐propellane.

**Scheme 111**
Ir‐catalyzed three‐component reaction using DMSO.

**Scheme 112**
Intramolecular cyclization with an enyne by Ru‐photocatalyst.

**Scheme 113**
Intramolecular cyclization with cyclic olefins by Ru‐photocatalyst.

**Scheme 114**
Intramolecular cyclization to give oxindoles by Ir‐photocatalyst.

**Scheme 115**
Intramolecular cyclization by Ni‐photocatalyst.

**Scheme 116**
Intramolecular dearomative cyclization by Ir‐photocatalyst.

**Scheme 117**
Intermolecular cyclization to give cyclopentanes by Ir‐photocatalyst.

**Scheme 118**
Intermolecular cyclization to give lactone by Ir‐photocatalyst.

**Scheme 119**
Intermolecular cyclization to give cyclopentyl hemiketals by Ir‐photocatalyst.

**Scheme 120**
Intermolecular cycloetherification by Ir‐photocatalyst.

**Scheme 121**
Intermolecular iminolactonization by Ir‐photocatalyst.

**Scheme 122**
Intermolecular cyclization with alkynes by Ir‐photocatalyst.

**Scheme 123**
Intermolecular dearomative cyclization to give spirocycles possessing a cyclohexadienone by Ir‐photocatalyst.

**Scheme 124**
Intermolecular dearomative cyclization to give spiroindolenines by Ir‐photocatalyst.

**Scheme 125**
Intermolecular dearomative cyclization to give oxa‐spirocycles by Ir‐photocatalyst.

**Scheme 126**
Tandem intermolecular bicyclization to give benzo‐fused bicycles by Ir‐photocatalyst.

**Scheme 127**
Intermolecular bicyclization involving alkynyl migration by Ir‐photocatalyst.

**Scheme 128**
Ring‐opening reaction with olefins and ATRA with alkynes by Ir‐photocatalyst.

**Scheme 129**
Intermolecular bicyclization with o‐diisocyanoarenes by Ir‐photocatalyst.

**Scheme 130**
Intermolecular cyclization via aza‐*ortho*‐quinone methide by Ru‐photocatalyst.

**Scheme 131**
Intermolecular cyclization with biphenyl isocyanide by Ir‐photocatalyst.

**Scheme 132**
The combination of cyano and isocyano group reactivity for intermolecular cyclization.

**Scheme 133**
Intermolecular cyclization *via* iminyl radical species by Ir‐photocatalyst.

**Scheme 134**
The construction of seven‐membered rings under Ir‐photocatalyst conditions.

**Scheme 135**
Intermolecular cyclization to give trifluoromethylated quaternary carbon compounds by Ir‐photocatalyst.

**Scheme 136**
Intermolecular cyclization to give cyclohexylidenehydrazine‐fused polycycles by Ir‐photocatalyst.

**Scheme 137**
Intermolecular cyclization to give chroman‐4‐ones by Ir‐photocatalyst.

**Scheme 138**
Rearrangement reaction by Ir‐photocatalyst.

**Scheme 139**
ATRS by Ru‐photocatalyst.

**Scheme 140**
Ring expansion under Ir‐photocatalyst system.

**Scheme 141**
The reaction of vinyl acetate under mpg‐CN‐photocatalyst system.

**Scheme 142**
The reaction of vinyl ether under Ru‐photocatalyst system.

**Scheme 143**
ATRS with enamide under Ir‐photocatalyst system.

**Scheme 144**
Ketone formation under Ru‐photocatalyst conditions.

**Scheme 145**
C(sp³)−C(sp³) cross‐couplings with alkylated Hantzsch ester by Ir‐photocatalyst.

**Scheme 146**
Ru‐photocatalyst/NHC enabling ring opening *tert*‐alkylation.

**Scheme 147**
Ru‐photocatalyst/NHC enabling formal allylic substitution.

**Scheme 148**
Allylation under Cu‐photocatalyst.

**Scheme 149**
Homocoupling under Ir‐photocatalyst conditions.

**Scheme 150**
*ortho*‐C−H tert‐alkylation under Ru‐photo catalyst conditions.

**Scheme 151**
*meta*‐C−H tert‐alkylation under Ru‐photo catalyst conditions.

**Scheme 152**
*tert*‐Alkylations of heteroarene C−H bonds under Ir‐photocatalyst conditions.

**Scheme 153**
p‐Anisaldehyde catalyzed ATRA.

**Scheme 154**
The addition reaction catalyzed by 4CzIPN.

**Scheme 155**
ATRA catalyzed by 4‐Ph‐pyridine.

**Scheme 156**
Three‐component reaction catalyzed by Eosin Y.

**Scheme 157**
Three‐component reaction catalyzed by 4CzIPN.

**Scheme 158**
Intermolecular cyclization by Eosin Y.

**Scheme 159**
Three‐component intermolecular cyclization by an organophotocatalyst.

**Scheme 160**
Intermolecular cyclizations of vinyl azides under organophotocatalyst conditions.

**Scheme 161**
Suzuki‐Miyaura type couplings catalyzed by Eosin Y.

**Scheme 162**
ATRS catalyzed by organophotocatalyst.

**Scheme 163**
C−H *tert*‐alkylation with a PXX catalyst.

**Scheme 164**
Three‐component reaction with olefins catalyzed by NHC.

**Scheme 165**
Three‐component reaction with 1,3‐enyne catalyzed by NHC.

**Scheme 166**
Intramolecular C−H cyclization by NHC catalyst.

**Scheme 167**
Intramolecular multi‐cyclization to give by NHC catalyst.

**Scheme 168**
Intramolecular multi‐cyclization by PQ catalyst.

**Scheme 169**
Intermolecular cyclization with α‐bromocarbonyl compound by NHC catalyst.

**Scheme 170**
Intermolecular cyclization with isonitriles by NHC catalyst.

**Scheme 171**
Intermolecular cyclization with vinyl azides by NHC catalyst.

**Scheme 172**
Aldehyde C−H *tert*‐alkylations by NHC catalyst.

**Scheme 173**
Cu/chiral Cbzbox‐catalyzed asymmetric 1,2‐difunctionalization with benzoxazole.

**Scheme 174**
Cu/chiral modified cinchona alkaloid ‐catalyzed asymmetric 1,2‐difunctionalization with alkyne.

**Scheme 175**
Cu/chiral modified cinchona alkaloid‐catalyzed asymmetric 1,2‐difunctionalization of enyne.

**Scheme 176**
Cu/chiral modified cinchona alkaloid‐catalyzed asymmetric 1,2‐difunctionalization with sulfoximine.

**Scheme 177**
Asymmetric three‐component reaction involving rearrangement and photocatalyst reaction.

**Scheme 178**
Asymmetric ATRC of α‐bromocarbonyls with metalloenzyme.

**Scheme 179**
Asymmetric ATRC of α‐bromocarbonyls by a Cu/box ligand catalyst.

**Scheme 180**
Intermolecular asymmetric ATRC reaction by chiral Ru complex.

**Scheme 181**
Asymmetric C−H cyclization by enzyme.

**Scheme 182**
Asymmetric lactonization reaction by Cu/asymmetric pybox ligand system

**Scheme 183**
Asymmetric cross‐coupling with allyl stannane.

**Scheme 184**
Photoinduced copper‐catalyzed asymmetric N‐tert‐alkylation.

**Scheme 185**
Asymmetric amination reaction by Ni/chiral box ligand catalyst.

**Scheme 186**
Ni/dioxide catalyzed asymmetric amination.

**Scheme 187**
Cinchona alkaloid derivatives catalyzed asymmetric cross‐coupling with oximes.

**Scheme 188**
L‐amino acid‐based urea catalyzed asymmetric cross‐coupling with carboxylic acids.

**Scheme 189**
Cinchona alkaloid derivatives catalyzed asymmetric cross‐coupling with phenols.

**Scheme 190**
Asymmetric alkynylation with Cu/chiral bisoxazoline phenyl amine catalyst system.

**Scheme 191**
Asymmetric coupling with 1‐alkenylZr catalyzed by a chiral Ni catalyst.

**Scheme 192**
Asymmetric coupling of amino acid derivatives catalyzed by Ir‐photocatalyst/chiral phosphoric acid.

**Scheme 193**
Decarboxylative asymmetric couplings catalyzed by organocatalyst and chiral phosphoric acid.

**Scheme 194**
Asymmetric C−H coupling catalyzed by Co/pybox.

**Scheme 195**
Asymmetric α‐*tert*‐alkylation of aldehydes catalyzed by Ru and organocatalyst.

**Scheme 196**
Asymmetric α‐ and γ‐alkylation of aldehydes catalyzed by organocatalyst.

**Scheme 197**
Selective radical addition of amino acid Schiff bases with α‐bromocarbonyl compounds.

**Scheme 198**
Organocatalyzed asymmetric dearomative addition of naphthol.

**Scheme 199**
Asymmetric tin hydride reduction of α‐bromoketone.

**Scheme 200**
Asymmetric reduction of α‐bromocarbonyl compound by ene‐reductase.

**Scheme 201**
Photo‐enzymatic reduction.

**Scheme 202**
Silver‐mediated stereoretentive amination and etherification of α‐bromocarboxamide.

**Scheme 203**
MAD‐mediated stereospecific allylation of α‐sulfonyl imides with allyl stannane.

**Scheme 204**
Me₃Al‐mediated stereospecific allylation of α‐sulfonyl imides with allyl stannane.

**Scheme 205**
Intramolecular stereospecific allylation and vinylation.

**Scheme 206**
Intramolecular S_N2 reaction.

**Scheme 207**
S_N2 reactions of chloromalonate derivatives with azide, thiol, and fluoride.

**Scheme 208**
S_N2 reactions of cyclic chloroketoesters with phenol.

**Scheme 209**
S_N2 reactions of bromomalonate derivatives with azide and phenol.

**Scheme 210**
Stereoretentive substitution of α‐halocarboxamides with *tert*‐alkyl alcohols.

**Scheme 211**
Stereospecific alkynylation of α‐bromocarboxamide.

**Scheme 212**
Synthesis of highly congested Z (*cis*)‐olefins.

**Scheme 214**
Cu‐catalyzed ATRS vs cyclization.

**Scheme 215**
PTH‐catalyzed ATRS vs Cyclization.

**Scheme 223**
Metal‐mediated oxyallyl cation reaction.

**Scheme 224**
Base promoted oxyallyl cation reaction.

**Scheme 225**
Generation of aza‐oxyallyl cation.

**Scheme 226**
Aza‐oxyallyl cation reactions.

**Scheme 227**
Reaction with phenylthiosilane.

**Scheme 228**
Reaction with tetraphenyldiphosphine disulfide

**Scheme 229**
Cascade C−S/C−N bonds formation.

**Scheme 230**
A combined α‐*tert*‐radical reaction and alkylgallium reaction.

**Scheme 231**
Visible light‐promoted radical‐mediated ring‐opening/cyclization.

**Scheme 232**
α‐*tert*‐Alkylation of aliphatic C−H bond.

See this image and copyright information in PMC

Cited by

Photoinduced copper-catalysed deracemization of alkyl halides.
Zhong F, Li R, Mai BK, Liu P, Fu GC. Zhong F, et al. Nature. 2025 Apr;640(8057):107-113. doi: 10.1038/s41586-025-08784-8. Epub 2025 Apr 2. Nature. 2025. PMID: 40175756
A General Platform for Copper-Catalyzed Atom Transfer Radical Addition with Electron-Deficient Olefins.
Wendlandt HC, Utley JA, Lee BJ, Ho TD, Hull KL. Wendlandt HC, et al. Org Lett. 2025 Jan 10;27(1):241-245. doi: 10.1021/acs.orglett.4c04260. Epub 2024 Dec 18. Org Lett. 2025. PMID: 39694876 Free PMC article.

References

1. Yan M., Lo J.C., Edwards J. T., Baran P. S., J. Am. Chem. Soc. 2016, 138, 12692–12714. - PMC - PubMed
1. Ling T., Rivas F., Tetrahedron 2016, 72, 6729–6777.
1. Douglas C. J., Overman L. E., PNAS 2004, 101, 5363–5367. - PMC - PubMed
1. Liu Y., Han S.-J., Liu W.-B., Stoltz B. M., Acc. Chem. Res. 2015, 48, 740–751. - PMC - PubMed
1. Deno N.C., J. Am. Chem. Soc. 1947, 69, 2233–2234.

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

α-Halocarbonyls as a Valuable Functionalized Tertiary Alkyl Source

Affiliation

α-Halocarbonyls as a Valuable Functionalized Tertiary Alkyl Source

Author

Affiliation

Abstract

Conflict of interest statement

Figures

Similar articles

Cited by

References

Publication types

Grants and funding

LinkOut - more resources

Full Text Sources

Research Materials

Abstract

Conflict of interest statement

Figures

Similar articles

Cited by

References

Publication types

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Research Materials