Categories: C-Br Bond Formation >
Synthesis of alkyl bromides
Name Reactions
Recent Literature
Substoichiometric amounts of thiourea additives mediate the halogenation of
alcohols under mild conditions. In the the absence of thiourea, oxidation of the
alcohol is observed, whereas the substrate can be recovered when excess thiourea is
used. Both bromination and chlorination were highly efficient for primary,
secondary, tertiary, and benzyl alcohols and tolerate a broad range of
functional groups.
A. R. Mohite, R. S. Phatake, P. Dubey, M. Agbaria, A. I. Shames, N. G.
Lemcoff, O. Reany, J. Org. Chem., 2020, 85,
12901-12911.
The use of a tetraethylammonium halide in the presences of [Et2NSF2]BF4
(XtalFluor-E) enables efficient chlorination and bromination reactions of a wide
range of alcohols. Iodination reactions are also possible albeit in lower yields.
As opposed to Appel reactions, water-soluble side products are generated, that
facilitate work-up.
M.-F. Pouliot, O. Mahé, J.-D. Hamel, J. Desroches, J.-F. Paquin, Org. Lett., 2012,
14, 5428-5431.
Alcohols were efficiently converted to alkyl halides using 1-n-butyl-3-methylylimidazolium
halide ioniq liquids in the presence of Brřnsted acids at room temperature. The
alkyl halide products were easily isolated from the reaction mixture via simple
decantation or extraction.
R. X. Ren, J. X. Wu, Org. Lett., 2001, 3,
3727-3728.
Ionic liquids [bmim][X] (X = Cl, Br, I, OAc, SCN) are highly efficient reagents
for nucleophilic substitution reactions of sulfonate esters derived from primary
and secondary alcohols. The newly developed protocol is very environmentally
attractive because the reactions use stoichiometric amounts of ionic liquids as
sole reagents without additional solvents and activating reagents. Moreover,
these ionic liquids can be readily recycled.
Y. Liu, Y. Xu, S. H. Jung, J. Chae, Synlett, 2012, 23,
2663-2666.
Nucleophilic fluorination using CsF or alkali metal fluorides was completed in
short reaction time in the presence of [bmim][BF4] affording the
desired products without any byproducts. Facile nucleophilic substitutions such
as halogenations, acetoxylation, nitrilation, and alkoxylations in the presence
of ionic liquids provided the desired products in good yields.
D. W. Kim, C. E. Song, D. Y. Chi, J. Org. Chem., 2003, 68,
4281-4285.
Silicaphosphine (Silphos), [P(Cl)3−n(SiO2)n] is a new
heterogeneous reagent that converts alcohols and thiols to their corresponding
bromides and iodides in the presence of molecular halogen in refluxing CH3CN
in high to quantitative yields. Separation of the Silphos oxide byproduct can be
achieved by a simple filtration.
N. Iranpoor, H. Firouzabadi, A. Jamalian, F. Kazemi, Tetrahedron, 2005,
61, 5699-5704.
The combination of Ph3P and easily available 1,2-dihaloethanes (XCH2CH2X; X =
Cl, Br, or I), was very effective for a mild deoxygenative halogenation of
alcohols and aldehydes. The use of (EtO)3P instead of Ph3P
enables a convenient purification process, as the byproduct (EtO)3P═O
could be removed by aqueous washing. A dehydroxy-fluorination proceeds well in
the presence of ICH2CH2I and CsF as fluoride source in DMF.
J. Chen, J.-H. Lin, J.-C. Xiao, Org. Lett.,
2018, 20, 3061-3064.
A deaminative carbon-centered radical formation process using an anomeric
amide reagent enables a direct conversion of amines to bromides, chlorides,
iodides, phosphates, thioethers, and alcohols. The overall implications of this
technology for interconverting amine libraries were evaluated via
high-throughput parallel synthesis and applied in the development of one-pot
diversification protocols.
B. D. Dherange, M. Yuan, C. B. Kelly, C. A. Reiher, C. Grosanu, K. J. Berger,
O. Gutierrez, M. D. Levin, J. Am. Chem. Soc.,
2023, 145, 17-24.
Treatment of primary, secondary, or tertiary alkyl fluorides with a catalytic
amount of titanocene dihalides, trialkyl aluminum, and polyhalomethanes as the
halogen source achieves a halogen exchange reaction in excellent yields under
mild conditions. In the case of a fluorine/iodine exchange, no titanocene
catalyst is needed. Only C-F bonds are activated under these conditions, whereas
alkyl chlorides, bromides, and iodides remained intact.
Y. Mizukami, Z. Song, T. Takahashi, Org. Lett.,
2015,
17, 5942-5945.
In a triphasic phase-vanishing system comprised of an alkane, perfluorohexanes,
and bromine, photoirradiation efficiently generate hydrogen bromide, which
underwent radical addition with 1-alkenes in the hydrocarbon layer to afford
terminal bromides in high yields.
H. Matsubara, M. Tsukida, D. Ishihara, K. Kuniyoshi, I. Ryu, Synlett, 2010,
2014-2018.
Hydrobromination reactions of alkenes with TMSBr and oxygen as common
reagents provide the anti-Markovnikov product in the presence of parts per
million amounts of a Cu(I) species (present in the commercial TMSBr), whereas Markovnikov product is formed in the
presence of 30 mol % iron(II) bromide.
D. A. Cruz, V. Sinka, P. de Armas, H. S. Steingruber, I. Fernández, V. S. Martín,
P. O. Miranda, J. I. Padrón, Org. Lett., 2021, 23,
6105-6109.
Hydrobromination reactions of alkenes with TMSBr and oxygen as common
reagents provide the anti-Markovnikov product in the presence of parts per
million amounts of a Cu(I) species (present in the commercial TMSBr), whereas Markovnikov product is formed in the
presence of 30 mol % iron(II) bromide.
D. A. Cruz, V. Sinka, P. de Armas, H. S. Steingruber, I. Fernández, V. S. Martín,
P. O. Miranda, J. I. Padrón, Org. Lett., 2021, 23,
6105-6109.
The combination of methanesulfonic acid and inorganic halide salts (CaCl2,
LiBr, LiI) mediates hydrochlorinations, hydrobrominations, and hydroiodinations
of unactivated alkenes in acetic acid. This approach uses readily available and
inexpensive reagents to provide alkyl halides in very good yields. An example of
deuteriochlorination using deuterated acetic acid as solvent is also
demonstrated.
X. Bertrand, P. Paquin, L. Chabaud, J.-F. Paquin, Synthesis, 2022, 54,
1413-1421.
Dual photoredox/cobalt catalysis enables a hydrohalogenation of aliphatic
alkenes with collidineˇHX salts to provide highly functionalized alkyl halides.
The catalysts convert a proton and a halide anion to a nucleophilic hydrogen
radical equivalent and an electrophilic halogen radical equivalent and deliver
them to an alkene moiety. This protocol enables the introduction of F, Cl, Br,
or I.
S. Shitutani, K. Nagao, H. Ohmiya, J. Am. Chem. Soc.,
2024, 146, 4375-4379.
The combination of 1,1,3,3-tetramethyldisiloxane (TMDS) and trimethylbromosilane
(Me3SiBr) enabled a direct bromination of carboxylic acids in the
presence of indium bromide (InBr3) as catalyst. The reducing system
was tolerant to several functional groups and produced the corresponding alkyl
bromides in very good yields.
T. Moriya, S. Yoneda, K. Kawana, R. Ikeda, T. Konakahara, N. Sakai, Org. Lett., 2012,
14, 4842-4845.
A deacylative halogenation of various methyl ketones to the corresponding
alkyl chlorides, bromides, and iodides in good yields with broad FG tolerance is
driven by the formation of a 1,2,4-triazole as an aromatic byproduct. The
reaction uses N'-methylpicolinohydrazonamide to form a prearomatic
intermediate and halogen atom-transfer reagents to quench the alkyl radical
intermediates.
Z. Zhang, Q. Zhu, D. Pyle, X. Zhou, G. Dong, J. Am. Chem. Soc.,
2023, 145, 21096-21103.
Under very mild oxidative conditions, 1,4-dihydropyridines (DHPs), derived
from aldehydes, generate C(sp3)-radicals that couple with halogen
radicals, which are generated from inexpensive halogen sources (NaBr, NaI, or
HCl), to yield alkyl halides. The reaction tolerates a broad range of functional
groups and achieves excellent site selectivity.
S. Liang, T. Kumon, R. A. Angnes, M. Sanchez, B. Xu, G. B. Hammond,
Org. Lett., 2019, 21, 3848-3854.
Silver-Catalyzed Decarboxylative Bromination of Aliphatic Carboxylic Acids
X. Tan, T. Song, Z. Wang, H. Chen, L. Cui, C. Li, Org. Lett.,
2017, 19, 1634-1637.
A bromide Vilsmeier reagent promotes the conversion of primary alkyl
dimethylthiocarbamates into alkyl bromides in high yields in the presence of
other non-acid sensitive and non-nucleophilic functional groups.
M. F. Moynihan, J. W. Tucker, C. J. Abelt, Synthesis, 2008,
3565-3568.
The preparation of alkenyl halides of any length from inexpensive starting
reagents is reported. Standard organic transformations were used to prepare
straight-chain α-olefin halides in excellent overall yields with no
detectable olefin isomerization and full recovery of any unreacted starting
material.
T. W. Baughman, J. C. Sworen, K. B. Wagener, Tetrahedron, 2004,
60, 10943-10948.
An efficient conversion of alcohols and β-amino alcohols to the corresponding
chlorides can be carried out at room temperature in methylene
chloride, using 2,4,6-trichloro[1,3,5]triazine and N,N-dimethyl formamide.
Addition of NaBr allows the synthesis of bromides. Optically active carbinols
react under inversion.
L. de Luca, G. Giacomelli, A. Porcheddu, Org. Lett., 2002,
4, 553-555.
In monobromination of diols, azeotropic removal of water decreases selectivities,
which in addition are concentration dependent. Bromo alcohols might behave like
surfactants, forming aggregates such as reverse micelles or water/oil
microemulsions, which lowers the reactivity.
J. M. Chong, M. A. Heuft, P. Rabbat, J. Org. Chem., 2000,
65, 5837-5838.
A metal-free electrochemical vicinal difunctionalization of various alkenes
with dibromomethane in alcohol as solvent provides β-bromo-α-alkyloxyalkanes
with good functional group tolerance under ambient conditions. Preliminary
mechanistic studies indicate the oxidation of bromine source occurs prior to
that of alkene substrate with the involvement of bromine radical during
electrolysis.
F. Luo, X. Chen, J. Yu, Y. Yin, X. Hu, Y. Hu, X. Liu, X. Chen, S. Zhang, Y.
Hu, Synthesis, 2023,
55, 1451-1459.
The combination of triphenylphosphine and copper(I) halide catalyzes an atom
transfer radical addition reaction of activated organic halides to terminal
alkenes under irradiation with 365 nm light using a light-emitting diode.
O. V. Fedorov, S. I. Scherbinina, V. V. Levin, A. D. Dilman, J. Org. Chem., 2019,
84, 11068-11079.
Halofluorination of alkenes in the presence of trihaloisocyanuric acids and HF•pyridine
results in the formation of vicinal halofluoroalkanes in good yields. The
reaction is regioselective leading to Markovnikov-oriented products and the
halofluorinated adducts follow anti-addition in the case of cyclohexene
and 1-methylcyclohexene.
L. T. C. Crespo, R. da S. Ribeiro, M. S. S. de Mattos, P. M. Esteves, Synthesis, 2010,
2379-2382.
Sm(OTf)3 is an effective catalysts for a versatile and efficient
halogen-promoted highly regio- and stereoselective Friedel-Crafts (F-C)
alkylation of electron-rich arenes with alkenes and α,β-unsaturated carbonyl
compounds in the presence of NBS or I2 as halogen sources.
S. Haira, B. Maji, S. Bar, Org. Lett., 2007,
9, 2783-2786.
A direct retro-Barbier fragmentation of cyclic tertiary alcohols proceeds under
mild conditions in the presence of bromine and potassium carbonate in chloroform
to provide bromoketones in high yields.
W.-C. Zhang, C.-J. Li, J. Org. Chem., 2000,
65, 5831-5833.
Iron(III) acetylacetonate catalyzes an oxidative ring opening of cyclic
ethers and acetals under visible light irradiation with unparalleled efficiency.
This photocatalytic radical chemistry approach enables the conversion of
relatively inert cyclic ethers into useful synthetic intermediates and
illustrates that simple Fe(III) complexes can initiate redox processes from
4LMCT excited states.
R. Lindroth, A. Ondrejková, C.-J. Wallentin, Org. Lett.,
2022, 24, 1662-1667.
A metal-free ring opening/halogenation of cycloalkanols, which combines both PPO/TBAX
oxidant system and blue LEDs irradiation, provides diverse γ, δ, and even more
remotely halogenated ketones in good yields under mild conditions.
R. Zhao, Y. Yao, D. Zhu, D. Chang, Y. Liu, L. Shi, Org. Lett.,
2018, 20, 1228-1231.
The reaction of unactivated alkenes with dibromofluoromethane under
photoredox catalysis provides 1-bromo-1-fluoroalkanes in THF as solvent.
1,3-Dibromo-1-fluoroalkanes were chemoselectively formed using DMF/H2O
as solvent.
F. Chen, X.-H. Xu, F.-L. Qing, Org. Lett., 2021, 23,
2364-2369.
A trifluoromethylation of alkenes or alkynes using trifluoromethanesulfonic
anhydride (Tf2O) as a trifluoromethylating reagent in the presence of CuX2
(X = Br, Cl), Zn powder, and 2,2'-bipyridine affords
bromo(chloro)trifluoromethylated products in good yields. CuX2 plays
a dual role as the catalyst and halide source, whereas 2,2′-bipyridine acts as
both the activation reagent and ligand.
Y. Ouyang, C.-L. Tong, X.-H. Xu, F.-L. Qing, Org. Lett., 2021, 23,
346-350.
A convenient, safe, and green protocol, that uses oxone/halide and Fenton
bromide, achieves a halogenative semipinacol rearrangement at room temperature.
The key feature of this method is the green in situ generation of reactive
halogenating species from oxidation of halide with oxone or H2O2,
which produces a nontoxic byproduct (potassium sulfate or water).
L. Song, Y. Zhou, H. Liang, H. Li, Y. Lai, H. Yao, R. Lin, R. Tong, J. Org. Chem., 2023, 88,
504-512.
C. Ye, J. M. Shreeve, J. Org. Chem.,
2004,
69, 8561-8563.
Unsaturated compounds such as alkenes, alkynes, allenes, and
methylenecyclopropanes (MCPs) can be dibrominated within minutes by NBS and
lithium bromide in THF at room temperature in good to excellent yields under
mild conditions.
L.-X. Shao, M. Shi, Synlett,
2006, 1269-1271.
A highly efficient deoxygenative haloboration of aldehydes provides secondary
α-haloboronates. Even tertiary α-haloboronates can be readily prepared via the
same strategy with ketones. Furthermore, enantioselective chloroboration of
carbonyls was successfully achieved to give chiral secondary or tertiary
α-chloroboronates.
D. Wang, J. Zhou, Z. Hu, T. Xu, J. Am. Chem. Soc.,
2022, 144, 22870-22876.