Iron(II) and Copper(I) Control the Total Regioselectivity in the Hydrobromination of Alkenes

Article abstract of DOI:10.1021/acs.orglett.1c02186

A new method that allows the complete control of the regioselectivity of the hydrobromination reaction of alkenes is described. Herein, we report a radical procedure with TMSBr and oxygen as common reagents, where the formation of the anti-Markovnikov product occurs in the presence of parts per million amounts of the Cu(I) species and the formation of the Markovnikov product occurs in the presence of 30 mol % iron(II) bromide. Density functional theory calculations combined with Fukui's radical susceptibilities support the obtained results.

Full text of DOI:10.1021/acs.orglett.1c02186

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Letter
Iron(II) and Copper(I) Control the Total Regioselectivity in the
Hydrobromination of Alkenes
Daniel A. Cruz, Victoria Sinka, Pedro de Armas, Hugo Sebastian Steingruber, Israel Fernández,
Víctor S. Martín, Pedro O. Miranda,* and Juan I. Padrón*
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ABSTRACT: A new method that allows the complete control of the regioselectivity of the
hydrobromination reaction of alkenes is described. Herein, we report a radical procedure with
TMSBr and oxygen as common reagents, where the formation of the anti-Markovnikov
product occurs in the presence of parts per million amounts of the Cu(I) species and the
formation of the Markovnikov product occurs in the presence of 30 mol % iron(II) bromide.
Density functional theory calculations combined with Fukui’s radical susceptibilities support
the obtained results.
complete regioselective control (with slight modifications and
no need to alter the nature of the process) remain unexplored.
Herein, we report the use of TMSBr and oxygen as common
reagents in a free radical hydrobromination process. Its
combination with different transition metals such as Cu(I)
and Fe(II) successfully leads to complete regioselectivity
control in the hydrobromination reaction of alkenes (Scheme
1b).
During our work on the synthesis of tetrahydropyrans
through Prins cyclization,8 traces of Markovnikov hydro-
brominated products of the alkene were detected when using
the Lewis acid system FeBr3/TMSBr in dry dichloromethane
at room temperature. To verify this result in detail, we decided
to carefully study the effect of each reagent. First, we set up a
reaction under nitrogen atmosphere and used an excess of
TMSBr as the brominating agent. After a ten-day reaction, we
observed the formation of a product that turned out to be the
anti-Markovnikov hydrobrominated olefin in a 70% yield.
Since abnormal addition products are widely accepted to be
formed via a radical pathway with the help of an initiator
(Scheme 1a), we decided to clarify the nature of the whole
process.
erminal olefins are valuable synthons in organic synthesis.
1,2
TIn addition to their abundance in natural products,
olefins can be modified into a great variety of functional groups
using many readily available processes.3,4 Among them, HX
additions are an important class of reactions that allow the
interconversion of alkenes into synthetically useful intermedi-
ates.5 This addition reaction shows a divergence in
regioselectivity from an ionic pathway that affords the
Markovnikov addition product to a free radical pathway that
gives rise to the anti-Markovnikov addition product. Among
these types of reactions, the hydrobromination reaction
typically requires quite harsh conditions that are not
compatible with several functional groups and, most
frequently, leads to the formation of a mixture of regioisomers
due to the occurrence of these two competitive processes
(Scheme 1a).6 Considering a common free radical scenario,
the Markovnikov addition product is not a trivial target as it
would imply the addition of a hydrogen atom to the olefin at
the first step, which is usually effected by transition metal
hydrides in a catalytic oxidation and reduction process.7 To
date, common radical reaction conditions able to achieve
Scheme 1. Hydrobromination Addition Reaction
Approaches
We initiated an optimization process by considering the
nature of the initial alkene, bromotrimethylsilane (TMSBr),
the proton source, oxygen, initiators, transition metals, and
solvents. The effect of these variables on the process was
carefully investigated (for a detailed explanation of the
Received: June 29, 2021
Published: July 28, 2021
© 2021 The Authors. Published by
American Chemical Society
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identification of the elements involved in the process, see the
Supporting Information).
On the other hand, the use of substrates with different
heteroatoms like allylthiophenol worked well (2p). The
versatility of the reaction was showcased by the use of
carbohydrate derivatives, which gave the primary bromide in
moderate to excellent yields and with no anomerization (2q
and 2r, respectively). When using the furan derivative 2s, the
reaction proceeded with complete chemoselectivity as the the
allylic position is more reactive than the vinylic one. Fukui’s
radical susceptibilities showed a divergence between the allylic
(higher values) and vinylic positions, indicating that the radical
addition should occur at the allylic position (see Figure S4 in
the Supporting Information). Moreover, substrates containing
esters and nitrogen also worked well, with excellent to
moderate yields (2t−2v). No reaction was observed in the
presence of a ketone (2w). The reaction was scalable up to 2 g
(2d, 89%) and no further purification was required (Figure 1).
With these results in hand, we focused on the idea of
reversing the reaction pathway toward the exclusive formation
of the corresponding Markovnikov product. The existence of a
putative amount of metalloradicals containing iron(II), which
are able to modulate the reactivity of S-adenosyl methionine
systems,10 showed us that the presence of iron(II) would act as
a modulator in the outcome of the reaction. Moreover, iron(II)
catalysts are present in a wide number of radical
processes,11−13 making them an attractive alternative for
modifying radical processes without altering their nature.
Before conducting the experiments, we carried out density
functional theory (DFT) calculations at the dispersion-
corrected PCM-B3LYP-D3/def2-SVP level on the
AcO(CH2)3CHCH2 substrate. According to the
computed Fukui’s radical susceptibilities (R), the radical
addition should preferentially occur at the terminal carbon
atom of the CC double bond, which is fully consistent with
the experimental results described below (Figure 2a). At
variance, the coordination of the alkene and carbonyl groups of
the substrate to FeBr2 should provoke a dramatic change in the
selectivity of the radical addition in view of the higher R value
that was computed for the internal carbon atom as compared
to that for the terminal one. Therefore, our calculations predict
that the presence of FeBr2 could efficiently revert the selectivity
After the optimization process, we developed an effective
and simple method that consists of the following components:
(a) water-saturated CH2Cl2, (b) oxygen (present in the
reaction media), (c) amylene (2-methyl-2-butene) as an
initiator, (d) TMSBr, and (e) Cu as the transition metal
(present in commercially available TMSBr batches). The
synergistic action of all and each of these species makes the
course of the reaction possible (Scheme 1b).9
Next, we decided to explore the scope of the reaction using
different substrates (Figure 1). When a plain 11 carbon chain
Figure 1. Reaction conditions. (a) Alkene (1.2 mmol, 1.0 equiv),
TMSBr (3.0 equiv), CH2Cl2 (0.1 M), saturated H2O (Milli-Q), O2
(present in the solvent and the Milli-Q water), amylene (170 ppm),
and CuBr (present in the commercial TMSBr). (b) Scope and yields
of the anti-Markovnikov hydrobromination of alkenes. (c) Markovni-
kov and anti-Markovnikov orientations in styrene derivatives.
was used, the reaction proceeded with a quantitative yield
(>99%) (2a). The introduction of a hydroxyl group inhibited
the reaction (2b). To get more complexity in the molecule, we
decided to use branched alkenes and different O-benzoylated
alcohols, diversifying their chain lengths. In all cases, the
reaction afforded the corresponding products in excellent to
quantitative yields (2c−2h). Next, when an aromatic substrate,
such as allylbenzene, was used, the reaction also proceeded
with a good yield (2i). This behavior was maintained when
trans-β-methylstyrenes were used (2j−2l). The introduction of
a halogenated group such as bromine proceeded with an
excellent yield of the product (2k), while the presence of a
nitro group gave only a moderate yield (2l). Finally, we
increased the complexity of the molecule using different
substituted aromatic homoallyl ethers (2m−2o). The yield of
the addition reaction was not affected by the presence of either
electron-withdrawing or electron-donating groups (2m, 2n).
Figure 2. Preferred radical addition in the hydrobromination of
AcO(CH2)3CHCH2.
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of the transformation and indicate that the coordination of the
CC double bond to the transition metal is mandatory to
produce the Markovnikov product (Figure 2b).
With these optimized reaction conditions in hand, we
selected representative substrates to confirm if the regiose-
lectivity of the hydrobromination reaction can be controlled
(Figure 3). In all cases, treatment of the substrates with the
FeBr2-TMSBr catalytic system afforded the corresponding
Markovnikov product in good to excellent yields. Thus, long-
chain substrates and nonprotected alcohols afforded the
desired products with good yields (3a, 3b). The use of O-
benzoylated alcohols also gave good to excellent yields (3c-
3e). When the reaction was carried out using secondary O-
benzoylated alcohols, although the reaction was clean, it
proceeded only with a moderate yield (3f, 3g). The use of
aromatic substrate like allylbenzene also proceeded with
excellent yield (3j), while the use of aromatic ethers gave
moderate yields (3m−3o), a pattern that was maintained when
different substituents (methyl and fluor) were introduced in
the ring (3m, 3n). The carbohydrate derivative 3r gave the
Markovnikov bromide in good yield and with no anomeriza-
tion. In this particular case, the brominated derivative was
attained as a diastereomeric mixture (3r). The use of a thiol
derivative also gave a good yield (3p), while the pyrrolidine
derivative gave a moderate yield (3v). In addition, the use of
substrates like diethyl allylmalonate and 2-allylcyclohexanone
proved to be successful (3u−3w).
A plausible mechanism of the anti-Markovnikov process is
proposed accordingly (Figure 4a). Cu(I) in the presence of O2
catalyzes the formation of the hydroperoxide A,14 and releases
a Cu(II) ion via single-electron transfer (SET). Then, the
oxygen−oxygen bond of the hydroperoxide breaks homolyti-
cally due to the action of Cu(I), producing the peroxyl radical
B. This radical initiates the chain reaction with HBr,15 forming
bromine radicals and the corresponding trimethylsilylether C.
Bromine radicals add to the alkene to form the most stable
radical intermediate D, which evolves toward the final product
via a reaction with HBr, which was generated in a parallel
process as indicated in Figure 4. Indeed, when the reaction was
carried out in the presence of deuterium oxide (D2O), the
hydrogen in the final bromoalkane 2 was entirely exchanged by
deuterium (Figure 4a; see the Supporting Information for
further details).
Encouraged by these results, BzO(CH2)4CHCH2
was treated with FeBr2−TMSBr in dichloromethane, resulting
in the exclusive formation of the Markovnikov reaction
product (Table S4 in the Supporting Information). We
screened different reaction conditions for the catalytic system
and found that 0.3 equiv of FeBr2 alongside 3.0 equiv of
TMSBr were the best (90% reaction yield). We also verified
whether oxygen was involved in the process. To this end, we
checked the following sets of reactions: (a) open-air, (b) under
a nitrogen atmosphere, and (c) under a nitrogen atmosphere
with deoxygenated DCM. The open-air reaction afforded a
quantitative yield, while that under a nitrogen atmosphere only
worked with a 30% yield due to the oxygen already present in
DCM. In the last case, i.e., under an inert atmosphere and
deoxygenated DCM, the reaction did not proceed at all. On
the other hand, a proton source is also necessary and comes
from the moisture of the air (see the Supporting Information).
Therefore, it became evident that the presence of oxygen and
moisture is essential for the success of the reaction. On the
contrary, the presence of amylene in the reaction media is
irrelevant, as it can be seen from the experimental results
(Table S4 in the Supporting Information).
With these optimized reaction conditions in hand, we
selected representative substrates to confirm if the regiose-
lectivity of the hydrobromination reaction could be controlled
(Figure 3). In all cases, the treatment of the substrates with the
In order to locate the rate-determining step of the reaction,
kinetic isotopic effects (KIE) studies were performed.16,17
A
comparison of the kinetic constants obtained with water and
deuterium oxide revealed a kinetic isotope effect of 3/4.
Therefore, the isotopic substitution bond is not broken during
the rate-determining step, which is consistent with the
hypothesis by Mayo et al.18 on the slow formation of bromine
radicals with oxygen.
In the radical Markovnikov process, FeBr2 in the presence of
O2 and TMSBr catalyzes the formation of bis(trimethylsilyl)-
peroxide E,14,19 which is an effective oxidant. The FeBr3
generated in the process is oxidized by the action of E to
give the iron(IV) species F. Next, the subsequent formation of
bromine radicals, which release the iron(III) species G, ensures
the regeneration of iron(II) in the system, as proposed by
Barton and Chabot (Figure 4b).20
Figure 3. Reaction conditions. (a) Alkene (1.2 mmol, 1.0 equiv),
FeBr2 (0.3 equiv), TMSBr (3.0 equiv), CH2Cl2 (0.1 M), O2 (present
in the air, the solvent, and H2O from moisture). (b) Scope and yields
of the Markovnikov hydrobromination of alkenes. (c) The
Markovnikov orientation in allyl benzene.
Once this bromine radical is formed, addition to the internal
carbon atom of the FeBr2-coordinated CC double bond of
H gives rise to the Markovnikov brominated product with the
concomitant regeneration of the FeBr2 due to the presence of
HBr, which is generated in a parallel process by reaction of the
TMSBr with the humidity that carries the oxygen (Figure
4b).21
FeBr2-TMSBr catalytic system afforded the corresponding
Markovnikov product in good to excellent yields. Thus, long-
chain substrates and nonprotected alcohols afforded the
desired products with good yields (3a and 3b, respectively).
The use of O-benzoylated alcohols also gave good to excellent
yields of the products (3c−3e).
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AUTHOR INFORMATION
Corresponding Authors
■
Pedro O. Miranda − Molecular Sciences Department, Instituto
de Productos Naturales y Agrobiología, Consejo Superior de
Investigaciones Científicas (IPNA-CSIC), 38206 La Laguna,
Tenerife, Islas Canarias, Spain; orcid.org/0000-0002-
2064-9160; Email: pmiranda@ipna.csic.es
Juan I. Padrón − Molecular Sciences Department, Instituto de
Productos Naturales y Agrobiología, Consejo Superior de
Investigaciones Científicas (IPNA-CSIC), 38206 La Laguna,
Tenerife, Islas Canarias, Spain; orcid.org/0000-0002-
0745-2259; Email: jipadron@ipna.csic.es
Authors
Daniel A. Cruz − “Síntesis Orgánica Sostenible, Unidad
Asociada al CSIC”, Departamento de Química Orgánica,
Instituto Universitario de Bio-Orgánica “Antonio González”
(CIBICAN), Universidad de La Laguna, 38206 La Laguna,
Tenerife, Islas Canarias, Spain
Victoria Sinka − Molecular Sciences Department, Instituto de
Productos Naturales y Agrobiología, Consejo Superior de
Investigaciones Científicas (IPNA-CSIC), 38206 La Laguna,
Tenerife, Islas Canarias, Spain
Pedro de Armas − Molecular Sciences Department, Instituto
de Productos Naturales y Agrobiología, Consejo Superior de
Investigaciones Científicas (IPNA-CSIC), 38206 La Laguna,
Tenerife, Islas Canarias, Spain
Hugo Sebastian Steingruber − “Síntesis Orgánica Sostenible,
Unidad Asociada al CSIC”, Departamento de Química
Orgánica, Instituto Universitario de Bio-Orgánica “Antonio
González” (CIBICAN), Universidad de La Laguna, 38206
La Laguna, Tenerife, Islas Canarias, Spain; Present
́
́
Address: Departamento de Quimica, Instituto de Quimica
del Sur, INQUISUR (CONICET-UNS), Universidad
́
Nacional del Sur, Avenida Alem 1253, 8000 Bahia Blanca,
Argentina
Israel Fernández − Departamento de Química Orgánica I y
Centro de Innovación en Química Avanzada (ORFEO-
CINQA), Facultad de Ciencias Químicas, Universidad
Complutense de Madrid, 28040 Madrid, Spain;
orcid.org/0000-0002-0186-9774
Figure 4. Proposed mechanisms for the anti-Markovnikov and
Markovnikov hydrobromination.
Víctor S. Martín − “Síntesis Orgánica Sostenible, Unidad
Asociada al CSIC”, Departamento de Química Orgánica,
Instituto Universitario de Bio-Orgánica “Antonio González”
(CIBICAN), Universidad de La Laguna, 38206 La Laguna,
Tenerife, Islas Canarias, Spain; orcid.org/0000-0003-
0300-9636
In summary, we have developed reaction conditions that
allow us efficient control of the regioselectivity of the radical
addition to CC double bonds in the hydrobromination
reaction (Markovnikov and anti-Markovnikov). The absence of
irradiation and heating makes the anti-Markovnikov addition
reaction proceed smoothly and rather spontaneous, in a simple
and scalable manner. At variance, the use of FeBr2 leads to the
exclusive formation of the corresponding Markonikov
regioisomer, with no need for metal hydrides and oxidation
and reduction processes.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02186
Notes
The authors declare no competing financial interest.
ASSOCIATED CONTENT
■
ACKNOWLEDGMENTS
■
sı
* Supporting Information
This research was supported by the Ministerio de Ciencia,
Innovación y Universidades (MCIU), la Agencia Estatal de
Investigación (AEI), Fondo Europeo de Desarrollo Regional
(FEDER), and ACIISI (Gobierno de Canarias) (PGC2018-
094503-B-C22, ProID2017010118, and PID2019-106184GB-
I00). V.S. thanks the Spanish MCIU for an F.P.U. fellowship.
D.A.C. and P.O.M. thank Cabildo de Tenerife for a
postdoctoral Agustín de Bethancourt transfer contract and a
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02186.
Complete experimental procedures, optimization, char-
acterization, kinetic isotopic effect, H and 13C NMR
spectra for all new compounds, and computational
details (PDF)
1
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(21) Several mechanistic studies, for both processes, were performed
(i.e., radical clock, radical scavengers, KIE experiments, EPR
spectroscopies, etc.) to prove the radical behavior of these reactions.
See the Supporting Information.
Tenerife 2030 Programme (TF INNOVA 2016-2021”)
contract alongside Marco Estratégico de Desarrollo Insular
(MEDI) and Fondo de Desarrollo de Canarias (FDCAN),
respectively. Thanks to F.L. and R.R. (CIQUS-USC) for the
help with the EPR spectroscopy.
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