Hexafluoroisopropanol-Promoted Haloamidation and Halolactonization of Unactivated Alkenes

Article abstract of DOI:10.1002/anie.202010846

Pyrrolidine and piperidine derivatives bearing halide functional groups are prevalent building blocks in drug discovery as halides can serve as an anchor for post-modifications. In principle, one of the simplest ways to build these frameworks is the haloa

Full text of DOI:10.1002/anie.202010846

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Accepted Article
Title: Hexafluoroisopropanol-Promoted Haloamidation and
Halolactonization of Unactivated Alkenes
Authors: Chenxiao Qi, Guillaume Force, Vincent Gandon, and David
Leboeuf
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Hexafluoroisopropanol-Promoted Haloamidation and
Halolactonization of Unactivated Alkenes
Chenxiao Qi,[a] Guillaume Force,[a] Vincent Gandon*[a,b] and David Leboeuf*[c]
[a]
C. Qi, Prof. Dr. V. Gandon
Institut de Chimie Moléculaire et des Matériaux d’Orsay (ICMMO), CNRS UMR 8182
Université Paris-Saclay
91405 Orsay, France.
E-mail: vincent.gandon@universite-paris-saclay.fr
Prof. Dr. V. Gandon
Laboratoire de Chimie Moléculaire (LCM), CNRS UMR 9168
Ecole Polytechnique, Institut Polytechnique de Paris
91128 Palaiseau, France
[b]
[c]
Dr. D. Lebœuf
Institut de Science et d’Ingénierie Supramoléculaires (ISIS), CNRS UMR 7006
Université de Strasbourg
67000 Strasbourg, France
E-mail: dleboeuf@unistra.fr
Supporting information for this article is given via a link at the end of the document.
Abstract: Pyrrolidine and piperidine derivatives bearing halide
functional groups are prevalent building blocks in drug discovery as
halides can serve as an anchor for post-modifications. In principle,
one of the simplest ways to build these frameworks is the
haloamination of alkenes. While several progresses have been made
in this field, notably the development of enantioselective versions, this
reaction is still fraught with limitations in terms of reactivity. Besides,
a major question remaining is to understand the mechanism at work.
The formation of a haliranium intermediate is typically mentioned, but
limited mechanistic evidence supports it. Herein, we report an efficient
metal- and oxidant-free protocol to achieve the haloamidation of
olefins, which is promoted by hexafluoroisopropanol, along with a DFT
investigation of the mechanism. We anticipate that these findings
should guide the future development of more complex transformations
in the field of halofunctionalization.
reaction because the halide is no longer available. Another issue
to take into account is the potential formation of an aziridinium
given that the nitrogen functionality is more nucleophilic than a
sulfonamide, which can not only lead to the formation of the 6-
membered ring through a ring-expansion but also to other side
products.[3f,4e-f] Although a large variety of transition metals, Lewis
acids or organocatalysts (used with or without an oxidant) have
been employed to trigger the transformation, methods exhibiting
a wide functional group compatibility are scarce.[1] To overcome
the current limitations tied to the haloamidation of unactivated
alkenes, we envisioned a strategy that would allow to both
activate the halide reagent, N-halosuccinimide (NXS) for instance,
and prevent the deactivation of the halide source, while operating
under mild reaction conditions to suppress the formation of
piperidine derivatives. In this respect, we considered the use of
hexafluoroisopropanol (HFIP) to be the solution best suited to fulfil
these requirements. In the last decade, HFIP has garnered a
growing attention owing to its remarkable intrinsic properties,
including its ability to stabilize carbocationic species and to be a
strong hydrogen bond donor, in addition to its low
nucleophilicity.[5-6] One of the keys to the success of our approach
would rely on the inherent capacities of HFIP, including its acidity
and its H-bond donating ability, to effectively activate the N-halo
succinimide reagent. In addition, we anticipated that, even if the
halide is sequestered by the nitrogen functional group, especially
the most basic ones, HFIP could favor its release, driving the
process to turn over.[7] Moreover, its high dielectric constant and
its low nucleophilicity would make it an ideal solvent to generate
cations, which are commonly proposed intermediates in
haloamidation processes. HFIP has already demonstrated its
efficiency as a solvent in halofunctionalizations.[8] However, the
reactivity described was limited to arene and oxygen nucleophiles,
which are less nucleophilic than amines, hence less prone to
quench the electrophile in a side reaction. In the study by the
Gulder group,[8a] the mechanistic proposal was based on the
putative formation of a haliranium intermediate, which was not
supported by either experimental or computational studies.
Introduction
The intramolecular difunctionalization of unactivated alkenes,
such as haloamidation reactions, is a powerful tool to build
molecular complexity by both creating a new ring and installing
halide functionalities, which are present in manifold bioactive
molecules and can also serve for further derivatizations.[1] It
therefore provides a rapid access to densely functionalized
pyrrolidines and piperidines, which are by far the most
represented 5- and 6-membered N-heterocycles in drug design
(Scheme 1).[2] When it comes to intramolecular haloamidation
reactions, sulfonamides have been primarily studied.[3] Yet, their
deprotection to obtain the parent amine is not always
straightforward, thereby limiting the utility of the transformation.
On the other hand, the reactivity of more basic nitrogen functional
groups such as carbamates, amides and ureas is less described,
apart from few notable transition-metal- or organocatalyst-based
methods.[4] One possible explanation might be that the strongly
basic nitrogen functionalities compete with the alkene moiety for
the electrophilic halide (N-halogenation vs C-halogenation). In
consequence, it might preclude, or at least slow down, the
1
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Scheme 1. Halofunctionalization of unactivated alkenes in the presence of HFIP
hexafluoroisopropanol (HFIPMe) to preclude any strong H-
bonding with the substrates shut down completely the reactivity.
Similarly, replacing HFIP by other alcohol solvents such as
isopropanol and ethanol that did not possess the same H-bonding
ability as HFIP did not mediate the reaction at −40 °C.[10] Finally,
we demonstrated that the reaction could also be achieved on a
Herein, we report our findings on a broadly applicable and efficient
metal- and oxidant-free haloamidation of unactivated alkenes
promoted by HFIP as an additive rather than a solvent, which
could also be extended to halolactonization with the same efficacy.
Furthermore, an in-depth investigation of this reaction by DFT
computations allowed us to better understand the mechanism of
this transformation and shed light on the key role played by HFIP,
discarding several mechanistic pathways postulated in precedent
reports on haloamidation.
Table 1. Reaction optimization for the formation of pyrrolidine 2a.
Results and Discussion
Conversion
[%] (yield,
trans/cis)
Br+
source
Entry
Solvent
T [°C]
t [h]
In our initial investigations, we studied the reactivity of N-tosyl
aminoalkene 1a to access bromo-pyrrolidine 2a (Table 1). To
optimize the efficacy and the selectivity of the haloamidation, we
explored a variety of reaction conditions featuring HFIP as an
activating agent and different bromine sources, starting with NBS.
When HFIP was employed as a solvent, the reaction reached its
full conversion in less than 5 min at rt, but the diastereoselectivity
was moderate (Entry 1). The selectivity could be slightly improved
by conducting the reaction at 0 C (Entry 2). Because of the high
cost of HFIP and its high corrosivity, we tested the possibility to
use it as an additive. At the outset, we explored the reaction in a
solvent mixture DCM/HFIP 5:1 (~10 equivalents of HFIP) (Entries
3-5). The best result was obtained at −40 C, providing compound
2a in 97% yield with a high diastereoselectivity (dr 6.5:1). Of note,
the selectivity significantly decreased at −78 C, which might be
explained by the fact that the reaction mixture froze at this
temperature. Operating at a lower concentration and screening
other sources of bromine did not improve the selectivity (Entries
6-8). Other combinations of solvents were also tested (Entries 9-
10) and, gratifyingly, performing the reaction in toluene led to the
targeted product 2a in 96% yield along with an excellent
diastereoselectivity (dr 9:1).[9] On the other hand, replacing HFIP
by another fluorinated alcohol such as trifluoroethanol (TFE)
proved to be detrimental to both the reaction rate and the
selectivity (Entry 11). Then, we evaluated the possibility to further
decrease the amount of HFIP (~5 equivalents) (Entries 12-13);
however, apart from slowing down the reaction, it did not have
any impact on the selectivity or the yield of the transformation. To
highlight the critical role of HFIP in this reaction, several control
experiments were conducted (Entries 14-16). In the absence of
HFIP, no reaction occurred. Switching from HFIP to O-methyl
1
NBS
NBS
NBS
NBS
NBS
NBS
BDMS
DBDMH
NBS
NBS
NBS
NBS
NBS
NBS
NBS
HFIP
20
0
0.05
0.2
0.2
1
100 (2.7:1)
100 (3.3:1)
100 (4.9:1)
2
HFIP
3
DCM/HFIP (5:1)
DCM/HFIP (5:1)
DCM/HFIP (5:1)
DCM/HFIP (10:1)[a]
DCM/HFIP (5:1)
DCM/HFIP (5:1)
MeNO2/HFIP (5:1)
Toluene/HFIP (5:1)
Toluene/TFE (5:1)
DCM/HFIP (10:1)
0
100 (97%,
6.5:1)
4
−40
−78
−40
−40
−40
−40
−40
−40
−40
−40
−40
−40
5
6
100 (4.4:1)
100 (6.3:1)
100 (5.3:1)
100 (4.4:1)
100 (6.2:1)
6
1
7
1
8
1
9
4
100 (96%,
9:1)
10
11
12
13
14
15
3
16
2
100 (5.6:1)
100 (6.4:1)
Toluene/HFIP
(10:1)
100 (95%,
9:1)
8
DCM
1
<5
<5
Toluene
3
Toluene/HFIPMe
(5:1)
16
17
18
NBS
NBS
NBS
−40
−40
−40
3
3
3
<5
<5
<5
Toluene/iPrOH
(5:1)
Toluene/EtOH (5:1)
[a] 0.075 M. NBS = N-bromosuccinimide. BDMS = bromodimethylsulfonium
bromide. DBDMH = 1,3-dibromo-5,5-dimethylhydantoin.
2
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Scheme 2. Scope and limitations of the halofunctionalization of unactivated alkenes. [a] HFIP (20 equiv). [b] HFIP (5 equiv). [c] in the presence of DCDMH (1.2
equiv).
97%). Even a highly deactivated substrate such as 1e which
larger scale (5 mmol) to afford 1.57 g of 2a (95% yield, dr 9:1).
incorporates a far less nucleophilic para-nitrostyrene moiety,
proved to be compatible with the optimized conditions, albeit at a
slower reaction rate (4 h vs 15 min). The reaction was also
extended to polycyclic aromatic hydrocarbons such as naphthyl
to yield the corresponding products 2f and 2g in high yields (91%
and 85%, respectively). The transformation is also tolerant to the
presence of electron-donating and -withdrawing groups at the
meta-position. However, in the case of an electron-donating
group (1h), the reaction had to be conducted at a lower
Then, we explored the scope of the transformation with a wide
range of N-protected aminoalkenes (Scheme 2). Depending on
the substrate, either DCM or toluene was employed in association
with HFIP as a solvent mixture. First, we evaluated the impact of
the substituents at the terminal position of the alkene. The
transformation worked smoothly with arenes bearing electron-
donating and, more importantly, -withdrawing groups at the para-
position to furnish the targeted products 2b-2e in high yields (86-
3
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postulated but they are not based on experimental or
computational evidences. In our case, DFT computations were
performed at the OPBE/6-31G(d,p) level of theory to gain insight
into the reaction mechanism.[13] A full discussion is presented in
the Supporting Information (SI) and only the main conclusions are
outlined here. The model substrate A (corresponding to 1a above)
was used in this study, as shown in Scheme 3. At first, we
envisioned that its reaction with NBS B might lead to the
bromination of the nitrogen atom as in C, or to that of the alkene
moiety to give either bromonium E or E’. Those are commonly
proposed intermediates for the haloamidation of alkenes. The
computed free energy is slightly negative for the former (-0.3
kcal/mol) and very high for the others (34.2 and 19.3 kcal/mol
respectively).
temperature (−40 C) to obtain 2h in a good yield (70%). The
reason is that, at 0 C, we observed a partial bromination of the
arene ring, resulting in the formation of 2h in 56% yield. On the
other hand, in the presence of electron-withdrawing groups (1i
and 1j), the reaction had to be executed at rt to reach its
completion, delivering 2i and 2j in 84% and 76% yields,
respectively. Of note, in the case of the trifluoromethyl group (1j),
20 equivalents of HFIP were required for activating the
electrophile. Lastly, substrate with an ortho-substituent (1k)
underwent the haloamidation to form 2k in 77% yield. Importantly,
the reaction was expanded to sterically hindered 1,1-disubstituted
alkenes such as 1l and 1m to give pyrrolidines 2l and 2m in
excellent yields (96% and 91%). Bicyclic structures such as 2n
were also accessed in 88% yield. Using this method enabled the
preparation of piperidines, notably spirocyclic compounds (2’o,
2’p and 2’s), in up to 89%yield, starting from substrates bearing
either a terminal alkene or a styrene moiety. In turn, with a 1,1-
dimethyl substitution on the alkene (1t), a mixture of piperidine 1’t
and 1t was obtained. In the case of 1u, while the haloamidation
worked without problem, the resulting product was not stable and
compound 2’’u was obtained in 89% following the elimination of
bromide. With respect to this protocol, the control of
2
stereocenters was not an issue, but the control of 3 ones was
more problematic and the overall selectivity was moderate (2v). It
is important to stress out that the reaction was not limited to
alkenes with
a (Z)-configuration as alkenes with a (E)-
Scheme 3. Free energies (G233, kcal/mol) of various bromine exchange
reactions between N-tosylaminoalkene A and NBS B.
configuration such as 1w could also be subjected to the optimized
conditions to afford pyrrolidine 2w in 88% yield with an excellent
control of the diastereoselectivity (dr 10:1). In that case, the
formation of the minor diastereoisomer might result from a syn-
addition to the alkene.
Based on those results, we evaluated the feasibility of the
cyclization from the N-Br product C (Scheme 4). The direct
formation of the final product G could be computed by reacting
the nitrogen with the internal alkene carbon of C’, which is a pre-
organized isomer of C, resulting in a formal insertion of the C=C
bond into the N-Br bond. While being markedly exergonic by 37.2
kcal/mol, this process requires to overcome a high activation
barrier of 42.2 kcal/mol and can thus be ruled out. Addition of the
terminal alkene carbon to give ammonium H also faces an
unsurmountable barrier of 39.3 kcal/mol. Then, a radical pathway
was studied. Intermediate C’ was re-optimized in the triplet state
to give the diradical species C’’. Although its cyclization could be
modeled through TSdirad, C’’ already lies too high on the energy
surface to make this approach viable (34.1 kcal/mol).[14] We also
re-investigated the cyclization under either neutral, ionic or radical
pathways, but could not model the formation of the final product
G (see the SI).
Then, we focused on the compatibility of the reaction with a large
range of protecting groups on the nitrogen (1a-1i). This protocol
offers a remarkable scope regarding nitrogen functional groups,
from sulfonamide to amides, carbamates and even ureas with
yields ranging from 62% to 96%. Nonetheless, in the case of
substrate 1g, which is more prone to generate an aziridinium
species, we had to slightly modified the reaction conditions by
using 5 equivalents of HFIP at −40 °C, which yielded 4g as a sole
product in 79% yield. In addition, our standard reaction conditions
could also be applied to unsaturated carboxylic acids to provide
bromo-lactones 5a-5d in high yields (up to 96%).
Encouraged by these results, we considered the iodoamidation
process, using N-iodosuccinimide as an iodide source, and the
intermolecular bromoamidation of p-fluorostyrene. In each case
(7a-7b and 8), the haloamidation reaction was accomplished in
high to excellent yields (75%-95%). Regarding the limitations of
this method, we failed to execute the chloroamidation reaction. In
the presence of N-chlorosuccinimide, no reaction occurred, and,
by replacing it by 1,3-dichloro-5,5-dimethylhydantoin (DCDMH),
we only observed the chlorination of the sulfonamide. Both
chloride sources appeared to be not sufficiently electrophilic to
trigger the targeted reaction. Additionally, in the case of a N-tosyl
amide functional group, the carbonyl ended up being more
nucleophilic than the sulfonamide and a subsequent elimination
of bromide led to furan 10 in 84% yield.[11]
While the transformation displayed a wide scope under our
standard protocol, the critical point was to determine the
mechanism of the haloamidation, which has been less studied
than that of halolactonization.[12] Several mechanisms have been
Scheme 4. Computed neutral and diradical pathways towards the final product
G from N-tosylaminoalkene C (G233, kcal/mol; S: singlet; T: triplet).
4
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On this basis, we suppose that, even if it is formed during the
reaction, the N-Br species C may not be a viable intermediate
towards G.[15,16] We thus hypothesized that the bromination of the
alkene moiety of A could be productive via either E or E’. We
found that if bromonium E’ forms, it readily eliminates through a
very low-lying transition state (Scheme 5). As for E, we found that
its cyclization into the diastereomeric ammoniums P or P’ is a
straightforward process that is only based on the conformational
change of the alkyl chain. A simple rotation around the C-C bond
is enough to trigger the cyclization.
Scheme 6. Incomplete bromonium pathway (G233, kcal/mol) of the bromo-
cyclization of N-tosylaminoalkene A in the presence of a 6-unit HFIP cluster.
moiety, but it did not promote the bromination. We then used the
nitrogen atom and, gratifyingly, we could locate a transition state
connecting A and B to ammonium P and succinimidate F (n = 0)
(Scheme 7). Of note, the ammonium intermediate has 3
stereogenic centers (2 C and 1 N) and thus 4 diastereomers are
expected. Only the most energetically favorable option is shown
here. The complete sequence involves first the formation of an
adduct between A and B, in which the alkene provides electron
density to the bromine -hole.[17] This weak non-covalent
interaction has a maximum electron density between the alkene
and the bromine of max = 0.0135 e.Å3, which does not provide
sufficient energy to compensate the entropic factor, hence the
endergonicity of 5.5 kcal/mol for the formation of adduct [A·B].
Conformer [A·B]’, preorganized for cyclization, is less stable by a
few kcal/mol. The non-covalent interaction between NBS and the
alkene involves more electron density, a value of max = 0.0233
e.Å3 being obtained. The bromonium transfer is achieved though
[TScyclization]0, which also involves the concomitant formation of the
C-N bond. The free energy of activation is of 20.9 kcal/mol and
the formation of ammonium P is endergonic by 0.9 kcal/mol.
Proton exchange between P and succinimidate F liberates 38.4
kcal/mol of free energy, generating the final products G and D (at
-37.5 kcal/mol on the potential energy surface). We then
introduced explicit HFIP molecules in the system (from n =1 to 6,
see the SI), which considerably lowered the free energy of
activation with an optimum of 3. In the case of a 3-unit HFIP
cluster H-bonded to a NBS carbonyl, the free energy of the
cyclization transition state [TScyclization]3 dropped to 14.2 kcal/mol,
while this step became appreciably exergonic (-14.9 kcal/mol).[18]
Of note, replacing HFIP by TFE resulted in a higher cyclization
barrier of 19.3 kcal/mol. This is in line with the experimental
results, which revealed that TFE is a fine additive for the reaction,
albeit at slower rate than the one in HFIP (Table 1, entry 11). Thus,
the lower pKa of TFE makes it less effective than HFIP for the
ionization of the N-Br bond.
Scheme 5. Computed evolution of bromoniums E and E’ (G233, kcal/mol).
With E as best candidate, it remained to explain how it could be
formed efficiently. As shown in Scheme 3, the formation of E from
A and B is endergonic by as much as 34.2 kcal/mol, but the
possible role of HFIP was only considered through the SMD
solvent model, not as explicit molecules. We added incrementally
H-bonded HFIP molecules to see their effect on the alkene
bromination step. One HFIP significantly lowered the free energy
to 25.8 kcal/mol, and, with up to six H-bonded HFIP molecules,
the free energy of this step was dramatically reduced to 13.1
kcal/mol (Scheme 6). Thus, this co-solvent provides a powerful
stabilization of the succinimidate. At this point, the following free
energy profile involving a 6-unit HFIP cluster was proposed. Of
course, more HFIP molecules could be involved, but it already
provides a reasonable picture. Compound A reacts with NBS H-
bonded to a (HFIP)6 cluster to give bromonium E and the
corresponding succinimidate F·(HFIP)6 lying at 13.1 kcal/mol on
the free energy surface. A simple rotation around the C-C bond
triggers the cyclization to ammonium P. This step requires only
2.6 kcal/mol of free energy of activation and is exergonic by 29.0
kcal/mol (placing P at -15.9 kcal/mol). TSanti is 2.1 kcal/mol lower
in energy than TSsyn, which is consistent with the experimentally
observed diastereoselectivity (see Table 1). A proton exchange
between P and the succinimidate F·(HFIP)6 to give the final
product G and succinimide is exergonic by 19.3 kcal/mol. The
bromination of the nitrogen atom of A to give C is exergonic by
2.4 kcal/mol when using H-bonded NBS. It is thus logical to isolate
such products when the cyclization cannot take place. However,
this process is easily reversible, and the bromine can be shifted
to the C=C bond.
At this point, what was missing was a transition state connecting
A and B·(HFIP)n to E and F·(HFIP)n. Despite all our efforts, we did
not find a transition state forming a bromonium intermediate. In
fact, it has been demonstrated that olefins are often incompetent
to capture an electrophile such as Cl+, and that the assistance of
a nucleophile to activate the alkene can be required.[12b] The
proximity of a nucleophile compensates the loss of electron
density during the attack and favors the formation of the C-Cl
bond. In our case, we tried to use the oxygen atoms of the SO2
In agreement with the work of Berkessel,[19] and our own findings
on the alkoxylate walk in H-bonded alcohol clusters,[20] it seems
probable that the acidity of HFIP increases after forming a H-
bonding network, so that the cluster can accommodate the
negative charge of succinimidate D. Thus, the role of HFIP in this
5
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granted access to the HPC resources of CINES under the
allocation 2020-A0070810977 made by GENCI.
Keywords: halofunctionalization • hexafluoroisopropanol • DFT
computations • unactivated alkenes • heterocycles
[1]
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[2]
[3]
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Adv. Synth. Catal. 2009, 351, 2358-2368; b) D. Huang, H. Wang, F. Xue,
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Scheme 7. Free energy profile (G233, kcal/mol) of the bromo-cyclization of N-
tosylaminoalkene A without HFIP or in the presence of a 3-unit HFIP cluster.
reaction is to facilitate the ionization of the N-Br bond of NBS,
notably by stabilizing the resulting succinimidate, and trigger a
cationic cyclization. What is true for NBS might also be true for
the N-bromination of substrates, whose formation may quench
the C-bromination process. Of course, in solution, more HFIP
molecules can be involved but our computations reveal, at least
qualitatively, a positive effect of the formation of a H-bonded NBS
rather than a free NBS in triggering a nucleophile-assisted alkene
bromination.
Conclusion
In summary, we have developed
a
broadly applicable
haloamidation of unactivated alkenes to provide a convenient
route to pyrrolidine and piperidine derivatives, as well as -
lactones. This transformation was efficiently and rapidly promoted
by HFIP as an additive under mild conditions and exhibits a
remarkable functional group tolerance, whether at the nitrogen or
alkene moiety. A key feature of this study is also our in-depth
investigations of the mechanism, including the role played by
HFIP, which was carried-out by means of DFT computations. In
contrast with previous reports, which suggested either the
formation of a haliranium or a N-bromoamide intermediate, our
investigations lean towards an activation of the alkene assisted
by a nitrogen nucleophile in order to trigger the cyclization, which
is in agreement with previous reports on halolactonization.
Further applications of this approach are underway in our
laboratory, including its extension to chlorofunctionalizations.
[4]
Acknowledgements
We gratefully thank the China Scholarship Council (CSC),
the CNRS, the Université Paris-Saclay and the Ecole
Polytechnique for the support of this work. This work was
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Synlett 2004, 18-29; b) I. A. Shuklov, N. V. Dubrovina, A. Börner,
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Amii, RSC Adv. 2015, 5, 17269-17282; d) J. Wencel-Delord, F. Colobert,
6
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made with the M06 and the M06-2X functionals, which resulted in a
reasonable agreement with the OPBE results (see the SI). We also
performed single point calculations using the double hybrid B2PLYP-D3
and mPW2PLYP functionals and the triple  6-311+G(d,p) basis set. The
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[9]
In reference 8a, it was mentioned that using morpholine as an additive
had a positive effect on the selectivity of the reaction. However, in our
case, it had no effect, whether on the diastereoselectivity or the reaction
time.
[10] We also attempted the reaction in the presence of a catalytic amount of
a Lewis acid (Ca(NTf2)2/nBu4NPF6) or a Brønsted acid (TfOH) (5 mol%),
without HFIP. While the reaction worked smoothly (full conversion in less
than one hour), the dr remained inferior (<5.5:1)
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[14] We cannot however exclude that UV irradiation or traces of a transition
metal could generate traces of radical C’’ from C and trigger a radical
chain mechanism through I.
[15] We are aware that intramolecular haloamidations starting from N-halo
precursors are feasible, see inter alia: a) I. A. Schulte-Wulwer, J. Helaja,
R. Gꢀttlich, Synthesis 2003, 1886-1890; b) reference 1f and the
references cited therein.
[16] We cannot exclude that C instead of NBS might function as the
brominating agent on a second molecule of A. To test this hypothesis,
we performed the reaction in the presence of 11. While the target product
was still generated, it was obtained in a lower yield and a modest
selectivity.
[17] L. Turunen, M. Erdélyi, Chem. Soc. Rev. 2020, 49, 2688-2700.
7
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Entry for the Table of Contents
Less but better: The use of hexafluoroisopropanol as an additive enables the halofunctionalization of unactivated alkenes with a
remarkable functional group tolerance under mild reaction conditions. DFT computations were carried out to shed light on the
mechanism of haloamidation featuring as a key step an alkene activation assisted by a nitrogen nucleophile.
Institute and/or researcher Twitter usernames: @djpleboeuf and @vincent_gandon
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