Complementary Site-Selective Halogenation of Nitrogen-Containing (Hetero)Aromatics with Superacids

Article abstract of DOI:10.1002/chem.202000902

Site-selective functionalization of arenes that is complementary to classical aromatic substitution reactions remains a long-standing quest in organic synthesis. Exploiting the generation of halenium ion through oxidative process and the protonation of the nitrogen containing function in HF/SbF₅, the chlorination and iodination of classically inert Csp²?H bonds of aromatic amines occurs. Furthermore, the superacid-promoted (poly)protonation of the molecules acts as a protection, favoring the late-stage selective halogenation of natural alkaloids and active pharmaceutical ingredients.

Full text of DOI:10.1002/chem.202000902

A Journal of
Accepted Article
Title: Complementary Site-Selective Halogenation of Nitrogen-
Containing (Hetero)Aromatics with Superacids
Authors: Alexander Mamontov, Agnès Martin-Mingot, Benoit Métayer,
Omar Karam, Fabien Zunino, Fodil Bouazza, and Sebastien
Thibaudeau
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To be cited as: Chem. Eur. J. 10.1002/chem.202000902
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Complementary Site-Selective Halogenation of Nitrogen-
Containing (Hetero)Aromatics with Superacids
Alexander Mamontov, [a,b] Agnès Martin-Mingot, [a] Benoit Métayer, [a,b] Omar Karam, [b] Fabien Zunino, [b]
Fodil Bouazza,* [b] Sébastien Thibaudeau*[a]
[a]
[b]
Dr. A. Mamontov, Dr. A. Martin-Mingot, Prof. S. Thibaudeau
Université de Poitiers, UMR-CNRS 7285, IC2MP, Superacid Group – Organic Synthesis Team, 4 rue Michel Brunet, TSA 51106, 86073 Poitiers Cedex 9,
France.E-mail : sebastien.thibaudeau@univ-poitiers.fr
Dr. B. Métayer, Dr. O. Karam, Dr. F. Zunino, Dr. F. Bouazza
@rtMolecule, 1 rue Georges Bonnet, Bâtiment B37, 86000 Poitiers, France
Supporting information for this article is given via a link at the end of the document.
Abstract: Site-selective functionalization of arenes that is
complementary to classical aromatic substitution reactions remains a
long-standing quest in organic synthesis. Exploiting the generation of
halenium ion through oxidative process and the protonation of the
nitrogen containing function in HF/SbF5, the chlorination and
iodination of classically inert Csp2-H bonds of aromatic amines occurs.
Furthermore, the superacid-promoted (poly)protonation of the
molecules acts as a protection, favoring the late-stage selective
halogenation of natural alkaloids and active pharmaceutical
ingredients
stoichiometric amount of Br2 suggesting that the in situ generated
HBr must be oxidized in solution to generate the reactive
bromenium ion, as already postulated by Sommer. [17] Here, we
disclose the non-innate selective chlorination and iodination of
aromatic amines (Figure 1D).
A)
®
®
The strategic role of organic synthesis is critical to the successful
discovery and development of new drugs.[1] Consequently,
synthetic methods able to afford new collections of bioactive
diverse molecules are awaited.[2] In this context, reaching
molecular sites that are not accessible by conventional methods
would overcome the prominence of innate electrophilic aromatic
halogenation.[3] The role of halogen-substituted arenes in drug
discovery[4] has tremendously increased over the past years
encouraging the development of new methods for their
transformation (Figure 1A) [5] Accordingly, it is somehow puzzling
that late-stage halogenation of elaborated nitrogen-containing
aromatics remains challenging.[6] Sandmeyer reaction is a classic
approach but it requires the pre-functionalization of the arenes.[7]
X2 and N-X reagents are also commonly used, but they can be
too reactive, unselective or, conversely, unreactive requiring the
presence of strong electron-donating groups or the use of an
appropriate activator.[8] Metal-catalyzed halogenations are also
well-established methods,[9] but need a pre-installed directing
group to control the regioselectivity of the halogenation. As for
electrophilic halogenation with N-X reagents, the halogenation
with polyhalogen salts[10] also takes place at innate aromatic
positions and oxidative halogenations[11] show the same limitation
(Figure 1B).[12] Alternatively, the use of halogenase enzymes[13] is
hold back due to selectivity difficulties and substrate-dependent
specificity.[14] In superacid, Jacquesy reported the bromination of
aniline in the presence of Br2 (Figure 1C).[15] Despite a poor
selectivity, the superacid-promoted electrophilic bromination of
aniline led partially to the formation of the 3-bromoaniline. This
suggests that the persistent protonation of the aniline in
superacid[16] partially modified the selectivity of the electrophilic
addition. Furthermore, the reaction needed only sub-
®
®
B)
C)
D)
Figure 1. A) Halogenated active pharmaceutical ingredients; B) Recently
reported electrophilic halogenation of aromatic amine derivatives on native
reactive sites; C) Reported unselective bromination of aniline with Br2 in
superacid; D) This work.
The strategy relies on the continuous formation of the halenium
ion by superacid oxidation of halide salts and on the modification
1
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of the functional group directing effect by protonation in superacid.
Moreover, the protection of the molecules by polyprotonation in
superacid[18] is applied to selectively halogenate natural products
and active pharmaceutical ingredients.
At the outset, 4-methylacetanilide 1a was selected as a
model substrate and submitted to superacid in the presence of
halide ion sources. No reaction occurred with sodium chloride in
neat HF or CF3SO3H in the absence of oxidant (Table 1, entries
1-3). Addition of the strong oxidant oxone in CF3SO3H led to the
formation of a complex mixture of compounds, including the
formation of polar hydroxylated products and of traces of 3-
methylacetanilide after isomerization of the starting material
(Table 1, entry 4).
The scope and functional group tolerance of this
transformation was next evaluated (Figure 2). The bromination
which seemed rather prone to favor polyhalogenation was not
further evaluated. Acetanilide 1b yielded products 2bX in good
yields using an excess of NaX. Gratifyingly, 4-halogeno
acetanilides 1c-1e were selectively chlorinated and iodinated in
position 3. While standard electrophilic aromatic halogenation of
4-halogen- or 4-alkyl-substituted aniline derivatives furnish their
2-halogenated analogue (Figure 1B), the 3-position is attained by
the
superacid-promoted
strategy.
Noteworthy,
4-
bromoacetanilide 1e led to chlorinated and iodinated products
that are classically difficult to be obtained by standard procedures.
Trifluoromethylated acetanilide 1f was efficiently converted to
products 2fCl and 2fI. To expand the reaction scope beyond, 3-
substituted acetanilides (1g-1k) were also submitted to the
halogenation protocol. Halogenation occurred in position 4 from
3-methyl-acetanilide 1g in good yields. Surprisingly, while the
chlorination of 3-fluoro 1h and 3-chloroacetanilide 1i occurred
predominantly in position 6, the iodination of the same substrate
1i led to the formation of the 4-iodinated product 2iI, a position
also chlorinated after reaction of brominated substrate 1j. A
difference of behaviour between chlorination and iodination was
also observed from 3-trifluoromethylated acetanilide 1k. The
iodination occurred in position 5 from this substrate when
chlorination occurred in position 4, this regioselectivity coming
probably from steric hindrance effect of the CF3 group. To our
delight, as expected, the halogenation of 2-alkyl and 2-halogeno-
substituted acetanilides occurred regioselectively at the non-
native position 5 of the aromatic ring (2lX-2oX), when classically
encountered halogenation from these substrates occurs in
position 4 (Figure 1B). From the trifluoromethylated substrate 1p,
the halogenation occurs in position 4. The nitro-substituted
acetanilide 1q was less reactive and deprotected chlorinated
amine 3 was obtained in poor yield after 48 hours reaction. The
iodinated tertiary amide 2rI and the non-protected aniline 5 could
also be directly synthesized from 1r and 4-methylaniline 4. The
formation of the iodinated product 2sI from the protected diamine
1s and of the 4-chloro-4-iodobenzene 7 from chlorobenzene 6
confirmed the extended scope of the method. The selectivity of
the method over competing α-halogenation of carbonyl function[19]
was also proved by the formation of product 9 from oxindole 8. To
summarize, this scope and limitation study revealed that in
superacid solutions, in which neutral acetamide function must be
in equilibrium with its protonated form, halogen atom(s) and alkyl
group(s) orientate the electrophilic addition (halogenation in
position 3 for substrates bearing alkyl or halogens in position 4 /
halogenation in position 5 for substrates bearing alkyl or halogens
in position 2). When no substituent is present, or from acetanilide
bearing a strong electronwithdrawing group (in 2- and 4-
trifluoromethyl acetanilides), the amide seems to orientate the
reaction. When acetanilide is substituted in position 3 with
halogen or trifluoromethyl groups, the regioselectivity is strongly
dependent on the nature of the inserted halogen and on the
electronic (and steric) repulsion between the inserted atom and
the ones already located on the ring.
Table 1. Halogenation of 4-methylacetanilide 1a in the presence of halide ion
source in superacid.
Entry
1
X- source
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
NaCl
NH4Cl
NaBr
NaI
Superacid
Conva Yield (%)b
c
CF3SO3H
/
2d
3
c
CF3SO3H
/
c
HF
/
CF3SO3He
/
f
4
5g
6g
7g
8
HF/SbF5 (7/1) h
HF/SbF5 (3/1) h
HF/SbF5 (2/1) h
HF/SbF5 (2/1) h
HF/SbF5 (2/1) h
HF/SbF5 (2/1) h
HF/SbF5 (2/1) h
HF/SbF5 (2/1) h
17
48
64
100 (78)
100 (76)
87 (72)i
90 (62)
9
10
11
12
j
NaF
/
[a] Conversion of 1a determined by crude mixture NMR analysis; [b] Yield after
purification by flash-chromatography; [c] No reaction; [d] Ambient temperature /
3 days; [e] Reaction conducted in the presence of 1.2 equiv. of oxone; [f]
Complex mixture; [g] 15 min. reaction time; [h] HF/SbF5 volumetric ratio /
substrate concentration in this solution is 0.75 mol.L-1; [i] Traces of
a
dibrominated product could be observed in the crude product. [j] No traces of
fluorinated products by 19F NMR analysis of the crude product.
Gratifyingly, the chlorinated product 2aCl was generated in
HF/SbF5 solutions, and increasing SbF5 amount favored the
reaction to fully convert 1a to 2aCl (Table 1, entries 5-8). No
significant impact of the counter cation was observed when
performing the reaction in the presence of ammonium chloride
(Table 1, entry 9). Under the same reaction conditions, the
brominated and iodinated analogues 2aBr and 2aI were
respectively obtained in 72% and 62% yield by performing the
reaction in the presence of NaBr and NaI, the reaction with NaBr
being less selective (Table 1, entries 10-11). As expected, no
fluorinated product was generated from 1a in the presence of NaF
(Table 1, entry 12).
2
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Figure 2. Chlorination and iodination of aromatics in superacid.
[a] 3.5 equiv. of NaX was used in the indicated cases; [b] Activation at room temperature was needed in some indicated cases; [c] Yield obtained after purification
by flash chromatography; [d] Products from polyhalogenation were concomitantly generated; [e] Undetermined side products formation; [f] Conversion determined
by 1H NMR analysis of the crude product; [g] Generated in a 92/8 ratio with its 2-iodoisomer; [h] yield of the major isomer obtained after purification.
3
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The following mechanism can be proposed to account for the polyiodination, monoiodinated product 2bI behaviour in superacid
halogenation reaction (Figure 3A). Ions A are obtained after solutions was evaluated by in situ low-temperature NMR
acetanilides protonation.[20] A beneficial effect of SbF5 amount on spectroscopy (see SI). The ion A2bI resulting from the O-protonation
reaction efficiency was demonstrated (Table 1, entries 3-6). This of the amide function was first generated (Figure 3C). A
can be directly correlated to the fact that when the concentration of diprotonated species A’2bI was also detected after few minutes and
SbF5 in HF is higher than 20 mol%, increasing amounts of non- gradually increased in solution over time. It must result from a
associated SbF5 appears.[21] Moreover, it is important to note that subsequent protonation of the iodine atom, evidenced by the
the chlorination of the substrates often requires longer reaction time deshielding of the C4 carbon atom at 109.9 ppm (+ 11.5 ppm
and excess of NaCl compared to the iodination process. This compared to ion A2b ).[24] This result accounts for the protonation of
I
difference of behavior was confirmed by comparing the reactivity of the inserted halogen, protecting the substrate from any undesired
some selected acetanilides in the presence of NaX after a short further halogenation. Under these highly acidic conditions, the
reaction time (Figure 3B). While slow chlorination occurs, the formation of the thermodynamically most stable product could have
iodination was quickly performed from the same substrates. These been hypothesized to explain the regioselectivity of the process.[25]
results follow a general trend in accordance with the redox The thermodynamically directed isomerization of products can only
properties of halogens and halide ions. Thus, as previously be explained by intramolecular isomerization within an arenium ion
demonstrated,[22] SbF5 act as an oxidant in HF/SbF5 solutions and intermediate. However, as shown for the halogenation of non-
oxidise chloride and iodide ions to generate elemental halogen in substituted acetanilide 1b, chlorination and iodination leads only to
solution.[23] This was confirmed by evidencing the formation of SbI3 the para product 2bX, and even after prolonged reaction time, no
and I2 by X-ray diffraction analysis of the crude powder collected product halogenated in meta position could be detected in the
after reaction of NaI in HF/SbF5 (see SI). The generated halenium crude (also confirmed by low-temperature NMR (Figure 3C). It
ion can then react with ion A to generate the intermediate B, suggests the absence of thermodynamically directed isomerization
precursor of products 2. To further understand the absence of of the iodinated product after reaction in the reaction conditions.[26]
Figure 3 A) Postulated superacid-promoted halogenation reaction mechanism; B) Comparison of the reactivity of selected acetanilides toward chlorination and
iodination after 20 minutes of reaction at -20 °C; C) 1H and 13C NMR spectrum of the superacid HF/SbF5 solution of compound 2bI at -20 °C.
in situ 1H NMR at -20 °C
A)
C)
t = 15 min
A2bI
A’2bI
t = 0 min
B)
in situ 13C NMR at -20 °C
t = 60 min
A2bI
A’2bI
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The generality of the proposed superacid-promoted
halogenation method for more complex nitrogen containing
derivatives, such as those that might be encountered in
pharmaceutical or agrochemical research, needed to be
assessed. Generating analogues of bioactive natural products
and/or active pharmaceutical ingredients through direct
functionalization of unactivated bonds is now considered as a
standard method in the medicinal chemist’s toolbox.[27] Thus, we
first investigated the late stage halogenation of lidocaïne 11a and
anticancer agent dasatinib 11b (Figure 4).
isomers could be detected in the reaction crude. One step further
in complexity, and consequently rising up the challenge for clean
and direct functionalization, the halogenation of the Pausinystalia
Yohimbe alkaloid 10g was tested. The iodination was shown to
be effective and led to the formation of 10- and 11-iodoyohimbine.
The former 11gI predominating as the major isomer could be
cleanly separated from its minor regioisomer. To our delight,
these data demonstrate that the method provides rapid and
efficient
access
to
analogues
of
indole-containing
pharmaceutically interesting compounds that could not be
generated by conventional methods or at the expense of
troublesome multi-step synthetic sequence.
To conclude, exploiting the unique chemical properties of
superacid, namely its oxidative properties and its capability to
polyprotonate
compounds,
a
site-selective
non-innate
halogenation of nitrogen-containing compounds has been
developed. Given tremendous momentum in the field of late stage
CH functionalization, this method proved its efficiency for the
direct halogenation of (poly)functionalized natural alkaloids and
active pharmaceutical ingredients, thereby offering a distinct
approach to control site-selectivity. This strategy can now be
considered as a new development in the field of chemical and
pharmaceutical industries. By protecting the molecules by
protonation, it opens perspectives to directly modify bioactive
compounds at any stage of a synthetic plan.
Acknowledgements
A. Mamontov thanks ANRT and @rtMolecule society for a PhD
grant. A. Mamontov, B. Métayer, A. Martin-Mingot, S. Thibaudeau
thank the University of Poitiers and the French CNRS. The
authors acknowledge financial support from the European Union
(ERDF) and "Région Nouvelle Aquitaine" (SUPERDIV project-
HABISAN program). The authors also thank the French fluorine
network (GIS-FLUOR).
Keywords: Late-stage • halogenation • diversity • reaction
mechanism • active pharmaceutical ingredients
Figure 4. Direct halogenation of bioactive pharmaceutical ingredients and
natural products.
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10.1002/chem.202000902
Chemistry - A European Journal
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Entry for the Table of Contents
Classical conditions
lidocaïne
analogue
X+
Superacid
halogenation
with NaX
vinburnine
analogue
Complementary site-selective halogenation of nitrogen containing arenes has been developed in superacid HF/SbF5 in the presence
of halide salts. By protecting the molecules by protonation, this method can also be applied to the late-stage selective halogenation of
natural alkaloids and active pharmaceutical ingredients
7
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