Hydroarylation of Alkenes Using Anilines in Hexafluoroisopropanol

Article abstract of DOI:10.1021/acscatal.0c00872

Providing new methods for the selective functionalization of small molecules is highly desirable, because installing molecular diversity in a desired position, for example, allows one to modulate bioactive molecules. This work reports a method for the selective functionalization of anilines using hexafluoroisopropanol (HFIP) as a solvent to promote an acid-catalyzed hydroarylation of olefins. Mechanistic experiments revealed that HFIP both protonates the alkene and selectively enables anilines toward the electrophilic aromatic substitution. This powerful strategy has been applied to the functionalization of the anti-inflammatory mefenamic acid with chemocontrol and regiocontrol.

Full text of DOI:10.1021/acscatal.0c00872

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Letter
Hydroarylation of Alkenes Using Anilines in HFIP
Ignacio Colomer
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.0c00872 • Publication Date (Web): 05 May 2020
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Page 1 of 8
ACS Catalysis
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Hydroarylation of Alkenes Using Anilines in HFIP
Ignacio Colomer*†‡
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†Department of Organic Chemistry, Universidad Autónoma de Madrid, Francisco Tomás y Valiente, 7, 28049, Spain.
‡ IMDEA Nanociencia, Faraday 9, Campus UAM, 28049 Madrid, Spain.
Supporting Information Placeholder
Electrophilic aromatic substitution, and in particular
Friedel-Crafts alkylation or acylation, is probably one of
the most recurrent tools to derivatise aromatic com-
pounds. While the traditional variants made use of acyl or
alkyl halides as electrophilic partners,2 an alternative
strategy employs alkenes in combination with strong ac-
ids to generate an electrophilic species in situ.3 However,
the use of anilines in Friedel-Crafts reactions proved to be
a challenging topic, as a results of: 1) low compatibility
of the basic amino group and the commonly used Lewis
acid catalysts, resulting in the deactivation of the latter, 2)
poor chemo- and regioselectivity, compared to their meth-
oxy counterparts, for example.4 Pioneering work using
gold catalysts in combination with weakly coordinating
ABSTRACT: Providing new methods for the selective
functionalization of small molecules is highly desirable,
as installing molecular diversity in a desire position al-
lows, for example, to modulate bioactive molecules. This
work reports a method for the selective functionalization
of anilines using HFIP as a solvent to promote an acid-
catalyzed hydroarylation of olefins. Mechanistic experi-
ments revealed that HFIP both protonates the alkene and
selectively enables anilines towards the electrophilic aro-
matic substitution. This powerful strategy has been ap-
plied to the functionalization of the anti-inflammatory
mefenamic acid with chemo- and regiocontrol.
KEYWORDS: Hydroarylation, aniline, alkene, HFIP,
mefenamic acid.
5
BARF salts opened the door for anilines to be used in
Lewis acid-catalyzed Friedel-Craft para-alkylation with
alkenes as electrophilic component (Scheme 1, Previous
work 2014).6 Later on this idea has been exploited using
aryl phosphonium (Scheme 1, Previous work 2015) 7 and
triphenylcarbenium salts (Scheme 1, Previous work
2018) 8 as alternative strong Lewis acids. Despite of being
great contributions, all without exception rely on the same
expensive and elaborated catalysts using weakly coordi-
nating BARF counteranion, with or without expensive
transition metal catalysts.
Bioactive molecules containing the aniline motif in
their chemical structure represent an important and heter-
ogeneous toolbox to target a diverse array of medical is-
sues. The aniline fragment is a ubiquitous structure in the
core of important commercialized drugs, including anaes-
thetic, antidepressant, anticancer or anti-inflammatory
medicines (Figure 1). Developing novel and selective
methods for the functionalization of anilines is highly de-
sirable and will provide a way to expand such a collection
of active molecules.1
Alternatively, Hexafluoroisopropanol (HFIP) has re-
cently emerged as an important solvent with interesting
properties that allows it to promote a unique reactivity.
HFIP is a non-nucleophilic fluorinated alcohol with
strong hydrogen-bond donor properties, establishing a
hydrogen-bond network that is responsible of its exacer-
bated acidity. 9 In this context HFIP has been reported to
Et
N
N
PhO
N
Cl
Ph
O
N
N
O
N
Et
N
N
activate carbonyl compounds,10 epoxides,11 alcohols,12
HO2C
14
halides,13 phenols
and more recently alkynes 15 or al-
Cl
Cl
Fentanyl
(opioid)
Nefazodone
(antidepressant)
kenes,16 however the latter are still underexplored.
Chlorambucil
(chronic lymphocytic leukemia,
Hodgkin and non-Hodgkin lymphoma)
This work reports a new strategy for the selective func-
tionalization of anilines with alkenes, using a very simple,
cheap and atom-economic catalytic system, where HFIP
plays the dual role of strong acid reacting with the olefin
but also enhancing the reactivity of the aniline (Scheme
1, this work).
O
Et
NH2
Me
CO2H
H
N
HN
Et
Me
O
N
Me
Me
HN
O
O
Lenalidomide
Mefenamic acid
(Nonsteroidal
anti-inflammatory)
Lidocaine
(local anaesthetic)
(multiple myeloma and
myelodysplastic syndromes)
Figure 1. Bioactive molecules containing the aniline structure.
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ACS Catalysis
Page 2 of 8
7 c
8 c
9 c
25 mol% NaOAc
25 mol% NaOAc
25 mol% NaOAc
TFE
AcOH
TFA
80 °C
80 °C
80 °C
0
traces
0
Scheme 1. Hydroarylation of alkenes using anilines
R1
R2
1
2
3
4
5
6
7
8
R2
R1
N
N
R3
R4
Catalyst
+
R3
R4
a
b
Me
NMR yield using 1,3,5-trimethoxybenzene as standard. 1.0 equivalent
c
H
Previous work
F
of alkene 2a was used. 2.0 equivalent of alkene 2a was used.
high temperatures
limited scope
x
With those optimal conditions in hand, the scope of the
reaction was then evaluated. With respect to the aniline
component, substitution on the nitrogen is well tolerated.
Among the model substrate with a methyl substituent
(Figure 2, 3a), other aliphatic mono-substituted examples
include benzylic, allylic or derivatives containing extra
functional groups (Figure 2, 3b, 3c and 3d). Aromatic
substitution is also viable, exclusively reacting via the ar-
omatic ring with the unsubstituted para position (Figure
2, 3e). Disubstituted anilines perform well in the reaction
and both acyclic and heterocyclic piperazine derivative
afforded the expected products (Figure 2, 3f and 3g). Fi-
nally, the challenging free aniline can be selectively al-
kylated, increasing the loading of NaOAc, to achieve a
respectable 60% isolated yield (Figure 2, 3h).
F
F
x
x
x
R
B
F
9
expensive catalysts
F
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poor regioisomeric ratios (ortho:para, C- vs. N-)
4
BARF
F
F
Me
Ph
Ph
K
+
N
N
Me
F
P
R
=
Ph
F
Me
2014
F
F
4
AuCl
2018
2015
This work
broad scope and functional group tolerance
simple and cheap: no need of elaborated catalyst
excellent chemo- and regioselectivity
mechanistic studies
√
√
√
√
√
OH
F3C
CF3
HFIP
NaOAc (cat.)
80 °C
The aromatic ring of the aniline can be extensively
modified and both ortho and meta positions have been in-
terrogated. Concerning the ortho position methyl, ethyl or
benzyl substituents are competent substrates (Figure 2, 3i,
3j and 3k), while aromatic substitution affords a beautiful
biphenyl derivate (Figure 2, 3l). Electron donating het-
eroatoms can be easily incorporated, for example, both
methoxy and hydroxy groups give the expected product
in excellent yields and exquisite para regiocontrol (Fig-
ure 2, 3m and 3n). Another interesting example of an
electron-rich hetero-substitution is the product of reacting
ortho-phenylenediamine where the monoalkylation is
achieved in high yields (Figure 2, 3o). Electron-with-
drawing substituents, such as halides performed ex-
tremely well, and both fluorine and chlorine derivatives
are formed in high yields (Figure 2, 3p and 3q). Unfortu-
nately, aldehyde and ester derivatives do not react (prob-
ably because HFIP interacts with the carbonyl moieties
and deactivate the aromatic ring). However, a carboxylic
acid is well tolerated and the product of reacting an-
thranilic acid is isolated in a respectable 69% (Figure 2,
3r). The meta position of the aromatic ring was investi-
gated in a similar manner and some representative exam-
ples illustrate the versatile scope. Both aliphatic and elec-
tron rich heteroatoms can be accommodated, albeit in
slightly diminished yield (Figure 2, 3s and 3t). Electron
deficient halides provide from excellent to good yields
starting from fluoro and moving to chloro or bromo sub-
stitution (Figure 2, 3u, 3v and 3w). In view of these re-
sults, where fluoro-containing example behaves ex-
tremely well and the productivity of methyl derivative is
compromised, it is sensible to state that the limitation in
the meta position might well be related to steric factors
rather than electronics. Not only does monosubstitution
works, but substrates bearing several substituents in
late stage drug functionalization
The study began using equimolecular amounts of ani-
line 1a and alkene 2a in HFIP at room temperature, with
a 14% yield of the hydroarylation product 3a (Table 1,
entry 1). Increasing the temperature to 40 °C or 60 °C had
little benefit, while using 80 °C doubled the yield up to
29% (Table 1, entries 2-4). Using excess of alkene (2.0
equivalents of 2a) has a positive effect with a 41% yield
(Table 1, entry 5). Finally, the use of additives (see sup-
porting information for further details) revealed that sub-
stochiometric amount of sodium acetate has a notably ef-
fect in the outcome of the reaction with an 81% yield (Ta-
ble 1, entry 6). The important effect of the solvent was
demonstrated using other acidic solvents, such as trifluo-
roethanol, acetic acid or trifluoroacetic acid providing no
satisfactory results in the hydroarylation reaction (Table
1, entries 7-9).
Table 1. Screening of conditions.
NHMe
NHMe
Additive
Ph
+
Solvent
Me
Ph
Temperature
Me
H
Me
1a
2a
3a
Entry
1b
Additive
Solvent
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
Temperature
25 °C
3a yield (%)a
-
14
19
25
29
41
81
2 b
3 b
4 b
5 c
-
40 °C
-
60 °C
-
80 °C
-
80 °C
6 c
25 mol% NaOAc
80 °C
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ACS Catalysis
different combinations complete the scope. Substituting
both ortho positions either with aliphatic substituents
(Figure 2, 3x) or with an aliphatic and a halide (Figure 2,
3y) gives very good results. Simultaneous ortho and meta
substitution is well tolerated, even in the bicyclic 1-ami-
nonaphthalene (Figure 2, 3z and 3aa).
thiophene derivative is isolated in 93% yield (Figure 2,
3af). Two aromatic rings can be incorporated and inter-
esting triarylmethane can be easily accessed (Figure 2,
3ag). Cyclic alkenes are viable substrates and tetrahy-
dronaphthyl derivative gives the expected product (Fig-
ure 2, 3ah). Lastly, trans-anethole, a 1,2-disubstituted al-
kene, can engage in the reaction, thus expanding the sub-
strate scope with an example that does not contain an all-
carbon quaternary centre (Figure 2, 3ai). While para-
methoxystyrene also works, styrene gives traces of the
product and other aliphatic alkenes, including 1-hexene,
3-hexene, 1-methylcyclohexene, 1-methylcyclopentene
or an internal cyclobutene, did not provide the desired
product, recovering the alkene starting material.
1
2
3
4
5
6
7
8
Finally, the alkene component was studied modifying
the model 1,1-disubstituted alkene, a-methylstyrene.
Both lineal, branched and cyclic aliphatic substitution is
well tolerated with excellent results (Figure 2, 3ab, 3ac
and 3ad). The aromatic ring tolerates functional groups
that can be used as a handle for further diversification, for
example an iodide in cross-coupling reactions (Figure 2,
3ae). Aromatic heterocycles can be accommodated and
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R1
R2
R1
R2
N
N
NaOAc
R4
R5
R6
R3
R6
R3
+
HFIP
R4
R5
80 °C, 12 h
H
1
H
2
3
H
N
N-substitution
OH
Me
Me
Me
OH
NHMe
NHBn
HN
HN
N
N
NH2
HN
Ph
Ph
Ph
Me
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
3h (60%)[a]
3g (62%)
3f (84%)
3e (84%)
3a (81%)
3c (80%)
3d (77%)
3b (98%)
ortho-substituted
meta-substituted
NHMe
Me
NH2
NH2
NH2
NH2
NHMe
NHMe
OMe
Et
Ph
Me
Me
OMe
Me
Ph
Ph
Me
Ph
Me
Ph
Me
Ph
Ph
Ph
Me
3k (72%)[a]
Me
Me
Me
Me
Me
Me
Me
Me
3j (79%)[a]
3l (70%)[a]
3t (61%)
3i (85%)
3m (81%)[a]
3s (64%)
NHMe
NHMe
NHMe
NH2
NH2
OH
NHMe
Cl
NH2
NHMe
CO2H
NH2
F
F
Cl
Me
Br
Me
Ph
Ph
Me
Ph
Ph
Me
3r (69%)[a]
Ph
Ph
Me
3q (90%)
Ph
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
3w (48%)
3v (54%)
3n (78%)[a]
3u (86%)
3o (71%)[a]
3p (81%)
alkene substitution
highly-substituted
NHMe
NHMe
NHMe
NHMe
NH2
NH2
Me
Cl
i-Pr
i-Pr
I
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
3y (79%)[a]
3x (71%)[a]
3ac (75%)
3ab (83%)
3ad (90%)
3ae (87%)
NHMe
NHMe
NHMe
NHMe
NH2
NH2
Me
F
Me
Ph
Ph
Me
3aa (65%)[a]
Ph
Me
3z (54%)[a]
Me
S
Me
Me
Me
Ph
Me
MeO
3ai (74%)
3af (93%)
3ag (72%)
3ah (69%)
General conditions: 0.2 mmol of aniline 1, 0.4 mmol of alkene 2 and 0.05 mmol of NaOAc in 1.0 mL of HFIP. [a] 1.0 equivalent of NaOAc was used.
Figure 2. Scope of the hydroarylation of alkenes using anilines in HFIP.
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ACS Catalysis
It is important to emphasize that in all cases an exquis-
ite C- (vs. N-) and para (vs. ortho) regiocontrol was ob-
served, a challenging limitation commonly stated in the
literature.17
Page 4 of 8
positions (see supporting information). Reacting anilines
1a or 1x with 1,2-disubstituted alkene 2i results in the
same deuterium labelling pattern (full D-incorporation in
the olefin carbon and high D-exchange in the ortho posi-
tions) and high anti/syn diastereoselection (Figure 3a,
3ai-D3 and 3an-D).18 A striking behaviour observed dur-
ing the scope evaluation is the total para selectivity in fa-
vour of the amino vs. the methoxy group (Figure 2, 3m
and 3t). In a competition experiment using equimolecular
amounts of aniline 1a and the exceptionally good Friedel-
Crafts substrate trimethoxybenzene 4,19 the hydroaryla-
tion product 3a is exclusively formed (Figure 3b), rein-
forcing the selective activation of anilines using
NaOAc/HFIP.
1
2
3
4
5
6
7
8
With the aim of fully understanding the role of HFIP
mechanistic experiments were designed to shed light into
this effective transformation. Using deuterated HFIP-OD,
the model aniline 1a and terminal alkene 2a, full incorpo-
ration of deuterium on the olefinic carbon confirms the
protonation of the alkene by the solvent HFIP. Moreover,
the ortho positions of the aniline suffer a high degree of
deuterium exchange (Figure 3a, 3a-D3) and treating ani-
line 1a with NaOAc in HFIP-OD (with no added alkene)
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12
13
14
15
16
17
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22
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ratifies this H-D exchange in both ortho and para
a) Deuterium labeling experiments
Me
Me
Ph
NHMe
NHR2
R1
NHMe
NH2
D
80%
D
80%
R1
NHMe
D
D
PMP
i-Pr
i-Pr
PMP
2i
2i
Me
80%
2a
80%
NaOAc
HFIP-OD
NaOAc
HFIP-OD
80 °C
d.r. = 80:20
Me
d.r. = 80:20
H
NaOAc
Ph
Me
C
H
Me
HFIP-OD
80 °C
80 °C
PMP
PMP
D (>99%)
1a (R1 = H; R2 = Me)
1x (R1 = i-Pr; R2 = H)
D (>99%)
3ai-D3 (from 1a)
D (>99%)
3an-D (from 1x)
1a
3a-D3
b) Competition experiments
Ph
4
F3C
F3C
3
2
1
OMe
3
2
NHMe
NHMe
OMe
4.0 equiv.
H
Me
H
δ+
2a
+
O
Me
Me
N
25 mol% NaOAc
MeO
OMe
Me
H
H
MeO
OMe
H
Ph
O
δ−
O
Ph
HFIP
O
Me
CF3
CF3
CF3
CF3
Me
12 h, 80 °C
Me
δ+
N
1a
4
H
3a
Not observed
1´
H
(1.0 equiv.)
(1.0 equiv.)
O
Proposed H-bonded
structure
1´´
2´´
3´´
c) NMR experiments
4´´
1H-1H NOESY-2D (400 MHz, CDCl3, recorded at 25 ºC)
1H NMR (400 MHz, CDCl3 with TMS, recorded at 25 ºC)
1a
(1.0 equiv.)
+
+
2a
(1.0 equiv.)
Bu4NOAc
(1.0 equiv.)
+
HFIP
(10.0 equiv.)
11..00
1a
(1.0 equiv.)
11..55
3
2
1
+
2a
(1.0 equiv.)
22..00
22..55
+
1a
(1.0 equiv.)
Bu4NOAc
(1.0 equiv.)
33..00
+
+
33..55
2a
(1.0 equiv.)
HFIP
(10.0 equiv.)
44..00
+
Bu4NOAc
(1.0 equiv.)
44..55
55..00
55..55
66..00
HFIP
66..55
77..00
77..55
7
7
.
.
5
5
7
7
.
.
0
0
6
6
.
.
5
5
6
6
.
.
0
0
5
5
.
.
5
5
5
5
.
.
0
0
4
4
.
.
55 44
ff22 ((ppppmm))
.
.
0
0
3
3
.
.
5
5
3
3
.
.
0
0
2
2
.
.
5
5
2
2
.
.
0
0
1
1
.
.
5
5
11..00
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
f1 (ppm)
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
d) Proposed reaction pathway
Me
Ph
H
Ph
Ph
H
NHMe
F3C
NHMe
H
Me
F3C
H
Me
2a
NHMe
H
δ+
O
H
δ+
N
Me
N
Bu4NOAc
OH
Ph
H
H
Me
H
H
Ph
δ−
O
O
Me
O
Me
H
Me
H
Me
CF3
CF3
CF3
CF3
O
O
Me
O
1a
δ+
N
or
CF3
CF3
O
H
H
F3C
CF3
O
Me
CF3
CF3
3a
H
HFIP
Figure 3. Mechanistic experiments.
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ACS Catalysis
In order to elucidate the potential interactions between
process is also required. Slightly modifying the general
conditions, lowering the temperature to 60 °C to prevent
decarboxylation observed at 80 °C,25 results in a remark-
ably highly selective and productive functionalization of
mefenamic acid. Four different alkenes from the scope
above were used to illustrate the viability of the process,
introducing the model dimethylbenzyl structure (Scheme
2, 3aj) but also diverse chemical motifs, such as a cyclo-
hexyl (Scheme 2, 3ak), an aryl iodide, that could poten-
tially be further functionalized (Scheme 2, 3al) or the het-
eroaromatic thiophene (Scheme 2, 3am).
1
the base (NaOAc), the aniline and HFIP, a set of NMR
experiments were designed, with CDCl3 as the supporting
solvent for its neutral behavior with respect to any inter-
actions between species, TMS was added as a reference
and Bu4NOAc (that also catalyzes the reaction, see sup-
porting information, additive screening) was used instead
of NaOAc for its better solubility in CDCl3. First the 1H-
NMR of individual species (HFIP, 1a, 2a and Bu4NOAc)
and binary mixtures of HFIP and every single species (1a,
2a and Bu4NOAc) were recorded (see supporting infor-
mation). This was followed by the 1H-NMR of all species
mixed together (1a, 2a and Bu4NOAc) with and without
HFIP (Figure 3c, left) where an upfield shift of the acetate
(Figure 3c left, pink) and a downfield shift of the aniline
(Figure 3c left, red) and HFIP (Figure 3c left, green) sig-
nals is clearly observed. Finally, both 1D-nOe (see sup-
porting information) and 2D-NOESY (Figure 3c right)
experiments revealed a strong spatial connection between
both the CH and OH of HFIP with the aniline and the ac-
etate signals (Figure 3c right, red and pink boxes respec-
tively and see supporting information for further details).
Taken together these results support the hydrogen-bond-
ing between the exceptionally acidic OH of the HFIP net-
work 20 and both the aniline and the acetate.21
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Scheme 2. Mefenamic acid selective derivatization.
CO2H
Me
H
N
Me
Me
Me
3aj (72%)
Ph
CO2H
Me
H
N
Me
2a
Me
Ph
2d
3ak (64%)
Me
CO2H
H
N
Me
2e
CO2H
Me
Mefenamic acid
H
N
Me
The overall reaction pathway would be in agreement
with an electrophilic aromatic substitution mechanism
(Figure 3d).22 While the alkene is protonated by HFIP,
producing a stabilized carbocationic intermediate, the
amino group of the aniline becomes “protected” via H-
bonding to HFIP. Therefore the aniline reacts selectively
with the electrophilic species via the aromatic ring (C- vs.
N-), generating a Wheland-type intermediate, what is
thought to be the rate determining step.22f Proton abstrac-
tion to rearomatize the aniline is achieved either by the
conjugated base of the proton source, or by the added base
(acetate) in a more productive manner, affording the ob-
served product.
Me
Me
2h
3al (62%)
CO2H
Me
Me
H
N
Ι
Me
Me
3am (71%)
S
General conditions: 0.2 mmol of mefenamic acid, 0.4 mmol of alkene 2
and 0.05 mmol of NaOAc in 1.0 mL of HFIP, 12 h, 60 °C.
In summary a new protocol for the hydroarylation of
alkenes using anilines has been developed, that entails the
use of HFIP as a unique solvent to promote the reaction.
Mechanistic experiments revealed that the acidic nature
of HFIP both serves to protonate the alkene and to pro-
mote the selective reaction of the aniline via hydrogen
bonding. The application of this new method has been
found in the selective functionalization of the anti-inflam-
matory drug mefenamic acid.
To illustrate the application of this method in the selec-
tive functionalization of bioactive molecules the anti-in-
flammatory mefenamic acid, also evaluated against Alz-
heimer’s disease with promising results, was used as a tar-
get.23 Efforts to build a library of derivatives from
mefenamic acid have previously used either the alkyla-
tion or acylation of the amino group and the amidation of
the carboxylic acid as diversity points. This simple strat-
egy has produced analogues of the parent compound
where the bioactivity was compromised, meaning that
both the amino and the carboxylic acid are essential to
preserve the active function.24 Selective modification of
the aromatic rings introducing molecular diversity would
open the door for a new family of derivatives. Mefenamic
acid is a particularly challenging example that exceeds the
scope presented above, where the amine shares two dis-
tinct aromatic groups, each one bearing different substit-
uents, both of them potentially reactive towards the hy-
droarylation process described. Thus a chemoselective
ASSOCIATED CONTENT
Supporting Information.
The Supporting Information is available free of charge on
the ACS Publications website.
Experimental procedures and characterization data of all
new compounds, including NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: ignacio.colomer@uam.es
Notes
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Page 6 of 8
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Promoters for the Metal-Free Direct Substitution Reaction of Allylic
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Friedel–Crafts Reaction of Benzyl Fluorides: Selective Activation of
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ACKNOWLEDGMENT
The project that gave rise to these results received the sup-
port of a Juan de la Cierva fellowship from the Spanish Min-
istry of Science (IJCI-2016-27405). The author also receives
founding from La Caixa foundation under the Junior Leader
program (LCF/BQ/PI19/11690020, ID 100010434). Prof.
Mariola Tortosa is acknowledged for her support.
9
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A new method for the selective functionalization of anilines with olefins using HFIP as a unique solvent to promote the reaction
has been developed. This new protocol involves cheap, mild and atom-economic conditions, where HFIP plays a double role
as strong acid protonating the alkene and activating the aniline towards the hydroarylation. This powerful method has been
applied in the selective derivatization of the anti-inflammatory mefenamic acid.
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R1
R1
R2
R2
N
N
R3
R4
R5
NaOAc (cat.)
+
HFIP
80 °C
R5
R3
R4
H
> 40 examples
H
9
broad scope and functional group tolerance
√
√
√
√
√
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simple and cheap: no need of elaborated catalyst
excellent chemo- and regioselectivity
mechanistic studies
drug functionalization
8
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