Regioselective hydroarylation reactions of C3 electrophilic N-acetylindoles activated by FeCl3: An entry to 3-(Hetero)arylindolines

Article abstract of DOI:10.1002/chem.201400284

A method for the direct and rare umpolung of the 3 position of indoles is reported. The activation of N-acetylindole with iron(III) chloride allows the C-H addition of aromatic and heteroaromatic substrates to the C2-C3 double bond of the indole nucleus to generate a quaternary center at C3 and leads regioselectively to 3-arylindolines. Optimization, scope (50 examples), practicability (gram scale, air atmosphere, room temperature), and mechanistic insights of this process are presented. Synthetic transformations of the indoline products into drug-like compounds are also described.

Full text of DOI:10.1002/chem.201400284

DOI: 10.1002/chem.201400284
Full Paper
&
Indoles
Regioselective Hydroarylation Reactions of C3 Electrophilic
N-Acetylindoles Activated by FeCl3: An Entry to 3-
(Hetero)arylindolines
Rodolphe Beaud, Rꢀgis Guillot, Cyrille Kouklovsky, and Guillaume Vincent*[a]
Abstract: A method for the direct and rare umpolung of the
3 position of indoles is reported. The activation of N-acetyl-
indole with iron(III) chloride allows the CÀH addition of aro-
matic and heteroaromatic substrates to the C2=C3 double
bond of the indole nucleus to generate a quaternary center
at C3 and leads regioselectively to 3-arylindolines. Optimiza-
tion, scope (50 examples), practicability (gram scale, air at-
mosphere, room temperature), and mechanistic insights of
this process are presented. Synthetic transformations of the
indoline products into drug-like compounds are also de-
scribed.
Introduction
The nucleophilicity of the indole nucleus at C3 is well estab-
lished.[1] In contrast, the electrophilic character of indoles has
been less studied but is a fascinating emerging topic.[2]
Nucleophiles can be added to the benzene portion of in-
doles,[3] however, we are particularly interested in the genera-
tion of sp3 carbon centers through the reaction of the C2=C3
bond of indoles 1. Logically it has been reported that the addi-
tion of an electrophile at C3 results in the generation of a C2
electrophilic imine or iminium species 2.[4] Indoles 4, which
contain a C3 electron-withdrawing group, are also electrophilic
at C2 through 1,4-addition (Scheme 1).[5]
In contrast, the introduction of nucleophiles at C3 requires
the umpolung of this position. Strategies to effect such a trans-
formation rely on oxidation of the indole nucleus to generate
N-hydroxyindoles 6,[6] 3-halogeno- or 3-seleno-indolines 7,[7] or
indolenium ions 8,[8] which are all electrophilic at C3
(Scheme 1).[9]
The latter C3 functionalization delivered indole derivatives
at a higher oxidation state than the indolines obtained by C2-
functionalization methods. If one wishes to obtain similar C3-
functionalized indolines, an umpolung that does not require
the preoxidation of indoles is needed.
In a seminal report, Nakatsuka and co-workers observed the
oligomerization of N-pivaloylindole (10) in the presence of
excess of AlCl3 by the formation of a CÀC bond between the
Scheme 1. Electrophilic indoles for the generation of sp3 carbon centers.
[a] R. Beaud, Dr. R. Guillot, Prof. C. Kouklovsky, Dr. G. Vincent
Institut de Chimie Molꢀculaire et des Matꢀriaux d’Orsay (ICMMO)
Equipe Mꢀthodologie, Synthꢁse et Molꢀcules Thꢀrapeutiques
Univ Paris Sud and CNRS
benzene portion of one molecule and the C3 position of an-
other indole molecule (Scheme 1).[10a] The authors were able to
extend this observation to the addition of electron-rich ben-
zene derivatives 13 to the C3 position of N-acylindoles 12 in
the presence of AlCl3, which is a very unusual hydroarylation
reaction of the electron rich C2=C3 bond of indoles.[10b,11] How-
ever, the substrate scope reported was very limited.
15 rue Georges Clemenceau, Bat 410, 91406, Orsay (France)
Fax: (+33)1-69-15-46-79
E-mail: guillaume.vincent@u-psud.fr
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201400284.
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efforts to make this reaction practical and useful to the syn-
thetic community by showcasing its broad scope and the sub-
sequent access to natural product-like and drug-like motifs.
Particular attention was paid to the introduction of heteroaryl
groups 15.
Results and Discussion
We initiated our investigation of the hydroarylation of N-acylin-
doles 12 by the study of the reaction between N-acetylskatole
(12a) and 4-methylanisole (13a); the results are compiled in
Table 1.
Table 1. Screening of promoters for the hydroarylation of N-acetylskatole
(12a) by 4-methylanisole (13a).
Entry
Promoter
[Equiv]
13a [equiv]
Yield [%]
Figure 1. Biologically active and/or natural products that contain the 3-ary-
lindoline moiety.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
AlCl3
AlCl3
Al(OTf)3
CuCl2
Cu(OTf)2
MgCl2
InCl3·2H2O
In(OTf)3
Sc(OTf)3
BF3·OEt2
BBr3
PdCl2
SiCl4
TiCl4
GaCl3
FeCl3
FeCl3
FeBr3
FeF3
4.5
2.6
2.6
2.6
2.6
2.6
2.6
2.6
2.6
2.6
2.6
2.6
2.6
2.6
2.6
2.6
1.0
2.6
2.6
2.6
2.6
2.6
2.6
2.6
2.6
3.0
5.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
78
23
0
0
0
0
0
0
0
3,3-Disubstituted indoline derivatives that incorporate an
aryl group at the 3 position are found in various families of
biologically relevant natural products or potential drugs[12–19]
(Figure 1). Examples include the antitumoral natural product
diazonamide A[12,13] of the benzofuroindoline family,[14,15] pyrro-
loindolines (such as the naseseazines or gliocladine C, which
contain a 3-indolylindoline framework), the recently isolated
spiroindimicin B, which features a rare 3,3-spiro-pyrrolylindolyl-
indoline core, and 3-aryl-N-acylindolines, which have recently
been reported to target the family of inhibitors of apoptosis
(IAP) proteins, over expressed in several cancers.[18]
trace
0
0
0
38
17
94
0
88
0
0
0
0
0
The C3 regioselective hydroarylation of electrophilic N-acy-
lindoles 12 appeared very attractive to us to devise a general
access to relevant 3-arylindolines 14 and 16 (Scheme 2). This
Friedel–Crafts-type cross-coupling reaction does not require
the prefunctionalization of both partners and is formally the
addition of a CÀH bond into the indole C2=C3 double bond.
In the context of an ongoing project to target the benzofur-
anoindoline core, we embarked on a general research program
directed towards the C3 umpolung of indoles.[20] We report our
FeCl2
K3FeCN6
Fe(acac)3
Fe(OTf)3
MsOH
CF3CO2H
HCl[a]
0
0
0
[a] 4.0m solution in dioxane. Tf=trifluoromethanesulfonyl, acac=acetyl-
acetonate, Ms=methanesulfonyl.
First we evaluated the conditions reported by Nakatsuka,
which involved a large excess of AlCl3 and electron-rich ben-
zene derivatives. Very promisingly, the reaction with AlCl3
(4.5 equiv) and 13a (5 equiv) in CH2Cl2 yielded 78% of the 3-
hydroarylated indoline 14a (Table 1, entry 1). When we tried to
lower the amounts of AlCl3 and 13a (2.6 and 2.0 equiv, respec-
tively) the yield of the reaction dropped to 23% (Table 1,
entry 2). Interestingly, replacement of aluminum chloride with
Scheme 2. Hydroarylation of N-acylindoles.
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aluminum triflate resulted in a loss of reactivity (Table 1,
entry 3). We next screened various Lewis acids to identify
a more-efficient promoter. Disappointingly, almost all of the
promoters evaluated under the typical conditions (Lewis acid
(2.6 equiv), 13a (2.0 equiv), 0.5m CH2Cl2) were ineffective
(Table 1, entries 4–13). TiCl4 and GaCl3 were able to promote
the reaction in modest yields of 38 and 17%, respectively
(Table 1, entries 14 and 15). Very rewardingly, FeCl3 demonstrat-
ed a unique and very high activity: 94% of indoline 14a was
isolated (Table 1, entry 16). The stoichiometry of FeCl3 was im-
portant because with only one equivalent, the reaction did not
occur (Table 1, entry 17). FeBr3 also mediated the hydroaryla-
tion in a useful yield of 88% (Table 1, entry 18). These iron(III)
halides[21] seemed very exclusive in this context because other
iron species, such as FeF3, FeCl2, K3FeCN6, Fe(acac)3 (acac=ace-
tylacetonate), and Fe(OTf)3 did not mediate the reaction
(Table 1, entries 19–23). Brønsted acids were also unable to
promote the reaction (Table 1, entries 24–26).
Scheme 3. Effect of the nitrogen substituent. [a] 1.5 h, [b] 12 h. Bn=benzyl.
Cbz (12ae) substrates did not lead to the expected hydroary-
lated products because the nitrogen substituent was rapidly
removed under the reaction conditions. The reaction of N-
methyl (12af) or NÀH skatole (12ag) resulted in unidentified
oxidation products.
With FeCl3 in hand as the optimal promoter, under air at-
mosphere at room temperature, we decided to study the influ-
ence of the solvent (Table 2).
Having discovered a suitable combination of nitrogen sub-
stituent and Lewis acid promoter, we progressed to study the
range of aromatic derivatives that could be added to the elec-
trophile 12a (Scheme 4).
Unsurprisingly, electron-rich benzene derivatives, such as thi-
oanisole (13b), phenol (13c), and anisole (13d) afforded high
yields of coupling products 14b–d, respectively, linked at the
para position of the benzene derivatives. 1,2,3-Trimethoxyben-
zene (13e) delivered the 3-(2,3,4-trimethoxyphen-1-yl)indoline
14e. Unfortunately, aniline derivatives 13 f did not react with
12a.
Table 2. Solvent effect in the hydroarylation of N-acetylskatole (12a) by
4-methylanisole (13a) with FeCl3.
Toluene, xylenes, and naphthalenes were also prone to effi-
ciently realize the hydroarylation. Indeed, toluene (13g) react-
ed at the para position and ortho-xylene (13h) delivered the 3-
(3,4-dimethylphen-1-yl)indoline 14h. Meta-xylene (13i) led to
the 3-(3,5-dimethylphen-1-yl)indoline 14i; the regioselectivity
on the xylene ring is governed by steric rather than electronic
effects. Naphthalene (13j) reacted at the 2 position, whereas
1-methylnaphthalene (13k) furnished a mixture of regioisom-
ers but 3-(1-methylnaphthalen-3-yl)indoline 14k was isolated
as the major isomer after recrystallization. On the other hand,
electron-deficient rings were significantly less reactive. Fluoro-
benzene (13l) led to indoline 14l in 9% yield; 4-nitroanisole
(13m) and 4-acetylanisole (13n) were unreactive.
Entry
Solvent
FeCl3 [equiv]
Yield [%]
1
2
3
4
5
6
7
8
CH2Cl2
acetone
THF
EtOAc
MeOH
CH3CN
EtNO2
heptane
2.6
2.6
2.6
2.6
2.6
2.6
2.6
2.6
94
0
0
0
0
0
15
15
Dichloromethane proved to be the most efficient solvent for
the reaction (Table 2, entry 1). No conversion was observed in
solvents that might coordinate FeCl3 (acetone, THF, EtOAc,
MeOH, CH3CN; Table 2, entries 2–6), and low yields of 14a
were recovered in nitroethane or heptane (Table 2, entries 7
and 8).
Heterocycles are widely present in the context of drug dis-
covery. Therefore, the formation of 3-heteroarylindolines by
our method would be highly desirable (Scheme 5).
Rewardingly, several heterocycles are efficient nucleophiles
for this reaction (Scheme 5). Indeed N-tosylindole (15a) deliv-
ered the C3–C3’ connected bis-indoline derivative 16a. Furan
(15b), thiophene (15c), and 2-methylthiophene (15d) reacted
predominantly at the C2 position. The moderate yield of the
furan–indoline adduct 16b could be explained by partial poly-
merization of furan under the reaction conditions. Utilization
of 3-methylbenzofuran (15e) and 3-methylbenzothiophene
(15 f) significantly improved the yield. However, N-tosylpyrrole
(15g) was not a suitable partner for the hydroarylation.
We also noticed that the reaction could be run at a concen-
tration of 1m in dichloromethane, which allowed the reaction
time to be reduced and gave an improved yield (Scheme 3).
With the optimized conditions in hand (13a (2.0 equiv),
FeCl3 (2.4 equiv), 1m in CH2Cl2, rt), we evaluated the influence
of the N-acyl group (Scheme 3). The initial acetyl group (12a)
was the best choice. The more electron-withdrawing benzoyl
(12ab) and trifluoroacetyl groups (12ac) resulted in reduced
yields of 66 and 17%, respectively, whereas pivaloyl (12ad) or
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Scheme 5. FeCl3-promoted hydroarylation of N-acetylskatole (12a) with het-
erocycles. [a] 13 (2 equiv), FeCl3 (2.4 equiv). [b] 13 (7.2 equiv), FeCl3 (7.6 equi).
[c] 13 (3 equiv), FeCl3 (3.4 equiv). r.r.=regioisomeric ratio; n.r.=no reaction
of 12a.
Scheme 4. FeCl3-promoted hydroarylation of N-acetylskatole (12a) with ben-
zene derivatives. [a] 13 (3 equiv), FeCl3 (3.4 equiv). [b] 13 (2 equiv), FeCl3
(2.4 equiv). n.r.=no reaction of 12a. Ac=acetyl.
Figure 2. Crystal structures of hydroarylated indolines 16e (left) and 16 f
(right).
We were able to obtain crystals of some of the hydroarylat-
ed adducts of 12a and to resolve their structure by X-ray crys-
tallography (Figure 2).[22] Interestingly, in the case of the 3-
methylbenzofuran adduct 16e, the oxygen atom of the benzo-
furan unit points in the opposite direction to the C2ÀC3 bond
of the indoline, whereas in sulfur analogue 16 f, the sulfur
atom points towards the benzene ring of the indoline.
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The scalability of this process was ascertained by the reac-
tion of 12a (1 g, 5.77 mmol) and 15 f (1.88 g, 12.8 mmol),
which yielded indoline 16 f (1.55 g, 4.82 mmol, 83%;
Scheme 6).
Scheme 6. Gram-scale hydroarylation.
After evaluation of the aromatic nucleophiles, the reactions
of electrophilic N-acetylindole 12 were surveyed with anisole
13d as the arylating agent (Scheme 7). The substitution at C3
was the first point under scrutiny. Increasing the steric hin-
drance slowed down the reaction but a good overall yield of
3-benzyl- and 3-phenylindolines 17a and 17b was obtained.
3,3,2-Trisubstituted-N-acetylindoline 17c was isolated with
a modest yield of 22% from 2,3-dimethyl-N-acetylindole, which
could be explained by partial deacylation of the starting N-ace-
tylindole by anisole (as a result, 4-methoxyacetophenone was
isolated in 35%).
In terms of functional group tolerance, ester groups or halo-
gens are tolerated in the C3 side chain, demonstrated by the
isolation of indolines 17d–h. A carbonyl group directly con-
nected to the 3 position of indole (17i) suppressed the reactiv-
ity, as did the presence of amides on the C3 side chain (17j
and 17k); in all cases, the starting indoles were recovered.
Electronic effects on the benzene portion of indoles 12 were
then evaluated. Pleasingly, electron-withdrawing groups (NO2,
CN, CO2Et), halides (Br), and electron-donating groups (OMe) at
the 5 position efficiently delivered the expected indolines 17l–
q. Similarly, hydroarylation occurred with an electron-with-
drawing group (NO2; 17r), halide (Cl; 17s), or electron-donat-
ing group (MeO; 17t) at the 6 position.
Having established that a vast array of functional groups on
12 are tolerated during the hydroarylation with 13d, the reac-
tion of diversely substituted N-acetylindole 12 and nucleophilic
heterocycles 15 were next examined (Scheme 8). The goal is to
show that this methodology is well suited for the rapid gener-
ation of building blocks for medicinal chemistry.
Heterocycles 15e and 15d could be efficiently added to 3-
(3-acetoxyprop-1-yl)-N-acetylindole to afford 18a and 18b, re-
spectively. Reaction of 15a with 3-(1-bromopropyl)-N-acetylin-
dole gave 18c. Nucleophile 15e reacted efficiently with 3-(2-
(methoxycarbonyl)eth-1-yl)-N-acetylindole to give 18d. Un-
fortunately, it was not possible to add heterocycle 15 f to hin-
dered 3-phenyl-N-acetylindole and 18e was not obtained,
even after 72h. N-Acetylindoles substituted at the 5 position
were suitable acceptors for heterocycles. Heterocycles 15c and
15e delivered the electron-poor 5-ethylcarboxylateindolines
18 f and 18g, respectively. Reaction of 15a, 15 f, and 15e with
5-bromo-N-acetylindole gave the 5-bromoindolines 18h–k. 5-
Scheme 7. FeCl3-promoted hydroarylation of diversely substituted N-acety-
lindole with anisole. [a] 13d (2 equiv), FeCl3 (2.2 equiv). [b] 17d’ and 17e’
were obtained from reaction with 13g.
Methoxy-N-acetylindole and 15e gave electron-rich 5-methox-
yindoline 18l. Finally, 6-chloro-N-acetylindole was successfully
coupled with 15a to yield 18m.
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Scheme 9. Determination of the KIE.
dicative that cleavage of the CÀH or CÀD bond of the nucleo-
phile is not the rate- or product-determining step.[23] Such be-
havior is observed for electrophilic substitution reactions in
which CÀH or CÀD bond cleavage is very fast during the rearo-
matization of Wheland intermediates.[24]
These experiments, and some previous observations, al-
lowed us to propose a mechanistic hypothesis (Scheme 10).
We observed that over two equivalents of FeCl3 are needed
for the reaction to proceed to completion (Table 1, entries 16
and 17). It seems reasonable to think that two molecules of
FeCl3 are involved in the mechanism. One equivalent of FeCl3
Scheme 8. FeCl3-promoted hydroarylation of diversely substituted N-acetyl-
indole with heterocycles. [a] 15 (4 equiv), FeCl3 (4.4 equiv). [b] 15 (5 equiv),
FeCl3 (5.4 equiv). Ts=p-toluenesulfonyl.
After demonstration of the large scope of the reaction, we
wanted to gain some mechanistic insights. To this end, deter-
mination of a kinetic isotope effect (KIE) was sought. Therefore,
we performed the competing hydroarylation of 12a with 13g
and [D8]-13g and interrupted the reaction at low conversion
(Scheme 9). The ratio of hydroarylated compounds 14g and
[D8]-14g was 1:1.
To complement this intermolecular experiment, an intramo-
lecular competition experiment was done. The reaction of 12a
and 4-[D]-1,2-xylene ([D]-13h) delivered a 1:1 mixture of indo-
lines Ind-[D]-14h and Xyl-[D]-14h, from cleavage of the CÀD
and CÀH bonds of monodeuterated xylene [D]-13h
(Scheme 9). The results of these inter- and intramolecular com-
petition experiments are representative of a KIE of 1. This is in-
Scheme 10. Mechanistic hypothesis.
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could undergo complexation by the oxygen atom of the car-
bonyl group (intermediate A). Consequently, the indole nitro-
gen lone pair could be delocalized in the carbonyl p system
(intermediate B) and, thus, break the aromaticity of the pyrrole
part of the indole. Therefore, the C2=C3 double bond should
be less electron rich at C3. Activation of this double bond by
a second molecule of FeCl3 might generate an intermediate
electrophile at C3 and trigger electrophilic substitution with an
electron-rich aromatic compound via the formation of Whe-
land intermediate C, as suggested by the KIE of the reaction.
The next event would be protonation of the C2 position by
the proton released from rearomatization of C, illustrated by
the reaction with [D]-13g (Scheme 9), in which the C2 position
of the indoline product is deuterated. We have also run reac-
tions with excess triethylamine or K2CO3 to neutralize conspic-
uous amounts of hydrogen chloride in solution and we ob-
served complete shutdown of the reaction. We believe that
these bases might neutralize the proton released from aroma-
tization of Wheland intermediate C, which is necessary for the
protonation of the C2 position. Finally, aqueous workup will
decomplex iron(III) from the acetyl moiety of D to give indoline
13.
Alternatively to our mechanistic proposal, activation of the
electron-rich aromatic partner could not be excluded. However,
we do not believe that the iron promoter performs a CÀH acti-
vation of the nucleophilic electron-rich arene because we
would have expected a KIE greater than kH/kD =1.[24b]
Finally, to showcase the versatility of the arylated indolines
13 some synthetic transformations were investigated.
3-Arylfuranoindolines 19a and 19b and 3-arylpyrranoindo-
lines 20a–d were readily obtained by double deacetylation of
the 3-aryl-3-acetoxyalkylindolines 17d and 17d’ and 17e,
17e’, 18a, and 18b, respectively, followed by a diisopropylazo-
dicarboxylate (DIAD) mediated oxidation (Scheme 11).[20,25] It
should be noted that reports of pyranoindolines or furanoindo-
lines that incorporate a 3-heteroaryl unit, such as compounds
20c and 20d, are very rare in the literature.[26]
To obtain nitrogen analogues of 19, nucleophilic substitution
of the bromide atoms on the C3 side chain in indole 17g by
para-toluenesulfonamide was first performed (Scheme 11).
Then the hydrolysis–oxidation sequence yielded 3-(4-methoxy-
phenyl)pyrroloindoline 21a, the core structure of the nasesea-
zines. The nitrogen analogues of 20, piperidinoindolines 22a
and 22b, which incorporate a 3-(4-methoxyphenyl) and a 3-(3’-
N-Ts-indolyl) group, respectively, were also synthesized effi-
ciently through the same strategy from 17h and 18c.[27]
In the absence of a group for intramolecular trapping, the
imine 23 could be isolated by hydrolysis of 14a and oxidation.
Allylation of 23 by the addition of a Grignard reagent delivered
the 3,3,2-trisubstituted indoline 24 in a 1.7:1 diastereomeric
ratio (d.r.) with attack of the allyl nucleophile from the less-hin-
dered face as the major pathway.[19k]
Scheme 11. Synthesis of arylated furanoindolines, pyranoindolines, pyrroloin-
doline, piperidinoindolines, and trisubstituted indolines.
which leads to functionalized indolines with an arylated qua-
ternary carbon center at C3. The generation of electrophilic in-
doles represents the rare umpolung of the indole nucleus,
which allows regioselective introduction of aryl and heteroaryl
groups at the 3 position of N-acetylindole. This robust reaction
employs cheap and nontoxic iron(III) chloride as promoter, pro-
ceeds at room temperature under air atmosphere, and is scala-
ble. It tolerates a broad scope of indole electrophiles and elec-
tron-rich aromatic nucleophiles. Mechanistic insights and func-
tionalization of the indolines obtained are also presented. We
anticipate that this cross-coupling will find useful applications
in natural product or medicinal chemistry because complexity
may be rapidly introduced with only N-acylation of the indole
as prefunctionalization.
Conclusion
We have described the conception of a method for the regio-
selective hydroarylation of N-acetylindole activated by FeCl3,
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c) T. Nagayoshi, S. Sakei, M. Hamana, Chem. Pharm. Bull. 1981, 29,
1920–1926; by in situ generation of C3-electrophilic indole intermedi-
ates from non-indolic starting materials: d) A. Wetzel, F. Gagosz, Angew.
Chem. 2011, 123, 7492–7496; Angew. Chem. Int. Ed. 2011, 50, 7354–
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New Technol. Med. 2006, 7, 59–62.
[11] For selected examples on the hydroarylation of alkenes, see: a) Y. Kuni-
nobu, T. Matsuki, K. Takai, J. Am. Chem. Soc. 2009, 131, 9914–9915; b) J.
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Experimental Section
General procedure for the hydroarylation of N-acetylindole
In one portion, electron-rich arene (2 equiv) and FeCl3 (2.6 equiv)
were successively added to a solution of 3-substituted indole deriv-
ative 12 (1 equiv) in CH2Cl2 (1.0m). The reaction was monitored by
TLC from 1 h onwards. After complete consumption of 12, the re-
action was quenched with brine and diluted with EtOAc. The
phases were separated and the aqueous phase was extracted with
EtOAc (ꢂ2). The combined organic phases were dried over Na2SO4,
filtered, and concentrated under vacuum. The crude oil was puri-
fied by flash column chromatography.
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Acknowledgements
We gratefully acknowledge the ANR (ANR-12-JS07–0002; JCJC
2012-CouPhIn), the Universitꢀ Paris Sud, and the CNRS for fi-
nancial support. R.B. thanks the Univ Paris Sud for a graduate
fellowship (ED 470).
Keywords: CÀH activation · electrophiles · heterocycles ·
indoles · iron
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Received: January 23, 2014
Published online on && &&, 0000
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FULL PAPER
&
Indoles
R. Beaud, R. Guillot, C. Kouklovsky,
G. Vincent*
&& – &&
Regioselective Hydroarylation
Reactions of C3 Electrophilic N-
Acetylindoles Activated by FeCl3: An
Entry to 3-(Hetero)arylindolines
Indole electrophiles: A method for the
direct and rare umpolung of the 3 posi-
tion of indoles is reported. The activa-
tion of N-acetylindole with iron(III) chlo-
ride allows the CÀH addition of aryl sub-
strates to the C2=C3 double bond of
the indole nucleus to regioselectively
generate 3-arylindolines with a quaterna-
ry center at C3 (see scheme).
&
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Chem. Eur. J. 2014, 20, 1 – 10
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ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!