Triflic Acid as an Efficient Br?nsted Acid Promoter for the Umpolung of N-Ac Indoles in Hydroarylation Reactions

Article abstract of DOI:10.1002/adsc.201701074

We report that triflic acid, a strong Br?nsted acid, is a very powerful alternative to FeCl₃ to mediate the hydroarylation of N?Ac indoles, which delivers regioselectively 3-arylindolines, 3,3-spiroindolines or 2-arylindolines. Mechanistic explorations point towards the existence of a highly electrophilic intermediate by simultaneous activation of the acetyl and of the C2=C3 bond by protons. (Figure presented.).

Full text of DOI:10.1002/adsc.201701074

Title: Triflic acid as an efficient Brønsted acid promoter for the
Umpolung of N-Ac indoles in hydroarylation reactions
Authors: Raj Kumar Nandi, Alejandro Pérez-Luna, Didier Gori,
Rodolphe Beaud, Regis Guillot, Cyrille Kouklovsky, Vincent
Gandon, and Guillaume Vincent
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701074
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10.1002/adsc.201701074
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Triflic acid as an efficient Brønsted acid promoter for the
umpolung of N-Ac indoles in hydroarylation reactions
Raj Kumar Nandi,a Alejandro Perez-Luna,b Didier Gori,a Rodolphe Beaud,a Régis
Guillot,a Cyrille Kouklovsky,a Vincent Gandona,c* and Guillaume Vincenta*
a
Institut de Chimie Moléculaire et des Matériaux d’Orsay (ICMMO), Univ. Paris-Sud, Université Paris-Saclay, CNRS
UMR 8182, 91405 Orsay cedex.
Phone number: + 33 1 69 15 75 48
E-mail: vincent.gandon@u-psud.fr; guillaume.vincent@u-psud.fr
Sorbonne Universités, UPMC Univ Paris 06, CNRS UMR 8232, Institut Parisien de Chimie Moléculaire (IPCM), FR
b
2769, Case 229, 4 place Jussieu, 75005 Paris, France.
Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Univ. Paris-Sud, Université Paris-Saclay, 1, av. de la
c
Terrasse, 91198 Gif-sur-Yvette, France.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
We have recently demonstrated that this reaction
acid, is a very powerful alternative to FeCl3 to mediate the proceeds via a polyactivated intermediate, in which
Abstract. We report that triflic acid, a strong Brønsted
hydroarylation of N-Ac indoles, which delivers
regioselectively 3-arylindolines, 3,3-spiroindolines or 2-
arylindolines. Mechanistic explorations point towards the
the acetyl is activated by FeCl3 to favour the
delocalization of the nitrogen lone pair into the
carbonyl system, and in which the C2=C3 bond is
activated by a proton to induce a Friedel-Crafts
reaction with arene 2 (Scheme 1).[7]
During the optimization process of the
hydroarylation of N-Ac indoles, we screened several
Lewis acids and FeCl3 proved to be rather exclusive
to promote the desired reaction. At that time, we
ruled out the fact that a proton could be the sole
promoter of the reaction. We recently started a more
thorough evaluation of Brønsted acids as promoters
(Table 1).
existence of
a highly electrophilic intermediate by
simultaneous activation of the acetyl and of the C2=C3
bond by protons.
Keywords: Indole; Umpolung; Hydroarylation; Brønsted
acid; Friedel-Crafts
The dearomative umpolung of the indole nucleus
is an emerging topic with an important synthetic
potential to access indoline derivatives of biological
relevance.[1-8] Most of the time, this reversal of
polarity[2a] involves the oxidation of the indole
nucleus[2b-j,3] or the presence of strong electron-
withdrawing groups.[2k-m] In this context, our group
developed several methods[3,4] to generate
electrophilic indoles to overturn the innate
nucleophilicity of indoles,[1a,5] including the C3-
regioselective FeCl3-mediated hydroarylation of N-
Ac indole 1 (Scheme 1)[3] which was inspired by
preliminary findings from Nakatsuka and co-
workers.[6]
Table 1. Evaluation of Brønsted acids as promoter of the
3-hydroarylation of N-Ac skatole with 4-methylanisole.
Entry
Isolated Yield
3a
Brønsted acid
1
2
3
4
5
6
7
HCl (excess)
0%
0%
84%
95%
0%
0%
0%
CF3CO2H (3 equiv.)
H2SO4 (2.5 equiv.)
CF3SO3H (2.5 equiv.)
MeSO3H (3 equiv.)
(+)-CSA (2.5 equiv.)
HNTf2 (2.2 equiv.)
Scheme
1.
Our
FeCl3-mediated
regioselective
hydroarylation of N-Ac indoles via a polyactivated
intermediate.
1
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10.1002/adsc.201701074
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We indeed envisioned that hydrogen chloride
could be generated from FeCl3 in the reaction
medium. Therefore, HCl gas was bubbled through a
mixture of N-Ac skatole 1a and anisole 2a, yet 3a
was not detected (entry 1). We continued our study
with strong Brønsted acids. Trifluoroacetic acid
(entry 2) did not deliver any coupling product.
However, 2.5 equivalents of sulfuric acid were able
to promote the reaction and delivered 3a in 84% yield
(entry 3). Triflic acid (TfOH) was even better and
provided the hydroarylated product in 95% yield
(entry 4).[9] Other sulfonic acids or triflimine (entries
5-7) were ineffective.
Encouraged by this improved result, we decided to
study the scope of the hydroarylation of N-Ac indoles
with TfOH as promoter and compared it with FeCl3
(Scheme 2). TfOH proved to be as efficient as FeCl3
for the intermolecular regioselective 3-hydroarylation
of N-Ac indoles substituted at the 3-position,[10]
whether we used anisole derivatives, thioanisole,
toluene, naphthalene[11] or phenols as the aromatic
nucleophile (indolines 3a-g). In the case of -
naphthol, a much better yield of 3g was obtained with
TfOH, because the oxidative dimerization of -
naphtol observed in the presence of FeCl3 was
suppressed. Heteroaromatic compounds were also
evaluated Indoline 3h was obtained from 2-
methylthioanisole in 60% yield, while furan
decomposed almost immediately in presence of
TfOH leading to less than 10% of 3i. Benzothiophene
and benzofuran were excellent nucleophiles in
presence of TfOH, leading to 3j and 3k in 86 and
99% yields. It is noteworthy that a mixture of two
regioisomers of 3j (relatively to the arene
nucleophile) were observed with TfOH, which is in
contrast with the FeCl3 conditions. Surprisingly, N-Ts
indole proved to be a poor nucleophile in these
conditions (indoline 3l). A similar efficiency between
FeCl3 and TfOH was noted when we investigated the
substitution at positions 3, 5 or 6 of the indole
nucleus (indolines 3m-ab). TfOH was superior in the
case of 6-cyanoindoline 3ac. A better yield was also
obtained with TfOH when the N-acetyl group on
skatole was replaced by a N-benzoyl (3ad).
Concerning the intramolecular reaction, TfOH proved
to be a better promoter than FeCl3 since 3,3-
spirocycles 4a-e were obtained with better yields. In
particular the thiophene-containing spirocyclic
derivative 4d was obtained in 97% yield with TfOH
in 2 hours, compared to 27% with FeCl3. We recently
established that if the N-Ac indole was unsubstituted
at the C3-position, the aryl nucleophile reacted at the
C2-position in presence of FeCl3.[4e,8] The same
regioselectivity was observed with TfOH for the
reaction with p-methyl anisole 2a, leading to 5a-c. In
the case of 5a, it was necessary to use only one
equivalent of the aromatic nucleophile to avoid the
opening of the C2-N bond by a second aryl
nucleophile which lead to 6. Notably, a large increase
of the yield was observed for 5-nitro indoline 5c.
Scheme 2. Regioselective hydroarylation of 3-substituted
N-Ac-indoles promoted by TfOH. a) reported in ref 4b; b)
reported in ref 4a; c) 3.4 equiv. of FeCl3 and 3 equiv. ArH;
d) 3 equiv. of TfOH; e) 3 equiv. of TfOH; f) reported in ref
7; g) reported in ref 4d; h) 1.07 equiv. of 2; i) reported in
ref 4e; j) 2.75 equiv. of 2.
2
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10.1002/adsc.201701074
Advanced Synthesis & Catalysis
While studying the scope of the C3-hydroarylation,
the stretching absorption band of the carbonyl at 1702
cm-1 (Figure 1, left). In the meantime, no clear new
band was observed, but rather a broad absorption
between 1625 and 1500 cm-1. Total disappearance of
the stretching of the carbonyl of the starting N-Ac
skatole was observed with 0.5 equivalent of TfOH
with formation of a band at 1625 cm-1. Upon addition
of additional 0.5 equivalent of TfOH (1 equivalent in
total) the broad absorption was transformed into a
sharp strong band at 1625 cm-1, which may represent
the association of the acetyl of N-Ac skatole with
TfOH in a 1:1 ratio (intermediate 8). Further addition
of TfOH did not induce any noteworthy change. We
then recorded the in situ IR spectra in presence of
anisole 2b in the reaction conditions. As soon as 2.5
equivalents of TfOH were added, the carbonyl
absorption band shifted from 1702 to 1625 cm-1
(Figure 1, right). The progressive disappearance of
this band, attributed to 1:1 N-Ac skatole-TfOH
intermediate 8, is accompanied by the formation of
the hydroarylation product carbonyl band at 1668 cm-
we turned our attention to a C-7 substituted indole
and we observed an unexpected behaviour of the
starting N-Ac indole (Scheme 3). 7-Methyl-N-Ac
skatole gives the hydroarylated product 3ae in only
20% and 33% with FeCl3 and TfOH, respectively.
The major product 7 is produced through the
migration of the acetyl from the nitrogen to the C2-
position. In absence of anisole, 7 was obtained in
90% yield with FeCl3. This result informed us that to
be fully operative, the amide bond should suffer no
destabilization from the C7-substituent and even then,
arylated indoline 3ae can be isolated in moderate
yield.
1
.
A study of the activation of N-Ac skatole with the
promoter by NMR was realized in order to improve
our understanding of its effect on reactivity.[13] The
proton NMR of N-Ac indole 1a with several amounts
of TfOH were recorded (Figure 2, top).
Scheme 3. Effect of the destabilization of the amide bond
conformation on the reactivity.
Overall, some limitations of the FeCl3 promoter in
the hydroarylation of N-Ac indoles have been
circumvented by the use of TfOH as an alternative
and very efficient promoter. Having established that
this reaction could operate with a Brønsted super acid
(TfOH) or a Lewis acid (FeCl3), we wondered
whether a mechanism comparable to the one that we
previously established for FeCl3[7] was also operative
with TfOH.
We conducted an in situ IR study to get insights
into the course of the reaction (Figure 1).[7,12]
1
Figure 2. H NMR of N-Ac skatole 1a in presence of
TfOH in CDCl3 (top) and selected 13C NMR data (bottom)
of N-Ac skatole 1a without triflic acid (A) and with 1
equivalent of TfOH (B) in CDCl3.
Figure 1. in situ IR monitoring of the reaction between N-
Ac skatole 1a and TfOH in 0.2M CH2Cl2 (left); reaction
between N-Ac skatole 1a, anisole 2b (2 equiv.) and TfOH
(2.5 equiv.) in 0.2M CH2Cl2 (right). .
Addition of 0.5 equivalent of TfOH had a major
impact on the chemical shifts: the methyl of the
acetyl moved downfield from 2.60 ppm to 3.05 ppm
and the H7 proton moved upfield from 8.45 ppm to
8.15 ppm due to the probable association of the
We started to monitor the effect of TfOH towards
N-Ac skatole 1a in the absence of the aromatic
nucleophile. Upon portion wise addition of TfOH to
1a, we indeed noticed the progressive vanishing of
3
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10.1002/adsc.201701074
Advanced Synthesis & Catalysis
Brønsted acid with the basic oxygen of 1a. In N-Ac
indoles unsubstituted at C7, the C=O bond and
benzene ring are in the same plane with the oxygen
pointing towards the benzene ring to avoid steric
interactions between the methyl of the acetyl and the
hydrogen at position 7 of the indole.[14] Consequently,
the latter displays a downfield 1H NMR signal around
8.5 ppm because of the deshielding magnetic
anisotropy of the carbonyl group. Obviously, the
protonation of the oxygen of the acetyl diminished
this effect. Upon addition of larger amounts of TfOH,
no major changes were observed for the proton NMR.
The carbon NMR of a mixture of 1:1 mixture of 1a
and TfOH was more instructive on the effect of this
activation of the oxygen of the acetyl on the reactivity
of the enamide system (Figure 2, bottom). Indeed, the
carbonyl peak is downfield-shifted by 7.5 ppm in
presence of TfOH. More interestingly, the chemical
shift of the C3 carbon increases from 118.4 ppm to
131.5 ppm while at the same time a slight decrease of
1.3 ppm for the C2 carbon is observed. These
experimental data were compared with theoretical
ones predicted by DFT (GIAO method) and are in
agreement.[15] We have demonstrated that the
presence of the TfOH promoter triggers the
Umpolung of the C2=C3 double in which the C3
carbon becomes the most electrophilic.
Figure 3. Hammett study of the hydroarylation reaction
with 5-substituted N-Ac skatoles (top) and 6-substituted N-
Ac skatoles (bottom).
Similarly to FeCl3, the Hammett study conducted
with TfOH showed that electron-withdrawing group
at the C5 and C6 positions of N-Ac skatole is
detrimental to the rate of the reaction (Figure 3).
Rather linear correlations, with the exception of the
methoxy group, were observed for both with
significant negative  values which could be
indicative of the existence of positive charges at the
C3 position and at the nitrogen.[7,15,16]
Moreover, the observed proportional increase of
the initial rate of the reaction with the amount of
TfOH from 1.5 equivalents (Figure 4), led us to
postulate that a polyactivated reactive species was
involved as in the case of the FeCl3-promoted
reaction.[7]
Figure 4. Influence of the stoichiometry of TfOH on the
initial rate of the hydroarylation.
4
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10.1002/adsc.201701074
Advanced Synthesis & Catalysis
The following stepwise general mechanism could
the C2=C3 double bond, no cyclization transition
state could be found. We could only observe a proton
shift from the oxygen to the phenyl group.
be presented (Scheme 4) which is similar to the one
we reported for the FeCl3-mediated reaction.[7]
Protonation of the acetyl of the N-Ac indoles is
accompanied by activation of the C2=C3 bond by a
proton at the more nucleophilic position of the
C3=C2 bond: C2 for 3-substituted N-Ac indoles or
C3 for unsubstituted N-Ac indoles. The positive
charge at C3 (A) or C2 (C) triggers the addition of
the electron-rich arene respectively at C3 (TSAB) or
C2 (TSCD). Aromatization of the resulting Wheland
intermediate B or D delivers 3-arylindoline 3 or 2-
arylindoline 5 and also releases a proton. The latter,
as well as TfOH, could activate the C2=C3 bond of 1
as suggested by an experiment with deuterated triflic
acid.[15,17]
Scheme 5. Computed Gibbs free energies of intermediates
and transition states relatively to A with solvent correction
(CH2Cl2) at M06-2X level.
In conclusion, we discovered that the promotion of
the unusual hydroarylation of N-Ac indoles is not
exclusively limited to the Lewis acid FeCl3. A strong
Brønsted acid such as TfOH is also very efficient to
mediate this reaction and even superior in some cases.
Similarly to the FeCl3-promoted reaction, in situ IR
monitoring, NMR and Hammett studies as well as
DFT explorations point towards a Friedel-Crafts
mechanism with an uncommon super electrophilic
intermediate.
Experimental Section
General procedure A for the hydroarylation of N-Ac
indoles with TfOH.
To a solution of the 3-substituted indole derivative 1 (1
equivalent) in CH2Cl2 (1.0 M), was successively added
electron-rich arene 2 (2.2 equivalents) and TfOH (2.5
equivalents) in one portion. After completion of the
reaction (checked by TLC) the reaction was quenched with
a saturated NaHCO3 aqueous solution and diluted with
CH2Cl2. The phases were separated. The aqueous phase
was then extracted twice with CH2Cl2. The combined
organic phases were then dried over MgSO4, filtered and
concentrated under vacuum. The crude oil was then
purified by flash column chromatography or preparative
TLC.
Scheme 4. Postulated mechanism.
We then performed DFT computations at M06-2X
level to evaluate the possibility of this dual activation
with protons on the intramolecular hydorarylation
leading to 4c (Scheme 5). With one proton at the
oxygen atom, a positive charge was found to be
delocalized on the acetamide. Upon activation of the
C2=C3 double bond with another proton, a second
positive charge is formed at C3 and a C-H bond at C2.
This polyactivated species A may be considered as a
General procedure B for the hydroarylation of N-Ac
indoles with FeCl3.
To a solution of the 3-substituted N-acetyl indole
derivative 1 in CH2Cl2 (1.0 M), was successively added
electron-rich arene 2 (2 or 3 equivalents) and FeCl3 (2.4 or
3.6 equivalents) in one portion. After completion of the
reaction (checked by TLC) the reaction was quenched with
a saturated NaCl aqueous solution and diluted with EtOAc.
The phases were separated. The aqueous phase was then
extracted twice with EtOAc. The combined organic phases
were then dried over Na2SO4, filtered and concentrated
under vacuum. The crude oil was then purified by flash
column chromatography.
superelectrophile involved in
a
Friedel-Crafts
mechanism.[18] The cyclization from A to Wheland
intermediate B was found to be appreciably exergonic
(11.0 kcal/mol with solvent correction) and the free
energy of activation (0.4 kcal/mol, TSAB) as low as
that found for the transition state of Scheme 1 with
two FeCl3 at the oxygen. The similarity between one
proton at oxygen and two FeCl3 at oxygen[7] was also
established by the charge at C3 (0.294 vs 0.293) and
the quite long C3-C distance of 2.52 Å (Scheme 5),
which is actually even longer than with two FeCl3
(2.22 Å). With two protons on the oxygen and one at
The NMR of C3-hydroarylated products shows a mixture
of two rotamers in a 9:1 ratio in CDCl3 at 300K due to the
slow rotation of the N-(CO) bond. Only, the major
regioisomer is described in this experimental section. Upon
5
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10.1002/adsc.201701074
Advanced Synthesis & Catalysis
heating at 340K in DMSO, only one compound is
observed.[15]
Preparative TLC purification (Petroleum ether/EtOAc: 7/3)
led to 3e as a red oil (137 mg, 0.45 mmol, 91%).
N-Acetyl-3-(5-methyl-2-methoxyphenyl)-3-
methylindoline (3a)
FeCl3: We reported the synthesis of 3e with FeCl3 with
General Procedure B in ref 4b.
TfOH: 3a was prepared from 1-acetyl-3-methylindole 1a
(86.6 mg, 0.5 mmol), 4-methylanisole 2a (135 mg, 1.1
mmol) as electron-rich arene and TfOH (110 L 1.25
mmol) in 0.5 mL of CH2Cl2 following General Procedure
A. Preparative TLC purification (Petroleum ether/EtOAc:
8/2) led to 3a as a yellow solid (139.8 mg, 0.474 mmol,
95%).
See ref 4b for full characterization of 3c.
N-Acetyl-3-(2-hydroxy-5-methylphenyl)-3-
methylindoline (3f)
TfOH: 3f was obtained from 1-acetyl-3-methylindole 1a
(173 mg, 1 mmol), p-cresol 2f (238 mg, 2.2 mmol) and
TfOH (220 L 2.5 mmol) in 1.0 mL of CH2Cl2 following
General Procedure A. Flash column chromatography
purification (Cyclohexane/EtOAc : 7/3 to 1/1) led to 3f as
a brown solid (280 mg, 0.99 mmol, 99%).
FeCl3: We reported the synthesis of 3a with FeCl3 with
General Procedure B in ref 4b.
H2SO4: Compound 3a was also obtained (248 mg, 0.84
mmol, 84%) by using H2SO4 (170 L, 2.5 mmol) instead
of TfOH in General Procedure A from 1-Acetyl-3-
methylindole 1a (173.3 mg, 1 mmol) and electron-rich
arene 4-methylanisole 2a (270 mg, 2.2 mmol).
FeCl3: We reported the synthesis of 3f with FeCl3 with
General Procedure B in ref 4a.
See ref 4a for full characterization of 3f.
See ref 4b for full characterization of 3a.
N-Acetyl-3-(2-hydroxynaphthalenyl)-3-methylindoline
(3g)
N-Acetyl-3-(4-methoxyphenyl)-3-methylindoline (3b)
TfOH: 3g was prepared from 1-acetyl-3-methylindole 1a
(86.7 mg, 0.5 mmol), -naphthol 2g (144 mg, 1.0 mmol) as
electron-rich arene and TfOH (110 L 1.25 mmol) in 1 mL
of CH2Cl2 following General Procedure A. Preparative
TLC purification (Petroleum ether/EtOAc: 6/4) led to 3g as
a brown solid (87 mg, 0.274 mmol, 55%).
TfOH: 3b was prepared from 1-acetyl-3-methylindole 1a
(86.6 mg, 0.5 mmol), anisole 2b (118 mg, 1 mmol) as
electron-rich arene and TfOH (110 L 1.25 mmol) in 0.5
mL of CH2Cl2 following General Procedure A. Preparative
TLC purification (Petroleum ether/EtOAc: 8/2) led to 3b
as a yellow solid (135 mg, 0.48 mmol, 96%).
FeCl3: 3g was prepared from 1-acetyl-3-methylindole 1a
(86.7 mg, 0.5 mmol), -naphthol 2g (150 mg, 1.04 mmol)
as electron-rich arene and FeCl3 (194 mg, 1.2 mmol) in 1
mL of CH2Cl2 following General Procedure B. Preparative
TLC purification (Petroleum ether/EtOAc: 6/4) led to 3g as
a brown solid (17 mg, 0.053 mmol, 11%).
FeCl3: We reported the synthesis of 3b with FeCl3 with
General Procedure B in ref 4a.
See ref 4a for full characterization of 3b.
N-Acetyl-3-(4-thiomethylphenyl)-3-methylindoline (3c)
Rf: 0.27 (Petroleum ether/EtOAc: 3/2); 1H NMR (250 MHz,
CDCl3) δ (ppm): 8.41 (d, J = 8.2 Hz, 1H). 7.70 – 7.56 (m,
3H), 7.37 – 7.03 (m, 7H), 4.25 (d, J = 10.7 Hz, 1H), 4.08
(d, J = 10.7 Hz, 1H), 2.26 (s, 3H) 1.89 (s, 3H); 13C NMR
(62.9 MHz, CDCl3) δ (ppm): 169.7, 154.8, 142.1, 141.0,
140.0, 133.6, 129.9, 128.3, 128.2, 127.2, 125.5, 124.8,
124.5, 124.3, 118.9, 117.4, 109.3, 65.8, 48.0, 27.3, 24.2; IR
(neat) υmax (cm-1): 3436, 1641, 1489, 1425, 1299, 653;
HRMS (ESI+): calculated: 340.1308, ([C21H19NNaO2]+;
[M+Na]+); found: 340.1307.
TfOH: 3c was prepared from 1-acetyl-3-methylindole 1a
(86.6 mg, 0.5 mmol), thioanisole 2c (129 L, 1.1 mmol) as
electron-rich arene and TfOH (110 L 1.25 mmol) in 0.5
mL of CH2Cl2 following General Procedure A. Preparative
TLC purification (Petroleum ether/EtOAc: 8/2) led to 3c as
a yellow solid (148.0 mg, 0.499 mmol, 99%).
FeCl3: We reported the synthesis of 3c with FeCl3 with
General Procedure B in ref 4a.
N-Acetyl-3-(5-methylthiophen-2-yl)-3-methylindoline
(3h)
See ref 4a for full characterization of 3c.
N-Acetyl-3-(4-methylphenyl)-3-methylindoline (3d)
TfOH: 3h was prepared from 1-acetyl-3-methylindole 1a
(86.6 mg, 0.5 mmol), 2-methylthiophene 2h (89.7 mg, 1.1
mmol) as electron-rich arene and TfOH (110 L 1.25
mmol) in 0.5 mL of CH2Cl2 following General Procedure
A. Preparative TLC purification (Petroleum ether/EtOAc:
8/2) led to 3h as a yellow oil (81.0 mg, 0.30 mmol, 60%).
TfOH: 3d was prepared from 1-acetyl-3-methylindole 1a
(86.6 mg, 0.5 mmol), toluene 2d (160 L, 1.5 mmol) as
electron-rich arene and TfOH (110 L 1.25 mmol) in 0.5
mL of CH2Cl2 following General Procedure A. Preparative
TLC purification (Petroleum ether/EtOAc: 8/2) led to 3d
as a yellow oil (87.9 mg, 0.33 mmol, 66%).
FeCl3: We reported the synthesis of 3h with FeCl3 with
General Procedure B in ref 4a.
FeCl3: We reported the synthesis of 3d with FeCl3 with
General Procedure B in ref 4a.
See ref 4a for full characterization of 3h.
See ref 4a for full characterization of 3d.
N-Acetyl-3-(3-methylbenzothiophen-2-yl)-3-
methylindoline (3j)
N-Acetyl-3-(naphthalen-2-yl)-3-methylindoline (3e)
TfOH: 3j was prepared from 1-acetyl-3-methylindole 1a
(86.6 mg, 0.5 mmol), 3-methylbenzothiophene 2j (163 mg,
1.1 mmol) as electron-rich arene and TfOH (110 L 1.25
mmol) in 0.5 mL of CH2Cl2 following General Procedure
A. Preparative TLC purification (Petroleum ether/EtOAc:
8/2) led to 3j with 2 other regioisomers (in a 1.5:1: ratio
TfOH: 3e was prepared from 1-acetyl-3-methylindole 1a
(86.6 mg, 0.5 mmol), naphthalene 2e (192 mg, 1.5 mmol)
as electron-rich arene and TfOH (110 L 1.25 mmol) in
0.5 mL of CH2Cl2 following General Procedure A.
6
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10.1002/adsc.201701074
Advanced Synthesis & Catalysis
respectively to the benzothiophene nucleophile) as a
yellow solid (138.0 mg, 0.43 mmol, 86%).
127.7 (2C), 124.7, 123.7, 116.9, 113.8 (2C), 63.7, 55.2,
51.1, 39.4, 26.7, 24.3, 23.1, 14.0; IR (NaCl), ν (cm-1): 1662,
1596, 1513, 1479, 1403, 1254, 1035, 757; HRMS (ESI+):
calculated: 346.1778 ([C21H25NNaO2]+;[M+Na]+); found:
346.1766.
FeCl3: We reported the synthesis of 3j with FeCl3 with
General Procedure B in ref 4a.
N-Acetyl-3-(4-methoxyphenyl)-3-benzylindoline (3o)
See ref 4a for full characterization of 3j.
TfOH: 3o was prepared from 1-acetyl-3-benzylindole 1d
(125 mg, 0.5 mmol), anisole 2b (120 mg, 1.1 mmol) as
electron-rich arene and TfOH (110 L 1.25 mmol) in 1.0
mL of CH2Cl2 following General Procedure A. Preparative
TLC purification (Petroleum ether/EtOAc: 8/2) led to 3o as
a pale yellow oil (152 mg, 0.426 mmol, 85%).
N-Acetyl-3-(3-methylbenzofuran-2-yl)-3-methylindoline
(3k)
TfOH: 3k was prepared from 1-acetyl-3-methylindole 1a
(86.6 mg, 0.5 mmol), 3-methylbenzofuran 2k (125 L, 1.1
mmol) as electron-rich arene and TfOH (110 L 1.25
mmol) in 1.0 mL of CH2Cl2 following General Procedure
A. Preparative TLC purification (Petroleum ether/EtOAc:
8/2) led to 3k as a yellow crystalline solid (151 mg, 0.49
mmol, 99%).
FeCl3: We reported the synthesis of 3o with FeCl3 with
General Procedure B in ref 4b.
See ref 4b for full characterization of 3o.
FeCl3: We reported the synthesis of 3k with FeCl3 with
General Procedure B in ref 4b.
N-Acetyl-3-(4-methoxyphenyl)-3-phenylindoline (3p)
See ref 4b for full characterization of 3k.
TfOH: 3p was prepared from 1-acetyl-3-phenylindole 1e
(59 mg, 0.25 mmol), anisole 2b (60 mg, 0.55 mmol) as
electron-rich arene and TfOH (55 L 0.62 mmol) in 250
L of CH2Cl2 following General Procedure A. Preparative
TLC purification (Petroleum ether/EtOAc: 7/3) led to 3p
as a pale yellow oil (85 mg, 0.247 mmol, 99%).
N-Acetyl-3-(4-methoxyphenyl)-3-ethylindoline (3m)
TfOH: 3m was prepared from 1-acetyl-3-ethyllindole 1b
(47 mg, 0.25 mmol), anisole 2b (60 mg, 0.55 mmol) as
electron-rich arene and TfOH (55 L, 0.625 mmol) in 0.5
mL of CH2Cl2 following General Procedure A. Preparative
TLC purification (Petroleum ether/EtOAc: 8/2) led to 3m
as a pale yellow oil (68 mg, 0.226 mmol, 91%).
FeCl3: We reported the synthesis of 3p with FeCl3 with
General Procedure B in ref 4b.
See ref 4b for full characterization of 3p.
FeCl3: 3m was prepared from 1-acetyl-3-ethylindole 1b
(45.0 mg, 0.24 mmol) following General Procedure B
using anisole 2b (80 mg, 0.72 mmol) as electron-rich arene
and FeCl3 (132.3 mg, 0.816 mmol) in 0.5 mL of CH2Cl2.
N-Acetyl-3-(4-methoxyphenyl)-3-cyclohexylindoline
(3q)
Flash
column
chromatography
purification
TfOH: 3q was prepared from 1-acetyl-3-cyclohexylindole
1f (120.5 mg, 0.5 mmol), anisole 2b (120 mg, 1.1 mmol)
as electron-rich arene and TfOH (110 L 1.25 mmol) in 1
mL of CH2Cl2 following General Procedure A. Preparative
TLC purification (Petroleum ether/EtOAc: 8/2) led to 3q
as a pale brown oil (147 mg, 0.421 mmol, 84%) along with
the C2-regioisomer (16.6 mg, 0.0498 mmol, 10%) as an
inseparable mixture of ortho/para isomers.
(Cyclohexane/EtOAc: 8/2) led to 3m as a pale yellow oil
(62 mg, 0.21 mmol, 87%).
1
Rf: 0.14 (Cyclohexane/EtOAc: 8/2); H NMR (250 MHz,
CDCl3) δ (ppm): 8.32 (d, J = 7.7 Hz, 1H), 7.31 – 7.19 (m,
3H), 7.11 – 7.02 (m, 2H), 6.88 (d, J = 8.2 Hz, 2H), 4.08 (s,
2H), 3.80 (s, 3H), 2.22 (s, 3H), 2.14 (q, J = 7.2 Hz, 2H),
0.84 (t, J = 7.2 Hz, 3H); 13C NMR (90 MHz, CDCl3) δ
(ppm): 168.5, 158.1, 143.1, 138.1, 136.9, 128.1, 127.7 (2C),
124.7, 123.7, 116.9, 113.8 (2C), 63.4, 55.2, 51.5, 32.1,
24.3, 9.1; IR (NaCl), ν (cm-1): 1666, 1596, 1512, 1481,
1402, 1252, 757; HRMS (ESI+): calculated: 296.1645
([C19H22NO2]+; [M+H]+); found: 296.1640.
FeCl3: We reported the synthesis of 3q with FeCl3 with
General Procedure B in ref 7.
See ref 7 for full characterization of 3q.
2-(N-Acetyl-3-(4-methoxyphenyl)-indolin-3-yl)ethyl
acetate (3r)
N-Acetyl-3-(4-methoxyphenyl)-3-butylindoline (3n)
TfOH: 3n was prepared from 1-acetyl-3-butylindole 1c (54
mg, 0.25 mmol), anisole 2b (60 mg, 0.55 mmol) as
electron-rich arene and TfOH (55 L 0.625 mmol) in 0.5
mL of CH2Cl2 following General Procedure A. Preparative
TLC purification (Petroleum ether/EtOAc: 8/2) led to 3n
as a pale yellow oil (72 mg, 0.222 mmol, 89%).
TfOH: 3r was prepared from 2-(N-acetyl-indol-3-yl)ethyl
acetate 1g (122 mg, 0.50 mmol) anisole 2b (120 mL, 1.1
mmol) as electron-rich arene and TfOH (150 L 1.7 mmol)
in 0.5 mL of CH2Cl2 following General Procedure A.
Preparative TLC purification (Petroleum ether/EtOAc: 8/2)
led to 3r as a pale yellow oil (131.4 mg, 0.372 mmol, 74%).
FeCl3: 3n was prepared from 1-acetyl-3-butylindole 1c
(55.1 mg, 0.256 mmol) following General Procedure B
using anisole 2b (85.5 mg, 0.768 mmol) as electron-rich
arene and FeCl3 (142 mg, 0.870 mmol) in 0.6 mL of
CH2Cl2. Flash column chromatography purification
(Cyclohexane/EtOAc: 8/2) led to 3n as a pale brown oil
(73.2 mg, 0.226 mmol, 88%).
FeCl3: We reported the synthesis of 3r with FeCl3 with
General Procedure B in ref 4b.
See ref 4b for full characterization of 3r.
2-(N-Acetyl-3-(4-methoxyphenyl)-indolin-3-yl)propyl
acetate (3s)
1
Rf: 0.2 (Petroleum ether/EtOAc: 8/2); H NMR (250 MHz,
CDCl3) δ (ppm): 8.32 (d, J = 8.0 Hz, 1H), 7.31 – 7.19 (m,
3H), 7.11 – 7.06 (m, 2H), 6.88 (d, J = 8.5 Hz, 2H), 4.09 (s,
2H), 3.80 (s, 3H), 2.23 (s, 3H), 2.16 – 2.07 (m, 2H), 1.38 –
1.06 (m, 4H), 0.88 (t, J = 7.0 Hz, 3H); 13C NMR (90 MHz,
CDCl3) δ (ppm): 168.5, 158.1, 142.8, 138.3, 137.3, 128.0,
TfOH: 3s was prepared from 3-(N-acetyl-indol-3-yl)propyl
acetate 1h (131 mg, 0.5 mmol), anisole 2b (120 L, 1.1
mmol) as electron-rich arene and TfOH (150 L 1.7 mmol)
in 0.5 mL of CH2Cl2 following General Procedure A.
7
This article is protected by copyright. All rights reserved.

10.1002/adsc.201701074
Advanced Synthesis & Catalysis
Preparative TLC purification (Petroleum ether/EtOAc: 8/2)
led to acetate 3s as a brownish oil (163 mg, 0.445 mmol,
89%).
TfOH: 3w was prepared from 1-acetyl-3-methyl-5-
bromoindole 1m (125 mg, 0.5 mmol), anisole 2b (120 L,
1.10 mmol) as electron-rich arene and TfOH (110 L 1.25
mmol) in 0.5 mL of CH2Cl2 following General Procedure
A. Preparative TLC purification (Petroleum ether/EtOAc:
8/2) led to 3w as a white solid (177 mg, 0.494 mmol, 98%).
FeCl3: We reported the synthesis of 3s with FeCl3 with
General Procedure B in ref 4b.
FeCl3: We reported the synthesis of 3w with FeCl3 with
General Procedure B in ref 4b.
See ref 4b for full characterization of 3s.
N-Acetyl-3-(4-methoxyphenyl)-3-(3-
bromopropyl)indoline (3t)
See ref 4b for full characterization of 3w.
N-Acetyl-3-(4-methoxyphenyl)-5-cyano-3-
TfOH:
3t
was
prepared
from
1-acetyl-3-(3-
methylindoline (3x)
bromopropyl)indole 1i (106 mg, 0.378 mmol), anisole 2b
(90 L, 0.83 mmol) as electron-rich arene and TfOH (84
L 0.907 mmol) in 0.4 mL of CH2Cl2 following General
Procedure A. Preparative TLC purification (Petroleum
ether/EtOAc: 8/2) led to 3t as a brownish oil (139 mg,
0.358 mmol, 95%).
TfOH: 3x was prepared from 1-acetyl-3-methyl-5-
cyanoindole 1n (100 mg, 0.50 mmol), anisole 2b (120 L,
1.10 mmol) as electron-rich arene and TfOH (154 L 1.74
mmol) in 0.5 mL of CH2Cl2 following General Procedure
A. Preparative TLC purification (Petroleum ether/EtOAc:
8/2) led to 3x as a pale yellow solid (92 mg, 0.298 mmol,
60%).
FeCl3: We reported the synthesis of 3t with FeCl3 with
General Procedure B in ref 4b.
FeCl3: We reported the synthesis of 3x with FeCl3 with
General Procedure B in ref 4b.
See ref 4b for full characterization of 3t.
N-Acetyl-3-(4-methoxyphenyl)-3-methyl-5-
methoxyindoline (3u)
See ref 4b for full characterization of 3x.
N-Acetyl-3-(4-methoxyphenyl)-3,6-dimethylindoline
TfOH: 3u was prepared from 1-acetyl-3-methyl-5-
methoxyindole 1k (52 mg, 0.25 mmol), anisole 2b (60 L,
0.55 mmol) as electron-rich arene and TfOH (55 L 0.62
mmol) in 400 L of CH2Cl2 following General Procedure
A. Preparative TLC purification (Petroleum ether/EtOAc:
7/3) led to 3u as a pale yellow oil (73 mg, 0.234 mmol,
94%).
(3y)
TfOH: 3y was also prepared from 1-acetyl-3,6-
dimethylindole 1o (94 mg, 0.5 mmol), anisole 2b (120 L,
1.10 mmol) as electron-rich arene and TfOH (110 L 1.25
mmol) in 500 L of CH2Cl2 following General Procedure
A. Preparative TLC purification (Petroleum ether/EtOAc:
8/2) led to 3y as a brown oil (139 mg, 0.471 mmol, 94%).
FeCl3: We reported the synthesis of 3u with FeCl3 with
General Procedure B in ref 4b.
FeCl3: 3y was prepared from 1-acetyl-3,6-dimethylindole
1o (70 mg, 0.374 mmol) following General Procedure B
using anisole 2b as electron-rich arene (121 mg, 1.12
mmol) and FeCl3 (206 mg, 1.17 mmol) in 0.5 mL of
CH2Cl2. Flash column chromatography purification
(Cyclohexane/EtOAc: 8/2) led to 3y as a brown oil (105
mg, 0.355 mmol, 95%).
See ref 4b for full characterization of 3u.
N-Acetyl-3-(4-methoxyphenyl)-3,5-dimethylindoline
(3v)
TfOH: 3v was prepared from 1-acetyl-3,5-dimethylindole
1k (94 mg, 0.5 mmol), anisole 2b (120 L, 1.10 mmol) as
electron-rich arene and TfOH (110 L 1.25 mmol) in 500
L of CH2Cl2 following General Procedure A. Preparative
TLC purification (Petroleum ether/EtOAc: 8/2) led to 3v as
a brown oil (140 mg, 0.474 mmol, 95%).
1
Rf: 0.28 (Cyclohexane/EtOAc: 8/2); H NMR (360 MHz,
CDCl3) δ (ppm): 8.12 (s, 1H), 7.15 (d, J = 8.8 Hz, 2H),
6.87 (s, 2H), 6.83 (d, J = 8.8 Hz, 2H), 4.10 (d, J = 10.2 Hz,
1H), 3.99 (d, J = 10.2 Hz, 1H), 3.78 (s, 3H), 2.38 (s, 3H),
2.17 (s, 3H), 1.73 (s, 3H); 13C NMR (90.5 MHz, CDCl3) δ
(ppm): 168.6, 158.4, 142.5, 139.2, 138.2, 137.0, 127.6 (2C),
124.9, 123.5, 117.8, 113.9 (2C), 66.4, 55.4, 47.1, 27.4,
24.3, 21.8; IR (NaCl), ν (cm-1): 2963, 2931, 2835, 1663,
1608, 1511, 1398, 1250, 1183, 1031, 832, 812; HRMS
(ESI+): calculated: 296.1645 ([C19H21NNaO2]+;[M+Na]+);
found: 296.1635.
FeCl3: 3v was prepared from 1-acetyl-3,5-dimethylindole
1k (82 mg, 0.438 mmol) following General Procedure B
using anisole 2b as electron-rich arene (142 mg, 1.314
mmol) and FeCl3 (242 mg, 1.49 mmol) in 0.6 mL of
CH2Cl2. Flash column chromatography purification
(Cyclohexane/EtOAc: 8/2 to 7/3) led to 3v as a brown oil
(126 mg, 0.426 mmol, 97%).
N-Acetyl-3-(4-methoxyphenyl)-3-methyl-6-
fluoroindoline (3z)
1
Rf : 0.12 (Cyclohexane/EtOAc : 8/2); H NMR (360 MHz,
CDCl3) δ (ppm) : 8.14 (d, J = 8.3 Hz, 1H), 7.16 (d, J = 8.8
Hz, 2H), 7.06 (d, J = 6.8 Hz, 1H), 6.84 (d, J = 8.8 Hz, 2H),
6.77 (br s, 1H), 4.09 (d, J = 10.4 Hz, 1H), 3.98 (d, J = 10.4
Hz, 1H), 3.79 (s, 3H), 2.28 (s, 3H), 2.16 (s, 3H), 1.73 (s,
3H); 13C NMR (75.5 MHz, CDCl3) δ (ppm) : 168.3, 158.3,
140.0, 139.9, 139.0, 133.7, 128.6, 127.6 (2C), 124.3, 116.8,
113.8 (2C), 66.1, 55.3, 47.3, 27.2, 24.2, 21.2; IR (NaCl), ν
(cm-1) : 2964, 2931, 2835, 1662, 1611, 1511, 1489, 1336,
1249, 1183, 1032, 830; HRMS (ESI+) : calculated:
296.1645 ([C19H22NO2]+;[M+H]+); found: 296.1643.
TfOH: 3z was prepared from 1-acetyl-3-methyl-6-
fluoroindole 1p (95 mg, 0.497 mmol), anisole 2b (120 L,
1.10 mmol) as electron-rich arene and TfOH (110 L 1.25
mmol) in 0.5 mL of CH2Cl2 following General Procedure
A. Preparative TLC purification (Petroleum ether/EtOAc:
8/2) led to 3z brown oil (139 mg, 0.464 mmol, 93%).
FeCl3: 3z was prepared from 1-acetyl-3-methyl-6-
fluoroindole 1p (100 mg, 0.523 mmol) following General
Procedure B using anisole 2b as electron-rich arene (170
mg, 1.57 mmol) and FeCl3 (288 mg, 1.78 mmol) in 0.5 mL
of CH2Cl2. Flash column chromatography purification
(Cyclohexane/EtOAc: 8/2) led to 3z as a brown oil (152
mg, 0.508 mmol, 97%).
N-Acetyl-3-(4-methoxyphenyl)-3-methyl-5-
bromoindoline (3w)
8
This article is protected by copyright. All rights reserved.

10.1002/adsc.201701074
Advanced Synthesis & Catalysis
1
Rf: 0.27 (Cyclohexane/EtOAc: 8/2); H NMR (360 MHz,
CDCl3) δ (ppm): 8.04 (dd, J = 10.7, 2.3 Hz, 1H), 7.14 (d, J
= 8.9 Hz, 2H), 6.89 (dd, J = 8.3, 5.6 Hz, 1H), 6.84 (d, J =
8.9 Hz, 2H), 6.73 (td, J = 8.4, 2.3 Hz, 1H), 4.14 (d, J =
10.2 Hz, 1H), 4.03 (d, J = 10.2 Hz, 1H), 3.79 (s, 3H), 2.17
(s, 3H), 1.73 (s, 3H); 13C NMR (90.5 MHz, CDCl3) δ
1.76 (s, 3H); 13C NMR (62.5 MHz, CDCl3) δ (ppm): 169.2,
158.7, 145.3, 142.6, 137.4, 128.4, 127.5 (2C), 124.7, 120.2,
119.1, 114.2 (2C), 111.8, 65.9, 55.4, 47.8, 27.2, 24.2; IR
(neat): υmax (cm-1): 1677, 1502, 1436, 1257, 1035, 735;
HRMS (ESI+): calculated: 329.1260, ([C19H18N2NaO2]+;
[M+Na]+); found : 329.1257.
1
(ppm): 168.9, 162.6 (d, JC-F = 241 Hz), 158.6, 143.4 (d,
3JC-F = 12 Hz), 138.8, 135.3, 127.5 (2C), 124.3 (3JC-F = 10
Hz), 114.1 (2C), 110.6 (2JC-F = 23 Hz), 105.0 (2JC-F = 29
Hz), 66.7, 55.4, 47.1, 27.6, 24.2; IR (NaCl), ν (cm-1): 2966,
2934, 2836, 1668, 1610, 1512, 1439, 1399, 1251, 1183,
1032, 833; HRMS (ESI+): calculated: 322.1214
([C18H18FNNaO2]+;[M+Na]+); found: 322.1208.
N-Benzoyl-3-(5-methyl-2-methoxyphenyl)-3-
methylindoline (3ad)
TfOH: 3ad was prepared from 1-benzoyl-3-methylindole
1s (231 mg, 0.98 mmol) following General Procedure A
using 4-methylanisole 2a (264 mg, 2.16 mmol) as electron-
rich arene and TfOH (220 L 2.5 mmol) in 1 mL of
CH2Cl2. Preparative TLC purification (Petroleum
ether/EtOAc: 8/2) led to 3ad as a yellow solid (296 mg,
0.82 mmol, 84%).
N-Acetyl-3-(4-methoxyphenyl)-3-methyl-6-
chloroindoline (3aa)
TfOH: 3aa was prepared from 1-acetyl-3-methyl-6-
chloroindole 1q (104 mg, 0.497 mmol), anisole 2b (120 L,
1.10 mmol) as electron-rich arene and TfOH (110 L, 1.25
mmol) in 0.5 mL of CH2Cl2 following General Procedure
A. Preparative TLC purification (Petroleum ether/EtOAc:
8/2) led to 3aa as pale brown oil (146 mg, 0.463 mmol,
93%).
FeCl3: We reported the synthesis of 3ad with FeCl3 with
General Procedure B in ref 4b.
See ref 4b for full characterization of 3ad.
N-Acetyl-3-(4-methoxyphenyl)-3,7-dimethylindoline
(3ae) and 2-Acetyl-3,7-dimethylindole (7)
FeCl3: We reported the synthesis of 3aa with FeCl3 with
General Procedure B in ref 4b.
TfOH: 3ae was prepared from 1-acetyl-3,7-dimethylindole
1v (47 mg, 0.25 mmol) using anisole 2b as electron-rich
arene and TfOH (55 L 0.625 mmol) in 250 L of CH2Cl2
following General Procedure A. Flash column
chromatography purification (Cyclohexane/EtOAc : 9/1 to
8/2) led to 3ae as a brownish oil (25 mg, 0.085 mmol,
34%) along with 7 as colourless crystals (22 mg, 0.117
mmol, 47%).
See ref 4b for full characterization of 3aa.
N-Acetyl-3-(4-methoxyphenyl)-3-methyl-6-
bromoindoline (3ab)
TfOH: 3ab was prepared from 1-acetyl-3-methyl-6-
bromoindole 1r (125 mg, 0.5 mmol), anisole 2b (120 L,
1.10 mmol) as electron-rich arene and TfOH (110 L, 1.25
mmol) in 1.0 mL of CH2Cl2 following General Procedure
A. Preparative TLC purification (Petroleum ether/EtOAc:
8/2) led to 3ab as a yellow solid (176 mg, 0.491 mmol,
98%).
FeCl3: 3ae was prepared from 1-acetyl-3,7-dimethylindole
1v (80 mg, 0.427 mmol) following General Procedure B
using anisole 2b as electron-rich arene (92 mg, 0.854
mmol) and FeCl3 (166.3 mg, 1.025 mmol) in 0.6 mL of
CH2Cl2. Flash column chromatography purification
(Cyclohexane/EtOAc : 9/1 to 8/2) led to 3ae as a brownish
oil (25 mg, 0.085 mmol, 20%) along with 7 as colourless
crystals (34 mg, 0.182 mmol, 43%).
FeCl3: 3ab was prepared from 1-acetyl-3-methyl-6-
bromoindole 1r (45.5 mg, 0.180 mmol), using anisole 2b
as electron-rich arene (58.5 mg, 0.541 mmol) and FeCl3
(99.5 mg, 0.614 mmol) in 0.5 mL of CH2Cl2 following
General Procedure B. Flash column chromatography
purification (Cyclohexane/EtOAc: 8/2) led to 3ab as a
yellow solid (64.0 mg, 0.180 mmol, 99%).
1
Data for 3y: Rf: 0.14 (Cyclohexane/EtOAc: 8/2); H NMR
(360 MHz, CDCl3) δ (ppm): 7.14-7.07 (m, 4H), 6.90 (dd, J
= 7.0, 1.9 Hz, 1H), 6.81 (d, J = 8.6 Hz, 2H), 4.13 (br s, 1H),
3.96 (d, J = 10.4 Hz, 1H), 3.77 (s, 3H), 2.33 (s, 3H), 2.09
(s, 3H), 1.68 (s, 3H); 13C NMR (90.5 MHz, CDCl3) δ
Rf: 0.31 (Petroleum ether/EtOAc: 7/3); 1H NMR (300 MHz, (ppm): 169.6, 158.3, 142.5, 141.7, 137.3, 130.2, 129.2,
CDCl3) δ (ppm): 8.47 (d, J = 1.8 Hz, 1H). 7.18 – 7.13 (m,
3H), 6.86 – 6.81 (m, 3H), 4.11 (d, J = 10.5 Hz, 1H), 4.01
(d, J = 10.5 Hz, 1H), 3.78 (s, 3H), 2.18 (s, 3H) 1.73 (s,
3H); 13C NMR (75 MHz, CDCl3) δ (ppm): 168.9, 158.4,
127.6 (2C), 125.7, 120.9, 113.8 (2C), 67.0, 55.2, 48.8, 24.9,
23.4, 20.3; IR (NaCl), ν (cm-1): 2961, 2930, 2835, 1669,
1608, 1511, 1386, 1374, 1250, 1183, 1031; HRMS (ESI+):
calculated: 318.1465 ([C19H21NNaO2]+;[M+Na]+); found:
143.3, 139.0, 138.2, 127.5 (2C), 127.0, 125.1, 121.5, 120.1, 318.1455.
113.9 (2C), 66.1, 55.3, 47.1, 27.2, 24.2; IR (neat) υmax (cm-
1): 2930, 1668, 1470, 1393, 1336, 1252, 1185, 1030, 834,
1
Data for 7: Rf: 0.43 (Cyclohexane/EtOAc: 8/2); H NMR
(360 MHz, CDCl3) δ (ppm): 8.90 (br s, 1H), 7.54 (d, J =
8.0 Hz, 1H), 7.17-7.04 (m, 2H), 2.64 (s, 3H), 2.64 (s, 3H),
2.49 (s, 3H); 13C NMR (62.9 MHz, CDCl3) δ (ppm): 190.6,
136.0, 132.7, 128.7, 126.8, 121.3, 120.5, 119.4, 119.0, 29.1,
16.6, 11.4; IR (NaCl), ν (cm-1): 3337, 2913, 1636, 1539,
1443, 1417, 1354, 1323, 1238, 971, 777, 744; HRMS
(ESI+): calculated: 210.0889 ([C12H13NNaO]+; [M+Na]+);
found: 210.0889
665;
HRMS
(ESI+):
calculated:
382.0413,
([C18H18BrNNaO2]+; [M+Na]+); found: 382.0402.
N-Acetyl-3-(4-methoxyphenyl)-3-methyl-6-
cyanoindoline (3ac)
TfOH: 3ac was prepared from 1-acetyl-6-cyano-3-
methylindole 1s (99 mg, 0.5 mmol), anisole 2b (120 L,
1.10 mmol) as electron-rich arene and TfOH (150 L, 1.7
mmol) in 0.5 mL of CH2Cl2 following General Procedure
A. Preparative TLC purification (Petroleum ether/EtOAc:
8/2) led to 3ac as a yellow solid (35 mg, 0.114 mmol,
23%).
1-(7'-methoxy-3',4'-dihydro-2'H-spiro[indoline-3,1'-
naphthalen]-1-yl)ethanone (4a)
TfOH: 4a was prepared from 1-acetyl-3-(3-(4-
methoxyphenyl)-propyl)indole 1w (154 mg, 0.5 mmol) and
TfOH (110 L 1.25 mmol) in 10 mL of CH2Cl2 following
General Procedure A. Preparative TLC purification
(Petroleum ether/EtOAc : 7/3) led to 4a as a yellow solid
(125 mg, 0.407 mmol, 81%).
Rf: 0.31(Petroleum ether/EtOAc: 7/3); 1H NMR (300 MHz,
CDCl3) δ (ppm): 8.59 (s, 1H). 7.35 (dd, J = 7.8, 1.5 Hz,
1H), 7.14 (dd, J = 6.6, 2.1 Hz, 2H), 7.05 (d, J = 7.5 Hz,
1H), 6.88 (dd, J = 6.6, 2.1 Hz, 2H) 4.20 (d, J = 10.5 Hz,
1H), 4.09 (d, J = 10.5 Hz, 1H), 3.80 (s, 3H), 2.22 (s, 3H)
9
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10.1002/adsc.201701074
Advanced Synthesis & Catalysis
FeCl3: We reported the synthesis of 4a with FeCl3 with
General Procedure B in ref 4d.
FeCl3: We reported the synthesis of 5a with FeCl3 with
General Procedure B in ref 4e.
See ref 4d for full characterization of 4a.
See ref 4e for full characterization of 5a.
1-(7'-methyl-3',4'-dihydro-2'H-spiro[indoline-3,1'-
naphthalen]-1-yl)ethanone (4b)
Data for 6: Rf: 0.11 (Petroleum ether/EtOAc: 8/2); 1H
NMR (250 MHz, CDCl3) δ (ppm): 7.62 (d, J = 8.0 Hz, 1H),
7.18 – 6.98 (m, 7H), 6.72 (d, J = 8.2 Hz, 2H), 6.59 (br s,
1H), 4.97 (t, J = 7.7 Hz, 1H), 3.52 (s, 6H), 3.19 (d, J = 7.7
Hz, 2H), 2.30 (s, 6H), 1.99 (s, 3H); 13C NMR (62.5 MHz,
CDCl3) δ (ppm): 168.6, 155.4, 132.7, 132.6, 131.4, 131.3,
129.9, 129.1, 127.9, 126.6, 125.1, 124.1, 111.7, 56.1, 38.4,
37.5, 24.1, 21.0; HRMS (ESI+): calculated: 426.2039
([C26H29NNaO3]+;[M+Na]+); found: 426.2026
TfOH: 4b was prepared from 1-acetyl-3-(3-(4-
methylphenyl)-propyl)indole 1x (145.5 mg, 0.5 mmol) and
TfOH (110 L 1.25 mmol) in 10.0 mL of CH2Cl2
following General Procedure A. Preparative TLC
purification (Petroleum ether/EtOAc:7/3) led to 5b as a
brownish solid (143 mg, 0.491 mmol, 98%).
N-Acetyl-2-(2-methoxy-5-methylphenyl)-5-
bromoindoline (5b)
FeCl3: We reported the synthesis of 4b with FeCl3 with
General Procedure B in ref 4d.
TfOH: 5b was prepared from 1-acetyl-5-bromoindole 1ac
(119 mg, 0.5 mmol) 4-methyl anisole 2a (136 mg, 1.11
mmol) as electron-rich arene and TfOH (110 L, 1.25
mmol) in 1.0 mL of CH2Cl2 following General Procedure
A. Preparative TLC purification (Petroleum ether/EtOAc:
8/2) led to 7b as a yellow solid (152 mg, 0.422 mmol,
84%).
See ref 4d for full characterization of 4b.
1-(3',4'-dihydro-2'H-spiro[indoline-3,1'-naphthalen]-1-
yl)ethanone (4c)
TfOH:
4c
was
prepared
from
1-acetyl-3-(3-
phenylpropyl)indole 1y (139 mg, 0.5 mmol) and TfOH
(110 L 1.25 mmol) in 10.0 mL of CH2Cl2 following
General Procedure A. Preparative TLC purification
(Petroleum ether/EtOAc : 7/3) led to 4c as a yellow solid
(121 mg, 0.437 mmol, 87%).
FeCl3: We reported the synthesis of 5b with FeCl3 with
General Procedure B in ref 4e.
See ref 4e for full characterization of 5b.
FeCl3: We reported the synthesis of 4c with FeCl3 with
General Procedure B in ref 4d.
N-Acetyl-2-(2-methoxy-5-methylphenyl)-5-
nitroindoline 5c
See ref 4d for full characterization of 4c.
TfOH: 5c was prepared from 1-acetyl 5-nitroindole 1ad
(103 mg, 0.504 mmol), 4-methyl anisole 2a (168 mg, 1.36
mmol) as electron-rich arene and TfOH (110 L, 1.25
mmol) in 0.5 mL of CH2Cl2 following General Procedure
A. Preparative TLC purification (Petroleum ether/EtOAc:
6/4) led to 5c as a light brown solid (161 mg, 0.493 mmol,
98%).
1-(6'-chloro-6,7-dihydro-5H-spiro[benzo[b]thiophene-
4,3'-indolin]-1'-yl)ethanone (4d)
TfOH: 4d was prepared from 1-acetyl-6-chloro-3-(3-
(thiophen-2-yl)propyl)indole 1z (80 mg, 0.25 mmol) and
TfOH (55 L, 0.625 mmol) in 5.0 mL of CH2Cl2 following
General Procedure A. Preparative TLC purification
(Petroleum ether/EtOAc : 7/3) led to 4d as a white solid
(77 mg, 0.242 mmol, 97%).
FeCl3: We reported the synthesis of 5c with FeCl3 with
General Procedure B in ref 4e.
See ref 4e for full characterization of 5c.
FeCl3: We reported the synthesis of 4d with FeCl3 with
General Procedure B in ref 4d.
Acknowledgements
See ref 4d for full characterization of 4d.
The research leading to these results has received funding from
the People Programme (Marie Curie Actions) of the European
Union's Seventh Framework Programme FP7/2007-2013/ under
REA grant agreement n° 623422 (IIF-2013 postdoctoral
fellowship to R.K.N.). RB thanks the MENESR for a PhD
fellowship. We also gratefully acknowledge the ANR (JCJC
program 2012, ANR-12-JS07-0002; “CouPhIn”), the Université
Paris Sud and the CNRS for financial support.
Diethyl 1-acetyl-2'H-spiro[indoline-3,1'-naphthalene]-
3',3'(4'H)-dicarboxylate (4e)
TfOH: 4e was prepared from diethyl 2-((1-acetyl-1H-indol-
3-yl)methyl)-2-benzylmalonate 1aa (210 mg, 0.5 mmol)
and TfOH (110 L 1.25 mmol) in 10 mL of ClCH2CH2Cl
following General Procedure A at 80 °C. Preparative TLC
purification (Petroleum ether/EtOAc: 7/3) led to 4e as a
colorless solid (159 mg, 0.378 mmol, 76%).
References
FeCl3: We reported the synthesis of 4e with FeCl3 with
General Procedure B at 80°C in ref 4d.
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10
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10.1002/adsc.201701074
Advanced Synthesis & Catalysis
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11
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10.1002/adsc.201701074
Advanced Synthesis & Catalysis
UPDATE
Triflic acid as an efficient Brønsted acid promoter
for the Umpolung of N-Ac indoles in
hydroarylation reactions
Adv. Synth. Catal. Year, Volume, Page – Page
Raj Kumar Nandi, Alejandro Perez-Luna, Didier
Gori, Rodolphe Beaud, Régis Guillot, Cyrille
Kouklovsky, Vincent Gandon* and Guillaume
Vincent*
12
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