Hexafluoroisopropanol: A powerful solvent for the hydrogenation of indole derivatives. Selective access to tetrahydroindoles or cis-fused octahydroindoles

Article abstract of DOI:10.1039/c2ob25980j

Pd/C in HFIP was used to hydrogenate indole derivatives under relatively mild conditions, leading to potential synthetic intermediates of bioactive compounds. Depending on their substitution, tetrahydroindoles or octahydroindoles could selectively be obtained.

Full text of DOI:10.1039/c2ob25980j

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PAPER
Hexafluoroisopropanol: a powerful solvent for the hydrogenation of indole
derivatives. Selective access to tetrahydroindoles or cis-fused
octahydroindoles†
Damien Clarisse,a Bernard Fenetb and Fabienne Fache*a
Received 21st May 2012, Accepted 19th June 2012
DOI: 10.1039/c2ob25980j
Pd/C in HFIP was used to hydrogenate indole derivatives under relatively mild conditions, leading to
potential synthetic intermediates of bioactive compounds. Depending on their substitution,
tetrahydroindoles or octahydroindoles could selectively be obtained.
by direct reduction of indoles. A two-step procedure including a
regioselective Birch reduction followed by a catalytic hydrogen-
Introduction
Hydrogenation of indole derivatives constitutes a powerful
method to access cyclic N-containing skeletons.1 Nevertheless, it
is difficult, due to the highly resonance-stabilized aromatic
nucleus and to the products themselves which could poison the
metal catalyst. Moreover, the hydrogenation of the indole moiety
may lead to three main classes of compounds, indolines, tetrahy-
droindoles or octahydroindoles and the control of the regioselec-
tivity still remains a problem. In the course of our study on the
hydrogenation of aromatic compounds,2,3 we have reported the
solvent dependent hydrogenation of substituted quinolines using
Rh/Al2O3 as a catalyst and either methanol or hexafluoroisopro-
panol (HFIP) as solvent to obtain either 1,2,3,4-tetrahydroquino-
lines or decahydroquinolines respectively. We thus decided to
test our system on indole derivatives. The indoline skeleton is an
ubiquitous structural motif in naturally occurring alkaloids and
many biological active compounds such as Duocarmycins or
Pentopril.4 Therefore, numerous transition metal catalytic
systems have been developed to reduce selectively of the pyrrole
ring.5 Other methods such as catalytic transfer hydrogenation in
formic acid6 or the use of trimethylamine/borane mixture were
also developed.7 Asymmetric versions were proposed too.8 As
for the 4,5,6,7-tetrahydroindole derivatives, they are classically
formed by multistep procedures such as microwave-assisted
aminolysis of 4-oxo-4,5,6,7-tetrahydrobenzofuran with different
primary amines,9 or from 1-(1-pyrrolidino)cyclohexene and
chloropyruvates.10 Only few examples have been reported so far
ation was developed to obtain selectively the tetrahydroderi-
vatves.11 These products are generally formed as intermediates
in the course of the total hydrogenation of indoles into octa-
hydroindoles.12 Nevertheless, tetrahydroindole derivatives con-
stitute a class of compounds of growing interest as they were
proved to be active for the treatment of neurodegenerative dis-
eases13 and in some cases may have comparable activity as
dopamine.14 As for octahydroindoles, this skeleton is present in
numerous bioactive products such as aerugunosins15 or angio-
tensin converting enzyme (ACE) inhibitors.16 Octahydroindoles
can also be used as ligands for catalytic asymmetric transform-
ations17 or as reversible organic hydrogen storage liquids for
hydrogen-powered fuel cells.18 Two main strategies can be pro-
posed to obtain this skeleton: the direct hydrogenation of indole
derivatives19 or the building of the core by successive chemical
reactions, including asymmetric procedures.20 If this last
approach has been widely developed, only few examples are
described in the case of hydrogenation of substituted indoles,
which limits its application to organic synthesis.
In this paper we want to report our results on the hydrogen-
ation of substituted indole derivatives. We will successively
examine how the nature of the catalyst and of the solvent as well
as the substitution of the different rings and of the nitrogen, may
influence the selectivity of the reaction.
Results and discussion
We first chose to select our standard conditions by studying the
hydrogenation of the unsubstituted indole. With the objective of
delivering simple and selective methods useful for organic che-
mists, we used only commercially available heterogeneous cata-
lysts. Classically, transition metal catalysts such as Pd, Ru, Rh or
Pt are used, with different support and/or oxidation degree.
Taking into account previous studies of this laboratory, we tested
aUniversité de Lyon, Université Lyon 1, ICBMS, équipe SURCOOF,
CNRS, UMR 5246, Bât. Raulin, 43 Bd du 11 Nov. 1918, 69622
Villeurbanne cedex, France. E-mail: fache@univ-lyon1.fr;
Fax: +33472448136; Tel: +33472448521
bCentre Commun de Résonnance Magnétique Nucléaire, Bâtiment
Curien, 3 rue Victor Grignard, 69622 Villeurbanne cedex, France
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c2ob25980j
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Table 1 Optimization of the reaction conditions
Table 2 Influence of the substitution of the pyrrole ring by electron
donating groups on the hydrogenation of indole derivatives
Yielda
(%)
Comp.
4 (a–c) t (h) 5(a–c)
Yielda (%)
Entry Catalyst
Solvent
P (bar) T (°C) t (h)
2
3
Entry R1, R2
6(a–c)
100 (72 : 28)b
123
2
Me, H
Me, H
Me, Me
Me, Me
CH2OH, H
CH2OH, H
a
a
b
b
c
8
1
22
8
48
8
0
82
10
0
0
40
1
2
3
4
5
6
7
8
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
PdO2
PtO2
RuO2
HFIP
HFIP
HFIP
HFIP
MeOH
MeOH
MeOH
TFEb
iPrOH
AcOH
HFIP
HFIP
HFIP
7
1
7
7
7
7
7
7
7
1
7
7
7
7
1
7
11
20
20
50
20
50
50
50
50
20
50
50
50
50
20
50
22
60
22
8
50
30
8
8
8
60
8
8
17
0
0
0
22
0
21
10
53
22
72
0
77
100
100
100
0
100
67
85
5
57
14
Traces
50
3c
4
100 (85)d (4 dia)
100 (80 : 20)b,e
40
5
6
c
a Estimated by 1H NMR, missing product is starting material; standard
conditions: indole 0.5 mmol, HFIP 1 mL, 5% Pd/C, 50 °C, 7 bar H2.
b Diastereoisomeric ratio. c Performed at 20 °C. d Isolated yield. e 10%
Pd/C.
9
10
11
12
13
14
15
16
100
0
100
51
8
8
22
8
0
0
33
14
Rh/Al2O3 HFIP
Rh/Al2O3 HFIP
Rh/Al2O3 MeOHc
We then tested indole derivatives bearing an electron donating
group on the pyrrole ring (Table 2).
59
Once again, the intermediates are the indoline derivatives
(Table 2, entries 2, 3, 6), which could explain why in the case of
monosubstituted indoles two diastereoisomers of the octa-
hydroindole derivatives were formed: the indolic compound was
first adsorbed on the catalyst surface. Then, the pyrrole ring was
reduced, leading to a racemic mixture of products. These two
enantiomers were re-adsorbed on the catalyst surface, the
benzene ring was hydrogenated in a cis manner, giving four
compounds, enantiomers two to two, and thus two diastereo-
isomers, easily detectable by NMR. We assume that the adsorp-
tion of the indoline intermediate bearing the substituent which
pointed towards the catalyst surface is more difficult which
induces a difference in reactivity and thus justifies the diastereo-
selectivity. In the case of the tetrahydroindole intermediate, the
pyrrole intermediate was also reduced in a cis way: a de-
sorption–adsorption process may occur after the reduction of the
first double bond and before the hydrogenation of the second
one, which may explain the two diastereoisomers. Nevertheless,
to a kinetic point of view, this is less favorable than a concomi-
tant hydrogenation of the two aromatic bonds and thus in the
case of the tetrahydroindole intermediate, the diastereoselectivity
should be higher.
5% of metal; catalyst used, Pd/C (10% w/w), Rh/Al2O3 (5% w/w).
a Estimated by 1H NMR, missing product is starting material; standard
conditions: indole 0.5 mmol, solvent 1 mL. b TFE: trifluoroethanol.
c 14% of tetrahydroindole were detected.
more specifically HFIP as solvent, whose intrinsic properties
turned out to be particularly interesting for the reduction of aro-
matic derivatives.2,3,21 Classical alcohols were also used as sol-
vents. Moreover, catalytic hydrogenation usually requires forcing
conditions, which could be diminished in the presence of acid,
probably because of the formation of the iminium ion with dis-
rupted aromaticity, which is then reduced more easily. We thus
tried AcOH, frequently used for the hydrogenation of aromatic
compounds. In a typical procedure, the indole derivative, the
solvent and the catalyst were charged in an autoclave for the
appropriate time under the requisite pressure. At the end of the
reaction, the catalyst was filtered on Celite, the solvent evapor-
1
ated and the reaction mixture analyzed by H NMR. Results on
the indole are summarized in Table 1.
HFIP turned out to be the best solvent. Using Pd/C under
7 bar of H2 pressure at 50 °C in HFIP allowed to reduce totally
the indole into octahydroindole in 8 h (entry 4). Whatever the
solvent, indoline seemed to be the reaction intermediate (entries
1, 5, 8, 9 and 10) as no tetrahydroindole derivative was detected
(except in the case of Rh/Al2O3 in MeOH, entry 16). In all
cases, only the cis isomer of the octahydroindole was obtained.
If there are numerous studies which claim access to cis-octahy-
droindole, to our knowledge, only Mokotoff and Hill have clearly
assigned the two C1 and the C7a protons chemical shifts.22
Comparison with these reported data and NOESY experiments
allowed us to confirm this stereochemistry (see ESI† part).
PtO2 (entry 12) and Rh/Al2O3 (entry 14) revealed to be as
efficient as Pd/C (entry 3) but for economical reason we chose
Pd/C.
In the case of compound 6a, a 72 : 28 ratio of two diastereo-
1
isomers was measured by H NMR analysis, on protons 2 and
7a. Nevertheless, it was not possible to attribute the relative
configuration of each center, despite all our efforts. In the case of
compound 4c, the intermediate 5c is an amino alcohol which
can act as a ligand for the palladium17 and thus reduce its
activity, which can explain the results, 48 h versus 8 h for the
reaction to go to completion (Table 2 entries 1 and 5). Two dia-
stereoisomers in a 80 : 20 ratio were obtained (entry 5) but it was
impossible to attribute the relative configuration of each center.
When an electron donating group was on the benzene ring, for
example in the case of the 6-methoxy indole, a mixture of cis
octahydroindole derivatives with a OMe, OH or H substituent on
the 6 position was obtained.
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We then examine the influence of an electron withdrawing
group on the reactivity of indole derivatives (Table 3).
and immunomodulators, has been obtained previously24 by
hydrogenation over Pd/C in iPrOH under 50 bar H2 in 5 h at
110–140 °C which are considerably harder conditions than ours!
When both the quantity of palladium and the reaction time
increased, only minor quantities of the octahydroindole deriva-
tive 6e were detected whereas Blankley et al.25 reported the com-
plete hydrogenation of the ethyl ester analog of 4e in AcOH–
EtOH using 10% Rh/C. When the ester is at position 3 (entries 2
and 3), the reduction was easier to perform, even though difficult
and both the tetrahydro derivative 7f and the octahydroindole 6f
can be isolated. A diastereoisomeric ratio of 73 : 27 was
measured in favor of the (3S*,3aS*,7aS*) isomer of 6f. When
the substituent is a carboxylic acid group (entry 4), in our stan-
dard conditions, decarboxylation occurs which has been already
reported in the literature on indole derivatives with palladium.26
Nevertheless, as no aromatic decarboxylated intermediates have
been detected, we assume that this reaction occurred after total
hydrogenation of the indole moiety. Using PtO2 in acetic acid at
atmospheric pressure of H2 allowed this problem to be overcome,
as described by Cativiela et al.27 Changing HFIP for iPrOH
allowed us to obtain selectively the tetrahydroderivative and also
to avoid decarboxylation (entry 5).
In these cases, the intermediates are the tetrahydroderivatives.
This is in agreement with the hypothesis of the formation of the
iminium salt intermediate: when an electron donating group is
present on the pyrrole ring, it stabilizes the iminium which is
then hydrogenated. In the case of an electron withdrawing group,
this iminium is not stable, maybe not formed at all, and then the
benzene ring is hydrogenated first. Moreover, when the ring is
substituted on C2, contributing structures show a rupture of the
benzene ring aromaticity versus a conservation of aromaticity
when substituted on C3, which is in agreement with the easier
formation of the tetrahydroindole intermediate in the first case.
In the case of compound 4e, the tetrahydroindole derivative 7e
was isolated exclusively (98% isolated yield, entry 1). This com-
pound, intermediate in the synthesis of anti-inflammatory agents
Table 3 Influence of the substitution of the pyrrole ring by an electron
withdrawing group on the hydrogenation of indole derivatives
With the access to natural products via the 2-carboxy-6-hydro-
xyoctahydroindole intermediate in mind, we thus examined the
possibility to obtain them by hydrogenation of compounds of
type 8. In the literature, several methods have been published to
build this skeleton by successive chemical reactions.28 Neverthe-
less, to our knowledge, no direct hydrogenation of the disubsti-
tuted indole have been reported so far (Table 4).
As for compounds 8 (a,b), the intermediates were the tetra-
hydroindole derivatives 9 (a,b). Even with more catalyst and
longer reaction time, it has not been possible for the reaction to
go to completion (entries 1 and 2). Moreover, in the case of com-
pound 9a, a complex mixture of compound 10a and demethyl-
ated or demethoxylated analogs was obtained. It has not been
possible to isolate compound 10a in its pure form. In the case of
the 6-hydroxyderivative 8b, compound 10b was not observed as
the hydrogenation stopped at the conjugated ketone derivative
11-(2R*,3aR*) which could be easily isolated (entries 3 and 4).
Yielda (%)
Comp.
Entry
R1, R2
4 (e–h)
t (h)
7 (e–h)
6 (e–h)
1
2
3
COOMe, H
H, COOMe
H, COOMe
COOH, H
COOH, H
H, COOH
e
f
f
g
g
h
8
86
48c
4
8
8
98b
0
48 (42)b
25b
0
52 (44)b
75b (73 : 27)d
4
0f
0
5e
6
45b
59
0g
a Estimated by 1H NMR, missing product is starting material; standard
conditions: indole 0.5 mmol, HFIP 1 mL, 5% Pd/C, 50 °C, 7 bar H2.
b Isolated yield. c Performed with 10% Pd/C. d Diastereoisomeric ratio.
e In iPrOH. f 100%
.
g 21% Starting material and 20%
.
Table 4 Hydrogenation of 2,6-disubstituted indole derivatives
Yielda (%)
Comp.
Entry
R
8 (a,b)
% Pd/C
t (h)
9 (a,b)
66b
10 (a,b)
11
1
2
3
4
5
Me
Me
H
H
H
a
a
b
b
b
5
10
5
10
20
8
48
8
8
24
34c
58c
0
0
0
0
0
38
42
38
45b (60)
50
28b (40)
50
1
a Estimated by H NMR, missing product is starting material; standard conditions: indole 0.5 mmol, HFIP 1 mL, 50 °C, 7 bar H2. b Isolated yield.
c Complex mixture of product 10 and demethylated/demethoxylated products.
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Table 5 Influence of the N-protection on the hydrogenation of indole derivatives
Yielda (%)
Comp.
Entry R, R1, R2
12 (a–g)
t (h)
13 (a–g)
14 (a–g)
15 (a–g)
132
233
3
Ac, H,H
Boc, H, H
Tos, H, H
Boc, H, OMe
Boc, COOMe, H
Boc, COOMe, OMe
Me, COOH, H
a
b
c
d
e
f
8
8
8
8
8
8
14
100
100 (99)b
0
0
0
0
0
0
0
0
47
4
53 (31)b
71 (47)b
63
534
6
20 (8)b
Trace
0
0
Trace
7
g
0
60 (48)b (2S*,3aS*,7aS*)
8c
Me, COOH, H
g
24
20
0
25
a Estimated by 1H NMR, missing product is starting material; standard conditions: indole 0.5 mmol, HFIP 1 mL, 5% Pd/C, 50 °C, 7 bar H2. b Isolated
yield. c 20 °C.
Forcing the reaction conditions has not a substantial effect on the
reaction progress (entry 5). Nevertheless, intermediate 11 could
be of interest as a careful choice of the reduction system might
lead to the trans octahydroindol intermediate, the trans junction
being present in some bioactive molecules such as Trandopril.29
Formation of compound 11 starting from intermediate of type 9
was difficult to explain. Increasing both the catalyst loading and
the reaction time did not significantly modify the 9 : 11 ratio
(entries 4 and 5). Therefore we can assume that compound 11
did not come from compound 9.
Substitution of the nitrogen group could also modify the reac-
tivity of indole derivatives (Table 5). Among the different pro-
tecting groups, the t-butoxycarbonyl group (Boc), easy to
introduce and easy to remove, was the most used. Thus Coulton
et al.30, with Rh/Al2O3 in EtOH–AcOH, selectively reduced
various substituted indoles N-Boc protected into indolines. With
PtO2 in AcOH, Cativiela et al.31 obtained exclusively the octa-
hydroindole derivative during the hydrogenation of indole-2-car-
boxymethyl ester N-Boc protected. With our system,
introduction of the Boc group on the nitrogen slows down the
reaction (compare Table 1 entry 4 and Table 5 entry 2) or even
modifies the mechanism: for example, in the case of the indole-
2-carboxymethyl ester 4e only the tetrahydroindole derivative 7e
was isolated whereas for the N-Boc protected compound 12e,
the indoline intermediate 13e was predominant (Table 3 entry 1
and Table 5 entry 5). The same tendency was observed for com-
pound 8a and its N-Boc-derivative 12f. Considering the contri-
buting structures, we assume that the introduction of the Boc
group on the nitrogen, because of its electron withdrawing prop-
erties, diminishes the aromaticity of the pyrrole ring which is
then easier to hydrogenate, leading to the indoline type inter-
mediate, whereas in the case of electron withdrawing group on
C2 or C3 positions, it is the aromaticity of the benzene ring
which is decreased, leading to the tetrahydroindole intermediate.
The acyl group has the same effect on indole as the Boc
one (entry 1). However, the N-sulfonyl indole 12c failed to
be reduced in our standard conditions (entry 3). This com-
pound seems to be harder to reduce than the other N-substi-
tuted indoles as observed by Chandrasekhar et al.35 In the
case of an electron donating N-protecting group such as the
methyl one, the reaction went slower (Table 3 entry 4 and
Table 5 entry 7), the decarboxylation was limited but not
suppressed.
As most of the natural products possessing the octahydro-
indole skeleton have an amide substituent at the 2-position,16 we
thus decided to test the hydrogenation of these derivatives which
would give a direct access to the desired octahydroindole com-
pounds (Table 6).
Whatever the tested substrate, the intermediate was always
the tetrahydroindole derivative 17 (a–e). In the case of unsub-
stituted nitrogen (entry 1), even harsher conditions (more pal-
ladium, longer reaction time) did not allow the reaction to go
to completion. With only one hydrogen substituent on the
nitrogen of the amide group, it has been possible to obtain
with good isolated yields the octahydroindole derivative.
When the substituent was the ethyl group (entry 2), a diaster-
eoisomeric ratio of 88 : 12 in favor of the (2S*,3aS*,7aS*)
isomer was measured. When the substituent was a chiral sub-
stituent, no specific induction was observed as a mixture of 4
diastereoisomers in the same proportions as with the ethyl
group was obtained (entry 6). In the case of disubstitution
(entry 5), indole 16c was totally hydrogenated and the octahy-
droindole derivative 18c was isolated with an excellent dia-
stereoisomeric ratio of 94 : 6 in favor of again the
(2S*,3aS*,7aS*) isomer. As for the Weinreb type amide (entry
7), the methoxy group was hydrogenolysed and the reactivity
of the resulting compound could be compared to those of
indole 16c.
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Table 6 Hydrogenation of 2-amido indole derivatives
Yielda (%)
Comp.
Entry R1, R2
16 (a–e)
t (h) Catalyst
17 (a–e)
18 (a–e)
1
2
3
4
5
6
H, H
H, Et
H, Et
Et, Et
Et, Et
a
b
b
c
c
d
48
48
5
3
48
48
10% Pd/C
10% Pd/C
5%Pd/C
5%Pd/C
5% Pd/C
10% Pd/C
56
9b
7
91b (88 : 12)
52b
0
62b (65)
0
34b (35)
93b (100) (ratio 94 : 6)
90c
8b (10)
7
Me, OMe
Me, OMe
e
e
e
24
39
24
5% Pd/C
5% Pd/C
10% PtO2
5b (10)
0
0
0
8d
56b
9
Me, OMe
25b
1
a Estimated by H NMR, missing product is starting material; standard conditions: indole 0.5 mmol, HFIP 1 mL, 50 °C, 7 bar H2. b Isolated yield.
c Complex mixture of 4 diastereoisomers. d 20 °C.
purified on silica gel.
Conclusions
In conclusion, a simple methodology to obtain tetrahydroindoles
and/or octahydroindoles from indoles in a one pot reaction has
been developed. Thus, the Pd/C-HFIP catalytic system has been
demonstrated to be efficient for the hydrogenation of substituted
indole derivatives, in mild conditions. Depending on the substi-
tuents, different compounds have been synthesized, and in par-
ticular various tetrahydoindoles have been isolated, which are
valuable intermediates for the pharmaceutical industry. More-
over, octahydroindoles substituted by an amide group at C2 have
been obtained with very good yield and diastereoselectivity, con-
stituting an interesting class of synthesis intermediates.
(3aR*,7aR*)-Octahydro-1H-indole·HFIP 3. Yellow oil; Rf
0.25 (CH2Cl2–MeOH 85 : 15); H3a H7a Relation determined by
NOESY; H NMR: (400 MHz, CDCl3) δ 7.68 (2H, br s), 4.26
1
(1H, sept, J = 6.5 Hz, HHFIP), 3.21–3.07 (2H, m, H2,7a), 2.97
(1H, ddd, J = 11.6, 9.6, 5.7 Hz, H2′), 2.14–2.03 (1H, m, H3a),
1.89–1.78 (2H, m, H3), 1.72–1.21 (8H, m, H4–7); 13C NMR:
(100 MHz, CDCl3) δ 69.9 (CH, sept, J = 33 Hz, CHFIP), 57.6
(CH, C7a), 43.3 (CH2, C2), 37.8 (CH, C3a), 29.4 (CH2, C3), 26.5,
26.4, 22.7, 21.7 (4CH2, C4–7); 19F NMR: (282 MHz, CDCl3)
δ −76.15 (s); IR: ν 2925, 2854, 1448, 1374, 1284, 1180, 1099,
730 cm−1; MS (ESI): calculated for C11H16N2O [M + H]+:
126.1 found 126.1.
Experimental section
General remarks
NMR spectra were recorded on a Bruker AC300, 400 or a
Bruker Advance III 500 MHz. HRMS Electron Impact (EI) or
ElectroSpray (ESI) determinations were made using a Finigan-
MAT 95 XL instrument. IR spectra (neat) were recorded on a
Nicolet IS 100. Melting points were measured with a B-540
Büchi. Rf were calculated using TLC silicagel 60 F254 Merck.
(2R*,3aS*,7aS*)-2-Methyloctahydro-1H-indole with (2S*,3aS*,-
7aS*)-2-methyloctahydro-1H-indole 6a. colorless oil; Rf 0.27
(CH2Cl2–MeOH 85 : 15); Mixture of diastereoisomers 72 : 28
A–B: 1H NMR: (300 MHz, CDCl3) δ 3.52–3.36 (0.7H, m, H2A),
3.24–3.12 (1H, m, H2B,7aA), 3.11–2.96 (1.3H, m, H1A,1B,7aB),
2.09–1.90 (1.6H, m, H3B,3aA,3aB), 1.77 (0.7H, ddd, J = 12.8, 8.0,
4.9 Hz, H3A), 1.67–1.18 (9.6H, m, H3′A,4A,4B,5A,5B,6A,6B,7A,7B,8B),
1.19–1.11 (2.4H, m, H8A). 13C NMR: (75 MHz, CDCl3) δ 58.0
(CH, C7aB), 56.9 (CH, C7aA), 53.2 (CH, C2B), 51.1 (CH, C2A),
General procedure for hydrogenation. The indole derivative
(0.5 mmol) was added to a solution of catalyst in 1 mL of
solvent and the solution was placed in an autoclave under hydro-
gen pressure at the requested temperature for a given time. The
catalyst was then filtered through Celite and the product was
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Methyl 4,5,6,7-tetrahydro-1H-indole-3-carboxylate 7f. White
solid; Rf 0.33 (ethyl acetate–petroleum ether 30 : 70); mp:
123–125 °C; H NMR: (400 MHz, CDCl3) δ 8.37 (1H, br s),
7.25 (1H, s), 3.78 (3H, s), 2.73 (2H, t, J = 5.8 Hz), 2.54 (2H, t,
J = 5.8 Hz), 1.86–1.69 (4H, m); 13C NMR: (100 MHz, CDCl3)
δ 166.3, 128.6, 122.4, 118.6, 113.7, 50.8, 23.4, 23.0, 22.8, 22.7;
IR: ν 3300, 2924, 2851, 1671, 1437, 1326, 1144 cm−1; HRMS
(ESI): calculated for C10H13NO2Na [M + Na]+: 202.0838 found
202.0848.
39.4 (CH2, C3B), 39.1 (CH2, C3A), 38.9 (CH, C3aA), 38.7 (CH,
3aB), 28.8 (2CH2, C4B,7B), 27.9 (CH2, C7A), 26.9 (CH2, C4A),
23.8 (CH2, C5B ou 6B), 23.6 (CH3, C8B), 23.1 (CH2, C5A ou 6A),
23.0 (CH3, C8B), 21.7 (CH2, C5B ou 6B), 21.5 (CH2, C5A ou 6A).
C
1
2,3-Dimethyloctahydro-1H-indole·HFIP 6b. Colorless oil;
mixture of 4 diastereoisomers; Rf 0.35 (CH2Cl2–MeOH: 85 : 15);
1H NMR: (400 MHz, CDCl3) δ 6.02 (2H, br s), 4.25 (1H, sept,
J = 6.5 Hz, HHFIP), 3.72–3.56 (0.6H, m), 3.48–3.39 (0.2H, m,
H), 3.38–3.27 (0.4H, m, H), 3.24–3.15 (0.4H, m), 3.14–3.04
(0.2H, m), 2.81–2.71 (0.2H, m), 2.43–2.27 (0.5H, m), 2.17–1.97
(0.5H, m), 1.96–1.48 (5H, m), 1.47–0.81 (10H, m); 13C NMR:
(100 MHz, CDCl3) δ 122.6 (CF3, q, J = 284 Hz, CHFIP), 69.4
(CH, sept., J = 34 Hz, CHFIP), 63.1, 61.5, 57.0, 56.4, 55.4, 54.5,
51.8, 45.7, 44.9, 42.8, 40.4, 39.4, 36.9, 30.8, 30.0, 28.7, 27.8,
26.4, 25.7, 25.4, 25.2, 25.1, 24.8, 23.5, 23.1, 23.0, 21.8, 21.2,
20.5, 20.4, 18.3, 17.0, 16.6, 16.3, 13.7, 12.8, 10.5. MS (ESI):
calculated for C10H20N [M + H]+: 154.2 found 154.2.
4,5,6,7-Tetrahydro-1H-indole-2-carboxylic acid 7g. White
solid; Rf 0.20 (ethyl acetate–petroleum ether 30 : 70); mp:
1
158–159 °C; H NMR: (400 MHz, CDCl3) δ 6.66 (1H, d, J =
2.6 Hz), 3.94 (2H, br s), 2.56 (2H, t, J = 5.6 Hz), 2.45 (2H, t,
J = 5.3 Hz), 1.85–1.57 (4H, m); 13C NMR: (100 MHz, CDCl3)
δ 165.8, 135.0, 120.6, 119.5, 116.5, 23.5, 23.1, 23.0, 22.8; IR:
ν 3315, 2923, 2852, 1658, 1456, 1180, 761 cm−1; HRMS (ESI):
calculated for C9H10NO2 [M − H]−: 164.0717 found 164.0722.
Methyl 6-methoxy-4,5,6,7-tetrahydro-1H-indole-2-carboxylate
9a. Yellow oil; Rf 0.51 (ethyl acetate–petroleum ether 60 : 40);
1H NMR: (300 MHz, CDCl3) δ 9.20 (1H, br s), 6.63 (1H, d, J =
2.3 Hz), 3.81 (3H, s), 3.74–3.62 (1H, m), 3.41 (3H, s), 2.96 (1H,
dd, J = 16.0, 5.2 Hz), 2.71–2.56 (2H, m), 2.56–2.42 (1H, m),
2.12–1.94 (1H, m), 1.88–1.73 (1H, m); 13C NMR: (75 MHz,
CDCl3) δ 162.1, 131.3, 121.2, 119.0, 114.1, 76.2, 56.3, 51.4,
29.3, 28.2, 19.9; IR: ν 3300, 2927, 1674, 1471, 1292, 1222,
(Octahydro-1H-indol-2-yl)methanol·HFIP 6c. Yellow oil; Rf
0.49 (CH2Cl2–MeOH 80 : 20); Mixture of two diastéréoisomères
80 : 20; 1H NMR (only one isomer can be clearly described):
(400 MHz, CDCl3) δ 5.96 (3H, s, H1,OH,11), 4.33 (1H, sept., J =
6.5 Hz, HHFIP), 3.71 (0.2H, dd, J = 11.5, 3.5 Hz, HB), 3.57–3.31
(3H, m, HCH2OH,2), 3.14 (1H, q, J = 5.3 Hz, H7a), 2.18–1.96
(1H, m, H3a), 1.76–1.13 (10H, m, H4,7); 13C NMR (the two
isomers can be described): (100 MHz, CDCl3) δ 122.8 (CF3, q,
J = 284 Hz, CHFIP), 69.9 (CH, sept., J = 32 Hz, CHFIP), 65.2
(CH2, C CH2OHA), 64.1 (CH2, CCH2OHB), 59.9, 58.0 (2CH,
1090 cm−1
; HRMS (ESI): calculated for C11H15NO3Na
[M + Na]+: 2 320 944 found 2 320 944.
Methyl 6-hydroxy-4,5,6,7-tetrahydro-1H-indole-2-carboxylate
9b. White solid; Rf 0.62 (CH2Cl2–MeOH 90 : 10); mp:
C
C
2B,7aB), 58.4, 57.5 (2CH, C2A,7aA), 38.4 (CH, C3aA), 38.1 (CH,
3aB), 32.8 (CH2, C3A), 32.2 (CH2, C3B), 28.3, 27.6, 23.0, 22.6
1
146–148 °C; H NMR: (400 MHz, MeOD–CDCl3 8 : 2) δ 6.60
(4CH2, C4–7B) 27.0, 27.0, 23.2, 21.6 (CH2, C4–7A); HRMS
(ESI): calculated for C9H18NO [M + H]+: 156.1383 found
156.1387.
(1H, s), 4.15–3.99 (1H, m), 3.77 (3H, s), 2.92 (1H, dd, J = 15.9,
4.8 Hz), 2.71–2.44 (3H, m), 1.95 (1H, d, J = 9.4 Hz), 1.83–1.67
(1H, m). 13C NMR: (100 MHz, MeOD–CDCl3 8 : 2) δ 163.1,
132.7, 121.5, 119.0, 115.0, 67.8, 51.4, 32.4, 20.6. IR: ν 3370,
3297, 2948, 2925, 2850, 1675, 1500, 1462, 1220, 1201,
Methyl octahydro-1H-indole-3-carboxylate 6f
(3S*,3aS*,7aS*)-6f. Colorless oil; Rf 0.53 (CH2Cl2–MeOH
80 : 20); H3, H3a, H7a Relation determined by NOESY: 1H
NMR: (500 MHz, CDCl3) δ 6.44 (1H, br s, H1), 3.70 (3H, s,
1038 cm−1
; HRMS (ESI): calculated for C10H13NO3Na
[M + Na]+: 218.0788 found 218.0786.
(2S*,3aS*)-Methyl 6-oxo-2,3,3a,4,5,6-hexahydro-1H-indole-2-
carboxylate 11. White solid; Rf 0.48 (CH2Cl2–MeOH 90 : 10);
mp: 146–148 °C; H2 H3a relation determined by NOESY 1H
NMR: (300 MHz, CDCl3) δ 6.13 (1H, br s, H1), 5.24 (1H, s,
H7), 4.43 (1H, dd, J = 10.4, 6.5 Hz, H2), 3.78 (3H, s, HMeO),
3.03–2.85 (1H, m, H3a), 2.60 (1H, dt, J = 12.3, 6.5 Hz, H3),
2.47–2.25 (2H, m, H5), 2.23–2.09 (1H, m, H4), 1.83–1.58 (2H,
m, H3′,4′); 13C NMR: (100 MHz, CDCl3) δ 197.2 (C, C6), 171.7,
171.0 (2C, C7a,CO), 94.9 (CH, C7), 60.0 (CH3, C2), 52.8 (CH,
CMeO), 40.7 (CH, C3a), 36.1 (CH2, C5), 34.3 (CH2, C3), 27.9
(CH2, C4); IR: ν 3294, 3158, 3032, 2918, 2850, 1730, 1619,
1542, 1199 cm−1; HRMS (ESI): calculated for C10H14NO3
[M + H]+: 196.0968 found 196.0968.
H
MeO), 3.65–3.37 (3H, m, H2,7a), 2.94–2.85 (1H, m, H3), 2.44
(1H, s, H3a), 1.88–1.47 (6H, m), 1.44–1.31 (2H, m); 13C NMR:
(125 MHz, CDCl3) δ 173.9 (C, CCO), 58.3 (CH, C7a), 52.4
(CH3, CMeO), 46.3 (CH2, C2), 46.3 (CH, C3), 42.5 (CH, C3a),
26.1, 26.1, 22.4, 21.7 (CH2, C4–7); IR: ν 3303, 2925, 2857,
1730, 1173, 914 cm−1. HRMS (ESI): calculated for C10H18NO2
[M + H]+: 184.1332 found 184.1328.
(3R*,3aS*,7aS*)-6f. Colorless oil; Rf 0.49 (CH2Cl2–MeOH
80 : 20); H3, H3a, H7a Relation determined by NOESY: 1H
NMR: (500 MHz, CDCl3) δ 3.66 (3H, s, HMeO), 3.53–3.40 (1H,
m, H2), 3.20 (1H, br s, H7a), 3.14–3.07 (2H, m, H2′,3), 2.24–2.11
(2H, m, H1,3a), 1.85 (1H, dd, J = 14.4, 2.0 Hz, H7), 1.71–1.56
(2H, M, H5,7′), 1.52–1.44 (1H, m, H6), 1.40–1.28 (2H, m, H4,6′),
1.19–1.11 (2H, m, H4′,5); 13C NMR: (125 MHz, CDCl3) δ 173.5
(C, CCO), 58.6 (CH, C7a), 51.6 (CH3, CMe), 49.2 (CH, C3), 46.2
(CH2, C2), 41.5 (CH, C3a), 27.2 (CH2, C7), 24.7 (CH2, C5), 22.8
(CH2, C4), 20.1 (CH2, C6); IR: 3250, 2927, 2853, 1729, 1434,
1194, 1171, 922 cm−1; HRMS (ESI): calculated for C10H18NO2
[M + H]+: 184.1332 found 184.1324.
t-Butyl 6-methoxyindoline-1-carboxylate 13d. Yellow oil; Rf
0.60 (ethyl acetate–petroleum ether 30 : 70); Rotamer mixture;
1H NMR: (400 MHz, CDCl3) δ 7.53 (0.5H, br s), 7.28–7.06
(0.5H, br s), 7.00 (1H, d, J = 8.1 Hz), 6.47 (1H, dd, J = 8.1, 2.4 Hz),
4.10–3.87 (2H, m), 3.79 (3H, s), 3.00 (2H, t, J = 8.7 Hz),
1.69–1.44 (9H, m, H11); 13C NMR: (100 MHz, CDCl3) δ 159.9,
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1
152.9, 144.6, 125.2, 124.0, 122.9, 109.0, 107.5, 101.6, 101.0,
81.8, 80.8, 56.8, 55.9, 48.2, 47.4, 32.4, 30.2, 30.1, 30.0, 29.0,
29.1, 28.9, 26.9, 26.7, 26.3, 25.3, 24.1, 21.4; IR: ν 3005, 2975,
2932, 2836, 1697, 1612, 1499, 1388, 1367, 1162, 852,
146–148 °C; H NMR: (400 MHz, CDCl3) δ 9.88 (1H, br s),
6.66 (1H, d, J = 2.3 Hz), 3.77 (3H, s), 3.34 (3H, s), 2.63 (2H, t,
J = 6.1 Hz), 2.53 (2H, t, J = 5.9 Hz), 1.88–1.64 (4H, m); 13C
NMR: (100 MHz, CDCl3) δ 162.0, 132.6, 121.3, 119.6, 114.0,
61.0, 33.2, 23.7, 23.1, 22.9, 22.8; IR: ν 3250, 2934, 2850, 1594,
763 cm−1
; HRMS (ESI): calculated for C14H19NO3Na
[M + Na]+: 272.1257 found 272.1258.
1235, 1129, 958 cm−1
;
HRMS (ESI): calculated for
C11H16N2O2Na [M + Na]+: 231.1104 found 231.1093.
1-t-Butyl 2-methyl 6-methoxyindoline-1,2-dicarboxylate 13f.
1
Colorless oil; Rf 0.50 (ethyl acetate–petroleum ether 30 : 70); H
N-Methyl-4,5,6,7-tetrahydro-1H-indole-2-carboxamide
17f.
NMR: (400 MHz, CDCl3) δ 7.57 (1H, br s), 6.97 (1H, d, J =
8.2 Hz), 6.50 (1H, dd, J = 8.2, 2.1 Hz), 4.87 (1H, br s),
3.85–3.71 (6H, m), 3.43 (1H, dd, J = 15.9, 11.7 Hz), 3.03 (1H,
dd, J = 15.9, 4.4 Hz), 1.79–1.33 (9H, m); 13C NMR: (100 MHz,
CDCl3) δ 172.7, 160.1, 151.7, 143.9, 124.7, 119.7, 109.3, 100.6,
81.5, 61.4, 55.7, 52.4, 32.1, 28.4; IR: ν 3002, 2976, 2935, 2867,
White solid; Rf 0.55 (CH2Cl2–MeOH 90 : 10); mp: 184–187 °C;
1H NMR: (400 MHz, MeOD) δ 6.42 (1H, s), 2.82 (3H, s), 2.55
(2H, t, J = 6.1 Hz), 2.44 (2H, t, J = 5.9 Hz), 1.84–1.64 (4H, m);
13C NMR: (100 MHz, MeOD) δ 164.8, 132.8, 124.6, 119.5,
110.6, 26.2, 24.9, 24.3, 23.8, 23.6; IR: ν 3356, 3165, 3086,
1574, 1497, 1248, 976 cm−1; HRMS (ESI): calculated for
C10H15N2O [M + H]+: 179.1179 found 179.1182.
1734, 1702, 1609, 1498, 1255, 1151, 1019, 912, 850, 763 cm−1
;
HRMS (ESI): calculated for C16H21NO5Na [M + Na]+:
330.1312 found 330.1303.
(2R*,3aR*,7aR*)-N-Ethyloctahydro-1H-indole-2-carboxamide
18b. Yellow oil; Rf 0.20 (CH2Cl2–MeOH 90 : 10); H2, H3a, H7a
1
(2S*,3aS*,7aS*)-1-Methyloctahydro-1H-indole-2-carboxylic
acid 15g. White solid; Rf 0.25 (CH2Cl2–MeOH: 85 : 15); mp:
Relation determined by NOESY: H NMR: (400 MHz, CDCl3)
δ 7.98 (1H, br s), 3.92 (1H, dd, J = 10.3, 5.6 Hz, H2), 3.58 (1H,
br s), 3.41–3.16 (3H, m, H7a,NCH2CH3), 2.35 (1H, ddd, J = 12.9,
10.3, 7.0 Hz, H3), 2.15–1.98 (1H, m, H3a), 1.79 (1H, dt, J =
12.9, 5.6 Hz, H3′), 1.67–1.19 (8H, m, H4–7), 1.14 (3H, t, J = 7.3 Hz,
1
157–159 °C; H2, H3a, H7a Relation determined by NOESY: H
NMR: (300 MHz, CDCl3) δ 7.95 (1H, br s), 3.64 (1H, dd, J =
10.2, 5.6 Hz, H2), 3.21 (1H, q, J = 5.4 Hz, H7a), 2.83 (3H, s,
H
Me). 13C NMR: (100 MHz, CDCl3) δ 174.4 (C, CCO), 58.9
H
Me), 2.55–2.27 (2H, m, H3a,3), 2.24–2.00 (1H, m, H3′),
1.96–1.83 (2H, m, H7), 1.81–1.18 (6H, m, H4,5,6); 1H NMR:
(500 MHz, C6D6) δ 4.09 (1H, br s), 3.48 (1H, dd, J = 10.2,
6.2 Hz, H2), 2.56 (1H, q, J = 5.8 Hz, H7a), 2.29 (3H, s, HMe),
2.14 (1H, ddd, J = 13.0, 10.2, 6.5 Hz, H3), 1.94 (1H, dt, J = 6.2,
13.0 Hz, H3′), 1.74–1.62 (1H, m, H3a), 1.50–1.42 (1H, m), 1.38
(1H, ddd, J = 14.2, 9.2, 4.5 Hz), 1.34–1.24 (1H, m), 1.24–1.13
(3H, m), 1.10–1.00 (1H, m), 0.95–0.81 (1H, m); 13C NMR:
(75 MHz, CDCl3) δ 171.1 (C, CCO), 71.4 (CH, C2), 68.5 (CH,
C7a), 42.0 (CH3, CMe), 37.0 (CH, C3a), 33.3 (CH2, C3), 26.3,
24.3, 22.2, 21.2 (4CH2, C4–7); IR: ν 3056, 2954, 2927, 2889,
2849, 2255, 1623, 1372, 1019 cm−1; HRMS (ESI): calculated
for C10H17NO2Na [M + Na]+: 206.1151 found 206.1152.
(CH, C2), 57.9 (CH, C7a), 38.1 (CH, C3a), 35.3 (CH2, C3), 34.1
(CH2, CNCH2CH3), 28.6, 27.2, 23.3, 22.0 (4CH2, C4–7), 14.9
(CH3, CMe); IR: ν 3300, 3073, 2928, 2856, 1660, 1563, 1379,
1276, 1081 cm−1; HRMS (ESI): calculated for C11H21N2O
[M + H]+: 197.1648 found 197.1650.
(2S*,3aR*,7aR*)-N-Ethyloctahydro-1H-indole-2-carboxamide
(2R*,3aR*,7aR*)-N-ethyloctahydro-1H-indole-2-carboxamide
18b. Yellow oil; Rf 0.20 (CH2Cl2–MeOH 90 : 10); Mixture of
1
diastereoisomers 88 : 12 A–B; H NMR: (300 MHz, CDCl3) δ
7.78 (0.85H, br s, H1A), 3.84 (0.15H, dd, J = 9.1, 6.6 Hz, H2B),
3.76 (0.85H, dd, J = 10.5, 5.2 Hz, H2A), 3.42–3.16 (2.85H, m,
H
7aA, NCH2CH3A, NCH2CH3B), 3.09 (0.15H, q, J = 5.0 Hz, H7aB),
N-Ethyl-4,5,6,7-tetrahydro-1H-indole-2-carboxamide 17b.
Yellow oil; Rf 0.62 (CH2Cl2–MeOH 90 : 10); 1H NMR:
(300 MHz, CDCl3) δ 9.51 (1H, br s), 6.34 (1H, d, J = 2.4 Hz),
6.05 (1H, s), 3.43 (2H, q, J = 7.2 Hz), 2.59 (2H, t, J = 6.0 Hz),
2.48 (2H, t, J = 5.7 Hz), 1.88–1.63 (4H, m), 1.20 (3H, t, J =
7.2 Hz); 13C NMR: (100 MHz, CDCl3) δ 161.5, 131.7, 123.9,
118.9, 107.6, 34.3, 23.7, 23.2, 22.9, 22.8, 15.3; IR: ν 3256,
2926, 2852, 1676, 1545, 1246, 842 cm−1; HRMS (ESI): calcu-
lated for C11H16N2O [M + H]+: 193.1335 found 193.1338.
2.41–1.90 (3.15H, m, H3A,3aA,9A,1B,3B,3aB,NHB), 1.87–1.70 (1H,
m, H3′A,3′B), 1.67–1.05 (11H, M, H4–7A,4–7B,CH3A,CH3B); 13C
NMR: (125 MHz, CDCl3) δ 175.4 (C, CCOA), 175.3 (C, CCOB),
58.9 (CH, C2A), 58.8 (CH, C2B), 57.7 (CH, C7aA), 57.4 (CH,
C
7aB), 38.1 (CH, C3aA), 38.0 (CH, C3aB), 35.8 (CH2, C3B), 35.4
(CH2, C3a), 33.6 (CH2, C NCH2CH3A), 33.6 (CH2, C NCH2CH3B),
29.1, 27.8, 27.4, 26.3, 23.5, 23.1, 21.8, 21.2 (8CH2, C4–7A,4–7B),
14.9 (CH3, C NCH2CH3B), 14.8 (CH3, C NCH2CH3A). HRMS
(ESI): calculated for C11H21N2O [M + H]+: 197.1648 found
197.1650.
N,N-Diethyl-4,5,6,7-tetrahydro-1H-indole-2-carboxamide 17c.
White solid; Rf 0.53 (ethyl acetate–petroleum ether 50 : 50); mp:
(2R*,3aR*,7aR*)-N,N-Diethyloctahydro-1H-indole-2-carbox-
amide 18c. Yellow solid; Rf 0.55 (CH2Cl2–MeOH 85 : 15); mp:
152–154 °C; mixture of diastereoisomers 94/6; H2, H3a, H7a
1
106–109 °C; H NMR: (300 MHz, CDCl3) δ 9.57 (1H, br s),
6.30 (1H, d, J = 2.1 Hz), 3.60 (4H, q, J = 7.0 Hz), 2.63 (2H, t,
J = 5.8 Hz), 2.53 (2H, t, J = 5.7 Hz), 1.91–1.65 (4H, m), 1.27
(6H, t, J = 7.0 Hz); 13C NMR: (75 MHz, CDCl3) δ 161.8, 131.0,
122.8, 118.9, 110.8, 42.1, 23.8, 23.2, 22.9, 22.7, 13.7; IR:
1
Relation determined by NOESY: H NMR: (500 MHz, MeOD)
δ 4.20 (0.07 H, dd, J = 10.3, 3.3 Hz, H2 minor), 4.12 (1H, dd, J =
10.0, 6.3 Hz, H2), 3.60–3.39 (2H, m, HNCH2CH3), 3.39–3.26
(3H, m, H7a, NCH2CH3), 2.42 (1H, ddd, J = 12.7, 10.0, 7.0 Hz,
H3), 2.23–2.14 (1H, m, H3a), 1.92–1.76 (2H, m, H7), 1.62–1.46
(5H, m, H3′,4′,5′,6), 1.41–1.26 (2H, m, H4,5), 1.22 (3H, t, J =
7.1 Hz, HMe), 1.14 (3H, t, J = 7.1 Hz, HMe); 13C NMR:
(125 MHz, MeOD) δ 172.9 (C, CCO), 59.6 (CH, C7a), 58.1
ν 3250, 2974, 2923, 2850, 1579, 1463, 1263, 1144, 828 cm−1
;
HRMS (ESI) calculated for C13H20N2ONa [M + Na]+: 243.1468
found 243.1465.
N-Methoxy-N-methyl-4,5,6,7-tetrahydro-1H-indole-2-carboxa-
mide 17e. White solid; Rf 0.76 (CH2Cl2–MeOH 90 : 10); mp:
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 6587–6594 | 6593

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2008, 47, 1202.
16 C. J. Blankley, J. S. Kaltenbronn, D. E. DeJohn, A. Werner,
L. R. Bennett, G. Bobowski, U. Krolls, D. R. Johnson, W. M. Pearlman,
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(CH, C2), 42.5 (CH2, C NCH2CH3), 41.6 (CH2, C NCH2CH3), 39.5
(CH, C3a), 37.3 (CH2, C3), 28.0 (CH2, C4), 27.1 (CH2, C7), 24.5
(CH2, C5), 22.3 (CH2, C6), 14.3 (CH3, CMe), 13.0 (CH3, CMe);
IR: ν 3050, 2925, 2855, 1641, 1549, 1285, 1089, 732 cm−1
;
HRMS (ESI) calculated for C13H25N2O [M + H]+: 225.1961
found 225.1961.
Acknowledgements
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We thank F. Albrieux, C. Duchamp and N. Henriques from the
Centre Commun de Spectrométrie de Masse (ICBMS
UMR-5246), for the assistance and access to the Mass Spec-
trometry facilities. D. Clarisse thanks the “Ministère Français de
l’Education Supérieure et de la Recherche” for financial support.
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