N -Iodosuccinimide-Mediated Oxidative Coupling of Indoles and Phenols: A Synthetic Study toward the Benzofuroindoline Moiety of Bipleiophylline

Article abstract of DOI:10.1055/s-0036-1592002

We report our efforts to apply an N -iodosuccinimide-mediated dearomative oxidative coupling of indoles and phenols to benzofuroindoline-containing polycyclic scaffolds related to the natural product bipleiophylline. Suitable conditions from N-substituted indoles are developed and applied to the synthesis of a hexacyclic model starting from a tetracyclic ABCE precursor.

Full text of DOI:10.1055/s-0036-1592002

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–F
special topic
A
en
N. Denizot et al.
Special Topic
Synthesis
N-Iodosuccinimide-Mediated Oxidative Coupling of Indoles and
Phenols: A Synthetic Study toward the Benzofuroindoline Moiety
of Bipleiophylline
Natacha Denizot
Régis Guillot
MeO
Cyrille Kouklovsky
Guillaume Vincent*
A
C
B
N
0
0
0
0
0-
0
0
3
3-
1
6
2
1-
3
2
0
MeO
NTs
H
OH
O
N
E
NTs
H
O
Institut de Chimie Moléculaire et des Matériaux d’Orsay
(ICMMO), Université Paris-Sud, Université Paris-Saclay,
CNRS, UMR 8182, 91405 Orsay Cedex, France
Guillaume.vincent@u-psud.fr
NIS, AgBF4
O
O
MeO
O
MeO
MeO
MeO
Dedicated to Prof. Marco A. Ciufolini
Published as part of the Special Topic Modern Dearomati-
zation Strategies in Synthesis
Received: 14.02.2018
Accepted after revision: 03.04.2018
Published online: 08.05.2018
(Scheme 1). In 2014, we reported an original method to
achieve the bioinspired dearomative assembly of 2,3-disub-
stituted-NH-indoles 4 and phenols 7 into benzofuro[2,3-
b]indolines 8 (Scheme 1).3a,5 The process relied on the oxi-
dation of the NH-indole partner with N-iodosuccinimide
(NIS) to give the 3-iodoindolenine 5.6 The latter can then be
converted into a transient 3-indolenium ion 6 with a silver
salt and an additive such as tin(IV) chloride or sodium hy-
droxide to allow the addition of the nucleophilic phenol to
this electrophilic intermediate.7 We now disclose our ef-
forts to implement this method to the synthesis of a benzo-
furoindoline-containing heptacyclic compound related to
bipleiophylline,8,9 and the outcome that drove us to develop
a new oxidative coupling method from indoles toward bi-
pleiophylline.
DOI: 10.1055/s-0036-1592002; Art ID: ss-2018-c0092-st
Abstract We report our efforts to apply an N-iodosuccinimide-mediat-
ed dearomative oxidative coupling of indoles and phenols to benzo-
furoindoline-containing polycyclic scaffolds related to the natural prod-
uct bipleiophylline. Suitable conditions from N-substituted indoles are
developed and applied to the synthesis of a hexacyclic model starting
from a tetracyclic ABCE precursor.
Key words oxidative coupling, indole, dearomatization, phenol,
benzofuroindoline, bipleiophylline
For the last 6 years, our group has been interested in the
development of bioinspired synthetic methods to access
benzofuroindoline frameworks which are found in several
natural products.1–3 Among them, bipleiophylline (1) is of
special interest due to its highly complex structure.4 A dou-
ble dearomative oxidative coupling between pleiocar-
pamine (2) and 2,3-dihydroxybenzoic acid (3) is thought to
be the biogenetic pathway toward this natural product
The biomimetic synthesis of bipleiophylline requires
having pleiocarpamine in hand. The synthesis of the penta-
cyclic framework of this alkaloid is a challenging task.10 In
particular, installation of the E ring from a tetracyclic ABCD
precursor is more difficult than expected because of the
highly strained nature of pleiocarpamine. Therefore, we en-
Biosynthesis of bipleiophylline
O
N
MeO
D
E
N
N
H
R3
C
H
H
N
H
O
N
R1
+
H
O
R2
[O]
B
HO2C
O
OH
N
OMe
pleiocarpamine (2)
N
O
H
OH
OH
3
O
A
OMe
O
benzofuro[2,3-b]indoline
bipleiophylline (1)
R4
Our NIS-mediated oxidative coupling
R4
R3
R3
BF4
R2
R3
3
I
then
AgBF4
NIS
R3
R2
R2
2
N
O
N
N
H
SnCl4
R2
N
OH
4
3-iodoindolenine
5
7
3-indolenium
8
H
6
Scheme 1 Bioinspired NIS-mediated oxidative coupling between 2,3-disubstituted-NH-indoles and phenols for the synthesis of benzofuro[2,3-b]indo-
lines related to bipleiophylline
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

B
N. Denizot et al.
Special Topic
Synthesis
visioned closing the E ring after the formation of the benzo-
furoindoline motif in order to give more flexibility to the
precursor 10 of the heptacyclic target 9, and therefore favor
the final cyclization (Scheme 2). To achieve this objective,
an intramolecular Michael addition of an ester attached to
the indoline nitrogen onto an α,β-unsaturated lactam em-
bedded in the D ring of 10 was planned. Our retrosynthesis
required the oxidative coupling between the phenol 7 and
the tetracyclic ABCD precursor 11 containing the required
unsaturation on lactam D. We previously reported a similar
oxidative coupling on an ABCD precursor lacking the double
bond on the D ring.3a
The key oxidative coupling with p-methoxyphenol (7a)
was then deployed to deliver the desired benzofuroindoline
15 in 18% yield, and the formation of the E ring could then
be studied. Unfortunately, despite our efforts, we were un-
able to alkylate the indole nitrogen with methyl bromo-
acetate, which would have left us with a precursor requir-
ing a final intramolecular Michael addition to form the E
ring. Deprotonation of the NH may have resulted in opening
of the benzofuroindoline and formation of an indolenine
appended by a phenolate.
As an alternative, we envisioned completing the hepta-
cyclic structure 9 via a nitrogen-malonate oxidative cou-
pling as the last step, which was inspired by Ma and Zhu
(Scheme 4).12 Therefore, as described by Martin, the inter-
molecular 1,4-addition of dimethyl malonate onto α,β-un-
saturated lactam 11 led to compound 16 as a mixture of
diastereoisomers.11 Unfortunately, our key NIS-mediated
oxidative coupling with p-methoxyphenol (7a) did not suc-
ceed. Evidently, the malonate part of the molecule is inter-
fering with the components of the reaction, presumably
due to its nucleophilicity or chelating ability.
R
R
1,4-addition
O
N
O
N
N
O
N
H
H
E
O
O
O
9
10
MeO
H
MeO
A
R
C
O
B
oxidative coupling
N-alkylation
N
+
CO2Me
N
D
H
O
N
H
OH
A
C
7
11
CO2Me
NaH,
O
N
B
N
H
H
N
THF, reflux
MeO
D
Scheme 2 Retrosynthesis of the heptacyclic benzofuroindoline part of
bipleiophylline yielding a tetracyclic ABCD precursor
H
H
11
CO2Me
16, 87% (dr 1:1)
MeO2C
NIS, 30 min
CH2Cl2 then
LiHMDS
then I2
Compound 11 was obtained in only 4 steps from trypt-
amine (12), according to Martin and co-workers (Scheme
3).11 A Bischler–Napieralski cyclization furnished dihydro-
β-carboline 13. N-Acylation and allylation of the latter was
followed by ring-closing metathesis with Grubbs I catalyst
to deliver 11.
9
X
O
N
O
MeO
OH
(2 equiv)
N
H
H
7a
17
AgBF4 (2 equiv)
SnCl4 (2 equiv)
MeO2C
CO2Me
Scheme 4 An attempt to form the benzofuroindoline moiety after the
1,4-addition
NH2
To overcome this issue, the third variation of our general
strategy was applied to again invert the order of the events
(Scheme 5). The NIS-mediated formation of the benzo-
furoindoline core would be performed on N-acetate indole
substrate 18, which would be followed by an intramolecular
Michael addition to close the E ring.
1. EtOCHO
reflux
CH2=CHC(O)Cl
AllylSnBu3
N
N
2. POCl3
CH2Cl2, rt
CH2Cl2, rt
H
N
H
12
13, 95% (2 steps)
Reproduced from Martin et al.
A
C
O
N
O
B
Grubbs I (4%)
CH2Cl2, rt
N
N
N
H
D
H
H
R
H
11, 76%
14, 74%
R
MeO
A
C
NIS (1.1 equiv), 15 min
CH2Cl2 then
O
OH
B
N
N
7
KHMDS, DMF
9
X
9
O
N
D
H
N
O
Br
MeO
OH
MeO2C
O
MeO2C
O
H
7a
N
10
18
(2.5 equiv)
N
H
O
N-alkylated indole
H
AgBF4 (2 equiv)
SnCl4 (2 equiv)
15, 18%
MeO
Scheme 5 Retrosynthesis with formation of the benzofuroindoline
moiety from an N-acetate ABCD precursor
Scheme 3 NIS-mediated synthesis of a benzofuroindoline-containing
hexacyclic framework from an NH-containing ABCD precursor
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

C
N. Denizot et al.
Special Topic
Synthesis
The oxidative coupling of phenol 7 with 18 involves an
N-substituted indole, while our method has been developed
with NH-indoles. This fact encouraged us to study the NIS-
mediated formation of benzofuroindolines with N-methyl-
tetrahydrocarbazole 19a as a model substrate (Table 1). Our
initial procedure from NH-indoles involves first treating the
N-H indole 4 with NIS to form the 3-iodoindolenine inter-
mediate 5, before adding the other components of the reac-
tion. When we applied this procedure to N-methyl-tetrahy-
drocarbazole 19a, and added phenol 7a, AgBF4 and the
additive 10 minutes after NIS, poor yields of benzofuroin-
doline 20a were obtained with tin(IV) chloride (Table 1, en-
try 1) or sodium hydroxide (Table 1, entry 2). An improved
but still modest yield of 25% was obtained without any ad-
ditive (Table 1, entry 3). Without AgBF4 nor any additive,
20a was obtained in 22% yield (Table 1, entry 4). In most
cases, we observed the formation of 3,3-spirooxindole 23
(Scheme 6), which results from a 1,2-shift of the substitu-
ent at the C2 position to the C3 position of 3-iodoindoleni-
um intermediate 21. We reasoned that 3-iodoindolenium
21 is more reactive than the corresponding 3-iodoindole-
nine 5. Therefore, we decided to add phenol 7a at the same
time as NIS, in order to immediately intercept the iminium
function of 21 with the hydroxy group of 7a and form inter-
mediate 22.13 Indeed, a 52% yield of benzofuroindoline 20a
was obtained by adding NIS, 7a and AgBF4 at the same time
(Table 1, entry 5). Reduced yields were obtained without
AgBF4 (Table 1, entries 6 and 7). Adding AgBF4 5 minutes af-
ter NIS and 7a did not impact on the yield since adduct 22 is
probably quite stable (Table 1, entries 8 and 9). With the
optimum conditions, N-acyl-tetrahydrocarbazole 19b was
converted into benzofuroindoline 20b in 36% yield (Table 1,
entry 10). The reduced yield of 20b, compared to 20a, can
be explained by the fact that 19b is less nucleophilic than
19a and therefore less reactive toward NIS.
Table 1 Oxidative Coupling with N-Substituted Indoles
MeO
NIS (1.1 equiv), CH2Cl2, rt
time 1, then
MeO
OH
O
N
R
N
(2.5 equiv)
R
additive, time 2
then AgBF4
19a, R = Me
19b, R = Ac
20a, R = Me
20b, R = Ac
Entry
R
Time 1
(min)
Additive
(equiv)
Time 2 AgBF4
Yielda
(min)
(equiv)
1
2
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ac
10
10
10
10
0
SnCl4 (5.0)
0
0
0
–
0
–
–
5
5
5
2.0
2.0
1.1
0
15%
0%
NaOH (5.0)
none
3
25%
22%
52%
28%
45%
52%
55%
36%
4
none
5
none
1.1
0
6
0
none
7b
8
0
none
0
0
none
1.1
1.6
2.0
9c
10
0
none
0
none
a Yield of isolated product.
b Reaction at reflux temperature.
c Reaction with NIS (1.6 equiv).
However, we were still eager to obtain a benzofuroindo-
line from a complex N-substituted indole amenable to con-
struction of the heptacyclic framework 9. Instead of a func-
tionalized ABCD compound such as 11, 16 or 18, we won-
dered if an ABCE tetracycle would be a suitable precursor to
construct the benzofuroindoline core, before forging the D
ring (Scheme 7). We selected α-(N-indolyl)diester 25,
which was described by Zhu and co-workers through N–C
bond formation via an intramolecular oxidative coupling of
the diester/N-indolyl dianion of β-tetrahydrocarboline 24
with I2.12a In addition, 25 lakes enolizable protons which
could be detrimental to the oxidative coupling, such as in
18. Eventually, treatment of 25 with phenol 7a and NIS, fol-
lowed by AgBF4, produced hexacyclic benzofuroindoline 26
in a mixture with a product, which may be a diastereo-
isomer (85:15 ratio), in a very useful yield of 55%.14
OMe
I
I
phenol
NIS
19
20
O
N
R
N
R
21
22
O
N
R
Of course, various strategies to build the missing D ring
from benzofuroindoline 26 could be designed. However,
keeping in mind that the benzofuroindoline part of bipleio-
phylline is built from a catechol, we needed to evaluate our
NIS-mediated oxidative coupling with a 1,2-diphenol. How-
ever, treatment of the NH-tetrahydrocarbazole 19c with
NIS followed by 3-methoxycatechol (27), AgBF4 and NaOH
did not lead to the expected benzofuroindoline (Scheme 8).
Instead, we isolated benzodioxinoindoline 28 in a modest
yield, the structure of which was ascertained by X-ray crys-
tal structure analysis.2a,b,15,16 It is thought that the imine
function of the 3-iodoindolenine is first intercepted by one
23
Scheme 6 Trapping of the 3-iodoindolenium ion 21 with the phenol
The stage was then set to evaluate these conditions with
2-(N-indolyl) acetate 18. Therefore, the indole nitrogen of
11 was first alkylated with methyl bromoacetate in the
presence of KHMDS. Unfortunately, the subsequent oxida-
tive coupling with p-methoxyphenol (7a) failed to provide
benzofuroindoline 10 (Scheme 7).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

D
N. Denizot et al.
Special Topic
Synthesis
between indoles and phenols on a tetracyclic substrate be-
fore constructing the remaining ring. Our previously re-
ported conditions for the dearomative coupling were suc-
cessfully applied to a NH indole ABCD precursor. New con-
ditions were developed for N-substituted indoles and
implemented in the synthesis of a hexacyclic target from an
ABCE compound.
MeO
KHMDS
DMF, rt then
7a
A
C
O
B
N
OH
N
(2.5 equiv)
11
X
10
D
Br
MeO2C
H
NIS, AgBF4
CH2Cl2, rt
MeO2C
18, 54%
Reproduced from Zhu et al.
CHO
CO2Me
H2N
CO2Me
1.
AcOH/H2O, rt
38%
LiHMDS, THF
–78 °C to rt
NTs
N
H
H
24
49%
2. TsCl, Et3N
CH2Cl2, rt
then I2, rt
MeO2C
N
All reactions were carried out under an atmosphere of air or argon.
Dichloromethane was distilled under argon over CaH2. THF was dis-
tilled under argon over Na with benzophenone. Unless otherwise
noted, all reagent-grade chemicals and other solvents were obtained
from commercial suppliers and were used as received. Reactions were
monitored by analytical thin-layer chromatography (TLC) with Merck
silica gel 60 F254 on aluminum sheets, and samples were visualized
under UV (254 nm) and/or by using KMnO4 solution followed by heat-
ing. Flash chromatography purifications were performed on silica gel
[Chromagel Si60ACC (70–200 μm)]. Preparative thin-layer chroma-
tography purifications were performed using Merck silica gel F254 on
glass plates and analyzed by UV light. Infrared spectra were recorded
as thin films on NaCl plates using a Perkin Elmer Spectrum one FT-IR
spectrophotometer. 1H NMR and 13C NMR spectra were recorded on
Bruker AC250 (250 MHz, 62.5 MHz), Bruker DRX300 (300 MHz, 75
MHz) and Bruker AM360 (360 MHz, 90 MHz) instruments; chemical
shifts (δ) are given in parts per million with respect to the residual
protonated solvent (δ = 7.24 and 77.1 ppm, CDCl3), which served as
an internal standard. High-resolution mass spectra (HRMS) were re-
corded with a Bruker Daltonics MicrOTOF-Q instrument using the
electrospray ionization (ESI) method. Tetracyclic ABCD indoles 11 and
16 were prepared according to Martin and co-workers,11 while tetracy-
clic ABCE indole 25 was synthesized according to Zhu and co-workers.12a
12
H
MeO2C
MeO
MeO
7a
A
C
B
N
OH
(2 equiv)
NIS (1.1 equiv)
NTs
H
O
NTs
E
N
O
H
AgBF4 (2 equiv)
CH2Cl2, rt
O
O
MeO
O
MeO
MeO
25, 70%
26, 55%
(85:15)
MeO
Scheme 7 NIS-mediated synthesis of a benzofuroindoline-containing
hexacyclic framework from an N-substituted ABCE precursor
of the hydroxy groups of 27 leading to intermediate 29,
which then cyclized by attack of the second hydroxy onto
the iodine.17 The reaction of N-methyl-tetrahydrocarbazole
19a with catechol 27 only led to traces of the corresponding
benzodioxinoindoline.
Benzofuroindoline 15
To a solution of ABCD tetracyclic indole 11 (29.0 mg, 0.122 mmol) in
CH2Cl2 (1.2 mL), NIS (30.0 mg, 0.133 mmol) was added at r.t. and the
solution was stirred for 15 min at the same temperature. The reaction
was then cooled to 0 °C and 4-methoxyphenol (7a) (38.0 mg, 0.306
mmol), AgBF4 (47.0 mg, 0.241 mmol), SnCl4 (0.240 mL of a 1 M solu-
tion in CH2Cl2, 0.240 mmol) were added. The resulting mixture was
stirred for 3 h and the temperature was slowly warmed to r.t. prior to
quenching with a saturated aqueous NH4Cl solution (1 mL). The solu-
tion was filtered through a pad of Celite and concentrated under re-
duced pressure. Preparative TLC chromatography (EtOAc) gave benzo-
furoindoline 15 in 18% yield (8.0 mg, 0.0222 mmol) as a yellow oil.
Scheme 8 NIS-mediated oxidative coupling with a catechol
Rf = 0.65 (EtOAc).
IR (NaCl): 3298, 1709, 1663, 1602, 1489, 1262, 1216, 811, 735 cm–1
.
The fact that the application of this NIS-mediated syn-
thesis of benzofuroindolines is not applicable to catechol
derivatives led us to develop, in collaboration with the
Evanno and Poupon group, a new biomimetic strategy via
the oxidation of catechols into their corresponding ortho-
quinones, which recently led to the hemisynthesis of bi-
pleiophylline.2a,b
In conclusion, different strategies to access a heptacyclic
benzofuroindoline model of bipleiophylline have been in-
vestigated. The key feature of our retrosynthetic logic was
to apply a dearomative NIS-mediated oxidative coupling
1H NMR (360 MHz, CDCl3): δ = 2.32 (dd, J = 11.4, 3.7 Hz, 1 H), 2.41 (dt,
J = 14.1, 3.7 Hz, 1 H), 2.64–2.69 (m, 1 H), 2.83 (td, J = 17.3, 5.3 Hz, 1 H),
3.13 (dt, J = 12.0, 3.9 Hz, 1 H), 3.76 (s, 3 H), 3.81–3.86 (m, 1 H), 4.02
(dd, J = 9.8, 6.3 Hz, 1 H), 5.93 (d, J = 9.4 Hz, 1 H), 6.53–6.57 (m, 1 H),
6.63 (s, 2 H), 6.67 (d, J = 7.5 Hz, 1 H), 6.79 (t, J = 7.4 Hz, 1 H), 6.93 (s, 1
H), 7.06 (t, J = 7.7 Hz, 1 H), 7.15 (d, J = 7.7 Hz, 1 H).
13C NMR (90 MHz, CDCl3): δ = 23.6, 31.6, 37.5, 53.5, 56.3, 58.0, 107.8,
109.7, 110.2, 110.3, 113.3, 120.9, 123.2, 125.4, 129.0, 131.6, 132.8,
137.1, 145.4, 147.3, 152.2, 155.2.
HRMS (ESI+): m/z [M + Na]+ calcd for C22H20N2O3Na: 383.1372; found:
383.1362.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

E
N. Denizot et al.
Special Topic
Synthesis
N-Methyl-benzofuroindoline 20a
Flash chromatography on silica gel (cyclohexane/EtOAc, 1:1) afforded
the N-substituted indole 18 in 54% yield (42.0 mg, 0.135 mmol) as a
yellow oil.
To a solution of N-methyl-tetrahydrocarbazole 19a (53.0 mg, 0.286
mmol) in CH2Cl2 (2.8 mL) at 0 °C were added p-methoxyphenol (7a)
(88.0 mg, 0.715 mmol) and NIS (103.0 mg, 0.458 mmol), followed af-
ter 5 min by AgBF4 (89.0 mg, 0.458 mmol). The resulting mixture was
slowly warmed to r.t. and stirred for 3 h. The reaction was quenched
by addition of a saturated aqueous NH4Cl solution (1 mL), and then
filtered through a pad of Celite. The filtrate was concentrated under
reduced pressure. Preparative TLC purification (cyclohexane/EtOAc,
95:5) afforded N-methyl-benzofuroindoline 20a (48.0 mg, 0.156
mmol) in 55% yield as a colorless oil.
Rf = 0.40 (EtOAc).
IR (NaCl): 3442, 3056, 2951, 1751, 1662, 1609, 1465, 1424, 1351,
1207, 1059, 817, 746, 731 cm–1
.
1H NMR (360 MHz, CDCl3): δ = 2.38 (tt, J = 17.4, 2.5 Hz, 1 H), 2.66
(ddd, J = 17.4, 4.1, 6.7 Hz, 1 H), 2.80–2.92 (m, 3 H), 3.77 (s, 3 H), 4.73
(d, J = 18.0 Hz, 1 H), 4.81 (d, J = 18.0 Hz, 1 H), 4.87 (dd, J = 13.5, 3.9 Hz,
1 H), 4.99–5.02 (m, 1 H), 6.12 (dd, J = 9.8, 2.9 Hz, 1 H), 6.66 (ddd, J =
9.4, 6.8, 2.1 Hz, 1 H), 7.15–7.27 (m, 3 H), 7.56 (d, J = 7.8 Hz, 1 H).
13C NMR (90 MHz, CDCl3): δ = 21.5, 32.1, 38.8, 45.8, 51.5, 52.9, 109.1,
111.6, 119.0, 120.6, 122.8, 125.9, 126.8, 133.4, 138.2, 138.3, 164.9,
169.0.
Rf = 0.70 (cyclohexane/EtOAc, 95:5).
IR (NaCl): 2935, 2856, 1603, 1487, 1205, 1030, 800, 746 cm–1
.
1H NMR (250 MHz, CDCl3): δ = 1.26–1.39 (m, 2 H), 1.40–1.47 (m, 1 H),
1.54–1.64 (m, 1 H), 1.69–1.90 (m, 2 H), 2.26–2.37 (m, 2 H), 2.97 (s, 3
H), 3.76 (s, 3 H), 6.53 (d, J = 8.0 Hz, 1 H), 6.60–6.62 (m, 2 H), 6.72 (t, J =
7.6 Hz, 1 H), 6.90 (d, J = 2.4 Hz, 1 H), 7.06 (d, J = 6.5 Hz, 1 H), 7.10 (dt,
J = 7.7, 1.3 Hz, 1 H).
13C NMR (62.5 MHz, CDCl3): δ = 20.0, 20.3, 28.3, 28.6, 32.5, 56.3, 56.5,
107.2, 109.8, 109.9, 112.3, 112.5, 119.0, 122.4, 128.2, 133.6, 134.0,
149.4, 153.0, 154.6.
HRMS (ESI+): m/z [M + H]+ calcd for C18H19N2O3: 311.1390; found:
311.1379.
Benzofuroindoline 26
To a solution of ABCE tetracyclic indole 25 (115.0 mg, 0.238 mmol) in
CH2Cl2 (2.4 mL) at 0 °C were added p-methoxyphenol (7a) (59.0 mg,
0.476 mmol) and NIS (59.0 mg, 0.262 mmol), followed after 3 min by
AgBF4 (92.3 mg, 0.476 mmol). The resulting mixture was slowly
warmed to r.t. and stirred for 4 h. The reaction was quenched by addi-
tion of a saturated aqueous NH4Cl solution (0.5 mL), then filtered
through a pad of Celite. The filtrate was concentrated under reduced
pressure. Preparative TLC purification (cyclohexane/EtOAc, 50:50) af-
forded benzofuroindoline 26 (80.0 mg, 0.132 mmol) in 55% yield as a
colorless oil.
HRMS (ESI+): m/z [M + H]+ calcd for C20H22NO2: 308.1645; found:
308.1641.
N-Acetyl-benzofuroindoline 20b
To a solution of N-acetyl-tetrahydrocarbazole 19b (61.0 mg, 0.286
mmol) in CH2Cl2 (3 mL) at 0 °C were added p-methoxyphenol (7a)
(88.0 mg, 0.715 mmol) and NIS (71.0 mg, 0.315 mmol), followed after
5 min by AgBF4 (111 mg, 0.572 mmol). The resulting mixture was
slowly warmed to r.t. and stirred for 3 h. The reaction was quenched
by addition of a saturated aqueous NH4Cl solution (1 mL), and then
filtered through a pad of Celite. The filtrate was concentrated under
reduced pressure. Preparative TLC purification (cyclohexane/EtOAc,
90:10) afforded N-acetyl-benzofuroindoline 20b (35.0 mg, 0.104
mmol) in 36% yield as a colorless oil.
Rf = 0.54 (cyclohexane/EtOAc, 50:50).
IR (NaCl): 2953, 1739, 1599, 1488, 1266, 1164, 1024, 740 cm–1
.
1H NMR (360 MHz, CDCl3): δ = 1.83 (dd, J = 12.8, 3.3 Hz, 1 H), 2.11 (dd,
J = 14.3, 3.3 Hz, 1 H), 2.33–2.37 (m, 1 H), 2.36 (s, 3 H), 2.43 (d, J = 16.4
Hz, 1 H), 2.58 (td, J = 12.4, 3.3 Hz, 1 H), 2.68 (dd, J = 14.1, 3.3 Hz, 1 H),
3.31 (d, J = 12.2 Hz, 1 H), 3.50–3.54 (m, 1 H), 3.59 (t, J = 2.5 Hz, 1 H),
3.68 (s, 3 H), 3.71 (s, 3 H), 3.78 (s, 3 H), 6.43 (d, J = 6.9 Hz, 1 H), 6.48–
6.55 (m, 2 H), 6.71 (d, J = 2.8 Hz, 1 H), 6.74–6.78 (m, 1 H), 7.01 (d, J =
7.5 Hz, 2 H), 7.19 (d, J = 8.2 Hz, 2 H), 7.60 (d, J = 8.2 Hz, 2 H).
Rf = 0.35 (cyclohexane/EtOAc, 90:10).
IR (NaCl): 2939, 1665, 1598, 1487, 1377, 1209, 1168, 1029, 755 cm–1
.
1H NMR (250 MHz, CDCl3): δ = 1.30–1.38 (m, 1 H), 1.44–1.51 (m, 1 H),
1.54–1.31 (m, 2 H), 1.87–1.64 (m, 1 H), 2.00–2.05 (m, 1 H), 2.30–2.38
(m, 1 H), 2.52 (s, 3 H), 2.66 (dt, J = 14.3, 4.8 Hz, 1 H), 3.71 (s, 3 H),
6.65–6.68 (m, 2 H), 6.79 (dd, J = 7.4, 1.1 Hz, 1 H), 7.11 (td, J = 7.4, 1.1
Hz, 1 H), 7.21 (td, J = 7.8, 1.5 Hz, 1 H), 7.35 (dd, J = 7.2, 1.5 Hz, 1 H),
8.17 (d, J = 8.1 Hz, 1 H).
13C NMR (62.5 MHz, CDCl3): δ = 18.1, 18.4, 24.7, 30.6, 31.6, 56.2, 57.7,
108.1, 109.6, 110.6, 113.6, 117.4, 122.0, 124.4, 128.5, 132.8, 134.2,
142.5, 150.9, 156.6, 170.5.
13C NMR (90 MHz, CDCl3): δ = 21.6, 23.0, 26.7, 32.4, 41.8, 51.6, 52.8,
53.5, 54.7, 56.1, 66.6, 106.1, 109.5, 109.9, 111.3, 112.6, 120.7, 122.8,
127.3 (2 C), 127.8, 129.9 (2 C), 131.8, 132.5, 136.1, 143.9, 145.8, 152.1,
154.9, 170.0, 170.4.
HRMS (ESI+): m/z [M + H]+ calcd for C32H33N2O8S: 605.1952; found:
605.1956.
Benzodioxinoindoline 28
To a solution of tetrahydrocarbazole 19c (51.0 mg, 0.298 mmol) in
CH2Cl2 (2 mL) under argon was added NIS (74.0 mg, 0.328 mmol). The
solution was stirred for 30 min, then cooled to 0 °C and 3-methoxyca-
thecol (27) (104.0 mg, 0.742 mmol), AgBF4 (116.0 mg, 0.596 mmol)
and NaOH (60 mg, 1.49 mmol) were added. The resulting mixture was
stirred for 3 h prior to being quenched with a saturated aqueous
NH4Cl solution (0.5 mL) and filtered through a pad of Celite. Prepara-
tive TLC (cyclohexane/EtOAc, 9:1) afforded benzodioxinoindoline
(13.0 mg, 0.042 mmol) in 14% yield as a white solid.
HRMS (ESI+): m/z [M + Na]+ calcd for C21H21NO3Na: 358.1414; found:
358.1411.
Methyl-2-(N-indolyl) Acetate 18
To a solution of ABCD tetracyclic indole 11 (60.0 mg, 0.252 mmol) in
degassed DMF (1.6 mL) under argon was added KHMDS (75.0 mg,
0.376 mmol) at r.t. The reaction was stirred 15 min, then methyl 2-
bromoacetate (0.03 mL, 0.353 mmol) was added dropwise and the re-
sulting mixture was stirred for 7 h at r.t. prior to being quenched with
a saturated aqueous NH4Cl solution. The solution was diluted with
H2O, extracted with EtOAc and the combined organic layers washed
with H2O and brine, dried and concentrated under reduced pressure.
Rf = 0.30 (cyclohexane/EtOAc, 9:1).
IR (NaCl): 3341, 2936, 1604, 1498, 1474, 1098, 1019, 746 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

F
N. Denizot et al.
Special Topic
Synthesis
1H NMR (300 MHz, CDCl3): δ = 1.50–1.60 (m, 2 H), 1.62–1.70 (m, 2 H),
1.73–1.80 (m, 2 H), 2.03–2.10 (m, 1 H), 2.33–2.40 (m, 1 H), 3.88 (s, 3
H), 4.34 (s, 1 H), 6.35 (dd, J = 8.1, 1.4 Hz, 1 H), 6.43 (dd, J = 8.1, 1.4 Hz,
1 H), 6.64 (d, J = 7.5 Hz, 1 H), 6.70 (d, J = 8.0 Hz, 1 H), 6.77 (t, J = 7.5 Hz,
1 H), 7.08 (td, J = 7.7, 1.2 Hz, 1 H), 7.21 (d, J = 7.4 Hz, 1 H).
13C NMR (90.6 MHz, CDCl3): δ = 20.7, 23.3, 31.5, 37.1, 56.6, 81.6, 94.2,
104.6, 109.7, 111.7, 120.2, 120.6, 122.6, 129.2, 131.6, 132.9, 143.9,
146.7, 149.3.
(c) Tomakinian, T.; Guillot, R.; Kouklovsky, C.; Vincent, G. Chem.
Commun. 2016, 52, 5443. (d) Tomakinian, T.; Kouklovsky, C.;
Vincent, G. Synlett 2015, 26, 1269. (e) Beaud, R.; Tomakinian, T.;
Denizot, N.; Pouilhès, A.; Kouklovsky, C.; Vincent, G. Synlett
2015, 26, 432. (f) Tomakinian, T.; Guillot, R.; Kouklovsky, C.;
Vincent, G. Angew. Chem. Int. Ed. 2014, 53, 11881. (g) Beaud, R.;
Guillot, R.; Kouklovsky, C.; Vincent, G. Angew. Chem. Int. Ed.
2012, 51, 12546.
(3) (a) Denizot, N.; Pouilhès, A.; Cucca, M.; Beaud, R.; Guillot, R.;
Kouklovsky, C.; Vincent, G. Org. Lett. 2014, 16, 5752. (b) Denizot,
N.; Guillot, R.; Kouklovsky, C.; Vincent, G. Chem. Eur. J. 2015, 21,
18953. (c) Tomakinian, T.; Hamdan, H. A.; Denizot, N.; Guillot,
R.; Baltaze, J.-P.; Kouklovsky, C.; Vincent, G. Eur. J. Org. Chem.
2017, 2757.
HRMS (ESI+): m/z [M + Na]+ calcd for C19H19NO3Na: 332.1257; found:
332.1247.
Funding Information
(4) Kam, T.-S.; Tan, S.-J.; Ng, S.-W.; Komiyama, K. Org. Lett. 2008, 10,
3749.
(5) For reviews on dearomatization of indoles, see: (a) Roche, S. P.;
Youte Tendoung, J.-J.; Tréguier, B. Tetrahedron 2015, 71, 3549.
(b) Denizot, N.; Tomakinian, T.; Beaud, R.; Kouklovsky, C.;
Vincent, G. Tetrahedron Lett. 2015, 56, 4413.
We gratefully acknowledge the ‘Fondation pour le développement de
la chimie des substances naturelles et ses applications; sous l’égide de
l’Académie des Sciences’ for a Ph.D. fellowship to N.D., the ANR (ANR-
15-CE29-0001, ‘Mount Indole’; ANR-12-JS07-0002, ‘CouPhIn’), Uni-
versité Paris-Sud and the CNRS for financial support.
A
g
e
n
ce
N
oaitnae
l
de
al
R
e
cherch
e
A(
N
R-15-C
E
2
9-0
0
0
1
A)
g
e
n
ce
N
oaitnae
l
de
al
R
e
cherch
e
A(
N
R-12S-J07-0
0
0
2)
(6) Inspired from: (a) Matsumoto, K.; Tokuyama, H.; Fukuyama, T.
Synlett 2007, 3137. (b) Ueda, H.; Satoh, H.; Matsumoto, K.;
Sugimoto, K.; Fukuyama, T.; Tokuyama, H. Angew. Chem. Int. Ed.
2009, 48, 7600. (c) For an oxidative coupling involving NIS and
indoles and a thorough discussion of the mechanistic pathways,
see: Newhouse, T.; Lewis, C. A.; Eastman, K. J.; Baran, P. S. J. Am.
Chem. Soc. 2010, 132, 7119.
Acknowledgment
We would like to thank Dr. Laurent Evanno and Prof. Erwan Poupon
for helpful discussions and Mr. Jean-Pierre Baltaze and Mr. Hussein
Abou Hamdam for assistance in NMR analysis.
(7) For a highlight on electrophilic indoles, see: Bandini, M. Org.
Biomol. Chem. 2013, 11, 5206.
(8) Hirasawa, Y.; Arai, H.; Rahman, A.; Kusumawati, I.; Zaini, N. C.;
Shirota, O.; Morita, H. Tetrahedron 2013, 69, 10869.
Supporting Information
Supporting information for this article is available online at
(9) The originally assigned structure of the natural product voacal-
gine A displayed the benzofuroindoline-containing heptacyclic
part of bipleiophylline (ref. 8), analogous to 9, before we revised
its structure (refs. 2a,b) to an isochromenoindoline-containing
heptacycle related to bipleiophylline.
(10) (a) Sakai, S.; Shinma, N. Heterocycles 1976, 4, 985. (b) Calverley,
M. J.; Banks, B. J.; Harley-Mason, J. Tetrahedron Lett. 1981, 22,
1635. (c) Bennasar, M. L.; Zulaica, E.; Jimenez, J. M.; Bosch, J.
J. Org. Chem. 1993, 58, 7756.
(11) Deiters, A.; Pettersson, M.; Martin, S. F. J. Org. Chem. 2006, 71,
6547.
(12) (a) Ren, W.; Tappin, N.; Wang, Q.; Zhu, J. Synlett 2013, 24, 1941.
(b) Teng, M.; Zi, W.; Ma, D. Angew. Chem. Int. Ed. 2014, 53, 1814.
(c) For an account on indole-enolate oxidative couplings, see: Zi,
W.; Zuo, Z.; Ma, D. Acc. Chem. Res. 2015, 48, 702.
(13) Vice, S. F.; Dmitrienko, G. I. Can. J. Chem. 1982, 60, 1233.
(14) The relative stereochemistry of 26 has been determined by a
NOESY experiment, see the Supporting Information.
(15) Omote, Y.; Tomotake, A.; Kashima, C. Tetrahedron Lett. 1984, 25,
2993.
(16) CCDC 1823386 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/getstructures.
https://doi.org/10.1055/s-0036-1592002.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
References
(1) For reviews on the synthesis of benzofuroindolines, see:
(a) Lachia, M.; Moody, C. J. Nat. Prod. Rep. 2008, 25, 227. (b) Ito,
Y.; Ueda, M.; Miyata, O. Heterocycles 2014, 89, 2029. For selected
syntheses of benzofuroindolines via the oxidative coupling of
indoles and phenols, see: (c) Burgett, A. W. G.; Li, Q.; Wei, Q.;
Harran, P. G. A. Angew. Chem. Int. Ed. 2003, 42, 4961. (d) Zhao, J.-
C.; Yu, S.-M.; Liu, Y.; Yao, Z.-J. Org. Lett. 2013, 15, 4300. (e) Ding,
H.; DeRoy, P. L.; Perreault, C.; Larivée, A.; Siddiqui, A.; Caldwell,
C. G.; Harran, S.; Harran, P. G. Angew. Chem. Int. Ed. 2015, 54,
4818. (f) Liu, K.; Tang, S.; Huang, P.; Lei, A. Nat. Commun. 2017,
8, 775. For syntheses of benzofuroindolines via the coupling of
indoles and para-quinones, see: (g) Tian, W.; Rao Chennama-
neni, L.; Suzuki, T.; Chen, D. Y.-K. Eur. J. Org. Chem. 2011, 1027.
(h) Shu, C.; Liao, L.-H.; Liao, Y.-J.; Hu, X.-Y.; Zhang, Y.-H.; Yuan,
W.-C.; Zhang, X.-M. Eur. J. Org. Chem. 2014, 4467. (i) Liao, L.;
Shu, C.; Zhang, M.; Liao, Y.; Hu, X.-Y.; Zhang, Y.; Wu, Z.; Yuan,
W.; Zhang, X.-M. Angew. Chem. Int. Ed. 2014, 53, 10471. (j) Liu,
Q.-J.; Zhu, J.; Song, X.-Y.; Wang, L.; Wang, S. R.; Tang, Y. Angew.
Chem. Int. Ed. 2018, 57, 3810.
(2) (a) Lachkar, D.; Denizot, N.; Bernadat, G.; Ahamada, K.;
Beniddir, M. A.; Dumontet, V.; Gallard, J.-F.; Guillot, R.; Leblanc,
K.; N’nang, E. O.; Turpin, V.; Kouklovsky, C.; Poupon, E.; Evanno,
L.; Vincent, G. Nat. Chem. 2017, 9, 793. (b) Denizot, N.; Lachkar,
D.; Kouklovsky, C.; Poupon, E.; Evanno, L.; Vincent, G. Synthesis
(17) For related oxidative double additions of alkoxides into indoles,
see ref. 13 and: Takayama, H.; Misawa, K.; Okada, N.; Ishikawa,
H.; Kitajima, M.; Hatori, Y.; Murayama, T.; Wongseripipatana, S.;
Tashima, K.; Matsumoto, K.; Horie, S. Org. Lett. 2006, 8, 5705.
2018,
50,
in
press,
DOI:
10.1055/s-0036-1591910.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F