Silver-Mediated Intramolecular Friedel-Crafts-Type Cyclizations of 2-Benzyloxy-3-bromoindolines: Synthesis of Isochromeno[3,4-b[ indolines and 3-Arylindoles

Article abstract of DOI:10.1055/s-0039-1690734

We disclose a silver-mediated intramolecular Friedel-Crafts-type cyclization of 2-benzyloxy-3-bromoindolines to afford an untapped family of isochromeno[3,4-b[indolines and 3-arylindoles, in which deformylative arylation of 2-(4-methoxybenzyloxy)-3-bromoindolines is reported for the first time. The isochromeno[3,4-b[indolines can be readily transformed into other heterocyclic moieties.

Full text of DOI:10.1055/s-0039-1690734

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–F
letter
A
en
T. Yamashiro et al.
Letter
Synlett
Silver-MediatedIntramolecularFriedel–Crafts-TypeCyclizationsof
2-Benzyloxy-3-bromoindolines: Synthesis of Isochromeno[3,4-b]
indolines and 3-Arylindoles
Friedel–Crafts-type cyclization
Toshiki Yamashiro
R2
R2
R2
Koji Yamada*
path a
R1
R1
Haruka Yoshida
Yutaro Tomisaka
Takahide Nishi
H
R1
path a
Br
path b
Ag
13 examples, up to 95% yield
O
O
O
N
Ts
N
Ts
H
N
Ts
isochromeno[3,4-b]indolines
Takumi Abe*
0
0
0
0-0
0
0
3-
1
7
2
9-1
0
9
7
path b
R2
Faculty of Pharmaceutical Sciences, Health Sciences University
of Hokkaido, Ishikari-tobetsu, Hokkaido 061-0293, Japan
kyamada@hoku-iryo-u.ac.jp
unprecedented
deformylative arylation
R2
+
R1
R1
HCHO
abe-t@hoku-iryo-u.ac.jp
11 examples, up to 85% yield
3-arylindoles
O
N
Ts
N
Ts
Received: 25.09.2019
OH
OH
Accepted after revision: 15.10.2019
Published online: 05.11.2019
DOI: 10.1055/s-0039-1690734; Art ID: st-2019-u0508-l
CO2H
H
H
N
N
N
N
Abstract We disclose a silver-mediated intramolecular Friedel–Crafts-
type cyclization of 2-benzyloxy-3-bromoindolines to afford an un-
tapped family of isochromeno[3,4-b]indolines and 3-arylindoles, in
which deformylative arylation of 2-(4-methoxybenzyloxy)-3-bromoin-
dolines is reported for the first time. The isochromeno[3,4-b]indolines
can be readily transformed into other heterocyclic moieties.
O
O
N
H
N
H
hyrtimomine A4
(–)-hyrtimomine B4
O
O
N
H
Key words Friedel–Crafts, cyclization, isochromeno[3,4-b]indolines,
deformylative arylation, 3-arylindoles, silver
N
H
O
H
MeO
voacalgine A5b
Chromenoindolines and isochromenoindolines form an
important group of pharmacologically active compounds
displaying, for example, antimalarial activity,1 anticancer
activity,2 antiplasmodial activity toward the chloroquine-
resistant strain FcB1 of Plasmodium falciparum,3 cytotoxici-
ty against KB, L1210 cells,4 and vincristine resistant human
KB (Figure 1).5 Recently, many useful approaches to chrom-
eno[2,3-b]indolines have been explored to develop more
potent biologically active compounds.6 On the other hand,
the synthesis of isochromeno[3,4-b]indolines has scarcely
developed until recently because of their complex struc-
tures including 3-arylindolines.7
In 2017, Vincent and co-workers reported a silver-medi-
ated oxidative coupling of indoles and tetrahydro--carbo-
lines with 2,3-dihydroxybenzoic acids for the construction
of isochromeno[3,4-b]indolines, affording the total synthe-
sis of voacalgine A and bipleiophylline (Scheme 1A).8
As a catalytic version of the oxidative coupling, Chen
and co-workers developed the Fe-mediated oxidative cou-
Figure 1 Selected chromenoindolines and isochromenoindolines alka-
loids
pling of indoles with 2,3-dihydroxybenzoic acids (Scheme
1B).9 These reactions require 2,3-disubstituted or 3-substi-
tuted indoles and 2,3-dihydroxybenzoic acids due to the
formation of an orthoquinone intermediate.
Apparently, these features restricted the access to vari-
ous substituted isochromeno[3,4-b]indolines. Accordingly,
the synthesis of isochromeno[3,4-b]indolines remains un-
exploited using these reactions and simple starting materi-
als.
As part of our ongoing investigations focused on the in-
dole chemistry,10 we were eager to tackle the challenges of
exploring a concise construction of isochromeno[3,4-b]in-
dolines bearing a variety of substituents because it could
lead to pharmacologically active compounds. Recently, we
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–F
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
T. Yamashiro et al.
Letter
Synlett
concluded that the initially expected isochromeno[3,4-b]in-
doles could not be obtained through the isotoluene inter-
mediate followed by cyclization (Scheme 1C, path a). The
failure of the benzyl Claisen rearrangement/cyclization pro-
tocol to construct chromeno[3,4-b]indole structures led us
to study a silver-mediated Friedel–Crafts-type cyclization of
3-bromoindolines.
(A) Vincent's work:8 Silver-mediated biomimetic oxidative coupling
OH
OH
O
NTs
O
[Ag]
N
O
H
(5 equiv)
O
OH
NTs
HCOOH
rt, MeCN
30%
CO2H
N
OH
H
ortho-quinone
isochromeno[3,4-b]indolines
CO2H
It is well known that the halogenophilicity of the silver
salts toward Csp3–halogen bonds can enable mild activation
and high functional group compatibility in the intermolec-
ular Friedel–Crafts reaction of 3-haloindolines with nucleo-
philes, as reported by Movassaghi,12 Qin,13 Ye,14 Vincent,15
and Tokuyama.16 We envisioned that a silver-mediated in-
tramolecular Friedel–Crafts-type cyclization of 2-benzyl-
oxy-3-bromoindolines would allow access to isochrome-
no[3,4-b]indolines. Herein, we describe a novel construc-
tion of isochromeno[3,4-b]indolines by a silver-mediated
Friedel–Crafts-type cyclization of easily available starting
materials (Scheme 1D, path a). An electron-donating group
on the benzyl moiety was shown to alter the normal reac-
tivity of the Friedel–Crafts-type cyclization, affording 3-
(B) Chen's work:9 Fe-Catalyzed biomimetic oxidative coupling
OH
OH
O
NTs
O
N
O
H
[Fe] (cat.)
O
OH
NTs
t-BuOOH
AcOH
5 °C, MeCN
63%
N
CO2H
OH
H
ortho-quinone
isochromeno[3,4-b]indolines
CO2H
(C) Our previous work:11 Tandem benzyl Claisen/Cope rearrangement
initially expected
H
benzyl
Claisen
path a
O
O
O
path a
N
Ts
N
Ts
N
Ts
isotoluene
isochromeno[3,4-b]indole
path b
4
Table 1 Reaction Condition Optimizationa
4
path b
Cope
3
H
3
O
N
Ts
O
N
Ts
H
Br
[Ag]
(D) This work: Silver-mediated Friedel–Crafts-type cylization of 2-benzyloxy-
3-bromoindolines through benzylic cations
O
H
solvent, time, rt
O
N
Ts
N
Ts
R1
R1
HO
R2
+
Br
NBS
1aa
2aa
N
N
Ts
Ts
Entry
Ag (equiv)
Solvent (mL)
Time (h)
Yield (%)b
R2
R2
1
2
Ag2O (5)
Ag2O (5)
Ag2O (5)
Ag2O (5)
Ag2O (5)
Ag2O (5)
Ag2O (5)
Ag2CO3 (5)
AgNTf2 (5)
AgCN (5)
AgOTf (5)
AgPF6 (5)
Ag2O (5)
Ag2O (3)
Ag2O (1.5)
Ag2O (0.5)
–
EtOAc (5)
CF3C6H5 (5)
toluene (5)
MeCN (5)
CHCl3 (5)
0.5
3
62
60
62
21
42
66
85
77
0
R2
a
R1
R1
R1
H
N
Br
path a
3
48
48
0.5
b
Ag
O
O
4
O
H
N
N
Ts
Ts
Ts
5
isochromeno[3,4-b]
benzylic cations
indolines
path b
6
TFE (5)
1
R2
7
MeNO2 (5)
MeNO2 (5)
MeNO2 (5)
MeNO2 (5)
MeNO2 (5)
MeNO2 (5)
MeNO2 (2)
MeNO2 (2)
MeNO2 (2)
MeNO2 (2)
MeNO2 (2)
0.5
1
R2
R2
8
+
R1
HCHO
R1
R1
9
2
+
O
10
11
12
13
14
15
16
17
24
29
0
N
N
N
Ts
Ts
spirofuroindolines
Ts
1
3-arylindoles
0.5
0.5
2
36
86
85
85
45
0
Scheme 1 Previous work on the synthesis of isochromeno[3,4-b]indo-
lines
2
have developed a direct C4 benzylation of indoles utilizing
24
24
2-benzyloxyindoles,
affording
4-benzyl-2-oxindoles
(Scheme 1C).11 This reaction involves the formation of iso-
toluene intermediates in situ via a benzyl Claisen rear-
rangement, which undergo Cope rearrangement and aro-
matization (Scheme 1C, path b). In these investigations, we
a Reaction conditions: 1aa (0.2 mmol), Ag salt, solvent, r.t.
b Isolated yields.
c Complex mixtures.
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–F

C
T. Yamashiro et al.
Letter
Synlett
arylindoles via an unprecedented ipso-attack on the ben-
zene ring/deformylative arylation sequences (Scheme 1D,
path b).
(entries 8–12). Finally, when 1.5 equivalent of Ag2O was
used in MeNO2 (0.1 M), good conversion into 2aa was ob-
served (entries 13–16). A control experiment without the
silver salt did not give product 2aa (entry 17).
Initially, the reaction was carried out using N-Ts 2-ben-
zyloxy-3-bromoindoline (1aa)11 and 5 equiv of Ag2O in EtO-
Ac at room temperature. As expected, the reaction proceed-
ed smoothly to afford isochromeno[3,4-b]indoline 2aa in
62% yield (Table 1, entry 1). To improve the yield of 2aa, op-
timization of the protocol by replacing Ag2O with other sil-
ver salts, replacing EtOAc with other solvents, and modulat-
ing the equivalent of silver salts and the solvent concentra-
tion was conducted. The most efficient solvent was MeNO2
(entries 1–7). Ag2O was the best silver salt for the transfor-
mation (entry 7), while all other silver salts studied, such as
Ag2CO3, AgNTf2, AgNO3, AgOTf, and AgPF6, gave lower yields
With the optimized conditions identified, the scope of
the reaction was investigated by using a variety of 2-benzyl-
oxy-3-bromoindolines 1 (Scheme 2). In general, a diverse
range of substrates 1 were successfully used to afford iso-
chromeno[3,4-b]indolines 2 up to 95% yield, although the
electronic nature of the substituents on the benzene-ring at
1 had an influence on the reaction efficiency. An electron-
donating group on the indole ring was not fully tolerated in
the Friedel–Crafts-type process (2ba, 2bc and 2bd), while
electron-withdrawing groups were compatible (2ca, 2cc,
2cd, 2da, 2ea, and 2fa). Specifically, substrates with chloro
R2
R2
R2
H
Br
R1
R1
R1
Ag2O (1.5 equiv)
MeNO2, rt
+
O
H
O
N
N
N
Ts
Ts
Ts
3
2
1
4-substituted benzyl ethers
5-H indolines
R2
5-MeO indolines
5-Cl indolines
R2
R2
R2
R2
R2
H
H
Cl
H
Cl
MeO
MeO
H
H
+
+
+
O
O
O
N
N
N
H
N
N
N
H
H
Ts
Ts
Ts
Ts
Ts
Ts
2aa (R2 = H):
3aa (R2 = H):
2ca (R2 = H):
3ca (R2 = H):
2ba (R1 = H):
3ba (R2 = H):
2 h, 85%
2 h, 0%
1 h, 90%
1 h, 0%
2ab (R2 = OMe):
3ab (R2 = OMe):
2 h, 28%
2 h, 0%
2cb (R2 = OMe):
3cb (R2 = OMe):
2bb (R2 = OMe):
3bb (R2 = OMe):
3 h, 0%
3 h, 66%
0.5 h, 0%c
0.5 h, 59%c
1 h, 0%
1 h, 75%
2ac (R2 = Me):
3ac (R2 = Me):
2cc (R2 = Me):
3cc (R2 = Me):
1 h, 84%
1 h, 7%
2bc (R2 = Me):
3bc (R2 = Me):
1 h, 90%
1 h, 6%
2ad (R2 = Cl):
3ad (R2 = Cl):
1 h, 22%
1 h, 2%
2cd (R2 = Cl):
3cd (R2 = Cl):
24 h, 12%
24 h, 0%
2bd (R2 = Cl):
3bd (R2 = Cl):
0.5 h, 43%c
0.5 h, 5%c
3 h, 5%c
3 h, 0%c
2ae (R2 = F):
3ae (R2 = F):
20 h, 19%
20 h, 20%
2af (R2 = NO2):
3af (R2 = NO2):
20 h, 0%
20 h, 0%
5-Br indolines
R2
4-Cl indolines
6-Cl indolines
R2
R2
R2
R2
R2
Cl
Cl
Br
Br
H
H
N
H
N
+
+
+
O
H
Cl
Cl
O
H
O
H
N
N
N
N
Ts
Ts
Ts
Ts
Ts
Ts
3da (R2 = H):
3fa (R2 = H):
2da (R2 = H):
2ea (R2 = H):
3ea (R2 = H):
2fa (R2 = H):
1 h, 0%
1 h, 0%
1 h, 83%
2 h, 95%
2 h, 0%
1 h, 83%
3db (R2 = OMe):
1 h, 71%
3fb (R2 = OMe):
1 h, 46%
2db (R2 = OMe):
1 h, 0%
2eb (R2 = OMe):
1 h, 0%
3eb (R2 = OMe):
1 h, 44%
2fb (R2 = OMe):
1 h, 0%
3-MeO benzyl ether
2-MeO benzyl ether
OMe
OMe
OMe
H
H
+
OMe
O
O
H
N
H
Ts
N
N
N
Ts
Ts
Ts
2ag: 1 h, 69%
3ag: 1 h, 0%
2ah: 1 h, 0%
3ah: 1 h, 85%
Scheme 2 Substrate scope of silver-mediated Friedel–Crafts-type cyclization of 2-benzyloxy-3-bromoindolines. Reagents and conditions: 1 (0.2 mmol)
and Ag2O (0.3 mmol, 1.5 equiv) in MeNO2 (2 mL) at r.t. (isolated yields given). a Ag2O (1.0 mmol, 5 equiv) was used.
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–F

D
T. Yamashiro et al.
Letter
Synlett
or bromo substituents were tolerated in the silver-mediat-
ed transformation. The halogen functional group allowed
further synthetic manipulations of the products through
transition-metal-catalyzed cross-couplings. A 4-methoxy
group on the benzyl moiety has been shown to alter the
normal reactivity of the Friedel–Crafts-type cyclization, af-
fording 3-arylindoles 3 with release of HCHO (3ab, 3bb,
3cb, 3db, 3eb, 3fb, and 3ah).
Notably, a reverse regioselectivity was observed (2ag,
ortho-attack) when a 3-methoxy substrate 1ag was used.
These results suggest that the para- or ortho-position to the
CH2O-group reacted to afford the arylated products 3 in this
transformation. The deformylative arylation has been
scarcely reported to date17 in contrast to the decarboxyl-
ative arylation.18,19 To our knowledge, this is the first exam-
ple of an arylation using benzyl ethers as the arylating re-
agent. Such 3-arylindoles are of great interest because of
their intriguing biological activities.20
Mg, MeOH
25% HBr/AcOH
MeNO2, rt, 1 h
Br
HO
82%
100 °C, reflux
0.5 h
N
N
H
Ts
4
5
66%
H
N
O
H
Ts
2aa
48% HBF4
BF3•OEt2
HO
MeNO2, rt, 12 h
MeNO2, rt, 2 h
N
N
Ts
52%
Ts
7
6
61%
Scheme 4 Synthetic elaborations of compound 2aa
aminoether (hemiaminal) B undergoes deformylation with
the aid of the indole nitrogen to give the 3-arylated product
3ab through aromatization of indolenium intermediate C.23
Given that the yield of 2ab is 0%, the substrate 1ab prefer-
entially favors intermediate B due to the stabilization of the
arenium intermediate B by the methoxy group. Thus, the
ipso-attack of the intermediate A occurs regiospecifically,
which generates the intermediate B and produces product
3ab.
To further show the synthetic use of this transforma-
tion, we conducted a 2.4 mmol (1aa, 1.1 g) scale reaction
(Scheme 3). The gram-scale reaction afforded the desired
product 2aa in 85% yield and the cyclization was as efficient
as the 0.2 mmol scale reaction (2aa: 85% yield, Scheme 2).
H
Br
Ag2O (1.5 equiv)
Friedel–Crafts-type cyclization
O
H
O
N
Ts
N
Ts
MeNO2, rt, 0.5 h
85%
MeO
MeO
OMe
ortho
-attack
path a
1aa
2aa
H
[Ag]
Br
path a
(1.1 g, 2.4 mmol)
(768 mg, 2.03 mmol)
path b
O
H
O
O
N
N
Scheme 3 Scale-up reaction
N
Ts
2ab
Ts
A
Ts
1ab
ipso-attack
path b
Encouraged by the applicability for the gram-scale reac-
tion, we further explored the synthetic utility of 2aa in or-
ganic synthesis (Scheme 4). The tosyl group of 2aa could be
readily removed upon treatment with Mg powder in meth-
anol under reflux conditions, to give 3-aryllindole 4 in 82%
yield. 2-Indolyl benzyl alcohols are utilized as intermedi-
ates for electroluminescent hosts.21 Treatment of 2aa with
HBr or HBF4 led to the formation of 5 or 6 via a ring-opening
reaction. Among the acids investigated, BF3·OEt2 afforded
dihydroindeno[2,1-b]indole 7 in 52% yield through a ring-
opening reaction and dehydrative cyclization.
Me
OMe
deformylative
arylation
OMe
O
+
HCHO
-H+
+
O
N
N
N
Ts
3ab
Ts
Ts
1,1-aminoether
(hemiaminal)
B
C
Scheme 5 Plausible mechanism
Based on the results presented in Scheme 2 and on pre-
vious reports,22,23 we propose a plausible reaction pathway
and deformylation mode to explain the chemistry of the de-
formylative arylation of 1ab (Scheme 5). Initially, 1ab
should give carbocation intermediate A upon reaction with
the silver complex. In pathway (a), ortho-attack by the 4-
MeO-benzyl moiety to the carbocation may occur to afford
2ab. In pathway (b), ipso-attack by the 4-MeO-benzyl moi-
ety to the carbocation may afford arenium intermediate B.22
Then, to restore the original aromatic structure, this 1,1-
In summary, we achieved a silver-mediated intramolec-
ular Friedel–Crafts-type cyclization of 2-benzyloxy-3-bro-
moindolines via the generation of benzyl cation intermedi-
ates. This is the first example of a construction of isochrom-
eno[3,4-b]indolines without using 2-hydroxybenzoic acids
as a substrate. This protocol exhibits a wide substrate scope
and proceeds under mild conditions. Furthermore, as a
demonstration of the synthetic potential of this protocol,
the derivatization of isochromeno[3,4-b]indolines was car-
ried out. On the other hand, a methoxy group on the benzyl
moiety has been shown to alter the normal reactivity of the
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–F

E
T. Yamashiro et al.
Letter
Synlett
Friedel–Crafts-type cyclization, affording 3-arylindoles via
an unprecedented ipso-attack on the benzene ring/de-
formylative arylation sequences. Future efforts will focus on
the intermolecular Friedel–Crafts-type cyclization and on
the development of an enantioselective variant of the reac-
tion.
Evanno, L.; Vincent, G. Nat. Chem. 2017, 9, 793. (b) Denizot, N.;
Lachkar, D.; Kouklovsky, C.; Poupon, E.; Evanno, L.; Vincent, G.
Synthesis 2018, 50, 4229.
(9) Ye, J.; Lin, Y.; Liu, Q.; Xu, D.; Wu, F.; Liu, B.; Gao, Y.; Chen, H. Org.
Lett. 2018, 20, 5457.
(10) (a) Abe, T.; Yamada, K. Org. Lett. 2016, 18, 6504. (b) Abe, T.;
Yamada, K. J. Nat. Prod. 2017, 80, 241. (c) Abe, T.; Takahashi, Y.;
Matsubara, Y.; Yamada, K. Org. Chem. Front. 2017, 4, 2124.
(d) Abe, T.; Suzuki, T.; Anada, M.; Matsunaga, S.; Yamada, K. Org.
Lett. 2017, 19, 4275. (e) Abe, T.; Yamada, K. Org. Lett. 2018, 20,
1469. (f) Abe, T.; Shimizu, H.; Takada, S.; Tanaka, T.; Yoshikawa,
M.; Yamada, K. Org. Lett. 2018, 20, 1589. (g) Abe, T.; Satake, S.;
Yamada, K. Heterocycles 2019, 99, 379. (h) Itoh, T.; Chiba, Y.;
Kawaguchi, S.; Koitaya, Y.; Yoneta, Y.; Yamada, K.; Abe, T. RSC
Adv. 2019, 9, 10420. (i) Abe, T.; Aoyama, S.; Ohmura, M.;
Taniguchi, M.; Yamada, K. Org. Lett. 2019, 21, 3367.
Funding Information
This work was financially supported by a Grant-in-Aid for Young Sci-
entists (B) (Grant No. 16K18849 for T. A.) from the Japan Society for
the Promotion of Science (JSPS).
J
a
p
a
n
S
o
c
i
etyforth
e
Pro
m
oti
o
n
of
S
c
i
e
n
c
e
(1
6
K
1
8
8
4
9)
Supporting Information
(11) Abe, T.; Kosaka, Y.; Asano, M.; Harasawa, N.; Mishina, A.;
Nagasue, M.; Sugimoto, Y.; Katakawa, K.; Sueki, S.; Anada, M.;
Yamada, K. Org. Lett. 2019, 21, 826.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690734.
S
u
p
p
orit
n
gInformati
o
n
S
u
p
p
orti
n
gInformati
o
n
(12) (a) Kim, J.; Movassaghi, M. J. Am. Chem. Soc. 2011, 133, 14940.
(b) Boyer, N.; Movassaghi, M. Chem. Sci. 2012, 3, 1798. (c) Boyer,
N.; Morrison, K. C.; Kim, J.; Hergenrother, P. J.; Movassaghi, M.
Chem. Sci. 2013, 4, 1646. (d) Coste, A.; Kim, J.; Adams, T. C.;
Movassaghi, M. Chem. Sci. 2013, 4, 3191. (e) Adams, T. C.;
Payette, J. N.; Cheah, J. H.; Movassaghi, M. Org. Lett. 2015, 17,
4268. (f) Loach, R. P.; Fenton, O. S.; Movassaghi, M. J. Am. Chem.
Soc. 2016, 138, 1057.
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© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–F