Modular synthesis of heptaarylindole

Article abstract of DOI:10.1039/c8ob00993g

The first synthesis of heptaarylindole (HAI) has been accomplished using a coupling/ring transformation strategy. Four readily prepared modular units (diarylthiophenes, 2-arylaziridines, arylboronic acids, and arylalkynes) were joined together to provide

Full text of DOI:10.1039/c8ob00993g

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DOI: 10.1039/C8OB00993G
Organic Biomolecular Chemistry
PAPER
Modular Synthesis of Heptaarylindole
Shin Suzuki,a Takashi Asako,b Kenichiro Itamib and Junichiro Yamaguchi*[3]
Received 00th January 20xx,
Accepted 00th January 20xx
The first synthesis of heptaarylindole (HAI) has been accomplished using a coupling/ring transformation strategy. Four
readily prepared modular units (diarylthiophenes, 2-arylaziridines, arylboronic acids, and arylalkynes) were joined together
to provide key ynamide intermediates. Subsequent inverse electron-demand intramolecular [4+2] cycloaddition furnished
pentaarylindoles (PAIs) regioselectively. This strategy was also applied to the synthesis of tetraarylazaindole with four
different aryl substituents. PAIs underwent further arylations at the C2- and N1-positions, providing HAI with seven
DOI: 10.1039/x0xx00000x
www.rsc.org/
different
aryl
substituents
with
virtually
complete
regioselectivity.
envisioned that a coupling/ring transformation strategy would
also be effective for the synthesis of HAI (a retrosynthetic
analysis is shown in Figure 1b). HAI would be generated from
pentaarylindole (PAI) by appendage of two aromatic units at
C2 and N1 (coupling reactions). In turn, PAI can be produced
by an inverse electron-demand intramolecular [4+2]
cycloaddition between thiophene S,S-dioxide and ynamide
moieties via ring transformation.6,7,8
Introduction
Nitrogen-containing benzoheteroles such as indoles and
azaindoles represent privileged structural motifs in functional
molecules such as pharmaceuticals, natural products and
ligands.1 In particular, aryl-substituted indoles have often been
found in bioactive molecules.2 To construct these skeletons,
cyclization using benzenoid precursors (e.g., Fischer, Larock,
and Bartoli indole synthesis) or cross-coupling reaction of
halogenated/metallated indoles have been used as
conventional and reliable methods.3 Recently, direct C–H
arylations of benzoheteroles have been extensively developed,
and regioselective C–H arylations of indoles have been
achieved at all positions through transition metal catalysis.4
Even when taking into consideration these notable
advancements, regioselective synthesis of multiply arylated
indoles remains challenging.
a) Examples for the synthesis of multiply arylated aromatics (Our previous work)
intermolecular [4+2]
cycloaddition
H
OMe
H
C–H arylation
cross-coupling
"dienophiles"
H
S
S
Ring transformation
Coupling
O
N
In related work, our group has recently developed a
programmed synthesis of multiply arylated aromatics by a
coupling/ring transformation approach (Figure 1a).5
Tetraarylthiophene S-oxides, prepared by regioselective C–H
arylations and cross-couplings followed by oxidation of the
thiophene, underwent [4+2] cycloaddition with various
HAB (2015)
hexaarylbenzene
PAP (2015, 2017)
pentaarylpyridine octaarylnaphthalene
OAN (2017)
OAA (2017)
(octaarylanthracene)
b) Modular synthesis of heptaarylindoles (This work)
dienophiles
to
provide
hexaarylbenzenes
(HABs),5a
X
H
H
N
N
H
–SO2
–[R]
+[O]
pentaarylpyridines (PAPs),5a,b octaarylnaphthalenes (OANs)5c
and octaarylanthracenes (OAAs)5c in a programmed manner.
Motivated by a challenge to synthesize multiply arylated
indoles, we decided to tackle the synthesis of fully arylated
indole, heptaarylindole (HAI), which has not been achieved so
far. Based on our synthesis of multiply arylated aromatics, we
N
R
arylation
HAI: heptaarylindole
PAI: pentaarylindole
Coupling
X = SO2
IED
intramolecular [4+2]
Ring transformation
Ts
N
H
H
H
H
H
H
S
S
O
O
H
H
N
Coupling
Br
NR
H
H
B(OH)2
four modular units
ynamide
intermediate
indole
Figure 1. a) Examples for the synthesis of multiply arylated aromatics. b) Modular
synthesis of heptaarylindoles.
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ARTICLE
Journal Name
Ar2
The ynamide intermediate would be formed by connecting
four modular units: diarylthiophenes, 2-arylaziridines,
arylboronic acids, and arylalkynes. Herein, we report the first
modular synthesis of HAI.
2
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Ar
Ts
N
DOI: 10.1039/C8OB00993G
Ar3
a.
Ar3
Sc(OTf)3
Zn(OTf)2
2
Ar1
S
2
Ar1
S
1
C5-alkylation
1
TsHN
2 steps
3
b. NBS [89–95%]
c. Ar4B(OH)2
2-bromothiophene
Results and discussion
C3-arylation
Pd[P(t-Bu)3]2
Synthesis of tetrasubstituted thiophene S,S-dioxide
NaOH [71%–quant]
Firstly, we synthesized tetrasubstituted thiophene S,S-
Ar4
Ar2
Ar4
Ar2
d. m-CPBA
dioxide
diarylthiophenes
step protocol involving cross-coupling and
arylation of 2-bromothiophene.9 To achieve a C5-alkylation of
, 2-aryl-N-tosylaziridines 2a: p-tolyl, 2b: phenyl) were
reacted with 1.5 equiv of in the presence of a catalytic
amount of Sc(OTf)3 and Zn(OTf)2 in dichloroethane to afford
C5-alkylated thiophenes in 79% yield (3acd from 1ac) and
5
(Scheme 1). The synthesis commenced from 2,4-
, which were readily prepared by our two-
-selective C–H
Ar3
Ar3
[70–85%]
1
Ar1
S
Ar1
S
b
O
O
TsHN
TsHN
5
4
1
2 (
1
Tetrasubstituted thiophene S,S-dioxides (yields in step c and d)
Me
MeO
Me
Me
Me
3
62% yield (3bdc from 1bd) as major isomers, containing small
S
S
amounts of undesired C3-alkylated thiophenes (7:1 to 9:1
t-Bu
t-Bu
O
O
O
O
ratio).10 Unfortunately, when electron-deficient aziridine
2
TsHN
TsHN
5acdf
5acde
such as 2-(3-(trifluoromethyl)phenyl)-N-tosylaziridine (2i) was
used, the desired products 3aci was obtained from 1ac with
decreased regioselectivity (8:3). Although this reaction
c. quant; d. 74% yield
c. 82% yield; d. 85% yield
n-Bu
Me
F3C
Me
required a small excess of thiophenes
unreacted thiophenes were recovered. Subsequent C3-
arylations of 3acd 3bdc and 3aci were achieved by sequential
bromination/Suzuki–Miyaura cross-coupling with arylboronic
acids to furnish tetrasubstituted thiophenes in excellent
1 to give high yields of 3,
Me
Me
1
S
S
O O
TsHN
,
O
O
TsHN
5bdcg
c. 97% yield; d. 74% yield
5bdch
c. 93% yield; d. 72% yield
4
yields (4acde, 82%; 4acdf, quant.; 4bdcg, 97%; 4bdch, 93%;
4acie: 70%) with virtually complete isomeric purities. Then, to
enhance the reactivity of the thiophene moiety as a diene,
MeO
CF3
oxidation of thiophenes
carried out. Treatment of
(m-CPBA) successfully provided the corresponding thiophene
S,S-dioxides in good yields.
4
into thiophene S,S-dioxides
5 was
S
O O
TsHN
t-Bu
4
with m-chloroperoxybenzoic acid
5acie
5
c. 70% yield d. 71% yield
Scheme 1. Synthesis of tetrasubstituted thiophene S,S-dioxides 5. Reaction conditions:
a) 1 (1.5 equiv), arylaziridines 2 (1.0 equiv), Sc(OTf)3 (5 mol%), Zn(OTf)2 (5 mol%), DCE,
RT, 16 h, 79% (9:1, 3acd), 62% (7:1, 3bdc); 67% (8:3, 3aci); b) NBS (1.1–1.2 equiv), CHCl3,
RT, 24 h, 89% (Br-3acd), 95% (Br-3bdc); c) ArB(OH)2 (3.0 equiv), Pd2(dba)3·CHCl3 (2.5
mol%), P(t-Bu)3·HBPh4 (5 mol%), NaOH (2.0 equiv), THF, reflux, 24 h, 82% (4acde),
quant. (4acdf), 97% (4bdcg), 93% (4bdch)b; 70% (4acie); d) m-CPBA (2.2–2.5 equiv),
CH2Cl2, 0 °C to RT, 24h, 85% (5acde), 74% (5acdf), 74% (5bdcg), 72% (5bdch) 70%
(5acie). b48 h.
Synthesis of ynamides and pentaarylindoles (PAIs)
With fully substituted thiophene S,S-dioxides
5
in hand, we
and
(Scheme 2a and 2b). After extensive
screening of N-alkynylations of 5 11
we found that a copper-
examined the synthesis of ynamide intermediate
pentaarylindoles (PAIs)
6
9
,
catalyzed alkynylation of sulfonamides with bromoalkynes
7 is
effective.11c To our delight, upon forming ynamide
6
,
intramolecular [4+2] cycloaddition between thiophene S,S-
dioxide and ynamide moieties spontaneously proceeded,
providing indolines
The synthesis of indolines
8
was accomplished for
8
as single isomers.12 Since a catalytic
bromoalkynes with a variety of functional aryl groups [4-
7
amount of CuSO4/phenanthroline (phen) was less effective for
N-alkynylation, use of 50 mol% CuSO4 and 100 mol% of phen
was needed for optimal results (see Table S1). With these
ethyl (7A), 3-thienyl (7B), 3-pyridyl (7C), 2,6-xylyl (7D), 6-
methoxynaphthyl (7E), 3-methyl (7F), 3,5-xylyl (7G), 2-thienyl
(
7H), 4-trifluoromethyl (7I), 4-methoxy (7J), 4-tert-butyl (7K),
4-fluoro (7L, and 4-ethylphenyl (7M)]. Then, indolines were
bearing five different aryl groups. Although
optimized conditions, thiophene S,S-dioxides
with bromoalkynes in the presence of CuSO4·5H2O/phen and
K3PO4 in toluene at 80 °C to afford the corresponding indolines
in moderate yields, along with recovery of unreacted
5 were reacted
8
7
converted to PAI
the oxidation of
9
8
was attempted using various oxidants such
as MnO2, DDQ and DDQ/FeCl3,13 this only gave starting
materials or complex mixtures. In contrast, after removal of
the tosyl group, oxidation of the resulting NH-indoline
8
thiophene S,S-dioxides
5.
smoothly provided PAI 9.
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DOI: 10.1039/C8OB00993G
Organic Biomolecular Chemistry
PAPER
A
Conversion of ynamide intermediate 5 to pentaarylindole (PAI:9)
5
Ar
Ar2
Ar2
a.
Br
Ar4
Ar2
Ar4
Ar2
Ar4
Ar4
7
Ar3
Ar3
b. Mg, MeOH;
CuSO4·5H2O
phen, K3PO4
Ar3
Ar3
MnO2, CH2Cl2
Ar1
S
Ar1
Ar5
S
O O
Ar1
Ar1
N
N
H
O
O
N-alkynylation
–SO2
Ts
TsHN
NTs
Ar5
Ar5
8
9
6
5
B
PAI 9: substrate scope (yields in step a and b)
Me
Me
MeO
F3C
Me
Me
Me
N
H
N
H
N
H
S
9A
a. 51%
b. 83%
9H
a. 48%
b. 76%
9L
a. 54%
b. 74%
X-ray
structure of 9A
Et
F
Me
Me
MeO
MeO
Me
Me
Me
CF3
Me
N
H
N
H
N
H
N
H
9B
a. 51%
b. 46%
9E
a. 60%
b. 67%
9I
a. 52%
b. 76%
9M
a. 38%
b. 70%
S
F3C
Et
MeO
Me
Me
MeO
F3C
Me
Me
Me
Me
N
H
N
H
N
H
9C
N
9F
a. 58%
b. 77%
9J
a. 49%
b. 68%
Me
a. 49%
b. 28%
MeO
Me
Me
MeO
F3C
Me
Me
Me
N
H
N
H
N
H
9D
a. 44%
b. 80%
9G
a. 52%
b. 83%
9K
a. 45%
b. 82%
Me
Me
Scheme 2. A) Synthesis of pentaarylindoles 9. B) Substrate scope. Reaction conditions: a) bromoalkynes 7 (1.2 equiv), CuSO4·5H2O (0.5 equiv), phen (1.0 equiv), K3PO4 (2.0 equiv),
toluene, 80 °C, 16 h; b) Mg (60 equiv), MeOH, THF, reflux, 24 h, then MnO2 (20 equiv), CH2Cl2, RT, 30 min. phen = phenanthroline. In the ORTEP drawing of pentaarylindole 9A,
hydrogen atoms are omitted for clarity and thermal ellipsoids are drawn at 50% probability.
To this end, treatment of
afforded the detosylated products, which were immediately The present method afforded PAIs 9A–9M with five different
oxidized with MnO2, providing PAIs in moderate to good aryl groups in a predictable and programmed manner.
8 with Mg turnings in MeOH/THF unambiguously confirmed by X-ray crystallographic analysis.
9
yields (over two steps). PAI 9A was crystallized from
chloroform/pentane and the structure of 9A was
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ARTICLE
Journal Name
Computational studies to elucidate the reaction mechanism of
intramolecular [4+2] cycloaddition
View Article Online
DOI: 10.1039/C8OB00993G
Dimerization of pentaarylindoles (PAIs)
To gain insight into the reaction mechanism of
As another form of derivatization of PAIs, the synthesis of
intramolecular [4+2] cycloaddition between thiophene S,S- decaarylated 2,2’-bis-indoles was attempted. It was envisaged
dioxide and ynamide moieties, DFT calculations of ynamide Ph- that an oxidative dimerization of pentaarylindoles ( : PAIs)
were carried out (Figure 2). DFT calculations (B3LYP/6- would directly produce decaarylated 2,2’-bis-indoles 13
9
6
31G(d)) suggested that the HOMO of Ph-6 is delocalized over (Scheme 4A). Although the trifluoroacetic acid-induced
the ynamide moiety. On the other hand, the LUMO is dimerization of 3-substituted indoles reported by Vranken and
delocalized over the thiophene S,S-dioxide moiety, indicating coworkers was applied to PAI 9A, the desired dimer 13 was not
that the reaction proceeds via an inverse electron-demand obtained.15 After extensive screening of oxidant, treatment of
Diels–Alder reaction.14
9A with copper(II) trifluoroacetate in a dichloroethane /
trifluoroacetic acid (TFA) mixture provided unexpected dimer
14 in 69% yield instead of 13. To our delight, 14 was
crystallized from toluene/pentane, and its structure was
unambiguously confirmed by X-ray crystallographic analysis.
The X-ray crystal structure of 14 revealed that not only a
dimerization of 9A, but also an additional carbon–carbon bond
formation occurred. Based on the mechanism of the previously
reported thallium(III)-promoted oxidative dimerization of
S
O
O
NTs
Ph-6
indoles,
a plausible reaction mechanism was proposed
(Scheme 4B).16 Initially, one-electron transfer from electron-
rich indole 9A to copper(II) generates an indole radical cation
species. Subsequent electrophilic substitution with another
indole 9A, followed by oxidative aromatization, provides the
2,2’-bis-indole 13. Furthermore, the indole dimer, which is
more electron-rich than the monomer, easily undergoes
further oxidation to promote an intramolecular electrophilic
substitution with the p-tolyl group at the C3-position of indole.
Finally, an oxidative aromatization of the resulting radical
cation species furnishes unexpected dimer 14. Although the
over-oxidation could not be suppressed for indole 9A, a 2,2’-
bis-indole was successfully obtained by changing the aryl
group on the C3-position of indole. Indeed, indole 9M, which
has an electron-deficient aryl group (m-CF3C6H4) at the C3-
position, was dimerized under the same conditions to afford
bis-indole 15 in 53% yield.
Figure 2. Frontier orbitals of ynamide Ph-6
.
Synthesis of multiply arylated 7-azaindoles
We applied this protocol to the synthesis of 7-azaindoles
12 using cyanamide instead of ynamide (Scheme 3).
Cyanamide intermediate 10, which was prepared from 4acde
in 6 steps, was refluxed in toluene to furnish 7-azaindolines 11
.
Subsequently, treatment of 11 with MnO2 afforded 7-
azaindole 12 in 61% yield (two steps in one pot). The structure
of 12 was also confirmed by X-ray crystallographic analysis.
MeO
MeO
Me
Me
Synthesis of heptaarylindole (HAI)
S
t-Bu
toluene
reflux
O
O
N
N
Ts
Next, we proceeded onto the final challenge of synthesizing
heptaarylindoles (HAIs), which are fully arylated forms of
indole (Scheme 5). Although C2-arylation of 9A by C–H
functionalization was attempted,4a,4b this did not provide any
C2-arylated products. Therefore, we resorted to a “one-pot C–
H arylation method”, which consists of a sequence of
NTs
10
11
C
N
then MnO2
toluene, reflux
[61% (2 steps)]
bromination of
9 and Suzuki–Miyaura cross-coupling reaction
MeO
Me
with arylboronic acids. To this end, 9A was reacted with N-
bromosuccinimide (NBS) in THF at 0 °C to afford C2-
bromoindole, which was coupled with 3-thienylboronic acid in
the presence of Pd2(dba)3/P(t-Bu)3 catalyst and potassium
fluoride to furnish hexaarylindole 16 in 90% yield. Finally, N-
arylation of 16 was achieved by SNAr reaction with aryl
fluoride: hexaarylindole 16 was deprotonated with potassium
hydride in DMF, followed by treatment with 1-fluoro-2,4-
dinitrobenzene to provide HAI 17A in 63% yield. X-ray
crystallographic analysis confirmed the structure of 17A, in
which the indole core was fully substituted by seven different
N
N
Ts
azaindole 12
X-ray structure of 12
Scheme 3. Synthesis of azaindoles 12. Reaction conditions: toluene, reflux, 24 h;
MnO2 (60 equiv), reflux, 24 h, 61% (one-pot). ORTEP drawing of 12 with 50%
thermal ellipsoid. All hydrogen atoms are omitted for clarity.
4 | Org.Biomol. Chem.
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DOI: 10.1039/C8OB00993G
Organic Biomolecular Chemistry
PAPER
A
Et
Me
Me
Me
MeO
Me
MeO
OMe
MeO
H
N
Cu(TFA)2 (2.0 equiv)
+
H
DCE/TFA (10:1)
80 °C, 2 h
N
H
N
N
H
N
H
OMe
9A
Et
Me
13 [0% yield]
Et
Et
Et
14 [69% yield]
B
Plausible mechanism (Aryl groups on the benzene portion are omitted for clarity.
Me
)
Me
Me
[Ox]
–e
9A
H
[Ox]
H
N
H
·
N
9A
–e
–2H
N
N
H
+
H
H
+
·
H
N
H
13
Me
Me
Me
Me
Me
X-ray
structure of 14
[Ox]
H
N
+
+
·
14
H
–e
–2H
N
H
·
N
H
N
H
Me
Et
C
MeO
CF3
MeO
CF3
H
N
Cu(TFA)2 (2.0 equiv)
N
H
N
H
DCE/TFA (10:1)
80 °C, 2 h
OMe
F3C
Et
15 [53% yield]
Et
9M
Scheme 4. A) Oxidative dimerization of PAI 9A; ORTEP drawing of 14 with 50% thermal ellipsoid. All hydrogen atoms are omitted for clarity. B) Plausible mechanism of
oxidative dimerization of PAI 9A. C) Oxidative dimerization of PAI 9M
.
aryl substituents. Lastly, a different aryl fluoride reagent was dimerization of PAI successfully led to the corresponding bis-
used to give heptaarylindole 17B
.
indole. By employing further arylation reactions, the first
synthesis of heptaarylindole with all different aryl substituents
was accomplished (17A: 4.8% yield over 10 steps from 2-
bromothiophene). Using this coupling/ring transformation
strategy, a variety of aryl groups could be installed onto
benzenoid cores, which is conventionally difficult to
functionalize regioselectively. This chemistry could also be
useful for the synthesis of multiply substituted indoles present
in bioactive compounds and natural products.17 Along with this
development of a new method for previously unattainable
Conclusions
In conclusion, we have developed a modular synthesis of
multiply arylated indoles. Inverse electron-demand
intramolecular [4+2] cycloaddition of fully substituted
thiophene S,S-dioxides with ynamide/cyanamide enabled the
synthesis of pentaarylindoles (PAIs) and tetraaryl-7-azaindoles
with perfect regioselectivity. Additionally, the oxidative
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ARTICLE
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MeO
MeO
Me
Me
2
3
a. NBS;
ArB(OH)2
Pd[P(t-Bu)3]2
KF
N
H
N
H
ꢀ(d) D. F. Taber and P. K. Tirunahari, Tetrahedron, 2011, 67
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,
S
C2-arylation
9A
16
4
5
Selected reviews: (a) N. Lebrasseur and I. Larrosa, In
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Et
NO2
b. KH;
N-arylation
O2N
F
MeO
Me
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,
7
,
N
S
NO2
7
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73, 3669; (d) S. Suzuki, K. Itami and J. Yamaguchi, Angew.
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17A
Et
X-ray crystal structure of 17A
NO2
MeO
Me
b. KH;
O2N
6
7
8
9
J. R. Dunetz and R. L. Danheiser, J. Am. Chem. Soc. 2005, 127,
CN
5776.
F
X. Ji, E. M. El-labbad, K. Ji, D. S. Lasheen, R. A. T. Serya, K. A.
Abouzid and B. Wang, Org. Lett. 2017, 19, 818.
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Chem. Int. Ed., 2016, 55, 3625.
16
N
S
N-arylation
CN
17B
S. Kirchberg, S. Tani, K. Ueda, J. Yamaguchi, A. Studer, and K.
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Et
NO2
10 M. K. Ghorai, D. P. Tiwari and N. Jain, J. Org. Chem., 2013, 78
,
Scheme 5. The synthesis of fully arylated indoles. Reaction conditions: a) NBS
7121.
(1.05 equiv), THF, 0 °C, 1 h, then ArB(OH)2 (3.0 equiv), Pd2(dba)3·CHCl3 (10 mol%),
P(t-Bu)3·HBPh4 (20 mol%), KF (3.0 equiv), reflux, 24 h, 90%; b) KH (13 equiv), DMF,
0 °C, 5 min, then aryl fluoride (5.0 equiv), RT, 1 h, 63% (17A); 35% (17B). ORTEP
drawing of 17A with 50% thermal ellipsoid. All hydrogen atoms are omitted for
clarity.
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Zhang and R. P. Hsung, Chem. Rev., 2010, 110, 5064; (b) J. R.
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12 The molecular structure of indoline 8J was determined by X-
ray crystallography analysis, thereby confirming the
formation of indolines (see the Supporting Information for
details).
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
13 (a) G. W. Gribble, (2016) Indoline Dehydrogenation, in Indole
Ring Synthesis: From Natural Products to Drug Discovery,
This work was supported by JSPS KAKENHI Grant Number
JP16H01011, JP16H01140, JP16H04148 (to J. Y.), the ERATO
program from JST (to K. I.), and a JSPS research fellowship for
young scientists (to S. S.). We also thanks Dr. Yasutomo
Segawa and Kenta Kato for assistance with X-ray crystal
structure analysis and computational studies. We thank Dr.
Yoshihiro Ishihara (Vertex Pharmaceuticals) for fruitful
discussion and critical comments. ITbM is supported by the
World Premier International Research Center (WPI) Initiative,
Japan.
John
Wiley
&
Sons,
Ltd,
Chichester,
UK.
doi: 10.1002/9781118695692.ch66. (b) S. S. Jang and S. W.
Youn, Org. Biomol. Chem., 2016, 14, 2200.
14 See the Supporting Information for details.
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Notes and references
1
(a) R. J. Sundberg, Indoles; Academic Press: San Diego, 1996;
(b) M. d’Ischia, A. Napolitano and A. Pezzella, In
Comprehensive Heterocyclic Chemistry III; A. R. Katritzky, C.
A. Ramsden, E. F. V. Scriven and R. J. K. Taylor, Eds.; Elsevier:
Oxford, 2008; Vol. 3, pp 353−388; (c) C. M. So, C. C. Yeung, C.
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