Synthesis of annulated bis-indoles through Au(i)/Br?nsted acid-catalyzed reactions of (1H-indol-3-yl)(aryl)methanols with 2-(arylethynyl)-1H-indoles

Article abstract of DOI:10.1039/c6ob02595a

A general method to access annulated bis-indoles from (1H-indol-3-yl)(aryl)methanols and 2-(arylethynyl)-1H-indoles under the catalysis of the Ph₃PAuOTf/Br?nsted acid binary catalyst system has been developed. The reaction was found to proceed in a highly efficient manner and benefit from easy-to-make starting materials, broad substrate scope and operational simplicity. The potential of this method has also been exemplified for the synthesis of pyrrole-annulated indoles using 2-(phenylethynyl)-1H-indoles and phenyl(1H-pyrrol-2-yl)methanols. Furthermore, the use of a ternary catalyst system, involving PdCl₂/Br?nsted acid/Ph₃PAuOTf catalysts, has been realized for the synthesis of annulated bis-indoles starting directly from 2-(phenylbuta-1,3-diyn-1-yl)aniline and (1H-indol-3-yl)(aryl)methanol. Mechanistically, this reaction is very interesting since the overall process involves three different catalytic cycles catalyzed by three different catalysts in a relay fashion.

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Synthesis of Annulated Bis-indoles through Au(I)/Brønsted Acid-
Catalyzed Reactions of (1H-indol-3-yl)(aryl)methanols with 2-
(arylethynyl)-1H-indoles
Received 00th January 20xx,
Accepted 00th January 20xx
Suleman M. Inamdar,a Rajesh G. Gonnadeb and Nitin T. Patil*ac
DOI: 10.1039/x0xx00000x
www.rsc.org/
A general method to access annulated bis-indoles from (1H-indol-3-yl)(aryl)methanol and 2-(arylethynyl)-1H-indole under
the catalysis of Ph3PAuOTf/Brønsted acid binary catalyst system have been developed. The reaction found to be
proceeded in a highly efficient manner and benefit from easy-to-make starting materials, broad substrate scope and
operational simplicity. The potential of the method has also been exemplified for the synthesis of pyrrole-annulated
indoles using 2-(phenylethynyl)-1H-indoles and phenyl(1H-pyrrol-2-yl)methanols. Furthermore, the use of ternary catalyst
system, involving PdCl2/Brønsted acid/Ph3PAuOTf catalysts, has been realized for the synthesis of annulated bis-indole
starting directly from 2-(phenylbuta-1,3-diyn-1-yl)aniline and (1H-indol-3-yl)(aryl)methanol. Mechanistically, the reaction is
very interesting since the overall process involves three diffferent catalytic cycles catalyzed by three different catalysts in a
relay fashion.
literature for the synthesis of bis-indoles and their analogs.11
Unfortunately, most of them are applicable only for accessing
bis(indolyl)methanes. A general and efficient approach for the
Introduction
Indoles are important structural units widely present in
many natural products and in pharmaceutically active
compounds. 1 As an emerging subclass, bis-indoles have
attracted great attention from synthetic chemists owing to
their occurrence in several natural products and wide range of
biological activities (Figure 1).2 One of the most promising
natural products belonging to this category is Flinderoles A-C
synthesis of structurally novel bis-indoles is necessary as these
methods would serve to provide a great opportunity to
accelerate biological studies of these interesting family of
bisindole dyads.
Figure 1 Examples of bis-indole containing natural products
(I)
which possesses promising antimalarial activity. 3 The
another important natural products are Staurosporine and its
analogues II isolated from the bacterium Streptomyces
and bioactive molecules.
H
N
O
Me
Me
N
(
)
Me
Me
R
R
N
staurosporeus which have medicinal properties such as
antimicrobial,4 cytotoxic,5 inhibition of protein kinase C (PKC),6
and platelet aggregation inhibition.7 Similarly, Iheyamine-A (III
R′
N
N
O
N
Me
MeO
II
)
NH
R'
and Iheyamine-B
(
IV
)
have been isolated from an
N
I
Me
R
ascidian, Polycitorella sp. which exhibited a cytotoxic activity
Flinderole-A (R = H), R
-Me
′ = α
Staurosporine, R = H, R′ = H
-Me 4-N-methyl-5-hydroxystaurosporine, R = Me, R
Flinderole-B (R = Me), R
′ = α
′ = β
′ = ΟΗ
against leukemia, colon, and lung cancer cell lines with IC50
value 0.001 mg/mL.8 The piperazinone alkaloid, Hamacanthins
5-hydroxystaurosporine, R = H, R′ = ΟΗ
Flinderole-C (R = Me), R
-Me
Me
Me
9
(V
)
shows significant antimicrobial activities against C.
C. neoformans and Bacillus subtilis.
Indolylpyrimidines VI) have been identified as potential
O
N
O
N
albicans,
N
H
MeO
N
(
III
MeO
N
synthetic antitumour agent having cytotoxicity against IGROVI
tumour cell line with GI50 = 0.01μM.10 Therefore, it is not
surprising why several methods are being reported in the
IV
N
H
Iheyamines-A
Iheyamines-B
R
NH
N
H
N
O
Br
N
Br
N
Ts
N
N
V
VI
HN
Ts
Hamacanthin
Indolylpyrimidines, R = H, Me, OMe
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The advent of merging metal catalysis with organocatalysis was obtained; albeit in 56% yield (entry 1). To investigate the
in molecular synthesis has emerged as an important topic for effect of the ligand on Au complexes, the catalyst such as
accessing a variety of aza-heterocyclic scaffolds. 12 Out of IPrAuOTf and CyJohnphosAuOTf were examined for their
various catalyst combinations, merging of metal with catalytic efficiency; however, none of them were found to be
phosphoric acid catalyst had proven substancial impact for superior (entries 2 and 3). Encouragingly, addition of 5 mol%
accessing aza-heterocyclic scaffolds.13 In particular, merging of BH in combination with 5 mol% Ph3PAuOTf enhanced the yield
gold catalysis with organocatalysis has emerged as powerful up to 70% (entry 4). With increase in the loading of BH (10
technique for accessing aza-heterocyclic scaffolds and other mol%), the yield of 3a was improved (92%)(entry 5). Next, we
valuable building blocks.14
screened PdCl2 and PtCl2 catalysts as such or in combination
Liu’s research group reported the gold-catalyzed tandem with BH; however, in none of the cases 3a was obtained even
cyclization of 1,2-bis(alkynyl)-2-en-1-ones with indoles to after reaction continued for 36 h (entries 6-9). As shown in
provide indole-fused polycyclic systems via a cascade reactions entries 10-12, the use of DCM, CHCl3 and CCl4 did not show
involving carbonyl-yne cyclization, Friedel-Crafts reaction and encouraging results.
indole-yne reaction (Scheme 1a).15 However, this method is
Table 1 Optimization of the reaction conditionsa
only limited to furan-annulated indoles. As a part of our
ongoing research on gold catalysis16 and merged organo/gold
catalysis,17 we envisaged that the Friedel-Crafts type reaction
between 3-indolyl alcohols
1 and 2-alkynylidoles 2 would
provide the corresponding indolyl-alkynes, which in the
presence of appropriate Au-catalysts would afford bis-indoles
in an apparently very simple way (Scheme 1b). Though there
exists several reports on the indole-alkyne chemistry,18 there is
no precedence on the synthesis of desired bisindoles through
proposed design.19 Herein, we report a facile approach to
entry
1
cat. M
Ph3PAuOTf
IPrAuOTf
solvent
DCE
Yield (%)b
56c
access
annulated
bis-indoles
from
(1H-indol-3-
yl)(aryl)methanols and 2-(arylethynyl)-1H-indoles in the
2
DCE
38c
presence of Ph3PAuOTf/Brønsted acid binary catalyst system.
3
CyJohnphosAuOTf
Ph3PAuOTf/BH
Ph3PAuOTf/BH
PdCl2
DCE
30c
4
DCE
70c,d
92c,e,f
NRg
Scheme 1 Catalytic approaches to indole-fused polycycles:
5
DCE
Known and present work
6
DCE
7
PtCl2
DCE
NRg
8
PdCl2/BH
DCE
41e,h,i
52e,h,i
58c,e
74c,e
62c,e
9
PtCl2/BH
DCE
10
11
12
Ph3PAuOTf/BH
Ph3PAuOTf/BH
Ph3PAuOTf/BH
DCM
CHCl3
CCl4
aReaction conditions: 0.115 mmol 1a, 0.115 mmol 2a, 5 mol%
MLn, solvent (2 mL), 80 °C, 12 h; bisolated yields; cLnAuOTf was
prepared in situ by mixing LnAuCl and AgOTf; d5 mol% BH
e
f
g
used; 10 mol% BH was used; reaction time 8 h; no reaction;
hreaction time 36 h; iyield refers to
6.
With the optimized conditions in hand (Table 1, entry 5),
we explored the generality of the reaction using 2-
(phenylethynyl)-1H-indole 2a with various (1H-indol-3-
yl)(aryl)methanol
1 bearing a variety of electron-deficient as
well as electron-rich substituents (Table 2). The reactions
proceeded well to afford the products 3a-m in the yields
ranging from 80–96%. It was observed that the increase of
bulk at R1 site has significant impact on the outcome of the
reaction. For instance, when phenyl was replaced with bulkier
naphthyl or anthracenyl groups, products 3b and 3c were
obtained in 88 and 83% yields, in contrast to 3a (92%). In case
of indolyl alcohols bearing electron-deficient aryl substituents
as R1 such as 3-fluoro 1d, 2-bromo,5-fluoro 1e, 2-bromo,4-
Results and discussion
We started our study by investigating the proposed
reactions of 1H-indol-3-yl)(phenyl)methanol 1a with 2-
(phenylethynyl)-1H-indole 2a in presence of various catalysts.
At first, the reaction was carried out in the presence of 5 mol
% Ph3PAuOTf (prepared in situ by mixing 5 mol% Ph3PAuCl and
5 mol% AgOTf) in DCE at 80 °C (Table 1). Pleasingly, product 3a
methyl 1f
,
the reaction proceeded well to afford the
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corresponding products in excellent yields (90-96%) as
compared to the substrate (1g) containing electron-rich 3-
methoxy-phenyl group (80%). Even with hetero-aromatic
substituents such as furan and thiophene, 1h and 1i reacted
well to give the corresponding products in 95 and 96% yield.
Be noted that substrates bearing aliphatic group at R1 such as
Me, Et are totally inert towards this reaction. On the other
hand, variation of substitution patterns as R2
(1j-m) did not
hamper the reaction efficiency and products (3j-m) were
obtained in very good yields (80-96%).
Table 2 Scope with respect to (1H-indol-3-yl)(aryl)methanols
aReaction conditions: 0.115 mmol 1a, 0.115 mmol 2, 5 mol%
Ph3PAuCl, 5 mol% AgOTf, 10 mol% BH, DCE (2 mL), 80 °C, 8 h.
With the successful development of proposed reaction, we
turned our attention to design analogous strategy for the synthesis
of pyrrolo-indole dyads (Scheme 2). When 2a was reacted with 4a
and 4b under the optimized reaction conditions, the desired
pyrrolo-indole dyads 5a and 5b were obtained in 62 and 68% yields,
respectively. While suitable crystals amenable for x-ray diffraction
studies were not obtained, the structure of 4a was confirmed with
the help of 2D NMR studies.21 The NOESY experiment clearly shows
the correlations of N-CH3 (3.71 δ) protons with Ha (5.85 δ), Hb (6.53
δ) and Hc (7.18 δ) protons.21
aReaction conditions: 0.115 mmol 1, 0.115 mmol 2a, 5 mol%
Ph3PAuCl, 5 mol% AgOTf, 10 mol% BH, DCE (2 mL), 80 °C, 8 h.
Next, we turned our attention to examine the tolerance of the
reaction towards 2-alkynyl indoles 2 with diverse substitution
patterns at R3, R4 and R5 (Table 3). It is evident that the reactions
proceeded well in all the cases to furnish products 3n-x in good to
excellent yields. Various N-protecting groups as R3 such as Me, Bn,
and allyl (2j-l) were well tolerated to afford the desired products
(3n-p). The X-ray crystallography data for 3n was obtained which
unequivocally confirms the structure. Both electron-withdrawing
and electron-donating aryl groups as R4 were well tolerated to give
the corresponding products (3q-3t) in excellent yields (80-95%).
Similarly, switching to hetero-aromatic substitution as R4 such as
pyridine (2f) the reaction smoothly afforded the corresponding
product 3u in 80% yield. Further, 2-alkynyl indoles bearing aliphatic
group (nhex) and TMS at R4 were prepared20 and subjected under
standard reaction conditions. However, reaction failed to yield the
desired products. Finally, the scope of methodology was further
extended for indolyl alkynes with various substituents as R5 to
afford the products (3v-x) in good yields.
Scheme
2 Reaction between 2-(phenylethynyl)-1H-indoles and
phenyl(1H-pyrrol-2-yl)methanols catalyzed by Au/Brønsted acid
catalysts
Table 3 Scope with respect to 2-(arylethynyl)-1H-indoles
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Next, we were pleased to find that 3a can be accessed from 2- the regeneration of Pd-catalyst.25 Simultaneously, the protonation
(phenylbuta-1,3-diyn-1-yl)aniline and (1H-indol-3- of alcohol 1a in presence of Brønsted acid catalyst (BH) generates
7
yl)(phenyl)methanol 1a in one-pot with the use of ternary catalyst intermediate iii. Subsequent C-O bond cleavage in intermediate iii
system involving PdCl2/Brønsted acid/Ph3PAuOTf catalysts (Scheme furnished phosphate-bound iminium ion iv. Next, the quenching of
3). Though the yield of 3a was moderate (38%), the reaction is iminium ion intermediate iv would take place with indole
mechanistically intriguing as the overall process comprises three nucleophile 2a delivering an intermediate 6 with the regeneration
different catalytic cycles catalyzed by three different catalysts in of BH. The alkyne moiety of 6, activated by Au(I) (cf. v), allows the
one-pot. It is interesting to note that the combination of intramolecular attack of indole nucleophile leading to spirocyclic
Ph3PAuOTf/Brønsted acid is unable to catalyse the reaction to yield intermediate vi.26 The intermediate vi can rearrange through a 1,2-
3a.22
shift27 to effect an expansion from a six- to a seven-membered ring
(viii) (cf. vii). Similarly, the mechanism for the synthesis of pyrrolo-
indole dyads from 2-(phenylethynyl)-1H-indoles and phenyl(1H-
pyrrol-2-yl)methanols catalyzed by Au/Brønsted acid catalysts is
depicted in Scheme 6.
Scheme 3 One-pot reaction of phenyl(1H-pyrrol-2-yl)methanol 1a
with 2-(phenylbuta-1,3-diyn-1-yl)aniline 7 under PdCl2/Brønsted
acid/Ph3PAuOTf catalysis
Beller and coworkers reported the reaction of indolyl-alkynes28
and pyrrolyl-alkynes29 that led to the formation of pyrroloazepinone
and azepino[3,4-b]indol-1-ones under the influence of metal
catalysts. In their cases, two different competing regioisomers, as a
result of two different migratory groups (vi, Scheme 5 and xii,
Scheme 6), were observed and the preference for the formation of
either of the products was found to be dependant on the type of
catalysts used. In the present studies, only single regioisomer was
obtained and the formation of that could be accounted for the
intermediates vii (Scheme 5) and xii (Scheme 6).
Ph
HO
i) 5 mol% PdCl2
10 mol% BH
Ph
Ph
NH
ii) 5 mol%
Ph3PAuOTf
DCE, 80 °C, 12 h
HN
N
NH2
H
Ph
1a
7
3a, 38%
To understand the mechanism, few control experiments were
conducted (Scheme 4). When 7 was treated with 5 mol% PdCl2,
intramolecular hydroamination occurred to provide 2-
(phenylethynyl)-1H-indole (2a) in 54% yield (Scheme 4, eq 1).22
When 1a and 2a were subjected to Brønsted acid catalysis, the
intermediate 6 was isolated in 88% yield. The intermediate 6, after
gold-catalyzed intramolecular 7-endo-dig hydroarylation, afforded
3a in 90% yield (Scheme 4, eq 2).23 Overall, the reaction involves
relay catalytic process24 in which first Pd-catalyzed intramolecular
cyclization of 7 to afford 2a followed by Brønsted acid catalyzed
Friedel-Crafts type reaction to get the indolyl alkyne intermediate 6
which underwent Au(I)-catalyzed intramolecular hydroarylation to
form product 3a.
Next, we endeavoured to make the reactions enantioselective
utilizing Ph3PAuMe and chiral BINOL-derived phosphoric acids
(BH*).30 As outlined in Scheme 7, the reaction of (1H-indol-3-
yl)(phenyl)methanol (1a) and 2-(phenylethynyl)-1H-indole (2a)
catalyzed by Ph3PAuMe and chiral Brønsted acid occurred and 3a
was obtained in 42% yield with 70% ee.31 The enantioinduction can
be accounted by the transition state involving H-bonding
interaction of catalyst with both the substrate as depicted in
Scheme 7. The bifunctional nature of the chiral phosphoric acid is
responsible for the concurrent activation of both the reaction
partners. Though modest in yield and ee, this experiment
demonstrated the feasibility of enantio-induction of higher
magnitude.
Scheme 4 Control experiments
Conclusions
In summary, we have developed binary catalytic system
consisting of Au(I) and Brønsted acid for addition-cyclization
reaction of (1H-indol-3-yl)(aryl)methanols and 2-(arylethynyl)-
1H-indole providing biologically and pharmaceutically
important annulated indoles in good to excellent yields. The
analogous strategy was also designed for the synthesis of
pyrrolo-indole dyads. Furthermore, one pot ternary catalytic
system consisting of Pd(II)/Brønsted acid/Au(I) for cyclization-
addition-cyclization reaction of 2-(phenylbuta-1,3-diyn-1-
yl)aniline and (1H-indol-3-yl)(aryl)methanol for the synthesis of
annulated indole has been established. Studies addressing the
higher enantioselective induction with metal and/or
organocatalysts are currently underway.
Based on knowledge gathered from control experiments, a
possible mechanism is depicted in Scheme 5. The reaction starts
with Pd-catalyzed activation of alkyne in
7 followed by
intramolecular hydroamination to get the intermediate ii (cf. i). The
intermediate ii would undergo protodepalladation to afford 2a with
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Scheme 5 A proposed mechanism for the formation of annulated bis-indoles
H
O
Ph
Ph
B
H
N
iii
H
N
H
B
iv
1a
BH
Ph
6
2a
HN
HN
Ph
N
[Pd]
Ph
H
Ph
[Au]
Ph
[Au]
N
v
HN
vi
H
ii
Au(I)
Pd(II)
Ph
NH
NH
NH
[Au]
[Pd]
HN
[Au]
Ph
Ph
Ph
H
Ph
3a
7
vii
i
NH2
viii
Scheme 6 A proposed mechanism for the formation of pyrrolo-indole dyads
Scheme 7 Attempting catalytic enantioselective version
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Acknowledgements
Generous financial support by the Board of Research in
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Nuclear
Science
(BRNS),
Mumbai
(Grant
No.
37(2)/14/12/2015/BRNS/10549) and the Council of Scientific
and Industrial Research (CSIR), New Delhi (Grant Nos. CSC0108
and CSC0130) is gratefully acknowledged. S.M.I. thanks CSIR
for the award of Research Associate (RA).
13 Reviews: (a) A. Parra, S. Reboredo, A. M. Martín Castro and J.
Alemán, Org. Biomol. Chem., 2012, 10, 5001; (b) M. Rueping, R.
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Commun., 2014, 50, 15124; (b) D.-F. Chen, Z.-Y. Han and L.-Z.
Gong, Acc. Chem. Res., 2014, 47, 2365; (c) X. Wu, M.-L. Li and L.-
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15 X. Xie, X. Du, Y. Chen and Y. Liu, J. Org. Chem., 2011, 76, 9175.
16 Selected recent examples: (a) P. S. Shinde, A. C. Shaikh and N. T.
Patil, Chem. Commun., 2016, 52, 8152; (b) A. B. Gade and N. T.
Patil, Org. Lett., 2016, 18, 1844; (c) A. C. Shaikh and N. T. Patil,
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Notes and references
1
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