Lewis acid-catalyzed double addition of indoles to ketones: Synthesis of bis(indolyl)methanes with all-carbon quaternary centers

Article abstract of DOI:10.1039/d0ob01916j

We report herein a Lewis acid-catalyzed nucleophilic double-addition of indoles to ketones under mild conditions. This process occurs with various ketones ranging from dialkyl ketones to diaryl ketones, thereby providing access to an array of bis(indolyl)

Full text of DOI:10.1039/d0ob01916j

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OrPgleanaisce&dBoionmotoaledcjuulsatr mChaermgiinstsry
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DOI: 10.1039/D0OB01916J
PAPER
Lewis Acid-Catalyzed Double Addition of Indoles to Ketones:
Synthesis of Bis(indolyl)methanes with All-Carbon Quaternary
Centers
Received 00th January 20xx,
Accepted 00th January 20xx
Si On Lee†, Jeongin Choi†, Seunghoon Kook†, and Sarah Yunmi Lee*a
DOI: 10.1039/x0xx00000x
We report herein a Lewis acid-catalyzed nucleophilic double-addition of indoles to ketones under mild conditions. This
process occurs with various ketones ranging from dialkyl ketones to diaryl ketones, thereby providing access to an array of
bis(indolyl)methanes bearing all-carbon quaternary centers, including tetra-aryl carbon centers. The products can be
transformed into bis(indole)-fused polycyclics and bis(indolyl)alkenes.
ketones have been described through the use of various
promotors including N-bromosuccinimide, iodine-based
organocatalysts, and Brønsted acids;8 however, the scope of
Introduction
Indole is a well-known privileged scaffolds due to their wide
occurrence in natural products as well as broad applications in
medicinal chemistry.1 Bis(indolyl)methanes, which contain two
indole units in a molecule, are recognized to be the core
structure of numerous biologically active compounds such as
potent anti-cancer agents.2 Thus, the development of efficient
methods to construct such compounds has been an active area
of studies.2,3 A majority of reported methods includes the
reactions of two equivalents of indoles with various aldehydes,
ethers, and alcohols that yield bis(indolyl)methanes containing
a tertiary carbon center at the junction of two indole units, in
the presence of various promotors including Lewis or Brønsted
acid catalysts, metal-based catalysts, enzymes, or under
electrochemical conditions. 3,4
ketones or the functional group tolerance of the process have
been rather unexplored. Recently, the photoinduced double-
additions of N-H indoles to dialkyl or aryl(alkyl) ketones have
been reported via the formation of a CF3 radical from CF3SO2Na
(Scheme 1c);9 while this process has allowed preparation of
various bis(indolyl)methanes with quaternary carbon centers,
the reactions with N-protected indoles or diaryl ketones have
not been included. Given the prominence importance of
bis(indolyl)compounds in medicinal chemistry,2 we sought to
develop an efficient process that occurs under mild conditions,
with a broader range of ketones as well as indoles for the
introduction of a diverse set of all-carbon quaternary centers to
bis(indolyl)methanes.
By comparison, progress to date in the synthesis of
bis(indolyl)methanes with an all-carbon quaternary center has
been less developed perhaps due to the challenge associated
with steric hindrance around such centers.5 Markovnikov
additions of indoles to terminal aryl alkynes catalyzed by various
metal-based catalysts or a main-group Lewis acid (LA), B(C6F5)3,
provides access to indole-adducts that bear a quaternary
carbon center (Scheme 1a).6 Indium(III)-catalyzed reactions
between vinyl azides and indoles also furnish
bis(indolyl)methanes of this type (Scheme 1b).7 While highly
useful, the products obtained from these processes have a
structural restriction that one of the substituent at the
quaternary center would always include a methyl group along
with two indole moieties. Double-addition reactions of indoles
to diverse ketones would have the potential to address this
challenge. Condensation reactions between indoles and
a.Department of Chemistry, Yonsei University, Seoul 03722, South Korea.
† These authors contributed equally.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
Scheme 1. Strategies for the synthesis of bis(indolyl)methanes with all-carbon
quaternary centers.
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Main group LAs such as boron and silicon-based LAs, which
Journal Name
Table 2. Catalytic Double Additions of N-Methylindole to Aryl(alkyl) Ketonesa
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DOI: 10.1039/D0OB01916J
can efficiently promote activation of ketones and therefore
facilitate nucleophilic additions,10 have been underexplored for
the coupling reactions between indoles and ketones. In this
report, we establish that B(C6F5)3 and PhSiCl3 can achieve the
synthesis of bis(indolyl)methanes by the two-fold addition
reactions of indoles to ketones. This process proceeds with a
broad range of ketones, including dialkyl ketones, aryl(alkyl)
ketones, and diaryl ketones. Bis(indolyl)compounds containing
various all-carbon quaternary centers, such as a tetra-aryl
carbon center, can be produced under mild conditions,
releasing H2O as the only by-product. Moreover, we present
palladium-catalyzed, intramolecular transformations of
bis(indolyl)methanes that generate useful bis(indole)
derivatives, bis(indole)-fused aromatic polycyclics as well as
bis(indolyl)alkenes.
Results and discussion
To develop a main group LA-catalyzed method for the double
addition reaction of N-methylindole (1a) to ketones, we studied
the effect of various LAs as catalysts on the yield of the reaction
between 1a and acetophenone (2a) or benzophenone (2b) in
toluene at 80 °C (Table 1; see Supporting Information for
details). The condensation reactions did not proceed in the
absence of a catalyst (entry 1). Boron Lewis acids could promote
the double additions of indole 1a to ketones (entries 2–3); in
particular, when the reactions were run with 10% B(C6F5)3,
bis(indolyl)methanes 3aa and 3ab bearing an all-carbon
quaternary center were obtained in 96% and 45% yields
respectively, after 16 h (entry 2). Whereas employing silanes,
zinc-based LAs, and AlCl3 for the coupling between indole 1a
and acetophenone (2a) led to the formation of product 3aa in
moderate to excellent yields, the use of such LAs as promoters
resulted in low yields of the reaction with 2b to produce the
tetra(aryl)methane (3ab) (entries 4–8). In general, the reactivity
of 2a toward the addition of indoles (up to 99% yield with
aReaction conditions: 1a (2 equiv), 2 (0.20 mmol), and catalyst (0.1 equiv) in
toluene (1 M) at 80 °C for 16 h; yield of the purified product. b10% B(C6F5)3. c10%
PhSiCl3 d4 equiv of 1a. e40°C.
B(C6F5)3 and PhSiCl3 as LA promotors, entries 2 and 5) was higher
than that of 2b. Based on these outcomes, we chose B(C6F5)3
and PhSiCl3 as our LAs for the synthesis of a variety of bis(indolyl)
compounds
3 by the reactions between indoles 1 and ketones
2
.
Under the LA-catalyzed conditions for the two-fold
additions of N-methylindole (1a), an array of aryl(alkyl) ketones
reacted to furnish the corresponding bis(indolyl)methanes
with an all-carbon quaternary center (Table 2); except for 3aa
2
Table 1. Catalytic Double Additions of N-Methylindole to Ketones: Effect of Catalysta
,
3ad, and 3ah products listed in Table 2 have not been
synthesized previously via other methods. Not only
acetophenone (2a) but also phenyl-substituted ketones bearing
ethyl, trifluoromethyl, and difluoromethyl group as an alkyl
substituent underwent the addition reactions, generating the
addition products in good yields (3aa
range of methyl ketones with phenyl rings that bear acetoxy,
hydroxy, and fluoro groups at the para-position (3af 3ai) and a
chloro group at the ortho-position 3ai), as well as
perfluorophenyl and 2-naphthyl groups 3aj and 3ak
–3ae). The reactions of a
–
(
(
)
proceeded smoothly under the double-addition conditions. The
products could contain heteroaryl substituents such as 2-thienyl,
2-furyl, and 2-pyridyl moieties at the quaternary carbon center
(3al
–3an). Moreover, cyclic ketones reacted with 1a, yielding
condensation products 3ao and 3ap
.
aReaction conditions: 1a (2 equiv), 2 (0.05 mmol), and catalyst (0.1 equiv) in
toluene (1 M) at 80 °C for 16 h. bDetermined by 1H NMR analysis with 1,1,2,2-
tetrachloroethane as an internal standard. c Run for 3 h.
The boron Lewis acid-catalyzed double-additions of N-
methylindole (1a) can be applied to the generation of sterically
encumbered tetra-arylmethanes (3ab and 3aq) through the
2 | J. Name., 2012, 00, 1-3
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Scheme 2. Catalytic Double Additions of N-Methylindole to Diaryl and Dialkyl
Ketones.
reactions with diaryl ketones 2b or 2q (Scheme 2a). Dialkyl
ketones were also suitable substrates in our LA-catalyzed
double additions of indoles (Scheme 2b and 2c). Employing
acetone as a reaction solvent with B(C6F5)3 as a catalyst resulted
in affording bis(indole)-adduct 3ar. Furthermore, ketones
containing an ethyl group (2s and 2t) were successfully coupled
with 1a under the silane-catalyzed conditions.
N-H indole and N-alkylindoles can be coupled with
acetophenone (2a) by a Lewis acid catalyst (Scheme 3a).
Whereas the reaction of N-H indole (1b) led to low yields of the
Scheme 4. Reactivity studies and a proposed catalytic pathway.
reaction of alkene
bis(indolyl)methane 3ac, indicating that alkene
5
with 1a produced <10% of
is not a
corresponding
substituted indoles such as ethyl-, benzyl- and allyl-substituted
substrates 1c 1e reacted to create the corresponding
bis(indolyl)methanes (3ca 3da and 3ea) in good yields. In
addition to the reactions of indoles, N-methylpyrrole (1f
bis(indolyl)compounds
(
3ba),
N-alkyl-
5
chemically and kinetically competent intermediate of the
double addition process (Scheme 4b). Finally, the generation of
compound 3’ by the dehydrative nucleophilic substitution13 of
tertiary alcohol 4’ with 1a in the presence of LA suggested the
intermediacy of the alcohol in the LA-catalyzed synthesis of
bis(indolyl)methanes (Scheme 4c).
(
–
)
,
)
underwent the catalytic double addition to 2a in 97% yield of
bis(pyrrolyl)methane 3fa (Scheme 3b).
During the studies of our LA-catalyzed additions, we made
observations that provided insights into the reaction
Scheme 4d describes the possible catalytic pathway for the
LA-catalyzed two-fold additions of indole
or silicon LA coordinates to ketone , and the nucleophilic
attack of indole to activated ketone creates the carbon-
carbon bond. The resulting zwitterionic species ( ) then
undergoes aromatization to provide the LA-coordinated alcohol
intermediate ( ), which can be captured by the second addition
of indole presumably by a SN1-type mechanism to furnish
1 to ketone 2. A boron
mechanism. Alkene side-product 5 was formed along with 18%
2
of bis(indolyl)methane 3ac by the reaction between indole 1a
and ketone 2c, likely resulting from the elimination of H2O from
the single-addition product, alcohol 4
(Scheme 4a).11,12 The
1
A
B
C
1
product 3, H2O, and the LA catalyst.
The bis(indolyl)compounds with all-carbon quaternary
centers that are generated in this condensation process can
undergo intramolecular coupling reactions under Pd-catalyzed
oxidative conditions, thereby affording bis(indole)-fused
polycyclic compounds 6, a motif found in natural products,
pharmaceuticals as well as organic electroluminescent
materials (Scheme 5a). 14 We also observed the generation of
unexpected alkene products 7aa and 7af, which can potentially
serve as valuable synthetic building blocks for the synthesis of
bis(indole) derivatives.15 Alkenes
7 were likely formed by the
Scheme 3. Catalytic Double Additions of N-H indole and N-alkylindoles to
Acetophenone.
rearrangement of the initially formed aromatic polycyclics
observed by 1H NMR spectroscopy (Scheme 5b).16
6, as
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Conclusions
In conclusion, we have developed a main group, Lewis acid-
catalyzed method for the double additions of indoles (and N-
methylpyrrole) to ketones to produce bis(indolyl)methanes
containing an all-carbon quaternary center, a family of
molecules that are prevalent in a broad range of natural
products and biologically active compounds. This process
proceeds through the formation of a tertiary alcohol as an
intermediate and releases H2O as the only by-product. The
products obtained in this process can be derivatized into other
important classes of bis(indole) derivatives, indole-fused
aromatic polycyclics and bis(indolyl)alkenes.
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Conflicts of interest
There are no conflicts to declare.
Acknowledgement
This work was supported by 1) Basic Science Research Program
through the National Research Foundation of Korea (NRF)
funded by the Ministry of Science, ICT & Future Planning
(2018R1C1B6005712), 2) Yonsei University Future-leading
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6 forms bis(indolyl)-alkene 7 is not
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