One-Pot Assembly of 3-Hydroxycarbazoles via Uninterrupted Propargylation/Hydroxylative Benzannulation Reactions

Article abstract of DOI:10.1021/acs.orglett.9b04472

A novel strategy for the synthesis of 3-hydroxycarbazoles involving the consecutive propargylation/palladium-catalyzed hydroxylative benzannulation of indole-2-carbonyls with propargylic alcohols has been exploited. This one-pot procedure leads to a wide range of substituted 3-hydroxycarbazoles in high yield with a broad substrate scope. The method was further extended to access furano-carbazole derivatives from dialkynols via tandem annulations.

Full text of DOI:10.1021/acs.orglett.9b04472

pubs.acs.org/OrgLett
Letter
One-Pot Assembly of 3‑Hydroxycarbazoles via Uninterrupted
Propargylation/Hydroxylative Benzannulation Reactions
Chada Raji Reddy,* Muppidi Subbarao, Puppala Sathish, Dattahari H. Kolgave,
and Ramachandra Reddy Donthiri
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sı Supporting Information
ABSTRACT: A novel strategy for the synthesis of 3-hydrox-
ycarbazoles involving the consecutive propargylation/palladium-
catalyzed hydroxylative benzannulation of indole-2-carbonyls with
propargylic alcohols has been exploited. This one-pot procedure
leads to a wide range of substituted 3-hydroxycarbazoles in high
yield with a broad substrate scope. The method was further
extended to access furano-carbazole derivatives from dialkynols via
tandem annulations.
arbazoles exemplify a class of privileged scaffolds as
wherein carbonyl functionality is the source of the hydroxyl
group to access 3-hydroxycarbazoles. The preparation of
7
C
valued pharmacophores in pharmaceutical chemistry and
1
,2
leading building blocks in organic synthesis. Additionally,
they also have found wide applications in photophysical
prefunctionalized alkoxy or carbonylated starting materials is
tedious because it involves a greater number of steps than
commercially accessible sources. Intermolecular annulations
for the synthesis of 3-hydroxycarbazoles remain to be less
3
materials such as organic light-emitting devices (OLEDs). In
particular, 3-hydroxycarbazole is a ubiquitous structural motif
present in numerous bioactive natural products as well as in
8
explored. For instance, Lee and Poudel developed base-
4
medicinally important agents (Figure 1). The wide range of
promoted condensations of 2-nitrocinnamaldehyde or 2-
applications makes these important frameworks an attractive
nitrochalcones with β-ketoesters or 1,3-diaryl-2-propanones
8a
synthetic target, and many efforts have been devoted to their
(
Scheme 1a). In most of these methods, either the carbonyl
5
construction.
or the alkoxy group is the source to generate the 3-hydroxy
functionality. A versatile one-pot intermolecular reaction to
Scheme 1. Intermolecular Annulations for the Direct
Synthesis of 3-Hydroxycarbazoles
Figure 1. Selected natural products having a 3-hydroxycarbazole
framework.
Usually, 3-hydroxycarbazoles are constructed using alkoxy-
substituted precursors by the dealkylation reaction to generate
5
the desired hydroxyl group. Kno
̈
lker and coworkers have
Received: December 13, 2019
developed an iron-mediated method toward the synthesis of
various carbazole natural products including 3-hydroxycarba-
1
c,6
zoles.
Alternatively, a few cyclization reactions have also
been reported involving carbonylated indole substrates,
©
XXXX American Chemical Society
https://dx.doi.org/10.1021/acs.orglett.9b04472
A
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provide diversely substituted 3-hydroxycarbazoles from readily
accessible starting materials is of great importance.
product 3a in 80% yield (Table 1, entry 4). In the absence of a
palladium catalyst, the reaction provided the intermediate in
92% yield (Table 1, entry 5), whereas in the absence of TfOH,
no reaction took place (Table 1, entry 6). The efficiency of
other acid catalysts, such as pTSA, In(OTf) , and FeCl , was
On the contrary, propargylic alcohols have extensively
served as suitable substrates with a wide range of electrophiles
and nucleophiles in the synthesis of numerous heterocyclic and
3
3
9
carbocyclic compounds in recent years. In a continuation of
also investigated in a one-pot reaction, and in all of the cases,
propargylated intermediate A was isolated (Table 1, entries 7−
9). Other palladium catalysts Pd(OAc) and PdCl in the
10
our work using 1-arylpropargylic alcohols, herein we wish to
report a novel one-pot [3 + 3] annulation of indole-2-
carbonyls with 1-aryl propargylic alcohols for the synthesis of
corresponding 3-hydroxycarbazoles via uninterrupted sequence
involving propargylation and hydroxylative benzannulation
reactions (Scheme 1b). To the best of our knowledge, a
strategy that installs the hydroxyl group externally at the third
position on the carbazole during the annulation (hydroxylative
benzannulation) has not been reported to date.
2
2
presence of 10 mol % PPh provided a low yield of the product
3
3a (Table 1, entries 10 and 11). Furthermore, it was also
observed that the addition of an acid and the palladium catalyst
together resulted in a low yield (64%) of the product 3a
(
Table 1, entry 12). The structure of 3a was also confirmed by
single-crystal X-ray analysis (Figure 2).
The study began by an unforeseen formation of 3-
hydroxycarbazole 3a in 38% yield from the reaction of 1a
with 2a and phenylboronic acid in the presence of Pd(PPh ) /
3
4
TfOH in DMF. Because no arylation on the alkyne was
observed, the same reaction in the absence of the phenyl-
boronic acid was tested, which gave an identical result (Table
1
, entry 1). Because the witnessed reaction provides a
a
Table 1. Optimization of Reaction Conditions
Figure 2. View of 3a, showing the atom-labeling scheme. Displace-
ment ellipsoids are drawn at the 30% probability level, and H atoms
are represented by circles of arbitrary radii. CCDC number 1971748.
reaction conditions [acid (20 mol %),
b
entry
palladium (5 mol %)]
product yield (%)
1
2
3
4
5
6
7
8
9
TfOH, Pd(PPh ) , DMF
3a
A
3a
3a
A
41
52
34
80
92
3
4
TfOH, Pd(PPh ) , THF
3
4
TfOH, Pd(PPh ) , CH CN
Having the optimized reaction condition, the generality of
this novel strategy was initially examined by the reaction of
indole-2-carboxaldehyde (1a) with different propargylic
alcohols (Scheme 2). A wide variety of 1-phenyl propargylic
3
4
3
TfOH, Pd(PPh ) , dioxane
3
4
TfOH, dioxane
Pd(PPh ) , dioxane
3
4
pTSA, Pd(PPh ) , dioxane
A
A
A
3a
3a
3a
76
91
73
32
27
64
3
4
In(OTf) , Pd(PPh ) , dioxane
3
3
4
Scheme 2. Scope of Propargylic Alcohols
FeCl , Pd(PPh ) , dioxane
3
3 4
10
11
12
TfOH, Pd(OAc) PPh , dioxane
2
3
TfOH, PdCl , PPh , dioxane
2
3
c
TfOH, Pd(PPh ) , dioxane
3
4
a
Unless otherwise stated, all of the reactions were performed using 0.5
mmol of 1a with 0.5 mmol of 2a in 3 mL of solvent and 20 mol % of
acid. After stirring at rt for 30 min, 5 mol % of palladium catalyst was
b
added, and the reaction was continued at 80 °C for 7 h. Isolated
c
yield. TfOH and palladium catalyst were added together.
conceptually divergent method to access 3-hydroxycarbazoles,
which constitutes a key structural motif in bioactive molecules,
we explored this reaction in more detail to optimize the
reaction conditions. Thus a reaction of 1a with 2a was carried
out in one pot by the sequential addition of TfOH (20 mol %)
and Pd(PPh ) (5 mol %) in THF, which provided only
3
4
intermediate A in 52% yield (Table 1, entry 2). Switching the
solvent to CH CN gave the carbazole 3a in 34% yield (Table
3
1
, entry 3). To our delight, the use of dioxane provided the
B
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alcohols (see the Supporting Information for the structures of
propargylic alcohols), with either electron-donating groups on
the aryl ring, such as Me and OMe (2b and 2c), or electron-
Scheme 4. Scope of 2-Acylindole
withdrawing groups, such as Br, NO , and CN (2d−f)
2
substituents and 1-(naphthalen-1-yl)-3-phenylprop-2-yn-1-ol
(
1
2g), were well endured in [3 + 3] annulation with indole
a to give the corresponding carbazoles 3b−g in good to high
yield. Similarly, propargylic alcohols having aryl (2h−j) or
alkyl (2k) groups tethered to the alkyne were also proved to be
suitable for the present one-pot reaction to deliver the 3-
hydroxycarbazoles 3h−k in good yield. 1-Arylpropargylic
alcohols with terminal alkynes 2l−n functioned well in this
consecutive propargylation/hydroxylative benzannulation with
1
a to afford the desired carbazoles 3l−n. Notably, 1H-indole-
2
-carbaldehyde (1b) was also well tolerated to react with 2a to
produce 68% of the corresponding product 3o.
However, propargylic alcohols with highly electron-rich
groups at C , such as 3,4,5-trimethoxyphenyl (2o), failed to
1
offer the desired carbazole 3p, and, instead, alkynylated-fused
carbazole 4a was isolated in 85% yield (Scheme 3). This might
be due to the high nucleophilic reactivity of the electron-rich
ring with the aldehyde followed by aromatization.
Scheme 3. Reaction of 1a with 2o
Scheme 5. One-Pot Synthesis of Furanocarbazoles
We next turned our interest to studying the scope of the
indole-2-carbonyl constituent of the reaction. As shown in
Scheme 4, a series of 1-methylindolyl-2-ketones underwent the
sequential propargylation/palladium-catalyzed hydroxylative
benzannulation with 1,3-diphenylprop-2-yn-1-ol (2a) under
the present operational conditions, affording the targeted 3-
hydroxycarbazoles 5 in high yield. 2-Indolyl phenyl ketone 1c
and aryl ketones bearing an electron-donating (OMe, 1d) or
an electron-withdrawing group (CF , 1e) on the phenyl ring
3
led to the corresponding carbazoles 5a−c in good yield.
Additionally, indolyl-2-ketone with heteroaryl (1f) was also a
suitable partner for this annulation and delivered the product
efficiently obtained from the respective 2,4-diyn-1-ol 6b,
generated from 1-naphthaldehyde (Scheme 5b).
To understand the source of the hydroxyl group,
5
d in 70% yield. Moreover, methyl (1g), n-propyl (1h),
intermediate A was treated under optimized reaction
cyclopropyl (1i), and cyclopentyl (1j) indoloyl-2-ketones
offered the desired 3-hydroxycarbazoles 5e−h in acceptable
yield. The reaction of 2-acetylindole with 1-trimethoxyphenyl
propargylic alcohol (2o) provided the corresponding carbazole
18
conditions by adding O-labeled H O, which provided the
2
18
18
mixture of O-incorporated products O-3a and 3a (Scheme
a). This supports the source of hydroxyl group as H O. The
6
2
treatment of 3-propargylated indole A with 5 mol % of
5
i in 78% yield.
Next, the feasibility of the developed one-pot annulation
Scheme 6. Control Experiments
process with 2,4-diyn-1-oles was investigated. It was predicted
that the generated hydroxycarbazole would undergo another
cyclization (furan formation) to provide furanocarbazole, a key
structural framework present in bioactive natural products and
11
compounds used for OLEDs. Interestingly, the reaction of 1-
4-methoxyphenyl)-5-phenylpenta-2,4-diyn-1-ol 6a with 1a
gave the envisaged furanocarbazole 7a in 59% yield (Scheme
a), involving uninterrupted propargylation, hydroxy-benzan-
(
5
nulation, and furan formation (two C−C and two C−O bond-
forming reactions). Likewise, furanocarbazole 7b (51%) was
C
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Letter
Pd(PPh ) in the absence of TfOH was found to be ineffective,
which suggests that TfOH is also required for the hydroxylative
benzannulation step.
orcid.org/0000-0003-1491-7381; Email: rajireddy@
iict.res.in
3
4
Other Authors
According to these experimental results and the previous
12
reports, a plausible reaction mechanism is proposed. As
Muppidi Subbarao − CSIR-Indian Institute of Chemical
Technology, Hyderabad, India, and Academy of Scientific
and Innovative Research (AcSIR), Ghaziabad, India
Puppala Sathish − CSIR-Indian Institute of Chemical
Technology, Hyderabad, India, and Academy of Scientific
and Innovative Research (AcSIR), Ghaziabad, India
Dattahari H. Kolgave − CSIR-Indian Institute of
Chemical Technology, Hyderabad, India, and Academy of
Scientific and Innovative Research (AcSIR), Ghaziabad,
India
shown in Scheme 7, initially, 1a undergoes the propargylation
Scheme 7. Proposed Mechanism
Ramachandra Reddy Donthiri − CSIR-Indian Institute
of Chemical Technology, Hyderabad, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.9b04472
Notes
The authors declare no competing financial interest.
with 2a in the presence of TfOH to give intermediate A. In the
presence of in-situ-generated Pd(II), intermediate A undergoes
hydropalladation to produce vinylpalladium complex B, which
upon β-elimination transforms to allene C. The hydration of C
in the presence of acid is expected to give D, and subsequent
cyclization followed by dehydration leads to the desired
product 3a. Nonetheless, the precise mechanism of the
reaction remained indistinct.
In conclusion, the synthesis of 3-hydroxycarbazoles by one-
pot consecutive reactions of propargylic alcohols with indole-2-
carbonyls has been established, involving palladium-catalyzed
hydroxylative benzannulation as the key step. The developed
protocol provides access to important diversely substituted 3-
hydroxycarbazoles in good to excellent yield. The method was
further extended to use 2,4-diyn-1-ols in the reaction, which
favored another cyclization to obtain the diannulated products,
furanocarbazoles. A broad substrate scope and mild reaction
conditions are the attractive features that make the present
method valuable.
ACKNOWLEDGMENTS
C.R.R., M.S., and R.R.D. thank the Council of Scientific and
Industrial Research (CSIR), New Delhi for research funding
■
(
Fast Track Translational Project) and fellowships. P.S. and
D.H.K. thank the University of Grants Commission (UGC),
New Delhi for the fellowship (CSIR-IICT Communication
No. IICT/Pubs./2019/424).
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