Construction of highly functionalized carbazoles via condensation of an enolate to a nitro group

Article abstract of DOI:10.1039/c5sc02407b

This paper describes a novel synthesis of highly functionalized and diverse carbazoles via transition-metal-free and mild base-promoted condensations of readily available 2-nitrocinnamaldehyde or 2-nitrochalcones with various β-ketoesters or 1,3-diaryl-2-

Full text of DOI:10.1039/c5sc02407b

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Construction of highly functionalized carbazoles
via condensation of an enolate to a nitro group†
Cite this: DOI: 10.1039/c5sc02407b
Tej Narayan Poudel and Yong Rok Lee*
This paper describes a novel synthesis of highly functionalized and diverse carbazoles via transition-metal-
free and mild base-promoted condensations of readily available 2-nitrocinnamaldehyde or 2-
nitrochalcones with various b-ketoesters or 1,3-diaryl-2-propanones. The method selectively forms four
bonds by the intramolecular conjugate addition of an enolate to the enal or chalcone bearing an o-nitro
group. This group then undergoes in situ N–O bond cleavage under non-reductive conditions in a one-
pot procedure. This protocol allows for the introduction of various functional groups at all positions of
the newly formed aromatic ring of the carbazole moiety. The utility of this methodology is further
illustrated by the concise synthesis of naturally occurring hyellazole and chlorohyellazole.
Received 4th July 2015
Accepted 2nd September 2015
DOI: 10.1039/c5sc02407b
www.rsc.org/chemicalscience
formation of a C–C or a C–N bond to construct the middle
pyrrole ring starting from arene building blocks (methods A and
Introduction
9
–16
The carbazole framework is found in a wide range of bioactive B, Fig. 2).
Also, the reaction of arynes with nitrosoarene and
1,2
17
natural products and pharmaceuticals (Fig. 1). These carba- the nitrogenation of biphenyl halides have been reported. The
3
4
zole-containing molecules show antiviral, antimalarial, and second strategy involves the installation of a new aromatic ring
5
antitumor activity. Some of them are currently being used as onto functionalized indole derivatives via benzannulation
6
18–23
lead compounds for drug development. Carbazoles are also (methods C and D, Fig. 2).
used as building blocks for the synthesis of functional mate-
Despite their own merits, most, if not all, of these methods
rials, such as organic light-emitting diodes (OLED), because of suffer from certain drawbacks, including low tolerance of
their wide band gap, high luminescence efficiency, and allowing functionality, limited substrate scope, not-easily accessible
7,8

exible modication of the parent skeleton.
Owing to the importance and usefulness of these carbazole- transition-metal catalysts, and harsh reaction conditions. In
starting materials, the necessity of complex and expensive
based compounds, various approaches for their construction particular, many existing methods require either highly elabo-
have been developed. The general and representative strategies rated biaryls or biarylamines to construct the central pyrrole
can be classied into two main types depending on how the
carbazole ring is constructed. The rst strategy relies on the
Fig. 1 Selected naturally occurring, pharmaceutical, or electroactive
carbazoles.
School of Chemical Engineering, Yeungnam University, Gyeongsan 712-749, Republic
of Korea. E-mail: yrlee@yu.ac.kr; Fax: +82-53-810-4631; Tel: +82-53-810-2529
†
Electronic supplementary information (ESI) available: Experimental procedures,
1
13
characterization data, H NMR and C NMR spectra for synthesized compounds.
X-ray structure and data for 7a. CCDC 1046362. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/c5sc02407b
Fig. 2 Diverse synthetic routes for carbazoles.
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moiety or pre-functionalized indole derivatives for benzannu- was also not formed (Table 1, entry 2), but with DBU (1 equiv.),
lation. Therefore, more environmentally benign and modular 3a was produced in 10% yield (Table 1, entry 3). Encouraged by
multi-bond forming approaches accommodating structurally this result, other bases were screened. With K CO (1 equiv.) for
2
3
simple building blocks as the feedstock are highly sought-aer 6 h, the yield of 3a increased to 67% (Table 1, entry 4). The
to improve on these shortcomings. In relation to the synthesis highest yield (81%) was achieved with 1.0 equivalent of Cs CO
of 3-hydroxy carbazoles, iron-mediated reactions have also been in reuxing toluene for 4 h (Table 1, entry 5). Increasing the
2
3
24
reported.
2 3
A recently-reported rhodium-catalyzed tandem amount of Cs CO to 1.5 equivalents (entry 6) or decreasing it to
annulation uses a new approach, where the [5 + 1] cycloaddition 0.1 equivalent (Table 1, entry 7) lowered the yield of 3a. Based on
of 3-hydroxy-1,4-enynes with CO generates three bonds and two these results, this transformation was found to be sensitive
25
rings. Yet, even for this transformation, various 3-hydroxy-1,4- towards the base strength used. For example, strong bases like
enyne reagents must be prepared by a multi-step route. NaOMe (1 equiv.) or DBU (1 equiv.) provided very little or no
In this regard, the new approach, depicted in E, accommo- desired product, while weak bases provided better yields.
dating a novel double annulation through the consecutive Among the screened bases, Cs CO was superior in terms of
construction of a pyrrole and a benzene moiety reects further both reaction time and yield for this reaction, probably due to
2
3
26
innovation (Fig. 2). A unique feature of the current reaction its mild and optimum base strength. In two other nonpolar
compared with all other reported pyrrole formations or ben- solvents (benzene or dichloroethane), 3a was produced in 35
zannulations is the formation of the carbazole nitrogen atom by and 51% yield, respectively, whereas 3a was not obtained in a
electrophilic attack on a nitro group rather than the use of an more polar solvent, such as methanol, DMSO, or water (Table 1,
amine nucleophile. Herein, we describe a unique tandem entries 8–12). The structure of 3a was established by spectro-
1
annulation followed by N–O bond cleavage without any external scopic analysis. The H NMR of 3a showed a characteristic
reductant for the synthesis of various functionalized 3-hydrox- singlet of the OH group at d 11.12 ppm and another broad
1
3
ycarbazoles from readily available 2-nitrocinnamaldehyde or 2- singlet for the NH proton at d 8.17 ppm. The C NMR showed
nitrochalcone and b-ketoesters or 1,3-diaryl-2-propanone.
the expected characteristic ester carbonyl carbon at d 171.6 ppm
and an aromatic carbon containing OH at d 157.7 ppm. The
structural conrmation of 3a was further evidenced by X-ray
crystallographic analysis of the related compound 7a (see ESI†).
With the optimized conditions in hand, the generality of this
reaction was explored by employing different b-ketoesters 2b–2i
Results and discussion
First, the reaction of 2-nitrocinnamaldehyde (1a) and methyl 2-
oxobutanoate (2a) was examined with several bases and solvents
to optimize the reaction conditions (Table 1). The initial
attempt with NaOMe (1 equiv.) in reuxing toluene for 12 h did
not provide product 3a (Table 1, entry 1), but produced an
intractable mixture. With triethylamine (1 equiv.), product 3a
(
Table 2). Reaction of 2-nitrocinnamaldehyde (1a) with several b-
ketoesters such as ethyl 2-oxobutanoate (2b), allyl 3-oxobutanoate
2c) and benzyl 3-oxobutanoate (2d), afforded the desired prod-
(
ucts 3b–3d in 79, 82 and 77% yield, respectively. Moreover, the
Table 2 Formation of carbazole 3b–3i by the reaction of 2-nitro-
a
cinnamaldehyde 1a with various b-ketoesters 2b–2i
Table 1 Optimization of the reaction conditions for the synthesis of
a
carbazole 3a
b
Entry
Base
Solvent
Condition
Yield (%)
1
2
3
4
5
6
7
8
9
NaOMe (1 equiv.)
TEA (1 equiv.)
DBU (1 equiv.)
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Benzene
DCE
Reux, 12 h
Reux, 12 h
Reux, 12 h
Reux, 6 h
Reux, 4 h
Reux, 4 h
Reux, 12 h
Reux, 12 h
Reux, 12 h
Reux, 12 h
Reux, 12 h
Reux, 12 h
0
0
10
67
81
78
32
35
51
0
2 3
K CO (1 equiv.)
Cs
2
Cs
2
Cs
2
Cs
2
Cs
2
Cs
2
Cs
2
Cs
2
CO
CO
CO
CO
CO
CO
CO
CO
3
(1 equiv.)
(1.5 equiv.)
(0.1 equiv.)
(1 equiv.)
(1 equiv.)
(1 equiv.)
(1 equiv.)
(1 equiv.)
3
3
3
3
3
3
3
1
1
1
0
1
2
MeOH
DMSO
Water
0
0
a
Reactions were performed on a 1.0 mmol scale according to the
a
b
Reactions were conducted on a 1.0 mmol scale of 1a. Isolated yield. standard conditions described in Table 1.
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reactions of other b-ketoesters such as ethyl 3-oxopentanoate (2e), Table 4 Formation of carbazoles 7a–7g from 1a or the 2-nitro-
a
chalcones and 6a or 6b
ethyl 3-oxohexanoate (2f), methyl 3-oxooctanoate (2g), methyl 3-
oxododecanoate (2h), and methyl 3-oxo-4-phenylbutanoate (2i)
provided the desired carbazoles 3e–3i in 73–78% yield.
The scope of the reaction was further extended by employing
a series of 2-nitrochalcones and b-ketoesters (Table 3). When 2-
nitrochalcone 4a was treated with allyl 3-oxobutanoate (2c),
ethyl 3-oxopentanoate (2e) or 3-oxo-4-phenylbutanoate (2i)
under optimized reaction conditions, the desired products 5a,
5b and 5c were formed in 75, 73 and 78% yield respectively.
Furthermore, 2-nitrochalcones 4b–4c, bearing electron-
donating or -withdrawing groups such as a methyl or bromo
substituent on the 1-phenyl group, and b-ketoesters 2b, 2d and
2e also provided the desired products 5d–5f in 76, 75, and 70%
yield, respectively. In addition, 2-nitrochalcones 4d–4f, having
electron-donating or -withdrawing groups such as a methoxy,
bromo and chloro substituent on the 3-phenyl group, produced
the expected carbazoles 5g–5k in good yield (70–78%).
The reactions between 2-nitrocinnamaldehyde (1a) or one of
the 2-nitrochalcones (4a, 4c, 4d, 4e and 4f) and 1,3-diary-
lpropan-2-ones 6a and 6b were examined to further demon-
strate the versatility of this carbazole formation (Table 4). The
reaction of 1a with 6a or 6b in reuxing toluene for 4 h afforded
a
Reactions were performed on a 1.0 mmol scale according to the
standard conditions described in Table 1.
the corresponding products 7a–7b in 81 and 80% yield, starting materials, the possibility of using the 2-nitrochalcones
respectively. Similarly, the treatment of the nitrochalcones (4a, bearing a heteroatom was examined, which would lead to the
4
c, 4d, 4e, and 4f) with 6a or 6b provided the products 7c–7g in formation of carbazole derivatives with extended structural
the range of 68–78% yield.
space. To our delight, the reactions of 8a or 8b with b-ketoesters
Having conrmed the general applicability of the reaction by 2b, 2d, and 2e provided the expected products 9a–9f in the range
using 2-nitrocinnamaldehyde and the 2-nitrochalcones as of 71–75% yield (Table 5).
We propose that the formation of the observed carbazole
products may involve a mechanism shown in Scheme 1. In a
Table
3 Formation of carbazoles 5a–5k from various 2-nitro- basic medium, enolate 10 derived from 2a undergoes Michael
a
chalcones (4a–4f) and several b-ketoesters (2a–2e and 2i)
addition onto 1a to give the new enolate intermediate 11, which
subsequently reacts with the nitro group to form the bicyclic
27
intermediate 12. The reorganization of the O–N–OH moiety in
Table
5 Formation of carbazoles 9a–9f from various 2-nitro-
a
chalcones (8a and 8b) and b-ketoesters (2b, 2d and 2e)
a
a
Reactions were performed on a 1.0 mmol scale according to the
Reactions were performed on a 1.0 mmol scale according to the
standard conditions described in Table 1.
standard conditions described in Table 1.
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Scheme
4
Synthesis of naturally occurring hyellazole (22) and
chlorohyellazole (23).
2 3
prolonged time using 2 equivalents of Cs CO for decar-
boethoxylation, carbazoles 21a–21d were obtained in 68–75%
yield.
The utility of this new protocol was demonstrated by the
conversion of 21b and 21d to biologically active natural prod-
ucts (Scheme 4). Upon treating 21b and 21d with iodomethane
Scheme 1 Proposed mechanism for the formation of 3a.
in reuxing acetone in the presence of K
2 to N–O–OH would generate 15 via 13 or 14. The base-induced and chlorohyellazole (23) were obtained in 94% and 92% yields,
elimination of the hydrogen peroxide from 15 would generate respectively. Our concise synthesis of hyellazole and chlor-
6, which would then undergo sequential double tautomeriza- ohyellazole was achieved in two steps from commercially
2 3
CO , hyellazole (22)
1
1
tion via 17 or 18 to generate the observed product 3a.
To obtain evidence for the formation of H
available starting materials in 67% and 63% overall yields,
during the respectively. This protocol has several advantages such as
2
O
2
reaction sequence, a control experiment was carried out with higher yields, lower cost, fewer steps, transition metal-free, and
29,30
added aryl boronic acid (Scheme 2). To our delight, this reaction environmentally benignity.
The identity of these two natural
involving 1a, 2a and 2-naphthyl boronic acid 19 under the products was conrmed by the comparison of their spectro-
29,30
standard reaction conditions provided product 3a (61%) scopic data with those previously reported.
together with 2-naphthol 20 in 31% yield. The formation of 2-
naphthol 20 implies the existence of in situ generated H
2 2
O in
Conclusions
the reaction, although other mechanistic possibilities cannot be
28
excluded.
A highly efficient, transition-metal-free, modular and opera-
tionally simple tandem annulation process was developed for
the synthesis of diverse carbazole derivatives starting from
readily available 2-nitrocinnamaldehydes or 2-nitrochalcones
and b-ketoesters or 1,3-diaryl-2-propanones. This synthetic
approach for the rapid construction of various functionalized
carbazoles involves the intramolecular addition of an enolate to
a nitro group and a unique in situ N–O bond cleavage under
non-reductive conditions. As an application of this new
synthetic methodology, a concise synthesis of naturally occur-
ring bioactive hyellazole and chlorohyellazole has been realized
in two steps.
Next, we broaden the carbazole structures to those that do
not carry a carboethoxy group at the 4-position (Scheme 3). By
carrying out the reaction at a higher temperature (145 C) for a
ꢀ
Scheme
2 2
2 Control experiment to detect H O in the reaction
pathway.
Acknowledgements
This research was supported by the Nano Material Technology
Development Program through the Korean National Research
Foundation (NRF) funded by the Korean Ministry of Education,
Science, and Technology (2012M3A7B4049675) and by the
Korea government (MSIP) (NRF-2014R1A2A1A11052391).
Notes and references
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Scheme 3 Formation of the decarboethoxylated carbazoles 21a–21d
from various 2-nitrochalcones and b-ketoesters.
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