Formal [4 + 2] benzannulation of 2-alkenyl indoles with aldehydes: A route to structurally diverse carbazoles and bis-carbazoles

Article abstract of DOI:10.1039/c8ob02875c

Construction of structurally diverse carbazoles and bis-carbazoles by protecting-group-free formal [4 + 2]-benzannulation of 2-alkenyl indoles and aldehydes is demonstrated. The sequence of four different reactions is executed in one-pot using readily available and cheap bottle reagents as catalysts rendering this method attractive. The incorporation of inexpensive and environmentally benign molecular oxygen as the oxidant into the final aromatization step enables tolerance of several functional groups.

Full text of DOI:10.1039/c8ob02875c

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Formal [4 + 2] benzannulation of 2-alkenyl indoles
with aldehydes: a route to structurally diverse
carbazoles and bis-carbazoles†
Cite this: DOI: 10.1039/c8ob02875c
Received 17th November 2018,
Accepted 10th December 2018
Ankush Banerjee, Avishek Guin, Shuvendu Saha, Anushree Mondal and
DOI: 10.1039/c8ob02875c
Modhu Sudan Maji
*
rsc.li/obc
Construction of structurally diverse carbazoles and bis-carbazoles formation of arene frameworks (Scheme 1a).8 Reported con-
by protecting-group-free formal [4 2]-benzannulation of structions of carbazoles by using expensive transition-metal-
+
2-alkenyl indoles and aldehydes is demonstrated. The sequence of catalyzed C–N-coupling strategies required the synthesis of
four different reactions is executed in one-pot using readily avail- elaborated N-protected aniline derivatives and can provide a
able and cheap bottle reagents as catalysts rendering this method mixture of two regioisomers, causing difficulties in purifica-
attractive. The incorporation of inexpensive and environmentally tion.8d Besides this, in many cases the protecting group
benign molecular oxygen as the oxidant into the final aromatiza- remains intact with the prepared carbazoles requiring
tion step enables tolerance of several functional groups.
additional steps to remove them. Similarly, transition-metal-
catalyzed C–C-coupling strategies with unsymmetrical diaryl
anilines can produce a mixture of four regioisomeric carba-
zoles, thus restricting their practical applicability.8e,f These
issues can be addressed by a second strategy, namely benz-
annulation, where a new highly substituted benzene ring can
be installed onto a pre-functionalized indole ring in order to
achieve carbazoles with diverse substitution patterns, impor-
tant for the development of new drugs and medicinally impor-
tant compounds.9–11 However, the benzannulation protocols
are not always straightforward as in many cases they start with
very specific substrates synthesized by tedious efforts
(Scheme 1b). Therefore, the synthesis of this class of hetero-
cycles by employing easily accessible starting materials and
Carbazoles are a privileged class of heterocycles owing to their
formidable presence in numerous natural products possessing
important biological activities.1,2 Miscellaneous carbazole
based drugs are either available in the market or under clinical
trials for the treatment of chronic diseases signifying their pro-
found effect in medicinal chemistry;3 for example, carprofen, a
non-steroidal carbazole containing drug, has been already
approved as an anti-inflammatory agent (Fig. 1).4 Very recently
RYDAPT (midostaurin), an indolocarbazole based drug, has
been ratified by the FDA for the treatment of blood cancer
known as acute myeloid leukaemia.5 SLM, a carbazole based
fluorophore, which inhibits the aggregation of β-amyloid pep-
tides in vitro, is a potential drug candidate to cure Alzheimer’s
disease.6 Apart from this, due to their high band gap, thermal,
electrical, and optical properties, carbazoles manifest their
ubiquitous potential as
a key building block in OLED
materials, hole transport materials, electroluminescent
materials, and photoconductors.7
Owing to the noteworthy utilities of these important
scaffolds, considerable efforts are devoted to streamlining
their synthesis; however acquiring carbazoles with defined
substitution patterns is still a daunting task. The reported
strategies can be classified into two major categories, first,
construction of the middle pyrrole ring via C–C or C–N bond
Department of Chemistry, Indian Institute of Technology Kharagpur,
Kharagpur 721302, India. E-mail: msm@chem.iitkgp.ac.in
†Electronic supplementary information (ESI) available: For ESI and NMR
spectra. See DOI: 10.1039/c8ob02875c
Fig. 1 Selected carbazole based natural products, drugs, and organic-
material.
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tion reaction by using molecular oxygen may be facilitated by
the basic nature of the reaction medium, without employing
any transition-metal-catalyst. Besides this economic viability,
due to its mild nature, we presumed that the incorporation of
oxygen as the sole oxidant can be more beneficial to install
diverse functional groups like long alkyl chain, terminal
alkenyl and alkynyl groups, ester, amide, alkoxy groups, etc, at
the C3-position of carbazoles, compared to the other oxidants
like Pd/C, DDQ, MnO2, etc. In addition, the strategy of one-pot-
sequential catalysis will render this method practical by cir-
cumventing several purification steps to one in a sequence of
four reactions.14
Keeping this strategy in mind, we began to optimize the
reaction conditions by choosing (E)-2-styryl-1H-indole 1a and
commercially available 1-hexanal 2h as prototypes. We found
that C3-alkenylation of 1a to generate B worked efficiently in
the THF solvent. To generate sulfone A, the reaction was con-
ducted at 60 °C temperature using 10 mol% PTSA·H2O as the
Brønsted acid catalyst in the presence of 1.2 equiv. PhSO2H.
The sulfone elimination step was executed at room tempera-
ture by using 2.5 equiv. of NaH and 10 mol% DBU. We
observed that for the final 6π-electrocyclization and oxidative
aromatization steps, temperature plays a pivotal role. The reac-
tion rate as well as yield of 3h was improved significantly upon
increasing the temperature to 180 °C for the final step in the
presence of decalin as the additional high boiling solvent
(70%).
After optimizing the reaction conditions, we first explored
the scope of this benzannulation reaction with diversely func-
tionalized aldehydes. Aryl acetaldehydes were found to be suit-
able reaction partners and the corresponding carbazoles were
obtained in excellent yields (3a–3d, 66–78%, Scheme 2).
Hetero-aryl acetaldehydes also underwent smooth conversion
to afford carbazoles 3e–3f in 77–79% yields. Next, we focused
to install several aliphatic functional groups at the C3-position
of the carbazole which is scarce in the literature. It is quite
Scheme 1 Selected strategies to synthesize carbazoles and our plan.
readily available bottle reagents as catalysts in an environmen- challenging to stitch aliphatic chains with carbazole rings
tally benign way is highly desirable in order to minimize these using traditional cross-coupling reactions without any pre-
shortcomings.
functionalizations. Several commercially available aldehydes
These issues are addressed in this work where a protecting successfully took part in the reaction and the corresponding
group free synthesis of carbazoles with defined substitutions carbazoles bearing primary- and secondary-alkyl chains and
is achieved using readily available aldehydes as the formal the benzyl moiety at the C3-position were obtained in excellent
[4 + 2] annulating agent. In this strategy, we intended to yields (3g–3j, 70–86%). To our joy, despite the high reac-
develop an organo-catalytic benzannulation method by apply- tion temperature, aldehydes bearing terminal double bond,
ing one-pot-sequential catalysis. As depicted in Scheme 1c, p-methoxybenzyl group and alkyne moiety also furnished carba-
2,3-dialkenyl-indole B will be generated in situ by applying our zoles 3k–3m in 42–53% yields. It should be noted that due to
previously developed alkenylation method,12 which upon the inherent reactivity of the triple bond and p-mehoxybenzyl
6π-electrocyclization will generate dihydro-carbazole C. Unlike group, these functional groups might not be sustainable under
previous reports where the key oxidation of C to carbazole 3 Pd/C or DDQ mediated aromatization reactions. Interestingly,
was conducted by using either a stoichiometric amount of aldehydes bearing ester and amide functional groups were also
expensive oxidant such as DDQ or by using expensive Pd/C as well tolerated under our reaction conditions to furnish 3n–3o in
the dehydrogenating agent, here we intended to use the environ- 41–57% yields, providing the opportunity for downstream
mentally benign molecular oxygen as the sole oxidant to serve chemical modifications. We further explored the scope by
the purpose.9h,j,13 Oxygen is readily available, inexpensive, and increasing the chain length of aldehydes bearing –OPMB and
produces water as the sole by-product, rendering it arguably –SPh groups, and in both cases desired carbazoles 3p–3q were
the best oxidant. We envisioned that this oxidative aromatiza- isolated in excellent yields (69–74%). Simple acetaldehyde was
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Scheme 3 Scope of 2-alkenylindoles. Reaction conditions: step 1: 1
(1.0 equiv.), aldehyde 2h (1.5 equiv.), PhSO2H (1.2 equiv.), PTSA·H2O
(10 mol%), THF, 60 °C; step 2: NaH (2.5 equiv.), DBU (10 mol%), THF,
room temperature; step 3: O2, decalin, 180 °C; isolated yield.
group free synthesis of unsymmetrical 3,9′-biscarbazole which
is still less explored in the literature. The 3,9′-biscarbazole core
structure present in various natural products like murrastifo-
line A, murrastifoline B, etc., exhibits promising pharmacologi-
cal properties.15 Besides this, 3,9′-biscarbazole oligomers
manifest enormous applicability in material chemistry owing
to their photoemission properties and high quantum efficien-
cies.16 Despite their own merits, the reported protocols to
achieve 3,9′-biscarbazoles show certain limitations such as the
lack of generality, complicated precursors, and multi-step syn-
thesis and required tedious efforts.15 Hence a general method
to synthesize challenging biscarbazoles without using a pro-
tecting group is highly desirable.
Scheme 2 Scope of aldehydes and ketone. Reaction conditions: Step
1: 1a (1.0 equiv.), aldehyde 2 (1.5 equiv.), PhSO2H (1.2 equiv.), PTSA·H2O
(10 mol%), THF, 60 °C; step 2: NaH (2.5 equiv.), DBU (10 mol%), THF,
room temperature; step 3: O2, decalin, 180 °C; isolated yield. aStep 1 at
room temperature and 1.5 equiv. PhSO2H. bPhSO2H (1.5 equiv.),
PTSA·H2O (40 mol%), CH2Cl2 was used in place of THF and NaH (3.0
equiv.).
Gratifyingly, we have accomplished the protecting group
free synthesis of unsymmetrical 3,9′-biscarbazole 5 by employ-
ing aldehyde 2s in 56% yield (Scheme 4). Analogously, the
methylene bridged 3,9′-biscarbazole 6 was also obtained in
45% yield. In a similar fashion the synthesis of methylene
also compatible to produce the corresponding 2-phenylcarba-
zole, albeit in relatively low yield (3r, 33%), providing a route
to synthesize difficult 2-aryl carbazoles in one step. Next we
investigated several ketones such as acetone, 3-pentanone and
acetophenone as annulating partners. However, only acetone
provided desired carbazole 3s in only 19% yield under slightly
modified reaction conditions.
Next, to generalize the reaction further, the scope of
2-alkenyl indoles was investigated using 1-hexanal as an alde-
hyde coupling partner. (E)-2-Styryl-1H-indole derivatives
bearing several functional groups reacted smoothly with
hexanal to provide the corresponding carbazoles in good to
excellent yields (4a–4d, 52–71%, Scheme 3). Gratifyingly, carba-
zoles 4e–4f bearing heteroaromatic functionalities at the C2-
position can also be readily prepared in excellent yields
(83–84%). To our delight, apart from 2,3-disubstitued carba-
zoles, several 1,3-disubstitued carbazoles can also be syn-
thesized using our protocol (4g–4h, 35–68%). Even synthesis of
trisubstituted carbazole 4i was also accomplished under our
reaction conditions.
After successfully accomplishing several structurally unique
Scheme 4 Synthesis of 3,9’-biscarbazole and methylene bridged 3,9’-
carbazoles, next, we undertook the challenge of protecting and 3,3’-biscarbazoles.
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Scheme 5 Synthesis of carbazoles by using Z-alkene 1a’.
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Conflicts of interest
There are no conflicts to declare.
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