Synthesis of Carbazoles by a Diverted Bischler-Napieralski Cascade Reaction

Article abstract of DOI:10.1021/acs.orglett.1c00785

An unforeseen twist in a seemingly trivial Bischler-Napieralski reaction led to the selective formation of an unexpected carbazole product. The reaction proved to be general, providing access to a range of diversely substituted carbazoles from readily available substrates. Judicious variation of substituents revealed a complex cascade mechanism comprising no less than 10 elementary steps, that could be diverted in multiple ways toward various other carbazole derivatives.

Full text of DOI:10.1021/acs.orglett.1c00785

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Letter
Synthesis of Carbazoles by a Diverted Bischler−Napieralski Cascade
Reaction
̆
Matteo Faltracco, Said Ortega-Rosales, Elwin Janssen, Razvan C. Cioc, Christophe M. L. Vande Velde,
and Eelco Ruijter*
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ABSTRACT: An unforeseen twist in a seemingly trivial Bischler−
Napieralski reaction led to the selective formation of an unexpected
carbazole product. The reaction proved to be general, providing
access to a range of diversely substituted carbazoles from readily
available substrates. Judicious variation of substituents revealed a
complex cascade mechanism comprising no less than 10 elementary
steps, that could be diverted in multiple ways toward various other
carbazole derivatives.
Scheme 1. (A) Unexpected Carbazole Formation; (B)
Bioactive Carbazoles
ince its first report in 1893, the Bischler−Napieralski
S
reaction has been widely employed for the synthesis of
dihydro-β-carbolines and -isoquinolines owing to its robust-
ness and broad functional group tolerance.1 Even currently, the
Bischler−Napieralski reaction and its contemporary variations
are still the object of intensive study in many areas, including
natural product synthesis.2 In light of our interest in bioactive
indole alkaloids and related compounds,3 we employed the
Bischler−Napieralski reaction to access a series of dihydro-β-
carbolines. However, when we subjected styrylacetamide 1a to
typical Bischler−Napieralski conditions (POCl3, MeCN, reflux,
1 h) we serendipitously found near-quantitative formation of 3-
phenylcarbazole (3a) instead of the expected dihydro-β-
carboline 2a (Scheme 1A). The structure of 3a was confirmed
by H and 13C NMR, HRMS, and X-ray crystallography.
1
Although carbazoles are less common than the related
indoles among natural products and medicinal compounds,
various carbazoles displaying interesting properties have been
reported (Scheme 1B).4 Notable examples include the
anticancer natural products staurosporine5 (and its clinically
used semisynthetic derivative, midostaurin6) and ellipticine.7
Recently, carbazole derivative 4 was identified as a lead for
new antitrypanosomiasis drugs,8 while glycozoline is known for
its antibacterial, antifungal, antifeedant, and anti-inflammatory
properties.9 Typical methods for the synthesis of carbazoles
involve high temperature, long reaction times, and often metal
catalysis (sometimes replaced by iodine or Lewis acids).10,11
Intrigued by our preliminary result, we decided to further
explore the synthetic potential of this novel, mild, and metal-
free route to carbazoles in more detail.
Pleasingly, we observed that all substrates underwent full
conversion within 1 h (Scheme 2). Both electron-withdrawing
and electron-donating substituents on the indole (R2) are
tolerated without significant influence on the yield, affording
the corresponding products 3b−k in mostly good yield, with 5-
Received: March 6, 2021
Published: March 31, 2021
Puzzled by the surprising, but highly efficient formation of
3a, we set out to investigate the generality of the process. A
series of diversely substituted tryptamides 1a−t was subjected
to the reaction conditions (POCl3, MeCN, reflux, 1 h).
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https://doi.org/10.1021/acs.orglett.1c00785
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a
Scheme 2. Scope of the Carbazole Formation
a
b
c
All reactions were performed with 0.2 mmol of 1a−t, 0.3 mmol of POCl3, refluxing in MeCN for 1 h. Performed on a 2 mmol scale. Obtained
by treatment of 2t with LiAlH4.
fluoro substitution giving the lowest yield (3h, 49%). Similarly,
N-alkyl substituents had very little effect on the reaction
outcome (3d−k). The effect of varying R3 substitution is more
significant. Electron-deficient arenes as R3 substituents perform
best (3l, 3n, and especially 3p). In contrast, products bearing
an electron-rich aryl (3m, 3o) or 3-thienyl R3 substituent (3q)
were obtained in lower yields. Interestingly, esters as the R3
substituent were also able to promote the transformation,
affording the corresponding carbazoles in high yield when the
indole core is unsubstituted (3r,s, R1 = R2 = H) and in
moderate yield when a 5-methoxy group is present (3t).
Treatment of 3t with LiAlH4 afforded the natural product
glycozoline (3u) which, together with 3s, has been isolated
from Clausena lansium.12
Scheme 3. Systematic Methyl Substitution
Once we established the generality of the reaction, we began
our mechanistic investigation by the systematic variation of the
substitution of the styrylacetic acid moiety in 1a (Scheme 3).
Reaction of the γ-methyl-substituted styrylacetamide 1u led to
a complex reaction mixture containing traces of the
corresponding regular Bischler−Napieralski product, but no
carbazole derivatives. Reaction of the β-methyl-substituted
substrate 1v gave 2-methylcarbazole 3v, while α-methyl-
substituted styrylacetamide 1w afforded 1-methylcarbazole 3w.
These results may be rationalized by either transfer of the
cinnamyl moiety to the indole C2 position or a complete
rearrangement of the starting material involving ring opening
of the indole moiety. The reaction of 1x, bearing a methyl
substituent at the indole C2 position, surprisingly afforded 4-
methyl-3-phenylcarbazole (3x). The formation of 3x can only
be rationalized by a methyl migration or ring opening of the
indole. Finally, we employed 13C-labeled substrate 1a*13 and
observed the incorporation of the 13C label at the 9a position
of carbazole 3a*.
which undergoes attack by the indole C3 position to give
spiroindolenine derivative 6. In the Bischler−Napieralski
reaction, 6 undergoes a rapid Plancher rearrangement, leading
to dihydro-β-carboline 2a after deprotonation of 7. In this case,
however, the presence of the styryl moiety makes tautomeriza-
tion to 8 more favorable. The resulting vinylogous enamine
attacks the protonated indolenine, leading to formation of the
tetracyclic scaffold 9. Then, β-elimination of the (protonated)
aromatic amine takes place, opening up the indoline ring in 10.
The resulting aniline 11 subsequently undergoes imine transfer
(via the bridged aminal 12) to form the carbazole framework.
The resulting dihydrocarbazole 13 finally undergoes attack by
Based on the results summarized in Scheme 3 and relevant
prior literature,14 we could postulate a mechanism to
rationalize the formation of 3a from 1a (Scheme 4). Plausibly,
the reaction is initiated by the formation of nitrilium ion 5,
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to 3a, Scheme 4), the 1,2-aryl migration of the aniline fragment
in 16 would re-establish the aromaticity of the system in the
final stage. It is interesting to note that aminal intermediate 17
has an internal mirror plane and the two iminium species 16
and 16′ are identical, thus leading to the formation of a single
carbazole product (14).
Scheme 4. Postulated Mechanism
Next, we focused our attention on intermediate 10 (Scheme
4), the tetracyclic core of which is present in a variety of
natural products.15 To target this scaffold, ring opening of the
indole (leading to 11, Scheme 4) needs to be prevented. Thus,
we synthesized C2 Br-substituted styrylacetamide 18a to offer
an alternative elimination pathway, interrupting the cascade at
this stage. Indeed, the reaction of 18a does undergo a diverted
pathway; however, the product was again a carbazole (19a,
Scheme 6), albeit with yet another surprising substitution
Scheme 6. C2 Bromide Diversion
pattern. The formation of 19a could be rationalized by an
alternative evolution of intermediate 20. At this point,
elimination of HBr is favored over indoline ring opening,
leading to 21. Similarly to the conversion of 13 to 3a (Scheme
4), attack of a chloride anion would terminate the cascade to
give carbazole 19a.
We then proceeded to demonstrate the generality of this
alternative transformation (Scheme 7). All desired products
19a−f were obtained in moderate to very good yield, although
we observed higher yields for products bearing electron-
withdrawing substituents such as halogens and CF3 (19b, 19d,
19e), yet the highest yield was observed for the unsubstituted
an unidentified nucleophile (most likely chloride) to give 3a
with aromatization as a strong thermodynamic driving force.
Once we established a plausible mechanism, we realized that
this complex, multistep transformation offers numerous
opportunities for interruption or diversion of the reaction by
judicious selection of substituents. First, we explored the
possibility of diverting the cascade process by considering the
equilibrium between 11, 12, and 13 that ultimately leads to the
formation of 3a. We reasoned that the nucleophilic attack that
takes place on the sp3 carbon of 13 could be avoided if the
aliphatic linker is replaced by an aromatic one. Indeed,
subjecting the phenylene-linked amide 1y to the cyclization
conditions afforded carbazole 14 in 75% yield (Scheme 5).
Based on the above-mentioned considerations, we expected
that the cascade would proceed analogously to the formation
of 3a until intermediate 17 and be interrupted at that stage.
However, aromatization proved too great a driving force also in
this case. As SN2 substitution is not possible in this case (cf. 13
a
Scheme 7. Scope of C2 Bromide Diversion
Scheme 5. Aromatic Linker Diversion
a
All reactions were performed with 0.2 mmol of 18a−f, 0.3 mmol of
POCl3, refluxing in MeCN for 1 h.
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Notes
product 19a. In contrast, the presence of a methyl substituent
led to a lower yield (19c), whereas replacing the phenyl ring
with a thienyl moiety reduced the yield significantly (19f).
In conclusion, we report the serendipitous discovery of a
diverted Bischler−Napieralski cascade reaction yielding
carbazoles. The method features metal-free conditions, good
yields, and high functional group tolerance. Systematic
experimentation allowed us to confidently establish a complex
multistep reaction mechanism, which allowed for straightfor-
ward further diversion or interruption of the reaction pathway
to give different carbazole regioisomers. Efforts to further
exploit the tetracyclic intermediates in the reaction in the total
synthesis of indole alkaloids are currently ongoing in our
laboratory.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by The Netherlands
Organisation for Scientific Research (NWO).We thank Xander
Schaapkens and Ad Ruigrok van de Werve for preliminary
experiments and Daniël Preschel for HRMS measurements (all
VUA). We thank the Hercules Foundation (Project AUGE/
11/029 “3D-SPACE: 3D Structural Platform Aiming for
Chemical Excellence”) for funding the diffractometer, and
Prof. Kristof Van Hecke (University of Ghent) for making
available diffractometer time.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
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REFERENCES
■
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1
Experimental details and characterization data, H and
13C NMR spectra, 2D NMR spectra (PDF)
FAIR data, including the primary NMR FID files, for
compounds 1a−y, 3a−x, 14, 18a−f and 19a−f (ZIP)
Accession Codes
CCDC 2062984 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Eelco Ruijter − Department of Chemistry & Pharmaceutical
Sciences, Amsterdam Institute of Molecular & Life Sciences
(AIMMS), Vrije Universiteit Amsterdam, 1081, HZ,
Amsterdam, The Netherlands; orcid.org/0000-0002-
1105-3947; Email: e.ruijter@vu.nl
Authors
Matteo Faltracco − Department of Chemistry &
Pharmaceutical Sciences, Amsterdam Institute of Molecular
& Life Sciences (AIMMS), Vrije Universiteit Amsterdam,
1081, HZ, Amsterdam, The Netherlands
Said Ortega-Rosales − Department of Chemistry &
Pharmaceutical Sciences, Amsterdam Institute of Molecular
& Life Sciences (AIMMS), Vrije Universiteit Amsterdam,
1081, HZ, Amsterdam, The Netherlands
Elwin Janssen − Department of Chemistry & Pharmaceutical
Sciences, Amsterdam Institute of Molecular & Life Sciences
(AIMMS), Vrije Universiteit Amsterdam, 1081, HZ,
Amsterdam, The Netherlands
Razvan C. Cioc − Organic Chemistry and Catalysis, Debye
Institute for Nanomaterials Science, Utrecht University, 3584,
CG, Utrecht, The Netherlands
Christophe M. L. Vande Velde − Faculty of Applied
Engineering, iPRACS, University of Antwerp, 2020
Antwerpen, Belgium
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̆
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