Regioselective Synthesis of Substituted Carbazoles, Bicarbazoles, and Clausine C

Article abstract of DOI:10.1021/acs.orglett.1c02449

Substituted carbazoles are efficiently constructed from 3-triflato-2-pyrones and alkynyl anilines. Multiple substituents are tolerated on the carbazole, and complete control of regiochemistry is observed. Complicated and sterically congested substitution patterns are produced. This strategy is also used to prepare substituted bicarbazoles and related biaryls. Finally, the method was showcased in a synthesis of the carbazole natural product clausine C.

Full text of DOI:10.1021/acs.orglett.1c02449

pubs.acs.org/OrgLett
Letter
Regioselective Synthesis of Substituted Carbazoles, Bicarbazoles,
and Clausine C
Gary L. Points, III and Christopher M. Beaudry*
Cite This: https://doi.org/10.1021/acs.orglett.1c02449
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Substituted carbazoles are efficiently constructed from 3-triflato-2-pyrones and alkynyl anilines. Multiple substituents
are tolerated on the carbazole, and complete control of regiochemistry is observed. Complicated and sterically congested substitution
patterns are produced. This strategy is also used to prepare substituted bicarbazoles and related biaryls. Finally, the method was
showcased in a synthesis of the carbazole natural product clausine C.
eterocycles represent privileged structures among
medicinal compounds. Carbazoles, especially naturally
occurring carbaozles, show exciting activities for the treatment
of cancers.1 For example, in 1965, Chakraborty discovered the
first carbazole natural product, murrayafoline A, from the tree
Murraya koenigii; murrayafoline A has antibiotic and antitumor
properties (Figure 1).2 Elliptinium acetate contains a carbazole
amines 1 to form substituted carbazoles 2. In the absence of
directing groups,8 the cyclization of molecules 1 tends to give
C−C bond formation at the least hindered carbon atoms. For
example, cyclization of 3 gives 4 as the major regioisomer, and
only trace amounts of 5 are formed.9
A second general method for carbazole synthesis involves
the cyclization (C−N bond formation) of 2-aminobiphenyls
(6). Again, selective formation of a single desired regioisomer
can be a problem. As an example, subjection of 7 to
photochemical conditions gave regioisomers 8 and 9 without
selectivity.10
H
Our group has become interested in methods for heterocycle
synthesis that do not depend on sterically directed
regioselective outcomes. Specifically, we are investigating
cyclizations where the substitution pattern of the starting
material directly leads to substitution in the product.11 We
recently found that substituted indolines and indoles can be
prepared from N-butynyl-3-amino-2-pyrones in the presence of
base.12 In this manuscript, we describe how alkyne-tethered 3-
anilido-2-pyrones (10) undergo intramolecular cycloadditions,
presumably giving intermediates 11, which rapidly lose CO2 to
form substituted carbazoles 12 (Scheme 1, bottom).13 The
reaction is high yielding, tolerates a wide variety of
substitution, and is completely regioselective. Moreover, the
method can be used to produce bicarbazoles, related biaryls,
and the substituted carbazole natural product, clausine C.
The starting materials for our carbazole synthesis were
prepared from simple 3-hydroxy-2-pyrones (13, Scheme 2).14
Figure 1. Biologically active carbazoles.
core structure. It is a DNA intercalator and a potent
topoisomerase II inhibitor that is used to treat breast cancer.3
Elliptinium acetate is based on the structure of the carbazole
natural product ellipticine. Finally, midostaurin, an analogue of
staurosporine, is a carbazole used to treat leukemia.4
Considering that carbazoles have potent biological activities,
it is perhaps unsurprising that chemists have developed many
methods for their construction. In fact, the discovery of
methods capable of constructing substituted carbazoles began
in the late 19th century5 and continues to be an active area of
research now.6
There are many dozens of distinct approaches to carbazole
synthesis, and comprehensive reviews have been written on
this topic.7 A theme that pervades the synthesis of substituted
carbazoles is the requirement for control of regiochemistry
when the fused tricyclic system is created. One general method
for carbazole synthesis involves the cyclization of diphenyl-
Received: July 22, 2021
https://doi.org/10.1021/acs.orglett.1c02449
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
Scheme 1. Carbazole Syntheses
Scheme 2. Scope of the Carbazole Synthesis
Triflation of 13 followed by C−N bond formation with alkynyl
aniline 14 gave key substrate 10.15
a
b
200 °C, 4 h, oil bath heating. Reaction performed on a 1 mmol
Gratifyingly, microwave heating of 10a in the presence of
base gave the substituted carbazole 12a in high yield.16 This
transformation could also be conveniently conducted with
conventional oil-bath heating to give 12a in excellent yield.
Moreover, the reaction was performed on a large scale (1
mmol) with no decrease in isolated yield.
Additional substrates were evaluated to investigate the
tolerance of the reaction to substitution. A wide variety of
alkyne substituents (R3) were tolerated. Carbazoles bearing
phenyl groups at C4 (12b and 12c) were formed in good
yields. The alkyne may also contain an sp3-hybridized carbon,
and 12d was prepared in high chemical yield. Silyl substitution
was also tolerated, and 12e was formed in good yield.
The pyrone may contain additional substituents; 2-bromo-4-
phenylcarbazole 12f and 2,3,4-trisubstituted carbazole 12g
were efficiently prepared. The pyrone could contain additional
alkyl substituents, and cyclopentanone-substituted carbazole
12h was prepared in high yield. Note that these carbazoles
would be particularly difficult to make by the cyclization of the
corresponding diphenylamines (e.g., Scheme 1, top).
Substitution was well tolerated on the phenyl ring of
substrate 10 (i.e., R1). Electron withdrawing trifluoromethyl
(12i), halogen (12j), and carbomethoxy groups (12k) were all
compatible with the reaction. Carbazoles bearing electron
donating groups were also successfully prepared in high yield
by this method. Specifically, dimethyl- (12l), methyl- (12m),
and methoxy-substituted (12n) carbazoles were all formed.
Carbazole 12o was prepared from the corresponding substrate
with two different alkyne groups; only the alkyne proximal to
the pyrone undergoes cycloaddition. Finally, carbazole 12p was
made from the corresponding starting material with sub-
stitution on the alkyne, phenyl, and pyrone functional groups.
Sterically hindered biaryl molecules are important for
modern materials applications, pharmaceuticals, and as ligands
scale.
for catalysis.17 Bicarbazole natural products are well-known.18
The carbazole synthesis was used in the preparation of
bicarbazoles and related molecules (Scheme 3). Alkyne 15 was
dimerized using the Glaser method to give diyne 16.19
Treatment with the standard conditions induced tandem
pericyclic cascades and produced bicarbazole 17 in excellent
yield. Starting materials bearing additional substitution were
also tolerated, and they gave more hindered bicarbazoles.
Specifically, alkyne 18 was dimerized to give 19. The pericyclic
cascade gave substituted bicarbazole 20. Such biaryls that have
multiple substituents surrounding the biaryl axis are typically
chiral molecules, with slow racemization rates at RT.20
Bicarbazole 20 displayed chemical shift inequivalent geminal
methylene protons, suggesting that the molecule has slow
rotation about the biaryl bond (i.e., atropisomerism).
Biaryls lacking C2-symmetry could also be prepared. Alkynyl-
aminopyrone 15 was coupled with bromoalkyne 21 to give
non-symmetric diyne 22. Heating this molecule gave a tandem
pericyclic cascade, and in situ oxidation12 led to formation of 4-
(4-indolyl)-carbazole 23. Finally, alkyne 15 could be advanced
to non-symmetric diyne 24 over four steps.21 Treatment of 24
under our standard conditions gave non-symmetric bicarbazole
25 in excellent yield.
Clausine C is a substituted carbazole natural product
originally isolated from the Asian shrub Clausena excavata
(Scheme 4).22 Clausine C has been prepared using several
different synthetic strategies,23 and we decided to showcase
our current method in a synthesis of this target. Commercially
available iodoaniline 26 underwent sequential cross-coupling
reactions with TMS-acetylene24 and 3,5-dibromo-2-pyrone25
to give compound 10p. Removal of the TMS protecting group
B
https://doi.org/10.1021/acs.orglett.1c02449
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Scheme 3. Biaryl Syntheses
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02449.
Experimental procedures, spectroscopic data, and
depiction of 1H and 13C NMR spectra for all new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Christopher M. Beaudry − Department of Chemistry, Oregon
State University, Corvallis, Oregon 97331, United States;
orcid.org/0000-0002-4261-2596;
Email: christopher.beaudry@oregonstate.edu
Author
Gary L. Points, III − Department of Chemistry, Oregon State
University, Corvallis, Oregon 97331, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02449
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors acknowledge financial support from the National
Science Foundation (CHE-1956401) and Oregon State
University.
Scheme 4. Synthesis of Clausine C
REFERENCES
■
(1) Issa, S.; Prandina, A.; Bedel, N.; Rongved, P.; Yous, S.; Le
Borgne, M.; Bouaziz, Z. Carbazole Scaffolds In Cancer Therapy: A
Review from 2012 to 2018. J. Enzyme Inhib. Med. Chem. 2019, 34,
1321−1346.
(2) Chakraborty, D. P.; Barman, B. K.; Bose, P. K. On the
constitution of murrayanine, a carbazole derivative isolated from
Murraya koenigii Spreng. Tetrahedron 1965, 21, 681−685.
(3) (a) Clarysse, A.; Brugarolas, A.; Siegenthaler, P.; Abele, R.;
Cavalli, F.; De Jager, R.; Renard, G.; Rozencweig, M.; Hansen, H. H.
Phase II Study of 9-Hydroxy-2N-methylellipticinium Acetate. Eur. J.
Cancer Clin. Oncol. 1984, 20, 243−247. (b) Juret, P.; Heron, J. F.;
Couette, J. E.; Delozier, T.; Le Talaer, J. Y. Hydroxy-9-methyl-2-
ellipticinium for Osseous Metastases from Breast Cancer: a 5-Year
Experience. Cancer Treat. Rep. 1982, 66, 1909−1916.
(4) Fischer, T.; Stone, R. M.; DeAngelo, D. J.; Galinsky, I.; Estey, E.;
Lanza, C.; Fox, E.; Ehninger, G.; Feldman, E. J.; Schiller, G. J.;
Klimek, V. M.; Nimer, S. D.; Gilliland, D. G.; Dutreix, C.; Huntsman-
Labed, A.; Virkus, J.; Giles, F. J. Phase IIB Trial of Oral Midostaurin
(PKC412), the FMS-Like Tyrosine Kinase 3 Receptor (FLT3) and
Multi-Targeted Kinase Inhibitor, in Patients with Acute Myeloid
Leukemia and High-Risk Myelodysplastic Syndrome with Either
Wild-Type or Mutated FLT3. J. Clin. Oncol. 2010, 28, 4339−4345.
(5) (a) Drechsel, E. Ueber Elektrolyse des Phenols mit Wechselstro-
men. J. Prakt. Chem. 1888, 38, 65−74. (b) Borsche, W. Ueber Tetra-
und Hexahydrocarbazolverbindungen und eine neue Carbazolsynth-
ese. Justus Liebigs Ann. Chem. 1908, 359, 49−80.
(6) For recent reports of carbazole synthesis, see: (a) Faltracco, M.;
Ortega-Rosales, S.; Janssen, E.; Cioc, R. C.; Vande Velde, C. M. L.;
Ruijter, E. Synthesis of Carbazoles by a Diverted Bischler−Napieralski
Cascade Reaction. Org. Lett. 2021, 23, 3100−3104. (b) Do, H. N.;
Quan, N. M.; Phuc, B. V.; Tinh, D. V.; Tien, N. Q.; Hga, T. T. T.;
Nguyen, V. T.; Hung, T. Q.; Dang, T. T.; Langer, P. Efficient Copper-
Catalysed Synthesis of Carbazoles by Double N-Arylation of Primary
Amines with 2,2’-Dibromobiphenyl in the Presence of Air. Synlett
gave key intermediate 10q (with a trace amount of 12q).
Isolation and subjection of 10q to our standard conditions
induced smooth formation of substituted carbazole 12q with
complete control of substituent regiochemistry. The combined
isolated yield of 12q over the two steps was 91%. Bromo-
carbazole 12q was converted into clausine C in good yield.26
Overall, this is a five-step synthesis of clausine C from 26 in
48.5% yield, which compares well with previous strategies.23,26
In conclusion, a new regioselective carbazole synthesis has
been discovered. The reaction allows for controlled sub-
stitution patterns at any carbazole position. Moreover, multiple
substituents are conveniently incorporated on the carbazole
framework. Symmetric and non-symmetric bicarbazoles and
related molecules can be prepared using this method. Finally,
we used the method in an efficient synthesis of the natural
product clausine C.
C
https://doi.org/10.1021/acs.orglett.1c02449
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
2021, 32, 611−615. (c) Kehl, A.; Schupp, N.; Breising, V. M.;
Schollmeyer, D.; Waldvogel, S. R. Electrochemical Synthesis of
Carbazoles by Dehydrogenative Coupling Reaction. Chem. - Eur. J.
2020, 26, 15847−15851.
(7) (a) Knölker, H.-J.; Reddy, K. R. Isolation and Synthesis of
Biologically Active Carbazole Alkaloids. Chem. Rev. 2002, 102, 4303−
4428. (b) Schmidt, A. W.; Reddy, K. R.; Knölker, H.-J. Occurrence,
Biogenesis, and Synthesis of Biologically Active Carbazole Alkaloids.
Chem. Rev. 2012, 112, 3193−3328.
(18) For examples, see: (a) Sako, M.; Ichinose, K.; Takizawa, S.;
Sasai, H. Short-step Syntheses of 4-Deoxycarbazomycin B, Sorazolon
E, and (+)-Sorazolon E2. Chem. - Asian J. 2017, 12, 1305−1308.
(b) Bringmann, G.; Tasler, S.; Endress, H.; Kraus, J.; Messer, K.;
Wohlfarth, M.; Lobin, W. Murrastifoline-F: First Total Synthesis,
Atropo-Enantiomer Resolution, and Stereoanalysis of an Axially
Chiral N,C-Coupled Biaryl Alkaloid. J. Am. Chem. Soc. 2001, 123,
2703−2711.
(19) (a) Glaser, C. Contribution to the Chemistry of Phenyl
Acetylenes. Ber. Dtsch. Chem. Ges. 1869, 2, 422−424. (b) Siemsen, P.;
Livingston, R. C.; Diederich, F. Acetylenic Coupling: A Powerful Tool
in Molecular Construction. Angew. Chem., Int. Ed. 2000, 39, 2632−
2657.
(20) Bringmann, G.; Mortimer, A. J. P.; Keller, P. A.; Gresser, M. J.;
Garner, J.; Breuning, M. Atroposelective Synthesis of Axially Chiral
Biaryl Compounds. Angew. Chem., Int. Ed. 2005, 44, 5384−5427.
(21) See the Supporting Information for details.
(22) Ito, C.; Katsuno, S.; Ohta, H.; Omura, M.; Kajiura, I.;
Furukawa, H. Constituents of Clausena excavata. Isolation and
Structural Elucidation of New Carbazole Alkaloids. Chem. Pharm.
Bull. 1997, 45, 48−52.
(23) For selected recent examples, see: (a) Akiyama, T.; Wada, Y.;
Yamada, M.; Shio, Y.; Honma, T.; Shimoda, S.; Tsurata, K.;
Tamenori, Y.; Haneoka, H.; Suzuki, T.; Harada, K.; Tsurugi, H.;
Mashima, K.; Hasegawa, J. Y.; Sato, Y.; Arisawa, M. Self-Assembled
Multilayer Iron(0) Nanoparticle Catalyst for Ligand-Free Carbon-
Carbon/Carbon-Nitrogen Bond-Forming Reactions. Org. Lett. 2020,
22, 7244−7249. (b) Zhang, P.; Li, B.; Niu, L.; Wang, L.; Zhang, G.;
Jia, X.; Zhnag, G.; Liu, S.; Ma, L.; Gao, W.; Qin, D.; Chen, J. Scalable
Electrochemical Transition-Metal-Free Dehydrogenative Cross-Cou-
pling Amination Enabled Alkaloid Clausines Synthesis. Adv. Synth.
Catal. 2020, 362, 2342−2347. (c) Yang, L.; Li, H.; Zhang, H.; Lu, H.
Palladium-Catalyzed Intramolecular C−H Amination in Water. Eur. J.
Org. Chem. 2016, 2016, 5611−5615.
(24) Ohta, Y.; Chiba, H.; Oishi, S.; Fujii, N.; Ohno, H. Construction
of Nitrogen Heterocycles Bearing an Aminomethyl Group by Copper-
Catalyzed Domino Three-Component Coupling-Cyclization. J. Org.
Chem. 2009, 74, 7052−7058.
(25) Lee, J.-H.; Cho, C.-G. Regioselective Palladium-Catalyzed
Aminations of 3,5-Dibromo-2-pyrone with Various Aryl and Alkyl
Amines. Tetrahedron Lett. 2003, 44, 65−67.
(8) For examples of directing groups being used to produce the
contra-steric regioisomer of substituted carbazoles, see: (a) Berndt,
A.; Gruner, M.; Schmidt, A. W.; Knölker, H.-J. Transition Metals in
Organic Synthesis, Part 111: First Total Synthesis and Structural
Revision of Antipathine A. Synlett 2013, 24, 2102−2106. (b) Zhao, J.;
Larock, R. C. Synthesis of Substituted Carbazoles, Indoles, and
Dibenzofurans by Vinylic to Aryl Palladium Migration. J. Org. Chem.
2006, 71, 5340−5348. (c) Li, P.; Li, Q.; Weng, H.; Diao, J.; Yao, H.;
Lin, A. Intramolecular Remote C−H Activation via Sequential 1,4-
Palladium Migration to Access Fused Polycycles. Org. Lett. 2019, 21,
6765−6769. (d) Yang, C.; Lin, K.; Huang, L.; Pan, W.-d.; Liu, S.
Facile Synthesis of Indolo[3,2-a]carbazoles via Pd-catalyzed Twofold
Oxidative Cyclization. Beilstein J. Org. Chem. 2016, 12, 2490−2494.
(9) Liégault, B.; Lee, D.; Huestis, M. P.; Stuart, D. R.; Fagnou, K.
Intramolecular Pd(II)-Catalyzed Oxidative Biaryl Synthesis Under
Air: Reaction Development and Scope. J. Org. Chem. 2008, 73, 5022−
5028.
(10) Tian, X.; Song, L.; Hashmi, A. S. K. Synthesis of Carbazoles and
Related Heterocycles from Sulfilimines by Intramolecular C−H
Aminations. Angew. Chem., Int. Ed. 2020, 59, 12342−12346.
(11) (a) Zhang, X.; Beaudry, C. M. Synthesis of Highly Substituted
Phenols and Benzenes with Complete Regiochemical Control. Org.
Lett. 2020, 22, 6086−6090. (b) Zhao, P.; Beaudry, C. M.
Enantioselective and Regioselective Pyrone Diels−Alder Reactions
of Vinyl Sulfones: Total Synthesis of (+)-Cavicularin. Angew. Chem.,
Int. Ed. 2014, 53, 10500−10503. (c) Chen, J.; Ferreira, A. J.; Beaudry,
C. M. Synthesis of Bis(indole) Alkaloids from Arundo donax: The
Ynindole Diels−Alder Reaction, Conformational Chirality, and
Absolute Stereochemistry. Angew. Chem., Int. Ed. 2014, 53, 11931−
11934.
(12) Points, G. L., III; Stout, K. T.; Beaudry, C. M. Regioselective
Formation fo Substituted Indoles: Formal Synthesis of Lysergic Acid.
Chem. - Eur. J. 2020, 26, 16655−16658.
(26) Naykode, M. S.; Tambe, S. D.; Lokhande, P. D. I2-Catalyzed
Total Synthesis of Collective 7-Oxygenated Carbazole Alkaloids:
Clauszoline-K, -L, Clausine-M, -N and Formal Synthesis of Siamenol.
ChemistrySelect 2017, 2, 567−570.
(13) There are many examples of alkyne-tethered pyrones
participating in Diels−Alder reactions. For examples, see:
(a) Moody, C. J.; Shah, P. Intramolecular Diels−Alder Reactions of
Pyrano[3,4-b]indol-3-ones. Tetrahedron Lett. 1988, 29, 2693−2696.
(b) Fan, F.; Dong, J.; Wang, J.; Song, L.; Song, C.; Chang, J. An
Intramolecular Pyranone Diels−Alder Cycloaddition Approach to
Cannabinol. Adv. Synth. Catal. 2014, 356, 1337−1342. (c) Baran, P.
S.; Burns, N. Z. Total Synthesis of ( )-Haouamine A. J. Am. Chem.
Soc. 2006, 128, 3908−3909. (d) Moody, C. J.; Shah. Diels−Alder
Reactivity of Pyrano[4,3-b]indol-3-ones. Part 3. Intramolecular
Diels−Alder Reactions. J. Chem. Soc., Perkin Trans. 1 1988, 3249−
3254. (e) Watanabe, S.; Nishikawa, T.; Nakazaki, A. Synthesis of Oxy-
Functionalized Steroidal Skeletons via Mizoroki−Heck and Intra-
molecular Diels−Alder Reactions. Org. Lett. 2019, 21, 7410−7414.
(f) Lee, J.-H.; Cho, C.-G. Total Synthesis of (−)-Neocosmosin A and
Intramolecular Diels−Alder Reaction of 2-Pyrone. Org. Lett. 2016, 18,
5126−5129.
NOTE ADDED AFTER ASAP PUBLICATION
Schemes 1 and 2 were corrected on August 23, 2021.
■
(14) All 2-pyrones used in this study were prepared according to
literature precedent. See the Supporting Information for details.
(15) Compounds 10f and 10p were prepared from the
corresponding 3-bromo-2-pyrone. See the Supporting Information
for details.
(16) We believe that the base may serve to partially deprotonate 10,
leading to a more electron-rich diene. See ref 12.
(17) Wencel-Delord, J.; Panossian, A.; Leroux, F. R.; Colobert, F.
Recent Advances and New Concepts for the Synthesis of Axially
Stereoenriched Biaryls. Chem. Soc. Rev. 2015, 44, 3418−3430.
D
https://doi.org/10.1021/acs.orglett.1c02449
Org. Lett. XXXX, XXX, XXX−XXX