Facile synthesis of indolo[3,2-a]carbazoles via Pd-catalyzed twofold oxidative cyclization

Article abstract of DOI:10.3762/bjoc.12.243

A rapid and efficient route has been developed for the synthesis of 9-methoxycarbonylindolo[3,2-a]carbazole derivatives. The key steps in this approach involved an aromatic amination and an oxidative biaryl coupling. Via the present route, indolo[3,2-a]carbazole derivatives are available in 3-4 steps based on commercially available starting materials.

Full text of DOI:10.3762/bjoc.12.243

Facile synthesis of indolo[3,2-a]carbazoles via Pd-catalyzed
twofold oxidative cyclization
Chao Yang1, Kai Lin2, Lan Huang2, Wei-dong Pan2 and Sheng Liu*2
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2016, 12, 2490–2494.
1Guizhou University, Guiyang, PR China and 2The Key Laboratory of
Chemistry for Natural Products of Guizhou Province, Chinese
Academy of Sciences, Guiyang, PR China
doi:10.3762/bjoc.12.243
Received: 21 August 2016
Accepted: 10 November 2016
Published: 22 November 2016
Email:
Sheng Liu* - lsheng@126.com
Associate Editor: I. R. Baxendale
* Corresponding author
© 2016 Yang et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
cyclization; indolo[3,2-a]carbazole; N-arylation; oxidative biaryl
coupling; palladium catalysis
Abstract
A rapid and efficient route has been developed for the synthesis of 9-methoxycarbonylindolo[3,2-a]carbazole derivatives. The key
steps in this approach involved an aromatic amination and an oxidative biaryl coupling. Via the present route, indolo[3,2-
a]carbazole derivatives are available in 3–4 steps based on commercially available starting materials.
Introduction
Many biologically active carbazole derivatives are of interest as a]carbazole derivatives. Previous literature aimed at providing
drug-like templates. The indolo[3,2-a]carbazole skeleton, one rapid and efficient access to indolo[3,2-a]carbazoles, however,
of the isomeric indolocarbazoles, was firstly identified from most of them have some disadvantages. Few methods were re-
nature in 2002 [1]. Up to now, four members of this family ported to be suitable for scale-up preparation and the introduc-
were isolated from marine organisms (Figure 1) [1-3]. Prelimi- tion of substituents to aromatic rings was also inconvenient. It
nary results of the antimicrobial and cytotoxicity assays indicat- could still be necessary to exploit more practical methods and
ed that these compounds have medicinal potentiality to target economic procedures to assemble these polycyclic molecules.
neurological and psychiatric disorders [1,2].
In this paper, we describe a concise, 3 to 4 steps procedure for
the synthesis of indolo[3,2-a]carbazoles via palladium-cata-
Several methods for the construction of the indolo[3,2- lyzed twofold oxidative cyclization.
a]carbazole skeleton were developed by Bergman [4,5], Cachet
[6], and Zhiping Li [7]. Very recently, we also reported a novel Findings
strategy toward indolo[3,2-a]carbazoles [8], and the key trans- The oxidative biaryl coupling reaction was originally described
formations involved a biomimetic transamination/aromatic over 30 years ago using stoichiometric palladium(II) [9,10].
cyclization sequence to deliver 9-methoxycarbonyl indolo[3,2- Quite recently, the reaction has been developed to proceed cata-
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Figure 1: Natural indolo[3,2-a]carbazole alkaloids.
lytically and widely applied as an atom economic approach to
carbazoles [11,12].
As an interest concerning the development of synthesis methods
for carbazoles, we considered that indolo[3,2-a]carbazoles 1
which represents racemosin B and its analogues also could be
conveniently delivered by bidirectional indole annulations from
methyl 2,4-dianilinobenzoates 2 (Scheme 1). Further disconnec-
tion of compounds 2 provided two commercially available basic
fragments: 2,4-dibromobenzoic acid and anilines. Bergman et
al. have described a synthetic route to indolo[3,2-b]carbazole by
adopting twofold oxidative biaryl coupling as a key step [13],
and the method has been further applied to the synthesis of
malasseziazoles by Knölker et al. [14]. However, the main chal-
lenge in retrosynthetic analysis was to achieve the regioselec-
tive cyclizaion, since the formation of undesired regioisomeric
monocyclized products would block the further cyclization. If
the reaction follows the designed sequence, it would allow us to
Scheme 1: Retrosynthetic analysis of indolo[3,2-a]carbazoles.
establish a novel and simple route to indolo[3,2-a]carbazole de- other anilines under the previous Buchwald–Hartwig condi-
rivatives.
tions to afford methyl 2,4-dianilinobenzoate (2f–p) with various
substituents at the aniline moieties.
Our investigation started with the preparation of methyl
2,4-dianilinobenzoates (2a–e, Scheme 2). The double Buch- Given the ease with which methyl 2,4-dianilinobenzoates could
wald–Hartwig coupling of methyl 2,4-dibromobenzoate 3 (ob- be assembled, further efforts were focused on the optimization
tained by treatment of dibromobenzoic acid with sulfuric acid in studies of the key bidirectional indole annulations using 2a as
methanol) with an excess of anilines in the presence of cesium the model substrate. To maximize efficiency and technical
carbonate and catalytic quantities of Pd(OAc)2 and BINAP simplicity, we prefer to employ air at ambient pressure as the
were processed smoothly. The desired methyl 2,4-dianilinoben- terminal oxidant, and hence only the combination of bases
zoates (2a–e) were obtained in good to excellent yield. In a (K2CO3 and NaOt-Bu) and solvents (AcOH, TFA, PivOH)
parallel synthesis, using the Houpis protocol [15], Cu-catalyzed were screened to promote the demanding transformation
selective monoaminations of the 2,4-dibromobenzoic acid at the (Table 1). Initial investigations were performed with 2a and cat-
2-position were achieved. After methyl esterification of ortho- alytic Pd(OAc)2 in AcOH at 110 °C under air (Table 1, entries 1
aminated benzoic acids, substrates 4a and b were treated with and 2). To our delight, the desired product could be formed
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Scheme 2: Reagents and conditions: (a) H2SO4, MeOH; (b) Ar-NH2, Pd(OAc)2, BINAP, dioxane, 100 °C; (c) 5 mol % Cu2O, K3PO4, DMA, 70 °C.
Table 1: Optimization studies for annulation conditions.a
entry
[Pd]
base (equiv)
solvent
t (°C)
yieldb
1
2
3
4
5
6
7
8
9
10 mol %
10 mol %
10 mol %
10 mol %
10 mol %
10 mol %
5 mol %
K2CO3 (0.1)
AcOH
AcOH
TFA
110
110
90
58%
68%
0%
NaOt-Bu (0.1)
NaOt-Bu (0.1)
K2CO3 (0.1)
AcOH
PivOH
PivOH
PivOH
PivOH
PivOH
120
120
120
120
140
120
0%c
51%
85%
35%d
45%
69%e
K2CO3 (0.1)
NaOt-Bu (0.1)
NaOt-Bu (0.1)
NaOt-Bu (0.1)
NaOt-Bu (0.1)
10 mol %
10 mol %
aA mixture of compound 2a (150 mg, 0.47 mmol), Pd(OAc)2 and basein 0.5 mL solvent was stirred and heated for 48 h under air (entries 1–3, 5–8).
bIsolated yield of 1a. cReaction was carried out under Ar. dIntermediate 5 was isolated in 42% yield from entry 7. eCompound 2a (1.5 g, 3.14 mmol)
with the catalyst in 7.5 mL PivOH was stirred for 72 h (entry 9).
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Beilstein J. Org. Chem. 2016, 12, 2490–2494.
without observing any byproduct, and the adoption of NaOt-Bu reaction time by enhancing the temperature from 120 °C to
as base gave a better yield. We next replaced the acetic acid 140 °C significantly decreased the yield (Table 1, entry 8), on
with other acidic solvents. The desired transformation could not account of decomposition of both the starting material and the
take place in TFA (Table 1, entry 3), however, PivOH [16] was product may occur. To examine whether the desired transfor-
found to be the preferred solvent (Table 1, entry 6). Moreover, mation was suitable for scale-up, a gram-scale synthesis of 2a
the 10 mol % of palladium was required for complete conver- was also achieved (Table 1, entry 9).
sion of 2a within 48 h (Table 1, entry 7). Since the only inter-
mediate 5 could be detected and isolated, it indicated that the With the optimized conditions in hand, the generality and scope
two cyclizations of 1a did not happen simultaneously but fol- of the reaction were also examined (Scheme 3). A range of pre-
lowed a particular sequence. Further attempts to shorten the cursors (2b–p) with various substituents were cyclized to afford
Scheme 3: Substrate scope for Pd-catalyzed twofold annulations.
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Beilstein J. Org. Chem. 2016, 12, 2490–2494.
5. Wahlström, N.; Bergman, J. Tetrahedron Lett. 2004, 45, 7273.
doi:10.1016/j.tetlet.2004.08.024
the desired products in moderate to good yields. Electron-with-
drawing groups (CF3, F) gave the highest yields. The introduc-
tion of electron-donating substituents such as methoxy and
acetylamino groups significantly reduced the reactivity, thus the
complete cyclization needed longer time and the yield was rela-
tively lower. Moreover, a chlorine atom at the aromatic ring
was tolerated under these conditions.
6. Dupeyre, G.; Lemoine, P.; Ainseba, N.; Michel, S.; Cachet, X.
Org. Biomol. Chem. 2011, 9, 7780. doi:10.1039/C1OB06108A
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doi:10.1021/ol5025053
8. Liang, L.-n.; Fan, T.-y.; Huang, T.; Yan, C.; Xu, M.; Liu, S.
Tetrahedron Lett. 2015, 56, 434. doi:10.1016/j.tetlet.2014.11.136
9. Yoshimoto, H.; Itatani, H. Bull. Chem. Soc. Jpn. 1973, 46, 2490.
doi:10.1246/bcsj.46.2490
The meta-substituted starting materials 2i and 2j gave good
regioselectivity. When a trifluoromethyl group was located at
the meta-position, only one regioisomer 1i was observed. How-
ever, the selectivity was reversed when acetyl was present at the
meta-position (5:1 for 2j). The main cyclized product of 2j was
the corresponding ortho-acetyl product 1j. Unexpectedly, the
reaction preferentially occurred at a more sterically hindered
position.
10.Åkermark, B.; Eberson, L.; Jonsson, E.; Pettersson, E. J. Org. Chem.
1975, 40, 1365. doi:10.1021/jo00897a048
11.Schmidt, A. W.; Reddy, K. R.; Knölker, H.-J. Chem. Rev. 2012, 112,
3193. doi:10.1021/cr200447s
12.Roy, J.; Jana, A. K.; Mal, D. Tetrahedron 2012, 68, 6099.
doi:10.1016/j.tet.2012.05.007
13.Tholander, J.; Bergman, J. Tetrahedron 1999, 55, 12577.
doi:10.1016/S0040-4020(99)00733-4
14.Kober, U.; Knölker, H.-J. Synlett 2015, 26, 1549.
doi:10.1055/s-0034-1380713
15.Houpis, I. N.; Weerts, K.; Nettekoven, U.; Canters, M.; Tan, H.; Liu, R.;
Wang, Y. Adv. Synth. Catal. 2011, 353, 538.
Conclusion
In conclusion, a twofold C−H activation protocol applied to
methyl 2,4-dianilinobenzoates facilitated a short and quick
access to the cyclized products. Via the present route,
indolo[3,2-a]carbazole derivatives are available in 3–4 steps
based on commercially available starting materials. The opera-
tional simplicity combined with the convenience for intro-
ducing substituents to the aromatic rings makes this method
useful.
doi:10.1002/adsc.201000800
16.Liégault, B.; Lee, D.; Huestis, M. P.; Stuart, D. R.; Fagnou, K.
J. Org. Chem. 2008, 73, 5022. doi:10.1021/jo800596m
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Supporting Information
Supporting Information File 1
Experimental part and NMR spectra of synthesized
compounds.
The license is subject to the Beilstein Journal of Organic
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Acknowledgements
The work was financially supported by NSFC (No. 21462013),
Qiankehe [2015] 2107 and West Light Foundation of The
Chinese Academy of Sciences.
doi:10.3762/bjoc.12.243
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