Palladium-Catalyzed [2 + 2 + 2] Annulation via Transformations of Multiple C-H Bonds: One-Pot Synthesis of Diverse Indolo[3,2- a]carbazoles

Article abstract of DOI:10.1021/acs.orglett.8b02465

A Pd-catalyzed novel cascade reaction has been developed for the synthesis of indolo[3,2a]carbazoles involving multiple C-H transformation-annulations between the indoles and alkynes. The method involves molecular oxygen as the sole oxidant and is an effective and step-economic process.

Full text of DOI:10.1021/acs.orglett.8b02465

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Palladium-Catalyzed [2 + 2 + 2] Annulation via Transformations of
Multiple C−H Bonds: One-Pot Synthesis of Diverse
Indolo[3,2‑a]carbazoles
K. Shiva Kumar,* Siddi Ramulu Meesa, and Praveen Kumar Naikawadi
Department of Chemistry, Osmania University, Hyderabad-500 007, India
S
* Supporting Information
ABSTRACT: A Pd-catalyzed novel cascade reaction has been developed for the synthesis of indolo[3,2a]carbazoles involving
multiple C−H transformation−annulations between the indoles and alkynes. The method involves molecular oxygen as the sole
oxidant and is an effective and step-economic process.
n recent years, transition-metal-catalyzed organic reactions
Scheme 1. Approaches to Synthesis of Indolo[3,2-
a]carbazoles
I
via C−H bond activation1 and functionalization2 have been
a highly intriguing research area. The main advantage of the
C−H activation/functionalization approach lies in its atom-
and step-economic process.3 Among the various versions of
C−H bond activations, double C−H bond activation of arene/
heteroarene−annulation of alkyne has been rapidly developed
in recent years.4 Catalysts such as Rh and Pd have been well-
investigated for this purpose by Jiao et al.,5 Dong et al.,6 Miura,
Satoh, and co-workers,7 Cheng et al.,8 Li et al.,9 and others.4c,10
However, to date, the multiple C−H transformation−
annulations of alkynes remain limited.11 As part of our
ongoing studies on the development of newer methodologies
for functionalized heteroaromatics12 and fused indoles13 and in
continuation of our interest, we investigated multiple Pd-
catalyzed C−H transformation−annulations between indoles
and alkynes for the first time. In the cascade reaction, three
new C−C bonds are rapidly formed to build the molecular
complexity, such as indolo[3,2-a]carbazoles.
The indolocarbazole framework has been found to be an
integral part of several natural products, bioactive molecules,
and drugs.14 Among those, Asteropusazle A (1), Asteropusazle
B (2), and Recemosin B (3) are notable examples for
indolo[3,2-a]carbazoles (see Figure 1). In addition, carbazole
scaffolds has been used extensively in the application of optical
and solar cells.15 Because of the isomeric forms of
indolocarbazoles,16 the [3,2-a]carbazole framework has not
been thoroughly studied. Consequently, various methods have
been developed for the synthesis of functionalized indolo[3,2-
a]carbazoles during the past several years.
Figure 1. Representative compounds with an indolo[3,2-a]carbazoles
structural motif.
Received: August 2, 2018
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.8b02465
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a b
,
Scheme 2. Cascade Multiple C−H Transformations−Annulation of Indoles 1 with Alkynes 2
a
b
Reaction conditions: indole 1 (0.763 mmol), alkyne 2 (0.381 mmol), Pd(OAc)2(0.076 mmol), DMSO (2 mL), 80 °C, 4 h under O2. Yields of
c
d
1
isolated products are given. Reaction performed on 1 mmol scale. Ratio of the regioisomers was determined by H NMR.
In 2016, Kotha’s group developed synthetic strategies to
prepare indolocarbazoles via a 2-fold Fischer indolization in
three steps (see Scheme 1a).17 Zhao and co-workers
successively demonstrated the formation of indolopyrrolocar-
bazoles from indoles and maleimides via double successive
oxidative Heck reactions and thermal electrocyclization (see
Scheme 1b).18 Acid catalyzed synthesis of indolo[3,2-a]-
carbazoles starting from indoles and diaryl-1,2-diones was
reported by Nair in 2008 (see Scheme 1c).19 While many of
these methods are effective, they require a multistep process
and/or prefunctionalized starting materials, excess usage of
metal oxidant, long reaction time, and limited functional group
tolerance.
However, these reports prompted us to envision the
possibility of Pd-catalyzed [2 + 2 + 2] annulation of indoles
with alkynes in a single pot, leading to indolo[3,2-a]carbazoles
under metal−oxidant free conditions. Synthesis of 2,3-linked
bi-indoles via Pd-catalyzed oxidative cross dimerization of
indoles has been explored by different groups.20
We started our optimization studies by using indole 1a and
diphenylacetylene 2a as the model substrates to give
indolocarbazole (3a). After optimization of the conditions
(see the Supporting Information for details), we found that the
following reaction conditions were established for the best
results: Pd(OAc)2 (10 mol %), O2 atm at 80 °C in DMSO (see
Table S1, entry 6, in the Supporting Information). The
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DOI: 10.1021/acs.orglett.8b02465
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Scheme 3. Cascade Multiple C−H Transformations−
Scheme 6. Proposed Reaction Mechanism
a b
,
Annulations of Azaindoles 5 with Alkynes 2
a
Reaction conditions: azaindole 5 (0.763 mmol), alkyne 2 (0.381
mmol), Pd(OAc)2 (0.076 mmol), DMSO (2 mL), 80 °C, 4 h under
b
O2. Yields of isolated products are given.
reacted smoothly to give indolo[3,2-a]carbazoles in high yields
(see Scheme 2, entries 3aa−eb). The presence of halogens on
indole ring did not change the reaction pathway and generated
the desired products in good yields (see Scheme 2, 3fa−3he
and 3ja). The strong electron-withdrawing indoles failed to
provide the desired product (3ia). A possible reason is that the
presence of an electron-withdrawing group may affect the C−
H transformation process significantly. Subsequently, N−ethyl
and benzyl indole tolerated the reaction conditions well and
generated the indolo[3,2-a]carbazoles products in good yields
(see Scheme 2, 3ma−3ob). Indoles having free NH, NAc, and
NTs were also tested, but the reaction did not proceed in these
cases.
Scheme 4. Cross-Over Experiment between 1a, 5, and 2a
We then evaluated the scope and limitations of the alkyne
substrate. The reaction was compatible with substituents at the
para-position on the benzene rings of internal alkynes, such as
Me− (3ab, 3db, 3eb, 3gb, 3hb, 3mb, and 3ob), MeO− (3ge,
3he, and 3me), and F− groups (3ac and 3hc), providing the
corresponding products in good yields (64%−70%). Fur-
thermore, a heterocyclic thiophene motif also served as a
suitable substrate, as exemplified by the synthesis of 3ad.
Notably, strong electron-deficient alkynes were not compatible
with this protocol (3af). The use of a terminal alkyne, e.g.,
hexyne (2g), afforded a mixture of two regioisomers in a 1:1
ratio (3ag + 3ag′). The nonsymmetrical alkynes, 2h and 2i,
reacted under these conditions to result a mixture of two
isomeric products, 3ah + 3ah′ and 3 mi + 3 mi′ in ratios of
1.2:1 (61% yield) and 1.4:1 (60% yield). Since the Rf values
were too close, the separation and isolation of individual
isomers were rather difficult.
Scheme 5. Mechanistic Studies
We further extended the scope of the developed chemistry
for the synthesis of an important class of heterocyclic scaffolds.
We successfully extended the multiple C−H transformation−
annulations to 7-azaindoles and the corresponding products
(6aa−6ad; see Scheme 3) were obtained in good yields
(65%−70%).
To understand the mode of C−H transformation, a cross-
over experiment was performed using a 1:1 mixture of 1a and 5
under the optimized conditions. The cross-over products, i.e.,
3aa and 6aa, along with the other two products, 7 and 7′, in a
1.6:1 ratio were isolated in this case (see Scheme 4). The Rf
structure of 3a was confirmed by nuclear magnetic resonance
(NMR), high-resolution mass spectroscopy (HRMS), and X-
ray crystallography.21
These optimized reaction conditions were then tested for
the multiple C−H transformation−annulation reactions of
various substituents on indoles 1a−1o with alkyne 2a−2i, as
summarized in Scheme 2. The indoles containing electron-
donating substitutes such as methyl methoxy and ethoxy
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DOI: 10.1021/acs.orglett.8b02465
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Experimental procedures, characterization details and 1H
and 13C NMR spectra of all new compounds (PDF)
values were also too close for compound 7 and 7′; hence, their
separation was difficult. The NMR data suggested the
formation of two isomers (see the experiment and the
Supporting Information) clearly indicating a nonconcerted
process for the observed multiple C−H bonds transformations.
To understand the possible reaction pathway, some control
experiments have been performed (see Scheme 5). First, N-
methylindole 1a was reacted with benzil 7 under the optimized
conditions but 2,3-linked bi-indole was obtained in 75% yield
instead of 3aa. This suggested that the alkyne may not be
converted to the 1,2-diketone during the reaction and the
reaction did not proceed via a simple condensation reaction
pathway (see Scheme 5a). This result also suggests that the
presently developed methodology involve multiple C−H
transformations−annulations with alkynes. As mentioned
above, the formation of indolo[3,2-a]carbazoles is assumed
to occur via the 2,3-linked bi-indole intermediate by a C−H
transformation. To confirm this, we performed a reaction
between 2,3-linked biindoles (4) and diphenylacetylene (2a).
Satisfyingly, this reaction afforded indolo[3,2-a]carbazoles 3aa
in 78% yield (Scheme 5b). We further examined the reaction
of 1a with 2a in the presence of 10 mol % Pd(OAc)2 in DMSO
at 80 °C for 4 h in the presence of nitrogen atmosphere, and
the indolo[3,2-a]carbazoles 3aa were not observed (see
Scheme 5c). This clearly shows that the oxygen plays an
essential role in the success of the present reaction.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: shivakumarkota@yahoo.co.in.
ORCID
K. Shiva Kumar: 0000-0002-1914-5037
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
K.S.K. thanks University Grants Commission (UGC), New
Delhi, India for the award of an Assistant Professorship under
the FRP and CSIR, India, for financial support [No. 02(0234)/
15/EMR-II].
REFERENCES
■
(1) For selected reviews on C−H activation, see: (a) Ackermann, L.
Chem. Rev. 2011, 111, 1315. (b) Yeung, C. S.; Dong, V. M. Chem. Rev.
2011, 111, 1215. (c) Li, B.; Dixneuf, P. H. Chem. Soc. Rev. 2013, 42,
5744 and references cited therein. . (d) Daugulis, O.; Roane, J.; Tran,
L. D. Acc. Chem. Res. 2015, 48, 1053. (e) Gensch, T.; Hopkinson, M.
N.; Glorius, F.; Wencel-Delord, J. Chem. Soc. Rev. 2016, 45, 2900.
(f) Bettadapur, K. R.; Kapanaiah, R.; Lanke, V.; Prabhu, K. R. J. Org.
Chem. 2018, 83, 1810 and references cited therein. .
(2) For selected reviews on C−H bond functionalization, see:
(a) Ackermann, L. Acc. Chem. Res. 2014, 47, 281. (b) Li, B.; Dixneuf,
P. H. Top. Organomet. Chem. 2014, 48, 119. (c) Guo, X.-X.; Gu, D.-
W.; Wu, Z.; Zhang, W. Chem. Rev. 2015, 115, 1622. (d) Song, G.; Li,
X. Acc. Chem. Res. 2015, 48, 1007. (e) Cernak, T.; Dykstra, K. D.;
Tyagarajan, S.; Vachal, P.; Krska, S. W. Chem. Soc. Rev. 2016, 45, 546
and references cited therein. .
Based on the literature precedents4c,5,20 and our exper-
imental observations, a plausible mechanism for this cascade
reaction is outlined in Scheme 6. Initially, electrophilic
palladiation occurs preferentially at the C3-position of indole,
followed by a subsequent migration of the C3−PdX bond to
the C-2 position of indole results in the formation of
intermediate E-1,22,20a further electrophilic palladation of the
second indole to form intermediate E-2, which, upon reductive
elimination, generates the 2,3-dimer of bi-indole (4), and the
formed Pd(0) is oxidized to Pd(II). The palladium diacetate
reacted with a 2,3-dimer of indole through C−H activation to
form intermediate E-3, and then E-3 coordinated with the
triple bond in alkyne (2) to produce a vinylic palladium(II)
intermediate E-4. A seven-membered palladacycle E-5 through
C−H activation then was formed from E-4 through a second
C−H activation. Finally, the intermediate E-5 afforded the
corresponding indolo[3,2-a]carbazoles derivative via reductive
elimination, along with the generation of Pd(0). Finally,
palladium acetate was regenerated from Pd(0) under oxygen to
complete the catalytic cycle.
In conclusion, a direct, one-pot and metal-based oxidant-free
synthesis of indolo[3,2-a]carbazoles has been developed for
the first time via the multiple Pd-catalyzed C−H trans-
formation−annulations of readily available indoles with alkynes
under O2. The present methodology is also extended to
azaindoles. The methodology may find broad applications in
the construction of indolo[3,2-a]carbazole-based libraries for
medicinal uses or natural product synthesis. Further studies
and applications of this method are currently in progress in our
laboratory.
(3) Ackermann, L.; Fenner, S. Org. Lett. 2011, 13, 6548 and
references cited therein. .
(4) (a) Umeda, N.; Tsurugi, H.; Satoh, T.; Miura, M. Angew. Chem.,
Int. Ed. 2008, 47, 4019. (b) Umeda, N.; Hirano, K.; Satoh, T.;
Shibata, N.; Sato, H.; Miura, M. J. Org. Chem. 2011, 76, 13. (c) Qi, Z.;
Yu, S.; Li, X. J. Org. Chem. 2015, 80, 3471. (d) Jin, T. N.; Zhao, J.;
Asao, N.; Yamamoto, Y. Chem. - Eur. J. 2014, 20, 3554. (e) Le Bras, J.;
Muzart, J. Synthesis 2014, 46, 1555.
(5) Shi, Z.; Ding, S.; Cui, Y.; Jiao, N. Angew. Chem., Int. Ed. 2009, 48,
7895.
(6) Li, S.; Wang, C.; Lin, H.; Zhang, X.; Dong, L. Org. Lett. 2015, 17,
3018.
(7) Iitsuka, T.; Hirano, K.; Satoh, T.; Miura, M. Chem. - Eur. J. 2014,
20, 385.
(8) Peng, H.; Yu, J.-T.; Jiang, Y.; Wang, L.; Cheng, J. Org. Biomol.
Chem. 2015, 13, 5354.
(9) Qi, Z.; Yu, S.; Li, X. J. Org. Chem. 2015, 80, 3471.
(10) (a) Li, P.; Zhang, X.; Fan, X. J. Org. Chem. 2015, 80, 7508.
(b) Ghosh, M.; Naskar, A.; Mishra, S.; Hajra, A. Tetrahedron Lett.
2015, 56, 4101.
(11) (a) Umeda, N.; Tsurugi, H.; Satoh, T.; Miura, M. Angew.
Chem., Int. Ed. 2008, 47, 4019. (b) Kianmehr, E.; Faghih, N.; Khan, K.
M. Org. Lett. 2015, 17, 414.
(12) Kumar, K. S.; Rajesham, B.; Kumar, N. P.; Ramulu, M. S.;
Dandela, R. Chem. Select 2018, 3, 4581.
ASSOCIATED CONTENT
(13) (a) Kumar, K. S.; Kumar, N. P.; Rajesham, B.; Kishan, G.;
Akula, S.; Kancha, R. K. New J. Chem. 2018, 42, 34. (b) Kumar, K. S.;
Bhaskar, B.; Ramulu, M. S.; Kumar, N. P.; Ashfaq, M. A.; Pal, M. Org.
Biomol. Chem. 2017, 15, 82. (c) Kumar, K. S.; Ramulu, M. S.;
Rajesham, B.; Kumar, N. P.; Voora, V.; Kancha, R. K. Org. Biomol.
Chem. 2017, 15, 4468.
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S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02465.
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Letter
(14) (a) Markad, S. B.; Argade, N. P. J. Org. Chem. 2016, 81, 5222.
(b) Markad, S. B.; Argade, N. P. Org. Lett. 2014, 16, 5470. (c) Samala,
S.; Mandadapu, A. K.; Saifuddin, M.; Kundu, B. J. Org. Chem. 2013,
78, 6769. (d) Li, J. J. Heterocyclic Chemistry in Drug Discovery; John
̈
Wiley & Sons: Hoboken, NJ, 2013. (e) Knolker, H.-J.; Reddy, K. R.
Chem. Rev. 2002, 102, 4303. (f) Merlic, C. A.; You, Y.; McInnes, D.
M.; Zechman, A. L.; Miller, M. M.; Deng, Q. Tetrahedron 2001, 57,
5199.
(15) (a) Gong, P.; Sun, J.; Xue, P.; Qian, C.; Zhang, Z.; Sun, J.; Lu,
R. Dyes Pigm. 2015, 118, 27. (b) Park, K. S.; Salunkhe, S. M.; Lim, I.;
Cho, C. G.; Han, S. H.; Sung, M. M. Adv. Mater. 2013, 25, 3351.
(c) Blouin, N.; Leclerc, M. Acc. Chem. Res. 2008, 41, 1110.
̈
(16) For a comprehensive review on carbazoles, see: Knolker, H. J.;
Reddy, K. R. Chem. Rev. 2002, 102, 4303.
(17) Kotha, S.; Saifuddin; Aswar, M. V. R. Org. Biomol. Chem. 2016,
14, 9868.
(18) An, Y.-L.; Yang, Z.-H.; Zhang, H.-H.; Zhao, S.-Y. Org. Lett.
2016, 18, 152.
(19) Nair, V.; Nandialath, V.; Abhilash, K. G.; Suresh, E. Org.
Biomol. Chem. 2008, 6, 1738.
(20) (a) Liang, Z. J.; Zhao, J. L.; Zhang, Y. H. J. Org. Chem. 2010,
75, 170. (b) Guchhait, S. K.; Chaudhary, V.; Rana, V. A.;
Priyadarshani, G.; Kandekar, S.; Kashyap, M. Org. Lett. 2016, 18,
1534.
(21) The molecular structure of compound 3a was established based
on single-crystal data analysis, which has been reported; see ref 19.
(22) Lane, B. S.; Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005,
127, 8050.
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