Pd-Catalyzed cascade cyclization of: O -alkynylanilines via C-H/C-N bond cleavage leading to dibenzo [a, c] carbazoles

Article abstract of DOI:10.1039/c8ob01386a

A new and efficient Pd-catalyzed cascade cyclization of biaryl-tethered o-alkynylanilines for the formation of dibenzo[a,c]carbazole derivatives has been reported. The use of the alkyl-substituted tertiary anilines together with the combination of the PdCl₂ catalyst with the MnO₂ oxidant and PivOH is vital for giving rise to 5-endo cyclization, C-N bond cleavage, and C-H bond activation in a cascade manner to produce the corresponding products with structural diversity.

Full text of DOI:10.1039/c8ob01386a

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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DOI: 10.1039/C8OB01386A
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Pd-Catalyzed cascade cyclization of o-alkynylanilines via C-H/C-N
bond cleavage leading to dibenzo[a,c]carbazoles
Sheng Zhang,a,b Hengmin Ma,a Hon Eong Ho,b Yoshinori Yamamoto,a,b Ming Bao*a and Tienan
Received 00th January 20xx,
Accepted 00th January 20xx
Jin*a,b,c
DOI: 10.1039/x0xx00000x
www.rsc.org/
A new and efficient Pd-catalyzed cascade cyclization of biaryl- Br coupling of 2-(2-bromoaryl)-3-arylindoles7 and C-H/C-H
tethered o-alkynylanilines has been reported for the formation of coupling of 2-(biphenyl-2-yl)-1H-indole,8 and tandem cross-
the dibenzo[a,c]carbazole derivatives. The use of the alkyl- coupling
reaction
of
2-(2-halophenyl)-indoles
with
substituted tertialy anilines together with the combination of the iodobenzenes9 have been reported as major synthetic methods
PdCl2 catalyst with the MnO2 oxidant and PivOH are vital for giving (Scheme 1a-c). In addition, the Pd-catalyzed dual or triple C-H
rise to the 5-endo cyclization, C-N bond cleavage, C-H bond functionalization of indoles with cyclic and acyclic
activation in a cascade manner to produce the corresponding diaryliodiniums, and annulative π-extension reaction of indole
prodcuts with structural diversity.
with 2,2'-diiodobiphenyl have been developed independently
by the Wu, Jana, and Itami groups as a new synthetic strategy
of DBCs (Scheme 1d-f).10-12 A general and facile synthetic
method other than starting from prefunctionalized indoles
towards structurally diverse DBCs is still highly desirable.
Introduction
The structurally and electronically intriguing features of
carbazole and its derivatives make them particularly attractive
in both pharmaceuticals and functional materials.1 The
carbazole derivatives are of great interests in pharmacological
activities, such as antibiotic and antifungal activities,2,3 DNA
intercalating drugs,4 CDK inhibitory properties.5 Moreover, the
carbazoles derivatives have been proved to be a promising
electron donating units for organic optoelectronic materials in
organic photovoltaics and organic light-emitting diodes.6
Among them, the fused cabazole derivatives of
dibenzo[a,c]carbazoles (DBCs) are expected to exhibit potential
biological activities and distinct optoelectronic properties due
to the carbazole moiety and the extended π-system. However,
in comparison with a number of the carbazole synthetic
methods,1 the synthetic methodologies for constructing DBCs
are limited. So far, the reported synthetic methods of DBCs are
mainly focused on the Pd-catalyzed cyclization of
prefunctionalized indoles. For example, intramolecular C-H/C-
Scheme 1 Reported Pd-catalyzed synthetic methods of dibenzo[a,c]carbazoles from
indoles and our method from o-alkynylanilines. (a) Intramolecular C-H/C-Br coupling:
Pd(OAc)2/PPh3, CsOAc, DMF, 120 oC. (b) Intramolecular C-H/C-H coupling: Pd(OPiv)2,
Cu(OPiv)2, DMF, 150 oC, (c) Tandem reaction with iodobenzene; Pd(OAc)2/PPh3, K2CO3,
DMSO, 120 oC. (d) Dual C-H functionalization with cyclic diaryliodoniums: Pd(OAc)2,
Na2CO3, DCE, 100 oC. (e) Triple C-H functionalization with diaryliodoniums: Pd(OAc)2,
K2HPO4, AcOH, HFIP, 110 oC. (f) Annulative π-extension reaction with 2,2'-diiodobiphenyl:
Pd(MeCN)4(BF4)2 (5 mol%), AgOPiv, TfOH, (CH2Cl)2, 50 oC. (g) This study: intramolecular
cascade cyclization of biaryl-tethered o-alkynylanilines.
a.State Key Laboratory of Fine Chemicals and School of Chemistry, Dalian University
of Technology, Dalian 116023, China. E-mail: mingbao@dlut.edu.cn
b.Department of Chemistry, Graduate School of Science, Tohoku University, Sendai
980-8578, Japan. E-mail: tjin@m.tohoku.ac.jp
c. Research and Analytical Center for Giant Molecules, Graduate School of Science,
Tohoku University, Sendai 980-8578, Japan
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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The Pd-catalyzed heteroannulation of o-alkynylanilines has
Journal Name
The optimization results using 2-(biphenyl]-2-ylethynyl)-N,N-
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been proved to be a powerful and attractive synthetic dimethylaniline 1a as a starting substraDteOI:a1r0e.1s0u39m/Cm8aOrBi0ze13d86inA
methodology for the construction of a variety of functional Table 1. When 1a was subjected with our previously developed
indoles and fused indole derivatives.13 In particular, the tandem oxidative condition15a of PdCl2 (10 mol%), MnO2 (3 equiv), and
cyclization of o-alkynylanilines bearing a N,N-dialky moiety PivOH (1 equiv), the corresponding DBC 2a was obtained in a
under Pd-catalyzed oxidative conditions has been emerged to high yield of 95% (entry 1). Pd(PPh3)2Cl2 and Pd(OAc)2 were also
be promising synthetic strategy for constructing various proved to be effective for producing high yields of 2a by
functional indoles and indole-fused polyheterocycles.14 On the combination with the MnO2 oxidant and the PivOH additive
other hand, we recently demonstrated that bis-biarylalkynes (entries
could undergo a Pd(II)-catalyzed dual C-H activation for Pd(CH3CN)4(BF4)2, and Pd2(dba)3 were examined to be less
constructing 9,9 -bifluorenylidenes under the effective, which afforded 2a in moderate yields along with the
PdCl2/MnO2/PivOH oxidation conditions via the formation of a recovered 1a (entries 4-6). The reaction of a in the absence of
2 and 3). Other catalysts such as Pd(OPiv)2,
'
1
palladacycle species.15a In light of the pioneering indole PivOH dramatically decreased the yield of 2a (entry 7),
synthetic methods14 and our recent interests in the Pd- suggesting that PivOH may play an important role in both
catalyzed C-H functionalization for constructing highly fused π- demethylation and C-H bond activation processes. Moreover,
conjugated polycycles,15 we reasoned that if a biary-tethered o- the reaction without using an oxidant gave a poor yield of 2a
alkynylaniline having a suitable N,N-dialky group is employed (entry 8), indicating that the use of oxidants are indispensable
under the Pd(II)-catalyzed oxidative conditions, the DBC for achieving a high yield of 2a in the present cascade cyclization.
scaffold could be formed through an intramolecular cascade Consequently, various oxidants were tested in the presence of
cyclization involving 5-endo cyclization, N-dealkylation, and C-H the PdCl2 catalyst and PivOH. The use of CuCl2 resulted in
bond activation. Herein, we report a new Pd-catalyzed cascade decomposition of 1a with a low yield of 2a, while Cu(OAc)2 and
cyclization of the biaryl-tethered o-alkynylanilines towards AgOAc were efficient oxidants to afford 2a in 78% and 76%
construction of structurally intriguing DBCs under yields, respectively (entries 9-11). o-Chloranil was tested to be
PdCl2/MnO2/PivOH oxidative systems. To the best of our an unsuitable oxidant, which resulted in
a complete
knowledge, this is the first DBC synthetic method from the o- decomposition of 1a without forming 2a (entry 12).
alkynylaniline substrates (Scheme 1f).16
Interestingly, the green oxidant of O2 (1 atm) could lead to the
corresponding product 2a in 70% yield (entry 13). It was noted
that among the solvents tested, the polar solvents such as
diemthylacetamide (DMAc, 95%), dimethylformamide (79%),
acetonitrile (77%), 1,4-dioxane (74%), and 1,2-dichloroethane
(72%), gave much higher yields of 2a than the use of the
nonpolar solvent of toluene (34%).
Table 1 Optimization of reaction conditionsa
Under the optimized reaction conditions, the N-substituent
effect on the reaction efficiency has been studied (Table 2). The
reaction with the secondary aniline 1b produced the 2-biaryl-
substituted indole 3b as a major product along with the
corresponding product 2a in 3% yield due to the facile
protonation of the corresponding indole-Pd species after the 5-
exo cyclization, indicating that the use of the tertiary aniline
substrates is crucial for the successful implementation of the
current cascade cyclization (entry 1). The N,N-dihexylaniline 1c
was also a suitable substrate for producing the corresponding
hexyl-protected DBC 2c in 89% yield at a higher reaction
temperature of 100 oC (entry 2). When the pyrrolidine-
substituted aniline 1d was used, the corresponding pyrrolidine
ring-opened pivalate ester 2d was formed a major product
Entry
1
2
3
4
5
6
7c
8
Cat. Pd
PdCl2
Oxidant
MnO2
MnO2
MnO2
MnO2
MnO2
MnO2
MnO2
_
2a (%)b
95 (93)
90
94
42
68
52
49
24
5
78
76
0
1a (%)b
0
0
Pd(PPh3)2Cl2
Pd(OAc)2
Pd(OPiv)2
Pd(CH3CN)4(BF4)2
Pd2(dba)3
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
0
56
23
41
28
68
10
0
24
0
6
9
CuCl2
10
11
12
13
Cu(OAc)2
AgOAc
o-chloranil
O2 (1 atm)
together with the chlorinated product 2d' as a minor product
(entry 3), suggesting that the dealkylation might be assisted by
the nucleophilic attack of PivOH. The reaction with the N-
benzyl-N-methylaniline 1e produced the corresponding methyl-
protected DBC 2a as a sole product without forming the benzyl-
protected DBC, indicating the facile deprotection property of
the benzyl moiety (entry 4). The reaction with the N-phenyl-N-
methylaniline 1f produced the phenyl-protected DBC 2f as a
single product in 67% yield (entry 5), indicating the advantage
of the present method for introducing varied N-protecting
groups.
PdCl2
PdCl2
70
a
Reaction conditions: 1a (0.3 mmol), Pd catalyst (10 mol%), oxidant (3 equiv),
PivOH (1 equiv) in DMAc (1.5 mL) at 80 °C for 12 h. 1H NMR yield determined
using CH2Br2 as an internal standard. Isolated yield is in parenthesis. Without
PivOH.
b
c
Results and discussion
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(12 h) for consumption of the starting substrate under the
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standard conditions (entries 1-3). DOSI:im10i.l1a0r3l9y/,C8OthB0e1386oA-
alkynylanilines 1i-k bearing electron-poor substituents such as
Table 2 Study of the N-substituent effecta
F and CF3 at the 4- or 5-position of the aniline moiety also did
not show significant efficiency differences (entries 4-6),
indicating the negligible electronic effect of the aniline moiety
on the nucleophilic 5-exo cyclization process. Similar electronic
effect was also observed from the reaction with substrates with
the substituents on the biphenyl group. For example, the
reactions with the anilines 1l and 1m having an electron-rich
methyl substituent and an electron-poor Cl substituent at the
Entry
1
2 (%)b
4'-position of the biphenyl group, respectively, afforded the
corresponding products 2l and 2m in similarly high yields within
6 hours (entries 7 and 8). Interestingly, the biphenyl-tethered
10-alkynylphenanthren-9-amine 1n also proceeded the present
cascade cyclization efficiently, giving rise to the highly π-
extended tetrabenzo[a,c,g,i]carbazole 2n in 87% yield (entry
9).12 The reaction also showed a high compatibility with the
heterocycle-composed biaryl moiety. For example, the reaction
with o-alkynylaniline 1o bearing 3-phenylbenzo[b]thiophene at
the alkynyl terminus produced the corresponding
benzothiphene-fused carbazole 2o in 67% yield (entry 10).
In order to further understand the mechanistic details, the
deuterium isotope experiment was carried out (Scheme 2). An
intermolecular competing reaction with a 1:1 mixture of the
protonated 1g and the perdeuterated 1g-d5 under the standard
conditions in the same reaction vessel at 60 oC for 40 min
produced the corresponding DBC products 2g and 2g-d4 with a
kinetic isotope effect (KIE) value of 3.82. This high KIE value
clearly indicates that the C-H activation step should be the rate-
determining. Moreover, the high KIE value also implies that the
demethylation presumably takes place prior to the C-H bond
activation,14c,17 because if the C-H bond activation take place
with the indolium intermediate
value is expected due to the electron-deficient nature of the
intermediate
B (see Scheme 3), the lower KIE
B.
a
Reaction conditions: 1 (0.3 mmol), PdCl2 (10 mol%), MnO2 (3 equiv), PivOH (1
equiv) in DMAc (1.5 mL) at 80 °C for 12 h. b Isolated yields.
Next, we investigated the electronic effect of substituents on Scheme 2 Intermolecular competing reaction between 1g and 1g-d5 in the same reaction
vessel.
the aniline and biphenyl moieties (Table 3). The reactions with
o-alkynylanilines 1g and 1h having an electron-donating methyl
group at the 4- and 5-positions of the aniline moiety,
respectively, did not affect the efficiency for achieving good
yields of the corresponding DBCs 2g and 2h, while the
perdeuterated aniline 1g’ required a prolonged reaction time
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DOI: 10.1039/C8OB01386A
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Table 3 Synthesis of various dibenzo[a,c]carbazole derivativesa
a Reaction conditions: 1 (0.3 mmol), PdCl2 (10 mol%), MnO2 (3 equiv), PivOH (1 equiv) in DMAc (1.5 mL) at 80 °C for 6 h. b Isolated yield.
On the basis of the experimental evidences, the plausible Subsequently, the nucleophilic attack of PivOH to the activated
reaction mechanism is outlined in Scheme 3. The coordination N-methyl group in the intermediate results in a demethylation
of the Pd(II) catalyst with the alkyne moiety of 1a leads to the reaction and a counter anion exchange of Pd(II) to yield the
B
5-endo cyclization to form a indolium-Pd intermediate
B.
indole-Pd(OPiv) intermediate
C
with releasing HCl and PivOMe.
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financial support. TJ thanks Japan Society for Promotion of
DOI: 10.1039/C8OB01386A
Science (JSPS) KAKENHI Grant Number 15KK0180 on Fostering
The ortho-C-H activation of the intermediate
pivalate-assisted transition state affords the seven-membered
C through a
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palladacycle
intermediate
D
D
. Subsequent reductive elimination of the
produces the corresponding product 2a and the
Joint International Research.
Pd(0) species. The Pd(0) species can be oxidized by MnO2 in the
presence of HCl, regenerating the active PdCl2 catalyst.15a
Notes and references
1
For selected reviews, see: (a) A. W. Schmidt, K. R. Reddy
and H.-J. Knölker, Chem. Rev., 2012, 112, 3193; (b) H.-J.
Knölker and K. R. Reddy, Chem. Rev., 2002, 102, 4303;
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2009, 48, 9608; (d) L. S. Tsutsumi, D. Gündisch and D.
Sun, Curr. Top. Med. Chem., 2016, 16, 1290.
W. Maneerat, T. Ritthiwigrom, S. Cheenpracha, T.
Promgool, K. Yossathera, S. Deachathai, W. Phakhodee
and S. Laphookhieo, J. Nat. Prod., 2012, 75, 741.
R. Fröde, C. Hinze, I. Josten, B. Schmidt, B. Steffan and
W. Steglich, Tetrahedron Lett., 1994, 35, 1689.
D. Pelaprat, A. Delbarre, I. L. Guen, J. B. L. Pecq and B.
P. Roques, J. Med. Chem., 1980, 23, 1336; (b) E. Lescot,
G. Muzard, J. Markovits, J. Belleney, B. P. Roques and J.
B. L. Pecq, J. Med. Chem., 1986, 29, 1731.
T. A. Engler, K. Furness, S. Malhotra, C. Sanchez-
Martinez, C. Shih, W. Xie, G. Zhu, X. Zhou, S. Conner, M.
M. Faul, K. A. Sullivan, S. P. Kolis, H. B. Brooks, B. Patel,
R. M. Schultz, T. B. DeHahn, K. Kirmani, C. D. Spencer, S.
A. Watkins, L. Considine and J. A. Dempsey, Bioorg. Med.
Chem. Lett., 2003, 13, 2261.
2
3
4
5
6
For selected reviews, see: (a) H. Jiang, J. Sun and J. Zhang,
Curr. Org. Chem., 2012, 16, 2014; (b) B. Wex and B. R.
Kaafarani, J. Mater. Chem. C, 2017, 5, 8622.
7
8
9
S. Cacchi, G. Fabrizi, A. Goggiamani and A. Iazzetti, Org.
Biomol. Chem., 2012, 10, 9142.
K. Saito, P. K. Chikkade, M. Kanai and Y. Kuninobu, Chem.
Eur. J. 2015, 21, 8365.
L. Wu, G. Deng and Y. Liang, Org. Biomol. Chem., 2017,
15, 6808.
Scheme 3 Plausible reaction mechanism.
10 Y. Wu, X. Peng, B. Luo, F. Wu, B. Liu, F. Song, P. Huang
and S.-J. Wen, Org. Biomol. Chem., 2014, 12, 9777.
11 S. K. Bhunia, A. Polley, R. Natarajan and R. Jana, Chem.
Eur. J., 2015, 21, 16786.
12 W. Matsuoka, H. Ito and K. Itami, Angew. Chem. Int. Ed.,
2017, 56, 12224.
13 For selected reviews, see: (a) I. Nakamura and Y.
Yamamoto, Chem. Rev., 2004, 104, 2127; (b) G. Zeni and
R. C. Larock, Chem. Rev., 2004, 104, 2285; (c) N. T. Patil
and Y. Yamamoto, Chem. Rev., 2008, 108, 3395; (d) T. Jin,
J. Zhao, N. Asao and Y. Yamamoto, Chem. Eur. J., 2014,
20, 3554.
14 (a) B.Yao, Q. Wang and J. Zhu, Angew. Chem. Int. Ed.,
2012, 51, 12311; (b) B. Yao, Q. Wang and J. Zhu, Angew.
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L. Zhang, X.-R. Song, X.-Y. Liu and Y.-M. Liang, J. Org.
Chem., 2012, 77, 9163; (d) B. Yao, Q. Wang and J. Zhu,
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Conclusions
In conclusion, we have developed for the first time a new and
efficient DBC synthetic methodology from the biaryl-tethered o-
alkynylanilines under the Pd-catalyzed oxidative conditions. The
present reaction proceeds through a cascade process involving
5-endo cyclization, demethylation, and ortho-C-H activation,
producing
the
corresponding
DBC
derivatives,
tetrabenzocarbazole, and benzothiophene-fused carbazole in
good to high yields. The present cascade cyclization provides a
general and useful synthetic method for constructing various
DBC structures, which will be further extended to the synthesis
of valuable bioactive compounds and highly π-extended
carbazole-fused functional materials.
15 (a) J. Zhao, N. Asao, Y. Yamamoto and T. Jin, J. Am. Chem.
Soc., 2014, 136, 9540; (b) J. Zhao, K. Oniwa, N. Asao, Y.
Conflicts of interest
There are no conflicts to declare.
Yamamoto and T. Jin, J. Am. Chem. Soc., 2013, 135
,
10222.
16
A
similar
reaction
type
from
2-((2-
azidophenyl)ethynyl)biphenyl by a cationic gold catalyst
for construction of DBC has been reported, see: J. Cai, B.
Wu, G. Rong, C. Zhang, L. Qiu and X. Xu, Org. Lett., 2018,
20, 2733.
Acknowledgements
We are grateful to the National Natural Science Foundation of
China (No. 21372035, 21573032, and 21602026) and the China
Postdoctoral Science Foundation (No. 2016M590226) for their
17 E. M. Simmons and J. F. Hartwig, Angew. Chem. Int. Ed.,
2012, 51, 3066.
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Table of Contents
Pd-Catalyzed cascade cyclization of o-alkynylanilines via C-H/C-N bond cleavage
leading to dibenzo[a,c]carbazoles
Sheng Zhang, Hengmin Ma, Hon Eong Ho, Yoshinori Yamamoto, Ming Bao* and Tienan Jin*
A new and efficient Pd-catalyzed cascade cyclization of biaryl-tethered o-alkynylanilines has
been reported for the formation of dibenzo[a,c]carbazole derivatives.