Synthesis of carbazoles based on gold-copper tandem catalysis

Article abstract of DOI:10.1039/C7CC00103G

An efficient synthetic method for carbazoles has been developed employing diazo anilinoalkynes as substrates. Sequential activation of the orthogonal functional groups embedded in diazo anilinoalkyne substrates by tandem gold-copper catalysis leads to the formation of highly substituted carbazoles. Substrate scope reveals a broad tolerability toward the substitution on aryl groups.

Full text of DOI:10.1039/C7CC00103G

View Article Online
View Journal
ChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: C. Park, S. choi, S.
Vunnam and S. Ha, Chem. Commun., 2017, DOI: 10.1039/C7CC00103G.
This is an Accepted Manuscript, which has been through the
Volume 52 Number
1 4 January 2016 Pages 1–216
Royal Society of Chemistry peer review process and has been
accepted for publication.
ChemComm
Accepted Manuscripts are published online shortly after
Chemical Communications
www.rsc.org/chemcomm
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1359-7345
COMMUNICATION
Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
first methanofullerene derivatives of Sc N@D5h-C80
=
3
rsc.li/chemcomm

Please do not adjust margins
ChemComm
Page 1 of 4
View Article Online
DOI: 10.1039/C7CC00103G
Journal Name
Synthesis of Carbazoles based on Gold-Copper Tandem Catalysis
Subin Choi,‡ Vunnam Srinivasulu,‡ Sujin Ha and Cheol-Min Park*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
An efficient synthetic method for carbazoles has been developed biarylamines as substrates: i) Diels-Alder reaction,4
employing diazo anilinoalkynes as substrates. Sequential electrocyclization,5 and benzannulation6 of substituted indoles,
activation of the orthogonal functional groups embedded in diazo ii) dehydrogenative cyclization7 of diarylamines, iii) nitrene
anilinoalkyne substrates by tandem gold-copper catalysis leads to insertion8 and N-arylation9 of biarylamines (Scheme 1).
the formation of highly substituted carbazoles. Substrate scope
Tandem catalysis offers many advantages including atom
reveals a broad tolerability toward the substitution on aryl groups. economy, environmental impact, issues with isolation of
unstable intermediates. Nevertheless, tandem catalysis
presents significant challenges including compatibility of
catalysts and solvents involved in individual catalytic cycles.10
Owing to their various useful properties including their
intriguing electrical and optical properties, there has been a
great deal of interest in carbazoles.1 Furthermore, a large
number of carbazole-containing compounds are under intense
investigation for their pharmacological activities including
antitumor, antibiotic, antioxidative, antiviral, and antimalarial.2
For example, staurosporine is an ATP-competitive kinase
inhibitor with anti-fungal and anti-hypertensive activity.
Clausenawalline A possesses cytotoxic activity against human
cancer cell lines. Claulansine A exhibits anti-inflammatory and
antitumor properties against various human cancer cell lines
(Figure 1).3
While the reported synthetic methods for carbazoles typically
require pre-assembled bicyclic substrates, we aimed to
develop
a method that enables bis-annulation from
monocyclic substrates in a single operation. To this end, our
approach has been carefully designed such that tandem gold-
copper dual catalysis sequentially activates orthogonal
functional groups by respective catalysts to allow direct
formation of products with higher complexity obviating the
isolation of intermediates. Thus, two consecutive annulations
employing diazo anilinoalkynes as substrates leads to the
formation of a carbazole scaffold.
Therefore, the increasing demand for carbazoles
necessitates the development of efficient synthetic methods.
Broadly, approaches for carbazole synthesis have been
reported by employing substituted indoles and diarylamines/
The ability of gold complexes for activation of C-C multiple
bonds has received a great deal of interest in the past
decade.11 Addition of various heteroatom nucleophiles onto
alkynes activated by gold complexes has proven to be a
powerful method for heterocycle synthesis.12 Given their
importance, many different approaches for the synthesis of
indoles have been developed including gold-catalyzed 5-endo
cyclization of anilinoalkynes.13 Meanwhile, the reactivity of
carbenes for heterocycle synthesis has been extensively
exploited by us14 and others.15 While there are a few reports
H
N
O
O
O
O
OH
H
N
N
N
N
O
H
H
H3C
HO
N
OMe
H
O
H3CO
NHCH3
i)
Staurosporine
Clausenawalline A
Claulansine A
Diels-Alder
Figure 1. Carbazole alkaloids
N
H
R2
O
ii)
X
This work
[ Pd ]
R4
R3 N2
N
H
R1
N
H
NH
R5
iii)
[ Rh, Pd, Cu ]
Y
Scheme 1. Synthetic Approaches to the Synthesis of Carbazoles
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 2 of 4
View Article Online
DOI: 10.1039/C7CC00103G
COMMUNICATION
Journal Name
Table 1. Optimization of Carbazole Formationa
for gold-catalyzed synthesis of carbazoles from indoles,16 to
the best of our knowledge, no literature examples have been
reported with sequential activation of multi-functional groups
with orthogonal reactivity by tandem gold-copper catalysis
(Scheme 1). With our continued interest in heterocycle
synthesis, we describe herein a new synthesis of carbazoles
that allows direct conversion of readily accessible simple
acyclic substrates into carbazoles with obviating the necessity
for isolation of intermediates, in contrast to the previous
methods, which involve stepwise synthesis.
We hypothesized that gold-catalyzed cycloisomerization of
diazo anilinoalkynes would provide indoles with a pendant
diazo group, which serves as a latent functionality. In the
second cycle, copper-catalyzed activation of the diazo group
should form a copper carbene complex, and subsequent
electrophilic substitution with indole would provide carbazole
after oxidation of dihydrocarbazole. In this approach, the
following few points are worthy of attention: 1) catalyst-
dependent selective activation of anilinoalkynes and diazo
groups. 2) chemoselective electrophilic substitution of
carbenes towards indoles over N-H insertion. We have
established a highly efficient synthetic route for the requisite
substrates (Scheme 2). Sonogashira coupling of iodoanilines
with keto alkynes prepared by alkylation of ketones with
propargyl bromide provided anilinoalkynes , which was
transformed into diazo anilinoalkynes by diazo transfer.
A
B
C
1
As an initial attempt, we began by screening various
catalysts and reaction conditions on diazo anilinoalkyne 1a as a
substrate (Table 1, I). A survey of various dirhodium catalysts
on diazo anilinoalkyne 1a gave mostly disappointing results
with complex mixtures, among which only Rh2(OAc)4 and
Rh2(esp)2 afforded minute quantities of carbazole 3a in 19%
and 10%, respectively (entries 1 and 4), via spontaneous
oxidation of dihydrocarbazole.17,18 The use of Cu(hfacac)2 gave
a similar result (20%, entry 6). With the array of reported
reactions on gold carbene complexes, we also examined gold
catalysts bearing various ligands. An initial attempt with
Au(PPh3)OTf under reflux conditions furnished carbazole 3a in
20%, whereas 2a was obtained in 91% when the reaction was
performed at RT (entries 7 and 8), despite the potential
deactivation of the cationic gold complexes by the free amine
in 1a. While mixtures of 2a and 3a were obtained with Au[P(t-
Bu)3]OTf and Au(SIPr)OTf, the use of Au(JohnPhos)SbF6 and
Au(JohnPhos)OTf provided 3a in 46% and 62%, respectively
(entries 10 - 13). On the other hand, the efficiency decreased
when PtCl2 was employed as a catalyst (entry 14). At this
a Reaction conditions : DCE (0.02 M), MnO2 addition at RT, All reactions were
b
performed under N2; hfb = heptafluorobutyrate, oct = octanoate, esp =
α,α,α′,α′-tetramethyl-1,3-benzenedipropionic acid, tpa = triphenyl acetate, hfacac
= hexafluoroacetylacetonate, NTf2 = bis(trifluoromethanesulfonyl)imide, OTf =
trifluoromethanesulfonate, JohnPhos
= 2-(di-t-butylphosphino)-1,1'-biphenyl,
SIPr = 1,3-bis[2,6-bis(1-methylethyl)phenyl]-4,5-dihydroimidazol-2-ylidene; c AgCl
removed by filtration; d N-H insertion product was obtained in 15% yield. See
supporting information.
juncture, we turned our attention to taking advantage of
indole 2a as an intermediate and examined the feasibility of
cyclization into carbazole 3a by the generation of metal
carbene complexes (Table 1, II). Whereas a mixture of
carbazole 3a (35%) and N-H insertion product (15%) was
obtained with the use of Rh2(OAc)4 (entry 15, see the
supporting information), copper salts proved to display better
conversion with Cu(hfacac)2 delivering 3a in 76% yield.
Furthermore, we found it beneficial for yields to perform the
oxidation with MnO2 at RT (entry 19). With these results in
hand, we set out to investigate tandem catalysis by combining
the two catalytic cycles, indole formation and subsequent
cyclization of carbene (Table 1, III). Gratifyingly, the
combination of Au(PPh3)OTf and Cu(hfacac)2 gave 3a in 72%
yield (entry 20). Further improvement in yield was achieved
Scheme 2. Preparation of Substrates
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 3 of 4
View Article Online
DOI: 10.1039/C7CC00103G
COMMUNICATION
Journal Name
Table 2. Substrate Scope
R1, R2,
Yield
(%)
R1, R2,
Yield
(%)
Entry
1
Product
Entry
9
Product
R3, R4, R5
R3, R4, R5
H, H,
H, CO2Me, H
4-Cl, H,
H, CO2Me, H
82
83
61
72
3a
3i
4-MeO, H,
H, CO2Me, H
H, Me,
H, CO2Me, H
2
3
10
11
65
3b
3c
3j
4-NO2, H,
H, CO2Me, H
H, H,
Me, CO2Me, H
70
3k
5-NO2, H,
H, CO2Me, H
4-NO2, H,
Me, CO2Me, H
4
5
6
66
68
72
12
13
14
49
3d
3l
4-CO2Me, H,
H, CO2Me, H
H, H,
H, COMe, H
78
3e
3m
4-CN, H,
H, CO2Me, H
H, H,
H, C(O)NMe2, H
79
3f
3n
4-F, H,
H, CO2Me, H
H, H,
H, P(O)(OMe)2, H
7
8
80
83
15
16
72
3g
3o
4-Me, H,
H, CO2Me, H
H, H,
H, CO2Me, 4-BrPh
50
3h
3p
when AgCl salt was removed from the cationic gold catalyst by compared to those with electron-deficient aryl groups. 4-
filtration (entry 21). A control experiment in the absence of the methoxyaniline gave carbazole 3b in 83%, while a substantially
gold catalyst failed to produce 3a (entry 22).
lower yield of 3c (61%) was obtained from an electron-
With the optimized reaction conditions in hand, we set out deficient substrate, 4-nitroaniline. Likewise, other electron-
to establish the substrate scope of the tandem catalytic deficient aryl substrates bearing ester and nitrile groups
carbazole synthesis (Table 2). With the anticipation that displayed the similar trend (3e and 3f). Although fluorine is
electronic effect may be among dominant factors that considered as an electron-withdrawing group, its electronic
influence the efficiency of the cyclization, we examined several influence was negligible in this reaction, providing
a
aryl groups bearing substituents with electron-donating and comparable yield with methyl substitution (3g and 3h
,
withdrawing capability. From the study, pronounced electronic respectively, 80% vs. 83%). Next, we turned our attention to
effect was observed that substrates with electron-rich aryl examine the influence of substitution on the tether. When
groups provided the corresponding carbazoles in higher yields compared to that with unsubstituted substrate 3a, tether
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 4 of 4
View Article Online
DOI: 10.1039/C7CC00103G
COMMUNICATION
Journal Name
Scheme 3. Proposed Mechanism
3
4
(a) P. Rongved, G. Kirsch, Z. Bouaziz, J. Jose and M. Le
Borgne, Eur. J. Med. Chem., 2013, 69, 465; (b) W.
Maneerat, T. Ritthiwigrom, S. Cheenpracha, U. Prawat and S.
Laphookhieo, Tetrahedron Lett., 2011, 52, 3303; (c) S. B.
Markad and N. P. Argade, J. Org. Chem., 2016.
(a) N. H. Krishna, A. P. Saraswati, M. Sathish, N. Shankaraiah
and A. Kamal, Chem. Commun., 2016; (b) M. F. Martínez-
Esperón, D. Rodríguez, L. Castedo and C. Saá, Org. Lett.,
2005, 7, 2213.
(a) V. Dhayalan, J. A. Clement, R. Jagan and A. K.
Mohanakrishnan, Eur. J. Org. Chem., 2009, 2009, 531; (b) J.
K. Laha and N. Dayal, Org. Lett., 2015, 17, 4742.
(a) T. Tsuchimoto, H. Matsubayashi, M. Kaneko, Y. Nagase,
5
6
T. Miyamura and E. Shirakawa, J. Am. Chem. Soc., 2008, 130
15823; (b) X. Zheng, L. Lv, S. Lu, W. Wang and Z. Li, Org.
Lett., 2014, 16, 5156.
,
7
8
9
(a) M. E. Budén, V. A. Vaillard, S. E. Martin and R. A. Rossi, J.
Org. Chem., 2009, 74, 4490; (b) C. Schuster, M. Rönnefahrt,
K. K. Julich-Gruner, A. Jäger, A. W. Schmidt and H.-J. Knölker,
Synthesis, 2016, 48, 150.
(a) B. J. Stokes, B. Jovanović, H. Dong, K. J. Richert, R. D. Riell
and T. G. Driver, J. Org. Chem., 2009, 74, 3225; (b) B. J.
substitution showed an adverse effect on the cyclization (3j
and 3k, respectively, 65% and 70%). When two negative
factors, electron-withdrawing group and tether substitution
were combined, the efficiency of the tandem reaction further
decreased (3l, 49%). In addition, we investigated the impact of
the functional groups adjacent to the diazo group. Ketone and
amide groups were well tolerated to afford the corresponding
carbazoles with high yields (3m and 3n, 78% and 79%).
Phosphonate gave 3o with slightly diminished but synthetically
useful yield (72%). Lastly, biaryl aniline 1p smoothly reacted to
give N-aryl substituted carbazole 3p (50%).
Stokes, K. J. Richert and T. G. Driver, J. Org. Chem., 2009, 74
6442.
,
(a) S. H. Cho, J. Yoon and S. Chang, J. Am. Chem. Soc., 2011,
133, 5996; (b) S. W. Youn, J. H. Bihn and B. S. Kim, Org. Lett.,
2011, 13, 3738.
10 (a) J. H. Kim, S. Y. Choi, J. Bouffard and S.-g. Lee, J. Org.
Chem., 2014, 79, 9253; (b) J. Um, H. Yun and S. Shin, Org.
Lett., 2016, 18, 484.
11 (a) J. Mo, D. Kang, D. Eom, S. H. Kim and P. H. Lee, Org. Lett.,
2013, 15, 26; (b) A. M. Asiri and A. S. Hashmi, Chem. Soc.
Rev., 2016, 45, 4471; (c) M. Bandini, Chem. Soc. Rev., 2011,
40, 1358.
12 (a) H.-S. Yeom, Y. Lee, J.-E. Lee and S. Shin, Org. Biomol.
Chem., 2009, 7, 4744; (b) R. Dorel and A. M. Echavarren,
Chem. Rev., 2015, 115, 9028.
13 (a) E. Chong and S. A. Blum, J. Am. Chem. Soc., 2015, 137
Mechanistically, the formation of carbazoles from diazo
anilinoalkyne is proposed to begin with gold-mediated
hydroamination of anilinoalkyne
3). Subsequent activation of the diazo group of
formation of copper carbene, which undergoes electrophilic
1
to form indole
2 (Scheme
2
results in the
,
10144; (b) I. Nakamura, U. Yamagishi, D. Song, S. Konta and
Y. Yamamoto, Angew. Chem. Int. Ed., 2007, 46, 2284.
cyclization with the indole moiety to afford carbazole
oxidation.
3 after
14 (a) Y. Jiang, V. Z. Y. Khong, E. Lourdusamy and C.-M. Park,
Chem. Commun., 2012, 48, 3133; (b) N. S. Y. Loy, S. Choi, S.
Kim and C.-M. Park, Chem. Commun., 2016; (c) N. S. Y. Loy,
S. Kim and C.-M. Park, Org. Lett., 2015, 17, 395; (d) Y. Jiang
In sum, we have successfully developed efficient synthesis
of carbazoles employing diazo anilinoalkynes as substrates
based on gold copper tandem catalysis. Each of the two
catalysts promotes sequential activation of the orthogonal
functionalities, alkynyl and diazo groups, resulting in the
formation of carbazoles via indoles as the intermediates. This
method has proven to offer a valuable synthetic tool for
carbazoles featuring a broad substrate scope.
and C.-M. Park, Chem. Sci., 2014, 5, 2347; (e) N. S. Y. Loy,
A. Singh, X. Xu and C.-M. Park, Angew. Chem. Int. Ed., 2013,
52, 2212; (f) Y. Jiang, W. C. Chan and C.-M. Park, J. Am.
Chem. Soc., 2012, 134, 4104; (g) X. Qi, L. Dai and C.-M. Park,
Chem. Commun., 2012, 48, 11244; (h) X. Qi, X. Xu and C.-
M. Park, Chem. Commun., 2012, 48, 3996; (i) X. Qi, Y.
Jiang and C.-M. Park, Chem. Commun., 2011, 47, 7848; (j) E.
This work was supported by the National Research
Foundation of Korea (NRF) grants (2014-011165, Center for
New Directions in Organic Synthesis (CNOS), NRF-
2014R1A2A2A01006060) funded by the Korean government
and UNIST (Ulsan National Institute of Science & Engineering)
Research Fund (1.170014.01).
Lourdusamy, L. Yao and C.-M. Park, Angew. Chem., 2010, 49
7963.
,
15 (a) J. He, Y. Shi, W. Cheng, Z. Man, D. Yang and C. Y. Li,
Angew. Chem. Int. Ed., 2016, 55, 4557; (b) V. V. Pagar and
R. S. Liu, Angew. Chem. Int. Ed., 2015, 54, 4923.
16 (a) Y. Qiu, W. Kong, C. Fu and S. Ma, Org. Lett., 2012, 14
6198; (b) B. Alcaide, P. Almendros, J. M. Alonso, E. Busto, I.
,
Fernández, M. P. Ruiz and G. Xiaokaiti, ACS Catal., 2015, 5,
3417.
17 (a) B. Alcaide, P. Almendros, J. M. Alonso, S. Cembellin, I.
Fernandez, T. M. del Campo and M. R. Torres, Chem.
Notes and references
1
(a) Y. Tao, Q. Wang, C. Yang, Q. Wang, Z. Zhang, T. Zou, J.
Qin and D. Ma, Angew. Chem. Int. Ed., 2008, 47, 8104; (b) J.
V. Grazulevicius, P. Strohriegl, J. Pielichowski and K.
Pielichowski, Prog. Polym. Sci., 2003, 28, 1297.
Commun., 2013, 49, 7779; (b)
B. Guo, X. Huang, C. Fu and
S. Ma, Chemistry – A European Journal, 2016, 22, 18343.
18 The structure of the dihydrocarbazole corresponding to 3a
has been confirmed by NMR (see the supplementary
information).
2
(a) T. A. Choi, R. Czerwonka, W. Fröhner, M. P. Krahl, K. R.
Reddy, S. G. Franzblau and H.-J. Knölker, ChemMedChem,
2006, 1, 812; (b) A. W. Schmidt, K. R. Reddy and H.-J.
Knölker, Chem. Rev., 2012, 112, 3193.
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins