Palladium-Catalyzed Regioselective Synthesis of 1-Hydroxycarbazoles Under Aerobic Conditions

Article abstract of DOI:10.1002/adsc.201801265

A palladium-catalyzed aerobic C?H amidation of N-Ts-2-amino-3′-hydroxylbiaryls has been developed to afford a diverse range of 1-hydroxycarbazoles with high regioselectivity and efficiency. This protocol benefits from operational simplicity, robustness, a

Full text of DOI:10.1002/adsc.201801265

Title: Palladium-Catalyzed Regioselective Synthesis of 1-
Hydroxycarbazoles Under Aerobic Conditions
Authors: So Won Youn, Young Ho Kim, and Yoon Hyung Jo
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10.1002/adsc.201801265
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Palladium-Catalyzed Regioselective Synthesis of 1-
Hydroxycarbazoles Under Aerobic Conditions
So Won Youn,a,* Young Ho Kim,a and Yoon Hyung Joa
a
Center for New Directions in Organic Synthesis, Department of Chemistry and Research Institute for Natural Sciences,
Hanyang University, Seoul 04763, Korea
Fax: (+82)-2-2298-0319; e-mail: sowony73@hanyang.ac.kr
Dedicated to Professor Yong Hae Kim on the occasion of his 80th birthday
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
One of the more common and straightforward
synthetic strategies for carbazole synthesis is
construction of the pyrrole nucleus through metal-
mediated C-C and/or C-N bond formation starting
from aniline derivatives bearing appropriate
functionality. In general, 1-oxygenated carbazoles
(e.g., 1-methoxycarbazoles) have been formed by 1)
oxidative cyclization of N-aryl-2-methoxyanilines
through a C–C bond formation (path a, Scheme 1a)[4];
2) oxidative C-H amin(d)ation of 2-amino-3-
methoxybiaryls through C–N bond formation (path
b)[5]; or 3) one-pot sequential Pd-catalyzed
Buchwald−Hartwig amination and cyclization of 2-
methoxyanilines with halogenated arenes through
simultaneous C–N and C–C bond formation (path
c).[6]
Abstract. A palladium-catalyzed aerobic C−H amidation
of N-Ts-2-amino-3'-hydroxylbiaryls has been developed
to afford a diverse range of 1-hydroxycarbazoles with
high regioselectivity and efficiency. This protocol
benefits from operational simplicity, robustness, and
sustainability with the use of ambient air as the sole
terminal oxidant. Further elaboration of the products
obtained from this process provides facile access to
various carbazole alkaloids including carbazolequinones
and biscarbazoles. A mechanism involving dual directing
group-assisted regioselective C–H activation at the more
sterically hindered C2'-position of 2-amino-3'-
hydroxylbiaryls is proposed.
Keywords: carbazoles; C-H activation; palladium
catalysis; regioselectivity
1-Oxygenated carbazoles[1] and carbazolequinones[2]
are ubiquitous structural motifs found in a wide range
of natural products, and they are known to exhibit
various biological activities (Figure 1).[3] Thus,
efficient and regioselective synthesis of, in particular,
1-oxygenated carbazoles is highly desirable.
Scheme 1. Synthesis of 1-oxygenated carbazoles.
All of these methods require 2-methoxyaniline
derivatives as a starting material, which are generally
prepared in tedious and often lengthy sequences of
steps from commercially available reagents. Due to
limited availability of diversely substituted 2-
Figure 1. Naturally occurring bioactive 1-oxygenated
carbazoles and carbazolequinones.
1
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10.1002/adsc.201801265
Advanced Synthesis & Catalysis
methoxyanilines, alternative protocols such as
oxidative C−H amin(d)ation of 2-amino-3'-
methoxybiaryls, which can be readily prepared from
2-bromoanilines and 3-methoxyphenylboronic acids
or 3-bromoanisoles, would be a new, complementary
and more efficient route to this scaffold through an
alternative C–N bond formation (Scheme 1b).
However, it is well precedented in the literature that
3-methoxycarbazoles are generally obtained as the
sole or major product through C-H activation at the
less sterically hindered C6'-position rather than the
C2'-position (Scheme 1b).[7-9] Thus, regioselective
synthesis of 1-oxygenated carbazoles from this type
of C3'-substituted substrate remains an unresolved
challenge. In view of their prevalence in bioactive
molecules[1] and their utility for further
carbazoles (Scheme 1c), which are not the
regioisomers preferentially obtained by oxidative
C−H amin(d)ation of the corresponding C3'-
substituted 2-aminobiaryls.
Table 1. Optimization studies.
Entry
2a
3a
Pd cat.
[mol%]
20
Ligand
[mol%]
-
NaOAc
[equiv]
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1
Oxone
T
[%][a] [%][a]
[equiv] [ºC]
transformation into carbazolequinones, biscarbazoles,
10-12]
and other alkaloids,[3,
development of such a
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
-
80
(44)
10
9
2
20
L1 (20)
L2 (20)
L3 (20)
L4 (20)
L5 (20)
L6 (20)
L7 (20)
L8 (20)
L9 (20)
L4 (10)
L4 (10)
L4 (10)
L4 (10)
L4 (10)
-
80
10
synthetic method is of great importance to provide
straightforward access to a diverse range of 1-
oxygenated carbazoles.
3
20
80
37
11
4
20
80
0
60
5
20
80
(70)
12
(11)
7
Inspired by the seminal work of Miura and Rawal
on hydroxyl-directed C-H functionalization under Pd
catalysis,[13-14] we have devised a strategy to
synthesize 1-hydroxycarbazoles via oxidative C-H
amidation of 2-amino-3'-hydroxylbiaryls taking
advantage of the free hydroxyl moiety as a potential
secondary directing group[15] for regiocontrolled C-H
activation (Scheme 1c). Instead of installation of O-
containing directing groups such as esters,
carbamates, or ethers, use of the free hydroxyl moiety
as a directing group would be more straightforward
and atom-/step-economical. Therefore, realization of
our proposed method would provide an attractive and
potentially powerful route for the expedient synthesis
of a wide range of 1-oxygenated carbazoles via a C-N
bond forming cyclization. However, the direct and
regioselective oxidative C-H amidation of free phenol
derivatives constitutes a challenge for several
reasons: 1) In addition to aforementioned
6
20
80
7
20
80
7
5
8
20
80
(40)
19
(41)
0
9
20
80
10
11
12
13
14[b]
15
16
17
18[b]
19[c]
20[c]
20
80
6
8
10
80
30
7
10
100
80
(68)
(66)
(75)
0
(18)
(19)
(22)
0
10
10
1
100
100
100
100
100
100
100
100
-
1
10
1
(24)
(30)
(74)
(18)
(10)
(77)
(8)
(13)
(18)
(7)
trace
(15)
10
L4 (10)
L4 (10)
L4 (10)
L4 (10)
L4 (10)
-
10
1
10
1
1
-
10
1
21[b,d]
[a]
10
1
-
Yields were determined by 1H NMR using
trichloroethylene as an internal standard. Values in
[b]
[c]
issues,[7-9]
in
general,
parentheses indicate isolated yields. For 12 h. Under
regiochemistry
argon atmosphere. [d] Under O2 (1 atm).
functionalization of phenols preferentially provides
the p-isomer or inseparable mixtures with low
selectivity. 2) Strong oxidants such as PhI(OAc)2
often employed in oxidative C−H amin(d)ation[16]
could affect the compatibility of free phenols, which
are well-known to be sensitive toward oxidative
decomposition.[17] 3) While significant progress has
been made in transition-metal-catalyzed C-H
functionalization of free phenols using a phenoxy
group as a directing group,[18-19] all precedented
methods lead to the formation of C-C and/or C-O
bonds, and synthetic methods for new C-N bond
formation via regioselective C-H amin(d)ation have
yet to be realized.[20]
Herein we report a Pd-catalyzed aerobic C−H
amidation for the synthesis of 1-hydroxycarbazoles
with high efficiency and regioselectivity. This
process involves a C–H activation at the more
sterically hindered C2'-position of N-Ts-2-amino-3'-
hydroxylbiaryls with the aid of a dual directing
group,[21] leading to formation of 1-oxygenated
In light of our recent success in the synthesis of
carbazoles using N-Ts-2-aminobiaryl derivatives,[7e]
we initially attempted the proposed reaction using 1a
as the test substrate under our previously reported
conditions (5 mol% Pd(OAc)2, Oxone, pTsOH in
PivOH/DMF at 25 ºC). Both the desired product 2a
and the regioisomer 3a were obtained in low yields
and selectivity (2a: 15%, 3a: 18%).[21] After
scrupulous examination of the reaction parameters,
we discovered that both yields and selectivity could
be improved when mesitylene and NaOAc were used
as the solvent and additive, respectively (Table 1,
entry 1). Considering several reports on the positive
effect of nitrogen ligands in various Pd-catalyzed
aerobic oxidation reactions,[22] we next extended our
investigation to a variety of nitrogen ligands (entries
2-10).[21] Much to our delight, bathocuproine (L4)
was identified as an effective ligand resulting in
further improvements of both reactivity and
2
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10.1002/adsc.201801265
Advanced Synthesis & Catalysis
regioselectivity (2a: 70%, 3a: 11%, entry 5). Further
optimization of the reaction conditions secured a
good yield of 2a with lower catalyst loading at higher
temperature after a shorter reaction time (entries 11-
14; entries 5 vs 14).
good to high yields. Heteroaromatic motifs such as
pyridine could also be incorporated to afford 8-
hydroxy-α-carboline 2y, a key motif present in
various bioactive molecules.[24] N,N'-Bistosyl-2,2"-
diamino-5'-hydroxy-[1,1';3',1"]terphen-
Control experiments showed that all reaction
parameters (Pd(OAc)2 catalyst, L4 ligand, NaOAc
additive, air oxidant) except Oxone as an oxidant
were indispensable for this transformation (entries
15-20), while a comparable yield of 2a was obtained
in the absence of Oxone (entries 14 vs 18). In
addition, reaction of 1a under an argon atmosphere
irrespective of the presence of Oxone resulted in a
drastically decreased conversion (entries 19-20),
while reaction under O2 (1 atm) had only a marginal
effect (entry 21). These results suggested that
ambient air was the sole effective oxidant in this
transformation.[23]
Table 2. Reaction of various arenediazonium salts and
styrenes.[a]
Very intriguingly, as proposed, C-H activation and
cyclization occurred predominantly at the more
sterically encumbered C2'-position between the two
possible sites to afford 1-hydroxycarbazole 2a as the
major isomer along with a small amount of 3-
hydroxycarbazole
3a.
This
uncommon
regioselectivity could be attributed to the presence of
the hydroxyl group at the C3'-position of 1a, which
acts as a secondary directing group, leading to C-N
bond formation at the more congested C2'-position
between the two substituents.[21] The influence of the
hydroxyl group could be ascertained by the fact that
cyclization of O-Me-1a took place exclusively at the
less sterically hindered C6'-position to afford the
corresponding 3-methoxycarbazole (O-Me-3a) in
83% yield under the optimized reaction conditions
(Scheme 2a). Furthermore, to showcase the
effectiveness of free hydroxyl group, other potential
secondary directing groups (e.g., -NHTs, -NHAc, -
O(2-Py), -OSi(OH)tBu2) have been examined under
the optimized reaction conditions.[21] However, all
reactions formed the corresponding 3-substituted
carbazoles as the sole or major product through C-H
activation at the less sterically hindered C6'-position,
clearly indicating the superiority of free hydroxyl
group as a secondary directing group.
[a]
Reaction conditions: 1 (1 equiv), Pd(OAc)2 (10 mol%),
L4 (10 mol%), and NaOAc (1 equiv) in mesitylene (0.1 M)
at 100 °C under aerobic conditions. Isolated yields are
provided. Other regioisomers (e.g., 3a) were obtained in 0-
25% yields. [b] In mesitylene and 1,2-dichlorobenzene (1:2,
Notably, subjecting 1a to the previously reported
C-H amin(d)ation protocols for carbazole synthesis[5,
0.1 M). [c] Debrominated product 2a was obtained in 9%
7, 9]
resulted in decomposition or very low conversion
[d]
favoring 3a,[21] demonstrating the remarkable
regiochemical selectivity of the method presented
herein. To the best of our knowledge, this represents
the first example in which a phenoxy group was used
as a directing group for a Pd-catalyzed oxidative C-N
bond formation at the more sterically hindered
position, favoring formation of the less common 1-
hydroxycarbazole.
yield.
were added.
After 12 h, another 10 mol% Pd(OAc)2 and L4
Having determined the optimized conditions as
entry 15 in Table 1, we set out to explore the scope of
this process (Table 2). A variety of substituents on
both aromatic rings of substrate 1 were well tolerated
irrespective of their positions and electronic
properties, leading to the formation of 1-
hydroxycarbazoles 2 as a single or major product in
3
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10.1002/adsc.201801265
Advanced Synthesis & Catalysis
Finally, the compatibility of this method with the
previous C-H etherification[17b-c, 19f] was examined. 1t
was selectively converted to 1- and 3-hydroxy-2-
phenylcarbazole 2t/3t in 77% overall yield with no
formation of dibenzofurans (Scheme 2d). This result
indicates that the hydroxyl group itself is not a
sufficient primary directing group to promote C-O
bond formation favorably over C-N bond formation,
and thus the present method is complementary to
prior methods for dibenzofuran synthesis from 2-
arylphenols.
To highlight the synthetic utility of this reaction,
some reactions were carried out on a larger scale (up
to 2 mmol). Compared to reactions generally
performed at the 0.1-0.2 mmol scale, to our delight,
comparable or only marginally decreased yields were
obtained.[21] Moreover, further derivatization of the 1-
hydroxycarbazoles obtained from this process has
been undertaken. As illustrated in Scheme 3a,
deprotection of the N-Ts group and methylation of
the hydroxyl group proceeded smoothly to give
various 1-hydroxy and 1-methoxy NH-free
carbazoles 4 including naturally occurring clausine E
(4c), clausenol (4d), murrayafoline A (4f), and
mukonine (4g). Given an intact bromo substituent in
2q as well as easy deprotection and methylation, we
envisioned the coupling reaction of O-methylated 2q
(O-Me-2q) with murrayafoline A (4f) for swift access
to murrastifoline B (5b). In the literature, there is
only one known example of the synthetic route to 5b
based on the path a strategy in Scheme 1, C-C bond
formation using a superstoichiometric amount of
Pd(OAc)2 to construct the lower carbazole ring and a
two-fold Buchwald–Hartwig coupling for the upper
carbazole ring.[4a] Gratifyingly, rapid synthesis of the
target molecule 5b was successfully achieved through
Ullmann-type coupling followed by removal of the
N-Ts group (Scheme 3b). In addition, oxidation and
oxidative dimerization were readily accomplished to
afford the natural and non-natural carbazolequinones
6a-b, biscarbazoles 6c-d, and biscarbazolequinone 6e
in good yields (Scheme 3c).[10-11]
Scheme 2.
yl 1z provided predominantly a mono cyclized
product 2z' in 52% yield along with the fused
pentacyclic indolo[2,3-b]carbazol-6-ol 2z in 14%
yield. Resubjecting 2z' to the standard reaction
conditions still gave only 20% yield of 2z together
with mostly recovered 2z'; however, particularly
noteworthy is the regioselective formation of both C-
N bonds at two ortho positions to a hydroxyl group
leading to only 2z without detectable formation of the
other regioisomer.
Mild reaction conditions and the use of air as the
sole sustainable oxidant in the absence of additional
strong oxidant ensure the hydroxyl group remains
intact as well as good functional-group tolerance.
Notably, exclusive or predominant formation of 2u
and 2v from C2'-chlorinated and brominated
substrates 1u and 1v, respectively, demonstrates this
new protocol is complementary to the Pd-catalyzed
Buchwald−Hartwig amination/cyclization, and the
remaining halide would be a useful handle for further
transformations (Scheme 2b).
Although an ester moiety at the C5'-position of 1r
is a potential secondary directing group, 2r was
obtained as the sole product, showing a non-directing
effect of the ester moiety of 1r in this reaction. As the
aforementioned outcome of O-Me-1a, when there are
both methoxy and hydroxyl substituents at the two
meta positions as in substrate 1n, C-H
functionalization took place selectively at the position
ortho to the hydroxyl and para to the methoxy group,
providing 2n as the only product (Scheme 2a).
Furthermore, in the case of substrate 1aa, C-N bond
formation occurred predominantly at the hydroxyl-
substituted benzene ring (2aa/3aa) rather than the
non-substituted benzene ring (2aa'), although the
regioselectivity for 2aa and 3aa decreased probably
due to steric hindrance (i.e., proximal 3 substituents,
Ts, OH, and Ph in 2aa) (Scheme 2c). All of these
findings suggest that a free hydroxyl group at the C3'-
position of 1 as a secondary directing group plays a
crucial role in the high reactivity and regioselectivity
for 2.
4
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10.1002/adsc.201801265
Advanced Synthesis & Catalysis
2012M3A7B4049644, 2014-011165, 2015R1A2A2A01002559,
and 2018R1A2A2A05018392).
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Scheme 3. Synthetic application.
In summary, we have developed a new Pd-
catalyzed aerobic intramolecular C−H amidation of
N-Ts-2-amino-3'-hydroxylbiaryls.
We
have
demonstrated that a dual directing group strategy
allows for regioselective functionalization of the
sterically more encumbered C–H bond, leading to the
facile formation of 1-hydroxycarbazoles. The
synthetic utility of this method in the synthesis of
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various
carbazole
alkaloids
including
carbazolequinones and biscarbazoles was also
demonstrated. The salient features of this protocol are
broad substrate scope, good functional group
tolerance, high and uncommon regioselectivity, high
sustainability and practicality using ambient air as a
green and safe oxidant under mild conditions.
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Experimental Section
General Procedure for the Pd-Catalyzed Regioselective
Synthesis of 1-Hydroxy-carbazoles 2. Substrate
1
(0.1~0.2 mmol, 1 equiv), Pd(OAc)2 (0.01~0.02 mmol, 10
mol%), bathocuproine (0.01~0.02 mmol, 10 mol%), and
NaOAc (0.1~0.2 mmol, 1 equiv) were dissolved in
mesitylene (1~2 mL, 0.1 M). The resulting mixture was
stirred at 100 °C in an oil bath under aerobic conditions (in
a closed vial with a screw cap). After the reaction was
completed, the reaction mixture was concentrated in vacuo.
The residue was purified by column chromatography on
silica gel to give the corresponding 1-hydroxycarbazole
product 2. Other regioisomers (e.g., 3a) were separable
from 2 and obtained in 0-25% yields. All reactions were
carried out 3-5 times repetitively and the average values of
chemical yields are given.
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Acknowledgements
This work was supported by both Basic Science Research
Program and Nano∙Material Technology Department Program
through the National Research Foundation of Korea (NRF)
funded
by
the
Korea
government
(MSIP)
(Nos.
5
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10.1002/adsc.201801265
Advanced Synthesis & Catalysis
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Advanced Synthesis & Catalysis
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COMMUNICATION
Palladium-Catalyzed Regioselective Synthesis of
1-Hydroxycarbazoles Under Aerobic Conditions
Adv. Synth. Catal. Year, Volume, Page – Page
So Won Youn,* Young Ho Kim, and Yoon Hyung
Jo
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