Temporary (P=O) directing group enabled carbazoleorthoarylationviapalladium catalysis

Article abstract of DOI:10.1039/d0cc07596e

A palladium-catalyzed, temporary P(O) directing group assisted C-H bond arylation of carbazoles was achieved. The release of the directing group occurs spontaneously in the reaction and the mechanistic studies indicate that acid is essential for N-P bond cleavage.

Full text of DOI:10.1039/d0cc07596e

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Temporary (P O) directing group enabled
carbazole ortho arylation via palladium catalysis†
Cite this: Chem. Commun., 2021,
57, 2021
Zhi-Chao Qi,a Qin-Xin Lou,a Yuan Niua and Shang-Dong Yang
*
ab
Received 19th November 2020,
Accepted 15th January 2021
DOI: 10.1039/d0cc07596e
rsc.li/chemcomm
A palladium-catalyzed, temporary P(O) directing group assisted
R2(O)P has been widely used as the DG in various C–H bond
C–H bond arylation of carbazoles was achieved. The release of functionalization transformations.14 Among them, palladium-
the directing group occurs spontaneously in the reaction and the catalyzed, R2(O)P-directed sp2 C–H bond arylation has been
mechanistic studies indicate that acid is essential for N–P bond realized by Lee,15 Shi16 and our group.17 Given the importance
cleavage.
of substituted carbazoles in pharmaceuticals and optoelectronic
materials, functionalization of the carbazole scaffold in a highly
Carbazole is an important nitrogen heterocyclic scaffold which regioselective manner is appealing. As mentioned before, the DG
widely exists among numerous natural indole alkaloids and was introduced onto the nitrogen atom of the carbazoles, to guide
pharmaceuticals.1 At the same time, carbazoles usually exhibit
interesting properties when applied as optoelectronic materials2 and
conducting polymers.3 Therefore, the development of methodolo-
gies for the rapid synthesis of functionalized carbazoles has drawn
significant attention over the past few decades.4 Representative
methods include transition-metal-catalyzed C–C cross-coupling
reactions,5 reductive cyclization of nitroarene6 and diaryliodonium
salt-based cyclization processes7 (a, Scheme 1). Recently, directing
group (DG) enabled C–H bond functionalization has become one of
the most powerful tools in synthetic chemistry.8 To date, several DGs
have been successfully used to realize C–H bond functionalization at
the C1/C8 positions of carbazoles (b, Scheme 1). In 2013, by using
pyridine and pyrimidyl as DGs, Wu and Chu reported the first
example of Pd(II)-catalyzed direct ortho-arylation of carbazoles.9 After
that, Kambe and Nageswar independently reported carbazole chal-
cogenation and arylation under palladium catalysis;10 then Kambe
further demonstrated a study of copper(II)-mediated thiolation of
carbazoles.11 In addition, Pd-catalyzed ortho-olefination of carba-
zoles by employing a (2-pyridyl)sulfonyl directing group was
achieved by the Carretero group.12 It is worth noting that Jana
and coworkers demonstrated a selective C–H functionalization of
unprotected carbazoles via an Au(I)-catalyzed carbene transfer
reaction.13
a State Key Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou 730000, P. R. China. E-mail: yangshd@lzu.edu.cn
b State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute
of Chemical Physics, Chinese Academy of Sciences, Lanzhou, 730000, P. R. China
† Electronic supplementary information (ESI) available. CCDC 2014884. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
Scheme 1 Different strategies for the carbazole synthesis.
d0cc07596e
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the selective functionalization. In all cases, the DG remains (3i) methyl ester (3j) and ethyl ester (3k), were also tolerated
tethered on the product (permanent DG), and additional steps under the reaction conditions. Due to the steric repulsion,
are required in order to remove it. Herein, we report a Pd(II)- o-methylbenzene based diaryliodonium triflate salts failed to
catalyzed C–H bond ortho-arylation of carbazoles by employing produce any desired product. The investigation of using asymmetric
a diphenylphosphine oxide (PQO) group (c, Scheme 1). In MesArIOTf salts as substrates showed great selectivity, with only
this reaction, ortho-arylation of carbazoles and the removal of introducing an Ar group onto the carbazole (3a–3e). Finally, a gram-
the PQO DG occur simultaneously, which represents the first scale reaction of this transformation was carried out with the
temporary DG strategy in carbazole functionalization.
product yield (see the ESI† for details).
In the initial studies, we selected (9H-carbazo-9-yl) diphenyl-
Then we examined the scope of the substituted carbazole.
phosphine oxide (1) with di-p-tolyliodonium triflate (2a) as the Carbazoles bearing a methyl group at different positions
model substrate to screen the reaction conditions (see the ESI† for (Table 2, 5a–5c) underwent facile arylation and provided the
details). When Pd(OAc)2 was selected as the catalyst, the desired corresponding products in 50–68% yields, and no diarylation
product 3a was obtained in 62% yield (Table S1, ESI†), while other product was detected. Subsequently, carbazoles with the C7
metal catalysts failed to provide the desired product. The structure position substituted with tertbutyl (5d–5f), ester (5i), tri
of 3a was unambiguously confirmed by X-ray analysis. Encouraged (isopropyl)phenyl (5j), and cyclohexyl (5k) groups could also
by these results, we examined the effect of solvents, additives and deliver the monoarylated products in high to excellent yields
the loading of Pd(OAc)2. 3a was obtained in 72% yield when using (45–96%). C3 position substituted carbazoles were also suitable
Pd(OAc)2 (8 mol%), TfOH (20 mol%) and CuO (1.8 equiv.) in 1,4- substrates for this transformation with the desired product
dioxane (0.05 M) for 24 h (Tables S2–S5, ESI†). Finally, when the produced in moderate to excellent yield (5g–5h, 38–90%).
amount of 2a was increased to 1.7 equiv., the desired product 3a Furthermore, by using 1l as the starting material, hyellazole
was obtained in 83% yield.
analogue 5l could be obtained in 30% yield under the opti-
In order to test the universality of the reaction, the scope of mized reaction conditions. More complicated molecules with a
diaryliodonium triflate salts was first explored. As shown in carbazole skeleton could also be arylated under our conditions
Table 1, symmetric diaryliodonium triflate salts bearing an (5m, 5n). Also, the functionalization of 3a provided direct
t
electron-donating group such as Me, OMe, Ph and Bu were access to compound 5o in 86% yield, which could be used as
nicely tolerated in the reaction, the desired products were a potential material for organic light-emitting diodes.
obtained in moderate to excellent yields (3a–3e, 54–83%). Less
In order to understand the reaction mechanism, we carried
efficient results were obtained when electron-withdrawing out several control experiments. When N-free carbazole was
group substituted symmetric diaryliodonium salts were used as a substrate under the standard conditions, the reaction
applied; for example, F, Cl and Br substituted substrates were
successfully converted into the desired product in 31–56% yield
Table 2 Scope of carbazole – P sourcea
(3f–3h), and these functional groups provide the possibility for
subsequent chemical transformation of the product. Other
electron-withdrawing substitutions, such as trifluoromethyl
Table 1 Scope of hypervalent iodine for arylationa
a
a
Reaction conditions 1 (0.1 mmol), 2a–2m (0.17 mmol), Pd(OAc)2
Reaction conditions: 1a–1n (0.1 mmol), 2a (0.17 mmol), Pd(OAc)2
(8 mol%), TfOH (20 mol%), and CuO (1.8 mmol) in 2 mL of 1,4- (8 mol%), TfOH (20 mol%), and CuO (1.8 equiv.) in 2 mL of 1,4-dioxane
b
c
b
dioxane at 60 1C for 24 h. Using Ar2IOTf. Using MesArIOTf.
at 60 1C for 24 h. Using Ph2IOTf instead of 2a.
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Scheme 3 Proposed mechanism.
preformed to investigate the source of hydrogen in the N–P cleavage
step (Scheme 2d). When 20% mol HOTf and 5 equivalents D2O were
added in the reaction, 3a was obtained in 45% yield with 64% N–D
ratio observed. If DOTf was used instead of HOTf, a minimal change
in the N–D ratio was detected. Moreover, Ph2P(O)OCD3 was also
obtained in 20% yield when 5 equivalents of CD3OD was added in
the reaction. These results demonstrated that in our transformation,
H2O is the hydrogen source to form the N–H bond, and it is also
responsible for the generation of HOP(O)Ph2.
On the basis of above results and reports in the literature, a
possible mechanism is presented in Scheme 3. PQO DG
enables the ortho-C–H bond activation to form the six-
membered Pd(II) intermediate A. Subsequent oxidative addition
of the Pd(II) complex with 2a produces the intermediate B, and
Int-8 is generated by reductive elimination of B. Then, Int-8
immediately reacts with TfOH to form the unstable ionic
intermediate 9. Finally, with the assistance of the H2O in the
system, 9 goes through N–P bond clevage to form products 3a
as well as HOP(O)Ph2 (10).18
Scheme 2 Investigation of the reaction mechanism.
failed to provide any product (Scheme 2a). This result indicated
that P(O)Ph2 as a DG is required for the C–H bond arylation
process. Int-8 could also serve as the intermediate in the
reaction; however, we were unable to isolate the Int-8 in the
reaction system. By using Int-8 (see the ESI† for its synthesis) as
a starting material, the N–P cleavage didn’t occur under the standard
reaction conditions, but 3a was obtained when di(p-methyl-
phenyl)iodonium triflate salt was added (Scheme 2b). These results
demonstrated that the C–C formation and N–P cleavage occur
simultaneously in the reaction. In order to explore the mechanism
for N–P bond cleavage, we selected Int-8 as the starting material and
more control experiments (Scheme 2c) were preformed. When only
20 mol% TfOH was used as a catalyst, product 3a was obtained in
89% yield, indicating that a catalytic amount of acid could promote
the N–P bond cleavage (Scheme 2c, 3). However, the yield of 3a
decreased dramatically when Pd(OAc)2 or CuO was added
(Scheme 2c, 1–2). When increasing the loading of TfOH or using
Cu(OTf)2 instead of CuO, the yield of 3a was increased to 48 and
78%, respectively. (Scheme 2c, 4–5). Cu(OTf)2 alone was unable to
promote the N–P bond cleavage (Scheme 2c, 6). By combining all of
In conclusion, we have shown the first example of a temporary
PQO DG enabled C–H arylation process, with a wide range of
1-phenyl-9H-carbazoles obtained under the reaction. The mecha-
nistic studies indicated that the release of the directing group
occurred spontaneously in the reaction and the acid played a key
role in this step.
We are grateful to the NSFC (No. 21532001) for financial
support.
the above results, we think that the acidity of the reaction system has Conflicts of interest
a significant influence on the N–P cleavage step. To further under-
stand the catalytic cycle, a mass spectrometry experiment was
There are no conflicts to declare.
conducted to question the reaction intermediates (details see the
ESI†). A signal peak in the ESI/MS at m/z 458.1656 was detected,
Notes and references
which corresponds to [M8 + H]+. Another signal peak at m/z 548.2150
is related to diarylated product 11, which might result from the
reaction of 2a with int-8. A signal peak in the three parallel ESI/MS at
m/z 219.0575 was detected, which indicates that HOP(O)Ph2 was
generated in the system. The results described above provide
evidence that int-8 was involved in this transformation. Finally,
deuterium experiments by using the int-8 as a substrate were
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