Palladium-Catalyzed C-H Bond Activation by Using Iminoquinone as a Directing Group and an Internal Oxidant or a Co-oxidant: Production of Dihydrophenanthridines, Phenanthridines, and Carbazoles

Article abstract of DOI:10.1021/acs.orglett.7b01956

A palladium-catalyzed C-H bond activation reaction, via a redox-neutral pathway, for the preparation of dihydrophenanthridine, phenanthridine, and carbazole derivatives from biaryl 2-iminoquinones is developed. The preinstalled iminoquinone was designed to act as a directing group for ortho C-H activation and an internal oxidant or a co-oxidant. This catalysis proceeded through the following sequence: C-H bond activation, coordination and insertion of activated olefins, β-hydride elimination, H-shift, insertion, and protonation or β-hydride elimination. In addition, carbazoles can be prepared efficiently by using this method without the addition of external oxidants.

Full text of DOI:10.1021/acs.orglett.7b01956

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed C−H Bond Activation by Using Iminoquinone as
a Directing Group and an Internal Oxidant or a Co-oxidant:
Production of Dihydrophenanthridines, Phenanthridines, and
Carbazoles
†
†
‡
§
,†
Selvam Raju, Pratheepkumar Annamalai, Pei-Ling Chen, Yi-Hung Liu, and Shih-Ching Chuang*
†Department of Applied Chemistry, National Chiao Tung University, Hsinchu 30010, Taiwan
‡Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan
§Instrumentation Center, National Taiwan University, Taipei 30010, Taiwan
*
S Supporting Information
ABSTRACT: A palladium-catalyzed C−H bond activation reaction, via
a redox-neutral pathway, for the preparation of dihydrophenanthridine,
phenanthridine, and carbazole derivatives from biaryl 2-iminoquinones is
developed. The preinstalled iminoquinone was designed to act as a
directing group for ortho C−H activation and an internal oxidant or a co-
oxidant. This catalysis proceeded through the following sequence: C−H
bond activation, coordination and insertion of activated olefins, β-hydride
elimination, H-shift, insertion, and protonation or β-hydride elimination. In addition, carbazoles can be prepared efficiently by
using this method without the addition of external oxidants.
henanthridine is a versatile scaffold and a critical building
Scheme 1. Previous Work and Our Findings
P
block for crucial heteroaromatic compounds. It is present
in various naturally occurring compounds such as phenan-
1
2
thridine alkaloids, fluorescent chromophores, biologically
3
4
active substances, and organic materials. In the past decades,
C−H bond functionalization reactions catalyzed by transition
metals have become atom-economic and eco-friendly reactions
and provide a new and useful approach in synthetic organic
chemistry for applications in the syntheses of bioactive5
heterocyclic compounds and material molecular structures.
Such reactions differ from conventional methods, which use
halogenated species as reactants. Phenanthridines and
carbazoles can be synthesized from common starting materials,
6
2
-arylanilines, through C−H bond activation. Miura reported
7
the first synthesis of dihydrophenanthridines (Scheme 1a)
from the reaction of N-tosyl-2-arylanilines with activated olefins
under palladium catalysis, and Youn and co-workers followed
8
this method. Li and co-workers reported a one-pot preparation
of phenanthridines via oxidative C−C bond cleavage cyclization9
of biaryl-2-amines with olefins using palladium as the catalyst.
Furthermore, phenanthridines were synthesized efficiently from
1
6
actinomycin antibiotics. Recently, poloxin-2, an ester carrying
the iminoquinone moiety, was found to induce mitotic arrest
and apoptosis in cultured human tumor cells in a study
elucidating the function of the Polo-like kinase 1 polo-box
10
2-isocyanobiaryls with appropriate oxidants as initiators. We
achieved palladium-catalyzed C2′−H activation of N-substi-
1
7
domain in living cells. Notably, N-acetyl p-benzoquinone
tuted 2-aminobiaryls followed by the insertion of [60]-
1
1
12
13
imine is a cytochrome P-450-mediated oxidation product of
fullerene, CO, and diphenylacetylene to yield full-
18
acetaminophen.
erobenzoazepines, phenanthridinones, and highly substituted
14
15
Metal-catalyzed redox-neutral C−H bond activation has
attracted the interest of scientists because no exotic oxidants are
naphthalenes, respectively. Gaunt and Miura developed a
method for synthesizing carbazoles from N-substituted 2-
aminobiphenyls through Pd(II)- and copper(II)-catalyzed
intramolecular coupling, respectively (Scheme 1b). Iminoqui-
none is a vital functionality in antineoplastic drugs and
Received: June 26, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01956
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
required to perform these reactions. Generally, these reactions
involve the cleavage of N−N or N−O bonds, and the cleaved
residue is released as a byproduct. These redox-neutral
reactions are found in ruthenium-, cobalt-, and rhodium-
Scheme 2. Substrate Scope Study
19
catalyzed C−H bond functionalization. Benzoquinone has
been frequently used as an oxidant in C−H functionalization,
20
but it is not tolerated in all metal-catalysis reactions. Here, we
propose using a new iminoquinone as a directing group,
through a combination of biaryl-2-amines and substituted p-
benzoquinones, and demonstrate that the substrates that are
provided with an iminoquinone moiety undergo imine group-
directed C−H bond activation with iminoquinone as an
internal oxidant or co-oxidant (Scheme 1c). This typical
reaction rendered the syntheses of dihydrophenanthridine,
phenanthridin-6(5H)-ylidenes, and carbazoles efficient.
First, we studied the reaction of iminoquinone 2a with
methyl acrylate (3a) in the presence of Pd(OAc) (10 mol %)
2
in 1 mL of t-AmOH with 0.5 mL of acetic acid as a cosolvent at
1
20 °C for 24 h. It produced dihydrophenanthridine 4a and
carbazole 7a in 61% with a molar ratio of 91:9 (Table 1, entry
a
Table 1. Optimization of Reaction Conditions
a
All reactions were carried out with 2 (0.1 mmol), 3 (0.3 mmol), and
Pd(OAc) (10 mol %) in 2 mL of PivOH under N at 120 °C for 24 h.
2
2
b
With 2 equiv of (vinylsulfonyl)benzene at 120 °C.
e
entry
solvent (mL)
cosolvent (mL)
4a/7a
yield (%)
acrylates without external oxidants under palladium catalysis
proceeded smoothly, affording their corresponding cyclization
products 4a−f in good to excellent yields (78%−94%), whereas
the reaction with phenyl acrylate produced product 4g in
moderate yield 66%. Besides acrylates, alkenyl substrates, such
as N,N-dimethyl acrylamide, (vinylsulfonyl)benzene and diethyl
vinyl phosphonates, also reacted with iminoquinones to give
cyclized products in moderate to good yields 64−88% (4h−j).
Furthermore, the reactions using other substituted iminoqui-
1
2
3
4
5
t-AmOH (1)
HFIP (1)
AcOH (0.5)
AcOH (0.5)
AcOH (0.5)
PivOH (0.5)
PivOH (1.0)
PivOH (1.0)
PivOH (1.0)
PivOH (1.0)
PivOH (2.0)
91:9
61
63
87:13
f
TFE (1)
ND
t-AmOH (1)
t-AmOH (1)
t-AmOH (1)
t-AmOH (1)
t-AmOH (1)
100:0
100:0
100:0
100:0
100:0
100:0
63
87
71
88
82
94
b
6
c
7
d
8
3
9
nones, such as R = 2,6-dimethyl and 2-tert-butyl, with methyl
f
10
t-AmOH (2)
ND
acrylate (3a) afforded their corresponding desired products 4k,l
a
1
All of the reactions were performed with 2a (25.9 mg, 0.1 mmol), 3a
25.8 mg, 0.3 mmol), and 10 mol % of Pd(OAc) as a catalyst under
N at 120 °C for 24 h unless otherwise stated. 100 °C. 110 °C. 130
in 84−85% yields. Last, the interplay of the electronic effect (R
2
(
and R ) on both the aryl rings also provided acceptable yields.
We noticed that the electronic effect from the top ring R did
2
b
c
d
1
2
e
1
°
C. Yields were measured using H NMR spectroscopy with
f
not exert much impact on the reaction yields (4m and 4n, 80%
mesitylene as an internal standard. ND = not detected.
2
and 77%, respectively), but that from the bottom ring R did
influence yields drastically (4o and 4p, 63% and 92%,
respectively). In short, dihydrophenanthridine can be efficiently
synthesized in a redox-neutral system with iminoquinone as a
directing group and an internal oxidant under palladium
catalysis.
1
). This reaction was examined with different alcoholic solvents
such as hexafluoroisopropanol (HFIP) and 2,2,2-trifluoroetha-
nol (TFE), but it only produced 63% of 4a and 7a in HFIP/
AcOH and gave no products in TFE/AcOH, respectively
(
entries 2 and 3). However, we found it more effective with use
We further evaluated other conditions for preparation of
phenanthridin-6(5H)-ylidenes (see the Table S1 in the
Supporting Information) and substrate scope with a variety of
substituted iminoquinone 2-aminobiaryls (2a−w) and activated
alkenes (3a−k), as shown in Scheme 3. As expected, a series of
of pivalic acid as a cosolvent. The reaction generated up to 87%
yield of product 4a with excellent selectivity; no carbazole was
observed under these conditions (entries 4 and 5).
Furthermore, we surveyed the reaction at temperatures of
n
100, 110, and 130 °C and noted that the reaction yield and
acrylates, such as Me, Et, Bu, cyclohexyl, and benzyl acrylates,
product selectivity did not change much, providing 71%, 88%,
and 82% yields, respectively (entries 6−8). To our delight, a
remarkable increase of reaction yield to 94% was observed
when pivalic acid was used as a sole solvent (entry 9). However,
a control experiment with t-AmOH as a sole solvent did not
produce 4a and 7a (entry 10).
The scope of the cyclization reaction was examined with
various iminoquinones (2a−w) and olefins (3a−j), as shown in
Scheme 2. The reactions of iminoquinone 2a with alkyl
were compatible with this protocol and produced good yields
of phenanthridin-6(5H)-ylidenes (5a−e) at 72%−83%. How-
ever, unexpectedly, reactions with (vinylsulfonyl)benzene (3i)
and acrylonitrile (3k) produced 5f−g in only moderate yields,
51% and 40%, respectively. Furthermore, reactions of
3
substituted iminoquinones, R = 2,6-dimethyl (2b), 2-methyl
(2c), and 2-tert-butyl (2d) with methyl acrylate afforded the
phenanthridin-6(5H)-ylidenes 5h−j in 56−92% yields. We
found that the substrate 2 with an electron-donating (methyl)
B
DOI: 10.1021/acs.orglett.7b01956
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Substrate Scope Study
iminoquinone as a directing group and an internal oxidant.
With Cu(OAc) /O as oxidants, however, compound 5a can be
2
2
produced in 36% yield accompanied by 29% of iminoquinone
Scheme S1c). Furthermore, with only oxygen as the oxidant, it
(
produced 5a in only 28% yield (Scheme S1d). Furthermore, we
observed that Cu(OAc) can oxidize 6 to produce iminoqui-
2
none 2a in 86% yield (Scheme S1e). Based on the results of the
above-mentioned experiments, we concluded that Cu(OAc) is
2
a key oxidant for converting 6 to iminoquinone 2a, whereas the
N-4-hydroxylphenyl functionality poorly directed C−H activa-
tion.
The mechanism of the iminoquinone-directed ortho C−H
activation was investigated through deuterium-labeling experi-
ments (Scheme S2). A kinetic isotope effect study revealed kH/
kD values of 3.0 and 1.26 for formation of 4a and 5a in a 10 min
reaction, indicating primary and secondary kinetic isotopic
effects, respectively. The reaction is initiated by an
iminoquinone-directed ortho C−H bond activation with
palladium(II), which gives rise to the ortho-metalated complex
I (Scheme 4). Palladacycle intermediate I undergoes insertion
Scheme 4. Proposed Catalytic Cycle
a
All reactions were carried out with 2a (0.1 mmol), 3 (0.3 mmol),
Pd(OAc) (10 mol %), and Cu(OAc) (0.5 equiv) in 1 mL of TFE at
2
2
b
1
20 °C for 24 h. 2 equiv of (vinylsulfonyl)benzene at 70 °C.
or -withdrawing group (trifluoromethoxy, fluoro, and chloro)
on the upper aryl ring reacted smoothly to deliver the
corresponding phenanthridin-6(5H)-ylidenes 5k−o in good
yields (80−94%). However, substrates bearing electron-
donating groups, such as methyl and methoxy groups, on the
bottom aryl ring afforded their corresponding product 5p at
and protonation to give carbazoles 7a through intermediate
VII. When palladacycle intermediate I reacts with activated
olefins, it undergoes insertion to form an eight-membered
palladacycle III. Subsequently, β-hydride elimination occurs
and results in an ortho-alkenylated hydride complex IV. The
putative palladium hydride complex undergoes an internal
hydride shift, reducing the iminoquinone moiety to furnish
complex V. Migratory insertion, a Michael-type nucleophilic
addition, then occurs, causing the formation of an intermediate
VI. Until this step, the valence charge of palladium is
considered to be +2. Further, the intermediate VI was
protonated by acidic solvent to give compound 4a. Thus,
compounds 4a and 7a were formed through a redox-neutral
pathway, and Pd(II) was regenerated to be involved in the next
cycle. In the absence of acidic solvent, intermediate VI went
through β-hydride elimination and removal of AcOH. It
produced phenanthridin-6(5H)-ylidenes (5a) and generated
5
8%, accompanied by a transesterification product 5p′ at 24%
as well as 5q at 60%. Substrates with electron-withdrawing
groups such as chloro and difluoro moieties afforded the
desired products (5r,s) in slightly low chemical yields (53%−
7
4%). Surprisingly, electronic effects between the aromatic
rings of 2-aminobiaryls (2) afforded the desired products (5t−
w) in moderate to good yields (58−92%) and with trans-
esterification products as minor products (5t′ and 5u′). Only
trace amounts of the trans-esterification products 5a′, 5k′, 5l′,
5
r′, and 5v′ were observed in other cases. Finally, a substrate
with the thienyl group produced 5x in a 66% yield. Thus, the
present redox-neutral reaction with Cu(OAc) as a co-oxidant
2
provided an efficient approach to accessing phenanthridin-
6
(5H)-ylidenes under the optimal reaction conditions with a
broad range of substrates.
In the control experiments, the reduced substrate 6
underwent this developed palladium-catalyzed reaction with
methyl acrylates to produce only trace amounts of 4a under the
optimized conditions (Scheme S1a). Similarly, compound 5a
was produced in only trace amounts from substrate 6 under the
standard condition (Scheme S1b). These two experiments
indicated that the reactions barely proceeded without
21
Pd(0). Finally, Pd(0) was oxidized to Pd(II) by Cu(II), which
furnished the catalytic cycle.
We found that the iminoquinone 2 can be transformed to the
N-4-hydroxyphenyl carbazoles 7a−e with 82−95% yields on
treatment with 10 mol % of Pd(OAc) in TFE at 120 °C. This
2
carbazole formation was tolerated with both electron-donating
C
DOI: 10.1021/acs.orglett.7b01956
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
and -withdrawing functionalities on both aryl rings of 2
(4) Tumir, L.-M.; Radic
Chem. 2014, 10, 2930.
́
Stojkovic,
́
M.; Piantanida, I. Beilstein J. Org.
(
Scheme 5). Finally, we attempted to remove the N-4-
(5) (a) Wencel-Delord, J.; Droge, T.; Liu, F.; Glorius, F. Chem. Soc.
Rev. 2011, 40, 4740. (b) Yoon, H.; Lossouarn, A.; Landau, F.; Lautens,
M. Org. Lett. 2016, 18, 6324.
Scheme 5. Substrate Scope Study
(
6) Guo, X.-X.; Gu, D.-W.; Wu, Z.; Zhang, W. Chem. Rev. 2015, 115,
622.
7) Miura, M.; Tsuda, T.; Satoh, T.; Pivsa-Art, S.; Nomura, M. J. Org.
Chem. 1998, 63, 5211.
1
(
(8) Kim, B. S.; Lee, S. Y.; Youn, S. W. Chem. - Asian J. 2011, 6, 1952.
(9) Liu, Y.-Y.; Song, R.-J.; Wu, C.-Y.; Gong, L.-B.; Hu, M.; Wang, Z.-
Q.; Xie, Y.-X.; Li, J.-H. Adv. Synth. Catal. 2012, 354, 347.
10) (a) Cao, J.-J.; Wang, X.; Wang, S.-Y.; Ji, S.-J. Chem. Commun.
014, 50, 12892. (b) Noel-Duchesneau, L.; Lagadic, E.; Morlet-Savary,
F.; Lohier, J.-F.; Chataigner, I.; Breugst, M.; Lalevee, J.; Gaumont, A.-
(
2
̈
́
C.; Lakhdar, S. Org. Lett. 2016, 18, 5900. (c) Song, B.; Xu, B. Chem.
Soc. Rev. 2017, 46, 1103. (d) Tobisu, M.; Koh, K.; Furukawa, T.;
Chatani, N. Angew. Chem., Int. Ed. 2012, 51, 11363.
hydroxylphenyl moiety, even though the present method is
limited to removing the protecting aryl group from amines.
However, the prepared phenanthridin-6(5H)-ylidene 5a can be
oxidized to produce 65% of deprotected phenanthridin-6(5H)-
(
11) Rajeshkumar, V.; Chan, F.-W.; Chuang, S.-C. Adv. Synth. Catal.
012, 354, 2473.
12) Rajeshkumar, V.; Lee, T.-H.; Chuang, S.-C. Org. Lett. 2013, 15,
1468.
2
(
2
2
one with 4 equiv of [bis(trifluoroacetoxy)iodo]benzene
(13) Annamalai, P.; Chen, W.-Y.; Raju, S.; Hsu, K.-C.; Upadhyay, N.
(
PIFA) at 0 °C.
In conclusion, we have demonstrated a strategy for the
S.; Cheng, C.-H.; Chuang, S.-C. Adv. Synth. Catal. 2016, 358, 3642.
(14) Jordan-Hore, J. A.; Johansson, C. C. C.; Gulias, M.; Beck, E. M.;
preparation of dihydrophenanthridines, phenanthridin-6(5H)-
ylidenes, and carbazoles with preinstalled iminoquinones as a
directing group and an internal oxidant or co-oxidant using
palladium catalysis.
Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 16184.
(15) Takamatsu, K.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2014,
16, 2892.
(16) Ma, H.; Jiang, X. Synlett 2007, 2007, 1679.
(
17) Scharow, A.; Raab, M.; Saxena, K.; Sreeramulu, S.; Kudlinzki, D.;
Gande, S.; Dotsch, C.; Kurunci-Csacsko, E.; Klaeger, S.; Kuster, B.;
Schwalbe, H.; Strebhardt, K.; Berg, T. ACS Chem. Biol. 2015, 10, 2570.
18) Dahlin, D. C.; Miwa, G. T.; Lu, A. Y.; Nelson, S. D. Proc. Natl.
ASSOCIATED CONTENT
̈
■
*
S
Supporting Information
(
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01956.
Acad. Sci. U. S. A. 1984, 81, 1327.
(19) (a) Zhou, Z.; Liu, G.; Chen, Y.; Lu, X. Org. Lett. 2015, 17, 5874.
(b) Kong, L.; Yu, S.; Zhou, X.; Li, X. Org. Lett. 2016, 18, 588.
(
c) Hummel, J. R.; Boerth, J. A.; Ellman, J. A. Chem. Rev. 2017, 117,
163. (d) Hu, W.; Li, J.; Xu, Y.; Li, J.; Wu, W.; Liu, H.; Jiang, H. Org.
Lett. 2017, 19, 678.
20) (a) Davis, D. C.; Walker, K. L.; Hu, C.; Zare, R. N.; Waymouth,
Full experimental procedures, characterization data, and
NMR spectra data (PDF)
Crystallographic data for 2e (CIF)
Crystallographic data for 4h (CIF)
Crystallographic data for 5a (CIF)
Crystallographic data for 5l′ (CIF)
9
(
R. M.; Dai, M. J. Am. Chem. Soc. 2016, 138, 10693. (b) Qin, Y.; Zhu,
L.; Luo, S. Chem. Rev. 2017, 117, 9433. (c) Qiu, Y.; Yang, B.; Zhu, C.;
Bac
21) Wrigglesworth, J. W.; Cox, B.; Lloyd-Jones, G. C.; Booker-
Milburn, K. I. Org. Lett. 2011, 13, 5326.
22) Nageswar Rao, D.; Rasheed, S.; Das, P. Org. Lett. 2016, 18,
142.
̈
kvall, J.-E. J. Am. Chem. Soc. 2016, 138, 13846.
(
AUTHOR INFORMATION
Corresponding Author
■
(
3
*E-mail: jscchuang@faculty.nctu.edu.tw.
ORCID
Shih-Ching Chuang: 0000-0002-6926-9812
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the Ministry of Science and Technology of Taiwan
for supporting this research financially (MOST104-2113-M-
■
009-014-MY3 and MOST105-2628-M-009-002-MY3).
REFERENCES
■
(
1) (a) Tang, C.; Yuan, Y.; Jiao, N. Org. Lett. 2015, 17, 2206.
b) Feng, M.; Tang, B.; Xu, H.-X.; Jiang, X. Org. Lett. 2016, 18, 4352.
(
(
2) (a) Duval, R.; Duplais, C. Nat. Prod. Rep. 2017, 34, 161. (b) Jin,
Y.; Jiang, M.; Wang, H.; Fu, H. Sci. Rep. 2016, 6, 20068.
3) (a) Liang, Z.; Ju, L.; Xie, Y.; Huang, L.; Zhang, Y. Chem. - Eur. J.
012, 18, 15816. (b) Gu, J.-W.; Zhang, X. Org. Lett. 2015, 17, 5384.
c) Yeung, C. S.; Zhao, X.; Borduas, N.; Dong, V. M. Chem. Sci. 2010,
, 331.
(
2
(
1
D
DOI: 10.1021/acs.orglett.7b01956
Org. Lett. XXXX, XXX, XXX−XXX