Pd(II)-Catalyzed One-Pot Multiple C-C Bond Formation: En Route Synthesis of Succinimide-Fused Unsymmetrical 9,10-Dihydrophenanthrenes from Aryl Iodides and Maleimides

Article abstract of DOI:10.1021/acs.orglett.0c00255

An expeditious approach has been developed for the synthesis of succinimide-fused unsymmetrical 9,10-dihydrophenanthrenes from simple aryl iodides and maleimides. The developed transformation, overall proceeding with high regioselectivity via a cascade approach through palladium(II)-catalyzed Micheal-type addition/C-H activation/intramolecular cross-dehydrogenative coupling (ICDC)/C-H activation, allows formation of four fundamental carbon-carbon bonds in one-pot fashion. The reactions tolerate broad functional groups and satisfy the parameters of atom and step economy. Detailed mechanistic studies were carried out to support the proposed synthetic pathway.

Full text of DOI:10.1021/acs.orglett.0c00255

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Letter
Pd(II)-Catalyzed One-Pot Multiple C−C Bond Formation: En Route
Synthesis of Succinimide-Fused Unsymmetrical 9,10-
Dihydrophenanthrenes from Aryl Iodides and Maleimides
Akanksha Singh Baghel, Yogesh Jaiswal, and Amit Kumar*
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ABSTRACT: An expeditious approach has been developed for the synthesis of succinimide-fused unsymmetrical 9,10-
dihydrophenanthrenes from simple aryl iodides and maleimides. The developed transformation, overall proceeding with high
regioselectivity via a cascade approach through palladium(II)-catalyzed Micheal-type addition/C−H activation/intramolecular cross-
dehydrogenative coupling (ICDC)/C−H activation, allows formation of four fundamental carbon−carbon bonds in one-pot fashion.
The reactions tolerate broad functional groups and satisfy the parameters of atom and step economy. Detailed mechanistic studies
were carried out to support the proposed synthetic pathway.
he formation of carbon−carbon bonds is a fundamental
Taspect of organic chemistry. Therefore, several well-
defined strategies have been designed and developed by
chemists in order to make the desired C−C bonds.1 However,
the construction of these bonds as per requirement is by no
means a routine task. In particular, the formation of multiple
C−C bonds in one-pot fashion by following environmental
and economic considerations is regarded as a major challenge
Figure 1. Representative examples of natural products containing
in contemporary science. In general, multiple C−C bonds
phenanthrene as core motifs.
formation can be accomplished in the one-step process via the
transition-metal catalyzed reactions. This domain, popularly
known as a cascade/domino reaction, has witnessed
application in the drug-discovery industry, as they act as
potential inhibitors of several key enzymes and regulate the
several key biological processes.6 Although there are plenty of
synthetic methods, in particular, transition-metal-catalyzed
reactions available in the literature to access these classes of
compounds, they mostly suffer from the requirement of
elaborate-to-access starting materials, limited substrate scope,
and multistep transformation.7 Hence, it is essential to design
extraordinary growth in the past few years.2
The functionalized aromatic compounds, in particular,
polycyclic aromatic hydrocarbons (PAHs), are high in demand
across the field of science owing to their unique electronic
properties.3 As these classes of compounds generally possess
an exceptional π-extended surface system, they hence are
extensively employed as key precursors for the construction of
organic semiconductors and chemiluminescent materials.4
Among these polycyclic aromatic compounds, phenanthrene
and its derivatives have their own importance due to their
ubiquitous presence as key structural motifs in several
medicinally active compounds and natural products (Figure
1).5 Indeed, these classes of compounds also have large
Received: January 17, 2020
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© XXXX American Chemical Society
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A

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a
and develop a method, which should avoid these drawbacks, as
mentioned earlier.
Table 1. Optimization of Reaction Conditions
Maleimides and succinimides also represent an important
class of organic molecules, which have been extensively
employed for the synthesis of nitrogen-containing polyheter-
ocyclic compounds and have a diverse range of applications
from the pharmaceutical industry to materials science.8 Indeed,
several research groups around the globe have utilized the
maleimide motifs as an effective coupling partner for the
synthesis of structurally diverse organic compounds via
transition-metal-catalyzed C−H bond activation/functionaliza-
tion reactions.9 For instance, Zhou and co-workers and
Jafarpour et al. have reported catalytic methods for the
synthesis of challenging mono- and diarylated maleimides via
oxidative Heck reactions.10 With this understanding and
continuation of our research interest in the development of
novel synthetic routes for functionalized organic molecules
from readily available starting materials,11 we anticipated that
the succinimide-fused 9,10-dihydrophenanthrene derivatives
could be synthesized expeditiously from aryl iodides and
maleimides via palladium(II)-catalyzed domino Micheal-type
addition/C−H activation followed by intramolecular cross-
dehydrogenative coupling (ICDC) (expected product, Scheme
1, eq ii). To our surprise, when the reaction was carried under
b
entry
solvent
ligand
silver salt
yield (%)
1
2
3
4
5
6
7
8
Chloroform
Chlorobenzene
Acetonitrile
1,4-Dioxane
Toluene
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
JohnPhos
JohnPhos
JohnPhos
JohnPhos
JohnPhos
JohnPhos
JohnPhos
JohnPhos
JohnPhos
JohnPhos
JohnPhos
SPhos
XPhos
DavePhos
P(Cy)3
CyJPhos
JohnPhos
JohnPhos
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
Ag2CO3
Ag2O
CH3CO2Ag
CF3CO2Ag
AgSbF6
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
−
11
48
n.r.
35
44
62
n.r.
11
8
9
10
11
12
13
14
15
16
17
18
33
n.r.
36
37
39
58
45
c
73
Scheme 1. Palladium-Catalyzed C−H Functionalization of
Maleimides with Aryl Iodides
trace
a
Reaction conditions: 1a (0.25 mmol), 2a (1 mmol), Pd(OAc)2 (10
mol %), AgBF4 (0.50 mmol), and JohnPhos (20 mol %) in 2.0 mL of
DCE at 130 °C for 48 h. Isolated yield of product. 3.0 equiv of
b
c
AgBF were used. DCE = 1,2-dichloroethane. n.r. = no reaction.
4
AgNO3, AgSbF6, CH3CO2Ag, and CF3SO3Ag (entries 7−11)
were also tested, and AgBF4 was found to be the best choice
among all silver salts. After that brief survey of solvents and
oxidants, a variety of ligands (mono- and bidentate) were
examined (entries 12−16), and JohnPhos has emerged as a
better ligand in terms of the yield (entry 6). Importantly, the
loading of a silver salt plays a critical role in enhancing the
efficiency of the overall reaction. For example, an increase in
the loading of AgBF4 from 2 to 3 equiv resulted in a higher
yield (73%) of the desired product 3a (entry 17). It is
important to note that only a trace amount of 3a was detected
in the absence of the silver salt (entry 18), and results
essentially illustrate the importance of the silver salt in the
desired transformation. However, a further increase and
decrease in reaction temperature was futile; there was no
improvement in the overall yield of the corresponding product
(for detailed optimization, see Supporting Information (SI)).
Surprisingly, under the optimized conditions, formation of
4,11-diarylated succinimide-fused 9,10-dihydrophenanthrene
was not observed. After careful optimization of reaction
parameters, we found that the reaction conditions described in
entry 17 were the best for further exploration.
With suitable reaction conditions in hand, the generality and
limitation of this novel domino transformation were examined
for the synthesis of diverse 4-arylated-succinimide-fused
unsymmetrical 9,10-dihydrophenanthrene 3 by varying N-
substituted maleimides (Scheme 2). For instance, maleimide
derivatives such as N-methyl, ethyl, n-butyl, n-hexyl, isopropyl,
and cyclohexyl reacted well with iodobenzene 2a under the
established reaction conditions to afford the desired products
(entries 3a−f) in uniformly good yields (up to 73%).
Furthermore, maleimides possessing N-aryl and benzyl also
the optimized conditions, unexpectedly, we obtained 4-
arylated-succinimide-fused unsymmetrical 9,10-dihydrophe-
nanthrenes (observed product, Scheme 1, eq ii). To the best
of our knowledge, this is the first report describing the
synthesis of succinimide-fused unsymmetrical 9,10-dihydro-
phenanthrenes from aryl iodides and maleimides via Pd(II)-
catalyzed threefold C−H activation in one-pot fashion. Indeed,
it is expected that the incorporation of succinimide skeletons
to the polyaromatic motifs may enhance the physical and
chemical properties and eventually will find wide application in
the field of material science.
We commenced our investigation with N-methylmaleimide
1a and iodobenzene 2a as a model substrate to optimize the
reaction conditions. For instance, when a mixture of 1a and 2a
was treated with palladium(II)-acetate (10 mol %) as the
desired catalyst, and AgBF4 as oxidant in chloroform solvent at
130 °C for 48 h under an argon atmosphere, the desired
product 3a was obtained, albeit in low yield (11%, Table 1,
entry 1). On the basis of the initial results, a detailed survey of
reaction conditions was carried out and the results are
summarized in Table 1. As the nature of the solvent plays a
crucial role in the transition-metal-catalyzed domino reaction,
we screened various solvents (entries 1−6). The best result
was obtained when dichloroethane used as a solvent (62%,
entry 6). Similarly, various other oxidants such as AgBF4,
B
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Scheme 2. Scope of Iterative C−H Functionalization with
Scheme 3. Substrate Scope with Various Aryl Iodides and N-
Substituted Maleimides
a
a
N-Substituted Maleimides
a
Reaction conditions: 1 (0.25 mmol), 2a (1 mmol), Pd(OAc)2 (10
mol %), AgBF4 (0.75 mmol), and JohnPhos (20 mol %) in 2.0 mL of
DCE at 130 °C for 48 h. Isolated yields are reported after purification.
served as good coupling partners in this reaction to afford the
corresponding products (entries 3g−i) in moderate yields.
Assessment of electronic effects on the aryl ring of N-aryl
maleimides found them to be minimal; both electron-donating
substituents, such as methyl and methoxy, and electron-
withdrawing groups, for instance, chloro and fluoro, effortlessly
gave the desired products (entries 3j−n) in optimum yields.
Next, we explored the substrate scope of the reaction with
respect to aryl iodides and maleimides (Scheme 3). We were
pleased to find that a range of alkyl, alkoxy, and halo
substituted aryl iodides at the para positions were well
tolerated under the reaction conditions. For instance, aryl
iodides bearing electron-donating groups (EDGs), such as
methyl, ethyl, and isopropyl, at the para positions of the
aromatic ring gave the corresponding products (entries 4a−c)
in moderate to good yields. Indeed, the halo-substituted
iodoarenes (F, Cl, and Br at the para-position) were well
accommodated and the products (entries 4d−f) were isolated
in good yields (up to 55%). Remarkably, the presence of a
strong electron-withdrawing group, such as the trifluoromethyl
group (−CF3), at the para-position of the aromatic ring did not
hamper the overall efficiency of the desired operation and
afforded the corresponding product 4g in high yield (73%).
Importantly, the structure of the desired compound was
confirmed by the single-crystal X-ray diffraction analysis of 4g
in addition to the spectroscopic evidence. Also, the reaction
conditions were tolerant for a sterically hindered substrate such
as para-tosyl-iodobenzene to produce the designed product 4h,
albeit in lower yield (30%). To further diversify the scope of
this transformation, aryl iodides containing either electron-
donating or electron-withdrawing groups were also reacted
with differentially N-substituted maleimides under similar
conditions and the desired products (4i−r) were isolated in
moderate to good yields (49−75%). It is important to note
that when ortho- and meta-substituted iodobenzene were
a
Reaction conditions: 1 (0.25 mmol), 2 (1 mmol), Pd(OAc)2 (10
mol %), AgBF4 (0.75 mmol), and JohnPhos (20 mol %) in 2.0 mL of
DCE at 130 °C for 48 h. Isolated yields are reported after purification
subjected to established conditions, as expected, no desired
product was formed. This can be attributed to the steric
factors. Similarly, when para-nitro/acetyl/hydroxy-substituted
iodobenzenes were treated under similar conditions, no desired
products were formed, and multiple spots were observed on
the TLC plate. The results presented herein are significant
from the points of view of atom and step efficiency.
In order to demonstrate the synthetic practicality of the
developed cascade approach, the scale-up reaction was
performed under the standard reaction conditions (Scheme
4, eq i). Fortunately, the desired product 3a was obtained in
60% yield, which is not a substantial decrease. Indeed, the
presence of the carbonyl group in the succinimide-fused 9,10-
dihydrophenanthrene makes venerable synthetic precursors
that are well suited for further synthetic manipulation. For
Scheme 4. Scale-up Synthesis and Synthetic Derivatization
of 3a
C
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instance, reaction with NaBH4 at room temperature
completely reduces one of the carbonyl groups to methylene
and delivers the corresponding dibenzo[e,g]isoindol-1-one 5 in
66% yield (Scheme 4, eq ii, right side). On the other hand,
DIBAl-H selectively reduces one of the carbonyl motifs to the
corresponding hydroxyl derivative 6 in good yield (76%),
which can be easily elaborated as per requirements (Scheme 4,
eq ii, left side).
Scheme 6. Plausible Catalytic Reaction Cycle
A few additional control experiments were carried out to
elucidate the reaction mechanism of this domino approach
(Scheme 5). For instance, the intermolecular competition
Scheme 5. Control Experiments
to species A to form complex B, followed by migratory
insertion affording the pallada-carba species C. Then, species C
undergoes oxidative addition followed by reductive elimination
to generate biarylated intermediate E. Concomitantly, the
intermediate E forms the seven-membered cyclometalated
species F via an intramolecular cross-dehydrogenative coupling
(ICDC) process followed by reductive elimination, giving the
intermediate G. Finally, the carbonyl oxygen directed
regioselective ortho-C−H activation was achieved via six-
membered palladacycle species H, followed by oxidative
addition/reductive elimination to procure the corresponding
product 3a and regenerate the palladium(II) salt.
In summary, we have developed an efficient and one-step
synthetic route for the synthesis of succinimide-fused unsym-
metrical 9,10-dihydrophenanthrenes from simple and readily
available starting materials. The developed protocol overall
proceeds via Pd(II)-catalyzed 3-fold C−H activation to
construct four C−C bonds in one-pot fashion, which is
otherwise difficult to achieve via the traditional approach.
Preliminary mechanistic experiments revealed that the reaction
proceeds by a stepwise process. Under the optimized reaction
conditions, various functionalized 9,10-dihydrophenanthrene
derivatives were synthesized in good to high yields. This
unprecedented transformation eventually satisfies the param-
eters of sustainable chemistry, such as atom and step economy.
We expect that the developed strategy will find wide
application in synthetic organic and material chemistry.
reaction between N-ethylmaleimide 1b with electron-rich and
electron-deficient aryl iodides 2i and 2k was performed under
the reported conditions, and the result eventually dictates that
the electron-deficient ring has a slightly higher preference for
this cascade approach over the electron-rich system. The ratio
of products was found in 4i:4k (1:1.3) (Scheme 5, eq i).
Similarly, when differentially substituted maleimides such as N-
ethylmaleimide 1b and N-phenyl-maleimide 1i were treated
with iodobenzene 2a, the desired products were obtained in a
ratio of 1.3:1 (3b:3i), which indicates that the reaction slightly
favors the N-ethylmaleimide over the N-phenyl-maleimide
(Scheme 5, eq ii). Next, we attempted to detect the formation
of possible intermediates in the reaction mixture through the
HRMS analysis (for details, see SI). For example, when the
reaction was performed under standard conditions for a short
period of time (12 h, Scheme 5, eq iii), HRMS analysis of the
crude reaction mixture showed three major m/z ([M + H]+)
ion peaks at 266.1176, 264.1019, and 340.1333, respectively,
and these m/z ion peaks correspond to the proposed
intermediates 7, 8 and product 3a. Furthermore, when the
same reaction mixture was continued for 24 h, the desired
product 3a was isolated in 44% yield. These results revealed
that 7 and 8 might be the possible intermediates in this
transformation and eventually suggest that the reaction
proceeds via a stepwise mechanism through diarylation (7)
followed by oxidative intramolecular cross-dehydrogenative
coupling (C−C bond) (8) and then regioselective C−H
activation.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00255.
Detailed information on experimental procedures,
characterization data, spectra, and crystallographic data
(PDF)
Based on the results of the aforementioned experiments and
literature precedence,12 a plausible reaction mechanism has
been proposed for this unprecedented transformation in
Scheme 6. We expect that the reaction likely initiated with
the formation of aryl palladium species A via oxidative addition
with iodobenzene 2a. Subsequently, maleimide 1a coordinates
Accession Codes
CCDC 1968917 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
D
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Letter
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AUTHOR INFORMATION
Corresponding Author
■
́
(b) Zhang, L.; Cao, Y.; Colella, N. S.; Liang, Y.; Bredas, J.-L.;
Amit Kumar − Department of Chemistry, Indian Institute of
Technology Patna, Bihta 801106, Bihar, India; orcid.org/
0000-0002-1683-7740; Email: amitkt@iitp.ac.in,
amitktiitk@gmail.com
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Molecules: From Benzene to Graphene. Acc. Chem. Res. 2009, 42,
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Authors
Akanksha Singh Baghel − Department of Chemistry, Indian
Institute of Technology Patna, Bihta 801106, Bihar, India
Yogesh Jaiswal − Department of Chemistry, Indian Institute of
Technology Patna, Bihta 801106, Bihar, India
(4) (a) Narita, A.; Wang, X.-Y.; Feng, X.; Mu
̈
llen, K. New advances
in nanographene chemistry. Chem. Soc. Rev. 2015, 44, 6616−6643.
(b) Wang, C.; Dong, H.; Hu, W.; Liu, Y.; Zhu, D. Semiconducting π-
Conjugated Systems in Field-Effect Transistors: A Material Odyssey
of Organic Electronics. Chem. Rev. 2012, 112, 2208−2267.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00255
Notes
(c) Figueira-Duarte, T. M.; Mullen, K. Pyrene-Based Materials for
̈
Organic Electronics. Chem. Rev. 2011, 111, 7260−7314. (d) Anthony,
J. E. The Larger Acenes: Versatile Organic Semiconductors. Angew.
Chem., Int. Ed. 2008, 47, 452−483.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
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Org. Lett. XXXX, XXX, XXX−XXX