Palladium-Catalyzed Cascade Cyclization of Alkene-Tethered Aryl Halides with o-Bromobenzoic Acids: Access to Diverse Fused Indolo[2,1- A[isoquinolines

Article abstract of DOI:10.1021/acs.orglett.9b02541

A novel palladium-catalyzed cascade cyclization of alkene-tethered aryl halides with o-bromobenzoic acids is described, which provides an efficient avenue for building various fused hexacyclic scaffolds containing indolo[2,1-a]isoquinoline in moderate to excellent yield. The method enables the construction of three C-C bonds through an intramolecular carbopalladation, C-H activation, and a decarboxylation sequence. Furthermore, dihydrocyclohepta[de]naphthalene-fused indolo[2,1-a]isoquinolines can be synthesized in moderate yield by constructing a seven-membered ring.

Full text of DOI:10.1021/acs.orglett.9b02541

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Palladium-Catalyzed Cascade Cyclization of Alkene-Tethered Aryl
Halides with o‑Bromobenzoic Acids: Access to Diverse Fused
Indolo[2,1‑a]isoquinolines
Xiumei Yang, Haiyan Lu, Xiaoming Zhu, Liwei Zhou, Guobo Deng, Yuan Yang,* and Yun Liang*
National & Local Joint Engineering Laboratory for New Petro-chemical Materials and Fine Utilization of Resources, Key Laboratory
of Chemical Biology and Traditional Chinese Medicine Research, Ministry of Education, Key Laboratory of the Assembly and
Application of Organic Functional Molecules of Hunan Province, Hunan Normal University, Changsha, Hunan 410081, China
*
S Supporting Information
ABSTRACT: A novel palladium-catalyzed cascade cyclization of alkene-tethered aryl halides with o-bromobenzoic acids is
described, which provides an efficient avenue for building various fused hexacyclic scaffolds containing indolo[2,1-
a]isoquinoline in moderate to excellent yield. The method enables the construction of three C−C bonds through an
intramolecular carbopalladation, C−H activation, and a decarboxylation sequence. Furthermore, dihydrocyclohepta[de]-
naphthalene-fused indolo[2,1-a]isoquinolines can be synthesized in moderate yield by constructing a seven-membered ring.
ndolo[2,1-a]isoquinolines represent an important class of
multifused N-heterocycles that is found in key structural
developed by Nevado, Li, and Xu in recent years (Scheme 2
(1)). However, on one hand, such methods for the synthesis
3
I
frameworks of numerous pharmaceuticals, biologically active
1
natural products, and functional materials. For example,
Scheme 2. Synthesis of Indolo[2,1-a]isoquinoline
Derivatives via Two Different Strategies
indolo[2,1-a]isoquinolines 1−4 have also received much
attention because they can be used as an inhibitor of tubulin
polymerization, a melatonin antagonist, an estrogen receptor
affinic cytostatic agent, and hole-transporting materials
(
HTMs) in organic light-emitting diodes (Scheme 1). In the
past several decades, considerable efforts have been devoted to
2
,3
construct indolo[2,1-a]isoquinoline derivatives. In particular,
an elegant radical cascade cyclization strategy has been
Scheme 1. Examples of Important Indolo[2,1-
a]isoquinolines
of indolo[2,1-a]isoquinoline derivatives remain underdevel-
oped due to the complexity of polycyclic fused ring core
scaffolds. On the other hand, the vast majority of the reported
methods have focused on the assembly of polysubstituted
indolo[2,1-a]isoquinolines, whereas this technology for the
Received: July 21, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02541
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
2b
a
synthesis of fused indolo[2,1-a]isoquinolines continues to be
an arduous challenge. Consequently, the development of new
efficient strategies that provide straightforward access to fused
indolo[2,1-a]isoquinolines is of significant importance in
consideration of the above.
Table 1. Optimization of the Reaction Conditions
Cascade (otherwise termed domino) reactions have
attracted considerable attention because they provide an
efficient and step-economical process to simultaneously
achieve the construction of multiple bonds in a single
operation. In addition, transition-metal-catalyzed C−H
functionalization reactions are interesting to scientific
b
entry
variation from the standard conditions
none
Pd(OAc)
PdCl (PPh ) instead of PdCl (dppf)
yield (%)
1
2
3
4
5
6
7
8
9
88
72
86
63
69
82
71
70
62
81
78
85
0
4
instead of PdCl (dppf)
2 2 2
2
3
2
2
2
Pd(PPh ) instead of PdCl (dppf)
2
3
4
2
researchers due to their high atom economy without
5
PPh
(10 mol %) was added
3
prefunctionalization of the starting materials. Accordingly,
Pt-Bu (10 mol %) was added
3
the introduction of the C−H bond activation strategy in the
P(3,5-(CF ) C H ) (10 mol %) was added
6
,7
3
2
6
3 3
domino process is extremely appealing.
In the field,
K CO or K PO instead of NaOAc
2
3
3
4
considerable progress has been made in the palladium-
catalyzed cascade cyclization of aryl halides bearing a tethered
Cs CO instead of NaOAc
2
3
10
11
12
13
14
15
16
Na CO instead of NaOAc
2 3
7
−11
alkene.
This protocol, reported initially by the group of
DMSO instead of DMF
DMA instead of DMF
MeCN or toluene instead of DMF
at 130 °C
at 150 °C
TBAB (0.5 equiv) was added
8
h,i
Grigg, undergoes intramolecular carbopalladation, followed
by C−H bond activation to form the key intermediate
palladacycle, which can furnish structurally diversified hetero-
polycycles by three different types of transformations,
81
76
90 (83)
8
9
including reductive elimination, a [1,4]-Pd shift, and a
reaction with various coupling partners.
nificant breakthroughs in this field have been reported
c
10,11
Recently, sig-
a
10,11
Reaction conditions: 1a (0.2 mmol), 2a (1.2 equiv), PdCl
2
(dppf)
2
2
(
5 mol %), NaOAc (3 equiv), and DMF (2 mL) at 140 °C under N
for 24 h. Isolated yield. 1a (1 mmol) and DMF (8 mL) were used.
through migratory insertion or oxidative addition of coupling
partners, such as aryl iodides, diaziridinones, arynes, and
activated alkynes, α-diazocarbonyl compounds, and dibromo-
methane, to palladacycles generated by regioselective C−H
activation, in particular, the ortho-C−H bond activation of aryl
b c
is applicable to scale up to 1 mmol of 1a, thus giving the
product 3aa in 83% yield (entry 16).
1
1
halides, thus leading to the synthesis of fused and spiro-
heteropolycycles. However, such examples for the synthesis of
fused heteropolycycles are quite rare. Inspired by these reasons
and our research interests in the tandem reactions involving
With the optimal reaction conditions in hand, we set out to
evaluate the generality of this protocol with respect to alkene-
tethered aryl halides (I and Br) 1 and o-bromobenzoic acids 2
(Scheme 3). Initially, a range of substrates 1b−l with
substituents on the indole ring or the iodo-bearing benzene
ring were investigated by employing o-bromobenzoic acid as
the coupling reagent. To our delight, various substituents,
1
0a,12a−e
palladacycles,
herein, we reported a new palladium-
catalyzed cascade cyclization of alkene-tethered aryl halides for
accessing fused hexacyclic scaffolds containing indolo[2,1-
a]isoquinoline by the use of o-bromobenzoic acids as a suitable
coupling partner (Scheme 2 (2)).
including Me, OMe, F, Cl, Br, and CF , were well tolerated,
3
and the desired products 3ba−la were afforded in 42−85%
yield. Importantly, substrate 1m bearing a phenyl group on the
alkene could smoothly undergo the cascade reaction to furnish
the target product 3ma in 80% yield. Subsequently, the optimal
reaction conditions were applicable to an array of o-
bromobenzoic acids 2b−l. Monosubstituted o-bromobenzoic
Our initial investigation focused on the cascade reaction of
-(2-(2-iodophenyl)-1H-indol-1-yl)-2-methylprop-2-en-1-one
1
(
1a) with o-bromobenzoic acid (2a) (Table 1). After an
extensive screening of the reaction parameters, we were
pleased to find that the treatment of 1a with 2a, PdCl (dppf)
2
2
(
5 mol %), NaOAc (3 equiv), and DMF (2 mL) at 140 °C
acids 2b−g containing Me, OMe, NH , F, and Cl groups
2
under a N atmosphere for 24 h could afford the desired
afforded the products 3ab−ag in 31−85% yield. The structure
of 3ad was unambiguously confirmed by single-crystal X-ray
crystallography. (See the Supporting Information (SI).)
Disubstituted (OMe and F) and fused o-bromobenzoic acids
could successfully be converted into the target products 3ah−
aj in 74, 54, and 84% yield, respectively. 3-Bromothiophene-2-
carboxylic acid and 4-bromonicotinic acid also exhibited high
reactivity, and the desired products 3ak and 3al were obtained
in 80 and 70% yield, respectively. It was noteworthy that o-
chlorobenzoic acid was also a competent substrate, albeit
providing a diminished yield in comparison with o-
bromobenzoic acid 1a. Finally, we unexpectedly found that
the extra addition of TBAB (0.5 equiv) had a positive effect on
the reaction because the vast majority of substrates 1 and 2
were transformed into the products 3 in higher yield (the
yields in parentheses with superscript b). We speculated that
TBAB could activate and stabilize palladium complexes in the
2
product 3aa in 88% yield (entry 1). Other palladium catalysts,
such as Pd(OAc) , PdCl (PPh ) , and Pd(PPh ) , proved to
2
2
3 2
3 4
be less efficient than PdCl (dppf) in terms of yield (entries 2−
2
2
4
). Control experiments revealed that ligands had a negative
effect for this cascade reaction because performing the reaction
with ligands, including PPh , Pt-Bu , and P(3,5-(CF ) C H ) ,
3
3
3 2
6
3 3
resulted in a lower yield (entries 5−7). The examination of
other bases, including K CO , K PO , Cs CO , and Na CO ,
2
3
3
4
2
3
2
3
indicated that all of them were inferior to NaOAc (entries 8−
1
0). Furthermore, the nature of solvents was found to be
crucial for the reaction: Using DMSO or DMA as a medium
led to a slightly diminished yield (entries 11 and 12), yet the
reaction was completely suppressed by replacing DMF with
MeCN or toluene as the solvent (entry 13). A lower or higher
temperature showed worse efficiency than the results at 140 °C
(
entries 14 and 14). Finally, the addition of TBAB afforded an
10d,13
almost the identical yield (entry 16). Gratifyingly, the reaction
catalytic cycle.
(See the SI.)
B
DOI: 10.1021/acs.orglett.9b02541
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Synthesis of Dihydronaphthalene-Fused
Indolo[2,1-a]isoquinolinones
Scheme 4. Synthesis of Dihydronaphthalene-Fused
Indolo[2,1-a]isoquinolines
a
a
a
Reaction conditions: 4 (0.2 mmol), 2 (1.2 equiv), PdCl (dppf) (5
2
2
mol %), NaOAc (3 equiv), and DMF (2 mL) at 140 °C under N for
2
b
c
2
4 h. TBAB (0.5 equiv) was added. Alkene-tethered aryl bromides
were used.
Scheme 5. Synthesis of Dihydrocyclohepta[de]naphthalene-
a
Fused Indolo[2,1-a]isoquinolines
a
Reaction conditions: 1 (0.2 mmol), 2 (1.2 equiv), PdCl (dppf) (5
2
2
mol %), NaOAc (3 equiv), and DMF (2 mL) at 140 °C under N for
2
b
c
2
4 h. TBAB (0.5 equiv) was added. Alkene-tethered aryl bromides
instead of alkene-tethered aryl iodides. o-Chlorobenzoic acid instead
d
e
of o-bromobenzoic acid. 38 h.
We next turned our attention to exploring the feasibility of
the reaction of 2-(2-iodophenyl)-1-(2-methylallyl)-1H-indole
a with o-bromobenzoic acid 2a (Scheme 4). Gratifyingly,
a
Reaction conditions: 1 or 4a (0.2 mmol), 2m (1.2 equiv),
PdCl (dppf) (5 mol %), NaOAc (3 equiv), TBAB (0.5 equiv), and
DMF (2 mL) at 140 °C under N for 24 h. Alkene-tethered aryl
bromides were used.
2
2
4
b
2
dihydronaphthalene-fused indolo[2,1-a]isoquinoline 5aa was
formed in 75% yield in the presence of TBAB, whereas the
yield of 5aa decreased to 53% without TBAB. Subsequently,
several 2-(2-iodophenyl)-1-(2-methylallyl)-1H-indoles and o-
bromobenzoic acids were examined in the presence or absence
of TBAB. For example, substrates 4b, 4d, 4h, and 4l were
subjected to the cascade cyclization with o-bromobenzoic acid
to provide the desired products in 64−79% yield. The reaction
of o-bromobenzoic acids (2h, 2j, and 2k) with 4a proceeded
favorably, and the corresponding products were afforded in
Scheme 6. Control Experiment and Possible Reaction
Mechanism
6
8−84% yield. Expectedly, for most of substrates, lower yields
of the products 5 were obtained by the removal of TBAB.
To highlight the applicability of this strategy, we attempted
to perform the reaction of 1a with 8-bromo-1-naphthoic acid
2
m (Scheme 5). Fortunately, the corresponding products
could be obtained in 60% yield by constructing a seven-
membered ring. Inspired by these results, substrates 1c, 1e, 1g,
and 4a were also investigated, and all of them underwent this
reaction to afford the target products in moderate yield.
As shown in Scheme 6, the isotope experiment was
performed by adding 3 equiv of D O under the standard
2
conditions. The results revealed that the reaction mechanism
involved the formation of palladacycle C. On the basis of our
mechanism for this transformation was proposed (Scheme 6).
Initially, the catalytic cycle starts with the oxidative addition of
10,11,12e−g
experimental results and previous work,
a possible
C
DOI: 10.1021/acs.orglett.9b02541
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Pd(0) to the C−I bond to form aryl−Pd(II) intermediate A,
which undergoes an intramolecular Heck reaction and a C−H
bond activation sequence to generate palladacycle C.
Subsequently, the oxidative addition of palladacycle C to the
C−Br bond of o-bromobenzoic acid affords Pd(IV)
intermediate D, which provides seven-membered palladacycle
E by a reductive elimination and decarboxylation sequence.
Finally, the reductive elimination of palladacycle E furnishes
the desired product 3aa or 5aa and regenerates Pd(0), which
continues to participate in the next cycle.
In conclusion, we have developed a novel palladium-
catalyzed intermolecular cascade reaction for the synthesis of
fused indolo[2,1-a]isoquinoline derivatives in which three C−
C bonds are formed via an intramolecular Heck reaction, C−H
activation, and decarboxylation sequence. The reaction
employs readily available reagents, including alkene-tethered
aryl halides and o-bromobenzoic acids, to construct interesting
fused hexacyclic scaffolds in moderate to excellent yield with a
broad substrate scope and good functional group tolerance.
Importantly, 8-bromo-1-naphthoic acid as a coupling partner
can be applicable to this approach, thus affording
dihydrocyclohepta[de]naphthalene-fused indolo[2,1-a]-
isoquinolines. This protocol opens up a new perspective to
access fused indolo[2,1-a]isoquinoline derivatives.
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E-mail: yuanyang@hunnu.edu.cn (Y.Y.).
E-mail: yliang@hunnu.edu.cn (Y.L.).
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ORCID
Guobo Deng: 0000-0002-5470-5706
Yuan Yang: 0000-0002-9061-1758
Yun Liang: 0000-0002-2550-9220
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the National Natural Science
Foundation of China (21572051, 21602057, 21901071, and
1971061), the Scientific Research Fund of Hunan Provincial
Education Department (18A002), and the Science and
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DOI: 10.1021/acs.orglett.9b02541
Org. Lett. XXXX, XXX, XXX−XXX