Palladium-Catalyzed Dual Annulation: A Method for the Synthesis of Norneocryptolepine

Article abstract of DOI:10.1021/acs.orglett.9b00287

A novel procedure for the Pd-catalyzed dual annulation reaction to synthesize the norneocryptolepine derivatives involving the concerted construction of two central heterocycles is reported. The further methylation of the norneocryptolepine to afford its alkaloid analog neocryptolepine implies that synthesis of various neocryptolepine derivatives is feasible. The oxidative addition of Pd(0) is indicated as the key step to activate the intramolecular addition of nitrile according to the mechanism study.

Full text of DOI:10.1021/acs.orglett.9b00287

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Palladium-Catalyzed Dual Annulation: A Method for the Synthesis of
Norneocryptolepine
Li-Hsuan Yeh, Hung-Kai Wang, Gangaram Pallikonda, Yu-Lun Ciou, and Jen-Chieh Hsieh*
Department of Chemistry, Tamkang University, New Taipei City 25137, Taiwan
S
* Supporting Information
ABSTRACT: A novel procedure for the Pd-catalyzed dual
annulation reaction to synthesize the norneocryptolepine
derivatives involving the concerted construction of two central
heterocycles is reported. The further methylation of the
norneocryptolepine to afford its alkaloid analog neocryptolepine
implies that synthesis of various neocryptolepine derivatives is
feasible. The oxidative addition of Pd(0) is indicated as the key
step to activate the intramolecular addition of nitrile according to the mechanism study.
orneocryptolepine (or norcryptotackieine), a natural
still restricts the scope to some extent. Therefore, a new route to
approach the quinindolines is still desired. In this concern,
transition-metal-catalyzed annulation reactions may possess the
potential to construct this tetra-fused heterocyclic skeleton in a
more flexible manner. However, only a few examples based on
Pd15d,f and Rh15g,h have been reported up to now (Scheme 1).
N
alkaloid isolated from the leaves of Justicia betonica,1 is
often used as an intermediate for the synthesis of its N-
methylated derivative, neocryptolepine.2 The highly structural
similarity causes these two alkaloids to share several focused
bioactivities, including inhibition of DNA topoisomerase II,3
antiplasmodial activity,4 activity against schistosomiasis,5
antibacterial activity,6 antitumor activity,3,7 etc. The source of
neocryptolepine (Cryptolepis sanguinolenta) was even used as
the traditional herbal medicine for the treatment of malaria and
other common diseases in West and Central Africa.8 Because of
the importance, many synthetic and pharmaceutical chemists
have paid a lot of attention to the synthesis of this quinindoline
core structure and its medicinal potential. However, synthesis of
this complicated tetra-fused heterocycle is not easy, and still,
only limited strategies have been reported to approach the
quinindoline derivatives to date.
Scheme 1. Synthesis of Quinindoline via Transition-Metal
Catalysis
Construction of a quinindoline scaffold mainly relies on three
synthetic pathways. The oldest fashion involved the extension of
an indole moiety from a functionalized quinoline through the
C−C or the C−N coupling.9 Although modification toward
various coupling processes has been carried out, this strategy has
often been reported in synthesizing a solo case of neo-
cryptolepine10 or with a limited scope of natural alkaloid
derivatives.11 The dual annulation of an N-alkynylaryl-N-aryl
carbodiimide through a diradical pathway is another method for
the synthesis of quinindolines that has appeared occasionally in
the literature.12 Despite the progress having been halted for a
decade, a very recent paper has revealed that the structural
diversity can be effectively broadened by a modified cationic
cyclization.13 The most commonly selected strategy emerging in
recent work is the ring expansion of an indole derivative.14 Due
to the continuous development in this strategy, various coupling
methods15 regarding the cyclization to furnish an extended
quinoline ring have been afforded in response to the diverse
structural requirement.
To increase the examples in the new synthetic pathway via the
transition-metal catalysis, we try to explore the new possibility
on the basis of our experience. Our continuous interest in the
catalytic annulation reactions by utilizing the C−N multiple
bonds as the reaction participants16,17 prompted us to develop a
new catalysis for the synthesis of quinindolines with versatile
substituents. Herein, we report the Pd-catalyzed dual annulation
Even though the structure library has been expanded by
accumulated research work, the limitation of synthetic methods
Received: January 23, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00287
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Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
b
entry
[M]
additive
solvent
temp (°C)
yield (%)
1
2
Cu2O
Cu(CH3CN)4BF4
Cu2O
Cu2O
CuI
Ni(cod)2
Ni(cod)2
Ni(cod)2
NiBr2(PPh3)2
CoI2(PPh3)2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd2(dba)3
Pd(OAc)2
Pd(PPh3)4
Pd(PPh3)4
DMSO
DMF
DMF
DMF
DMF
1,4-dioxane
1,4-dioxane
1,4-dioxane
CH3CN
DMF
1,4-dioxane
DMF
DMF
120
120
100
120
120
100
100
120
100
120
100
100
120
120
120
120
120
120
27
36
15
83
63
19
26
28
21
trace
0
c
3
BF3·OEt2
BF3·OEt2
BF3·OEt2
c
4
c
5
6
d
7
PPh3
PPh3
Zn
d
8
e
9
e
10
Zn
11
12
13
14
0
86
42
17
96 (93)
92
0
DMF
DMF
DMF
DMF
d
15
PPh3
PPh3
f g
h
16 ,
f i
17 ,
18
DMF
a
b
Reaction conditions: s1 (0.2 mmol, 1.0 equiv), [M] (10 mol %), solvent (2.0 mL), indicated temperature, under N2, 24 h. 1H NMR yield based
c
d
e
f
g
h
i
on internal standard mesitylene. 40 mol % BF3·OEt2. 20 mol % PPh3. 3.0 equiv of Zn. 8.0 mL of DMF. 5 mol % Pd(PPh3)4. Isolated yield. 3
mol % Pd(PPh3)4 and 3 mol % PPh3, 40 h.
reaction through an intramolecular addition of nitrile to
synthesize the norneocryptolepine derivatives.
Pd-catalyzed annulation reaction (Scheme 2). As indicated, the
reactions proceeded smoothly for a wide range of substrates.
Both of the electron-donating and the electron-withdrawing
groups are able to be well tolerated, and the yields clearly depend
on the electron density of every structural subunit. In general,
the products with an electron-deficient group on the quinoline
moiety were afforded in higher yields than those with an
electron-donating group. Substrates with the groups on the para
position to bromide affect the yields a lot (n2−n4), while the
yields for the substrates with the groups on the ortho position to
bromide are not so different (n5−n7). Notably, the amino
groups are also able to be fitted on the scaffold (n8, n9, and
n17); these amino derivatives have been reported to possess
some focused bioactivities, such as the antiplasmodial activity
and the inhibition of β-hematin formation.15a The easy access to
these structural types will significantly contribute to the
development of their structure−activity relationships in the
related pharmaceutical research. Products with the dimethoxy
groups and an extended dioxole ring on the quinoline moiety
(n10−n12) were generated in good yields. The fused ring
system could be extended to the benzoquinoline analog, and the
corresponding product n13 was provided in 83% yield.
The diverse substituents on the indole moiety were carefully
examined as well. It is interesting to note that the electron-
donating and the weak electron-withdrawing groups did not
result in an obvious difference in the reaction yield (n14−n18),
but the strong electron-withdrawing group CF3 provided a
comparably lower yield than others (n19). Also, products with
the disubstituted electron-donating groups (n20 and n21) were
obtained in higher yields than the monosubstituted structures.
Moreover, a wide range of structural diversity is available to be
established by the free combinations of the substituents on
different moieties. Thus, we created several structures (n22−
We started our initial study from the survey of transition-
metal catalysts by using compound s1 as the model substrate
(Table 1). In the beginning, our research focused on the copper
catalysis (entries 1−5); after a series of tests, we found that the
Cu2O/BF3·OEt2 catalytic system can provide the product n1 in
83% NMR yield (entry 4). However, the catalytic efficiency is
insufficient to be considered as a catalytic reaction (20 mol % Cu
loading). Further tunings of the reaction conditions were unable
to result in any improvement. We then turned our target to other
transition-metal catalysts, which have been known to participate
in a coupling reaction through activating a carbon−halide bond.
Several nickel, palladium, and cobalt complexes were thus
selected for the examinations, and the results are summarized in
Table 1 (entries 6−17) as well. The nickel complexes showed
low efficiency in this reaction; the best performance was
accomplished in only 28% yield by using Ni(cod)2/PPh3 as the
catalyst and 1,4-dioxane as the solvent (entry 8). The cobalt
complex is inactive; most of the substrate s1 was not able to be
converted, and only a trace amount of desired product n1 was
observed (entry 10). The palladium complexes were found to
have higher catalytic efficacy than others, and the Pd(PPh3)4 was
found to be the best catalyst in this reaction (entry 13). In
addition, lower concentration and additional phosphine ligand
are helpful for this catalysis. A nearly quantitative yield was
obtained in the presence of 5 mol % Pd(PPh3)4 in a quarter
concentration of DMF (entry 16). Further decrease of the
catalyst loading leads to slightly lower yield even with an
additional phosphine ligand (entry 17). The blank reaction in
DMF did not exhibit any reactivity (entry 18).
After the optimized condition was established, the substrate
scope was then investigated to understand the capacity of this
B
DOI: 10.1021/acs.orglett.9b00287
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Organic Letters
Letter
a
Scheme 2. Scope of the Reaction
Scheme 3. Synthesis of the Neocryptolepine
To verify the reaction pathway, several control experiments
have been conducted to understand the nature of the reaction
(Scheme 4), and we can obtain the information via observation
Scheme 4. Control Experiments
a
b
NMR yield. Determined by GC-MS after working up.
of different intermediates determined by NMR and GC-MS.
First, no reaction can proceed without catalyst or additive; the
intramolecular addition of aniline to nitrile can be executed only
with Lewis acid. The stronger Lewis acid tends to afford more
o1. Second, when a reaction proceeded in the presence of the
Pd(PPh3)4, we did not observe o1 but there was a trace amount
of a1 and o2. This result suggests that the oxidative addition of a
C−Br bond should be prior to the addition of aniline to nitrile.
We then replaced the substrate s1 with s1c and s1o and found
that, while the oxidative addition of a C−X bond is retarded, the
formation of the corresponding hydrogenated intermediates o1
and a1 is inhibited as well. However, when a C−I bond (s1i) was
utilized as the target of oxidative addition, the reaction rate is
faster than all other substrates, which indicates that the oxidative
addition is the key step to dominate the reaction. Third, addition
of D2O as the deuterium source was conducted as well to
monitor the change of intermediates. Interestingly, it was found
that the reaction was not affected by additional D2O; only s1 and
n1 were observed in the crude NMR spectra, and the GC-MS
analysis demonstrated that only a1 and a1′ are the detected
intermediates.
a
Reactions were carried out using 0.4 mmol (1.0 equiv) s with 5 mol
% Pd(PPh3)4 in 16 mL DMF at 120 °C for 24 h. Isolated yield.
n35) to reveal the reaction capacity, and the product n35 has
been verified by the single-crystal X-ray diffraction analysis for
additional confirmation.
As reported in previous literature,9a,12a the neocryptolepine
can be obtained by a methylation of the norneocryptolepine
(n1). Here, we show our synthetic route to lead to these two
alkaloids within four steps starting from two commercially
available compounds (Scheme 3). This strategy represents an
efficient pathway to reach these two alkaloids and implies that all
products are feasibly converted to their corresponding neo-
cryptolepine derivatives. Furthermore, the dual annulation
reaction can proceed in gram scale without significant loss of
the reaction yield.
C
DOI: 10.1021/acs.orglett.9b00287
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
On the basis of the previous reports16,17 and the above results,
a proposed reaction pathway accounting for this Pd-catalyzed
dual annulation is shown in Scheme 5. The reaction is initiated
ACKNOWLEDGMENTS
■
We thank the Ministry of Science and Technology of Republic of
China (MOST 107-2113-M-032-006) for financial support of
this research.
Scheme 5. Proposed Reaction Pathway
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*E-mail: jchsieh@mail.tku.edu.tw.
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