Palladium-Catalyzed Stereoselective Aza-Wacker-Heck Cyclization: One-Pot Stepwise Strategy toward Tetracyclic Fused Heterocycles

Article abstract of DOI:10.1021/acs.orglett.0c03552

Palladium-catalyzed intramolecular tandem cyclization reactions were conducted for the synthesis of densely cis/cis-fused aza-tetracyclic structures. The process involved a palladium(II)-catalyzed aerobic aza-Wacker reaction, followed by a palladium(0)-catalyzed Heck reaction. The effects of the solvent and benzene substitution pattern on the one-pot, two-step cascade reaction were studied systematically, and a probable mechanism was proposed. Strained pentahydrobenzo[f]cyclopenta[hi]indolizin-6-one and racemic γ-lycorane can also be synthesized rapidly using this palladium-catalyzed aza-Wacker-Heck cyclization reaction.

Full text of DOI:10.1021/acs.orglett.0c03552

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Letter
Palladium-Catalyzed Stereoselective Aza-Wacker−Heck Cyclization:
One-Pot Stepwise Strategy toward Tetracyclic Fused Heterocycles
Rong-Shiow Tang, Li-Yuan Chen, Chin-Hung Lai, and Ta-Hsien Chuang*
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ABSTRACT: Palladium-catalyzed intramolecular tandem cycliza-
tion reactions were conducted for the synthesis of densely cis/cis-
fused aza-tetracyclic structures. The process involved a palladium-
(II)-catalyzed aerobic aza-Wacker reaction, followed by a
palladium(0)-catalyzed Heck reaction. The effects of the solvent
and benzene substitution pattern on the one-pot, two-step cascade
reaction were studied systematically, and a probable mechanism
was proposed. Strained pentahydrobenzo[f ]cyclopenta[hi]-
indolizin-6-one and racemic γ-lycorane can also be synthesized
rapidly using this palladium-catalyzed aza-Wacker−Heck cycliza-
tion reaction.
Scheme 1. Domino Reactions for Preparing cis/cis-Fused
Structures from Unactivated and Activated Alkenes
alladium-catalyzed reactions are powerful and versatile
tools in organic synthesis because of the capacity of
P
palladium to be used as both electrophilic [Pd(II)] and
nucleophilic [Pd(0)] catalysts.1 For example, the Pd(II)-
catalyzed oxidative amination of alkenes (i.e., aza-Wacker
reaction) is an efficient and simple method for the preparation
of a number of nitrogen-containing heterocyclic compounds.2,3
To the best of our knowledge, only a few aza-Wacker
cyclization reactions involving secondary amides have been
reported.4 This is because highly acidic nitrogen nucleophiles
(e.g., sulfonamides) are typically required, which require harsh
reaction conditions for their removal, limiting their application
in organic synthesis. Intramolecular Pd-catalyzed cascade
sequences have been developed to synthesize fused polycyclic
N-heterocycles.5 However, it is difficult to avoid β-hydrogen
elimination in some Pd-catalyzed oxidative tandem aza-
Wacker−Heck cyclization reactions, which inhibits the
subsequent olefin insertion in the alkylpalladium complex.6
Lycorine-type amaryllidaceae alkaloids, possessing a pyrrolo-
[de]phenanthridine ring system (galanthan) as the core
skeleton, exhibit several interesting biological activities (e.g.,
antitumor and antiviral activities).7 These diverse biological
activities have stimulated interest in the construction of the
galanthan tetracyclic skeleton.8,9 Recently, Lo et al.6a reported
the construction of an aza-tricyclic system by Pd-catalyzed
aerobic oxidative cyclization of unactivated alkenyl amides.
Unfortunately, the 6/5/5 fused aza-tricycle systems were
obtained in low yields because of the high ring strain (Scheme
1, eq 1). Moreover, Liu et al.10 reported a Pd-catalyzed cascade
reaction between resonance-stabilized methoxycarbonyl acet-
amides bearing o-haloaryl moieties and carbonyl-activated
olefins to construct the galanthan framework. However, 6/5/6
fused aza-tricycles are more difficult to synthesize via Pd-
catalyzed annulation than their 6/5/5 derivatives (Scheme 1,
eq 2). Hence, the development of an efficient one-pot cascade
cyclization of ring-containing unactivated alkenyl amides for
the synthesis of 6/5/6 fused aza-tricycles is needed.
We began developing a one-pot, two-step approach to
produce galanthan-7-ones (1) using a Pd-catalyzed aza-
Wacker−Heck reaction of unactivated alkenyl amides (2)
bearing o-bromophenyl moieties. In the first step, a Pd(II)-
catalyzed aza-Wacker reaction is used to fabricate N-
benzoylindole intermediate 3. When the starting material is
completely consumed, phosphine ligands (e.g., Ph2PPy and n-
Bu3P) are introduced to generate the requisite Pd(0) complex
Received: October 24, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03552
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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in situ. Tetracyclic galanthan-7-ones (1) can be formed via
subsequent Pd(0)-catalyzed Heck reaction. A series of starting
materials (2a−q) can be easily obtained in 68−89% yields
upon reacting commercially available 2-bromo-benzoic acids
(4a−q) with thionyl chloride, followed by the addition of 2-
(cyclohex-2-enyl)ethylamine (5)11 and N,N-diisopropylethyl-
amine (DIPEA) (Scheme 2). This synthetic strategy allows
access to a strained B−C−D ring system of ring A-substituted
tetracyclic fused heterocycles.
Table 1. Optimization of the One-Pot, Two-Step Cascade
Reaction Using Model Compound 2a
a
step
1
time
(h)
step
2
time
(h)
ligand
(equiv
of y)
equiv
entry of x
3a
(%)
b
solvent
1a (%)
1
2
3
0.5
0.4
0.4
DMSO
DMSO
DMSO
2
3
3
91
90
−
−
−
−
−
15
−
−
73 {9}
Scheme 2. Strategy for the Synthesis of Galanthan-7-ones
(1)
Ph2PPy
(1.6)
4
0.4
DMSO
3
−
n-Bu3P
(1.6)
15
77 {4}
5
6
0.3
0.3
DMSO
DMSO
7
7
90
−
−
20
−
14 Ph2PPy
(1.2)
48 {16}
7
0.3
DMSO
7
10 n-Bu3P
20
60 {6}
(1.2)
c
8
9
10
11
12
13
0.2
0.4
0.4
0.4
0.4
0.4
DMSO
DMSO
toluene
DMF
dioxane
CH3CN
15
24
6
6
6
87
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
d
32
trace
5
5
6
26
a
All of the screening reactions were carried out on a 0.2 mmol scale
under an oxygen atmosphere (balloon) in a 7 mL glass vial, and the
b
yield was determined upon isolation of the target product. The
c
values in braces show the yields of compound 6a. With 90%
d
conversion. Under an argon atmosphere (balloon), with 45%
conversion.
A one-pot, two-step cascade reaction was developed using a
series of 2-bromo-N-[2-(cyclohex-2-enyl)ethyl]benzamides
(2a−q) to afford a variety of galanthan-7-ones (1).
Unsubstituted benzamide 2a was selected as a model
compound to test the feasibility of the tandem cyclization
reaction (Table 1). Initially, Pd-catalyzed aerobic cyclization
was conducted in the presence of 0.2−0.5 equiv of Pd(OAc)2
at 65 °C in DMSO under an oxygen atmosphere to produce
the key bicyclic intermediate 3a.12 cis-Hexahydroindole 3a can
be obtained in 87−91% yield, but >0.2 equiv of Pd(OAc)2 was
needed to complete the reaction within 15 h (entries 1, 2, 5,
and 8 in Table 1). When the reaction was conducted in the
presence of 0.4 equiv of Pd(OAc)2 at 65 °C in DMSO under
an argon-filled balloon for 24 h, incomplete conversion of 2a to
3a was observed (entry 9). These results suggest that oxygen is
essential in the first step of the cascade reaction. The effect of
the solvent (DMSO, toluene, DMF, dioxane, and CH3CN) on
the cyclization reaction was also explored under the same
conditions, but only DMSO provided adduct 3a in high yield
(entry 2 vs entries 10−13). This result indicates that DMSO
acts as a ligand and coordinates to the Pd(II) metal center,
thus promoting intramolecular oxidative amination.2b,13
Furthermore, 1.6 equiv of Ph2PPy or n-Bu3P [4 times the
number of moles of Pd(OAc)2] was added to the aza-Wacker
reaction solution to generate the Pd(0) complex in situ, which
was then heated at 110 °C in a sealed vessel for 15 h. To our
delight, the intramolecular Heck reaction was successfully
conducted in DMSO to give cis/cis-fused galanthan-7-one 1a in
good yields (73% and 77%; entries 3 and 4, respectively). This
result indicates that the Pd(II)-catalyzed aerobic aza-Wacker
reaction and Pd(0)-catalyzed Heck reaction can be conducted
in a one-pot manner. However, the conversion of intermediate
3a to 1a was incomplete even when the second step was
allowed to continue for a long period of time; this was
attributed to the formation of insufficient Pd(0) when 0.3
equiv of Pd(OAc)2 was used in the one-pot, two-step reaction
(entries 6 and 7). Comparing entries 3 and 4 and entries 6 and
7 revealed that n-Bu3P was a better ligand than Ph2PPy
because the double-bond migration product (6a) was
produced in slightly greater yield when using Ph2PPy as the
ligand (Table 1). Finally, when the optimized reaction
conditions were fine-tuned (entry 4), the one-pot, two-step
Pd-catalyzed aza-Wacker−Heck reaction could be conducted
on a 1 mmol scale under a slow stream of oxygen rather than
using an oxygen-filled balloon. Galanthan-7-one 1a and isomer
6a were obtained in 70% and 9% yields, respectively (entry 1 in
Table 2).
A series of 2-bromo-N-[2-(cyclohex-2-enyl)ethyl]-
benzamides (2b−q), bearing different substituents on the
phenyl ring, were evaluated to investigate the effect of the
substituent on the yield of the one-pot, two-step aza-Wacker−
Heck reaction. The yields obtained for ring A-substituted
galanthan-7-ones 1b−q are listed in Table 2. Benzamides 2b−
d and 2f−h, bearing strongly activating (e.g., 3-OCH3, 4-
OCH3, and 5-OCH3, respectively) and weakly activating (e.g.,
3-CH3, 4-CH3, and 5-CH3, respectively) substituents,
produced galanthan-7-ones 1b−d and 1f−h, respectively, in
improved yields (76−82%) compared to those of their
unsubstituted derivative 1a (entry 1 vs entries 2−4 and 6−
8). However, 6-methoxybenzamide 2e and 6-methylbenzamide
2i gave slightly lower yields of galanthan-7-one 1e (68%) and
1i (64%), along with more of their corresponding double-bond
migration products [6e (11%) and 6i (11%)] (entry 1 vs
B
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Table 2. Effects of Substituents on the Yield of the One-Pot,
Two-Step Aza-Wacker−Heck Reaction
Scheme 3. A Plausible Mechanism for the One-Pot, Two-
Step Aza-Wacker−Heck Reaction
a
entry
2
R3
R4
R5
R6
1 (%); 6 (%)
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
H
OCH3
H
H
H
CH3
H
H
H
F
H
H
H
CF3
H
H
H
OCH3
H
H
H
CH3
H
H
H
F
H
H
H
CF3
H
H
H
H
OCH3
H
H
H
CH3
H
H
H
F
H
H
H
CF3
H
H
H
H
H
1a (70); 6b (9)
1b (82); 6b (5)
1c (77); 6c (8)
1d (81); 6d (3)
OCH3 1e (68); 6e (11)
H
H
H
CH3
H
H
H
F
H
H
H
CF3
1f (80); 6f (3)
1g (76); 6g (5)
1h (78); 6h (5)
1i (64); 6i (11)
1j (80); 6j (−)
1k (77); 6k (4)
1l (79); 6l (6)
1m (75); 6m (5)
1n (70); 6n (4)
1o (71); 6o (4)
1p (70); 6p (−)
9
10
11
12
13
14
15
16
17
hexahydroindole 3a. Subsequent β-hydride elimination of A
releases key intermediate 3a and a PdII−H species
(PdIILnHOAc) (step b). This PdII−H species may undergo
reductive elimination (step c), followed by O2 oxidation with
HOAc to regenerate the LnPdII(OAc)2 catalyst via Pd0Ln (step
d).15
H
H
b
H
1q (16); 6q (−)
a
All of the reactions were carried out on a 1 mmol scale under a slow
b
stream of oxygen. Product 1q was obtained in 55% yield using 1.0
and 0.4 equiv of Pd(OAc)2 in the first and second steps, respectively.
After completion of the aza-Wacker reaction, n-Bu3P was
added to reduce LnPdII(OAc)2 to a zero-valent palladium
complex [Pd(0)L′m, i.e., Pd0(PBu3)3(OAc)−]; n-Bu3P is
oxidized to its corresponding phosphine oxide via OAc−P(n-
entries 5 and 9). Unfortunately, double-bond isomerization
could not be suppressed upon addition of 1.0 equiv of AgNO3
in the second step, which typically acts as a trapping agent for
hydrohalic acids, probably due to the formation of DMSO-
solvated Ag(I) ions.14
16
+
Bu)3 (step e). Then, the oxidative addition of Pd(0)L′m to
bromide 3a, followed by syn-carbopalladation, affords
alkylpalladium(II) complex B with all-cis ring junctions (step
f). The cis/cis-fused product (1a) is then produced via β-
hydride elimination of B, followed by the release of a
hydridopalladium(II) bromide species (PdIIL′mHBr) (step
g).17 Finally, the PdII−H species undergoes reductive
elimination to regenerate the active Pd(0)L′m catalyst species;
the base (DIPEA) shifts this equilibrium toward the Pd(0)L′m
catalyst by quenching the HBr formed during the reaction
(step h). In contrast, the minor isomeric product (6a) is
produced via reinsertion of PdIIL′mHBr into product 1a (step
i), followed by β-hydride elimination (step j).6a Unfortunately,
formation of the side product (6a) cannot be inhibited by
adding AgNO3.
Benzamides 2j−m, bearing weakly deactivating fluoro
substituents on the phenyl rings, were next examined.
Surprisingly, no double-bond migration product was obtained
from 3-fluorobenzamide 2j (entry 10). In particular, the yield
of the double-bond migration product (6m) was lower than
those of 6e and 6i, bearing 6-OCH3 and 6-CH3, respectively
(entry 13 vs entries 5 and 9). Fluorinated galanthan-7-ones
1j−m were obtained in 75−80% yield (entries 10−13,
respectively). These results indicate that the fluoro substituent
on the phenyl ring may disfavor the double-bond migration
step. Furthermore, when benzamides 2n−q, bearing strongly
deactivating trifluoromethyl substituents on the phenyl rings,
were tested, their corresponding galanthan-7-one products
(1n−q) and their isomers were obtained in lower combined
yields, especially for 6-trifluoromethylgalanthan-7-one 1q
(entry 1 vs entries 14−17). Nevertheless, a higher yield of
1q (55%) could be obtained using a stoichiometric amount of
Pd(OAc)2 (footnote b in Table 2) and by prolonging the
reaction time (30 h) in the first step. These results suggest that
the cyclization reaction may be retarded because the
trifluoromethyl group deactivates the benzamide moiety.
On the basis of the aforementioned results, we propose a
plausible mechanism for the one-pot, two-step aza-Wacker−
Heck reaction using 2a as the model substrate (Scheme 3).
The reaction sequence begins with the coordination of the
amide and the alkene to LnPdII(OAc)2, followed by syn-
aminopalladation to afford cis-hydroxyindolyl palladium(II)
complex A (step a), as evidenced by the isolation of cis-
The one-pot, two-step Pd-catalyzed aza-Wacker−Heck
reaction was also extended to the synthesis of tetracyclic
fused heterocycle 9 with a more strained B−C−D ring system
(Scheme 4). The cyclopentene precursor (8) was obtained
from benzoic acid 4a and 2-(cyclopent-2-enyl)ethylamine
(7)18 in 81% yield by the same method as that used for the
synthesis of benzamides 2. Pd-catalyzed aerobic cyclization of
Scheme 4. Synthesis of More Strained Tetracyclic Fused
Heterocycle 9
C
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Authors
8 could be completed in 4 h, but a longer reaction time (48 h)
was needed for the Pd-catalyzed Heck reaction under the
cyclohexene-optimized reaction conditions (entry 4 in Table
1), probably because the 5/5/6 cis/cis-fused aza-tricycle is
more strained than the 6/5/6 cis/cis-fused aza-tricycle. No
double-bond migration product was observed, and tetracyclic
fused product 9 was obtained in 68% yield via the one-pot,
two-step Pd-catalyzed aza-Wacker−Heck reaction.
Recently, racemic γ-lycorane (11) was synthesized in a
concise manner by intramolecular acylal cyclization, Heck
reaction, high-pressure (60 bar) olefin hydrogenation, and
carbonyl reduction.19 The target product (11) can also be
produced by our developed one-pot reaction, followed by
olefin hydrogenation and carbonyl reduction (Scheme 5). The
Rong-Shiow Tang − School of Pharmacy, China Medical
University, Taichung 406040, Taiwan
Li-Yuan Chen − School of Pharmacy, China Medical
University, Taichung 406040, Taiwan
Chin-Hung Lai − Department of Medical Applied Chemistry,
Chung Shan Medical University, Taichung 40201, Taiwan
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03552
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Scheme 5. Synthesis of ( )-γ-Lycorane (11) Using the One-
Pot, Two-Step Aza-Wacker−Heck Cyclization Reaction
This project was financially supported by the Ministry of
Science and Technology, Taiwan (MOST 108-2113-M-039-
006), China Medical University (CMU 108-MF-72), and
Chung Shan Medical University (CSMU-INT-108-11).
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one-pot cyclization precursor (2r) was obtained from benzoic
acid 4r in 76% yield. Although a mixture of galanthan-7-one 1r
(73%) and its isomer (6r) (5%) was produced using the Pd-
catalyzed aza-Wacker−Heck reaction, the conversion of the
mixture of 1r and 6r to galanthan-7-one (10) can be
conducted at a lower pressure of hydrogen (85 psi), due to
the presence of nonconjugated double bonds. LiAlH4
reduction of lactam 10 produced γ-lycorane (11) in 80% yield.
In summary, we have developed a Pd-catalyzed aza-
Wacker−Heck cyclization reaction to construct the galanthan
skeleton. A series of ring A-substituted galanthan-7-ones and
pentahydrobenzo[f ]cyclopenta[hi]indolizin-6-one can be pre-
pared in good yields by this one-pot sequential C−N and C−C
bond-forming process. Racemic γ-lycorane was obtained from
2-bromo-4,5-methylenedioxybenzoic acid with an overall yield
of 42.6%. Efforts to determine the anticancer structure−activity
relationship in terms of the benzene substitution pattern of
cyclopenta[b]indol-3-yl-acetic acids using a palladium-cata-
lyzed aza-Wacker−Heck cyclization reaction are currently
underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03552.
Experimental procedures, characterization data, and
NMR spectra of new compounds 1, 2, 3a, 6, 8, and 9
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
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Catalyzed [4 + 2] Heterocyclization Sequence for Polyheterocycle
Generation. Org. Lett. 2018, 20, 5877−5880. (b) Alicea, J.; Wolfe, J.
P. Synthesis of Substituted Tetrahydroindoloisoquinoline Derivatives
Ta-Hsien Chuang − School of Pharmacy, China Medical
University, Taichung 406040, Taiwan; orcid.org/0000-
0001-7850-9366; Email: thchuang@mail.cmu.edu.tw
D
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