Pd(II)-catalyzed one-step construction of cycloalkane-fused indoles and its application in formal synthesis of (±)-aspidospermidine

Article abstract of DOI:10.1021/ol500662f

A highly efficient, redox-free Pd(II)-catalyzed tandem cyclization reaction initiated by intramolecular aminopalladation of alkynes followed by nucleophilic addition to nitriles is developed. This method provides a versatile approach for the synthesis of six- to eight-membered ring-fused indoles in one step and has also shown advantages in the formal synthesis of (±)-aspidospermidine.

Full text of DOI:10.1021/ol500662f

Letter
pubs.acs.org/OrgLett
Pd(II)-Catalyzed One-Step Construction of Cycloalkane-Fused Indoles
and Its Application in Formal Synthesis of ( )-Aspidospermidine
Guoqin Xia, Xiuling Han,* and Xiyan Lu*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Road, Shanghai, 200032, China
S
* Supporting Information
ABSTRACT: A highly efficient, redox-free Pd(II)-catalyzed
tandem cyclization reaction initiated by intramolecular amino-
palladation of alkynes followed by nucleophilic addition to
nitriles is developed. This method provides a versatile
approach for the synthesis of six- to eight-membered ring-
fused indoles in one step and has also shown advantages in the
formal synthesis of ( )-aspidospermidine.
Scheme 1. Aminopalladation-Initiated Nucleophilic Addition
to Nitriles
yclohexa[b]indoles, as well as cyclopenta-, cyclohepta-,
Cand cycloocta[b]indoles, are found to be core structures
in a broad category of natural products and synthetic
pharmaceuticals.1 To date, much work has been directed
toward the installation of five- to eight-membered rings onto
indoles. The most commonly used method is the Fischer indole
synthesis which, although very powerful, still holds some
drawbacks such as harsh reaction conditions and the use of
various kinds of highly functionalized hydrazines and cyclo-
ketones which are not very easily accessed.2 Recently, although
many novel methods for the synthesis of cycloalkane-fused
indoles have been reported,3 methods to install the above ring
systems onto indoles in a single step are still rare.4 In addition,
if a functional group such as a carbonyl group can be
introduced in the fused indoles, considerable conveniences may
be achieved in the further transformations.
In recent years, transition-metal-catalyzed nucleophilic
addition reactions to nitriles have been developed as efficient
approaches for the synthesis of aryl ketones and other useful
compounds.5−7 These reactions exhibit many advantages
compared to the classical Grignard reaction. They are normally
catalytic, atom-economic, easily handled, and tolerant of many
functional groups. Generally, the nitrile group is less reactive
than other carbon−heteroatom multiple bonds such as
carbonyl group or imines in palladium chemistry. However,
from our previous work, it was found that the vinylpalladium
species can add to nitriles easily in some acetoxypalladation-
initiated reactions due to the increased polarity of the C−Pd
bond caused by the electron-donating effect of the oxygen atom
at the α-position.8 On the basis of this work, we wondered if
the electron-donating effect of the nitrogen atom at the α-
position (Scheme 1, species A) could also increase the polarity
of the C−Pd bond, which may promote the nucleophilic
addition to the nitriles. As far as we know, such tandem
reactions initiated by an aminopalladation of an alkyne and an
addition to the nitriles as the quenching step of the carbon−
palladium bond have not been reported.
With these considerations in mind, we initiated our
explorations by using 1a as the model substrate. It was
proposed that a Pd(II) intermediate B can be easily formed
through trans-aminopalladation of substrate 1a in Scheme 1,9
and the subsequent addition of the C−Pd bond to the nitrile
group led to the expected cyclohexa[b]indole (Scheme 1,
pathway a). According to the literature, the C−Pd bond in
species B is not stable: it undergoes protonolysis very easily,
especially when the reaction counterpart is an inert nitrile
group (Scheme 1, pathway b).10 We may enable the expected
pathway in two ways: one strategy is to stabilize the C−Pd
bond in species B by adding ligands, another way is to activate
the nitrile group.
First, we tested several Pd(II) catalysts using 2,2′-bipyridine
as the ligand. Pd(OAc)2, PdCl2, and some cationic Pd(II)
catalysts showed no reactivity under the neutral conditions
(Table 1, entries 1−6), while under the basic conditions,
cyclization product 2a cannot be detected, and only
protonolysis product 3 was formed even when no catalyst
Received: March 3, 2014
© XXXX American Chemical Society
A
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Letter
a
a
Table 1. Optimization of the Reaction Conditions
Table 2. Construction of Cyclohexa[b]indole
b
R1
R2
X
yield (%)
product
entry
R
b
entry
catalyst
Pd(OAc)2
ligand
additives
(yield, %)
1
2
Ts
Ms
Boc
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
H
H
H
H
H
H
H
H
H
H
H
H
H
Et
C(CO2Me)2 (1a)
C(CO2Me)2 (1b)
C(CO2Me)2 (1c)
C(CO2Me)2 (1d)
C(CO2Me)2 (1e)
C(CO2Me)2 (1f)
C(CO2Me)2 (1g)
C(CO2Me)2 (1h)
NTs (1i)
99 (2a)
94 (2b)
0
1
2
3
4
bpy
bpy
bpy
bpy
N.R.
N.R.
N.R.
N.R.
N.R.
N.R.
Pd(TFA)2
c
3
Pd(CH3CN)4(BF4)2
PdCl2
4
4-Me
5-MeO
4-Cl
4-CF3
4-F
95 (2d)
98 (2e)
79 (2f)
75 (2g)
90 (2h)
94 (2i)
trace
5
c
5
(bpy)Pd(H2O)2(OTf)2
6
6
[(bpy)Pd(μ−
7
OH)]2(OTf)2
8
7
8
Pd(OAc)2
Pd(OAc)2
LiBr
3 (trace)
3
9
H
bpy
bpy
bpy
bpy
bpy
dppp
Cs2CO3
Cs2CO3
HOAc
10
11
H
O (1j)
d
9
3
H
CH2 (1k)
96 (2k)
e
10
Pd(OAc)2
Pd(OAc)2
2a (99)
2a (92)
N.R.
a
The reaction was carried out using 1 (0.2 mmol), Pd(OAc)2 (5 mol
%), and bpy (10 mol %) at reflux for 8 h in dioxane/HOAc (2.0:0.5).
Isolated yield. The starting material was recovered when HOAc was
11
TsOH·H2O
HOAc
e
12
b
c
f
13
Pd(OAc)2
HOAc
N.R.
used as the acid, and the reaction became complicated when TsOH·
a
The reaction was carried out using 1a (0.2 mmol), Pd(II) catalyst (5
mol %), ligand (10 mol %), and additives (2 equiv) at reflux for 8 h in
H2O was added.
b
dioxane (2.0 mL). Yield of 2a was isolated yield. The yield of 3 was
To expand the scope of this cyclization reaction further,
substrate 4a (Scheme 2) was tried for the synthesis of
c
d
not determined. MeOH/H2O (1:1) was used as the solvent. MeCN
e
was used as the solvent. Dioxane/HOAc (4:1) was used as the
solvent. The amount of dppp was 1.2 equiv based on palladium
f
Scheme 2. Construction of Cyclohepta- and
Cycloocta[b]indoles
acetate.
a
was added (Table 1, entries 7−9). Finally, to our delight, when
the reaction was conducted under acidic conditions, the
expected cascade cyclization proceeded very smoothly to give
product 2a in high yield, indicating that the addition of an acid
may enhance the reactivity of the nitrile group. With acetic acid
as the additive, almost quantitative yield was obtained, while
TsOH·H2O also provided 92% yield (Table 1, entries 10 and
11). Dioxane was found to be the best solvent for the reaction.
Control tests showed that no reaction occurred in the absence
of the catalyst (Table 1, entry 12). Other bidentate ligands such
as dppp inhibited the cyclization (Table 1, entry 13).
Having established the optimal conditions, we set out to
investigate the substrate scope of this cyclization reaction for
the synthesis of cyclohexa[b]indoles. First, substrates with
electron-withdrawing groups on the nitrogen atom were tested.
It was found that the tosyl group was most suitable for the
reaction, and the mesyl group gave a slightly lower yield. No
cyclization product was formed when the substituent is a Boc
(Table 2, entries 1−3). Substrate without substituent on the
nitrogen atom was also tried, and no product was detected
under the same conditions. Then, the substituents on the
benzene ring were investigated. Substrates with electron-
donating groups such as methyl or methoxy gave excellent
yields, while electron-withdrawing groups such as trifluor-
omethyl gave a lower yield (Table 2, entries 4−7). Substrate
with a fluorine atom on the benzene ring also worked well
(Table 2, entry 8). Finally, the synthesis of the heterocyclic ring
fused indoles was explored. Substrate 1i (X = NTs) can be
transformed to the product 2i efficiently. However, substrate 1j
(X = O) only provided a trace of the product (Table 2, entries
9 and 10). Moreover, an α-substituted nitrile also gave the
excellent yield (Table 2, entry 11).
a
The reaction was carried out using 4a−f (0.2 mmol), Pd(OAc)2 (5
mol %), bpy (10 mol %), and TsOH·H2O (2 equiv) at reflux for 5−8 h
in dioxane.
cyclohepta[b]indole. Disappointingly, no expected product was
detected under the standard conditions for cyclohexa[b]-
indoles. It was suggested that intermolecular acetoxypalladation
of the alkyne might also occur in the first step in the presence
of acetic acid, which made the reaction complicated.8 We then
tried other acids such as H3PO4 and TsOH·H2O. Fortunately,
when 2 equiv of TsOH·H2O was added, cyclization product 5a
was obtained in 83% yield. Some other substrates were also
examined for the synthesis of cyclohepta[b]indoles. Substrates
containing a nitrogen atom gave excellent yields (Scheme 2, 5c
and 5d). Using these optimal conditions, cycloocta[b]indoles
were also formed successfully (Scheme 2, 5e and 5f), which
were previously not very easily accomplished. In the literature,
B
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Letter
only a few examples were reported on installing eight-
membered rings onto indoles but with poor conversion or
requiring equivalents of metals.4d,11
Scheme 5. Synthetic Routes for ( )-Aspidospermidine
Having installed six- to eight-membered rings onto indoles
successfully, we set out to investigate the construction of
cyclopenta[b]indoles. The tandem cyclization did not occur at
all and only protonolysis product 7 was obtained when
substrate 6 was used for the reaction (Scheme 3, eq a).
Scheme 3. Construction of Cyclopenta[b]indoles
Sonogashira coupling without purification.15 The coupling
product was treated with p-toluenesulfonyl chloride, and
compound 12 was obtained in 61% yield over two steps from
11. Compound 12 was transformed to 13 successfully in 89%
yield using the method described in this paper. It was
noteworthy that this reaction can be conducted on a multigram
scale, and the catalyst amount can be reduced to 1 mol %. Then
13 was transformed to 14 via reductive amination, and 14 was
used directly for the next step without purification. The
carbonyl group in 14 was reduced to hydroxy group using
LiAlH4, after which the Ts group was removed using KOH as
the base and EtOH as the solvent under 80 °C. The crude
product was worked up with acetic acid and led to amino
alcohol 15 in 65% yield over three steps. The transformation of
15 to ( )-aspidospermidine has been reported.14c
Interestingly, when compound 8 was used under the standard
conditions for cyclohexa[b]indoles, the carbon−palladium
bond added to the carbonyl group preferentially to form
product 9 in 75% yield (Scheme 3, eq b). These results
indicated that carbonyl groups are more reactive than nitrile
groups in this reaction.
To gain further insight into the possible mechanism, a
control experiment was conducted. Substrate 3 was employed
using the same conditions as Scheme 2, but no reaction
occurred at all (Scheme 4), indicating that our reaction is a
Scheme 4. Control Experiment for the Possible Mechanism
In conclusion, we have developed a highly efficient method
for the construction of six- to eight-membered ring-fused
indoles via intramolecular aminopalladation of alkynes followed
by nucleophilic addition to nitriles. For cyclohepta[b]indoles
and cycloocta[b]indoles, TsOH·H2O must be used instead of
HOAc to avoid the acetoxypalladation-initiated side reactions.
Still unclear is the failure of constructing cyclopenta[b]indoles
using this method, and study on this subject is ongoing. This
reaction was catalyzed by palladium(II) without the necessity of
a redox system. The method has shown its application in the
formal synthesis of ( )-aspidospermidine and may find further
applications in the synthesis of other indole alkaloids.
tandem cyclization (as shown in Scheme 1, pathway a), but not
a one-pot, two-step process (first formation of 3, followed by
Friedel−Crafts type reaction or palladium catalyzed nucleo-
philic addition).12
Because of the general fact that cyclohexa[b]indole cores are
privileged heterocyclic ring systems found in a large number of
indole alkaloids, we became interested in applications of this
method in the synthesis of natural products. ( )-Aspidosper-
midine was then chosen as the target molecule. As a
representative member of the indole alkaloids isolated from
aspidosperma,13 aspidospermidine has attracted many chemists’
interests due to its unique fused-ring system. So far there have
been dozens of articles about synthetic approaches to racemic
and optically active aspidospermidine.14 We hoped to construct
the skeleton of this compound using our method as a key step.
The newly formed carbonyl group would undergo further
transformations to provide great conveniences in the later
processes (Scheme 5).
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, compound characterization data, and
copies of NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
The synthesis was started with the starting material 10.
Compound 11 was obtained in 88% yield via a nucleophilic
substitution with butyronitrile using LDA as the base. Then a
similar nucleophilic reaction was performed by reacting 11 with
1-iodo-3-butyne, and the product was used directly for the next
*E-mail: xylu@mail.sioc.ac.cn.
*E-mail: xlhan@mail.sioc.ac.cn.
Notes
The authors declare no competing financial interest.
C
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Organic Letters
Letter
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13334.
ACKNOWLEDGMENTS
■
We thank the National Basic Research Program of China
(2011CB808706), National Natural Science Foundation of
China (21232006, 21272249), and Chinese Academy of
Sciences for financial support.
REFERENCES
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