Pd-catalyzed cascade cyclization by intramolecular heck insertion of an allene-allylic amination sequence: Application to the synthesis of 3,4-fused tricyclic indoles

Article abstract of DOI:10.1021/acs.orglett.5b00973

A novel Pd-catalyzed cascade cyclization by intramolecular Heck insertion of an allene-allylic amination sequence was developed. Allenes tethered to ortho-iodoaniline derivatives at the meta-position were reacted with 5-10 mol % of Pd catalyst and 4 equiv

Full text of DOI:10.1021/acs.orglett.5b00973

Letter
pubs.acs.org/OrgLett
Pd-Catalyzed Cascade Cyclization by Intramolecular Heck Insertion
of an Allene−Allylic Amination Sequence: Application to the
Synthesis of 3,4-Fused Tricyclic Indoles
Shun-ichi Nakano, Naoya Inoue, Yasumasa Hamada, and Tetsuhiro Nemoto*
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan
S
* Supporting Information
ABSTRACT: A novel Pd-catalyzed cascade cyclization by intramolecular
Heck insertion of an allene−allylic amination sequence was developed.
Allenes tethered to ortho-iodoaniline derivatives at the meta-position were
reacted with 5−10 mol % of Pd catalyst and 4 equiv of K2CO3 in DMSO
at 90 °C, producing 3,4-fused tricyclic 3-alkylidene indoline derivatives in
moderate to excellent yield. The reaction products were divergently
transformed into three types of 3,4-fused tricyclic indole derivatives,
successfully demonstrating the versatile properties of the reaction
products.
3,4-Fused tricyclic indole skeletons are found in various
bioactive natural products and pharmaceuticals. Most of these
molecules possess a functionalized medium-size ring bridging
the C3- and C4-positions of the indole (Figure 1). This class
Expensive 4-haloindoles or their derivatives are therefore
often utilized as starting materials for the preparation of such
indole derivatives.1,2b−h,3d Recently, efficient construction of
the target skeleton was achieved using simple linear substrates
with an anilinic or aromatic ring moiety based on such
processes as intramolecular Fischer indole synthesis,4 intra-
molecular Larock indole synthesis,5 Rh-catalyzed intramolec-
ular dearomatizing [3 + 2] annulation of α-imino carbenoids,6
and Rh-catalyzed C−H activation.7
Allenes generally react with an aryl halide in the presence of
a Pd(0) catalyst to give the corresponding π-allylpalladium(II)
species through a Heck insertion process.8 Subsequent
nucleophilic addition to the π-allylpalladium(II) species
provides 2-aryl-3-substituted propene derivatives.9 We hy-
pothesized that treatment of allenes tethered to ortho-
iodoaniline derivatives at the meta-position I with a Pd(0)
catalyst in the presence of base would lead to the formation of
bicyclic π-allylpalladium(II) intermediates II through an
intramolecular Heck insertion process, which could be then
transformed into 3,4-fused tricyclic 3-alkylidene indoline
derivatives III via an intramolecular allylic amination (Scheme
1). Various isomerization protocols from 3-alkylidene indo-
lines into functionalized indole derivatives have been
reported,10 indicating that several types of 3,4-fused indole
derivatives are accessible using compound III as a common
precursor. Herein, we report a novel Pd-catalyzed cascade
cyclization by intramolecular Heck insertion of an allene−
allylic amination sequence that produces 3,4-fused tricyclic 3-
alkylidene indoline derivatives. The reaction products were
successfully transformed into three types of 3,4-fused tricyclic
indole derivatives.
Figure 1. Selected examples of biologically active 3,4-fused tricyclic
indoles.
of compounds is an attractive target in synthetic organic
chemistry due to the ubiquity of the structural motif in
bioactive molecules, as well as their characteristic structures.
Considerable efforts have focused on the development of a
synthetic method for this skeleton. The formation of the 3,4-
fused tricyclic indole framework generally involves building
the third ring onto a prefunctionalized indole substrate.1−3
Direct functionalization of the indole C4-position, however, is
difficult due to the low reactivity toward electrophiles.
Received: April 4, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00973
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Reaction Design
Table 1. Optimization of the Reaction Conditions
a
entry
solvent
base
ligand
PPh3
yield (%)
1
toluene
dioxane
CH3CN
DMF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Li2CO3
Cs2CO3
Ag2CO3
KOAc
0
0
2
PPh3
3
PPh3
33
64
72
31
42
0
4
PPh3
5
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
PPh3
First, a model substrate for the target cascade cyclization
was prepared using readily available compound 111 as the
starting material (Scheme 2). Reduction of the nitro group
followed by protection of the resulting amine with a tosyl
group afforded compound 2 in 70% yield (two steps). The
ester moiety in 2 was transformed into a bromomethyl group
by a two-step reaction sequence involving DIBAL-H reduction
and bromination (76% yield, two steps). The obtained benzyl
bromide derivative 3 was coupled with the known allenyl
compound 412 to give the model substrate 5a in 84% yield.
6
PPh3
7
PPh3
8
PPh3
9
PPh3
42
58
55
77
78
45
59
63
10
KOt-Bu
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
PPh3
b
11
PPh3
12
13
14
15
16
17
P(o-tol)3
P(2-furyl)3
XPhos
AsPh3
DPPE
DPPF
Scheme 2. Synthesis of Model Substrate 5a
75
a
b
Monodentate ligands: 12 mol %, bidentate ligands: 6 mol %. This
reaction was performed in DMSO (0.05 M).
a
Scheme 3. Substrate Scope
The reaction conditions were optimized using 5 mol % of
Pd(dba)2 and 4 equiv of K2CO3 at 90 °C (Table 1). Solvent
effect studies revealed that polar aprotic solvents were suitable
for this transformation, and the desired product 6a was
obtained in 72% yield using DMSO as the solvent (entries 1−
5). Reactions with other metal carbonates or other potassium
bases produced less satisfactory results (entries 6−10). The
yield was less satisfactory when the reaction concentration was
increased (entry 11). The effect of phosphorus ligands was
then investigated in DMSO using K2CO3 as a base (entries
12−17). Among the examined ligands, tri(2-furyl)phosphine
was the most effective ligand for this cascade cyclization, and
compound 6a was obtained in 78% yield (entry 13).
Under the optimal conditions, we examined the substrate
scope of the developed process using 5 mol % of Pd catalyst
(Scheme 3).13 In addition to tosyl derivative 6a, methane-
sulfonyl and 2,4,6-triisopropylbenzenesulfonyl derivatives 6b
and 6c were obtained from the corresponding allenyl
substrates 5a−c in 67−78% yield. Although the yield was
moderate, carboxybenzyl-protected substrate 5d was also
applicable to this reaction, and compound 6d was obtained
in 46% yield. The chemical yield improved to 57% when 10
mol % of Pd catalyst was used. The present cascade
a
Reactions were performed in DMSO (0.01 M) in the presence of 10
mol % of Pd(dba)2 and 24 mol % of P(2-furyl)3.
B
DOI: 10.1021/acs.orglett.5b00973
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
cyclization also proceeded using 1,3-disubstituted allenes 5e−
g as substrates, affording 2-substituted 3,4-fused tricyclic 3-
alkylidene indoline derivatives 6e−g in 74−86% yield. When
1,1-disubstituted allene derivative 5h and α-branched allene
derivative 5i were used, the corresponding products 6h and 6i
were obtained in moderate yield. The reaction using N-tosyl-
tethered-type substrate 5j and quaternary α-amino acid
derivative 5k proceeded under the same reaction conditions,
providing compounds 6j and 6k in 72 and 79% yield,
respectively. The yield of 6k improved to 94% yield using 10
mol % of Pd catalyst. Moreover, the reaction of 5l, bearing a
CH2-unit-longer tether than that in 5a, gave the correspond-
ing eight-membered ring-fused tricyclic 3-alkylidene indoline
derivative 6l in 68% yield when using 10 mol % of Pd
catalyst.
studies on the application of this process to natural product
synthesis, as well as mechanistic investigation into the reaction
pathway,14 are in progress.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedure, compound characterization, and
NMR charts. The Supporting Information is available free
of charge on the ACS Publications website at DOI: 10.1021/
acs.orglett.5b00973.
AUTHOR INFORMATION
■
Corresponding Author
Transformations of the reaction products into 3,4-fused
tricyclic indole derivatives were further examined (Scheme 4).
*E-mail: tnemoto@faculty.chiba-u.jp.
Notes
The authors declare no competing financial interest.
Scheme 4. Transformations of the Reaction Products into
3,4-Fused Tricyclic Indole Derivatives
ACKNOWLEDGMENTS
■
This work was supported by JSPS KAKENHI Grant No.
15K07850, Suzuken Memorial Foundation, and Chiba
University.
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derivatives. Using allenes tethered to ortho-iodoaniline
derivatives at the meta-position as substrates, an intra-
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the synthetic utility of the developed cascade process. Further
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D
DOI: 10.1021/acs.orglett.5b00973
Org. Lett. XXXX, XXX, XXX−XXX