Pd(0)-catalyzed alkenylation and allylic dearomatization reactions between nucleophile-bearing indoles and propargyl carbonate

Article abstract of DOI:10.1021/ol501704q

Spiroindolenine derivatives were synthesized by intermolecular Pd-catalyzed dearomatization of indoles. The reaction between nucleophile bearing indoles and propargyl carbonate proceeds in a cascade fashion providing spiroindolenines or spiroindolines in

Full text of DOI:10.1021/ol501704q

Letter
pubs.acs.org/OrgLett
Pd(0)-Catalyzed Alkenylation and Allylic Dearomatization Reactions
between Nucleophile-Bearing Indoles and Propargyl Carbonate
Run-Duo Gao, Chuan Liu, Li-Xin Dai, Wei Zhang, and Shu-Li You*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Lu, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: Spiroindolenine derivatives were synthesized by
intermolecular Pd-catalyzed dearomatization of indoles. The
reaction between nucleophile bearing indoles and propargyl
carbonate proceeds in a cascade fashion providing spiroindole-
nines or spiroindolines in good to excellent yields.
tional dual electrophile has great potential to build spirocyclic
indolenine derivatives in a very convergent and direct manner
(Scheme 1). To the best of our knowledge, only sparse
examples utilizing such a reaction pattern have been reported.5
η3-π-allenylpalladium intermediates, generated from propargyl
carbonates in the presence of Pd (0) catalyst, are known to
react with carbonucleophiles to form π-allylic intermediates.6
We envisaged that the cascade reaction between nucleophile
bearing indoles and propargyl carbonate could be enabled by
Pd (0) catalyst providing a straightforward synthesis of
spiroindolenine. Herein we report a cascade reaction sequence
whereby an intermolecular alkenylation of a malonate with a
propargyl carbonate is followed by cyclization of the indole
moiety onto the resulting π-allyl species (Scheme 1).
At the outset, substituted indole 1a and propargyl carbonate
2 were chosen as the model substrates to test our hypothesis.
Initially, various ligands were tested in the presence of 2.5 mol
% of Pd2dba3 with THF as the solvent. As shown in Table 1,
monodentate ligand (4-MeOC6H3)3P or X-Phos did not afford
any desired product (entries 1 and 2, Table 1). To our delight,
the reaction with dppf could provide the desired product 3a in
17% yield (entry 3, Table 1). Other bidentate ligands such as
dppe, dppb, and dppp were also tested, and dppp could provide
the best result (21% yield, entries 4−6, Table 1). Thus, in the
presence of 2.5 mol % of Pd2dba3 and 5.5 mol % of dppp, we
then tested various solvents including dioxane, o-xylene, DMF,
and DMA (entries 7−10, Table 1). The reaction with DMA
provided the highest isolated yield of 3a (49% yield, entry 10,
Table 1).
olycyclic skeletons embedded within indoline moieties
Prepresent important structure motifs in numerous natural
products and pharmaceuticals.1 For the construction of these
valuable scaffolds, the strategy of dearomatization of indole
derivatives involving a cascade sequence has recently attracted
much attention due to its synthetic efficiency.2 Among them,
the synthesis of C-3 spirocyclic indolines are particularly
challenging. In this area, successful approaches have taken
advantage of the nucleophilicity of indoles and a preinstalled
intramolecular electrophile (Scheme 1, eq 1).3 In these cases,
relatively long synthetic routes are required for preparing such
designed substrates. We and other groups have reported
transition-metal catalyzed allylic dearomatizatation reactions of
indole derivatives to provide sprioindolenines (Scheme 1, eq
2).4 In contrast, an intermolecular cascade sequence of a simple
indole which contains a tethered nucleophile with a bifunc-
Scheme 1. Pd(0)-Catalyzed Reactions between Nucleophile-
Bearing Indoles and Propargyl Carbonate
Further screening of the ratio of 2 to 1a revealed that 1.3
equiv of 2 was optimal for this reaction (entries 10−12, Table
1). When the reaction was operated at 80 °C, an increased yield
was achieved (75%, entry 13, Table 1). Further examination of
substrate concentration led to the highest yield (96% yield,
entry 18, Table 1) at a low substrate concentration.
Received: June 12, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol501704q | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Optimization of the Reaction Conditions
Scheme 3. Substrate Scope for One-Pot Dearomatization
and Reduction
Scheme 4. Substrate Scope for One-Pot Dearomatization,
Reduction, and N-Acetylation
c
temp
(°C)
time
(h)
c
yield
(%)
a
entry
ligand
solvent
X
(mol/L)
b
1
L1
THF
50
50
50
50
50
50
50
50
50
50
50
50
80
80
80
80
80
80
24
24
24
24
24
24
24
24
24
24
24
24
12
12
12
12
12
12
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
2.0
4.0
1.3
1.3
1.3
1.3
1.3
1.3
0.067
0.067
0.067
0.067
0.067
0.067
0.067
0.067
0.067
0.067
0.067
0.067
0.067
0.2
NR
NR
17
b
2
X-Phos
dppf
THF
3
THF
4
dppe
dppb
dppp
dppp
dppp
dppp
dppp
dppp
dppp
dppp
dppp
dppp
dppp
dppp
dppp
THF
NR
17
5
THF
6
THF
21
7
dioxane
o-xylene
DMF
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
NR
NR
38
8
9
10
11
12
13
14
15
16
17
18
49
45
41
75
42
0.1
71
0.05
80
0.04
89
0.033
96
a
Reaction conditions: 1a (0.2 mmol), 2 (0.26 mmol), Pd2dba3 (2.5
b
mol %), and L (5.5 mol %) in solvent. Reaction conditions: 1a (0.2
mmol), 2 (0.26 mmol), Pd2dba3 (2.5 mol %), and L (11 mol %) in
THF. Isolated yield.
Interestingly, when a methyl was introduced to the 2-position
of the indole moiety, a satisfactory yield (3c, 83% yield) was
obtained. A preliminary enantioselective study disclosed that
product 3c could be obtained in 73% yield and 52% ee by using
(R)-SEGPHOS as the ligand. However, when more bulky
substituents were tested, significant decreasing of yields was
found (3d, 46% yield and 3e, 12% yield). Finally, improvement
of the yield could be realized by using SEGPHOS as the ligand
(3e, 69% yield and 3f, 76% yield).
c
Scheme 2. Substrate Scope
In general, the spiroindolenine product bearing no
substituent at the C2 position of the corresponding indole is
not stable under acidic conditions. To address this problem,
one-pot reaction by including an in situ reduction was carried
out to convert the imine moiety to the corresponding amine. As
shown in Scheme 3, for substrate 1a, the reduction product 4a
was obtained in an excellent yield (89%). Under this operation,
several substrates by varying the ester group or the substituent
on the indole ring were investigated. In all cases, the substrates
bearing a substituent (6-F, 6-Cl, 6-OMe) regardless of the
electronic property could be smoothly converted to dearom-
atized products in reasonable yields.
As shown in Scheme 3, since the in situ reduction operation
could only provide the substrates with a 6-substituent in good
yields, further manipulation of the product was necessary. Thus,
a further protection of amine by reacting with acetic anhydride
was added to the one-pot procedure. The results are shown in
Scheme 3. Subjecting substrate 1b into this three-step, one-pot
procedure led to the isolation of amide 5a in 77% yield. For
Under the optimized reaction conditions [0.2 mmol 1, 0.26
mmol 2, 2.5 mol % Pd2dba3, 5.5 mol % dppp, DMA (6 mL), 80
°C], the scope of the reaction was then explored. As
summarized in Scheme 2, the substrate 1b bearing ethyl ester
also worked well to afford product 3b in 63% yield.
B
dx.doi.org/10.1021/ol501704q | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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indole moiety, moderate to good yields were achieved (5b−e,
Scheme 4). The substrate with a methyl group at the C7
position could also be tolerated (5f, 28% yield, Scheme 4). The
moderate yield was mainly caused by the steric hindrance of the
methyl group during the acetylation of amine step. Finally, the
structure of the products was determined by an X-ray
crystallographic analysis of a single crystal of 5d.7
In summary, we have developed an intermolecular Pd-
catalyzed dearomatization of nucleophile bearing indoles, which
provides an efficient synthesis of spiroindolenine and spiroindo-
line derivatives. Further extension of the reaction scope and
development of a highly enantioselective variant are currently
ongoing in our laboratory.
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During revision of this manuscript, an elegant report on Pd-catalyzed
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and analysis data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: slyou@sioc.ac.cn.
Notes
The authors declare no competing financial interest.
(6) For a review, see: (a) Tsuji, J. Palladium Reagents and Catalysts:
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ACKNOWLEDGMENTS
■
We thank the National Basic Research Program of China (973
Program 2010CB833300), National Natural Science Founda-
tion of China (21025209, 21121062, 21272252, 21332009),
and the Science and Technology Commission of Shanghai
Municipality (13JC1406900) for generous financial support.
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2011, 353, 73. (f) Yoshida, M.; Sugimura, C. Tetrahedron Lett. 2013,
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