Palladium-Catalyzed Carbonylative Dearomatization of Indoles

Article abstract of DOI:10.1021/acs.orglett.9b01868

An interesting palladium-catalyzed dearomative carbonylation of N-(2-bromobenzoyl)indoles has been developed. The catalytic system is composed of commercially available Pd(OAc)₂ and DPPP and uses alcohols and anilines as nucleophiles to afford moderate to good yields of the desired products. This method provides a straightforward access to diverse fused indoline esters and amides with good functional group tolerance. Remarkably, this is the first example of carbonylative dearomatization.

Full text of DOI:10.1021/acs.orglett.9b01868

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Palladium-Catalyzed Carbonylative Dearomatization of Indoles
Hai Wang and Xiao-Feng Wu*
Leibniz-Institut fur Katalyse e.V.an der Universitat Rostock, Albert-Einstein-Straße 29a, 18059 Rostock, Germany
̈
̈
S
* Supporting Information
ABSTRACT: An interesting palladium-catalyzed dearomative
carbonylation of N-(2-bromobenzoyl)indoles has been
developed. The catalytic system is composed of commercially
available Pd(OAc)2 and DPPP and uses alcohols and anilines
as nucleophiles to afford moderate to good yields of the
desired products. This method provides a straightforward
access to diverse fused indoline esters and amides with good
functional group tolerance. Remarkably, this is the first example of carbonylative dearomatization.
Scheme 1. Transition-Metal-Catalyzed Dearomative
Reactions of Indoles
n recent years, as one of the most powerful methods for the
Iconstruction of fused or spiro polycyclic units, which are
ubiquitously found in numerous natural products and bioactive
compounds, the transition-metal-catalyzed dearomative reac-
tion has attracted much attention.1 Many elegant dearomative
reactions have been reported involving anilines,2 phenols,3
indoles,4 pyrroles,5 and other substrates.3e,h,6 Among them,
indoles are a very important class of organic heterocyclic
compounds with a variety of biological activities and advanced
applications.7 Hence, the development of new procedures for
the synthesis and transformation of indole derivatives is always
in demand.8 In 2012, Wu, Yao and their co-workers disclosed a
straightforward method for the synthesis of isoindolinonefused
indolines via an intramolecular Heck reaction and dearomative
process (Scheme 1, eq a).9 In 2015, Jia and co-workers
reported the first example of a palladium-catalyzed enantiose-
lective reductive-Heck dearomative reaction using sodium
formate as the hydride source (Scheme 1, eq b).10 In 2017, an
example of a nickel-catalyzed asymmetric reductive-Heck
dearomative reaction of indoles using water as the proton
source was reported by the Zhou group (Scheme 1, eq b).11
Lin, Yao and their co-workers developed an attractive process
for an oxidative-Heck dearomative reaction of indoles with
palladium as the catalyst.12 In general, the benzylic palladium
species was formed during the Heck dearomative reaction of
indoles. By trapping the benzylic palladium species with
different nucleophiles such as cyanides,13 organoboron
reagents,14 alkynes,15 azoles,16 and H-phosphonates,17 a series
of palladium-catalyzed diastereoselective dearomative bisfunc-
tionalizations of N-(2-bromobenzoyl)indoles have been
established by the research groups of Jia and Lautens,
respectively (Scheme 1, eq c).
On the other hand, carbonylative transformation has been
an attractive topic for both academia and industry for a long
time.18 Even though many novel palladium-catalyzed carbon-
ylation reactions have been developed and applied, no example
on carbonylative dearomatization has been realized to date.
Herein, we disclosed the first example of carbonylative
dearomatization (Scheme 1, eq d). With palladium as the
catalyst, N-(2-bromobenzoyl)indoles were carbonylated with
alcohols and anilines to give the corresponding indoline esters
and amides in moderate to good yields.
Received: May 30, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01868
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Screening of Optimal Reaction Conditions
Scheme 2. Substrate Scope of N-(2-Bromobenzoyl)indoles
and Anilines
a
b
c
entry
base
temp
CO
ligand
dppp
dppp
dppp
dppp
dppp
yield
9%
16%
0%
19%
26%
dr
a
Reaction conditions: 1 (0.2 mmol), anilines (4.0 equiv), Pd(OAc)2
(10 mol %), dppp (10 mol %), Na2WO4·2H2O (1.0 equiv), toluene
(2.0 mL), CO (5 bar), 100 °C, 24 h, isolated yields.
1
2
3
4
5
HCOONa
Et3N
DBU
K2CO3
Na2WO4·
2H2O
100 °C
100 °C
100 °C
100 °C
100 °C
5 bar
5 bar
5 bar
5 bar
5 bar
1:1
2:1
1:2
2:1
catalyst and DPPP as the ligand, we carried out the
dearomative carbonylation reaction under 5 bar of CO using
2.0 equiv of HCOONa as the base in 2.0 mL of toluene at 100
°C for 20 h. To our delight, the desired product 2a was formed
in 9% yield with a 1:1.4 diastereomer ratio (dr) (Table 1, entry
1); meanwhile, byproducts 3a, 4a, 5a, and 6a were produced as
well. To further improve the yield of the desired product 2a, a
series of optimizations were performed, and the results are
summarized in Table 1. Several bases were screened, and the
obtained results show that the best yield (26%) of 2a can be
obtained by employing Na2WO4·2H2O as the base (Table 1,
entry 5). With strong base DBU, the starting material 1a
decomposed and reacted with aniline in the presence of CO
gas producing a large amount of byproduct 5a N-phenyl-
phthalimide. By lowering the equivalents of Na2WO4·2H2O
from 2.0 to 1.2 equiv, the yield of 2a increased from 26% to
50% (Table 1, entry 7). However, no desired product was
observed in the absence of base (Table 1, entry 6).
The effects of the reaction temperature and CO gas pressure
were also tested. The yield of the target product decreased
dramatically by increasing or decreasing the temperature/CO
pressure (Table 1, entries 7−10). Only a trace amount of the
desired product could be detected even when the reaction was
performed at 120 °C; a large amount of byproduct 5a was
produced (Table 1, entry 9). By employing 1.0 equiv of
Na2WO4·2H2O as the base and increasing the loading of
aniline, the yield of 2a can be further improved. The reaction is
able to give the best yield (57%) of 2a with 2:1 dr and a 53%
isolated yield when using 4.0 equiv of aniline as the
nucleophilic reagent (Table 1, entry 14). A series of phosphine
ligands were also screened subsequently (Table 1, entries 15−
20). No desired product could be detected when dppm or
Xantphos was used as the ligand (Table 1, entries 15 and 16).
By using dppb, dppe, dppf, and rac-BINAP as the ligand, the
reaction can proceed but with lower reaction efficiency
compared with dppp (Table 1, entries 17−20). The influences
of palladium precursors and solvents were investigated as well,
6
7
−
100 °C
100 °C
5 bar
5 bar
dppp
dppp
0%
50%
d
d
Na2WO4·
2:1
2:1
2H2O
8
Na2WO4·
80 °C
5 bar
5 bar
2 bar
10 bar
5 bar
5 bar
5 bar
5 bar
5 bar
5 bar
5 bar
5 bar
5 bar
dppp
dppp
dppp
dppp
dppp
dppp
dppp
dppm
19%
2H2O
d
9
Na2WO4·
120 °C
100 °C
100 °C
100 °C
100 °C
100 °C
100 °C
100 °C
100 °C
100 °C
100 °C
100 °C
Trace
2H2O
d
10
11
12
13
14
15
16
17
18
19
20
Na2WO4·
26%
2:1
3:1
2:1
2:1
2:1
2H2O
d
Na2WO4·
26%
2H2O
e
Na2WO4·
50%
2H2O
ef
,
Na2WO4·
53%
2H2O
eg
,
Na2WO4·
57%
2H2O
(53%)
ef
,
Na2WO4·
0%
2H2O
ef
,
Na2WO4·
Xantphos 0%
2H2O
ef
,
Na2WO4·
dppb
dppe
14%
1:1
1:1
1:1
2:1
2H2O
ef
,
Na2WO4·
36%
13%
17%
2H2O
ef
,
Na2WO4·
dppf
2H2O
ef
,
Na2WO4·
BINAP
2H2O
a
Reaction conditions: 1a (0.2 mmol), aniline (2.0 equiv), Pd(OAc)2
(10 mol %), dppp (10 mol %), Na2WO4·2H2O (2.0 equiv), toluene
b
(2.0 mL), CO (5 bar), 100 °C, 20 h, nd = not detected. Determined
c
by GC using hexadecane as the internal standard. Determined by
d
e
GC. Na2WO4·2H2O (1.2 equiv). Na2WO4·2H2O (1.0 equiv).
Aniline (3.0 equiv). Aniline (4.0 equiv).
f
g
Initially, N-(2-bromobenzoyl)indole 1a was chosen as the
model substrate, and using aniline as the nucleophilic reagent
in the presence of commercially available Pd(OAc)2 as the
B
DOI: 10.1021/acs.orglett.9b01868
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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Scheme 3. Substrate Scope of N-Benzoyl Indoles with
Methanol
Scheme 4. Substrate Scope of N-Benzoyl Indole with
a
a
Different Alcohols
a
Reaction conditions: Substrate (0.2 mmol), Pd(OAc)2 (10 mol %),
dppp (10 mol %), Na2WO4·2H2O (2.0 equiv), LiBr (20 mol %),
toluene (1.2 mL), ROH (0.8 mL), CO (5 bar), 120 °C, 48 h, isolated
yields.
Scheme 5. Possible Reaction Pathway
a
Unless otherwise stated, all the reactions were run using the
following reaction conditions: (Condition A) Substrate (0.2 mmol),
Pd(OAc)2 (5 mol %), dppp (5 mol %), Na2WO4·2H2O (2.0 equiv),
LiBr (20 mol %), toluene (1.6 mL), MeOH (0.4 mL), CO (2 bar), N2
(3 bar), 120 °C, 24 h, isolated yields; (Condition B) Substrate (0.2
mmol), Pd(OAc)2 (10 mol %), dppp (10 mol %), Na2WO4·2H2O
(2.0 equiv), LiBr (20 mol %), toluene (1.6 mL), MeOH (0.4 mL),
CO (5 bar), 100 °C, 24 h, isolated yields. [b] Pd(OAc)2 (10 mol %),
b
dppp (10 mol %). Pd(OAc)2 (10 mol %), dppp (10 mol %).
but without improved results (for details, see Supporting
Information). After extensive experimentation, the optimal
conditions were established as Pd(OAc)2 (10 mol %), dppp
(10 mol %), aniline (4.0 equiv), Na2WO4·2H2O (1.0 equiv),
CO (5 bar) in toluene (2.0 mL) at 100 °C for 20 h (Table 1,
entry 14).
With the optimized reaction conditions in hand, the scope of
various N-(2-bromobenzoyl)indoles 1 with different anilines
was subsequently examined (Scheme 2). In general, the
corresponding products can be obtained in moderate yields.
Interestingly, a single diastereomer of the corresponding
product 2c was obtained, which might be due to the steric
effect of the 2-substituted chlorine of aniline. It is also
important to mention that due to the transamidation reaction
between anilines and N-(2-bromobenzoyl)indoles, byproduct
5a and analogues always present in the reaction mixture.
Together with the other byproducts 3a, 4a, 6a, and analogues,
and also the poor solubility of amides, it is quite a challenge to
purify the desired product from a mixture of amides.
C
DOI: 10.1021/acs.orglett.9b01868
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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In order to overcome the challenges mentioned, we studied
this carbonylative dearomatization reaction with alcohols as
the nucleophiles (for details on fine optimization, see
Supporting Information). To our delight, under the conditions
of Condition A [(Pd(OAc)2 (5 mol %), dppp (5 mol %),
Na2WO4·2H2O (5.0 equiv), LiBr (20 mol %), toluene (1.6
mL), MeOH (0.4 mL), CO (2 bar), N2 (3 bar), 120 °C, 24 h]
or Condition B [(Pd(OAc)2 (10 mol %), dppp (10 mol %),
Na2WO4·2H2O (2.0 equiv), LiBr (20 mol %), toluene (1.6
mL), MeOH (0.4 mL), CO (5 bar), 100 °C, 24 h], the
dearomative carbonylation of N-(2-bromobenzoyl)indole 1a
proceeded well and the corresponding ester products 7a/7a′
can be easily isolated in moderate yields. The scope of N-
benzoyl indoles is summarized in Scheme 3, which shows that
both electron-deficient and -rich aryl bromides can be
successfully converted to the corresponding products in
moderate to good yields (45−75%) under Condition A and
Condition B. As we expected, a low reaction temperature gives
a higher diastereomer ratio. Notably, the product 7e was
obtained under Condition A with a single diastereomer in 45%
yield due to the steric effect of the 2-substituted methyl.
Interestingly, 2-phenylindole can also be successfully trans-
formed to product 7m in 45% yield and a single diastereomer
was formed, which also could be attributed to the steric bulk of
the phenyl group.
Subsequently, we tested this dearomative carbonylation of
N-(2-bromobenzoyl)indole 1a with different alcohols (Scheme
4). The tested alcohols, including ethanol, propanol, butanol,
hexanol, octanol, cyclobutylmethanol, and cyclohexylmethanol,
are all able to provide the corresponding esters in moderate to
good yields (33−82%). Interestingly, when using trifluoroe-
thanol as a nucleophilic reagent, the reaction gave the
corresponding product 7o in good yield (82%). However, no
desired product could be observed when benzyl alcohol was
tested as the nucleophile.
General comments, general procedure, optimization
details, analytic data, and NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: xiao-feng.wu@catalysis.de.
ORCID
Xiao-Feng Wu: 0000-0001-6622-3328
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the analytical department of Leibniz-Institute for
Catalysis at the University of Rostock for their excellent
analytical service. We also appreciate the general support from
̈
Professor Armin Borner and Professor Matthias Beller in
LIKAT.
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reaction pathway is proposed in Scheme 5. Initially, the
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bromide 1a giving aryl-palladium complex A, which is followed
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In summary, a new and straightforward palladium-catalyzed
dearomative carbonylation procedure toward diverse fused
indoline esters and amides has been established. By using
commercially available Pd(OAc)2 and a dppp catalyst system,
N-(2-bromobenzoyl)indoles undergo a dearomatization and
carbonylation process to give the desired esters and amides
with broad functional group tolerance. Remarkably, this is the
first example of carbonylative dearomatization.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01868.
D
DOI: 10.1021/acs.orglett.9b01868
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