Synthesis of Indole-2-carboxylate Derivatives via Palladium-Catalyzed Aerobic Amination of Aryl C-H Bonds

Article abstract of DOI:10.1021/acs.orglett.6b01592

A direct oxidative C-H amination affording 1-acetyl indolecarboxylates starting from 2-acetamido-3-arylacrylates has been achieved. Indole-2-carboxylates can be targeted with a straightforward deacetylation of the initial reaction products. The C-H amination reaction is carried out using a catalytic Pd(II) source with oxygen as the terminal oxidant. The scope and application of this chemistry is demonstrated with good to high yields for numerous electron-rich and electron-poor substrates. Further reaction of selected products via Suzuki arylation and deacetylation provides access to highly functionalized indole structures.

Full text of DOI:10.1021/acs.orglett.6b01592

Letter
pubs.acs.org/OrgLett
Synthesis of Indole-2-carboxylate Derivatives via Palladium-
Catalyzed Aerobic Amination of Aryl C−H Bonds
Kyle Clagg,† Haiyun Hou,† Adam B. Weinstein,‡,∥ David Russell,§ Shannon S. Stahl,*,‡
and Stefan G. Koenig*,†
†Small Molecule Process Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
‡Department of Chemistry, University of WisconsinMadison, 1101 University Avenue, Madison, Wisconsin 53706, United States
§Small Molecule Analytical Chemistry and Quality Control, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080,
United States
S
* Supporting Information
ABSTRACT: A direct oxidative C−H amination affording 1-
acetyl indolecarboxylates starting from 2-acetamido-3-arylacry-
lates has been achieved. Indole-2-carboxylates can be targeted
with a straightforward deacetylation of the initial reaction
products. The C−H amination reaction is carried out using a
catalytic Pd(II) source with oxygen as the terminal oxidant.
The scope and application of this chemistry is demonstrated
with good to high yields for numerous electron-rich and electron-poor substrates. Further reaction of selected products via
Suzuki arylation and deacetylation provides access to highly functionalized indole structures.
he construction of C−N bonds is of fundamental
Scheme 1. Selective Oxidative Intramolecular C−H
Functionalization Reactions with 2-Acetamido-3-
arylacrylates
T
importance in the synthesis of biologically active organic
molecules. Cross-coupling reactions between aryl halides and
nitrogen nucleophiles in the presence of palladium catalysts
(Buchwald−Hartwig coupling) provide an effective means of
generating aryl C−N bonds.1,2 In the interest of streamlining the
synthesis of complex molecules, significant effort has been
devoted to the development of palladium-catalyzed methods for
the generation of aryl C−N bonds by direct oxidative
functionalization of aryl C−H bonds.3,4 A challenge with these
reactions is the ability to couple the palladium-mediated
oxidative transformation of the substrate with atom-econom-
ically attractive molecular oxygen (O2) as the terminal oxidant.
Prior studies in the development of palladium-catalyzed
intramolecular aryl C−H aminations5 have uncovered methods
for the synthesis of indazoles from arylhydrazones,6 lactams from
α-aryl-N-methoxyamides,7 benzimidazoles from N-arylbenzami-
dines,8 indolines from β-arylethylamines,9,10 indoles from α-aryl
oxime acetates,11 carbazoles from 2-aminobiphenyls,12,13 and,
most recently, indoles from (Z)-NTs-dehydroamino acid esters
using Oxone as the oxidant.14 Notably, the only example in which
O2 was used as the terminal oxidant was the carbazole synthesis,
and a limited substrate scope was demonstrated under the
reported conditions.12,13d
acetylglycine via Erlenmeyer−Plochl chemistry.16 This method-
̈
ology has been used extensively in the synthesis of unnatural
amino acids and is amenable to large-scale processes.17 Previous
reports employing 2-acetamido-3-arylacrylate substrates under
oxidative conditions have yielded oxazoles from alkene
functionalization (Scheme 1, upper reaction pathway).18,19 In
contrast, while 2-toluenesulfonamido-3-arylacrylates were shown
to form indoles via palladium(II) catalysis with Oxone, the
equivalent 2-acetamido substrates failed to do so.14 Here we
show that aryl C−H amination with the latter substrates
proceeds with Pd(II) catalysis and that these are capable of
using O2 as the stoichiometric oxidant.
Here we report the discovery of a palladium-catalyzed aerobic
amination of aryl C−H bonds for the synthesis of indole-2-
carboxylate derivatives (Scheme 1). We envisioned that indole-2-
carboxylates, which are useful building blocks in the synthesis of
indole-containing bioactive molecules,15 could be derived from
the intramolecular aryl C−H amination of 2-acetamido-3-
arylacrylates. These substrates are particularly attractive because
they are readily accessible from benzaldehyde derivatives and N-
We initiated our study by testing ethyl 2-acetamido-3-
phenylacrylate (1a) under the aerobic oxidation conditions
reported by Buchwald for carbazole synthesis (Table 1, entry
Received: June 1, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01592
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Organic Letters
Letter
Table 1. Initial Investigation of Intramolecular Aerobic C−H
Amination of Ethyl 2-Acetamido-3-phenylacrylate
Table 2. Evaluation of the Substrate Scope of the
Intramolecular C−H Amination of Ethyl 2-Acetamido-3-
arylacrylates
a
1H NMR yields (%)
entry
mol % Pd(OAc)2 DMSO:Tol T (°C)
1a
2a
3a
1H NMR yields
1
2
3
4
5
6
7
8
9
10
10
10
10
10
10
10
7
1:0
1:0
3:1
1:1
1:3
1:9
0:1
1:1
1:1
1:1
1:1
120
80
80
80
80
80
80
80
80
80
80
45
16
10
2
23
61
69
77
80
50
1
22
23
21
15
12
13
0
a
(%)
entry
substrate (R)
T (°C)
1
2
isolated yield (%)
95
1
2
3
4
1a (H)
80
80
0
100
b
2
1b (p-Me)
1c (m-Me)
1d (o-Me)
1e (2-Naph)
1f (p-Ph)
0
0
94
67
31
80
5
100
80
89
77
0
92
85
c
85
60
36
0
10
5
5
100
80
25
11
0
77 (2:1)
83
62 (5:3)
86
5
35
49
0
6
7
8
9
b
b
10
c
7
12
0
1g (m-Ph)
1h (o-Ph)
1i (p-F)
80
88
80
11
7
80
0
90
87
56
a
1H NMR yields relative to PhTMS added at the end of the reaction.
Without 3 Å MS. With 2 equiv of PhI(OAc)2.
80
31
7
65
cd
,
b
b
c
10
11
12
13
14
15
16
17
1j (m-F)
120
100
80
80 (3:2)
45
83 (4:3)
b
1k (p-CF3)
1l (m-CF3)
1m (p-NMe2)
1n (p-OMe)
1o (m-OMe)
39
48
29
14
0
45
b
38
36
1).12 This catalyst system employed dimethyl sulfoxide as the
solvent, allowing carbazole synthesis at high temperatures (120
°C) in reasonable yields for most substrates. Under these
conditions, substrate 1a reacted to give a mixture of acetylated
indole product 2a and indole product 3a in 45% total yield. In
contrast to Buchwald’s findings, lowering the temperature
facilitated the C−H amination but not the deacetylation (entry
2). Introduction of toluene as a cosolvent improved the yield of
indole product 2a to an extent (entries 3−6). Lowering the
loading of the palladium catalyst from 10 to 7 mol % was
tolerated, but the yield of indole began to drop at 5 mol %
(entries 8 and 9). Introduction of diacetoxyiodobenzene, a
strong oxidant commonly employed to access Pd(IV) species,20
resulted in complete decomposition of the substrate without
formation of the desired indole product (entry 11).
80
57
50
b
80
72
59
b
100
100
80
89
66
e
1p (p-5-Pyr)
29
30
69
59
b
1q (p-Cl)
69
63
a
1H NMR yields relative to PhTMS added at the end of the reaction
time. Unless otherwise indicated, only 5-substituted indole products
b
were observed from meta-substituted substrates. Products isolated as
N-H indoles following optional deacetylation as indicated in the
graphic. The ratio refers to a regioisomeric mixture of products, with
the least sterically demanding product predominating in each case.
The reaction was run in 1:1 DMSO-d6/p-xylene-d10. p-5-Pyr refers
c
d
e
to 5-pyrimidyl-substituted at the para position of the substrate.
In a screen of various palladium(II) sources, Pd(OAc)2 was
revealed to be superior (see the Supporting Information). In the
absence of any palladium, no detectable product was observed in
the reaction mixture. Ligand additives that have been employed
previously for C−H activation21 inhibited the conversion, while
protic additives (AcOH, PivOH, and water) had little impact.
With the optimized conditions for the unsubstituted arene, we
analyzed the reaction conversion over the course of 24 h and
identified the minimum reaction time to be 20 h.
With robust conditions for the aerobic intramolecular aryl C−
H amination of substrate 1a in hand (10 mol % Pd(OAc)2, 24 h
reaction time), we explored the scope of the reaction. In the
absence of a nitrogen protecting group, 2-amino-3-phenyl-
acrylate failed to undergo the C−H amination.22 N-Benzoyl and
N-tosyl blocking groups were also tested. The N-benzoyl-
substituted system gave no desired product, whereas the N-tosyl
substrate resulted in decent conversion to the indole.23 As we
believed the N-acetyl group to be superior to N-tosyl in terms of
ease of substrate preparation, yield, and cleavability, we decided
to proceed with the former and vary the substitution on the
arene.
phenyl-substituted arenes gave reasonable conversions (entries
2−4 and 6−8), while both electron-withdrawing and -donating
groups were poorly tolerated. Resubjecting the challenging
substrates to higher temperatures, however, led to a marked
increase in yield (entries 5, 10, 11, and 15). The reason for this
improvement is not presently understood, though it may be
attributed to a higher energy barrier for palladium-mediated C−
H activation. Most meta-substituted substrates led to the
corresponding 5-substituted indole products on the basis of
steric control (entries 3, 7, 12, and 15), while 2-naphthyl- and m-
fluoro-substituted substrates led to mixtures of isomers (entries 5
and 10).
We then tested the reaction tolerance further by exploring
more complex substrates, including ones with a distal heterocycle
and a halogen substituent. While the initial result for the 5-
pyrimidyl substrate was low (18% NMR yield), running the
reaction at higher temperature gave an improved yield (Table 2,
entry 16). This successful result indicated that certain hetero-
cycles should be tolerated in the C−H amination to support
convergent approaches to indoles via this methodology. With
ethyl 2-acetamido-3-(4-chlorophenyl)acrylate, the original tem-
perature (80 °C) balanced C−H amination with subsequent
deacetylation (entry 17). Interestingly, no dechlorination was
We applied the conditions to a range of substrates, as
illustrated in Table 2. Initially, we observed that only methyl- and
B
DOI: 10.1021/acs.orglett.6b01592
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
observed in the reaction, enabling subsequent functionalization
to access diverse indole structures from a common intermediate.
With the 1-acetyl-6-chloroindole-2-carboxylate 2q in hand, we
then tested the compatibility of the compound in various C−C
cross-coupling reactions, as conditions that utilize indoles as the
electrophilic coupling partner are uncommon.24 The strongly
basic conditions of Negishi and Kumada-type reactions cleaved
the N-acetyl group and afforded none of the desired product
above trace quantities (data not shown). In contrast, certain
Suzuki cross-coupling conditions were effective and delivered the
desired ethyl 6-phenyl-1H-indole-2-carboxylate (3f) from cross-
coupling and deacetylation in a single pot (Table 3, entry 1).25
amidate species that can metalate the arene to afford the chelated
Pd(II)−(aryl)(amidate) species. Subsequent C−N reductive
elimination can afford the indole product and a ligated Pd(0)
species capable of undergoing oxidation by O2 to regenerate
catalytic Pd(OAc)2. Previous studies of Pd-catalyzed aerobic
oxidation reactions in DMSO provided evidence for the
involvement of both molecular and nanoparticle catalysis.27
Presently available data cannot distinguish between these two
possibilities, but this issue warrants attention in future studies.
In summary, we have identified an aerobic palladium-catalyzed
aryl C−H amination strategy for the synthesis of indole-2-
carboxylates from 2-acetamido-3-arylacrylates with application
to a diverse set of substrates. Notably, the mild and selective
conditions tolerated electron-rich and electron-poor substrates,
chlorinated arenes, and a heteroaromatic-substituted example.
The chlorinated arenes also enable direct Suzuki cross-coupling
following indole formation, allowing one to sidestep the N−H
deprotection step prior to the coupling reaction. Moreover, the
halogen substitution also holds promise as a handle for the
introduction of boronic acid and boronate ester equivalents and
rapid access to these types of indole building blocks. Our
methodology complements existing approaches to indoles and
should allow expedited installation of the heterocycle onto
bioactive molecules.
Table 3. Evaluation of Suzuki Coupling with Ethyl 1-Acetyl-6-
chloroindole-2-carboxylate
HPLC area %
entry
boronic acid
solvent
2q
3q
2X
3X
ASSOCIATED CONTENT
■
1
2
3
4f
4r
4s
4t
5:1 dioxane/H2O
1:2 dioxane/H2O
1:2 dioxane/H2O
1:4 dioxane/H2O
2
1
0
0
0
77
73
0
0
0
3
0
76
0
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01592.
17
a
b
4
86
a
b
The reaction was run with 4.2 equiv of K3PO4·H2O. The isolated
Full experimental details and characterization data for all
isolated compounds (PDF)
yield of 3t was 80% following chromatography.
We tested three more boronic acid coupling partners (4r−t) to
challenge what the acetyl protecting group could tolerate (entries
2−4). The phenolic partner 4r was completely incompatible, and
5-aminopyrimidyl reagent 4s gave a low yield of the desired
product 3s. On the other hand, fluoropyridylboronic acid 4t was
more effective in the one-pot Suzuki/deacetylation, giving access
to important structures related to those under investigation for
metabolic disorders.26
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: stahl@chem.wisc.edu.
*E-mail: koenig.stefan@gene.com.
Present Address
∥A.B.W.: Department of Chemistry, Yale University, 225
Prospect Street, P.O. Box 208107, New Haven, CT 06520.
Previous studies12,13 provide the basis for a plausible
mechanism for the Pd-catalyzed oxidative cyclization reaction
to afford indoles (Scheme 2). The substrate acetamide can
undergo metathesis with an acetate ligand to afford a Pd(II)−
Author Contributions
All of the authors were employed at their respective institutions
during completion of the work. K.C., H.H., and A.B.W.
contributed equally to the experimental results.
Scheme 2. Simplified Catalytic Mechanism for Pd-Catalyzed
Oxidative Cyclization of 2-Acetamido-3-arylacrylates
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the NIH for financial support (R01 GM67173
for A.B.W. and S.S.S.) and the Genentech Summer Internship
Program for supporting H.H. during the project. In addition, the
authors thank Marie-France Morissette for analytical support and
Francis Gosselin and Allen Hong (Genentech, Inc.) for helpful
discussions on the manuscript.
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DOI: 10.1021/acs.orglett.6b01592
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