Gold-Catalyzed C-H Annulation of Anthranils with Alkynes: A Facile, Flexible, and Atom-Economical Synthesis of Unprotected 7-Acylindoles

Article abstract of DOI:10.1002/anie.201508309

The gold-catalyzed C-H annulation of anthranil derivatives with alkynes offers a facile, flexible, and atom-economical one-step route to unprotected 7-acylindoles. An intermediate α-imino gold carbene, generated by an intermolecular reaction, promotes ortho-aryl C-H functionalization to afford the target products. The transformation proceeds with a broad range of substrates under mild conditions. Moreover, the obtained functionalized indole products represent a versatile platform for the construction of diverse indolyl frameworks.

Full text of DOI:10.1002/anie.201508309

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International Edition: DOI: 10.1002/anie.201508309
German Edition: DOI: 10.1002/ange.201508309
Gold Catalysis
À
Gold-Catalyzed C H Annulation of Anthranils with Alkynes: A Facile,
Flexible, and Atom-Economical Synthesis of Unprotected
7-Acylindoles
Hongming Jin, Long Huang, Jin Xie, Matthias Rudolph, Frank Rominger, and
A. Stephen K. Hashmi*
À
Abstract: The gold-catalyzed C H annulation of anthranil
derivatives with alkynes offers a facile, flexible, and atom-
economical one-step route to unprotected 7-acylindoles. An
intermediate a-imino gold carbene, generated by an intermo-
the development of a general synthetic strategy for the
efficient construction of a diversified scaffold of 7-acylindole
would be highly desirable.
In recent years, transition-metal-catalyzed synthesis of
functionalized indoles has experienced significant develop-
ment.[1f,4] Gold catalysis[5,6,7e] in particular has had a strong
impact on this field of synthetic chemistry. For instance, gold-
catalyzed intramolecular annulation[5] of 2-alkynyl arylazides
has opened up an efficient access to indolyl[6b,d] and pseu-
doindoxyl[6a,c] skeletons, based on a-imino gold carbenes as
key electrophilic intermediates. However, access to a-imino
gold carbenes through intramolecular nitrene transfer can
limit the generality and flexibility of the obtained products.
Regarding this drawback, an intermolecular approach for the
generation of a gold nitrene en route to functionalized
heterocyclic compounds would represent an attractive strat-
egy. In line with this principle, Davies et al. and Ye et al. were
able to accomplish gold-catalyzed intermolecular cycloaddi-
tion for the preparation of polysubstituted oxazoles[7a,b] and
pyrroles.[7c] Very recently, the gold-catalyzed intermolecular
transformation of benzyl azides with ynamides was also
reported by Yeꢀs group.[7d] However, the a-imino gold
carbenes that are produced through the intermolecular
approach have so far been limited to polarized alkynes.
Inspired by these reports and in continuation of our work on
indole chemistry,[8] we envisioned that a gold-catalyzed
intermolecular transformation of anthranil with alkynes
could produce a-imino gold carbene intermediates. Based
on the high electrophilicity of the a-imino gold carbenoid, an
À
lecular reaction, promotes ortho-aryl C H functionalization to
afford the target products. The transformation proceeds with
a broad range of substrates under mild conditions. Moreover,
the obtained functionalized indole products represent a versa-
tile platform for the construction of diverse indolyl frame-
works.
I
ndoles have attracted immense attention owing to their
ubiquitous presence in natural products, materials, and
pharmaceuticals.[1] Among indoles, 7-acylindoles serve not
only as a class of bioactive molecules (Scheme 1) but also as
Scheme 1. Selected bioactive compounds based on 7-acylindoles.
À
intramolecular ortho-aryl C H insertion could then afford the
desired 7-formyl indoles (Scheme 2). Herein, we report our
key building blocks with orthogonal chemical reactivity.[2]
However, traditional methodologies[3] such as the Fischer,
Larock, or Bartoli syntheses usually show low functional-
group tolerance, and difficulties in installing aldehydes and
ketones make it a challenge to construct 7-acylindoles. Hence,
results on the unprecedented gold-catalyzed C H annulation
À
[*] H. Jin, L. Huang, J. Xie, M. Rudolph, F. Rominger, A. S. K. Hashmi
Institut für Organische Chemie, Universität Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
E-mail: hashmi@hashmi.de
A. S. K. Hashmi
Chemistry Department, Faculty of Science
King Abdulaziz University
Jeddah 21589, Saudi Arabia
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201508309.
Scheme 2. Planned gold-catalyzed annulation of anthranils with
alkynes.
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Table 1: Optimization of the Reaction Conditions.[a]
Table 2: Scope of the synthesis of anthranils with ynamides.[a,b]
Entry
Catalyst
Solvent
T
[8C]
Yield
[%][b]
1
2
3
4
5
6
7
8
none
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
PhCF3
PhMe
PhCl
CH2Cl2
CH3CN
THF
Et2O
RT
0
0
0
0
0
0
À20
À20
À20
À20
À20
À20
À20
À20
À20
À20
À20
n.d.
36
49
33
64
35
73
84
74
Ph3PAuCl/AgNTf2
JohnPhosAuCl/AgNTf2
tBuXPhosAuCl/AgNTf2
(ArO)3PAuCl[c]/AgNTf2
AuBr3
IPrAuCl/AgNTf2
IPrAuCl/AgNTf2
IPrAuCl/AgSbF6
IPrAuCl/AgBF4
IPrAuCl/AgOTf
IPrAuCl/AgNTf2
IPrAuCl/AgNTf2
IPrAuCl/AgNTf2
IPrAuCl/AgNTf2
IPrAuCl/AgNTf2
IPrAuCl/AgNTf2
IPrAuCl/AgNTf2
9
10
11
12
13
14
15
16
17
18
58
32
90 (85)[d]
81
71
72
22
46
30
[a] Reaction conditions: 1a (0.3 mmol), 2a (0.2 mmol); a solution of 1a
(1 mL) was added over 3 mins to a solution of 2a (1 mL) and the catalyst
at the given temperature, with a reaction time of 1 h. [b] Measured by
1H NMR with 4-(dimethylamino)benzaldehyde as the internal standard.
n.d.=not detected. [c] Ar=2,4-di-tert-butylphenyl. [d] Yield of isolated
product.
of anthranils with alkynes under mild reaction conditions.
Notably, the reaction also proceeds smoothly with ynamides,
non-polarized alkynes, and non-terminal alkynes. The process
enables the facile, flexible, and atom-economical synthesis of
7-acylindolyl frameworks.
[a] Reaction conditions: 1 (0.3 mmol), 2 (0.2 mmol); a solution of
1 (1 mL) was added over 3 min to a solution of 2 (1 mL) and 5 mol%
IPrAuCl/AgNTf2 at À208C, and then the mixture was stirred for 1 h.
[b] Yield of isolated product. [c] Reaction temperature: 658C; 4 Š MS.
[d] A mixture of ClCH2CH2Cl (0.5 mL) and PhCF3 (1.5 mL) as solvent.
Initially, we performed a screening of the reaction
conditions with ynamide 1a, since such substrates usually
possess high reactivity in gold-catalyzed reactions as a result
of their electronic properties[7a–d,9] (Table 1). Treatment of
ynamide 1a and anthranil 2a with Ph3PAuCl/AgNTf2 at 08C
afforded the expected product 3a in 36% yield (entry 2). The
control experiment without catalyst showed no reaction even
at room temperature (entry 1). Among the screened gold
catalysts, the catalyst with an NHC ligand (entry 7) showed
higher activity than those with phosphane and phosphite
ligands (entries 3–5). AuBr3 was also less efficient (entry 6).
The yield increased to 84% upon decreasing the reaction
temperature to À208C (entry 8). Further improvement was
achieved by screening different silver salts (entries 9 and 10)
and solvents (entries 11–18). Finally, up to 90% yield of 3a
was gained by employing 5 mol% IPrAuCl/AgNTf2 as the
catalyst in PhCF3 at À208C (entry 12).
Perumalꢀs group.[4g] Among the tested protecting groups on
the ynamides, besides tosyl and mesyl, the oxazolidinone-
derived ynamide also underwent annulation to afford the
product 3j in moderate yield. Non-terminal ynamides were
also investigated. While the targeted product 3k was prepared
from phenyl-substituted ynamide in good yield, the alkyl-
substituted ynamide afforded the unsaturated product 3l’
rather than 3l. Various substituted anthranils were applied for
the synthesis of diversified 7-acylindoles (3m–3y). Owing to
the mild reaction conditions, a large array of functional
groups, including chloride (3p), bromide (3q, 3r), acetal (3o),
ester (3n), alkene (3v), and a,b-unsaturaed ketone (3w–3y)
substituents were all tolerated, which enormously enhances
the range of obtained substrates. The reaction of anthranils
with electron-donating groups usually proceeded with higher
yields, which suggests an electrophilic aromatic substitution
mechanism. For a structural confirmation of the 7-acylindolyl
framework, a single-crystal X-ray structure analysis[10] of 3q
was conducted (Figure 1).
Under the optimized conditions, the scope of the reaction
was explored (Table 2). Ynamides reacted with excellent to
moderate yields (3a–3j). A broad set of substituents at the
ynamide nitrogen atom turned out to be compatible. 7-Formyl
indole 3e, which was prepared from N-(2-bromophenyl)
ynamide in good yield, is a potential precursor for the
synthesis of 1,2-fused indoles according to a method from
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Table 3: Scope with respect to the alkynes.[a,b]
Figure 1. Solid-state molecular structure of 3q.
[a] Reaction conditions: 6 (0.8 mmol) and 2 (0.2 mmol) were heated for
4 h at 658C in 2 mL PhCF3. [b] Yield of isolated product.
Scheme 3. The reaction of anthranil with aryl alkynyl ether.
The transformation was not limited to ynamides. Treat-
ment of anthranil with aryl alkynyl ether 4a under the
standard reaction condition furnished the 2-oxo product 5a in
63% yield (Scheme 3, Step 1). 7-Formyl oxindole 5a’, a prom-
ising novel antioxidant,[11] was easily synthesized through
hydrolysis of 5a under acid condition (Scheme 3, Step 2).
To extend the substrate scope further, non-polarized
alkynes were used too. However, owing to their decreased
reactivity, the reaction did not work under the standard
conditions. But by raising the temperature and extending the
reaction time, the yield of the expected product could be
gradually increased.[12] A more efficient conversion rate of
anthranil was enabled by the addition of 10 mol% MsOH
(which might facilitate the deauration process) and by using
an excess of alkyne (MsOH alone is not catalytically active).
Following this procedure afforded the products in moderate
yields. Under the adjusted conditions, both alkyl and aryl
alkynes were suitable for the construction of C2-functiona-
lyzed and C2,C3-diarylated products (Table 3, 7a–7i). The 7-
substituted indole 7j, which is a key precursor for synthesizing
pyrrolquinolone derivatives,[13] could conveniently be pre-
pared despite the conjugated double bond.
Scheme 4. Conversion of an unsymmetrical alkyne.
Owing to the presence of both electrophilic and nucleo-
philic sites, 7-formyl indoles have been utilized as flexible
scaffolds for the syntheses of 1,7-fused indoles, most of which
exhibit significant biological activity.[13,14] While numerous
studies have focused on the reactions of indoles with electro-
philes, we focused our attention on nucleophilic transforma-
tions of 7-acyl indoles. For instance, reduction of 3g afforded
the 7-alkylated product 3g’, and the unprotected 7-alkynyl
indole 3g’’ could be obtained easily in excellent yield through
Seyferth–Gilbert homologation (Scheme 5).
Scheme 5. Application to the preparation of diverse 7-substituted
indoles.
Finally, we used an unsymmetrically alkyl/aryl-substituted
alkyne. In this case, a low yield of 2-alkyl-3-aryl indol 7k was
obtained (assigned by NOE) and no other indole isomer was
formed (Scheme 4). The low yield might result from a com-
peting hyride-shift pathway if the carbenoid is formed next to
the alkyl tether (similar to the formation of 3l’).
In summary, a novel, short, and atom-economical syn-
À
thesis of 7-acyl indoles through gold-catalyzed C H annula-
tion of anthranils with alkynes was developed. The substrate
scope is remarkably broad and the benign reaction conditions
tolerate a diverse set of functional groups, which further
strengthens the synthetic impact of this method. The obtained
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the enormous gain in molecular complexity, we believe that
this method will serve as powerful tool for organic synthesis.
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À
Keywords: alkynes · C H functionalization · gold carbenoids ·
gold catalysis · indoles
How to cite: Angew. Chem. Int. Ed. 2016, 55, 794–797
Angew. Chem. 2016, 128, 804–808
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Received: September 5, 2015
Published online: November 26, 2015
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