A novel one-pot synthesis of N-acylindoles from primary aromatic amides

Article abstract of DOI:10.1055/s-2007-1000875

A novel one-pot synthesis of N-acylindoles via tandem cycloalkylation- annelation is described. This approach is based on the use of a strong solid-acid catalyst, montmorillonite K-10, and microwave irradiation under solvent-free conditions. The tandem cy

Full text of DOI:10.1055/s-2007-1000875

410
LETTER
A Novel One-Pot Synthesis of N-Acylindoles from Primary Aromatic Amides
Synthesis of
N-
Acylind
o
oles hammed Abid, Omar De Paolis, Béla Török*
Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Blvd, Boston, MA 02125, USA
Fax +1(617)2876030; E-mail: bela.torok@umb.edu
Received 10 September 2007
Most methods for the preparation of N-acylindoles in-
Abstract: A novel one-pot synthesis of N-acylindoles via tandem
cycloalkylation–annelation is described. This approach is based on
the use of a strong solid-acid catalyst, montmorillonite K-10, and
microwave irradiation under solvent-free conditions. The tandem
volve two or more steps, and often result in substituted
products. Ideally, their synthesis should involve one step,
directly from simple, readily available substrates. In this
cycloalkylation of amides and annelation of intermediate pyrroles study we report a convenient one-pot synthesis of N-
were completed in minutes and provided good yields with high se-
acylindoles from commercially available aromatic amides
lectivities for the indoles. The safe, easy to handle catalyst, and the
and 2,5-dimethoxytetrahydrofuran using montmorillonite
convenience of the product isolation make this process an attractive,
K-10 as a catalyst. Our approach provides an environmen-
environmentally benign alternative for the synthesis of N-acylin-
tally benign alternative for the above-mentioned process-
doles.
es.4 It is based on a one-pot, tandem cycloalkylation–
Keywords: amides, solid-acid catalysis, microwave heating, N-
annelation process, from readily available, simple starting
acylindole
materials, and does not require the separate synthesis of
the indole skeleton. The combination of solid-acid cataly-
sis, solvent-free conditions, and microwave activation re-
The indole skeleton is prevalent in a wide range of biolog-
sults in high yields, reduces reaction times, and produces
ically and pharmacologically active compounds.1 Many
no waste or byproducts. The products are unsubstituted N-
classical procedures have been reported for the synthesis
acylindoles, therefore the 2- and 3-positions are preserved
of indoles.2 Apart from traditional methods such as the
for further functionalization.
Fischer,1f,3a,b the Reissert,3c,d and the Madelung proto-
cols,3e,f several transition-metal-assisted intermolecular
annelation and intramolecular cyclization methods have
been developed.3g–l Increased environmental regulations
and safety concerns, however, necessitate the develop-
ment of new, sustainable synthetic methods. It is especial-
ly true for N-acylindoles that are usually synthesized from
indoles by a strong base and subsequent acyl chloride ad-
dition,4a or by DCC-induced coupling of indoles with car-
boxylic acids.4b
First, we explored the efficiency of the catalyst in the cy-
cloalkylations of aromatic amides to form the expected N-
acylpyrroles. Similar cyclizations of arylamines and sul-
fonamides with bifunctional alkylating agents were facil-
itated by montmorillonites8,9c,d and triflic acid,9e
respectively. The expected N-acylpyrroles, however, did
not appear in the product mixture. Instead, they underwent
a successive electrophilic annelation producing the corre-
sponding N-acylindoles (Scheme 1).
The application of solid-acid catalysts to replace tradition-
al, harmful, and corrosive mineral acids is a rapidly grow-
ing area in organic syntheses. Solid-acid catalysts
including clays, zeolites, metal oxides, and acidic ion-ex-
change resins have been widely used to develop clean and
environmentally friendly synthetic processes.5 The cata-
lyst of choice in this work is montmorillonite K-10. It is a
well known, widely used clay-based solid-acid catalyst in
synthetic organic chemistry.6 It offers several advantages
over conventional liquid acids; it is a solid, noncorrosive,
inexpensive, and easily reusable. Most importantly, it is
commercially available and can be used without any pre-
treatment. The significant surface area (220–270 m2g–1) of
K-10 ensures excellent reaction rates. The Hammett acid-
ity (H0) value of K-10 is about –8 indicating strong acidi-
ty.6 It is an excellent catalyst for microwave-assisted
organic synthesis (MAOS), which has attracted consider-
able attention over the past two decades.7
O
O
MeO
OMe
O
N
NH2
K10, MW, 80 °C
4–10 min
R
R
R = H, 4-Me, 4-OMe, 4-O2N, 4-F,
4-Cl, 4-Ph, 4-F3C
O
N
R
yield up to 85%
Scheme 1 Microwave-assisted, K-10 catalyzed synthesis of N-
acylindoles from aromatic amides and 2,5-dimethoxytetrahydrofuran
In order to optimize the reaction parameters, we carried
out several test reactions using benzamide and 2,5-
dimethoxytetrahydrofuran as alkylating agents. We stud-
ied the effect of reaction temperature, reactant ratio, and
reaction time. The use of K-10 catalyst and microwave ir-
SYNLETT 2008, No. 3, pp 0410–0412
x
x.
x
x.
2
0
0
8
Advanced online publication: 21.12.2007
DOI: 10.1055/s-2007-1000875; Art ID: S06907ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of N-Acylindoles
411
radiation enabled us to carry out the synthesis at a mild As the data demonstrate, in each case the reactions took
temperature (80 °C). After a thorough optimization of the place efficiently showing a moderate substituent effect.
experimental conditions, we were able to obtain the corre- Electron-donating substituents facilitated the reaction,
sponding N-acylindole in good yield and high selectivity while slower reaction rates and lower yields were ob-
in a short reaction time. The amount of alkylating agent served in the case of strongly electron-withdrawing sub-
had a significant effect on the chemoselectivity of reac- stituents such as CF3 or NO2. Carbazole derivatives
tion. The maximum yield of indole was obtained at 2.0 formed as a byproduct in the reaction, however, their
molar equivalents of 2,5-dimethoxytetrahydrofuran. Oth- amounts did not exceed 1–2%. Using excess of 2,5-
er amounts always resulted in the formation of pyrrole and dimethoxytetrahydrofuran (up to 3 mol equiv), longer re-
indole mixtures even after extended reaction time and ex- action times, and elevated temperatures did not improve
cess of alkylating agent.
the yield of the carbazoles. We attribute this surprising
phenomenon to the reduced activity of the N-acylindoles
toward electrophilic substitution.
Using the optimized reaction conditions, we explored the
scope of the methodology. A wide variety of commercial-
ly available aromatic amides were tested in the reaction. The proposed model for the mechanism of the reaction is
All reactions were carried out in a CEM Discover micro- summarized below (Scheme 2). Literature data and our
wave reactor at constant temperature (80 °C). Reactants own experimental results,9 suggested that 2,5-dimeth-
and the catalyst were carefully mixed in 3 mL of dichlo- oxytetrahydrofuran underwent rearrangement on the sur-
romethane. After five minutes stirring, the solvent was face of the catalyst. This rearrangement resulted in the
evaporated producing a dry powder. This procedure en- formation of 1,4-butanedial. It immediately reacted with
sured an even distribution of the reactants adsorbed on the the amide and cyclized into pyrrole. The reaction follows
surface of K-10. This dry mixture was transferred into a the mechanism of the well-known Paal–Knorr cycliza-
glass reaction tube and was irradiated at 80 °C for the tions.
specified time. Results are summarized in Table 1.
Due to the high reactivity of pyrrole towards electrophilic
substitution, it immediately underwent an annelation with
Table 1 Microwave-Assisted K-10-Catalyzed Synthesis of N-
the excess 1,4-butanedial and formed the corresponding
indole. Based on the results, we suggest that successive
annelation occured in a stepwise manner. We propose that
first, one of the formyl groups reacted with the heteroaro-
matic ring after proper activation. The activation occurred
on the surface acid centers of K-10. After the hydroxy-
alkylation occurred, 1 mol of water was eliminated from
the intermediate. It is reasonable to suggest that the first
hydroxyalkylation occurred in the 2-position according to
the higher activity of this site. Then, the ring closure took
place via the same hydroxyalkylation–dehydration se-
quence in the 3-position. The highly polar surface condi-
tions make the concerted process highly improbable.
Acylindoles from Aryl Amides and 2,5-Dimethoxytetrahydrofuran10
O
K-10
N
MeO
OMe
MW, 80 °C
Ar
NH2
O
O
Ar
Entry Ar
Time (min) Selectivity (%)a Yield (%)b
1
2
3
4
5
6
7
8
9
Ph
5
4
4
93
84
90
75
89
95
77
86
89
85
78
82
60
80
85
65
76
73
4-MeC6H4
4-MeOC6H4
4-NO2C6H4 10
In conclusion, the described one-pot solid-acid-catalyzed
cyclization–annelation approach represents an efficient
protocol for the synthesis of a wide variety of N-acylin-
doles from commercially available amides. This method
provides the products in good yields and high selectivities
in short reaction times. Solvent-free conditions, solid-acid
catalyst, reaction times and the trouble-free product isola-
tion make the process attractive for the green synthesis of
the target compounds.
4-FC6H4
5
6
4-ClC6H4
4-CF3C6H4 30
4-PhC6H4
6
naphth-2-yl
6
a Overall selectivity of the N-acylindole in the product mixture, deter-
mined by GC-MS.
b Isolated yields after flash chromatography.
MeO
NH2
OMe
MeO
OMe
K-10
K-10
O
O
O
OHC CHO
OHC CHO
N
N
MW, 80 °C
– 2 H2O
MW, 80 °C
– 2 H2O
COPh
COPh
Scheme 2 Suggested mechanism for K-10-catalyzed synthesis of N-acylindoles via electrophilic cycloalkylation and annelation
Synlett 2008, No. 3, 410–412 © Thieme Stuttgart · New York

412
M. Abid et al.
LETTER
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were purchased from Aldrich and used without further
purification. The 1H NMR and 13C NMR spectra were
obtained on a 300 MHz Varian NMR spectrometer in
CDCl3. Tetramethylsilane or the residual solvent signal was
used as reference. The mass spectrometric identification of
the products was carried out on an Agilent 6850 GC and
5973 MS system (70 eV electron impact ionization) using a
30 m long DB-5 type column (J&W Scientific). The melting
points were uncorrected and were recorded on a MEL-
TEMP apparatus.
Acknowledgment
The financial support provided by University of Massachusetts Bo-
ston and National Institute of Health (AG025777-02) is gratefully
acknowledged.
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General Procedure for the Synthesis of N-Acylindoles:
An amide (1.0 mmol) and 2,5-dimethoxytetrahydrofuran
(2.0 mmol) were dissolved in 3 mL of CH2Cl2 in a round-
bottomed flask, then K-10 (500 mg) was added. After 5 min
stirring, the solvent was removed to obtain the mixture of
reactants adsorbed on the catalyst surface. The dry mixture
was transferred into a glass reaction vial and irradiated in the
microwave reactor (CEM Discover Benchmate, 80 °C).
During optimization, the progress of the reaction was
monitored by TLC and GC-MS to determine the necessary
reaction times. After satisfactory conversion, CH2Cl2 was
added to the cold mixture, and the product was separated
from the catalyst by filtration. The products were isolated as
crystals or oils and purified by flash chromatography. All
products showed satisfactory spectral data (MS, 1H and 13
C
NMR). Here, the full spectral characterization is given for
only the previously unknown products. Such data for the
known compounds synthesized in this study are available
from the authors.
1-(4-Fluorobenzoyl) indole (Table 1, Entry 5): mp 82.9–
84.3 °C (MeOH); 1H NMR (300.12 MHz, CDCl3): d = 8.36
(d, J = 7.8 Hz, 1 H), 7.79–7.74 (m, 2 H), 7.61 (d, J = 7.8 Hz,
1 H), 7.41–7.29 (m, 2 H), 7.27–7.18 (m, 3 H), 6.61 (d,
J = 3.9 Hz, 1 H) ppm; 13C NMR (75.474 MHz, CDCl3): d =
166.6, 132.0, 131.8, 127.4, 126.9, 125.1, 124.2, 123.6,
121.1, 120.1, 116.4, 115.8, 108.9 ppm; MS for
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Proced. Int 2008, 40, 1.
C15H10FNO(239): m/z (%) = 239 (40) [M+], 123 (100), 116
(5), 95 (30), 75 (15).
Biphenyl-4-yl(1H-indole-1-yl)methanone (Table 1, Entry
8): mp 98.2–100.1 °C (MeOH); 1H NMR (300.12 MHz,
CDCl3): d = 8.43 (d, J = 8.1 Hz, 1 H), 7.84–7.80 (m, 2 H),
7.76–7.67 (m, 2 H), 7.66–7.60 (m, 3 H), 7.52 (m, 3 H), 7.37–
7.32 (m, 3 H), 6.65 (d, J = 3.6 Hz, 1 H) ppm; 13C NMR
(75.474 MHz, CDCl3): d = 166.0, 144.9, 130.0, 129.1, 128.4,
128.4, 127.7, 127.6, 127.4, 126.9, 121.0, 116.5, 108.7 ppm;
MS for C21H15NO(297): m/z (%) = 297 (30) [M+], 181 (100),
152 (60), 116 (15), 77 (5).
Synlett 2008, No. 3, 410–412 © Thieme Stuttgart · New York

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