Solvent-free solid acid-catalyzed electrophilic annelations: A new green approach for the synthesis of substituted five-membered N-heterocycles

Article abstract of DOI:10.1002/adsc.200606200

An effective microwave-induced, solid acid-catalyzed, environmentally benign synthesis of substituted pyrroles, indoles and carbazoles under solvent-free conditions is described. The new synthetic methodology is based on the use of a considerably strong solid acid, K-10 montmorillonite. Both the cyclialkylation of amines and annelation of pyrroles and indoles have been completed within minutes and provided excellent (75-98%) yields with practically 100% selectivity.

Full text of DOI:10.1002/adsc.200606200

FULL PAPERS
DOI: 10.1002/adsc.200606200
Solvent-Free Solid Acid-Catalyzed Electrophilic Annelations: A
New Green Approach for the Synthesis of Substituted Five-Mem-
bered N-Heterocycles
a,b
b
a,b,
Mohammed Abid, Andrew Spaeth, and BØla Tçrçk *
a
University of Massachusetts Boston, 100 Morrissey Blvd. Boston, MA 02125, USA
Phone: (+1)-617-287-6159; fax: (+1)-617-287-6030; e-mail: bela.torok@umb.edu
Michigan Technological University, 1400 Townsend Drive, Houghton, MI 49931-1295, USA
b
Received: April 25, 2006; Accepted: August 8, 2006
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: An effective microwave-induced, solid roles and indoles have been completed within mi-
acid-catalyzed, environmentally benign synthesis of nutes and provided excellent (75–98%) yields with
substituted pyrroles, indoles and carbazoles under practically 100% selectivity.
solvent-free conditions is described. The new syn-
thetic methodology is based on the use of a consider-
ably strong solid acid, K-10 montmorillonite. Both Keywords: carbazoles; indoles; K-10 montmorillon-
the cyclialkylation of amines and annelation of pyr- ite; microwave heating; pyrroles; solid acids
[
6]
Introduction
velopment and natural product chemistry. Methods
for carbazole syntheses are usually based on transition
Five-membered, nitrogen-containing heterocycles, metal-mediated reactions, for example, Diels–Alder
such as pyrroles, indoles, and carbazoles are impor- reactions, reductive cyclization of 2-nitrobiphenyls
[
7]
tant building blocks in an extensive number of biolog- and double arylation of primary amines.
ically active compounds. These heterocyclic moieties
[
1]
Another rapidly growing area in organic syntheses
are of exceptional interest in pharmaceutical applica- is the application of solid acid catalysis to replace the
tions as they represent the core part of several drugs. traditional effective, but harmful and corrosive miner-
Examples include anti-inflammatory, antitumor, anti- al acids such as sulfuric acid. Solid acid catalysts, in-
[
2]
allergic, antiviral and anti-hypertensive compounds.
cluding clays, zeolites, metal oxides, and acidic ion-ex-
The importance of these heterocycles provides signifi- change resins, have been widely used to develop clean
[
8]
cance and actuality for developing new methods for and environmentally benign synthetic processes.
[3]
their syntheses. Due to strengthening environmental Our catalyst of choice in developing a new method
regulations and safety concerns, the development of for the synthesis of 5-membered N-heterocycles is a
environmentally responsible synthetic methods is also synthetic clay, montmorillonite K-10. It is a well-
highly desirable. Although the Fischer indole synthe- known and widely used solid acid catalyst in synthetic
sis and many other efficient methods had been report- organic chemistry. An overwhelming number of
ed, the development of green synthetic methods for papers, reviews and books deal with its synthetic ap-
the preparation of these hererocycles is still in the plications. As such it is considered a well-character-
forefront of synthesis research. ized, unique, solid acid reference catalyst. It is also a
[
9]
[
4]
[
9]
Most synthetic methods are based on the construc- green acid catalyst, but most importantly, K-10 mont-
tion of the pyrrole moiety on prefunctionalized aryl morillonite is a commercially available material and
[
4]
precursors, which involves multiple steps. Recent can be used without any pretreatment. It offers sever-
methods use C-3 functionalized pyrroles as starting al advantages over classical liquid acids; it is solid,
[
5]
materials for the preparation of indoles. Carbazole non-corrosive, inexpensive and easily reusable. Also,
2
À1
derivatives have also been widely used for building K-10 has high active surface area (220–270 m g )
electroluminescent materials and polymers having that ensures excellent reaction rates. The Hammett
electrical and thermal conductivity. A recent review acidity (H ) value for K-10 is ca. À8 indicating strong
o
[
9]
describes wide applications of carbazoles in drug de- acidity. It is also an excellent catalyst for micro-
Adv. Synth. Catal. 2006, 348, 2191 – 2196
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2191

Mohammed Abid et al.
FULL PAPERS
wave-assisted organic synthesis. This area has also at-
[
10]
tracted considerable attention in recent years.
Continuing our efforts in developing environmen-
tally benign processes, herein we report an effective,
new, one-step process to synthesize substituted pyr-
roles, indoles and carbazoles. Our approach is based
on a new pathway, namely a solid acid-catalyzed Frie-
del–Crafts cyclialkylation/annelation. The combina-
tion of solid acid catalysis, solvent-free conditions and
microwave irradiation results in excellent yields, re-
duces the reaction times and represents a highly eco-
friendly approach.
Results and Discussion
The Friedel–Crafts reaction is one of the most impor-
[
11]
tant CÀC bond forming methodologies.
Friedel–
Crafts cyclization reactions, either of intramolecular
or intermolecular nature, can lead to useful carbocy-
clic compounds, such as quinolines, lactones, con-
[
12,13]
densed aromatics, and cyclic aromatic ketones.
The intramolecular pathway involves a substituted ar-
omatic substrate, which undergoes cyclization due to
the close spatial arrangement of two reacting centers.
In contrast, bimolecular Friedel–Crafts cyclizations of
a single aromatic moiety with bifunctional electro-
philes are more difficult to carry out as competitive
Scheme 1.
intermolecular reactions might significantly decrease of solvent. Evaporation of the solvent gives the dry
the selectivity of cyclization. However, due to the mixture of catalyst and reactants adsorbed on its sur-
higher reactivity of N-heterocycles, the use of a bi- face. The dry mixture is then irradiated by micro-
functional substrate is appealing for the formation of waves for the specified time. The results are summar-
indoles and carbazoles. Our basic idea is that a selec- ized in Table 1.
tive electrophilic annelation on pyrroles can provide
As the data indicate, the reactions provide practi-
indoles, and eventually lead to carbazoles (Scheme 1). cally quantitative yields in very short reaction times.
A similar method had been reported for the synthesis The reactivity of different amines plays only a minor
of the target compounds, however, the use of p-tolue- role in the process, even the longest reaction takes
nesulfonic acid or HCl as catalyst, benzene as solvent, place within 6 min providing a 98% yield. In addition,
40 h reaction time and the at best moderate yields the reaction proceeds with 100% selectivity without
(
average yield 45–55%) did not represent a novel ap- by-product formation. It was observed that the prod-
[14]
proach. Our own experiments with sulfuric acid as uct did not undergo secondary reactions even after an
catalyst showed even worse features (less than 10% extended time of irradiation.
yield). Besides their corrosive and harmful nature, the
The excellent results obtained with primary amines
low yields and significant polymerization of pyrrole prompted us to extend the scope of the reaction to
clearly indicated that these liquid acids cannot be the synthesize higher analogues such as indoles and car-
catalyst of choice for the above detailed electrophilic bazoles. The same methodology has been applied
annelation process.
In order to show the general nature and efficiency ed indoles. The results are tabulated in Table 2.
of our new method we initially carried out the synthe- As shown, the reactions provide the expected sub-
using pyrroles as starting materials to obtain substitut-
sis of substituted pyrroles using aromatic and aliphatic stituted indoles in good to excellent yields. The sub-
primary amines and 2,5-hexanedione in a K-10 mont- stituents on the pyrrole ring significantly affect the
morillonite-catalyzed, microwave-assisted reaction. rate and the reactivity of substrates. Pyrrole itself un-
This process, an efficient modification of the Paal– dergoes cyclialkylation in a very short (2 min) reac-
[15]
Knorr synthesis,
is formally a solid acid-catalyzed tion providing practically quantitative yield. N-Alkyl-
cyclialkylation on the nitrogen of the amines. The pyrroles also react readily and give good to excellent
general procedure involves the adsorption of reac- yields, however, in longer reactions. The nature of the
tants on the catalyst surface with a minimum amount substituent clearly affects the reaction rates and
2192
www.asc.wiley-vch.de
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2006, 348, 2191 – 2196

Synthesis of Substituted Five-Membered N-Heterocycles
FULL PAPERS
Table 1. K-10 montmorillonite catalyzed synthesis of substi-
tuted pyrroles under microwave irradiation at constant
Table 2. K-10 Montmorillonite catalyzed synthesis of substi-
tuted indoles under microwave irradiation at constant
(908C) temperature.
(
908C) temperature.
[
[
a]
b]
Yields of the isolated products after flash chromatogra-
phy, 100% selectivity for all products observed by GC-
MS.
New compounds.
pyrroles having strong electron-withdrawing substitu-
[
[
a]
Yields of the isolated products after flash chromatogra- ents (e.g. 2-acetyl or 2-formyl) provide the corre-
phy, 100% selectivity for all products observed by GC-
sponding indoles only in traces even after extended
reaction times (25–30 min).
MS.
b]
New compounds.
To further widen the scope of the process, several
substituted indole derivatives were used as substrates
in the reaction, expecting the corresponding carbazole
yields. In the presence of electron-donating substitu- derivatives. A wide variety of indoles possessing elec-
ents (e.g., entry 5) the rate is higher than with elec- tron-donor and electron-withdrawing substituents
tron-withdrawing substituents (e.g., entry 6) following have been studied. The results are summarized in
the general rules of Friedel–Crafts chemistry. The se- Table 3.
lectivity is excellent, the expected indoles exclusively
The data indicate the usefulness of our method.
form in the reaction. Interestingly, this selectivity re- Indole and substituted indole derivatives readily un-
mains very high even at increased (2:1) diketone/pyr- dergo electrophilic annelation under the same reac-
role ratios, indicating that the theoretical one-pot pro- tion conditions providing a wide variety of substituted
cess from pyrroles to carbazoles does not occur. As a carbazoles. The reaction times and yields do not show
limitation of the method, it is worth mentioning that significant substituent effects, the yields are excellent
Adv. Synth. Catal. 2006, 348, 2191 – 2196
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
2193

Mohammed Abid et al.
FULL PAPERS
Table 3. K-10 montmorillonite catalyzed synthesis of substi-
tuted carbazoles under microwave irradiation at constant
product has not been detected at all. This suggests
that water elimination occurs immediately after the
hydroxyalkylation, the second cyclization step only
takes place after dehydration.
(
908C) temperature.
Conclusions
In conclusion, a new, effective, solid acid-catalyzed
synthesis of substituted pyrroles, indoles and carba-
zoles is described. This method provides the products
in very high yields and excellent selectivities in very
short reaction times. In addition to efficiency, the sol-
vent-free environment, solid acid catalysis, very limit-
ed energy consumption, and waste-free nature makes
the process very attractive for the environmentally
benign synthesis of these important heterocycles. Our
work represents the first effective method that is
based on successive electrophilic annelation for the
synthesis of all three classes of these N-heterocycles.
Experimental Section
Materials
All starting materials were purchased from Aldrich and
were used without further purification. Solvents used were
all Fisher products with a minimum purity of 99.5%. K-10, a
solid acid catalyst is commercially available from Aldrich
and was used as received.
[
[
a]
NMR Analysis
Yields of the isolated products after flash chromatogra-
phy, 100% selectivity for all products observed by GC-
MS.
Many of the products synthesized during this study are
known (8 out of 26) and their spectral characterization
showed satisfactory agreement with former literature data.
Nevertheless, we have provided full spectral characterization
b]
New compounds.
1
13
of all products synthesized in this study. The H, and
C
in most cases and the reactions are completed within spectra were obtained on a 400 MHz superconducting
3
–12 min. Similarly to the previous examples (Table 1 Varian Innova400 NMR spectrometer, in CDCl3 solvent
and Table 2), the exclusive formation of carbazoles with tetramethylsilane as internal standards. The tempera-
ture was 258C (accuracy Æ18C) and controlled by the
has been observed.
Varian control unit.
While the synthesis of pyrroles (Table 1) follows
the general Paal–Knorr-type mechanism there are
two possibilities to describe the mechanism of indole
GC-MS analysis
and carbazole formation. The first is a step by step al-
The mass spectrometric identification of the products has
kylation, the second is a concerted reaction path. The been carried out with a Shimadzu QP5050 and an Agilent
concerted cyclization is highly unlikely under the ex- 6850 gas chromatograph-5973N mass spectrometer system
tremely polar conditions and due to the surface (70 eV electron impact ionization) using a 30 m long DB-5
type column (J&W Scientific).
bound active intermediate serious steric hindrance ap-
plies. Considering the polarity, acid strength and het-
General Experimental Procedure for the Microwave-
Assisted K-10 Montmorillonite-Catalyzed
Electrophilic Annelation of Pyrroles and Indoles
erogeneous nature of K-10 montmorillonite we sug-
gest that the annelation occurs in two consecutive al-
kylation-dehydration reactions. This is partially sup-
ported by the reaction of pyrrole with a monofunc-
tional reagent, 2-hexanone, which showed the
The reactions have been carried out in a focused CEM Dis-
cover Benchmate microwave reactor, using the open vessel
exclusive formation of the C=C bonded product even technique. After optimization the system has been set up to
at low conversion values, while the hydroxyalkylated a standard temperature (908C) for the reactions. The tem-
2194
www.asc.wiley-vch.de
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2006, 348, 2191 – 2196

Synthesis of Substituted Five-Membered N-Heterocycles
FULL PAPERS
perature has been measured and kept constant using an in-
frared temperature controller.
[5] L. Ackermann, L. Kaspar, C. J. Gschrei, Chem.
Commun. 2004, 2824; A. R. Katritzky, S. Ledoux, S.
Nair, J. Org. Chem, 2003, 68, 5728.
[6] Y. Zhang, T. Wada, L. Wang, T. Aoyama, H. Sasabe,
Chem. Commun. 1996, 2325; Y. Zhang, T. Wada, H.
Sasabe, Chem. Commun. 1996, 621; M. Guan, Z. Q.
Bian, Y. F. Zhou, F. Y. Li, Z. J. Li, C. H. Huang, Chem.
Commun. 2003, 2708; D. Curiel, A. Cowley, P. D. Beer,
Chem. Commun. 2005, 236; H. J. Knolker, K. R.
Reddy, Chem. Rev. 2002, 102, 4303.
[7] J. Zhao, R. C. Larock, Org. Lett. 2005, 7, 701; R. B.
Bedford, C. S. Cazin, Chem. Commun. 2002, 2310; Z.
Liu, R. C. Larock, Org. Lett. 2004, 6, 3739; X. Cai, V.
Snieckus, Org. Lett. 2004, 6, 2293; K. Masatane, T. J.
Yutaka, J. Heterocycl. Chem. 1981, 18, 709; P. A. Cran-
well, J. E. Saxton, J. Chem. Soc. Abstracts 1962, 3482.
Pyrrole (1mmol) and 2,5-hexanedione (1.5 mmol) were
dissolved in 10 mL of dichloromethane. 500 mg of K-10
montmorillonite were added to the mixture which was then
stirred for 2 min. The solvent was evaporated under
vacuum. The dry mixture was then transferred into a vial
and inserted to the cavity of the microwave reactor. All re-
actions have been carried out under atmospheric pressure.
The progress of the reaction was monitored by GC-MS.
When the reaction was completed the product was dissolved
in CH Cl , separated from catalyst by filtration and the sol-
2
2
vent was removed under vacuum. The crude 4,7-dimethylin-
dole was purified by flash chromatography to obtain the
pure product.
Similar procedures were followed in case of pyrrole and
carbazole syntheses except amines and indoles served as
starting materials, respectively.
[
8] A. Corma, Chem. Rev. 1995, 95, 559; B. C. Gates, Catal-
ysis by Solid Acids, in: Encyclopedia of Catalysis, (Ed.:
I. Horvµth), Wiley, New York, 2003, Vol. 2, p. 104;
A. C. K. Yip, F. L. Y. Lam, X. J. Hu, Chem. Commun.
The complete spectroscopic characterization of the prod-
ucts is provided in the Supporting Information.
2
005, 3218.
Supporting Information
[9] M. Balogh, P. Lµszló, Organic Chemistry Using Clays,
Springer-Verlag, Berlin, Heidelberg, 1993; A. Li, T. Li,
T. Ding, Chem. Commun. 1997, 1389; G. Szçllçsi, B.
Tçrçk, L. Baranyi, M. Bartók, J. Catal. 1998, 179, 61 9;
M. L. Kantam, B. M. Choudary, C. V. Reddy, K. K.
Rao, F. Figueras, Chem. Commun. 1998, 1 033; B.
Tçrçk, G. London, M. Bartók, Synlett 2000, 631; K.
Ebitani, M. Ide, T. Mitsudome, T. Mizugaki, K.
Kaneda, Chem. Commun. 2002, 690; M. Abid, B.
Tçrçk, Adv. Synth. Catal. 2005, 347, 1797.
Details of reaction conditions and full spectroscopic charac-
terization of each product are provided in the Supporting
Information.
Acknowledgements
[
[
10] R. S. Varma, R. Dahiya, S. Kumar, Tetrahedron
Lett.1997, 38, 2039; P. Walla, C. O. Kappe, Chem.
Commun. 2004, 5, 594; A. Miyazawa, K. Tanaka, T. Sa-
kakura, M. Tashiro, H. Tashiro, G. K. S. Prakash, G. A.
Olah, Chem. Commun. 2005, 2104; A. Loupy, Micro-
waves in Organic Synthesis Wiley-VCH, Weinheim,
Financial support from University of Massachusetts Boston,
Michigan Technological University and NIH (R-15
AG025777–01) is gratefully acknowledged.
2
005; C. O. Kappe, A. Stadler, Microwaves in Organic
and Medicinal Chemistry, Wiley-VCH, Weinheim, 2005.
11] H. Heaney, in: Comprehensive Organic Synthesis, Vol.
References
2
1
, (Eds.: B. M. Trost, I. Fleming), Pergamon, Oxford,
991, p 733 and 753; G. A. Olah, R. Krishnamurti,
[
1] G. W. Gribble, J. Chem. Soc., Perkin Trans. 1 2000,
1
045; T. A. Gilchrist, J. Chem. Soc., Perkin Trans. 1
G. K. S. Prakash, in: Comprehensive Organic Synthesis,
Vol. 1(Eds.: B. M. Trost, I. Fleming), Pergamon,
Oxford, 1991, p. 293; N. Yonezawa, T. Hino, T. Ikeda,
Recent Res. Dev. in Synth. Org. Chem. 1998, 1, 21 3;
G. A. Olah, (Ed.), Friedel–Crafts and Related Reactions,
Wiley, New York, 1963–1965; G. A. Olah, B. Tçrçk, T.
Shamma, M. Tçrçk, G. K. S. Prakash, Catal. Lett. 1996,
42, 5; T. Beregszµszi, B. Tçrçk, . Molnµr, G. A. Olah,
G. K. S. Prakash, Catal. Lett. 1997, 48, 83; B. Tçrçk, I.
Kiricsi, . Molnµr, G. A. Olah, J. Catal. 2000, 193, 132;
G. A. Olah, B. Tçrçk, J. P. Joschek, I. Bucsi, P. M. Este-
vez, G. Rasul, G. K. S. Prakash, J. Am. Chem. Soc.
2002, 124, 11379.
1
998, 615; A. Nobuyoshi, O. Akihiko, M. Chikara, T.
Tatsuya, O. Masami S. Hiromitsu, J. Med. Chem. 1999,
2, 2946; P. S. Baran, J. M. Richter, D. W. Lin, Angew.
4
Chem. Int. Ed. 2005, 44, 609; M. Tçrçk, M. Abid, S. C.
Mhadgut, B. Tçrçk, Biochemistry 2006, 45, 5377.
[
[
[
2] P. Kohling, A. M. Schmidt, P. Eilbracht, Org. Lett. 2003,
5
8
4
6
, 3213; S. Yang, W. A. Denny, J. Org. Chem. 2002, 67,
958; S. Caron, E. Vazquez, J. Org. Chem. 2003, 68,
104; B. Jiang, C. Yang, J. Wang, J. Org. Chem. 2002,
7, 1396; G. Bringmann, S. Tasler, H. Endress, J. Muhl-
bacher, Chem. Commun. 2001, 761.
3] C. Rosenbaum, C. Katzka, A. H. Marzinzik, H. Wald-
mann, Chem. Commun. 2003, 1822; B. Tçrçk, M. Abid,
G. London, J. Esquibel, M. Tçrçk, S. C. Mhadgut, P.
Yan, G. K. S. Prakash, Angew. Chem. Int. Ed. 2005, 44,
[12] C. F. Koelsch, H. Hochmann, C. D. Le Claire, J. Am
Chem. Soc. 1943, 65, 59; R. T. Hart, R. F. Tebbe, J. Am.
Chem. Soc. 1950, 72, 3286; C. K. Bradsher, Chem. Rev.
1987, 87, 1277; H. Kusama, Y. Yamashita, K. Narasaka,
Chem. Lett. 1995, 5; S. Hanessian, M. Mauduit, E.
Demont, C. Talbot, Tetrahedron 2002, 58, 1 485; D. A.
Klumpp, D. N. Baek, G. K. S. Prakash, G. A. Olah, J.
3
086; J. M. Kremsnerm, C. O. Kappe, Eur. J. Org.
Chem. 2005, 3672.
4] E. Fischer, F. Jourdan, Ber. dtsch. chem. Ges. 1883, 16,
2
241; B. Robinson, The Fischer Indole Synthesis, John
Wiley & Sons, Chichester, 1982.
Adv. Synth. Catal. 2006, 348, 2191 – 2196
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
2195

Mohammed Abid et al.
FULL PAPERS
Org. Chem. 1997, 62, 6666; . Molnµr, I. Ledneczki, I.
Bucsi, M. Barttók, Catal. Lett. 2003, 89, 1 .
13] . Molnµr, B. Tçrçk, I. Bucsi, A. Fçldvµri, Top. Catal.
P. V. R. Shannon, J. Chem. Soc., Perkin Trans.1 1977,
1698.
[
[15] J. Robertson, R. J. D. Hatley, Chem. Commun. 1999,
1455; G. Minetto, L. F. Raveglia, M. Taddei, Org. Lett.
2004, 6, 389; B. K. Banik, S. Samajdar, I. Banik, J. Org.
Chem. 2004, 69, 213; S. G. Salamone, G. B. Dudley,
Org. Lett. 2005, 7, 4443.
1
998, 6, 9; G. K. S. Prakash, P. Yan, B. Tçrçk, G. A.
Olah, Catal. Lett. 2003, 87, 109.
[
14] C. Kashima, S. Hibi, T. Maruyama, Y Omote, Tetrahe-
dron Lett. 1986, 27, 2131; A. H. Jackson, P. R. Jenkins,
2196
www.asc.wiley-vch.de
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2006, 348, 2191 – 2196