Bronsted acid-catalyzed Nazarov cyclization of pyrrole derivatives accelerated by microwave irradiation

Article abstract of DOI:10.1016/j.bmcl.2009.04.109

The Bronsted acid-catalyzed Nazarov cyclization of pyrrole derivatives was developed. Microwave irradiation accelerated the Nazarov cyclization significantly at 40 °C to give cyclopenta[b]pyrrole derivatives in excellent yields with high trans selectivity

Full text of DOI:10.1016/j.bmcl.2009.04.109

Bioorganic & Medicinal Chemistry Letters 19 (2009) 3764–3766
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Brønsted acid-catalyzed Nazarov cyclization of pyrrole derivatives accelerated
by microwave irradiation
*
Prabhakar Bachu, Takahiko Akiyama
Department of Chemistry, Faculty of Science, Gakushuin University, 1-5-1 Mejiro, Toshima-ku, Tokyo 171-8588, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The Brønsted acid-catalyzed Nazarov cyclization of pyrrole derivatives was developed. Microwave irradi-
ation accelerated the Nazarov cyclization significantly at 40 °C to give cyclopenta[b]pyrrole derivatives in
excellent yields with high trans selectivity.
Received 2 March 2009
Revised 21 April 2009
Accepted 22 April 2009
Available online 3 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
This paper is dedicated to Professor Carlos F.
Barbas III for the Tetrahedron Young
Investigator Award.
Keywords:
Nazarov cyclization
Brønsted acid
Microwave irradiation
Cyclopentanone
Pyrrole
In recent years, the construction of cyclopentanones via electro-
cyclic reactions has played an important role in synthetic organic
chemistry because of the widespread occurrence of the structural
features in many natural products.1 Along this line, roseophilin
1,2 yuehchukene 2,3 and paspaline 34 are representative cyclopen-
tanones that are not only medicinally relevant but also architectur-
ally intriguing, as depicted in Figure 1. Roseophilin 1, which was
isolated from Streptomyces griseoviridis, is a potent cytotoxic agent
plied to the synthesis of several natural products, including pep-
tides and carbohydrates.10
Surprisingly, very few reports are available on the Nazarov
cyclization of pyrrole derivatives.7f,i,8e Given the significance of
the biological aspect of cyclopenta[b]pyrrole 4 derivatives, com-
bined with our continuing interest in Brønsted acid-catalyzed reac-
against K562 cells (chronic myeloid leukemia model; IC50
,
,
HN
0.34
0.88
l
l
M) and KB cells (nasopharyngeal carcinoma model; IC50
M). Yuehchukene 2, which was isolated from the roots of
H
Cl
H
O
N
H
Murraya paniculata, exhibits estrogenic and antiestrogenic activi-
ties as well as potent anti-implantation activity. Paspaline 3, which
was isolated from Claviceps paspali, shows potent tremorgenic
activity.
NH
N
OMe
H
The Nazarov cyclization5,6 is a very versatile process for the syn-
thesis of cyclopentanones, and it is well known that Lewis7 or
Brønsted acids8 promote this reaction. Microwave-assisted expedi-
ent synthesis has also attracted considerable interest in recent
years.9 The advantages of the microwave-assisted organic synthe-
sis (MAOS) include short reaction time, diminished side reactions,
increased yields, and improved reproducibility. MAOS has been ap-
Yuehchukene 2
Roseophilin 1
H
N
O
H
N
R1
H
O
R
H
OH
Paspaline 3
cyclopenta[b]pyrrole 4
* Corresponding author. Tel.: +81 3 3986 0221; fax: +81 3 5992 1029.
E-mail address: takahiko.akiyama@gakushuin.ac.jp (T. Akiyama).
Figure 1. Cyclopenta[b]pyrrole based natural products and core structure 4.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.04.109

P. Bachu, T. Akiyama / Bioorg. Med. Chem. Lett. 19 (2009) 3764–3766
3765
Table 1
Table 2
Optimization of Nazarov cyclization
Tf2NH-catalyzed Nazarov cyclizationa
H
N
O
O
O
H
N
Entry
Substrate
Time (h)
Product
Yieldb (%)
O
H
N
O
OMe
+
O
H
N
O
H
O
O
OMe
O
5a
6a
7
N
OMe
1
6
81
OMe
5a
6a
Entry
Acid (mol %)
Solvent
Temp
Time (h)
Yield of 6aa (%)
1
2
3
4
5
6
7
8
9
TsOHe (20%)
CSAf (20%)
Toluene
Toluene
MeCNc
MeCN
MeCN
MeCN
MeCN
MeCN
Toluene
Toluene
DCEb
80
80
60
rt
rt
35
24
24
34
135
37
12
6
9
6
6
12
6
33i
No reaction
O
H
N
TfOHg (20%)
Tf2NHh (20%)
Tf2NH (30%)
Tf2NH (30%)
Tf2NH (30%)
Tf2NH (30%)
Tf2NH (30%)
Tf2NH (30%)
Tf2NH (30%)
Tf2NH (30%)
46j
32
55
50
72
78
25
69
62
81
O
O
H
N
OMe
OMe
2
3
4
5
6
7
14
82
95
89
83
94
5b
6b
40, MWd
40, MW
40
40, MW
40
Cl
Cl
10
11
12
O
DCE
40, MW
H
N
O
O
H
O
a
Isolated yield.
N
b
c
d
e
f
OMe
DCE = dichloroethane.
MeCN = acetonitrile.
MW = microwave.
TsOH = 4-toluenesulfonic acid.
CSA = camphorsulfonic acid.
TfOH = trifluoromethanesulfonic acid.
Tf2NH = trifluoromethanesulfonimide.
1:0.4 mixture of 6a and 7.
OMe
9
6c
5c
OMe
OMe
g
h
i
O
H
O
O
j
H
N
1:0.5 mixture of 6a and 7.
O
N
OMe
OMe
6d
9
5d
tions,11,12 we turned our attention to the development of a simple
and flexible method that is viable for producing closely related
cyclopenta[b]pyrrole derivatives. We herein report our preliminary
studies on the microwave-assisted Brønsted acid-catalyzed Naza-
rov cyclization of polarized pyrrole derivatives.
O
H
N
O
O
H
O
At the outset, we selected dienone 5a as the model substrate
and screened the Brønsted acid for the Nazarov cyclization. The re-
sults are shown in Table 1. Upon treatment of 5a with 20 mol %
TsOH at 80 °C, the enone underwent Nazarov cyclization to furnish
6a in a low yield (entry 1). No reaction was observed with 20 mol %
CSA at 80 °C (entry 2). Use of 30 mol % Tf2NH13 (entry 5) turned out
to be more promising than that of TfOH (entry 3) even though it
again resulted in incomplete conversion. It is noted that the reac-
tion at higher temperature with extended hours of heating resulted
in the formation of a significant amount of decarboxylated com-
pound of 4-phenyl-4,5-dihydrocyclopenta[b]pyrrol-6(1H)-one 714
accompanied by the cyclized product of 6a. Hence, it is vital to
firstly maintain the reaction temperature below 60 °C and sec-
ondly, shorten the reaction time to obtain 6a in good yield.
We were pleased to discover that even though the reaction did
not proceed to completion after 12 h (entry 6) with a sub-stoichi-
ometric amount of Tf2NH in acetonitrile alone, the reaction rate
was improved significantly by microwave irradiation (entries 7
and 8). Having secured an efficient approach to the cyclization of
5 in 30 mol % Tf2NH in acetonitrile under microwave irradiation,
we focused our subsequent efforts on the solvent system. We con-
ducted the reaction in toluene and dichloroethane (entries 9–12).
Dichloroethane was found to be the optimal solvent under stan-
dard microwave irradiation at 40 °C for 6 h, affording 6a in 81%
yield. When this reaction was conducted thermally at 40 °C for
12 h, 62% of 6a was obtained.
N
OMe
OMe
14
6e
5e
NO2
NO2
O
O
H
O
H
N
O
N
OMe
8
OMe
5f
6f
MeO
MeO
O
O
H
N
O
O
O
O
H
N
OMe
OMe
OMe
13
15
80
70
6g
5g
O
H
N
H
N
O
8
OMe
5h
6h
With the optimized reaction conditions in hand, we set out to
define the scope of the Nazarov cyclization of a range of pyrrole
derivatives 5 (Table 2).15 The cyclization of polarized reactants
5c, 5f, and 5g bearing electron-donating components at the b-posi-
a
Reaction conditions: 1 mmol of dienone, 30 mol % of Tf2NH, DCE, 40 °C, MW.
Isolated yields.
b

3766
P. Bachu, T. Akiyama / Bioorg. Med. Chem. Lett. 19 (2009) 3764–3766
6. For comprehensive reviews on Nazarov chemistry, see: (a) Habermas, K. L.;
Denmark, S. E.; Jones, T. K.. In Organic Reactions; John Wiley & Sons: New York,
1994; Vol. 45; (b) Christiane, S. R.; Maurice, S. Synthesis 1983, 429; (c) Tius, M.
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Chem. Soc. 2007, 129, 498. and reference cited therein; (b) Walz, I.; Bertogg, A.;
Togni, A. Eur. J. Org. Chem. 2007, 2650; (c) Aggarwal, V. K.; Belfield, A. J. Org. Lett.
2003, 5, 5075; (d) Lin, G. Y.; Yang, C. Y.; Liu, R. S. J. Org. Chem. 2007, 72, 6753; (e)
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Fujiwara, M.; Kawatsura, M.; Hayase, S.; Nanjo, M.; Itoh, T. Adv. Synth. Catal.
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Synlett 2008, 1009; (h) Chiu, P.; Li, S. Org. Lett. 2004, 6, 613; (i) Malona, J. A.;
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Ishikura, M.; Imaizumi, K.; Katagiri, N. Heterocycles 2000, 53, 2201; (c)
Fernández-Mateos, A.; Mateos Burón, L.; Martín de la Nava, E. M.; Rubio
González, R. J. Org. Chem. 2003, 68, 3585; (d) Fernández-Mateos, A. F.; Martín de
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Sannigrahi, M.; Hisaindee, S. J. Org. Chem. 2001, 66, 954; (g) Amere, M.;
Blanchet, J.; Lasne, M.-C.; Rouden, J. Tetraheron Lett. 2008, 49, 2541; (h)
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tion proceeded smoothly to give the corresponding products in
excellent isolated yields (entries 3, 6, and 7). In the presence of
electron-withdrawing components of 5b and 5e, the reaction rate
was slightly reduced (entries 2 and 5) although the desired product
was also obtained in excellent isolated yields. On the other hand,
5d that had an additional aromatic ring system gave a slightly
higher yield than 5a (entries 4 and 1). Finally, 5h bearing a b-alkyl
group gave cyclized product 6h in moderate yield with a low reac-
tion rate (entry 8). Only one diastereomer with a trans relationship
between an
a-methoxycarbonyl group and a b-phenyl or alkyl
group was obtained after column chromatography in all the cases
examined. This 3,4-trans relative stereochemistry was supported
by previous results.7f
In conclusion, we have developed a simple, efficient, and cost-
effective cyclization of polarized pyrrole derivatives using Tf2NH
(30 mol %) in dichloroethane at 40 °C under microwave irradiation.
Studies directed towards the synthesis of bioactive natural prod-
ucts and explorative works on asymmetric Nazarov cyclization
using this methodology are ongoing.
9. For recent reviews, see: (a) Mavandadi, F.; Pilotti, A. Drug Discovery Today 2006,
11, 165; (b) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250.
10. (a) Bachu, P.; Sperry, J.; Brimble, M. A. Tetrahedron 2008, 64, 4827; (b) Bachu, P.;
Gibson, J. S.; Sperry, J.; Brimble, M. A. Tetrahedron: Asymmetry 2007, 18, 1618;
(c) Bejugam, M.; Flitsch, S. L. Org. Lett. 2004, 6, 4001; (d) Murry, J. K.; Gellman,
S. H. Org. Lett. 2005, 7, 1517; (e) Matsushita, T.; Hinou, H.; Fumoto, M.;
Kurogochi, M.; Fujitani, N.; Shimizu, H.; Nishimura, S.-I. J. Org. Chem. 2006, 71,
3051; (f) Gorske, B. C.; Jewell, S. A.; Guerard, E. J.; Blackwell, H. E. Org. Lett.
2005, 7, 1521.
Acknowledgements
This work was partially supported by a Grants-in Aid for JSPS
Fellows from the Japanese Society for Promotion of Science, Japan.
P.B. thanks the JSPS Postdoctoral Fellowships for ForeignResearchers.
11. (a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem., Int. Ed. 2004, 43,
1566; (b) Yamanaka, M.; Itoh, J.; Fuchibe, K.; Akiyama, T. J. Am. Chem. Soc. 2007,
129, 6756; (c) Itoh, J.; Fuchibe, K.; Akiyama, T. Angew. Chem., Int. Ed. 2008, 47,
4016. see also references cited therein.
Supplementary data
12. For reviews on Brønsted acid catalysis, see: (a) Akiyama, T.; Itoh, J.; Fuchibe, K.
Adv. Synth. Catal. 2006, 348, 999; (b) Akiyama, T. Chem. Rev. 2007, 107, 5744.
13. For recent example of the Tf2NH-catalyzed reactions, see: (a) Ishihara, K.;
Hiraiwa, Y.; Yamamoto, H. Synlett 2001, 1851; (b) Cossy, J.; Lutz, F.; Alauze, V.;
Meyer, C. Synlett 2002, 45; (c) Zhang, L.; Kozmin, S. A. J. Am. Chem. Soc. 2004,
126, 10204; (d) Takasu, K.; Nagao, S.; Ihara, M. Adv. Synth. Catal. 2006, 348,
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Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2009.04.109.
References and notes
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references cited therein.
14. Identified by 1H NMR, isolated as a mixture of 6a and 7.
15. General procedure for the Nazarov cyclization. A mixture of dienone (1.0 mmol)
and Tf2NH (0.3 mmol) in dichloroethane (1.5 mL) in glass vial was flushed with
argon for 1 min and sealed with cap. The resulting mixture was stirred at 40 °C
TM
in microwave reactor (Biotage Initiator , Focused microwave heating system)
for the time shown in Table 2. When the reaction was complete (as indicated
by TLC analysis) the organic solvent was removed under reduced pressure and
the residue was purified by either flash column chromatography or preparative
thin layer chromatography using hexane–ethyl acetate as eluent to yield the
corresponding cyclized product.