4-Toluenesulfonic acid: an environmentally benign catalyst for Nazarov cyclizations

Article abstract of DOI:10.1016/j.tetlet.2008.02.091

An efficient metal-free catalytic protocol for the electrocyclization of α-alkoxydienones to cyclopentenones (Nazarov reaction) in near to quantitative yields is described. The key parameters are the use of inexpensive 4-toluenesulfonic acid in 5 mol % at

Full text of DOI:10.1016/j.tetlet.2008.02.091

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2541–2545
4-Toluenesulfonic acid: an environmentally benign catalyst
for Nazarov cyclizations
*
´ ˆ
Mukkanti Amere, Jerome Blanchet, Marie-Claire Lasne, Jacques Rouden
Laboratoire de Chimie Mole´culaire et Thioorganique, ENSICAEN, Universite´ de Caen-Basse Normandie, CNRS,
6 Boulevard du Mare´chal Juin, 14050 Caen Cedex, France
Received 1 February 2008; revised 14 February 2008; accepted 18 February 2008
Available online 21 February 2008
Abstract
An efficient metal-free catalytic protocol for the electrocyclization of a-alkoxydienones to cyclopentenones (Nazarov reaction) in near
to quantitative yields is described. The key parameters are the use of inexpensive 4-toluenesulfonic acid in 5 mol % at room temperature
in acetonitrile or under solvent-free conditions. The versatility of the transformation is demonstrated with unpolarized dienones with
good regioselectivities and excellent yields.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Nazarov reaction; Electrocyclic reactions; Enones; Organocatalysis; Sulfonic acids; Solvent-free reactions
Cyclopentenones are structural features frequently
encountered in natural products.1 The Nazarov reaction,
which is the electrocyclization of conjugated dienones
(divinyl ketones),2 is a well-known and atom economic
route to these structures. However, this methodology
requires most often an acidic activation. Recently, a
catalyst-free Nazarov reaction3 has been described in ionic
liquids under microwave heating. The high temperature
used and the poor stereoselectivity limit such conditions
to the rapid synthesis of simple cyclopentenones. Whereas
Lewis acids have been successfully used under catalytic
conditions, yielding cyclopentenones with excellent control
of regioselectivity and enantioselectivity,4 Bro¨nsted acids
either mineral or organic5,6 require at least a stoichiometric
amount to promote the electrocyclization. Surprisingly,
only a few examples of Nazarov reaction using a catalytic
amount of Bro¨nsted acid (Scheme 1) have been reported to
date. Neat damascenones were isomerized at 180 °C by
TsOH (1%) into a mixture of compounds including the
Nazarov product.7 The same acid (0.5 equiv) in aromatic
O
O
O
O
R3
R
R2
R1
R2
R1
R3
R4
S
OH
AH
R4
O
O
R
O
S
Reactive U-form
H
A-
R3
H
H
O
O
R2
R1
R3
R4
R2
R1
R4
III
I
H
A-
R3
O
R2
R1
4π
conrotatory
R4
II
Scheme 1. Mechanism for the Bro¨nsted acid-catalyzed Nazarov reaction.
solvents and under reflux afforded hexahydroindenones
from cyclohexenyl vinyl ketones.8 TsOH (0.1 equiv) was
also shown to be able to transform a0-hydroxyenones into
cyclopentenones, although in moderate yields.9 Recently,
10 mol % of TsOH was used to build, from conformation-
ally favorable divinyl ketones, the five-membered ring of
fusicoauritone.10 Shindo et al.11 reported the synthesis of
5-oxycyclopent-2-enones from b-alkoxy divinyl ketones
catalyzed by TfOH (0.1 mol %), more efficient than TsOH.
*
Corresponding author. Tel.: +33 2 31 45 2893; fax: +33 2 31 45 2877.
E-mail address: jacques.rouden@ensicaen.fr (J. Rouden).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.091

2542
M. Amere et al. / Tetrahedron Letters 49 (2008) 2541–2545
Finally Rueping et al.,12 described the first enantioselective
catalytic Nazarov reaction of a-alkoxy dienones. It was
mediated by N-triflyl phosphoramides derived from
BINOL. These results and the need for a simple, clean,
and cheap organocatalyst for the Nazarov reaction
prompted us to report our own results. We described here
the efficient catalysis of the Nazarov electrocyclization,
using 5 mol % of TsOH in organic solvents or under
solvent-free conditions, of a variety of substrates, including
unpolarized divinyl ketones.
We first searched for a suitable and simple Bro¨nsted acid
catalyst for the Nazarov cyclization of dienone 1a (Table
1). Sulfonic acids such as TsOH or (+)-CSA used in
20 mol % amount, in acetonitrile, transformed divinyl
ketone 1a into cyclopentenone 1b in quantitative 1H
NMR yields after 3–4 h at room temperature (Table 1,
entries 1–2). Optically pure (+)-CSA produced a racemic
mixture of purified 1b. TFA catalyzed the reaction too,
but required a longer reaction time (entry 3). Cyclopente-
none 1b was obtained with picric acid although this catalyst
was less efficient (entry 4). With less acidic compounds, the
BINOL-derived phosphate13 or aspartic acid, no product
was detected in the reaction mixture (entries 5 and 6).
The previous results led us to optimize the solvent of the
cyclization of dienone 2a using TsOH as a catalyst decreas-
ing its amount to 5 mol %. As shown in Table 2, a strong
solvent effect was observed. Acetonitrile (entry 1), halo-
genated (entries 2–3) and aromatic solvents (entry 4) led
to good to excellent yields of cyclopentenone 2b at room
temperature, whereas THF was not appropriate (entry 9).
These results, except the one observed in acetonitrile, are
in good agreement with the solvent effects reported in the
electrocyclization of 2a in the presence of BINOL-N-triflyl
phosphoramide.12 In other polar (acetone, DMF, entries 8
Table 2
Solvent effect in the organocatalyzed Nazarov reaction
O
O
O
O
5% TsOH
solvent, rt
Ph
Ph
2b
2a
Solventa
Entry
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
MeCN
CHCl3
CH2Cl2
Toluene
MeOH
EtOH
Et2O
Acetone
THF
DMF
No
15
15
15
15
24
24
24
24
24
24
4
94
91
90
85
75
40
25
25
10
10
89
10
11
a
1 mL/mmol.
Isolated yields.
b
and 10), apolar (Et2O, entry 7), or protic solvents (MeOH,
EtOH, entries 5–6), the conversion was slower and lower
yields of cyclopentenone 2b were obtained, even after
24 h reaction time (entries 5–10). Finally, the reaction
was carried out in the absence of any solvent (entry 11).
The yield of cyclopentenone 2b was similar to that obtained
in acetonitrile (entry 1) but in a shorter reaction time.
Hence, further Nazarov cyclizations were carried out in
acetonitrile and under solvent-free conditions at room
temperature.
The scope of the reaction was then examined (Table 3).
Various mono and disubstituted 2-alkoxy-1,4-pentadien-3-
ones underwent cyclization smoothly to afford the corres-
ponding cyclopentenones in yields higher than 80%.14 In
most of the cases, the reactions were clean and the product
did not require any purification. As expected, the reactions
were regioselective placing the double bond at the ring-
junction with the dihydropyrane ring. The presence of a
bulky substituent a to the carbonyl and a small or no sub-
stituent at the b position favor the reactive U-form of the
dienone and thus the ring closure. The higher reactivity
of dienones 10a and 3a compared, respectively, to those
of 2a and 4a could be attributed to the presence of a phenyl
group or of a double bond in b-position to the carbonyl
enhancing the stabilization of the divinyl cation intermedi-
ate I (Scheme 1). The ring closure could also be accelerated
by the release of the allylic strain in 3a and the steric
hindrance between the methyl and the phenyl in 10a. The
catalyst loading can be reduced to 1 mol % without
significant change in reaction time, yield, and eventually
diastereoselectivity as it was shown with substrates 7a
and 10a. The higher reactivity of dienone 2a in the Nazarov
reaction under solvent-free conditions was confirmed with
other substrates (entries 1, 3–11).
Table 1
Evaluation of Bro¨nsted acids in Nazarov cyclization
O
O
O
O
Brönsted acid
MeCN, rt
CH3
CH3
1a
1b
Entry
Bro¨nsted acid
Mol (%)
Time (h)
Yielda (%)
1
2
3
4
TsOH
20
20
20
20
3
4
130
130
100
100
93
(+)-CSAb
TFA
Picric acid
40
O
P
O
O
5
20
130
0
OH
(+)
6
Aspartic acid
100
98
0
a
1
Determined by H NMR using 4,40-di-t-butylbiphenyl as internal
Particularly, the less reactive dienone 4a afforded 4b in
96% yield after 24 h whereas only 80% were obtained in
standard.
b
CSA: camphorsulfonic acid.

M. Amere et al. / Tetrahedron Letters 49 (2008) 2541–2545
2543
Table 3
TsOH-catalyzed Nazarov cyclization of a-alkoxy dienone 1a–11aa
O
O
O
O
O
O
O
O
R1
R2
O
O
H
H
R1
H
H
R2
1a-10a
1b-10b
11a
11b
11c
Entry
Products
R1
R2
MeCN, time (h)
Yieldb (%)
syn/anti c
Neat, time (h)
Yieldb (%)
syn/antic
1
2
3
4
5
1b
2b
3b
4b
5b
6b
7b
8b
9b
10b
11b
H
H
H
H
Me
i-Pr
Bn
Me
Me
Me
—
Me
Ph
1-Propenyl
n-Pr
H
H
H
Me
Et
Ph
—
8
8
10
72
4
3
2
5
4
95
94
90
80
97
98
98
96
97
97
93
4
4
5
24
2
2
2
3
2
1
92
89
93
96
97
97
98
93
97
95
94
6
7d
8
1.44:1
3.35:1
49:1
1.44:1e
1.56:1
3.54:1
24:1
3.54:1e
9
10d
11
a
2
4
2
Reactions were carried out with 1 mmol of dienone, 5 mol % of TsOH at room temperature. 1 mL/mmol for the reactions carried out in MeCN.
Isolated yields.
Syn and anti isomers were identified by comparison with literature data and the ratio was determined by 1H NMR.
No change in the reaction efficiency was observed with 1 mol % of catalyst for substrates 7a and 10a.
Diastereomeric ratio 11b/11c.
b
c
d
e
acetonitrile after 72 h (entry 4). Diastereoselectivity was
were conveniently prepared in good yields by the reaction
of the lithium enolate of 1-acetylcyclohexene to the corres-
ponding aldehydes.4c Reaction of 12a with 5 mol % of
TsOH in acetonitrile at 25 °C gave 26% of both regioisom-
ers b and c, whereas heating to 95–100 °C in toluene led to
mixture 12b–12c in 86% yield (entries 1 and 2). The reac-
tion was faster with substrate 13a bearing an electron-
enriched phenyl group at the b-position of the carbonyl
group (2 h, 92% yield, entry 3), whereas with a 4-nitro-
phenyl substituent the cyclization of 14a occurred with a
lower rate (24 h, 82% yield, entry 4).15 The major regio-
isomers 12b–14b were the ones with the less substituted
double bond. According to the conrotatory mode of
cyclization and based on literature precedents,2 we attri-
buted a 3,4-trans relative stereochemistry to the substi-
tuents of cyclopentenones 12b–14b. To our knowledge,
only one example of catalyzed Nazarov reaction of
unpolarized substrates such as 12a–14a was described. It
was mediated by a copper complex and the expected
adducts were obtained in 30–42% yields.16,17
low for all disubstituted products except for 10b. The high
syn selectivity observed for this compound, higher to that
previously reported (6:1),12 could result from the kinetic
protonation of intermediate III (Scheme 1) from the less
hindered side of the enol.
The excellent yields for the Nazarov cyclization of alk-
oxy-activated substrates led us to attempt the reaction with
unpolarized dienones 12a–14a (Table 4). These compounds
Table 4
TsOH-catalyzed Nazarov cyclization of unpolarized substrates
O
O
O
5% TsOH
+
Toluene,
95-100 °C
R1
R1
R2
R1
R2
R2
major
minor
12-14a
12-14b
12-14c
Finally, with the aim of developing supported reagent
based reactions,18 commercially available resins functional-
ized by sulfonic acids were envisaged to catalyze the Naza-
rov reaction. Amberlyst-15 (A-15) was tested with divinyl
ketone 10a (Scheme 2).19 In acetonitrile at room tempera-
ture the cyclization occurred rapidly followed by the open-
ing of the dihydropyrane ring affording compound 15 in
92% yield. This compound has been recently obtained in
the metal-catalyzed reaction.4b Heating 10a in toluene at
70 °C in the presence of A-15 yielded Nazarov product
10b quantitatively.
Entry
Dienone
R1
R2
Time (h)
Yielda (%)
b:cb
1
2
3
4
a
12a
12a
13a
14a
H
H
OMe
H
H
H
OMe
NO2
24
10
2
26c
86d
92
3.35
3.16
5.25
2.70
24
82e
Isolated yields of both regioisomers starting from 1 mmol of dienones.
Ratio of the regioisomers measured after separation of each isomer by
b
chromatography.
c
The reaction was carried out at 25 °C.
6% starting material recovered.
12% starting material recovered.
d
e

2544
M. Amere et al. / Tetrahedron Letters 49 (2008) 2541–2545
J. Am. Chem. Soc. 2007, 129, 498–499 and references cited therein; (i)
O
O
HO
A-15
A-15
Bartali, L.; Larini, P.; Guarna, A.; Occhiato, E. G. Synthesis 2007,
1733–1737; (j) Walz, I.; Bertogg, A.; Togni, A. Eur. J. Org. Chem.
2007, 2650–2658.
Me
Ph
O
O
Me
Ph
MeCN
toluene
Me
O
70 °C
1 h
rt, 2 h
92%
5. For selected references of Bro¨nsted acids used in Nazarov reactions,
see H3PO4/HCO2H: (a) Oda, M.; Yamazaki, T.; Kajioka, T.;
Miyatake, R.; Kuroda, S. Liebigs Ann. Rec. 1997, 2563–2566; (b)
Kraft, P.; Cadalbert, R. Synthesis 2002, 2243–2253; polyphosphoric
acid: (c) Minami, T.; Nakayama, M.; Fujimoto, K.; Matsuo, S. J.
Chem. Soc., Chem. Commun. 1992, 190–191; HClO4: (d) Chiu, P.; Li,
S. Org. Lett. 2004, 6, 613–616; HClO4/Ac2O: (e) Fernandez Mateos,
A.; Martin de la Nava, E. M.; Rubio Gonzalez, R. Tetrahedron 2001,
57, 1049–1057; (f) Fernandez Mateos, A.; Mateos Buron, L.; Martin
de la Nava, E. M.; Rubio Gonzalez, R. J. Org. Chem 2003, 68, 3585–
3592; HCl: (g) Casson, S.; Kocienski, P. J. Chem. Soc., Perkin Trans.
1 1994, 1187–1191; (h) Cheng, K. F.; Cheung, M.-K. J. Chem. Soc.,
Ph
HO(H2C)3
97%
15
10a
10b
Scheme 2. Nazarov cyclization catalyzed by resin supported sulfonic acid.
In summary, we have shown that TsOH (5%) in acetoni-
trile or under solvent-free conditions exhibits a high cata-
lytic performance for the Nazarov reaction of a-alkoxy
dienones and unpolarized substrates. In many cases, the
product obtained did not require any purification. This
metal-free simple methodology, in which a cheap solid
sulfonic acid was used, offers superior ecological viability
over the often practiced Nazarov reactions conducted
under drastic conditions and stoichiometric quantities of
Bro¨nsted acids. It should be compatible with the highly
functionalized molecules, and thus attractive for the syn-
thesis of complex natural products. The use of a poly-
mer-supported catalyst (Amberlyst-15) afforded, in a
preliminary experiment, either the Nazarov product or
the 2-hydroxy-cyclopentenone, depending on the reaction
conditions. Efforts to exploit this dual reactivity are
underway. We are also currently developing chiral sulfonic
acids for their application in enantioselective Nazarov
cyclization.
Perkin Trans.
1 1996, 1213–1218; H2SO4: (i) Clive, D. L. J.;
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1353; (d) Kajioka, T.; Oda, M.; Yamada, S.; Kawamori, Y.;
Miyatake, R.; Kuroda, S. Synthesis 1999, 1, 184–187; (e) Kerr, D.
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Acknowledgments
10. Williams, D. R.; Robinson, L. A.; Nevill, C. R.; Reddy, J. P. Angew.
Chem., Int. Ed. 2007, 46, 915–918.
We gratefully acknowledge the CNRS (Centre National
de la Recherche Scientifique) for a fellowship to M.A.,
‘PunchOrga’ Network (Poˆle Universitaire Normand de
11. Shindo, M.; Yaji, K.; Kita, T.; Shishido, K. Synlett 2007, 1096–
1100.
12. Rueping, M.; Ieawsuwan, W.; Antonchick, A. P.; Nachtsheim, B. J.
Angew. Chem., Int. Ed. 2007, 46, 2097–2100.
13. The phosphoric acid derivative was prepared from optically pure
BINOL. The Nazarov reaction was performed in refluxing aceto-
nitrile. However, beside degradation compounds, less than 10% yield
of 1b was obtained. Therefore, the enantiomeric excess was not
measured.
`
Chimie Organique), ‘Ministere de la Recherche et des
´
Nouvelles Technologies’, the ‘Region Basse Normandie’,
and the European Union (FEDER funding) for funding.
We are grateful to one referee for helpful comments.
14. General procedure for the Nazarov cyclization of 2-alkoxy-1,4-penta-
dien-3-ones 1a–11a. TsOH (10 mg, 0.05 mmol, 5 mol %) was added to
2-alkoxy-1,4-pentadien-3-one (1.0 mmol) either neat or in CH3CN
(1.0 mL). The reaction mixture was flushed with nitrogen and was
stirred at room temperature until the disappearance of
starting material (TLC monitoring). After completion, the crude
product was dissolved in diethyl ether (50 mL) and washed with
aqueous NaHCO3 (15 mL). After separation, the organic layer was
washed with brine (80 mL), dried over MgSO4, filtered and concen-
trated under vacuum. Most of the substrates gave clean reactions and
no purification was needed. When required, the purification was
carried out by flash column chromatography (8–10% of EtOAc in
cyclohexane).
References and notes
1. For a recent review, see: Gibson, S. E.; Lewis, S. E.; Mainolfi, N. J.
Organomet. Chem. 2004, 689, 3873–3890 and references cited therein.
2. For comprehensive reviews on Nazarov chemistry, see: (a) Habermas,
K. L.; Denmark, S. E.; Jones, T. K. Org. React. 1994, 45, 1–158; (b)
Santelli-Rouvier, C.; Santelli, M. Synthesis 1983, 429–442; (c) Tius,
M. A. Eur. J. Org. Chem. 2005, 2193–2206; (d) Frontier, A. J.;
Collison, C. Tetrahedron 2005, 61, 7577–7606; (e) Pellissier, H.
Tetrahedron 2005, 61, 6479–6517.
3. Douelle, F.; Tal, L.; Greaney, M. F. Chem. Commun. 2005, 660–
662.
15. General procedure for the Nazarov cyclization of a,b-dialkyl-b0-aryl-
divinyl ketones 12a–14a (unpolarized substrates). TsOH (10 mg,
0.05 mmol, 5 mol %) was added to divinyl ketone 12a–14a (1.0 mmol)
in toluene (1.5 mL). The reaction mixture was flushed with nitrogen
and was heated at 100 °C until the disappearance of starting material
(TLC monitoring). After completion of the reaction, the crude
product was dissolved in EtOAc (50 mL) and washed with aqueous
NaHCO3 (15 mL). After separation, the organic layer was washed
with brine (80 mL), dried over MgSO4, filtered and concentrated
4. For selected catalytic reactions, see: (a) Giese, S.; West, F. G.
Tetrahedron 2000, 56, 10221–10228; (b) Bee, C.; Leclerc, E.; Tius, M.
A. Org. Lett. 2003, 5, 4927–4930; (c) Liang, G. X.; Gradl, S. N.;
Trauner, D. Org. Lett. 2003, 5, 4931–4934; (d) Aggarwal, V. K.;
Beffield, A. J. Org. Lett. 2003, 5, 5075–5078; (e) Liang, G. X.;
Trauner, D. J. Am. Chem. Soc. 2004, 126, 9544–9545; (f) West, F. G.;
Lin, G. Y.; Yang, C. Y.; Liu, R. S. J. Org. Chem. 2007, 72, 6753–6757;
(g) Nie, J.; Zhu, H. W.; Cui, H. F.; Hua, M. Q.; Ma, J. A. Org. Lett.
2007, 9, 3053–3056; (h) He, W.; Huang, J.; Sun, X. F.; Frontier, A. J.

M. Amere et al. / Tetrahedron Letters 49 (2008) 2541–2545
2545
under vacuum. Regioisomers b and c were separated by flash column
chromatography (silica gel, EtOAc/cyclohexane).
Frontier, A. J.; Eisenberg, R. J. Am. Chem. Soc. 2004, 126, 6864–
6865.
16. (a) He, W.; Sun, X.; Frontier, A. J. J. Am. Chem. Soc. 2003, 125,
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A.; Kellenberger, C. A.; Frontier, A. J. J. Am. Chem. Soc. 2008, 130,
1003–1011.
17. Under iridium catalysis, a substrate similar to 13a did not cyclize due
to the stabilization of its unreactive S-form, see: Janka, M.; He, W.;
18. For a ‘Fully automated multi-step solution phase synthesis using
polymer-supported reagents’, see: Vickerstaffe, E.; Warrington, B. H.;
Ladlow, M.; Ley, S. L. Org. Biomol. Chem. 2003, 1, 2419–2422.
19. For an example of Nazarov reaction catalyzed by A-15, see: Occhiato,
E. G.; Prandi, C.; Ferrali, A.; Guarna, A.; Venturello, P. J. Org.
Chem. 2003, 68, 9728–9741 and references cited therein.