Organic Process Research & Development 2005, 9, 629−633
Unusual Nazarov Cyclization in Near-Critical Water
Tuomo Leikoski,† Juha Kaunisto,‡ Martti Alkio,‡ Olli Aaltonen,*,‡ and Jari Yli-Kauhaluoma*,†
Drug DiscoVery and DeVelopment Technology Center, Faculty of Pharmacy, P.O. Box 56 (Viikinkaari 5 E), FI-00014,
UniVersity of Helsinki, Finland, and VTT Processes, Technical Research Centre of Finland, P.O. Box 1602
(Biologinkuja 7, Otaniemi), FI-02044 VTT, Finland
Scheme 1
Abstract:
The Nazarov reaction of trans,trans-dibenzylidene acetone in
near-critical water with or without additional carbon dioxide
produces 2,3-diphenyl-2-cyclopentenone instead of the conven-
tional Nazarov product, 3,4-disubstituted 2-cyclopentenone. The
use of organic solvents and strong mineral acids, generally
required for this reaction, is avoided by using water and
carbonic acid as a proton source. After an optimization
procedure, 38% yield of 2,3-diphenyl-2-cyclopentenone was
obtained. The presence of carbon dioxide had a clear positive
effect on yield.
furnishes the final 2,3-substituted 3 with formal 1,2-shift of
the carbonyl group. The normal 3,4-substituted Nazarov
product 2 would be obtained after direct deprotonation of
the oxyallyl cation 5. In fact, Hirano et al. observed also
formation of the conventional 3,4-disubstituted 2-cyclopen-
tenones in the presence of less nucleophilic solvent, where
deprotonation can compete with the nucleophilic substitution
by the solvent.2
Introduction
The Nazarov reaction is an acid-catalyzed cyclization of
divinyl ketones to 2-cyclopentenones.1 The reaction has been
used in construction of many complex, natural, and biologi-
cally important target molecules and their synthetic inter-
mediates possessing the cyclopentenone moiety, such as
jasmonoids2 and prostanoids.3 The Nazarov reaction involves
a conrotatory 4π electrocyclization of the pentadienyl cation,
and it is therefore considered as a pericyclic reaction. The
pericyclic reactions are highly useful in the construction of
carbon-carbon bonds.
The Nazarov reaction produces normally 3,4-disubstituted
2-cyclopentenones 2 from â,â′-disubstituted cross conjugated
divinyl ketones 1 (Scheme 1). However, Hirano et al. have
reported about the abnormal Nazarov reaction, in which the
main product is a 2,3-disubstituted 2-cyclopentenone 3.2,4
They postulated that this unexpected product is formed by
the addition of a hydroxylic solvent, such as water or
carboxylic acid, to the oxyallyl cation 5 after the electrocyclic
ring closure of the protonated divinyl ketone 4 (Scheme 2).
This would give rise to the hydroxy- or acyloxycyclopen-
tenone intermediate 6, which isomerises to 7. After removal
of water, the second oxyallyl cation 8 isomerises to the most
stable cation 9, deprotonation or deacylation of which
Despite its usefulness as a simple one-step procedure, the
Nazarov reaction suffers from some limiting drawbacks,
including harsh reaction conditions with high temperature
and the use of strong acid (typically used as a solvent or as
a catalyst; e.g., 47% HBr/HOAc (1:3), BF3‚Et2O/CH2Cl2,
85% H3PO4/90%HCO2H (1:1), and SnCl4/CH2Cl2), chlori-
nated solvents, variable yields, and poor regioisomeric
control. The objective of our study was to perform the
Nazarov reaction in hot, near-critical water, which would
serve as a source of proton donating oxonium ions instead
of strong acids, due to the increased ion product of water at
elevated temperatures. The ionization constant of water is
maximized at 250 °C where it is 3 orders of magnitude higher
than that at room temperature.5 The term near-critical water
refers to liquid water at 250-300 °C which approaches but
remains below the critical temperature of plain water (374
°C). Further, water’s dielectric constant drops rapidly with
increasing temperature rendering it a good solvent for polar
organic compounds. At 300 °C water exhibits a polarity and
density similar to those of acetone at room temperature.6
Water above the critical temperature (374 °C) has been
studied recently as a new medium for the pericyclic Diels-
Alder reactions7 and subcritical water as a medium for the
pericyclic ene reactions8 due to the high solubility of the
reagents.
* Corresponding authors. (Jari Yli-Kauhaluoma) Fax: +358 9 191 59556.
Telephone: +358 9 191 59170. E-mail: Jari.Yli-Kauhaluoma@helsinki.fi. (Olli
Aaltonen) Fax: +358 20 722 7026. Telephone: +358 20 722 5301. E-mail:
Another objective of our work was to find out how the
addition of carbon dioxide would affect the conversion and
yield. The use of carbonic acid as a catalyst, instead of strong
† University of Helsinki.
‡ Technical Research Centre of Finland.
(1) Nazarov, I. N. Usp. Chim. 1949, 18, 377. Nazarov, I. N. Usp. Chim. 1951,
20, 71. Santelli-Rouvier, C.; Santelli, M. Synthesis 1983, 429.
(2) Hirano, S.; Takagi, S.; Hiyama, T.; Nozaki, H. Bull. Chem. Soc. Jpn. 1980,
53, 169.
(5) Patrick, H. R.; Griffith, K.; Liotta, C. L.; Eckert, C. A. Ind. Eng. Chem.
Res. 2001, 40, 6063.
(3) Jadhav, K. S.; Thakur, S. B.; Bhattacharyya, S. C. Indian J. Chem. 1978,
16B, 280.
(4) Hirano, S.; Tagaki, S.; Hiyama, T.; Nozaki, H. Tetrahedron Lett. 1974,
1429.
(6) Katritzky, A. R.; Allin, S. M.; Siskin, M. Acc. Chem. Res. 1996, 29, 399.
(7) Korzenski, M. B.; Kolis, J. W. Tetrahedron Lett. 1997, 38, 5611.
(8) Laitinen, A.; Takebayashi, Y.; Kyla¨nlahti, I.; Yli-Kauhaluoma, J.; Sugeta,
T.; Otake, K. Green Chem. 2004, 6, 49.
10.1021/op050075t CCC: $30.25 © 2005 American Chemical Society
Published on Web 08/09/2005
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