Nazarov-type reactions in water

Full text of DOI:10.1002/asia.200800461

COMMUNICATION
DOI: 10.1002/asia.200800461
Nazarov-type Reactions in Water
Masaya Kokubo and Shu Kobayashi*[a]
¯
In the last decade, chemical reactions in water have
compounds.[3] We are interested in Nazarov reactions in
water, and envision a dual role for water, namely as solvent
and trapping agent.
become a subject of great interest from several aspects.[1]
Water is an inexpensive, non-toxic, and environmentally
benign solvent. In addition, unique reactivities and selectivi-
ties are often observed in water. In this paper, we describe
Nazarov-type reactions where the reaction course is changed
in water when compared to that in an organic solvent.
We have recently developed surfactant-type catalysts,
which create hydrophobic areas with organic materials in
water to accelerate organic reactions. We selected 2-alkoxy-
1,4-pentadiene-3-one 1a as a model substrate for the Naza-
rov-type reaction and a scandium salt as a water-compatible
Lewis acid.[4] When 1a was treated in water in the presence
of 10 mol% of Sc(OSO3C12H25)3 (Sc(DS)3, a Lewis acid–sur-
factant-combined catalyst (LASC)),[5] at room temperature
for 24 h, the reaction proceeded and a mixture of 15% of 2-
alkoxy-2-cyclopentenone 5a and 82% of a-diketone 6a was
isolated (Table 1, entry 1). Gratifyingly, the expected water-
trapping adduct 6a was obtained as a major product. We
then optimized the reaction conditions, and found that the
concentration of the substrate and the catalyst was impor-
tant for improving product selectivities (Table 1, entries 1–
4). As the concentration was decreased, the selectivity was
improved, and ultimately 6a was obtained as the sole prod-
uct in 89% yield when the reaction was carried out at 0.17m
(Table 1, entry 4). We also examined catalyst loadings
(Table 1, entries 5–7), and demonstrated that a reduction to
5 mol% provided no significant loss in the yield (Table 1,
The Nazarov reaction is one of the most versatile methods
for the synthesis of cyclopentenones from divinyl ketones.
The reaction is believed to proceed via a conrotatory 4p-
electron cyclization of a 3-oxopentadienyl cation (2) to an
oxallyl cation (3) in the presence of an acid (Scheme 1). In
the conventional Nazarov reaction, proton elimination of
oxallyl cation 3 leads to cyclopentenone derivative 5.[2] On
the other hand, when suitable cation-trapping agents are
present, the oxallyl cation (3) can be converted to various
Table 1. Optimization of reaction conditions.
Scheme 1. Nazarov reaction.
Entry Cat. loading
[mol %]
Conc.
[M]
Yield of 5a
Yield of 6a
[%][a]
[%][a]
[a] M. Kokubo, Prof. Dr. S. Kobayashi
Department of Chemistry
1
2
3
4
5
6
10
10
10
10
20
5
1.0
0.5
15
8
5
trace
trace
trace
trace
73
82
89
89
89
92
90
66
6
School of Science and Graduate School of Pharmaceutical Sciences
The University of Tokyo
The HFRE Division, ERATO, JST
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax : (+81)3-5684-0634
0.33
0.17
0.17
0.17
0.17
0.17
7
2
10
E-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp
8[b]
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.200800461.
[a] Isolated yield. [b] ScACTHNUTRGNEUNG(OTf)3 was used as a catalyst in DME/H2O (9:1).
526
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2009, 4, 526 – 528

entry 6). When the catalyst loading was reduced to 2 mol%,
the yield dropped to 66% (Table 1, entry 7). On the other
hand, when this reaction was carried out using 10 mol% of
amine-trapping Nazarov-type products were obtained in the
presence of activated dry SiO2 and stoichiometric amounts
of primary and secondary amines under solvent-free condi-
tions.[3b] Before conducting the reaction of 1a in the pres-
ence of 10 mol% of Sc(DS)3 and 100 mol% of diisopropyl-
ScACHTUNGTRENNUNG(OTf)3 as a catalyst in a mixed solvent of dimethoxy-
ethane (DME) and water (9:1), the reaction proceeded
smoothly, but conventional Nazarov-type product 5a was
obtained as a major product (Table 1, entry 8).[6]
Several 2-alkoxy-1,4-pentadiene-3-ones were employed
under optimized reaction conditions (Table 2). Cyclic sub-
strates gave the desired water-trapping adducts in good to
AHCTUNGTREGaNUNN mine (iPr2NH) in water, we envisioned two possibilities; 1)
an amine-trapping adduct would be obtained as per the Tius
case; or 2) the water-trapping adduct 6a would still be ob-
tained arising from the presence of a large amount of water.
Unexpectedly, when 1a was treated in water under these
conditions, neither the amine-
Table 2. Substrate scope of water-trapping Nazarov reactions.[a]
trapping adduct nor 6a was
obtained; instead the conven-
tional Nazarov-type product
5a was produced in high yield.
Several other substrates were
tested and the results are sum-
marized in Scheme 3.[9] In the
reactions of cyclic substrates,
Entry
Starting Material
Product
Yield [%][b]
1
2
3
4
1a: R1 =Me, R2 =H
1b: R1 =iPr, R2 =H
1c: R1 =tPr, R2 =H
1d: R1 =Bu, R2 =H
1e: R1 =R2 =Me
89
90 (90)[c]
88
94
5
79[d]
93[d]
80
6[c]
7
1 f: R1 =R2 =-(CH2)4-
1g: R1 =iPr, R2 =H
1h: R1 =Me, R2 =H
1i: R1 =R2 =Me
X=O
R3 =O
ACHTNGUETRNNU(G CH2)2OH
8
9
10
11
45 (80)[e]
80
the
conventional
Nazarov
products were obtained exclu-
sively, and no side products
were detected. It is noted that
1j: R1 =Et, R2 =H
1k: R1 =Me, R2 =Ph
62
87
[a] The reaction was carried out in the presence of Sc(DS)3 (5 mol %) in water at 0.17m at room temperature
for 24 h. [b] Isolated yield. [c] The reaction was carried out at 1.0m. [d] A single diastereomer was obtained.[2a]
[e] NMR yield.
the
reactions
proceeded
smoothly at room temperature
in the presence of a catalytic
high yields (Table 2, entries 1–7). In some cases, the reac-
tions could be carried out at higher concentrations (1.0m,
Table 2, entries 2 and 6). We also examined acyclic sub-
strates (Table 2, entries 8–11), and found that the reactions
proceeded to afford the desired a-diketones in moderate to
high yields. These compounds are employed as flavourings
and odorants and are contained in many natural products
and foods.[7] It is noteworthy that this synthetic procedure
provides a one-step synthesis of these compounds in water.
Furthermore, a catalytic asymmetric Nazarov-type reac-
tion was examined. As a preliminary result, the water-trap-
ping adduct 6a was obtained in good yield with moderate
enantioselectivity, when Sc(DS)3 was combined with chiral
bipyridine 7[8] (Scheme 2). Although both the yield and the
Scheme 3. Nazarov reactions with diisopropylamine.
enantioselectivity were not optimized, this result has shown
the possibility of catalytic enantioselective Nazarov-type re-
actions in water and supports the Sc-involved reaction
mechanism of the Nazarov-type reactions in water.
Next, we examined the Nazarov-type reactions in the
presence of amines. Recently, Tius et al. reported that
amount of a water-compatible Lewis acid and a stoichiomet-
ric amount of an amine in water. On the other hand, in the
case of an acyclic substrate (1j), a mixture of the conven-
tional Nazarov product 5j and the water-trapping adduct 6j
was obtained. In all cases, no amine-trapping adducts were
observed.
In conclusion, we have developed Nazarov-type reactions
in water. Different reaction courses compared with those in
organic solvents were observed in water. In the presence of
a surfactant-type catalyst (LASC), water-trapping products
were obtained exclusively. It is noted that in a water–organic
homogeneous solvent system with a water-compatible Lewis
acid, a conventional Nazarov product was produced prefer-
entially. Conventional Nazarov products were also obtained
Scheme 2. Enantioselective Nazarov-type reaction in water.
Chem. Asian J. 2009, 4, 526 – 528
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
527

S. Kobayashi and M. Kokubo.
COMMUNICATION
A. M. Arif, F. G. West, Org. Lett. 2003, 5, 2747; e) A. Yungai, F. G.
West, Tetrahedron Lett. 2004, 45, 5445. Azido trapping reactions:
f) A. Rostami, Y. Wang, A. M. Arif, R. McDonald, F. G. West, Org.
Lett. 2007, 9, 703. Alcohol trapping reactions: g) M. Shindo, K. Yaji,
T. Kita, K. Shishido, Synlett 2007, 1096. See also, h) W. He, J. Huang,
X. Sun, A. J. Frontier, J. Am. Chem. Soc. 2007, 129, 498; i) M. Ruep-
ing, W. Ieawsuwan, A. P. Antonchick, B. J. Nachtsheim, Angew.
Chem. 2007, 119, 2143–2146; Angew. Chem. Int. Ed. 2007, 46, 2097–
2100; j) R. Noyori, Y. Ohnishi, M. Kato, Bull. Chem. Soc. Jpn. 1975,
48, 2881.
in water in the presence of an amine and no amine-trapping
products were detected. Furthermore, an enantioselective
Nazarov-type reaction in water using a chiral Sc catalyst has
been demonstrated. These results are unprecedented and
provide a valuable extension to information available re-
garding organic reactions in water.
Acknowledgements
[4] a) S. Kobayashi, S. Nagayama, T. Busujima, J. Am. Chem. Soc. 1998,
120, 8287; b) S. Kobayashi, C. Ogawa, Chem. Eur. J. 2006, 12, 5954.
[5] a) S. Kobayashi, T. Wakabayashi, Tetrahedron Lett. 1998, 39, 5389;
b) K. Manabe, Y. Mori, T. Wakabayashi, S. Nagayama, S. Kobayashi,
J. Am. Chem. Soc. 2000, 122, 7202.
This work was partially supported by a Grant-in-Aid for scientific re-
search from Japan Society of the Promotion of Science (JSPS).
[6] In an organic solvent, Nazarov adduct 5a was obtained in high yield;
Keywords: cyclization
· ketones · Nazarov reaction ·
10 mol% ScACTHNURGTNEUNG(OTf)3 and MS 4 A (100 mg/0.6 mmol 1a) in 0.5m di-
surfactants · water chemistry
chloroethane (DCE) at room temperature for 1 h, 90% yield.
[7] S. Antoniotti, N. Alezra, X. Fernandez, E. DuÇach, Flavour Fra-
grance J. 2004, 19, 373.
[8] a) C. Bolm, M. Zehnder, D. Bur, Angew. Chem. 1990, 102, 206;
Angew. Chem. Int. Ed. Engl. 1990, 29, 205; b) C. Bolm, M. Ewald, M.
Felder, G. Schlingloff, Chem. Ber. 1992, 125, 1169; c) S. Ishikawa, T.
Hamada, K. Manabe, S. Kobayashi, Synthesis 2005, 13, 2176.
[9] When benzylamine was used instead of diisopropylamine, a Michael
adduct was obtained.
[1] a) Organic Reactions in Water (Ed.: U. M. Lindstrçm), Blackwell,
Oxford, 2007; b) Aqueous-Phase Organometallic Catalysis, 2nd ed.
(Eds.: B. Cornis, W. A. Herrmann), Wiley-VCH, Weinheim, 2004;
c) C.-J. Li, T.-H. Chan, Organic Reactions in Aqueous Media, Wiley,
New York, 1997; d) Organic Synthesis in Water (Ed.: P. A. Grieco),
Blackie Academic and Professional, London, 1998; e) S. Kobayashi,
Pure Appl. Chem. 2007, 79, 235.
[2] a) G. Liang, S. N. Gradl, D. Trauner, Org. Lett. 2003, 5, 4931. For re-
views of the Nazarov reaction: b) M. Harmata, Chemtracts 2004, 17,
416; c) M. A. Tius, Eur. J. Org. Chem. 2005, 2193; d) A. Frontier, C.
Collison, Tetrahedron 2005, 61, 7577; e) H. Pellissier, Tetrahedron
2005, 61, 6479, and references therein.
[3] Alkene and arene trapping reactions: a) J. A. Bender, A. E. Blize,
C. C. Browder, S. Giese, F. G. West, J. Org. Chem. 1998, 63, 2430.
Amine trapping reactions: b) F. Dhoro, T. E. Kristenesen, V. Stock-
mann, G. P. A. Yap, M. A. Tius, J. Am. Chem. Soc. 2007, 129, 7256.
Allylic silane trapping reactions: c) S. Giese, L. Kastrup, D. Stiens,
F. G. West, Angew. Chem. 2000, 112, 2046; Angew. Chem. Int. Ed.
2000, 39, 1970. Diene trapping reactions: d) Y. Wang, B. D. Schill,
Received: December 11, 2008
Published online: February 11, 2009
528
www.chemasianj.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2009, 4, 526 – 528