An efficient synthesis of 3,4-dihydropyran-2-one derivatives by Lewis base-catalyzed tandem Michael addition and lactonization

Article abstract of DOI:10.1246/cl.2004.1454

A convenient one-pot preparation of 3,4-dihydropyran-2-one derivatives by Michael addition of silyl enolate derived from phenyl ester with α,β-unsaturated ketones in the presence of a Lewis base catalyst such as tetrabutylammonium phenoxide was developed. In this catalytic cycle, 3,4-dihydropyran-2-ones were produced in good to excellent yields via intramolecular cyclization of in situ formed Michael-adducts.

Full text of DOI:10.1246/cl.2004.1454

1454
Chemistry Letters Vol.33, No.11 (2004)
An Efficient Synthesis of 3,4-Dihydropyran-2-one Derivatives
by Lewis Base-catalyzed Tandem Michael Addition and Lactonization
Takashi Tozawa,y;yy Hidehiko Fujisawa,y;yy and Teruaki Mukaiyamaꢀy;yy
yCenter for Basic Research, The Kitasato Institute (TCI), 6-15-5 Toshima, Kita-ku, Tokyo 114-0003
yyKitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641
(Received August 10, 2004; CL-040943)
A convenient one-pot preparation of 3,4-dihydropyran-2-
one derivatives by Michael addition of silyl enolate derived from
phenyl ester with ꢀ,ꢁ-unsaturated ketones in the presence of a
Lewis base catalyst such as tetrabutylammonium phenoxide
was developed. In this catalytic cycle, 3,4-dihydropyran-2-ones
were produced in good to excellent yields via intramolecular
cyclization of in situ formed Michael-adducts.
-OPh
M+
R3
O
O
OSiMe3
OPh
R1
R2
R1
1
R2
R4
2
5
O
R3
R4
3
M+
O- R4
O
3,4-Dihydropyran-2-ones are widely used as useful synthet-
ic intermediates for the preparation of 2-pyranones,1 ꢂ-lac-
tones,2 cyclic enamines,3 and so on. In spite of the approaches
developed for the synthesis of 3,4-dihydropyran-2-ones, effec-
tive ones are not many. Among the few, an intramolecular cyc-
lization via Michael addition has often been considered as one of
the most synthetically efficient and powerful strategies because
it allows a wide variety of 3,4-dihydropyran-2-one derivatives
to be prepared by one-pot procedure.4 For example, nucleophilic
Michael additions of metalated enolates such as lithium enolate
of ester,5 silyl enolates derived from thioesters,4a and lithium
enolates of N-acylbenzotriazoles4b to ꢀ,ꢁ-unsaturated ketones
afforded 3,4-dihydropyran-2-ones.
Recently, several Lewis base-catalyzed Michael reactions
between silyl enolates and ꢀ,ꢁ-unsaturated carbonyl compounds
were introduced from our laboratory.6 They are useful methods
for the synthesis of various 1,5-dicarbonyl compounds since they
proceed smoothly by using readily available Lewis base cata-
lysts such as lithium benzamide,6a lithium succinimide,6a and
lithium acetate.6b In order to demonstrate the usefulness of these
Lewis base-catalyzed reactions further, the application of the
Michael addition to the synthesis of 3,4-dihydropyran-2-one de-
rivatives was planned.
R3
OPh
R1 R2
4
Me3SiOPh
Scheme 1.
work as a suitable leaving group to facilitate the intramolecular
cyclization of in situ formed enolate intermediates 4 and behave,
at the same time, as active species 1 via regeneration in the
above catalytic cycle.
In the first place, reaction of chalcone 3a and TMS enolate
2a was tried, and various catalysts were screened (Table 1). In
the case when a catalytic amount of potassium or tetrabutylam-
monium phenoxide was used, the reactions completed immedi-
ately at ꢁ78 ꢂC in THF and afforded the corresponding 3,4-dihy-
dropyran-2-one 5a in excellent yields even when 1 mol % of tet-
rabutylammonium phenoxide was used (Entries 3–6). On the
other hand, the lithium phenoxide-catalyzed reaction resulted
in low conversion (Entry 1). In addition, the reactions were ini-
tiated similarly by potassium tert-butoxide or tetrabutylammoni-
um fluoride (TBAF) (Entries 7 and 8). These results indicated
that the yields of the above reaction were dependent on the na-
ture of the counter cations, and tetrabutylammonium was found
In this communication, a convenient one-pot preparation of
3,4-dihydropyran-2-one derivatives by tandem Michael addition
and lactonization between silyl enolate derived from phenyl es-
ter and ꢀ,ꢁ-unsaturated ketones in the presence of a Lewis base
catalyst such as tetrabutylammonium phenoxide is described.
A proposed catalytic cycle for the Lewis base-catalyzed
Michael addition and sequential lactonization is illustrated in
Scheme 1: namely, trimethylsilyl (TMS) enolates 2, activated
by a nucleophilic attack of the phenoxide ion on the silicon atom,
react with the ꢀ,ꢁ-unsaturated ketones 3 in the presence of a
Lewis base catalyst such as metal or ammonium phenoxide 1
to form enolate intermediates 4 and TMS ether of phenol. The
in situ formed enolate intermediates 4 attack intramolecularly
the ester carbonyl group to form the corresponding 3,4-dihydro-
pyran-2-ones 5 along with elimination of phenoxide ion. The
TMS enolate derived from phenyl ester was chosen as a starting
material since it was considered that the phenoxy group would
Table 1. Effect of a variety of catalysts
Ph
O
O
OSiMe3
OPh
Catalyst
O
+
THF, −78 °C, Time
Ph
Ph
Ph
3a
2a (1.6 equiv.)
5a
Entry
Catalyst/mol %
Time/h
Yielda/%
1
2
3
4
5
6
7
8
LiOPh (10)
NaOPh (10)
KOPh (10)
Bu4NOPh (10)
Bu4NOPh (5)
Bu4NOPh (1)
KOt-Bu (10)
TBAF (10)
5
3
<20
91
92
98
99
91
92
98
0.5
0.5
0.5
0.5
0.5
0.5
aIsolated yield.
Copyright Ó 2004 The Chemical Society of Japan

Chemistry Letters Vol.33, No.11 (2004)
1455
Table 2. Synthesis of various 3,4-dihydropyran-2-ones
R3
Table 3. Reactions of TMS enolate 2b or 2c with chalcone 3a
in the presence of tetrabutylammonium phenoxide
O
O
OSiMe3
OPh
O
Bu4NOPh (5 mol %)
1) Bu4NOPh (10 mol %)
OSiMe3
+
O
R3
R4
THF, −78 °C, 0.5 h
THF, −78 °C, 0.5 h
+
Products
X
R4
2a
5
3
2) 1 M HClaq, THF
Ph
Ph
(1.6−2.0 equiv.)
3a
2b or 2c
(1.6 equiv.)
Entry
R3
R4
Yielda/%
Products (Yielda /%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-ClC6H4
4-MeOC6H4
4-Me2NC6H4
1-Naphthyl
99
99
92
72
70
89
87
71
85
98
84
78
52
80
77
Entry
1
X
O
Ph
O
O
Me3SiO Ph
Ph
OMe
+
Ph
OMe
OMe
(2b)
6 (85)
7 (15)
St-Bu
Ph
Me
i-Pr
PhCO
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
O
O
O
2
St-Bu
+
Ph
(2c)
4-ClC6H4
Ph
5a (59)
8 (39)
4-MeOC6H4
4-Me2NC6H4
i-Pr
i-Bu
t-Bu
PhCH=CH
aIsolated yield.
References and Notes
1
a) D. Rosenthal, P. Grabowich, E. F. Sabo, and J. Fried, J.
Am. Chem. Soc., 85, 3971 (1963). b) T. Kume, H. Iwasaki,
Y. Yamamoto, and K. Akiba, Tetrahedron Lett., 29, 3825
(1988).
aIsolated yield.
2
3
4
A. K. Mandal and D. G. Jawalkar, J. Org. Chem., 54, 2364
(1989).
S. H. Thang and D. J. Rigg, Synth. Commun., 23, 2355
(1993).
a) S. Kobayashi and M. Moriwaki, Synlett, 1997, 551. b)
A. R. Katritzky and O. V. Denisko, J. Org. Chem., 67,
3104 (2002).
D. A. Oare and C. H. Heathcock, J. Org. Chem., 55, 157
(1990).
to be particularly effective.
Next, the reactions of TMS enolate 2a with various ꢀ,ꢁ-un-
saturated ketones by using 5 mol % of tetrabutylammonium
phenoxide were tried at ꢁ78 ꢂC in THF (Table 2).7 In most cas-
es, the reactions proceeded smoothly to provide the desired 3,4-
dihydropyran-2-ones in good to excellent yields. It was found
that various types of ꢀ,ꢁ-unsaturated ketones having alkyl or ar-
yl substituents at the R3 or R4 positions could successfully be
employed in this procedure.
5
6
a) T. Mukaiyama, T. Nakagawa, and H. Fujisawa, Chem.
Lett., 32, 56 (2003). b) T. Nakagawa, H. Fujisawa, Y. Nagata,
and T. Mukaiyama, Chem. Lett., 33, 1016 (2004).
Typical experimental procedure is as follows (Table 2, Entry
1): a) Preparation of a THF solution of tetrabutylammonium
phenoxide;8 To phenol (198 mg, 2.1 mmol) was added tetra-
butylammonium hydroxide in methanol (37 wt %, 1.40 g,
2.0 mmol). After the mixture was stirred for 0.5 h, the solvent
was removed under reduced pressure. The residue was azeo-
troped with toluene (2 mL ꢃ 3), and then dissolved in THF
(20 mL) to give a 0.1 M solution of tetrabutylammonium
phenoxide. b) General procedure for the preparation of 3,4-
dihydropyran-2-ones from TMS enolate 2a and ꢀ,ꢁ-unsatu-
rated ketones; To a THF solution of tetrabutylammonium
phenoxide (0.15 mL, 0.015 mmol) was added a solution of
chalcone (62.5 mg, 0.3 mmol) in THF (1.2 mL) and a solution
of TMS enolate 2a (113 mg, 0.48 mmol) in THF (0.65 mL) at
ꢁ78 ꢂC. After the mixture was stirred for 0.5 h at the same
temperature, it was quenched with 1 M HCl aq and the mix-
ture was extracted with EtOAc. The organic layer was wash-
ed with brine, dried over anhydrous Na2SO4, and evaporated.
The crude product was purified by preparative TLC to give
the corresponding 3,4-dihydropyran-2-one (83.0 mg, 99%).
a) I. B. Dicker, G. M. Cohen, W. B. Farnham, W. R. Hertler,
E. D. Laganis, and D. Y. Sogah, Polym. Prepr. (Am. Chem.
Soc., Div. Polym. Chem.), 28, 106 (1987). b) M. A. Rahim,
Y. Matsui, T. Matsuyama, and Y. Kosugi, Bull. Chem. Soc.
Jpn., 76, 2191 (2003).
Then, the influence of other TMS enolates that are derived
from methyl ester or thioester on this Michael addition and se-
quential lactonization process was investigated (Table 3). When
the reaction of TMS enolate derived from methyl isobutyrate 2b
with chalcone was carried out by using 10 mol % of tetrabutyl-
ammonium phenoxide, the cyclized product was not detected
at all although the Michael-adduct 6 was obtained in 85% yield
together with 1,2-addition product, silyl ether 7, in 15% yield
(Entry 1). On the other hand, a similar reaction of TMS enolate
derived from S-tert-butyl thioisobutyrate 2c proceeded to afford
the 3,4-dihydropyran-2-one 5a in moderate yield with undesired
formation of a conjugate adduct of thiolate 8 (Entry 2). These re-
sults showed that the TMS enolate derived from phenyl ester
worked effectively for this catalytic tandem reaction.
Thus, an efficient method for the synthesis of 3,4-dihydro-
pyran-2-one derivatives via phenoxide-catalyzed tandem Mi-
chael addition and lactonization between silyl enolate derived
from phenyl ester and ꢀ,ꢁ-unsaturated ketones was developed.
The present reaction presents new possibility in the field of
Lewis base-catalyzed reactions and, in addition, catalytic tan-
dem addition–cyclization procedures. Further investigation on
this reaction is now in progress.
7
8
This study was supported in part by the Grant of the 21st
Century COE Program from Ministry of Education, Culture,
Sports, Science and Technology (MEXT), Japan.
Published on the web (Advance View) October 9, 2004; DOI 10.1246/cl.2004.1454