A convenient and versatile approach to 2,3-dihydro-4H-pyran-4-ones via tandem aldol reaction-conjugate addition

Article abstract of DOI:10.1016/j.tetlet.2006.01.010

Aldol reaction of enones 1a-c with aldehydes followed by intramolecular conjugate addition proceeded smoothly to afford corresponding 2,3-dihydro-4H-pyran-4-ones in high yields under mild conditions.

Full text of DOI:10.1016/j.tetlet.2006.01.010

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1537–1539
A convenient and versatile approach to 2,3-dihydro-
4H-pyran-4-ones via tandem aldol reaction-conjugate addition
Bo Gao,a Zhipeng Yu,a Zhengyan Fua and Xiaoming Fenga,b,
*
aKey Laboratory of Green Chemistry and Technology (Sichuan University), Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, China
bState Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
Received 21 November 2005; revised 4 January 2006; accepted 4 January 2006
Abstract—Aldol reaction of enones 1a–c with aldehydes followed by intramolecular conjugate addition proceeded smoothly to
afford corresponding 2,3-dihydro-4H-pyran-4-ones in high yields under mild conditions.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1
2,3-Dihydro-4H-pyran-4-ones are highly versatile syn-
thetic intermediates for the preparation of biologically
important compounds,1 such as carbohydrates,1a–c
antibiotics,1d and toxins.1e–g These compounds used
to be prepared using hetero-Diels–Alder reaction of
carbonyl compounds with Danishefsky’s dienes2 and
other activated dienes3 in the last two decades. Re-
cently, Gouverneur’s group reported a novel entry to
2,3-dihydro-4H-pyran-4-ones by oxidative cyclization
of b-hydroxyenones with Palladium(II).4 However,
the reaction did not tolerate the presence of a substitu-
ent on the vinylic carbon adjacent to the carbonyl
group, which prevented the formation of 2,5-disubsti-
tuted 2,3-dihydro-4H-pyran-4-ones. More recently,
Winkler’s group disclosed a one-step synthesis of 2,6-
disubstituted 2,3-dihydro-4H-pyran-4-ones from b-eth-
oxy a,b-unsaturated lactones.5
aldol adducts by H NMR analysis.8 They were then
completely converted into the desired products 3a–c
through intramolecular conjugate addition.
Our studies were started with the reaction of enone 1a,
LDA, and benzaldehyde. Enone 1a (45 lL, 0.375 mmol)
was added via syringe to a THF solution of LDA (2 M
in THF/n-heptane) under nitrogen atmosphere for
the formation of lithium enolate firstly.9 After 20 min,
benzaldehyde (26 lL, 0.25 mmol) was added, followed
by stirring at the same temperature for 24 h. Then the
reaction was quenched with sat. NH4Cl (aq) and
treated with TFA (200 lL) in the same pot for 2 h at
ambient temperature to yield 5-methyl-2-phenyl-
2,3-dihydro-4H-pyran-4-one 3a. The effects of LDA
O
O
OH
Ph
LDA
O
R1
R1
Although the hetero-Diels–Alder reaction of Danishef-
sky’s dienes provides one of the most convenient
approaches to this ring system,2 the preparation and
purification of Danishefsky’s dienes are found to be
troublesome.6 It would be synthetically useful if Dani-
shefsky’s dienes were replaced by easily available and
stable materials. Accordingly, we wish to develop an
alternative protocol to synthesize these heterocycles
from enones 1a–c,7 the key materials for the preparation
of Danishefsky’s dienes (Scheme 1). The intermediates
2a–c of these reactions were isolated and assigned as
+
H
Ph
THF, -78 ºC
R2 OCH3
R2 OCH3
1a, R1 = CH3, R2 = H;
1b, R1 = H, R2 = CH3;
1c, R1 = H, R2 = H.
2a-c
O
O
TFA
r.t.
R1
R1
R2
R2
MeO
O
Ph
Ph
O
3a-c
*
Corresponding author. Tel./fax: +86 28 8541 8249; e-mail: xmfeng@
scu.edu.cn
Scheme 1.
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.010

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B. Gao et al. / Tetrahedron Letters 47 (2006) 1537–1539
Table 2. Tandem aldol reaction-conjugate addition of enones 1a–c
loading, benzaldehyde concentration, and reaction tem-
perature were studied. When 0.8 equiv of LDA was
used, 43% yield was obtained (entry 1). Increasing
LDA loading to 1.6 equiv resulted in higher yields (en-
tries 2 and 3). When 3.0 equiv of LDA was used, yield
was decreased significantly (entry 4). Then, 1.6 equiv
of LDA was chosen as optimum loading. When the con-
centration of benzaldehyde was lowered from 0.5 to
0.25 M, the yield was somewhat sacrificed (entry 5 vs
3). Encouragingly, 94% isolated yield was achieved
when the concentration of benzaldehyde was increased
to 1.0 M (entry 6). Further increase of the concentration
to 1.25 M led to less satisfying yield (entry 7). Studies on
the temperature effect revealed that À78 ꢁC was the opti-
mum temperature for this reaction. Raising the reaction
temperature to À45 ꢁC led to lower yield (entry 8). It
was noteworthy that when the temperature was elevated
to above À10 ꢁC, only trace amount of the product was
observed (entries 9 and 10) (Table 1).
with aldehydesa
Entry
Enone
Aldehyde
Yield (%)b
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
Benzaldehyde
94
81
85
92
95
83
86
80
81
84
87
91
83
87
81
75
76
93
58
2-Methylbenzaldehyde
3-Methylbenzaldehyde
4-Methylbenzaldehyde
2-Chlorobenzaldehyde
3-Chlorobenzaldehyde
4-Chlorobenzaldehyde
2-Nitrobenzaldehyde
3-Nitrobenzaldehyde
3-Methoxybenzaldehyde
4-Methoxybenzaldehyde
4-Fluorobenzaldehyde
1-Naphthaldehyde
2-Furaldehyde
9
10
11
12
13
14
15
16
17
18
19
(E)-3-Phenyl-2-propenal
n-Hexanal
Cyclohexanecarbaldehyde
Benzaldehyde
Benzaldehyde
With these results in hand, we decided to explore the
generality of this protocol. Firstly, a variety of aromatic
and aliphatic aldehydes were subjected to the reaction
with enone 1a. As shown in Table 2, substituted benzal-
dehyde, both electron-donating groups and electron-
withdrawing groups, could give good yields (entries 2–
12). Fused aromatic aldehyde (entry 13) and hetero-aro-
matic aldehyde (entry 14) also gave high yields. More
significant examples were the reactions of (E)-3-phe-
nyl-2-propenal (entry 15) and n-hexanal (entry 16),
which reacted with enone 1a in much higher yields than
with activated diene.6b Cyclohexanecarbaldehyde (entry
17), which is more hindered at alpha position than n-
hexanal (entry 16) also gave good yield as the latter
did. Then, enones 1b and 1c were chosen to examine
the tolerance of substitutes on enones. The reaction of
enone 1b with benzaldehyde proceeded smoothly to give
rise to the desired product in 93% yield (entry 18). How-
ever, enone 1c was reacted with benzaldehyde in poor
yield (entry 19).
a All reactions were carried out in THF with 1.5 equiv of enones 1a–c
and 1.6 equiv of LDA at À78 ꢁC as detail in the typical experimental
procedure.10
b Isolated yield based on aldehyde.
avoiding thus the use of activated dienes possessing
one or two oxygen-containing donating groups. Further
work is in progress to develop enantioselective version
of this transformation.
Acknowledgments
The authors thank the National Natural Science Foun-
dation of China (Nos. 20225206, 20390055, and
20472056) and the Ministry of Education of China
(Nos. 20030610021 and 104209) for financial support.
In conclusion, the present work has shown that the
approach can be used for the synthesis of structurally
diversed disubstituted dihydropyrones in high yields.
An attractive feature of this method is the possibility
to obtain these heterocycles from simple substrates,
References and notes
1. For examples, see: (a) Danishefsky, S. J.; Pearson, W. H.;
Segmuller, B. E. J. Am. Chem. Soc. 1985, 107, 1280–1285;
(b) Danishefsky, S. J.; DeNinno, M. P. Angew. Chem., Int.
Ed. Engl. 1987, 26, 15–23; (c) Danishefsky, S. J.; Bilodeau,
M. T. Angew. Chem., Int. Ed. 1996, 35, 1380–1419; (d)
Danishefsky, S. J.; Selnick, H. G.; Zelle, R. E.; DeNinno,
M. P. J. Am. Chem. Soc. 1988, 110, 4368–4378; (e)
Rainier, J. D.; Allwein, S. P.; Cox, J. M. Org. Lett. 2000,
2, 231–234; (f) Cox, J. M.; Rainier, J. D. Org. Lett. 2001,
3, 2919–2922; (g) Yamashita, Y.; Saito, S.; Ishitani, H.;
Kobayashi, S. J. Am. Chem. Soc. 2003, 125, 3793–3798;
(h) Williams, D. R.; Heidebrecht, R. W., Jr. J. Am. Chem.
Soc. 2003, 125, 1843–1850.
Table 1. Optimization studies
Entry LDA Loading Benzaldehyde Temp (ꢁC) Yield (%)b
(equiv)a
concn (M)
1
2
3
4
5
6
7
8
9
0.8
1.0
1.6
3.0
1.6
1.6
1.6
1.6
1.6
1.6
0.5
0.5
0.5
0.5
0.25
1.0
1.25
1.0
1.0
1.0
À78
À78
À78
À78
À78
À78
À78
À45
À10
0
43
69
78
26
68
94
84
72
2. (a) Jørgensen, K. A. Angew. Chem., Int. Ed. 2000, 39,
3558–3588; (b) Jørgensen, K. A. Eur. J. Org. Chem. 2004,
2093–2102.
´
3. (a) Barluenga, J.; Aznar, F.; Fernandez, M. Tetrahedron
Lett. 1995, 36, 6551–6554; (b) Evans, P. A.; Nelson, J. D.
J. Org. Chem. 1996, 61, 7600–7602; (c) Evans, P. A.;
Nelson, J. D.; Manangan, T. Synlett 1997, 968–970; (d)
Huang, Y.; Rawal, V. H. J. Am. Chem. Soc. 2002, 124,
9662–9663.
Trace
Trace
10
a Based on benzaldehyde.
b Isolated yield.

B. Gao et al. / Tetrahedron Letters 47 (2006) 1537–1539
1539
4. Reiter, M.; Ropp, S.; Gouverneur, V. Org. Lett. 2004, 6,
91–94.
3.72 (s, 3H, OCH3), 3.79 (s, 1H, OH), 2.87–2.86 (m, 2H,
CH2).
5. Winkler, J. D.; Oh, K. Org. Lett. 2005, 7, 2421–2423.
6. (a) Wang, B.; Feng, X.-M.; Cui, X.; Liu, H.; Jiang, Y.-Z.
Chem. Commun. 2000, 1605–1606; (b) Huang, Y.-Z.; Feng,
X.-M.; Wang, B.; Zhang, G.-L.; Jiang, Y.-Z. Synlett 2002,
2122–2124; (c) Fu, Z.-Y.; Gao, B.; Yu, Z.-P.; Yu, L.;
Huang, Y.-Z.; Feng, X.-M.; Zhang, G.-L. Synlett 2004,
1772–1775; (d) Gao, B.; Fu, Z.-Y.; Yu, Z.-P.; Yu, L.;
Huang, Y.-Z.; Feng, X.-M. Tetrahedron 2005, 61, 5822–
5830.
9. LDA is one of the most important and convenient
Bronsted bases for the enolization of a,b-unsaturated
carbonyl compounds. For examples, (a) Stork, G.; Kraus,
G. A. J. Am. Chem. Soc. 1976, 98, 2351–2352; (b) Faller, J.
W.; Smart, C. J. Tetrahedron Lett. 1979, 20, 4911–4914; (c)
Clive, D. L. J.; Bergstra, R. J. J. Org. Chem. 1991, 56,
4976–4977; (d) see Refs. 6b, 6c, and 7a.
10. A typical experimental procedure is given for the synthesis
of 5-methyl-2-phenyl-2,3-dihydro-4H-pyran-4-one 3a: To
a solution of LDA (200 lL, 2 M in THF/n-heptane,
0.4 mmol) in THF (0.25 mL) was added enone 1a (45 lL,
0.375 mmol) via syringe at À78 ꢁC under nitrogen atmo-
sphere. After the mixture was stirred for 20 min, benzal-
dehyde (26 lL, 0.25 mmol) was added. The reaction was
allowed to stir at À78 ꢁC for 24 h, after which it was
quenched with sat. NH4Cl (aq) and treated with TFA
(200 lL). After stirring for 2 h at ambient temperature, the
reaction was quenched with sat. NaHCO3 (aq) and
extracted with ether (4 · 5 mL). The organic layers were
dried over Na2SO4 and concentrated. The residue was
purified by flash chromatography (petroleum ether–ether,
9:1) to yield 5-methyl-2-phenyl-2,3-dihydro-4H-pyran-4-
one (44 mg, 94% yield), white solid, mp = 46–48 ꢁC. 1H
NMR (600 MHz, CDCl3): d = 7.46–7.40 (m, 5H, Ph–H),
7. Enone 1a was prepared according to the reported proce-
dure: (a) Miyashita, M.; Yamasaki, T.; Shiratani, T.;
Hatakeyama, S.; Miyazawa, M.; Irie, H. Chem. Commun.
1997, 1787; (b) see Ref. 6c; Enone 1b was prepared
according to the reported procedure: (c) Smissman, E. E.;
Voldeng, A. N. J. Org. Chem. 1964, 29, 3161–3165. Enone
1c was prepared according to the same procedure as for
1a.
8. 1H NMR data of compounds 2a–c: Compound 2a: 1H
NMR (400 MHz, CDCl3): d = 7.41–7.20 (m, 6H, Ph–H
and @CH), 5.20–5.17 (m, 1H, Ph–CHO), 3.96 (d, 1H,
J = 2.4 Hz, OH), 3.84 (s, 3H, OCH3), 2.94–2.83 (m, 2H,
1
CH2), 1.72 (s, 3H, @CACH3). Compound 2b: H NMR
(600 MHz, CDCl3): d = 7.24–7.11 (m, 5H, Ph–H), 5.26 (s,
1H, @CH), 5.03 (m, 1H, Ph–CHO), 3.89 (d, 1H,
J = 2.2 Hz, OH), 3.49 (s, 3H, OCH3), 2.68 (d, 2H,
J = 6.1 Hz, CH2), 2.19 (s, 3H, @CACH3). Compound
2c: 1H NMR (600 MHz, CDCl3): d = 7.63 (d, 1H,
J = 12.7 Hz, @CHO), 7.40–7.34 (m, 5H, Ph–H), 5.59
(d, 1H, J = 12.7 Hz, @CH), 5.20–5.18 (m, 1H, Ph–CH),
3
7.39 (s, 1H, @CH), 5.41 (dd, J(H,H) = 14.6, 3.2 Hz, 1H,
Ph–CHO), 2.94–2.88 (m, 1H, CHAHB), 2.73–2.69 (m, 1H,
CHAHB), 1.76 (s, 3H, CH3). 13C NMR (150 MHz,
CDCl3): d = 192.59, 159.49, 138.27, 128.80, 128.78,
126.05, 114.14, 80.99, 43.21, 10.51.