Highly efficient approach to 4-ethoxy-5,6-dihydro-6,6-disubstituted pyran-2-ones using a combinational Lewis acid-base system

Article abstract of DOI:10.1002/adsc.200505383

The first efficient approach to 5,6-dihydro-6,6-disubstituted pyran-2-ones was successfully achieved from the reaction between commercially available ethyl 3-ethoxybut-2-enoate and ketones in the presence of BF₃· Et₂O, InBr₃

Full text of DOI:10.1002/adsc.200505383

FULL PAPERS
DOI: 10.1002/adsc.200505383
Highly Efficient Approach to
-Ethoxy-5,6-dihydro-6,6-disubstituted Pyran-2-ones using a
Combinational Lewis Acid-Base System
4
a
a
a
a, b,
Jie Liu, Xing Li, Jun Wang, Xiaoming Feng *
a
Key Laboratory of Green Chemistry & Technology (Sichuan University), Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, Peopleꢀs Republic of China
State Key Laboratory of Applied Organic Chemistry, Lanzhou 730000, Peopleꢀs Republic of China
Fax: (þ86)-28-8541-8249, e-mail: xmfeng@scu.edu.cn
b
Received: October 1, 2005; Accepted: February 24, 2006
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: The first efficient approach to 5,6-dihydro- phatic, and heterocyclic ketones were converted to
6,6-disubstituted pyran-2-ones was successfully ach- the corresponding d-lactones containing quaternary
ieved from the reaction between commercially availa- carbon atom centers in excellent yields (up to 99%)
ble ethyl 3-ethoxybut-2-enoate and ketones in the under mild conditions.
presence of BF ·Et O, InBr and LDA. BF ·Et O
3
2
3
3
2
and InBr were employed as the Lewis acid to activate Keywords: dihydropyrones; dual activation; ketones;
3
the ketone and LDA was employed as the Lewis base lactones; lithium diisopropylamide; quaternary car-
to activate ethyl 3-ethoxybut-2-enoate. Aromatic, ali- bon atom center
Introduction
Results and Discussion
The unequivocal chemical synthesis of d-lactones, which
Preliminary Trials
are important intermediates in the synthesis of a variety
[
1,2]
of structures with biological and medical significance,
such as antifungal and antitumor agents, has attracted Acetophenone was reacted with Brassardꢀs diene in our
wide attention in organic chemistry. There are several initial study as outlined in Table 1. A series of Lewis
synthetic methodologies to afford d-lactones, such as acids was screened, but they inefficiently mediated the
[
3]
the annulation of open-chain precursors, the derivati- cycloaddition of carbonyl dienophiles with Brassardꢀs
[
3e]
zation from a 2,3-dihydropyran-4-one, and the two- diene.
step addition reaction of enes to dicarbonyl com- To overcome the low reactivity of acetophenone, the
[
3f]
[8]
pounds. One of the convenient routes to d-lactones dual activation strategy was used. A Lewis base such
is based on a hetero-Diels–Alder reaction of Brassardꢀs as fluoride anion (TBAF) and N-oxides have been re-
[
9,10]
diene with suitable aldehydes and results in 5,6-dihydro- ported to activate the silylated nucleophiles.
There-
6-substituted pyran-2-ones as the products. Previously fore we tested the combination of a fluoride anion
we reported an example of the highly enantioselective (TBAF) or N-oxides and Lewis acid to activate Bras-
hetero-Diels–Alder reaction of Brassardꢀs diene with ar- sardꢀs diene and acetophenone, respectively. But no
[
4]
omatic aldehydes. Later, another example of the hy- product was observed. Considering the reactivity of
drogen bond-promoted hetero-Diels–Alder reaction Brassardꢀs diene, ethyl 3-ethoxybut-2-enoate (1b), the
of aldehydes with Brassardꢀs diene was also developed intermediate for the synthesis of Brassardꢀs diene, was
[5]
by Dingꢀs group. However, until recently only few ex- investigated in this reaction. Ester 1b could easily be
amples of the synthesis of the 5,6-dihydro-6,6-disubsti- converted to 1c by treatment with lithium diisopropyl-
[
6]
tuted pyran-2-one have been reported. The synthesis amide (LDA). Compared with 1a, the nucleophilicity
[
11]
of d-lactones with four non-hydrogen substituents, that of 1c was much higher. As shown by experiment, 1c
[
7]
is, quaternary carbon centers, is still a challenge. These could smoothly react with acetophenone activated by
facts prompted us to search for an efficient route to syn- a Lewis acid or two Lewis acids.
thesize 5,6-dihydro-6,6-disubstituted pyran-2-ones.
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Jie Liu et al.
[a]
Table 1. Hetero-Diels–Alder reaction of brassardꢀs diene with acetophenone catalyzed by Lewis acids.
[
b]
Entry
Lewis acid
BF ·Et O
TiCl4
ZnCl2
Yb(OTf)3
Sc(OTf)3
Catalyst loading [mol %]
Time [h]
Yield [%]
1
2
3
4
5
6
7
8
9
50
50
50
50
50
64
64
64
64
64
64
48
48
48
48
16
3
2
N.D
N.D
N.D
N.D
N.D
12
10
N.D
7
Et AlCl
50
2
BF ·Et O/Et AlCl
50/20
50/20
50/20
50/20
3
2
2
BF ·Et O/TiCl
3
2
4
BF ·Et O/Yb(OTf)
3
3
2
10
BF ·Et O/InCl
3 2 3
[
a]
All reactions were performed with acetophenone (0.25 mmol) and Brassardꢀs diene (0.375 mmol) in the presence of a Lewis
acid (50 mol %) at room temperature in CH Cl (1.0 mL) for 48 or 64 h.
Yield of isolated products.
2
2
[
b]
BF ·Et O possessed catalytic ability. 26% adduct was
3
2
obtained after 12 hours (Table 2, entry 1). In the course
of this reaction, THF was a necessary solvent to convert
1
b to 1c. It had an adverse effect in the next addition step
Figure 1. Structures of compounds 1a, 1b, and 1c.
with acetophenone. In another parallel experiment,
when THF was removed before the Lewis acid and ke-
tone were added, the yield was raised to 41% (Table 2,
Lewis Acid Survey
entry 2). This result indicated that BF ·THF was
3
Avariety of Lewis acids was screened as catalysts for the formed, and this complex led to a lower catalytic activity.
reaction (Table 2). The initial attempt revealed that As the catalyst loading increased, the yield rose steadily
[a]
Table 2. The reaction of ethyl 3-ethoxybut-2-enoate with acetophenone.
[
b]
Entry
Catalyst
Catalyst loading [mol %]
Yield [%]
[
c]
1
2
3
4
5
6
7
8
9
0
1
2
BF ·Et O
50
50
100
20
50
50/20
50/20
50/20
50/20
50/20
50/20
50/20
26
41
61
54
27
30
53
43
55
93
50
99
3
2
BF ·Et O
3
2
BF ·Et O
3
2
InBr3
InBr3
BF ·Et O/Zr(O-i-Pr)
3
2
4
BF ·Et O/Zn(OTf)
3
2
2
BF ·Et O/LiCF SO
3
2
3
3
BF ·Et O/AlEt Cl
3
2
2
1
1
1
BF ·Et O/TiCl
3 2 4
BF ·Et O/InCl
3
3
2
BF ·Et O/InBr
3
2
3
[
[
[
a]
All the reactions were carried out according to the given standard procedure (see Method 2 in the Experimental Section).
Yield of isolated product.
THF was not removed.
b]
c]
940
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Approach to 4-Ethoxy-5,6-dihydro-6,6-disubstituted Pyran-2-ones
FULL PAPERS
[a]
Table 3. Effects of the conditions on the reaction.
[
b]
Entry
Catalyst loading [mol %]
Solvent
Time [h]
Temp. [8C]
Yield [%]
1
2
3
4
5
6
7
8
9
0
1
2
3
50/20
50/20
50/20
50/20
50/20
50/20
20/20
50/10
50/5
50/20
50/20
50/20
50/20
CH Cl
12
12
12
12
12
2
12
12
12
12
12
12
12
25
25
25
0
50
25
25
25
25
25
25
25
25
99
31
24
30
0
70
50
81
71
32
trace
0
2
2
Et O
2
toluene
CH Cl
2
2
2
2
2
2
2
2
2
2
CH Cl
2
CH Cl
2
CH Cl
2
CH Cl
2
CH Cl
2
[
[
[
[
c]
d]
e]
e]
1
1
1
1
CH Cl
2
CH Cl
2
CH Cl
2
THF
0
[
[
[
[
[
a]
All the reactions were carried out according to the given standard procedure (see Method 2 in the Experimental Section).
Yield of isolated product.
The ratio of 1b to 2a was 2: 1.
The ratio of 1b to 2a was 1.5: 1.
b]
c]
d]
e]
BF ·Et O, InBr , LDA were added to the reaction system together.
3
2
3
(
Table 2, entry 3). Further improvement, however, was were added to the reaction system together, the reaction
not achieved by increasing the catalyst loading. InBr3 did not occur (Table 3, entries 12 and 13). In summary,
also exhibited a certain catalytic ability with moderate extensive screening showed that the optimized catalytic
yield (Table 2, entries 4 and 5). To our delight, when reaction conditions were 0.25 mmol of ketones, 3 equivs.
BF ·Et O and other Lewis acid were employed at the of 1b, 50 mol % BF ·Et O, 20 mol % InBr and 3 equivs.
3
2
3
2
3
same time, the yield was dramatically improved (Ta- of LDA in 2.0 mL of CH Cl at room temperature.
2
2
ble 2, entries 5–12). A Lewis acid-assisted process
[
12]
may occur in this system. On the basis of these results,
the combination of BF ·Et O and InBr was a good sys- Substrate Generality
3
2
3
tem for this reaction.
Encouraged by the result obtained from acetophenone,
we investigated the reactions of 1b with a variety of ke-
tones, most of which gave rise to products in high yields
Optimization of the Conditions
(
up to 99%, Table 4). The transformation proceeded
Having identified BF ·Et O and InBr as viable activa- with a similar reaction time of 12 hours (Table 4). As
3
2
3
tors, an optimization of other the reaction conditions can be seen from the data, the reactivity was associated
was undertaken to lead to further improvements in the with electronic and steric effects closely. With the en-
reaction. Solvent screening revealed that CH Cl could hancement of groupꢀs electron-donating capability
2
2
provide products in 99% yield, and other solvents, from Cl, CH to OCH , the reactivity increased (Table 4,
3
3
such as Et O, toluene gave rather poor yields (Table 3, entries 4, 6, 7). Interestingly, with the enhancement of
2
entries 1–3). The reaction temperature evidently influ- groupꢀs electron-withdrawing capability from Cl to
enced the yields (Table 3, entries 4 and 5). By lowering NO , the reactivity also increased (Table 4, entries 4
2
the temperature, the reactivity was reduced. However, and 5). This indicated that appropriate electronegative
no product was detected at 508C. InBr might play an groups on substituted ketones could give high yields.
3
important role in this reaction. With reducing the load- The bulkier ortho-group, like isopropyl and tert-butyl,
ing of InBr , the yield decreased from 99% to 71% (Ta- could achieve only moderate yield (Table 4, entries 12
3
ble 3, entries 8 and 9). Otherwise, as the ratio of 1b to 2a and 13), which could be attributed to the steric effect.
reduced to 1.5:1, the yield decreased sharply (Table 3, The results from the Table 4 suggested that aromatic ke-
entries 10 and 11). Unfortunately, on changing the pro- tones were superior to aliphatic ketones. Moreover, it is
cedure of this reaction whereby BF ·Et O, InBr , LDA worthwhile to note that the heterocyclic ketone was
3
2
3
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Jie Liu et al.
[a]
Table 4. Catalytic reactions of ethyl 3-ethoxybut-2-enoate with different ketones catalyzed by BF ·Et O, InBr , and LDA.
3
2
3
[
b]
Entry
1
Ketones
Products
Yield [%]
99
2a
2b
3a
2
3
3b
3c
72
65
2c
4
2d
3d
68
5
6
7
2e
2f
3e
3f
82
99
98
2g
3g
8
9
2h
2i
3h
3i
98
88
81
1
0
2j
3j
1
1
1
2
2k
2l
3k
3l
85
75
1
1
3
4
2m
2n
3m
3n
65
66
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Approach to 4-Ethoxy-5,6-dihydro-6,6-disubstituted Pyran-2-ones
FULL PAPERS
Table 4 (cont.)
[
b]
Entry
Ketones
Products
Yield [%]
15
16
17
2o
2p
2q
3o
3p
3q
86
63
65
[
[
a]
All the reactions were carried out according to the given standard procedure (see Method 2 in the Experimental Section).
Yield of isolated product, satisfactory spectral data were obtained for the new compounds (see Supporting Information).
b]
transformed with moderate yield (Table 4, entry 16). Typical Procedure for the Synthesis of 5,6-Dihydro-
However, the active ketone gave the corresponding 6,6-disubstituted Pyran-2-ones
product only in 65% yield (Table 4, entry 17), which
4
-Ethoxy-5,6-dihydro-6-methyl-6-phenylpyran-2-one (3a);
might be due to its steric hindrance.
Method 1: BF ·Et O (15 mL, 0.125 mmol) (or other Lewis
3
2
acids) was stirred with acetophenone (30 mL, 0.25 mmol) in
CH Cl (0.5 mL) at room temperature for 30 min under an
2
2
N atmosphere, followed by addition of Brassardꢀs diene 1a
2
Conclusion
(
85 mL, 0.375 mmol).The reaction mixture was stirred for
6
4 h at room temperature, before being quenched with 5 drops
In summary, we have developed an efficient synthetic
method for the formation of 5,6-dihydro-6,6-disubstitut-
ed pyran-2-ones with excellent yields. Moreover, the
of TFA. After stirring for additional 2 h, the mixture was neu-
tralized with saturated NaHCO (2.0 mL) and partitioned be-
tween CH Cl and water twice. The combined organic layers
3
2
2
preparation of the oxygen-heterocycle adducts from were washed with saturated brine, dried over anhydrous
commercially available materials (ethyl 3-ethoxybut-2- Na SO and concentrated under vacuum. The residue was pu-
2
4
enoate) with short reaction times, mild conditions and rified by flash chromatography on silica gel (eluent 3:1 petro-
leum ether:ethyl acetate) to afford the cycloadduct 3a; yield:
good substrate adaptability make this approach highly
1
6%.
practical. The corresponding products containing a qua-
ternary carbon atom center are key structural subunits
of some natural products. Further mechanistic studies
and realization of the enantioselective version of this
transformation are underway in our laboratory.
4
-Ethoxy-5,6-dihydro-6-methyl-6-phenylpyran-2-one
(
(
3a); Method 2: To a solution of ethyl 3-ethoxybut-2-enoate
1b) (118 mg, 0.75 mmol) in dry THF (1.0 mL ) was added
LDA (0.4 mL, 2 M in hexane, 0.75 mmol) at ꢀ788C under
an N atmosphere. After the mixture had been stirred for 1 h,
2
the solvents were removed under vacuum. The residue was re-
dissolved in CH Cl (1.0 mL) and then treated with a solution
2
2
containing 15 mL (0.125 mmol) of BF ·Et O, 30 mL
3
2
Experimental Section
(
0.25 mmol) of acetophenone, and 17.7 mg (0.05 mmol) of
InBr in CH Cl (1.0 mL). The reaction mixture was stirred at
3
2
2
room temperature for 12 h and monitored by TLC. After com-
pletion, the reaction mixture was concentrated under reduced
pressure and purified by flash chromatography (petroleum
ether:ethyl acetate, 3:1) to afford 3a.
General Remarks
1
H NMR spectra were recorded at 300 and 400 MHz. The
chemical shifts are reported in ppm downfield to the CDCl
3
1
13
resonance (d¼7.27) for H NMR. CNMR data were collect-
ed at 100 and 75 MHz with complete proton decoupling. The
chemical shifts are reported in ppm downfield to the central
1
3
CDCl resonance (d¼77.0) for C NMR. Coupling constants
3
1
in H NMR spectra are given in Hz. HR-MS were recorded
on a Bruker-APEX-2 (SIMS). Ketones obtained from com- Acknowledgements
mercial sourceswere used directly without further purification.
Toluene, THF, Et O were distilled freshly from sodium/benzo-
The authors thank the Natural Science Foundation of China
2
phenone ketyl. CH Cl was distilled freshly from CaH . Bras-
(Nos. 20225206, 20390055 and 20472056), the Ministry of Edu-
cation of China (Nos. 104209, 20030610021, and others) and
Sichuan University (No. 2004CF07) for financial support.
2
2
2
sadꢀs diene 1a was prepared from ethyl 3-ethoxybut-2-
[13]
[14]
enoate according to a literature procedure.
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Adv. Synth. Catal. 2006, 348, 939 – 944