R. Gao, D. J. Canney / Tetrahedron Letters 50 (2009) 5914–5916
5915
Table 1
O
O
O
Synthetic route to 3,3-diethyl-5-(2-hydroxyethyl)dihydrofuran-2(3H)-one and reac-
tion conditions attempted to optimize yield
R
O
Lewis acid, (CH2O)n
CH2Cl2, rt
O
O
+
O
OH
1. H2SO4, (CH O) , AcOH, 70oC
O
O
2
n
1c
4
3c
2. 40% NaOH, reflux
O
O
BBr3
CH2Cl2, -78oC
R=ethyl, H
3. H2SO4
OH
1c
3c
Scheme 1. Synthesis of 3,3-diethyl-5-(2-hydroxyethyl)dihydrofuran-2(3H)-one
(3c) using a previously reported Prins reaction.
Mole ratio of AcOH
Time (h)
Temperature (°C)
Yielda (%)
10
30
50
100
50
50
12
12
12
12
24
48
12
70
70
70
70
70
50b
90
45
63
77
76
77
67
74
lactone with aqueous base and then acid affords the desired
hydroxyethyl lactones (Table 2) in moderate to good yield.
The modified Prins reaction was first attempted with allylic es-
ter 1c. Hence, paraformaldehyde was treated with a catalytic
amount of sulfuric acid in glacial acetic acid at 90 °C. Ester 1c
was then added and the mixture stirred at 70 °C for 12 h to afford
the protected 1,3-diol intermediate. Treatment with aqueous
NaOH followed by acidification with H2SO4 provided the target lac-
tone–alcohol 3c in 45% yield.
50
a
Isolated yield.
b
Starting material was not consumed in 36 h (TLC). Temperature raised to 70 °C
for additional 12 h after which starting material was fully consumed.
Efforts to optimize reaction conditions included the use of dif-
ferent molar ratios of acetic acid and various reaction times and
temperatures (Table 1). For example, the synthesis of 3c described
above (yield = 45%) used a molar ratio of acetic acid = 10, and a
reaction time of 12 h at 70 °C. The yields of 3c were improved to
77% by increasing the molar ratio of acetic acid (reaction time
and temperature remained constant). This observation may be
attributed to a more efficient capturing of the carbocation in the
presence of higher concentrations of acetic acid. Reactions times
of 12 h are sufficient for the conditions tested herein since no
improvement in the yield was observed with longer times.
To explore the scope of the reaction, allylic esters or acids with
various substituents (1a–g) were investigated. Compounds 1a–g
are unsubstituted (1a) or contain aliphatic or aromatic groups at
In order to confirm that the reaction goes through the seven-
membered lactone intermediate proposed above, selected inter-
mediates (2a, 2c, 2d, and 2f) were isolated, characterized, and
yields were calculated (Table 2). The spectroscopic and analytical
data for these compounds can be found in Supplementary data
and are consistent with the seven-membered lactones shown in
Figure 2.
The target lactones prepared using this approach may serve as
key synthetic intermediates in a wide range of reactions (e.g., Mits-
unobu, Sonogashira, Wittig, and substitution reactions). The versa-
tility of the compounds makes them excellent fragments for
parallel synthesis in drug discovery efforts where lactone moieties
are of interest. In our hands, similar hydroxyethyl lactone precur-
sors have been utilized to prepare amines, amides, carbamates,
ethers, and esters.7 Several of these compounds were found to ex-
hibit anticonvulsant activity or to bind to muscarinic receptors.
Using this improved method, several hydroxyethyl lactone inter-
mediates reported herein have been used to prepare novel lac-
tone-based ligands for muscarinic receptors. Screening of those
ligands is underway and the results of those efforts will be re-
ported elsewhere.
the a-carbon. These starting materials were readily prepared using
previously published procedures7,10 and afford the target lactone
intermediates in moderate to good yields (see Table 2). These data
indicate that the newly described modified Prins reaction is supe-
rior to the previous method for the synthesis of these substituted
lactones. The esters and acids included in the present work have
symmetrical substituents adjacent to the carbonyl (except 1a) in
order to avoid multiple chiral centers in the final lactones. Asym-
metric centers are often kept to a minimum in drug discovery pro-
grams to simplify the interpretation of biological screening data
However, the fact that unsubstituted compound 3a was success-
fully prepared in modest yield suggests that the presence of a sin-
gle substituent at the alpha position would lead to acceptable
yields of alpha ‘monosubstituted’ lactones using the method re-
ported herein.
In summary, substituted furanones are an important class of
heterocyclic compounds that find utility as synthetic intermediates
in organic synthesis and are common components in numerous
pharmacologically important ligands and drugs. A more efficient
method for the preparation of substituted furanones has been
developed wherein readily prepared allylic esters or acids are re-
acted under Prins reaction conditions catalyzed by a protic acid
to provide structurally diverse substituted furanones in moderate
O
O
O
O
H
H
R1
R1
R1
R1
R1
R1
OH
O
O
O
OH
O
H
O
O
OH
H
O
O
O
O
O
intramolecular
proton transfer
O
R1
R1
H
R1
R1
recyclization
-EtOH
R1
R1
O
O
H
O
OH
O
O
7-membered lactone intermediates
target lactones
Figure 2. Proposed mechanism to target furanones via caprolactone intermediates.
Gao, Rong
