The Synthesis and Photochemical Studies of 3(2H)-Furanones:
A Continuation of the Search for Medicinal Compounds
Laura Hanold
Advisor: Dr. Abraham Yousef
Honors Summer Research Program
Summer 2009
1
Abstract
The purpose of this research is to continue the synthesis and photochemical studies of
3(2H)-furanones from the summer honors research performed in 2008. Originally
inspired by the discovery of inotilone, a compound with a 3(2H)-furanone core that was
found to have anti-inflammatory properties, the current focus of this research is to
synthesize inotilone derivatives for antibacterial and antitumor testing. Synthesis of 2-(phydroxybenzylidene)-5-methyl-3(2H)-furanone was attempted; however, optimization of
the reactions is necessary to efficiently synthesize this compound. In addition to the
synthesis of inotilone derivatives, syntheses of other 3(2H)-furanones for photochemical
studies were performed. 2,2-Dimethyl-5-phenyl-3(2H)-furanone was successfully
synthesized in a 12% overall yield. Irradiation of this compound resulted in dimerization
similar to that of 5-phenyl-3(2H)-furanone. A new synthetic pathway for the formation
of 5-phenyl-3(2H)-furanone and 2,5-dimethyl-2-phenyl-3(2H)-furanone was attempted
but was found to be unsuccessful; however, future research will be performed in an
attempt to facilitate these reactions.
2
Introduction
The purpose of this research is to continue the synthesis and photochemical studies of
3(2H)-furanones performed during the 2008 honors summer research. The idea
originated from the discovery of inotilone in 2006. Inotilone (1, Figure 1), a compound
containing a 3(2H)-furanone core, was isolated from the fruiting body of the mushroom
Inonotus sp. and was found to have inhibitory activity towards the enzyme
cyclooxengenase-2 (COX-2), the enzyme responsible for the inflammation produced in
rheumatoid arthritis.1 Inotilone’s selective inhibition of COX-2, as opposed to COX-1,
an enzyme involved in regulatory processes of the digestive tract,2 is comparable to other
anti-inflammatory medications, as shown in Table 1, making inotilone a promising
candidate for medicinal testing. Because inotilone, like many other compounds
possessing a 3(2H)-furanone core, displays medicinal properties, the study inotilone
analogues as well as other 3(2H)-furanones has become the focus of this research.
Figure 1 Inotilone (1) and 2-benzylidene-5-methyl-3(2H)-furanone (2)
Table 1 COX-2 selectivity of inotilone and synthetic drugs3
compound
IC50 (μM)
COX-1
COX-2
inotilone
meloxicam
nimesulide
celecoxib
0.36
4.8
9.2
15
0.03
0.43
0.52
0.04
COX-2
Selectivity
12
11
18
375
3
In the summer of 2008, 2-benzylidene-5-methyl-3(2H)-furanone (2, Figure 1) was
synthesized and tested for activity against breast cancer and Corynebacterium
pseudodiphtheriae. Although compound 2 did not display antitumor activity against the
breast cancer cell line, it did display potential antibacterial activity towards
Corynebacterium pseudodiphtheriae, a bacterium related to Corynebacterium diphtheriae
which produces the diphtheria toxin. Due to this activity, it is possible that this inotilone
derivative as well as others may display activity against the diphtheria causing bacteria.
Thus, additional inotilone derivatives will be synthesized in the hopes of elucidating the
structural aspects that may contribute to its potential antibacterial activity.
Although compound 2 did not display inhibitory activity against breast cancer cell
lines, other 3(2H)-furanones have displayed cytotoxic activity in previous studies. A
study performed in 2003, indicated that the 3(2H)-furanone compounds shown in Figure
2 displayed activity against gastric and colorectal carcinomas; however, they did not
display activity against lung carcinomas.4 Similarly two compounds synthesized in 2008,
shown in Figure 3, displayed activity against the DLA cell line.5
Figure 2 Two 3(2H)-furanones with activity against gastric and colorectal carcinomas4
4
Figure 3 Two 3(2H)-furanones with activity against DLA cell lines5
Such studies demonstrate that the cytotoxic activity of 3(2H)-furanones may differ
between tumor cell lines, and structure plays a major role in these differences. Therefore,
it is possible that while compound 2 did not display inhibitory activity against breast
cancer cell lines, 2-(p-hydroxybenzylidene)-5-methyl-3(2H)-furanone (3), shown in
Figure 4, might display such inhibitory activity. Thus, synthesis of compound 3 will be a
major focus of this research. It is also possible that both compound 2 and 3 could display
activity against colorectal and ovarian cancer cell lines. Future studies of activity against
these cancer cell lines will be performed in collaboration with Dr. Eva Schmelz of the
Corporate Research Center of Virginia Tech.
Figure 4 Structure of 2-(p-hydroxybenzylidene)-5-methyl-3(2H)-furanone (3)
In addition to the synthesis of inotilone derivatives for antibacterial and antitumor
studies, the synthesis and photochemical studies of other 3(2H)-furanones will be a focus
of this research. Previous photochemical studies of 3(2H)-furanones have demonstrated
the ability of such furanones to rearrange upon irradiation. Such photoreactivity has
created an interest in the photochemical studies of 3(2H)-furanones since photoreactive
compounds may cause photosensitivity when used as medications. In 1976, irradiation of
5
2,5-diphenyl-3(2H)-furanone resulted in rearrangement to form 4,5-diphenyl-2(5H)furanone as shown in Figure 5 below.6 Additionally, a photochemical study performed in
1985 demonstrated photorearrangement of 5-ethyl-2,2-dimethyl-3(2H)-furanone to form
5-ethyl-3,3-dimethyl-2(3H)-furanone, as shown in Figure 6 below.7
Figure 5 Proposed mechanism of rearrangement of 2,5-diphenyl-3(2H)-furanone6
Figure 6 Proposed mechanism of rearrangement of 5-ethyl-2,2-dimethyl-3(2H)furanone7
Because previous studies demonstrated photoreactivity of 3(2H)-furanones, irradiation
of 5-phenyl-3(2H)-furanone (4) was performed during the summer honors research of
2008, resulting in the formation of dimer 5, as shown in Figure 7. Since this result
differed from previous photorearrangements, another focus of this research will be to
study the photochemistry of 2,2-dimethyl-5-phenyl-3(2H)-furanone (6, Figure 8) in order
to determine the effect of substitution around the furanone ring on the photoreactivity of
the compounds.
6
Figure 7 Photodimerization of 5-phenyl-3-(2H)-furanone (4)
Figure 8 Structure of 2,2-dimethyl-5-phenyl-3(2H)-furanone (6)
Results and Discussion
The synthesis of 2-(p-hydroxybenzylidene)-5-methyl-3(2H)-furanone (3) was
attempted via the 6 step synthetic pathway presented by Shamshina and Snowden, shown
in Scheme 1.8 The reaction began with the synthesis of 4-(trimethylsiloxy)pent-3-en-2one (7). Using hexane as the solvent, 2,4-pentandione was reacted with triethyl amine
and trimethylsilyl chloride to form 7. Since this reaction was moisture sensitive, the flask
was flame dried and sparged with argon. Compound 7 was purified via vacuum
distillation, resulting in a 54% yield.
After purification compound 7 was reacted with LDA and trimethylsilyl chloride in
THF to form 2,4-bis(trimethylsiloxy)penta-1,3-diene (8). This reaction was also moisture
7
sensitive, so the flask was flame dried and sparged with argon. Compound 8 was purified
via vacuum distillation, resulting in a 37 % yield.
Compound 8 was refluxed in methylene chloride in the presence of Nbromosuccinamide to form 1-bromopentane-2,4-dione (9). Compound 9 degraded during
silica gel chromatography; therefore, the crude product was used in the synthesis of 5methyl-3(2H)-furanone (10). Compound 9 was allowed to stir in ether in the presence of
potassium carbonate for approximately 1 day; however, compound 10 was not obtained.
This result could be due to the insufficient basicity of potassium carbonate.
Scheme 1 Synthesis of 2-(p-hydroxybenzylidene)-5-methyl-3(2H)-furanone (3)8
Since 5-methyl-3(2H)-furanone, could not be synthesized via the pathway shown in
Scheme 1, the synthetic pathway (Scheme 2) used in the 2008 honors summer research
was used to successfully synthesize 5-methyl-3(2H)-furanone in five steps, beginning
8
with the synthesis of ethyl diacetoacetate (12). Ethyl acetoacetate was reacted with
pyridine and acetyl chloride, using methylene chloride as a solvent and magnesium
chloride as a catalyst, to form compound 12. Due to the moisture sensitivity of the
reaction, the reaction was performed under dry conditions as stated above. Compound 12
was purified via vacuum distillation, resulting in a 50% yield.
After purification compound 12 was reacted with bromine, using ether as a solvent
and glacial acetic acid as a catalyst, to form ethyl α,α′-dibromodiacetoacetate (13) in a
117% crude yield. The 2008 honors summer research indicated that dibromide 13 was
instable and could not be purified; thus, the crude product was used in third step of the
reaction.
Crude dibromide 13 was reacted with sodium iodide in acetone to afford the diiodide.
Instability of this compound required that it be reacted immediately to form 4carbethoxy-5-methyl-3(2H)-furanone (14); thus, the sodium bromide was filtered off, and
the diiodide was reacted with sodium thiosulfate in water to form furanone ester 14.
Compound 14 was purified via silica gel column chromatography, resulting in a 13%
yield.
Compound 14 was refluxed in the presence of sulfuric acid to afford compound 10 in
a 97% crude yield. In order to obtain higher yields of 2-(p-hydroxybenzylidene)-5methyl-3(2H)-furanone, synthesis of 5-methyl-3-trimethylsiloxyfuran (11, Scheme 1)
was attempted by reacting compound 10 with LDA and trimethylsilyl chloride in THF;
however, synthesis of 11 was unsuccessful. Thus, until the synthesis presented in
Scheme 1 can be optimized, the 2008 synthetic pathway presented in Scheme 2 will be
used to synthesize future inotilone derivatives.
9
Scheme 2 Synthesis of 5-methyl-3(2H)-furanone (10)
Synthesis of 2,2-dimethyl-5-phenyl-3(2H)-furanone (6, Scheme 3) was accomplished
in three steps,9 beginning with the formation of 1-phenyl-4-hydroxy-4-methyl-2-pentyn1-ol (15). Using THF as a solvent, 2-methyl-3-butyn-2-ol was reacted with nbutyllithium and benzaldehyde to form compound 15. This reaction was moisture
sensitive, so the reaction was performed under dry conditions. Compound 15 was
purified via silica gel column chromatography, resulting in a 74% yield.
After purification, compound 15 was reacted with chromium trioxide, using water and
acetone as solvent and concentrated sulfuric acid as a catalyst to form 1-phenyl-4hydroxy-4-methyl-2-pentyn-1-one (16) in a 53% yield. Purification was unnecessary, so
compound 16 was reacted with diethyl amine in ethanol to form 2,2-dimethyl-5-phenyl3(2H)-furanone (6). Compound 6 was rapidly filtered through a short plug of silica gel
10
with methylene chloride in order to remove highly polar impurities, resulting in a 31 %
yield.
Scheme 3 Synthesis of 2,2-dimethyl-5-phenyl-3(2H)-furanone
After purification, compound 6 was irradiated in benzene with 300 nm light as shown
in Scheme 4. Similar to irradiation of 5-phenyl-3(2H)-furanone, irradiation of compound
6 resulted in dimerization. This result is analogous to the result obtained by Wolff and
Agosta in 1985, providing further support that irradiation of 5-phenyl-3(2H)-furanones
results in dimerization. It is hoped that a three dimensional structure of the 2,2-dimethyl5-phenyl-3(2H)-furanone dimer 17 will be obtained through X-ray crystallographic
analysis in future research.
Scheme 4 Photodimerization of 2,2-dimethyl-5-phenyl-3(2H)-furanone (6)
In order to perform additional photochemical studies, synthesis of 5-phenyl-3(2H)furanone (4) and of 2-methyl-2,5-diphenyl-3(2H)-furanone (20) were attempted using a
similar pathway as was used to synthesize compound 6. The attempted synthesis of
compound 4 (Scheme 5) began with the synthesis of 1-phenyl-4-hydroxy-2-butyn-1-one
11
(18).10 Propargyl alcohol was reacted with n-butyllithium and zinc chloride in THF to
form a zinc chloride intermediate. The zinc chloride intermediate was then reacted with
benzoyl chloride, using palladium-tetrakis(triphenylphosphine) as a catalyst, to form
compound 18 in a 120% crude yield. Cyclization compound 18 was attempted in the
presence of diethyl amine and ethanol; however, due to the lack of substitution at carbon
4, the hydroxyl group is unable to leave, as shown in the third step of the proposed
mechanism in Figure 9. The inability of the hydroxyl group to leave hinders the
cyclization process. Thus, tosylation of the hydroxyl group was attempted to facilitate
cyclization.11 Compound 18 was reacted with p-toluenesulfonyl chloride and pyridine in
methylene chloride. However, the compound did not react, resulting a mixture of
compound 18 and toluenesulfonic acid. It is hoped that tosylation of compound 18 can
be achieved in future research in order to facilitate cyclization and formation of 5-phenyl3(2H)-furanone.
Scheme 5 Attempted synthesis of 5-phenyl-3(2H)-furanone (4)
12
Figure 9 Proposed mechanism for cyclization of compound 18
Synthesis of 2-methyl-2,5-diphenyl-3(2H)-furanone (19, Scheme 6) was attempted
beginning with the formation of 5-hydroxy-5-phenyl-3-hexyn-2-one (20).10 2-phenyl-3butyn-2-ol was reacted with n-butyllithium and zinc chloride in THF in order to form the
zinc chloride intermediate. The zinc chloride intermediate was immediately reacted with
acetyl chloride to form compound 20. Compound 20 was purified via silica gel
chromatography, resulting in a 42% yield. Cyclization to form compound 19 was
attempted by reacting compound 20 with diethyl amine in ethanol; however, cyclization
did not occur. It is suspected that this result is due to the difference in electronics caused
by the absence of a phenyl group next to the carbonyl group. Tosylation of the hydroxyl
group will be attempted in future research in order to determine if the presence of a good
leaving group will facilitate the cyclization process.
13
Scheme 6 Attempted synthesis of 2,5-dimethyl-2-phenyl-3(2H)-furanone (19)
Summary
Synthesis of 2-(p-hydroxybenzylidene)-5-methyl-(2H)-furanone (3) was attempted
using the reactions presented in Scheme 1. However, compound 3 could not be
synthesized using this pathway. Thus, the reactions presented in Scheme 2 will be used
towards the synthesis of compound 3 until the pathway presented in Scheme 1 can be
optimized.
2,2-Dimethyl-5-phenyl-3(2H)-furanone (6) was successfully synthesized. Like 5phenyl-3(2H)-furanone (4), compound 6 was able to be purified without degradation.
Thus, photochemical studies were performed. Irradiation of compound 6 resulted in
dimerization, as was found in the 1985 photochemical studies,7 indicating that 5-phenyl3(2H)-furanones are likely to undergo photodimerization.
In order to perform additional photochemical studies, the synthesis of compound 4 and
2,5-dimethyl-2-phenyl-3(2H)-furanone (19) was attempted using a similar pathway as
was used for compound 6. However, cyclization of the hydroxyalkynones was
unsuccessful. In the case of compound 4, it is likely that the lack of substitution on the
hydroxyl-bearing carbon hinders the cyclization process. Before cyclization can occur,
the hydroxyl group needs to leave. With the lack of substitution on the carbon, this
process would result in instability and is, therefore, unable to occur. In the case of
14
compound 19, the carbonyl carbon lacks a phenyl group, which could change the
electronics of the system, preventing cyclization from occurring. Tosylation of the
hydroxyl groups will be performed in the future to determine whether cyclization to form
compounds 4 and 19 can occur.
Along with optimization of the synthesis of compounds 3, 4, and 19, future research
will include the synthesis of various inotilone derivatives for testing against breast
cancer, colorectal cancer, and ovarian cancer cell lines as well as against
Corynebacterium pseudodiphtheriae. It is hoped that such testing will help to elucidate
the structural aspects that may contribute to antitumor and antibacterial properties. In
addition to the synthesis of inotilone derivatives for medicinal studies, various 3(2H)furanones will be synthesized for photochemical studies in order to determine the effects
of substitution around the furanone ring on the photoreactivity of the compounds.
Experimental
Synthesis of 4-(trimethylsiloxy)pent-3-en-2-one (7)
To a flame dried 250 mL round bottom flask, 100 mL dry hexanes were added, and the
flask was sparged with argon. To the stirred hexane, 2,4-pentanedione (1.05 mL, 10.2
mmol), triethyl ammine (1.70 mL, 12.2 mmol), and TMSCl (1.40 mL, 11.0 mmol) were
added. The reaction was allowed to stir for 16 hours and 50 min. The salts were
removed by vacuum filtration with the aid of hexanes, and the solvents were removed in
vacuo. The product was purified via vacuum distillation. Yield 0.9403 g, 54 %; 1H
NMR(400MHz, CDCl3) δ = 5.51 (s) and 5.44 (s, 1H total), 2.19 (s, 3H), 2.04 (s) and 1.97
(s, 3H total), 0.25 (s) and 0.21 (s) and 0.06 (s, 9H total).
15
Synthesis of 2,4-bis(trimethylsiloxy)penta-1,3-diene (8)
To a flame dried 100 mL round bottom flask, 50 mL dry THF was added. The flask was
sparged with argon and cooled to -78 °C. Diisopropyl amine (0.92 mL, 6.56 mmol) and
1.6 M n-butyllithium (4.10 mL, 6.56 mmol) were added. After 15 min, 4(trimethylsiloxy)pent-3-en-2-one (7, 0.9219 g, 5.35 mmol) was added slowly over 3
minutes. The solution was allowed to stir for approximately 40 minutes then TMSCl
(0.85 mL, 6.70 mmol) was added. The solution was warmed to 0 °C and allowed to stir
for 1 hour 15 minutes. The solvents were removed in vacuo, and the salts were resuspended in 30 mL hexane. The salts were filtered off, rinsing with 30 mL hexane. The
hexanes were removed in vacuo and the product was distilled via vacuum distillation.
Yield 0.4857 g, 37 %; 1H NMR(400MHz, CDCl3) δ = 5.19 (s) and 4.31 (s, 1H total), 4.73
(d, J = 6.88 Hz) and 4.22 (d, J = 17.88 Hz, 2H total), 2.00 (s) and 1.85 (s, 3H total), 0.23
(s), 0.21 (s), 0.20 (s), and 0.19 (s, 18H total).
Synthesis of 1-bromopentane-2,4-dione (9)
To 2,4-bis(trimethylsiloxy)penta-1,3-diene (8, 0.4857 g, 1.99 mmol), 2 mL freshly
distilled methylene chloride and N-bromosuccinamide (0.5391 g, 3.02 mmol) were
added. The mixture was refluxed at 40-45 °C for 1.5 hours, after which it was cooled and
diluted with 5 mL methylene chloride. The solution was rinsed with 3 x 15 mL distilled
waster. Organic layer was dried over magnesium sulfate and filtered while rinsing with
30 mL methylene chloride. The solvents were removed in vacuo. Crude yield 0.3957 g,
111 % 1H NMR(400MHz, CDCl3) δ = 5.75 (s, 1H), 3.81 (s, 2H), 2.08 (s, 3H).
Attempted Synthesis of 5-methyl-3(2H)-furanone (10)
16
To a flame dried 25 mL round bottom flask, 1-bromopentane-2,4-dione (9, 0.0751 g, 0.42
mmol), 1.5 mL dry ether, and potassium carbonate (0.1440 g, 1.04 mmol) were added.
The reaction mixture was allowed to stir under argon at room temperature for 23 hours
and 35 minutes. The reaction mixture was then filtered through Celite while rinsing with
anhydrous ether. The solvents were removed via rotary evaporator at 23 °C. 1H NMR
analysis indicated that 5-methyl-3(2H)-furanone (10) was not present in the product
mixture.
Synthesis of ethyl diacetoacetate (12)
To a flame dried 250 mL round bottom flask, magnesium chloride (4.8327 g, 50.8 mmol)
was added. While sparging with argon, 45 mL methylene chloride was added. The
reaction mixture was cooled to 0 °C. Ethyl acetoacetate (6.5 mL, 51.8 mmol) and
pyridine (8.2 mL, 101.8 mmol) were added. The reaction mixture was allowed to stir for
25 minutes then acetyl chloride (4 mL, 56.3 mmol) was added. The solution was allowed
to stir for 15 minutes at 0 °C, followed by 1 hour at room temperature. After 1 hour at
room temperature, 6M HCl (20 mL) was added. The organics were extracted with 3 x 25
mL methylene chloride. The combined organic layers were dried over magnesium
sulfate, filtered, and concentrated in vacuo. The product was purified via vacuum
distillation. Yield: 4.1229 g, 49.6 %; 1H NMR(400MHz, CDCl3) δ = 4.23 (q, J = 7.32 Hz,
2H), 2.33 (s, 6H), 1.29 (t, J = 7.36 Hz, 3H); 13C NMR(400MHz, CDCl3) δ = 196.7, 167.2,
108.7, 60.76, 26.06, 14.28.
Synthesis of ethyl α,α′-dibromodiacetoacetate (13)
To a 100 mL flame dried round bottom flask, 25 mL dry ether, ethyl diacetoacetate (12,
1.9237 g, 11.2 mmol), and 3 drops of glacial acetic acid were added. The reaction
17
mixture was allowed to stir at 0 °C for 35 minutes then bromine (1.5 mL, 29.1 mmol)
was added. The reaction mixture was allowed to stir at room temperature for 1 hour and
10 minutes, after which the mixture was poured into 30 mL distilled water. The organic
layer was extracted. The organics were extracted twice more from the aqueous layer
using 2 x 30 mL ether. The combined organic layers were dried over magnesium sulfate,
filtered, and concentrated in vacuo. Crude yield: 4.12 g, 117 %, 1H NMR(400MHz,
CDCl3) δ = 4.38-4.34 (m, 6H), 1.38-1.36 (m, 5H).
Synthesis of 4-carbethoxy-5-methyl-3(2H)-furanone (13)
To an Erlenmeyer flask, sodium iodide (4.5428 g, 30.3 mmol) and 46.5 mL acetone were
added. Ethyl α,α′-dibromodiacetoacetate (12, 3.64 g, 11.6 mmol) was transferred to a
100 mL round bottom flask along with the sodium iodide solution. The reaction mixture
was allowed to stir for approximately 25 minutes. The sodium bromide was filtered off,
and sodium thiosulfate (6.2252 g, 39.4 mmol), dissolved in 15 mL distilled water, was
added. The solution was allowed to stir for 3 hours and 15 minutes, after which the
organics were extracted with 4 x 20 mL ether. The combined organic layers were dried
over magnesium sulfate, filtered, and concentrated via rotary evaporator. The product
was purified via silica gel column chromatography, using 10:1 → 1:1 hexane:ethyl
acetate. Pure yield: 0.25 g, 13 %; 1H NMR(400MHz, CDCl3) δ = 4.54 (s, 2 H), 4.23 (q, J
= 6.84 Hz, 2H), 2.55 (s, 3H), 1.27 (t, J = 6.88, 3H).
Synthesis of 5-methyl-3(2H)-furanone (10)
To a 50 mL round bottom flask, 4-carbethoxy-5-methyl-3(2H)-furanone (13, 0.25 g, 1.47
mmol) was transferred with the aid of methylene chloride. The solvent was removed in
vacuo, and 2M sulfuric acid (21 mL) was added. While sparging with argon, the solution
18
was refluxed for 2 hours. After allowing the flask to cool, the solution was rinsed with
30 mL brine, and the organics were extracted with 5 x 30 mL methylene chloride. The
combined organic layers were dried over magnesium sulfate, filtered, and concentrated in
vacuo between 26 °C and 29 °C. Crude yield: 0.14 g, 97.1 %; 1H NMR(400MHz,
CDCl3) δ = 5.47 (s, 1H), 4.48 (s, 2H), 2.22 (s, 3H).
Attempted Synthesis of 5-methyl-3-trimethylsiloxyfuran (11)
To a flame dried 25 mL round bottom flask, 4.5 mL dry THF were added and cooled to
-78 °C. While sparging with argon, diisopropylamine (0.27 mL, 1.96 mmol) and nbutyllithium (1.2 mL, 1.92 mmol) were added and allowed to stir at -78 °C for 20
minutes. After 20 minutes, 5-methyl-3(2H)-furanone (10, 0.16 g, 1.63 mmol), dissolved
in 5.5 mL dry THF, was added dropwise to the reaction mixture over 3 minutes. The
solution was allowed to stir at -78 °C for 30 minutes. TMSCl (0.25 mL, 19.7 mmol) was
added, and the reaction mixture was allowed to stir at room temperature for
approximately 1.5 hours. After 1.5 hours, hexane was added to precipitate the lithium
salts. The solution was filtered through Celite with the aid of hexanes, and the filtrate
was concentrated in vacuo. 1H NMR indicated that 5-methyl-3-trimethylsiloxyfuran (11)
was not obtained.
Synthesis of 1-phenyl-4-hydroxy-4-methyl-2-penyn-1-ol (15)
To a flame dried 100 mL round bottom flask, dry THF (30 mL) and a stir bar were added.
The flask was sparged with nitrogen and cooled to -78 °C. 2-Methyl-3-butyn-2-ol (0.575
g, 5.93 mmol) and n-butyllithium (6 mL, 9.6 mmol) were added. The mixture was
allowed to stir for 21 minutes, after which benzaldehyde (0.45 mL, 4.46 mmol) was
added. The reaction mixture was then allowed to stir at room temperature for 2 hours.
19
The solvents were concentrated in vacuo, and the product was acidified to pH 4-5 with
HCl. The organics were extracted with methylene chloride (3 x 40 mL) then rinsed with
distilled water (30 mL). The organic layer was extracted and dried over magnesium
sulfate. The solvents were concentrated in vacuo. The product was purified via silica gel
chromatography, using 20:1 → 1:1 hexane:ethyl acetate, affording a white solid. Yield:
0.63 g, 74 %; mp. 69-72 °C; rf (2:1 hexane:ethyl acetate) 0.14; 1H NMR(400MHz,
CDCl3) δ = 7.52 (d, J = 7.32 Hz, 2H), 7.36 (m, 3H), 5.48 (s, 1H), 1.55 (s, 6H).
Synthesis of 1-phenyl-4-hydroxy-4-methyl-2-pentyn-1-one (16)
To a 100 ml round bottom flask, chromium trioxide (0.50 g, 3.29 mmol), distilled water
(11 mL), and concentrated sulfuric acid (0.35 mL, cat.) were added along with a stir bar.
1-Phenyl-4-hydroxy-4-methyl-2-pentyn-1-ol (15, 0.42 g, 2.21 mmol) in 30 mL acetone
was added slowly to the reaction mixture, affording a murky dark brown mixture. The
mixture was allowed to stir for approximately 23 hours at room temperature. The
solvents were concentrated in vacuo and the product was rinsed with 50 mL distilled
water. The organics were extracted with methylene chloride (3 x 50 mL). The organic
layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a
yellow oil. Yield: 0.34 g, 53.1 %; rf (2:1 hexane:ethyl acetate) 0.47; 1H NMR(400MHz,
CDCl3) δ = 8.07 (d, J = 7.8 Hz, 2H), 7.55 (t, J = 7.32 Hz, 1H), 7.41 (t, J = 7.76 Hz, 2H),
1.64 (s, 6H).
Synthesis of 2,2-dimethyl-5-phenyl-3(2H)-furanone (6)
To a 100 ml round bottom flask, 1-phenyl-4-hydroxy-4-methyl-2-pentyn-1-one (16, 0.29
g, 1.55 mmol) and ethanol (60 mL) were added. While stirring, diethyl amine (2.45 mL,
23.64 mmol) in 21 mL ethanol was added to the reaction mixture. The reaction mixture
20
was allowed to stir for 45 minutes at room temperature. The solvents were concentrated
in vacuo. The product was rinsed with water (30 mL), and the organics were extracted
with methylene chloride (4 x 35 mL). The combined organic layers were dried over
magnesium sulfate, filtered, and concentrated in vacuo. Purification was performed by
dissolving the product in methylene chloride and filtering it through a short plug of silica
gel, rinsing with 130 mL methylene chloride. The solvents were removed in vacuo to
afford a red-orange solid. Yield: 90 mg, 30.8 %; mp. 55-59 °C; rf (2:1 hexane:ethyl
acetate) 0.56; 1H NMR(400MHz, CDCl3) δ = 7.80 (d, J = 8.24 Hz, 2H), 7.50 (t, J = 7.36
Hz, 1H), 7.45 (t, J = 7.32 Hz, 2H), 1.46 (s, 6H); 13C NMR(400MHz, CDCl3) δ = 207.2,
183.6, 132.7, 129.2, 128.9, 127.3, 98.6, 89.1, 23.2.
Photolysis of 2,2-dimethyl-5-phenyl-3(2H)-furanone
To a quartz test tube, 2,2-dimethyl-5-phenyl-3(2H)-furanone (0.0200 g, 0.10 mmol) and
benzene (10 mL) were added. The tube was sparged with argon for 30 minutes. The
solution was irradiated at 300 nm for 22.5 hours. The solvents were removed in vacuo.
1H NMR indicates the formation of dimer 17. The product was purified via silica gel
chromatography (20:1→2:1 hexane:ethyl acetate) to afford a white solid. Yield: 9.6 mg,
1.57%; rf (2:1 hexane:ethyl acetate) 0.71; 1H NMR(400MHz, CDCl3) δ = 7.36 (d, J =
6.84 Hz, 4H), 7.26 (m, 6H), 3.71 (s, 2H), 1.42 (s, 6H), 0.86 (s, 6H); 13C NMR(400MHz,
CDCl3) δ = 214.0, 137.7, 128.3, 128.0, 127.2, 85.5, 84.3, 47.3, 24.7, 24.5.
Synthesis of 4-hydroxy-1-phenyl-2-butyn-1-one (18)
To a flame dried 100 mL round bottom flask, THF (20 mL) and propargyl alcohol (0.30
mL, 5 mmol) were added. The flask was cooled to -78 °C and sparged with argon. A 1.6
M n-butyllithium solution (6.5 mL, 10.4 mmol) was added dropwise over 5 minutes. The
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flask was warmed to -15 °C and allowed to stir for 15 minutes, after which, 1.26 M zinc
chloride (4 mL, 5.04 mmol) was added. After an additional 20 minutes at -15 °C, the
flask was warmed to 0 °C, and palladium-tetrakis(triphenylphosphine) (0.0160 g) was
added. The solution was stirred for 20 minutes at 0 °C then benzoyl chloride (0.70 mL,
6.04 mmol) was added. The reaction mixture was allowed to stir at room temperature for
35 minutes. Hexane was added and the mixture was poured into 10 mL of 2.3 M
ammonium chloride. Concentrated ammonia (1 mL) was added. The layers were
separated. The organics were extracted from the aqueous layer with 2 x 15 mL ethyl
ether. The combined organic layers were rinsed with 2 x 15 mL saturated ammonium
chloride and dried over magnesium sulfate. The solvents were removed in vacuo. Crude
yield: 0.96 g, 120 %; 1H NMR(400MHz, CDCl3) δ = 8.06 (d, J = 7.32 Hz, 2H), 7.55 (t, J
= 7.32 Hz, 1H), 7.30 (t, J = 7.8 Hz, 2H), 4.91 (d, J = 2.32 Hz, 2H), 2.53 (t, J = 2.28 Hz,
1H). 13C NMR(400MHz, CDCl3) δ = 165.9, 133.4, 129.9, 129.5, 128.5, 77.86, 75.19,
52.56.
Attempted Synthesis of 5-phenyl-3(2H)-furanone (4)
To a 250 mL round bottom flask, 1-phenyl-4-hydroxy-2-butyn-1-one (18, 0.244 g, 1.52
mmol) and 60 mL anhydrous ethanol were added. Diethyl amine (2.3 mL, 2.22 mmol)
diluted with 21 mL ethanol was added dropwise over 25 minutes. The reaction mixture
was allowed to stir at room temperature for 1.5 hours, then 2 drops of distilled water were
added and the mixture was allowed to stir for 30 minutes. After 30 minutes, 2 drops of
6M HCl were added, and the mixture was allowed to stir for 1 hour and 20 minutes, after
which, the solution was allowed to reflux for approximately 66 hours. The solvents were
removed in vacuo, and the product was diluted with 40 mL distilled water. The organics
22
were extracted with 6 x 30 mL methylene chloride, dried over magnesium sulfate,
filtered, and concentrated in vacuo. 1H NMR indicated that impure starting material was
obtained.
Attempted synthesis of 1-phenyl-4-toluenesulfonyloxy-2-butyn-1-one
To a flame dried 25 mL round bottom flask, 1.5 mL dry methylene chloride, 1-phenyl-4hydroxy-2-butyn-1-one (18, 0.2396 g, 1.50 mmol), and p-toluenesulfonyl chloride (0.46
g, 2.41 mmol) were added. The reaction flask was sparged with argon, pyridine (0.26
mL, 3.23 mmol) was added, and the reaction mixture was allowed to stir at room
temperature. After 19.5 hours the solution was diluted with 20 mL methylene chloride.
The organic layer was rinsed consecutively with 20 mL distilled water, 20 mL 1M HCl,
20 mL saturated sodium bicarbonate, and 20 mL of brine. The organic layer was dried
over magnesium sulfate, filtered, and concentrated in vacuo. 1H NMR indicated that
starting material and toluenesulfonic acid remained.
Synthesis of 5-hydroxy-5-phenyl-3-hexyn-2-one (20)
To a flame dried 100 mL round bottom flask, 2-phenyl-3-butyn-2-ol (0.7345 g, 5.02
mmol) and dry THF (20 mL) were added. The flask was sparged with argon and cooled
to -78 °C. A 1.6 M solution of n-butyllithium (6.5 mL, 10.4 mmol) was added over a
period of 3 minutes. After 30 minutes, the solution was warmed to -10 °C, and 1.26 M
zinc chloride in THF (4 mL, 5.04 mmol) was added. The solution was allowed to stir for
10 minutes. The solution was warmed to 0 °C and allowed to stir for 15 minutes, after
which acetyl chloride (0.40 mL, 5.62 mmol) was added and allowed to stir for 10 minutes
before warming to 25 °C. The solution was allowed to stir at 25 °C for 40 minutes then
2.34 M ammonium chloride (15 mL) and concentrated ammonium hydroxide (1 mL)
23
were added. The organics were extracted with 2 x 20 mL ethyl ether. The combined
organic layers were washed twice with 10 mL saturated ammonium chloride, dried over
magnesium sulfate, filtered, and concentrated in vacuo. The product was purified via
silica gel column chromatography (10:1 Hexane:ethyl acetate). Yield 0.40 g, 42 %; rf
(2:1 hexane:ethyl acetate) 0.57; 1H NMR(400MHz, CDCl3) δ = 7.59 (d, J = 7.32 Hz, 2H),
7.37 (t, J = 7.8 Hz, 2H), 7.30 (t, J = 7.32 Hz, 1H), 2.82 (s, 1H), 2.08 (s, 3H), 1.90 (s, 1H).
C NMR(400MHz, CDCl3) δ = 168.72, 142.23, 128.5, 128.0, 124.9, 83.1, 75.73, 75.42,
13
32.19, 21.82.
Attempted Synthesis of 2-methyl-2,5-diphenyl-3(2H)-furanone (19)
To a 250 mL round bottom flask containing 5-hydroxy-5-phenyl-3-hexyn-2-one (20, 0.40
g, 2.14 mmol), anhydrous ethanol (85 mL) was added. Diethyl amine (3.32 mL, 32
mmol) diluted with 29 mL anhydrous ethanol was added dropwise to the stirred reaction
mixture over 13 minutes. The reaction mixture was allowed to stir at room temperature
for approximately 1 hour. The solvents were removed in vacuo. The product was rinsed
with 30 mL distilled water, and the organics were extracted with 3 x 35 mL methylene
chloride. The combined organic layers were dried over magnesium sulfate, filtered and
concentrated in vacuo. 1H NMR indicated that only starting material was present.
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