Further enolate alkylation studies of 2,5-dimethyl-3(2H)-furanone

Article abstract of DOI:10.1055/s-2004-831300

Heterocyclic ketones, such as 2,5-dimethyl-3(2H)-furanone, provide multifunctional intermediates to various compounds. One property of these that has proven useful is the ability to alkylate the γ′-position of the dienolate. This report demonstrates the versatility of γ′-dienolate substitutions as employed toward syntheses of certain natural products and highly reactive electrophiles provide the best substrates for efficient substitution.

Full text of DOI:10.1055/s-2004-831300

LETTER
2081
Further Enolate Alkylation Studies of 2,5-Dimethyl-3(2H)-furanone
Enolate
A
lkylation
r
Studies
u
of 2,5-Dime
r
thyl-3(2
H
y
)-furanone S. Caine,a Mark E. Arant*b
a
Department of Chemistry, The University of Alabama, Tuscaloosa, AL 35487, USA
b
Department of Chemistry, University of Louisiana at Monroe, 700 University Avenue, Monroe, LA 71209, USA
Fax +1(318)3423334; E-mail: arant@ulm.edu
Received 17 June 2004
MBOM chloride had to be synthesized using known pro-
cedures.7
Abstract: Heterocyclic ketones, such as 2,5-dimethyl-3(2H)-fura-
none, provide multifunctional intermediates to various compounds.
One property of these that has proven useful is the ability to alkylate
the g¢-position of the dienolate. This report demonstrates the versa-
tility of g¢-dienolate substitutions as employed toward syntheses of
certain natural products and highly reactive electrophiles provide
the best substrates for efficient substitution.
Incorporation of the blocking groups was accomplished
by treatment of 2 with tert-butyllithium and quenching the
subsequent enolate with the appropriate chloromethyl
ether. Yields for these reactions were usually greater than
80% after column chromatography. Attack of the tert-bu-
tyl anion on either the carbonyl carbon or at the b¢-posi-
tion was not observed. There was not any evidence of O-
substitution of the enolate’s oxygen either.
Key words: alkylations, natural products, heterocycles, protecting
Groups, ketones
Each furanone derivative 3 was then subjected to g¢-alkyl-
ation studies. All blocking groups survived g¢-dienolate
formation (Scheme 1).
Synthetic investigations of certain heliangolide sesquiter-
penes, such as eremantholide A (1), have subjected 2,5-
dimethyl-3-(2H)furanone1 (2) to a variety of enolate stud-
ies involving alkylations with halides2 and aldol
condensations3 at the a- and g¢-positions (Figure 1). Most
of these studies has been focused on developing method-
ologies toward the 11-oxabicyclo[6.2.1]undecanone ske-
leton. In the previously reported studies, cyclization was
achieved by forming a g¢-d¢ bond.4 However, it is believed
that formation of an a-b bond should produce higher
yields of that key framework. To secure compounds facil-
itating this annulation, the a-carbon of 2 must be blocked
temporarily. This report seeks to detail some of the initial
findings in this study.
Scheme 1 Incorporation of a-blocking group.
Explored first was the reaction of allyl bromide with the
g¢-dienolate of 3a. Two compounds were isolated from
the reaction, the starting furanone and 4a in 26% yield.
Allylation of 3b produced 4b (30%) and 4b¢ (40%,
Scheme 2).
The alkylating agent was changed from allyl bromide to
methyl iodide to provide simpler 1H NMR spectra to fur-
ther investigate the polyalkylation discovery. HMPA was
also added to the conditions. These alterations resulted in
a mixture of 3b (40%) and 5a (60%).8 This mixture was
then subjected to halved amounts of base, hexamethyl-
phosphoramide (HMPA), and methyl iodide previously
added. The reaction mixture was 20% 3b, 60% 5a, and
20% 5b (R = Bn, R¢ = CH3) reflecting similar rates for
alkylation and proton exchange between the alkylated
compounds and the g¢-dienolate (Figure 2).
Figure 1 Eremantholide A and 2,5-dimethyl-3(2H)-furanone.
Since alkoxymethyl ethers are frequently used protecting
agents,5 they were considered as potential blocking
groups for the furanone. They could be easily integrated
by simple alkylation procedures.2 The ethers studied were
2-(trimethylsilyl)ethoxymethyl (SEM), benzyloxymethyl
(BOM), and p-methoxbenzyloxymethyl (MBOM). SEM
and BOM chlorides were commercially available,6 but
Increasing the amounts of methyl iodide and HMPA did
show improvements in the monoalkylation yield, al-
though 5b was present in varying amounts. For example,
increasing from 1.0 to 2.0 equivalents of HMPA and from
1.1 to 3.5 equivalents of methyl iodide gave 5a in 79%,
which was isolated by distillation.9
SYNLETT 2004, No. 12, pp 2081–2086
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Advanced online publication: 24.08.2004
DOI: 10.1055/s-2004-831300; Art ID: S03104ST
© Georg Thieme Verlag Stuttgart · New York

2082
D. S. Caine, M. E. Arant
LETTER
O
A phenylsulfenyl group at the g¢-position was then intro-
duced to attenuate the reactivity of the dienolate. After
alkylation, it could then undergo oxidative elimination12
to yield the g¢-d¢ unsaturation present in the natural prod-
ucts. Quenching the lithium dienolate with phenylsulfenyl
chloride, prepared immediately before use,13 provided the
desired sulfenyl furanone 8 in 65% yield. Base selection
proved critical in this substitution. Conditions using LDA
did form 814 in 33% but also resulted in substantial forma-
tion (33%) of the thioamine, PhSNCH(CH3)2. The alter-
native base, t-BuLi, demonstrated no reaction with
phenylsulfenyl chloride. Additionally, no polysubstitu-
tion was observed in the reaction with the g¢-dienolate.
a, b
3a
OR
O
4a
R = (CH3)3SiCH2CH2
O
O
OR
OR
O
4b
a, b
3b
R = Bn
O
Once isolated, 8 was deprotonated (t-BuLi) and methylat-
ed (MeI). NMR revealed a mixture of 9a and 9b
(Scheme 4). Separation of the monomethyl and dimethyl
compounds proved impossible by column chromatogra-
phy. Oxidation of the sulfide15 to the sulfoxide 10 and sul-
fone 11 with MCPBA followed by individual alkylations
(NaHMDS, then MeI) gave similar results (Figure 3). An-
other furanone system with a g¢-phosphonate group was
found to have the same polysubstitution problem.16
4b'
Scheme 2 Alkylations at the d¢ positions of 3a and 3b. a = t-BuLi,
b = BrCH2CH=CH2.
O
O
BOM
BOM
O
O
5a
5b
O
1) t-BuLi
Figure 2 g¢-Methylation products of 3b.
3b
BOM
PhS
2) PhSCl
O
At this juncture, another furanone was synthesized and
studied to determine conditions for exclusive monosubsti-
tution. The benzyl system was chosen due to its lesser ex-
pense, ease of separation from the starting material
(distillation), and comparatively simple 1H NMR spectral
characteristics. Also, the sodium dienolates were selected
with the anticipation of greater reactivity. When 2-benzyl-
2,5-dimethyl-3(2H)-furanone (6)10 was treated with dim-
syl sodium (NaCH2SOCH3) and quenched with ethyl io-
dide, 7a was isolated in 35% yield. Changing to sodium
bis(trimethylsilyl)amide (NaHMDS) and HMPA resulted
in isolation of 41% 6, 29% 7a, and 30% 7b (Scheme 3).
8
O
BOM
PhS
O
1) t-BuLi
9a
8
O
2) CH3I
BOM
PhS
O
9b
Scheme 4 g¢-Phenylsulfenylation and subsequent alkylation.
O
R
O
O
O
O
BOM
BOM
O
PhS
PhS
O
O
O
7a
O
1) Base
2) C2H5I
R
10
11
O
O
6
Figure 3 The sulfoxide and sulfone of 9.
R
R = C6H5CH2
O
Since sulfonates undergo substitution more rapidly than
the corresponding iodides,17 mesylates, tosylates, and tri-
flates were considered as alternative alkylation sources.
Quenching the dienolate of 3b with methyl methane-
sulfonate did not effect alkylation of the furanone. In-
stead, methyl ethanesulfonate was isolated along with the
starting furanone. Apparently, the g¢-dienolate abstracted
an a-proton from the mesylate, which in turn underwent a
self methylation. Ethyl p-toluenesulfonate did not react at
all with the 3b dienolate.
7b
Scheme 3 Ethylation studies of the 2-benzyl furanone derivative.
Noyori and coworkers reported that organozinc additives
could increase the efficiency of enolate alkylations.11 Fol-
lowing their conditions [1.5 equiv EtI, 3.0 equiv HMPA,
and 1.0 equiv (CH3)2Zn], the lithium dienolate was gener-
ated with t-BuLi. The product mixture contained 3% of 6,
23% 7a, and 73% 7b.
Synlett 2004, No. 12, 2081–2086 © Thieme Stuttgart · New York

LETTER
Enolate Alkylation Studies of 2,5-Dimethyl-3(2H)-furanone
2083
When exposed to methyl trifluoromethanesulfonate, the trations, or addition of HMPA did not give the desired re-
g¢-dienolate of 3c gave 90% of the 5-ethyl compound 1218 sults.
without noticeable 3c or dimethylation. Pentyl trifluo-
Successful deprotection was obtained by treating the
carbinol 14 with sodium amide in ammonia. The reaction
proceeded to a 50% yield. In an attempt to remove the en-
tire group in one step, triethylamine was added to the hy-
romethanesulfonate, generated in CCl419 and decanted by
cannula into the g¢-dienolate solution, provided the 5-hex-
yl derivative 1320 in 50% yield (Scheme 5).
drogenation to invoke removal of formaldehyde. It was
noted that the addition of the amine changed chemoselec-
tivity of the Pd(OH)2 catalyst. The products isolated were
the 4,5-dihydro-3(2H)-furanones 15a and 15b in a 2:1
mixture, still possessing benzyl groups (Scheme 7).25 Re-
ductive benzylic cleavages were known to decelerate in
the presence of aliphatic amines, but those studies were
Scheme 5 g¢-Alkylation with triflates.
restricted to palladium on carbon. Those reagents simply
reduced any isolated double bonds present in the sub-
strate.26 Pearlman’s catalyst is also capable of reducing
Attention was then turned to the removal of the protective
both conjugated systems and benzyl ethers simultaneous-
ly.27 It is noteworthy that the conjugated double bond in
the furanone that had previously survived hydrogenation
with the same catalyst, pressure, and reaction times was
reduced selectively in the presence of the benzyl ether.
ethers. Loss of formaldehyde after ether cleavage would
regenerate the monosubstituted a-position in anticipation
of subsequent annulation attempts.
The SEM group did not respond to traditional treatment
with fluoride.21 In fact, proton NMR revealed the condi-
tions destroyed the furanone ring system and left the SEM
group intact.
O
BOM
O
Reductive benzylic cleavage in 3b could not be accom-
plished by hydrogenation over palladium.22 Extending re-
action times and changing pH proved futile. Finally,
Pearlman’s catalyst [20% Pd(OH)2/C] succeeded in re-
moving the benzyl group.23 The reductions typically aver-
aged greater than 80% yields with the primary
contaminant being starting material (<5%, easily removed
by chromatography) after six hours at approximately 40
psi. Longer reaction times did not dramatically improve
yields (3–5% increases). No reductions in the furanone
ring were noted. Oxidative cleavage of the p-methoxyben-
zyl group in 3c using published conditions (2,3-dichloro-
4,5-dicyanobenzoquinone, DDQ)5b yielded the carbinol
1424 in only 58% yield (Scheme 6).
15a
H2, Et3N
3b
O
Pd(OH)2/C
BOM
O
15b
Scheme 7 Reduction of the furanone ring.
Currently, systems are being developed that sequentially
combine the alkylation and deprotection conditions de-
scribed herein to form the 11-oxabicyclo[6.2.1]unde-
canone backbone. Once the methodology is established, it
will be applied to the total synthesis of the heliangolides.
O
H2
3b
OH
Pd(OH)2/C
O
General.
14
Commercially available and/or reagent grade solvents and reagents
were used, usually without further purification. All non-aqueous re-
actions were performed under an atmosphere of dry nitrogen, unless
otherwise stated. Glassware was flame-dried under a positive nitro-
gen flow. Tetrahydrofuran (THF), anhydrous diethyl ether (Et2O),
and 1,2-dimethoxyethane (DME) were distilled from sodium-ben-
zophenone ketyl under a nitrogen atmosphere immediately before
use. Methylene chloride (CH2Cl2) and dimethyl sulfoxide (DMSO)
were distilled from calcium hydride prior to use.
Scheme 6 Catalytic debenzylation of 3b.
With removal of the benzyl group, the expected retro-al-
dol did not occur. The b-hydroxyketone 15 demonstrated
exceptional stability. Therefore, base-initiated dehy-
droxymethylation was considered. Compounds employed
in this investigation were sodium hydride, t-butyllithium,
potassium t-butoxide, n-butyllithium, potassium hydride, Proton NMR spectra were obtained in deuterated chloroform unless
otherwise noted. Chemical shift values are expressed in d-units with
and sodium amide. The hydrides were used in dimethox-
yethane (DME), tetrahydrofuran (THF), or dimethylform-
amide (DMF). Retro-aldol attempts with the other bases
were conducted in t-butyl alcohol (t-BuOK) and DME or
THF for the alkyllithiums. Altering temperatures, concen-
tetramethylsilane (TMS) as an internal standard.
General Alkoxymethylations of 2.
To a solution containing 7 mL of 1.7 M t-BuLi (12 mmol, 1.1 equiv)
in hexanes and 20 mL of THF, cooled to –78 °C, was added 1.13 g
(10 mmol) of 2,5-dimethyl-3(2H)-furanone (2) in 20 mL of THF,
Synlett 2004, No. 12, 2081–2086 © Thieme Stuttgart · New York

2084
D. S. Caine, M. E. Arant
LETTER
dropwise. The solution was stirred for 30 min after the addition was
complete to allow formation of the enolate. Next, the alkoxymethyl
chloro ether14 (1.0–1.6 equiv) was added and the dry-ice bath was
removed to allow the solution to warm to r.t. After stirring for 1 h at
r.t., the solution was poured into 25 mL of H2O and extracted with
three 20 mL portions of Et2O. The combined organic layers were
dried over MgSO4 and the solvents were removed by vacuum. Fura-
none 3a was purified by column chromatography (1:4 EtOAc–hex-
anes over silica gel) to give the desired product in 83% yield. This
compound had the following spectral properties: IR (neat): 3105,
2975, 2930, 1700, 1605, 1450, 1385, 1340, 1245, 1105, 960, 850,
830 cm–1. 1H NMR (CDCl3): d = 5.42 (s, 1 H), 3.56 (s, 2 H), 3.54
(m, J = 8.0 Hz, 2 H), 2.26 (s, 3 H), 1.36 (s, 3 H), 0.91 (t, J = 8.0 Hz,
2 H), 0.01 (s, 9 H). HRMS: m/e calcd for C9H9O3 [M+ – TMS):
169.0865; observed: 169.0684. Furanone 3b was purified by vacu-
um distillation (bp 116 °C at 0.025 mm) with a yield of 79%. The
compound had the following spectral properties: IR (neat): 3105,
3060, 3020, 2980, 2930, 2860, 1695, 1600, 1450, 1380, 1340, 1245,
1175, 1100, 1010, 975, 910, 765, 680, 645 cm–1. 1H NMR (CDCl3):
d = 7.30 (m, 5 H, ArH), 5.69 (m, 2 H), 5.40 (s, 1 H), 5.04 (m, 4 H),
4.52 (ABq, J = 12.3 Hz, 2 H), 3.58 (q, J = 10.6 Hz, 2 H), 2.72 (p,
J = 7.1 Hz, 1 H), 2.41 (t, J = 7.0 Hz, 4 H), 1.34 (s, 3 H). HRMS:
m/e calcd for C13H17O2 [M+ – OCH2C6H5]: 205.1229; observed:
205.1227.
Preparation of 2-Benzyloxymethyl-5-ethyl-2-methyl-3(2H)-
furanone (5a).
To a solution containing 37 mmol of LDA (1.0 equiv, made from
14.8 mL of 2.5 M BuLi in hexanes and 3.74 g (5.18 mL) of diiso-
propylamine) and HMPA (9.47 g, 53 mmol, 1.4 equiv) in 70 mL of
THF, cooled to –78 °C, was added dropwise 8.60 g (37 mmol) of
furanone 3b in 20 mL of THF. The solution was stirred for 1 h after
the addition was complete to allow formation of the g-dienolate.
Next, 18.20 g (128 mmol, 3.5 equiv) of MeI was added and the dry-
ice bath was removed to allow the solution to warm to r.t. After stir-
ring for 12 h at r.t., the solution was poured into 100 mL of H2O and
extracted with three 50 mL portions of Et2O. The combined organic
layers were washed with 100 mL of sat. aq NaHSO3 and 50 mL of
H2O and dried over MgSO4 and the solvents were removed by vac-
uum. The resulting oil was then vacuum distilled (bp 120 at 0.025
mm) to yield 7.17 g (79% yield) of the desired monomethylated
compound in greater than 90% purity. The 5-ethyl furanone 5a had
the following spectral properties: IR (neat): 3110, 3040, 2980, 2940,
2880, 1690, 1590, 1445, 1380, 1180, 1105, 1090, 940, 800, 740,
695 cm–1. 1H NMR (CDCl3): d = 7.30 (m, 5 H, ArH), 5.42 (s, 1 H),
4.53 (ABq, J = 12.3 Hz, 2 H), 3.60 (s, 2 H), 2.53 (q, J = 7.5 Hz, 2
H), 1.36 (s, 3 H), 1.24 (t, J = 7.5 Hz, 3 H). HRMS: m/e calcd for
C15H18O3: 246.1256; observed: 246.1268.
1
1105, 1090, 955, 800, 735, 690 cm–1. H NMR (CDCl3): d = 7.30
(m, 5 H, ArH), 5.43 (s, 1 H), 4.54 (ABq, J = 12.3 Hz, 2 H), 3.60 (s,
2 H), 2.26 (s, 3 H), 1.36 (s, 3 H). HRMS: m/e calcd for C14H16O3:
232.1099; observed: 232.1103. Furanone 3c purified by column
chromatography (1:1 Et2O–pentane) in a yield of 58%. The com-
pound had the following spectral properties: IR (neat): 3120, 3060,
3030, 2940, 2860, 1695, 1590, 1510, 1450, 1385, 1340, 1295, 1250,
1170, 1100, 1025, 950, 815, 740, 720 cm–1. 1H NMR (CDCl3): d =
7.21 (d, J = 8.6 Hz, 2 H, ArH), 6.86 (d, J = 8.6 Hz, 2 H, ArH), 5.42
(s, 1 H), 4.47 (ABq, J = 11.9 Hz, 2 H), 3.80 (s, 3 H), 3.56 (s, 2 H),
2.25 (s, 3 H), 1.35 (s, 3 H). HRMS: m/e calcd for C15H18O4:
262.1205; observed: 262.1195.
General g¢-Subtitution Procedure.
g¢-Ethylation of 2-Benzyl-2,5-dimethyl-3(2H)-furanone (6):
Dimsyl Sodium Approach.
To a solution containing of 1.2 mL of 1.7 M t-BuLi (2.1 mmol, 1.0
equiv) in hexanes and 10 mL of THF, cooled to –78 °C, was added
dropwise 0.50 g (2.1 mmol) of furanone 3a in 20 mL of THF. The
solution was stirred for 30 min after the addition was complete to
allow formation of the g-dienolate. Next, 1.39 g (11 mmol) of allyl
bromide was added and the dry-ice bath was removed to allow the
solution to warm to r.t. After stirring for 1 h at r.t., the solution was
poured into 30 mL of H2O and extracted with three 20 mL portions
of Et2O. The combined organic layers were washed with 20 mL of
sat. aq NaHSO3 and 30 mL of H2O and dried over MgSO4. The sol-
vents were removed by vacuum. 2-methyl-2-(2-trimethylsi-
lyl)ethoxymethyl-5-[1-(2-propen-1-yl)-3-buten-1-yl]-3(2H)-furan-
one (4a) was purified by column chromatography (1:5 EtOAc–hex-
anes over silica gel) to give 0.17 g (26% yield). The compound had
the following spectral properties: IR (neat): 3105, 3090, 2960, 2930,
2880, 1720, 1615, 1445, 1360, 1250, 1105, 1015, 915, 850, 835,
800 cm–1. 1H NMR (CDCl3): d = 5.75 (m, 2 H), 5.38 (s, 1 H), 5.08
(d, J = 12.4 Hz, 2 H), 5.05 (d, J = 3.9 Hz, 2 H), 3.52 (m, 4 H), 2.72
(quintet, J = 7.1 Hz, 1 H) 2.38 (t, J = 7.1 Hz, 4 H), 1.33 (s, 3 H), 1.36
(s, 3 H), 0.90 (m, 2 H), 0.01 (s, 9 H). HRMS: m/e calcd for C13H17O2
[M+ – O(CH2)2TMS]: 205.1229; observed: 205.1240. When the di-
enolate of 3b was treated with 3.7 equiv of allyl bromide, the mono-
and diallylated compounds were isolated. These were separated by
preparative TLC (1:4 EtOAc–hexanes). 2-Benzyloxymethyl-2-
methyl-5-(3-buten-1-yl)-3(2H)-furanone (4b, 0.35 g, 30% yield)
had the following spectral properties: IR (neat): 3075, 3020, 2980,
2920, 2860, 1700, 1595, 1490, 1440, 1370, 1180, 1105, 1090, 915,
800, 730, 690 cm–1. 1H NMR (CDCl3): d = 7.30 (m, 5 H, ArH), 5.79
(m, 1 H), 5.44 (s, 1 H), 5.07 (d, J = 17 Hz, 1 H), 5.02 (d, J = 10.7
Hz, 1 H), 4.52 (ABq, J = 12.3 Hz, 2 H), 3.60 (s, 2 H), 2.62 (t, J = 7.4
Hz, 2H), 2.41 (q, J = 7.0 Hz, 2 H), 1.35 (s, 3 H). HRMS: m/e calcd
for C17H20O3: 272.1412; observed: 272.1399. 2-Benzyloxymethyl-
2-methyl-5-[1-(2-propen-1-yl)-3-buten-1-yl]-3(2H)-furanone (4b¢,
0.54 g, 40% yield) had the following spectral properties: IR (neat):
3075, 3015, 2980, 2920, 2860, 1700, 1640, 1590, 1490, 1445, 1365,
To NaH (0.14 g, 5.8 mmol, 2.34 equiv), washed with hexanes to re-
move the mineral oil, was carefully added 10 mL of freshly distilled
DMSO. After the evolution of hydrogen had stopped, the furanone
6 (0.50 g, 2.5 mmol) in 2 mL of THF was added dropwise to the so-
lution of dimsyl sodium. The solution was stirred for 30 min and EtI
(1.56 g, 10 mmol, 4.0 equiv) was added and stirring continued for
1 h. Next, 50 mL of H2O was added and the mixture was washed
with three 50 mL portions of Et2O. The combined ether layers were
then washed with 20 mL of sat. aq NaHSO3 and 20 mL of H2O and
dried over MgSO4. The Et2O was removed by vacuum and the re-
sulting oil was subjected to column chromatography (1:5 EtOAc–
hexanes over silica gel) to give 2-benzyl-2-methyl-5-propyl-3(2H)-
furanone (7a, 0.20 g, 35%). The furanone possessed the following
spectral properties: IR (neat): 3100, 3050, 3020, 2960, 2920, 1695,
1585, 1440, 1370, 1170, 1105, 1050, 1030, 940, 800, 730, 695
cm–1. 1H NMR (CDCl3): d = 7.20 (m, 5 H, ArH), 5.20 (s, 1 H), 3.00
(ABq, J = 13.9 Hz, 2 H), 2.32 (t, J = 7.5 Hz, 2 H), 1.53 (m, 2 H) 1.38
(s, 3 H), 0.84 (t, J = 7.3 Hz, 3 H). HRMS: m/e calcd for C15H18O2:
230.1307; observed. 230.1308.
g¢-Ethylation of 2-Benzyl-2,5-dimethyl-3(2H)-furanone (6):
NaHMDS Approach.
To a solution containing 2.5 mL of 1.0 M NaHMDS (2.5 mmol, 1.0
equiv) in THF and 1.29 mL (1.33 g, 7.4 mmol, 3.0 equiv) of HMPA,
cooled to –78 °C, was added dropwise 0.50 g (2.5 mmol) of fura-
none 6 in 5 mL of THF. The solution was stirred for 30 min at 0 °C
after the addition was complete to allow formation of the g-dieno-
late. Next, 0.44 g (2.8 mmol, 1.12 equiv) of EtI was added and the
ice bath was removed to allow the solution to warm to r.t. After stir-
ring for 1 h at r.t., the solution was poured into 25 mL of sat. aq
NH4Cl and extracted with two 20 mL portions of Et2O. The com-
bined organic layers were washed with 10 mL of sat. aq NaHSO3
and 10 mL of H2O and dried over MgSO4 and the solvents were re-
moved by vacuum. The resulting oil was then subjected to column
Synlett 2004, No. 12, 2081–2086 © Thieme Stuttgart · New York

LETTER
Enolate Alkylation Studies of 2,5-Dimethyl-3(2H)-furanone
2085
chromatography to yield the compound 7a (0.33 g, 29%) which
showed the same spectral properties as those reported above, and 2-
benzyl-5-(1-ethylpropyl)-2-methyl-3(2H)-furanone (7b, 0.38 g,
30%). The furanone 7b had the following spectral properties: IR
(neat): 3100, 3080, 3040, 2965, 2925, 2875, 1695, 1575, 1460,
H, ArH), 5.18 (s, 1 H), 3.00 (ABq, J = 13.9 Hz, 2 H), 2.06 (s,
3 H), 1.38 (s, 3 H). HRMS: m/e calcd for C13H14O2:
202.0994; observed: 202.1001.
(11) Mortia, Y.; Suzuki, M.; Noyori, R. J. Org. Chem. 1989, 54,
1785.
(12) Trost, B. Acc. Chem. Res. 1978, 11, 453.
1
1445, 1365, 1255, 1105, 1050, 1000, 935, 800, 730, 695 cm–1. H
NMR (CDCl3): d = 7.20 (m, 5 H, ArH), 5.23 (s, 1 H), 3.00 (ABq,
J = 13.9 Hz, 2 H), 2.22 (quintet, J = 7.0 Hz, 1 H), 1.50 (m, 4 H),
1.37 (s, 3 H), 0.70 (m, 6 H). HRMS: m/e calcd for C17H22O2:
258.1620; observed: 258.1608.
(13) Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis,
Vol. 5; John Wiley and Sons: New York, 1975, 523.
(14) Analytical data of compound 8: 65% yield. IR (neat): 3100,
3050, 3020, 2920, 2860, 1695, 1580, 1470, 1445, 1430,
1360, 1180, 1100, 1060, 800, 735, 695 cm–1. 1H NMR
(CDCl3): d = 7.39–7.22 (m, 10 H, ArH), 5.46 (s, 1 H), 4.51
(ABq, J = 12.3 Hz, 2 H), 3.82 (s, 2 H), 3.59 (ABq, J = 8.8
Hz, 2 H), 1.31 (s, 3 H). HRMS: m/e calcd for C20H20SO3:
340.1133; observed: 340.1145..
(15) 2-Benzyloxymethyl-2-methyl-5-phenylsulfinylmethyl-3
(2H)-furanone (10, 25% yield 1:1 mixture of diastereomers):
IR (neat): 3120, 3060, 3005, 2090, 2930, 2860, 1695, 1595,
1440, 1400, 1360, 1100, 1085, 1045, 965, 905, 870, 800,
745, 690, 650 cm–1. 1H NMR (CDCl3): d = 7.62–7.25 (m, 10
H, ArH), 5.55 (s, 0.5 H), 5.35 (s, 0.5 H), 4.48 (m, 2 H), 3.95
(m, 2 H), 3.51 (m, 2 H), 1.30 (s, 1.5 H) 1.13 (s, 1.5 H).
HRMS: m/e calcd for C20H20SO4: 356.1082; observed:
356.1070. 2-Benzyloxymethyl-2-methyl-5-phenylsulfonyl-
methyl-3 (2H)-furanone (11, 19% yield): IR (neat): 3110,
3060, 3010, 2090, 2930, 2860, 1700, 1600, 1440, 1400,
1365, 1330, 1150, 1120, 1095, 1070, 965, 900, 840, 810,
740, 690 cm–1. 1H NMR (CDCl3): d = 7.62–7.25 (m, 10 H,
ArH), 5.58 (s, 1 H), 4.46 (ABq, J = 12.1 Hz, 2 H), 4.30
(ABq, J = 14.1 Hz, 2 H), 3.51 (ABq, J = 10.8 Hz, 2 H), 1.20
(s, 3 H). HRMS: m/e calcd for C14H15O3 [M+ – C6H5SO2]:
231.1021; observed: 231.1019.
g¢-Ethylation of 2-Benzyl-2,5-dimethyl-3(2H)-furanone (6):
Dimethylzinc Approach.
To a solution containing 3.8 mL of 1.5 M t-BuLi (2.5 mmol, 1.0
equiv) in hexanes and THF, cooled to –78 °C, was added dropwise
0.50 g (2.5 mmol) of furanone 6 and 1.29 mL (1.33 g, 7.4 mmol, 3.0
equiv) in 5 mL of THF. After 10 min, 1.24 mL of 2.0 M (CH3)2Zn
(2.5 mmol, 1.0 equiv) was added. The solution was stirred for 30
min and EtI (0.30 g, 3.8 mmol, 1.5 equiv) was added. The solution
was maintained at –78 °C for 10 min, and then was allowed to warm
to 0 °C for 40 min. The solution was then poured into 25 mL of sat.
aq NH4Cl and extracted with two 20 mL portions of Et2O. The com-
bined organic layers were washed with 10 mL of sat. aq NaHSO3
and 10 mL of H2O and dried over MgSO4. The solvents were re-
moved by vacuum and the resulting oil was then subjected to col-
umn chromatography (1:5 EtOAc–hexanes) to yield 7a (0.13 g,
23%) and 7b (0.47 g, 73%).
Acknowledgment
This work was partially supported by
a research grant
(5R01CA41688) from the National Institutes of Health.
(16) Tsuge, O.; Kanemasa, S.; Suga, H. Chem. Lett. 1987, 323.
(17) Bates, R. B.; Taylor, S. R. J. Org. Chem. 1993, 58, 4469.
(18) Furanone 12 (85% yield after column chromatography, 3:1
Et2O–hexanes): IR (neat): 3110, 3020, 2980, 2930, 2860,
1700, 1595, 1510, 1460, 1380, 1360, 1300, 1250, 1170,
1100, 1030, 920, 815, 750, 730 cm–1. 1H NMR (CDCl3): d =
7.21 (d, J = 8.5 Hz, 2 H, ArH), 6.86 (d, J = 8.5 Hz, 2 H,
ArH), 5.42 (s, 1 H), 4.47 (ABq, J = 11.9 Hz, 2 H), 3.80 (s, 3
H), 3.56 (s, 2 H), 2.53 (q, J = 7.5 Hz, 2 H), 1.35 (s, 3 H), 1.24
(t, J = 7.5 Hz, 3 H). HRMS: m/e calcd for C16H20O4:
276.1362; observed: 276.1352.
References
(1) (a) Venturello, C.; D’Aloisio, R. Synthesis 1977, 754.
(b) Chimichi, S.; Boccalini, M.; Cosimelli, B.; Acqua, F. D.;
Viola, G. Tetrahedron 2003, 59, 5215.
(2) (a) Smith, A. B. III.; Levenberg, P. A.; Jerris, P. J.;
Scarborough, R. M. Jr.; Wovkulich, P. M. J. Am. Chem. Soc.
1981, 103, 1501. (b) Caine, D. S.; Paige, M. A. Synlett 1999,
1391.
(3) Smith, A. B. III.; Levenberg, P. A.; Jerris, P. J.;
Scarborough, R. M.; Wovkulich, P. M. J. Am. Chem. Soc.
1981, 103, 219.
(4) (a) Caine, D.; Arant, M. E. Tetrahedron Lett. 1994, 35,
6795. (b) Takao, K.; Ochiai, H.; Yoshida, K.; Hashizuka, T.;
Koshimura, H.; Tadano, K.; Ogawa, S. J. Org. Chem. 1995,
60, 8179. (c) Boeckman, R. K. Jr.; Yoon, S. K.; Heckendorn,
D. K. J. Am. Chem. Soc. 1991, 113, 9682.
(19) Beard, C. D.; Baum, K.; Grakauskas, V. J. Org. Chem. 1973,
38, 3673.
(20) Furanone 13 (50% after column chromatography, 3:1 Et2O–
hexanes). IR (neat): 3110, 3040, 2940, 2850, 1690, 1595,
1510, 1450, 1380, 1360, 1290, 1250, 1160, 1100, 1080,
1020, 970, 810, 750, 730 cm–1. 1H NMR (CDCl3): d = 7.20
(d, J = 8.4 Hz, 2 H, ArH), 6.85 (d, J = 8.4 Hz, 2 H, ArH),
5.41 (s, 1 H), 4.47 (ABq, J = 11.9 Hz, 2 H), 3.80 (s, 3 H),
3.56 (s, 2 H), 2.51 (q, J = 7.5 Hz, 2 H), 1.65 (m, 2 H), 1.38–
1.24 (m, 6 H), 1.34 (s, 3 H), 0.88 (t, J = 6.6 Hz, 3 H). HRMS:
m/e calcd for C12H19O2 [M+ – CH3OC6H4CH2O): 195.1385;
observed: 195.1387.
(5) (a) Stork, G.; Isobe, M. J. Am. Chem. Soc. 1975, 97, 6260.
(b) Masaki, Y.; Iwata, I.; Mukai, I.; Oda, H.; Nagashima, H.
Chem. Lett. 1989, 659. (c) Lipshutz, B. H.; Moretti, R.;
Crow, R. Tetrahadron Lett. 1989, 30, 15.
(6) SEM-Cl is available from Aldrich and BOM-Cl from Sigma-
Aldrich.
(21) (a) Lipshutz, B. H.; Miller, T. A. Tetrahedron Lett. 1989, 30,
7149. (b) Suzuki, K.; Matusumoto, T.; Tomooka, K.;
Matsumoto, K.; Tsuchihashi, G. I. Chem. Lett. 1987, 113.
(22) Heathcock, C. H.; Ratcliff, J. R. J. Am. Chem. Soc. 1971, 93,
1746.
(23) (a) Pearlman, W. M. Tetrahedron Lett. 1967, 23, 1663.
(b) Hanessian, S.; Liak, T. J.; Vanasse, B. Synthesis 1981,
396. (c) The catalyst showed reduced activity as it was
exposed to the atmosphere. Its activity returned upon drying
under mild heat and vacuum.
(7) (a) Kozikowski, A. P.; Wu, J. P. Tetrahedron Lett. 1987, 28,
5125. (b) Corey, E. J.; Bock, M. G. Tetrahedron Lett. 1975,
16, 3269.
(8) Composition determined from 1H NMR.
(9) Trace amounts of 3b (2.5%) and 5c (2.5%) were noted in the
1H NMR spectrum of the reaction mixture.
(10) Analytical data of compound 6: 84.3% yield; bp 100 °C at
0.025 mm. IR (neat): 3100, 3080, 3040, 2980, 2920, 1695,
1600, 1490, 1450, 1430, 1385, 1350, 1150, 1110, 1060, 965,
940, 790, 730, 695 cm–1. 1H NMR (CDCl3): d = 7.20 (m, 5
(24) Carbinol 14: IR (neat): 3400, 3100, 2920, 2860, 1660, 1530,
1510, 1445, 1395, 1345, 1335, 1170, 1120, 1060, 960 cm–1.
Synlett 2004, No. 12, 2081–2086 © Thieme Stuttgart · New York

2086
D. S. Caine, M. E. Arant
LETTER
1H NMR (CDCl3): d = 5.44 (s, 1 H), 3.74 (ABq, J = 11.7 Hz,
2 H), 2.28 (s, 3 H), 1.38 (s, 3 H). HRMS: m/e calcd for
C7H10O3: 142.0630; observed: 142.0625.
1 H), 4.48 (ABq, J = 12.2 Hz, 2 H), 3.58 (ABq, J = 9.7 Hz,
2 H), 2.63 (dd, Jab = 18.0 Hz, Jbc = 6.1 Hz, 1 H), 2.16 (dd,
Jab = 17.5 Hz, Jbc = 10.6 Hz, 1 H), 1.39 (d, J = 6.1 Hz, 3 H),
(25) The resulting oil contained greater than 95% of the
tetrahydrofuranone 15 in a yield of 93%. The major isomers
existed as the (2R,5S)/(2S,5R) racemate in a 2:1 ratio.
Dihydrofuranone 15a was presumably favored by steric
repulsion between the catalyst and the BOM group. The
compound possessed these spectral properties: IR (neat):
3400, 3060, 3040, 2980, 2920, 2860, 1720, 1630, 1490,
1450, 1400, 1380, 1365, 1320, 1230, 1200, 1170, 1100,
1035, 970, 930, 920, 870, 820, 730, 695 cm–1. 1H NMR
(CDCl3) major diastereomer 15a: d = 7.30 (m, 5 H), 4.65 (m,
1.18 (s, 3 H); minor diastereomer 15b: d = 7.30 (m, 5 H),
4.54 (ABq, J = 12.0 Hz, 2 H), 4.33 (m, 1 H), 3.52 (ABq,
J = 10.1 Hz, 2 H), 2.55 (dd, Jab = 17.6 Hz, Jbc = 5.6 Hz, 1 H),
2.25 (dd, Jab = 18.2 Hz, Jbc = 9.5 Hz, 1 H), 1.45 (d, J = 6.0
Hz, 3 H), 1.14 (s, 3 H). HRMS: m/e calcd for C14H18O3:
234.1256; observed: 234.1234.
(26) Czech, B. P.; Bartsch, R. A. J. Org. Chem. 1984, 49, 4076.
(27) For example: Nicolau, K. C.; Hwang, C. K.; Marron, B. E.;
DeFrees, S. A.; Couladouros, E. A.; Abe, Y.; Carroll, P. J.;
Snyder, J. P. J. Am. Chem. Soc. 1990, 112, 3040.
Synlett 2004, No. 12, 2081–2086 © Thieme Stuttgart · New York