Multisubstituted α,β-unsaturated γ-lactones from 1-chlorovinyl p-tolyl sulfoxides and tert-butyl carboxylates using Pummerer-type cyclization as the key reaction

Article abstract of DOI:10.1055/s-0030-1259987

The addition reaction of 1-chlorovinyl p-tolyl sulfoxides, derived from aldehydes and chloromethyl p-tolyl sulfoxide, with the lithium enolate of tert-butyl carboxylates gave adducts in quantitative yields. Treatment of the adducts with trifluoroacetic anhydride in the presence of sodium iodide resulted in the formation of γ-lactones bearing a p-tolylsulfanyl group at the γ-position through Pummerer-type cyclization. Oxidation of the sulfanyl group to the sulfinyl group followed by thermal syn-elimination gave α,β-unsaturated γ-lactones (γ-butenolides) in moderate to good yields. Trapping the intermediates of the addition reaction with iodoalkanes gave alkylated adducts, from which α,γ;- and β,γ-disubstituted γ-butenolides were obtained. These procedures provide a good way to synthesize multisubstituted γ-butenolides from aldehydes. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1259987

PAPER
1435
Multisubstituted a,b-Unsaturated g-Lactones from 1-Chlorovinyl p-Tolyl
Sulfoxides and tert-Butyl Carboxylates Using Pummerer-Type Cyclization as
the Key Reaction
Takashi Katae, Shimpei Sugiyama, Tsuyoshi Satoh*
Graduate School of Chemical Sciences and Technology, Tokyo University of Science, Ichigaya-Funagawara-machi 12, Shinjuku-ku,
Tokyo 162-0826, Japan
Fax +81(3)52614631; E-mail: tsatoh@rs.kagu.tus.ac.jp
Received 20 January 2011; revised 8 February 2011
position, in good to high yields by using Pummerer-type
Abstract: The addition reaction of 1-chlorovinyl p-tolyl sulfoxides,
cyclization.3 g-Sulfanyl g-lactones 6 were oxidized with
derived from aldehydes and chloromethyl p-tolyl sulfoxide, with
m-chloroperbenzoic acid (MCPBA)4 and the resulting
the lithium enolate of tert-butyl carboxylates gave adducts in quan-
sulfoxides were heated under reflux in pyridine5 to afford
titative yields. Treatment of the adducts with trifluoroacetic anhy-
dride in the presence of sodium iodide resulted in the formation of a-, b-substituted and a,b-disubstituted g-butenolides 7 in
g-lactones bearing a p-tolylsulfanyl group at the g-position through
Pummerer-type cyclization. Oxidation of the sulfanyl group to the
sulfinyl group followed by thermal syn-elimination gave a,b-unsat-
urated g-lactones (g-butenolides) in moderate to good yields. Trap-
ping the intermediates of the addition reaction with iodoalkanes
gave alkylated adducts, from which a,g- and b,g-disubstituted
g-butenolides were obtained. These procedures provide a good way
to synthesize multisubstituted g-butenolides from aldehydes.
moderate to good yields. When the intermediates 4 were
trapped with iodoalkanes,6 alkylated adducts 8 were ob-
tained. From 8, a,g- and b,g-disubstituted g-butenolides 9
were obtained. In this paper, the results described above
are presented in detail.
R1
COOt-Bu
TolS(O)CH2Cl
R2
H
Cl
R2
H
2
R2
H
R1CH2COOt-Bu
LDA
Key words: g-butenolide, g-lactones, a,b-unsaturated g-lactones,
sulfoxides, Pummerer reaction
S(O)Tol
H2O
O
2 steps
Cl
S(O)Tol
Li
THF
1
3
4
R1
a,b-Unsaturated g-lactone (g-butenolide) is a skeletal
structure that is quite often found in biologically active
natural products.1 g-Butenolides are also very important
compounds in synthetic organic chemistry. Although a
few methods for the synthesis of g-butenolides and natural
products having the g-butenolide skeletal structure have
been reported,2 development of new methods for the syn-
thesis of such compounds is still an important subject in
organic synthesis. In previous studies, we reported a new
synthesis, including an asymmetric synthesis, of g-lac-
tones from 1-chlorovinyl p-tolyl sulfoxides and tert-butyl
carboxylates using Pummerer-type cyclization as the key
reaction.3 In a continuation of our interest in developing
new methods for the synthesis of g-lactones, we recently
established a method for the synthesis of multisubstituted
g-butenolides from aldehydes by using our methods.
COOt-Bu
S(O)Tol
TFAA
NaI
O
O
R2
H
O
O
STol
1) MCPBA
2) pyridine
reflux
MeCN
Cl
H
R2
R2
R1
R1
7
5
6
R1
COOt-Bu
S(O)Tol
O
1) TFA
2) TFAA, NaI
R2
H
O
R3
R3I
4
3) MCPBA
4) pyridine, reflux
Cl
R3
R2
R1
8
9
Scheme 1
A representative result illustrating this study starting from
3-phenylpropanal is reported as follows (Scheme 2). 1-
Chlorovinyl p-tolyl sulfoxide 10 was synthesized from 3-
phenylpropanal and chloromethyl p-tolyl sulfoxide in
quantitative yield as a mixture of two geometrical iso-
mers.3d Treatment of the mixture of 10 with the lithium
enolate of tert-butyl acetate resulted in the formation of
adduct 11 in quantitative yield as a mixture of two diaste-
reomers. The mixture of adduct 11 was treated with
TFAA (5 equiv) in the presence of NaI (5 equiv) in aceto-
nitrile at –40 °C to give g-lactones 12, bearing a p-tolyl
sulfanyl group at the g-position, in 93% yield through
Pummerer-type cyclization.3 The product 12 was found to
be a 10:1 mixture of two separable diastereomers, and the
main product was shown to have trans configuration by
1H NMR analysis.
Thus, as shown in Scheme 1, 1-chlorovinyl p-tolyl sulf-
oxides 3 were synthesized from aldehydes 1 with chlo-
romethyl p-tolyl sulfoxide 2 in two steps in almost
quantitative yields.3d Addition reaction of 3 with the lithi-
um enolate of tert-butyl carboxylates gave adducts 5
through lithium a-sulfinyl carbanion intermediates 4.
Treatment of adducts 5 with trifluoroacetic anhydride
(TFAA) in the presence of NaI resulted in the formation
of g-lactones 6, bearing a p-tolylsulfanyl group at the g-
SYNTHESIS 2011, No. 9, pp 1435–1441
x
x
.
x
x
.2
0
1
1
Advanced online publication: 01.04.2011
DOI: 10.1055/s-0030-1259987; Art ID: F13111SS
© Georg Thieme Verlag Stuttgart · New York

1436
T. Katae et al.
PAPER
PhH2CH2C
H
Table 1 Conditions for the Thermal Elimination of Sulfoxide 13
Cl
MeCOOt-Bu
PhCH2CH2CHO
O
O
ref. 3d
LDA, THF
–78 °C, 99%
O
S(O)Tol
O
solvent
S(O)Tol
10
reflux, time
CH2CH2Ph
CH2CH2Ph
15
t-BuOOCH2C
TFAA (5 equiv)
NaI (5 equiv)
O
S(O)Tol
Cl
O
STol
13
PhH2CH2C
H
MeCN, –40 °C
93%
Yield of 15 (%)a
H
Entry
Solvent
Time (h)
CH2CH2Ph
12
11
1
2
3
4
5
6
7
pyridine
toluene
DMF
3
3
65
40
69
67
61
76
75
(trans/cis = 10:1)
O
O
O
S(O)Tol
O
MCPBA
3
pyridine
reflux
3 h
CHCl3, 0 °C
90%
CH2CH2Ph
CH2CH2Ph
DMSO
DMF
3
13a (trans)
13b (cis)
14
12
12
24
double bond
migration
O
pyridine
pyridine
O
+
13 (17%; 13a/13b = 5:6)
CH2CH2Ph
15 (65%)
a Isolated yield.
Scheme 2
yields. g-Sulfinyl g-lactones 16 used in entries 3–5 were
synthesized from benzaldehyde, 2-thiophenecarboxalde-
hyde and 2-furaldehyde, respectively, with tert-butyl ace-
tate. The yields of b-substituted g-butenolides 17c–e were
good, however, because of the unstable nature of the furan
ring, the yield of 17e was found to be somewhat low
(entry 5). By applying this procedure, a,b-disubstituted g-
butenolides 17f–h were obtained in up to 94% yield
(entries 6–8).
Without separation of the two diastereomers, the sulfanyl
group in 12 was oxidized with MCPBA in chloroform at
0 °C to give sulfoxide 13 in 90% yield as a mixture of two
configurational isomers (13a and 13b). Thermal syn-elim-
ination of sulfoxide 13 in refluxing pyridine5 resulted in
the formation of g-butenolide 15, having a 2-phenylethyl
group at the b-position, in 65% yield, and a mixture of sulf-
oxide 13 was recovered in 17% yield. Clearly, the thermal
syn-elimination of 13 was not complete. In this reaction,
the initially produced b,g-unsaturated g-lactone 14 was
not observed at all. Moreover, separation of 15 and 13 by
silica gel column chromatography was found to be
straightforward.
Table 2 Synthesis of a-, b-, and a,b-Disubstituted g-Butenolide 17
from 16
O
O
O
S(O)Tol
O
pyridine
reflux, 12 h
R2
R2
R1
R1
We further investigated the conditions for the thermal syn-
elimination of 13; the results are summarized in Table 1.
Thus, 13 was heated under reflux for three hours in either
pyridine, toluene, N,N-dimethylformamide (DMF) or
dimethylsulfoxide (DMSO) (entries 1–4), and toluene
was found to be the only unsuitable solvent. Compound
13 was then heated at reflux for 12 hours in N,N-dimeth-
ylformamide or pyridine (entries 5 and 6), and it was
found that the best yield (76%) was obtained by using the
conditions given in entry 6. The yield of 15 was not affect-
ed by prolonging the heating to 24 hours (entry 7). As a
result, the conditions shown in entry 6 were found to be
the conditions of choice and these conditions were thus
used throughout this study.
16
17
Entry 16
17
Yield (%)a
R1
R2
H
1
2
3
PhCH2CH2
17a
17b
17c
90
Ph
H
H
78b
82
Ph
(trans/cis = 4:1)
4
5
6
7
8
H
H
2-thienyl (trans/cis = 3.1:1) 17d
76
65
72
94
56
2-furyl (trans/cis = 2:1)
17e
17f
17g
17h
PhCH2CH2 PhCH2CH2
PhCH2CH2 2-thienyl
PhCH2CH2 2-furyl
With optimized conditions for the thermal syn-elimina-
tion in hand, the substrate scope of this procedure was in-
vestigated; the results are summarized in Table 2.
a Isolated yield.
g-Sulfinyl g-lactones 16 used in entries 1 and 2 were syn-
thesized from methyl formate7 and tert-butyl 4-phenylbu-
tyrate and ethyl phenylacetate, respectively. a-Substituted
g-butenolides 17a and 17b were obtained in good to high
b Ethyl phenylacetate was used as the ester and the adduct was hydro-
lyzed to a carboxylic acid by treatment with KOH in methanol before
applying TFAA/NaI.
Synthesis 2011, No. 9, 1435–1441 © Thieme Stuttgart · New York

PAPER
Multisubstituted a,b-Unsaturated g-Lactones
1437
Next, we planned for the synthesis of g-substituted g- Table 3 Synthesis of a,g- and b,g-Disubstituted g-Butenolides 25
from 24
butenolides. A representative example is reported starting
from 1-chlorovinyl p-tolyl sulfoxide (18)7 (Scheme 3).
S(O)Tol
R3
O
O
O
R3
O
pyridine
Thus, the reaction of the lithium enolate of tert-butyl 4-
phenylacetate (4.5 equiv) with 18 at –78 °C resulted in the
formation of the lithium a-sulfinyl carbanion intermediate
19. Addition of iodomethane (5 equiv) to the carbanion
gave methylated adduct 20 in quantitative yield.6 Initially,
20 was treated with TFAA/NaI; however, no lactone for-
mation reaction was observed. To overcome this problem,
the tert-butyl ester group in 20 was converted into the cor-
responding carboxylic acid under conventional conditions
to give 21 in 91% yield. Carboxylic acid 21 was then treat-
ed with TFAA/NaI in acetonitrile to afford the desired g-
methylated g-lactone 22 in 73% yield. Methylated g-lac-
tone 22 was oxidized with MCPBA and the resultant sulf-
oxide (99% yield) was heated under reflux in pyridine to
afford the desired g-substituted g-butenolide 23 in 59%
yield.
reflux, 12 h
R2
R2
R1
R1
24
25
Entry 24
25 Yield (%)a
R1
R2
H
R3
CH2CH=CH2
1
2
3
PhCH2CH2
25a 44
H
H
2-thienyl Me (trans/cis = 1:1) 25b 48
2-furyl Me (trans/cis = 1:1) 25c 20
a Isolated yield.
Table 4 Synthesis of g-Butenolides 28 Bearing a Dibenzylamino
Group at the a-Position
Bn2N
R2
Bn2NCH2COOt-Bu
(7.5 equiv)
R2
H
S(O)Tol
Cl
COOt-Bu
S(O)Tol
MeI
Ph(CH2)3COOt-Bu
(4.5 equiv)
H
Cl
t-Bu
Cl
COO
(5 equiv)
LDA, THF, –45 °C, 1 h
up to 99%
PhH2CH2C
LDA, THF
3
Cl
99%
S(O)Tol
18
Li
H
–78 °C, 15 min
26
S(O)Tol
O
O
O
O
STol
19
1) MCPBA
TFAA, NaI
MeCN
COOH
COOt-Bu
2) pyridine
reflux, 12 h
TFA
Bn2N
R2
Bn2N
R2
PhH2CH2C
Cl
PhH2CH2C
Cl
CH2Cl2, r.t.
24 h, 91%
27
28
S(O)Tol
S(O)Tol
Entry 27
R2
Yield (%)a,b 28
Yield (%)a,c
20
21
1
2
3
4
27a
27b
27c
27d
H
33
28a
50
67
59
33
O
O
STol 1) MCPBA, CHCl3
0 °C, 99%
O
O
TFAA, NaI
PhCH2CH2
2-thienyl
2-furyl
85d
81e
71f
28b
28c
28d
MeCN
–40 °C
73%
2) pyridine, reflux
12 h, 59%
PhH2CH2C
PhH2CH2C
22
23
Scheme 3
a Isolated yield.
b Yield from 26.
c Two-step overall yield from 27.
d Ratio trans/cis not determined.
e Ratio trans/cis = 7:1.
Other examples for the synthesis of g-substituted g-
butenolides 25 are summarized in Table 3. The procedure
carried out with allyl iodide is shown in entry 1. Although
the yield was moderate, a,g-disubstituted g-butenolide,
bearing an allyl group at the g-position 25a, was obtained.
Entries 2 and 3 show the synthesis of b,g-disubstituted g-
butenolides. Again, the yield for the b,g-disubstituted g-
butenolide, bearing a furyl group at the g-position, was
found to be low (entry 3).
f Ratio trans/cis = 3:1.
to 85% yield. Finally, oxidation with MCPBA followed
by thermal syn-elimination of 27 resulted in the formation
of the desired a-amino-substituted g-butenolides 28 in up
to 67% yield.
In conclusion, a method for the synthesis of multisubsti-
tuted g-butenolides was realized by Pummerer-type cy-
clization of 4-chloro-4-(p-tolylsulfinyl)butyric acid
esters, which were synthesized from aldehydes, with
TFAA/NaI as the key reaction. Although a synthesis of
fully substituted g-butenolides could not be achieved, the
procedure presented in this paper would contribute to the
synthesis of several g-butenolides.
Finally, the procedure described above was extended to
the synthesis of a-amino-substituted g-butenolides 28.
The complete sequence is shown in Table 4. At first, 1-
chlorovinyl p-tolyl sulfoxide 3 was treated with the lithi-
um enolate of N,N-dibenzylglycine tert-butyl ester (7.5
equiv) in tetrahydrofuran at –45 °C for one hour to give
adduct 26 in almost quantitative yield as a mixture of two
diastereomers with respect to the carbon bearing the R2
group.7 Adduct 26 was treated with TFAA/NaI under the
aforementioned conditions to give g-sulfanyl g-lactones,
bearing a dibenzylamino group at the a-position 27, in up
All melting points were measured with a Yanaco MP-S3 apparatus
and are uncorrected. 1H NMR spectra were measured from samples
dissolved in CDCl3 with JEOL JNM-LA 300, 500, Bruker DPX
Synthesis 2011, No. 9, 1435–1441 © Thieme Stuttgart · New York

1438
T. Katae et al.
PAPER
400, or AV 600 spectrometers. Electron-impact mass spectra (MS)
were obtained at 70 eV by direct insertion with a HITACHI M-80B
mass spectrometer. IR spectra were recorded with a Perkin–Elmer
Spectrum One FTIR instrument. Silica gel 60 N (Kanto Chemical)
containing 0.5% fluorescence reagent 254 and a quartz column
were used for column chromatography; products with UV absorp-
tion were detected by UV irradiation. In experiments requiring an-
hydrous solvents and reagents, THF was distilled from diphenyl
ketyl. Diisopropylamine, pyridine, toluene, DMF and DMSO were
distilled from CaH2. All reactions involving air- or water-sensitive
compounds were routinely conducted in glassware that was flame-
dried under a positive pressure of argon. Compounds 3-phenyl-5H-
furan-2-one (17b),8 4-phenyl-5H-furan-2-one (17c),9 4-thiophen-2-
yl-5H-furan-2-one (17d),9 2¢H-[2,3¢]bifuranyl-5¢-one (17e)10 are all
known in the literature.
Yield: 42.7 mg (76%); colorless crystals; mp 52.5–53 °C (hexane–
EtOAc).
IR (KBr): 2948, 1784, 1733 (CO), 1635, 1173, 1130, 1038, 998,
892, 846, 757, 716, 704 cm–1.
1H NMR (500 MHz): d = 2.7–2.79 (m, 2 H), 2.88–2.97 (m, 2 H),
4.65–4.69 (m, 2 H), 5.84–5.89 (m, 1 H), 7.15–7.35 (m, 5 H).
MS: m/z (%) = 188 (30) [M]+, 97 (21), 91 (100).
HRMS: m/z [M]+ calcd for C12H12O2: 188.0834; found: 188.0837.
3-(2-Phenylethyl)-5H-furan-2-one (17a)
Colorless oil.
IR (neat): 2929, 1747 (CO), 1497, 1454, 1348, 1203, 1082, 1069,
1050, 831, 751, 700 cm–1.
1H NMR (400 MHz): d = 2.59–2.71 (m, 2 H), 2.85–2.98 (m, 2 H),
tert-Butyl 3-[Chloro(p-tolylsulfinyl)methyl]-5-phenylpen-
tanoate (11)
4.71–4.78 (m, 2 H), 6.98–7.06 (m, 1 H), 7.14–7.35 (m, 5 H).
MS: m/z (%) = 188 (33) [M]+, 91 (100).
HRMS: m/z [M]+ calcd for C12H12O2: 188.0834; found: 188.0831.
tert-Butyl acetate (3.4 mL, 25 mmol) was added to a solution of
LDA (25 mmol) in anhydrous THF (62.5 mL) at –78 °C with stir-
ring. The solution was stirred for 15 min, then a solution of 10 (1.52
g, 5 mmol) in THF (5 mL) was added. The reaction mixture was
stirred for 10 min at –78 °C, and the reaction was quenched by add-
ing sat. aq NH4Cl (50 mL). The mixture was extracted with CHCl3
(2 × 50 mL) and the product was purified by silica gel column chro-
matography (hexane–EtOAc) to afford 113d (2.1 g, 99%) as a color-
less oil.
3,4-Di(2-phenylethyl)-5H-furan-2-one (17f)
Colorless oil.
IR (neat): 2927, 1747 (CO), 1671, 1496, 1454, 1081, 1068, 1030,
752, 701 cm–1.
1H NMR (400 MHz): d = 2.37–2.57 (m, 6 H), 2.71–2.81 (m, 2 H),
4.48 (s, 2 H), 7.00–7.08 (m, 2 H), 7.10–7.34 (m, 8 H).
MS: m/z (%) = 292 (57) [M]+, 91 (100).
HRMS: m/z [M]+ calcd for C20H20O2: 292.1462; found: 292.1461.
4-(2-Phenylethyl)-5-(p-tolylsulfanyl)dihydrofuran-2-one (12)
A solution of NaI (3.75 g, 25 mmol) in MeCN (90 mL) was stirred
for 15 min at –40 °C. TFAA (3.47 mL, 25 mmol) was added drop-
wise with stirring at –40 °C and the solution was stirred for 15 min.
Ester 11 (2.1 g, 5 mmol) in MeCN (5 mL) was added dropwise at
–40 °C with stirring and the reaction mixture was stirred for 10 min.
The reaction was quenched by adding sat. aq NaHCO3 (25 mL) fol-
lowed by sat. aq Na2SO3 (25 mL). The mixture was extracted with
CHCl3 (2 × 50 mL), the organic layer was dried over MgSO4 and
the solvent was evaporated. The residue was purified by silica gel
column chromatography (hexane–EtOAc) to give 12.
3-(2-Phenylethyl)-4-thiophen-2-yl-5H-furan-2-one (17g)
Colorless crystals; mp 101–101.5 °C (hexane–EtOAc).
IR (KBr): 2934, 1744 (CO), 1732 (CO), 1641, 1451, 1423, 1351,
1082, 1038, 723, 701 cm–1.
1H NMR (400 MHz): d = 2.91 (m, 4 H), 5.09 (s, 2 H), 7.16 (dd,
J = 3.7, 5.1 Hz, 1 H), 7.19–7.24 (m, 2 H), 7.28–7.33 (m, 4 H), 7.60
(dd, J = 1.1, 5.1 Hz, 1 H).
Yield: 1.45 g (93%); colorless oil; ca. 10:1 mixture of two diaste-
reomers.
Anal. Calcd for C16H14O2S: C, 71.08; H, 5.22; S, 11.86. Found: C,
70.98; H, 5.19; S, 11.83.
IR (neat): 2923, 1789 (CO), 1494, 1454, 1205, 1144, 957, 813, 751,
701, 457 cm–1.
1H NMR (500 MHz): d = 1.66–1.82 (m, 1 H), 2.01–2.16 (m, 1 H),
2.17–2.30 (m, 1 H), 2.31–2.46 (m, 1 H), 2.34 (s, 3 H), 2.51–2.8 (m,
3 H), 5.34 (d, J = 6.36 Hz, 0.91 H), 5.78 (d, J = 6.93 Hz, 0.09 H),
7.07–7.47 (m, 9 H).
4¢-(2-Phenylethyl)-2¢H-[2,3¢]bifuranyl-5¢-one (17h)
Colorless crystals; mp 61.5–62 °C (hexane–EtOAc).
IR (KBr): 2934, 1731 (CO), 1659, 1342, 1172, 1065, 1040, 1022,
928, 770, 760, 697 cm–1.
1H NMR (400 MHz): d = 2.82–2.97 (m, 4 H), 5.01 (s, 2 H), 6.55
(dd, J = 1.8, 3.5 Hz, 1 H), 6.65 (d, J = 3.5 Hz, 1 H), 7.12–7.39 (m,
5 H), 7.59 (d, J = 1.8 Hz, 1 H).
MS: m/z (%) = 312 (8) [M]+, 189 (20), 143 (16), 129 (100), 124
(35), 117 (12), 91 (64).
HRMS: m/z [M]+ calcd for C19H20O2S: 312.1183; found: 312.1182.
Anal. Calcd for C16H14O3: C, 75.57; H, 5.55. Found: C, 75.25; H,
5.44.
4-(2-Phenylethyl)-5H-furan-2-one (15)
MCPBA (85.1 mg, 0.37 mmol) was added to a solution of 12 (103
mg, 0.33 mmol) in CHCl3 (6 mL) at 0 °C with stirring. The solution
was stirred for 30 min, and the reaction was quenched by adding sat.
aq Na2SO3 (5 mL) and sat. aq NaHCO3 (5 mL). The mixture was ex-
tracted with CHCl3 (2 × 20 mL) and the organic layer was washed
with 5% aq NaOH (10 mL) and dried over MgSO4. The product was
purified by silica gel column chromatography (hexane–EtOAc) to
give 134b (98.5 mg, 90%) as a colorless oil. A solution of g-sulfinyl
g-lactone 13 (98.5 mg, 0.3 mmol) in distilled pyridine (6 mL) was
heated at reflux for 12 h. Toluene (6 mL) was added and the mixture
was evaporated three times. The residue was purified by silica gel
column chromatography (hexane–EtOAc) to afford 15.
tert-Butyl 4-Chloro-2-(2-phenylethyl)-4-(p-tolylsulfinyl)pen-
tanoate (20)
tert-Butyl 4-phenylbutyrate (440 mg, 2 mmol) was added to a solu-
tion of LDA in anhydrous THF (12 mL) at –78 °C with stirring. The
mixture was stirred for 15 min, then a solution of 18 (100 mg, 0.5
mmol) in anhydrous THF (1 mL) was added. After stirring the mix-
ture for 5 min at –78 °C, MeI (354 mg, 2.5 mmol) was added and
the mixture was stirred for 5 min. The reaction was quenched by ad-
dition of sat. aq NH4Cl (30 mL) and the mixture was extracted with
CHCl3 (2 × 30 mL). The combined organic layers were dried
(MgSO4), filtered, and the filtrate was evaporated to give a residue,
which was purified by silica gel column chromatography (hexane–
EtOAc) to afford methylated adduct 20.4b
Synthesis 2011, No. 9, 1435–1441 © Thieme Stuttgart · New York

PAPER
Multisubstituted a,b-Unsaturated g-Lactones
1439
Yield: 208 mg (99%); colorless crystals.
IR (neat): 3101, 1748 (CO), 1615, 1423, 1320, 1168, 1056, 961, 845
cm–1.
5-Methyl-3-(2-phenylethyl)-5-(p-tolylsulfanyl)dihydrofuran-2-
one (22)
1H NMR (400 MHz): d = 1.65 (d, J = 6.6 Hz, 3 H), 5.42 (dq,
J = 1.3, 6.6 Hz, 1 H), 6.14 (d, J = 1.3 Hz, 1 H), 7.16 (dd, J = 3.8,
5.1 Hz, 1 H), 7.30 (dd, J = 1.0, 3.8 Hz, 1 H), 7.57 (dd, J = 1.0,
5.1 Hz, 1 H).
MS: m/z (%) = 180 (95) [M]+, 165 (13), 137 (88), 108 (100), 69
(12), 65 (10), 63 (10).
Trifluoroacetic acid (TFA, 0.56 mL, 7.5 mmol) was added to a so-
lution of 20 (208 mg, 0.5 mmol) in CHCl3 (10 mL) at r.t. The reac-
tion mixture was stirred for 1 d and the reaction was quenched by
addition of sat. aq NaHCO3 (20 mL). The mixture was extracted
with CHCl3 (3 × 20 mL) and the aqueous layer was separated. The
aqueous layer was acidified with aq 10% HCl and extracted with
CHCl3 (3 × 20 mL). The combined organic layers were evaporated
to give carboxylic acid 21 (172 mg, 91%) as colorless crystals.
HRMS: m/z [M]+ calcd for C9H8O2S: 180.0245; found: 180.0245.
2¢-Methyl-2¢H-[2,3¢]bifuranyl-5¢-one (25c)
Colorless oil.
A solution of NaI (0.67 g, 4.5 mmol) in MeCN (16.2 mL) was
stirred for 15 min at –40 °C then TFAA (0.62 mL, 4.5 mmol) was
added dropwise with stirring at –40 °C and the solution was stirred
for 15 min. Carboxylic acid 21 (172 mg, 0.45 mmol) in MeCN (1
mL) was added dropwise at –40 °C with stirring and the reaction
mixture was stirred for 10 min. The reaction was quenched by addi-
tion of sat. aq NaHCO3 (15 mL) followed by sat. aq Na2SO3 (15
mL). The mixture was extracted with CHCl3 (2 × 30 mL) and the or-
ganic layer was dried over MgSO4. The solvent was evaporated and
the residue was purified by silica gel column chromatography (hex-
ane–EtOAc) to give 224b (112 mg, 73%) as colorless crystals.
IR (neat): 3125, 1748 (CO), 1634, 1321, 1214, 1169, 1085, 1054,
1026, 987, 757 cm–1.
1H NMR (400 MHz): d = 1.63 (d, J = 6.7 Hz, 3 H), 5.36 (dq,
J = 1.4, 6.7 Hz, 1 H), 6.17 (d, J = 1.4 Hz, 1 H), 6.57 (dd, J = 1.8,
3.6 Hz, 1 H), 6.76 (d, J = 3.6 Hz, 1 H), 7.61 (d, J = 1.8 Hz, 1 H).
MS: m/z (%) = 164 (93) [M]+, 149 (27), 121 (100), 92 (66), 63 (21).
HRMS: m/z [M]+ calcd for C9H8O3: 164.0472; found: 164.0471.
3-Dibenzylamino-5-(p-tolylsulfanyl)dihydrofuran-2-one (27a)
A solution of N,N-dibenzylglycine tert-butyl ester (1.17 g, 3.75
mmol) in THF (5 mL) was added to a solution of LDA (3.75 mmol)
in anhydrous THF (18 mL) at –45 °C with stirring. The solution was
stirred for 15 min, then 18 (0.1 g, 0.5 mmol) was added. The solu-
tion was stirred for 1 h at –45 °C, and the reaction was quenched by
adding sat. aq NH4Cl (20 mL). The mixture was extracted with
CHCl3 (2 × 20 mL) and the organic layer was washed with sat. aq
NH4Cl (2 × 20 mL). The product was purified by silica gel column
chromatography (hexane–EtOAc) to afford the adduct (0.189 g,
74%) as colorless crystals.
5-Methyl-3-(2-phenethyl)-5H-furan-2-one (23)
MCPBA (80.5 mg, 0.35 mmol) was added to a solution of 22 (112
mg, 0.32 mmol) in CHCl3 (4 mL) at 0 °C with stirring. The solution
was stirred for 30 min, and the reaction was quenched by addition
of sat. aq Na2SO3 (3 mL) and sat. aq NaHCO3 (3 mL). The mixture
was extracted with CHCl3 (3 × 20 mL) and the organic layer was
washed with 5% aq NaOH (5 mL) and dried over MgSO4. The prod-
uct was purified by silica gel column chromatography (hexane–
EtOAc) to give g-sulfinyl g-lactone (113 mg, 99%) as colorless
crystals.
A solution of NaI (0.277 g, 1.85 mmol) in MeCN (6.7 mL) was
stirred for 15 min at –40 °C, TFAA (0.257 mL, 1.85 mmol) was
added dropwise with stirring at –40 °C and the solution was stirred
for 15 min. The adduct (0.189 g, 0.37 mmol) in MeCN (3 mL) was
added dropwise to the solution of NaI and TFAA at –40 °C drop-
wise with stirring and the reaction mixture was stirred for 10 min.
The reaction was quenched by addition of sat. aq NaHCO3 (5 mL)
followed by sat. aq Na2SO3 (5 mL). The mixture was extracted with
CHCl3 (2 × 10 mL), the organic layer was dried over MgSO4, and
the solvent was evaporated. The residue was purified by silica gel
column chromatography (hexane–EtOAc) to give 27a7 (49.8 mg,
33%).
The g-sulfinyl g-lactone (113 mg, 0.32 mmol) was heated at reflux
in distilled pyridine (6 mL) for 12 h. To the solution was added tol-
uene (6 mL) and the mixture was evaporated three times. The resi-
due was purified by silica gel column chromatography (hexane–
EtOAc) to afford 23.
Yield: 38.2 mg (59%); colorless oil.
IR (neat): 2932, 1748 (CO), 1497, 1455, 1320, 1119, 1095, 1082,
1029, 1013, 751, 701 cm–1.
1H NMR (400 MHz): d = 1.35 (d, J = 7.0 Hz, 3 H), 2.54–2.66 (m,
2 H), 2.83–2.93 (m, 2 H), 4.89–4.99 (m, 1 H), 6.83–6.88 (m, 1 H),
7.12–7.23 (m, 3 H), 7.24–7.32 (m, 2 H).
MS: m/z (%) = 202 (39) [M]+, 173 (9), 157 (25), 65 (12).
3-Dibenzylamino-5H-furan-2-one (28a)
MCPBA (31.1 mg, 0.135 mmol) was added to a solution of 27a
(49.8 mg, 0.123 mmol) in CHCl3 (4 mL) at 0 °C with stirring. The
solution was stirred for 30 min, and the reaction was quenched by
addition of sat. aq Na2SO3 (3 mL) and sat. aq NaHCO3 (3 mL). The
mixture was extracted with CHCl3 (3 × 10 mL), and the organic lay-
er was washed with 5% aq NaOH (6 mL) and dried over MgSO4.
The product was purified by silica gel column chromatography
(hexane–EtOAc) to give the g-sulfinyl g-lactone (36.6 mg, 71%).
The g-sulfinyl g-lactone (36.6 mg, 0.087 mmol) in distilled pyridine
(6 mL) was heated at reflux for 12 h, then toluene (6 mL) was added
and the mixture was evaporated three times. The residue was puri-
fied by silica gel column chromatography (hexane–EtOAc) to af-
ford 28a.
HRMS: m/z [M]+ calcd for C13H14O2: 202.0995; found: 202.0996.
5-Allyl-3-(2-phenylethyl)-5H-furan-2-one (25a)
Colorless oil.
IR (neat): 2924, 1752 (CO), 1497, 1455, 1335, 1087, 1060, 1032,
997, 924, 749, 701 cm–1.
1H NMR (400 MHz): d = 2.28–2.51 (m, 2 H), 2.56–2.72 (m, 2 H),
2.83–2.94 (m, 2 H), 4.83–4.94 (m, 1 H), 5.07–5.13 (m, 1 H), 5.14–
5.17 (m, 1 H), 5.59–5.76 (m, 1 H), 6.84–6.90 (m, 1 H), 7.13–7.24
(m, 3 H), 7.26–7.34 (m, 2 H).
MS: m/z (%) = 228 (36) [M]+, 187 (20), 169 (8), 141 (9), 129 (8), 65
(8).
HRMS: m/z [M]+ calcd for C15H16O2: 228.1150; found: 228.1150.
Yield: 17 mg (70%); colorless oil.
IR (neat): 3030, 1748 (CO), 1634, 1495, 1455, 1351, 1120, 1079,
1057, 1017, 773, 747, 699 cm–1.
1H NMR (500 MHz): d = 4.49 (s, 4 H), 4.68 (d, J = 2.3 Hz, 2 H),
5.71 (t, J = 2.3 Hz, 1 H), 7.18–7.37 (m, 10 H).
5-Methyl-4-thiophen-2-yl-5H-furan-2-one (25b)
Colorless oil.
Synthesis 2011, No. 9, 1435–1441 © Thieme Stuttgart · New York

1440
T. Katae et al.
PAPER
MS: m/z (%) = 279 (39) [M]+, 188 (100), 91 (88), 65 (13).
HRMS: m/z [M]+ calcd for C18H17NO2: 279.1260; found: 279.1261.
1H NMR (500 MHz): d = 2.23 (s, 2.25 H), 2.32 (s, 0.75 H), 3.40 (d,
J = 13.9 Hz, 1.5 H), 3.53 (dd, J = 9.8, 11.2 Hz, 0.75 H), 3.69–3.83
(m, 2 H), 3.96 (d, J = 13.7 Hz, 0.5 H), 4.04 (d, J = 11.2 Hz, 0.75 H),
4.17 (dd, J = 7.6, 12 Hz, 0.25 H), 4.27 (d, J = 12 Hz, 0.25 H), 5.46
(d, J = 9.8 Hz, 0.75 H), 5.76 (d, J = 3.3 Hz, 0.25 H), 5.87 (d,
J = 7.6 Hz, 0.25 H), 6.17–6.22 (m, 0.75 H), 6.33 (dd, J = 1.9,
3.3 Hz, 0.25 H), 6.39 (dd, J = 1.9, 3.2 Hz, 0.75 H), 7.06–7.44 (m,
15 H).
3-Dibenzylamino-4-(2-phenylethyl)-5-(p-tolylsulfanyl)dihydro-
furan-2-one (27b)
Colorless oil.
IR (neat): 3028, 1771 (CO), 1494, 1455, 1216, 1139, 960, 753, 699
cm–1.
1H NMR (500 MHz): d = 1.67–1.9 (m, 2 H), 2.20 (s, 3 H), 2.28–
2.41 (m, 1 H), 2.45–2.68 (m, 2 H), 3.44–3.59 (m, 3 H), 3.8 (d,
J = 13.6 Hz, 2 H), 5.11 (d, J = 9.2 Hz, 1 H), 7.02–7.12 (m, 4 H),
7.17–7.40 (m, 15 H).
MS: m/z (%) = 507 (10) [M]+, 356 (17), 340 (100), 91 (81).
HRMS: m/z [M]+ calcd for C33H33NO2S: 507.2248; found:
MS: m/z (%) = 469 (8) [M]+, 302 (39), 216 (68), 91 (100).
HRMS: m/z [M]+ calcd for C29H27NO3S: 469.1714; found:
469.1716.
4¢-Dibenzylamino-2¢H-[2,3¢]bifuranyl-5¢-one (28d)
Colorless oil.
IR (neat): 3029, 1748 (CO), 1638, 1494, 1454, 1350, 1090, 1079,
1067, 1042 cm–1.
507.2264.
1H NMR (500 MHz): d = 4.35 (s, 4 H), 4.98 (s, 2 H), 6.41–6.46 (m,
1 H), 6.48–6.52 (dd, J = 1.8, 3.4 Hz, 1 H), 7.20–7.34 (m, 10 H),
7.45–7.5 (m, 1 H).
MS: m/z (%) = 345 (58) [M]+, 254 (72), 210 (15), 107 (13), 91
(100), 65 (13).
3-Dibenzylamino-4-(2-phenylethyl)-5H-furan-2-one (28b)
Colorless oil.
IR (neat): 3028, 1749 (CO), 1495, 1454, 1128, 1110, 1076, 1029,
750, 700 cm–1.
1H NMR (500 MHz): d = 2.26–2.46 (m, 4 H), 4.20 (s, 4 H), 4.35 (s,
2 H), 6.9–7.0 (m, 2 H), 7.14–7.36 (m, 13 H).
HRMS: m/z [M]+ calcd for C22H19NO3: 345.1368; found: 345.1371.
MS: m/z (%) = 383 (4) [M]+, 292 (88), 91 (100).
Acknowledgment
HRMS: m/z [M]+ calcd for C26H25NO2: 383.1878; found: 383.1871.
This work was supported by a Grant-in-Aid for Scientific Research
No. 19590018 and 22590021 from the Ministry of Education, Cul-
ture, Sports, Science and Technology, Japan, and by a TUS Grant
for Research Promotion from Tokyo University of Science, which
are gratefully acknowledged.
3-Dibenzylamino-4-thiophen-2-yl-5-(p-tolylsulfanyl)dihydrofu-
ran-2-one (27c)
Colorless oil (ca. 7:1 mixture of two diastereomers).
IR (neat): 3028, 1779 (CO), 1494, 1455, 1215, 1135, 959, 815, 751,
698 cm–1.
1H NMR (500 MHz): d = 2.22 (s, 2.62 H), 2.32 (s, 0.38 H), 3.47 (d,
J = 13.8 Hz, 1.75 H), 3.67 (dd, J = 9.8, 11.3 Hz, 0.87 H), 3.77 (d,
J = 13.8 Hz, 1.75 H), 3.85 (d, J = 13.8 Hz, 0.25 H), 3.91 (d,
J = 11.3 Hz, 0.87 H), 3.99 (d, J = 13.8 Hz, 0.25 H), 4.25–4.3 (m,
0.25 H), 5.34 (d, J = 9.8 Hz, 0.87 H), 5.81–5.85 (m, 0.13 H), 6.40–
6.44 (m, 0.13 H), 6.68–6.73 (m, 0.87 H), 6.93 (dd, J = 3.6, 5.1 Hz,
0.13 H), 6.97 (dd, J = 3.6, 5.1 Hz, 0.87 H), 7.06–7.32 (m, 13.26 H),
7.38–7.46 (m, 1.75 H).
References
(1) For some selected papers concerning the isolation and
structure determination of the natural products with a g-
butenolide as the skeletal structure, see: (a) Missakian, M.
G.; Burreson, B. J.; Scheuer, P. J. Tetrahedron 1975, 31,
2513. (b) Williams, D.; Andersen, R. J.; Duyne, G. D. V.;
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MS: m/z (%) = 485 (9) [M]+, 318 (52), 232 (62), 208 (15), 91 (100).
HRMS: m/z [M]+ calcd for C29H27NO2S2: 485.1484; found:
485.1485.
3-Dibenzylamino-4-thiophen-2-yl-5H-furan-2-one (28c)
Colorless oil.
IR (neat): 3029, 1748 (CO), 1634, 1495, 1455, 1427, 1350, 1122,
1067, 1043, 751, 699 cm–1.
1H NMR (500 MHz): d = 4.27 (s, 4 H), 4.98 (s, 2 H), 6.97 (dd,
J = 1.1, 3.7 Hz, 1 H), 7.06 (dd, J = 3.7, 5.1 Hz, 1 H), 7.19–7.37 (m,
10 H), 7.52 (dd, J = 1.1, 5.1 Hz, 1 H).
MS: m/z (%) = 361 (54) [M]+, 270 (100), 226 (27), 91 (95).
HRMS: m/z [M]+ calcd for C22H19NO2S: 361.1143; found:
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butenolides, see: (a) Hollingworth, G. J.; Richecoeur, A. M.
E.; Sweeney, J. J. Chem. Soc., Perkin Trans. 1 1996, 2833.
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(d) Mallinger, A.; Gall, T. L.; Mioskowski, C. Synlett 2008,
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Narasimhulu, G.; Reddy, N. S.; Reddy, P. J. Tetrahedron
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2010, 66, 187. (i) Tang, B.; Bray, C. D.; Pattenden, G.;
Rogers, J. Tetrahedron 2010, 66, 2492.
4¢-Dibenzylamino-2¢-(p-tolylsulfanyl)-3¢,4¢-dihydro-2¢H-
[2,3¢]bifuranyl-5¢-one (27d)
Colorless oil (ca. 3:1 mixture of two diastereomers).
IR (neat): 3028, 1779 (CO), 1494, 1455, 1211, 1135, 1012, 960,
813, 741, 699 cm–1.
Synthesis 2011, No. 9, 1435–1441 © Thieme Stuttgart · New York

PAPER
(3) (a) Satoh, T.; Sugiyama, S.; Ota, H. Tetrahedron Lett. 2002,
43, 3033. (b) Satoh, T.; Sugiyama, S.; Kamide, Y.; Ota, H.
Tetrahedron 2003, 59, 4327. (c) Satoh, T.; Kamide, Y.;
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2006, 47, 8771. (b) Shimizu, H.; Fukuda, S.; Sugiyama, S.;
Satoh, T. Synthesis 2009, 1323.
Multisubstituted a,b-Unsaturated g-Lactones
1441
(6) Yamashita, H.; Satoh, T. Tetrahedron 2009, 65, 613.
(7) Kido, M.; Sugiyama, S.; Satoh, T. Tetrahedron: Asymmetry
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Synthesis 2011, No. 9, 1435–1441 © Thieme Stuttgart · New York