A study of the conjugate addition of thionucleophiles to 2(5H)-furanones

Article abstract of DOI:10.1002/ejoc.200300693

Several new 4-thio-4,5-dihydro-2(3H)-furanones were prepared by the conjugate addition reactions of different thioacids, dithioacids, xanthates and dithiocarbamates to 2(5H)-furanones. When 5-methyl-2(5H)-furanone was used as the electrophilic substrate, the reaction was diastereoselective affording exclusively the cis-α,β-disubstituted butanolides. Some adducts were selectively hydrolysed to deliver a free thiol functionality. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200300693

FULL PAPER
A Study of the Conjugate Addition of Thionucleophiles to 2(5H)-Furanones
[a]
[a]
[a]
[a]
´
Felix Busque, Pedro de March,* Marta Figueredo, Josep Font, and
[a]
´
¨
Lluısa Gonzalez
Keywords: Lactones / Michael addition / Sulfur / Nucleophiles / Furanones
Several new 4-thio-4,5-dihydro-2(3H)-furanones were pre-
pared by the conjugate addition reactions of different thio-
acids, dithioacids, xanthates and dithiocarbamates to 2(5H)-
furanones. When 5-methyl-2(5H)-furanone was used as the
electrophilic substrate, the reaction was diastereoselective
affording exclusively the cis-α,β-disubstituted butanolides.
Some adducts were selectively hydrolysed to deliver a free
thiol functionality.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
Butenolides and butanolides are ubiquitous in nature as
structural subunits in a wide variety of natural products,
many of which are bioactive.[1] There are also a wide variety
of pharmacologically active non-natural products bearing
these heterocycles as the active site.[2] Furthermore, these
lactones have been extensively used as building blocks in
synthesis.[3] On the other hand, the conjugate addition of
nucleophiles to α,β-unsaturated carbonyl groups is a very
versatile synthetic reaction that successfully yields new
carbonϪcarbon or carbonϪheteroatom bonds.[4] Conse-
quently, it is not surprising that α,β-unsaturated butyrolac-
tones have been frequently used as Michael acceptors, and
other butyrolactones as Michael donors. In particular, the
strategy of a sequential Michael addition of different nu-
cleophiles to an α,β-butenolide, followed by trapping of the
resulting lactone enolate with various electrophiles, has
been widely employed in the synthesis of both racemic and
non-racemic compounds (Scheme 1). Most of these ex-
amples involve the use of a carbanion as the nucleophile[5]
and a proton or an alkyl halide as the electrophile. This
tandem addition has been extensively utilized for the prep-
aration of a large number of lignans.[5a,5eϪ5g,5o,5r,5tϪ5w]
Nevertheless, the number of cases dealing with nitrogen[5n,6]
or oxygen[5d,5j,5n,7] nucleophiles is very scarce and there is
only one example using a phosphorous[8] or a silicon[9] ion.
The nucleophilic addition of the thiol group has a promi-
nent role in several biological reactions. To the best of our
knowledge, the first example of the conjugate addition of a
sulfur nucleophile to an α,β-unsaturated butyrolactone was
reported by Fuchs[10] in the late 1960s. This author studied
Scheme 1
the addition of thioacetic acid to 2(5H)-furanone (1) and 5-
methyl-2(5H)-furanone, (2; Scheme 1). While the latter re-
action afforded a 90% yield of the expected Michael ad-
ducts, the former led to a mixture of 4- and 3-acetylthio-
substituted furanones, along with an unidentified com-
pound. The other described examples of sulfur nucleophile
additions to α,β-butenolides deal with aliphatic or aromatic
thiols.[5n,11] Considering these precedents, we decided to in-
vestigate the conjugate addition of various sulfur nucleo-
philes derived from carboxylic and carbonic acids to the
α,β-unsaturated lactones 1 and 2 (Scheme 2).
The use of such thionucleophiles could provide the pos-
sibility of selective hydrolysis of the sulfur function to de-
liver a free thiol functionality at the β-position of the lac-
tone. Herein, we report the successful isolation of several
new 4,5-dihydro-2(3H)-furanones bearing a sulfur atom at
the 4-position.
[a]
´
`
Departament de Quımica, Universitat Autonoma de Barcelona,
08193 Bellaterra, Spain
Fax: (internat.) ϩ34-935811265
E-mail: pere.demarch@uab.es
1492
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200300693
Eur. J. Org. Chem. 2004, 1492Ϫ1499

Conjugate Addition of Thionucleophiles to 2(5H)-Furanones
FULL PAPER
Scheme 2
Results and Discussion
The nucleophiles selected for this study included achiral
and enantiopure thioacids, dithioacids, xanthates, and dithio-
carbamic acids (Scheme 3). Thioacetic acid (3) and thio-
benzoic acid (4) are commercially available, and enantio-
pure thioacid 5 has already been described by our group.[12]
Dithioacids 6 and 7 were synthesized following previously
described procedures,[13] while salts 8 and 9 were prepared
in situ by reaction of the Grignard reagent precursors with
carbon disulfide.[14] The unknown salt 10 was obtained by
reaction of the imine derived from camphor and aniline[15]
Scheme 3
with LDA and carbon disulfide and it was also allowed to gate additions to α,β-butenolides afforded exclusively the
react in situ due to its instability. Ethyl xanthate (11),[16] trans-isomers.[5a,5e,5g,5h,5k,5oϪ5r]
menthyl xanthate (12),[17] and dithiocarbamate salt 13[18]
The reactions between the enantiopure thioacid 5 and the
were prepared following literature methods. Table 1 sum- lactones 1 and 2 furnished the new solid compounds 18 and
marises the results of the reactions between these nucleo- 19 in 92% and 72% yield, respectively (Table 1, Entries 5
philes and lactones 1 and 2.
and 6). Unfortunately, in both cases a roughly 1:1 mixture
The initial reactions, performed with thioacids 3 and 4 of two diastereoisomers was formed, product 19 consisting
and lactone 1, were run in dichloromethane solution at only of both cis-disubstituted stereoisomers. Repeated crys-
room temperature in the presence of a catalytic amount of tallization from ethyl acetate/hexane afforded enriched frac-
triethylamine (TEA). These experiments furnished excellent tions (ca. 19:1) of each stereoisomer of 18, albeit in small
yields of the expected adducts 14,[10] as a colourless oil, and quantities. In the case of 19 all our efforts to obtain a pure
15, isolated as a white solid (Scheme 4; Table 1, Entries 1 stereoisomer were unsuccessful.
and 2). All the proton absorptions of compound 15 could
Next, we focused our attention on the dithioacids. The
be assigned by NOE experiments, which allowed us to reactions of nucleophiles 6 and 7 with butenolide 1 afforded
identify the signals of all the other products by comparison. 80% and 87% yield of the new compounds 20 and 21 as
Attempts to trap the enolate formed by β-addition of the yellow solids (Scheme 5; Table 1, Entries 7 and 8), while the
thiocarboxylates to 1 with methyl iodide were unsuccessful, addition of salts 8 and 9 to lactone 1 in THF solution at 0
but the α-methyl derivatives could be prepared by conjugate °C led to the isolation of the new crystalline compounds 22
addition of 3 and 4 to butenolide 2, although more rigorous and 23 in 64% and 50% yield, respectively (Table 1, Entries
experimental conditions were required, namely 50 °C with- 9 and 10). Due to its instability, salt 10 was allowed to react
out solvent (Table 1, Entries 3 and 4). Both compounds 16, in situ with the butenolide 1 in THF at room temperature
an oil, and 17, a solid, were isolated in 95% and 90% yield, in the presence of acetic acid, providing compound 24, a
respectively, as a unique diastereoisomer. Their cis relative yellow solid, in 57% yield, once again without any dia-
stereochemistry was secured by an NOE experiment on 17: stereoselectivity (Table 1, Entry 11). The yields of the reac-
presaturation of the signal at δ ϭ 3.04 ppm (3-H) caused a tions with dithioacids are somewhat lower than those pre-
6.5% NOE on the methyl group and an 8% NOE on 4-H viously reported for the reactions with thioacids.
(δ ϭ 4.59 ppm), while irradiation of the methyl group had
When the butenolide 1 was treated with the xanthate 11
no effect on 4-H. This completely diastereoselective pro- in chloroform at room temperature in the presence of two
tonation process discloses a new access to cis α,β-disubsti- equivalents of acetic acid, compound 25 was isolated as an
tuted butanolides, since most previous syntheses by conju- oil in 35% yield (Scheme 6; Table 1, Entry 12). The modest
Eur. J. Org. Chem. 2004, 1492Ϫ1499
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1493

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F. Busque, P. de March, M. Figueredo, J. Font, L. Gonzalez
FULL PAPER
Table 1. Conjugate addition reactions of different thioacids, dithioacids, xanthates, and dithiocarbamates to 2(5H)-furanones
Entry
Electrophile
Nucleophile
Conditions
Product (yield, %)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1
1
2
2
1
2
1
1
1
1
1
1
1
1
3
4
CH2Cl2, room temp., TEA
CH2Cl2, room temp., TEA
neat, 50 °C, TEA
14 (91)
15 (90)
16 (95)
17 (90)
18 (92)
19 (72)
20 (80)
21 (87)
22 (64)
23 (50)
24 (57)
25 (35)
26 (18)
29 (50)
3
4
neat, 50 °C, TEA
5
CH2Cl2, room temp., TEA
neat, 50 °C, TEA
5
6
CH2Cl2, room temp., TEA
CH2Cl2, room temp., TEA
THF, 0 °C
7
8
9
THF, 0 °C
10
11
12
13
THF, room temp., AcOH
CHCl3, room temp., AcOH
CHCl3, room temp., AcOH
CHCl3, room temp., AcOH
Scheme 5
Scheme 4
yield of this addition reaction was attributed to the low sta-
bility of the starting xanthate. From the reaction of 1 with
the enantiopure xanthate 12, the conjugate addition prod-
uct 26 was isolated in 18% yield (Table 1, Entry 13), once
again as a roughly 1:1 diastereoisomeric mixture, along with
several decomposition by-products such as menthol, the
thioether 27[19] and the disulfide 28.[20]
In view of the lack of diastereoselectivity observed for all
the above chiral sulfur donors, a last attempt was carried Scheme 6
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Eur. J. Org. Chem. 2004, 1492Ϫ1499

Conjugate Addition of Thionucleophiles to 2(5H)-Furanones
FULL PAPER
out using the known enantiopure dithiocarbamate 13[18] as
the nucleophile. The addition reaction of 13 to 1 did not
proceed in the absence of a proton source and various trials
in different solvents furnished thiourea as the only isolable
product. However, when the reaction was performed in the
presence of one equivalent of acetic acid in chloroform
5985B instrument at 70 eV; only peaks with intensities higher than
20% are reported, unless they belong to the molecular ions or to
other significant fragments. The butenolide 1 is commercially avail-
able or can be easily prepared following the procedure described by
Price.[21] Lactone 2 was obtained by isomerization of 4,5-dihydro-3-
methylene-2(3H)-furanone using RhCl3·3 H2O.[22]
solution at room temperature, a roughly 1:1 diastereoiso- 4-Acetylthio-4,5-dihydro-2(3H)-furanone (14): A solution of 1 (765
µL, 10.8 mmol) in CH2Cl2 (9 mL) was treated with thioacetic acid
(767 µL, 10.8 mmol) and two drops of a dilute solution of triethyl-
amine in CH2Cl2. The mixture was stirred at room temperature for
21 h, washed with water (3 ϫ 5 mL) and concentrated to yield an
oil (1.7 g), which was purified by flash chromatography (hexane/
ethyl acetate, 2:1) to afford 1.60 g (9.9 mmol, 91% yield) of 14. An
analytical sample was obtained by distillation, b.p. 124Ϫ126 °C/
meric mixture of the new compound 29 was isolated as a
solid in 50% yield (Table 1, Entry 14). Thiourea and the
dimeric compounds 27 and 28 were also identified as by-
products. All attempts to separate the diastereoisomers of
29 failed.
Having prepared thioesters 14 and 16 with excellent
yields, we explored the selective hydrolysis of this function.
Treatment of 14 with methanol, in either an acidic or basic
medium, produced the hydrolysis of both the thioester and
0.07 Torr. IR (film): ν˜ ϭ 2966, 1785, 1693, 1166, 1131, 1018 cmϪ1
.
1H NMR (400 MHz): δ ϭ 4.67 (dd, J5,5 ϭ 9.8, J5,4 ϭ 6.7 Hz, 1 H,
5-H), 4.22 (m, 1 H, 4-H), 4.15 (dd, J5,5 ϭ 9.8, J5,4 ϭ 5.5 Hz, 1 H,
the lactone functional groups. Reaction of 14 with p-tol- 5-H), 2.95 (dd, J3,3 ϭ 17.7, J3,4 ϭ 8.5 Hz, 1 H, 3-H), 2.47 (dd,
J3,3 ϭ 17.7, J3,4 ϭ 6.4 Hz, 1 H, 3-H), 2.34 (s, 3 H, CH3) ppm. 13C
NMR (62.5 MHz): δ ϭ 194.1 (COS), 174.3 (CO), 72.7 (C-5), 37.2
(C-4), 33.7 (C-3), 30.2 (CH3) ppm. MS: m/z (%) ϭ 160 (1) [Mϩ],
43 (100). C6H8O3S (160.19): calcd. C 44.99, H 5.03, S 20.02; found
C 44.91, H 5.12, S 19.94.
uidine[10b] gave the known thiol 30[10b] in 78% yield, while
16 afforded the new compound 31 in 75% yield (Scheme 7).
4-Benzoylthio-4,5-dihydro-2(3H)-furanone (15): A solution of 1 (765
µL, 10.8 mmol) in CH2Cl2 (9 mL) was treated with thiobenzoic
acid (1.2 mL, 10.8 mmol) and two drops of a dilute solution of
triethylamine in CH2Cl2. The mixture was stirred at room tempera-
ture for 21 h, washed with water (3 ϫ 5 mL) and concentrated to
yield an oil (2.6 g), which was purified by flash chromatography
(hexane/ethyl acetate, 2:1) to afford 2.20 g (9.8 mmol, 90% yield)
of 15 as a solid, m.p. 67Ϫ69 °C (ethyl acetate/pentane). IR (KBr):
Scheme 7
1
ν˜ ϭ 2994, 2931, 1778, 1658, 1215, 1166, 913, 688 cmϪ1. H NMR
(400 MHz): δ ϭ 7.88 (d, J ϭ 7.3 Hz, 2 H, 2 Ph), 7.60 (t, J ϭ 7.3 Hz,
1 H, Ph), 7.45 (t, J ϭ 7.3 Hz, 2 H, 2 Ph), 4.77 (dd, J5,5 ϭ 9.8,
J5,4 ϭ 6.7 Hz, 1 H, 5-H), 4.40 (m, 1 H, 4-H), 4.26 (dd, J5,5 ϭ 9.8,
J5,4 ϭ 5.2 Hz, 1 H, 5-H), 3.05 (dd, J3,3 ϭ 18.0, J3,4 ϭ 8.8 Hz, 1 H,
3-H), 2.59 (dd, J3,3 ϭ 18.0, J3,4 ϭ 6.4 Hz, 1 H, 3-H) ppm. 13C
NMR (62.5 MHz): δ ϭ 190.1 (COS), 174.3 (CO), 135.8/133.8/
128.6/127.0 (Ph), 72.9 (C-5), 37.2 (C-4), 33.7 (C-3) ppm. MS: m/z
(%) ϭ 222 (1) [Mϩ], 105 (100), 77 (35). C11H10O3S (222.26): calcd.
C 59.44, H 4.53, S 14.43; found C 59.49, H 4.51, S 14.36.
Conclusion
In summary, several new 4-thio-4,5-dihydro-2(3H)-fu-
ranones derived from the nucleophilic addition of different
sulfur functionalities to α,β-butenolide 1 have been pre-
pared. The reactions with thioacids proceed with excellent
yields and some thioesters have been selectively hydrolysed
to the corresponding thiols. In general, dithioacids, xan-
thates and dithiocarbamates give lower yields and less-
stable addition products. The addition of thioacids to the
α,β-unsaturated lactone 2 provides a new access to cis-α,β-
disubstituted butanolides. None of the chiral analogues of
the sulfur nucleophiles under study provided significant dia-
stereoselectivity in the formation of the new stereogenic
centre at C-4.
cis-4-Acetylthio-3-methyl-4,5-dihydro-2(3H)-furanone (16): The but-
enolide 2 (200 mg, 2.04 mmol) was treated with thioacetic acid (217
µL, 3.06 mmol) and two drops of a dilute solution of triethylamine
in CH2Cl2. The mixture was stirred at 50 °C for 3 days, dissolved
in CH2Cl2 (4 mL), washed with water (4 mL) and concentrated to
yield an oil (420 mg), which was purified by flash chromatography
(hexane/ethyl acetate, 3:1) to afford 368 mg (2.12 mmol, 95% yield)
of 16. An analytical sample was obtained by distillation, b.p.
99Ϫ101 °C/0.01 Torr. IR (film): ν˜ ϭ 2980, 2924, 2860, 1778, 1693,
1166, 1131, 1039 cmϪ1. 1H NMR (250 MHz): δ ϭ 4.55 (dd, J5,5
10.2, J5,4 ϭ 5.8 Hz, 1 H, 5-H), 4.36 (m, 1 H, 4-H), 4.15 (dd, J5,5
ϭ
Experimental Section
ϭ
10.2, J5,4 ϭ 3.3 Hz, 1 H, 5-H), 2.93 (quint, J3,Me ϭ J3,4 ϭ 7.3 Hz,
1 H, 3-H), 2.34 (s, 3 H, CH3CO), 1.18 (d, JMe,3 ϭ 7.3 Hz, 3 H,
CH3) ppm. 13C NMR (62.5 MHz): δ ϭ 193.9 (COS), 177.2 (COO),
71.7 (C-5), 44.2 (C-4), 37.2 (C-3), 30.7 (CH3CO), 11.3 (CH3) ppm.
MS: m/z (%) ϭ 174 (0.4) [Mϩ], 132 (7), 114 (9), 43 (100). C7H10O3S
(174.22): calcd. C 48.26; H 5.78, S 18.41; found C 48.01, H 5.79,
S 18.20.
General Remarks: The reaction mixtures were stirred magnetically.
The organic extracts were dried with anhydrous sodium sulfate.
Reaction solutions were concentrated using a rotary evaporator at
5Ϫ10 Torr. Flash chromatography was performed using Merck
silica gel (230Ϫ400 mesh). Infrared spectra were recorded with a
Nicolet 5 ZDX spectrophotometer. 1H and 13C NMR spectra were
recorded with Bruker AC-250-WB or AM-400-WB instruments at
250 or 400 MHz and 62.5 or 100 MHz, respectively, in CDCl3 solu-
cis-4-Benzoylthio-3-methyl-4,5-dihydro-2(3H)-furanone (17): The
tions. Mass spectra were performed with a HewlettϪPackard butenolide 2 (200 mg, 2.04 mmol) was treated with thiobenzoic acid
Eur. J. Org. Chem. 2004, 1492Ϫ1499
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F. Busque, P. de March, M. Figueredo, J. Font, L. Gonzalez
FULL PAPER
(330 µL, 3.06 mmol) and two drops of a dilute solution of triethyl-
2920, 2868, 1785, 1665, 1159, 1082, 1018, 842 cmϪ1 1H NMR
.
amine in CH2Cl2. The mixture was stirred at 50 °C for 2 days, (250 MHz): δ ϭ 4.63 (dd, J5,5 ϭ 10.2, J5,4 ϭ 6.1 Hz) and 4.62 (dd,
dissolved in CH2Cl2 (4 mL), washed with water (4 mL) and concen-
trated to yield a solid material (530 mg), which was purified by
flash chromatography (hexane/diethyl ether, 1:1) to afford 432 mg
(1.83 mmol, 90% yield) of 17 as a solid, m.p. 54Ϫ55 °C (ethyl ace-
tate/hexane). IR (KBr): ν˜ ϭ 3140, 3026, 2994, 2868, 1764, 1679,
J
J
5,5 ϭ 10.2, J5,4 ϭ 6.1 Hz) (1 H, 5-H), 4.42 (m, 1 H, 4-H), 4.20 (dd,
5,5 ϭ 10.2, J5,4 ϭ 3.7 Hz) and 4.14 (dd, J5,5 ϭ 10.2, J5,4 ϭ 3.7 Hz)
(1 H, 5-H), 3.00 (quint, J3,Me ϭ J3,4 ϭ 7.3 Hz, 1 H, 3-H), 2.46Ϫ2.33
(m, 1 H, 6Ј-H), 2.03Ϫ1.86 (m, 2 H, 5Ј-H, 6Ј-H), 1.76Ϫ1.65 (m, 1
H, 5Ј-H), 1.25 (d, JMe,3 ϭ 7.3 Hz) and 1.24 (d, JMe,3 ϭ 7.3 Hz) (3
1208, 1173, 997, 899, 688 cmϪ1. 1H NMR (400 MHz): δ ϭ 7.92 (d, H, CH3), 1.10 (s, 3 H, CH3), 1.02 (s, 3 H, CH3), 0.94 (d, J ϭ 3.6 Hz,
J ϭ 7.3 Hz, 2 H, 2 Ph), 7.58 (t, J ϭ 7.3 Hz, 1 H, Ph), 7.44 (t, J ϭ 3 H, CH3) ppm. 13C NMR (62.5 MHz): δ ϭ 195.4 and 195.3
7.3 Hz, 2 H, 2 Ph), 4.66 (dd, J5,5 ϭ 9.8, J5,4 ϭ 5.5 Hz, 1 H, 5-H),
4.59 (m, 1 H, 4-H), 4.28 (dd, J5,5 ϭ 9.8, J5,4 ϭ 3.0 Hz, 1 H, 5-H),
(COS), 177.1 (C-3Ј), 176.9 (C-2), 95.8 and 95.6 (C-1Ј), 71.6 and
71.1 (C-5), 55.4 and 55.3 (C-7Ј), 54.7 and 54.6 (C-4Ј), 43.3 and 43.2
(C-4), 37.1 and 36.9 (C-3), 31.03 and 30.96 (C-5Ј), 28.6 (C-6Ј), 16.6
(CH3), 16.5 (CH3), 11.4 and 11.3 (CH3), 9.5 and 9.4 (CH3) ppm.
3.04 (quint, J3,Me ϭ J3,4 ϭ 7.3 Hz, 1 H, 3-H), 1.28 (d, JMe,3
ϭ
7.3 Hz, 3 H, CH3) ppm. 13C NMR (100 MHz): δ ϭ 190.0 (COS),
177.3 (COO), 136.1/134.0/128.7/127.3 (Ph), 72.0 (C-5), 44.3 (C-4), MS: m/z (%) ϭ 312 (3) [Mϩ], 125 (63), 97 (55), 83 (100), 67 (21),
37.5 (C-3), 11.5 (CH3) ppm. MS: m/z (%) ϭ 236 (1) [Mϩ], 105
(100), 77 (41). C12H12O3S (236.29): calcd. C 61.00, H 5.12, S 13.57;
found C 61.11, H 5.10, S 13.50.
55 (61), 43 (26), 41 (60). C15H20O5S (312.38): calcd. C 57.67, H
6.45, S 10.26; found C 57.68, H 6.49, S 10.36.
4-[(2-Amino-1-cyclopenten-1-yl)(thiocarbonyl)thio]-4,5-dihydro-
2(3H)-furanone (20): A solution of 1 (191 µL, 2.7 mmol) in CH2Cl2
(5 mL) was treated with dithioacid 6 (472 mg, 3.0 mmol) and two
drops of a dilute solution of triethylamine in CH2Cl2. The mixture
was stirred at room temperature for 2 days, then washed with water
(3 ϫ 5 mL) and concentrated to yield a solid residue (815 mg),
which was purified by flash chromatography (hexane/ethyl acetate,
3:1) to afford 521 mg (2.1 mmol, 80% yield) of 20 as a yellow solid,
(4RS)-{[(1S,4R)-4,7,7-Trimethyl-3-oxo-2-oxabicyclo[2.2.1]hept-1-
yl)carbonylthio}-4,5-dihydro-2(3H)-furanone (18a and 18b): A solu-
tion of 1 (198 µL, 2.8 mmol) in CH2Cl2 (6 mL) was treated with
thioacid 5 (600 mg, 2.8 mmol) and two drops of a dilute solution
of triethylamine in CH2Cl2. The mixture was stirred at room tem-
perature for 5 days, washed with water (6 mL) and concentrated to
yield a solid (1.8 g), which was purified by flash chromatography
(hexane/ethyl acetate, 2:1) to give 767 mg (2.6 mmol, 92% yield) of
a 1:1 mixture of diastereoisomers 18a and 18b as a solid. Pure
samples of each diastereoisomer were obtained by means of suc-
cessive crystallizations in ethyl acetate/hexane. 18a/18b: (less-
m.p. 100Ϫ101 °C (ethyl acetate/hexane). IR (KBr): ν˜
ϭ
3400Ϫ3000, 2959, 2889, 2824, 1778, 1609, 1468, 1278, 1173, 1018,
1
955, 793 cmϪ1. H NMR (250 MHz): δ ϭ 5.98 (br. s, 2 H, NH2),
4.77 (dd, J5,5 ϭ 9.5, J5,4 ϭ 7.3 Hz, 1 H, 5-H), 4.67 (m, 1 H, 4-H),
4.27 (dd, J5,5 ϭ 9.5, J5,4 ϭ 5.1 Hz, 1 H, 5-H), 3.03 (dd, J3,3 ϭ 18.3,
J3,4 ϭ 8.8 Hz, 1 H, 3-H), 2.71 (t, J ϭ 7.3 Hz, 2 H, 2 ϫ 3Ј-H/2 ϫ
5Ј-H), 2.61 (t, J ϭ 7.3 Hz, 2 H, 2 ϫ 3Ј-H/2 ϫ 5Ј-H), 2.55 (dd,
1
soluble diastereoisomer). M.p. 185Ϫ187 °C. H NMR (250 MHz):
δ ϭ 4.72 (dd, J5,5 ϭ 9.5, J5,4 ϭ 7.3 Hz, 1 H, 5-H), 4.20 (m, 2 H, 5-
H, 4-H), 3.00 (dd, J3,3 ϭ 18.3, J3,4 ϭ 8.8 Hz, 1 H, 3-H), 2.48 (dd,
J3,3 ϭ 18.3, J3,4 ϭ 6.6 Hz, 1 H, 3-H), 2.43Ϫ2.32 (m, 1 H, 6Ј-H),
2.01Ϫ1.82 (m, 2 H, 5Ј-H, 6Ј-H), 1.72Ϫ1.60 (m, 1 H, 5Ј-H), 1.06 (s,
3 H, CH3), 0.98 (s, 3 H, CH3), 0.89 (s, 3 H, CH3) ppm. 13C NMR
(62.5 MHz): δ ϭ 195.9 (COS), 177.1 (C-3Ј), 174.1 (C-2), 95.6 (C-
1Ј), 72.4 (C-5), 55.4 (C-7Ј), 54.8 (C-4Ј), 36.4 (C-4), 33.7 (C-3), 31.0
J3,3 ϭ 18.3, J3,4 ϭ 5.8 Hz, 1 H, 3-H), 1.83 (m, 2 H, 2 ϫ 4Ј-H) ppm.
13C NMR (62.5 MHz): δ ϭ 197.7 (CS), 175.5 (CO), 169.4 (C-2Ј),
118.1 (C-1Ј), 73.4 (C-5), 40.0 (C-4), 36.3/33.3/32.5 (C-3/C-3Ј/C-5Ј),
20.4 (C-4Ј) ppm. MS: m/z (%) ϭ 243 (8) [Mϩ], 159 (32), 126 (100).
C10H13NO2S2 (243.35): calcd. C 49.36, H 5.38, N 5.76, S 26.35;
found C 49.40, H 5.40, N 5.70, S 26.33.
(C-5Ј), 28.6 (C-6Ј), 16.6 (CH3), 16.3 (CH3), 9.5 (CH3) ppm. [α]2D0
ϭ
Ϫ89 (c ϭ 1.1, chloroform). 18a/18b: (more-soluble diastereoiso-
4-{[2-(N-Methylamino)-1-cyclopenten-1-yl](thiocarbonyl)thio}-4,5-
dihydro-2(3H)-furanone (21): A solution of 1 (82 µL, 1.2 mmol) in
CH2Cl2 (3 mL) was treated with dithioacid 7 (200 mg, 1.2 mmol)
and two drops of a dilute solution of triethylamine in CH2Cl2. The
mixture was stirred at room temperature for 7 h, washed with water
(3 ϫ 2 mL) and concentrated to yield a solid (369 mg), which was
purified by flash chromatography (hexane/ethyl acetate, 2:1) to af-
ford 260 mg (1.0 mmol, 87% yield) of 21 as a yellow solid, m.p.
122Ϫ124 °C (ethyl acetate/pentane). IR (KBr): ν˜ ϭ 2945, 2896,
mer). M.p. 154Ϫ155 °C. 1H NMR (250 MHz): δ ϭ 4.71 (dd, J5,5 ϭ
9.5, J5,4 ϭ 7.3 Hz, 1 H, 5-H), 4.23 (m, 1 H, 4-H), 4.13 (dd, J5,5
ϭ
9.5, J5,4 ϭ 5.8 Hz, 1 H, 5-H), 3.00 (dd, J3,3 ϭ 18.3, J3,4 ϭ 8.8 Hz,
1 H, 3-H), 2.51 (dd, J3,3 ϭ 18.3, J3,4 ϭ 6.6 Hz, 1 H, 3-H),
2.43Ϫ2.32 (m, 1 H, 6Ј-H), 2.01Ϫ1.82 (m, 2 H, 5Ј-H, 6Ј-H),
1.72Ϫ1.60 (m, 1 H, 5Ј-H), 1.06 (s, 3 H, CH3), 0.98 (s, 3 H, CH3),
0.89 (s, 3 H, CH3) ppm. 13C NMR (62.5 MHz): δ ϭ 195.9 (COS),
177.1 (C-3Ј), 174.1 (C-2), 95.6 (C-1Ј), 72.5 (C-5), 55.4 (C-7Ј), 54.8
(C-4Ј), 36.5 (C-4), 33.5 (C-3), 30.9 (C-5Ј), 28.6 (C-6Ј), 16.6 (CH3),
16.3 (CH3), 9.5 (CH3) ppm. [α]2D0 ϭ Ϫ22 (c ϭ 0.9, chloroform).
Mixture of 18a and 18b: IR (KBr): ν˜ ϭ 2973, 1785, 1764, 1665,
1187, 1018, 850 cmϪ1. MS: m/z (%) ϭ 298 (5) [Mϩ], 181 (21), 125
(77), 97 (53), 83 (100), 55 (33), 41 (27). C14H18O5S (298.35): calcd.
C 56.36, H 6.08, S 10.75; found C 56.17, H 6.09, S 10.78.
1778, 1609, 1489, 1343, 1278, 1159 cmϪ1 1H NMR (400 MHz):
.
δ ϭ 4.80 (dd, J5,5 ϭ 9.4, J5,4 ϭ 7.0 Hz, 1 H, 5-H), 4.72 (m, 1 H, 4-
H), 4.29 (dd, J5,5 ϭ 9.4, J5,4 ϭ 4.6 Hz, 1 H, 5-H), 3.07 (d, JMe,NH ϭ
3.7 Hz, 3 H, CH3), 3.04 (dd, J3,3 ϭ 18.3, J3,4 ϭ 8.5 Hz, 1 H, 3-H),
2.72 (t, J ϭ 7.9 Hz, 2 H, 2 ϫ 3Ј-H/2 ϫ 5Ј-H), 2.68 (t, J ϭ 7.9 Hz,
2 H, 2 ϫ 3Ј-H/2 ϫ 5Ј-H), 2.58 (dd, J3,3 ϭ 18.3, J3,4 ϭ 6.1 Hz, 1 H,
3-H), 1.87 (quint, J4Ј,5Ј ϭ J4Ј,3Ј ϭ 7.9 Hz, 2 H, 2 ϫ 4Ј-H) ppm. 13C
NMR (100 MHz): δ ϭ 190.7 (CS), 175.3 (CO), 172.2 (C-2Ј), 118.6
(C-1Ј), 73.5 (C-5), 39.7 (C-4), 33.4/33.2/32.7/31.4 (C-3/C-3Ј/C-5Ј/
CH3), 20.3 (C-4Ј) ppm. MS: m/z (%) ϭ 257 (20) [Mϩ], 242 (1), 173
(33), 171 (25), 140 (100). C11H15NO2S2 (257.37): calcd. C 51.33, H
5.87, N 5.44, S 24.92; found C 51.26, H 5.99, N 5.35, S 24.86.
cis-3-Methyl-4-{[(1S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]-
hept-1-yl]carbonylthio}-4,5-dihydro-2(3H)-furanone (19a and 19b):
A mixture of the butenolide 2 (345 mg, 3.5 mmol), the thioacid 5
(899 mg, 4.2 mmol) and two drops of a dilute solution of triethyl-
amine in CH2Cl2 was stirred at 50 °C for 6 days. The resultant
mixture was dissolved in CH2Cl2 (5 mL), washed with water (5 mL)
and concentrated to yield a solid residue (1.04 g), which was puri-
fied by flash chromatography (hexane/ethyl acetate, 2:1) to afford
4-Methyl(thiocarbonyl)thio-4,5-dihydro-2(3H)-furanone (22):
A
solution of carbon disulfide (123 mg, 1.62 mmol) was added to a
787 mg (2.5 mmol, 72% yield) of a 1:1 mixture of diastereoisomers solution of methylmagnesium chloride (0.81 mmol) in dry THF
19a and 19b as a solid, m.p. 150Ϫ151 °C. IR (KBr): ν˜ ϭ 2973, (2 mL) at 0 °C, and the mixture was warmed to room temperature.
1496
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 1492Ϫ1499

Conjugate Addition of Thionucleophiles to 2(5H)-Furanones
FULL PAPER
After 4 h at room temperature, the red solution was treated with
(dd, J3,3 ϭ 18.3, J3,4 ϭ 9.1 Hz, 1 H, 3-H), 2.95 (d, J4Ј,5Ј ϭ 3.1 Hz,
the butenolide 1 (68 mg, 0.81 mmol) and glacial acetic acid (46 µL, 1 H, 4Ј-H), 2.60 (dd, J3,3 ϭ 18.3, J3,4 ϭ 6.4 Hz) and 2.59 (dd, J3,3 ϭ
0.81 mmol). The mixture was stirred at room temperature for 16 h,
acidified with 1  HCl solution to pH 2 and extracted with diethyl
ether (3 ϫ 5 mL). The organic phases were combined and concen-
trated to yield an oil (150 mg), which was purified by flash chroma-
tography (hexane/ethyl acetate, 9:1) to afford 92 mg (0.52 mmol,
64% yield) of 22 as a solid, m.p. 30Ϫ31 °C (ethyl acetate/pentane).
IR (KBr): ν˜ ϭ 2987, 2924, 2865, 1778, 1370, 1194, 1166, 1025, 864
18.3, J3,4 ϭ 6.4 Hz) (1 H, 3-H), 1.95 (m, 1 H), 1.80Ϫ1.55 (m, 2 H),
1.50Ϫ1.30 (m, 2 H), 0.80 (s, 3 H, CH3), 0.78 (s, 3 H, CH3), 0.65 (s,
3 H, CH3) ppm. 13C NMR (100 MHz): δ ϭ 187.4 (CS), 175.5/174.5
(CO/C-2Ј), 136.6/128.9/127.9/126.8 (Ph), 126.1 (C-3Ј), 73.9 and
73.7 (C-5), 57.8 (C-1Ј), 54.2 (C-7Ј), 51.4 (C-4Ј), 39.7 and 39.6 (C-
4), 33.9 and 33.7 (C-3), 29.6 (C-6Ј), 25.8 (C-5Ј), 19.7 (CH3), 18.9
(CH3), 13.0 (CH3) ppm. MS: m/z (%) ϭ 387 (17) [Mϩ], 303 (28),
cmϪ1. 1H NMR (400 MHz): δ ϭ 4.75 (dd, J5,5 ϭ 9.8, J5,4 ϭ 7.0 Hz, 301 (59), 270 (100), 226 (22), 212 (20), 194 (41), 77 (47), 55 (24),
1 H, 5-H), 4.51 (m, 1 H, 4-H), 4.27 (dd, J5,5 ϭ 9.8, J5,4 ϭ 4.5 Hz, 45 (33), 41 (38). C21H25NO2S2 (387.56): calcd. C 65.08, H 6.50, N
1 H, 5-H), 3.09 (dd, J3,3 ϭ 18.3, J3,4 ϭ 9.2 Hz, 1 H, 3-H), 2.81 (s, 3.61, S 16.55; found C 65.10, H 6.49, N 3.65, S 16.50.
3 H, CH3), 2.55 (dd, J3,3 ϭ 18.3, J3,4 ϭ 5.5 Hz, 1 H, 3-H) ppm.
4-Ethoxy(thiocarbonyl)thio-4,5-dihydro-2(3H)-furanone (25):
A
13C NMR (100 MHz): δ ϭ 223.6 (CS), 174.2 (CO), 71.9 (C-5), 43.9
solution of the xanthate 11 (216 mg, 1.35 mmol) in CHCl3 (2 mL)
at room temperature was treated with the butenolide 1 (88 µL,
1.25 mmol) and glacial acetic acid (153 µL, 2.50 mmol). The mix-
ture was stirred at room temperature for 4 days, acidified with 10%
HCl solution to pH 2 and extracted with chloroform (3 ϫ 5 mL).
The organic phases were combined and concentrated to yield an
oil (167 mg), which was purified by flash chromatography (hexane/
ethyl acetate, 2:1) to afford 91 mg (0.44 mmol, 35% yield) of 25 as
an oil. IR (film): ν˜ ϭ 2987, 1785, 1229, 1166, 1053 cmϪ1. 1H NMR
(400 MHz): δ ϭ 4.75 (dd, J5,5 ϭ 9.8, J5,4 ϭ 7.0 Hz, 1 H, 5-H), 4.61
(q, J ϭ 7.3 Hz, 2 H, CH2), 4.41 (m, 1 H, 4-H), 4.30 (dd, J5,5 ϭ 9.8,
J5,4 ϭ 5.2 Hz, 1 H, 5-H), 3.03 (dd, J3,3 ϭ 18.3, J3,4 ϭ 9.2 Hz, 1 H,
3-H), 2.56 (dd, J3,3 ϭ 18.3, J3,4 ϭ 6.1 Hz, 1 H, 3-H), 1.40 (t, J ϭ
7.3 Hz, 3 H, CH3) ppm. 13C NMR (100 MHz): δ ϭ 211.4 (CS),
174.2 (CO), 72.5/70.6 (C-5/CH2), 42.6 (C-4), 33.2 (C-3), 13.6 (CH3)
ppm. MS: m/z (%) ϭ 206 (8) [Mϩ], 161 (1), 122 (45), 85 (100), 84
(21), 75 (72), 55 (36), 45 (25). C7H10O3S2 (206.28): calcd. C 40.76,
H 4.89, S 31.09; found C 40.79, H 4.86, S 31.28.
(C-4), 38.8 (CH3), 32.8 (C-3) ppm. MS: m/z (%) ϭ 176 (19) [Mϩ],
92 (31), 85 (54), 59 (100). C6H8O2S2 (176.26): calcd. C 40.89, H
4.57, S 36.38; found C 40.90, H 4.53, S 36.37.
4-Ethyl(thiocarbonyl)thio-4,5-dihydro-2(3H)-furanone (23): A solu-
tion of carbon disulfide (344 µL, 5.71 mmol) was added to a 25%
solution of ethylmagnesium chloride in THF (1.64 mL, 4.76 mmol)
in dry THF (5 mL) at 0 °C, and the mixture was stirred for 10 min
at the same temperature. The resulting red solution was then
treated with a solution of butenolide 1 (337 µg, 4.76 mmol) in THF
(1 mL). The mixture was stirred at 0 °C for 45 min, quenched with
saturated NH4Cl solution and extracted with diethyl ether (3 ϫ
5 mL). The organic phases were combined and concentrated to
yield an oil (716 mg), which was purified by flash chromatography
(hexane/diethyl ether, 7:3) to afford 452 mg (2.38 mmol, 50% yield)
of 23 as a red solid, m.p. 24Ϫ25 °C (ethyl acetate/pentane). IR
(KBr): ν˜ ϭ 2973, 2931, 1778, 1159, 1025 cmϪ1 1H NMR
.
(400 MHz): δ ϭ 4.67 (dd, J5,5 ϭ 10.4, J5,4 ϭ 6.7 Hz, 1 H, 5-H),
4.46 (m, 1 H, 4-H), 4.16 (dd, J5,5 ϭ 10.4, J5,4 ϭ 4.3 Hz, 1 H, 5-H),
3.02 (dd, J3,3 ϭ 18.3, J3,4 ϭ 9.1 Hz, 1 H, 3-H), 2.89 (q, J ϭ 7.3 Hz,
2 H, CH2), 2.47 (dd, J3,3 ϭ 18.3, J3,4 ϭ 5.2 Hz, 1 H, 3-H) 1.25 (t,
J ϭ 7.3 Hz, 3 H, CH3) ppm. 13C NMR (100 MHz): δ ϭ 216.8 (CS),
174.2 (CO), 71.7 (C-5), 44.4/43.0 (C-4/CH2), 32.5 (C-3), 14.9 (CH3)
ppm. MS: m/z (%) ϭ 190 (14) [Mϩ], 106 (42), 85 (59), 73 (100), 45
(31). C7H10O2S2 (190.28): calcd. C 44.18, H 5.30, S 33.70; found C
44.01, H 5.28, S 33.75.
(4RS)-4-[(1R,2S,5R)-Menthyloxy(thiocarbonyl)thio]-4,5-dihydro-
2(3H)-furanone (26): A solution of xanthate 12 (1.0 g of 47% purity,
2.5 mmol) in CHCl3 (3 mL) at room temperature was treated with
butenolide 1 (88 µL, 1.25 mmol) and glacial acetic acid (142 µL,
2.50 mmol). The mixture was stirred at room temperature for 20 h,
acidified with 1  HCl solution to pH 2 and extracted with chloro-
form (3 ϫ 5 mL). The organic phases were combined and concen-
trated to yield an oil (575 mg), which was purified by flash chroma-
tography (CH2Cl2/diethyl ether, 9:1) affording the following frac-
(4RS)-4-{[(1R,4S)-2-N-Phenylamino-1,7,7-trimethylbicyclo- tions: i) 335 mg of a complex mixture; ii) 10 mg (0.05 mmol, 4%
[2.2.1]hept-2-en-3-yl](thiocarbonyl)thio}-4,5-dihydro-2(3H)- yield) of disulfide 28[20] as a solid; and iii) 35 mg (0.13 mmol, 10%
furanone (24a and 24b): A solution of freshly prepared (1R,4R)-N-
(1,7,7-trimethylbicyclo[2.2.1]hept-2-ylidene)phenylamine[15] (0.50 g, ane/CH2Cl2, 1:3) of the less-polar fraction afforded menthol
yield) of thioether 27[19] as a solid. A second chromatography (hex-
2.20 mmol) in dry THF (2 mL) was added to a solution of LDA
at 0 °C, prepared from a solution of diisopropylamine (370 µL,
2.64 mmol) in dry THF (5 mL) and 1.6  nBuLi in hexane yield) as an oil. IR (film): ν˜ ϭ 2959, 2913, 2823, 1785, 1257, 1222,
(136 mg, 0.88 mmol), furanone 1 (23 mg, 0.27 mmol) and a 1:1
mixture of both diastereoisomers of 26 (73 mg, 0.23 mmol, 18%
1
(1.65 mL, 2.64 mmol). The solution was stirred at 0 °C for 2 h and
was then treated with carbon disulfide (265 µL, 4.40 mmol). The
red mixture was warmed to room temperature, stirred for 4 h and
treated with the butenolide 1 (156 µL, 2.20 mmol) and glacial acetic
acid (126 µL, 2.20 mmol). The mixture was stirred at room tem-
perature for 16 h, acidified with 1  HCl solution to pH 2 and
extracted with diethyl ether (3 ϫ 5 mL). The organic phases were
combined and concentrated to yield a red oil (614 mg), which was
purified by flash chromatography (hexane/ethyl acetate, 9:1) to af-
ford 486 mg (1.25 mmol, 57% yield) of a 1:1 mixture of both dia-
stereoisomers of 24 as a yellow solid, m.p. 144Ϫ145 °C (ethyl ace-
tate/pentane). IR (KBr): ν˜ ϭ 3124, 3087, 2959, 2898, 2765, 1778,
1581, 1496, 1342, 1270, 1173 cmϪ1. 1H NMR (400 MHz): δ ϭ 7.35
1166, 1053 cmϪ1. H NMR (400 MHz): δ ϭ 5.45 (m, 1 H, CHO),
4.77 (dd, J5,5 ϭ 9.5, J5,4 ϭ 7.6 Hz) and 4.76 (dd, J5,5 ϭ 9.7, J5,4
7.9 Hz) (1 H, 5-H), 4.40 (m, 1 H, 4-H), 4.30 (dd, J5,5 ϭ 9.7, J5,4
ϭ
ϭ
5.5 Hz, 1 H, 5-H), 3.02 (dd, J3,3 ϭ 18.3, J3,4 ϭ 8.5 Hz, 1 H, 3-H),
2.56 (dd, J3,3 ϭ 18.3, J3,4 ϭ 6.1 Hz) and 2.55 (dd, J3,3 ϭ 18.3,
J3,4 ϭ 6.1 Hz) (1 H, 3-H), 2.15 (m, 1 H), 1.85Ϫ1.40 (m, 5 H),
1.15Ϫ0.95 (m, 2 H), 0.90 (m, 1 H), 0.90 (d, J ϭ 7.3 Hz, 3 H, CH3),
0.89 (d, J ϭ 7.3 Hz, 3 H, CH3), 0.78 (d, J ϭ 7.3 Hz, 3 H, CH3)
ppm. 13C NMR (100 MHz): δ ϭ 210.8 and 210.7 (CS), 174.2 (CO),
85.3 (C-1Ј), 72.54 and 72.50 (C-5), 47.1 (C-2Ј), 42.41 and 42.38 (C-
4), 39.4 (C-6Ј), 33.9 (C-4Ј), 33.3 (C-3), 31.3 (C-5Ј), 26.5 (C-7Ј), 23.6
(C-3Ј), 21.8 (CH3), 20.4 (CH3), 16.8 (CH3) ppm. MS: m/z (%) ϭ
316 (1) [Mϩ], 138 (21), 123 (26), 96 (27), 95 (56), 82 (36), 81 (86), 71
(100), 69 (30), 67 (33), 57 (26), 55 (43), 43 (34), 41 (43). C15H24O3S2
(316.48): calcd. C 56.93, H 7.64, S 20.26; found C 56.73, H 7.62,
(m, 3 H, 3 Ph), 7.22 (m, 2 H, 2 Ph), 4.85 (dd, J5,5 ϭ 9.5, J5,4
7.0 Hz, 1 H, 5-H), 4.71 (m, 1 H, 4-H), 4.33 (dd, J5,5 ϭ 9.5, J5,4
ϭ
ϭ
5.2 Hz) and 4.31 (dd, J5,5 ϭ 9.5, J5,4 ϭ 5.2 Hz) (1 H, 5-H), 3.05 S 20.40.
Eur. J. Org. Chem. 2004, 1492Ϫ1499
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1497

´
´
F. Busque, P. de March, M. Figueredo, J. Font, L. Gonzalez
FULL PAPER
(4RS)-4-{[(R)-N-α-Methylbenzylamino](thiocarbonyl)thio}-4,5-
dihydro-2(3H)-furanone (29): A solution of butenolide 1 (191 µL,
2.7 mmol) in CHCl3 (6 mL) at room temperature was treated with
dithiocarbamate 13 (1.06 g, 3.3 mmol) and glacial acetic acid (158
µL, 2.7 mmol). The mixture was stirred at room temperature for 3
days, acidified with 10% HCl solution to pH 2 and extracted with
CH2Cl2 (3 ϫ 6 mL). The organic phases were combined and con-
centrated to yield a solid (939 mg), which was purified by flash
chromatography (hexane/ethyl acetate, 3:1) affording the following
fractions: i) 565 mg of a complex mixture; ii) 98 mg (0.4 mmol, 15%
yield) of disulfide 28[20] as a solid; and iii) 102 mg (0.5 mmol, 19%
yield) of thioether 27[19] as a solid. A second chromatography (hex-
ane/ethyl acetate, 4:1) of the less-polar fraction afforded 370 mg
(1.30 mmol, 50% yield) of a 1:1 mixture of both diastereoisomers
of 29 as a white solid and the thiourea derived from carbamate 13
(180 mg, 0.55 mmol). 29: M.p. 122Ϫ123 °C (ethyl acetate/pentane).
IR (film): ν˜ ϭ 3268, 2998, 2980, 2860, 1778, 1496, 1377, 1173, 1018,
(d, JMe,3 ϭ 7.3 Hz, 3 H, CH3) ppm. 13C NMR (100 MHz): δ ϭ
177.3 (CO), 73.8 (C-5), 39.6/39.2 (C-3/C-4), 10.7 (CH3) ppm. MS:
m/z (%) ϭ 132 (19) [Mϩ], 74 (90), 72 (80), 59 (36), 55 (100), 45
(53), 41 (91). C5H8O2S (132.18): calcd. C 45.43, H 6.10, S 24.26;
found C 45.51, H 6.20, S 24.24.
Acknowledgments
We gratefully acknowledge financial support of Ministerio de Cien-
´
cia y Tecnologıa (Project BQU2001Ϫ2600) and CIRIT (Project
2001SGR 00178).
[1]
[1a]
For some examples see:
H. Takayama, T. Ichikawa, T. Ku-
wajima, M. Kitajima, H. Seki, N. Aimi, M. G. Nonato, J. Am.
[1b]
Chem. Soc. 2000, 122, 8635Ϫ8639.
Y. Sugimoto, S. C. M.
Wigchert, J. W. J. F. Thuring, B. Zwanenburg, J. Org. Chem.
[1c]
1998, 63, 1259Ϫ1267.
Yamamura, Tetrahedron Lett. 1995, 36, 6267Ϫ6270.
V. Marquez, N. E. Lewin, P. M. Blumberg, Synlett 1994,
M. Ueda, T. Shigemori-Suzuki, S.
[1d]
969, 702 cmϪ1 1H NMR (400 MHz): δ ϭ 7.33Ϫ7.25 (m, 5 H, 5
.
J. Lee,
Ph), 5.65 (m, 1 H, CHNH), 4.70 (m, 1 H, 5-H), 4.63 (m, 1 H, 4-
H), 4.32 (dd, J5,5 ϭ 9.8, J5,4 ϭ 4.3 Hz) and 4.27 (dd, J5,5 ϭ 9.8,
J5,4 ϭ 3.7 Hz) (1 H, 5-H), 3.01 (dd, J3,3 ϭ 18.6, J3,4 ϭ 9.1 Hz) and
[1e]
206Ϫ208.
D. C. Ayres, J. D. Loike, Lignans; Cambridge
[1f]
University Press: New York, 1990.
C. W. Jefford, D. Jaggi,
A. W. Sledeski, J. Boukouvalas, Studies in Natural Products
2.98 (dd, J3,3 ϭ 18.6, J3,4 ϭ 8.5 Hz) (1 H, 3-H), 2.54 (dd, J3,3
ϭ
Chemistry; Elsevier: Amsterdam, 1989. [1g]H. M. R. Hoffmann,
18.6, J3,4 ϭ 5.2 Hz) and 2.51 (dd, J3,3 ϭ 18.6, J3,4 ϭ 4.9 Hz) (1 H,
3-H), 1.55 (d, J ϭ 6.7 Hz, 3 H, CH3) ppm. 13C NMR (62.5 MHz):
δ ϭ 193.1 (CS), 175.2 (CO), 141.0/128.8/127.9/126.4 (Ph), 73.6 and
73.4 (C-5), 56.1 (CH-NH), 43.6 (C-4), 33.6 (C-3), 21.0 (CH3) ppm.
MS: m/z (%) ϭ 281 (1) [Mϩ], 197 (7), 163 (8), 105 (100).
C13H15NO2S2 (281.39): calcd. C 55.49, H 5.37, N 4.98, S 22.79;
found C 55.42, H 5.28, N 4.94, S 22.67.
[1h]
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(1.09 g, 6.8 mmol) in benzene (1 mL) was treated with p-toluidine
(729 mg, 6.8 mmol). After stirring the solution under reflux for 1 h,
a few drops of hexane were added and the mixture was cooled to 0
°C. The resulting precipitate was filtered and washed with benzene
(2 mL). The filtrate was washed with 1  HCl solution and concen-
trated under reduced pressure to yield an oil (1.6 g), which was
purified by flash chromatography (hexane/ethyl acetate, 2:1) to af-
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2558, 1778, 1166, 1011 cmϪ1. H NMR (400 MHz): δ ϭ 4.48 (dd,
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5.8 Hz, 1 H, 5-H), 3.62 (m, 1 H, 4-H), 2.84 (dd, J3,3 ϭ 18.3, J3,4
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1.89 (d, J ϭ 7.3 Hz, 1 H, SH) ppm. 13C NMR (100 MHz): δ ϭ
174.7 (CO), 75.5 (C-5), 38.2 (C-4), 32.7 (C-3) ppm. MS: m/z (%) ϭ
118 (48) [Mϩ], 100 (44), 60 (100), 59 (33), 58 (31), 45 (31), 43 (42).
C4H6O2S (118.15): calcd. C 40.66, H 5.12, S 27.14; found C 41.07,
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p-toluidine (729 mg, 6.8 mmol). After stirring the solution under
reflux for 1 h, a few drops of hexane were added and the mixture
was cooled to 0 °C. The resulting precipitate was filtered and
washed with benzene (2 mL). The filtrate was washed with 1  HCl
solution and concentrated under reduced pressure to yield an oil
(1.7 g), which was purified by flash chromatography (hexane/ethyl
acetate, 2:1) to afford 627 mg (5.1 mmol, 75% yield) of 31. An ana-
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www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1499