Efficient syntheses of thiono and dithio analogues of tetronic acid

Article abstract of DOI:10.1055/s-2006-950351

Thiono and dithio lactone analogues of 4-hydroxyfuran2(5H)-one (tetronic acid) were synthesized in three steps from tetronic acid and thiolotetronic acid. Their usefulness in pharmacomodulation were exemplified by the synthesis of thio analogues of 4-aza-

Full text of DOI:10.1055/s-2006-950351

PAPER
4163
Efficient Syntheses of Thiono and Dithio Analogues of Tetronic Acid
Thiono and
Dithi
a
otetronic
A
p
cid haël Labruère, Stéphanie Desbène-Finck, Philippe Helissey, Sylviane Giorgi-Renault*
Laboratoire de Chimie Thérapeutique, UMR CNRS-Université René Descartes (Paris 5), Faculté des Sciences Pharmaceutiques et
Biologiques, 4 avenue de l’Observatoire, 75270 Paris Cedex 06, France
Fax + 33(1)43291403; E-mail: Sylviane.Giorgi-Renault@univ-paris5.fr
Received 20 July 2006; revised 4 September 2006
the starting material. The corresponding thionotetronic
acid 4 was isolated in 85% yield. Unfortunately, attempt-
ed acidic hydrolysis of 4 into thionotetronic acid 7 was un-
successful and only tetronic acid (1) was isolated.
Abstract: Thiono and dithio lactone analogues of 4-hydroxyfuran-
2(5H)-one (tetronic acid) were synthesized in three steps from
tetronic acid and thiolotetronic acid. Their usefulness in pharmaco-
modulation were exemplified by the synthesis of thio analogues of
4-aza-2,3-didehydropodophyllotoxins.
For this reason, we then investigated an alternative protec-
tive group for the enol function. The 4-benzyl ether 5 was
prepared according to Sato et al.6 and then treated with
Lawesson’s reagent to afford the (benzyloxy)thionolac-
tone 6 in excellent yield. Removal of the protective group
was achieved by heating 6 in trifluoroacetic acid. Accord-
ing to this scheme, the thionotetronic acid 7 was synthe-
sized from tetronic acid (1) in three steps and in 65%
overall yield.
Key words: tetronic acid, thionolactones, dithiolactones, azapodo-
phyllotoxins, Lawesson’s reagent
We have previously described a multicomponent reaction
for the one-pot synthesis of 4-aza-2,3-didehydropodo-
phyllotoxins.1 In a systematic structure–activity study
concerning the lactone moiety, we were interested in pre-
paring sulfur analogues of tetronic acid [4-hydroxyfuran-
2(5H)-one (1)] replacing either the exocyclic oxygen
(thionotetronic acid 7), or both oxygens (dithiotetronic
acid 11).
In the same way, the dithiotetronic acid 11 could be ob-
tained starting from thiotetronic acid 8.7
HO
HO
HS
L.R.
2,4-Bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphenate-
2,4-disulfide, known as Lawesson’s reagent (L.R.), has
been commonly used for the efficient conversion of a
wide range of carbonyl to thiocarbonyl compounds.2 It is
also a useful reagent for the transformation of five- and
six-membered lactones into thionolactones.3 The thion-
ation of lactones with phosphorus pentasulfide frequently
affords a mixture of all three types of sulfur-containing
lactone, i.e. thiolo, thiono, and dithio derivatives.3a,4
S
O
O
toluene
reflux
O
8
1
O
O
DMF
r.t.
CsF
BnBr
DMF
r.t.
CsF
BnBr
2: 70%
MeO
BnO
BnO
O
O
O
S
O
O
56: 70%
9: 60%
3
This study reports on the synthesis of thionotetronic acid
[4-hydroxyfuran-2(5H)-thione (7)] and dithiotetronic acid
[4-hydroxythiophene-2(5H)-thione (11)] in a few steps.
The first results dealing with their usefulness in pharma-
comodulation were exemplified by the synthesis of thio-
analogues of 4-aza-2,3-didehydropodophyllotoxins.
toluene
reflux
L.R. toluene
reflux
L.R. toluene
reflux
L.R.
MeO
BnO
BnO
O
S
O
S
S
S
6: 95%
4: 85%
10: 70%
The reaction of tetronic acid (1) with an excess of Lawes-
son’s reagent in refluxing toluene produced a complex
mixture of products from which no pure material could be
isolated. When using an equimolar amount of reagent, no
reaction occurs at the lactone carbonyl and only the 4-sul-
fanyllactone 25 was isolated in 70% yield (Scheme 1).
Treatment of 2 with a second amount of Lawesson’s re-
agent under the same conditions results only in a mixture
of inseparable compounds.
TFA
HO
60° C
60° C
TFA
HO
O
S
S
S
7: 98%
11: 98%
Scheme 1
Consequently, the same reaction was attempted using
commercially available 4-methoxyfuran-2(5H)-one (3) as
With the two tetronic sulfur derivatives in hand, we decid-
ed to investigate their usefulness for the pharmacomodu-
lation of the lactone moiety of 4-aza-2,3-didehydro-
podophyllotoxins according to our previously described
one-pot procedure1 (Table 1). Good results were obtained
with thionotetronic acid 7, the desired 4-azapodophyllo-
SYNTHESIS 2006, No. 24, pp 4163–4166
x
x.
x
x
.
2
0
0
6
Advanced online publication: 02.11.2006
DOI: 10.1055/s-2006-950351; Art ID: Z15006SS
© Georg Thieme Verlag Stuttgart · New York

4164
R. Labruère et al.
PAPER
toxin 12a was isolated in excellent yield. In the case of of organic molecules. With the examples of podophyllo-
dithiotetronic acid 11, a mixture of dihydroquinoline 12b toxin analogues, we have shown that they could be used
and corresponding quinoline was obtained. Due to its in- for the pharmacomodulation of biologically active deriv-
stability, derivative 12b could not be isolated: it has only atives.
been characterized by 1H NMR. Whereas the one-pot re-
action starting from N-methylaniline was very efficient
TLC was carried out on Merck GF 254 silica gel plates. Flash chro-
for the preparation of the N-methyl-4-aza-2,3-didehydro-
podophyllotoxin analogues either in the thiono or in the
dithio series (compounds 12c and 12d).
matography was performed on Merck silica gel 70 (30–70 mm). El-
emental analyses were performed at the C.N.R.S. Analysis
Laboratory, Gif-sur-Yvette. 1H and 13C NMR spectra were recorded
on Bruker AC 300 spectrometer. IR spectra were obtained on a Per-
kin-Elmer 1600 spectrophotometer
Table 1 Synthesis of Sulfur-Containing 4-Aza-2,3-didehydropodo-
phyllotoxin Analogues 12
4-Sulfanylfuran-2(5H)-one (2)
R
N
R
A soln of tetronic acid 1 (1 g, 10 mmol) and Lawesson’s reagent
(2.02 g, 5 mmol) in anhyd toluene (50 mL) was refluxed for 15 h
under N2. After cooling, the mixture was filtered off. The solvent
was eliminated under reduced pressure and the residue was purified
by flash chromatography (CH2Cl2–EtOAc, 9:1) to give 2 as an oil;
yield: 0.81 g (70%) (Lit.5 8%).
NH
HO
O
O
O
X
X
O
CHO
EtOH
S
S
R = H, Me
MeO
OMe
4-(Benzyloxy)thiophen-2(5H)-one (9)
MeO
OMe
OMe
A mixture of acid 87 (1.16 g, 10 mmol), CsF (3 g, 20 mmol), and
BnBr (2.4 mL, 20 mmol) in anhyd DMF (30 mL) was stirred at r.t.
for 48 h. Sat. aq Na2CO3 (100 mL) was added, and the resulting soln
was extracted with Et2O. After drying (Na2SO4), the solvent was
evaporated in vacuo and the residue was purified by flash chroma-
tography (CH2Cl2) affording 9; yield: 1.24 g (60%); mp 88 °C.
OMe
12
R
X
O
S
Product
12a
Yielda (%)
H
90
H
12b
~15b
72
IR (KBr): 1663, 1596, 1403, 1329, 1246, 1207, 1132, 797, 695, 670
cm–1.
1H NMR (CDCl3): d = 3.95 (s, 2 H, H5), 5.00 (s, 2 H, CH2), 5.60 (s,
1 H, H3), 7.40–7.45 (m, 5 H, arom).
Me
Me
O
S
12c
12d
75
13C NMR (CDCl3): d = 35.0 (C5), 74.5 (CH2), 103.6 (C3), 128.1
(2 × CH), 128.9 (2 × CH), 129.1 (CH), 134.2 (Cq), 181.5 (C4),
195.6 (C=O).
a Yields of isolated products except for 12b.
b Unstable derivative, only characterized by 1H NMR.
Anal. Calcd for C11H10O2S: C, 64.05; H, 4.89. Found: C, 63.97; H,
5.06.
It is noteworthy that a first attempt to prepare 12a by re-
action of Lawesson’s reagent with the corresponding lac-
tone resulted in aromatization to give a quinoline-lactone.
Only the N-methylthiono analogue 12c can be obtained by
this method but in very poor yield (12%).
Thionation of Lactones; General Procedure
A soln of lactones 3, 5, or 9 (2.4 mmol) and Lawesson’s reagent
(985 mg, 2.4 mmol) in anhyd toluene (20 mL) was refluxed for 15
h under N2. After cooling, the mixture was filtered. The solvent was
eliminated under reduced pressure and the residue was purified by
flash chromatography (CH2Cl2–cyclohexane, 8:2). Recrystalliza-
tion (Et2O) afforded thiolactone or dithiolactone.
Consequently, the strategy using a sulfur-containing lac-
tone as one of the three components in the one-pot synthe-
sis represents an efficient method for preparing the
desired new podophyllotoxins derivatives.
4-Methoxyfuran-2(5H)-thione (4)
Characterization of all new derivatives was achieved on
the basis of infrared, and NMR analyses. The lactones 2
and 5 and the thiololactone derivative 9 exhibit a strong
infrared C=O stretching band near 1780 and 1660 cm–1,
respectively, whereas thiono- 4, 6, 7, 12a, and 12c and
dithiolactones 10, 11, and 12d do not show absorption in
the 1640–1800 cm–1 region, but a C=S stretching band
around 1090–1170 cm–1. In the 13C NMR spectra, it is
noted that replacement of the intracyclic oxygen by sulfur
induced a 12–22 ppm deshift for the C=O or correspond-
ing C=S absorptions and a 29–33 ppm shift for the C5. Im-
portant chemical shifts were also found for C3.
Yield: 85%; mp 64 °C.
IR (KBr): 1594, 1382, 1365, 1310, 1196, 1157, 1124, 973, 892, 843
cm–1.
1H NMR (CDCl3): d = 3.95 (s, 3 H, OCH3), 5.00 (s, 2 H, H5), 5.90
(s, 1 H, H3).
13C NMR (CDCl3): d = 59.9 (OCH3), 75.6 (C5), 105.4 (C3), 181.4
(C4), 214.2 (C=S).
Anal. Calcd for C5H6O2S: C, 46.14; H, 4.65. Found: C, 46.11; H,
4.63.
4-(Benzyloxy)furan-2(5H)-thione (6)
Yield: 95%; mp 134 °C.
In conclusion, we have developed a facile three-step syn-
thesis of thionotetronic acid 7 and dithiotetronic acid 11
starting from tetronic acid (1) and thiotetronic acid (8).
These compounds are useful precursors for a wide variety
IR (KBr): 1591, 1580, 1370, 1356, 1310, 1156, 1127, 960, 811, 757,
710 cm–1.
1H NMR (CDCl3): d = 5.00 (s, 2 H, H5), 5.10 (s, 2 H, CH2), 5.95 (s,
1 H, H3), 7.40–7.45 (m, 5 H, arom).
Synthesis 2006, No. 24, 4163–4166 © Thieme Stuttgart · New York

PAPER
Thiono and Dithiotetronic Acid
4165
13C NMR (CDCl3): d = 75.3 (CH2), 76.0 (C5), 106.3 (C3), 128.3
(2 × CH), 129.1 (2 × CH), 129.5 (CH), 133.5 (Cq), 180.3 (C4),
214.3 (C=S).
Hz, H3), 5.95 (s, 1 H, OCH2O), 6.00 (s, 1 H, OCH2O), 6.50 (s, 2 H,
H2¢, H6¢), 6.60 (s, 1 H, H5 or H8), 6.60 (s, 1 H, H5 or H8), 10.40 (s,
1 H, NH).
Anal. Calcd for C11H10O2S: C, 64.05; H, 4.89. Found: C, 63.88; H,
4.97.
13C NMR (DMSO-d6): d = 41.6 (C9), 56.3 (2 × OCH3), 60.3
(OCH3), 73.2 (C3), 98.1 (C5 or C8), 101.8 (OCH2O), 105.5 (C2¢,
C6¢), 110.1 (C5 or C8), 111.7 (Cq), 118.0 (Cq), 129.7 (Cq), 136.4
(Cq), 142.6 (Cq), 144.4 (Cq), 147.0 (Cq), 153.0 (C3¢, C5¢), 160.0
(Cq), 209.1 (C=S).
4-(Benzyloxy)thiophene-2(5H)-thione (10)
Yield: 70%; mp 126 °C.
IR (KBr): 1559, 1336, 1316, 1198, 1163, 1024, 925, 840, 749, 699,
628 cm–1.
Anal. Calcd for C21H19NO6S 0.5 H2O: C, 59.71; H, 4.77; N, 3.32.
Found: C, 59.59; H, 4.56; N, 3.28.
1H NMR (CDCl3): d = 4.15 (s, 2 H, H5), 5.05 (s, 2 H, CH2), 6.30 (s,
(9RS)-6,7-(Methylenedioxy)-9-(3,4,5-trimethoxyphenyl)-4,9-di-
hydrothieno[3,4-b]quinoline-1(3H)-thione (12b)
Yield: ~15%.
1H NMR (CDCl3): d = 3.75 (s, 6 H, OCH3), 3.80 (s, 3 H, OCH3),
3.95 (d, 1 H, J = 18 Hz, H3), 4.05 (d, 1 H, J = 18 Hz, H3), 5.25 (s,
1 H, H9), 5.90 (s, 1 H, OCH2O), 5.95 (s, 1 H, OCH2O), 6.50 (s, 2 H,
H2¢, H6¢), 6.55 (s, 1 H, H5 or H8), 6.60 (s, 1 H, H5 or H8), 8.50 (s,
1 H, NH).
1 H, H3), 7.40–7.45 (m, 5 H, arom).
13C NMR (CDCl3): d = 42.7 (C5), 75.0 (CH2), 118.7 (C3), 128.1
(2 × CH), 129.0 (2 × CH), 129.2 (CH), 133.9 (Cq), 181.8 (C4),
226.9 (C=S).
Anal. Calcd for C11H10OS2: C, 59.42; H, 4.53. Found: C, 59.40; H,
4.49.
Deprotection of Benzyloxy Derivatives; General Procedure
A soln of benzyloxy derivatives 6 or 10 (2 mmol) in TFA (10 mL)
was stirred at 60 °C for 30 min. After elimination of TFA under re-
duced pressure, the residue was triturated with CH2Cl2. The result-
ing solid product was collected and recrystallized to afford the
desired acid.
(9RS)-4-Methyl-6,7-(methylenedioxy)-9-(3,4,5-trimethoxy-
phenyl)-4,9-dihydrofuro[3,4-b]quinoline-1(3H)-thione (12c)
Yield: 72%; mp >260 °C.
IR (KBr): 1642, 1600, 1502, 1485, 1383, 1329, 1214, 1173, 1123,
1036, 1012 cm–1.
4-Hydroxyfuran-2(5H)-thione (7)
Yield: 98%; mp 174 °C (MeOH–CH2Cl2).
1H NMR (CDCl3): d = 3.30 (s, 3 H, NCH3), 3.80 (s, 9 H, OCH3),
5.10 (s, 1 H, H9), 5.10 (d, 1 H, J = 18 Hz, H3), 5.20 (d, 1 H, J = 18
Hz, H3), 5.95 (s, 1 H, OCH2O), 6.00 (s, 1 H, OCH2O), 6.50 (s, 2 H,
H2¢, H6¢), 6.65 (s, 2 H, H5, H8).
13C NMR (CDCl3): d = 35.2 (NCH3), 42.0 (C9), 56.2 (2 × OCH3),
60.8 (OCH3), 72.2 (C3), 95.1 (C5 or C8), 101.8 (OCH2O), 105.8
(C2¢, C6¢), 110.7 (C5 or C8), 113.6 (Cq), 119.4 (Cq), 132.0 (Cq),
136.8 (Cq), 140.8 (Cq), 144.9 (Cq), 147.5 (Cq), 152.9 (C3¢, C5¢),
159.6 (Cq), 209.4 (C=S).
IR (KBr): 3410, 1594, 1577, 1560, 1378, 1331, 1230, 1153, 1120,
897 cm–1.
1H NMR (DMSO-d6): d = 5.10 (s, 2 H, H5), 5.70 (s, 1 H, H3).
13C NMR (DMSO-d6): d = 76.7 (C5), 106.0 (C3), 184.7 (C4), 215.6
(C=S).
Anal. Calcd for C4H4O2S 0.25 H2O: C, 39.82; H, 3.76. Found: C,
40.01; H, 3.45.
Anal. Calcd for C22H21NO6S·0.25 H2O: C, 61.17; H, 5.02; N, 3.24.
Found: C, 61.19; H, 4.76; N, 3.15.
4-Hydroxythiophene-2(5H)-thione (11)
Yield: 98%; mp 114 °C (MeOH–CH2Cl2).
(9RS)-4-Methyl-6,7-(methylenedioxy)-9-(3,4,5-trimethoxy-
phenyl)-4,9-dihydrothieno[3,4-b]quinoline-1(3H)-thione (12d)
Yield: 75%; mp 240 °C.
IR (KBr): 3438, 1618, 1578, 1560, 1438, 1322, 1216, 1192, 1154,
1010, 670 cm–1.
1H NMR (DMSO-d6): d = 4.25 (s, 2 H, H5), 6.05 (s, 1 H, H3).
13C NMR (DMSO-d6): d = 43.3 (C5), 119.5 (C3), 187.4 (C4), 225.5
(C=S).
IR (KBr): 1630, 1590, 1561, 1479, 1364, 1224, 1198, 1124, 1040
cm–1.
1H NMR (CDCl3): d = 3.50 (s, 3 H, NCH3), 3.75 (s, 6 H, OCH3),
3.80 (s, 3 H, OCH3), 4.05 (d, 1 H, J = 18 Hz, H3), 4.25 (d, 1 H, J =
18 Hz, H3), 5.40 (s, 1 H, H9), 6.00 (s, 1 H, OCH2O), 6.05 (s, 1 H,
OCH2O), 6.50 (s, 2 H, H2¢, H6¢), 6.70 (s, 1 H, H5 or H8), 6.75 (s, 1
H, H5 or H8).
13C NMR (CDCl3): d = 34.8 (NCH3), 37.2 (C9), 43.2 (C3), 56.1 (2 ×
OCH3), 61.0 (OCH3), 95.3 (C5 or C8), 101.5 (OCH2O), 105.3 (C2¢,
C6¢), 110.2 (C5 or C8), 120.2 (Cq), 125.7 (Cq), 132.8 (Cq), 137.0
(Cq), 140.6 (Cq), 145.2 (Cq), 147.4 (Cq), 152.8 (C3¢, C5¢), 161.0
(Cq), 217.3 (C=S).
Anal. Calcd for C4H4OS2: C, 36.34; H, 3.04. Found: C, 36.31; H,
3.00.
One-Pot Synthesis of 4-Aza-2,3-didehydropodophyllotoxin
Analogues; General Procedure
An equimolar mixture of aniline, 3,4,5-trimethoxybenzaldehyde,
and sulfur-containing lactone in EtOH was refluxed for 1 h. The
precipitate was filtered off and purified by flash chromatography
and/or recrystallization (EtOH).
Anal. Calcd for C22H21NO5S2·0.25 H2O: C, 58.98; H, 4.84; N, 3.13.
Found: C, 58.61; H, 4.49; N, 2.99.
(9RS)-6,7-(Methylenedioxy)-9-(3,4,5-trimethoxyphenyl)-4,9-di-
hydrofuro[3,4-b]quinoline-1(3H)-thione (12a)
Yield: 90%; mp >260 °C.
Acknowledgment
IR (KBr): 3505, 1640, 1602, 1561, 1508, 1460, 1438, 1396, 1383,
1243, 1199, 1125 cm–1.
1H NMR (DMSO-d6): d = 3.60 (s, 3 H, OCH3), 3.70 (s, 6 H, OCH3),
4.95 (s, 1 H, H9), 5.25 (d, 1 H, J = 18 Hz, H3), 5.45 (d, 1 H, J = 18
Laboratoires Servier are gratefully thanked for support of this rese-
arch and the MNSER for a doctoral fellowship to Raphaël Labruère.
C. Dos Reis is acknowledged for technical assistance.
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R. Labruère et al.
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(3) (a) Scheibye, S.; Kristensen, J.; Lawesson, S.-O.
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Synthesis 2006, No. 24, 4163–4166 © Thieme Stuttgart · New York