Synthesis of substituted 1,2,3,4-tetrahydro-1-thiacarbazole and spiro[pyrrolidinone-3,3′-indolinones] through a common intermediate obtained by condensation of indolin-2-one, (aryl)aldehydes, and Meldrum's acid

Article abstract of DOI:10.1002/1099-0690(200210)2002:20<3481::AID-EJOC3481>3.0.CO;2-C

Trimolecular adducts resulting from condensation between indolin-2-one (or indoline-2-thione), (aryl)aldehydes, and Meldrum's acid are useful intermediates for the synthesis of either 1,2,3,4-tetrahydro-1-thiacarbazoles or spiro[pyrrolidino-3,3′-oxindoles] related to the natural product horsfiline. These latter compounds were obtained in a three-step procedure characterized by acyl azide formation, Curtius rearrangement, and subsequent thermal spiro cyclization. The relative stereochemistry of the spiro derivatives was determined by comparison of NOESY data and calculated conformational analyses. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.

Full text of DOI:10.1002/1099-0690(200210)2002:20<3481::AID-EJOC3481>3.0.CO;2-C

FULL PAPER
Synthesis of Substituted 1,2,3,4-Tetrahydro-1-thiacarbazole and
Spiro[pyrrolidinone-3,3Ј-indolinones] through a Common Intermediate Obtained
by Condensation of Indolin-2-one, (Aryl)aldehydes, and Meldrum’s Acid
[a]
[a]
[a]
[a]
[a]
´
´
Fabien Cochard, Marie Laronze, Elise Prost, Jean-Marc Nuzillard, Franck Auge,
Christian Petermann,[a] Philippe Sigaut,[a] Janos Sapi,[a] and Jean-Yves Laronze*[a]
Keywords: Nitrogen heterocycles / NMR spectroscopy / Peptidomimetics / Spiro compounds / Sulfur heterocycles
Trimolecular adducts resulting from condensation between
indolin-2-one (or indoline-2-thione), (aryl)aldehydes, and
Meldrum’s acid are useful intermediates for the synthesis of
either 1,2,3,4-tetrahydro-1-thiacarbazoles or spiro[pyrrolid-
ino-3,3Ј-oxindoles] related to the natural product horsfiline.
arrangement, and subsequent thermal spiro cyclization. The
relative stereochemistry of the spiro derivatives was deter-
mined by comparison of NOESY data and calculated con-
formational analyses.
These latter compounds were obtained in a three-step pro- ( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
cedure characterized by acyl azide formation, Curtius re-
2002)
Introduction
We recently reported a simple synthesis of β-substituted
tryptophans based on a trimolecular condensation invol-
ving indole, aldehydes, and Meldrum’s acid as the key
step.[1] In view of the close pkHA values of indoline-2-
thione[2] and indole, it was speculated that replacement of
the latter by 1 (X ϭ S) (Scheme 1) might afford trimolecular
adduct of type 2 (X ϭ S), a possible intermediate for the
preparation of thiacarbazoles 3. Although 3- and 4-substi-
tuted thiacarbazoles have been prepared as analgesics and
inflammation inhibitors,[3] no attention had been paid to
their 2-functionalized derivatives, accessible from 2.
The related indolo-1,3-thiazine skeleton is present in
cyclobrassinin, a frequently isolated metabolite from the
Cruciferae family.[4] Cyclobrassinin has been reported to
possess cancer-preventing properties in the in vitro develop-
ment of mice carcinogen-induced mammary lesions.[5]
A similar trimolecular approach with indolin-2-one (ox-
indole) 1 (X ϭ O) as nucleophile should give the analogous
trimolecular adduct 2 (X ϭ O), from which it might be
possible to prepare the functionalized spiro[pyrrolidinone-
3,3Ј-indolone] derivatives 4, related to the simple oxindole
alkaloid horsfiline.[6]
Scheme 1
Here we report a convergent pathway that allows the pre-
paration of both thiopyranoindole 3 and spirooxindoles 4
by simple functional group transformations (Scheme 1).
[a]
`
UMR 6013 ‘‘Isolement, Structure, Transformations et Synthese
Results and Discussion
´
´
de Produits Naturels’’, IFR 53 Biomolecules, Faculte de
´
Pharmacie, Universite de Reims Champagne-Ardenne,
51, rue Cognacq-Jay, 51096 Reims cedex, France
Fax: (internat.) ϩ33Ϫ326918025
Initially, indoline-2-thione 1 (X ϭ S) was treated with
benzaldehyde and Meldrum’s acid according to our previ-
E-mail: jy.laronze@univ-reims.fr
Eur. J. Org. Chem. 2002, 3481Ϫ3490  2002 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/02/1020Ϫ3481 $ 20.00ϩ.50/0
3481

J.-Y. Laronze et al.
FULL PAPER
Scheme 2
ous findings.[1] Contrary to expectations, the only isolated
compound was cycloadduct 7, resulting from the [4ϩ2]-
cycloaddition of two Knoevenagel adducts 6 (Scheme 2).
Such a reaction has already been described in the literature
when indoline-2-thione is treated with benzaldehyde.[7]
As 3-arylidene-2-indolinones are less prone to self-con-
densation,[8] we examined reactions between oxindole, Mel-
drum’s acid, and aldehydes, postponing the introduction of
a sulfur atom at position 2 to a later stage of the synthesis.
Under Yonemitsu’s conditions[9] (CH3CN, -proline;
Conditions A), trimolecular condensation with oxindole
gave a much more complex reaction mixture than in the
case of indole (Scheme 3, Table 1). It appeared that the re-
versibility of the process prevented the isolation of the
formed trimolecular adduct 8 by conventional chromato-
graphy on silica gel: in addition to recovered starting mat-
erials, the Knoevenagel intermediate 10, the ‘double-con-
densed’ product 12, or the ring-cleaved diacid 13 could be
isolated, depending on the used aldehyde (Scheme 4). It
must be noticed that, in some occassions, Knoevenagel’s
derivative 9, another postulated intermediate, can be isol-
ated in minute amounts.
Table 1. Yields and ratios of 8 and 11, depending on the experi-
mental conditions
Entry R
Condi- Yield 8 Yield 11 Other
tions
(%)
(%)
products (%)
1
2
a: H
A
B
C
A
Ϫ
29
38
Ϫ
Ϫ
Ϫ
Ϫ
12 (2)
Ϫ
Ϫ
b: Ph
56
Ϫ
(100:0)[a]
B
Ϫ
66
Ϫ
(92:8)[a]
Ϫ
3
4
c: (2,5-OMe)Ph A
Ϫ
Ϫ
10c[b] (31)
ϩ 13[c] (35)
Ϫ
B
59
(60:40)[a]
d: (2-NO2)Ph
e: (4-F)Ph
A
B
trace
Ϫ
Ϫ
Ϫ
Ϫ
36
(100:0)[a]
51
5
B
Ϫ
Ϫ
(100:0)[a]
[a]
[b]
[c]
Diastereomer ratio. Two isomers, 60:40. One diastereomer.
Scheme 4
When R ϭ Ph, however, the equilibrium was pushed to-
wards the trimolecular adduct 8b (one diastereomer) by its
spontaneous crystallization (56%) from the reaction mix-
ture (Scheme 3).
Scheme 3
3482
Eur. J. Org. Chem. 2002, 3481Ϫ3490

Substituted 1,2,3,4-Tetrahydro-1-thiacarbazole and Spiro[pyrrolidinone-3,3Ј-indolinones]
FULL PAPER
Since this target adduct was removed from the reaction which precluded the presence of any thiocarbonyl function.
mixture by crystallization, we turned our attention to our Moreover, the base peak in the EI mass spectrum, at m/z ϭ
recently described procedure for 2-substituted indoles,[10] in 236, corresponded to 3b, with the sulfur atom attached to
which the corresponding adducts were isolated as stable tri- the indole 2-position.
ethylamine salts.
A few years ago we published a short synthesis, starting
Indeed, condensation of oxindole with Meldrum’s acid from 2-hydroxy-5-methoxytryptamine and formaldehyde,
and benzaldehyde or 2,5-dimethoxybenzaldehyde in dry for the preparation of simple oxindole alkaloid horsfi-
acetonitrile in the presence of one equivalent of triethyl- line.[14] Since that time, a number of chemical approaches
amine (Conditions B) smoothly gave the corresponding toward these spiranic oxindoles have been reported, either
crystalline adduct triethylamine salts 11b and 11c to explore new synthetic methods[15] or to obtain derivatives
(Scheme 3).
of biological interests.[16]
The disappearance of the malonic proton (δ ϭ 4.61 ppm
We have recently reported a simple synthesis for the pre-
in 8b) and a strongly deshielded (δ ϭ 75.7 ppm vis-a-vis paration of some spiro[pyrrolidinone-3,3Ј-indole] deriva-
δ ϭ 49.3 ppm in 8b) quaternary carbon in 11b attested to tives starting from 2-substituted indoles, aldehydes, and
the location of a negative charge on the malonic carbon Meldrum’s acid.[10] Continuing our activity in the field of
and not on the indolic C(3) one. Indeed, in 11b, the two functionalized spirooxindoles, related to horsfiline, we won-
coupled protons [doublets (J ϭ 11.0 Hz) at δ ϭ 3.83 ppm dered if a similar approach, starting from oxindole-type tri-
and δ ϭ 4.74 ppm] are linked to the carbons at δ ϭ 44.9 molecular adducts 8 or 11, could be used for these purposes.
and 46.7 ppm, respectively. These latter have been shown,
Ring opening of the 1,3-dioxane-4,6-dione appendages of
by HMQC and HMBC correlation spectrums, to be the trimolecular adducts 8a, 8b, 11b, and 11c in boiling tert-
benzylic carbon and the indole C(3) carbon, respectively. butyl alcohol smoothly gave the ester-acids 15a, 15b, and
Similar measurements were carried out on adduct salt 11c. 15c as mixtures of diastereomers. Treatment of these with
Although no salt precipitation was observed in the re- diphenylphosphoryl azide (DPPA) in the presence of tri-
mainder of the series [R ϭ H, (2-NO2)-Ph, (4-F)-Ph], the ethylamine afforded the corresponding acyl azides, which
presence of triethylamine proved to be essential for the were subjected, without isolation, to thermal Curtius re-
formation and stabilization of trimolecular adducts 8a, 8d, arrangement to afford isocyanates 16a, 16b, and 16c. These
and 8e. These could be isolated in neutral form after acid spontaneously cyclized to the spirooxindole derivatives 17a,
workup followed by rapid purification by column chroma- 17b, and 17c in 50Ϫ74% overall yields, as a mixture of two
tography (Scheme 3).
diastereomers in the case of 17a and as mixtures of three
With formaldehyde (R ϭ H) under Conditions B or C[11] diastereomers (of the four possible) for 17b and 17c, named
(microwave oven irradiation), the yield of the reaction did I, II, III in descending order of importance (Scheme 6)
not exceed that of the two-step procedure recently described (Table 2).
by Rajeswaran et al.[12]
It is important to note that only one racemic diastere-
omer was obtained in each case for derivatives 8, whereas
mixtures (each with one isomer as major compound) were
isolated for salts 11 (Scheme 3).
With the trimolecular adducts to hand, the phenyl-substi-
tuted 8b was chosen for thionation. Treatment of 8b with
Lawesson’s reagent[13] (2.2 equivalents) at 80 °C afforded
the target thiopyranoindole 3b, the result of a thionation/
ring closure/decarboxylation process (Scheme 5).
Scheme 6. (a) tBuOH, reflux; (b) DPPA, Et3N, CH3CN, 50 °C
Their separation could not be achieved by chromato-
graphy. Fortunately, in the case of 17b, the minor compo-
nent III (M.p. 188Ϫ189 °C) could be isolated by crystalliza-
tion from diethyl ether, which allowed measurement of
Scheme 5. (a) Lawesson’s reagent, dry toluene, 80 °C, 3 days
NMR spectroscopic data.
In the mother liquor, it was easily possible to distinguish
The alternative structure 14 can be discounted on the ba- the NMR signals of the major isomer I from those of the
sis of the chemical shift of C(3) methylene (δ ϭ 48.3 ppm), remaining minor isomer II.
Eur. J. Org. Chem. 2002, 3481Ϫ3490
3483

J.-Y. Laronze et al.
FULL PAPER
The data in Table 4 unambiguously show that the
(3R*,4ЈR*,5ЈS*) isomer, in which all distances are less than
0.31 nm, is not present in the isomer mixture. For the
others, the correlation is particularly satisfying; this could
be due to the high degree of rigidity of these molecules.
The shielding (δ ϭ 6.0 ppm) of the H(4) oxindole proton
in isomer II is the result of its proximity to the symmetry
axis of the C(4Ј)-attached phenyl ring. This effect is severely
diminished for isomer III (δ ϭ 6.9 ppm) and no longer ex-
ists for isomer I (δ ϭ 7.4 ppm) (Scheme 7).
Table 2. Yields and ratios of spiro derivatives 17
Entry Starting
material
R
Yield 15 Yield 17 17 Isomer
(%)
(%)
ratio
[a]
1
2
3
4
8a
H
Ph
Ph
79[a]
90[b]
45[b]
70
74
74
50
8b
47:33:20[c]
47:33:20[c]
53:34:13[c]
11b
11c
(2,5-MeO)Ph 45[c]
[a]
[b]
[c]
Isomer ratio 50:50.
Mixture of four isomers.
Mixture of
three isomers.
In order to determine the relative configurations of car-
bon atoms 3, 4Ј, and 5Ј, we used correlation measurements
1
(HMQC, HMBC) to assign every H NMR signal for each
isomer of 17b (pure III, 80:20 mixture of I/II).
As it is well known that stereochemical relationships of
hydrogens attached to a five-membered ring cannot confi-
dently be assigned by coupling constant values and/or NOE
measurements,[18] we decided to use comparison of quanti-
tative NOE data (NOESY)[19] with conformational analyses
obtained by calculation.
In this study, the configuration of the spiranic 3,3Ј car-
bon was arbitrary set as R*.
The distances between the oxindole proton H(4) and the
pyrrolidinone protons H(4Ј) and H(5Ј) are representative
of their forward or backward location, respectively, on the
pyrrolidinone plane, whereas the H(4Ј)ϪH(5Ј) distance in-
dicates their cis or trans relationship. These NOESY calcu-
lated distances are collected in Table 3.
Table 3. Calculated distances (nm) between H(4), H(4Ј), and H(5Ј)
by NOESY for isomers I, II, III of 17b
Isomer 17b
d(4-4Ј)
d(4-5Ј)
d(4Ј-5Ј)
[a]
[a]
[b]
I
II
III
0.24
Scheme 7
[a]
0.23
0.31
[a]
0.26
In summary, a short route to 1-thiacarbazol-2-one and
3-spiranic oxindole derivatives through a common interme-
diate has been described. This method provides sufficient
flexibility to permit the incorporation of various substitu-
ents into this spirocyclic system.
[a]
[b]
No visible NOE cross peak: d Ͼ 0.4 nm.
No measurement
was possible.
After that, we calculated the average of the above-men-
tioned distances for all conformations, for each of the four
isomers, by two different methods. The first is based on a
Monte-Carlo selection[20] and the second on a molecular
dynamics method.[21]
Experimental Section
Whatever the chosen method, the calculated distances are
almost identical, and are reported on Table 4.
General Remarks: Melting points were determined on a Reichert
Thermovar hot-stage apparatus and are uncorrected. IR (film or
KBr) spectra were measured with a Bomem FTIR instrument. UV
spectra were obtained with a UNICAM 8700 UV/Vis spectropho-
Table 4. Calculated distances (nm) between H(4), H(4Ј), and H(5Ј)
by molecular dynamic (and by the Monte-Carlo method, if differ-
ent) for the four possible isomers (racemates) 17b
1
tometer in MeOH. H NMR (300 MHz) and 13C NMR (75 MHz)
spectra were acquired on a Bruker AC 300 spectrometer in CDCl3,
with TMS as internal standard, or in [D6]DMSO. Mass spectra
were recorded with a VG Autospec apparatus. Elemental analyses
were carried out by the Microanalysis Service of the University of
Reims. All solvents were purified by standard literature methods.
Diphenylphosphoryl azide was purchased from Aldrich. Chroma-
tography was performed on 60 silica gel (Merck) with hexane/
CH2Cl2, cyclohexane/ethyl acetate, CH2Cl2, and CH2Cl2/MeOH as
Isomer 17b
d(4-4Ј)
d(4-5Ј)
d(4Ј-5Ј)
Inferred 17b
isomer
(3R*,4ЈR*,5ЈR*) 0.25 (0.26) 0.50 (0.54) 0.30 (0.31) I
(3R*,4ЈS*,5ЈR*) 0.42
(3R*,4ЈS*,5ЈS*) 0.43
(3R*,4ЈR*,5ЈS*) 0.31
0.52 (0.54) 0.23 (0.24) II
0.23 (0.24) 0.30 (0.31) III
0.23
0.23
Ϫ
3484
Eur. J. Org. Chem. 2002, 3481Ϫ3490

Substituted 1,2,3,4-Tetrahydro-1-thiacarbazole and Spiro[pyrrolidinone-3,3Ј-indolinones]
FULL PAPER
eluents. Reactions were monitored by TLC with Merck TLC alumi-
A solution of oxindole, Meldrum’s acid, aldehyde, and triethyl-
nium sheets (Kieselgel 60F254). Microwave irradiation was carried amine in dry acetonitrile was irradiated in a 250-Watt microwave
out in a Normalab Analis Normatron 112 oven. The stereochem-
ical study of isomers 17bI, II, and III was carried out at 500 MHz
oven until TLC monitoring showed no further conversion of oxin-
dole. The colored solution was diluted with diethyl ether and ex-
on a DRX 500 Bruker NMR spectrometer (HMBC, delay: 40 ms). tracted with a 5% aqueous solution of citric acid. The aqueous
Build-up curves of NOE effects were drawn from data collected by
using the noesyst standard acquisition program and six mixing
times ranging from 50 to 700 ms.[19] The minimum energy con-
formations were determined by Monte-Carlo searches with the
MacroModel software.[20] For the molecular dynamic studies, all
molecules plots were drawn with Insight II version 98.0 from
molecular simulations, Inc. (MSI). Conformational searches were
performed with MSI’s Discover version 2.98 module.[21] Energy
calculations were made with the consistent forcefield (CFF91). All
calculations were performed on Silicon Graphics Octane.
layer was washed several times with diethyl ether. The combined
organic layers were dried with anhydrous MgSO4, filtered, and con-
centrated under reduced pressure. The crude product was purified
by column chromatography on silica gel (eluent: CH2Cl2/CH3OH).
5-[(2Ј,3Ј-Dihydro-2Ј-oxo-1H-indol-3Ј-yl)methyl]-2,2-dimethyl-1,3-
dioxane-4,6-dione (8a): This compound was synthesized from par-
aformaldehyde according to GPB, with extraction: paraformal-
dehyde (0.174 g, 5.26 mmol) and triethylamine (0.733 mL,
5.26 mmol) were added to Meldrum’s acid (0.757 g, 5.26 mmol) in
acetonitrile (6 mL). The mixture was stirred for 2 h at 50 °C. Oxin-
dole (0.700 g, 5.26 mmol) was then added successively to the yellow
solution, which was stirred for 2 days. The solution was diluted
with diethyl ether (4 mL) and extracted with citric acid solution
(5%, 8 mL). The aqueous layer was washed with diethyl ether (2 ϫ
7 mL), the combined organic layers were dried, filtered, and con-
centrated, and the crude solid was purified by column chromato-
graphy to obtain 8a as a yellow powder (eluent: CH2Cl2/CH3OH,
92:8). Yield: 0.440 g (29%). M.p. 135Ϫ137 °C (ref.[12] m.p.
148Ϫ149 °C).
Spiro Compound 7: Meldrum’s acid (0.482 g, 3.35 mmol), benzal-
dehyde (0.337 mL, 3.35 mmol), and triethylamine (0.466 mL,
3.35 mmol) were stirred at room temperature in dry acetonitrile
(7 mL) for 1 h. A solution of indoline-2-thione (0.500 g, 3.35 mmol)
in dry acetonitrile (10 mL) was added dropwise to the reaction mix-
ture and the mixture was stirred at room temperature for 12 h. The
crude orange solid was purified twice by column chromatography
on silica gel (eluent: cyclohexane/ethyl acetate, 90:10) and crystal-
lized (CH3OH) to afford 7 as a beige powder. Yield: 0.527 g (40%).
M.p. 215Ϫ216 °C (ref.[7] M.p. 216.5Ϫ218 °C).
The compound was also synthesized from paraformaldehyde ac-
cording to GPC: oxindole (0.400 g, 3 mmol), Meldrum’s acid
(0.476 g, 3.3 mmol), paraformaldehyde (0.180 g, 4.5 mmol), and
triethylamine (1.68 mL, 12 mmol) in acetonitrile (50 mL) were
heated under reflux for 2 h 40 min. The green solution was diluted
with diethyl ether (10 mL) and extracted with citric acid solution
(5%, 40 mL). The aqueous layer was washed with diethyl ether (2
ϫ 35 mL). The combined organic layers were dried, filtered, and
concentrated, and the crude green solid (1.072 g) was purified by
column chromatography to afford 8a (eluent: CH2Cl2/CH3OH,
92:8). Yield: 0.333 g (38%).
General Procedures for the Preparation of Compounds 8 and 11.
General Procedure A (GPA): Meldrum’s acid and the aldehyde were
suspended under nitrogen atmosphere in dry acetonitrile at room
temperature (room temp.) for 10 min. A solution of oxindole and
-proline in dry acetonitrile was then added, and the mixture was
stirred under nitrogen atmosphere at room temperature. The reac-
tion was stopped when TLC monitoring showed no further conver-
sion of oxindole. Two workups of the reaction mixture were used:
filtration, when the product precipitated, or concentration under
reduced pressure followed either by column chromatography on sil-
ica gel (eluent: CH2Cl2/CH3OH, 94:6) or by crystallization (diethyl
ether or hexane/CH2Cl2). When R ϭ (2,5-OMe)Ph, the Knoevena-
gel adduct 10c was obtained after the purification of the diacid’s
13 mother liquor by column chromatography on silica gel (eluent:
CH2Cl2).
5-[(2Ј,3Ј-Dihydro-2Ј-oxo-1H-indol-3Ј-yl)(phenyl)methyl]-2,2-dimeth-
yl-1,3-dioxane-4,6-dione (8b): This compound was synthesized from
benzaldehyde according to GPA, with filtration: Meldrum’s acid
(1.080 g, 7.51 mmol) and benzaldehyde (0.823 mL, 8.26 mmol)
were stirred in acetonitrile (18 mL). Oxindole (1.0 g, 7.51 mmol)
and -proline (0.043 g, 0.38 mmol) in acetonitrile (12 mL) were
then added to the orange mixture and stirring was continued for
15 h. The yellow precipitate was filtered under reduced pressure,
washed with cold acetonitrile (2 ϫ 9 mL), and dried under reduced
pressure to afford 8b as a pale yellow powder (one diastereomer).
Yield: 1.537 g (56%). M.p. 171 °C. IR (film): ν˜ ϭ 3177 cmϪ1 (br),
3079 (br), 3034 (br), 2949, 2897, 2864, 1778 (s, CO), 1746 (s, CO),
1703 (s, CO), 1620, 1472, 1341, 1306 (s), 1206 (s), 1067, 1013, 752.
UV: λmax ϭ 212 nm, 253, 272. 1H NMR ([D6]DMSO): δ ϭ 1.70 [s,
3 H, C(CH3)2], 1.80 [s, 3 H, C(CH3)2], 3.85 (dl, J ϭ 11.9 Hz, 1 H,
CH-Ph), 4.42 (d, J ϭ 11.9 Hz, 1 H, 3Ј-H), 4.61 (sl, 1 H, 5-H), 5.94
(d, J ϭ 7.7 Hz, 1 H, 4Ј-H), 6.68 (t, J ϭ 7.7 Hz, 1 H, 5Ј-H), 6.88
(d, J ϭ 7.7 Hz, 1 H, 7Ј-H), 7.15 (t, J ϭ 7.7 Hz, 1 H, 6Ј-H),
7.35Ϫ7.50 (m, 3 H, 3ЈЈ-H, 4ЈЈ-H, 5ЈЈ-H), 7.69 (d, J ϭ 7.2 Hz, 2 H,
2ЈЈ-H, 6ЈЈ-H), 10.6 (s, 1 H, NH) ppm. 13C NMR ([D6]DMSO): δ ϭ
26.5 [C(CH3)2], 28.3 [C(CH3)2], 42.9 (C-3Ј), 43.9 (CHPh), 49.3 (C-
5), 105.0 [C(CH3)2], 109.7 (C-7Ј), 121.1 (C-5Ј), 124.3 (C-4Ј), 127.1
(C-4ЈЈ), 128.1 (C-6Ј), 128.6, 129.3 (C-3Јa), 130.3, 140.9, 142.5 (C-
7Јa), 164.4 (CO), 164.5 (CO), 178.0 (NHCO) ppm. MS (EI): m/z
(%) ϭ 365 (2) [Mϩ], 307 (38), 263 (25), 221 (100), 193 (25), 174 (25),
144 (25), 133 (56), 131 (68). C21H19NO5 (365.4): calcd. C 69.03, H
5.24, N 3.83; found C 68.87, H 4.86, N 3.84.
General Procedure B (GPB): The aldehyde and triethylamine were
successively added to a solution of Meldrum’s acid in dry aceto-
nitrile. The reaction mixture was stirred under nitrogen atmosphere
either at room temperature or at 50 °C. Oxindole was then added,
and the reaction mixture was stirred at room temperature under
nitrogen atmosphere until no further conversion of oxindole was
observed (TLC). Two workups of the reaction mixture were used:
either filtration under reduced pressure when the trimolecular ad-
duct precipitated in its salt form 11, or extraction followed by col-
umn chromatography on silica gel, when the adduct was obtained
as its neutral form 8. When the reaction mixture was extracted to
remove the excess of triethylamine, it was first diluted in diethyl
ether, and then washed with a 5% aqueous solution of citric acid.
The aqueous layer was washed several times with diethyl ether. The
combined organic layers were dried with anhydrous MgSO4 and
filtered. The product could then be isolated either by concentration
of the acetonitrile filtrate under reduced pressure until it started
to crystallize, or by column chromatography on silica gel (eluents:
CH2Cl2 and CH2Cl2/CH3OH).
General Procedure
C (GPC): The molar ratio of oxindole,
Meldrum’s acid, and aldehyde was as described by Nemes and
Laronze.[11]
Eur. J. Org. Chem. 2002, 3481Ϫ3490
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J.-Y. Laronze et al.
FULL PAPER
5-[(2Ј,3Ј-Dihydro-2Ј-oxo-1H-indol-3Ј-yl)(2ЈЈ-nitrophenyl)methyl]-
2,2-dimethyl-1,3-dioxane-4,6-dione (8d): This compound was syn-
thesized from 2-nitrobenzaldehyde according to GPB, with extrac-
(NHCO). MS (EI): m/z (%) ϭ 281 (51) [Mϩ Ϫ CO2CO(CH3)2], 239
(100), 211 (39), 133 (51). MS (FAB): m/z (%) ϭ 384 (1) [Mϩ ϩ H],
326 (20), 282 (10), 193 (41), 149 (100), 133 (34). C21H18FNO5
tion followed by chromatography: 2-nitrobenzaldehyde (1.135 g, (383.4): calcd. C 65.79, H 4.73, N 3.65; found C 65.20, H 4.50,
7.52 mmol) and triethylamine (1.057 mL, 7.52 mmol) were added
successively to Meldrum’s acid (1.084 g, 7.52 mmol) in acetonitrile
(1.5 mL). The mixture was stirred for 1 h at room temp. Oxindole
(1.0 g, 7.52 mmol) was then added to the orange solution, which
was stirred for 42 h. The brown solution was diluted with diethyl
ether (2 mL) and extracted with citric acid solution (5%, 2 mL).
The aqueous layer was washed with diethyl ether (2 ϫ 3 mL). The
combined organic layers were dried, filtered and concentrated, and
the crude solid was purified by column chromatography to afford
8d (one diastereomer) as a beige powder (eluent: CH2Cl2/CH3OH,
95:5). Yield: 1.110 g (36%). M.p. 162Ϫ163 °C. IR (KBr): ν˜ ϭ 3205
cmϪ1 (br), 3073, 2881, 1773 (CO), 1738 (s, CO), 1698 (s, CO), 1527
(s), 1346, 1336, 1310 (s), 1200, 752. UV: λmax ϭ 253 nm, 261, 274.
1H NMR ([D6]DMSO): δ ϭ 1.75 [s, 3 H, C(CH3)2], 1.82 [s, 3 H,
C(CH3)2], 4.32 [d, J ϭ 11.9 Hz, 1 H, CH-(2ЈЈ-NO2-Ph)], 4.55 (dd,
J ϭ 11.9 Hz, 1 H, 3Ј-H), 4.79 (sl, 1 H, 5-H), 5.81 (d, J ϭ 7.5 Hz,
1 H, 4Ј-H), 6.70 (t, J ϭ 7.5 Hz, 1 H, 5Ј-H), 6.87 (d, J ϭ 7.5 Hz, 1
H, 7Ј-H), 7.16 (t, J ϭ 7.5 Hz, 1 H, 6Ј-H), 7.70 (t, J ϭ 8.0 Hz, 1 H,
4ЈЈ-H), 7.95 (t, J ϭ 8.0 Hz, 1 H, 5ЈЈ-H), 8.03 (d, J ϭ 8.0 Hz, 1 H,
3ЈЈ-H), 8.59 (d, J ϭ 8.0 Hz, 1 H, 6ЈЈ-H), 10.67 (s, 1 H, NH) ppm.
13C NMR ([D6]DMSO): δ ϭ 26.4 [C(CH3)2], 28.4 [C(CH3)2], 37.7
[CH-(2ЈЈ-NO2-Ph)], 42.7 (C-3Ј), 48.1 (C-5), 105.1 [C(CH3)2], 109.9
(C-7Ј), 121.5 (C-5Ј), 123.3 (C-4Ј), 124.6 (C-3ЈЈ), 128.4 (C-6Ј), 128.8
(C-3Јa), 129.2 (C-4ЈЈ), 132.4 (C-6ЈЈ), 133.4 (C-5ЈЈ), 134.4 (C-1ЈЈ),
142.4 (C-7Јa), 150.7 (C-2ЈЈ), 164.5 (CO), 165.0 (CO), 177.4
(NHCO) ppm. MS (EI): m/z (%) ϭ 411 (1) [Mϩ ϩ 1], 281 (28),
239 (100), 220 (66), 219 (43), 218 (35), 211 (32), 133 (80), 119 (74).
C21H18N2O7 (410.4): calcd. C 61.46, H 4.42, N 6.82; found C 61.27,
H 4.35, N 6.73.
N 3.59.
Triethylammonium Salt 11b: This compound was synthesized from
benzaldehyde according to GPB, with filtration: benzaldehyde
(0.764 mL, 7.52 mmol) and triethylamine (1.057 mL, 7.52 mmol)
were added successively to Meldrum’s acid (1.084 g, 7.52 mmol) in
acetonitrile (4 mL). The mixture was stirred for 1 h at room temp.
Oxindole (1.0 g, 7.52 mmol) was then added to the yellow solution.
After 119 h stirring, the vivid yellow suspension was filtered and
washed with acetonitrile (2 ϫ 4 mL) to obtain 11b (mixture of two
inseparable diastereomers in a ratio of 92:8) as a white powder.
Yield: 2.328 g (66%). M.p. 165Ϫ167 °C. IR (KBr): ν˜ ϭ 3140 cmϪ1
(br), 3079, 3001, 1709 (s, CO), 1580 (s), 1566 (s), 1472, 1389, 1204,
1115, 745. UV: λmax ϭ 263 nm, 274. The relative proportions of
the two isomers were determined by 1H NMR spectroscopy. For
1H and 13C NMR analyses, only the major isomer could be
ascribed: 1H NMR ([D6]DMSO): δ ϭ 1.18 (t, J ϭ 7.2 Hz, 9 H,
N(CH2CH3)3], 1.53 [s, 6 H, C(CH3)2], 3.07 [q, J ϭ 7.2 Hz, 6 H,
N(CH2CH3)3], 3.83 (d, J ϭ 11.0 Hz, 1 H, CH-Ph), 4.74 (d, J ϭ
11.0 Hz, 1 H, 3Ј-H), 5.95 (d, J ϭ 7.5 Hz, 1 H, 4Ј-H), 6.48 (t, J ϭ
7.5 Hz, 1 H, 5Ј-H), 6.73 (d, J ϭ 7.5 Hz, 1 H, 7Ј-H), 6.98 (t, J ϭ
7.5 Hz, 1 H, 6Ј-H), 7.07Ϫ7.20 (m, 3 H, 3ЈЈ-H, 4ЈЈ-H, 5ЈЈ-H), 7.42
(d, J ϭ 7.3 Hz, 2 H, 2ЈЈ-H, 6ЈЈ-H), 10.0 (s, 1 H, NH) ppm. 13C
NMR ([D6]DMSO): δ ϭ 8.8 [N(CH2CH3)3], 26.3 [C(CH3)2], 44.9
(CHPh), 45.9 [N(CH2CH3)3], 46.7 (C-3Ј), 75.5 (C-5), 99.7
[C(CH3)2], 108.5 (C-7Ј), 119.8 (C-5Ј), 125.2 (C-4Ј), 126.6 (C-4ЈЈ),
127.2 (C-3ЈЈ, C-5ЈЈ), 128.4 (C-6Ј), 128.9 (C-2ЈЈ, C-6ЈЈ), 130.7 (C-
3Јa), 142.8 (C-1ЈЈ), 146.5 (C-7Јa), 165.1 (CO), 165.2 (CO), 178.1
(NHCO) ppm. MS (EI): m/z (%) ϭ 263 (10) [Mϩ Ϫ CO2-
CO(CH3)2], 222 (93), 221 (100), 193 (41), 165 (37), 144 (46).
C27H34N2O5 (466.6): calcd. C 69.50, H 7.34, N 6.00; found C 69.69,
H 7.28, N 5.81.
5-[(2Ј,3Ј-Dihydro-2Ј-oxo-1H-indol-3Ј-yl)(4ЈЈ-fluorophenyl)methyl]-
2,2-dimethyl-1,3-dioxane-4,6-dione (8e): This compound was syn-
thesized from 4-fluorobenzaldehyde according to GPB, with extrac-
tion followed by crystallization: 4-fluorobenzaldehyde (0.81 mL,
7.52 mmol) and triethylamine (1.057 mL, 7.52 mmol) were added
Triethylammonium Salt 11c: This compound was synthesized from
2,5-dimethoxybenzaldehyde according to GPB, with filtration: 2,5-
successively to Meldrum’s acid (1.084 g, 7.52 mmol) in acetonitrile dimethoxybenzaldehyde (1.249 g, 7.52 mmol) and triethylamine
(2 mL). The mixture was stirred for 1 h at room temp. Oxindole
(1.0 g, 7.52 mmol) was then added to the yellow solution, which
was stirred for 45 h. The dark yellow solution was diluted with
diethyl ether (2 mL) and extracted with citric acid solution (5%,
2 mL). The aqueous layer was washed with diethyl ether (2 ϫ
3 mL). The combined organic layers were dried and filtered, and
the solution was concentrated until 8e started to crystallize. After
filtration and washing (2 ϫ 4 mL of acetonitrile), 8e (one diastere-
omer) was obtained as a white crystalline powder. Yield: 1.456 g
(1.057 mL, 7.52 mmol) were added successively to Meldrum’s acid
(1.084 g, 7.52 mmol) in acetonitrile (4 mL). The mixture was stirred
for 1 h at room temp. Oxindole (1.0 g, 7.52 mmol) was then added
to the orange solution. After 118 h stirring, the vivid orange sus-
pension was filtered and washed with acetonitrile (2 ϫ 4 mL) to
obtain 11c (mixture of two inseparable diastereomers in a ratio,
60:40) as a pale orange powder. Yield: 2.338 g (59%). M.p.
133Ϫ135 °C. IR (KBr): ν˜ ϭ 3165 cmϪ1 (br), 2992, 2931, 2830, 1713
(s, CO), 1557 (s), 1497, 1461, 1386, 1210 (s), 1044, 747. UV: λmax ϭ
(51%). M.p. 159 °C. IR (KBr): ν˜ ϭ 3175 cmϪ1 (br), 3073 (s), 2942, 253 nm, 267, 283, 301. The relative proportion of the two isomers
1
2861, 1779 (CO), 1743 (s, CO), 1703 (s, CO), 1617, 1507, 1472, (M for major, m for minor) was determined by H NMR spectros-
1336, 1311 (s), 1225, 1205 (s), 1064, 1019, 833, 752. UV: λmax
ϭ
copy: 1H NMR ([D6]DMSO): δ ϭ 1.23Mϩm [t, J ϭ 7.3 Hz, 18 H, 2
251 nm, 261, 271, 279. 1H NMR ([D6]DMSO): δ ϭ 1.72 [s, 3 H, ϫ N(CH2CH3)3], 1.48M [s, 6 H, C(CH3)2], 1.54m [s, 6 H, C(CH3)2],
C(CH3)2], 1.79 [s, 3 H, C(CH3)2], 3.86 [d, J ϭ 11.9 Hz, 1 H, CH-
(4ЈЈ-F-Ph)], 4.38 (d, J ϭ 11.9 Hz, 1 H, 3Ј-H), 4.62 (s, 1 H, 5-H),
3.05Mϩm [q, J ϭ 7.3 Hz, 12 H, 2 ϫ N(CH2CH3)3], 3.19m (s, 3 H,
OCH3), 3.60M (s, 3 H, OCH3), 3.68M (s, 3 H, OCH3), 3.76m (s, 3
5.97 (d, J ϭ 6.5 Hz, 1 H, 4Ј-H), 6.72 (t, J ϭ 6.5 Hz, 1 H, 5Ј-H), H, OCH3), 4.30m (d, J ϭ 6.9 Hz, 1 H, 3Ј-H), 4.34M [d, J ϭ 11.1 Hz,
6.88 (d, J ϭ 6.5 Hz, 1 H, 7Ј-H), 7.18 (t, J ϭ 6.5 Hz, 1 H, 6Ј-H), 1 H, CH-(2ЈЈ,5ЈЈ-diOMe-Ph)], 4.61m [d, J ϭ 6.9 Hz, 1 H, CH-
7.28 (d, J ϭ 8.8 Hz, 1 H, 3ЈЈ-H), 7.29 (d, J ϭ 8.8 Hz, 1 H, 5ЈЈ-H), (2ЈЈ,5ЈЈ-diOMe-Ph)], 4.62M (d, J ϭ 11.1 Hz, 1 H, 3Ј-H), 6.26m (d,
7.71 (d, J ϭ 8.8 Hz, 1 H), 7.73 (d, J ϭ 8.8 Hz, 1 H), 10.6 (s, 1 J ϭ 7.4 Hz, 1 H, 4Ј-H), 6.47m (t, J ϭ 7.4 Hz, 1 H, 5Ј-H), 6.49m (d,
H, NH) ppm. 13C NMR ([D6]DMSO): δ ϭ 26.5 [C(CH3)2], 28.3 J ϭ 8.8 Hz, 1 H, 3ЈЈ-H), 6.57m (dd, J ϭ 3.1, 8.8 Hz, 1 H, 4ЈЈ-H),
[C(CH3)2], 43.0, 43.1, 49.2 (C-5), 105.0 [C(CH3)2], 109.7 (C-7Ј),
6.60M (dd, J ϭ 3.0, 8.8 Hz, 1 H, 4ЈЈ-H), 6.67M (d, J ϭ 8.8 Hz, 1
115.2 (C-3ЈЈ), 115.4 (C-5ЈЈ), 121.2 (C-5Ј), 124.2 (C-4Ј), 128.1 (C- H, 3ЈЈ-H), 6.68m (d, J ϭ 7.4 Hz, 1 H, 7Ј-H), 6.75M (d, J ϭ 7.5 Hz,
6Ј), 129.2 (C-3Јa), 132.2, 132.3, 137.0 (C-1ЈЈ), 142.5 (C-7Јa), 161.6 1 H, 7Ј-H), 6.80M (t, J ϭ 7.5 Hz, 1 H, 5Ј-H), 6.92m (t, J ϭ 7.4 Hz,
(d, J ϭ 244.4 Hz, C-F, C-4ЈЈ), 164.5 (CO), 165.7 (CO), 177.8 1 H, 6Ј-H), 7.07M (t, J ϭ 7.5 Hz, 1 H, 6Ј-H), 7.08M (d, J ϭ 7.5 Hz,
3486
Eur. J. Org. Chem. 2002, 3481Ϫ3490

Substituted 1,2,3,4-Tetrahydro-1-thiacarbazole and Spiro[pyrrolidinone-3,3Ј-indolinones]
FULL PAPER
1 H, 4Ј-H), 7.30m (d, J ϭ 3.1 Hz, 1 H, 6ЈЈ-H), 7.42M (d, J ϭ 3.0 Hz, [C(CH3)2], 109.9 (C-7), 122.6 (C-5), 123.8 (C-4), 128.1 (C-6), 129.2
1 H, 6ЈЈ-H), 9.90Mϩm (s, 2 H, 2 ϫ NH) ppm. 13C NMR
(C-3a), 141.0 (C-7a), 165.3 (CO), 165.4 (CO), 165.8 (2 ϫ CO),
([D6]DMSO): δ ϭ 8.8Mϩm [2 ϫ N(CH2CH3)3], 26.2m [C(CH3)2], 180.2 (NHCO) ppm. C22H23NO9. MS (EI): m/z (%) ϭ 446 (98)
26.3M [C(CH3)2], 35.6m [CH-(2ЈЈ,5ЈЈ-diOMe-Ph)], 36.3M [CH-
(2ЈЈ,5ЈЈ-diOMe-Ph)], 45.8Mϩm [2 ϫ N(CH2CH3)3], 47.0M (C-3Ј),
47.8m (C-3Ј), 55.1M (OCH3), 55.3m (OCH3), 55.7m (OCH3), 56.2M
(OCH3), 75.4M (C-5), 75.6m (C-5), 99.2m [C(CH3)2], 99.4M
[C(CH3)2], 107.8m (C-7Ј), 108.1M (C-7Ј), 109.9M (C-4ЈЈ), 110.0m (C-
4ЈЈ), 110.7m (C-3ЈЈ), 111.1M (C-3ЈЈ), 116.0M (C-6ЈЈ), 116.4m (C-6ЈЈ),
117.1m (C-5Ј), 119.5M (C-5Ј), 125.3m (C-4Ј), 125.4M (C-4Ј), 126.1m
(C-6Ј), 126.6M (C-6Ј), 130.6m (C-3Јa), 131.6M (C-3Јa), 135.8m (C-
1ЈЈ), 136.3M (C-1ЈЈ), 142.8M (C-7Јa), 142.9m (C-7Јa), 151.4m (C-2ЈЈ),
151.9M (C-2ЈЈ), 152.9m (C-5ЈЈ), 153.1M (C-5ЈЈ), 165.8m (2 ϫ CO),
165.9M (2 ϫ CO), 178.3M (NHCO), 179.8m (NHCO) ppm. MS
(EI): m/z (%) ϭ 281 (36) [Mϩ Ϫ CH2(CO2)2C(CH3)2], 250 (100).
C29H38N2O7 (526.6): calcd. C 66.14, H 7.27, N 5.32; found C 66.38,
H 7.02, N 5.20.
[Mϩ ϩ 1], 187 (40), 145 (100), 117 (52).
1,2,3,4-Tetrahydro-4-phenyl-1-thiacarbazol-2-one (3b): A solution of
8b (0.300 g, 0.82 mmol) and Lawesson’s reagent (0.400 g,
0.98 mmol) in dry toluene was heated and stirred at 80 °C under
nitrogen atmosphere for 3 days. After concentration under reduced
pressure, the crude product was diluted with CH2Cl2 to obtain an
orange suspension, which was filtered. The mother liquor was puri-
fied by column chromatography on silica gel (eluent: CH2Cl2) to
afford 3b as a pale yellow foam. Yield: 0.086 g (31%). IR (film):
ν˜ ϭ 3418 cmϪ1 (br), 1645 (s, CO), 1404, 1017, 951. UV: λmax
ϭ
1
224 nm, 284, 326. H NMR ([D6]DMSO): δ ϭ 3.22 (dd, J ϭ 5.0,
16.7 Hz, 1 H, CH2), 3.39 (dd, J ϭ 5.0, 16.7 Hz, 1 H, CH2), 4.78 (t,
J ϭ 5.0 Hz, 1 H, CH-Ph), 6.96 (tl, J ϭ 7.7 Hz, 1 H, 5Ј-H),
7.04Ϫ7.18 (m, 2H indole), 7.19Ϫ 7.34 (m, 5 H aromatic), 7.39 (dl,
J ϭ 8.6 Hz, 2 H, 2ЈЈ-H, 6ЈЈ-H) ppm. 13C NMR ([D6]DMSO): δ ϭ
36.2 (CHPh), 48.3 (CH2), 108.6 (C-3Ј), 111.3 (C-7), 117.5, 119.6,
121.3, 124.3, 126.2, 127.0 (C-4ЈЈ), 127.4, 128.6, 137.2 (C-7Јa), 142.3,
197.0 (CO) ppm. C17H13NOS. MS (EI): m/z (%) ϭ 279 (48) [Mϩ],
236 (100). HRMS (m/z ϭ 279, C17H13NOS) calcd. 279.0707; found
279.0718. HRMS (m/z ϭ 237, C15H11NS) calcd. 237.0616; found
237.0612. HRMS (m/z ϭ 236, C15H10NS calcd. 236.0575; found
236.0534. C17H13NOS (279.4): calcd. C 73.09, H 4.69, N 5.01;
found C 72.92, H 4.61, N 4.69.
5-[(2Ј,5Ј-Dimethoxybenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione
(10c) and 2-[(2Ј,3Ј-Dihydro-2Ј-oxo-1H-indol-3Ј-yl)(2ЈЈ,5ЈЈ-dimeth-
oxyphenyl)methyl]malonic Acid (13): This compound was synthe-
sized from 2,5-dimethoxybenzaldehyde according to GPA, with
concentration followed by crystallization: Meldrum’s acid (0.108 g,
0.75 mmol) and 2,5-dimethoxybenzaldehyde (0.137 g, 0.83 mmol)
were stirred in acetonitrile (4 mL). Oxindole (0.100 g, 0.75 mmol)
and -proline (0.004 g, 0.04 mmol) in acetonitrile (2 mL) were
then added to the yellow solution, which was stirred for 50 h. After
concentration, the crude yellow solid (0.381 g) was crystallized
(hexane/CH2Cl2, 70:30) to obtain 13 (one diastereomer) as a vivid
yellow powder. Yield: 0.102 g (35%). M.p. 157 °C. IR (film): ν˜ ϭ
3250 cmϪ1 (br), 3181, 2994, 2947, 2830, 1694 (s, CO), 1591 (s),
1215, 1046, 750. UV: λmax ϭ 261 nm, 294. 1H NMR (CDCl3): δ ϭ
3.55 (s, 6 H, 2 ϫ OCH3), 3.79 (d, J ϭ 12.5 Hz, 1 H), 3.87 (d, J ϭ
12.5 Hz, 1 H), 5.31 (s, 1 H, 2-H), 6.87 (d, J ϭ 8.0 Hz, 1 H), 7.02
(t, J ϭ 8.0 Hz, 1 H), 7.21 (t, J ϭ 8.0 Hz, 1 H), 7.24 (d, J ϭ 8.0 Hz,
1 H), 8.13 (s, 1 H, NH) ppm. 13C NMR (CDCl3): δ ϭ 35.5, 48.9,
55.1, 55.2, 55.3, 108.5 (C-7Ј), 109.6, 110.8, 115.5 (C-6ЈЈ), 121.0,
125.2, 126.4, 130.0 (C-3Јa), 132.9 (C-1ЈЈ), 141.1 (C-7Јa), 151.2,
153.0, 167.8 (CO), 168.0 (CO), 183.1 (NHCO) ppm. MS (EI): m/z
(%) ϭ 385 (39) [Mϩ], 384 (100), 320 (27), 293 (48). HRMS: calcd.
385.1161; found 385.1130. From the mother liquor of 13, Knoeven-
agel adduct 10c (two isomers, 60:40) was isolated after a column
General Procedure for the Preparation of Compounds 15 from 8 or
11: A pale suspension of 8 or 11 in dry tert-butyl alcohol was
heated under reflux under nitrogen atmosphere, during which it
became progressively colored and dissolved. The stirring was con-
tinued until no further conversion of the starting material 8 or 11
was observed (TLC). After concentration under reduced pressure,
the crude mixture was purified by column chromatography on silica
gel (eluent: CH2Cl2/CH3OH) to obtain 15 as a mixture of insepa-
rable diastereomers.
2-tert-Butoxycarbonyl-3-(2Ј,3Ј-dihydro-2Ј-oxo-1H-indol-3Ј-yl)-
propionic Acid (15a): This compound was synthesized from 8a, ac-
cording to the above GP. A white suspension of 8a (0.265 g,
0.92 mmol) in tert-butyl alcohol (20 mL) was heated under reflux
for 1 h 30 min, during which it progressively became a pale yellow
solution. The crude beige solid (0.334 g) was purified by column
chromatography to obtain 15a (two inseparable diastereomers, ra-
tio, 50:50) as a yellow, amorphous solid (eluent: CH2Cl2/CH3OH,
92:8). Yield: 0.221 g (79%). M.p. 57Ϫ59 °C (mixture). IR (film):
ν˜ ϭ 3310 cmϪ1 (br), 3261, 2980, 2933, 1732 (s, CO), 1716 (s, CO),
chromatography (eluent: CH2Cl2). Yield: 0.069 g (31%). M.p. 119
[17]
°C (ref
M.p. 120Ϫ121 °C).
1,3-Bis[(2Ј,2Ј-dimethyl-4Ј,6Ј-dioxo-1,3-dioxan-5Ј-yl)methyl]-2,3-
dihydro-2-oxo-1H-indole (12): This compound was synthesized
from paraformaldehyde according to GPA, with concentration fol-
lowed by chromatography: Meldrum’s acid (1.080 g, 7.51 mmol) 1707 (s, CO), 1622, 1472, 1369, 1298, 1255, 1227, 1147, 742. UV:
and paraformaldehyde (0.248 g, 8.26 mmol) were stirred in aceto- λmax ϭ 250 nm, 284. The relative proportions of the two isomers
nitrile (18 mL). Oxindole (1.0 g, 7.51 mmol) and -proline (A:B, ratio 50:50) were determined by H NMR spectroscopy: H
(0.043 g, 0.38 mmol) in acetonitrile (12 mL) were then added to the
NMR (CDCl3): δ ϭ 1.43B [s, 9 H, C(CH3)3], 1.47A [s, 9 H,
1
1
beige mixture, which was stirred for 17 h 30 min. After concentra- C(CH3)3], 2.30Ϫ2.60AϩB (m, 4 H, 2 ϫ CH2), 3.49Ϫ3.61AϩB (m, 2
tion, the crude brown solid was purified by column chromato-
H, 2 ϫ 3Ј-H), 3.78B (t, J ϭ 7.5 Hz, 1 H, 2-H), 3.88A (t, J ϭ 7.4 Hz,
1 H, 2-H), 6.90Ϫ7.10AϩB (m, 4 H), 7.12Ϫ7.31AϩB (m, 4 H), 9.69B
graphy to obtain 12 as a pale yellow powder (eluent: CH2Cl2/
CH3OH, 94:6). Yield: 0.078 g (2%). M.p. Ͼ 350 °C. IR (film): ν˜ ϭ (s, 1 H, NH), 9.76A (s, 1 H, NH), 10.67AϩB (sl, 2 H, 2 ϫ CO2 H)
3111 cmϪ1, 2994, 2922, 1771 (br, CO), 1703 (CO), 1701 (s, CO),
ppm. 13C NMR (CDCl3): δ ϭ 27.7AϩB [2 ϫ C(CH3)3], 29.2B (CH2),
1557 (s), 1470, 1416, 1206, 1128, 760. UV: λmax ϭ 258 nm, 263. 1H 29.4A (CH2), 43.5B (C-3Ј), 43.6A (C-3Ј), 49.3B (C-2), 49.6A (C-2),
NMR (CDCl3): δ ϭ 1.60Ϫ1.80 (4s, 12 H, 2 ϫ C(CH3)2], 2.50Ϫ5.30 82.4B [C(CH3)3], 82.5A [C(CH3)3], 110.3B (C-7Ј), 110.5A (C-7Ј),
(m, 7 H, 2 ϫ CH2, 3-H, , 2 ϫ 5Ј-H), 6.90 (d, J ϭ 8.0 Hz, 1 H, 4- 122.6B (C-5Ј), 122.7A (C-5Ј), 124.2B (C-4Ј), 124.3A (C-4Ј), 128.2AϩB
H), 7.05 (t, J ϭ 8.0 Hz, 1 H, 5-H), 7.21 (d, J ϭ 8.0 Hz, 1 H, 7-H), (2 ϫ C-6Ј), 128.3B (C-3Јa), 128.5A (C-3Јa), 141.1B (C-7Јa), 141.2A
7.26 (t, J ϭ 8.0 Hz, 1 H, 6-H) ppm. 13C NMR (CDCl3): δ ϭ 26.4 (C-7Јa), 167.9B [CO2C(CH3)3], 168.0A [CO2C(CH3)3], 173.5B
[C(CH3)2], 26.5 [C(CH3)2], 28.4 [C(CH3)2], 28.5 [C(CH3)2], 41.1 (2
ϫ C-5Ј), 41.4 (C-3), 49.5 (CH2), 49.8 (CH2), 105.3 [C(CH3)2], 105.6
(CO2 H), 173.7A (CO2H), 181.1AϩB (2 ϫ NHCO) ppm. MS (EI):
m/z (%) ϭ 305 (1) [Mϩ], 187 (27), 145 (100). C16H19NO5·1/2H2O
Eur. J. Org. Chem. 2002, 3481Ϫ3490
3487

J.-Y. Laronze et al.
FULL PAPER
(314.3): calcd. C 61.13, H 6.11, N 4.45; found C 61.52, H 6.00, 6.62Ϫ6.79BϩC (m,
N 4.52.
4
H), 6.80Ϫ6.92AϩBϩCϩD (m,
H), 7.06Ϫ7.19BϩCϩD (m,
3
5
H),
H),
6.93Ϫ7.05AϩBϩCϩD (m,
4
7.19Ϫ7.36AϩCϩD (m, 3 H), 7.50B (d, J ϭ 7.0 Hz, 1 H), 9.91B (s, 1
H, NH), 10.10D (s, 1 H, NH), 10.21A (s, 1 H, NH), 10.28C (s, 1
H, NH) ppm. 13C NMR ([D6]DMSO): δ ϭ 27.4 [C(CH3)3], 27.5
[C(CH3)3], 28.0 [C(CH3)3], 28.1 [C(CH3)3], 48.3 (C-3Ј), 48.7 (C-3Ј),
55.1, 55.4, 55.5, 55.6, 55.9, 56.4, 56.5, 79.4 [C(CH3)3], 79.5
[C(CH3)3], 80.1 [C(CH3)3], 81.2 [C(CH3)3], 108.9 (C-7Ј), 109.4 (C-
7Ј), 111.3, 112.0, 112.6, 112.9, 113.2, 115.5, 120.8 (C-5Ј), 121.0 (C-
5Ј), 121.1 (C-5Ј), 125.1 (C-4Ј), 126.2 (C-4Ј), 127.5 (C-6Ј), 128.0 (C-
6Ј), 128.1 (C-3Јa), 128.4 (C-3Јa), 128.7 (C-3Јa), 128.8 (C-3Јa), 142.2,
142.5, 143.6, 151.5, 151.6, 152.4, 152.5, 168.2, 168.9, 169.1, 169.4,
172.5, 177.8 (NHCO), 178.4 (NHCO), 179.1 (NHCO) ppm. MS
(EI): m/z (%) ϭ 281 (46) [Mϩ Ϫ CH2CO2HCO2C(CH3)3], 251 (55),
250 (100). C24H27NO7·2H2O (477.5): calcd. C 60.36, H 6.54, N
2.93; found C 59.72, H 5.84, N 2.66.
2-tert-Butoxycarbonyl-3-[(2Ј,3Ј-dihydro-2Ј-oxo-1H-indol-3Ј-yl)]-
hydrocinnamic Acid (15b): This compound was synthesized from
8b, according to the above GP. A pale yellow suspension of 8b
(1.0 g, 2.74 mmol) in tert-butyl alcohol (48 mL) was heated under
reflux for 2 h 30 min, during which it progressively became a vivid
yellow solution. The crude yellow solid was purified by column
chromatography to obtain 15b (four inseparable diastereomers, ra-
tio, 40:40:10:10) as a pale yellow amorphous solid (eluent: CH2Cl2/
CH3OH, 80:20). Yield: 0.939 g (90%). It was also synthesized from
11b by the above GP: A white suspension of 11b (1.9 g, 4.08 mmol)
in tert-butyl alcohol (60 mL) was heated under reflux for 2 h 20,
during which it progressively became a vivid yellow solution. The
crude yellow oil (2.017 g) was purified by column chromatography
to obtain 15b (four inseparable diastereomers, ratio, 40:40:10:10)
as a pale yellow, amorphous solid (eluent: CH2Cl2/CH3OH, 80:20). General Procedure for the Preparation of Compounds 17 from 15:
Yield: 0.693 g (45%). M.p. 144 °C (mixture). IR (film): ν˜ ϭ 3408
Diphenylphosphoryl azide (DPPA) and triethylamine were added
cmϪ1 (br), 3217 (br), 3063, 3032, 2980, 2933, 1721 (s, CO), 1703 (s, successively to a suspension of the mixture of isomers 15 in dry
CO), 1694 (s, CO), 1622 (s), 1603, 1472, 1393, 1369 (s), 1337, 1302,
1252, 1152 (s), 750, 700. UV: λmax ϭ 250 nm, 284. The relative
proportions of the four isomers {(A):[B], ratio, (40:40):[10:10]}
were determined by 1H NMR spectroscopy: 1H NMR
([D6]DMSO): δ ϭ 0.99A [s, 9 H, C(CH3)3], 1.03A [s, 9 H, C(CH3)3],
1.47B [s, 9 H, C(CH3)3], 1.49B [s, 9 H, C(CH3)3], 3.89Ϫ4.18AϩB (m,
acetonitrile. The suspension was then heated at 50 °C under nitro-
gen atmosphere, while it progressively became colored and dis-
solved. The stirring was continued until no further conversion of
the starting material 15 was observed (TLC). The reaction mixture
was diluted in diethyl ether and extracted with a 5% aqueous solu-
tion of citric acid. The aqueous layer was washed several times with
11 H), 4.68A (d, J ϭ 12.0 Hz, 1 H), 6.50Ϫ6.62AϩB (m, 4 H, 4 ϫ diethyl ether. The combined organic layers were filtered, dried with
4Ј-H), 6.70Ϫ6.85A (m, 1 H), 6.90Ϫ7.19AϩB (m, 28 H), 7.41A (d, anhydrous MgSO4, and concentrated under reduced pressure. The
J ϭ 7.0 Hz, 1 H, 7Ј-H), 7.48B (d, J ϭ 6.9 Hz, 1 H, 7Ј-H), 7.66A (d,
crude product was then purified by column chromatography on
J ϭ 7.0 Hz, 1 H, 7Ј-H), 9.99A (s, 1 H, NH), 10.09B (s, 1 H, NH), silica gel (eluent: CH2Cl2/CH3OH) to obtain 17 as a mixture of di-
10.21A (s, 1 H, NH), 10.24B (s, 1 H, NH) ppm. 13C NMR astereomers.
([D6]DMSO): δ ϭ 27.2 [C(CH3)3], 27.4 [C(CH3)3], 27.8 [C(CH3)3],
27.9 [C(CH3)3], 45.6, 46.1, 46.5, 46.6, 48.0, 48.8, 49.9, 50.2, 54.7
(C-2), 54.8 (C-2), 58.4 (C-2), 79.7 [C(CH3)3], 79.9 [C(CH3)3], 81.3
[C(CH3)3], 81.5 [C(CH3)3], 109.0 (2 ϫ C-7Ј), 109.1 (C-7Ј), 109.2 (C-
7Ј), 121.1 (C-5Ј), 121.2 (C-5Ј), 121.3 (C-5Ј), 121.4 (C-5Ј), 124.1,
126.0, 126.7, 126.9 (C-3Јa), 127.2, 127.4, 127.45 (C-3Јa), 129.0 (2
ϫ CH), 129.4, 137.5 (C-1ЈЈ), 137.6 (C-1ЈЈ), 138.0 (C-1ЈЈ), 142.3 (C-
7Јa), 142.4 (C-7Јa), 143.2 (C-7Јa), 143.3 (C-7Јa), 168.2
(CO2C(CH3)3], 168.5 (CO2C(CH3)3], 171.0 (CO2 H), 171.2 (CO2
H), 176.9 (NHCO), 177.5 (NHCO), 177.6 (NHCO), 178.1 (NHCO)
ppm. C22H23NO5. MS (EI): m/z (%) ϭ 382 (1) [Mϩ], 281 (30), 222
(62), 221 (100), 133 (53). C22H23NO5·H2O (399.4): calcd. C 66.15,
H 6.31, N 3.50; found C 66.05, H 5.76, N 3.48.
Spiro Compound 17aI,II: This compound was synthesized accord-
ing to the GP: DPPA (0.126 mL, 0.59 mmol) and triethylamine
(0.083 mL, 0.59 mmol) were added successively to 15a (0.163 g,
0.53 mmol) in acetonitrile (10 mL). The suspension was heated for
2-tert-Butoxycarbonyl-3-(2Ј,3Ј-dihydro-2Ј-oxo-1H-indol-3Ј-yl)-3- 1 h 40 min until it had become a pale yellow solution. The mixture
(2ЈЈ,5ЈЈ-dimethoxyphenyl)propionic Acid (15c): This compound was
synthesized from 11c, according to the above GP: a yellow suspen-
sion of 11c (1.5 g, 2.85 mmol) in tert-butyl alcohol (50 mL) was
heated under reflux for 2 h 30 min, during which it progressively
became a orange solution. The crude amorphous orange solid
was diluted with diethyl ether (4 mL) and extracted with a 5%
aqueous solution of citric acid (10 mL). The aqueous layer was
washed with diethyl ether (2 ϫ 10 mL). The combined organic
layers were dried, filtered, and concentrated, and the crude product
was purified by column chromatography. A mixture of two insepa-
(1.479 g) was purified by column chromatography to obtain 15c rable diastereomers 17aI,II (ratio, 50:50) was obtained as a white
(four inseparable diastereomers, ratio, 66:22:9:3) as an orange, crystalline powder (eluent: CH2Cl2/CH3OH, 94:6). Yield: 0.114 g
amorphous solid (eluent: CH2Cl2/CH3OH, 85:15). Yield: 0.676 g
(70%). M.p. 174Ϫ176 °C (mixture). IR (film): ν˜ ϭ 3205 cmϪ1 (br),
(45%). M.p. 144Ϫ145 °C (mixture). IR (KBr): ν˜ ϭ 3266 cmϪ1 (br), 2978, 2932, 1732 (s, CO), 1714 (s, CO), 1620, 1471, 1369, 1248,
2984, 2940, 1721 (s, CO), 1717 (s, CO), 1709 (s, CO), 1622, 1601, 1155. UV: λmax ϭ 253 nm, 289. The relative proportions of the two
1
1503, 1472, 1368, 1308, 1225 (s), 1150 (s), 1047, 750. UV: λmax
ϭ
isomers (I/II, ratio, 50:50) were determined by H NMR spectros-
253 nm, 294. The relative proportions of the four isomers
copy: 1H NMR (CDCl3): δ ϭ 1.50IϩII [s, 18 H, 2 ϫ C(CH3)3], 2.50I
(A:B:C:D, ratio, 66:22:9:3) were determined by H NMR spectro- (dd, J ϭ 5.6, 13.7 Hz, 1 H, CHH), 2.72II (dd, J ϭ 8.6, 13.5 Hz, 1
1
scopy: H NMR ([D6]DMSO): δ ϭ 0.97A [s, 9 H, C(CH3)3], 1.02C
H, CHH), 2.95II (dd, J ϭ 5.9, 13.5 Hz, 1 H, CHH), 3.09I (dd, J ϭ
5.6, 13.7 Hz, 1 H, CHH), 4.43II (dd, J ϭ 5.9, 8.6 Hz, 1 H, 5Ј-H),
1
[s, 9 H, C(CH3)3], 1.39B [s, 9 H, C(CH3)3], 1.41D [s, 9 H, C(CH3)3],
3.03B (s, 3 H, OCH3), 3.31B (s, 3 H, OCH3), 3.45A (s, 3 H, OCH3), 4.53I (dd, J ϭ 5.6, 9.0 Hz, 1 H, 5Ј-H), 6.86II (d, J ϭ 7.4 Hz, 1 H,
4.07B (d, J ϭ 5.33 Hz, 1 H, 3Ј-H), 4.21A (sl, 1 H, 3Ј-H), 4-H), 6.88I (d, J ϭ 7.6 Hz, 1 H, 4-H), 7.02IϩII (t, J ϭ 7.6 Hz, 2 H,
4.41Ϫ4.69AϩBϩCϩD (m, 4 H, 4 ϫ 2-H), 6.49Ϫ6.61AϩCϩD (m, 6 H), 2 ϫ 5-H), 7.12Ϫ7.23IϩII (m, 4 H, 2 ϫ C-6, 2 ϫ C-7), 7.63II (s, 1
3488
Eur. J. Org. Chem. 2002, 3481Ϫ3490

Substituted 1,2,3,4-Tetrahydro-1-thiacarbazole and Spiro[pyrrolidinone-3,3Ј-indolinones]
FULL PAPER
H, 1Ј-H), 7.71I (s, 1 H, 1Ј-H), 9.52II (s, 1 H, 1-H), 9.59I (s, 1 H, 1- (0.100 mL, 0.72 mmol) were added successively to 15c (0.287 g,
H) ppm. 13C NMR (CDCl3): δ ϭ 27.9IϩII [C(CH3)3], 34.7II (CH2),
35.0I(CH2), 53.9II (C-5Ј), 54.2I (C-5Ј), 57.8II (C-3), 57.9I (C-3),
0.65 mmol) in acetonitrile (10 mL). The yellow suspension was
heated for 4 h until it had become a yellow solution. The mixture
82.9IϩII [C(CH3)3], 110.5II (C-7), 110.7I (C-7), 122.7II (C-5), 122.8I was diluted with diethyl ether (6 mL) and extracted with a 5%
(C-5), 122.9II (C-4), 123.5I (C-4), 129.1II (C-6), 129.2I (C-6), 129.3II aqueous solution of citric acid (12 mL). The aqueous layer was
(C-3a), 129.4I (C-3a), 141.8IϩII (C-7a), 169.5II (C-2Ј), 170.1I (C-2Ј), washed with diethyl ether (2 ϫ 12 mL). The combined organic
177.1II (C-2), 177.6I (C-2) ppm. C16H18N2O4. MS (EI): m/z (%) ϭ
layers were dried, filtered, and concentrated, and the crude product
302 (ϫ 40, 14) [Mϩ], 246 (11), 201 (20), 174 (28), 146 (100). (0.612 g) was purified by column chromatography. A mixture of
C16H18N2O4·1/2H2O (311.3): calcd. C 61.72, H 6.15, N 8.99; found
C 62.21, H 5.95, N 8.90.
three inseparable diastereomers 17cI,II,III (ratio, 53:34:13) was ob-
tained as a white crystalline powder (eluent: CH2Cl2/CH3OH,
92:8). Yield: 0.144 g (50%). M.p. 188Ϫ189 °C (mixture). IR (film):
ν˜ ϭ 3215 cmϪ1 (br), 1734 (s, CO), 1716 (s, CO), 1622, 1502, 1471,
1226, 1159. UV: λmax ϭ 254 nm, 295. The relative proportions of
Spiro Compound 17bI,II and 17bIII: This compound was synthe-
sized according to the GP: DPPA (0.093 mL, 0.43 mmol) and trie-
thylamine (0.061 mL, 0.43 mmol) were added successively to 15b
(0.150 g, 0.39 mmol) in acetonitrile (10 mL). The suspension was
heated for 2 h 30 min until it had become a yellow solution. The
mixture was diluted with diethyl ether (4 mL) and extracted with a
5% aqueous solution of citric acid (9 mL). The aqueous layer was
washed with diethyl ether (2 ϫ 10 mL). The combined organic
layers were dried, filtered, and concentrated, and the crude product
(0.333 g) was purified by column chromatography. A mixture of
three diastereomers 17bI,II,III (ratio, 47:33:20), was obtained as
a white crystalline powder (eluent: CH2Cl2/CH3OH, 98:2). Yield:
0.111 g (74%). The relative proportions of the three isomers (I/II/
III, ratio, 47:33:20) were determined by 1H NMR spectroscopy.
The minor component (3R*,4ЈS*,5ЈS*)-17bIII was isolated by crys-
tallization from diethyl ether. M.p. 188Ϫ189 °C. 1H NMR
(CDCl3): δ ϭ 1.35 [s, 9 H, C(CH3)3], 4.42 (d, J ϭ 8.2 Hz, 1 H, 4Ј-
H), 4.85 (d, J ϭ 8.2 Hz, 1 H, 5Ј-H), 6.53 (s, 1 H, 1Ј-H), 6.72 (d,
J ϭ 7.8 Hz, 1 H, 7-H), 6.83Ϫ6.89 (m, 2 H, 4-H, 5-H), 7.11 (t, J ϭ
7.8 Hz, 1 H, 6-H), 7.12Ϫ7.22 (m, 5 H, 2ЈЈ-H, 3ЈЈ-H, 4ЈЈ-H, 5ЈЈ-H,
6ЈЈ-H), 7.71 (s, 1 H, 1-H) ppm. 13C NMR (CDCl3): δ ϭ 27.8
[C(CH3)3], 52.7 (C-4Ј), 58.3 (C-5Ј), 63.9 (C-3), 83.2 [C(CH3)3],
110.2 (C-7), 122.5 (C-5), 125.0 (C-4), 125.6 (C-3a), 127.8 (C-4ЈЈ),
128.2, 128.3, 129.2 (C-6), 135.0 (C-1ЈЈ), 141.1 (C-7a), 168.5
(CO2tBu), 171.5 (C-2Ј), 174.9 (C-2) ppm. C22H22N2O4 (378.4):
calcd. C 69.83, H 5.86, N 7.40; found C 69.26, H 5.76, N 7.42.
From the mother liquor of 17bIII, (3R*,4ЈR*,5ЈR*)-17bI and
(3R*,4ЈS*,5ЈR*)-17bII were isolated as a mixture. The relative pro-
portions of the two isomers (I/II, ratio, 80:20) were determined by
1H NMR spectroscopy. M.p. 127Ϫ129 °C (mixture). IR (film): ν˜ ϭ
3227 cmϪ1 (br), 3070, 1734 (s, CO), 1717 (s, CO), 1622, 1471, 1369,
1242, 1157, 746. UV: λmax ϭ 256 nm, 265, 289. 1H NMR (CDCl3):
δ ϭ 1.09II [s, 9 H, C(CH3)3], 1.28I [s, 9 H, C(CH3)3], 3.97I (d, J ϭ
10.3 Hz, 1 H, 4Ј-H), 4.11II (d, J ϭ 6.6 Hz, 1 H, 4Ј-H), 5.23I (d, J ϭ
10.3 Hz, 1 H, 5Ј-H), 5.48II (d, J ϭ 6.6 Hz, 1 H, 5Ј-H), 5.99II (d,
J ϭ 7.8 Hz, 1 H, 4-H), 6.63II (t, J ϭ 7.8 Hz, 1 H, 5-H), 6.68II (s, 1
H, 1Ј-H), 6.69I (d, J ϭ 7.8 Hz, 1 H, 7-H), 6.79I (s, 1 H, 1Ј-H),
6.80II (d, J ϭ 7.8 Hz, 1 H, 7-H), 6.83Ϫ6.89IϩII (m, 13 H), 7.40I (d,
J ϭ 7.8 Hz, 1 H, 4-H), 7.68I (s, 1 H, 1-H), 8.12II (s, 1 H, 1-H) ppm.
13C NMR (CDCl3): δ ϭ 27.4II [C(CH3)3], 27.6II [C(CH3)3], 52.3II
(C-4Ј), 55.5II (C-4Ј), 57.1I (C-5Ј), 58.8II (C-5Ј), 64.0II (C-3), 64.8I
(C-3), 82.5II [C(CH3)3], 82.7I [C(CH3)3], 109.8II (C-7), 110.2I (C-7),
122.6II (C-5), 123.0I (C-5), 123.9I (C-4), 124.6II (C-3a), 126.5I (C-
3a), 126.8II (C-4), 127.9I (C-4ЈЈ), 128.1I, 128.2IϩII, 128.3II, 128.4II,
129.1II (C-6), 129.3I (C-6), 133.1I (C-1ЈЈ), 136.6II (C-1ЈЈ), 141.6II
(C-7a), 142.1I (C-7a), 168.2II (CO2tBu), 169.3I (CO2tBu), 171.6I (C-
2Ј), 171.7II (C-2Ј), 174.5I (C-2), 175.9II (C-2) ppm. C22H22N2O4.
MS (EI): m/z (%) ϭ 378 (1) [Mϩ], 322 (17), 277 (16), 222 (100).
C22H22N2O4·1/2H2O (387.4): calcd. C 68.20, H 5.98, N 7.23; found
C 68.08, H 5.83, N 7.17.
1
the three isomers (I/II/III, ratio, 53:34:13) were determined by H
NMR spectroscopy: 1H NMR (CDCl3): δ ϭ 1.13II [s, 9 H,
C(CH3)3], 1.25I [s, 9 H, C(CH3)3], 1.44III [s, 9 H, C(CH3)3], 3.27I
(s, 3 H, OCH3), 3.29II (s, 3 H, OCH3), 3.33III (s, 3 H, OCH3), 3.64I
(s, 3 H, OCH3), 3.70III (s, 3 H, OCH3), 3.72II (s, 3 H, OCH3), 4.69II
(d, J ϭ 7.1 Hz, 1 H, 4Ј-H), 4.76I (d, J ϭ 10.3 Hz, 1 H, 4Ј-H), 4.82III
(d, J ϭ 6.2 Hz, 1 H, 4Ј-H), 5.06I (d, J ϭ 10.3 Hz, 1 H, 5Ј-H),
5.38II (d, J ϭ 7.1 Hz, 1 H, 5Ј-H), 6.02II (d, J ϭ 7.6 Hz, 1 H, 4-H),
6.40Ϫ6.69IϩIIϩIII (m,
9
H), 6.71Ϫ6.92IϩIIϩIII (m,
3
H),
6.98Ϫ7.11IϩIIϩIII (m, 6 H), 7.22Ϫ7.97IϩIIϩIII (m, 6 H), 9.12I (s, 1
H, 1-H), 9.65II (s, 1 H, 1-H), 9.69III (s, 1 H, 1-H) ppm. 13C NMR
(CDCl3): δ ϭ 27.3II [C(CH3)3], 27.5I [C(CH3)3], 27.7III [C(CH3)3],
45.1II (C-4Ј), 45.8I (C-4Ј), 54.8III (OCH3), 55.5I (OCH3), 55.6I
(OCH3), 55.65III (OCH3), 55.7II (OCH3), 55.8II (OCH3), 57.6I (C-
5Ј), 57.8III (C-5Ј), 58.1II (C-5Ј), 62.6III (C-3), 63.6II (C-3), 64.4I (C-
3), 82.0II [C(CH3)3], 82.1I [C(CH3)3], 82.2III [C(CH3)3], 109.9I (C-
7), 110.7II (C-7), 111.5I, 112.4II, 112.7II, 112.8III, 113.7I, 114.2II (C-
6ЈЈ), 114.3III (C-6ЈЈ), 114.9I (C-6ЈЈ), 121.8IIϩIII (2 ϫ C-5), 122.2I (C-
5), 123.3I (C-3a), 124.5I (C-4), 125.0II (C-3a), 125.7II (C-4), 126.0II
(C-5Ј), 126.1III (C-5Ј), 126.9I (C-5Ј), 128.6IIϩIII (2 ϫ C-6), 128.7I
(C-6), 141.9I (C-7a), 142.2II (C-7a), 151.7IIϩIII, 151.8I, 153.0III
,
153.1I, 153.2II, 168.5II (CO2C(CH3)3], 169.2I (CO2C(CH3)3], 172.0I
(C-2Ј), 172.7II (C-2Ј), 172.8III (C-2Ј), 175.2I (C-2), 177.0II (C-2)
ppm. C24H26N2O6. MS (EI): m/z (%) ϭ 438 (1) [Mϩ], 382 (7), 337
(19), 282 (100), 223 (33). HRMS: calcd. 438.1779; found 438.1791.
C24H26N2O6 (438.5): calcd. C 65.74, H 5.98, N 6.39; found C 65.19,
H 6.16, N 6.27.
Acknowledgments
This work was financed by the ADIR Company (Laboratoires
`
Servier), by the Ministere de la Recherche et de la Technologie, and
by the CNRS (Centre National de la Recherche Scientifique), to
which our gratitude is expressed.
[1]
´
C. Nemes, L. Jeannin, J. Sapi, M. Laronze, H. Seghir, F. Auge,
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1990, 38, 1396Ϫ1399.
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