Diels-Alder reactivity of 4-aryl-1-phthalimido-2-siloxy-1,3-butadienes

Article abstract of DOI:10.1016/j.tet.2005.04.076

The reaction of (1Z,3E) and (1E,3E) 4-aryl-1-phthalimido-2-trialkylsiloxy- 1,3-butadienes with maleimides and quinones has been studied. The observed exo-stereospecifity can be attributed to the simultaneous presence of the phthalimido and aryl groups, which produce strong hindrance during the endo approach.

Full text of DOI:10.1016/j.tet.2005.04.076

Tetrahedron 61 (2005) 6871–6878
Diels–Alder reactivity of
4-aryl-1-phthalimido-2-siloxy-1,3-butadienes
a
a
a
a
Esther Caballero,a, Dulce Alonso, Rafael Pelaez, Concepcion Alvarez, Pilar Puebla,
´
*
´
Francisca Sanz, Manuel Medarde and Fernando Tome
´
b
a
a,
*
´
a
´ ´ ´
Laboratorio de Quımica Organica y Farmaceutica, Facultad de Farmacia, Campus Miguel de Unamuno, 37007 Salamanca, Spain
b
´
Servicio difraccion de Rayos X, Salamanca, Spain
Received 16 February 2005; revised 13 April 2005; accepted 20 April 2005
Abstract—The reaction of (1Z,3E) and (1E,3E) 4-aryl-1-phthalimido-2-trialkylsiloxy-1,3-butadienes with maleimides and quinones has
been studied. The observed exo-stereospecifity can be attributed to the simultaneous presence of the phthalimido and aryl groups, which
produce strong hindrance during the endo approach.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Diels–Alder reactions carried out with this family of 1-(aryl
or heteroaryl)-3-trialkylsiloxy-1,3-butadienes, the endo
cycloadducts were obtained.
Trialkylsiloxy-1,3-butadienes have been used as versatile
reagents for the synthesis of functionalized ring systems via
the Diels–Alder cycloaddition reaction. The most well
known is 1-methoxy-3-trimethylsiloxy-1,3-butadiene,
Danishefsky’s diene (I)1 (Fig. 1), which shows high
reactivity towards a large number of dienophiles. Some
time ago we began a line of research aimed at the synthesis
of new siloxydienes, analogues of Danishefsky’s diene, that
contain at position C-1 an aromatic ring (the siloxy moiety
lying at position C-3) and are useful for the synthesis, via
Diels–Alder reaction, of 3-arylcyclohexenone derivatives as
intermediates for the synthesis of more complex polycyclic
systems related to marine alkaloids. As aryl groups we used
phenyl, carrying electron donor or withdrawing groups
(OMe, NO2),2 or heterocyclic moieties3 such as indole,
pyrrole or thiophene, these dienes showing high reactivity
with dienophiles such as maleimides or quinones. In all the
Due to the presence of amino groups and derivatives in a
large number of natural and synthetic products, we were
interested in the development of new dienes that, in addition
to these functional groups, would contain nitrogen group-
ings able to be transformed into the amino derivatives by
simple transformations. To this end, 1-phthalimido-4-(aryl
or heteroaryl)-2-trialkylsiloxy-1,3-butadienes (II) (Fig. 1)
were designed. The incorporation of both siloxy and amino
substituents into the diene structure has received little
attention, although in recent years Rawal’s group has been
actively studying the chemistry of 1-amino-3-siloxy-1,3-
butadienes (III) (Fig. 1).4 These authors have shown that
these dienes are highly reactive and that they undergo
Diels–Alder reaction with complete regiocontrol and in
some cases with exceptional diastereoselectivity. In our
case, we are interested in the development of similar dienes,
but changing the position between both groups. This change
should lead to 1-amino-4-aryl-2-trialkylsiloxy-2-cyclo-
hexenes that might be useful in the synthesis of different
types of alkaloids.5 The literature contains some references
to studies on trialkylsilyl enol ethers aimed at introducing
a-amino functionalization. Treatment with CAN/NaN3
accompanied by hydrolysis of the siloxy group gives
a-azidoketones,6 whereas treatment with (TsN)2Se allows
the enol function to be preserved and a-N-tosylamino-
siloxyderivatives7 to be obtained.
Figure 1.
Keywords: Aminosiloxybutadienes; Synthesis; Diels–Alder.
*
Corresponding authors. Tel.: C34 07923294528; fax: C34 07923294515
(E.C.); (F.T.); e-mail: escab@usal.es
In our case, we are currently attempting to obtain 1-amino-
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.04.076

6872
E. Caballero et al. / Tetrahedron 61 (2005) 6871–6878
Figure 2.
Scheme 1. Reagents and conditions: (i) PPh3/THF/reflux; (ii) Na2CO3/MeOH–H2O, rt; (iii) Ar-CHO (1 equiv), C6H6, reflux; (iv) Potassium phthalimide, DMF,
100 8C; (v) TIPSOTf, or TBDMSOTf, Et3N, CH2Cl2, 50 8C.
4-aryl-2-trialkylsiloxy-2-cyclohexenes through the Diels–
Alder reaction by the use of conveniently functionalized
dienes. First, we chose the phthalimido group as a precursor
of the amino group. In this sense some preliminary studies
have recently been published.8 1Z,3E-1-Phthalimido-4-(3-
indolyl)-2-siloxy-1,3-butadiene (1a), prepared from 1,3-
dichloroacetone, was assayed in the Diels–Alder reaction
with maleimides and quinones as dienophiles. The reaction
products 2 and 3 displayed the exo stereochemistry (Fig. 2),
as deduced from NMR spectroscopy and X-ray diffraction
studies, unlike the results obtained with related disubstituted
dienes lacking the phthalimido substituent at C-1.2a
2-nitroderivative 8. From this synthetic intermediate, both
stereoisomers 10a/10b and 11a/11b were obtained in a 3:1
ratio, by means of silylenolization in 2 h whereas from the
3-indole derivative 9 only 1a was produced. In the latter
case, longer reaction times (3 h or more) led to a mixture of
1a and its stereoisomer 1b in a 3:2 ratio.
The 3E configuration was established for all of these
compounds by analysis of their 1H NMR data, which
showed a large coupling constant (15.6 Hz) between H-3
and H-4. The 1Z configuration in 10a was deduced from the
correlations observed between H-1 and H-4 protons in
ROESY experiments (Fig. 3). Other correlations observed
between the H-1 and H-3, H-4 and TBDMS could be
explained in terms of the existence of an equilibrium
between the cisoid and the transoid conformers of 10a.
Diene 10b was more unstable than 10a, as observed after
In this full paper we present further information from
studies carried out with diene 1a, its 1E,3E stereoisomer 1b
and related dienes carrying a 2-nitrophenyl group at C-4.
2. Results and discussion
Following a similar methodology to that previously
described8 (Scheme 1), intermediate 4 was prepared from
1,3-dichloroacetone and converted into the chloroenones 5
and 6; very low yields were obtained. However, the
nucleophilic substitution on 4 with potassium phthalimide
took place conveniently to produce phosphorane 7, which
was coupled with 2-nitrobenzaldehyde, yielding the
Figure 3. Selected ROESY correlations for 10a.

E. Caballero et al. / Tetrahedron 61 (2005) 6871–6878
6873
Scheme 2. endo/exo Selectivity between 1aC1b and N-methylmaleimide.
20 h in CDCl3 solution, in which it isomerized to 10a,
accompanied by its transformation into enone 8.
dienes in solution, and either a higher reactivity of diene 1a
(kinetic control) or a higher stability of its adduct(s)
(thermodynamic control). Molecular mechanics calcu-
lations (as implemented in the MM2 forcefield of Macro-
model v.5.5) were carried out for representative endo and
exo Diels–Alder transition states of the reaction between 1a
or 1b and N-methylmaleimide and for the resulting
cycloadducts. The stabilities of exo (2a) and endo (2a0)
cycloadducts from 1a (1Z,3E) were similar, but lower than
those of cycloadducts that could be produced from 1b
(1E,3E).
As reported, the different reaction time conditions allowed
us to prepare 1a (1Z,3E) or the 1aC1b (1Z/E,3E) mixture,
and hence we were able to use either the single stereoisomer
or the mixture to study Diels–Alder reactivity.
In the first instance, we carried out the reaction between 1a
and maleimides (N-H, N-methyl, N-benzyl) and 2,5-
dichloroquinone, which gave exclusively the exo adducts
2a–d and 3.
Additionally, the exo transition state from 1a was calculated
to be 6.8–9.0 kJ/mol more stable than the endo one, and
more than 30 kJ/mol more stable than those from 1b. These
observations suggest that the reaction would be controlled
kinetically, yielding the less stable cycloadduct from the
more reactive diene 1Z,3E through the more stable exo
transition state. The interconversion of 1a and 1b under the
Following the same methodology, we performed the
reaction between N-methylmaleimide and the mixture
1aC1b (in 3:2 ratio), but only the exo cycloadduct 2a
was obtained with no reaction product derived from the E,E
stereoisomer 1b (Scheme 2). This implies a fast (as
compared to the Diels–Alder reaction) equilibration of the
Scheme 3. Diels–Alder reactivity of 1a, 1b with quinones.

6874
E. Caballero et al. / Tetrahedron 61 (2005) 6871–6878
reaction conditions accounts for the formation of the
cycloadducts derived only from the more reactive 1a
without the appearance of products derived from the less
reactive 1b. This interconversion was confirmed by
refluxing pure 1a in toluene, resulting in the formation of
the equilibrium mixture 1aC1b in a 3:2 ratio.
separate. We decided to use these mixtures in the Diels–
Alder reaction with N-methylmaleimide and compare the
results with those obtained from the 1aC1b mixture. The
reaction was carried out at a diene/dienophile 1:2 molar
ratio in refluxing toluene, but no reaction was observed after
2 days. No evolution of the reaction was detected, even
when EtAlCl2 (20%) was added as catalyst and the reaction
was heated to reflux. This lower reactivity could be
explained in terms of the presence of two electron-
withdrawing groups, the 2-nitrophenyl and the phthalimido
moieties. We have previously shown that when only one of
these electron-withdrawing groups is present, as is the case
of 4-(2-nitrophenyl)-2-trialkylsiloxy-1,3-butadiene,2b the
Diels–Alder reaction proceeds adequately.
Next, we carried out several experiments with 1a and
differently substituted quinones (Scheme 3, entries a and d),
and they gave the same stereochemical results as those
observed with the maleimides. Thus, exo cycloadducts 3 and
15 were obtained. The structure of compound 3, previously
described, has now been confirmed by X-ray diffraction
studies.9 Figure 4 shows an ORTEP diagram in which the
phthalimido and the chloro substituents occupy a pseudo-
equatorial disposition and the indolyl an pseudo-axial
disposition.
In view of the good results obtained in the previous Diels–
Alder reaction using the crude of the reaction produced in
the synthesis of dienes (carrying the excess of triflate
reagent), we decided to check the reactivity of dienes 10 and
11 again. The mixture 11a and 11b (3:1 ratio), without
removing the excess of the triisopropyltriflate, was reacted
with N-methylmaleimide and naphthoquinone, yielding 16
and 17 (Fig. 5) as the only reaction products after
purification by chromatography and crystallization. In
these products the exo stereochemistry was also proposed
based on the 1H NMR studies and it was confirmed by X-ray
studies of 17.9 The formation of other stereoisomers from 11
1
was not detected by H NMR of the reaction product.
Figure 5.
Figure 4. X-ray crystallographic analysis of 3.
However, when mixtures of dienes 1a and 1b were reacted
with an excess of quinones, mixtures of 3C12 and 13C14
were observed in the NMR spectra (Scheme 3, entries b and
c). The main differences between them correspond to the
H-2 of the indole (8.56 and 8.54 ppm) and H-3a (4.27 and
4.24 ppm) (values for 3/12). In these cases, both dienes
(1Z,3E and 1E,3E) afforded the corresponding adducts,
contrary to the case of maleimides, where only adducts from
diene 1a were observed. The observed ratio between 3 and
12 was the same as that of the starting dienes, implying that
both dienes have similar reactivities against the dichloro-
quinone and, since the reaction time (7 h) was similar to
those of maleimides, that diene 1b would be more reactive
in this case than in the former one. When the reaction time
required for the complete disappearance of diene was longer
(20 h), as in the case of 2-chloroquinone, a higher ratio of
the reaction product 13 derived from the 1Z,3E stereoisomer
(1a) was observed. This indicates that in the equilibrium
mixture diene 1a is still more reactive than 1b.
From the above results, a noteworthy preference for the exo
stereochemistry in the Diels–Alder reaction between the
title dienes and maleimides or quinones can be deduced.
Regardless of the nature of the C-4 aryl group, the presence
of the phthalimido moiety on the C-1 of the diene produced
a complete change of the preferred endo-stereochemistry of
4-aryl-2-siloxy-1,3-butadienes to the exo-stereochemistry
now observed. This change would be due to the presence of
a bulky N-substituent in the C-1 position of the diene and
also to secondary interactions between the phthalimido and
the aromatic ring with the dienophiles during the exo
approach. In the case of 1-amino-3-siloxybutadienes,
endo/exo mixtures, depending on the substituents of
amino group have been observed. A combination of steric
and electronic effects of dienes and dienophiles has been
proposed to explain the factors influencing the stereo-
selectivity of these cycloadditions.10 In any case, the high
exo-stereoselectivity now observed by us has not been
previously described.
The dienes containing the 2-nitrophenyl moiety 10 and 11
were obtained as mixtures 1Z/1E (3:1) that were difficult to
After optimizing the Diels–Alder reaction, some transform-
ations on the cycloadducts 2 were carried out to replace the

E. Caballero et al. / Tetrahedron 61 (2005) 6871–6878
6875
Scheme 4. Reagents and conditions: (i) HCl, CH2Cl2, rt; (ii) NH2NH2$H2O, EtOH, reflux; (iii) DDQ, C6H6, reflux; (iv) NH2NH2$H2O, THF, rt.
phthalimido by an amino group. These transformations are
of interest in the application of this methodology to the
synthesis of more elaborated polycyclic systems with fused
heterocycles in their structures. Unfortunately, the usual
deprotection of the phthalimido to the amino group by
treatment with hydrazine11 failed to produce any observable
change. Other deprotection reactions such as treatment with
methylamine,12 also failed and thus we decided to check
other transformations prior to the use of deprotecting agents.
1-Phthalimido-2-trialkylsiloxy-4-aryl-1,3-butadienes were
highly reactive when the crude of the silylation enone
reaction was used. The stereochemistry of the cycloadducts,
regardless of the structure of the aromatic moiety, changed
from the usually preferred endo when position C-4 was not
substituted to the exo, when the bulky N-phthalimido was
present in this position. The present methodology offers a
way to obtain fused cyclohexene rings containing amino
(under the protected phthalimido moiety) and an aromatic
(heteroaromatic) groups as substituents. The resulting
cycloadducts are versatile synthetic intermediates for the
preparation of diverse heterocyclic systems.
When cycloadduct 2a was treated with hydrochloric acid,
two reaction products were isolated: compound 18 resulting
from the double-bond migration, and the expected ketone 19
(Scheme 4). This migration has been observed for related
cycloadducts carrying the double bond and the trialkyl-
siloxy substituent at the same position, producing com-
pounds with the unsaturation closer to the ring system
junction.13 The preferred conformation of ketone 19 was
similar to that of compound 2a, as revealed by the large
coupling constants between H-3a and H-4 or H-7 and H-7a
4. Experimental
Melting points were determined on a Bu¨chi 510 instrument
and are uncorrected. NMR spectra were recorded on Bruker
400 MHz DRX spectrometer in CDCl3 as solvent with TMS
as internal standard. Mass spectra were obtained by EI or
FAB methods on a VGTS-250 mass spectrometer. Micro-
analyses were carried out on Perkin-Elmer 2400 CHN. Flash
chromatography was performed with Merck 60 silica gel
(0.063–0.2 or 0.040–0.063 mm).
1
in the H NMR spectrum, in agreement with the pseudo-
equatorial disposition of the phthalimido and indol-3-yl
moieties. Ketone 19 gave hydrazone 20 by treatment with
hydrazine but no product containing the amino function at
the C-4 position was detected.
4.1. Preparation of (E)-N-[4-(aryl or 3-indolyl)-2-oxo-3-
butenyl]phthalimide 8 and 9
Another key step in the synthesis of fused polycyclic
systems is the aromatization of the central cyclohexene ring
to the corresponding benzene ring. In the present case, it is
of interest to know whether this process takes place with or
without elimination of the phthalimido moiety. Mainten-
ance of the nitrogenated function is necessary for the
construction of fused heterocycles, such as oxazoles. The
aromatization of 2a to 21 under DDQ standard conditions
occurred in high yield, preserving the phthalimido moiety.
Treatment of 21 with hydrazine afforded the expected
deprotection of the amino group, thus obtaining the
aminophenol derivative 22.
To 1,3-dicholoroacetone (7.0 g, 55 mmol), a solution of
triphenylphosphine (13.1 g, 50 mmol) in THF (33 mL) was
added and the mixture was refluxed for 4 h. The mono-
phosphonium chloride thus formed was isolated by filtration
(15.6 g, 73%) and then treated with a solution of Na2CO3/
MeOH–H2O (1:1) at rt. After 30 min a precipitate appeared,
4, and was filtered from the solution (12.2 g, 89%). To a
suspension of 4 (3 mmol) in dry benzene, a solution of the
2-nitrobenzaldehyde (1 mmol) or N-(phenylsulphonyl)-3-
indolylcarbaldehyde (1 mmol) was added. Compound 5
(54%) was obtained after reflux for 24 h, purification by
chromatography and crystallization. In the case of 6, the
reaction was much slower and after 4 days at reflux it was
isolated in 15% yield.
3. Conclusions
We have efficiently prepared new trisubstituted dienes
and studied their reactivity against different dienophiles.
A solution of 4 (1.5 g, 4.25 mmol) in DMF (5 mL) was

6876
E. Caballero et al. / Tetrahedron 61 (2005) 6871–6878
added dropwise to a stirred suspension of potassium
phthalimide (2.4 g, 12.7 mmol) in DMF (35 mL) and left
to reflux for 45 min. After extraction with EtOAc, it was
washed with water and brine, dried and evaporated in vacuo,
and the residue was crystallized (ether/MeOH) to obtain 7
(1.1 g, 62%). To phosphorane 7 (1.5 mmol), under the same
conditions described previously, the corresponding alde-
hyde (1 mmol) was added to give, after 2 h of reaction, 8
(78%). Phosphorane 7 (1 mmol) and N-(phenylsulphonyl)-
3-indolylcarbaldehyde (2 mmol), under the conditions
described previously, yielded 9 (79%) after 72 h of reaction.
H-3, 6Pht), 7.75 (2H, dd, JZ5.2, 3.2 Hz, H-4, 5Pht), 7.68
(1H, dd, JZ7.6, 0.8 Hz, H-6Ar), 7.59 (1H, td, JZ8.0,
0.8 Hz, H-5Ar), 7.45 (1H, d, JZ15.6 Hz, H-4), 7.40 (1H, td,
JZ8.4, 0.8 Hz, H-4Ar), 6.73 (1H, d, JZ15.6 Hz, H-3), 5.95
(1H, s, H-1), 0.90 (9H, TBDMS), 0.00 (6H, TBDMS). 13C
NMR (d ppm) 166.3 (2-C), 149.8 (C), 148.2 (C), 134.4
(2-CH), 133.0 (CH), 132.3 (2-C), 131.7 (C), 129.3 (CH),
128.5 (CH), 128.1 (CH), 125.6 (CH), 124.8 (CH), 123.6
(2-CH), 105.2 (CH), 25.6 (3-CH3), 18.2 (C), K4.2 (2-CH3).
4.2.2. Characteristic signals for 10b. 1H NMR (d ppm) 7.34
(1H, d, JZ15.3 Hz, H-4), 6.53 (1H, d, JZ15.3 Hz, H-3),
5.80 (1H, s, H-1).
4.1.1. Data for 4. White solid. Mp 180 8C (MeOH/H2O); 1H
NMR (d ppm) 7.8–7.2 (15H, m), 4.28 (1H, d, JZ23.8 Hz),
4.02 (2H, s).
4.3. Diels–Alder reaction. General procedure
4.1.2. Data for 5. Yellow solid. 1H NMR (d ppm) 8.10 (1H,
d, JZ16.0 Hz), 8.06 (1H, d, JZ8.4 Hz), 8.1–7.5 (3H, m),
6.82 (1H, d, JZ16.0 Hz), 4.34 (2H, s).
The corresponding diene (obtained without removing the
excess of triisopropylsilyltriflate) (1 equiv) and dienophile
(maleimides or quinones) (2–2.2 equiv) were dissolved in
dry toluene and allowed to react at reflux for several hours
under Ar atmosphere. The reaction products were purified
by chromatography and crystallization to give compounds
3, 13–17.
1
4.1.3. Data for 6. Yellow solid. H NMR (d ppm) 8.0–7.3
(9H, m), 7.94 (1H, s), 7.84 (1H, d, JZ15.8 Hz), 7.09 (1H, d,
JZ15.8 Hz), 4.28 (2H, s).
4.1.4. Data for 7. White solid. Mp 222 8C (ether/MeOH);
1H NMR (d ppm) 7.81 (2H, dd, JZ5.0, 3.3 Hz), 7.7–7.5
(15H, m), 7.39 (2H, dd, JZ5.3, 3.3 Hz), 4.46 (2H, s), 3.68
(1H, d, JZ23.0 Hz).
4.3.1. (6)(1R,4S,4aR,8aS)-2-[4-(1-Benzenesulfonyl-1H-
indol-3-yl)-4a,7-dichloro-5,8-dioxo-2-triisopropylsiloxy-
1,4,4a,5,8,8a-hexahydro-1-naphthyl]isoindole-1,3-dione
(3). After 7 h reflux, 3 was isolated in 85% yield as a brown
1
solid. Mp 242 8C (hexane/AcOEt). H NMR (d ppm) 8.56
4.1.5. Data for 8. Yellow solid. Mp 180 8C (ether); 1H NMR
(d ppm) 8.18 (1H, d, JZ16.4 Hz), 8.10 (1H, d, JZ8.2 Hz),
7.90 (2H, dd, JZ5.2, 3.2 Hz), 7.7–7.5 (3H, m), 7.76 (2H,
dd, JZ5.2, 3.2 Hz), 6.70 (1H, d, JZ16.4 Hz), 4.85 (2H, s).
Anal. Calcd for C18H12N2O5: C, 64.29; H, 3.60; N, 8.33.
Found: C, 64.46; H, 3.83; N, 8.15. HRMS m/z calcd for
C18H12N2O5 336.0746, found 336.0792.
(1H, s, H-2 Ind), 8.2–7.2 (13H, Ar), 7.17 (1H, s, H-1), 5.12
(1H, dd, JZ6.0, 1.2 Hz, H-6), 5.04 (1H, dt, JZ10.8, 1.2 Hz,
H-4), 4.77 (1H, dd, JZ6.0, 1.2 Hz, H-7), 4.27 (1H, d, JZ
10.8 Hz, H-3a), 1.0–0.9 (TIPS). 13C NMR (d ppm) 186.6
(C), 186.5 (C), 167.6 (C), 166.8 (C), 145.7 (C), 144.3 (C),
137.4 (C), 135.4 (C), 134.6 (2-CH), 133.9 (CH), 133.6 (CH),
131.8 (C), 131.4 (C), 131.1 (C), 129.1 (2-CH), 126.8
(2-CH), 124.7 (CH), 123.9 (CH), 123.8 (2-CH), 123.2 (CH),
121.8 (C), 120.1 (CH), 114.0 (CH), 104.7 (CH), 69.4 (C),
54.2 (CH), 49.1 (CH), 34.4 (CH), 17.6 (6-CH3), 12.7
(3-CH). HRMS m/z Calcd for C41H40Cl2N2O7SSi 802.1703,
found 802.1780.
4.1.6. Data for 9. Yellow solid. Mp 184 8C (ether); 1H NMR
(d ppm) 8.02 (1H, dd, JZ7.2, 2.0 Hz), 7.94 (1H, s), 7.9–7.3
(12H, m), 7.83 (1H, d, JZ16.4 Hz), 6.93 (1H, d, JZ
16.4 Hz), 4.78 (2H, s). Anal. Calcd for C26H18N2O5S: C,
66.37; H, 3.86; N, 5.95; S, 6.82. Found: C, 66.08; H, 4.12;
N, 6.03; S, 6.66. HRMS m/z calcd for C26H18N2O5S
470.0936, found 470.0951.
Characteristic signals for 12. 1H NMR (d ppm) 8.54 (1H, s,
H-2 Ind), 4.24 (1H, d, JZ10.8 Hz, H-3a).
4.2. General procedure for the preparation of 2-trialkyl-
siloxy-4-(2-nitrophenyl)-1-phthalimido-1,3-butadienes
(10 and 11)
4.3.2. (6)(1R,4S,4aR,8aS)-2-[4-(1-Benzenesulfonyl-1H-
indol-3-yl)-4a-chloro-5,8-dioxo-2-triisopropylsiloxy-
1,4,4a,5,8,8a-hexahydro-1-naphthyl]isoindole-1,3-dione
1
(13). After 20 h reflux, a mixture 8:2 ratio (in H NMR) of
13 and 14 was isolated in 79% yield as a brown solid. Data
To a solution of enone 8 (1 mmol) in CH2Cl2 (20 mL) under
Ar, Et3N (5.4 mmol) and tert-butyldimethyl- or triiso-
propylsilyltriflate (4 mmol) were added dropwise. The
reaction mixture was allowed to react at 50 8C for 2 h, and
then Et3N (1 mmol) was added. The mixture was diluted in
CH2Cl2, washed with aqueous saturated NaHCO3 and brine,
dried (Na2SO4) and the solvent evaporated.
1
for 13: H NMR (d ppm) 8.58 (1H, s, H-2 Ind), 8.1–7.2
(13H, Ar), 6.91 (1H, d, JZ10.4 Hz, H1), 6.67 (1H, dd, JZ
10.4, 2.0 Hz, H-2), 5.13 (1H, dd, JZ6.0, 1.2 Hz, H-6), 5.06
(1H, dt, JZ10.8, 1.2 Hz, H-4), 4.76 (1H, dd, JZ6.0, 1.2 Hz,
H-7), 4.13 (1H, dd, JZ10.8, 2.0 Hz, H-3a), 1.0–0.9 (TIPS).
13C NMR (d ppm) 193.8 (C), 189.0 (C), 127.0 (2-C), 144.4
(C), 138.1 (C), 137.6 (C), 137.1 (C), 137.0 (CH), 134.5
(2-CH), 133.6 (CH), 131.9 (C), 131.5 (C), 131.2 (C), 129.0
(2-CH), 127.0 (2-CH), 124.6 (CH), 123.9 (2-CH), 123.6
(CH), 123.1 (CH), 122.1 (C), 120.2 (CH), 114.0 (CH), 104.5
(CH), 69.1 (C), 54.4 (CH), 49.3 (CH), 34.4 (CH), 16.6
(6-CH3), 13.7 (3-CH). HRMS m/z calcd for C41H41ClN2-
O7SSi 768.2092, found 768.2105.
The corresponding reaction product was purified by flash
chromatography on SiO2 eluting with hexane/ether (1:1) to
give 10a (63%) and 10b (21%).
4.2.1. Data for 10a. Yellow oil. 1H NMR (d ppm) 7.93 (1H,
dd, JZ8.4, 1.2 Hz, H-3Ar), 7.89 (2H, dd, JZ5.2, 3.2 Hz,

E. Caballero et al. / Tetrahedron 61 (2005) 6871–6878
6877
Characteristic signals for 14. 1H NMR 8.53 (d ppm) (1H, s,
H-2 Ind), 4.11 (1H, dd, JZ10.8, 2.0 Hz, H-3a).
saturated NaHCO3 dried and evaporated. The reaction
product was chromatographed on silica (hexane/EtOAc 7:3)
to give 18 (38 mg, 50%) and 19 (22 mg, 36%).
4.3.3. (6)(1R,4R,4aS,9aS)-2-[4-(1-Benzenesulfonyl-1H-
indol-3-yl-9,10-dioxo-2-triisopropylsiloxy-1,4,4a,9,9a,
10-hexahydro-1-anthryl]isoindole-1,3-dione (15). After
13 h reflux, 15 was isolated in 90% as a white solid. Mp
225 8C (hexane/AcOEt). 1H NMR (d ppm) 8.11 (1H, s, H-2
Ind), 8.3–7.2 (17H, Ar), 5.25 (1H, dd, JZ5.2, 1.6 Hz, H-6),
4.89 (1H, dd, JZ11.2, 1.6 Hz, H-4), 4.80 (1H, d, JZ5.2 Hz,
H-7), 3.89 (1H, dd, JZ11.2, 4.8 Hz, H-3a), 3.40 (1H, d, JZ
4.8 Hz, H-7a), 1.0–0.9 (TIPS). 13C NMR (d ppm) 195.1 (C),
194.7 (C), 167.8 (C), 167.6 (C), 145.7 (C), 137.9 (C), 135.8
(C), 134.8 (CH), 134.6 (2-CH), 134.3 (CH), 134.1 (CH),
134.1 (C), 133.6 (CH), 133.1 (C), 131.9 (2-C), 129.3 (C),
129.0 (2-CH), 127.4 (CH), 127.2 (2-CH), 127.0 (CH), 126.7
(CH), 124.8 (CH), 124.1 (C), 123.3 (2-CH), 118.5 (CH),
114.2 (CH), 103.5 (CH), 50.7 (CH), 48.3 (CH), 47.3 (CH),
28.7 (CH), 17.7 (6-CH3), 12.4 (3-CH). HRMS m/z calcd for
C45H44N2O7SSi 784.2716, found 784.2726.
4.4.1. (6)(3aS,4R,7aS)-4-(1-Benzenesulfonyl-1H-indol-3-
yl)-2-methyl-7-phthalimido-6-triisopropylsiloxy-3a,
4,5,7a-tetrahydroisoindole-1,3-dione (18). White solid.
1
Mp 252 8C (ether/MeOH). H NMR (d ppm) 8.04 (1H, d,
JZ8.2 Hz, H-7 Ind), 7.93 (1H, s, H-2 Ind), 7.56 (1H, d, JZ
7.2 Hz, H-4 Ind), 7.35 (1H, t, JZ8.2 Hz, H-6 Ind), 7.3–8.2
(10H, m, Ar), 4.20 (1H, m, H-7), 4.04 (1H, dd, JZ8.0,
2.4 Hz, H-3a), 3.42 (1H, t, JZ8.0 Hz, H-7a), 3.02 (3H, s,
N-Me), 2.86 (1H, ddd, JZ16.8, 2.8, 1.2 Hz, H-6), 2.38 (1H,
d, JZ16.8 Hz, H-6), 1.0–0.8 (TIPS). 13C NMR (d ppm)
177.2 (C), 175.2 (C), 167.8 (C), 166.0 (C), 149.7 (C), 133.9
(CH), 133.8 (CH), 138.2 (C), 134.7 (C), 133.5 (CH), 132.5
(C), 132.2 (C), 129.5 (C), 129.1 (2-CH), 127.4 (2-CH),
124.9 (CH), 123.6 (CH), 123.5 (CH), 123.3 (CH), 123.1
(CH), 122.3 (C), 118.6 (CH), 113.7 (CH), 102.1 (C), 44.2
(CH), 41.3 (CH), 32.3 (CH2), 28.1 (CH), 25.1 (CH3), 16.9
(6-CH3), 12.8 (3-CH). Anal. Calcd for C40H43N3O7SSi: C,
65.10; H, 5.87; N, 5.69; S, 4.35. Found: C, 65.34; H, 6.00;
N, 5.91; S, 4.19.
4.3.4. (6)(3aS,4R,7R,7aS)-2-Methyl-7-(2-nitrophenyl)-4-
phthalimido-5-triisopropylsiloxy-3a,4,7,7a-tetrahydro
isoindole-1,3-dione (16). After 7 h reflux, 16 was isolated in
87% yield as a yellow solid. 1H NMR (d ppm) 7.90 (1H, dd,
JZ7.8, 1.5 Hz, H-3Ar), 7.79 (1H, dd, JZ7.8, 1.5 Hz,
H-6Ar), 7.71 (1H, td, JZ7.8, 1.5 Hz, 1H, H-5Ar), 7.45 (1H,
dt, JZ7.8, 1.5 Hz, H-4Ar), 7.7–8.0 (4H, m, Pht), 5.10 (1H,
dt, JZ8.0, 2.4 Hz, H-4), 4.91 (1H, t, JZ2.4 Hz, H-6), 4.50
(1H, dt, JZ8.0, 2.4 Hz, H-7), 3.82 (1H, t, JZ8.0 Hz, H-3a),
3.27 (1H, t, JZ8.0 Hz, H-7a), 2.99 (3H, s, N-Me), 1.1–0.8
(TIPS). 13C NMR (d ppm) 176.3 (2-C), 167.7 (2-C), 149.4
(C), 147.4 (C), 138.1 (C), 134.1 (2-CH), 133.5 (CH), 131.9
(2-C), 130.6 (CH), 128.0 (CH), 124.6 (CH), 123.4 (2-CH),
103.8 (CH), 46.1 (CH), 45.4 (CH), 42.8 (CH), 35.1 (CH),
24.8 (CH3), 17.7 (6-CH3), 12.4 (3-CH). HRMS m/z calcd for
C32H37N3O7Si 603.2401 found, 603.2479.
4.4.2. (6)(3aS,4R,7R,7aS)-7-(1-Benzenesulfonyl-1H-
iso-
indol-3-yl)-2-methyl-4-phthalimidotetrahydro
indole-1,3,5-trione (19). White solid. Mp 196 8C (ether/
MeOH). 1H NMR (d ppm) 7.98 (1H, d, JZ8.2 Hz, H-7 Ind),
7.70 (1H, s, H-2 Ind), 7.55 (1H, d, JZ7.3 Hz, H-4 Ind), 7.35
(1H, t, JZ7.2 Hz, H-6 Ind), 7.2–8.0 (10H, m, Ar), 5.09 (1H,
d, JZ12.1 Hz, H-4), 4.17 (1H, dd, JZ12.0, 9.4 Hz, H-3a),
3.93 (1H, td, JZ11.0, 4.8 Hz, H-7), 3.73 (1H, dd, JZ11.0,
9.4 Hz, H-7a), 2.98 (3H, s, N-Me), 2.93 (2H, m, H-6). 13C
NMR (d ppm) 199.1 (C), 175.3 (2-C), 167.4 (2-C), 138.0
(C), 135.3 (C), 134.3 (2-CH), 133.8 (CH), 131.7 (2-C),
129.2 (2-CH), 126.9 (2-CH), 125.2 (CH), 124.1 (CH), 123.8
(2-CH), 123.4 (CH), 121.3 (C), 119.0 (CH), 117.4 (C), 114.1
(CH),54.1(CH),43.9(CH),43.7(CH2),39.0(CH), 30.4(CH),
25.1 (CH3). Anal. Calcd for C31H23N3O7S: C, 64.02; H, 3.99;
N, 7.22; S, 5.51. Found: C, 64.34; H, 4.020; N, 7.51; S, 5.19.
4.3.5. (6)(1R,4R,4aS,9aS)-2-[4-(2-Nitrophenyl-9,10-
dioxo-2-triisopropylsiloxy-1,4,4a,9,9a,10-hexahydro-1-
anthryl]isoindole-1,3-dione (17). After 7 h reflux, 17 was
1
isolated in 84% yield as a brown solid. H NMR (d ppm)
4.4.3. (6)(3aS,4R,7R,7aS)-7-(1-Benzenesulfonyl-1H-
indol-3-yl)-5-hydrazono-2-methyl-4-phthalimido hexa-
hydroisoindole-1,3-dione (20). One millimole of 19 in
EtOH was treated with 3 mmol of hydrazine hydrate for
24 h at reflux. By crystallization, 20 was isolated in 90%
yield as a yellow solid. Mp 239 8C (ether/MeOH). 1H NMR
(d ppm) 7.96 (1H, d, JZ8.2 Hz, H-7 Ind), 7.72 (1H, s, H-2
Ind), 7.52 (1H, d, JZ7.3 Hz, H-4 Ind), 7.33 (1H, t, JZ
7.2 Hz, H-6 Ind), 7.2–8.0 (10H, m, Ar), 5.26 (1H, d, JZ
12.0 Hz, H-4), 4.38 (1H, dd, JZ12.0, 9.2 Hz, H-3a), 3.68
(1H, td, JZ9.0, 4.0 Hz, H-7), 3.59 (1H, t, JZ9.2 Hz, H-7a),
2.94 (3H, s, N-Me), 2.93 (2H, m, H-6). 13C NMR (d ppm)
175.8 (2-C), 167.9 (2-C), 141.1 (C), 138.1 (C), 134.0
(2-CH), 135.3 (C), 132.0 (2-C), 133.7 (CH), 129.2 (2-CH),
126.9 (2-CH), 126.0 (CH), 125.8 (C), 124.1 (CH), 123.8
(2-CH), 123.5 (CH), 121.9 (C), 119.1 (CH), 114.1 (CH),
49.3 (CH), 43.5 (CH), 39.2 (CH), 31.7 (CH2), 30.4 (CH),
24.9 (CH3). Anal. Calcd for C31H24N4O6: C, 64.10; H, 4.17;
N, 9.85; S, 5.52. Found: C, 63.90; H, 4.46; N, 9.88; S, 5.49.
8.41 (1H, dd, JZ8.1, 1.2 Hz, H-6Ar), 8.17 (1H, dd, JZ7.5,
1.2 Hz, H-9), 7.96 (1H, dd, JZ7.5, 1.2 Hz, H-2), 7.92 (1H,
dd, JZ8.1, 1.2 Hz, H-3Ar), 7.76 (1H, td, JZ8.0, 1.2 Hz,
1H, H-5Ar), 7.7–7.9 (6H, m, H-1, H-10, Pht), 7.46 (1H, dt,
JZ8.1, 1.2 Hz, H-4Ar), 5.08 (1H, d, JZ5.2 Hz, H-7), 5.05
(1H, dd, JZ5.2, 1.2 Hz, H-6), 4.95 (1H, dd, JZ10.8,
1.2 Hz, H-4), 4.00 (1H, dd, JZ10.8, 4.8 Hz, H-3a), 3.82
(1H, d, JZ4.8 Hz, H-7a), 1.1–0.8 (TIPS). 13C NMR (d ppm)
195.2 (C), 193.6 (C), 167.6 (2C), 148.9 (C), 146.9 (C), 137.3
(C), 134.8 (CH), 134.6 (CH), 133.5 (C), 133.4 (CH), 132.8
(CH), 131.8 (2-CH), 131.7 (2-C), 130.3 (C), 128.0 (CH),
127.4 (CH), 127.3 (CH), 127.0 (CH), 123.3 (2-CH), 104.2
(CH), 51.9 (CH), 48.3 (CH), 47.5 (CH), 33.8 (CH), 17.3
(6-CH3), 12.7 (3-CH). HRMS m/z calcd for C37H38N2O7Si
650.2448, found 650.2526.
4.4. Hydrolysis of cycloadduct 2a (18 and 19)
Compound 2a (75 mg, 0.10 mmol) dissolved in 4 mL of
CH2Cl2 was treated with concentrated HCl (360 ml) and
then stirred for 24 h. The reaction mixture was washed with
4.4.4. 7-(1-Benzenesulfonyl-1H-indol-3-yl)-2-methyl-4-
phthalimido-5-triisopropylsiloxyisoindole-1,3-dione

6878
E. Caballero et al. / Tetrahedron 61 (2005) 6871–6878
(21). To 2a (50 mg, 0.07 mmol) dissolved in benzene
(4 mL) was added DDQ (22 mg, 0.09 mmol), and the
mixture was refluxed for 24 h. The crude reaction was
diluted in AcOEt, washed with NaHCO3 and brine, dried
References and notes
1. Danishefsky, S. J.; DeNinno, M. P. Angew. Chem., Int. Ed.
Engl. 1987, 26, 15–23.
´
2. (a) Adeva, M.; Sahagun, H.; Caballero, E.; Pelaez-Lamamie de
1
and evaporated to yield 21 (38 mg, 75%). Red solid. H
NMR (d ppm) 8.20 (1H, s, H-2 Ind), 8.01 (1H, d, JZ7.0 Hz,
H-7 Ind), 7.3–8.1 (12H, m, Ar), 7.38 (1H, s, H-6), 3.07 (3H,
s, N-Me), 1.1–0.9 (TIPS). 13C NMR (d ppm) 173.1 (C),
172.6 (C), 166.5 (C), 165.8 (C), 158.1 (C), 138.0 (C), 134.9
(C), 134.4 (2-CH), 134.0 (CH), 132.7 (2-C), 129.2 (2-CH),
128.0 (CH), 127.3 (2-CH), 126.5 (C), 125.0 (CH), 124.5 (C),
124.4 (CH), 123.6 (CH), 123.9 (2-CH), 121.0 (C), 120.1 (C),
119.6 (CH), 118.3 (C), 116.0 (C), 114.0 (CH), 24.0 (CH3),
17.3 (6-CH3), 12.7 (3-CH).
´
Clairac, R.; Medarde, M.; Tome, F. J. Org. Chem. 2000, 65,
3387–3394. (b) Adeva, M.; Buono, F.; Caballero, E.; Medarde,
´
M.; Tome, F. Synlett 2000, 832–834.
3. Caballero, E.; Longieras, N.; Zausa, E.; Del Rey, B.; Medarde,
´
M.; Tome, F. Tetrahedron Lett. 2001, 42, 7233–7236.
4. Kozmin, S. A.; Iwama, T.; Huang, Y.; Rawal, V. H. J. Am.
Chem. Soc. 2002, 124, 4628–4641.
5. (a) Berlinck, R. G. S.; Britton, R.; Piers, E.; Lim, L.; Roberge,
M.; Moreira da Rocha, R.; Andersen, R. J. J. Org. Chem. 1998,
63, 9850–9856. (b) Britton, R.; de Oliveira, J. H. H. L.;
Andersen, R. J.; Berlinck, R. G. S. J. Nat. Prod. 2001, 64,
254–255.
4.4.5. 4-Amino-7-(1-benzenesulfonyl-1H-indol-3-yl)-5-
hydroxy-2-methylisoindole-1,3-dione (22). One millimole
of 21 in THF was treated with an excess of hydrazine
hydrate for 20 h at rt. The reaction product was submitted to
6. Magnus, P.; Barth, L. Tetrahedron Lett. 1992, 33, 2777–2780.
7. Magnus, P.; Lacour, J.; Coldham, I.; Mugrage, B.; Bauta,
W. B. Tetrahedron 1995, 51, 11087–11110.
1
chromatography to give 22 in 41% yield as a red solid. H
NMR (d ppm) 8.02 (1H, dd, JZ7.2, 1.6 Hz, H-7 Ind), 7.98
(1H, s, H-2 Ind), 7.4–8.0 (5H, m, Ar), 7.38 (1H, s, H-6), 7.28
(1H, t, JZ7.2 Hz, H-6 Ind), 7.19 (1H, t, JZ7.2 Hz, H-5
Ind), 6.98 (1H, s, H-6), 3.08 (3H, s, N-Me). 13C NMR (d
ppm) 169.6 (C), 168.7 (C), 167.6 (C), 147.9 (C), 143.0 (C),
140.3 (C), 138.0 (C), 135.1 (C), 134.7 (C), 133.8 (CH),
129.2 (2-CH), 127.1 (2-CH), 126.6 (CH), 124.6 (CH), 123.3
(CH), 120.0 (CH), 118.9 (CH), 117.3 (C), 113.6 (CH), 102.6
(C), 23.5 (CH3). HRMS m/z calcd for C23H17N3O5S
447.0889, found 447.0892.
´
8. Caballero, E.; Alonso, D.; Pelaez, R.; Alvarez, C.; Puebla, P.;
´
´
Sanz, F.; Medarde, M.; Tome, F. Tetrahedron Lett. 2004, 45,
1631–1634.
9. Crystallographic data (excluding structure factors) for 3 and 17
has been deposited at the Cambridge Crystallographic Data
Centre as supplementary material no. CCDC 268249-268250.
10. Kozmin, S. A.; Janey, J. M.; Rawal, V. H. J. Org. Chem. 1999,
64, 3039–3052.
11. Sasse, A.; Kiec-Kononowicz, K.; Stara, H.; Motyl, M.;
Reidemeister, S.; Ganellin, C. R.; Ligneau, X.; Schwartz,
J. C.; Schunack, W. J. Med. Chem. 1999, 42, 593–600.
12. Wolfe, S.; Hasan, S. K. Can. J. Chem. 1970, 48, 3572–3579.
Acknowledgements
´
13. Crilley, M. M. L.; Larsen, D. S.; Stoodley, R. J.; Tome, F.
Financial support was provided by the Spanish MCyT and
the European FEDER Funds (PPQ2000-1179; CTQ2004-
Tetrahedron Lett. 1993, 34, 3305–3308.
´
00369/BQU) and from Junta de Castilla y Leon (SA048/03).
C. Alvarez thanks the Spanish MCyT for a predoctoral
grant.