Complete and remarkable reversal of chemoselectivity in [4 + 2] cycloadditions involving electron-poor indoles as dienophiles. Diels-Alder versus hetero-Diels-Alder processes

Article abstract of DOI:10.1021/jo034719b

The reaction between indole-3-carboxaldehyde 1a or indole-3-glyoxalate 1b and 2,3-dimethylbutadiene under thermal activation leads exclusively to the Diels-Alder cycloadducts resulting from the participation of the indole 2,3-carbon-carbon double bond. The concomitant use of zinc chloride and high pressure (16 kbar) induces the primary cycloadduct to react further, and biscycloadducts 11 and 12 are now isolated in high yields, the result of two consecutive [4 + 2] processes on, first, the indole 2,3 C=C bond and, second, the 3-carbonyl unit. The possibility of using two different dienes in a tandem, sequential process is demonstrated by the preparation of tetracycle 13. Interactions between the carbonyl dienophile and Danishefsky diene yield exclusively yet another type of product, namely the γ-dihydropyranones arising from the sequential [4 + 2] heterocycloaddition, hydrolysis of the silyl enol ether, and loss of methanol. Isolation of the Mukaiyama-type adduct 16 indicates that a stepwise mechanism may be involved, at least under zinc chloride catalysis. N,N-Disubstituted indole-3-glyoxamides undergo the expected, usual Diels-Alder process, with the 2,3 C=C bond acting as dienophile, and cycloadducts of the type 3 are obtained in high yields, regardless of the mode of activation. Remarkably, however, N-monosubstituted indole-3-glyoxamides react almost exclusively as heterodienophiles, the 3-carbonyl unit being now the preferred site of reactivity, and y-dihydropyranones of the type 6 are isolated in yields ranging from 72 to 92%. Conformational analysis of the Diels-Alder adducts based on both ¹H NMR spectrometry and X-ray diffraction data indicates that the newly created cyclohexene and cyclohexanone rings adopt a pseudoboat conformation.

Full text of DOI:10.1021/jo034719b

Com p lete a n d Rem a r k a ble Rever sa l of Ch em oselectivity in [4 + 2]
Cycloa d d ition s In volvin g Electr on -P oor In d oles a s Dien op h iles.
Diels-Ald er ver su s Heter o-Diels-Ald er P r ocesses
Antony Chre´tien, Isabelle Chataigner, Nathalie L’He´lias, and Serge R. Piettre*
Laboratoire des Fonctions Azote´es et Oxyge´ne´es Complexes, UMR CNRS 6014,
IRCOF-Universite´ de Rouen, Rue Tesnie`res, F-76821 Mont Saint Aignan, France
serge.piettre@univ-rouen.fr
Received May 28, 2003
The reaction between indole-3-carboxaldehyde 1a or indole-3-glyoxalate 1b and 2,3-dimethylbuta-
diene under thermal activation leads exclusively to the Diels-Alder cycloadducts resulting from
the participation of the indole 2,3-carbon-carbon double bond. The concomitant use of zinc chloride
and high pressure (16 kbar) induces the primary cycloadduct to react further, and biscycloadducts
11 and 12 are now isolated in high yields, the result of two consecutive [4 + 2] processes on, first,
the indole 2,3 CdC bond and, second, the 3-carbonyl unit. The possibility of using two different
dienes in a tandem, sequential process is demonstrated by the preparation of tetracycle 13.
Interactions between the carbonyl dienophile and Danishefsky diene yield exclusively yet another
type of product, namely the γ-dihydropyranones arising from the sequential [4 + 2] heterocycload-
dition, hydrolysis of the silyl enol ether, and loss of methanol. Isolation of the Mukaiyama-type
adduct 16 indicates that a stepwise mechanism may be involved, at least under zinc chloride
catalysis. N,N-Disubstituted indole-3-glyoxamides undergo the expected, usual Diels-Alder process,
with the 2,3 CdC bond acting as dienophile, and cycloadducts of the type 3 are obtained in high
yields, regardless of the mode of activation. Remarkably, however, N-monosubstituted indole-3-
glyoxamides react almost exclusively as heterodienophiles, the 3-carbonyl unit being now the
preferred site of reactivity, and γ-dihydropyranones of the type 6 are isolated in yields ranging
from 72 to 92%. Conformational analysis of the Diels-Alder adducts based on both 1H NMR
spectrometry and X-ray diffraction data indicates that the newly created cyclohexene and
cyclohexanone rings adopt a pseudoboat conformation.
In tr od u ction
cally active alkaloids.3-5 Because of their high electron
density, such systems have been mostly studied as
The Diels-Alder (DA) reaction has proven to be a
convenient way to assemble complex six-membered cycles
due to its versatility as well as its high regio- and
stereoselectivities.1 The scope of this class of cycloaddition
is very large and allows not only the synthesis of
cyclohexene derivatives but also of a variety of hetero-
cycles by swapping carbon atoms on the diene and/or the
dienophile component with heteroatoms (O, N, S for
instance; the so-called hetero-Diels-Alder (HDA) reac-
tion).2
(3) (a) Takahashi, T.; Ishida, H.; Kohmoto, M. Bull Chem. Soc. J pn
1976, 49, 1725-1726. (b) Raasch, M. S. J . Org. Chem. 1980, 45, 856-
867. (c) Benson, S. C.; Palabrica, C. A.; Snyder, J . K. J . Org. Chem.
1987, 52, 4610-4614. (d) Ba¨ckwall, J .-E.; Plobeck, N. A. J . Org. Chem.
1990, 55, 4528-4531. (e) Gieseler, A.; Steckhan, E.; Wiest, O.; Knoch,
F. J . Org. Chem. 1991, 56, 1405-1411. (f) Markgraf, J . H.; Patterson,
D. E. J . Heterocycl. Chem. 1996, 33, 109-111. (g) Haberl, U.; Steckhan,
E.; Blechert, S.; Wiest, O. Chem. Eur. J . 1999, 5, 2859-2865. (h) Hsieh,
M.-F.; Rao, P. D.; Liao, C. C. Chem. Commun. 1999, 1441-1442. (i)
Lee, L.; Snyder, J . K. Adv. Cycloaddit. 1999, 6, 119-171. (j) Benson,
S. C.; Lee, L.; Yang, L.; Snyder, J . K. Tetrahedron 2000, 56, 1165-
1180. (k) Bodwell, G. J .; Li, J . Org. Lett. 2002, 4, 127-130. (l) Bodwell,
G. J .; Li, J . Angew. Chem., Int. Ed. 2002, 41, 3261-3262.
(4) (a) Wenkert, E.; Moeller, P. D. R.; Piettre, S. R. J . Am. Chem.
Soc. 1988, 110, 7188-7194. (b) Kraus, G. A.; Raggon, J .; Thomas, P.
J .; Bougie, D. Tetrahedron Lett. 1988, 29, 5605-5608. (c) Kraus, G.
A.; Bougie, D. J . Org. Chem. 1989, 55, 2425-2428. (d) Padwa, A.;
Brodney, M. A.; Dimitroff, M. J . Org. Chem. 1998, 63, 5304-5305. (e)
Lynch, S. M.; Bur, S. K.; Padwa, A. Org. Lett. 2002, 4, 4643-4645. (f)
Biolatto, B.; Kneeteman, M.; Paredes, E.; Mancini, P. J . Org. Chem.
2001, 66, 3906-3912. (g) Kishbaugh, T. L. S.; Gribble, G. W. Tetra-
hedron Lett. 2001, 42, 4783-4785.
It has been known for a while that indoles can react
as dienophiles in Diels-Alder cycloadditions to lead to
nitrogenated polycycles useful in the synthesis of biologi-
(1) See, for example: (a) Carruthers, W. Cycloaddition Reactions
in Organic Synthesis; Pergamon: Oxford, UK, 1990 (b) Oppolzer, W.
Combining C-C bonds. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Paquette, L. A., Eds.; Pergamon Press: Oxford, UK,
1991; Vol. 5, Chapter 4.1. (c) Fringuelli, F.; Taticchi, A. The Diels-
(5) (a) Gieseler, A.; Steckhan, E.; Wiest, O. Synlett, 1990, 275-277.
(b) Gieseler, A.; Steckhan, E.; Wiest, O.; Knoch, F. J . Org. Chem. 1991,
56, 1405-1411. (c) Wiest, O.; Steckhan, E.; Grein, F. J . Org. Chem.
1992, 57, 4034-4037. (d) Wiest, O.; Steckhan, E. Tetrahedron Lett.
1993, 40, 6391-6394. (e) Haberl, U.; Steckhan, E.; Blechert, S.; Wiest,
O. Chem. Eur. J . 1999, 5, 2859-2865. (f) Raasch, M. S. J . Org. Chem.
1980, 45, 867-870. (g) Markgraf, J . H.; Patterson, D. E. J . Heterocycl.
Chem. 1996, 33, 109-111.
Alder Reaction; J ohn Wiley
& Sons: Chichester, UK, 2002. (d)
Nicolaou, K. C.; Snyder, S. C.; Montagnon, T.; Vassilikogiannakis, G.
Angew. Chem., Int. Ed. 2002, 41, 1668-1698.
(2) See, for example: (a) Boger, D. L.; Weinreb, S. N. In Hetero
Diels-Alder Methodology in Organic Synthesis; Wasserman, H. H., Ed.;
Academic Press: San Diego, CA, 1987; Vol. 47. (b) Tietze, L. F.;
Kettschau, G. Top. Curr. Chem. 1997, 189, 1-120.
10.1021/jo034719b CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/19/2003
7990
J . Org. Chem. 2003, 68, 7990-8002

Diels-Alder versus Hetero-Diels-Alder Processes
SCHEME 1
F IGUR E 1. Structures of aspidospermine (4) and akuam-
micine (5).
electron-rich dienophiles in the inverse-electron-demand
version of the reaction.3 Fewer examples of their use in
normal-electron-demand Diels-Alder cycloadditions have
been reported.4 This latter behavior usually requires the
presence of two electron-withdrawing substituents (EWG)
on the N-CdC moiety of the indole nuclei.6 Thus, for
instance, the strong acceleration of the process resulting
from placing both a sulfonyl group on the nitrogen atom
and a carbonyl or nitro unit in position 3 of the dienophile
component leads to the efficient formation of the desired
cycloadducts 3 (Scheme 1).4a A carbon-centered electron-
withdrawing group in position 3 of the dienophile usually
impedes the rearomatization of the five-membered cycle
whose structure now bears a quaternary center at the
ring junction, a feature of many alkaloids (e.g., Aspi-
dosperma and Strychnos alkaloids) (Figure 1). A draw-
back of the process is the very high temperatures needed
to overcome the inherent inertness of the aromatic
reactant.4 This has kept the methodology from being
applicable to sensitive substrates in the total synthesis
of complex molecules. We recently developed a much
milder thermal access to these derivatives by taking
advantage of the positive effect of high pressure on the
rate of Diels-Alder reactions.7 In addition, combining
high pressures and Lewis acid catalysis results in a
biactivation of the process: under these conditions, the
[4 + 2] cycloadditions occur at room temperature.
SCHEME 2
SCHEME 3a
Classical electron-rich dienes have long been shown to
also react with carbon-heteroatom double or triple bonds
(typically CdO, CdS, CdN, or CtN) to afford six-
membered cycloadducts.2 Dihydropyrans, for example,
have been efficiently generated from aldehydes or ke-
tones. Once again, activation by either Lewis acid ca-
talysis or high pressure (or both) induces these reactions
to occur under much milder conditions. The literature
reports few examples of heterodienophiles competing
with all-carbon dienophiles in [4 + 2] processes;8 in these
cases, the all-carbon dienophilic component was found
to be deactivated. In the course of our studies on the
dienophilicity of five-membered aromatic heterocycles, we
observed complete and sometimes unexpected inversion
of the chemoselectivity in reactions of indoles with
electron-rich dienes. The 2,3-double bond reacted with
some dienes in all-carbon Diels-Alder cycloadditions,
whereas the carbonyl function of the electron-withdraw-
ing group proved to be the most reactive site with other
dienes, thereby getting involved in a cycloaddition process
as a heterodienophile. In addition, cycloadducts of the
a
Reagents and conditions: (i) ZnCl2 (10 mol %), 16 kbar, 25 °C
(62%).
type 3 sometime reacted further with the diene to
generate bisadducts of type 7. We report herein results
regarding the chemoselectivity and show to what extent
the reactivity of the aromatic dienophile can be modu-
lated to favor either the classical process or the hetero-
Diels-Alder reaction (Scheme 2).
Resu lts a n d Discu ssion
We previously reported that the cycloaddition between
indole 1a , bearing a formyl group in position 3, and
cyclohexadiene 2a leads to diastereomeric products 8, the
result of a pericyclic process between the diene and the
aromatic double bond (Scheme 3).7 High pressure and
Lewis acid catalysis increased both the yields and the
endo/exo ratio from 80:20 to >98:2; not a trace of
heterocycloadduct was detected in the crude reaction
mixtures.
(6) The presence of only one electron-withdrawing substituent on
the indole nitrogen has been reported to be sufficient in the case of an
intramolecular cycloaddition. See ref 4d,e.
(7) Chataigner, I.; Hess, E.; Toupet, L.; Piettre, S. R. Org. Lett. 2001,
3, 515-518.
(8) See, for example: (a) Keana, J . F. W.; Eckler, P. E. J . Org. Chem.
1976, 41, 2850-2854. (b) Sano, T.; Toda, J .; Kashiwaba, N.; Ohshima,
T.; Tsuda, Y. Chem. Pharm. Bull. 1987, 35, 479-500.
In d ole-3-ca r boxa ld eh yd e a n d -3-glyoxyla te: Th e
Ca se of 2,3-Dim eth ylbu ta d ien e. (a ) In d ole-3-ca r box-
J . Org. Chem, Vol. 68, No. 21, 2003 7991

Chre´tien et al.
diene,9 and extraction of the compound from the crude
mixture using a Soxhlet apparatus does not lead to any
improvement. This polymerization is favored by both
pressure and Lewis acid catalysis and is difficult to
control under these conditions. The amount of diene was
further decreased in an attempt to maximize the forma-
tion of monoadduct 10, at the expense of bisadducts 11.
Thus, the use of either 2 or 1 equiv of diene under
otherwise identical conditions led to 50:50 and 100:0
mixtures of 9/11, respectively, albeit in low conversion
(entries 9 and 10). Despite its low practical utility, the
later experiment unambiguously shows that the all-
carbon Diels-Alder process is kinetically favored under
these conditions and confirms the higher reactivity of the
aromatic double bond over the formyl group. The as-
sumed sequence of events was further verified by com-
pressing to 12 kbar the primary cycloadduct 9 with diene
2b (6 equiv) in the presence of 10 mol % of zinc chloride;
this experiment furnished an identical 2:1 diastereomeric
ratio of bisadducts 11a and 11b, isolated in 70% yield.10
SCHEME 4
These results prompted us to perform the heterocy-
cloaddition on the monoadduct 9 with a different diene,
i.e., trans-1-methoxy-3-trimethylsilyloxy-1,3-diene (2c,
Danishefsky diene). Under the same conditions and after
acidic hydrolysis of the enol ether function, the mixed
bisadduct 13 was isolated in 37% yield, thus demonstrat-
ing the feasibility of a sequential tandem reaction (Scheme
5). As zinc chloride might react with this acid-sensitive
diene in an undesired manner, a more gentle, lanthanide
catalyst was used. A much better 76% yield was indeed
obtained when the heterocycloaddition was carried out
with 10 mol % of EuFOD.11 As before, 13 was isolated as
a 2:1 mixture of diastereomers, and crystallization of the
major isomer in a mixture of heptanes and ethyl acetate
afforded a material suitable for X-ray diffraction analysis
(Figure 2). The observed relative configuration (1aS*,
4aR*,2′R*) suggests a preferential approach from the
more accessible Re face of the carbonyl function on the
primary adduct, which implies a more favorable confor-
mation placing the carbonyl group above the tolyl cycle
(Figure 3). Such a conformation has been previously
observed by X-ray crystallography analysis of an analo-
gous primary cycloadduct (Figure 4).6
a ld eh yd e. A similar result is obtained when the cycload-
dition of 1a is conducted under thermal conditions (195
°C) with 2,3-dimethylbutadiene (2b): the exclusive for-
mation of compound 9 is observed, and the product is
isolated in a good, 83% yield (Scheme 4; Table 1, entry
1). Not unexpectedly, the use of a Lewis acid allows for
lower reaction temperatures and decreases the time
needed to reach a similar conversion (entry 2). In this
case, crude 1H NMR spectrometry data indicate the
presence of a structurally different product in minor
amounts (13%) (see below). Compressing a mixture of
indole 1a and dimethylbutadiene (2b) (12 equiv) in the
presence of a catalytic amount of zinc chloride (10 mol
%) to 12 kbar for 48 h at room temperature induces a
67% conversion and the formation of the same cycload-
duct 9, together with a large amount of polymeric
material (entry 3). Attempts to solve the problem arising
from the polymerization process included decreasing the
amount of diene. Thus, lowering it to 6 and then 4 equiv
indeed resulted in much more workable crude mixtures,
but at the expense of the conversion (entries 4 and 5).
The problem is circumvented by increasing the pressure
to 16 kbar: with 4 equiv of diene, the conversion
increased to 69% in only 24 h and attained completion
within 60 h. The ratio of the two different types of product
evolves from an initial value of 40:60 to 5:95 (entries 6
and 7). Full optimization of the conditions is reached with
(b) In d ole-3-glyoxyla te. Ketoesters, in particular
those derived from ketomalonates or glyoxylates, are
known to behave as heterodienophiles in cycloadditions
with enriched dienes.2 This observation raises the ques-
tion of the behavior of indole derivative 1b, bearing a
methyl ketoester functionality, in such reactions. The
thermal cycloaddition between 1b and dimethylbutadiene
2b leads to the exclusive formation of monocycloadduct
10, the result of the condensation of the diene on the
1
6 equiv of diene in 24 h (entry 8). 1D and 2D H and 13C
NMR and mass spectrometry analyses indicate that the
new compounds result from the interaction of the dieno-
phile with 2 equiv of diene 2b and allow the assignment
to diastereomeric tetracyclic structures 11a and 11b.
These compounds arise from a double cycloaddition
process on (i) the 2,3-indole CdC and (ii) the carbonyl
group. Using a large excess of diene generates a problem
on a practical level. For instance, a 12 equiv excess leads
in many cases to a discrepancy between the conversion
rates and the isolated yields: these are often lower than
expected on the basis of the crude NMR spectra. Indeed,
the cycloadduct is trapped in a dense polymeric matrix
resulting from the competing polymerization of the
(9) The relative rates of both cycloaddition and polymerisation
processes involved here can be unequally influenced by various factors
among which the quality of the Lewis acid catalyst, or of the solvent,
for example. The overall result can thus vary somewhat, depending
on the experiment and lead to differences in reproducibility of yields
and ratios. Nevertheless, the general trends observed in these experi-
ments are reproducible.
(10) The use of pressure alone has the disadvantage of producing a
large amount of polymers. Thus, while a complete conversion is
observed and cycloadduct 10 is formed in an exclusive manner at 50
°C, the reaction is of little practical use (entry 11). Despite many efforts,
these conditions could not been translated into good isolated yields.
(11) EuFOD is europium tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-
3,5-octanedionate).
7992 J . Org. Chem., Vol. 68, No. 21, 2003

Diels-Alder versus Hetero-Diels-Alder Processes
TABLE 1. Rea ction s betw een In d ole Dien op h iles a n d Dim eth ylbu ta d ien e 2b. F or m a tion of th e Mon o- vs
Biscycloa d d u cts
ratioa,b
yielda,f (%) of
entry
indole
2b (equiv)
Lewis acid
T (°C)
time (h)
P (kbar)
convn (%)
9/11 or 10/12
9/11 or 10/12
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
12
12
12
6
4
4
4
6
2
1.1
12
12
12
4
195
110
25
25
25
25
25
25
25
25
50
190
110
25
80
48
48
48
48
24
60
24
48
24
48
72
48
72
24
48
85
77
67
39
25
100:0
87:13
97:3
83:0
ndd
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
Zn Cl2
ZnCl2
ZnCl2
12
12
12
16
16
16
16
16
16
ndd
97:3
ndd
100:0
40:60
5:95
ndd
69
ndd
100
100
24
ndd
2:98
0:90c
ndd
46:54
100:0
100:0
100:0
71:29
30:70
0:100
100:0
11
ndd
100
100
45
100
95
nde
91:0
ZnCl2
ZnCl2
Zn Cl2
ndd
12
16
16
31:69c
0:82c
nde
6
12
25
50
100
a
b
9/11 for indole 1a ; 10/12 for indole 1b. Determined by NMR spectrometry on crude reaction mixtures. c Overall yield of the 2:1
diastereomeric mixture. Not determined. e Extensive polymerization. f 11a /11b for indole 1a ; 12a /12b for indole 1b.
d
SCHEME 5a
F IGURE 3. Facial selectivity in cycloaddition between 9 and
2c.
a
Reagents and conditions: (i) EuFOD (10 mol %); (ii) TFA (76
% overall).
thermal conditions) or bisadducts 11 and 12 (favored
under high pressure and Lewis acid catalysis). The
aromatic double bond proved the more reactive toward
dimethylbutadiene in the cycloaddition process. In a
second step, under hyperbaric conditions and in the
presence of a Lewis acid catalyst, the carbonyl group
reacted as dienophile in a second hetero-Diels-Alder
step. The double cycloaddition can be performed either
in a one-pot operation or stepwise, and this allows for
the synthesis of mixed biscycloadducts arising from a
sequential process involving two different dienes.
In d ole-3-ca r boxa ld eh yd e a n d -3-glyoxyla te: Th e
Ca se of Da n ish efsk y Dien e. (a ) In d ole-3-ca r boxa l-
d eh yd e. We previously reported that indole-3-carboxal-
dehyde derivative 1a reacts with Danishefsky diene 2c
under thermal or hyperbaric activation to deliver normal
Diels-Alder cycloadduct of the type 3.7 New data gath-
ered since then (including 2D-NMR experiments) showed
the misassignment of several nuclei, which led us to
revise the structure of the product.13 Regardless of the
reaction conditions, hydrolysis of the initial adduct
actually leads to the exclusive isolation of heterocycload-
duct 14 (Scheme 6), the result of the interaction between
the carboxaldehyde unit of 1a and 2c. The lack of an
electron-withdrawing substituent on carbon 3 of product
14 keeps it from further reacting with the diene.
F IGURE 2. ORTEP drawing of bisadduct 13.
aromatic double bond of the indole (Table 1, entry 12).
Here again, the use of zinc chloride allows a decrease in
both the temperature and the reaction time; however,
while the conversion reaches only 45%, the formation of
bisadducts 12a and 12b can already be observed (entry
13). As in the case of the 3-formyl indole derivative,
combining high pressure and Lewis acid catalysis en-
hances the subsequent heterocycloaddition and furnishes
the bisadducts 12 with a good 82% yield (entries 14 and
15).12
Under thermal activation (Table 2, entry 1), the enone
14 was isolated in a good 82% yield after triggering both
These experiments unambiguously demonstrate that
a careful choice of the activation mode allows the selective
formation of either monoadducts 9 and 10 (formed under
(12) The use of pressure alone parallels what had been obtained
from indole 1a (Table 1, entry 16).9
J . Org. Chem, Vol. 68, No. 21, 2003 7993

Chre´tien et al.
SCHEME 6a
ratio and an overall 77% yield (Figure 5). Quantitative
conversion of both intermediates 16 and 17 to 14 can be
separately achieved under acidic conditions (TFA in
dichloromethane at room temperature). These observa-
tions suggest that, even when catalyzed by a zinc-based
Lewis acid, this heterocycloaddition may go through a
two-step mechanism via a Mukaiyama aldol reaction
pathway, at least to some extent.15 NMR analysis of crude
mixtures from cycloadditions performed under high pres-
sure and zinc chloride catalysis (entry 5) also revealed
the presence of the same acyclic intermediate 17 together
with 14 in a 36:64 ratio, whereas in the absence of Lewis
acid, only the cyclized compounds 14 and 16 were
observed (see entry 3).
2-Substituted indoles are known to be less reactive
toward electron-rich dienes in classical Diels-Alder
cycloadditions than their 3-substituted counterparts.4a
When reacted with diene 2c, the 2-formyl indole deriva-
tive 18 does indeed participate as a heterodienophile
rather than all-carbon dienophile.16 The faster zinc
chloride catalyzed reaction leads to the sole compound
19 in 84% yield (Scheme 7).
a
After TFA hydrolysis.
TABLE 2. Rea ction s betw een In d ole 1a a n d
Da n ish efsk y Dien e 2c
2c
convna yield of
entry (equiv)
reaction conditions
170 °C, 24 h
ZnCl2 cat. 110 °C, 24 h
12 kbar, 45 °C, 96 h
ZnCl2 cat. 25 °C, 72 h
11 kbar, ZnCl2 cat., 25 °C, 24 h
(%)
14 (%)
1
2
3
4
5
12
12
12
2
100
80
100
100
85c
82
56
99
b
2
70
a
Determined by NMR spectrometry on crude reaction mixtures.
b
Isolation of 14, 16 and 17 in a 53:31:16 ratio and in an overall
77% yield. c Presence of 14 and 17 in the crude mixture.
(b) In d ole-3-glyoxyla te. The reactivity and chemose-
lectivity of ketoester-derived indole 1b toward Danishef-
sky diene was next investigated and shown to be similar
to that of 1a : thus, exclusive heterodienophilicity is
observed in the cycloadditions with 2c. Carrying out this
reaction under 12 kbar and at room temperature, with a
2-fold excess of diene, provides the corresponding dihy-
dropyranone 15 in 60% isolated yield (Scheme 6). Worthy
of note is the fact that these structures represent an entry
into the synthesis of unnatural carbohydrates bearing an
indolyl moiety in position 5 of the oxacycle.
In d ole-3-glyoxa m id es a n d Da n ish efsk y Dien e.
When indole 1c and diene 2c were heated to 180 °C for
48 h, a complete conversion was observed; acidic hydroly-
sis of the silyl enol ether afforded a 4:1 mixture of endo/
exo cycloadduct 20a /20b, isolated in fair yields (Scheme
8; Table 3, entry 1). No other product could be observed
on the crude reaction material (NMR spectrometry), and
the structure of the major diastereomer 20a , which
features a trans relationship between the ketoamide and
the methoxy substituents, was further confirmed by
X-ray analysis (Figure 4).17 A completely reversed
chemoselectivity (when compared to 1a or 1b) is thus
observed as the aromatic 2,3-double bond proves to be
the only reactive site in this case, and this all-carbon
cycloaddition affords adducts 20 bearing a lateral chain
(C-C-N) suitable for the construction of the D ring of
the Aspidosperma alkaloids skeleton (Figure 1). The keto
function of the electron-withdrawing group at position 3
was completely inert toward enriched dienes, and no
hetero-Diels-Alder reactions took place under a variety
the hydrolysis of the silyl enol ether group and the loss
of methanol upon acidic treatment. Zinc chloride catalysis
also promoted the heterocycloaddition, but conversion
and isolated yields were lower (entry 2), whereas high
pressures had a more beneficial effect and led to a nearly
quantitative formation of the dihydropyranone (entry 3).
These observations are in line with the sensitivity of 2c
toward high temperatures and Lewis acids such as zinc
chloride.
The mechanism of the hetero-Diels-Alder reaction has
been studied in detail, and two different modes have been
proposed, namely the traditional, concerted Diels-Alder-
type cycloaddition or the stepwise condensation involving
a Mukaiyama-type aldol reaction.14 Both the Lewis acid
catalyst and the solvent have been reported to have a
dramatic influence on the mechanistic course: the Mu-
kaiyama pathway has been observed with titanium- or
boron-based catalysts, while the concerted Diels-Alder
pathway has been proposed in reactions catalyzed by
europium-, chromium-, and zinc-based Lewis acids in
tetrahydrofuran. The zinc chloride catalyzed cycloaddi-
tion between indole 1a and diene 2c should thus proceed
through the concerted mechanism. When the reaction
was performed at room temperature rather than at 110
°C, a total consumption of the starting material occurred
within 72 h (Table 2, entry 4). Chromatography of the
crude mixture on triethylamine-pretreated silica allowed
the isolation of compounds 14, 16, and 17 in a 53:31:16
(13) Similarities in the chemical shifts and multiplicities of the
aldehyde hydrogen in putative structure (i) with the C-2 hydrogen of
compound 14, on one hand, and C-2 hydrogen of structure (i) with H-2′
to the cyclic oxygen atom in the product, on the other hand, generated
the misassignment. Inspection of the ORTEP drawing of analogous
structure 20a indicated the possibility for the aldehyde hydrogen in
(i) to be in the shielding cone of the p-tolyl group.
(15) The solvent used in this heterocycloaddition (dichloromethane)
may provide an explanation, as recently observed by Baldoli, C.;
Maiorana, S.; Licandro, E.; Zinzalla, G.; Lanfranchi, M.; Tiripicchio,
A. Tetrahedron: Asymmetry 2001, 12, 2159-2167.
(16) A recent publication reports on the reaction between an imine
generated from 18 and Danishefsky diene 2c. See: Kuethe, J . T.;
Dormer, P. G.; Reamer, R. A.; Mathre, D. J .; Reider, P. J . Tetrahedron
Lett. 2002, 43, 29-32.
(17) Endo addition can be defined as “that particular spatial
arrangement of reactants in which the more bulky side of the diene is
under the more bulky side of the dienophile”, meaning the indole part
in this case. See: Fringuelli, F.; Taticchi, A. in Dienes in the Diels-
Alder Reaction; J ohn Wiley and Sons Ltd: New York, 1990; pp 1-44.
(14) (a) Bednarski, M.; Danishefsky, S. J . Am. Chem. Soc. 1983, 105,
3716-3717. (b) Danishefsky, S. J .; Larson, E.; Askin, D., Kato, N. J .
Am. Chem. Soc. 1985, 107, 1246-1255.
7994 J . Org. Chem., Vol. 68, No. 21, 2003

Diels-Alder versus Hetero-Diels-Alder Processes
SCHEME 9a
a
Reagents and conditions: (i) (COCl)2, Et2O, 0 °C, 30 min; (ii)
R1R2NH, Et2O, 0-25 °C, overnight; (iii) TsCl, DIPEA, DMAP cat.,
CH2Cl2, 1 h; (iv) NaH, MeI, DMF, 0 °C.
easily prepared by sequential treatment of indole 21 with
oxalyl chloride, quenching of the resulting acid chloride
with the requisite chiral amine, and tosylation of the
3-acylindole (Scheme 9). While interaction of 1d and 2c
gave rise to little reaction in refluxing toluene and in the
presence of EuFOD (Table 3, entry 6), a strikingly
different result was obtained when compressing a CH2-
Cl2 solution of the same substrates and catalyst to 12
kbar. Hydrolysis of the crude mixture yielded a material
whose NMR data indicated complete consumption of the
starting ketoamide and the formation of two structurally
different compounds. In this case, the major transforma-
tion was found to be a hetero-Diels-Alder reaction
involving the 3-keto group.18 Thus, indole 1d delivered
cycloadduct 25, isolated in 76% yield as a 2:1 diastere-
omeric mixture. A minor fraction was also collected and
shown to contain bisadducts 29 (9%) (entry 7). Similarly,
the naphthyl analogue 1e, when placed under the same
hyperbaric conditions, underwent total conversion and
furnished heterocycloadducts 26 (86% isolated yield; a
2:1 mixture of diastereomers), along with some bisad-
ducts 30 (entry 9). The site selectivity and yields were
optimized in the absence of EuFOD, and 4-dihydropyrone
25, now the exclusive product after hydrolysis, was
isolated in excellent yields (entry 8). The constant 2:1
diastereomeric mixture observed in all these cases obvi-
ously reflects the limited induction power of the (R)-CH-
(Me)Ar unit in these processes.
F IGURE 4. ORTEP diagram of adduct 20a (endo).
F IGURE 5. Isolated intermediates from the HDA process.
SCHEME 7a
a
Reagents and conditions: (i) 2c, ZnCl2 (10 mol %), CH2Cl2,
25 °C (84%).
SCHEME 8
The remarkable reversal of chemoselectivity (compare
entries 4 and 8, Table 3) led us to consider other
substrates in an attempt to rationalize this behavior.
Comparison of N,N-diethylketoamide 1c and N-(methyl)-
of conditions. A 12 kbar compression at 45 °C led to a
similar result (entry 2). Zinc chloride catalysis in reflux-
ing toluene resulted in the decomposition of the diene
and left the indole untouched (entry 3). Finally, the
optimized conditions required the combination of high
pressures and the mild europium Lewis acid catalysis
(entry 4). The cycloaddition now took place at room
temperature, leading quantitatively to a 4:1 endo/exo
mixture of diastereomers, separated by chromatography
on silica gel.
(18) To the best of our knowledge, the only reported case of a
ketoamide undergoing a [4 + 2] heterocycloaddition involves unsatur-
ated 3-oxopyrrolidinone of the type 31 and Danishefsky diene 2c, when
either heated at 130 °C or compressed at 10 kbar. Compound 31
delivered either normal Diels-Alder cycloadducts 32 and heterocy-
cloadducts 33 in variable amounts or exclusively the same cycloadducts
33, depending on the conditions and the substituents. See: (a) Tsuda,
Y.; Hosoi, S.; Katagiri, N.; Kaneko, C.; Sano, T. Heterocycles 1992, 33,
497-502. (b) Tsuda, Y.; Hosoi, S.; Katagiri, N.; Kaneko, C.; Sano, T.
Chem. Pharm. Bull. 1993, 41, 2087-2095.
Attempts to develop diastereoselective versions of this
reaction led us to apply the same sequence of reactions
to chiral ketoamides 1d and 1e. Starting materials were
J . Org. Chem, Vol. 68, No. 21, 2003 7995

Chre´tien et al.
TABLE 3. Rea ction s betw een In d ole-3-glyoxa m id es 1c-i a n d Da n ish efsk y Dien e 2c
a
b
Determined by NMR spectrometry on crude reaction mixtures. Overall yield of the diastereomeric mixture. c 10 mol % catalysis.
Degradation of the reaction mixture. e 5 mol % catalysis. f Isolated as a mixture of four diastereomers. A poor diastereoselectivity was
d
g
observed in this case.22 Obtained as a mixture of eight diastereomers.
h
benzyl analogue 1d indicates the N-H bond in the latter.
To verify its implication, the secondary N-ethylketoamide
1f was prepared and subjected to the action of diene 2c
under essentially the same conditions (entries 10 and 11).
A complete consumption of the starting material resulted
in the presence of EuFOD, and heterocycloadduct 27 was
obtained in 88% yield. Here again, a complete reversal
of chemoselectivity occurred as neither the normal Diels-
Alder adduct (of the type 3) nor the biscycloadduct (of
the type 7) could be observed in the crude mixture (1H
NMR spectrometry analysis). To further determine the
involvement of the N-H bond in this process, the mono-
N-substituted ketoamide 1d was methylated (NaH, MeI)
to afford indole 1g (Scheme 9). When placed under the
same conditions, a sluggish transformation occurred,
leaving 45% of unconsumed starting material (entry 12).
7996 J . Org. Chem., Vol. 68, No. 21, 2003

Diels-Alder versus Hetero-Diels-Alder Processes
Increasing the pressure to 16 kbar led to a complete
conversion and, this time, isolation of the normal Diels-
Alder cycloadducts 23 (of the type 3) in 57% yield (entry
13).
The striking difference of reactivity between the sec-
ondary and tertiary ketoamides, regardless of the reac-
tion conditions, clearly reflects the influence of the second
alkyl group. Thus, a secondary ketoamide (i.e., featuring
an N-H bond) gives rise to heterocycloadducts of the type
6 in a largely predominant or exclusive manner (entries
7-11).19 Installing a methyl group on the ketoamide
nitrogen completely reverses the chemoselectivity, and
the cycloadducts of type 3 are now the exclusive products
(entries 1-4, 12, and 13).
F IGURE 6. Numbering in type 7 bisadducts.
TABLE 4. Selected 1H NMR Ch em ica l Sh ifts a n d
Cou p lin g Con sta n ts of 20a , 20b, a n d 13
20a (endo) (ppm)
(J (Hz))
20b (exo) (ppm)
(J (Hz))
13 (2′R) (ppm)
(J (Hz))
1H
1a
1
5.20 (6.0; 6.4)
2.85 (6.4; 16.4)
3.07 (6.0; 16.4)
2.23 (8.3; 18.3)
2.48 (3.4; 18.3)
4.81 (3.4; 8.3)
5.41 (2.3; 5.6)
3.01 (5.6; 17.0)
3.21 (2.3; 17.0)
1.88 (2.3; 18.5)
2.56 (3.0; 18.5)
4.67 (2.3; 3.2)
4.06 (4.5; 4.9)
2.30 (m)
2.58 (4.9; 14.7)
The competitive (albeit slower) formation of bisadducts
of the type 7 from dienophiles 1d and 1e, when catalyzed
by EuFOD, indicates that different factors play a role in
this reaction (entries 7 and 9).20 The presence of an aryl
moiety in the direct vicinity of the acyclic nitrogen may
somewhat alter the site selectivity reversal due to the
steric hindrance generated by the substituents on the
amide nitrogen, and/or a possible π-stacking interaction
(between the aryl substituent of the amide group and the
indole ring). To evaluate the influence of these param-
eters, amides 1h and 1i, featuring the fully saturated
analogue of the R-(methyl)benzyl substituent, were pre-
pared in a similar way (Scheme 9). Compressing a
mixture of indole 1h and diene 2c (6 equiv) led to an 80%
conversion and the exclusive formation of dihydropyrane
29 (of the type 6) (entry 14). Addition of EuFOD (10 mol
%) increased the conversion and allowed the isolation of
the product in 72% yield (entry 15). Again, a reversal of
chemoselectivity is observed with N,N-dialkylamide 1i:
not a trace of heterocycloadducts (of the type 6 or 7) was
found to have formed and the normal Diels-Alder
products 24 could be isolated in 81% yield (a mixture of
four diastereomers) (entry 16). One of these adducts could
be separated from the mixture by recrystallization from
heptanes/dichloromethane. On the basis of previous data
on both diastereomers of 20, a relative assignment of the
1H NMR spectrometry signal corresponding to an endo
cycloadduct can confidently be made.21
3
4
2.03 (14.9)
2.51 (14.9)
2′
3′
4.06 (4.9; 4.9)
2.31 (4.9; 14.7)
2.58 (4.9; 14.7)
Obviously, the dienophilic component seems to represent
a borderline case, and small changes in the electronic
and/or structural parameters induce the carbonyl group
to become more reactive toward more polar dienes. The
results compiled in Table 3 show that the energy differ-
ence between the two processes is most probably tenuous.
Additional experiments will be needed to shed light on
this phenomenon; work addressing this issue is in
progress in these laboratories.
Con for m a t ion a l An a lyses of t h e Cycloa d d u ct s.
Three different molecules, namely 20a , 20b, and 13, were
chosen to analyze the conformations adopted by the
1
molecules in solution. The various H NMR spectrometry
chemical shifts and coupling constants for hydrogens in
positions 1a, 1, 3, 4, 2′, and 3′ (Figure 6) are compiled in
Table 4.
In the endo diastereomer 20a , the structure was solved
by using X-ray diffraction on a monocrystal and features
a concave boat-shape conformation for the cyclohexanone
ring. Such a conformation arises from the presence of a
five-membered cycle encompassing three sp2 atoms.23 The
nearly identical coupling constant values between hy-
drogen 1a and both axial and equatorial hydrogens in
position 1 (6.0 and 6.4 Hz) indicate similar dihedral
angles between these atoms.24 In the case of hydrogen 4,
To our knowledge, such a complete reversal of chemose-
lectivity has not been reported in the literature so far.
(19) It should be noted that published NMR studies of the different
conformations in secondary amides indicate a preference for the
transoid conformation; see: Stewart, W. E.; Siddall, T. H. Chem. Rev.
1970, 70, 517-551. In the case of the secondary ketoamides discussed
in this work, the probable intramolecular hydrogen bond is reflected
by the presence of a single conformer, as indicated by 1H and 13C NMR
3
the observed J values reflect a slight torsion of the C-C
bonds of the pseudoboat. Indeed, the trans relationship
between the methoxy and the ketoamide groups should
yield dihedral angle values of 60 and 180° for hydrogens
3 with respect to hydrogen 4. The values of 3.4 and 8.3
Hz are indicative of smaller angles, in accordance with
a decrease of the 1,4-steric interaction between H1ax and
H4. Of particular note is the fact that the two carbonyl
functions are in different planes, as shown by the ORTEP
spectrometries. For
a secondary ketoamide featuring a transoid
conformation for the amide group, two different hydrogen bonds may
be invoked, depending on the conformation adopted by the dicarbonyl
unit. Thus, a transoid conformation will allow hydrogen bonding with
the oxygen atom of the keto group, while a cisoid conformation may
achieve such a hydrogen bond with one of the sulfonyl oxygen atoms.
Chelation with europium (for example) may thus involve either both
the amide oxygen and the sulfonyl oxygen, or the oxygen atoms of both
carbonyl groups, respectively. Clearly, the situation arising from the
chelation of tertiary amides will be different. The presence of a
hydrogen bond in secondary amides may result in a distortion of the
-system, and
a deconjugation between the electron withdrawing
substituent and the 2,3-indole CdC bond, thus translating in
different chemoselectivity.
(20) Inasmuch as the heterocycloaddition suppresses the electron-
withdrawing group on the indole ring, the normal [4 + 2] cycloaddition
must occur prior to the hetero Diels-Alder reaction in the process
leading to bisadducts of the type 7 (29 and 30).
a
(22) Analysis of the unseparable, purified mixture revealed the
presence of two major compounds, whose relative stereochemistry could
not be ascertained.
(23) Maddaluno, J .; Gaonac’h, O.; Marcual, A.; Toupet, L.; Giesner-
Prettre, C. J . Org. Chem. 1996, 61, 5290-5306.
(24) Axial and equatorial nomenclature is used to differenciate
geminal hydrogens (pseudo).
(21) J H4-H3) 3.4, 7.9 Hz.
J . Org. Chem, Vol. 68, No. 21, 2003 7997

Chre´tien et al.
drawing of the molecule (Figure 4), thus suggesting an
absence of conjugation between these groups; this may
result from negative interactions between the oxygen
atoms of the methoxy substituent on one hand and either
one of the carbonyl functions on the other hand.
Exp er im en ta l Section
Unless otherwise stated, 1H NMR (300 MHz) and 13C NMR
(75 MHz) spectra were recorded in deuterated chloroform
relative to (CH3)4Si and CDCl3, respectively. Chemical shifts
are expressed in parts per million (ppm). Low-resolution and
high-resolution mass spectra were recorded on Unicam ATI
Automass and J EOL 500 spectrometers, respectively. IR
spectra were recorded on Perkin-Elmer 16PC FT-IR spectrom-
eters.
Gen er a l P r oced u r e for th e Tosyla tion of In d ole. A
mixture of the indole derivative (1 equiv), DMAP (cat.),
(i-Pr)2EtN (1.3-1.5 equiv), and TsCl (1.0-1.1 equiv) was
stirred at room temperature for the requisite time. After
quenching with 0.1 N HCl, the reaction mixture was extracted
with CH2Cl2. The combined organic layers were dried and
concentrated under reduced pressure. The residue was purified
by flash chromatography on silica gel.
The exo counterpart 20b of this molecule now possesses
the methoxy group in axial position; the increased
resultant steric hindrance with axial hydrogen 1 may
induce a twisting of the boat-shape conformation to
3
diminish these interactions. The observed J values for
H1a are in accordance with such a situation. Thus, when
compared to the endo isomer (vide supra), both coupling
constants are smaller (2.3 and 5.6 Hz). The small 3J
values observed for hydrogen 4 confirm the twist and
correspond to approximate dihedral angles of 40 and 70°.
Gen er a l P r oced u r e for th e N-Meth yla tion of In d ole-
3-glyoxa m id e. To a suspension of NaH (60% in oil) (1.2 equiv)
in dry DMF was added, at 0 °C, the indoleglyoxamide (1 equiv).
The mixture was stirred for 15 min, and then MeI (1.5 equiv)
was added dropwise. The resulting mixture was stirred until
completion of the reaction (TLC monitored). The reaction was
quenched with water and extracted with EtOAc. After con-
centration under reduced pressure, the residue was purified
by flash chromatography on silica.
A similar concave boat-shape conformation of the cycle
resulting from the normal Diels-Alder reaction also
exists in bisadduct 13, as shown by the computer-
generated graphic obtained from X-ray diffraction data
3
(Figure 2). Here again, the J values for hydrogen 1a are
in accordance with the adoption of such a conformation
in solution. The hydrogens in position 2′ and 3′ of the
dihydropyranone ring display a typical ABX pattern.
2-Oxo-N-(1-p h en yleth yl)-2-[1-(tolu en e-4-su lfon yl)-1H-
in d ol-3-yl]a ceta m id e (1d ). Prepared according to the gen-
eral procedure using 22d (292 mg, 1 mmol), DMAP (10 mg),
(i-Pr)2EtN (226 µL, 1.3 mmol), and TsCl (190 mg, 1 mmol) in
CH2Cl2 (3 mL). The reaction was stirred for 1 h and the product
purified by flash chromatography (heptanes/EtOAc 4:1) to give
Con clu sion
The products arising from the reaction of electron-poor
indoles with 1,3-dienes strongly depend on (i) the type
of the electron-withdrawing substituent on position 3 of
the indole, (ii) the diene involved in the cycloaddition
process, and (iii) the method of activation. Thus, the
thermal reaction between either indole-3-carboxaldehyde
1a or indole-3-glyoxylate 1b and 2,3-dimethylbuta-1,3-
diene yields the expected Diels-Alder adducts 9 or 10.
Biactivation with zinc chloride and pressures up to 12
kbar furnish the same monocycloadducts 9 or 10, along
with minor amounts of bisadducts 11 or 12. Forcing the
conditions (ZnCl2, 16 kbar) leads to the nearly exclusive
formation of bisadducts 11 or 12 in high yields. The data
unambiguously demonstrate that the preferred site of
reactivity is the indole 2,3 carbon-carbon double bond
and are in line with previous results obtained with other
four-π-electron partners such as cyclohexadiene. The
involvment of the 3-carbonyl unit as heterodienophile
occurs efficiently only under forcing conditions.
1d as a white solid (439 mg, 98%, mp 169-170 °C): [R]20
)
D
1
+57.3 (c 1, CHCl3); H NMR δ 1.54 (d, J ) 7.1 Hz, 3H), 2.29
(s, 3H), 5.04-5.14 (m, 1H), 7.19-7.33 (m, 9H), 7.56 (d, J )
7.9 Hz, 1H), 7.81 (d, J ) 8.3 Hz, 2H), 7.90-7.93 (m, 1H), 8.24-
8.27 (m, 1H), 9.36 (s, 1H); 13C NMR δ 21.5, 21.8, 49.1, 113.2,
115.9, 122.7, 125.0, 125.8, 126.0 (2C), 127.3 (2C), 127.6, 128.1,
128.8 (2C), 130.2 (2C), 134.1, 134.3, 138.5, 142.3, 145.9, 160.1,
181.7; IR (KBr) ν 3354, 1654, 1646, 1374, 1297, 1171 cm-1
;
MS (EI) m/z (relative intensity) 446 [M+•] (12), 298 (28), 155
(41), 91 (100). Anal. Calcd for C25H22N2O4S: C, 67.25; H, 4.97;
N, 6.27; S, 7.18. Found: C, 67.29; H, 4.98; N, 6.28; S, 7.19.
N-(1-Na p h th a len -1-yleth yl)-2-oxo-2-[1-(tolu en e-4-su lfo-
n yl)-1H-in d ol-3-yl]a ceta m id e (1e). Prepared according to
the general procedure using 22e (342 mg, 1 mmol), DMAP (10
mg), (i-Pr)2EtN (226 µL, 1.3 mmol), and TsCl (200 mg, 1.05
mmol) in CH2Cl2 (4 mL). The reaction was stirred for 1 h and
the product purified by flash chromatography (cyclohexane/
EtOAc 17:3) to give 1e as a white solid (479 mg, 97%, mp 71
1
°C): [R]20 ) +14.3 (c 1, CHCl3); H NMR δ 1.77 (d, J ) 6.8
D
Hz, 3H), 2.36 (s, 3H), 5.93-6.04 (m, 1H), 7.27 (d, J ) 8.3 Hz,
2H), 7.33-7.62 (m, 7H), 7.71 (d, J ) 8.3 Hz, 1H), 7.83 (d, J )
8.3 Hz, 1H), 7.89 (d, J ) 8.3 Hz, 2H), 7.97-8.01 (m, 1H), 8.14
(d, J ) 8.3 Hz, 1H), 8.29-8.33 (m, 1H), 9.47 (s, 1H); 13C NMR
δ 21.0, 21.5, 45.0, 113.1, 115.9, 122.5, 122.7, 122.8, 125.0, 125.2,
125.8 (2C), 126.6, 127.3 (2C), 128.1, 128.4, 128.9, 130.1 (2C),
130.7, 133.8, 134.1, 134.3, 137.6, 138.5, 145.9, 160.0, 181.6;
IR (KBr) ν 3373, 1681, 1648, 1380, 1177 cm-1; MS (EI) m/z
(relative intensity) 496 [M+•] (17), 298 (27), 170 (89), 155 (87),
144 (11), 91 (100). Anal. Calcd for C29H24N2O4S: C, 70.14; H,
4.87; N, 5.64; S, 6.46. Found: C, 70.25; H, 5.25; N, 5.77; S,
6.18.
The use of an electron-enriched diene such as Dan-
ishefsky’s diene induces a reversal of the site selectivity,
the γ-dihydropyranones being now the exclusive adducts
formed in the process, regardless of the activation type.
The study indicates that a two-step, Mukaiyama-type
pathway may be followed under ZnCl2 catalysis.
Indole-3-ketoamides 1c-i constitute a unique set of
dienophiles in the reaction with Danishefsky’s diene. The
results reported in this paper indicate that the site of
reactivity is strongly dependent on both the number of
substituent(s) on the acyclic nitrogen atom and their
nature. Mono-N-substituted ketoamides undergo an het-
erocycloaddition reaction on the keto moiety in a nearly
exclusive fashion, while a reversed site-selectivity occurs
with the involvment of the indole 2,3-double bond as the
only reacting entity in the case of N,N-disubstituted
analogues (1c, 1g, 1i).
N-Eth yl-2-oxo-2-[1-(tolu en e-4-su lfon yl)-1H-in d ol-3-yl]-
a ceta m id e (1f). Prepared according to the general procedure
using 22f (223 mg, 0.5 mmol), DMAP (10 mg), (i-Pr)2EtN (0.70
mL, 4 mmol), and TsCl (0.61 g, 3.2 mmol) in CH2Cl2 (10 mL).
The reaction was stirred for 1 h and the mixture purified by
flash chromatography (cyclohexane/EtOAc 17:3) to give 1f as
a white solid (0.69 g, 62%, mp 54 °C): 1H NMR (300 MHz,
CDCl3) δ 1.20 (t, J ) 7.5 Hz, 3H), 2.30 (s, 3H), 3.33-3.43 (m,
2H), 7.21 (d, J ) 8.3 Hz, 2H), 7.26-7.36 (m, 3H), 7.82 (d, J )
7998 J . Org. Chem., Vol. 68, No. 21, 2003

Diels-Alder versus Hetero-Diels-Alder Processes
8.3 Hz, 2H), 7.90-7.94 (m, 1H), 8.25-8.28 (m, 1H), 9.37 (s,
1H); 13C NMR (75 MHz, CDCl3) δ 14.4, 21.5, 34.2, 113.1, 115.9,
122.7, 125.0, 125.8, 127.2 (2C), 128.1, 130.2 (2C), 134.1, 134.3,
138.4, 145.9, 161.0, 181.9; IR (KBr) ν 3385, 1684, 1654, 1381,
resultant mixture was transferred into a high-pressure vessel
and compressed at the desired pressure and the desired
temperature. After the decompression, the solvent and excess
diene were evaporated under reduced pressure. Chromatog-
raphy of the residue on silica led to the isolation of the
cycloadduct(s).
Ca ta lyzed Rea ction s u n d er High P r essu r e. To a stirred
solution of the requisite indole derivative 1 in dry dichlo-
romethane was added the Lewis acid at room temperature.
The mixture was stirred for 15 min. Hydroquinone and
distilled diene 2 were then added, and the resultant mixture
was transferred into a high-pressure vessel and compressed
at the desired pressure and temperature. After decompression,
the mixture was evaporated under reduced pressure. Chro-
matography of the residue on silica led to the isolation of the
cycloadduct(s).
The ketones resulting from the hydrolysis of the silyl enol
ether in the case of cycloadducts derived from Danishefsky
diene were obtained in the following manner. After reaction,
removal of the excess diene was achieved by bulb-to-bulb
distillation under reduced pressure (50 °C/0.1bar). The residue
(0.3 mmol scale) was then stirred overnight in methanol (2
mL) in the presence of silica (100 mg). Filtration and purifica-
tion as above delivered the desired products.
Gen er a l P r oced u r e for Th er m a l Cycloa d d ition s. A
vessel containing the requisite indole and diene in dry de-
gassed toluene was sealed and then heated in a sand bath at
the desired temperature. After cooling, the solvents and excess
diene were removed under reduced pressure and the residue
chromatographed.
1291, 1178 cm-1; MS (CI) m/z (relative intensity) 371 [M+
+
1] (86), 217 (50), 144 (100). Anal. Calcd for C19H18N2O4S: C,
61.61; H, 4.90; N, 7.56; S, 8.65. Found: C, 61.64; H, 4.96; N,
7.51; S, 8.54.
N-Meth yl-2-oxo-N-(1-p h en yleth yl)-2-[1-(tolu en e-4-su l-
fon yl)-1H-in d ol-3-yl]a ceta m id e (1g). Prepared according to
the general procedure using 1d (223 mg, 0.5 mmol) and NaH
(60% in oil) (24 mg, 0.6 mmol, MeI (47 µL, 0.75 mmol). The
reaction was stirred for 75 min at 0 °C. The product was
purified by flash chromatography (cyclohexane/EtOAc 4:1) to
give 1f as a white solid (151 mg, 66%, mp 140 °C): [R]20
)
D
1
+34.5 (c 1, CHCl3); (two rotamers) H NMR δ 1.56 and 1.59
(d, J ) 7.0 Hz, 3H), 2.30 (s, 3H), 2.62 and 2.74 (s, 3H), 5.04
and 6.04 (q, J ) 7.0 Hz, 1H), 7.18-7.37 (m, 9H), 7.76 (d, J )
8.3 Hz, 1H), 7.79 (d, J ) 8.3 Hz, 1H), 7.85-7.91 (m, 1H), 8.19-
8.25 (m, 1H), 8.27 and 8.34 (s, 1H); 13C NMR δ 15.1, 16.7, 21.3,
26.6, 29.4, 50.3, 55.2, 113.0, 117.4 and 117.7, 122.4 and 122.5,
124.9 and 124.9, 125.9 and 126.0, 126.8 and 126.8, 127.0 (2C),
127.6 and 127.7, 128.4 (2C), 128.5 (2C), 130.1 (2C), 133.8, 134.6
and 134.7, 135.2, 135.4, 138.3 and 138.9, 146.0 and 146.0,
166.0, 166.4, 186.2, 186.5; IR (KBr) ν 2929, 1655, 1633, 1385,
1172 cm-1; MS (EI) m/z (relative intensity) 460 [M+•] (15), 298
(7), 155 (34), 134 (44), 105 (62), 91 (100). Anal. Calcd for
C
26H24N2O4S: C, 67.81; H, 5.25; N, 6.08; S, 6.96. Found: C,
67.98; H, 5.22; N, 6.03; S, 6.82.
N-(1-Cycloh exyleth yl)-2-oxo-2-[1-(tolu en e-4-su lfon yl)-
1H-in d ol-3-yl]a ceta m id e (1h ). Prepared according to the
general procedure using 22h (1.20 g, 4 mmol), DMAP (20 mg),
(i-Pr)2EtN (1.05 mL, 6 mmol), and TsCl (0.84 g, 4.4 mmol) in
CH2Cl2 (20 mL). The reaction was stirred for 2 h and the
product purified by flash chromatography (cyclohexane/EtOAc
Gen er a l P r oced u r e for th e Hyd r olysis of Heter o-
Diels-Ald er Cycloa d d u cts. After the reaction, the excess
diene was removed by bulb-to-bulb distillation under reduced
pressure (60 °C/0.2 mmHg). A solution of trifluoroacetic acid
(2%) in CH2Cl2 was added to the residue at 0 °C, and the
solution was stirred for 15-30 min.25 An aqueous saturated
solution of NaHCO3 was added, and the reaction mixture was
extracted three times with CH2Cl2. After concentration of the
organic phases under reduced pressure, the residue was
purified by flash chromatography on silica.
9:1) to give 1h as a white solid (1.62 g, 90%, mp 51 °C): [R]20
D
) +6.3 (c 1, CHCl3); 1H NMR δ 1.00-1.80 (m, 11H), 1.20 (d, J
) 6.8 Hz, 3H), 2.37 (s, 3H), 3.84-3.98 (m, 1H), 7.28 (d, J )
8.5 Hz, 2H), 7.32-7.40 (m, 3H), 7.89 (d, J ) 8.5 Hz, 2H), 7.97-
8.00 (m, 1H), 8.31-8.35 (m, 1H), 9.45 (s, 1H); 13C NMR δ 17.4,
21.3, 25.8 (2C), 26.1, 28.8, 28.9, 42.7, 49.6, 113.0, 115.8, 122.5,
124.8, 125.6, 127.0 (2C), 128.0, 129.9 (2C), 133.9, 134.2, 138.2,
145.7, 160.3, 181.9; IR (KBr) ν 3366, 1684, 1648, 1595, 1382
cm-1; MS (EI) m/z (relative intensity) 452 [M+•] (5), 298 (37),
155 (55), 115 (12), 91 (100). Anal. Calcd for C25H28N2O4S: C,
66.35; H, 6.24; N, 6.19; S, 7.08. Found: C, 66.38; H, 6.17; N,
5.99; S, 6.78.
2,3-Dim et h yl-9-(t olu en e-4-su lfon yl)-1,4,9,9a -t et r a h y-
d r oca r ba zole-4a -ca r ba ld eh yd e (9). Purification of the resi-
due by flash chromatography (heptanes/EtOAc 9:1): mp ) 112
1
°C; H NMR δ 1.51 (s, 3H), 1.66 (s, 3H), 2.15 (d, J ) 14.5 Hz,
1H), 2.26 (s, 3H), 2.37-2.50 (m, 1H), 2.45 (d, J ) 14.5 Hz,
1H), 2.53 (dd, J ) 5.6, 14.7 Hz, 1H), 4.49 (dd, J ) 5.6, 7.2 Hz,
1H), 6.93 (dd, J ) 1.5, 7.5 Hz, 1H), 6.99 (dd, J ) 7.2, 7.5 Hz,
1H), 7.10 (d, J ) 8.3 Hz, 2H), 7.21 (ddd, J ) 1.5 Hz, 7.2, 8.3
Hz, 1H), 7.51 (d, J ) 8.3 Hz, 2H), 7.62 (d, J ) 8.3 Hz, 1H),
9.02 (s, 1H); 13C NMR δ 19.0, 19.0, 21.4, 35.0, 37.1, 61.3, 62.4,
116.1, 124.1, 124.7, 126.0, 127.1 (2C), 127.4, 129.4, 129.4 (2C),
131.0, 133.7, 142.5, 144.1, 196.3; MS (EI) m/z 381 (53), 352
(93), 299 (100), 196 (54), 155 (71), 91 (75); IR (NaCl) 2875,
1736, 1606, 1357, 1173; exact mass m/z calcd for C22H23NO3S
381.1399, found 381.1395.
N-(1-Cycloh exyl-eth yl)-N-m eth yl-2-oxo-2-[1-(tolu en e-4-
su lfon yl)-1H-in d ol-3-yl]-a ceta m id e (1i): Prepared accord-
ing to the general procedure using 1h (223 mg, 0.5 mmol), NaH
(60% in oil) (24 mg, 0.6 mmol), MeI (47 µL, 0.75 mmol). The
reaction was stirred for 2 h at 0 °C. The product was purified
by flash chromatography (cyclohexane/EtOAc 17:3) to give 1i
as a white solid (80 mg, 34%, mp 61-63%): [R]20 ) +29.3 (c
D
1, CHCl3); (two rotamers) 1H NMR (200 MHz) δ 0.64-1.81 (m,
11H), 1.23 and 1.25 (d, J ) 6.8 Hz, 3H), 2.37 (s, 3H), 2.82 and
2.94 (s, 3H), 3.26-3.42 and 4.40-4.53 (m, 1H), 7.28 (d, J )
8.0 Hz, 2H), 7.36-7.43 (m, 2H), 7.84 (d, J ) 8.0 Hz, 2H), 7.93-
7.98 (m, 1H), 8.27-8.35 (m, 2H); 13C NMR (50 MHz) δ 15.2
and 16.2, 21.2, 25.5 (2C), 25.6 and 25.6, 25.8, 29.0, 29.4 and
29.5, 29.6 and 29.9, 39.4 and 39.9, 52.8 and 58.6, 112.9, 117.3
and 117.6, 122.3 and 122.4, 124.7, 125.8 and 126.7, 126.9 (2C),
129.9 (2C), 133.7 and 134.5, 135.2 and 135.2, 145.9, 166.2 and
166.6, 186.4 and 186.6; IR (KBr) ν 2926, 1653, 1636, 1383, 1173
cm-1; MS (EI) m/z (relative intensity) 466 [M+•] (7), 383 (7),
298 (66), 155 (50), 140 (46), 111 (29), 91 (100). Anal. Calcd for
[2,3-Dim et h yl-9-(t olu en e-4-su lfon yl)-1,4,9,9a -t et r a h y-
d r oca r ba zol-4a -yl]oxoa cetic Acid Meth yl Ester (10). Pu-
rification of the residue by flash chromatography (heptanes/
EtOAc 9:1): 1H NMR δ 1.44 (s, 3H), 1.64 (s, 3H), 2.27 (s, 3H),
2.28-2.68 (m, 2H), 2.38 (d, J ) 14.7 Hz, 1H), 2.62 (d, J ) 14.7
Hz, 1H), 3.56 (s, 3H), 4.81 (dd∼t, J ) 5.5 Hz, 1H), 6.95 (dd-t,
J ) 7.5 Hz, 1H), 7.03-7.22 (m, 2H), 7.09 (d, J ) 8.3 Hz, 2H),
7.51 (d, J ) 8.3 Hz, 2H), 7.50-7.58 (m, 1H); 13C NMR δ 19.1,
19.2, 21.5, 37.2, 37.9, 52.4, 61.0, 64.4, 115.8, 124.3, 125.0, 125.7,
127.3 (2C), 127.8, 129.4 (3C), 130.8, 134.3, 142.9, 144.0, 162.6,
193.7; MS (EI) m/z 439 (23), 352 (100), 298 (38), 196 (41); IR
(NaCl) 2924, 1736, 1597, 1477, 1459, 1356, 1168; exact mass
m/z calcd for C24H25NO5S 439.1454, found 439.1448.
C
26H30N2O4S: C, 66.93; H, 6.48; N, 6.00; S, 6.87. Found: C,
66.99; H, 6.12; N, 5.97; S, 6.56.
Gen er a l P r oced u r e for th e High -P r essu r e Rea ction s.
Non ca ta lyzed Rea ction s. To a solution of the requisite
indole, in dry dichloromethane at room temperature under
argon, were added hydroquinone (10 mg) and the diene. The
(25) In the case of the cycloadducts 26 and 29, it was necessary to
use
a solution of 10% of TFA in CH2Cl2 during 18 h at room
temperature.
J . Org. Chem, Vol. 68, No. 21, 2003 7999

Chre´tien et al.
4a -(4,5-Dim e t h yl-3,6-d ih yd r o-2H -p yr a n -2-yl)-2,3-d i-
m eth yl-9-(tolu en e-4-su lfon yl)-4,4a,9,9a-tetr ah ydr o-1H-car -
ba zole (11a ). Purification of the residue by flash chromatog-
raphy (heptanes/EtOAc 9:1) (major diastereomer): 1H NMR
δ 0.70-0.95 (m, 1H), 1.20 (s, 3H), 1.34 (s, 3H), 1.36 (s, 3H),
1.64 (s, 3H), 1.20-1.30 (m, 1H), 1.92 (d, J ) 14.3 Hz, 1H),
2.26 (s, 3H), 2.15-2.30 (m, 1H), 2.55 (d, J ) 14.7 Hz, 1H),
2.63 (dd, J ) 4.1, 14.7 Hz, 1H), 2.92 (dd, J ) 3.4, 10.9 Hz,
1H), 3.50-3.70 (m, 2H), 4.21 (dd∼t, J ) 4.1 Hz, 1H), 6.83-
7.15 (m, 5H), 7.56-7.65 (m, 3H); 13C NMR δ 13.6, 18.1, 19.2,
19.4, 21.5, 30.8, 37.6, 38.6, 53.7, 65.2, 70.4, 79.3, 114.7, 123.2,
123.5, 124.0, 124.1, 126.0, 127.0, 127.4 (2C), 128.0, 129.4 (2C),
135.1, 136.0, 143.0, 143.7. 11b (minor diastereomer): 1H NMR
δ 0.70-0.95 (m, 1H), 1.19 (s, 3H), 1.24 (s, 3H), 1.34 (s, 3H),
1.42 (s, 3H), 1.30-1.40 (m, 1H), 2.11 (d, J ) 14.3 Hz, 1H),
2.26 (s, 3H), 2.15-2.75 (m, 4H), 3.50-3.70 (m, 2H), 3.98 (dd∼t,
J ) 5.3 Hz, 1H), 6.83-7.15 (m, 5H), 7.56-7.65 (m, 3H); 13C
NMR δ 13.6, 18.3, 19.2, 19.3, 21.5, 30.4, 36.5, 37.7, 53.9, 66.0,
70.2, 78.5, 114.7, 123.1, 123.6, 124.0, 125.1, 126.0, 127.0, 127.4
(2C), 128.0, 129.4 (2C), 135.2, 135.5, 143.0, 143.7; MS (EI) m/z
463 (30), 352 (100), 299 (10), 271 (8), 196 (45); IR (NaCl) 2922,
1597, 1478, 1458, 1357, 1169, 1091; exact mass m/z calcd for
(100). Anal. Calcd for C26H27NO4S: C, 69.46; H, 6.05; N, 3.12;
S, 7.13. Found: C, 69.37; H, 5.92; N, 3.44; S, 6.98.
2-[1-(Tolu en e-4-su lfon yl)-1H-in d ol-3-yl]-2,3-d ih yd r op y-
r a n -4-on e (14). Purification of the residue by flash chroma-
tography (heptanes/EtOAc 7:3): 1H NMR δ 2.28 (s, 3H), 2.76
(dd, J ) 3.8, 16.8 Hz, 1H), 2.99 (dd, J ) 12.8, 16.8 Hz, 1H),
5.47 (d, J ) 6.0 Hz, 1H), 5.64 (dd, J ) 3.8, 12.8 Hz, 1H), 7.18
(d, J ) 8.3 Hz, 2H), 7.21 (dd∼t, J ) 7.9 Hz, 1H), 7.30 (dd, J )
7.9, 8.7 Hz, 1H), 7.38 (d, J ) 6.0 Hz, 1H), 7.53 (d, J ) 7.9 Hz,
1H), 7.54 (s, 1H), 7.72 (d, J ) 8.3 Hz, 2H), 7.94 (d, J ) 8.7 Hz,
1H); 13C NMR δ 21.6, 41.4, 74.6, 107.5, 113.8, 119.3, 120.0,
123.5, 124.0, 125.3, 126.9 (2C), 128.2, 130.0 (2C), 134.9, 135.2,
145.3, 162.8, 191.5; MS (EI) m/z 367 (72), 297 (100), 212 (22),
184 (28), 142 (96), 115 (54), 91 (48); IR (NaCl, cm-1) 2950, 1681,
1661, 1601, 1192, 1157; exact mass m/z calcd for C20H17NO4S
367.0879, found 367.0866.
4-Oxo-2-[1-(tolu en e-4-su lfon yl)-1H-in d ol-3-yl]-3,4-d ih y-
d r o-2H-p yr a n -2-ca r boxylic Acid Meth yl Ester (15). Pu-
rification of the residue by flash chromatography (heptanes/
EtOAc 2:1): 1H NMR δ 2.28 (s, 3H), 3.16 (d, J ) 16.6 Hz, 1H),
3.36 (d, J ) 16.6 Hz, 1H), 3.66 (s, 3H), 5.39 (d, J ) 6.0 Hz,
1H), 7.18 (d, J ) 8.7 Hz, 2H), 7.20-7.30 (m, 2H), 7.31 (d, J )
6.0 Hz, 1H), 7.60 (s, 1H), 7.70 (d, J ) 8.7 Hz, 2H), 7.68-7.75
(m, 1H), 7.89 (d, J ) 8.3 Hz, 1H); 13C NMR δ 21.6, 43.2, 53.6,
82.9, 108.0, 113.6, 118.0, 121.4, 123.7, 125.1, 125.3, 127.0 (2C),
127.1, 130.0 (2C), 134.7, 135.2, 145.4, 160.6, 169.0, 189.1; MS
(EI) m/z 425 (68), 366 (100), 355 (59), 296 (73), 200 (36), 155
(25), 91 (40); IR (NaCl, cm-1) 2970, 1752, 1680, 1597, 1447,
1374, 1273, 1190; exact mass (EI) m/z calcd for C22H19NO6S
425.0933, found 425.0930.
C
28H33NO3S 463.2181, found 463.2186.
2-[2,3-Dim eth yl-9-(tolu en e-4-su lfon yl)-1,4,9,9a -tetr a h y-
d r oca r ba zol-4a -yl]-4,5-d im eth yl-3,6-d ih yd r o-2H-p yr a n -2-
ca r boxylic Acid Meth yl Ester (12a ). Purification of the
residue by flash chromatography (heptanes/EtOAc 9:1) (major
diastereomer): 1H NMR δ 0.70-0.92 (m, 1H), 1.02 (s, 3H),
1.10-1.40 (m, 2H), 1.28 (s, 3H), 1.29 (s, 3H), 1.54-1.74 (m,
1H), 1.62 (s, 3H), 2.05 (dd, J ) 3.6, 14.7 Hz, 1H), 2.28 (s, 3H),
2.66 (dd, J ) 3.6, 14.7 Hz, 1H), 3.60 (s, 3H), 3.70-3.90 (m,
1H), 4.00-4.20 (m, 1H), 4.60 (dd-t, J ) 3.6 Hz, 1H), 6.85
(ddd-dt, J ) 0.8, 7.5 Hz, 1H), 6.98-7.30 (m, 2H), 7.17 (d, J )
7.9 Hz, 2H), 7.50-7.70 (m, 3H); 13C NMR δ 13.5, 18.5, 19.0,
19.3, 21.5, 33.1, 36.7, 37.2, 51.9, 56.7, 64.0, 66.8, 81.7, 113.6,
121.1, 123.1, 123.2, 126.4, 126.8, 127.1, 127.5 (2C), 128.3, 129.7
(2C), 134.6, 135.6, 143.2, 143.9, 172.4. 12b (minor diastere-
omer): 1H NMR δ 0.80-1.40 (m, 8H), 1.21 (s, 3H), 1.50-1.70
(m, 1H), 1.58 (s, 3H), 1.87 (d, J ) 14.3 Hz, 1H), 2.10-2.25 (m,
1H), 2.28 (s, 3H), 2.47-2.60 (m, 1H), 3.40-3.55 (m, 1H), 3.58
(s, 3H), 3.70-3.90 (m, 1H), 4.80 (dd-t, J ) 3.8 Hz, 1H), 6.80-
6.90 (m, 1H), 6.98-7.30 (m, 4H), 7.50-7.70 (m, 3H); 13C NMR
δ 13.5, 18.4, 19.2, 19.7, 21.5, 32.7, 37.1, 37.5, 51.7, 56.7, 65.3,
66.9, 82.5, 113.8, 122.1, 122.7, 122.8, 125.5, 126.3, 126.5, 127.5,
127.5 (2C), 129.4 (2C), 133.5, 135.7, 143.5, 144.0, 172.5; MS
(EI) m/z 521 (8), 352 (100), 298 (5), 196 (31), 170 (23); IR (NaCl)
2921, 1734, 1596, 1476, 1458, 1354, 1266, 1167, 1092; exact
mass m/z calcd for C30H33NO5S 521.2236, found 521.2224.
5-Hyd r oxy-1-m eth oxy-5-[1-(tolu en e-4-su lfon yl)-1H-in -
d ol-3-yl]p en t-1-en -3-on e (16): 1H NMR δ 2.28 (s, 3H), 2.90-
3.00 (m, 2H), 3.64 (s, 3H), 3.83 (d, J ) 3.0 Hz, 1H), 5.36 (m,
1H), 5.52 (d, J ) 12.8 Hz, 1H), 7.14 (d, J ) 8.3 Hz, 2H), 7.10-
7.20 (m, 1H), 7.24 (dd∼t, J ) 7.2 Hz, 1H), 7.48 (s, 1H), 7.50-
7.58 (m, 1H), 7.57 (d, J ) 12.8 Hz, 1H), 7.69 (d, J ) 8.3 Hz,
2H), 7.90 (d, J ) 8.3 Hz, 1H); 13C NMR δ 22.0, 47.3, 58.2, 64.5,
106.2, 114.1, 120.6, 123.2, 123.6, 124.6, 125.2, 127.3 (2C),
129.1, 130.3 (2C), 135.6, 135.8, 145.4, 164.3, 199.6; MS (CI
isobutane) m/z 400 (M + H+), 300; IR (NaCl) 3400, 3000, 1731,
1681, 1596, 1461, 1376, 1183.
2-Meth oxy-6-[1-(tolu en e-4-su lfon yl)-1H-in d ol-3-yl]tet-
r a h yd r op yr a n -4-on e (17) (major isomer): 1H NMR δ 2.27
(s, 3H), 2.44-2.80 (m, 3H), 2.56 (dd, J ) 8.7, 15.1 Hz, 1H),
3.50 (s, 3H), 4.76 (dd, J ) 3.0, 8.7 Hz, 1H), 4.88 (dd, J ) 4.1,
9.8 Hz, 1H), 7.17 (d, J ) 8.3 Hz, 2H), 7.15-7.20 (m, 1H), 7.28
(dd-t, J ) 7.8 Hz, 1H), 7.51 (s, 1H), 7.50-7.58 (m, 1H), 7.72
(d, J ) 8.3 Hz, 2H), 7.93 (d, J ) 8.3 Hz, 1H); 13C NMR δ 21.5,
46.2, 47.7, 56.7, 67.2, 101.3, 113.7, 120.0, 121.5, 123.1, 123.3,
125.1, 126.9 (2C), 128.4, 129.9 (2C), 135.0, 135.3, 145.1, 204.4.
(Minor isomer): 1H NMR δ 2.27 (s, 3H), 2.44-2.80 (m, 4H),
3.38 (s, 3H), 5.18 (d, J ) 3.4 Hz, 1H), 5.28 (dd, J ) 4.7, 9.8
Hz, 1H), 7.17 (d, J ) 8.3 Hz, 2H), 7.15-7.20 (m, 1H), 7.28 (dd-
t, J ) 7.8 Hz, 1H), 7.51 (s, 1H), 7.50-7.58 (m, 1H), 7.72 (d, J
) 8.3 Hz, 2H), 7.93 (d, J ) 8.3 Hz, 1H); 13C NMR δ 21.5, 46.6,
47.2, 55.4, 64.5, 99.8, 113.8, 120.0, 121.8, 122.8, 123.3, 125.1,
126.9 (2C), 128.3, 129.9 (2C), 135.0, 135.3, 145.1, 203.6; MS
(EI) m/z 399 (38), 367 (37), 297 (12), 212 (38), 184 (100); exact
mass (CI isobutane) m/z calcd for C21H21NO5S 399.1141, found
399.1130.
2-[2,3-Dim eth yl-9-(tolu en e-4-su lfon yl)-1,4,9,9a -tetr a h y-
d r oca r ba zol-4a -yl]-2,3-d ih yd r op yr a n -4-on e (13). Purifica-
tion of the residue by flash chromatography (heptanes/EtOAc
3:1) (minor diastereomer): 1H NMR δ 1.00-2.62 (m, 9H), 1.44
(s, 3H), 2.28 (s, 3H), 3.32 (dd, J ) 2.6, 15.3 Hz, 1H), 4.03-
4.07 (m, 1H), 5.15-5.19 (m, 1H), 6.83 (d, J ) 8.7 Hz, 1H),
6.81-7.25 (m, 5H), 7.54 (d, J ) 8.3 Hz, 2H), 7.83 (d, J ) 8.7
Hz, 1H); 13C NMR δ 19.2, 19.3, 21.5, 35.5, 36.1, 37.4, 52.9, 64.8,
82.8, 106.6, 115.3, 124.6, 126.2, 126.7, 126.9 (2C), 129.0, 129.8,
130.9 (2C), 133.3, 134.4, 142.9, 144.8, 163.0, 192.1. (Major
diastereomer): 1H NMR δ 1.23 (d, J ) 15.4 Hz, 1H), 1.41 (s,
3H), 1.46 (ddd, J ) 1.5, 3.0, 15.4 Hz, 1H), 1.65 (s, 3H), 2.03 (d,
J ) 14.9 Hz, 1H), 2.23 (s, 3H), 2.31 (d, J ) 13.6 Hz, 1H), 2.51
(d, J ) 14.9 Hz, 1H), 2.58 (dd, J ) 4.9, 14.7 Hz, 1H), 3.55 (dd,
J ) 2.6, 15.4 Hz, 1H), 4.06 (dd (≈t), J ) 4.7, 4.7 Hz, 1H), 5.14
(dd, J ) 1.1, 5.8 Hz, 1H), 6.86-6.97 (m, 2H), 7.01 (d, J ) 5.8
Hz, 1H), 7.10 (d, J ) 8.1 Hz, 2H), 7.15 (dd, J ) 1.9, 8.3 Hz,
1H), 7.55 (d, J ) 8.1 Hz, 2H), 7.65 (d, J ) 8.3 Hz, 1H); 13C
NMR δ 19.3, 19.4, 21.5, 36.8, 37.4, 37.5, 53.2, 64.6, 83.3, 106.8,
115.7, 124.4 (2C), 126.6, 126.8, 127.2 (2C), 129.1, 129.9 (2C),
134.0, 134.4, 142.9, 145.0, 162.9, 191.7; IR (KBr) ν 2926, 1669,
1589, 1359, 1169 cm-1, MS (EI) m/z (relative intensity) 449
[M+•] (80), 352 (62), 297 (16), 196 (79), 142 (38), 115 (39), 91
2-[1-(Tolu en e-4-su lfon yl)-1H -in d ol-2-yl]-2,3-d ih yd r o-
p yr a n -4-on e (19). Purification of the residue by flash chro-
matography (heptanes/EtOAc 7:3): 1H NMR δ 2.25 (s, 3H),
2.89 (dd, J ) 6.4, 17.0 Hz, 1H), 2.97 (dd, J ) 9.4, 17.0 Hz,
1H), 5.46 (d, J ) 6.0 Hz, 1H), 6.25 (dd, J ) 6.4, 9.4 Hz, 1H),
6.74 (s, 1H), 7.12 (d, J ) 8.1 Hz, 2H), 7.18 (m, 1H), 7.24 (d, J
) 6.0 Hz, 1H), 7.29 (m, 1H), 7.44 (d, J ) 7.9 Hz, 1H), 7.62 (d,
J ) 8.1 Hz, 2H), 8.08 (d, J ) 8.7 Hz, 1H); 13C NMR δ 21.5,
41.4, 73.4, 107.6, 111.7, 114.9, 212.5, 124.0, 125.8, 126.5 (2C),
128.4, 129.7 (2C), 135.5, 136.4, 137.3, 145.1, 162.1, 191.4; MS
(EI) m/z 367 (54), 233 (34), 232 (29), 212 (39), 184 (32), 142
8000 J . Org. Chem., Vol. 68, No. 21, 2003

Diels-Alder versus Hetero-Diels-Alder Processes
(44), 91 (100); IR (NaCl) 2359, 1676, 1594, 1369, 1149; exact
mass (EI) m/z calcd for C20H17NO4S 367.0879, found 367.0862.
N,N-Dieth yl-2-[4-m eth oxy-2-oxo-9-(tolu en e-4-su lfon yl)-
1,2,3,4,9,9a-h exah ydr ocar bazol-4a-yl]-2-oxoacetam ide (20).
Purification of the residue by flash chromatography (heptanes/
EtOAc 2:1) 20a (major diastereomer): 1H NMR δ 0.69 (t, J )
7.2 Hz, 3H), 1.04 (t, J ) 7.2 Hz, 3H), 2.14-2.60 (m, 2H), 2.23
(dd, J ) 8.3, 18.3 Hz, 1H), 2.28 (s, 3H), 2.48 (dd, J ) 3.4, 18.3
Hz, 1H), 2.57-3.48 (m, 2H), 2.85 (dd, J ) 6.4, 16.4 Hz, 1H),
3.07 (dd, J ) 6.0, 16.4 Hz, 1H), 3.19 (s, 3H), 4.81 (dd, J ) 3.4,
8.3 Hz, 1H), 5.20 (dd, J ) 6.0, 6.4 Hz, 1H), 6.97 (m, 1H), 7.12
(d, J ) 7.9 Hz, 2H), 7.16-7.30 (m, 2H), 7.53-7.64 (m, 3H);
13C NMR δ 11.4, 12.3, 20.5, 38.0, 38.6, 40.5, 43.6, 56.3, 60.4,
63.7, 76.0, 114.7, 123.6, 125.9, 126.5, 126.9 (2C), 128.6 (2C),
129.1, 133.1, 141.5, 143.3, 164.3, 196.5, 204.7; MS (EI) m/z 399
(3), 344 (7), 284 (16), 242 (29), 184 (37), 156 (28), 138 (19), 100
(100). Anal. Calcd for C26H30N2O6S: C, 62.63; H, 6.06; N, 5.62;
S, 6.43. Found: C, 62.58; H, 6.21; N, 5.41; S, 6.44. 20b (minor
diastereomer): 1H NMR δ 0.61 (t, J ) 7.2 Hz, 3H), 1.05 (t, J
) 7.2 Hz, 3H), 1.88 (dd, J ) 2.3, 18.5 Hz, 1H), 2.05-2.42 (m,
2H), 2.28 (s, 3H), 2.56 (dd, J ) 3.0, 18.5, 1H), 3.01 (dd, J )
5.6, 17.0 Hz, 1H), 3.08-3.43 (m, 2H), 3.21 (dd, J ) 2.3, 17.0
Hz, 1H), 3.25 (s, 3H), 4.67 (dd, J ) 2.3, 3.0 Hz, 1H), 5.41 (dd,
J ) 2.3, 5.6 Hz, 1H), 6.95 (m, 1H), 7.11 (d, J ) 7.9 Hz, 2H),
7.43 (m, 1H), 7.59 (m, 1H), 7.66 (d, J ) 7.9 Hz, 2H), 7.68 (m,
1H); 13C NMR δ 11.3, 12.3, 20.6, 36.4, 38.1, 40.4, 43.2, 55.7,
60.4, 62.9, 79.4, 115.1, 123.6, 125.2, 126.5, 126.9 (2C), 128.6
(2C), 129.6, 132.8, 141.1, 143.3, 164.1, 193.9, 205.6; MS (DCI,
isobutane) m/z 499 (39), 345 (100), 157 (56); exact mass (DCI,
isobutane) m/z calcd for C26H30N2O6S 499.1903, found 499.1907.
Gen er a l P r oced u r e for th e Syn th esis of th e In d ole-3-
glyoxa m id e. To a stirred and cooled solution of indole in dry
ether under argon was added oxalyl chloride (1.1-1.25 equiv)
dropwise. After 30-60 min at 0 °C, the reaction mixture was
evaporated under reduced pressure, and dry ether (5-10 mL)
was added to the residue and evaporated twice in order to
remove the excess oxalyl chloride. Then, to a cooled solution
of the crude product in dry ether (10-20 mL) was added the
amine (2.0 equiv), and the mixture was stirred overnight at
room temperature under argon. A saturated aqueous solution
of NaHCO3 was added, and the solution was extracted with
CH2Cl2. After drying over MgSO4, the solvent was evaporated
under vacuum.
2-(1H-Indol-3-yl)-2-oxo-N-(1-phenylethyl)acetamide (22d).
Purification by flash chromatography (heptanes/EtOAc 2:1)
(83%, mp 213 °C).26
2-(1H -In d ol-3-yl)-N -(1-n a p h t h a le n -1-yle t h yl)-2-oxo-
a ceta m id e (22e). Purification by flash chromatography and
elution with heptanes/EtOAc (7:3 first, then 1:1) (69%, mp 189
°C).27
N-Eth yl-2-(1H-in d ol-3-yl)-2-oxoa ceta m id e (22f). Oxalyl
chloride (0.52 mL, 6 mmol) was added dropwise to a solution
of indole 21 (588 mg, 5 mmol) in dry ether (10 mL) at 0 °C.
The mixture was stirred for 30 min and evaporated under
reduced pressure; the residue was washed twice with ether (2
× 10 mL). To a slurry of the crude product in ether (10 mL)
were sequentially added EtNH2‚HCl (652 mg, 8 mmol) and
(i-Pr)2EtN (1.40 mL, 8 mmol) at 0 °C. Stirring was continued
overnight at room temperature. The resultant mixture was
poured into water (10 mL) and extracted three times with
dichloromethane (3 × 10 mL). The combined organic phases
were dried and evaporated to give a crude product, isolated
as a yellow solid (1023 mg, 95%), and used without purification
in the next step.28
N -(1-Cycloh e xyle t h yl)-2-(1H -in d ol-3-yl)-2-oxoa ce t -
a m id e (22h ). Prepared according to the general procedure
using indole (588 mg, 5 mmol), oxalyl chloride (515 µL, 6
mmol), and 1(R)-cyclohexylethylamine (1490 µL, 10 mmol). The
reaction mixture was stirred overnight at rt. After concentra-
tion of the crude mixture, the residue was dissolved in hot
EtOAc and filtered through silica to give 22h as a pale yellow
solid (1298 mg, 87%, mp 192 °C): [R]25D ) -21.0 (c 0.5, CHCl3);
1H NMR δ 0.99-1.77 (m, 11H), 1.20 (d, J ) 6.8 Hz, 3H), 3.84-
3.97 (m, 1H), 7.28-7.47 (m, 4H), 8.43 (d, j ) 7.2 Hz, 1H), 9.10
(d, J ) 3.0 Hz, 1H), 9.26 (bs, 1H); 13C NMR δ 17.8, 26.1 (2C),
26.3, 28.9, 29.2, 43.1, 49.7, 111.6, 113.4, 122.4, 123.4, 124.1,
126.7, 135.7, 138.3, 161.7, 181.0; IR (KBr) ν 3333, 3273, 1654,
1602, 1232 cm-1; MS (EI) m/z (relative intensity) 299 [M+•
]
(2), 144 (100), 116 (9), 89 (9). Anal. Calcd for C18H22N2O2: C,
72.46; H, 7.43; N, 9.39. Found: C, 72.18; H, 7.44; N, 9.13; S,
6.78.
2-[4-Meth oxy-2-oxo-9-(tolu en e-4-su lfon yl)-1,2,3,4,9,9a -
h exa h yd r oca r ba zol-4a -yl]-N-m et h yl-2-oxo-N-(1-p h en yl-
eth yl)a ceta m id e (23).29 Purification of the residue by flash
chromatography (cyclohexane/EtOAc 7:3) (two diastereomers,
1:1): 1H NMR δ 1.25 and 1.40 (d, J ) 7.0 Hz, 3H), 2.04 and
2.20 (s, 3H), 2.31-2.45 (m, 1H), 2.36 (s, 3H), 2.54 and 2.69
(dd, J ) 3.4, 18.3 Hz and 4.9, 18.1 Hz, 1H), 3.00-3.33 and
5.74 (m and q, J ) 7.0 Hz, 3H), 3.25 and 3.29 (s, 3H), 4.94
and 5.26 (dd, J ) 3.4, 7.5 Hz and 2.3, 4.9 Hz, 1H), 5.27-5.35
(m, 1H), 6.07 (d, J ) 7.1 Hz, 1H), 6.69 (d, J ) 8.3 Hz, 1H),
6.95-7.35 (m, 7H), 7.37-7.51 (m, 1H), 7.53 (d, J ) 8.3 Hz,
1H), 7.64 (d, J ) 8.3 Hz, 1H), 7.69 and 7.82 (d, J ) 7.9 Hz,
1H); 13C NMR δ 14.9 and 15.8, 21.3 and 21.4, 26.9 and 27.9,
39.4 and 39.6, 44.4 and 44.8, 50.2 and 55.5, 57.4 and 57.9, 60.0
and 60.9, 64.9 and 66.3, 77.9, 115.8 and 116.0, 124.3 and 124.6,
126.4 and 126.6, 127.1, 127.2 and 127.3, 127.5 and 127.7, 127.6,
127.8 and 127.9, 128.2, 128.6, 129.6, 130.0 and 130.2, 134.1,
137.2 and 138.3, 142.6 and 143.8, 144.4, 165.3 and 165.9, 197.7
and 198.1, 205.5 and 205.8; IR (KBr) ν 3395, 1724, 1636, 1597,
1165 cm-1; MS (CI) m/z (relative intensity) 561 [MH+] (91),
405 (100), 357 (51), 185 (45), 157 (52), 105 (82). Anal. Calcd
for C31H32N2O6S: C, 66.41; H, 5.75; N, 5.00; S, 5.72. Found:
C, 66.35; H, 5.71; N, 5.11; S, 5.66.
N-(1-Cycloh exyleth yl)-2-[4-m eth oxy-2-oxo-9-(tolu en e-
4-su lfon yl)-1,2,3,4,9,9a-h exah ydr ocar bazol-4a-yl]-N-m eth -
yl-2-oxoa ceta m id e (24). Purification of the residue by flash
chromatography (cyclohexane/EtOAc 4:1) (major diastere-
omer): 1H NMR δ 0.78-1.72 (m, 11H), 0.99 (d, J ) 6.8 Hz,
3H), 1.88 (s, 3H), 2.30-2.38 (m, 1H), 2.32 (s, 3H), 2.49-2.57
(m, 1H), 3.01 (dd, J ) 6.4, 16.2 Hz, 1H), 3.11 (dd, J ) 6.4,
16.2 Hz, 1H), 3.26 (s, 3H), 4.14-4.24 (m, 1H), 4.88 (dd, J )
3.4, 7.9 Hz, 1H), 5.33 (dd ≈ t, J ) 6.4, 6.4 Hz, 1H), 7.05 (dd ≈
t, J ) 7.5, 7.5 Hz, 1H), 7.17 (d, J ) 8.3 Hz, 2H), 7.20-7.36 (m,
1H), 7.63 (d, J ) 8.3 Hz, 2H), 7.69 (m ≈ d, 2H); 13C NMR δ
15.1, 21.4, 25.7, 25.8, 26.0, 27.6, 29.2, 29.7, 39.5, 39.8, 44.5,
52.7, 57.3, 61.0, 64.8, 76.5, 115.9, 124.4, 126.9, 127.5, 127.6
(2C), 129.5 (2C), 130.1, 134.0, 142.5, 144.3, 166.2, 197.8, 205.7;
IR (NaCl) ν 2925, 1718, 1630, 1597, 1356, 1168 cm-1; MS (EI)
m/z (relative intensity) 566 [M+•] (3), 411 (50), 298 (38), 284
(45), 220 (48), 184 (52), 155 (50), 111 (55), 91 (100); HRMS
calcd for C31H38N2O6S (M+•) 566.2451, found 566.2445.
4-Oxo-2-[1-(tolu en e-4-su lfon yl)-1H-in d ol-3-yl]-3,4-d ih y-
d r o-2H -p yr a n -2-ca r b oxylic Acid (1-P h en ylet h yl)a m id e
(25). Purification of the residue by flash chromatography
(heptanes/EtOAc 1:1) (major diastereomer): 1H NMR δ 1.46
(d, J ) 6.8 Hz, 3H), 2.25 (s, 3H), 3.17 (d, J ) 17.0 Hz, 1H),
3.25 (d, J ) 17.0 Hz, 1H), 5.00-5.10 (m, 1H), 5.40 (d, J ) 6.0
Hz, 1H), 6.68 (d, J ) 7.9 Hz, 1H), 7.01-7.25 (m, 10H), 7.39 (d,
J ) 7.9 Hz, 1H), 7.53 (s, 1H), 7.62 (d, J ) 8.3 Hz, 2H), 7.86 (d,
J ) 8.7 Hz, 1H); 13C NMR δ 21.2, 21.5, 43.1, 49.1, 84.0, 108.5,
113.6, 118.3, 120.9, 123.5, 125.2, 125.8, 126.0 (2C), 126.8 (2C),
127.0, 127.5, 128.6 (2C), 129.9 (2C), 134.5, 135.2, 141.9, 145.3,
158.7, 167.5, 189.7; IR (KBr) ν 3413, 1732, 1670, 1372, 1175
cm-1; MS (EI) m/z (relative intensity) 514 [M+•] (7), 393 (17),
366 (90), 296 (12), 212 (57), 155 (29), 91 (100); HRMS calcd
(26) Primafiore, G.; Da Settimo, F.; Taliani, S.; Morini, A. M.;
Novellino, E.; Greco, G.; Lovecchia, A.; Besnard, F.; Trincavelli, L.;
Costoc, B.; Martini, C. J . Med. Chem. 2001, 44, 2286-2297.
(27) Kawate, T.; Yamonaka, M.; Nagawa, M. Heterocycles 1999, 50,
1033-1039.
(28) (a) Brimblecombe, R. W.; Downing, D. F.; Green, D. M.; Hunt,
R. R. Brit. J . Pharmacol. 1964, 23, 43-54. (b) Alemany, A.; Fernandy
Alvarey, E.; Nieto Lopez, O.; Rubio Herraey, M. E. Bull. Soc. Chim.
Fr. 1974, 12, 2883-2888.
J . Org. Chem, Vol. 68, No. 21, 2003 8001

Chre´tien et al.
for C29H26N2O5S [M+•] 514.1563, found 514.1558. (Minor di-
astereomer): 1H NMR δ 1.35 (d, J ) 6.8 Hz, 3H), 2.26 (s, 3H),
3.12 (d, J ) 17.0 Hz, 1H), 3.20 (d, J ) 17.0 Hz, 1H), 4.98-
5.08 (m, 1H), 5.34 (d, J ) 6.4 Hz, 1H), 6.74 (d, J ) 7.9 Hz,
1H), 7.12-7.29 (m, 10H), 7.59 (s, 1H), 7.59-7.61 (m, 1H), 7.66
(d, J ) 8.3 Hz, 2H), 7.89 (d, J ) 8.3 Hz, 1H); 13C NMR δ 21.2,
21.5, 43.2, 49.1, 84.1, 108.6, 113.8, 118.4, 120.9, 123.7, 125.3,
125.9, 126.0 (2C), 126.9 (2C), 127.2, 127.7, 128.8 (2C), 130.0
(2C), 134.6, 135.4, 142.1, 145.3, 158.6, 167.4, 189.5; IR (KBr)
ν 3413, 1732, 1670, 1372, 1175 cm-1; MS (EI) m/z (relative
intensity) 514 [M+•] (3), 393 (9), 366 (50), 296 (6), 212 (35),
155 (24), 91 (100); HRMS calcd for C29H26N2O5S [M+•] 514.1563,
found 514.1553.
135.2, 145.2, 158.6, 167.3, 189.7; IR (KBr) ν 3422, 1684, 1604,
1265, 1176 cm-1; MS (EI) m/z (relative intensity) 520 [M+•
]
(11), 366 (95), 296 (58), 212 (100), 155 (40), 91 (85); HRMS
calcd for C29H32N2O5S [M+•] 520.2032, found 520.2015. (Minor
diastereomer): 1H NMR δ 0.82-1.75 (m, 11H), 1.01 (d, J )
6.8 Hz, 3H), 2.34 (s, 3H), 3.20 (d, J ) 17.0 Hz, 1H), 3.33 (d, J
) 17.0 Hz, 1H), 3.77-3.90 (m, 1H), 5.47 (d, J ) 6.2 Hz, 1H),
6.30 (d, J ) 9.0 Hz, 1H), 7.20-7.35 (m, 2H), 7.23 (d, J ) 7.9
Hz, 2H), 7.28 (d, J ) 6.2 Hz, 1H), 7.64 (d, J ) 7.9 Hz, 1H),
7.64 (s, 1H), 7.74 (d, J ) 8.3 Hz, 2H), 7.96 (d, J ) 8.3 Hz, 1H);
13C NMR δ 17.8, 21.5, 26.0 (2C), 26.2, 28.8, 29.1, 42.9, 43.4,
49.9, 84.3, 108.6, 113.8, 118.7, 120.9, 123.6, 125.3, 125.7, 126.9
(2C), 127.2, 130.0 (2C), 134.6, 135.3, 145.3, 158.8, 167.4, 189.6;
IR (KBr) ν 3420, 1684, 1375, 1265, 1176 cm-1; MS (EI) m/z
(relative intensity) 520 [M+•] (15), 452 (12), 366 (23), 312 (15),
4-Oxo-2-[1-(tolu en e-4-su lfon yl)-1H-in d ol-3-yl]-3,4-d ih y-
d r o-2H-p yr a n -2-ca r boxylic Acid (1-Na p h th a len -1-yleth -
yl)a m id e (26). Purification of the residue by flash chroma-
tography (cyclohexane/EtOAc 2:1) (major diastereomer): 1H
NMR δ 1.71 (d, J ) 6.8 Hz, 3H), 2.31 (s, 3H), 3.24 (d, J ) 17.0
Hz, 1H), 3.37 (d, J ) 17.0 Hz, 1H), 5.45 (d, J ) 6.0 Hz, 1H),
5.83-5.92 (m, 1H), 6.73 (d, J ) 8.3 Hz, 1H), 6.94-7.05 (m,
2H), 7.14 (d, J ) 8.3 Hz, 2H), 7.18 (d, J ) 6.0 Hz, 1H), 7.23-
7.29 (m, 1H), 7.32-7.43 (m, 4H), 7.59 (s, 1H), 7.61 (d, J ) 8.3
Hz, 2H), 7.71 (d, J ) 8.3 Hz, 1H), 7.76-7.82 (m, 2H), 7.90 (d,
J ) 8.3 Hz, 1H); 13C NMR δ 20.0, 21.6, 43.3, 45.1, 81.2, 108.7,
113.6, 118.3, 121.1, 122.6, 122.9, 123.5, 124.9, 125.1, 125.8,
126.0, 126.6, 126.8 (2C), 127.0, 128.6, 128.7, 129.9 (2C), 130.9,
133.7, 134.6, 135.2, 136.7, 145.2, 158.5, 167.2, 189.5. (Minor
diastereomer): 1H NMR δ 1.61 (d, J ) 6.8 Hz, 3H), 2.35 (s,
3H), 3.20 (d, J ) 16.6 Hz, 1H), 3.27 (d, J ) 16.6 Hz, 1H), 5.34
(d, J ) 6.2 Hz, 1H), 5.86-5.96 (m, 1H), 6.72 (d, J ) 8.3 Hz,
1H), 7.01 (d, J ) 6.2 Hz, 1H), 7.22-7.37 (m, 4H), 7.43-7.56
(m, 4H), 7.66 (s, 1H), 7.67 (d, J ) 6.8 Hz, 1H), 7.75 (d, J ) 8.3
Hz, 2H), 7.84 (d, J ) 7.5 Hz, 1H), 7.87-7.91 (m, 1H), 7.98 (d,
J ) 8.7 Hz, 2H); 13C NMR δ 19.9, 21.6, 43.4, 45.0, 84.1, 108.6,
113.9, 118.5, 120.8, 122.7, 123.2, 123.6, 125.1, 125.3, 125.7,
126.1, 126.8, 127.0 (2C), 127.2, 128.8, 128.9, 130.0 (2C), 131.0,
133.9, 134.7, 135.4, 137.0, 145.3, 158.5, 167.2, 189.4; IR (NaCl)
ν 3367, 2922, 1675, 1598, 1174 cm-1; MS (EI) m/z (relative
intensity) 564 [M+•] (5), 393 (37), 366 (33), 296 (27), 210 (28),
155 (95), 140 (50), 129 (42), 91 (100); HRMS calcd for
212 (20), 158 (100), 91 (29); HRMS calcd for C29H32N2O5S [M+•
520.2032, found 520.2040.
]
2-[4-Meth oxy-2-oxo-9-(tolu en e-4-su lfon yl)-1,2,3,4,9,9a -
h exa h yd r oca r ba zol-4a -yl]-4-oxo-3,4-d ih yd r o-2H-p yr a n -2-
ca r boxylic Acid (1-P h en yleth yl)a m id e (29).29 Purification
of the residue by flash chromatography (cyclohexane/EtOAc
3:2) (two diastereomers, 1:1): 1H NMR δ 1.53 (d, J ) 6.8 Hz,
3H), 2.29 and 2.33 (s, 3H), 2.30-2.54 (m, 3H), 2.78 (ddd, J )
1.7, 5.3, 15.1 Hz, 1H), 2.93-3.03 (m, 2H), 3.27 and 3.35 (s,
3H), 4.01-4.16 (m, 2H), 5.06-5.17 (m, 1H), 5.47 (d, J ) 6.4
Hz, 1H), 6.70 (d, J ) 8.3 Hz, 1H), 7.08-7.32 (m, 9H), 7.46 (d,
J ) 7.9 Hz, 1H), 7.60 (bs, 1H), 7.69 (d, J ) 8.7 Hz, 2H), 7.93
(d, J ) 8.7 Hz, 1H); 13C NMR δ 21.2, 21.5, 30.0, 43.0, 43.2,
44.3, 49.0, 56.4, 56.7, 58.1, 74.9, 76.8, 84.1, 108.6, 113.7, 118.4,
120.9, 123.5, 125.2, 125.8, 126.0 (2C), 126.9 (2C), 127.1, 127.5,
128.6 (2C), 129.9 (2C), 134.6, 135.3, 141.9, 145.2, 158.5, 167.3,
189.5, 206.1, 207.7; IR (NaCl) ν 3364, 2929, 1715, 1681, 1600,
1172 cm-1; MS (EI) m/z (relative intensity) 514 [M+• - C5H8O2]
(8), 393 (19), 366 (95), 212 (43), 155 (22), 91 (100). Anal. Calcd
for C34H34N2O7S: C, 66.43; H, 5.58; N, 4.56; S, 5.22. Found:
C, 66.37; H, 5.94; N, 4.55; S, 5.26.
2-[4-Meth oxy-2-oxo-9-(tolu en e-4-su lfon yl)-1,2,3,4,9,9a -
h exa h yd r oca r ba zol-4a -yl]-4-oxo-3,4-d ih yd r o-2H-p yr a n -2-
ca r boxylic Acid (1-Na p h th yleth yl)a m id e (30).29 Purifica-
tion of the residue by flash chromatography (cyclohexane/
EtOAc 2:1) (two diastereomers): 1H NMR δ 1.71 (d, J ) 6.8
Hz, 3H), 2.29 and 2.33 (s, 3H), 2.30-2.54 (m, 3H), 2.78 (ddd,
J ) 1.5, 5.1, 14.9 Hz, 1H), 2.95-3.03 (m, 2H), 3.27 and 3.35
(s, 3H), 4.01-4.14 (m, 2H), 5.45 (d, J ) 6.0 Hz, 1H), 5.79-
5.97 (m, 1H), 6.70 (d, J ) 8.3 Hz, 1H), 6.94-7.63 (m, 7H), 7.14
(d, J ) 8.3 Hz, 2H), 7.19 (d, J ) 6.0 Hz, 1H), 7.61 (d, J ) 8.3
Hz, 2H), 7.71 (d, J ) 8.7 Hz, 1H), 7.76-7.82 (m, 2H), 7.90 (d,
J ) 8.7 Hz, 1H); 13C NMR δ 20.0, 21.5, 30.0, 43.1, 43.4, 44.4,
45.1, 56.4, 56.8, 58.2, 75.0, 76.9, 84.2, 108.7, 113.6, 118.3, 121.1,
122.6, 122.9, 123.5, 124.9, 125.1, 125.8, 126.0, 126.6, 126.8
(2C), 127.0, 127.5, 128.6, 128.7, 129.9 (2C), 130.9, 133.7, 134.6,
135.2, 136.8, 145.2, 158.5, 167.2, 189.4, 206.2, 207.7; IR (NaCl)
C
33H28N2O5S (M+•) 564.1719, found 564.1704.
4-Oxo-2-[1-(tolu en e-4-su lfon yl)-1H-in d ol-3-yl]-3,4-d ih y-
d r o-2H-p yr a n -2-ca r boxylic Acid Eth yla m id e (27). Puri-
fication of the residue by flash chromatography (cyclohexane/
EtOAc 9:11): 1H NMR δ 1.05 (t, J ) 7.2 Hz, 3H), 2.26 (s, 3H),
3.15-3.33 (m, 4H), 5.37 (d, J ) 6.2 Hz, 1H), 6.9 (bs, 1H), 7.16
(d, J ) 8.7 Hz, 2H), 7.22 (d, J ) 6.2 Hz, 1H), 7.15-7.30 (m,
2H), 7.63 (s, 1H), 7.63-7.66 (m, 1H), 7.69 (d, J ) 8.7 Hz, 2H),
7.90 (d, J ) 8.3 Hz, 1H); 13C NMR δ 14.4, 21.3, 34.6, 43.2,
83.9, 108.2, 113.5, 118.6, 120.9, 123.5, 125.1, 125.6, 126.7 (2C),
127.1, 129.9 (2C), 134.3, 135.1, 145.3, 158.9, 168.0, 189.7; IR
(KBr) ν 3350, 1683, 1602, 1271, 1173 cm-1; MS (EI) m/z
(relative intensity) 438 [M+•] (17), 366 (100), 296 (78), 212 (28),
155 (26), 91 (34); HRMS calcd for C23H22N2O5S (M+•) 438.1249,
found 438.1248.
4-Oxo-2-[1-(tolu en e-4-su lfon yl)-1H-in d ol-3-yl]-3,4-d ih y-
d r o-2H-p yr a n -2-ca r boxylic Acid (1-Cycloh exyleth yl)a m -
id e (28). Purification of the residue by flash chromatography
(cyclohexane/EtOAc 7:3) (major diastereomer): 1H NMR δ
0.68-1.70 (m, 11H), 1.09 (d, J ) 6.8 Hz, 3H), 2.33 (s, 3H),
3.21 (d, J ) 16.8 Hz, 1H), 3.32 (d, J ) 16.8 Hz, 1H), 3.77-
3.90 (m, 1H), 5.44 (d, J ) 6.0 Hz, 1H), 6.32 (d, J ) 8.7 Hz,
1H), 7.19-7.35 (m, 2H), 7.22 (d, J ) 8.1 Hz, 2H), 7.27 (d, J )
6.0 Hz, 1H), 7.63-7.67 (m, 1H), 7.66 (s, 1H), 7.73 (d, J ) 8.1
Hz, 2H), 7.95 (d, J ) 8.3 Hz, 1H); 13C NMR δ 17.6, 21.4, 25.7
(2C), 26.0, 28.5, 28.8, 42.7, 43.2, 49.8, 84.2, 108.5, 113.7, 118.7,
120.9, 123.5, 125.2, 125.7, 126.8 (2C), 127.0, 129.9 (2C), 134.5,
ν 3368, 2925, 1719, 1690, 1598, 1175 cm-1
.
Ack n ow led gm en t. The “Re´gion Haute-Normandie”
and Novelect are gratefully acknowledged for support
allowing the purchase of the hyperbar reactors.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
compounds 9, 12, 16, 20a , 22d , 23, and 26 and 13C NMR
spectra of compounds 1d , 9, 10, 12, 14, 16, 17, 19, 26, and 29.
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O034719B
(29) This compound was isolated as a 1:1 mixture of diastereomers;
hence, no assignment of the 13C NMR signals is reported.
8002 J . Org. Chem., Vol. 68, No. 21, 2003