Tuning the reactivity and chemoselectivity of electron-poor pyrroles as dienophiles in cycloadditions with electron-rich dienes

Article abstract of DOI:10.1016/j.tet.2005.06.016

Activation by Lewis acid catalysis and high pressure allows pyrrole derivatives to react with electron-rich dienes in normal electron demand [4+2] cycloadditions, provided that the aromatic ring is substituted by at least two electron-withdrawing groups. The dienophilic behavior of the heterocycle is expressed through the involvement of either the aromatic carbon-carbon double bond in an all-carbon process or the carbonyl moiety of the substituent in a heterocycloaddition reaction. In this regard, the nature of the heterocyclic substituents is shown to have a dramatic influence and to direct both the reactivity and the chemoselectivity of the cycloaddition.

Full text of DOI:10.1016/j.tet.2005.06.016

Tetrahedron 61 (2005) 7907–7915
Tuning the reactivity and chemoselectivity of electron-poor
pyrroles as dienophiles in cycloadditions with electron-rich dienes
*
´
Antony Chretien, Isabelle Chataigner and Serge R. Piettre
´ ´ ´ ´ `
Laboratoire des Fonctions Azotees & Oxygenees Complexes de l’IRCOF, Universite de Rouen, UMR 6014 CNRS, Rue Tesnieres,
F-76821 Mont St Aignan Cedex, France
Received 8 March 2005; revised 1 June 2005; accepted 7 June 2005
Available online 28 June 2005
Abstract—Activation by Lewis acid catalysis and high pressure allows pyrrole derivatives to react with electron-rich dienes in normal
electron demand [4C2] cycloadditions, provided that the aromatic ring is substituted by at least two electron-withdrawing groups. The
dienophilic behavior of the heterocycle is expressed through the involvement of either the aromatic carbon–carbon double bond in an all-
carbon process or the carbonyl moiety of the substituent in a heterocycloaddition reaction. In this regard, the nature of the heterocyclic
substituents is shown to have a dramatic influence and to direct both the reactivity and the chemoselectivity of the cycloaddition.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
In contrast, the literature mentions only a few reports on
pyrrole derivatives acting as dienophiles in inverse electron-
demand cycloaddition reactions.5 Even scarcer are the cases
relating to the involvement of this heteroaromatic cycle as
dienophile in normal electron-demand [4C2]. To our
knowledge, before our work,6 the only example was
published 15 years ago.7 This behavior required the
presence of two electron-withdrawing substituents on the
N–C]C moiety of the aromatic ring. Thus, pyrrole 4,
bearing both an acetyl group on carbon 3 of the heterocycle
and a benzenesulfonyl unit on position 1, reacted with
isoprene to deliver compounds 5 as a 1:2 regioisomeric
mixture (Scheme 1). Interestingly, these cycloadducts
feature a quaternary carbon at the ring junction and are
irreversibly dearomatized during the process. However,
harsh conditions (195 8C, 72 h) had to be used and the
isolated yield was low, thus forbidding the practical
development of this approach and its use in the synthesis
of products encompassing a five-membered nitrogen
heterocycle (e.g., tazettine 6). This result nevertheless
pointed out the feasibility of such a reaction.
The Diels–Alder (DA) cycloaddition represents an efficient
tool for the convergent and stereocontrolled synthesis of
functionalized polycyclic systems.1 The scope of the
reaction is large and allows the synthesis of cyclohexene
derivatives but also of a variety of heterocycles by swapping
carbon atoms on the diene and/or dienophile with
heteroatoms (O, N, S for instance; the so-called hetero-
Diels–Alder reaction (HDA)).2
The use of five-membered aromatic heterocycles in these
cycloadditions is almost as old as the reaction itself, and
different possibilities have been described, depending on the
substrate.3 In this context, pyrrole 1 was soon considered as
diene by involving either all four p-electrons of the
heterocycle or only two of them, as in 2 and 3 (Fig. 1).4
Figure 1. Structures of pyrroles 1–3 and tazettine 6.
Keywords: Pyrrole; Diels–Alder reaction; Heterocycloaddition; Chemo-
selectivity; High pressure.
*
Corresponding author. Fax: C33 235522970;
e-mail: serge.piettre@univ-rouen.fr
Scheme 1.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.06.016

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A. Chretien et al. / Tetrahedron 61 (2005) 7907–7915
7908
We recently reported that the analogous process involving
the more reactive indole derivatives can be carried out in an
efficient manner when activated by the combined action of a
Lewis acid and high pressures.8
regioselective fashion, exclusively furnishing cycloadduct
10 after hydrolysis (Fig. 2).11
2. Results and discussion
The more pronounced aromatic character of pyrrole led us
to consider the activating effect of a third electron
withdrawing substituent to generate a usable cycloaddition
process. Thus, the known and easily accessible trisubstituted
pyrrole 79 was selected as the first substrate to study this
dienophilic behavior. The choice of the 2,4-regioisomer
was dictated by the nearly complete lack of reactivity of
electron-poor five-membered heterocycles bearing an
electron withdrawing group on carbon 2, thereby warranting
a probable site selectivity on the heterocycle.6,10 In addition
the documented interaction between 2,4-biscarbomethoxy-
furan 8 and Danishefsky’s diene 9 was reported to involve
the C4,C5 carbon–carbon double bond in a complete
Reacting pyrrole 7 with excess 2,3-dimethylbuta-1,3-diene
11 at 100 8C for 72 h in the presence of zinc chloride
(10% mol) led to an 85% consumption of the starting
substrate. Purification of the crude residue furnished a
material whose mass spectrometry indicated the presence of
a 1:1 cycloadduct (21% isolated yield). Further analyses led
to the identification of structure 12, the result of an hetero
Diels–Alder process between the 4-keto unit and the diene
(Table 1, entry 1). Activation by either high pressure alone
(entry 2), or a combination of high pressure and Lewis acid
(entry 3) did not change the course of the reaction. Low
conversion rates are believed to be the result of the
competitive polymerization process which (i) slows the
diffusion rate down and (ii) decreases the diene concen-
tration.12 As the resultant polymer also renders isolation
difficult, attempts to solve these problems included
diminishing the number of equivalents of diene. This led to
a slightly better but still modest 28% isolated yield (entry 4).
The use of Danishefsky’s diene 9 led to an analogous
chemoselectivity, the 4-keto moiety proving once again to
Figure 2. Structures of furan 8, diene 9 and cycloadduct 10.
Table 1. Reaction between pyrrole 7 and diene 11
Entry
11 (equiv)
P (GPa)
T (8C)
Cat.a
t (h)
Conv.b (%)
Yield (%)
21
1
2
3
4
12
12
12
4
10K4
1.6
1.6
1.2
100
25
25
25
ZnCl2
—
ZnCl2
ZnCl2
72
24
24
72
85
14
36
52
c
—
c
—
28
a 0.1 Catalysed (0.1 equiv) was used was used.
b Conversion.
c Not isolated.
Table 2. Cycloaddition between pyrrole 7 and diene 9
Entry
7 (equiv)
P (GPa)
Cat.a
T (h)
Conv.b (%)
Ratio 13:14
Yield (%)
13
14
1
2
3
1.5
2
12
10K4
1.2
—
—
EuFOD
20
72
24
100
100
53
92:8
76:24
45:55
90
66
18
5
18
24
1.6
a 0.1 Catalysed (0.1 equiv) was used was used.
b Conversion.

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7909
Table 3. Cycloaddition between diacetylpyrroles 15 and dienes 9, 11 and 18
Entry
Dienophile Diene
(equiv)
P (GPa)
T (8C)
Cat.a
t (h)
Conv.(%)b
Product
endo/exo
Yield (%)
1
2
3
4
5
6
7
8
15a
15a
15a
15a
15a
15a
15b
15b
15b
15b
15b
15b
15b
11 (12)
11 (12)
11 (6)
11 (6)
18 (6)
9 (6)
11 (12)
11 (6)
11 (6)
18 (6)
18 (6)
9 (6)
10K4
1.2
1.2
1.2
130
50
50
50
50
50
130
50
50
50
50
50
50
ZnCl2
—
168
72
72
72
36
72
24
72
72
36
36
36
72
38
0
16a
16a
16a
16a
16b/17b
16c/17c
16d
16d
16d
16e/17e
16e/17e
16f/17f
16f/17f
—
—
—
—
7/93
—
—
—
—
—
35/65
58/42
60/40
19
—
40
48c
31
0d
ZnCl2
ZnCl2
ZnCl2
EuFOD
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
EuFOD
EuFOD
47
59
44
23
100
100
96
76
100
69
80
1.2
1.6
10K4
1.2
0e
80
64c
9
1.2
1.2
1.6
1.6
f
10
11
12
13
—
70
48g,h
61g,h
9 (6)
1.6
a Unless otherwise indicated, 0.1 equiv of catalyst was used.
b Conversion.
c One equivalent of catalyst was used.
d Compound 19a was isolated in 16% yield (see text).
e Complete degradation occured.
f
Not isolated.
g Diasteromeric cycloadducts 20a and 20b were isolated after hydrolysis of the silyl enol ether.
h Compound 19b was isolated in 15 and 18% yield, respectively (see text).
be the most reactive site. Thus treatment of pyrrole 7 with 9
(1.5 equiv) at room temperature led to a complete
conversion after 20 h (Table 2, entry 1). Purification of the
crude oil led to the isolation of cycloadduct 13 in a much
better, 90% yield. The minor formation of bisadducts 14, the
result of two sequential hetero Diels–Alder processes, was
also observed (5% isolated yield). Carrying out the reaction
under a pressure of 1.2 GPa decreased the ratio 13:14
(entry 2). Attempts to maximize the formation of 14
involved the use of higher pressures, increasing the number
of equivalents of diene, and activation by a Lewis acid. This
led to the formation of a 45:55 mixture of 13:14, which were
separated by chromatography on silica (entry 3).
a simple ketone as heterodienophile is much less common.2,
13 Hence 2,4-diacetyl-1-p-tosylpyrrole (15a)14,15 as singled
out as the best available candidate to pursue the present
study. Heating a toluene solution of 15a and dimethylbu-
tadiene 11 at 130 8C (pressure tube) for 7 days in the
presence of zinc chloride (0.1 equiv) led to a 38%
conversion (Table 3, entry 1). Purification of the crude
resulting sample gave the all-carbon cycloadduct 16a in low
yield. However, this result was very encouraging as
chemoselectivity and site selectivity in favor of the C4,C5
carbon–carbon double bond proved to be complete.16 This
result was in complete accordance with previous data
gathered on indoles and furans.6,8,11 The need for Lewis
acid activation was verified by carrying out the same
reaction in either the presence or the absence of zinc
chloride under high pressure (entries 2 and 3).17 Thus,
conducting the reaction under a pressure of 1.2 GPa, at
50 8C and in the presence of the same Lewis acid led to a
slightly higher conversion which, this time translated into an
isolated yield of 40% (entry 3). Increasing the amount of
ZnCl2 to one full equivalent led to an optimized yield of
48% (entry 4). The use of cyclohexa-1,3-diene 18, a four
p-electron partner frozen in a cisoid conformation, led to
essentially the same result, the expected diastereomeric
cycloadducts 16b and 17b being isolated in moderate yield
(entry 5). The relative stereochemistry was assigned
according to NOESY experiments (Fig. 3). Interestingly,
the major diastereomer produced in this case is the one
defined as exo, that is corresponding to the approach where
the dienic part and the b-acetyl group are superimposed.18
The exclusive hetero Diels–Alder processes arising from
reactions between 7 and dienes 9 or 11 point to the low
reactivity of the pyrrole carbon–carbon double bonds. Both
aldehyde and ketoester carbonyl units have been reported to
react as heterodienophiles and to constitute a useful access
to dihydropyrans.2 Although this reaction is in general much
slower than the classical all-carbon Diels–Alder cyclo-
addition, it may become a competitive or exclusive pathway
when the all-carbon dienophile becomes less reactive.
Recently, work from this laboratory has shown that tenuous
changes in electron-poor indoles may induce a complete
reversal of chemoselectivity in their cycloaddition reactions
with dienes.8b
The acetyl unit was next selected as electron withdrawing
group. Indeed, literature data indicated that involvement of

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A. Chretien et al. / Tetrahedron 61 (2005) 7907–7915
7910
thermal sensitivity of the substrate was highlighted by its
completedegradationwhenheatedat130 8Cinthepresenceof
ZnCl2 (entry 7). Activation by high pressures proved once
again to be crucial. Thus subjecting substrate 15b and 6 equiv
of 11 to a pressure of 1.2 GPa at 50 8C and in the presence of
ZnCl2 led to a complete conversion and the regioselective
formation of adduct 16d (80% isolated yield) (entry 8). In the
case of 15b, increasing the amount of ZnCl2 from 0.1 to
1 equiv resulted in a drop of the yield (compare entries 8 and
9). The reaction with cyclohexa-1,3-diene 18 illustrated once
again the dramatic improvement induced by the triflyl group
(entries 10 and 11). Optimized conditions led to a complete
conversion and furnished a 70% isolated yield of a 35:65
mixture of endo and exo stereoisomers (16e and 17e,
respectively, entry 11), the latter being the major one.
Reaction with the electronically enriched diene 9 yielded
a 69% conversion after 36 h under 1.6 GPa, and 80%
conversion after 72 h (entries 12 and 13). Hydrolysis
generated a mixture of three adducts which were separated
by chromatography. The two first adducts proved to be the
expected endo and exo adducts resulting from reaction
between the diene and the C4]C5 aromatic double bond (a
6:4 diastereomeric mixture), isolated as keto derivatives 20a
and 20b in 48 and 61% yield (entries 12 and 13, respectively).
Further elution afforded heterocycloadduct 19b (15 and 18%
isolated yield, respectively). In this case, the site selectivity
was unambiguously determined by carrying out HMBC
NMR experiments.
Figure 3. NOESY correlations observed on 16b and 16e, and 17b and 17e.
The reaction between 15a and Danishefsky’s diene 9 in the
presence of EuFOD indicated a low conversion (entry 6).
Purification of the crude mixture led to the isolation of a 1:1
adduct, whose analytical data pointed to structure 19a, the
result of an heterocycloaddition involving the carbonyl unit
on position 2. Presumably, the electron-poor heterocycle
acts as a global electron withdrawing substituent, thereby
inducing the ketone behavior to parallel the known ketoester
and ketoamide reactivities.2,8b
Attempts to further increase the reactivity and reverse the
chemoselectivity in favor of the pyrrolyl C2,C3 carbon–carbon
double bond included replacing the p-tosyl group with a
trifluoromethanesulfonyl (triflyl) unit, a more powerful
activating group.19 Hence, pyrrole 15b was prepared by
interacting 2,3-diacetylpyrrole15 with N,N-bistriflylphenyli-
mide under basic conditions (78% isolated yield).20 The
Thus the triflyl group did succeed in playing a dual role: not
only does it increase the reactivity of the C4,C5 carbon–carbon
double bond of the aromatic five-membered cycle, but, in
addition, it is able to reverse the chemoselectivity, the carbon–
carbon double bond being now the favor site of reactivity.
These results induced us to examine the effect of the triflyl
group on the less reactive, monoacetylated pyrrole, and to
compare it to the analogous tosylated substrate 21a (Fig. 4).
Figure 4. Structures of cycloadducts 19a, 19b, 20a, 20b, 24a and 24b.
Table 4. Cycloaddition between acetylpyrroles 21 and dienes 9, 11 and 18
Entry
R1
Diene (equiv)
P (GPa)
Cat.a
t (h)
Conv. (%)b
endo/exo
Yield (%)
c
1
2
3
4
5
6
7
pTol
pTol
pTol
CF3
CF3
CF3
CF3
11 (6)
18 (6)
9 (6)
11 (6)
11 (6)
18 (6)
9 (6)
1.2
1.6
1.6
1.2
1.6
1.6
1.6
ZnCl2
ZnCl2
EuFOD
ZnCl2
ZnCl2
ZnCl2
EuFOD
36
36
72
36
36
36
72
Traces
50
7
31
91
97
23
—
5/95
—
—
—
—
25
—
d
24
80
49
13/87
—
e
—
a 0.1 equiv of catalyst was used.
b Conversion.
c Not isolated.
d Compound 24a was isolated in 7% yield.
e Compound 24b was isolated in 15% yield.

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7911
Not surprisingly, reaction between the latter and any of the
above diene (9, 11 or 18) under hyperbaric conditions
proved sluggish, delivering the desired adducts in 25%
isolated yield, at best (Table 4, entries 1–3). Reaction of the
corresponding triflyl derivative 21b21,22 with dimethyl-
butadiene, however, confirmed the above observations:
under a pressure of 1.2 GPa and in the presence of 10% mol
ZnCl2, a 31% conversion was observed after 36 h, which
became nearly quantitative when the same reaction was
carried out under 1.6 GPa (entries 4 and 5). The desired
cycloadduct 22a was then isolated in 80% yield. A complete
conversion was also obtained with cyclohexa-1,3-diene 18
and a 13:87 mixture of endo/exo cycloadducts were isolated
in 49% yield (entry 6). The use of Danishefsky’s diene,
however, did not lead in this case to a reversal of
chemoselectivity and heterocycloadduct 24b, resulting
from a pericyclic process involving the 3-carbonyl unit as
the 2p component, was obtained in low yield (entry 7).23
respectively. IR spectra were recorded on Perkin–Elmer
16PC FT-IR spectrometers. The crude organic extracts were
dried over magnesium sulfate. Unless otherwise stated, the
products are colorless oils.
4.1. General procedure for the tosylation of pyrrole
A mixture of the pyrrole derivative (1 equiv), DMAP (cat.),
(iPr)2EtN (1.3 equiv), and TsCl (1–1.3 equiv) was stirred at
room temperature for 1 h under argon. After quenching with
a 1 N HCl aqueous solution, the reaction mixture was
extracted with CH2Cl2. The combined organic layers were
dried and concentrated under reduced pressure.
4.1.1. [5-Formyl-1-(toluene-4-sulfonyl)-1H-pyrrol-3-yl]-
oxo-acetic acid methyl ester (7). Prepared according to the
general procedure using (5-formyl-1H-pyrrol-3-yl)oxo-
acetic acid, methyl ester (1.81 g, 10 mmol), DMAP
(20 mg), (iPr)2EtN (2.26 mL, 13 mmol), and TsCl (1.91 g,
10 mmol) in CH2Cl2 (20 mL). The residue was purified by
crystallization from CH2Cl2/heptane to give 7 as a white
The results described clearly indicate that similar levels of
energy exist for the carbon–carbon double bond of aromatic
pyrrole, when substituted by electron withdrawing sub-
stituents, on the one hand, and the acyl group of the
substituent(s) in position 2 or 4, on the other hand. The
structural and electronic nature of the diene definitely plays
a role on the chemoselectivity of the reaction. The triflyl
group, however, may counteract the tendency of electron-
rich dienes to react in a hetero Diels–Alder fashion, and
will induce in most cases the pyrrole C2–C3 double bond
(1,3-disubstituted cases) or C4–C5 double bond (1,2,4-
trisubstituted cases) to behave instead as the reacting
dienophile.
1
solid (2.80 g, 84%, mp 149 8C). H NMR d 2.44 (s, 3H),
3.98 (s, 3H), 7.38 (d, JZ7.9 Hz, 2H), 7.65 (d, JZ1.9 Hz,
1H), 7.91 (d, JZ7.9 Hz, 2H), 8.64 (d, JZ1.9 Hz, 1H), 9.90
(s, 1H). 13C NMR d 21.8, 53.3, 122.2, 124.2, 128.3 (2C),
130.3 (2C), 133.7, 135.3, 147.0 (2C), 161.3, 176.9, 178.4.
IR (NaCl) n 3360, 3154, 1728, 1682, 1548, 1380, 1180,
1146, 1052 cmK1. MS (EI) m/z (relative intensity) 335
[MC%] (5), 276 (100), 155 (78), 91 (94), 65 (29). HRMS
calcd for C21H26NO4S: (MC%) 335.0464. Found: 335.0451.
4.1.2. 1-[5-Acetyl-1-(toluene-4-sulfonyl)-1H-pyrrol-3-yl]
ethanone (15a). Prepared according to the general
procedure using 1-(5-acetyl-1H-pyrrol-3-yl)-ethanone
(0.76 g, 5 mmol), DMAP (10 mg), (iPr)2EtN (1.13 mL,
6.5 mmol), and TsCl (1.24 g, 6.5 mmol) in CH2Cl2 (10 mL).
The residue was purified by chromatography on silica and
elution with a mixture heptane/EtOAc (3:2) to give 15a as a
3. Conclusion
The nature of the substituents on the N-tosylpyrrole nucleus
plays a crucial role in the course of the cycloaddition
reaction. Thus, formyl- and ketoester- substituted pyrroles
undergo a hetero-Diels–Alder process resulting from their
involvement as heterodienophiles, while the carbonyl group
of unactivated ketones is almost inert, thereby allowing
the aromatic carbon–carbon double bond of the pyrrole to
behave as a dienophile—albeit in low yields. Biactivation
by high pressures and Lewis acid leads to an increase in
isolated yields. In this regard, replacement of the p-tosyl
group with a triflyl one results in a dramatic change by
further activating the latter reaction enough to afford good
isolated yields of dearomatized cycloadducts encompassing
a quaternary center at the ring junction. This methodology
may now be used in the synthesis of natural and non-natural
products, and in the production of scaffolds for the
preparation of libraries.
1
white solid (1.42 g, 93%, mp 170 8C). H NMR d 2.38 (s,
3H), 2.44 (s, 3H), 2.51 (s, 3H), 7.35 (d, JZ7.9 Hz, 2H), 7.41
(d, JZ1.9 Hz, 1H), 7.94 (d, JZ7.9 Hz, 2H), 8.33 (d, JZ
1.9 Hz, 1H). 13C NMR d 21.5, 26.8, 27.0, 121.6, 125.3,
128.5 (2C), 129.3 (2C), 132.6, 133.8, 134.5, 145.4, 186.1,
191.9. IR (NaCl) n 3334, 3144, 1682, 1552, 1470, 1362,
1126 cmK1. MS (EI) m/z (relative intensity) 305 [MC%] (6),
241 (28), 226 (20), 155 (48), 91 (100), 65 (21). Anal. Calcd
for C15H15NO4S: C, 59.00; H, 4.95; N, 4.59; S, 10.50.
Found: C, 59.46; H, 5.28; N, 4.67; S, 10.12.
4.1.3. 1-(5-Acetyl-1-trifluoromethanesulfonyl-1H-pyr-
rol-3-yl)ethanone (15b). A mixture of the pyrrole 1-(5-
acetyl-1H-pyrrol-3-yl)-ethanone (0.61 g, 4 mmol), DMAP
(20 mg), (iPr)2EtN (1.39 mL, 8 mmol), and PhNTf2 (1.79 g,
5 mmol) in CH2Cl2 (10 mL) was stirred in CH2Cl2 (10 mL)
at room temperature for 4 days under argon. After
quenching with saturated aqueous NaHCO3, the reaction
mixture was extracted with CH2Cl2. The combined organic
layers were washed with 1 N HCl, dried and concentrated
under reduced pressure. The residue was purified by flash
chromatography on silica and elution with a mixture
cyclohexane/EtOAc (9:1) to give 15b as a white solid
4. Experimental
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 Jeol 500 spectrometers,
1
(0.88 g, 78%, mp 78 8C). 19F NMR d K67.42. H NMR d
2.51 (s, 3H), 2.54 (s, 3H), 7.52 (d, JZ1.7 Hz, 1H), 8.01 (d,

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7912
JZ1.7 Hz, 1H). 13C NMR d 26.8, 27.2, 117.3, 122.5, 127.7,
133.2, 135.8, 185.9, 191.2. IR (NaCl) n 3132, 1686, 1416,
1212, 1132 cmK1. MS (EI) m/z (relative intensity) 283 [MC
%] (85), 268 (100), 118 (67), 69 (92). Anal. Calcd for
C9H8F3NO4S: C, 38.17; H, 2.85; N, 4.95; S, 11.32. Found:
C, 38.19; H, 2.74; N, 4.88; S, 11.41.
behind a safety shield at the desired temperature. After
cooling, the solvents and excess diene were removed under
reduced pressure and the residue was chromatographed.
4.4.1. 2-[5-Formyl-1-(toluene-4-sulfonyl)-1H-pyrrol-3-
yl]-4,5-dimethyl-3,6-dihydro-2H-pyran-2-carboxylic
acid methyl ester (12). Elution with a mixture of heptane/
EtOAc (4:1) gave the product. 1H NMR d 1.42 (s, 3H), 1.62
(s, 3H), 2.30 (d, JZ17.0 Hz, 1H), 2.33 (s, 3H), 2.70 (d, JZ
17.0 Hz, 1H), 3.64 (s, 3H), 3.91 (d, JZ15.1 Hz, 1H), 4.19
(d, JZ15.1 Hz, 1H), 7.09 (d, JZ2.1 Hz, 1H), 7.24 (d, JZ
8.5 Hz, 2H), 7.58 (d, JZ2.1 Hz, 1H), 7.72 (d, JZ8.5 Hz,
2H), 9.83 (s, 1H). 13C NMR d 13.6, 18.3, 21.6, 37.6, 52.6,
66.7, 75.6, 121.4, 121.9, 123.6, 126.2, 127.5 (2C), 128.1,
130.0 (2C), 133.2, 134.8, 146.0, 171.8, 178.7. IR (NaCl) n
2922, 1738, 1674, 1378, 1178, 1092 cmK1. MS (CI) m/z
(relative intensity) 418 [MHC] (100), 264 (14), 157 (11).
HRMS calcd for C21H24NO6S: (MHC) 418.1324. Found:
418.1327.
4.1.4. 1-(1-Trifluoromethanesulfonyl-1H-pyrrol-3-yl)
ethanone (21b). A solution of 1-(1H-Pyrrol-3-yl)-ethanone
(436 mg, 4 mmol) and (iPr)2EtN (1.4 mL, 8 mmol) in
CH2Cl2 (20 mL) was cooled to K78 8C under argon. Triflic
anhydride (845 mL, 5 mmol) was added dropwise, and after
30 min of stirring at the same temperature, the resultant
solution was poured into 2 N NaOH aqueous solution and
extracted with CH2Cl2. The combined organic layers were
then poured into a 6 N HCl aqueous solution, stirred
vigorously at room temperature for 15 min and finally
extracted with CH2Cl2. Drying of the organic layers,
filtration and evaporation under reduced pressure delivered
the crude product which was immediately purified by
Ku¨gelrohr distillation (0.05 mmHg, 80–90 8C) to give an oil
(761 mg, 79%, mp 34 8C) which crystallized upon standing.
19F NMR d K76.28. 1H NMR d 2.48 (s, 3H), 6.88 (m, 1H),
7.15 (m, 1H), 7.68 (m, 1H). 13C NMR d 27.4, 114.3, 118.9,
123.3, 125.8, 131.2, 192.0. IR (NaCl) n 3129, 1687, 1235,
1210, 1153, 1060 cmK1. MS (EI) m/z (relative intensity)
241 [MC%] (50), 226 (100), 142 (6), 93 (81), 69 (75). Anal.
Calcd for C7H6F3NO3S: C, 34.86; H, 2.51; N, 5.81; S,
13.29. Found: C, 34.82; H, 2.55; N, 5.69; S, 13.26.
4.4.2. 2-[5-Formyl-1-(toluene-4-sulfonyl)-1H-pyrrol-3-
yl]-4-oxo-3,4-dihydro-2H-pyran-2-carboxylic
acid
methyl ester (13). Elution with a 3:2 mixture of heptane/
EtOAc yielded cycloadduct 13. 1H NMR d 2.37 (s, 3H), 2.93
(d, JZ16.8 Hz, 1H), 3.25 (d, JZ16.8 Hz, 1H), 3.71 (s, 3H),
5.43 (d, JZ6.0 Hz, 1H), 7.10 (d, JZ1.9 Hz, 1H), 7.29 (d,
JZ7.9 Hz, 2H), 7.35 (d, JZ6.0 Hz, 1H), 7.64 (d, JZ
1.9 Hz, 1H), 7.76 (d, JZ7.9 Hz, 2H), 9.87 (s, 1H). 13C NMR
d 21.7, 43.9, 53.8, 81.9, 108.2, 120.9, 124.3, 126.1, 127.7
(2C), 130.3 (2C), 133.6, 134.5, 146.5, 160.9, 169.0, 178.6,
188.6. IR (NaCl) n 2956, 1740, 1682, 1596, 1460, 1378,
1224, 1178, 1090 cmK1. MS (CI) m/z (relative intensity)
404 [MHC] (100). HRMS calcd for C19H18NO7S: (MHC)
404.0804. Found: 404.0806.
4.2. General procedure for the high-pressure reactions
Non-catalyzed reactions. To a solution of the requisite
pyrrole, in dry dichloromethane (0.2 M) at room tempera-
ture under argon, was added the freshly distilled diene
(6 equiv). The resultant mixture was transferred into a high-
pressure vessel and compressed at the requisite pressure and
temperature. After decompression, the solvent and excess
diene were evaporated under reduced pressure. Chromato-
graphy of the residue on silica and elution led to the
isolation of the cycloadduct(s).
4.4.3. 4-Oxo-2-[5-(4-oxo-3,4-dihydro-2H-pyran-2-yl)-1-
(toluene-4-sulfonyl)-1H-pyrrol-3-yl]-3,4-dihydro-2H-
pyran-2-carboxylic acid methyl ester (14). Biscyclo-
adduct was obtained by elution with a mixture of heptane/
EtOAc (1:1) (two diastereomers). 1H NMR d 2.37 and 2.37
(s, 3H), 2.62 and 2.65 (dd, JZ4.1, 17.0 Hz, 1H), 2.83 (dd,
JZ12.8, 17.0 Hz, 1H), 2.93 (d, JZ16.6 Hz, 1/2H), 2.94 (d,
JZ16.9 Hz, 1⁄2H), 3.21 (d, JZ16.6 Hz, 1⁄2H), 3.22 (d, JZ
16.9 Hz, 1⁄2H), 3.71 (s, 3H), 5.38–5.43 (m, 2H), 5.86 and
5.87 (dd, JZ4.1, 12.8 Hz, 1H), 6.40 (m, 1H), 6.99 and 7.03
(d, JZ6.0 Hz, 1H), 7.27 (d, JZ8.3 Hz, 2H), 7.32 and 7.33
(d, JZ6.0 Hz, 1H), 7.43 and 7.43 (d, JZ1.5 Hz, 1H), 7.65
(d, JZ8.3 Hz, 2H). 13C NMR d 21.6, 40.4 and 40.4, 43.6
and 43.7, 53.6, 71.7, 82.0, 107.5 and 108.0, 112.4 (2C),
122.1 and 122.2, 123.2 and 123.2, 127.1 and 127.2 (2C),
129.9 and 130.0 (2C), 131.4, 135.3, 145.8 and 145.8, 161.0
and 161.0, 161.5 and 161.7, 169.2 and 169.3, 188.9 and
188.9, 190.9. IR (NaCl) n 3060, 1682, 1596, 1400, 1374,
The ketones resulting from hydrolysis of the silyl enol ether
in the case of cycloadducts derived from Danishefsky diene
were obtained in the following manner: after the reaction,
removal of excess diene was achieved by bulb-to-bulb
distillation under reduced pressure (50 8C/0.1 bar). The
residue (0.3 mmol scale) was then stirred overnight in
methanol (2 mL) in the presence of silica. Filtration and
purification as above delivered the desired products.
4.3. Catalyzed reactions under high pressure
The experimental procedure is identical, except that the
Lewis acid at room temperature was first added to the
pyrrole solution. The mixture was stirred for 30 min and
the diene (6 equiv) were added.
1224, 1174, 1092, 1038 cmK1
. HRMS calcd for
C23H22NO8S: (MHC) 472.1066. Found: 472.1046.
4.4.4. 1-[2-Acetyl-5,6-dimethyl-1-(toluene-4-sulfonyl)-
1,4,7,7a-tetrahydroindol-3a-yl]ethanone (16a). Elution
with a 7:3 mixture of heptane/EtOAc furnished derivative
16a. 1H NMR d 1.53 (s, 3H), 1.58 (s, 3H), 1.77 (s, 3H), 1.96
(m, 2H), 2.14–2.24 (m, 1H), 2.32–2.46 (m, 1H), 2.35 (s,
3H), 2.39 (s, 3H), 4.33 (ddwt, JZ4.1 Hz, 1H), 5.40 (s, 1H),
7.23 (d, JZ7.9 Hz, 2H), 7.46 (d, JZ7.9 Hz, 2H). 13C NMR
4.4. General procedure for thermal cycloadditions
A vessel containing the requisite pyrrole, the diene
(12 equiv), hydroquinone (10 mg per mmol of substrate)
in dry degassed toluene was sealed and heated in a sand bath

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A. Chretien et al. / Tetrahedron 61 (2005) 7907–7915
7913
d 19.4, 19.5, 21.6, 25.8, 28.7, 37.0, 37.6, 64.0, 64.7, 123.2,
125.1, 127.6, 128.5 (2C), 129.6 (2C), 130.8, 144.6, 147.4,
194.9, 206.0. IR (NaCl) n 2926, 1702, 1354, 1166, 1090,
814, 660 cmK1. HRMS calcd for C21H26NO4S: (MHC)
388.1583. Found: 388.1584.
4.4.9. 2-(4-Acetyl-1-trifluoromethanesulfonyl-1H-pyr-
rol-2-yl)-2-methyl-2,3-dihydro-pyran-4-one (19b).
Eluted with mixtures of cyclohexane/EtOAc (7:3–3:7). 19F
NMR d K68.17. 1H NMR d 1.73 (s, 3H), 2.50 (s, 3H), 2.83
(d, JZ16.6 Hz, 1H), 2.92 (d, JZ16.6 Hz, 1H), 5.46 (d, JZ
6.0 Hz, 1H), 7.11 (d, JZ1.9 Hz, 1H), 7.26 (d, JZ6.0 Hz,
1H), 7.42 (d, JZ1.9 Hz, 1H). 13C NMR d 26.9, 27.3, 46.9,
79.9, 106.8, 119.5, 122.2, 126.8, 130.5, 135.6, 160.6, 185.5,
190.5. IR (NaCl) n 2925, 1688, 1681, 1598, 1415,
1223 cmK1. MS (CI) m/z (relative intensity) 352 [MHC]
(100), 251 (18), 220 (42). HRMS calcd for C13H12F3NO5S:
(MHC) 352.0466. Found: 352.0469.
4.4.5.
1-[4-Acetyl-3-(toluene-4-sulfonyl)-3-aza-tri-
cyclo[5.2.2.0.2,6]undeca-4,8-dien-6-yl]ethanone (16b/
17b) Elution with a mixture of cyclohexane/EtOH (95:5)
1
led to the isolation of the major, exo diastereomer 17b. H
NMR d 1.17–1.25 (m, 2H), 1.61–1.70 (m, 1H), 1.70 (s, 3H),
1.83–1.93 (m, 1H), 2.40 (s, 3H), 2.58 (s, 3H), 2.73–2.75 (m,
1H), 3.03–3.04 (m, 1H), 4.17 (d, JZ3.0 Hz, 1H), 5.65 (s,
1H), 6.05 (ddwt, JZ7.3 Hz, 1H), 6.24 (ddwt, JZ7.3 Hz,
1H), 7.28 (d, JZ8.3 Hz, 2H), 7.55 (d, JZ8.3 Hz, 2H). 13C
NMR d 16.8, 21.6, 21.8, 25.1, 28.4, 34.5, 34.7, 64.3, 66.5,
121.8, 128.3 (2C), 129.6 (2C), 131.2, 132.8, 132.9, 144.5,
146.0, 195.1, 202.9. IR (NaCl) n 2946, 1701, 1615, 1597,
1354, 1164 cmK1. MS (EI) m/z (relative intensity) 385 [MC
%] (4), 264 (17), 187 (18), 155 (31), 91 (100). HRMS calcd
for C21H24NO4S: (MHC) 386.1426. Found: 386.1410.
4.4.10. 2,3a-Diacetyl-4-methoxy-1-trifluoromethane-
sulfonyl-1,3a,4,5,7,7a-hexahydro-indol-6-one (20a/20b).
Elution with mixtures of cyclohexane/EtOAc (7:3–3:7)
gave the major, endo diastereomer 20a. 19F NMR d K72.21.
1H NMR d 2.32 (dd, JZ9.8, 181 Hz, 1H), 2.35 (s, 3H), 2.39
(s, 3H), 2.70 (dd, JZ5.7, 160 Hz, 1H), 2.74 (dd, JZ4.5,
181 Hz, 1H), 2.78 (dd, JZ4.9, 160 Hz, 1H), 3.32 (s, 3H),
4.08 (dd, JZ4.5, 98 Hz, 1H), 5.17 (dd, JZ4.9, 5.7 Hz, 1H),
6.26 (s, 1H). 13C NMR d 28.2, 29.4, 40.0, 43.4, 57.3, 63.7,
66.2, 77.4, 119.4, 121.8, 144.6, 189.9, 203.6, 206.8; IR
(NaCl) n 2925, 1712, 1624, 1602, 1391, 1211 cmK1. MS
(CI) m/z (relative intensity) 384 [MHC] (100), 352 (32), 252
(82), 220 (11). HRMS calcd for C14H17F3NO6S: (MHC)
384.0729. Found: 384.0732. Further elution delivered the
minor, exo diastereomer 20b. 19F NMR d K72.05. 1H NMR
d 2.28 (dd, JZ2.8, 185 Hz, 1H), 2.33 (s, 3H), 2.36 (s, 3H),
2.82 (dd, JZ3.8, 185 Hz, 1H), 2.88 (d, JZ41 Hz, 2H), 3.31
(s, 3H), 4.15 (dd, JZ2.8, 38 Hz, 1H), 5.75 (t, JZ4.1 Hz,
1H), 5.85 (s, 1H). 13C NMR d 25.9, 28.4, 37.5, 41.6, 57.2,
61.2, 66.4, 78.8, 118.8, 119.3, 144.9, 190.1, 199.7, 204.2. IR
(NaCl) n 2925, 1712, 1624, 1602, 1391, 1211 cmK1. MS
(CI) m/z (relative intensity) 384 [MHC] (31), 352 (100), 252
(88), 220 (22). HRMS calcd for C14H17F3NO6S: (MHC)
384.0729. Found: 384.0724.
4.4.6. 1-(2-Acetyl-5,6-dimethyl-1-trifluoromethanesulfo-
nyl-1,4,7,7a-tetrahydro-indol-3a-yl)ethanone (16d).
Product 16d was obtained by eluting with a 85:15 mixture
1
of cyclohexane/EtOAc. 19F NMR d K71.68. H NMR d
1.65 (s, 3H), 1.76 (s, 3H), 2.17–2.41 (m, 4H), 2.26 (s, 3H),
2.33 (s, 3H), 5.11 (ddwt, JZ4.9 Hz, 1H), 5.81 (s, 1H). 13C
NMR d 19.1, 19.4, 26.4, 28.1, 36.2, 36.9, 64.8, 65.4, 119.6,
125.4, 125.8, 126.6, 144.0, 190.3, 204.7. IR (NaCl) n 2921,
1707, 1625, 1389, 1200, 1153 cmK1. MS (EI) m/z (relative
intensity) 366 [MC%] (15), 278 (63), 189 (50), 174 (45), 146
(100), 131 (36), 91 (40). Anal. Calcd for C15H18F3NO4S: C,
49.31; H, 4.97; N, 3.83; S, 8.78. Found: C, 49.24; H, 5.04;
N, 3.79; S, 8.52.
4.4.7. 1-(4-Acetyl-3-trifluoromethanesulfonyl-3-azatri-
cyclo[5.2.2.02,6]undeca-4,8-dien-6-yl)ethanone (16e/17e).
Elution with a 3:1 mixture of heptane/EtOAc delivered
4.4.11. 1-[3-(Toluene-4-sulfonyl)-3-aza-tricyclo[5.2.2.02,6]-
undeca-4,8-dien-6-yl]-ethanone (22b/23b). Elution with a
3:2 mixture of cyclohexane/CH2Cl2 yielded the major, exo
diastereomer 23b. 1H NMR d 1.03–1.30 (m, 2H), 1.66–1.82
(m, 1H), 1.70 (s, 3H), 1.94–2.04 (m, 1H), 2.39 (s, 3H), 2.78
(dt, JZ2.6, 5.2 Hz, 1H), 3.05–3.10 (m, 1H), 4.13 (dd, JZ
1.1, 3.8 Hz, 1H), 4.89 (d, JZ4.1 Hz, 1H), 6.10–6.20 (m,
2H), 6.45 (d, JZ4.1 Hz, 1H), 7.28 (d, JZ8.3 Hz, 2H), 7.65
(d, JZ8.3 Hz, 2H). 13C NMR d 17.5, 21.6, 21.7, 25.1, 34.2,
34.6, 63.0, 69.6, 111.6, 127.6 (2C), 129.8 (2C), 132.7,
132.9, 133.7, 133.8, 144.1, 205.2. IR (NaCl) n 2941, 1706,
1594, 1351, 1163 cmK1. MS (CI) m/z (relative intensity)
344 [MHC] (68), 264 (100), 154 (95), 136 (70), 91 (46).
HRMS calcd for C19H22NO3S: (MHC) 344.1320. Found:
344.1328.
1
the major diastereomer 17e (exo). 19F NMR d K71.09. H
NMR d 1.30–1.80 (m, 4H), 2.21 (s, 3H), 2.43 (s, 3H), 2.98–
3.02 (m, 2H), 4.90 (d, JZ26 Hz, 1H), 5.90 (s, 1H), 6.17–
6.30 (m, 2H). 13C NMR d 15.8, 21.9, 25.9, 28.0, 34.4 (2C),
66.1, 66.9, 120.0, 123.9, 132.2, 133.7, 143.3, 190.6, 202.6.
IR (NaCl) n 2953, 1707, 1617, 1390, 1199 cmK1. MS (CI)
m/z (relative intensity) 364 [MHC] (100), 284 (8), 232 (13),
152 (10). HRMS calcd for C15H16F3NO4S: (MHC)
364.0831. Found: 364.0826.
4.4.8. 2-[4-Acetyl-1-(toluene-4-sulfonyl)-1H-pyrrol-2-
yl]-2-methyl-2,3-dihydro-pyran-4-one (19a). Eluent:
cyclohexane/EtOAc (7:3). H NMR d 1.74 (s, 3H), 2.35
1
(s, 3H), 2.42 (s, 3H), 2.82 (d, JZ16.6 Hz, 1H), 2.94 (d, JZ
16.6 Hz, 1H), 5.43 (d, JZ6.2 Hz, 1H), 6.97 (d, JZ1.9 Hz,
1H), 7.25 (d, JZ6.2 Hz, 1H), 7.32 (d, JZ8.3 Hz, 2H), 7.74
(d, JZ1.9 Hz, 1H), 7.88 (d, JZ8.3 Hz, 2H). 13C NMR d
21.9, 27.2, 27.9, 47.3, 80.5, 106.8, 121.2, 126.7, 127.8,
128.7 (2C), 129.6 (2C), 133.8, 135.5, 145.3, 161.2, 186.2,
191.4. IR (NaCl) n 2920, 1733, 1676, 1595, 1173 cmK1. MS
(EI) m/z (relative intensity) 373 [MC%] (21), 239 (16), 155
(30), 148 (32), 91 (100), 65 (31). HRMS calcd for
C19H20NO5S: (MHC) 374.1062. Found: 374.1059.
4.4.12. 1-(5,6-Dimethyl-1-trifluoromethanesulfonyl-
1,4,7,7a-tetrahydroindol-3a-yl)-ethanone (22d). Obtained
from elution with a 65:35 mixture of cyclohexane/CH2Cl2.
19F NMR d K73.76. 1H NMR d 1.68 (s, 3H), 1.74 (s, 3H),
2.15–2.33 (m, 3H), 2.23 (s, 3H), 2.50 (dd, JZ4.7, 14.9 Hz,
1H), 4.97–5.03 (m, 1H), 5.15 (d, JZ4.3 Hz, 1H), 6.28 (d,
JZ4.3 Hz, 1H). 13C NMR d 19.4, 19.7, 26.0, 36.0, 37.2,
62.9, 66.8, 114.4, 120.1, 126.1, 126.6, 130.6, 205.9. IR

´
A. Chretien et al. / Tetrahedron 61 (2005) 7907–7915
7914
(NaCl) n 2916, 1712, 1398, 1227, 1192 cmK1. HRMS calcd
Chem. Soc. 1948, 70, 1161–1166. (e) Allen, C. F. H.; Gates,
J. W. J. Am. Chem. Soc. 1943, 65, 1283–1285.
for C13H16F3NO3S: (MHC) 324.0894. Found: 324.0881.
4. For pyrroles involved in cycloadditions as dienes, see for
example: (a) Mandell, L.; Blanchard, W. A. J. Am. Chem. Soc.
1957, 79, 6198–6201. (b) Kitzing, R.; Fuchs, R.; Joyeux, M.;
Prinzbach, H. Helv. Chim. Acta 1968, 51, 888–895. (c) Bansal,
R. C.; McCulloch, A. W.; McInnes, A. G. Can. J. Chem. 1969,
47, 2391–2394. (d) Liu, M. T. H.; Chishti, N. H. J. Org. Chem.
1980, 45, 4515–4519. (e) Jones, R. A.; Sepulvada Arques, J.
Tetrahedron 1981, 37, 1597–1599. (f) Drew, M. G. B.;
George, A. V.; Isaacs, N. S.; Rzepa, H. S. J. Chem. Soc.,
4.4.13. 1-(3-Trifluoromethanesulfonyl-3-azatricyclo-
[5.2.2.02,6]undeca-4,8-dien-6-yl)-ethanone (22e/23e). The
major diastereomer 23e (exo) by elution with a 92:8 mixture
1
of cyclohexane/EtOAc. 19F NMR d K74.24. H NMR d
1.09–1.36 (m, 2H), 1.76–1.82 (m, 2H), 2.17 (s, 3H), 2.95
(dddwdt, JZ2.6, 5.1 Hz, 1H), 3.06–3.13 (m, 1H), 4.77 (dd,
JZ1.1, 2.6 Hz, 1H), 5.20 (d, JZ4.1 Hz, 1H), 6.15–6.26 (m,
2H), 6.34 (d, JZ4.1 Hz, 1H). 13C NMR d 16.6, 22.0, 25.5,
34.3 (2C), 64.4, 69.6, 113.3, 120.0, 130.4, 132.4, 133.8,
Perkin Trans.
1 1985, 1277–1284. For cycloadditions
204.0. IR (NaCl) n 2950, 1713, 1398, 1225, 1195 cmK1
.
involving vinyl pyrroles as diene, see: (g) Vessels, J. T.;
Janicki, S. Z.; Petillo, P. A. Org. Lett. 2000, 2, 73–76.
(h) Moskalev, N. V.; Gribble, G. W. Tetrahedron Lett. 2002,
43, 197–201.
HRMS calcd for C13H14F3NO3S: (MC%) 321.0643. Found:
321.0646.
¨
5. (a) Seitz, G.; Kampchen, T. Arch. Pharm. 1978, 311, 728–735.
4.4.14. 2-Methyl-2-(1-trifluoromethanesulfonyl-1H-pyr-
rol-3-yl)-2,3-dihydro-pyran-4-one (24b). Elution with a
4:1 mixture of cyclohexane/EtOAc afforded the desired
product. 19F NMR d K76.52. 1H NMR d 1.74 (s, 3H), 2.90
(d, JZ16.6 Hz, 1H), 3.00 (d, JZ16.6 Hz, 1H), 5.53 (d, JZ
6.0 Hz, 1H), 6.50 (dd, JZ3.4, 1.5 Hz, 1H), 7.07–7.10 (m,
1H), 7.10–7.15 (m, 1H), 7.27 (d, JZ6.0 Hz, 1H). 13C NMR
d 27.3, 47.1, 80.3, 106.6, 113.7, 118.7, 119.0, 123.2, 133.5,
160.9, 191.3. IR (NaCl) n 3142, 2982, 1677, 1597, 1419,
1233, 1209, 1147 cmK1. MS (EI) m/z (relative intensity)
309 [MC%] (1), 239 (86), 148 (12), 104 (100). HRMS calcd
for C11H11NO4S: (MHC) 310.0361. Found: 310.0355.
(b) Cobb, R. L.; Vives, V. C.; Mahan, J. E. J. Org. Chem. 1978,
43, 931–936. (c) Li, J.-H.; Snyder, J. K. J. Org. Chem. 1993,
58, 516–519. (d) Hsieh, M. F.; Peddinti, R. K.; Liao, C.-C.
Tetrahedron Lett. 2001, 42, 5481–5484. (e) Yu, Z.-X.; Dang,
Q.; Wu, Y.-D. J. Org. Chem. 2001, 66, 6029–6036.
6. Preliminary results regarding the involvement of pyrroles as
dienophiles in normal-demand cycloadditions were reported.
´
See: Chretien, A.; Chataigner, I.; Piettre, S. R. Chem.
Commun. 2005, 1351–1353.
7. Wenkert, E.; Moeller, P. D. R.; Piettre, S. R. J. Am. Chem. Soc.
1988, 110, 7188–7194.
8. (a) Chataigner, I.; Hess, E.; Toupet, L.; Piettre, S. R. Org. Lett.
´
2001, 3, 515–518. (b) Chretien, A.; Chataigner, I.; L’Helias,
´
N.; Piettre, S. R. J. Org. Chem. 2003, 68, 7990–8002.
Acknowledgements
9. Pyrrole 7 was prepared according to the following procedure:
Demopoulos, B. J.; Anderson, H. J.; Loader, C. E.; Faber, K.
Can. J. Chem. 1983, 61, 2415–2422.
´
The ‘Region Haute-Normandie’ and Novelect are gratefully
acknowledged for support allowing the purchase of the
hyperbar reactors. The authors thank Mr. Mehdi Hippon for
help in the preparation of compounds 15a and 15b.
10. Gribble, G. W. Tetrahedron Lett. 2001, 42, 4783–4785.
11. Wenkert, E.; Piettre, S. R. J. Org. Chem. 1988, 53, 5850–5861.
12. For a discussion on the importance of diffusion in reactions
under pressure, see for example: (a) Le Noble, W. J.; Kelm, H.
¨
Angew. Chem., Int. Ed. Engl. 1980, 19, 841–856. (b) Klarner,
F.-G.; Diedrich, M. K.; Wigger, A. E. Effect of Pressure on
Organic Reactions. In Chemistry Under Extreme or Non-
classical Conditions; van Eldik, R., Hubbard, C. D., Eds.;
Wiley: New York, 1997.
References and notes
1. For general reviews, see: (a) Carruthers, W. Cycloaddition
Reactions in Organic Synthesis; Pergamon: Oxford, UK, 1990.
(b) Oppolzer, W. Combining C–C p Bonds. In Trost, B. M.,
Fleming, I., Paquette, L. A., Eds.; Comprehensive Organic
Synthesis; Pergamon: Oxford, UK, 1991; Vol. 5.
(c) Fringuelli, F.; Taticchi, A. The Diels–Alder Reaction;
Wiley: Chichester, UK, 2002. (d) Corey, E. J. Angew. Chem.,
Int. Ed. 2002, 41, 1650–1667. (e) Nicolaou, K. C.; Snyder,
S. C.; Montagnon, T.; Vassilikogiannakis, G. Angew. Chem.,
Int. Ed. 2002, 41, 1668–1698.
13. For aromatic and aliphatic ketones involved in hetero-Diels–
Alder cycloadditions, see: (a) Jurczak, J.; Chmielewski, M.;
Filipek, S. Synthesis 1979, 41–42. (b) Midland, M. M.;
Graham, R. S. J. Am. Chem. Soc. 1984, 106, 4294–4296.
(c) Kirby, A. J.; Ryder, H. J. Chem. Soc., Perkin Trans. 1 1990,
617–626. (d) Brouard, C.; Pornet, J.; Miginiac, L. Synth.
Commun. 1994, 24, 3047–3053. (e) Chino, K.; Takata, T.;
Endo, T. Synth. Commun. 1996, 26, 2145–2154. (f) Huang, Y.;
Rawal, V. H. J. Am. Chem. Soc. 2002, 124, 9962–9663.
(g) Pierres, C.; George, P.; van Hijfte, L.; Ducep, J.-B.; Hibert,
M.; Mann, A. Tetrahedron Lett. 2003, 44, 3645–3647.
14. Diacetylpyrrole was prepared by a sequential, double Friedel–
Crafts reaction on pyrrole, according to the published
procedures, see: (a) Cadamuro, S.; Degani, L.; Dughera, S.;
Fochi, R.; Gatti, A.; Piscopo, L. J. Chem. Soc., Perkin Trans. 1
1993, 273–283. (b) Alonso, D. O.; Buldain, G.; Frydman, B.
J. Org. Chem. 1984, 49, 2619–2622.
2. See for example: (a) Boger, D. L.; Weinreb, S. N. In
Wasserman, H. H., Ed.; Hetero Diels–Alder Methodology in
Organic Synthesis; Academic: San Diego, CA, 1987; Vol. 47.
(b) Tietze, L. F.; Kettschau, G. Top. Curr. Chem. 1997, 189,
1–120. (c) Joergensen, K. A. Eur. J. Org. Chem. 2004,
2093–2102.
3. For early examples of heterocycles being involved in Diels–
Alder cycloadditions (including furan and thiophene), see:
(a) Diels, O.; Alder, K. Ber. 1929, 62, 557. (b) Diels, O.; Alder,
K. Ann. 1931, 490, 243. (c) Clapp, D. B. J. Am. Chem. Soc.
1939, 61, 2733–2735. (d) Woodward, R. B.; Baer, H. J. Am.
15. 2,4-Diacetylpyrrole was tosylated according to literature
procedure. See: Masquelin, T.; Broger, E.; Mu
¨ller, K.; Schmid,
R.; Obrecht, D. Helv. Chim. Acta 1994, 77, 1395–1411.

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7915
16. Examples of possible side-products include cycloadduct i and
biscycloadduct ii; however, none of these were isolated, or
even detected in the crude mixture.
shown the beneficial effect of the triflyl group, allowing the
desired transformation to reach completion under milder
conditions and in shorter times. Chataigner, I.; Piettre, S. R.
Unpublished results.
20. Pyrrolyl substrate 15b was easily prepared by reacting the
pyrrole derivative with N,N-bistriflylimide. See: Hendrickson,
J. B.; Bergeron, R. Tetrahedron Lett. 1973, 4607–4610.
21. 3-Acetylpyrrole was prepared according to the following
procedure: Kakushima, M.; Hamel, P.; Frenette, R.; Rokak, J.
J. Org. Chem. 1983, 48, 3214–3219.
22. 3-Acetylpyrrole was triflated using the procedure of Abell.
See: Abell, A. D.; Nabbs, B. K.; Battersby, A. R. J. Am. Chem.
Soc. 1998, 120, 1741–1746.
17. Various Lewis acids (among which AlMe3, MeAlCl2, Me2-
AlCl, ZnCl2, EuFOD, for example) were checked for their
abilities to catalyze the reaction. Zinc chloride proved to be the
most efficient one.
23. The exclusive site selectivity observed in the hetero Diels–
Alder reaction of 15a and 15b to generate dihydropyrans 19a
and 19b, respectively, in connection with the formation of 24a
and 24b, seems to indicate the higher reactivity of an acyl
group in a versus b position to the sulfonamide. Such a
behavior might result from the possible chelation of the Lewis
acid by both the reacting carbonyl group and the sulfonyl unit
in the former case only.
18. endo Addition can be defined as ‘that particular arrangement
of reactants in which the more bulky side of the diene is under
the more bulky side of the dienophile’, meaning the pyrrole
part in this case1c In this precise case, the volume of the
transition state leading to the exo diasteromer is probably more
compact than the one delivering the endo cycloadduct.
19. Analogous reactions conducted with indole derivatives have