A novel attractive interaction in the Diels-Alder reaction of N-protected pyrroles with allene-1,3-dicarboxylates

Article abstract of DOI:10.1016/S0040-4039(01)02033-0

The endo/exo selectivities of Diels-Alder reactions of N-protected pyrroles with allene-1,3-dicarboxylates were studied under Lewis acid assisted and thermal reaction conditions. A novel attractive effect between the N-protective carbonyl group of pyrrole and the ester group of allene-1,3-dicarboxylates operates to control the selectivity in the above Diels-Alder reaction. This new attractive effect to give the exo adduct is more effective than the Alder orbital effect.

Full text of DOI:10.1016/S0040-4039(01)02033-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 9237–9240
A novel attractive interaction in the Diels–Alder reaction of
N-protected pyrroles with allene-1,3-dicarboxylates
Kiyoharu Nishide, Shogo Ichihashi, Hiroyuki Kimura, Takahiro Katoh and Manabu Node*
Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8414, Japan
Received 31 August 2001; revised 9 October 2001; accepted 26 October 2001
Abstract—The endo/exo selectivities of Diels–Alder reactions of N-protected pyrroles with allene-1,3-dicarboxylates were studied
under Lewis acid assisted and thermal reaction conditions. A novel attractive effect between the N-protective carbonyl group of
pyrrole and the ester group of allene-1,3-dicarboxylates operates to control the selectivity in the above Diels–Alder reaction. This
new attractive effect to give the exo adduct is more effective than the Alder orbital effect. © 2001 Published by Elsevier Science
Ltd.
The Diels–Alder reactivity of N-acylpyrrole toward a
typical dienophile such as maleic anhydride is known to
be lower than that of cyclopentadiene and furan. Con-
sequently, high pressure is required for the reaction of
N-benzoylpyrrole with maleic anhydride1 and for N-
acetylpyrrole with an acetylenic dienophile.2 However,
allene-1,3-dicarboxylates react well with N-alkoxycar-
bonylpyrrole and with cyclopentadiene and furan.3 We
had developed a one-pot synthesis of allene-1,3-dicar-
boxylates from 1,3-acetonedicarboxylates with DMC,4
and a novel crystallization-induced asymmetric trans-
and thermal reaction conditions (Methods I and II).
The results are summarized in Table 1. The reaction of
dimethyl allene-1,3-dicarboxylate with N-methoxycar-
bonyl- or N-benzyloxycarbonylpyrrole promoted by
aluminum chloride in dichloromethane at −78°C gave
the Diels–Alder products A, which were a mixture (ca.
1: 2) of the endo and exo adducts (entries 1 and 3). The
same Diels–Alder adducts were also obtained in the
reactions heated at 90°C in toluene (entries 26 and 4).
In the reaction of N-Boc-pyrrole promoted by alu-
minum chloride the exo selectivity varied to endo selec-
tivity, whereas the thermal reaction without Lewis acid
gave a slightly exo selective adducts (entries 5 and 6).
Changing the alkoxy group of the allene-1,3-dicarboxy-
late to ethyl and cyclohexyl significantly increased the
endo selectivity in aluminum chloride assisted reactions,
although the selectivity was not observed under thermal
conditions (entries 7–10). This alteration of the selectiv-
ity depending on the reaction conditions was also
formation from a diastereomeric mixture of di-(−)-L-
menthyl allene-1,3-dicarboxylates, which was applied to
an asymmetric synthesis of (−)-epibatidine.5 The nor-
mal endo stereoselectivity of cyclopentadiene3a,b and
furan3c in the Diels–Alder reaction with allene-1,3-
dicarboxylates has been extensively studied. In the syn-
thesis of (−)-epibatidine, we found that the Diels–Alder
reaction of di-(−)-L-menthyl allene-1,3-dicarboxylate
with N-Boc-pyrrole proceeded to give the endo adduct
exclusively,5 while the endo/exo selectivity in the reac-
tions of dimethyl allene-1,3-dicarboxylates differed
markedly.6 This observation prompted us to examine
the origins of the endo and exo selectivity. We report
herein a new aspect on the endo/exo selectivity of the
Diels–Alder reaction of N-protected pyrroles with
allene-1,3-dicarboxylates.
observed for the reactions of di-(−)-L-menthyl (R)-
allene-1,3-dicarboxylate5 with N-Boc-pyrrole (entries 11
and 12). Changing the nitrogen substituent of the
pyrrole to a bulky pivaloyl group also increased the
endo selectivity (entries 13 and 14). This was especially
true in the reaction of p-toluenesulfonylpyrrole with
dimethyl allene-1,3-dicarboxylate, which gave the endo
adduct exclusively, even though the reaction was con-
ducted under thermal conditions (entries 15 and 16).
Reactions of N-protected pyrroles with allene-1,3-dicar-
boxylates were carried out under Lewis acid assisted
In the above reactions, the electron deficient N-pro-
tected pyrroles reacted as a diene in Diels–Alder reac-
tions to give the cycloadducts A as a major product.
However, a small amount (less than 10%) of the
Friedel–Crafts product B was also obtained in some
* Corresponding author. Tel.: +81-75-595-4639; fax: +81-75-595-4775;
e-mail: node@mb.kyoto-phu.ac.jp
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)02033-0

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K. Nishide et al. / Tetrahedron Letters 42 (2001) 9237–9240
reactions (entries 2–4, 6–9, 11, 13 and 14). It was
observed that the Friedel–Crafts reaction and the
Diels–Alder reaction were competitive under thermal
and Lewis acid catalyzed reaction conditions. On the
other hand, the reactions of the electron rich pyrroles
with dimethyl allene-1,3-dicarboxylate gave exclusively
2-alkenylated pyrroles B7 (entries 17–20). The regio-
and stereoselectivities relating to the position of the
pyrrole moiety and the E/Z isomer of the a,b-unsatu-
rated ester moiety were completely regulated in the
reaction.8 The predominance of the Friedel–Crafts
alkylation of the electron rich pyrroles can be
attributed to the high stability of the ionic intermediate
C, as shown in Scheme 1.
mol) than the endo adduct. We tried to confirm whether
or not the Diels–Alder reaction was in equilibrium
under the reaction conditions I and II. In the reactions
using the endo adducts (R=Me, R%=Boc) and (R=c-
Hex, R%=Boc), both endo adducts were recovered in
85–92% yield under conditions I (−78°C, 1 day, 9 equiv.
of N-Boc-pyrrole) and conditions II (90°C, 2 day, 9
equiv. of N-Boc-pyrrole), and no exo adducts were
detected in the reaction mixture. Therefore, these
results confirmed that the Diels–Alder reaction in Table
1 was kinetically controlled.
Compared with the highly endo selective Diels–Alder
reaction of cyclopentadiene3a,b or furan3c with allene-
1,3-dicarboxylate, the endo/exo selectivity in the above
Diels–Alder reaction of pyrroles could not be rational-
ized based solely on Alder’s rule and steric effects.
According to semi-empirical PM3 calculations, the exo
adduct (R=Me, R%=Boc) is more stable (by 0.7 kcal/
Table 1. The reaction of allene-1,3-dicarboxylate with N-protected pyrroles
R'
CO2R
CO2R
N
RO2C
Method I or II
CO2R
H
CO2R
•
+
N
R'
(10 eq.)
N
or
H
R'
CO2R
A
B
Entry
R
R%
Methoda
Time (days)
Product
Yield (%)
Endo:exo
1
2
3
4
5
6
7
8
Me
CO2Me
CO2Bn
I
II
I
II
I
II
I
II
I
II
I
II
I
II
I
1
2
1
1
0.5
2
1
2
2
A
65
64
78
63c
53
91d
73
66e
60
69f
85
84
77
96g
62
70
93
93
87
70
35:65
37:63
33:67
37:63
67:33
45:55
100:0
50:50
100:0
49:51
100:0
50:50
67:33
54:46
100:0
100:0
–
Ab
Ab
Ab
A
Me
t
Me
CO2 Bu
Ab
Ab
Ab
Ab
A
t
Et
CO2 Bu
t
9
c-Hex
CO2 Bu
10
11
12
13
14
15
16
17
18
19
20
2
t
(−)-Menthyl
CO2 Bu
2.5
3.5
1
2
1
3
1
1
1
Ab
A
Me
Me
Me
Me
Pivaloyl
p-Tos
Me
Ab
Ab
A
II
I
II
I
A
B
B
B
–
–
–
Bn
II
0.5
B
a Method I: AlCl3 (1.2 equiv.) was added in dichloromethane at −78°C.
Method II: The reaction mixture was heated at 90°C in toluene.
b The Friedel–Crafts type product B was observed in less than 10% yield.
c The Z-isomers of A (exo, 8%) was observed.
d The Z-isomers of A (endo, 7%; exo, 10%) was observed.
e The Z-isomers of A (exo, 9%) was observed.
f The Z-isomers of A (exo, 13%) was observed.
g The Z-isomers of A (endo, 5%; exo, 14%) was observed.
OR
Friedel-Crafts
RO2C
H
reaction
CO2R
H
•
O
B
H
N
CO2R
N R'
R'
H
R' = Me, Bn
C
Scheme 1.

K. Nishide et al. / Tetrahedron Letters 42 (2001) 9237–9240
9239
a view from upper side ( Newman projection )
small steric effect
Alder's orbital interaction
Nucleophile-electrophile interaction
MeO2C
MeO2C
H
MeO2C
OMe
O+Al-Cl3
MeO2C
H
O
Me
O
O
OMe
Y
OY
•
O
•
•
O
OMe
O+Al-Cl3
H
Al-Cl3
O+
H
OMe
O
O
•
H
H
H
O
O
Y
OMe
Ts-2
Ts-4
Ts-1
N
H
<
N
H
<
O
N
H
1 : ~ 2
Y = Me, Bn, tBu
N
N
1 : 2
N
O
OY
YO
H
Y
H
Y = Me, Bn
O
exo
O
exo
endo
endo
steric effect
O-tBu
large steric effect
Cl3Al-
RO2C
O+
RO2C
RO2C
H
RO2C
H
OR
O
O
O
tBu
R
•
O+
Al-Cl3
tBu
•
•
•
O
H
OR
H
OR
OR
O
O
Al-Cl3
O+
Ts-3
H
H
OR
H
H
O
H
=
N
O
OtBu
>>
O
O
N
N
N
N
O
N
tBu
O
H
tBu
H
R = Me, Et,
R = Et, c-Hex,
Menthyl
O
O
c-Hex, Menthyl
H
endo
exo
exo
endo
MeO2C
H
steric effect
tBu
MeO2C
H
O
OMe
O
MeO2C
H
MeO2C
OMe
•
•
O
O
O
severe
steric effect
•
•
H
O
H
O
H
O
O-Me
Ts-5
Ts-6
OMe
O
OMe
H
O
>>>
exclusive
H
H
N
O
S
N
≥
N
S
N
tBu
O
tBu
N
Me
H
Me
endo
exo
exo
endo
Scheme 2. Comparison of transition states in Diels–Alder reaction.
Namely, the exo selectivity in entries 1–4 was very
curious since these molecules lack significant steric hin-
drance in the endo transition state so that the usual
endo selectivity would be expected by secondary orbital
control (the Alder rule). Therefore, it was suggested
that another new attractive interaction might exist in
the exo transition state in this Diels–Alder reaction of
the dimethyl allene-1,3-dicarboxylate with N-alkoxycar-
bonylpyrrole. Transition state energy calculations (R=
Me, R%=CO2Me) using semi-empirical PM3 revealed
that the energy of the exo transition state was 0.77
kcal/mol more stable than that of the endo transition
state.9 This energy difference corresponded well with
the exo selectivity of these reactions. We thought the
attractive nucleophile–electrophile interaction10 as a
candidate of the new attractive interaction, which
would operate between one of the two oxygens of an
ester group in the dienophile and the carbonyl carbon
of N-alkoxycarbonyl- or N-acylpyrrole. The proposed
transition states in the Diels–Alder reaction are illus-
trated in Scheme 2. The endo and exo transition states
in the reactions of N-alkoxycarbonylpyrroles with
dimethyl allene-1,3-dicarboxylate (entries 1–6) are
depicted as Ts-1 (thermal) and Ts-2 (AlCl3 assisted). If
the energy of the new interaction is larger than that of
the Alder orbital interaction, the exo selectivity can be
explained reasonably well except for the Lewis acid
assisted reaction of N-Boc-pyrrole (entry 5), in which
considerable steric interactions between the Me group
of the ester and the t-Bu group of the carbamate would
have to be added (Ts-4). Next, the transition states in
the reaction of N-Boc-pyrrole with allene-1,3-dicar-
boxylates bearing the bulky R group (entries 7–12) are
depicted as Ts-3 (thermal) and Ts-4 (AlCl3 assisted).
The exo predominance is diminished in Ts-3 by the
small steric repulsion between the t-butoxyl group and
the bulky R (Et, c-Hex, menthyl) groups of the esters
(entries 8, 10 and 12). On the other hand, the high endo
selectivity in the Lewis acid assisted reactions (entries 7,
9 and 11) can be rationalized by the large steric repul-
sion between the ester moiety coordinated with the
Lewis acid and the tert-butoxycarbonyl group in Ts-4.
The difference of the endo selectivity in the reaction of
the pyrroles having N-pivaloyl and N-sulfonyl sub-
stituents (entries 13–16) can also be attributed to the
presence or the absence of the new attractive interac-
tion based on the bulkiness of the N-protective groups
in the transition states, Ts-5 and Ts-6.
It should be noted that this new attractive interaction is
more effective than the Alder secondary orbital control
in the above reactions. Such a fundamental effect in the
Diels–Alder reaction of pyrrole derivatives had not
been known until now because of the low reactivity of
pyrroles. However, we were able to observe this novel
effect by using less hindered and highly reactive allene
derivatives as dienophiles. Further studies are under
way in our laboratory.
References
1. Drew, M. G. B.; George, A. V.; Isaacs, N. S.; Rzepa, H.
S. J. Chem. Soc., Perkin Trans. 1 1985, 1277–1284.
2. Kotsuki, H.; Mori, Y.; Nishizawa, H.; Ochi, M.; Ma-
tsuoka, K. Heterocycles 1982, 19, 1915–1920.
3. (a) Ikeda, I.; Honda, K.; Osawa, E.; Shiro, M.; Aso, M.;
Kanematsu, K. J. Org. Chem. 1996, 61, 2031–2037; (b)
Aso, M.; Ikeda, I.; Kawabe, T.; Shiro, M.; Kanematsu,
K. Tetrahedron Lett. 1992, 33, 5787–5790; (c) Ikeda, I.;
Gondo, A.; Shiro, M.; Kanematsu, K. Heterocycles 1993,
36, 2669–2672.
4. Node, M.; Fujiwara, T.; Ichihashi, S.; Nishide, K. Tetra-
hedron Lett. 1998, 39, 6331–6334.
5. Node, M.; Nishide, K.; Fujiwara, T.; Ichihashi, S. J.
Chem. Soc., Chem. Commun. 1998, 2363–2364.

9240
K. Nishide et al. / Tetrahedron Letters 42 (2001) 9237–9240
side chain were observed in the reaction of the electron
6. (a) Pavri, N. P.; Trudell, M. L. Tetrahedron Lett. 1997,
deficient pyrroles.
38, 7993–7996; (b) Kozikowski, A. P.; Floyd, W. C.;
Kuniak, M. P. J. Chem. Soc., Chem. Commun. 1977,
582–583.
9. Transition state energy calculations were performed using
Spartan ver. 5.0 of Wavefunction, Inc. on Silicon Graph-
ics O2 computer system.
10. (a) Schweizer, W. B.; Procter, G.; Kaftory, M.; Dunitz, J.
D. Helv. Chim. Acta 1978, 61, 2783–2808; (b) Procter, G.;
Britton, D.; Dunitz, J. D. Helv. Chim. Acta 1981, 64,
471–477.
7. The same type of Friedel–Crafts alkylation of pyrrole
with a,b-unsaturated iminium salts was reported recently:
Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc.
2001, 123, 4370–4371.
8. The E- and Z-isomers of the double bond of the pyrrole