Recognition-induced control and acceleration of a pyrrole Diels-Alder reaction

Article abstract of DOI:10.1016/S0040-4039(01)00149-6

The formation of two hydrogen bonds between an amidopyridine and a carboxylic acid controls the stereochemical outcome and significantly accelerates the rate of the Diels-Alder cycloaddition between a benzoylpyrrole and a maleimide.

Full text of DOI:10.1016/S0040-4039(01)00149-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2377–2380
Recognition-induced control and acceleration of a pyrrole
Diels–Alder reaction
Raphae¨l Bennes,a Marcos Sapro´ Babiloni,b Wayne Hayesb,* and Douglas Philpa,*
aSchool of Chemistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
bDepartment of Chemistry, University of Reading, Whiteknights, Reading RG6 6AD, UK
Received 16 January 2001; accepted 25 January 2001
Abstract—The formation of two hydrogen bonds between an amidopyridine and a carboxylic acid controls the stereochemical
outcome and significantly accelerates the rate of the Diels–Alder cycloaddition between a benzoylpyrrole and a maleimide. © 2001
Published by Elsevier Science Ltd.
The study of the chemistry of derivatives of 7-azabicy-
clo [2.2.1]heptane 1 has been given fresh impetus by the
discovery1 of the natural product (−)-epibatidine 2
which displays powerful analgesic properties. In princi-
ple, the bicyclic skeleton 1 should be accessible
synthetically2 through a [4+2] Diels–Alder cycloaddi-
tion between a pyrrole derivative and a suitable 2p
component in an analogous manner to that employed
in the synthesis of 7-oxabicyclo[2.2.1]heptane deriva-
tives. In practice, however, the resonance energy of
pyrrole (ca. 29 kcal mol−1, cf. furan 16 kcal mol−1)
mitigates against its use as a 4p component in a
cycloaddition reaction, preferring instead to react as a
vinylogous enamine.
hydrogen bonding interactions between an amidopy-
ridine and a carboxylic acid to accelerate and facilitate
several Diels–Alder reactions, including some which are
thermodynamically disfavoured at ambient temperature
and pressure. The recalcitrant nature of pyrrole as a
diene made it an obvious target for the extension of our
recognition-based methodology.
Accordingly, we designed the diene 3 and the maleimide
4 as partners in a Diels–Alder cycloaddition. We envis-
aged that the recognition between the amidopyridine
and the carboxylic acid would both accelerate and
control the outcome of the cycloaddition between 3 and
4. Additionally, we designed diene 5 and dienophile 6
as control compounds as they possess the same reactive
functionality as 3 and 4, but lack the requisite recogni-
tion sites.
N
Cl
H
N
H
N
1
2
O
O
O
N
Various physical and chemical approaches including the
use of Lewis acid catalysts3 and high pressure,4 have
been developed to overcome the low reactivity of
pyrrole as a diene. We have become interested in
exploiting recognition processes to accelerate and direct
the outcome of chemical reactions. Our previous work5
has focussed on the use of recognition sites located on
the two reactive partners, which allows the formation
of a complex in which the reaction becomes pseudo-
intramolecular. We have demonstrated the use of
N
N
H
N
N
3
5
4
6
CO2H
O
O
O
O
N
N
CO2Me
CH3
O
We have demonstrated the utility of molecular mechan-
ics calculations in predicting stereoselectivity in Diels–
Alder cycloadditions through the identification of
intramolecular hydrogen bonds in the products. We
have found5 that the product with the greatest number
of intramolecular hydrogen bonds is favoured strongly.
* Corresponding authors. Present Address: Centre for Biomolecular
Sciences, School of Chemistry, University of St. Andrews, North
Haugh, St. Andrews, Fife KY16 9ST, UK (D.P.).
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)00149-6

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R. Bennes et al. / Tetrahedron Letters 42 (2001) 2377–2380
Figure 1. Calculated lowest energy conformations for (a) exo-7 and (b) endo-7. Dotted lines represent hydrogen bonds.
Hence, we carried out molecular mechanics cal-
culations6 on the products of the reaction between 3
and 4 in order to determine which of the two
diastereoisomeric cycloadducts—exo-7 or endo-7—
would be formed preferentially.
In order to elucidate whether the lowest energy confor-
mations of exo-7 and endo-7 were representative of the
family of low energy conformations available to these
two molecules, we generated a representative set of low
energy conformations by Monte Carlo methods. The
resultant sets of conformations were filtered to remove
those which had calculated energies >50 kJ higher than
the conformations shown in Fig. 1. The distances
between the pyridine nitrogen atom and the carboxylic
acid proton (Distance A, Fig. 2) and that between the
amide proton and the carbonyl oxygen atom of the
carboxylic acid (Distance B, Fig. 2) were determined
The calculated lowest energy conformations of these
two cycloadducts are shown in Fig. 1. It is clear that, in
these two conformations at least, exo-7 can form two
intramolecular hydrogen bonds, whereas endo-7 does
not contain any stabilising intramolecular hydrogen
bonds.
O
18
16
14
12
10
8
N
N
H
H
O
O
N
H
N
O
CO2H
6
O
4
N
N
H
Distance
A
2
Distance
B
H
O
O
2 4 6 8 10 12 14 16
Distance B/A
Figure 2. Structures of the 30 lowest energy conformations of exo-7 and endo-7 expressed as a function of key hydrogen bond
distances. Open circles represent the location of conformations of exo-7 and open triangles represent the location of conforma-
tions of endo-7.

R. Bennes et al. / Tetrahedron Letters 42 (2001) 2377–2380
2379
pyrrole ring to the corresponding cycloadduct. We
therefore turned to the use of high pressure in order to
facilitate the reaction between 3 and 4. Accordingly, we
prepared 200 mM solutions of 3 and 4 in CD2Cl2.
Equal volumes of these two solutions were mixed and
the resulting solution compressed to 10 kbar for vary-
ing periods of time. The reaction mixture was then
for the 30 lowest energy conformations. This data was
used to generate a scatterplot (Fig. 2) in which the low
energy conformations of exo-7 and endo-7 are located
as a function of these two distances.
It is clear from the results presented in Fig. 2 that the
low energy conformations of exo-7 and endo-7 occupy
quite different regions of conformational space. More
than 70% of the low energy conformations of exo-7
sampled contain at least one stabilising intramolecular
hydrogen bond. By contrast, endo-7 prefers to adopt
extended conformations that contain no stabilising
intramolecular hydrogen bonds. These results indicate
that the recognition-mediated reaction should show a
strong preference for the formation of the exo
cycloadduct.
1
analysed by 250 MHz H NMR spectroscopy and the
percentage conversion of 3 and 4 to cycloadduct 7 was
determined. For comparison purposes, the same set of
reactions was performed under identical conditions
between 5 and 6, which lack recognition sites. The
results are presented in Fig. 3.
From these data it is clear that the recognition-medi-
ated reaction proceeds at a significantly faster rate than
the control reaction under the conditions employed. It
1
In order to test this hypothesis, we embarked on the
synthesis of the target pyrroles 3 and 5 (Scheme 1).
Reaction of the appropriate aromatic amine with one
equivalent of isophthaloyl chloride in THF at room
temperature afforded the corresponding monoamides in
either 60 or 65% yield. Reaction of these amides with
the lithium salt of pyrrole, generated by treatment of
pyrrole with n-butyllithium at room temperature,
afforded the target dienes 3, in 20% yield, and 5, in 30%
yield. The synthesis of 4 was accomplished by treatment
of b-alanine with maleic anhydride in glacial acetic
acid. Ester 6 was prepared by treatment of 4 with
methyl iodide and caesium carbonate in dimethyl-
formamide.
was also clear from the H NMR spectra of the reac-
tion mixtures that the stereochemical outcome of the
reaction was significantly different between the two sets
of reactions. However, in order to assign the stereo-
chemistry of the cycloadducts unambiguously, it was
necessary to record NMR spectra at low temperature to
remove line broadening which arises as a result of
rotation about the R2NꢀCꢁO bond in the cycloadduct
which is relatively slow on the NMR timescale.
In the case of the recognition mediated reaction
1
between 3 and 4, the 400 MHz H NMR spectrum of
the reaction mixture, recorded at −10°C in CD2Cl2,
displayed a sharp resonance at l 5.47 corresponding to
In order to determine the influence of recognition pro-
cess on the cycloaddition reaction, a series of reactions
were carried out between 3 and 4. All attempts to
achieve a successful conversion of 3 and 4 to 7 at
ambient pressure failed. This outcome is unsurprising
since even the facilitation afforded by the presence of
two intramolecular hydrogen bonds in exo-7 (ca. 4 kcal
mol−1) is far less than the loss of resonance energy
experienced by the system upon transformation of the
80
70
60
50
40
30
20
10
0
O
O
Cl
Cl
O
O
X
NH
R
X
N
R
Cl
Et3N / THF
X = N; R = H
X = CH; R = CH3
rt
X = N; R = H 60%
3
6
10
15
20
X = CH; R = CH3 65%
O
O
Time / h
X
N
R
N
N
Li+
Figure 3. Percentage conversion to product for the recogni-
tion-mediated reaction between 3 and 4 (filled bars) and for
the control reaction between 5 and 6. In the case of the
reaction between 3 and 4, only the exo cycloadduct is
observed. In the case of the reaction between 5 and 6, only
the endo cycloadduct is observed.
THF / rt / 3h
3: X = N; R = H 20%
5: X = CH; R = CH3 30%
Scheme 1.

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R. Bennes et al. / Tetrahedron Letters 42 (2001) 2377–2380
the bridgehead proton (H1) in cycloadduct 7. This
chemical shift and the absence of any significant cou-
pling between H1 and H2 is only consistent4 with the
product of the reaction between 3 and 4 having exo
stereochemistry.
neering and Physical Sciences Research Council
(GR/M42824) and by the University of Reading.
References
1. Spand, T. F.; Garraffo, H. M.; Edwards, M. W.; Daly, J.
W. J. Am. Chem. Soc. 1992, 114, 3475.
O
N
O
N
N
N
exo-7
endo-7
H
H
2. Chen, Z.; Trudell, M. L. Chem. Rev. 1996, 96, 1179.
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4302.
O
O
H
H
N
N
N
N
O
O
CO2H
O
CO2H
H2
H2
H1
H1
O
In the case of the control reaction between 5 and 6, the
4. (a) Drew, M. G. B.; George, A. V.; Isaacs, N. S.; Rzepa,
H. S. J. Chem. Soc., Perkin Trans. 1 1985, 1277; (b)
Kotsuki, H.; Mori, Y.; Nishizawa, H.; Ochi, M.; Mat-
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5. (a) Booth, C. A.; Philp, D. Tetrahedron Lett. 1998, 39,
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1087; (d) Booth, C. A. Ph.D. Thesis; University of Birm-
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versity of Birmingham: UK, 2000.
6. All molecular mechanics calculations were carried out
using the AMBER* forcefield as implemented in Macro-
model (Version 5.0: Mohamadi, F.; Richards, N. G. J.;
Guida, W. C.; Hendrickson, T.; Still, W. C. J. Comput.
Chem. 1990, 11, 440) together with the GB/SA solvation
model for CHCl3. All calculations were performed on a
Silicon Graphics Indigo2 computer. Conformational
searching was carried out using 10 000 step Monte Carlo
simulations, and all conformation located within 50 kJ of
the global minimum were minimised.
1
400 MHz H NMR spectrum of the reaction mixture,
recorded at −10°C in CD2Cl2, displayed a sharp reso-
nance at l 5.35 corresponding to the bridgehead proton
(H1) in cycloadduct. This chemical shift and the signifi-
cant coupling (3JHH=5.7 Hz) between H1 and H2 are
only consistent4 with the product of the reaction
between 5 and 6 having endo stereochemistry.
In conclusion, we have demonstrated the rational
design of a recognition-based system which is capable
of accelerating the Diels–Alder cycloaddition between a
benzoylpyrrole and a maleimide under high pressure
conditions. Further, the use of molecular recognition
facilitates the formation of the disfavoured7 exo
cycloadduct (exo-7) with complete selectivity through
the intermediacy of two hydrogen bonds which persist
in exo-7. Therefore, the overall effect of the introduc-
tion of molecular recognition is both to accelerate the
reaction and to reverse the product stereochemistry.
Acknowledgements
7. It should be noted that under high pressure conditions, the
endo cycloadduct will be favoured as it has a more com-
pact transition state and, hence, a larger change in the free
volume as the system moves towards the transition state.
This research was supported by the University of Birm-
ingham (Postgraduate Studentship to RMB), the Engi-
.
.