Regioselective synthesis of tetrasubstituted pyrroles by 1,3-dipolar cycloaddition and spontaneous decarboxylation

Article abstract of DOI:10.1021/ol8022193

We developed a novel regioselective synthesis of tetrasubstituted pyrroles via the classic 1,3-dipolar cycloaddition of α,β-unsaturated benzofuran-3(2H)-one and azlactones (1) followed by spontaneous decarboxylation. The complete regiochemical control of tetrasubstituted pyrroles was confirmed by the orthogonal synthesis of complementary regioisomers (7a and 7b) simply by using different azlactones (1a and 1b, respectively).

Full text of DOI:10.1021/ol8022193

ORGANIC
LETTERS
2009
Vol. 11, No. 1
17-20
Regioselective Synthesis of
Tetrasubstituted Pyrroles by 1,3-Dipolar
Cycloaddition and Spontaneous
Decarboxylation
Yongju Kim, Jonghoon Kim, and Seung Bum Park*
Department of Chemistry, Seoul National UniVersity, Seoul 151-747, Korea
sbpark@snu.ac.kr
Received September 23, 2008
ABSTRACT
We developed a novel regioselective synthesis of tetrasubstituted pyrroles via the classic 1,3-dipolar cycloaddition of r,ꢀ-unsaturated benzofuran-
3(2H)-one and azlactones (1) followed by spontaneous decarboxylation. The complete regiochemical control of tetrasubstituted pyrroles was
confirmed by the orthogonal synthesis of complementary regioisomers (7a and 7b) simply by using different azlactones (1a and 1b, respectively).
Many bioactive natural products and synthetic drugs
contain a pyrrole moiety as their key skeleton.1 Pyrrole is
one of the well-known heterocycles that displays remarkable
biological activities such as antibacterial,2 antiviral,3 anti-
tumor,4 antioxidative,5 and anti-inflammatory properties.6
In particular, tetra- and pentasubstituted pyrroles have been
identified as pharmacophores for the anti-inflammatory and
anticancer drug: atorvastatin (Lipitor), a top-selling drug that
is used as an antihyperlipidemic agent.7 Therefore, highly
substituted pyrroles have been one of the major targets in
synthetic chemistry. Many methods for the efficient synthesis
of pyrrole have been reported, which can be categorized as
follows: the classical Paal-Knorr synthesis,8 the Hantzsch
procedure,9 cyclization,10 and cycloaddition strategies.7d,11
Although these synthetic protocols have been proven to be
(1) (a) Boger, D. L.; Boyce, C. W.; Labroli, M. A.; Sehon, C. A.; Jin,
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Hudak, V.; Malakian, K.; Lockhead, S.; Olland, A.; Svenson, K.; Terefenko,
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Zhang, P.; Winnerker, R. C.; Wrobel, J. J. Med. Chem. 2005, 48, 5092. (b)
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Kumakura, S.; Inoue, S.; Suzuki, K.; Nakao, A.; Kawara, A.; Kimura, T.
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10.1021/ol8022193 CCC: $40.75
Published on Web 12/02/2008
2009 American Chemical Society

useful for the synthesis of pyrrole derivatives, the desired
products are yielded as regioisomeric mixtures, particularly
in the case of cycloaddition strategies, which limits the scope
of synthetic modification. Further, there are only a limited
number of synthetic reports on the control of the regiochem-
istry of pyrroles prepared via cycloaddition.7d,11 In fact, most
of the reported cycloaddition approaches have used sym-
metric alkynes to avoid the regioselectivity issue or have
achieved only low regioselectivity when using nonsymmetric
alkynes or alkenes.
cycloaddition was generally achieved using disubstituted
alkynes as dipolarophiles, and the best regioselectivity was
achieved in the regioisomeric ratio of 5:1.11c We confirmed
the complete regiochemical control of tetrasubstituted pyr-
roles by the orthogonal synthesis of complementary regio-
isomers (7a and 7b) simply using different azlactones (1a
and 1b) from N-acetylated phenylalanine and N-2-phenyl-
acetylated alanine, respectively (Scheme 1). The two resulting
To address this issue, we pursued a regioselective synthesis
of tetrasubstituted pyrroles 3 via the 1,3-dipolar cycloaddition
of R,ꢀ-unsaturated benzofuran-3(2H)-ones 210c with azlac-
tones 1,11a,12 followed by spontaneous decarboxylation. To
accelerate the 1,3-dipolar cycloaddition, we introduced Lewis
acids and bases to activate azlactones 1.12d After a systematic
screening of a variety of Lewis acids [AgOAc, AgOTf,
Ag2O, Cu(OAc)2, Cu2O] and bases [2,6-lutidine, TEA,
DBU], we found that though AgOAc successfully catalyzed
the cycloaddition of 1 with 2, the presence of base did not
significantly influence the reaction rate. In addition, compared
to the conventional thermal reaction, microwave irradiation13
gave better results in terms of yields and reaction time.
Therefore, we finalized the optimization of the standard
condition as follows: microwave irradiation with 10 mol %
AgOAc in anhydrous THF. As shown in Figure 1, 2 serves
Scheme 1
.
Orthogonal Synthesis of Complementary
Regioisomers
regioisomers were confirmed by X-ray crystallography and
1
1D NOE H NMR spectroscopy (see Supporting Informa-
tion). Therefore, we can incorporate four different substit-
uents on pyrroles simply by using different building blocks
and thus maximize the molecular diversity on the pyrrole
core skeleton.
To gain insight into the mechanism of this transformation,
various substituents at the R1 and R2 positions of dipolaro-
philes 2 were probed for their electronic effects in the 1,3-
dipolar cycloaddition reaction. Upon substituting R2 with
electron-donating groups, the reaction time was found to
increase from 10 to 35 min (Table 1, entries 1-4). Similarly,
when R1 was substituted with electron-donating groups and
a 2-methoxyphenyl moiety was fixed at the R2 position, the
reduction of reaction rate was observed (Table 1, entries 4,
5, and 7). By using electron-withdrawing groups such as a
bromo or nitro group at the R1 position, the 1,3-dipolar
cycloaddition of 2 with 2-methyl-4-phenyloxazol-5(4H)-one
4 exhibited excellent regioselectivity and yields (Table 1,
Figure 1. Potential mechanism for regioselective pyrrole synthesis
via [3 + 2] cycloaddition and spontaneous decarboxylation.
(9) (a) Hantzsch, A. Ber. Dtsch. Chem. Ges. 1890, 23, 1474. (b) Palacios,
F.; Aparico, D.; de los Santos, J. M.; Vicario, J. Tetrahedron 2001, 57,
1961. (c) Trautwein, A. W.; Su¨ꢀmuth, R. D.; Jung, G. Bioorg. Med. Chem.
Lett. 1998, 8, 2381.
as nonsymmetric dipolarophiles leading to the formation of
a unique bridge-head intermediate II through the regio-
selective [3 + 2] cycloaddition with 1,3-dipole 1 (azlac-
tones).12c,d The transient intermediate II was converted to
pyrrole derivatives through spontaneous decarboxylation and
subsequent ring opening of benzofuran-3(2H)-one, which is
a key step for this transformation.
The nearly complete control of the regiochemistry in
tetrasubstituted pyrroles was achieved in high to excellent
yields via the unique combination of R,ꢀ-unsaturated ben-
zofuran-3(2H)-one 2 with azlactones 1. To the best of our
knowledge, the generation of pyrroles through [3 + 2]
(10) (a) Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J. Am. Chem.
Soc. 2001, 123, 2074. (b) Tejedor, D.; Gonzalez-Cruz, D.; Garcia-Tellado,
F.; Marrero-Tellado, J. J.; Rodriguez, M. L. J. Am. Chem. Soc. 2004, 126,
8390. (c) Dawood, K. M. Tetrahedron 2005, 61, 5229.
(11) (a) Padwa, A.; Pearson, W. H. Synthetic Applications of 1,3-Dipolar
Cycloaddition Chemistry Toward Heterocycles and Natural Products; John
Wiley: New York, 2002. (b) Misra, N. C.; Panda, K.; Junjappa, H. J. Org.
Chem. 2006, 72, 1246. (c) Dhawan, R.; Arndtsen, B. A. J. Am. Chem. Soc.
2004, 126, 468. (d) Cyr, D. J. S.; Arndtsen, B. A. J. Am. Chem. Soc. 2007,
129, 12366. (e) Kamijo, S.; Kanazawa, C.; Yamamoto, Y. J. Am. Chem.
Soc. 2005, 127, 9260. (f) Palmer, D. C. Oxazoles: Synthesis, Reactions,
and Spectroscopy; Wiley-Interscience: New York, 2003.
(12) (a) Dhawan, R.; Dghaym, R. D.; Arndtsen, B. A. J. Am. Chem.
Soc. 2003, 125, 1474. (b) Be´langer, G.; April, M.; Dauphin, E.; Roy, S. J.
Org. Chem. 2007, 72, 1104. (c) Melhado, A. D.; Luparia, M.; Toste, F. D.
J. Am. Chem. Soc. 2007, 129, 12638. (d) Peddibhotla, S.; Tepe, J. J. J. Am.
Chem. Soc. 2004, 126, 12776.
(13) (a) Lerestif, J. M.; Perrocheau, J.; Tonnard, F.; Bazureau, J. P.;
Hamelin, J. Tetrahedron 1995, 51, 6757. (b) D´ıaz-Ortiz, A.; D´ıez-Barra,
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785.
(8) (a) Paal, C. Ber. Dtsch. Chem. Ges. 1885, 18, 367. (b) Trost, B. M.;
Doherty, G. A. J. Am. Chem. Soc. 2000, 122, 3801. (c) Braun, R. U.;
Mueller, T. J. J. Synthesis 2004, 2391.
18
Org. Lett., Vol. 11, No. 1, 2009

Table 1. Electronic Effect of R,ꢀ-Unsaturated Benzofuranones
entry
cpd
R1
R2
time (min)
regioisomeric ratioa
yield (%)
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5-Br
5-Br
5-Br
5-Br
5-NO2
5-OMe
5-OMe
4-OMe
2-nitrophenyl
phenyl
10
25
25
35
15
35
45
75
.99:1
.99:1
.99:1
.99:1
.99:1
98:2
90
87
93
94
87
87
85
84
2-ethylphenyl
2-methoxyphenyl
2-methoxyphenyl
2-bromophenyl
2-methoxyphenyl
2-methoxyphenyl
5g
5h
91:9
97:3
a Regioisomeric ratio was determined by LC-MS of crude product.
entries 1-5). However, when a methoxy substituent was
introduced at the R1 position, only moderate regioselectivity
was obtained, even when an electron-withdrawing group was
present at R2 position (Table 1, entries 6-8). In general, we
witnessed a decrease in the regioselectivity along with an
extension in the reaction time. Thus, we successfully
demonstrated the substrate generality of R,ꢀ-unsaturated
benzofuran-3(2H)-ones 2 using various substituents at the
R1 and R2 positions. We also confirmed that our novel
synthetic protocol for tetrasubstituted pyrroles can offer
excellent regioselectivity when the substituent at R1 position
is an electron-withdrawing group, particularly a 5-bromo
group.
lowest unoccupied molecular orbital (LUMO), whereas
azlactone 1 acts as the highest occupied molecular orbital
(HOMO) of the [3 + 2] cycloaddition. To rationalize this
reaction pattern, theoretical calculation was carried out using
Materials Studio 4.2 program.14 The frontier molecular
orbital (FMO) energy calculation generates HOMO and
LUMO energies of 2 and 4, either as dipole or as dipolaro-
phile. As shown in Table 2, ∆E(|LUMO(2) - HOMO(4)|)
is systematically smaller than ∆E(|HOMO(2) - LUMO(4)|),
which is consistent with the experimental presumption, that
is, that 2 serves as LUMO and 4 as HOMO.
At this point, we proceeded to validate the reaction
generality using various substituents at the R2, R3, and R4
positions with a fixed 5-bromo group at the R1 position in
order to ensure high regioselectivity (Table 3). The tolerance
at the R2 position was demonstrated through the introduction
of various heterocyclic moieties: 4-pyridinyl (7a-j), 2-meth-
On the basis of the fact that electron-withdrawing groups
on either R1 and R2 positions of dipolarophile 2 can
significantly enhance the reaction rate, we could speculate
that R,ꢀ-unsaturated benzofuran-3(2H)-one 2 acts as the
Table 2. HOMO and LUMO Energy of Individual Reaction Partners: R,ꢀ-Unsaturated Benzofuran-3(2H)-ones 2 and
2-Methyl-4-phenyloxazol-5(4H)-one 4
HOMO (eV)
LUMO (eV)
4 LUMO (eV)
4 HOMO (eV)
∆E(|HOMO(2) - LUMO(4|)
∆E(|LUMO(2) - HOMO(4)|)
2
5
-5.95799
-4.00029
-5.60133
-3.40989
-5.51526
-3.36442
-5.32601
-3.24972
-5.50824
-3.40798
-5.32013
-3.28923
-4.89808
-2.86642
-4.97911
-2.70919
-1.78575
-5.96607
-1.78575
-5.96607
-1.78575
-5.96607
-1.78575
-5.96607
-1.78575
-5.96607
-1.78575
-5.96607
-1.78575
-5.96607
-1.78575
-5.96607
4.17224
1.96578
3.81558
2.55618
3.72951
2.60165
3.54026
2.71635
3.72249
2.55809
3.53438
2.67684
3.11233
3.09965
3.19337
3.25688
2a
2b
2c
2d
2e
2f
5a
5b
5c
5d
5e
5f
2g
2h
5g
5h
Org. Lett., Vol. 11, No. 1, 2009
19

Table 3. Diversity of Pyrrole Synthesis via [3 + 2] Cycloaddition
compd
R2 (aldehyde)
R3 (amino acid)
R4 (acyl)
yielda (%)
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
4-pyridinyl
4-pyridinyl
4-pyridinyl
4-pyridinyl
4-pyridinyl
4-pyridinyl
4-pyridinyl
4-pyridinyl
4-pyridinyl
4-pyridinyl
2-methoxyphenyl
4-methoxyphenyl
3-nitrophenyl
2-thiophenyl
benzyl
methyl
phenyl
isobutyl
2-(methylthio)ethyl
(Phe)
(Ala)
(Phg)
(Leu)
(Met)
methyl
benzyl
90
75
93
79
70
86
97
94
91
95
91
97
91
84
methyl
methyl
methyl
methyl
cyclohexyl
phenyl
benzyl
n-butyl
methyl
methyl
methyl
methyl
(1H-imidazol-5-yl)methyl (His)
phenyl
phenyl
phenyl
phenyl
methyl
phenyl
phenyl
phenyl
(Phg)
(Phg)
(Phg)
(Phg)
(Ala)
(Phg)
(Phg)
(Phg)
a Yield was obtained on the basis of the recovered starting materials 6.
oxyphenyl (7k), 4-methoxyphenyl (7l), 3-nitrophenyl (7m),
and 2-thiophenyl group (7n). In addition, the scope of the
substituents at the R3 positions of azlactones 1 was system-
atically expanded by using natural or unnatural amino acids
(Phe, Ala, Leu, Met, His, and Phg). In case of Met and His,
the desired pyrroles 7e and 7f were prepared in moderate to
good yields even with the presence of unprotected internal
nucleophiles. Finally, the introduction of various substituents
at the R4 position was pursued by using different acylating
agents (acetyl, benzoyl, 2-phenylacetyl, pentanoyl, and cyclo-
hexanecarbonyl). In all the cases of this study, substitutents
at the R4 position did not influence the regioselectivity and
reaction rate except in the case of benzoylation, which
demonstrated the slightly reduced regioselectivity (see Sup-
porting Information).
molecular diversity on biologically useful tetrasubstituted
pyrroles can be introduced by simply changing easily
accessible moieties, i.e., hydroxyacetophenones (R1), alde-
hydes (R2), amino acids (R3), and acylating agents (R4);
further, we could achieve high regioselectivity and good to
excellent yields. Further modification and diversification as
well as the associated biological evaluation of these tetra-
substituted pyrroles will be reported in due course.
Acknowledgment. This work is supported by (1) the
Korea Science and Engineering Foundation (KOSEF); (2)
MarineBio Technology Program funded by Ministry of Land,
Transport, and Maritime Affairs (MLTM), Korea; and (3)
the Research Program for New Drug Target Discovery grant
from the Ministry of Education, Science & Technology
(MEST). Y.K. and J.K. are grateful for the fellowship award
of the Brain Korea 21 Program.
In conclusion, we developed a novel regioselective syn-
thesis of tetrasubstituted pyrroles via the classic 1,3-dipolar
cycloaddition of R,ꢀ-unsaturated benzofuran-3(2H)-one 2 and
azlactones 1 followed by spontaneous decarboxylation. In
particular, we could achieve excellent regioselectivity when
2 was substituted with electron-withdrawing groups. Thus,
Supporting Information Available: Experimental details,
1
X-ray structure, and copies of H and 13C NMR spectra of
all compounds 5a-7n. This material is available free of
charge via the Internet at http://pubs.acs.org.
(14) (a) Coppola, B. P.; Noe, M. C.; Schwartz, D. J.; L. Abdon, R.;
Trost, B. M. Tetrahedron 1994, 50, 93. (b) Domingo, L. R. Theor. Chem.
Acc. 2000, 104, 240.
OL8022193
20
Org. Lett., Vol. 11, No. 1, 2009