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Pyrrole Syntheses by Multicomponent Coupling Reactions.

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Heterocycle Synthesis
Pyrrole Syntheses by Multicomponent Coupling
Genevive Balme*
cyclization · multicomponent reactions · nitrogen
heterocycles · pyrroles · synthetic methods
Pyrroles represent an important class
of heterocycles that display remarkable
pharmacological—antibacterial, antiviral, anti-inflammatory, antitumoral, and
antioxidant—activities.[1] Furthermore,
they are useful intermediates in the
synthesis of natural products as well as
in heterocyclic chemistry[2] and they are
widely used in materials science.[3] As a
consequence, many synthetic methods
are known for the construction of the
pyrrole structure.[4] The most frequently
used methods include the classical
Hantzsch procedure,[5] the cyclocondensation of primary amines with 1,4-dicarbonyl compounds (Paal–Knorr synthesis),[6] and various cycloaddition strategies.[7] Whereas these methods have
proven very useful for the synthesis of
pyrrole derivatives, they generally involve multistep synthetic operations
that limit the scope of these reactions.
Multicomponent strategies offer significant advantages over classical linear
syntheses by combining a series of
reactions from easily available and simple precursors without the need for
isolation of the intermediates[8] to allow
the construction of complex molecules.
Such reactions are thus economically
and environmentally attractive and have
become an important area of research in
organic chemistry.
Within this context, an elegant fourcomponent reaction for the construction
[*] Dr. G. Balme
Laboratoire de Chimie Organique 1
Universit< Claude Bernard, Lyon 1, CPE
43, Bd. du 11 Novembre 1918, 69622
Villeurbanne (France)
Fax: (+ 33) 472-431-214
of substituted pyrroles was recently
reported by M4ller and co-workers.[9]
This new multicomponent approach developed on from their earlier discovery
that the Sonogashira coupling reaction
of 1-arylprop-2-yn-1-ols 1 with electrondeficient aryl or heteroaryl halides 2
followed by a base-catalyzed isomerization reaction of the coupled products
leads to the corresponding chalcones 3
(Scheme 1).[10] Building on the results of
Scheme 1. Coupling–isomerization sequence
that leads to chalcones: a) [PdCl2(PPh3)2]
(2 mol %), CuI (1 mol %), Et3N, THF, reflux;
b) Et3N.
ly integrated in a one-pot domino sequence to yield highly substituted
pyrrole derivatives in rather good yields
(Scheme 2). Thus, after the reaction of
various 1-arylprop-2-yn-1-ols 1 with
electron-deficient aryl bromides 2 under
the reaction conditions of the Sonogashira coupling–isomerization sequence
in boiling triethylamine, the newly
formed enones 3 were treated with an
aldehyde 4 in the presence of a catalytic
amount of a thiazolium salt. After the
complete conversion of 3 into the corresponding diketone 5, the subsequent
addition of primary amines 6 and acetic
acid to the reaction mixture yielded the
expected tri- or tetrasubstituted pyrroles
7. Three or four diverse functionalities
(one from each of the components 1, 2,
and 4, as well as 6 when R2 ¼
6 H) were
introduced into the products.
One of the limitation of the Paal–
Knorr reaction for the construction of
the pyrrole ring is the accessibility of the
1,4-dicarbonyl precursors. As illustrated
in the previous example, the classical
Stetter addition of aldehydes to unsaturated carbonyl electrophiles is often
these pioneering studies, M4ller and
collaborators developed an integrated
procedure for the synthesis of pyrroles
based on the reactivity
of the newly formed
enone functionality.
To this end, the palladium-catalyzed enone
synthesis was combined with a Stetter
reaction to give 1,4diketone intermediates,[11] which were
treated with primary
amines in a subsequent Paal–Knorr cyScheme 2. Palladium-catalyzed four-component assembly of
clocondensation reac- pyrroles starting from 1-arylprop-2-yn-1-ols: a) [PdCl (PPh ) ]
3 2
tion. These three re- (2 mol %), CuI (1 mol %), Et3N, reflux; b) AcOH, D. R1 = aryl,
actions were efficient- heteroaryl; R2 = H, Bn (benzyl), (CH2)2OH, CH2C(O)NH2.
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200461073
Angew. Chem. Int. Ed. 2004, 43, 6238 –6241
used for this purpose. However, during
the condensation reaction, a self-condensation of aldehydes (benzoin condensation) often occurs. Recently,
Scheidt and co-workers demonstrated
that the reaction of acylsilanes 8 with
unsaturated conjugate acceptors 9 promoted by a thiazolium salt 10 in the
presence of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) provides an attractive alternative to the classical Stetter addition of aldehydes (Scheme 3).[12]
This reaction is thought to proceed
through the addition of the carbene
catalyst 11 to 8 followed by a 1,2-silyl
group shift (Brook rearrangement) to
give the silylated intermediate 12. The
alcohol (iPrOH) then generates the acyl
anion nucleophile 13, which undergoes
selective addition to the conjugate acceptor 9 that then, after elimination of
the heterocyclic catalyst, leads to the
corresponding diketones 14. During this
process, the formation of benzoin products is not observed owing to the lower
electrophilicity of the acylsilanes 8 relative to aldehydes.
Based of this concept, a novel threecomponent approach to the synthesis of
pyrrole derivatives was developed by
the same group by the combination of
Scheme 5. Ruthenium-catalyzed propargyl alkylation of 1-arylprop-2-yn-1-ols with ketones: a) 19
(10 %), NH4BF4 (20 %). Cp* = pentamethylcyclopentadienyl.
this new variant of the Stetter reaction
with a Paal–Knorr condensation.[13] To
this end, the thiazolium-catalyzed coupling reaction of an aryl or alkyl acylsilane with a chalcone was monitored to
completion by TLC (thin-layer chromatography) analysis. Treatment of the
resulting 1,4-dicarbonyl compound in
situ with a primary amine in the presence of p-toluenesulfonic acid and molecular sieves produces the corresponding trisubstituted pyrrole derivative 15
(Scheme 4). Remarkably, in this process,
various electron-donating or electronwithdrawing aryl substituents may be
incorporated on either side of the unsaturated ketone.
Another creative convergent approach to pyrrole derivatives that starts
from 1-arylprop-2-yn-1-ols 1 was recently developed by Uemura, Hidai, and co-
Scheme 3. Thiazolium-catalyzed addition of acylsilane to unsaturated carbonyl electrophiles to
yield 1,4-dicarbonyl products: a) DBU, THF; b) iPrOH. DBU = 1,8-diazabicyclo[5.4.0]undec-7ene; R = (CH2)2OH.
Scheme 4. A sequential three-component synthesis of pyrrole derivatives by using a Sila–Stetter/
Paal–Knorr strategy: a) 10 (10 mol %), DBU (30 mol %), THF, iPrOH (4 equiv), 70 8C; b) TsOH,
molecular sieves (4 F), 70 8C. Ts = p-toluenesulfonyl; R1 = aryl, alkyl; R2 = H, aryl, alkyl.
Angew. Chem. Int. Ed. 2004, 43, 6238 –6241
workers.[14] In an early example, this
group reported a ruthenium-catalyzed
substitution of the propargyl group in
the 1-aryl-substituted propargyl alcohol
of type 1 with a dialkyl ketone such as
acetone (16) in the presence of NH4BF4
which leads to the corresponding gketoacetylene 17 (Scheme 5).[15] The
proposed mechanism involves the formation of the allenylidene complex 18
from the reaction of propargyl alcohol 1
with the thiolate-bridged diruthenium
complex 19. This is followed by a
nucleophilic attack of the enolate carbon of the ketone on the electrophilic
gC atom of the reactive intermediate 18.
Taking advantage of the formation of
water during this process, Uemura, Hidai, and co-workers further developed
an ingenious strategy for the one-pot
synthesis of substituted furans 21 by a
combination of the above Ru-catalyzed
reaction with the hydration of the alkyne moiety of 17 which was promoted
by a second catalyst in the medium
(Scheme 6). Under the reaction conditions, an intramolecular cyclization of
the newly formed 1,4 diketone 20 results
in the formation of the expected furans.
The success of this domino reaction is
highly dependent on the ability of the
two catalysts to promote sequentially the
three specific reactions: the ruthenium
catalyst 19 and PtCl2 give the best
The authors have extended these
elegant studies to the one-pot synthesis
of pyrroles 24 by carrying out this novel
multicomponent reaction in the presence of
various aniline derivatives 22. The reaction is considered to proceed through
the platinum-catalyzed nucleophilic attack of anilines on the carbon–carbon
triple bond of the g-ketoalkyne intermediate that leads to 23, followed by an
intramolecular cyclization to yield the
pyrroles 24.[16]
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
plex. Strong ligands such tional groups: Most combinations of
triphenylphosphine aliphatic/aromatic imines, acid chlorwere ineffective for the ides, and electron-rich or electron-poor
preparation of m4nch- alkynes are compatible with the mild
nones. A more labile li- reaction conditions and give access to a
gand such as the bulky variety of densely substituted pyrroles.
Interestingly, the reaction was found to
played a significant role in proceed with complete regioselectivity
sufficiently stabilizing in- with unsymmetrical alkynes and even
termediate 27 while still acetylene participated efficiently in this
allowing subsequent cat- process.
alysis steps (Scheme 5). In
The four creative metal-catalyzed
a typical procedure, a multicomponent one-pot assemblies of
mixture of imine 25, acid pyrroles highlighted herein elegantly
chloride 26, alkyne 31, demonstrate that multicomponent reacEtNiPr2, P(o-tolyl)3 (15 tions are a powerful tool for the intromol %), and the palladi- duction of molecular diversity in an
um catalyst 32 (generated efficient, economic, and environmentalScheme 6. Sequential ruthenium/platinum-catalyzed threeby the pretreatment of ly friendly way. Without doubt many
component assembly reactions of furans and pyrroles starting
(5 innovative methodologies for the synfrom 1-arylprop-2-yn-1-ols: a) 19 (10 mol %), NH4BF4
mol %) with the imine thesis of this important structure will
(20 mol %); b) PtCl2 (20 mol %).
and the acid chloride) in continue to emerge from this very
acetonitrile/THF was stir- stimulating research area.
red under CO (4 atm)at
More recently, a convergent four- 65 8C during 16 h. This optimized protocomponent assembly of substituted pyr- col produced substituted pyrrole deriv[1] a) P. A. Jacobi, L. D. Coults, J. S. Guo,
roles was developed by Dhawan and atives 33 in good yields. This strategy
S. I. Leung, J. Org. Chem. 2000, 65, 205 –
Arndtsen.[17] The strategy is based on tolerates the presence of many func213; b) A. F4rstner, Angew. Chem. 2003,
the ability of m4nchnones (1,3-oxazolium-5-oxides) to react with acetylenic
dipolarophiles to produce bicyclic intermediates that undergo a cycloreversion
reaction to yield pyrroles.[18] A recent
paper from this laboratory[19] described
the first catalytic synthesis of m4nchnones from a palladium-mediated threecomponent coupling of an imine, an acid
(Scheme 7). A new synthesis of diprotected a-amino acid derivatives 30 was
developed by the addition of methanol
in the reaction mixture to trap these
reactive intermediates. In this process,
oxidative addition of imine 25 and acid Scheme 7. Proposed mechanism for the palladium-catalyzed three-component assembly of
chloride 26 to palladium(0) gives the Pd- mInchnones—synthesis of a-amino acid derivatives.
chelated amide complex 27. Then, insertion of carbon monoxide into the Pd
C bond followed by a b-hydride elimination via the metalloketene complex 28
produces a metal-free m4nchnone 29.
The combination of the three-component assembly of m4nchnones 29 with
a cycloaddition process with acetylenic
dipolarophiles 31 present in the reaction
mixture leads to a remarkably concise
and efficient synthesis of pyrrole derivScheme 8. The four-component assembly of pyrroles which involves an intermolecular 1,3-cycloatives (Scheme 8). It was found that the addition of mInchnones with alkynes: a) 32 (5 mol %), P(o-tolyl) (15 mol %), iPr NEt, CH CN/
success of this methodology depends on THF. Tol = p-tolyl; An = p-C6H4OCH3 ; R1, R2, R3 = aryl, alkyl; R4, R5 = H, aryl, electron-withdrawing
the nature of the Pd–phosphine com- groups.
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2004, 43, 6238 –6241
115, 3706 – 3728; Angew. Chem. Int. Ed.
2003, 42, 3528 – 3603.
D. L. Boger, C. W. Boyce, M. A. Labrili,
C. A. Sehon, Q. Jin, J. Am. Chem. Soc.
1999, 121, 54 – 62.
a) L. Groenendaal, E.-W. Meijer,
J. A. J. M. Vekemans in Electronic Materials: The Oligomer Approach (Eds.:
K. M4llen, G. Wegner), Wiley-VCH,
Weinheim, 1997; b) V. M. Domingo, C.
Aleman, E. Brillas, L. Julia, J. Org.
Chem. 2001, 66, 4058 – 4061.
For reviews on pyrrole synthesis, see:
R. J. Sundberg in Comprehensive Heterocyclic Chemistry, Vol. 2 (Eds.: A. R.
Katritzky, C. W. Rees, E. F. V. Scriven),
Pergamon, Oxford, 1996, pp. 119 – 206;
V. F. Ferreira, M. C. B. V. De Souza,
A. C. Cunha, L. O. R. Pereira, M. L. G.
Ferreira, Org. Prep. Proced. Int. 2001,
33, 411 – 454.
For recent examples of the Hantzsch
synthesis, see: a) F. Palacios, D. Aparico,
J. M. de los Santos, J. Vicario, Tetrahedron 2001, 57, 1961 – 1972; b) A. W.
Trautwein, R. D. S4ßmuth, G. Jung,
Bioorg. Med. Chem. Lett. 1998, 8,
2381 – 2384.
For recent examples of the Paal–Knorr
synthesis, see: a) B. M. Trost, G. A.
Doherty, J. Am. Chem. Soc. 2000, 122,
3801 – 3810; b) B. Quiclet-Sire, L. Quintero, G. Sanchez-Jimenez, S. Z. Zard,
Synlett 2003, 75 – 78; c) M. R. Tracey,
Angew. Chem. Int. Ed. 2004, 43, 6238 –6241
R. P. Hsung, R. H. Lambeth, Synthesis
2004, 918 – 922.
a) A. R. Katritzky, S. Zhang, M. Wang,
H. C. Kolb, P. J. Steel, J. Heterocycl.
Chem. 2002, 39, 759 – 765; b) J. L. Bullington, R. R. Wolff, P. F. Jackson, J.
Org. Chem. 2002, 67, 9439 – 9442; c) K.I. Washizuka, S. Minakata, I. Ryu, M.
Komatsu, Tetrahedron 1999, 55, 12 969.
For recent reviews, see: a) G. Balme, E.
Bossharth, N. Monteiro, Eur. J. Org.
Chem. 2003, 4101 – 4111; b) C. Hulme,
V. Gore, Curr. Med. Chem. 2003, 10, 51 –
80; c) R. V. A. Orru, M. de Greef, Synthesis 2003, 1471 – 1499; d) J. Zhu, Eur. J.
Org. Chem. 2003, 1133 – 1144; e) H.
BienaymM, C. Hulme, G. Oddon, P.
Schmitt, Chem. Eur. J. 2000, 6, 3321 –
3329; f) A. DNmling, I. Ugi, Angew.
Chem. 2000, 112, 3300 – 3344; Angew.
Chem. Int. Ed. 2000, 39, 3168 – 3210;
g) L. F. Tietze, A. Modi, Med. Res. Rev.
2000, 20, 304 – 322; h) L. Weber, K.
Illgen, M. Almstetter, Synlett 1999,
366 – 374; i) S. L. Dax, J. J. McNally,
M. A. Youngman, Curr. Med. Chem.
1999, 6, 255 – 270.
R. Braun, K. Zeitter, T. J. J. M4ller, Org.
Lett. 2001, 3, 3297 – 3300.
T. J. J. M4ller, M. Ansorge, D. Aktah,
Angew. Chem. 2000, 112, 1323 – 1326;
Angew. Chem. Int. Ed. 2000, 39, 1253 –
[11] J. S. Johnson, Angew. Chem. 2004, 116,
1348 – 1350; Angew. Chem. Int. Ed.
2004, 43, 1326 – 1328.
[12] A. E. Mattson, A. R. Bharadwaj, K. A.
Scheidt, J. Am. Chem. Soc. 2004, 126,
2314 – 2315.
[13] A. R. Bharadwaj, K. A. Scheidt, Org.
Lett. 2004, 6, 2465 – 2468.
[14] Y. Nishibayashi, M. Yoshikawa, Y. Inada, M. D. Milton, M. Hidai, S. Uemura,
Angew. Chem. 2003, 115, 2785 – 2788;
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[15] Y. Nishibayashi, I. Wakiji, Y. Ishii, S.
Uemura, M. Hidai, J. Am. Chem. Soc.
2001, 123, 3393 – 3394.
[16] This reaction could also be considered as
a formal Paal–Knorr reaction. Indeed,
another possible mechanistic hypothesis
is that the formation of imines, by the
reaction of anilines on the carbonyl of
intermediate 17 to generate water, occurs first. This would be followed by
hydration of the alkyne moiety to lead to
the corresponding ketoimine, which is
closely related to intermediate 23.
[17] R. Dhawan, B. A. Arndtsen, J. Am.
Chem. Soc. 2004, 126, 468 – 469.
[18] B. Santiago, C. R. Dalton, E. W. Huber,
J. M. Kane, J. Org. Chem. 1995, 60,
4947 – 4950.
[19] R. D. Dghaym, R. Dhawan, B. A.
Arndtsen, Angew. Chem. 2001, 113,
3328 – 3330; Angew. Chem. Int. Ed.
2001, 40, 3228 – 3230.
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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