Catalytic multicomponent synthesis of highly substituted pyrroles utilizing a one-pot sila-stetter/paal-knorr strategy

Article abstract of DOI:10.1021/ol049044t

(Equation Presented) A multicomponent synthesis of highly substituted pyrroles catalyzed by thiazolium salts has been disclosed. The reaction employs an acyl anion conjugate addition reaction of acylsilanes (sila-Stetter) and unsaturated ketones to generate 1,4-dicarbonyl compounds in situ. The subsequent addition of various amines promotes a Paal-Knorr reaction, affording the desired pyrrole nucleus in an efficient one-pot process.

Full text of DOI:10.1021/ol049044t

ORGANIC
LETTERS
2004
Vol. 6, No. 14
2465-2468
Catalytic Multicomponent Synthesis of
Highly Substituted Pyrroles Utilizing a
One-Pot Sila-Stetter/Paal−Knorr Strategy
Ashwin R. Bharadwaj and Karl A. Scheidt*
Northwestern UniVersity, Department of Chemistry, 2145 Sheridan Road,
EVanston, Illinois 60208
scheidt@northwestern.edu
Received May 24, 2004
ABSTRACT
A multicomponent synthesis of highly substituted pyrroles catalyzed by thiazolium salts has been disclosed. The reaction employs an acyl
anion conjugate addition reaction of acylsilanes (sila-Stetter) and unsaturated ketones to generate 1,4-dicarbonyl compounds in situ. The
subsequent addition of various amines promotes a Paal−Knorr reaction, affording the desired pyrrole nucleus in an efficient one-pot process.
The pyrrole heterocycle is an important structural attribute
in many bioactive natural products,1 therapeutic compounds,2
and new organic materials.3 Consequently, the efficient
assembly of this class of molecule is a significant objective
in synthetic chemistry. The construction of the pyrrole ring
system typically involves a multistep approach from pre-
formed intermediates, such as the classic Paal-Knorr cy-
clization reaction of 1,4-dicarbonyl compounds and amines.4
More contemporary transition-metal-based strategies include
the addition of chromium carbenes to dipolarophiles,5a the
copper(I)-catalyzed cycloisomerization of alkynyl imines,5b
and rhodium-catalyzed reactions, either N-H insertions5c or
the combination of isonitriles and 1,3-diketones.5d However,
an alternate and more direct strategy is the combination of
multiple reactants in a single flask to afford the pyrrole core.
Herein, we report the realization of a one-pot, multicompo-
nent assembly of highly substituted pyrroles (3) utilizing a
sila-Stetter/Paal-Knorr sequence between acylsilanes (1),
unsaturated carbonyl compounds (2), and amines catalyzed
by thiazolium salt 4 (Scheme 1, eq 1).
Scheme 1. General Multicomponent Pyrrole Synthesis
(1) (a) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435-446 and references
therein. (b) Hoffmann, H.; Lindel, T. Synthesis 2003, 1753-1783. (c)
Fu¨rstner, A. Angew. Chem., Int. Ed. 2003, 42, 3582-3603. (d) Lindquist,
N.; Fenical, W.; Van Duyne, G. D.; Clardy, J. J. Org. Chem. 1988, 53,
4570-4574. (e) Boger, D. L.; Boyce, C. W.; Labroli, M. A.; Sehon, C. A.;
Jin, Q. J. Am. Chem. Soc. 1999, 121, 54-62.
(2) (a) Colotta, V.; Cecchi, L.; Melani, F.; Filacchioni, G.; Martini, C.;
Giannaccini, G.; Lucacchini, A. J. Med. Chem. 1990, 33, 2646-2651. (b)
Cozzi, P.; Mongelli, N. Curr. Pharm. Des. 1998, 4, 181-201. (c) Huffman,
J. W. Curr. Med. Chem. 1999, 6, 705-720.
(3) (a) Curran, D.; Grimshaw, J.; Perera, S. D. Chem. Soc. ReV. 1991,
20, 391-404. (b) Deronzier, A.; Moutet, J.-C. Curr. Top. Electrochem.
1994, 3, 159-200. (c) Lee, C. F.; Yang, L. M.; Hwu, T. Y.; Feng, A. S.;
Tseng, J. C.; Luh, T. Y. J. Am. Chem. Soc. 2000, 122, 4992-4993 and
references therein.
Multicomponent reactions (MCRs) are becoming increas-
ingly prevalent due to their improved efficiency, reduced
waste, and rapid access of structural diversity.6 In this vein,
transition-metal-catalyzed MCRs have been developed for
the synthesis of pyrroles.7 However, as an alternative
organocatalytic MCR approach,8 we envisioned harnessing
the thiazolium-catalyzed sila-Stetter reaction9 to synthesize
1,4-dicarbonyl compounds in situ that can then be directly
converted to pyrroles simply upon the addition of an amine.
10.1021/ol049044t CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/09/2004

Notably, this single flask approach avoids transition-metal
catalysts that can contaminate final compounds, employs
readily available materials, and has the potential to directly
install a number of elements of diversity around the pyrrole
nucleus.
Table 1. Optimization of Sila-Stetter/Paal-Knorr Reaction
Conditionsa
Our exploration of the feasibility of this one-pot reaction
sequence relied on our development of the sila-Stetter
reaction.9 As a component of our comprehensive program
investigating acylsilanes as efficient acyl anion precursors,
we hypothesized that the Paal-Knorr cyclization conditions
could be directly linked with our sila-Stetter process. The
combination of an amine base (DBU, 1,8-diazabicyclo[5.4.0]-
undec-7-ene) and commercially available thiazolium salt 4
produces the necessary nucleophilic zwitterionic catalyst in
situ which promotes the acyl anion conjugate addition of
acylsilane 1a10 to R,â-unsaturated ketones (2). To optimize
the conversion of the resulting intermediate 1,4-dicarbonyl
compound into the desired pyrrole structure, various reaction
conditions were investigated (Table 1, eq 2).
Initially, a limited range of Brønsted acids was added
directly to the reaction after consumption of the conjugate
acceptor (5) followed by aniline and 4 Å molecular sieves
(entries 1-4). Gratifyingly, after heating the reaction for an
additional 8 h, the substituted pyrroles were isolated in
moderate to good yields. The overall process is only mildly
dependent on acid composition, with the best yield (70%,
entry 5) obtained with p-toluenesulfonic acid (TsOH) and
only 20 mol % of thiazolium precatalyst 4. The observed
one-pot, optimal yield for this sequential process indicates
that the sila-Stetter and Paal-Knorr reactions are each g80%
efficient on average. In addition, a tetrasubstituted pyrrole
(C1-C4) can be accessed utilizing an R,â-disubstituted
unsaturated ketone (entry 7).
entry
R
R1
acid
4 (mol %) yielde (%) pyrrole
1
2
3
4
5
6
7
4Me-Ph
4Me-Ph
4Me-Ph
4Me-Ph
4Me-Ph
4Me-Ph
Ph
H
H
H
H
H
H
TFAb
H2SO4
HClc
TsOHd
TsOHd
TsOHd
30
30
30
30
20
10
20
52
54
63
62
70
48
35
6
6
6
6
6
6
7
c
COPh TsOHd
a Reaction conditions: 20 mol % of 4 and 30 mol % of DBU (1,8-
diazabicyclo[5.4.0]undec-7-ene), 4 equiv of i-PrOH; 0.8 M at 70 °C for 8
h. Amine, acid, and 4 Å sieves then added for an additional 8 h. See the
Supporting Information for details. b 1 equiv. c Catalytic acid. d 2 equiv.
e Isolated yield after purification.
With the optimal acyl anion addition/pyrrole formation
conditions identified, the scope of this reaction sequence was
examined (Table 2, eq 3). To this end, assorted acylsilanes
Table 2. Scope of the Sila-Stetter/Paal-Knorr Reactiona
yieldb
(4) (a) Knorr, L. Chem. Ber. 1884, 17, 1635-1642. (b) Paal, C. Chem.
Ber. 1885, 18, 367-371. (c) Amarnath, V.; Anthony, D. C.; Amarnath, K.;
Valentine, W. M.; Wetterau, L. A.; Graham, D. G. J. Org. Chem. 1991,
56, 6924-6931. (d) Pyrroles, Part II; Jones, R. A., Ed; Wiley: New York,
1992. (e) Gribble, G. W. In ComprehensiVe Heterocyclic Chemistry II;
Katrizky, A. R., Rees, C. W., Scriven, E. F., Eds.; Pergamon Press: Oxford,
1996; Vol. 2, p 207. For a solid-phase approach to the synthesis of pyrroles
from 1,4-dicarbonyl compounds, see: Raghavan, S.; Anuradha, K. Synlett
2003, 711-713.
(5) (a) Merlic, C. A.; Baur, A.; Aldrich, C. C. J. Am. Chem. Soc. 2000,
122, 7398-7399. (b) Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J. Am.
Chem. Soc. 2001, 123, 2074-2075. (c) Wang, Y. L.; Zhu, S. Z. Org. Lett.
2003, 5, 745-748. (d) Takaya, H.; Kojima, S.; Murahashi, S. I. Org. Lett.
2001, 3, 421-424.
(6) (a) Marko, I. E.; Mekhalfia, A.; Murphy, F.; Bayston, D. J.; Bailey,
M.; Janousek, Z.; Dolan, S. Pure Appl. Chem. 1997, 69, 565-570. (b) Orru,
R. V.; de Greef, M. Synthesis 2003, 1471-1499. For a recent example of
a multicomponent organocatalytic process, see: Frantz, D. E.; Morency,
L.; Soheili, A.; Murry, J. A.; Grabowski, E. J. J.; Tillyer, R. D. Org. Lett.
2004, 5, 843-846.
(7) (a) Braun, R. U.; Zeitler, K.; Mu¨ller, T. J. J. Org. Lett. 2001, 3, 3297-
3300. (b) Dhawan, R.; Arndtsen, B. A. J. Am. Chem. Soc. 2004, 126,
468-469.
(8) For recent reviews on organocatalysis, see: (a) Dalko, P. I.; Moisan,
L. Angew. Chem., Int. Ed. 2001, 40, 3726-3748. (b) List, B. Synlett 2001,
1675-1686. (c) Schreiner, P. R. Chem. Soc. ReV. 2003, 32, 289-296.
(9) Mattson, A. E.; Bharadwaj, A. R.; Scheidt, K. A. J. Am. Chem. Soc.
2004, 126, 2314-2315.
(10) For reviews on acylsilanes in organic chemistry, see: (a) Bonini,
B. F.; Comes-Franchini, M.; Fochi, M.; Mazzanti, G.; Ricci, A. J.
Organomet. Chem. 1998, 567, 181-189. (b) Cirillo, P. F.; Panek, J. S.
Org. Prepr. Proced. Int. 1992, 24, 553-582. (c) Moser, W. H. Tetrahedron
2001, 57, 2065-2084. For a recent example of acylsilanes employed as
acyl anions in the benzoin reaction, see: Xin, L. H.; Potnick, J. R.; Johnson,
J. S. J. Am. Chem. Soc. 2004, 126, 3070-3071.
entry
R
X
R1
R2
(%) pyrrole
1
2
3
4
5
6
7
8
9
Ph
SiMe3
SiMe3
SiMe3
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
66
71
61
69
71
70
62
58
69
80
9
4-Me-Ph
4-Cl-Ph
cyclohexyl SiPhMe2 Ph
10
11
12
13
6
14
15
16
17
CH3
Ph
Ph
SiPhMe2 Ph
SiMe3
SiMe3
SiMe3
SiMe3
SiMe3
4-Me-Ph
3-Me-Ph
4-Cl-Ph
4-OMe-Ph Ph
Ph 4-Cl-Ph
Ph
4-Cl-Ph
10 Ph
a Reaction conditions: 20 mol % of 4 and 30 mol % of DBU, 4 equiv
of i-PrOH; 0.8 M at 70 °C for 8 h. Amine, TsOH, and 4 Å sieves then
added for an additional 8 h. b Isolated yield after purification.
and R,â-unsaturated ketones were employed with aniline
added as the amine component. The process is tolerant of
aryl acylsilanes (entries 1-3) as well as alkyl acylsilanes
(entries 4 and 5). Additionally, the substituents on the silyl
group can be either trialkyl (SiMe3) or aryldialkyl (SiPhMe2)
without affecting conversion or yield. With regard to the
electrophilic component, various aryl substituents can be
incorporated onto the unsaturated ketone scaffold to afford
good yields of the polyaromatic pyrroles (entries 6-10).
Currently, R,â-unsaturated ketones possessing acidic protons
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Org. Lett., Vol. 6, No. 14, 2004

For example, substituted anilines are good nucleophiles for
this reaction whether they are electron-rich or electron-
deficient (entries 1-3). The direct addition of ammonium
acetate to the reaction affords a good yield (62%) of the N-H
pyrrole (entry 4). Unbranched primary amines such as meth-
ylamine (70% yield, entry 5) and benzylamine (65% yield,
entry 7) along with branched primary amines (cyclohex-
ylamine, entry 8, 63%) can be efficiently incorporated into
the pyrrole framework. Additionally, optically active primary
amines can be utilized for this reaction. Related chiral pyrrole
compounds have been used in the synthesis of indolizidine
alkaloids,11 and they have been identified as highly selective
potential treatments for diabetes.12 The addition of (S)-R-
methylbenzylamine or (R)-sec-butylamine affords the chiral
pyrroles in moderate yield (entries 9 and 10). Interestingly,
the controlled addition (1.5 equiv) of a diamine, such as 1,4-
phenylenediamine, affords the monopyrrole in good yield
(entry 11, 70%). This process has the potential to access
unsymmetrical aryl-bridged bis-pyrroles, a class of com-
pounds that show promise as new magnetic materials.13
Table 3. Survey of Amines for Pyrrole Synthesisa
Although this multihour process affords good yields of
pyrroles, we felt that a more efficient means of heating could
reduce the time required and thus improve the overall
process. Gratifyingly, the use of microwave heating drasti-
cally reduces the reaction time.14
The first heating cycle for 15 min at 160 °C combines 1a
and R,â-unsaturated ketone 29 in the presence of 20 mol %
4, 30 mol % DBU, and 4 equiv of 2-propanol. This sequence
is followed by the addition of aniline and TsOH and a second
15 min heating cycle at 160 °C and smoothly affords the
desired pyrrole (6) in 55% yield in only 30 min (Scheme 2).
This streamlined approach generates the target heterocycle
in 3% of the time required using conventional heating (30
min vs 16 h).
Scheme 2. Microwave-Assisted Sila-Stetter/Paal-Knorr
Reaction
a Reaction Conditions: 20 mol % of 4 and 30 mol % of DBU, 4 equiv
of i-PrOH; 0.8 M at 70 °C for 8 h. Amine, TsOH,and 4 Å sieves then
added for an additional 8 h. b Isolated yield after purification.
(11) (a) Jefford, C. W.; Tang, Q.; Zaslona, A. J. Am. Chem. Soc. 1991,
113, 3513-3518. (b) Sardina, F. J.; Rapoport, H. Chem. ReV. 1996, 96,
1825-1872.
(12) Liu, K. G.; Lambert, M. H.; Ayscue, A. H.; Henke, B. R.; Leesnitzer,
L. M.; Oliver, W. R.; Plunket, K. D.; Xu, H. E.; Sternbach, D. D.; Willson,
T. M. Bioorg. Med. Chem. Lett. 2001, 11, 3111-3113.
(13) Domingo, V. M.; Alema´n, C.; Brillas, E.; Julia´, L. J. Org. Chem.
2001, 66, 4058-4061 and references therein.
(e.g., (E)-1-phenylbut-2-en-1-one or (E)-4-phenylbut-3-en-
2-one) do not proceed to 100% conversion and have not been
examined fully in the context of this reaction.
(14) Minetto, G.; Raveglia, L. F.; Taddei, M. Org. Lett. 2004, 6, 389-
392. For a review on the use of microwave irradiation in organic synthesis,
see: Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001,
57, 9225-9283.
The modularity of this pyrrole-forming reaction sequence
is demonstrated by intercepting the 1,4-dicarbonyl com-
pounds formed in situ with various amines (Table 3, eq 4).
Org. Lett., Vol. 6, No. 14, 2004
2467

Our proposed working catalytic cycle (Scheme 3) involves
the addition of a neutral carbene/zwitterionic species (I,
generated in situ from the exposure of thiazolium salt I to
DBU) to an acylsilane.15 This nucleophilic addition initiates
attenuated reactivity of the acylsilane, nucleophile III
undergoes preferential addition to the more electrophilic R,â-
unsaturated ketone. The resulting intermediate IV reforms
the acyl anion carbonyl which liberates the heterocyclic
catalyst (I) and subsequently produces the 1,4-dicarbonyl
compound V. Once the starting R,â-unsaturated ketone is
consumed, the direct addition of a primary amine, acid, and
dehydrating agent (4 Å molecular sieves) to reaction followed
by heating generates the desired pyrroles via the standard
Paal-Knorr reaction manifold (6-28).
Scheme 3. Proposed Catalytic Cycle
In conclusion, the process described herein is an efficient
one-pot catalytic assembly of pyrroles via the thiazolium-
catalyzed acyl anion conjugate addition of acylsilanes. This
approach utilizes a neutral organic molecule as a catalyst, is
multicomponent in nature, and can rapidly install substitution
at multiple positions of the pyrrole nucleus. Further exten-
sions of this sila-Stetter/heterocycle formation strategy and
applications of these methodologies are underway and will
be reported in future publications.
Acknowledgment. Financial support for this work has
been provided by Northwestern University and an NSF
CAREER Award to K.A.S. (CHE-0348979). We thank Jon
Pokorski (Appella Group, NU) for assistance with mass
spectrometry, Wacker Chemical Corp. for providing orga-
nosilanes, and Biotage, Inc., for the use of a microwave
reactor.
a 1,2-silyl group migration (Brook rearrangement)16 and
produces intermediate enolsilane II. The alcohol additive
present in the reaction effectively desilylates II, thereby
generating the “Breslow intermediate” III.17 Due to the
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL049044T
(15) For mechanistic discussions of the related thiazolium-catalyzed
benzoin reaction, see: (a) Breslow, R.; Schmuck, C. Tetrahedron Lett. 1996,
37, 8241-8242. (b) Chen, Y. T.; Barletta, G. L.; Haghjoo, K.; Cheng, J.
T.; Jordan, F. J. Org. Chem. 1994, 59, 7714-7722. (c) White, M. J.; Leeper,
F. J. J. Org. Chem. 2001, 66, 5124-5131.
(16) (a) Brook, A. G.; LeGrow, G. E.; MacRae, D. M. Can. J. Chem.
1967, 45, 239-253. (b) Brook, A. G. Acc. Chem. Res. 1974, 7, 77-84.
(17) (a) Breslow, R. J. Am. Chem. Soc. 1958, 79, 3719-3726. (b)
Breslow, R.; Kim, R. Tetrahedron Lett. 1994, 35, 699-702. The use of
3-octanol in the reaction affords 3-trimethylsilyloxyoctane (observed by
gas chromatography), thus implicating the alcohol as the ultimate silyl
acceptor.
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Org. Lett., Vol. 6, No. 14, 2004