α-Unsubstituted Pyrroles by NHC-Catalyzed Three-Component Coupling: Direct Synthesis of a Versatile Atorvastatin Derivative

Article abstract of DOI:10.1002/chem.201703008

A practical one-pot cascade reaction protocol provides direct access to valuable 1,2,4-trisubstituted pyrroles. The process involves an N-heterocyclic carbene (NHC)-catalyzed Stetter-type hydroformylation using glycolaldehyde dimer as a novel C1 building-block, followed by a Paal-Knorr condensation with primary amines. The reaction makes use of simple and commercially available starting-materials and catalyst, an important feature regarding applicability and utility. Low catalyst loading under mild reaction conditions afforded a variety of 1,2,4-substituted pyrroles in a transition-metal-free reaction with high step economy and good yields. This methodology is applied in the synthesis of a versatile Atorvastatin precursor, in which a variety of modifications at the pyrrole core structure are possible.

Full text of DOI:10.1002/chem.201703008

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Accepted Article
Title: α-Unsubstituted Pyrroles by NHC-Catalyzed Three-Component
Coupling - Direct Synthesis of a Versatile Atorvastatin Derivative
Authors: Mirco Fleige and Frank Glorius
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10.1002/chem.201703008
Chemistry - A European Journal
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α-Unsubstituted Pyrroles by NHC-Catalyzed Three-Component
Coupling - Direct Synthesis of a Versatile Atorvastatin Derivative
Mirco Fleige and Frank Glorius*[a]
Abstract: A practical one-pot cascade reaction protocol provides
direct access to valuable 1,2,4-trisubstituted pyrroles. The process
involves an N-heterocyclic carbene (NHC)-catalyzed Stetter-type
hydroformylation using glycolaldehyde dimer as a novel C1 building-
block, followed by a Paal-Knorr condensation with primary amines.
The reaction makes use of simple and commercially available
starting-materials and catalyst, an important feature regarding
applicability and utility. Low catalyst loading under mild reaction
conditions afforded a variety of 1,2,4-substituted pyrroles in a
transition-metal free reaction with high step economy and good yields.
This methodology is applied in the synthesis of a versatile Atorvastatin
precursor which allows a variety of modifications at the pyrrole core
structure.
Pyrroles represent important core structures, appearing in a
variety of natural products,1 organic materials2 and
pharmaceuticals (Scheme 1a).3 Amongst others, 1,2,4-
triarylpyrroles are key scaffolds of several bioactive compounds.4
Consequently, it is of high relevance to create a diverse set of
synthetic strategies to build up this scaffold.5 During Paal-Knorr
pyrrole synthesis, 1,4-dicarbonyl compounds condense with
primary amines.6 However, the general Paal-Knorr pyrrole
synthesis for the generation of 1,2,4-trisubstituted pyrroles
Scheme 1. a) Examples of pyrrole motives in natural products (left), organic
materials (middle) and pharmaceuticals (right). b) One-pot Stetter-type
hydroformylation and Paal-Knorr condensation.
requires either a multi-step synthesis and/or pre-functionalization
of starting materials. A multi-step synthesis of the 1,2,4-
triarylsubstitued pyrroles has been achieved by Montgomery et al.
from readily available enones via a sequential Ni-catalyzed
reductive coupling with alkynes, followed by ozonolysis and Paal-
Although the Stetter-reaction/Paal-Knorr sequence is an often
applied synthetic strategy for the formation of pyrroles, an efficient
one-pot three-component coupling involving an aldehyde, amine
and Michael-acceptor has not been reported, to the best of our
knowledge. This is attributed to the fact that the Paal-Knorr
synthesis usually requires acidic reaction media, which makes it
necessary to add acid after the rather basic NHC-catalyzed
reaction is complete.17 Encouraged by Chi’s report on a Stetter-
type hydroformylation of chalcones, which makes use of C6/C5-
sugars as formaldehyde equivalents18 we investigated other
Knorr
condensation.7
Alternatively,
a
Au(I)-catalyzed
hydroamination cascade reaction has been established by Li and
Liu et al., which gave access to differently substituted pyrroles in
two steps from commercially available starting materials.8 Less
selective and efficient syntheses of 1,2,4-triarylpyrroles have also
been reported using Ti9 or Pd10 catalysis or acid promoted
hydrolysis of pyrrole-2-carboxylates.11 Recently, Zhang reported
a metal-free strategy to obtain this particular substitution pattern
of pyrroles via an iodine promoted condensation/cyclization
reaction of acetophenones with anilines.12 Unfortunately, only
homo-coupling of the acetophenone derivatives could be
achieved.
The NHC-catalyzed Stetter-reaction is a powerful tool for
hydroacylation of Michael acceptors, that can serve as pyrrole
precursors.13-15 A famous example of an industrial application of
the Stetter reaction followed by a pyrrole synthesis is Pfizer’s
synthesis of Atorvastatin (Lipitor®), a fully substituted pyrrole.
(Scheme 1a right).16
potential
formaldehyde
sources
for
NHC-catalyzed
hydroformylation reactions. When we added an amine to a Stetter
reaction of glycolaldehyde dimer, we surprisingly observed the
Paal-Knorr reaction product under basic reaction conditions
(Scheme 1b). Herein, we report this reaction as a one-pot Stetter-
type hydroformylation/Paal-Knorr reaction for the synthesis of
complex pyrroles.
We started the optimization of this reaction by treating 4-
fluorochalcone (1a)
with
glycolaldehyde
dimer (2),
p-
toluidine (3a) with 20 mol% of thiazolium salt 4 and 20 mol%
K3PO4 in acetonitrile (0.1 M) to generate the desired pyrrole 5a in
53% yield (table 1, entry 1). Variation to other polar solvents did
not improve the yield (entry 2). Diminishing the catalyst/base
loading to 5 mol% increased the formation of 5a to 66% yield
(entry 3). We speculated, that due to the lower catalyst
concentration, side reactions would be suppressed and the
[a]
M. Fleige and Prof. Dr. F. Glorius
Westfälische Wilhelms-Universität Münster
Organisch-Chemisches Institut
Corrensstrasse 40, 48149 Münster (Germany)
E-mail: glorius@uni-muenster.de
Supporting information for this article is given via a link at the end of
the document.
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product formation could be enhanced. Switching the base
(entry 4) as well as varying the temperature (entry 5) did not
improve the yield (for detailed optimization data see the
Supporting Information). Finally, dilution of the reaction mixture to
0.03 M improved the yield to 76% of 5a (entry 6). Diminished
Employing unsubstituted trans-chalcone (1b) yielded pyrrole 5b
in good yield. Electron-donating substituents on both aromatic
rings of the chalcone afforded the corresponding pyrroles 5c – 5e
in 85 – 72% yield. Chalcones substituted with halides gave access
to pyrroles 5f – 5j in good yields. Ortho-substitution was tolerated
and yielded pyrrole 5k. Disubstituted arenes at the chalcone were
also successfully converted to the pyrroles 5l and 5m.19 In
addition, cyclic chalcones were successfully converted to the
yields
were
obtained
by
employing
glucose
and
paraformaldehyde under these conditions as C1-surrogate (60%,
53%). Surprisingly, aqueous formaldehyde solution still gave
access to pyrrole 5a in 50% yield.
corresponding
dihydroindenopyrrole 5n
and
dihydrobenzoindole 5o in modest yields. Gratifyingly, the
catalyst/base loading for chalcone 1a could be lowered to
2.5 mol% while maintaining the isolated yield of pyrrole 5a.
Table 1. Optimization of reaction conditions.
Next, we investigated the scope of the amine coupling partner
(Scheme 3). Unsubstituted aniline gave access to pyrrole 5p in
72% yield. 4-Haloanilines led to the respective pyrroles 5q – 5s in
61 – 76% of yield. Electron donating substituents afforded the
corresponding pyrroles 5t, 5u in good yields. Employing anilines
with one ortho- or meta-substituent did not impede the generation
of pyrroles 5v, 5w. Sterically encumbered mesityl aniline afforded
54% of pyrrole 5x. Furthermore, an acetylene functionalized
aniline was successfully converted to pyrrole 5y. Gratefully, this
method could also be applied for aliphatic and benzylic amines
yielding pyrroles 5za and 5zb. Here, we observed a beneficial
effect on the overall yield, when the amine was added after the
hydroformylation reaction was complete. Employing ammonium
acetate gave rise to the N-unsubstituted pyrrole 5zc in
synthetically usefull yield.19 The reaction can also be performed in
the absence of amines to afford 1,4-dicarbonyl compounds with
2.5 mol% catalyst/base loading within 30 minutes.20
Entry
Changes of initial conditions
-
Yield (%)a
53
1
2
3
4
5
6
DMF or DMSO or EtOH
5 mol% NHC salt/K3PO4
5 mol% NHC salt/K2CO3
5 mol% NHC salt/K3PO4, 100 °C or 140 °C
5 mol% NHC salt/K3PO4, 0.03 M
33/28/28
66
60
38/63
76
a
Reaction conditions: 0.1 mmol 1a, 1.0 equiv. 2, 2.0 equiv. 3a at 120 °C for
16 h.Yields were determined by 19F NMR analysis of the crude mixture using
1-fluoronaphthalene as internal standard.
With the optimized reaction conditions in hand, we assessed the
generality of the substrate scope (Scheme 2).
a
Scheme. 3 Reaction conditions: 0.3 mmol chalcone 1, 1.0 equiv. 2,
Scheme 2. a Reaction conditions: 0.3 mmol chalcone 1a-o, 1.0 equiv. 2,
2.0 equiv. 3a, 5 mol% NHC salt 4, 5 mol% K3PO4, 9 mL MeCN at 120 °C
for 16 h. 2.5 mol% NHC salt 4 and 2.5 mol% K3PO4 were employed.
2.0 equiv. 3b-n, 5 mol% NHC salt 4, 5 mol% K3PO4, 9 mL MeCN at 120 °C
for 16 h. Isolated yields are given. b The corresponding amine was added
after 30 min of reaction time. c Ammonium acetate was employed as amine
source.
b
Isolated yields are given.
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To demonstrate the synthetic applicability of the methodology, we
applied the protocol for the synthesis of a versatile Atorvastatin
analogue 8. Michael acceptor 6 was transformed into pyrrole 8
via our one-pot approach in good yields. This particular
Atorvastatin derivative, to the best of our knowledge, is
unprecedented in the literature.21 The practicability of this method
is demonstrated by performing a large scale reaction (3 mmol)
while maintaining similar yields of pyrrole 8. In comparison to the
industrially employed sequential Stetter/Paal-Knorr reaction, this
method leads to an α-unsubstituted pyrrole which makes
precursor 8 to be a versatile base structure. Furthermore, the
industrial synthesis of Atorvastatin is restricted to arene moieties
in the α-position and is much more difficult to derivatize in
comparison to our method. Since the α-position is unsubstituted,
modifications using literature protocols provided various
substitution patterns of pyrrole 8. Protected Lipitor® precursor 9
intermediate B undergoes a retro-benzoin C–C bond cleavage to
generate the one carbon nucleophile C and one equivalent of
formaldehyde. Both, the protonated species B and C could be
observed by mass spectrometry, suggesting their existence in the
catalytic cycle.24 Stetter-reaction of the carbon nucleophile C with
Michael acceptor 1 furnishes 1,4-dicarbonyl 8 and releases the
catalyst. Subsequently, dicarbonyl 8 undergoes Paal-Knorr
condensation with primary amine 3 to afford the desired pyrrole 5.
In addition we monitored the course of the reaction over time. It
revealed that the NHC-catalyzed Stetter reaction is already
completed within 10 minutes and nearly no chalcone is left. Over
the period of 10 hours, the 1,4-dicarbonyl intermediate is
condensed to the desired pyrrole.24
was synthesized via
a Heck-type cross coupling reaction
employing 1-bromo-4-fluorobenzene as reaction partner.
Bromination of the α -positon was achieved with NBS affording 10
in excellent yield providing a handle for further derivatization.
Likewise cyanated pyrrole 11 gives the possibility for further
postfunctionalization of the introduced cyano-moiety to access
further Atorvastatin derivatives. Fluorinated compounds
tremendously influence the chemical and biological properties of
pharmaceutical products.22 The pharmaceutically relevant
thiotrifluoromethyl-group was successfully installed in the α-
position giving rise to pyrrole 12 in very good yield.
Scheme 5. Proposed reaction mechanism.
In summary, we have developed a direct and efficient one-pot
three component-coupling to 1,2,4-trisubstituted pyrroles from
readily available starting materials under mild conditions with low
catalyst loadings. This approach facilitates a direct synthesis of a
variety of pyrroles via rapid Stetter-type hydroformylation/Paal-
Knorr three component reaction. Additionally the reaction was
shown to be scalable. Furthermore, we were able to extend this
methodology in the synthesis of an Atorvastatin precursor which
allows a variety of unprecedented modifications of the α-position
via straight forward procedures.
Acknowledgements
We are grateful to Karin Gottschalk (University of Münster) for
skillful technical assistance. We thank Johannes Ernst, Andreas
Lerchen, Dr. Daniel Janssen-Müller, Dr. Andreas Rühling and Dr.
Roman Honeker (University of Münster) for helpful discussions
and proofreading of the manuscript. Generous financial support
by the Deutsche Forschungsgemeinschaft (IRTG 2027) is
gratefully acknowledged.
Scheme 4. Reaction conditions: a 6 (0.3 mmol), 1.0 equiv. 2, 5 mol% NHC
salt 4, 5 mol% K3PO4, 3 mL MeCN, 120 °C, 16 h; then 2.0 equiv. 7, 120 °C,
b
4 h.
1.5 equiv.1-bromo-4-fluorobenzene, 1.5 equiv. KOAc, 5 mol%
Keywords: NHC organocatalysis • one-pot • three-component
coupling • pyrroles • Atorvastatin •
Pd(OAc)2, DMA (0.2 M), 150 °C. c 1.1 equiv. NBS , THF (0.1 M), − 78 °C.
d 1.7 equiv. CSI, MeCN:DMF (1:1 0.25 M), − 78 °Ce 1.3 equiv. Phth-SCF3,
10 mol% NaCl, DMF (0.2 M), 90 °C. Isolated yields are given.
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COMMUNICATION
Entry for the Table of Contents
Layout 2:
COMMUNICATION
Mirco Fleige and Prof. Dr. Frank Glorius*
Page No. – Page No.
α-Unsubstituted Pyrroles by NHC-
Catalyzed Three-Component
Coupling - Direct Synthesis of
Versatile Atorvastatin Derivative
Three at a Stroke: Herein, we report a metal-free one-pot three-component
coupling of readily available starting materials and catalyst to generate valuable
pyrroles. The process involves an N-heterocyclic carbene (NHC) catalyzed Stetter-
type hydroformylation using glycolaldehyde dimer as a novel C1 building-block,
followed by a Paal-Knorr condensation. Furthermore, this methodology is applied in
the synthesis of a versatile Atorvastatin precursor and derivatives of it.
This article is protected by copyright. All rights reserved.