Nitroalkenes as Latent 1,2-Biselectrophiles - A Multicatalytic Approach for the Synthesis of 1,4-Diketones and Their Application in a Four-Step One-Pot Reaction to Polysubstituted Pyrroles

Article abstract of DOI:10.1021/acs.joc.7b00830

An NHC-catalyzed nitro-Stetter/elimination/Stetter reaction sequence employs nitroalkenes as latent 1,2-dication synthons providing a novel access to highly useful symmetrical and unsymmetrical 2-aryl substituted 1,4-diketone building blocks from commercially available aldehyde precursors. For less activated (aliphatic) aldehydes, a cooperative catalytic strategy has been developed via the merger of NHC and H-bonding catalysis. To further showcase the versatility of our approach, a great variety of these unprecedented 1,4-diketones are used to efficiently synthesize polysubstituted pyrroles - including those with hetaryl substituents - in good to excellent yields in a multicatalytic metal-free, four-step one-pot cascade reaction under mild, yet robust, conditions.

Full text of DOI:10.1021/acs.joc.7b00830

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Article
Nitroalkenes as latent 1,2-biselectrophiles – A multicatalytic
approach for the synthesis of 1,4-diketones and their application
in a 4-step one-pot reaction to polysubstituted pyrroles
Patrick J. W. Fuchs, and Kirsten Zeitler
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00830 • Publication Date (Web): 23 Jun 2017
Downloaded from http://pubs.acs.org on June 23, 2017
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Page 1 of 13
The Journal of Organic Chemistry
Nitroalkenes as latent 1,2-biselectrophiles – A multicatalytic
approach for the synthesis of 1,4-diketones and their application in a
4-step one-pot reaction to polysubstituted pyrroles
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Patrick J. W. Fuchs and Kirsten Zeitler*
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Institut für Organische Chemie, Universität Leipzig, Johannisallee 29, D-04103 Leipzig, Germany.
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KEYWORDS multicatalysis, NHC catalysis, heterocycles, multicomponent reaction, domino reaction, pyrroles
ABSTRACT: A NHC-catalyzed Nitro-Stetter/elimination/Stetter reaction sequence employs nitroalkenes as latent
1,2-dication synthons providing a novel access to highly useful symmetrical and unsymmetrical 2-aryl substituted
1,4-diketone building blocks from commercially available aldehyde precursors. For less activated (aliphatic) aldehydes a
cooperative catalytic strategy has been developed via the merger of NHC and H-bonding catalysis. To further showcase
the versatility of our approach a great variety of these unprecedented 1,4-diketones are used to efficiently synthesize
polysubstituted pyrroles – including those with hetaryl substituents – in good to excellent yields in a multicatalytic metal-
free, 4-step one–pot-cascade reaction under mild, yet robust conditions.
the carbonyl´s α-position, while functionalization of an
INTRODUCTION
1,2-dianion (route E) can be achieved with alkynes4 or as
1,4-Diketones are highly important building blocks for a
great variety of bioactive compounds. Apart from their
abundant occurrence in natural products and their
significance as synthetic precursors for 1,4-diols, they
have witnessed great interest especially for the
construction of heteroaryl subunits, which are privileged
motifs in medicinal as well as material chemistry.1
Following classical Paal-Knorr conditions2 a wide range of
5-membered heterocycles,3 such as furans, pyrroles,
thiophenes can be conveniently accessed as other routes
allow for the synthesis of cyclopentenones, benzenes4 and
biphenols.5
recently shown by the group of Bertus by a titanium
mediated formal insertion of 1,2-dianions into acyl
cyanohydrins.16 However, the need of elaborate
precursors, harsh reaction conditions as well as limitation
to non-functionalized or only symmetrical 1,4-diketones
are among the drawbacks of the current methodologies.
Scheme 1. Different retrosynthetic strategies for
1,4-diketones.
Due to this prevalence and to exploit the great versatility
of this precursor numerous competent synthetic
,
protocols have been developed,6 7 albeit all of them with
specific limitations.
As the dissonant connectivity of the 1,4-dicarbonyl motif
is difficult to realize by classical reactivity,8 umpolung
approaches9 or redox pathways have been followed to
alter the original reactivity of the corresponding building
blocks. However, especially the synthesis of un-
symmetrically functionalized 1,4-dicarbonyl compounds
can prove challenging and hence the development of new
methods is highly desirable. As illustrated in Scheme 1
progress in the field may strongly rely on changes in the
retrosynthetic analysis.
Based on this analysis and the attractiveness of a
convergent three-component strategy we recently
questioned whether an electronically reverse strategy of
employing 1,2-biselectrophiles as a C2-carbon source
(pathway D) together with two acyl anions, catalytically
generated from simple aldehydes, could be used for the
catalytic synthesis of 1,4-diketones. Moreover, we hoped
that this approach would allow for direct integration in an
Probably one of the most famous examples of
a
traditional, conjugate addition approach is the Stetter
reaction with catalytically generated acyl anions
(pathway A).10 Alternative nucleophilic acylations are
reported with in situ generated acyl radicals11 or via
Pd-mediated carbonylative 1,4-additions.12,13 The reverse
approach (route B) using homoenolate equivalent
synthons together with electrophilic acyl derivatives14 has
also been established. Coupling of two C2 subunits
according to pathway C15 requires the reactivity reversal of
one-pot
Paal-Knorr-type
sequence
to
access
polysubstituted pyrroles.
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Page 2 of 13
Highly substituted pyrroles are known as a privileged It has been established that β-nitro carbonyl compounds
class of nitrogen containing heterocycles,17 being
widespread in a variety of biological active substances
such as pharmaceuticals, agrochemicals and natural
products.18 In addition, polysubstituted pyrrole
derivatives are applied as versatile building blocks in
modern organic chemistry3,19 as well as in materials
science.20 Hence, the search for novel, broadly applicable
pyrrole syntheses has triggered considerable attention.21
Despite, even with these recent advances, current
methods are unfortunately not without their limitations,
particularly with regard to the application of advanced
precursors which require time-consuming pre-synthesis
and often costly additional steps.22 Moreover, the
common use of (often expensive) metal catalytic
methods23,24 may potentially cause well-known problems
of product contamination, while rather rare, metal-free
protocols suffer from harsh reaction conditions or
advanced starting materials.25 Addressing some of the
mentioned drawbacks, the concept of multicomponent
can readily eliminate HNO2 under mild acidic or basic
conditions.31 The electrophilic character of nitro alkenes
allows for the attack of acyl anion 2, generated by an
N-heterocyclic carbene (NHC) catalyst (such as A) in a so-
called nitro-Stetter reaction,32 to furnish β-nitro ketone 3.
In combination with their ready commercial availability it
renders nitro olefins attractive 1,2—dication synthons.
Elimination of nitrous acid would lead to a subsequent
Michael acceptor 4 with an electrophilic position at the
former NO2-substituted carbon atom; the nitro group
hence serves as a traceless activating and directing group.
Furthermore, the proposed latent 1,2-biselectrophilic
nitroalkenes are well known to allow for additional
activation with H-bond catalysts33 such as thiourea
catalyst B and therefore provide a further handle for
tuning the reaction conditions of the nitro-Stetter
reaction for less activated substrates.34 The newly
harnessed acceptor 4 could then be attacked by a second
acyl anion equivalent 5 to form the desired 1,4-diketone 6
in a classical Stetter reaction.10 Subsequent treatment with
amines applying Paal-Knorr conditions would provide
access to polysubstituted pyrroles 7.
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reactions (MCR) for pyrrole syntheses as
a waste
reducing, step and atom economic method has gained
increasing interest.26
From a structural point of view current methodology
often lacks the possibility to introduce hetaryl
substituents at the pyrrole core; such triarylpyrrolo
motifs, however, are important scaffolds in medicinal
chemistry (Scheme 2), such as for p38 mitogen-activated
protein kinases (MAS) inhibittors27 or as glucagon
receptor antagonist like L-168,049.28
Scheme 3. Strategy of latent 1,2-biselectrophiles for
the synthesis of 1,2,3,5 substituted pyrroles.
Scheme 2. Example applications of triarylpyrrolo
compounds.
R
Het
N
Ar1
MLn
N
Ar2
N
H
N
N
triarylpyrroles
Cl
Br
OBu
(PyPyr)-complexes
L-168,049
Furthermore, 2-pyridylpyrroles (PyPyr) are interesting
bidentate ligands for organometallic catalysts as they are
known to stabilize high oxidation states.29
Herein, we report a novel multicatalytic MCR approach of
using nitroalkenes as latent 1,2-biselectrophiles for the
generation of 1,4-diketones. We further disclose the
extension to a 4-step one-pot reaction to synthetically
relevant 1,2,3,5-substituted pyrroles by employing only
simple, commercially available starting materials.
With water and HNO2 as the only secondary reaction
products
this
catalytic
nitro-Stetter/elimination/
Stetter/Paal-Knorr sequence would be additionally
attractive due to its high atom economy.
RESULTS AND DISCUSSION
DESIGN PLAN
We commenced our studies with β-nitrostyrene (9a) and
pyridine carboxaldehyde (8) as our model substrates for the
latent 1,2-biselectrophile generation (Table 1). Aryl sub-
stituted nitroalkenes were supposed to facilitate the crucial
elimination of HNO2.35
Based on the synthetic power of NHC-catalyzed
umpolung30 of aldehydes we hypothesized that
a
multicomponent approach of catalytically generated
acylanion equivalents together with a suitable bis-
electrophilic alkene surrogate could lead to a large variety
of
1,4-diketones
6
and
their
corresponding
polysubstituted pyrroles 7 (Scheme 3).
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The Journal of Organic Chemistry
Table 1. Optimization of the reaction conditions.a
of Michael acceptor 11 the reaction was clean and reached
1
2
3
4
5
6
7
8
full conversion (entries 5-7). Stepwise increasing amounts of
base proved to favour the desired diketone 12 and the yield
of the reaction could be raised to its quantitative formation
(entries 6 and 7). Ultimately, we decided to use 1.0
equivalents of base to establish robust conditions that ensure
complete elimination and would be applicable to a broad
range of substrates. It is noteworthy, that this procedure is
also amenable to efficient batch scale-up, providing diketone
12 in 85% yield on 1.5 mmol scale (entry 8).
Yieldb Yieldb Yieldb
Base
Entry Base
Solvent
loading
[mol %]
10
in %
11
in %
12
in %
9
1
NaOAc tAmOH 40
NaOAc acetone 40
32
12
54
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With this optimized conditions for our novel 1,4-diketone
synthesis in hand, we aimed to demonstrate the
versatility of this approach by expanding the 3-step-one-
pot-reaction to a 4-step-cascade with a terminal Paal-
Knorr reaction to access tetrasubstituted pyrroles 14.
Next, we evaluated the scope of the reaction with respect
to the substituted β-nitrostyrene fragments 9a-m and
different amines (Table 2). The extension to this one-pot
pyrrole formation was successful for our initial model
substrate 9a providing pyrroles 14a and 14b in almost
quantitative yields (entry 1,2).
2
3
4
5
6
26
50
39
31
16
5
58
45
19
NaOAc Et2O
DIPEA Et2O
40
40
40
70
28
0
K2CO3
K2CO3
Et2O
Et2O
69
97
3
0
100
7
K2CO3
K2CO3
Et2O
Et2O
100
100
0
0
0
0
(90)c
8d
85c
a
Conditions: Aldehyde 8 (Py = 2-pyridyl) (0.38 mmol),
nitroalkene 9a (0.25 mmol), cat. A (10 mol %), base
(x mol %), solvent (2 mL) for 14 h at rt, then aldehyde 8
Table 2. 4-Step one-pot cascade to pyrroles - Scope of
different β-nitrostyrene-derivatives.a
b
1
(0.25 mmol) for 7 h at 50 °C. Yield determined by H NMR
spectroscopy using dibromomethane (1 equiv) as internal
c
d
standard. Isolated yield. Reaction was performed on a
1.5 mmol scale.
Our initial investigations were aimed to validate the
general feasibility of our approach for a single aldehyde to
furnish symmetrical substituted 1,4-diketones 12. Based
on these results we would then examine the scope of this
reaction by employing two different aldehydes to
generate unsymmetrical diketo products. It was apparent
from the outset of our studies that - already for a single
aldehyde - the mixture of possible products (nitro-Stetter
adduct 10, elimination product 11 and the desired
1,4-diketone 12) would pose a major challenge. To find
suitable conditions we started with reaction parameters
typical for a nitro-Stetter reaction of aliphatic alde-
hydes,32a which we slightly modified by the use of achiral
catalyst A and higher temperature (rt to 50 °C for 7 h) to
promote the elimination and the sequential addition of a
second equivalent of pyridyl aldehyde 8 (entry 1) as its
NHC-derived acyl anion. All three products including
diketone 12 were formed, therefore confirming the
viability of β-nitrostyrenes as a latent 1,2-biselectrophiles.
Furthermore, NHC-catalyst A proved to be competent to
promote both the the nitro-Stetter and the Stetter
reaction. An initial solvent screening with acetone (entry
2) and diethylether as a non-protic polar solvent (entry 3)
Product Yieldb
Entry R1
R2
14a-m
14a
in %
97
1
Ph (9a)
CH2-Ph
2
Ph (9a)
(CH2)2-Ph 14b
95
4-OMe-
14c
3
Ph (9a)
95
Ph
4
Ph (9a)
H
14d
14e
14f
98
94
77
92
59
74
44
nd
nd
70
5
4-OMe-Ph (9e)
4-Br-Ph (9f)
3-Br-Ph (9g)
3-CN-Ph (9h)
2-F-Ph (9i)
CH2-Ph
CH2-Ph
CH2-Ph
CH2-Ph
CH2-Ph
CH2-Ph
CH2-Ph
CH2-Ph
H
6
7
8c
14g
14h
14i
9
10
11
12
13
a
2-Me-Ph (9j)
2,4,6-Me-Ph (9k)
CH3(CH2)4 (9l)
Furyl (9m)
14j
14k
14l
14m
Conditions: Aldehyde 8 (0.38 mmol), nitroalkene 9a-m
revealed
a slightly increased overall yield with a
(0.25 mmol), cat. A (10 mol %), K2CO3 (0.25 mmol), Et2O
(2 mL) for 16 h at rt, then aldehyde 8 (0.25 mmol) for 8 h at
50 °C, then amine (0.75 mmol) and acetic acid (2 mL) for
remarkable cut for elimination product 11. As the rapid
decomposition of Michael acceptor 11 was well-preceden-
ted, and also observed during work-up procedures36 we
selected diethylether as the solvent for further
investigations. While an amine base (entry 4), was
detrimental, changing to K2CO3 as alternative inorganic
base showed promising results. With undetectable yields
b
1.5 d at 70 °C in a screw-top reaction tube. Yield of isolated
c
product. Milder conditions for the last step were used:
benzylamine (1.4 mmol), acetic acid (0.75 mmol, 3.0 equiv)
and heating overnight at 50 °C.
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As expected the reaction is not limited to aliphatic amines conditions similar to entry 5 of our first screening (Table
1
2
3
4
5
6
7
8
and showed an excellent yield of 95% for the MCR using
less nucleophilic aromatic amine (entry 3). Moreover,
direct access to N-unsubstituted pyrroles is possible by
employing ammonium acetate as a nitrogen source (95%;
entry 4). Variations of the nitrostyrene´s aryl substituent
with different electron donating and withdrawing groups
were also well tolerated (entries 5-9). Notably, small
ortho-substitutents had no influence on the product yield
(74% yield for 14i; entry 9). However, higher sterical
demand as shown for the 2-methyl substituent results in
lower yields, but still being useful for an operationally
simple 4-step one-pot process (44% for pyrrole 14j; entry
10). Two sterically demanding substituents at the ortho-
position are the current limitation for this one-pot
reaction (entry 11). Moreover, as 2-alkyl nitroalkenes
hardly show any elimination32b-e to the corresponding
Michael acceptors, no product formation was observed
(entry 12). Finally, pyrrole formation also efficiently
proceeds with heteroaryl substituted nitroalkenes, as
shown for furyl derivative 14m (entry 13).
1, entry 5), but now stopped the reaction before heating
and addition of the second aldehyde amount. Lowering
the aldehyde amount (entry 3) together with increased
catalyst loading to ensure full conversion (entry 4) nicely
favoured formation of the targeted nitro-Stetter
product 10. Finally, upon sequential addition of the
second aldehyde altered reaction conditions (base,
temperature) are required to then promote the
eliminative formation of Michael acceptor 11 thus
avoiding further (NHC-catalyzed) side reactions.
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10
11
12
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With these further optimized conditions in hand we
finally examined the generality of our approach to both
synthesize unsymmetrically substituted 1,4-diketones 17
and to carry out their straightforward conversion into the
corresponding pyrroles 18a-g. Scheme
4 shows re-
presentative examples for each new class of substituents.
As illustrated in part A, formation of 1,4-diketones is
achieved with good efficiency, albeit partly with lower
yields as for the corresponding pyrrole products further
highlighting the benefits of our cascade approach.
As mentioned previously, the synthesis of unsymmetrical
diketones has often proved challenging and lowering the
scope of the corresponding methodology. After our
promising results with a single aldehyde, we therefore
aimed to further broaden the synthetic scope in order to
Scheme 4. Unsymmetric polysubstituted pyrroles –
Scope of different aldehydes.a,b
20 mol % cat. A
20 mol % cat. B (optional)
30 mol % K2CO3
Ph
then:
Ph
acetic acid,
R1
O
R1
NO2
O
N
O
NH2
Et2O, rt, 6-24 h
R2
R1
then: 120 mol % K2CO3
Ph
R2
provide
access
to
unsymmetrically
substituted
Ph
40 °C, 1-2.5 d
O
Ph
18a-g
15
9a
17
1,4-diketones by using two different aldehydes.
1.5 equiv
1.1 equiv
R2
16
The key challenges for this cross-addition approach to the
nitroalkene as our biselectrophile surrogate are rather
manifold. As an excess of unreacted first aldehyde would
unavoidably lead to the formation of the undesired
symmetrical diketone, its full consumption during the
nitro-Stetter catalysis needs to be guaranteed. Moreover,
due to the lability of the intermediate Michael acceptor 11
(vide supra), HNO2 elimination needs to be suppressed
until the addition of the second aldehyde.
O
A
N
O
O
O
O
Ph
O
17a, 93%c
N
Ph
O
Ph
O
17b, 53%c,d
17c, 66%c,d
Ph
N
B
N
Ph
Ph
Ph
Ph
N
O
N
N
N
18b, 36%e
Table 3. Optimization of reaction conditions.a
Ph
Ph
18a, 38%e
18c, 42%e
Ph
N
O
N
18d, 84%
Ph
Ph
N
O
N
Yieldb
11
Yieldb
12
Yieldb
10
Aldehyde
Ph
N
K2CO3
Catalyst
loading
[mol %]
N
18e, 74%d
Ph
Ph
18g, 76%d
Entry loading loading
[mol %]
in %
in %
in %
[equiv]
Ph
18f, 21%d
a
Conditions: Aldehyde 15 (0.28 mmol), nitroalkene 9a
1
40
30
30
30
1.5
1.5
1.1
1.1
10
10
10
20
61
7
30
(0.25 mmol), cat. A (20 mol %), thiourea cat. B (20 mol %),
K2CO3 (30 mol %), Et2O (2 mL) for 6-24 h at rt, then aldehyde
16 (0.38 mmol) and K2CO3 (120 mol %) for 1-2.5 d at 40 °C
(diketone formation, part A), then benzylamine (1.4 mmol)
and acetic acid (0.75 mmol) for 16 h at 50 °C (pyrroles, part B).
2
3
4
68
68
74
1
30
12
17
traces
8
b
Yield of isolated product. c For diketones (part A): the
a
Conditions: Aldehyde 8 (x equiv), nitroalkene 9a
(0.25 mmol), cat. A (x mol %), K2CO3 (x mol %), Et2O (2 mL)
for 14 h at rt. Yield determined by H NMR spectroscopy
reaction was stopped before the addition of the amine and
acetic acid. d 1.5 equiv of aldehyde 15 and different amounts
of K2CO3 (40 mol % + 110 mol %) were added. e No thiourea
cat. B was required; toluene was used as solvent and the final
step was performed with benzylamine (0.75 mmol) and
acetic acid (2 mL) for 2.5 d at 100 °C (70 °C for 18c).
b
1
using dibromomethane (1 equiv) as internal standard.
Table 3 shows the further optimization of step 1 and
illustrates the influence of base on the observed product
distribution (entries 1-3). We began this screening with
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Starting with 2-pyridine carboxaldehyde as the initial (septet), m (multiplet); coupling constants (J) are given in
1
2
3
4
5
6
7
8
aldehyde heteroaromatic, aromatic and aliphatic
aldehydes were competent reaction partners providing
the corresponding pyrrole products 18a-c with overall
yields of around 40% (approx. 80% for each step) and
offering convenient access to hetaryl substituted
triarylpyrrolo motifs. Longer reaction times for the
second Stetter reaction (2.5 days instead of overnight
reaction, see Table 2) paired with the fast decomposing
2-pyridyl substituted Michael acceptor 11 may contribute
to the partly observed lower yields. To further broaden
the scope to allow the implementation of other starting
aldehydes of lower reactivity, we built on the initially
proposed concurrent activation of nitroalkene 9a with
Hertz (Hz). High resolution mass was recorded on an Agilent
Q-TOF 6540 UHD, Finnigan MAT95 or Bruker APEX II.
All reactions were monitored by thin-layer chromato-
graphy; visualization was accomplished with UV light
and/or appropriate stains (KMnO4, anisaldehyde or
vanillin). Standard flash chromatography procedures
(SiO2, size 40−63 µm) were followed. All reactions were
carried out under a protective atmosphere of dry nitrogen
using oven-dried glassware unless otherwise stated.
Solvents for the catalytic reactions were purchased at
absolute quality. Solvents for chromatography (acetone,
Et2O, DCM, EtOAc, hexanes) were technical grade and
distilled prior to use. K2CO3, in the text referred as
“predried”, was finely ground in a mortar and then heated
for at least 20 minutes at 650 °C at high vacuum. All
aldehydes are commercially available and were distilled
under reduced pressure prior to use. All nitroalkenes are
commercially available, however nitroalkenes 9e-h,k,m,37
9i,j38 and 9l39 were prepared according to published
protocols. Triazolium salt A is commercially available.
Thiourea B was synthesized according to a known
procedure described by Wang.40
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60
thiourea
B as H-bonding catalyst. This synergistic
catalytic strategy allowed us to employ other
heteroaromatic aldehydes like furfural with a very good
yield (84%; 18d). Moreover, we were able to expand the
scope to aliphatic aldehydes with high yields (74-76%;
18e, 18g). The here obtained higher yields as compared to
the corresponding 1,4-diketones 17b and 17c (vide supra)
exemplify the advantage of the cascade procedure. Side
reactions, e. g. caused by the aliphatic aldehydes´ α-aci-
dity or homobenzoin formation, can lead to tricky
separation problems at the diketone stage. Notably,
despite these challenges even pyrrole 18f, bearing two
aliphatic substituents, could be synthesized, albeit with a
lower overall yield of 21%; however, still highly useful with
respect to the operational simplicity of the method and
the readily available starting materials.
Experimental Details.
General Procedure A: Screening Experiments for
Optimized Conditions. An oven-dried screw-capped
schlenk tube equipped with a magnetic stir bar was
heated up to 650 °C (using a heat gun). After cooling to
room temperature 38.4 mg nitroalkene 9a (0.250 mmol,
1.00 equiv), a base and 9.07 mg catalyst A (0.0250 mmol,
0.100 equiv) were added under a nitrogen atmosphere.
The tube was then evacuated and purged four times with
nitrogen and dissolved in 2 mL solvent (0.125 m). 40.2 mg
2-pyridine carbaldehyde 8 (0.380 mmol, 1.50 equiv) was
added; the reaction mixture was stirred at room
temperature for 14 h. Then a second amount of 26.8 mg 2-
pyridine carbaldehyde 8 (0.250 mmol, 1.00 equiv) was
added to the mixture which was heated then to 50 °C for
7 h. The yield was determined by NMR using
dibromomethane as internal standard.
Given the generality of this approach and the possibility
to easily integrate heterocyclic arenes, which are common
scaffolds in targets relevant to medicine and material
sciences, we expect this protocol to be useful for a wide
range of complex molecules.
CONCLUSION
In summary, we have developed a highly convergent
access to symmetrical and unsymmetrical 1,4-diketones
using nitrostyrenes as simple latent 1,2-biselectrophilic
building blocks in combination with commercially
available aldehydes as acylanion precursors via NHC
catalysis. Our multicatalytic metal-free, 4-step one–pot
General Procedure B: Preparation of 2,5-Dipyridyl
Substituted Pyrroles. An oven-dried screw-capped schlenk
tube equipped with a magnetic stir bar was heated up to
650 °C (using a heat gun). After cooling to room
temperature a nitroalkene (0.250 mmol, 1.00 equiv),
34.6 mg “predried” K2CO3 (0.250 mmol, 1.00 equiv) and
9.07 mg catalyst A (0.0250 mmol, 0.100 equiv) were added
Nitro-Stetter/elimination/Stetter/Paal-Knorr
reaction
sequence provides access to polysubstituted pyrroles,
including up-to-date difficult to synthesize heteroaryl
substituted scaffolds, under mild conditions.
under
a nitrogen atmosphere. The tube was then
EXPERIMENTAL SECTION
evacuated and purged four times with nitrogen and
dissolved in 2 mL Et2O (0.125 m). 40.2 mg 2-pyridine
carbaldehyde 8 (0.380 mmol, 1.50 equiv) was added
followed by four freeze-pump-thaw cycles. The reaction
mixture was stirred at room temperature overnight. Then
a second amount of 26.8 mg 2-pyridine carbaldehyde 8
(0.250 mmol, 1.00 equiv) was added to the mixture and
was heated to 50 °C for 8 hours. Upon complete
consumption an amine (0.750 mmol, 3.00 equiv) and
2 mL acetic acid were added successively and heated for
1.5 days at 70 °C. The crude reaction mixture was
General Information. Unless otherwise noted, all
commercially available compounds were used as provided
without further purification. NMR spectra were recorded
on a Bruker Avance 300 (300.13 MHz), Varian MERCURY
plus (300.08 MHz), Bruker Avance III 400 (400.13 MHz)
and Varian MERCURY plus (399.95 MHz) using the
solvent peak as internal reference (CDCl3: δ H 7.26;
δ C 77.16). Multiplicities are indicated, s (singlet), d
(doublet), t (triplet), q (quartet), quint (quintet), sept
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Page 6 of 13
transferred to a separating funnel and 15 mL of a 3 m capped schlenk tube equipped with a magnetic stir bar
1
2
3
4
5
6
7
8
NaOH solution was added. The aqueous layer was
extracted four times with DCM (10 mL). The organic
layers were combined and dried over anhydrous NaSO4,
filtered, and concentrated under reduced pressure. The
crude product was purified by column chromatography to
obtain the corresponding pyrrole.
was heated up to 650 °C (using a heat gun). After cooling
to room temperature 38.4 mg nitroalkene 9a (0.250
mmol, 1.0 equiv), 8.20 mg sodium acetate (0.100 mmol,
0.40 equiv) and 9.07 mg catalyst A (0.0250 mmol,
0.10 equiv) were added under a nitrogen atmosphere. The
tube was then evacuated and purged four times with
nitrogen and dissolved in
2 mL tert-amyl alcohol
General Procedure C: Preparation of Unsymmetrical
1,4-Diketones. An oven-dried screw-capped schlenk tube
equipped with a magnetic stir bar was heated up to 650 °C
(using a heat gun). After cooling to room temperature
nitroalkene 9a, “predried” K2CO3, thiourea derivative B
and catalyst A were added under a nitrogen atmosphere.
The tube was then evacuated and purged four times with
nitrogen and dissolved in 2 mL Et2O followed by the
addition of the first aldehyde and a sequence of four
freeze-pump-thaw cycles. The reaction mixture was
stirred at room temperature until complete conversion of
the nitroalkene 9a (6 h to 1 d, TLC control). For
(0.125 M). Then 40.2 mg 2-pyridine carbaldehyde 8 (0.375
mmol, 1.5 equiv) was added. The resulting reaction
mixture was stirred at room temperature for 20 h. The
crude product was purified by column chromatography.
Yield after column chromatography (flash gel (2-25 µm);
hexanes/ethyl acetate 33/1 to 4/1): 21.5 mg (0.0840 mmol,
34%), colorless oil. Rf (hexanes/ethyl acetate 4:1): 0.49.
1H NMR (400 MHz, CDCl3): 8.70 (d, J = 4.9 Hz, 1H), 8.08
(d, J = 8.0 Hz, 1H), 7.82 (td, J = 7.7, 1.7 Hz, 1H), 7.49 – 7.39
(m, 3H), 7.36 – 7.24 (m, 3H), 6.26 (dd, J = 10.2, 5.0 Hz, 1H),
5.38 (dd, J = 14.6, 10.2 Hz, 1H), 4.72 (dd, J = 14.6, 5.0 Hz,
1H). 13C NMR (101 MHz, CDCl3): 197.1, 151.6, 149.2, 137.2,
133.5, 129.3 (2C), 129.1 (2C), 128.4, 127.7, 123.2, 75.9, 48.6.
HRMS (ESI): Exact mass calculated for C14H12N2NaO3
([M+Na]+): 279.0740, mass found: 279.0738.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
consecutive elimination-Stetter reaction sequence
a
second amount of “predried” K2CO3 and the second
aldehyde were added to the mixture. The resulting
mixture was heated to 40 °C until complete formation of
the respective Stetter product (1 d, TLC control). The
crude products were purified by column chromatography
to obtain the 1,4-diketones.
2-Phenyl-1-(pyridin-2-yl)prop-2-en-1-one (11).
For
the
synthesis of elimination product 11 an oven-dried screw-
capped schlenk tube equipped with a magnetic stir bar
was heated up to 650 °C (using a heat gun). After cooling
to room temperature 38.4 mg nitroalkene 9a (0.250
mmol, 1.0 equiv), 34.6 mg “predried” K2CO3 (0.250 mmol,
1.0 equiv) and 9.07 mg catalyst A (0.0250 mmol,
0.10 equiv) were added under a nitrogen atmosphere. The
tube was then evacuated and purged four times with
nitrogen and dissolved in 2 mL Et2O (0.125 M). 28.1 mg
2-pyridine carbaldehyde 8 (0.260 mmol, 1.05 equiv) was
added followed by a sequence of four freeze-pump-thaw
cycles. The reaction mixture was stirred for one day at
room temperature. The crude product was purified by
column chromatography. Yield after column chromato-
graphy (flash gel; hexanes/ethylacetate 4/1): 20.0 mg
(0.0980 mmol, 38%), colorless oil. Rf (hexanes/ethyl
General Procedure D: Preparation of Unsymmetrical
2,5-Substituted Pyrroles. An oven-dried screw-capped
schlenk tube equipped with a magnetic stir bar was
heated up to 650 °C (using a heat gun). After cooling to
room temperature nitroalkene 9a, “predried” K2CO3 and
catalyst A were added under a nitrogen atmosphere.
Furthermore, if the first aldehyde is not 2-pyridine
carbaldehyde, the thiourea derivative B was added as
cocatalyst. The tube was then evacuated and purged four
times with nitrogen and dissolved in 2 mL Et2O or toluene
(0.125 m), followed by the addition of the first aldehyde
and a sequence of four freeze-pump-thaw cycles. The
reaction mixture was stirred at room temperature until
complete conversion of the nitroalkene 9a (6 h to 1 d, TLC
control). For consecutive elimination-Stetter reaction
sequence a second amount of “predried” K2CO3 and the
second aldehyde were added to the mixture. The resulting
mixture was heated to 40 °C until complete formation of
the respective Stetter product (1 d to 2.5 d, TLC control).
To generate the corresponding pyrroles benzylamine and
acetic acid were added successively and heated until
completion (16 h to 2.5 d, TLC control). The crude
reaction mixture was either directly purified by column
chromatography or transferred in a separating funnel
followed by adding 15 mL of a 3 M NaOH solution. The
aqueous layer was extracted four times with DCM
(10 mL). The combined organic layers were dried over an-
hydrous NaSO4, filtered, and concentrated under reduced
pressure. The crude products were purified by column
chromatography to obtain the corresponding pyrroles.
1
acetate 4:1): 0.37. H NMR (400 MHz, CDCl3): 8.65 (d, J =
4.8 Hz, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.84 (td, J = 7.7, 1.7
Hz, 1H), 7.45 – 7.38 (m, 3H), 7.37 – 7.29 (m, 3H), 6.19 (s,
1H), 5.95 (s, 1H). 13C NMR (101 MHz, CDCl3): 196.2, 154.9,
149.2, 147.8, 137.4, 137.1, 128.5 (2C), 128.3, 127.6 (2C), 126.5,
124.9, 124.3. HRMS (ESI): Exact mass calculated for
C14H12NO ([M+H]+): 210.0913, mass found: 210.0914.
2-Phenyl-1,4-di(pyridin-2-yl)butane-1,4-dione (12). 1,4-Dike-
tone 12 was prepared according to general procedure A
using 34.6 mg “predried” K2CO3 (0.250 mmol, 1.00 equiv)
and Et2O as a solvent. The crude product was purified by
column
chromatography.
Yield
after
column
chromatography (flash gel; hexanes/ethyl acetate 2/1):
71.4 mg (0.230 mmol, 90%), yellowish oil. Rf
(hexanes/ethyl acetate 4:1): 0.26. H NMR (400 MHz,
CDCl3): 8.74 (d, J = 4.9 Hz, 1H), 8.69 (d, J = 4.9 Hz, 1H),
8.06 (d, J = 7.9 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.83 – 7.74
(m, 2H), 7.55 – 7.49 (m, 2H), 7.49 – 7.44 (m, 1H), 7.43 –
7.38 (m, 1H), 7.32 – 7.25 (m, 2H), 7.23 – 7.16 (m, 1H), 6.07
1
3-Nitro-2-phenyl-1-(pyridin-2-yl)propan-1-one (10). For the
synthesis of nitro-Stetter product 10 an oven-dried screw-
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The Journal of Organic Chemistry
98%), colorless oil. Rf (hexanes/ethyl acetate 4:1): 0.26.
(dd, J = 11.2, 3.6 Hz, 1H), 4.46 (dd, J = 19.1, 11.1 Hz, 1H), 3.80
(dd, J = 19.1, 3.6 Hz, 1H). 13C NMR (101 MHz, CDCl3): 200.3,
200.0, 153.1, 152.8, 149.1, 149.0, 138.3, 136.9, 136.9, 129.1 (2C),
128.7 (2C), 127.3, 127.1, 127.0, 122.9, 121.9, 46.0, 42.9. HRMS
(ESI): Exact mass calculated for C20H17N2O2 ([M+H]+):
317.1285, mass found: 317.1281.
1H NMR (400 MHz, CDCl3): 10.66 (bs, 1H), 8.56 – 8.51 (m,
2H), 7.65 – 7.58 (m, 1H), 7.58 – 7.53 (m, 1H), 7.52 – 7.46
(m, 2H), 7.43 – 7.30 (m, 4H), 7.27 – 7.23 (m, 1H), 7.08 –
6.98 (m, 2H), 6.75 (s, 1H).13C NMR (101 MHz, CDCl3):
150.5, 150.0, 149.3 (2C), 137.1, 136.5, 136.0, 132.0, 129.4 (2C),
128.7 (3C), 126.9, 126.6, 121.1, 121.0, 120.2, 118.6, 111.0. HRMS
(ESI): Exact mass calculated for C20H16N3 ([M+H]+):
298.1339, mass found: 298.1334.
1
2
3
4
5
6
2,2'-(1-Benzyl-3-phenyl-1H-pyrrole-2,5-diyl)dipyridine (14a).
Pyrrole 14a was prepared according to general
procedure B using 37.3 mg nitroalkene 9a and 80.0 mg
benzylamine. Yield after column chromatography (flash
gel; first DCM, then hexanes/acetone 30/1 to 20/1): 94.3
mg (0.243 mmol, 97%), colorless solid. mp: 161–162 °C.
Rf (hexanes/acetone 4:1): 0.24. 1H NMR (300 MHz, CDCl3):
8.71 (d, J = 4.8 Hz, 1H), 8.58 (d, J = 4.8 Hz, 1H), 7.69 – 7.53
(m, 2H), 7.39 (td, J = 7.8, 1.8 Hz, 1H), 7.25 – 6.94 (m, 11H),
6.81 (s, 1H), 6.74 – 6.67 (m, 2H), 6.02 (s, 2H). 13C NMR
(75.5 MHz, CDCl3): 152.5, 152.3, 149.5, 148.9, 139.7, 136.5,
136.1, 136.1, 134.3, 132.9, 128.5 (2C), 128.3 (2C), 128.0 (2C),
127.2, 126.5, 126.5 (2C), 125.9, 125.8, 122.7, 121.9, 121.1, 112.2,
48.9. HRMS (ESI): Exact mass calculated for C27H21N3Na
([M+Na]+): 410.1628, mass found: 410.1631.
7
8
9
2,2'-(1-Benzyl-3-(4-methoxyphenyl)-1H-pyrrole-2,5-diyl)
dipyridine (14e). Pyrrole 14e was prepared according to
general procedure B using 44.8 mg nitroalkene 9e and
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
80.0
mg
benzylamine.
Yield
after
column
chromatography
(flash
gel;
first
DCM,
then
hexanes/acetone 25/1 to 20/1): 98.0 mg (0.240 mmol,
94%), yellowish solid. mp: 141–143 °C. Rf (hexanes/acetone
1
4:1): 0.24. H NMR (300 MHz, CDCl3): 8.70 (d, J = 4.9 Hz,
1H), 8.57 (d, J = 4.9, 1H), 7.66 – 7.53 (m, 2H), 7.39 (td, J =
7.7, 1.9 Hz, 1H), 7.17 – 6.94 (m, 8H), 6.80 – 6.73 (m, 3H),
6.72 – 6.65 (m, 2H), 6.00 (s, 2H), 3.77 (s, 3H). 13C NMR
(75.5 MHz, CDCl3): 158.0, 152.6, 152.5, 149.5, 149.0, 139.9,
136.4, 136.0, 134.3, 132.6, 129.6 (2C), 128.8, 128.0 (2C), 127.1,
126.5 (2C), 126.5, 125.4, 122.6, 121.8, 121.0, 113.8 (2C), 112.1,
55.3, 48.8. HRMS (ESI): Exact mass calculated for
C28H24N3O ([M+H]+): 418.1914, mass found: 418.1914.
2,2'-(1-Phenethyl-3-phenyl-1H-pyrrole-2,5-diyl)dipyridine (14b).
Pyrrole 14b was prepared according to general
procedure B using 37.3 mg nitroalkene 9a and 90.9 mg
phenethylamine. Yield after column chromatography
(flash gel; hexanes/ethyl acetate 33/1 to 2.5/1): 94.7 mg
(0.237 mmol, 95%), colorless oil. Rf (hexanes/ethyl acetate
4:1): 0.26. 1H NMR (400 MHz, CDCl3): 8.84 (dd, J = 4.8 Hz,
1H), 8.73 (d, J = 4.8 Hz, 1H), 7.72 (td, J = 7.7, 1.9 Hz, 1H),
7.65 (d, J = 8.0 Hz, 1H), 7.54 (td, J = 7.7, 1.9 Hz, 1H), 7.30 –
7.14 (m, 10H), 7.09 (d, J = 7.8 Hz, 1H), 7.03 – 6.96 (m, 2H),
6.82 (d, J = 2.0 Hz, 1H), 4.95 – 4.83 (m, 2H), 3.08 – 2.96
(m, 2H). 13C NMR (101 MHz, CDCl3): 152.7, 152.5, 149.5,
148.8, 139.4, 136.4, 136.3, 136.1, 133.2, 132.3, 128.8 (2C), 128.5
(2C), 128.29 (2C), 128.28 (2C), 127.2, 126.1, 125.8, 125.1, 122.5,
121.9, 120.9, 111.6, 47.4, 38.1. HRMS (ESI): Exact mass
calculated for C28H24N3 ([M+H]+): 402.1964, mass found:
402.1960.
2,2'-(1-Benzyl-3-(4-bromophenyl)-1H-pyrrole-2,5-diyl)
dipyridine (14f). Pyrrole 14f was prepared according to
general procedure B using 57.0 mg nitroalkene 9f and
80.0
chromatography
mg
benzylamine.
(flash
Yield
first
after
DCM,
column
then
gel;
hexanes/acetone 30/1 to 20/1): 89.8 mg (0.190 mmol,
77%), yellowish solid. mp: 160–162 °C. Rf (hexanes/acetone
1
4:1): 0.39. H NMR (300 MHz, CDCl3): 8.71 (d, J = 4.9, 1H),
8.58 (d, J = 4.9, 1H), 7.69 – 7.52 (m, 2H), 7.42 (td, J = 7.7,
1.9 Hz, 1H), 7.35 – 7.27 (m, 2H), 7.18 – 6.93 (m, 8H), 6.76
(s, 1H), 6.72 – 6.64 (m, 2H), 5.98 (s, 2H). 13C NMR (75.5
MHz, CDCl3): 152.4, 152.1, 149.7, 149.0, 139.6, 136.5, 136.2,
135.2, 134.5, 133.1, 131.4 (2C), 130.0 (2C), 128.1 (2C), 127.1,
126.6, 126.5 (2C), 124.4, 122.7, 122.1, 121.2, 119.7, 111.8, 48.9.
HRMS (ESI): Exact mass calculated for C27H21BrN3
([M+H]+): 466.0914, mass found: 466.0913.
2,2'-(1-(4-Methoxyphenyl)-3-phenyl-1H-pyrrole-2,5-
diyl)dipyridine (14c). Pyrrole 14c was prepared according
to general procedure B using 37.3 mg nitroalkene 9a
and 92.4 mg 4-methoxyanillin. Yield after column
2,2'-(1-Benzyl-3-(3-bromophenyl)-1H-pyrrole-2,5-diyl)
dipyridine (14g). Pyrrole 14g was prepared according to
general procedure B using 57.0 mg nitroalkene 9g and
chromatography
(flash
gel;
first
DCM,
then
hexanes/acetone 30/1 to 7/1): 95.9 mg (0.238 mmol, 95%),
colorless oil. Rf (hexanes/acetone 4:1): 0.21. 1H NMR
(400 MHz, CDCl3): 8.52 (t, J = 4.4 Hz, 2H), 7.47 – 7.38 (m,
2H), 7.32 – 7.27 (m, 2H), 7.25 – 7.17 (m, 2H), 7.17 – 7.08 (m,
4H), 7.08 – 7.00 (m, 3H), 6.87 (d, J = 8.0 Hz, 1H), 6.75 –
6.67 (m, 2H), 3.74 (s, 3H). 13C NMR (101 MHz, CDCl3):
158.6, 152.2, 151.2, 149.3, 149.1, 136.1, 135.77, 135.7, 134.6,
133.8, 132.2, 130.1 (2C), 128.4 (2C), 128.2 (2C), 127.1, 125.9,
125.5, 122.4, 121.9, 120.9, 113.6 (2C), 112.6, 55.4. HRMS (ESI):
Exact mass calculated for C27H22N3O ([M+H]+): 404.1757,
mass found: 404.1754.
80.0
mg
benzylamine.
Yield
after
column
chromatography
(flash
gel;
first
DCM,
then
hexanes/acetone 30/1 to 20/1): 89.8 mg (0.23 mmol, 92%),
brownish solid. mp: 96–97 °C. Rf (hexanes/acetone 4:1):
1
0.40. H NMR (400 MHz, CDCl3): 8.74 (m, 1H), 8.60 (m,
1H), 7.70 – 7.54 (m, 2H), 7.53 – 7.40 (m, 2H), 7.35 – 7.22
(m, 1H), 7.17 (m, 1H), 7.06 (m, 7H), 6.85 – 6.78 (m, 1H),
6.73 (m, 2H), 6.02 (s, 2H). 13C NMR (101 MHz, CDCl3):
152.3, 151.8, 149.7, 149.0, 139.5, 138.3, 136.5, 136.1, 134.4, 133.2,
131.1, 129.7, 128.7, 128.0 (2C), 127.0, 126.9, 126.5, 126.4 (2C),
123.9, 122.6, 122.4, 122.2, 121.2, 111.7, 48.8. HRMS (ESI):
Exact mass calculated for C27H21BrN3 ([M+H]+): 466.0914,
mass found: 466.0913.
2,2'-(3-Phenyl-1H-pyrrole-2,5-diyl)dipyridine (14d). Pyrrole
14d was prepared according to general procedure B
using 37.3 mg nitroalkene 9a and 57.8 mg ammonium
acetate. Yield after column chromatography (flash gel;
hexanes/ethyl acetate 99/1 to 5/1): 72.6 mg (0.244 mmol,
2-(1-Benzyl-2,5-di(pyridin-2-yl)-1H-pyrrol-3-yl)benzonitrile (14h).
Pyrrole 14h was initially prepared according to general
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procedure B using 43.5 mg nitroalkene 9h. However,
Page 8 of 13
8.49 (m, 2H), 7.75 – 7.46 (m, 5H), 7.17 – 6.94 (m, 2H), 6.88
(d, J = 2.7 Hz, 1H), 6.51 (d, J = 1.3 Hz, 2H). 13C NMR (101
MHz, CDCl3): 150.3, 150.0, 149.8, 149.32, 149.25, 141.2, 136.5,
136.3, 132.2, 129.6, 121.4, 121.3, 120.5, 118.6, 115.3, 111.4, 109.8,
107.2. HRMS (ESI): Exact mass calculated for C18H14N3O
([M+H]+): 288.1131, mass found: 288.1128.
1
2
3
4
5
6
7
8
milder conditions were used for the Paal-Knorr reaction
by adding first 147 mg benzylamine (1.4 mmol, 5.5 equiv)
then 45.0 mg acetic acid (0.75 mmol, 3.0 equiv) and
heating the reaction overnight at 50 °C. Yield after
column chromatography (hexanes/ethyl acetate 2/1):
60.3 mg (0.17 mmol, 59%), yellowish oil. Rf (hexanes/ethyl
1-(Furan-2-yl)-2-phenyl-4-(pyridin-2-yl)butane-1,4-dione (17a).
1,4-Diketone 17a was prepared according to general
procedure C using 37.3 mg nitroalkene 9a (0.250 mmol,
1.0 equiv), 10.4 mg K2CO3 (0.0750 mmol, 0.30 equiv),
thiourea B (0.0500 mmol, 0.20 equiv), 18.1 mg catalyst A
(0.0500 mmol, 0.20 equiv) and 17.2 mg 26.4 mg furfural
(0.280 mmol, 1.1 equiv). For the elimination-Stetter
reaction sequence 41.5 mg K2CO3 (0.300 mmol, 1.2 equiv)
and 40.3 mg 2-pyridine carbaldehyde (0.38 mmol, 1.5
equiv) were used. Yield after column chromatography
(flash gel; hexanes/EtOAc 33/1 to 3/1): 70.5 mg (0.231
mmol, 93%), colorless oil. Rf (hexanes/EtOAc 4/1): 0.19.
1H NMR (400 MHz, CDCl3): 8.66 (d, J = 4.8 Hz, 1H), 7.98
(d, J = 7.8 Hz, 1H), 7.79 (td, J = 7.7, 1.8 Hz, 1H), 7.56 – 7.52
(m, 1H), 7.48 – 7.38 (m, 3H), 7.29 (t, J = 7.5 Hz, 2H), 7.25 –
7.19 (m, 2H), 6.49 – 6.44 (m, 1H), 5.07 (dd, J = 10.5, 3.8 Hz,
1H), 4.39 (dd, J = 19.1, 10.5 Hz, 1H), 3.62 (dd, J = 19.1, 3.8
Hz, 1H). 13C NMR (75 MHz, CDCl3): 199.7, 187.9, 153.0,
152.4, 149.1, 146.5, 138.4, 136.9, 129.0 (2C), 128.5 (2C), 127.43,
127.39, 121.9, 118.1, 112.3, 48.9, 42.3. HRMS (ESI): Exact mass
calculated for C19H16NO3 ([M+H]+): 306.1124, mass found:
306.1117.
1
acetate 2:1): 0.26. H NMR (300 MHz, CDCl3): 8.72 (d,
J = 4.9 Hz, 1H), 8.58 (d, J = 4.9 Hz, 1H), 7.69 – 7.62 (m, 1H),
7.56 (dt, J = 8.0, 1.1 Hz, 1H), 7.52 – 7.43 (m, 2H), 7.42 – 7.36
(m, 2H), 7.29 – 7.22 (m, 1H), 7.22 – 7.16 (m, 1H), 7.15 – 7.09
(m, 1H), 7.05 – 6.95 (m, 4H), 6.80 (s, 1H), 6.72 – 6.65 (m,
2H), 5.94 (s, 2H). 13C NMR (101 MHz, CDCl3): 151.9, 151.4,
149.9, 148.8, 139.2, 137.4, 136.8, 136.4, 134.4, 133.5, 132.6,
131.6, 129.3, 129.1, 128.1 (2C), 126.9, 126.7, 126.4 (2C), 123.2,
122.8, 122.6, 121.4, 119.1, 112.4, 111.7, 49.0. HRMS (ESI):
Exact mass calculated for C28H21N4 ([M+H]+): 413.1760,
mass found: 413.1750.
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2,2'-(1-Benzyl-3-(2-fluorophenyl)-1H-pyrrole-2,5-diyl)
dipyridine (14i). Pyrrole 14i was prepared according to
general procedure B using 41.8 mg nitroalkene 9i and
80.0
chromatography
mg
benzylamine.
(flash
Yield
first
after
DCM,
column
then
gel;
hexanes/acetone 30/1 to 20/1): 75.3 mg (0.19 mmol, 74%),
brownish solid. mp: 140–141 °C. Rf (hexanes/acetone 4:1):
1
0.33. H NMR (300 MHz, CDCl3): 8.68 (d, J = 4.9 Hz, 1H),
8.58 (d, J = 4.9 Hz, 1H), 7.67 – 7.54 (m, 2H), 7.42 – 7.34 (m,
1H), 7.19 – 7.05 (m, 4H), 7.05 – 6.92 (m, 6H), 6.83 (d, J =
1.8 Hz, 1H), 6.75 – 6.67 (m, 2H), 6.11 (s, 2H). 13C NMR (75.5
3,6-Diphenyl-1-(pyridin-2-yl)hexane-1,4-dione (17b). 1,4-Di-
ketone 17b was prepared according to general
procedure C using 37.3 mg nitroalkene 9a (0.25 mmol,
1.0 equiv), 13.8 mg K2CO3 (0.100 mmol, 0.40 equiv),
17.2 mg thiourea B (0.0500 mmol, 0.20 equiv), 18.1 mg
catalyst A (0.0500 mmol, 0.20 equiv) and 50.3 mg
3-phenylpropionaldehyde (0.380 mmol, 1.5 equiv). For the
elimination-stetter reaction sequence 38.0 mg K2CO3
(0.280 mmol, 1.1 equiv) and 40.3 mg 2-pyridine
carbaldehyde (0.380 mmol, 1.5 equiv) were used. Yield
after column chromatography (flash gel; hexanes/EtOAc
50/1 to 4/1): 45.3 mg (0.132 mmol, 53%), yellowish oil. Rf
(hexanes/ethyl acetate 4:1): 0.50. 1H NMR (400 MHz,
CDCl3): 8.67 (d, J = 4.7 Hz, 1H), 8.01 (d, J = 7.9 Hz, 1H),
7.82 (td, J = 7.7, 1.7 Hz, 1H), 7.50 – 7.42 (m, 1H), 7.34 – 7.19
(m, 7H), 7.19 – 7.14 (m, 1H), 7.12 – 7.06 (m, 2H), 4.44 – 4.25
(m, 2H), 3.42 (dd, J = 18.5, 3.3 Hz, 1H), 3.01 – 2.87 (m, 2H),
2.87 – 2.75 (m, 2H). 13C NMR (101 MHz, CDCl3): 208.4,
200.0, 153.1, 149.1, 141.2, 138.0, 136.9, 129.1 (2C), 128.5 (2C),
128.4 (2C), 128.3 (2C), 127.6, 127.4, 126.0, 121.9, 53.7, 43.3,
41.7, 29.8. HRMS (ESI): Exact mass calculated for
C23H22NO2 ([M+H]+): 344.1645, mass found: 344.1640.
1
MHz, CDCl3): 160.0 (d, JCF = 245 Hz), 152.6, 152.3, 149.5,
149.0, 139.8, 136.4, 136.0, 134.3, 134.2 (d, 2JCF = 14 Hz), 131.8
3
3
(d, JCF = 4 Hz), 128.0 (2C), 127.8 (d, JCF = 8 Hz), 126.50
3
4
(2C), 126.47, 126.2, 124.0 (d, JCF = 14 Hz), 123.8 (d, JCF = 4
2
Hz), 122.7, 121.8, 121.0, 119.1, 115.8 (d, JCF = 22 Hz), 113.3 (d,
4JCF = 3 Hz), 48.9. 19F NMR (377 MHz, CDCl3): -114.8.
HRMS (ESI): Exact mass calculated for C27H21FN3
([M+H]+): 406.1714, mass found: 406.1709.
2,2'-(1-Benzyl-3-o-tolyl-1H-pyrrole-2,5-diyl)dipyridine (14j).
Pyrrole 14j was prepared according to general procedure
B using 40.8 mg nitroalkene 9j and 80.0 mg benzylamine.
Yield after column chromatography (flash gel; first DCM,
then hexanes/acetone 30/1 to 20/1): 44.2 mg (0.11 mmol,
44%), colorless solid. mp: 153–155 °C. Rf (hexanes/acetone
4:1): 0.45. 1H NMR (300 MHz, CDCl3): 8.67 – 8.56 (m, 2H),
7.66 – 7.52 (m, 2H), 7.31 – 7.18 (m, 2H), 7.17 – 7.06 (m, 4H),
7.06 – 6.97 (m, 4H), 6.76 – 6.68 (m, 3H), 6.67 – 6.63 (m,
13
1H), 6.19 (s, 2H), 2.08 (s, 3H). C NMR (101 MHz, CDCl3):
152.4, 152.1, 149.0, 148.9, 140.2, 136.9, 136.5, 136.3, 136.0,
134.6, 133.5, 131.2, 130.1, 128.0 (2C), 126.8, 126.4, 126.3 (2C),
126.0, 125.8, 125.6, 122.8, 121.2, 121.1, 113.7, 49.1, 20.5. HRMS
(ESI): Exact mass calculated for C28H24N3 ([M+H]+):
402.1965, mass found: 402.1965.
1-(Furan-2-yl)-3,6-diphenylhexane-1,4-dione (17c). 1,4-Dike-
tone 17c was prepared according to general procedure C
using 37.3 mg nitroalkene 9a (0.250 mmol, 1.0 equiv), 13.8
mg K2CO3 (0.100 mmol, 0.40 equiv), 17.2 mg thiourea B
2,2'-(3-(Furan-2-yl)-1H-pyrrole-2,5-diyl)dipyridine
(14m).
Pyrrole 14m was prepared according to general
procedure B using 34.8 mg nitroalkene 9m and 57.8 mg
ammonium acetate. Yield after column chromatography
(flash gel; hexanes/ethyl acetate 99/1 to 2/1): 50.1 mg
(0.174 mmol, 70%), colorless oil. Rf (hexanes/ethyl acetate
(0.0500 mmol, 0.20 equiv), 18.1 mg catalyst
A
(0.0500 mmol, 0.20 equiv) and 50.3 mg 3-phenylpropion-
aldehyde (0.380 mmol, 1.5 equiv). For the elimination-
Stetter reaction sequence 38.0 mg K2CO3 (0.275 mmol,
1.1 equiv) and 36.0 mg furfural (0.380 mmol, 1.5 equiv)
1
4:1): 0.29. H NMR (300 MHz, CDCl3): 10.68 (s, 1H), 8.62 –
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The Journal of Organic Chemistry
were used. Yield after column chromatography (flash gel; 128.1 (2C), 127.6, 127.1, 126.7, 126.3, 126.2 (2C), 125.9, 121.5,
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5
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hexanes/EtOAc 33/1 to 3/1, hexanes/Et2O 33/1 to 2.5/1):
54.7 mg (0.165 mmol, 66%), yellowish oil. Rf
(hexanes/EtOAc 4/1): 0.47. H NMR (400 MHz, CDCl3):
110.6, 48.7. HRMS (ESI): Exact mass calculated for
C28H23N2 ([M+H]+): 387.1856, mass found: 387.1848.
1
2-(1-Benzyl-5-phenethyl-3-phenyl-1H-pyrrol-2-yl)pyridine (18c).
Pyrrole 18c was prepared according to general
procedure D using 37.3 mg nitroalkene 9a (0.250 mmol,
1.0 equiv), 10.4 mg K2CO3 (0.0750 mmol, 0.30 equiv),
18.1 mg catalyst A (0.0500 mmol, 0.20 equiv), 29.5 mg
2-pyridine carbaldehyde (0.28 mmol, 1.1 equiv) and
toluene as the solvent. For the elimination-Stetter
reaction sequence 41.5 mg K2CO3 (0.300 mmol, 1.2 equiv)
and 50.3 mg 3-phenylpropionaldehyde (0.380 mmol,
1.5 equiv) were used. Initially 80.0 mg benzylamine
(0.750 mmol, 3.0 equiv), then 2 mL acetic acid were added
for the Paal-Knorr reaction. Moreover, the reaction vessel
was heated at 70 °C. The crude reaction mixture was ex-
tracted as described in general procedure D. Yield after
column chromatography (flash gel; DCM): 43.2 mg (0.10
mmol, 42%), yellowish oil. Rf (DCM): 0.42. 1H NMR
(400 MHz, CDCl3): 8.67 (d, J = 5.1 Hz, 1H), 7.48 – 7.40 (m,
1H), 7.34– 7.28 (m, 3H), 7.26 – 7.10 (m, 11H), 7.07 (d, J =
8.0 Hz, 1H), 6.90 – 6.83 (m, 2H), 6.29 (s, 1H), 5.50 (s, 2H),
3.02 – 2.94 (m, 2H), 2.94 – 2.84 (m, 2H). 13C NMR (101
MHz, CDCl3): 152.3, 148.9, 141.6, 139.1, 136.8, 136.5, 135.6,
128.62 (2C), 128.55 (2C), 128.53 (2C), 128.47, 128.46 (2C),
128.3 (2C), 127.0, 126.9, 126.2, 126.0 (2C), 125.7, 125.2, 121.4,
107.9, 47.6, 35.2, 28.7. HRMS (ESI): Exact mass calculated
for C30H27N2 ([M+H]+): 415.2169, mass found: 415.2165.
7.59 (d, J = 1.6 Hz, 1H), 7.40 – 7.14 (m, 9H), 7.14 – 7.07 (m,
2H), 6.55 (dd, J = 3.6, 1.7 Hz, 1H), 4.43 (dd, J = 10.1, 4.1 Hz,
1H), 3.92 (dd, J = 17.8, 10.0 Hz, 1H), 3.05 (dd, J = 17.8, 4.1
Hz, 1H), 3.00 – 2.74 (m, 4H). 13C NMR (101 MHz, CDCl3):
208.2, 187.3, 152.4, 146.5, 141.0, 137.7, 129.2 (2C), 128.42 (2C),
128.41 (2C), 128.3 (2C), 127.7, 126.0, 117.3, 112.3, 53.0, 43.2,
41.7, 29.8. HRMS (ESI): Exact mass calculated for
C22H20NaO3 ([M+Na]+): 355.1305, mass found: 355.1301.
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2-(1-Benzyl-5-(furan-2-yl)-3-phenyl-1H-pyrrol-2-yl)pyridine (18a).
Pyrrole 18a was prepared according to general
procedure D using 37.3 mg nitroalkene 9a (0.250 mmol,
1.0 equiv), 10.4 mg K2CO3 (0.075 mmol, 0.3 equiv), 18.1 mg
catalyst A (0.0500 mmol, 0.2 equiv), 29.5 mg 2-pyridine
carbaldehyde (0.280 mmol, 1.1 equiv) and toluene as the
solvent. For the elimination-Stetter reaction sequence
41.5 mg K2CO3 (0.300 mmol, 1.2 equiv) and 36.0 mg
furfural (0.380 mmol, 1.5 equiv) were used. Initially
80.0 mg benzylamine (0.750 mmol, 3.0 equiv), then 2 mL
acetic acid were added for the Paal-Knorr reaction.
Moreover, the reaction vessel was heated at 100 °C. The
crude reaction mixture was extracted as described in
general procedure D. Yield after column chromato-
graphy (flash gel; DCM): 36.0 mg (0.0960 mmol, 38%),
1
yellowish solid. mp: 135–136 °C. Rf (DCM): 0.37. H NMR
(400 MHz, CDCl3): 8.68 (d, J = 5.0 Hz, 1H), 7.45 – 7.42 (m,
1H), 7.39 (td, J = 7.7, 1.8 Hz, 1H), 7.25– 7.19 (m, 4H), 7.18 –
7.06 (m, 5H), 6.99 (d, J = 8.0 Hz, 1H), 6.79 (d, J = 7.9 Hz,
2H), 6.69 (s, 1H), 6.43– 6.36 (m, 1H), 6.31 (d, J = 3.3 Hz,
1H), 5.63 (s, 2H). 13C NMR (101 MHz, CDCl3): 151.9, 149.2,
147.1, 141.8, 138.9, 136.2, 136.0, 130.7, 128.5 (2C), 128.24 (2C),
128.22 (2C), 127.0, 126.8, 126.7, 126.1 (2C), 125.9, 125.8, 121.7,
111.2, 110.3, 107.4, 48.9. HRMS (ESI): Exact mass calculated
for C26H21N2O ([M+H]+): 377.1648, mass found: 377.1646.
2-(1-Benzyl-5-(furan-2-yl)-4-phenyl-1H-pyrrol-2-yl)pyridine (18d).
Pyrrole 18d was prepared according to general
procedure D using 37.3 mg nitroalkene 9a (0.250 mmol,
1.0 equiv), 10.4 mg K2CO3 (0.0750 mmol, 0.30 equiv),
18.1 mg catalyst A (0.0500 mmol, 0.20 equiv), 17.2 mg
thiourea B (0.0500 mmol, 0.20 equiv), 26.4 mg furfural
(0.280 mmol, 1.1 equiv) and Et2O as the solvent. For the
elimination-Stetter reaction sequence 41.5 mg K2CO3
(0.300 mmol, 1.2 equiv) and 40.3 mg 2-pyridine
carbaldehyde (0.38 mmol, 1.5 equiv) were used. Initially
147 mg benzylamine (1.38 mmol, 5.5 equiv), then 45 mg
acetic acid (0.75 mmol, 3.0 equiv) were added for the
Paal-Knorr reaction. Moreover, the reaction vessel was
heated at 50 °C. The crude reaction mixture was directly
submitted to column chromatography. Yield after column
chromatography (2x; flash gel; DCM): 78.8 mg (0.21
mmol, 84%), yellowish solid. mp: 103–162 °C. Rf (DCM):
2-(1-Benzyl-3,5-diphenyl-1H-pyrrol-2-yl)pyridine (18b).
Pyrrole 18b was prepared according to general
procedure D using 37.3 mg nitroalkene 9a (0.250 mmol,
1.0 equiv), 10.4 mg K2CO3 (0.0750 mmol, 0.30 equiv), 18.1
mg catalyst A (0.0500 mmol, 0.20 equiv), 29.5 mg
2-pyridine carbaldehyde (0.280 mmol, 1.1 equiv) and
toluene as the solvent. For the elimination-Stetter
reaction sequence 41.5 mg K2CO3 (0.300 mmol, 1.2 equiv)
and 39.8 mg benzaldehyde (0.380 mmol, 1.5 equiv) were
used. Initially 80.0 mg benzylamine (0.750 mmol, 3.0
equiv), then 2 mL acetic acid were added for the Paal-
Knorr reaction. Moreover, the reaction vessel was heated
at 100 °C. The crude reaction mixture was extracted as
described in general procedure D. Yield after column
chromatography (flash gel; DCM): 35.2 mg (0.091 mmol,
36%), yellowish solid. mp: 96–97 °C. Rf (DCM): 0.39.
1H NMR (400 MHz, CDCl3): 8.68 (d, J = 5.1 Hz, 1H), 7.51 –
7.46 (m, 2H), 7.41 – 7.30 (m, 4H), 7.25 – 7.19 (m, 4H), 7.18
– 7.13 (m, 1H), 7.10 – 7.05 (m, 1H), 7.04 – 6.99 (m, 3H), 6.91
(d, J = 8.0 Hz, 1H), 6.62 – 6.54 (m, 2H), 6.47 (s, 1H), 5.52 (s,
2H). 13C NMR (101 MHz, CDCl3): 152.3, 149.0, 139.2, 137.8,
136.3 (2C), 133.3, 130.1, 129.6 (2C), 128.6 (4C), 128.3 (2C),
1
0.56. H NMR (400 MHz, CDCl3): 8.59 (d, J = 5.1 Hz, 1H),
7.71 – 7.62 (m, 1H), 7.61 – 7.54 (m, 1H), 7.54 – 7.48 (m, 1H),
7.37 – 7.28 (m, 4H), 7.26 – 7.07 (m, 5H), 6.96 – 6.86 (m,
3H), 6. 48 – 6.37 (m, 1H), 6. 32 – 6.27 (m, 1H), 5.81 (s, 2H).
13C NMR (101 MHz, CDCl3): 152.2, 148.7, 145.6, 142.9, 139.6,
136.8, 135.7, 133.8, 128.3 (2C), 128.2 (2C), 127.6 (2C), 126.7
(2C), 126.4 (2C), 126.0, 124.1, 122.4, 121.2, 112.3, 111.6, 111.1,
49.4. HRMS (ESI): Exact mass calculated for C26H21N2O
([M+H]+): 377.1643, mass found: 377.1648.
2-(1-Benzyl-5-phenethyl-4-phenyl-1H-pyrrol-2-yl)pyridine (18e).
Pyrrole 18e was prepared according to general
procedure D using 37.3 mg nitroalkene 9a (0.25 mmol,
1.0 equiv), 13.8 mg K2CO3 (0.100 mmol, 0.40 equiv),
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18.1 mg catalyst A (0.0500 mmol, 0.20 equiv), 17.2 mg
thiourea (0.0500 mmol, 0.20 equiv), 50.3 mg
36.0 mg furfural (0.380 mmol, 1.5 equiv) were used.
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4
5
6
7
8
B
Initially 147 mg benzylamine (1.38 mmol, 5.5 equiv), then
45.0 mg acetic acid (0.75 mmol, 3.0 equiv) were added for
the Paal-Knorr reaction. Moreover, the reaction vessel
was heated at 50 °C. The crude reaction mixture was
directly submitted to column chromatography. Yield after
column chromatography (flash gel; DCM): 76.7 mg
3-phenylpropionaldehyde (0.380 mmol, 1.5 equiv) and
Et2O as the solvent. For the elimination-stetter reaction
sequence 38.0 mg K2CO3 (0.280 mmol, 1.1 equiv) and
40.3 mg 2-pyridine carbaldehyde (0.380 mmol, 1.5 equiv)
were used. Initially 147 mg benzylamine (1.40 mmol, 5.5
equiv), then 45.0 mg acetic acid (0.750 mmol, 3.0 equiv)
were added for the Paal-Knorr reaction. Moreover, the
reaction vessel was heated at 50 °C. The crude reaction
mixture was directly submitted to column chromato-
graphy. Yield after column chromatography (flash gel;
hexanes/EtOAc 50/1): 76.5 mg (0.19 mmol, 74%),
yellowish oil. Rf (hexanes/ethyl acetate 4:1): 0.67.
1H NMR (400 MHz, CDCl3): 8.65 – 8.51 (m, 1H), 7.71– 7.65
(m, 1H), 7.63 – 7.58 (m, 1H), 7.58 – 7.53 (m, 2H), 7.47 (t, J =
7.6 Hz, 2H), 7.37 – 7.27 (m, 5H), 7.27 – 7.20 (m, 2H), 7.14 –
7.07 (m, 3H), 7.07 – 7.00 (m, 2H), 6.90 (s, 1H), 5.93 (s, 2H),
3.12 – 2.99 (m, 2H), 2.89 – 2.76 (m, 2H). 13C NMR (101
MHz, CDCl3): 152.0, 148.0, 141.3, 139.6, 137.2, 136.9, 134.0,
131.3, 128.6 (2C), 128.5 (4C), 128.3 (2C), 128.1 (2C), 127.0,
126.2, 126.0 (2C), 125.9, 123.8, 122.1, 120.6, 112.5, 48.4, 36.6,
27.5. HRMS (ESI): Exact mass calculated for C30H27N2
([M+H]+): 415.2169, mass found: 415.2169.
1
(0.19 mmol, 76%), yellowish oil. Rf (DCM): 0.95. H NMR
(400 MHz, CDCl3): 7.58 – 7.52 (m, 2H), 7.50 – 7.41 (m, 3H),
7.41 – 7.19 (m, 7H), 7.14 – 7.02 (m, 4H), 6.73 (s, 1H), 6.44 –
6.39 (m, 1H), 6.28 – 6.22 (m, 1H), 5.32 (s, 2H), 3.07 – 2.97
(m, 2H), 2.81 – 2.71 (m, 2H). 13C NMR (101 MHz, CDCl3):
147.6, 141.5, 141.3, 138.8, 137.0, 131.2, 128.9 (2C), 128.6 (4C),
128.4 (2C), 128.1 (2C), 127.3, 126.2, 125.9 (2C), 125.8, 124.5,
123.3, 111.2, 109.5, 106.3, 48.4, 36.7, 27.6. HRMS (ESI): Exact
mass calculated for C29H26NO ([M+H]+): 404.2009, mass
found: 404.2006.
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ASSOCIATED CONTENT
Supporting Information. Additional data for screening of
best conditions and copies of 1H NMR, 13C, NMR and 19F NMR
spectra for all new compounds (PDF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
1-Benzyl-2,5-diphenethyl-3-phenyl-1H-pyrrole (18f). Pyrrole
18f was prepared according to general procedure D
using 37.3 mg nitroalkene 9a (0.25 mmol, 1.0 equiv),
13.8 mg K2CO3 (0.100 mmol, 0.40 equiv), 18.1 mg catalyst A
(0.0500 mmol, 0.20 equiv), 17.2 mg thiourea B (0.0500
mmol, 0.20 equiv), 50.3 mg 3-phenylpropionaldehyde
(0.380 mmol, 1.5 equiv) and Et2O as the solvent. For the
elimination-Stetter reaction sequence 38.0 mg K2CO3
(0.280 mmol, 1.1 equiv) and 50.3 mg 3-phenylpropion-
aldehyde (0.380 mmol, 1.5 equiv) were used. Initially
147 mg benzylamine (1.40 mmol, 5.5 equiv), then 45.0 mg
acetic acid (0.750 mmol, 3.0 equiv) were added for the
Paal-Knorr reaction. Moreover, the reaction vessel was
heated at 50 °C. The crude reaction mixture was directly
submitted to column chromatography. Yield after column
chromatography (flash gel; DCM): 23.1 mg (0.0520 mmol,
AUTHOR INFORMATION
Corresponding Author
* E-mail: kzeitler@uni-leipzig.de
Funding Sources
Generous funding by the Deutsche Forschungsgemeinschaft
(DFG, FOR 1296) is gratefully acknowledged.
REFERENCES
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(7) For selected recent synthetic methods, see: (a) Yin, H.;
Nielsen, D. U.; Johansen, M. K.; Lindhardt, A. T.;
Skrydstrup, T. ACS Catal. 2016, 6, 2982–2987. (b)
Stepherson, J. R.; Fronczek, F. R. Kartika, R. Chem.
Commun. 2016, 52, 2300–2303. (c) Kwon, Y.; Schatz, D. J.;
West, F. G. Angew. Chem., Int. Ed. 2015, 54, 9940–9943.
(d) Baran P. S.; DeMartino, M. P. Angew. Chem., Int. Ed.
2006, 45, 7083–7086 and references cited therein.
(8) Yang, K. S.; Nibbs, A. E.; Türkmen, Y. E.; Rawal, V. H. J. Am.
Chem. Soc. 2013, 135, 16050–16053 and references cited
therein.
1
21%)41, yellowish oil. Rf (DCM): 0.94. H NMR (400 MHz,
CDCl3): 7.54 – 7.49 (m, 2H), 7.46 – 7.40 (m, 2H), 7.39 –
7.17 (m, 12H), 7.12 – 7.04 (m, 2H), 6.98 – 6.91 (m, 2H), 6.27
(s, 1H), 5.04 (s, 2H), 3.02 – 2.92 (m, 4H), 2.85 – 2.75 (m,
4H). 13C NMR (101 MHz, CDCl3): 141.8, 141.5, 138.7, 137.7,
132.4, 128.9 (2C), 128.53 (2C), 128.52 (2C), 128.50 (4C),
128.42, 128.37 (2C), 127.9 (2C), 127.3, 126.19, 126.16, 125.7
(2C), 125.4, 121.8, 106.2, 46.8, 37.3, 35.4, 28.8, 27.6. HRMS
(ESI): Exact mass calculated for C33H32N ([M+H]+):
442.2529, mass found: 442.2534.
1-Benzyl-5-(furan-2-yl)-2-phenethyl-3-phenyl-1H-pyrrole (18g).
Pyrrole 18g was prepared according to general
procedure D using 37.3 mg nitroalkene 9a (0.250 mmol,
1.0 equiv), 13.8 mg K2CO3 (0.100 mmol, 0.40 equiv),
18.1 mg catalyst A (0.0500 mmol, 0.20 equiv), 17.2 mg
thiourea B (0.0500 mmol, 0.20 equiv), 50.3 mg
3-phenylpropionaldehyde (0.380 mmol, 1.5 equiv) and
Et2O as the solvent. For the elimination-Stetter reaction
sequence 38.0 mg K2CO3 (0.275 mmol, 1.1 equiv) and
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(9) (a) Bugaut, X.; Glorius, F. Chem. Soc. Rev. 2012, 41, 3511–3522.
Gevorgyan, V. Chem. Rev. 2013, 113, 3084–3213. (c) Patil, N.
1
2
3
4
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7
8
(b) Seebach, D. Angew. Chem., Int. Ed. 1979, 18, 239–258.
(10) (a) Yetra, S. R.; Patra, A.; Biju, A. T. Synthesis 2015, 47,
1357–1378. (b) Christmann, M. Angew. Chem., Int. Ed. 2005,
44, 2632–2634. (c) Mattson, A. E.; Bharadwaj, A. R.;
Scheidt, K. A. J. Am. Chem. Soc. 2004, 126, 2314–2315.
(d) Stetter, H. Angew. Chem., Int. Ed. 1976, 15, 639–647.
(11) Ryu, I.; Kusano, K.; Yamazaki, H.; Sonoda, N. J. Org. Chem.
1991, 56, 5003–5005.
T.; Yamamoto, Y. Chem. Rev. 2008, 108, 3395–3442.
(24) For selected examples, see: (a) Torres, G. M.; Quesnel, J.
S.; Bijou, D.; Arndtsen, B. A. J. Am. Chem. Soc. 2016, 138,
7315–7324. (b) Pusch, S.; Kowalczyk, D.; Opatz, T. J. Org.
Chem. 2016, 81, 4170–4178. (c) Gilbert, Z. W.; Hue, R. J.;
Tonks, I. A. Nat. Chem. 2016, 8, 63–68. (d) Yu, S.; Xiong,
M.; Xie, X.; Liu, Y. Angew. Chem., Int. Ed. 2014, 53, 11596–
11599. (e) Jiang, Y.; Park, C.-M. Chem. Sci. 2014, 5, 2347–
2351. (f) Braun, R. U.; Zeitler, K.; Müller, T. J. J. Org. Lett.
2001, 3, 3297–3300.
(25) For selected examples, see: (a) Reekie, T. A.; Donckele, E.
J.; Manenti, G.; Puntener, S.; Trapp, N.; Diederich, F. Org.
Lett. 2016, 18, 2252–2255. (b) Xu, H.; Wang, F.-J.; Xin, M.;
Zhang, Z. Eur. J. Org. Chem. 2016, 925–929. (c) Zheng, Y.;
Wang, Y.; Zhou, Z. Chem. Commun. 2015, 51, 16652–16655.
(d) Vivekanand, T.; Vinoth, P.; Agieshkumar, B.; Sampath,
N.; Sudalai, A.; Menéndez, J. C.; Sridharan, V. Green Chem.
2015, 17, 3415–3423.
(12) For selected examples, see: (a) Custar, D. W.; Le, H.;
Morken, J. P. Org. Lett. 2010, 12, 3760–3763. (b) Seyferth,
D.; Hui, R. C. J. Am. Chem. Soc. 1985, 107, 4551–4553.
9
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12
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16
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18
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21
22
23
24
25
26
27
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29
30
31
32
33
34
35
36
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38
39
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42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
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58
59
60
(13) For
a related versatile carbonylative Heck reaction
employing substituted allylic alcohols, see ref. 7a.
(14) (a) Shen, Z.-L.; Goh, K. K. K.; Cheong, H.-L.; Wong, C. H.
A.; Lai, Y.-C.; Yang, Y.-S.; Loh, T.-P. J. Am. Chem. Soc. 2010,
132, 15852–15855. (b) Nomura, K.; Matsubara, S. Chem.
Asian J. 2010, 5, 147–152. (c) Ryu, I.; Ikebe, M.; Sonoda, N.;
Yamato, S.; Yamamura, G.; Komatsu, M. Tetrahedron Lett.
2002, 43, 1257–1259. (d) Aoki, S.; Fujimura, T.; Nakamura,
E.; Kuwajima, I. Tetrahedron Lett. 1989, 30, 6541–6544.
(15) (a) see ref. 7a. (b) Jang, H.-Y.; Hong, J.-B.; MacMillan, D. W.
C. J. Am. Chem. Soc. 2007, 129, 7004–7005. (c) see ref. 7d.
(d) Yasuda, Tsuji, M. S.; Shigeyoshi, Y.; Baba, A. J. Am. Chem.
Soc. 2002, 124, 7440–7447. (e) Ito, Y.; Konoike, T.; Harada, T.;
Saegusa, T. J. Am. Chem. Soc. 1977, 99, 1487–1493.
(16) Setzer, P.; Beauseigneur, A.; Pearson-Long; M. S. M.;
Bertus, P. Angew. Chem., Int. Ed. 2010, 49, 8691–8694.
(17) Trofimov, B. A.; Mikhaleva, A. I.; Schmidt, E. Y.;
Sobenina, L. N. The Chemistry of Pyrroles; CRC Press:
Boca Raton, 2015.
(18) For selected reviews, see: (a) Bhardwaj, V.; Gumber, D.;
Abbot, V.; Dhiman, S.; Sharma, P. RSC Adv. 2015, 5, 15233–
15266. (b) Bailly, C. Mar. Drugs 2015, 13, 1105–1123.
(c) Young, I. S.; Thornton, P. D.; Thompson, A. Nat. Prod.
Rep. 2010, 27, 1801–1839. (d) Fan, H.; Peng, J.; Hamann, M.
T.; Hu, J.-F. Chem. Rev. 2008, 108, 264–287. (e) Biava, M.;
Porretta, G. C.; Manetti, F. Mini-Rev. Med. Chem. 2007, 7,
65–78. (f) Gupton, J. T. Top. Heterocycl. Chem. 2006, 2, 53–
92. (g) Bellina, F.; Rossi, R. Tetrahedron 2006, 62, 7213–
7256. (h) Walsh, C. T.; Garneau-Tsodikova, S.; Howard-
Jones, A. R. Nat. Prod. Rep. 2006, 23, 517–531. (i) Fürstner,
A. Angew. Chem., Int. Ed. 2003, 42, 3582–3603.
(19) For a selected review, see: (a) Mal, D.; Shome, B.; Dinda, B.
K. in Heterocycles in Natural Product Synthesis, ed.
Majumdar, K. C.; Chattopadhyay, S. K. Wiley-VCH,
Weinheim, 2011, p. 187; for a selected example, see: (b)
Gröst, C.; Berg, T. Org. Biomol. Chem. 2015, 13, 3866–3870.
(20) (a) Khajuria, R.; Dham, S.; Kapoor, K. K. RSC Adv. 2016, 6,
37039–37066. (b) Takase, M.; Yoshida, N.; Narita, T.; Fujio,
T.; Nishinaga, T.; Iyoda, M. RSC Adv. 2012, 2, 3221–3224.
(c) Lazerges, M.; Chane-Ching, K. I.; Aeiyach, S.; Chelli, S.;
Peppin-Donnat, M.; Billon, M.; Lombard, C.; Maurel, F.;
Jouini, M. J. Solid State Electrochem. 2009, 13, 231–238.
(d) Domingo, V. M.; Alemán, C.; Brillas, E.; Juliá, L. J. Org.
Chem. 2001, 66, 4058–4061.
(26) For selected reviews, see: (a) Estévez, V.; Villacampa, M.;
Menéndez, J. C. Chem. Soc. Rev. 2014, 43, 4633–4657.
(b) Cioc, R. C.; Ruijter, E.; Orru, R. V. A. Green Chem. 2014,
16, 2958–2975.
(27) de Laszlo, S. E.; Visco, D.; Agarwai, L.; Chang, L.; Chen, J.;
Croft, G.; Forsyth, A.; Flétcher, D.; Frantz, B.; Hacker, C.;
Hanlon, W.; Harper, C.; Kostura, M.; Li, B.; Luell, S.;
MacCoss, M.; Mantlo, N.; O’Neill, E. A.; Orevillo, C.; Pang,
M.; Parsons, J.; Rolando, A.; Sahly, Y.; Sidler, K.; Widmer, W.
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(28) (a) Cascieri, M. A.; Koch, G. E.; Ber, E.; Sadowski, S. J.;
Louizides, D.; de Laszlo, S. E.; Hacker, C.; Hagman, W. K.;
MacCoss, M.; Chicchi, G. C.; Vicario, P. P. J. Biol. Chem.
1999, 274, 8694–8697; (b) de Laszlo, S. E.; Hacker, C.; Li,
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Chem. Soc. 2009, 131, 12703–12713.
(30) For an insightful, recent review on NHC catalysis, see:
Flanigan, D. M.; Romanov-Michailidis, F.; White, N. A.;
Rovis, T. Chem. Rev. 2015, 115, 9307–9387.
(31) (a) Patterson, J. W.; McMurry, J. E. Chem. Commun. 1971,
488–489; (b) Ono, N.; Tamura, R.; Eto, H.; Hamamoto, I.;
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3678–3684; (c) Ballini, R.; Bosica, G. Tetrahedron 1995, 51,
4213–4222; (d) Arai, N.; Narasaka, K. Bull. Chem. Soc. Jpn.
1997, 70, 2525–2534; (e) Steward, K. M.; Johnson, J. S. Org.
Lett. 2011, 13, 2426–2429.
(32) For selected publications on NHC-catalyzed nitro-Stetter
reactions, see: (a) DiRocco, D. A.; Noey, E. L.; Houk, K. N.;
Rovis, T. Angew. Chem., Int. Ed. 2012, 51, 2391–2394.
(b) DiRocco, D. A.; Rovis, T. J. Am. Chem. Soc. 2011, 133,
10402–10405. (c) Um, J. M.; DiRocco, D. A.; Noey, E. L.;
Rovis, T.; Houk, K. N. J. Am. Chem. Soc. 2011, 133, 11249–
11254. (d) DiRocco, D. A.; Oberg, K. M.; Dalton, D. M.;
Rovis, T. J. Am. Chem. Soc. 2009, 131, 10872–10874.
(e) Mattson, A. E.; Zuhl, A. M.; Reynolds, T. E.; Scheidt, K.
A. J. Am. Chem. Soc. 2006, 128, 4932–4933. For a dual
catalytic nitro-Stetter-Michael-aldol-reaction, please see:
(f) Hong, B. C.; Dange, N. S.; Hsu, C.-S.; Liao, J.-H. Org.
Lett. 2010, 12, 4812–4815.
(21) For a selected review, see: Leeper, F. J.; Kelly, J. M. Org.
Prep. Proc. Int. 2013, 45, 171–210.
(22) (a) Chen, G.-Q.; Zhang, X.-N.; Wei, Y.; Tang, X.-Y.; Shi, M.
Angew. Chem., Int. Ed. 2014, 53, 8492–8497. (b) Kim, C.-E.;
Park, S.; Eom, D.; Seo, B.; Lee, P. H. Org. Lett. 2014, 16,
1900–1903. (c) Shen, J.; Cheng G.; Cui, X. Chem. Commun.
2013, 49, 10641–10643.
(23) For selected reviews, see: (a) Zhou, N.-N.; Zhu, H.-T.;
Yanga, D.-S.; Guan, Z.-H. Org. Biomol. Chem. 2016, 14,
7136–7149. (b) Gulevich, A. V.; Dudnik, A. S.; Chernyak, N.;
(33) For a comprehensive review on H-bonding catalysis, see:
Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713–
5743.
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Page 12 of 13
(34) For seminal examples, see: (a) ref. 32e. (b) Jin, Z.; Xu, J.;
1
2
3
4
5
6
7
8
Yang, S.; Song, B.-A.; Chi, Y. R. Angew. Chem., Int. Ed. 2013,
52, 12354–12358. (c) for a review on cooperative NHC
catalysis, see: Wang, M. H.; Scheidt, K. A. Angew. Chem.,
Int. Ed. 2016, 55, 14912–14922.
(35) Tiwari, B.; Zhang, J.; Chi, Y. R. Angew. Chem., Int. Ed. 2012,
51, 1911–1914.
(36) Both β-nitroketone 10 (34%) and Michael acceptor 11
(38%) were isolated, but showed rapid decomposition
during and after their isolation.
9
(37) Cai, S.; Zhang, S.; Zhao, Y.; Wang, D. Z. Org. Lett. 2013, 15,
2660–2663.
10
11
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(38) Cheng, P.; Chen, J.-J.; Huang, N.; Wang, R.-R.; Zheng, Y.-
T.; Liang, Y.-Z. Molecules 2009, 14, 3176–3186.
(39) Boyce, G. R.; Johnson, J. S. J. Org. Chem. 2016, 81, 1712–1717.
(40) Lu, A.; Wang, Z.; Zhou, Z.; Chen, J.; Wang, Q. J. Agric.
Food Chem. 2015, 63, 1378–1384.
(41) Product contains an 2% impurity of the corresponding
furane, which could not be separated from the pyrrole.
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Table of Contents artwork
NHC
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
Paal -
Knorr
NHC
H-
bond
Multistep
MCR
R4
NO2
cooperative // cascade
catalysis
> 15 examples
up to 98% yield
= latent
traceless
activating group
biselectrophile
R1 = hetaryl, aliphat; R2 = (het)aryl, aliphat; R3 = aliphat, aryl, H; R4 = aryl, hetaryl
1
27
28
29
Taylor, A. P.; Robinson, R. P.; Fobian, Y. M.; Blakemore, D. C.; Jones L. H.; Fadeyi, O. Org. Biomol. Chem. 2016, 14, 6611–6637.
(a) Paal, C. Chem. Ber. 1884, 17, 2756–2767. (b) Knorr, L. Chem. Ber. 1884, 17, 2863–2870.
Baumann, M.; Baxendale, I. R.; Ley, S. V.; Nikbin, N. Beilstein J. Org. Chem. 2011, 7, 442–495.
Ziffle, V. E.; Cheng, P.; Clive, D. L. J. J. Org. Chem. 2010, 75, 8024–8038.
Guo, F.; Konkol, L. C.; Thomson, R. J. J. Am. Chem. Soc. 2011, 133, 18–20.
For reviews, see: (a) Miyakoshi, T. Org. Prep. Proced. Int. 1989, 21, 659–704. (b) Piancatelli, G.; D’Auria, M.; D’Onofrio, F. Synthesis 1994, 867–889.
For selected recent synthetic methods, see: (a) Yin, H.; Nielsen, D. U.; Johansen, M. K.; Lindhardt, A. T.; Skrydstrup, T. ACS Catal. 2016, 6, 2982–2987. (b) Stepherson, J. R.; Fronczek, F. R. Kartika, R. Chem. Commun. 2016, 52, 2300–2303. (c)
Kwon, Y.; Schatz, D. J.; West, F. G. Angew. Chem., Int. Ed. 2015, 54, 9940–9943. (d) Baran P. S.; DeMartino, M. P. Angew. Chem., Int. Ed. 2006, 45, 7083–7086 and references cited therein.
Yang, K. S.; Nibbs, A. E.; Türkmen, Y. E.; Rawal, V. H. J. Am. Chem. Soc. 2013, 135, 16050–16053 and references cited therein.
(a) Bugaut, X.; Glorius, F. Chem. Soc. Rev. 2012, 41, 3511–3522. (b) Seebach, D. Angew. Chem., Int. Ed. 1979, 18, 239–258.
(a) Yetra, S. R.; Patra, A.; Biju, A. T. Synthesis 2015, 47, 1357–1378. (b) Christmann, M. Angew. Chem., Int. Ed. 2005, 44, 2632–2634. (c) Mattson, A. E.; Bharadwaj, A. R.; Scheidt, K. A. J. Am. Chem. Soc. 2004, 126, 2314–2315. (d) Stetter, H.
Angew. Chem., Int. Ed. 1976, 15, 639–647.
2
3
4
5
6
7
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
8
9
10
11
12
Ryu, I.; Kusano, K.; Yamazaki, H.; Sonoda, N. J. Org. Chem. 1991, 56, 5003–5005.
For selected examples, see: (a) Custar, D. W.; Le, H.; Morken, J. P. Org. Lett. 2010, 12, 3760–3763. (b) Seyferth, D.; Hui, R. C. J. Am. Chem. Soc. 1985, 107, 4551–4553.
13 For a related versatile carbonylative Heck reaction employing substituted allylic alcohols, see ref. 7a.
14
(a) Shen, Z.-L.; Goh, K. K. K.; Cheong, H.-L.; Wong, C. H. A.; Lai, Y.-C.; Yang, Y.-S.; Loh, T.-P. J. Am. Chem. Soc. 2010, 132, 15852–15855. (b) Nomura, K.; Matsubara, S. Chem. Asian J. 2010, 5, 147–152. (c) Ryu, I.; Ikebe, M.; Sonoda, N.; Yamato,
S.; Yamamura, G.; Komatsu, M. Tetrahedron Lett. 2002, 43, 1257–1259. (d) Aoki, S.; Fujimura, T.; Nakamura, E.; Kuwajima, I. Tetrahedron Lett. 1989, 30, 6541–6544.
(a) see ref. 7a. (b) Jang, H.-Y.; Hong, J.-B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2007, 129, 7004–7005. (c) see ref. 7d. (d) Yasuda, Tsuji, M. S.; Shigeyoshi, Y.; Baba, A. J. Am. Chem. Soc. 2002, 124, 7440–7447. (e) Ito, Y.; Konoike, T.; Harada, T.;
15
Saegusa, T. J. Am. Chem. Soc. 1977, 99, 1487–1493.
16
Setzer, P.; Beauseigneur, A.; Pearson-Long; M. S. M.; Bertus, P. Angew. Chem., Int. Ed. 2010, 49, 8691–8694.
Trofimov, B. A.; Mikhaleva, A. I.; Schmidt, E. Y.; Sobenina, L. N. The Chemistry of Pyrroles; CRC Press: Boca Raton, 2015.
For selected reviews, see: (a) Bhardwaj, V.; Gumber, D.; Abbot, V.; Dhiman, S.; Sharma, P. RSC Adv. 2015, 5, 15233–15266. (b) Bailly, C. Mar. Drugs 2015, 13, 1105–1123. (c) Young, I. S.; Thornton, P. D.; Thompson, A. Nat. Prod. Rep. 2010, 27,
1801–1839. (d) Fan, H.; Peng, J.; Hamann, M. T.; Hu, J.-F. Chem. Rev. 2008, 108, 264–287. (e) Biava, M.; Porretta, G. C.; Manetti, F. Mini-Rev. Med. Chem. 2007, 7, 65–78. (f) Gupton, J. T. Top. Heterocycl. Chem. 2006, 2, 53–92. (g) Bellina, F.;
Rossi, R. Tetrahedron 2006, 62, 7213–7256. (h) Walsh, C. T.; Garneau-Tsodikova, S.; Howard-Jones, A. R. Nat. Prod. Rep. 2006, 23, 517–531. (i) Fürstner, A. Angew. Chem., Int. Ed. 2003, 42, 3582–3603.
17
18
19
For a selected review, see: (a) Mal, D.; Shome, B.; Dinda, B. K. in Heterocycles in Natural Product Synthesis, ed. Majumdar, K. C.; Chattopadhyay, S. K. Wiley-VCH, Weinheim, 2011, p. 187; for a selected example, see: (b) Gröst, C.; Berg, T. Org.
Biomol. Chem. 2015, 13, 3866–3870.
20
((a) Khajuria, R.; Dham, S.; Kapoor, K. K. RSC Adv. 2016, 6, 37039–37066. (b) Takase, M.; Yoshida, N.; Narita, T.; Fujio, T.; Nishinaga, T.; Iyoda, M. RSC Adv. 2012, 2, 3221–3224. (c) Lazerges, M.; Chane-Ching, K. I.; Aeiyach, S.; Chelli, S.; Peppin-
Donnat, M.; Billon, M.; Lombard, C.; Maurel, F.; Jouini, M. J. Solid State Electrochem. 2009, 13, 231–238. (d) Domingo, V. M.; Alemán, C.; Brillas, E.; Juliá, L. J. Org. Chem. 2001, 66, 4058–4061.
For a selected review, see: Leeper, F. J.; Kelly, J. M. Org. Prep. Proc. Int. 2013, 45, 171–210.
(a) Chen, G.-Q.; Zhang, X.-N.; Wei, Y.; Tang, X.-Y.; Shi, M. Angew. Chem., Int. Ed. 2014, 53, 8492–8497. (b) Kim, C.-E.; Park, S.; Eom, D.; Seo, B.; Lee, P. H. Org. Lett. 2014, 16, 1900–1903. (c) Shen, J.; Cheng G.; Cui, X. Chem. Commun. 2013, 49,
21
22
10641–10643.
23
For selected reviews, see: (a) Zhou, N.-N.; Zhu, H.-T.; Yanga, D.-S.; Guan, Z.-H. Org. Biomol. Chem. 2016, 14, 7136–7149. (b) Gulevich, A. V.; Dudnik, A. S.; Chernyak, N.; Gevorgyan, V. Chem. Rev. 2013, 113, 3084–3213. (c) Patil, N. T.;
Yamamoto, Y. Chem. Rev. 2008, 108, 3395–3442.
24
For selected examples, see: (a) Torres, G. M.; Quesnel, J. S.; Bijou, D.; Arndtsen, B. A. J. Am. Chem. Soc. 2016, 138, 7315–7324. (b) Pusch, S.; Kowalczyk, D.; Opatz, T. J. Org. Chem. 2016, 81, 4170–4178. (c) Gilbert, Z. W.; Hue, R. J.; Tonks, I. A.
Nat. Chem. 2016, 8, 63–68. (d) Yu, S.; Xiong, M.; Xie, X.; Liu, Y. Angew. Chem., Int. Ed. 2014, 53, 11596–11599. (e) Jiang, Y.; Park, C.-M. Chem. Sci. 2014, 5, 2347–2351. (f) Braun, R. U.; Zeitler, K.; Müller, T. J. J. Org. Lett. 2001, 3, 3297–3300.
For selected examples, see: (a) Reekie, T. A.; Donckele, E. J.; Manenti, G.; Puntener, S.; Trapp, N.; Diederich, F. Org. Lett. 2016, 18, 2252–2255. (b) Xu, H.; Wang, F.-J.; Xin, M.; Zhang, Z. Eur. J. Org. Chem. 2016, 925–929. (c) Zheng, Y.; Wang, Y.;
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Both β-nitroketone 10 (34%) and Michael acceptor 11 (38%) were isolated, but showed rapid decomposition during and after their isolation.
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Product contains an 2% impurity of the corresponding furane, which could not be separated from the pyrrole.
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