Efficient [Cu(NHC)]-Catalyzed Multicomponent Synthesis of Pyrroles

Article abstract of DOI:10.1002/asia.201701045

Efficient [Cu(NHC)]-catalyzed syntheses of pyrroles via two and three-component coupling methods are described. Various 1,2-, 1,2,3-, 1,2,3,5- and fully substituted pyrroles were readily accessible through a suitable choice of ketone, primary amine and diol in a three-component reaction. The N-unsubstituted pyrrole formation is also feasible through a two-component reaction involving a β-amino alcohol and a ketone.

Full text of DOI:10.1002/asia.201701045

CHEMISTRY
AN ASIAN JOURNAL
www.chemasianj.org
Accepted Article
Title: Efficient Copper-(N-Heterocyclic Carbene) Catalyzed
Multicomponent Synthesis of Pyrroles
Authors: Abdul Majeed Seayad and Tuan Thanh Dang
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Efficient Copper-(N-Heterocyclic Carbene) Catalyzed
Multicomponent Synthesis of Pyrroles
Tuan Thanh Dang,[b] and Abdul Majeed Seayad*[a]
Abstract: Efficient Cu-NHC catalyzed syntheses of pyrroles via two
and three-component coupling methods are described, for the first
time. Various 1,2-, 1,2,3-, 1,2,3,5- and fully substituted pyrroles were
readily accessible through suitable choice of ketone, primary amine
and diol in a three-component reaction. The N-unsubstituted pyrrole
formation is also feasible through a two-component reaction involving
a -amino alcohol and a ketone.
alcohol activation could undergo suitable condensation/coupling
reaction in situ leading to the formation of several interesting
target molecules.[7b] This type of two or multi-component reaction
avoids the isolation step and hence improves step-economy in
creating molecular complexities. An important application of AD is
the formation of aromatic N-heterocycles[13] such as pyridines,
quinolines, pyrimidines and pyrroles through two- or three-
component reactions (Scheme 1).
Pyrrole is an essential structural motif in biological systems (e.g.
in vitamin B12, heme, chlorophyll, bilirubin, etc.) and important in
many modern synthetic applications including pharmaceuticals
and advanced materials.[1] Some of the naturally occurring
pyrroles such as Lamellarins, Rhazinicine, Palau’amine, etc. have
shown promising therapeutic application potential.[1,2] Several
best-selling drugs (See supporting information), including Lipitor®,
Sunitinib have pyrrole core structure.[1]
Other important
applications of various pyrroles are in solar cells, molecular optics,
conducting polymers and gas sensing.[3] In line with the growing
application of various pyrroles, last several decades have
witnessed tremendous improvements for its synthesis from the
classical Hantzsch, van Leusen, Knorr and Paal-Knorr methods
to novel catalytic protocols.[1,4] Many of these newer catalytic
protocols require pre-synthesis of suitably functionalized
substrates that are obtained through classical protocols, thus
generating large amount of toxic waste.[5] Therefore, the direct
synthesis of pyrroles using inexpensive and readily available
starting materials such as ketones, amines and alcohols seems
to be the preferable choice.
Scheme 1. Syntheses of pyrroles via transition metals catalyzed cyclization
reactions.
In recent past, activation of alcohols/diols to use it as
sustainable alkylating agents has been extensively developed via
transition metal catalyzed conversion to the more reactive
carbonyl intermediate, with the concomitant generation of metal
hydrides or release of H2 based on which two novel research
directions have been advanced. First is the “borrowing hydrogen”
(BH)[6] or the so-called “hydrogen autotransfer” protocol leading to
saturated products (N- and C-alkylation) using alcohols, releasing
water as the only by-product. Second is the acceptorless
dehydrogenation (AD)[7] leading to unsaturated products from
alcohols, diols and polyols with the liberation of hydrogen and
water. The main difference between these two protocols is that
the abstracted hydrogen molecule is liberated in AD, whereas the
hydrogen is used in a consecutive hydrogenation step in the BH
strategy. The carbonyl intermediates resulting from the initial
One of the first examples of AD strategy for the formation of
pyrrole was reported by Crabtree and co-workers, in 2011, using
a
ruthenium-diamine-diphosphine catalyzed two component
coupling involving a primary amine and 2,5-hexanediol (scheme
1a) to yield N-alkyl-2,5-dimethylpyrroles in up to 48% at a
temperature of 125 oC for 18 h under neat conditions.[14] An
efficient iridium-PNP-pincer catalyst was reported by Michlik and
Kempe in 2013 for the two component coupling between a
secondary alcohol and a -aminoalcohol to form N-unsubstituted
2,5 or 2,3,5-substituted pyrroles in excellent yields in THF as a
o
solvent (Scheme 1b).[15] Although the temperature (90 C) and
catalyst loadings (0.03 – 0.5 mol%) were lower, more than one
equivalent of base (KOtBu) was required to achieve near
quantitative yields. Later on, a ruthenium pincer catalyst was
reported by Milstein and co-workers for this two component
reaction that yields up to 88% in refluxing toluene for 24 h in the
presence of 0.5 equivalent of KOtBu.[16] Saito and co-workers[17a]
described a similar approach for the Ru catalyzed synthesis of
pyrroles from the corresponding -aminoalcohol and a ketone,
whereas Shimizu and coworkers[17b] used supported platinum
catalysts in presence of sec-alcohols instead of ketone.. Beller
and co-workers have reported a three component reaction
involving a primary amine or ammonia, a ketone and a diol
(Scheme 1c) using ruthenium-Xantphos catalyst in the presence
[a]
Dr. A. M. Seayad
Organic Chemistry
Institute of Chemical and Engineering Sciences
8 Biomedical Grove, #07-01 Neuros, Singapore 138665
E-mail: abdul_seayad@ices.a-star.edu.sg
Dr. T. T. Dang
[b]
Department of Chemistry
Vietnam National University
Hanoi. 19 Le Thanh Tong street, Hanoi, Vietnam
Supporting information for this article is given via a link at the end of
the document.
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COMMUNICATION
of 0.2 equivalents of KOtBu in t-amyl alcohol as a solvent at 130
oC for 16 h of reaction providing access to various substituted
pyrroles in up to 92% yield.[18] The challenge still remaining is to
develop environmentally and economically competent catalytic
systems, especially using relatively inexpensive non-noble metal
catalysts that enable the easy access of various substituted
complexes were used, prompted us to develop it further towards
the formation of aromatic heterocycles such as pyrroles through
a possible acceptorless dehydrogenation (AD) strategy. We
choose the three component reaction of 2-phenylethanamine (1a),
acetophenone (2a) and ethylene glycol (3) as a model reaction
(Table 1). About 22% yield of the desired product (4a) was
pyrroles either through two or three component reaction. Recently, achieved when 1equiv. of ketone (2a) and 1.5 equiv. of amine (1a)
Milstein and co-workers have reported a cobalt-pincer complex
catalyzed pyrrole synthesis following Crabtree protocol providing
up to 90% yield at 150 C in toluene in the presence of catalytic
were used in the presence of excess of 3 and 1 equiv. of LiOH at
a temperature of 140 oC with a readily available copper-NHC
catalyst Cu-1 (entry 1).
o
amount (5 mol%) of KOtBu and NaHBEt3.[19] Herein, we report, for
the first time, an in situ formed copper-N-heterocyclic carbene
complex (Cu-NHC) as an efficient non-noble metal catalyst for
the synthesis of various pyrroles through both three-component
and two-component cyclization reactions under neat conditions
from readily available feedstock.
A close examination of the reaction mixture indicated the
formation of about 5% of 2-phenethyl alcohol as a (transfer)-
hydrogenation product of 2a along with various intermediates
leading to the product 4a. In order to improve the product yield,
the ratio between amine and ketone was investigated and found
that a ratio of 1:2 gives a promising yield of 36% for the pyrrole
product 4a (entry 2). The corresponding saturated complex Cu-2
gave a lower yield of 29%. The yield was improved to 54% and
48% with the corresponding mesityl complexes such as Cu-3 and
Cu-4 respectively. In order to find an optimum N-heterocyclic
carbene (NHC) ligand, we conducted further optimization using
the in situ formed Cu-NHC complexes.
Table 1. Optimizations for Cu-NHC catalyzed synthesis of pyrrole a
The in situ formed Cu-NHC complexes from CuCl and the
corresponding imidazolium salts gave similar results as that of the
preformed complexes Cu-1 to Cu-4. However, when the
imidazolium salt with N-aliphatic substitution such as isopropyl
group was used, a promising yield of 63% was obtained (entry 6),
which was further improved to 75% (entry 7) upon using CuBr as
the copper precursor. Under these conditions CuI gave a lower
performance and hence CuBr was selected for further evaluation.
L2 with N-cyclohexyl group gave a very low yield of 5%, while N-
tBu (L3) group gave up to 42% yield. Unlike the case of N-
aromatic substituted imidazolium salts (entries 1-5), the in situ
formed Cu-NHC complex from N-aliphatic substituted saturated
precursor L4 gave higher yield (83%) compared to the
corresponding unsaturated precursor L3. This was more
pronounced with N-adamentyl group (entry 13 vs 12) and an
impressive yield of 94% was achieved with a combination of CuBr
and L6. Benzimidazolium salts and thiazolium salts have shown
promises (see SI).
Entry
Cu source
Ligand
Base
(equiv.)
Yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Cu-1
Cu-1
Cu-2
Cu-3
Cu-4
CuCl
CuBr
Cul
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
-
-
-
-
LiOH (1)
LiOH (1)
LiOH (1)
LiOH (1)
LiOH (1)
LiOH (1)
LiOH (1)
LiOH (1)
LiOH (1)
LiOH (1)
LiOH (1)
LiOH (1)
LiOH (1)
LiOtBu (1)
LiOtBu (0.5)
LiOtBu (0.25)
22c
36
29
54
48
63
75
32
5
42
83
51
94
97
96
94
-
L1
L1
L1
L2
L3
L4
L5
L6
L6
L6
L6
We examined the effect of base (see SI) that has influence on
both the formation of Cu-NHC complex as well as activation of OH
groups. K2CO3 as a base gave poor yield while, near quantitative
yield was achieved with LiOtBu (entry 14). Reducing the
concentration of base had very little effect on the reaction
outcome and up to 94% yield was achieved with 0.25 equivalent
of LiOtBu (entry 16). Under these conditions and in the absence
of NHC-ligand, the reaction did occur to a small extend to give a
yield of about 10%, which didn’t improve even after 48h of
reaction. This shows that in situ formed Cu-NHC catalyst is the
key to drive the reaction to completion. In the absence of copper
salts the reaction was negligible.
a Amine (1 mmol), acetophenone (2 mmol), ethylene glycol (1 mL), [Cu] (2
mol%), ligand (2.2 mol%). Yields were determined by 1H-NMR using
b
mesitylene as an internal standard. c Amine (1.5 mmol), acetophenone (1
mmol), ethylene glycol (1 mL).
In our continued effort to develop efficient and sustainable
protocols for alcohol activation towards various alkylation
reactions following borrowing hydrogen (BH) strategy,[20] we
evaluated copper[21] as a potential inexpensive non-noble metal
catalyst. The initial observation of enhanced formation of imines
for N-alkylation reactions, especially when copper-NHC[22]
The optimized condition was further examined to check if
the reaction proceeds through AD or partial (transfer)
hydrogenation was involved. About 46% of the transfer
hydrogenated product (2b-H) of the ketone (2b) was observed
under the optimized reaction (see SI for details). When using
equivalent amount of ketone and amine, the yield of both the
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10.1002/asia.201701045
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pyrrole and the alcohol by-product decreased considerably. This
indicates the possible involvement of both acceptorless
dehydrogenation and hydrogen acceptor pathways, and both
have a comparable share for the pyrrole formation when using the
present copper-NHC catalyst system. A detailed mechanistic
investigation is currently in progress.
ketones could be used and the corresponding pyrroles 4k and 4l
were isolated in 84% and 63% respectively. With aliphatic methyl
ketones such as 2-heptanone gave a mixture of two equal
regioisomers (4m, 4n) in 62% yield. Aryl amines such as anilines
showed lower reactivity, however, with 4 mol% of catalyst, up to
81% of 4o was achieved when 3,4-dimethyl aniline was used for
a reaction time of 48 h. Similarly 3,5-dimethyl aniline gave a
moderate yield of 53% (4p).
In order to prepare highly substituted pyrroles, we choose
substituted 1,2-diols as the diol component. As shown in Scheme
3, 1,2,3,5-substututed pyrroles 4q – 4t were formed in 55 – 86%
isolated yields when various acetophenone derivatives and
substituted primary amines were used together with 1,2-
dihydroxybutane. Synthesis of fully substituted pyrrole 4u was
achieved in very good isolated yield of 84% when 1-tetralone was
used
under
similar
condition.
Interestingly,
1,2-
dihydroxycyclohexane could also be used resulting in the
formation of the corresponding fully substituted pyrrole 4v in 65%
isolated yield.
Scheme 2. Synthesis of 1,2- and 1,2,3-substituted pyrroles. [a]catalyst 4mol%,
Scheme 3. Synthesis of highly substituted pyrroles
48h
With the optimized condition in hand (Table 1, entry 16), we
extended the substrate scope for this Cu-NHC catalyzed three
component reaction to access various pyrroles. The use of
substituted and unsubstituted aryl methyl ketones with various
amines and ethylene glycol gave a range of 1,2- and 1,2,3-
substituted pyrroles (4a – 4i) in moderate to excellent isolated
yields. The standard reaction gave an isolated yield of 86% (4a),
while p-methyl acetophenone gave 89% yield of 4b. Primary
amines without substitution in the aliphatic carbon chain showed
a small decrease in the yield compared to that of 2-phenthylamine
and the corresponding pyrroles 4d – 4f were isolated in up to 75 %
yield. The moderate yields observed with 2-heptylamine and
cyclohexylamine could be due to the steric factors. However,
enhanced yields were achieved with NEt2 (4g, 95%) and
morpholine (4h, 86%) substituted ethylamines. It is interesting to
note that primary hydroxyl group was tolerated and an excellent
yield of N-hexanol substituted pyrrole 4i was formed in 92% yield.
In addition to aryl methyl ketones, aryl aliphatic or aryl cyclic
Scheme 4. Synthesis of N-unsubstituted pyrroles
N-unsubstituted pyrroles could be obtained if ammonia or -
aminoalcohol is used in a three-component or two-component
reaction respectively under suitable conditions. We were
delighted to see that the present Cu-NHC catalyst system is also
effective for the two component reaction. As shown in scheme 4,
2,5- (5a, 5b) and 2,3,5- (5c) substituted pyrroles were synthesized
up to 64% isolated yield using a suitable ketone (p-methyl
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737-738; c) B. P. J. de Lacy Costello, P. Evans, N. Guernion, N. M.
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or 2-aminobutanol). Though this reaction showed near complete
conversion and more than 90% crude yield, the isolation of pure
compound was troublesome[23] resulting in moderate isolated
yields.
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In conclusion, we report an in situ formed Cu-NHC complex
as an efficient non-noble metal catalyst in the presence of small
amounts of LiOtBu as an efficient catalyst system for the
synthesis of pyrroles. A bulky and saturated imidazolium carbene
ligand such as SIAd was found to be the best compromise
together with CuBr as the copper precursor. A series of 1,2-,
1,2,3-, 1,2,3,5- and fully substituted pyrroles were readily
accessible in up 95% isolated yields through a three component
reaction involving a suitable ketone, a primary amine and a diol
under neat conditions. This Cu-NHC catalyst system was also
effective in the formation of N-unsubstituted pyrroles through a
two-component reaction involving a suitable -aminoalcohol and
a ketone. Thus the present Cu-NHC catalysts system provides a
convenient and inexpensive alternative to the noble metal
catalysts for synthesizing various substituted pyrroles through
both a three component and a two component reactions.
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Experimental Section
In a representative experiment, Cu precursor CuBr (2.9 mg, 2 mol%),
SIAd.HCl (8.3 mg, 2.2 mol%), LiOtBu (20.0 mg, 25 mol%), amine (1.0
mmol), ketone (2.0 mmol) were charged under argon-atmosphere in a
Radleys carrousel reaction tube. After adding 1 mL of diol, carrousel tube
was closed, placed in the Radleys 12-place carrousel system and was
degassed using argon. The carrousel tube was opened to the argon line
and heated to the desired temperature under stirring. The top part of the
reaction tube was cooled to 5 oC to prevent loss of reactants. After the
desired reaction time, the reaction mixture was allowed to cool to room
temperature and diluted with acetonitrile (5 mL). SiO2 (400mg) was added
into the crude mixture. The organic solvent was removed under vacuum
and then the product was purified by column chromatography (see
supporting information for details).
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Acknowledgements
This work was funded by GSK-EDB Singapore Partnership for
Green and Sustainable Manufacturing and the Institute of
Chemical and Engineering Sciences (ICES), Agency for Science,
Technology and Research (A*STAR), Singapore. The authors
acknowledge Mrs Lim Yi Wee for the help with preparative HPLC
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Keywords: pyrrole synthesis • acceptorless dehydrogenation •
borrowing hydrogen strategy • Cu catalysis • N-heterocyclic
carbene • nitrogen heterocycle •
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[23] The purification was done by initial column chromatography followed by
preparative HPLC. See supporting information.
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10.1002/asia.201701045
Chemistry - An Asian Journal
COMMUNICATION
Entry for the Table of Contents
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COMMUNICATION
Cu-NHC catalyst efficiently convert
readily available diols, ketones, -
aminoalcohols and amines to various
substituted pyrroles through a two- or
three- component reaction in up to
95% isolated yields.
T. T. Dang and A. M. Seayad*
Page No. – Page No.
Efficient Copper-(N-Heterocyclic
Carbene) Catalyzed Multicomponent
Synthesis of Pyrroles
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