Iodine-Promoted One-pot Synthesis of Highly Substituted 4-Aminopyrroles and Bis-4-aminopyrrole from Aryl Methyl Ketones, Arylamines, and Enamines

Article abstract of DOI:10.1002/adsc.201800899

An iodine-promoted one-pot synthesis of functionally diverse and highly substituted 4-aminopyrroles directly from aryl methyl ketones, arylamines, and enamines was developed. The reaction involves in-situ oxidation of aryl methyl ketone to glyoxal, subsequent imine formation by aniline, followed by nucleophilic addition of enamine, and cyclization to afford highly substituted 4-aminopyrroles. This reaction involved the formation of two C?N bonds and one C?C bond by a formal [1+1+3] annulation approach. The present method provides an interesting framework of two 4-aminopyrrole units directly attached to a biphenyl core by the reaction of 4,4′-diacyl biphenyl, amine, and enamine groups. This Hantzsch-type one-pot reaction provides diverse 4-aminopyrroles, which could be useful in medicinal/material chemistry. (Figure presented.).

Full text of DOI:10.1002/adsc.201800899

Title: Iodine-Promoted One-pot Synthesis of Highly Substituted 4-
Aminopyrroles and bis-4-Aminopyrrole from Aryl Methyl Ketones,
Aryl Amines, and Enamines
Authors: Hitesh Jalani, Jyotirling Mali, Hyejun Park, Jae Kyun Lee,
Kiho Lee, Kyeong Lee, and Yongseok Choi
This manuscript has been accepted after peer review and appears as an
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the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800899
Link to VoR: http://dx.doi.org/10.1002/adsc.201800899

10.1002/adsc.201800899
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Iodine-Promoted One-pot Synthesis of Highly Substituted 4-
Aminopyrroles and Bis-4-aminopyrrole from Aryl Methyl
Ketones, Arylamines, and Enamines
Hitesh B. Jalania,§, Jyotirling R. Malib,§, Hyejun Parka, Jae Kyun Leec, Kiho Leed,
Kyeong Leeb*, Yongseok Choia*
a
School of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea. E-mail:
ychoi@korea.ac.kr
b
College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Republic of Korea. E-mail: kaylee@dongguk.edu
Center for Neuromedicine, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea.
c
d
College of Pharmacy, Korea University, Sejong-ro 2511, Republic of Korea.
§These authors contributed equally to this work.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
have attracted attention as these methods provide a
powerful and straightforward method for the conversion of
substituted methyl ketones towards diverse oriented
heterocyclic systems. [9-11]
Abstract. An iodine-promoted one-pot synthesis of
functionally diverse and highly substituted 4-aminopyrroles
directly from aryl methyl ketones, arylamines, and
enamines was developed. The reaction involves in-situ
oxidation of aryl methyl ketone to glyoxal, subsequent
imine formation by aniline, followed by nucleophilic
addition of enamine, and cyclization to afford highly
substituted 4-aminopyrroles. This reaction involved the
formation of two C-N bonds and one C-C bond by a formal
[1+1+3] annulation approach. The present method provides
an interesting framework of two 4-aminopyrrole units
directly attached to a biphenyl core by the reaction of 4,4’-
diacyl biphenyl, amine, and enamine groups. This
Hantzsch-type one-pot reaction provides diverse 4-
aminopyrroles, which could be useful in medicinal/material
chemistry.
Keywords: 4-Aminopyrroles; Kornblum oxidation;
Enamines; Hantzsch-type one-pot approach.
Pyrrole is one of the simplest and biologically
important heterocycles present in a variety of natural
products and medicines such as heme, chlorophyll,
porphyrins, marine-derived Marino pyrrole-A, pseudilin,
lamellarin-G, Atorvastatin, and Sunitinib.[1-3] In view of the
importance of pyrroles in diverse fields, various synthetic
methods have been developed for the synthesis of
substituted pyrroles.[4] One of the most common and
classical approach to access this scaffold is the Hantzsch
pyrrole synthesis, which involves the reaction of
chloroacetone, acetoacetic ester, and aqueous ammonia.[5]
Despite the availability of numerous methods,[6] the access
to suitably functionalized pyrroles is essential for progress
in the field of biology[7] and material science.[8] This has
motivated chemists to develop newer synthetic routes,
particularly concise, efficient, and straightforward
approaches. Over the past few years, novel methodologies
using iodine-mediated transformations of methyl ketones
Scheme 1. Application of methyl ketones towards diverse
scaffolds and strategy for highly substituted 4-
aminopyrroles.
Wu and co-workers employed a versatile self-sorting
tandem reaction of methyl ketone, iodine, and dimethyl
sulfoxide (DMSO) in the presence of copper oxide to
synthesize a cis-trans mixture of 2-(methylthio)-1,4-
diphenylbut-2-ene-1,4-diones (Scheme 1, eq. 1).[11a] They
designed an elegant synthesis pathway of an iodine-
catalyzed Povarov-type reaction of arylamine with two
different methyl ketones (Scheme 1, eq. 2), wherein the
1
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10.1002/adsc.201800899
Advanced Synthesis & Catalysis
catalytic amount of the HI co-product serves as a promoter
to accelerate quinoline synthesis.[12] Following this, in
2016, the same research group reported the iodine
promoted synthesis of pyridines using α-amino acids and
two molecules of methyl ketone (Scheme 1, eq. 3).[13]
Subsequently, they reported the iodine-promoted synthesis
of furan-3-methanethiol from methyl ketones and hydroxy
methyl sulfonates (Scheme 1, eq. 4).[14] During the
preparation of this manuscript, Wu and co-workers
reported the synthesis of trisubstituted pyrrole-2-
carbaldehydes from methyl ketones, anilines, and alkyl
aryl ketones (Scheme 1, eq. 5).[15] In addition to Wu and
co-workers, the Li and Tu groups contributed towards the
synthesis of interesting heterocycles directly from aryl
glyoxals as starting materials.[16]
4-aminopyrroles using phenylglyoxal (1ab) with p-
toluidine (2a) and methyl 3-aminobut-2-enoate (3a). When
the reaction was carried out at 80 °C in ethanol without a
catalyst, surprisingly, the reaction proceeded within 6 h to
afford (4a) in 21% yield (Table 1, entry 1). This result
encouraged us to test various catalysts to find the suitable
conditions to prepare 4-aminopyrroles. It is well known
that protic acids can catalyze various reactions, therefore,
using 50 mol% of p-toluenesulfonic acid (PTS) at 80 °C in
ethanol afforded (4a) with 59% yield (Table 1, entry 2).
Considering the role of iodine in the reaction, it is possible
that trace amounts of HI, generated during the reaction,
might be enough as a catalyst for this process. Therefore,
some control experiments were performed using different
amounts of HI (Table 1, entries 10-12). It can be seen that
5 mol% HI is sufficient to catalyze the reaction, resulting
in (4a) with a good yield at 110 °C after 1 h. After several
screenings, we found that heating phenylglyoxal (1aa) in
the presence of iodine (50 mol%) at 130 °C for 1 h,
followed by the addition of p-toluidine (2a) and methyl 3-
aminobut-2-enoate (3a) at 130 °C, and heating again for
another 1 h provided the desired product (4a) in good yield
(79%). These reaction conditions were then applied to
acetophenone.
Considering the significance of iodine-mediated
oxidation of methyl ketones, we were interested in a recent
report by Wu and coworkers[12] that detailed the one-pot
synthesis of substituted quinolines under the influence of a
co-product promoted Povarov reaction of acetophenones,
arylamines, and α-keto esters (Scheme 1, eq. 2). During the
synthesis of quinolines, the transient formation of a highly
active C-acyl imine ion in the postulated mechanism
particularly attracted our initial attention. Upon
examination of Wu’s proposed mechanism, we envisioned
that replacing activated α-keto esters with an enamine such
as methyl-3-aminobut-2-enoate would permit the
nucleophilic addition of enamine onto the C-acylimine ion,
which could then be followed by intra-molecular
cyclization to yield 4-aminopyrroles (Scheme 1, eq. 6).
Therefore, we considered the possibility of preparing 4-
aminopyrroles (4a) via a byproduct catalyzed approach,
wherein the reaction of aromatic ketones with iodine
generates HI as a byproduct during iodination and
Kornblum oxidation. HI, in turn, could promote cyclization
after the addition of enamine to the C-acylimine ion.
Yield[b]
Entry
1
Catalyst (mol%)
No Catalyst
PTS (50)
I2 (20)
Temp (°C)
80
Solvent
Ethanol
Ethanol
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
(%)
21
59
59
62
65
70
72
75
79
68
64
60
[
a]Reaction conditions: 1a (0.5 mmol), I2 (0.25 mmol), 2 (0.5
2
80
mmol) and 3a (0.75 mmol) in DMSO (2 mL).
[b]Isolated yield.
3
100
100
100
100
110
120
130
110
110
110
4
I2 (30)
Scheme 2. Substrate scope for arylamines. [a, b]
5
I2 (40)
6
I2 (50)
7
I2 (50)
With established reaction conditions in hand, we
focused on exploring the substrate scope with respect to
various amines for the one-pot synthesis of 4-
aminopyrroles. We explored various aromatic amines and
the desired products were obtained in satisfactory yields
(Scheme 2). Interestingly, both electron-rich and electron-
deficient anilines could be smoothly converted to the
desired products (79-15%, 4a-k). In general, aromatic
amines containing electron-rich substituents, such as
methyl, methoxy, phenyl, and 4-morpholinophenyl groups,
showed better activities with good yields (97-63%, 4a-d).
Amines bearing electron-withdrawing substituents like 4-
chloro, 4-nitro, 4-acetyl, and 3,5-dichloro resulted in
comparatively lower yields (62-60%, 4e-h). 1-
8
I2 (50)
9
I2 (50)
10
11
12
HI (5)
HI (10)
HI (15)
[a]Reaction conditions: 1aa (0.5 mmol), 2a (0.5 mmol), 3a (0.75
mmol), DMSO (2 mL).
[b]Isolated yield.
Table 1. Optimization of reaction conditions. [a, b]
Kornblum oxidation of acetophenone in the presence
of iodine and DMSO resulted in phenylglyoxal, and hence,
we initially optimized the procedure for the preparation of
2
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10.1002/adsc.201800899
Advanced Synthesis & Catalysis
Naphthylamine was suitable for this protocol and resulted
in (4i) with a 71% yield. Substrates bearing heterocyclic
scaffolds, such as 2-aminopyridine also functioned well
and resulted in the corresponding pyridine containing 4-
aminopyrrole (4j) with reasonably good yield (62%).
However, bulky 3,5-ditertbutylaniline gave poor (15%)
yield of (4k), but from the diversity point of view, such
compounds are worth exploring even though they resulted
in low yields.
Figure 1. X-ray single crystal structure of 4s.
Next, we explored various methyl ketones for the one-
pot synthesis of 4-aminopyrroles as described in Scheme 4.
The reactions were mild enough to be compatible with a
broad range of acetophenone bearing electron-donating
and electron-withdrawing groups (4v-4aa). These reactions
somewhat gave lower yields compared to the parent
acetophenone. Surprisingly, acetophenone substrates
bearing diverse substitutions are being used to construct
various heterocycles, however, to the best of our
knowledge, the reactions of 4,4’-diacyl biphenyl have not
been explored for the synthesis of bis-pyrroles. An
interesting framework of two symmetrical 4-aminopyrrole
units directly attached to a biphenyl core was developed by
the treatment of 4,4’-diacyl biphenyl with p-toluidine and
enamine under slightly modified reaction conditions
(Supporting Information), provided with (4ab), (42%
yield). Similarly, 4-fluoroaniline (4ac, 35%), and p-
anisidine (4ad, 34%) have furnished bis-pyrroles with
moderate yields. We expect that use of 4,4’-diacyl
biphenyl to construct bis-pyrroles will certainly attract the
attention of synthetic and medicinal chemists. In addition
to this, pyrroles such as (4y) could be transformed to
dihydropyrrolo[3,2-b]indoles[19] using intra-molecular
Buchwald-Hartwig cross coupling conditions.
Encouraged by the good tolerance and generality of
amines in the one-pot synthesis of 4-aminopyrroles, we
concentrated on exploring various enamines, as described
in Scheme 3. The reactions were mild enough to be
compatible with a broad range of enamines, such as ethyl
3-aminobut-2-enoate, tert-butyl 3-aminobut-2-enoate, and
ethyl 3-amino-5-methylhex-2-enoate (74-69%; 4l-n).
Interestingly, methyl 3-aminobut-2-one (4o) also
underwent the reaction with 72% yield and this compound
can be further functionalized due to the presence of methyl
ketone. Bulky diphenylmethane enamine also provided the
expected product (4p) with 71% yield. Furthermore, the
optimized conditions could be applied to various enamines
bearing aromatic substituents, such as phenyl, 3-tolyl, and
2-fluorophenyl groups, which satisfactorily reacted to give
very good yields (74-68%, 4q-s). X-ray single crystal
analysis of compound (4s)[17] provided information about
the substituent pattern in the pyrrole scaffold (Figure 1). N-
substituted
enamines,
such
as
ethyl
3-(4-
methoxyphenylamino)but-2-enoate, provided
a
typical
fully substituted 4-aminopyrrole (4t) with 66% yield.
Furthermore, heteroaryl enamines, such as ethyl 3-amino-
3-(thiophen-2-yl)acrylate gave the corresponding product
(4u) with a reasonable yield of 56%. Thus, the present one-
pot protocol is useful for the exploration of various
enamines[18] in synthesizing the corresponding 4-
aminopyrroles.
[a]Reaction conditions: 1a (0.5 mmol), I2 (0.25 mmol), 2a (0.5
mmol) and 3 (0.75 mmol) in DMSO (2 mL).
[b]Isolated yield.
[a]Reaction conditions: 1a (0.5 mmol), I2 (0.25 mmol), 2a (0.5
mmol) and 3 (0.75 mmol) in DMSO (2 mL).
[b]Isolated yield.
Scheme 4. Substrate scope for aryl methyl ketones and
arylamines. [a, b]
After establishing the scope of all three components in
the present method, the reaction mechanism was
Scheme 3. Substrate scope for enamines. [a, b]
3
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10.1002/adsc.201800899
Advanced Synthesis & Catalysis
considered. Acetophenone (1a) was reacted with iodine in
DMSO at 130 °C to obtain phenylglyoxal (1aa), and the
corresponding hydrated form (1ab) in quantitative yield
(Scheme 5, i). The reaction of (1a) with enamine (3a) in
the presence of p-toluenesulfonic acid using ethanol at
reflux temperature (without aniline), resulted in 4-
hydroxypyrrole (5a) (Scheme 5, ii), suggesting the
formation of phenylglyoxal followed by its reaction with
susceptible to nucleophilic attack by the amino group of
enamine and allows intra-molecular cyclization in a 5-exo-
trig manner to give 11. Finally, it undergoes sequential
dehydration to give 12 followed by 1,3-hydrogen shift to
afford the desired pyrroles (4). In the case of substituted
enamine, it is directly cyclized to 13, which undergoes
dehydration to yield highly substituted 4-aminopyrrole (4).
This pathway is regioselective and leads to 4-
aminopyrroles which is supported by the X-ray single
crystal structure analysis of 4s as shown in Figure 1.
enamine
to
give
4-hydroxylpyrrole.
Replacing
acetophenone with α-iodoacetophenone (1a’), which was
identified as a probable precursor of α-keto aldehyde (1aa),
the desired product (4a) was obtained in good yield, both
with iodine (50 mol%) and without additional iodine
(Scheme 5, iii). When C-acylimine (from glyoxals and
amine) was tested in the presence of HI, the desired
product (4a) was formed with an excellent yield.
However, the adduct was isolated in poor yields when
the reaction was conducted in the absence of HI (Scheme 5,
iv), indicating that the catalytic amount of HI generated as
a co-product during upstream iodination and Kornblum
oxidation may be responsible for the process. Interestingly,
employing p-toluenesulfonic acid (50 mol%) as a catalyst,
the desired product (4a) was obtained with 59% yield
(Scheme 5, v), suggesting that the reaction can also
proceed in presence of an acid catalyst.
Scheme 6. Plausible reaction mechanism.
In conclusion, a Hantzsch-type one-pot synthesis of
biologically interesting 4-aminopyrroles was developed by
iodine-mediated reactions of readily available building
blocks, such as aryl methyl ketones, arylamines, and
enamines. This protocol provides regioselective access to
functionally diverse 4-aminopyrroles. In addition, the bis-
pyrroles synthesized by the present protocol could be
useful in the generation of compound libraries of bis-4-
aminopyrroles. Due to the potential biological activity of
these scaffolds and the applicability of this protocol in
synthesizing bis-pyrrole molecules, we hope this
methodology will gain attention from the chemistry
community. Further work on bis-pyrroles is currently
undergoing in our laboratory.
Experimental Section
Scheme 5. Control experiments.
General procedure for the synthesis of substituted 4-
aminopyrroles and bis-4-aminopyrroles
On the basis of our findings and previous reports,[12]
a
possible mechanism can be proposed using acetophenone
(1), aniline (2), and methyl 3-aminobut-2-enoate (3) as the
model substrates (Scheme 6). The initial iodination of
acetophenone generates α-iodo ketone (5) in situ, which is
then converted to phenyl glyoxals (6) due to Kornblum
oxidation under the employed reaction conditions and
releases HI as a co-product. The reaction of aniline (2)
with the formyl group of phenylglyoxal results in C-
Procedure A
A sealed tube was charged with acetophenone (0.5 mmol)
and iodine (50 mol %) at room temperature, and then dried
solvent DMSO (2 mL) was added. The resulting mixture
was stirred at 130 ℃. After the disappearance of the
reactants (approx. 1-2 hours, monitored by TLC), p-
toluidine (0.5 mmol) and enamine (0.75 mmol) were added
at 130 ℃ and allowed to react for another 1 h. After the
reaction was completed, 50 mL of water was added to the
mixture, followed by extraction with ethyl acetate. The
extract was washed with Na2S2O3 solution, dried over
anhydrous Na2SO4 and evaporated. The crude mixture was
acylimine (7). Subsequent nucleophilic attack by methyl 3-
[18]
aminobut-2-enoate
on iminocarbon (8) affords the
enamino-β-ketoamine adduct (9). The carbonyl group of
this adduct is protonated by HI to allow 10, which becomes
4
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10.1002/adsc.201800899
Advanced Synthesis & Catalysis
purified by column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate) to afford 4.
[4] a) V. Este´vez, M. Villacampa, J. C. Mene´ndez,
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Procedure B
A sealed tube was charged with substituted acetophenone
(1 eq.) and iodine (50 mol %) at room temperature, and
then dried solvent DMSO (2 mL) was added. The resulting
mixture was stirred at 130 ℃ after disappearance of the
reactants (approx. 1-2 hours, monitored by TLC), p-
toluidine (1.5 eq.) and enamine (2 eq.) were added at
130 ℃ and allowed to react for another 1 h. After the
reaction was completed, 50 mL of water was added to the
mixture, followed by extraction with ethyl acetate. The
extract was washed with a Na2S2O3 solution, dried over
anhydrous Na2SO4 and evaporated. The crude mixture was
purified by column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate) to afford 4.
A. N. Pandya, V.
Sudarsanam, K. K. Vasu,
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Control Experiment:
Phenylglyoxal 1a (0.5 mmol) was dissolved in dry ethanol
(3 mL), p-toluene sulfonic acid (50 mol%) and enamine 3a
(0.75 mmol) were added and heated at 80 ℃. Up on
completion of the reaction, the solvent was removed and
the crude mixture was purified by column chromatography
on silica gel (eluent: petroleum ether/ethyl acetate) to
afford 5a.
[10] T. T. Tidwell, Synthesis 1990, 10, 857.
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Lett., 2006, 8, 2245-2248; b) J. Zhang, X. Wu, Q, Gao,
X, Geng, P, Zhao, Y.-D. Wu, A.-X. Wu, Org. Lett.
2017, 19, 408−411; c) J.-C. Xiang, Z.-X. Wang, Y.
Cheng, J.-T. Ma, M. Wang, B.-C. Tang, Y.-D. Wu,
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Acknowledgements
This work was supported by grants from the National
Research Foundation of Korea, Ministry of Science and
ICT (2018R1A5A2023127) and the Korea Health
Technology R & D Project, Ministry of Health & Welfare,
Republic of Korea (HI15C0789). We are thankful to Prof.
Hongjian Lu of ICBMS, Nanjing University, China for
generously providing the enamines used in this study.
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10.1002/adsc.201800899
Advanced Synthesis & Catalysis
COMMUNICATION
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This article is protected by copyright. All rights reserved.