Ru(ii)-Catalyzed, Cu(ii)-mediated carbene migratory insertion in the synthesis of trisubstituted pyrroles from isoxazoles

Article abstract of DOI:10.1039/d1ob00255d

A convenient, “one-pot” synthesis of trisubstituted pyrrolesviaa Ru(ii)-catalyzed, Cu(ii)-mediated reaction of substituted isoxazoles with sulfonylhydrazones has been developed. A series of highly functionalized pyrroles are obtainedviaa synergistic forma

Full text of DOI:10.1039/d1ob00255d

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Biomolecular Chemistry
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Ru(II)-Catalyzed, Cu(II)-mediated carbene
migratory insertion in the synthesis of
trisubstituted pyrroles from isoxazoles†
Cite this: Org. Biomol. Chem., 2021,
19, 3428
Pravin Kumar, Santosh Kumar Keshri and Manmohan Kapur
*
A convenient, “one-pot” synthesis of trisubstituted pyrroles via a Ru(II)-catalyzed, Cu(II)-mediated reaction
of substituted isoxazoles with sulfonylhydrazones has been developed. A series of highly functionalized
pyrroles are obtained via a synergistic formation of new C−C and C−N bonds. Mechanistic investigations
were carried out to propose the plausible pathway. This protocol provides a facile and expeditious
approach for the synthesis of various heterocyclic compounds bearing the pyrrole skeleton.
Received 9th February 2021,
Accepted 18th March 2021
DOI: 10.1039/d1ob00255d
rsc.li/obc
pyrroles via the reaction of isoxazoles with 1,2,3-triazoles.7
Sridhar and co-workers have also reported a Cu(OTf)2 cata-
Introduction
Pyrroles are privileged heterocycles and a key component of lyzed synthesis of 2,4,5-trisubstituted pyrroles from
several natural products and pharmaceuticals, and have α-diazoketones.8 A Pd(II)-catalyzed synthesis of 2,3,5-trisubsti-
proven to possess a wide variety of pharmacological pro- tuted pyrroles has been reported by Wang and co-workers
perties.1 Densely-substituted pyrroles often belong to a signifi- where the acyclic form of isoxazoles (the enaminone) has been
cant set of compounds possessing a wide variety of potential used to achieve a diverse array of substituted pyrroles.9
pharmaceutical applications including antibacterial, anti- Recently our group reported a ruthenium and copper-co-cata-
inflammatory, anti-oxidant, and anti-fungal properties.2 The lyzed method for the synthesis of densely-substituted pyrro-
synthesis of substituted pyrroles has been a long-standing les.10a The method consists of a two-step synthesis, a Pd(II)-
objective of research with an aim to obtain structural diversity, catalyzed C(4)–H alkenylation of isoxazoles followed by a ruthe-
high reaction efficiency and controlled regioselectivity. nium and copper co-catalyzed cyclization. In the same context,
Traditionally, these molecules have been synthesized via con-
densation and aromatization of 1,3-dicarbonyl or carbonyl
compounds with ammonia or its derivatives.3,4
Over the years, remarkable progress has been made by
various research groups for the efficient synthesis of densely-
substituted pyrroles.5 In this regard, methodologies involving
the synthesis of these important building blocks by utilizing
isoxazoles or their ring-opened forms (enaminones) have been
developed. For example, in 2015, Tang and co-workers
reported a Rh(II)-catalyzed cycloaddition reaction of N-sulfonyl
triazoles with isoxazoles to achieve substituted pyrroles
(Scheme 1).6 The N-sulfonyl triazoles act as a diazo precursor
leading to the generation of metal carbene under rhodium cat-
alysis. Novikov’s group reported a Rh(II)-catalyzed synthesis of
Department of Chemistry, Indian Institute of Science Education and Research
Bhopal, Bhauri, Bhopal Bypass road, Bhopal 462066, MP, India.
E-mail: mk@iiserb.ac.in
†Electronic supplementary information (ESI) available: Experimental details and
copies of 1H and 13C NMR and X-ray analysis data. CCDC 1997416 and 2060949.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/d1ob00255d
Scheme 1 Synthesis of trisubstituted pyrroles: some previous works
and the present work.
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an improved one-pot protocol has also been recently developed
by our group for the synthesis of these trisubstituted pyrro-
Results and discussion
les.10b Recently, Chen and co-workers reported an iron- In our initial attempts, the reaction of 3,5-diphenylisoxazole
mediated ring-opening and rearrangement cascade synthesis (1a) with acetophenone sulfonylhydrazone (2a), in Cu(OAc)2 (2
of polysubstituted pyrroles from 4-alkenylisoxazoles.10c The equiv.) in DCE, at 120 °C did not yield any product (entry 1,
copper-mediated synthesis of polysubstituted pyrroles has also Table 1). A similar observation was made in the case of Cu
been reported by Huang and co-workers.10d
(OTf)2 (entry 2, Table 1). Formation of the product was
Very recently Jin and co-workers disclosed a highly regio- achieved when the reaction was carried out with Cu(OAc)2 (2
selective, Ag(I)-catalyzed synthesis of multisubstituted pyr- equiv.) and Ag2CO3 (1 equiv.) (entry 3, Table 1). While screen-
roles.11 Several other approaches have also been successfully ing the solvents, it was found that THF and toluene did not
developed by various research groups by employing annulation yield any product (entries 4 and 5 Table 1). Thereafter, we
strategies to achieve densely functionalized pyrroles.12 Despite further screened various catalyst systems (such as Co(OAc)2,
these advances, the utilization of isoxazoles as versatile start- RuCl3, Sc(OTf)3, Ph3PAuNTf2, and [Ru(p-cym)Cl2]2) (see the
ing materials in their synthesis still remains a very attractive ESI† for further details) and gratifyingly, with [Ru(p-cym)Cl2]2
choice.
(5 mol%), AgSbF6 (20 mol%), and Cu(OAc)2·H2O (1.5 equiv.) in
Isoxazoles serve as versatile intermediates for the synthesis DCE as the solvent, at 120 °C, (entry 12, Table 1), the trans-
of a variety of valuable scaffolds13–15 and have been extensively formation was found to be effective and afforded the desired
employed in various catalytic transformations in the synthesis product in 65% yield.
of several useful heterocycles as well as pharmaceutically-rele-
Furthermore, to check the exact role played by ruthenium,
vant molecules.16 On the other hand, hydrazones are we performed the reaction in the absence of the Ru-catalyst,
treated as important organic synthons for the construction of and only a trace amount of the product was formed which
complex molecules.17 Also, they have been widely explored in suggested that the ruthenium catalyst was necessary for the
various catalytic transformations such as insertions, transformation (entry 13, Table 1). We then checked the feasi-
cyclizations and 1,2-migrations in the synthesis of acyclic, car- bility of the reaction in the absence of copper acetate but did
bocyclic and heterocyclic molecules.18,19 We report herein, a not obtain the desired product (entry 13, Table 1), which con-
ruthenium and copper-mediated carbene migratory insertion firmed that the copper co-catalyst played a crucial role in the
in the synthesis of trisubstituted pyrroles from isoxazoles and formation of the product. At lower temperatures, complete
sulfonylhydrazones
(Scheme 1).
under
mild
reaction
conditions conversion of starting materials was not observed and among
the several screened solvents, DCE was observed to afford the
best yields (see the ESI† for further details). To explore the sub-
strate scope for the general validity of the present investi-
gations, a variety of substituted isoxazoles with substituted
acetophenone sulfonylhydrazones were screened under the
optimized conditions and the outcome of the study is sum-
marized in Table 2. The reaction of acetophenone sulfonylhy-
drazone with 3,5-diaryl isoxazoles possessing electron-neutral
and electron-donating substituents such as p-Me, p-OMe and
o-OMe at the 3-aryl ring, furnished the corresponding pyrrole
Table 1 Optimization studiesa,b,c
Yieldb
product in good yields (3a–3c, 3f, Table 2).
Entry Conditions
(%)
However, the presence of fluorine-substituents at the ortho-
and para-position of the 3-aryl ring of 3,5-diarylisoxazoles,
lowered the rate of reactions and furnished the product with
reduced yields (3e, 3g, Table 2). This reduced yield could be
attributed to the presence of an electron withdrawing group on
the isoxazole which reduces its reactivity and in turn slows
down the migratory insertion steps. Moreover, during the
course of reaction it was also found that over time some
amount of acetophenone sulfonylhydrazone converted into the
corresponding acetophenone, thereby reducing the concen-
tration of sulfonylhydrazone in the reaction mixture and
further, the presence of this corresponding acetophenone in
the reaction mixture leads to side reactions and to some extent
also hampers the rate of the reaction. Interestingly, the reactiv-
ity of 3-naphthyl-5-phenylisoxazole with acetophenone sulfo-
nylhydrazone was found to be quite similar to that with 3,5-
diarylisoxazole and gave the desired product in 56% yield (3h,
1
2
3
4
5
6
7
8
9
Cu(OAc)2·H2O (2 eq.), DCE, 24 h
Cu(OTf)2 (2 eq.), DCE, 24 h
n.d.
n.d.
30
n.d.
n.d.
n.d.
Trace
35
Cu(OAc)2·H2O, Ag2CO3, DCE, 24 h
Cu(OAc)2·H2O, Ag2CO3, THF, 24 h
Cu(OAc)2·H2O, Ag2CO3, toluene, 24 h
Co(OAc)2·H2O, Ag2CO3, DCE, 24 h
Sc(OTf)3, Cu(OAc)2·H2O, Ag2CO3, DCE, 24 h
RuCl3 (10), Cu(OAc)2·H2O, Ag2CO3, DCE, 24 h
[RuCl2(p-cym)]2, Cu(OAc)2·H2O, AgSbF6, DCE, 24 h 47
[RuCl2(p-cym)]2, Cu(OAc)2·H2O, AgSbF6, toluene,
24 h
10
40c
11
[RuCl2(p-cym)]2, Cu(OAc)2·H2O, AgSbF6, dioxane,
n.d.c
24 h
12
13
14c
[RuCl2(p-cym)]2, Cu(OAc)2·H2O, AgSbF6, DCE, 24 h 65c
Cu(OAc)2·H2O, AgSbF6, DCE, 24 h
[RuCl2(p-cym)]2, AgSbF6, DCE, 24 h
Trace
n.d.c
a Unless otherwise mentioned all reactions were performed with 1a
(0.15 mmol), 2a (0.18 mmol), catalyst (0.0075 mmol) and additive
(0.225/0.15 mmol) in 2 mL solvent, in a sealed tube at 120 °C.
b Isolated yield. c AgSbF6 (0.03 mmol); n.d. = not detected.
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Table 2 Substrate scope for the synthesis of trisubstituted pyrrolesa
reacted well with acetophenone sulfonylhydrazone to furnish
the corresponding 2-alkyl substituted pyrroles in moderate
yields (3m–3o, Table 2). Substituted acetophenone sulfonylhy-
drazones containing electron-donating or electron-withdraw-
ing substituents at the para-position of the aryl ring, were also
tolerated for this transformation.
The reactivity of the isoxazole with p-fluoro acetophenone
sulfonylhydrazone was found to be slightly higher than that of
p-OMe acetophenone sulfonylhydrazone (3p–3r, 3u, 3v,
Table 2). A m-NO2 substitution on the acetophenone sulfonyl-
hydrazone was also tolerable and furnished the desired
product upon reaction with 3,5-diphenylisoxazole and
5-phenyl-3-(p-tolyl)isoxazole (3s, 3t, Table 2).
The reaction was not limited only to the substituent at the
C3-aryl ring of 3,5-diarylisoxazoles but also worked with sub-
strates containing a variety of substituents on the C5-aryl ring,
to yield the respective trisubstituted pyrroles in moderate to
good yields (3x, 3y, Table 2). C5-Alkyl substituted isoxazole was
also a good substrate for this transformation and afforded the
product in good yields (3z, Table 2). Unfortunately for us, the
tosylhydrazones derived from propiophenone and other alkyl
ketones did not react at all and formation of the product was
not observed (3aa, 3ab, Table 2). When the reaction was
carried out with the isoxazole bearing methyl substituents at
3- and 5-positions of the isoxazole ring, the expected pyrrole
product was not obtained, instead, the unexpected formation
of the tosyl adducts 3ad and 3ae, respectively, was observed
(Table 2). Also, the tosylhydrazone derived from cyclohexanone
was not compatible under this condition and formation of the
product was not observed.
Further experiments were carried out to gain insights into
the mechanistic pathway of the transformation. First, the reac-
tion of acetophenone sulfonylhydrazone with enaminone 1a′
(ring-opened form of isoxazole) was performed under copper-
mediated conditions, in the absence of the Ru-catalyst, in DCE
at 120 °C and it resulted in the expected product (Scheme 2A).
This indicated that ruthenium may be necessary only for the
first step of the transformation. With the same enaminone,
under ruthenium catalysis, the formation of the pyrrole
product was not observed when the copper acetate was
excluded (Scheme 2B). This study indicated that copper acetate
is necessary for the transformation from the enaminone to the
pyrrole product.
a Unless otherwise mentioned all reactions were performed with 1a
(0.15 mmol), 2a (0.18 mmol), catalyst (0.0075 mmol) and Cu
(OAc)2·H2O (0.225 mmol), AgSbF6 (0.03 mmol) in 2 mL solvent, in a
sealed tube.
To understand the exact role of the ruthenium catalyst, an
experiment was carried out in the absence of the Ru-catalyst
Table 2). Isoxazoles containing electron neutral and electron- with 3,5-diphenylisoxazole and acetophenone sulfonylhydra-
donating substituents such as m-Me and m-OMe at the 3-aryl zone (Scheme 2C) and the poor outcome of the experiment
ring also reacted well with acetophenone sulfonylhydrazone to indicated that the Ru-catalyst is required to accelerate the clea-
furnish the desired product in acceptable yields (3i, 3j, vage of the N−O bond.
Table 2). However, the presence of electron-withdrawing sub-
To understand the role of acetophenone sulfonylhydrazone,
stituents such as m-CF3 at the 3-aryl ring of 3,5-diarylisoxazole a reaction was carried out with acetophenone and 3,5-dipheny-
lowered the rate of the reaction and the trisubstituted pyrrole lisoxazole under similar conditions which afforded only a trace
was observed in reduced yields (3k, Table 2). The reaction amount of enaminone 1a′ with no formation of the pyrrole
worked quite well with disubstituted aryl isoxazoles to give the product (Scheme 2D). This indicated that acetophenone sulfo-
corresponding products in good yields (3l, Table 2). C3-Alkyl nylhydrazone is necessary and the reaction seemed to proceed
substituted isoxazoles were also suitable substrates and through the formation of a copper–carbene intermediate.
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Scheme 3 Plausible pathway for pyrrole synthesis.
conditions with cyclohexene (2.0 eq.), this resulted only in a
trisubstituted pyrrole with no adduct with cyclohexene
(Scheme 2H), indicating that the metal carbene intermediate
may have a rather short existence in the reaction mixture.
Based on the above experimental results and the literature
reports,7,8,20 a plausible reaction mechanism is proposed in
Scheme 3. Initially, p-toluenesulfonyl hydrazone (2a) upon
heating gives the corresponding diazo compound (B), which in
the presence of Cu(II) gives the copper carbene intermediate
(C) with the release of N2.
On the other hand, the intermediate (A) which is generated
by the active ruthenium complex, reacts with copper carbene
intermediate (C) to give compound (E) via a carbene migratory
insertion reaction, followed by a ring opening via N−O bond
cleavage to give (F) and its corresponding tautomer (G). After
this, (G) can undergo radical-promoted cyclization either via a
tosyl radical (path a) or via Cu(II) (path b),21b to give the inter-
mediate (J) which on subsequent oxidation21c with the help of
Cu(II) or Cu(I), gives the final pyrrole product (3). The inter-
mediate (F) was detected in ESI-HRMS (Ar = p-MeO-Ph) which
seemed to indicate that the pathway probably involved (F) as
an intermediate.
Scheme 2 Control experiments and radical trap experiments.
Moreover, to check the possibility of a single electron transfer
pathway, a series of experiments were carried out in the pres-
ence of various radical trap agents.
In the case of TEMPO, complete inhibition of the trans-
formation was observed (Scheme 2E), and within a few
minutes, a complex mixture was observed in the reaction
mixture and despite our best efforts, a TEMPO-adduct with
any of the proposed intermediates was not observed.
Additionally, complete inhibition was also observed when the
Conclusion
reaction was carried out in the presence of the galvinoxyl In summary, we have developed a simple and convenient “one-
radical and in this case, the formation of Ts-radical adduct 4 pot” synthesis of trisubstituted pyrroles via a Ru(II)-catalyzed,
was confirmed by HRMS (Scheme 2F). Furthermore, when 2.0 Cu(II)-mediated reaction of substituted isoxazoles with sulfo-
equivalents of 1,1-diphenylethylene were used, the formation nylhydrazones under mild reaction conditions. This protocol
of desired product 3a was achieved in 71% yield with the results in a synergistic formation of new C−C and C−N bonds,
detection of the adduct 4a in 30% yield (Scheme 2G). Both which provides a simple and efficient method for the synthesis
these results indicated that the reaction may involve a Ts- of highly functionalized pyrroles. Mechanistic investigations
radical. Experiments were carried out to trap the in situ-gener- were carried out to propose a reaction pathway. This method-
ated carbene intermediate by the reaction of 3,5-diphenylisoxa- ology is expected to have promising application in the syn-
zole with acetophenone sulfonylhydrazone under standard thesis of various heterocyclic scaffolds and natural products.
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Conflicts of interest
There are no conflicts to declare.
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Acknowledgements
We thank SERB-India (EMR/2016/004298) and CSIR-India (02
(361)/19/EMR-II) for the funding. PK and SKK thank
UGC-India and CSIR-India respectively for their research fel-
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