Catalyst control in positional-selective C-H alkenylation of isoxazoles and a ruthenium-mediated assembly of trisubstituted pyrroles

Article abstract of DOI:10.1021/acs.orglett.9b00446

High levels of catalyst control are demonstrated in determining the positional selectivity in C-H alkenylation of isoxazoles. A cationic rhodium-mediated, strong-directing group promotes C(sp²)-H activation at the proximal aryl ring whereas, the palladium-mediated electrophilic metallation leads to the C(sp²)-H activation at the distal position of the directing group. Synthetic elaboration of this C-H alkenylation product via ruthenium and copper co-catalysis leads to an efficient method for the assembly of densely substituted pyrroles.

Full text of DOI:10.1021/acs.orglett.9b00446

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Catalyst Control in Positional-Selective C−H Alkenylation of
Isoxazoles and a Ruthenium-Mediated Assembly of Trisubstituted
Pyrroles
Pravin Kumar and Manmohan Kapur*
Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhopal Bypass Road, Bhauri, Bhopal 462066
MP, India
S
* Supporting Information
ABSTRACT: High levels of catalyst control are demonstrated in determining the positional selectivity in C−H alkenylation of
isoxazoles. A cationic rhodium-mediated, strong-directing group promotes C(sp2)-H activation at the proximal aryl ring
whereas, the palladium-mediated electrophilic metallation leads to the C(sp2)-H activation at the distal position of the directing
group. Synthetic elaboration of this C−H alkenylation product via ruthenium and copper co-catalysis leads to an efficient
method for the assembly of densely substituted pyrroles.
Scheme 1. Catalyst Control in Positional-Selective C−H
Alkenylations
ontrol of positional selectivity within a reacting species is
1
Cone of the most important aspects of organic chemistry.
In recent years, controlling this site or positional selectivity in
transition-metal-catalyzed C−H functionalization reactions has
become increasingly better understood.2,3 In addition to the
widely employed method of using directing groups to govern
site selectivity, steric and electronic effects, solvent, ligand, and
catalyst control are increasingly popular techniques for
selective C−H bond functionalization.4
Isoxazoles are ubiquitous scaffolds that can be found in a
variety of life-saving drugs and pharmaceuticals, as well as in
biologically active natural products.5−7 In addition, isoxazoles
serve as versatile intermediates8,9 and have been extensively
employed in various catalytic transformations to afford a
diverse array of synthetically useful heterocycles, as well as
biologically relevant molecules.10 Therefore, the transition-
metal-catalyzed direct C−H functionalization of isoxazoles has
emerged as an important aspect in synthetic organic chemistry.
In 2008, Wu and co-workers reported the o-arylations as well
as alkylations of 3,5-diarylisoxazoles using phenyl and
alkylboronic acids in the presence of stoichiometric amount
of palladium salts.11 In 2014, Patel and co-workers also
reported the palladium-catalyzed ortho-aroylations and acetox-
ylations of 3,5-diarylisoxazoles.12 In this report, we disclose a
catalyst-controlled, positional-selective C−H alkenylation of
substituted isoxazoles (Scheme 1). In this work, a cationic
rhodium-mediated, strong-directing group promoted C−H
activation results in the proximal C−H bond functionalization.
In contrast, a covalent Pd catalyst prefers an electrophilic C−H
activation pathway to yield the distal C−H bond functionaliza-
tion. The product of the Pd catalysis was then successfully
elaborated to yield densely functionalized pyrroles via a
ruthenium and copper co-catalyzed transformation.
We began our efforts by screening a variety of reaction
conditions (see the Supporting Information (SI) for details) to
achieve the proximal C−H bond functionalization. Our
attempts to optimize the reaction conditions using ruthenium
catalysis resulted primarily in N−O bond cleavage of isoxazole
to give keto-amines, along with the formation of a trace
amount of the desired o-olefinated product (see the SI for
details). Under rhodium catalysis, the N−O bond cleavage was
not observed and the o-olefinated product was obtained in a
decent yield. After considerable optimizations, the best
conditions were found to be [Cp*RhCl2]2 (1 mol %),
AgSbF6 (20 mol %), Cu(OAc)2·H2O (2 equiv), and
CH3CO2H (1 equiv) in tetrahydrofuran (THF) at 100 °C.
In order to explore the generality of the present investigations,
a variety of substituted isoxazoles were coupled with various
activated olefins using the optimized conditions to afford
various o-olefinated products in moderate to good yield
Received: February 2, 2019
© XXXX American Chemical Society
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(Scheme 2). In all cases, the site selectivity was exclusive and
no C−H olefinations arising out of electrophilic metallation
In 2011, Wheeler and co-workers had reported the direct
alkenylation of the isoxazole ring,14 whereas the direct
arylations of isoxazoles using aryl iodides was reported by
Nakamura and co-workers.15 The coupling of alkenes and
alkynes with 3,5-dimethyl-4-iodoisoxazole, 3-ethoxy-4-iodo-5-
methylisoxazole has also been reported.16 Based on our
previous experience of C−H functionalization at distal
positions within heterocycles,17 we successfully switched the
selectivity of the C−H olefination from the proximal arene ring
C−H to the isoxazole C(4)−H by employing electrophilic
metallation. Upon screening a variety of catalyst systems in
different solvents to explore the selective olefination at the
isoxazole ring, we found that Pd(OAc)2, along with AgOAc (1
equiv) and Ag2CO3 (2 equiv) in THF at 110 °C, was the
optimum condition (Scheme 3). The absence of silver acetate
Scheme 2. Substrate Scope for ortho-Alkenylation of 3,5-
a
Diarylisoxazole
Scheme 3. Substrate Scope for C(4)−H Alkenylation of 3,5-
Diarylisoxazole and Subsequent Transformation to
a
Pyrroles
a
a
b
All yields are isolated yields. bYield for the reaction on 1 mmol scale.
All yields are isolated yields. Values in parentheses indicate yield
over two steps. cYield for reaction on 1 mmol scale. dDirectly
synthesized from corresponding crude alkenylated product.
were detected at the isoxazole ring. With 3,5-diarylisoxazole,
electron-donating substituents on the 3-aryl ring did not
hamper the reaction outcome and the corresponding o-
alkenylated products were obtained in good yields. However,
the presence of electron-withdrawing substituents in the 3-aryl
ring resulted in a sluggish rate of reaction and the
corresponding olefinated product were furnished in slightly
reduced yields (Scheme 2). The site selectivity was
unambiguously proven by X-ray crystallographic analysis of 3z.
The transformation worked well with almost all the activated
olefins that were screened, including acrylates, acrylonitriles,
styrenes, vinyl sulfones, as well as enones (Scheme 2). The
reaction worked well with α,β-unsaturated lactones, as well as
cyclic enones. In some cases, the β-hydride elimination
product was not observed; instead, the hydroarylation product,
arising out of protodemetallation of the intermediate obtained
after the migratory insertion, was observed.13 In the case of 6-
membered α,β-unsaturated lactones with 2-fluoro isoxazole
mixture of product (hydroarylation and alkenylation) was
obtained (3ap and 3ap′; see Scheme 2). The reaction worked
decently with monosubstituted (3al, Scheme 2) as well as a
silyl-substituted isoxazole (3aj and 3ak; see Scheme 2).
Interestingly, the reaction worked quite well for the C(sp2)-
H olefination with a C5-vinyl substituent, thereby generating a
very interesting diene system (3ah and 3ai; see Scheme 2).
led to sluggish rate of reaction whereas oxidants other than
silver carbonate led to the formation of o-olefinated product.
With this optimized condition the scope of the present
alkenylation reaction was further extended to various
substituted activated alkenes and the reaction was found to
be quite general (Scheme 3).
The utility of direct C-4 alkenylations of isoxazole was
examined in the synthesis of pyrroles. When we subjected our
synthesized C-4 olefinated isoxazoles under conditions such as
FeCl2·4H2O (10 mol %) in acetonitrile,18 we unfortunately
could not get the desired pyrrole product. After considerable
optimization (see the SI for further details) and we found that
the cooperative catalysis involving RuCl3·xH2O (5 mol %),
Cu(OAc)2 (1 equiv) in DCE at 110 °C gave the desired
pyrrole (Scheme 3) in very decent yield. The reaction worked
well with all the substrates and we were able to synthesize a
variety of trisubstituted pyrroles with moderate to good yields.
The outcome of the cyclization was directly dependent on the
initial palladium-mediated C(4)−H olefination of the isoxazole
moiety. The palladium-mediated C−H olefination reaction
seemed to work well with activated olefins such as acrylates but
did not work with styrenes. The ruthenium catalyst was found
to be necessary for the transformation to pyrroles; the reaction
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did not work without it. This indirectly indicated that the
transformation was not just a copper-mediated one.
Experiments were conducted to gain more insights into the
plausible pathways of the transformations (Scheme 4). To
D2O, considerable deuteration was found at the relevant sites
of the recovered starting material in both the rhodium- as well
as palladium-catalyzed reactions (Scheme 4).
Interestingly, in the case of the rhodium catalysis, the
reaction in the presence of the coupling partner did not yield
any deuteration at the aryl ring, indicating that the further steps
were faster than the demetallation. In the case of palladium
catalysis, the reaction in the presence of coupling partner
yielded a significant amount of deuteration in recovered
starting materials with no deuterium incorporation in the
product (Scheme 4). Kinetic isotope effect studies performed
via parallel reactions as well as competitive reactions indicated
an absence of primary kinetic isotope effect for both the
rhodium- as well as the palladium-catalyzed transformations.
This proved that the C−H activation is not the rate-limiting
step for both the transformations. It is quite possible that either
the carbometallation or the β-hydride elimination could be the
rate-limiting step in these reactions. Based on these
observations and literature reports,18−20 plausible mechanisms
for the transformations are depicted in Scheme 5.
Scheme 4. Reversibility of Metalation and Kinetic Studies
In the case of the rhodium-catalyzed transformation,
generation of the cationic catalyst is followed by a directed
C−H activation, most probably via a base-assisted internal
electrophilic substitution (BIES) reaction.21a The site
selectivity is governed by the preference of the rhodium
catalyst for the strongly coordinating isoxazole nitrogen. The
protic medium may play a role in facilitating this step. The fact
that substrate 1g reacted faster than 1t (Scheme 4) indicated
that a BIES mechanism could be operative instead of the
concerted metallation−deprotonation (CMD) pathway.21b
This is followed by coordination of the olefin to the
cyclometalated intermediate, followed by carborhodation and
subsequent β-hydride elimination to yield the proximal C−H
functionalization product. The rhodacycles A as well as C were
detected in HRMS (Scheme 5). In the palladium-catalyzed
transformation, it is possible that, because of the considerable
covalency of Pd(OAc)2, the preference for the softer mode of
activation (electropalladation) is higher, thereby leading to
metallation at the isoxazole ring.
After the formation of the C4-palladated intermediate, the
subsequent steps are similar to the rhodium-catalyzed
transformation. Our hypothesis is also supported by the fact
check the reversibility of the C−H metallation, the reactions
were performed in the presence of D2O or CD3CO2D.
Although the reaction was slightly sluggish in the presence of
Scheme 5. Plausible Pathway for the Positional-Selective Transformations and the Ru-Mediated Pyrrole Synthesis
C
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that the reaction in the combination of Pd(OAc)2 and
Cu(OTf)2 also resulted in C−H olefination at the proximal
C3-aryl ring, similar to the rhodium-catalyzed transformation
(see the SI for details). This clearly indicates that the cationic
nature of the catalyst (hard) prefers coordination to the (hard)
nitrogen directing group. At this moment, the role of copper in
the conversion of 4 to 5 is not very clear. As mentioned earlier,
Khlebnikov and co-workers had reported an Fe(II)-mediated
transformation of 4-vinylisoxazoles to pyrroles, where an iron-
carbene pathway was proposed. In our case, the Fe(II)-
mediated pathway did not work and the reaction did not work
with just stoichiometric amounts of Cu(II). Thus, Ru was
necessary for this transformation. Although the reaction
worked well with a Ru(II) catalyst ([RuCl2(p-cym)]2 (5
mol %) and Cu(OAc)2 (1 equiv), it performed much better
with RuCl3 (5 mol %) and Cu(OAc)2 (1 equiv). As shown in
Scheme 5, it is possible that a ruthenium-carbene intermediate
may be involved in the pathway, which is followed by a 1,5-
cyclization to yield the pyrrole product. This Ru- and Cu-
mediated cooperative catalysis to yield a pyrrole product did
not work with the olefination products arising out of the Rh-
catalyzed reaction, since the molecular framework for the
cyclization is unavailable in that case.
To conclude, we have demonstrated a catalyst-controlled,
positional-selective C−H olefination of substituted isoxazoles.
The proximal site selectivity in the rhodium-catalyzed
transformation is governed by the cationic nature of the
catalyst and the strong coordination to the nitrogen of the
isoxazole, whereas the distal site selectivity in the palladium-
catalyzed transformation is governed by the more covalent
nature of the catalyst. The synthetic elaboration of the
palladium-mediated C−H olefination product is demonstrated
by a ruthenium- and copper-mediated cooperative catalysis in
the synthesis of densely substituted pyrroles.
ACKNOWLEDGMENTS
■
We thank SERB, India for supporting this work. P.K. thanks
UGC-India for a Research Fellowship. We thank the CIF,
IISERB, for the analytical data and the Director, IISERB, for
the funding and infrastructural facilities. We also thank the
Reviewers for their insightful suggestions.
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new compounds (PDF)
Accession Codes
CCDC 1884277 and 1884314 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mk@iiserb.ac.in.
ORCID
Manmohan Kapur: 0000-0003-2592-6726
Funding
Funding by SERB-India, through Grant No. EMR/2016/
004298/OC, is appreciated.
Notes
The authors declare no competing financial interest.
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DOI: 10.1021/acs.orglett.9b00446
Org. Lett. XXXX, XXX, XXX−XXX