Rh(III)-Catalyzed Chemodivergent Annulations between Indoles and Iodonium Carbenes: A Rapid Access to Tricyclic and Tetracyclic N-Heterocylces

Article abstract of DOI:10.1021/acs.orglett.1c01167

Herein, we report an acid-controlled highly tunable selectivity of Rh(III)-catalyzed [4 + 2] and [3 + 3] annulations of N-carboxamide indoles with iodonium ylides lead to form synthetically important tricyclic and tetracyclic N-heterocycles. Here, iodonium ylide serves as a carbene precursor. The protocol proceeds under operationally simple conditions and provides novel tricyclic and tetracyclic scaffolds such as 3,4-dihydroindolo[1,2-c]quinazoline-1,6(2H,5H)-dione and 1H-[1,3]oxazino[3,4-a]indol-1-one derivatives with a broad range of functional group tolerance and moderate to excellent yields. Furthermore, the protocol synthetic utility was extended for various chemical transformations and was easily scaled up to a large-scale level.

Full text of DOI:10.1021/acs.orglett.1c01167

pubs.acs.org/OrgLett
Letter
Rh(III)-Catalyzed Chemodivergent Annulations between Indoles and
Iodonium Carbenes: A Rapid Access to Tricyclic and Tetracyclic
N‑Heterocylces
Saiprasad Nunewar, Sanjeev Kumar, Harishchandra Pandhare, Srinivas Nanduri,
and Vinaykumar Kanchupalli*
Cite This: Org. Lett. 2021, 23, 4233−4238
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ABSTRACT: Herein, we report an acid-controlled highly tunable selectivity of Rh(III)-catalyzed [4 + 2] and [3 + 3] annulations of
N-carboxamide indoles with iodonium ylides lead to form synthetically important tricyclic and tetracyclic N-heterocycles. Here,
iodonium ylide serves as a carbene precursor. The protocol proceeds under operationally simple conditions and provides novel
tricyclic and tetracyclic scaffolds such as 3,4-dihydroindolo[1,2-c]quinazoline-1,6(2H,5H)-dione and 1H-[1,3]oxazino[3,4-a]indol-1-
one derivatives with a broad range of functional group tolerance and moderate to excellent yields. Furthermore, the protocol
synthetic utility was extended for various chemical transformations and was easily scaled up to a large-scale level.
precursors.6 Henceforth, this protocol has emerged as a robust
n nitrogen heterocycles, indole and pyrrole scaffolds are
Icentral structural motifs and can be found in a large number tool for a wide variety of C−H functionalizations with
carbenes.7 However, many reports employed diazo compounds
of natural products, pharmaceuticals, and manufactured
functional molecules.1 In particular, pyrimido[1,6-a]indol-
1(2H)-ones, pyrrolo[1,2-c]pyrimidin-1(2H)-ones, and 1H-
[1,3]oxazino[3,4-a]indol-1-one scaffolds are an integral part
of fluorescent materials and diverse biologically active
as carbene precursors, which are highly explosive and toxic in
nature. To overcome these difficulties, Wang and co-workers,8
Glorious and co-workers,9 Aissa and co-workers,10 Chang and
co-workers,11 and Li and co-workers12 introduced nondiazo
carbene counterparts such as hydrazones, triazoles, sulfoxo-
nium ylides, enynones, and iodonium ylides, which are
successfully utilized in various sp2 and sp3 C−H functionaliza-
tions.13 The carbene precursors have been shown enormous
diversity in the above-mentioned C−H functionalizations;
however, regiodivergent and chemodivergent synthetic trans-
formations by the identical catalyst system with operationally
simple method remains very limited.
compounds such as 5-HT3 receptor antagonists, antihyper-
tensive agents, CNS depressants, and others.2,3 Consequently,
the synthesis of these derivatives gained considerable attention
in both organic and medicinal chemistry.4 Although numerous
methods have been well-developed to assemble these moieties,
most of the methods involve multiple synthetic steps and harsh
reaction conditions. Therefore, developing a scope to establish
direct approaches with easily available starting materials and
mild reaction conditions is highly desirable.
The past decade has witnessed the burgeoning of the
directing-group-assisted transition-metal-catalyzed C−H func-
tionalizations with carbene precursors, which are widely
applied in alkylations, alkenylations, arylations, and annula-
tions.5 Note that, for the first time, Yu et al. reported Rh(III)-
catalyzed C−H alkylation of arene C−H bonds with carbene
Received: April 8, 2021
Published: May 21, 2021
https://doi.org/10.1021/acs.orglett.1c01167
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4233−4238
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On the other hand, it is great privilege to any catalysis
researcher to develop a single catalytic system performing
multiple reactions with common substrates via tunable
reactivity. The tunable reactivity can alter the reaction pathway
and brings the diversity in synthesis/outcome. In this regard,
recently, N-carboxamide indoles and carbene precursors have
been utilized for such tunable selective reactions via transition-
metal-catalyzed C−H functionalization, because of their high
flexibility and diverse reactivity.14,15 For example, Zeng and co-
workers pioneered in Rh(III)-catalyzed [4 + 2] annulation of
N-alkylaminocarbonyl indole with α-acyl diazo compounds for
rapid assembly of 2H-pyrimido[1,6-a]indol-1-one derivatives
(Scheme 1a).16 Cui and co-workers developed in Rh(III)-
that the formation of the [4 + 2] annulation product 3a and [3
+ 3] annulation product 4a in yields of 10% and 25% (see the
SI for details). After detail optimization studies, to our delight,
the catalytic system comprising [RhCp*Cl2]2, AgOAc and
DCM as solvent delivered the desired [4 + 2] annulation
product 3a in 92% yield. After that, a complete selectivity
switch was observed by using a catalytic system comprising
[RhCp*Cl2]2, AgOAc, AcOH, and acetone as the solvent, and
it delivered the [3 + 3] annulation product 4a in 85% yield
(see the SI for a detailed optimization). We hypothesized that
the additive with acid combination might facilitate the
formation of [3 + 3] annulation product by activating the
amide carbonyl group toward the oxygen attack for the
formation of 4a.15d
Having identified suitable reaction conditions, turning our
attention to the substrate scope, we initially probed variations
for the [4 + 2] annulation (Scheme 2). Indole having N-
methoxyamide and N-ethoxyamide substituents reacted
smoothly and furnished the corresponding desired products
in excellent yields (3a and 3b). However, sterically hindered
N-alkoxy carbamoyl indoles such as N-isopropoxy and N-tert
butoxy substituents deliver the [3 + 3] annulation product
Scheme 1. Overview of the Work
a b
,
Scheme 2. Scope of [4 + 2] Annulation
catalyzed [3 + 3] annulation of N-carboxamide indoles and
diazonaphthalen-2(1H)-ones for fused oxazinones synthesis
(Scheme 1b).17 Very recently, Yu group disclosed the synthesis
of dihydropyrimidoindolone and tricyclic [1,3]oxazino[3,4-
a]indol-1-ones derivatives via Rh(III)-catalyzed cascade [4 +
2]/[3 + 3] annulations of N-carbamoyl indoles with
sulfoxonium ylides (Scheme 1c).18 Although these reactions
provide an attractive route to indole C−H annulation, limited
substrate scope, prolonged reaction time and harsh reaction
conditions made them less attractive.
To the best of our knowledge, transition-metal-catalyzed
chemodivergent annulation of indoles with iodonium ylides
has not been reported previously. Herein, we report, for the
first time, acid-controlled Rh(III)-catalyzed chemodivergent
annulations of N-alkoxy-1H-indole-1-carboxamides and iodo-
nium ylides. The reaction affords a wide range of 2H-
pyrimido[1,6- a]indol-1-ones and 1H-[1,3]oxazino[3,4-a]-
indol-1-ones with moderate to excellent yields under mild
reaction conditions (Scheme 1d). The desired analogues are
core structures of many biologically active compounds.2,3
To test the tunable selectivity, we commenced our
investigation by using N-ethoxy-1H-indole-1-carboxamide
(1a) and 2-(phenyl-λ3-iodaneylidene)cyclohexane-1,3-dione
(2a) as the model substrates. Initial experiments revealed
that a combination of [RhCp*Cl2]2 and AgOAc is beneficial
for the reaction (see the Supporting Information for a detailed
optimization). Based on that, we were delighted to observe
a
Conditions:1 (0.1 mmol), 2a (0.11 mmol), DCM (2.0 mL).
Isolated yield. cThe reaction was run for 6 h. dHFIP (1.0 mL), 80 °C,
b
10 h.eThe reaction was run for 2 h.
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a b
,
(4a) instead of [4 + 2] annulation (3c and 3d). We assumed
that, because of the bulkiness of the corresponding products
(3c and 3d) may encourage the nucleophilic attack by the enol
oxygen followed by the elimination of hindered byproduct
NH2OR, leading to favors the formation of 4 instead of 3. 3-
Alkyl-substituted indoles were also well-tolerated and delivered
the targeted products in good to excellent yields (3e and 3f).
The structure of 3e was confirmed by X-ray crystallography.
Gratifyingly, indole having either electron-donating or
electron-withdrawing substituents (OBn, Me, OMe, F, Cl,
Br, and I) reacted with iodonium ylide (2a) to generate the
desired products 3 in good to excellent yields (3g−3p).
Notably, when π-electron withdrawing groups (CN and NO2)
were subjected to the described optimized conditions, the
annulated product was formed in moderate levels of yield (3q
and 3r). We reasoned that the substituents might be creating
the poor electron density at indole C2-position. To our delight,
pyrrole-substituted N-carboxyamides also performed well and
produced the corresponding products in moderate to good
yields (3s−3u). In contrast, alkyl-derived N-carbamoyl indoles
(1v, 1x, and 1y) failed to provide the desired annulated
product, presumably because of the inability to participate in
the oxidative addition step.
Scheme 3. Scope of [3 + 3] Annulations
a
Conditions:1 (0.1 mmol), 2a (0.11 mmol), Acetone (2.0 mL).
b
c
Isolated yield. The reaction was run for 3 h.
Furthermore, we explored the scope of this transformation
by modulating the carbene precursors (see Scheme 2). To our
delight, the reaction occurred in good to excellent yields with a
variety of substituents at the C5 position of cyclohexane-1,3-
dione-derived ylides. The substitutions Me, diMe, Ph, p-tolyl,
and anisole were well-tolerated and afforded the desired
products (3v−3z). In contrast, we were pleased to find that
1,3-diphenylpropane-1,3-dione-derived iodonium ylides are
well-facilitated for the [4 + 2] annulation, thus resulting in
the corresponding tricyclic products in good to excellent yields
(3aa−3ae). Note that, for the first time, these ylides were
utilized in direct C−H functionalization reactions. However,
cyclopentane-1,3-dione-derived iodonium ylide (2d) and
aliphatic iodonium ylides (2m and 2n) did not proceed
under standard conditions, it demonstrated that the trans-
formation is sensitive to the size and nature of the dione
compounds.
a
Scheme 4. One-Pot Reaction and Large-Scale Synthesis
a
b
Conditions: Isolated yield. The reaction was run for 5 h.
Furthermore, we investigated the substrate scope for the
formation of [1,3]oxazino[3,4-a]indol-1-one derivatives 4
under the optimized reaction conditions (Scheme 3). Various
substitutions on indole such as H, Me, OMe, OBn, and
tetracyclopentanes were well-tolerated and afforded the
corresponding cyclized products in high yields (4a−4e). To
our delight, diverse halogen-substituted indoles also underwent
the [3 + 3] cyclization to afford the desired products in good
to excellent yields (4f−4l), which are suitable substrates for
various cross-coupling reactions. Notably, the π-electron-
withdrawing groups at indole caused slow reactivity, resulting
in diminished yields of corresponding annulated product
(4m−4n). Interestingly, diverse iodonium precursors partici-
pated efficiently in the [3 + 3] annulation, thus offering the
respective products in excellent yields (4o−4r). The structure
of 4r was confirmed by X-ray crystallography. Notably, the
reaction was efficient with pyrrole substituted N-carboxyamide
and produced 4s in decent yield.
the yield of one-pot fashion was comparable with the stepwise
pathway. Furthermore, a large scale reaction was performed
and reacting 4.9 mmol of indole carboxyamide 1a with 6.37
mmol of iodonium ylide 2a under aforementioned reaction
conditions, yielding the desired products 3a in 87% yield (1.26
g) and 4a in 80% yield (0.99 g) (Scheme 4b). Next, selected
transformations of 3 and 4 were carried out to exhibit the
synthetic potential of these approaches (see the details in the
SI).19
In order to gain more insights on the reaction mechanism, a
series of control experiments were performed (Scheme 5). A
deuterium incorporation experiment was performed by treating
1b with MeOH-d4 under standard reaction conditions, and the
results showed that 57% and 48% of deuteration at C2 position
of indole, which demonstrated that the C−H bond cleavage is
reversible in both synthetic transformations (Scheme 5a). The
intermolecular competition reactions and parallel reactions
gave low KIE values (KIE < 1), indicated that the C−H
cleavage did not participate in the rate-limiting step (see
Schemes 5b and 5c).
To our curiosity on step economy process, we have
developed a one-pot protocol for the synthesis of tri- and
tetracyclic derivatives by combining in situ formation of
iodonium ylide from the 1,3-dicarbonyl compound followed by
Rh(III)-catalyzed C−H annulation (Scheme 4a). Satisfyingly,
On the basis of literature precedents and our preliminary
mechanistic results,12,15d,18 a possible catalytic cycle was
proposed, which is shown in Scheme 6. A five membered
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Scheme 5. Mechanistic Studies
ASSOCIATED CONTENT
■
sı
* Supporting Information
X-ray crystallographic analysis (CIF files for compound 3e
(CCDC no. 2067730) and 4r (2067731) and spectroscopic
data for synthesized compounds. . The Supporting Information
is available free of charge at https://pubs.acs.org/doi/10.1021/
acs.orglett.1c01167.
Additional experimental procedures (PDF)
Accession Codes
CCDC 2067730−2067731 contain the supplementary crys-
tallographic 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.
Scheme 6. Proposed Mechanism
AUTHOR INFORMATION
■
Corresponding Author
Vinaykumar Kanchupalli − National Institute of
Pharmaceutical Education and Research (NIPER),
Hyderabad 500 037, Telangana, India; orcid.org/0000-
0002-2298-4376; Email: vinaykumariiserb@gmail.com,
vinay.niperhyd@nic.in
Authors
Saiprasad Nunewar − National Institute of Pharmaceutical
Education and Research (NIPER), Hyderabad 500 037,
Telangana, India
Sanjeev Kumar − National Institute of Pharmaceutical
Education and Research (NIPER), Hyderabad 500 037,
Telangana, India
Harishchandra Pandhare − National Institute of
Pharmaceutical Education and Research (NIPER),
Hyderabad 500 037, Telangana, India
Srinivas Nanduri − National Institute of Pharmaceutical
Education and Research (NIPER), Hyderabad 500 037,
Telangana, India; orcid.org/0000-0002-6671-2022
rhodium species such as B is formed by the C−H bond
cleavage of N-alkoxycarbamoyl indoles (1) at C2 position with
active rhodium catalyst A. The coordination of iodonium ylide
(2) to the metal center in B followed by loss of iodobenzene,
affords the metal carbene species C. The subsequent migratory
insertion gives intermediate D, which undergoes protonation
to deliver the intermediate E and regenerate the active catalyst
species A. The intermediate E followed two different
annulation pathways. In path a, the ketone carbonyl is then
nucleophilically attacked by the amide NH group, followed by
dehydration, to yield the [4 + 2] annulation product 3. On the
other hand, in path b, the acid activates the amide group
toward nucleophilic attack by the enol oxygen, leading to
favors the formation of [3 + 3] annulation product 4, by the
elimination of NH2OR. We hypothesized that the acid additive
stimulates the elimination process through protonation.
In summary, we have described an acid controlled Rh(III)-
catalyzed chemodivergent annulations of N-alkoxycarbamoyl
indoles and iodonium ylides, which provided a synthetically
important tri- and tetracyclic N-heterocycles under operation-
ally simple conditions. This protocol features broad substrate
scope, good tolerance of functional groups, moderate to high
yields. The efficiency of this methodology, further demon-
strated by a large-scale and one-pot synthesis of desired
products. In addition, the annulated products successfully
transformed to diverse synthetic analogues. The biological
applications of this strategy are in progress in our laboratory,
and we anticipate that these privileged motifs will show wide
applications in pharmaceutical field.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01167
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Authors S. Nunewar, S. Kumar, and H. Pandhare sincerely
thank the Department of Pharmaceuticals (DoP), India and
National Institute of Pharmaceutical Education and Research
(NIPER), Hyderabad for the fellowship. Authors S. Nanduri
and V. Kanchupalli thank NIPER-Hyderabad for the financial
support, and V. Kanchupalli expresses his gratitude toward the
DST-Inspire faculty (No. DST/INSPIRE/04/2018/001660)
for his fellowship. We thank Dr. Neeraj Kumar for useful
discussions. NIPERH Research Communication No. NIPER-
H/2020/170.
DEDICATION
■
Dedicated to Dr. Shashi Bala Singh on the occasion of her 63rd
birthday.
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Supporting Information. Please see the details in page 5 in the
Supporting Information.
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