Palladium-catalyzed [3+3] annulation between diarylamines and α,β-unsaturated acids through C-H activation: Direct access to 4-substituted 2-quinolinones

Article abstract of DOI:10.1002/chem.201500774

A C-H activation strategy has been successfully employed for the high-yielding synthesis of a diverse array of 4-substituted 2-quinolinone species by a palladium-catalyzed dehydrogenative coupling involving diarylamines. This intermolecular annulation app

Full text of DOI:10.1002/chem.201500774

DOI: 10.1002/chem.201500774
Communication
&
CÀH Activation
Palladium-Catalyzed [3+3] Annulation between Diarylamines and
a,b-Unsaturated Acids through CÀH Activation: Direct Access to
4-Substituted 2-Quinolinones
Rajesh Kancherla, Togati Naveen, and Debabrata Maiti*[a]
Abstract: A CÀH activation strategy has been successfully
employed for the high-yielding synthesis of a diverse
array of 4-substituted 2-quinolinone species by a palladi-
um-catalyzed dehydrogenative coupling involving diaryla-
mines. This intermolecular annulation approach incorpo-
rates readily available a,b-unsaturated carboxylic acids as
the coupling partner by suppressing the facile decarboxy-
lation. Based on preliminary mechanistic studies, a reaction
sequence is proposed, involving ortho palladation, p-coor-
dination, b-migratory insertion, and b-hydride elimination.
Scheme 1. Synthesis of 4-substituted 2-quinolinones.
Quinolinones are an important class of heterocyclic com-
pounds.[1] In particular 4-aryl-2-quinolinones occur naturally[2]
and exhibit unique biological properties.[3] They are inhibitors
of acyl coenzyme A and cholesterol acyltransferase, and are
also potent openers of calcium-activated K+ channels.[4] The 4-
aryl-2-quinolinone derivative tipifarnib is known to exhibit anti-
cancer activity.[5] In addition, various 2-alkoxyquinolines can be
derived from 2-quinolinones for their use as ligands in CÀH ac-
tivation reactions.[6] Various methods for the synthesis of 2-qui-
nolinones have been reported[4a,7] and considerable attention
has been paid in recent times to the development of 4-substi-
tuted 2-quinolinones.[8]
and coumarin.[9] Inspired by these studies, we envisaged the
synthesis of 4-substituted 2-quinolinones by employing an un-
explored variant of Fujiwara–Moritani-type coupling[10] be-
tween simple diarylamines and widely available a,b-unsaturat-
ed carboxylic acids. This approach (with or without a directing
group) remained problematic due to the facile decarboxylation
of a,b-unsaturated acid-derived intermediates. Systematic ex-
ploration revealed that trifluoroacetic acid (TFA) could suppress
decarboxylation under our reaction conditions and thus al-
lowed the formation of 4-substituted 2-quinolinones.[11] The
optimized reaction conditions (condition A; Table 1), with di-
phenylamine (1a, 0.5 mmol), cinnamic acid (2a, 0.25 mmol),
palladium pivalate (Pd(OPiv)2, 10 mol%), 1,10-phenanthroline
(20 mol%), and TFA (4 equiv) in methanol (2 mL) using
Cu(OAc)2 (0.5 equiv) or air (oxygen) as oxidant produced 1,4-
diaryl-2-quinolinone (3a) in 98% yield (isolated: 93%).[11]
Systematic variation of substituents at the para (3a–g), meta
(3h–j), and ortho (3k–m) positions on the cinnamic acids were
studied to reveal the electronic and steric dependence
(Table 1). Although all of the substrates reacted successfully,
electron-rich cinnamic acids gave better yields (e.g., 3b vs.
3g). Various halides at ortho or para positions were well toler-
ated (3d–f, 3l, and 3m). Introduction of functional groups
such as 3-CF3 (3h, 80%), 4-CO2Me (3g, 71%) and 3-NO2 (3i,
47%) on the aryl ring did not alter the outcome of the reac-
tion. Similarly, hydroxycinnamic acids also gave the desired
compounds in preparatively useful yields (3j and 3u). Sterically
congested trimethoxycinnamic acid could also be employed
under the standard reaction condition (3x, 81%). As expected,
substituted diarylamines formed quinolinones in excellent
yields (3n–r, 3v). However, various monoarylamines (ArNHR;
With a view to 4-substituted 2-quinolinone synthesis, Tsuji
and co-workers reported the iridium catalyzed reaction of N-ar-
ylcarbamoyl chlorides with internal alkynes (Scheme 1).[8d]
However this intermolecular reaction did not work with termi-
nal alkynes (e.g., 1-decyne and phenylacetylene) and therefore
failed to yield 4-alkyl- and 4-aryl-2-quinolinones. Recently, Yu
and co-workers successfully constructed 1,4-diaryl-2-quinoli-
nones from propionamides and aryl iodides by a palladium-
catalyzed CÀH activation method (Scheme 1).[8a] Unfortunately,
this novel method could not incorporate aliphatic and hetero-
cyclic substituents at the 4-position of quinolinone. Indeed,
direct synthesis of such moieties is yet to be reported. We re-
cently developed a palladium-catalyzed CÀH activation path-
way for synthesizing heterocycles such as indole, benzofuran
[a] Dr. R. Kancherla, T. Naveen, Prof. D. Maiti
Department of Chemistry, Indian Institute of Technology Bombay
Powai, Mumbai-400076 (India)
E-mail: dmaiti@chem.iitb.ac.in
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500774.
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Table 1. Scope with symmetrical diphenylamines and aromatic acrylic
Table 2. Scope with aliphatic acrylic acids.
acids.
Yields given correspond to isolated products.
Table 3. Scope with heterocyclic acrylic acids.
Yields given correspond to isolated products.
R=H, Me, Et, iPr, Ts and Ac) either formed mixtures of insepa-
rable compounds or gave low yields of the desired quinoli-
none products.
Aliphatic coupling partners are distinct from their aromatic
counterparts due to electronic differences and are often prob-
lematic in Pd-catalyzed coupling reactions due to their tenden-
cy to undergo b-hydride elimination, which often leads to un-
desired side products.[12] Interestingly, 4-alkyl-N-phenyl-2-quino-
linone species (5a–i) were successfully synthesized in 51–99%
yields by employing a number of aliphatic acrylic acids
(Table 2). Notably, the reactivity of the acrylic acids was found
to increase with increasing chain length (5d–i).
Yields given correspond to isolated products.
The scope of the method was further tested by employing
heterocyclic acrylic acids to produce 4-heteroaryl-N-phenyl-2-
quinolinones (7a–h) in good yields (Table 3). Among the heter-
ocyclic substrates, 3-thienyl acrylic acid gave the maximum
yield (7a, 91%). Due to incomplete conversion of the starting
materials, a significant decrease in yields was observed in case
of 7d [35% and 82% based on recovered starting materials
(brsm)] and 7h (37% and 80% brsm).
Next, we investigated the reactivity of unsymmetrical diaryl-
amines under standard conditions (Tables 4 and 5). Diphenyl
amines with 2-OMe (10a; 80%), 2-Me (10e; 50%), 2-F (10b
and 10d; 46% and 25%, respectively), and 2-Cl (10c; 30%)
substituents underwent successful annulation with different
acrylic acids.
Interestingly, with ortho-substituted unsymmetrical diaryl-
amines, in spite of the possibility of forming regioisomeric mix-
tures, only one product was generated exclusively (10a–e).
This is ascribed to the steric factors, where the palladation on
the o-substituted ring was disfavored, thereby allowing olefina-
tion of the unsubstituted aryl ring. Incomplete conversion of
the carboxylic acids was found to be responsible for low yields
of the desired products 10b–e (Table 4).
A preference for cyclization of the electron-rich aromatic
ring was observed with differentially substituted unsymmetri-
cal diarylamines (Table 5). In case of 4-morpholino-N-phenylani-
line (11 a), a 42% isolated yield of the major product 12aA
was obtained through cyclization towards electron rich aryl
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in order to understand the reactivity and reaction mecha-
nism.[11] Based on these competition experiments and the re-
sults in Table 1, Table 2, Table 3, we found that electron rich
acrylic acids as well as electron rich diphenylamines were cy-
clized preferentially over neutral and electron deficient
analog.[11]
Table 4. o-Substituted unsymmetrical diphenylamines.
Intra- and intermolecular competition experiments with deu-
terium-labeled diphenylamines were carried out to probe the
reaction mechanism. Cyclization at the undeuterated aryl
group was observed preferentially with respect to the [D5]aryl
moiety in [D5]diphenylamine ([PH1]/[PD1]=4.0; Scheme 2a). Ad-
Yields given correspond to isolated products.
Table 5. Scope with unsymmetrical diphenylamines.
Scheme 2. Intra- and intermolecular deuterium labeling experiments.
Amine
Products
ditionally, intermolecular competition between [D10]- and
simple (undeuterated) diphenylamine gave a product-distribu-
tion value of 4.3 ([PH2]/[PD2]; Scheme 2b). These higher values
indicate that CÀH bond cleavage is irreversible and can be in-
volved in either the turnover-limiting or product-determining
step.[13] Notably, both N,N-diphenylcinnamide (13) and N-acyl-
diphenylamine (14) failed completely to produce 3a under the
standard reaction conditions (Scheme 3a and b). Detection of
the other plausible intermediate D (Scheme 4) was difficult,
due to its effective annulation in the presence of TFA to give
E. In the absence of TFA, ortho olefinated intermediate D un-
derwent facile decarboxylative coupling to produce a 1,3-diary-
lindole instead of 2-quinolinone (3a). Cinnamic acid (without
diarylamine) under the standard reaction condition gave
a 10% yield of methylcinnamate. This observation further indi-
Yields given correspond to isolated products; [a] two isomers were ob-
tained as an inseparable mixture.
ring. The similar reactivity pattern was also found in case of
11 b, which gave 12bA as the major product. Using 3-(phenyl-
amino)phenol (11 c), both the regioisomers 12cA and 12cB
were obtained in 1:1 ratio.
A number of competition experiments between electronical-
ly different acrylic acids and diphenyl amines were carried out
Scheme 3. Mechanistic study.
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cated that a,b-unsaturated carboxylic acid directly participates
in the CÀC coupling reaction to give D. Structurally similar
ortho-olefinated intermediate 16 was formed under the stan-
dard reaction conditions by reacting diphenylamine with
methyl methacrylate (15), which further supports D as a feasi-
ble intermediate in the reaction pathway (Scheme 3c).
Keywords: annulation
catalysis · N heterocycles · palladium
·
CÀH activation
· homogeneous
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Acknowledgements
This activity was supported by Science and Engineering Re-
search Board, India (No. SB/S5/GC-05/2013). Financial support
received from DST under the Fast Track Scheme (R.K.) and CSIR
(T.N.) is gratefully acknowledged. Palladium catalysts were ob-
tained as a gift from Johnson Matthey Chemicals, MIDC Taloja,
India.
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Received: February 25, 2015
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COMMUNICATION
&
CÀH Activation
R. Kancherla, T. Naveen, D. Maiti*
&& – &&
Palladium-Catalyzed [3+3]
Annulation between Diarylamines and
a,b-Unsaturated Acids through CÀH
Activation: Direct Access to 4-
Substituted 2-Quinolinones
4-substituted 2-quinolinone species
are been synthesized in high yields by
a palladium-catalyzed dehydrogenative
coupling involving diarylamines. This in-
termolecular annulation approach incor-
porates readily available a,b-unsaturat-
ed carboxylic acids as the coupling part-
ner by suppressing decarboxylation.
&
&
Chem. Eur. J. 2015, 21, 1 – 6
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ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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