Ligand-enabled triple C-H activation reactions: One-pot synthesis of diverse 4-aryl-2-quinolinones from propionamides

Article abstract of DOI:10.1002/anie.201403878

Diverse 4-aryl-2-quinolinones are prepared from propionamides in one pot by ligand-promoted triple sequential C-H activation reactions and a stereospecific Heck reaction. In these cascade reactions, three new C-C bonds and one C-N bond are formed to rapidly build molecular complexity from propionic acid. Building complexity: Diverse 4-aryl-2-quinolinones such as 1 are prepared from propionamides in one pot by pyridine ligand-promoted triple sequential C-H activation reactions and a stereospecific Heck reaction. In these cascade reactions, three new C-C bonds and one C-N bond are formed to rapidly build molecular complexity from propionic acid.

Full text of DOI:10.1002/anie.201403878

Angewandte
Chemie
DOI: 10.1002/anie.201403878
Cascade C-H Activation
Hot Paper
À
Ligand-Enabled Triple C H Activation Reactions: One-Pot Synthesis
of Diverse 4-Aryl-2-quinolinones from Propionamides**
Youqian Deng, Wei Gong, Jian He, and Jin-Quan Yu*
Dedicated to Professor Bjçrn ꢀkermark on the occasion of his 80th birthday
Abstract: Diverse 4-aryl-2-quinolinones are prepared from
propionamides in one pot by ligand-promoted triple sequential
À
C H activation reactions and a stereospecific Heck reaction. In
À
À
these cascade reactions, three new C C bonds and one C N
bond are formed to rapidly build molecular complexity from
propionic acid.
3
À
L
igand-controlled or ligand-accelerated C(sp ) H activation
with PdII catalysts has recently emerged as a promising
strategy for developing new catalytic transformations.[1–3]
3
À
Notable examples include the cross-coupling of g-C(sp ) H
bonds of protected amines with arylboron reagents enabled
by mono-protected amino acid ligands[1] as well as b-arylation
4-Aryl-2-quinolinone derivatives constitute a valuable class of
biologically active compounds, including natural products[5]
and medicinal compounds[6] (Scheme 1). Moreover, they may
serve as valuable synthetic intermediates to 2-(pseudo)halo-
quinolines as well as 2-alkoxyquinolines for use as ligands
3
À
of primary and secondary C(sp ) H bonds promoted by
pyridine and quinoline ligands.[2] The compatibility of these
3
À
ligands with C(sp ) H activation and subsequent functional-
ization steps offers unprecedented opportunities to discover
new catalytic reaction pathways by influencing the reactivity
of various potential organopalladium intermediates. In par-
ticular, if a common ligand can be identified to promote
in C H activation reactions.[2] Considering the broad interest
À
in 4-aryl-2-quinolinones,[7] this newly developed one-pot
procedure could prove useful in synthetic and medicinal
chemistry.
À
cascade C H activation reactions, molecular complexity and
diversity can be readily generated from simple starting
[4]
À
materials by sequential and diverse C H functionalizations.
Indeed cascade reactions involving a Heck reaction and
À
a subsequent C H activation step provide an elegant route
for the synthesis of spirodihydroquinolin-2-ones.[4f] However,
À
cascade C H activation reactions of simple aliphatic sub-
strates leading to complexity have not been demonstrated.
Inspired by our studies of ligand-controlled b-arylation
3
[2]
Scheme 1. Biologically active 4-aryl-2-quinolinones.
À
reactions of primary and secondary C(sp ) H bonds, we
3
À
envisioned that sequential arylation of the b-C(sp ) H bonds
of propionamide followed by seven-membered cyclopallada-
tion/amidation would result in a one-pot procedure for the
preparation of 4-aryl-3,4-dihydro-2-quinolinones [Eq. (1)].
Herein we report the unexpected discovery of a novel proce-
Our initial efforts were largely prompted by the prospect
that simple and abundant starting materials (e.g. propionic
acid) can be potentially transformed into complex molecules
À
À
dure that combines three sequential C H activation reactions
of propionamide and a stereospecific Heck reaction in one pot
to afford a diverse range of 4-aryl-2-quinolinones [Eq. (2)].
by multiple C H functionalizations. Thus, amide 1a, derived
from propionic acid, was subjected to various arylation
conditions previously developed in our laboratory in order
À
to achieve diarylation and subsequent ligand promoted C H
lactamization [Eq. (1)]. We found, through extensive screen-
ing of palladium catalysts and solvents, that a combination of
PdCl2 and 2-alkoxylquinoline ligand L1[2b] in t-AmylOH
[*] Dr. Y. Deng,[+] Dr. W. Gong,[+] J. He, Prof. Dr. J.-Q. Yu
Department of Chemistry, The Scripps Research Institute (TSRI)
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
E-mail: yu200@scripps.edu
À
catalyzed the sequential C H activations/oxidative carbon–
[+] These authors contributed equally to this work.
carbon bond forming reaction of 1a to afford the unexpected
4-phenyl-2-quinolinone 3a in 58% yield, along with a 17%
yield of b-phenylated propionamide product 2a (Table 1, for
detailed screening, see the Supporting Information). The
control experiment in the absence of ligand showed that 2a
[**] We gratefully acknowledge The Scripps Research Institute and the
NIH (NIGMS, 2R01GM084019) for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201403878.
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Table 1: Reaction discovery and ligand screening.[a,b,c]
Table 2: Scope of aryl iodides.[a,b,c]
[a] ArF =(4-CF3)C6F4. [b] 1a (0.2 mmol), PdCl2 (0.02 mmol), Ag2CO3
(0.6 mmol), PhI (0.8 mmol), ligand (0.04 mmol), t-AmylOH (0.5 mL),
1408C, 24 h. [c] Yield determined by NMR spectroscopy with CH2Br2 as
the internal standard.
[a] ArF =(4-CF3)C6F4. [b] 1a (0.2 mmol), PdCl2 (0.02 mmol), Ag2CO3
(0.6 mmol), ArI (0.8 mmol), 2,5-lutidine (0.04 mmol), t-AmylOH
(0.5 mL), 1408C, 24 h. [c] Yields of isolated products.
was formed in 11% yield as the only product. The observed
dramatic impact of ligand L1 on this reaction prompted us to
further test a variety of pyridine- or quinoline-based ligands.
Surprisingly, the use of simple pyridine L3 as the ligand
provided 3a in 68% yield and 2a in 23% yield. 2-Picoline
(L6) and 3-picoline (L7) also gave comparable yields. 2,6-
Dimethoxypyridine (L9) is highly selective for monoaryla-
tion, albeit in a relatively low yield (42% yield). Further
investigation reveals that lutidines L10, L11, and L12 are
more effective than other pyridine ligands, affording the
cyclized product 3a in 80–84% yields.
With these conditions in hand, we examined the scope of
aryl iodides with 1a to test the feasibility of preparing
a variety of 4-aryl-2-quinolinones 3 (Table 2). Reactions with
mono- or dimethyl substituted phenyl iodides yield 4-aryl-2-
quinolinones 3b–3e in 68–75% yields, with intramolecular
amidation occurring at the less hindered position of the aryl
group. para-Methoxyphenyl iodide was also reactive, afford-
ing the desired product 3 f in 60% yield. Electron-withdraw-
ing fluoro, chloro and trifluoromethyl groups are also well
tolerated (3g–3i), while the presence of a para-ester group
decreased the yield to 44% (3j).
While one-pot synthesis of 4-aryl-2-quinolinones from
a simple propionamide demonstrates excellent step economy,
the incorporation of two identical aryl groups into the
products results in limited structural diversity. In order to
address this issue, we envisioned the installation of two
distinct arenes through the mono-selective arylation of 1a to
yield various hydrocinnamic acid derivatives, followed by
subsequent secondary arylation with a different aryl iodide to
furnish heterodiaryl 2-quinolinones. Thus, we established
moderately effective ligandless conditions for mono-arylation
of 1a and prepared hydrocinnamic acid amides 2a–2e on
gram scale (see Supporting Information). Hydrocinnamide 2a
was then further reacted with different aryl iodides (Ar2I)
under ligand-mediated conditions to afford a set of diverse 4-
aryl-2-quinolinones 3k–3q in 62–86% yield, with the Ar2
group introduced regioselectively at the 4-position of the 2-
quinolinone moiety (Table 3). While the use of other less
hindered ligands L3 and L7 afforded the same regioselectiv-
ity, the yields decreased significantly (see Supporting Infor-
mation). Hydrocinnamides 2b–2e were also reacted with PhI
under the standard conditions to afford various 4-aryl-2-
quinolinones 3r–3u in 60–81% yield. Notably, previous
syntheses of 4-aryl-2-quinolinones by sequential Heck reac-
À
tion/C H lactamization use acrylamide as the starting mate-
rial and proceed through three distinct steps catalyzed by
three different catalysts.[7c] In addition, this method gave
a mixture of regioisomers when two different aryls are
incorporated into the products.
Considering that various 4-aryl-2-quinolinones contain
different aryl groups (Ar) on the nitrogen, we made efforts to
broaden the reaction scope by using differentially substituted
propionamide substrates 1, prepared from different anilines
and propionyl chloride (Table 4). Thus, cascade products 3v–
3z were prepared in 62–75% yield with 2,6-difluoro or
dichloro substitutions on the aryl ring (Ar). Further studies
show that the 2,6-disubstitutions are required for sufficient
reactivity. The amides derived from simple anilines also
proceeded to afford 3a1–3i1 in 40–54% yield. Methoxy (3e1),
OTs (3 f1), chloro (3h1), and bromo (3i1) groups on the aryl
ring are also amenable to further synthetic elaborations.
2
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Table 3: Incorporation of two different aryl groups.[a,b,c]
Scheme 2. Synthetic applications.
Initially, it appeared plausible that the reaction pathway
involves sequential b-arylations followed by dehydrogenation
2
À
via Pd insertion, and finally intramolecular C(sp ) H amida-
tion [Eq. (2)]. However, as illustrated in Table 3, incorpora-
tion of the second aryl is exclusively selective for the 4-
position of the 2-quinolinone ring. This result reveals that the
second aryl is consistently in a trans relationship with the
[a] ArF =(4-CF3)C6F4. [b] 2 (0.2 mmol), PdCl2 (0.02 mmol), Ag2CO3
(0.4 mmol), Ar2I (0.6 mmol), 2,5-lutidine (0.04 mmol), t-AmylOH
(0.5 mL), 1408C, 24 h. [c] Yields of isolated products.
À
amide directing group prior to the C H lactamization. These
observed results are inconsistent with a mechanism involving
consecutive b-arylations followed by Pd-mediated dehydro-
genation. In order to account for this selectivity, we instead
propose participation of a stereospecific Heck reaction of
a cinnamide intermediate with the second aryl iodide
coupling partner.[12]
Table 4: The scope of the N-aryl group.[a,b]
As such, we present the following mechanism: b-arylation
3
À
of the primary C(sp ) H bond affords hydrocinnamide 2. Pd-
3
À
insertion into the secondary C(sp ) H bond followed by b-
hydride elimination would then yield cinnamide intermediate
7,[13] which allows for subsequent Heck coupling with a second
[14]
À
aryl iodide. Intramolecular C H amidation
would then
provide the 4-aryl-2-quinolinone product 3 (Scheme 3). The
reaction of independently prepared 7 with ArI also gave the
desired quinolinones, thus verifying the viability of 7 as an
intermediate (see Supporting Information).
[a] 1 (0.2 mmol), PdCl2 (0.02 mmol), Ag2CO3 (0.6 mmol), PhI
(0.8 mmol), 2,5-lutidine (0.04 mmol), t-AmylOH (0.5 mL), 1408C, 24 h.
[b] Yields of isolated products.
Although the yields remain to be improved, this one-pot
procedure utilizing inexpensive propionic acid as the starting
material could prove broadly useful for medicinal chemistry.
The use of para-methoxyaniline[8] also allowed us to
establish a new route for the deprotection of N-substituted
lactams.[9] Thus, 4-phenyl-2-quinolinone 3e1 (prepared using
our newly developed one-pot procedure) was deprotected to
yield lactam 4, which is a known precursor for the synthesis of
drug molecules such as 5[10] and 6[11] (Scheme 2).
Scheme 3. Proposed catalytic pathway.
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In conclusion, we have developed an unprecedented
À
pyridine ligand-promoted cascade C H activation of
propionamides under oxidative palladium catalysis, which
provides a one-pot procedure for the preparation of diverse 4-
aryl-2-quinolinones from propionic acid. This cascade reac-
À
À
tion involves the cleavage of five C H bonds, two C I bonds,
À
À
and one N H bond, and the formation of three C C bonds
À
and one C N bond via four different types of palladium
catalytic cycles. Further studies on the scope, mechanism, and
synthetic application of this reaction are underway in our
laboratory.
Received: April 1, 2014
Published online: && &&, &&&&
Keywords: amidation · arylation · C-H activation ·
dehydrogenation · quinolinone
.
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Cascade C-H Activation
Y. Deng, W. Gong, J. He,
J.-Q. Yu*
&&&& — &&&&
À
Ligand-Enabled Triple C H Activation
Reactions: One-Pot Synthesis of Diverse
4-Aryl-2-quinolinones from
Building complexity: Diverse 4-aryl-2-
quinolinones are prepared from propion-
amides in one pot by pyridine ligand-
reaction. In these cascade reactions,
À
À
three new C C bonds and one C N bond
are formed to rapidly build molecular
complexity from propionic acid.
À
Propionamides
promoted triple sequential C H activa-
tion reactions and a stereospecific Heck
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!