3-Amino-1-methyl-1 H-pyridin-2-one-Directed PdII Catalysis: C(sp3)-H Activated Diverse Arylation Reaction

Article abstract of DOI:10.1021/acs.orglett.8b01618

A new bidentate directing group, 3-amino-1-methyl-1H-pyridin-2-one, is introduced to achieve a powerful Pd^II metallacycle for selective γ-C(sp³)-H activation and arylation of aromatic and aliphatic carboxylic acid derivatives. The versatility of the directing group is validated for remote arylation of β-C(sp³)-H, β-C(sp²)-H, and γ-C(sp²)-H to achieve therapeutically important 2-pyridone analogues and arylated acid synthons. The traceless removal of the directing group to retrieve the directing element and carboxylic acids makes this method more interesting.

Full text of DOI:10.1021/acs.orglett.8b01618

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
II
3
3
‑Amino-1-methyl‑1H‑pyridin-2-one-Directed Pd Catalysis: C(sp )−H
Activated Diverse Arylation Reaction
†
,‡
†
,‡
,‡
,†
Tanmay K. Pati, Sudipto Debnath, Mrinalkanti Kundu,* Uttam Khamrai,* and Dilip K. Maiti*
†Department of Chemistry, University of Calcutta, 92 APC Road, Kolkata 700009, India
‡TCG Lifesciences Private Limited, Sector V, Salt Lake City, Kolkata 700091, India
*
S Supporting Information
ABSTRACT: A new bidentate directing group, 3-amino-1-methyl-1H-
II
pyridin-2-one, is introduced to achieve a powerful Pd metallacycle for
3
selective γ-C(sp )−H activation and arylation of aromatic and aliphatic
carboxylic acid derivatives. The versatility of the directing group is validated
3
2
2
for remote arylation of β-C(sp )−H, β-C(sp )−H, and γ-C(sp )−H to
achieve therapeutically important 2-pyridone analogues and arylated acid
synthons. The traceless removal of the directing group to retrieve the
directing element and carboxylic acids makes this method more interesting.
he immense potential of C−H bond activation for organic
H arylation on dipeptides employing a metal-chelated N-(2-
9
T
transformations using organometallic catalysts has been
pyridyl) sulfonamide. Recently, Maiti et al. reported the
3
realized in robust and efficient methods for carbon−carbon
pioneering work for distal γ-C(sp )−H arylation of aliphatic
10
10f
(
C−C) and carbon−heteroatom (C−X) bond formation over
carboxylic acid derivatives using 8-aminoquinoline as the
directing group (i, Scheme 1).
1
the decades. Several monodentate directing groups are
reported for palladium-catalyzed direct C−C and C−X
1
c,2
3
coupling.
However, catalysis by bidentate directing groups
Scheme 1. γ-C(sp )−H Activated Functionalization Strategy
1c,2c
in combination with metal catalysts
is now emerging as a
more powerful tool to achieve valuable transformations, which
might not be possible with conventional monodentate
3
systems. Arylation reactions are carried out under palladium-,
rhodium-, iridium-, copper-, and nickel-mediated catalysis on
4
,5
2
electron-rich heterocycles. In this context, selective C(sp )−
3
H- and C(sp )−H-activated functionalization using 8-amino-
quinoline as a bidentate ligand by Daugulis et al. is very
interesting and significant because it is effective for site-selective
arylation of aliphatic, alicyclic, and aromatic carboxamide
6
2
derivatives. The C(sp )−H activation is favored by precoordi-
nation of the arene-π-cloud to the transition metal as well as
subsequent formation of an aryl−metal bond that is typically
more stable than the corresponding alkyl−metal bond.
However, from both kinetic and thermodynamic viewpoints,
2
-Pyridone is a core structure of a wide range of compounds,
which displayed important biological activities such as
1
1a
jasmonate signaling inhibitor (Jarin-1),
ICE inhibitor
human leukocyte
(Figure 1). It has also been used as a
1
1b
11c
3
(
interleukin-1B),1
CB2 antagonist,
metal-catalyzed functionalization of nonactivated C(sp )−H
bonds is relatively trickier than that of slightly more acidic
1d
elastase inhibitor
11e
2
3
ligand for olefination of arenes. Recently, we were engaged in
the synthesis of 2-pyridone derivatives for their potential
application in medicinal chemistry, as synthons for industrial
manufacturing, and as organocatalysts for enantioselective
C(sp )−H bonds. Moreover, γ-C(sp )−H activation suffers
difficulties because of formation of a less favored six-membered
cyclopalladation transition state involving alkyl C−H bonds.
Corey et al. established that the presence of a phthalimido
group at the α-position was beneficial for the arylation of γ-
12
synthesis of nitrostyrenes (ee ≥95%). Further, we envisaged
3
7
C(sp )−H bonds in valine using a bidentate directing group.
3
8
Progress on γ-C(sp )−H functionalization was desired, and it
Received: May 22, 2018
3
is noteworthy that Carratero et al. performed a remote C(sp )−
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01618
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
3
Table 1. Development and Optimization of γ-C(sp )−H
Arylation
a
time
(h)
yield
(%)
entry
catalyst (mol %)
base
solvent
b
1
2
3
4
5
6
7
8
9
Cu(OAc) (10)
CF CO Na
t-BuOH
t-BuOH
t-BuOH
t-BuOH
IPA
24
24
24
24
24
24
24
24
24
16
32
24
24
24
24
24
24
24
24
24
24
<5
24
40
57
<5
10
64
71
47
35
69
<5
20
67
57
30
15
60
45
<5
<5
2
3
2
Pd(OAc) (1)
CF CO Na
3 2
2
Pd(OAc) (5)
CF CO Na
3 2
2
Pd(OAc) (10)
CF CO Na
3 2
2
b
b
Pd(OAc) (10)
CF CO Na
3 2
2
Figure 1. Bioactive 3-amino-2-pyridone derivatives.
Pd(OAc) (10)
CF CO Na
t-AmylOH
DCE
2
3
2
Pd(OAc) (10)
CF CO Na
3 2
2
that 3-amino-1-methyl-1H-pyridin-2-one (AMP, 1) might be
employed as a powerful directing group for activation of several
types of C−H bonds through significant improvement of
reactivity and selectivity of a suitable chelated metal, which will
be able to furnish an array of therapeutically important 2-
pyridone-bearing new compounds through late-stage C−H
activation. According to our hypothesis, N,O-bidentate amides
will be transformed into the required 5- and 6-membered
metallacycles (2−5, Scheme 2) through activation of close
Pd(OAc) (10)
CF CO Na
dioxane
toluene
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
2
3
2
Pd(OAc) (10)
CF CO Na
3 2
2
10
11
12
13
14
15
16
17
18
19
20
21
Pd(OAc) (10)
CF CO Na
3 2
2
Pd(OAc) (10)
CF CO Na
3 2
2
b
,
c
Pd(OAc) (10)
CF CO Na
3 2
2
d
Pd(OAc) (10)
CF CO Na
3 2
2
Pd(PhCN) Cl (10)
CF CO Na
3 2
2
2
PdCl (dppf) (10)
CF CO Na
3 2
2
2
Pd(PPh ) (10)
CF CO Na
3 2
3
4
Pd (dba) (10)
CF CO Na
3 2
2
3
Scheme 2. Formation of Designed AMP Metallacycles
Pd(OAc) (10)
CH CO Na dioxane
2
3
2
Pd(OAc) (10)
Ag CO3
2
dioxane
dioxane
dioxane
2
b
b
Pd(OAc) (10)
K CO3
2
2
Pd(OAc) (10)
Cs CO3
2
2
a
Monoarylated product isolated exclusively by column chromatog-
raphy with traces of diarylated product (<5%, LCMS chromatogram).
b
c
As per LCMS chromatogram (products not isolated). Reaction
d
performed at 25 °C. 100 °C.
of aprotic 1,2-dichloroethane (DCE) and 1,4-dioxane, yields
were greatly enhanced (64% and 71%, respectively, entries 7,
8
). The yield was insignificant on use of nonpolar toluene
3
2
vicinity γ-C(sp )−H (2) and γ-C(sp )−H (3) as well as β-
(entry 9). The yield dropped to 35% with decreased reaction
time (16 h), and remained comparable (69%) upon heating for
32 h (entries 10 and 11). The reaction was attempted at 25 and
100 °C, and formation of the desired product was significantly
reduced (entries 12 and 13). Ligand-modified Pd(II) and Pd(0)
catalysts were not effective (entries 14−17). Changing the base
(CH CO Na and Ag CO ) also decreased the yield to 60% and
45%, respectively (entries 18 and 19). Inferior reaction
performance was observed with the use of other bases, such
as K CO and Cs CO (entries 20 and 21).
The substrate scope of the γ-C(sp )−H arylation was
investigated using various aryl iodides (Scheme 3) under the
optimized reaction conditions (entry 8, Table 1). A wide range
of aryl iodides worked well as a coupling partner with amide
substrate (6). Both electron-donating and electron-deficient
aryl iodides were tolerated for the regioselective insertion to
3
2
C(sp )−H (4) and β-C(sp )−H (5), which will eventually
perform C−C coupled arylation. Herein, we report an
unprecedented selective arylation strategy of a remote γ-
C(sp )−H bond for both aliphatic and aromatic carboxylic acid
derivatives using a new 2-pyridinone-based N,O-bidentate
directing group (ii, iv, Scheme 1). To validate the γ-C(sp )−
H arylation catalysis as a general strategy, we also established
3
3
3
2
2
3
3
2
AMP as a versatile directing group for β-C(sp )−H, β-C(sp )−
2
H, and γ-C(sp )−H arylation.
2
3
2
3
13
3
We synthesized 3-amino-2-pyridone 1 according to our
hypothesis and transformed it into the corresponding amide 6
(
Supporting Information). Compound 6 was subjected to
arylation with 4-iodoanisole as an arylating agent in the
presence of Cu(OAc) (10 mol %) catalyst, AgOAc, and
CF CO Na under heating at 150 °C (oil bath temperature) in
tert-butyl alcohol, and a trace of 7a was obtained (entry 1, Table
). Gratifyingly, upon use of Pd(OAc) (1 mol %), the γ-sp C−
H bond arylation reaction successfully afforded the desired
monoarylated product 7a with 24% yield (entry 2). The yield
was improved to 40% and 57% upon an increase of catalyst
loading (5 and10 mol %, entries 3 and 4). Our studies showed
that the yield was drastically reduced (entries 5 and 6) when
relatively low boiling protic polar solvents isopropyl alcohol
2
3
2
3
unactivated γ-C(sp )−H bond. For instance, an electron-rich
3
1
aryl iodide, p-methyliodobenzene, resulted a yield of 77% after
isolation of 7c by CombiFlash chromatography, whereas m-
methyliodobenzene provided 64% yield (7d). A negligible
quantity of the desired product (<5%, not shown) was detected
from o-methyliodobenzene, which might be due to severe steric
crowding in the transition state. Interestingly, the yield was
relatively improved (7e, 45%) upon use of -nitroiodobenzene.
2
3
(
IPA) and tert-amyl alcohol were used. Interestingly, upon use
These results indicate that γ-C(sp )−H arylation of the
B
DOI: 10.1021/acs.orglett.8b01618
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
3
3
Scheme 3. Synthesized γ-C(sp )−H Arylated Products
Scheme 4. γ-C(sp )−H Bond Activated Arylation of Fluorine
Substrates
3
Scheme 5. β-C(sp )−H Activated Arylation
aliphatic amide is favored by electron deficient aryl iodides.
Screening with aryl iodides possessing p-nitro, p-ester, p-fluoro,
p-cyano, and p-chloro displayed formation of the corresponding
arylated products (7f−j) in higher yield (60−84%). Corre-
sponding N-benzyl-DG (6b) was also employed to obtain the
desired product 7k with moderate yield (68%).
It is well established that fluorine-containing aryl moieties are
highly important in pharmaceuticals and agrochemicals. In
going forward and considering our main objective in this work
3
as C(sp )−H bond activation, we chose fluorine-containing
substrate 8 (Scheme 4) as our next starting material for
arylation. We are delighted to report that exclusive mono-
arylated products were obtained under the optimized reaction
conditions. Activated aryl iodides such as 4-Me, 3-Me, and 4-
OMe resulted higher yield (9b−d, 70−78%) with respect to
unsubstituted PhI (9a, 65%). The yield was significantly
reduced in the case of deactivated aryl iodides (9e−h, 53−
General applicability of the catalytic C−C coupling strategy
3
2
6
6%). In contrast to the purely aliphatic γ-C(sp )−H bond
was visualized for even C(sp )−H-activated arylation. The
arylation (Scheme 3), herein electron-donating group bearing
precursor 12 and 13 were tested successfully to achieve arylated
2
aryl iodides appeared to be more effective for benzylic γ-
desired products 14a and 14b through β-C(sp )−H activation,
3
2
C(sp )−H bond arylation of amide 8.
as well as 15a and 15b involving γ-C(sp )−H functionalization.
3
2
After successful γ-C(sp )−H arylation, we explored our
Both of the C(sp )−H bonds were efficiently arylated in 10−14
3
protocol for β-C(sp )−H arylation, and amide 10 was chosen
h at 100 °C (Scheme 6) to obtain the desired products in 70−
3
to be the next substrate (Scheme 5). To our delight, β-C(sp )−
82% yield.
II
H-arylated compounds (11a−h) were obtained using both
electron-deficient and electron-rich aryl as well as heterocyclic
thiophene iodides in good yield (68−88%). In contrary to the
previous two reactions (Schemes 3 and 4), herein both the γ-
Finally, diversity of the Pd -DG-AMP-catalyzed C−H
activation was employed for arylation of a chiral amino acid
derivative (16, Scheme 7). Herein, phthalimide-protected L-
valine amide (16) was selectively transformed into the desired
γ-arylated product (17, dr 4:1) despite an available β-hydrogen
and labile chiral center.
3
3
C(sp )−H and β-C(sp )−H bonds activated arylation reactions
(
Scheme 5) were favored at the benzylic position with activated
aryl iodides. Reproducibility and scalability of this method were
successfully tested by performing a gram-scale reaction (11a).
Further, a traceless removal of the directing group was
established (Scheme 8) through treatment of arylated product
C
DOI: 10.1021/acs.orglett.8b01618
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
2
2
Scheme 6. β-C(sp )−H and γ-C(sp )−H Activated Arylation
leading to a generation of cyclometalated II. Oxidative addition
of aryl iodide will form a putative intermediate III of Pd ,
IV
which may immediately undergo reductive elimination with C−
C coupled arylation (IV). Finally, the product 7 will be released
II
through regeneration of Pd procatalyst for the next pallada-
cycle.
In conclusion, we report a new N,O-directing group AMP for
II
3
Pd -catalyzed selective distal C(sp )−H arylation. The general-
ity of the strategy is validated through arylation of several types
3
2
of C(sp )−H as well as C(sp )−H at the β- and γ-positions of
the amide analogues.This C−H activation method opens up a
new window to synthesize therapeutically important 2-pyridone
compounds, acid synthons, and new amino acid derivatives
through late-stage C−H activation, which will find considerable
application in the chemical science and its allied branches.
3
Scheme 7. γ-C(sp )−H Arylation of L-Amino Acid Derivative
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01618.
Detailed experimental procedures, spectroscopic data
and NMR spectra (PDF)
(
(
11a) with LiOH at 100 °C to obtain the desired arylated acid
18) along with the recovered DG-AMP (1).
AUTHOR INFORMATION
Corresponding Authors
■
Scheme 8. Hydrolysis and Recovery of DG-AMP and Acid
*
*
*
E-mail: mrinal.kundu@tcgls.com.
E-mail: uttam.khamrai@tcgls.com.
E-mail: dkmchem@caluniv.ac.in.
ORCID
Mrinalkanti Kundu: 0000-0002-0907-6699
Dilip K. Maiti: 0000-0001-8743-2620
Notes
In our studies, we observed that the reaction did not occur in
the absence of AgOAc, procatalyst Pd , or DG-AMP. Thus, the
II
The authors declare no competing financial interest.
combination of these compounds is crucial for sustaining the
catalytic cycle. With the control experiments and literature
6
b,14
ACKNOWLEDGMENTS
reports,
we propose the following mechanism through a
■
II
IV
Pd /Pd redox cycle with our new DG-AMP (Scheme 9). We
Research facility (T.K.P.) from TCGLS, financial support
(CSIR Project No. 02(0250)/15/EMR-II), and a research
fellowship (SRF to S.D.) from CSIR, India, are gratefully
acknowledged.
presume that Pd(OAc) first complexes with the bidentate DG
2
to generate an active catalyst I with the expulsion of AcOH.
II
3
The reactive Pd -DG activates a C(sp )-Hin the close vicinity
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Scheme 9. Possible Catalytic Cycle with the DG-AMP
■
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