Palladium-Catalyzed β-Arylation of Amide via Primary sp3C-H Activation

Article abstract of DOI:10.1021/acs.organomet.8b00325

A β-arylation of primary sp³C-H bonds on simple amides such as pivalamides with aryl iodides/CF₃CO₂Ag has been established successfully at 120 °C in a Pd(OAc)₂ (catalyst)/CF₃CH₂OH (solvent) system. Pivalamides including ^tBuCONH₂, ^tBuCONHR, and ^tBuCONR₂ undergo the arylations smoothly to afford β-aryl pivalamides in moderate to good yields. Various aryl iodides are available bearing either electron-donating or electron-withdrawing substituted groups in the coupling reactions.

Full text of DOI:10.1021/acs.organomet.8b00325

Article
Cite This: Organometallics XXXX, XXX, XXX−XXX
Palladium-Catalyzed β‑Arylation of Amide via Primary sp3C−H
Activation
Ren Zhao and Wenjun Lu*
Department of Chemistry, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, PR China
S
* Supporting Information
ABSTRACT: A β-arylation of primary sp3C−H bonds on
simple amides such as pivalamides with aryl iodides/
CF3CO2Ag has been established successfully at 120 °C in a
Pd(OAc)2 (catalyst)/CF3CH2OH (solvent) system. Pivala-
t
t
t
mides including BuCONH2, BuCONHR, and BuCONR2
undergo the arylations smoothly to afford β-aryl pivalamides
in moderate to good yields. Various aryl iodides are available
bearing either electron-donating or electron-withdrawing
substituted groups in the coupling reactions.
Scheme 1. Palladium-Catalyzed β-Arylation of sp3C−H
INTRODUCTION
■
Bonds from Amides
The formation of new C−C bonds from normal alkyl sp3C−H
bonds through a coupling reaction is always a challenging
objective to researchers in chemical synthesis.1 In the past
decade, an efficient method was developed dramatically, which
is a transition metal-catalyzed arylation of alkyl sp3C−H bonds
with arylating reagents under assistance of directing groups.
For example, Daugulis and co-workers disclosed an early
example on catalytic β-arylation of alkyl sp3C−H bonds on 8-
aminoquoline amides with aryl iodides/AgOAc in 2005,2 in
which CONH-8-quinoline as a special directing group could
coordinate strongly with palladium complex not only to lead a
β-sp3−H bond cleavage but also to stabilize a five-membered
palladacycle, a key intermediate to form the target sp3C−sp2C
bond. After that, other groups also successfully explored many
palladium-catalyzed β-arylations of amides directed by different
CONH−FGs (FG = functional group) with various arylating
reagents via C−H activation (Scheme 1).3−11 For the
regioselective β-arylations of alkyl sp3C−H bonds without
special directing groups, the reports are found rarely, including
use of transient directing groups generated from common
functional groups such as carbonyl groups in situ under
reaction conditions.12 In 2007, Yu and co-workers reported
that a Pd(II)-catalyzed β-mono- and diarylation of pivalic acid
with iodobenzene/Ag2CO3 could proceed smoothly in the
at 120 °C. It is reasonably assumed that a critical Pd(IV)
species weakly coordinated with O atom of simple amide
group, a five-membered palladacycle should be stabilized by
the Thorpe−Ingold effect under weak acidic conditions during
these couplings (Scheme 1).15 In fact, β-arylated pivalamides
could be found in some of the biological active products
(Scheme 2).16
t
presence of K2HPO4/NaOAc in BuOH at 130 °C, which is a
direct β-arylation of carboxylic acid.13 However, catalytic β-
arylations of simple amides have not been found until now.
In our studies related to primary sp3C−H activation, we
have established Pd(II)-catalyzed oxidative β-acyloxylation and
β-mesylation of simple amides bearing CONHR groups with
carboxylic acids and methanesulfonic anhydrides, respec-
tively.14 Herein we report a Pd(II)-catalyzed arylation of
primary β-sp3C−H bonds on simple amides such as
pivalamides containing CONH2, CONHR, or CONR2 groups
with aryl iodides/CF3CO2Ag (AgTFA) in CF3CH2OH (TFE)
RESULTS AND DISCUSSION
■
According to the previous work, the catalytic system consists of
Pd(OAc)2(catalyst)/acid or TFE, which is very effective in the
functionalization of inert alkyl and aryl C−H bonds via C−H
activation.14,17 Thus, in the investigation of β-arylation of N-
butylpivalamide (1a) with p-iodonitrobenzene (2a), the
Received: May 17, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.8b00325
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time (see the Supporting Information), we found that 3a could
be generated in 65% isolated yield from 1a and 2a (1 equiv/3
equiv) when Pd(OAc)2 (10 mol %) and AgTFA (3 equiv) was
added in three batches in TFE at 120 °C (entry 12).
Scheme 2. Biological Active Products Containing the β-
Arylation Amides Structure
The catalytic arylations of various N-substituted amides with
p-iodonitrobenzene (2a) were studied further, and the results
are shown in Scheme 3. For N-alkyl pivalamides, not only
Scheme 3. Palladium-Catalyzed β-Arylation of N-
a
Substituted Pivalamides with p-Iodonitrobenzene
Pd(OAc)2(10 mol %)/TFE/silver salt system was still tested
first. As shown in Table 1, no products were detected if
Table 1. Palladium-Catalyzed β-Arylation of N-
a
Butylpivalamide
b
c
entry
Ag salts
solvent
additive
yield (%)
1
2
3
4
5
Ag2CO3
Ag2O
TFE
TFE
TFE
TFE
TFE
AcOH
DCE
DCE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
0
0
0
60
40
36
6
AgOAc
AgTFA
AgOAc
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
TFA
TFA
d
6
7
8
9
6
e
30
30
0
71(65)
0
12
30
5
f
10
11
12
13
14
15
16
g
h
Na2CO3
NaHCO3
KH2PO4
K2HPO4
a
Conditions: 1a (0.1 mmol), 2a (0.3 mmol), Pd(OAc)2 (0.01 mmol,
10 mol %), Ag salts (0.3 mmol), solvent (0.3 mL), 120 °C, 48 h.
b
TFA (0.2 mmol, entries 5 and 8); others (0.1 mmol, entries 13−16).
c
1
The yield is based on 1a and detected by H NMR analysis using
CH2Br2 as an internal standard. The isolated yield is in parentheses.
d
N-Butyl-3-hydroxy-2,2-dimethylpropanamide is produced in 20%
e
f
yield. PdCl2 instead of Pd(OAc)2. Pd(TFA)2 instead of Pd(OAc)2.
g
h
Without palladium catalysts. Catalysts and Ag salts are added in
three batches.
a
Ag2CO3, Ag2O, or AgOAc was used as an iodine scavenger just
in TFE (entries 1−3). Fortunately, when AgTFA was
employed, a target product, β-aryl N-butylpivalamide (3a)
was produced in 60% yield under identical conditions (entry
4), indicating that AgTFA was more useful than any other
silver salts in the arylation.17b In the cases of AgOAc/TFE/
CF3CO2H(TFA) or AgTFA/AcOH instead of AgTFA/TFE,
the yield of 3a was decreased, and a β-oxygenated byproduct
was formed in AcOH (entries 5 and 6). In other solvents such
as dichloroethane (CH2ClCH2Cl, DCE), the yield was very
poor (entries 7 and 8). When some weak bases were added in
the solution, the arylation was also hampered (entries 13−16).
Without palladium catalysts, no reaction happened (entry 11).
Compared with PdCl2, (CF3CO2)2Pd (Pd(TFA)2), and others,
Pd(OAc)2 was an effective catalyst in this reaction. After
screening the amounts of substrate, catalyst, and silver salt and
other reaction conditions including temperature and reaction
Conditions: 1 (0.1 mmol), 2a (0.3 mmol), Pd(OAc)2 (10 mol %),
AgTFA (0.3 mmol), TFE (0.3 mL), 120 °C, 48 h. Catalysts and Ag
salts are added in three batches. The yield is based on the substrate 1
and detected by 1H NMR analysis using CH2Br2 as an internal
standard. The isolated yield is in parentheses. 2a (0.12 mmol),
AgTFA (0.12 mmol). 2a (0.5 mmol), AgTFA (0.5 mmol).
b
c
linear but also branched aliphatic substituted amides under-
went the arylations smoothly to generate the β-aryl amides
(3a−3e) in moderate to good isolated yields. Cyclic aliphatic
substituted amides especially containing four-, five-, or six-
membered ring could give their corresponding compounds
(3f−3h) in 48−65% yields, and N-(adamantan-1-yl)-
pivalamide afforded its β-arylated product (3i) in 75% yield
under same conditions. Heterocyclic aliphatic substituted
pivalamide (1j) was also available in the arylation. For N-
benzyl amides containing strong electron-withdrawing group
B
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such as −NO2 or −CF3 groups on aromatic rings, the yields of
their products (3k−3p) were 47−73%. Methyl 4-(pivalami-
domethyl)-benzoate (1t), N-(4-(methylsulfonyl)benzyl)-
pivalamide (1u), and N-(3,4-dichlorobenzyl)pivalamide (1v)
could also give their β-aryl amides (3t−3v) in moderate yields.
Meanwhile, halogen atoms such as fluorine, chlorine, or
bromine at the para positions of aromatic rings were tolerant
in the couplings (3q−3s). However, neither N-benzyl amides
without electron-withdrawing groups nor N-aryl amides could
be arylated effectively since many byproducts were generated
under the reaction conditions, like in the β-mesylation of
amides.14b When there were both primary and secondary β-
sp3C−H bonds on the amide substrates such as N-(4-
nitrobenzyl)-2,2-dimethylhexanamide (1w) and N-(4-nitro-
benzyl)-2,2-dimethylbutanamide (1x), only primary sp3C−H
bonds were arylated successfully. Certainly, for the amides with
only secondary β-sp3C−H bonds, no arylation occurred (3aa),
showing a perfect selectivity in the functionalization of primary
sp3C−H bonds. Since the Thorpe−Ingold effect might be very
important in the couplings, as shown in Scheme 1, the simple
amides containing α-H could not give their β-arylated products
(3y and 3z).
Scheme 4. Palladium-Catalyzed β-Arylation of Pivalamides
with Aryl Iodides
a
Moreover, not only N-substituted pivalamides but also
pivalamide and N,N-disubstituted pivalamides were tested in
the β-arylations with a verity of iodobenzenes (Scheme 4). In
the coupling reactions of N-alkyl pivalamide 1a with
iodobenzene and its derivatives bearing electron-donating
groups including −OMe, −NPhth, and −Me, 1a was used in
excess to avoid biaryls generated from aryl iodides under the
reaction conditions (4a−4d). The aryl iodides substituted by
various electron-withdrawing groups such as −Br, −Cl, −F,
−Ms, −CHO, −COMe, −CO2Me, −NO2, −CF3, and so on.
were available to react with 1 equiv of 1a, and most of the
target products (4e−4s) were obtained in moderate to good
yields. Interestingly, pivalamide with −CONH2 group could
also be used as the substrate in the couplings (4t−4w), and the
yield of β-aryl pivalamide (4w) was up to 72%. In the
comparison with the β-arylation of pivalic acid under weak
basic conditions,13 only β-monoaryl pivalic acid (4x) was
produced in 66% yield in this coupling reaction. In the case of
N,N-dialkyl pivalamides, it was found that they were more
reactive than N-alkyl pivalamides and pivalamides, and the
yields of their β-aryl pivalamide products were 55−81% (4y−
4ae). It is remarkable that β-monoaryl pivalamides (4ac−4ae)
from 2,2-dimethyl-1-(pyrrolidin-1-yl)propan-1-one, 2,2-di-
methyl-1-(piperidin-1-yl)propan-1-one and N,N-dibutylpivala-
mide could be prepared in 81, 72, and 70% yields respectively,
just using 1.2 equiv of 2a/AgTFA under the reaction
conditions. In contrast, in the couplings of the same three
N,N-disubstituted pivalamides, when the loading of 2a/AgTFA
was 3 equiv, the corresponding β-diaryl pivalamides (4af−4ah)
were generated in 65−77%. It means that the selectivity of
mono- and diaryl products could be under control, depending
on the amount of inert aryl iodide/AgTFA added in the
arylations of some active pivalamides.
On the basis of the current and previous studies, a proposed
reaction mechanism on the β-arylation of pivalamide is shown
in Scheme 5. The first step is a sp3C−H activation, in which a
Pd(II) species coordinates with an amide group and cleaves its
β-sp3C−H bond to form an alkyl−Pd(II) five-membered ring
intermediate. Other two methyl groups can stabilize this five-
membered ring intermediate through the Thorpe−Ingold
effect, and Pd(II) seems prefer to coordinate with O atom of
a
Conditions: 1 (0.1 mmol), 2 (0.3 mmol), Pd(OAc)2 (10 mol %),
AgTFA (0.3 mmol), TFE (0.3 mL), 120 °C, 48 h. Catalysts and Ag
salts are added in three batches. The yield is based on the substrates 1
and detected by 1H NMR analysis using CH2Br2 as an internal
standard. The isolated yield is in parentheses. 1 (1.0 mmol), 2 (0.1
mmol), AgTFA (0.1 mmol). The yield is based on 2. 2 (0.12 mmol),
b
c
AgTFA (0.12 mmol).
C
DOI: 10.1021/acs.organomet.8b00325
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Article
1
detected by H NMR analysis using CH2Br2 as an internal standard.
The residue was purified by preparative TLC or silica gel column
chromatogrphy to afford the desired product.
Scheme 5. Proposed Reaction Mechanism
Method C. A reaction tube (15 mL) with magnetic stir bar was
charged with the amide (1 mmol), aryl iodide (0.1 mmol), Pd(OAc)2
(0.01 mmol, 2.2 mg), AgTFA (0.1 mmol, 22.3 mg), and TFE (0.30
mL). The tube was sealed and heated to 120 °C for at least 48 h until
the amide was consumed. The crude reaction mixture was cooled to
room temperature, diluted with EtOAc, and filtered with Celite, and
the cake was washed with EtOAc. The combined solvents were
removed under reduced pressure. The crude product was detected by
1H NMR analysis using CH2Br2 as an internal standard. The residue
was purified by preparative TLC or silica gel column chromatography
to afford the desired product.
sp2CO to afford a rigid ring. The secondary step is an
oxidation of the Pd(II) intermediate by iodobenzene to form a
Pd(IV) species. The final step is a reductive elimination of the
Pd(IV) species to give the target β-arylated amide and the
Pd(II) catalyst to complete the catalytic cycle. The Pd(IV)
species with strong reductive ability is beneficial to give the
coupling product during the reductive elimination.
In summary, we developed a Pd(II)-catalyzed coupling
reaction of primary β-sp3C−H bonds on simple amides with
aryl iodides to afford β-aryl amides in moderate to good yields
in the presence of AgTFA as an iodine scavenger in TFE. In
the β-arylations, the amide substrates without special func-
tional groups including N-alkyl or benzyl pivalamides, N,N-
dialkyl pivalamides, pivalamide, and similar amides are
available, and either electron-rich or -deficient aryl iodides
are compatible. Some N,N-dialkyl pivalamides can provide β-
diaryl products using aryl iodide/TFA in excess.
Method D. A reaction tube (15 mL) with magnetic stir bar was
charged with the amide (0.1 mmol), aryl iodide (0.5 mmol),
Pd(OAc)2 (0.01 mmol, 2.2 mg), AgTFA (0.5 mmol, 22.3 mg), and
TFE (0.30 mL). The tube was sealed and heated to 120 °C for at least
48 h until the amide was consumed. The crude reaction mixture was
cooled to room temperature, diluted with EtOAc, and filtered with
Celite, and the cake was washed with EtOAc. The combined solvents
were removed under reduced pressure. The crude product was
1
detected by H NMR analysis using CH2Br2 as an internal standard.
The residue was purified by preparative TLC or silica gel column
chromatography to afford the desired product.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.8b00325.
Details for optimization of the reaction conditions, 1
mmol scale example, preparations and characterization
of compounds and spectroscopic data (PDF)
EXPERIMENTAL SECTION
■
General information. NMR spectra were obtained on a Varian
Mercury 400 plus instrument, Bruker AMX-400 instrument (400
MHz for 1H, 101 MHz for 13C and DEPT-135) and Bruker AMX-500
AUTHOR INFORMATION
Corresponding Author
*E-mail: luwj@sjtu.edu.cn.
instrument (500 MHz for 1H, 126 MHz for 13C and DEPT-135). 19
F
■
NMR spectra were recorded on Bruker AMX-400 instrument (376
MHz) and Bruker AMX-500 instrument (470 MHz). HRMS data
were recorded on ACQUITYTM UPLC and Q-TOF MS Premier.
Melting points were obtained on an INESA SGW X-4 melting point
apparatus. All commercial materials were used as received unless
otherwise noted. Solvents were distilled before use. Flash chromatog-
raphy was performed on silica gel (200−300 mesh).
ORCID
Ren Zhao: 0000-0002-7602-6085
Wenjun Lu: 0000-0001-8077-7060
Notes
General Procedures. Method A. A reaction tube (15 mL) with
magnetic stir bar was charged with the amide (0.1 mmol), aryl iodide
(0.10 mmol), Pd(OAc)2 (0.01 mmol, 2.2 mg), AgTFA (0.10 mmol,
22.3 mg), and TFE (0.30 mL). The tube was sealed and heated to 120
°C for 16 h. Then after being cooled to room temperature, the second
batch of aryl iodide (0.10 mmol) and AgTFA (0.10 mmol, 22.3 mg)
was added to the tube. The mixture was heated for another 16 h. After
cooling to room temperature, the third batch of aryl iodide (0.10
mmol) and AgTFA (0.10 mmol, 22.3 mg) was added to the tube. The
resulting mixture was heated for at least 16 h until the amide was
consumed. The crude reaction mixture was diluted with EtOAc and
filtered with Celite, and the cake was washed with EtOAc. The
combined solvents were removed under reduced pressure. The crude
product was detected by 1H NMR analysis using CH2Br2 as an
internal standard. The residue was purified by preparative TLC or
silica gel column chromatogrphy to afford the desired product.
Method B. A reaction tube (15 mL) with magnetic stir bar was
charged with the amide (0.1 mmol), aryl iodide (0.12 mmol),
Pd(OAc)2 (0.01 mmol, 2.2 mg), AgTFA (0.12 mmol, 22.3 mg), and
TFE (0.30 mL). The tube was sealed and heated to 120 °C for at least
48 h until the amide was consumed. The crude reaction mixture was
cooled to room temperature, diluted with EtOAc, and filtered with
Celite, and the cake was washed with EtOAc. The combined solvents
were removed under reduced pressure. The crude product was
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China
(Grant No. 21372153) for financial support.
■
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