Palladium-Catalyzed β-C?H Arylation of Ketones Using Amino Amide as a Transient Directing Group: Applications to Synthesis of Phenanthridinone Alkaloids

Article abstract of DOI:10.1002/adsc.201800489

The direct arylation of aromatic and aliphatic ketones was carried out via palladium-catalyzed inert C?H bond functionalization with 2-amino-N-isopropyl-acetamide as a new catalytic transient directing group. The reaction showed excellent functional group compatibility and site selectivity. We demonstrated that α-amino amide forming N,N-bidentate coordination with Pd catalyst is more favorable for the β-arylation of ketones than α-amino acid forming N,O-bidentate coordination with Pd catalyst under relatively mild conditions. This elegant approach provides straightforward access to important structural motifs in organic and medicinal chemistry and is demonstrated here in the efficient synthesis of phenanthridinone alkaloids. (Figure presented.).

Full text of DOI:10.1002/adsc.201800489

Title: Pd-Catalyzed β-C–H Arylation of Ketones Using Amino Amide
as a Transient Directing Group: Applications to Synthesis of
Phenanthridinone Alkaloids
Authors: Junliang Wang, Cong Dong, Liangfei Wu, Mingkai Xu, Jun
Lin, and kun wei
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800489
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10.1002/adsc.201800489
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Palladium-Catalyzed -CH Arylation of Ketones Using Amino
Amide as a Transient Directing Group: Applications to
Synthesis of Phenanthridinone Alkaloids
Junliang Wang,a Cong Dong,a Liangfei Wu,a Mingkai Xu,c Jun Lin*b and Kun Wei*a
a
School of Chemical Science and Technology, Yunnan University, Kunming, 650091 (P. R. China). E-mail:
kunwei@ynu.edu.cn
b
Key Laboratory of Medicinal Chemistry for Natural Resource (Ministry of Education), Yunnan University. Kunming,
650091 (P. R. China). E-mail: linjun@ynu.edu.cn
Institute of Applied Ecology, Chinese Academy of Science. Shenyang, 110016 (P. R. China).
c
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. The direct arylation of aromatic and aliphatic relatively mild conditions. This elegant approach provides
ketones was carried out via palladium-catalyzed inert CH straightforward access to important structural motifs in
bond functionalization with 2-amino-N-isopropyl-acetamide organic and medicinal chemistry and is demonstrated here
as a new catalytic transient directing group. The reaction in the efficient synthesis of phenanthridinone alkaloids.
showed excellent functional group compatibility and site
selectivity. We demonstrated that-amino amide forming
N,N-bidentate coordination with Pd catalyst is more
favorable for the -arylation of ketones than -amino acid
forming N,O-bidentate coordination with Pd catalyst under
Keywords: palladium-catalyzed; arylation of ketones;
transient directing group; phenanthridinone alkaloids
metal center. Upon CH activation and subsequent
functionalization, the TDG would dissociate from the
product after the activation is accomplished with a
catalytic amount of this temporary directing group.
This strategy allows shorter reaction sequences,
resulting in environmental advantages, unique
regioselectivities, and use of easily accessible starting
materials.
Introduction
In the past two decades, there has been great interest
in CH bond functionalization carried out by using
transition metal complexes in organic chemistry,
because these reactions can convert unactivated CH
bonds into new CC and Cheteroatom bonds.[1-6]
However, the development of transition metal
The strategy has been successfully implemented in
CH bond functionalization of ketones and
aldehydes.[16-20] Recently, through employing an
amino acid as a TDG, Yu and co-workers described
palladium-catalyzed arylation of o-alkyl benz-
aldehydes and aliphatic ketones.[21] Soon after, a
similar transformation was also realized by using 3-
aminopropanoic acids,[22] acetohydrazide,[23] 2-amino-
2-methyl-propionic acid,[24] anthranilic acid[24, 25], or
-benzyl -alanine,[26] which form N,O-bis-
coordinated complexes with Pd(II) catalyst and
promote the CH activation process. In addition, N-
tosylethylene-diamine was shown to form a N,N-
bidentate directing group with an imine linkage for
arylation of aldehydes, which was limited to
utilization of tertiary aldehydes and afforded poor
selectivity of the monoarylated product.[27]
Nevertheless, mild and selective transformations of
this type remain to be further exploited, and direct
inert CH functionalization of ketones using transient
N,N-bidentate coordination with Pd(II) has not yet
been reported, even for the efficient synthesis of
natural products. One of the most used and versatile
complexes
capable
of
selective,
catalytic
functionalization of CH bonds is a principal
challenge.
In order to control selectivity and facilitate
reactivity in CH activation reactions, the strategy of
introducing directing groups into the substrate is
usually exploited.[7-15] Through coordination of the
metal with the directing group, cyclometalation
processes have proceeded to realize CH bond
activation as well as positional selectivity. However,
this approach still includes some limitations for
synthetic applications, because the substrate is firstly
connected with the directing group before it can be
coordinated with the metal and it is necessary to
remove the directing group at the end of the reaction,
which diminishes the efficiency of the reaction. In
addition, the conditions for installation or removal of
the directing groups are sometimes incompatible with
other functional groups present in advanced synthetic
intermediates. A reasonable solution to this problem
would be to devise a transient directing group (TDG)
that can be reversibly linked to the substrate and the
1
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10.1002/adsc.201800489
Advanced Synthesis & Catalysis
Table 1. Optimization of reaction conditions.
Pd source
(10 mol%)
Ligand
Yield
(%)a
Solvent
Entry
(50 mol%)
(HFIP/AcOH)
Pd(OAc)2
Pd(OAc)2
L1
L1
HFIP
12
20
1
2
Scheme 1. Pd-catalyzed CH arylation of ketones.
AcOH
HFIP/AcOH
(1 : 1)
HFIP/AcOH
(3 : 1)
HFIP/AcOH
(5 : 1)
HFIP/AcOH
(9 : 1)
HFIP/AcOH
(14 : 1)
HFIP/AcOH
(9 : 1)
HFIP/AcOH
(9 : 1)
HFIP/AcOH
(9 : 1)
HFIP/AcOH
(9 : 1)
HFIP/AcOH
(9 : 1)
HFIP/AcOH
(9 : 1)
HFIP/AcOH
(9 : 1)
HFIP/AcOH
(9 : 1)
HFIP/AcOH
(9 : 1)
HFIP/AcOH
(9 : 1)
HFIP/AcOH
(9 : 1)
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
Pd(acac)2
PdCl2
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L8
L9
34
41
3
4
aminoquinolines and picolinic acid presented
catalytic action by N,N-bidentate coordination with
Pd(II) (Scheme 1A).[28-32] Significantly, the use of the
N,N-bis-coordination of the peptide backbone in CH
functionalizations of tri- and tetrapeptides[33] (Scheme
1B) led us to speculate that an -amino amide could
serve as a suitable transient directing group. We
envisioned that an elaborated TDG, e.g., -amino
amide, could be reversibly tethered to ketones via an
imine linkage under appropriate conditions, which
might effectively facilitate inert CH arylation of
ketones by N,N-bidentate coordination with Pd(II).
Herein, we report a new class of TDG utilized to
promote -arylation of ketones that will greatly
enrich the toolbox for synthesis of key intermediates
in chemical synthesis and ubiquitous structural units
in biologically active natural products and
pharmaceuticals[34] (Scheme 1C). Preliminary
mechanistic studies have been performed. In addition,
we have developed a one-pot method for the efficient
synthesis of phenanthridinone alkaloids.
48
5
53
6
16
7
85(80)e
32
8b
9c
10d
11
12
13
14
15
16
17
18
19
20
21
22
23
6
5
8
11
Pd(PPh3)2Cl2
Pd(CH3CN)2Cl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
45
20
trace
0
0
HFIP/AcOH
(9 : 1)
HFIP/AcOH
(9 : 1)
HFIP/AcOH
(9 : 1)
HFIP/AcOH
(9 : 1)
trace
29
Results and Discussion
To establish the viability of the -CH arylation of
trace
4
ketones, we synthesized a series of TDGs that were
designed
to
offer
potential
N,N-bidentate
coordination through varied amides (L1-L8) (Table
1). We commenced our investigation of palladium-
catalysed -arylation of 3-methyl-2-pentanone (1a)
with methyl 4-iodobenzoate (2a) in the presence of
10 mol% of Pd(OAc)2 and 1.5 equiv. of AgTFA with
2-amino-N-isopropylacetamide L1 as a transient
directing group at 100 °C for 24 hours (Table 1).
Initially, a series of different volume ratios of
hexafluoroisopropyl alcohol (HFIP) and acetic acid
HFIP/AcOH
(9 : 1)
5
Reaction conditions: 1a (0.4 mmol), 2a (0.2 mmol), Pd
source (0.02 mmol), ligand (0.1 mmol), silver
trifluoroacetate (AgTFA) (0.3 mmol), solvent (1 mL),
a
1
100 °C, 24 h. Yields were determined by H NMR
b
using dibromomethane as the internal standard.
c
d
80 °C, 24 h. 60 °C, 24 h. Reaction performed using
30 mol% ligand. e Isolated yield.
2
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10.1002/adsc.201800489
Advanced Synthesis & Catalysis
(AcOH) as the cosolvent were tested, and the
results were summarized in Table 1 (entries 1-7).
When a 9:1 mixture of HFIP and acetic acid as
the cosolvent was used, a relatively high yield
(53%) of the desired arylated product 3a was
achieved (entry 6). Next, other reaction
parameters, including temperatures and amounts
of TDG, were screened. As revealed in Table 1
(entries 8 and 9), the temperature has a significant
impact on the catalytic effect. It was then noticed
that the yield was obviously improved by
decreasing the reaction temperature from 100 °C
to 80 °C. In addition, the TDG loading screening
showed that low loading is not beneficial for the
reaction (entry 10). Then, the examination of
different palladium catalysts revealed that this
reaction can be catalyzed by Pd(TFA)2, Pd(acac)2,
PdCl2, Pd(PPh3)2Cl2, Pd(CH3CN)2Cl2, albeit with
lower efficiency compared with Pd(OAc)2
(entries 11-15).
Table 2. Palladium-catalyzed C(sp3)
H arylation of
ketones.
Following the above investigation, the
screening of TDGs was conducted, (entries 16-
23).
When
commercially
available
N-
isopropylethylene-diamine (L2) was used, only a
trace amount of 3a was obtained (entry 16). The
data suggested that the carbonyl group is very
important. When TDG L3 was investigated, the
product was not observed (entry 17), which
suggested that the carbonyl group must be located
between two nitrogen atoms. Also, L4 was
completely ineffective, which indicated that the
6-membered palladacycle intermediate is not
suitable for this process (entry 18). Furthermore,
the presence of an

-tert-butyl group had
negative effects on C(sp3)

H arylation (entry 19).
To further investigate the role of the directing
groups, several TDGs containing bulky groups
were synthesized, but rather poor yields were
observed (entries 20-22). As a comparison, when
glycine (L9) was used as a TDG,[19] only 5%
yield was achieved (entry 23). This result
suggested that the 2-amino-N-isopropylacetamide
L1 rather than its hydrolysate facilitates the
transformation, and N,N-bidentate coordination
Conditions: ketones 1 (0.4 mmol, 2.0 equiv), ArI 2 (0.2
mmol, 1.0 equiv), Pd(OAc)2 (10 mol%), AgTFA (1.5
equiv), HFIP : AcOH = 9 : 1 (0.2 M), under air, 80 °C, 24
h. Yields correspond to the yields of isolated products.
*Reaction performed at 100 °C.
between Pd and TDG is more favorable for the -
3e). Electron-rich aryl iodides with alkoxy,
methyl, and tert-butyl substituents afforded the
arylation of ketones than that of N,O-bidentate
coordination under optimal reaction conditions.
According to the above results, the highest NMR
yield (85%) was obtained when the reaction was
carried out to 24 h with 10 mol% of Pd(OAc)2, 50
mol% of L1, and 1.5 equiv. of AgTFA in
HFIP/AcOH (9:1) at 80 °C.
corresponding products in moderate yields (3f
-
3k). When we changed the placement of the
methoxyl group from the para-position to the
meta-position, a significant improvement in the
yield was observed (3f
containing biphenyl units were tolerated,
providing moderate yields (3l 3m). Lastly,
screening of arylation with heteroaryl iodides
showed that no product was obtained (3n 3o).
Next, we surveyed the aliphatic ketone scope
of the H arylation (Table 2). A variety
-C(sp3)
of simple linear ketones were well tolerated,
giving excellent to good yields (3p 3q 3s).
Significantly, when 3-methylbutan-2-one (1q
and symmetrical 3-pentanone (1s) bearing two
, 3g). Also, aryl iodides
After determining the optimal conditions, we
carried out a substrate scope study of aliphatic
ketones and aryl iodides. The results were
summarized in Table 2. Firstly, the substrate
scope of the aryl iodides was examined for
arylation, using 3-methyl-2-pentanone as the
model substrate. Electron-deficient aryl iodides
bearing ester, nitrotrifluoromethyl, and fluorine
substituents were well tolerated to give the
,
,


,
,
)
arylated products in good to moderate yields (3a
-
unactivated
C

H
sites were used, high
3
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10.1002/adsc.201800489
Advanced Synthesis & Catalysis
monoselectivity was observed. Also, the arylation
of branched ketone only provided a trace yield
Table 3. C(sp2)H arylation of aromatic ketones.
(
3r). Furthermore, we found that
methylene C(sp3)
H bonds of cyclic ketones
provided the corresponding syn products with
excellent diastereoselectivity (3t
3v).[35]
-arylation of

-
We also surveyed the scope of aromatic
ketones and aryl iodides under optimized
conditions. As illustrated in Table 3,
acetophenones with electron-donating or
-
withdrawing substituents and different halogen
substitutions underwent arylation to give the
products in excellent to moderate yields (5a-5j).
Also, the ortho-C
acetonaphthone with a variety of aryl iodides was
achieved to afford the target products in excellent
to moderate yields (5k
iodides containing biphenyl units were tolerated,
providing excellent to good yields (5t 5u).

H
arylation of 2-
-5s). Furthermore, aryl
,
To provide insight into the reaction mechanism, a
series of deuteration experiments were performed
(Scheme 2). The intramolecular kinetic isotope effect
(KIE) of the palladium-catalyzed CH functionali-
zation was found to be kH/kD = 2.2 [Scheme 2 (1)].
Moreover, the intermolecular KIE of kH/kD = 2.3 was
investigated with independent reactions of substrates
4a and 4a-d5 [Scheme 2 (2)]. These experimental
results are indicative of a kinetically relevant CH
metalation step.[36]
Based on the above results and the previous
reports,[27, 33, 37-39] we propose a plausible reaction
mechanism for the
-CH arylation of aliphatic
ketones and aromatic ketones (Scheme 3).
Condensation of ketones with the ligand 2-amino-
N-isopropylacetamide provides the imine
intermediate
amide to a palladium species followed by a ligand
exchange process generates palladium complex
Cyclopalladation of intermediate gives rise to
the [5,5]-bicyclic palladium intermediate via a
site-selective C H bond activation process, and
oxidative addition of the intermediate with an
aryl iodide generates the palladium(IV) species
A
. Coordination of this α-imino
Conditions: ketones (0.2 mmol, 1.0 equiv), ArI (0.4
mmol, 2.0 equiv), Pd(OAc)2 (10 mol %), AgTFA (1.5
equiv), HFIP : AcOH = 9 : 1 (0.2 M), under air,
100 °C, 24 h. Yields correspond to the yields of
isolated products.
B
.
B
C

C
D
.
Reductive elimination of this palladium complex
followed by a ligand dissociation process and
iodide abstraction by AgTFA provides the α-
imino amide
product,
E
, which releases the desired
and ligand 2-amino-N-
isopropylacetamide.
To further demonstrate the potential
application of this transformation, we selected
phenanthridinone and phenaglydon (natural
products) as synthetic targets, and successfully
synthesized the two compounds based on a one-pot
method (Scheme 4). Using phenanthridinone as an
example, after the arylation of compound 4a based on
the above optimized conditions was completed, the
reaction mixture was concentrated in vacuo.
Subsequently, sodium azide and silica sulfuric acid
were added.[40,41] The reaction mixture was stirred for
Scheme 2. Deuteration experiments.
4
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10.1002/adsc.201800489
Advanced Synthesis & Catalysis
Experimental Section
General Methods and Materials
Melting points were obtained on a XT-4 melting-point
apparatus and were uncorrected. The infrared (IR) spectra
were measured on a Nicolet Avatar iS10 Fourier transform
infrared (FTIR) spectrometer with 4 cm-1 resolution and 32
scans between wavenumber of 4000 cm−1 and 400 cm−1.
Samples were prepared as KBr disks with 1 mg of samples
in 100 mg of KBr. Proton nuclear magnetic resonance (1H
NMR) spectra were recorded on a Bruker Avance 400 or
500 spectrometer at 400 or 500 MHz. Carbon-13 nuclear
magnetic resonance (13C NMR) was recorded on a Bruker
Avance 400 or 500 spectrometer at 100 or 125 MHz. High
resolution mass spectral (HRMS) data were obtained with
an ionization mode of electrospray ionization (ESI). All the
solvents and commercially available reagents were
purchased from commercial sources and used directly.
Ligands L2, L3, and L9 were purchased from TCI, and the
other ligands L1[42], L4[42], L5[42], L6[42], L7[43], L8[44] and
starting materials 6[45], 4a-d[46], and 4a-d5[46] were prepared
according to literature procedures
(see the supporting information for more details).
Scheme 3. Proposed reaction mechanism.
Typical Procedure for Palladium-Catalyzed CH
Arylation of Aliphatic Ketones
12 h at 70 °C. After continuous Schmidt reaction,
deacetylation, and amination, a 45% yield of
phenanthridinone, the desired product, was obtained.
To a 15-mL reaction tube were added Pd(OAc)2 (4.5 mg,
0.02 mmol), L1 (11.6 mg, 0.1 mmol), silver
trifluoroacetate (66.3 mg, 0.3 mmol), ketone substrate (0.4
mmol), and aryl iodide (0.2 mmol), followed by the
mixture of HFIP (0.9 mL) and acetic acid (0.1 mL). The
tube was then sealed, and the reaction mixture was stirred
at room temperature for 15 min before being heated to
80 °C for 24 h. The mixture was cooled to room
temperature and concentrated under reduced pressure. The
crude reaction mixture was purified on silica gel using
hexanes/EtOAc as the eluent to afford the desired product.
General Procedure for ortho-CH Arylation of
Scheme 4. Synthetic applications.
Aromatic Ketones
To a 15-mL reaction tube were added Pd(OAc)2 (4.5 mg,
0.02 mmol), L1 (11.6 mg, 0.1 mmol), AgTFA (66.3 mg,
0.3 mmol), aromatic ketones (0.2 mmol), aryl iodide (0.4
mmol), HFIP (0.9 mL), and acetic acid (0.1 mL). The tube
was then sealed, and the mixture was stirred at room
temperature for 15 min before being heated to 100 °C for
24 h. The reaction mixture was cooled to room temperature,
filtered via Celite, exhaustively washed with ethyl acetate,
and then the filtrate was concentrated under reduced
pressure. The resulting residue was purified on silica gel
using hexanes/EtOAc as the eluent to provide the biaryl
products.
Conclusion
In summary, palladium-catalyzed arylation of
ketones was achieved via a
functionalization process with 2-amino-N-
isopropylacetamide as a new transient directing
group. A range of unactivated methyl as well as
cyclic methylene CH bonds were efficiently
functionalized. The transformation showed
excellent functional group compatibility and
diastereoselectivity
conditions. Compared with glycine, the
-CH bond
Synthesis of Phenanthridine Skeletal Amaryllidaceae
Alkaloids
under
relatively
mild
-amino

amide produced better results via N,N-bidentate
coordination between Pd and TDG. Furthermore,
we developed a one-pot method and successfully
completed the synthesis of two phenanthridinone
alkaloids based on the arylation of ketones. This
study offers valuable insight for the future
development of transient directing groups to
To a 15-mL reaction tube were added Pd(OAc)2 (4.5 mg,
0.02 mmol), L1 (11.6 mg, 0.1 mmol), AgTFA (66.3 mg,
0.3 mmol), acetophenone (24 mg, 0.2 mmol), methyl 2-
iodobenzoate 2b (105 mg, 0.4 mmol) or methyl 2-iodo-4-
methylbenzoate 6 (110 mg, 0.4 mmol), HFIP (0.9 mL), and
AcOH (0.1 mL). The tube was then sealed, and the mixture
was stirred at room temperature for 15 min before being
heated to 100 °C for 24 h. The reaction mixture was then
cooled to room temperature and concentrated under
reduced pressure. To the crude reaction mixture was added
silica sulfuric acid SSA (760 mg, 2 mmol) and NaN3 (52
mg, 0.8 mmol). The mixture was stirred at 70 °C for 12 h,
and the progress of the reaction was monitored by thin-
layer chromatography (TLC). After the reaction was
complete, ethyl acetate (15 mL) was added to the reaction
mixture, and silica sulfuric acid was removed by filtration.
The filtrate was then washed with water (10 ml), dried over
promote inert CH functionalization, which
should find broad applications in the synthesis of
drug molecules and natural products. Further
efforts to enable enantioselective selectivity with
this reaction using chiral amides are currently
underway in our laboratory.
5
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10.1002/adsc.201800489
Advanced Synthesis & Catalysis
anhydrous MgSO4, and the solvent evaporated in a vacuum
to give the crude product. The resulting residue was
purified by column chromatography (eluting with
petroleum ether/ethyl acetate) to provide the
phenanthridin-6(5H)-one or phenaglydon.
[17] For selected reviews, see: a) P. Dydio, Reek, J. N. H.
Chem. Sci. 2014, 5, 2135; b) G. Rousseau, B. Breit,
Angew. Chem. Int. Ed. 2011, 50, 2450.
[18] For selected reviews and examples, see: a) Y. J. Park,
J.-W. Park, C.-H. Jun, Acc. Chem. Res. 2008, 41, 222;
b) D.-Y. Lee, I.-J. Kim, C.-H. Jun, Angew. Chem. Int.
Ed. 2002, 41, 3031; c) C.-H. Jun, K.-Y. Chung, J.-B.
Hong, Org. Lett. 2001, 3, 785; d) C.-H. Jun, D.-Y.
Lee, J.-B. Hong, Tetrahedron Lett. 1997, 38, 6673.
Acknowledgements
This work was supported by the Program for CAS “Light of
West China”. The authors gratefully acknowledge the
Program for Changjiang Scholars and Innovative Research
Team in University (IRT17R94), the NSFC (81760621), the
Foundation of “Yunling Scholar” Program of Yunnan
Province (C6183005), and Innovative Research Team (in
Science and Technology) in University of Yunnan Province
for financial support.
[19] P. W. Tan, N. A. B. Juwaini, J. Seayad, Org. Lett.
2013, 15, 5166-5169.
[20] F. Mo, G. Dong, Science 2014, 345, 68-72.
[21] F. L. Zhang, K. Hong, T. J. Li, H. Park, J. Q. Yu,
Science 2016, 351, 252-256.
[22] a) K. Yang, Q. Li, Y. B. Liu, G. G. Li, H. B. Ge, J.
Am. Chem. Soc. 2016, 138, 12775-12778; b) L. Pan,
K. Yang, G. G. Li, H. B. Ge, Chem. Commun.
2018, 54, 2759-2762.
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Advanced Synthesis & Catalysis
FULL PAPER
Palladium-Catalyzed -CH Arylation of Ketones
Using Amino Amide as a Transient Directing
Group: Applications to Synthesis of Phenanthri-
dinone Alkaloids
Adv. Synth. Catal. Year, Volume, Page – Page
Junliang Wang,a Cong Dong,a Liangfei Wu,a
Mingkai Xu,c Jun Lin*b and Kun Wei*a
8
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