Palladium-catalyzed β-C-H arylation of aliphatic aldehydes and ketones using amino amide as a transient directing group

Article abstract of DOI:10.1021/acs.orglett.9b00366

This paper describes a new amino-amide-based transient directing group (TDG). The TDG can exhibit better performance in the Pd-catalyzed arylation of aliphatic aldehydes and ketones. This reaction showed good substrate compatibility and regioselectivity. The results indicated that 3-amino-N-isopropylpropionamide was more beneficial to the β-arylation of aliphatic aldehydes than other TDGs under relatively mild conditions.

Full text of DOI:10.1021/acs.orglett.9b00366

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Palladium-Catalyzed β‑C−H Arylation of Aliphatic Aldehydes and
Ketones Using Amino Amide as a Transient Directing Group
Cong Dong, Liangfei Wu, Jianwei Yao, and Kun Wei*
School of Chemical Science and Technology, Yunnan University, Kunming 650091 People’s Republic of China
S
* Supporting Information
ABSTRACT: This paper describes a new amino-amide-based
transient directing group (TDG). The TDG can exhibit better
performance in the Pd-catalyzed arylation of aliphatic aldehydes
and ketones. This reaction showed good substrate compatibility
and regioselectivity. The results indicated that 3-amino-N-
isopropylpropionamide was more beneficial to the β-arylation of
aliphatic aldehydes than other TDGs under relatively mild
conditions.
amino acids as a TDG. In the reaction, a catalytic amount of
amino acid was reversibly involved in C(sp3)−H activation.
Note that aliphatic aldehydes cannot be transformed by their
method (Scheme 1A). Recently, Ge and co-workers used 3-
aminopropionic acid as a TDG to complete the Pd-catalyzed
arylation of aliphatic aldehydes and ketones (Scheme 1B).40,41
ransition-metal-catalyzed reactions are of great significance
Tin modern organic synthesis. In the past two decades,
transition-metal-catalyzed C−H bond activation has been a hot
topic in the field of organic synthesis. In particular, it plays an
important role in the functionalization of nonactivated C−H
bonds.1−3 In that light, the C−H functionalization process
enables the synthesis of pharmaceuticals, natural products, and
chemical materials to be significantly simplified.4 Particularly,
directed C−H activation has emerged as an efficient step in the
formation of C−C bonds and an atom-economic strategy.5−8 To
date, the γ,δ-C−H bond arylation of the amino group,9,10 the
β,γ,δ-C−H bond arylation of aldehyde and ketone,11−13 and the
arylation of remote orientation have been achieved.14,15
Scheme 1. Pd-Catalyzed β-C−H Arylation of Aliphatic
Aldehydes and Ketones
Aliphatic aldehydes and ketones are regarded as common
structural moieties and the key intermediates in pharmaceut-
icals, natural products, and chemical synthesis.16,17 In addition,
carbonyl compounds also show great value in organic
conversion.18−20 However, only a few documents elaborated
the C−H functionalization of aldehyde/ketone orientation over
transition metal catalysts.21−24 Such methodology is severely
hindered by the aldehyde’s weak coordinating capacity, the
sensitivity toward oxidation, and the undesired insertion of
metal into the acyl C−H bond. To overcome those problems, a
method using preinstalled imine or oxime directing group (DG)
C−H function was reported. Nevertheless, installing or
removing DG was sometimes incompatible with the existence
of advanced intermediates of other functional groups.6,25−32
To solve this challenge, some researchers proposed the
concept of a transient directing group (TDG). That is, the DG is
reversibly combined with the substrate and the metal to play a
directing role.33−35 Previously, Jun’s group employed 2-
aminopyridine as a TDG, and the C−H bond functionalization
of aldehyde was achieved by Rh catalyst.36−39 This method was
then successfully applied to the Pd catalytic C(sp3)−H
activation response.28 Yu’s group first reported the Pd-catalyzed
arylation of o-alkyl benzaldehydes and ketones with natural
Inspired by the successful identification of TDGs for ketones
(Scheme 1C),13,42 we explored an amino amide which could be
used as a TDG for the β-C−H activation of both aliphatic
aldehydes and ketones. When we investigated the effect of the
DG; we observed that a six-membered ring formed by chelation
with Pd(II), and the DG was more effective than the five-
membered ring.43−45 Therefore, we hypothesized that amino
Received: January 28, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00366
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
amide could further promote β-C−H activation by forming the
six-membered chelation. Herein, we designed a modified β-
alanine (3-aminoalaninamide) as a new TDG to arylate the
unactivated β-C−H bonds of aliphatic aldehydes and ketones
simultaneously (Scheme 1D).
Table 1. Optimization of Reaction Conditions
At the beginning of the experiment, we synthesized a series of
amino amide compounds to investigate their role in Pd-
catalyzed arylation of aldehydes and ketones (L1−L8) (Table
1). We carried out a model reaction with 2-methylbutanal (1a)
and methyl 4-iodobenzoate (2a) as substrates (Table 1). We
screened many common solvents. Among them, hexafluor-
oisopropanol (HFIP) and acetic acid as cosolvents showed good
solvation effects (Table 1, entries 1−7, and Supporting
Information (SI)). When HFIP and acetic acid (9:1) were
used as a mixed solvent, 3a was obtained in a relatively high yield
of 82% (entry 6). Then we screened the temperature and the
amount of TDG of the reaction. As described in Table 1, when
we decreased the reaction temperature from 100 to 80 °C
(entries 11 and 6), the yield was significantly improved. The
above-mentioned results suggested that temperature has a
significant effect on the reaction. Screening of the amount of
catalyst indicated that either low or high loading was not
beneficial for the reaction (entries 8 and 9). Other reaction
parameters, including transition metal catalysts and the types of
additives, were tested. Pd(TFA)2, Pd(acac)2, PdCl2, Pd-
(PPh3)2Cl2, and Pd(CH3CN)2Cl2 can catalyze the reaction,
but the yield was greatly reduced compared to that with
Pd(OAc)2 (entries 12−17). As shown in Table 1 (entries 18−
20), only AgF showed a certain promotion of the product yield,
and AgOAc and Ag2CO3 were inactive.
Following that, we screened the TDGs (entries 21−27), and
when TDG L2 was used, no target product was found. This
result suggested that the carbonyl group should be located
between two nitrogen atoms. To further elucidate the role of
DG, TDG L3 containing a small size structure unit was
synthesized, and the yield was found to be greatly reduced (entry
22). Meanwhile, we synthesized several TDGs containing a large
size structure unit, and low yields were also obtained (entries
24−26). Therefore, it can be presumed that the moderate size of
the structure moiety attached to the N atom of the amide is
critical, and either overly large or small sizes were disadvanta-
geous to the reaction. Particularly, when L7 was used as TDG,
the yield is trace, which suggested that a five-membered
palladacycle intermediate was unsuitable for this process
(entry 26). Compared to L8, L1 exhibits good catalytic activity.
Therefore, we speculate that L1 does not act through its
hydrolysate. By analyzing the data in Table 1, we obtained an
optimal reaction condition 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
for 24 h.
yield
b
entry
metal
ligand additive
solvent
HFIP
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)
(%)
1
2
3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
L1
L1
L1
AgTFA
AgTFA
AgTFA
36.4
trace
45.5
4
5
6
7
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
Pd(pph3)4
PdCl2
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L8
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgOAc
40.9
50
82
48
c
8
41
d
9
45.5
45.5
54.5
34.2
43.2
41
e
10
f
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
18.2
45.5
34.1
NR
NR
29.5
NR
38.6
trace
50
Pd(pph3)2Cl2
Pd(MeCN)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
Pd(OAc)2
Pd(OAc)2
HFIP/AcOH
(9:1)
HFIP/AcOH
(9:1)
Ag2CO3 HFIP/AcOH
(9:1)
AgF
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)
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
Under optimal conditions, we next examined the scope of
substrates of aliphatic aldehydes and aryl iodides (Scheme 2).
We used 2-methylbutyraldehyde (1a; see SI) as a substrate, and
other aryl iodides reacted with it. Both electron-deficient and
electron-rich aryl iodides gave moderate to good yields (3a, 3b,
3c, 3d, 3f). When investigating the effect of different
substitution positions on the benzene ring on the reaction
yield, we found that the yield was higher when the substituent
was in the para position (3a, 3g, 3f, 3h), but this phenomenon
was not observed for methoxy (3c, 3e). We also screened
heteroaryl iodides, but unfortunately, we did not observe the
products (3n, 3o). Importantly, when 2-methylpropionalde-
hyde (1b; see SI) having two reaction sites was used, only one
45.5
trace
trace
a
Conditions: 1a (0.4 mmol), 2a (0.2 mmol), Pd source (0.02 mmol),
ligand (0.1 mmol), AgTFA (0.3 mmol), solvent (1 mL), 80 °C, 24 h.
Yields correspond to isolated products. With 30 mol % of ligand.
b
c
d
e
f
With 70 mol % of ligand. 60 °C, 24 h. 100 °C, 24 h.
B
DOI: 10.1021/acs.orglett.9b00366
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Organic Letters
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Scheme 2. Pd-Catalyzed β-C(sp3)−H Arylation of Aliphatic
Scheme 3. Pd-Catalyzed β-C(sp3)−H Arylation of Aliphatic
a
a
Aldehydes
Ketones
a
Conditions: aliphatic aldehydes 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
isolated products.
monosubstituted product was observed (3k). In addition, we
also obtained high diastereomeric products when cyclic
aldehyde was used as a substrate (3m).
a
Based on this strategy, we then explored the arylation of
aliphatic ketones (4a; see SI) and investigated the range of
aliphatic ketones and aryl iodides under new conditions
(Scheme 3). Both electron-deficient and electron-rich aryl
iodides gave moderate to good yields (5a, 5b, 5c, 5d, 5l), and
then, when examining the effect on reaction yield of different
substitution positions of the substituent on the benzene ring, we
obtained a conclusion similar to that of the aldehyde (5a, 5b, 5d,
5e, 5f, 5g), in which the yield was higher than that when the
substituent was in the para position. We also examined other
types of iodobenzene and obtained a moderate yield (5m, 5n,
5o). Various chain ketones were also screened and gave good to
moderate yields (5p, 5r, 5v, 5w, 5x). Particularly, when 3-
methyl-2-butanone (4b; see SI), 2-methyl-3-pentanone (4e; see
SI), and symmetrical 3-pentanone (4c; see SI) having two or
more reaction sites were used, only one monosubstituted
product was observed (5p, 5v, 5w). In addition, we also
obtained high diastereomeric products when cyclic aldehyde
was used as a substrate (5q, 5s, 5t).
Conditions: aliphatic 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 isolated
products.
Scheme 4. Proposed Reaction Mechanism
On the basis of our experiments and previous research
results,13 we proposed a plausible reaction mechanism for Pd-
catalyzed arylation of aliphatic aldehydes and ketones with
amino amide as a TDG (Scheme 4). First, the aldehyde and 3-
amino-N-isopropylpropionamide as TDG are condensed to
form the imine intermediate A. Next, the β-imino amide
intermediate is coordinated with Pd to form a palladium
complex B. Again, intermediate B eliminates one molecule of
acetic acid to form the [5,6]-bicyclic palladium intermediate C,
and then, intermediate D is formed by the oxidative addition of
intermediate C with an aryl iodide. Finally, intermediate D forms
intermediate E by reductive elimination accompanying a ligand
dissociation process and iodide abstraction by AgTFA to release
the desired product and TDG 3-amino-N-isopropylpropiona-
mide.
C
DOI: 10.1021/acs.orglett.9b00366
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Organic Letters
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In summary, 3-amino-N-isopropylpropionamide as a new
TDG is effectively involved in Pd-catalyzed arylation of aliphatic
aldehydes and ketones. The TDG is found effective for the
activation of the C−H bond of the unactivated methyl group and
the cyclic methylene group. This reaction showed good
substrate compatibility and regioselectivity. The results
indicated that 3-amino-N-isopropylpropionamide was more
beneficial to the β-arylation of aliphatic aldehydes than other
TDGs under relatively mild conditions. The β-amino amide
produced results by the [5,6]-bicyclopalladium intermediate
between Pd and TDG better than those of glycinamide. This
research broadens the range of applications for TDGs. The same
TDG can be applied to activate the inert C−H bond of aliphatic
aldehydes and ketones simultaneously. At present, our
laboratory attempts to find a new amide-like DG with better
universality based on previous research, which can make it
suitable for C−H activation of all types of aldehydes and
ketones.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b00366.
(16) Dyachenko, V. D.; Karpov, E. N. Aliphatic aldehydes in the
synthesis of carbo- and heterocycles: Part II. Synthesis of six- and seven-
membered rings, bicyclic compounds, and macrocycles. Russ. J. Org.
Chem. 2011, 47 (1), 1−29.
(17) Kim, H. Y.; Walsh, P. J. Efficient approaches to the stereoselective
synthesis of cyclopropyl alcohols. Acc. Chem. Res. 2012, 45 (9), 1533−
1547.
Experimental details, spectral and analytical data for all
reaction products (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: kunwei@ynu.edu.cn.
ORCID
(18) Shang, M.; Sun, S. Z.; Dai, H. X.; Yu, J. Q. Cu(II)-mediated C-H
amidation and amination of arenes: exceptional compatibility with
heterocycles. J. Am. Chem. Soc. 2014, 136 (9), 3354−3357.
(19) Cheng, G. J.; Yang, Y. F.; Liu, P.; Chen, P.; Sun, T. Y.; Li, G.;
Zhang, X.; Houk, K. N.; Yu, J. Q.; Wu, Y. D. Role of N-acyl amino acid
ligands in Pd(II)-catalyzed remote C-H activation of tethered arenes. J.
Am. Chem. Soc. 2014, 136 (3), 894−897.
Kun Wei: 0000-0002-3125-7461
Notes
The authors declare no competing financial interest.
(20) Mukaiyama, T. Explorations into new reaction chemistry. Angew.
Chem., Int. Ed. 2004, 43 (42), 5590−5614.
ACKNOWLEDGMENTS
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The mechanism for the rhodium-catalyzed decarbonylation of
aldehydes: a combined experimental and theoretical study. J. Am.
Chem. Soc. 2008, 130 (15), 5206−5215.
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).
(22) Murphy, S. K.; Dong, V. M. Enantioselective hydroacylation of
olefins with rhodium catalysts. Chem. Commun. 2014, 50 (89), 13645−
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DOI: 10.1021/acs.orglett.9b00366
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