Palladium-Catalyzed N-Acylation of Tertiary Amines by Carboxylic Acids: A Method for the Synthesis of Amides

Article abstract of DOI:10.1021/acs.orglett.0c01869

A palladium-catalyzed N-acylation of tertiary amines by carboxylic acids was achieved through C-N cleavage. This reaction showed a wide substrate scope. Both aromatic and aliphatic acids served well as the acylating reagents and coupled with tertiary amines to produce the corresponding amides in good to excellent yields. With the strategy, bioactive carboxylic acids were also efficiently modified, highlighting the synthetic value of the process in organic synthesis.

Full text of DOI:10.1021/acs.orglett.0c01869

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Letter
Palladium-Catalyzed N‑Acylation of Tertiary Amines by Carboxylic
Acids: A Method for the Synthesis of Amides
Zhaohui Li,† Long Liu,† Kaiqiang Xu, Tianzeng Huang, Xinyi Li, Bin Song, and Tieqiao Chen*
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ABSTRACT: A palladium-catalyzed N-acylation of tertiary amines
by carboxylic acids was achieved through C−N cleavage. This
reaction showed a wide substrate scope. Both aromatic and
aliphatic acids served well as the acylating reagents and coupled
with tertiary amines to produce the corresponding amides in good
to excellent yields. With the strategy, bioactive carboxylic acids
were also efficiently modified, highlighting the synthetic value of the process in organic synthesis.
Scheme 1. Mechanistic Proposal for the N-Acylation of
Tertiary Amines by Carboxylic Acids
ertiary amines commonly occur in many pharmaceuticals,
materials, and industrial chemicals.1 Therefore, cleaving
T
C−N bonds in relevant compounds and employing the
resulting fragments in organic synthesis have attracted a
great deal of attention from chemists. However, due to the
high dissociation energy, it is difficult to split such a C−N
bond. Generally, the cleavage of C−N bonds strongly depends
on two strategies,2 i.e., α-C−H oxidation with the use of
superstoichiometric oxidants forming imine cations3 and
pretransformation of the tertiary amines into the active
quaternary ammonium salts.4 Obviously, these reactions
would suffer from synthetic issues in terms of oxidative side
reactions, isolation, and (or) low step economy. Without a
doubt, if C−N bonds could be directly cleaved without using
additional activating reagents for amines, it would be greatly
appreciated. However, the established transformations required
the assistance of directing groups5 or special allyl amines as
substrates.6 Only a few examples have been reported for the
conversion of general tertiary amines.7 Herein, we report a
palladium-catalyzed N-acylation of tertiary amines by carbox-
ylic acids (Scheme 1C). With the strategy, a wide range of
amides, including both aromatic and aliphatic ones, were
produced in good to high yields. It should be noted that
electron-deficient benzoic acids could be transformed into
amides in moderate yields using superstoichiometric PPh3/I2/
Et3N.8 Mediated by CuI, phenylacetic acids and cinnamic acids
were efficiently amidated by aliphatic tertiary amines with the
use of 3 equiv of CCl4 as an oxidant.9 Aromatic acids showed
low efficiency under the reaction conditions. By using excessive
polyhalomethanes or peroxides as the oxidants, the amidation
of benzoylformic acids with tertiary amines also took place.10
It was reported that acyl metal complexes generated from RI
and CO gas were capable of coupling with tertiary amines to
produce the corresponding amides (Scheme 1A).11 It is also
known that carboxylic acids could be activated in situ by an
anhydride to give the asymmetric anhydrides, which could be
oxidatively added by low-valent metals such as nickel,
palladium, and rhodium to produce the acyl−metal complexes
(Scheme 1B).12 We envision that carboxylic acids might be
used as the acyl sources for amide synthesis under suitable
reaction conditions, thus avoiding the use of toxic CO gas
(Scheme 1C). The N-acylation of triethylamine with 1-
naphthoic acid was first undertaken using Piv2O as the
promoter. It was found that this reaction could be mediated by
5 mol % Pd(OAc)2/TFP at 120 °C to produce the
corresponding amide 3a in 96% yield (Table 1, entry 1).
Other selected palladium catalysts such as PdCl2, Pd(acac)2,
and Pd(TFA)2 could also promote the reaction, but Pd(dba)2
gave a low yield (Table 1, entries 2−5). When the reaction was
Received: June 4, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01869
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
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Letter
a
other anhydrides such as Boc2O and Ac2O were selected
instead of Piv2O to in situ activate 1a, low yields were given
(Table 1, entries 29 and 30, respectively).
Table 1. Optimization of Reaction Conditions
With the optimal reaction conditions at hand, the substrate
scope was subsequently investigated. As shown in Table 2, in
Table 2. Palladium-Catalyzed Amidation of Carboxylic
Acids with Tertiary Amines or DMF
catalyst
(5 mol %)
ligand
(5 mol %)
solvent
(1.0 mL)
temp
(°C)
yield of 3a
b
a
entry
(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Pd(OAc)2
PdC12
TFP
TFP
TFP
TFP
TFP
TFP
TFP
TFP
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
p-xylene
Cy
PhCI
DCE
dioxane
DMF
CH3CN
toluene
toluene
toluene
toluene
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
130
110
120
120
96
94
87
79
10
nd
nd
nd
19
76
13
59
39
87
14
6
Pd(acac)2
Pd(TFA)2
Pd(dba)2
Ni(OAc)2
Cu(OAc)2
none
c
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
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
Pd(OAc)2
Pd(OAc)2
TFP
TFP
d
none
PPh3
PPh2Cy
DPPM
DPPP
DPPB
DPPF
X-phos
1,10-phen
TFP
TFP
TFP
TFP
TFP
TFP
TFP
TFP
TFP
e
e
e
e
8
e
30
16
85
72
90
70
86
71
77
94
60
33
trace
e
f
29
30
TFP
TFP
g
a
Reaction conditions: acid 1a (0.2 mmol), Et3N 2a (0.6 mmol),
Pd(OAc)2 (5 mol %), TFP [tris(2-furyl)phosphine, 5 mol %], Piv2O
(trimethylacetic anhydride, 1.5 equiv), toluene (1 mL), N2, 120 °C,
b
c
15 h. GC yield using tridecane as an internal standard. With 10 mol
d
e
% TFP. With 2.5 mol % TFP. With 2.5 mol % ligand.
Abbreviations: DPPM, bis(diphenylphosphino)methane; DPPP, 1,3-
bis(diphenylphosphino)propane; DPPB, 1,4-bis(diphenylphosphino)-
butane; DPPF, 1,1′-bis(diphenylphosphino)ferrocene. With 1.5 equiv
of Boc2O instead of Piv2O. With 1.5 equiv of Ac2O instead of Piv2O.
f
a
Reaction conditions: acid 1 (0.2 mmol), amine 2 (0.6 mmol),
g
Pd(OAc)2 (5 mol %), TFP (5 mol %), Piv2O (1.5 equiv), toluene (1
mL), in N2, 120 °C, 15 h. GC yield using tridecane as an internal
b
standard. The data in parentheses are the isolated yields. At 150 °C.
c
d
mediated by Ni(OAc)2 or Cu(OAc)2 or in the absence of a
metal catalyst, no 3a was detected (Table 1, entries 6−8). The
loading amount of ligand seemed to be essential to the
reaction. When 10 mol % TFP was used, the yield of 3a
decreased dramatically to 19% (Table 1, entry 9). The yield of
3a also decreased with the decrease in the level of TFP (Table
1, entries 10 and 11). The ligands were subsequently screened
with TFP being the best choice (Table 1, entries 12−19). The
reaction also took place in other selected solvents such as p-
xylene, Cy (cyclohexane), PhCl, DCE, dioxane, DMF, and
MeCN, despite the fact that the yields slightly decreased
(Table 1, entries 20−26, respectively). Further increasing the
reaction temperature to 130 °C did not enhance the yield,
while the yield decreased to 60% when the reaction was carried
out at 110 °C (Table 1, entries 27 and 28, respectively). When
Piv2O (3 equiv). DMF (3 equiv) was used.
addition to 1a, 2-naphthoic acid was also transformed into the
expected amide 3b in 70% yield by the strategy. Benzoic acids
bearing both electron-rich and electron-deficient groups
coupled readily with triethyl amine, producing the correspond-
ing amides in high yields (3c−3l). It should be noted that the
substrates with strong steric hindrance worked well (3e and
3j). Halo groups like F and Br survived in the present catalytic
system (3k and 3l). Heterocyclic carboxylic acids could also be
applied to the N-acylation with Et3N (3n−3p). Cinnamic acids
also acted as the correct substrates (3q and 3r). Under the
reaction conditions, aliphatic carboxylic acids could also couple
with Et3N, but the yield decreased with the increase in steric
B
https://dx.doi.org/10.1021/acs.orglett.0c01869
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
hindrance (3s−3u).13 When a diacid was used, the
corresponding diamide was produced in 77% yield (3v).
Tripropyl amine was also N-acylated with 1a, giving 3w in 70%
yield.14 However, when trioctyl amine was used, only a trace
amount of product was detected (3x). The result might be
ascribed to the high boiling point of the byproduct ester. The
reaction also progressed sluggishly to N,N-dimethyl aniline
probably due to the strong steric hindrance and low
nucleophility (3y). Interestingly, with an increase in the
reaction temperature to 150 °C, DMF could also be used as
the source of nitrogen for the amidation of carboxylic acids
(3z−3ab).
situ activated by Piv2O to produce an asymmetric anhydride
A.12 The resulting A subsequently underwent oxidative
addition with the active Pd(0) catalyst to give species B,12
followed by reductive elimination to produce intermediate C
and to regenerate the active Pd(0) catalyst.11,15 Intermediate C
upon heating finally yielded the desired amide 3 and the
byproduct ester D.11,15 It should be noted that the reaction of
the Pd(0) complex with asymmetric anhydride A could also
t
generate BuC(O)-Pd-O(O)R species and thus finally yielded
13
t
the byproduct amide BuC(O)NR2. The oxidative addition
would be affected by the steric hindrance of the R group;
therefore, the yield of coupling product 3 decreased with the
increase in steric hindrance, when aliphatic carboxylic acids
were used. Before reductive elimination, ligation of amine 2
with the palladium atom of complex B would be required.
Thus, the loading of phosphine ligand TFP was essential,
because excessive TFP would hamper the coordination
between 2 and palladium. In this reaction, a 1:1 ratio (Pd:P)
was the best choice. Meanwhile, the steric hindrance and the
nucleophility of amines 2 also affected the yield. Finally, as
described above, Et3N and (n-Pr)3N worked well, while tri(n-
octyl) amine did not under the reaction conditions. It was
deduced that the generation of D with a low boiling point
would promote the decomposition of compound C, thus
promoting the reaction to move forward.
To our delight, this reaction could be applied to the
modification of bioactive carboxylic acids. As shown in Scheme
2, 3-methylflavone-8-carboxylic acid is a clinical drug for
Scheme 2. Palladium-Catalyzed Amidation of Bioactive
a
Carboxylic Acids
In summary, we disclosed a novel N-acylation of tertiary
amines by carboxylic acids through C−N cleavage. This
reaction avoided the use of superstoichiometric oxidants and
was conducted in one pot. Both aromatic and aliphatic
carboxylic acids, including the bioactive ones, worked well
under the reaction conditions. This reaction not only provided
a facile method for the synthesis of amides but also enriched
the toolbox for transformation of tertiary amines through C−N
cleavage.
a
These reactions were conducted under the standard conditions. GC
yield using tridecane as an internal standard. The data in parentheses
are the isolated yields. At 150 °C. DMF was used.
b
coronary heart disease. It is also an intermediate of M-
cholinergic receptor blocker. It was found that the drug reacted
readily with both Et3N and DMF under the indicated reaction
conditions, producing the corresponding amides 3ac and 3ad
in the same yields. Probenecid is a clinical drug for
hyperuricemia with chronic gouty arthritis and gouty stone.
It also proved to be the right substrate, furnishing the coupling
products in high yields (3ae and 3af). Ibuprofen is widely used
for antipyretic, analgesic, and inflammatory purposes. It also
worked well in the current catalytic system, and the expected
amides 3ag and 3ah were smoothly generated in high yields.
The mechanism, especially the manner of C−N cleavage, is
not fully clarified at present. On the basis of the
literature,11,12,15 we proposed a plausible catalytic cycle for
this reaction. As shown in Scheme 3, carboxylic acid was first in
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01869.
General information, experimental procedures, charac-
1
terization data, and copies of H and 13C NMR spectra
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
Tieqiao Chen − Key Laboratory of Ministry of Education for
Advanced Materials in Tropical Island Resources, Hainan
Provincial Key Lab of Fine Chemicals, Hainan Provincial Fine
Chemical Engineering Research Center, Hainan University,
Haikou 570228, China; orcid.org/0000-0002-9787-9538;
Email: chentieqiao@hnu.edu.cn
Scheme 3. Proposed Mechanism for N-Acylation of Tertiary
Amines by Carboxylic Acids
a
Authors
Zhaohui Li − Key Laboratory of Ministry of Education for
Advanced Materials in Tropical Island Resources, Hainan
Provincial Key Lab of Fine Chemicals, Hainan Provincial Fine
Chemical Engineering Research Center, Hainan University,
Haikou 570228, China
Long Liu − Key Laboratory of Ministry of Education for
Advanced Materials in Tropical Island Resources, Hainan
Provincial Key Lab of Fine Chemicals, Hainan Provincial Fine
a
Ligands have been omitted for the sake of clarity.
C
https://dx.doi.org/10.1021/acs.orglett.0c01869
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Chemical Engineering Research Center, Hainan University,
Haikou 570228, China; orcid.org/0000-0002-6472-5057
Kaiqiang Xu − Key Laboratory of Ministry of Education for
Advanced Materials in Tropical Island Resources, Hainan
Provincial Key Lab of Fine Chemicals, Hainan Provincial Fine
Chemical Engineering Research Center, Hainan University,
Haikou 570228, China
Tianzeng Huang − Key Laboratory of Ministry of Education for
Advanced Materials in Tropical Island Resources, Hainan
Provincial Key Lab of Fine Chemicals, Hainan Provincial Fine
Chemical Engineering Research Center, Hainan University,
Haikou 570228, China
Xinyi Li − Key Laboratory of Ministry of Education for
Advanced Materials in Tropical Island Resources, Hainan
Provincial Key Lab of Fine Chemicals, Hainan Provincial Fine
Chemical Engineering Research Center, Hainan University,
Haikou 570228, China
pubs.acs.org/OrgLett
Letter
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Bin Song − Key Laboratory of Ministry of Education for
Advanced Materials in Tropical Island Resources, Hainan
Provincial Key Lab of Fine Chemicals, Hainan Provincial Fine
Chemical Engineering Research Center, Hainan University,
Haikou 570228, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01869
Author Contributions
†Z.L. and L.L. contributed equally to this work.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
Partial financial support from the HNNSFC (219MS005) and
the NSFC (21871070) is gratefully acknowledged.
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t
(13) The byproduct amide BuC(O)NR2 was detected by GC and
GC-MS when aliphatic carboxylic acids were used.
t
(14) Due to the relatively high boiling point of byproduct BuC(O)
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detected by GC and GC-MS under the reaction conditions.
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