Catalytic Ester and Amide to Amine Interconversion: Nickel-Catalyzed Decarbonylative Amination of Esters and Amides by C?O and C?C Bond Activation

Article abstract of DOI:10.1002/anie.201611819

An efficient nickel-catalyzed decarbonylative amination reaction of aryl and heteroaryl esters has been achieved for the first time. The new amination protocol allows the direct interconversion of esters and amides into the corresponding amines and represents a good alternative to classical rearrangements as well as cross coupling reactions.

Full text of DOI:10.1002/anie.201611819

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201611819
German Edition: DOI: 10.1002/ange.201611819
Amination
Catalytic Ester and Amide to Amine Interconversion:
Nickel-Catalyzed Decarbonylative Amination of Esters and Amides by
À
À
C O and C C Bond Activation
Huifeng Yue, Lin Guo, Hsuan-Hung Liao, Yunfei Cai, Chen Zhu, and Magnus Rueping*
Dedicated to Professor Lutz F. Tietze on the occasion of his 75th birthday
Abstract: An efficient nickel-catalyzed decarbonylative ami-
nation reaction of aryl and heteroaryl esters has been achieved
for the first time. The new amination protocol allows the direct
interconversion of esters and amides into the corresponding
amines and represents a good alternative to classical rearrange-
ments as well as cross coupling reactions.
A
romatic amines are important synthetic building blocks in
chemistry because of their application in the preparation of
pharmaceuticals, biologically active molecules, natural prod-
ucts, polymers, as well as functional materials.[1] Accordingly,
the development of new methodologies to access these
valuable molecules continues to be of great importance in
synthetic organic chemistry.[1] Conventionally, the palladium-
catalyzed Buchwald–Hartwig reaction represents a valuable
2
À
C(sp ) N bond-formation method which makes a great con-
tribution to this field.[2] Although palladium is dominating the
field, and a considerable number of powerful catalytic systems
for the conversion of aryl (pseudo) halides into aromatic
amines has been reported, recent efforts are devoted to the
disclosure of improved protocols based on nonprecious metal
catalysts. Particular attention has been drawn to the use of
inexpensive and earth-abundant nickel catalysts,[3] along with
Scheme 1. a) Classical carboxylic acid to amine interconversions by
rearrangements. b) Classical amide-bond formations by ester amine
coupling. c) Direct transformation of either esters or amides into
amines.
2
[4–8]
À
easily available and versatile C(sp ) O electrophiles.
carboxylic acid derivatives as substrates have not been
realized before. Traditionally, either acids or ester derivatives
are transformed into amines using multistep sequences, and
involve classical rearrangements (Scheme 1a).
Amides are typically rather stable functional groups, part
of peptides and proteins, and are less prone to hydrolysis,
when compared to ester derivatives. They can simply be
prepared by the reaction of esters with amines, and many
different protocols, including a recent nickel-catalyzed pro-
tocol[13] for the amide formation, have been described
(Scheme 1b).
Despite the advances in this field, it is still highly desirable
to further explore different electrophilic coupling partners for
metal-catalyzed amination reactions with the aim of devel-
oping protocols based on cheaper, more-stable, and readily
available substrates. Considerable progress has been achieved
in metal-catalyzed decarboxylative and decarbonylative
cross-coupling reactions using carboxylic acids and its deriv-
atives.[9–12]
However, to the best of our knowledge, metal-catalyzed
2
À
C(sp ) N bond formations by a decarbonylative process with
Given the enormous interest in efficient protocols for the
preparation of amines and limitations associated with the
classical rearrangement reactions, we became interested in
developing a direct catalytic amination of aryl and heteroaryl
esters, in which the ester moiety would be replaced by an
amine to yield aromatic amines in a one-step process
(Scheme 1c). Herein, we report an unprecedented decarbon-
ylative amination protocol for the direct interconversion of
esters, as well as amides, into aryl amines (Scheme 1c). To
prevent the undesired amide-bond formation when reacting
esters with amines (Scheme 1b), we decided to use imines as
nucleophiles instead. This approach would also allow further
[*] H. Yue, L. Guo, H.-H. Liao, Y. Cai, C. Zhu, Prof. Dr. M. Rueping
Institute of Organic Chemistry, RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany)
E-mail: magnus.rueping@rwth-aachen.de
Prof. Dr. M. Rueping
King Abdullah University of Science and Technology (KAUST)
KAUST Catalysis Center (KCC)
Thuwal, 23955-6900 (Saudi Arabia)
E-mail: magnus.rueping@Kaust.edu.sa
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201611819.
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functionalization, as well as direct access to primary aromatic
amines.
increased to 56% when 2 equivalents of benzophenone imine
and 3 equivalents of K3PO4 were used (entry 12).
Therefore, our initial experiments in developing the new
decarbonylative amination started with phenyl naphthalene-
2-carboxylate (1a) and commercially available benzophe-
none imine (2; Table 1). Among the different metals tested,
LiCl as a Lewis acid additive was found to have
a beneficial effect on our decarbonylative amination, and
may be due to coordination to the carbonyl group (Table 1,
entry 13). Extending the reaction time and increasing the
temperature slightly, significantly improved the yield
(entries 14 and 15). Under the optimized reaction conditions
the desired product was isolated in 87% yield upon acidic
hydrolysis. A slightly lower yield (80%) was obtained with
Ni(OAc)2·4H2O as the catalyst (entry 18). Control experi-
ments showed that no amination product was observed in the
absence of [Ni(cod)2] or dcype ligand (entries 16 and 17).
When secondary amines, such as morpholine were used, the
aminolysis reaction of the ester substrate occurred, thus
affording the undesired amide product 4.[13] Other esters such
as methyl and benzyl esters were not suitable for this
transformation as it allows for a chemoselective amination
of differently protected esters (Scheme 2).
Table 1: Optimization of the reaction conditions.[a]
Entry
[Ni]
Ligand
(x mol%)
Base
(2 equiv)
Additive
(2 equiv)
Yield
[%][b]
1
2
3
4
5
6
7
8
[Ni(cod)2]
[Ni(cod)2]
[Ni(cod)2]
[Ni(cod)2]
[Ni(cod)2]
[Ni(cod)2]
[Ni(cod)2]
[Ni(cod)2]
[Ni(cod)2]
[Ni(cod)2]
[Ni(cod)2]
[Ni(cod)2]
[Ni(cod)2]
[Ni(cod)2]
[Ni(cod)2]
[Ni(cod)2]
–
IPr·HCl (20)
PnBu3 (20)
PCy3 (20)
dcype (10)
dcypf (10)
dcype (20)
dcype (20)
dcype (20)
dcype (20)
dcype (20)
dcype (20)
dcype (20)
dcype (20)
dcype (20)
dcype (20)
–
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Li2CO3
K2CO3
Na2CO3
K3PO4
NaOtBu
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
–
–
–
–
–
–
–
–
–
–
–
–
LiCl
LiCl
LiCl
LiCl
LiCl
–
0
0
0
14
trace
17
21
31
31
42
0
56
63
84
87
0
9
10
11
12[c]
13[c]
14[c,d]
15[c–e]
16[c–e]
17[c–e]
18[c–e]
19[c–e]
20[c–e]
dcype (20)
dcype (20)
dcype (20)
dcype (20)
0
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
80
63
77
Mn[f]
Et3SiH[g]
Scheme 2. Nickel-catalyzed decarbonylative amination of the naphthyl
ester 1a.
[a] IPr·HCl=1,3-bis(2,6- diisopropylphenyl)imidazolium chloride,
dcype=1,2-bis(dicyclohexylphosphino)-ethane, dcypf=1,1’-bis(dicyclo-
hexylphosphino) ferrocene. Reaction conditions: phenyl naphthalene-2-
carboxylate (1a; 0.2 mmol), benzophenone imine 2 (0.3 mmol), [Ni-
(cod)2] (0.02 mmol), ligand (0.02 mmol or 0.04 mmol), base (0.4 mmol)
in toluene (1 mL) at 1608C, 12 h. [b] Yield of isolated products.
[c] Benzophenone imine 2 (2 equiv), K3PO4 (3 equiv). [d] 48 h. [e] 1708C.
[f] Mn powder (1.5 equiv). [g] Et3SiH (20 mol%). cod=1,5-cycloocta-
diene.
With the optimized reaction conditions in hand, the scope
with respect to the aryl esters was examined (Table 2). The
results show that a range of aromatic and heteroaromatic
esters having various substitution patterns were tolerated in
this newly developed ester to amine transformation, thus
giving the corresponding primary amines in moderate to high
yields. As anticipated, naphthyl esters (1a–c) underwent this
decarbonylative amination protocol in good to high yields.
nickel complexes proved to be good catalysts for the
decarbonylation. The nature of the ligand critically affected
the efficiency of our transformation. No reaction occurred
when IPr·HCl was applied as a ligand (entry 1). The use of
monodentate phosphine ligands such as P(n-Bu)3 and PCy3
also gave no desired product (entries 2 and 3). However,
bidentate phosphine ligands were suitable for this reaction
and 14% yield was obtained when 1,2-bis (dicyclohexylphos-
phino)ethane (dcype) was used. Increasing the ratio of nickel
to bidentate phosphine ligand from 1:1 to 1:2 was beneficial
for this transformation (entry 4 versus 6). Various bases were
next examined and K3PO4 was found to be the optimal choice.
Reactions in the presence of other bases gave either lower
yields (Li2CO3, K2CO3, Na2CO3), or even no desired product
(NaOtBu), and indicated that the base plays a crucial role in
this reaction (entries 6–11). The yield of the coupling product
À
Although protocols for the amination of the C OMe bond
under nickel catalysis have been reported,[4] we were pleased
to find that methoxy groups are well tolerated in our
amination protocol (3c and 3j). Furthermore, not only
simple biphenyl ester gave the desired products (3e and 3 f)
in good yields, but also a series of biphenyl ester derivatives
possessing fluoro (1g), trifluoromethyl (1h), and tertiary
butyl substituents (1i) efficiently underwent this transforma-
tion. Simple phenyl derivatives are more challenging sub-
strates than p-extended systems.[3e] However, we were pleased
to find that under our catalytic system, simple phenyl ester
derivatives, possessing either electron-donating or electron-
withdrawing functional groups, could be converted into the
corresponding amines in moderate to good yields. The
chemoselectivity of this new amination protocol was nicely
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Table 2: Scope with respect to the aryl esters.[a]
To demonstrate the applicability of this newly developed
amination methodology, an aryl amide was also used as
a different electrophile. Minor modification of the standard
reaction conditions by changing the ligand from dcype to dppf
allowed the decarbonylative amination of the amide 5 with
benzophenone imine to proceed, thus showing the potential
of our amination protocol in the development of versatile
aroyl compounds as electrophiles (Scheme 3).
Scheme 3. Nickel-catalyzed decarbonylative amination of naphthyl
amide. dppf=1,1’-bis(diphenylphosphanyl)ferrocene.
Based on our results and previous studies,[14,15] a mecha-
nism for this new nickel-catalyzed decarbonylative amination
reaction is proposed (Scheme 4). Oxidative addition of the
Scheme 4. Proposed mechanism for the new nickel-catalyzed decar-
bonylative amination of aryl esters.
0
À
[LnNi ] complex A into the C(acyl) O bond of aryl ester
gives an acyl nickel(II) intermediate (B), which subsequently
undergoes CO migration and ligand exchange with benzo-
phenone imine, with the assistance of a base to afford an aryl-
imine nickel(II) intermediate C. Reductive elimination pro-
duces a [LnNi0CO] (D) and the amination product. Finally,
extrusion of CO from D regenerates the active LnNi0 catalyst
A.
[a] Reaction conditions: aryl ester 1a–r (0.2 mmol), benzophenone imine
2 (0.4 mmol), [Ni(cod)2] (0.02 mmol), dcype (0.04 mmol), K3PO4
(0.6 mmol), LiCl (0.4 mmol) in toluene (1 mL) at 1708C, 48 h. [b] Work
up: reduction by NaBH4 (10 equiv) in methanol (5 mL).
In summary, we have developed the first catalytic
decarbonylative amination protocol which allows, for the
first time, the transfer of a series of readily available aryl and
heteroaryl esters, and even amides, to the corresponding
amines. In contrast to classical multistep rearrangement
procedures, the method relies on the use of either [Ni-
(cod)2]/dcype catalytic system or the use of a nickel(II) salt to
directly provide the desired amines. Considering the substrate
scope of this protocol, the method provides a new and
efficient route to aryl amines from readily available esters.
The protocol shows good chemoselectivity, and functional
illustrated by the fact that sensitive functional groups such as
methoxy, methylthio, ketone, ester, and cyano on the phenyl
ring were perfectly accommodated, thus providing opportu-
nities for further functionalization (3j–n). Gratefully, our
decarbonylative amination transformation could be readily
extended to heterocyclic esters derived from quinoline,
pyridine, and thiophene, thus affording the corresponding
heteroaryl primary amines in moderate to high yields (3o–q).
It is noteworthy that the corresponding secondary amine 3r
could also be obtained by reductive hydrogenation of the
ketimine intermediate instead of acidic hydrolysis.
À
À
À
groups including C OMe, C SMe, C F, and CN moieties,
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Acknowledgements
H.Y. and L.G. acknowledge the China Scholarship Council.
H.-H.L. acknowledges the DAAD for a doctoral fellowship,
Y.C. acknowledges the Alexander von Humboldt-Foundation
for a fellowship. Support by King Abdullah University of
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The authors declare no conflict of interest.
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Manuscript received: December 5, 2016
Final Article published: && &&, &&&&
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Communications
Amination
H. Yue, L. Guo, H.-H. Liao, Y. Cai, C. Zhu,
M. Rueping*
&&&& — &&&&
An efficient nickel-catalyzed decarbonyla-
tive amination reaction of readily avail-
able aryl and heteroaryl esters has been
developed. This new amination protocol
shows high tolerance towards a variety of
aryl and heteroaryl esters, thus providing
Catalytic Ester and Amide to Amine
Interconversion: Nickel-Catalyzed
Decarbonylative Amination of Esters and
a practical and versatile access to valua-
ble primary amines. cod=1,5-cycloocta-
diene.
À
À
Amides by C O and C C Bond Activation
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www.angewandte.org
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