Nickel-Catalyzed Decarbonylative Amination of Carboxylic Acid Esters

Article abstract of DOI:10.1021/jacs.9b13531

The reaction of carboxylic acid derivatives with amines to form amide bonds has been the most widely used transformation in organic synthesis over the past century. Its utility is driven by the broad availability of the starting materials as well as the kinetic and thermodynamic driving force for amide bond formation. As such, the invention of new reactions between carboxylic acid derivatives and amines that strategically deviate from amide bond formation remains both a challenge and an opportunity for synthetic chemists. This report describes the development of a nickel-catalyzed decarbonylative reaction that couples (hetero)aromatic esters with a broad scope of amines to form (hetero)aryl amine products. The successful realization of this transformation was predicated on strategic design of the cross-coupling partners (phenol esters and silyl amines) to preclude conventional reactivity that forms inert amide byproducts.

Full text of DOI:10.1021/jacs.9b13531

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Nickel-Catalyzed Decarbonylative Amination of Carboxylic Acid
Esters
Christian A. Malapit,† Margarida Borrell,† Michael W. Milbauer, Conor E. Brigham,
and Melanie S. Sanford*
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ABSTRACT: The reaction of carboxylic acid derivatives with amines to form amide bonds has been the most widely used
transformation in organic synthesis over the past century. Its utility is driven by the broad availability of the starting materials as well
as the kinetic and thermodynamic driving force for amide bond formation. As such, the invention of new reactions between
carboxylic acid derivatives and amines that strategically deviate from amide bond formation remains both a challenge and an
opportunity for synthetic chemists. This report describes the development of a nickel-catalyzed decarbonylative reaction that couples
(hetero)aromatic esters with a broad scope of amines to form (hetero)aryl amine products. The successful realization of this
transformation was predicated on strategic design of the cross-coupling partners (phenol esters and silyl amines) to preclude
conventional reactivity that forms inert amide byproducts.
arboxylic acids are abundant, inexpensive, and stable
compounds, and these properties render them attractive
main group element (M). Appropriate selection of M would
provide an amine nucleophile, M−NR2, that is inert to
background acyl transfer but can selectively engage a metal
catalyst via transmetalation.8 A catalytic cycle that leverages
this approach is shown in Figure 1C. First, ArC(O)X reacts
with a low-valent metal catalyst via oxidative addition and
carbonyl deinsertion to afford an arylmetal intermediate (B).9
Intermediate B then undergoes transmetalation with M−NR2
and subsequent C(sp2)−NR2 coupling to release the targeted
aryl amine product. The success of this cycle relies on strategic
design of M−NR2, ArC(O)X, and the metal catalyst such that
(i) background acyl transfer between M−NR2 and ArC(O)X is
slow; (ii) B undergoes facile transmetalation with M−NR2;
(iii) carbonyl deinsertion is fast relative to transmetalation
(since reaction between M−NR2 and metal acyl intermediate
A would afford the undesired amide byproduct; Figure 1C);10
and (iv) other key steps of the catalytic cycle (oxidative
addition, C(sp2)−N coupling) are energetically feasible. This
report describes the successful realization of this trans-
formation, using a nickel phosphine catalyst to couple aromatic
ester electrophiles with in situ generated silyl amines.
C
building blocks for organic synthesis. As such, metal-catalyzed
decarbonylative or decarboxylative reactions that employ aryl
carboxylic acid derivatives [ArC(O)X] as coupling partners
have gained tremendous attention over the past two decades.1,2
A variety of (hetero)aryl carbon−carbon, carbon−sulfur,
carbon−boron, carbon−silicon, carbon−halogen, and other
carbon−heteroatom linkages can be formed using this
approach.1 However, methods for the decarbonylative or
decarboxylative coupling of ArC(O)X (Ar = aryl) with amines
to afford aryl C(sp2)−N bonds (Figure 1A) remain limited.
While a few such transformations have been reported, they
often have a very narrow scope with respect to the carboxylic
acid and/or amine coupling partner.3−6 For example, most
decarboxylative methods require strong electron-withdrawing
groups on the arene ring or weakly nucleophilic N-groups to
form carbamates.5,6 In decarbonylative reactions, couplings
involving nonstabilized 1° or 2° amines remain challenging,
largely due to the competing amide formation with these
strongly nucleophilic partners (Figure 1A, conventional
reactivity).3 This is exemplified by Rueping’s recent report of
Ni-catalyzed decarbonylative amination of phenyl esters. As
shown in Figure 1B, this transformation is effective for weakly
nucleophilic benzophenone imine. In contrast, the use of more
nucleophilic amines such as morpholine,3 aniline, and indole
results in exclusive formation of the amide product.
On the basis of the criteria outlined above, trimethylsilyl
(TMS)-substituted amines such as the M−NR2 nucleophile
are expected to slow background acyl transfer while facilitating
base-free transmetalation8 between TMS−NR2 and B. To
identify a suitable ArC(O)X coupling partner, we evaluated the
background reaction of TMS−morpholine with three carbox-
The paucity of methods to convert carboxylic acid
derivatives to amines is particularly noteworthy because the
products are of high value in medicinal chemistry.7 As such,
new, general, and practical approaches to forge (hetero)aryl
C(sp2)−N bonds from abundant starting materials have the
potential for widespread application.
Received: December 16, 2019
We hypothesized that undesired background amide
formation could be mitigated by masking the amine with a
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free morpholine as the nucleophile led to a high yield of the
amide product with all three electrophiles (Figure 2A, [M] =
H).
We next examined the coupling of TMS−morpholine with
1-F and 1-OPh in the presence of Ni−bisphosphine catalysts
(Figure 2B). Importantly, Ni phosphine complexes are known
to participate in oxidative addition and carbonyl deinsertion
with diverse ArC(O)X electrophiles.1 Bisphosphine supporting
ligands were chosen on the basis of their ability to effect
C(sp2)−N coupling at NiII centers.11 Representative results
with dppf and dcype are shown in Figure 2 (see the Supporting
Information (SI) for larger ligand screen). Consistent with the
fast background reaction, amide formation dominated with 1-
Cl and 1-F under catalytic conditions. In contrast, with 1-OPh,
decarbonylative coupling to afford aryl amine 4 proceeded in
modest to high yield with dppf and dcype, respectively. Under
the optimized conditions (10 mol % Ni/dcype in toluene at
150 °C), 1-OPh reacted with TMS-morpholine to afford 4 in
90% yield with >19:1 selectivity for amine 4 versus amide 3.
We next explored the scope of this transformation and found
that it is general for a variety of electron-deficient and electron-
neutral carboxylic acid esters (Figure 3A).12 Substituents such
as trifluoromethyl, methyl ester, nitrile, ketone, and phenyl
ether (4−9) are well tolerated. Competing cross-coupling is
not observed at methyl ester (5) or boronate ester (10) sites.
Various N-containing heteroaryl carboxylic acid esters such as
pyridine, quinoline, and quinoxaline derivatives are converted
to N-heteroaryl amines (12−14) in moderate to excellent
yields. S- and O-containing heteroaryl esters such as
benzothiophene (15), benzofuran (16), chromone (17), and
thiazoles (20) are also converted to the desired amine
products. Esters derived from carboxylic acid containing
drugs such as probenecid (18), bexarotene (19), and
febuxostat (20) afford good to excellent yields. This trans-
formation is also general with respect to the amine coupling
partner (Figure 3B). Utilizing the probenecid ester 18-OPh as
the electrophile, various TMS-amines react smoothly to yield
18, 25, 27, and 28. More stable triethylsilyl (TES)- and
triisopropylsilyl (TIPS)-protected amines are effective coupling
partners but provide lower yields of 25.
Figure 1. Proposed strategy for the catalytic decarbonylation of
carboxylic acid derivatives to aryl amines.
ylic acid derivatives: acid chloride 1-Cl, acid fluoride 1-F, and
aryl ester 1-OPh. Heating TMS-morpholine with 1-Cl or 1-F
at 100 °C for 1 h resulted in undesired acyl transfer to afford
amide 3 in high yield (Figure 2A, [M] = TMS). In contrast,
the less electrophilic 1-OPh showed <5% amide formation
under analogous conditions. Notably, as expected, the use of
While TMS-amines are straightforward to synthesize, their
commercial availability is limited. In addition, some derivatives
are susceptible to hydrolysis. Thus, the in situ formation of
these species from readily available amine starting materials
would significantly enhance the practicality of this method.
After some optimization, we identified the commercial silyl
transfer reagent N-methyl-N-(trimethylsilyl)trifluoroacetamide
(MSTFA) as effective for the rapid, room-temperature
conversion of diverse HNR2 to TMS-NR2. Indeed, the direct
addition of HNR2 and MSTFA to the standard coupling
conditions resulted in effective Ni-catalyzed decarbonylative
coupling (Figure 3B). Secondary dialkyl and diaryl N-
heterocycles13 such as morpholines (18), piperidines (21,
22), piperazines (23), pyrrolidines (24), indoles (25), and
carbazoles (26) underwent coupling in good to excellent yields
under these conditions. Furthermore, both primary aryl (28−
30) and alkyl amines (31−34) afforded secondary aryl amine
products in good yields. In the few cases where background
acyl transfer reactivity was observed (31−34), prestirring of
HNR2 with MSTFA for 1 h prior to catalysis resulted in
selective generation of the desired aryl amine.
Figure 2. (A) Uncatalyzed reaction of 1-X with morpholine and
TMS-morpholine at 100 °C for 1 h. (B) Ni-catalyzed reaction of 1-X
with TMS-morpholine at 150 °C for 24 h. Yields determined via 19F
NMR spectroscopy.
Traditional metal-catalyzed couplings between aryl electro-
philes and amines typically require stoichiometric quantities of
B
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Figure 3. Scope of Ni-catalyzed decarbonylative amination. (a) Using TMS-amine. (b) TMS−amine was generated in situ by premixing the amine
with MSTFA. (c) Using TES−indole or (d) TIPS-indole. (e) Reagents were weighed on benchtop. For additional substrates that were found to be
challenging under the optimized conditions, see the SI.
an exogenous inorganic base to promote metalation of the
amine coupling partner.14 This is a key limitation of the
Buchwald−Hartwig amination of aryl halides, and significant
recent effort has focused on identifying milder bases for these
C
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Figure 4. Mechanistic studies: stoichiometric reactions for the fundamental steps in decarbonylative amination. See the SI for details on reaction
conditions.
transformations.15 In contrast, the current method eliminates
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
■
the need for an exogenous base for C(sp2)−N coupling. As
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such, base-sensitive amine substrates16 are well tolerated and
https://pubs.acs.org/doi/10.1021/jacs.9b13531.
deliver aryl amine products (24, 33, 34) in good yields.
We then focused on eliminating the need for air-sensitive
Ni(cod)2 as the nickel source. These investigations revealed
that the use of Ni(CO)2(PPh3)2, an air-stable and commercial
reagent, as Ni(0) source affords aryl amine 28 in good yield
(Figure 3C). All of the catalysts and reagents were weighed on
the benchtop without the requirement of an inert glovebox.
Finally, we conducted stoichiometric studies to interrogate
the proposed reaction mechanism. The reaction of phenyl ester
8-OPh with Ni(cod)2/dcype in toluene at 80 °C for 3 h
resulted in oxidative addition/carbonyl deinsertion to afford
(dcype)Ni(Ph)(OPh) (B) in 60% yield (Figure 4A).17 A NiII
acyl intermediate (A in Figure 1C) was not detected by 31P
NMR spectroscopy during this reaction, suggesting that
carbonyl deinsertion is fast under these conditions. Notably,
reactions performed at 60 °C or lower did not afford
observable conversion of 8-OPh due to slow oxidative
addition. The treatment of B with TMS−indole in toluene at
room temperature for 1 h resulted in transmetalation to form
NiII complex C in quantitative yield (Figure 4B). Complex C is
stable and isolable at room temperature. Aryl C(sp2)−N bond-
forming reductive elimination was only observed upon heating
at 120 °C, which afforded aryl amine product 35 in 65% yield
after 16 h. These studies show the feasibility of each proposed
step of the proposed catalytic cycle. Furthermore, they
demonstrate that in this stoichiometric system, C(sp2)−N
bond formation is the most challenging step of the sequence.
In conclusion, we developed a Ni-catalyzed decarbonylative
conversion of esters to aryl amines. The generality, selectivity,
and base-free nature of this transformation render it
complementary to existing Pd/Ni-catalyzed methods for the
construction of (hetero)aryl amines. Current limitations,
including low reactivity of electron rich and sterically hindered
aryl esters (see the SI), and the requirement of high
temperatures and catalyst loading, will be addressed by future
mechanistic and method development studies.
X-ray crystal structure file for complex B (CIF)
X-ray crystal structure file complex C (CIF)
Experimental details, characterization data, and NMR
spectra of compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Melanie S. Sanford − Department of Chemistry, University of
Michigan, Ann Arbor, Michigan 48109, United States;
orcid.org/0000-0001-9342-9436; Email: mssanfor@
umich.edu
Authors
Christian A. Malapit − Department of Chemistry, University of
Michigan, Ann Arbor, Michigan 48109, United States;
orcid.org/0000-0002-8471-4208
Margarida Borrell − Department of Chemistry, University of
Michigan, Ann Arbor, Michigan 48109, United States
Michael W. Milbauer − Department of Chemistry, University of
Michigan, Ann Arbor, Michigan 48109, United States;
orcid.org/0000-0003-4984-8179
Conor E. Brigham − Department of Chemistry, University of
Michigan, Ann Arbor, Michigan 48109, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.9b13531
Author Contributions
†These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge J. W. Kampf for X-ray crystallographic
analyses of compounds B and C. We acknowledge financial
support from NIH NIGMS (GM073836), the Danish National
Research Foundation (Carbon Dioxide Activation Center;
CADIAC), and the Spanish Ministry of Science (PhD grant to
M.B.; BES-2016-076349).
D
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(17) Complex B does not undergo C(sp2)−O bond-forming
reductive elimination even upon heating at 150 °C for 24 h. This is
consistent with the observation that diaryl ether side products are not
detected during catalysis.
F
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