Nickel-Catalyzed Deaminative Acylation of Activated Aliphatic Amines with Aromatic Amides via C-N Bond Activation

Article abstract of DOI:10.1021/acs.orglett.9b04497

Deaminative functionalization of aliphatic primary amines has great synthetic utility. Herein, we describe a Ni-catalyzed reductive deaminative cross-electrophile coupling reaction between Katritzky salts and aromatic amides. This work provides examples of the synthesis of various ketones from alkylpyridinium salts, including both primary and secondary alkylamines. Given its mild reaction conditions and high functional group tolerance, this cross-coupling strategy is expected to be useful for late-stage functionalization of complex compounds.

Full text of DOI:10.1021/acs.orglett.9b04497

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Letter
Nickel-Catalyzed Deaminative Acylation of Activated Aliphatic
Amines with Aromatic Amides via C−N Bond Activation
Chu-Guo Yu and Yutaka Matsuo*
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ABSTRACT: Deaminative functionalization of aliphatic primary amines has great synthetic utility. Herein, we describe a Ni-
catalyzed reductive deaminative cross-electrophile coupling reaction between Katritzky salts and aromatic amides. This work
provides examples of the synthesis of various ketones from alkylpyridinium salts, including both primary and secondary alkylamines.
Given its mild reaction conditions and high functional group tolerance, this cross-coupling strategy is expected to be useful for late-
stage functionalization of complex compounds.
liphatic primary amines are a feedstock with high natural
with nucleophilic reagents to realize deaminative functionaliza-
Aabundance. They are also prevalent in many biologically tion. However, there have been few reports of cross-
electrophile coupling transformations using amines as alkyl
electrophile precursors. Very recently, one example of cross-
electrophile coupling was achieved between Katritzky salts and
halides (Scheme 1 B).7b,c,14 However, the scope of these
reactions remains limited and the pursuit of various electro-
philic counterparts for use in reductive cross-electrophile
coupling is necessary for deaminative functionalization of
amines.
Amides play a key role in various areas of chemistry given
their ubiquitous nature in proteins, polymers, and pharma-
ceuticals.15 C−N bond cleavage remains a challenge in cross-
coupling reactions due to the low reactivity of amides due to
amidic resonance.15a,16 In 2015, a mere handful of examples
about activation of carbonyl C−N bonds were first reported.17
Recently, transition-metal-catalyzed activation of carbonyl C−
N bonds through a wide range of straightforward methods to
generate acyl−metal intermediates through insertion of a metal
into the amide bonds has become a thriving area in cross-
active natural products, synthetic intermediates, and drug
molecules.1 The use of inexpensive, readily available, and
abundant primary alkyl amines has the advantage of avoiding
the use of halogenated hydrocarbons. Activation/functionaliza-
tion of C−N bonds in amines has been used for C−C and C−
X bond formation.2 Notably, Watson and co-workers showed
that Katritzky salts (2,4,6-triphenylpyridinium salts) can be
used as alkyl radical precursors in Suzuki−Miyaura cross-
coupling reactions (Scheme 1 A).3 These redox-active species
are prepared via a straightforward, chromatography-free
process involving condensation of unactivated primary amines
with a bench-stable, commercially available pyrylium salt.4 In
addition, Glorius et al. demonstrated that Katritzky salts can be
used as alkyl halide surrogates to generate alkyl radicals in
Minisci reactions under visible-light-induced photoredox
conditions (Scheme 1A).5 These exciting seminal reports
have drawn much attention from organic chemists for the use
of primary amines as radical precursors. Recent studies have
demonstrated the great potential of Katritzky salts as radical
precursors in deaminative functionalization, including boryla-
tion,6 alkynylation/alkenylation,7 arylation,8 alkyl-Heck-type
reactions,9 allylation,10 alkylation,11 carbonylation,9b,12 and C-
heteroatom bond-forming reactions13 (Scheme 1 A). In these
examples, the Katritzky salts serve as electrophiles that react
Received: December 16, 2019
https://dx.doi.org/10.1021/acs.orglett.9b04497
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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a
Scheme 1. Aliphatic Amines for Ketone Synthesis in
Reductive Cross-Coupling
Table 1. Optimization of the Reaction Conditions
b
entry
modification from standard conditions
yield (%)
1
2
3
4
5
6
7
8
none
78 (72)
67
56
0
70
43
trace
55
16
45
66
40
trace
trace
0
NiCl2·DME instead of NiBr2·DME
Ni(COD)2 instead of NiBr2·DME
2a′ instead of 2a
L1 instead of 1,10-phen
L2 instead of 1,10-phen
L3 instead of 1,10-phen
L4 instead of 1,10-phen
L5 instead of 1,10-phen
Zn instead of Mn
DMA instead of NMP
DMF instead of NMP
THF instead of NMP
dioxane instead of NMP
no Mn or no Ni/1,10-phen
no MgCl2
9
10
11
12
13
14
15
16
coupling reactions of amides.18 Selective C−N bond cleavage
has been developed into a powerful transformations for the
synthesis of ketones and esters by Garg,19 Zou,20 Szostak,21
Rueping,22 and others.23 However, the use of amides as
electrophilic precursors remains limited,24 especially in
reductive cross-coupling reactions, which is one of the most
active areas of research.25 In this letter, we report the first
nickel-catalyzed deaminative acylation of activated aliphatic
amines with aromatic amides via acyl C−N bond activation by
insertion of nickel into the bond (Scheme 1C).
68
a
Reaction conditions: Katritzky salts 1a (1.2 equiv), 2a (0.2 mmol),
NiBr2·DME (10 mol %), 1,10-phen (10 mol %), Mn0 (2.0 equiv),
MgCl2 (1.0 equiv), in 2.0 mL of NMP at 60 °C for 12 h under Ar
atmosphere. Yield determined by GC using benzophenone as an
internal standard. Isolated yield in parentheses. See the Supporting
Information for details.
b
We hypothesized that the acyl−nickel intermediates would
be oxidized by alkyl radical generated from the pyridinium salt
via single-electron transfer (SET),14a−c followed by generation
of ketone as a reduction product. To investigate reductive
cross-coupling reactions between aliphatic amines and
aromatic amides, we began with Katritzky salt 1a and activated
amide 2a. N-Acylsuccinimides 2a with high reactivity results
from the moderate twist and electronic activation of the amide
bond (twist = approximately 70°, resonance energy = close to
0 kcal/mol) according to the literature.16b After evaluating
various reaction parameters, we obtained the desired product
in an acceptable yield with 10 mol % NiBr2·DME as catalyst,
10 mol % 1,10-phenanthroline (1,10-phen) as a bidentate
nitrogen ligand, and 2.0 equiv Mn0 as a reducing agent at 60
°C under argon atmosphere (entry 1, in Table 1). In the
process of optimizing the reaction conditions, we found that
when NiCl2·DME or Ni(COD)2 was used as the catalyst, the
yield decreased slightly (entries 2 and 3). Selecting amide 2a′
instead of 2a, we observed no formation of the desired
product, with recovery of starting material 2a′ (entry 4). The
cleavage of C−N bond of amides is difficult due to amidic
resonance,16,17 so the recovery of starting material 2a′ under
these standard conditions is acceptable. To examine the effects
of different ligands, we used various nitrogen ligands instead of
1,10-phen (entries 5−9). The results show that suitable
electron density on the ligand was crucial for the coupling
reaction. When zinc was used as the reducing reagent, the yield
decreased markedly to 45% (entry 10). This result well
supports our presumption that a reductive metal species is
important for this transformation. The choice of the solvent
markedly influenced the reaction outcome (entries 11−14),
which is very common in cross-coupling reactions. Control
experiments indicated that NiBr2·DME, ligand, and Mn0 are
essential (entry 15) and that MgCl2 has a beneficial effect on
the reaction (entry 16).
Under the optimized reaction conditions, we turned our
attention to exploring the substrate scope of this reductive
deaminative acylation with various activated aliphatic amines
and aromatic amides (Scheme 2). Various substituted aromatic
amides underwent coupling in fair to good yield (3−10).
Electron-rich aromatic amides (4, 6, and 7) could be used as
substrates, but the presence of a mildly electron-withdrawing
substituent (5) resulted in decreased yield. Disappointingly,
reactions with aromatic amides bearing strong electron-
withdrawing groups (−COOMe, −CF3) failed to give the
desired ketone products. It is worth noting that a nitrogen-
containing heteroaryl amide (8) reacted to give the ketone
product in moderate yield. An acylamino substituent (9), a
protic functional group, was also a compatible structural motif.
The reductive cross-coupling with naphthamide (10)
successful generated a product that was easily detectable
under a UV lamp.
A variety of functional groups in the Katritzky salt were
tolerated. Alkyl pyridinium salts bearing an additional handle
for further modification via Suzuki coupling, such as an aryl
chloride (11), reacted to give the desired product in good
yield. The substrate prepared from the dopamine derivative 2-
(benzo[d][1,3]dioxol-5-yl)ethan-1-amine (12) smoothly
B
https://dx.doi.org/10.1021/acs.orglett.9b04497
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Letter
pyridinium salts (21, 22, and 23) could be used in this
protocol, though the yields were around 50%.
Scheme 2. Scope of Aryl/Heteroaryl Amides and Alkyl
Pyridinium Salts
a
Furthermore, to examine the applicability of our developed
protocol in late-stage functionalization, a series of Katritzky
salts were synthesized from natural products and pharmaceut-
ical intermediates. Gratifyingly, the acylation was successful
with these druglike substrates (24−30). For example, Katritzky
salts derived from amino acids (24, 25) reacted smoothly.
Also, acylation of the pyridinium salt of the antiarrhythmic
drug mexiletine (26) was effective. Amine intermediates used
for synthesizing the lipid-lowering drug atorvastatin (Lipitor,
27) and the gastrokientic agent mosapride (28) also coupled
well.3,11c Other biologically active derivatives from leelamine
(29) and primaquine (30) could be transformed to the desired
deaminative acylated products in fair yield.
To gain insight into the mechanism of this transformation, a
series of mechanistic experiments were conducted (Scheme 3).
Scheme 3. Mechanistic Experiments
We observed ring-opened product 31 in 46% yield when
cyclopropylmethylpyridinium 1v was used. Also, when the
radical scavenger TEMPO [(2,2,6,6-tetramethylpiperidin-1-
yl)oxyl] was added to the reaction system, the acylation was
completely inhibited, with no product 3 being detected and the
TEMPO-trapped adduct 33 being formed. These results
suggest that this reaction likely proceeds via a radical
mechanism.
Based on the literature on the nickel-catalyzed reductive
cross-coupling of Katritzky salts and amides with aryl
halides,14,24 we propose a plausible mechanism (Scheme 4).
Initially, the active Ni(0) catalyst, which is formed via
reduction of Ni(II) salt by Mn0, undergoes oxidative addition
Scheme 4. Proposed Mechanism
a
As Table 1 (entry 1), 0.20 mmol scale, 60 °C, 12 h. Yields after
b
purification. Gram scale reaction (in 2 mmol), see the SI for details.
underwent the transformation. Importantly, this reaction
process was shown to be suitable for obtaining products
bearing various functional groups, such as alkenyl (13),
electron-rich 2-thienyl (15), basic 2-pyridyl (16), and protic
groups (indole 17, unprotected sulfamine 18). A Katritzky salt
with a β-electron-withdrawing group was effective (14).
Moreover, saturated heterocycles such as piperazine (19),
pyrrolidine (20), piperidine (23), and ketal (27) were also
tolerated. It is noteworthy that secondary alkyl-substituted
C
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12045. (b) Kong, D.; Moon, P. J.; Lundgren, R. J. Radical Coupling
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Ni(II) intermediate E by pyridinium salts via SET.3 This
Ni(II) intermediate E can be reduced by Mn0 to regenerate the
active Ni(0) catalyst used in the next catalytic cycle.
In summary, we developed a new Ni-catalyzed cross-
electrophile coupling reaction between amides and alkyl
amine−derived alkylpyridinium salts. Considering the avail-
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to use primary and secondary alkylpyridinium salts, this
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diverse ketones. In addition, the reaction tolerated a broad
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groups and derivatives of bioactive molecules. Further studies
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04497.
Experimental procedures and 1H and 13C NMR spectral
data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Yutaka Matsuo − University of Science and Technology of
China, Hefei, China, and Nagoya University, Nagoya,
Japan; orcid.org/0000-0001-9084-9670;
Email: matsuo@ustc.edu.cn
Other Author
Chu-Guo Yu − University of Science and Technology of
China, Hefei, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.9b04497
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the high-level human resource
funding in University of Science and Technology of China and
Strategic International Research Cooperative Program (SI-
CORP, Grant Number JPMJSC18H1), Japan Science and
Technology Agency (JST).
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