Direct Catalytic Decarboxylative Amination of Aryl Acetic Acids

Article abstract of DOI:10.1002/anie.201912518

The decarboxylative coupling of a carboxylic acid with an amine nucleophile provides an alternative to the substitution of traditional organohalide coupling partners. Benzoic and alkynyl acids may be directly aminated by oxidative catalysis. In contrast, methods for intermolecular alkyl carboxylic acid to amine conversion, including amidate rearrangements and photoredox-promoted approaches, require stoichiometric activation of the acid unit to generate isocyanate or radical intermediates. Reported here is a process for the direct chemoselective decarboxylative amination of electron-poor arylacetates by oxidative Cu catalysis. The reaction proceeds at (or near) room temperature, uses native carboxylic acid starting materials, and is compatible with protic, electrophilic, and other potentially complicating functionality. Mechanistic studies support a pathway in which ionic decarboxylation of the acid generates a benzylic nucleophile which is aminated in a Chan–Evans–Lam-type process.

Full text of DOI:10.1002/anie.201912518

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Direct Catalytic Decarboxylative Amination of Aryl Acetic Acids
Authors: Duanyang Kong, Patrick Moon, Odey Bsharat, and Rylan J.
Lundgren
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201912518
Angew. Chem. 10.1002/ange.201912518
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10.1002/anie.201912518
Angewandte Chemie International Edition
RESEARCH ARTICLE
Direct Catalytic Decarboxylative Amination of Aryl Acetic Acids
Duanyang Kong, Patrick J. Moon, Odey Bsharat, and Rylan J. Lundgren*[a]
C(sp2)–N units in arylquinazolines,[9] or intramolecular
Abstract: The decarboxylative coupling of a carboxylic acid with an
amine nucleophile provides an alternative to the substitution of
traditional organohalide coupling partners. Benzoic and alkynyl acids
may be directly aminated via oxidative catalysis. By contrast, methods
for intermolecular alkyl carboxylic acid to amine conversion, including
amidate rearrangements and photoredox-promoted approaches,
require stoichiometric activation of the acid unit to generate
isocyanate or radical intermediates. We report a process for the direct
chemoselective decarboxylative amination of electron-poor
arylacetates via oxidative Cu catalysis. The reaction proceeds at (or
near) room temperature, uses native carboxylic acid starting materials,
and is compatible with protic, electrophilic, and other potentially
complicating functionality. Mechanistic studies support a pathway in
decarboxylative aminations that require picolyl amine directing
groups.[10] Existing methods for intermolecular decarboxylative
cross-coupling of carboxylic acids and NH-nucleophiles to
generate C(sp3)–N bonds require stoichiometric activation of the
acid. These approaches include Curtius-type rearrangements[11]
and photoredox-mediated coupling of N-hydroxyphthalimide
esters[12] and iodonium carboxylates[13] (Figure 1B). The
isocyanate
intermediates
generated
in
Curtius-type
rearrangements[11a] may be incompatible with nucleophilic
functional groups, and photoredox-mediated processes are
limited to weakly nucleophilic substrates like imides,[12a]
anilines,[12b, 13a] sulfonamides,[13] and select N-heterocycles.[13a]
which ionic decarboxylation of the acid generates
a benzylic
We have described a family of reactions that use electron-
poor arylacetates as benzylic nucleophile surrogates in transition
metal catalyzed cross-couplings.[14] Compared to the use
organometallic benzylating reagents, these reactions enable
coupling under mild conditions while tolerating functional groups
that would be incompatible with highly basic species. We became
interested in expanding this approach to the development of a
Chan-Evans-Lam type decarboxylative coupling of unmodified
C(sp3)-carboxylic acids with alkyl amine partners (Figure 2A).[15]
This process would complement existing Cu-catalyzed oxidative
coupling reactions of alkyl boronic acid derivatives with anilines or
amides that use peroxide-based oxidants[16] or decarboxylative
halogenation/substitution procedures of b-carboxy acids.[17]
nucleophile which is aminated in a Chan-Evans-Lam type process.
Introduction
Carboxylic acids are a widely available, structurally diverse
class of molecules. The decarboxylative conversion of acids into
other functional groups is a valuable approach in synthetic
chemistry.[1] Owing to the importance of amines in a range of
applied fields, effort has been placed on realizing decarboxylative
amination processes[2] that complement C–N bond forming
reactions such as substitutions of organohalides[3] and activated
alcohols[3] and reductive amination of carbonyls.[4]
Our mechanistic hypothesis was based on the established
individual elementary steps similar to the Chan-Evans-Lam
reaction (Figure 2B).[5b, 5c] The key step involves the generation of
a benzyl anion by ionic decarboxylation.[14] The capture of this
species by a Cu-catalyst could form a Cu(amido)(benzyl) complex
Cu-catalyzed direct oxidative amination under conditions
similar to that of the Chan-Evans-Lam reaction[5] has been
established for both C(sp)- and C(sp2)-carboxylates.[6] These
processes are complementary to substitution of alkynyl and aryl
(pseudo)halide electrophiles.[7] Electron-poor benzoic acids
undergo decarboxylation and coupling with several classes of
nitrogen nucleophiles at elevated temperatures (140–170 °C)
A Decarboxylative Chan-Evans-Lam Reaction of C(sp2)- or C(sp)-Carboxylates
6b]
(Figure 1A). Both weakly nucleophilic NH-partners[6a,
and
R
[Cu], +/– [Pd]
CO2K
R
N
simple alkyl amines have been demonstrated; however simple
alkyl amines require dual Pd/Cu catalysis.[6c] Cu-catalyzed C(sp)–
N decarboxylative alkynylation has been limited to weakly
nucleophilic NH partners (carbamates, lactams, indoles,
sulfoximines).[8]
For C(sp3)-carboxylate amination, reports are limited to
decarboxylative condensation processes that ultimately generate
N
Ar
R'
Ar
H
R'
[O]
140–170 ºC
B
Photoredox Mediated Decarboxylative Amination of C(sp3)-Esters
O
O
R
N
O
R''
N
R''
N
[cat], hv
O
R'
R
or
R''
H
R''
room temperature
OR
I
R'
O
R
[a]
Dr. D. Kong, Dr P. M. Moon, O. Bsharat, Prof. R. J. Lundgren
Department of Chemistry
O
Ar
R'
University of Alberta
Edmonton, Alberta, T6G 2G2, Canada
E-mail: rylan.lundgren@ualberta.ca
Figure 1. Methods for the catalytic intermolecular amination of carboxylic acid
derived groups to form C(sp3)–N bonds.
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201912518
Angewandte Chemie International Edition
RESEARCH ARTICLE
conditions to give the benzylic amine product 2 in 92% yield
(Figure 3A). The free acid could be used instead of the K-
carboxylate by adding K2CO3 with no change in efficiency (94%
yield). Ambient air is a suitable oxidant (50% yield of 2); however,
MnO2 resulted in higher yield and is inexpensive (~$0.10/g). Use
of pure O2 atmosphere provided effectively no product. Peroxide,
persulfate, or other metal-based oxidants were less productive.
Pd-, Ni-, Co-, and Fe-based catalysts afforded non-zero yields but
were inferior to a range of simple Cu-salts such as CuI, Cu(OAc)2,
Cu(OTf)2.[18] Amination under halide-free conditions rule out a
halogenation/substitution pathway. The reaction proceeds best in
polar, aprotic solvents, the use of DMSO, DMA, or NMP also
resulted in good yields of 2 (61–83%). In cases where product
yields are modest, the remaining mass balance is largely
protodecarboxylated material.
A Direct Decarboxylative Amination by Oxidative Catalysis [This Work]
R''
carbon nucleophile
N
H
R''
R''
N
O
base
[cat]
oxidant
Ar
Ar
Ar
OH
R''
R
R
R
direct coupling of carboxylate
chemoselective alkylation of basic amines
R
H2N
NaN3
R
HN
HN
R
B Mechanistic Framework
HN
Cu
CuX2
X– + [O]
CuIX
HX
N
X
Ar
N
Ar
CO2K
The mild decarboxylative amination conditions and efficient
reactivity enable exceptional chemoselectivity, which was rapidly
evaluated by a functional group compatibility screen (see SI for
complete details).[18] Protic nucleophiles including NH-
heterocycles, anilines, NH-amides, sulfonamides, phenols,
R
R
CO2 + KX
N
X
N
Cu
R
Cu
Ar
ionic decarboxylation
generates nucleophile
Chan–Lam
redox pathway
Ar
R
A Reaction Development: Variation of Key Reaction Parameters
[O]
+
X–
O
C High-Value Alkylated Benzylic Amine Targets
30% CuI
N
OK
HN
Me
5 equiv. MnO2
30 oC, DMF
standard conditions
N
NO2
NO2
AcHN
AMG 628
O
H
N
H
N
N
NMe
N
N
Me
Me
S
N
N
N
O
F
1
2
Me
Imatinib
Ph
N
N
deviation from std.
conv. 1 (%) 2 (%)
catalyst system
conv. 1 (%) 2 (%)
N
N
N
O
NHOH
NEt
Panobinostat
N
N
NH
none
>99
>99
>99
80
92
94
50
<2
Cu(OAc)2
Cu(OTf)2
Pd(OAc)2
>99
>99
>99
91
92
HN
Me
O
acid + 1 equiv. K2CO3
air instead of MnO2
O2 instead of MnO2
N
Me
40
<15
F
H2N
NH2
NiI2, CoI2, or Fe(OAc)2 63–99
Me
NH
F
O
N
OMe
OH
Me
Eluxadoline
Abemaciclib
N
B
Selective Alkylation of Complex Targets
N
H
Me
O
Me
Me
F
HO2C
Et
Cl
Ar
Et
Figure 2. Overview of the process developed, mechanistic hypothesis, and
molecules that contain alkylated benzylic amine units.
Me
N
F
30% CuI
MnO2
N
N
Cl
Cl
O
Ar
Me
N
H2N
N
N
NH
Cl
O
which could undergo disproportionation to Cu(III) and subsequent
reductive elimination to generate a benzylic amine product.[5],[16b]
A terminal oxidant would regenerate active Cu(II) species.[5]
Given the mild reaction conditions and exceptional functional
group compatibility of mechanistically related Cu-catalyzed
C(sp2)–N oxidative aminations of aryl boron nucleophiles, a
process following this path should have the opportunity to share
similar characteristics and potentially be of value in generating
polyfunctionalized benzylic amines (Figure 2C).
3 direct oxidative amination
57% yield
[Ru], [Cu]
blue led
H2N
N
photoredox amination
<5% yield
(NHPI)O2C Cy
HO2C
Et
N
Ar
N
H
N
N
30% CuI
MnO2
Et
N
Ar
N
H
N
4 direct oxidative amination
54% yield
NH
[Ir], [Cu]
blue led
5 photoredox amination
14% yield (indazole N-alkylation)
Results and Discussion
MesI O2C
Cy 2
We selected piperidine as a target amine nucleophile for
catalytic oxidative benzylation due to the inability of established
photoredox methods to engage this class of substrate.[17]
Figure 3. Key reaction parameters and application in chemoselective amine
alkylation. Conversions and yields determined by calibrated 1H NMR
spectroscopy using an internal standard. Ar = 2-NO2C6H4. See the SI for
complete details.
Carboxylate
1 underwent direct decarboxylative amination
promoted by CuI/MnO2 mixtures under operationally simple
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10.1002/anie.201912518
Angewandte Chemie International Edition
RESEARCH ARTICLE
alcohols and other carboxylic acids were tolerated, with the
by simple nitro-group functionalizations. Conversion to anilines
(50, 51) and further modifications by facile aromatic substitution
gives access to products of arene deamination (52), iodination
(53), hydroxylation (54) or Heck cross-coupling (55) in overall
yields of 52–76%.
standard reaction giving >75% of product
2 and <20%
consumption of the additive in competition studies. Despite the
likelihood of a benzylic nucleophile being generated as an
intermediate (see below), electrophilic groups are preserved,
including alkyl and aryl halides, boron Lewis acids, aldehydes,
and Michael acceptors.[17b]
The scope and functional group compatibility studies
described above illustrate strengths and limitations of
a
The chemoselectivity of the decarboxylative amination was
demonstrated in the late-stage benzylation of complex targets
(Figure 3B). Under the standard conditions the alkylation of
Crizotinib occurs exclusively at the piperidyl NH over the
aminopyridine unit (3, 57% yield). Benzylation of an
aminoindazole substrate occurs exclusively at the secondary
amine position to generate 4 (54% yield). Photoredox methods
fail to deliver reasonable yields of decarboxylative alkylation
products under the host of conditions examined and when C–N
bond formation does occur it is predominantly at the less
nucleophilic NH position.[18c]
decarboxylative Chan-Evans-Lam approach to C(sp3)-amination.
In comparison to substitution reactions of alkyl halides or
reductive aminations of carbonyls, two of the top ten most used
reactions in medicinal chemistry,[20] the decarboxylative process
is currently restricted to coupling electron-poor arylacetates and
alkyl amines. Our standard conditions enable C–N bond formation
in the presence of typically reactive alkyl halide, ketone, and
aldehyde functional groups. Arylacetates can be constructed
using arene substrates via alkylation processes (SnAr, cross-
coupling, oxidative alkylation),[21] contrasting methods for benzylic
electrophile synthesis that involve C–H or benzyl alcohol
halogenation. In this light, while not a general solution for benzylic
amine synthesis, decarboxylative amination can serve as a
complementary strategy where high chemoselectivity for an alkyl
amine nucleophile is required.
Under the optimized conditions, a host of alkyl amine
nucleophiles and electron-poor aryl acetic acids can be
decarboxylatively cross-coupled (Figure 4). Both cyclic and
acyclic secondary amines in addition to primary amines undergo
benzylation in moderate to excellent yields (2, 6–25). Included are
examples of amines featuring unprotected alcohol groups (11, 21
24), various potentially reactive amide or aniline groups (12–14,
16), and electrophilic or potentially oxidizable groups (15, 18).
When primary amine substrates were used, bis-alkylation was not
observed enabling facile isolation of the alkylated products (22–
25). Marketed amine-containing drug molecules bearing sensitive
functionality including aryl fluorides and chlorides, functionalized
N- and S-heterocycles and a tetrasubstituted olefin could be
alkylated in good yields (Paroxetine, Debenzyldonepezil,
Desloratadine, Crizotinib, Fasudil, and Duloxetine; 3, 26–30). In
some cases, the addition of Zn(OAc)2 was found to be useful to
suppress undesirable protodecarboxylation. The supporting
information section contains details on less successful N–H
partners (very bulky amines, anilines, amides; see Figure S5) and
reactions with C-, and S-based nucleophiles (malonates, aryl
sulfides, sulfinates; see Figure S6).
Showcasing the method’s potential utility in complex
molecule synthesis, the formal synthesis of a family of histone
deacetylase/bromodomain/extra-terminal protein (HDAC/BET)
inhibitors[22] was accomplished using a decarboxylative azidation
protocol (Figure 5). NaN3 could be used as an easily reducible
ammonia surrogate to access primary amines in high yield[20]
Decarboxylative azidation of 56 to form 57 was conducted on
gram scale (1 gram of product) in 92% yield. Target 57 contains
differentiated amino-precursor units that were chemoselectively
reduced and acylated to yield the key amino tetrahydroquinoline
pharmacophore. Azide reduction and carbamate installation,
acetal
deprotection,
and
one-pot
nitro-group
reduction/diastereoselective reductive amination afforded the
advanced intermediate of DUAL946 (58) in 61% yield over 4 steps.
In order to investigate the possibility of decarboxylation by
C–CO2 homolysis to generate a radical intermediate,[23] alkene
functionalized substrate 59 was subjected to the standard Cu-
catalyzed conditions. Only direct amination (60, 64% yield) and
protodecarboxylation (61, 27%) were observed. In contrast to
A diversity of electron-deficient aryl acetates proved suitable
partners for amination, including 4- and 2-nitro (31, 36), 4- and 2-
cyano (32, 37), 4-sulfonyl (33), 4-acetyl (34), and 4-pyridyl (35)
derivatives (Figure 4). Substituents on the aryl acetic acid partner
were well tolerated, including halogens (39, 43) or trifluoromethyl
groups (49) and electron-donating methoxy (40, 44, 45) or
dimethylamino (41) groups. Successful benzylation was achieved
using aryl acetic acids bearing other sensitive functionality such
as free or silyl-protected alcohols (38, 47), olefins, and acetals
(see below). The process is currently restricted to electronically
activated benzylic partners that form a stabilized anion; however,
a varied series of targets could be obtained in good overall yields
photoredox-mediated
pathways
involving
alkyl
radical
intermediates,[9],[10] no cyclized products were obtained (Figure
6A).
Mechanistic studies support a pathway in which the acid
substrate undergoes an ionic decarboxylation to generate a
carbanion intermediate. In the absence of Cu and oxidant, the
combination of protic additives piperidine or ethanol and
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10.1002/anie.201912518
Angewandte Chemie International Edition
RESEARCH ARTICLE
R1
N
O
30% CuI
Ar
R1
N
Ar
R2
OK
H
R2
5 equiv. MnO2
DMF
R
R
or acid + K2CO3
1.5–3 equiv.
A Amine scope [with aryl acetate 1]
X
CH2 2 85% [A]
HN
HN
O
HN
HN
HN
HN
O
N
O
HN
O
S
6 76% [A]
7 81% [A]a
NH
NH
S
OH
NH2
X
H
NBoc 8 84% [A]a
NMe 9 69% [A]
10
68% [A]
11
81% [A]
14
75% [B]
12
68% [A]
13
80% [A]a
15
62% [B]
H2N
Me
Me
23
OH
H2N
HN
Me
Me
20
X
R
HN
HN
H2N
HN
Me
H2N
Bn
OH
CH NH2 16 48% [A]
X
Me
N
N
H
17 73% [A]
CHO 18 53% [A]a
22
57% [A]a
19
81% [A]
21
54% [A]
24
54% [A]
25
57% [A]a
R
55% [A]a
52% [A]a
HN
Cl
N
O
O
HN
HN
S
O
NH2
N
N
HN
N
HN
O
O
O
HMeN
O
S
O
Me
Cl
Cl
N
N
OMe
F
OMe
26 63% (1:1 dr) [A]a
Paroxetine
28 87% [A]a
Desloratadine
3 57% (1:1 dr) [A]a
Crizotinib
29 72% [A]a
Fasudil
27 79% [A]a
Debenzyldonepezil
30 84% (1:1 dr) [B]
(S)-Duloxetine
F
B Aryl acetate scope [with piperidine unless stated]
O
O O
S
O2N
NC
NO2
CO2K
CN
N
Me
Me
CO2K
CO2K
CO2K
CO2K
CO2K
CO2K
31
47% [A]b
32
58% [A]c
33
64% [A]c
34
43% [A]c
35
53% [A]
36
62% [A]b
37
46% [A]c
O2N
F3C
O2N
OMe
CO2K
Me
R, R'
Cl, n-Pr
R, R'
H, (CH2)2OTBS
Br, n-Pr
43 67% [A]d
44 79% [A]a
45 74% [A]a,f
46 73% [A]
47 86% [A]
38 81% [A]a
39 72% [A]d
40 91% [A]
41 87% [A]
42 75% [A]d,e
NO2
CO2K
R
NO2
CO2K
CO2K
Me
OMe, n-Pr
OMe, n-Pr
H, Me
OMe, n-Pr
NMe2, n-Pr
CF3, Me
R
R'
48
88% [A]b
49
84% [A]b,e
R'
H, (CH2)2OH
OMe
I
HO
MeO2C
H2N
F3C
O
O
O
NBoc
N
N
N
N
N
Cl
N
Cl
Me
Me
Me
Me
Me
NH2
Me
50
67% [two steps]
51
76% [two steps]
52
63% [three steps]
53
52% [three steps]
54
60% [three steps]
55
63% [three steps]
Figure 4. Scope of direct decarboxylative amination of aryl acetic acids. Yields are of isolated material under the standard conditions from Figure 2. Condition [A]:
procedure with potassium aryl acetate, Condition [B]: Using aryl acetic acid and K2CO3, [a] 1.5 equiv. amine, 25 mol% Zn(OAc)2,1H NMR yield, [b] Cu(OAc)2 instead
of CuI, [c] CuBr2 instead of CuI, [d] 1 equiv. Zn(OAc)2, [e] 1:1 DCE/DMF, [f] Using 1-Boc-piperazine. See SI for experimental details and less successful examples.
O
O
H
N
CO2iPr
2. PPh3
3. ClCO2Pr
1. CuI, NaN3
MnO2
O
O
O
O
HN
HO
i
N
H
HN
N
OiPr
Me
Me
Me
5
Br
O
Br
Br
[ref 22]
CO2H
NO2
56 [1.1 g]
N3
NO2
57 92% [1.0 g]
4. HCl
5. CuCl, KBH4
N
H
Me
DUAL946
[GSK]
Ac
58 61% (6:1 dr) [4 steps]
Figure 5. Decarboxylative azidation and application toward the preparation of DUAL946 intermediate. See the supporting information for details and additional
scope examples using NaN3.
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10.1002/anie.201912518
Angewandte Chemie International Edition
RESEARCH ARTICLE
A Probing Reactive Intermediate with Alkene-Tethered Substrate
A
Alternative Substrates as Mechanistic Probes
HN
HN
standard
Ar
N
Ar
N
Ar
H
conditions
CO2K
Ar
N
CO2K
63
standard conditions
<2%
NO2
59
60 64%
61 27%
amination prior to decarboxylation unlikely: amino acid does not decarboxylate
direct coupling
direct protonation
B Impact of Additives on Protodecarboxylation
HN
Ar
i. impact of protic additives
Ar
100
CO2Et
N
piperidine
EtOH
80
Et
CO2Et
<2%
standard conditions
62
Et
64
60
40
20
additive
H
CO2K
Me
acid is required for amination: aryl acetic ester does not undergo amination
no additive
NO2
NO2
EtOH + 30% Cu(OTf)2
rt, DMF
Me
0
0
62
1
HN
2
4
6
Ar
Ar
N
Time,(h)
ii. impact of additives in the presence of oxidant
100
Cs2CO3
standard conditions
Me
Me
66, 11%
piperidine
65
80
60
40
20
0
additive
oxidant
62
benzylic nucleophile generated by deprotonation forms product in low yield
Evidence of Chan-Evans-Lam Type Redox Pathway
no additive
(MnO2•H2O)
H
CO2K
Me
B
30% CuI
NO2
NO2
rt, DMF
30% Cu(OTf)2
Me
62
1
HN
Ar
0
2
4
6
Ar
CO2K
Et
N
Time,(h)
cat. Cu(OAc)2
under N2 - no MnO2
Et
Figure 6. Mechanistic investigations into the nature of reactive intermediate
1
2
generated upon decarboxylation.
product generated without MnO2
consistent with two Cu(II) equiv.
required for one equiv. of product
carboxylate 1 in DMF resulted in only protodecarboxylation
product 62 (Figure 6B–i). The trapping of the putative nucleophilic
intermediate with aldehyde electrophiles is also possible under
the standard conditions in the absence of catalyst and oxidant.[18d]
Protodecarboxylation of 1 in the presence of ethanol (a non-
productive nucleophile) is suppressed when Cu(OTf)2 is added,
and 1 is largely recovered after quenching.
[O] in Fig 2B = Cu(II)
MnO2 oxidizes Cu(I) back to Cu(II)
under the standard conditions
When 1 and the terminal oxidant, partially hydrated MnO2,
were combined in DMF with piperidine or ethanol,
protodecarboxylation is the dominant pathway. The addition of
piperidine resulted in only ~10% of amination product product 2
and nearly 90% protonated product 62 (Figure 6B–ii). When CuI
or Cu(OTf)2 is added to a mixture of 1, ethanol, and hydrated
MnO2, protodecarboxylation is suppressed. These studies help
confirm MnO2 alone is not capable of productively oxidizing the
substrate or intermediates generated from it; instead the water
that accompanies activated MnO2 quenches the carbanion
without the presence of a Cu catalyst. Cu slows the rate of
decarboxylation, we speculate that ionic decarboxylation is driven
by the formation of a charge-separated ion pair in polar aprotic
solvents, which is in agreement with past observations.[14b]
Dimerization products are not observed under the standard
conditions and the control reactions described above, further
suggesting a benzylic radical is not generated in the process.[25]
Figure 7. A) Use of alternative substrates support mechanism in which aryl
acetate decarboxylation occurs prior to amination. B) Reaction stoichiometry in
Cu(II) reflects a Chan-Lam type disproportionation redox pathway. Ar = 2-NO2-
C6H4 or 4-NO2-C6H4. See the SI for complete details.
through subjecting alternative substrates and potential reaction
intermediates to the standard reaction conditions (Figure 7A).
Neither a-aryl amino acetate 63 nor a-aryl ester substrate 64
undergoes decarboxylation under the standard conditions to form
benzyl amine product. These observations rule out an oxidative
carbonyl a-amination pathway.[26] In the presence of Cs2CO3,
alkylated nitroarene 65 provides some benzylated amine product.
Decomposition of the putative benzyl nucleophile intermediate is
observed under these and an array of related basic conditions,
highlighting the importance of
a
controlled release of
organometallic species via decarboxylation to achieve efficient
cross-coupling. Finally, in the absence of additional oxidant,
various loadings of Cu(OAc)2 deliver product with less than 0.5
turnover number (Figure 7B). This observation is consistent with
Support for ionic decarboxylation of the acid substrate as
the first step in a Chan-Evans-Lam redox pathway was obtained
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10.1002/anie.201912518
Angewandte Chemie International Edition
RESEARCH ARTICLE
[8] a) W. Jia, N. Jiao, Org. Lett. 2010, 12, 2000-2003; b) D. L. Priebbenow,
P. Becker, C. Bolm, Org. Lett. 2013, 15, 6155-6157.
[9] Y. Yan, M. Shi, B. Niu, X. Meng, C. Zhu, G. Liu, T. Chen, Y. Liu, RSC
Adv. 2016, 6, 36192-36197.
two equivalents of Cu(II) being required to form one equivalent of
product, analogous to the Chan-Evans-Lam type redox
mechanism.
[10] Z.-J. Liu, X. Lu, G. Wang, L. Li, W.-T. Jiang, Y.-D. Wang, B. Xiao, Y.
Fu, J. Am. Chem. Soc. 2016, 138, 9714-9719.
[11] a) J. Aubé, C. Fehl, R. Liu, M. C. McLeod, H. F. Motiwala, in
Comprehensive Organic Synthesis II (2nd Ed) (Ed.: P. Knochel), Elsevier,
Amsterdam, 2014, pp. 598-635; b) A. K. Ghosh, M. Brindisi, A. Sarkar,
ChemMedChem 2018, 13, 2351-2373.
[12] a) W. Zhao, R. P. Wurz, J. C. Peters, G. C. Fu, J. Am. Chem. Soc.
2017, 139, 12153-12156; b) R. Mao, A. Frey, J. Balon, X. Hu, Nat. Catal.
2018, 1, 120-126.
[13] a) Y. Liang, X. Zhang, D. W. C. MacMillan, Nature 2018, 559, 83-88;
b) Y. Sakakibara, E. Ito, T. Fukushima, K. Murakami, K. Itami, Chem. Eur.
J. 2018, 24, 9254-9258; For other radical amination of benzylic radicals
see: c) Z. K Ni, Q. Zhang, T. Xiong, Y. Y. Zheng, Y. Li, H. W. Zhang, J. P.
Zhang, Q. Liu, Angew. Chem. Int. Ed. 2012, 51, 1244- 1247; d) S. Kramer,
Org. Lett. 2019, 21. 65-69; For an example of benzylic amination via
fluorosulfonamide reagents see: e) Z. X. Fang, Y. Feng, H. Dong, D. S. Li,
T. D. Tang, Chem. Commun. 2016, 52, 11120-11123.
[14] a) P. J. Moon, Z. Wei, R. J. Lundgren, J. Am. Chem. Soc. 2018, 140,
17418-17422; b) P. J. Moon, A. Fahandej-Sadi, W. Qian, R. J. Lundgren,
Angew. Chem. Int. Ed. 2018, 57, 4612-4616; c) D. Kong, P. J. Moon, W.
Qian, R. J. Lundgren, Chem. Commun. 2018, 54, 6835-6838; For earlier
reports: d) R. Shang, Z. W. Yang, Y. Wang, S. L. Zhang, L. Liu, J. Am.
Chem. Soc. 2010, 132, 14391-14393; e) R. Shang, Z. Huang, L. Chu, Y.
Fu, L. Liu, Org. Lett. 2011, 13, 4240-4243; f) Z. R. Xu, Q. Wang, J. P. Zhu,
Angew. Chem. Int. Ed. 2013, 52, 3272-3276.
Conclusion
In summary, chemoselective N-benzylation of alkyl amines
can be achieved directly from native carboxylic acids in the
presence of protic or electrophilic groups via oxidative Cu-
catalysis. Building on previous studies that use aryl or alkynyl
acids as substrates, an ionic decarboxylation pathway enables
the liberation of a benzylic nucleophile to allow for efficient
oxidative trapping with basic alkyl amines, including those found
in complex pharmaceuticals. The scope of reaction partners
complements radical decarboxylative amination approaches. The
benzylic amine products can be expediently diversified,
showcasing this method’s potential in complex molecule
synthesis. Efforts are underway to apply this concept in the
development of related chemoselective ionic decarboxylative
cross-coupling reactions.
[15] Z.-J. Liu, X. Lu, G. Wang, L. Li, W.-T. Jiang, Y.-D. Wang, B. Xiao, Y.
Fu, J. Am. Chem. Soc. 2016, 138, 9714-9719.
[16] a) S. Sueki, Y. Kuninobu, Org. Lett. 2013, 15, 1544-1547; b) S. A.
Rossi, K. W. Shimkin, Q. Xu, L. M. Mori-Quiroz, D. A. Watson, Org. Lett.
2013, 15, 2314-2317.
Acknowledgements
We acknowledge NSERC Canada and the Canadian Foundation
for Innovation for support. We are grateful to NSERC Canada
(Discovery, Discovery Accelerator, and Idea to Innovation Grants
to R.J.L., CGS-D Fellowship to P.J.M), the Killam Trusts (I.W.K.
Fellowship to P.J.M) and the Canadian Foundation for Innovation
for support of this work. Dr. Shoshana Bachman is acknowledged
for helpful discussions.
[17] a) J. Zhang, Y. Shao, Y. Wang, H. Li, D. Xu, X. Wan, Org. Biomol.
Chem. 2015, 13, 3982-3987; b) J. Zhang, J. Jiang, Y. Li, Y. Zhao, X. Wan,
Org. Lett. 2013, 15, 3222-3225.
[18] a) See Figure S1 in the supporting information for additional
optimization details; b) See Figures S2 and S3 in the supporting
information; c) See Figure S4 for a more detailed analysis of the NH-
functional group compatibility of photoredox-type decarboxylative
aminations; d) Benzaldehyde can be trapped in ~80% yield, see Figure S8
for details.
[19] K. D. Collins, F. Glorius, Nat. Chem. 2013, 5, 597.
[20] D. G. Brown, J. Boström, J. Med. Chem. 2016, 59, 4443-4458.
[21] Selected synthetic methods to generate aryl acetates: a) M. Makosza,
Chem. Eur. J. 2014, 20, 5536-5545; b) M. R. Biscoe, S. L. Buchwald, Org.
Lett. 2009, 11, 1773-1775; c) M. Jørgensen, S. Lee, X. Liu, J. P. Wolkowski,
J. F. Hartwig, J. Am. Chem. Soc. 2002, 124, 12557-12565; d) L. J. Gooßen,
Chem. Commun. 2001, 669-670; e) P. J. Moon, S. Yin, R. J. Lundgren, J.
Am. Chem. Soc. 2016, 138, 13826-13829; f) G. Wu, Y. Deng, C. Wu, Y.
Zhang, J. Wang, Angew. Chem. Int. Ed. 2014, 53, 10510-10514; g) A. T.
Londregan, K. Burford, E. L. Conn, K. D. Hesp, Org. Lett. 2014, 16, 3336-
3339.
Keywords: amination • decarboxylation • copper •
chemoselectivity • oxidative coupling
[1] a) T. Qin, J. Cornella, C. Li, L. R. Malins, J. T. Edwards, S. Kawamura,
B. D. Maxwell, M. D. Eastgate, P. S. Baran, Science 2016, 352, 801; b) T.
Patra, D. Maiti, Chem. Eur. J. 2017, 23, 7382-7401; c) J. Schwarz, B.
König, Green Chem. 2018, 20, 323-361.
[2] S. Arshadi, S. Ebrahimiasl, A. Hosseinian, A. Monfared, E. Vessally,
RSC Adv. 2019, 9, 8964-8976.
[22] S. J. Atkinson, P. E. Soden, D. C. Angell, M. Bantscheff, C. W. Chung,
K. A. Giblin, N. Smithers, R. C. Furze, L. Gordon, G. Drewes, I. Rioja, J.
Witherington, N. J. Parr, R. K. Prinjha, Medchemcomm 2014, 5, 342-351.
[23] a) E. Nyfeler, P. Renaud, Org. Lett. 2008, 10, 985-988; b) C. Liu, X.
Wang, Z. Li, L. Cui, C. Li, J. Am. Chem. Soc. 2015, 137, 9820-9823; c) Y.
Zhu, X. Li, X. Wang, X. Huang, T. Shen, Y. Zhang, X. Sun, M. Zou, S.
Song, N. Jiao, Org. Lett. 2015, 17, 4702-4705.
[3] C. C. Marvin, in Comprehensive Organic Synthesis II (Second Edition)
(Ed.: P. Knochel), Elsevier, Amsterdam, 2014, pp. 34-99.
[4] A. F. Abdel-Magid, S. J. Mehrman, Org. Proc. Res. Dev. 2006, 10, 971-
1031.
[5] a) J. X. Qiao, P. Y. S. Lam, in Boronic Acids, Wiley-VCH Verlag GmbH
& Co. KGaA, 2011, pp. 315-361; b) P. Y. S. Lam, in Synthetic Methods in
Drug Discovery, Vol 1, Vol. 52 (Eds.: D. Blakemore, P. Doyle, Y. Fobian),
2016, pp. 242-383; c) A. E. King, B. L. Ryland, T. C. Brunold, S. S. Stahl,
Organometallics 2012, 31, 7948-7957.
[24] L. Capaldo, L. Buzzetti, D. Merli, M. Fagnoni, D. Ravelli, J. Org. Chem.
2016, 81, 7102-7109.
[25] Benzyl radicals are established to dimerize in the absence of trapping
substrate, for a recent example see: a) D. W. Manley, J. C. Walton, Org.
Lett. 2014, 16, 5394-5397; For the decarboxylative benzylation of
aldehydes using aryl acetic acids and proceeding through a benzylic anion,
see: b) K. Donabauer, M. Maity, A. L. Berger, G. S. Huff, S. Crespi, B.
König, B. Chem. Sci. 2019 10, 5162-5166.
[6] a) Y. Zhang, S. Patel, N. Mainolfi, Chem. Sci. 2012, 3, 3196-3199; b)
W. J. Sheng, Q. Ye, W. B. Yu, R. R. Liu, M. Xu, J. R. Gao, Y. X. Jia,
Tetrahedron Lett. 2015, 56, 599-601; c) M. P. Drapeau, J. Bahri, D. Lichte,
L. J. Goossen, Angew. Chem. Int. Ed. 2019, 58, 892-896; d) P. Ruiz-
Castillo, S. L. Buchwald, Chem. Rev. 2016, 116, 12564-12649; e) S.
Bhunia, G. G. Pawar, S. V. Kumar, Y. Jiang, D. Ma, Angew. Chem. Int. Ed.
2017, 56, 16136-16179.
[7] a) P. Ruiz-Castillo, S. L. Buchwald, Chem. Rev. 2016, 116, 12564-
12649; b) J. Bariwal, E. Van der Eycken, Chem. Soc. Rev. 2013, 42, 9283-
9303.
[26] R. W. Evans, J. R. Zbieg, S. L. Zhu, W. Li, D. W. C. MacMillan, J. Am.
Chem. Soc. 2013, 135, 16074-16077.
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10.1002/anie.201912518
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RESEARCH ARTICLE
Entry for the Table of
Contents
RESEARCH ARTICLE
Duanyang Kong, Patrick J. Moon, Odey
Bsharat, and Rylan J. Lundgren*
R''
N
H
R''
R''
N
base
[Cu]
MnO2
chemoselective alkylation of basic amines
Ar
Ar
Ar
CO2H
Page No. – Page No.
R''
R
R
R
Direct Catalytic Decarboxylative
Amination of Aryl Acetic Acids
direct coupling of carboxylate
The direct, chemoselective amination of aryl acetic acids is reported. The process
enables late-stage alkylation of drug targets without interference from other protic
groups or electrophiles. Mechanistic studies support the generation of a benzylic
nucleophile which is aminated in Chan-Lam type redox pathway.
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