Decarboxylative ipso Amination of Activated Benzoic Acids

Article abstract of DOI:10.1002/anie.201812068

In the presence of a bimetallic Pd/Cu system with 1,10-phenanthroline as the ligand and either air or N-methylmorpholine N-oxide as the oxidant, electron-deficient benzoic acids undergo oxidative decarboxylative coupling with unprotected amines. This operationally simple aniline synthesis is widely applicable with respect to the amine and gives good yields, even on multigram scale. The orthogonality of this reaction to other Pd-catalyzed cross-couplings allows the concise synthesis of multisubstituted arenes by sequential C?C, C?Cl, and C?N functionalizations. Mechanistic investigations suggest the intermediacy of a hypervalent Pd species.

Full text of DOI:10.1002/anie.201812068

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Accepted Article
Title: Decarboxylative ipso-Amination of Activated Benzoic Acids
Authors: Martin Pichette Drapeau, Janet Bahri, Dominik Lichte, and
Lukas J Goossen
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10.1002/anie.201812068
Angewandte Chemie International Edition
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Decarboxylative ipso-Amination of Activated Benzoic Acids
Martin Pichette Drapeau, Janet Bahri,1 Dominik Lichte,1 and Lukas J. Gooßen*
decarboxylative couplings allow regiospecific C–C bond
formation, such as the synthesis of biaryls[10] or aryl ketones[11]
from aryl halides. Oxidative decarboxylative CH arylations
mostly call for stoichiometric amounts of metal salts such as
silver,[12] but protocols catalytic in metal have recently started to
emerge,[13] O2 being used as terminal oxidant in one instance.[14]
Decarboxylative C(sp2)heteroatom bond-forming reactions are
also possible via oxidative pathways,[15] which are mostly based
on stoichiometric metal salts, e.g. our alkoxylation of benzoates[16]
and Jia’s arylations of electron-poor anilines (path e).[17] Only in
Hoover’s decarboxylative thiolation / selenolation[18] and Mainolfi’s
arylation of (sulfon)amides (path e),[19] O2 is used as the terminal
oxidant.
Abstract: In the presence of a bimetallic Pd/Cu-system with 1,10-
phenanthroline as the ligand and air or NMO as oxidants, electron-
deficient benzoic acids undergo oxidative decarboxylative coupling
with unprotected amines. This operationally simple aniline synthesis
is widely applicable with regard to the amine and gives good yields
even on multi-gram scale. The orthogonality of this reaction to other
Pd-catalyzed cross-couplings allows the concise synthesis of multi-
substituted arenes via sequential C–C, C–Cl and C–N
functionalizations.
Mechanistic
investigations
suggest
the
intermediacy of hypervalent Pd species.
Substituted anilines are an essential class of compounds in life
sciences and functional materials. Among the top 200 drugs from
2016, 25% contain at least one C(sp2)N bond.[1] Methods for the
selective synthesis of N-arylamines are, thus, a mainstay of the
organic chemistry toolbox (Scheme 1).[2] Beyond the historical
SNAr reaction of electron-poor aryl halides (path a),[3] N-
alkylanilines are mainly accessed by modified Ullmann
condensations[4] and Buchwald-Hartwig aminations (path b).[5]
Oxidative aminations via Chan-Evans-Lam coupling (path c)[6] are
complementary, since they use boron compounds rather than
(pseudo)halides as the aryl source. However, they suffer from the
high cost of these substrates. Directed CH functionalizations of
arenes have opened up further opportunities for the regioselective
introduction of amine substituents into arenes (path d).[7]
Nevertheless, the installation and removal of the directing groups
add further steps to the synthetic sequence.[8]
Since the advent of decarboxylative couplings, it has been a
primary goal to extend this concept to simple amines as coupling
partners,[20] thus enabling the synthesis of anilines from benzoic
acids. However, over almost a decade, all attempts were
frustrated by the many potential side reactions of basic amines
under the forcing conditions of oxidative decarboxylative
couplings, such as the thermal condensation of ammonium
benzoates, the oxidative dimerization of anilines with formation of
azobenzenes, the oxidative decomposition of aliphatic amines via
imine/enamine formation and the protodecarboxylation with
primary or secondary ammonium carboxylates as proton sources.
HNR2
amine
binding
ArNR2
trans-
metalation
c) Chan-Evans-Lam
reductive
elimination
d) Directed CH amination
b) Ullmann and
Buchwald-Hartwig
Y = OH, Pin
oxidation
Order of amine binding and
transmetalation may be inverted
Cu or Pd
X = Hal, OTf, OTs, etc.
Scheme 2. Mechanistic blueprint for a decarboxylative ipso-amination of
benzoic acids.
TM-free
a) SNAr (o,p-EWG)
e) Decarboxylative
We have now tackled this formidable challenge using a
holistically optimized Pd/Cu bimetallic system based on the
mechanistic blueprint outlined in Scheme 2. We reasoned that a
Pd catalyst is likely to mediate the desired cross-coupling cycle,
which involves base-assisted amide transfer[21] and arylation of
the Pd center by an in situ-generated arylcopper species.[22] The
concluding steps, (re)oxidation of Pd and reductive elimination,[23]
also appeared feasible in any order. Depending on whether the
(re)oxidation of Pd takes place before or after reductive
elimination of the arylamine product, a PdII/PdIV[24] or a Pd0/PdII[25]
cycle, respectively, would result. The elementary steps of a
Pd0/PdII cycle have been seen in similar form for phosphine
complexes in Buchwald’s and Hartwig’s aminations.[26] Aerobic
oxidation of PdII to PdIV and reductive elimination with formation
of a C–heteroatom bond from a PdIV species have been
postulated by Mirica for the oxidation of arenes to phenols[24a] and
Stahl for the synthesis of carbazoles via intramolecular CN
formation.[24b]
ipso-amination
Scheme 1. Synthetic methods to selectively access N-alkylanilines via arylation
chemistry.
In recent years, the discovery of decarboxylative cross-
couplings has enabled the use of benzoic acids as aryl sources.[9]
These are easily available at low cost in wide structural diversity
and in substitution patterns that are often complementary to those
of
the
aforementioned
aryl
sources.
Redox-neutral
[a]
Dr. M. Pichette Drapeau, Dr. J. Bahri, D. Lichte, Prof. Dr. L. J.
Gooßen
ZEMOS, Fakultät für Chemie und Biochemie
Ruhr-Universität Bochum
Universitätsstr. 150, 44801 Bochum, Germany
E-mail: lukas.goossen@rub.de
Equal contribution1
In search of a Pd/Cu catalyst system that would favor the
desired decarboxylative amination over the wealth of possible
side reactions, we used the reaction of preformed potassium 2-
nitrobenzoate (1a) and morpholine (2a) as a model and
Supporting information for this article and ORCID identification for
the authors is given via a link at the end of the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201812068
Angewandte Chemie International Edition
COMMUNICATION
when 1 equivalent of KOtBu is employed, albeit with a slightly
eroded 58% yield. Control experiments confirmed that the
omission of Pd, Cu, or the ligand completely shut down the
decarboxylative amination.
systematically tested metal precursors, oxidants, additives, and
solvents. The catalyst development and optimization are detailed
in the Supporting Information. Remarkably, phosphine ligands
and bases, both fixtures of state-of-the-art Buchwald-Hartwig
Table 1. Scope of the decarboxylative ipso-amination of electron-poor benzoic acidsa
Pd / Cu / 1,10-phen
Oxidant
>40 examples
Cyclic and acyclic amines, electron-rich anilines
Oxidant : Air or NMO
Phosphines and bases unrequired
Methods AE
2
14
35
n
R1 = R2 = H, 3ad
A: 81% R1 = R2 = H, 3ag
B: 63%
R = H, 3aa
A: 76%
A: 66%
A: 71%
A: 81%
A: 70%
A: 79%
A: 72%
A: 36%
n = 1, 3fh B: 63%
n = 5, 3fi B: 56%
R1 = Cl, R2 = H, 3dd A: 68%
R1 = R2 = OMe, 3kd A: 69%
3jj B: 77%
R1 = CO2Me, R2 = H, 3fg B: 61%
R = Me, 3ba
R = OMe, 3ca
R = Cl, 3da
R1 = H, R2 = OMe, 3jg
B: 76%
R = F, 3ea
R = CO2Me, 3fa
R = CF3, 3ga
R = NO2, 3ha
R1 = R2 = H, 3ae
A: 70%
3jm B: 41%
3jl B: 43%
3fk B: 55%
R1 = Cl, R2 = H, 3de A: 65%
R1 = R2 = OMe, 3ke A: 59%
R1 =H, R2 = Me, R3 = O, 3ia
R1 =H, R2 = OMe, R3 = O, 3ja
A: 52%
A: 75%
A: 74%
A: 74%
A: 63%
R1 =OMe, R2 = OMe, R3 = O, 3ka
R1 =H, R2 = H, R3 = S, 3ab
R1 = R2 = H, 3af
A: 80%
3fn B: 41%
3fo B: 51% (+ 20% of 3fh)
R1 =H, R2 = H, R3 = CH2, 3ac
R1 = Cl, R2 = H, 3df A: 70%
R1 = R2 = OMe, 3kf A: 64%
R1 = CO2Me, R2 = H, R3 = Cl, 3fp C: 70% D: 46%
R = Me, 3mq C: 31%
R= OMe, 3nq
5 C: 36%
R1 = H, R2 = Cl, 3ap
R1 = Cl, R2 = H, R3 =OMe, 3dq
C: 87% D: 80%
E: 65%
C: 84% D: 79%
E: 67%
C: 78% D: 62%
E: 55%
C: 70% D: 20%
C: 39%
R1 = H, R2 = OMe, 3aq
R1 = CF3, R2 = H, R3 =OMe, 3gq
E: 50%
C: 30%
C: 80% D: 84%
E: 70%
C: 84% D: 64%
R1 = H, R2 = CO2Me, 3ar C: 65% D: 73%
R1 = R2 = OMe, 3jq
R1 = Br, R2 = H, R3 =OMe, 3lq
R1 = H, R2 = R3 = OMe, 3as
C: 78% D: 77%
R1 = CO2Me, R2 = R3 = OMe, 3fs
a Isolated yields. Method A: 1 (0.25 mmol), 2 (2 equiv.), Pd(NH3)4(HCO3)2 (10 mol%), CuI (10 mol%), 1,10-phen. (1 equiv.), anisole/DMAc 3:2 (0.05 M), 145 °C,
16 h, under air; Method B: 1 (0.25 mmol), 2 (5 equiv.), Pd(NH3)4(HCO3)2 (10 mol%), CuI (25 mol%), 1,10-phen. (1 equiv.), NMO (2 equiv.), anisole/DMAc 1:1
(0.05 M), 145 °C, 3 h; Method C: 1 (0.5 mmol), 2 (2 equiv.), Pd(NH3)4(HCO3)2 (10 mol%), CuI (10 mol%), 1,10-phen. (1 equiv.), NMO (1 equiv.), anisole/DMAc
3:2 (0.05 M), 145 °C, 3 h; Method D: 1 (0.5 mmol), 2 (1.2 equiv.), Pd(NH3)4(HCO3)2 (10 mol%), CuI (10 mol%), 1,10-phen. (50 mol%), NMO (1 equiv.), NMP
(0.125 M), 145 °C, 3 h; Method E: same as conditions D, but at 120 °C for 16 h.
reactions, had little effect on the reaction outcome. Instead, the
use of excess 1,10-phenanthroline and elaborate solvent
optimization were the decisive factors to push the reaction
towards the desired pathway. Extensive optimization revealed
that the model reaction proceeds best in the presence of 10 mol%
of both Pd(NH3)4(HCO3)2 and CuI and 1 equivalent of 1,10-
phenanthroline in a 3:2 anisole/DMAc mixture at 145 °C for 16 h.
N-methylmorpholine N-oxide (NMO) was the most effective
oxidant (81% of 3aa), but high yields were also obtained when
stirring the reactions under an air atmosphere without any
additional oxidant being present (76% of 3aa). The desired
transformation is also possible starting from 2-nitrobenzoic acid
Remarkably, the protocol based on air oxygen as terminal
oxidant (Table 1, method A) proved to be widely applicable to the
coupling of potassium 2-nitrobenzoates with various cyclic
secondary amines, among them piperidines bearing nitrile, ester,
or dioxolane groups (3aa-3kf). The coupling of acyclic aliphatic
amines such as phenethylamine (2g) proved to be a greater
challenge (3ag-3fo). Optimal yields are obtained when increasing
the quantity of CuI to 25 mol% and using NMO as stoichiometric
oxidant at a shortened reaction time of 3 h (method B). For
primary amines bound to tertiary carbons such as
cyclohexylamine (2l) and 2-heptylamine (2m), the increased
steric hindrance contributes to a slight erosion in yields. It is
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10.1002/anie.201812068
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COMMUNICATION
remarkable that the strongly hindered secondary acyclic amines
N-methylhexylamine (2n) and di-n-butylamine (2o) can be used
in the current protocol.
Several control experiments were conducted to shed light on
the reaction mechanism and identify its limiting factors (Scheme
4). Phenanthroline-Pd diacetate (I) was treated with p-anisidine
(2q), and the formation of Pd amide species II was confirmed by
The use of the mild oxidant NMO efficiently suppressed
oxidative dimerization even of electron-rich anilines. Thus, a wide
range of electron-rich and electron-deficient diarylamines (3ap-
3nq) were obtained in high yields and exclusive selectivity for the
monoarylation products at a CuI loading of 10% (method C). In
arylations of anilines, the amine excess can be reduced to 1.2
equivalents and the loading of 1,10-phenanthroline to 50 mol%
(method D). Moreover, the reaction temperature can be reduced
to only 120 °C, one of the lowest reported for a decarboxylative
C(sp2)heteroatom bond formation (method E).
1
in situ H NMR and ESI-MS (i). In reactions of benzoate 1a with
morpholine (2a) and N-deuterated morpholine, a kinetic isotope
effect (KIE) of only kH/kD = 1.2 was observed for the formation of
3aa (ii). This low KIE and the fact that Pd amide formation occurs
smoothly at room temperature show that neither amine
coordination nor deprotonation are rate-determining even with the
amine being the strongest base in the reaction mixture. We also
confirmed by in situ ESI-MS that the reaction of phenanthroline-
Pd phenyl iodide (III) with p-anisidine (2q) leads to the Pd amide
species IV (iii), indicating that the amine binding and
transmetallation steps are feasible in either order. Remarkably, no
liberation of diarylamine 9q from this intermediate was observed
even when heating it to 150 °C for 3 h (iv). However, upon addition
of NMO, diarylamine 9q was detected by GC and GC-MS,
whereas the addition of a CuII oxidant did not lead to formation of
9q. Diarylamine 3aq was also synthesized in 80% GC yield by
reaction of the corresponding phenanthroline-Pd aryl iodine
complex III with 2q in the presence of NMO. This yield is identical
to the one obtained in the catalytic version (Table 1). These
experiments confirm that an oxidation step is required to enable
reductive elimination of arylamines from the palladium catalyst. It
also suggests that NMO rather than copper acts as the oxidant.
These observations are in excellent agreement with the catalytic
cycle outlined in Scheme 2.
The functional group tolerance of the reaction was investigated
using various 2-nitrobenzoates bearing electron-donating or
withdrawing substituents at the ortho, meta and para positions.
Various common functionalities including halogens and esters
were tolerated even when using air as terminal oxidant (Table 1,
method A). The limit is reached for the extremely electron-
deficient 2,4-dinitrobenzoic acid (1h), which couples with
morpholine (2a) to give a low 36% yield of 3ha along with
protodecarboxylation product.
Similar to the early decarboxylative biaryl synthesis, this
prototype protocol is, at this early stage, mostly limited to ortho-
nitrobenzoate
substrates.
However,
potassium
2-
(methylsulfonyl)benzoate (4) was also successfully coupled,
indicating that this is not an intrinsic limitation (Table 1). Attempted
cross-couplings of 2-fluoro, 2-methoxy and other 2-substituted
benzoates led to protodecarboxylation byproducts, whereas non-
activated benzoates did not decarboxylate at the low
temperatures required by the sensitive amine substrates. The role
of the ortho-nitro function was tested by using ortho-amide
substituted benzoates (both anilide- and benzamide-derived)
without leading to the ipso-amination product. While this does not
entirely rule out chelation assistance of an ortho group, these
results point toward the transformation being driven by electronic
factors.
Amine binding
(i)
NMP, 23 o
30 min
C
2q
II
I
Observed by 1H NMR
Signals at m/z = 467.20 and 408.23
Method A
1 h
(ii)
The reaction sequence in Scheme 3 showcases the synthetic
opportunities opened up by the orthogonality of the
decarboxylative ipso-amination to other Pd-catalyzed cross-
1a
2a
3aa
Parallel kH/kD = 1.2: Amine binding not rate-determining
coupling
reactions.
2-Nitro-4-chloro-benzoate
1d
was
decarboxylatively coupled with a functionalized piperidine (2d) on
10 mmol scale, leading to 3dd in 78% isolated yield (2.1 g). The
reaction is easy to perform since neither anhydrous conditions nor
an inert atmosphere are required. The aryl chloride moiety that
was left untouched in this reaction step was utilized as a leaving
group in a Sonogashira reaction, introducing an alkyne moiety (6).
The nitro group was reduced to another amine (7), which was
utilized as leaving group in a one-pot Sandmeyer process leading
to fluoroalkyl compound 8.
(iii)
NMP, 23 o
30 min
C
2q
Oxidation and reductive elimination
IV
III
Signal at m/z=485.05
Oxidant
NMP, 23 oC, 30 min
(iv)
then 150 oC, 3 h
2q
9q/3aq
Pd/XPhos
method A
Oxidant
Yield of amine
0%
R = H: 10%, R = NO2: 80%
50%
78%
(2.1 g scale)
III
1d
3dd
6
none
NMO
CuCl2
0%
cat. CuSCN
Na2S2O4/H2O
60%
TMSCF3/tBuONO
Scheme 4. Mechanistic studies (see the SI for experimental details).
8
51%
7
The decarboxylation step is not rate-determining for electron-
deficient benzoates, since 2-methoxy, methylcarboxy and
carboxaldehyde are all fully consumed, but lead to
protodecarboxylation byproducts. Because the amine bonding
and oxidation[24a] steps are not rate-determining either, the
Scheme 3. Sequential arene substitutions via orthogonal catalytic arylations
(see the SI for experimental details).
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10.1002/anie.201812068
Angewandte Chemie International Edition
COMMUNICATION
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a
wider range of arenecarboxylic acids.
Nonetheless, transmetallation cannot be ruled out as rate-
determining step at this stage. The treatment of phenanthroline-
Pd amide acetate II with aryl–metal reagents led to the formation
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In conclusion, the long-awaited extension of decarboxylative
C(sp2)couplings to non-activated aliphatic and aromatic amine
substrates was made possible by a bimetallic Pd/Cu system in
combination with air or NMO as terminal oxidant. Key features of
this protocol are its user-friendliness, cost-efficiency and
orthogonality to other Pd-catalyzed couplings. Preliminary
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Experimental Section
Large-scale synthesis: A 500 mL round-bottom flask equipped with a
Teflon-coated stirring bar was charged under air with Pd(NH3)4(HCO3)2
(297 mg, 1 mmol, 10 mol%), CuI (190 mg, 1 mmol, 10 mol%), 1,10-
phenanthroline (1.82 g, 10 mmol, 1 equiv.) and 4-chloro-2-nitro potassium
benzoate (10 mmol, 1 equiv.), after which non-dried anisole (120 mL),
DMAc (80 mL) and 4-cyanopiperidine (1.77 mL, 20 mmol, 2 equiv.) were
successively added and the mixture was stirred under an air atmosphere
at 145 °C for 16 h. After completion of the reaction, the resulting mixture
was diluted with ethyl acetate (100 mL) and water (50 mL). Following
phase separation, the aqueous layer was extracted 3 times with ethyl
acetate (50 mL). The combined organic phases were washed once with
water (20 mL) and once with brine (20 mL), then dried over anhydrous
MgSO4 and the organic phase was evaporated under reduced pressure
(rotary evaporator). The residue was purified by column chromatography
(gradient of cyclohexane/ethyl acetate 100:0 to 60:40) to give 2.1 g of 3dd
(78% yield).
Acknowledgements
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We thank the DFG (EXC/1069 “RESOLV” and SFB/TRR 88
“3MET”) for generous financial support. M.P.D. thanks the
Alexander von Humboldt Foundation and the Fonds de
Recherche du Québec – Nature et Technologies (FRQNT) for
postdoctoral fellowships. We thank Enis Yalcinkaya, Julian
Stoesser, Nico Pirkl and Daniel Sowa Prendes for technical
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Keywords: amination • benzoic acids • decarboxylation •
bimetallic catalysis • hypervalent palladium
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M. Pichette Drapeau, J. Bahri, D. Lichte,
L. J. Gooßen*
CuI / 1,10-phen
43 examples
up to 87%
air or NMO
145 oC, 316 h
Page No. – Page No.
EWG: NO2 / SO2Me
Decarboxylative ipso-Amination of
Activated Benzoic Acids
Secondary cyclic, primary and secondary aliphatic amines
Electron-rich and poor anilines
An oxidative decarboxylative coupling of benzoic acids with unprotected amines
has been achieved using bimetallic Pd/Cu catalysis. This simple aniline synthesis
only requires air or NMO as oxidants, is amenable to multi-gram scale and allows
orthogonality to traditional Pd-catalyzed cross-couplings. Mechanistic investigations
suggest the intermediacy of hypervalent Pd species.
This article is protected by copyright. All rights reserved.