Amide Synthesis by Nickel/Photoredox-Catalyzed Direct Carbamoylation of (Hetero)Aryl Bromides

Article abstract of DOI:10.1002/anie.202000224

Herein, we report a one-electron strategy for catalytic amide synthesis that enables the direct carbamoylation of (hetero)aryl bromides. This radical cross-coupling approach, which is based on the combination of nickel and photoredox catalysis, proceeds at ambient temperature and uses readily available dihydropyridines as precursors of carbamoyl radicals. The method's mild reaction conditions make it tolerant of sensitive-functional-group-containing substrates and allow the installation of an amide scaffold within biologically relevant heterocycles. In addition, we installed amide functionalities bearing electron-poor and sterically hindered amine moieties, which would be difficult to prepare with classical dehydrative condensation methods.

Full text of DOI:10.1002/anie.202000224

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Accepted Article
Title: Amide Synthesis by Nickel/Photoredox-Catalyzed Direct
Carbamoylation of (Hetero)Aryl Bromides
Authors: Nurtalya Alandini, Luca Buzzetti, Gianfranco Favi, Tim
Schulte, Lisa Candish, Karl Collins, and Paolo Melchiorre
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202000224
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10.1002/anie.202000224
Angewandte Chemie International Edition
Photoredox Catalysis
Amide Synthesis by Nickel/Photoredox-Catalyzed Direct
Carbamoylation of (Hetero)Aryl Bromides**
Nurtalya Alandini, Luca Buzzetti, Gianfranco Favi, Tim Schulte, Lisa Candish, Karl D. Collins, and
Paolo Melchiorre*
Abstract: Herein, we report a one-electron strategy for catalytic
amide synthesis that enables the direct carbamoylation of
(hetero)aryl bromides. This radical cross-coupling approach,
which is based on the combination of nickel and photoredox
catalysis, proceeds at ambient temperature and uses readily
available dihydropyridines as precursors of carbamoyl radicals.
The method’s mild reaction conditions make it tolerant of
sensitive-functional-group-containing substrates and allow the
installation of an amide scaffold within biologically relevant
heterocycles. In addition, we installed amide functionalities
bearing electron-poor and sterically hindered amine moieties,
which would be difficult to prepare with classical dehydrative
condensation methods.
scale.[7] This explains why the pharmaceutical industry has recently
posed a great emphasis into methods for amide bond formation that
avoid poor atom economy reagents.[8]
Catalytic methods for amide synthesis have the potential to
minimize waste, improve the environmental burden, and lower costs
of the process.[5] Some recent key advances include the use of group
IV metal salts[9] or boron compounds[10] as catalysts and the
development of Pd-catalyzed aminocarbonylation - the three-
component coupling of an aryl halide with an amine and carbon
monoxide.[11] However, the need for toxic gaseous CO and copious
amounts of molecular sieves as drying agents complicates the use of
these catalytic methods. In addition, most of the protocols require
severe reaction conditions and elevated temperatures, which limit the
tolerance for substrates with sensitive functional groups. Therefore,
there is still a need for catalytic amide synthesis approaches that
operate at room temperature, offer a broad substrate scope, and avoid
the use of excess drying agents.[12]
Herein, we describe the ambient temperature catalytic conversion
of aryl and heteroaryl bromides to their corresponding amides
enabled by the combination of nickel and photoredox catalysis
(Figure 1).[13] We used readily available, cheap and stable 4-
carbamoyl-1,4-dihydropyridines 1 that, upon single-electron transfer
(SET) oxidation, can generate carbamoyl radicals.[14] The ability of a
nickel catalysts to undergo oxidative addition with aromatic bromides
2 while engaging in radical capture mechanisms secured the
formation of the cross-coupled amide products 3.[15]
Introduction
A
mides are widespread structural units in nature, since the amide
bond is the core linkage of natural proteins and peptides.[1] This
moiety is also present in polymers, agrochemicals, and
pharmaceutical molecules.[2] For example, 70% of the top 50 selling
small molecule drugs of 2018 contain an amide bond linkage.[3]
Despite the prevalence and importance of amides, improved methods
for their synthesis are still highly sought-after,[4] especially if they can
offer high efficiency and reduced environmental impact.[5] This is
because the most common methods for amide preparation –
dehydrative condensation – typically use stoichiometric amounts of
high molecular weight coupling reagents, which are often expensive,
toxic, and/or potentially explosive.[6] While often tolerable on a small
scale, this inefficiency has significant implications when it comes to
the manufacture of bio-active molecules, such as drugs or
agrochemicals, which may need to be synthesized on multi-ton
[]
Prof. Dr. P. Melchiorre
ICREA – Passeig Lluís Companys 23, 08010 Barcelona, Spain
N. Alandini, Dr. L. Buzzetti, and Prof. Dr. P. Melchiorre
ICIQ - Institute of Chemical Research of Catalonia
the Barcelona Institute of Science and Technology,
Avenida Països Catalans 16 – 43007, Tarragona, Spain
E-mail: pmelchiorre@iciq.es
Figure 1. The presented radical cross-coupling approach to amide synthesis
Homepage: http://www.iciq.org/research/research_group/prof-paolo-
melchiorre/
under photoredox-nickel dual catalysis.
The method requires mild reaction conditions and avoids the need
for any dehydrating agents. It offers a wide scope allowing the
straightforward preparation of secondary and tertiary amides and the
direct installation of an amide scaffold within biologically relevant
heterocycles. In addition, we installed amide functionalities bearing
electron-poor amine moieties, which would be difficult to prepare
with classical dehydrative condensation methods.
Dr. G. Favi, Department of Biomolecular Sciences, University of
Urbino "Carlo Bo", Urbino, Italy
T. Schulte, Dr. L. Candish, Dr. K. D. Collins, Small Molecule
Innovations, Bayer AG, Pharmaceuticals, Aprather Weg 18a, 42113
Wuppertal, Germany
[]
Financial support was provided by MICIU (CTQ2016-75520-P), the
AGAUR (Grant 2017 SGR 981), and the European Research
Council (ERC-2015-CoG 681840 - CATA-LUX). N.A. thanks H2020-
MSCA-ITN-2016 (722591 – PHOTOTRAIN) for a predoctoral
fellowship. L.B. thanks MINECO for a predoctoral fellowship
(CTQ2013-45938-P).
1
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10.1002/anie.202000224
Angewandte Chemie International Edition
Results and Discussion
Table 1. Optimization studies and control experiments.[a]
Developing this protocol required a suitable carbamoyl radical
precursor. The choice of substrate 1 was motivated by the notion that
4-alkyl-1,4-dihydropyridines can generate alkyl[16] and acyl[17]
radicals under oxidative conditions. We therefore surmised that
dihydropyridines 1, adorned with a carbamoyl moiety, would provide
the target carbamoyl radical upon SET oxidation by a photoredox
catalyst. We developed a straightforward synthesis of 1 from the
dihydropyridine derivative C bearing a carboxyl moiety at the C4-
position (Scheme 1). The bench-stable intermediate C[18] can be
easily prepared in one step and on multigram scale from cheap and
commercially available amino crotonate A and glyoxylic acid B.
Subsequent condensation with amines in the presence of
stoichiometric amounts of isobutylchloroformate D delivers the 4-
carbamoyl-1,4-dihydropyridines 1 in excellent yields.
entry
Deviation from standard conditions
[%] yield 3a[b]
1
2
3
4
5
6
7
8
9
none
99
99
1,4-dioxane instead of THF
acetone instead of THF
EtOAc instead of THF
33
99
non-degassed condition
H2O (10 equiv.)
90
87
34W Kessil 456 nm (1 mmol)
immersion-well reactor (15 mmol)
no 4CzIPN, nickel or light
91[c]
72[c]
0
[a]
Reactions performed on a 0.1 mmol scale at ambient temperature for 16 h
under illumination by a single high-power (HP) blue LED (λmax = 460 nm,
irradiance = 100±3 mW/cm2) and using 1.5 equiv. of 1a and Na2CO3. [b] Yield
determined by 1H NMR analysis of the crude mixture using trichloroethylene as
the internal standard. [c] Yield of isolated 3a. LED = light-emitting diode; Na2CO3
= sodium carbonate.
Scheme 1. Synthesis of the Carbamoyl Radical Precursor 1; AcOH: acetic acid;
DCM: dichloromethane.
Using the optimized conditions described in Table 1, entry 1, we
tested the generality of the nickel/photoredox-catalyzed
carbamoylation process. We first evaluated the scope of the
(hetero)aryl bromides (Figure 2). A wide range of aryl bromides,
bearing both electron-rich and electron-poor substituents, underwent
the carbamoylation with the (L)-alanine-derived dihydropyridine 1a
in moderate to excellent yields (adducts 4-13). High yields were
achieved with bromobenzene (4) and bromonaphthalene (5). An
ortho-substituent was well-tolerated (6), while an ortho-ortho’-
disubstituted aryl bromide remained unreactive, possibly because of
steric hindrance (results not shown). The ability to tolerate aryl
boronates (adduct 8) and chlorides (11) demonstrated that the
protocol is orthogonal to classical metal-catalyzed cross-coupling
reactions and allows further functionalization. We then evaluated the
compatibility with unprotected polar functional groups, which is an
important criterion for assessing a method’s applicability to complex
molecule synthesis and drug discovery.[23] Aryl bromides bearing
sensitive functional groups, including aldehydes (12), unprotected
alcohols (13), ketones and Boc-protected amines (18 and 22), amides
(15 and 20), and sulfonamide moieties (21) underwent the reaction
smoothly. Our approach displayed a good level of tolerance towards
heterocyclic substituents containing oxygen (15), nitrogen (16), and
sulfur atoms (19). Functionalized aryl bromides bearing L-menthol
(14), 2',3'-O-isopropylideneuridine (17), and glycine (20) were
tolerated, highlighting the method’s potential for complex molecule
synthesis. Given the prevalence of nitrogen-containing heterocycles
in biologically active molecules,[24] we then evaluated the tendency
of (hetero)aryl bromides to undergo the carbamoylation process.
Pyridines (23-24), pyrimidine (25), pyrazine (26), quinoline (28),
unprotected benzotriazole (29), imidazo[1,2-a]pyridine (31), and
furo[2,3-d]pyrimidine (32) could all be functionalized. The protocol
also provides a direct approach to carbamoylated caffeine (27) and
carbazole (30), which would be difficult to access through traditional
With the carbamoyl radical precursor in hand, we started our
investigations (Table 1) by evaluating the cross-coupling reaction
between the (L)-alanine-derived dihydropyridine 1a (Eox (1a•+/1a) =
+1.39
V
vs. Ag/Ag+ in acetonitrile, CH3CN) and 4-
bromobenzotrifluoride 2a.[19] The experiments were conducted at
ambient temperature, using a single high-power (HP) blue LED
emitting at 460 nm, a slight excess of 1 (1.5 equiv.) and in the
presence of NiCl2 glyme (5 mol%), 4-4’-dimethoxy-2-2’-bipyridine
(dMeObpy) as the ligand (10 mol%), and the organic photocatalyst
4CzIPN.[20] When performing the reaction in tetrahydrofuran (THF)
or 1,4-dioxane, the cross-coupling amide product 3 was obtained in
quantitative yield (entries 1 and 2). The reaction also proceeds in
“industrially preferred” solvents[21] (acetone and ethyl acetate
(EtOAc), entries 3 and 4 respectively), therefore offering a good
versatility to avoid potential substrate solubility issues. As a proof of
the method’s robustness, the reaction could be performed without
degassing the solvent (entry 5)[22] and in the presence of water (entry
6), which only marginally affected the efficiency of the process. This
reaction was also amenable to scale-up with no significant difference
in reactivity using a simple experimental set-up (1.0 mmol, entry 7).
The use of an immersion-well reactor (experimental details in Section
D3 of the Supporting Information) allowed us to perform the process
on a relevant preparative scale and without the need of re-
optimization (entry 8, 15 mmol scale), delivering product 3 in 72%
yield (> 3 g). Control experiments confirmed that the reaction could
not proceed in the absence of light, the photocatalyst, or nickel (entry
9). As a testament of the mild conditions of the system, we confirmed
that, in all these experiments, no racemization of the enantiopure
alanine scaffold occurred during the process.
2
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10.1002/anie.202000224
Angewandte Chemie International Edition
amidation methods because the carboxylic acid precursors are not
readily available.
Figure 2. Scope of (hetero)aryl bromides. Reactions performed on 0.1 mmol scale at ambient temperature for 16 h under illumination by a single blue LED (λmax = 460
nm) and using dihydropyridines (1.5 equiv.), Na2CO3 (1.5 equiv.) in THF (0.05M). Yields of products refer to isolated material after purification (average of two runs
[b]
[c]
per substrate). [a] Performed in 1,4-dioxane (0.05 M) using 3 mol% of the photocatalyst.
0.2 mmol scale. 0.2 mmol scale in 1,4-dioxane (0.025 M). Boc: tert-
butyloxycarbonyl.
We then focused on the scope of the carbamoyl radical precursors
(Figure 3). We first evaluated aminoacidic residues other than alanine
that could be coupled with 4-bromobenzotrifluoride 2a.[25] Glycine
(33), phenylalanine (34), and valine (35) could be installed in the
amide products in excellent yields. There was good tolerance of the
presence of free alcohols within serine (36) and tyrosine (37) and of
an unprotected nitrogen in tryptophan (38). The reaction also
proceeded efficiently when using the methionine-derived
dihydropyridine, affording amide 39 bearing the S-methyl thioether
group. Peptides are generally considered poor drug candidates
because of their low oral bioavailability.[26] However, modifications,
including N-terminal-capping, can improve their bioavailability and
stability.[26b] Our method enabled the coupling of a dipeptide with 2a
to provide the N-aroyl capped dipeptide 40 in high yield.
moclobemide 51, in moderate to high yields. An aniline-containing
carbamoyl group could also be installed, although an electron-rich
aryl bromide was needed to secure high reactivity (adducts 52 and 53).
Tertiary amides bearing morpholines (54), piperidines (55),
pyrrolidines (56), and piperazines (57) were successfully obtained in
good yields, while acyclic tertiary amides were achieved in moderate
yields (58-59). These results suggest that our protocol can
complement amide formation strategies based on isocyanates, as they
are limited to the synthesis of primary and secondary amides.[11f,27]
Finally, we evaluated the possibility of installing amide
functionalities bearing either sterically hindered or electron-poor
amine moieties, which would be difficult to prepare by classical
dehydrative condensation methods. Amides bearing electron-poor
anilines (60 and 61), pyridines (62), and hindered fragments (63-64)
could all be effectively prepared using this nickel/photoredox dual
catalysis approach.
Further evaluation of the dihydropyridines amenable to this
strategy revealed that a variety of N-alkyl carbamoyl groups could be
tolerated, delivering secondary amides, including the drug molecule
3
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10.1002/anie.202000224
Angewandte Chemie International Edition
Figure 3. Scope of carbamoyl radical precursors. Reactions performed on 0.1 mmol scale at ambient temperature for 16 h under illumination by a single blue LED
(λmax = 460 nm) and using dihydropyridines (1.5 equiv.), Na2CO3 (1.5 equiv.) in THF (0.05 M). Yields of products refer to isolated material after purification (average of
two runs per substrate). [a] Performed in 1,4-dioxane (0.05 M).
A possible mechanism for the nickel/photoredox-catalyzed
carbamoylation process is proposed in Figure 4. Photoexcitation of
Conclusion
the organic photocatalyst 4CzIPN (E1/2 (4CzIPN*/4CzIPN•−) = +1.43
V vs. SCE in CH3CN)[20] forms an oxidant strong enough to take an
In summary, we have reported a catalytic method for amide
electron from the dihydropyridine radical precursor 1 (Ered (1a•+/1a)
synthesis that occurs at ambient temperature. The chemistry exploits
the ability of readily available 4-carbamoyl-1,4-dihydropyridines 1 to
generate carbamoyl radicals upon SET oxidation by a visible-light-
= +1.39 V vs. Ag/Ag+ in CH3CN). This SET event triggers the
formation of the carbamoyl radical I. Simultaneously, the Ni0
complex II undergoes oxidative addition with aromatic bromide 2 to
afford the NiII complex III. This intermediate intercepts the
nucleophilic carbamoyl radical I to form the NiIII intermediate IV,
which, after reductive elimination, forges the desired C(sp2)–C(sp2)
bond in the cross-coupled amide product 3. Finally, the ensuing NiI
intermediate (Ered [NiI/Ni0] ≈ -1.13 V vs Ag+/AgNO3 in DMF)[28]
undergoes SET reduction by the reduced form of the photoredox
catalyst (E1/2 (4CzIPN/4CzIPN•−) = -1.24 V vs. SCE in CH3CN),
completing the catalytic cycle while regenerating both active catalysts.
activated photoredox catalyst. This carbamoyl radical generation was
used to develop a nickel cross coupling process to synthesize
(hetero)aryl amides from readily available aryl bromides. This
method tolerates unprotected polar functional groups and
heterocycles, and it could be applied to the carbamoylation of
complex molecules. We also demonstrated that the process is directly
scalable without re-optimization. These findings, along with the
experimental simplicity and the low cost and the stability of the
substrates, suggest that this catalytic approach to amide synthesis can
effectively complement conventional carbonylation chemistry and be
useful in life science endeavours.
4
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10.1002/anie.202000224
Angewandte Chemie International Edition
Figure 4. Proposed mechanism.
H. Jatoi, G. G. Pawar, F. Robert, Y. Landais, Chem. Commun. 2019, 55,
466–469.
Keywords: amides • cross-coupling • nickel catalysis • photoredox
catalysis • radical chemistry
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Angewandte Chemie International Edition
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Angewandte Chemie International Edition
Photoredox Catalysis
Nurtalya Alandini, Luca Buzzetti, Gianfranco Favi,
Tim Schulte, Lisa Candish, Karl D. Collins, and
Paolo Melchiorre* __________ Page – Page
Amide Synthesis by Nickel/Photoredox-
Catalyzed Direct Carbamoylation of
(Hetero)Aryl Bromides
Teaming up for Amide Synthesis. A catalytic method for amide synthesis
is detailed that proceeds at ambient temperature and enables the direct
carbamoylation of (hetero)aryl bromides. This method is based on the
combination of nickel and photoredox catalysis and uses readily available
dihydropyridines as precursors of carbamoyl radicals. The protocol has
been developed in the framework of an academic-industrial collaboration.
7
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