Nickel-catalyzed C-N bond activation: Activated primary amines as alkylating reagents in reductive cross-coupling

Article abstract of DOI:10.1039/c9sc00783k

Nickel-catalyzed reductive cross coupling of activated primary amines with aryl halides under mild reaction conditions has been achieved for the first time. Due to the avoidance of stoichiometric organometallic reagents and external bases, the scope regarding both coupling partners is broad. Thus, a wide range of substrates, natural products and drugs with diverse functional groups are tolerated. Moreover, experimental mechanistic investigations and density functional theory (DFT) calculations in combination with wavefunction analysis have been performed to understand the catalytic cycle in more detail.

Full text of DOI:10.1039/c9sc00783k

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Nickel-catalyzed C–N bond activation: activated
primary amines as alkylating reagents in reductive
cross-coupling†
Cite this: DOI: 10.1039/c9sc00783k
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
a
Huifeng Yue, ‡a Chen Zhu, ‡a Li Shen,a Qiuyang Geng,a Katharina J. Hock,
b
ab
Tingting Yuan,a Luigi Cavallo
and Magnus Rueping
*
*
Nickel-catalyzed reductive cross coupling of activated primary amines with aryl halides under mild reaction
conditions has been achieved for the first time. Due to the avoidance of stoichiometric organometallic
reagents and external bases, the scope regarding both coupling partners is broad. Thus, a wide range of
substrates, natural products and drugs with diverse functional groups are tolerated. Moreover,
experimental mechanistic investigations and density functional theory (DFT) calculations in combination
with wavefunction analysis have been performed to understand the catalytic cycle in more detail.
Received 14th February 2019
Accepted 12th March 2019
DOI: 10.1039/c9sc00783k
rsc.li/chemical-science
herein describe the rst Ni-catalyzed deaminative reductive
cross-coupling of activated primary amines with aryl halides,
1. Introduction
providing a versatile method for the transformation of amino
groups to aryl motifs under mild conditions (Scheme 1).
Transition-metal-catalyzed cross-coupling reactions play an
important role in modern organic synthesis.1 Among them,
reductive cross-coupling which uses two electrophiles as
coupling partners represents an attractive catalytic platform for
the formation of diverse chemical bonds.2 Due to the avoidance
of stoichiometric organometallic reagents this transformation
oen possesses a broader substrate scope. Traditionally, alkyl
halides,3 which may have limited stability and availability, have
been used as alkyl electrophiles. Recently, N-hydroxyph-
thalimide esters, anhydrides, benzyl oxalates, tosylates and
mesylates have been reported as alkyl coupling partners.4
However, the use of primary amines as readily available, cheap,
green and stable alkylating reagents in reductive cross-coupling
has not been described. Recently, bench-stable pyridinium salts
have been reported to be attractive substrates in deaminative
cross-coupling with boronic acids.5 In this transformation, the
radical is generated via a single electron transfer (SET) pathway
between the pyridinium salt and the nickel catalyst. In addition,
an alkyl radical can be formed by a photoinduced SET process6
or by an elegant metal-free formation of a boron-based electron-
donor–acceptor (EDA) complex7 under blue light irradiation.
Also, a Lewis base promoted C–N borylation has been reported.8
As part of our continuing efforts in metal catalyzed functional
group interconversion and the activation of inert bonds,9 we
2. Results and discussion
We started our investigation by evaluating the reductive cross-
coupling of cyclohexylamine derived pyridinium salt 1a and
iodobenzene 2a using NiCl2$dme as the catalyst, bipyridine
ligand L1 as the ligand and a reducing agent (Table 1). Since
solvents typically play an important role in cross-coupling
reactions, we rst tested several solvents (entries 1–5) and
found DMA to be the optimal solvent. Subsequently the ratio of
reactants 1a and 2a was evaluated (entries 6 and 7) and the yield
was improved to 61%. Bidentate as well as tridentate N-con-
taining ligands L1–L4 can be applied (entries 8–10) and L1, L2,
aInstitute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, D-52074
Aachen, Germany. E-mail: magnus.rueping@rwth-aachen.de
bKAUST Catalysis Center, KCC, King Abdullah University of Science and Technology,
KAUST, Thuwal 23955-6900, Saudi Arabia
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c9sc00783k
Scheme 1 Diverse activation modes of pyridinium salts and the
advantages of this novel deaminative reductive cross-coupling
protocol.
‡ These authors contributed equally to this work.
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Table 1 Optimization of the reaction conditionsa
underwent this reaction smoothly, giving the corresponding
products in excellent yields (3a and 3b).
In addition, a wide range of functional groups including
ketone (3c and 3d), triuoromethyl (3e), triuoromethoxy (3f),
triuoromethylthio (3g), tosyl (3h), cyano (3i and 3m), methoxy
(3j), methylthio (3k), t-butyl (3l), uoro (3m, 3r and 5k), and
ester (5j) were well tolerated under the mild reaction conditions,
highlighting the high chemoselectivity of this newly developed
deaminative reductive cross-coupling reaction. Use of disub-
stituted aryl bromide and bicyclic substrates including phtha-
lides and naphthyl halides also gave the products 3m–3p in
good yields. It is noteworthy that pharmaceutically relevant 3-
and 4- bromopyridines could be applied to this protocol with
good to high efficiency (3q–3s, 5n). Next, the scope of pyr-
idinium salts was explored. A wide range of structurally diverse
pyridinium salts were suitable substrates for this trans-
formation. Cyclic and acyclic secondary amine substrates could
undergo this deaminative arylation reaction in good to excellent
yield (4a–4g) and the same applies for N-heterocyclic pyr-
idinium salts (4h and 4i) (Table 2b).
It should be mentioned that when we applied primary alkyl
pyridinium salts to this protocol, the reaction did not occur.
However, simply switching the ligand from L2 to L4 and slightly
raising the reaction temperature to 60 ꢀC allowed this trans-
formation to occur smoothly. A series of primary alkyl pyr-
idinium salts bearing diverse functional groups such as amine,
acetal, dioxole, cyclohexenyl, thiophene, and pyridine were
suitable coupling partners for this deaminative reductive cross-
coupling, leading to products 4n–4s. Notably, chloro (4k),
unprotected OH and indole NH groups were also tolerated (4t
and 5f), providing the option for further functionalization.
Moreover, methylation reaction, which is challenging in
reductive cross-coupling, was also realized via the utilization of
methyl pyridinium salts (Table 2c). Importantly, our newly
developed protocol could also be readily extended to a wide
range of complex molecules derived from natural products and
drugs. As such pregnenolone, galactopyranose, probenecid,
adamantane carboxylic acid, and cholestanol derivatives could
be transformed to the corresponding products 5a–5e in good to
excellent yield. Moreover, a series of pyridinium salts derived
from drugs or drug intermediates, including tryptamine, mex-
iletine, amphetamine, Lipitor intermediate, and dopamine, all
underwent the mild coupling protocol with good to excellent
efficiency (5f–5n). Use of Mosapride derived pyridinium salts
gave product 5o in a lower yield (Table 2d).
Entry [Ni]
Ligand Reductant Solvent
Yieldb (%)
1
NiCl2$dme
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L2
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Zn
Mg
Mn
Mn
Mn
Mn
—
DMA
DMF
CH3CN
THF
29
11
10
16
0
61
36
61
49
60
51
15
35
35
8
2
3
4
NiCl2$dme
NiCl2$dme
NiCl2$dme
NiCl2$dme
NiCl2$dme
NiCl2$dme
NiCl2$dme
NiCl2$dme
NiCl2$dme
NiBr2$dme
5
Toluene
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
6c
7d
8c
9c
10c
11c
12c
13c
14c
15c
16c
17c,e
18c
19c
20c
Ni(OAc)2$4H2O L2
Ni(acac)2
NiCl2$6H2O
NiCl2$dme
NiCl2$dme
NiCl2$dme
—
L2
L2
L2
L2
L2
L2
—
99
81
0
6
0
NiCl2$dme
NiCl2$dme
L2
a
Reaction conditions: Katritzky pyridinium salt 1a (0.1 mmol),
iodobenzene 2a (0.1 mmol), [Ni] (0.01 mmol), ligand (0.01 mmol),
b
reductant (2 equiv.) in 1.0 ml solvent at rt. GC yield using decane as
the internal standard. The ratio of 1a to 2a was set at 1.5 : 1. The
ratio of 1a to 2a was set at 1 : 2. Bromobenzene was used instead of
iodobenzene.
c
d
e
and L4 showed a similar efficiency, providing the desired
product in about 60% yield. With the readily available and
cheap bipyridine L2, we examined a series of nickel catalysts,
including NiBr2$dme, Ni(OAc)2$4H2O, Ni(acac)2, and NiCl2-
$6H2O. However lower yields were observed (entries 11–14). The
yield was signicantly improved to 99% when Mn powder was
used as a reductant (entry 16), whereas the utilization of Mg
powder gave the desired product in only 8% yield (entry 15).
Besides aryl iodides, the protocol was also applied to aryl
bromides. When bromobenzene was used, the desired product
was also obtained in a good yield (entry 17). Control experi-
ments demonstrated that the nickel catalyst, ligand, and
reductant are all essential for the success of this transformation
(entries 18–20).
With the optimized reaction conditions in hand, the scope of
aryl halides was rst evaluated (Table 2a). A wide variety of aryl
halides bearing electron-donating, electron-neutral, and
electron-withdrawing functional groups could be successfully
converted into the corresponding products in good to excellent
yields. For example, phenyl and biphenyl iodides and bromides
Additionally, a gram-scale reaction was successfully con-
ducted using 1a and 4-iodobiphenyl 2b in the presence of only
5 mol% nickel catalyst and the desired product 3b was obtained
in 96% yield (Scheme 2a), demonstrating the practicability of
our newly developed deaminative reductive cross-coupling
methodology. Also, byproduct 6, which is potentially a useful
organic base, could be isolated in 85% yield. To shed light on
the mechanism of this transformation, an experiment was
conducted with the radical trapping reagent TEMPO (2,2,6,6-
tetramethyl-1-piperidinyloxy, 2 equiv.).5a,c The reaction was
suppressed and no product 5m was detected (Scheme 2b).
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Table 2 Scope of substratesa
a
Reaction conditions: pyridinium salt 1 (0.30 mmol), aryl halide 2 (0.20 mmol), NiCl2$dme (0.02 mmol), L2 (0.02 mmol, for secondary alkyl) or L4
(0.02 mmol, for primary alkyl), Mn powder (0.40 mmol) in 1.0 ml DMA at rt (for secondary alkyl) or 60 ꢀC (for primary alkyl); yields aer purication.
b
GC yield. c The ratio of pyridinium salt to aryl halide 1 : 3, 100 ꢀC, NMR yield.
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Also, ring-opened product 9 was generated in 55% yield
when a substrate bearing a cyclopropane motif 8 was used
(Scheme 2c).5a,c Both these results suggest the involvement of an
alkyl radical in this transformation. When ligand L5 which is
effective for chain-walking reductive cross-coupling10 was used
in our catalytic system, non-walking and chain-walking prod-
ucts (4e and 4e0, 5h and 5h0) were obtained with a ratio of 4 : 1,
suggesting an oxidative addition of aryl halide to Ni0 to give
a NiII intermediate prior to alkyl radical generation. Since the
NiIII intermediate generated from addition of the alkyl radical to
the NiII intermediate is less likely to undergo the chain-walking
step due to steric hindrance the non-chain-walking product is
the major product.
Furthermore, detailed DFT calculations were performed to
rationalize our newly designed catalytic reaction (Scheme 3;
computational methods, see ESI†). As a model system, we
investigated the reaction of phenyl bromide with A1 in the
presence of NiCl2$dme, bpy as the ligand and Mn as the
reducing agent. The reaction starts with the complexation of the
ligand bpy to the NiII precatalyst, followed by reduction to form
the active Ni0 catalyst B (Scheme S1 in ESI†). The catalytic
process is initiated by oxidative addition of phenyl bromide to
Ni0 via transition state B-TS with an energy barrier of
11.7 kcal molꢁ1. The formed NiII intermediate C is reduced by
Mn, leading to intermediate D with a free energy gain of
6.9 kcal molꢁ1. In the next step, A1 is coordinated to D, followed
by SET reduction of A1 to generate radical A2 and NiII inter-
mediate F. The radical A2 is prone to undergo C–N bond
cleavage with an energy barrier of 19.9 kcal molꢁ1, liberating the
alkyl radical A3 and the aromatic pyridine A4. At this point, alkyl
Scheme 2 Gram-scale reaction and mechanism investigation.
Scheme 3 DFT-Computed energy profile for the nickel-catalyzed reductive cross-coupling reaction of aryl halides and pyridinium salts. Free
energies in solution (in kcal molꢁ1) at the SMD(DMA)-M06/Def2-QZVPP//uB97xD/Def2-TZVP(Ni,Mn)/Def2-SVP (non-metal) level are displayed.
Selected DFT optimized geometries are listed. Bond lengths are in A˚.
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radical A3 adds to NiII intermediate F to form NiIII intermediate the pyridinium salt were conducted (see ESI†) and reversible
G. Subsequently, the C–C bond cross-coupling product A5 is peaks at ꢁ0.94 V vs. SCE were observed, suggesting the exis-
formed via reductive elimination from NiIII with an energy tence of stable radical intermediate A2. In order to understand
barrier of 4.9 kcal molꢁ1
.
the C–N bond dissociation, we performed localized orbital
Finally, the NiI intermediate H is further reduced by Mn to locator (LOL) – p analysis12 and multi-center bond order
regenerate the Ni0 active catalyst B and initiate the next catalytic calculations (Iring
)
for the whole process (Fig. 1c). Before the
13
cycle.
SET reduction, the central pyridine ring has full aromaticity
Subsequently, we focused on the origin of the SET reduction (Iring ¼ 0.05 in A1, for comparison, Iring ¼ 0.05 in benzene and
of the pyridinium salt and the generation of the alkyl radical.11 pyridine12c). Aer the reduction the aromaticity is lost and the
The molecular orbital plots (Fig. 1a) show that the SOMO of E free energy is 3.0 kcal molꢁ1 higher (Iring ¼ 0 in A2). With the
corresponds to the singly occupied MO predominantly localized C–N bond dissociating, the aromaticity is partially regained (c.f.
2
on the dz -orbital of Ni. At the same time, the LUMO of E Iring ¼ 0.01 in transition state A2TS). Aer the generation of
corresponds to a p-orbital delocalized around the central alkyl radicals, the aromaticity of A3 is fully restored (Iring ¼ 0.05
nitrogen-containing aromatic ring of the pyridinium salt. in A3) with a free energy gain of 5.5 kcal molꢁ1
However, aer A2 is displaced away from the Ni species, the
.
SOMO becomes localized on the central aromatic ring of the
pyridinium salt. This indicates that upon separation of the Ni
3. Conclusions
and pyridyl fragments the unpaired electron transfers from Ni In summary, we have developed a new deaminative reductive
to the pyridinium salt and delocalizes around the central cross-coupling of aryl halides with pyridinium salts derived
aromatic ring. Spin density analysis further supported this from readily available alkyl amines. Due to the avoidance of
process. The unpaired electron density is localized on the Ni- stoichiometric organometallic reagents and external bases, the
center when the pyridinium salt is coordinated to the NiI- scope is rather broad as demonstrated using the many different
complex, as in E (Fig. 1b, le), while it is transferred to the substrates employed (>55 examples). In addition, the chemo-
central pyridine ring as the pyridine moiety A2 dissociates from selectivity of this protocol is good and functional groups,
the Ni complex (Fig. 1b, middle). Subsequently, the C–N bond including cyano, methoxy, methylthio, uoro as well as chloro,
dissociates and the spin density is further transferred to the sp3- unprotected OH and indole NH groups, are well tolerated.
carbon atom, indicating generation of the alkyl radical (Fig. 1b, Importantly, the cross-coupling reaction can be scaled-up using
right). Additionally, cyclic voltammetry (CV) measurements of a lower amount of nickel catalyst without diminishing the yield,
demonstrating the practicability of this protocol. Furthermore,
experimental mechanistic investigations and DFT calculations
combined with wavefunction analysis have been conducted to
gain insight into the catalytic process.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
H. Y. acknowledges the China Scholarship Council. C. Z.
acknowledges the King Abdullah University of Science and
Technology (KAUST) for support and the KAUST Super-
computing Laboratory for providing computational resources of
the supercomputer Shaheen II.
Notes and references
1 (a) T. J. Colacot, New Trends in Cross-Coupling: Theory and
Applications, RSC Publishing, Cambridge, 2014; (b)
¨
A. d. Meijere, S. Brase and M. Oestreich, Metal-Catalyzed
Cross-Coupling Reactions and More, Wiley-VCH, Weinheim,
2014.
¨
2 (a) C. E. Knappke, S. Grupe, D. Gartner, M. Corpet,
Fig. 1 (a) Molecular orbital plots: SOMO of E (left), LUMO of E (middle)
and SOMO of Eb (right). (b) Spin density plots of E (left), Eb (middle) and
A2TS (right). (c) Localized orbital locator (LOL) – p plots of A1, A2,
A2TS, and A3 with multi-center bond order of the central nitrogen-
containing aromatic ring Iring listed below.
C. Gosmini and A. Jacobi von Wangelin, Chem.–Eur. J.,
2014, 20, 6828–6842; (b) J. Gu, X. Wang, W. Xue and
H. Gong, Org. Chem. Front., 2015, 2, 1411–1421; (c)
D. J. Weix, Acc. Chem. Res., 2015, 48, 1767–1775.
This journal is © The Royal Society of Chemistry 2019
Chem. Sci.

View Article Online
Chemical Science
Edge Article
3 D. A. Everson, R. Shrestha and D. J. Weix, J. Am. Chem. Soc.,
2010, 132, 920–921.
Kalthoff, F. J. Klauck, M. J. James and F. Glorius, Chem.–
Eur. J., 2018, 24, 17210–17214.
4 Examples of reductive cross couplings with N-
hydroxyphthalimide esters: (a) K. M. Huihui, J. A. Caputo,
Z. Melchor, A. M. Olivares, A. M. Spiewak, K. A. Johnson,
T. A. DiBenedetto, S. Kim, L. K. G. Ackerman and
D. J. Weix, J. Am. Chem. Soc., 2016, 138, 5016–5019; (b)
L. Huang, A. M. Olivares and D. J. Weix, Angew. Chem., Int.
Ed., 2017, 56, 11901–11905; (c) N. Suzuki, J. L. Hofstra,
K. E. Poremba and S. E. Reisman, Org. Lett., 2017, 19,
2150–2153; (d) H. Li, C. P. Breen, H. Seo, T. F. Jamison,
Y.-Q. Fang and M. M. Bio, Org. Lett., 2018, 20, 1338–1341;
(e) X. Lu, X.-X. Wang, T.-J. Gong, J.-J. Pi, S.-J. He and Y. Fu,
Chem. Sci., 2019, 10, 809–814; anhydrides: (f) H. Chen,
L. Hu, W. Ji, L. Yao and X. Liao, ACS Catal., 2018, 8,
10479–10485; benzyl oxalates: (g) X.-B. Yan, C.-L. Li,
W.-J. Jin, P. Guo and X.-Z. Shu, Chem. Sci., 2018, 9, 4529–
4534; tosylates and mesylates: (h) J. H. Liu, C. T. Yang,
X. Y. Lu, Z. Q. Zhang, L. Xu, M. Cui, X. Lu, B. Xiao, Y. Fu
and L. Liu, Chem.–Eur. J., 2014, 20, 15334–15338.
8 J. Hu, G. Wang, S. Li and Z. Shi, Angew. Chem., Int. Ed., 2018,
57, 15227–15231.
9 Examples: (a) M. Leiendecker, C. C. Hsiao, L. Guo,
N. Alandini and M. Rueping, Angew. Chem., Int. Ed., 2014,
53, 12912–12915; (b) L. Guo, A. Chatupheeraphat and
M. Rueping, Angew. Chem., Int. Ed., 2016, 55, 11810–11813;
(c) L. Guo, C.-C. Hsiao, H. Yue, X. Liu and M. Rueping, ACS
Catal., 2016, 6, 4438–4442; (d) L. Guo, X. Liu, C. Baumann
and M. Rueping, Angew. Chem., Int. Ed., 2016, 55, 15415–
15419; (e) X. Liu, C. C. Hsiao, I. Kalvet, M. Leiendecker,
L. Guo, F. Schoenebeck and M. Rueping, Angew. Chem., Int.
Ed., 2016, 55, 6093–6098; (f) H. Yue, L. Guo, S. C. Lee,
X. Liu and M. Rueping, Angew. Chem., Int. Ed., 2017, 56,
3972–3976; (g) H. Yue, L. Guo, H. H. Liao, Y. Cai, C. Zhu
and M. Rueping, Angew. Chem., Int. Ed., 2017, 56, 4282–
4285; (h) H. Yue, C. Zhu and M. Rueping, Angew. Chem.,
Int. Ed., 2018, 57, 1371–1375.
10 F. Chen, K. Chen, Y. Zhang, Y. He, Y.-M. Wang and S. Zhu, J.
Am. Chem. Soc., 2017, 139, 13929–13935.
5 For leading work, see: (a) C. H. Basch, J. Liao, J. Xu, J. J. Piane
and M. P. Watson, J. Am. Chem. Soc., 2017, 139, 5313–5316; 11 (a) Molecular orbital plot, spin density plot, and LOL-p plot
(b) J. Liao, W. Guan, B. P. Boscoe, J. W. Tucker,
J. W. Tomlin, M. R. Garnsey and M. P. Watson, Org. Lett.,
2018, 20, 3030–3033; (c) S. Plunkett, C. H. Basch,
S. O. Santana and M. P. Watson, J. Am. Chem. Soc., 2019,
141, 2257–2262.
were visualized by VMD, see: W. Humphrey, A. Dalke and
K. Schulten, J. Mol. Graphics, 1996, 14, 33–38; (b) Molecular
orbitals, spin density, LOL–p, and multi-center bond order
were analyzed by Multiwfn 3.6. see: T. Lu and F. Chen, J.
Comput. Chem., 2012, 33, 580–592.
6 (a) F. J. Klauck, M. J. James and F. Glorius, Angew. Chem., Int. 12 (a) H. Schmider and A. Becke, J. Mol. Struct.: THEOCHEM,
Ed., 2017, 56, 12336–12339; (b) X. Jiang, M.-M. Zhang,
W. Xiong, L.-Q. Lu and W.-J. Xiao, Angew. Chem., Int. Ed.,
2019, 58, 2402–2406; (c) F. J. Klauck, H. Yoon, M. J. James,
2000, 527, 51–61; (b) V. Tsirelson and A. Stash, Acta
Crystallogr., Sect. B: Struct. Sci., 2002, 58, 780–785; (c)
H. Jacobsen, Can. J. Chem., 2008, 86, 695–702.
M. Lautens and F. Glorius, ACS Catal., 2018, 9, 236–241; (d) 13 (a) M. Giambiagi, M. S. de Giambiagi and K. C. Mundim,
M. Ociepa, J. Turkowska and D. Gryko, ACS Catal., 2018, 8,
11362–11367.
7 (a) J. Wu, L. He, A. Noble and V. K. Aggarwal, J. Am. Chem.
Soc., 2018, 140, 10700–10704; (b) F. Sandfort, F. Strieth-
Struct. Chem., 1990, 1, 423–427; (b) P. Bultinck, R. Ponec
and S. Van Damme, J. Phys. Org. Chem., 2005, 18, 706–718;
(c) E. Matito, Phys. Chem. Chem. Phys., 2016, 18, 11839–
11846.
Chem. Sci.
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